ENTITYA	TYPEA	IDA	DATABASEA	ENTITYB	TYPEB	IDB	DATABASEB	EFFECT	MECHANISM	RESIDUE	SEQUENCE	TAX_ID	CELL_DATA	TISSUE_DATA	MODULATOR_COMPLEX	TARGET_COMPLEX	MODIFICATIONA	MODASEQ	MODIFICATIONB	MODBSEQ	PMID	DIRECT	NOTES	ANNOTATOR	SENTENCE	SIGNOR_ID	SCORE
Kallidin	smallmolecule	CHEBI:6102	ChEBI	BDKRB2	protein	P30411	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257465	0.8
palmitoyl-CoA(4-)	smallmolecule	CHEBI:57379	ChEBI	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	precursor of			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267124	0.8
PLK1	protein	P53350	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser146	LLTFPNSsPGLRRQK								phosphorylation:Ser36;Thr40	HPGFDAEsYTFTVPR;DAESYTFtVPRRHLE	23972993	t	For phosphorylated residues see Figure 7	lperfetto	Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP	SIGNOR-274054	0.302
CDK2	protein	P24941	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									19114991	t		lpetrilli	In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity	SIGNOR-182967	0.733
TP53INP1	protein	Q96A56	UNIPROT	MAP1LC3B	protein	Q9GZQ8	UNIPROT	up-regulates	binding			9606									22421968	t		gcesareni	Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir)	SIGNOR-196673	0.301
HCK	protein	P08631	UNIPROT	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	up-regulates activity	phosphorylation	Tyr788	SLEKHSWyHGPVSRN	9606									16912036	t		Manara	Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 	SIGNOR-260813	0.2
MICU3	protein	Q86XE3	UNIPROT	 MCU_MICU3_variant	complex	SIGNOR-C501	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270872	0.632
PTPN11	protein	Q06124	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	dephosphorylation	Tyr530	FTSTEPQyQPGENL	9606									17974954	t			Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B	SIGNOR-248671	0.639
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	GPSM3	protein	Q9Y4H4	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000876						phosphorylation:Ser35	STTRPWRsAPPSPPP	22843681	t		lperfetto	Mutation of serine 35 completely abrogates the 14-3-3 interaction (e.g. Fig. 2, B–F), suggesting that phosphorylation of serine 35 is obligatory for 14-3-3 binding|The GPSM3/14-3-3 interaction is seen to stabilize GPSM3 from degradation and also support the nuclear exclusion of both proteins.	SIGNOR-264866	0.2
Factor Va-Xa	complex	SIGNOR-C318	SIGNOR	F2	protein	P00734	UNIPROT	up-regulates activity	cleavage												11983337	t		lperfetto	This activation is accomplished at a physiologically relevant rate by the prothrombinase complex, a macromolecular association of the serine protease factor Xa (fXa) with its cognate cofactor, factor Va (fVa), and substrate, prothrombin|Factor Va Increases the Affinity of Factor Xa for Prothrombin 	SIGNOR-263546	0.657
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXA2	protein	Q9Y261	UNIPROT	down-regulates	phosphorylation			9606									14500912	t			�Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression.	SIGNOR-254978	0.2
AKAP11	protein	Q9UKA4	UNIPROT	IQGAP2	protein	Q13576	UNIPROT	up-regulates activity	binding			9606									21776420	t		miannu	We show that IQGAP2 is regulated by an interaction with the A-kinase anchoring protein AKAP220. Phosphorylation of IQGAP2 via AKAP220-anchored PKA leads to enhanced Rac binding. Since AKAPs function to direct PKA toward specific substrates, we proposed that the formation of an IQGAP2/AKAP220/PKA ternary complex sharpens the response to cAMP.	SIGNOR-273740	0.45
GLI1	protein	P08151	UNIPROT	PTCH1	protein	Q13635	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002572								16571352	f		lperfetto	Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1.	SIGNOR-209620	0.708
NEDD4L	protein	Q96PU5	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000938								23778145	t		miannu	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 	SIGNOR-253461	0.331
PIP3	smallmolecule	CHEBI:16618	ChEBI	PDPK1	protein	O15530	UNIPROT	up-regulates activity	relocalization			9534									9637919	t		lperfetto	In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation.	SIGNOR-58313	0.8
ACO1	protein	P21399	UNIPROT	citrate(3-)	smallmolecule	CHEBI:16947	ChEBI	down-regulates quantity	chemical modification			9606									24068518	t		miannu	Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained.	SIGNOR-266242	0.8
RNGTT	protein	O60942	UNIPROT	mRNA_capping	phenotype	SIGNOR-PH178	SIGNOR	up-regulates quantity	chemical modification			9606									9512541	f		lperfetto	The human mRNA 5'-capping enzyme cDNA was identified. Three highly related cDNAs, HCE1 (human mRNAcappingenzyme1), HCE1A and HCE1B , were isolated from a HeLa cDNA library. The HCE1 cDNA has the longest ORF, which can encode a 69 kDa protein. A short region of 69 bp in the 3'-half of the HCE1 ORF was missing in HCE1A and HCE1B , and, additionally, HCE1B has an early translation termi	SIGNOR-268356	0.7
mTORC1	complex	SIGNOR-C3	SIGNOR	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								35318320	t		miannu	 Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT.	SIGNOR-273843	0.749
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser363	LKNKTESsLLAKLEE	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276208	0.389
MAP2K4	protein	P45985	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates activity	phosphorylation	Tyr185	TSFMMTPyVVTRYYR	9606	BTO:0000007								9724739	t		gcesareni	MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53	SIGNOR-249654	0.74
PRKCB	protein	P05771	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Ser619	SLPKINRsASEPSLH	9606									8288587	t		gcesareni	Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. the sites of pkc-mediated raf-1 phosphorylation are deduced to be ser497 and ser619.	SIGNOR-37478	0.42
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr46	GGTLFSTtPGGTRII	9606									23486913	t		lperfetto	These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation	SIGNOR-217114	0.753
FGFR3	protein	P22607	UNIPROT	FGFR3	protein	P22607	UNIPROT	up-regulates activity	phosphorylation	Tyr577	RRPPGLDySFDTCKP	9606	BTO:0000007								11294897	t		lperfetto	Ligand stimulation leads to autophosphorylation of fgfr3 the absence of y577 (3y-577f) or y760 (3y-760f) resulted in a modest decrease in activity.	SIGNOR-106726	0.2
STK4	protein	Q13043	UNIPROT	FOXO4	protein	P98177	UNIPROT	up-regulates	phosphorylation			9606									18394876	t		gcesareni	The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1	SIGNOR-178193	0.406
chloramphenicol	chemical	CHEBI:17698	ChEBI	MT-CO1	protein	P00395	UNIPROT	down-regulates quantity	chemical inhibition			9606	BTO:0002552								23148581	t		Monia	Chloramphenicol treatment suppressed mitochondria translation of mtDNA-encoded cytochrome c oxidase subunit I (Cox I) in H1299 cell.	SIGNOR-261068	0.8
PRKCZ	protein	Q05513	UNIPROT	MARK3	protein	P27448	UNIPROT	down-regulates	phosphorylation	Thr564	RGTASRStFHGQPRE	9606									15084291	t		lperfetto	Hpar-1a, t564, is phosphorylated in vivo and by apkc in vitro.This study establishes a novel functional link between two central determinants of cellular polarity, apkc and par-1, and suggests a model by which apkc may regulate par-1 in polarized cells	SIGNOR-124221	0.2
MYO1C	protein	O00159	UNIPROT	B-WICH complex	complex	SIGNOR-C447	SIGNOR	form complex	binding			9606									21559432	t		miannu	The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 	SIGNOR-268820	0.335
OGT	protein	O15294	UNIPROT	PFKM	protein	P08237	UNIPROT	down-regulates activity	glycosylation	Ser530	VVIPATVsNNVPGSD	9606									26399441	t		lperfetto	Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 	SIGNOR-267584	0.354
CSNK2A2	protein	P19784	UNIPROT	GTF2A1L	protein	Q9UNN4	UNIPROT	up-regulates activity	phosphorylation	Ser356	VDGSGDTsSNEEIGS	-1									12107178	t		llicata	ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.	SIGNOR-250991	0.424
GAP43	protein	P17677	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				10090									21938722	f		miannu	Growth associated protein 43 (Gap43) is a neuron-specific phosphoprotein, which plays critical role in axon growth and synapses functions during neurogenesis. 	SIGNOR-266769	0.7
OXGR1	protein	Q96P68	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257368	0.2
CALM3	protein	P0DP25	UNIPROT	PPP3CB	protein	P16298	UNIPROT	up-regulates	binding			9606									11796223	t		miannu	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-266338	0.593
AURKB	protein	Q96GD4	UNIPROT	KIF2C	protein	Q99661	UNIPROT	down-regulates	phosphorylation	Ser192	VNSVRRKsCLVKEVE	9606									17567953	t		lperfetto	Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres.	SIGNOR-155898	0.72
DDR2	protein	Q16832	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	binding			9606									16186108	t		gcesareni	Collectively, our findings are consistent with the following mechanism for src-dependent ddr2 activation and signaling: 1) ligand binding promotes phosphorylation of tyr-740 in the ddr2 activation loop by src;2) tyr-740 phosphorylation stimulates intramolecular autophosphorylation of ddr2;3) ddr2 autophosphorylation generates cytosolic domain phosphotyrosines that promote the formation of ddr2 cytosolic domain-shc signaling complexes.	SIGNOR-140724	0.402
PPP1CC	protein	P36873	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	dephosphorylation	Ser37	NVLSPLPsQAMDDLM	9606									16501611	t			Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.	SIGNOR-248500	0.323
AKT1	protein	P31749	UNIPROT	CABLES1	protein	Q8TDN4	UNIPROT	down-regulates activity	phosphorylation	Thr415	AFGARRNtIDSTSSF	-1									25361894	t		miannu	Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex.Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis.	SIGNOR-276757	0.347
Pyridostigmine	chemical	CHEBI:8665	ChEBI	BCHE	protein	P06276	UNIPROT	down-regulates activity	chemical inhibition			-1									20627738	t		Luana	The compounds 3-[(dimethylamino)carboxyl]oxy]-N,N,N-trimethylammonium methyl sulfate, better known as neostigmine methyl sulfate (3),1 and 3-[(dimethylcarbamoyl)oxy]-1-methylpyridinium bromide, pyridostigmine bromide (4)2 (Figure 1) are well known peripheral cholinesterase inhibitors 	SIGNOR-257880	0.8
MAPK14	protein	Q16539	UNIPROT	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	up-regulates	transcriptional regulation			10116									11904165	f		ggiuliani	These data indicate that TGF-beta1-induced p38 activation is involved in TGF-beta1-stimulated collagen synthesis.	SIGNOR-255958	0.7
HOXC6	protein	P09630	UNIPROT	S100B	protein	P04271	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002253								17488478	t		Luana	HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells.	SIGNOR-261646	0.2
MBTPS2	protein	O43462	UNIPROT	SREBF1	protein	P36956	UNIPROT	up-regulates activity	cleavage			10029	BTO:0000246								10419520	t			In order to activate transcription, the NH2-terminal domain of the SREBP must be released from the membrane so that it can enter the nucleus. This release has been studied most extensively for one of the SREBPs, namely, SREBP-2. However, the mechanism appears to be similar for the other SREBPs (SREBP-1a and -1c) (1). Release of the NH2-terminal domain is accomplished by a two-step proteolytic event that is regulated by sterols (3). In sterol-depleted mammalian cells, this proteolysis is initiated by the Site-1 protease (S1P), which cleaves human SREBP-2 between the Leu522-Ser523 bond in the sequence RSVL S (4). This cleavage requires formation of a complex between SREBP and SCAP, a polytopic membrane protein of the ER, and it is prevented when this complex is disrupted	SIGNOR-267499	0.638
LIMS4	protein	P0CW20	UNIPROT	IPP complex	complex	SIGNOR-C380	SIGNOR	form complex	binding												16493410	t		lperfetto	Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton.	SIGNOR-265766	0.2
NFY	complex	SIGNOR-C1	SIGNOR	ZDHHC5	protein	Q9C0B5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									28775165	t			Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y	SIGNOR-261151	0.2
PLK1	protein	P53350	UNIPROT	PTPN1	protein	P18031	UNIPROT	up-regulates activity	phosphorylation	Ser286	KFIMGDSsVQDQWKE	9606	BTO:0000567						phosphorylation:Ser386	LRGAQAAsPAKGEPS	23348582	t		lperfetto	Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B.|Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. 	SIGNOR-272990	0.363
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1696	SPSYSPTsPSYSPTS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248741	0.727
Factor FVIIa:TF	complex	SIGNOR-C319	SIGNOR	F8	protein	P00451	UNIPROT	down-regulates activity	cleavage	Arg355	CPEEPQLrMKNNEEA	-1									10350471	t		lperfetto	N-Terminal sequencing along with time courses of proteolysis indicated that VIIa-TF/PL cleaved factor VIII first at R740, followed by concomitant cleavage at R336 and R372. |hus, heavy chain cleavage of factor VIII by VIIa-TF/PL produces an inactive factor VIII cofactor no longer capable of activation by thrombin.	SIGNOR-263643	0.468
MMP1	protein	P03956	UNIPROT	COL1A1	protein	P02452	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly776	IGPPGPAgAPGDKGE	-1									17318226	t		lperfetto	In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4. 	SIGNOR-272336	0.387
PPP3CA	protein	Q08209	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates activity	dephosphorylation	Ser75	EIRSRHSsYPAGTED	9606	BTO:0000007								10195903	t			Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 	SIGNOR-248694	0.451
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity	phosphorylation			9606		BTO:0000887;BTO:0001103;BTO:0001760							20138985	t		lperfetto	Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1.	SIGNOR-217586	0.72
HOXA10	protein	P31260	UNIPROT	IGFBP1	protein	P08833	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003697								17350963	f		miannu	The functional role of HOXA10 in IGFBP1 expression was further explored using human endometrial stromal cells (HSC). Overexpression of HOXA10 in HSC resulted in a decrease of IGFBP1 mRNA, whereas silencing HOXA10 caused an increase of IGFBP1 mRNA, even in the presence of H + dbcAMP. These data demonstrate that HOXA10 negatively influences IGFBP1 expression in decidualizing cells. 	SIGNOR-254467	0.421
daunorubicin	chemical	CHEBI:41977	ChEBI	ABCC1	protein	P33527	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002206								9647783	t		Simone Vumbaca	Unconjugated Dox and Dau failed to inhibit the transport of LTC4, whereas 30 microM GS-Dox or GS-Dau conjugates completely inhibited the transport.	SIGNOR-261086	0.8
PRKACA	protein	P17612	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	unknown	phosphorylation	Thr90	NKQDRTLtIVDTGIG	9606									21919888	t		lperfetto	Thr90 phosphorylation of hsp90_ by protein kinase a regulates its chaperone machinery	SIGNOR-176614	0.459
CEBPB	protein	P17676	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity	transcriptional regulation			10090									16431920	t		fspada	These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome	SIGNOR-143952	0.719
RPS6KA1	protein	Q15418	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser362	AAAHRKGsSSNEPSS	9606									8248197	t		gcesareni	We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling.	SIGNOR-37154	0.545
CREB1	protein	P16220	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0001009								10753867	f		lperfetto	Creb activity by akt signaling leads to increased bcl-2 promoter activity and cell survival.	SIGNOR-76558	0.438
Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	GABA-A (a6-b1-g2) receptor	complex	SIGNOR-C334	SIGNOR	up-regulates				9606									33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors	SIGNOR-268586	0.2
STAT3	protein	P40763	UNIPROT	FOXP3	protein	Q9BZS1	UNIPROT	down-regulates				9606									18156621	f			Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA)	SIGNOR-254364	0.592
PTAFR	protein	P25105	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257387	0.413
STK11	protein	Q15831	UNIPROT	MARK2	protein	Q7KZI7	UNIPROT	up-regulates	phosphorylation	Thr208	TFGNKLDtFCGSPPY	9606									14976552	t		lperfetto	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122628	0.569
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	XBP1	protein	P17861	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser68	RQRLTHLsPEEKALR	9606	BTO:0001109								23277279	t		miannu	Phosphorylation of XBP-1u by ERK is critical for the increased interaction of XBP-1u and FoxO1.	SIGNOR-276438	0.2
PRKACA	protein	P17612	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates	phosphorylation			9606									10464286	t		gcesareni	Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation.	SIGNOR-265344	0.2
DIO	proteinfamily	SIGNOR-PF83	SIGNOR	3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	up-regulates quantity	chemical modification			9606									34674502	t		scontino	Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule. 	SIGNOR-267044	0.8
MAPK14	protein	Q16539	UNIPROT	TAB1	protein	Q15750	UNIPROT	down-regulates activity	phosphorylation	Ser423	QMVNGAHsASTLDEA	9606									19393267	t		lperfetto	Egfr-mediated phosphorylation of tab1 was completely inhibited by a chemical inhibitor and sirna of p38alpha. The phosphorylation of tab1 was occurred at ser-423 and thr-431, the residues underlying the p38-mediated feedback inhibition of tak1.	SIGNOR-185580	0.817
midostaurin	chemical	CHEBI:63452	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258248	0.8
BHLHE40	protein	O14503	UNIPROT	BHLHE40	protein	O14503	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000944								14672706	f	 	lperfetto	We show here an autofeedback loop of Dec1 encoding a basic helix–loop–helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression.	SIGNOR-253715	0.2
FYN	protein	P06241	UNIPROT	ITPR1	protein	Q14643	UNIPROT	up-regulates	phosphorylation	Tyr353	NAQEKMVySLVSVPE	9606									14761954	t		lperfetto	We have identified tyrosine 353 (tyr353) in the ip3-binding domain of type 1 ip3r (ip3r1) as a phosphorylation site for fyntyrosine phosphorylation of ip3r1 increased ip3 binding at low ip3 concentrations (<10 nm).	SIGNOR-121795	0.501
C5	protein	P01031	UNIPROT	C5AR1	protein	P21730	UNIPROT	up-regulates activity	binding			9606					cleavage:Arg751;Arg677	HKDMQLGrLHMKTLL;KEILRPRrTLQKKIE			1847994	t	complement C5a (anaphylatoxin) fragment: PRO_0000005988	lperfetto	The chemotactic receptor for human C5a anaphylatoxin|The human C5a receptor was cloned from U937 and HL-60 cells and identified by high affinity binding when expressed in COS-7 cells.	SIGNOR-263457	0.748
MAPK3	protein	P27361	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Thr312	ISYDIPPtPGNTYQI	10029	BTO:0000246								15379552	t		lperfetto	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-249463	0.618
CDK1	protein	P06493	UNIPROT	RAD9A	protein	Q99638	UNIPROT	up-regulates activity	phosphorylation	Ser277	SHSQDLGsPERHQPV	9606	BTO:0000567								12734188	t		lperfetto	Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9.	SIGNOR-101043	0.37
1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester	chemical	CHEBI:92418	ChEBI	CHRM2	protein	P08172	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258635	0.8
PRKCA	protein	P17252	UNIPROT	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation	Ser656	RAEFLNKsVQKSSGV	9606		BTO:0000887;BTO:0001260							8182108	t		gcesareni	Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase.	SIGNOR-36792	0.365
GATA2	protein	P23769	UNIPROT	ETV2	protein	O00321	UNIPROT	up-regulates activity	binding			10090									24583263	t		irozzo	Transcriptional assays with the Spi1 promoter-reporter demonstrated that Gata2 cooperates with Etv2 and augments the transcriptional activity of Etv2.The protein-protein interaction between Etv2 and Gata2 is mediated by the Ets and Gata domains. Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation.	SIGNOR-256008	0.443
GFs	stimulus	SIGNOR-ST12	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity				9606									23300340	f		lperfetto	Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation	SIGNOR-245402	0.7
ADRB2	protein	P07550	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257192	0.318
PRKCB	protein	P05771	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	up-regulates	phosphorylation	Ser40	SREVFDFsQRRKEYE	9606									12198130	t		miannu	Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress	SIGNOR-91830	0.393
(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	ADRA2A	protein	P08913	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257453	0.8
MT-CO1	protein	P00395	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267746	0.662
IL13	protein	P35225	UNIPROT	IL4R	protein	P24394	UNIPROT	up-regulates activity	binding			9606									19880493	t		lperfetto	IL-4 and IL-13 have overlapping but distinct effects on MFs, dependent on a common IL-4R, with profound changes in the expression of a range of cellular proteins and functions broadly implicated in the regulation of inflammation and repair.	SIGNOR-249528	0.893
MEGF10	protein	Q96KG7	UNIPROT	ABCA1	protein	O95477	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								17205124	t		miannu	ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level. 	SIGNOR-265165	0.339
AURKB	protein	Q96GD4	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Ser13	ITSAARRsYVSSGEM	-1									12686604	t		lperfetto	We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro.	SIGNOR-100165	0.449
CSNK2A1	protein	P68400	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates	phosphorylation	Thr231	ALKEEPQtVPEMPGE	9606									1516134	t		lperfetto	Casein kinase ii is a negative regulator of c-jun dna binding and ap-1 activitywe show that two of these sites, thr-231 and ser-249, are phosphorylated by casein kinase ii (ckii).	SIGNOR-19607	0.574
AKT1	protein	P31749	UNIPROT	LONP1	protein	P36776	UNIPROT	up-regulates activity	phosphorylation	Ser181	NESDVVEsLDEIYHT	9606	BTO:0001061								31406245	t		lperfetto	In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity.	SIGNOR-265725	0.255
CHEK1	protein	O14757	UNIPROT	SNCB	protein	Q16143	UNIPROT	unknown	phosphorylation	Tyr127	EDPPQEEyQEYEPEA	9606									21699177	t		llicata	Chk preferentially phosphorylates recombinant _-synuclein at tyrosine-127	SIGNOR-174590	0.2
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	LIN28A	protein	Q9H9Z2	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269246	0.53
regorafenib	chemical	CHEBI:68647	ChEBI	NTRK1	protein	P04629	UNIPROT	down-regulates activity	chemical inhibition			9606									24756792	t		miannu	In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically.	SIGNOR-259212	0.8
INSR	protein	P06213	UNIPROT	ADRB2	protein	P07550	UNIPROT	down-regulates activity	phosphorylation	Tyr350	RRSSLKAyGNGYSSN	10029	BTO:0000246								8557631	t			Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors. 	SIGNOR-251301	0.385
FYN	protein	P06241	UNIPROT	CD300LB	protein	A8K4G0	UNIPROT	up-regulates activity	phosphorylation	Tyr188	EPGEQPIyMNFSEPL	9534									16920917	t		lperfetto	As CD300b phosphorylation was occurring only in the presence of both c-Fyn and DAP-12, we addressed whether tyrosine phosphorylation was required for association of CD300b and DAP-12. For this purpose, we generated a set of HA-tagged CD300b mutants affecting the transmembrane lysine (K158L), the cytoplasmic tyrosine (Y188F) or both residues.|As expected, the CD300b double mutant could neither recruit DAP-12 nor become phosphorylated in the presence of c-Fyn kinase (Fig. 5⇑C). Association between CD300b and DAP-12 was maintained in absence of the c-Fyn kinase, indicating that phosphorylation of the adaptor was not essential for the formation of the complex (data not shown)	SIGNOR-264771	0.314
Delta(9)-tetrahydrocannabinol	smallmolecule	CHEBI:66964	ChEBI	CNR1	protein	P21554	UNIPROT	up-regulates activity	chemical activation			9606		BTO:0000142							29751001	t		miannu	Endocannabinoids (eCBs) are the body’s natural agonists for cannabinoid receptors (G protein-coupled CB1 and CB2) that also recognize Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana. 	SIGNOR-264267	0.8
MAPK1	protein	P28482	UNIPROT	TPR	protein	P12270	UNIPROT	up-regulates	phosphorylation	Thr2116	VGRGLQLtPGIGGMQ	9606									18794356	t		miannu	Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore.	SIGNOR-181018	0.382
NFIA	protein	Q12857	UNIPROT	ANOS1	protein	P23352	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268872	0.2
STK3	protein	Q13188	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	phosphorylation	Thr1041	EHAFYEFtFRRFFDD	9606									23431053	t		milica	MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation	SIGNOR-201278	0.592
NDEL1	protein	Q9GZM8	UNIPROT	DYNC1H1	protein	Q14204	UNIPROT	up-regulates activity	binding			10090	BTO:0000938								11163259	t		miannu	LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex	SIGNOR-252159	0.709
belinostat	chemical	CHEBI:61076	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257742	0.8
TSSK4	protein	Q6SA08	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates	phosphorylation	Ser119	EILSRRPsYRKILND	9606	BTO:0000007								15964553	t		gcesareni	Tssk5, a novel member of the testis-specific serine/threonine kinase family, phosphorylates creb at ser-133, and stimulates the cre/creb responsive pathway.	SIGNOR-138289	0.597
RUNX2	protein	Q13950	UNIPROT	SNAI3	protein	Q3KNW1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001610								22641097	f		miannu	 Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells.	SIGNOR-255083	0.2
CD47	protein	Q08722	UNIPROT	Ankyrin complex	complex	SIGNOR-C383	SIGNOR	form complex	binding			9606	BTO:0000424								22465511	t		lperfetto	The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) 	SIGNOR-266016	0.376
ROS	stimulus	SIGNOR-ST2	SIGNOR	GSTA4	protein	O15217	UNIPROT	up-regulates				9534	BTO:0004055								12646569	f		lperfetto	We have also provided evidence that the mitochondrial GSTA4-4 level markedly increases in COS cells under oxidative stress conditions, suggesting its critical role in maintaining the GSH homeostasis under conditions of chemical and oxidative stress	SIGNOR-264797	0.7
AHR	protein	P35869	UNIPROT	CYP1B1	protein	Q16678	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001033								16115918	f		miannu	Expressions of CYP1B1 mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1.	SIGNOR-253733	0.505
CPSF3	protein	Q9UKF6	UNIPROT	mRNA_polyadenylation	phenotype	SIGNOR-PH200	SIGNOR	up-regulates				9606									30507380	f		lperfetto	Replication-dependent (RD) core histone mRNA produced during S-phase is the only known metazoan protein-coding mRNA presenting a 3' stem-loop instead of the otherwise universal polyA tail. A metallo β-lactamase (MBL) fold enzyme, cleavage and polyadenylation specificity factor 73 (CPSF73), is proposed to be the sole endonuclease responsible for 3' end processing of both mRNA classes.	SIGNOR-268336	0.7
FBXO11	protein	Q86XK2	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	neddylation	Lys321	SSPQPKKkPLDGEYF	9606									17098746	t		miannu	Fbxo11 promotes the neddylation of p53 and inhibits its transcriptional activity / we found that fbxo11 also neddylates p53 on two lysines, lys-320 and lys-321	SIGNOR-150673	0.658
(S)-malate(2-)	smallmolecule	CHEBI:15589	ChEBI	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	up-regulates quantity	precursor of			9606									24068518	t		miannu	Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle	SIGNOR-266282	0.8
LYN	protein	P07948	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates activity	phosphorylation	Tyr564	SKHKEDVyENLHTKN	9606	BTO:0000007								10574931	t			Lyn phosphorylates SHPTP1 at the C-terminal Tyr-564 site. Lyn-mediated phosphorylation of SHPTP1 stimulates SHPTP1 tyrosine phosphatase activity.	SIGNOR-251409	0.724
AKT1	protein	P31749	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates	phosphorylation	Thr39	LKKIRLDtETEGVPS	9606									18354084	t		lperfetto	Akt phosphorylates cdk2 at threonine 39 residue both in vitro and in vivo. Although cdk2 threonine 39 phosphorylation mediated by akt enhances cyclin-a binding, it is dispensable for its basal binding and the kinase activity.	SIGNOR-178058	0.335
PRKG2	protein	Q13237	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates activity	phosphorylation	Ser556	HAKASRTsSKHKEDV	9606	BTO:0002181								21177494	t		miannu	 PKGII directly phosphorylated and stimulated SHP-1 activity	SIGNOR-276286	0.2
KATNA1	protein	O75449	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	down-regulates				9606									19287380	f		miannu	Katanin, one of the best-characterized microtubule (MT) severing proteins, is composed of two subunits: catalytic p60-katanin, and regulatory p80-katanin. p60-katanin triggers MT reorganization by severing them. MT reorganization is essential for both mitotic cells and post-mitotic neurons in numerous vital processes such as intracellular transport, mitosis, cellular differentiation and apoptosis. 	SIGNOR-271794	0.7
GTF3C2	protein	Q8WUA4	UNIPROT	TFIIIC	complex	SIGNOR-C392	SIGNOR	form complex	binding			9606									29378333	t		lperfetto	Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains	SIGNOR-266187	0.868
GSK3B	protein	P49841	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser33	QQQSYLDsGIHSGAT	9606		BTO:0000586	SIGNOR-C110						16293724	t		gcesareni	This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway.	SIGNOR-141799	0.856
INS	protein	P01308	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates				9606		BTO:0000887;BTO:0001103							8250835	f		gcesareni	The results suggest that ser-9 phosphorylation underlies the reported gsk3 beta inhibition by insulin and that gsk3 may represent a point of convergence of two major growth-factor-stimulated protein kinase cascades.	SIGNOR-37220	0.47
PRKCD	protein	Q05655	UNIPROT	PRKCD	protein	Q05655	UNIPROT	unknown	phosphorylation	Ser302	TQRASRRsDSASSEP	9606									19366211	t		llicata	This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop.	SIGNOR-185291	0.2
VEGFA	protein	P15692	UNIPROT	KDR	protein	P35968	UNIPROT	up-regulates	binding			9606	BTO:0000801;BTO:0000876								17658244	t		gcesareni	Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability.	SIGNOR-157100	0.815
RBM10	protein	P98175	UNIPROT	TNF	protein	P01375	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30403180	f		irozzo	These data indicated that RBM10 overexpression induced osteosarcoma cell apoptosis via promoting the production of TNF-α that appear to act as an autocrine factor regulating osteosarcoma programmed cell death.	SIGNOR-259153	0.2
AMOT	protein	Q4VCS5	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	relocalization			9606									21808241	t		gcesareni	Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms.	SIGNOR-175779	0.728
CAST	protein	P20810	UNIPROT	CAPN2	protein	P17655	UNIPROT	down-regulates activity	binding			9606	BTO:0000590								25969760	t		lperfetto	In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain 	SIGNOR-251609	0.901
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser366	PGGSRAHsSHLKSKK	9606	BTO:0001321								15659650	t		lperfetto	The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage.	SIGNOR-75633	0.784
MYC	protein	P01106	UNIPROT	CDK6	protein	Q00534	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001271								12835716	f		gcesareni	The degradation of c-myc protein decreases the expression of the cell cycle regulators cdk4 and cdk6, which reversibly slows down the cell cycle.	SIGNOR-102737	0.466
pomalidomide	chemical	CHEBI:72690	ChEBI	CRBN	protein	Q96SW2	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								22552008	t		miannu	 Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.	SIGNOR-259283	0.8
TUBA1A	protein	Q71U36	UNIPROT	Neuron_migration	phenotype	SIGNOR-PH67	SIGNOR	up-regulates				9606	BTO:0000007								19185337	f		miannu	We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching.	SIGNOR-269725	0.7
USP9X	protein	Q93008	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	deubiquitination	Lys519	DYPRQSIkETPCWIE	10090	BTO:0000165								20016939	t		gcesareni	Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4.	SIGNOR-236855	0.633
RUNX3	protein	Q13761	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	binding			9606									19800882	t		gcesareni	To investigate the possible mechanism of the down-regulation of hes-1 by runx3, we performed western blot and reporter assay and found that runx3 suppressed intracellular domain of notch1 (icn1)-mediated transactivation of notch signaling while it did not alter the expression of icn1 and recombination signal binding protein-j kappa (rbp-j) in smmc7721 cells.	SIGNOR-188338	0.677
NOTCH1	protein	P46531	UNIPROT	SNW1	protein	Q13573	UNIPROT	up-regulates	binding			9606									11404076	t		gcesareni	Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip.	SIGNOR-86125	0.584
PIN4	protein	Q9Y237	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	isomerization			9606	BTO:0000599								23720771	t		lperfetto	In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events	SIGNOR-265756	0.2
ACLY	protein	P53396	UNIPROT	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	up-regulates quantity	chemical modification			9606									19286649	t		miannu	ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor.	SIGNOR-267102	0.8
CyclinD3/CDK6	complex	SIGNOR-C234	SIGNOR	PFKL	protein	P17858	UNIPROT	down-regulates activity	phosphorylation			-1									28607489	t		miannu	In vitro kinase reactions revealed that all three PFK1 isoforms (PFKP, PFKL, PFKM) and PKM2 were phosphorylated by cyclin D3-CDK6 (Extended Data Fig. 2a–d, Supplementary Table 4).	SIGNOR-276451	0.2
STAT5A	protein	P42229	UNIPROT	Erythrocyte_differentiation 	phenotype	SIGNOR-PH104	SIGNOR	up-regulates				9606	BTO:0004408								15353555	f		miannu	Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors.	SIGNOR-256074	0.7
EIF2B5	protein	Q13144	UNIPROT	Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269138	0.81
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DRA	protein	P01903	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-253998	0.425
BMI1	protein	P35226	UNIPROT	CDKN2A	protein	P42771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24392140	t		lperfetto	In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity,	SIGNOR-253385	0.47
CAK complex	complex	SIGNOR-C456	SIGNOR	RARG	protein	P13631	UNIPROT	up-regulates activity	phosphorylation	Ser79	EMVPSSPsPPPPPRV	9534	BTO:0000298								10748061	t		miannu	Retinoic acid receptor gamma (RARgamma) is phosphorylated in COS-1 cells at two conserved serine residues located in the N-terminal region (serines 77 and 79 in RARgamma1 and serines 66 and 68 in RARgamma2) that contains the activation function AF-1. These serines are phosphorylated in vitro by cdk7, a cyclin-dependent kinase associated to cyclin H and MAT1 in the CAK complex (cdk7.cyclin H. MAT1), that is found either free or as a component of the transcription/DNA repair factor TFIIH. 	SIGNOR-275968	0.393
PPM1A	protein	P35813	UNIPROT	IRF3	protein	Q14653	UNIPROT	down-regulates activity	dephosphorylation			9606									27419230	t		miannu	In contrast, coexpression of wild-type PPM1A, but not its D239N or R174G mutant, abolished IRF3 activation (XREF_FIG).|We found that PPM1A abolished the C-terminal phosphorylation of IRF3 (XREF_FIG), whereas depletion of PPM1A expression improved virus induced pIRF3 level (XREF_FIG and XREF_FIG).	SIGNOR-277152	0.25
CDR2	protein	Q01850	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates activity	binding												20383333	t		lperfetto	Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis.	SIGNOR-252000	0.513
IKK-complex	complex	SIGNOR-C14	SIGNOR	IKBKG	protein	Q9Y6K9	UNIPROT	down-regulates activity	phosphorylation	Ser68	LRDAIRQsNQILRER	9606				SIGNOR-C14					17977820	t		lperfetto	In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I	SIGNOR-209788	0.928
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	METTL3	protein	Q86U44	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser43	RNPEAALsPTFRSDS	9606	BTO:0000007								33217317	t		miannu	 Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.	SIGNOR-265953	0.2
hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	carbamoyl phosphate(2-)	smallmolecule	CHEBI:58228	ChEBI	up-regulates quantity	precursor of			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-267417	0.8
PRKAA1	protein	Q13131	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates activity	phosphorylation	Ser539	SLFNVSPsCSSFNSP	10090		BTO:0001103	SIGNOR-C15						17609368	t		lperfetto	AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter	SIGNOR-228654	0.561
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	PPP3CA	protein	Q08209	UNIPROT	up-regulates	chemical activation			9606									21880741	t		gcesareni	Except for nfat5, nfatc1c4 are activated upon a rise in intracellular ca2+, which stimulates the serine/threonine phosphatase activity of calcineurin the ca2+-calcineurin signal is the most important signal for regulating nfat activation, but the signal that leads to ca2+ influx during neural tube differentiation is still unclear.	SIGNOR-176367	0.8
ARHGAP22	protein	Q7Z5H3	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260478	0.523
CENPT	protein	Q96BT3	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265204	0.718
SH3PXD2B	protein	A1X283	UNIPROT	NOXA1	protein	Q86UR1	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								20943948	t		lperfetto	Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation	SIGNOR-264707	0.355
PDPK1	protein	O15530	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates	phosphorylation			9606									15209375	t		gcesareni	One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.	SIGNOR-126066	0.391
AR	protein	P10275	UNIPROT	SEPTIN7	protein	Q16181	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001321								16281084	f	 	 	 After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes.	SIGNOR-253677	0.2
NLRC4	protein	Q9NPP4	UNIPROT	NLRC4 inflammasome	complex	SIGNOR-C223	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256404	0.743
PPP1CA	protein	P62136	UNIPROT	DDX58	protein	O95786	UNIPROT	up-regulates activity	dephosphorylation	Ser8	MTTEQRRsLQAFQDY	9606	BTO:0000007								23499489	t		lperfetto	We identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.|endogenous RIG-I and MDA5 that interacted with PP1 exhibited markedly decreased phosphorylation levels at S8 and S88, respectively 	SIGNOR-264581	0.2
MUSK	protein	O15146	UNIPROT	WNT11	protein	O96014	UNIPROT	up-regulates	binding			9606									23151663	t		gcesareni	Like ror, musk has an extracellular region with homolgogy to the frizzled crd, binding of which by wnt11 stimulates a pcp-like pathway during neuromuscular development	SIGNOR-199518	0.47
SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									16452181	f		irozzo	C-myc is a direct target of SWI/SNF complex–dependent promoter repression. These results indicate that repression of c-myc is indeed dependent on the activity of SWI/SNF–related complexes and specifically on complexes that contain ARID1A.	SIGNOR-256292	0.408
PRKD1	protein	Q15139	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser155	GRLKRERsMSENAVR	9606	BTO:0002181								34010649	t		miannu	PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-277558	0.2
P2RY10	protein	O00398	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257348	0.2
CASP9	protein	P55211	UNIPROT	Caspase 9 complex	complex	SIGNOR-C229	SIGNOR	form complex	binding												29500231	t		lperfetto	The caspase-9 CARD has been thought to be principally involved in recruitment to the apoptosome, but its roles outside this interaction have yet to be uncovered. In this work, we show that the CARD is involved in physical interactions with the catalytic core of caspase-9 in the absence of the apoptosome; this interaction requires a properly formed caspase-9 active site. 	SIGNOR-256397	0.2
URB597	chemical	CID:1383884	PUBCHEM	FAAH	protein	O00519	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207615	0.8
5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-)	smallmolecule	CHEBI:58475	ChEBI	(6S)-5,6,7,8-tetrahydrofolate(2-)	smallmolecule	CHEBI:57453	ChEBI	up-regulates quantity	precursor of			9606									33179964	t		miannu	The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP.	SIGNOR-267323	0.8
DVL1	protein	O14640	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									15735151	t		amattioni	Activated DVL binds and inhibits the phosphorylation of beta-catenin by GSK3B, blocking beta-catenin degradation so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1.	SIGNOR-134285	0.799
IGF1R	protein	P08069	UNIPROT	CSK	protein	P41240	UNIPROT	up-regulates				9606									10026153	f		lperfetto	The results suggest that c-src and csk are involved in igf-ir and ir signaling and that the interaction of csk with the igf-ir may play a role in the decrease in c-src activity following igf-i stimulation	SIGNOR-64676	0.353
P2RY11	protein	Q96G91	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256931	0.2
TNF	protein	P01375	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates				9606									11287630	f		lperfetto	Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase	SIGNOR-244458	0.496
PTPN1	protein	P18031	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates activity	dephosphorylation			9606									24590766	t		miannu	Here, we show that PTP1B regulates CD40 and BAFF-R signaling and dephosphorylates the mitogen-activated protein kinase p38.|Specifically, PTP1B counteracts p38 mitogen-activated protein kinase activation by directly dephosphorylating Tyr182 of this kinase.	SIGNOR-277167	0.455
PIM1	protein	P11309	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606	BTO:0000007								16403219	t		miannu	Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.	SIGNOR-250392	0.379
PRKACA	protein	P17612	UNIPROT	CACNB2	protein	Q08289	UNIPROT	up-regulates activity	phosphorylation	Ser514	SAPIRSAsQAEEEPS										10441130	t		miannu	Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation	SIGNOR-249714	0.416
COL4A4	protein	P53420	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									12778132	t			Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6)	SIGNOR-254668	0.7
PRKCD	protein	Q05655	UNIPROT	PRKCD	protein	Q05655	UNIPROT	unknown	phosphorylation	Thr218	TAANSRDtIFQKERF	9606									19366211	t		llicata	This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop.	SIGNOR-185303	0.2
TXK	protein	P42681	UNIPROT	CTLA4	protein	P16410	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr201	SPLTTGVyVKMPPTE	9606									9813138	t		lperfetto	We demonstrate that rlk (resting lymphocyte kinase) is capable of phosphorylating ctla-4 at the yvkm motif. Consistent with this finding, rlk is capable of providing conditions for the binding of the sh2 domains of pi 3-kinase to the receptor. Ctla-4 is therefore the first known substrate for rlk suggesting the possibility that this kinase may participate in ctla-4 function	SIGNOR-61624	0.513
BTK	protein	Q06187	UNIPROT	TEC	protein	P42680	UNIPROT	up-regulates	phosphorylation	Tyr206	RLERGQEyLILEKND	9606									12573241	t		lperfetto	Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated	SIGNOR-98086	0.473
LYN	protein	P07948	UNIPROT	NMT1	protein	P30419	UNIPROT	unknown	phosphorylation	Tyr180	YTLLNENyVEDDDNM	-1									11594778	t			Human NMT was found to be phosphorylated by non-receptor tyrosine kinase family members of Lyn. a site-directed mutagenesis study indicated that substitution of tyrosine 100 with phenylalanine served NMT as a poor substrate for the Lyn kinase.	SIGNOR-251404	0.354
SMURF1	protein	Q9HCE7	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates activity	ubiquitination			9606									17317136	t		lperfetto	Recruitment of WW and HECT domain E3-ubiquitin ligases Smurf1 and 2 to induce type I receptor ubiquitination and subsequent receptor degradation;	SIGNOR-153414	0.681
TGFB1	protein	P01137	UNIPROT	TSHB	protein	P01222	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									14623893	t		miannu	TGF-β inhibits thyroid-stimulated hormone (TSH)-induced NIS mRNA and protein levels in a dose-dependent manner. This effect takes place at the transcriptional level, as TGF-β inhibits TSH-induced transcription	SIGNOR-251991	0.2
60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	up-regulates													25901680	f		lperfetto	Ribosomes are translational machineries that catalyse protein synthesis.	SIGNOR-262413	0.7
ZFYVE9	protein	O95405	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	relocalization			9606									9865696	t		lperfetto	We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex.	SIGNOR-232126	0.855
CSNK2A1	protein	P68400	UNIPROT	GTF2A1L	protein	Q9UNN4	UNIPROT	up-regulates activity	phosphorylation	Ser357	DGSGDTSsNEEIGST	-1									12107178	t		llicata	ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.	SIGNOR-250871	0.435
DNAJC3	protein	Q13217	UNIPROT	EIF2AK4	protein	Q9P2K8	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								25329545	t		gcesareni	€ we show that p58IPK is a general inhibitor of the eIF2 kinases in that it also interacts with GCN2	SIGNOR-246204	0.561
PRKCZ	protein	Q05513	UNIPROT	BAX	protein	Q07812	UNIPROT	down-regulates activity	phosphorylation	Ser184	VAGVLTAsLTIWKKM	9606									17525161	t		lperfetto	Protein kinase czeta abrogates the proapoptotic function of bax through phosphorylation. Overexpression of wild type or the constitutively active a119d but not the dominant negative k281w pkczeta mutant results in bax phosphorylation at serine 184.	SIGNOR-155111	0.2
PRKACA	protein	P17612	UNIPROT	KCNN2	protein	Q9H2S1	UNIPROT	down-regulates	phosphorylation	Ser569	SRRRRSSsTAPPTSS	9606									16513649	t		llicata	Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization	SIGNOR-145044	0.2
APC-c	complex	SIGNOR-C150	SIGNOR	APC-c	complex	SIGNOR-C150	SIGNOR	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								22086178	t		miannu	Cdc20 is a co-activator of the anaphase-promoting complex/cyclosome (APC/C complex), which recruits substrates at particular phases of the cell cycle and mediates their degradation. Overexpression of Cdc20 resulted in decreased levels of both endogenous Sp100 protein and overexpressed Sp100 mRNA in HEK 293 cells. Our results suggested that sp100 is a novel substrate of Cdc20 and it is degraded by the ubiquitination pathway. The intact D-box of Sp100 was necessary for this process. 	SIGNOR-272725	0.881
SMARCD3	protein	Q6STE5	UNIPROT	Muscle cell-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C483	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex.	SIGNOR-270732	0.741
morphine	chemical	CHEBI:17303	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258931	0.8
SEPTIN6	protein	Q14141	UNIPROT	SEPT6/SEPT2	complex	SIGNOR-C71	SIGNOR	form complex	binding			9606									16914550	t		miannu	We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains.	SIGNOR-148892	0.2
STUB1	protein	Q9UNE7	UNIPROT	S100P	protein	P25815	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									23344957	t		miannu	S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.	SIGNOR-272919	0.296
ZBED1	protein	O96006	UNIPROT	RPS10	protein	P46783	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								17220279	t		Luana	HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid.	SIGNOR-266083	0.2
MAPK1	protein	P28482	UNIPROT	PARP1	protein	P09874	UNIPROT	up-regulates	phosphorylation	Thr373	AATPPPStASAPAAV	9606	BTO:0000938	BTO:0000142							16627622	t		esanto	Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation.	SIGNOR-146224	0.534
TGFBI	protein	Q15582	UNIPROT	A3/b1 integrin	complex	SIGNOR-C161	SIGNOR	up-regulates activity	binding												26387839	t		lperfetto	 BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers	SIGNOR-253267	0.43
IL10RA	protein	Q13651	UNIPROT	Phagocytosis	phenotype	SIGNOR-PH97	SIGNOR	up-regulates													19837374	f		apalma	Treatment of monocytes with IL-10 as compared to IL-15 resulted in a two-fold greater level of phagocytosis and binding of latex beads. In summary, IL-10, in comparison to IL-15, induces greater macrophage endocytic function	SIGNOR-255442	0.7
STAR	protein	P49675	UNIPROT	cholesterol	smallmolecule	CHEBI:16113	ChEBI	up-regulates quantity	relocalization												17579211	t		lperfetto	StAR transfers cholesterol from the outer to the inner mitochondrial membranes, where the enzyme complex of cholesterol side chain cleavage cytochrome P450 (P450scc) converts it to the first steroid, pregnenolone	SIGNOR-265727	0.8
INSR	protein	P06213	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Tyr174	TIPSQRRyVYYYSYL	-1									23995781	t		miannu	Our results show that the kinase region of IRβ subunit physically binds to PTEN and phosphorylates on Y27 and Y174. In the current study, we discovered that IR also downregulates PTEN through tyrosine phosphorylation and suggest that Y27 and 174 are the two key tyrosines.	SIGNOR-276471	0.455
PRKCA	protein	P17252	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser170	SFKLSGFsFKKNKKE	-1									8422248	t		lperfetto	These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III.	SIGNOR-248931	0.72
CDK12	protein	Q9NYV4	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates activity	phosphorylation	Thr169	TEAPAVVtEEEDDDE	9606	BTO:0004828								32483448	t		lperfetto	Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway	SIGNOR-273110	0.2
SOCS4	protein	Q8WXH5	UNIPROT	CUL5	protein	Q93034	UNIPROT	up-regulates activity	binding			9534	BTO:0000298								24210661	t		miannu	SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1.	SIGNOR-272141	0.507
RNF8	protein	O76064	UNIPROT	H1-2	protein	P16403	UNIPROT	down-regulates	polyubiquitination			9606	BTO:0000815								30517763	t		miannu	ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. 	SIGNOR-272928	0.2
JAKMIP1	protein	Q96N16	UNIPROT	GABBR1	protein	Q9UBS5	UNIPROT	up-regulates quantity				9534	BTO:0004055								14718537	f		SARA	Reduction in the Marlin-1 protein levels interferes with the translation, assembly, or stability of GABAB receptors during the maturation of cortical neurons.	SIGNOR-260988	0.536
FRZB	protein	Q92765	UNIPROT	WNT1	protein	P04628	UNIPROT	down-regulates	binding			9606		BTO:0000671							9326585	t		gcesareni	We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos,	SIGNOR-51762	0.534
MT-ND4L	protein	P03901	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 	SIGNOR-262147	0.692
MECOM	protein	Q03112	UNIPROT	ANGPT1	protein	Q15389	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15889140	t		Luana	We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2 	SIGNOR-266059	0.2
NOTCH1	protein	P46531	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001253							12107827	f		gcesareni	Addition of jag-1 peptide induced ikkalpha mediated nf-kappab activation, as well as increased ppargamma expression.	SIGNOR-90455	0.347
MMP9	protein	P14780	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272376	0.7
MAPK3	protein	P27361	UNIPROT	HNRNPK	protein	P61978	UNIPROT	down-regulates	phosphorylation	Ser284	RRDYDDMsPRRGPPP	9606									16564677	t		gcesareni	Erk phosphorylation drives cytoplasmic accumulation of hnrnp-k and inhibition of mrna translation mitogen-activated protein kinase/extracellular-signal-regulated kinase (mapk/erk) efficiently phosphorylates hnrnp-k both in vitro and in vivo at serines 284 and 353.	SIGNOR-145375	0.351
PIK3R4	protein	Q99570	UNIPROT	PIK3C3	protein	Q8NEB9	UNIPROT	up-regulates	binding			9606									8999962	t		gcesareni	Recombinant p150 associated with ptdins 3-kinase in vitro in a stable manner, resulting in a 2-fold increase in lipid kinase activity.	SIGNOR-45664	0.938
LYN	protein	P07948	UNIPROT	PRKCD	protein	Q05655	UNIPROT	up-regulates activity	phosphorylation	Tyr52	VQKKPTMyPEWKSTF	-1									9692543	t			Lyn was found to phosphorylate Lyn-associated and recombinant PKC-delta in vitro and the tyrosine 52 phosphorylated PKC-delta was recruited to associate with the Lyn SH2 domain.	SIGNOR-251408	0.537
MAPK8IP1	protein	Q9UQF2	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates	binding			9606									10490659	t		gcesareni	Both jip1 and jip2 selectively bind the mapkk isoform mkk7.	SIGNOR-70848	0.715
NMUR2	protein	Q9GZQ4	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257292	0.409
CRX	protein	O43186	UNIPROT	RBP3	protein	P10745	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								15277472	f		miannu	 KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. 	SIGNOR-253821	0.39
HDLBP	protein	Q00341	UNIPROT	Chromosome_segregation	phenotype	SIGNOR-PH44	SIGNOR	up-regulates				9606									33941620	f		miannu	Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer.	SIGNOR-266695	0.7
MAPK14	protein	Q16539	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation	Ser7	sPAPLSPL	9606	BTO:0000150								22128155	t		gcesareni	Ogether, our results suggest that p38 phosphorylation of foxo3a on ser-7 is essential for its nuclear relocalization in response to doxorubicin	SIGNOR-252960	0.513
NF1	protein	P21359	UNIPROT	ADCY7	protein	P51828	UNIPROT	up-regulates				9606	BTO:0000938								24431436	f		miannu	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-204246	0.291
AMPK	complex	SIGNOR-C15	SIGNOR	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates	phosphorylation	Ser155	FPLRKTVsEPNLKLR	9606									21892142	t		lperfetto	Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs).	SIGNOR-216554	0.281
CBP/p300	complex	SIGNOR-C6	SIGNOR	FLI1	protein	Q01543	UNIPROT	down-regulates	acetylation			9606									21321929	t		lperfetto	We have previously demonstrated that in response to transforming growth factor _ (tgf_), fli-1 activity is repressed through a series of sequential posttranslational modifications, consisting of protein kinase c_ (pkc_)-induced thr312 phosphorylation, acetylation by p300/creb binding protein-associated factor, and detachment from the collagen promoter.	SIGNOR-172109	0.296
LATS2	protein	Q9NRM7	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser397	TYHSRDEsTDSGLSM	9606	BTO:0000007								20048001	t		lperfetto	We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition	SIGNOR-218038	0.815
GTP(4-)	chemical	CHEBI:37565	ChEBI	2'-3'-cGAMP(2-)	smallmolecule	CHEBI:143093	ChEBI	up-regulates quantity	precursor of												23258413	t		lperfetto	Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family.	SIGNOR-276595	0.8
PTPN6	protein	P29350	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Tyr654	RNEGVATyAAAVLFR	9606									20840866	t		lperfetto	Because SHP-1 can dephosphorylate residues Y86 and Y654 on the \u03b2-catenin protein, these residues were therefore mutated into phenylalanine and the transcriptional activity of the subsequent \u03b2-catenin mutants analyzed: \u03b2-catenin/Y86F, \u03b2-catenin/Y654F and \u03b2-catenin/Y86F/Y654F. As shown in  Fig.\u00a03 B, the mutants \u03b2-catenin/Y86F, \u03b2-catenin/Y654F and \u03b2-catenin/Y86F/Y654F had a significantly reduced transcriptional activity in comparison to wild-type \u03b2-catenin.|SHP-1 inhibits \u03b2-catenin function by inducing its degradation and interfering with its association with TATA-binding protein.	SIGNOR-277014	0.539
RRAGC	protein	Q9HB90	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates	binding			9606				SIGNOR-C3					20006481	t		gcesareni	Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor.	SIGNOR-162054	0.939
trimipramine	chemical	CHEBI:9738	ChEBI	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			9606									9537821	t		miannu	At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. 	SIGNOR-258742	0.8
MALT1	protein	Q9UDY8	UNIPROT	TAB2	protein	Q9NYJ8	UNIPROT	up-regulates	binding			9606	BTO:0000782								17948050	t		gcesareni	Tab2/tak1 associate with ubiquitinated malt1 upon t-cell stimulation.	SIGNOR-158551	0.59
MVD	protein	P53602	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates quantity by stabilization				9534									12646231	f		miannu	An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B)	SIGNOR-265888	0.2
ITK	protein	Q08881	UNIPROT	TEC	protein	P42680	UNIPROT	up-regulates	phosphorylation	Tyr206	RLERGQEyLILEKND	9606									12573241	t		lperfetto	Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated	SIGNOR-98090	0.381
DPYSL2	protein	Q16555	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606	BTO:0000938								25040932	f		lperfetto	In the non-phosphorylated state, CRMP2 binding to tubulin induces the promotion of tubulin polymerisation leading to dendrite outgrowth while	SIGNOR-264842	0.7
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	RPTOR	protein	Q8N122	UNIPROT	up-regulates	phosphorylation	Ser722	PRLRSVSsYGNIRAV	9606				SIGNOR-C3					18722121	t		llicata	Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity	SIGNOR-252773	0.2
MAPK1	protein	P28482	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Thr739	SEGSGTAtPSALITT	9606									11904305	t		gcesareni	Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1.	SIGNOR-116166	0.629
SALL4	protein	Q9UJQ4	UNIPROT	NANOG	protein	Q9H9S0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16840789	t		Luana	We conclude that the Nanog enhancer activity is regulated by both Sall4 and Nanog. 	SIGNOR-266079	0.785
PIK3CA	protein	P42336	UNIPROT	MTOR	protein	P42345	UNIPROT	up-regulates				9606									18721898	f		lperfetto	Phosphoinositide 3-kinase (pi3k)-dependent activation of the rheb-mtor pathway triggers the simultaneous local synthesis of tc10 and par3.	SIGNOR-180453	0.529
TNK2	protein	Q07912	UNIPROT	KDM3A	protein	Q9Y4C1	UNIPROT	down-regulates activity	phosphorylation	Tyr1114	ITPEDRKyGTTNLHL	9606	BTO:0000093								25148682	t		miannu	We report that ACK1 phosphorylates the ER co-activator, KDM3A, a H3K9 demethylase, at an evolutionary conserved tyrosine 1114 site in a heregulin-dependent manner, even in the presence of tamoxifen.	SIGNOR-276842	0.377
PRKD1	protein	Q15139	UNIPROT	ATP7B	protein	P35670	UNIPROT	up-regulates activity	phosphorylation	Ser1121	AHSERPLsAPASHLN	9606	BTO:0000599								21189263	t		lperfetto	ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking.	SIGNOR-272295	0.302
MRPL48	protein	Q96GC5	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262348	0.667
CDK2	protein	P24941	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates	phosphorylation	Ser200	YSGDSDAsSPRSNCS	9606			SIGNOR-C16						21902831	t		gcesareni	Cyclin e/cdk2 can phosphorylate myod at serine 200, which causes ubiquitination and degradation of this transcription factor during g1, preventing its accumulation and a commitment to differentiation.	SIGNOR-176509	0.538
ACSS2	protein	Q9NR19	UNIPROT	acetyl-CoA(4-)	smallmolecule	CHEBI:57288	ChEBI	up-regulates quantity	chemical modification												10843999	t		lperfetto	The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP.	SIGNOR-271826	0.8
CPM	protein	P14384	UNIPROT	HBA1	protein	P69905	UNIPROT	down-regulates activity	cleavage	Tyr141	STVLTSKyR	-1									8635221	t		miannu	Both human plasma carboxypeptidase N (CPN) and membrane-bound carboxypeptidase M (CPM) released the C-terminal arginine (alpha-Arg141) of the alpha chain of human adult hemoglobin. Thus, the hydrolysis of hemoglobin by CPM and CPN demonstrated the contribution of the alpha-Arg141 residue to sustaining the tetrameric structure of hemoglobin and its normal oxygen affinity and vasoactivity.	SIGNOR-256507	0.2
CYFIP1	protein	Q7L576	UNIPROT	NHS	protein	Q6T4R5	UNIPROT	up-regulates activity	binding			9606									20332100	t		miannu	We show that the WHD of NHS interacts with the Abi family of proteins, HSPC300, Nap1 and Sra1, and is important for the localization of NHS to the leading edge.	SIGNOR-253575	0.2
MAP3K8	protein	P41279	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates	phosphorylation			9606									22435554	t		gcesareni	Furthermore, we found that immunoprecipitated tpl-2 could directly phosphorylate and activate both mek-1 and mkk4 (also known as sek-1)	SIGNOR-196744	0.539
(R)-2-hydroxyglutarate(2-)	smallmolecule	CHEBI:15801	ChEBI	TET2	protein	Q6N021	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001883								29090344	t		miannu	Various studies have tried to investigate how the accumulation of R2-HG promotes leukemogenesis in cooperation with other frequently observed mutations in AML. An important role appears to be the ability of R2-HG to competitively inhibit multiple αKG-dependent dioxygenases. While TET2 normally catalyzes the conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), inhibition of TET2 by R2-HG has been found to result in a hypermethylated gene signature in HSPCs, which overlaps with the signatures of both IDH and TET2-mutated leukemic cells. 	SIGNOR-261829	0.8
USP2	protein	O75604	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates activity	deubiquitination	Lys502	LSQQEGIkM	-1									29490279	t		miannu	Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1.	SIGNOR-273605	0.2
PRKCB	protein	P05771	UNIPROT	ANXA1	protein	P04083	UNIPROT	up-regulates	phosphorylation	Ser27	EYVQTVKsSKGGPGS	9606									24103589	t		lperfetto	The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization.	SIGNOR-202784	0.2
PPP1CA	protein	P62136	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	dephosphorylation	Ser37	NVLSPLPsQAMDDLM	9606									16501611	t			Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.	SIGNOR-248557	0.32
RAP1GDS1	protein	P52306	UNIPROT	RAC2	protein	P15153	UNIPROT	up-regulates	binding			9606									21242305	t		miannu	Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob	SIGNOR-171421	0.513
COPS3	protein	Q9UNS2	UNIPROT	SOS1	protein	Q07889	UNIPROT	up-regulates quantity by stabilization	binding			9606									30631038	t		miannu	Our observations characterizing the interaction between CSN3 and the Sos1 HD suggest that this domain not only functions regulating Sos-GEF autoinhibition but is also involved in other functional roles, such as the control of Sos protein stability and homeostasis by modulating the degradation and intracellular levels of Sos1.	SIGNOR-256217	0.2
ACVR1	protein	Q04771	UNIPROT	AMOT/MPP5/INADL/LIN7C	complex	SIGNOR-C27	SIGNOR	up-regulates	phosphorylation			9606									9748228	t		fspada	Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2	SIGNOR-210093	0.2
antigen	smallmolecule	CHEBI:59132	ChEBI	BCR-Dk	complex	SIGNOR-C435	SIGNOR	up-regulates activity	binding			9606	BTO:0000776								32323266	t		scontino	The recognition of antigen by the BCR initiates BCR signaling cascade.	SIGNOR-268204	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser380	HQLFRGFsFVATGLM	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-250555	0.2
FLT3	protein	P36888	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation			10090	BTO:0001516								14981546	t			These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation.	SIGNOR-261522	0.443
SUMO1	protein	P63165	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates activity	sumoylation	Lys65	QQCQAEAkCPKLLPC	9534	BTO:0000298								9756909	t		lperfetto	We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins |We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites. The PML mutant with Lys to Arg substitutions in all three sites is expressed normally, but cannot be sentrinized|Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies.	SIGNOR-270542	0.771
CSNK2A1	protein	P68400	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	down-regulates activity	phosphorylation	Thr896	KNSECDPtPSHRGQL	9606	BTO:0000567								31167143	t		miannu	Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations. 	SIGNOR-276733	0.2
CDC14B	protein	O60729	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser705	TPSAMKSsPQIPHQT	9606									20236090	t			Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3.	SIGNOR-248337	0.552
ARPC2	protein	O15144	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	form complex	binding			9606									12479800	t			The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc	SIGNOR-251514	0.958
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	DNM1L	protein	O00429	UNIPROT	up-regulates activity	phosphorylation	Ser585	WRGMLKTSKAEELLA	9606	BTO:0000007								17301055	t		Barakat	Drp1 was specifically phosphorylated at Ser-585 by Cdk1/cyclin B, which stimulated the mitochondrial fission in mitosis. From these results, we concluded that mitochondrial morphology is regulated by Drp1-dependent mitochondrial fission in mitotic cells	SIGNOR-274131	0.38
ATG12	protein	O94817	UNIPROT	ATG12/5/16L1	complex	SIGNOR-C109	SIGNOR	form complex	binding			9606		BTO:0000007							18321988	t		lperfetto	Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex).	SIGNOR-226689	0.864
STK38	protein	Q15208	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser146	GRKRRQTsMTDFYHS	9606	BTO:0000007								21262772	t	no	lperfetto	More importantly, with the direct regulation of p21 stability by phosphorylation on Ser 146, we define here the first downstream signaling mechanisms by which NDR kinases can control G1/S progression.|NDR kinases regulate p21 stability by phosphorylation of S146 on p21. |	SIGNOR-272961	0.2
PLK1	protein	P53350	UNIPROT	PINX1	protein	Q96BK5	UNIPROT	down-regulates	phosphorylation	Ser110	SDKKEKKsFSLEEKS	9606									20573420	t		lperfetto	Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation.	SIGNOR-166317	0.37
SRC	protein	P12931	UNIPROT	ENG	protein	P17813	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr614	TAALWYIySHTRSPS	9606	BTO:0002828								25070888	t		miannu	We identified epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) as Src-activators that induce endoglin turnover following (612)YIY(614) phosphorylation. 	SIGNOR-276654	0.395
sirolimus	chemical	CHEBI:9168	ChEBI	LILRB2	protein	Q8N423	UNIPROT	down-regulates quantity by repression				9606									18652845	f		miannu	Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells.	SIGNOR-255477	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	EGR1	protein	P18146	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11085989	f		miannu	We also show for the first time that leptin rapidly stimulates the mRNA expression of the zinc finger transcription factor, Egr-1, in the hypothalamus of mice. Our transfection results suggest that this regulation by leptin occurs by activation of theegr-1 promoter via activation of SHP-2 and of the ERK pathway. 	SIGNOR-263507	0.2
CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	PER2	protein	O15055	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f		lperfetto	Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253682	0.752
FARSA	protein	Q9Y285	UNIPROT	Phenylalanyl-tRNA synthetase	complex	SIGNOR-C473	SIGNOR	form complex	binding			9606									20223217	t		miannu	Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers.	SIGNOR-270436	0.994
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	TWIST1	protein	Q15672	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								21502402	t	inferred from 70% family members	llicata	Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro	SIGNOR-270209	0.2
PAK1	protein	Q13153	UNIPROT	ILK	protein	Q13418	UNIPROT	up-regulates	phosphorylation	Thr173	DTFWKGTtRTRPRNG	9606									17420447	t		lperfetto	We found that pak1 phosphorylates ilk at threonine-173 and serine-246 in vitro and in vivo. together, these results suggest that ilk is a pak1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin.	SIGNOR-154307	0.421
BMS-554417	chemical	CID:54754526	PUBCHEM	INSR	protein	P06213	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190458	0.8
LNX1	protein	Q8TBB1	UNIPROT	PBK	protein	Q96KB5	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								22889411	t		miannu	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272898	0.383
KIF3B	protein	O15066	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									28290984	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272516	0.7
NEUROG3	protein	Q9Y4Z2	UNIPROT	NEUROG2	protein	Q9H2A3	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19028584	f		miannu	Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated.	SIGNOR-254633	0.2
PPP3CC	protein	P48454	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates				9606		BTO:0001103							11062529	f		gcesareni	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-83740	0.432
CFI	protein	P05156	UNIPROT	C3	protein	P01024	UNIPROT	down-regulates activity	cleavage			9606		BTO:0000089							26806831	t		lperfetto	FH also serves as cofactor for the serine protease factor I (FI) that cleaves C3b into iC3b, unable to form C3 convertase (Fig 1B).	SIGNOR-263489	0.874
CAMK2B	protein	Q13554	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	phosphorylation	Ser1303	NKLRRQHsYDTFVDL		BTO:0003036								8940188	t		llicata	By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons.	SIGNOR-250688	0.589
WASF2	protein	Q9Y6W5	UNIPROT	WAVE complex	complex	SIGNOR-C271	SIGNOR	form complex	binding			9606	BTO:0000567								15070726	t		lperfetto	Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex. 	SIGNOR-261871	0.907
E2F1	protein	Q01094	UNIPROT	ELF4	protein	Q99607	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20805247	f		miannu	 we determined that E2F1 specifically binds to MEF promoter and transactivates MEF. 	SIGNOR-253849	0.249
CUDC-101	chemical	CID:24756910	PUBCHEM	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									20143778	t		miannu	By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively.	SIGNOR-262262	0.8
RPS6KA3	protein	P51812	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									10464286	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-70436	0.2
CBL	protein	P22681	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	ubiquitination			9606									11498022	t		gcesareni	Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor	SIGNOR-109688	0.506
BST1	protein	Q10588	UNIPROT	NAD(+)	smallmolecule	CHEBI:15846	ChEBI	down-regulates quantity	chemical modification			9606									18626062	t		miannu	The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR.	SIGNOR-264250	0.8
PAX8	protein	Q06710	UNIPROT	TPO	protein	P07202	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001073							27347897	t		scontino	TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8.	SIGNOR-267277	0.41
ketoprofen	chemical	CHEBI:6128	ChEBI	PTGS1	protein	P23219	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001061								18667313	t		Luana	Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2. 	SIGNOR-257810	0.8
PAK2	protein	Q13177	UNIPROT	SYN1	protein	P17600	UNIPROT	unknown	phosphorylation	Ser9	NYLRRRLsDSNFMAN	10116									12237306	t		miannu	Recombinant PAK2 could also phosphorylate the Ser9 and Ser551 residues. 	SIGNOR-250236	0.331
Anacetrapib	chemical	CID:11556427	PUBCHEM	CETP	protein	P11597	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189605	0.8
acyl-CoA	smallmolecule	CHEBI:17984	ChEBI	1-phosphatidyl-1D-myo-inositol	smallmolecule	CHEBI:16749	ChEBI	up-regulates quantity	precursor of			-1									18772128	t		miannu	The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils.	SIGNOR-267243	0.8
EP300	protein	Q09472	UNIPROT	SMAD7	protein	O15105	UNIPROT	up-regulates	acetylation	Lys64	RAGCCLGkAVRGAKG	9606									12408818	t		gcesareni	Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300	SIGNOR-95165	0.476
SMAD1/4	complex	SIGNOR-C85	SIGNOR	CEBPB	protein	P17676	UNIPROT	up-regulates activity	binding			9606									18854943	t		fferrentino	This Smad1/4 complex can directly interact with Shn-2 and C/EBP a on the PPAR g promoter thus, resulting in the transcriptional activation of PPAR g	SIGNOR-253552	0.541
CDK1	protein	P06493	UNIPROT	RECQL4	protein	O94761	UNIPROT	up-regulates activity	phosphorylation	Ser251	EVSIRVGsPQPSSSG	9606	BTO:0002181								29229926	t		miannu	 During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs.	SIGNOR-277375	0.362
NEK2	protein	P51955	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr210	TNEIFYCtFRRLDPE	10090	BTO:0000584								34315872	t		miannu	NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. 	SIGNOR-277314	0.2
CDK9	protein	P50750	UNIPROT	SUPT5H	protein	O00267	UNIPROT	up-regulates	phosphorylation	Thr799	PLQDGSRtPHYGSQT	9606									16427012	t		lperfetto	We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif	SIGNOR-143935	0.769
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606									20457564	f		gcesareni	The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules.	SIGNOR-245039	0.7
NLRX1	protein	Q86UT6	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	down-regulates activity	binding			9606									21703539	t		Giorgia	Immunoprecipitation experiments showed that NLRX1 interacted with TRAF6 and TRAF3, but not with TRAF2 or TRAF5. These results further suggest that NLRX1 specifically inhibits TLR-induced TRAF6-dependent NF-kB signaling through targeting TRAF6.	SIGNOR-260364	0.484
EIF2S1	protein	P05198	UNIPROT	ATF4	protein	P18848	UNIPROT	down-regulates quantity	transcriptional regulation			9606									27629041	t		miannu	ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2alpha, the core of ISR. This leads to global attenuation of Cap dependent translation while concomitantly initiates the preferential translation of ISR specific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. eIF2alpha phosphorylation causes a reduction in global protein synthesis while allowing the translation of selected genes including activating transcription factor 4 (ATF4), aiding cell survival and recovery	SIGNOR-260169	0.627
PRKACA	protein	P17612	UNIPROT	PJA2	protein	O43164	UNIPROT	up-regulates activity	phosphorylation	Ser342	RHEAKQRsVQRWREA	-1									21423175	t		miannu	In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h).	SIGNOR-276316	0.2
PLK1	protein	P53350	UNIPROT	CENPQ	protein	Q7L2Z9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr123	RLLQQCEtLKVPPKK	9606	BTO:0000567								25670858	t		lperfetto	Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 	SIGNOR-265231	0.57
clonidine	chemical	CHEBI:46631	ChEBI	ADRA2B	protein	P18089	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258904	0.8
SOD1	protein	P00441	UNIPROT	EIF2AK3	protein	Q9NZJ5	UNIPROT	up-regulates activity	binding			10090	BTO:0004488								18519638	t	P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)		SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK	SIGNOR-262787	0.278
BRCA1-C complex	complex	SIGNOR-C299	SIGNOR	TP53BP1	protein	Q12888	UNIPROT	up-regulates activity	relocalization												25400280	t		lperfetto	Additional to the role of the BRCA1–C complex in 53BP1 repositioning and initiation of resection, end resection is extended to facilitate RPA loading and subsequent RPA‐Rad51 exchange prior to sister strand invasion	SIGNOR-263230	0.611
NLGN1	protein	Q8N2Q7	UNIPROT	NRXN3	protein	Q9HDB5	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264169	0.823
TRIM59	protein	Q8IWR1	UNIPROT	ECSIT	protein	Q9BQ95	UNIPROT	down-regulates activity	binding			9606	BTO:0000567; BTO:0002181								22588174	t		Giorgia	In this study, we showed that one of the TRIM family ubiquitin ligases, TRIM59, interacts with ECSIT as an adaptor protein required for the TLR-mediated transduction pathway. The B-box and RING domains of TRIM59 are important for interaction with ECSIT.|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation.|Luciferase reporter assays using reporter plasmids including NF-kappaB responsive element, interferon beta (IFN-beta) promoter and interferon-sensitive response element (ISRE) showed that overexpression of TRIM59 repressed their transcriptional activities, whereas knockdown of TRIM59 enhanced their transcriptional activities.	SIGNOR-260369	0.534
EP300	protein	Q09472	UNIPROT	MEF2D	protein	Q14814	UNIPROT	up-regulates	binding			9606									11796223	t		lperfetto	Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription.	SIGNOR-232162	0.732
PI4KA	protein	P42356	UNIPROT	1-phosphatidyl-1D-myo-inositol 4-phosphate	smallmolecule	CHEBI:17526	ChEBI	up-regulates quantity	chemical modification			9606									10101268	t		miannu	The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 	SIGNOR-269103	0.8
AKT1	protein	P31749	UNIPROT	KDM5A	protein	P29375	UNIPROT	up-regulates activity	phosphorylation	Ser287	RQRKGTLsVNFVDLY	-1									27292631	t		miannu	We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment.	SIGNOR-274062	0.309
BMP4	protein	P12644	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	up-regulates activity	binding			10090	BTO:0000165								11282024	t		lperfetto	Bmp-4 and gdf-5 are known to bind to activin	SIGNOR-235376	0.847
PRKACA	protein	P17612	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates	phosphorylation	Thr159	DNKLRRYtTFSKRKT	10090									12809504	t		llicata	Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha. 	SIGNOR-188177	0.259
CSNK2A2	protein	P19784	UNIPROT	AQP4	protein	P55087	UNIPROT	down-regulates activity	phosphorylation	Ser276	AAQQTKGsYMEVEDN	9615	BTO:0000837								11742978	t		llicata	We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII.	SIGNOR-250974	0.344
RNF144B	protein	Q7Z419	UNIPROT	NPM1	protein	P06748	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000772								20864535	t		miannu	NPMc degradation was mediated by the ubiquitin-proteasome pathway involving the IBR-type RING-finger E3 ubiquitin ligase IBRDC2, and genetic correction of FA-A or FA-C lymphoblasts prevented NPMc ubiquitination. As shown in Fig. 4C, knockdown of IBRDC2, an IBR-type RING-finger E3 ubiquitin ligase (21), significantly reduced NPMc ubiquitination and restored NPMc stability in FA-A cells	SIGNOR-271490	0.2
PRKAA1	protein	Q13131	UNIPROT	MLXIPL	protein	Q9NP71	UNIPROT	down-regulates	phosphorylation			9606			SIGNOR-C15						21892142	t		gcesareni	Ampk has also been suggested to phosphorylate the glucose-sensitive transcription factor chrebpthe dna binding activity, as assayed in a gel-shift assay of the truncated chrebp, was gradually inactivated with time by treatment with ampk	SIGNOR-176494	0.428
PTK2	protein	Q05397	UNIPROT	BCAR1	protein	P56945	UNIPROT	unknown	phosphorylation	Tyr664	EGGWMEDyDYVHLQG										11604500	t		lperfetto	FAK phosphorylates CAS-SBD tyrosines 668 and/or 670, driving an SH2-mediated recruitment of Src which then phosphorylates CAS-SD.	SIGNOR-249111	0.805
ARAF	protein	P10398	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates	phosphorylation	Ser218	VSGQLIDsMANSFVG	9606	BTO:0000567								8621729	t		lperfetto	Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling|The immunoprecipitates were assayed for GST-MEK1 activation. D, activation of MEK1 by A-Raf requires the presence of serine residue 218 and 222.	SIGNOR-236451	0.728
CSNK2A1	protein	P68400	UNIPROT	PML	protein	P29590	UNIPROT	down-regulates	phosphorylation	Ser565	VISSSEDsDAENSSS	9606	BTO:0000551								16873060	t		llicata	Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517.	SIGNOR-148310	0.347
MAPK1	protein	P28482	UNIPROT	ZFP36	protein	P26651	UNIPROT	unknown	phosphorylation	Ser228	PPGDLPLsPSAFSAA	10090	BTO:0000944								7768935	t		lperfetto	By a combination of protease digestion experiments and site-directed mutagenesis strategies, we found that serine 220 was phosphorylated by p42 MAP kinase in vitro. Expression of mutant TTP in fibroblasts confirmed that serine 220 was one of the major, mitogen-stimulated phosphorylation sites on the protein in intact cells. |It is not obvious how phosphorylation of TTP at serine 220 would alter DNA binding, since this residue lies well outside of the putative zinc finger region, which is between amino acids 95 to 159 in the mouse protein	SIGNOR-249456	0.468
SNAP91	protein	O60641	UNIPROT	VAMP2	protein	P63027	UNIPROT	up-regulates quantity	binding			9606	BTO:0000938								26903854	t		miannu	 the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. Furthermore, recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval.	SIGNOR-264112	0.615
PRKACA	protein	P17612	UNIPROT	CUL5	protein	Q93034	UNIPROT	up-regulates activity	phosphorylation	Ser730	MKMRKKIsNAQLQTE	9534	BTO:0000298								10898738	t		miannu	Elimination of the S730 but not the T325 PKA phosphorylation site of VACM-1 resulted in a complete inhibition of the VACM-1 activity, thus suggesting a direct effect of PKA on the VACM-1 receptor.	SIGNOR-250352	0.327
FOXO6	protein	A8MYZ6	UNIPROT	IDH1	protein	O75874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25648147	t		miannu	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260092	0.2
LRFN5	protein	Q96NI6	UNIPROT	PTPRS	protein	Q13332	UNIPROT	up-regulates activity	binding			9606									27225731	t		miannu	SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1). 	SIGNOR-264088	0.377
KLF10	protein	Q13118	UNIPROT	SIN3A	protein	Q96ST3	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								11438660	t		miannu	detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.	SIGNOR-222394	0.458
DYRK1A	protein	Q13627	UNIPROT	FOXO6	protein	A8MYZ6	UNIPROT	down-regulates	phosphorylation			9606									19188143	t		gcesareni	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity	SIGNOR-183680	0.311
imatinib methanesulfonate	chemical	CHEBI:31690	ChEBI	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	down-regulates activity	chemical inhibition			9606	BTO:0000740								15206509	t		miannu	Imatinib mesylate (Gleevec/Glivec, Novartis, Basel, Switzerland), formerly called STI571, is a specific and potent inhibitor of the BCR-ABL tyrosine kinase, the molecular hallmark of chronic myeloid leukaemia. 	SIGNOR-259357	0.8
BCORL1	protein	Q5H9F3	UNIPROT	HDAC4	protein	P56524	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								17379597	t		irozzo	BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor.	SIGNOR-259112	0.438
CHUK	protein	O15111	UNIPROT	FOXA2	protein	Q9Y261	UNIPROT	down-regulates	phosphorylation	Ser111	PHLSPSLsPLGGQAA	9606									22196886	t		lperfetto	Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression	SIGNOR-195316	0.2
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGB3	protein	Q9Y5G1	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265685	0.2
PP2Ca_R1A_Bd 	complex	SIGNOR-C133	SIGNOR	PDPK1	protein	O15530	UNIPROT	down-regulates activity	dephosphorylation			9606									21075311	t		gcesareni	Here, we show that PPP2R2B, encoding the B55² regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55²-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation.	SIGNOR-243515	0.286
SRC	protein	P12931	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates activity	phosphorylation	Tyr1166	DIYETDYyRKGGKGL	-1									7493944	t		lperfetto	The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.	SIGNOR-246268	0.564
MAPK3	protein	P27361	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Ser567	DSSRFPMsPRPDSVH	10029	BTO:0000246								15379552	t		lperfetto	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-249462	0.618
ALDOA	protein	P04075	UNIPROT	glycerone phosphate(2-)	smallmolecule	CHEBI:57642	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266483	0.8
AKT1	protein	P31749	UNIPROT	NCOR1	protein	O75376	UNIPROT	down-regulates	phosphorylation	Ser1450	TVRSRHTsVVSSGPS	9606	BTO:0001271								23940660	t		llicata	Akt-induced phosphorylation of n-cor at serine 1450 contributes to its misfolded conformational dependent loss (mcdl) in acute myeloid leukemia of the m5 subtype.	SIGNOR-198913	0.436
CDK9	protein	P50750	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser392	FKTEGPDsD	9606									23603988	t		gcesareni	We recently demonstrated that through their physical interaction, cdk9 phosphorylates p53 on ser-392, leading to p53 stability and accumulation	SIGNOR-201935	0.551
LPAR6	protein	P43657	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606									15856019	t		gcesareni	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13.	SIGNOR-135822	0.385
RUNX2	protein	Q13950	UNIPROT	COL2A1	protein	P02458	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11331591	f		gcesareni	In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast	SIGNOR-107169	0.453
AKT2	protein	P31751	UNIPROT	NFKB1	protein	P19838	UNIPROT	up-regulates				9606									17604717	f		gcesareni	Several studies have demonstrated that akt signaling can activate the nf-kb transcription factor downstream of a variety of stimuli, such as tumor necrosis factor (tnfalfa)	SIGNOR-156530	0.335
GHR	protein	P10912	UNIPROT	MAP2K5	protein	Q13163	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0005787	BTO:0001103							23612709	t		miannu	The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 	SIGNOR-255452	0.2
IRAK4	protein	Q9NWZ3	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser320	QRSRKRLsQDAYRRN	9606	BTO:0000130								17217339	t		lperfetto	Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.These results strongly support the observation that irak-4 is a kinase for p47phox in vivo. We also detected the signature of phosphorylation at ser320 and ser345	SIGNOR-152015	0.39
Viral_dsRNA	stimulus	SIGNOR-ST21	SIGNOR	DDX58	protein	O95786	UNIPROT	up-regulates				9606									19052324	t		miannu	Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ.	SIGNOR-260141	0.7
IRAK4	protein	Q9NWZ3	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Thr80	DQHSISYtLSRAQTV	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276131	0.643
CDKL5	protein	O76039	UNIPROT	CDKL5	protein	O76039	UNIPROT	up-regulates activity	phosphorylation	Tyr171	NNANYTEyVATRWYR	-1									16935860	t		miannu	Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif.	SIGNOR-245876	0.2
PRKACA	protein	P17612	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser621	PKINRSAsEPSLHRA	9606									11971957	t		gcesareni	We have mapped all camp-induced phosphorylation sites in raf-1, showing that serines 43, 259, and 621 are phosphorylated by pka in vitro and induced by camp in vivo	SIGNOR-86137	0.481
YWHAZ	protein	P63104	UNIPROT	GEM	protein	P55040	UNIPROT	up-regulates quantity by stabilization	binding			9534	BTO:0000298								14701738	t		miannu	In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase	SIGNOR-261725	0.307
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	KLHL3	protein	Q9UH77	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser433	PMNTRRSsVGVGVVE	9534	BTO:0000298								25313067	t	done	miannu	We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation.	SIGNOR-273780	0.2
HRH1	protein	P35367	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257318	0.2
CTCF	protein	P49711	UNIPROT	TERT	protein	O14746	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16326864	t		miannu	CTCF binds the proximal exonic region of hTERT and inhibits its transcription	SIGNOR-253832	0.335
CEBPB	protein	P17676	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								15044620	f		miannu	 C/EBPbeta activates the endogenous MDR1 gene of MCF-7 cells, and this activation was associated with a novel C/EBPbeta interaction region within the proximal MDR1 promoter (-128 to -75).	SIGNOR-253771	0.455
PRKACA	protein	P17612	UNIPROT	AICDA	protein	Q9GZX7	UNIPROT	unknown	phosphorylation	Ser38	YVVKRRDsATSFSLD	9606	BTO:0000776								18417471	t		llicata	We have found using sf9 insect cells to overexpress human gst-aid that a small fraction of the enzyme is phosphorylated at ser38 and thr27 and at two residues not reported previously, ser41 and ser43	SIGNOR-178244	0.329
BMPR1B	protein	O00238	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates activity	phosphorylation			9606									19620713	t		lperfetto	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-255265	0.628
YES1	protein	P07947	UNIPROT	GLO1	protein	Q04760	UNIPROT	up-regulates activity	phosphorylation	Tyr136	GIAVPDVySACKRFE	-1									34838714	t		miannu	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276185	0.2
CHKA	protein	P35790	UNIPROT	choline	smallmolecule	CHEBI:15354	ChEBI	down-regulates quantity	chemical modification												27149373	t		lperfetto	Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes	SIGNOR-275637	0.8
MET	protein	P08581	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr861	PIGNQHIyQPVGKPD	9606									16782899	t		llicata	Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain	SIGNOR-147199	0.475
TBX5	protein	Q99593	UNIPROT	SNCG	protein	O76070	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20802524	f		miannu	TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. 	SIGNOR-255255	0.2
ANGPTL1	protein	O95841	UNIPROT	TEK	protein	Q02763	UNIPROT	up-regulates	binding			9606									10051567	t		gcesareni	Ang3 and ang4 are agonists of tie2, but mouse ang3 has strong activity only on endothelial cells of its own species.	SIGNOR-65110	0.521
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates quantity by destabilization	cleavage	Glu612	IKTEEISeVKMDAEF	-1									8943232	t		lperfetto	The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261766	0.502
PLCB2	protein	Q00722	UNIPROT	1D-myo-inositol 1,4,5-trisphosphate(6-)	smallmolecule	CHEBI:203600	ChEBI	up-regulates quantity	chemical modification			9606									23994464	t		apalma	The first phase of this signal is likely mediated by phospholipase Cβ (PLCβ) enzymes leading to the generation of IP3 and concomitant release of Ca2+ from intracellular stores	SIGNOR-255017	0.8
PRKCA	protein	P17252	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates	phosphorylation	Thr159	DNKLRRYtTFSKRKT	10090									12809504	t		llicata	Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha. 	SIGNOR-188181	0.248
PPP1R9A	protein	Q9ULJ8	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates				10090	BTO:0001976								15996550	f		miannu	Neurabin and spinophilin are preferentially expressed in neurons, where they are highly localized to dendritic spines via an interaction with F-actin. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc	SIGNOR-269180	0.7
GSK3B	protein	P49841	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity	phosphorylation	Thr1938	HREKKEStPSTASLP	10116	BTO:0000938								29642012	t		lperfetto	In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity.	SIGNOR-275763	0.2
YAP1	protein	P46937	UNIPROT	TEAD	proteinfamily	SIGNOR-PF22	SIGNOR	up-regulates activity	binding			9606									23431053	t		miannu	YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death	SIGNOR-230719	0.94
PEX3	protein	P56589	UNIPROT	PEX19	protein	P40855	UNIPROT	up-regulates activity	binding			-1									15007061	t		miannu	PEX3 is required for PEX19 to dock at peroxisomes, interacts specifically with the docking domain of PEX19, and is required for recruitment of the PEX19 docking domain to peroxisomes. 	SIGNOR-253026	0.953
FERMT2	protein	Q96AC1	UNIPROT	FBLIM1	protein	Q8WUP2	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								24165133	t		miannu	Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 	SIGNOR-266102	0.776
F7	protein	P08709	UNIPROT	Factor FVIIa:TF	complex	SIGNOR-C319	SIGNOR	form complex	binding			9606		BTO:0000131							32665005	t		lperfetto	During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury.	SIGNOR-263555	0.932
UBXN1	protein	Q04323	UNIPROT	Protein_degradation	phenotype	SIGNOR-PH96	SIGNOR	up-regulates				9606									15362974	f		miannu	Our working hypothesis is that SAKS1 acts as scaffolding protein to enhance the unfolding and proteolytic destruction of a subset of proteins. PNGase removes high-mannose-containing oligosaccharides from MGPs [30], and our results suggest this may be facilitated by the formation of a complex between PNGase, VCP, SAKS1 and ubiquitinated MGPs, as illustrated schematically in Figure 7(B). PNGase has been reported to bind to the S4 component of the proteasome [30], so that the deglycosylation of MGPs by PNGase, followed by VCP-catalysed unfolding, may facilitate their destruction by the proteasome.	SIGNOR-261059	0.7
S100A8	protein	P05109	UNIPROT	AGER	protein	Q15109	UNIPROT	up-regulates activity	binding			9606									28137827	t		miannu	RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33	SIGNOR-261919	0.323
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1892	TPKYSPTsPTYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120232	0.321
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr45	PGGTLFStTPGGTRI	9606	BTO:0000007		SIGNOR-C3						9465032	t		lperfetto	Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size.	SIGNOR-55701	0.924
F2RL1	protein	P55085	UNIPROT	DUSP6	protein	Q16828	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	 PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 	SIGNOR-254853	0.2
SP1	protein	P08047	UNIPROT	SLC19A3	protein	Q9BZV2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			7227	BTO:0001677								15217784	f		miannu	In transiently transfected Drosophila SL2 cells, both SP1 and SP3 transactivated the SLC19A3 minimal promoter in a dose-dependent manner and in combination demonstrated an additive stimulatory effect.	SIGNOR-255215	0.274
PRKCA	protein	P17252	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates	phosphorylation	Ser42	AKKKSKIsASRKLQL	9606		BTO:0000887							15769444	t		lperfetto	Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.	SIGNOR-134613	0.349
BMP10	protein	O95393	UNIPROT	ACVRL1	protein	P37023	UNIPROT	up-regulates	binding			9606									17068149	t		acerquone	Taken together, our results sug- gest that bmp9 and bmp10 are two spe- cific alk1 ligands that may physiologi- cally trigger the effects of alk1 on angiogenesis	SIGNOR-150201	0.698
NCOA1	protein	Q15788	UNIPROT	PCK2	protein	Q16822	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f		miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-255066	0.285
NRAS	protein	P01111	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates				9606									17845852	f		gcesareni	Ras and akt signaling enhances the nuclear localization of gli1, counteracting its suppression by other modifiers that retain it in the cytoplasm, such as suppressor of fused (sufu)	SIGNOR-157773	0.29
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2E1	protein	P51965	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271325	0.709
MYC	protein	P01106	UNIPROT	CDKN2B	protein	P42772	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001271								12835716	f		gcesareni	Miz1 is a zinc finger transcription factor with an n-terminal poz domain. Complexes with myc, bcl-6 or gfi-1 repress expression of genes like cdkn2b (p15(ink4)) or cdkn1a (p21(cip1)).	SIGNOR-102746	0.588
SRC_kinase_family	proteinfamily	SIGNOR-PF32	SIGNOR	Chemotaxis	phenotype	SIGNOR-PH93	SIGNOR	up-regulates				9606									15526160	f		apalma	The SFK family of tyrosine kinases is named after its prototypic family member c-Src. SCF-induced chemotaxis of Mo7 cells was dependent on SFK activity	SIGNOR-254996	0.7
FYN	protein	P06241	UNIPROT	SLAMF1	protein	Q13291	UNIPROT	up-regulates activity	phosphorylation	Tyr281	EKKSLTIyAQVQKPG	9534	BTO:0000298								11806999	t			All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327. 	SIGNOR-251181	0.647
TELO2	protein	Q9Y4R8	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates quantity by stabilization	binding			9606	BTO:0000007								20427287	t		miannu	MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. 	SIGNOR-272001	0.532
CDK1	protein	P06493	UNIPROT	PRPS1	protein	P60891	UNIPROT	up-regulates activity	phosphorylation	Ser103	RQDKKDKsRAPISAK										31253668	t		lperfetto	CDK1 contributes to upregulation of PRPS1 activity by phosphorylating PRPS1 at S103|In conclusion, compared with upregulation of PRPS1 expression levels, increased PRPS1 activity, which is marked by S103 phosphorylation	SIGNOR-265728	0.257
SRC	protein	P12931	UNIPROT	DAB1	protein	O75553	UNIPROT	up-regulates activity	phosphorylation	Tyr232	SQKKEGVyDVPKSQP	10090	BTO:0000938								11279201	t		lperfetto	Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons.	SIGNOR-247084	0.43
EXOC8	protein	Q8IYI6	UNIPROT	Exocyst_EXOC6 variant	complex	SIGNOR-C492	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270791	0.939
MAP2K2	protein	P36507	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates activity	phosphorylation			10090									11730323	t			Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs	SIGNOR-258996	0.733
KAT2A	protein	Q92830	UNIPROT	H3C15	protein	Q71DI3	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269609	0.2
[4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone	chemical	CHEBI:91441	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193615	0.8
sunitinib	chemical	CHEBI:38940	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates	chemical inhibition			9606									21993628	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-176766	0.8
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	FOXO4	protein	P98177	UNIPROT	up-regulates	phosphorylation	Thr455	ALGTPVLtPPTEAAS	9606	BTO:0000848	BTO:0001253							20959475	t		lperfetto	Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451).	SIGNOR-168766	0.2
ELF3	protein	P78545	UNIPROT	SPRR2A	protein	P35326	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								10773884	f	 	 	Interestingly, ELF3 suppressed basal keratin 4 promoter activity in both esophageal and cervical epithelial cancer cell lines, a novel result, while simultaneously activating the late-differentiation linked SPRR2A promoter.	SIGNOR-254292	0.408
LAMTOR4	protein	Q0VGL1	UNIPROT	LAMTOR	complex	SIGNOR-C26	SIGNOR	form complex	binding			9606									20381137	t		lperfetto	Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant	SIGNOR-164778	0.923
MAPK1	protein	P28482	UNIPROT	METTL3	protein	Q86U44	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser43	RNPEAALsPTFRSDS	9606	BTO:0000007								33217317	t		miannu	 Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.	SIGNOR-265950	0.276
CLCC1	protein	Q96S66	UNIPROT	PIGBOS1	protein	A0A0B4J2F0	UNIPROT	up-regulates activity	binding			9606									31653868	t		Simone	The PIGBOS microprotein interacts with the ER protein CLCC1. PIGBOS localizes to the mitochondrial outer membrane where itinteracts with the ER protein CLCC1 at ER–mitochondria contact sites. PIGBOS-CLCC1 interaction is necessary for PIGBOS function	SIGNOR-261040	0.2
DICER1	protein	Q9UPY3	UNIPROT	DICER1/hAgo2/PRKRA	complex	SIGNOR-C41	SIGNOR	form complex	binding			9606									23661684	t		miannu		SIGNOR-143105	0.892
RET	protein	P07949	UNIPROT	PDPK1	protein	O15530	UNIPROT	up-regulates activity	phosphorylation	Tyr9	ARTTSQLyDAVPIQS	10029									12738763	t		lperfetto	Ret/ptc (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (pdk1) ret/ptc phosphorylates a specific tyrosine (y9) residue located in the n-terminal region of pdk1.	SIGNOR-235863	0.2
LTC4S	protein	Q16873	UNIPROT	glutathionate(1-)	smallmolecule	CHEBI:57925	ChEBI	down-regulates quantity	chemical modification			9606									27365393	t		miannu	Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4).	SIGNOR-277259	0.8
PRKACA	protein	P17612	UNIPROT	PIN1	protein	Q13526	UNIPROT	down-regulates activity	phosphorylation	Ser16	PGWEKRMsRSSGRVY	9606									11723108	t		llicata	Pka and pkc readily phosphorylated pin1 and its ww domain in summary, we have demonstrated that phosphorylation of the pin1 ww domain on ser16 regulates its ability to function as a pser/thr-binding module. |To examine the importance of Ser16 of Pin1, it was mutated to Glu to mimic pSer, and the mutant Pin1S16E failed to bind mitotic phosphoproteins 	SIGNOR-112164	0.2
NVP-BSK805 dihydrochloride	chemical	CID:57339395	PUBCHEM	JAK2	protein	O60674	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194934	0.8
GPS1	protein	Q13098	UNIPROT	COP9 signalosome variant 2	complex	SIGNOR-C487	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270765	0.921
ZNHIT1	protein	O43257	UNIPROT	H2AZ1	protein	P0C0S5	UNIPROT	unknown				9606		BTO:0000887							20473270	f		gcesareni	The chromatin-remodelling complex snf2-related cbp activator protein (srcap) regulates chromatin structure in yeast by modulating the exchange of histone h2a for the h2a.z variant. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation.	SIGNOR-165610	0.2
PTP4A3	protein	O75365	UNIPROT	ITGB1	protein	P05556	UNIPROT	down-regulates activity	dephosphorylation	Tyr783	DTGENPIyKSAVTTV	9606									23092334	t		miannu	In this study, we demonstrate that PRL-3 directly binds to integrin \u03b21 and dephosphorylates integrin \u03b21-Y783, a key residue for integrin \u03b21 function [ ].|These results indicate that PRL-3 dephosphorylates integrin \u03b21 in vitro and in vivo.	SIGNOR-277050	0.507
TUBA3D	protein	P0DPH8	UNIPROT	Neuron_migration	phenotype	SIGNOR-PH67	SIGNOR	up-regulates				9606	BTO:0000007								19185337	f		miannu	We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching.	SIGNOR-269723	0.7
SSH1	protein	Q8WYL5	UNIPROT	LIMK1	protein	P53667	UNIPROT	down-regulates activity	dephosphorylation			9606									23153585	t		miannu	In addition to its cofilin\u2013phosphatase activity, SSH1 can also dephosphorylate LIMK1 and LIMK2, although LIMK1 is a better substrate than LIMK2  [63] .|SSH1 suppresses the kinase activity of LIMK1 toward cofilin by dephosphorylation at Thr 508 in the kinase catalytic domain and other autophosphorylated residues [63].	SIGNOR-277096	0.616
SATB1	protein	Q01826	UNIPROT	MYB	protein	P10242	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17343824	f		miannu	We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 	SIGNOR-255135	0.2
aldosterone	smallmolecule	CHEBI:27584	ChEBI	NR3C2	protein	P08235	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								8282004	t		miannu	The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4).	SIGNOR-258712	0.8
TWIST1	protein	Q15672	UNIPROT	NR2F1	protein	P10589	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255531	0.253
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	EDC3	protein	Q96F86	UNIPROT	down-regulates activity	binding			10029	BTO:0000246								20051463	t		miannu	14-3-3 binding to EDC3 resulted in a significant decrease in the binding of several key mRNA regulatory factors such as PABP and Y-box-binding protein 1 to EDC3.	SIGNOR-262630	0.2
CSNK2A2	protein	P19784	UNIPROT	SLC18A2	protein	Q05940	UNIPROT	unknown	phosphorylation	Ser513	GEDEESEsD	-1									9045708	t		llicata	Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. 	SIGNOR-251037	0.311
DCX DET1-COP1	complex	SIGNOR-C24	SIGNOR	CRTC2	protein	Q53ET0	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys212	LDGEMDPkVPAIEEN	9606	BTO:0000007								17805301	t		miannu	 In the presence of relevant cofactors (DDB1, DET1), COP1 promoted the ubiquitination of wild-type but not COP1-interaction defective VP/AA TORC2 (Fig. 3e). COP1 also stimulated the ubiquitination of TORC2(K213R) but had no effect on TORC2(K628R), suggesting an important role for Lys 628 in this regard (Fig. 3e). We performed mass spectrometry studies to characterize residues in TORC2 that undergo COP1-mediated ubiquitination. This analysis revealed one major (Lys 628) and one minor (Lys 213) site on TORC2	SIGNOR-271666	0.2
NANOG	protein	Q9H9S0	UNIPROT	AFP	protein	P02771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086;BTO:0005511								15983365	f		miannu	 Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 	SIGNOR-254621	0.453
SND1	protein	Q7KZF4	UNIPROT	STAT6	protein	P42226	UNIPROT	up-regulates activity	binding			-1									12234934	t		irozzo	STAT6 interacted with p100 in vitro and in vivo. Here, we show that the TAD of STAT6 is interacting with p100. p100 was found to enhance the STAT6-mediated transcription [.].	SIGNOR-259134	0.493
DEAF1	protein	O75398	UNIPROT	EN1	protein	Q05925	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000375								31145909	t		Gianni	Deaf1 is the first transcription factor implicated in the regulation of En1, a critical determinant of eccrine fate, within keratinocytes.	SIGNOR-269062	0.2
CDK5	protein	Q00535	UNIPROT	TPPP	protein	O94811	UNIPROT	down-regulates activity	phosphorylation	Thr14	PAKAANRtPPKSPGD	-1									17693641	t		miannu	 Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP.	SIGNOR-262933	0.414
STRN4	protein	Q9NRL3	UNIPROT	PPP2CA	protein	P67775	UNIPROT	up-regulates activity	binding			10090	BTO:0000938								29802198	t		miannu	The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms	SIGNOR-261697	0.587
MAP3K5	protein	Q99683	UNIPROT	DAXX	protein	Q9UER7	UNIPROT	up-regulates	phosphorylation	Ser176	TNAENTAsQSPRTRG	9606									19789335	t		gcesareni	Our data demonstrated that ask1 controls the cytoplasmic localization of daxx (fig.1). our results indicate that daxx not only activates ask1 but also is a downstream target of ask1 and that accumulated daxx further activates ask1. Thus, the daxx-ask1 positive feedback loop amplifying jnk/p38 signaling plays an important role in the cell-killing effects of stressors, such as tnfalpha.	SIGNOR-188321	0.835
NAA10	protein	P41227	UNIPROT	NatA	complex	SIGNOR-C415	SIGNOR	form complex	binding			9606	BTO:0000007								15496142	t		miannu	Protein acetyltransferases and deacetylases have been implicated in oncogenesis, apoptosis and cell cycle regulation. Most of the protein acetyltransferases described acetylate epsilon-amino groups of lysine residues within proteins. We now describe the human homologue of Nat1p, NATH (NAT human), as the partner of the hARD1 (human ARD1) protein. Included in the characterization of the NATH and hARD1 proteins is the following: (i) endogenous NATH and hARD1 proteins are expressed in human epithelial, glioma and promyelocytic cell lines; (ii) NATH and hARD1 form a stable complex, as investigated by reciprocal immunoprecipitations followed by MS analysis; (iii) NATH-hARD1 complex expresses N-terminal acetylation activity; (iv) NATH and hARD1 interact with ribosomal subunits, indicating a co-translational acetyltransferase function	SIGNOR-267224	0.95
PRKCQ	protein	Q04759	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								26431586	f		lperfetto	It is known that the teta isoform of the PKC family promotes the fusion of myoblasts and regulates the expression of caveolin-3 and beta1D integrin [15]. Of note, it has also been demonstrated that PKCepsilon expression increases during insulin-induced myogenic differentiation of the C2C12 cells.	SIGNOR-241525	0.2
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser37	NVLSPLPsQAMDDLM	9606									15659650	t		lperfetto	The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. On activation, both of these kinases also phosphorylate multiple sites in the p53 N-terminal domain. These include Ser15, Thr18, Ser20, and Ser37, which are all DNA-damageinducible sites	SIGNOR-153475	0.784
RDH10	protein	Q8IZV5	UNIPROT	retinol	smallmolecule	CHEBI:50211	ChEBI	down-regulates quantity	chemical modification			9606									21621639	t		lperfetto	Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS10	SIGNOR-265119	0.8
CDK1	protein	P06493	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates activity	phosphorylation	Ser105	TGAGAAGsPAQQHAH										26375055	t		lperfetto	We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity	SIGNOR-276520	0.261
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	MAPK6	protein	Q16659	UNIPROT	up-regulates	phosphorylation	Ser705	TPSAMKSsPQIPHQT	9606									20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.	SIGNOR-216805	0.373
RFX5	protein	P48382	UNIPROT	RFX complex	complex	SIGNOR-C104	SIGNOR	form complex	binding			-1									10825209	t		miannu	RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes	SIGNOR-221565	0.893
SP3	protein	Q02447	UNIPROT	MAOB	protein	P27338	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11259630	f		miannu	Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2. 	SIGNOR-253870	0.2
ARNTL	protein	O00327	UNIPROT	CRY1	protein	Q16526	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f			Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253626	0.932
ETS1	protein	P14921	UNIPROT	GP6	protein	Q9HCN6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12377757	f	 	miannu	 We have determined that the GP6 sequence -191 to -39 represents the core promoter and that transcription is driven largely by GATA-1 (-176) and c-Ets-1 (-45) sites within this segment.	SIGNOR-254082	0.2
MAPK1	protein	P28482	UNIPROT	TFEB	protein	P19484	UNIPROT	down-regulates activity	phosphorylation	Ser142	AGNSAPNsPMAMLHI	9606	BTO:0000567								21617040	t		gcesareni	Evidence for ERK2-mediated TFEB phosphorylation came from ERK2-TFEB coimmuno-precipitation (fig. S12C) in normal but not in starved medium and from a peptide-based kinase assay showing that mutation of Ser142 to alanine abolished ERK2-mediated phosphorylation (	SIGNOR-248279	0.425
PLK2	protein	Q9NYY3	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates activity	phosphorylation	Ser129	NEAYEMPsEEGYQDY	9606									19889641	t		lperfetto	Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. Pathological serine 129 phosphorylation regulates membrane accumulation of mutant alpha-synuclein.	SIGNOR-182155	0.491
ANAPC10	protein	Q9UM13	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	form complex	binding												16896351	t		lperfetto	The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex.	SIGNOR-252009	0.916
MLL2 complex	complex	SIGNOR-C88	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606									24680668	t		miannu	Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation.	SIGNOR-268799	0.2
CAMK2D	protein	Q13557	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Thr594	LHGKKNStVDCNGVV	9606									33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275778	0.48
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	form complex	binding												23729744	t		apalma	The released NICD translocates directly to the nucleus, where it forms a transcriptional complex with the DNA-binding protein CSL (CBF1, Suppressor of Hairless, Lag1), Mastermind (Mam) and transcriptional co-activators to drive the expression of Notch target genes	SIGNOR-255377	0.95
methiothepin	chemical	CHEBI:64203	ChEBI	HTR2B	protein	P41595	UNIPROT	down-regulates activity	chemical inhibition			10036	BTO:0000452								9459568	t		miannu	The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-	SIGNOR-258687	0.8
EGFR	protein	P00533	UNIPROT	CCDC50	protein	Q8IVM0	UNIPROT	down-regulates activity	phosphorylation	Tyr217	MAEEKKAyKKAKERE	9606	BTO:0000567								19059208	t		miannu	We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling.	SIGNOR-262850	0.425
RIPK1	protein	Q13546	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	phosphorylation	Ser161	IADLGLAsFKMWSKL	-1									18408713	t		miannu	These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1)	SIGNOR-276158	0.2
CSNK2A1	protein	P68400	UNIPROT	GBF1	protein	Q92538	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser297	TDSGLEFsSQTTSKE	9606	BTO:0002181								29898406	t		miannu	We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation.	SIGNOR-277398	0.2
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	KDM5A	protein	P29375	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273467	0.8
GNAS	protein	Q5JWF2	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates quantity				9606									12145344	f		lperfetto	HETEROTRIMERIC G PROTEINS are essential for cell signaling throughout the body. The stimulatory G protein, Gs, couples activation of a host of different transmembrane receptors to adenylyl cyclase stimulation, leading to intracellular generation of cAMP 	SIGNOR-268692	0.8
PLK1	protein	P53350	UNIPROT	TOP2A	protein	P11388	UNIPROT	up-regulates	phosphorylation	Ser1337	LDSDEDFsDFDEKTD	9606									18171681	t		llicata	Plk1 phosphorylates ser(1337) and ser(1524) of topoiialpha plk1-associated phosphorylation is essential for the functions of topoiialpha in mitosis	SIGNOR-160233	0.493
CSNK2A1	protein	P68400	UNIPROT	NR1H3	protein	Q13133	UNIPROT	down-regulates	phosphorylation	Ser198	SLPPRASsPPQILPQ	9606	BTO:0000801								18250151	t		llicata	Ck2? Also phosphorylated lxr? At s198 in vitro, suggesting that ck2 may be a bona fide s198 kinase. our results show that macrophage lxr? Phosphorylation at s198 affects the transcriptional activity of the receptor in a gene-specific manner (fig. ?(Fig.3a)3a) and restricts the repertoire of genes regulated by lxr?	SIGNOR-160640	0.2
PBX3	protein	P40426	UNIPROT	FGF8	protein	P55075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003560								10026229	t		miannu	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 	SIGNOR-265779	0.2
IGF1R	protein	P08069	UNIPROT	PIK3R3	protein	Q92569	UNIPROT	up-regulates	binding			9606					phosphorylation:Tyr1346	SFDERQPyAHMNGGR 			9415396	t		gcesareni	Moreover, we found that the insulin-like growth factor-1 receptor (igf-ir) bound to p55pik;the interaction occurred at the receptor tyrosine 1316 and involved both p55pik sh2 domains.	SIGNOR-52683	0.804
F2RL1	protein	P55085	UNIPROT	TNFRSF12A	protein	Q9NP84	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254837	0.2
CSNK2B	protein	P67870	UNIPROT	CDC34	protein	P49427	UNIPROT	unknown	phosphorylation	Ser236	DDSGTEEs	9606									12037680	t		llicata	CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm. 	SIGNOR-251060	0.357
IGF1R	protein	P08069	UNIPROT	PCNA	protein	P12004	UNIPROT	up-regulates activity	phosphorylation	Tyr250	DMGHLKYyLAPKIED	-1									28924044	t		miannu	In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination.	SIGNOR-277252	0.2
OPRK1	protein	P41145	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256853	0.435
SPI1	protein	P17947	UNIPROT	Monocyte_differentiation 	phenotype	SIGNOR-PH101	SIGNOR	up-regulates activity				10090	BTO:0000725								8079170	f			Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. [...]An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor.	SIGNOR-259954	0.7
P2RY6	protein	Q15077	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257277	0.375
PLK4	protein	O00444	UNIPROT	TUBGCP6	protein	Q96RT7	UNIPROT	up-regulates activity	phosphorylation	Ser1176	ISLGESVsDMAPARP	-1									22302995	t		miannu	Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication.	SIGNOR-262904	0.691
NFKBIE	protein	O00221	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates	binding			9606	BTO:0001271								12835716	t		lperfetto	Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe	SIGNOR-217361	0.571
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	MYC	protein	P01106	UNIPROT	up-regulates activity	phosphorylation			-1									32482868	t	inferred from 70% family members	lperfetto	ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation 	SIGNOR-270030	0.2
CALM2	protein	P0DP24	UNIPROT	Calcineurin	complex	SIGNOR-C155	SIGNOR	up-regulates	binding			9606									11796223	t		miannu	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-266331	0.475
KEAP1	protein	Q14145	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	down-regulates	binding			9606									24997453	t		miannu	Keap1 is an oxidative stress-sensing protein and is a negative regulator of nuclear factor-erythroid-2-related factor 2 (nrf2).	SIGNOR-205229	0.808
N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide	chemical	CHEBI:91409	ChEBI	MST1R	protein	Q04912	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190407	0.8
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	NANOS3	protein	P60323	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269259	0.358
PHF21A	protein	Q96BD5	UNIPROT	BHC complex	complex	SIGNOR-C353	SIGNOR	form complex	binding			9606	BTO:0000567; BTO:0000007								15325272	t		miannu	BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells	SIGNOR-264502	0.731
GNAQ	protein	P50148	UNIPROT	PLCE1	protein	Q9P212	UNIPROT	up-regulates	binding			9606									17251915	t		gcesareni	Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate manymolecules, including phospholipases, ion channels and lipid kinases.	SIGNOR-152609	0.286
UBTF	protein	P17480	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	up-regulates activity	binding			9606									15970593	t		lperfetto	Therefore, we propose that SL1 directs PIC formation, functioning in core promoter binding, RNA polymerase I recruitment, and UBF stabilization and that SL1-promoter complex formation is a necessary prerequisite to the assembly of functional and stable PICs that include the UBF activator in mammalian cells. 	SIGNOR-269568	0.484
FFAR1	protein	O14842	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256799	0.2
PRKCA	protein	P17252	UNIPROT	ITGB2	protein	P05107	UNIPROT	unknown	phosphorylation	Thr760	LFKSATTtVMNPKFA	9606	BTO:0000751								11700305	t		lperfetto	Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |	SIGNOR-249125	0.347
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	LFNG	protein	Q8NES3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22298955	f		gcesareni	Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta.	SIGNOR-254336	0.2
COPS4	protein	Q9BT78	UNIPROT	COP9 signalosome variant 1	complex	SIGNOR-C489	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270773	0.941
PLAG1	protein	Q6DJT9	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									11888928	f		miannu	Plagl1 has been shown to prevent the proliferation of tumor cells by inducing cell cycle arrest and apoptosis	SIGNOR-256658	0.7
ATM	protein	Q13315	UNIPROT	MCM3	protein	P25205	UNIPROT	unknown	phosphorylation	Ser535	ATDDPNFsQEDQQDT	9606									15210935	t		lperfetto	Atm phosphorylates mcm3 on s535 in response to ionizing radiation. Second, atr phosphorylates mcm2 on s108 in response to multiple forms of dna damage and stalling of replication forksthe functional consequences of mcm2 s108 and mcm3 s535 phosphorylation are not clear	SIGNOR-126308	0.459
TBK1	protein	Q9UHD2	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Ser405	SHPLSLTsDQYKAYL	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178411	0.817
NFATC4	protein	Q14934	UNIPROT	GPC6	protein	Q9Y625	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								21871017	t		miannu	 NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype.	SIGNOR-264023	0.2
TLE5	protein	Q08117	UNIPROT	SIX6	protein	O95475	UNIPROT	down-regulates activity	binding			-1									12441302	t		lperfetto	Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. AES abrogates SIX3- and SIX6-induced phenotypes	SIGNOR-234589	0.2
SREBF1	protein	P36956	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates activity				10090									9539737	f		gcesareni	Finally, we demonstrate directly that cells expressing ADD1/SREBP1 produce and secrete lipid molecule(s) that bind directly to PPARgamma, displacing the binding of radioactive thiazolidinedione ligands	SIGNOR-170607	0.461
9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone	chemical	CID:71748056	PUBCHEM	EGFR	protein	P00533	UNIPROT	down-regulates activity	chemical inhibition			-1									24556163	t		miannu	This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine 	SIGNOR-262237	0.8
FOXO1	protein	Q12778	UNIPROT	FBXO32	protein	Q969P5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21798082	f		lperfetto	Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome.	SIGNOR-236540	0.44
CSF2	protein	P04141	UNIPROT	CSF3R	protein	Q99062	UNIPROT	up-regulates	binding			9606	BTO:0000130								7691413	t		gcesareni	A g-csfr expression plasmid was introduced into interleukin-3 (il-3)-dependent mouse myeloid precursor fdc-p1 cells that normally do not respond to g-csf. G-csf stimulated proliferation of the transformants these results suggested that the g-csfr, but not the il-3/gm-csf receptors, transduced the neutrophilic differentiation signal into cells.	SIGNOR-31963	0.586
CD79B	protein	P40259	UNIPROT	BCR-Dk	complex	SIGNOR-C435	SIGNOR	form complex	binding			9606	BTO:0000776								32323266	t		scontino	BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition.	SIGNOR-268197	0.641
CDK5	protein	Q00535	UNIPROT	PIP5K1C	protein	O60331	UNIPROT	down-regulates	phosphorylation	Ser650	DERSWVYsPLHYSAQ	9606									15738269	t		lperfetto	The interaction of talin with phosphatidylinositol(4) phosphate 5 kinase type i gamma (pipki gamma) regulates pi(4,5)p2 synthesis at synapses and at focal adhesions. Here, we show that phosphorylation of serine 650 (s650) within the talin-binding sequence of human pipki gamma blocks this interaction. At synapses, s650 is phosphorylated by p35/cdk5 and mitogen-activated protein kinase at rest, and dephosphorylated by calcineurin upon stimulation.	SIGNOR-134455	0.371
SMAD7	protein	O15105	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates activity	binding			9606									30017632	t		miannu	Smad7 inhibits both transforming growth factor β (TGF-β)- and BMP-induced Smad signaling. Smad7 can use both surfaces in its interaction with the ALK-2, -3, and -4 receptors, but only the basic groove is used in the interaction between Smad7 and the TGF-β type I receptor (TβRI, also known as ALK-5). 	SIGNOR-260438	0.781
MRPL37	protein	Q9BZE1	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262360	0.683
PRPF8	protein	Q6P2Q9	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270641	0.772
GRK2	protein	P25098	UNIPROT	ADRA2A	protein	P08913	UNIPROT	down-regulates activity	phosphorylation	Ser311	DALDLEEsSSSDHAE	10029	BTO:0000246								7876239	t			The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization.	SIGNOR-251440	0.2
PRTN3	protein	P24158	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Val61	TVETVFSvDEFSASV	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263600	0.381
MMP8	protein	P22894	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272375	0.7
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	MAPT	protein	P10636	UNIPROT	up-regulates	dephosphorylation	Ser516	GDRSGYSsPGSPGTP	9606		BTO:0000142							20308788	t	The effect has been demonstrated using P10636-8	lperfetto	Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro.	SIGNOR-164659	0.2
ATF4	protein	P18848	UNIPROT	YARS1	protein	P54577	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269431	0.2
Integrator complex	complex	SIGNOR-C265	SIGNOR	GADD45B	protein	O75293	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									25675981	f		lperfetto	The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes.	SIGNOR-261478	0.2
10-formyltetrahydrofolate(2-)	smallmolecule	CHEBI:57454	ChEBI	formate	smallmolecule	CHEBI:15740	ChEBI	up-regulates quantity	precursor of			9606									18767138	t		lperfetto	Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate	SIGNOR-268248	0.8
MAPK1	protein	P28482	UNIPROT	GABRR1	protein	P24046	UNIPROT	unknown	phosphorylation	Ser434	LTLASERsSPQRKSQ	-1									12175859	t		miannu	Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation	SIGNOR-262748	0.289
DNM1	protein	Q05193	UNIPROT	Synaptic_vesicle_recycling	phenotype	SIGNOR-PH161	SIGNOR	up-regulates				9606	BTO:0000938								10823955	f		miannu	The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca2+-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling. 	SIGNOR-264118	0.7
AKT1	protein	P31749	UNIPROT	MTOR	protein	P42345	UNIPROT	unknown	phosphorylation	Ser2448	RSRTRTDsYSAGQSV	9606									10910062	t		lperfetto	Although AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. Transient transfection assays with mTOR mutants bearing Ala substitutions at Ser2448 and/or Thr2446 indicated that AKT-dependent mTOR phosphorylation was not essential for either PHAS-I phosphorylation or p70S6K activation in HEK cells.	SIGNOR-251099	0.928
AKT1	protein	P31749	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation	Ser259	SQRQRSTsTPNVHMV	9606	BTO:0000222	BTO:0000887;BTO:0001760							10576741	t		gcesareni	Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity.	SIGNOR-252588	0.687
AR	protein	P10275	UNIPROT	SCN9A	protein	Q15858	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									24493753	t		miannu	In neuroblastoma ND7 cells, a nuclear interaction between the developmentally regulated transcription factor Brn-3a and AR resulted in a complex which bound to multiple elements within the promoter region of SCN9A (Nav1.7) and upregulated channel expression.	SIGNOR-253466	0.2
TFE3	protein	P19532	UNIPROT	GAA	protein	P10253	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276820	0.282
SGK2	protein	Q9HBY8	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606	BTO:0000007								11154281	t		lperfetto	Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis.	SIGNOR-252990	0.514
MLL-ENL	fusion protein	SIGNOR-FP7	SIGNOR	DOT1L	protein	Q8TEK3	UNIPROT	up-regulates activity	binding			10090	BTO:0004052								23996074	t		irozzo	In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL. The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1	SIGNOR-255870	0.2
RNF135	protein	Q8IUD6	UNIPROT	DDX58	protein	O95786	UNIPROT	up-regulates activity	ubiquitination	Lys907	GVQTLYSkWKDFHFE	9606	BTO:0000007								19017631	t		miannu	Our data suggest that Riplet/RNF135 is a novel factor of the RIG-I pathway that is involved in the evoking of human innate immunity against RNA virus infection, and activates RIG-I through ubiquitination of its C-terminal region. 	SIGNOR-265568	0.756
ADORA3	protein	P0DMS8	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256814	0.428
LCK	protein	P06239	UNIPROT	SIGLEC10	protein	Q96LC7	UNIPROT	up-regulates	phosphorylation	Tyr667	ESQEELHyATLNFPG	9606									11733002	t		lperfetto	These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2	SIGNOR-112495	0.263
HRH3	protein	Q9Y5N1	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256832	0.412
SIRT5	protein	Q9NXA8	UNIPROT	SHMT2	protein	P34897	UNIPROT	down-regulates activity	post translational modification	Lys280	IVTTTTHkTLRGARS										34929314	t	desuccinylation	lperfetto	Mitochondrial serine hydroxymethyl transferase (SHMT2) is a rate-limiting enzyme that catalyzes the catabolism of serine and drives the proliferation of osteosarcoma cells and colon cancer cells. SIRT5 directly mediates the desuccinylation of Lysine 280 on SHMT2. Therefore, SIRT5 is a candidate target to inhibit serine catabolism	SIGNOR-267644	0.237
SLBP	protein	Q14493	UNIPROT	H2BC1	protein	Q96A08	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265393	0.2
CDCA8	protein	Q53HL2	UNIPROT	CPC	complex	SIGNOR-C554	SIGNOR	form complex	binding			9606									23175282	t		miannu	It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A).	SIGNOR-275423	0.85
MAPK1	protein	P28482	UNIPROT	RBFOX2	protein	O43251	UNIPROT	unknown	phosphorylation	Thr7	tPGYHGFP	10090									22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262761	0.2
LFNG	protein	Q8NES3	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	down-regulates	binding			9606									11346656	t		gcesareni	Although both manic fringe (mfng) and lunatic fringe (lfng) decreased the binding of jagged1 to notch2 and not that of delta1, the decrease by mfng was greater in degree than that by lfng. We also found that both fringe proteins reduced jagged1-triggered notch2 signaling, whereas neither affected delta1-triggered notch2 signaling.	SIGNOR-107705	0.685
ibuprofen	chemical	CHEBI:5855	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates activity	chemical inhibition			-1									9057869	t		miannu	Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). 	SIGNOR-258604	0.8
BMPR1B	protein	O00238	UNIPROT	SMAD5	protein	Q99717	UNIPROT	up-regulates	phosphorylation			9606									19620713	t		gcesareni	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-187193	0.667
PTK6	protein	Q13882	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Tyr315	TFCGTPEyLAPEVLE	9606									15994200	t		gcesareni	These observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis.	SIGNOR-252617	0.454
PTPN9	protein	P43378	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	9606									16679294	t		gcesareni	Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action	SIGNOR-146668	0.263
prazosin	chemical	CHEBI:8364	ChEBI	ADRA1A	protein	P35348	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258473	0.8
BTRC	protein	Q9Y297	UNIPROT	NFKBIB	protein	Q15653	UNIPROT	down-regulates quantity by destabilization	binding			9534	BTO:0004055								10514424	t		miannu	Interaction with beta-TrCP is also necessary for ubiquitination of IkappaBbeta upon stimulation of cells, and deletion of the F-box in beta-TrCP abolishes its ability to ubiquitinate IkappaBbeta. Therefore, these results indicate that beta-TrCP plays a critical role in the activation of NF-kappaB by assembling the ubiquitin ligase complex for both phosphorylated IkappaBalpha and IkappaBbeta.β-TrCP recognizes IκBα phosphorylated at Ser-32 and Ser-36 through its WD40 domain, whereas the F-box motif recruits additional proteins including Skp1 and Cullin to form the Skp1-cullin-F-box (SCF) ubiquitin ligase complex	SIGNOR-272554	0.564
clotrimazole	chemical	CHEBI:3764	ChEBI	NR1I2	protein	O75469	UNIPROT	up-regulates activity	chemical activation			9606									9770465	t		miannu	In addition to rifampicin, other known inducers of human CYP3A4 expression, including nifedipine and clotrimazole, also activated hPAR.	SIGNOR-259065	0.8
UBIAD1	protein	Q9Y5Z9	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0000362								30518913	f		miannu	This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells. 	SIGNOR-256205	0.7
CCR3	protein	P51677	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity				9606	BTO:0000399								10706854	t			Activation of ERK2 and p38 by eotaxin is mediated through CCR3.	SIGNOR-256093	0.301
DYRK1A	protein	Q13627	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates	phosphorylation	Thr310	VPPLPKVtPTKELQQ	9606		BTO:0000142							16733250	t		lperfetto	Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins.	SIGNOR-146910	0.405
MITF	protein	O75030	UNIPROT	BEST1	protein	O76090	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004595								14982938	f		miannu	 These studies define the VMD2 promoter region sufficient to drive RPE-specific expression in the eye, identify positive regulatory regions in vitro, and suggest that MITF as well as other E-box binding factors may act as positive regulators of VMD2 expression.	SIGNOR-254586	0.386
ABCC9	protein	O60706	UNIPROT	KATP channel	complex	SIGNOR-C274	SIGNOR	form complex	binding			9606									28842488	t		lperfetto	ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits.	SIGNOR-262057	0.621
SNX5	protein	Q9Y5X3	UNIPROT	IGF2R	protein	P11717	UNIPROT	down-regulates quantity	binding			9606	BTO:0000567								32150533	t		miannu	 Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.	SIGNOR-269442	0.552
RORA	protein	P35398	UNIPROT	CAV3	protein	P56539	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15199055	f	 	 	Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle.	SIGNOR-254255	0.2
EGFR	protein	P00533	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1110	GSVQNPVyHNQPLNP	10090	BTO:0002882								16122376	t	Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer	lperfetto	EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work	SIGNOR-236516	0.2
MAPK1	protein	P28482	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser636	SGDYMPMsPKSVSAP	9606									12510059	t		gcesareni	Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1.	SIGNOR-249407	0.667
PRKACA	protein	P17612	UNIPROT	KCNN2	protein	Q9H2S1	UNIPROT	down-regulates	phosphorylation	Ser567	SSSRRRRsSSTAPPT	9606									16513649	t		llicata	Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization	SIGNOR-145032	0.2
TFE3	protein	P19532	UNIPROT	UVRAG	protein	Q9P2Y5	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells	SIGNOR-276829	0.267
5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium	smallmolecule	CHEBI:137981	ChEBI	5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-)	smallmolecule	CHEBI:77657	ChEBI	up-regulates quantity	precursor of			9606									33179964	t		miannu	The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS).	SIGNOR-267316	0.8
RIMBP3C	protein	A6NJZ7	UNIPROT	RIMS2	protein	Q9UQ26	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264367	0.267
NPLOC4	protein	Q8TAT6	UNIPROT	UFD1	protein	Q92890	UNIPROT	up-regulates activity	binding			9606									20442859	t		miannu	These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes.	SIGNOR-252422	0.2
MAPK3	protein	P27361	UNIPROT	NCKIPSD	protein	Q9NZQ3	UNIPROT	up-regulates	phosphorylation			9606									14559906	t		gcesareni	Spin90 was phosphorylated by erk1, which was, itself, activated by cell adhesion and platelet-derived growth factor. Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck	SIGNOR-118747	0.432
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	DNM1L	protein	O00429	UNIPROT	down-regulates activity	phosphorylation	Ser637	VPVARKLsAREQRDC	-1									31063459	t		lperfetto	For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission	SIGNOR-262551	0.2
3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one	chemical	CHEBI:91346	ChEBI	AKT1	protein	P31749	UNIPROT	down-regulates activity	chemical inhibition												25309440	t		lperfetto	Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway.	SIGNOR-262010	0.8
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	CASP9	protein	P55211	UNIPROT	up-regulates activity	cleavage			9606									14585074	t		lperfetto	Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation	SIGNOR-256453	0.622
FSCN1	protein	Q16658	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				10090	BTO:0000526								21706053	f		miannu	Plexin-B3 interacts with the actin-binding protein fascin-1. The present finding suggests fascin-1 as a potential effector of plexin-B3 to mediate the signal of Sema5A in glioma cells.Sema5A and plexin-B3 remodel F-actin cytoskeleton and induce fascin-1 translocation in glioma cells.	SIGNOR-268375	0.7
GRIK3	protein	Q13003	UNIPROT	D-serine	smallmolecule	CHEBI:16523	ChEBI	up-regulates quantity	relocalization			9606	BTO:0002609								12393813	t		lperfetto	Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine	SIGNOR-268274	0.8
ERG	protein	P11308	UNIPROT	ENG	protein	P17813	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22235125	f	 	miannu	 It has been shown that ERG is a positive regulator of several EC-restricted genes including VE-cadherin, endoglin, and von Willebrand factor, and a negative regulator of other genes such as interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1. 	SIGNOR-253916	0.2
CROCC	protein	Q5TZA2	UNIPROT	Centrosome_separation	phenotype	SIGNOR-PH177	SIGNOR	down-regulates				9606	BTO:0000567								24035387	t		miannu	C-Nap1 and rootletin have been previously reported to be the important centrosome linker components involved in centrosome cohesion.	SIGNOR-273706	0.7
AP-3 complex	complex	SIGNOR-C247	SIGNOR	AP-3/clathrin vescicle	complex	SIGNOR-C250	SIGNOR	form complex	binding			9606									23103167	t		lperfetto	Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors	SIGNOR-260668	0.485
ponatinib	chemical	CHEBI:78543	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates activity	chemical inhibition			-1									23430109	t		lperfetto	AP24534 also inhibited SRC (IC50: 5.4 nM) and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases (Table 1 and Table S1)	SIGNOR-261985	0.8
EPAS1	protein	Q99814	UNIPROT	KDM4B	protein	O94953	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271584	0.2
MARK2	protein	Q7KZI7	UNIPROT	KIF13B	protein	Q9NQT8	UNIPROT	down-regulates activity	phosphorylation	Ser1381	KLSRRSIsSPNVNRL	9534	BTO:0000298								20194617	t		miannu	We report here the identification of GAKIN/KIF13B as a novel in vivo substrate for Par1b and present evidence that GAKIN/KIF13B plays a critical role in axon formation in neurons, which is negatively regulated by Par1b-mediated phosphorylation. Par1b phosphorylates GAKIN/KIF13B at both Ser1381 and Ser1410.	SIGNOR-262955	0.425
SH2B1	protein	Q9NRF2	UNIPROT	BLNK	protein	Q8WV28	UNIPROT	down-regulates activity	dephosphorylation			9606	BTO:0000776								32323266	t		scontino	SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK.	SIGNOR-268446	0.2
IL10	protein	P22301	UNIPROT	SCN5A	protein	Q14524	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0000938	BTO:0001264							23357618	f		miannu	Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α.	SIGNOR-253496	0.2
PCCB	protein	P05166	UNIPROT	PCC	complex	SIGNOR-C414	SIGNOR	form complex	binding			9606									15890657	t		miannu	Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. 	SIGNOR-267183	0.887
H4C1	protein	P62805	UNIPROT	Nucleosome_H2A.Z.2 variant	complex	SIGNOR-C323	SIGNOR	form complex	binding			-1									24311584	t		miannu	In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined.	SIGNOR-263712	0.2
GSK2126458	chemical	CID:25167777	PUBCHEM	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192901	0.8
Interferon-type-I	proteinfamily	SIGNOR-PF50	SIGNOR	IFNAR	complex	SIGNOR-C243	SIGNOR	up-regulates activity	binding			9606									11278538	t		miannu	Interferons have antiviral, antigrowth and immunomodulatory effects. The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. 	SIGNOR-260331	0.2
MAPK14	protein	Q16539	UNIPROT	RPS6KA4	protein	O75676	UNIPROT	up-regulates	phosphorylation	Ser343	TRLEPVYsPPGSPPP	9606	BTO:0000567								10806207	t		llicata	Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity.	SIGNOR-77208	0.586
Calcineurin	complex	SIGNOR-C155	SIGNOR	PPP1R1A	protein	Q13522	UNIPROT	unknown	dephosphorylation	Ser67	LKSTLAMsPRQRKKM	10116									11278334	t			In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation.	SIGNOR-252334	0.387
INO80B	protein	Q9C086	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270846	0.636
INS	protein	P01308	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates activity				9606									10358076	f		lperfetto	Insulin disrupts irs-dependent transactivation by fkhr, and phosphorylation of ser-256 by pkb is necessary and sufficient to mediate this effect.	SIGNOR-68155	0.495
NFATC2	protein	Q13469	UNIPROT	MEF2A	protein	Q02078	UNIPROT	up-regulates	binding			9606									11796223	t		lperfetto	Upon dephosphorylation by calcineurin, nfatc2, also referred to as nfatp/nfat1, translocates to the nucleus where it directly associates with mef2a and -d. Nfatc2 stimulates mef2-dependent transcription by facilitating recruitment of the p300 coactivator to mef2-response elements.	SIGNOR-117586	0.396
BID	protein	P55957	UNIPROT	BAK1	protein	Q16611	UNIPROT	up-regulates	binding			9606									17289999	t		gcesareni	We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome c. these data support a two-class model for bh3 domains: bid-like domains that activate bax, bak and bad-like domains that sensitize by occupying the pocket of antiapoptotic members.	SIGNOR-152992	0.815
FYN	protein	P06241	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation	Tyr427	ELFDDPSyVNVQNLD	9606									9741627	t		lperfetto	Shc is subsequently phosphorylated at tyrosine 317 and recruits grb2	SIGNOR-60160	0.721
PTPRG	protein	P23470	UNIPROT	ITGB2	protein	P05107	UNIPROT	down-regulates activity				9606									25624455	f		miannu	PTPRG activation inhibits chemoattractant induced LFA-1 affinity triggering and mediated adhesion in human primary monocytes.we show that PTPRG is a novel negative regulator of LFA-1 high-affinity-state triggering and mediated arrest by chemoattractants in human primary monocytes. Notably, PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role (37). In our context, SRC appears inhibited by PTPRG activation (Table I), thus making it unlikely that the antiadhesive effect of PTPRG is mediated by SRC activation.	SIGNOR-254735	0.263
(D-Ala(2)-mephe(4)-gly-ol(5))enkephalin	chemical	CHEBI:272	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258784	0.8
CSNK1A1	protein	P48729	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	up-regulates activity	binding			9606									19293931	t		lperfetto	In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)]	SIGNOR-227964	0.658
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO4	protein	P98177	UNIPROT	down-regulates	phosphorylation	Ser262	TFRPRSSsNASSVST	9606									16272144	t		lperfetto	Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression	SIGNOR-141420	0.2
KSR2	protein	Q6VAB6	UNIPROT	ARAF	protein	P10398	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								29433126	t		miannu	 In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. 	SIGNOR-273875	0.533
MRE11	protein	P49959	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates	binding			9606									18854157	t		gcesareni	One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase.	SIGNOR-181628	0.2
4-[6-[4-(methoxycarbonylamino)phenyl]-4-(4-morpholinyl)-1-pyrazolo[3,4-d]pyrimidinyl]-1-piperidinecarboxylic acid methyl ester	chemical	CHEBI:94742	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck;ATP-competitive inhibitor mTOR	gcesareni		SIGNOR-207809	0.8
Non-erythrocytic spectrin	complex	SIGNOR-C385	SIGNOR	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates	binding			9606									24302288	t		lperfetto	Spectrin is a member of the F-actin-crosslinking protein superfamily. 	SIGNOR-266031	0.7
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	JUNB	protein	P17275	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9694870	f		lperfetto	Here we report the identification of Smad Binding Elements (SBEs) composed of the sequence CAGACA in the promoter of the JunB gene, an immediate early gene that is potently induced by TGF-beta, activin, and bone morphogenetic protein (BMP) 2. Two JunB SBEs are arranged as an inverted repeat that is transactivated in response to Smad3 and Smad4 co-overexpression and shows inducible binding of a Smad3- and Smad4-containing complex in nuclear extracts from TGF-beta-treated cells.	SIGNOR-59476	0.559
ESR1	protein	P03372	UNIPROT	PGR	protein	P06401	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11000528	f		gcesareni	We observed the transcriptional inhibition of the progesterone and glucocorticoid receptors when eralpha was cotransfected	SIGNOR-82161	0.607
SREBF1	protein	P36956	UNIPROT	PK	proteinfamily	SIGNOR-PF80	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									16308421	t	inferred from family member	gcesareni	Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk)	SIGNOR-270288	0.34
RIPK1	protein	Q13546	UNIPROT	TAB2	protein	Q9NYJ8	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								15327770	t		lperfetto	TNF_ induced the polyubiquitination of RIP and the association of polyubiquitinated RIP with TAB2.	SIGNOR-128406	0.858
CHEK1	protein	O14757	UNIPROT	E2F3	protein	O00716	UNIPROT	up-regulates	phosphorylation	Ser124	PALGRGGsGGGGGPP	9606									19917728	t		llicata	These results suggest that e2f3a is directly phosphorylated by chk kinases and that the phosphorylation of serine 124 is required for the posttranslational induction of e2f3a protein by chemotherapy.	SIGNOR-161758	0.335
SWI/SNF ACTL6A-ARID1A-SMARCA2 variant	complex	SIGNOR-C470	SIGNOR	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	up-regulates				9606									30397315	f		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269828	0.7
HNF1A	protein	P20823	UNIPROT	Aldolase	proteinfamily	SIGNOR-PF75	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								8383844	f	inferred from family member	miannu	 Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators	SIGNOR-270224	0.317
MTA1	protein	Q13330	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000812								18719363	f		miannu	 MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG.	SIGNOR-254594	0.425
PRKACA	protein	P17612	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Ser295	FKLGGRDsRSGSPMA	-1									2413024	t		miannu	Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-164	SIGNOR-250014	0.352
CDK7	protein	P50613	UNIPROT	CAK complex	complex	SIGNOR-C456	SIGNOR	form complex	binding			9606									30860024	t		lperfetto	CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 	SIGNOR-269319	0.958
HRH2	protein	P25021	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257424	0.252
protriptyline	chemical	CHEBI:8597	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606									9537821	t		miannu	Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 	SIGNOR-258737	0.8
CSNK1A1	protein	P48729	UNIPROT	FOXO6	protein	A8MYZ6	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity.	SIGNOR-183667	0.2
PAK1	protein	Q13153	UNIPROT	ARHGDIA	protein	P52565	UNIPROT	down-regulates	phosphorylation	Ser174	KGMLARGsYSIKSRF	9606									15225553	t		lperfetto	Pak1 binds and phosphorylates rhogdi both in vitro and in vivo at ser101 and ser174. This resulted in dissociation of rac1-rhogdi, but not rhoa-rhogdi, complexes, as determined by in vitro assays of complexation and in vivo by coimmunoprecipitation analysis. We observed that cdc42-induced rac1 activation is inhibited by expression of pak1 autoinhibitory domain. The dissociation of rac1 from rhogdi and its subsequent activation stimulated by pdgf or egf is also attenuated by pak1 autoinhibitory domain, and this is dependent on the ability of rhogdi to be phosphorylated at ser101/174.	SIGNOR-126654	0.595
CSNK2B	protein	P67870	UNIPROT	FGF14	protein	Q92915	UNIPROT	up-regulates activity	phosphorylation	Ser230	VTPSKSTsASAIMNG	9606	BTO:0000938								26917740	t		lperfetto	 Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.	SIGNOR-275745	0.273
PITX1	protein	P78337	UNIPROT	GNRH1	protein	P01148	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									19106114	f		miannu	 Knockdown of PITX1 or PITX2 isoforms impaired GNRH1 induction, and endogenous PITX1 bound to the candidate PITX binding site on the LHB promoter. 	SIGNOR-254921	0.336
MAPK13	protein	O15264	UNIPROT	KRT8	protein	P05787	UNIPROT	up-regulates	phosphorylation	Ser74	TVNQSLLsPLVLEVD	9606									11788583	t		lperfetto	Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.	SIGNOR-114075	0.2
regorafenib	chemical	CHEBI:68647	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates activity	chemical inhibition			9606									26254357	t		miannu	A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF	SIGNOR-259179	0.8
methotrexate	chemical	CHEBI:44185	ChEBI	DHFR	protein	P00374	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0004254								23581023	t		miannu	Methotrexate, a structural analogue of folic acid, is one of the most frequently used chemotherapeutics, especially in haematological malignancies, various solid tumours and also inflammatory disorders. Methotrexate interferes with folate metabolism, mainly by inhibition of dihydrofolate reductase, resulting in the suppression of purine and pyrimidine precursor synthesis. 	SIGNOR-258481	0.8
PRKD1	protein	Q15139	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	unknown	phosphorylation	Ser155	FPLRKTVsEPNLKLR	-1									15738054	t		lperfetto	We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro.	SIGNOR-249275	0.492
PRKCD	protein	Q05655	UNIPROT	ELAVL1	protein	Q15717	UNIPROT	up-regulates	phosphorylation	Ser221	QAQRFRFsPMGVDHM	9606									20086103	t		lperfetto	Tandem phosphorylation of serines 221 and 318 by protein kinase cdelta coordinates mrna binding and nucleocytoplasmic shuttling of hurstabilization of mrna by the ubiquitous rna binding protein human antigen r (hur), a member of the embryonic lethal abnormal vision (elav) protein family, requires canonical binding to au-rich element (are)-bearing target mrna and export of nuclear hur-mrna complexes to the cytoplasm. In human mesangial cells (hmc) both processes are induced by angiotensin ii (angii) via protein kinase cdelta (pkcdelta)-triggered serine phosphorylation of hur.	SIGNOR-163524	0.622
CHUK	protein	O15111	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser932	CDSGVETsFRKLSFT	10090	BTO:0000944		SIGNOR-C14	SIGNOR-C13					11297557	t		lperfetto	The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk.	SIGNOR-235442	0.737
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2T	protein	Q9NPD8	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271316	0.682
SCAP	protein	Q12770	UNIPROT	SREBF1	protein	P36956	UNIPROT	up-regulates activity	relocalization			10029	BTO:0000246								12202038	t			SCAP contains two domains: an NH2-terminal membrane attachment domain with eight membrane-spanning helices (Nohturfft et al., 1998b) and a long COOH-terminal extension that contains multiple copies of a WD40 repeat sequence, which forms a propeller-like structure that binds to the COOH-terminal domains of the SREBPs, thereby permitting the escort function	SIGNOR-267501	0.716
PRKAA2	protein	P54646	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000876								21673972	t		lperfetto	These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes	SIGNOR-217457	0.258
CCR3	protein	P51677	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates				9606									11591790	f			We and others have recently found that eotaxin activates extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein (MAP) kinases in eosinophils, and that these kinases are indispensable for eosinophil chemotaxis and degranulation	SIGNOR-254358	0.251
ATR	protein	Q13535	UNIPROT	POLH	protein	Q9Y253	UNIPROT	up-regulates	phosphorylation	Ser601	EMDLAHNsQSMHASS	9606									21242293	t		lperfetto	Atr-mediated phosphorylation of dna polymerase _ is needed for efficient recovery from uv damage. We show that, after uv irradiation, pol_ becomes phosphorylated at ser601 by the ataxia-telangiectasia mutated and rad3-related (atr) kinase. Atr-dependent phosphorylation of pol_ is necessary to restore normal survival and postreplication repair	SIGNOR-171290	0.425
JAK3	protein	P52333	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates	phosphorylation	Tyr694	LAKAVDGyVKPQIKQ	9606									19088846	t		gcesareni	For these assays, coexpression of wt jak3 with stat5a was found to result in tyrosine phosphorylation of stat5a (lane 2) mediated by jak3, since stat5a coexpressed with the kinase-inactive k855a mutant form of jak3 was not tyrosine phosphorylated.	SIGNOR-182817	0.85
F2RL2	protein	O00254	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257033	0.2
ITGAV	protein	P06756	UNIPROT	Av/b6 integrin	complex	SIGNOR-C179	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253209	0.864
LAMB1	protein	P07942	UNIPROT	Laminin-10	complex	SIGNOR-C182	SIGNOR	form complex	binding												11821406	t		lperfetto	The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia.	SIGNOR-253230	0.708
NCOA1	protein	Q15788	UNIPROT	RARA	protein	P10276	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16606617	f		irozzo	We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR.	SIGNOR-255932	0.696
STAT3	protein	P40763	UNIPROT	Cell_growth	phenotype	SIGNOR-PH33	SIGNOR	up-regulates				10090									11426647	f			Constitutive activation of Stat3 signaling is accompanied by upregulation of cyclin D1, c-Myc, and Bcl-x, changes consistent with subversion of normal cellular growth and survival control mechanisms.	SIGNOR-252090	0.7
TRAF2	protein	Q12933	UNIPROT	MAP3K14	protein	Q99558	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									20651737	t		lperfetto	Under resting conditions cellular inhibitor of apoptosis (ciap) proteins target nuclear factor-kb (nf-kb)-inducing kinase (nik) for ubiquitylation and proteasomal degradation.	SIGNOR-167066	0.568
NADPH(4-)	smallmolecule	CHEBI:57783	ChEBI	PGD	protein	P52209	UNIPROT	down-regulates activity	binding			9606									34765544	t		miannu	We determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH. PGDH is the onl yrate-limiting unidirectional enzyme susceptible to allosteric inhibition by NADPH	SIGNOR-267372	0.8
PPP1CA	protein	P62136	UNIPROT	SP3	protein	Q02447	UNIPROT	down-regulates activity	dephosphorylation			9606									12684058	t		miannu	Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression.	SIGNOR-251953	0.2
RPS24	protein	P62847	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262427	0.915
CDK1	protein	P06493	UNIPROT	RANBP2	protein	P49792	UNIPROT	up-regulates activity	phosphorylation	Ser2251	ASPLASSerPVRKNL	-1									26051540	t		irozzo	Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment.	SIGNOR-259119	0.452
tandutinib	chemical	CHEBI:90237	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258296	0.8
FYN	protein	P06241	UNIPROT	PRKAA2	protein	P54646	UNIPROT	down-regulates activity	phosphorylation	Tyr436	EWKVVNAyHLRVRRK	10090	BTO:0000944								27626315	t		miannu	Here we identified that Fyn phosphorylates the α subunit of AMPK on Y436 and inhibits AMPK enzymatic activity without altering the assembly state of the AMPK heterotrimeric complex. 	SIGNOR-277279	0.26
ZEB2	protein	O60315	UNIPROT	CTBP1	protein	Q13363	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								12743039	t		Luisa	The two members of the ZEB family of zinc finger factors (ZEB-1/deltaEF1 and ZEB-2/SIP1) regulate TGFbeta/BMP signaling in opposite ways: ZEB-1/deltaEF1 synergizes with Smad-mediated transcriptional activation, while ZEB-2/SIP1 represses it. Here we report that these antagonistic effects by the ZEB proteins arise from the differential recruitment of transcriptional coactivators (p300 and P/CAF) and corepressors (CtBP) to the Smads. Thus, while ZEB-1/deltaEF1 binds to p300 and promotes the formation of a p300-Smad transcriptional complex, ZEB-2/SIP1 acts as a repressor by recruiting CtBP.	SIGNOR-268953	0.487
PRKACA	protein	P17612	UNIPROT	YWHAZ	protein	P63104	UNIPROT	down-regulates activity	phosphorylation	Ser58	VVGARRSsWRVVSSI	9606									16376338	t		llicata	Phosphorylation by pka leads to modulation of 14-3-3zeta dimerization and affect its interaction with partner proteins. Substitution of ser58 to ala completely abolished phosphorylation of 14-3-3zeta by pka.	SIGNOR-143373	0.546
STAT3	protein	P40763	UNIPROT	FOXP3	protein	Q9BZS1	UNIPROT	down-regulates				9606									18156621	f			Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA)	SIGNOR-254304	0.592
SACM1L	protein	Q9NTJ5	UNIPROT	Receptor_mediated_ endocytosis	phenotype	SIGNOR-PH121	SIGNOR	down-regulates				9534	BTO:0001444								22253445	f		lperfetto	Ectopic Expression of Sac1 Phosphatase Inhibits SARS-CoV S-mediated Entry	SIGNOR-260735	0.7
MEN1	protein	O00255	UNIPROT	KMT2A	protein	Q03164	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								15640349	t		irozzo	However, menin dramatically increases the amount of MLL bound at the p27Kip1 and p18Ink4c loci, suggesting that it either directly or indirectly promotes MLL recruitment to these targets. Once recruited, MLL could enhance transcription by a number of mechanisms.Overall, the data suggest that transcriptional regulation by menin involves increasing MLL protein association with target loci.	SIGNOR-255890	0.718
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	TSPYL2	protein	Q9H2G4	UNIPROT	up-regulates activity	phosphorylation	Thr340	GRLVSHStPIRWHRG	9606	BTO:0000567								11395479	t		llicata	We observed that a CDA1 mutant with the two consensus CDK phosphorylation sites abolished (S20A and T340A) disabled its capacity to inhibit cell growth, indicating that these sites are important for the function of this protein. Furthermore, we showed that these sites are phosphorylated by cyclin/CDKs in vitro, suggesting that these kinases may regulate CDA1 function in vivo. 	SIGNOR-250753	0.345
SP1	protein	P08047	UNIPROT	PON1	protein	P27169	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								15380450	f		miannu	 These data suggest that Sp1 acts as a positive regulator of PON1 transcription, and that an interaction between Sp1 and PKC is a key mechanism for the effect of Sp1 on PON1 transcription.	SIGNOR-255212	0.271
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser721	PVVSGDTsPRHLSNV	9606									12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249321	0.754
ERG	protein	P11308	UNIPROT	CXCL8	protein	P10145	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001949								19359602	f	 	miannu	 ERG can inhibit the activity of the IL-8 promoter in a dose dependent manner. 	SIGNOR-253912	0.2
sorafenib tosylate	chemical	CHEBI:50928	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									16757355	t		miannu	Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 	SIGNOR-259225	0.8
MAPK1	protein	P28482	UNIPROT	EXOC7	protein	Q9UPT5	UNIPROT	up-regulates	phosphorylation	Ser250	SSSGVPYsPAIPNKR	9606									22595671	t		lperfetto	Erk1/2 phosphorylation enhances the binding of exo70 to other exocyst components and promotes the assembly of the exocyst complex in response to epidermal growth factor (egf) signaling.	SIGNOR-197543	0.338
CHEK2	protein	O96017	UNIPROT	PPP2R5C	protein	Q13362	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000007								15380617	t		gcesareni	Found that chk2 associated with the b' regulatory subunit of protein phosphatase pp2a. In vitro kinase assays showed that b'gamma3 was a potent chk2 substrate. This phosphorylation increased the catalytic phosphatase activity of pp2a.	SIGNOR-129255	0.327
MPG	protein	P29372	UNIPROT	IGBP1	protein	P78318	UNIPROT	down-regulates quantity by destabilization	monoubiquitination			9606	BTO:0000007								22613722	t		miannu	 We show MID1-dependent monoubiquitination of α4 triggers calpain-mediated cleavage and switches α4's activity from protective to destructive, resulting in increased Tau phosphorylation. MID1 serves as the E3 ligase for α4 (2B), leading to a conformational change in α4 whereby the UIM of α4 binds in cis to the covalently attached ubiquitin (Ub; 3). This structural rearrangement then leads to calpain-mediated cleavage of the C terminus of α4 (4), allowing for polyubiquitination of PP2Ac by a currently unknown E3 ligase (5) and subsequent degradation by the proteasome.	SIGNOR-272040	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	PTGS2	protein	P35354	UNIPROT	up-regulates quantity by expression				9606									17705188	f		lperfetto	Inflammatory stimuli can activate IkappaB kinase (IKK) signalsome and subsequently the nuclear factor kappa B (NF-kappaB), which influences gene expression of cyclooxygenase-2 (Cox-2) along with other transcription factors.	SIGNOR-260262	0.373
SNRPA1	protein	P09661	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270655	0.767
MAP3K20	protein	Q9NYL2	UNIPROT	MAP3K20	protein	Q9NYL2	UNIPROT	up-regulates	phosphorylation	Thr162	SRFHNHTtHMSLVGT	9606									15342622	t		gcesareni	Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation.	SIGNOR-128581	0.2
AURKB	protein	Q96GD4	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	down-regulates activity	phosphorylation	Thr151	RSYSRLEtLGSASTS	-1									23901111	t		miannu	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. 	SIGNOR-276117	0.614
PTPN1	protein	P18031	UNIPROT	STAM2	protein	O75886	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Tyr291	KSEPEPVyIDEDKMD	9606									20504764	t			Together, the results presented here demonstrate that PTP1B can influence RTK signaling in a previously unrecognized manner. We show that PTP1B directly targets STAM2, part of the ESCRT-0 endosomal sorting complex, and we provide the first evidence that tyrosine phosphorylation affects STAM localization and function. This regulatory mechanism could impact signaling downstream of numerous cell surface receptors that are ubiquitinated and recognized by this conserved sorting machinery.	SIGNOR-248406	0.485
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation			9606									17900900	t		lperfetto	 We have recently found that AMPK phosphorylates human FOXO3 in mammalian cells at novel regulatory sites that are distinct from the AKT sites	SIGNOR-216481	0.397
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	TLRs	proteinfamily	SIGNOR-PF20	SIGNOR	up-regulates				9606									20404851	f		lperfetto	the discovery of Toll-like receptors (TLRs) in the mid-1990s showed that pathogen recognition by the innate immune system is instead actually specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs)	SIGNOR-216295	0.7
CSNK2A1	protein	P68400	UNIPROT	GTF2A1	protein	P52655	UNIPROT	up-regulates activity	phosphorylation	Ser316	VEEEPLNsEDDVSDE	-1									11278496	t		llicata	We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function.	SIGNOR-250876	0.388
CXCL11	protein	O14625	UNIPROT	CXCR3	protein	P49682	UNIPROT	up-regulates activity	binding			9606	BTO:0000782								12750173	t		miannu	The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells.	SIGNOR-260971	0.769
MAST3	protein	O60307	UNIPROT	PTEN	protein	P60484	UNIPROT	unknown	phosphorylation			9606									15951562	t		gcesareni	Furthermore, binding of PTEN to the PDZ domains from microtubule-associated serine/threonine kinases facilitated PTEN phosphorylation at its C terminus by these kinases.	SIGNOR-138080	0.586
HIC1	protein	Q14526	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21277938	f	 	miannu	 HIC1, via its BTB/POZ domain, forms a transcriptional repressor complex with Sirt1 [8] that binds directly to Sirt1 promoter itself, repressing its transcription. 	SIGNOR-254419	0.607
CALM1	protein	P0DP23	UNIPROT	PPP3CB	protein	P16298	UNIPROT	up-regulates	binding			9606									11796223	t		gcesareni	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-114101	0.694
KDM5B	protein	Q9UGL1	UNIPROT	FOXG1	protein	P55316	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								12657635	t		miannu	Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression	SIGNOR-223878	0.412
RIPK1	protein	Q13546	UNIPROT	TAB2	protein	Q9NYJ8	UNIPROT	up-regulates activity	binding			9606	BTO:0000007;BTO:0000661								16603398	t		lperfetto	Taken together, these results indicate that polyubiquitination of RIP1 mediates the independent re- cruitment of TAB2 and NEMO, which in turn recruits TAK1 and IKK, respectively, to TNF-R1.	SIGNOR-145861	0.858
ATF6	protein	P18850	UNIPROT	Chaperone-mediated protein folding	phenotype	SIGNOR-PH120	SIGNOR	up-regulates				9606									31226023	f		miannu	Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network	SIGNOR-260182	0.7
PRC1	protein	O43663	UNIPROT	KIF14	protein	Q15058	UNIPROT	up-regulates activity	binding			9606									16431929	t		miannu	KIF14 interacts with PRC1 and citron kinase. We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. I	SIGNOR-266423	0.618
IL20RB	protein	Q6UXL0	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates				9606	BTO:0000782;BTO:0000876								12941475	f		gcesareni	Il-20 induces cheratin proliferation and stat-3 signal transduction pathway	SIGNOR-86305	0.49
HSPA1A	protein	P0DMV8	UNIPROT	PACRG	protein	Q96M98	UNIPROT	up-regulates quantity by stabilization	binding			-1									12150907	t		miannu	Our in vitro data suggest that CHIP competes with Hsp70 in binding to Parkin, probably via suppression of the ATPase activity of Hsc/Hsp70 (Figure 4E).In fact, it acts as an inhibitory factor that suppresses the ubiquitination of Pael-R mediated by Parkin in vitro, and Hsp70 enhances the efficiency of folding of overexpressed Pael-R in vivo.	SIGNOR-272890	0.2
SIRT7	protein	Q9NRC8	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	deacetylation	Lys19	TGGKAPRkQLATKVA										22722849	t		lperfetto	SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. 	SIGNOR-275870	0.2
MAPK3	protein	P27361	UNIPROT	MRTFA	protein	Q969V6	UNIPROT	down-regulates	phosphorylation	Ser454	TGSTPPVsPTPSERS	9606									18694962	t	Translocation from Nuleus to Cytoplasm	gcesareni	Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization.	SIGNOR-179963	0.2
ATM	protein	Q13315	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	unknown	phosphorylation	Ser6	sQLDSDFS	9606									12697768	t		llicata	To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1	SIGNOR-100649	0.869
PRKACA	protein	P17612	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity	phosphorylation	Ser907	TDASRRSsEASQSDG	9606									10693759	t		lperfetto	Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3.	SIGNOR-75355	0.445
LETM1	protein	O95202	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	up-regulates quantity	relocalization			10090									29123128	t		lperfetto	Others have suggested that LETM1 plays an essential role in mitochondrial K+ homeostasis by mediating the mitochondrial K+/H+ exchange	SIGNOR-262542	0.8
NLGN4X	protein	Q8N0W4	UNIPROT	NRXN2	protein	Q9P2S2	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264155	0.76
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates	binding			9606									8929531	t		gcesareni	14-3-3 blocks bad activity by promoting ser-155 phosphorylation, which induces the dissociation of bad and bcl-xl. in the presence of survival factor il-3, cells phosphorylated bad on two serine residues embedded in 14-3-3 consensus binding sites. Only the nonphosphorylated bad heterodimerized with bcl-x(l) at membrane sites to promote cell death.	SIGNOR-44855	0.2
DLGAP5	protein	Q15398	UNIPROT	SHANK1	protein	Q9Y566	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264598	0.458
PRKCH	protein	P24723	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates	phosphorylation	Ser742	GEKSFRRsVVGTPAY	9606									10197446	t		llicata	These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748.	SIGNOR-66734	0.362
nitric oxide	smallmolecule	CHEBI:16480	ChEBI	GUCY1A2-B2	complex	SIGNOR-C137	SIGNOR	up-regulates activity	chemical activation			9606									15036565	t		gcesareni	One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP)	SIGNOR-243961	0.8
linifanib	chemical	CHEBI:91435	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193666	0.8
Dynorphin A	smallmolecule	CHEBI:4727	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258793	0.8
SRC	protein	P12931	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	up-regulates	phosphorylation			9606									12707358	t		lperfetto	These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation.	SIGNOR-217442	0.384
SREBF2	protein	Q12772	UNIPROT	ABCG8	protein	Q9H221	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21123766	f		miannu	 these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α.	SIGNOR-254456	0.432
JAK2	protein	O60674	UNIPROT	FGF14	protein	Q92915	UNIPROT	up-regulates activity	phosphorylation	Tyr158	Y-->S	9606	BTO:0000938								32599005	t		lperfetto	JAK2 regulates Nav1.6 channel function via FGF14Y158 phosphorylation|Patch-clamp electrophysiology revealed that through Y158, JAK2 controls FGF14-dependent modulation of Nav1.6 channels. In hippocampal CA1 pyramidal neurons, the JAK2 inhibitor Fedratinib reduced firing by a mechanism that is dependent upon expression of FGF14.	SIGNOR-275747	0.2
TP53	protein	P04637	UNIPROT	NLRC4	protein	Q9NPP4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15580302	f		miannu	 Here we show that Ipaf, a human CED-4 homologue and an activator of caspase-1, is induced by p53. Overexpression of p53 by transfection in U2OS and A549 cells increased Ipaf mRNA levels. 	SIGNOR-255439	0.426
TFAP2A	protein	P05549	UNIPROT	LNPEP	protein	Q9UIQ6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003420								15894523	f	 	miannu	Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. 	SIGNOR-255402	0.284
SMO	protein	Q99835	UNIPROT	GNAT1	protein	P11488	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-199168	0.264
PRKCZ	protein	Q05513	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates activity	phosphorylation	Ser181	DQGSLCTsFVGTLQY	9606									10022904	t		lperfetto	Activation of IkappaB kinase beta by protein kinase C isoforms. | Interestingly, recombinant active zetaPKC and alphaPKC are able to stimulate in vitro the activity of IKKbeta but not that of IKKalpha. In addition, evidence is presented here that recombinant zetaPKC directly phosphorylates IKKbeta in vitro, involving Ser177 and Ser181. Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-kappaB pathway at the level of IKKbeta activation and IkappaB degradation.	SIGNOR-249016	0.495
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1696	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120196	0.321
DYRK2	protein	Q92630	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates	phosphorylation	Ser243	PGETPPLsPIDMESQ	9606	BTO:0000150								22307329	t		lperfetto	Degradation of c-jun/c-myc is a critical process for the g(1)/s transition, which is initiated upon phosphorylation by glycogen synthase kinase 3 ? (gsk3?). However, a specific kinase or kinases responsible for priming phosphorylation events that precede this gsk3? Modification has not been definitively identified. Here, we found that the dual-specificity tyrosine phosphorylation-regulated kinase dyrk2 functions as a priming kinase of c-jun and c-myc.The finding that kinase-active dyrk2 phosphorylated gst_c-jun210_310-wt by detection with an anti_phospho_c-jun(ser243) antibody demonstrated that dyrk2 is a ser243 kinase in vitro	SIGNOR-195771	0.259
DFFA	protein	O00273	UNIPROT	DFFB	protein	O76075	UNIPROT	down-regulates	binding			9606	BTO:0000567								9108473	t		amattioni	Dff is a heterodimer of 40 kda and 45 kda subunits.	SIGNOR-29729	0.927
CDK2	protein	P24941	UNIPROT	CCNA2	protein	P20248	UNIPROT	up-regulates	phosphorylation	Ser154	PMDGSFEsPHTMDMS	9606									10652300	t		lperfetto	Here we present evidence from in vitro and in vivo assay systems that the degradation of human cyclin a can be inhibited by kinase-inactive mutants of cdk2 and cdc2cdk2 can phosphorylate cyclin a on ser-154	SIGNOR-74466	0.976
GPR161	protein	Q8N6U8	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606									23332756	t			Shh signaling directs Gpr161 to be internalized from cilia, preventing its activity.	SIGNOR-259936	0.384
RNF115	protein	Q9Y4L5	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								23418353	t		miannu	RNF126 and Rabring7 associate with the EGFR through a ubiquitin-binding zinc finger domain and both E3 ubiquitin ligases promote ubiquitylation of EGFR. In HeLa cells depleted of either RNF126 or Rabring7 the EGFR is retained in a late endocytic compartment and is inefficiently degraded.	SIGNOR-272104	0.383
SMARCA2	protein	P51531	UNIPROT	Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270688	0.821
AURKA	protein	O14965	UNIPROT	AURKA	protein	O14965	UNIPROT	up-regulates	phosphorylation	Thr288	APSSRRTtLCGTLDY	9606									24867643	t		lperfetto	The upstream pak1 kinase can phosphorylate aurora a at t288, autophosphorylation appears to be the essential mode of activation. Our experiments suggest that phosphorylation of t288 is important for regulation of the aurora2 kinase both for its activity and its stability	SIGNOR-205106	0.2
PTPRJ	protein	Q12913	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									1715686	t		gcesareni	Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta.	SIGNOR-21303	0.309
belinostat	chemical	CHEBI:61076	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257953	0.8
PRKAA1	protein	Q13131	UNIPROT	USP10	protein	Q14694	UNIPROT	up-regulates activity	phosphorylation	Ser76	DTLPRTPsYSISSTL	9606	BTO:0001109								26876938	t		miannu	Under energy stress, USP10 activity in turn is enhanced through AMPK-mediated phosphorylation of Ser76 of USP10. 	SIGNOR-277207	0.313
STAT1	protein	P42224	UNIPROT	M1_polarization	phenotype	SIGNOR-PH54	SIGNOR	up-regulates				9606									19029990	f		lperfetto	STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others.	SIGNOR-249496	0.7
BLVRB	protein	P30043	UNIPROT	biliverdin(2-)	smallmolecule	CHEBI:57991	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000759							7929092	t		lperfetto	This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. 	SIGNOR-275524	0.8
AHSP	protein	Q9NZD4	UNIPROT	HBA1	protein	P69905	UNIPROT	up-regulates quantity by stabilization	binding			9606									18179859	t	Regulation	miannu	α-Hemoglobin stabilizing protein (AHSP) binds α-hemoglobin (Hb), avoiding its precipitation and its pro-oxidant activity. 	SIGNOR-251770	0.771
TP53	protein	P04637	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									7958853	f		gcesareni	The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop.	SIGNOR-34962	0.968
PRKAA2	protein	P54646	UNIPROT	HNF4A	protein	P41235	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser313	GKIKRLRsQVQVSLE	10029	BTO:0000246								12740371	t		miannu	AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. Phosphorylation of HNF4α on Ser-304 reduces protein stability.	SIGNOR-250322	0.375
CTLA4	protein	P16410	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity				9606	BTO:0000782								16227604	f		Barakat	Akt phosphorylation in cells stimulated by CD3/CD28/CTLA-4 or CD3/CD28/PD-1 aAPCs did not have detectable phosphorylated Akt at any time point, indicating that CTLA-4 and PD-1 signaling blocked rather than delayed Akt activation.	SIGNOR-275409	0.589
SP7	protein	Q8TDD2	UNIPROT	BGLAP	protein	P02818	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004058; BTO:0000165								11792318	f		Giulio Giuliani	To test whether Osx could activate typical osteoblast genes, we transfected an Osx expressing vector into both C2C12 and C3H10T1/2 cells. Our results showed that Osx produced an induction of osteocalcin RNA in both cell types.	SIGNOR-255409	0.507
PRKCA	protein	P17252	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Ser840	VRSAFTTsTVVRMHV	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249278	0.425
GCC2	protein	Q8IWJ2	UNIPROT	IGF2R	protein	P11717	UNIPROT	up-regulates activity	relocalization												18195106	t		lperfetto	Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector	SIGNOR-253085	0.509
MAP3K6	protein	O95382	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation	Thr180	RHTDDEMtGYVATRW	9534									8622669	t		Manara	These data indicate that MKK6 phosphorylates p38 MAP kinase on Thr-180 and Tyr-182, the sites of phosphorylation that activate p38 MAP kinase	SIGNOR-260915	0.2
NAA38	protein	Q9BRA0	UNIPROT	NatC	complex	SIGNOR-C417	SIGNOR	form complex	binding			9606									19398576	t		miannu	 We here identify and characterize the human NatC (hNatC) complex, containing the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31. This complex associates with ribosomes, and hMak3 acetylates Met-Leu protein N termini in vitro, suggesting a model in which the human NatC complex functions in cotranslational N-terminal acetylation.	SIGNOR-267235	0.672
PRKACA	protein	P17612	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates	phosphorylation												16293631	t			We report that activation of PKA retains Gli1 in the cytoplasm. Conversely, inhibition of PKA activity promotes nuclear accumulation of Gli1.We provide direct evidence to support that the cAMP/PKA signaling axis regulates Gli1 protein localization primarily through a site at Thr374. .These data suggest that Thr374 is an important PKA site responsible for PKA phosphorylation and for the transcriptional activity of Gli1. 	SIGNOR-253539	0.53
CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	PER1	protein	O15534	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f		lperfetto	Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253681	0.72
ARHGAP35	protein	Q9NRY4	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260492	0.889
MTOR	protein	P42345	UNIPROT	UVRAG	protein	Q9P2Y5	UNIPROT	up-regulates activity	phosphorylation	Ser550	KITSLSSsLDTSLDF	9606	BTO:0001938								26139536	t		miannu	MTOR phosphorylates UVRAG at serine 550 and serine 571	SIGNOR-276920	0.419
SUZ12/EZH2/YY1	complex	SIGNOR-C102	SIGNOR	PAX7	protein	P23759	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000165;BTO:0002314								20887952	t		lperfetto	TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter.	SIGNOR-235583	0.331
CDK3	protein	Q00526	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2513	EHPFLTPsPESPDQW	-1									25344755	t		lperfetto	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273169	0.245
PRKCE	protein	Q02156	UNIPROT	SLC4A3	protein	P48751	UNIPROT	up-regulates activity	phosphorylation	Ser67	EKPSRSYsERDFEFH	9606	BTO:0000007								11739292	t		lperfetto	We conclude that following Ang II stimulation of cells, PKCepsilon phosphorylates serine 67 of the AE3 cytoplasmic domain, inducing the Ang II-induced increase in anion transport observed in the hypertrophic myocardium.	SIGNOR-249127	0.313
AURKB	protein	Q96GD4	UNIPROT	SSU72	protein	Q9NP77	UNIPROT	down-regulates activity	phosphorylation	Ser19	CSSNQNRsMEAHNIL										24149858	t		lperfetto	Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72. 	SIGNOR-275530	0.257
GSK3B	protein	P49841	UNIPROT	CLOCK	protein	O15516	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser427	ALERFDHsPTPSASS	9606	BTO:0002181								19946213	t		miannu	We have identified a conserved cluster of serines that include, Ser431, which is a prerequisite phosphorylation site for the generation of BMAL dependent phospho-primed CLOCK and for the potential GSK-3 phosphorylation at Ser427. 	SIGNOR-276270	0.348
TRADD	protein	Q15628	UNIPROT	TRAF2	protein	Q12933	UNIPROT	up-regulates activity	binding			10090									14585074	t		lperfetto	Tradd mediates recruitment of the traf2 adaptor protein	SIGNOR-118770	0.865
FBXW7	protein	Q969H0	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	down-regulates quantity by destabilization	ubiquitination												26971449	t		lperfetto	We then examined the effect of necdin on ubiquitin-dependent degradation of PGC-1α using Rnf34, a PGC-1α E3 ubiquitin ligase22. Rnf34 reduced the PGC-1α level, and necdin completely inhibited the reduction (Fig. 4i). In addition, necdin strongly suppressed Rnf34-mediated ubiquitination of PGC-1α (Fig. 4j). Necdin also protected PGC-1α against ubiquitination mediated by Fbxw7, another PGC-1α E3 ubiquitin ligase23 (Fig. 4k). These data indicate that necdin stabilizes PGC-1α by inhibiting its degradation in the ubiquitin-proteasomal system.	SIGNOR-253394	0.406
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	BGN	protein	P21810	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15536164	f	 	miannu	 Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG. 	SIGNOR-254797	0.2
STK4	protein	Q13043	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates activity	phosphorylation	Thr177	VAGQLTDtMAKRNTV	9534									12223493	t		lperfetto	Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationwas also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues	SIGNOR-247573	0.2
SH2B1	protein	Q9NRF2	UNIPROT	SYK	protein	P43405	UNIPROT	down-regulates activity	dephosphorylation			9606	BTO:0000776								32323266	t		scontino	SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK.	SIGNOR-268445	0.2
ATM	protein	Q13315	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1466	KSSEYPIsQNPEGLS	9606	BTO:0000150								10550055	t		lperfetto	The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks	SIGNOR-72060	0.813
PPARG	protein	P37231	UNIPROT	CXCR2	protein	P25025	UNIPROT	up-regulates quantity by expression	transcriptional regulation												18292390	t		lperfetto	EMSA, ChIP, and transient transfection assays indicate that PPAR-gamma activates the CXCR2 promoter by binding to a PPAR response element (PPRE).	SIGNOR-271682	0.267
FOXN4	protein	Q96NZ1	UNIPROT	PTF1A	protein	Q7RTS3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001175								17075007	f		Luana	 We conclude that Foxn4 functions upstream of Ptf1a to activate its expression, thereby regulating the generation of amacrine and horizontal cells during retinogenesis.	SIGNOR-261608	0.475
phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	SOS1	protein	Q07889	UNIPROT	up-regulates	chemical activation			9606									17486115	t		gcesareni	Phosphatidic acid interacts with a defined site in the sos ph domain with high affinity and specificity	SIGNOR-154676	0.8
ITGB8	protein	P26012	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257729	0.449
MAPK1	protein	P28482	UNIPROT	PDE4D	protein	Q08499	UNIPROT	down-regulates	phosphorylation	Ser715	YQSTIPQsPSPAPDD	9606									10828059	t	The effect has been demonstrated using Q08499-5	gcesareni	These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro.	SIGNOR-77571	0.36
CTDSPL	protein	O15194	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	dephosphorylation	Ser204	NHSMDAGsPNLSPNP	9606	BTO:0000007								17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248306	0.398
GDNF	protein	P39905	UNIPROT	DNM2	protein	P50570	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization.	SIGNOR-252173	0.2
CSNK2A1	protein	P68400	UNIPROT	IGF2R	protein	P11717	UNIPROT	unknown	phosphorylation	Ser2409	LHGDDQDsEDEVLTI	9606									8318012	t		lperfetto	The two sites phosphorylated by ck ii in vivo and in vitro are ser82 and ser157.	SIGNOR-37831	0.486
PRKACA	protein	P17612	UNIPROT	CD44	protein	P16070	UNIPROT	up-regulates	phosphorylation	Ser697	AVEDRKPsGLNGEAS	9606									16785995	t		lperfetto	Pka can phosphorylate ser316 directly cd44 s291a and s316a mutants may disrupt downstream signalling events by displacing endogenous cd44 from plasma membrane microdomains.	SIGNOR-147208	0.2
FASN	protein	P49327	UNIPROT	WNT1	protein	P04628	UNIPROT	up-regulates activity				9606									18838960	f		lperfetto	Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer	SIGNOR-242881	0.252
MAPK1	protein	P28482	UNIPROT	CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	up-regulates	phosphorylation			9606									12359725	t		lperfetto	In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e.	SIGNOR-217499	0.387
UCK1	protein	Q9HA47	UNIPROT	uridine 5'-monophosphate(2-)	smallmolecule	CHEBI:57865	ChEBI	up-regulates quantity	chemical modification												11306702	t		lperfetto	Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. 	SIGNOR-275858	0.8
PRKCD	protein	Q05655	UNIPROT	LIMK2	protein	P53671	UNIPROT	down-regulates	phosphorylation	Ser283	EGTLRRRsLRRSNSI	9606									15923181	t	Translocation from Cytosol to Nucleus	flangone	Activation of pkc by phorbol ester treatment of endothelial cells stimulated limk2 phosphorylation at ser-283 and inhibited nuclear import of limk2	SIGNOR-137927	0.258
EML4-ALK	fusion protein	SIGNOR-FP8	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates				9606									28370702	f		lperfetto	A specific subtype of non-small cell lung cancer (NSCLC) characterized with an EML4-ALK fusion gene, which drives constitutive oncogenic activation of ALK kinase. We demonstrated that exogenous introduction of EML4-ALK protein with the substitution of lysine 1610 to an alanine in these two cell lines reduced the phosphorylation levels of AKT, one of downstream oncogenic molecules in the EML4-ALK pathway, and suppressed the growth of the two cell lines.	SIGNOR-253218	0.2
GABRG2	protein	P18507	UNIPROT	GABA-A (a4-b1-g2) receptor	complex	SIGNOR-C333	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263761	0.625
AKT1	protein	P31749	UNIPROT	TWIST1	protein	Q15672	UNIPROT	up-regulates	phosphorylation	Ser42	GGRKRRSsRRSAGGG	9606									20400976	t		llicata	Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis.	SIGNOR-164884	0.451
CDK5	protein	Q00535	UNIPROT	HTT	protein	P42858	UNIPROT	up-regulates	phosphorylation	Ser1199	EQASVPLsPKKGSEA	9606	BTO:0000938								17611284	t		lperfetto	Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage.	SIGNOR-156840	0.46
TGFB1	protein	P01137	UNIPROT	DNAH10	protein	Q8IVF4	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000667								31836722	f		miannu	The protein expression of DNAH10 was assessed by Western blot analysis after stimulation of primary keratinocytes (P4) with inflammatory cytokine TNFα or growth factor TGF-β1 and their combination (Fig. 5C). Treatment with TNFα, TGF-β1, and their combination down regulated the expression of DNAH10 in keratinocytes after a 24-h-stimulation. 	SIGNOR-265552	0.2
MAPK3	protein	P27361	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation			9606		BTO:0000176							14967450	t		lperfetto	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-121997	0.59
NDFIP2	protein	Q9NV92	UNIPROT	NEDD4	protein	P46934	UNIPROT	up-regulates activity	relocalization			9606	BTO:0002181								26363003	t		SARA	Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2.	SIGNOR-260996	0.586
RUNX3	protein	Q13761	UNIPROT	CHUK	protein	O15111	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255090	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ABI1	protein	Q8IZP0	UNIPROT	up-regulates	phosphorylation			9606									21419341	t	inferred from 70% family members	gcesareni	We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1.	SIGNOR-270161	0.2
ARNT	protein	P27540	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates activity	binding												14764593	t	 	lperfetto	 The functional transcription factor exists as a heterodimeric complex consisting of HIF-1alpha and the aryl hydrocarbon receptor nuclear translocator (ARNT). Association of HIF-1 with ARNT is required for its activity; however, no other role has been ascribed to this interaction. 	SIGNOR-253720	0.777
CDK7	protein	P50613	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser371	AHSSHLKsKKGQSTS	9606									9315650	t		llicata	The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase.	SIGNOR-51280	0.47
GATA1	protein	P15976	UNIPROT	FCER1A	protein	P12319	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000732								11971001	f	 	 	Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells	SIGNOR-254288	0.316
ERBB3	protein	P21860	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001130								15542423	f		gcesareni	Suspected erbb receptor involvement in prostate cancer originates partly from the realization that these proteins are capable of promoting the transcriptional activity of the androgen receptor (ar), her2/her3 effects on ar included effects on protein stability and stimulation of dna binding to ar target genes.	SIGNOR-130443	0.52
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	PAK2	protein	Q13177	UNIPROT	up-regulates activity	phosphorylation	Thr134	LKFYDSNtVKQKYLS	9606	BTO:0004828								32483448	t		lperfetto	Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway	SIGNOR-273111	0.2
LYN	protein	P07948	UNIPROT	YY1	protein	P25490	UNIPROT	down-regulates activity	phosphorylation	Tyr383	IHTGDRPyVCPFDGC	9606	BTO:0002181								26198631	t		miannu	In the case of Lyn overexpression, single mutations at either tyrosine 8, 254, or 383 severely reduced Lyn-mediated YY1 phosphorylation, suggesting that these three sites may be targets of Lyn in vivo (Fig. 3, A and B).	SIGNOR-276928	0.2
CSF3	protein	P09919	UNIPROT	CSF2RA	protein	P15509	UNIPROT	up-regulates	binding			9606									10572088	t		gcesareni	Granulocyte-macrophage colony-stimulating factor (gm-csf) is an important hematopoietic cytokine that exerts its effects by interaction with the gm-csf receptor (gmr) on the surface of responsive cells. The gm-csf receptor consists of two subunits: gmralpha, which binds gm-csf with low affinity, and gmrbeta, which lacks intrinsic ligand-binding capability but complexes with gmralpha to form a high-affinity receptor (gmralpha/beta).	SIGNOR-72511	0.456
NKX2-1	protein	P43699	UNIPROT	TPO	protein	P07202	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001073							27347897	t		scontino	TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8.	SIGNOR-267278	0.389
MAP2K3	protein	P46734	UNIPROT	MAPK12	protein	P53778	UNIPROT	up-regulates	phosphorylation			9606									11062067	t		fstefani	Mkk3, mkk4 and mkk6 all show a strong preference for phosphorylation of the tyrosine residue of the thr-gly-tyr motifs in their known substrates sapk2a/p38, sapk3/p38 gamma and sapk4/p38 delta. we therefore examined the phosphorylation of sapk2a/p38, sapk3/p38? And sapk4/p38? By mkk3, mkk4 and mkk6, which are all known to be capable of activating these enzymes in vitro.	SIGNOR-83718	0.632
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MBP	protein	P02686	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000142							16401070	t	inferred from 70% family members	lperfetto	Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence.	SIGNOR-270195	0.2
PIAS1	protein	O75925	UNIPROT	PRDM1	protein	O75626	UNIPROT	up-regulates	sumoylation	Lys816	PLVPVKVkQETVEPM	9606									22555612	t		miannu	Blimp_1 is subjected to pias1_mediated sumoylation at lysine 816 / it appears that sumo_modified blimp_1 is a more potent transcriptional repressor.	SIGNOR-197265	0.329
PPM1D	protein	O15297	UNIPROT	H2AX	protein	P16104	UNIPROT	down-regulates	dephosphorylation	Ser140	GKKATQAsQEY	9606									20118229	t		gcesareni	Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-h2ax and suppresses dna double strand break repair. Here, we demonstrate that the wild-type p53-induced phosphatase 1 (wip1) also dephosphorylates gamma-h2ax at serine 139 in vitro and in vivo.	SIGNOR-163693	0.2
AKT1	protein	P31749	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity	phosphorylation	Thr700	MESRRQAtVSWDSGG	-1									23264741	t		miannu	 Here we show that soluble growth factors enhance integrin signaling through Akt phosphorylation of FAK at Ser695 and Thr700. 	SIGNOR-276436	0.44
ERCC6	protein	Q03468	UNIPROT	APEX1	protein	P27695	UNIPROT	down-regulates activity	binding			9606									17567611	t	Regulation	miannu	CSB stimulates the AP site incision activity of APE1 on normal (i.e. fully paired) and bubble AP-DNA substrates, with the latter being more pronounced (up to 6-fold). This activation is ATP-independent, and specific for the human CSB and full-length APE1 protein. CSB and APE1 were also found in a common protein complex in human cell extracts, and recombinant CSB, when added back to CSB-deficient whole cell extracts, resulted in increased total AP site incision capacity. 	SIGNOR-251932	0.429
PPP2R2B	protein	Q00005	UNIPROT	PDPK1	protein	O15530	UNIPROT	down-regulates activity	binding			9606									21075311	t		gcesareni	Here, we show that PPP2R2B, encoding the B55² regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55²-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation.	SIGNOR-243511	0.336
ELANE	protein	P08246	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Thr74	SVLTGKLtTVFLPIV	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263587	0.404
(S)-verapamil	chemical	CHEBI:77736	ChEBI	ABCC1	protein	P33527	UNIPROT	up-regulates activity	chemical activation			10036									17646169	t		Federica	(S)-Verapamil acts as a “killer” by activation of MRP1-mediated GSH efflux, leading to the death of potentially resistant tumor cells.	SIGNOR-261081	0.8
alvocidib	chemical	CHEBI:47344	ChEBI	CDK6	protein	Q00534	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192385	0.8
MAPK1	protein	P28482	UNIPROT	ATP1A1	protein	P05023	UNIPROT	down-regulates activity	phosphorylation	Ser16	KYEPAAVsEQGDKKG	1792	BTO:0003069								14976217	t		miannu	Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit.	SIGNOR-262940	0.509
PIM1	protein	P11309	UNIPROT	ABCG2	protein	Q9UNQ0	UNIPROT	up-regulates activity	phosphorylation	Thr362	GEKKKKItVFKEISY	9606	BTO:0001130								18056989	t		lperfetto	Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells|This is further corroborated by our finding that the plasma membrane localization and drug-resistant activity of BCRP were compromised by T362A mutation.	SIGNOR-264420	0.366
PRKG1	protein	Q13976	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates activity	phosphorylation	Ser700	FGEKRKNsILNPINS	-1									1377674	t		lperfetto	Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC.	SIGNOR-248850	0.521
FGFR3	protein	P22607	UNIPROT	FGFR3	protein	P22607	UNIPROT	up-regulates activity	phosphorylation	Tyr647	RDVHNLDyYKKTTNG	9606	BTO:0000007								11294897	t		lperfetto	Ligand stimulation leads to autophosphorylation of fgfr3 the two tyrosine residues in the YYKK Motif of the activation loop of fgfrs are required for kinase activity of fgfr1 and fgfr3.	SIGNOR-106730	0.2
SRC	protein	P12931	UNIPROT	SH3PXD2B	protein	A1X283	UNIPROT	up-regulates activity	phosphorylation	Tyr508	DMSASAGyEEISDPD	9606									20943948	t		lperfetto	C-Src-mediated phosphorylation of NoxA1 and Tks4 induces the reactive oxygen species (ROS)-dependent formation of functional invadopodia in human colon cancer cells|Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation.	SIGNOR-264705	0.523
Exosome_Complex	complex	SIGNOR-C255	SIGNOR	FUS	protein	P35637	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000793								27460707	t	P35637:p.Arg495_Tyr526del (mutation increasing interaction)		We hypothesized that FUS could be secreted via the exosome pathway. We tested and confirmed that FUS was indeed present in exosomes in both SH-SY5Y and N2A cells (Fig. 6 and Supplemental Fig. 2). It is also noted that the level of the R495X mutant in exosomes was significantly higher than that of WT or the R521G mutant. |It raises the possibility that the exosome-mediated secretion of FUS may contribute to the cell-to-cell propagation of FUS pathology. 	SIGNOR-262812	0.234
INSR	protein	P06213	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	phosphorylation	Tyr632	GRKGSGDyMPMSPKS	10029	BTO:0000246								7651388	t		lperfetto	Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir).	SIGNOR-236741	0.911
AURKB	protein	Q96GD4	UNIPROT	YY1	protein	P25490	UNIPROT	up-regulates	phosphorylation	Ser180	KKGGGKKsGKKSYLS	9606									23226345	t		lperfetto	Aurora b kinase phosphorylates yy1 on serine 184 and to a lesser extent serine 180 at the g2/m stage of the cell cycle (fig. 7). We show that yy1 is rapidly dephosphorylated as the cells exit mitosis, likely by pp1. Also, our data indicates that phosphorylation at serine 180 and serine 184 can affect the dna binding activity of yy1	SIGNOR-200075	0.377
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PLA2G4A	protein	P47712	UNIPROT	up-regulates	phosphorylation			9606									8381049	t	inferred from 70% family members	gcesareni	Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane.	SIGNOR-270192	0.2
IMMT	protein	Q16891	UNIPROT	PINK1	protein	Q9BXM7	UNIPROT	up-regulates activity	binding			-1									27153535	t		miannu	MIC60 Is Crucial for Parkin Recruitment and Transiently Interacts with PINK1	SIGNOR-266301	0.409
UBE4B	protein	O95155	UNIPROT	ATXN3	protein	P54252	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								14749733	t		miannu	Mammalian E4B (UFD2a), a ubiquitin chain assembly factor (E4), copurified with the polyubiquitylation activity for ataxin-3. E4B interacted with, and thereby mediated polyubiquitylation of, ataxin-3.  Collectively, these data suggest that E4B promotes the degradation of ataxin-3, and that this effect surmounts the stabilization of ataxin-3 conferred by expansion of the polyglutamine tract.	SIGNOR-271502	0.595
MMP14	protein	P50281	UNIPROT	FGA	protein	P02671	UNIPROT	down-regulates quantity by destabilization	cleavage	Leu105	NNKDSHSlTTNIMEI	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain	SIGNOR-263619	0.2
PTK6	protein	Q13882	UNIPROT	EPS8	protein	Q12929	UNIPROT	up-regulates activity	phosphorylation	Tyr525	NRHIDRNyEPLKTQP	9606									28214294	t		miannu	Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis. 	SIGNOR-263190	0.366
Adechlorin	chemical	CID:125913	PUBCHEM	ADA	protein	P00813	UNIPROT	down-regulates activity	chemical inhibition			9606									2433905	t		miannu	2'-Chloropentostatin is a new inhibitor of adenosine deaminase isolated from the fermentation broth of an unidentified actinomycete, ATCC 39365. It contains the aglycone of coformycin, i.e. 3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-o1, coupled to the unusual carbohydrate, 2'-chloro-2'-deoxyribose. 2'-Chloropentostatin is a slightly weaker inhibitor of rat and human adenosine deaminases than coformycin, and considerably weaker than pentostatin. Unlike pentostatin, which appears to undergo a two-stage interaction with adenosine deaminase, 2'-chloropentostatin forms a single enzyme-inhibitor complex. The enzyme-inhibitor complex between adenosine deaminase and 2'-chloropentostatin was much more rapidly dissociable than the complex with pentostatin. 	SIGNOR-259262	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	SLC25A27	protein	O95847	UNIPROT	up-regulates quantity by expression	transcriptional regulation												20385226	t		lperfetto	We present the first direct evidence that UCP4 is regulated by NF-kappaB, mediated via a functional NF-kappaB site in its promoter region, and that UCP4 has a significant role in NF-kappaB prosurvival signaling, mediating its protection against MPP(+) toxicity.|NF-kappaB inhibition significantly suppressed the MPP(+)-induced increase in UCP4 expression.	SIGNOR-268984	0.2
DIP2A	protein	Q14689	UNIPROT	ABL2	protein	P42684	UNIPROT	up-regulates activity	binding			10090	BTO:0003102								33622779	t		miannu	Here, using cultured hippocampal neurons pooled from both sexes of mice, we provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability.	SIGNOR-266593	0.2
PRKCD	protein	Q05655	UNIPROT	CXCR4	protein	P61073	UNIPROT	down-regulates activity	phosphorylation	Ser338	KGKRGGHsSVSTESE	9606									10521508	t		Manara	Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization.	SIGNOR-260900	0.2
S1PR3	protein	Q99500	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257330	0.357
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	JUN	protein	P05412	UNIPROT	up-regulates activity				9606	BTO:0000093								8415704	t			PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site	SIGNOR-259940	0.2
MAPK7	protein	Q13164	UNIPROT	MAPK7	protein	Q13164	UNIPROT	up-regulates activity	phosphorylation	Ser567	VLSDNDRsLLERWTR	9606	BTO:0000567								20667468	t		miannu	Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803.	SIGNOR-259823	0.2
UTS2R	protein	Q9UKP6	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257164	0.268
ELMO2	protein	Q96JJ3	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			10090	BTO:0001909								25533347	t		miannu	We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth.	SIGNOR-266821	0.566
KMT2E	protein	Q8IZD2	UNIPROT	NCR2	protein	O95944	UNIPROT	up-regulates activity	binding			9606	BTO:0000737								23958951	t		miannu	We identify natural cytotoxicity receptor NKp44 (NKp44L), a novel isoform of the mixed-lineage leukemia-5 protein, as a cellular ligand for NKp44. Unlike the other MLL family members, NKp44L is excluded from the nucleus, but expressed at the cell-surface level; its subcellular localization is being associated with the presence of a specific C-terminal motif. Strikingly, NKp44L has not been detected on circulating cells isolated from healthy individuals, but it is expressed on a large panel of the tumor and transformed cells. 	SIGNOR-260045	0.52
olodaterol	chemical	CHEBI:82700	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			-1									20371707	t		Luana	In vitro, olodaterol showed a potent, nearly full agonistic response at the hbeta(2)-AR (EC(50) = 0.1 nM; intrinsic activity = 88% compared with isoprenaline) and a significant selectivity profile (241- and 2299-fold [corrected] against the hbeta(1)- and hbeta(3)-ARs, respectively). 	SIGNOR-257834	0.8
PAK4	protein	O96013	UNIPROT	ITGB5	protein	P18084	UNIPROT	up-regulates	phosphorylation	Ser759	REFAKFQsERSRARY	9606									20507994	t		llicata	Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration.	SIGNOR-165702	0.463
SRC	protein	P12931	UNIPROT	PBK	protein	Q96KB5	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr74	NPICNDHyRSVYQKR	9606	BTO:0000038								27016416	t		miannu	Phosphorylation of TOPK at Y74, Y272 by Src increases the stability of TOPK and promotes tumorigenesis of colon	SIGNOR-277218	0.404
TAOK2	protein	Q9UL54	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	up-regulates	phosphorylation			9606									23431053	t	inferred from 70% of family members	gcesareni	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.	SIGNOR-269939	0.283
PTPRG	protein	P23470	UNIPROT	DAB1	protein	O75553	UNIPROT	down-regulates activity	dephosphorylation	Tyr198	EDVEDPVyQYIVFEA	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254697	0.2
Liprin-alpha	proteinfamily	SIGNOR-PF82	SIGNOR	KIF1A	protein	Q12756	UNIPROT	up-regulates activity	binding			10116	BTO:0003102								30021165	t		miannu	Kinesin-3 Family Member KIF1A Interacts with Liprin-α and TANC2. TANC2 and Liprin-α Recruit KIF1A-Driven DCVs in Dendritic Spines. Upon Ca2+/CaM binding, KIF1A is activated, allowing for DCV loading and motility. KIF1A-driven DCVs are recruited in dendritic spines by liprin-α and TANC2, which ensure a precise mechanism of synaptic tagging for the vesicles.	SIGNOR-266892	0.2
SLBP	protein	Q14493	UNIPROT	H2AW	protein	Q7L7L0	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265409	0.2
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	binding			9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	In this study, we demonstrate that akt also regulates the activity of fkhrl1, a member of the forkhead family of transcription factors. In the presence of survival factors, akt phosphorylates fkhrl1, leading to fkhrl1's association with 14-3-3 proteins and fkhrl1's retention in the cytoplasm. Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252818	0.702
SPATA13	protein	Q96N96	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260576	0.707
UBE2D1	protein	P51668	UNIPROT	MPG	protein	P29372	UNIPROT	up-regulates activity	binding			-1									25207814	t		miannu	Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E)	SIGNOR-271927	0.2
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	YAP1	protein	P46937	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									23431053	t		lperfetto	This cascade of phosphorylation allows the binding of scfbetatrcp that promotes the ubiquitination and degradation of yap.	SIGNOR-217187	0.372
SPOP	protein	O43791	UNIPROT	CUL3	protein	Q13618	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								34599168	t		miannu	Here we show that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP binds Geminin at endogenous level and regulates DNA replication. SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. 	SIGNOR-268927	0.919
entinostat	chemical	CHEBI:132082	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191478	0.8
SREBF1	protein	P36956	UNIPROT	VLDL_assembly	phenotype	SIGNOR-PH62	SIGNOR	up-regulates				9606									11111091	f		miannu	SREBP1 increased the expression of MTP and increased the assembly and secretion of VLDL containing apo B100. SREBP1 induced the expression of the genes regulating the synthesis of all VLDL lipids	SIGNOR-252112	0.7
SMAD3	protein	P84022	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	binding			9606									14638857	t		gcesareni	Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd	SIGNOR-254325	0.718
CDK2	protein	P24941	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates activity	phosphorylation	Thr515	QKYSMDNtPHTPTPF		BTO:0000007								10593981	t		llicata	Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. 	SIGNOR-250739	0.711
PTH	protein	P01270	UNIPROT	PTH1R	protein	Q03431	UNIPROT	up-regulates	binding			9606									18981475	t		gcesareni	Here we show that binding of pth to its receptor pth1r induced association of lrp6, a coreceptor of wnt, with pth1r. The formation of the ternary complex containing pth, pth1r, and lrp6 promoted rapid phosphorylation of lrp6, which resulted in the recruitment of axin to lrp6, and stabilization of beta-catenin.	SIGNOR-182039	0.764
CDK2	protein	P24941	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser104	FPPLNSVsPSPLMLL	9606			SIGNOR-C83						10428798	t		gcesareni	Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity.	SIGNOR-69710	0.491
UTS2R	protein	Q9UKP6	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257377	0.409
TP63	protein	Q9H3D4	UNIPROT	SUN1	protein	O94901	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0005098								28595999	t		lperfetto	Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets.	SIGNOR-263278	0.2
MAPK14	protein	Q16539	UNIPROT	SLC9A1	protein	P19634	UNIPROT	up-regulates	phosphorylation	Ser726	IDPASPQsPESVDLV	9606									11604491	t		llicata	Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728.	SIGNOR-111043	0.552
DDX21	protein	Q9NR30	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity	binding			9606	BTO:0000007 ; BTO:0001282								11823437	t		SARA	C-Jun and RHII/Gu proteins interact in human cells at their endogenous level of expression. The helicase activity of RHII/Gu specifically facilitates c-Jun-mediated transcription.	SIGNOR-260977	0.468
BKM120	chemical	CHEBI:71954	ChEBI	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190389	0.8
IL4R	protein	P24394	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0000801;BTO:0000876	BTO:0000887;BTO:0000763;BTO:0001260							12704343	t		milica	IL-4Rα, γc, and IL-13Rα1 all contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectively. Il-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells.	SIGNOR-100774	0.705
MMP1	protein	P03956	UNIPROT	COL3A1	protein	P02461	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly774	IGPPGPAgQPGDKGE	-1									17318226	t		lperfetto	In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4. 	SIGNOR-272339	0.358
adrenaline	smallmolecule	CHEBI:33568	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)	SIGNOR-257878	0.8
Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	up-regulates				9606									30397315	f		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270700	0.7
PRKCD	protein	Q05655	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser379	DLILNRCsESTKRKL	9606	BTO:0000130								12056906	t		esanto	Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?.	SIGNOR-89248	0.459
PTPN1	protein	P18031	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	dephosphorylation	Tyr1007	VLPQDKEyYKVKEPG	9606	BTO:0000007								11970898	t			Immunoblots with phospho-specific antibodies confirmed that PTP1B suppresses phosphorylation of the Jak2 activation site tyrosines (Y1007/Y1008) and Stat3 in a dose-dependent manner	SIGNOR-248404	0.79
AHCYL2	protein	Q96HN2	UNIPROT	PAPOLB	protein	Q9NRJ5	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								19224921	t		lperfetto	Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner.	SIGNOR-268332	0.2
NDUFA7	protein	O95182	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24].	SIGNOR-262158	0.817
BMP2	protein	P12643	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates				9606									22298955	f		lperfetto	Neogenin, a transmembranous protein, was reported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation.	SIGNOR-195561	0.64
4-oxobutanoate	smallmolecule	CHEBI:57706	ChEBI	succinate(2-)	smallmolecule	CHEBI:30031	ChEBI	up-regulates quantity	precursor of			9606									19300440	t		miannu	Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix.	SIGNOR-266615	0.8
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	RAD52	protein	P43351	UNIPROT	up-regulates activity	phosphorylation	Tyr104	DLNNGKFyVGVCAFV	9606									23836560	t		Manara	Have found that BCR-ABL1 interacts with the C-terminal portion of RAD52, resulting in tyrosine phosphorylation of Y104 located in RAD52 DNA II and enhanced nuclear foci formation	SIGNOR-262531	0.2
MAPK8	protein	P45983	UNIPROT	BMF	protein	Q96LC9	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								12591950	t		miannu	Activated JNK causes BimL and Bmf phosphorylation in vivo. It is known that UV radiation causes the release of Bim and Bmf from dynein and myosin V motor complexes and that these proteins cause Bax/Bak-dependent apoptosis . The results of this study demonstrate that JNK can engage this apoptotic pathway by phosphorylation of BH3-only proteins, including Bim and Bmf.	SIGNOR-250116	0.677
PRKCG	protein	P05129	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	phosphorylation	Ser1323	ALAPRSVsLKDKGRF	-1									11306676	t		lperfetto	These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels.	SIGNOR-249088	0.408
TXK	protein	P42681	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates	phosphorylation	Tyr113	SSFEEDDyESPNDDQ	9606	BTO:0000782								8892604	t		lperfetto	Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function	SIGNOR-44665	0.717
USP15	protein	Q9Y4E8	UNIPROT	BRAP	protein	Q7Z569	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0000007								23105109	t		miannu	Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. 	SIGNOR-272030	0.27
HLF	protein	Q16534	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606									23415677	f		miannu	Ectopic hlf expression inhibits apoptosis in murine and human cells, suggesting that hlf is regulating a conserved transcriptional program that inhibits cell death.	SIGNOR-201034	0.7
Non-structural protein 10	protein	P0C6X7-PRO_0000037317	UNIPROT	MT-ND4L	protein	P03901	UNIPROT	down-regulates activity	binding			9606	BTO:0000764								16157265	t		lperfetto	This result suggests that the nsp10 protein could affect the activities of NADH and cytochrome oxidase II via a direct interaction while being involved in viral replication.	SIGNOR-260253	0.2
KCNIP3	protein	Q9Y2W7	UNIPROT	PDYN	protein	P01213	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12667101	f		miannu	 As a transcriptional repressor, DREAM may control the expression of the endogenous opioid gene prodynorphin amongst others, and itself is exquisitely regulated by second messenger molecules, protein kinases and other transcription factors. 	SIGNOR-254540	0.363
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation			10029	BTO:0000246								15379552	t	inferred from 70% family members	lperfetto	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-270060	0.2
PTPN5	protein	P54829	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	down-regulates activity	dephosphorylation	Tyr1474	GSSNGHVyEKLSSIE	9606									19625523	t		lperfetto	In addition, STEP 61 dephosphorylates the tyr 1472 on the NR2B subunit of the NMDAR, which promotes internalization of the NMDAR complex.	SIGNOR-276991	0.564
FES	protein	P07332	UNIPROT	BCR	protein	P11274	UNIPROT	down-regulates	phosphorylation	Tyr279	PPLEYQPyQSIYVGG	9606	BTO:0000007								8955135	t		lperfetto	In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1.	SIGNOR-45334	0.375
PRKACA	protein	P17612	UNIPROT	PDE4D	protein	Q08499	UNIPROT	up-regulates	phosphorylation			9606									8663227	t		llicata	Phosphorylation and activation of a camp-specific phosphodiesterase by the camp-dependent protein kinase.	SIGNOR-42515	0.562
DEPTOR	protein	Q8TB45	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	down-regulates activity	binding			9606	BTO:0000007								19446321	t			DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival	SIGNOR-251658	0.718
HSD3B1	protein	P14060	UNIPROT	androst-4-ene-3,17-dione	smallmolecule	CHEBI:16422	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000056							2139411	t		lperfetto	The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione.	SIGNOR-268638	0.8
NEXMIF	protein	Q5QGS0	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				10116	BTO:0000938								27822498	f		miannu	The X-Linked Autism Protein KIAA2022/KIDLIA Regulates Neurite Outgrowth via N-Cadherin and δ-Catenin Signaling. We found that KIDLIA is distributed exclusively in the nucleus	SIGNOR-269659	0.7
MAP3K10	protein	Q02779	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates	phosphorylation	Ser379	AGAPGALsPSYDGGL	9606									19801649	t		llicata	Mlk2 inhibits e47 transactivation activity on the trkb promote	SIGNOR-161540	0.2
NatB 	complex	SIGNOR-C416	SIGNOR	Protein_acetylation	phenotype	SIGNOR-PH189	SIGNOR	up-regulates				9606									21351257	f		miannu	About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity.	SIGNOR-267232	0.7
BACH1	protein	O14867	UNIPROT	GAPDH	protein	P04406	UNIPROT	up-regulates quantity	transcriptional regulation			9606									31257027	t			BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells.	SIGNOR-259339	0.2
 Core Binding Factor complex	complex	SIGNOR-C214	SIGNOR	SPI1	protein	P17947	UNIPROT	up-regulates quantity by expression	methylation			10090	BTO:0002884								22012064	t		irozzo	Furthermore, we show that both MLL and AML1/CBFβ are required for maintaining the H3K4-me3 mark at the PU.1 upstream regulatory element (URE) and promoter region, and for full PU.1 gene expression.	SIGNOR-255875	0.53
acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	Fatty_Acid_Biosynthesis	phenotype	SIGNOR-PH190	SIGNOR	up-regulates activity				9606									10893421	f			Acetyl-CoA carboxylase (ACC) catalyzes the first committed step of the fatty acid synthetic pathway. Although ACC has often been proposed to be a major rate-controlling enzyme of this pathway, no direct tests of this proposal in vivo	SIGNOR-267383	0.7
cabozantinib	chemical	CHEBI:72317	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000184								26536165	t		miannu	Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. 	SIGNOR-262243	0.8
glycine	smallmolecule	CHEBI:15428	ChEBI	GLRA3	protein	O75311	UNIPROT	up-regulates activity	chemical activation			9606		BTO:0001175;BTO:0001279;BTO:0000146							18721822	t		miannu	The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. 	SIGNOR-264982	0.8
ABL2	protein	P42684	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates	phosphorylation	Tyr386	YRARVANyQRDGPMC	9606									12950161	t		lperfetto	C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases	SIGNOR-86684	0.345
GRIP1	protein	Q9Y3R0	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates	binding			9606									11062529	t		gcesareni	The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis.	SIGNOR-83883	0.377
STK4	protein	Q13043	UNIPROT	TNNI3	protein	P19429	UNIPROT	unknown	phosphorylation	Thr51	SRKLQLKtLLLQIAK	9606		BTO:0000671							18986304	t		llicata	Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143).	SIGNOR-182061	0.2
TFE3	protein	P19532	UNIPROT	CLCN7	protein	P51798	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276814	0.289
ZMYM2	protein	Q9UBW7	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates activity	binding			9606	BTO:0000599								32439918	t		miannu	Here we have identified the zinc-finger proteins ZMYM2 and ZMYM4 as novel B-MYB binding proteins. B-MYB has been implicated in cell cycle progression at two steps, namely at the G1/S- and the G2/M-transition. ZMYM2 is required for the G1/S-transition in HepG2 cells.	SIGNOR-269801	0.2
PRKCA	protein	P17252	UNIPROT	GRIA4	protein	P48058	UNIPROT	unknown	phosphorylation	Thr850	EAKRMKLtFSEAIRN	-1									10366608	t		lperfetto	In addition, we identified threonine 830 as a potential PKC phosphorylation site.	SIGNOR-249017	0.551
CSNK2A1	protein	P68400	UNIPROT	HCLS1	protein	P14317	UNIPROT	unknown	phosphorylation	Thr16	DVSVSVEtQGDDWDT	9606									10806407	t		llicata	 The in vivo Ser/Thr phosphorylation of HS1 is enhanced by okadaic acid and reduced by specific inhibitors of casein kinase (CK)2. In vitro, HS1 is an excellent substrate for either CK2 alpha subunit alone (Km = 47 nM) or CK2 holoenzyme | It is likely therefore that Thr16 and/or Thr23 account for the phosphate incorporated into HS1 threonyl residue(s) upon incubation with CK2.	SIGNOR-250885	0.311
NPY	protein	P01303	UNIPROT	NPY4R	protein	P50391	UNIPROT	up-regulates	binding			9606		BTO:0000142							7592911	t		gcesareni	Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid.	SIGNOR-29633	0.68
TP53	protein	P04637	UNIPROT	AIFM1	protein	O95831	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23506862	t		miannu	P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.	SIGNOR-267462	0.36
CLK2	protein	P49760	UNIPROT	PTPN1	protein	P18031	UNIPROT	up-regulates activity	phosphorylation	Ser242	MDKRKDPsSVDIKKV	-1									10480872	t		llicata	The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. 	SIGNOR-250775	0.327
ARHGAP15	protein	Q53QZ3	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260470	0.562
belinostat	chemical	CHEBI:61076	ChEBI	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257744	0.8
MAPK13	protein	O15264	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	down-regulates activity	phosphorylation	Thr1609	LGPYEAVtPLTKAAD	-1									24703952	t		lperfetto	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK 	SIGNOR-264449	0.2
CSNK2A1	protein	P68400	UNIPROT	PGR	protein	P06401	UNIPROT	unknown	phosphorylation	Ser81	TQDQQSLsDVEGAYS	-1									7983041	t		llicata	Although human PR contains 11 potential CKII consensus sequences, CKII in vitro phosphorylated purified PR-B only at Ser81 suggesting that this may be an authentic site for CKII in vivo.	SIGNOR-250926	0.358
RIMS1	protein	Q86UR5	UNIPROT	RAB3A	protein	P20336	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								31679900	t		miannu	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264381	0.799
GCG	protein	P01275	UNIPROT	GCGR	protein	P47871	UNIPROT	up-regulates	binding			9606	BTO:0000007								22863277	t		milica	In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function.	SIGNOR-198504	0.769
STUB1	protein	Q9UNE7	UNIPROT	PRKN	protein	O60260	UNIPROT	up-regulates activity	binding			-1									12150907	t		miannu	In this study, we found that CHIP promotes Parkin-mediated Pael-R ubiquitination and subsequent degradation. In vitro ubiquitination assays suggested that only a combination of both Parkin and its cofactor CHIP function as a ubiquitin ligase, which is able to sufficiently ubiquitinate Pael-R in vivo (Figure 6). 	SIGNOR-272888	0.2
EP300	protein	Q09472	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates	binding			9606			SIGNOR-C6						12419246	t		gcesareni	Thus, Ski/SnoN represses TGFβ signaling by multiple mechanisms. In addition to recruitment of a transcriptional repressor complex and dissociation of the transcriptional coactivator p300/CBP from the Smads	SIGNOR-95462	0.414
pizotifen	chemical	CHEBI:50212	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9205951	t		miannu	The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively.	SIGNOR-258617	0.8
FHIT	protein	P49789	UNIPROT	MMP14	protein	P50281	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18077326	f		miannu	In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin.	SIGNOR-159876	0.282
TLR9	protein	Q9NR96	UNIPROT	MYD88	protein	Q99836	UNIPROT	up-regulates activity	binding			10090									22664090	t		miannu	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266742	0.701
GYS2	protein	P54840	UNIPROT	UDP-alpha-D-glucose(2-)	chemical	CHEBI:58885	ChEBI	down-regulates quantity	chemical modification			9606									26882899	t		miannu	Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor.	SIGNOR-267937	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation	Ser301	SSSPNNLsPTGWSQP	9606									16407412	t		lperfetto	Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a.	SIGNOR-244685	0.2
PAK5	protein	Q9P286	UNIPROT	PAK5	protein	Q9P286	UNIPROT	up-regulates activity	phosphorylation	His22	SNFEHRVhTGFDPQE	-1									12860998	t		miannu	Active form of Cdc42, but not Rac1 and Rho, protein was able to activate the purified GST-Pak5 autophosphorylation and kinase activity. Mutations of Pak5, which disrupted the interaction of Cdc42 and Pak5, also abolished the induction of autophosphorylation.  The H19L/H22L mutant of Pak5 was insensitive to the Cdc42-induced autophosphorylation. 	SIGNOR-250249	0.2
vorinostat	chemical	CHEBI:45716	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257923	0.8
STAT3	protein	P40763	UNIPROT	S100A9	protein	P06702	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									18809714	f		miannu	Accumulation of myeloid-derived suppressor cells (MDSCs) associated with inhibition of dendritic cell (DC) differentiation is one of the major immunological abnormalities in cancer and leads to suppression of antitumor immune responses. The molecular mechanism of this phenomenon remains unclear. We report here that STAT3-inducible up-regulation of the myeloid-related protein S100A9 enhances MDSC production in cancer.	SIGNOR-261931	0.381
N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester	chemical	CHEBI:94306	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000785								31016515	t		Gianni	We explored the anti-tumor effect and the molecular mechanism of cay10603, a potent HDAC6 inhibitor in Burkitt's lymphoma cells.	SIGNOR-262205	0.8
NR1I2	protein	O75469	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000003								18540626	f		miannu	 Among approximately 40 kinds of phytochemicals, tangeretin and ginkgolides A and B markedly induced the PXR-dependent transcriptional activity and also the activity of the human MDR1 promoter. The expression levels of MDR1 mRNA as well as of CYP3A4 mRNA, another gene regulated by PXR, were significantly increased by these phytochemicals.	SIGNOR-254834	0.472
PPARGC1A	protein	Q9UBK2	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates				9606									19491292	f		gcesareni	Nuclear pgc-1alpha and foxo3a respond in a reciprocal manner following aicar treatment.	SIGNOR-252970	0.568
TGFBR1	protein	P36897	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	phosphorylation	Ser467	SVRCSSMs	9534									9346908	t		lperfetto	Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals.	SIGNOR-235995	0.819
TRIP12	protein	Q14669	UNIPROT	CDKN2A	protein	Q8N726	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								20208519	t		miannu	ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. 	SIGNOR-266781	0.601
PTPRF	protein	P10586	UNIPROT	DAPK1	protein	P53355	UNIPROT	up-regulates	dephosphorylation	Tyr491	CAAWHGYySVAKALC	9606									17803936	t		amattioni	Lar tyrosine phosphatase dephosphorylates dapk at py491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of dapk	SIGNOR-157706	0.2
MC1R	protein	Q01726	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256813	0.458
MSL1	protein	Q68DK7	UNIPROT	MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	form complex	binding			9606		BTO:0000567							16227571	t		miannu	We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. 	SIGNOR-263942	0.85
KAT2A	protein	Q92830	UNIPROT	H3Y2	protein	P0DPK5	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkATAWQAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269598	0.2
FBXW7	protein	Q969H0	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007						phosphorylation:Ser62	LLPTPPLsPSRRSGL	15103331	t		lperfetto	We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1	SIGNOR-249638	0.754
CDK1	protein	P06493	UNIPROT	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr234	SFKKQEKtPKTPKGP	9606									14670079	t		gcesareni	We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication.	SIGNOR-120330	0.534
HDAC1	protein	Q13547	UNIPROT	MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263839	0.815
PHKA2	protein	P46019	UNIPROT	PHKG1	protein	Q16816	UNIPROT	down-regulates activity	binding			9606									10487978	t			Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.	SIGNOR-267404	0.689
TERF2	protein	Q15554	UNIPROT	ATM	protein	Q13315	UNIPROT	down-regulates activity	binding						SIGNOR-C306						18680434	t		lperfetto	It is not yet clear how the presence of TRF2 at telomeres averts the activation of the ATM kinase.> In this regard, overexpression of TRF2can dampen the activation of the ATM kinase, even at nontelomeric sites of DNA damage (95). Furthermore, TRF2 can interact with the ATM kinase as well as with the Mre11 complex 	SIGNOR-263323	0.673
SB-705498	chemical	CID:9910486	PUBCHEM	TRPV1	protein	Q8NER1	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206826	0.8
JAK2	protein	O60674	UNIPROT	STAT1/STAT3	complex	SIGNOR-C118	SIGNOR	up-regulates activity	phosphorylation			9606									15526160	t		miannu	Downstream of JAKs are the signal transducers and activators of transcription (STATs), which are phosphorylated by JAKs. 	SIGNOR-254999	0.806
TRIM25	protein	Q14258	UNIPROT	KLF5	protein	Q13887	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0001538								21542805	t		miannu	 The oestrogen-inducible E3 ligase EFP (oestrogen-responsive finger protein) was identified as a key player in oestrogen-mediated degradation of KLF5, as knockdown and overexpression of EFP increased and decreased KLF5 protein levels respectively, and the decrease continued even when protein synthesis was blocked. 	SIGNOR-271908	0.495
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser694	QTSKRHDsDTFPELK	9606	BTO:0000150								20085797	t		lperfetto	We identify a novel akt phosphorylation site in brca1 at s694 which is responsive to activation of these signaling pathways. These data suggest akt phosphorylation of brca1 increases total protein expression by preventing proteasomal degradation	SIGNOR-244164	0.2
AKT3	protein	Q9Y243	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	phosphorylation	Ser196	KLRRRFSsLHFMVEV	9606									9812896	t		gcesareni	Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity	SIGNOR-61565	0.497
CSNK2A1	protein	P68400	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates	phosphorylation	Ser63	GILARRPsYRKILKD	9606									8663317	t		lperfetto	Camk ii phosphorylates only ser63 (corresponding to ser133 of creb), which is essential for the activation, and not ser72 (corresponding to ser142 of creb), which is a negative regulation site	SIGNOR-42565	0.3
PPP3CA	protein	Q08209	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates	dephosphorylation			9606	BTO:0000782								15276472	t		gcesareni	Once activated, calcineurin directly dephosphorylates members of the nuclear factor of activated t-cells (nfat) transcription factor family in the cytoplasm, promoting their translocation into the nucleus.	SIGNOR-127248	0.817
CBL	protein	P22681	UNIPROT	PDGFRA	protein	P16234	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									10347229	t		lperfetto	Cbl overexpression in nih3t3 cells enhanced the ubiquitination and degradation of the platelet-derived growth factor receptor-alpha (pdgfralpha)	SIGNOR-68024	0.467
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ZNF322	protein	Q6U7Q0	UNIPROT	up-regulates activity	phosphorylation	Thr150	LVHQRSHtGEKPYLC	9606	BTO:0002552								31399647	t		miannu	We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A.	SIGNOR-276754	0.2
SOX6	protein	P35712	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	binding			10090	BTO:0000011								26893351	t			SOX6 interacts with β-catenin in adipocytes, suggesting an inhibition of WNT/β-catenin signaling, thereby promoting adipogenesis.	SIGNOR-256073	0.64
TRIM21	protein	P19474	UNIPROT	TRIM5	protein	Q9C035	UNIPROT	up-regulates quantity	monoubiquitination			9606	BTO:0000567								18312418	t		miannu	Here, we show that TRIM5alpha functions as a RING-finger-type E3 ubiquitin ligase both in vitro and in vivo and ubiquitinates itself in cooperation with the E2 ubiquitin-conjugating enzyme UbcH5B. Thus, the ubiquitination of TRIM5alpha is catalyzed by itself and Ro52. Unexpectedly, although TRIM5alpha is ubiquitinated, our results have revealed that the proteasome inhibitors MG115 and MG132 do not stabilize it in HeLa cells, suggesting that the ubiquitination of TRIM5alpha does not lead to proteasomal degradation. Importantly, TRIM5alpha is clearly conjugated by a single ubiquitin molecule (monoubiquitination). Our monoubiquitin-fusion assay suggests that monoubiquitination is a signal for TRIM5alpha to translocate from cytoplasmic bodies to the cytoplasm.	SIGNOR-271672	0.35
SRC	protein	P12931	UNIPROT	CNKSR1	protein	Q969H4	UNIPROT	up-regulates activity	phosphorylation	Tyr519	PPREEDCySETEAED										26319181	t		lperfetto	We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. 	SIGNOR-275918	0.485
ADGRG1	protein	Q9Y653	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							31515243	t		lperfetto	Binding of collagen III to ADGRG1 provides a canonical example of adhesion GPCR interactions with ECM proteins (Luo et al., 2011). Identified by an in vitro biotinylation/proteomics approach, extracellular interactions with collagen III were subsequently proven capable of activating ADGRG1-mediated signaling via Gα12/13 followed by RhoA activation to regulate corticogenesis	SIGNOR-272345	0.2
BLOC-2	complex	SIGNOR-C252	SIGNOR	KIF13A	protein	Q9H1H9	UNIPROT	up-regulates activity	binding			9606									30404817	t		lperfetto	Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis.	SIGNOR-260702	0.26
2-N,6-N-Bis(2,3-dihydroxy-N-benzoyl)-L-serine amide	chemical	CHEBI:1219	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			-1									7576010	t		miannu	 D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole.	SIGNOR-258436	0.8
AURKA	protein	O14965	UNIPROT	NEDD1	protein	Q8NHV4	UNIPROT	up-regulates activity	phosphorylation	Ser405	FDDTGKSsLGDMFSP	9606	BTO:0001938								31028180	t		lperfetto	Microtubule nucleation during central spindle assembly requires NEDD1 phosphorylation on serine 405 by Aurora A| In the absence of Aurora A, the HURP (also known as DLGAP5) and NEDD1 proteins that are involved in nucleation of microtubules fail to concentrate in the midzone. 	SIGNOR-272965	0.539
PRKCA	protein	P17252	UNIPROT	INSR	protein	P06213	UNIPROT	unknown	phosphorylation	Ser1064	KTVNESAsLRERIEF	-1									7926007	t		lperfetto	Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites.	SIGNOR-248906	0.354
MAPK14	protein	Q16539	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606	BTO:0000093								11258706	t		lperfetto	P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.	SIGNOR-105737	0.765
CSNK2B	protein	P67870	UNIPROT	IKZF1	protein	Q13422	UNIPROT	down-regulates	phosphorylation	Ser101	GSHRDQGsSALSGVG	9606	BTO:0001271								21750978	t		miannu	We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway	SIGNOR-174840	0.2
CDK1	protein	P06493	UNIPROT	PPP1R13L	protein	Q8WUF5	UNIPROT	up-regulates activity	phosphorylation	Ser113	LHPYSPLsPKGRPSS	9606									30105797	t	done	miannu	Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53. 	SIGNOR-273586	0.52
TBK1	protein	Q9UHD2	UNIPROT	DDAH2	protein	O95865	UNIPROT	down-regulates activity	phosphorylation	Ser253	QEALQKLsDVTLVPV										33850055	t		lperfetto	TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o	SIGNOR-275646	0.2
ERCC2	protein	P18074	UNIPROT	TFIIH	complex	SIGNOR-C457	SIGNOR	form complex	binding			9606									30860024	t		lperfetto	Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 	SIGNOR-269312	0.865
HIPK2	protein	Q9H2X6	UNIPROT	ZBTB4	protein	Q9P1Z0	UNIPROT	down-regulates activity	phosphorylation	Thr797	ERPGGTPtPVIAYSK	-1									19448668	t		miannu	The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4.	SIGNOR-262881	0.387
PRKCG	protein	P05129	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates	phosphorylation	Ser42	AKKKSKIsASRKLQL	9606		BTO:0000887							15769444	t		lperfetto	Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.	SIGNOR-134632	0.2
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CDK2	protein	P24941	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258176	0.8
IRX1	protein	P78414	UNIPROT	UGT8	protein	Q16880	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed.	SIGNOR-261665	0.2
PIK-90	chemical	CID:6857685	PUBCHEM	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252653	0.8
PRDM1	protein	O75626	UNIPROT	FCER2	protein	P06734	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000776								11342629	f	 		In this study, we report that PRDI-BF1/Blimp1 can bind to the same functional element in the human CD23b promoter to which BCL-6 and IRF-4 had previously been shown to bind, and that, like BCL-6, Blimp1 can repress IRF-4-transactivating ability	SIGNOR-253926	0.259
BMPR1A	protein	P36894	UNIPROT	BMPR2	protein	Q13873	UNIPROT	up-regulates	binding			10090									10712517	t		gcesareni	Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors	SIGNOR-75652	0.615
CDON	protein	Q4KMG0	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	unknown	binding			10090	BTO:0000165;BTO:0000222;BTO:0002181		SIGNOR-C21						22337877	t		lperfetto	Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts	SIGNOR-235551	0.2
TGFBR1	protein	P36897	UNIPROT	SPTBN1	protein	Q01082	UNIPROT	up-regulates	phosphorylation			9606									12543979	t		gcesareni	This suggests that, upon stimulation with tgf-beta1, phosphorylation of elf could induce a conformational change that reduces its affinity for ankyrin and tropomyosin and facilitates an association with smad3 and smad4 instead.	SIGNOR-97626	0.501
ITGB1BP1	protein	O14713	UNIPROT	Av/b6 integrin	complex	SIGNOR-C179	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257663	0.272
SETDB1	protein	Q15047	UNIPROT	SETDB1/NLK/CHD7	complex	SIGNOR-C189	SIGNOR	form complex	binding			10090									21952300	t		FFerrentino	The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43.	SIGNOR-253522	0.528
PARP1	protein	P09874	UNIPROT	THBD	protein	P07204	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001289								21489980	f		miannu	Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells. We propose that methylation of the TM promoter is responsible for silencing of TM expression in MM tissue, a process that is regulated by PARP1.	SIGNOR-254893	0.2
CAMK2G	protein	Q13555	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity	phosphorylation	Thr642	RSVKRNStVDCNGVV	9606	BTO:0000938								32611770	t		lperfetto	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275795	0.274
CABIN1	protein	Q9Y6J0	UNIPROT	MEF2D	protein	Q14814	UNIPROT	down-regulates				9606									17172641	f		gcesareni	Thus, cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress mef2 transcriptional activity.	SIGNOR-151208	0.788
NFATC2	protein	Q13469	UNIPROT	NF90-NF45	complex	SIGNOR-C443	SIGNOR	up-regulates activity	binding			9606	BTO:0000782								33555115	t		miannu	Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2-like sequences in rDNA promoter upon T-cell activation in vitro. NF45/NF90‐mediated rDNA transcription contributes to T‐cell activation by interacting with NFATc2 in the nucleolus	SIGNOR-268492	0.254
1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates				9606									18593525	f		gcesareni	Dag and ip3 initiate further signal transduction pathways through activation of protein kinase c (pkc) and intracellular calcium release.	SIGNOR-179288	0.8
TGFB1	protein	P01137	UNIPROT	TFAP4	protein	Q01664	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000452								21228219	f		miannu	TGFβ effectively inhibits expression of SALL2 and its regulator AP4 when added to quiescent fibroblasts. 	SIGNOR-255428	0.2
PTPRJ	protein	Q12913	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	dephosphorylation			9606									25386896	t		lperfetto	Our data demonstrate that CD148 promotes E-cadherin cell adhesion by regulating Rac1 activity, concomitant with modulation of p120, \u03b2-catenin, and Src tyrosine phosphorylation, and that this effect requires E-cadherin and p120 association.|Taken together, it is likely that CD148 dephosphorylation of \u03b2-catenin enhances the cadherin cell adhesion independent of Rho family GTPases.	SIGNOR-276992	0.497
MEF2C	protein	Q06413	UNIPROT	CPT1B	protein	Q92523	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000167								15356291	f		miannu	 Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1beta promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1beta gene promoter by MEF2C and PPARalpha-RXRalpha, a precise arrangement of its binding sites was essential.	SIGNOR-254583	0.2
AP-2 complex	complex	SIGNOR-C245	SIGNOR	DAB2	protein	P98082	UNIPROT	up-regulates activity	binding			9606	BTO:0004784; BTO:0000567								11247302	t		Giorgia	Dab2 is alternatively spliced and its localization depends on a region of the protein that contains two DPF motifs that are present in the p96 Dab2 protein and absent in the p67 splice variant. This region is sufficient to confer Dab2 binding to the alpha‐adaptin subunit of the clathrin adaptor protein, AP‐2.|These findings suggest that in addition to previously reported signal-transduction functions, Dab2 could also act as an adaptor protein that may regulate protein trafficking.	SIGNOR-260391	0.49
ULK1	protein	O75385	UNIPROT	HK1	protein	P19367	UNIPROT	up-regulates activity	phosphorylation	Ser124	NIVHGSGsQLFDHVA	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274034	0.26
HCK	protein	P08631	UNIPROT	ADAM15	protein	Q13444	UNIPROT	up-regulates	phosphorylation	Tyr735	LKGPTCQyRAAQSGP	9606	BTO:0000661								11741929	t		lperfetto	Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling.	SIGNOR-112923	0.362
Host translation inhibitor nsp1	protein	P0DTD1-PRO_0000449619	UNIPROT	RPS3	protein	P23396	UNIPROT	down-regulates activity	binding			-1									33188728	t		miannu	Nsp1 Locks the 40S in a Conformation Incompatible with mRNA Loading and Disrupts Initiation Factor Binding. Molecular interactions between C-Nsp1 and 40S ribosome components, including uS3, h18, and uS5. 	SIGNOR-262507	0.2
PPM1A	protein	P35813	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates	dephosphorylation			9606				SIGNOR-C110					10644691	t		acerquone	Pp2c utilizes axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that pp2c is a positive regulator of wnt signal transduction and mediates its effects through the dephosphorylation of axin.	SIGNOR-74231	0.446
UBE2T	protein	Q9NPD8	UNIPROT	FANCL	protein	Q9NW38	UNIPROT	up-regulates activity	ubiquitination			-1									24389026	t		lperfetto	Using the Fanconi Anemia pathway exclusive E3-E2 pair, FANCL-Ube2T, we report the atomic structure of the FANCL RING-Ube2T complex|Our structural and biochemical analyses suggest that, in a cellular environment with multiple E2s present, FANCL will preferentially select Ube2T.	SIGNOR-263263	0.898
ATM	protein	Q13315	UNIPROT	NHEJ1	protein	Q9H9Q4	UNIPROT	unknown	phosphorylation	Ser251	ASLQGIDsQCVNQPE	9606									18644470	t		lperfetto	Here, we have identified two major in vitro dna-pk phosphorylation sites in the c-terminal region of xlf, serines 245 and 251. We show that these represent the major phosphorylation sites in xlf in vivo and that serine 245 is phosphorylated in vivo by dna-pk, while serine 251 is phosphorylated by ataxia-telangiectasia mutated (atm).	SIGNOR-179528	0.574
SRC	protein	P12931	UNIPROT	CHRNA7	protein	P36544	UNIPROT	down-regulates	phosphorylation	Tyr386	ASNGNLLyIGFRGLD	9606									16251431	t		gcesareni	?7 Neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and src-family kinases	SIGNOR-141307	0.2
AKT1	protein	P31749	UNIPROT	NHEJ1	protein	Q9H9Q4	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr181	LIRDRLKtEPFEENS	9606	BTO:0000567								25661488	t		miannu	Akt1 phosphorylates XLF at T181 Here, we report that Akt phosphorylates XLF at Thr181 to trigger its dissociation from the DNA ligase IV/XRCC4 complex, and promotes its interaction with 14-3-3β leading to XLF cytoplasmic retention, where cytosolic XLF is subsequently degraded by SCF(β-TRCP) in a CKI-dependent manner. 	SIGNOR-276881	0.367
AURKA	protein	O14965	UNIPROT	SKI	protein	P12755	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser326	RRVPRVSsEPPASIR	-1									26138431	t		miannu	Here we show that AURKA phosphorylates in vitro the transcripcional co-repressor Ski on aminoacids Ser326 and Ser383. Phosphorylations on these aminoacids decreased Ski protein half-life	SIGNOR-276918	0.2
HTR2B	protein	P41595	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256886	0.268
cortisol	smallmolecule	CHEBI:17650	ChEBI	NR3C2	protein	P08235	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								8282004	t		miannu	The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4).	SIGNOR-258707	0.8
ADCY9	protein	O60503	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates quantity	chemical modification			9606									15385642	t		miannu	Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions.	SIGNOR-265005	0.8
KDM5B	protein	Q9UGL1	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264302	0.2
AURKA	protein	O14965	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	phosphorylation	Ser380	ATLARRDsLQKPGLE	9606									21822051	t		lperfetto	In the present study, aurora a was demonstrated to phosphorylate lats2 on serine 380 (s380) during mitosistogether, the results suggest that the aurora a-lats1/2-aurora b axis might be a novel pathway that regulates accurate mitotic progression by ensuring the proper mitotic localization of lats2.	SIGNOR-175939	0.388
ULK2	protein	Q8IYT8	UNIPROT	ENO1	protein	P06733	UNIPROT	down-regulates activity	phosphorylation	Ser282	QLADLYKsFIKDYPV	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274037	0.2
ABL1	protein	P00519	UNIPROT	CRK	protein	P46108	UNIPROT	down-regulates activity	phosphorylation	Tyr221	GGPEPGPyAQPSVNT	9606									21602891	t		lperfetto	Abl induces phosphorylation at y251 in vivo, and that the kinetics of phosphorylation at y251 and the negative regulatory y221 site in vitro are similar.	SIGNOR-173845	0.752
CBP/p300	complex	SIGNOR-C6	SIGNOR	MYOD1	protein	P15172	UNIPROT	up-regulates	acetylation			9606		BTO:0000887							10944526	t		lperfetto	Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.	SIGNOR-217220	0.633
GRK2	protein	P25098	UNIPROT	SMO	protein	Q99835	UNIPROT	up-regulates	phosphorylation			9606									21695114	t		gcesareni	We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins	SIGNOR-174539	0.2
CSNK1D	protein	P48730	UNIPROT	PPP5C	protein	P53041	UNIPROT	up-regulates activity	phosphorylation	Thr362	LFSEDGVtLDDIRKI	9606	BTO:0000007								29141220	t		miannu	 Here, we show an "on/off switch" mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90. 	SIGNOR-277373	0.34
KAT6A	protein	Q92794	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates	binding			9606			SIGNOR-C54						11742995	t		miannu	The activation domain of aml1 is required for its interaction with moz / moz activates aml1_mediated transcription	SIGNOR-113056	0.477
KAT2A	protein	Q92830	UNIPROT	H3-5	protein	Q6NXT2	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269608	0.2
PRKCB	protein	P05771	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser25	QAFELILsPRSKESV	9606									9271428	t		gcesareni	Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation.	SIGNOR-50594	0.2
NDUFB11	protein	Q9NX14	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4	SIGNOR-262164	0.738
PRKCG	protein	P05129	UNIPROT	VTN	protein	P04004	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser381	RNRKGYRsQRGHSRG	-1									9030777	t		lperfetto	Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin.	SIGNOR-248964	0.288
ARRB2	protein	P32121	UNIPROT	INPP5D	protein	Q92835	UNIPROT	up-regulates activity	binding			9606									24817116	t		lperfetto	We identified a new adaptor beta-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells.	SIGNOR-261428	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									24743741	f			Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases.	SIGNOR-254374	0.7
RPS6KA5	protein	O75582	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates	phosphorylation	Ser119	EILSRRPsYRKILND	9606	BTO:0000567								9687510	t		lperfetto	Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb.	SIGNOR-59458	0.721
BAD	protein	Q92934	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								15694340	t		lperfetto	Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2	SIGNOR-133759	0.841
GEM	protein	P55040	UNIPROT	ROCK2	protein	O75116	UNIPROT	down-regulates activity	binding			9534	BTO:0000298								16757346	t		miannu	We have found that Gem binds specifically to ROKβ in the coiled‐coil domain adjacent to the Rho binding site. The interaction between Gem and ROKβ leads to inhibition of MLC and MBS phosphorylation but not phosphorylation of LIMK, indicating that Gem exerts its effect by altering the substrate specificity of ROKβ	SIGNOR-261717	0.294
RB1	protein	P06400	UNIPROT	Cell_cycle_progress 	phenotype	SIGNOR-PH42	SIGNOR	down-regulates				9606									21524151	f		lperfetto	Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time.	SIGNOR-267284	0.7
ANK3	protein	Q12955	UNIPROT	GABARAP	protein	O95166	UNIPROT	up-regulates activity	binding			10090	BTO:0003102								30504823	t		miannu	Importantly, the 480 kDa ankyrin-G isoform has also been shown to stabilize GABAergic synapses on the soma and AIS of excitatory pyramidal neurons by interacting with the GABAA receptor-associated protein (GABARAP) to inhibit GABAA receptor endocytosis	SIGNOR-266709	0.454
DYRK2	protein	Q92630	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser527	QDIDSRLsPGGSLAD	9606	BTO:0000007								26407194	t		miannu	 We further found that DYRK2 phosphorylated Ser527 of TBK1, which is essential for the recruitment of NLRP4 and for the E3 ubiquitin ligase DTX4 to degrade TBK1. 	SIGNOR-276939	0.422
RAD50	protein	Q92878	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates	binding			9606									21763684	t		gcesareni	One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase.	SIGNOR-175053	0.806
bis(2-ethylhexyl) phthalate	chemical	CHEBI:17747	ChEBI	HCAR2	protein	Q8TDS4	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). 	SIGNOR-268772	0.8
MAP3K8	protein	P41279	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000007								15466476	t		lperfetto	Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases.	SIGNOR-244904	0.556
INSR	protein	P06213	UNIPROT	CALM1	protein	P0DP23	UNIPROT	down-regulates	phosphorylation	Tyr100	FDKDGNGyISAAELR	9606									3415247	t		lperfetto	The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.	SIGNOR-24782	0.412
TGFB2	protein	P61812	UNIPROT	TGFBR3	protein	Q03167	UNIPROT	up-regulates	binding			9606									10746731	t		gcesareni	Betaglycan binds tgf-b isoforms with high affinity and increases the functional interaction between tgf-b and its type ii and type i signalling receptors.	SIGNOR-76473	0.533
EGR2	protein	P11161	UNIPROT	GFI1	protein	Q99684	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									16923394	f		miannu	Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene.	SIGNOR-256041	0.315
AURKA	protein	O14965	UNIPROT	SKI	protein	P12755	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser383	LSAFRPWsPAVSASE	-1									26138431	t		miannu	Here we show that AURKA phosphorylates in vitro the transcripcional co-repressor Ski on aminoacids Ser326 and Ser383. Phosphorylations on these aminoacids decreased Ski protein half-life	SIGNOR-276917	0.2
calcitriol	smallmolecule	CHEBI:17823	ChEBI	propan-2-ol	smallmolecule	CHEBI:17824	ChEBI	up-regulates quantity	precursor of												30080183	t		lperfetto	Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH).	SIGNOR-270573	0.8
HECTD3	protein	Q5T447	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								28636940	t		miannu	 By western blot, we observed robust degradation of endogenous native CRAF in untransformed HEK293 cells treated with control siRNA 24 hr after the addition of AUY922, but this was substantially reduced in cells in which HECTD3 was knocked down, confirming that endogenous CRAF is a bona fide degradation target of HECTD3 	SIGNOR-272328	0.2
PRKCD	protein	Q05655	UNIPROT	TBL1XR1	protein	Q9BZK7	UNIPROT	up-regulates activity	phosphorylation	Ser123	AAASQQGsAKNGENT	9606									18374649	t		Manara	In addition, we describe that the functions and the specificity of these two highly- related exchange factors is tightly regulated by signal-induced phosphorylation events at the level of target gene promoters, as exemplified by the role of TBLR1 phosphorylation at Ser 123 by PKCδ upon retinoic acid or estrogen stimulation.	SIGNOR-260903	0.2
GATA3	protein	P23771	UNIPROT	T-lymphocyte_diff	phenotype	SIGNOR-PH112	SIGNOR	up-regulates activity				10090									22267605	f			Transcription factor GATA-3 is known to be vital for the development of T cells at multiple stages in the thymus and for Th2 differentiation in the peripheral organs	SIGNOR-259953	0.7
WNK4	protein	Q96J92	UNIPROT	STK39	protein	Q9UEW8	UNIPROT	up-regulates activity	phosphorylation	Ser371	VRRVPGSsGHLHKTE										16990453	t		lperfetto	Vitari et al. (76) and Moriguchi et al. (52) demonstrated that WNK4 bound and phosphorylated PASK at Thr-233 and Ser-373 in mammalian cells.| this phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1	SIGNOR-264641	0.521
SRC	protein	P12931	UNIPROT	CLTC	protein	Q00610	UNIPROT	up-regulates	phosphorylation	Tyr1477	LFITEEDyQALRTSI	9606									10089883	t		gcesareni	Egf-mediated clathrin phosphorylation is followed by clathrin redistribution to the cell periphery and is the product of downstream activation of src kinase by egf receptor (egfr) signaling	SIGNOR-65714	0.416
NUMB	protein	P49757	UNIPROT	ITCH	protein	Q96J02	UNIPROT	up-regulates	binding			9606									20818436	t		gcesareni	Numb activates the catalytic activity of itch, releasing it from an inhibitory intramolecular interaction between its homologous to e6-ap c-terminus and ww domains.	SIGNOR-167844	0.598
MLLT10	protein	P55197	UNIPROT	SS18/MLLT10	complex	SIGNOR-C75	SIGNOR	form complex	binding			9606									11423977	t		miannu	Based on these results, a model is proposed in which the syt and af10 proteins act in concert as bipartite transcription factors	SIGNOR-108924	0.437
CDK1	protein	P06493	UNIPROT	MAP4	protein	P27816	UNIPROT	unknown	phosphorylation	Ser696	PNKELPPsPEKKTKP	9606	BTO:0000567								10791892	t		miannu	We have shown that MAP4 is phosphorylated in vivo in mitotic HeLa cells at eight sites. Five of these were phosphorylated by p34cdc2 kinase. Two of the five p34cdc2 kinase phosphorylation sites were shown to be Ser696 and Ser787 in the proline-rich region	SIGNOR-277461	0.512
PIN1	protein	Q13526	UNIPROT	IFNB1	protein	P01574	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								16699525	t		lperfetto	To investigate the temporal regulation of IRF3-dependent transcription by Pin1, we used a rapid-response luciferase reporter gene. Real-time reporter gene assays showed that suppression of endogenous Pin1 expression substantially prolonged both IRF3-dependent transcription and IFN-beta promoter activation after poly(I)dotpoly(C) stimulation (Fig. 4c,d). Consistent with the inhibitory effects of Pin1 on the IFN-beta promoter	SIGNOR-252289	0.2
GRK4	protein	P32298	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser373	SMGTLRTsISVERQI	9606	BTO:0000007								11517230	t			Expression of GRK4α drastically increased the basal level of32P incorporation into B2R. GRK4α elevated the basal phosphorylation of Ser339 and Ser346/Ser348. phosphorylation of specific residues was correlated with the initiation of receptor internalization and the regulation of its desensitization.	SIGNOR-251193	0.292
glycine	smallmolecule	CHEBI:15428	ChEBI	N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-)	smallmolecule	CHEBI:143788	ChEBI	up-regulates quantity	precursor of			9606									34283828	t		miannu	In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR).	SIGNOR-267297	0.8
CDC42	protein	P60953	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity				9606									18976935	f		lperfetto	Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner. 	SIGNOR-253370	0.28
CALM3	protein	P0DP25	UNIPROT	PPP3CA	protein	Q08209	UNIPROT	up-regulates	binding			9606									11796223	t		miannu	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-266343	0.644
EP300	protein	Q09472	UNIPROT	PLAG1	protein	Q6DJT9	UNIPROT	up-regulates	acetylation			9606									16207715	t		miannu	Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.	SIGNOR-140915	0.314
HTR2C	protein	P28335	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256877	0.284
PTEN	protein	P60484	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity				9606	BTO:0001332								19903340	f		lperfetto	PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression	SIGNOR-244439	0.656
4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid	chemical	CHEBI:125628	ChEBI	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194527	0.8
citrate(3-)	smallmolecule	CHEBI:16947	ChEBI	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	up-regulates quantity	precursor of			9606									19286649	t		miannu	ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor.	SIGNOR-267100	0.8
MAPK3	protein	P27361	UNIPROT	CAD	protein	P27708	UNIPROT	up-regulates	phosphorylation	Thr456	KVYFLPItPHYVTQV	9606									15890648	t		lperfetto	Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol	SIGNOR-137179	0.2
SRC	protein	P12931	UNIPROT	RHOU	protein	Q7L0Q8	UNIPROT	down-regulates activity	phosphorylation	Tyr254	SKSWWKKyCCFV	9606	BTO:0002552								20547754	t		miannu	Regulation of the Rho family small GTPase Wrch-1/RhoU by C-terminal tyrosine phosphorylation requires Src. Phosphorylation at Y254 negatively regulates Wrch-1-mediated biological functions.Serum-stimulated tyrosine phosphorylation and relocalization of Wrch-1 decreases its activation of downstream effectors in a Y254-dependent manner.	SIGNOR-259814	0.536
amitriptyline	chemical	CHEBI:2666	ChEBI	CHRM2	protein	P08172	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8100134	t		miannu	Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 	SIGNOR-258700	0.8
MAPK1	protein	P28482	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates				9606									18481201	f		gcesareni	In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation.	SIGNOR-178639	0.488
RPS6KB1	protein	P23443	UNIPROT	LTC4S	protein	Q16873	UNIPROT	down-regulates activity	phosphorylation	Ser36	ARRAFRVsPPLTTGP	-1									27365393	t		miannu	Here, we identified Ser(36) as the major p70S6k phosphorylation site, along with a low frequency site at Thr(40), using an in vitro phosphorylation assay combined with mass spectrometry. Cellular LTC4S activity is suppressed by PKC-mediated phosphorylation, and recently a downstream p70S6k was shown to play an important role in this process. 	SIGNOR-277256	0.2
MDM2	protein	Q00987	UNIPROT	DYRK2	protein	Q92630	UNIPROT	down-regulates quantity by destabilization	ubiquitination												19965871	t		lperfetto	Under normal conditions, nuclear and not cytoplasmic DYRK2 is ubiquitinated by MDM2, resulting in its constitutive degradation.|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. 	SIGNOR-275579	0.551
metaproterenol	chemical	CHEBI:6792	ChEBI	ADRB1	protein	P08588	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)	SIGNOR-257873	0.8
PRKCA	protein	P17252	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation	Thr174	KVPVTHEtQEECLGM	-1									27368100	t		miannu	These results suggest that PKC activates JAK2 and thereby STAT3 by directly phosphorylating T174 and S518. 	SIGNOR-277262	0.262
SGI-1776	chemical	CID:24795070	PUBCHEM	PIM	proteinfamily	SIGNOR-PF34	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-259435	0.8
RPS6KB1	protein	P23443	UNIPROT	PIP5K1C	protein	O60331	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr553	QPRYRRRtQSSGQDG										27780861	t		miannu	Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. These data suggest that S6K1-mediated PIPKIγ90 phosphorylation regulates cell migration and invasion by controlling PIPKIγ90 degradation.	SIGNOR-277282	0.2
RAPGEF5	protein	Q92565	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183735	0.414
PRKDC	protein	P78527	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates activity	phosphorylation	Thr2609	LTPMFVEtQASQGTL	9606									12186630	t		lperfetto	 We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function.	SIGNOR-249154	0.2
RIPK1	protein	Q13546	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates activity	phosphorylation	Ser970	HSQCLNSsPLSHHSQ	9606									11369754	t		lperfetto	These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994.	SIGNOR-108257	0.431
PAICS	protein	P22234	UNIPROT	5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-)	smallmolecule	CHEBI:77657	ChEBI	up-regulates quantity	chemical modification			9606									33179964	t		miannu	The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS).	SIGNOR-267318	0.8
prednisolone	chemical	CHEBI:8378	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									8335191	t	Crohn's Disease	gcesareni		SIGNOR-251701	0.8
perfluorohexanesulfonic acid	chemical	CHEBI:132448	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			-1									23764977	t		miannu	Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. 	SIGNOR-268761	0.8
FYN	protein	P06241	UNIPROT	PRKCQ	protein	Q04759	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000782								10383400	t		miannu	Further indications of direct interaction are that p59fyn potentiates ?PKC Catalytic activity and that ?PKC Is a substrate for tyrosine phosphorylation by p59fyn.	SIGNOR-68798	0.351
HCK	protein	P08631	UNIPROT	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	up-regulates	phosphorylation	Tyr177	ADAEKPFyVNVEFHH	9606									9407116	t		lperfetto	The src family kinase hck interacts with bcr-abl by a kinase-independent mechanism and phosphorylates the grb2-binding site of bcr	SIGNOR-53964	0.2
AKT1	protein	P31749	UNIPROT	GAB2	protein	Q9UQC2	UNIPROT	down-regulates	phosphorylation	Ser159	LLRERKSsAPSHSSQ	9606									11782427	t		lperfetto	Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation.	SIGNOR-252468	0.688
RHOH	protein	Q15669	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	binding			9606	BTO:0000661								17028588	t		irozzo	These findings suggest that RhoH is a critical regulator of thymocyte development and TCR signaling by mediating recruitment and activation of Zap70.	SIGNOR-259084	0.472
NR1H4	protein	Q96RI1	UNIPROT	ABCB4	protein	P21439	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000575								14527955	f		miannu	Here we show that the MDR3 gene is trans-activated by the farnesoid X receptor (FXR) via a direct binding of FXR/retinoid X receptor alpha heterodimers to a highly conserved inverted repeat element (a FXR response element) at the distal promoter (-1970 to -1958).	SIGNOR-254833	0.428
PRKACA	protein	P17612	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1100	QGCRRRHsSETFSST	9606									17360977	t		lperfetto	Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223	SIGNOR-235675	0.2
CBL	protein	P22681	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			10090	BTO:0000944								10347229	t		miannu	 Overexpression of wild type Cbl in NIH3T3 cells led to an enhancement of the ligand-dependent ubiquitination and subsequent degradation of the PDGFRbeta, as observed with PDGFRalpha.	SIGNOR-272549	0.612
bremazocine	chemical	CHEBI:3171	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258778	0.8
JAK2	protein	O60674	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates	phosphorylation												7888666	t		apalma	We found that IL-5 induced two GAS-binding proteins in the nuclear extract from eosinophils. One of them was identified as STAT1 (p91).	SIGNOR-255071	0.8
cysteine	smallmolecule	CHEBI:15356	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264759	0.7
CSNK2A1	protein	P68400	UNIPROT	AQP4	protein	P55087	UNIPROT	down-regulates activity	phosphorylation	Ser276	AAQQTKGsYMEVEDN	9615	BTO:0000837								11742978	t		llicata	We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4-Cter proteins in which only one out of the three C-terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. 	SIGNOR-250826	0.426
NUP88	protein	Q99567	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262076	0.618
GRB10	protein	Q13322	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			10090	BTO:0001516								23246379	t			Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation	SIGNOR-255946	0.34
SPDYA	protein	Q5MJ70	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000007								33015044	t		lperfetto	Speedy/RINGO A, a noncanonical activator of CDK2, was recently identified as a key regulator for CDK2 recruitment to meiotic telomeres	SIGNOR-263310	0.786
chlorphenamine	chemical	CHEBI:52010	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									12781173	t		Luana	Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine.	SIGNOR-257896	0.8
USP1	protein	O94782	UNIPROT	FANCI	protein	Q9NVI1	UNIPROT	down-regulates activity	deubiquitination							SIGNOR-C302					18985065	t		lperfetto	Phosphorylation of FANCI may also turn the ubiquitinated ID complex into a poor substrate for deubiquitination by the USP1–UAF1 complex, resulting in increased levels of monoubiquitinated FANCD2.	SIGNOR-263272	0.654
STAT3	protein	P40763	UNIPROT	STAT1/STAT3	complex	SIGNOR-C118	SIGNOR	form complex	binding			10090	BTO:0000667								15284024	t		lperfetto	Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min.	SIGNOR-235664	0.596
NEK6	protein	Q9HC98	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Ser53	EGGQLNEsMDHGGVG	-1									12023960	t		miannu	Here we demonstrate that in addition to phosphorylating S6K1 and SGK1 at their hydrophobic motif, NEK6 also phosphorylates S6K1 at two other sites and phosphorylates SGK1 at one other site in vitro. Analysis of the peptides phosphorylated by NEK6 (Fig 2), performed in the present study has confirmed this, and identified two novel sites on S6K1 (Ser53 and Ser403) as major sites of NEK6 phosphorylation.	SIGNOR-262952	0.375
PRSS21	protein	Q9Y6M0	UNIPROT	RAD21	protein	O60216	UNIPROT	up-regulates	cleavage			9606									11875078	t		miannu	Rad21 is a component of the cohesin complex that holds sister chromatids together during mitosis and repairs double-strand dna breaks. Interestingly, rad21 is cleaved by a caspase-like esp1/separase at the onset of anaphase to trigger sister chromatid separation.	SIGNOR-115426	0.2
ARNTL	protein	O00327	UNIPROT	MAGEL2	protein	Q9UJ55	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								22208286	t		miannu	Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization.	SIGNOR-253517	0.378
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	MAPT	protein	P10636	UNIPROT	up-regulates	dephosphorylation	Ser721	PVVSGDTsPRHLSNV	9606		BTO:0000142							20308788	t	The effect has been demonstrated using P10636-8	lperfetto	Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro.	SIGNOR-164667	0.2
RPS6KA5	protein	O75582	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates activity	phosphorylation	Ser63	GILARRPsYRKILKD	10090	BTO:0000452								11909979	t		lperfetto	Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts 	SIGNOR-249144	0.678
PRKACA	protein	P17612	UNIPROT	NFKB1	protein	P19838	UNIPROT	up-regulates	phosphorylation	Ser337	FVQLRRKsDLETSEP	9606				SIGNOR-C13					17959673	t		llicata	In this study, we demonstrate that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase a (pkac) is essential for nf-kappab dna binding and transactivation activity. treatment with h89 and knockdown of pkac in cells led to the inhibition of phosphorylation at p50 ser(337) and p65 ser(276) and loss of dna binding by nf-kappab.	SIGNOR-158595	0.487
(6R)-5,10-methylenetetrahydrofolate(2-)	smallmolecule	CHEBI:15636	ChEBI	(6R)-5,10-methenyltetrahydrofolate	smallmolecule	CHEBI:57455	ChEBI	up-regulates quantity	precursor of			9606									18767138	t		lperfetto	Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate	SIGNOR-268246	0.8
GALR3	protein	O60755	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256862	0.425
USF1	protein	P22415	UNIPROT	POMC	protein	P01189	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19389701	f		gcesareni	Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes	SIGNOR-185575	0.25
LPAR4	protein	Q99677	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257170	0.2
PFKFB4	protein	Q16877	UNIPROT	beta-D-fructofuranose 2,6-bisphosphate	smallmolecule	CHEBI:28602	ChEBI	down-regulates quantity	chemical modification			-1									30553771	t			PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species	SIGNOR-267272	0.8
SNAI1	protein	O95863	UNIPROT	HPGD	protein	P15428	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									19010907	f	 	miannu	 We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression. 	SIGNOR-254237	0.295
L-arginine	chemical	CHEBI:16467	ChEBI	SLC38A9	protein	Q8NBW4	UNIPROT	up-regulates activity	chemical activation			9606									29053970	t			SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins	SIGNOR-254895	0.8
ZNRF3	protein	Q9ULT6	UNIPROT	FZD2	protein	Q14332	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								22575959	t		gcesareni	Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6	SIGNOR-197414	0.297
POT1	protein	Q9NUX5	UNIPROT	TERT	protein	O14746	UNIPROT	up-regulates	binding			9606									17237768	t		miannu	We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme.	SIGNOR-152327	0.675
pirenzepine	chemical	CHEBI:8247	ChEBI	CHRM1	protein	P11229	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								2704370	t		miannu	In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 	SIGNOR-258394	0.8
F10	protein	P00742	UNIPROT	F2	protein	P00734	UNIPROT	up-regulates activity	cleavage			10090		BTO:0000131							25769543	t		lperfetto	The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin.	SIGNOR-263539	0.436
GRK5	protein	P34947	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser375	GTLRTSIsVERQIHK	9606	BTO:0000007								11517230	t			Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251209	0.466
SAE1	protein	Q9UBE0	UNIPROT	SAE1/SAE2 complex	complex	SIGNOR-C294	SIGNOR	form complex	binding			-1									15660128	t		lperfetto	E1 enzymes facilitate conjugation of ubiquitin and ubiquitin-like proteins through adenylation, thioester transfer within E1, and thioester transfer from E1 to E2 conjugating proteins. Structures of human heterodimeric Sae1/Sae2-Mg.ATP and Sae1/Sae2-SUMO-1-Mg.ATP complexes were determined at 2.2 and 2.75 A resolution, respectively.	SIGNOR-263003	0.815
PAH	protein	P00439	UNIPROT	phenylalanine	smallmolecule	CHEBI:28044	ChEBI	down-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors	SIGNOR-263988	0.8
CDT1	protein	Q9H211	UNIPROT	CDT1	protein	Q9H211	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								14672932	t			We further show that Cdc6 physically associates with Cdt1 via its N-terminal noncatalytic domain, a region we had previously shown to be essential for Cdc6 function.	SIGNOR-261682	0.2
ATM	protein	Q13315	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Ser50	TSTMPNSsQSSHSSS	9606	BTO:0000007								10973490	t		lperfetto	Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to iratm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro.	SIGNOR-81407	0.83
DYRK2	protein	Q92630	UNIPROT	SIAH2	protein	O43255	UNIPROT	up-regulates	phosphorylation	Thr26	PPPQPQHtPSPAAPP	9606									22878263	t		llicata	In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis.	SIGNOR-198737	0.42
PRKCG	protein	P05129	UNIPROT	GRK2	protein	P25098	UNIPROT	up-regulates activity	phosphorylation	Ser29	ATPAARAsKKILLPE	9606	BTO:0000007								11042191	t		lperfetto	Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells. 	SIGNOR-249060	0.2
BRAF	protein	P15056	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser222	LIDSMANsFVGTRSY	-1									8413257	t		lperfetto	Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1.	SIGNOR-39054	0.779
PTGER1	protein	P34995	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256811	0.433
ATM	protein	Q13315	UNIPROT	DCLRE1C	protein	Q96SD1	UNIPROT	up-regulates	phosphorylation	Ser645	NLSTNADsQSSSDFE	9606									16874298	t		lperfetto	The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo	SIGNOR-148323	0.603
CDK3	protein	Q00526	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Ser811	IYISPLKsPYKISEG	9606									15084261	t		gcesareni	The active form of prb is underphosphorylated. Cdk3/cyclin-c-mediated phosphorylation at ser-807 and ser-811 is required for g0-g1 transition.	SIGNOR-124212	0.454
PTPRJ	protein	Q12913	UNIPROT	LAT	protein	O43561	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000782								11259588	t		flangone	We propose that cd148 negatively regulates tcr signaling by interfering with the phosphorylation and function of plcgamma1 and lat	SIGNOR-105787	0.359
MAPK3	protein	P27361	UNIPROT	ARHGEF2	protein	Q92974	UNIPROT	up-regulates	phosphorylation	Thr679	PGVELLLtPREPALP	9606	BTO:0000567								18211802	t		gcesareni	Activates rhoa and as a result regulates actin assembly.	SIGNOR-160420	0.294
CAD	protein	P27708	UNIPROT	(S)-dihydroorotate	smallmolecule	CHEBI:30864	ChEBI	up-regulates quantity	chemical modification			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-267420	0.8
LEF1	protein	Q9UJU2	UNIPROT	ELANE	protein	P08246	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004850								14594802	f		miannu	We find that LEF-1 and CBFalpha co-activate ELA2 expression.	SIGNOR-254550	0.259
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser33	QQQSYLDsGIHSGAT	9606									11955436	t		lperfetto	Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC).	SIGNOR-227897	0.892
LTF	protein	P02788	UNIPROT	ITLN1	protein	Q8WWA0	UNIPROT	up-regulates activity	binding			9606									23921499	t			Intelectin 1 (IntL) is known as a lectin expressed in intestinal epithelia and also as a receptor for an iron-binding protein, lactoferrin (LF). 	SIGNOR-272500	0.369
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr37	PPGDYSTtPGGTLFS	9606									12747827	t		lperfetto	Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e.	SIGNOR-236694	0.753
PTEN	protein	P60484	UNIPROT	PTK6	protein	Q13882	UNIPROT	down-regulates activity	dephosphorylation	Tyr342	RLIKEDVyLSHDHNI	-1									29142193	t		lperfetto	PTEN inhibits PTK6 activity and downstream signaling in prostate cancer cells.|Using an in vitro phosphatase assay, we observed that PTEN was able to dephosphorylate PTK6 at tyrosine residue 342 in a dose dependent manner.	SIGNOR-276975	0.427
PLK1	protein	P53350	UNIPROT	NINL	protein	Q9Y2I6	UNIPROT	down-regulates activity	phosphorylation	Ser686	LEELHEKsQEVIWGL	-1									12852856	t		lperfetto	Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction	SIGNOR-103348	0.688
JAK2	protein	O60674	UNIPROT	EPOR	protein	P19235	UNIPROT	up-regulates activity	phosphorylation	Tyr426	ASAASFEyTILDPSS										12441334	t			JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2	SIGNOR-251349	0.806
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	KCNMA1	protein	Q12791	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								31152168	t		miannu	The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. The BK channel can be allosterically activated by both changes in the membrane voltage (voltage-dependent activation pathway) and intracellular [Ca2+] concentration (calcium-dependent activation pathway)	SIGNOR-269199	0.8
ARHGAP26	protein	Q9UNA1	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260481	0.613
HPS4	protein	Q9NQG7	UNIPROT	BLOC-3	complex	SIGNOR-C253	SIGNOR	form complex	binding			9606									20048159	t		lperfetto	Two of these genes, HPS1 and HPS4, encode components of the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Herein we show that recombinant HPS1-HPS4 produced in insect cells can be efficiently isolated as a 1:1 heterodimer.	SIGNOR-260692	0.744
E2F1	protein	Q01094	UNIPROT	ISYNA1	protein	Q9NPH2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								15464731	f	 	lperfetto	Human myo-inositol 1-phosphate synthase (IP synthase; E.C. 5.5.1.4), encoded by ISYNA1, catalyzes the de novo synthesis of inositol 1-phosphate from glucose 6-phosphate.|Here, we have characterized the minimal promoter of ISYNA1 and show that it is upregulated by E2F1.	SIGNOR-254130	0.316
SBF1	protein	O95248	UNIPROT	Myelination	phenotype	SIGNOR-PH206	SIGNOR	up-regulates				10090									20937701	f		miannu	Reduced sciatic nerve axons and normal myelination in the absence of Mtmr5. However, Mtmr5−/− mice had significantly fewer total myelinated axons in sciatic nerves than wild-type controls (Fig. 5G). 	SIGNOR-269812	0.7
ATM	protein	Q13315	UNIPROT	RAD17	protein	O75943	UNIPROT	unknown	phosphorylation	Ser646	ETWSLPLsQNSASEL	9606									10608806	t		lperfetto	We determined a general phosphorylation consensus sequence for atm and identified putative in vitro targets by using glutathione s-transferase peptides as substrates. Putative atm in vitro targets include p95/nibrin, mre11, brca1, rad17, pts, wrn, and atm (s440) itself.	SIGNOR-73520	0.841
phentolamine	chemical	CHEBI:8081	ChEBI	ADRA1A	protein	P35348	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258445	0.8
prostaglandin G2(1-)	smallmolecule	CHEBI:82629	ChEBI	prostaglandin H2(1-)	smallmolecule	CHEBI:57405	ChEBI	up-regulates quantity	precursor of			-1									7592599	t		Luana	[14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2,	SIGNOR-269777	0.8
tandutinib	chemical	CHEBI:90237	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258297	0.8
PPP2CA	protein	P67775	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	dephosphorylation	Ser37	NVLSPLPsQAMDDLM	9606									14712210	t			Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage| Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37. 	SIGNOR-248619	0.573
BMPR1A	protein	P36894	UNIPROT	SMAD1/5/8	proteinfamily	SIGNOR-PF35	SIGNOR	up-regulates activity	phosphorylation			10090	BTO:0004058								19620713	t		ggiuliani	The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17).	SIGNOR-255831	0.773
ATM	protein	Q13315	UNIPROT	DAXX	protein	Q9UER7	UNIPROT	down-regulates	phosphorylation	Ser564	LEEESPVsQLFELEI	9606									23405218	t		gcesareni	The main phosphorylation site of daxx is identified to be ser564, which is a direct target of atm. Phosphorylation of endogenous daxx at ser564 occurs rapidly during the dna damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of daxx from mdm2, stabilizes mdm2, and inhibits dna damage-induced p53 activation.	SIGNOR-200889	0.514
MLL-AF9	fusion protein	SIGNOR-FP5	SIGNOR	RUNX1	protein	Q01196	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24449215	f		miannu	However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions.	SIGNOR-260128	0.2
KIT	protein	P10721	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			10090	BTO:0000141								18179858	t		irozzo	KIT mutations within the carboxy-terminal region of the cytoplasmic tyrosine kinase domain (TK2), such as KITD816V, stabilize the KIT activation loop conformation in its active form.Previous studies have demonstrated hyperactivation of p85α regulatory subunit of class IA phosphatidylinositol-3-kinase (PI3K) in cell lines expressing the activation loop mutant of KIT. Although p85α is hyperphosphorylated and constitutively bound to KITD814V in cell-line models.	SIGNOR-256121	0.709
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	chemical	CHEBI:95082	ChEBI	BRD3	protein	Q15059	UNIPROT	down-regulates activity	chemical inhibition			-1									24015967	t		Gianni	This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation	SIGNOR-262203	0.8
PIP4K2A	protein	P48426	UNIPROT	1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-)	smallmolecule	CHEBI:58456	ChEBI	up-regulates quantity	chemical modification			9606									9367159	t		Gianni	The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities'. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K	SIGNOR-268864	0.8
MAP3K7	protein	O43318	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	phosphorylation			9606									9278437	t		lperfetto	Mitogen-activated protein kinase kinase 4 (mkk4)/stress-activated protein kinase/extracellular signal-regulated kinase (sek1), a dual-specificity kinase that phosphorylates and activates jnk, synergized with tak1 in activating jnk.Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway.	SIGNOR-50618	0.697
NatA	complex	SIGNOR-C415	SIGNOR	Protein_acetylation	phenotype	SIGNOR-PH189	SIGNOR	up-regulates				9606									21351257	f		miannu	About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity.	SIGNOR-267229	0.7
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GABA-A	proteinfamily	SIGNOR-PF61	SIGNOR	up-regulates quantity	phosphorylation			9606	BTO:0000938								25600368	t		miannu	The endocytosis of GABAARs is regulated by the interaction of the AP2 complex with β and γ2 subunits. Phosphorylation of β3 (S408/S409) and γ2 (Y365/Y367) by PKA/PKC and Src/Fyn, respectively, prevents binding to AP2 and thus stabilizes these receptors at the cell surface.	SIGNOR-264991	0.2
CTNNB1	protein	P35222	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates	binding			9606									10775268	t		gcesareni	Ctnnb1 forms a ternary complex with lef1 and ep300 that is disrupted by ctnnbip1 binding	SIGNOR-76987	0.693
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser180	GSSASFIsDTFSPYT	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248370	0.598
PHIP	protein	Q8WWQ0	UNIPROT	Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	up-regulates activity	binding			9606	BTO:0000664								30018425	t		miannu	One member of the CRL4 complex, the WD-40 containing protein RepID (DCAF14/PHIP), selectively binds and activates a group of replication origins. Here we show that RepID recruits the CRL4 complex to chromatin prior to DNA synthesis, thus playing a crucial architectural role in the proper licensing of chromosomes for replication. In the absence of RepID, cells rely on the alternative ubiquitin ligase, SKP2-containing SCF, to progress through the cell cycle.	SIGNOR-266963	0.333
CSNK2A2	protein	P19784	UNIPROT	AQP4	protein	P55087	UNIPROT	down-regulates activity	phosphorylation	Ser285	MEVEDNRsQVETDDL	9615	BTO:0000837								11742978	t		llicata	We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII.	SIGNOR-250975	0.344
DSCAM	protein	O60469	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	down-regulates				9606	BTO:0000938								30745319	f		miannu	Nuclear DSCAM and DSCAML1 impair neurite outgrowth. this demonstrates that enhanced nuclear translocation of the DSCAM and DSCAML1 ICDs profoundly impairs neurite outgrowth and development of primary cortical neurons.	SIGNOR-264276	0.7
TLN1	protein	Q9Y490	UNIPROT	ITGB7	protein	P26010	UNIPROT	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257633	0.578
MAML1	protein	Q92585	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	up-regulates	binding			9606									11101851	t		gcesareni	Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1.	SIGNOR-84835	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PPARGC1A	protein	Q9UBK2	UNIPROT	down-regulates activity	phosphorylation	Ser571	RMRSRSRsFSRHRSC	9606		BTO:0000759							17554339	t		lperfetto	Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1alpha At ser570 Is required for akt to inhibit recruitment of pgc-1alpha To chromatin.	SIGNOR-155532	0.2
H2BC11	protein	P06899	UNIPROT	Nucleosome_H3.1 variant	complex	SIGNOR-C324	SIGNOR	form complex	binding			-1									21812398	t		miannu	The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 	SIGNOR-263720	0.2
PIK3CB	protein	P42338	UNIPROT	PIK3CB	protein	P42338	UNIPROT	down-regulates activity	phosphorylation	Ser1070	TVRKDYRs	-1									12502714	t		lperfetto	Autophosphorylation sites of both pi3k isoforms were mapped to c-terminal serine residues of the catalytic p110 subunit (i.e. serine 1070 of p110 beta and serine 1101 of p110 gamma). autophosphorylation of p110 beta On serine 1070 results in down-regulation of the lipid kinase activity of pi3k beta	SIGNOR-96776	0.2
Calcineurin	complex	SIGNOR-C155	SIGNOR	DNM1L	protein	O00429	UNIPROT	up-regulates activity	dephosphorylation	Ser637	VPVARKLsAREQRDC	9606									18838687	t			When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.	SIGNOR-252315	0.275
DRAM2	protein	Q6UX65	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30755245	f		irozzo	DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression.	SIGNOR-259146	0.312
KDM6A	protein	O15550	UNIPROT	HOXA10	protein	P31260	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24561908	t		miannu	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260020	0.271
STK11	protein	Q15831	UNIPROT	BRSK1	protein	Q8TDC3	UNIPROT	up-regulates	phosphorylation	Thr189	VGDSLLEtSCGSPHY	9606									14976552	t		lperfetto	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122413	0.463
PI3K	complex	SIGNOR-C156	SIGNOR	PIP3	smallmolecule	CHEBI:16618	ChEBI	up-regulates quantity	chemical modification			9606									12040186	t		lperfetto	The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3].	SIGNOR-252713	0.8
IL1B	protein	P01584	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32446778	f	doi: 10.1016/j.cytogfr.2020.05.003 	miannu	Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α)	SIGNOR-260855	0.528
HLTF	protein	Q14527	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000664								11756191	f	Regulation of transcription	miannu	DNA-dependent adenosine triphosphatase (helicaselike transcription factor) activates beta-globin transcription in K562 cells. Overexpression of HLTF in K562 cells does not affect the endogenous levels of gamma- and epsilon-globin message, but it markedly activates beta-globin transcription.	SIGNOR-251812	0.2
Ast-487	chemical	CID:11409972	PUBCHEM	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259693	0.8
GATA3	protein	P23771	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									15632071	f		fspada	Constitutive expression of both gata-2 and gata-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor gamma (ppargamma) promoter and suppression of its basal activity	SIGNOR-132955	0.356
PRKCE	protein	Q02156	UNIPROT	KIR3DL1	protein	P43629	UNIPROT	down-regulates	phosphorylation	Ser415	QRKITRPsQRPKTPP	9606									17911614	t		gcesareni	Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.	SIGNOR-158129	0.2
CREB1	protein	P16220	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11557984	t			CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo	SIGNOR-256150	0.536
ANXA1	protein	P04083	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									27426034	f		miannu	Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups	SIGNOR-261939	0.412
PTK2	protein	Q05397	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									9416004	t		gcesareni	Pi3-kinase has also been shown to bind fak in a cell cell adhesion-dipendent manner at the major autophosphorylation site y397. This association could live to activation of pi3-kinase and its downstream effectors.	SIGNOR-252726	0.551
HEY1	protein	Q9Y5J3	UNIPROT	RBPJ	protein	Q06330	UNIPROT	down-regulates	binding			9606									16682003	t		gcesareni	These findings suggest a novel mechanism for negative feedback on notch signaling that requires rbp-jkappa to interact physically with hrt and hes.	SIGNOR-146687	0.645
L-isoprenaline	chemical	CHEBI:6257	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257457	0.8
HES1	protein	Q14469	UNIPROT	CTNND2	protein	Q9UQB3	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0001033								21106062	f		miannu	Coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression.	SIGNOR-251877	0.354
MAPK3	protein	P27361	UNIPROT	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation	Ser164	FGHSAAVsPTFMPRS	9606									12050114	t		gcesareni	Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk	SIGNOR-88736	0.36
WNT4	protein	P56705	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131832	0.636
HIF1A	protein	Q16665	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27141364	f		irozzo	STAT3 and HIF-1α cooperatively enhance PD-L1 expression in EML4-ALK-translocated pADC cells under hypoxia. Taken together, these findings suggest that EML4-ALK might increase HIF-1α expression under hypoxia by enhancing transcription and inhibiting ubiquitination of HIF-1α, resulting in the stabilization of HIF-1α, consequently contributing to HIF-1α-mediated upregulation of PD-L1 under hypoxia.	SIGNOR-259092	0.286
Ast-487	chemical	CID:11409972	PUBCHEM	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259694	0.8
PLCG2	protein	P16885	UNIPROT	1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	up-regulates quantity	chemical modification			9606									23000145	t		scontino	Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).	SIGNOR-268454	0.8
PKMYT1	protein	Q99640	UNIPROT	CDK1	protein	P06493	UNIPROT	down-regulates	phosphorylation	Thr14	IEKIGEGtYGVVYKG	9606	BTO:0000567								9001210	t	Preference on the part of Myt1Hu for the cyclin-bound form of Cdc2	gcesareni	Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory.	SIGNOR-45725	0.739
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MCL1	protein	Q07820	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								18676833	t	inferred from 70% family members	fstefani	We then showed that erk could phosphorylate mcl-1 at two consensus residues, thr 92 and 163, which is required for the association of mcl-1 and pin1, resulting in stabilization of mcl-1.	SIGNOR-270158	0.2
ABL1	protein	P00519	UNIPROT	PRKN	protein	O60260	UNIPROT	down-regulates	phosphorylation	Tyr143	SPAGRSIyNSFYVYC	9606		BTO:0000142							20823226	t		llicata	Here we show that the nonreceptor tyrosine kinase c-abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin e3 ligase activity and protective function.	SIGNOR-167853	0.2
aloxistatin	chemical	CHEBI:101381	ChEBI	CTSB	protein	P07858	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								32142651	t		miannu	Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines.	SIGNOR-260281	0.8
ATR	protein	Q13535	UNIPROT	DBF4	protein	Q9UBU7	UNIPROT	down-regulates	phosphorylation	Ser502	FSTDNSGsQPKQKSD	9606									22123827	t		lperfetto	Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication.	SIGNOR-177805	0.643
CERS1	protein	P27544	UNIPROT	ceramide	smallmolecule	CHEBI:17761	ChEBI	up-regulates quantity	chemical modification			9606									26887952	t	done	miannu	 Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity. 	SIGNOR-273993	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	BRSK2	protein	Q8IWQ3	UNIPROT	up-regulates activity	phosphorylation	Thr260	VDAARRLtLEHIQKH	-1									16870137	t		miannu	BRSK2 is activated by cyclic AMP-dependent protein kinase A through phosphorylation at Thr260	SIGNOR-276056	0.2
rRNA_transcription	phenotype	SIGNOR-PH145	SIGNOR	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	up-regulates													25838379	f		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by means of single-particle electron cryogenic microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three ribosomal RNA molecules.	SIGNOR-262600	0.7
CDK5RAP2	protein	Q96SN8	UNIPROT	TUBG1	protein	P23258	UNIPROT	up-regulates activity	binding			9606	BTO:0002181								17959831	t		Giulio	Immunoprecipitation of CDK5RAP2 specifically coprecipitated _TuRC components, as detected on immunoblots of _-tubulin and GCP3 (Figure 3A).| Perturbing CDK5RAP2 function delocalized gamma-tubulin from the centrosomes and inhibited centrosomal microtubule nucleation, thus leading to disorganization of interphase microtubule arrays and formation of anastral mitotic spindles. Together, CDK5RAP2 is a pericentriolar structural component that functions in gammaTuRC attachment and therefore in the microtubule organizing function of the centrosome.	SIGNOR-260310	0.637
SMARCA4	protein	P51532	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	form complex	binding			9606									15627498	t		miannu	We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers.	SIGNOR-132922	0.912
HSPA8	protein	P11142	UNIPROT	CFTR	protein	P13569	UNIPROT	down-regulates quantity	binding			9606	BTO:0000007								21148293	t		miannu	JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. JB12 drives Hsc70 to associate with CFTR and the RMA1 E3 complex	SIGNOR-271492	0.658
4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone	chemical	CHEBI:91395	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191406	0.8
OXTR	protein	P30559	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257266	0.533
GRPR	protein	P30550	UNIPROT	PLA2G1B	protein	P04054	UNIPROT	up-regulates	binding			9606									17251915	t		gcesareni	Grpr stimulation activates phospholipase a2 (pla2) and cyclooxygenase 2 (cox2), which leads to prostaglandin e2 (pge2) production and ep receptor stimulation.	SIGNOR-152756	0.257
CAMK1	protein	Q14012	UNIPROT	KRT18	protein	P05783	UNIPROT	unknown	phosphorylation	Ser53	ISVSRSTsFRGGMGS	9606									7523419	t		flangone	Ser-52 in k18 is not glycosylated and matches consensus sequences for phosphorylation by cam kinase..these kinases can phosphorylate k18 in vitro predominantly at that site	SIGNOR-27398	0.2
PRKCG	protein	P05129	UNIPROT	ANXA1	protein	P04083	UNIPROT	up-regulates	phosphorylation	Ser27	EYVQTVKsSKGGPGS	9606									24103589	t		lperfetto	The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization.	SIGNOR-202788	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CASP8	protein	Q14790	UNIPROT	down-regulates	phosphorylation	Ser387	YLEMDLSsPQTRYIP	9606		BTO:0000149							20937773	t		lperfetto	In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by cdk1na interference-mediated silencing of cyclin b1 or treatment with the cdk1 inhibitor ro-3306 enhances the fas-mediated activation and processing of procaspase-8 in mitotic cells/cyclin b1 on ser-387	SIGNOR-216737	0.381
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	up-regulates				9606									24168260	f		miannu	NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis	SIGNOR-260446	0.7
TYK2	protein	P29597	UNIPROT	TYK2	protein	P29597	UNIPROT	up-regulates activity	phosphorylation	Tyr1054	AVPEGHEyYRVREDG	9606	BTO:0000452								8702790	t		lperfetto	These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055The K930R mutant, bearing a mutation in the ATP binding site, is catalytically inactive (Fig. 3B, lanes 5 and 6). This protein is not basally phosphorylated, while the wt and the Y1054F/Y1055F proteins are (Fig. 3A), suggesting that autophosphorylation is responsible for the basal level of phosphorylation.	SIGNOR-43088	0.2
CD2AP	protein	Q9Y5K6	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates quantity	binding			9606	BTO:0000007;BTO:0001938								29175910	t		lperfetto	One such regulator is the adaptor protein CD2AP, which delivers capping proteins to the barbed ends of polymerizing F-actin. Capping growing filaments can promote the formation of actin branches by increasing the G-actin pool available to form branches	SIGNOR-264769	0.7
STK3	protein	Q13188	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	phosphorylation	Thr1041	EHAFYEFtFRRFFDD	9606									21808241	t		gcesareni	Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2.	SIGNOR-175801	0.592
Calcineurin	complex	SIGNOR-C155	SIGNOR	BAD	protein	Q92934	UNIPROT	up-regulates activity	dephosphorylation	Ser99	PFRGRSRsAPPNLWA	9606	BTO:0000007								10195903	t			Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.	SIGNOR-252332	0.412
S1PR2	protein	O95136	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257349	0.448
PTH1R	protein	Q03431	UNIPROT	CYP24A1	protein	Q07973	UNIPROT	up-regulates quantity													28363951	f		lperfetto	These PTH actions are mainly mediated by Gsalpha signaling, which induces the expression of the gene encoding 25-hydroxyvitamin D 1alpha-hydroxylase (Cyp27b1) and destabilizes the transcript encoding vitamin D 24-hydroxylase (Cyp24a1) 	SIGNOR-270555	0.293
SEMA3B	protein	Q13214	UNIPROT	PLXNA2	protein	O75051	UNIPROT	up-regulates activity	binding			9606	BTO:0001176;BTO:0002036								25335892	t		miannu	We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin. 	SIGNOR-261812	0.651
TRAF2	protein	Q12933	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	ubiquitination			10090	BTO:0002572								15175328	t		miannu	Taken together, these data suggest that Traf2 may be the E3 ubiquitin ligase that initiates TNF-α signaling, potentially by ubiquitinating Rip1. In the absence of Traf2, TNF-alpha-induced ubiquitination of Rip1 is impaired, suggesting that Traf2 may be the E3 ubiquitin ligase responsible for the TNF-alpha-dependent, ubiquitination of Rip1. Finally, recruitment of the ubiquitinated Tak1 complex is dependent on the presence of Rip1, suggesting that Rip1 ubiquitination rather than its phosphorylation is critical in signaling.	SIGNOR-271423	0.891
AKT1	protein	P31749	UNIPROT	DLX5	protein	P56178	UNIPROT	up-regulates	phosphorylation			9606									22298955	t		gcesareni	Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5.	SIGNOR-195546	0.267
ETV6	protein	P41212	UNIPROT	BBC3	protein	Q96PG8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002883								16828711	f	 	miannu	 Forced expression of TEL stimulated transcription via the p53-responsive element and increased the expression of cellular target genes for p53 such as cell cycle regulator p21 and apoptosis inducer Puma.	SIGNOR-254137	0.2
EGFR	protein	P00533	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates	phosphorylation			9606									14967450	t		lperfetto	The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation	SIGNOR-121962	0.728
MAPK12	protein	P53778	UNIPROT	SH3BP5	protein	O60239	UNIPROT	unknown	phosphorylation	Ser421	SKSQSSTsPEGQALE	-1									15158451	t		miannu	 Activated SAPK3 phosphorylates the mitochondrial protein Sab. we have identified serine 321 as the major site of phosphorylation by both SAPK3 and JNK2. SAPK3 but not JNK2 also phosphorylates serine 391	SIGNOR-250141	0.454
IRAK1	protein	P51617	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Thr288	QCPVGFNtLAFPSMK	9606	BTO:0000007								12496252	t		lperfetto	In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation	SIGNOR-96751	0.758
IQSEC2	protein	Q5JU85	UNIPROT	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	up-regulates quantity	relocalization			9606		BTO:0000142							27009485	t		miannu	BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.	SIGNOR-264916	0.2
HTR6	protein	P50406	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257443	0.252
ZSTK-474	chemical	CHEBI:90545	ChEBI	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207941	0.8
AURKB	protein	Q96GD4	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	phosphorylation	Ser183	CPHHERCsDSDGLAP	9606									22611192	t		gcesareni	We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma).	SIGNOR-197598	0.708
CDK2	protein	P24941	UNIPROT	DLG1	protein	Q12959	UNIPROT	up-regulates	phosphorylation	Ser443	FLGQTPAsPARYSPV	9606									19066288	t		llicata	We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. phosphorylation on ser158 and ser442 enhances nuclear expression of dlg1	SIGNOR-182765	0.286
NF90-NF45	complex	SIGNOR-C443	SIGNOR	DNA-PK	complex	SIGNOR-C107	SIGNOR	up-regulates activity	binding			-1									9442054	t		miannu	These proteins are NF90 and NF45, which are the 90- and 45-kDa subunits of a protein known to bind specifically to the antigen receptor response element of the interleukin 2 promoter, and the alpha, beta, and gamma subunits of eukaryotic translation initiation factor eIF-2. We also show that NF90, NF45, and eIF-2 beta are substrates for DNA-PK in vitro. In addition, recombinant NF90 promotes formation of a complex between DNA-PKcs, Ku, and DNA, and antibodies to recombinant NF90 or recombinant NF45 immunoprecipitate DNA-PKcs in vitro. Together, our data suggest that NF90, in complex with NF45, interacts with DNA-PKcs and Ku on DNA and that NF90 and NF45 may be important for the function of DNA-PK.	SIGNOR-268489	0.414
GATAD2B	protein	Q8WXI9	UNIPROT	MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263845	0.765
Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	GABA-A (a4-b1-g2) receptor	complex	SIGNOR-C333	SIGNOR	up-regulates				9606									33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors	SIGNOR-268582	0.2
USP7	protein	Q93009	UNIPROT	RPS27A	protein	P62979	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270824	0.638
PTPRB	protein	P23467	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates	dephosphorylation	Tyr1356	YVHVNATyVNVKCVA	9606									16101282	t		gcesareni	Ptp1b and shp-2 are bound to the c-met receptor to control its activity. Although the binding of ptp1b increases when there is a decrease in c-met activation and acts as a negative regulator of the receptor, the increased binding and phosphorylation of shp-2 coincide with maximal stimulation of c-met, acting as a positive regulator.	SIGNOR-139560	0.371
TGFb	proteinfamily	SIGNOR-PF5	SIGNOR	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f	inferred from 70% family members	lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-270216	0.7
CDK1	protein	P06493	UNIPROT	TSC1	protein	Q92574	UNIPROT	unknown	phosphorylation	Thr417	SLPQATVtPPRKEER	9606									14551205	t		llicata	In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain.	SIGNOR-86696	0.503
PRKAG2	protein	Q9UGJ0	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	form complex	binding			9606									16054041	t		gcesareni	Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits.	SIGNOR-139176	0.736
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Pro)	smallmolecule	CHEBI:29177	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269493	0.8
ANK2	protein	Q01484	UNIPROT	PPP2R5A	protein	Q15172	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0003324								19840192	t		miannu	Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. 	SIGNOR-266729	0.287
acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	hexadecanoic acid	smallmolecule	CHEBI:15756	ChEBI	up-regulates quantity	precursor of			9606									15507492	t		miannu	Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the de novo biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH. 	SIGNOR-268089	0.8
HDLBP	protein	Q00341	UNIPROT	HDL_assembly	phenotype	SIGNOR-PH61	SIGNOR	up-regulates				9606									9925647	f		miannu	HBP/vigilin binds HDL and apoA-I on ligand blots; conceivably therefore apoA-I may interact with cytoplasmic vigilin promoting changes in cholesterol flux.	SIGNOR-266692	0.7
NMUR2	protein	Q9GZQ4	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257010	0.252
PPP1R15A	protein	O75807	UNIPROT	PPP1CC	protein	P36873	UNIPROT	up-regulates activity	binding			9606									27629041	t		miannu	Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning 15. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival	SIGNOR-260174	0.686
PF-3845	chemical	CID:25154867	PUBCHEM	FAAH	protein	O00519	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206049	0.8
MAPK1	protein	P28482	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr46	GGTLFSTtPGGTRII	9606	BTO:0000007								11691836	t		lperfetto	The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding 	SIGNOR-249393	0.649
prednisone	chemical	CHEBI:8382	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									4188963	t	dermatitis	gcesareni		SIGNOR-251705	0.8
PRKCA	protein	P17252	UNIPROT	KCNJ4	protein	P48050	UNIPROT	down-regulates activity	phosphorylation	Thr53	IFTTCVDtRWRYMLM	-1									10206975	t		miannu	These results therefore indicate that Kir2.3 is directly modulated by PKC phosphorylation of its channel protein and threonine 53 is the PKC phosphorylation site in Kir2.3.	SIGNOR-275965	0.2
FLT3	protein	P36888	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0001545								17851558	t		miannu	Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML.	SIGNOR-260124	0.42
SOX11	protein	P35716	UNIPROT	SPAST	protein	Q9UBP0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22574173	f		miannu	 we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11. 	SIGNOR-254886	0.371
MACF1	protein	Q9UPN3	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates				9606	BTO:0000938								16815997	f		gcesareni	In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes.	SIGNOR-147451	0.446
LATS1	protein	O95835	UNIPROT	PRPS1	protein	P60891	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser285	EDKMKHCsKIQVIDI	-1									34465890	t		miannu	 Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness.	SIGNOR-276505	0.2
TGFB1	protein	P01137	UNIPROT	ITGA2	protein	P17301	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001596								1744142	f		lperfetto	TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way.	SIGNOR-253354	0.29
MAPK9	protein	P45984	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9606									19118012	t		gcesareni	Phosphorylation by activated jnk protects c-jun from ubiquitination;phosphorylation of c-jun on ser73 by jnk is sufficient to protect c-jun from ubiquitination c-jun is targeted for ubiquitination by its association with inactive c-jun nh2-terminal kinase (jnk). Phosphorylation by activated jnk protects c-jun from ubiquitination, thus by prolonging its half-life targets of the jnk signal transduction pathway include the transcription factors atf2 and c-jun apoptosis, altered;apoptosis, induced;transcription, altered;cell growth, altered;jnk1(disrupts);pin1(induces);dna(disrupts) transcription, altered;cell growth, altered;jnk1(disrupts);pin1(induces);dna(disrupts)	SIGNOR-183017	0.881
IKBKB	protein	O14920	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	phosphorylation	Ser468	AVFTDLAsVDNSEFQ	9606	BTO:0000150;BTO:0000782			SIGNOR-C13					16046471	t		lperfetto	Rela is phosphorylated at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k). We now present evidence that suggests that the upstream kinase ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. Ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536.	SIGNOR-138903	0.882
RPS6KA5	protein	O75582	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	phosphorylation	Ser276	SMQLRRPsDRELSEP	9606				SIGNOR-C13					12628924	t		gcesareni	Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276.	SIGNOR-99210	0.706
WWTR1	protein	Q9GZV5	UNIPROT	DVL1	protein	O14640	UNIPROT	down-regulates	binding			9606									22153608	t	Activation of Wnt signaling induces the hyperphosphorylation of Dishevelled (DVL), and this, via a poorly understood mechanism, ultimately leads to a rise in beta-Catenin levels and to the activation of beta-Catenin target genes.	gcesareni	Taz binds to dvl proteins, thereby inhibiting dvl phosphorylation by casein kinase 1-delta and -epsilon kinases (ck1d/e), thus promoting beta-catenin degradation.	SIGNOR-195212	0.364
clemastine	chemical	CHEBI:3738	ChEBI	P2RX7	protein	Q99572	UNIPROT	up-regulates activity	chemical activation			9606									21262970	t		Luana	Clemastine potentiates the human P2X7 receptor by sensitizing it to lower ATP concentrations.	SIGNOR-257893	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Ser1071	SFLQRYSsDPTGALT	9606	BTO:0000007								10347170	t		llicata	 We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. 	SIGNOR-250621	0.378
canertinib	chemical	CHEBI:61399	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191009	0.8
LIF	protein	P15018	UNIPROT	LIFR	protein	P42702	UNIPROT	up-regulates	binding			9606									9143707	t		gcesareni	Lif binds at low-affinity to lifr, the structure of which is closely related to that of gp130 (42). Lifr then becomes heterodimerized with gp130 to form the high-affinity and signaling-competent complex (43). Osm utilizes this type of heterodimer, i.e. the lifr/gp130 complex (43, 44).	SIGNOR-48111	0.751
TDG	protein	Q13569	UNIPROT	Base-excision_repair	phenotype	SIGNOR-PH222	SIGNOR	up-regulates													23545420	f		lperfetto	The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1).	SIGNOR-275713	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606	BTO:0000938								9346240	t		lperfetto	Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins	SIGNOR-244144	0.2
RNF125	protein	Q96EQ8	UNIPROT	IFIH1	protein	Q9BYX4	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0005029								17460044	t		miannu	Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production.	SIGNOR-271646	0.644
CCNE2	protein	O96020	UNIPROT	CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	form complex	binding			9606									19665013	t		lperfetto	The eukaryotic cell cycle is controlled by different cyclins and their associated kinases (murray and hunt, 1993). In mammalian cells, levels of cycline and its associated kinase, cdk2, rise in late g1/early s-phase when dna replication is initiated	SIGNOR-187454	0.931
UNG	protein	P13051	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									27875297	f		lperfetto	Uracil N-glycosylase 2 (UNG2), the nuclear isoform of UNG, catalyzes the removal of uracil or 5-fluorouracil lesions that accumulate in DNA following treatment with the anticancer agents 5-fluorouracil and 5-fluorodeoxyuridine (floxuridine), a 5-fluorouracil metabolite. By repairing these DNA lesions before they can cause cell death, UNG2 promotes cancer cell survival and is therefore critically involved in tumor resistance to these agents. 	SIGNOR-264889	0.7
PRKACA	protein	P17612	UNIPROT	TH	protein	P07101	UNIPROT	up-regulates activity	phosphorylation	Ser40	GQGAPGPsLTGSPWP	-1									11359875	t		miannu	HTH1 was phosphorylated at Ser40 by PKA. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation. phosphorylationof hTH1‚4 at Ser40, to a stoichiometry of up to 1.0 molphosphate per mol TH subunit, dramatically increases their binding to 14-3-3 proteins.	SIGNOR-250061	0.374
CSNK1D	protein	P48730	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates	phosphorylation	Ser314	SREQSTDsGLGLGCY	9606									24715453	t		lperfetto	LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)	SIGNOR-234438	0.342
CLIP1	protein	P30622	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates	binding												17889670	t		lperfetto	Microtubule plus end binding proteins (+TIPs) localize to the dynamic plus ends of microtubules, where they stimulate microtubule growth and recruit signaling molecules. Three main +TIP classes have been identified (XMAP215, EB1, and CLIP-170)	SIGNOR-264830	0.7
MAPK3	protein	P27361	UNIPROT	HSPB8	protein	Q9UJY1	UNIPROT	up-regulates	phosphorylation	Ser27	PFRDSPLsSRLLDDG	9606									22721717	t		lperfetto	Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation	SIGNOR-197932	0.346
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	ITGB8	protein	P26012	UNIPROT	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259012	0.2
SERPINE1	protein	P05121	UNIPROT	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	up-regulates				9606									29474926	f		miannu	 Plasminogen activator inhibitor-1 (PAI-1) formed in the injured alveolar epithelium also contributes to pulmonary fibrosis in a manner that involves vitronectin binding.	SIGNOR-260588	0.7
ETFB	protein	P38117	UNIPROT	ETF	complex	SIGNOR-C463	SIGNOR	form complex	binding			9606									33450351	t		miannu	Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors.	SIGNOR-269452	0.944
MAPK3	protein	P27361	UNIPROT	ARRB1	protein	P49407	UNIPROT	down-regulates	phosphorylation	Ser412	EEEDGTGsPQLNNR	9606									19153083	t		gcesareni	Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation	SIGNOR-183484	0.705
JAK2	protein	O60674	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606	BTO:0000599								9575217	t		lperfetto	Inactive cytoplasmic STATs are recruited to the activated receptor by docking of the STAT SH2 domain to selected receptor tyrosine phosphopeptides, where they are in turn phosphorylated on a single tyrosine by Jak kinases. Has been identified tyrosine 705 of Stat3 as the likely site of phosphorylation by Jak kinases during signal transduction.	SIGNOR-238638	0.812
AURKA	protein	O14965	UNIPROT	CETN2	protein	P41208	UNIPROT	up-regulates	phosphorylation	Ser170	LRIMKKTsLY	9606	BTO:0000150								21731694	t		llicata	Our studies show that aurora a phosphorylates centrin at serine 170 in vitro and that the serine 170 phosphorylation affects the stability of centrin by regulating its interaction with apc/c. finally we demonstrated that phosphorylation of centrin serine 170 is an absolute requirement for aurora a-mediated centriole amplification.	SIGNOR-174686	0.495
KIF1C	protein	O43896	UNIPROT	RAB6B	protein	Q9NRW1	UNIPROT	up-regulates quantity	relocalization			-1									20360680	t		miannu	Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation.	SIGNOR-266878	0.2
17alpha-hydroxyprogesterone	smallmolecule	CHEBI:17252	ChEBI	androst-4-ene-3,17-dione	smallmolecule	CHEBI:16422	ChEBI	up-regulates quantity	precursor of			9606		BTO:0001363;BTO:0000050;BTO:0000056							17192295	t		lperfetto	THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones.	SIGNOR-268650	0.8
(S)-duloxetine	chemical	CHEBI:36795	ChEBI	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			-1									18387300	t		Luana	Selective inhibition of serotonin (5-HT) and noradrenaline (NA) reuptake (SNRI) has been shown to be an attractive dual pharmacology approach for the treatment of a number of diseases.1,2 For example, dual 5- HT/NA reuptake inhibitor duloxetine (1) has shown clinical efficacy in the treatment of depression, pain, and urinary incontinence.	SIGNOR-257775	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BCL6	protein	P41182	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000782;BTO:0000785								9649500	t	inferred from 70% family members	gcesareni	Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway.	SIGNOR-270140	0.2
PGAM	proteinfamily	SIGNOR-PF78	SIGNOR	3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	down-regulates quantity	chemical modification			9606									24786789	t		miannu	Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle.	SIGNOR-266513	0.8
MC5R	protein	P33032	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268712	0.435
MID1IP1	protein	Q9NPA3	UNIPROT	ACACA	protein	Q13085	UNIPROT	up-regulates activity	binding			10029	BTO:0000457								20952656	t		miannu	Recently, we reported the discovery that MIG12, a 183 amino acid protein, binds to ACC1 and ACC2, which induces polymerization and subsequently increases the enzymatic activity of the protein	SIGNOR-267111	0.383
alvimopan	chemical	CHEBI:135686	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			-1									18313920	t		Luana	A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors.	SIGNOR-257774	0.8
SIRT6	protein	Q8N6T7	UNIPROT	SREBF1	protein	P36956	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								25083875	t		miannu	SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1.Importantly, SIRT6 also controls SREBP-1 recruitment to target promoters, such as Fasn, and helps maintain proper cyclic transcription. In fact, circadian metabolomics analyses reveal that SIRT6 controls lipid metabolism, contributing to the regulation of pathways involved in fatty acid synthesis and beta oxidation, triglyceride storage, signaling, and cellular membrane lipids.	SIGNOR-268158	0.38
940929-33-9	chemical	CID:49867937	PUBCHEM	KIF11	protein	P52732	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206724	0.8
CNR1	protein	P21554	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257211	0.265
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	NIBAN1	protein	Q9BZQ8	UNIPROT	unknown	phosphorylation	Ser602	ASPARRAsAILPGVL	9606									22510990	t		llicata	We demonstrate here that ultraviolet irradiation induces phosphorylation of niban at s602 by akt, which increases the association of niban with nucleophosmin and disassociation of nucleophosmin from the mdm2 complex.	SIGNOR-197053	0.2
TOM40 complex	complex	SIGNOR-C421	SIGNOR	ATF5	protein	Q9Y2D1	UNIPROT	down-regulates activity	relocalization												31387448	t		lperfetto	Central to the mtUPR is the transcription factor ATF5. When stress causes protein import and/or electron transport chain dysfunction ATF5 accumulates in the nucleus to transcribe mitochondrial chaperones and protease genes |Under normal conditions, ATF5 is imported into and sequestered within mitochondria.	SIGNOR-267685	0.2
AGT	protein	P01019	UNIPROT	AGTR1	protein	P30556	UNIPROT	up-regulates activity	binding			10116	BTO:0004578								17346243	t			AT(1) receptor (AngII type-1 receptor), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of AngII, and this receptor is predominantly expressed in cardiovascular cells, such as VSMCs (vascular smooth muscle cells)	SIGNOR-252293	0.847
MK-2461	chemical	CID:44137946	PUBCHEM	PDGFRB	protein	P09619	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194390	0.8
ADRA1D	protein	P25100	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257080	0.568
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR2B	protein	P41595	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264286	0.8
SF3B2	protein	Q13435	UNIPROT	SF3b	complex	SIGNOR-C442	SIGNOR	form complex	binding			9606									32140746	t		lperfetto	Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a).	SIGNOR-268404	0.921
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9606									14585074	f		amattioni	Activation of the nf-kb pathway regulates a variety of ant-apoptotic factors	SIGNOR-96834	0.7
RPL38	protein	P63173	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262461	0.861
BRF2	protein	Q9HAW0	UNIPROT	TFIIIB	complex	SIGNOR-C393	SIGNOR	form complex	binding												29378333	t		lperfetto	Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1).	SIGNOR-266191	0.712
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CIITA	protein	P33076	UNIPROT	down-regulates	phosphorylation			9606									18245089	t	inferred from 70% family members	gcesareni	In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.	SIGNOR-270173	0.2
PRKCA	protein	P17252	UNIPROT	PTPN11	protein	Q06124	UNIPROT	unknown	phosphorylation	Ser595	GLMQQQKsFR	9606									11781100	t		lperfetto	 In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta.	SIGNOR-249138	0.329
HNF4G	protein	Q14541	UNIPROT	HAS2	protein	Q92819	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003723								23896584	t		Luana	Transcription was activated by HNF4G in reporter assays using the promoter/enhancer region of the HAS2 gene. The endogenous expression of the HAS2 gene was suppressed by knockdown of HNF4G.	SIGNOR-261626	0.345
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2A	protein	P49459	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271327	0.778
terazosin	chemical	CHEBI:9445	ChEBI	ADRA1D	protein	P25100	UNIPROT	down-regulates activity	chemical inhibition			9606									9379432	t		miannu	Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication	SIGNOR-258670	0.8
WNT7B	protein	P56706	UNIPROT	FZD10	protein	Q9ULW2	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0000763;BTO:0001260							15923619	t		gcesareni	Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling	SIGNOR-137934	0.632
DLK2	protein	Q6UY11	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	binding			9606									21419176	t		gcesareni	In this work, we demonstrate, for the first time, that dlk2 interacts with itself, with dlk1, and with the same notch1 receptor region as dlk1 does. We demonstrate also that the interaction of dlk2 with notch1 similarly results in an notch signaling in preadipocytes and mouse embryo fibloblasts.	SIGNOR-172864	0.294
P2RY6	protein	Q15077	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257398	0.2
dexamethasone	chemical	CHEBI:41879	ChEBI	CEBPB	protein	P17676	UNIPROT	up-regulates				9606									11279134	f		fspada	The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin	SIGNOR-106472	0.8
SP3	protein	Q02447	UNIPROT	ASNS	protein	P08243	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								11867623	t		Luana	Sp1 and Sp3 Activate Transcription Driven by the AS Promoter	SIGNOR-268020	0.2
SIRT7	protein	Q9NRC8	UNIPROT	ATM	protein	Q13315	UNIPROT	down-regulates activity	deacetylation	Lys3016	VLMRLQEkLKGVEEG										30944854	t		lperfetto	Here, we report that sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. |Upon DNA damage, ATM is activated via a series of highly organized machineries, including acetylation by the histone acetyltransferase TIP60 at lysine 3016	SIGNOR-275890	0.368
SP1	protein	P08047	UNIPROT	MET	protein	P08581	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									9223667	t		lperfetto	Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region.	SIGNOR-241490	0.326
DUSP7	protein	Q16829	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates activity	dephosphorylation			10029	BTO:0000246								12907755	t			Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR	SIGNOR-248726	0.318
ruxolitinib	chemical	CHEBI:66919	ChEBI	JAK2	protein	O60674	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258277	0.8
PPP1CB	protein	P62140	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates	dephosphorylation	Thr450	TAQMITItPPDQDDS	9606									20186153	t		gcesareni	Akt activation is achieved through a series of phosphorylation steps, the first being akt phosphorylation at thr-450 by jnk kinases. Pp-1 acts as a major phosphatase to dephosphorylate akt at thr-450 and thus modulate its functions.	SIGNOR-163965	0.394
EVL	protein	Q9UI08	UNIPROT	Axonal_growth_cone_formation	phenotype	SIGNOR-PH199	SIGNOR	up-regulates				9606									18508258	f		miannu	Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance.	SIGNOR-268391	0.7
PRKCD	protein	Q05655	UNIPROT	HMGA1	protein	P17096	UNIPROT	down-regulates	phosphorylation	Ser44	PGTALVGsQKEPSEV	9606									10617144	t		fspada	In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64	SIGNOR-73606	0.267
WNT3	protein	P56703	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131823	0.635
EP300	protein	Q09472	UNIPROT	ALOX15	protein	P16050	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000018								12517954	f	 	lperfetto	IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300.	SIGNOR-254097	0.2
PRKD2	protein	Q9BZL6	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser275	DNVRYGIsNIDTTIE										34010649	t		lperfetto	The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-275949	0.2
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser378	SKKGQSTsRHKKLMF	9606									10710310	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-75641	0.784
DZIP3	protein	Q86Y13	UNIPROT	H2AC20	protein	Q16777	UNIPROT	up-regulates activity	monoubiquitination	Lys119	IQAVLLPkKTESHKA	9606	BTO:0000007								18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271754	0.2
CSNK2A2	protein	P19784	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser29	VSHWQQQsYLDSGIH	-1									12432063	t		miannu	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin. 	SIGNOR-275995	0.453
CSNK2A1	protein	P68400	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr102	RAAMFPEtLDEGMQI	-1									12432063	t		miannu	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin. 	SIGNOR-275996	0.54
GLUD1	protein	P00367	UNIPROT	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	down-regulates quantity	chemical modification			9913									11254391	t			Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate.	SIGNOR-266917	0.8
PIK3CA	protein	P42336	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	phosphorylation	Ser608	ENTEDQYsLVEDDED	-1									14729945	t		miannu	We find that p110 alpha phosphorylates p85 alpha Ser608 in vivo with significant stoichiometry. However, p110 beta is far less efficient at phosphorylating p85 alpha Ser608, identifying a potential difference in the mechanisms by which these two isoforms are regulated. The p85 alpha Ser608 phosphorylation was increased by treatment with insulin, platelet-derived growth factor, and the phosphatase inhibitor okadaic acid. The functional effects of this phosphorylation are highlighted by mutation of Ser608, which results in reduced lipid kinase activity and reduced association of the p110 alpha catalytic subunit with p85 alpha. 	SIGNOR-276004	0.934
CCNA1	protein	P78396	UNIPROT	G1/S_transition	phenotype	SIGNOR-PH50	SIGNOR	up-regulates													15829981	f		lperfetto	Cyclin A1 contributes to G1 to S cell cycle progression in somatic cells. Cyclin A1 overexpression enhances S phase entry consistent with an oncogenic function. Finally, cyclin A1 might be a therapeutic target since its silencing inhibited leukemia cell growth.	SIGNOR-252255	0.7
SMARCC1	protein	Q92922	UNIPROT	GBAF	complex	SIGNOR-C467	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269786	0.642
PPP2CA	protein	P67775	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	down-regulates activity	dephosphorylation	Ser472	RPHFPQFsYSASGRE	10090									15367694	t			Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes	SIGNOR-248652	0.725
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606									24168260	f		miannu	NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis	SIGNOR-260445	0.7
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	RXRA	protein	P19793	UNIPROT	down-regulates activity	phosphorylation			9606									17604322	t	inferred from 70% family members	lperfetto	In colon cancer cells, the Ras/mitogen‚Äêactivated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‚Äêmutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 	SIGNOR-269995	0.2
GOT2	protein	P00505	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	chemical modification			9606									31422819	t			Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate.	SIGNOR-266922	0.8
GRPEL2	protein	Q8TAA5	UNIPROT	TIM23 complex	complex	SIGNOR-C423	SIGNOR	form complex	binding												32074073	t		lperfetto	The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE.	SIGNOR-267700	0.501
bisphenol A	chemical	CHEBI:33216	ChEBI	AHR	protein	P35869	UNIPROT	up-regulates activity	chemical activation			-1									31995776	t		miannu	This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity.In our study, BPs showed AhR agonist activity only at the highest concentrations, and the mixture did not differ from the single BPs.	SIGNOR-268735	0.8
UBE3C	protein	Q15386	UNIPROT	CAND2	protein	O75155	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000165								12692129	t		miannu	We show that KIAA10 indeed associates with 26 S proteasomes in mammalian cells but that this interaction is likely to depend on contacts with a subunit(s) besides S2/Rpn1. Most importantly, we provide strong evidence that TIP120B (TBP-interacting protein 120B (22)) is a specific substrate that is targeted for degradation in skeletal muscle through KIAA10-catalyzed polyubiquitination.	SIGNOR-271454	0.399
CDK18	protein	Q07002	UNIPROT	PTK2	protein	Q05397	UNIPROT	down-regulates activity				9606	BTO:0000567								28361970	f		lperfetto	PCTK3/CDK18 regulates cell migration and adhesion by negatively modulating FAK activity	SIGNOR-264561	0.2
JAK3	protein	P52333	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates activity	phosphorylation	Tyr1034	AIETDKEyYTVKDDR	-1									12559972	t			Phosphorylation by recombinant JAK3 of a peptide substrate corresponding to the JAK1 activation loop (KAIETDKEYYTVKD)	SIGNOR-251363	0.515
3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[(3-methyl-4-oxo-6-quinazolinyl)amino]phenyl]benzamide	chemical	CHEBI:91354	ChEBI	RAF1	protein	P04049	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190146	0.8
H2AZ1	protein	P0C0S5	UNIPROT	Nucleosome_H2A.Z.1 variant	complex	SIGNOR-C322	SIGNOR	form complex	binding			-1									24311584	t		miannu	In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined.	SIGNOR-263715	0.2
ROCK2	protein	O75116	UNIPROT	DPYSL2	protein	Q16555	UNIPROT	up-regulates	phosphorylation	Thr555	DNIPRRTtQRIVAPP	9606	BTO:0000938								10818093	t		lperfetto	Rho-kinase phosphorylated crmp-2 at thr-555 in vitro.we demonstrated that crmp-2 is phosphorylated by rho-kinase in drg neurons during lpa-induced growth cone collapse.	SIGNOR-77543	0.393
TAF2	protein	Q6P1X5	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269574	0.535
CSNK2A3	protein	Q8NEV1	UNIPROT	FGF14	protein	Q92915	UNIPROT	up-regulates activity	phosphorylation	Ser228	PGVTPSKsTSASAIM	9606	BTO:0000938								26917740	t		lperfetto	 Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.	SIGNOR-275742	0.272
ATM	protein	Q13315	UNIPROT	DYRK2	protein	Q92630	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr106	NKRTVLTtQPNGLTT										19965871	t	Phosphosites were derived from Figure 3	lperfetto	ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. 	SIGNOR-275576	0.538
RPS6KA1	protein	Q15418	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606	BTO:0000007								10837486	t		lperfetto	Rsk1, and survival factor signaling stimulate phosphorylation of bad at ser-155, blocking the binding of bad to bcl-xl.	SIGNOR-78020	0.404
LCK	protein	P06239	UNIPROT	DAPP1	protein	Q9UN19	UNIPROT	up-regulates activity	phosphorylation	Tyr139	KVEEPSIyESVRVHT										10880360	t		lperfetto	Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins.	SIGNOR-249373	0.631
IRAK4	protein	Q9NWZ3	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Thr86	YTLSRAQtVVVEYTH	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276128	0.643
TSC22D3	protein	Q99576	UNIPROT	RELA	protein	Q04206	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								11468175	t			GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits.	SIGNOR-253297	0.381
BRSK1	protein	Q8TDC3	UNIPROT	CAST	protein	P20810	UNIPROT	up-regulates activity	phosphorylation	Ser45	KSQSTKLsVVHEKKS	10090	BTO:0000142								27626661	t		miannu	Here, we show that an AZ cytomatrix protein CAST and an AZ-associated protein kinase SAD-B coordinately regulate STD by controlling reloading of the AZ with release-ready synaptic vesicles. SAD-B phosphorylates the N-terminal serine (S45) of CAST, and S45 phosphorylation increases with higher firing rate. 	SIGNOR-263051	0.2
LEPR	protein	P48357	UNIPROT	SH2B1	protein	Q9NRF2	UNIPROT	up-regulates activity	binding												27154742	t		lperfetto	The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex	SIGNOR-253077	0.34
GRM6	protein	O15303	UNIPROT	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							20055706	t		miannu	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264084	0.322
JAK2	protein	O60674	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr718	IPERDSRySQPLHEE	9606	BTO:0001963								19287004	t		miannu	Furthermore, JAK2, but not JAK1, directly bound to and phosphorylated ASK1 at Tyr-718, leading to an enhanced association of ASK1 with SOCS1 and subsequent ASK1 degradation. 	SIGNOR-276145	0.374
NLGN2	protein	Q8NFZ4	UNIPROT	MAGI2	protein	Q86UL8	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							22626542	t		miannu	 S-SCAM is a member of the membrane-associated guanylate kinase (MAGUK) family of PDZ-domain-containing proteins that include the synaptic organising molecule PSD-95. The PDZ domain of S-SCAM binds to the C-terminal tail of NL2, forming a ternary complex at the cell membrane (Figure 2b). The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 	SIGNOR-265444	0.413
PIM1	protein	P11309	UNIPROT	HBP1	protein	O60381	UNIPROT	up-regulates activity	phosphorylation	Ser372	SAVYVLSsMARQRRA	9606	BTO:0002181								28348080	t		miannu	 Pim-1 binds to and phosphorylates the transcription factor high mobility group box transcription factor 1 (HBP1), activating it.	SIGNOR-277346	0.2
RBM15	protein	Q96T37	UNIPROT	SON	protein	P18583	UNIPROT	up-regulates	binding			9606									19786495	t		miannu	Here we report that the human nxf1-binding protein rbm15 binds specifically to human dbp5 and facilitates its direct contact with mrna in vivo.	SIGNOR-188264	0.241
CTTNBP2NL	protein	Q9P2B4	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates activity	binding			10116									23015759	t		miannu	CTTNBP2NL interacts with cortactin and targets cortactin to stress fibers.	SIGNOR-261695	0.365
TGFBR2	protein	P37173	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates activity	phosphorylation	Ser409	LRLDPTLsVDDLANS	9606	BTO:0000972				phosphorylation:Ser213	TRKLMEFsEHCAIIL 			9155023	t		lperfetto	Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function.	SIGNOR-246743	0.2
SLC1A7	protein	O00341	UNIPROT	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	up-regulates quantity	relocalization			9606									26687113	t		miannu	After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5).	SIGNOR-264806	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PDE11A	protein	Q9HCR9	UNIPROT	up-regulates activity	phosphorylation	Ser117	GNLQRRAsQKELRKS	-1									18312413	t		miannu	The N-terminus has two phosphorylation sites for cyclic nucleotide monophosphate-dependent protein kinases (Ser117, Ser168). Phosphorylation of both by cAMP-dependent protein kinase decreased the EC50 value for cGMP from 72 to 23 μm. Effect of phosphorylations at Ser117 and Ser162. Here, serine phosphorylation by the catalytic subunit of cAK, albeit not known whether at position 117, 162 or both, increased cGMP affinity about threefold.	SIGNOR-276153	0.2
MAPK1	protein	P28482	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Thr325	TELEPLCtPVVTCTP	9606									12972619	t		lperfetto	We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2.	SIGNOR-236010	0.784
NRG1	protein	Q02297	UNIPROT	ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	up-regulates	binding			9606									14967450	t	inferred from 70% of family members	gcesareni	The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4.	SIGNOR-269870	0.904
PRKACA	protein	P17612	UNIPROT	DSP	protein	P15924	UNIPROT	down-regulates activity	phosphorylation	Ser2849	RSGSRRGsFDATGNS	9606	BTO:0000567								7525582	t		miannu	HeLa cells treated with forskolin indicated that stimulation of protein kinase A in transfected cells could decrease the interaction of DP.AN.SerC23 with keratin IF networks. phosphorylation of Ser-C23 could destabilize interactions that occur either directly through this 20 residue sequence or that are dependent on its correct conformation	SIGNOR-250353	0.334
PRKCA	protein	P17252	UNIPROT	CD5	protein	P06127	UNIPROT	unknown	phosphorylation	Thr434	MSFHRNHtATVRSHA	9606									11123317	t		lperfetto	Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. 	SIGNOR-249070	0.345
AKT1	protein	P31749	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates activity	phosphorylation	Ser429	PQRERKSsSSSEDRN	9606	BTO:0000007								10869359	t			Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo	SIGNOR-251472	0.47
DOK1	protein	Q99704	UNIPROT	AX/b2 integrin	complex	SIGNOR-C171	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257683	0.301
RBBP7	protein	Q16576	UNIPROT	MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263836	0.827
YWHAQ	protein	P27348	UNIPROT	GEM	protein	P55040	UNIPROT	up-regulates quantity by stabilization	binding			9534									14701738	t		miannu	In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase	SIGNOR-261714	0.269
EEF1A2	protein	Q05639	UNIPROT	Ala-tRNA(Ala)	smallmolecule	CHEBI:17732	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269523	0.8
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Thr371	LLAKLEEtKEYQEPE	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276210	0.389
PBK	protein	Q96KB5	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	unknown	phosphorylation			9606									16982762	t		gcesareni	Pbk/topk could phosphorylate histone h3 at ser10 in vitro and in vivo, and mediated its growth-promoting effect through histone h3 modification.	SIGNOR-265364	0.2
AT-406	chemical	CID:25022340	PUBCHEM	BIRC3	protein	Q13489	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189957	0.8
Zalospirone	chemical	CID:163925	PUBCHEM	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029									9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258864	0.8
CDK1	protein	P06493	UNIPROT	FEN1	protein	P39748	UNIPROT	down-regulates activity	phosphorylation	Ser187	MDCLTFGsPVLMRHL	9606	BTO:0000007								12853968	t		lperfetto	Phosphorylation of human fen1 by cyclin-dependent kinase modulates its role in replication fork regulation.As a functional consequence of phosphorylation by cdk1-cyclin a in vitro, endo- and exonuclease activities of fen1 are reduced whereas its dna binding is not affected.	SIGNOR-103535	0.456
MAPK1	protein	P28482	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates	phosphorylation	Ser664	KKTSGPLsPPTGPPG	9606									15851026	t		llicata	Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. s664 is the primary erk phosphorylation site on tsc2 in vitro and in vivo	SIGNOR-135696	0.668
PRKCD	protein	Q05655	UNIPROT	OPRD1	protein	P41143	UNIPROT	unknown	phosphorylation	Ser344	CGRPDPSsFSRAREA	9606									11085981	t		lperfetto	In the current study, we identified a PKC-mediated phosphorylation site in the delta-opioid receptor (DOR) and demonstrated that activation of PKC by stimulation of other types of GPCR or increase in intracellular Ca2+concentration in HEK 293 cells induces heterologous phosphorylation of DOR. Our results further established that DOR phosphorylation at Ser-344 by PKC results in internalization of DOR in HEK 293 cells through a beta-arrestin- and clathrin-mediated mechanism.	SIGNOR-249063	0.311
KMT5C	protein	Q86Y97	UNIPROT	H4C1	protein	P62805	UNIPROT	down-regulates activity	methylation	Lys21	GGAKRHRkVLRDNIQ	-1									24396869	t		miannu	SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation. 	SIGNOR-266650	0.2
PRKD1	protein	Q15139	UNIPROT	SSH1	protein	Q8WYL5	UNIPROT	down-regulates	phosphorylation	Ser937	SNLTRSSsSDSIHSV	9606									21525957	t		gcesareni	Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1.	SIGNOR-173437	0.494
LCK	protein	P06239	UNIPROT	PRDX1	protein	Q06830	UNIPROT	down-regulates activity	phosphorylation	Tyr194	DVQKSKEyFSKQK	-1									20178744	t		miannu	Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.	SIGNOR-276277	0.2
gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	GABA-B receptor	complex	SIGNOR-C336	SIGNOR	up-regulates activity	chemical activation			9606									9872316	t	brain	lperfetto	GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals.	SIGNOR-263795	0.8
MRPL50	protein	Q8N5N7	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262338	0.675
HCK	protein	P08631	UNIPROT	WAS	protein	P42768	UNIPROT	up-regulates activity	phosphorylation	Tyr291	AETSKLIyDFIEDQG	9534									12235133	t			Src family kinase Hck induces phosphorylation of WASp-Tyr(291). Phosphorylation of tyrosine 291 enhances the ability of WASp to stimulate actin polymerization and filopodium formation. 	SIGNOR-251268	0.572
MCU	protein	Q8NE86	UNIPROT	 MCU_MICU3_variant	complex	SIGNOR-C501	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270869	0.679
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	MAPK6	protein	Q16659	UNIPROT	up-regulates	phosphorylation	Thr698	KSIQATLtPSAMKSS	9606									20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.	SIGNOR-216809	0.373
CASP3	protein	P42574	UNIPROT	KDM4C	protein	Q9H3R0	UNIPROT	down-regulates activity	cleavage			9606									29207681	t		miannu	JMJD2C as a novel substrate for caspase-3 (cysteine-aspartic acid protease-3), and cleavage of JMJD2C by caspase-3 led to inactivation of JMJD2C demethylase activity and elevation of H3K9 methylation levels.	SIGNOR-263870	0.2
HMOX1	protein	P09601	UNIPROT	STC2/HMOX1	complex	SIGNOR-C244	SIGNOR	form complex	binding				BTO:0000298								22503972	t		Giorgia	Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme.	SIGNOR-260388	0.352
CDK2	protein	P24941	UNIPROT	NPAT	protein	Q14207	UNIPROT	up-regulates	phosphorylation	Thr1350	ISRTTSAtPLKDNTQ	9606									10995387	t		llicata	Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter.	SIGNOR-82141	0.458
FUS	protein	P35637	UNIPROT	SNRNP70	protein	P08621	UNIPROT	up-regulates activity	binding			9606									26124092	t			FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP	SIGNOR-262823	0.446
Synaptonemal_complex	complex	SIGNOR-C351	SIGNOR	Meiotic_recombination	phenotype	SIGNOR-PH162	SIGNOR	up-regulates				9606									33262143	f		miannu	The synaptonemal complex (SC) is a meiosis-specific structure formed between homologous chromosomes during prophase that promotes DSB formation and biases repair of DSBs to homologs over sister chromatids.	SIGNOR-264204	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ACLY	protein	P53396	UNIPROT	unknown	phosphorylation	Ser455	PAPSRTAsFSESRAD	10116	BTO:0000443								12107176	t		gcesareni	Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B.	SIGNOR-245259	0.2
PGM1	protein	P36871	UNIPROT	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	down-regulates quantity	chemical modification			9606									32898648	t		miannu	Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P).	SIGNOR-267931	0.8
NCOA1	protein	Q15788	UNIPROT	CYP7A1	protein	P22680	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f		miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-255063	0.451
MAPK14	protein	Q16539	UNIPROT	MAP3K11	protein	Q16584	UNIPROT	down-regulates	phosphorylation			9606									20626350	t		gcesareni	Jnk and p38 mapk activation have antagonistic effects in many cases. From a mechanicistic point of view, the p38 mapk pathway can negatively regulate jnk activity at the level of map3ks, either by phosphorylating mlk3 or the tak1 regulatory subunit tab2	SIGNOR-166605	0.31
CSNK1E	protein	P49674	UNIPROT	CSNK1E	protein	P49674	UNIPROT	down-regulates activity	phosphorylation	Thr407	SRIPASQtSVPFDHL	9606	BTO:0000007								10542239	t		llicata	Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T	SIGNOR-250814	0.2
STAT6	protein	P42226	UNIPROT	KDM6B	protein	O15054	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19567879	f		lperfetto	We demonstrate that IL-4dependent Jmjd3 expression is mediated by STAT6, a major transcription factor of IL-4mediated signaling. After IL-4 stimulation, activated STAT6 is increased and binds to consensus sites at the Jmjd3 promoter.	SIGNOR-249539	0.445
mTORC1	complex	SIGNOR-C3	SIGNOR	NRBF2	protein	Q96F24	UNIPROT	up-regulates activity	phosphorylation	Ser120	SPLSQKYsPSTEKCL	9606									28059666	t		miannu	Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association.	SIGNOR-265877	0.2
SCRIB	protein	Q14160	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates activity	binding			9606	BTO:0000007								20622900	t		miannu	These two KIM sites are found at N- and C-terminal locations on hScrib, and both are essential for directing the interaction between ERK and hScrib, but with the C-terminal site having the strongest affinity for ERK. One of the most likely consequences of this interaction is to inhibit ERK translocation to the nucleus.	SIGNOR-263067	0.373
PRKCG	protein	P05129	UNIPROT	TOP2A	protein	P11388	UNIPROT	up-regulates activity	phosphorylation	Ser29	EDAKKRLsVERIYQK	9606	BTO:0000567								12569090	t		lperfetto	Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. | Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides. 	SIGNOR-249196	0.365
ATM	protein	Q13315	UNIPROT	RPA2	protein	P15927	UNIPROT	unknown	phosphorylation	Thr21	YGGAGGYtQSPGGFG	9606									14872059	t		llicata	Atm and dna?PK Phosphorylate rpa32 thr21in vitro and in vivo	SIGNOR-121865	0.803
PPP1CA	protein	P62136	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates	dephosphorylation			9606									20186153	t		lperfetto	Several stps have been reported to negatively regulate akt pathway. It has been shown that pp1 dephosphorylates akt and regulates cell survival.	SIGNOR-244436	0.436
SS18	protein	Q15532	UNIPROT	GBAF	complex	SIGNOR-C467	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269782	0.64
PRKACA	protein	P17612	UNIPROT	CAD	protein	P27708	UNIPROT	down-regulates	phosphorylation	Ser1406	GAGGRRLsSFVTKGY	9606									17206380	t		gcesareni	Protein kinase a phosphorylation at thr456 of the multifunctional protein cad antagonizes activation by the map kinase cascade.	SIGNOR-151816	0.311
NFKB1	protein	P19838	UNIPROT	BIRC3	protein	Q13489	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9733516	f		gcesareni	Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2	SIGNOR-59951	0.648
MAPK9	protein	P45984	UNIPROT	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation	Ser164	FGHSAAVsPTFMPRS	9606									12050114	t		gcesareni	Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro.	SIGNOR-88748	0.346
MTA1	protein	Q13330	UNIPROT	COP1	protein	Q8NHY2	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0001938								19805145	t		miannu	MTA1 destabilizes COP1 by promoting its autoubiquitination. in addition to polyubiquitination of its substrates, COP1 also catalyzes its autoubiquitination for degradation as a part of an autoregulatory mechanism	SIGNOR-271892	0.2
WNK4	protein	Q96J92	UNIPROT	SLC12A3	protein	P55017	UNIPROT	up-regulates activity	phosphorylation	Thr50	SHLTHSStFCMRTFG	-1									22342722	t	Q9BYP7:p.Glu562Lys (mutation causing interaction);Q9BYP7:p.Asp564Ala (mutation causing interaction);Q9BYP7:p.Gln565Glu (mutation causing interaction)	lperfetto	Threonine 48 was identified as the WNK4 phosphorylation site at mouse NCC|. Thus, WNK4 stimulates NCC in three ways: (1) direct phosphorylation and in turn increasing NCC protein abundance; (2) facilitating the phosphorylation of NCC by SPAK/OSR1 indirectly, and (3) phosphorylating and activating SPAK/OSR1.|Evidences from early studies using Xenopus oocytes and mammalian cells indicate that WNK4 inhibits NCC and PHAII-causing mutations relieve the inhibition	SIGNOR-264631	0.598
RPS6KB1	protein	P23443	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser78	PAYSRALsRQLSSGV	9606									19593530	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	lperfetto	Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk.	SIGNOR-186955	0.315
Sanglifehrin A	chemical	CID:5388925	PUBCHEM	IMPDH2	protein	P12268	UNIPROT	down-regulates activity	chemical inhibition			9606									28076787	t		Monia	We show that the mammalian target of SFA is inosine-50 -monophosphate dehydrogenase 2 (IMPDH2); Biochemical characterization reveals that PPIA-SFA does not inhibit the catalytic activity of IMPDH2 but rather, it modulates cell growth via binding to the cystathionine-b-synthase (CBS) domain.	SIGNOR-261099	0.8
MAPK1	protein	P28482	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Thr453	SGPIIIRtPTVGPNG	9606									11904305	t		gcesareni	Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1.	SIGNOR-116162	0.629
MLL2 complex	complex	SIGNOR-C88	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	binding			9606									16603732	t		miannu	Eralpha directly binds to the mll2 complex through two lxxll motifs in a region of mll2 near the c terminus in a ligand-dependent manner. Disrupting the interaction between eralpha and the mll2 complex with small interfering rnas specific against mll2 or an mll2 fragment representing the interacting region with eralpha significantly inhibited the eralpha transcription activity.	SIGNOR-145868	0.466
DTX1	protein	Q86Y01	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	ubiquitination			10090	BTO:0000165								11226752	t		gcesareni	Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis	SIGNOR-236870	0.773
PIM1	protein	P11309	UNIPROT	SKP2	protein	Q13309	UNIPROT	up-regulates activity	phosphorylation	Ser64	SNLGHPEsPPRKRLK	9606	BTO:0000567								20663873	t		miannu	We found that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser(64) and Ser(72), we have identified Thr(417) as a unique Pim-1 phosphorylation target. Phosphorylation of Thr(417) controls the stability of Skp2 and its ability to degrade p27. 	SIGNOR-259818	0.346
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1693	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273070	0.636
CDK7	protein	P50613	UNIPROT	RARA	protein	P10276	UNIPROT	up-regulates	phosphorylation	Ser77	EIVPSPPsPPPLPRI	9606	BTO:0000567								9230306	t		llicata	However, only the coexpression of cdk7 stimulated ser-77 phosphorylation in vivo and enhanced transactivation by rar alpha, but not by a s77a rar mutant.	SIGNOR-49693	0.526
KAT5	protein	Q92993	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates activity	acetylation	Lys3016	VLMRLQEkLKGVEEG										30944854	t		lperfetto	Here, we report that sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. |Upon DNA damage, ATM is activated via a series of highly organized machineries, including acetylation by the histone acetyltransferase TIP60 at lysine 3016	SIGNOR-275891	0.794
PHF10	protein	Q8WUB8	UNIPROT	SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270598	0.681
progesterone	smallmolecule	CHEBI:17026	ChEBI	Corticotropin	protein	P01189-PRO_0000024969	UNIPROT	down-regulates													24631756	f		lperfetto	ACTH and corticosterone responses to the same acute stress stimulus are higher in the pro-estrus phase of the cycle, when the serum concentrations of estrogen are the highest (Viau and Meaney, 1991). In the same study, it was shown that progesterone inhibits the sensitizing effects of estrogen on ACTH release during stress, as the ACTH levels and HPA output decreased with increasing amounts of progesterone in the estrous and diestrous phases. 	SIGNOR-268727	0.8
MAPK3	protein	P27361	UNIPROT	PAX5	protein	Q02548	UNIPROT	down-regulates activity	phosphorylation	Ser189; Ser283	SGILGITsPSADTNK;DMKANLAsPTPADIG	9606	BTO:0003079								22593617	t		Gianni	In this study, we demonstrated that PAX5 was phosphorylated by ERK1/2 in vitro and in vivo at serines 189 and 283. This phosphorylation attenuated the transcriptional repression of BLIMP1 by PAX5.	SIGNOR-269086	0.25
CHD8	protein	Q9HCK8	UNIPROT	NEUROD4	protein	Q9HD90	UNIPROT	down-regulates quantity	transcriptional regulation			10090									32839322	t		Gianni	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268918	0.2
NDUFS8	protein	O00217	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46].	SIGNOR-262182	0.846
RNF4	protein	P78317	UNIPROT	NFYA	protein	P23511	UNIPROT	up-regulates activity	binding			9606									15496512	t		miannu	Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter.	SIGNOR-252229	0.2
GSK3A	protein	P49840	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000938								7566348	t		fstefani	The ability of p42 map and p44 map kinases, glycogen synthase kinases 3 alpha and 3 beta (gsk-3 alpha and gsk-3 beta) to phosphorylate tau in transfected cos cells was investigated. Both gsk-3 alpha and gsk-3 beta phosphorylated tau to produce a phf-like state of phosphorylation but the map kinases failed to induce such a transformation in tau.	SIGNOR-29364	0.44
CYP27B1	protein	O15528	UNIPROT	calcitriol	smallmolecule	CHEBI:17823	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000671							12050193	t		lperfetto	The rate-limiting, hormonally regulated step in the biological activation of vitamin D is its 1alpha-hydroxylation to 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] in the kidney, catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha. 	SIGNOR-270559	0.8
UBE2D2	protein	P62837	UNIPROT	TRIM9	protein	Q9C026	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							20085810	t		miannu	Collectively, these results indicated that TRIM9 is an E3 ligase for its self-ubiquitination and that the ubiquitination of TRIM9 likely serves as a signal for proteasomal degradation. As shown in Fig. 1A, TRIM9 was ubiquitinated by itself when incubated with UbcH5b. In contrast, ubiquitination was observed when incubated with other E2 enzymes. These results suggest that TRIM9 cooperates with UbcH5b for its self-ubiquitination. N	SIGNOR-271420	0.4
NBR1	protein	Q14596	UNIPROT	GABARAPL1	protein	Q9H0R8	UNIPROT	up-regulates	binding			9606	BTO:0000007								19250911	t		gcesareni	We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family	SIGNOR-184264	0.735
HIF3A	protein	Q9Y2N7	UNIPROT	EPAS1	protein	Q99814	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000972								21479871	t		Luana	None of the long HIF-3α variants was capable of efficient induction of an HRE reporter in overexpression experiments, but instead inhibited the transcriptional activation of the reporter by HIF-1 and HIF-2. 	SIGNOR-261616	0.508
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1623	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273097	0.745
STAT5A	protein	P42229	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0001096								14530308	f		apalma	Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells	SIGNOR-256583	0.7
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	ABCB1	protein	P08183	UNIPROT	up-regulates activity	dephosphorylation	Ser671	RKRSTRRsVRGSQAQ	9606	BTO:0000007								24333728	t			Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp	SIGNOR-272514	0.2
2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline	smallmolecule	CHEBI:94276	ChEBI	GLI1	protein	P08151	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150;BTO:0001130								17494766	t		gcesareni	Gant61 was able to efficiently block gli1 as well as gli2-induced transcription	SIGNOR-154753	0.8
CDK1	protein	P06493	UNIPROT	PITPNM1	protein	O00562	UNIPROT	up-regulates	phosphorylation	Ser382	DFIDAFAsPVEAEGT	9606									15125835	t		lperfetto	Here we show that, at the onset of mitosis, cdk1 phosphorylates the peripheral golgi protein nir2 at multiple sites;of these, s382 is the most prominent. Phosphorylation of nir2 by cdk1 facilitates its dissociation from the golgi apparatus, and phospho-nir2(ps382) is localized in the cleavage furrow and midbody during cytokinesis.	SIGNOR-124638	0.477
TGFBR2	protein	P37173	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates activity	phosphorylation	Tyr259	KGRFAEVyKAKLKQN	-1									9169454	t		lperfetto	Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor.	SIGNOR-48859	0.2
BMPR2	protein	Q13873	UNIPROT	BMPR1A	protein	P36894	UNIPROT	up-regulates	phosphorylation			9606			SIGNOR-C29	SIGNOR-C29					18756288	t		gcesareni	Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1.	SIGNOR-180545	0.615
OGT	protein	O15294	UNIPROT	PFKP	protein	Q01813	UNIPROT	down-regulates activity	glycosylation	Ser540	VMVPATVsNNVPGSD	9606	BTO:0000018								26399441	t		lperfetto	Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 	SIGNOR-267583	0.26
BCL2	protein	P10415	UNIPROT	BAX	protein	Q07812	UNIPROT	down-regulates activity	binding			9606	BTO:0000776;BTO:0000785								8183370	t		lperfetto	Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax.	SIGNOR-36898	0.619
KDM1A	protein	O60341	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									15620353	t		miannu	 Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. 	SIGNOR-264508	0.2
CHEK2	protein	O96017	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Ser379	SKILGETsLMRTLCG	9606	BTO:0000007								18644861	t		lperfetto	Regulation of chk2 ubiquitination and signaling through autophosphorylation of serine 379.Thus, auto-/transphosphorylation of s379 is required for chk2 ubiquitination and effector function	SIGNOR-179537	0.2
ADX-47273	chemical	CID:11383075	PUBCHEM	MGluR	proteinfamily	SIGNOR-PF55	SIGNOR	up-regulates	chemical activation			9606									Other	t	Selleck|inferred from family member	gcesareni		SIGNOR-270276	0.8
GOT1	protein	P17174	UNIPROT	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	up-regulates quantity	chemical modification			9606									26003525	t		miannu	Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and α-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer.	SIGNOR-267509	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Thr220	QSNYIPEtPPPGYIS	9606		BTO:0000763							12193595	t		lperfetto	Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction.	SIGNOR-244731	0.2
DUSP1	protein	P28562	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates activity	dephosphorylation	Thr202	HDHTGFLtEYVATRW	10116									7535768	t			We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively	SIGNOR-248462	0.778
SARS1	protein	P49591	UNIPROT	Ser-tRNA(Ser)	smallmolecule	CHEBI:29162	ChEBI	up-regulates quantity	chemical modification			9606									24095058	t		miannu	As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis	SIGNOR-270498	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	DNMT1	protein	P26358	UNIPROT	up-regulates	phosphorylation	Ser143	RTPRRSKsDGEAKPE	9606									21151116	t		lperfetto	Akt1 kinase colocalizes and directly interacts with dnmt1 and phosphorylates ser143. Phosphorylated dnmt1 peaks during dna synthesis, before dnmt1 methylation. Depletion of akt1 or overexpression of dominant-negative akt1 increases methylated dnmt1, resulting in a decrease in dnmt1 abundance. In mammalian cells, phosphorylated dnmt1 is more stable than methylated dnmt1.	SIGNOR-244232	0.2
CDH4	protein	P55283	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity				10090									18701479	t		lperfetto	Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS.	SIGNOR-253103	0.277
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PCBP2	protein	Q15366	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr213	SASFPHTtPSMCLNP	10090	BTO:0000667								17475908	t		miannu	All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells.	SIGNOR-262671	0.2
STK11	protein	Q15831	UNIPROT	SNRK	protein	Q9NRH2	UNIPROT	up-regulates activity	phosphorylation	Thr173	QPGKKLTtSCGSLAY	9606									15733851	t		Manara	We demonstrate that LKB1 activates SNRK by phosphorylating the T‐loop residue (Thr173)	SIGNOR-260824	0.374
HNRNPU	protein	Q00839	UNIPROT	ZFY	protein	P08048	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation												17174306	f		lperfetto	In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs.	SIGNOR-262287	0.2
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	PARP1	protein	P09874	UNIPROT	down-regulates activity	cleavage			10090	BTO:0000331								11907276	t		amattioni	Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process	SIGNOR-256465	0.767
SRC	protein	P12931	UNIPROT	TNS3	protein	Q68CZ2	UNIPROT	up-regulates	phosphorylation	Tyr1256	KGCSNEPyFGSLTAL	9606	BTO:0000150;BTO:0000551;BTO:0000848								19732724	t		llicata	Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate	SIGNOR-187851	0.417
XRCC3	protein	O43542	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567		SIGNOR-C301						23438602	t		lperfetto	We examined the effect of XRCC3 depletion on redistribution of RAD51 upon IR damage|Interestingly, cells expressing the XRCC3 S225A phosphomutant showed compromised chromatin loading of RAD51 upon IR damage (Fig. 4G) while the nuclear and cytosolic fractions of RAD51 were largely unchanged|It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation.	SIGNOR-263258	0.737
RPS12	protein	P25398	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262440	0.764
PP121	chemical	CHEBI:50915	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206301	0.8
WNT6	protein	Q9Y6F9	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131894	0.576
MK-2461	chemical	CID:44137946	PUBCHEM	FLT3	protein	P36888	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194378	0.8
MLL-AF9	fusion protein	SIGNOR-FP5	SIGNOR	DOT1L	protein	Q8TEK3	UNIPROT	up-regulates activity	binding			10090	BTO:0004052								23996074	t		irozzo	In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL.The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1	SIGNOR-255869	0.2
FOXE1	protein	O00358	UNIPROT	MSX1	protein	P28360	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									21177256	f	 	miannu	The MSX1 and TGF-β3 up-regulation in response to FOXE1 at both transcriptional and translational levels and the recruitment of FOXE1 to specific binding motifs, together with the transactivation of the promoters of these genes, indicate that MSX1 and TGF-β3 are direct FOXE1 targets.	SIGNOR-254173	0.395
TCF4	protein	P15884	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20459685	f	 	miannu	 Cd2+ reduced the interaction of beta-catenin with AJ components (E-cadherin, alpha-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling. 	SIGNOR-255388	0.347
PCSK7	protein	Q16549	UNIPROT	ATF6	protein	P18850	UNIPROT	up-regulates	phosphorylation			9606									12076252	t		gcesareni	We discovered that azc, an agent that causes the formation of abnormal proteins, stimulates the stress-activated kinase p38 mapk, which phosphorylates atf6	SIGNOR-89813	0.2
TGFBI	protein	Q15582	UNIPROT	a7/b1 integrin	complex	SIGNOR-C126	SIGNOR	up-regulates activity	binding												26387839	t		lperfetto	 BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers	SIGNOR-253266	0.417
PDPK1	protein	O15530	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	up-regulates	phosphorylation	Thr305	TDAATMKtFCGTPEY	9606		BTO:0000887;BTO:0001103;BTO:0001760							9512493	t		gcesareni	The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma)	SIGNOR-55937	0.635
Telatinib	chemical	CID:9808844	PUBCHEM	PDGFRB	protein	P09619	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207230	0.8
PRKCG	protein	P05129	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	down-regulates	phosphorylation	Thr115	GTIAKSGtKAFMEAL	9606									24117238	t		lperfetto	Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity.	SIGNOR-202812	0.26
CSNK2A1	protein	P68400	UNIPROT	CAPZA1	protein	P52907	UNIPROT	up-regulates	phosphorylation	Ser9	ADFDDRVsDEEKVRI	9606									15831458	t		lperfetto	We demonstrate that ser9 of cpalpha is phosphorylated by protein kinase ck2 in vitro, that cpalpha is phosphorylated in vivo. Finally, we demonstrate that ckip-1 and ck2 inhibit the activity of actin capping protein at the barbed ends of actin filaments.	SIGNOR-135422	0.2
PRKACA	protein	P17612	UNIPROT	GPKOW	protein	Q92917	UNIPROT	up-regulates activity	phosphorylation	Thr316	GTASSRKtLWNQELY	-1									21880142	t		miannu	PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites.	SIGNOR-266308	0.311
CD40	protein	P25942	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								12324477	f		gcesareni	Cd40 ligation up-regulated bcl-2 and bcl-xl as much as 9.7- (p < 0.01) and 6.8-fold (p < 0.01), respectively (fig. 2, b and c). Under similar conditions, cd27 ligation also up-regulated bcl-2 and bcl-xl as much as 5.0- (p < 0.01) and 3.9-fold (p < 0.01), respectively.	SIGNOR-93387	0.439
pazopanib	chemical	CHEBI:71219	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258262	0.8
NTRK3	protein	Q16288	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	binding			9606	BTO:0000938								10092678	t		gcesareni	We demonstrate that the phosphotyrosine binding domain of frs-2 directly binds the trk receptors at the same phosphotyrosine residue that binds the signaling adapter shc, suggesting a model in which competitive binding between frs-2 and shc regulates differentiation versus proliferation.	SIGNOR-65958	0.72
PTPMT1	protein	Q8WUK0	UNIPROT	1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-)	smallmolecule	CHEBI:60110	ChEBI	down-regulates quantity	chemical modification			10090									21641550	t		lperfetto	PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis.	SIGNOR-267026	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	ARHGAP26	protein	Q9UNA1	UNIPROT	unknown	phosphorylation			-1									9525907	t	inferred from 70% family members	miannu	In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling.	SIGNOR-270058	0.2
PDGFRA	protein	P16234	UNIPROT	PDGFRA	protein	P16234	UNIPROT	up-regulates activity	phosphorylation	Tyr762	SDIQRSLyDRPASYK	9823									9546424	t		miannu	Tyr-762 is an autophosphorylation site in the human platelet-derived growth factor (PDGF) alpha-receptor. Crk proteins associate with phosphorylated Tyr-762 in the PDGF a-receptor in vivo	SIGNOR-249716	0.2
zotepine	chemical	CHEBI:32316	ChEBI	HTR1E	protein	P28566	UNIPROT	down-regulates activity	chemical inhibition			9534	BTO:0000298								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258557	0.8
AMHR2	protein	Q16671	UNIPROT	BMPR1B	protein	O00238	UNIPROT	up-regulates	binding			9606									14746809	t		gcesareni	See table2	SIGNOR-121596	0.439
HIF1A	protein	Q16665	UNIPROT	KDM1A	protein	O60341	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271573	0.268
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MAP3K8	protein	P41279	UNIPROT	up-regulates activity	phosphorylation	Ser413	LERKRLLsRKELELP	9606	BTO:0000007								12138205	t			Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator.	SIGNOR-251481	0.2
CBLB	protein	Q13191	UNIPROT	PIK3R1	protein	P27986	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000782								11087752	t		miannu	Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells.Here it is shown that Cbl-b interacts with and induces ubiquitin conjugation to the p85 regulatory subunit of phosphatidylinositol 3-kinase, an upstream regulator of Vav. 	SIGNOR-272583	0.495
HOXA13	protein	P31271	UNIPROT	EPHA7	protein	Q15375	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16314414	f		miannu	We show that hoxd13 andhoxa13activate transcription from the epha7 promoter and that a mutation of thehoxa13/hoxd13 binding site was sufficient to abolish activation.	SIGNOR-142428	0.296
MAPKAPK2	protein	P49137	UNIPROT	PDE4A	protein	P27815	UNIPROT	down-regulates activity	phosphorylation	Ser152	SFLYRSDsDYDMSPK	9606	BTO:0000801								21323643	t		miannu	Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP. 	SIGNOR-263078	0.356
BCL6	protein	P41182	UNIPROT	FCER2	protein	P06734	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000776								11342629	f	 	 	In this study, we report that PRDI-BF1/Blimp1 can bind to the same functional element in the human CD23b promoter to which BCL-6 and IRF-4 had previously been shown to bind, and that, like BCL-6, Blimp1 can repress IRF-4-transactivating ability	SIGNOR-253928	0.292
CSNK2B	protein	P67870	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	phosphorylation	Ser29	VSHWQQQsYLDSGIH	9606	BTO:0000007								12432063	t		llicata	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin	SIGNOR-251065	0.587
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1651	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273065	0.636
BRCA1	protein	P38398	UNIPROT	MRE11/RAD50/NBS1	complex	SIGNOR-C147	SIGNOR	up-regulates activity	binding												10426999	t		lperfetto	BRCA1 encodes a tumor suppressor that is mutated in familial breast and ovarian cancers. Here, it is shown that BRCA1 interacts in vitro and in vivo with hRad50, which forms a complex with hMre11 and p95/nibrin. Upon irradiation, BRCA1 was detected in discrete foci in the nucleus, which colocalize with hRad50.| These data suggest that BRCA1 is important for the cellular responses to DNA damage that are mediated by the hRad50-hMre11-p95 complex.	SIGNOR-251501	0.767
CDK1	protein	P06493	UNIPROT	APLP2	protein	Q06481	UNIPROT	unknown	phosphorylation	Thr736	VEVDPMLtPEERHLN	9606		BTO:0000142							9109675	t		lperfetto	A cytoplasmic domain peptide from aplp2 is phosphorylated in vitro by protein kinase c and cdc2 kinase. Aplp2 is phosphorylated by cdc2 kinase at a site homologous to the cdc2 kinase site phosphorylated in app.	SIGNOR-47483	0.338
Nalorphine	chemical	CHEBI:7458	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258814	0.8
belinostat	chemical	CHEBI:61076	ChEBI	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257748	0.8
CSF2	protein	P04141	UNIPROT	CSF2RA	protein	P15509	UNIPROT	up-regulates activity	binding			9606	BTO:0000801								18551128	t		lperfetto	The GM-CSF receptor (CSF2R) is a heterodimer composed of a specific ligand-binding subunit (CSF2Ralpha) and a common signal-transduction subunit (CSF2Rbeta)	SIGNOR-249501	0.851
ATM	protein	Q13315	UNIPROT	SP1	protein	P08047	UNIPROT	unknown	phosphorylation	Ser101	DLTATQLsQGANGWQ	9606									18619531	t		llicata	Thus, phosphorylation of ser-101 on sp1 is a general response to dna damage, dependent on both atm and atr.	SIGNOR-179435	0.422
SFXN1	protein	Q9H9B4	UNIPROT	L-serine	chemical	CHEBI:17115	ChEBI	up-regulates quantity	relocalization			9606									30442778	t		lperfetto	SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism.	SIGNOR-268245	0.8
SNS-314 Mesylate	chemical	CID:24995523	PUBCHEM	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207099	0.8
MAPK3	protein	P27361	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser732	RRVRKLPsTTL	9534									9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-219345	0.705
S100A8	protein	P05109	UNIPROT	Calprotectin complex	complex	SIGNOR-C293	SIGNOR	form complex	binding												9867828	t		lperfetto	Using the two-hybrid system we analyzed the dimerization of MRP8 (S100A8) and MRP14 (S100A9), two S100 proteins expressed in myeloid cells. It is reported that the MRP8-MRP14 heteromer is the clearly preferred complex in both man and mouse.	SIGNOR-262832	0.716
MAPKAPK2	protein	P49137	UNIPROT	ZFP36L1	protein	Q07352	UNIPROT	down-regulates	phosphorylation	Ser92	RFRDRSFsEGGERLL	9606									18326031	t		lperfetto	Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation.	SIGNOR-161278	0.604
mTORC2	complex	SIGNOR-C2	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Thr479	FSYSASGtA	9606	BTO:0000093								24670654	t		gcesareni	Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation	SIGNOR-252444	0.634
CDK1	protein	P06493	UNIPROT	CSNK2B	protein	P67870	UNIPROT	up-regulates	phosphorylation	Ser209	QAASNFKsPVKTIR	9606	BTO:0000785								7578274	t		lperfetto	In cells, the casein kinase ii beta-subunit is phosphorylated at an autophosphorylation site and at a site (ser-209) that is maximally phosphorylated in mitotic cells. These studies provide strong biochemical evidence that p34cdc2 is the enzyme that phosphorylates ser-209 on the beta-subunit of ckii in mitotic cells.	SIGNOR-29462	0.471
PGAM	proteinfamily	SIGNOR-PF78	SIGNOR	2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	up-regulates quantity	chemical modification			9606									24786789	t		miannu	Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle.	SIGNOR-266516	0.8
MAP3K5	protein	Q99683	UNIPROT	DAXX	protein	Q9UER7	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser184	QSPRTRGsRRQIQRL	9606	BTO:0000567								19789335	t		lperfetto	we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1.	SIGNOR-109684	0.835
motesanib	chemical	CHEBI:51098	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194569	0.8
CDK1	protein	P06493	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Thr48	VCPDVPRtPVGKFLG	9606			SIGNOR-C17						10864927	t		gcesareni	Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b.	SIGNOR-78428	0.853
MTMR3	protein	Q13615	UNIPROT	1-phosphatidyl-1D-myo-inositol 3-phosphate(3-)	smallmolecule	CHEBI:58088	ChEBI	down-regulates quantity	chemical modification			9606									18429927	t		miannu	PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 	SIGNOR-269810	0.8
sunitinib	chemical	CHEBI:38940	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000776								20185585	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-163944	0.8
BMP2	protein	P12643	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	up-regulates	binding			9606									7791754	t		lperfetto	Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.	SIGNOR-217532	0.856
nintedanib	chemical	CHEBI:85164	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190299	0.8
CHEK1	protein	O14757	UNIPROT	CDC7	protein	O00311	UNIPROT	up-regulates	phosphorylation			9606									20068082	t		gcesareni	Chk1 directly phosphorylates essential s-phase kinases cdc7.	SIGNOR-163161	0.724
PNMT	protein	P11086	UNIPROT	noradrenaline	smallmolecule	CHEBI:33569	ChEBI	down-regulates quantity	chemical modification			9606									7961964	t	brain	lperfetto	In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline).	SIGNOR-264008	0.8
PIGS	protein	Q96S52	UNIPROT	PIGK	protein	Q92643	UNIPROT	up-regulates activity	binding			10090	BTO:0000095								11483512	t		miannu	To determine roles for PIG-S and PIG-T, we disrupted these genes in mouse F9 cells by homologous recombination. PIG-S and PIG-T knockout cells were defective in transfer of GPI to proteins, particularly in formation of the carbonyl intermediates. We also demonstrate that PIG-S and PIG-T form a protein complex with GAA1 and GPI8, and that PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8.	SIGNOR-261362	0.941
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	CASP8	protein	Q14790	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000149							24342355	t	inferred from 70% family members	lperfetto	We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity	SIGNOR-270118	0.2
PIK-90	chemical	CID:6857685	PUBCHEM	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206226	0.8
3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	Thermogenesis 	phenotype	SIGNOR-PH192	SIGNOR	up-regulates				9606									24692351	f		scontino	TH plays a significant role in energy expenditure through both central and peripheral actions. TH maintains basal metabolic rate, facilitates adaptive thermogenesis, modulates appetite and food intake, and regulates body weight.	SIGNOR-267491	0.7
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDE1	protein	Q9NXR1	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr243	LDDSTGGtPLTPAAR	9606	BTO:0000007								16682949	t	done	miannu	Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. 	SIGNOR-274084	0.525
BBS4	protein	Q96RK4	UNIPROT	BBsome complex	complex	SIGNOR-C288	SIGNOR	form complex	binding			9606	BTO:0004910								19081074	t		lperfetto	We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 	SIGNOR-262560	0.777
HRAS	protein	P01112	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								8052307	t		lperfetto	In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k	SIGNOR-236443	0.922
ACE2	protein	Q9BYF1	UNIPROT	APLN	protein	Q9ULZ1	UNIPROT	up-regulates activity	cleavage			-1									11815627	t		miannu	ACE2 hydrolyzes the hormone apelin-13 with high catalytic efficiency and cleaves apelin-36, whose C-terminal 13 amino acids are identical to those of apelin-13. 	SIGNOR-256316	0.435
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Phe634	VHHQKLVfFAEDVGS	-1									10605825	t		lperfetto	In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D.	SIGNOR-261771	0.502
RTKs	proteinfamily	SIGNOR-PF38	SIGNOR	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9606									17306385	t		miannu	Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase 	SIGNOR-256166	0.2
IYD	protein	Q6PHW0	UNIPROT	3,5-diiodo-L-tyrosine	smallmolecule	CHEBI:15768	ChEBI	down-regulates quantity	chemical modification			9606									28153798	t		scontino	MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide.	SIGNOR-267036	0.8
PTPRG	protein	P23470	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	dephosphorylation	Tyr530	FTSTEPQyQPGENL	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254726	0.312
IKBKB	protein	O14920	UNIPROT	TSC1	protein	Q92574	UNIPROT	down-regulates	phosphorylation	Ser487	AAISRELsEITTAEA	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression.	SIGNOR-183688	0.627
AML1-ETO	fusion protein	SIGNOR-FP1	SIGNOR	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates activity	binding			9606	BTO:0004136								10208431	t		miannu	The AML1/ETO fusion protein is essential to the development of t(8;21) acute myeloid leukemia (AML) and is well recognized for its dominant-negative effect on the coexisting wild-type protein AML1. On physical interaction, AML1/ETO can form a complex with wild-type AML1 on chromatin, and the runt homology domain of both proteins are responsible for their interactions. More importantly, the relative binding signals of AML1 and AML1/ETO on chromatin determine which genes are repressed or activated by AML1/ETO. Further analysis of coregulators indicates that AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex. AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex	SIGNOR-260094	0.2
PTPRJ	protein	Q12913	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates	dephosphorylation	Tyr1365	NVKCVAPyPSLLSSE	9606	BTO:0000150;BTO:0000551								12475979	t		gcesareni	Hepatocyte growth factor receptor tyrosine kinase met is a substrate of the receptor protein-tyrosine phosphatase dep-1	SIGNOR-96347	0.591
FYN	protein	P06241	UNIPROT	CD5	protein	P06127	UNIPROT	unknown	phosphorylation	Tyr453	ASHVDNEySQPPRNS	-1									11298344	t			Tyrosine-mutated CD5 molecules have been used to show that residues Y429 and Y463 are targeted in vivo by protein tyrosine kinases following cell stimulation with anti-CD3 mAb or pervanadate. This is in agreement with data from direct in vitro kinase assays using purified recombinant Lck and Fyn protein tyrosine kinases.	SIGNOR-251151	0.505
KAT2A	protein	Q92830	UNIPROT	H3C15	protein	Q71DI3	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269601	0.2
SOX8	protein	P57073	UNIPROT	FOXK2	protein	Q01167	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000410								32550913	t		miannu	We showed for the first time that Aurora-A interacts directly with SOX8 and phosphorylates the protein at Ser327 to further regulate the SOX8/FOXK1 axis, which modulates cell senescence and glycolysis, ultimately leading to cisplatin resistance.. Our results showed that SOX8 targets FOXK1, thereby regulating its transcription, which has significant impacts on senescence, glycolysis and chemoresistance in ovarian cancer.	SIGNOR-273613	0.293
ATM	protein	Q13315	UNIPROT	METTL3	protein	Q86U44	UNIPROT	up-regulates activity	phosphorylation	Ser43	RNPEAALsPTFRSDS										32615088	t		miannu	Here, we report that, in response to DSBs, the RNA methyltransferase METTL3 is activated by ATM-mediated phosphorylation at S43.	SIGNOR-265969	0.2
NR3C1	protein	P04150	UNIPROT	KLF5	protein	Q13887	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000746								27777311	t			We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα	SIGNOR-256118	0.297
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	STK4	protein	Q13043	UNIPROT	up-regulates activity	cleavage	Asp349	RVASTMTdGANTMIE	9534	BTO:0004055								11517310	t		lperfetto	In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus.	SIGNOR-256445	0.6
SCN1A	protein	P35498	UNIPROT	Action_potential 	phenotype	SIGNOR-PH82	SIGNOR	up-regulates				9606									26043074	f		miannu	The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons.	SIGNOR-253448	0.7
MAPK3	protein	P27361	UNIPROT	PLA2G4A	protein	P47712	UNIPROT	up-regulates	phosphorylation	Ser505	LNTSYPLsPLSDFAT	9606									8381049	t		gcesareni	Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane.	SIGNOR-38434	0.644
PKN2	protein	Q16513	UNIPROT	MEFV	protein	O15553	UNIPROT	down-regulates activity	phosphorylation	Ser242	SGKMRPRsLEVTIST	10090	BTO:0004732								27270401	t	no	miannu	PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. 	SIGNOR-275463	0.357
RPS6KB1	protein	P23443	UNIPROT	PDCD4	protein	Q53EL6	UNIPROT	down-regulates	phosphorylation	Ser67	KRRLRKNsSRDSGRG	9606	BTO:0000007	BTO:0001253							18296647	t		gcesareni	Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.	SIGNOR-160989	0.599
CSNK2A2	protein	P19784	UNIPROT	SAT1	protein	P21673	UNIPROT	unknown	phosphorylation	Ser149	RRGASDLsSEEGWRL	-1									8954982	t		llicata	Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149.	SIGNOR-251035	0.329
GRB2	protein	P62993	UNIPROT	ABL1	protein	P00519	UNIPROT	up-regulates	binding			9606	BTO:0001271								8402896	t	GRB2 binds BCR-ABL with SH2 domain	gcesareni	We demonstrate that bcr-abl exists in a complex with grb-2 in vivo. Binding of grb-2 to bcr-abl is mediated by the direct interaction of the grb-2 sh2 domain with a phosphorylated tyrosine, y177, within the bcr first exon.	SIGNOR-39049	0.561
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PDZK1	protein	Q5T2W1	UNIPROT	up-regulates activity	phosphorylation	Ser505	MAKERAHsTASHSSS	10029	BTO:0000457								16174736	t	done	miannu	Metabolic labeling experiments and phosphoamino acid analysis revealed that PDZK1 is phosphorylated at Ser residues within this region. Point-mutation analysis demonstrated that PDZK1 is phosphorylated at Ser-509. Interestingly, a mutant PDZK1, in which Ser-509 was replaced with Ala, lost the ability to up-regulate SR-BI protein.	SIGNOR-273784	0.2
DDHD2	protein	O94830	UNIPROT	1-acyl-sn-glycerol 3-phosphate	smallmolecule	CHEBI:16975	ChEBI	up-regulates quantity	chemical modification			9606									22922100	t		miannu	Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 	SIGNOR-269655	0.8
MAPK7	protein	Q13164	UNIPROT	MAPK7	protein	Q13164	UNIPROT	up-regulates activity	phosphorylation	Ser731	DPLPPVFsGTPKGSG	9606	BTO:0000567								20667468	t		miannu	Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803.	SIGNOR-259821	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	IL1B	protein	P01584	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001103							20219869	f		apalma	Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6.	SIGNOR-255355	0.57
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259019	0.409
F2RL1	protein	P55085	UNIPROT	WWOX	protein	Q9NZC7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	 PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 	SIGNOR-254854	0.2
SDCBP	protein	O00560	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates activity				9534	BTO:0001444								25122212	f		Luana	Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation.	SIGNOR-260753	0.2
CAV1	protein	Q03135	UNIPROT	SLC1A6	protein	P48664	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								26690923	t		miannu	EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. 	SIGNOR-264810	0.2
MAPK8	protein	P45983	UNIPROT	ARHGAP8	protein	P85298	UNIPROT	up-regulates activity	phosphorylation	Ser455	TKPTLPPsPLMAARR										28092672	t		lperfetto	Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation.	SIGNOR-275550	0.334
MBTPS2	protein	O43462	UNIPROT	SREBF2	protein	Q12772	UNIPROT	up-regulates activity	cleavage			10029	BTO:0000246								10419520	t			In order to activate transcription, the NH2-terminal domain of the SREBP must be released from the membrane so that it can enter the nucleus. This release has been studied most extensively for one of the SREBPs, namely, SREBP-2. However, the mechanism appears to be similar for the other SREBPs (SREBP-1a and -1c) (1). Release of the NH2-terminal domain is accomplished by a two-step proteolytic event that is regulated by sterols (3). In sterol-depleted mammalian cells, this proteolysis is initiated by the Site-1 protease (S1P), which cleaves human SREBP-2 between the Leu522-Ser523 bond in the sequence RSVL S (4). This cleavage requires formation of a complex between SREBP and SCAP, a polytopic membrane protein of the ER, and it is prevented when this complex is disrupted	SIGNOR-267498	0.661
WNK1	protein	Q9H4A3	UNIPROT	STK39	protein	Q9UEW8	UNIPROT	up-regulates	phosphorylation	Ser371	VRRVPGSsGHLHKTE	9606									17190791	t		gcesareni	Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1).	SIGNOR-151667	0.457
4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide	chemical	CHEBI:94504	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191433	0.8
HIF1A	protein	Q16665	UNIPROT	PKG	proteinfamily	SIGNOR-PF77	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567;BTO:0000972								8089148	f	inferred from family member	miannu	Hypoxia-inducible factor 1 (HIF-1) activates erythropoietin gene transcription in Hep3B cells subjected to hypoxia. HIF-1 activity is also induced by hypoxia in non-erythropoietin-producing cells, suggesting a more general regulatory role. We now report that RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 (1% O2, cobalt chloride, or desferrioxamine). Sequences from the ALDA, PFKL, and PGK1 genes containing HIF-1 binding sites mediated hypoxia-inducible transcription in transient expression assays.	SIGNOR-270291	0.482
EGR1	protein	P18146	UNIPROT	FAP	protein	Q12884	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								20515787	f	 	 	Down-regulation of EGR1 resulted in a significant reduction in endogenous FAP mRNA expression. These findings identify the basal transcriptional requirements of FAP gene expression and show EGR1 is an important regulator of FAP expression.	SIGNOR-254248	0.2
PIM1	protein	P11309	UNIPROT	MARK3	protein	P27448	UNIPROT	down-regulates	phosphorylation	Thr90	AIKIIDKtQLNPTSL	9606									15319445	t		gcesareni	Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1.	SIGNOR-128264	0.427
MC4R	protein	P32245	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268707	0.501
SSTR5	protein	P35346	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256969	0.283
COL4A3	protein	Q01955	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									12778132	t			Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6)	SIGNOR-254667	0.7
antigen	smallmolecule	CHEBI:59132	ChEBI	BCR-Ml	complex	SIGNOR-C434	SIGNOR	up-regulates activity	binding			9606	BTO:0000776								32323266	t		scontino	The recognition of antigen by the BCR initiates BCR signaling cascade.	SIGNOR-268203	0.8
PRKCA	protein	P17252	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates	phosphorylation	Thr638	TRGQPVLtPPDQLVI	9606									15277524	t		lperfetto	Pkc
 is frequently autophosphorylated on two c-terminal sites, the turn motif (thr- 638 in human pkc
) and the hydrophobic site (ser-657 in human pkc
). Thus, it is becoming clear that autophosphorylation of pkc can be a regulated event and that it has significant impact on pkc function	SIGNOR-127257	0.2
BRD4	protein	O60885	UNIPROT	KDM5C	protein	P41229	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30921702	f		miannu	 KDM5C was transcriptionally upregulated by bromodomain-containing protein 4 (BRD4), and knockdown KDM5C sensitized the therapeutic effects of CRPC cells to the bromodomain and extraterminal (BET) inhibitor. 	SIGNOR-264311	0.334
NEK6	protein	Q9HC98	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Ser403	DDSTLSEsANQVFLG	-1									12023960	t		miannu	Here we demonstrate that in addition to phosphorylating S6K1 and SGK1 at their hydrophobic motif, NEK6 also phosphorylates S6K1 at two other sites and phosphorylates SGK1 at one other site in vitro. Analysis of the peptides phosphorylated by NEK6 (Fig 2), performed in the present study has confirmed this, and identified two novel sites on S6K1 (Ser53 and Ser403) as major sites of NEK6 phosphorylation.	SIGNOR-262953	0.375
OXTR	protein	P30559	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606									30739093	t		miannu	OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq).	SIGNOR-270331	0.409
ESR2	protein	Q92731	UNIPROT	SCN9A	protein	Q15858	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938	BTO:0001264							22169964	f		miannu	17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice	SIGNOR-253473	0.2
DLK1	protein	P80370	UNIPROT	SOX9	protein	P48436	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19254573	f		fspada	Pref-1 inhibits adipocyte differentiation through upregulating sox9 expression.	SIGNOR-184277	0.402
AKT1	protein	P31749	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	up-regulates	phosphorylation			9606	BTO:0001454								19609947	t		lperfetto	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-217460	0.643
SYK	protein	P43405	UNIPROT	PIP5K1B	protein	O14986	UNIPROT	down-regulates activity	phosphorylation	Tyr105	FGIKPDDyLYSICSE	9534	BTO:0004055								19553680	t		miannu	We identified spleen tyrosine kinase (Syk), which is activated by oxidants, as a candidate PIP5Kbeta kinase in this pathway, and mapped the oxidant-sensitive tyrosine phosphorylation site to residue 105. The PIP5KbetaY105E phosphomimetic is catalytically inactive and cytosolic, whereas the Y105F non-phosphorylatable mutant has higher intrinsic lipid kinase activity and is much more membrane associated than wild type PIP5Kbeta. 	SIGNOR-276227	0.2
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates activity	phosphorylation	Thr175	GLLPFLLtHKKRLTD	-1									19661060	t		miannu	Activation of the TRPV4 ion channel is enhanced by phosphorylation. TRPV4 is phosphorylated in response to activation of PKC. We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.	SIGNOR-276228	0.2
MAPK1	protein	P28482	UNIPROT	SPHK2	protein	Q9NRA0	UNIPROT	up-regulates	phosphorylation	Ser387	PATVEPAsPTPAHSL	9606									17311928	t		llicata	Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1	SIGNOR-153379	0.431
BLOC1S1	protein	P78537	UNIPROT	BLOC-1	complex	SIGNOR-C381	SIGNOR	form complex	binding			9606									22203680	t		lperfetto	We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter.	SIGNOR-265936	0.721
MAPK7	protein	Q13164	UNIPROT	MEF2A	protein	Q02078	UNIPROT	up-regulates	phosphorylation	Thr319	TPVVSVTtPSLPPQG	9606	BTO:0000567								10849446	t		lperfetto	We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo.	SIGNOR-236579	0.699
CSNK2A1	protein	P68400	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	up-regulates	phosphorylation			9606									19623618	t		gcesareni	Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex.CK1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays.	SIGNOR-187209	0.308
PRKACA	protein	P17612	UNIPROT	CACNA1H	protein	O95180	UNIPROT	down-regulates activity	phosphorylation	Ser1107	LPDSRRGsSSSGDPP	9606									19131331	t		miannu	 Here, we identify protein kinase A (PKA) as a molecular switch that allows Gbeta(2)gammax dimers to effect voltage-independent inhibition of Ca(v)3.2 channels. Inhibition requires phosphorylation of Ser(1107), a critical serine residue on the II-III loop of the channel pore protein. S1107A prevents inhibition of unitary currents by recombinant Gbeta(2)gamma(2) dimers but does not disrupt dimer binding nor change its specificity. 	SIGNOR-263110	0.2
NLGN3	protein	Q9NZ94	UNIPROT	NRXN2	protein	Q9P2S2	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264152	0.825
UVB radiation	stimulus	SIGNOR-ST17	SIGNOR	PAH	protein	P00439	UNIPROT	up-regulates				9606									9204951	f		miannu	UVB light induces GTP-CH.-1 to increase the de novo synthesis of 6-BH4 in association with a concomitant increase in PAH activities, thus providing more L-tyrosine. 	SIGNOR-252207	0.7
MAPK1	protein	P28482	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Ser65	FLMECRNsPVTKTPP	9606	BTO:0000007								11691836	t		lperfetto	The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding 	SIGNOR-249390	0.649
SP1	protein	P08047	UNIPROT	ALOX5	protein	P09917	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19781662	f	 	 	The 5-LO promoter possesses a unique GC-rich region which contains consensus sequences for the transcription factors Sp1 and Egr-1 (GC-boxes) which are important for basal transcriptional activity	SIGNOR-254032	0.253
ARHGAP8	protein	P85298	UNIPROT	LAMTOR3	protein	Q9UHA4	UNIPROT	up-regulates activity	binding												28092672	t		lperfetto	Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation.	SIGNOR-275551	0.255
PRKCB	protein	P05771	UNIPROT	HABP4	protein	Q5JVS0	UNIPROT	down-regulates activity	phosphorylation	Thr375	GRGARGGtRGGRGRI	9606	BTO:0004974								14699138	t		lperfetto	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249253	0.293
PKN1	protein	Q16512	UNIPROT	PKN1	protein	Q16512	UNIPROT	up-regulates activity	phosphorylation	Thr64	ENLRRATtDLGRSLG	-1									10467162	t		lperfetto	Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect.	SIGNOR-249019	0.2
MAPK3	protein	P27361	UNIPROT	NFATC1	protein	O95644	UNIPROT	down-regulates	phosphorylation	Ser172	YRDPSCLsPASSLSS	9606									10652349	t	Translocation from Nucleus to Cytoplasm	esanto	We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats.	SIGNOR-74564	0.513
RPS6KA1	protein	Q15418	UNIPROT	L1CAM	protein	P32004	UNIPROT	up-regulates activity	phosphorylation	Ser1152	RSKGGKYsVKDKEDT	10116	BTO:0001009								8663493	t		lperfetto	Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152.	SIGNOR-248948	0.484
CLTA	protein	P09496	UNIPROT	AP-1/clathrin vescicle	complex	SIGNOR-C251	SIGNOR	form complex	binding			9606									23103167	t		lperfetto	Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors	SIGNOR-260678	0.755
STK3	protein	Q13188	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates	phosphorylation	Thr735	DTEWRSVtLPRDLQS	9606									18794806	t		lperfetto	Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3	SIGNOR-181056	0.2
YAP1	protein	P46937	UNIPROT	MCM3	protein	P25205	UNIPROT	up-regulates quantity by expression	transcriptional regulation					BTO:0001939							30224758	f		lperfetto	 By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 	SIGNOR-276568	0.2
HBA1	protein	P69905	UNIPROT	ADAMTS13	protein	Q76LX8	UNIPROT	down-regulates activity				9606									15367436	f	Regulation of binding	miannu	Incubation of hemoglobin, recombinant and from lysed erythrocytes, with normal plasma revealed an ADAMTS13 inhibitory effect at hemoglobin concentrations of 2 g/L or higher.	SIGNOR-251749	0.2
FLT3	protein	P36888	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity				10090									14981546	f			These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation.	SIGNOR-261521	0.297
PTPN14	protein	Q15678	UNIPROT	BCAR1	protein	P56945	UNIPROT	down-regulates	dephosphorylation	Tyr128	SKAQQGLyQVPGPSP	9606	BTO:0000586								22710723	t		lperfetto	We show that p130 crk-associated substrate (p130cas) is a direct substrate of ptpn14 and that ptpn14 specifically regulates p130cas phosphorylation at tyrosine residue 128 (y128) in colorectal cancer (crc) cells. We engineered crc cells homozygous for a p130cas y128f knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation	SIGNOR-197923	0.404
UBAP2L	protein	Q14157	UNIPROT	BMI1	protein	P35226	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								25185265	t		Sara	We identified UBAP2L as a novel BMI1-interacting protein. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex	SIGNOR-261315	0.493
F2RL2	protein	O00254	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257234	0.2
TLX1	protein	P31314	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates activity	binding			9606	BTO:0000661								15897879	t	2	miannu	ectopic HOX11 expression resulted in hyperphosphorylation of the retinoblastoma protein (Rb), which correlated with inhibition of the major Rb serine/threonine phosphatase PP1.	SIGNOR-240725	0.2
wortmannin	chemical	CHEBI:52289	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									8162590	t		gcesareni	The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase.	SIGNOR-36557	0.8
3-iodo-L-tyrosine	smallmolecule	CHEBI:27847	ChEBI	3,5-diiodo-L-tyrosine	smallmolecule	CHEBI:15768	ChEBI	up-regulates quantity	precursor of			9606									28153798	t		scontino	The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines.	SIGNOR-267037	0.8
TAF4	protein	O00268	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263921	0.88
PRKCA	protein	P17252	UNIPROT	PLCG1	protein	P19174	UNIPROT	down-regulates	phosphorylation	Ser1248	HGRAREGsFESRYQQ	9606	BTO:0000782;BTO:0000661								1370476	t		llicata	The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl.	SIGNOR-17905	0.538
CSNK2A1	protein	P68400	UNIPROT	VDR	protein	P11473	UNIPROT	up-regulates	phosphorylation	Ser208	SFSNLDLsEEDSDDP	9606									17368182	t		lperfetto	Casein kinase ii (ckii) phosphorylates vdr both in vitro and in vivo at serine 208 within the hinge domain. This phosphorylation does not affect the ability of vdr to bind dna, but increases its ability to transactivate target promoters	SIGNOR-153711	0.342
SP1	protein	P08047	UNIPROT	LORICRIN	protein	P23490	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000667								12200429	f		miannu	Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity. 	SIGNOR-254538	0.2
PRKD1	protein	Q15139	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates	phosphorylation	Ser486	RPLSRAQsSPAAPAS	9606	BTO:0000782								15623513	t		lperfetto	Protein kinase d1 (pkd1) was activated after tcr engagement, interacted with hdac7, and phosphorylated three serines (ser155, ser318, and ser448) at its n terminus, leading to its export from the nucleus.	SIGNOR-132902	0.492
FRS2	protein	Q8WU20	UNIPROT	PTPN11	protein	Q06124	UNIPROT	up-regulates	phosphorylation			9606									9632781	t		gcesareni	In addition to the direct interactions with grb2, tyrosine-phosphorylated frs2 forms a complex with the sh2 domain-containing protein tyrosine phosphatase shp2. This interaction results in tyrosine phosphorylation of shp2 and complex formation between shp2 and grb2. the catalytic activity of shp2 is essential for a sustained map kinase response and for potentiation of fgf-induced neurite outgrowth in pc12 cells	SIGNOR-58196	0.772
ARHGEF12	protein	Q9NZN5	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606	BTO:0001271								11094164	t		gcesareni	Here, we show that larg can activate rho in vivo	SIGNOR-84657	0.902
POU5F1	protein	Q01860	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004180								23041284	t		flangone	Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription.	SIGNOR-242103	0.471
Mubritinib	chemical	CID:6444692	PUBCHEM	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194581	0.8
methoxamine	chemical	CHEBI:6839	ChEBI	ADRA1D	protein	P25100	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258448	0.8
CDK5RAP2	protein	Q96SN8	UNIPROT	BUB1B	protein	O60566	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19282672	t		Giulio	These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter	SIGNOR-260312	0.274
CDK13	protein	Q14004	UNIPROT	EIF4B	protein	P23588	UNIPROT	up-regulates activity	phosphorylation	Ser422	RERSRTGsESSQTGT	9606	BTO:0001109								36882522	t		lperfetto	CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. 	SIGNOR-273115	0.254
MYC	protein	P01106	UNIPROT	PRODH	protein	O43272	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22615405	f		miannu	 MYC not only inhibited POX/PRODH, but also markedly increased the enzymes of proline biosynthesis from glutamine, including P5C synthase and P5C reductase 1. 	SIGNOR-254608	0.2
NEDD4	protein	P46934	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. 	SIGNOR-272753	0.463
KAT2B	protein	Q92831	UNIPROT	H3C15	protein	Q71DI3	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269618	0.2
FGR	protein	P09769	UNIPROT	HCLS1	protein	P14317	UNIPROT	unknown	phosphorylation	Tyr222	MEAPTTAyKKTTPIE	-1									10066823	t			We have now identified tyrosine 222 as the HS1 residue phosphorylated by the Src family protein kinases c-Fgr and Lyn. this interaction is weakened by phosphorylation of Tyr-222, through an allosteric mechanism that ultimately causes the detachment of fully phosphorylated HS1 from c-Fgr.	SIGNOR-251144	0.447
RSPO2	protein	Q6UXX9	UNIPROT	SDC4	protein	P31431	UNIPROT	up-regulates	binding			9606									21397842	t	Thrombospondin domains	gcesareni	We show that rspo3 binds syndecan 4 (sdc4) and that together they activate wnt/pcp signaling.	SIGNOR-172719	0.268
N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide	chemical	CHEBI:94525	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257975	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	BMI1	protein	P35226	UNIPROT	up-regulates activity	phosphorylation	Ser316	ANRPRKSsVNGSSAT	9606	BTO:0001033								22505453	t		lperfetto	The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate	SIGNOR-249581	0.2
torkinib	chemical	CHEBI:90679	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206313	0.8
APH1B	protein	Q8WW43	UNIPROT	PSENEN	protein	Q9NZ42	UNIPROT	up-regulates	binding			9606									12522139	t		gcesareni	Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex.	SIGNOR-97110	0.94
C5AR2	protein	Q9P296	UNIPROT	SELL	protein	P14151	UNIPROT	down-regulates quantity by repression													1847994	f		lperfetto	The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 	SIGNOR-263467	0.2
TIMM10	protein	P62072	UNIPROT	TIM22 complex	complex	SIGNOR-C424	SIGNOR	form complex	binding			9606	BTO:0000007								32901109	t		lperfetto	Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK).	SIGNOR-267701	0.709
PRKCA	protein	P17252	UNIPROT	GRIN1	protein	Q05586	UNIPROT	up-regulates activity	phosphorylation	Ser896	SSFKRRRsSKDTSTG	10116	BTO:0000938								15936117	t		miannu	Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890. 	SIGNOR-263177	0.427
PRKD2	protein	Q9BZL6	UNIPROT	PKD2	protein	Q13563	UNIPROT	up-regulates activity	phosphorylation	Ser801	SSLPRPMsSRSFPRS	9615	BTO:0000837								20881056	t		miannu	Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. These results suggest that growth factor-stimulated, protein kinase D-mediated phosphorylation of polycystin-2 is essential for its ER channel function and links extracellular stimuli to its effects on cell growth and intracellular calcium regulation.	SIGNOR-276284	0.2
DNMT3B	protein	Q9UBC3	UNIPROT	DNMT1/DNMT3B	complex	SIGNOR-C43	SIGNOR	form complex	binding			9606									12145218	t		miannu	We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation	SIGNOR-90845	0.783
GAD1	protein	Q99259	UNIPROT	gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	up-regulates quantity	chemical modification			9606									32041144	t		miannu	Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce γ-aminobutyric acid (GABA), which exhibits several well-known physiological functions.	SIGNOR-267552	0.8
MAOB	protein	P27338	UNIPROT	dopamine	smallmolecule	CHEBI:18243	ChEBI	down-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO.	SIGNOR-264002	0.8
IKBKB	protein	O14920	UNIPROT	BCL10	protein	O95999	UNIPROT	up-regulates activity	phosphorylation	Ser144	NSDESNFsEKLRAST	9606	BTO:0000007								16818229	t		miannu	Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling.	SIGNOR-276289	0.765
GRK6	protein	P43250	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser366	EPIQMENsMGTLRTS	9606	BTO:0000007								11517230	t			Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251207	0.292
IL11	protein	P20809	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates	binding			9606									9143707	t		gcesareni	Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-4	SIGNOR-48033	0.703
AKT1	protein	P31749	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates	phosphorylation	Ser215	SGRAREAsGAPTSSK	9606	BTO:0000938								17470458	t		acerquone	The work presented here is the first demonstration that phosphorylation at s215 and s792 by akt regulates ligand binding, and the subcellular distribution of the receptor	SIGNOR-154631	0.605
ATM	protein	Q13315	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates				9606									10097108	f		gcesareni	Atm also contributes to the cdc25c activity, particularly in ir-damaged cells, by activating chk2.	SIGNOR-65966	0.51
A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257708	0.562
TNKS	protein	O95271	UNIPROT	TARDBP	protein	Q13148	UNIPROT	up-regulates quantity by stabilization	binding			10116		BTO:0000142							32409565	t		lperfetto	Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation.	SIGNOR-262115	0.2
HDAC1	protein	Q13547	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16431920	f		fspada	These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome	SIGNOR-143955	0.446
STAT1	protein	P42224	UNIPROT	CIITA	protein	P33076	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000801								19029990	f		lperfetto	STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others.	SIGNOR-249498	0.524
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGB1	protein	Q9Y5G3	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265703	0.2
RAF1	protein	P04049	UNIPROT	STK4	protein	Q13043	UNIPROT	down-regulates	binding			9606									22898666	t		gcesareni	Raf1 binding to mst2 sarah domain interdicts mst2 homodimerization and autoactivation, and recruits protein phosphates 2a thereby promoting mst2 inactivation.	SIGNOR-191843	0.275
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2V1	protein	Q13404	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271321	0.563
MLXIPL	protein	Q9NP71	UNIPROT	ELOVL6	protein	Q9H5J4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								27524233	t		Luana	In this study, we clearly show that mouse and human Elovl6 are direct targets of ChREBP. 	SIGNOR-267945	0.409
TNFSF13	protein	O75888	UNIPROT	TNFRSF13B	protein	O14836	UNIPROT	up-regulates	binding			9606									10956646	t		gcesareni	Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys.	SIGNOR-81308	0.699
85375-15-1	chemical	CID:6917797	PUBCHEM	SLC6A1	protein	P30531	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206960	0.8
HTR1E	protein	P28566	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256705	0.423
PZP	protein	P20742	UNIPROT	MMP9	protein	P14780	UNIPROT	down-regulates activity	binding			-1									9344465	t		lperfetto	Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261802	0.355
CAY10505	chemical	CID:1204893	PUBCHEM	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190859	0.8
mTORC2	complex	SIGNOR-C2	SIGNOR	MYC	protein	P01106	UNIPROT	up-regulates				9606									24856037	f		miannu	MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity 	SIGNOR-256171	0.361
MTCP1	protein	P56278	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271								10983986	t		miannu	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-81677	0.34
NRBF2	protein	Q96F24	UNIPROT	PIK3C3	protein	Q8NEB9	UNIPROT	down-regulates activity	binding			9606	BTO:0001938				phosphorylation:Ser113;Ser120	AEDAEGQsPLSQKYS;SPLSQKYsPSTEKCL			28059666	t		miannu	NRBF2 S113 and S120 phosphorylation negatively regulates autophagy. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity.	SIGNOR-265879	0.678
LRRC4B	protein	Q9NT99	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								19467332	t		miannu	A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles	SIGNOR-264052	0.379
CHD3	protein	Q12873	UNIPROT	MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263843	0.801
STK39	protein	Q9UEW8	UNIPROT	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation	Thr105	LQTFGHNtMDAVPKI	9606	BTO:0000007								21321328	t		miannu	 We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A).	SIGNOR-276306	0.596
WT1	protein	P19544	UNIPROT	SOD1	protein	P00441	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9867871	t		miannu	The human copper-zinc superoxide dismutase gene (SOD1) proximal promoter is regulated by Sp1, Egr-1, and WT1 via non-canonical binding sites. Egr-1 and two splicing variants of the Egr-related protein WT1 were able to transactivate the SOD1 promoter in co-transfection experiments.	SIGNOR-253898	0.268
CDK6	protein	Q00534	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Ser276	VHPATPIsPGRASGM	9606									16046550	t	The effect has been demonstrated using Q01196-8.	gcesareni	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-138961	0.598
MAPKAPK2	protein	P49137	UNIPROT	PIAS1	protein	O75925	UNIPROT	up-regulates	phosphorylation	Ser522	DTSYINTsLIQDYRH	9606		BTO:0001253							23202365	t		llicata	T he mitogen-activated protein kinase (mapk)-activated protein kinase-2 is a proinflammatory kinase and phosphorylates pias1 at the ser522 residue. Activation of mapk-activated protein kinase-2 enhances p53-sumoylation, but a pias1 phosphorylation mutant, pias1-s522a, abolished this p53-sumoylation, suggesting a critical role for pias1-s522 phosphorylation in its sumo ligase activity.	SIGNOR-199944	0.2
MAPK9	protein	P45984	UNIPROT	JUNB	protein	P17275	UNIPROT	down-regulates	binding			9606									9405416	t		gcesareni	Jnk targets junb ubiquitination	SIGNOR-53827	0.671
HOXD12	protein	P35452	UNIPROT	MAF	protein	O75444	UNIPROT	down-regulates activity	binding			-1									11036080	t		miannu	Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.	SIGNOR-221887	0.373
SMAD9	protein	O15198	UNIPROT	SMAD8/SMAD4	complex	SIGNOR-C206	SIGNOR	form complex	binding			9606									20957627	t		lperfetto	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.	SIGNOR-255268	0.67
COL21A1	protein	Q96P44	UNIPROT	DDR1	protein	Q08345	UNIPROT	up-regulates activity	binding			9606	BTO:0001282								17318226	t		lperfetto	The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75. 	SIGNOR-272341	0.2
AURKB	protein	Q96GD4	UNIPROT	NDC80	protein	O14777	UNIPROT	down-regulates	phosphorylation	Ser5	sVSSGGAG	9606									20471944	t		lperfetto	To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant).	SIGNOR-165562	0.842
AKT1	protein	P31749	UNIPROT	NR4A1	protein	P22736	UNIPROT	down-regulates activity	phosphorylation	Ser351	GRRGRLPsKPKQPPD	9606									11274386	t		lperfetto	We show that akt interacts with nur77 and inactivates nur77 by phosphorylation at ser-350	SIGNOR-252466	0.719
EID3	protein	Q8N140	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	down-regulates				10090									23720823	f		miannu	Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. The novel inhibitor of differentiation Eid3 is an FRG1/Suv4-20h1 target involved in the myogenic defects caused by FRG1 over-expression. Eid3 is down-regulated upon muscle differentiation and behaves as a myogenic inhibitor gene. 	SIGNOR-266641	0.7
Papain-like proteinase	protein	P0C6X7-PRO_0000037311	UNIPROT	IRF3	protein	Q14653	UNIPROT	down-regulates activity	deubiquitination			9606									25481026	t		miannu	Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response.	SIGNOR-260249	0.2
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser516	GDRSGYSsPGSPGTP	9606		BTO:0000142							20308788	t	The effect has been demonstrated using P10636-8	lperfetto	Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in alzheimer's disease (ad). Gsk-3beta phosphorylated tau at many sites, with ser199, thr205, and ser396 being the most favorable sites in cells.	SIGNOR-164651	0.729
TGFB1	protein	P01137	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates activity	binding			9606									16885528	t		lperfetto	The active form of TGF-beta is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge.	SIGNOR-148605	0.2
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	succinate(2-)	smallmolecule	CHEBI:30031	ChEBI	up-regulates quantity	precursor of			9606									11431483	t		miannu	Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. 	SIGNOR-269686	0.8
BLK	protein	P51451	UNIPROT	FCGR2C	protein	P31995	UNIPROT	up-regulates activity	phosphorylation	Tyr294	YETADGGyMTLNPRA	-1									8756631	t		miannu	Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation	SIGNOR-262672	0.2
BAZ2B	protein	Q9UIF8	UNIPROT	H3-4	protein	Q16695	UNIPROT	down-regulates activity	binding			9606							acetylation:Lys15	ARKSTGGkAPRKQLA	31999386	t		miannu	The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation.	SIGNOR-266620	0.2
IRX3	protein	P78415	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003324								21825130	t		Luana	Irx3 directly represses Cx43 transcription 	SIGNOR-266044	0.282
ITGB2	protein	P05107	UNIPROT	AM/b2 integrin	complex	SIGNOR-C170	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253192	0.744
PIM1	protein	P11309	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser166	SSRRRAIsETEENSD	9606									18467333	t		gcesareni	Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt.	SIGNOR-178615	0.397
NRAS	protein	P01111	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9606									21779497	t		lperfetto	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k	SIGNOR-252700	0.665
INCENP	protein	Q9NQS7	UNIPROT	AURKB	protein	Q96GD4	UNIPROT	up-regulates	binding			9606									12925766	t		gcesareni	Using recombinant proteins, we found that aurora b kinase activity was stimulated by incenp and that the c-terminal region of incenp was sufficient for activation.	SIGNOR-86218	0.973
CDK2	protein	P24941	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser130	SGEQAEGsPGGPGDS	9606									15964852	t		lperfetto	Cdk2 destabilizes p21 via the cy2 cyclin-binding motif and p21 phosphorylation at ser-130.	SIGNOR-149416	0.953
PRKCD	protein	Q05655	UNIPROT	TACSTD2	protein	P09758	UNIPROT	down-regulates activity	phosphorylation	Ser322	GELRKEPsL	9606	BTO:0001109								31177095	t	done	miannu	 Analyses using HCT116 cells expressing WT Trop-2 (HCT116/WT) or Trop-2 alanine-substituted at Ser-303 (HCT116/S303A) or Ser-322 (HCT116/S322A) revealed that Trop-2 is phosphorylated at Ser-322. sing protein kinase C (PKC) inhibitors and PKC-specific siRNAs, we found that PKCα and PKCδ are responsible for Trop-2 phosphorylation. 	SIGNOR-273820	0.2
UV stress	stimulus	SIGNOR-ST7	SIGNOR	MAP3K4	protein	Q9Y6R4	UNIPROT	up-regulates				9606									9305639	f		lperfetto	Overexpression of a dominant-negative MTK1 mutant [MTK1(K/R)] strongly inhibited the activation of the p38 pathway by environmental stresses (osmotic shock, UV and anisomycin)[]These results indicate that MTK1 is a major mediator of environmental stresses that activate the p38 MAPK pathway	SIGNOR-226605	0.7
GNG3	protein	P63215	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606									17419683	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt	SIGNOR-154258	0.357
SHH	protein	Q15465	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates				9606	BTO:0000222;BTO:0002314	BTO:0000887							17688959	f		lperfetto	Most importantly, we report that shh induces mapk/erk and phosphoinositide 3-kinase (pi3k)-dependent akt phosphorylation and that activation of both signaling pathways is essential for shh's signaling in muscle cells. However, the effect of shh on akt phosphorylation is more robust than that on mapk/erk, and data suggest that shh influences these pathways in a manner similar to igf-i.	SIGNOR-244446	0.484
SDHB	protein	P21912	UNIPROT	SDH	complex	SIGNOR-C400	SIGNOR	form complex	binding			9606									16143825	t		miannu	Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively.	SIGNOR-266272	0.965
tazarotene	chemical	CHEBI:32184	ChEBI	RARG	protein	P13631	UNIPROT	up-regulates activity	chemical activation			9534									19058965	t		Luana	Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes. 	SIGNOR-258029	0.8
F2RL1	protein	P55085	UNIPROT	RARG	protein	P13631	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	 PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 	SIGNOR-254858	0.2
MAPK1	protein	P28482	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser425	TKGSGLGsPTSSFNS	9606	BTO:0000007								18204439	t		lperfetto	Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation.	SIGNOR-252959	0.71
STK11	protein	Q15831	UNIPROT	PTEN	protein	P60484	UNIPROT	unknown	phosphorylation	Ser385	RYSDTTDsDPENEPF	9606	BTO:0001938								15987703	t		lperfetto	We provide evidence suggesting that LKB1 phosphorylates PTEN at residue S385 in combination either with S380, T382 or T383	SIGNOR-247446	0.624
PRKCA	protein	P17252	UNIPROT	ICOSLG	protein	O75144	UNIPROT	up-regulates activity	phosphorylation	Ser285	RDRCLQHsYAGAWAV	9606	BTO:0000567								24837102	t	done	miannu	PKCα and PKCβ are required for phosphorylation of ICOSL and ICOSL-mediated cytokine induction. Therefore, S285 is required for PKC substrate (serine) phosphorylation of ICOSL, and each of the upstream arginines is similarly required for this phosphorylation. 	SIGNOR-273798	0.2
AURKB	protein	Q96GD4	UNIPROT	RPRD1B	protein	Q9NQG5	UNIPROT	up-regulates activity	phosphorylation	Ser145	KATEEKKsLKRTFQQ										30518842	t		lperfetto	Mechanistically, we revealed that CREPT/RPRD1B interacted with Aurora B to regulate the expression of Cyclin B1 in gastric cancer cells. Interestingly, Aurora B phosphorylates S145 in a well-conserved motif of CREPT/RPRD1B. We proposed that phosphorylation of CREPT/RPRD1B by Aurora B is required for promoting the transcription of Cyclin B1	SIGNOR-265499	0.2
KDM6A	protein	O15550	UNIPROT	ELK3	protein	P41970	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									29736013	t		miannu	Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase	SIGNOR-260037	0.2
MDH2	protein	P40926	UNIPROT	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	up-regulates quantity	chemical modification			9606									24068518	t		miannu	Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle	SIGNOR-266286	0.8
CDC25B	protein	P30305	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates	dephosphorylation			9606				SIGNOR-C17					7880537	t		gcesareni	Cdc25 dephosphorylates cdc2/cdk1 within the activation loop of the kinase domain to achieve full activity of the cyclin-cdk complex	SIGNOR-34541	0.823
CASP8	protein	Q14790	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates activity	cleavage	Asp345	EEWEAQRdSHLGPHR	-1									10069390	t		lperfetto	Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.	SIGNOR-261760	0.376
GAS6	protein	Q14393	UNIPROT	AXL	protein	P30530	UNIPROT	up-regulates	binding			9606									16362042	t		gcesareni	Receptor tyrosine kinases of the axl family are activated by the vitamin k-dependent protein gas6. We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function.	SIGNOR-143109	0.906
SRC	protein	P12931	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates	phosphorylation	Tyr188	SFVGTLQyLAPELLE	9606				SIGNOR-C14					12645577	t		gcesareni	These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation.	SIGNOR-99314	0.369
MAPK1	protein	P28482	UNIPROT	NUP153	protein	P49790	UNIPROT	unknown	phosphorylation	Ser529	SPMFKFSsPIVKSTE	9606									19767751	t		llicata	These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport.	SIGNOR-188123	0.397
C3	protein	P01024	UNIPROT	C5 convertase complex	complex	SIGNOR-C312	SIGNOR	form complex	binding								cleavage:Arg748	ASHLGLArSNLDEDI			31331124	t	complement C3b fragment: PRO_0000005911	lperfetto	C3b associates with C3 convertase to form C5 convertase and cleaves C5.	SIGNOR-263448	0.2
TNF	protein	P01375	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates				9606									11287630	f		gcesareni	Irs-1 tyrosine phosphorylation by tnf was blocked by rapamycin, an inhibitor of the mammalian target of rapamycin (mtor), a downstream target of akt. these results suggest that tnf impairs insulin signaling through irs-1	SIGNOR-106599	0.406
MAPK11	protein	Q15759	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	down-regulates activity	phosphorylation	Thr1609	LGPYEAVtPLTKAAD	-1									24703952	t		lperfetto	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK 	SIGNOR-264447	0.2
QRICH1	protein	Q2TAL8	UNIPROT	YARS2	protein	Q9Y2Z4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269413	0.2
RET	protein	P07949	UNIPROT	RET	protein	P07949	UNIPROT	up-regulates	phosphorylation	Tyr1062	TWIENKLyGMSDPNW	9606									14711813	t		lperfetto	Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesret short and middle isoforms contain 16 tyrosine residues in their intracellular domains, and ret long isoforms have two additional tyrosines in the c-terminal tail. Among these tyrosines, tyr905, tyr1015, tyr1062, and tyr1096 are thought to be phosphorylated to become binding sites for grb7/grb10, phospholipase c_, shc/snt(frs2)/enigma, and grb2, respectively.	SIGNOR-121141	0.2
AURKB	protein	Q96GD4	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates	phosphorylation	Ser1403	CHKTKLKsILEILSK	9606									22099307	t		lperfetto	Aurora-b mediated atm serine 1403 phosphorylation is required for mitotic atm activation and the spindle checkpoint	SIGNOR-177280	0.444
CDC14B	protein	O60729	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	up-regulates	dephosphorylation			9606									18662541	t		lperfetto	The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1	SIGNOR-227927	0.255
PRKAA1	protein	Q13131	UNIPROT	PRKAB1	protein	Q9Y478	UNIPROT	up-regulates	phosphorylation	Ser108	SKLPLTRsHNNFVAI	9606			SIGNOR-C15	SIGNOR-C15					17728241	t		gcesareni	Mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of ampk by a-769662 in cells and in vitro, while only partially reducing activation by amp	SIGNOR-157553	0.923
RET	protein	P07949	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates	phosphorylation	Tyr182	TDDEMTGyVATRWYR	9606									8622669	t		gcesareni	Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme.	SIGNOR-40497	0.338
BTK	protein	Q06187	UNIPROT	DAPP1	protein	Q9UN19	UNIPROT	up-regulates activity	phosphorylation	Tyr139	KVEEPSIyESVRVHT	-1									11524430	t		llicata	We present a number of lines of evidence that in vivo, Src-type tyrosine kinases are responsible for the phosphorylation of tyrosine 139 in DAPP-1. | Although Btk appears to phosphorylate DAPP-1 relatively efficiently both in Sf9 cells and in vitro, we find no evidence that in either B cells or PAE cells Btk family kinases phosphorylate DAPP-1.	SIGNOR-250602	0.658
ELF1	protein	P32519	UNIPROT	IL2RA	protein	P01589	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000661								7862168	f	2	miannu	The interleukin 2 receptor alpha-chain (IL-2R alpha) gene is rapidly and potently induced in T cells in response to mitogenic stimuli. Previously, an inducible enhancer between nucleotides -299 and -228 that contains NF-kappa B and CArG motifs was identified. We now report the characterization of a second essential positive regulatory element located between nucleotides -137 and -64 that binds Elf-1 and HMG-I(Y). Transcription from the IL-2R alpha promoter was inhibited when either the Elf-1 or the HMG-I(Y) binding site was mutated. Coexpression of both proteins activated transcription of the -137 to -64 element in COS-7 cells.	SIGNOR-240193	0.2
FGFR1	protein	P11362	UNIPROT	SYNCRIP	protein	O60506	UNIPROT	down-regulates	phosphorylation	Tyr373	RVKKLKDyAFIHFDE	9606									12601080	t		lperfetto	Novel in vivo tyrosine phosphorylation sites were found in the fgfr-1, phospholipase cgamma, p90 ribosomal s6 kinase, cortactin, and ns-1-associated protein-1. Syncrip, was very recently found to be phosphorylated in response to insulin treatment of 3t3-l1 adipocytes (32). Phosphorylation of syncrip was accommodated by the insulin receptor tyrosine kinase in vitro but was inhibited upon binding of rna. Tyrosine phosphorylation at tyr-373 in the third rna recognition motif domain of nsap1/syncrip can possibly influence its rna binding properties and thus link fgfr-1 signaling to mrna metabolism.	SIGNOR-98704	0.2
2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	up-regulates quantity	precursor of			9606									29767008	t		miannu	Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits.	SIGNOR-266523	0.8
PRKACA	protein	P17612	UNIPROT	DYNLRB1	protein	Q9NP97	UNIPROT	up-regulates	phosphorylation	Ser73	LTFLRIRsKKNEIMV	9606									23333499	t		llicata	Our results show that km23-1 is required for camp-responsive element (cre) transcriptional activation by tgf_, with s73-km23-1 being required for the cre-dependent tgf_ stimulation of fibronectin (fn) transcription.	SIGNOR-200456	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	MYOD1	protein	P15172	UNIPROT	down-regulates				9606		BTO:0001103							20219869	t		apalma	Furthermore, NF-kB activation can cause destabilization of MyoD mRNA and degradation of MyoD protein (35, 49), which would further impede muscle differentiation	SIGNOR-255352	0.284
tamoxifen citrate	chemical	CHEBI:9397	ChEBI	ESR2	protein	Q92731	UNIPROT	down-regulates activity	chemical inhibition			9606									20512796	t		miannu	Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth.	SIGNOR-259300	0.8
NFATC2	protein	Q13469	UNIPROT	GPC6	protein	Q9Y625	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								21871017	t		miannu	 NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype.	SIGNOR-264021	0.363
MAPK3	protein	P27361	UNIPROT	DUSP6	protein	Q16828	UNIPROT	down-regulates	phosphorylation	Ser197	SATDSDGsPLSNSQP	9606									15632084	t		amattioni	Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3	SIGNOR-132979	0.849
DNAJB9	protein	Q9UBS3	UNIPROT	HSPA5	protein	P11021	UNIPROT	up-regulates activity	binding			-1									12356756	t		miannu	When BAP was added to BiP (2:1 molar ratio of BAP:BiP), it increased the ATPase activity of BiP by about 2-fold, which was similar to the increase observed when the J domain of ERdj4 was added to BiP (Fig.5). When both BAP and the J domain were added to BiP, the rate of ATP hydrolysis by BiP was stimulated by about 4-fold over basal levels, indicating that both BAP and ERdj4 positively regulate the ATPase activity of BiP 	SIGNOR-261044	0.558
WNT2	protein	P09544	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131730	0.661
MAPKAPK5	protein	Q8IW41	UNIPROT	TH	protein	P07101	UNIPROT	up-regulates	phosphorylation	Ser19	KGFRRAVsELDAKQA	9606									12421349	t	The effect has been demonstrated using P07101-3	gcesareni	Recombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation of both ser40 and ser19 induced a high-affinity binding of 14-3-3 proteins, but only the interaction of 14-3-3 with ser19 increased the hth1 activity.	SIGNOR-95479	0.2
TFIIH	complex	SIGNOR-C457	SIGNOR	RARA	protein	P10276	UNIPROT	unknown	phosphorylation	Ser77	EIVPSPPsPPPLPRI	9606									11955452	t		llicata	Thus, we demonstrate that the cdk7 kinase of tfiih phosphorylates the nuclear receptor, then allowing ligand-dependent control of the activation of the hormone-responsive genes.	SIGNOR-269332	0.272
NEU1	protein	Q99519	UNIPROT	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	down-regulates activity	binding			9606	BTO:0003554								32164705	t		miannu	NEU1 disrupts FN/ α5β1 interaction. taken together, strongly indicate that overexpressed NEU1 inhibits the Akt pathway by disrupting FN-integrin α5β1 interaction.	SIGNOR-260658	0.2
ROCK1	protein	Q13464	UNIPROT	LIMK1	protein	P53667	UNIPROT	up-regulates activity	phosphorylation	Thr508	PDRKKRYtVVGNPYW	9606									10652353	t		lperfetto	Rho-associated kinase rock activates lim-kinase 1 by phosphorylation at threonine 508 within the activation loop.	SIGNOR-74569	0.6
KIT	protein	P10721	UNIPROT	STAP1	protein	Q9ULZ2	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								10679268	t		miannu	 STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells.	SIGNOR-261820	0.484
PRKCD	protein	Q05655	UNIPROT	DAB2	protein	P98082	UNIPROT	down-regulates	phosphorylation	Ser24	QAAPKAPsKKEKKKG	9606									10542228	t		gcesareni	Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2.	SIGNOR-71764	0.3
CSK	protein	P41240	UNIPROT	CSK	protein	P41240	UNIPROT	up-regulates activity	phosphorylation	Tyr304	DVCEAMEyLEGNNFV	-1									9148770	t		llicata	Taken together these results indicate that Csk can be phosphorylated in vivo at Tyr-184 by an as yet unknown tyrosine kinase, and that autophosphorylation of Tyr-304 occurs only at abnormally high Csk concentrations in vitro. Furthermore, Tyr-304 is required for the maintenance of the structure of the Csk kinase domain.	SIGNOR-250778	0.2
PRKAA1	protein	Q13131	UNIPROT	CFTR	protein	P13569	UNIPROT	down-regulates activity	phosphorylation	Ser737	EPLERRLsLVPDSEQ	9606									19095655	t		Luana	AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions	SIGNOR-259858	0.474
EEF2K	protein	O00418	UNIPROT	EEF2	protein	P13639	UNIPROT	down-regulates	phosphorylation	Thr57	RAGETRFtDTRKDEQ	9606	BTO:0000007								12194824	t		gcesareni	The activation of eef2 kinase by ampk, resulting in the phosphorylation and inactivation of eef2, provides a novel mechanism for the inhibition of protein synthesis.	SIGNOR-91751	0.781
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser197	APRRRAAsMDSSSKL	10090	BTO:0004245								10217147	t			Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo.	SIGNOR-252838	0.908
ATF6	protein	P18850	UNIPROT	HYOU1	protein	Q9Y4L1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001088								20861013	f		miannu	 We recently found that in cultured gastric cells, expression of endoplasmic reticulum (ER) chaperones (such as 150-kDa oxygen-regulated protein (ORP150) and glucose-regulated protein 78 (GRP78)) is induced by NSAIDs and confers protection against NSAID-induced apoptosis, which is important in the development of NSAID-induced gastric lesions. In this study we have found that co-culture of gastric cells with H. pylori suppresses the expression of ER chaperones. This suppression was regulated at the level of transcription and accompanied by a reduction in the level of activating transcription factor 6 (ATF6), one of the transcription factors for ER chaperone genes.	SIGNOR-253752	0.414
CALM1	protein	P0DP23	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	binding			9606									24379783	t		lperfetto	Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer	SIGNOR-251615	0.754
CSNK2A2	protein	P19784	UNIPROT	KLF1	protein	Q13351	UNIPROT	up-regulates activity	phosphorylation	Thr23	ALGPFPDtQDDFLKW	10090	BTO:0004475								9722526	t	2	miannu	Regulation of erythroid Krppel-like factor (EKLF) transcriptional activity by phosphorylation of a protein kinase casein kinase II site within its interaction domain. the transactivation capability of EKLF is augmented by co-transfection of CKIIalpha. in vitro assays demonstrate that CKIIalpha interacts with EKLF, and that the EKLF interaction domain is phosphorylated by CKII only at Thr-41	SIGNOR-241365	0.348
sphingosine 1-phosphate	smallmolecule	CHEBI:37550	ChEBI	S1PR2	protein	O95136	UNIPROT	up-regulates	chemical activation			9606									23450633	t		gcesareni	S1p action on yap in 293a (or hacat) cells is mediated by s1p2 rather than s1p1 or s1p3 (of ? Ve known s1p receptors) and lpa receptors 1 and 3 (of six).	SIGNOR-192117	0.8
F2R	protein	P25116	UNIPROT	CD44	protein	P16070	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254851	0.252
MAPK1	protein	P28482	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates	phosphorylation	Ser641	DIKILIAsPSPTHIH	9606	BTO:0000567								18519666	t		lperfetto	We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_	SIGNOR-178723	0.572
HDAC1	protein	Q13547	UNIPROT	UBE2D3	protein	P61077	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000356								21044962	f		miannu	 knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene.	SIGNOR-255175	0.267
AKT2	protein	P31751	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates	phosphorylation	Ser939	SFRARSTsLNERPKS	9606									12172553	t		gcesareni	We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex.	SIGNOR-91388	0.719
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser250	TGSPAELsPTTLSPV	9606		BTO:0000763;BTO:0000149							10197981	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-66763	0.739
SP1	protein	P08047	UNIPROT	SP1/STAT3	complex	SIGNOR-C74	SIGNOR	form complex	binding			9606									19723038	t		miannu	Sp1 and stat3 seem to synergistically augment renalase transcription.	SIGNOR-187790	0.467
MCM3	protein	P25205	UNIPROT	MCM	complex	SIGNOR-C268	SIGNOR	form complex	binding			9606									19946136	t			The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication.	SIGNOR-261673	0.77
ROCK2	protein	O75116	UNIPROT	PPP1R12A	protein	O14974	UNIPROT	down-regulates activity	phosphorylation	Thr853	PREKRRStGVSFWTQ	-1									12220642	t		lperfetto	Rho kinase is known to control smooth muscle contractility by phosphorylating the 110 kDa myosin-targetting subunit (MYPT1) of the myosin-associated form of protein phosphatase 1 (PP1M). Phosphorylation of MYPT1 at Thr695 has previously been reported to inhibit the catalytic activity of PP1. Here, we show that the phosphorylation of Thr850 by Rho kinase dissociates PP1M from myosin, providing a second mechanism by which myosin phosphatase activity is inhibited.	SIGNOR-249164	0.778
BUB1	protein	O43683	UNIPROT	CDC20	protein	Q12834	UNIPROT	down-regulates activity	phosphorylation	Ser72	SKVQTTPsKPGGDRY	9606	BTO:0000567								15525512	t		llicata	Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. 	SIGNOR-250607	0.992
MAPK1	protein	P28482	UNIPROT	DOCK1	protein	Q14185	UNIPROT	unknown	phosphorylation	Thr1772	QQTPPPVtPRAKLSF	10090	BTO:0000944								22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262769	0.255
PFKM	protein	P08237	UNIPROT	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35.	SIGNOR-266467	0.8
F2RL3	protein	Q96RI0	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257044	0.357
PTPRH	protein	Q9HD43	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr999	YASSNPEyLSASDVF	9606									10734133	t		gcesareni	These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase	SIGNOR-76084	0.273
CKMT2	protein	P17540	UNIPROT	N-phosphocreatine	smallmolecule	CHEBI:17287	ChEBI	up-regulates quantity	chemical modification			9606									18502307	t		miannu	Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 	SIGNOR-265789	0.8
PTPN6	protein	P29350	UNIPROT	ROS1	protein	P08922	UNIPROT	down-regulates	dephosphorylation	Tyr2274	KNREGLNyMVLATEC	9606									11266449	t		gcesareni	Phosphorylated ros strongly and directly associates with shp-1.Overexpression Of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation	SIGNOR-105919	0.375
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	MARK3	protein	P27448	UNIPROT	down-regulates	phosphorylation	Thr95	DKTQLNPtSLQKLFR	9606									15319445	t		gcesareni	Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1.	SIGNOR-259430	0.2
IKBKE	protein	Q14164	UNIPROT	IRF1	protein	P10914	UNIPROT	down-regulates activity	phosphorylation	Ser215	DLYNFQVsPMPSTSE	9606	BTO:0000007								24396068	t		miannu	We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity. 	SIGNOR-276480	0.357
PRKCE	protein	Q02156	UNIPROT	KRT18	protein	P05783	UNIPROT	unknown	phosphorylation	Ser53	ISVSRSTsFRGGMGS	-1									1374067	t		lperfetto	In conclusion, we have shown that the PKCe catalytic fragment physically associates with and phosphorylates CK8/18 HT29 cells. The nature of this association and its physiological significance remain to be determined.	SIGNOR-248847	0.334
CRTC2	protein	Q53ET0	UNIPROT	G6PC1	protein	P35575	UNIPROT	up-regulates quantity	transcriptional regulation			9606									26652733	t			Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-256103	0.2
MRPS23	protein	Q9Y3D9	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261435	0.671
MSH6	protein	P52701	UNIPROT	MSH2/MSH6	complex	SIGNOR-C60	SIGNOR	form complex	binding			9606									15064730	t		miannu	The human msh2/6 complex is essential for mismatch recognition during the repair of replication errors.	SIGNOR-123708	0.803
PI4KA	protein	P42356	UNIPROT	1-phosphatidyl-1D-myo-inositol(1-)	smallmolecule	CHEBI:57880	ChEBI	down-regulates quantity	chemical modification			9606									10101268	t		miannu	The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 	SIGNOR-269095	0.8
6-phospho-D-gluconate	smallmolecule	CHEBI:16863	ChEBI	D-ribulose 5-phosphate	smallmolecule	CHEBI:17363	ChEBI	up-regulates quantity	precursor of			9606									34775382	t		miannu	6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule.	SIGNOR-267059	0.8
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Thr32	QSRPRSCtWPLPRPE	9606									16272144	t		lperfetto	Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression	SIGNOR-252855	0.908
MRAP2	protein	Q96G30	UNIPROT	MC1R	protein	Q01726	UNIPROT	down-regulates activity	binding			10029	BTO:0000246								19329486	t		miannu	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252365	0.506
PPP1R1B	protein	Q9UD71	UNIPROT	PPP1CA	protein	P62136	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								10604473	t		miannu	DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚ 	SIGNOR-264957	0.582
HOXA11	protein	P31270	UNIPROT	HOXA10	protein	P31260	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001549								17688409	f		miannu	Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression. 	SIGNOR-254469	0.298
CYLD	protein	Q9NQC7	UNIPROT	BCL3	protein	P20749	UNIPROT	down-regulates	deubiquitination			9606	BTO:0001286								16713561	t		gcesareni	Cyld binds and deubiquitinates bcl-3in cyld+/+ keratinocytes, tpa or uv light triggers the translocation of cyld from the cytoplasm to the perinuclear region, where cyld binds and deubiquitinates bcl-3, thereby preventing nuclear accumulation of bcl-3 and p50/bcl-3- or p52/bcl-3-dependent proliferation.	SIGNOR-146774	0.527
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation			9606		BTO:0001260							10514499	t	inferred from 70% family members	lperfetto	Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin.	SIGNOR-270049	0.2
CASP1	protein	P29466	UNIPROT	RNF31	protein	Q96EP0	UNIPROT	down-regulates activity	cleavage	Asp348	GTGGLEPdLARGRWA	9606	BTO:0005111								32122970	t		miannu	We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death.	SIGNOR-272192	0.2
PEX1	protein	O43933	UNIPROT	PEX5	protein	P50542	UNIPROT	up-regulates activity	binding			10029									16314507	t			Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. ​(Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner. 	SIGNOR-253618	0.566
MAPK3	protein	P27361	UNIPROT	HSPB8	protein	Q9UJY1	UNIPROT	up-regulates	phosphorylation	Thr87	GVPAEGRtPPPFPGE	9606									22721717	t		lperfetto	Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation	SIGNOR-197936	0.346
TOP2A	protein	P11388	UNIPROT	Chromosome_segregation	phenotype	SIGNOR-PH44	SIGNOR	up-regulates				9606									20562910	f		lperfetto	Topoisomerase IIalpha (topoIIalpha) is an essential mammalian enzyme that topologically modifies DNA and is required for chromosome segregation during mitosis.	SIGNOR-242530	0.7
HES1	protein	Q14469	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates activity	transcriptional regulation			10090	BTO:0000165								10066785	t		gcesareni	Notch signaling up-regulated HES1 mRNA expression within 1 h and subsequently reduced expression of MyoD mRNA	SIGNOR-243181	0.299
RHEB	protein	Q15382	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				10090	BTO:0000011								19299511	t		lperfetto	These results suggest that Rheb induces alteration in the binding of 4E-BP1 with mTORC1 to regulate mTORC1 activation.	SIGNOR-235355	0.791
pemetrexed disodium	chemical	CHEBI:63722	ChEBI	GART	protein	P22102	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002058								14596699	t		miannu	Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). 	SIGNOR-259291	0.8
apomorphine	chemical	CHEBI:48538	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258374	0.8
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT16	protein	Q9UBV4	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242718	0.268
CSNK2A1	protein	P68400	UNIPROT	CBX5	protein	P45973	UNIPROT	up-regulates	phosphorylation	Ser14	RTADSSSsEDEEEYV	9606									21245376	t		gcesareni	Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability.	SIGNOR-171707	0.354
BKM120	chemical	CHEBI:71954	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252656	0.8
ARG1	protein	P05089	UNIPROT	L-ornithine	smallmolecule	CHEBI:15729	ChEBI	up-regulates quantity	chemical modification			9606									14617280	t		miannu	Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC)	SIGNOR-255545	0.8
ACTB	protein	P60709	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates quantity	binding			9606									28233384	t		lperfetto	Here, we report the highest resolution, cryo-EM structures of actin filaments with bound ATP analog β,γ-imidoadenosine 5′-triphosphate (AMPPNP) (3.1 Å) and ADP with inorganic phosphate (ADP-Pi) (3.1 Å) as well as a 3.6-Å resolution structure of the ADP filament. These structures of the three well-characterized nucleotide states of actin monomers and filaments 	SIGNOR-261879	0.7
TBX5	protein	Q99593	UNIPROT	MTSS1	protein	O43312	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20802524	f		miannu	TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. 	SIGNOR-255254	0.253
MMP1	protein	P03956	UNIPROT	COL1A2	protein	P08123	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly775	NGPPGPAgSRGDGGP	-1									17318226	t		lperfetto	In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4. 	SIGNOR-272337	0.412
DOCK10	protein	Q96BY6	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260549	0.501
MAPK8	protein	P45983	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Ser312	TESITATsPASMVGG	9606									18728222	t		gcesareni	Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1.	SIGNOR-180532	0.767
RIPK1	protein	Q13546	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates	phosphorylation			9606									11369754	t		gcesareni	These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994.	SIGNOR-108260	0.431
CALM1	protein	P0DP23	UNIPROT	CAMKK1	protein	Q8N5S9	UNIPROT	up-regulates	binding			9606									10770941	t		lperfetto	The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases	SIGNOR-232178	0.755
CNOT6	protein	Q9ULM6	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	form complex	binding			9606									19558367	t		lperfetto	In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules.	SIGNOR-268309	0.812
alpha-D-ribose 1-phosphate(2-)	smallmolecule	CHEBI:57720	ChEBI	D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	up-regulates quantity	precursor of			9606									17804405	t		miannu	Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase.	SIGNOR-267074	0.8
CH5132799	chemical	CID:49784945	PUBCHEM	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190952	0.8
KIF20B	protein	Q96Q89	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272528	0.7
PRKG1	protein	Q13976	UNIPROT	VASP	protein	P50552	UNIPROT	unknown	phosphorylation	Ser239	GAKLRKVsKQEEASG	9606									14679200	t		lperfetto	Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro	SIGNOR-120351	0.73
PI-103	chemical	CHEBI:90524	ChEBI	PRKDC	protein	P78527	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206175	0.8
GSK1292263	chemical	CID:24996872	PUBCHEM	GPR119	protein	Q8TDV5	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-192859	0.8
STK3	protein	Q13188	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates activity	phosphorylation	Ser226	LNPQWNEsFTFKLKP	9606	BTO:0002181								26414765	t		miannu	Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα. 	SIGNOR-277177	0.2
8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione	chemical	CHEBI:92539	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190687	0.8
MLL/SET subcomplex	complex	SIGNOR-C87	SIGNOR	MLL1 complex	complex	SIGNOR-C89	SIGNOR	form complex	binding			9606									24680668	t		miannu	The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation.	SIGNOR-204819	0.75
LAMTOR1	protein	Q6IAA8	UNIPROT	LAMTOR	complex	SIGNOR-C26	SIGNOR	form complex	binding			9606									20381137	t		lperfetto	Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant	SIGNOR-164769	0.922
PMP22	protein	Q01453	UNIPROT	MPZ	protein	P25189	UNIPROT	up-regulates activity	binding			9606									10212299	t		miannu	Our data provide the first direct evidence for the formation of P0–PMP22 complexes at the plasma membrane. These protein interactions probably participate in holding adjacent Schwann cell membranes together and in stabilizing myelin compaction. 	SIGNOR-251898	0.593
ARHGAP19	protein	Q14CB8	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260471	0.55
PTK6	protein	Q13882	UNIPROT	STAP2	protein	Q9UGK3	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								10980601	t		gcesareni	The phosphorylation of and association with bks by brk was also dependent on the sh2-like domain present within bks.bks is a substrate for the kinase activity of brk and has the characteristics of an adaptor protein.	SIGNOR-81489	0.714
BAD	protein	Q92934	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	down-regulates				9606	BTO:0000830								15526160	f		miannu	C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo.	SIGNOR-254953	0.7
DUSP1	protein	P28562	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates activity	dephosphorylation			10090									17158101	t		gcesareni	Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis.	SIGNOR-236867	0.798
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	RORB	protein	Q92753	UNIPROT	down-regulates activity	chemical inhibition			9606									12958591	t		miannu	ATRA and related retinoids inhibit ROR beta but not ROR alpha transcriptional activity suggesting that high-affinity, subtype-specific ligands could be designed for the identification of ROR beta target genes. Our results identify ROR beta as a retinoid-regulated nuclear receptor, providing a novel pathway for retinoid action.	SIGNOR-266845	0.8
CDK2	protein	P24941	UNIPROT	CDX2	protein	Q99626	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser287	EPLSPVSsLQASVPG	9606									16027724	t		llicata	Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. 	SIGNOR-250728	0.489
MAPK3	protein	P27361	UNIPROT	GRB10	protein	Q13322	UNIPROT	up-regulates	phosphorylation	Ser150	PELCGPGsPPVLTPG	9606									15952796	t		lperfetto	Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation	SIGNOR-138171	0.304
SRC	protein	P12931	UNIPROT	DAG1	protein	Q14118	UNIPROT	down-regulates	phosphorylation	Tyr892	PYRSPPPyVPP	9606		BTO:0000887;BTO:0001103							12795607	t		lperfetto	Tyrosine 892 is now thought to be the principal site for recognition by the c-src tyrosine kinase;. We show that upon tyrosine phosphorylation, beta-dystroglycan undergoes a profound change in its sub-cellular localization (e.g., from the plasma membrane to an internal membrane compartment). One possibility is that the net negative charge at position 892 causes the redistribution of beta-dystroglycan to this intracellular vesicular location	SIGNOR-101655	0.53
COL1A1	protein	P02452	UNIPROT	DDR1	protein	Q08345	UNIPROT	up-regulates	binding			9606									9659900	t		gcesareni	We report that the collagens serve as ligands for the previously orphan family of discoidin domain-containing receptor-like tyrosine kinases.	SIGNOR-58779	0.343
ABL1	protein	P00519	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates activity	phosphorylation	Tyr536	QKGQESEyGNITYPP	9606									8692915	t		Manara	The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites.	SIGNOR-260820	0.423
PPP2CB	protein	P62714	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	dephosphorylation			9606									18160256	t			Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248614	0.487
FBXW7	protein	Q969H0	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates quantity by destabilization	ubiquitination			9606									15546612	t		lperfetto	Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.	SIGNOR-254310	0.633
1-(3-chlorophenyl)piperazine	chemical	CHEBI:10588	ChEBI	HTR2B	protein	P41595	UNIPROT	up-regulates activity	chemical activation			10036	BTO:0000452								9459568	t		miannu	The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-	SIGNOR-258684	0.8
AKT1	protein	P31749	UNIPROT	SH2B2	protein	O14492	UNIPROT	up-regulates activity	phosphorylation	Ser598	SARSRSNsAERLLEA	10090									16141217	t		gcesareni	This study identifies APS as a novel physiological substrate for PKB and the first serine phosphorylation site on APS	SIGNOR-252557	0.409
PIM1	protein	P11309	UNIPROT	RP9	protein	Q8TA86	UNIPROT	unknown	phosphorylation	Ser214	RKHKSSKsNEGSDSE	-1									10931201	t		miannu	PAP-1 was phosphorylated in vitro by Pim-1, but not a kinase-negative Pim-1 mutant. The two serine residues of PAP-1 at amino acids 204 and 206 near the C-terminus were phosphorylated by Pim-1. PAP-1 is thus thought to be a target protein for Pim-1 kinase. 	SIGNOR-263030	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser363	TSRTPKDsPGIPPSA	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-250554	0.2
NPPA	protein	P01160	UNIPROT	NPR1	protein	P16066	UNIPROT	up-regulates	binding			9606									15911069	t		gcesareni	Natriuretic peptide receptor-a (npra) is the biological receptor of the peptide hormones atrial natriuretic peptide (anp) and brain natriuretic peptide (bnp)	SIGNOR-137600	0.883
CTDSP1	protein	Q9GZU7	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	dephosphorylation	Ser187	NSHPFPHsPNSSYPN	9606	BTO:0000552								17085434	t			Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)	SIGNOR-248798	0.476
DDX20	protein	Q9UHI6	UNIPROT	FOXL2	protein	P58012	UNIPROT	up-regulates	binding			9606		BTO:0000975							16153597	t		miannu	Dp103 further increased the cell killing effect induced by foxl2 probably due to the direct association of dp103 with foxl2 protein.	SIGNOR-140388	0.458
RERE	protein	Q9P2R6	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000932								11331249	t		miannu	We detected RERE protein mainly in the nucleus, where it colocalizes with the promyelocytic leukemia protein in promyelocytic leukemia oncogenic domains (PODs). Overexpression of RERE recruits a fraction of the proapoptotic protein BAX to PODS: This observation correlates with RERE-induced apoptosis, which occurs in a caspase-dependent manner.	SIGNOR-264485	0.2
RAD23B	protein	P54727	UNIPROT	RPA3	protein	P35244	UNIPROT	up-regulates activity	binding												24086043	t		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275700	0.502
ABCA1	protein	O95477	UNIPROT	APOA1	protein	P02647	UNIPROT	up-regulates activity	binding			9606									15347662	t		miannu	The stimulation of cellular cholesterol and phospholipid efflux by apolipoprotein A-I is mediated by the activity of the ATP-binding cassette transporter A1 (ABCA1). ABCA1 forms a high affinity complex with apoA-I by binding amphipathic helices within the apolipoprotein. VFVNFA sequence is required for ABCA1 to form a complex with apoA-I and to transfer cholesterol to the apolipoprotein.	SIGNOR-252100	0.783
NEFH	protein	P12036	UNIPROT	Neurofilament bundle assembly	phenotype	SIGNOR-PH72	SIGNOR	up-regulates				9606									8376466	f		miannu	Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons.	SIGNOR-252390	0.7
MAPK1	protein	P28482	UNIPROT	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation	Ser759	KTPDGNKsPAPKPSD	9606		BTO:0001260							10514499	t		lperfetto	Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin.	SIGNOR-71033	0.524
TFAP2A	protein	P05549	UNIPROT	ADM	protein	P35318	UNIPROT	up-regulates quantity by expression	transcriptional regulation												9480831	t	 	 	These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells.	SIGNOR-254048	0.271
BAK1	protein	Q16611	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	up-regulates				9606									21210296	f		gcesareni	Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore.	SIGNOR-170963	0.502
HSD17B11	protein	Q8NBQ5	UNIPROT	estrone	smallmolecule	CHEBI:17263	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000056							16166196	t		lperfetto	A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis.	SIGNOR-268663	0.8
LATS2	protein	Q9NRM7	UNIPROT	YWHAG	protein	P61981	UNIPROT	up-regulates	phosphorylation	Ser59	VVGARRSsWRVISSI	9606									21118956	t		lperfetto	Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions,	SIGNOR-170139	0.336
ITGB6	protein	P18564	UNIPROT	Av/b6 integrin	complex	SIGNOR-C179	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253210	0.864
GRPR	protein	P30550	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257372	0.503
BCOR	protein	Q6W2J9	UNIPROT	HOXA9	protein	P31269	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									26847029	f		irozzo	Importantly, our results showed that BCOR is a repressor of HoxA cluster of genes (HoxA5, HoxA7 and HoxA9) in myeloid cells. Knock-down of HoxA5, HoxA7 and HoxA9 significantly decreased the clonogenic growth of Bcor mutant and wild type cells, demonstrating the Hox genes, as targets of BCOR, played an important role in mediating BCOR’s function in regulating myeloid cell proliferation.	SIGNOR-256014	0.253
B4GALT1	protein	P15291	UNIPROT	UDP(3-)	smallmolecule	CHEBI:58223	ChEBI	up-regulates quantity	chemical modification			9606									16157350	t		miannu	Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 	SIGNOR-268470	0.8
LCK	protein	P06239	UNIPROT	VAV1	protein	P15498	UNIPROT	unknown	phosphorylation	Tyr142	SVGDEDIySGLSDQI	-1									10669745	t			Lck recognizes preferentially the tyrosine residue of Vav located at position 174 and, with significantly less affinity, those present at positions 142 and 160. It is now clear that this posttranslational modification will be involved in the activation of Vav, in the regulation of the strength of the signals emanating from this molecule, and also in the negative regulation of its function.	SIGNOR-251389	0.776
PRKCG	protein	P05129	UNIPROT	CD5	protein	P06127	UNIPROT	up-regulates	phosphorylation	Thr436	FHRNHTAtVRSHAEN	9606									11123317	t		amattioni	Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation.	SIGNOR-85183	0.348
MRPL55	protein	Q7Z7F7	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262335	0.595
CSF1R	protein	P07333	UNIPROT	CSF1R	protein	P07333	UNIPROT	up-regulates	phosphorylation	Tyr699	DPEGGVDyKNIHLEK	9606									15297464	t		lperfetto	Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins.	SIGNOR-127536	0.2
ARFGAP1	protein	Q8N6T3	UNIPROT	LRRK2	protein	Q5S007	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000142							22363216	t	The effect has been demonstrated using Q8N6T3-2	flangone	The gtp hydrolysis activity of lrrk2 is markedly enhanced by arfgap1 supporting a role for arfgap1 as a gtpase-activating protein for lrrk2.Lrrk2 and arfgap1 interact in vitro in mammalian cells and in vivo in brain, and co-localize in the cytoplasm and at golgi membranes	SIGNOR-196264	0.598
EPHB1	protein	P54762	UNIPROT	EPHB1	protein	P54762	UNIPROT	up-regulates activity	phosphorylation	Tyr928	SAIKMVQyRDSFLTA	10029	BTO:0000246								12223469	t			 Co-immunoprecipitation was used to confirm the interaction of Grb7 with the cytoplasmic domain of EphB1 as well as the full-length receptor in intact cells. This interaction is mediated by the SH2 domain of Grb7 and requires tyrosine autophosphorylation of EphB1. We also found that EphB1 could phosphorylate Grb7 and mutation of either Tyr-928 or Tyr-594 to Phe decreased this activity.	SIGNOR-251123	0.2
GPKOW	protein	Q92917	UNIPROT	DHX16	protein	O60231	UNIPROT	up-regulates quantity	binding			9606	BTO:0000567								25296192	t		miannu	In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16. 	SIGNOR-266312	0.843
HIC1	protein	Q14526	UNIPROT	ACKR3	protein	P25106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									23340301	f	 	miannu	 we showed that CXCR7 promoter in prostate cancer cells is negatively regulated by HIC1, which may be responsible for prostate cancer progression.	SIGNOR-254238	0.29
GSK3B	protein	P49841	UNIPROT	HDAC4	protein	P56524	UNIPROT	down-regulates	phosphorylation	Ser298	ACSSAPGsGPSSPNN	9606									21118993	t		lperfetto	The double mutation of serines 298/302 into alanines, but also the sole mutation of serine 302, abolishes hdac4 phosphorylation by gsk3_we have shown that cells lacking gsk3_ are unable to degrade hdac4 after serum starvation	SIGNOR-170144	0.37
PPP1CA	protein	P62136	UNIPROT	CASP2	protein	P42575	UNIPROT	up-regulates activity	dephosphorylation	Ser164	STDTVEHsLDNKDGP	-1									19531356	t		llicata	nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2.	SIGNOR-248564	0.2
MTOR	protein	P42345	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser299	SSPTLSSsPPVLCNP	9606									22017875	t		llicata	Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome.	SIGNOR-176853	0.747
PRKAA2	protein	P54646	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates	phosphorylation			9606		BTO:0000887	SIGNOR-C15						22207502	t		gcesareni	Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway.	SIGNOR-195324	0.379
AURKA	protein	O14965	UNIPROT	NSD2	protein	O96028	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser56	SKAQLSSsLQEGVMQ										35389552	t		lperfetto	Mechanistically, Aurora A phosphorylated NSD2 at S56 residue to protect the protein from cleavage and degradation, thus methylation of Aurora A and phosphorylation of NSD2 bilaterally formed a positive regulating loop.	SIGNOR-275512	0.2
RET	protein	P07949	UNIPROT	GRB7	protein	Q14451	UNIPROT	up-regulates	binding			9606									8631863	t		gcesareni	Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell	SIGNOR-41765	0.552
CSNK2A1	protein	P68400	UNIPROT	GPI	protein	P06744	UNIPROT	down-regulates activity	phosphorylation	Ser185	GPRVWYVsNIDGTHI	9606	BTO:0000459								15637053	t		llicata	It is known that human PGI/AMF is phosphorylated at Ser(185) by protein kinase CK2 (CK2) | These results demonstrate that phosphorylation affects the allosteric kinetic properties of the enzyme, resulting in a less active form of PGI, whereas non-phosphorylated protein species retain cytokine activity. 	SIGNOR-250869	0.338
ixabepilone	chemical	CHEBI:63605	ChEBI	TUBB3	protein	Q13509	UNIPROT	down-regulates activity	chemical inhibition			9606									18945860	t		miannu	Ixabepilone, the first drug in a new class of microtubule-stabilizing agents called epothilones, offers a new treatment option for patients with metastatic or locally advanced breast cancer who are refractory to standard chemotherapy.	SIGNOR-259349	0.8
CDK1	protein	P06493	UNIPROT	NUP50	protein	Q9UKX7	UNIPROT	down-regulates	phosphorylation	Ser221	KVAAETQsPSLFGST	9606									19767751	t		gcesareni	These results suggest that both ERK and Cdk1 directly phosphorylate Nup50 at Ser221 in intact cells|Notably, erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin.	SIGNOR-188061	0.395
HRAS	protein	P01112	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	binding			9606									21779497	t		lperfetto	The first RAS effector pathway to be identified was the RAF-MEK-ERK pathway. This pathway is an essential, shared element of mitogenic signaling involving tyrosine kinase receptors, leading to a wide range of cellular responses, including growth, differentiation, inflammation, and apoptosis.23 The RAF family of proteins (Raf-1, A-Raf, and B-Raf) is serine/threonine kinases that bind to the effector region of RAS-GTP, thus inducing translocation of the protein to the plasma membrane.	SIGNOR-236656	0.934
PRKACA	protein	P17612	UNIPROT	CAMKK1	protein	Q8N5S9	UNIPROT	down-regulates activity	phosphorylation	Thr108	SPRAWRRPtIESHHVAI	10116									10187789	t			In vitro, CaMKK is phosphorylated by PKA and this is associated with inhibition of enzyme activity. The major site of phosphorylation is threonine 108, although additional sites are phosphorylated with lower efficiency.	SIGNOR-256115	0.2
HOXA9	protein	P31269	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	down-regulates				9606	BTO:0000725								14701735	f		irozzo	Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function.	SIGNOR-255864	0.7
PDK3	protein	Q15120	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	phosphorylation	Ser232	NRYGMGTsVERAAAS	-1									11485553	t		lperfetto	Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.	SIGNOR-109613	0.866
WNT10B	protein	O00744	UNIPROT	FZD1	protein	Q9UP38	UNIPROT	up-regulates activity	binding			9606									19008118	t		FFerrentino	In mesenchymal precursor cells, Wnt10b (and Wnt10a) binding to frizzled (FZD1)	SIGNOR-253511	0.651
SRC	protein	P12931	UNIPROT	CFL1	protein	P23528	UNIPROT	down-regulates	phosphorylation	Tyr68	GQTVDDPyATFVKML	9606									19802004	t		lperfetto	Tyrosine phosphorylation of cofilin at y68 by v-src leads to its degradation through ubiquitin-proteasome pathway	SIGNOR-188352	0.57
ZAP70	protein	P43403	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	phosphorylation	Tyr315	MPMDTSVyESPYSDP	9606	BTO:0000661								11828374	t		lperfetto	We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function.	SIGNOR-247048	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	up-regulates				9606									18483217	f			PDGF signaling has been implicated in several fibrotic conditions and is assumed to play a role in driving proliferation of cells with a myofibroblast phenotype.	SIGNOR-254373	0.7
RIMS2	protein	Q9UQ26	UNIPROT	RAB3C	protein	Q96E17	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								31679900	t		miannu	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264378	0.575
MYC	protein	P01106	UNIPROT	UBTF	protein	P17480	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000539								15282543	t		lperfetto	MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter. 	SIGNOR-269644	0.365
PPP2CA	protein	P67775	UNIPROT	MAP3K3	protein	Q99759	UNIPROT	down-regulates	dephosphorylation	Thr516	GASKRLQtICMSGTG	9606									20448038	t		lperfetto	Overexpression of pp2a catalytic subunit (pp2ac) beta-isoform results in dephosphorylation of mekk3 at thr-516 and ser-520 and termination of mekk3-mediated nf-kappab activation.	SIGNOR-165237	0.379
CADPS	protein	Q9ULU8	UNIPROT	SNAP25	protein	P60880	UNIPROT	up-regulates activity	binding			9606	BTO:0000938			SIGNOR-C346					24363652	t		miannu	 CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1	SIGNOR-264338	0.376
EP300	protein	Q09472	UNIPROT	KPNA2	protein	P52292	UNIPROT	up-regulates	acetylation	Lys22	HRFKNKGkDSTEMRR	9606									15342649	t		lperfetto	Ampk triggered the acetylation of importin alpha1 on lys(22), a process dependent on the acetylase activity of p300	SIGNOR-128625	0.363
CENPE	protein	Q02224	UNIPROT	BUB1B	protein	O60566	UNIPROT	up-regulates activity	binding			-1									12925705	t		miannu	CENP-E binds to and directly stimulates the kinase activity of purified BubR1 in vitro. 	SIGNOR-266118	0.84
BRCA1-BARD1 complex	complex	SIGNOR-C297	SIGNOR	LARP7	protein	Q4G0J3	UNIPROT	down-regulates quantity by destabilization	ubiquitination												32726637	t		lperfetto	Here, we demonstrate that upon genotoxic stress, BRCA1 together with BARD1 catalyzes the K48 polyubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degrades it through the 26S ubiquitin-proteasome pathway. 	SIGNOR-275581	0.2
PTGS2	protein	P35354	UNIPROT	prostaglandin F2alpha	smallmolecule	CHEBI:15553	ChEBI	up-regulates	chemical modification			9606									11751058	t		gcesareni	Cox catalyzes two enzymatic activities;namely, the conversion of aa to the hydroperoxy endoperoxide pgg2, followed by its subsequent reduction to the labile product pgh2. Pgh2_ is the common substrate for a number of different cell-specific synthases, which convert pgh2_ to the individual pgs or tx, including pge2, pgi2_ (prostacyclin), pgd2, pgf2alfa, and txa2.	SIGNOR-113291	0.8
OPTN	protein	Q96CV9	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								20174559	t		lperfetto	Using biochemical experiments we showed that optineurin interacts with the protein kinase TBK1 and the ubiquitin ligase TRAF3. Furthermore, a mutation in optineurin that prevents the interaction with the small protein modifier ubiquitin (D474N) ablated the negative regulatory function of optineurin.	SIGNOR-262276	0.786
MAPK3	protein	P27361	UNIPROT	NFATC4	protein	Q14934	UNIPROT	up-regulates	phosphorylation	Ser676	SNGRRKRsPTQSFRF	9606									15657420	t		lperfetto	The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity.	SIGNOR-133276	0.294
(R)-salbutamol	chemical	CHEBI:8746	ChEBI	ADRB1	protein	P08588	UNIPROT	up-regulates activity	chemical activation			10030									20590599	t		Luana	Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. 	SIGNOR-257866	0.8
FGFR1	protein	P11362	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates	phosphorylation	Tyr327	PLLREETyDVPPAFA	9606									12601080	t		lperfetto	Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas.	SIGNOR-98500	0.259
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1714	SPTSPSYsPTSPSYS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248753	0.727
POU3F2	protein	P20265	UNIPROT	POU3F2	protein	P20265	UNIPROT	up-regulates activity	binding			9606									11029584	t		miannu	These experiments lead to the conclusion that the full-length Brn-2 protein can interact with full-length Brn-2. Assay of homodimerization properties of Brn-2 protein on the b2s1 dimer recognition sequence also demonstrated cooperativity, indicating that protein-protein contacts would be important for synergistic interactions between the Brn-2 subunits.	SIGNOR-221824	0.2
SMAD7	protein	O15105	UNIPROT	SMURF2	protein	Q9HAU4	UNIPROT	up-regulates activity	binding			9534	BTO:0001538								11163210	t		miannu	Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways. 	SIGNOR-272937	0.865
quinpirole	chemical	CHEBI:75401	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			-1									7576010	t		miannu	 D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole.	SIGNOR-258441	0.8
CFL1	protein	P23528	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	down-regulates quantity	binding			9606	BTO:0000132								27871158	t		lperfetto	Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers.	SIGNOR-261836	0.7
WNT4	protein	P56705	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates				9606		BTO:0000887;BTO:0001103							9753670	f		gcesareni	Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm.	SIGNOR-60370	0.299
SRC	protein	P12931	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates	phosphorylation	Tyr853	HLGRVLGyGAFGKVV	9606									20431062	t		lperfetto	Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk.	SIGNOR-165055	0.491
PPARGC1A	protein	Q9UBK2	UNIPROT	SOD2	protein	P04179	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20089851	f	Regulation	miannu	 PGC-1α has been reported to induce Mn-SOD expression 	SIGNOR-251762	0.383
ATM	protein	Q13315	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates	phosphorylation	Ser696	NVLSVALsQRTTVPE	9606									21095582	t		lperfetto	Here we show that hypoxia results in ataxia telangiectasia mutated (atm)-dependent phosphorylation of hypoxia-inducible factor 1-alpha (hif-1_) on serine(696) and mediates downregulation of mtorc1 signaling. phosphorylation of hif-1_ by atm is required for its stability	SIGNOR-169999	0.443
D2HGDH	protein	Q8N465	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity													26178471	f		lperfetto	Here we show that wild-type D2HGDH elevates α-KG levels	SIGNOR-253131	0.8
WWTR1	protein	Q9GZV5	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606									23075495	f		gcesareni	Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis.	SIGNOR-199208	0.7
CTDSP2	protein	O14595	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation	Ser250	TGSPAELsPTTLSPV	9606									17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248298	0.421
NFIA	protein	Q12857	UNIPROT	EPHA4	protein	P54764	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268894	0.2
IKBKB	protein	O14920	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	down-regulates activity	phosphorylation	Ser418	TTENRFHsLPFSLTK	9606	BTO:0000661								15870263	t		gianni	In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits.	SIGNOR-266436	0.529
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	4-hydroxy-17beta-estradiol	smallmolecule	CHEBI:62845	ChEBI	up-regulates quantity	precursor of			9606	BTO:0000093								8790407	t		Luana	These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens.	SIGNOR-269753	0.8
Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	Axonal_growth_cone_formation	phenotype	SIGNOR-PH199	SIGNOR	up-regulates				9606	BTO:0000938								21106647	f		miannu	Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. 	SIGNOR-268384	0.7
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	PLEC	protein	Q15149	UNIPROT	down-regulates	phosphorylation	Thr4539	GGLIEPDtPGRVPLD	9606	BTO:0000567								8626512	t		lperfetto	Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane.	SIGNOR-216908	0.396
PBX1	protein	P40424	UNIPROT	FGF8	protein	P55075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003560								10026229	t		miannu	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 	SIGNOR-265803	0.275
NAT8L	protein	Q8N9F0	UNIPROT	N-acetyl-L-aspartate(2-)	smallmolecule	CHEBI:16953	ChEBI	up-regulates quantity	chemical modification			9606									19524112	t		miannu	The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA.	SIGNOR-267523	0.8
SIRT7	protein	Q9NRC8	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	deacetylation	Lys38	PATGGVKkPHRYRPG										30653310	t		lperfetto	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 	SIGNOR-275886	0.2
Flesinoxan	chemical	CID:57347	PUBCHEM	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3).	SIGNOR-258950	0.8
RAD1	protein	O60671	UNIPROT	TOPBP1	protein	Q92547	UNIPROT	up-regulates	binding			9606									18594563	t		gcesareni	The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner	SIGNOR-179379	0.604
SMURF1	protein	Q9HCE7	UNIPROT	CUEDC1	protein	Q9NWM3	UNIPROT	unknown	ubiquitination			-1									20804422	t		miannu	Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay.	SIGNOR-272682	0.2
imatinib	chemical	CHEBI:45783	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck;VIRAL ABL	gcesareni		SIGNOR-193372	0.8
MAPK1	protein	P28482	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates	phosphorylation	Ser295	PARPRSPsQTRKGPP	9606		BTO:0000142							15262992	t		lperfetto	Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2.	SIGNOR-126863	0.268
BMPR1B	protein	O00238	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates	phosphorylation	Ser465	HNPISSVs	9606									9335504	t		llicata	The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1.	SIGNOR-52670	0.628
TRIM2	protein	Q9C040	UNIPROT	NEFL	protein	P07196	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								18687884	t		miannu	Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination.	SIGNOR-271776	0.441
MAPK12	protein	P53778	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser637	VDLSKVTsKCGSLGN	-1									9199504	t		miannu	Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective.	SIGNOR-250085	0.504
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	AMPH	protein	P49418	UNIPROT	unknown	phosphorylation	Ser272	EEPSPLPsPTASPNH	-1									11113134	t		llicata	Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. 	SIGNOR-250644	0.361
NR3C1	protein	P04150	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000746								27777311	f			We observed GR binding on or near Cebpβ, Cebpδ, Klf5, Klf9, Cebpα, and Pparγ gene loci at 4 h but not at 0 h of adipogenesis. Thus, at least one of the mechanisms by which GR promotes adipogenesis in culture is by directly activating the expression of multiple adipogenic TFs.	SIGNOR-256120	0.401
PKG	proteinfamily	SIGNOR-PF77	SIGNOR	3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa.	SIGNOR-266507	0.8
STK3	protein	Q13188	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates activity	phosphorylation	Thr228	PQWNESFtFKLKPSD	9606	BTO:0002181								26414765	t		miannu	Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα. 	SIGNOR-277176	0.2
GSK3B	protein	P49841	UNIPROT	SPAG5	protein	Q96R06	UNIPROT	up-regulates	phosphorylation	Thr111	PIPQISStPKTSEEA	9606									18055457	t		lperfetto	Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta	SIGNOR-159578	0.274
DNMT3B	protein	Q9UBC3	UNIPROT	BAG4	protein	O95429	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001109								18413740	f	 	lperfetto	In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+)	SIGNOR-254113	0.2
GRM7	protein	Q14831	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264350	0.7
CDK2	protein	P24941	UNIPROT	CHEK1	protein	O14757	UNIPROT	up-regulates	phosphorylation	Ser301	IQSNLDFsPVNSASS	9606									21765472	t		lperfetto	Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency	SIGNOR-175083	0.535
TSPOAP1	protein	O95153	UNIPROT	RIMS1	protein	Q86UR5	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264363	0.2
AP1S1	protein	P61966	UNIPROT	AP-1 complex	complex	SIGNOR-C248	SIGNOR	form complex	binding			9606									21097499	t		lperfetto	Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)	SIGNOR-260684	0.862
CHAMP1	protein	Q96JM3	UNIPROT	Chromosome_segregation	phenotype	SIGNOR-PH44	SIGNOR	up-regulates				9606	BTO:0000567								21063390	f		miannu	Proper attachment of microtubules to kinetochores is essential for accurate chromosome segregation. These data suggest that CAMP is required for maintaining kinetochore-microtubule attachment during biorientation.	SIGNOR-264901	0.7
HCRT	protein	O43612	UNIPROT	HCRTR1	protein	O43613	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000142							9491897	t		gcesareni	Identification and initial biological characterization of two orexins as well as their two receptors	SIGNOR-53667	0.765
CSNK1E	protein	P49674	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation	Ser1420	YVVHGPAsVPLGYVP	9606									16513652	t		gcesareni	We find that ckiepsilon binds to lrp5 and lrp6 in vitro and in vivo and identify three ckiepsilon-specific phosphorylation sites in lrp6. Two of the identified phosphorylation sites, ser1420 and ser1430, influence wnt signaling in vivo,	SIGNOR-145049	0.266
FYN	protein	P06241	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	unknown	phosphorylation			9606									15537652	t		gcesareni	Here we provide evidence that fyn kinase, a member of the src kinase family, is involved in the uvb-induced phosphorylation of histone h3 at serine 10	SIGNOR-265330	0.2
MLNR	protein	O43193	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257132	0.409
NRAS	protein	P01111	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606									21779497	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. It was also described that ras interacts with pi3k in a direct manner.llysine residue 227 is essential for the interaction of ras with pi3k	SIGNOR-175228	0.709
3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	PRKAR2B	protein	P31323	UNIPROT	down-regulates activity	chemical inhibition			9606									26687711	t			Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 	SIGNOR-258762	0.8
GLI2	protein	P10070	UNIPROT	FOXF1	protein	Q12946	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0005738								23034409	f	 	miannu	 we propose that chromatin looping between SDR and FOXF1 allows GLI2 to increase FOXF1 activity specifically in lung endothelium.	SIGNOR-254216	0.403
HTR3C	protein	Q8WXA8	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606		BTO:0000142							18761359	f		miannu	The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release. 	SIGNOR-264320	0.7
GSK3B	protein	P49841	UNIPROT	STMN3	protein	Q9NZ72	UNIPROT	up-regulates activity	phosphorylation	Ser60	SFEVILKsPSDLSPE	-1									22577147	t		lperfetto	Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta	SIGNOR-264882	0.268
N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-)	smallmolecule	CHEBI:143788	ChEBI	N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-)	smallmolecule	CHEBI:147286	ChEBI	up-regulates quantity	precursor of			9606									33179964	t		miannu	The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner.	SIGNOR-268102	0.8
Translation release factor ERF1-ERF3	complex	SIGNOR-C494	SIGNOR	protein polypeptide chain	smallmolecule	CHEBI:16541	ChEBI	up-regulates quantity	chemical modification			9606									29735640	t		miannu	Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3–guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide. 	SIGNOR-270818	0.8
PRKG1	protein	Q13976	UNIPROT	VASP	protein	P50552	UNIPROT	down-regulates	phosphorylation	Thr278	LARRRKAtQVGEKTP	9606									12576312	t		lperfetto	Vasodilator-stimulated phosphoprotein activation of serum-response element-dependent transcription occurs downstream of rhoa and is inhibited by cgmp-dependent protein kinase phosphorylation. Three phosphorylation sites have been identified in vasp: ser157, ser239, and thr278, all of which can be phosphorylated by either pka or pkg in vitro	SIGNOR-98139	0.73
DGC	complex	SIGNOR-C217	SIGNOR	NRXN1	protein	Q9ULB1	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							11470830	t		miannu	In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan.	SIGNOR-265446	0.351
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	SCNN1B	protein	P51168	UNIPROT	down-regulates quantity by destabilization	phosphorylation			-1									11805112	t	inferred from 70% family members	lperfetto	Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.	SIGNOR-270050	0.2
SLC25A13	protein	Q9UJS0	UNIPROT	aspartic acid	smallmolecule	CHEBI:22660	ChEBI	up-regulates quantity	relocalization			9606									12084073	t		miannu	Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. 	SIGNOR-265157	0.8
MAP2K7	protein	O14733	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates	phosphorylation	Thr183	AGTSFMMtPYVVTRY	9606									9312068	t		gcesareni	Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues.	SIGNOR-51199	0.686
PRKCB	protein	P05771	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser290	GRIVARNsRKMAFRA	-1									9677319	t		lperfetto	Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases.	SIGNOR-249007	0.308
NODAL	protein	Q96S42	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0004094								15531507	f	Regulation	miannu	Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7.	SIGNOR-251934	0.7
PTPRB	protein	P23467	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates activity	dephosphorylation	Tyr81	WEVGSITyDTLSAQA	9606									32653904	t		miannu	VE-PTP inhibition enhances eNOS activity to improve endothelial function and decrease blood pressure indirectly, through the activation of Tie-2 and the CD31/VE, cadherin, and VEGFR2 complex, and directly by dephosphorylating eNOS Tyr81.|VE-PTP, on the other hand, formed a complex with eNOS in endothelial cells and directly dephosphorylated eNOS Tyr81 in vitro.	SIGNOR-277041	0.271
clofarabine	chemical	CHEBI:681569	ChEBI	POLB	protein	P06746	UNIPROT	down-regulates activity	chemical inhibition			9606									1707752	t		miannu	Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase.	SIGNOR-258358	0.8
MAPK1	protein	P28482	UNIPROT	TNFRSF1A	protein	P19438	UNIPROT	down-regulates activity	phosphorylation	Thr280	FSPTPGFtPTLGFSP	-1									11606045	t		lperfetto	Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation.|Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a	SIGNOR-249453	0.515
AFAP1L2	protein	Q8N4X5	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								19060924	t		miannu	RET/PTC induced robust tyrosine phosphorylation of XB130, which promoted its subsequent association with the p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase). We identified tyrosine 54 of XB130 as the major target of RET/PTC-mediated phosphorylation and a critical binding site for the SH2 domains of p85alpha.	SIGNOR-263193	0.2
TOPBP1	protein	Q92547	UNIPROT	ATRIP	protein	Q8WXE1	UNIPROT	up-regulates	binding			9606									20068082	t		gcesareni	Topbp1 directly activates atr/atrip and promotes atr-mediated chk1 phosphorylation.	SIGNOR-163214	0.789
PRKCD	protein	Q05655	UNIPROT	ADRB2	protein	P07550	UNIPROT	down-regulates activity	phosphorylation	Ser345	ELLCLRRsSLKAYGN	-1									1848190	t		lperfetto	We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling.	SIGNOR-248857	0.358
CKMT1A	protein	P12532	UNIPROT	N-phosphocreatine	smallmolecule	CHEBI:17287	ChEBI	up-regulates quantity	chemical modification			9606									18502307	t		miannu	Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 	SIGNOR-265790	0.8
PRKCE	protein	Q02156	UNIPROT	TRPV1	protein	Q8NER1	UNIPROT	up-regulates activity	phosphorylation	Ser502	YFLQRRPsMKTLFVD	9606	BTO:0000007								11884385	t		lperfetto	Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues. | Patch clamp analysis of the point mutants where Ser or Thr residues were replaced with Ala in the total 16 putative phosphorylation sites showed that two Ser residues, Ser(502) and Ser(800) were involved in the potentiation of the capsaicin-evoked currents by either PMA or ATP.	SIGNOR-249141	0.2
LINC complex	complex	SIGNOR-C303	SIGNOR	NXF1	protein	Q9UBU9	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								28831067	t		lperfetto	SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1.	SIGNOR-263297	0.307
OGA	protein	O60502	UNIPROT	PFKM	protein	P08237	UNIPROT	up-regulates activity	deglycosylation	Ser530	VVIPATVsNNVPGSD	9606									26399441	t		lperfetto	Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 	SIGNOR-267607	0.2
JAK2	protein	O60674	UNIPROT	SLC6A8	protein	P48029	UNIPROT	down-regulates activity	relocalization			443947	BTO:0000964								22407360	t		miannu	Janus-activated kinase-2 (JAK2) participates in the regulation of the Na⁺-coupled glucose transporter SGLT1 and the Na⁺-coupled amino acid transporter SLC6A19. JAK2 is a novel regulator of the creatine transporter SLC6A8, which downregulates the carrier, presumably by interference with carrier protein insertion into the cell membrane.	SIGNOR-265781	0.2
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr45	PGGTLFStTPGGTRI	9606									9465032	t		lperfetto	Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size.	SIGNOR-217090	0.753
BTF3	protein	P20290	UNIPROT	RRAS2	protein	P62070	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17312387	f		miannu	 BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others.	SIGNOR-253766	0.261
ATF2	protein	P15336	UNIPROT	GCH1	protein	P30793	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16149046	f		miannu	Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2.	SIGNOR-252226	0.2
adenosine	smallmolecule	CHEBI:16335	ChEBI	ADORA2A	protein	P29274	UNIPROT	up-regulates activity	binding			-1									14662005	t		Luana	Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3.	SIGNOR-268420	0.8
ACLY	protein	P53396	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	down-regulates quantity by destabilization	chemical modification			9606									19286649	t		miannu	ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor.	SIGNOR-268081	0.8
C3AR1	protein	Q16581	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606	BTO:0001669								9108406	f		lperfetto	 In summary, these findings indicate that C3a and C5a serve as chemotaxins for human mast cells. Anaphylatoxin-mediated recruitment of mast cells might play an important role in hypersensitivity and inflammatory processes.	SIGNOR-263472	0.7
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									10710310	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-75629	0.784
caffeine	chemical	CHEBI:27732	ChEBI	PDE2A	protein	O00408	UNIPROT	down-regulates activity	chemical inhibition												36476859	t		lperfetto	We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice. 	SIGNOR-275729	0.8
BRAF	protein	P15056	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									29731393	f		miannu	Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2	SIGNOR-267362	0.2
GABBR1	protein	Q9UBS5	UNIPROT	GABA-B receptor	complex	SIGNOR-C336	SIGNOR	form complex	binding			9606	BTO:0000007								9872316	t	brain	lperfetto	Heterodimerization is required for the formation of a functional GABA(B) receptor.|These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2. 	SIGNOR-263742	0.678
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000675								23616010			lperfetto	The results revealed that PAR2-AP and FVIIa could upregulate c-Jun expression and c-Jun phosphorylation in SW620 cells in a time-dependent manner. The effect of FVIIa was significantly blocked by anti-TF and anti-PAR2 antibodies. Protein kinase C_ (PKC_) inhibitor safingol and extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor U0126 abrogated the activation of c-Jun	SIGNOR-236767	0.2
ATG7	protein	O95352	UNIPROT	MAP1LC3B	protein	Q9GZQ8	UNIPROT	up-regulates	binding			9606									22170151	t		gcesareni	These results indicated that the fap motif of atg7 is indispensable for formation of the atg3-lc3 e2-substrate intermediate through the interaction of atg7 with atg3.	SIGNOR-195239	0.869
CRH	protein	P06850	UNIPROT	CRHR1	protein	P34998	UNIPROT	up-regulates	binding			9606									11416224	t		gcesareni	Crf and ucn bind and activate crf-r1 with similarly high affinities.	SIGNOR-108713	0.957
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	EP300	protein	Q09472	UNIPROT	up-regulates	phosphorylation	Ser2315	RSPQPVPsPRPQSQP	9606									17623675	t		lperfetto	Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression.	SIGNOR-244634	0.2
CDKN1A	protein	P38936	UNIPROT	Cell_cycle_block	phenotype	SIGNOR-PH10	SIGNOR	up-regulates				9606									24470334	f			The cell cycle regulator p21 is induced early in myoblast differentiation and functions to block cell cycle progression	SIGNOR-267286	0.7
Aldolase	proteinfamily	SIGNOR-PF75	SIGNOR	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266482	0.8
JUN	protein	P05412	UNIPROT	SPI1	protein	P17947	UNIPROT	up-regulates activity	binding			9606	BTO:0004136								12393465	t		apalma	These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1.	SIGNOR-255660	0.572
SQSTM1	protein	Q13501	UNIPROT	SOD1	protein	P00441	UNIPROT	down-regulates quantity by destabilization	binding			10090	BTO:0002572								19765191	t	P00441:p.Ala5Val (mutation causing interaction)		 This study provides a novel molecular mechanism by which mutant SOD1 can be recognized by p62 in an ubiquitin-independent fashion and targeted for the autophagy-lysosome degradation pathway.	SIGNOR-262801	0.529
FGF12	protein	P61328	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253412	0.323
AKT1	protein	P31749	UNIPROT	CDKN1C	protein	P49918	UNIPROT	down-regulates	phosphorylation	Ser282	FFAKRKRsAPEKSSG	9606	BTO:0000150								23421998	t		lperfetto	Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination	SIGNOR-252535	0.459
RAB6A	protein	P20340	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				10116									25492866	f		miannu	Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons	SIGNOR-266873	0.7
MAL	protein	P21145	UNIPROT	Myelination	phenotype	SIGNOR-PH206	SIGNOR	up-regulates													15337780	f		SimoneGraziosi	Our results demonstrate a critical role for MAL in the maintenance of central nervous system paranodes	SIGNOR-269228	0.7
regorafenib	chemical	CHEBI:68647	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206412	0.8
FGFR2	protein	P21802	UNIPROT	PTEN	protein	P60484	UNIPROT	unknown	phosphorylation	Tyr240	RREDKFMyFEFPQPL	9606									22891331	t		llicata	Fgfrs phosphorylate pten at tyrosine 240	SIGNOR-191793	0.439
LEPR	protein	P48357	UNIPROT	NPY	protein	P01303	UNIPROT	down-regulates quantity													27154742	f		lperfetto	Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production	SIGNOR-253075	0.469
EIF3_complex	complex	SIGNOR-C401	SIGNOR	EIF1	protein	P41567	UNIPROT	up-regulates activity	stabilization			9606									17581632	t		lperfetto	EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 	SIGNOR-269152	0.604
SIRT5	protein	Q9NXA8	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									31815138	f		Monia	Western blot showed that Sirt5 overexpression upregulated Nrf2. Sirt5 attenuates apoptosis through Nrf2/HO-1 and Bcl-2. 	SIGNOR-261208	0.313
IRF3	protein	Q14653	UNIPROT	SOCS2	protein	O14508	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22291912	f		miannu	 SOCS2 induction by LPS was dependent on the type I IFN regulated transcription factors IRF1 and IRF3 as shown by using silencing RNAs for IRFs. 	SIGNOR-254495	0.372
PRKAA1	protein	Q13131	UNIPROT	G6PC1	protein	P35575	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21892142	f		gcesareni	Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation	SIGNOR-176475	0.2
LCK	protein	P06239	UNIPROT	DEF6	protein	Q9H4E7	UNIPROT	up-regulates activity	phosphorylation	Tyr144	MVPDEVEyLLKKVLS	9606	BTO:0000661								18976935	t		lperfetto	Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway|These results indicate that SLAT undergoes Lck-dependent phosphorylation on Tyr-144 and Tyr-133 upon TCR and CD28 stimulation.	SIGNOR-253368	0.515
PRKDC	protein	P78527	UNIPROT	RPA2	protein	P15927	UNIPROT	down-regulates activity	phosphorylation	Ser13	FESYGSSsYGGAGGY	-1									9295339	t		lperfetto	We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13	SIGNOR-248982	0.598
LATS1	protein	O95835	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser397	TYHSRDEsTDSGLSM	9606	BTO:0000007								20048001	t		lperfetto	We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition	SIGNOR-218034	0.835
AMPK	complex	SIGNOR-C15	SIGNOR	ULK1/Atg13/Fip200	complex	SIGNOR-C100	SIGNOR	up-regulates activity	phosphorylation			9606									23863160	t		lperfetto	Under energy deprivation, AMPK positively regulates ULK1 to induce autophagy, with various studies revealing that AMPK binds to and phosphorylates ULK1	SIGNOR-209913	0.408
mTORC1	complex	SIGNOR-C3	SIGNOR	SGK1	protein	O00141	UNIPROT	up-regulates activity	phosphorylation	Ser422	AEAFLGFsYAPPTDS	-1									18570873	t		lperfetto	Mtor phosphorylated sgk1, but not sgk1-s422a, in vitro. Sgk1 phosphorylated p27 in vitro. These data implicate sgk1 as an mtorc1 (mtor-raptor) substrate. mtor may promote g1 progression in part through sgk1 activation	SIGNOR-217078	0.608
WNT3A	protein	P56704	UNIPROT	FZD1	protein	Q9UP38	UNIPROT	up-regulates activity	binding			9606	BTO:0000222								10601008	t		gcesareni	Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have a complex and partially overlapping pattern of expression in different regions of the embryo, and many of them (fz1, 3, 7, 8 and 9) have specific expression in the epithelial somites as well as in the newly formed myotomes.	SIGNOR-73036	0.789
GALR3	protein	O60755	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257206	0.293
NEIL1	protein	Q96FI4	UNIPROT	Base-excision_repair	phenotype	SIGNOR-PH222	SIGNOR	up-regulates													23545420	f		lperfetto	The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1).	SIGNOR-275718	0.7
METTL21C	protein	Q5VZV1	UNIPROT	VCP	protein	P55072	UNIPROT	up-regulates activity	methylation	Lys315	AIAPKREkTHGEVER	10090	BTO:0002319								29719249	t			We reveal that METTL21C trimethylates p97 on the Lys315 residue and found that loss of this modification reduced p97 hexamer formation and ATPase activity in vivo.	SIGNOR-255918	0.314
RPL4	protein	P36578	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262460	0.855
IL7	protein	P13232	UNIPROT	IL7R	protein	P16871	UNIPROT	up-regulates	binding			9606	BTO:0000782								8204885	t		fspada	Antibody r34.34 was further found to be directed against an epitope interfering with binding of interleukin-7 (il-7) to pre-alp cells. Expression cloning from a pre-alp cdna library showed that r34.34 antigen is cdw127, the 75- to 80-kd il-7 receptor. Proliferation of the b-lineage all cell lines reh and mieliki was inhibited by il-7, and this effect was specifically reverted by moab r34.34. In addition, antibody r34.34 specifically inhibited il-7-dependent proliferation of normal bcp, pre-alp cells, and peripheral t cells. These results imply that both inhibitory and proliferative effects of il-7 can be mediated through the same receptor on various lineages.	SIGNOR-37012	0.912
PRKACA	protein	P17612	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates activity	phosphorylation	Ser39	TTSTRTYsLGSALRP	-1									2500966	t		miannu	Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure.	SIGNOR-250067	0.313
LY2940680	chemical	CID:49848070	PUBCHEM	SMO	protein	Q99835	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193805	0.8
IKBKB	protein	O14920	UNIPROT	NFKBIB	protein	Q15653	UNIPROT	down-regulates	phosphorylation			9606									9346241	t		gcesareni	We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation	SIGNOR-52932	0.757
MAPK10	protein	P53779	UNIPROT	PPM1J	protein	Q5JR12	UNIPROT	down-regulates	phosphorylation	Ser93	HAGRAVQsPPDTGRR	9606									18553930	t		gcesareni	Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells.	SIGNOR-178926	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	BCL6	protein	P41182	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000782;BTO:0000785								9649500	t	inferred from 70% family members	gcesareni	Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway.	SIGNOR-270011	0.2
DLG1	protein	Q12959	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates activity	binding			9606	BTO:0000782								17187070	t		Barakat	Dlgh1 immunoprecipitates were specifically enriched for activated p38 phosphorylated at Thr180 and Tyr182; phosphorylated p38 was not detected in the unbound fraction from stimulated samples	SIGNOR-274143	0.625
romidepsin	chemical	CHEBI:61080	ChEBI	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257989	0.8
EEF1A1P5	protein	Q5VTE0	UNIPROT	Val-tRNA(Val)	smallmolecule	CHEBI:29164	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269559	0.8
PIK-75 Hydrochloride	chemical	CID:45265864	PUBCHEM	PRKDC	protein	P78527	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206214	0.8
TUBA4A	protein	P68366	UNIPROT	Neuron_migration	phenotype	SIGNOR-PH67	SIGNOR	up-regulates				9606	BTO:0000007								19185337	f		miannu	We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching.	SIGNOR-269730	0.7
MAPK3	protein	P27361	UNIPROT	PCBP2	protein	Q15366	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser189	YRPKPSSsPVIFAGG	9606									17475908	t		miannu	We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 	SIGNOR-262915	0.329
EGFR	protein	P00533	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates	phosphorylation	Tyr627	KGDKQVEyLDLDLDS	9606	BTO:0000527;BTO:0000017								9890893	t		lperfetto	Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689).	SIGNOR-236392	0.751
HCK	protein	P08631	UNIPROT	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	up-regulates activity	phosphorylation	Tyr775	QGWVPSNyITPVNSL	9606									16912036	t		Manara	Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 	SIGNOR-260811	0.2
AKT1	protein	P31749	UNIPROT	GATA2	protein	P23769	UNIPROT	down-regulates	phosphorylation	Ser401	QTRNRKMsNKSKKSK	9606	BTO:0000876								15837948	t	PI-3K/Akt-dependent manner.	fspada	We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity	SIGNOR-135614	0.54
AKAP8	protein	O43823	UNIPROT	PRKACA	protein	P17612	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								19531803	t		Giulio	To determine whether AKAP95 and p105 were present in a complex in mammalian cells, FLAG-tagged AKAP95 wascoexpressed with Myc-tagged p105 in human embryonic kidney (HEK) 293 cells. Immunoprecipitation of either protein pulled down a complex containing AKAP95, p105, and PKA-Ca (Fig. 6D).|The identification of a PKA phosphorylation site in the C-terminal region of p105 suggests that p105 is a candidate substrate for AKAP95-targeted PKA.	SIGNOR-260302	0.3
fenoterol	chemical	CHEBI:149226	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1). 	SIGNOR-257869	0.8
eribulin mesylate	chemical	CHEBI:70710	ChEBI	TUBB1	protein	Q9H4B7	UNIPROT	down-regulates activity	chemical inhibition			9606									16940412	t		miannu	The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin.	SIGNOR-259345	0.8
PP2Ca_R1A_Bd 	complex	SIGNOR-C133	SIGNOR	MAP3K5	protein	Q99683	UNIPROT	up-regulates activity	dephosphorylation	Ser966	NEYLRSIsLPVPVLV	9606									27858941	t		miannu	DAB2IP also mediates recruitment of PP2A to ASK1, binding both proteins through its C2 domain; this favors removal of the inhibitory S967 phosphorylation and further activation of ASK1	SIGNOR-254756	0.291
CD19	protein	P15391	UNIPROT	LYN	protein	P07948	UNIPROT	up-regulates activity	binding			10090	BTO:0000776								25673924	t		lperfetto	CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades.	SIGNOR-242894	0.765
CSNK2A1	protein	P68400	UNIPROT	PSEN2	protein	P49810	UNIPROT	unknown	phosphorylation	Ser19	EVCDERTsLMSAESP	-1									8972483	t		llicata	In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. 	SIGNOR-250932	0.311
IL1B	protein	P01584	UNIPROT	GCH1	protein	P30793	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000766							10435048	f		miannu	IL-1 beta induces expression of GTP cyclohydrolase-1 which leads to increased generation of BH4 and activation of eNOS. 	SIGNOR-252224	0.35
LAMC2	protein	Q13753	UNIPROT	Laminin-5	complex	SIGNOR-C184	SIGNOR	form complex	binding												9211848	t		lperfetto	Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2.	SIGNOR-253237	0.567
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1668	SPSYSPTsPSYSPTS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248739	0.727
PRKCA	protein	P17252	UNIPROT	GMFB	protein	P60983	UNIPROT	unknown	phosphorylation	Ser53	DEELEGIsPDELKDE	-1									9030586	t		lperfetto	Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively.	SIGNOR-248960	0.327
PRKCA	protein	P17252	UNIPROT	LMNA	protein	P02545	UNIPROT	up-regulates activity	phosphorylation	Ser403	QRSRGRAsSHSSQTQ	-1									7925482	t		lperfetto	Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence.	SIGNOR-248903	0.369
RNF7	protein	Q9UBF6	UNIPROT	ROS	stimulus	SIGNOR-ST2	SIGNOR	down-regulates				9606									23136067	f		miannu	We examined potential role of SAG in conferring cellular radioresistance, based upon two pieces of evidence. First, SAG is an antioxidant protein that scavenges ROS. R	SIGNOR-271445	0.7
MAPKAPK2	protein	P49137	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates	phosphorylation	Ser119	EILSRRPsYRKILND	9606									17389598	t		lperfetto	Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2.	SIGNOR-153944	0.679
EIF2S1	protein	P05198	UNIPROT	HBG1	protein	P69891	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24714526	f		miannu	Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy.	SIGNOR-251819	0.2
TIMP3	protein	P35625	UNIPROT	MMP14	protein	P50281	UNIPROT	down-regulates activity	binding			10090	BTO:0005300								28709001	t			FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis.	SIGNOR-255908	0.586
LEPR	protein	P48357	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0001282								18718905	t		miannu	These observations indicate that leptin stimulates tyrosine phosphorylation of STAT3 via LEPRb but independent of JAK2.	SIGNOR-263492	0.751
ARAP3	protein	Q8WWN8	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260456	0.447
CDK1	protein	P06493	UNIPROT	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr234	SFKKQEKtPKTPKGP	10090			SIGNOR-C17						11278991	t		lperfetto	CDK1-cyclin B phosphorylates NPM/B23 on Thr234.	SIGNOR-235530	0.534
NFKBIE	protein	O00221	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates	binding			9606	BTO:0001271			SIGNOR-C13					12835716	t		gcesareni	Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe	SIGNOR-102774	0.52
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	PBK	protein	Q96KB5	UNIPROT	unknown	phosphorylation	Thr9	EGISNFKtPSKLSEK	9606									15541388	t		lperfetto	Topk-thr-9 was phosphorylated by cdk1/cyclin b and topk significantly associates with mitotic spindles.	SIGNOR-216896	0.568
TOB2	protein	Q14106	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	down-regulates activity	binding			9606	BTO:0000567								18377426	t		miannu	We found that Tob associates with the CCR4-NOT complex. The carboxyl-terminal half of Tob interacted with Cnot1, a core protein of the CCR4-NOT complex. We further showed that the deadenylase activity associated with the complex was suppressed in vitro by Tob. 	SIGNOR-273615	0.354
CAMK2A	protein	Q9UQM7	UNIPROT	ETS2	protein	P15036	UNIPROT	down-regulates	phosphorylation	Ser246	FPKSRLSsVSVTYCS	9606									19182667	t		lperfetto	Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters	SIGNOR-183596	0.2
PPP2CA	protein	P67775	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	down-regulates	dephosphorylation			9606									2826472	t		gcesareni	Protein phosphatase 2a inactivates the mitogen-stimulated s6 kinase from swiss mouse 3t3 cells	SIGNOR-23575	0.709
PBX1	protein	P40424	UNIPROT	FGF8	protein	P55075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003560								10026229	t		miannu	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 	SIGNOR-265777	0.275
SMARCC2	protein	Q8TAQ2	UNIPROT	SWI/SNF ACTL6A-ARID1A-SMARCA2 variant	complex	SIGNOR-C470	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269823	0.834
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	CASP9	protein	P55211	UNIPROT	down-regulates activity	phosphorylation			9606									12792650	t	inferred from 70% family members	lperfetto	Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk	SIGNOR-270084	0.2
EIF2AK2	protein	P19525	UNIPROT	EIF2S1	protein	P05198	UNIPROT	down-regulates	phosphorylation	Ser52	MILLSELsRRRIRSI	9606									16179259	t		lperfetto	The antiviral protein kinase pkr inhibits protein synthesis by phosphorylating the translation initiation factor eif2alpha on ser51the protein kinases pkr, hri, perk, and gcn2 specifically phosphorylate ser51 on the _ subunit of the translation initiation factor eif2, a gtp binding protein that delivers the initiator methionyl-trna to the small ribosomal subunit in the first step of translation initiation. Phosphorylation of eif2_ converts eif2 from a substrate to an inhibitor of its gdp-gtp exchange factor eif2b, thereby blocking protein synthesis	SIGNOR-140656	0.717
ITGB1BP1	protein	O14713	UNIPROT	AE/b7 integrin	complex	SIGNOR-C186	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257665	0.29
prednisolone	chemical	CHEBI:8378	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									13760840	t		gcesareni		SIGNOR-251700	0.8
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	CHEK2	protein	O96017	UNIPROT	up-regulates activity				9606									19151762	f		lperfetto	Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68	SIGNOR-242605	0.7
ID3	protein	Q02535	UNIPROT	MYOD/HEB	complex	SIGNOR-C128	SIGNOR	down-regulates activity	binding			10090									9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241137	0.462
AMH	protein	P03971	UNIPROT	AMHR2	protein	Q16671	UNIPROT	up-regulates	binding			9606									8119126	t		acerquone	The results point to anti-m?llerian Hormone (amh) being the most likely candidate ligand for c14.	SIGNOR-36215	0.799
STK25	protein	O00506	UNIPROT	PDCD10	protein	Q9BUL8	UNIPROT	unknown	phosphorylation	Thr43	VNLSAAQtLRAAFIK	9606									19370760	t		llicata	Stk25 phosphorylates ccm3 at serine 39 and threonine 43	SIGNOR-185392	0.791
CSNK2A1	protein	P68400	UNIPROT	CLTB	protein	P09497	UNIPROT	unknown	phosphorylation	Ser13	GFFSSSEsGAPEAAE	-1									3128543	t		llicata	To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites.	SIGNOR-250843	0.313
CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	PUM1	protein	Q14671	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			9606									31320642	t		lperfetto	In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins	SIGNOR-268351	0.373
AQP5	protein	P55064	UNIPROT	CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	up-regulates activity	binding								phosphorylation:Ser156	STDSRRTsPVGSPAL			18583321	t		lperfetto	We performed immunoprecipitation and western blotting analysis in transfected cell lines using CDK4 and cyclin D1 antibodies. As expected, cells transfected with AQP5 WT showed an increase of the CDK4/cyclin D1 complex, whereas cells transfected with vector did not|hAQP5 Increases Phosphorylation of Retinoblastoma Protein through Cyclin D1/CDK4 Complex	SIGNOR-272089	0.249
PRKCA	protein	P17252	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser465	LKHVTQSsRKLIRAD	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-129264	0.392
IGF1R	protein	P08069	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									18595745	t		gcesareni	Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively)	SIGNOR-252690	0.686
IL10RA	protein	Q13651	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates activity				9606	BTO:0000801								26260587	t			IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes.	SIGNOR-253589	0.801
PRKAA2	protein	P54646	UNIPROT	EEF2K	protein	O00418	UNIPROT	up-regulates activity	phosphorylation	Ser398	DSLPSSPsSATPHSQ	-1									14709557	t		miannu	Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398. phosphorylation of eEF2 kinase at Ser-398 leads to an increase in its activity.	SIGNOR-250158	0.48
PTPRJ	protein	Q12913	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	down-regulates	dephosphorylation			9606									12771128	t	inferred from 70% of family members	gcesareni	A dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation.	SIGNOR-269897	0.2
PTCHD1	protein	Q96NR3	UNIPROT	VPS35	protein	Q96QK1	UNIPROT	up-regulates quantity	binding			10090		BTO:0000142							29118110	t		miannu	Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus	SIGNOR-266653	0.2
dactolisib	chemical	CHEBI:71952	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000848								21803746	t	ATP-competitive inhibitor of PI3K and mTOR	gcesareni	The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific	SIGNOR-175715	0.8
SMARCD1	protein	Q96GM5	UNIPROT	Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	form complex	binding			10090	BTO:0001086								19279220	t		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270722	0.748
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1920	SPTYSPTsPKYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120244	0.321
UCHL3	protein	P15374	UNIPROT	RPS27A	protein	P62979	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270828	0.793
CALM2	protein	P0DP24	UNIPROT	PPP3CA	protein	Q08209	UNIPROT	up-regulates	binding			9606									11796223	t		miannu	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-266327	0.597
tandutinib	chemical	CHEBI:90237	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207212	0.8
ERN1	protein	O75460	UNIPROT	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	down-regulates activity				9606									31226023	f		miannu	The kinase activity of IRE1 also activates a signaling cascade that ultimately activates c-Jun N-terminal kinase (JNK)	SIGNOR-260177	0.323
IL26	protein	Q9NPH9	UNIPROT	IL10RB	protein	Q08334	UNIPROT	up-regulates	binding			9606									17208301	t		gcesareni	See table 2	SIGNOR-151917	0.586
CDK9	protein	P50750	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Ser208	DAGSPNLsPNPMSPA	9606									19914161	t		lpetrilli	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161581	0.607
PRKCA	protein	P17252	UNIPROT	RAF1	protein	P04049	UNIPROT	unknown	phosphorylation	Ser497	ATVKSRWsGSQQVEQ	9606									12551925	t		gcesareni	For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1.	SIGNOR-37844	0.538
MAPK9	protein	P45984	UNIPROT	NFATC3	protein	Q12968	UNIPROT	down-regulates	phosphorylation	Ser165	RESSLSPsPASSISS	9606	BTO:0000782								9374467	t		lperfetto	Ser163 and ser165 represent the major sites of in vitro phosphorylation of nfat4 by jnk. / the negative regulation of nfat4 nuclear accumulation caused by jnk provides a mechanism for cell type?specific Responses to extracellular stimulation	SIGNOR-53368	0.698
5-carboxamidotryptamine	chemical	CHEBI:48292	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9550290	t		miannu	Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists.	SIGNOR-258888	0.8
E2F2	protein	Q14209	UNIPROT	TFDP1	protein	Q14186	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								8832394	t	2	miannu	The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3.	SIGNOR-240550	0.727
GDAP1	protein	Q8TB36	UNIPROT	Mitochondrial_fission	phenotype	SIGNOR-PH143	SIGNOR	up-regulates				9606									33610749	f		lperfetto	However, it remains elusive if additional proteins are involved in the regulation of mitochondrial fission, such as proposed fission factor GDAP1 	SIGNOR-272977	0.7
MTOR	protein	P42345	UNIPROT	ULK2	protein	Q8IYT8	UNIPROT	down-regulates	phosphorylation			9606									19211836	t		gcesareni	Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2	SIGNOR-183961	0.768
BAD	protein	Q92934	UNIPROT	BCL2L2	protein	Q92843	UNIPROT	down-regulates	binding			9606									15694340	t		gcesareni	Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2.	SIGNOR-133805	0.553
SAE1/SAE2 complex	complex	SIGNOR-C294	SIGNOR	MBD4	protein	O95243	UNIPROT	up-regulates activity	sumoylation	Lys377	HLHTDILkRGSEMDN										31476572	t		lperfetto	MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro.	SIGNOR-275681	0.2
STXBP1	protein	P61764	UNIPROT	SNARE_complex 	complex	SIGNOR-C346	SIGNOR	up-regulates activity	transcriptional regulation			9606	BTO:0000938								30267828	t		miannu	 In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2.	SIGNOR-263970	0.835
PKN1	protein	Q16512	UNIPROT	MARCKS	protein	P29966	UNIPROT	down-regulates activity	phosphorylation	Ser170	SFKLSGFsFKKNKKE	-1									8557118	t		gcesareni	PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163.	SIGNOR-249671	0.372
Dinaciclib	chemical	CID:46926350	PUBCHEM	CDK9	protein	P50750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191331	0.8
PRKCB	protein	P05771	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser38	SVPEFPLsPPKKKDL	9606									9271428	t		gcesareni	Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation.	SIGNOR-50598	0.2
5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid	chemical	CHEBI:76223	ChEBI	PTGS1	protein	P23219	UNIPROT	down-regulates activity	chemical inhibition			-1									22091869	t		Luana	 Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2. 	SIGNOR-258323	0.8
PRKCA	protein	P17252	UNIPROT	DGKD	protein	Q16760	UNIPROT	down-regulates activity	phosphorylation	Ser70	QNNSFQRsKRRYFKL	9534									15228384	t		lperfetto	The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain.	SIGNOR-249266	0.373
AURKA	protein	O14965	UNIPROT	SOX8	protein	P57073	UNIPROT	up-regulates activity	phosphorylation	Ser327	SAPSASAsPTETGPP	9606	BTO:0000410								32550913	t		miannu	We showed for the first time that Aurora-A interacts directly with SOX8 and phosphorylates the protein at Ser327 to further regulate the SOX8/FOXK1 axis, which modulates cell senescence and glycolysis, ultimately leading to cisplatin resistance.	SIGNOR-273548	0.2
AKT1	protein	P31749	UNIPROT	HTT	protein	P42858	UNIPROT	unknown	phosphorylation	Ser419	GGRSRSGsIVELIAG	9606	BTO:0000938								12062094	t		llicata	We demonstrate that huntingtin is a substrate of akt and that phosphorylation of huntingtin by akt is crucial to mediate the neuroprotective effects of igf-1.	SIGNOR-252590	0.569
YWHAE	protein	P62258	UNIPROT	GRIN2C	protein	Q14957	UNIPROT	up-regulates quantity by stabilization	binding			10090									19477150	t		miannu	Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. These data are all consistent with a model in which NR1 and NR2C oligomerize, PKB phosphorylates S1096, and 14-3-3ε binds to phosphorylated NR2C thereby promoting NR2C-containing NMDA receptor surface expression in cerebellar granule cells. 	SIGNOR-262622	0.322
CSNK2B	protein	P67870	UNIPROT	SEC63	protein	Q9UGP8	UNIPROT	up-regulates activity	phosphorylation	Ser748	DSEGFEDsFEEEEEE	9606	BTO:0000599								23287549	t		lperfetto	Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62.	SIGNOR-265272	0.2
AP1	complex	SIGNOR-C154	SIGNOR	IL6	protein	P05231	UNIPROT	up-regulates	transcriptional regulation			9606	BTO:0000801								20086235	f			JNK phosphorylates proteins that are part of AP-1, in particular c-Jun and activating transcription factor 2 (ATF-2). With dominant-negative mutants, antisense RNA, inhibitors, and genetic ablation, it has been shown that JNK and c-Jun play a major role in IL-1–induced expression of genes encoding IL-6 and IL-8 and other IL-1–responsive genes	SIGNOR-254513	0.628
PRKCD	protein	Q05655	UNIPROT	G6PD	protein	P11413	UNIPROT	up-regulates	phosphorylation	Ser180	FGRDLQSsDRLSNHI	9606		BTO:0001260							20649491	t		lperfetto	A pkc activator, significantly increased g6pd phosphorylation and activity, whereas single (s210a, t266a) and double (s210a/t266a) mutations at sites flanking the g6pd active site significantly inhibited phosphorylation, shifted the isoelectric point, and reduced enzyme activity.	SIGNOR-167049	0.2
PD173074	chemical	CHEBI:63448	ChEBI	FGFR1	protein	P11362	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205725	0.8
RNF123	protein	Q5XPI4	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								25860612	t		miannu	 Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling.	SIGNOR-272221	0.406
BGJ-398	chemical	CHEBI:63451	ChEBI	FGFR3	protein	P22607	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190269	0.8
FOXA1	protein	P55317	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									19127412	f		miannu	Overexpression of foxa1 promoted apoptosis	SIGNOR-183153	0.7
MAPK1	protein	P28482	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Thr229	HFFKNIVtPRTPPPS	9606	BTO:0000661								12760422	t		lperfetto	Thr94 in bovine myelin basic protein is a second phosphorylation site for 42-kDa mitogen-activated protein kinase (ERK2).	SIGNOR-249419	0.57
FGF12	protein	P61328	UNIPROT	SCN5A	protein	Q14524	UNIPROT	down-regulates activity	binding			9606		BTO:0000199							20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253416	0.596
PKN1	protein	Q16512	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates	phosphorylation			9606									17251915	t		gcesareni	Rho can sensitize the ar to low levels of circulating androgens by promoting the nuclear translocation of a transcriptional co-activator, fhl2 (four and a half lim domains 2), which binds ar, and by stimulating protein kinase n (pkn), which phosphorylates ar directly.	SIGNOR-152762	0.571
GABRB2	protein	P47870	UNIPROT	GABA-A (a4-b2-d) receptor	complex	SIGNOR-C326	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263744	0.46
MTMR3	protein	Q13615	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	down-regulates activity				9606	BTO:0000007								26787466	t		lperfetto	The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity.	SIGNOR-245108	0.312
PRKACA	protein	P17612	UNIPROT	CSK	protein	P41240	UNIPROT	up-regulates activity	phosphorylation	Ser364	ALREKKFsTKSDVWS	9606	BTO:0000782								11181701	t		lperfetto	Activation of the cooh-terminal src kinase (csk) by camp-dependent protein kinase inhibits signaling through the t cell receptor.Pka phosphorylates csk at s364 in vitro and in vivo leading to a two- to fourfold increase in csk activity that is necessary for camp-mediated inhibition of tcr-induced interleukin 2 secretion.	SIGNOR-105229	0.343
RREB1	protein	Q92766	UNIPROT	KLK3	protein	P07288	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001321								17550981	f	 	 	RREB-1 bound to the prostate-specific antigen (PSA) promoter as assessed by chromatin immunoprecipitation. Transient expression of RREB-1 down-regulated AR-mediated promoter activity and suppressed expression of PSA protein.	SIGNOR-253661	0.2
MYLIP	protein	Q8WY64	UNIPROT	LDLR	protein	P01130	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									30896554	t		miannu	The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells. 	SIGNOR-271485	0.716
PRKAA2	protein	P54646	UNIPROT	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation	Ser317	SHLASPPsLGEMQQL	9606			SIGNOR-C15						19584320	t		gcesareni	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-186633	0.483
FRK	protein	P42685	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr391	PFLNSGTyHSRDEST	9606	BTO:0002035								35723276	t		miannu	Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP. 	SIGNOR-275455	0.278
TFIID	complex	SIGNOR-C343	SIGNOR	TFIIA	complex	SIGNOR-C395	SIGNOR	up-regulates activity	relocalization			9606									8990153	t		lperfetto	PIC assembly begins with TFIID recognizing the TATA element, followed by coordinated accretion of TFIIB, the nonphosphorylated form of pol II (pol IIA) plus TFIIF, TFIIE, and TFIIH.	SIGNOR-269307	0.601
POU4F1	protein	Q01851	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates activity	binding			9606									9448000	t	2	miannu	The POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect.	SIGNOR-241275	0.532
CSNK2A1	protein	P68400	UNIPROT	PSMA3	protein	P25788	UNIPROT	unknown	phosphorylation	Ser243	AEKYAKEsLKEEDES	-1									8619999	t		llicata	Several C8 protein constructs allow the location of the CKII phosphorylation sites to be the COOH terminal portion of the protein, and direct mutational analyses show that Ser-243 and Ser-250 are the residues of the C8 subunit phosphorylated by CKII. The in vitro phosphorylation of the proteasome by CKII does not affect its proteolytic activity (on proteins or fluorogenic synthetic peptides), therefore suggesting its involvement in the interaction of the proteasome with other cellular proteins, i.e. in the formation of the 26S complex and/or in the interaction with the nuclear translocation machinery.	SIGNOR-250938	0.389
AKT1	protein	P31749	UNIPROT	DLC1	protein	Q96QB1	UNIPROT	unknown	phosphorylation	Ser766	VTRTRSLsACNKRVG	10116									16338927	t		gcesareni	We have demonstrated that Ser-322 is phosphorylated upon insulin stimulation of intact cells and that this site is directly phosphorylated in vitro by PKB and ribosomal S6 kinase, members of the AGC (protein kinases A, G, and C) family of insulin-stimulated protein kinases	SIGNOR-252550	0.509
CNOT9	protein	Q92600	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	form complex	binding			9606									19558367	t		lperfetto	In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules.	SIGNOR-268303	0.2
DHRS9	protein	Q9BPW9	UNIPROT	retinol	smallmolecule	CHEBI:50211	ChEBI	down-regulates quantity	chemical modification			9606									21621639	t		lperfetto	Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS10	SIGNOR-265116	0.8
R547	chemical	CID:6918852	PUBCHEM	CCNE1	protein	P24864	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206355	0.8
ETS1	protein	P14921	UNIPROT	TBX22	protein	Q9Y458	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								25373698	t		miannu	TBX22 is an X-linked gene, which encodes a T-box-containing transcription factor. Loss-of-function mutation in the X-linked TBX22 promoter disrupts an ETS-1 binding site and leads to cleft palate. We first link the transcription factor ETS-1 to TBX22 pathway during embryonic palatogenesis.	SIGNOR-265565	0.2
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	CRKL	protein	P46109	UNIPROT	up-regulates	phosphorylation	Tyr207	IPEPAHAyAQPQTTT	9606	BTO:0001271								9053848	t		lperfetto	Tyrosine 207 in crkl is the bcr/abl phosphorylation sitephosphorylation of y207 provides a binding site for the crkl sh2 domain and potentially for other sh2-containing proteins.	SIGNOR-46893	0.2
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	CHEK1	protein	O14757	UNIPROT	up-regulates				9606									26527132	f		lperfetto	Checkpoint kinase 1 (CHK1) is a key component of the ATR-dependent DNA damage response pathway that protects cells from RS by preventing replication fork collapse and activating homologous DNA repair.	SIGNOR-242616	0.7
RIMBP3B	protein	A6NNM3	UNIPROT	RIMS1	protein	Q86UR5	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264364	0.352
F2RL1	protein	P55085	UNIPROT	THBS1	protein	P07996	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254842	0.258
HOXB7	protein	P09629	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates activity	binding			9606	BTO:0002419			SIGNOR-C106					17308091	t		miannu	Ku70 and Ku80 associated with HOXB7 in vivo. Ku70/Ku80 heterodimer formation is a prerequisite for HOXB7 binding. interaction between Ku70/80 and HOXB7 may affect the catalytic activity of DNA-PK. HOXB7 stimulates DNA-PK activity	SIGNOR-226063	0.338
WNT3A	protein	P56704	UNIPROT	Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	up-regulates activity	binding												18697834	t		Simone Vumbaca	Wnt1, Wnt3a and Wnt5a all induced a statistically greater degree of proliferation than control cells	SIGNOR-255650	0.802
SIX1	protein	Q15475	UNIPROT	Six1/Dach	complex	SIGNOR-C122	SIGNOR	form complex	binding			10090									14628042	t		llicata	The phosphatase function of Eya switches the function of Six1-Dach from repression to activation,	SIGNOR-238029	0.615
RXRB	protein	P28702	UNIPROT	NR4A2	protein	P43354	UNIPROT	up-regulates	binding			9606	BTO:0000938								9636132	t		lperfetto	The recent discovery that the nuclear transcription factor, nurr1, in heterodimeric tandem with rxr, is unequivocally necessary for the expression of dopaminergic neurons	SIGNOR-58309	0.426
JAG2	protein	Q9Y219	UNIPROT	NOTCH3	protein	Q9UM47	UNIPROT	up-regulates	binding			9606									11006133	t		gcesareni	These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors.	SIGNOR-82401	0.608
MAPK3	protein	P27361	UNIPROT	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation	Ser164	FGHSAAVsPTFMPRS	9606	BTO:0000782								12151396	t		gcesareni	Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk	SIGNOR-91063	0.36
WNK3	protein	Q9BYP7	UNIPROT	SLC12A6	protein	Q9UHW9	UNIPROT	down-regulates activity	phosphorylation	Thr1048	YQEKVHMtWTKDKYM	9606									24043619	t		Manara	WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048. 	SIGNOR-260910	0.457
PTH2	protein	Q96A98	UNIPROT	PTH2R	protein	P49190	UNIPROT	up-regulates	binding			9606		BTO:0000142;BTO:0000671							11861531	t		gcesareni	Subsequent efforts led to the isolation and definition of the primary structure of a novel peptide, referred to as tip39, from bovine hypothalamus and the synthetic peptide was shown to efficiently activate human, rat, and zebrafish pth2 receptors	SIGNOR-115124	0.755
PML	protein	P29590	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									15093545	f		gcesareni	The promyelocytic leukemia (pml) protein is a potent growth suppressor and proapototic factor	SIGNOR-124320	0.7
CSNK2A1	protein	P68400	UNIPROT	SPIB	protein	Q01892	UNIPROT	down-regulates	phosphorylation	Ser146	PALEVSDsESDEALV	9606									10618498	t		lperfetto	Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability	SIGNOR-73887	0.44
TP53INP2	protein	Q8IXH6	UNIPROT	GABARAPL2	protein	P60520	UNIPROT	up-regulates	binding			9606									19056683	t		gcesareni	Tp53inp2 binds to lc3 as well as to lc3-related proteins gabarap and gabarap-like2.	SIGNOR-182611	0.589
H3-4	protein	Q16695	UNIPROT	Nucleosome_H3.1t variant	complex	SIGNOR-C325	SIGNOR	form complex	binding			-1									20498094	t		miannu	A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. 	SIGNOR-263725	0.2
SL0101	chemical	CID:10459196	PUBCHEM	RPS6KA3	protein	P51812	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207075	0.8
ORC4	protein	O43929	UNIPROT	ORC	complex	SIGNOR-C419	SIGNOR	form complex	binding			9606									32808929	t		lperfetto	The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA	SIGNOR-267564	0.965
MAPK1	protein	P28482	UNIPROT	DUSP6	protein	Q16828	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser159	DGSCSSSsPPLPVLG	9606									15632084	t		gcesareni	In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3.	SIGNOR-132967	0.901
SCYL1	protein	Q96KG9	UNIPROT	CEP250	protein	Q9BV73	UNIPROT	down-regulates activity	relocalization			9606	BTO:0000567								24769208	t		lperfetto	Moreover, TEIF closely co-localized with C-NAP1 at the proximal ends of centrioles, and centriolar loading of TEIF stimulated by EGF/Akt could displace C-NAP1, resulting in centrosome splitting.	SIGNOR-265497	0.2
MAPK3	protein	P27361	UNIPROT	TH	protein	P07101	UNIPROT	up-regulates	phosphorylation	Ser62	SYTPTPRsPRFIGRR	9606									7901013	t		gcesareni	In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11	SIGNOR-34678	0.495
DCX DET1-COP1	complex	SIGNOR-C24	SIGNOR	TRiC	complex	SIGNOR-C539	SIGNOR	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								24298020	t		miannu	Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not.The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.COP1 functions as an E3 ligase by forming a supercomplex that also includes heterodimeric substrate receptor DET1, adaptor DDB1, scaffold Cul4A, and RBX1 to recruit the E2 enzyme	SIGNOR-272873	0.2
CDC25A	protein	P30304	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates activity	dephosphorylation	Thr14	IEKIGEGtYGVVYKG	9606									10454565	t			Phosphatase activity of Cdc25A is critical for its activating capacity (data not shown). In this context, it should also be mentioned that Cdc25A is able to activate cyclin B-Cdk1 in vitro	SIGNOR-248479	0.837
mTORC1	complex	SIGNOR-C3	SIGNOR	MAF1	protein	Q9H063	UNIPROT	down-regulates	phosphorylation	Ser68	PPQTSGLsPSRLSKS	9606									20516213	t		lperfetto	The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly.	SIGNOR-217145	0.467
GH1	protein	P01241	UNIPROT	GHR	protein	P10912	UNIPROT	up-regulates	binding			9606									7862673	t		gcesareni	The hghr only binds primate gh. Arg43 in hghr interacts with asp171 of hgh.	SIGNOR-34129	0.854
DOT1L	protein	Q8TEK3	UNIPROT	MYCBP2	protein	O75592	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001321								32814769	t		miannu	Overexpression of DOT1L decreased the expression of HECTD4 and MYCBP2 in LNCaP, C42B, and 22rv1 cells (Supplementary Fig. 5c), suggesting that DOT1L plays a role in repressing these targets either directly or indirectly.	SIGNOR-267151	0.2
PDPK1	protein	O15530	UNIPROT	SGK3	protein	Q96BR1	UNIPROT	up-regulates activity	phosphorylation	Ser486	DDAFVGFsYAPPSED										10548550	t		miannu	SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB.	SIGNOR-250278	0.472
RET	protein	P07949	UNIPROT	RET	protein	P07949	UNIPROT	up-regulates	phosphorylation	Tyr1090	TNTGFPRyPNDSVYA	9606									14711813	t		llicata	Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites.	SIGNOR-121145	0.2
PARP1	protein	P09874	UNIPROT	MRE11	protein	P49959	UNIPROT	up-regulates activity	relocalization			9606									19629035	t			PARP1 collaborates with Mre11 to promote replication fork restart after release from replication blocks, most likely by recruiting Mre11 to the replication fork to promote resection of DNA.	SIGNOR-272478	0.2
PLK1	protein	P53350	UNIPROT	STK38	protein	Q15208	UNIPROT	down-regulates activity	phosphorylation	Thr7	tPCSSMSN	9606	BTO:0000567								26057687	t		miannu	Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis. 	SIGNOR-276914	0.321
TRRAP	protein	Q9Y4A5	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269288	0.735
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr18	EPPLSQEtFSDLWKL	9606									10710310	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-75645	0.784
CREB1	protein	P16220	UNIPROT	GCH1	protein	P30793	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16149046	f		miannu	Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2.	SIGNOR-252227	0.2
HLX	protein	Q14774	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20008130	f		Luana	In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.	SIGNOR-261624	0.2
1-naphthol	chemical	CHEBI:10319	ChEBI	UGT1A1	protein	P22309	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								21030469	t		Luana	Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation.	SIGNOR-258163	0.8
CHUK	protein	O15111	UNIPROT	NFKB2	protein	Q00653	UNIPROT	up-regulates activity	phosphorylation	Ser866	TAEVKEDsAYGSQSV	10090	BTO:0000785								15084608	t		lperfetto	Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52.	SIGNOR-124226	0.784
UBE3A	protein	Q05086	UNIPROT	RAD23A	protein	P54725	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0000298								10373495	t		miannu	 Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP.  E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B.	SIGNOR-272550	0.499
SOX2	protein	P48431	UNIPROT	ABCC3	protein	O15438	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21531766	f		miannu	 ID4-mediated SOX2 induction enhanced ABCC3 and ABCC6 expression through direct transcriptional regulation, indicating that ID4 regulates the chemoresistance of iGSCs by promoting SOX2-mediated induction of ABC transporters. 	SIGNOR-255181	0.298
N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide	chemical	CHEBI:94793	ChEBI	MAP2K2	protein	P36507	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189933	0.8
PRKG1	protein	Q13976	UNIPROT	PPP1R17	protein	O96001	UNIPROT	up-regulates	phosphorylation	Thr68	KKPRRKDtPALHIPP	9606	BTO:0001011								10051666	t		miannu	 Recombinant human G-substrate was phosphorylated efficiently by cGMP-dependent protein kinase exclusively at Thr residues, and it was recognized by antibodies specific for rabbit phospho-G-substrate. The amino acid sequences surrounding the sites of phosphorylation in G-substrate are related to those around Thr-34 and Thr-35 of the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and inhibitor-1, respectively, two potent inhibitors of protein phosphatase 1. 	SIGNOR-263148	0.646
AKT2	protein	P31751	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	phosphorylation	Ser552	QDTQRRTsMGGTQQQ	9606									17287208	t		lperfetto	Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activitywe have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo.	SIGNOR-152958	0.552
HDAC2	protein	Q92769	UNIPROT	SNAI2	protein	O43623	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									23836662	f	 	miannu	 We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes.	SIGNOR-254156	0.554
MAP1LC3C	protein	Q9BXW4	UNIPROT	NBR1	protein	Q14596	UNIPROT	down-regulates	binding			9606	BTO:0000007								19250911	t		gcesareni	We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. . downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1.	SIGNOR-184258	0.546
PAK4	protein	O96013	UNIPROT	PAK4	protein	O96013	UNIPROT	up-regulates	phosphorylation	Ser474	KEVPRRKsLVGTPYW	9606									20926745	t		gcesareni	Intracellular localization;enzymatic activity, induced;cell growth, altered;	SIGNOR-168301	0.2
SMURF1	protein	Q9HCE7	UNIPROT	SMAD6	protein	O43541	UNIPROT	down-regulates activity	relocalization			9606									22298955	t		lperfetto	Smurf1, with its WW domain, specifically binds to the PY motif of Smad6 and transports Smad6 into the cytoplasm.	SIGNOR-105931	0.824
2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline	smallmolecule	CHEBI:94276	ChEBI	GLI2	protein	P10070	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150;BTO:0001130								17494766	t		gcesareni	Gant61 was able to efficiently block gli1 as well as gli2-induced transcription	SIGNOR-154756	0.8
DIABLO	protein	Q9NR28	UNIPROT	XIAP	protein	P98170	UNIPROT	down-regulates activity	binding			9606	BTO:0000007;BTO:0000567								11583623	t	Smac/DIABLO released from mitochondria	amattioni	Smac/diablo, an inhibitor of xiap, is released from mitochondria upon receiving apoptotic stimuli and binds to the bir2 and bir3 domains of xiap, thereby inhibiting its caspase-inhibitory activity	SIGNOR-110831	0.912
phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	PIP5K1A	protein	Q99755	UNIPROT	up-regulates	chemical activation			9606									17245604	t		gcesareni	All pip5k isoforms are stimulated by pa.	SIGNOR-152542	0.8
CCL21	protein	O00585	UNIPROT	CCR7	protein	P32248	UNIPROT	up-regulates	binding			9606		BTO:0000671							11970971	t		gcesareni	The regulated expression of the chemokine secondary lymphoid tissue chemokine (slc/ccl21) and its corresponding receptor, ccr7.	SIGNOR-117566	0.779
TNF	protein	P01375	UNIPROT	SCN9A	protein	Q15858	UNIPROT	up-regulates activity				10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253488	0.254
JUN	protein	P05412	UNIPROT	STAR	protein	P49675	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19022561	f		miannu	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 	SIGNOR-254875	0.262
USP28	protein	Q96RU2	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates quantity by stabilization	deubiquitination												18662541	t		lperfetto	Usp28 deubiquitylates and consequently stabilizes Claspin in response to DNA damage	SIGNOR-274057	0.2
GSK3B	protein	P49841	UNIPROT	EIF2B5	protein	Q13144	UNIPROT	down-regulates	phosphorylation	Ser540	MDSEEPDsRGGSPQM	9606									18701453	t		lperfetto	Gsk3_ phosphorylates eif2b_ at ser-539 (ser-535 in the rat sequence) and inactivates it	SIGNOR-180022	0.561
ARNT	protein	P27540	UNIPROT	HIF-1 complex	complex	SIGNOR-C418	SIGNOR	form complex	binding			9606									27692180	t		miannu	HIF-1 consists of two subunits, HIF-1α and HIF-1β. While HIF-1β protein is constitutively expressed and present in excess, HIF-1α protein has a short half-life	SIGNOR-267448	0.777
F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	Dendritic_spine_morphogenesis	phenotype	SIGNOR-PH183	SIGNOR	up-regulates				9606									14684878	f		miannu	Dendritic spines are small protrusions found on dendrites of principal neurons of mammalian brain. Serving as postsynaptic compartments for individual excitatory inputs, spines show rapid movements and shape changes that are influenced by synaptic activity. The structural modifications of spines are believed to represent morphological correlates of synaptic plasticity. The form and motility of spines are determined mainly by the actin cytoskeleton	SIGNOR-266597	0.7
ACTR8	protein	Q9H981	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270848	0.618
TP53	protein	P04637	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates	binding			9606									16151013	t	Cytosolic p53	amattioni	P53 also accumulates in the cytoplasm where it directly activates bax to promote mitochondrial outer membrane permeabilization.	SIGNOR-140242	0.743
PSMC4	protein	P43686	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263371	0.871
PTPN1	protein	P18031	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates activity	dephosphorylation	Tyr566	SLNQEDIyITTESLT	10029									12907755	t			PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 	SIGNOR-248421	0.478
MAPK3	protein	P27361	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation			9606									12832467	t		lperfetto	Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.	SIGNOR-102648	0.705
SLC9A9	protein	Q8IVB4	UNIPROT	hydron	chemical	CHEBI:15378	ChEBI	down-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265599	0.8
SYK	protein	P43405	UNIPROT	PAX5	protein	Q02548	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0003079								27181361	t		Gianni	PAX5 tyrosine phosphorylation by SYK co-operatively functions with its serine phosphorylation to cancel the PAX5-dependent repression of BLIMP1: A mechanism for antigen-triggered plasma cell differentiation.	SIGNOR-269084	0.434
PRKCD	protein	Q05655	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation	Ser139	EEWTRHGsFVNKPTR	9606									16963224	t	The effect has been demonstrated using P29353-2	gcesareni	Pkc delta phosphorylates p52shca at ser29 to regulate erk activation in response to h2o2.	SIGNOR-149398	0.549
POLR3A	protein	O14802	UNIPROT	Viral_dsRNA	stimulus	SIGNOR-ST21	SIGNOR	up-regulates				9606									19631370	t		miannu	Here we show that the cytosolic poly(dA-dT) DNA is converted into 5′-ppp RNA to induce IFN-β through the RIG-I pathway. Biochemical purification led to the identification of DNA-dependent RNA polymerase III (Pol-III) as the enzyme responsible for synthesizing 5′-ppp RNA from the poly(dA-dT) template. Inhibition of RNA Pol-III prevents IFN-β induction by transfection of DNA or infection with DNA viruses. 	SIGNOR-265563	0.7
ERBB4	protein	Q15303	UNIPROT	PIK3CB	protein	P42338	UNIPROT	up-regulates	binding			9606									16729043	t		gcesareni	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146882	0.463
PTPN1	protein	P18031	UNIPROT	NTRK2	protein	Q16620	UNIPROT	down-regulates activity	dephosphorylation	Tyr706	RDVYSTDyYRVGGHT	9606	BTO:0000793								26214522	t		Luana	Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling	SIGNOR-264554	0.388
BDNF	protein	P23560	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606		BTO:0000142							32603820	f		miannu	BDNF is a central driver of synaptic plasticity and memory formation and its decreased levels may contribute to the degeneration of specific neuronal populations and progressive atrophy of neurons in the AD-affected brain	SIGNOR-265063	0.7
TP53	protein	P04637	UNIPROT	TNFRSF10B	protein	O14763	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14585074	f	Nuclear p53	amattioni	Cd95l, cd95, and the trail death receptors are induced by the tumour suppressor p53	SIGNOR-113707	0.635
GSK3B	protein	P49841	UNIPROT	EIF2B5	protein	Q13144	UNIPROT	down-regulates	binding			9606									21798082	t		gcesareni	Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b).	SIGNOR-175621	0.561
PCBD1	protein	P61457	UNIPROT	FXYD2	protein	P54710	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		 BTO:0000482							24204001	f		miannu	 Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT.	SIGNOR-254908	0.355
CLOCK	protein	O15516	UNIPROT	CLOCK/BMAL2	complex	SIGNOR-C196	SIGNOR	form complex	binding												19605937	t	 	lperfetto	Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription	SIGNOR-253711	0.669
SATB1	protein	Q01826	UNIPROT	AREG	protein	P15514	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000664								17343824	f		miannu	We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 	SIGNOR-255133	0.249
AURKA	protein	O14965	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity	phosphorylation			9606	BTO:0001225								19060929	t		lperfetto	The recombinant human aurka protein phosphorylated the gsk-3beta protein at ser 9 in a concentration-dependent manner, in vitro. The phosphorylation of beta-catenin (ser33/37/thr41) by gsk-3beta is known to target beta-catenin towards degradation. In line with our findings, the increase in phospho-gsk-3beta level was accompanied by a significant decrease in beta-catenin phosphorylation (ser33/37/thr41) and accumulation of beta-catenin protein.	SIGNOR-227923	0.348
TAF1A	protein	Q15573	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									15970593	t		lperfetto	Gene promoters with a TATA box tend to be bound by the SAGA complex which includes TBP, SUPT3H, and GCN5 (Basehoar et al., 2004; Rodríguez-Navarro, 2009). Therefore, it was thought that TATA-containing genes were mainly regulated by the SAGA complex, while TATA-less genes were independently regulated by TFIID (Pugh and Tjian, 1991; Basehoar et al., 2004). However, recent studies in yeast indicate that most genes utilize both TFIID and SAGA, and that the relative contribution of each complex likely depends on the individual context 	SIGNOR-269591	0.353
Tosedostat	chemical	CID:15547703	PUBCHEM	LAP3	protein	P28838	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207417	0.8
YWHAQ	protein	P27348	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates	relocalization			9606									20068082	t		gcesareni	Cdc25c: nuclear exclusion/cytoplasmic sequestration via binding to 14-3-3 proteins.	SIGNOR-163237	0.555
3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid	chemical	CHEBI:91194	ChEBI	LPAR2	protein	Q9HBW0	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193561	0.8
MMP3	protein	P08254	UNIPROT	DCN	protein	P07585	UNIPROT	down-regulates quantity by destabilization	cleavage	Ser240	ISRVDAAsLKGLNNL	-1									9148753	t		miannu	Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.	SIGNOR-256353	0.659
STAT1	protein	P42224	UNIPROT	TBX21	protein	Q9UL17	UNIPROT	up-regulates				9606									16386358	f			T-bet is a transcription factor detected in Th1, but not in Th0 or Th2 cells. Its expression is up-regulated by IFN-gamma, through a STAT-1-dependent mechanism	SIGNOR-254293	0.506
TRIM31	protein	Q9BZY9	UNIPROT	KIF21B	protein	O75037	UNIPROT	up-regulates activity	binding												24086586	t			Here we show that the ubiquitin E3 ligase TRIM3, also known as BERP, interacts with KIF21B via its RBCC domain ||he E3-ligase function of TRIM3 is not involved in KIF21B degradation, however TRIM3 depletion reduces the motility of the motor. Together, our data suggest that TRIM3 is a regulator in the modulation of KIF21B motor function	SIGNOR-272479	0.2
NELFB	protein	Q8WX92	UNIPROT	NELF	complex	SIGNOR-C521	SIGNOR	form complex	binding			9606									18628398	t		miannu	The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. 	SIGNOR-271402	0.852
adenosine	smallmolecule	CHEBI:16335	ChEBI	PI4K2A	protein	Q9BTU6	UNIPROT	down-regulates activity	chemical inhibition			-1									21704602	t		Luana	Both PI4K2A and PI4K2B were inhibited by adenosine at concentrations that do not significantly inhibit PI4KA and PI4KB actitvity	SIGNOR-258317	0.8
arachidonic acid	smallmolecule	CHEBI:15843	ChEBI	PLA2G4A	protein	P47712	UNIPROT	up-regulates				9606									15878913	f		miannu	 AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription.	SIGNOR-255393	0.8
CASP8	protein	Q14790	UNIPROT	CASP6	protein	P55212	UNIPROT	up-regulates	cleavage			9606									9727491	t		gcesareni	Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them.	SIGNOR-59857	0.722
TWIST2	protein	Q8WVJ9	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000093								19581928	f	 	miannu	 we showed aberrant IL-6 production and STAT3 activation in MCF-7 cells that constitutively express Twist, a metastatic regulator and direct transcriptional repressor of E-cadherin. 	SIGNOR-255536	0.454
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates	phosphorylation	Tyr868	GSVEMCRyDPLQDNT	9606	BTO:0000007								20304997	t		lperfetto	Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity	SIGNOR-236298	0.2
2-methylpropanethioic acid S-[2-[[[1-(2-ethylbutyl)cyclohexyl]-oxomethyl]amino]phenyl] ester	chemical	CHEBI:95001	ChEBI	CETP	protein	P11597	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191265	0.8
BCAR1	protein	P56945	UNIPROT	NAB2	protein	Q15742	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								22431919	f		miannu	In MCF-7 cells, we identified a positive feedback loop where p130(Cas) positively regulates EGR1 and NAB2, which in turn induce p130(Cas) expression.	SIGNOR-253891	0.2
PRKACA	protein	P17612	UNIPROT	GABBR2	protein	O75899	UNIPROT	down-regulates activity	phosphorylation	Ser893	EHIQRRLsLQLPILH	9534	BTO:0001538								11976702	t		miannu	Here we show that the functional coupling of GABA(B)R1/GABA(B)R2 receptors to inwardly rectifying K(+) channels rapidly desensitizes. This effect is alleviated after direct phosphorylation of a single serine residue (Ser892) in the cytoplasmic tail of GABA(B)R2 by cyclic AMP (cAMP)-dependent protein kinase (PKA). 	SIGNOR-263150	0.2
ATM	protein	Q13315	UNIPROT	KHSRP	protein	Q92945	UNIPROT	up-regulates	phosphorylation	Ser670	GPGAPPGsQPDYSAA	9606									21329876	t		lperfetto	The atm kinase directly binds to and phosphorylates ksrp, leading to enhanced interaction between ksrp and pri-mirnas and increased ksrp activity in mirna processing	SIGNOR-172127	0.435
NKX3-1	protein	Q99801	UNIPROT	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	binding			9606									16697957	t		miannu	NKX3.1 also binds HDAC1 and releases p53 from p53-MDM2-HDAC1 complex, promoting p53 acetylation and activity. 	SIGNOR-251549	0.376
MAPK3	protein	P27361	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									20068231	t		gcesareni	Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.	SIGNOR-163258	0.728
sepantronium bromide	chemical	CHEBI:139608	ChEBI	BIRC5	protein	O15392	UNIPROT	down-regulates activity	chemical inhibition			9606									25659731	t		miannu	The survivin suppressant YM155 (Sepantronium Bromide) has pre-clinical activity against a range of solid cancers and leukemias, although data in AML is limited. These data suggest that YM155-mediated inhibition of survivin is a potentially beneficial therapeutic strategy for AML, particularly paediatric disease, and warrants further evaluation.	SIGNOR-262245	0.8
ABL1	protein	P00519	UNIPROT	WASF3	protein	Q9UPY6	UNIPROT	up-regulates activity	phosphorylation	Tyr151	KKDGLKFyTDPSYFF	9606	BTO:0000815								17623672	t			WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3.	SIGNOR-262299	0.565
sorafenib tosylate	chemical	CHEBI:50928	ChEBI	RTKs	proteinfamily	SIGNOR-PF38	SIGNOR	down-regulates activity	chemical inhibition			-1									16757355	t		miannu	Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I.	SIGNOR-259454	0.8
dihydrofolate(2-)	smallmolecule	CHEBI:57451	ChEBI	(6S)-5,6,7,8-tetrahydrofolate(2-)	smallmolecule	CHEBI:57453	ChEBI	up-regulates quantity	precursor of			9606									21876184	t		lperfetto	Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. 	SIGNOR-268259	0.8
FBXO6	protein	Q9NRD1	UNIPROT	CHEK1	protein	O14757	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								19716789	t		miannu	 Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint.	SIGNOR-271879	0.511
MAPK1	protein	P28482	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates	phosphorylation	Ser516	VSRVPYPsPTCVKSE	9606	BTO:0001130								18511414	t		gcesareni	Map kinase-dependent phosphorylation at ar ser-515 was supported by the decrease in intensity of the slower migrating 23-kda band after treatment with both egf and increasing concentrations of the map kinase inhibitor, u0126	SIGNOR-178718	0.526
MAPK13	protein	O15264	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser25	QAFELILsPRSKESV	9606	BTO:0000782								8325880	t		gcesareni	Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase|The present study shows that the MAP kinase has a 20-fold preference for Ser25 as opposed to Ser38 of Op18, while cdc2 kinases have a 5-fold preference for the Ser38 residue.	SIGNOR-37848	0.389
RXRA	protein	P19793	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates	binding			9606									11237216	t		gcesareni	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-105445	0.73
DPF2	protein	Q92785	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	down-regulates				9606	BTO:0000725								24332853	f		miannu	Here, DPF2 appears to be another important regulator of myeloid differentiation that can cooperate with PRMT4 to maintain the “stemness” of HSPCs. 	SIGNOR-261969	0.7
MAPKAPK2	protein	P49137	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser15	FSLLRGPsWDPFRDW	9606									20626350	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	gcesareni	Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27.	SIGNOR-166629	0.803
EEF1A2	protein	Q05639	UNIPROT	Gly-tRNA(Gly)	smallmolecule	CHEBI:29156	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269541	0.8
CPE	protein	P16870	UNIPROT	Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	up-regulates activity	cleavage			9606									25767437	t		miannu	 First, OT preprohormone is produced, that will be cleaved and matured by successive enzymes. The OT gene encodes for the Pre-Pro-OT-Neurophysin I (pre-pro-hormone), which is cleaved by different enzymes to give rise to different OT intermediate forms and to the Neurophysin I, and finally to the mature amidated form that is released (Figure ​2).	SIGNOR-270338	0.2
MAPK1	protein	P28482	UNIPROT	ARRB1	protein	P49407	UNIPROT	down-regulates	phosphorylation	Ser412	EEEDGTGsPQLNNR	9606									10347142	t		gcesareni	Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation	SIGNOR-67630	0.717
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	PRKAR1A	protein	P10644	UNIPROT	up-regulates	phosphorylation	Ser83	DSREDEIsPPPPNPV	9606	BTO:0000093								16582606	t		lperfetto	In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue.	SIGNOR-216729	0.306
PAH	protein	P00439	UNIPROT	tyrosine	smallmolecule	CHEBI:18186	ChEBI	up-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors	SIGNOR-263989	0.8
MINK1	protein	Q8N4C8	UNIPROT	KCNH2	protein	Q12809	UNIPROT	up-regulates	binding			9606									9230439	t		miannu	Herg, a human homologue of the ether-a-go-go gene of the fruitfly drosophila melanogaster, encodes aproteinthat produces the rapidly activating cardiac delayed rectifier (i[kr]). / our results show that mink physically associates with herg and that the interaction leads to increased ikr current density.	SIGNOR-49869	0.289
TAGLN2	protein	P37802	UNIPROT	ACTB	protein	P60709	UNIPROT	down-regulates activity	binding												21577206	t		lperfetto	Taken together, our data propose a novel, oncogene-tumor suppressor interplay, where oncogenic PFTK1 confers HCC cell motility through inactivating the actin-binding motile suppressing function of TAGLN2 via phosphorylation.	SIGNOR-265104	0.421
LCK	protein	P06239	UNIPROT	FOXP3	protein	Q9BZS1	UNIPROT	down-regulates	phosphorylation	Tyr342	NMRPPFTyATLIRWA	9606									24155921	t		llicata	Lck phosphorylated tyr-342 of foxp3 by immunoprecipitation and in vitro kinase assay, and the replacement of tyr-342 with phenylalanine (y342f) abolished the ability to suppress mmp9 expression.	SIGNOR-203089	0.412
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	up-regulates				9606									22298955	f		gcesareni	Similar synergy is found in notch and bmp crosstalk: activating notch signaling enhanced bmp-induced alp activity and formation of calcified nodules in vitro.	SIGNOR-254335	0.362
STK4	protein	Q13043	UNIPROT	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	up-regulates	phosphorylation			9606									21808241	t	inferred from 70% of family members	gcesareni	Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2.	SIGNOR-269859	0.626
RNF216	protein	Q9NWF9	UNIPROT	TIRAP	protein	P58753	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								16968706	t		miannu	Triad3A promotes proteolytic degradation of adapter proteins. A, Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins.	SIGNOR-271607	0.396
NR3C1	protein	P04150	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	down-regulates activity				10090	BTO:0000944								11742987	f	inferred from 70% of family members	gcesareni	Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation.	SIGNOR-269898	0.2
ABL1	protein	P00519	UNIPROT	DGCR8	protein	Q8WYQ5	UNIPROT	up-regulates activity	phosphorylation	Tyr267	KRRTEEKyGGDSDHP	9606	BTO:0000007								26126715	t		miannu	The kinase ABL phosphorylates the microprocessor subunit DGCR8 to stimulate primary microRNA processing in response to DNA damage. When coexpressed in HEK293T cells, ABL phosphorylated DGCR8 at Tyr(267). 	SIGNOR-262604	0.2
CP-91149	chemical	CID:9843900	PUBCHEM	PYGL	protein	P06737	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191112	0.8
ATM	protein	Q13315	UNIPROT	DBF4	protein	Q9UBU7	UNIPROT	down-regulates	phosphorylation	Thr449	DDIRQNFtQLPLHKN	9606									22123827	t		lperfetto	Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication.	SIGNOR-177801	0.385
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH6	protein	P55285	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265846	0.8
GLI2	protein	P10070	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates						BTO:0004300							29205155	f		areggio	Molecularly, Gli2 is the principle transcription factor in the Gli family to mediate the anti-adipogenic and anti-lipogenic effects of Hh signaling	SIGNOR-256224	0.278
adenosine	smallmolecule	CHEBI:16335	ChEBI	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	precursor of			9606									18957298	t		miannu	Adenosine is an endogenous inhibitor of excitatory synaptic transmission with potent anticonvulsant properties in the mammalian brain. Given adenosine's important role in modulating synaptic transmission, several mechanisms exist to regulate its extracellular availability. One of these is the intracellular enzyme adenosine kinase (ADK), which phosphorylates adenosine to AMP.	SIGNOR-265465	0.8
TFAP2B	protein	Q92481	UNIPROT	ADIPOQ	protein	Q15848	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19325541	f	 	miannu	 A transcription factor, TFAP2B, has been shown to participate in the regulation of adipocyte metabolism, by facilitating glucose uptake and lipid accumulation, while simultaneously reducing insulin sensitivity, and recently a direct function for TFAP2B as an inhibitor of adiponectin expression was observed. 	SIGNOR-255421	0.374
RELA	protein	Q04206	UNIPROT	BMP4	protein	P12644	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000018								17350185	t		Luana	Co-transfection with pCMV4-RelA alone or in combination with pCMV4p50 repressed pSLA4.1 EX-Lux activity by approximately 75 percent in both H441 and A549 cells 	SIGNOR-266087	0.2
RBX1	protein	P62877	UNIPROT	Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	form complex	binding			9606									22649780	t		gcesareni	The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors	SIGNOR-234799	0.831
SIN3A	protein	Q96ST3	UNIPROT	TERT	protein	O14746	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18505829	f		miannu	We investigated the mechanism of NFX1-91 repression of the hTERT promoter and demonstrated that NFX1-91 interacts with the corepressor mSin3A/HDAC to maintain the deacetylated status at the hTERT promoter, thus providing a mechanism by which NFX1-91 represses hTERT expression.	SIGNOR-226363	0.311
GOLGA7	protein	Q7Z5G4	UNIPROT	ZDHHC9	protein	Q9Y397	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16000296	t		miannu	DHHC9 and GCP16 form a protein complex, and DHHC9 requires GCP16 for protein fatty acyltransferase activity and protein stability. 	SIGNOR-261353	0.676
MAPK1	protein	P28482	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser255	ELSPTTLsPVNHSLD	9606		BTO:0000763							12193595	t		miannu	Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction.	SIGNOR-91722	0.711
CDK1	protein	P06493	UNIPROT	RANBP2	protein	P49792	UNIPROT	up-regulates activity	phosphorylation	Ser2246	SSSVHASerPLASSP	-1									26051540	t		irozzo	Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment.	SIGNOR-259118	0.452
A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	IL1B	protein	P01584	UNIPROT	up-regulates quantity by expression				9606									24241034	f		lperfetto	Importantly, autocrine and paracrine interactions of α9β1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-α and IL-1β in synovial macrophages.	SIGNOR-253314	0.311
sunitinib	chemical	CHEBI:38940	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates	chemical inhibition			9606									20185585	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-163941	0.8
BMS 794833	chemical	CID:44155856	PUBCHEM	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190419	0.8
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CDK5	protein	Q00535	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189993	0.8
PPP2CA	protein	P67775	UNIPROT	PTTG1	protein	O95997	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Thr66	ATRKALGtVNRATEK	9606	BTO:0000567								24781523	t		miannu	CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase	SIGNOR-276376	0.301
COL1A1	protein	P02452	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									21949456	f			Collagen is the major structural protein in skeletal muscle ECM;...Several studies suggest that perimysial collagen is predominantly type I	SIGNOR-254662	0.7
CYP2R1	protein	Q6VVX0	UNIPROT	vitamin D	smallmolecule	CHEBI:27300	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000759							30080183	t		lperfetto	Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. 	SIGNOR-270569	0.8
alvocidib hydrochloride	chemical	CHEBI:90998	ChEBI	CDK6	protein	Q00534	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192470	0.8
KDM3B	protein	Q7LBC6	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9534									16603237	t		miannu	We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation.	SIGNOR-266636	0.2
pazopanib	chemical	CHEBI:71219	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001949								18620382	t		Luana	Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively.	SIGNOR-257736	0.8
CyclinC/CDK3	complex	SIGNOR-C545	SIGNOR	G0/G1_transition	phenotype	SIGNOR-PH219	SIGNOR	up-regulates													37104883	f		lperfetto	Among them, CDK3 is critically important because it triggers the transitions of G0 to G1 and G1 to S phase through binding to cyclin C and cyclin E1, respectively. 	SIGNOR-273190	0.7
SNRPD3	protein	P62318	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270662	0.733
BCR	protein	P11274	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260526	0.583
D-fructofuranose 6-phosphate(2-)	smallmolecule	CHEBI:61527	ChEBI	2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-)	smallmolecule	CHEBI:58725	ChEBI	up-regulates quantity	precursor of			9606									21310273	t		miannu	GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans	SIGNOR-268098	0.8
MAPK1	protein	P28482	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser214	PTSSDPGsPFQMPAD	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3	SIGNOR-161605	0.59
OPA1	protein	O60313	UNIPROT	Mitochondrial_fusion	phenotype	SIGNOR-PH218	SIGNOR	up-regulates				9606									25486875	f		lperfetto	OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria	SIGNOR-272987	0.7
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	ID1	protein	P41134	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18025157	f			We show that the ID1 and ID2 promoters are activated by PML-RARα but, unexpectedly, not by wild-type RARα/RXR. In contrast, PML-RARα transactivated the promoter more than 12-fold in an ATRA-dependent fashion.	SIGNOR-255728	0.2
FZD8	protein	Q9H461	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates activity	binding			9606	BTO:0000971								21078818	t		amattioni	Ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane domain receptor Frizzled (Fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (LRP5/6) to activate Wnt–Beta-catenin signaling.	SIGNOR-169635	0.717
STAT5A	protein	P42229	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15626738	t			FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells	SIGNOR-261552	0.267
PRKACA	protein	P17612	UNIPROT	LASP1	protein	Q14847	UNIPROT	down-regulates activity	phosphorylation	Ser146	MEPERRDsQDGSSYR	9606									12571245	t		lperfetto	Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration	SIGNOR-97938	0.311
KAT2B	protein	Q92831	UNIPROT	H3C15	protein	Q71DI3	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269626	0.2
TNFRSF1A	protein	P19438	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity													17151142	f			[...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation	SIGNOR-253600	0.38
VPS18	protein	Q9P253	UNIPROT	PLK2	protein	Q9NYY3	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								16203730	t		miannu	VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4. 	SIGNOR-271550	0.2
SGK2	protein	Q9HBY8	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606									11154281	t		lperfetto	Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 	SIGNOR-249130	0.512
EEF1A1P5	protein	Q5VTE0	UNIPROT	Arg-tRNA(Arg)	smallmolecule	CHEBI:18366	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269545	0.8
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Thr220	QSNYIPEtPPPGYIS	9606									12193595	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-91742	0.739
KIF7	protein	Q2M1P5	UNIPROT	GLI3	protein	P10071	UNIPROT	up-regulates quantity by stabilization	binding			10090									19592253	t		lperfetto	These results suggest a role for Kif7 in coordinating Hh signal transduction at the tip of cilia and preventing Gli3 cleavage into a repressor form in the presence of Hh.	SIGNOR-209614	0.56
RORA	protein	P35398	UNIPROT	CPT1B	protein	Q92523	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001103								15199055	f	 	 	Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle.	SIGNOR-254256	0.2
CDH4	protein	P55283	UNIPROT	CDH2	protein	P19022	UNIPROT	down-regulates quantity by repression				10090	BTO:0000165								18701479	f		lperfetto	Taken together, these data show that (a) R-cadherin decreases the expression of M-cadherin and (b) N-cadherin and M-cadherin only slightly accumulate at the cell contacts in R-cadherin–expressing myoblasts.	SIGNOR-253107	0.491
ANK3	protein	Q12955	UNIPROT	DAG1	protein	Q14118	UNIPROT	up-regulates quantity	relocalization			10090		BTO:0001103							19109891	t		miannu	We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4.	SIGNOR-266714	0.262
HDAC3	protein	O15379	UNIPROT	HDAC1	protein	Q13547	UNIPROT	up-regulates	binding			9606				SIGNOR-C12					23213415	t		gcesareni	Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes.	SIGNOR-199964	0.512
hydrogen peroxide	smallmolecule	CHEBI:16240	ChEBI	MAPK7	protein	Q13164	UNIPROT	up-regulates				9606		BTO:0000142							11782488	f		gcesareni	These findings suggest that c-src mediated bmk1 activation by h(2)o(2) may counteract ischemic cellular damage probably through the activation of mef2c transcription factor.	SIGNOR-113758	0.8
HECTD4	protein	Q9Y4D8	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001321								32814769	t		miannu	 We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. 	SIGNOR-267148	0.2
TBX3	protein	O15119	UNIPROT	CDKN2A	protein	Q8N726	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									25211658	t		lperfetto	TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS	SIGNOR-249603	0.406
MAPKAPK2	protein	P49137	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation	Ser119	EILSRRPsYRKILND	9606									20626350	t		lperfetto	Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2.	SIGNOR-166619	0.679
E2F1	protein	Q01094	UNIPROT	CD2AP	protein	Q9Y5K6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								22880102	f	 	lperfetto	Transcriptional activation of the human CD2AP promoter by E2F1	SIGNOR-254129	0.2
COL18A1	protein	P39060	UNIPROT	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	up-regulates	binding			9606									12682293	t		gcesareni	The activity of human endostatin is mediated by alpha 5 beta 1 integrin.	SIGNOR-99871	0.537
PTK6	protein	Q13882	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Tyr326	EVLEDNDyGRAVDWW	9606	BTO:0000150	BTO:0001129							20606012	t		gcesareni	Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6.	SIGNOR-252622	0.454
BRCA1	protein	P38398	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001130								22832221	f		gcesareni	Brca1/e2f1/ctipbinding to atm promoter activates atm transcription.	SIGNOR-198467	0.813
PRKCA	protein	P17252	UNIPROT	GRIA1	protein	P42261	UNIPROT	unknown	phosphorylation	Ser832	LIEFCYKsRSESKRM	9606									8663994	t		lperfetto	In addition, protein kinase C specifically phosphorylates Ser-831 of GluR1 in HEK-293 cells and in cultured neurons.	SIGNOR-248950	0.704
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT2	protein	P09544	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242724	0.309
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Thr739	SEGSGTAtPSALITT	9606		BTO:0000887;BTO:0001260							20150555	t		lperfetto	Moreover, we showed that sp1 is a novel mitotic substrate of cdk1/cyclin b1 and is phosphorylated by it at thr 739 before the onset of mitosis.	SIGNOR-216940	0.424
ceramide	smallmolecule	CHEBI:17761	ChEBI	sphingomyelin	smallmolecule	CHEBI:64583	ChEBI	up-regulates quantity	precursor of			9606									18184806	t		miannu	Ceramide is a common precursor for both sphingomyelin and glycosphingolipids, which are ubiquitous components of membranes in mammalian cells and play important roles in cell growth, differentiation, and apoptosis 	SIGNOR-268497	0.8
IRAK4	protein	Q9NWZ3	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000801								17337443	t		lperfetto	Analyses of embryonic fibroblasts and macrophages obtained from IRAK-4 KD mice demonstrate lack of cellular responsiveness to stimulation with IL-1beta or a Toll-like receptor 7 (TLR7) agonist. IRAK-4 kinase deficiency prevents the recruitment of IRAK-1 to the IL-1 receptor complex and its subsequent phosphorylation and degradation.	SIGNOR-153458	0.672
HSCB	protein	Q8IWL3	UNIPROT	iron-sulfur cluster	smallmolecule	CHEBI:30408	ChEBI	up-regulates activity	relocalization												27714045	t		lperfetto	Cluster transfer from ISCU to recipient apoproteins is assisted by a dedicated chaperone/cochaperone (HSPA9/HSC20) system that facilitates cluster release from the primary scaffold ISCU and transfer to recipient apoproteins or to intermediate carriers	SIGNOR-262130	0.8
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CDK3	protein	Q00526	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189987	0.8
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	carbamoyl phosphate(2-)	smallmolecule	CHEBI:58228	ChEBI	up-regulates quantity	precursor of			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-267416	0.8
STAT3	protein	P40763	UNIPROT	HGF	protein	P14210	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11278729	t		lperfetto	Coexpression of activated c-Src and Stat3 synergistically induced strong HGF promoter activity in SP1 cells	SIGNOR-251742	0.608
1-[4-[1-(1,4-dioxaspiro[4.5]decan-8-yl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-pyrazolo[3,4-d]pyrimidinyl]phenyl]-3-methylurea	chemical	CHEBI:91364	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck;ATP-competitive inhibitor mTOR	gcesareni		SIGNOR-207800	0.8
FOXP3	protein	Q9BZS1	UNIPROT	T-reg_differentiation	phenotype	SIGNOR-PH91	SIGNOR	up-regulates				9606									15785758	f		mrosina	Viewed as a whole, the available data demonstrate essential involvement of Foxp3 in the development and function of CD4 + CD25 + T reg cells.	SIGNOR-254970	0.7
SIRT7	protein	Q9NRC8	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	deacetylation	Lys38	PATGGVKkPHRYRPG										30653310	t		lperfetto	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 	SIGNOR-275882	0.2
NEK2	protein	P51955	UNIPROT	PPP1CC	protein	P36873	UNIPROT	down-regulates	phosphorylation	Thr318	TPPRGMItKQAKK	9606									10880350	t		gcesareni	Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity.	SIGNOR-78603	0.502
PSMD6	protein	Q15008	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263350	0.885
DRD5	protein	P21918	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257156	0.285
4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one	chemical	CHEBI:94732	ChEBI	MAPK10	protein	P53779	UNIPROT	down-regulates	chemical inhibition			9606									18922779	t		gcesareni	Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell.	SIGNOR-181644	0.8
IKBKE	protein	Q14164	UNIPROT	IRF1	protein	P10914	UNIPROT	down-regulates activity	phosphorylation	Ser219	FQVSPMPsTSEATTD	9606	BTO:0000007								24396068	t		miannu	We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity. 	SIGNOR-276478	0.357
PRKCA	protein	P17252	UNIPROT	CD5	protein	P06127	UNIPROT	up-regulates	phosphorylation	Thr434	MSFHRNHtATVRSHA	9606									11123317	t		amattioni	Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation.	SIGNOR-85175	0.345
CSNK2A1	protein	P68400	UNIPROT	PSEN2	protein	P49810	UNIPROT	unknown	phosphorylation	Ser7	sDSEEEVC	-1									8972483	t		llicata	In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. 	SIGNOR-250936	0.311
ERC1	protein	Q8IUD2	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	up-regulates	binding			9606									15218148	t		lperfetto	Elks likely functions by recruiting ikappabalpha to the ikk complex and thus serves a regulatory function for ikk activation.	SIGNOR-217448	0.594
SIRT7	protein	Q9NRC8	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	deacetylation			9606									18239138	t		gcesareni	We found that sirt7 interacts with p53 and efficiently deacetylates p53 in vitro, which corresponds to hyperacetylation of p53 in vivo.	SIGNOR-160539	0.514
pazopanib hydrochloride	chemical	CHEBI:71217	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-201250	0.8
PPP1CB	protein	P62140	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	dephosphorylation	Ser75	LGYEPEGsASPTPPY	9606									17318175	t			The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 	SIGNOR-248567	0.2
OBSCN	protein	Q5VST9	UNIPROT	ANK2	protein	Q01484	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0003324								19840192	t		miannu	Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. 	SIGNOR-266726	0.512
CDH10	protein	Q9Y6N8	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265850	0.568
CADPS	protein	Q9ULU8	UNIPROT	VAMP2	protein	P63027	UNIPROT	up-regulates activity	binding			9606	BTO:0000938			SIGNOR-C346					24363652	t		miannu	 CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly.	SIGNOR-264340	0.44
MYB	protein	P10242	UNIPROT	GSTM1	protein	P09488	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									14576818	t	 	 	Functional analysis of the GSTM1 promoter using reporter assays indicated that both the DNA binding and transactivation domains of Myb were required for transcriptional activation	SIGNOR-253975	0.2
MAP4K5	protein	Q9Y4K4	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates				9606									9405407	f		gcesareni	Here we report the identification of a tnf-responsive serine/threonine protein kinase termed gck related (gckr) that likely signals via mitogen-activated protein kinase (mapk)/extracellular signal-regulated kinase (erk) kinase kinase 1 (mekk1) to activate the sapk pathway.	SIGNOR-53779	0.432
PPARGC1A	protein	Q9UBK2	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									20404331	f		lperfetto	Capacity of PGC-1alpha and PGC-1beta to inhibit FoxO3 and NFkappaB actions and proteolysis helps explain how exercise prevents muscle atrophy.overexpression of PGC-1_ inhibits muscle wasting induced by denervation, starvation, and even caFoxO3 expression	SIGNOR-217966	0.403
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SMN1	protein	Q16637	UNIPROT	up-regulates quantity by stabilization	phosphorylation			9606	BTO:0000007								19103745	t		lperfetto	PKA increases SMN complex formation and SMN stability.|As expected, SMN was phosphorylated by PKA (Fig. ​(Fig.6D).6D).	SIGNOR-253114	0.2
CSNK2A1	protein	P68400	UNIPROT	XRCC1	protein	P18887	UNIPROT	up-regulates	phosphorylation	Ser485	QDNGAEDsGDTEDEL	9606									20471329	t		lperfetto	Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair	SIGNOR-165419	0.404
MAPKAPK2	protein	P49137	UNIPROT	KRT20	protein	P35900	UNIPROT	up-regulates activity	phosphorylation	Ser13	RSFHRSLsSSLQAPV	-1									20724476	t		miannu	P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13.	SIGNOR-263071	0.2
rivaroxaban	chemical	CHEBI:68579	ChEBI	F10	protein	P00742	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206550	0.8
CDH6	protein	P55285	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265868	0.56
STAT5A	protein	P42229	UNIPROT	PIM	proteinfamily	SIGNOR-PF34	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									15498859	t		lperfetto	Pim-1 is know to be up regulated by signal transducer and activator of transcription 5 (stat5)	SIGNOR-259436	0.423
IFNG	protein	P01579	UNIPROT	SOCS1	protein	O15524	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19482358	f		lperfetto	IFN-_ induces socs1 gene expression through an inducible factor	SIGNOR-236809	0.538
uridine	smallmolecule	CHEBI:16704	ChEBI	uridine 5'-monophosphate(2-)	smallmolecule	CHEBI:57865	ChEBI	up-regulates quantity	precursor of												11306702	t		lperfetto	Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. 	SIGNOR-275856	0.8
Rix1 complex	complex	SIGNOR-C373	SIGNOR	Ribosome biogenesis	phenotype	SIGNOR-PH164	SIGNOR	up-regulates				9606	BTO:0000007								22190736	f		miannu	In this study, we show that LAS1L forms a protein complex with PELP1, TEX10, NOL9, SENP3, and WDR18. Our data demonstrate that all the components of the LAS1L complex cosediment with the pre-60S ribosomal particle and are required for proper processing of the 32S rRNA intermediate.These findings demonstrate that the LAS1L complex is critical for ribosome biogenesis and cell proliferation and provide additional evidence that multiple protein complexes have distinct functions in the synthesis of eukaryotic ribosomes.	SIGNOR-265473	0.7
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates activity	phosphorylation	Ser876	QGLAERIsVL										12058027	t		lperfetto	Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.	SIGNOR-275950	0.2
PPP1R3B	protein	Q86XI6	UNIPROT	PP1	proteinfamily	SIGNOR-PF54	SIGNOR	up-regulates	binding			9606		BTO:0000759							36551183	t		miannu	In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)	SIGNOR-271736	0.702
imatinib	chemical	CHEBI:45783	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193375	0.8
CSNK2A1	protein	P68400	UNIPROT	XRCC1	protein	P18887	UNIPROT	up-regulates activity	phosphorylation	Ser475	IDIEGVQsEGQDNGA	10029	BTO:0002640								15066279	t		llicata	We show that inhibiting XRCC1 phosphorylation by mutation of the CK2 phosphorylation sites or preventing CK2 activity using a highly specific inhibitor ablates the rapid repair of cellular DNA single-strand breaks by XRCC1. | 	SIGNOR-250972	0.404
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1651	SPTSPSYsPTSPSYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii	SIGNOR-203520	0.77
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	CDKN2A	protein	Q8N726	UNIPROT	up-regulates activity				9606									25101116	f		lperfetto	ARF: a versatile DNA damage response ally at the crossroads of development and tumorigenesis. Alternative reading frame (ARF) is a tumor suppressor protein that senses oncogenic and other stressogenic signals. It can trigger p53-dependent and -independent responses with cell cycle arrest and apoptosis induction being the most prominent ones.	SIGNOR-245493	0.7
PCM1	protein	Q15154	UNIPROT	CETN2	protein	P41208	UNIPROT	up-regulates	relocalization			9606									12403812	t		miannu	Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome	SIGNOR-94990	0.511
GRK5	protein	P34947	UNIPROT	ADRB2	protein	P07550	UNIPROT	unknown	phosphorylation	Ser401	VPSDNIDsQGRNCST	-1									8662852	t			 we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). 	SIGNOR-251196	0.682
CDC42	protein	P60953	UNIPROT	USP6	protein	P35125	UNIPROT	up-regulates	relocalization			9606									12612085	t		miannu	In quiescent cells, tre17 is localized to intracellular filamentous and punctate structures in the cytoplasm, folded in an inactive conformation. Upon growth factor addition, cdc42 and rac1 become activated and recruit tre17 to the plasma membrane. Stable membrane localization of tre17 also requires polymerized actin. This recruitment process leads to a conformational change in tre17, such that the n-terminal portion of the molecule further stimulates the accumulation of cortical actin.	SIGNOR-98935	0.366
PRKACA	protein	P17612	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	down-regulates activity	phosphorylation	Ser496	ATPQRSGsVSNYRSC	9606									27784766	t		Luana	These data indicate a novel regulatory role of PKC to inhibit AMPKα1 in human cells. As PKC activation is associated with insulin resistance and obesity, PKC may underlie the reduced Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487. | AMPK activity reported in response to overnutrition in insulin-resistant metabolic and vascular tissues.	SIGNOR-259865	0.401
ULK1	protein	O75385	UNIPROT	ATG13	protein	O75143	UNIPROT	up-regulates	phosphorylation			9606									19211835	t		gcesareni	Ulks directly phosphorylate atg13	SIGNOR-183957	0.915
PRKDC	protein	P78527	UNIPROT	RPA2	protein	P15927	UNIPROT	unknown	phosphorylation	Thr21	YGGAGGYtQSPGGFG	-1									9139719	t		lperfetto	In this study, we show that efficient phosphorylation of HSSB-p34 by DNA-PK requires Ku as well as DNA. The DNA-PK phosphorylation sites in HSSB-p34 have been mapped at Thr-21 and Ser-33. Kinetic studies demonstrated that a phosphate residue is first incorporated at Thr-21 followed by the incorporation of a second phosphate residue at Ser-33.	SIGNOR-248972	0.598
EIF1AX	protein	P47813	UNIPROT	Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	up-regulates activity	relocalization			9606									12514125	t		lperfetto	Translation initiation factor 1A (eIF1A) is predicted to bind in the decoding site of the 40S ribosome and has been implicated in recruitment of the eIF2-GTP-Met-tRNA i Met ternary complex (TC) and ribosomal scanning. 	SIGNOR-269147	0.712
CLK1	protein	P49759	UNIPROT	RBM17	protein	Q96I25	UNIPROT	up-regulates activity	phosphorylation	Ser288	DATEKDAsKKSDSNP	9534	BTO:0001538								23519612	t		miannu	 In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 	SIGNOR-262709	0.324
BRAF	protein	P15056	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser248	SVQSDIWsMGLSLVE	-1									8413257	t		lperfetto	Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1.	SIGNOR-39058	0.779
KIRREL3	protein	Q8IZU9	UNIPROT	CASK	protein	O14936	UNIPROT	up-regulates activity	binding			9606		BTO:0000232							33853164	t		miannu	A Missense De Novo Variant in the CASK-interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia. KIRREL3 is a gene important for the central nervous system development-in particular for the process of neuronal migration, axonal fasciculation, and synaptogenesis-and colocalizes and cooperates in neurons with CASK gene. 	SIGNOR-269078	0.471
CSNK2A2	protein	P19784	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates activity	phosphorylation	Ser1126	TEEFSSEsDMEESKE	9606	BTO:0000938								19064667	t		lperfetto	 We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275762	0.2
NF1	protein	P21359	UNIPROT	HRAS	protein	P01112	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000938								24431436	t		miannu	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-204357	0.807
GSPT1	protein	P15170	UNIPROT	Translation release factor ERF1-ERF3	complex	SIGNOR-C494	SIGNOR	form complex	binding			9606									29735640	t		miannu	Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex. 	SIGNOR-270814	0.972
F8	protein	P00451	UNIPROT	Factor VIIIa-IXa	complex	SIGNOR-C320	SIGNOR	form complex	binding			10090		BTO:0000131							25769543	t		lperfetto	The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin.	SIGNOR-263553	0.758
PRPF31	protein	Q8WWY3	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270643	0.776
APOA1	protein	P02647	UNIPROT	ABCA1	protein	O95477	UNIPROT	up-regulates quantity by stabilization	binding			9606									12869555	t		miannu	ApoA-I stabilization of ABCA1 is mediated by reduced PEST sequence phosphorylation, which in turn leads to decreased calpain proteolysis of ABCA1.	SIGNOR-252101	0.783
PRKCA	protein	P17252	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser22	FGGPGTAsRPSSSRS	-1									2500966	t		lperfetto	We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65.	SIGNOR-248878	0.289
ADIPOQ	protein	Q15848	UNIPROT	ADIPOR2	protein	Q86V24	UNIPROT	up-regulates	binding			9606									16622416	t		milica	Two adiponectin receptors, adipor1 and adipor2, have recently been identified.	SIGNOR-146173	0.765
PTPRJ	protein	Q12913	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation	Tyr205	IMLNSKGyTKSIDIW	9606									19494114	t		gcesareni	In this study we show that one of these potential targets, the erk1/2, is indeed a direct dep-1 substrate in vivo.	SIGNOR-161536	0.415
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GRK7	protein	Q8WTQ7	UNIPROT	down-regulates activity	phosphorylation	Ser36	ELQRRRRsLALPGLQ	-1									15946941	t		miannu	 We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA.Phosphorylation of GRK1 and GRK7 by PKA reduces the ability of GRK1 and GRK7 to phosphorylate rhodopsin in vitro. 	SIGNOR-276035	0.2
GATA6	protein	Q92908	UNIPROT	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression				9606	BTO:0000195								24317510	f		lperfetto	Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. 	SIGNOR-253153	0.281
SGK1	protein	O00141	UNIPROT	SMO	protein	Q99835	UNIPROT	down-regulates	binding			9606									25790864	t		gcesareni	SGK1 is known to inhibit another intrinsic pathway, the Hedgehog pathway, through downregulation of SMO and the GLI transcription factor family	SIGNOR-251673	0.2
FLT3	protein	P36888	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16146838	f		lperfetto	Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1.	SIGNOR-249635	0.623
ATM	protein	Q13315	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1497	EPGVERSsPSKCPSL	9606	BTO:0000551								19683496	t		gcesareni	However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci.	SIGNOR-187591	0.813
GSK3A	protein	P49840	UNIPROT	ARHGAP31	protein	Q2M1Z3	UNIPROT	up-regulates activity	phosphorylation	Thr789	PPAPPPPtPLEESTP	10090	BTO:0000944								17158447	t		miannu	We show that GSK-3alpha and -beta interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation. 	SIGNOR-262878	0.344
PRKACA	protein	P17612	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity	phosphorylation	Ser865	YLSSRRSsGISPCFS	9606									10693759	t		lperfetto	Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3.	SIGNOR-75347	0.445
AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269022	0.7
DGC	complex	SIGNOR-C217	SIGNOR	AQP4	protein	P55087	UNIPROT	up-regulates quantity	binding			9606	BTO:0000938;BTO:0002606								22626543	t		miannu	 In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses.	SIGNOR-265443	0.313
LIMK2	protein	P53671	UNIPROT	CFL1	protein	P23528	UNIPROT	down-regulates activity	phosphorylation	Ser3	sGVAVSDG	9606	BTO:0000567								11171090	t		lperfetto	We report here that limk1 and limk2 phosphorylate both cofilin and actin-depolymerizing factor (adf) specifically at ser-3 and exhibit partially distinct substrate specificity when tested using site-directed cofilin mutants as substrates	SIGNOR-105098	0.757
RPS6	protein	P62753	UNIPROT	Ribosome biogenesis	phenotype	SIGNOR-PH164	SIGNOR	up-regulates				10090									23318442	f		Luana	Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program	SIGNOR-264619	0.7
[4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone	chemical	CHEBI:91441	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193612	0.8
SERPINE1	protein	P05121	UNIPROT	Fibrinolysis	phenotype	SIGNOR-PH6	SIGNOR	down-regulates				9606									10368279	f		gcesareni	Pai-1 is the physiological inhibitor of the fibrinolytic pathway	SIGNOR-68481	0.7
TAB1	protein	Q15750	UNIPROT	ROR2	protein	Q01974	UNIPROT	down-regulates	phosphorylation			9606									18762249	t		gcesareni	Tak1 (tgf-beta activated kinase 1), a map3k, interacts with ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich (stp) domain	SIGNOR-180566	0.281
ARRB2	protein	P32121	UNIPROT	SLC9A5	protein	Q14940	UNIPROT	down-regulates activity	relocalization												21296876	t		lperfetto	Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs)	SIGNOR-275506	0.406
JAK1	protein	P23458	UNIPROT	JAK3	protein	P52333	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000782								17259970	t		milica	Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity.	SIGNOR-152914	0.515
GSK3B	protein	P49841	UNIPROT	KAT5	protein	Q92993	UNIPROT	up-regulates	phosphorylation	Ser86	TKNGLPGsRPGSPER	9606									21658600	t		gcesareni	We demonstrate that gsk-3 phosphorylates serine 86 of the p53-acetyltransferase tip60. A tip60(s86a) mutant was less active to induce p53 k120 acetylation, histone 4 acetylation, and expression of puma	SIGNOR-174049	0.376
ASXL2	protein	Q76L83	UNIPROT	TET2	protein	Q6N021	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									28516957	f		miannu	Interestingly, this identified a number of genes known to promote leukemogenesis (either alone or in the context of AML1-ETO leukemia) as differentially expressed by ASXL2 loss. These include downregulation of TET2 as well as NOTCH2 with ASXL2 loss in human AML1-ETO-expressing cells, downregulation of which have been previously shown to functionally promote myeloid leukemogenesis when altered in expression	SIGNOR-260074	0.344
CSNK2A1	protein	P68400	UNIPROT	STARD10	protein	Q9Y365	UNIPROT	down-regulates	phosphorylation	Ser284	GGAGGEGsDDDTSLT	9606	BTO:0002181								17561512	t		gcesareni	Interestingly, hypotonic extracts prepared from hek293t cells expressing the serine to alanine mutant exhibited increased lipid transfer activity compared with those from wild-type stard10-expressing cells, suggesting that, in a cellular context, phosphorylation on serine 284 negatively regulates stard10 activity	SIGNOR-155740	0.383
DYRK1B	protein	Q9Y463	UNIPROT	HNF1A	protein	P20823	UNIPROT	up-regulates	phosphorylation	Ser249	IQRGVSPsQAQGLGS	9606		BTO:0000887;BTO:0001103							11980910	t		lperfetto	Mirk phosphorylates hnf1 at amino acid 249mkk3 enhanced mirk kinase activity and the transcriptional activation of hnf1alpha by mirk	SIGNOR-86728	0.517
SRC	protein	P12931	UNIPROT	DAPK1	protein	P53355	UNIPROT	down-regulates activity	phosphorylation	Tyr490	HCAAWHGyYSVAKAL	9606	BTO:0002181								17803936	t		miannu	 Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation. 	SIGNOR-276074	0.277
PLCD4	protein	Q9BRC7	UNIPROT	1D-myo-inositol 1,4,5-trisphosphate	smallmolecule	CHEBI:16595	ChEBI	up-regulates	chemical modification			9606									9125218	t		gcesareni	A key pathway is the hydrolysis of PIP2 . This is mediated by PLC, and yields the two second messengers 1,4,5-IP3 and DAG	SIGNOR-195516	0.8
PTPN11	protein	Q06124	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates activity	dephosphorylation	Tyr32	QNHFVDEyDPTIEDS	9606	BTO:0000007								26617336	t			Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling.	SIGNOR-252094	0.669
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606	BTO:0000848								18246127	t		lperfetto	To understand the mechanisms underlying B-RAF effects on cell survival we initially analysed the Bcl-2 family protein, Bad, that is phosphorylated by RSK1 at the inhibitory serine-75 residue in a MEK-dependent manner in melanoma cells	SIGNOR-252784	0.2
KLHL3	protein	Q9UH77	UNIPROT	WNK4	protein	Q96J92	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								23453970	t		miannu	Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein.	SIGNOR-272105	0.604
SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	CDKN2B	protein	P42772	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18332116	f		irozzo	HSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15INK4b and p16INK4a, but not of p14ARF.Reexpression of hSNF5 in MRT cells overcomes epigenetic silencing and mediates transcriptional activation of p15INK4b and p16INK4a	SIGNOR-256300	0.293
RANBP3	protein	Q9H6Z4	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	relocalization			9606									20704570	t		lperfetto	Importantly, PPM1A facilitates the interaction of dephosphorylated Smad2/3 with RanBP3, a nuclear export factor [75]. As a result, PPM1A-mediated dephosphorylation of Smad2/3 promotes nuclear export of Smad2/3 and shuts off TGF-_-induced anti-proliferative and transcriptional responses	SIGNOR-232107	0.398
UBE2I	protein	P63279	UNIPROT	MITF	protein	O75030	UNIPROT	down-regulates	ubiquitination	Lys308	SEARALAkERQKKDN	9606									10673502	t		lperfetto	Furthermore, we identified lysine 201 as a potential ubiquitination site. A lysine to arginine mutation abolished mitf (k201r) degradation by hubc9 in vivo.	SIGNOR-75117	0.546
SB 431542	chemical	CHEBI:91108	ChEBI	TGFBR1	protein	P36897	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206706	0.8
CSNK1E	protein	P49674	UNIPROT	CSNK1E	protein	P49674	UNIPROT	down-regulates activity	phosphorylation	Thr325	GQLRGSAtRALPPGP	9606	BTO:0000007								10542239	t		llicata	Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T	SIGNOR-250811	0.2
RARB	protein	P10826	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates activity	binding			9606									15650024	t	inferred from family member	gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs	SIGNOR-267807	0.398
GSK3B	protein	P49841	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation			9606									18045539	t		gcesareni	Phosphorylation at the gsk3 sites represses the transcriptional activity of smad1 by enhancing proteasomal degradation of psmad1cter	SIGNOR-159484	0.517
PRKCH	protein	P24723	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates	phosphorylation	Ser876	QGLAERIsVL	9606									12058027	t		gcesareni	Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs.	SIGNOR-89431	0.2
F2RL1	protein	P55085	UNIPROT	SDC4	protein	P31431	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254844	0.2
TNFRSF17	protein	Q02223	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates				9606									10903733	f		miannu	Bcma overexpression induces nf-kb activation	SIGNOR-79510	0.285
ARHGAP35	protein	Q9NRY4	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260493	0.712
RPS6KA5	protein	O75582	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	unknown	phosphorylation	Ser758	TSTETRSsSSESSHS	9606									15568999	t		lperfetto	Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known.	SIGNOR-131407	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	KIF22	protein	Q14807	UNIPROT	up-regulates	phosphorylation	Thr463	QGAPLLStPKRERMV	9606									12727876	t		lperfetto	Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes	SIGNOR-216793	0.374
85375-15-1	chemical	CID:6917797	PUBCHEM	SLC6A13	protein	Q9NSD5	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207066	0.8
pemetrexed disodium	chemical	CHEBI:63722	ChEBI	DHFR	protein	P00374	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002058								14596699	t		miannu	Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). 	SIGNOR-259290	0.8
CBX1	protein	P83916	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	binding			9606							methylation:Lys10	RTKQTARkSTGGKAP	19111658	t		miannu	 A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 	SIGNOR-264492	0.2
MAPKAPK2	protein	P49137	UNIPROT	PARN	protein	O95453	UNIPROT	down-regulates	phosphorylation	Ser557	NHYYRNNsFTAPSTV	9606									20932473	t		lperfetto	Mk2 phosphorylates parn, blocking gadd45_ mrna degradation. Parn can serve as a direct substrate for mk2, and demonstrating that ser-557 is the dominant mk2 phosphorylation site.	SIGNOR-168377	0.383
PTPRJ	protein	Q12913	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	dephosphorylation			9606									18348712	t		gcesareni	As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors.	SIGNOR-252727	0.264
ASF1A	protein	Q9Y294	UNIPROT	MDC1	protein	Q14676	UNIPROT	up-regulates activity	binding			9606	BTO:0002181								33503415	t		miannu	Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks.	SIGNOR-277621	0.317
MYOG	protein	P15173	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates				9606		BTO:0000887							8288123	f		lperfetto	The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enancers.	SIGNOR-37461	0.7
NOG	protein	Q13253	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	down-regulates	binding			9606		BTO:0000142							12478285	t	Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function	lperfetto	Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmpby blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors	SIGNOR-217541	0.584
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser315	DFRSRTNsNASTVSG	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252827	0.908
CALM2	protein	P0DP24	UNIPROT	CAMKK1	protein	Q8N5S9	UNIPROT	up-regulates	binding			9606									10770941	t		miannu	The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases	SIGNOR-266328	0.5
NR2F1	protein	P10589	UNIPROT	PCDH19	protein	Q8TAB3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000142							34215582	t		miannu	We demonstrated that high expression of COUP-TFI induces MEC cell fate and protocadherin 19 expression. We next demonstrated that COUP-TFI is able to directly bind to a conserved Sp1/COUP-TFI binding site in the Pcdh19 promoter region by chromatin immunoprecipitation (ChIP) (Fig. 6, E and F).	SIGNOR-267223	0.2
ABL1	protein	P00519	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates activity	phosphorylation	Tyr536	QKGQESEyGNITYPP	-1									12468540	t		gcesareni	Incorporation of Pmp at the 536 site led to 4-fold stimulation of the SHP-1 tyrosine phosphatase activity whereas incorporation at the 564 site led to no effect	SIGNOR-246236	0.423
tacrolimus (anhydrous)	chemical	CHEBI:61049	ChEBI	PPP3CA	protein	Q08209	UNIPROT	down-regulates	chemical inhibition			9606									15276472	t		gcesareni	Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins.	SIGNOR-127239	0.8
CDK1	protein	P06493	UNIPROT	LATS1	protein	O95835	UNIPROT	up-regulates	phosphorylation	Ser613	EKKQITTsPITVRKN	9606			SIGNOR-C17						12372621	t		lperfetto	Warts is a serine/threonine kinase and a dynamic component of the mitotic apparatus. We have found that cdc2/cyclin b forms a complex with a fraction of warts in the centrosome and phosphorylates the ser613 site of warts during mitosisit can be speculated that phosphorylation of warts by cdc2/cyclin b promotes a protein complex formation on the mitotic apparatus at early mitosis, which may be required for subsequent activation of warts kinase at the metaphase-anaphase transition.	SIGNOR-94160	0.397
ATR	protein	Q13535	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									11865061	t		gcesareni	Nhibition of atr kinase activity substantially reduces hypoxia-induced phosphorylation of p53 protein on serine 15 as well as p53 protein accumulation.	SIGNOR-115134	0.731
DYRK1A	protein	Q13627	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation	Ser330	RLSPIMAsTELDEVQ	9606									19188143	t		gcesareni	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition.	SIGNOR-183674	0.367
PRKCA	protein	P17252	UNIPROT	DLX3	protein	O60479	UNIPROT	up-regulates activity	phosphorylation	Thr134	KKVRKPRtIYSSYQL	-1									11343707	t		lperfetto	Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3.	SIGNOR-249097	0.311
PRKAA1	protein	Q13131	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser172	GQLVRNDsLWHRSDS	9606									26816379	t		gcesareni	A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission.	SIGNOR-249656	0.2
MLL-AF4	fusion protein	SIGNOR-FP4	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0000725								21389315	f		irozzo	Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair. 	SIGNOR-255873	0.7
SLC36A4	protein	Q6YBV0	UNIPROT	proline	smallmolecule	CHEBI:26271	ChEBI	up-regulates quantity	relocalization			8355									21097500	t		lperfetto	HPAT4 in Xenopus oocytes mediated sodium-independent, electroneutral uptake of [(3)H]proline, with the highest rate of uptake when the uptake medium pH was 7.4 and an affinity of 3.13 μM. Tryptophan was also an excellently transported substrate with a similarly high affinity (1.72 μM). 	SIGNOR-264736	0.8
HCK	protein	P08631	UNIPROT	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	up-regulates activity	phosphorylation	Tyr845	TASDGKLyVSSESRF	9606									16912036	t		Manara	Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 	SIGNOR-260815	0.2
CSNK1E	protein	P49674	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates activity	phosphorylation	Ser142	TGTESMVsHRRERAR	9606									16965538	t		lperfetto	Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development.	SIGNOR-217849	0.621
NCKIPSD	protein	Q9NZQ3	UNIPROT	NCK1	protein	P16333	UNIPROT	unknown	binding			9606									14559906	t		gcesareni	Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck	SIGNOR-118750	0.652
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TAL1	protein	P17542	UNIPROT	down-regulates	phosphorylation	Thr90	EARHRVPtTELCRPP	9606	BTO:0000782;BTO:0001271								15930267	t		miannu	Akt phosphorylates tal1 oncoprotein and inhibits its repressor activity. / our results show that akt specifically phosphorylates thr90 of the tal1 protein within its transactivation domain in vitro and in vivo.	SIGNOR-137942	0.2
vemurafenib	chemical	CHEBI:63637	ChEBI	BRAF	protein	P15056	UNIPROT	down-regulates activity	chemical inhibition			9606									23094782	t		miannu	Metastatic melanoma is an aggressive disease resistant to chemotherapy. Recent clinical trials have reported improved survival for two novel agents; ipilimumab, a humanized, IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and vemurafenib , a BRAF (v-raf murine sarcoma viral oncogene homolog B1) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene.	SIGNOR-259281	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates activity	phosphorylation	Ser162	FDIVSRGsTADLDGL	9606									19661060	t		Manara	We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.	SIGNOR-260885	0.2
AEP complex	complex	SIGNOR-C117	SIGNOR	MEIS1	protein	O00470	UNIPROT	up-regulates quantity by expression				9606									20854876	f		irozzo	Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented.	SIGNOR-256144	0.392
CSNK2A1	protein	P68400	UNIPROT	EIF2B5	protein	Q13144	UNIPROT	up-regulates activity	phosphorylation	Ser717	LKEAEEEsSEDD	9606	BTO:0000007								11500362	t		llicata	Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro. 	SIGNOR-250859	0.394
VEGFD	protein	O43915	UNIPROT	KDR	protein	P35968	UNIPROT	up-regulates	binding			9606									9435229	t		gcesareni	Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors.	SIGNOR-55163	0.2
JWOGUUIOCYMBPV-GMFLJSBRSA-N	chemical	CID:6918328	PUBCHEM	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000567								17868033	t		Simone Vumbaca	Apicidin inhibited rhHDACs 2 and 3 in the nanomolar range.	SIGNOR-261127	0.8
KIT	protein	P10721	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates activity	phosphorylation	Tyr568	EEINGNNyVYIDPTQ	9606	BTO:0001271								12824176	t		lperfetto	Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth./ Tyr-568 and tyr-570 are significantly phosphorylated	SIGNOR-102633	0.2
PRKCD	protein	Q05655	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser170	SFKLSGFsFKKNKKE	-1									8422248	t		lperfetto	These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III.	SIGNOR-248930	0.469
CTSG	protein	P08311	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Leu38	RSSKGRSlIGKVDGT	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263584	0.518
MITF	protein	O75030	UNIPROT	ACP5	protein	P13686	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0003292								11481336	f		miannu	 The combination of MITF and PU.1 synergistically activated the TRAP promoter in transient assays. 	SIGNOR-254584	0.354
MECP2	protein	P51608	UNIPROT	FKBP5	protein	Q13451	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									16002417	t		Luana	These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress.	SIGNOR-264542	0.312
RXRB	protein	P28702	UNIPROT	NR2F1	protein	P10589	UNIPROT	up-regulates	binding			9606									10900149	t		gcesareni	Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site	SIGNOR-79449	0.277
TTBK1	protein	Q5TCY1	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser519	SGYSSPGsPGTPGSR	9606	BTO:0000938								16923168	t	The effect has been demonstrated using P10636-8	lperfetto	Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation.	SIGNOR-148974	0.464
SIM1	protein	P81133	UNIPROT	ARNT	protein	P27540	UNIPROT	up-regulates activity	binding			-1									9020169	t	2	miannu	We demonstrate that both SIM1 and SIM2 can heterodimerize via their helix-loop-helix·PAS regions with ARNT, but not with AHR, and that they do not form homodimers. Furthermore, SIM1 may have a dual role, both negatively affecting AHR·ARNT binding to the XRE and also acting in concert with ARNT as a novel DNA-binding heterodimer.	SIGNOR-240759	0.545
BRD8	protein	Q9H0E9	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269304	0.645
PRKACA	protein	P17612	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates	phosphorylation	Ser857	PPYNRAVsLDSPVSV	9606									22505454	t		gcesareni	Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites.	SIGNOR-196961	0.34
BMPR2	protein	Q13873	UNIPROT	BMPR1A	protein	P36894	UNIPROT	up-regulates	binding			9534									7791754	t		fspada	Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.	SIGNOR-33440	0.615
glutamine	smallmolecule	CHEBI:28300	ChEBI	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				9606	BTO:0000567								22749528	f		Luana	Leucine and Glutamine Activate Glutaminolysis and mTORC1	SIGNOR-268008	0.8
CS	protein	O75390	UNIPROT	citrate(3-)	smallmolecule	CHEBI:16947	ChEBI	up-regulates quantity	chemical modification			9606									3013232	t		miannu	Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond.	SIGNOR-266240	0.8
AKT2	protein	P31751	UNIPROT	BCL3	protein	P20749	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser41	KRPLRAPsPEPAAPR	-1									28689659	t		miannu	Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA. 	SIGNOR-277359	0.273
PKNOX1	protein	P55347	UNIPROT	HOXA1	protein	P49639	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								9582372	t		miannu	Our results are consistent with a primary interaction of the YPWM motif of HOXA1 with the homeodomain of PBX. HOX proteins are dependent upon cofactors of the PBX family for specificity of DNA binding.	SIGNOR-220242	0.57
ATM	protein	Q13315	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Ser33	TQSQGSSsQSQGISS	9606	BTO:0000007								10973490	t		lperfetto	Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir	SIGNOR-81399	0.83
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser12	KTLYSFFsPSPARKR	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276087	0.283
ABL1	protein	P00519	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates activity	phosphorylation	Tyr386	YRARVANyQRDGPMC	9606									12777400	t		Manara	These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386	SIGNOR-260770	0.412
BCL11A	protein	Q9H165	UNIPROT	HBG2	protein	P69892	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004911								20395365	f	Regulation	miannu	BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors.	SIGNOR-251800	0.46
ADSS2	protein	P30520	UNIPROT	Nucleotide_synthesis	phenotype	SIGNOR-PH179	SIGNOR	up-regulates				9606									10496970	f		miannu	Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP.	SIGNOR-267834	0.7
ACVR1B	protein	P36896	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	phosphorylation			9606									11389842	t	Indirect_regulation of phosphorylation	miannu	Nodal Induces Smad Phosphorylation through ALK4 in a Cripto-Dependent Manner	SIGNOR-251943	0.795
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser12	KTLYSFFsPSPARKR	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276093	0.275
MAPK3	protein	P27361	UNIPROT	NR3C2	protein	P08235	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser361	TLRDVVPsPDTQEKG	9606	BTO:0005043								22798426	t		miannu	 Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276106	0.358
PLK1	protein	P53350	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	down-regulates activity	phosphorylation	Thr151	RSYSRLEtLGSASTS	-1									23901111	t		miannu	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. 	SIGNOR-276122	0.693
PRKN	protein	O60260	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000938								12666095	t		lperfetto	Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R).	SIGNOR-249705	0.2
HOXD13	protein	P35453	UNIPROT	MEIS1	protein	O00470	UNIPROT	up-regulates activity	binding			-1									9343407	t	2	miannu	We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets.	SIGNOR-241235	0.513
RPS6KA1	protein	Q15418	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606	BTO:0000007								10558990	t		lperfetto	The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival.	SIGNOR-180910	0.404
PTPN2	protein	P17706	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606									30230471	f		lperfetto	In keeping with the overall improvement in insulin sensitivity we found that insulin-induced IR Y1162/Y1163 tyrosine phosphorylation and activation and downstream PI3K/AKT signaling in the liver (as monitored by AKT Ser-473 phosphorylation) were dramatically enhanced by POMC TCPTP deficiency (Figure 4h).|This would suggest that TCPTP deletion, or decreased TCPTP in POMC neurons in response to feeding, represses HGP by enhancing IR signaling and permitting POMC neurons to be activated by insulin.	SIGNOR-276956	0.604
RHOA	protein	P61586	UNIPROT	PFN1	protein	P07737	UNIPROT	up-regulates activity				9606	BTO:0000815								22820501	t		lperfetto	We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells. 	SIGNOR-253109	0.551
AURKB	protein	Q96GD4	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	down-regulates activity	phosphorylation	Ser126	NPEAESSsKEGELDA	-1									23901111	t		miannu	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. 	SIGNOR-276123	0.614
SMAD2/STAT3/EP300	complex	SIGNOR-C203	SIGNOR	IL17A	protein	Q16552	UNIPROT	up-regulates	transcriptional regulation			9606									26194464	t		MARCO ROSINA	Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes.	SIGNOR-255027	0.48
KMT5B	protein	Q4FZB7	UNIPROT	H4C1	protein	P62805	UNIPROT	down-regulates activity	methylation	Lys21	GGAKRHRkVLRDNIQ	-1									24396869	t		miannu	SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation. 	SIGNOR-266651	0.2
ETS1	protein	P14921	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20392592	f	 	miannu	 High ETS1 expression levels in all resistant MCF-7 sublines may lead to the upregulation of the transcription of MDR1 gene.	SIGNOR-254077	0.2
TRAF2	protein	Q12933	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates	binding			9606									18635759	t		gcesareni	Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades.	SIGNOR-179476	0.705
pazopanib hydrochloride	chemical	CHEBI:71217	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-201037	0.8
N-[5-[(2R)-2-methoxy-1-oxo-2-phenylethyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-1-piperazinyl)benzamide	chemical	CHEBI:94490	ChEBI	AURKC	protein	Q9UQB9	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191280	0.8
EGFR	protein	P00533	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			-1	BTO:0000567								16729043	t		lperfetto	We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K.	SIGNOR-236327	0.921
1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea	chemical	CHEBI:91327	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207296	0.8
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRIA4	protein	P48058	UNIPROT	up-regulates activity	chemical activation			9606									30825796	t		miannu	In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses	SIGNOR-264611	0.8
NEK6	protein	Q9HC98	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates activity	phosphorylation	Ser377	PPFNPNVsGPNDLRH	-1									12023960	t		miannu	In contrast, we demonstrate for the first time that NEK6 phosphorylates SGK1 efficiently at its hydrophobic motif in vitro and peptide-mapping analysis indicates that this is the major site of phosphorylation (Fig 3). Ser377 is a more minor site of phosphorylation located in the kinase domain of SGK1, which has not been reported to undergo phosphorylation previously. the phosphorylation of the hydrophobic motif of SGK1 in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1 	SIGNOR-262954	0.344
CNTFR	protein	P26992	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates				9606									10582086	f		gcesareni	Signal transduction by cntf requires that it bind first to cntfr alpha, permitting the recruitment of gp130 and lifr beta, forming a tripartite receptor complex. Cntf-induced heterodimerization of the beta receptor subunits leads to tyrosine phosphorylation (through constitutively associated jaks), and the activated receptor provides docking sites for sh2-containing signaling molecules, such as stat proteins.	SIGNOR-72771	0.276
LRP6	protein	O75581	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	relocalization			9606									12897152	t		amattioni	The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism.	SIGNOR-104493	0.829
SMAD6	protein	O43541	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	binding			9606				SIGNOR-C85					12857866	t		gcesareni	Smad6 also inhibits bmp signaling by forming a complex with smad1 and by interfering with complex formation between smad1 and smad4	SIGNOR-103621	0.56
SH2B1	protein	Q9NRF2	UNIPROT	CD79A	protein	P11912	UNIPROT	down-regulates activity	dephosphorylation			9606									32323266	t		scontino	SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK.	SIGNOR-268457	0.2
sunitinib	chemical	CHEBI:38940	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			9606									20570526	t		Luana	Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors],	SIGNOR-257851	0.8
MYC	protein	P01106	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									29731393	f		miannu	Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2	SIGNOR-267363	0.535
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr70	RNSPVTKtPPRDLPT	9606	BTO:0000007								10942774	t		lperfetto	Mammalian target of rapamycin-dependent phosphorylation of phas-i in four (s/t)p sites detected by phospho-specific antibodies.	SIGNOR-236702	0.753
WDR83	protein	Q9BRX9	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates	binding			9606									15118098	t		lperfetto	Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex.	SIGNOR-244964	0.512
afatinib	chemical	CHEBI:61390	ChEBI	ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	down-regulates activity	chemical inhibition			9606	BTO:0002058								24643470	t		miannu	This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively.	SIGNOR-259443	0.8
TP53	protein	P04637	UNIPROT	SIAH1	protein	Q8IUQ4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14985507	t		gcesareni	Northern blot analysis with a specific probe demonstrates an increase in siah-1b transcription on activation of endogenous and inducible exogenous p53. To explore whether this effect is directly mediated by p53 we analyzed 20 kb of chromosome x dna, containing the siah-1b locus. A p53-binding site was identified in the siah-1b promoter, located at nucleotides -2155/-2103 relative to the translational start site.	SIGNOR-122986	0.382
R547	chemical	CID:6918852	PUBCHEM	CDK1	protein	P06493	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258272	0.8
SOD1	protein	P00441	UNIPROT	KARS1	protein	Q15046	UNIPROT	down-regulates quantity by destabilization	binding			9534	BTO:0004055								18715867	t	P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction)		In the presence of mutant SOD1, mitoKARS displays a high propensity to misfold and aggregate prior to its import into mitochondria, becoming a target for proteasome degradation.	SIGNOR-262800	0.2
SMAD1/5/8/SMAD4	complex	SIGNOR-C215	SIGNOR	FBXO30	protein	Q8TB52	UNIPROT	down-regulates				10090		BTO:0000887							24076600	f			BMP-Smad1/5/8 signaling negatively regulates a gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1)	SIGNOR-256488	0.2
AARS1	protein	P49588	UNIPROT	alanine	smallmolecule	CHEBI:16449	ChEBI	down-regulates quantity	chemical modification			9606									32314272	t		miannu	Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N).	SIGNOR-270446	0.8
YARS1	protein	P54577	UNIPROT	tRNA(Tyr)	smallmolecule	CHEBI:29182	ChEBI	down-regulates quantity	chemical modification			9606									16429158	t		miannu	YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr	SIGNOR-270517	0.8
TLE1	protein	Q04724	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	down-regulates activity	binding			-1									19460168	t			Our data shows that Groucho/TLE repression requires two sites of interaction in LEF-1 and that a central, conserved amino acid sequence within the primary region (F S/T/P/xx y I/L/V) is critical.	SIGNOR-260109	0.676
MAPKAPK5	protein	Q8IW41	UNIPROT	RHEB	protein	Q15382	UNIPROT	down-regulates activity	phosphorylation	Ser130	LHMERVIsYEEGKAL	9606	BTO:0000007								21336308	t		miannu	Phosphorylation of Rheb at Ser 130 by PRAK impairs the nucleotide-binding ability of Rheb and inhibits Rheb-mediated mTORC1 activation. 	SIGNOR-276313	0.412
TRADD	protein	Q15628	UNIPROT	TRAF1	protein	Q13077	UNIPROT	up-regulates	binding			9606									10629108	t		amattioni	Tradd mediates recruitment of traf1/2	SIGNOR-73913	0.682
SIRT7	protein	Q9NRC8	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	deacetylation	Lys19	TGGKAPRkQLATKAA										22722849	t		lperfetto	SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. 	SIGNOR-275874	0.2
CHFR	protein	Q96EP1	UNIPROT	HLTF	protein	Q14527	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								20388495	t		miannu	CHFR functions as a ubiquitin ligase for HLTF to regulate its stability and functions. CHFR negatively regulates and ubiquitinates HLTF. Taken together, this is the first report identifying the regulatory mechanism of HLTF by CHFR, suggesting that CHFR-mediated downregulation of HLTF may help protect against cancer.	SIGNOR-271460	0.496
SMURF2	protein	Q9HAU4	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	ubiquitination			9606									22298955	t		gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-153417	0.713
CSNK2A1	protein	P68400	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates activity	phosphorylation	Ser838	LVFDYEGsGSEAASL	10090	BTO:0000944								10671552	t		llicata	Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | All mutants showed a clear reduction in phosphorylation. Phosphorylation was completely abolished in the single mutant S855A and the double mutant S853/855A, and phosphorylation in S840A and S853A mutants was reduced to 43 and 28% that of wt GST-ECT. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion.	SIGNOR-250839	0.41
MAPKAPK2	protein	P49137	UNIPROT	TH	protein	P07101	UNIPROT	up-regulates activity	phosphorylation	Ser19	KGFRRAVsELDAKQA	-1									11359875	t		miannu	MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation.	SIGNOR-250149	0.498
MECP2	protein	P51608	UNIPROT	TFF1	protein	P04155	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000093								15870696	f		miannu	 Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters	SIGNOR-254572	0.2
CDK1	protein	P06493	UNIPROT	VCPIP1	protein	Q96JH7	UNIPROT	down-regulates activity	phosphorylation	Ser768	TPTKAPYsPTTSKEK										23500464	t		lperfetto	We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97. 	SIGNOR-265038	0.518
CDK4	protein	P11802	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Ser780	STRPPTLsPIPHIPR	9606			SIGNOR-C18						23336272	t		gcesareni	Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression.	SIGNOR-200483	0.927
TGFBR1	protein	P36897	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								18922473	t		gcesareni	We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors	SIGNOR-241918	0.439
TGFB1	protein	P01137	UNIPROT	PAX6	protein	P26367	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001874								17251190	f	Regulation	miannu	The effect of TGFbeta on Pax6 expression was studied in the FHL124 lens epithelial cell line and was found to cause up to a 50% reduction in Pax6 mRNA levels within 24 h. Pax6-stimulated activity of the Pax6 promoter is repressed by TGFβ signalling.	SIGNOR-251874	0.278
MSTN	protein	O14793	UNIPROT	ACVR2B	protein	Q13705	UNIPROT	up-regulates activity	binding			10090									11459935	t		gcesareni	The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA	SIGNOR-235153	0.663
39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	up-regulates													25838379	f		lperfetto	The highly divergent ribosomes of human mitochondria (mitoribosomes) synthesize 13 essential proteins of oxidative phosphorylation complexes.	SIGNOR-262333	0.7
PPP1R9B	protein	Q96SB3	UNIPROT	TIAM1	protein	Q13009	UNIPROT	up-regulates quantity	binding			9534	BTO:0000298								12531897	t		miannu	Spinophilin binding promotes the plasma membrane localization of Tiam1 and enhances the ability of Tiam1 to activate p70 S6 kinase.	SIGNOR-269175	0.433
SF3B1	protein	O75533	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270653	0.823
RNF216	protein	Q9NWF9	UNIPROT	TLR8	protein	Q9NR97	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								31385713	t		miannu	E3 ligase RNF216 (ring finger protein 216) targets TLR8 for ubiquitination and degradation. 	SIGNOR-272257	0.26
FLT3	protein	P36888	UNIPROT	SPI1	protein	P17947	UNIPROT	down-regulates quantity by repression	transcriptional regulation												16146838	f		lperfetto	Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1.	SIGNOR-249634	0.611
CDK1	protein	P06493	UNIPROT	RANBP2	protein	P49792	UNIPROT	up-regulates activity	phosphorylation	Thr2153	LDIPLQThrPHKLVD	-1									26051540	t		irozzo	Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment.	SIGNOR-259117	0.452
AMP	smallmolecule	CHEBI:456215	ChEBI	PRPS1	protein	P60891	UNIPROT	down-regulates activity	chemical inhibition												29074724	t		lperfetto	PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP	SIGNOR-265737	0.8
PCDH15	protein	Q96QU1	UNIPROT	TMC1	protein	Q8TDI8	UNIPROT	up-regulates activity	binding			9606	BTO:0000007	BTO:0000630							25114259	t		lperfetto	Although several studies show that the tip links, composed of PCDH15 and CDH23, are required for normal mechanotransduction, it is unclear how they are coupled to the transduction machinery. Likewise, it has been demonstrated that the transmembrane channel-like proteins TMC1 and TMC2 are required for mechanosensitive responses in hair cells, but how they interact with other components of the mechanotransduction complex is not known. Here, we show that TMC1 and TMC2 can interact with PCDH15, thereby establishing a critical connection between the tip link and these putative components of the mechanotransduction channel in hair cells.	SIGNOR-262582	0.463
PRKACA	protein	P17612	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates activity				10090	BTO:0000011								20638365	f			Here we showed that cAMP-induced activation of protein kinase A (PKA) and Akt is essential for the transcriptional activation of PPAR-gamma	SIGNOR-253019	0.2
SOD1	protein	P00441	UNIPROT	Protein_aggregates	phenotype	SIGNOR-PH142	SIGNOR	up-regulates				10090	BTO:0004488								29371591	t	P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction)		Incubating SOD1G93A or SOD1G85R, another well-established misfolded SOD1 mutant, in the absence of recombinant MIF resulted in an exponential increase in thioflavin T (ThT) fluorescence (which correlates with amyloid aggregate formation)	SIGNOR-262796	0.7
GSK3B	protein	P49841	UNIPROT	TSC2	protein	P49815	UNIPROT	up-regulates activity	phosphorylation			10116	BTO:0003293								16959574	t		lperfetto	Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation.	SIGNOR-149380	0.721
sorafenib tosylate	chemical	CHEBI:50928	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									16757355	t		miannu	Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 	SIGNOR-259223	0.8
PRKAA1	protein	Q13131	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	up-regulates				9606		BTO:0000887;BTO:0001103							19262508	f		gcesareni	The acute actions of ampk on lipid oxidation alter the balance between cellular nad+ and nadh, which acts as a messenger to activate sirt1	SIGNOR-184473	0.406
WDFY3	protein	Q8IZQ1	UNIPROT	ATG5	protein	Q9H1Y0	UNIPROT	up-regulates quantity	binding			9606	BTO:0000452								20417604	t		miannu	Alfy is recruited to intracellular inclusions and scaffolds a complex between p62(SQSTM1)-positive proteins and the autophagic effectors Atg5, Atg12, Atg16L and LC3. Alfy directly interacts with Atg5 and can be found in a complex with Atg5, Atg12 and Atg16L	SIGNOR-266791	0.617
HMGCS2	protein	P54868	UNIPROT	acetoacetyl-CoA	smallmolecule	CHEBI:15345	ChEBI	down-regulates quantity	chemical modification												29597274	t		lperfetto	Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis	SIGNOR-267659	0.8
PIK3CG	protein	P48736	UNIPROT	PIP3	smallmolecule	CHEBI:16618	ChEBI	up-regulates	chemical modification			9606									21779497	t		gcesareni	The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2)	SIGNOR-175244	0.8
CCNY	protein	Q8ND76	UNIPROT	CDK14	protein	O94921	UNIPROT	up-regulates	binding			9606									20059949	t		gcesareni	L63 and its vertebrate homolog pftk are regulated by the membrane tethered g2/m cyclin, cyclin y, which mediates binding to and phosphorylation of lrp6.	SIGNOR-162920	0.824
RXRB	protein	P28702	UNIPROT	RARB	protein	P10826	UNIPROT	up-regulates	binding			9606									1310351	t		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16677	0.65
PDPK1	protein	O15530	UNIPROT	MAP2K2	protein	P36507	UNIPROT	up-regulates	phosphorylation	Ser226	LIDSMANsFVGTRSY	9606									15175348	t		gcesareni	The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation.	SIGNOR-125176	0.259
ECM	stimulus	SIGNOR-ST20	SIGNOR	AX/b2 integrin	complex	SIGNOR-C171	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259053	0.7
NUDCD2	protein	Q8WVJ2	UNIPROT	PAFAH1B1	protein	P43034	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000567								20133715	t		miannu	The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability.	SIGNOR-252167	0.452
MAPK3	protein	P27361	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser104	FPPLNSVsPSPLMLL	9606	BTO:0000567								17615152	t		gcesareni	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity	SIGNOR-156860	0.692
A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	UTF1	protein	Q5T230	UNIPROT	up-regulates quantity by expression				10090									18757303	f		lperfetto	Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1.	SIGNOR-253281	0.257
ACOT4	protein	Q8N9L9	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	chemical modification												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271806	0.8
ponatinib	chemical	CHEBI:78543	ChEBI	STAT5A	protein	P42229	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000830								23539538	t		miannu	Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells	SIGNOR-259274	0.8
FLT3LG	protein	P49771	UNIPROT	FLT3	protein	P36888	UNIPROT	up-regulates	binding			9606									10080542	t		gcesareni	Flt3 ligand (fl) is an early-acting potent co-stimulatory cytokine that regulates proliferation and differentiation of a number of blood cell lineages. Its receptor flt3/flk2 belongs to class iii receptor tyrosine kinases that also include the receptors for colony-stimulating factor 1	SIGNOR-65564	0.881
CYP17A1	protein	P05093	UNIPROT	dehydroepiandrosterone	chemical	CHEBI:28689	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0001363;BTO:0000050;BTO:0000056							17192295	t		lperfetto	THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones.	SIGNOR-268651	0.8
DYRK1A	protein	Q13627	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation			9606									19188143	t		gcesareni	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity	SIGNOR-252905	0.521
DDB1	protein	Q16531	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates	binding			9606	BTO:0000567								9418871	t		miannu	We show that ddb, a putative dna repair protein, associates with the activation domain of e2f1 / expression of ddb specifically stimulated e2f1-activated transcription	SIGNOR-54096	0.358
ID3	protein	Q02535	UNIPROT	TCF4	protein	P15884	UNIPROT	down-regulates activity	binding			10090	BTO:0004058			SIGNOR-C129					9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241379	0.47
DUSP1	protein	P28562	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606									10617468	t		lperfetto	The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1	SIGNOR-73614	0.799
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	FBLIM1	protein	Q8WUP2	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								24165133	t	inferred from 70% family members	miannu	Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 	SIGNOR-269956	0.2
ARID1A	protein	O14497	UNIPROT	Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	form complex	binding			10090	BTO:0001086								19279220	t		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Here, we show that BAF complexes are required for the self-renewal and pluripotency of mouse ES cells but not for the proliferation of fibroblasts or other cells. Proteomic studies reveal that ES cells express distinctive complexes (esBAF) defined by the presence of Brg (Brahma-related gene), BAF155, and BAF60A, and the absence of Brm (Brahma), BAF170, and BAF60C. 	SIGNOR-270714	0.729
sirolimus	chemical	CHEBI:9168	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates activity	chemical inhibition			9606									7566123	t		Monia	Consistent with an essential role for FRAP kinase activity in vivo, autophosphorylation of FRAP is inhibited by FKBP12-rapamycin.	SIGNOR-261074	0.8
MFGE8	protein	Q08431	UNIPROT	Av/b5 integrin	complex	SIGNOR-C178	SIGNOR	up-regulates activity	binding			10116	BTO:0000452								31958465	t		miannu	Milk fat globule-EGF factor 8 (MFGE8), a protein known as lactadherin in humans, contains C domains interacting with extracellular matrices and epidermal growth factor–like domains with an RGD motif binding to integrins αvβ3 and αvβ5.	SIGNOR-260645	0.523
DEPTOR	protein	Q8TB45	UNIPROT	MTOR	protein	P42345	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								19446321	t			DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival	SIGNOR-251657	0.747
sunitinib	chemical	CHEBI:38940	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates	chemical inhibition			9606									21993628	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-176751	0.8
AKT3	protein	Q9Y243	UNIPROT	STK3	protein	Q13188	UNIPROT	down-regulates	phosphorylation	Thr117	IIRLRNKtLIEDEIA	9606	BTO:0000150								20231902	t		gcesareni	Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation.	SIGNOR-164306	0.274
AZD1480	chemical	CID:16659841	PUBCHEM	JAK2	protein	O60674	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190167	0.8
EP300	protein	Q09472	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606									20660310	f		amattioni	Switch to beta-catenin/p300-mediated gene expression is an essential first step in initiating normal cellular differentiation	SIGNOR-229780	0.7
TGFBR1	protein	P36897	UNIPROT	EEF1A1	protein	P68104	UNIPROT	down-regulates	phosphorylation	Ser300	EMHHEALsEALPGDN	9606									20832312	t		llicata	Phosphorylation of eEF1A1 at Ser300 by T_R-I results in inhibition of mRNA translation	SIGNOR-167943	0.351
LETM1	protein	O95202	UNIPROT	Mitochondrial respiratory chain complex III	complex	SIGNOR-C279	SIGNOR	up-regulates				9606	BTO:0000567								18628306	f		lperfetto	LETM1 knockdown obviously reduced the formation of the supercomplexes (Fig. 5C, arrowhead). Complexes I and IV failed to form, and the assembly of complex III was significantly decreased. By contrast, the assembly of complex II (succinate dehydrogenase) and complex V (ATP synthase) – which are not proton pumps – was unaffected.	SIGNOR-262546	0.291
ASAP2	protein	O43150	UNIPROT	ARF5	protein	P84085	UNIPROT	up-regulates activity	gtpase-activating protein			-1									10022920	t		miannu	Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain.  In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6.  Pap protein exhibits Arf GAP activity in vitro. 	SIGNOR-269707	0.512
2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	up-regulates quantity	precursor of			9606									29767008	t		miannu	Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits.	SIGNOR-266522	0.8
CDK5	protein	Q00535	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates	phosphorylation	Ser794	LSNCTKKsPNKIASG	9606	BTO:0000938								19151707	t		lperfetto	Here we show that cdk5 (cyclin-dependent kinase 5), activated by dna damage, directly phosphorylates atm at ser 794 in post-mitotic neurons. Phosphorylation at ser 794 precedes, and is required for, atm autophosphorylation at ser 1981, and activates atm kinase activity	SIGNOR-183454	0.427
EML4-ALK	fusion protein	SIGNOR-FP8	SIGNOR	HIF1A	protein	Q16665	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27141364	f		irozzo	EML4-ALK enhanced HIF-1α expression through increasing transcription and decreasing ubiquitination of HIF-1α.	SIGNOR-259172	0.2
PPP2CA	protein	P67775	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates activity	dephosphorylation	Ser87	AAAGPALsPVPPVVH	9606									15225643	t			The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A.	SIGNOR-248624	0.457
LYST	protein	Q99698	UNIPROT	RAB5A	protein	P20339	UNIPROT	down-regulates activity	binding			7227									33725482	t		lperfetto	Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment	SIGNOR-266001	0.27
CAMK2A	protein	Q9UQM7	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates activity	phosphorylation	Ser103	RGLKRSLsEMEIGMV										10753652	t		llicata	Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. | Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. | The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors.	SIGNOR-250638	0.376
BAZ2B	protein	Q9UIF8	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	binding			9606							acetylation:Lys15	ARKSTGGkAPRKQLA	31999386	t		miannu	The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation.	SIGNOR-266619	0.2
F2RL1	protein	P55085	UNIPROT	TSPAN15	protein	O95858	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21072196	f		miannu	 PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 	SIGNOR-254862	0.2
CSNK2A2	protein	P19784	UNIPROT	FGF14	protein	Q92915	UNIPROT	up-regulates activity	phosphorylation	Ser230	VTPSKSTsASAIMNG	9606	BTO:0000938								26917740	t		lperfetto	 Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.	SIGNOR-275741	0.312
LCK	protein	P06239	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation	Tyr323	DEPVADPyDQSFESR	10090	BTO:0000782								15735648	t		miannu	Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323.	SIGNOR-276029	0.452
IL34	protein	Q6ZMJ4	UNIPROT	CSF1R	protein	P07333	UNIPROT	up-regulates activity	binding			9606	BTO:0000876	BTO:0001103							24890514	t		apalma	The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34)	SIGNOR-255569	0.909
CNTN6	protein	Q9UQ52	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	relocalization			9606	BTO:0000938								15082708	t		gcesareni	Here, we establish that nb-3, a member of the f3/contactin family, acts as a novel notch ligand to participate in oligodendrocyte generation. Nb-3 triggers nuclear translocation of the notch intracellular domain and promotes oligodendrogliogenesis from progenitor cells and differentiation of oligodendrocyte precursor cells via deltex1.	SIGNOR-254318	0.572
3-phenanthryl hydrogen sulfate	chemical	CHEBI:37459	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			-1									7576010	t		miannu	The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1.	SIGNOR-258439	0.8
MCOLN1	protein	Q9GZU1	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									26000950	t			Induction of autophagy and lysosomal biogenesis via TFEB required MCOLN1-mediated calcineurin activation, linking lysosomal calcium signaling to both calcineurin regulation and autophagy induction.	SIGNOR-255308	0.8
IL17A	protein	Q16552	UNIPROT	KLF2	protein	Q9Y5W3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23332504	f		fspada	Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic.	SIGNOR-192477	0.288
RET	protein	P07949	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates	phosphorylation	Thr180	RHTDDEMtGYVATRW	9606									7535770	t		gcesareni	Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme.	SIGNOR-28059	0.338
AP-1/clathrin vescicle	complex	SIGNOR-C251	SIGNOR	oligopeptide	smallmolecule	CHEBI:25676	ChEBI	up-regulates quantity	relocalization			9606									25720354	t		scontino	APCs cell surface receptors facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. It is in these compartments that internalized antigen proteolysis and peptide–MHC class II complex formation takes place.	SIGNOR-267860	0.8
MIF	protein	P14174	UNIPROT	CXCR4	protein	P61073	UNIPROT	up-regulates activity	binding			10090	BTO:0000876								17435771	t		gcesareni	We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF [] By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis.	SIGNOR-252062	0.381
MAPK3	protein	P27361	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr355	NFSSSPStPVGSPQG	10090									14592976	t		lperfetto	Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG)	SIGNOR-249117	0.38
lysophosphatidic acids	smallmolecule	CHEBI:32957	ChEBI	LATS1	protein	O95835	UNIPROT	down-regulates				10090									22863277	f		milica	Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2.	SIGNOR-198517	0.8
HES1	protein	Q14469	UNIPROT	RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	down-regulates activity	binding			10090		BTO:0000562							16682003	t		lperfetto	Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression.	SIGNOR-209756	0.674
CSNK1A1	protein	P48729	UNIPROT	RAPGEF2	protein	Q9Y4G8	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1248	AADSGRGsWTSCSSG	9606	BTO:0002181								24290981	t		miannu	Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase.	SIGNOR-276604	0.2
CDKN2A	protein	P42771	UNIPROT	CDK2	protein	P24941	UNIPROT	down-regulates	binding			9606									10022885	t		gcesareni	However, induction of p16(ink4a) also causes marked inhibition of cdk2 activity.	SIGNOR-64431	0.494
LPAR3	protein	Q9UBY5	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates	binding			9606									11093753	t		gcesareni	Lpa3 can couple to gi/o	SIGNOR-84562	0.434
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SOS1	protein	Q07889	UNIPROT	down-regulates	phosphorylation	Ser1178	IMSKHLDsPPAIPPR	9606									20724475	t		lperfetto	ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process.	SIGNOR-244743	0.2
N(6)-(1,2-dicarboxylatoethyl)-AMP(4-)	smallmolecule	CHEBI:57567	ChEBI	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	precursor of			9606									22812634	t		miannu	ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case	SIGNOR-268067	0.8
CSNK2A1	protein	P68400	UNIPROT	XRCC1	protein	P18887	UNIPROT	up-regulates	phosphorylation	Ser518	GEDPYAGsTDENTDS	9606	BTO:0000567								15367657	t		lperfetto	Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523	SIGNOR-128893	0.404
NCBP1	protein	Q09161	UNIPROT	mRNA-nucleus_export	phenotype	SIGNOR-PH127	SIGNOR	up-regulates				9606									26382858	f		lperfetto	The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. 	SIGNOR-268361	0.7
PDPK1	protein	O15530	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates activity	phosphorylation	Thr256	EHNSTTStFCGTPEY	-1									10191262	t		miannu	PDK1 activates SGK in vitro by phosphorylating Thr256.	SIGNOR-250275	0.634
EFNA1	protein	P20827	UNIPROT	EPHA2	protein	P29317	UNIPROT	up-regulates	binding			9606									9576626	t		tpavlidou	Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm	SIGNOR-56901	0.935
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1882	SPTSPTYsPTTPKYS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120228	0.321
CASP3	protein	P42574	UNIPROT	PTCH1	protein	Q13635	UNIPROT	down-regulates activity	cleavage	Asp1405	CPGYPETdHGLFEDP	9606									12907805	t		lperfetto	Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain.	SIGNOR-104585	0.327
MASP2	protein	O00187	UNIPROT	C2	protein	P06681	UNIPROT	up-regulates activity	cleavage	Ser20	LYPGLADsAPSCPQN	9606	BTO:0000392								11907111	t		lperfetto	The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase	SIGNOR-263419	0.415
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				9606									18423396	f		fspada	Akt1/pkbalpha was found to be the major regulator of phosphorylation and nuclear export offoxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation.	SIGNOR-252911	0.7
ATM	protein	Q13315	UNIPROT	BUB1	protein	O43683	UNIPROT	up-regulates	phosphorylation	Ser314	SHEDLPAsQERSEVN	9606									22099307	t		lperfetto	We also demonstrate that mitotically activated atm phosphorylates bub1, a critical kinetochore protein, on ser314. Atm-mediated bub1 ser314 phosphorylation is required for bub1 activity and is essential for the activation of the spindle checkpoint	SIGNOR-177276	0.475
PITX1	protein	P78337	UNIPROT	POU1F1	protein	P28069	UNIPROT	up-regulates activity	binding			-1									8755540	t		miannu	A novel OTX-related homeodomain transcription factor has been identified on the basis of its ability to interact with the transactivation domain of the pituitary-specific POU domain protein, Pit-1. P-OTX is able to independently activate and to synergize with Pit-1 on pituitary-specific target gene promoters.	SIGNOR-219740	0.484
gamma-secretase	complex	SIGNOR-C98	SIGNOR	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates activity	cleavage			9606									25610395	t		lperfetto	The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins.	SIGNOR-254328	0.666
sirolimus	chemical	CHEBI:9168	ChEBI	LILRB4	protein	Q8NHJ6	UNIPROT	down-regulates quantity by repression				9606									18652845	f		miannu	Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells.	SIGNOR-255478	0.8
ATF5	protein	Q9Y2D1	UNIPROT	CYP2B6	protein	P20813	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18332083	f		miannu	We induced endoplasmic reticulum stress by means of amino acid limitation or selective chemicals, and assessed the time course response of ATF5 and CYP2B6. We found a post-transcriptional up-regulation of ATF5 and a parallel induction of CYP2B6 mRNA.	SIGNOR-253751	0.2
SMAD2/SMAD4	complex	SIGNOR-C8	SIGNOR	NANOG	protein	Q9H9S0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002861								18682241	t		flangone	We also find that SMADs bind with the NANOG promoter and that SMAD2/3 activity enhances NANOG promoter activity.	SIGNOR-242044	0.535
KDM5B	protein	Q9UGL1	UNIPROT	CBX4	protein	O00257	UNIPROT	up-regulates activity	binding			9606									19336002	t		miannu	Our results clearly showed that the PcG protein hPc2 interacted with the N-terminus of JARID1B both in vivo and in vitro. It is interesting that the C-terminus of hPc2 was essential for the interaction and transcriptional co-repression.	SIGNOR-226447	0.408
sphingosine 1-phosphate	smallmolecule	CHEBI:37550	ChEBI	S1PR1	protein	P21453	UNIPROT	up-regulates	chemical activation			9606									16794003	t		gcesareni	The evidence suggests that s1p acting on s1p receptors coupled to gq	SIGNOR-147227	0.8
BMS-554417	chemical	CID:54754526	PUBCHEM	IGF1R	protein	P08069	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190455	0.8
NR5A1	protein	Q13285	UNIPROT	CYP11B2	protein	P19099	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002588								21169726	f		miannu	Inhibitory SF-1 was found to decrease the sensitivity of CYP11B2 and aldosterone to Ang II stimulation, whereas a down-regulation of SF-1 enhanced basal CYP11B2 expression and aldosterone production in H295R cells. 	SIGNOR-254867	0.494
SHOC2	protein	Q9UQ13	UNIPROT	MRAS	protein	O14807	UNIPROT	up-regulates	binding			9606									10783161	t		gcesareni	Sur-8 interacts with ras and raf and is able to form a ternary complex with the two proteins. Thus, sur-8 may function as a scaffold that enhances ras-map kinase signal transduction by facilitating the interaction between ras and raf.	SIGNOR-77082	0.682
PRKCA	protein	P17252	UNIPROT	CDKN2D	protein	P55273	UNIPROT	up-regulates	phosphorylation	Thr141	RRDARGLtPLELALQ	9606									22558186	t		lperfetto	Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively.we propose a sequential phosphorylation model for p19 in which modification at s76 would enable a second phosphorylation event at t141. The phosphorylation-induced structural changes could have functional implicancies for p19 in the dna damage response	SIGNOR-197289	0.2
PDPK1	protein	O15530	UNIPROT	PRKCD	protein	Q05655	UNIPROT	up-regulates activity	phosphorylation	Thr507	FGESRAStFCGTPDY	9606	BTO:0000007								9748166	t		miannu	PDK1 phosphorylated the activation loop sites of PKCzeta and PKCdelta in vitro and in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner in vivo in human embryonic kidney (293) cells. PKCδ was also phosphorylated in the activation loop site (T505) 	SIGNOR-250269	0.558
CSNK2A1	protein	P68400	UNIPROT	CD5	protein	P06127	UNIPROT	up-regulates	phosphorylation	Ser483	SMQPDNSsDSDYDLH	9606									9834084	t		lperfetto	In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461)	SIGNOR-62307	0.348
SHMT1	protein	P34896	UNIPROT	glycine zwitterion	smallmolecule	CHEBI:57305	ChEBI	up-regulates quantity	chemical modification			9606									11802770	t		miannu	 HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine.	SIGNOR-269689	0.8
RIMS1	protein	Q86UR5	UNIPROT	RAB3C	protein	Q96E17	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								31679900	t		miannu	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264382	0.427
STK11	protein	Q15831	UNIPROT	SNRK	protein	Q9NRH2	UNIPROT	up-regulates activity	phosphorylation	Thr173	QPGKKLTtSCGSLAY	9606	BTO:0000567								15733851	t		lperfetto	we identify the sucrose non-fermenting protein (SNF1)-related kinase (SNRK), a largely unstudied AMPK subfamily member, as a novel substrate for LKB1. We demonstrate that LKB1 activates SNRK by phosphorylating the T-loop residue (Thr173),	SIGNOR-247493	0.374
KDM2B	protein	Q8NHM5	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				10090	BTO:0000011								25533466	f		miannu	Here, we show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. These results suggest that FBXL10 represses adipogenesis by targeting a noncanonical PRC1 complex to repress key genes (e.g. Pparg) that control conversion of pluripotent cells into the adipogenic lineage.	SIGNOR-252243	0.7
PIK3CA	protein	P42336	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity				9606		BTO:0000586							16293724	f		lperfetto	We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein;G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt	SIGNOR-235914	0.811
WNT5A	protein	P41221	UNIPROT	ROR1	protein	Q01973	UNIPROT	up-regulates	binding			9606									22343533	t		gcesareni	Ror1 and ror2 bind wnt5a.	SIGNOR-196133	0.737
GRIK2	protein	Q13002	UNIPROT	D-serine	smallmolecule	CHEBI:16523	ChEBI	up-regulates quantity	relocalization			9606	BTO:0002609								12393813	t		lperfetto	Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine	SIGNOR-268273	0.8
MAP4K4	protein	O95819	UNIPROT	MAP3K11	protein	Q16584	UNIPROT	up-regulates activity	phosphorylation	Thr738	EEEPRGGtVSPPPGT	9606	BTO:0000007								34511598	t		miannu	The MAP4K4 and MLK3 associates with each other, and MAP4K4 phosphorylates MLK3 on Thr738 and increases MLK3 kinase activity and downstream signaling.	SIGNOR-277571	0.309
3-[8-amino-1-(2-phenyl-7-quinolinyl)-3-imidazo[1,5-a]pyrazinyl]-1-methyl-1-cyclobutanol	chemical	CHEBI:91402	ChEBI	IGF1R	protein	P08069	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193675	0.8
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH9	protein	Q9ULB4	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265849	0.8
PCSK6	protein	P29122	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000666								25527501	t		Giorgia	Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation.	SIGNOR-260366	0.2
CCL2	protein	P13500	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606									32446778	f		Luana	In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatory response. 	SIGNOR-261317	0.7
KIT	protein	P10721	UNIPROT	SLA	protein	Q13239	UNIPROT	down-regulates activity	phosphorylation	Tyr120	SETKKGFySLSVRHR	9534									24284075	t		miannu	Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity	SIGNOR-263140	0.2
PRKACA	protein	P17612	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates	phosphorylation			9606									17419683	t		gcesareni	In vertebrates,pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation	SIGNOR-154276	0.445
UBA52	protein	P62987	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262459	0.799
HOPX	protein	Q9BPY8	UNIPROT	FLG	protein	P20930	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000667								21256618	f		miannu	 In the present study, we performed transcriptional profiling of cultured primary human keratinocytes and noted a robust induction of HOP upon calcium-induced cell differentiation. Overexpression of HOP using a lentiviral vector up-regulated FLG and LOR expression during keratinocyte differentiation. 	SIGNOR-254463	0.2
PIK-90	chemical	CID:6857685	PUBCHEM	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206223	0.8
CSNK1A1	protein	P48729	UNIPROT	CDK5	protein	Q00535	UNIPROT	up-regulates activity	phosphorylation	Ser159	GIPVRCYsAEVVTLW	-1									10500146	t		miannu	We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro. Ser(159) in cdk5 is homologous to the regulatory Thr(160) in cdk2.	SIGNOR-275966	0.303
SRC	protein	P12931	UNIPROT	PRKCI	protein	P41743	UNIPROT	up-regulates	phosphorylation	Tyr265	RVIGRGSyAKVLLVR	9606									11713277	t		llicata	Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain.	SIGNOR-111920	0.512
AKT1	protein	P31749	UNIPROT	BMI1	protein	P35226	UNIPROT	up-regulates activity	phosphorylation	Ser316	ANRPRKSsVNGSSAT										22505453	t		lperfetto	The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate	SIGNOR-252559	0.45
IFNB1	protein	P01574	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates				9606									10918594	f		gcesareni	Early events in type i ifn signaling are tyrosine phosphorylation of the type i ifn receptor subunits (ifnar1 and ifnar2), and the activation of the receptor-associated tyk-2 and jak-1 janus kinases	SIGNOR-80100	0.522
TRPM6	protein	Q9BX84	UNIPROT	TRPM6	protein	Q9BX84	UNIPROT	down-regulates activity	phosphorylation	Thr1851	FNQVKPQtIPYTPRF	9606									18258429	t		Manara	Autophosphorylation of Threonine1851 in the Kinase Domain Is Essential for the Inhibitory Effect of RACK1	SIGNOR-260922	0.2
MAPK1	protein	P28482	UNIPROT	AEBP1	protein	Q8IUX7	UNIPROT	up-regulates activity	phosphorylation	Thr621	GEPEFRYtAGIHGNE	10090	BTO:0000944								15654748	t		miannu	We show that DNA binding by AEBP1 requires both the N- and C-terminal domains of AEBP1, and MAPK interaction with AEBP1 (through its N terminus) results in enhanced DNA binding. A threonine at position 623 within the C-terminal domain of AEBP1 plays an important role in DNA binding by AEBP1, because the mutation results in decreased DNA binding by AEBP1, which leads to a decrease in the transcriptional repression ability of AEBP1. We also show that in vitro phosphorylation of AEBP1 by MAPK is greatly reduced upon mutation of T623. These results suggest that MAPK regulates the transcriptional activity of AEBP1 by a novel dual mechanism, in which MAPK interaction enhances and subsequent phosphorylation decreases the DNA-binding ability of AEBP1.	SIGNOR-262897	0.2
CAPN1	protein	P07384	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000590								25969760	t		lperfetto	Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase	SIGNOR-251586	0.301
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			9534	BTO:0000298				phosphorylation:Tyr177				8402896	t		gcesareni	BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation	SIGNOR-248199	0.2
RAPGEF5	protein	Q92565	UNIPROT	RAP1A	protein	P62834	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								21791615	t		miannu	We found here that cAMP-dependent activation of Epac1 and Rap1 but not PKA is able to activate CaMKI to mediate Ser47 (S47) phosphorylation in GCM1. Epac1 and Epac2 proteins were identified as cAMP-binding proteins with guanine nucleotide exchange factor (GEF) activities for the small GTPases, Rap1 and Rap2	SIGNOR-262682	0.638
N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide	chemical	CHEBI:91439	ChEBI	TBK1	protein	Q9UHD2	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190795	0.8
lysophosphatidic acids	smallmolecule	CHEBI:32957	ChEBI	LATS2	protein	Q9NRM7	UNIPROT	down-regulates				10090	BTO:0002572								22863277	f		milica	Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2.	SIGNOR-198520	0.8
RCOR1	protein	Q9UKL0	UNIPROT	BHC complex	complex	SIGNOR-C353	SIGNOR	form complex	binding			9606	BTO:0000567; BTO:0000007								15325272	t		miannu	BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells	SIGNOR-264498	0.823
PTPRF	protein	P10586	UNIPROT	DAPK1	protein	P53355	UNIPROT	up-regulates	dephosphorylation	Tyr490	HCAAWHGyYSVAKAL	9606									17803936	t		gcesareni	Here, we show that the leukocyte common antigen-related (lar) tyrosine phosphatase dephosphorylates dapk at py491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of dapk.	SIGNOR-157702	0.2
SRGAP3	protein	O43295	UNIPROT	WASF1	protein	Q92558	UNIPROT	up-regulates	binding			9606									12447388	t		miannu	Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo.	SIGNOR-95967	0.57
GNAI1	protein	P63096	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	down-regulates				9606									23994464	f		apalma	The G alpha I subunit inhibits adenylyl cyclase activity and therefore reduces cytoplasmic cAMP levels	SIGNOR-255008	0.8
WNT11	protein	O96014	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates activity	binding			9606	BTO:0000551;BTO:0000848								16273260	t		gcesareni	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-141428	0.643
SNAI1	protein	O95863	UNIPROT	PLAU	protein	P00749	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19055748	f		lperfetto	We demonstrated by both cDNA microarrays and real-time quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts.	SIGNOR-252263	0.327
PRDM1	protein	O75626	UNIPROT	PAX5	protein	Q02548	UNIPROT	down-regulates quantity	transcriptional regulation			10090									12052884	t		Gianni	Blimp-1 binds a site on the Pax-5 promoter in vitro and in vivo and represses the Pax-5 promoter in a binding-site-dependent manner.	SIGNOR-269089	0.518
RPS18	protein	P62269	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262433	0.881
DPM complex	complex	SIGNOR-C289	SIGNOR	dolichyl beta-D-mannosyl phosphate	smallmolecule	CHEBI:17624	ChEBI	up-regulates quantity	chemical modification			9606									10835346	t		lperfetto	Dolichol-phosphate-mannose (DPM) synthase generates mannosyl donors for glycosylphosphatidylinositols, N-glycan and protein O- and C-mannosylation.	SIGNOR-262566	0.8
XAF1	protein	Q6GPH4	UNIPROT	XIAP	protein	P98170	UNIPROT	down-regulates	binding			9606									17613533	t		gcesareni	Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3.	SIGNOR-155637	0.576
ULK1	protein	O75385	UNIPROT	PRKAG3	protein	Q9UGI9	UNIPROT	down-regulates	phosphorylation			9606				SIGNOR-C15					21460634	t		gcesareni	Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity phosphorylation of ampk by ulk1 represents a negative feedback circuit.	SIGNOR-173053	0.38
HCRT	protein	O43612	UNIPROT	HCRTR2	protein	O43614	UNIPROT	up-regulates	binding			9606									9491897	t		gcesareni	Identification and initial biological characterization of two orexins as well as their two receptors	SIGNOR-55848	0.768
SLC25A12	protein	O75746	UNIPROT	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	down-regulates quantity	relocalization			9606									12084073	t		miannu	Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. 	SIGNOR-265154	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	RANBP3	protein	Q9H6Z4	UNIPROT	unknown	phosphorylation	Ser126	VKRERTSsLTQFPPS	9606									18280241	t		llicata	Akt regulates ranbp3 phosphorylation in vitro and in vivo	SIGNOR-160900	0.2
IKBKB	protein	O14920	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	down-regulates activity	phosphorylation	Ser418	TTENRFHsLPFSLTK	9606	BTO:0000938								24614225	t		lperfetto	Thus, serine 418 is phosphorylated in vivo.Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204716	0.529
SMURF1	protein	Q9HCE7	UNIPROT	SMAD9	protein	O15198	UNIPROT	down-regulates	ubiquitination			9606									22298955	t		gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-195669	0.656
IL1B	protein	P01584	UNIPROT	DIO	proteinfamily	SIGNOR-PF83	SIGNOR	down-regulates quantity by repression	transcriptional regulation			10116									9397972	f	inferred from family member	scontino	From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y.	SIGNOR-270241	0.2
AKT1	protein	P31749	UNIPROT	SP7	protein	Q8TDD2	UNIPROT	up-regulates	phosphorylation			9606									21619873	t		gcesareni	Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5	SIGNOR-252514	0.435
ABCA7	protein	Q8IZY2	UNIPROT	APOA1	protein	P02647	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								12917409	t		miannu	ATP-binding cassette transporter A7 (ABCA7) binds apolipoprotein A-I and mediates cellular phospholipid but not cholesterol efflux. HEK293 cells overexpressing ABCA7 showed specific binding and cross-linking of lipid-poor apoA-I. ABCA7 expression increased cellular phosphatidylcholine and sphingomyelin efflux to apoA-I in a manner similar to ABCA1 but had no effect on cholesterol efflux.	SIGNOR-265178	0.449
AKT1	protein	P31749	UNIPROT	CARD11	protein	Q9BXL7	UNIPROT	up-regulates activity	phosphorylation	Ser644	NLMFRKFsLERPFRP	-1									24548923	t		miannu	Akt phosphorylates S637 and S645 in the linker region of Carma1 	SIGNOR-276621	0.538
BGJ-398	chemical	CHEBI:63451	ChEBI	FGFR1	protein	P11362	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190263	0.8
CSNK1A1	protein	P48729	UNIPROT	GLI2	protein	P10070	UNIPROT	down-regulates	phosphorylation			9606									16611981	t		gcesareni	Gli2 can also be phosphorylated directly by ck-1 at the non-optimal sites	SIGNOR-146112	0.549
GATA1	protein	P15976	UNIPROT	CBFB	protein	Q13951	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0004475								19825991	f	 	miannu	Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors. 	SIGNOR-254190	0.491
doxorubicin	chemical	CHEBI:28748	ChEBI	TOP2A	protein	P11388	UNIPROT	down-regulates activity	chemical inhibition			9606									19377506	t			An important reason why Top2 has held the interest of researchers studying cancer was the discovery that active anti-cancer drugs, notably etoposide and doxorubicin target Top2	SIGNOR-261911	0.8
ADAM10	protein	O14672	UNIPROT	CD44	protein	P16070	UNIPROT	up-regulates activity	cleavage			9606									26284334	t		miannu	The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. 	SIGNOR-259847	0.354
AKT1	protein	P31749	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser106	PLNSVSPsPLMLLHP	9606									11108261	t		lperfetto	Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt.	SIGNOR-84967	0.757
CASP8	protein	Q14790	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									14585074	f		amattioni	Downstream of caspase-8 activation, apoptosis induction takes place	SIGNOR-256639	0.7
CTNNB1	protein	P35222	UNIPROT	α-Catenin	proteinfamily	SIGNOR-PF72	SIGNOR	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265813	0.923
CHUK	protein	O15111	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	phosphorylation	Ser536	SGDEDFSsIADMDFS	9606	BTO:0000567		SIGNOR-C14	SIGNOR-C13					10521409	t		lperfetto	Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta.	SIGNOR-71270	0.841
CDK1	protein	P06493	UNIPROT	CSNK2A1	protein	P68400	UNIPROT	up-regulates	phosphorylation	Ser362	ISSVPTPsPLGPLAG	9606	BTO:0000527								19941816	t		gcesareni	The mitotic phosphorylation sites on the alpha subunit of casein kinase ii can be phosphorylated in vitro by p34cdc2.	SIGNOR-161839	0.361
ERBB4	protein	Q15303	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			9606									16729043	t		gcesareni	Egfr and erbb4 had several docking sites for grb2, while erbb3 was characterized by six binding sites for pi3k. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength.	SIGNOR-146876	0.823
SF3A3	protein	Q12874	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270663	0.736
D-serine	smallmolecule	CHEBI:16523	ChEBI	NMDA receptor_2A	complex	SIGNOR-C347	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0002609								12393813	t		lperfetto	D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically 	SIGNOR-268277	0.8
NFAT5	protein	O94916	UNIPROT	LCN2	protein	P80188	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000815								22266867	t	done	miannu	 As expected, the depletion of NFAT5 decreased the S100A4 and LCN2 mRNA levels (Figure 3a). In addition, chromatin immunoprecipitation (ChIP) assay using NFAT5 antibody indicated that NFAT5 was bound to the S100A4 and LCN2 promoters (Figure 3b, Supplementary Figure S3), as expected (Chen et al., 2009).	SIGNOR-274114	0.334
Succinyl-CoA ATP variant	complex	SIGNOR-C398	SIGNOR	succinyl-CoA(5-)	smallmolecule	CHEBI:57292	ChEBI	down-regulates quantity	chemical modification			9606									27487822	t		miannu	In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions.	SIGNOR-266267	0.8
HOXA11	protein	P31270	UNIPROT	PRL	protein	P01236	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003697								19727442	t		Luana	HoxA-11 enhanced upregulation of PRL only in differentiated cells.	SIGNOR-261630	0.359
APBA1	protein	Q02410	UNIPROT	STXBP1	protein	P61764	UNIPROT	up-regulates activity	binding			10116									9395480	t		miannu	Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1.	SIGNOR-264035	0.689
Angiotensin-2	protein	P01019-PRO_0000032458	UNIPROT	AGTR2	protein	P50052	UNIPROT	up-regulates activity	binding			9606									32201502	t		MIANNU	Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways	SIGNOR-260237	0.2
CD28	protein	P10747	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606	BTO:0000782								18006698	t		gcesareni	Cd28 can bind directly to pi3k by a well-characterized ymnm binding motif in its cytoplasmic domain.	SIGNOR-159322	0.376
G3BP1	protein	Q13283	UNIPROT	Stress_granules	phenotype	SIGNOR-PH124	SIGNOR	up-regulates				9606	BTO:0002181								23279204	f		SARA	G3BP1 and G3BP2 form homo‐ and hetero‐multimers to induce SGs	SIGNOR-260984	0.7
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGA6	protein	Q9Y5G7	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265716	0.2
SF1	protein	Q15637	UNIPROT	FUS	protein	P35637	UNIPROT	down-regulates	binding			9606									9660765	t		miannu	We speculate that zfm1 may inhibit transcription driven by the ntds of tls	SIGNOR-58967	0.54
FOXA1	protein	P55317	UNIPROT	SFTPB	protein	P07988	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12161428	f	 	miannu	 A homeodomain and a forkhead transcription factor, NKX2.1 and HNF-3, respectively, are known activators of Sp-B transcription	SIGNOR-254181	0.287
NOTCH1	protein	P46531	UNIPROT	IL7R	protein	P16871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								22577461	f		miannu	E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r.	SIGNOR-197452	0.328
PPP2CA	protein	P67775	UNIPROT	MKNK1	protein	Q9BUB5	UNIPROT	down-regulates	dephosphorylation	Thr255	ITTPELTtPCGSAEY	9606									20927323	t		gcesareni	Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e.	SIGNOR-168314	0.492
PELI3	protein	Q8N2H9	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates				9606									12874243	f		gcesareni	Pellino3 leads to activation of c-jun and elk-1, but not nf-kappab.	SIGNOR-103986	0.2
ER stress	stimulus	SIGNOR-ST9	SIGNOR	ERN1	protein	O75460	UNIPROT	up-regulates				9606									18065414	f		miannu	Our findings suggest that MTHFR is up-regulated by ER stress and that this effect is mediated by IRE1 and c-Jun.	SIGNOR-253145	0.7
CEP135	protein	Q66GS9	UNIPROT	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	up-regulates activity	binding			-1									27477386	t		miannu	Here, we analyzed in detail the microtubule-binding activity of human CEP135 (HsCEP135).  Biochemical, cryo-electron, and fluorescence microscopy analyses revealed that in vitro HsCEP135-N interacts with tubulin, protofilaments, and microtubules and induces the formation of microtubule bundles	SIGNOR-269678	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	relocalization			10090	BTO:0002572								18423396	t		lperfetto	Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation	SIGNOR-252837	0.908
CAMK2B	protein	Q13554	UNIPROT	RETREG1	protein	Q9H6L5	UNIPROT	up-regulates activity	phosphorylation	Ser151	AQLWRSLsESWEVIN	-1									31930741	t		miannu	Under ER-stress conditions, activated CAMK2B phosphorylates the reticulon-homology domain of FAM134B, which enhances FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand for ER-phagy. 	SIGNOR-273554	0.2
CDK1	protein	P06493	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Thr130	PAQLLCStPNGLDRG	9606			SIGNOR-C17						10864927	t		gcesareni	Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b.	SIGNOR-78424	0.853
AMOTL2	protein	Q9Y2J4	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates				9606	BTO:0001176								21937427	f		lperfetto	 Taking together, our data indicate that Amotl2 plays a pivotal role in polarity, migration and proliferation of angiogenic endothelial cells.	SIGNOR-271871	0.7
PI-103	chemical	CHEBI:90524	ChEBI	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206169	0.8
NPFFR1	protein	Q9GZQ6	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257103	0.254
RPL34	protein	P49207	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262467	0.831
CDK8	protein	P49336	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates	phosphorylation			9606									15546612	t		gcesareni	Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.	SIGNOR-254312	0.534
MAPK3	protein	P27361	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									12110590	t		gcesareni	Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway.	SIGNOR-90529	0.728
CDK12	protein	Q9NYV4	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1868	SPTSPKYsPTSPKYS	9606									22012619	t		miannu	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176797	0.775
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	AGAP2	protein	Q99490	UNIPROT	up-regulates	phosphorylation	Ser985	THLSRVRsLDLDDWP	9606	BTO:0001130								19176382	t		lperfetto	In addition, we have found that activated akt can bind and phosphorylate ggap2 at serine 629, which enhances gtp binding by ggap2.	SIGNOR-244132	0.2
CDK2	protein	P24941	UNIPROT	PTPN12	protein	Q05209	UNIPROT	down-regulates activity	phosphorylation	Ser19	QRVQAMKsPDHNGED	9606	BTO:0000815								28842430	t		miannu	In the present study, we found that S19 site phosphorylation of PTPN12 by CDK2 discharged its antitumor activity by down-regulation of its inhibitory role in cell migration, but not affecting its other regulatory functions.	SIGNOR-277366	0.391
MDH2	protein	P40926	UNIPROT	(S)-malate(2-)	smallmolecule	CHEBI:15589	ChEBI	down-regulates quantity	chemical modification			9606									24068518	t		miannu	Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle	SIGNOR-266284	0.8
PRKCA	protein	P17252	UNIPROT	KCNMA1	protein	Q12791	UNIPROT	up-regulates	phosphorylation	Ser1200	SHSSQSSsKKSSSVH	9606									19592459	t		gcesareni	Results showed that mutating s1076 altered the effect of pkc activation on bk(ca) channels in hek-293 cells	SIGNOR-186755	0.2
SMAD5	protein	Q99717	UNIPROT	SATB2	protein	Q9UPW6	UNIPROT	up-regulates quantity	transcriptional regulation			10090									22219353	t		Gianni	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268939	0.262
AARS1	protein	P49588	UNIPROT	tRNA(Ala)	smallmolecule	CHEBI:29170	ChEBI	down-regulates quantity	chemical modification			9606									32314272	t		miannu	Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N).	SIGNOR-270445	0.8
GSK690693	chemical	CHEBI:90677	ChEBI	AKT1	protein	P31749	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252462	0.8
MUC12	protein	Q9UKN1	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity	binding			9606	BTO:0000037								32596961	t		miannu	MUC12 promoted the recruitment of c-Jun on the promoter of TGF-β1, leading to its transcription.	SIGNOR-265474	0.259
HECW2	protein	Q9P2P5	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	binding			9606	BTO:0000093								27119228	t		miannu	NEDL2 acts as a scaffold protein to promote GDNF-stimulated Akt activation. biochemical analysis indicated that NEDL2 appears to act like a scaffold protein to recruit SHC, Grb2, PI3K (p110 and p85), PDK1 and Akt together to promote the signaling transduction. NEDL2 binds p85, p110 and Akt with different domains	SIGNOR-269459	0.2
EIF1	protein	P41567	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	down-regulates activity				9606									14600024	f		lperfetto	Binding of eIF1 to the 40S subunit would block access of the 60S	SIGNOR-269144	0.263
EXOC6B	protein	Q9Y2D4	UNIPROT	Exocyst_EXOC6B variant	complex	SIGNOR-C491	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270781	0.751
GSK1059615	chemical	CHEBI:71955	ChEBI	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192777	0.8
MTOR	protein	P42345	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	up-regulates													29789464	f		Luana	The mTOR complexes are essential to neurogenesis and the establishment of neural circuits. | Activation of mTOR complexes exerts profound effects on all the processes of neurogenesis, including dendrite formation.	SIGNOR-265771	0.7
BBC3	protein	Q9BXH1	UNIPROT	BAK1	protein	Q16611	UNIPROT	up-regulates	binding			9606									22492984	t		gcesareni	Bim, and puma bind with high affinity to all pro-survival proteins	SIGNOR-196929	0.392
1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	PRKCA	protein	P17252	UNIPROT	up-regulates	binding			9606									12954613	t	PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine.	gcesareni	C1a domain is critical for the dag-induced activation of pkcalfa.Furthermore, calcium and diacylglycerol activate protein kinase c, resulting in the phosphorylation of a large variety of substrates.	SIGNOR-100254	0.8
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	PER2	protein	O15055	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									17876059	t		miannu	Here, the authors show that the F-box protein beta-transducin repeat containing protein 1 (beta-TrCP1) as part of the E3 ubiquitin ligase complex is an essential component of the mammalian circadian oscillator. Down-regulation of endogenous beta-TrCP1 as well as expression of a dominant-negative form both result in lengthening of the circadian period in oscillating fibroblasts. These phenotypes are due to an impaired degradation of PERIOD (PER) proteins, since expression of beta-TrCP interaction-deficient PER2 variants--but not wild-type PER2--results in a dramatic stabilization of PER2 protein as well as in the disruption of circadian rhythmicity. 	SIGNOR-268055	0.466
AGTR1	protein	P30556	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606									11313903	t		gcesareni	These neuropeptide gpcrs are coupled to the activation of phospholipase c, and therefore to calcium ele- vation and protein kinase c (pkc) activation, through g proteins of the alfaq family.	SIGNOR-106932	0.628
XL147	chemical	CHEBI:71957	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252659	0.8
PIAS1	protein	O75925	UNIPROT	STAT1	protein	P42224	UNIPROT	down-regulates	binding			9606									14699505	t		gcesareni	Pias1 inhibits binding of stat1 dimers to the response elements in the promoters of target genes	SIGNOR-120548	0.786
GRK6	protein	P43250	UNIPROT	SLC9A3R1	protein	O14745	UNIPROT	down-regulates activity	phosphorylation	Ser290	PALVRSAsSDTSEEL	9606									10446210	t			GRK6A phosphorylates NHERF on Ser289, the primary site of constitutive phosphorylation of NHERF in HEK-293 cells. The interaction of NHERF and NHE3 is mediated by the region of NHERF encompassing the second PDZ domain and the tail (25), and it is therefore reasonable that phosphorylation of the serine-rich stretch in the center of this region (including Ser289) might affect the physical interaction of NHERF with NHE3.	SIGNOR-251214	0.414
Avasimibe	chemical	CID:166558	PUBCHEM	SOAT1	protein	P35610	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190119	0.8
PXN	protein	P49023	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity				9606	BTO:0000182				phosphorylation:Tyr88	PQSSSPVyGSSAKTS			27447856	f		lperfetto	Together, our data suggest that phosphorylation of paxillin Y88 activates AKT through the paxillin-p130Cas-p85/PI3K-AKT signaling axis and promotes colorectal tumorigenesis	SIGNOR-263979	0.917
EEF1A1	protein	P68104	UNIPROT	Met-tRNA(Met)	chemical	CHEBI:16635	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269504	0.8
IFNL2	protein	Q8IZJ0	UNIPROT	IL10RB	protein	Q08334	UNIPROT	up-regulates	binding			9606									12469119	t		gcesareni	Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.	SIGNOR-96209	0.686
MSH2/MSH6	complex	SIGNOR-C60	SIGNOR	BLM	protein	P54132	UNIPROT	up-regulates	binding			9606									15064730	t		lperfetto	We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro	SIGNOR-217223	0.61
MAPK8	protein	P45983	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser312	TESITATsPASMVGG	10116	BTO:0004428								12510059	t		lperfetto	Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylationOne of the specific Ser phosphorylation sites in IRS-1 that has been proposed to negatively modulate the insulin signal is Ser312 (numbered according to the human sequence). Prior studies have demonstrated that IRS-1 associates with and is phosphorylated by JNK in vitro on Ser312	SIGNOR-236591	0.767
PTPRG	protein	P23470	UNIPROT	ITGAL	protein	P20701	UNIPROT	down-regulates activity				9606									25624455	f		miannu	PTPRG activation inhibits chemoattractantinduced LFA-1 affinity triggering and mediated adhesion in human primary monocytes. we show that PTPRG is a novel negative regulator of LFA-1 high-affinity-state triggering and mediated arrest by chemoattractants in human primary monocytes. Notably, PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role (37). In our context, SRC appears inhibited by PTPRG activation (Table I), thus making it unlikely that the antiadhesive effect of PTPRG is mediated by SRC activation.	SIGNOR-254736	0.2
EEF1A2	protein	Q05639	UNIPROT	Phe-tRNA(Phe)	smallmolecule	CHEBI:29153	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269540	0.8
ABI1	protein	Q8IZP0	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	binding			9606									17395426	t		gcesareni	Here we uncover a novel interaction between abi-1 and the cbl ubiquitin ligase and show that abi-1 mediates cbl accumulation to the plasma membrane upon stimulation by egf.	SIGNOR-154162	0.379
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT8A	protein	Q9H1J5	UNIPROT	down-regulates activity				9606	BTO:0000815								21113658	f		lperfetto	For example, SOSTDC1 decreases Wnt signaling by impeding the binding of Wnt8 to the LRP6 receptor	SIGNOR-242742	0.381
ERBB3	protein	P21860	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			9606									14967450	t		gcesareni	All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor. In this study, we identify grb2 as a specific binding partner to tyrosines y1199 and y1268 of erbb3.	SIGNOR-121971	0.832
VARS1	protein	P26640	UNIPROT	Val-tRNA(Val)	smallmolecule	CHEBI:29164	ChEBI	up-regulates quantity	chemical modification			9606									30755602	t		miannu	Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 	SIGNOR-270530	0.8
CABIN1	protein	Q9Y6J0	UNIPROT	MEF2A	protein	Q02078	UNIPROT	down-regulates				9606									17172641	f		gcesareni	Thus, cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress mef2 transcriptional activity.	SIGNOR-151202	0.666
TNFRSF17	protein	Q02223	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates				9606									10903733	f		miannu	Overexpression of bcma activates jnk	SIGNOR-79507	0.2
CERK	protein	Q8TCT0	UNIPROT	ceramide	smallmolecule	CHEBI:17761	ChEBI	down-regulates quantity	chemical modification			9606									34202192	t		miannu	Another relevant enzyme is Ceramide kinase (CerK), which phosphorylates Cer to produce Ceramide 1-phosphate (C1P). 	SIGNOR-268500	0.8
MAPK14	protein	Q16539	UNIPROT	MKNK1	protein	Q9BUB5	UNIPROT	up-regulates activity	phosphorylation			-1									9155018	t			These results indicate that MNK1 is a novel class of protein kinase that is activated through both the ERK and p38 MAP kinase signaling pathways	SIGNOR-253011	0.656
PRKCA	protein	P17252	UNIPROT	F11R	protein	Q9Y624	UNIPROT	unknown	phosphorylation	Ser284	KVIYSQPsARSEGEF	9606	BTO:0000130;BTO:0000876								11027562	t		gcesareni	We also demonstrated phosphorylation of ser 284, a putative pkc phosphorylation site, by immunoblotting with anti-phosphoserine-jam antibody in thrombin-stimulated platelets.	SIGNOR-83037	0.327
SDHD	protein	O14521	UNIPROT	Mitochondrial respiratory chain complex II	complex	SIGNOR-C278	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites	SIGNOR-262187	0.925
TIMM29	protein	Q9BSF4	UNIPROT	TIM22 complex	complex	SIGNOR-C424	SIGNOR	form complex	binding			9606	BTO:0000007								32901109	t		lperfetto	Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK).	SIGNOR-267707	0.2
BCL7A	protein	Q4VC05	UNIPROT	Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	form complex	binding			10090	BTO:0001086								19279220	t		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270723	0.514
PGR	protein	P06401	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	binding			9606	BTO:0000150								12612073	t		gcesareni	Here we identify two domains of prb, erid-i and -ii, mediating a direct interaction with the ligand-binding domain of eralpha.	SIGNOR-98807	0.607
NR0B2	protein	Q15466	UNIPROT	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									17909097	f	inferred from family member	gcesareni	As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells	SIGNOR-267791	0.2
TBX1	protein	O43435	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001176								20439995	f	Regulation of expression	miannu	Tbx1 plays a critical role in lymphatic vessel development and regulates the expression of Vegfr3, a gene that is essential for lymphangiogenesis. Tbx1 activates Vegfr3 transcription in endothelial cells (ECs) by binding to an enhancer element in the Vegfr3 gene.	SIGNOR-251869	0.313
CCND1	protein	P24385	UNIPROT	CDK4	protein	P11802	UNIPROT	up-regulates	binding			9606	BTO:0000150								23562856	t		gcesareni	D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb,	SIGNOR-201666	0.964
lidocaine	chemical	CHEBI:6456	ChEBI	SCN5A	protein	Q14524	UNIPROT	down-regulates activity	chemical inhibition			8355	BTO:0000964								8786356	t		miannu	Surprisingly, hH1-beta 1 Na channels were threefold more sensitive to rested-state block by lidocaine (402 +/- 36 microM, n = 4-22) than were mu 1-beta 1 Na channels (1,168 +/- 34 microM, n = 7-19). 	SIGNOR-258499	0.8
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate	smallmolecule	CHEBI:18348	ChEBI	1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	up-regulates quantity	precursor of			9606									23000145	t		scontino	Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).	SIGNOR-268451	0.8
SYN1	protein	P17600	UNIPROT	RAB3A	protein	P20336	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								15265865	t		miannu	Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. The interaction between synapsin I and Rab3A was confirmed by photoaffinity labeling experiments on purified synaptic vesicles and by the formation of a chemically cross-linked complex between synapsin I and Rab3A in intact nerve terminals. The data indicate that synapsin I is a novel Rab3 interactor on synaptic vesicles and suggest that the synapsin-Rab3 interaction may participate in the regulation of synaptic vesicle trafficking within the nerve terminals.	SIGNOR-269181	0.601
CEBPB	protein	P17676	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates				10090	BTO:0000011								25451943	f		gcesareni	Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) β plays an essential role.	SIGNOR-238297	0.7
PTK2	protein	Q05397	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr407	IIDEEDTyTMPSTRD	9606		BTO:0000671							15694384	t		llicata	Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925.	SIGNOR-133837	0.2
TIMP1	protein	P01033	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	down-regulates													17326328	f		lperfetto	There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3	SIGNOR-252272	0.7
PDGFRB	protein	P09619	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	phosphorylation	Tyr419	RLIEDNEyTARQGAK	9606	BTO:0002057								15489898	t		gcesareni	The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells.	SIGNOR-247979	0.587
MAPK14	protein	Q16539	UNIPROT	TWIST1	protein	Q15672	UNIPROT	up-regulates	phosphorylation	Ser68	GGGDEPGsPAQGKRG	9606	BTO:0000150								21502402	t		llicata	Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro	SIGNOR-173409	0.273
FBXW11	protein	Q9UKB1	UNIPROT	PER1	protein	O15534	UNIPROT	down-regulates	ubiquitination			9606									15917223	t		miannu	We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1	SIGNOR-137758	0.482
MZF1	protein	P28698	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26010542	t		irozzo	The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCα gene transcription activity.	SIGNOR-256337	0.394
ATM	protein	Q13315	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	up-regulates	phosphorylation	Ser831	EPVEQDSsQPSLPLV	9606									22621922	t		gcesareni	Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm.	SIGNOR-197615	0.869
TRIM33	protein	Q9UPN9	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	binding			9606	BTO:0000574;BTO:0002625;BTO:0000414								16751102	t		lperfetto	The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. Tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses.	SIGNOR-236060	0.567
3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide	chemical	CHEBI:131156	ChEBI	CHEK2	protein	O96017	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190206	0.8
CDKN1A	protein	P38936	UNIPROT	CCNB1	protein	P14635	UNIPROT	down-regulates	binding			9606									19158493	t		gcesareni	P21-mediated degradation of cyclin b1 in response to dna damage is necessary for the maintenance of g2 cell cycle arrest.	SIGNOR-183498	0.823
aspartic acid	smallmolecule	CHEBI:22660	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264754	0.7
CHRM4	protein	P08173	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256686	0.43
FGF2	protein	P09038	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates				9606									20974802	f	inferred from 70% of family members	gcesareni	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription.	SIGNOR-269929	0.599
LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates activity	phosphorylation	Ser89	AQHVRSHsSPASLQL	9606									22658639	t		miannu	In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus.	SIGNOR-256187	0.2
UHMK1	protein	Q8TAS1	UNIPROT	SYN1	protein	P17600	UNIPROT	unknown	phosphorylation	Ser438	GSHGQTPsPGALPLG	9606									10880969	t		lperfetto	We also identified a tryptic peptide of synapsin i phosphorylated by kis	SIGNOR-78899	0.381
LYN	protein	P07948	UNIPROT	BCR-Ml	complex	SIGNOR-C434	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000776								32323266	t		scontino	The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases.	SIGNOR-268209	0.697
TRAF2	protein	Q12933	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	ubiquitination	Lys377	NEPSLQSkLQDEANY	9606									9712898	t		lperfetto	Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2.	SIGNOR-59689	0.891
GSK3A	protein	P49840	UNIPROT	PPARA	protein	Q07869	UNIPROT	up-regulates activity	phosphorylation	Ser280	FHCCQCTsVETVTEL	10116	BTO:0003324								30745182	t		miannu	Fatty acids (FAs) upregulate GSK-3α, which phosphorylates PPARα at Ser280 in the ligand-binding domain (LBD). This modification ligand independently enhances transcription of a subset of PPARα targets, selectively stimulating FA uptake and storage, but not oxidation, thereby promoting lipid accumulation. 	SIGNOR-277431	0.2
N-[(4-chlorophenyl)methyl]-2-[(2R,6S)-5,12-dioxo-2-phenyl-1-oxa-4-azacyclododec-8-en-6-yl]acetamide	chemical	CHEBI:94175	ChEBI	SHH	protein	Q15465	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0001253							19151731	t		gcesareni	More recently, robotnikinin was identified as a compound that binds to shh and blocks its ability to induce pathway activity at the level of ptch.	SIGNOR-183465	0.8
YAP1	protein	P46937	UNIPROT	CCNA2	protein	P20248	UNIPROT	up-regulates quantity by expression	transcriptional regulation					BTO:0001939							30224758	f		lperfetto	 By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 	SIGNOR-276563	0.33
FOXE1	protein	O00358	UNIPROT	TPO	protein	P07202	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001073							27347897	t		scontino	TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8	SIGNOR-267279	0.392
CDK1	protein	P06493	UNIPROT	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr237	KQEKTPKtPKGPSSV	9606			SIGNOR-C17						12058066	t		gcesareni	Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association.	SIGNOR-89601	0.534
SRC	protein	P12931	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	up-regulates	phosphorylation			9606									12645577	t		lperfetto	These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation.	SIGNOR-217439	0.384
EXOC7	protein	Q9UPT5	UNIPROT	Exocyst_EXOC6B variant	complex	SIGNOR-C491	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270782	0.914
HDAC1	protein	Q13547	UNIPROT	RELN	protein	P78509	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19029285	f		miannu	 induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. 	SIGNOR-254577	0.282
sphingosine 1-phosphate(1-)	smallmolecule	CHEBI:60119	ChEBI	S1PR1	protein	P21453	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257577	0.8
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1735	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273068	0.636
PAK1	protein	Q13153	UNIPROT	SNAI1	protein	O95863	UNIPROT	up-regulates	phosphorylation	Ser246	QACARTFsRMSLLHK	9606	BTO:0000150								15833848	t		lperfetto	Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions.	SIGNOR-135605	0.411
CASP1	protein	P29466	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	cleavage	Asp329	EMEEDSYdSFGEPSY	-1									10069390	t		lperfetto	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261748	0.325
ATG3	protein	Q9NT62	UNIPROT	GABARAPL2	protein	P60520	UNIPROT	up-regulates activity	binding			-1									16303767	t		lperfetto	Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme)	SIGNOR-141926	0.869
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	USP14	protein	P54578	UNIPROT	up-regulates activity	phosphorylation	Ser432	THQGRSSsSGHYVSW	9606	BTO:0000007								26523394	t		lperfetto	Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt.	SIGNOR-265055	0.2
nifedipine	chemical	CHEBI:7565	ChEBI	NR1I2	protein	O75469	UNIPROT	up-regulates activity	chemical activation			9606									9770465	t		miannu	In addition to rifampicin, other known inducers of human CYP3A4 expression, including nifedipine and clotrimazole, also activated hPAR.	SIGNOR-259066	0.8
MRE11/RAD50/NBS1	complex	SIGNOR-C147	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates													17713585	f		lperfetto	The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs).|Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein--nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB.	SIGNOR-251502	0.7
GIT1	protein	Q9Y2X7	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001260							14523024	t		gcesareni	Git1 interaction with plcgamma is required for plcgamma activation based on inhibition of tyrosine phosphorylation	SIGNOR-118454	0.537
S3I-201	chemical	CHEBI:91224	ChEBI	STAT3	protein	P40763	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194847	0.8
BTRC	protein	Q9Y297	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	ubiquitination			9606									11359933	t		gcesareni	An e3 ubiquitin ligase complex roc1-scffbw1a consisting of roc1, skp1, cullin1, and fbw1a (also termed trcp1) induces ubiquitination of smad3.	SIGNOR-108237	0.397
RELA	protein	Q04206	UNIPROT	BCL2A1	protein	Q16548	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								10049356	f		gcesareni	Here we show thata1,abcl-2homolog up-regulated in primary lymphocytes by different mitogens, represents a novel class of rel/nf-kb-regulated prosurvival genes.	SIGNOR-65020	0.5
MAP2K5	protein	Q13163	UNIPROT	MAPK7	protein	Q13164	UNIPROT	up-regulates activity	phosphorylation	Thr219	AEHQYFMtEYVATRW	9606	BTO:0000567								20667468	t		miannu	ERK5 is a member of the mitogen-activated protein kinase (MAPK) family that, after stimulation, is activated selectively by dual phosphorylation in the TEY motif by MAPK kinase 5 (MEK5). ERK5 is activated selectively by dual phosphorylation on Thr218 and Tyr220 in the TEY motif by its only upstream kinase, MEK5, a member of the MEK 	SIGNOR-259824	0.69
GRK5	protein	P34947	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser373	SMGTLRTsISVERQI	9606	BTO:0000007								11517230	t			Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251208	0.466
NFKB1	protein	P19838	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	binding			9606									9450761	t		lperfetto	Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna	SIGNOR-55378	0.699
prostaglandin E2	smallmolecule	CHEBI:15551	ChEBI	PTGER2	protein	P43116	UNIPROT	up-regulates	chemical activation			9606									15299086	t		gcesareni	Pge2 acts via four ep receptors termed ep1 to ep4.	SIGNOR-127735	0.8
SRC	protein	P12931	UNIPROT	RAPGEF1	protein	Q13905	UNIPROT	up-regulates	phosphorylation	Tyr504	APIPSVPyAPFAAIL	9606									15320955	t		llicata	C3g is activated upon phosphorylation at tyrosine 504 c3g is phosphorylated in vivo on y504 upon coexpression with src or hck, two members of the src family tyrosine kinases.	SIGNOR-128273	0.659
KRAS	protein	P01116	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									29731393	f		miannu	Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2	SIGNOR-267361	0.437
HDAC4	protein	P56524	UNIPROT	MEF2A	protein	Q02078	UNIPROT	down-regulates	binding			9606		BTO:0000887							10737771	t		gcesareni	We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2.	SIGNOR-76231	0.581
GSK3B	protein	P49841	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr269	HNSTTTWtGSRTAPY	10090	BTO:0000944								25373906	t		miannu	In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region. 	SIGNOR-276441	0.408
TTN	protein	Q8WZ42	UNIPROT	TCAP	protein	O15273	UNIPROT	unknown	phosphorylation	Ser157	GALRRSLsRSMSQEA	10090									9804419	t		lperfetto	These data indicate that the activation of titin kinase in differentiating myocytes and the resulting phosphorylation of telethonin are involved in the reorganization of the cytoskeleton during myofibrillogenesis.	SIGNOR-246925	0.905
GSK3B	protein	P49841	UNIPROT	GFI1	protein	Q99684	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser98	RPPSPSAsPASEKSM	9606	BTO:0000498								31289136	t		miannu	GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation.	SIGNOR-277465	0.2
acetylcholine	smallmolecule	CHEBI:15355	ChEBI	CHRM1	protein	P11229	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258630	0.8
CDK1	protein	P06493	UNIPROT	MPLKIP	protein	Q8TAP9	UNIPROT	up-regulates	phosphorylation	Ser93	YPGSYSRsPAGSQQQ	9606									17310276	t		lperfetto	Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1	SIGNOR-153304	0.348
AURKC	protein	Q9UQB9	UNIPROT	TACC1	protein	O75410	UNIPROT	up-regulates activity	phosphorylation	Ser228	ELVPSRRsKLRKPKP	-1									21531210	t		miannu	Aurora-C interacts with and phosphorylates the transforming acidic coiled-coil 1 protein. The results demonstrated that TACC1 is phosphorylated by Aurora-C on a serine at position 228. although the patho-physiological meaning of TACC1 phosphorylation by Aurora-C in normal and in malignant somatic cells remains to be fully investigated, our observations suggest that Aurora-C has a role in the later stage of mitosis, when an interaction with TACC1 may be relevant for the correct progression of the cell cycle. 	SIGNOR-262663	0.41
TNF	protein	P01375	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004914								14586405	f			We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues.	SIGNOR-253606	0.489
VX-745	chemical	CHEBI:90528	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates	chemical inhibition			9606									11892915	t		gcesareni	Vx-745 was reported to be active against several isotypes of p38 mapk, including p38alpha, p38beta and p38gamma	SIGNOR-115782	0.8
solifenacin	chemical	CHEBI:135530	ChEBI	CHRM3	protein	P20309	UNIPROT	down-regulates activity	chemical inhibition			-1									21524581	t		Luana	The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference	SIGNOR-258313	0.8
edrophonium	chemical	CHEBI:251408	ChEBI	ACHE	protein	P22303	UNIPROT	down-regulates activity	chemical inhibition			-1									9301662	t		miannu	With the aim of performing a rigorous test of the anti-AChE properties of our compounds, the kinetics of enzyme inhibition were studied in purified enzyme preparations. The inhibition data are shown in Table 1. Additionally, known competitive inhibitors of AChE (procainamide and edrophonium) were included in the study for comparative purposes.	SIGNOR-258667	0.8
XAF1	protein	Q6GPH4	UNIPROT	BIRC3	protein	Q13489	UNIPROT	down-regulates	binding			9606									17613533	t		gcesareni	Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3	SIGNOR-155288	0.4
AKAP5	protein	P24588	UNIPROT	PPP3CC	protein	P48454	UNIPROT	up-regulates activity	relocalization			10116	BTO:0004553								20694001	t			Using a viral-mediated molecular replacement strategy in rat hippocampal slices, we found that AKAP is required for NMDA receptor-dependent long-term depression solely because of its interaction with calcineurin	SIGNOR-261291	0.265
PTPRH	protein	Q9HD43	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	9606									10734133	t		gcesareni	These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase	SIGNOR-76072	0.273
RXRB	protein	P28702	UNIPROT	RARG	protein	P13631	UNIPROT	up-regulates	binding			9606									1310351	t		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16683	0.7
BCL2L1	protein	Q07817	UNIPROT	HIP1	protein	O00291	UNIPROT	down-regulates				9606									11007801	f		miannu	Hip-1 activity was found to be independent of the ded-containing caspase 8 but was significantly inhibited by the antiapoptotic protein bcl-x(l), implicating the intrinsic pathway of apoptosis in hip-1-induced cell death.	SIGNOR-82460	0.2
RAI1	protein	Q7Z5J4	UNIPROT	PER3	protein	P56645	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000614							22578325	f		miannu	Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. 	SIGNOR-266841	0.396
N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide	chemical	CHEBI:91393	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194340	0.8
3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	PRKAR2A	protein	P13861	UNIPROT	down-regulates activity	chemical inhibition			9606									26687711	t			Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 	SIGNOR-258761	0.8
cabozantinib	chemical	CHEBI:72317	ChEBI	RET	protein	P07949	UNIPROT	down-regulates activity	chemical inhibition			9606									21606412	t		miannu	XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models.	SIGNOR-259321	0.8
PTPRJ	protein	Q12913	UNIPROT	RET	protein	P07949	UNIPROT	down-regulates	dephosphorylation	Tyr905	DVYEEDSyVKRSQGR	9606									16778204	t		gcesareni	Ptprj expression induces dephosphorylation of the ret(c634r) and, probably via an indirect mechanism, ret/ptc1 oncoproteins on two key ret autophosphorylation sites (tyr1062 and tyr905). in line with this finding, adoptive ptprj expression reduced the oncogenic activity of ret	SIGNOR-147165	0.281
Caspase 8 complex	complex	SIGNOR-C231	SIGNOR	CASP3	protein	P42574	UNIPROT	up-regulates activity	cleavage			10090	BTO:0002572								10988287	t		amattioni	The temporal pattern of caspase-8 cleavage is consistent with the possibility that it may function upstream of caspase-3 during p53-dependent apoptosis.	SIGNOR-256451	0.713
PRKAA1	protein	Q13131	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000222	BTO:0000887;BTO:0001103;BTO:0001760							19491292	f		gcesareni	Activation of ampk reduced p21 protein and mrna expression, which was associated with re- duced g1/s cell cycle transition and p21 promoter activity.	SIGNOR-186061	0.2
TNF	protein	P01375	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity				9606									16813528	f		lperfetto	These observations suggest that tnf-alpha activates p38 map kinase during the inflammatory response at the injured growth plate, and tnf-alpha-p38 signaling seems to be required for marrow mesenchymal cell proliferation and migration at the growth plate injury site and in cell culture.	SIGNOR-147369	0.631
CSNK2A2	protein	P19784	UNIPROT	SMC3	protein	Q9UQE7	UNIPROT	unknown	phosphorylation	Ser1067	GDVEGSQsQDEGEGS	9606									18442975	t		gcesareni	Our data provide evidence that phosphorylation of a core cohesin subunit smc3 by atm plays an important role in dna damage response and suggest that a constitutive phosphorylation by ck2 may affect intra-s phase checkpoint by modulating smc3 phosphorylation by atm.	SIGNOR-178487	0.2
PPP1CA	protein	P62136	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	dephosphorylation	Ser15	PSVEPPLsQETFSDL	9606									16501611	t			Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.	SIGNOR-248556	0.32
sunitinib	chemical	CHEBI:38940	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									21993628	t		gcesareni	The action of kit kinase inhibitors, especially imatinib, sunitinib, dasatinib and pkc412, on different primary and secondary mutants is discussed.	SIGNOR-176760	0.8
AR	protein	P10275	UNIPROT	NAT1	protein	P18440	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17210686	f	 	lperfetto	Induction of human arylamine N-acetyltransferase type I by androgens in human prostate cancer cells|We show that NAT1 activity is induced by R1881 in androgen receptor (AR)-positive prostate lines 22Rv1 and LNCaP	SIGNOR-253684	0.2
VRK3	protein	Q8IV63	UNIPROT	DUSP3	protein	P51452	UNIPROT	up-regulates activity	binding												27346674	t		lperfetto	Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding	SIGNOR-275546	0.693
QRICH1	protein	Q2TAL8	UNIPROT	FARSB	protein	Q9NSD9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269404	0.2
PRKACA	protein	P17612	UNIPROT	CACNA1H	protein	O95180	UNIPROT	down-regulates activity	phosphorylation	Ser1144	AWSSRRSsWSSLGRA	9606									19131331	t		miannu	 Here, we identify protein kinase A (PKA) as a molecular switch that allows Gbeta(2)gammax dimers to effect voltage-independent inhibition of Ca(v)3.2 channels. Inhibition requires phosphorylation of Ser(1107), a critical serine residue on the II-III loop of the channel pore protein. S1107A prevents inhibition of unitary currents by recombinant Gbeta(2)gamma(2) dimers but does not disrupt dimer binding nor change its specificity. 	SIGNOR-263111	0.2
PCGF1	protein	Q9BSM1	UNIPROT	Noncanonical PRC1	complex	SIGNOR-C151	SIGNOR	form complex	binding			10090									25533466	t		miannu	 inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR.	SIGNOR-255279	0.712
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH19	protein	Q9H159	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265836	0.8
MAPK3	protein	P27361	UNIPROT	MYL1	protein	P05976	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150;BTO:0001130								16854453	t		gcesareni	Activation of raf/mek/erk cascade can also result in the phosphorylation of the antiapoptotic mcl-1 protein and the pro-apoptotic bim protein.	SIGNOR-148002	0.291
MK-2461	chemical	CID:44137946	PUBCHEM	MST1R	protein	Q04912	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194387	0.8
phenylalanine	smallmolecule	CHEBI:28044	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264758	0.7
CSNK1E	protein	P49674	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	phosphorylation	Ser400	SRDESTDsGLSMSSY	9606							phosphorylation:Ser127	PQHVRAHsSPASLQL 	23431053	t		milica	Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ	SIGNOR-201165	0.401
NFKB2	protein	Q00653	UNIPROT	RELB	protein	Q01201	UNIPROT	up-regulates activity	binding			9606									19098713	t		lperfetto	The map3k14-activated chuk/ikka homodimer phosphorylates nfkb2/p100 associated with relb, inducing its proteolytic processing to nfkb2/p52 and the formation of nf-kappa-b relb-p52 complexes. The nf-kappa-b heterodimeric relb-p52 complex is a transcriptional activator.	SIGNOR-182835	0.749
MAPK8IP3	protein	Q9UPT6	UNIPROT	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	up-regulates	binding			9606									15767678	t	inferred from 70% of family members	gcesareni	The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.	SIGNOR-269886	0.74
PPP2CA	protein	P67775	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	dephosphorylation	Ser253	APRRRAVsMDNSNKY	9606									20110348	t		gcesareni	Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a.	SIGNOR-252973	0.411
KDM5A	protein	P29375	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264300	0.2
HIF1A	protein	Q16665	UNIPROT	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	up-regulates				9606									17415528	f			HIF-1 has been known as a major transcription factor for the induction of virtually all genes encoding glucose transporters and glycolytic enzymes, which allows hypoxic tumor cells to take up glucose more efficiently and metabolize pyruvate to lactate	SIGNOR-259381	0.7
ITGB1BP1	protein	O14713	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257640	0.757
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	SUN1	protein	O94901	UNIPROT	down-regulates activity	phosphorylation	Ser113	HVSRQVTsSGVSHGG	9606	BTO:0000567								28831067	t		lperfetto	The SUN1-NXF1 association is at least partly regulated by a protein kinase C (PKC) which phosphorylates serine 113 (S113) in the N-terminal domain leading to reduced interaction.	SIGNOR-263281	0.2
PLK1	protein	P53350	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates	phosphorylation	Thr68	SSLETVStQELYSIP	9606									12493754	t		gcesareni	Plk1 overexpression enhances phosphorylation of chk2 at thr-68.	SIGNOR-96637	0.504
CSNK2A1	protein	P68400	UNIPROT	CBX5	protein	P45973	UNIPROT	up-regulates	phosphorylation	Ser12	TKRTADSsSSEDEEE	9606									21245376	t		gcesareni	Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability.	SIGNOR-171699	0.354
TRIM27	protein	P14373	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates				9606		BTO:0000671							12807881	f		miannu	We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38.	SIGNOR-102031	0.275
CDK2	protein	P24941	UNIPROT	PTPN2	protein	P17706	UNIPROT	unknown	phosphorylation	Ser304	LSPAFDHsPNKIMTE	9606									15030318	t		llicata	Our studies identify ser-304 as a major phosphorylation site in human tcptp, and the tc45 variant as a novel mitotic cdk substrate.	SIGNOR-123471	0.365
CYLD	protein	Q9NQC7	UNIPROT	TRAF2	protein	Q12933	UNIPROT	down-regulates activity	deubiquitination			9606									12917691	t		lperfetto	Cyld also interacts directly with tumour-necrosis factor receptor (tnfr)-associated factor 2 (traf2), an adaptor molecule involved in by members of the family of tnf/nerve growth factor receptors. (articolo-abstract)	SIGNOR-117860	0.664
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	AMPH	protein	P49418	UNIPROT	unknown	phosphorylation	Ser285	NHTLAPAsPAPARPR	-1									11113134	t		llicata	Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. 	SIGNOR-250646	0.361
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGC4	protein	Q9Y5F7	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265715	0.2
inosine	smallmolecule	CHEBI:17596	ChEBI	adenosine	smallmolecule	CHEBI:16335	ChEBI	up-regulates quantity	precursor of			-1									15926889	t		Luana	Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates	SIGNOR-269734	0.8
SH3RF1	protein	Q7Z6J0	UNIPROT	RAC2	protein	P15153	UNIPROT	up-regulates	binding			9606									9482736	t		gcesareni	Posh interacts with the gtp form of rac but not the gdp form	SIGNOR-55811	0.266
MMP2	protein	P08253	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272364	0.7
EIF4H	protein	Q15056	UNIPROT	EIF4A1	protein	P60842	UNIPROT	up-regulates activity	binding			-1									11418588	t			Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability	SIGNOR-261294	0.795
EPHA2	protein	P29317	UNIPROT	EPHA2	protein	P29317	UNIPROT	up-regulates	phosphorylation	Tyr735	KYLANMNyVHRDLAA	9606									18387945	t		lperfetto	The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells.	SIGNOR-178177	0.2
PAQosome co-chaperone complex	complex	SIGNOR-C516	SIGNOR	Chaperone-mediated protein folding	phenotype	SIGNOR-PH120	SIGNOR	up-regulates				9606									29203338	f		miannu	The PAQosome, an R2TP-Based Chaperone for Quaternary Structure Formation. The Rvb1-Rvb2-Tah1-Pih1/prefoldin-like (R2TP/PFDL) complex is a unique chaperone that provides a platform for the assembly and maturation of many key multiprotein complexes in mammalian cells. Here, we propose to rename R2TP/PFDL as PAQosome (particle for arrangement of quaternary structure) to more accurately represent its unique function.	SIGNOR-270920	0.7
DLGAP2	protein	Q9P1A6	UNIPROT	SHANK2	protein	Q9UPX8	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264590	0.843
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	BCL2L1	protein	Q07817	UNIPROT	down-regulates	phosphorylation	Thr115	LTSQLHItPGTAYQS	9606									10617621	t		lperfetto	Sapk phosphorylates bcl-x(l) on threonine 47 (thr-47) and threonine 115 (thr-115) in vitro and in vivo. In contrast to wild-type bcl-x(l), a mutant bcl-x(l) with the two threonines substituted by alanines (ala-47, ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis	SIGNOR-73638	0.2
CDK9	protein	P50750	UNIPROT	SUPT5H	protein	O00267	UNIPROT	up-regulates	phosphorylation	Thr768	MTSTYGRtPMYGSQT	9606									16427012	t		lperfetto	We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif	SIGNOR-143919	0.769
CSNK2A1	protein	P68400	UNIPROT	MYCN	protein	P04198	UNIPROT	unknown	phosphorylation	Ser261	TSGEDTLsDSDDEDD	-1									1425701	t		llicata	Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263.	SIGNOR-250920	0.458
MMP25	protein	Q9NPA2	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272369	0.7
NGF	protein	P01138	UNIPROT	SCN9A	protein	Q15858	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0003306								24493753	f		miannu	Long-term (more than 24 h) treatment with nerve growth factor (NGF) upregulated Nav1.7 functional expression in the strongly metastatic MAT-LyLu rat PCa cell line; acute application had no effect	SIGNOR-253495	0.379
HDAC2	protein	Q92769	UNIPROT	CoREST-HDAC complex	complex	SIGNOR-C105	SIGNOR	form complex	binding			9606	BTO:0000567								11171972	t		miannu	Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function.	SIGNOR-222127	0.692
DLK2	protein	Q6UY11	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates activity	binding			10090		BTO:0002572							21419176	t		lperfetto	Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts.	SIGNOR-219377	0.294
NEK8	protein	Q86SG6	UNIPROT	NEK8	protein	Q86SG6	UNIPROT	up-regulates activity	phosphorylation	Thr162	SSKSKAYtVVGTPCY	-1									11864968	t		miannu	Multimerization and autophosphorylation of Nek8 are important for its activation.Our data suggests that one site for Nek8 autophosphorylation may be Thr-210 within the activation loop.	SIGNOR-250298	0.2
STK3	protein	Q13188	UNIPROT	MOB1B	protein	Q7L9L4	UNIPROT	up-regulates	phosphorylation	Thr35	LLKHAEAtLGSGNLR	9606									23431053	t		milica	Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity	SIGNOR-201294	0.809
EP300	protein	Q09472	UNIPROT	P300/PCAF	complex	SIGNOR-C7	SIGNOR	form complex	binding			9606									21131905	t		lperfetto	Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators.	SIGNOR-170273	0.654
GATA3	protein	P23771	UNIPROT	GLS2	protein	Q9UI32	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000356								31577957	t		Luana	Thus, GATA3 contributes to the elevated expression of GLS2 in luminal-subtype breast cancers.	SIGNOR-268034	0.34
DYRK2	protein	Q92630	UNIPROT	SIAH2	protein	O43255	UNIPROT	up-regulates	phosphorylation	Thr119	PTCRGALtPSIRNLA	9606									22878263	t		llicata	In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis.	SIGNOR-198733	0.42
FAM13B	protein	Q9NYF5	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260504	0.427
MIB1	protein	Q86YT6	UNIPROT	PCM1	protein	Q15154	UNIPROT	down-regulates	ubiquitination			9606	BTO:0001938								24121310	t		miannu	 We demonstrate that the E3 ubiquitin ligase MIB1 is a new component of centriolar satellites, which interacts with and ubiquitylates AZI1 and PCM1 and suppresses primary cilium formation. 	SIGNOR-272878	0.378
LPAR	proteinfamily	SIGNOR-PF2	SIGNOR	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			10090	BTO:0000944								15856019	t	inferred from 70% family members	milica	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13.	SIGNOR-269965	0.2
GRK2	protein	P25098	UNIPROT	OPRD1	protein	P41143	UNIPROT	down-regulates activity	phosphorylation	Ser363	RVTACTPsDGPGGGA	9606	BTO:0000007								11040053	t		gcesareni	Taken together, we have demonstrated that agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus.	SIGNOR-249660	0.2
ATXN7	protein	O15265	UNIPROT	CRX	protein	O43186	UNIPROT	down-regulates activity	binding			10090									11580893	t		miannu	We found that ataxin-7 and CRX colocalize and coimmunoprecipitate. We observed that polyglutamine-expanded ataxin-7 can dramatically suppress CRX transactivation.	SIGNOR-223226	0.627
RAD51B	protein	O15315	UNIPROT	RAD51B/RAD51C	complex	SIGNOR-C65	SIGNOR	form complex	binding			9606									11751636	t		miannu	We show that two of them, rad51b and rad51c, are associated in a stable complex. Rad51b-rad51c complex has ssdna binding and ssdna-stimulated atpase activities.	SIGNOR-111383	0.645
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates	dephosphorylation			9606									21880741	t		gcesareni	Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.	SIGNOR-176373	0.613
succinyl-CoA(5-)	smallmolecule	CHEBI:57292	ChEBI	succinate(2-)	smallmolecule	CHEBI:30031	ChEBI	up-regulates quantity	precursor of			9606									27487822	t		miannu	In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions.	SIGNOR-266266	0.8
CTDSPL2	protein	Q05D32	UNIPROT	HBG1	protein	P69891	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000664								20932329	f	Regulation of transcription	miannu	CTD small phosphatase like 2 (CTDSPL2) can increase ε- and γ-globin gene expression in K562 cells and CD34+ cells derived from umbilical cord blood.	SIGNOR-251778	0.2
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	TOP2A	protein	P11388	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0003492								21254166	t		miannu	Evidence that Fbw7 acts as the E3-ligase mediating the degradation of topoIIα in HDAC inhibitor-treated PLC5 cells. 	SIGNOR-276302	0.35
nilotinib	chemical	CHEBI:52172	ChEBI	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194640	0.8
Osmotic_stress	stimulus	SIGNOR-ST28	SIGNOR	HNRNPA1	protein	P09651	UNIPROT	down-regulates activity	relocalization			9606	BTO:0000312								33172210	f			We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne	SIGNOR-262816	0.7
CTTNBP2NL	protein	Q9P2B4	UNIPROT	STRN4	protein	Q9NRL3	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								23015759	t		miannu	Although CTTNBP2 and CTTNBP2NL are different in terms of tissue and subcellular distribution, our data indicate that, similar to CTTNBP2NL, CTTNBP2 associates with members of the striatin family, namely striatin and zinedin. Moreover, CTTNBP2 is critical for the distribution of striatin and zinedin in dendritic spines. The role of CTTNBP2 in the regulation of the synaptic distribution of striatin and zinedin suggests that CTTNBP2 regulates synaptic signaling through PP2A. 	SIGNOR-261701	0.687
NEU1	protein	Q99519	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity				9606	BTO:0003554								32164705	f		Giorgia	Taken together, these findings indicate that NEU1 overexpression reduces cell proliferation and enhances cell apoptosis through by downregulation of FN-integrin β1-mediated Akt signaling pathway.	SIGNOR-260659	0.2
EZR	protein	P15311	UNIPROT	Platelet_aggregation	phenotype	SIGNOR-PH81	SIGNOR	up-regulates				9606	BTO:0000132								35267019	f		miannu	Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. Taken together, these results suggest that Rev-erbα potentiates platelet activation via an OPHN-1-mediated RhoA/ERM signalling pathway.	SIGNOR-268432	0.7
HDAC4	protein	P56524	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates	deacetylation			9606									22298955	t		gcesareni	Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation.	SIGNOR-195603	0.54
GARS1	protein	P41250	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									24898252	t		miannu	Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 	SIGNOR-270479	0.8
RPA2	protein	P15927	UNIPROT	MRE11	protein	P49959	UNIPROT	up-regulates	binding			9606									19586055	t		fstefani	The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex.	SIGNOR-186648	0.2
PFKFB4	protein	Q16877	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates activity	phosphorylation	Ser857	PPYNRAVsLDSPVSV	9606	BTO:0000007								29615789	t			PFKFB4, a regulatory enzyme that synthesizes an allosteric stimulator of glycolysis2, was found to be a robust stimulator of SRC-3 that co-activates estrogen receptor (ER). PFKFB4 phosphorylates SRC-3 at serine 857 (S857) enhancing its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient SRC-3 mutant S857A (SRC-3S857A) significantly abolishes SRC-3-mediated transcriptional output	SIGNOR-267269	0.333
MYCT1	protein	Q8N699	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000670;BTO:0000738								30283340	f		miannu	Overexpression of MYCT1 Inhibits Proliferation and Induces Apoptosis in Human Acute Myeloid Leukemia HL-60 and KG-1a Cells in vitro and in vivo	SIGNOR-261729	0.7
RFX1	protein	P22670	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12032779	f		miannu	 Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. 	SIGNOR-253829	0.2
NUMA1	protein	Q14980	UNIPROT	TUBB2A	protein	Q13885	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116936	0.2
NVP-AEW541	chemical	CID:11476171	PUBCHEM	INSR	protein	P06213	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194895	0.8
MAPK1	protein	P28482	UNIPROT	SORBS3	protein	O60504	UNIPROT	unknown	phosphorylation			9606									15184391	t	The effect has been demonstrated using O60504-2	llicata	Vinexin was directly phosphorylated by erk2 upon stimulation with egf at the serine 189 of vinexin _.	SIGNOR-125224	0.396
3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	PRKACA	protein	P17612	UNIPROT	up-regulates	chemical activation			9606									16293724	t		gcesareni	Pge2 receptors are coupled to the G protein Gs, which causes accumulation of cyclic adenosine monophosphate (cAMP) and activates protein kinase a (PKA), we confirmed that PGE2 treatment or transfection of cells with the active catalytic subunit of PKA also stimulated the activity of a cAMP-responsive-element driven reporter gene (CRE-luc).	SIGNOR-141786	0.8
MAP3K2	protein	Q9Y2U5	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates	phosphorylation			9606									11343802	t		gcesareni	Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation	SIGNOR-107692	0.424
HNF4A	protein	P41235	UNIPROT	F12	protein	P00748	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								9794469	f	 	miannu	Orphan receptor hepatocyte nuclear factor-4 antagonizes estrogen receptor alpha-mediated induction of human coagulation factor XII gene. In conclusion, our findings address a direct role for HNF-4 in modulating estrogen-dependent transcription of the FXII gene promoter.	SIGNOR-254073	0.221
IL7R	protein	P16871	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates	binding			9606	BTO:0000776								18445337	t		milica	For instance, jak1 is associated with the ? Subunits of ?c Cytokines such as il-7r? And IL-4R. jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation.	SIGNOR-178494	0.623
MMP9	protein	P14780	UNIPROT	PZP	protein	P20742	UNIPROT	down-regulates quantity by destabilization	cleavage	Leu778	WKAGAFClSEDAGLG	-1									9344465	t		lperfetto	The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261785	0.355
PRKCD	protein	Q05655	UNIPROT	PLD2	protein	O14939	UNIPROT	up-regulates	phosphorylation	Thr566	FIQRWNFtKTTKAKY	9606									20733000	t	Translocation from Cytoplasm to the Edge of Lamellipodia	gcesareni	Finally, we show that thr566 of pld2 is directly phosphorylated by pkc and that pld2 mutation in this region prevents pld2 activation, pld2 translocation to the edge of lamellipodia, rac translocation, and cell spreading after integrin activation	SIGNOR-167577	0.476
NKX2-5	protein	P52952	UNIPROT	ANKRD1	protein	Q15327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0003265								9043061	f			Finally, a carp promoter-lacZ transgene, which displays cardiac-specific expression in wild-type and Nkx2-5(+/-) background, was also significantly reduced in Nkx2-5(-/-) embryos, indicating that Nkx2-5 either directly or indirectly regulates carp promoter activity during in vivo cardiogenesis as well as in cultured cardiac myocytes	SIGNOR-253646	0.343
STAT4	protein	Q14765	UNIPROT	PRF1	protein	P14222	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000914								12372421	f		miannu	 IL-12-induced expression of the perforin gene in NK cells is directly regulated by STAT4, which binds, most likely as a homo-tetramer, to the tandem STAT-binding sequences in the perforin gene promoter.	SIGNOR-255245	0.413
LPAR1	protein	Q92633	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates	binding			9606									12393875	t		gcesareni	We conclude that lpa(1) receptors couple to a g(i)-phosphoinositide 3-kinase-tiam1 pathway to activate rac.	SIGNOR-94635	0.537
FGF2	protein	P09038	UNIPROT	MMP13	protein	P45452	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15564063	f		miannu	 Increased expression of RUNX2 in OA cartilage may contribute to increased expression of MMP-13. FGF2, which is present in OA synovial fluid, activated RUNX2 via the MEK/ERK pathway and increased MMP-13 expression. 	SIGNOR-255079	0.432
2-[[2-[[2-[[2-[[2-amino-3-(4-hydroxyphenyl)-1-oxopropyl]amino]-1-oxoethyl]amino]-1-oxoethyl]amino]-1-oxo-3-phenylpropyl]amino]-4-methylpentanoic acid	chemical	CHEBI:91634	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258805	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	TCF3	protein	P15923	UNIPROT	down-regulates quantity by destabilization	phosphorylation			10090	BTO:0000944								14592976	t	inferred from 70% family members	lperfetto	Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG)	SIGNOR-270009	0.2
NEK2	protein	P51955	UNIPROT	PP1	proteinfamily	SIGNOR-PF54	SIGNOR	down-regulates	phosphorylation			9606									10880350	t		lperfetto	Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity. / threonine-307 and -318 appear to be equally well phosphorylated by nek2	SIGNOR-264655	0.503
EML4-ALK	fusion protein	SIGNOR-FP8	SIGNOR	HIF1A	protein	Q16665	UNIPROT	up-regulates quantity by stabilization				9606									27141364	f		irozzo	EML4-ALK enhanced HIF-1α expression through increasing transcription and decreasing ubiquitination of HIF-1α.	SIGNOR-259173	0.2
ROCK2	protein	O75116	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates activity	phosphorylation	Ser20	KRPQRATsNVFAMFD	9606									8702756	t		miannu	 Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. 	SIGNOR-261709	0.633
PTPN5	protein	P54829	UNIPROT	MOB1B	protein	Q7L9L4	UNIPROT	up-regulates activity	dephosphorylation	Tyr26	IPEGSHQyELLKHAE	9606									28675297	t		miannu	PTPN5 dephosphorylates\nMob1a at Y26 residue.	SIGNOR-277058	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	NOX5	protein	Q96PH1	UNIPROT	unknown	phosphorylation	Ser547	TMRKSQRsSKGSEIL	-1									21642394	t		miannu	In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475.	SIGNOR-276332	0.2
AKT2	protein	P31751	UNIPROT	UPF1	protein	Q92900	UNIPROT	up-regulates activity	phosphorylation	Thr151	FCNGRGNtSGSHIVN	9606	BTO:0002181								35675814	t		miannu	AKT-Mediated UPF1 Phosphorylation at T151 Promotes UPF1 Helicase Activity	SIGNOR-277595	0.2
PRKCA	protein	P17252	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Ser619	SLPKINRsASEPSLH	9606									12551925	t		gcesareni	Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation.	SIGNOR-97648	0.538
PTPN5	protein	P54829	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	down-regulates activity	dephosphorylation	Tyr1474	GSSNGHVyEKLSSIE	10090	BTO:0004102								20427654	t		lperfetto	 These previous results, together with the present findings, indicate that STEP61 dephosphorylates the NR2B subunit at its regulatory tyr1472 site, and dephosphorylation of this site leads to internalization of the NMDAR complex from neuronal surface membranes.	SIGNOR-265744	0.564
PRKCE	protein	Q02156	UNIPROT	TICAM2	protein	Q86XR7	UNIPROT	up-regulates	phosphorylation	Ser16	NSCPLSLsWGKRHSV	9606									16757566	t		llicata	Here we show that tram is transiently phosphorylated by pkcepsilon on serine-16 our study provides a possible target for these molecules in lps signaling. Dag may activate pkc?, Leading to the phosphorylation and activation of tram.	SIGNOR-146991	0.592
INS	protein	P01308	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	binding			9606									2550426	t		lperfetto	Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds.	SIGNOR-23001	0.932
AKT1	protein	P31749	UNIPROT	TERT	protein	O14746	UNIPROT	up-regulates	phosphorylation	Ser824	AVRIRGKsYVQCQGI	9606									10224060	t		gcesareni	Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins.	SIGNOR-67317	0.722
ICAM3	protein	P32942	UNIPROT	AD/b2 integrin	complex	SIGNOR-C172	SIGNOR	up-regulates activity	binding												8777714	t		lperfetto	A novel leukointegrin, alpha d beta 2, binds preferentially to ICAM-3.	SIGNOR-253371	0.596
MPO	protein	P05164	UNIPROT	APOA1	protein	P02647	UNIPROT	down-regulates activity	oxidation			9606									20043647	t		miannu	When apolipoprotein A-I (apoA-I), the major HDL protein, was oxidized by MPO, its ability to promote cellular cholesterol efflux by ABCA1 was impaired. Moreover, oxidized apoA-I was unable to activate lecithin:cholesterol acyltransferase (LCAT), which rapidly converts free cholesterol to cholesteryl ester, a critical step in HDL maturation	SIGNOR-252102	0.418
F10	protein	P00742	UNIPROT	F7	protein	P08709	UNIPROT	up-regulates activity	cleavage	Arg212	NASKPQGrIVGGKVC	9606		BTO:0000131							12524220	t		lperfetto	The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa.	SIGNOR-263523	0.52
PPARGC1A	protein	Q9UBK2	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090		BTO:0001103		SIGNOR-C13					20404331	f		lperfetto	In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB	SIGNOR-217969	0.36
NRXN1	protein	Q9ULB1	UNIPROT	NLGN2	protein	Q8NFZ4	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							22626542	t		miannu	 The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites.	SIGNOR-265452	0.819
3-(9-Fluoro-2-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-(imidazo[1,2-a]pyridin-3-yl)-1H-pyrrole-2,5-dione	chemical	CID:10029385	PUBCHEM	GSK3B	protein	P49841	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000183								31562256	t		miannu	 Indeed, we demonstrated that the selective GSK3 inhibitor LY2090314 significantly reduced cell proliferation in control pancreatic cancer cell lines	SIGNOR-262539	0.8
MAP3K3	protein	Q99759	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	binding			9606	BTO:0000298								9162092	t		lperfetto	These data indicate that mkk3 is preferentially activated by mekk3, whereas mkk4 is activated both by mekk2 and mekk3.	SIGNOR-48628	0.586
IGF1R	protein	P08069	UNIPROT	SIRPA	protein	P78324	UNIPROT	up-regulates				9606		BTO:0000887;BTO:0001260							11779860	f		gcesareni	These studies indicate that igf-ir stimulates phosphorylation of shps-1 which is critical for shp-2 recruitment to the plasma membrane and for its recruitment to the igf-ir	SIGNOR-113640	0.373
TP53	protein	P04637	UNIPROT	FASLG	protein	P48023	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9841917	f	Nuclear p53	amattioni	Cd95l, cd95, and the trail death receptors are induced by the tumour suppressor p53	SIGNOR-62379	0.415
CIITA	protein	P33076	UNIPROT	RFX5	protein	P48382	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								9177217	t	2	miannu	RFX5 can activate transcription only in cooperation with CIITA. RFX5 and CIITA associate to form a complex capable of activating transcription from class II major histocompatibility complex promoters. In this complex, promoter specificity is determined by the DNA binding domain of RFX5 and the general transcription apparatus is recruited by the acidic activation domain of CIITA.	SIGNOR-240980	0.755
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	MRTFA	protein	Q969V6	UNIPROT	down-regulates	phosphorylation			9606									18694962	t	Translocation from Nuleus to Cytoplasm	gcesareni	Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization.	SIGNOR-269996	0.2
ASXL1	protein	Q8IXJ9	UNIPROT	CDKN2B	protein	P42772	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									26470845	t		lperfetto	Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals	SIGNOR-241759	0.28
phosphatidylinositol 4-phosphate	smallmolecule	CHEBI:37530	ChEBI	Receptor_mediated_ endocytosis	phenotype	SIGNOR-PH121	SIGNOR	up-regulates				9534									22253445	f		lperfetto	Further research suggested that PI4P plays an essential role in SARS-CoV spike-mediated entry, which is regulated by the PI4P lipid microenvironment. 	SIGNOR-260745	0.7
NUP214	protein	P35658	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	binding			9606				SIGNOR-C9					12917407	t		gcesareni	We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import	SIGNOR-117647	0.542
BBC3	protein	Q9BXH1	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity	binding			9606	BTO:0001938								11463392	t		lperfetto	Puma localizes to the mitochondria, interacts with bcl-2, and function to induce cytochrome c release	SIGNOR-109506	0.649
PRKD2	protein	Q9BZL6	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser172	GQLVRNDsLWHRSDS										34010649	t		lperfetto	The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-275941	0.2
IL17A	protein	Q16552	UNIPROT	KLF3	protein	P57682	UNIPROT	up-regulates	transcriptional regulation			9606									23332504	f		fspada	Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic. 	SIGNOR-210114	0.2
CNOT3	protein	O75175	UNIPROT	TNFRSF11A	protein	Q9Y6Q6	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003292								24550297	t		Luana	Our results reveal that CNOT3 is a critical regulator of bone mass acting on bone resorption through posttranscriptional down-regulation of RANK mRNA stability, at least in part, even in aging-induced osteoporosis.	SIGNOR-261572	0.2
USP8	protein	P40818	UNIPROT	RNF41	protein	Q9H4P4	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0002181								23750007	t		irozzo	Ubiquitin-specific protease 8 (USP8), an RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins.	SIGNOR-259105	0.875
PLK1	protein	P53350	UNIPROT	CHEK2	protein	O96017	UNIPROT	unknown	phosphorylation	Thr26	SQPHGSVtQSQGSSS	-1									12493754	t		lperfetto	Plk1 overexpression enhances phosphorylation of Chk2 at Thr-68. Plk1 phosphorylates recombinant Chk2 in vitro.	SIGNOR-249180	0.504
NEK1	protein	Q96PY6	UNIPROT	ATR	protein	Q13535	UNIPROT	up-regulates activity	binding												28426283	t		lperfetto	It was reported that NEK1 associates with ATR/ATRIP and primes it for activation in response to a variety of genotoxic agents	SIGNOR-275841	0.2
PTEN	protein	P60484	UNIPROT	RAB7A	protein	P51149	UNIPROT	up-regulates activity	dephosphorylation	Ser72	AGQERFQsLGVAFYR	9606									26869029	t		lperfetto	PTEN dephosphorylates Rab7 on two conserved residues S72 and Y183, which are necessary for GDP dissociation inhibitor (GDI)-dependent recruitment of Rab7 on to late endosomes and subsequent maturation.	SIGNOR-276960	0.383
imiquimod	chemical	CHEBI:36704	ChEBI	TLR8	protein	Q9NR97	UNIPROT	up-regulates activity	chemical activation			9606									15661881	t		miannu	Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively.	SIGNOR-259245	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation			9606									14967450	t		lperfetto	Akt negatively regulates the raf and gsk-3 kinases and the cell cycle regulatory transcription factor fkhr.	SIGNOR-244333	0.2
halothane	chemical	CHEBI:5615	ChEBI	KCNK3	protein	O14649	UNIPROT	up-regulates activity	chemical activation			10090									20519544	t		Luana	We further demonstrate that TASK channels are required for normal sensitivity to immobilizing effects of halothane and isoflurane and to sedative/hypnotic effects of halothane.	SIGNOR-257846	0.8
MSH2	protein	P43246	UNIPROT	BLM	protein	P54132	UNIPROT	up-regulates	binding			9606			SIGNOR-C60						15064730	t		miannu	We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro	SIGNOR-123699	0.601
TLR4	protein	O00206	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606	BTO:0001545								28137827	f		miannu	S100A9 induces differentiation of acute myeloid leukemia cells through TLR4.	SIGNOR-261923	0.7
PRKACA	protein	P17612	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation			9606		BTO:0001103							21902831	t		gcesareni	Phosphorylation of CREB by PKA allows it to initiate the transcription of genes that contain a CRE element, two of which are PAX3 and MYF5.	SIGNOR-176560	0.563
TRAF6	protein	Q9Y4K3	UNIPROT	MAP1LC3B	protein	Q9GZQ8	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002181								30806153	t		miannu	TRAF6 catalyzes K63-linked polyubiquitination of LC3B and promotes the formation of the LC3B-ATG7 and LC3B-CTNNB1 complexes.	SIGNOR-277439	0.3
LAMA3	protein	Q16787	UNIPROT	Laminin-5	complex	SIGNOR-C184	SIGNOR	form complex	binding												9211848	t		lperfetto	Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2.	SIGNOR-253235	0.559
PRKCA	protein	P17252	UNIPROT	THOC5	protein	Q13769	UNIPROT	up-regulates	phosphorylation	Ser5	sSKKRKPK	9606	BTO:0000801;BTO:0000876								15221008	t		llicata	We conclude m-csf-mediated activation of pkcalpha can potentiate fmip action to initiate survival/differentiation signaling.	SIGNOR-126568	0.332
Host translation inhibitor nsp1	protein	P0DTD1-PRO_0000449619	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	down-regulates activity	binding			9606	BTO:0002552								33188728	t		miannu	Our structure of the SARS-CoV-2 Nsp1 protein bound to the 40S ribosomal subunit establishes a mechanistic basis of the cellular effects of Nsp1, revealing a multifaceted mechanism of inhibition of the host protein synthesis at the initiation stage by the virusThis shows that Nsp1 not only plugs the mRNA entry channel but also keeps the 40S subunit in a conformation that is incompatible with mRNA loading.	SIGNOR-262518	0.2
CSNK2A1	protein	P68400	UNIPROT	EIF5	protein	P55010	UNIPROT	up-regulates	phosphorylation	Ser390	KEAEEESsGGEEEDE	9606									18649047	t		gcesareni	We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2.	SIGNOR-179546	0.402
CD27	protein	P26842	UNIPROT	BIK	protein	Q13323	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12324477	f		gcesareni	Bik expression was weakly but significantly down-regulated by cd27 but up-regulated by cd40.	SIGNOR-93323	0.2
sonidegib	chemical	CHEBI:90863	ChEBI	SMO	protein	Q99835	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193630	0.8
MAP3K5	protein	Q99683	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates	phosphorylation			9606									19920149	t		gcesareni	Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7	SIGNOR-161766	0.576
MRPS14	protein	O60783	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606	BTO:0000934								25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261456	0.717
seliciclib	chemical	CHEBI:45307	ChEBI	CDK2	protein	P24941	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206571	0.8
trametinib	chemical	CHEBI:75998	ChEBI	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	lperfetto		SIGNOR-244871	0.8
HES1	protein	Q14469	UNIPROT	PTGDS	protein	P41222	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002605								15743775	f		miannu	 knock-down of Hes-1 mRNA by RNA interference significantly enhanced the L-PGDS mRNA level, indicating that the L-PGDS gene expression is repressed by the Notch-Hes signaling. 	SIGNOR-255424	0.2
MAT2B	protein	Q9NZL9	UNIPROT	GIT1	protein	Q9Y2X7	UNIPROT	up-regulates activity	binding			9606	BTO:0000599								23325601	t		miannu	We found both MAT2B variants interact with GIT1. MAT2B directly promoted binding of GIT1 and ERK2 to MEK1. MAT2B and GIT1 interact and are overexpressed in most human liver and colon cancer specimens. MAT2B and GIT1 require each other to activate MEK1/ERK and increase growth. 	SIGNOR-261244	0.409
TEAD	proteinfamily	SIGNOR-PF22	SIGNOR	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates activity	binding			9606									26258633	t		miannu	YAP/TAZ/TEAD and AP-1 form a complex that synergistically activates target genes directly involved in the control of S-phase entry and mitosis. 	SIGNOR-277658	0.36
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser37	YLDSGIHsGATTTAP	9606		BTO:0000586							16293724	t		lperfetto	This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway.	SIGNOR-227889	0.892
SMAD5	protein	Q99717	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				10090	BTO:0002729								23993924	f		flangone	Engagement of BMP4-mediated signaling in adult mouse ovary-derived OSCs cultured in vitro drives differentiation of these cells into IVD oocytes through Smad1/5/8 activation and transcriptional up-regulation of key meiosis-initiating genes.	SIGNOR-242059	0.7
BMP2	protein	P12643	UNIPROT	SMAD1/5/8	proteinfamily	SIGNOR-PF35	SIGNOR	up-regulates				9606									22298955	f	inferred from 70% of family members	lperfetto	Neogenin, a transmembranous protein, was reported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation.	SIGNOR-269848	0.69
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CAPN2	protein	P17655	UNIPROT	up-regulates	phosphorylation			9606									14993287	t	inferred from 70% family members	lperfetto	Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo.	SIGNOR-270179	0.2
PAX3	protein	P23760	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	up-regulates activity	binding			9606									20006729	t		gcesareni	Pax3 binds to lef1 pax3 activity may directly effect the expression of factors regulated by signal transduction pathways dependent on lef1.	SIGNOR-162100	0.438
AREL1	protein	O15033	UNIPROT	PIAS4	protein	Q8N2W9	UNIPROT	down-regulates quantity by destabilization	ubiquitination										phosphorylation:Ser18;Thr783	MVMSFRVsDLQMLLG;T>782	27162139	t		lperfetto	In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFβ signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCζ and GSK3β. Specifically, PKCζ phosphorylation of PIAS4 and GSK3β phosphorylation of FIEL1 are both essential for the degradation of PIAS4.	SIGNOR-275575	0.412
RNF111	protein	Q6ZNA4	UNIPROT	SMAD7	protein	O15105	UNIPROT	down-regulates	binding			9606									14657019	t		gcesareni	Arkadia physically interacts with inhibitory smad, smad7, and induces its poly-ubiquitination and degradation.	SIGNOR-119663	0.725
BRD7	protein	Q9NPI1	UNIPROT	BRD2	protein	P25440	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000192								12600283	f		miannu	 BRD7 protein could respectively interact with proteins, BRD2 and BRD3, and BRD7 could up-regulate the expression levels of BRD2 and BRD3 genes in mRNA level to some extent.	SIGNOR-253763	0.421
GSK3B	protein	P49841	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser49	CHRLPPGsLSSTPLS	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159458	0.26
ID2	protein	Q02363	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates activity	binding			10090	BTO:0000222								8380166	t	2	miannu	Id1 and Id2 interacted strongly with MyoD and Myf-5.Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-240268	0.557
FLT3	protein	P36888	UNIPROT	XRCC5	protein	P13010	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									21228325	f		fcortellessa	We detected an approximately 5-fold decrease in Ku86 expression in early pro-B cells from FLT3/ITD mice compared with the wild-type controls. These data support the finding that FLT3/ITD mutations exert a suppressive role on Ku86 expression.	SIGNOR-261684	0.2
RARA	protein	P10276	UNIPROT	CCNA1	protein	P78396	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002136								11090075	t		miannu	RARα is involved in the regulation of cyclin A1. Further studies using ligands selective for various retinoic acid receptors suggested that cyclin A1 expression is negatively regulated by activated RARα.	SIGNOR-249636	0.246
PPP3CB	protein	P16298	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates activity	dephosphorylation	Ser99	PFRGRSRsAPPNLWA	9606	BTO:0000007								10195903	t			Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 	SIGNOR-248384	0.34
DDR1	protein	Q08345	UNIPROT	CXCL5	protein	P42830	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003303								34237033	f		miannu	 We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis.	SIGNOR-277731	0.2
CXCL5	protein	P42830	UNIPROT	Neutrophil_activation	phenotype	SIGNOR-PH211	SIGNOR	up-regulates				9606	BTO:0000130								34237033	f		miannu	 We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis.	SIGNOR-277732	0.7
TBK1	protein	Q9UHD2	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser36	RHDSGLDsMKDEEYE	9606									11815618	t		lperfetto	Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha.	SIGNOR-246643	0.468
CDK5	protein	Q00535	UNIPROT	CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	form complex	binding			9606									11331872	t		lperfetto	Induced p35 forms a complex with Cdk5 and activates its kinase activity	SIGNOR-250683	0.942
P2RY4	protein	P51582	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257288	0.2
TNFAIP1	protein	Q13829	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates quantity	binding			9606									19782033	t		miannu	 BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.	SIGNOR-264235	0.356
ATG13	protein	O75143	UNIPROT	ULK2	protein	Q8IYT8	UNIPROT	up-regulates	binding			9606									19225151	t		gcesareni	He mammalian atg13 binds both ulk1 and ulk2 and mediates the interaction of the ulk proteins with fip200. The binding of atg13 stabilizes and activates ulk and facilitates the phosphorylation of fip200 by ulk	SIGNOR-184123	0.741
CSNK2A1	protein	P68400	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	down-regulates activity	phosphorylation	Ser882	DGSKTSSsDTLSEEK	9606	BTO:0000567								31167143	t		miannu	Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations. 	SIGNOR-276730	0.2
CCND1	protein	P24385	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									18177723	f		andrea cerquone perpetuini	Cyclin D1 is necessary for proliferation of different cell types, including myogenic cells.	SIGNOR-255412	0.7
MAPK8	protein	P45983	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	phosphorylation	Tyr701	DGPKGTGyIKTELIS	10090	BTO:0001086								24913968	t			SP600125 prevented phosphorylation of STAT1 at Tyr701 site [..] Western blot analysis confirmed that blocking p-JNK using SP600125 markedly reduced STAT3 localization in the nucleus and STAT1 phosphorylation	SIGNOR-251101	0.459
DAPK1	protein	P53355	UNIPROT	RPL5	protein	P46777	UNIPROT	unknown	phosphorylation			9606									18283219	t		lperfetto	Here we adapted this strategy to successfully screen for dapk substrates. We report the identification of two substrates, ribosomal protein l5 and mcm3.	SIGNOR-160954	0.2
PCM1	protein	Q15154	UNIPROT	CETN3	protein	O15182	UNIPROT	up-regulates	relocalization			9606									12403812	t		miannu	Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome	SIGNOR-95016	0.302
IL4	protein	P05112	UNIPROT	IL4R	protein	P24394	UNIPROT	up-regulates	binding			9606									12704343	t		milica	IL-4R Is a 140-kd protein that binds il-4 with high affinity	SIGNOR-100762	0.941
PI3K	complex	SIGNOR-C156	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity				9606		BTO:0000150							12167717	f		lperfetto	PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473,	SIGNOR-252710	0.785
AKT1	protein	P31749	UNIPROT	UBE2S	protein	Q16763	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr152	AARARLLtEIHGGAG	9606	BTO:0000007								27593939	t		lperfetto	Mechanistically, Akt1 physically interacted with and phosphorylated UBE2S at Thr 152, enhancing its stability by inhibiting proteasomal degradation.	SIGNOR-265078	0.448
CAMK4	protein	Q16566	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates	phosphorylation	Ser119	EILSRRPsYRKILND	9606									17389598	t		gcesareni	Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb.	SIGNOR-153940	0.698
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	Leu-tRNA(Leu)	smallmolecule	CHEBI:16624	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270414	0.8
RPL27	protein	P61353	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262474	0.843
STAT6	protein	P42226	UNIPROT	ARG1	protein	P05089	UNIPROT	up-regulates					BTO:0000801	BTO:0001103							25386178	f		apalma	Cytokines like IL-4 or IL-13 lead to STAT6 phosphorylation with consecutive arginase expression and varying further aspects of M2 polarization (mannose receptor, Ym1, Fizz1)	SIGNOR-255557	0.418
PPP1CC	protein	P36873	UNIPROT	IFIH1	protein	Q9BYX4	UNIPROT	up-regulates activity	dephosphorylation	Ser88	EALRRTGsPLAARYM	9606	BTO:0000007								25865883	t		lperfetto	A recent study has revealed that PP1alpha and PP1gamma phosphatases are responsible for dephosphorylating MDA5 and are essential for its activation. |PP1gamma mediates dephosphorylation of MDA5 not only at Ser-88 but also at other Ser/Thr residues. 	SIGNOR-264578	0.249
FOS	protein	P01100	UNIPROT	STAR	protein	P49675	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19022561	t		miannu	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 	SIGNOR-254878	0.262
AMPK	complex	SIGNOR-C15	SIGNOR	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser172	GQLVRNDsLWHRSDS	9606	BTO:0001938								26816379	t		gcesareni	A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission.	SIGNOR-249655	0.2
PGK1	protein	P00558	UNIPROT	3-phosphonato-D-glyceroyl phosphate(4-)	smallmolecule	CHEBI:57604	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa.	SIGNOR-266502	0.8
MMP3	protein	P08254	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272373	0.7
MAP2K5	protein	Q13163	UNIPROT	MAPK7	protein	Q13164	UNIPROT	up-regulates	phosphorylation			9606									12912994	t		gcesareni	Mek5 is the mapk kinase that phosphorylates and activates erk5 in response to growth factors, oxidative stress, and hyperosmotic conditions.	SIGNOR-104631	0.69
PLK1	protein	P53350	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	down-regulates activity	phosphorylation	Ser1618	LTKAADIsLDNLVEG	-1									24703952	t		lperfetto	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Addition of the inhibitors for PLK1 and the p38 MAPK leads to a complete loss of pT1609/pS1618 signal within 3 hr in mitotic cells 	SIGNOR-264413	0.615
ELANE	protein	P08246	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Val48	KVDGTSHvTGKGVTV	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263589	0.404
PTK2B	protein	Q14289	UNIPROT	ASAP2	protein	O43150	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								10022920	t		miannu	 Tyrosine phosphorylation of Pap by Pyk2 or Src kinases. We have identified a new Pyk2 binding protein designated Pap. Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain. We demonstrate that Pap forms a stable complex with Pyk2 and that activation of Pyk2 leads to tyrosine phosphorylation of Pap in living cells. 	SIGNOR-269704	0.541
ABL1	protein	P00519	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates activity	phosphorylation	Tyr88	KGSLPEFyYRPPRPP	-1									17254966	t			Lyn and Abl phosphorylate Y88 of p27 in vitro. phosphorylation of Y88 in p27 impaired its ability to inhibit the bound kinase complex	SIGNOR-251426	0.578
TGFB1	protein	P01137	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates	binding			9606									26194464	t		MARCO ROSINA	TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI).	SIGNOR-255031	0.84
HRH2	protein	P25021	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257375	0.252
SP1	protein	P08047	UNIPROT	PHGDH	protein	O43175	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18378410	f		miannu	Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y.	SIGNOR-255208	0.2
AKT1	protein	P31749	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser253	APRRRAVsMDNSNKY										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249626	0.908
DKK1	protein	O94907	UNIPROT	KREMEN2	protein	Q8NCW0	UNIPROT	up-regulates	binding			9606									12050670	t		gcesareni	Dkk1 has been shown to inhibitwnt by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to blockwnt/beta-catenin . Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of thewntreceptor lrp6 from the plasma membranekremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane	SIGNOR-88882	0.59
PRKACA	protein	P17612	UNIPROT	FXYD1	protein	O00168	UNIPROT	up-regulates activity	phosphorylation	Ser83	EEGTFRSsIRRLSTR	-1									15621037	t		miannu	 PKA-dependent, alpha 1-specific NKA activation may be mediated through phosphorylation of the accessory protein PLM, rather than direct alpha1 subunit phosphorylation. we propose that phosphorylation of the small accessory protein phospholemman (PLM) by PKA at serine 68 is responsible for the observed isoform-specific activation of NKA.	SIGNOR-263117	0.429
PRKCH	protein	P24723	UNIPROT	PTPN11	protein	Q06124	UNIPROT	unknown	phosphorylation	Ser576	CAEMREDsARVYENV	9606									11781100	t		lperfetto	 In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta	SIGNOR-249137	0.312
KLF4	protein	O43474	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by repression	transcriptional regulation												17308127	t		lperfetto	Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element. 	SIGNOR-270544	0.578
NFIL3	protein	Q16649	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates				10090	BTO:0003104								10082541	f		lperfetto	NFIL3 inhibits apoptosis without affecting Bcl-xL expression.	SIGNOR-256653	0.7
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	WWC1	protein	Q8IX03	UNIPROT	unknown	phosphorylation			9606		BTO:0000149							24269383	t	inferred from 70% family members	llicata	We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro.	SIGNOR-270121	0.2
1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methyl-1-piperazinyl)anilino]-2-prop-2-enyl-3-pyrazolo[3,4-d]pyrimidinone	chemical	CHEBI:91414	ChEBI	WEE1	protein	P30291	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194423	0.8
ADX-47273	chemical	CID:11383075	PUBCHEM	GRM5	protein	P41594	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-189338	0.8
PRKCB	protein	P05771	UNIPROT	PA2G4	protein	Q9UQ80	UNIPROT	unknown	phosphorylation	Thr366	QSSASRKtQKKKKKK	9606									11325528	t		lperfetto	We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC.	SIGNOR-249093	0.286
IKBKB	protein	O14920	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	unknown	phosphorylation			9606									15489227	t		lperfetto	Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.	SIGNOR-217376	0.865
GPC6	protein	Q9Y625	UNIPROT	WNT5A	protein	P41221	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								31756413	t		miannu	GPC6 binds to Wnt5a and inhibits its release from producing cells. Based on theseresults, and in our finding that GPC6 inhibits non-canonical Wnt signaling in the developing intestine,we tested the hypothesis that GPC6 binds to Wnt5aat the surface of the Wnt5a-producing mesenchymalcells and restrains its release from them. 	SIGNOR-264030	0.383
CDH1	protein	P12830	UNIPROT	Epithelial-mesenchymal_transition	phenotype	SIGNOR-PH45	SIGNOR	down-regulates													15601859	f		lperfetto	A hallmark characteristic of epithelial tumor progression as well as some processes of normal development is the loss of the epithelial phenotype and acquisition of a motile or mesenchymal phenotype. Such epithelial to mesenchymal transitions are accompanied by the loss of E-cadherin function by either transcriptional or posttranscriptional mechanisms.	SIGNOR-252261	0.7
VEGFA	protein	P15692	UNIPROT	FLT1	protein	P17948	UNIPROT	up-regulates	binding			9606	BTO:0004980								14704231	t		gcesareni	Vegf exerts its action by binding to vegfr-1 and vegfr-2.	SIGNOR-121132	0.839
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	Mitotic_checkpoint	phenotype	SIGNOR-PH28	SIGNOR	down-regulates													15549093	f		lperfetto	The critical target of the G2 checkpoint is the mitosis-promoting activity of the cyclin B/CDK1 kinase, whose activation after various stresses is inhibited by ATM/ATR, CHK1/CHK2 and/or p38-kinase-mediated subcellular sequestration, degradation and/or inhibition of the CDC25 family of phosphatases that normally activate CDK1 at the G2/M boundary	SIGNOR-251496	0.7
α-Catenin	proteinfamily	SIGNOR-PF72	SIGNOR	CDH1	protein	P12830	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000586								21598020	t		miannu	Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14	SIGNOR-265817	0.2
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1647	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120092	0.316
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	TIAM1	protein	Q13009	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser329	DVNAGEGsEFADSGI	9606	BTO:0002181								25124033	t		miannu	Phosphorylation of Ser329, Ser334, and Thr340 in Tiam1 is required for its interaction with βTrCP1. The proteolysis of Tiam1 is prevented by βTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site.	SIGNOR-276674	0.2
GART	protein	P22102	UNIPROT	N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-)	smallmolecule	CHEBI:147286	ChEBI	up-regulates quantity	chemical modification			9606									33179964	t		miannu	The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner.	SIGNOR-267305	0.8
CASP8	protein	Q14790	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates activity				-1									10988287	f		lperfetto	One indirect means through which caspase-8 might regulate caspase-9 activation is through a bcl-2-regulated pathway.	SIGNOR-81811	0.59
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates activity	phosphorylation	Thr175	GLLPFLLtHKKRLTD	-1									19661060	t		miannu	 We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.	SIGNOR-276231	0.2
TBX21	protein	Q9UL17	UNIPROT	GATA3	protein	P23771	UNIPROT	down-regulates				9606									16386358	f			Conversely, T-bet is capable of inhibiting GATA-3 (Szabo et al., 2000). The mutual inhibition between GATA-3 and T-bet ensures that Th1 and Th2 cells express one or the other molecule (T-bet in Th1, and GATA-3 in Th2), but not both	SIGNOR-254295	0.753
GATA1	protein	P15976	UNIPROT	ZFPM1	protein	Q8IX07	UNIPROT	up-regulates activity	binding			9606									21853041	t		miannu	GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1.	SIGNOR-256059	0.791
MYC	protein	P01106	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12835716	t		gcesareni	C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation	SIGNOR-102731	0.512
IL1B	protein	P01584	UNIPROT	DIO1	protein	P49895	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									9397972	f		scontino	From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y.	SIGNOR-267486	0.2
PTBP2	protein	Q9UKA9	UNIPROT	HNRNPH1	protein	P31943	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								11003644	t		lperfetto	Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA.	SIGNOR-261269	0.399
S100G	protein	P29377	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									31731478	t		miannu	Intracellular calcium ion content is tightly regulated for the maintenance of cellular functions and cell survival. Calbindin-D9k (CaBP-9k) is responsible for regulating the distribution of cytosolic free-calcium ions.	SIGNOR-268517	0.8
PRKACA	protein	P17612	UNIPROT	PJA2	protein	O43164	UNIPROT	up-regulates activity	phosphorylation	Thr389	RVITQREtENNQMTS	-1									21423175	t		miannu	In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h).	SIGNOR-276323	0.2
LLGL1	protein	Q15334	UNIPROT	Scribble_complex_DLG3-LLGL1_variant	complex	SIGNOR-C507	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270895	0.579
LDHB	protein	P07195	UNIPROT	(S)-lactate	smallmolecule	CHEBI:16651	ChEBI	up-regulates quantity	chemical modification			9606									24929216	t		lperfetto	Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase.	SIGNOR-267657	0.8
MAP2K2	protein	P36507	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates	binding			9606									18596912	t		gcesareni	The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform.	SIGNOR-179393	0.2
PTPRT	protein	O14522	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606	BTO:0001109;BTO:0000182								17360477	t	brain	lperfetto	Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T|Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position.	SIGNOR-263981	0.531
SP7	protein	Q8TDD2	UNIPROT	Osteoblast_differentiation	phenotype	SIGNOR-PH9	SIGNOR	up-regulates				10090									11792318	f		Giulio Giuliani	Our results established that the novel transcription factor Osx is required for osteoblast differentiation and hence for bone formation.	SIGNOR-255449	0.7
DOT1L	protein	Q8TEK3	UNIPROT	MCL1	protein	Q07820	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27856324	f		irozzo	Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4.	SIGNOR-255881	0.2
NAALAD2	protein	Q9Y3Q0	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	chemical modification			9606									10085079	t		miannu	The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated.	SIGNOR-267542	0.8
WKYMVm	chemical	CID:457933	PUBCHEM	FPR2	protein	P25090	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257493	0.8
PRKCD	protein	Q05655	UNIPROT	SLC29A1	protein	Q99808	UNIPROT	up-regulates activity	phosphorylation	Ser281	QPTNESHsIKAILKN	9606									25725289	t		Manara	 Phosphorylation of hENT1 by PKC has effects on both the function and subcellular trafficking of hENT1	SIGNOR-260888	0.2
palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	precursor of			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267881	0.8
A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257706	0.56
NRF1	protein	Q16656	UNIPROT	ENOX1	protein	Q8TC92	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23939472	f		miannu	We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons.	SIGNOR-261368	0.268
BMPR2	protein	Q13873	UNIPROT	BMPR1B	protein	O00238	UNIPROT	up-regulates	binding			9606									10712517	t		gcesareni	Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii).	SIGNOR-75655	0.608
CSNK2A1	protein	P68400	UNIPROT	PIAS1	protein	O75925	UNIPROT	up-regulates	phosphorylation	Ser467	IDLTIDSsSDEEEEE	9606									19217413	t		llicata	Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process.	SIGNOR-184043	0.337
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	BCR	protein	P11274	UNIPROT	down-regulates activity	phosphorylation	Tyr328	YSPRSFEdCGGGYTP	9606									9467953	t		Manara	Thus, we propose that the phosphorylation of tyrosine 328 and 360 within Bcr by Bcr ± Abl will drastically interfere with Bcr's kinase role in either signal transduction or some other cellular mechanism.	SIGNOR-260829	0.2
ATM	protein	Q13315	UNIPROT	FBXO31	protein	Q5XUX0	UNIPROT	up-regulates	phosphorylation	Ser278	LMKFIYTsQYDNCLT	9606	BTO:0000150;BTO:0001130								19412162	t		lperfetto	We find that dna damage induced by gamma-irradiation results in increased fbxo31 levels, which requires phosphorylation of fbxo31 by the ddr-initiating kinase atm	SIGNOR-185635	0.416
DNAAF10	protein	Q96MX6	UNIPROT	PAQosome co-chaperone complex	complex	SIGNOR-C516	SIGNOR	form complex	binding			9606									30484152	t		miannu	The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92. 	SIGNOR-270921	0.2
DAPT	chemical	CHEBI:86193	ChEBI	APP	protein	P05067	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191292	0.8
PTPRC	protein	P08575	UNIPROT	JAK3	protein	P52333	UNIPROT	up-regulates	dephosphorylation			9606	BTO:0000776;BTO:0003076								11994288	t		gcesareni	These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3,	SIGNOR-87157	0.468
PLK3	protein	Q9H4B4	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Ser198	SDELMEFsLKDQEAK	9606									14968113	t		lperfetto	Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation	SIGNOR-122094	0.721
CDC25A	protein	P30304	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates activity	dephosphorylation			9606	BTO:0000093								11154267	t		lperfetto	Expression of Cdc25A mRNA and protein was induced by E(2) in control and p16(INK4a)-expressing MCF-7 cells; however, functional activity of Cdc25A was inhibited in cells expressing p16(INK4a). Inhibition of Cdc25A activity in p16(INK4a)-expressing cells was associated with depressed Cdk2 activity	SIGNOR-245449	0.824
HCFC1	protein	P51610	UNIPROT	ZBTB17	protein	Q13105	UNIPROT	down-regulates activity	binding			9534	BTO:0001538								12244100	t		miannu	We show here that HCF-1 directly binds to the Myc-interacting protein Miz-1. HCF-1 Represses Gal4-Miz-1-mediated Transcriptional Activation	SIGNOR-223590	0.35
BAG3	protein	O95817	UNIPROT	SIRT5	protein	Q9NXA8	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30910998	f		Monia	Ectopic BAG3 expression decreases the interaction between GLS and SIRT5. we demonstrated that BAG3 overexpression decreased SIRT5 expression in HepG2 cells (Fig. 5d).	SIGNOR-261205	0.2
GNGT1	protein	P63211	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606									17419683	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt	SIGNOR-154261	0.408
SUZ12	protein	Q15022	UNIPROT	SUZ12/EED	complex	SIGNOR-C76	SIGNOR	form complex	binding			9606									16712789	t		miannu	Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2.	SIGNOR-146761	0.942
CEP76	protein	Q8TAP6	UNIPROT	PLK1	protein	P53350	UNIPROT	down-regulates activity	binding			9606	BTO:0001938								27065329	t		miannu	Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase. Cep76 is preferentially phosphorylated by cyclin A/CDK2 at a single site S83, and this event is crucial to suppress centriole amplification in S phase. Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification. 	SIGNOR-262731	0.408
DYRK3	protein	O43781	UNIPROT	AKT1S1	protein	Q96B36	UNIPROT	down-regulates	phosphorylation			9606				SIGNOR-C3					23415227	t		lperfetto	When dyrk3 is active, it allows stress granule dissolution, releasing mtorc1 for signaling and promoting its activity by directly phosphorylating the mtorc1 inhibitor pras40	SIGNOR-201002	0.348
MAPK14	protein	Q16539	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser46	AMDDLMLsPDDIEQW	9606	BTO:0000093								17535811	t		lperfetto	P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.	SIGNOR-155246	0.765
IGF1R	protein	P08069	UNIPROT	PCNA	protein	P12004	UNIPROT	up-regulates activity	phosphorylation	Tyr133	LGIPEQEySCVVKMP	-1									28924044	t		miannu	In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination.	SIGNOR-277254	0.2
PKN1	protein	Q16512	UNIPROT	PKN1	protein	Q16512	UNIPROT	up-regulates activity	phosphorylation	Thr531	PNATGTGtFSPGASP	-1									10467162	t		lperfetto	Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect.	SIGNOR-249020	0.2
EIF3M	protein	Q7L2H7	UNIPROT	EIF3_complex	complex	SIGNOR-C401	SIGNOR	form complex	binding			-1									16920360	t		miannu	Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 	SIGNOR-266388	0.933
TFDP1	protein	Q14186	UNIPROT	CCNE1	protein	P24864	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253857	0.552
SKIL	protein	P12757	UNIPROT	SMAD1/4	complex	SIGNOR-C85	SIGNOR	down-regulates	binding			9606									22298955	t		lperfetto	Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7	SIGNOR-217709	0.688
THRB	protein	P10828	UNIPROT	GATA2	protein	P23769	UNIPROT	down-regulates activity	binding			9606		BTO:0001073							29407449	t		scontino	We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2.	SIGNOR-267256	0.2
SOX3	protein	P41225	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9606									10549281	t		gcesareni	Two additional sox proteins, xsox17alfa and xsox3, likewise bind to beta-catenin and inhibit its tcf-mediated signaling activity.	SIGNOR-72039	0.475
EIF4G2	protein	P78344	UNIPROT	EIF2S2	protein	P20042	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								29530922	t		miannu	Unlike eIF4GI/II, DAP5 binds eIF2β, a subunit of the eIF2 complex that delivers methionyl-tRNA to ribosomes. 	SIGNOR-266385	0.743
BRAF	protein	P15056	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates activity	phosphorylation	Ser614	SHQFEQLsGSILWMA	9606	BTO:0002181								27345148	t		miannu	The phosphorylation of S614 is mitogen inducible and the result of autophosphorylation. These data suggest that phosphorylation at this site is inhibitory, and part of the physiological shut-down mechanism of BRAF signalling.	SIGNOR-277255	0.2
CDK16	protein	Q00536	UNIPROT	PRKAR1A	protein	P10644	UNIPROT	up-regulates activity	phosphorylation	Ser83	DSREDEIsPPPPNPV	9606	BTO:0000567								25605337	t		lperfetto	PCTK1 regulates spindle orientation in a kinase-dependent manner. Phosphoproteomic analysis together with an RNA interference screen revealed that PCTK1 regulates spindle orientation through phosphorylation of Ser83 on KAP0, a regulatory subunit of protein kinase A (PKA)	SIGNOR-273018	0.275
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	KCNJ1	protein	P48048	UNIPROT	up-regulates activity	phosphorylation	Ser4	sSRNVFDT	-1									12221079	t		miannu	We conclude that ROMK1 is a substrate of PKC and that serine residues 4 and 201 are the two main PKC phosphorylation sites that are essential for the expression of ROMK1 in the cell surface.	SIGNOR-275989	0.2
panobinostat	chemical	CHEBI:85990	ChEBI	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257753	0.8
EEF1A1P5	protein	Q5VTE0	UNIPROT	Ala-tRNA(Ala)	smallmolecule	CHEBI:17732	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269543	0.8
ZAP70	protein	P43403	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates activity	phosphorylation	Tyr145	PVEDDADyEPPPSND	9606									12817019	t		lperfetto	Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase.	SIGNOR-102515	0.798
PHKG1	protein	Q16816	UNIPROT	PYGL	protein	P06737	UNIPROT	up-regulates activity	phosphorylation	Ser15	QEKRRQIsIRGIVGV	9606	BTO:0002049								22225877	t			It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15	SIGNOR-267399	0.532
GNAQ	protein	P50148	UNIPROT	TRIOBP	protein	Q9H2D6	UNIPROT	up-regulates activity	binding			-1									17606614	t			We show that the C-terminal Rho-specific DH-PH cassette of Trio is similarly activated by Galpha(q)	SIGNOR-256494	0.2
STC2	protein	O76061	UNIPROT	STC2/HMOX1	complex	SIGNOR-C244	SIGNOR	form complex	binding				BTO:0000298								22503972	t		Giorgia	Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme.	SIGNOR-260387	0.352
RAC1	protein	P63000	UNIPROT	BAIAP2	protein	Q9UQB8	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								19171758	t		miannu	In this study, we report that Kank disrupts the function of active Rac1 through IRSp53. The binding between IRSp53 and Kank inhibits the association of active Rac1 with IRSp53 rather than the association of active cdc42 with IRSp53. Kank inhibits the formation of lamellipodia and membrane ruffles induced by active Rac1 in NIH3T3 cells.	SIGNOR-265554	0.728
CENPS	protein	Q8N2Z9	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265205	0.2
DLG4	protein	P78352	UNIPROT	LRFN2	protein	Q9ULH4	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								21736948	t		miannu	 SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. Interactions between SALMs 1–3 and PSD-95 family proteinscould serve a number of functions. SALM1 and SALM2, which lack the ability to interact with a presynaptic ligand and thus cannot be directly targeted to sites of early synaptic adhesion, may require PSD-95 binding for their localization to early synapses.	SIGNOR-264094	0.74
UVB radiation	stimulus	SIGNOR-ST17	SIGNOR	MC1R	protein	Q01726	UNIPROT	up-regulates				9606									9767234	f		miannu	Melanocyte-stimulating hormone (MSH) receptor binding activity and melanocortin-1 receptor (MC1-R) gene expression on normal human melanocytes have been studied as responses to the effects of ultraviolet B (UVB), interleukin-1 (IL-1), endothelin-1 (ET-1) and tumour necrosis factor-alpha (TNF-alpha), which are known as UV sensitive regulators of melanocytic function. MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression.	SIGNOR-252388	0.7
EGFR	protein	P00533	UNIPROT	CTNND1	protein	O60716	UNIPROT	unknown	phosphorylation	Tyr228	YPGGSDNyGSLSRVT	9606	BTO:0000017								14996911	t		llicata	In A431 cells, epidermal growth factor induced striking p120 phosphorylation at Y228. Y228-phosphorylated p120 localized to adherens junctions and lamellipodia, and was significantly enhanced in cells around the colony periphery.	SIGNOR-251092	0.625
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CDK2	protein	P24941	UNIPROT	up-regulates	phosphorylation	Thr160	GVPVRTYtHEVVTLW	9606				SIGNOR-C16					12359725	t		lperfetto	In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e.	SIGNOR-244614	0.2
PRKCA	protein	P17252	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser328	QDAYRRNsVRFLQQR	9606									12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89166	0.538
Calcineurin	complex	SIGNOR-C155	SIGNOR	Chemorepulsion_of_axon	phenotype	SIGNOR-PH198	SIGNOR	up-regulates				9606									15363394	f		miannu	In this study, we have identified CaMKII and CaN-PP1 as the downstream effectors of localized Ca2+ signals in mediating attractive and repulsive turning responses of growth cones, respectively. Local Ca2+ elevation activates CaMKII and CaN-PP1 for attraction and repulsion, respectively.	SIGNOR-268386	0.7
adenosine	smallmolecule	CHEBI:16335	ChEBI	ADORA1	protein	P30542	UNIPROT	up-regulates activity	binding			-1									14662005	t		Luana	Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3.	SIGNOR-268419	0.8
LSM3	protein	P62310	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270633	0.791
PRKDC	protein	P78527	UNIPROT	POU2F1	protein	P14859	UNIPROT	down-regulates	phosphorylation	Ser232	LTQLPQQsQANLLQS	9606									9368058	t		lperfetto	Through a similar strategy, t226 and s232 were characterized as the dna-pk phosphorylation sites	SIGNOR-53258	0.335
MAPKAPK3	protein	Q16644	UNIPROT	HSPB1	protein	P04792	UNIPROT	unknown	phosphorylation	Ser82	RALSRQLsSGVSEIR	-1									8774846	t		miannu	MAPKAP kinase-3 and MAPKAP kinase-2 phosphorylated peptide substrates with similar kinetic constants and phosphorylated the same serine residues in HSP27 at the same relative rates.The three serine residues in HSP27 phosphorylated by MAPKAPK2 were also phosphorylated at the same relative rates by MAPKAP-K3 (Ser-82>>Ser-78 >Ser-15)	SIGNOR-250161	0.672
RAP1GDS1	protein	P52306	UNIPROT	RHOC	protein	P08134	UNIPROT	up-regulates	binding			9606									21242305	t		miannu	Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc	SIGNOR-171399	0.303
oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	up-regulates quantity	precursor of			9606									30193097	t		miannu	 PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP). 	SIGNOR-266586	0.8
HNuRF	complex	SIGNOR-C448	SIGNOR	EN2	protein	P19622	UNIPROT	up-regulates quantity by expression				9606									14609955	f		miannu	Human NURF (hNURF) is enriched in brain, and we demonstrate that it regulates human Engrailed, a homeodomain protein that regulates neuronal development in the mid-hindbrain. Furthermore, we show that hNURF potentiates neurite outgrowth in cell culture. Taken together, our data suggess a role for an ISWI complex in neuronal growth. ) ChIP assays localize hNURF specifically to engrailed-1 (en-1) and engrailed-2 (en-2) promoters.	SIGNOR-268840	0.308
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				10090									20219869	f		areggio	Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation.	SIGNOR-255120	0.7
WNT10B	protein	O00744	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131631	0.606
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser268	VALPPGAsPQRSRSP	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248688	0.613
tyrosine	smallmolecule	CHEBI:18186	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264757	0.7
belinostat	chemical	CHEBI:61076	ChEBI	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257954	0.8
RNF183	protein	Q96D59	UNIPROT	TNFRSF10B	protein	O14763	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								31889078	t		miannu	RNF183 mediated K63-linked ubiquitination and lysosomal degradation of DR5.	SIGNOR-272212	0.2
GH1	protein	P01241	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001939								15665309	t		Luana	Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells	SIGNOR-261628	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PPP2R5C	protein	Q13362	UNIPROT	down-regulates	phosphorylation			9606									16456541	t	inferred from 70% family members	gcesareni	Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit.	SIGNOR-270101	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MTOR	protein	P42345	UNIPROT	unknown	phosphorylation	Thr2446	NKRSRTRtDSYSAGQ	9606									10910062	t			AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR. 	SIGNOR-251482	0.2
CDC25A	protein	P30304	UNIPROT	CDK4	protein	P11802	UNIPROT	up-regulates activity	dephosphorylation	Tyr17	AEIGVGAyGTVYKAR	9606									27485204	t		miannu	Cdc25A mainly promotes G1-S transition by dephosphorylating CDK4 (Y17)-cyclin D, CDK6 (Y24)-cyclin D and CDK2 (T14 and Y15)-cyclin E/A complexes and G2-M progression by dephosphorylating CDK1 (T14 and Y15)-cyclin A/B    .|Cdc25A mainly promotes G1-S transition by dephosphorylating CDK4 (Y17)-cyclin D, CDK6 (Y24)-cyclin D and CDK2 (T14/Y15)-cyclin E/A complexes and G2-M progression by dephosphorylating CDK1 (T14/Y15)-cyclin A/B .	SIGNOR-277138	0.694
GSK3A	protein	P49840	UNIPROT	BCL3	protein	P20749	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser406	PSSSPSQsPPRDPPG	9606	BTO:0000007								15469820	t		miannu	In this report, we show that BCL-3 is a substrate for the protein kinase GSK3 and that GSK3-mediated BCL-3 phosphorylation, which is inhibited by Akt activation, targets its degradation through the proteasome pathway.	SIGNOR-276012	0.401
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1735	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273093	0.745
XL765	chemical	CHEBI:71958	ChEBI	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207875	0.8
CAMP	protein	P49913	UNIPROT	FPR2	protein	P25090	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0000876								11015447	t		gcesareni	Ll-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and t cells to sites of microbial invasion by interacting with fprl1.	SIGNOR-82701	0.55
8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	chemical	CHEBI:93369	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10116		BTO:0000601							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258540	0.8
SUN1	protein	O94901	UNIPROT	TERB1	protein	Q8NA31	UNIPROT	up-regulates activity	binding			9606	BTO:0000007		SIGNOR-C303	SIGNOR-C305					33015044	t		lperfetto	In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | It will be of great interest to test this hypothesis to fully understand the mechanisms of stable telomere–NE connection and telomere movement along the NE driven by the LINC complex.	SIGNOR-263299	0.2
PIP3	smallmolecule	CHEBI:16618	ChEBI	WDR45	protein	Q9Y484	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0001938								28561066	t		miannu	All WIPI members fold into seven-bladed β-propeller proteins that bind PtdIns3P and co-localize at nascent autophagosomes.	SIGNOR-268475	0.8
FYN	protein	P06241	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	down-regulates activity	phosphorylation	Tyr374	PLPPAPAyLSSPLAL	9606	BTO:0000007								23131831	t		miannu	Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation. 	SIGNOR-276371	0.363
FGF11	protein	Q92914	UNIPROT	SCN4A	protein	P35499	UNIPROT	down-regulates activity	binding			9606		BTO:0001103							20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253434	0.2
KLF10	protein	Q13118	UNIPROT	TGFBI	protein	Q15582	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								18359287	t		lperfetto	Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia.	SIGNOR-253212	0.244
YAP1	protein	P46937	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	binding			9606		BTO:0000562							23607968	t		gcesareni	Additionally, the hippo and wnts also cooperate in the nucleus, where yap interacts with beta-catenin and induces the expression of canonical wnt target genes, such as sox2 and snai2 in mouse heart tissue.	SIGNOR-201939	0.547
CSNK2A1	protein	P68400	UNIPROT	CLIP1	protein	P30622	UNIPROT	up-regulates	phosphorylation	Ser1364	DDLNNYDsDDQEKQS	9606									20664522	t		lperfetto	Herein, we have identified polo-like kinase 1 (plk1) and casein kinase 2 (ck2) as two kinases of clip-170 and mapped s195 and s1318 as their respective phosphorylation sites.Plk1- and ck2-associated phosphorylations of clip-170 are involved in the timely formation of kinetochore-microtubule attachments in mitosis	SIGNOR-167168	0.298
midostaurin	chemical	CHEBI:63452	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition												16969355	t		lperfetto	Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases	SIGNOR-261982	0.8
(2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide	chemical	CHEBI:91449	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-204490	0.8
MAP2K6	protein	P52564	UNIPROT	MAPK11	protein	Q15759	UNIPROT	up-regulates	phosphorylation			9606									9430721	t		gcesareni	The p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms.	SIGNOR-54947	0.688
DAPK3	protein	O43293	UNIPROT	DAPK3	protein	O43293	UNIPROT	up-regulates	phosphorylation	Thr180	EFKNIFGtPEFVAPE	9606									15611134	t		gcesareni	Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates.	SIGNOR-132459	0.2
Host translation inhibitor nsp1	protein	P0C6X7-PRO_0000037309	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates activity				9606	BTO:0000007								17715225	f		miannu	SARS-CoV nsp1 inhibits c-Jun expression and phosphorylation.	SIGNOR-262505	0.2
AKT1	protein	P31749	UNIPROT	DNMT1	protein	P26358	UNIPROT	up-regulates	phosphorylation	Ser143	RTPRRSKsDGEAKPE	9606									21151116	t		gcesareni	Akt1 kinase colocalizes and directly interacts with dnmt1 and phosphorylates ser143. Phosphorylated dnmt1 peaks during dna synthesis, before dnmt1 methylation. Depletion of akt1 or overexpression of dominant-negative akt1 increases methylated dnmt1, resulting in a decrease in dnmt1 abundance. In mammalian cells, phosphorylated dnmt1 is more stable than methylated dnmt1.	SIGNOR-170530	0.544
DMTF1	protein	Q9Y222	UNIPROT	THBS1	protein	P07996	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004532								19816943	t		Luana	 Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. 	SIGNOR-261587	0.2
PRKCA	protein	P17252	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Ser266	FGYGGRAsDYKSAHK	-1									2413024	t		lperfetto	MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 	SIGNOR-248873	0.503
PPP2CA	protein	P67775	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	down-regulates	dephosphorylation			9606									12840032	t	inferred from 70% of family members	gcesareni	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).	SIGNOR-269896	0.2
SYN1	protein	P17600	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates activity	binding			9606	BTO:0000938								15265865	t		miannu	Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. 	SIGNOR-269187	0.7
Brivanib alaninate	chemical	CID:11154925	PUBCHEM	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190732	0.8
SPART	protein	Q8N0X7	UNIPROT	ITCH	protein	Q96J02	UNIPROT	up-regulates activity	binding			9606									19580544	t		miannu	 Cytosolic endogenous spartin is mono-ubiquitinated and we demonstrate that it interacts via a PPXY motif with the ubiquitin E3 ligases AIP4 [atrophin-interacting protein 4; ITCH (itchy E3 ubiquitin protein ligase homologue] [corrected] and AIP5 (WWP1). Surprisingly, the PPXY motif, AIP4 and AIP5 are not required for spartin's ubiquitination, and so we propose that spartin acts as an adaptor for these proteins.	SIGNOR-261306	0.2
SNAPIN	protein	O95295	UNIPROT	BLOC-1	complex	SIGNOR-C381	SIGNOR	form complex	binding			9606									22203680	t		lperfetto	We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter.	SIGNOR-265935	0.713
KDR	protein	P35968	UNIPROT	KDR	protein	P35968	UNIPROT	up-regulates	phosphorylation	Tyr996	EEAPEDLyKDFLTLE	9606									10102632	t		lperfetto	Autophosphorylation of kdr in the kinase domain is required for maximal vegf-stimulated kinase activity and receptor internalizationthe intensity of vegf-induced autophosphorylation is significantly reduced when using receptor mutated at y996, confirming that this is a major site of autophosphorylation. Second, tyrosines 951 and 996 are the only two tyrosines in the receptor's kinase insert domain, and there is strong evidence from studies using the pdgfr and cfms that autophosphorylation of tyrosines in this domain leads to important signaling events.	SIGNOR-66040	0.2
LCK	protein	P06239	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	down-regulates activity	phosphorylation	Tyr354	SSNQELIyEGRRLVL	9606	BTO:0002181								28618271	t		miannu	The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. 	SIGNOR-276724	0.2
PIAS1	protein	O75925	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	sumoylation	Lys276	NVVYRDLkLENLMLD	10090	BTO:0002572								23884910	t		gcesareni	Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity.	SIGNOR-252737	0.387
FER	protein	P16591	UNIPROT	JUP	protein	P14923	UNIPROT	up-regulates activity	phosphorylation	Tyr550	AAGTQQPyTDGVRME	10116	BTO:0004604								14517306	t			The tyrosine kinase Fer, which modifies beta-catenin Tyr142, lessening its association with alpha-catenin, phosphorylates plakoglobin Tyr549 and exerts the contrary effect: it raises the binding of plakoglobin to alpha-catenin. Fer stimulation, through modification of Tyr549, causes diminished binding of plakoglobin to components of desmosomes (desmoplakin) and increased interaction with adherens junction proteins (α-catenin)	SIGNOR-251134	0.504
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TP53RK	protein	Q96S44	UNIPROT	up-regulates	phosphorylation	Ser250	RLRGRKRsMVG	9606									17712528	t		gcesareni	Here we show that such an activation of prpk is mediated by another kinase, akt/pkb, which phosphorylates prpk at ser250.	SIGNOR-157467	0.2
Caspase 8 complex	complex	SIGNOR-C231	SIGNOR	CASP3	protein	P42574	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000007								16964285	t		amattioni	Casp8 induces apoptosis by directly activating casp3.	SIGNOR-256458	0.713
IRF5	protein	Q13568	UNIPROT	IL1B	protein	P01584	UNIPROT	up-regulates	transcriptional regulation			10090									26315890	f		svumbaca	IL-1b was present in the sera of wild-type mice but was not detected in the sera of IRF5-/- mice	SIGNOR-255340	0.297
CSNK1D	protein	P48730	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser212	SVKLRGSsLFMDTEK	-1									24817118	t		miannu	Casein kinase 1-mediated N-terminal Weee1 phosphorylation is required for interaction with the F-box protein β-TrCP.MS/MS spectra of human Wee1 identifying serine 212 as phosphorylated after incubation with recombinant CK1δ.	SIGNOR-276631	0.314
USF1	protein	P22415	UNIPROT	CTSD	protein	P07339	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								9731700	f		miannu	Overexpression of cathepsin D (CD), a ubiquitous lysosomal protease, is closely associated with a poor clinical outcome for patients with breast cancer. Estrogen greatly induces transcription of the CD gene in estrogen receptor (ER)-positive breast cancer cells. These experiments suggest a model for ER stimulation of the CD promoter in which recruitment of USF-1/2 to the promoter is required for activation of transcription.	SIGNOR-255595	0.386
MYCBP2	protein	O75592	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001321								32814769	t		miannu	 We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. 	SIGNOR-267149	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ARRB2	protein	P32121	UNIPROT	up-regulates activity	phosphorylation	Thr276	FCKVYTItPLLSDNR	10090	BTO:0002572								26324936	t	done	miannu	ERK1/2-dependent βarr2 phosphorylation on S14 and T276 induces CXCR4 intracellular sequestration.	SIGNOR-274019	0.2
ITGB1BP1	protein	O14713	UNIPROT	A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257659	0.356
CAMK2A	protein	Q9UQM7	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Ser1081	TGALTEDsIDDTFLP	9606	BTO:0000007								10347170	t		llicata	 We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. 	SIGNOR-250622	0.378
CBL	protein	P22681	UNIPROT	FRS2	protein	Q8WU20	UNIPROT	down-regulates	ubiquitination			9606									11997436	t		lperfetto	The experiments presented in this report illustrate that in response to fgf stimulation, cbl is recruited by grb2 binding to the frs2_ multiprotein complex, resulting in ubiquitination of frs2_ and fgfr. grb2 functions as a link between frs2_ and cbl;grb2 is bound to tyrosine-phosphorylated frs2_ by means of its sh2 domain and to a proline-rich region in the c terminus of cbl by means of its sh3 domains.	SIGNOR-87166	0.557
CDC42	protein	P60953	UNIPROT	PAK1	protein	Q13153	UNIPROT	up-regulates activity	binding			10090	BTO:0000142								8107774	t		gcesareni	A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways.	SIGNOR-248243	0.941
HOXB13	protein	Q92826	UNIPROT	TCF4	protein	P15884	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001033								15928669	f	 	miannu	In prostate cancers, HOXB13 negatively regulates beta-catenin/TCF4-mediated transactivation and subsequently inhibits cell growth. 	SIGNOR-254476	0.2
TNF	protein	P01375	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253482	0.2
TWIST2	protein	Q8WVJ9	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255503	0.2
MTNR1B	protein	P49286	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257102	0.252
MAPK8	protein	P45983	UNIPROT	MCL1	protein	Q07820	UNIPROT	up-regulates	phosphorylation	Thr163	TDGSLPStPPPAEEE	9606	BTO:0000150								18676833	t		gcesareni	Mcl-1 can be rapidly degraded by certain death-inducing signals, but it is able to be readily induced by diverse survival cytokines such as epidermal growth factor, vascular endothelial growth factor, granulocyt-macrophage colony-stimulating factor, and interleukin 3 through phosphatidy-linositol-3-oh kinase/akt, mek/mapk, or janus-activated kinase/stat signaling cascades	SIGNOR-179816	0.543
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr730	SNCTNELyMMMRDCW	10116	BTO:0002809;BTO:0001009								8622701	t		lperfetto	In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1	SIGNOR-235686	0.2
MAPK1	protein	P28482	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser195	PNSSYPNsPGSSSST	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3	SIGNOR-161597	0.59
MRE11	protein	P49959	UNIPROT	NBN	protein	O60934	UNIPROT	up-regulates	binding			9606									17713585	t		esanto	The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50.	SIGNOR-157475	0.2
FLT4	protein	P35916	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates activity	phosphorylation	Tyr1333	ARGGQVFyNSEYGEL	9606	BTO:0000394								12881528	t		lperfetto	Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail.	SIGNOR-104084	0.2
MAPK8	protein	P45983	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser383	IHFWSTLsPIAPRSP	9606									8846788	t		gcesareni	However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity.	SIGNOR-44356	0.494
GNAQ	protein	P50148	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates	binding			9606									9235901	t		gcesareni	Galfaq/11 subunits also activate p21ras	SIGNOR-50104	0.631
CSNK1D	protein	P48730	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	phosphorylation	Ser330	MEEDSYDsFGEPSYP	-1									9558331	t		llicata	In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites.	SIGNOR-250801	0.371
IL21	protein	Q9HBE4	UNIPROT	BCL6	protein	P41182	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782;BTO:0000785								22486304	f		miannu	Interleukin-21 inhibits humoral response to an hiv dna vaccine by enhancing bcl-6 andpax-5expression.	SIGNOR-196918	0.408
PD318088	chemical	CID:10231331	PUBCHEM	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	lperfetto		SIGNOR-244927	0.8
PCDHA7	protein	Q9UN72	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-265667	0.2
NUPR1	protein	O60356	UNIPROT	ATF4	protein	P18848	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								19946894	f	 	lperfetto	Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4.	SIGNOR-253731	0.396
LPAR1	protein	Q92633	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606									20331961	t		gcesareni	The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits)	SIGNOR-164682	0.524
CSNK2B	protein	P67870	UNIPROT	CTDP1	protein	Q9Y5B0	UNIPROT	down-regulates activity	phosphorylation	Ser740	TKAQRENsPAAFPDR	9606	BTO:0000567								12591939	t		llicata	We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified 	SIGNOR-251064	0.332
SMARCA5	protein	O60264	UNIPROT	B-WICH complex	complex	SIGNOR-C447	SIGNOR	form complex	binding			9606									21559432	t		miannu	The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 	SIGNOR-268825	0.49
COLGALT1	protein	Q8NBJ5	UNIPROT	ADIPOQ	protein	Q15848	UNIPROT	up-regulates activity	palmitoylation			9606	BTO:0000007								28428430	t			We conclude that GLT25D1 regulates HMW adiponectin secretion and lipid accumulation, consistent with changes in mice after high-fat feeding. These results suggest a novel function of GLT25D1 leading to decreased HMW adiponectin secretion in early obesity.	SIGNOR-261149	0.2
RPSA	protein	P08865	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262414	0.839
Nucleosome_H3.1t variant	complex	SIGNOR-C325	SIGNOR	Transcritpional_activation	phenotype	SIGNOR-PH205	SIGNOR	down-regulates				9606									15623580	f		lperfetto	All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage.	SIGNOR-273454	0.7
irinotecan	chemical	CHEBI:80630	ChEBI	TOP1MT	protein	Q969P6	UNIPROT	down-regulates activity	chemical inhibition			9606									15170677	t		miannu	Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin; CPT-11) is a widely used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I)	SIGNOR-259315	0.8
SRC	protein	P12931	UNIPROT	AP2B1	protein	P63010	UNIPROT	down-regulates	phosphorylation	Tyr737	THRQGHIyMEMNFTN	9606									18938240	t		gcesareni	The phosphorylation of beta2-adaptin on tyrosine residue 737 (y737) negatively regulates its interaction with betaarrestin.	SIGNOR-181743	0.276
iron-sulfur cluster	smallmolecule	CHEBI:30408	ChEBI	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	up-regulates activity	chemical activation												26083061	t		lperfetto	Respiratory chain complexes I–III depend on Fe-S clusters for function	SIGNOR-262135	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser104	FPPLNSVsPSPLMLL	9606	BTO:0000567								17615152	t		lperfetto	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity	SIGNOR-244647	0.2
EEF1A1	protein	P68104	UNIPROT	Thr-tRNA(Thr)	smallmolecule	CHEBI:29163	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269516	0.8
MYC	protein	P01106	UNIPROT	HLA-C	protein	P10321	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000848								8206526	f		miannu	 In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene.	SIGNOR-254602	0.259
EPHB1	protein	P54762	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	relocalization												26319181	t		lperfetto	The phosphorylated CNK1 interacts with ephrinB1. The binding of ephrinB1 to CNK1 connects RhoA and p115RhoGEF with ephrinB1-associated MKK4, promoting JNK activation and cell migration.	SIGNOR-275922	0.2
FLI1	protein	Q01543	UNIPROT	ANKRD26	protein	Q9UPS8	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000843								24430186	t		lperfetto	In healthy individual, RUNX1/FLI1 complex negatively regulates ANKRD26 gene expression in MKs.	SIGNOR-266070	0.288
HIPK2	protein	Q9H2X6	UNIPROT	PPM1D	protein	O15297	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser85	PLPDAGAsPAPSRCC										23871434	t		lperfetto	WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation|Analysis of the phosphoamino acids of WIP1 revealed that both Ser85 and Ser54 are phosphorylation sites, confirming that HIPK2 is a protein kinase for WIP1 phosphorylation at Ser54 as well as Ser85 	SIGNOR-275481	0.431
ABL1	protein	P00519	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates activity	phosphorylation	Tyr231	NANGEAVyCKFHYKT	9606	BTO:0000093								12777400	t		lperfetto	The SH3 domains of c-Abl and Arg bound directly to catalase at a P293FNP site. c-Abl and Arg phosphorylated catalase at Tyr231 and Tyr386 in vitro and in the response of cells to H2O2	SIGNOR-101298	0.412
SMARCD1	protein	Q96GM5	UNIPROT	Muscle cell-specific SWI/SNF ARID1B variant	complex	SIGNOR-C482	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270707	0.789
MAPK14	protein	Q16539	UNIPROT	COL1A1	protein	P02452	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22298955	f		gcesareni	(tak1) and tak1 binding protein 1 (tab1) play a pivotal role as upstream sig-nal transducers by activating the mkk3-p38 mapk signaling cascade that leads to the induction of type i collagen expression by tgf-beta1.	SIGNOR-192796	0.277
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000007								12832467	t	inferred from 70% family members	lperfetto	Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.	SIGNOR-270006	0.2
gemcitabine	chemical	CHEBI:175901	ChEBI	RRM2	protein	P31350	UNIPROT	down-regulates activity	chemical inhibition			-1									2233693	t		miannu	Direct assays of partially purified ribonucleoside diphosphate reductase (EC 1.17.4.1) demonstrated 50% inhibition by 4 microM dFdC 5'-diphosphate; dFdC 5'-triphosphate was much less inhibitory. We conclude that dFdC 5'-diphosphate acts as an inhibitor of ribonucleoside diphosphate reductase.	SIGNOR-258387	0.8
PTPN2	protein	P17706	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	dephosphorylation	Tyr1021	PNEGDNDyIIPLPDP	10090	BTO:0002572								14966296	t			The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP. 	SIGNOR-248390	0.545
PRKACA	protein	P17612	UNIPROT	APOBEC3B	protein	Q9UH17	UNIPROT	down-regulates activity	phosphorylation	Thr214	LVLRRRQtYLCYEVE	-1									31165764	t		miannu	Here we show that protein kinase A (PKA) physically binds to A3B and phosphorylates Thr214.	SIGNOR-277455	0.2
GALR3	protein	O60755	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256998	0.281
romidepsin	chemical	CHEBI:61080	ChEBI	HDAC4	protein	P56524	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257991	0.8
PTPRE	protein	P23469	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Tyr187	HTGFLTEyVATRWYR	9606									12754301	t		llicata	The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling|These enzymes are joined by the large family of dual-specificity phosphatases, which are structurally similar to tyrosine phosphatases but which can dephosphorylate both residues of the activation loop	SIGNOR-248448	0.398
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1864	SPKYSPTsPKYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269358	0.718
terbutaline	chemical	CHEBI:9449	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			10030									20590599	t		Luana	Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)	SIGNOR-257872	0.8
SLC9A3R1	protein	O14745	UNIPROT	ADRB2	protein	P07550	UNIPROT	up-regulates activity	binding			-1									9671706	t		lperfetto	The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the beta2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange. NHERF contains two PDZ domains, the first of which is required for its interaction with the beta2 receptor. 	SIGNOR-262598	0.581
H4C1	protein	P62805	UNIPROT	BRD2	protein	P25440	UNIPROT	up-regulates activity	relocalization			9606					acetylation:Lys21	GGAKRHRkVLRDNIQ			12776177	t		lperfetto	Thus, the TIP60 HAT complex is recruited to MYC-target genes and, probably with other other HATs, contributes to histone acetylation in response to mitogenic signals.	SIGNOR-262062	0.2
XAV939	chemical	CHEBI:62878	ChEBI	TNKS2	protein	Q9H2K2	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207833	0.8
NVP-BEP800	chemical	CID:25210273	PUBCHEM	HSP90AB1	protein	P08238	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194904	0.8
POMT1	protein	Q9Y6A1	UNIPROT	POMT 	complex	SIGNOR-C372	SIGNOR	form complex	binding			9606	BTO:0000007								16698797	t		miannu	 Here we have shown that POMT1 forms a complex with POMT2 and the complex possesses protein O-mannosyltransferase activity. Results indicate that POMT1 and POMT2 associate physically and functionally in vivo.  Mutations in the POMT1 and POMT2 genes are considered to be the cause of Walker-Warburg syndrome. Here, we have demonstrated that POMT1 and POMT2 form a functional complex in vivo using immunoprecipitating techniques. Furthermore, we showed that the mutations of POMT1 protein found in WWS patients do not prevent complex formation with POMT2 but they do abolish activity of the complex.	SIGNOR-265428	0.586
IRF5	protein	Q13568	UNIPROT	IL1B	protein	P01584	UNIPROT	up-regulates	transcriptional regulation			9606	BTO:0000801								21240265	f			Among the genes with differences in expression in the M1 and M2 subsets are those regulated by IRF5, including IL12A, IL12B, IL23A, IL1B, TNF, CCL3(encoding MIP-1α), RANTES, CD1A, CD40, CD86 and CCR7	SIGNOR-254510	0.297
ITCH	protein	Q96J02	UNIPROT	ERBB4	protein	Q15303	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								17463226	t		miannu	Interaction with the ErbB-4 receptors occurs via the WW domains of AIP4/Itch. Functional analyses demonstrate that AIP4/Itch is recruited to the ErbB-4 receptor to promote its polyubiquitination and degradation, thereby regulating stability of the receptor and access of receptor intracellular domains to the nuclear compartment. 	SIGNOR-272618	0.589
MDM2	protein	Q00987	UNIPROT	TP73	protein	O15350	UNIPROT	down-regulates activity	binding			9606									17700533	t		miannu	Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis. 	SIGNOR-255470	0.83
SB-202190	chemical	CHEBI:79090	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206697	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001103							20219869	f		apalma	Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6.	SIGNOR-255357	0.622
SPAG9	protein	O60271	UNIPROT	MAPK11	protein	Q15759	UNIPROT	up-regulates	binding			9606	BTO:0000222								17074887	t	p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors.	gcesareni	Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants.	SIGNOR-150147	0.421
STK38	protein	Q15208	UNIPROT	STK38	protein	Q15208	UNIPROT	up-regulates	phosphorylation	Thr444	DWVFINYtYKRFEGL	9606									12493777	t		lperfetto	We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo	SIGNOR-96683	0.2
ABL1	protein	P00519	UNIPROT	CDK5	protein	Q00535	UNIPROT	up-regulates activity	phosphorylation	Tyr15	EKIGEGTyGTVFKAK	9534	BTO:0000298								10896159	t		gcesareni	Phosphorylation of Cdk5 by c-Abl occurs on tyrosine 15 (Y15), which is stimulatory for p35/Cdk5 kinase activity.	SIGNOR-245288	0.567
CTH	protein	P32929	UNIPROT	L-cystathionine dizwitterion	smallmolecule	CHEBI:58161	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000671;BTO:0000759;BTO:0002688							19961860	t		lperfetto	 the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production.	SIGNOR-275822	0.8
KDM4C	protein	Q9H3R0	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	demethylation	Lys37	APATGGVkKPHRYRP	9606									29207681	t		miannu	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 	SIGNOR-263864	0.2
APH1A	protein	Q96BI3	UNIPROT	PSENEN	protein	Q9NZ42	UNIPROT	up-regulates	binding			9606									12522139	t		gcesareni	Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex.	SIGNOR-97104	0.962
HCRTR2	protein	O43614	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257008	0.254
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CALM3	protein	P0DP25	UNIPROT	up-regulates	chemical activation			10090									10448861	t		miannu	Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1.	SIGNOR-266334	0.8
NTRK1	protein	P04629	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	phosphorylation			9606									8384556	t		gcesareni	The nerve growth factor (ngf) receptor/trk associated with and phosphorylated phospholipase c gamma (plc gamma)	SIGNOR-38538	0.637
FLI1	protein	Q01543	UNIPROT	Monocyte_differentiation 	phenotype	SIGNOR-PH101	SIGNOR	up-regulates activity				10090	BTO:0000725								23320737	f			The transcription factor Fli-1 regulates monocyte, macrophage and dendritic cell development in mice	SIGNOR-259972	0.7
RUNX1	protein	Q01196	UNIPROT	ELF4/RUNX1	complex	SIGNOR-C47	SIGNOR	form complex	binding			9606	BTO:0001271								10207087	t		miannu	We readily detected an in vivo physical interaction between mef and aml1 proteins in kasumi-1 cells/ coexpression of mef and aml1b synergistically activates promoter function	SIGNOR-66963	0.357
MYC	protein	P01106	UNIPROT	Enolase	proteinfamily	SIGNOR-PF74	SIGNOR	up-regulates quantity	transcriptional regulation			10116									10823814	t	inferred from family member	miannu	C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.	SIGNOR-267785	0.423
GFI1	protein	Q99684	UNIPROT	EGR2	protein	P11161	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									16923394	f		irozzo	Importantly, overexpression of Gfi-1 in these cells resulted in the attenuation of both Egr-1 and Egr-2 expression, but not Nab-2. 	SIGNOR-256133	0.315
AKT1	protein	P31749	UNIPROT	TAL1	protein	P17542	UNIPROT	down-regulates	phosphorylation	Thr90	EARHRVPtTELCRPP	9606	BTO:0000782;BTO:0001271								15930267	t		miannu	Akt phosphorylates tal1 oncoprotein and inhibits its repressor activity. / our results show that akt specifically phosphorylates thr90 of the tal1 protein within its transactivation domain in vitro and in vivo.	SIGNOR-252479	0.384
FZD6	protein	O60353	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates activity	binding			9606									22944199	t		amattioni	When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.	SIGNOR-198828	0.666
HES5	protein	Q5TA89	UNIPROT	NEUROG2	protein	Q9H2A3	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938								30030829	f		lperfetto	The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 	SIGNOR-265143	0.421
HDAC2	protein	Q92769	UNIPROT	HPGD	protein	P15428	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									19010907	f	 	miannu	 We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression. 	SIGNOR-254236	0.2
Erythrocytic spectrin	complex	SIGNOR-C384	SIGNOR	Membrane_disruption	phenotype	SIGNOR-PH151	SIGNOR	down-regulates				9606									24302288	f		lperfetto	Spectrin is multifunctional, and spectrin-based networks are important for maintaining the shape and mechanical properties of erythrocytes.	SIGNOR-266028	0.7
THR	proteinfamily	SIGNOR-PF84	SIGNOR	RARA	protein	P10276	UNIPROT	up-regulates	binding			9606									15650024	t	inferred from family member	gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-270313	0.2
TAOK1	protein	Q7L7X3	UNIPROT	MARK2	protein	Q7KZI7	UNIPROT	up-regulates activity	phosphorylation	Thr208	TFGNKLDtFCGSPPY	-1									18424437	t		miannu	MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase.	SIGNOR-276164	0.424
MLL-AF4	fusion protein	SIGNOR-FP4	SIGNOR	AEP complex	complex	SIGNOR-C117	SIGNOR	up-regulates activity	binding			9606	BTO:0005261								19956800	t		irozzo	Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription.	SIGNOR-255877	0.2
GALR1	protein	P47211	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256966	0.252
CAMK2A	protein	Q9UQM7	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser16	KELEKRAsGQAFELI	9606	BTO:0000661								9686569	t		gcesareni	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16.	SIGNOR-59354	0.376
CDK1	protein	P06493	UNIPROT	MAP4	protein	P27816	UNIPROT	down-regulates	phosphorylation	Ser787	KAPEKRAsPSKPASA	9606	BTO:0000567								9398320	t		lperfetto	Map4 is phosphorylated by cdc2 kinase in mitotic hela/ phosphorylation by cdc2 kinase decreased the microtubule-stabilizing ability of map4, suggesting that there are critical phosphorylation sites among the five major cdc2 kinase-dependent phosphorylation sites [spots 4 (ser-696), 5, 6, 9, and 10 (ser-787)].	SIGNOR-53739	0.512
MAPK3	protein	P27361	UNIPROT	NUP50	protein	Q9UKX7	UNIPROT	down-regulates	phosphorylation	Ser221	KVAAETQsPSLFGST	9606									19767751	t		gcesareni	Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin.	SIGNOR-188151	0.2
CDK5	protein	Q00535	UNIPROT	PRKN	protein	O60260	UNIPROT	down-regulates	phosphorylation	Ser131	HTDSRKDsPPAGSPA	9606		BTO:0000142							17327227	t		llicata	Phosphorylation by cdk5 decreased the auto-ubiquitylation of parkin both in vitro and in vivo.	SIGNOR-153445	0.2
TRIM24	protein	O15164	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	ubiquitination			9606									19844164	t		miannu	New ring-domain e3-ubiquitin ligase trim24 that targets p53 for degradation	SIGNOR-188726	0.548
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	HDAC4	protein	P56524	UNIPROT	up-regulates activity	phosphorylation			-1									30661366	t		miannu	 In vitro kinase assays have established that Ser584 and Ser265/266 are phosphorylated by protein kinase A (PKA). Overexpression of site-specific HDAC4 mutants (S584A, S265/266A) in HEK 293T cells, followed by HDAC activity assays, revealed the mutants to be less active than the wild-type protein. 	SIGNOR-277425	0.2
Naphtho[1,2-d]thiazol-2-amine	chemical	CID:94880	PUBCHEM	KCNN2	protein	Q9H2S1	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								18955585	t		Luana	Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. 	SIGNOR-258027	0.8
EFNA1	protein	P20827	UNIPROT	EPHA7	protein	Q15375	UNIPROT	up-regulates	binding			9606									9576626	t		gcesareni	The best known function is their role in the guidance of migration of axons and cells in the nervous system through repulsive interactions	SIGNOR-56965	0.806
SMAD1	protein	Q15797	UNIPROT	SMAD1/4	complex	SIGNOR-C85	SIGNOR	form complex	binding			9606									8893010	t		ggiuliani	Conversely, Smad1 and DPC4 formed a complex when the cells were stimulated with BMP4 but not with activin of TGF-beta.	SIGNOR-255774	0.655
CRTC2	protein	Q53ET0	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	binding			9606									26652733	t			The cAMP-response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a coactivator known to be specific to CREB and plays a central role in the glucagon-mediated activation of gluconeogenesis in the early phase of fasting	SIGNOR-256102	0.909
WEE1	protein	P30291	UNIPROT	CDK1	protein	P06493	UNIPROT	down-regulates	phosphorylation	Tyr15	EKIGEGTyGVVYKGR	9606									16096060	t		gcesareni	The wee1 kinase phosphorylates and inhibits cyclin-dependent kinase 1 (cdk1), thereby delaying entry into mitosis until appropriate conditions have been met	SIGNOR-139491	0.854
clenbuterol	chemical	CHEBI:174690	ChEBI	ADRB1	protein	P08588	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. 	SIGNOR-257862	0.8
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2J2	protein	Q8N2K1	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271373	0.464
PIK3CA	protein	P42336	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity				9606		BTO:0000150							19573809	f		lperfetto	However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth	SIGNOR-236436	0.811
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity	phosphorylation			10090									11730323	t			Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs	SIGNOR-258989	0.747
N2,N4-Dibenzylquinazoline-2,4-diamine	chemical	CID:676352	PUBCHEM	VCP	protein	P55072	UNIPROT	down-regulates activity	chemical inhibition			-1									21383145	t		Monia	DBeQ (1) is a reversible and selective inhibitor of p97	SIGNOR-261100	0.8
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	GAS2	protein	O43903	UNIPROT	up-regulates	cleavage	Asp278	MLQISRVdGKTSPIQ	9606									10564664	t		gcesareni	We now demonstrate that gas2 is a substrate of caspase-3 but not of caspase-6. Proteolytic processing both in vitro and in vivo is dependent on aspartic residue 279.	SIGNOR-256439	0.428
BORA	protein	Q6PGQ7	UNIPROT	PLK1	protein	P53350	UNIPROT	up-regulates	phosphorylation			9606									18615013	t		gcesareni	Bora/aurora-a-dependent phosphorylation is a prerequisite for plk1 to promote mitotic entry after a checkpoint-dependent arrest.	SIGNOR-179425	0.78
DDHD1	protein	Q8NEL9	UNIPROT	1-acyl-sn-glycerol 3-phosphate	smallmolecule	CHEBI:16975	ChEBI	up-regulates quantity	chemical modification			9606									22922100	t		miannu	Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 	SIGNOR-269656	0.8
PTPRF	protein	P10586	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	9606									1303753	t		gcesareni	Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product.	SIGNOR-16235	0.563
UBE3A	protein	Q05086	UNIPROT	SCRIB	protein	Q14160	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									11027293	t		miannu	Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase	SIGNOR-272573	0.536
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	MYOD1	protein	P15172	UNIPROT	down-regulates activity	binding			9606									12244043	t		areggio	Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes	SIGNOR-254986	0.625
PLK1	protein	P53350	UNIPROT	PRKN	protein	O60260	UNIPROT	up-regulates activity	phosphorylation	Ser378	AYHEGECsAVFEASG	9606	BTO:0002181								26387737	t		miannu	 Parkin Is Phosphorylated by Plk1 at Ser378 and Activated during Mitosis 	SIGNOR-276938	0.2
BBC3	protein	Q9BXH1	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								15694340	t		lperfetto	Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis.	SIGNOR-133811	0.751
P2RX7	protein	Q99572	UNIPROT	PLD2	protein	O14939	UNIPROT	up-regulates				9606									8573088	f		mrosina	This study shows that extracellular ATP, acting through the P2Z purinoceptor, stimulated PLD activity in human lymphocytes.	SIGNOR-254966	0.2
GYS1	protein	P13807	UNIPROT	UDP-alpha-D-glucose(2-)	chemical	CHEBI:58885	ChEBI	down-regulates quantity	chemical modification			9606									26882899	t		miannu	Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor.	SIGNOR-267938	0.8
AKT1	protein	P31749	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	phosphorylation	Ser71	YDRLRPLsYPQTDVF	9606	BTO:0000848								10617634	t			Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1	SIGNOR-252576	0.714
SMAD3	protein	P84022	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	binding			9534									9670020	t		lperfetto	Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGF-beta type I receptor, and this oligomerization does not require Smad4	SIGNOR-217227	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ILF3	protein	Q12906	UNIPROT	up-regulates activity	phosphorylation	Ser647	RGRGRGGsIRGRGRG	9606									20870937	t		llicata	Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser647 and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA. 	SIGNOR-168169	0.2
GHSR	protein	Q92847	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257380	0.451
SRC	protein	P12931	UNIPROT	GlyR	proteinfamily	SIGNOR-PF62	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000938	BTO:0000142;BTO:0000671							11882681	t	inferred from family member	gcesareni	These findings indicate that glyr function is upregulated by ptks and this modulation is dependent on the tyrosine-413 residue of the beta subunit.	SIGNOR-267796	0.274
PI3K	complex	SIGNOR-C156	SIGNOR	MTOR	protein	P42345	UNIPROT	up-regulates				9606									18721898	f		lperfetto	Phosphoinositide 3-kinase (pi3k)-dependent activation of the rheb-mtor pathway triggers the simultaneous local synthesis of tc10 and par3.	SIGNOR-252705	0.562
aclidinium	chemical	CHEBI:65346	ChEBI	CHRM2	protein	P08172	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000131								19653626	t		Luana	This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects.	SIGNOR-258049	0.8
IKBKB	protein	O14920	UNIPROT	COPS5	protein	Q92905	UNIPROT	down-regulates activity	phosphorylation	Ser201	KPPDEGPsEYQTIPL	-1									31950832	t		lperfetto	Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. 	SIGNOR-275518	0.336
SP1	protein	P08047	UNIPROT	UGCG	protein	Q16739	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000738								15342415	f		miannu	 the results suggest that transcriptional up-regulation of GCS through DOX-induced activation of Sp1 is one potential mechanism to regulate ceramide increase and apoptosis in HL-60/ADR cells.	SIGNOR-255205	0.2
MAPK3	protein	P27361	UNIPROT	NCOA1	protein	Q15788	UNIPROT	up-regulates	phosphorylation	Ser1185	GTPPASTsPFSQLAA	9606	BTO:0001130								12163482	t		lperfetto	Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein	SIGNOR-91139	0.271
4-Iodo-3-nitrobenzamide	chemical	CID:9796068	PUBCHEM	PARP1	protein	P09874	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193474	0.8
OPRK1	protein	P41145	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256989	0.355
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MRTFA	protein	Q969V6	UNIPROT	down-regulates	phosphorylation			9606									18694962	t	Translocation from Nuleus to Cytoplasm	gcesareni	Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization.	SIGNOR-270131	0.2
PRKACA	protein	P17612	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates activity	phosphorylation	Ser63	GILARRPsYRKILKD	-1									9016641	t		miannu	PKA catalytic subunit phosphorylates ATF-1 at Ser63 and that phosphorylation is essential for efficient DNA binding by ATF-1.	SIGNOR-250336	0.438
MMP13	protein	P45452	UNIPROT	FGA	protein	P02671	UNIPROT	down-regulates quantity by destabilization	cleavage	Leu442	TSKGDKElRTGKEKV	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain 	SIGNOR-263613	0.2
PRKCA	protein	P17252	UNIPROT	TNNI3	protein	P19429	UNIPROT	up-regulates activity	phosphorylation	Ser24	APIRRRSsNYRAYAT	-1									11121119	t		lperfetto	In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation.	SIGNOR-249067	0.349
PTPRR	protein	Q15256	UNIPROT	PXN	protein	P49023	UNIPROT	down-regulates activity	dephosphorylation	Tyr88	PQSSSPVyGSSAKTS	9606									20133777	t			Here, we show that paxillin is a direct substrate of PTPRT and that PTPRT specifically regulates paxillin phosphorylation at tyrosine residue 88 (Y88) in colorectal cancer (CRC) cells. We engineered CRC cells homozygous for a paxillin Y88F knock-in mutant and found that these cells exhibit significantly reduced cell migration and impaired anchorage-independent growth,	SIGNOR-248720	0.2
ZEB1	protein	P37275	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15311212	f		miannu	 known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT.	SIGNOR-255158	0.674
LRIG1	protein	Q96JA1	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates	binding			9606		BTO:0001253							15282549	t		gcesareni	Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation	SIGNOR-127304	0.726
DLG4	protein	P78352	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	relocalization			9606									9278515	t	brain	lperfetto	The PDZ domains of PSD-95 and related proteins interact with the COOH-terminal sequences of K+channels and NMDA2 receptors (3). By these interactions, PSD-95 may mediate the clustering of K+ channels and NMDA receptors at synapses.	SIGNOR-264195	0.817
BLOC1S2	protein	Q6QNY1	UNIPROT	BLOC-1	complex	SIGNOR-C381	SIGNOR	form complex	binding			9606									22203680	t		lperfetto	We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter.	SIGNOR-265937	0.717
Host translation inhibitor nsp1	protein	P0DTD1-PRO_0000449619	UNIPROT	RPS2	protein	P15880	UNIPROT	down-regulates activity	binding			-1									33188728	t		miannu	Nsp1 Locks the 40S in a Conformation Incompatible with mRNA Loading and Disrupts Initiation Factor Binding. Molecular interactions between C-Nsp1 and 40S ribosome components, including uS3, h18, and uS5. 	SIGNOR-262508	0.2
KDM1A	protein	O60341	UNIPROT	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	down-regulates				9606									28720390	f		gianni	The Lysine-specific demethylase 1, KDM1A/LSD1, plays a central role in the regulation of Pol II transcription through the removal of the activation mark (mono- and dimethyl lysine 4 of histone H3). LSD1 is often deregulated in human cancers, and it is frequently overexpressed in human solid cancers and leukemia.	SIGNOR-268728	0.7
SB-202190	chemical	CHEBI:79090	ChEBI	MAPK11	protein	Q15759	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206694	0.8
ATM	protein	Q13315	UNIPROT	PPP1R2	protein	P41236	UNIPROT	down-regulates	phosphorylation	Ser44	DEELSKKsQKWDEMN	9606									18250156	t		gcesareni	Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1.	SIGNOR-160648	0.2
SNIP1	protein	Q8TAD8	UNIPROT	CBP/p300	complex	SIGNOR-C6	SIGNOR	down-regulates	binding			9606									10887155	t		lperfetto	In this study, we characterize a novel nuclear protein, termed snip1 its principal mechanism of action appears to be through transcription by binding to cbp/p300 and interfering with the ability of these coactivators to interact with smad4	SIGNOR-217661	0.589
MAPK8	protein	P45983	UNIPROT	YWHAZ	protein	P63104	UNIPROT	down-regulates	phosphorylation	Ser184	FYYEILNsPEKACSL	9606									15071501	t	JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8.	gcesareni	Jnk phosphorylated 14-3-3 at ser-184 and 14-3-3 at ser-186 both in vitro and in vivo, and such phosphorylation reduced the affinity of 14-3-3 proteins for bax	SIGNOR-124020	0.379
dehydroepiandrosterone	chemical	CHEBI:28689	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									9489820	t	systemic lupus erythematosus	gcesareni		SIGNOR-251707	0.8
MMP19	protein	Q99542	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272386	0.7
DVL2	protein	O14641	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates activity	binding			9606									17529994	t		amattioni	Dishevelled (dvl) transduces the wnt signal by interacting with the cytoplasmic axin complex.	SIGNOR-155221	0.655
apomorphine	chemical	CHEBI:48538	ChEBI	DRD3	protein	P35462	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258375	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Ser588	QTLSDSLsGSSLYST	9606	BTO:0000007								17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-252883	0.398
PTPRJ	protein	Q12913	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Tyr1092	TFLPVPEyINQSVPK	9606	BTO:0000567								19836242	t			We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173	SIGNOR-248698	0.504
chloroquine	chemical	CHEBI:3638	ChEBI	IL6	protein	P05231	UNIPROT	down-regulates quantity				9606									32283152	f		miannu	Chloroquine inhibits the production and release of TNF and IL-6, which indicates that chloroquine may suppress the cytokine storm in patients infected with COVID-19.	SIGNOR-260854	0.8
PAX3-FOXO1	fusion protein	SIGNOR-FP12	SIGNOR	IGF1R	protein	P08069	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25211658	t		miannu	Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA.	SIGNOR-251568	0.2
SKP2	protein	Q13309	UNIPROT	SCF-SKP2	complex	SIGNOR-C136	SIGNOR	form complex	binding			9606									15340381	t		gcesareni	The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions.	SIGNOR-243560	0.925
CDO1	protein	Q16878	UNIPROT	SHH	protein	Q15465	UNIPROT	up-regulates	binding			9606		BTO:0000887							16647304	t		gcesareni	Cdo and boc bind shh through a high-affinity interaction with a specific fibronectin repeat that is essential for activity. We propose a model where cdo and boc enhance shh signaling within its target field.	SIGNOR-146461	0.2
PTEN	protein	P60484	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates				9606									17845852	f	PTEN is a suppressor of RAS-AKT function	gcesareni	Moreover, suppressors of ras akt function, such as the tumor-suppressor pten, and the attenuation of ras signaling involved in senescence, could be thus viewed as modulators of the gli code	SIGNOR-157776	0.362
FOXO1	protein	Q12778	UNIPROT	CDKN2D	protein	P55273	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17873901	f		gcesareni	Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity	SIGNOR-157839	0.276
STUB1	protein	Q9UNE7	UNIPROT	HSPA8	protein	P11142	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0001538								11676916	t		miannu	BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association	SIGNOR-272588	0.731
CSNK2A2	protein	P19784	UNIPROT	EEF1B2	protein	P24534	UNIPROT	unknown	phosphorylation	Ser112	GSDDEEEsEEAKRLR	-1									8547318	t		llicata	EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent.	SIGNOR-250988	0.342
PDK1	protein	Q15118	UNIPROT	ITGB3	protein	P05106	UNIPROT	down-regulates activity	phosphorylation	Thr779	LYKEATStFTNITYR	-1									10896934	t		miannu	PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3.	SIGNOR-250264	0.31
POLD2	protein	P49005	UNIPROT	DNA polymerase delta 	complex	SIGNOR-C376	SIGNOR	form complex	binding			-1									12403614	t		lperfetto	Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme.	SIGNOR-265516	0.921
DLG3	protein	Q92796	UNIPROT	NMDA receptor_2C	complex	SIGNOR-C349	SIGNOR	up-regulates activity	relocalization					BTO:0000227							32904533	t		lperfetto	DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses.	SIGNOR-266008	0.67
alvimopan	chemical	CHEBI:135686	ChEBI	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			-1									18313920	t		Luana	A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors.	SIGNOR-257773	0.8
acadesine	chemical	CHEBI:28498	ChEBI	AMPK	complex	SIGNOR-C15	SIGNOR	up-regulates	chemical activation			9606									16879084	t		lperfetto	The activation of the ampk pathway by exendin-4 was induced by aicar, which was inhibited by compound c.	SIGNOR-217478	0.8
UHMK1	protein	Q8TAS1	UNIPROT	SF1	protein	Q15637	UNIPROT	up-regulates	phosphorylation	Ser80	PPNPEDRsPSPEPIY	9606									23175611	t	The effect has been demonstrated using Q15637-2	gcesareni	Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding.	SIGNOR-199793	0.417
PI4K2B	protein	Q8TCG2	UNIPROT	ADP(3-)	smallmolecule	CHEBI:456216	ChEBI	up-regulates quantity	chemical modification			9606									10101268	t		miannu	The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 	SIGNOR-269102	0.8
PYGL	protein	P06737	UNIPROT	glycogen	smallmolecule	CHEBI:28087	ChEBI	down-regulates quantity	chemical modification			9606									3346228	t			Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267392	0.8
9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone	chemical	CID:71748056	PUBCHEM	ERBB2	protein	P04626	UNIPROT	down-regulates activity	chemical inhibition			-1									24556163	t		miannu	This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine 	SIGNOR-262233	0.8
NR1I2	protein	O75469	UNIPROT	RXRA	protein	P19793	UNIPROT	up-regulates	binding			9606									11706036	t		gcesareni	The constitutive androstane receptor (car, nr1i4), like fxr and pxr, binds dna as a heterodimer with rxr?	SIGNOR-111624	0.546
ITK	protein	Q08881	UNIPROT	SIGLEC10	protein	Q96LC7	UNIPROT	up-regulates	phosphorylation	Tyr667	ESQEELHyATLNFPG	9606									11733002	t		lperfetto	These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2	SIGNOR-112475	0.2
CUL1	protein	Q13616	UNIPROT	SCF-FBW7	complex	SIGNOR-C135	SIGNOR	form complex	binding			9606									15340381	t		gcesareni	The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions.	SIGNOR-243763	0.925
IKZF2	protein	Q9UKS7	UNIPROT	LNPEP	protein	Q9UIQ6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003420								15894523	f	 	miannu	Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. 	SIGNOR-255404	0.2
POU2F1	protein	P14859	UNIPROT	GFI1B	protein	Q5VTD9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19965638	f	 	miannu	HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. 	SIGNOR-254432	0.2
NHLRC1	protein	Q6VVB1	UNIPROT	DVL2	protein	O14641	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								22223637	t		miannu	We have also found that malin enhances K48- and K63-linked ubiquitination of dishevelled2 that could lead to its degradation through both proteasome and autophagy. Altogether, our results indicate that malin regulates Wnt signaling pathway through the degradation of dishevelled2 and suggest possible deregulation of Wnt signaling in Lafora disease.	SIGNOR-272005	0.474
PLK1	protein	P53350	UNIPROT	NPM1	protein	P06748	UNIPROT	up-regulates	phosphorylation	Ser4	sMDMDMSP	9606	BTO:0000567								15190079	t		gcesareni	Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.	SIGNOR-125666	0.435
JAK2	protein	O60674	UNIPROT	GAB2	protein	Q9UQC2	UNIPROT	up-regulates	phosphorylation	Tyr643	TSDEKVDyVQVDKEK	9606	BTO:0000130								18644434	t		lperfetto	In vitro, activated jak2 directly phosphorylated specific gab2 tyrosine residues. Mutagenesis studies revealed that gab2 tyrosine 643 (y643) was a major target of jak2 in vitro, and a key residue for jak2-dependent phosphorylation in intact cells. Mutation of gab2 y643 inhibited g-csf-stimulated erk1/2 activation and shp2 binding to gab2.	SIGNOR-179488	0.495
Phenelzine	chemical	CHEBI:8060	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9537821	t		miannu	Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 	SIGNOR-258744	0.8
ATP7A	protein	Q04656	UNIPROT	copper(1+)	smallmolecule	CHEBI:49552	ChEBI	up-regulates quantity	relocalization												28389643	t		lperfetto	Menkes disease (MD) is caused by mutations in ATP7A, encoding a copper- transporting P-type ATPase which exhibits copper-dependent trafficking. ATP7A is found in the Trans-Golgi Network (TGN) at low copper concentrations, and in the post-Golgi compartments and the plasma membrane at higher concentrations. 	SIGNOR-272298	0.8
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	GATA2	protein	P23769	UNIPROT	up-regulates activity	binding			10090	BTO:0001516								10938104	t			We provide evidence that GATA-2 can physically associate with PML-RARα. Functional experiments further demonstrated that this interaction has the capacity to render GATA-dependent transcription inducible by retinoic acid, raising the possibility that GATA target genes may be involved in the molecular pathogenesis of APL.	SIGNOR-259941	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PFKFB2	protein	O60825	UNIPROT	unknown	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606	BTO:0000567								12853467	t			14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling.	SIGNOR-251484	0.2
U0126.EtOH	chemical	CHEBI:90692	ChEBI	MAP2K1	protein	Q02750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207603	0.8
NR3C1	protein	P04150	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates activity				10090	BTO:0000944								11742987	f	inferred from 70% of family members	gcesareni	Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation.	SIGNOR-269920	0.618
CAMK2A	protein	Q9UQM7	UNIPROT	CACNA1B	protein	Q00975	UNIPROT	down-regulates	phosphorylation	Ser2120	ERRQPSSsSSEKQRF	9606	BTO:0000938								16982421	t		gcesareni	Here, we report a direct modulation of ca(v)2.2 channel inactivation properties by 14-3-3, a family of signaling proteins involved in a wide range of biological processes.Wild-type gst fusion proteins containing the putative 14-3-3-binding motif (aa 2076__?2140) werein vitro phosphorylated at s2126 by either camkii or pka, as detected by thesequence- and phosphorylation-specific antibody, anti-ps2126 (middle panel). Phosphorylation of s2126 significantly increases its binding to recombinant 14-3-3?	SIGNOR-149684	0.322
NCAPH2	protein	Q6IBW4	UNIPROT	TERF1	protein	P54274	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								31026066	t		miannu	Taken together these observations suggest that NCAPH2 promotes telomere stability, possibly through a direct interaction with the TRF1 shelterin component, and prevents telomere dysfunction resulting from impaired DNA replication.	SIGNOR-263914	0.2
RBL2	protein	Q08999	UNIPROT	Cell_cycle_progress 	phenotype	SIGNOR-PH42	SIGNOR	down-regulates				10090	BTO:0000165								10801445	f		gcesareni	Although forced expression of either p130 or pRb in mouse C2 myoblasts efficiently blocked cell cycle progression, only p130 inhibited the differentiation program.	SIGNOR-241946	0.7
TERB1	protein	Q8NA31	UNIPROT	TTM complex	complex	SIGNOR-C305	SIGNOR	form complex	binding			9606	BTO:0000007								30718482	t		lperfetto	Meiotic specific proteins TERB1, TERB2, and MAJIN form a stable complex that plays a critical role in regulating the recruitment of telomeres to the NE	SIGNOR-263302	0.2
RPS6KB2	protein	Q9UBS0	UNIPROT	PDCD4	protein	Q53EL6	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000007	BTO:0001253							18296647	t		gcesareni	Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.	SIGNOR-160992	0.45
3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates activity	binding			9606									29407449	t		scontino	T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb.	SIGNOR-267276	0.8
N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide	chemical	CHEBI:95008	ChEBI	MCL1	protein	Q07820	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207465	0.8
ETV3	protein	P41162	UNIPROT	ETV3	protein	P41162	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000944								22028471	t		miannu	ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation.	SIGNOR-262778	0.2
MAPK1	protein	P28482	UNIPROT	KHDRBS1	protein	Q07666	UNIPROT	up-regulates	phosphorylation	Thr72	PLLPPSAtGPDATVG	9606									12478298	t		lperfetto	In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites	SIGNOR-96414	0.652
AURKA	protein	O14965	UNIPROT	PHLDA1	protein	Q8WV24	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser95	PLCLLRVsLLCALRA	9606	BTO:0006218								21807936	t		miannu	Aurora A directly phosphorylates PHLDA1 leading to its degradation. Aurora A phosphorylates PHLDA1 at Ser 98. 	SIGNOR-273545	0.423
FBXW7	protein	Q969H0	UNIPROT	PSEN1	protein	P49768	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								12354302	t		miannu	SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production SEL-10 protein is a homologue of yeast Cdc4, a member of the SCF (Skp1-Cdc53/CUL1-F-box protein) E2-E3 ubiquitin ligase family. In this study, we show that human SEL-10 interacts with PS1 and enhances PS1 ubiquitination, thus altering cellular levels of unprocessed PS1 and its N- and C-terminal fragments. These observations suggest that SEL-10 mediated ubiquitination of PS1-CTF and PS1-NTF leads to their degradation.	SIGNOR-272600	0.507
NEFL	protein	P07196	UNIPROT	Neurofilament L/H	complex	SIGNOR-C208	SIGNOR	form complex	binding			9606	BTO:0000938								19468066	t		miannu	Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H	SIGNOR-255272	0.446
AHSA1	protein	O95433	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	up-regulates activity	binding			9606									16696853	t		miannu	The N-terminal region of Aha1 interacts with the central domain of Hsp90 and stimulates Hsp90 ATPase activity	SIGNOR-252211	0.767
NRXN1	protein	P58400	UNIPROT	DAG1	protein	Q14118	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							22626542	t		miannu	 The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 	SIGNOR-265459	0.401
CSNK1A1	protein	P48729	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser286	SSMSSCGsSGYFSSS	9606									22017877	t		llicata	Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291.	SIGNOR-176871	0.2
KLF1	protein	Q13351	UNIPROT	Erythrocyte_differentiation 	phenotype	SIGNOR-PH104	SIGNOR	up-regulates				9606	BTO:0000725								28026072	f		irozzo	Activation of KLF1 at day 10 of the differentiation process when hematopoietic progenitor cells were present, enhanced erythroid commitment and differentiation.	SIGNOR-256086	0.7
MCHR2	protein	Q969V1	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257439	0.252
USF1	protein	P22415	UNIPROT	FOSL1	protein	P15407	UNIPROT	down-regulates activity	binding			10090									9160889	t	2	miannu	USF specifically interacts with Fra1. USF was repressing this modest Fra1 transactivation	SIGNOR-240975	0.479
CTNNB1	protein	P35222	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									23645839	f		apalma	For example, prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion	SIGNOR-255695	0.7
PTPRJ	protein	Q12913	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates	dephosphorylation	Tyr1054	FGLARDIyKDPDYVR	9606									18936167	t		gcesareni	The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2.	SIGNOR-181672	0.687
VKORC1	protein	Q9BQB6	UNIPROT	Reduced Vitamin K	smallmolecule	CHEBI:8784	ChEBI	up-regulates quantity	chemical modification			9606									31226734	t		lperfetto	The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form	SIGNOR-265901	0.8
Fluocinonide	chemical	CHEBI:5109	ChEBI	SMO	protein	Q99835	UNIPROT	up-regulates activity	chemical activation			10090									20439738	t		gcesareni	We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling.	SIGNOR-248218	0.8
AURKA	protein	O14965	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	phosphorylation	Ser215	DRNTFRHsVVVPYEP	9606									15469940	t		llicata	Here we show that p53 is phosphorylated by the mitotic kinase aurora-a at serine 215. Unlike most identified phosphorylation sites of p53 that positively associate with p53 function (brooks, c. L., and gu, w. (2003) curr. Opin. Cell biol. 15, 164-171), the phosphorylation of p53 by aurora-a at ser-215 abrogates p53 dna binding and transactivation activity.	SIGNOR-129809	0.771
MAPK1	protein	P28482	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates activity	phosphorylation	Ser62	LLPTPPLsPSRRSGL	9534	BTO:0004055								8386367	t		lperfetto	Transactivation of gene expression by myc is inhibited by mutation at the phosphorylation sites thr-58 and ser-62.	SIGNOR-235700	0.725
PRKCE	protein	Q02156	UNIPROT	TRPV1	protein	Q8NER1	UNIPROT	up-regulates activity	phosphorylation	Ser801	VPLLREAsARDRQSA	9606	BTO:0000007								11884385	t		lperfetto	Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues. | Patch clamp analysis of the point mutants where Ser or Thr residues were replaced with Ala in the total 16 putative phosphorylation sites showed that two Ser residues, Ser(502) and Ser(800) were involved in the potentiation of the capsaicin-evoked currents by either PMA or ATP.	SIGNOR-249142	0.2
RNF216	protein	Q9NWF9	UNIPROT	TICAM1	protein	Q8IUC6	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								16968706	t		miannu	Triad3A promotes proteolytic degradation of adapter proteins. A, Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins.	SIGNOR-271609	0.362
MYC	protein	P01106	UNIPROT	HLA-F	protein	P30511	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									8206526	f		miannu	 In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene.	SIGNOR-254605	0.2
LPAR1	protein	Q92633	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257400	0.432
PPP3CB	protein	P16298	UNIPROT	FLNA	protein	P21333	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser2152	TRRRRAPsVANVGSH	9606									16442073	t			Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation.	SIGNOR-248362	0.2
SKP1	protein	P63208	UNIPROT	Noncanonical PRC1	complex	SIGNOR-C151	SIGNOR	form complex	binding			10090									25533466	t		miannu	 inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR.	SIGNOR-255278	0.452
ZBTB47	protein	Q9UFB7	UNIPROT	CBFA2T3/ZNF651	complex	SIGNOR-C197	SIGNOR	form complex	binding			9606	BTO:0000007								20116376	t			Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex.	SIGNOR-253957	0.467
WNT5A	protein	P41221	UNIPROT	FZD4	protein	Q9ULV1	UNIPROT	up-regulates activity	binding			9606									16602827	t		areggio	We show that in addition to its inhibitory function, Wnt5a can also activate beta-catenin signaling in the presence of the appropriate Frizzled receptor, Frizzled 4.	SIGNOR-258954	0.728
imiquimod	chemical	CHEBI:36704	ChEBI	TLR7	protein	Q9NYK1	UNIPROT	up-regulates activity	chemical activation			9606									15661881	t		miannu	Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively.	SIGNOR-259244	0.8
SETBP1	protein	Q9Y6X0	UNIPROT	SET	protein	Q01105	UNIPROT	up-regulates	binding			9606									22566606	t		miannu	Setbp1 was shown to form a complex with set and pp2a, enhancing the stability of set and its inhibition of pp2a.	SIGNOR-197324	0.492
KAT6A	protein	Q92794	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271;BTO:0000785		SIGNOR-C54						11965546	t		miannu	Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation.	SIGNOR-117332	0.313
RPS6KA1	protein	Q15418	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									15994958	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-138467	0.2
apixaban	chemical	CHEBI:72296	ChEBI	F10	protein	P00742	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189865	0.8
NEDD4	protein	P46934	UNIPROT	LYN	protein	P07948	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0001931								10683340	t		miannu	These findings suggest that LMP2A recruits Nedd4-like ubiquitin-protein ligases and B-cell signal transduction molecules, resulting in the degradation of LMP2A and Lyn by a ubiquitin-dependent mechanism. 	SIGNOR-272558	0.439
tryptophan	smallmolecule	CHEBI:27897	ChEBI	Trp-tRNA(Trp)	smallmolecule	CHEBI:29159	ChEBI	up-regulates quantity	precursor of			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 	SIGNOR-270516	0.8
RBBP6	protein	Q7Z6E9	UNIPROT	YBX1	protein	P67809	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									18851979	t		miannu	RBBP6 interacts with multifunctional protein YB-1 through its RING finger domain, leading to ubiquitination and proteosomal degradation of YB-1	SIGNOR-271773	0.322
HRAS	protein	P01112	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606									21779497	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k we show here, however, that in vivo there are marked quantitative differences in the ability of ki- and ha-ras to activate raf-1 and phosphoinositide 3 kinase. the mechanism of raf-1 activation is complex, but it is clear that one important role of ras is to recruit raf-1 to the plasma membrane where a series of events is initiated that ultimately leads to full raf-1 activation. These events include tyrosine, serine, and threonine phosphorylation plus interactions with ras, phospholipids, 14-3-3 proteins and their associated proteins, and possibly dimerization.	SIGNOR-175195	0.813
CDK4	protein	P11802	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Thr179	PQSNIPEtPPPGYLS	9606									19114991	t		lpetrilli	In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity	SIGNOR-182822	0.748
PRKCB	protein	P05771	UNIPROT	GAP43	protein	P17677	UNIPROT	unknown	phosphorylation	Ser41	AATKIQAsFRGHITR	-1									2140056	t		lperfetto	We conclude that serine-41 is the protein kinase C phosphorylation site of neuromodulin and that phosphorylation of this amino acid residue blocks binding of calmodulin to neuromodulin.	SIGNOR-248859	0.353
(2s)-1-{[5-(3-Methyl-1h-Indazol-5-Yl)pyridin-3-Yl]oxy}-3-Phenylpropan-2-Amine	chemical	CID:11314340	PUBCHEM	AKT1	protein	P31749	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259688	0.8
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	GRB2	protein	P62993	UNIPROT	down-regulates	phosphorylation	Tyr209	TGMFPRNyVTPVNRN	9606	BTO:0000017								11726515	t		lperfetto	Phosphorylation of grb2 by bcr/abl or egf receptor reduced its sh3-dependent binding to sos in vivo, but not its sh2-dependent binding to bcr/abl. Tyr209 within the c-terminal sh3 domain of grb2 was identified as one of the tyrosine phosphorylation sites	SIGNOR-112354	0.2
LRP6	protein	O75581	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates quantity by destabilization	relocalization			9606	BTO:0000007								18632848	t		lperfetto	The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism.	SIGNOR-227939	0.723
NOTCH1	protein	P46531	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782;BTO:0001271;BTO:0000785								16847353	f		gcesareni	We identified c-myc as a direct target of notch1	SIGNOR-147944	0.658
CDX2	protein	Q99626	UNIPROT	UGT1A10	protein	Q9HAW8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000195								15044625	t	 	 	Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.	SIGNOR-253968	0.259
BCL2L11	protein	O43521	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								18498746	t		lperfetto	We show that mutation of the phosphorylation site Thr-112 causes decreased binding of Bim to the antiapoptotic protein Bcl2 and can increase cell survival.	SIGNOR-178676	0.811
GSK3B	protein	P49841	UNIPROT	CCNE1	protein	P24864	UNIPROT	down-regulates	phosphorylation	Thr395	PLPSGLLtPPQSGKK	9606									14536078	t		gcesareni	Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380	SIGNOR-118559	0.456
beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266476	0.8
MAP3K5	protein	Q99683	UNIPROT	MAP2K3	protein	P46734	UNIPROT	up-regulates activity	phosphorylation	Ser218	ISGYLVDsVAKTMDA	9606									19920149	t		lperfetto	Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7	SIGNOR-161763	0.582
G6PC3	protein	Q9BUM1	UNIPROT	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	up-regulates quantity	chemical modification			9606									12093795	t		miannu	Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis	SIGNOR-266566	0.8
IKBKB	protein	O14920	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser932	CDSGVETsFRKLSFT	9606	BTO:0000459			SIGNOR-C13					10469655	t		lperfetto	Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway.	SIGNOR-70473	0.848
STOML2	protein	Q9UJZ1	UNIPROT	CD3E	protein	P07766	UNIPROT	up-regulates activity	binding			9606	BTO:0000661								18641330	t		Giorgia	We observed that SLP-2 steadily associated with the CD3-epsilon chain of the TCR complex under resting conditions and during the 60 min of stimulation|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling.	SIGNOR-260375	0.2
PHF12	protein	Q96QT6	UNIPROT	TLE3	protein	Q04726	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								11390640	t		miannu	We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE.	SIGNOR-266993	0.2
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr730	SNCTNELyMMMRDCW	10116									19224897	t		lperfetto	Furthermore, under conditions in which wild-type or mutant FGFR1 are overexpressed, Y463, Y583, Y585, and Y730 are dispensable for tyrosine phosphorylation of Shc, the mitogen-activated protein kinase (MAPK) response, and stimulation of FGFR1-mediated cell proliferation and differentiation	SIGNOR-236191	0.2
lurasidone	chemical	CHEBI:70735	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10030									20404009	t		Luana	In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype.	SIGNOR-257839	0.8
GSK3B	protein	P49841	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Thr41	GIHSGATtTAPSLSG	9606		BTO:0000586	SIGNOR-C110						16293724	t		gcesareni	This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway.	SIGNOR-141807	0.856
CSNK2A2	protein	P19784	UNIPROT	NKX3-1	protein	Q99801	UNIPROT	up-regulates	phosphorylation	Thr89	AAPEEAEtLAETEPE	9606	BTO:0001130								16581776	t		llicata	In vitro kinase assays followed by mass spectrometric analyses demonstrated that ck2 phosphorylated recombinant nkx3.1 on thr89 and thr93. We have also determined that nkx3.1 is degraded primarily through a proteasomal pathway, suggesting that phosphorylation by ck2 protects nkx3.1 from degradation.	SIGNOR-145501	0.321
PTP4A3	protein	O75365	UNIPROT	KRT8	protein	P05787	UNIPROT	down-regulates activity	dephosphorylation	Ser74	TVNQSLLsPLVLEVD	9606	BTO:0000586								19115206	t			the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL-3-interacting protein. Indeed, treatment with the PRL-3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431|The site-specific phosphorylation of keratins induces the disassembly of these filaments, and the balance between their phosphorylation and dephosphorylation controls the continuous exchange of intermediate filament subunits between a soluble pool and polymerized filaments	SIGNOR-248340	0.276
AKT1	protein	P31749	UNIPROT	MTOR	protein	P42345	UNIPROT	up-regulates	phosphorylation			9606		BTO:0001103							15829723	t		apalma	Once phosphorylated, Akt can act on a broad spectrum of substrates that can influence cell survival and proliferation and protein synthesis (65). Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K	SIGNOR-255107	0.928
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RRAS	protein	P10301	UNIPROT	up-regulates activity	phosphorylation	Ser186	S-->L	9606	BTO:0002181								27086924	t		miannu	 In this study, we report that TC21 and R-Ras are phosphorylated on a conserved serine, Ser186 and Ser201, respectively, in intact cells. This residue is located in the C-terminal hypervariable region of the proteins and is not conserved in M-Ras. We show that the MAP kinases ERK1/2 phosphorylate TC21 and R-Ras on this C-terminal serine residue both in vitro and in vivo. 	SIGNOR-277220	0.2
PKD1	protein	P98161	UNIPROT	SIAH1	protein	Q8IUQ4	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								23001567	t		miannu	Full-length PC1 bound, stabilized and colocalized with Jade-1 and inhibited Jade-1 ubiquitination. Jade-1 ubiquitination was mediated by Siah-1, an E3 ligase that binds PC1.	SIGNOR-272916	0.338
MIR9-1HG	protein	Q13536	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002874								10995546	t		Luana	CROC-4: a novel brain specific transcriptional activator of c-fos expressed from proliferation through to maturation of multiple neuronal cell types.	SIGNOR-261569	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165;BTO:0000222	BTO:0000887;BTO:0001103							10409765	f		lperfetto	Nf-kappab regulation of cyclin d1 occurs at the transcriptional level and is mediated by direct binding of nf-kappab to multiple sites in the cyclin d1 promoter.	SIGNOR-235648	0.483
4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine	chemical	CHEBI:91419	ChEBI	CDK2	protein	P24941	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190179	0.8
MAPK3	protein	P27361	UNIPROT	RPS3	protein	P23396	UNIPROT	up-regulates	phosphorylation	Thr42	SGVEVRVtPTRTEII	9606									15950189	t		lperfetto	Erk phosphorylates threonine 42 residue of ribosomal protein s3.	SIGNOR-137175	0.359
RHEB	protein	Q15382	UNIPROT	PLD1	protein	Q13393	UNIPROT	up-regulates	binding			9606									18550814	t		gcesareni	Rheb binds and activates pld1 in vitro in a gtp-dependent manner, strongly suggesting that pld1 is a bona fide effector for rheb.	SIGNOR-178892	0.554
POMC	protein	P01189	UNIPROT	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258410	0.639
CSNK1D	protein	P48730	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates	phosphorylation	Ser262	DSEDYSLsEEGQELS	9606									20708156	t		gcesareni	Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination	SIGNOR-167517	0.351
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	ECT2	protein	Q9H8V3	UNIPROT	down-regulates	phosphorylation	Thr373	VSMLSLNtPNSNRKR	9606									16170345	t		lperfetto	We show that phosphorylation of ect2 at threonine-341 (t341) affects the autoregulatory mechanism of ect2. In g2/m phase, ect2 was phosphorylated at t341 most likely by cyclin b/cyclin-dependent kinase 1 (cdk1) ect2 is biologically active even when it is not phosphorylated at t341	SIGNOR-216864	0.5
BS-181 hydrochloride	chemical	CID:49867928	PUBCHEM	CDK7	protein	P50613	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190783	0.8
BRCA1	protein	P38398	UNIPROT	Cell_cycle_progress 	phenotype	SIGNOR-PH42	SIGNOR	down-regulates													15549093	f		lperfetto	The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination	SIGNOR-267282	0.7
GAN	protein	Q9H2C0	UNIPROT	ATG16L1	protein	Q676U5	UNIPROT	down-regulates quantity	ubiquitination			9534	BTO:0000298								30770803	t		miannu	Here we identify Gigaxonin24, an E3 ligase mutated in a fatal neurodegenerative disease called giant axonal neuropathy (GAN)25, as the first regulator of ATG16L1. Gigaxonin poly-ubiquitinates and controls the degradation of ATG16L1, and is essential to activate autophagy.	SIGNOR-268948	0.2
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	BLM	protein	P54132	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002181								26028025	t		miannu	We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.	SIGNOR-276912	0.279
PRKCD	protein	Q05655	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates	phosphorylation	Thr143	RGKFKRPtLRRVRIS	9606									24585778	t		miannu	Length-dependent activation is modulated by cardiac troponin i bisphosphorylation at ser23 and ser24 but not by thr143 phosphorylation. Thr143 is a known target of protein kinase c (pkc) whose activity is increased in cardiac disease	SIGNOR-204666	0.276
TNFRSF10D	protein	Q9UBN6	UNIPROT	TNFSF10	protein	P50591	UNIPROT	down-regulates	binding			9606									9382840	t		amattioni	One function of trail-r4 may be inhibition of trail cytotoxicy. Dcr2 functions as an inhibitory apo2l receptor.	SIGNOR-53447	0.718
PRKACA	protein	P17612	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1222	ESSSTRRsSEDLSAY	9606		BTO:0000975							17360977	t		lperfetto	Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223	SIGNOR-236729	0.2
ZNF503	protein	Q96F45	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									25538248	f		Monia	We asked whether higher pFAK staining in cells expressing Zpo2 correlates with reduced E-cadherin levels. Immunostaining for E-cadherin in the EpH4.9 and PyMT stable cell lines indicated a decrease in overall E-cadherin staining in Zpo2-overexpressing cells compared with the control (Fig. 6C). Similarly, Western blot analysis indicated a reduction in E-cadherin expression in Zpo2-expressing cells compared with the control (Fig. 6D).	SIGNOR-261190	0.2
AKT2	protein	P31751	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606									23552696	t		lperfetto	Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1	SIGNOR-245420	0.606
PTPRB	protein	P23467	UNIPROT	ALK	protein	Q9UM73	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000785								17681947	t		gcesareni	Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation.	SIGNOR-157175	0.34
SL-327	chemical	CHEBI:92211	ChEBI	MAPK7	protein	Q13164	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000938	BTO:0000142							11160424	t		gcesareni	Pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity (impey et al., 1999) and neuronal survival (villalba and journot, 1997;meyerfranke et al., 1998;skaper et al., 1998;anderson and tolkovsky, 1999;singer et al., 1999;bi et al., 2000). Interestingly, erk5 activation by egf in cos7 cells is also blocked by these inhibitors, (kamakura et al., 1999), suggesting that the erk5 pathway may also regulate cellular processes credited previously to erk1/2.	SIGNOR-104936	0.8
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1875	SPTSPKYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273064	0.636
UVB radiation	stimulus	SIGNOR-ST17	SIGNOR	TNF	protein	P01375	UNIPROT	up-regulates				9606									19005488	f		miannu	UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. UVB and IL-1alpha treatment synergistically enhanced TNF-alpha secretion and mRNA levels in human keratinocytes, similar to the findings reported previously in human fibroblasts.	SIGNOR-252208	0.7
RAB7A	protein	P51149	UNIPROT	PSMA7	protein	O14818	UNIPROT	up-regulates activity	binding			10036									14998988	t		Sara	Rab7 Forms a Complex with the Proteasome 
-Subunit XAPC. In this study the proteasome alpha-subunit XAPC7 (also known as PSMA7, RC6-1, and HSPC in mammals) was identified to interact specifically with Rab7 and was recruited to multivesicular late endosomes through this interaction. 	SIGNOR-261303	0.349
CUL3	protein	Q13618	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									19782033	t		miannu	 BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.	SIGNOR-264238	0.406
GSK3B	protein	P49841	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser37	YLDSGIHsGATTTAP	9606		BTO:0000586	SIGNOR-C110						16293724	t		gcesareni	This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway.	SIGNOR-141803	0.856
GNE	protein	Q9Y223	UNIPROT	N-acyl-D-mannosamine 6-phosphate(2-)	smallmolecule	CHEBI:57666	ChEBI	up-regulates quantity	chemical modification												10745088	t		lperfetto	UDP-GlcNAc 2-epimerase is a bifunctional enzyme and catalyzes the first two steps of neuraminic acid synthesis in the cytosol, the conversion of UDP-N-acetylglucosamine to ManAc and the phosphorylation to ManAc-6-phosphate.	SIGNOR-266074	0.8
MAP2K4	protein	P45985	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	phosphorylation	Thr261	LVDSIAKtRDAGCRP	-1									9162092	t			Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4.	SIGNOR-251421	0.2
PRKCB	protein	P05771	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	phosphorylation	Ser1303	NKLRRQHsYDTFVDL	-1									11306676	t		lperfetto	These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels.	SIGNOR-249084	0.371
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2D2	protein	P62837	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271323	0.846
Complement C1 complex	complex	SIGNOR-C309	SIGNOR	C4B	protein	P0C0L5	UNIPROT	up-regulates activity	cleavage	Gly1446	TPLQLFEgRRNRRRR	-1									9087411	t		lperfetto	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263430	0.63
DPY30	protein	Q9C005	UNIPROT	MLL/SET subcomplex	complex	SIGNOR-C87	SIGNOR	form complex	binding			9606									24680668	t		miannu	Dimethylation of h3k4 requires a sub-complexincluding wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation.	SIGNOR-204747	0.885
PRKACA	protein	P17612	UNIPROT	RGS14	protein	O43566	UNIPROT	up-regulates activity	phosphorylation	Ser260	NAALRREsQGSLNSS	-1									12534294	t		miannu	RGS14 is phosphorylated in vitro at Ser258 and Thr494 by PKA. cAMP-induced phosphorylation as an important modulator of RGS14 function since phosphorylation could enhance RGS14 binding to Galpha(i)-GDP	SIGNOR-250045	0.343
DOK1	protein	Q99704	UNIPROT	ITGB2	protein	P05107	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257680	0.301
HMOX1	protein	P09601	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0000848								17148680	f		irozzo	Here we investigated the effects of HO-1 overexpression in murine and human melanoma cells. The most important findings of our study are that 1) overexpression of HO-1 augments the proliferation [.]	SIGNOR-256295	0.7
ENPP1	protein	P22413	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	down-regulates quantity	chemical modification												20923972	t			Phosphodiesterases Catalyze Hydrolysis of cAMP-bound to Regulatory Subunit of Protein Kinase A and Mediate Signal Termination	SIGNOR-253018	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	LIPE	protein	Q05469	UNIPROT	down-regulates	phosphorylation	Ser855	EPMRRSVsEAALAQP	9606									9636039	t		gcesareni	Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase.	SIGNOR-58251	0.2
17alpha-hydroxyprogesterone	smallmolecule	CHEBI:17252	ChEBI	11-deoxycortisol	smallmolecule	CHEBI:28324	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000050							25855791	t		lperfetto	Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively	SIGNOR-268642	0.8
GMPS	protein	P49915	UNIPROT	5'-xanthylic acid	smallmolecule	CHEBI:15652	ChEBI	down-regulates quantity	chemical modification			9606									6698284	t		miannu	The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2).	SIGNOR-267337	0.8
GABA-A (a2-b1-g2) receptor	complex	SIGNOR-C331	SIGNOR	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	relocalization			9606									18790874	t	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263811	0.8
NLK	protein	Q9UBE8	UNIPROT	TCF4	protein	P15884	UNIPROT	down-regulates	phosphorylation			9606									2861485	t		gcesareni	Whereas lef-1 and tcf-4 phosphorylation by nlk (nemo-like kinase) leads to less lef/tcf/beta-catenin complex binding to dna and to lef-1/tcf-4 degradation	SIGNOR-24147	0.2
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1784	TPTSPNYsPTSPSYS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248826	0.849
NCBP1	protein	Q09161	UNIPROT	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates activity	relocalization			9606									26382858	t		lperfetto	The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. 	SIGNOR-268363	0.8
TTK	protein	P33981	UNIPROT	CDCA8	protein	Q53HL2	UNIPROT	up-regulates	phosphorylation	Thr88	QALEEAAtADLDITE	9606									19530738	t		lperfetto	First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form.	SIGNOR-186151	0.472
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259018	0.409
N-(2-chlorophenyl)-4-[[2-[4-[2-(4-ethyl-1-piperazinyl)-2-oxoethyl]anilino]-5-fluoro-4-pyrimidinyl]amino]benzamide	chemical	CHEBI:91365	ChEBI	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190029	0.8
EHF	protein	Q9NZC4	UNIPROT	SPRR1B	protein	P22528	UNIPROT	up-regulates quantity by expression	transcriptional regulation												12682075	f	 	 	Consistent with this, overexpression of EBS-binding proteins ESE-1 and ESE-3 significantly stimulated SPRR1B promoter activity. Furthermore, preceding SPRR1B transcription, PMA up-regulated mRNA expression of ETS family members such as ESE-1 and ESE-3	SIGNOR-254280	0.241
KDM3A	protein	Q9Y4C1	UNIPROT	H3-2	protein	Q5TEC6	UNIPROT	up-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									16603237	t		miannu	Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. 	SIGNOR-276843	0.2
MAPK1	protein	P28482	UNIPROT	PTTG1	protein	O95997	UNIPROT	up-regulates	phosphorylation	Ser165	LFQLGPPsPVKMPSP	9606									10906323	t		gcesareni	Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function.	SIGNOR-79515	0.359
MYC	protein	P01106	UNIPROT	HLA-B	protein	P01889	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000848								8206526	f		miannu	 In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. We show here that transcription of the HLA-B locus, which is mainly affected by c-Myc, is downmodulated at the level of initiation of transcription.	SIGNOR-254606	0.268
LINC complex	complex	SIGNOR-C303	SIGNOR	TTM complex	complex	SIGNOR-C305	SIGNOR	up-regulates activity	relocalization												30718482	t		lperfetto	Together, we conclude that both the TTM complex and SUN1 (the LINC complex) contribute to the stable telomere–NE association.	SIGNOR-263305	0.2
NPM1	protein	P06748	UNIPROT	FBP1	protein	P09467	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003081;BTO:0000849								30616754	t		lperfetto	For instance, nucleophosmin (NPM1) and zinc-finger protein X-linked (ZFX) bind to the E-box and ZFX binding site on the FBP1 promoter, respectively, and restrain FBP1 expression to facilitate aerobic glycolysis in PDAC and melanoma	SIGNOR-267594	0.2
RGCC	protein	Q9H4X1	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates activity	binding			9606	BTO:0001685								11687586	t		miannu	 RGC-32 was physically associated with cyclin-dependent kinase p34CDC2 and increased the kinase activity in vivo and in vitro. In addition, RGC-32 was phosphorylated by p34CDC2-cyclin B1 in vitro. Mutation of RGC-32 protein at Thr-91 prevented the p34CDC2-mediated phosphorylation and resulted in loss of p34CDC2 kinase enhancing activity.	SIGNOR-262726	0.546
SEMA4D	protein	Q92854	UNIPROT	PLXNB1	protein	O43157	UNIPROT	up-regulates	binding			9606									12198496	t		gcesareni	Binding of sema 4d to plexin b1 stimulates the tyrosine kinase activity of met, resulting in tyrosine phosphorylation of both receptors.	SIGNOR-92201	0.801
F2	protein	P00734	UNIPROT	F8	protein	P00451	UNIPROT	up-regulates activity	cleavage	Arg391	SPSFIQIrSVAKKHP	-1									10350471	t		lperfetto	Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689.	SIGNOR-263640	0.746
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PSMD2	protein	Q13200	UNIPROT	up-regulates activity	phosphorylation	Ser361	ENNRFGGsGSQVDSA	-1									31843888	t	done	miannu	Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B). 	SIGNOR-273898	0.2
ACP3	protein	P15309	UNIPROT	adenosine	smallmolecule	CHEBI:16335	ChEBI	up-regulates quantity	chemical modification			-1									18940592	t		Luana	Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord.	SIGNOR-269739	0.8
ZFP91	protein	Q96JP5	UNIPROT	MAP3K14	protein	Q99558	UNIPROT	up-regulates	ubiquitination			9606									20682767	t		gcesareni	Zfp91 interacts with and promotes the lys(63)-linked ubiquitination of nik and subsequent processing of p100 to p52.	SIGNOR-167331	0.515
ERBB4	protein	Q15303	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	binding			9606									16829981	t		gcesareni	Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow.	SIGNOR-147841	0.589
VIPAS39	protein	Q9H9C1	UNIPROT	CHEVI complex	complex	SIGNOR-C269	SIGNOR	form complex	binding			9606	BTO:0000007								29778605	t		lperfetto	It has been recently suggested that VPS33B and VIPAR comprise two subunits of a novel multi-subunit tethering complex (named "CHEVI")	SIGNOR-261831	0.782
oxandrolone	chemical	CHEBI:7820	ChEBI	AR	protein	P10275	UNIPROT	up-regulates activity	chemical activation			9606									10077001	t		miannu	The anabolic steroids, oxandrolone and fluoxymesterone, have high inhibition constants for binding, yet induce the N/C interaction and stabilize AR at relatively low ligand concentrations and are AR agonists in vivo.	SIGNOR-259265	0.8
AKT1	protein	P31749	UNIPROT	ITGB3	protein	P05106	UNIPROT	down-regulates activity	phosphorylation	Thr779	LYKEATStFTNITYR	9606	BTO:0000132								10896934	t		gcesareni	A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. These observations suggest that activation of PDK1 and/or Akt/PKB in platelets may modulate the binding activity and/or specificity of beta(3) for signaling molecules.	SIGNOR-252552	0.596
ATM	protein	Q13315	UNIPROT	PPP2R5D	protein	Q14738	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0001938								21460856	t		miannu	In the present study, we demonstrate that ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56γ3, B56γ2 and B56δ, after DNA damage. We further show that phosphorylation of B56γ3 at Ser510 leads to an increase in B56γ3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. we show that Ser510 phosphorylation significantly enhances the ability of B56γ3 to inhibit cell proliferation and anchorage-independent growth.	SIGNOR-276319	0.301
NCOA1	protein	Q15788	UNIPROT	OTC	protein	P00480	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f		miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-255062	0.2
EGFR	protein	P00533	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	phosphorylation	Tyr783	EGRNPGFyVEANPMP	9606									9176240	t		gcesareni	In contrast, egf-induced tyrosine phosphorylation of plc-gamma 1 was rather small, indicating that tyrosine phosphorylation of plc-gamma 1 is not proportional to changes in plc activity. These results suggest that autophosphorylation of theegfr may induce a conformational change of its kinase domain which enhances its kinase activity with exogenous substrates and may induce association with phospholipase c-gamma by increasing its affinity to a domain containing tyr-771.	SIGNOR-48872	0.835
FOXO1	protein	Q12778	UNIPROT	TRIM63	protein	Q969Q1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21798082	f		lperfetto	Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome.	SIGNOR-235712	0.416
L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	up-regulates quantity	precursor of			9606									30158707	t		miannu	Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction.	SIGNOR-267822	0.8
TRIM58	protein	Q8NG06	UNIPROT	DDX58	protein	O95786	UNIPROT	up-regulates activity	ubiquitination	Lys172	ENWPKTLkLALEKER										23499489	t		lperfetto	Specifically, the ubiquitin E3 ligase TRIM25 ubiquitinates K172 in the CARD2 of RIG-I, which is essential for the efficient interaction of RIG-I with MAVS and thereby for antiviral signal transduction 	SIGNOR-264582	0.2
FGFR2	protein	P21802	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	phosphorylation			9606									22726438	t		gcesareni	Inhibition of basal fgf receptor signaling by dimeric grb2.	SIGNOR-197980	0.764
ATM	protein	Q13315	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates	phosphorylation	Ser1401	LQGEEIKsQNSQEST	9606									12086603	t		lperfetto	These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint	SIGNOR-90109	0.782
CENPN	protein	Q96H22	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265210	0.716
ASXL1	protein	Q8IXJ9	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates activity	binding			9606									21047783	t		miannu	Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ. 	SIGNOR-260064	0.2
CKM complex	complex	SIGNOR-C406	SIGNOR	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606									15546612	t		gcesareni	Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.	SIGNOR-273150	0.379
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	VCP	protein	P55072	UNIPROT	up-regulates	phosphorylation	Ser748	RFARRSVsDNDIRKY	9606	BTO:0000150								16551632	t		llicata	Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I	SIGNOR-145292	0.2
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser119	SFSSTSVsSLEAEAY	9606									20305697	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-164633	0.575
Shelterin complex	complex	SIGNOR-C306	SIGNOR	Telomere_maintenance	phenotype	SIGNOR-PH148	SIGNOR	up-regulates													33015044	f		lperfetto	The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1	SIGNOR-263309	0.7
MYC	protein	P01106	UNIPROT	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000664;BTO:0004465								26179066	t		lperfetto	In the present study we demonstrate that MYC and its partner MAX bind to the BCR promoter, leading to up-regulation of BCR and BCR/ABL1 at both transcriptional and protein levels.|Here we describe a regulatory pathway modulating BCR and BCR/ABL1 expression, showing that the BCR promoter is under the transcriptional control of the MYC/MAX heterodimer.	SIGNOR-272143	0.2
MAPK1	protein	P28482	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr355	NFSSSPStPVGSPQG	10090									14592976	t		lperfetto	Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG)	SIGNOR-249451	0.367
GADD45A	protein	P24522	UNIPROT	CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	down-regulates	binding			9606									10362260	t		lperfetto	Gadd45 has now been found to directly inhibit the activity of cdc2/cyclin b1 complex	SIGNOR-217508	0.678
IL2	protein	P60568	UNIPROT	NAB2	protein	Q15742	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								22128144	f	 	miannu	We observe that the CD8(+) T-cell autocrine growth factor IL-2 coordinately increases Nab2 expression and decreases TRAIL expression. 	SIGNOR-253894	0.358
LYN	protein	P07948	UNIPROT	PPP1R8	protein	Q12972	UNIPROT	down-regulates activity	phosphorylation	Tyr335	NEPKKKKyAKEAWPG	-1									11104670	t			Lyn phosphorylates both Tyr-264 and Tyr-335, but that the phosphorylation of Tyr-335 is dependent on the association of NIPP1 with RNA. The inhibitory potency of the C-terminal site of NIPP1 was decreased by phosphorylation of Tyr-335 and by the addition of RNA. 	SIGNOR-251406	0.317
proline	smallmolecule	CHEBI:26271	ChEBI	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									25386178	f		apalma	Ornithine, via the enzyme OAT, is also a precursor amino acid for the synthesis of proline, which itself is essential for the synthesis of collagen.	SIGNOR-255550	0.7
A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269023	0.7
SRC	protein	P12931	UNIPROT	WWOX	protein	Q9NZC7	UNIPROT	up-regulates	phosphorylation	Tyr33	TTKDGWVyYANHTEE	9606									15070730	t		llicata	The tyrosine kinase, src, phosphorylates wwox at tyrosine 33 in the first ww domain and enhances its binding to p73.	SIGNOR-123819	0.494
CHEK2	protein	O96017	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser178	LFTQRQNsAPARMLS	9606									12676583	t	Phosphorylation is the signal for ubiquitination	gcesareni	We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases.	SIGNOR-99725	0.837
GBE1	protein	Q04446	UNIPROT	glycogen	smallmolecule	CHEBI:28087	ChEBI	up-regulates quantity	chemical modification			9606									26199317	t		miannu	Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked glucose chains, to increase solubility of the glycogen polymer. In eukaryotes, glycogenin (EC 2.4.1.186) initiates the synthesis of the linear glucan chain (2), which is elongated by glycogen synthase (GYS, EC 2.4.1.11) (3), functioning in concert with glycogen branching enzyme (GBE, EC 2.4.1.18) to introduce side chains	SIGNOR-267942	0.8
SRSF3	protein	P84103	UNIPROT	NXF1	protein	Q9UBU9	UNIPROT	up-regulates	binding			9606									18364396	t		miannu	9g8 and srp20 also enhance the tap rna-binding activity	SIGNOR-178111	0.667
USP9X	protein	Q93008	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	deubiquitination	Lys519	DYPRQSIkETPCWIE	9606									22298955	t		gcesareni	Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4.	SIGNOR-195697	0.633
FLI1	protein	Q01543	UNIPROT	Megakaryocyte_differentiation 	phenotype	SIGNOR-PH103	SIGNOR	up-regulates				9606	BTO:0000565								28052010	f		irozzo	The ETS-related transcription factor Fli-1 affects many developmental programs including erythroid and megakaryocytic differentiation, and is frequently de-regulated in cancer. 	SIGNOR-256087	0.7
RPS6KA1	protein	Q15418	UNIPROT	CARHSP1	protein	Q9Y2V2	UNIPROT	unknown	phosphorylation	Ser52	TRRTRTFsATVRASQ	9606		BTO:0000671							15910284	t		lperfetto	These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf	SIGNOR-137482	0.337
SIK2	protein	Q9H0K1	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	phosphorylation	Ser1490	AILNPPPsPATERSH	9606	BTO:0006293								35277657	t		miannu	Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/β-catenin signaling pathway activation.	SIGNOR-275404	0.2
UBN1	protein	Q9NPG3	UNIPROT	HIRA complex 1	complex	SIGNOR-C461	SIGNOR	form complex	binding			9606									30285846	t		miannu	H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex.	SIGNOR-269433	0.714
MAPK8	protein	P45983	UNIPROT	BCL2L11	protein	O43521	UNIPROT	up-regulates	phosphorylation	Thr116	SCDKSTQtPSPPCQA	9606									12591950	t	The effect has been demonstrated using O43521-2	gcesareni	Here, we demonstrate that jnk phosphorylates two members of the bh3-only subgroup of bcl2-related proteins (bim and bmf) that are normally sequestered by binding to dynein and myosin v motor complexes. Phosphorylation by jnk causes release from the motor complexes	SIGNOR-98396	0.751
Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	GABA-A (a2-b1-g2) receptor	complex	SIGNOR-C331	SIGNOR	up-regulates				9606									33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors	SIGNOR-268580	0.2
CXCL11	protein	O14625	UNIPROT	ACKR3	protein	P25106	UNIPROT	up-regulates activity	binding			9606	BTO:0000093								16940167	t		Luana	This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell alpha chemoattractant (I-TAC; also known as CXCL11)	SIGNOR-268415	0.624
NEK2	protein	P51955	UNIPROT	PPP1CC	protein	P36873	UNIPROT	down-regulates	phosphorylation	Thr307	EKKKPNAtRPVTPPR	9606									10880350	t		miannu	Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity. / threonine-307 and -318 appear to be equally well phosphorylated by nek2	SIGNOR-78306	0.502
ruxolitinib	chemical	CHEBI:66919	ChEBI	JAK3	protein	P52333	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206673	0.8
MMP12	protein	P39900	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272380	0.7
MAPK8	protein	P45983	UNIPROT	SARM1	protein	Q6SZW1	UNIPROT	down-regulates activity	phosphorylation	Ser548	AAREMLHsPLPCTGG										30333228	t		lperfetto	C-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD+ cleavage activity to inhibit mitochondrial respiration|Here, we report that NAD+ cleavage activity of SARM1 is regulated by its own phosphorylation at serine 548. The phosphorylation of SARM1 was mediated by c-jun N-terminal kinase (JNK) under oxidative stress conditions, resulting in inhibition of mitochondrial respiration concomitant with enhanced activity of NAD+ cleavage. Nonphosphorylatable mutation of Ser-548 or treatment with a JNK inhibitor decreased SARM1 activity.	SIGNOR-275554	0.434
SLC34A2	protein	O95436	UNIPROT	phosphate(3-)	smallmolecule	CHEBI:18367	ChEBI	up-regulates quantity	relocalization			9606		BTO:0000671							11009570	t		lperfetto	Three families of NPCs have been reported to date. The type I family consists of a single species (NaPi-1), which has thus far been found only in rabbit kidney.28 The type II family consists of six species homologues, NaPi 2 to 7, that are expressed predominantly in renal epithelial tissues.The type III family is the most recently identified and consists of two members, Pit-1 (also called Glvr-1) and Pit-2 (also called Ram-1).34 	SIGNOR-270578	0.8
BMI1	protein	P35226	UNIPROT	BMI1	protein	P35226	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								23239878	t		gcesareni	Here, we report that BMI1 autoactivates its own promoter via an E-box present in its promoter.	SIGNOR-245344	0.2
PLK1	protein	P53350	UNIPROT	KIF2C	protein	Q99661	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser621	ALIPGNLsKEEEELS	9606	BTO:0000567								25504441	t		miannu	Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. 	SIGNOR-276862	0.804
etanercept	chemical	CHEBI:4875	ChEBI	TNF	protein	P01375	UNIPROT	down-regulates activity	binding			9606									25455504	t			Etanercept is a recombinant human TNF receptor p75Fc fusion protein that binds with high affinity to the soluble and transmembrane forms of TNF, thereby acting as a decoy receptor for TNF and, prevents TNF-mediated inflammatory cellular responses by competitive inhibition	SIGNOR-272490	0.8
PRKACA	protein	P17612	UNIPROT	SLC2A2	protein	P11168	UNIPROT	down-regulates activity	phosphorylation	Ser503	AAEFQKKsGSAHRPK	9534	BTO:0004055								8626492	t		miannu	GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity.	SIGNOR-250050	0.313
AKT1	protein	P31749	UNIPROT	FBXO31	protein	Q5XUX0	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser33	AETAAADsEPDTDPE	9606	BTO:0002181								29343641	t		miannu	Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT.	SIGNOR-277376	0.2
STAT1	protein	P42224	UNIPROT	IL12A	protein	P29459	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000801								19029990	f		lperfetto	STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others.	SIGNOR-249499	0.528
NR0B2	protein	Q15466	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	down-regulates quantity by repression	transcriptional regulation			9606									11368516	f	inferred from family member	gcesareni	Shp (short heterodimer partner) is an orphan nuclear receptor lacking a dna binding domain that interacts with nuclear receptors (nr) including thyroid receptor (tr), retinoic acid receptors (rar and rxr), and estrogen receptors alpha and beta (eralpha and erbeta). Shp acts as a negative regulator of these receptors by inhibiting dna binding and transcriptional activation.	SIGNOR-267806	0.378
ZAP70	protein	P43403	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000782								29440413	t		miannu	We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. These results identify a tight negative feedback loop in which ZAP-70-activated p38 reciprocally phosphorylates ZAP-70 and destabilizes the signaling complex.	SIGNOR-277385	0.457
MAPK1	protein	P28482	UNIPROT	RSPH3	protein	Q86UC2	UNIPROT	up-regulates activity	phosphorylation	Thr286	AFLDRPPtPLFIPAK	9606									19684019	t		miannu	ERK1/2 phosphorylate RSPH3. the extent of radiolabeled phosphate incorporation into RSPH3 T286A was much less than that into wild-type RSPH3, suggesting that threonine 286 is the major ERK1/2 phosphorylation site in cells. ERK2 also phosphorylates RSPH3 on threonine 243 to a lesser extent. Phosphorylation of the double mutant T243V/T286A RSPH3 was no more than 20% that of wild-type RSPH3 (Fig. 4, C and D).	SIGNOR-262838	0.2
SP1	protein	P08047	UNIPROT	CD151	protein	P48509	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20149781	f		miannu	 SP1 is required for basal activation and chromatin accessibility of CD151 promoter in liver cancer cells.	SIGNOR-255195	0.2
TSC22D3	protein	Q99576	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	relocalization			9606	BTO:0000738								20018851	t			GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells.	SIGNOR-256146	0.306
PLK1	protein	P53350	UNIPROT	KIF2C	protein	Q99661	UNIPROT	up-regulates activity	phosphorylation	Ser632	EELSSQMsSFNEAMT	9606	BTO:0000567								25504441	t		miannu	Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. 	SIGNOR-276863	0.804
CSNK2A1	protein	P68400	UNIPROT	HOXB7	protein	P09629	UNIPROT	down-regulates activity	phosphorylation	Thr204	KTAGPGTtGQDRAEA	10090	BTO:0002882								11290787	t		llicata	Thus, we concluded that CKII can phosphorylate HOXB7 in vitro and that this phosphorylation occurs at both of the CKII target sites, S133 and T204. | Wild-type HOXB7 inhibited the differentiation of 32D cells, whereas mutations in the Pbx-binding pentapeptide motif or the DNA-binding homeodomain, as well as internal deletions of the N-terminal unique region, blocked this effect. Interestingly, mutations eliminating two target sites for casein kinase II, the glutamate-rich C terminus, or the first 14 amino acids of HOXB7, led to enhanced 32D differentiation. 	SIGNOR-250897	0.35
NFIX	protein	Q14938	UNIPROT	EPHA5	protein	P54756	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268909	0.2
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2D4	protein	Q9Y2X8	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271375	0.683
MRPS16	protein	Q9Y3D3	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606	BTO:0000934								25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261454	0.766
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	BHMT	protein	Q93088	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16953798	f		miannu	 SAM and MTA down-regulate BHMT expression in HepG2 cells in part by inducing NF-kappaB, which acts as a repressor for the human BHMT gene. While SAM's mechanism is NF-kappaB-dependent, MTA has both NF-kappaB-dependent and -independent mechanisms.	SIGNOR-254659	0.2
ELF4	protein	Q99607	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19380490	f		miannu	We found that elf4/mef activates mdm2 expression	SIGNOR-185490	0.391
MAPK8	protein	P45983	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser20	PLSQETFsDLWKLLP	10090	BTO:0004831								11896587	t		lperfetto	Serine 20 phosphorylation of p53 has been shown to be required for the activation of p53 following UV radiation. we determined the role of map kinases in uvb-induced phosphorylation and found that jnks are directly involved in the phosphorylation of p53 at serine 20	SIGNOR-106538	0.79
PTPRG	protein	P23470	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates activity	dephosphorylation	Tyr1059	DIYKDPDyVRKGDAR	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254708	0.255
USP7	protein	Q93009	UNIPROT	MDM4	protein	O15151	UNIPROT	up-regulates	deubiquitination			9606									16082221	t		gcesareni	Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins.	SIGNOR-139453	0.748
MITF	protein	O75030	UNIPROT	PMEL	protein	P40967	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12819038	f		miannu	 The results of the present work demonstrate that the essential melanocyte-specific transcription factor MITF regulates expression of the genes encoding the melanoma tumor markers MLANA and SILV. MITF up- or down-regulation is seen to correspondingly modulate expression of MLANA and SILV in parallel directions, at both mRNA and protein levels.	SIGNOR-254589	0.446
MAF	protein	O75444	UNIPROT	ETS1	protein	P14921	UNIPROT	down-regulates	binding			9606									9566892	t		miannu	Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity.	SIGNOR-56808	0.436
RUVBL1	protein	Q9Y265	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269292	0.732
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	CSNK1A1	protein	P48729	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000670								26131937	t		gcesareni	We demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1a) by the E3 ubiquitin ligase CUL4€“RBX1€“DDB1€“CRBN (known as CRL4CRBN)	SIGNOR-236907	0.384
BCS1L	protein	Q9Y276	UNIPROT	LETM1	protein	O95202	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								18628306	t		lperfetto	LETM1 was co-precipitated with BCS1L and formation of the LETM1 complex depended on BCS1L levels, suggesting that BCS1L stimulates the assembly of the LETM1 complex.	SIGNOR-262543	0.477
MRGPRX2	protein	Q96LB1	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257434	0.2
ROCK1	protein	Q13464	UNIPROT	MAPK8IP3	protein	Q9UPT6	UNIPROT	up-regulates	phosphorylation	Ser364	TRLDRTGsSPTQGIV	9606									15767678	t		gcesareni	Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis.	SIGNOR-134584	0.339
PRKCB	protein	P05771	UNIPROT	IBTK	protein	Q9P2D0	UNIPROT	down-regulates	phosphorylation	Ser1200	ASSLHSVsSKSFRDF	9606	BTO:0000776								21482705	t		llicata	We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane.	SIGNOR-173383	0.334
MAPK3	protein	P27361	UNIPROT	LCK	protein	P06239	UNIPROT	up-regulates activity	phosphorylation	Ser59	EGSNPPAsPLQDNLV	9606	BTO:0000567								8618896	t		lperfetto	Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation.	SIGNOR-249469	0.547
PRKN	protein	O60260	UNIPROT	HIF3A	protein	Q9Y2N7	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000793								27551449	t	Parkinson	miannu	Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of IPAS at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur. 	SIGNOR-263089	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	LIPE	protein	Q05469	UNIPROT	up-regulates activity	phosphorylation	Ser950	EGFHPRRsSQGATQM										19018281	t		miannu	 Our results demonstrate that PKA activates human HSL against lipid substrates in vitro primarily through phosphorylation of Ser649 and Ser650. 	SIGNOR-276174	0.2
MAPK8IP3	protein	Q9UPT6	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates	binding			9606									10523642	t		gcesareni	Overexpression of full-length jsap1 in cos-7 cells led to a considerable enhancement of jnk3 activation, and modest enhancement of jnk1 and jnk2 activation, by the mekk1-sek1 pathwaythe regions of jsap1 that bound jnk, sek1, and mekk1 were distinct from one another. Jnk and mekk1 also bound jsap1 in vitro, suggesting that these interactions are direct.	SIGNOR-71471	0.526
alvocidib hydrochloride	chemical	CHEBI:90998	ChEBI	CDK2	protein	P24941	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192461	0.8
STK11	protein	Q15831	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates				9606									14657655	f		gcesareni	Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent.	SIGNOR-119892	0.385
TGFBR2	protein	P37173	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9606									19114990	t		lperfetto	In immunoprecipitation esperiments, the TGF _ RII receptor was found to be constitutively associated with p85, the regulatory subunity of PI3K	SIGNOR-252731	0.42
PRKCA	protein	P17252	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates	phosphorylation	Ser27	DRHLRSEsQRQRREI	9606		BTO:0000671							9166747	t		gcesareni	Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling.	SIGNOR-48681	0.418
IL4R	protein	P24394	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates				9606									20824124	t			Several cytokine receptors share subchains and targets. For example, the common gamma chain (CGC) is shared by IL2, IL4, IL7, IL9 and IL15 receptors that lead to the activation of STAT5	SIGNOR-254298	0.538
HCK	protein	P08631	UNIPROT	HCK	protein	P08631	UNIPROT	down-regulates	phosphorylation	Tyr522	YTATESQyQQQP	9606									10934191	t		gcesareni	We demonstrate that autophosphorylation of the recombinant src family kinase hck leads to a 20-fold increase in its specific enzymatic activity.	SIGNOR-76996	0.2
INPPL1	protein	O15357	UNIPROT	PIP3	smallmolecule	CHEBI:16618	ChEBI	down-regulates	chemical modification			9606									9111325	t		gcesareni	Sip specifically and markedly reduced the level of phosphatidylinositol (3,4,5) triphosphate [ptdins(3,4,5)p3] generated in oocytes in response to insulin	SIGNOR-47537	0.8
CLCN3	protein	P51790	UNIPROT	chloride	smallmolecule	CHEBI:17996	ChEBI	down-regulates quantity	relocalization			9606									29845874	t		miannu	ClC-3 is a strongly outwardly rectifying, electrogenic 2Cl/H exchanger with biophysical properties that closely resemble those of its close homologues ClC-4 and ClC-5	SIGNOR-265422	0.8
CASP3	protein	P42574	UNIPROT	PARP1	protein	P09874	UNIPROT	down-regulates activity	cleavage			10090	BTO:0000331								11907276	t		amattioni	Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process	SIGNOR-116178	0.767
FHIT	protein	P49789	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates				9606	BTO:0000551								16407838	f		miannu	Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis	SIGNOR-252625	0.382
CHKB	protein	Q9Y259	UNIPROT	ethanolaminium(1+)	smallmolecule	CHEBI:57603	ChEBI	down-regulates quantity	chemical modification												29928787	t		lperfetto	In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells.	SIGNOR-275640	0.8
CSNK2A2	protein	P19784	UNIPROT	MS4A1	protein	P11836	UNIPROT	unknown	phosphorylation	Ser231	KSNIVLLsAEEKKEQ	9606	BTO:0000776								7678037	t		llicata	These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells.	SIGNOR-251011	0.311
Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor.	SIGNOR-266449	0.8
THRA	protein	P10827	UNIPROT	OXT	protein	P01178	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									6153132	f		lperfetto	The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances.	SIGNOR-268550	0.2
VEPH1	protein	Q14D04	UNIPROT	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000938								22055343	f	In the neuronal differentiation	lperfetto	Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9	SIGNOR-269858	0.2
TTC5	protein	Q8N0Z6	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								15448695	t		miannu	DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY	SIGNOR-262646	0.544
PKM	protein	P14618	UNIPROT	RBBP8	protein	Q99708	UNIPROT	up-regulates activity	phosphorylation	Thr126	ELMNERNtLQEENKK	9606	BTO:0002036								30297868	t		miannu	Here, we uncover an unexpected mechanism through which pyruvate kinase M2 (PKM2), the highly expressed PK isoform in cancer cells and a master regulator of cancer metabolic reprogramming, integrates with the DDR to directly promote DNA double-strand break (DSB) repair. In response to ionizing radiation and oxidative stress, ATM phosphorylates PKM2 at T328 resulting in its nuclear accumulation.	SIGNOR-277413	0.2
PRKCA	protein	P17252	UNIPROT	ARX	protein	Q96QS3	UNIPROT	up-regulates activity	phosphorylation	Ser174	VSISRSKsYRENGAP	9606	BTO:0002181								30419043	t		miannu	We confirm that ARX is phosphorylated by PRKCA and demonstrate phosphorylation at serine 174. We demonstrate that phosphorylation is required for correct transcriptional activity of the ARX protein using transcriptome-wide analysis of gene expression of phospho-null mutants (alanines replacing serines) compared to ARX wild-type (ARX-WT) overexpressed in pancreatic alpha TC cells.	SIGNOR-277418	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PAPOLA	protein	P51003	UNIPROT	up-regulates activity	phosphorylation	Ser545	PTSATKTsPLNSSGS	10090	BTO:0000964								34048556	t		lperfetto	Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity.	SIGNOR-268342	0.2
gossypol	chemical	CHEBI:28584	ChEBI	BCL2	protein	P10415	UNIPROT	down-regulates	chemical inhibition			9606									23336025	t		gcesareni	Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol.	SIGNOR-200469	0.8
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	NANOG	protein	Q9H9S0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001086								19279133	t		flangone	Here, we show that Smad2/3, the downstream effectors of Activin/Nodal signalling, bind and directly control the activity of the Nanog gene in hESCs.	SIGNOR-242055	0.433
TNF	protein	P01375	UNIPROT	SCN9A	protein	Q15858	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253479	0.254
TFEB	protein	P19484	UNIPROT	MTM1	protein	Q13496	UNIPROT	up-regulates quantity by expression	transcriptional regulation												30145926	f		lperfetto	Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 	SIGNOR-276800	0.2
CBFbeta-MYH11	fusion protein	SIGNOR-FP3	SIGNOR	TP53	protein	P04637	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									9834241	f		miannu	CBFbeta-SMMHC, Expressed in M4eo Acute Myeloid Leukemia, Reduces p53 Induction and Slows Apoptosis in Hematopoietic Cells Exposed to DNA-damaging Agents Reduced p53 induction may be caused in part by direct inhibition of p53 gene transcription, because p53 mRNA levels were reduced by CBFβ-SMMHC. Attenuated p53 induction and slowed apoptosis may contribute to leukemogenesis by CBFβ-SMMHC.	SIGNOR-256132	0.2
CDK7	protein	P50613	UNIPROT	CDK4	protein	P11802	UNIPROT	up-regulates	phosphorylation	Thr172	YSYQMALtPVVVTLW	9606									8139570	t		lperfetto	Phosphorylation of cdk4 on threonine 172 by a cdk-activating kinase (cak). therefore, formation of the cyclin d-cdk4 complex and phosphorylation of the bound catalytic subunit are independently regulated, and in addition to the requirement for cak activity, serum stimulation is required to promote assembly of the complexes in mammalian cells.	SIGNOR-36549	0.568
CDKN2A	protein	Q8N726	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates activity	relocalization			9606									23416275	t		fstefani	We propose that p14(arf) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53.	SIGNOR-192697	0.757
CSNK2A2	protein	P19784	UNIPROT	ACACA	protein	Q13085	UNIPROT	unknown	phosphorylation	Ser29	GSVSEDNsEDEISNL	-1									2900140	t		llicata	Phosphorylation at site 6 by casein kinase-2 is in good agreement with previous studies on the specificity of this kinase, which is known to phosphorylate serine residues followed by an acidic cluster	SIGNOR-250973	0.311
MAPK3	protein	P27361	UNIPROT	PCBP2	protein	Q15366	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr213	SASFPHTtPSMCLNP	9606	BTO:0000664								17475908	t		miannu	We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 	SIGNOR-262917	0.329
NUP50	protein	Q9UKX7	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262068	0.576
anthra[1,9-cd]pyrazol-6(2H)-one	chemical	CHEBI:90695	ChEBI	NTRK1	protein	P04629	UNIPROT	down-regulates	chemical inhibition			9606									21159646	t		gcesareni	In comparison, in the same assay conditions, the previously reported mps1 inhibitor sp600125 (13) was 10-fold less potent than nms-p715 on mps1 and, in addition, it was highly unspecific, being more active on at least 12 kinases including mitotic kinases.	SIGNOR-170617	0.8
PDK1	protein	Q15118	UNIPROT	PDHA2	protein	P29803	UNIPROT	down-regulates	phosphorylation	Ser291	TYRYHGHsMSDPGVS	9606									16436377	t		gcesareni	Human pdh1 and rat pdh2 were expressed previously and were shown to have different specific activities and the ability to be phosphorylated by pdk1 and pdk2	SIGNOR-143966	0.483
MLLT11	protein	Q13015	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0001939; BTO:0002768; BTO:0000815								26079538	f		irozzo	In addition, enhanced AF1q expression promotes breast cancer cell proliferation, migration, mammosphere formation, and chemo-resistance.	SIGNOR-259107	0.7
GABRA4	protein	P48169	UNIPROT	GABA-A (a4-b2-d) receptor	complex	SIGNOR-C326	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263745	0.513
MACROD2	protein	A1Z1Q3	UNIPROT	acetate	smallmolecule	CHEBI:30089	ChEBI	up-regulates quantity	chemical modification			9606									32257385	t		miannu	MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins	SIGNOR-269842	0.8
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGA5	protein	Q9Y5G8	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265717	0.2
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	Metabolism	phenotype	SIGNOR-PH77	SIGNOR	up-regulates													18391974	f			Forkhead proteins, and FoxO1 in particular, play a significant role in regulating whole body energy metabolism.	SIGNOR-253016	0.7
IL1RL1	protein	Q01638	UNIPROT	MYD88	protein	Q99836	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16286016	t		miannu	As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation. 	SIGNOR-277704	0.641
IL1RL1	protein	Q01638	UNIPROT	IRAK4	protein	Q9NWZ3	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16286016	t		miannu	As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation. 	SIGNOR-277705	0.587
IL13RA1	protein	P78552	UNIPROT	TYK2	protein	P29597	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0000801;BTO:0000876	BTO:0000887;BTO:0000763;BTO:0001260							12704343	t		milica	IL-4R, ?c, and IL-13R1 All contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectivelyil-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells.	SIGNOR-100756	0.547
PRKCD	protein	Q05655	UNIPROT	TP73	protein	O15350	UNIPROT	up-regulates	phosphorylation	Ser289	GQVLGRRsFEGRICA	9606									12097319	t		llicata	The results show that pkcdeltacf phosphorylates the p73beta transactivation and dna-binding domains. pkcdeltacf-mediated phosphorylation of p73beta is associated with accumulation of p73beta and induction of p73beta-mediated transactivation.	SIGNOR-90279	0.311
DOK1	protein	Q99704	UNIPROT	ITGB7	protein	P26010	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257695	0.329
IL1RL1	protein	Q01638	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16286016	t		miannu	As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation. 	SIGNOR-277706	0.587
IL1RL1	protein	Q01638	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16286016	t		miannu	As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation. 	SIGNOR-277707	0.577
CSF1	protein	P09603	UNIPROT	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606									33505964	f		miannu	 Exosomes from tumor cells package assorted proteins and chemokines with immunomodulatory capability, including CSF-1, CCL2, and TGF-β, to promote M2-like characterization of TAMs	SIGNOR-277708	0.7
CCL2	protein	P13500	UNIPROT	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606									33505964	f		miannu	 Exosomes from tumor cells package assorted proteins and chemokines with immunomodulatory capability, including CSF-1, CCL2, and TGF-β, to promote M2-like characterization of TAMs	SIGNOR-277709	0.7
DRAM2	protein	Q6UX65	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30755245	f		irozzo	Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors.	SIGNOR-259141	0.2
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1696	SPSYSPTsPSYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269373	0.718
midostaurin	chemical	CHEBI:63452	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									12124173	t			PKC412 is a potent inhibitor of mutant FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors.	SIGNOR-256308	0.8
PRKACA	protein	P17612	UNIPROT	HDAC8	protein	Q9BY41	UNIPROT	down-regulates	phosphorylation	Ser39	AKIPKRAsMVHSLIE	9606									14701748	t		lperfetto	Negative regulation of histone deacetylase 8 activity by cyclic amp-dependent protein kinase athe pka phosphoacceptor site of hdac8 is ser(39)	SIGNOR-120643	0.47
CACNA1C	protein	Q13936	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606		BTO:0000227							30849329	f		miannu	Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]).	SIGNOR-264330	0.7
TRIM25	protein	Q14258	UNIPROT	FBXW7	protein	Q969H0	UNIPROT	down-regulates activity	ubiquitination	Lys412	VWSAVTGkCLRTLVG	9606	BTO:0002181								31186535	t		miannu	This newly stabilized TRIM25 then directly ubiquitinates Lys412 of FBXW7α, a core subunit of the SKP1-Cullin-F-box (SCF) ubiquitin ligase complex involved in Myc ubiquitination, thereby stabilizing Myc. 	SIGNOR-277457	0.268
ELK1	protein	P19419	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16297876	f		irozzo	We demonstrated that both Elk-1 and MZF-1 were highly expressed in human poor differentiated HCC cells and involved in the up-regulation of PKCa, which was essential for cell migration and invasion. Over-expression assay confirmed that the PKCa expression may be modulated by these two factors at the transcriptional level.	SIGNOR-256282	0.417
BOC	protein	Q9BWV1	UNIPROT	CDON/BOC/PTCH1	complex	SIGNOR-C95	SIGNOR	form complex	binding			10090									21664576	t		lperfetto	Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands.	SIGNOR-209599	0.511
PRKCA	protein	P17252	UNIPROT	LCK	protein	P06239	UNIPROT	unknown	phosphorylation	Ser42	TLLIRNGsEVRDPLV	-1									8506364	t		lperfetto	In vitro kinase assays show that Ser-59 can be uniquely phosphorylated by mitogen-activated protein kinase and that Ser-42 can be phosphorylated by either protein kinase A or protein kinase C.	SIGNOR-248936	0.327
AKT1	protein	P31749	UNIPROT	XIAP	protein	P98170	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser87	VGRHRKVsPNCRFIN	9606		BTO:0001023							14645242	t		lperfetto	Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin.	SIGNOR-119488	0.638
DLK1	protein	P80370	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				9606									22640926	f		fspada	We conclude that DLK1(PREF1) is well expressed in human ASC and acts as a negative regulator of adipogenesis.	SIGNOR-197634	0.7
IL12B	protein	P29460	UNIPROT	IL12RB1	protein	P42701	UNIPROT	up-regulates	binding			9606									7527811	t		fspada	Characterization of the p40 proteins for binding and bioactivity showed that both the p40 monomer and dimer inhibited 125i-labeled il-12 binding to il-12r, but the 80-kda species, having a 50% inhibitory concentration (ic50) of 20 to 70 ng/ml, was at least 20-fold more effective than the monomer. The results suggest that the il-12 p40 subunit contains the essential epitopes for receptor binding.	SIGNOR-27690	0.663
GREB1	protein	Q4ZG55	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	binding			9606	BTO:0000599								31462641	t		miannu	GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Binding of GREB1 to Smad2/3 inhibits transcription	SIGNOR-265884	0.2
ILK	protein	Q13418	UNIPROT	MYL12B	protein	O14950	UNIPROT	up-regulates activity	phosphorylation	Thr19	KKRPQRAtSNVFAMF	9606									11278951	t		lperfetto	Integrin-linked kinase cdna was cloned, sequenced, expressed in e. coli, and shown to phosphorylate myosin light chain in the absence of ca(2+) at ser(19) and thr(18). Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activation of myosin light chain kinase, and phosphorylation of the 20-kDa light chain of myosin at Ser(19).Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activa	SIGNOR-106427	0.319
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000007								14976264	f		lperfetto	Sirt1 inhibited foxo3's ability to induce cell death.	SIGNOR-252939	0.7
EPHA2	protein	P29317	UNIPROT	EPHA2	protein	P29317	UNIPROT	up-regulates	phosphorylation	Tyr772	EDDPEATyTTSGGKI	9606									18387945	t		lperfetto	The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells.	SIGNOR-178181	0.2
AKT2	protein	P31751	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates	phosphorylation	Ser939	SFRARSTsLNERPKS	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex.	SIGNOR-183636	0.719
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates activity				9606	BTO:0000801								10973958	f		lperfetto	NF-kB-, AP-1-, and Smad3-driven promoters all require p300/CREB-binding protein for their transactivation. Previous studies have suggested that NF-kB- and AP-1-driven promoters can be inhibited by competitive recruitment of coactivators such as p300/CPB to other unrelated promoters. We hypothesized that NF-kB and AP-1 compete with Smad3 for limiting quantities of p300. This hypothesis predicts that added p300 should alleviate TGF-b1/Smad3-mediated inhibition of inflammatory genes. Conversely, increasing doses of TGF-b1/Smad3 would compete away even overexpressed p300 from NF-kB/AP- 1-driven promoters.	SIGNOR-249554	0.337
CID 132010322	chemical	CID:132010322	PUBCHEM	BRD2	protein	P25440	UNIPROT	down-regulates activity	chemical inhibition			9606									31969702	t		Luana	ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4 	SIGNOR-261103	0.8
EIF3E	protein	P60228	UNIPROT	MCM7	protein	P33993	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0002181								17310990	t		irozzo	Our data show that INT6 interacts with a C-terminal domain of MCM7. Collectively, our observations suggest that INT6 restrains the increased degradation of MCM7 occurring during DNA replication by protecting its polyubiquitylated derivatives from the proteasome activity.	SIGNOR-259154	0.341
CREBBP	protein	Q92793	UNIPROT	P300/PCAF	complex	SIGNOR-C7	SIGNOR	form complex	binding			9606									21131905	t		lperfetto	Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators.	SIGNOR-170262	0.639
BAX	protein	Q07812	UNIPROT	CYCS	protein	P99999	UNIPROT	up-regulates	relocalization			9606									10629050	t	Translocation from Mitochondria to Cytosol	amattioni	The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease	SIGNOR-73898	0.687
AML1-ETO	fusion protein	SIGNOR-FP1	SIGNOR	JUN	protein	P05412	UNIPROT	down-regulates activity	binding			9606	BTO:0004136								12393465	t	RUNX1-RUNX1T1 fusion protein (AML-ETO)	apalma	 Here we show that AML1-ETO blocks the transcriptional activity of PU.1 by displacing its coactivator c-Jun.	SIGNOR-255670	0.2
PI4K2B	protein	Q8TCG2	UNIPROT	1-phosphatidyl-1D-myo-inositol 4-phosphate	smallmolecule	CHEBI:17526	ChEBI	up-regulates quantity	chemical modification			9606									10101268	t		miannu	The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 	SIGNOR-269101	0.8
MRPS33	protein	Q9Y291	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261444	0.678
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CAMK2D	protein	Q13557	UNIPROT	up-regulates activity	chemical activation			9606									19725819	t		areggio	Upon binding of the Ca2+/calmodulin complex to the binding domain of CaMKII, it is activated via autophosphorylation, then remaining active independent of of Ca2+ levels.	SIGNOR-255953	0.8
MAP3K14	protein	Q99558	UNIPROT	CHUK	protein	O15111	UNIPROT	up-regulates activity	phosphorylation	Ser180	DQGSLCTsFVGTLQY	9606				SIGNOR-C14					9520446	t		lperfetto	NIK preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa.	SIGNOR-55946	0.684
2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-4-quinazolinyl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide	chemical	CHEBI:91367	ChEBI	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190245	0.8
CEBPD	protein	P49716	UNIPROT	TNFAIP6	protein	P98066	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000801								23028973	f	 	 	CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions.	SIGNOR-254057	0.262
TRAPPC9	protein	Q96Q05	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								15951441	t		miannu	We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates. 	SIGNOR-269673	0.503
PDPK1	protein	O15530	UNIPROT	PGK1	protein	P00558	UNIPROT	up-regulates activity	phosphorylation	Thr243	IGGGMAFtFLKVLNN	9606	BTO:0002036								30029001	t		miannu	PDPK1 Phosphorylates PGK1 T243. Macrophages increase PGK1 pT243 to reduce the 3-PG affinity of PGK1, which alters the equilibrium of the PGK1-catalyzed reaction toward glycolysis, promoting tumor cell proliferation.	SIGNOR-277402	0.2
SIRT3	protein	Q9NTG7	UNIPROT	CYP11A1	protein	P05108	UNIPROT	up-regulates quantity by stabilization	deacetylation	Lys148	LKKSAAWkKDRVALN	9606	BTO:0002588								22585829	t		lperfetto	Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.|Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis.	SIGNOR-268717	0.2
MKNK1	protein	Q9BUB5	UNIPROT	PLA2G4A	protein	P47712	UNIPROT	up-regulates activity	phosphorylation	Ser727	RQNPSRCsVSLSNVE	9606	BTO:0000007								10978317	t		lperfetto	The results suggest that MNK1 or a closely related kinase is responsible for in vivo phosphorylation of cPLA2 on Ser-727.	SIGNOR-226633	0.559
VRK2	protein	Q86Y07	UNIPROT	DTNBP1	protein	Q96EV8	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser297	ELRAKPPsSSSTCTD	-1									30062698	t		miannu	 We show that VRK2 phosphorylates Ser 297 and Ser 299 of dysbindin using in vitro kinase assay. In addition, we found that VRK2-mediated phosphorylation of dysbindin enhanced ubiquitination of dysbindin and consequently resulted in the decrease in its protein stability through western blotting. 	SIGNOR-277403	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	HTT	protein	P42858	UNIPROT	unknown	phosphorylation	Ser419	GGRSRSGsIVELIAG	9606	BTO:0000938								12062094	t		llicata	We demonstrate that huntingtin is a substrate of akt and that phosphorylation of huntingtin by akt is crucial to mediate the neuroprotective effects of igf-1.	SIGNOR-89696	0.2
TCF4	protein	P15884	UNIPROT	NRXN1	protein	Q9ULB1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22777675	f	 	miannu	 we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays.	SIGNOR-255391	0.277
HSPA5	protein	P11021	UNIPROT	UPR	phenotype	SIGNOR-PH131	SIGNOR	up-regulates													28286085	f		lperfetto	The HSPA5 gene encodes the binding immunoglobulin protein (BiP), an Hsp70 family chaperone localized in the ER lumen.|When unfolded/misfolded proteins in the ER overwhelm the capacity of protein folding machinery, BiP can initiate the unfolded protein response (UPR), decrease unfolded/misfolded protein load, induce autophagy, and crosstalk with apoptosis machinery to assist in the cell survival decision. 	SIGNOR-265282	0.7
PGK1	protein	P00558	UNIPROT	PGK1	protein	P00558	UNIPROT	up-regulates activity	phosphorylation	Tyr324	GPESSKKyAEAVTRA	-1									31492635	t		miannu	PGK1 functions not only as a glycolytic enzyme but also as a protein kinase intermolecularly autophosphorylating itself at Y324 for activation. 	SIGNOR-277482	0.2
HERC2	protein	O95714	UNIPROT	XPA	protein	P23025	UNIPROT	down-regulates	ubiquitination			9606									20304803	t		miannu	Herc2 may ubiquitinate xpa and thus target it for proteolytic degradation	SIGNOR-164595	0.394
PLK1	protein	P53350	UNIPROT	BRCA2	protein	P51587	UNIPROT	unknown	phosphorylation	Ser205	LATPPTLsSTVLIVR	9606	BTO:0001938								12815053	t		lperfetto	Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation.	SIGNOR-249218	0.556
SIK3	protein	Q9Y2K2	UNIPROT	CRTC2	protein	Q53ET0	UNIPROT	down-regulates activity	phosphorylation	Ser171	SALNRTSsDSALHTS	9606	BTO:0000567								16306228	t		lperfetto	We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression 	SIGNOR-249172	0.62
GRM1	protein	Q13255	UNIPROT	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							20055706	t		miannu	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264077	0.385
CAMK2A	protein	Q9UQM7	UNIPROT	RCHY1	protein	Q96PM5	UNIPROT	down-regulates	phosphorylation	Thr154	ICLEDIHtSRVVAHV	9606									17568776	t		lperfetto	Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53	SIGNOR-156068	0.3
CAMK2D	protein	Q13557	UNIPROT	CACNB2	protein	Q08289	UNIPROT	up-regulates	phosphorylation	Thr554	RGLSRQEtFDSETQE	9606									20194790	t	The effect has been demonstrated using Q08289-2	gcesareni	We recently identified ca(v)1.2 beta(2a) residues critical for camkii phosphorylation (thr 498) beta(2a) thr 498 and leu 493 are required for ca(v)1.2 activation by camkii in native cells.	SIGNOR-164067	0.399
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1644	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273092	0.745
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1693	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273095	0.745
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Thr458	CKTPSSNtLDDYMSC	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276222	0.389
CSNK2A1	protein	P68400	UNIPROT	ATXN3	protein	P54252	UNIPROT	up-regulates activity	phosphorylation	Ser347	LQAAVTMsLETVRND	9606	BTO:0000007								19542537	t		miannu	Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). The main phosphorylation of ATXN3 in vivo thus occurred at serine residues within the three conserved UIMs.	SIGNOR-276224	0.2
SLC24A2	protein	Q9UI40	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264399	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0003324								25323588	t		miannu	Earlier studies found that expression of active Akt increases mitochondrial HK activity and the anti-apoptotic effect of Akt required mitoHK	SIGNOR-267577	0.498
Guanabenz	chemical	CHEBI:5553	ChEBI	ADRA2A	protein	P08913	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258909	0.8
FAM162A	protein	Q96A26	UNIPROT	VDAC1	protein	P21796	UNIPROT	up-regulates activity	binding			9606	BTO:0001061								15082785	t		Giulio	HGTD-P was coprecipitated with VDAC but not with ANT or cyclophilin D (Fig. 7A, left upper panel).|However, it is not clear at present whether HGTD-P participates directly in channel formation in association with VDAC or modulates its channel-forming activity.	SIGNOR-260293	0.2
MAPK1	protein	P28482	UNIPROT	NEFH	protein	P12036	UNIPROT	up-regulates activity	phosphorylation	Ser518	SPEKEAKsPVKEEAK	10116	BTO:0000938								9592082	t		lperfetto	The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation. 	SIGNOR-249423	0.375
MLL-AF4	fusion protein	SIGNOR-FP4	SIGNOR	DOT1L	protein	Q8TEK3	UNIPROT	up-regulates activity	binding			9606	BTO:0005014								27856324	t		irozzo	Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4.	SIGNOR-255882	0.2
CSNK2A1	protein	P68400	UNIPROT	GYS1	protein	P13807	UNIPROT	unknown	phosphorylation	Ser645	RPASVPPsPSLSRHS	-1									2117608	t		llicata	With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action.	SIGNOR-250879	0.334
PTPN6	protein	P29350	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates	dephosphorylation	Tyr1197	STAENAEyLRVAPQS	9606									9733788	t		tpavlidou	The sh2-domain ptpase shp-1 binds to and dephosphorylates autophosphorylated egfr and may participate in modulation of egfr signaling in epithelial cells. Reduced shp-1 binding to the egfr y1173f mutant resulted in a reduced receptor dephosphorylation by coexpressed shp-1 and less interference with egf-dependent mitogen-activated protein kinase stimulation.	SIGNOR-59965	0.425
NFE2L2	protein	Q16236	UNIPROT	TKT	protein	P29401	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22789539	f		miannu	We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). 	SIGNOR-267356	0.271
dabrafenib	chemical	CHEBI:75045	ChEBI	RAF1	protein	P04049	UNIPROT	down-regulates activity	chemical inhibition			-1									24720932	t		miannu	Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations	SIGNOR-259218	0.8
ADGRG1	protein	Q9Y653	UNIPROT	ADGRG1	protein	Q9Y653	UNIPROT	up-regulates activity	cleavage												24949629	t			Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); | We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation.	SIGNOR-253980	0.2
STAT6	protein	P42226	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates activity	binding			9606	BTO:0000801								10982806	t		lperfetto	STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site	SIGNOR-249553	0.426
F2R	protein	P25116	UNIPROT	LATS1	protein	O95835	UNIPROT	down-regulates				9606	BTO:0000007								22972936	f	Here we report that stimulation of protease-activated receptors (PARs) activates YAP/TAZ by decreasing phosphorylation and increasing nuclear localization.	milica	Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase.	SIGNOR-192045	0.2
PP121	chemical	CHEBI:50915	ChEBI	PRKDC	protein	P78527	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206304	0.8
CDK2AP1	protein	O14519	UNIPROT	CDK2	protein	P24941	UNIPROT	down-regulates activity	binding												22427660	t		lperfetto	The ubiquitously expressed CDK2AP1 protein is the only known specific inhibitor of CDK2, making it an important component of cell cycle regulation during G1-to-S phase transition. 	SIGNOR-264781	0.452
4.1 complex	complex	SIGNOR-C386	SIGNOR	SPTB	protein	P11277	UNIPROT	up-regulates activity	binding			9606	BTO:0000424								22465511	t		lperfetto	The junctional complex is focused around a hub or ‘junction’ arising from lateral connections between protein 4.1, actin and beta spectrin (the first of which stabilises the actin spectrin association via direct binding to both proteins [8]).	SIGNOR-266041	0.362
quetiapine	chemical	CHEBI:8707	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029									9760039	t		miannu	Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3).	SIGNOR-258842	0.8
CSNK2A1	protein	P68400	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates activity	phosphorylation	Ser133	NAIRYIEsLQELLRE	-1									9461343	t		llicata	Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity. 	SIGNOR-250922	0.311
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MST1R	protein	Q04912	UNIPROT	up-regulates	phosphorylation	Ser1394	VRRPRPLsEPPRPT	9606									14505491	t		lperfetto	Akt/pkb phosphorylates ron ser-1394, thus providing a docking site for 14-3-3based on these results, we propose a mechanism based on msp-ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing	SIGNOR-118053	0.2
ABL1	protein	P00519	UNIPROT	GPX1	protein	P07203	UNIPROT	up-regulates activity	phosphorylation	Tyr98	EILNSLKyVRPGGGF	9606									12893824	t		lperfetto	GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress.	SIGNOR-104324	0.472
SMAD3	protein	P84022	UNIPROT	FOXA1	protein	P55317	UNIPROT	down-regulates activity	binding			9606									18003659	t		miannu	TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function. 	SIGNOR-254168	0.337
CYCS	protein	P99999	UNIPROT	APAF1	protein	O14727	UNIPROT	up-regulates activity	binding			9606									9267021	t	Cytochrome C released from mitochondria	lperfetto	Once released from mitochondria, cytochrome c binds to Apaf-1, which may trigger the activation of caspase-3 in the presence of dATP.	SIGNOR-50585	0.786
DNMT3A	protein	Q9Y6K1	UNIPROT	HOXA9	protein	P31269	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24280869	f		miannu	 HOXA9 is significantly upregulated in both categories of DNMT3A modifications and this has been associated with poor prognosis in AML before (Figure 3d). In fact, almost the entire HOXA and HOXB cluster were significantly upregulated in AML samples with either epimutation or mutation in DNMT3A.	SIGNOR-256128	0.346
JAG2	protein	Q9Y219	UNIPROT	JAG1	protein	P78504	UNIPROT	up-regulates				10090	BTO:0000165;BTO:0000222								9315665	f		gcesareni	Immunohistochemistry revealed coexpression of jagged2 and notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human jagged2 with murine c2c12 myoblasts inhibited myogenic differentiation, accompanied by increased notch1 and the appearance of a novel 115-kda notch1 fragment. Exposure of c2c12 cells to jagged2 led to increased amounts of notch mrna as well as mrnas for a second notch receptor, notch3, and a second notch ligand, jagged1. Constitutively active forms of notchl in c2c12 cells also induced increased levels of the same set of mrnas, suggesting positive feedback control of these genes initiated by binding of jagged2 to notch1.	SIGNOR-236888	0.387
DTL	protein	Q9NZJ0	UNIPROT	Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								24962565	t		miannu	TDG Is Polyubiquitinated by CRL4Cdt2 E3 Ubiquitin Ligase in a PIP Degron-dependent Manner	SIGNOR-272848	0.683
(R)-carnitine	smallmolecule	CHEBI:16347	ChEBI	O-palmitoyl-L-carnitine	smallmolecule	CHEBI:17490	ChEBI	up-regulates quantity	precursor of			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267118	0.8
SRC	protein	P12931	UNIPROT	SLC6A4	protein	P31645	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr47	SGQISNGySAVPSPG	10116	BTO:0000132								21992875	t		miannu	We found that 1) SERT exists in a tyrosine-phosphorylated form, 2) inhibition of tyrosine kinase(s) reduces SERT expression levels by facilitating SERT protein degradation, 3) Src-kinase activity up-regulates SERT protein expression with a concomitant increase in 5-HT uptake and tyrosine phosphorylation, and 4) mutation of Tyr47 or Tyr142 abolishes src-induced increases in transport function and phosphorylation of SERT. 	SIGNOR-276385	0.262
GNA13	protein	Q14344	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates	binding			9606									23450633	t		gcesareni	Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism.	SIGNOR-192111	0.555
MAP2K6	protein	P52564	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation			9606									10480932	t		lperfetto	We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta.	SIGNOR-70607	0.733
staurosporine	chemical	CHEBI:15738	ChEBI	PRKCH	protein	P24723	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258286	0.8
PDCD1	protein	Q15116	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates activity				9606	BTO:0000782								22740686	f		Barakat	MEK1/2 was phosphorylated and activated upon activation of T cells through TCR-CD3 and CD28, which resulted in phosphorylation of its downstream target ERK1/2, as determined by Western blotting analysis with an antibody specific for ERK1/2 phosphorylated at Thr202 and Tyr204, markers of activation. PD-1 substantially inhibited the activation of MEK1/2 and ERK1/2 	SIGNOR-275410	0.268
RPS6KA5	protein	O75582	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates activity	phosphorylation	Ser376	EKLFQGYsFVAPSIL	9606									15568999	t		lperfetto	Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro.	SIGNOR-131391	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SMAD4	protein	Q13485	UNIPROT	up-regulates	phosphorylation	Thr277	GSRTAPYtPNLPHHQ	9606									12801888	t		lperfetto	Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4.	SIGNOR-244739	0.2
CDK1	protein	P06493	UNIPROT	GATA2	protein	P23769	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr176	HLFGFPPtPPKEVSP	9606	BTO:0000007								25670854	t		miannu	GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. Substitution of threonine 176 to alanine in GATA2 inhibited binding with Fbw7, and the ubiquitylation and degradation of GATA2 by Fbw7 was suppressed. The CPD kinase, which mediates the phosphorylation of Thr(176), was cyclin B-cyclin-dependent kinase 1 (CDK1). 	SIGNOR-276884	0.362
felodipine	chemical	CHEBI:585948	ChEBI	NR3C2	protein	P08235	UNIPROT	down-regulates activity	chemical inhibition			-1									18250364	t		Luana	Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression. 	SIGNOR-257766	0.8
MAPK1	protein	P28482	UNIPROT	SHOC2	protein	Q9UQ13	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr507	GLGENLLtHLPEEIG	9606	BTO:0000007								30865892	t		miannu	Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation.	SIGNOR-277442	0.329
RNF125	protein	Q96EQ8	UNIPROT	DDX58	protein	O95786	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0005029								17460044	t		miannu	Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production.	SIGNOR-271647	0.658
SLBP	protein	Q14493	UNIPROT	H2AZ1	protein	P0C0S5	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265408	0.2
teniposide	chemical	CHEBI:75988	ChEBI	TOP2B	protein	Q02880	UNIPROT	down-regulates activity	chemical inhibition			9606									1329225	t		miannu	Recognition of transient DNA breaks induced by teniposide, etoposide, and other podophyllotoxin analogues established not only that their site of activity was DNA but also that their cytotoxic effect was dose-dependent. Extensive investigation has further indicated that a primary mechanism of action of these agents involves inhibition of the catalytic activity of eukaryote topoisomerase II and, more important, the consequent stabilization of the normally transient covalent intermediate formed between the DNA substrate and the enzyme. 	SIGNOR-259330	0.8
XIAP	protein	P98170	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates quantity by destabilization	binding			9606									11242052	t		lperfetto	A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis	SIGNOR-105702	0.92
PIP3	smallmolecule	CHEBI:16618	ChEBI	AKT1	protein	P31749	UNIPROT	up-regulates activity	relocalization			9606									23119004	t		lperfetto	Binding of igf to igf-ir activates pi3k to generate pip3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including akt and pdk1.	SIGNOR-252642	0.8
STK11	protein	Q15831	UNIPROT	SIK2	protein	Q9H0K1	UNIPROT	up-regulates	phosphorylation	Thr175	KSGELLAtWCGSPPY	9606									14976552	t		llicata	A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold.	SIGNOR-122788	0.458
ANGPT1	protein	Q15389	UNIPROT	TEK	protein	Q02763	UNIPROT	up-regulates	binding			9606									9204896	t		gcesareni	Angiopoietin-1 (ang1) is an angiogenic factor that signals through the endothelial cell-specific tie2 receptor tyrosine kinase.	SIGNOR-49355	0.79
JAK3	protein	P52333	UNIPROT	JAK3	protein	P52333	UNIPROT	up-regulates	phosphorylation	Tyr904	SLRLVMEyLPSGCLR	9606									18250158	t		lperfetto	Y904 and y939 are required for optimal jak3 autophosphorylation and kinase activity in vitro	SIGNOR-160664	0.2
HCK	protein	P08631	UNIPROT	ADAM15	protein	Q13444	UNIPROT	up-regulates	phosphorylation	Tyr715	LVMLGASyWYRARLH	9606									11741929	t		lperfetto	Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling.	SIGNOR-112919	0.362
PRKACA	protein	P17612	UNIPROT	CACNA1D	protein	Q01668	UNIPROT	up-regulates activity	phosphorylation	Ser1700	VNSDRRDsLQQTNTT	-1									19074150	t		miannu	 We recently demonstrated that PKA activation led to increased alpha(1D) Ca(2+) channel activity in tsA201 cells by phosphorylation of the channel protein. Western blotting showed that the N terminus and C terminus were phosphorylated. Serines 1743 and 1816, two PKA consensus sites, were phosphorylated by PKA and identified by mass spectrometry.	SIGNOR-263108	0.374
Deltorphin B	chemical	CHEBI:81498	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258785	0.8
SIRT1	protein	Q96EB6	UNIPROT	Cell_cycle_block	phenotype	SIGNOR-PH10	SIGNOR	up-regulates				9606	BTO:0000007								14976264	f		lperfetto	Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress	SIGNOR-217878	0.7
KMT2A	protein	Q03164	UNIPROT	MLL1 complex	complex	SIGNOR-C89	SIGNOR	form complex	binding			9606									24680668	t		miannu	The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation.	SIGNOR-204813	0.2
PP2Ca_R1A_Bd 	complex	SIGNOR-C133	SIGNOR	GSK3B	protein	P49841	UNIPROT	up-regulates activity	dephosphorylation	Ser9	SGRPRTTsFAESCKP	9606	BTO:0000007								20080667	t		miannu	DAB2IP interacts via its C2 domain with GSK3β, recruiting phosphatase PP2A for S9 de-phosphorylation and leading to GSK3β activation.	SIGNOR-254754	0.422
tRNA(Val)	smallmolecule	CHEBI:29183	ChEBI	Val-tRNA(Val)	smallmolecule	CHEBI:29164	ChEBI	up-regulates quantity	precursor of			9606									30755602	t		miannu	Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 	SIGNOR-270531	0.8
CDK5	protein	Q00535	UNIPROT	CLOCK	protein	O15516	UNIPROT	up-regulates	phosphorylation	Thr451	AVSDPSStPTKIPTD	9606									24235147	t		lperfetto	Cdk5 phosphorylates clock at the thr-451 and thr-461 residues in association with transcriptional activation of clock.	SIGNOR-203227	0.335
GNB/GNG	complex	SIGNOR-C202	SIGNOR	CACNA1B	protein	Q00975	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20655485	t		miannu	The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release.	SIGNOR-265067	0.399
SCN8A	protein	Q9UQD0	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606									27262167	t		miannu	Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential.	SIGNOR-253406	0.8
MYC	protein	P01106	UNIPROT	DHODH	protein	Q02127	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003291								18628958	t		miannu	 PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria. 	SIGNOR-267382	0.354
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1721	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273048	0.556
D-glucopyranose	smallmolecule	CHEBI:4167	ChEBI	lactose	smallmolecule	CHEBI:17716	ChEBI	up-regulates quantity	precursor of			9606									16157350	t		miannu	Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 	SIGNOR-268474	0.8
PTGIR	protein	P43119	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256806	0.508
tamoxifen	chemical	CHEBI:41774	ChEBI	ESR1	protein	P03372	UNIPROT	down-regulates activity	chemical inhibition			9606									20512796	t		miannu	Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth. 	SIGNOR-258587	0.8
AML1-ETO	fusion protein	SIGNOR-FP1	SIGNOR	JAK2	protein	O60674	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0001271								22740448	f		miannu	Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced.	SIGNOR-260120	0.2
CSNK2A2	protein	P19784	UNIPROT	GTF2A1	protein	P52655	UNIPROT	up-regulates activity	phosphorylation	Ser316	VEEEPLNsEDDVSDE	-1									11278496	t		llicata	We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function.	SIGNOR-250997	0.382
CDC20	protein	Q12834	UNIPROT	MCC	complex	SIGNOR-C382	SIGNOR	form complex	binding			9606	BTO:0000567								25092294	t		miannu	The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. 	SIGNOR-265976	0.978
FSTL3	protein	O95633	UNIPROT	MSTN	protein	O14793	UNIPROT	down-regulates	binding			9606	BTO:0000222;BTO:0002314	BTO:0000887;BTO:0001103							23038772	t		gcesareni	Fstl3 inhibits myostatin via its n-terminal domain.	SIGNOR-199063	0.696
FZD3	protein	Q9NPG1	UNIPROT	CXCL1	protein	P09341	UNIPROT	up-regulates	binding			9606									17251915	t		gcesareni	In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families.	SIGNOR-152597	0.2
TXK	protein	P42681	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates	phosphorylation	Tyr113	SSFEEDDyESPNDDQ	9606									10660534	t		lperfetto	Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function	SIGNOR-74844	0.717
FZD3	protein	Q9NPG1	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates activity	binding			9606									22944199	t		amattioni	When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.	SIGNOR-134288	0.646
RCSD1	protein	Q6JBY9	UNIPROT	CAPZA1	protein	P52907	UNIPROT	up-regulates	binding			-1									15850461	t		miannu	An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B). Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263088	0.689
Obatoclax mesylate	chemical	CID:46930996	PUBCHEM	BCL2L2	protein	Q92843	UNIPROT	down-regulates activity	chemical inhibition			-1									23515850	t		lperfetto	Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro	SIGNOR-262024	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BANP	protein	Q8N9N5	UNIPROT	down-regulates activity	phosphorylation	Thr352	PSEPMMStPPPASEL	9606	BTO:0000567								26080397	t		miannu	ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68. 	SIGNOR-266378	0.2
PPARGC1A	protein	Q9UBK2	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates				9606									19491292	f		gcesareni	Nuclear pgc-1alpha and foxo3a respond in a reciprocal manner following aicar treatment.	SIGNOR-186058	0.403
PBX3	protein	P40426	UNIPROT	FGF8	protein	P55075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003560								10026229	t		miannu	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 	SIGNOR-265805	0.2
EID1	protein	Q9Y6B2	UNIPROT	EP300	protein	Q09472	UNIPROT	down-regulates activity	binding												11073989	t		lperfetto	Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity.	SIGNOR-253379	0.431
RXRA	protein	P19793	UNIPROT	RARG	protein	P13631	UNIPROT	up-regulates	binding			9606									1310351	t		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16671	0.671
3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates				9606									24692351	f		scontino	Skeletal muscle has been recognized as a key TH target for contractile function, regeneration, and transport as well as for metabolism and glucose disposal (237, 238). TH stimulation favors transition to fast-twitch fibers and transition to a faster myosin heavy chain (MHC) form.	SIGNOR-267619	0.7
MMP10	protein	P09238	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272378	0.7
MAPK14	protein	Q16539	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr37	PPGDYSTtPGGTLFS	9606	BTO:0003316								11777913	t		miannu	4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E. 	SIGNOR-250098	0.444
MAPK3	protein	P27361	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606	BTO:0001271	BTO:0000671							14551213	t		gcesareni	The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1	SIGNOR-118596	0.709
PRKCD	protein	Q05655	UNIPROT	ADRB2	protein	P07550	UNIPROT	down-regulates activity	phosphorylation	Ser262	GHGLRRSsKFCLKEH	-1									1848190	t		lperfetto	We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling.	SIGNOR-248855	0.358
SREBF2	protein	Q12772	UNIPROT	LRP1	protein	Q07954	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20980003	f		miannu	 In the present study we report that specific silencing of either SREBP-1 or SREBP-2 enhanced LRP1 whereas overexpression of the active SREBP isoforms decreased LRP1 expression.	SIGNOR-254461	0.334
PSMA7	protein	O14818	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263365	0.821
UNC5C	protein	O95185	UNIPROT	DCC	protein	P43146	UNIPROT	down-regulates activity	binding			9606		BTO:0001484							25881791	t		miannu	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268165	0.657
ABL1	protein	P00519	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates activity	phosphorylation	Tyr315	ETRICKIyDSPCLPE	9534	BTO:0000298								10212258	t			C-Abl phosphorylates Rad51 in vitro and in vivo. phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. c-Abl phosphorylates Rad51 Tyr315	SIGNOR-251434	0.764
GLI3	protein	P10071	UNIPROT	MYCN	protein	P04198	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17419683	f		gcesareni	Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. .Hedgehog Signals induce cellular proliferation through upregulation of n-myc, cyclin d/e, and foxm1.	SIGNOR-154237	0.365
AZD-8055	chemical	CHEBI:91329	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck;ATP-competitive inhibitor mTOR	gcesareni		SIGNOR-190215	0.8
MARCHF5	protein	Q9NX47	UNIPROT	MARCHF5	protein	Q9NX47	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								16874301	t		miannu	Rapid degradation of MITOL by autoubiquitination activity. Taken together, these results suggested that MITOL strictly controls its protein expression level by rapid degradation of MITOL through the PHD-dependent autoubiquitination activity.	SIGNOR-271895	0.2
CDK1	protein	P06493	UNIPROT	MAP4	protein	P27816	UNIPROT	down-regulates activity	phosphorylation	Ser787	KAPEKRAsPSKPASA	9606	BTO:0000567								10791892	t		miannu	We have shown that MAP4 is phosphorylated in vivo in mitotic HeLa cells at eight sites. Five of these were phosphorylated by p34cdc2 kinase. Two of the five p34cdc2 kinase phosphorylation sites were shown to be Ser696 and Ser787 in the proline-rich region. Mutation of Ser787 to Glu strikingly reduced the MAP4's MT-polymerization activity, while Glu-mutation at Ser696 did not. These results suggest that Ser787 could be the critical phosphorylation site causing MTs to be dynamic at mitosis.	SIGNOR-277459	0.512
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation	Thr451	PIPKALGtPVLTPPT	9606	BTO:0000848	BTO:0001253							20959475	t		lperfetto	Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451).	SIGNOR-252955	0.704
GABA-A (a6-b2-d) receptor	complex	SIGNOR-C328	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000227							18790874	f	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263782	0.7
PGM2	protein	Q96G03	UNIPROT	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	down-regulates quantity	chemical modification			9606									32898648	t		miannu	Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P).	SIGNOR-268115	0.8
CDH3	protein	P22223	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265865	0.845
NDUFS6	protein	O75380	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24].	SIGNOR-262180	0.837
RPS6KB1	protein	P23443	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser636	SGDYMPMsPKSVSAP	10090									15306821	t		lperfetto	Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin.	SIGNOR-127912	0.781
MAML1	protein	Q92585	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12370315	f		gcesareni	It has been shown that maml1 binds directly to the ankyrin repeat region of notch1 and forms a dna-binding complex with icn and csl	SIGNOR-94029	0.921
IGF1R	protein	P08069	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates	phosphorylation	Tyr896	EPKSPGEyVNIEFGS	9606									17827393	t		gcesareni	Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K).	SIGNOR-157750	0.864
ROCK2	protein	O75116	UNIPROT	IRF4	protein	Q15306	UNIPROT	up-regulates	phosphorylation	Ser448	HRSIRHSsIQE	9606	BTO:0000782								20697158	t		miannu	Carock2 phosphorylated irf4 at either of 2 distinct phosphorylation sites, s446 and s447 / rock2-mediated phosphorylation of irf4 regulated the synthesis of il-17 and il-21 and the differentiation of th17 cells.	SIGNOR-167471	0.428
PCDHA8	protein	Q9Y5H6	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-265671	0.2
TGFB2	protein	P61812	UNIPROT	KRT1	protein	P04264	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16258965	f	Regulation	miannu	Immunolocalization of the epithelial marker cytokeratin demonstrates decreased staining by 48 hr after the addition of TGFβ1 or TGFβ2	SIGNOR-251885	0.2
CSNK2A1	protein	P68400	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser29	VSHWQQQsYLDSGIH	-1									12432063	t		miannu	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin. 	SIGNOR-275998	0.54
RDH5	protein	Q92781	UNIPROT	retinal	smallmolecule	CHEBI:15035	ChEBI	up-regulates quantity	chemical modification			9606									21621639	t		lperfetto	Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11	SIGNOR-265114	0.8
MAPK3	protein	P27361	UNIPROT	RXRA	protein	P19793	UNIPROT	down-regulates activity	phosphorylation	Thr82	HSMSVPTtPTLGFST	9606									17604322	t		lperfetto	In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 	SIGNOR-262959	0.501
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	KAT5	protein	Q92993	UNIPROT	up-regulates activity	phosphorylation	Ser90	LPGSRPGsPEREVPA	9606	BTO:0000567								12468530	t		llicata	Baculovirus-based expression and purification of Tip60 combined with mass spectrometry allowed the identification of serines 86 and 90 as two major sites of phosphorylation in vivo. The phosphorylation of Tip60 was found to modulate its histone acetyltransferase activity. One of the identified phosphorylated serines, Ser-90, was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylatedin vitro by the cyclin B/Cdc2 complex.	SIGNOR-250642	0.428
AKT1	protein	P31749	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation			9606									14967450	t		gcesareni	Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1.	SIGNOR-121944	0.845
CDK5	protein	Q00535	UNIPROT	DPYSL3	protein	Q14195	UNIPROT	up-regulates activity	phosphorylation	Thr514	TTTPKGGtPAGSARG	9606									16611631	t		lperfetto	Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-145971	0.588
BMP2	protein	P12643	UNIPROT	SMAD9	protein	O15198	UNIPROT	up-regulates				9606									22298955	f		gcesareni	Neogenin, a transmembranous protein, was re-ported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation.	SIGNOR-195567	0.635
alvocidib hydrochloride	chemical	CHEBI:90998	ChEBI	CDK5	protein	Q00535	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192467	0.8
MAPK3	protein	P27361	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser345	QARPGPQsPGSPLEE	9606									8626435	t		esanto	Upon activation, several serine residues on the cytosolic oxidase subunit p47phox become phosphorylated. Mitogen-activated protein kinase phophorylated only the peptide containing ser345/348.	SIGNOR-40821	0.432
DLG2	protein	Q15700	UNIPROT	Scribble_complex_DLG2-LLGL2_variant	complex	SIGNOR-C503	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270881	0.484
PRKACA	protein	P17612	UNIPROT	NFKB1	protein	P19838	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser937	ETSFRKLsFTESLTS										19531803	t		lperfetto	Ser940 of p105 was phosphorylated by PKA to a similar extent, whereas no phosphorylation of the same sequence occurred when Ser940 was substituted by Ala|Mechanistically, phosphorylation of p105 at Ser940 by PKA appeared to attenuate the extent of IKK-dependent phosphorylation of p105 at Ser935, which could in turn influence the rate of activation of NF-kappaB	SIGNOR-260327	0.487
TLR2	protein	O60603	UNIPROT	MYD88	protein	Q99836	UNIPROT	up-regulates activity	binding			10090									22664090	t		miannu	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266740	0.659
GAD1	protein	Q99259	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	down-regulates quantity	chemical modification			9606									32041144	t		miannu	Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce γ-aminobutyric acid (GABA), which exhibits several well-known physiological functions.	SIGNOR-267551	0.8
Complement C1 complex	complex	SIGNOR-C309	SIGNOR	C4B	protein	P0C0L5	UNIPROT	up-regulates activity	cleavage	Arg756	KGQAGLQrALEILQE	-1									9087411	t		lperfetto	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263427	0.63
GDP	smallmolecule	CHEBI:17552	ChEBI	GNAQ	protein	P50148	UNIPROT	down-regulates	chemical inhibition			9606									12040175	t		gcesareni	Agonist binding triggers a conformational change in the receptor, which catalyses the dissociation of gdp from the alfa subunit followed by gtp-binding to galfa and the dissociation of galfa from gbetagamma subunits1.	SIGNOR-88229	0.8
IL33	protein	O95760	UNIPROT	IL1RL1	protein	Q01638	UNIPROT	up-regulates activity	binding			9606	BTO:0001679								16286016	t		miannu	We report a member of the IL-1 family, IL-33, which mediates its biological effects via IL-1 receptor ST 2, activates NF-kappaB and MAP kinases, and drives production of T(H)2-associated cytokines from in vitro polarized T(H)2 cells. In vivo, IL-33 induces the expression of IL-4, IL-5, and IL-13 and leads to severe pathological changes in mucosal organs.The binding of IL-33 to cells that express ST2 results in the activation of NF-κB and MAP kinases. Administration of purified IL-33 either in vitro or in vivo leads to the production of TH2-associated cytokines.	SIGNOR-277711	0.923
MRGPRX2	protein	Q96LB1	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256787	0.2
MYO7A	protein	Q13402	UNIPROT	TIP-LINK complex	complex	SIGNOR-C291	SIGNOR	form complex	binding			10090		BTO:0000630							23217710	t		lperfetto	The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction.	SIGNOR-262577	0.631
ERBB3	protein	P21860	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			9606									16729043	t		gcesareni	All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor. In this study, we identify grb2 as a specific binding partner to tyrosines y1199 and y1268 of erbb3.	SIGNOR-146858	0.832
trimipramine	chemical	CHEBI:9738	ChEBI	SLC6A3	protein	Q01959	UNIPROT	down-regulates activity	chemical inhibition			9606									9537821	t		miannu	At the human dopamine transporter, sertraline and nomifensine were the most potent with KD's of 25±2 and 56±3, respectively. Except for these two compounds, most antidepressants were not potent at the human dopamine transporter. 	SIGNOR-258740	0.8
ARHGAP1	protein	Q07960	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260459	0.903
IFNA1	protein	P01562	UNIPROT	IFNAR2	protein	P48551	UNIPROT	up-regulates	binding			9606									11278538	t		gcesareni	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-104641	0.611
SYP	protein	P08247	UNIPROT	Synaptic_vesicle_recycling	phenotype	SIGNOR-PH161	SIGNOR	up-regulates				9606	BTO:0000938								33769286	f		miannu	This study reveals that Syp has a single physiological role in SV recycling, the accurate trafficking, and retrieval of SybII.	SIGNOR-264111	0.7
CKM complex	complex	SIGNOR-C406	SIGNOR	SMAD1	protein	Q15797	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser187	NSHPFPHsPNSSYPN	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-273145	0.346
TP53BP2	protein	Q13625	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	binding			9606									11839776	t		gcesareni	53bp2 interacts with the tumour suppressor p53 and enhances p53-mediated activation of transcription, possibly by facilitating the dephosphorylation of one or more sites on p53	SIGNOR-114762	0.895
MAPK10	protein	P53779	UNIPROT	HNRNPK	protein	P61978	UNIPROT	up-regulates activity	phosphorylation	Ser353	DSAIDTWsPSEWQMA	9606	BTO:0000007								11259409	t		miannu	JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein.	SIGNOR-250083	0.345
AURKB	protein	Q96GD4	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	phosphorylation	Thr211	EYLDDRNtFRHSVVV	9606									22611192	t		gcesareni	We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma).	SIGNOR-197606	0.708
PRKCA	protein	P17252	UNIPROT	ADRA1B	protein	P35368	UNIPROT	down-regulates activity	phosphorylation	Ser402	GSLERSQsRKDSLDD	9534	BTO:0000298								9353340	t		lperfetto	 Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. 	SIGNOR-248986	0.399
PLK1	protein	P53350	UNIPROT	SUZ12	protein	Q15022	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser541	KRTKASMsEFLESED										25855382	t		lperfetto	PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|In SUZ12, residues 539, 541 and 546 phosphorylated by Plk1 in vitro	SIGNOR-275555	0.371
HNF4A	protein	P41235	UNIPROT	GFER	protein	P55789	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								18513187	f		miannu	 We also confirmed that activation and repression of hHSS transcription induced by Sp1 and HNF4alpha resulted from binding of these factors to these two cis-elements respectively. Overexpression of HNF4alpha led to a dramatic repression of the promoter activity and, in contrast, the activity was markedly elevated by overexpression of Sp1. 	SIGNOR-254449	0.2
BRD4	protein	O60885	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates activity	binding			9606									32544088	t		lperfetto	In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4 and the in vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. |Together, these studies suggest that Brd4 enhances p300-mediated histone acetylation.	SIGNOR-262064	0.436
metformin	chemical	CHEBI:6801	ChEBI	G6PC1	protein	P35575	UNIPROT	up-regulates quantity by expression				9606									17909097	f		gcesareni	In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp.	SIGNOR-158056	0.8
PLK4	protein	O00444	UNIPROT	TUBGCP6	protein	Q96RT7	UNIPROT	up-regulates activity	phosphorylation	Ser1195	HGHVSDAsISLGESV	-1									22302995	t		miannu	Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication.	SIGNOR-262905	0.691
DDHD1	protein	Q8NEL9	UNIPROT	phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	down-regulates quantity	chemical modification			9606									22922100	t		miannu	Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 	SIGNOR-269650	0.8
PPM1E	protein	Q8WY54	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	dephosphorylation	Thr423	PEQSKRStMVGTPYW	10116									11864573	t			The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX.	SIGNOR-248761	0.308
BRCA1	protein	P38398	UNIPROT	RNASEL	protein	Q05823	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15940267	f		miannu	We propose that BRCA1 may be an upstream regulator of RNaseL, acting in concert with IFN-gamma to transcriptionally activate 2,5 OAS, leading to the downstream activation of RNaseL and apoptosis.	SIGNOR-253762	0.321
HRH1	protein	P35367	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257251	0.2
UMPS	protein	P11172	UNIPROT	UMP	smallmolecule	CHEBI:16695	ChEBI	up-regulates quantity	chemical modification			9606									2912371	t		miannu	Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase).	SIGNOR-267440	0.8
CREB1	protein	P16220	UNIPROT	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity	transcriptional regulation			9600	BTO:0000567								26652733	t	inferred from family member		Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-270250	0.2
PRKCE	protein	Q02156	UNIPROT	IQGAP1	protein	P46940	UNIPROT	up-regulates	phosphorylation	Ser1443	DKMKKSKsVKEDSNL	9606									15355962	t		gcesareni	Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth.	SIGNOR-128718	0.2
PTPRG	protein	P23470	UNIPROT	SHC1	protein	P29353	UNIPROT	down-regulates activity	dephosphorylation	Tyr349	EEPPDHQyYNDFPGK	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254723	0.2
MAPK3	protein	P27361	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser294	QLSKWPGsPTSRSSD	9606									19282669	t		lperfetto	Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway	SIGNOR-184569	0.583
TP53	protein	P04637	UNIPROT	ZDHHC5	protein	Q9C0B5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									28775165	t			Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y	SIGNOR-261150	0.2
GOT2	protein	P00505	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	chemical modification			9606									31422819	t		miannu	This is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1).	SIGNOR-267513	0.8
CAMK2G	protein	Q13555	UNIPROT	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	up-regulates activity	phosphorylation												12609872	t	inferred from family member	llicata	Direct phosphorylation of the GluR1 subunit of postsynaptic AMPA receptors by Ca(2+)/calmodulin-dependent protein kinase II (CaM-KII) is believed to be one of the major contributors to the enhanced strength of glutamatergic synapses in CA1 area of hippocampus during long-term potentiation. | Validity of the approach was confirmed by modeling, and silence analysis was applied then to the GluR1 AMPA receptor mutated at S831, the site phosphorylated by CaM-KII during long-term potentiation. Silence analysis indicates that a negative charge at S831 is a critical determinant for the enhanced channel function as a charge carrier. Silence and variance analyses, when applied to the same sets of data, were in agreement on the receptor regulation upon mutations.	SIGNOR-270234	0.614
PTPN1	protein	P18031	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	down-regulates activity	dephosphorylation	Tyr393	ASFNTDPyVREFGIM	9606									25175024	t		miannu	Taken together, our results indicate that Tyr 393 of AGO2 is hyperphosphorylated in response to PTP1B inactivation and may contribute to H-RAS V12 -induced development of senescence.|We identified phospho-Tyr 393 of argonaute 2 (AGO2) as a direct substrate of PTP1B.	SIGNOR-277120	0.2
PAK1	protein	Q13153	UNIPROT	PGM1	protein	P36871	UNIPROT	up-regulates	phosphorylation	Thr467	SANDKVYtVEKADNF	9606	BTO:0001271								15378030	t		gcesareni	The signaling kinase p21-activated kinase 1 (pak1) binds to, phosphorylates and enhances the enzymatic activity of phosphoglucomutase 1 (pgm),	SIGNOR-127135	0.349
DRD1	protein	P21728	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257181	0.285
LRFN2	protein	Q9ULH4	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606	BTO:0000938								21736948	f		miannu	This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments.	SIGNOR-264099	0.7
VEGFC	protein	P49767	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001103;BTO:0000763							9435229	t		gcesareni	Vegf-c, was isolated as a ligand for the tyrosine kinase vegfr-3 (flt4)	SIGNOR-55205	0.934
JAK1	protein	P23458	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606									19723038	t		lperfetto	The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases. These include epidermal growth factor receptor (egfr) kinase, src, janus-activated kinases (jak), and extracellular signal-regulated kinase (erk).	SIGNOR-187775	0.793
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SCRIB	protein	Q14160	UNIPROT	unknown	phosphorylation	Ser1448	TSRQSPAsPPPLGGG	9606	BTO:0000007								20622900	t		miannu	HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further.	SIGNOR-263064	0.2
CDK9	protein	P50750	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser392	FKTEGPDsD	9606									23603988	t		gcesareni	We recently demonstrated that through their physical interaction, cdk9 phosphorylates p53 on ser-392, leading to p53 stability and accumulation	SIGNOR-201931	0.551
IL33	protein	O95760	UNIPROT	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606	BTO:0006111								36660926	t		miannu	IL-33 secreted by pericytes and CAFs promotes M2 polarization and induced MMP9 expression in M2 TAMs facilitating metastasis development via the IL-33-ST2-NF-κB-MMP9-laminin pathway in a mouse model of pancreatic cancer 	SIGNOR-277712	0.7
MAPK1	protein	P28482	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser380	HQLFRGFsFVATGLM	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252748	0.751
PTPRC	protein	P08575	UNIPROT	LYN	protein	P07948	UNIPROT	down-regulates activity	dephosphorylation	Tyr508	YTATEGQyQQQP	10090	BTO:0000776								10415030	t			CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)	SIGNOR-248354	0.651
NEK6	protein	Q9HC98	UNIPROT	KIF20A	protein	O95235	UNIPROT	down-regulates activity	phosphorylation	Ser244	LSTSLKRsVYIESRI	9606	BTO:0000567								28630147	t	done	miannu	We show that Nek9, Nek6, and the kinesin Mklp2 form a signaling module, which is required for Mklp2 to localize to the central spindle in anaphase. Nek6 also phosphorylates Mklp2 at Ser244, inhibiting its bundling activity until anaphase onset.	SIGNOR-273891	0.355
AT9283	chemical	CID:11696609	PUBCHEM	ABL1	protein	P00519	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190008	0.8
MTHFD2	protein	P13995	UNIPROT	10-formyltetrahydrofolate(2-)	smallmolecule	CHEBI:57454	ChEBI	up-regulates quantity	chemical modification			9606									16100107	t		lperfetto	Magnesium and phosphate ions enable NAD binding to methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase|One of the enzymes in this pathway, the NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC),5 catalyzes the interconversion of 5,10-methylenetetrahydrofolate (methylene-THF) and 10-formyltetrahydrofolate (formyl-THF) in mammalian mitochondria.	SIGNOR-268256	0.8
SRC	protein	P12931	UNIPROT	CTTN	protein	Q14247	UNIPROT	down-regulates	phosphorylation	Tyr446	GTEPEPVySMEAADY	9606									12601080	t		lperfetto	Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity	SIGNOR-98712	0.795
IKBKB	protein	O14920	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates activity	phosphorylation	Ser932	CDSGVETsFRKLSFT	9606	BTO:0000007			SIGNOR-C13					11158290	t		lperfetto	Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway.	SIGNOR-104811	0.848
PPM1D	protein	O15297	UNIPROT	GPI	protein	P06744	UNIPROT	down-regulates activity	dephosphorylation			9606									28185954	t		miannu	The WIP1 mediated inhibition of NLK activity markedly decreased the phosphorylation of lymphoid enhancer binding factor 1 (LEF1), enhancing its interaction with beta-catenin.|Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development.	SIGNOR-277155	0.241
SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	PRDM14	protein	Q9GZV8	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269234	0.615
PDE1A	protein	P54750	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	down-regulates quantity	chemical modification			9606									22014080	t			PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values	SIGNOR-253398	0.8
MAPK8	protein	P45983	UNIPROT	MAPK8IP1	protein	Q9UQF2	UNIPROT	up-regulates activity	phosphorylation	Thr103	LIDATGDtPGAEDDE	9534	BTO:0000298								12756254	t		miannu	After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1.	SIGNOR-250128	0.879
PRKACA	protein	P17612	UNIPROT	MYOM2	protein	P54296	UNIPROT	down-regulates	phosphorylation	Ser76	RVCAKRVsTQEDEEQ	9606		BTO:0000887							9529381	t		llicata	This binding is regulated in vitro by phosphorylation of a single serine residue (ser76) in the immediately adjacent amino-terminal domain mp1. M-protein phosphorylation by camp-dependent kinase a inhibits binding to myosin lmm.	SIGNOR-56395	0.2
N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	chemical	CHEBI:91418	ChEBI	MET	protein	P08581	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258214	0.8
CAPN3	protein	P20807	UNIPROT	CDK5R1	protein	Q15078	UNIPROT	up-regulates activity	cleavage			9606									25969760	t		lperfetto	Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain	SIGNOR-251604	0.265
RORA	protein	P35398	UNIPROT	NTRK2	protein	Q16620	UNIPROT	up-regulates quantity by expression	transcriptional regulation												28608249	t		lperfetto	Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005).	SIGNOR-265137	0.269
ASPA	protein	P45381	UNIPROT	acetic acid	smallmolecule	CHEBI:15366	ChEBI	up-regulates quantity	chemical modification			9606									17194761	t		miannu	N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain.	SIGNOR-267527	0.8
P2RY13	protein	Q9BPV8	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256892	0.2
CHUK	protein	O15111	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser932	CDSGVETsFRKLSFT	9606	BTO:0000567			SIGNOR-C13					10469655	t		lperfetto	All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391).	SIGNOR-70457	0.737
DSCAML1	protein	Q8TD84	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	down-regulates				9606									30745321	f		miannu	The DSCAM/L1 transcriptome data sets also contained a significant number of genes known to regulate synapse formation or function.Increased nuclear DSCAM levels inhibit synapse formation	SIGNOR-264281	0.7
AKT2	protein	P31751	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites.	SIGNOR-252867	0.757
L-serine	chemical	CHEBI:17115	ChEBI	D-serine	smallmolecule	CHEBI:16523	ChEBI	up-regulates quantity	precursor of			10090		BTO:0000142							12393813	t		lperfetto	High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media.	SIGNOR-268271	0.8
AKT3	protein	Q9Y243	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252879	0.697
PAK1	protein	Q13153	UNIPROT	CTBP1	protein	Q13363	UNIPROT	down-regulates activity	phosphorylation	Ser158	REGTRVQsVEQIREV	9606									12872159	t		lperfetto	Pak1 phosphorylates ctbp selectively on ser158 within a putative regulatory loop, triggering ctbp cellular redistribution and blocking ctbp ak1 superphosphorylates ctbp and inhibits ctbp dehydrogenase activitycorepressor functions.	SIGNOR-103943	0.414
NLK	protein	Q9UBE8	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	down-regulates	phosphorylation	Ser166	TYSDEHFsPGSHPSH	9606									12556497	t		gcesareni	Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk.	SIGNOR-97808	0.751
PRKCB	protein	P05771	UNIPROT	BTK	protein	Q06187	UNIPROT	down-regulates activity	phosphorylation	Ser180	GSLKPGSsHRKTKKP	9606	BTO:0003076								11598012	t		lperfetto	We provide direct evidence that PKCbeta acts as a feedback loop inhibitor of Btk activation. Inhibition of PKCbeta results in a dramatic increase in B-cell receptor (BCR)-mediated Ca2+ signaling. We identified a highly conserved PKCbeta serine phosphorylation site in a short linker within the Tec homology domain of Btk. Mutation of this phosphorylation site led to enhanced tyrosine phosphorylation and membrane association of Btk, and augmented BCR and FcepsilonRI-mediated signaling in B and mast cells, respectively. | This deductive analysis indicated that PKCbeta phosphorylates S180 in the region bisecting the Btk motif (BM) and the PRR of the TH domain.	SIGNOR-249110	0.39
sirolimus	chemical	CHEBI:9168	ChEBI	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates				9606									16452206	f		gcesareni	We now show that mtor inhibition induces insulin receptor substrate-1 expression and abrogates feedback the pathway, resulting in akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, rad001.	SIGNOR-144156	0.8
TBX3	protein	O15119	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002267								25211658	t		lperfetto	TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS	SIGNOR-249602	0.309
SPOP	protein	O43791	UNIPROT	DEK	protein	P35659	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								25278611	t		miannu	Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E).	SIGNOR-272826	0.45
MAPK3	protein	P27361	UNIPROT	PPARA	protein	Q07869	UNIPROT	up-regulates activity	phosphorylation	Ser12	ESPLCPLsPLEAGDL	9606									10187842	t		lperfetto	We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution.	SIGNOR-249473	0.584
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	RARG	protein	P13631	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								19058965	t		Luana	Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes. 	SIGNOR-258030	0.8
BMP1	protein	P13497	UNIPROT	COL5A2	protein	P05997	UNIPROT	up-regulates activity	cleavage	Glu1253	SEVKMDAeFRHDSGY	9606	BTO:0002974								11741999	t		miannu	BMP-1 Can Efficiently Cleave Pro-α1(V) N-propeptides and Pro-α2(V) C-propeptides and Less Efficiently Cleave Pro-α1(V) C-propeptides in Vitro. BMP-1 efficiently cleaves pro-α2(V) C-propeptides at a single site between residues 1250 (Glu) and 1251 (Asp). 	SIGNOR-256343	0.59
PRKACA	protein	P17612	UNIPROT	PPP1R8	protein	Q12972	UNIPROT	down-regulates activity	phosphorylation	Ser178	TAHNKRIsTLTIEEG	-1									9407077	t		miannu	NIPP-1 is the RNA-binding subunit of a major species of protein phosphatase-1 in the nucleus. The purified recombinant protein was a potent (Ki = 9.9 +/- 0.3 pM) and specific inhibitor of protein phosphatase-1 and was stoichiometrically phosphorylated by protein kinases A and CK2. At physiological ionic strength, phosphorylation by these protein kinases drastically decreased the inhibitory potency of free NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A	SIGNOR-250032	0.496
GPI	protein	P06744	UNIPROT	AMFR	protein	Q9UKV5	UNIPROT	up-regulates	binding			9606									12527360	t		gcesareni	Pgi is a housekeeping gene encoding phosphoglucose isomerase (pgi) a glycolytic enzyme that also functions as a cytokine (autocrine motility factor (amf)/neuroleukin/maturation factor) upon secretion from the cell and binding to its 78 kda seven-transmembrane domain receptor (gp78/amf-r)	SIGNOR-97270	0.546
CSF1	protein	P09603	UNIPROT	CSF1R	protein	P07333	UNIPROT	up-regulates activity	binding			9606	BTO:0000876	BTO:0001103							24890514	t		apalma	The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34)	SIGNOR-255568	0.936
ITGB1BP1	protein	O14713	UNIPROT	AD/b2 integrin	complex	SIGNOR-C172	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257654	0.292
TWIST1	protein	Q15672	UNIPROT	MYB	protein	P10242	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255529	0.249
ESR1	protein	P03372	UNIPROT	TGFA	protein	P01135	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000356								11517191	f	 	 	ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression	SIGNOR-253942	0.509
CYP11B1	protein	P15538	UNIPROT	cortisol	smallmolecule	CHEBI:17650	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000050							9814482	t		lperfetto	Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol.	SIGNOR-268678	0.8
U2AF1	protein	Q01081	UNIPROT	U2AF1/U2AF2	complex	SIGNOR-C78	SIGNOR	form complex	binding			9606									8647433	t		miannu	The splicing factor u2af (u2 snrnp auxiliary factor) is a heterodimer with subunits of 65 and 35 kd (u2af65 and u2af35).	SIGNOR-41945	0.2
NR3C1	protein	P04150	UNIPROT	PER2	protein	O15055	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19805059	t		miannu	GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription	SIGNOR-268049	0.479
PRKG1	protein	Q13976	UNIPROT	FHOD1	protein	Q9Y613	UNIPROT	up-regulates	phosphorylation	Ser1131	AARERKRsRGNRKSL	9606		BTO:0000887;BTO:0001260							21106951	t		lperfetto	Pkgi also directly phosphorylates fhod1, and studies with wild-type and mutant fhod1-derived peptides identify ser-1131 in the fhod1 c terminus as the unique pkgi phosphorylation site in fhod1. phosphorylation of three conserved residues within the dad domain activates fhod1 while binding to rac regulates fhod1 subcellular localization	SIGNOR-170094	0.361
DLD	protein	P09622	UNIPROT	PDH	complex	SIGNOR-C402	SIGNOR	form complex	binding			9606									20160912	t		miannu	The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently.	SIGNOR-266545	0.851
POU5F1	protein	Q01860	UNIPROT	LEFTY2	protein	O00292	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254940	0.431
AGT	protein	P01019	UNIPROT	TRPC6	protein	Q9Y210	UNIPROT	up-regulates activity				9606									24850910	f			We demonstrated that Ang II evokes concentration-dependent activation of podocyte TRPC6 channels 	SIGNOR-253331	0.311
GSK3B	protein	P49841	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	down-regulates activity	phosphorylation	Thr2068	LLDEYNVtPSPPGTV	9606	BTO:0000007								12794074	t		lperfetto	We show that gsk-3beta directly binds at c-terminal of the notch2 ankyrin repeats and phosphorylates thr-2068 and/or ser-2070, thr-2074, and thr-2093.	SIGNOR-101570	0.495
AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial.	SIGNOR-264941	0.8
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1668	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120096	0.316
MAPK14	protein	Q16539	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates activity	phosphorylation			9606									21902831	t		lperfetto	As a permissive environment is created at these loci, p38 further stimulates gene expression through the phosphorylation of additional myogenic transcription factors, including mef2c and e47.	SIGNOR-176551	0.683
CDK1	protein	P06493	UNIPROT	NUCKS1	protein	Q9H1E3	UNIPROT	down-regulates activity	phosphorylation	Ser181	LKATVTPsPVKGKGK	-1									12413487	t		miannu	 putative phosphorylation site for Cdk1 is present in the DNA-binding domain peptide. This site, corresponding to Ser 181 in the NUCKS primary structure, is phosphorylated in vitro by Cdk1 with a Km of approximately 35 μM [7]. Phosphorylation of Ser 181 in the synthetic, DNA-binding domain peptide reduces its affinity for DNA-by 100%.	SIGNOR-261959	0.489
PKN3	protein	Q6P5Z2	UNIPROT	ARHGAP18	protein	Q8N392	UNIPROT	up-regulates activity	phosphorylation	Thr158	RVETVSQtLRKKNKQ	-1									33092266	t		lperfetto	We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA.|These results support our data from phosphoproteomic screen and suggest that ARHGAP18 can be phosphorylated by PKN3 on Thr154, Ser156 and Thr158.	SIGNOR-264572	0.2
JUN	protein	P05412	UNIPROT	SERPINA3	protein	P01011	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002600								11027208	f		miannu	We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. 	SIGNOR-254808	0.2
KCNC1	protein	P48547	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			9606									11506885	t		miannu	Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height	SIGNOR-265586	0.8
MRPL17	protein	Q9NRX2	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262340	0.698
Elongator complex	complex	SIGNOR-C466	SIGNOR	TUBA1B	protein	P68363	UNIPROT	up-regulates activity	acetylation			9606	BTO:0000007								19185337	t		miannu	Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. 	SIGNOR-269719	0.256
FZD3	protein	Q9NPG1	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates	binding			9606									14977528	t		gcesareni	Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families.	SIGNOR-122889	0.246
TAF3	protein	Q5VWG9	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263930	0.812
P2RY13	protein	Q9BPV8	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257299	0.2
INTS13	protein	Q9NVM9	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261469	0.2
LMO1	protein	P25800	UNIPROT	TAL1	protein	P17542	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271								9020185	t		miannu	Transcriptional activity of tal1 in t cell acute lymphoblastic leukemia (t-all) requires rbtn1 or -2	SIGNOR-46114	0.726
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1665	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273041	0.556
CLTB	protein	P09497	UNIPROT	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	form complex	binding			9606									24789820	t		lperfetto	AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly. 	SIGNOR-260666	0.76
FST	protein	P19883	UNIPROT	MSTN	protein	O14793	UNIPROT	down-regulates activity	binding			10090									24627466	t		lperfetto	Follistatin (FST) is a member of the tissue growth factor beta family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. FST315-deltaHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function.	SIGNOR-251717	0.751
EEF1A1	protein	P68104	UNIPROT	mTORC2	complex	SIGNOR-C2	SIGNOR	form complex	binding			9606									25628925	t		lperfetto	Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)	SIGNOR-205606	0.303
KIT	protein	P10721	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	binding			9534									7509796	t			Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells	SIGNOR-255948	0.716
MAPK1	protein	P28482	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser106	PLNSVSPsPLMLLHP	9606	BTO:0000567								17615152	t		gcesareni	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity	SIGNOR-156852	0.657
3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide	chemical	CHEBI:92223	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-203476	0.8
EGFR	protein	P00533	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates activity				10090									26592448	f			Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC	SIGNOR-252092	0.48
MMP16	protein	P51512	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272384	0.7
PRKCZ	protein	Q05513	UNIPROT	TRAF2	protein	Q12933	UNIPROT	unknown	phosphorylation	Ser55	QCGHRYCsFCLASIL	9606	BTO:0000785								19336568	t		llicata	Here, we report that protein kinase czeta phosphorylates traf2 at ser(55), within the ring domain of the protein, after tnfalpha stimulation	SIGNOR-184941	0.41
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO4	protein	P98177	UNIPROT	down-regulates	phosphorylation			9606									21620960	t		gcesareni	Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity.	SIGNOR-174021	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation			9606									12050114	t	inferred from 70% family members	gcesareni	Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation.	SIGNOR-270123	0.2
CDC14A	protein	Q9UNH5	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser684	IGIPQFHsPVGSPLK	9606									20236090	t			Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3.	SIGNOR-248830	0.627
CSNK2A2	protein	P19784	UNIPROT	PPP1R8	protein	Q12972	UNIPROT	up-regulates activity	phosphorylation	Ser204	KNSRVTFsEDDEIIN	-1									9407077	t		llicata	Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2.	SIGNOR-251023	0.484
SP1	protein	P08047	UNIPROT	CYP1B1	protein	Q16678	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12801909	f		miannu	 It was suggested that mutual interaction of XRE2 and XRE3 is important for transcriptional regulation, and that the Sp1 binding to the Sp1-like motif (-824) enhances both the constitutive and inducible transcriptional activities of the human CYP1B1 gene.	SIGNOR-255196	0.27
FGFR2	protein	P21802	UNIPROT	GLO1	protein	Q04760	UNIPROT	up-regulates activity	phosphorylation	Tyr136	GIAVPDVySACKRFE	-1									34838714	t		miannu	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276184	0.2
CRYAB	protein	P02511	UNIPROT	CRYGD	protein	P07320	UNIPROT	up-regulates activity	binding			-1									20621668	t		miannu	Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age.	SIGNOR-253621	0.536
CDK6	protein	Q00534	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Ser249	DTRQIQPsPPWSYDQ	9606	BTO:0002181								16046550	t	The effect has been demonstrated using Q01196-8.	gcesareni	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-138953	0.598
A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269012	0.7
ACTB	protein	P60709	UNIPROT	Neural progenitor-specific SWI/SNF	complex	SIGNOR-C477	SIGNOR	form complex	binding			9606									25195934	t		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270619	0.489
GRK5	protein	P34947	UNIPROT	GRK5	protein	P34947	UNIPROT	up-regulates activity	phosphorylation	Ser484	VLDIEQFsTVKGVNL	-1									8144599	t			Autophosphorylation of GRK5 occurs primarily at residues Ser-484 and Thr-485. Phospholipid-stimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5.	SIGNOR-251201	0.2
paracetamol	chemical	CHEBI:46195	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000876								17884974	t		Luana	Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man	SIGNOR-257757	0.8
PPY	protein	P01298	UNIPROT	NPY4R	protein	P50391	UNIPROT	up-regulates	binding			9606		BTO:0000142							7592911	t		gcesareni	Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid.	SIGNOR-24230	0.637
FGF11	protein	Q92914	UNIPROT	SCN5A	protein	Q14524	UNIPROT	down-regulates activity	binding			9606		BTO:0000199							20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253418	0.2
GTF3C3	protein	Q9Y5Q9	UNIPROT	TFIIIC	complex	SIGNOR-C392	SIGNOR	form complex	binding			9606									29378333	t		lperfetto	Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains	SIGNOR-266186	0.877
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GRK7	protein	Q8WTQ7	UNIPROT	down-regulates activity	phosphorylation	Ser36	ELQRRRRsLALPGLQ	9606									15946941	t		Luana	Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA. 	SIGNOR-260840	0.2
GRK3	protein	P35626	UNIPROT	OPRM1	protein	P35372	UNIPROT	down-regulates activity	phosphorylation	Thr182	VKALDFRtPRNAKII	8355		BTO:0000512							11060299	t		gcesareni	These results demonstrate that the T180A mutation probably blocks GRK3- and arr3-mediated desensitization of MOR by preventing a critical agonist-dependent receptor phosphorylation and suggest a novel GRK3 site of regulation not yet described for other G-protein-coupled receptors	SIGNOR-247915	0.2
ATF2	protein	P15336	UNIPROT	SIRT4	protein	Q9Y6E7	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0002572								33861966	t		miannu	Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). 	SIGNOR-267831	0.2
MAFA	protein	Q8NHW3	UNIPROT	NKX6-1	protein	P78426	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17149590	f		miannu	 the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA.	SIGNOR-254564	0.442
A-966492	chemical	CID:16666333	PUBCHEM	PARP2	protein	Q9UGN5	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-203622	0.8
PRKG1	protein	Q13976	UNIPROT	PRKG1	protein	Q13976	UNIPROT	up-regulates	phosphorylation	Ser65	TTRAQGIsAEPQTYR	9606									12080049	t		miannu	Serines 64 and 79 are homologous residues that are juxtaposed to the autoinhibitory pseudosubstrate site in cgmp-dependent protein kinase type ialpha and type ibeta (pkg-ialpha and pkg-ibeta), respectively. Autophosphorylation of this residue is associated with activation of type i pkgs.	SIGNOR-89839	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									20068231	t		Luana	Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.	SIGNOR-260755	0.2
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1934	SPTYSPTsPKGSTYS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269359	0.718
STAT3	protein	P40763	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression				9606		BTO:0001103							21408055	f		andrea cerquone perpetuini	Additionally, cMyc, a STAT3 downstream gene, was significantly up-regulated in SCs at T24 versus PRE [...]An increase in the number of cMyc+ SCs indicated that human SCs were induced to proliferate under the control of STAT3 signaling.	SIGNOR-255413	0.744
CKM complex	complex	SIGNOR-C406	SIGNOR	E2F1	protein	Q01094	UNIPROT	down-regulates activity	phosphorylation	Ser375	PVDEDRLsPLVAADS	9606									18794899	t		lperfetto	E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1.	SIGNOR-273149	0.37
CYP19A1	protein	P11511	UNIPROT	testosterone	smallmolecule	CHEBI:17347	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000975							27702664	t		lperfetto	The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively	SIGNOR-268671	0.8
betrixaban	chemical	CHEBI:140421	ChEBI	F10	protein	P00742	UNIPROT	down-regulates activity	chemical inhibition			-1									19297154	t		Luana	Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor.	SIGNOR-257817	0.8
RPS6KA5	protein	O75582	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606									12763138	t		gcesareni	The stat3-mediated transactivation was reduced by blocking the stat3 serine phosphorylation with the mek inhibitor u0126 or by expression of kinase-inactive msk1.	SIGNOR-101251	0.393
PIM1	protein	P11309	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Thr157	GIRKRPAtDDSSTQN	9606									18593906	t		gcesareni	We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro.	SIGNOR-179296	0.39
MAPK14	protein	Q16539	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser130	SGEQAEGsPGGPGDS	9606									12058028	t		gcesareni	The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro.	SIGNOR-89436	0.457
BMPR1A	protein	P36894	UNIPROT	SMAD5/SMAD4	complex	SIGNOR-C205	SIGNOR	up-regulates activity	phosphorylation			9606									9442019	t		ggiuliani	In this study, we isolated human Smad5 and found that Smad5 was involved in BMP-2 signaling cascades, which mediate the bone-inducing effects of BMP-2. Smad5 was directly serine-phosphorylated by BMPIR through a physical interaction. The activated Smad5 subsequently formed a complex with DPC4, and this complex was then translocated to the nucleus.	SIGNOR-255779	0.679
CDK1	protein	P06493	UNIPROT	CSNK2A1	protein	P68400	UNIPROT	up-regulates	phosphorylation	Ser370	PLGPLAGsPVIAAAN	9606									7592773	t		lperfetto	Four residues within this domain, thr-344, thr-360, ser-362, and ser-370, conform to the minimal consensus sequence for p34cdc2 phosphorylationthe high stoichiometry of phosphorylation suggests that phosphorylation could regulate functional properties of ckii and that it could in some way participate in the burst of phosphorylation that accompanies the activation of p34graphic at the ggraphic-m transition	SIGNOR-29521	0.361
CREB1	protein	P16220	UNIPROT	BDNF	protein	P23560	UNIPROT	up-regulates quantity	transcriptional regulation			9606		BTO:0000142							32603820	t		miannu	Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF. 	SIGNOR-265062	0.504
PRKCA	protein	P17252	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser558	VPTYESAsIRRFQEG	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-129268	0.392
PRKG1	protein	Q13976	UNIPROT	PTS	protein	Q03393	UNIPROT	up-regulates	phosphorylation	Ser19	AQVSRRIsFSASHRL	9606		BTO:0000142							10531334	t		gcesareni	Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps	SIGNOR-71680	0.26
SLC1A5	protein	Q15758	UNIPROT	L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	up-regulates quantity	relocalization			9606									26724577	t			Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine.	SIGNOR-266914	0.8
UDP-D-galactose	smallmolecule	CHEBI:18307	ChEBI	UDP(3-)	smallmolecule	CHEBI:58223	ChEBI	up-regulates quantity	precursor of			9606									16157350	t		miannu	Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 	SIGNOR-268473	0.8
PCSK7	protein	Q16549	UNIPROT	CDC25B	protein	P30305	UNIPROT	down-regulates	phosphorylation			9606									11333986	t		gcesareni	We propose that regulation of cdc25b phosphorylation by p38 is a critical event for initiating the g2/m checkpoint after ultraviolet radiation	SIGNOR-107423	0.2
CDK2	protein	P24941	UNIPROT	SMAD3	protein	P84022	UNIPROT	unknown	phosphorylation	Ser204	NHSMDAGsPNLSPNP	-1									15241418	t		llicata	Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo.	SIGNOR-250749	0.733
LY2603618	chemical	CID:11955855	PUBCHEM	CHEK1	protein	O14757	UNIPROT	down-regulates activity	chemical inhibition			9606									33261142	t		miannu	 Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. 	SIGNOR-262538	0.8
CSF2RA/CSF2RB	complex	SIGNOR-C212	SIGNOR	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity				9606	BTO:0000876	BTO:0001103							19436055	f		apalma	As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of beta-c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways	SIGNOR-255586	0.2
PRPS1	protein	P60891	UNIPROT	5-phospho-α-D-ribose 1-diphosphate	smallmolecule	CHEBI:58017	ChEBI	up-regulates quantity	chemical modification			9606									16939420	t		miannu	PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP.	SIGNOR-267079	0.8
UBE3A	protein	Q05086	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								18298802	t		miannu	 An in vivo ubiquitination assay was done to reveal that E6AP promoted the ubiquitination of TSC2 independent of HPV16 E6. We further found that TSC2 bound E6AP in the presence as well as in the absence of HPV16 E6. The binding regions on E6AP and TSC2 have been identified as amino acid (aa) 260-316, aa 428-500 and aa 1-175, aa 1251-1807, respectively. Taken together, degradation of TSC2 is mediated by E6AP ubiquitin ligase.	SIGNOR-271396	0.617
FKBP4	protein	Q02790	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates activity	binding			10090	BTO:0000947								19545546	t			We noted that FK506 altered nuclear localization of the GR and inhibited expression of GR-responsive genes. Furthermore, si-RNA knockdown of FKBP4 gene, coding for the immunophilin FKBP52, inhibited cortisol-activated GR nuclear translocation	SIGNOR-252034	0.709
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	RAD23B	protein	P54727	UNIPROT	up-regulates													24086043	f		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein).	SIGNOR-275688	0.7
KCNB1	protein	Q14721	UNIPROT	VAPA	protein	Q9P0L0	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000007								29941597	t		lperfetto	Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions.	SIGNOR-262122	0.2
CDK9	protein	P50750	UNIPROT	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15546612	f		gcesareni	Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells.	SIGNOR-130703	0.2
RNF111	protein	Q6ZNA4	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000165;BTO:0000222								17341133	t		lperfetto	Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblastsarkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling.	SIGNOR-236873	0.672
CDK5	protein	Q00535	UNIPROT	PARP1	protein	P09874	UNIPROT	down-regulates activity	phosphorylation	Ser785	LRGGSDDsSKDPIDV	-1									21922195	t		miannu	These results would suggest that the phosphorylation of PARP-1 via Cdk5's kinase activity is necessary for its persistence at damage sites.Based on these results and the recruitment data, we hypothesize that the phosphorylation of the PARP-1 protein by Cdk5 on one or more of the serines 782, 785, and 786 results in an attenuation of its ribosylating activity facilitating its persistence at the sites of DNA damage.	SIGNOR-276358	0.261
CTSK	protein	P43235	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													11920402	f		lperfetto	Cathepsins K and S have been implicated in various aspects of extracellular matrix degradation and inflammatory responses. 	SIGNOR-253318	0.7
GABRD	protein	O14764	UNIPROT	GABA-A (a4-b2-d) receptor	complex	SIGNOR-C326	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263746	0.393
FBXO32	protein	Q969P5	UNIPROT	Protein_degradation	phenotype	SIGNOR-PH96	SIGNOR	up-regulates				10090									11717410	f			Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases	SIGNOR-255342	0.7
BTRC	protein	Q9Y297	UNIPROT	ATF2	protein	P15336	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0002572								33861966	t		miannu	Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). 	SIGNOR-267830	0.2
ENO3	protein	P13929	UNIPROT	2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	down-regulates quantity	chemical modification			9606									29767008	t		miannu	Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits.	SIGNOR-266530	0.8
TNKS	protein	O95271	UNIPROT	RNF146	protein	Q9NTX7	UNIPROT	up-regulates activity				9606	BTO:0000007								21478859	f		lperfetto	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 	SIGNOR-263338	0.713
alanine	smallmolecule	CHEBI:16449	ChEBI	Ala-tRNA(Ala)	smallmolecule	CHEBI:17732	ChEBI	up-regulates quantity	precursor of			9606									32314272	t		miannu	Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N).	SIGNOR-270452	0.8
CBL	protein	P22681	UNIPROT	LRIG1	protein	Q96JA1	UNIPROT	down-regulates	ubiquitination			9606		BTO:0001253							15282549	t		gcesareni	We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.	SIGNOR-127289	0.572
CABLES1	protein	Q8TDN4	UNIPROT	CDK2	protein	P24941	UNIPROT	down-regulates activity	binding			-1									25361894	t		miannu	Our study also showed that Cables1 increases the level of p21 and decreases the level of pRb, but does not affect the other cell cycle-related proteins we studied. Induction of apoptosis by Cables1, which occurs partially through inhibiting Cdk2 activity and upregulating p21, is prevented by Akt phosphorylation and 14-3-3 binding.	SIGNOR-276759	0.472
ATM	protein	Q13315	UNIPROT	COP1	protein	Q8NHY2	UNIPROT	down-regulates	phosphorylation	Ser387	SDDSRTAsQLDEFQE	9606									16931761	t		lperfetto	Atm engages autodegradation of the e3 ubiquitin ligase cop1 after dna damage. We observed that in response to dna damage, atm phosphorylated cop1 on ser(387) and stimulated a rapid autodegradation mechanism	SIGNOR-149082	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser732	RRVRKLPsTTL	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-250556	0.2
HECW2	protein	Q9P2P5	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9606	BTO:0000093								27119228	t		miannu	NEDL2 acts as a scaffold protein to promote GDNF-stimulated Akt activation. biochemical analysis indicated that NEDL2 appears to act like a scaffold protein to recruit SHC, Grb2, PI3K (p110 and p85), PDK1 and Akt together to promote the signaling transduction. NEDL2 binds p85, p110 and Akt with different domains	SIGNOR-269458	0.2
Cadherins	proteinfamily	SIGNOR-PF71	SIGNOR	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265812	0.2
DMTF1	protein	Q9Y222	UNIPROT	ECT2	protein	Q9H8V3	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0004532								19816943	f		Luana	 Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. 	SIGNOR-261589	0.2
KIF1A	protein	Q12756	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272522	0.7
PSMD4	protein	P55036	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606									29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263347	0.899
CSNK2A1	protein	P68400	UNIPROT	CTDP1	protein	Q9Y5B0	UNIPROT	down-regulates activity	phosphorylation	Ser740	TKAQRENsPAAFPDR	9606	BTO:0000567								12591939	t		llicata	We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified 	SIGNOR-250845	0.381
DAB2IP	protein	Q5VWQ8	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	down-regulates				9606									27858941	f		miannu	DAB2IP inactivation promotes tumor growth and survival, development, and proliferation of CSC, and resistance to chemo- and radiotherapy. It induces EMT, increases cell migration and invasion, and counteracts pro-apoptotic signaling.	SIGNOR-254779	0.7
ECM	stimulus	SIGNOR-ST20	SIGNOR	AD/b2 integrin	complex	SIGNOR-C172	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259055	0.7
TESK2	protein	Q96S53	UNIPROT	CFL1	protein	P23528	UNIPROT	down-regulates activity	phosphorylation	Ser3	sGVAVSDG	9606	BTO:0000567								11418599	t		lperfetto	Like tesk1, tesk2 phosphorylated cofilin specifically at ser-3 and induced formation of actin stress fibers and focal adhesions.	SIGNOR-108753	0.518
CSNK2A1	protein	P68400	UNIPROT	TCOF1	protein	Q13428	UNIPROT	up-regulates activity	phosphorylation	Thr210	TSSSSDEtDVEGKPS	9606	BTO:0000567								25064736	t		lperfetto	Phosphorylated Thr 210 in Treacle is the major interaction site for NBS1|A purified GST fragment of this region was efficiently phosphorylated by CK2 in vitro (Supplementary Fig. 4; T-2) and this fragment pulled down the MRN complex from Hela nuclear extracts only when previously phosphorylated by CK2 	SIGNOR-265086	0.309
PRKCQ	protein	Q04759	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates activity	phosphorylation	Thr495	TGITRKKtFKEVANA	9606	BTO:0001853								24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251636	0.2
ING1	protein	Q9UK53	UNIPROT	SIRT2	protein	Q8IXJ6	UNIPROT	down-regulates activity	binding			9606									14522900	t		miannu	We found that p33(ING1b) physically interacts with hSIR2, reverses its ability to induce the AFP promoter, and induces acetylation of p53 residues at Lys(373) and/or Lys(382).	SIGNOR-254486	0.463
PRKACA	protein	P17612	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates activity	phosphorylation	Ser660	FSAERRNsILTETLH	-1									1377674	t		miannu	CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795. 	SIGNOR-250349	0.466
KMT2A	protein	Q03164	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0002181								22012064	t		irozzo	Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation.Furthermore, we demonstrate that MLL binds to a region of AML1 (that is conserved in AML2 and AML3) and increases AML1 (AML2 and AML3) protein levels	SIGNOR-255707	0.549
MAPK14	protein	Q16539	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	down-regulates activity	phosphorylation	Thr1609	LGPYEAVtPLTKAAD	-1									24703952	t		lperfetto	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK 	SIGNOR-264446	0.284
CDK5	protein	Q00535	UNIPROT	NFAT5	protein	O94916	UNIPROT	up-regulates	phosphorylation	Thr135	TVQQHPStPKRHTVL	9606	BTO:0000007								21209322	t		lperfetto	High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. n hek293 cells, mass spectrometry shows phosphorylation of tonebp/orebp-s120, -s134, -t135, and -s155.	SIGNOR-170886	0.2
SF3A3	protein	Q12874	UNIPROT	SF3a	complex	SIGNOR-C345	SIGNOR	form complex	binding			9606	BTO:0000567								8349644	t		miannu	Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. 	SIGNOR-263949	0.974
EEF1E1	protein	O43324	UNIPROT	Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	form complex	binding			9606									32644155	t		miannu	In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes).	SIGNOR-270360	0.907
PAK	proteinfamily	SIGNOR-PF13	SIGNOR	VIM	protein	P08670	UNIPROT	down-regulates activity	phosphorylation			-1									11895474	t	inferred from 70% family members	miannu	In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK. 	SIGNOR-269975	0.2
CSNK2A1	protein	P68400	UNIPROT	DDX58	protein	O95786	UNIPROT	down-regulates	phosphorylation	Ser855	PKPKQFSsFEKRAKI	9606									21068236	t		lperfetto	Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of rig-i are phosphorylated by casein kinase ii (ck2) in the resting state of the cell and dephosphorylated when cells are infected by rna virus. Mutation at aa position 770 or 854 to 855 of rig-i renders it constitutively active	SIGNOR-169404	0.2
SRC	protein	P12931	UNIPROT	ACLY	protein	P53396	UNIPROT	up-regulates activity	phosphorylation	Tyr1006	PATPLLDyALEVEKI	9606	BTO:0000007								32420483	t	done	miannu	 We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells.	SIGNOR-274107	0.268
NSD3	protein	Q9BZ95	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates activity	binding			9606	BTO:0002181								28205554	t		irozzo	Indeed, dose-dependent TR-FRET and affinity pull-down assay confirmed the interaction of NSD3-s with MYC. Supporting functional significance of the interaction, co-expression of NSD3-s, but not the MYC-binding defective fragment of NSD3-s (1–347), stabilized MYC protein and increased MYC transcriptional activity as revealed by a MYC-driven reporter assay.	SIGNOR-259200	0.2
INSR	protein	P06213	UNIPROT	IRS4	protein	O14654	UNIPROT	up-regulates activity	phosphorylation			10090									25905389	t		lperfetto	The binding of insulin to the subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the _ subunit of the IR and triggers the signaling cascades (Fig. 3). Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including IRS1-4, Shc, and Gab 1, Cbl, APS, and P60dok.	SIGNOR-217897	0.502
CHEVI complex	complex	SIGNOR-C269	SIGNOR	SEC22B	protein	O75396	UNIPROT	up-regulates activity	relocalization			9606									27319744	t		lperfetto	VPS33B association with VIPAS39, α-tubulin, and SEC22B was identified by co-immunoprecipitation, mass spectra, and immunoblotting in human embryonic kidney 293T (HEK293T) cells. Also, pull-down experiments revealed that VIPAS39 bound to intact VPS33B; in contrast, α-tubulin and SEC22B separately interacted with the sec1-like domains of VPS33B. Vps33b deficiency in megakaryocytes disturbs the redistribution of Vipas39 and Sec22b to proplatelets, and interrupted the co-localization of Sec22b with Vwf-positive vesicles	SIGNOR-261832	0.385
TDGF1	protein	P13385	UNIPROT	ACVR1B	protein	P36896	UNIPROT	up-regulates activity	binding			9606									19874624	t	Regulation	miannu	Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors.	SIGNOR-251938	0.717
EGFR	protein	P00533	UNIPROT	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates	phosphorylation	Tyr570	SSNFDSIyICPSTFA	9606									20029029	t		gcesareni	A negative feedback loop consisting of egfr-mediated phosphorylation of hdac6 tyr(570) resulted in reduced deacetylase activity and increased acetylation of alpha-tubulin.	SIGNOR-162431	0.452
CD3	complex	SIGNOR-C432	SIGNOR	ZAP70	protein	P43403	UNIPROT	up-regulates activity	binding			9534									1423621	t			We have recently identified a 70 kd tyrosine phosphoprotein (ZAP-70) that associates with zeta and undergoes tyrosine phosphorylation following TCR stimulation|Moreover, tyrosine phosphorylation and association of ZAP-70 with zeta require the presence of src family PTKs and provide a potential mechanism by which the src family PTKs and ZAP-70 may interact to mediate TCR signal transduction.	SIGNOR-252304	0.683
MET	protein	P08581	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr397	SVSETDDyAEIIDEE	9606									16782899	t		llicata	Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain	SIGNOR-147183	0.475
3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid	chemical	CHEBI:91194	ChEBI	LPAR3	protein	Q9UBY5	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193564	0.8
TNFSF10	protein	P50591	UNIPROT	TNFRSF10B	protein	O14763	UNIPROT	up-regulates	binding			9606									14585074	t		amattioni	Trail interacts with tril-r1 and trail-r2 and activetes them	SIGNOR-101313	0.932
CTH	protein	P32929	UNIPROT	L-cysteine zwitterion	smallmolecule	CHEBI:35235	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000671;BTO:0000759;BTO:0002688							19961860	t		lperfetto	 the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production.	SIGNOR-275824	0.8
ARAP2	protein	Q8WZ64	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260455	0.473
SRC	protein	P12931	UNIPROT	VAV3	protein	Q9UKW4	UNIPROT	up-regulates	phosphorylation	Tyr173	EDEGGEVyEDLMKAE	9606	BTO:0000785								17998938	t		gcesareni	Activation of rac1 and the exchange factor vav3 are involved in npm-alk signaling in anaplastic large cell lymphomas.	SIGNOR-159240	0.331
PLK1	protein	P53350	UNIPROT	SUZ12	protein	Q15022	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser539	RPKRTKAsMSEFLES										25855382	t		lperfetto	PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|In SUZ12, residues 539, 541 and 546 phosphorylated by Plk1 in vitro	SIGNOR-275557	0.371
TIAM2	protein	Q8IVF5	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260578	0.572
PGM2	protein	Q96G03	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	up-regulates quantity	chemical modification			9606									32898648	t		miannu	Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P).	SIGNOR-267934	0.8
NDUFA4	protein	O00483	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267752	0.523
ARMC10	protein	Q8N2F6	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	binding			9606	BTO:0000971;BTO:0005814								17904127	t		miannu	Co-immunoprecipitation and GST pull-down assays have demonstrated that SVH-B directly interacts with p53. In both BEL-7404 cells and p53-null Saos-2 cells transfected with a temperature-sensitive mutant of p53, V143A, ectopically expressed SVH-B suppresses the transcriptional activity of p53, and suppression of SVH by RNA interference increases the transcriptional activity of p53. Our results suggested the function of SVH-B in accelerating growth and inhibition of apoptosis is related to its inhibitory binding to p53.	SIGNOR-266414	0.2
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BC4	protein	P62807	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSVYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271986	0.2
CDK2	protein	P24941	UNIPROT	PPP1CA	protein	P62136	UNIPROT	down-regulates activity	phosphorylation	Thr320	NPGGRPItPPRNSAK	9606									12202491	t		gcesareni	Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity	SIGNOR-92265	0.385
RPS6KA3	protein	P51812	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									15994958	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-138471	0.2
NDUFB3	protein	O43676	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1	SIGNOR-262166	0.8
LRP4	protein	O75096	UNIPROT	MUSK	protein	O15146	UNIPROT	up-regulates activity	binding			9606		BTO:0000887							23458718	t		miannu	AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer. 	SIGNOR-273850	0.72
RFC1	protein	P35251	UNIPROT	RF-C complex	complex	SIGNOR-C375	SIGNOR	form complex	binding												12930972	t		lperfetto	RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned 	SIGNOR-265505	0.858
VARS1	protein	P26640	UNIPROT	valine	smallmolecule	CHEBI:27266	ChEBI	down-regulates quantity	chemical modification			9606									30755602	t		miannu	Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 	SIGNOR-270526	0.8
FOXJ1	protein	Q92949	UNIPROT	Axonemal_Dynein	proteinfamily	SIGNOR-PF66	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000939								23822649	t		miannu	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266939	0.2
RIN1	protein	Q13671	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates	binding			9606									11784866	t		gcesareni	We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1.	SIGNOR-113970	0.58
KDM5B	protein	Q9UGL1	UNIPROT	NANOG	protein	Q9H9S0	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000815								31776402	t		lperfetto	Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes.	SIGNOR-273451	0.314
GSK3B	protein	P49841	UNIPROT	CDX2	protein	Q99626	UNIPROT	unknown	phosphorylation	Ser295	LQASVPGsVPGVLGP	-1									16027724	t			GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines)	SIGNOR-251230	0.389
GNA12	protein	Q03113	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates	binding			9606									23450633	t		gcesareni	Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism.	SIGNOR-192108	0.539
AKAP12	protein	Q02952	UNIPROT	PKA	proteinfamily	SIGNOR-PF17	SIGNOR	up-regulates activity	relocalization												14657015	t		lperfetto	A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. 	SIGNOR-271837	0.2
TNF	protein	P01375	UNIPROT	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004914								22190977	f			Exposure of RA FLSs to TNF-α (10 ng/ml) led to increase of Hes-1, a target gene of Notch signaling, and a marked upregulation of Notch 2, Delta-like 1, and Delta-like 3 mRNA levels.	SIGNOR-253605	0.2
ADSS1	protein	Q8N142	UNIPROT	GDP	smallmolecule	CHEBI:17552	ChEBI	up-regulates quantity	chemical modification			9606									10496970	t		miannu	Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 	SIGNOR-267350	0.8
MLLT11	protein	Q13015	UNIPROT	TCF7	protein	P36402	UNIPROT	up-regulates activity	binding			-1									26079538	t		irozzo	Here, we show that AF1q specifically binds to T-cell-factor-7 (TCF7) in the Wnt signaling pathway and results in transcriptional activation of CD44 as well as multiple downstream targets of the TCF7/LEF1. Super-shift and electrophoretic mobility shift assay (EMSA) further confirmed that AF1q directly interacted with TCF7 and enhanced the binding affinity of the complex	SIGNOR-259108	0.476
gamma-secretase	complex	SIGNOR-C98	SIGNOR	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	cleavage												23729744	t		apalma	Receptor–ligand engagement triggers a second NECD cleavage (S2 cleavage) by a metalloproteinase ADAM (known as Kuzbanian in Drosophila melanogaster), which in turn facilitates a further crucial signaling cleavage within the Notch transmembrane domain by a γ-secretase complex that contains Presenilin (S3 cleavage)	SIGNOR-255372	0.666
CSNK1A1	protein	P48729	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation	Ser321	NSNASTVsGRLSPIM	9606									20110348	t		lperfetto	Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export	SIGNOR-163676	0.2
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1920	SPTYSPTsPKYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120064	0.781
SENP3	protein	Q9H4L4	UNIPROT	Rix1 complex	complex	SIGNOR-C373	SIGNOR	form complex	binding			9606	BTO:0000007								22190735	t		miannu	LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes.	SIGNOR-265468	0.796
PRKACA	protein	P17612	UNIPROT	ACLY	protein	P53396	UNIPROT	up-regulates activity	phosphorylation	Ser455	PAPSRTAsFSESRAD	-1									10653665	t		miannu	Phosphorylation of Recombinant Human ATP:Citrate Lyase by cAMP-Dependent Protein Kinase Abolishes Homotropic Allosteric Regulation of the Enzyme by Citrate and Increases the Enzyme Activity. Ser 454, which is phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PKA)	SIGNOR-250328	0.313
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	RGCC	protein	Q9H4X1	UNIPROT	up-regulates activity	phosphorylation	Thr111	ALLSATVtPQKAKLG	9606	BTO:0001685								11687586	t		miannu	 RGC-32 was physically associated with cyclin-dependent kinase p34CDC2 and increased the kinase activity in vivo and in vitro. In addition, RGC-32 was phosphorylated by p34CDC2-cyclin B1 in vitro. Mutation of RGC-32 protein at Thr-91 prevented the p34CDC2-mediated phosphorylation and resulted in loss of p34CDC2 kinase enhancing activity.	SIGNOR-262725	0.458
FFAR3	protein	O14843	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256821	0.2
CAK complex	complex	SIGNOR-C456	SIGNOR	RARG	protein	P13631	UNIPROT	up-regulates activity	phosphorylation	Ser77	SEEMVPSsPSPPPPP	9534	BTO:0000298								10748061	t		miannu	Retinoic acid receptor gamma (RARgamma) is phosphorylated in COS-1 cells at two conserved serine residues located in the N-terminal region (serines 77 and 79 in RARgamma1 and serines 66 and 68 in RARgamma2) that contains the activation function AF-1. These serines are phosphorylated in vitro by cdk7, a cyclin-dependent kinase associated to cyclin H and MAT1 in the CAK complex (cdk7.cyclin H. MAT1), that is found either free or as a component of the transcription/DNA repair factor TFIIH. 	SIGNOR-275969	0.393
FADS2	protein	O95864	UNIPROT	arachidonoyl-CoA	smallmolecule	CHEBI:15514	ChEBI	up-regulates quantity	chemical modification			9606									15189125	t		miannu	Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity.	SIGNOR-267912	0.8
DLX5	protein	P56178	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity	transcriptional regulation			9606									19497851	t		gcesareni	Here we demonstrate by luciferase assay that the MYC promoter is specifically activated by overexpression of DLX5 and that two DLX5 binding sites in the MYC promoter are important for transcriptional activation of MYC. We also show that DLX5 binds to the MYC promoter both in vitro and in vivo and that transfection of a DLX5 expression plasmid promotes the expression of MYC in a dose-dependent manner in mammalian cells	SIGNOR-241914	0.278
FKBP5	protein	Q13451	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates	binding			9606									25790864	t		gcesareni	When not associated with glucocorticoids, glucocorticoid receptors are predominantly found in the cytoplasm as part of a multimeric molecular chaperone complex that includes several heat shock proteins (HSPs), such as HSP70 and HSP90, the HSP90_binding protein p23 (also known as PTGES3) and proteins that help to bind HSP90 such as FK506_binding protein 5 (FKBP5).	SIGNOR-251666	0.736
BUB1	protein	O43683	UNIPROT	CDC20	protein	Q12834	UNIPROT	down-regulates activity	phosphorylation	Ser161	QKATPGSsRKTCRYI	9606	BTO:0000567								15525512	t		llicata	Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. 	SIGNOR-250605	0.992
vandetanib	chemical	CHEBI:49960	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207624	0.8
nilotinib	chemical	CHEBI:52172	ChEBI	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	down-regulates activity	chemical inhibition			9606	BTO:0001056								23409026	t		miannu	Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. 	SIGNOR-259269	0.8
TFIIH	complex	SIGNOR-C457	SIGNOR	E2F1	protein	Q01094	UNIPROT	down-regulates	phosphorylation	Thr433	DCDFGDLtPLDF	9606									10428966	t		lperfetto	These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase.  here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain.	SIGNOR-269354	0.324
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC4	protein	P56524	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258017	0.8
ZDHHC5	protein	Q9C0B5	UNIPROT	S1PR1	protein	P21453	UNIPROT	up-regulates activity	palmitoylation			9606	BTO:0000793								29185452	t			We propose that DHHC5-mediated palmitoylation of S1P1R determines Gi coupling and its signalling in a spatio/temporal manner.	SIGNOR-261140	0.2
TRIB3	protein	Q96RU7	UNIPROT	ACACA	protein	Q13085	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								16794074	t		miannu	TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).	SIGNOR-271600	0.277
LARS1	protein	Q9P2J5	UNIPROT	Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	form complex	binding			9606									32644155	t		miannu	In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes).	SIGNOR-270355	0.2
BTK	protein	Q06187	UNIPROT	DDX41	protein	Q9UJV9	UNIPROT	up-regulates activity	phosphorylation	Tyr414	DVIQEVEyVKEEAKM	10090	BTO:0002572								25704810	t		miannu	The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site. 	SIGNOR-266404	0.417
SMAD7	protein	O15105	UNIPROT	TAB2	protein	Q9NYJ8	UNIPROT	up-regulates	binding			9606		BTO:0001253							17384642	t		lperfetto	The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling	SIGNOR-153917	0.55
PPP2CA	protein	P67775	UNIPROT	EEF2	protein	P13639	UNIPROT	up-regulates	dephosphorylation	Thr59	GETRFTDtRKDEQER	9606							phosphorylation:Thr59	GETRFTDtRKDEQER 	8386634	t		gcesareni	Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2	SIGNOR-38566	0.413
ATR	protein	Q13535	UNIPROT	RPA2	protein	P15927	UNIPROT	unknown	phosphorylation	Ser33	GFGSPAPsQAEKKSR	9606									19843584	t		llicata	Atr phosphorylates s33 in response to replication stress	SIGNOR-188666	0.747
PRKACA	protein	P17612	UNIPROT	SYN1	protein	P17600	UNIPROT	down-regulates activity	phosphorylation	Ser9	NYLRRRLsDSNFMAN	-1									10571231	t		miannu	Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I 	SIGNOR-250058	0.344
QRICH1	protein	Q2TAL8	UNIPROT	YARS1	protein	P54577	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269412	0.2
EIF2B4	protein	Q9UI10	UNIPROT	EIF2S3	protein	P41091	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269137	0.686
2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	chemical	CHEBI:93768	ChEBI	INSR	protein	P06213	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192871	0.8
ERBB2	protein	P04626	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								15173068	t		gcesareni	The results presented here show for the first time that er redistribution to the cytoplasm and its interaction with her2 are important downstream effects of her2 overexpression, that erk1/2 is important for er cytoplasmic localization, and that subcellular localization of er may play a mechanistic role in determining the responsiveness of breast cancer cells to tamoxifen.	SIGNOR-124962	0.591
5-[6-[(4-methyl-1-piperazinyl)methyl]-1-benzimidazolyl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]-2-thiophenecarboxamide	chemical	CHEBI:91333	ChEBI	PLK1	protein	P53350	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192991	0.8
PRKACA	protein	P17612	UNIPROT	SRSF1	protein	Q07955	UNIPROT	up-regulates	phosphorylation	Ser119	YGPPSRRsENRVVVS	9606									22393468	t		llicata	Here, we show that pka phosphorylates srsf1 on serine 119 in vitro. Phosphorylation of srsf1 on this site enhanced the rna binding capacity of srsf1 in vivo	SIGNOR-196397	0.2
ICOSLG	protein	O75144	UNIPROT	ICOS	protein	Q9Y6W8	UNIPROT	up-regulates activity	binding			9606									27559335	t			ICOSL expression is largely restricted to professional antigen-presenting cells (APCs), including B cells [in which ICOSL is regulated by BAFFR and non-canonical NFκB signaling (20)], macrophages, and dendritic cells (DCs) (12, 17, 21, 22), but is also expressed by certain endothelial cells (23) and lung epithelium	SIGNOR-272497	0.2
ROBO2	protein	Q9HCK4	UNIPROT	CFL1	protein	P23528	UNIPROT	up-regulates quantity by expression	post transcriptional regulation			-1									16226035	t		miannu	Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation.	SIGNOR-268378	0.26
CASC3	protein	O15234	UNIPROT	Exon junction complex	complex	SIGNOR-C369	SIGNOR	form complex	binding			-1									16923391	t		miannu	 The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. 	SIGNOR-265241	0.922
MTOR	protein	P42345	UNIPROT	ISCU	protein	Q9H1K1	UNIPROT	up-regulates	phosphorylation	Ser14	FRLRRAAsALLLRSP	9606			SIGNOR-C3						23508953	t		llicata	Here, we demonstrate that mtorc1 associates with iscu and phosphorylates iscu at serine 14. This phosphorylation stabilized iscu protein.	SIGNOR-201595	0.2
SCRIB	protein	Q14160	UNIPROT	Scribble_complex_DLG4-LLGL2_variant	complex	SIGNOR-C505	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270888	0.529
TP53	protein	P04637	UNIPROT	BIRC5	protein	O15392	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11965534	f		acerquone	Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53.	SIGNOR-117328	0.544
AMP	smallmolecule	CHEBI:456215	ChEBI	adenosine	smallmolecule	CHEBI:16335	ChEBI	up-regulates quantity	precursor of			-1									31461341	t		Luana	Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine.	SIGNOR-269741	0.8
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Thr48	VCPDVPRtPVGKFLG	9606									10864927	t		lperfetto	Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b.	SIGNOR-216773	0.839
CDR2	protein	Q01850	UNIPROT	AURKA	protein	O14965	UNIPROT	up-regulates quantity by expression	transcriptional regulation												20383333	f		lperfetto	Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology	SIGNOR-252023	0.2
PTPN1	protein	P18031	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	10090	BTO:0000944								11579209	t		lperfetto	Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor.	SIGNOR-235503	0.778
SRC	protein	P12931	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates	phosphorylation	Tyr694	LAKAVDGyVKPQIKQ	9606									11641791	t		gcesareni	Src can thus directly tyrosine-phosphorylate the activation site of stat5 (tyr 694 in stat5a), and src may contribute to epo-induced signal transduction via stat5.	SIGNOR-111078	0.741
RPS6KA1	protein	Q15418	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser286	SSMSSCGsSGYFSSS	9606									22017877	t		lperfetto	We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1	SIGNOR-176883	0.507
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	RGCC	protein	Q9H4X1-2	UNIPROT	up-regulates activity	phosphorylation	Ser47	MKRRSSAsVSDSSGF	9606	BTO:0000567								19162005	t		miannu	Akt phosphorylated GST-RGC-32 in vitro, and CDC2 was also able to phosphorylate RGC-32.  Akt failed to phosphorylate RGC-32 S45A-S47A mutant. These data indicate that Ser 45 and Ser 47 may be the RGC-32 phosphorylation sites for Akt kinase.	SIGNOR-262628	0.2
CABIN1	protein	Q9Y6J0	UNIPROT	HIRA complex 2	complex	SIGNOR-C462	SIGNOR	form complex	binding			9606									30285846	t		miannu	H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex.	SIGNOR-269438	0.518
AR	protein	P10275	UNIPROT	UBE2C	protein	O00762	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19632176	t		miannu	The evolution of prostate cancer from an androgen-dependent state (ADPCa) to one that is androgen-independent (AIPCa) marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in AIPCa is poorly understood. We have defined the direct AR-dependent target genes in both AIPCa and ADPCa by generating AR-dependent gene expression profiles and AR cistromes. In contrast to ADPCa, AR selectively up-regulates M-phase cell cycle genes in AIPCa including UBE2C, a gene that inactivates the M-phase checkpoint. 	SIGNOR-251543	0.408
PRKCA	protein	P17252	UNIPROT	SLC6A9	protein	P48067-2	UNIPROT	down-regulates activity	phosphorylation	Ser239	LIRGVKSsGKVVYFT	9823									21864610	t		miannu	We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 	SIGNOR-262918	0.337
WNT7A	protein	O00755	UNIPROT	Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-253130	0.76
PLAU	protein	P00749	UNIPROT	PLAUR	protein	Q03405	UNIPROT	up-regulates	binding			9606									16456079	t		gcesareni	The urokinase plasminogen activator binds to its cellular receptor with high affinity and initiates signaling cascades that are implicated in pathological processes including tumor growth, metastasis, and inflammation.	SIGNOR-144306	0.888
SP1	protein	P08047	UNIPROT	ID1	protein	P41134	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18025157	f			We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein.	SIGNOR-255748	0.2
SP1	protein	P08047	UNIPROT	SOD1	protein	P00441	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8921911	f	 	miannu	 Studies using two mutant versions of this promoter, in which the Sp1 and C/EBP-related factor binding sites were deleted, respectively, revealed that Sp1 and C/EBP-related factors activate the transcription of SOD1 gene. the binding of Sp1 to the proximal upstream region of the Cu/Zn SOD might explain the expression of Cu/Zn SOD in a wide variety of cells.	SIGNOR-253899	0.297
XIAP	protein	P98170	UNIPROT	CASP7	protein	P55210	UNIPROT	down-regulates quantity by destabilization	binding			-1									11583623	t		lperfetto	Xiap is an endogenous inhibitor of caspase-7	SIGNOR-110840	0.854
RPS6KA1	protein	Q15418	UNIPROT	WWC1	protein	Q8IX03	UNIPROT	up-regulates	phosphorylation	Thr929	STIIRSKtFSPGPQS	9606		BTO:0000149							24269383	t		llicata	Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2.	SIGNOR-203298	0.342
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000938								20444238	t	inferred from 70% family members	gcesareni	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-270164	0.2
DNMBP	protein	Q6XZF7	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260547	0.554
ACE2	protein	Q9BYF1	UNIPROT	Angiotensin 1-7	protein	P01019-PRO_0000420660	UNIPROT	up-regulates quantity	cleavage			9606									32201502	t		miannu	At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function.	SIGNOR-260227	0.2
REL	protein	Q04864	UNIPROT	CSRP1	protein	P21291	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14522018	f	 	 	We conclude that c-Rel regulates CRP expression without the requirement of binding to a kappaB site, and binds directly to C/EBPbeta to facilitate the binding of C/EBPbeta to the CRP promoter	SIGNOR-254063	0.2
PRKCZ	protein	Q05513	UNIPROT	AQP9	protein	O43315	UNIPROT	up-regulates	phosphorylation	Ser11	EGAEKGKsFKQRLVL	9606									21873454	t		lperfetto	Wt-pkc_-mediated phosphorylation of wt aqp9 in vitro. In the experiments, substitution of ser11 to ala markedly inhibited phosphorylation. the s11a mutation in fibroblasts caused a smoother cell periphery with fewer aqp9-induced filopodia	SIGNOR-176278	0.2
FFAR2	protein	O15552	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257342	0.2
MCU	protein	Q8NE86	UNIPROT	MCU_MICU1_variant	complex	SIGNOR-C500	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270865	0.715
UBR5	protein	O95071	UNIPROT	TOPBP1	protein	Q92547	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									11714696	t		miannu	Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with gamma-H2AX nuclear foci in DNA breaks.	SIGNOR-272667	0.474
TP53	protein	P04637	UNIPROT	GADD45A	protein	P24522	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23576563	f		gcesareni	P53 acetylated at k120 subsequently bound to the promoters of its target apoptotic genes, bax and gadd45, to promote their expression and lead to apoptosis.	SIGNOR-201679	0.648
ATR	protein	Q13535	UNIPROT	PARP1	protein	P09874	UNIPROT	down-regulates activity	phosphorylation	Ser179	FRPEYSAsQLKGFSL	9606	BTO:0000018								33811702	t		miannu	Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments. This site-specific phosphorylation inactivates PARP1, inhibiting ionophore-induced necrosis.	SIGNOR-277551	0.365
NEK7	protein	Q8TDX7	UNIPROT	KIF14	protein	Q15058	UNIPROT	up-regulates activity	phosphorylation	Ser1217	PIKNLHSsHSSGLMD	9606	BTO:0000565								28630147	t		miannu	Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). 	SIGNOR-266420	0.38
PRKN	protein	O60260	UNIPROT	PHGDH	protein	O43175	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys330	SAFSPHTkPWIGLAE	9606	 BTO:0000018;BTO:0003885								32478681	t		Luisa	Parkin binds to PHGDH and degrades it through ubiquitination to inhibit serine synthesis, which contributes greatly to the tumor-suppressive function of Parkin. 	SIGNOR-269075	0.2
SLC12A6	protein	Q9UHW9	UNIPROT	chloride	smallmolecule	CHEBI:17996	ChEBI	down-regulates quantity	relocalization												21613606	t		lperfetto	Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12). 	SIGNOR-264638	0.8
CDK1	protein	P06493	UNIPROT	AKAP12	protein	Q02952	UNIPROT	up-regulates activity	phosphorylation	Thr767	ESFKRLVtPRKKSKS	9606	BTO:0000007								23063527	t		lperfetto	Mass spectrometry, molecular, and cellular approaches show that CDK1/Cyclin B1 phosphorylates Gravin on threonine 766 to prime the recruitment of the polo-like kinase Plk1 at defined phases of mitosis. 	SIGNOR-271839	0.329
PAF1	protein	Q8N7H5	UNIPROT	PAF1C	complex	SIGNOR-C471	SIGNOR	form complex	binding			9606	BTO:0000567								20178742	t		miannu	Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A). 	SIGNOR-269833	0.879
PRKCG	protein	P05129	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates activity	phosphorylation	Thr495	TGITRKKtFKEVANA	9606									24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251633	0.2
PTMS	protein	P20962	UNIPROT	NR3C1	protein	P04150	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								16150697	t		miannu	Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner	SIGNOR-268460	0.334
SPOP	protein	O43791	UNIPROT	GMNN	protein	O75496	UNIPROT	down-regulates activity	ubiquitination			9606	BTO:0000007								34599168	t		miannu	SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. This poly-ubiquitination of Geminin prevents DNA replication over-firing by indirectly blocking the association of Cdt1 with the MCM protein complex, an interaction required for DNA unwinding and replication. 	SIGNOR-268926	0.2
mTORC1	complex	SIGNOR-C3	SIGNOR	RPS6KB2	protein	Q9UBS0	UNIPROT	up-regulates	phosphorylation			9606									17510057	t		lperfetto	In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size.	SIGNOR-217074	0.586
AKT1	protein	P31749	UNIPROT	ALYREF	protein	Q86V81	UNIPROT	up-regulates	phosphorylation	Thr219	GGGTRRGtRGGARGR	9606									18562279	t		llicata	Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export.	SIGNOR-252518	0.461
MAPK1	protein	P28482	UNIPROT	CAD	protein	P27708	UNIPROT	up-regulates	phosphorylation	Thr456	KVYFLPItPHYVTQV	9606									15890648	t		lperfetto	Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol	SIGNOR-137171	0.391
NFIA	protein	Q12857	UNIPROT	ETV5	protein	P41161	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268874	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CD83	protein	Q01151	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19164127	f	 	miannu	 We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. 	SIGNOR-254781	0.262
NCK1	protein	P16333	UNIPROT	PAK1	protein	Q13153	UNIPROT	up-regulates	binding			9606									11157752	t		lperfetto	Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors.	SIGNOR-235947	0.697
SOSTDC1	protein	Q6X4U4	UNIPROT	BMP7	protein	P18075	UNIPROT	down-regulates activity				10090									18032587	f		lperfetto	SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7	SIGNOR-242752	0.761
CXCL1	protein	P09341	UNIPROT	Neutrophil_activation	phenotype	SIGNOR-PH211	SIGNOR	up-regulates				9606	BTO:0000130								35022267	f		miannu	Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site.	SIGNOR-277721	0.7
CXCL2	protein	P19875	UNIPROT	Neutrophil_activation	phenotype	SIGNOR-PH211	SIGNOR	up-regulates				9606	BTO:0000130								35022267	f		miannu	Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site.	SIGNOR-277722	0.7
AXL	protein	P30530	UNIPROT	Epithelial-mesenchymal_transition	phenotype	SIGNOR-PH45	SIGNOR	up-regulates activity	binding			9606	BTO:0000130								35022267	t		miannu	Gas6 and its main receptor AXL are overexpressed in pancreatic cancer and their expression correlates with poor prognosis.Gas6/AXL signalling in cancer cells is associated with tumour cell proliferation, epithelial mesenchymal transition and metastases.	SIGNOR-277723	0.7
Neutrophil_activation	phenotype	SIGNOR-PH211	SIGNOR	GAS6	protein	Q14393	UNIPROT	up-regulates				9606	BTO:0000130								35022267	f		miannu	Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site.	SIGNOR-277724	0.7
AXL	protein	P30530	UNIPROT	Metastasis	phenotype	SIGNOR-PH107	SIGNOR	up-regulates				9606									35022267	f		miannu	Gas6 and its main receptor AXL are overexpressed in pancreatic cancer and their expression correlates with poor prognosis.Gas6/AXL signalling in cancer cells is associated with tumour cell proliferation, epithelial mesenchymal transition and metastases.	SIGNOR-277725	0.7
EID1	protein	Q9Y6B2	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates													11073990	f		lperfetto	Thus, EID-1 binds both Rb and p300 and is a novel repressor of MyoD function.	SIGNOR-253378	0.351
PRKAA2	protein	P54646	UNIPROT	CRTC2	protein	Q53ET0	UNIPROT	down-regulates	phosphorylation	Ser171	SALNRTSsDSALHTS	9606			SIGNOR-C15						16308421	t		gcesareni	Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2	SIGNOR-142211	0.471
CNOT9	protein	Q92600	UNIPROT	GIGYF2	protein	Q6Y7W6	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								20878056	t		miannu	Through interaction analysis of RQCD1 with full-length or partial proteins of GIGYF1 and GIGYF2, segments corresponding to 620-665th and 667-712th amino acids were identified as potential interacting regions on GIGYF1 and GIGYF2, respectively, with RQCD1. we found that RQCD1 was required for enhancement of the interaction of Grb10 with GIGYF1 and GIGYF2	SIGNOR-260058	0.2
NCAPG2	protein	Q86XI2	UNIPROT	Condensin II	complex	SIGNOR-C342	SIGNOR	form complex	binding			9606									32445620	t		miannu	The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction.	SIGNOR-263911	0.857
CXCL5	protein	P42830	UNIPROT	Metastasis	phenotype	SIGNOR-PH107	SIGNOR	up-regulates				9606	BTO:0000584								34237033	f		miannu	 We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis.	SIGNOR-277733	0.7
ECT2	protein	Q9H8V3	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260550	0.702
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SYN2	protein	Q92777	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000938								10571231	t		miannu	 Synapsins are exclusively localized to synaptic vesicles, which they coat as peripheral membrane proteins; they probably constitute one of the most abundant neuronal PKA substrates. Our study reveals an unexpectedly dynamic state of synapsins in nerve terminals: any changes in PKA or CaM Kinase I activity will modulate the amount of synapsin on synaptic vesicles. PKA Activation Triggers Synapsin Dissociation	SIGNOR-264109	0.2
PHB2	protein	Q99623	UNIPROT	MEF2A	protein	Q02078	UNIPROT	down-regulates	binding			10090	BTO:0000165	BTO:0000887							15173318	t		lperfetto	Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation.	SIGNOR-235840	0.314
DCK	protein	P27707	UNIPROT	CDK1	protein	P06493	UNIPROT	down-regulates activity	binding												22850745	t		lperfetto	We demonstrate that dCK interacts with cyclin-dependent kinase 1 (Cdk1) after IR and that the interaction inhibits Cdk1 activity both in vitro and in vivo. 	SIGNOR-275805	0.387
AAK1	protein	Q2M2I8	UNIPROT	AP1M1	protein	Q9BXS5	UNIPROT	up-regulates	phosphorylation	Thr144	QEGHKLEtGAPRPPA	9606	BTO:0000938								11877461	t		lperfetto	Aak1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and ap2 in clathrin-coated pits and at the leading edge of migrating cells. Aak1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by aak1 results in a decrease in ap2-stimulated transferrin internalization. Together, these results provide strong evidence that aak1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis.	SIGNOR-115589	0.2
CUDC-101	chemical	CID:24756910	PUBCHEM	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									20143778	t		miannu	By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively.	SIGNOR-262264	0.8
RPS6KA3	protein	P51812	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser167	GGRERLAsTNDKGSM	9606	BTO:0000150								19112174	t		gcesareni	S6k1 regulates estrogen receptor alpha (eralpha) by phosphorylating it on serine 167, leading to transcriptional activation of eralpha.	SIGNOR-182958	0.412
NFIA	protein	Q12857	UNIPROT	SLIT1	protein	O75093	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268892	0.26
TM9SF4	protein	Q92544	UNIPROT	MTOR	protein	P42345	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								29125601	t		miannu	TM9SF4 inhibited mTOR activity in HEK293 cells. Under nutrient starvation, TM9SF4 functions to facilitate mTOR inactivation, resulting in an enhanced autophagic flux, which serves to protect cells from apoptotic cell death.	SIGNOR-266703	0.2
BID	protein	P55957	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	down-regulates activity	binding			9606	BTO:0000093								22464442	t		lperfetto	Overexpression of antiapoptotic proteins including Bcl-XL and/or Bcl-2 contributes to tumor initiation, progression, and resistance to therapy by direct interactions with proapoptotic BH3 proteins. Release of BH3 proteins from antiapoptotic proteins kills some cancer cells and sensitizes others to chemotherapy. Binding of Bcl-XL and Bcl-2 to the BH3 proteins Bad, Bid, and the three major isoforms of Bim was measured for fluorescent protein fusions in live cells using fluorescence lifetime imaging microscopy and fluorescence resonance energy transfer.	SIGNOR-209675	0.853
RIPK1	protein	Q13546	UNIPROT	CASP8	protein	Q14790	UNIPROT	up-regulates activity	binding			9606									12887920	t		amattioni	Tradd and rip1 associate with fadd and caspase-8, forming a cytoplasmic complex	SIGNOR-104255	0.907
SNAI1	protein	O95863	UNIPROT	PXDN	protein	Q92626	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								29305973	t		miannu	TGF-β1 induced Snai1 binding to the PXDN promoter (as assessed by chromatin immunoprecipitation-PCR) and significantly repressed luciferase reporter gene expression, as did Snai1 overexpression. 	SIGNOR-265249	0.2
IKBKB	protein	O14920	UNIPROT	COMT	protein	P21964	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000100								19291302	f	Regulation of expression	miannu	TNFα-dependent COMT downregulation was indeed mediated by the NF-κB pathway. Transient expression of p65, the essential component of NF-κB complexes, or IKKβ, the major positive regulator of NF-κB activition, significantly decreased P2-COMT reporter expression.	SIGNOR-251965	0.2
HDAC1	protein	Q13547	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates activity	deacetylation			10090									24463822	t			The ability of HDAC1 to cause muscle atrophy required its deacetylase activity and was linked to the induction of several atrophy genes by HDAC1, including atrogin-1, which required deacetylation of FoxO3a	SIGNOR-256486	0.377
PIK3C2A	protein	O00443	UNIPROT	PIPP	smallmolecule	CID:24755493	PUBCHEM	up-regulates	chemical modification			9606									23119004	t	D3 position	gcesareni	Pi3ks phosphorylate the d3 position of membrane phosphatidylinositides to generate phosphatidylinositol 3,4,5-triphosphate (pip3);	SIGNOR-199364	0.8
IGF1	protein	P05019	UNIPROT	PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	up-regulates				10090	BTO:0000165;BTO:0002314	BTO:0000887;BTO:0001103;BTO:0001760							10448861	f	inferred from 70% of family members	lperfetto	Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1.	SIGNOR-269890	0.279
EGR1	protein	P18146	UNIPROT	LHB	protein	P01229	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									19106114	f		miannu	EGR1 bound to two binding sites on the LHB promoter and this binding was increased by GNRH1. Mutation of either site or knockdown of endogenous EGR1 decreased basal and/or GNRH1-regulated promoter activity. 	SIGNOR-254919	0.407
CDC42BPA	protein	Q5VT25	UNIPROT	CDC42BPA	protein	Q5VT25	UNIPROT	up-regulates activity	phosphorylation	Ser234	MEDGTVQsSVAVGTP	9534	BTO:0000298								11283256	t		miannu	N terminus-mediated dimerization and transautophosphorylation are essential for MRCKα catalytic activity. Three mutations, S234A, T240A, and T403A, strongly affected the in vitro autophosphorylation activity of FLAG-MRCKα-CAT1–473 (Fig. ​(Fig.5D).5D).	SIGNOR-275974	0.2
HTR1D	protein	P28221	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256864	0.409
MAPK3	protein	P27361	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser383	IHFWSTLsPIAPRSP	9606									7889942	t		gcesareni	Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-34657	0.582
CDK2	protein	P24941	UNIPROT	TOB2	protein	Q14106	UNIPROT	up-regulates activity	phosphorylation	Ser254	PAPQSQLsPNAKEFV	-1									32404348	t		miannu	Taken together, these observations strongly support the notion that several different CDK-cyclin complexes are involved in the phosphorylation of Tob2 at S254.A more detailed regulatory context of Tob2 phosphorylation at S254 is provided by our findings from mass-spec and in vitro kinase analyses that suggest connections to PP2B and PP2C phosphatases and CDK-cyclin complexes, particularly CDK1, CDK2, and CDK4 (Table 1; Supplemental Table S2).One possibility is that the phosphorylation of S254 helps stabilize the interaction of Tob2 with the Ccr4–Not complex, which could contribute to Tob2's ability to recruit the entire Ccr4–Not complex and thus further enhances deadenylation. 	SIGNOR-273601	0.248
IRF3	protein	Q14653	UNIPROT	ABCC2	protein	Q92887	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15185298	f		miannu	Expression of recombinant human IRF3 increased MRP2 promoter activity. 	SIGNOR-254533	0.2
CSNK2A1	protein	P68400	UNIPROT	IP6K2	protein	Q9UHH9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser356	AEDLEDLsEESADES	9606	BTO:0000007								21262846	t		miannu	CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation.	SIGNOR-273625	0.257
POGLUT1	protein	Q8NBL1	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	up-regulates	binding			9606									22872643	t		gcesareni	O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. O-glucose can be elongated by xylose to the trisaccharide, xylalfa1-3xylalfa1-3glcbeta1-o-ser, whose synthesis is catalyzed by the consecutive action of three glycosyltransferases. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus.	SIGNOR-198716	0.557
MAPK3	protein	P27361	UNIPROT	BCL6	protein	P41182	UNIPROT	down-regulates	phosphorylation	Ser333	KGLVSPQsPQKSDCQ	9606	BTO:0000782;BTO:0000785								9649500	t		gcesareni	Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway.	SIGNOR-58489	0.416
HIF1A	protein	Q16665	UNIPROT	STC2	protein	O76061	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18394600	t		Giorgia	With the ChIP assay, we demonstrated the direct binding of HIF-1alpha to STC2 promoter. These findings support the notion that HIF-1 is a potent stimulator of STC2 expression. Collectively, this is the first report to show that STC2 was aberrantly hypermethylated in human cancer cells. The findings demonstrated that STC2 epigenetic inactivation may interfere with HIF-1 mediated activation of STC2 expression.	SIGNOR-260389	0.302
PRKACA	protein	P17612	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Thr548	KKVAVVRtPPKSPSS	9606									21215781	t	The effect has been demonstrated using P10636-8	lperfetto	However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules	SIGNOR-171066	0.442
C3	protein	P01024	UNIPROT	C3 convertase complex (C3bBb)	complex	SIGNOR-C314	SIGNOR	form complex	binding			9606		BTO:0000089			cleavage:Arg748	ASHLGLArSNLDEDI			26489954	t	complement C3b fragment: PRO_0000005911	lperfetto	Surface‐associated C3b recruits FB, which leads to FB activation and the formation of C3bBb, the AP C3 convertase, which cleaves more C3 and amplifies complement activation. In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over)	SIGNOR-263485	0.903
MAPK1	protein	P28482	UNIPROT	BMF	protein	Q96LC9	UNIPROT	up-regulates	phosphorylation	Ser74	DKATQTLsPASPSQG	9606	BTO:0000785								22258404	t		llicata	Phosphomimetic mutation of this site (s74d) moderately enhanced bmf apoptotic activity in vivo.22 here, we demonstrate a previously unrecognized mode of regulation of bmf. We show that b-raf-mek-erk2 signaling regulates bmf phosphorylation at serine 74 and serine 77. Phosphorylation of serine 77 downregulates the pro-apoptotic activity of bmf.	SIGNOR-195471	0.256
(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	ADRA1A	protein	P35348	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258456	0.8
PRKG2	protein	Q13237	UNIPROT	PLCB3	protein	Q01970	UNIPROT	down-regulates activity	phosphorylation	Ser1105	LDRKRHNsISEAKMR	10116									11278298	t		lperfetto	PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG.	SIGNOR-249078	0.508
TG101209	chemical	CHEBI:90304	ChEBI	JAK2	protein	O60674	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207263	0.8
TARS1	protein	P26639	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									25824639	t		miannu	Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 	SIGNOR-270503	0.8
CDK4	protein	P11802	UNIPROT	PELP1	protein	Q8IZL8	UNIPROT	up-regulates	phosphorylation	Ser477	ADALKLRsPRGSPDG	9606	BTO:0000150								20807815	t		llicata	Using site-directed mutagenesis and in vitro kinase assays, we identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we identified pelp1 as a novel substrate of cdks and found that cdk phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function.	SIGNOR-167770	0.36
EGFR	protein	P00533	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1110	GSVQNPVyHNQPLNP	9606									10653583	t	Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer	lperfetto	After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine.	SIGNOR-236483	0.2
SPI1	protein	P17947	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606									20861919	f		apalma	In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation.	SIGNOR-256372	0.7
CSNK2A1	protein	P68400	UNIPROT	PPP1R2	protein	P41236	UNIPROT	up-regulates activity	phosphorylation	Ser87	GDDEDACsDTEATEA	-1									8288648	t		llicata	Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action.	SIGNOR-250929	0.311
TARBP2	protein	Q15633	UNIPROT	DICER1	protein	Q9UPY3	UNIPROT	up-regulates	binding			9606									16142218	t		miannu	Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si? Or mi?RISCs In mammalian cells, but it may also facilitate the cleavage of pre?miRNAs By dicer.	SIGNOR-140226	0.938
CDKN2A	protein	P42771	UNIPROT	CDK4	protein	P11802	UNIPROT	down-regulates	binding			9606									16161044	t		gcesareni	The cdk-inhibitor p16 is a tumor suppressor gene that is inactivated in many forms of cancer. In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm.	SIGNOR-140409	0.902
GRK2	protein	P25098	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates	phosphorylation	Thr567	QGRDKYKtLRQIRQG	9606									15843435	t		llicata	Grk2 phosphorylates glutathione s-transferase (gst)-ezrin, but not an ezrin fusion protein lacking threonine 567 (t567), in vitro. These results suggest that t567, the regulatory phosphorylation site responsible for maintaining ezrin in its active conformation, represents the principle site of grk2-mediated phosphorylation.	SIGNOR-135622	0.2
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	PHF2	protein	O75151	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273464	0.8
PRKCB	protein	P05771	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Thr373	TVLVKDStNRDSLDM	9606	BTO:0000938	BTO:0000142							12486117	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-96632	0.289
GSK3B	protein	P49841	UNIPROT	NFKB1	protein	P19838	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser907	QAHSLPLsPASTRQQ	10090	BTO:0000452								12871932	t			GSK-3 beta forms an in vivo complex with and specifically phosphorylates NF-kappa B1/p105 at Ser-903 and Ser-907 in vitro. GSK-3 beta has a dual effect on p105: it stabilizes p105 under resting conditions and primes p105 for degradation upon tumor necrosis factor (TNF)-alpha treatment. Indeed, constitutive processing of p105 to p50 occurs at a higher rate in cells lacking GSK-3 beta with respect to wild-type cells and can be reduced upon reintroduction of GSK-3 beta by transfection. S903A and S907A point mutations impair p105 proteolysis in response to TNF-α.	SIGNOR-251252	0.396
EGFR	protein	P00533	UNIPROT	ABCA1	protein	O95477	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2054	GGNKRKLsTAMALIG	9606	BTO:0000567								12196520	t		lperfetto	We further provide in vitro evidence that epidermal growth factor receptor (EGFR)-mediated phosphorylation regulated ABCA1 ubiquitination |The EGFR selective inhibitor PD168393 blocked the EGFR-ABCA1 interaction and abolished ABCA1Ser2054 phosphorylation|	SIGNOR-264419	0.299
MAPK8IP1	protein	Q9UQF2	UNIPROT	MAPK8	protein	P45983	UNIPROT	down-regulates	binding			9606									15141161	t		gcesareni	The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus	SIGNOR-124727	0.879
CSNK2B	protein	P67870	UNIPROT	CDC34	protein	P49427	UNIPROT	unknown	phosphorylation	Ser203	APAPDEGsDLFYDDY	9606	BTO:0000567								11546811	t		llicata	CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm. 	SIGNOR-251057	0.357
FERMT3	protein	Q86UX7	UNIPROT	FBLIM1	protein	Q8WUP2	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								24165133	t		miannu	Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 	SIGNOR-266104	0.504
MARK1	protein	Q9P0L2	UNIPROT	MAP4	protein	P27816	UNIPROT	down-regulates activity	phosphorylation	Ser1073	KAQAKVGsLDNVGHL	-1									8631898	t		miannu	Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 	SIGNOR-250169	0.449
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser370	KKTIVNDsRESCVEE	9606	BTO:0001938								23277204	t		lperfetto	Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity.	SIGNOR-264666	0.2
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	KDM6A	protein	O15550	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273462	0.8
SRC	protein	P12931	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates	phosphorylation	Tyr523	REDSVLSyETVTQME	9606									24981431	t		llicata	These results indicate that psd-95 phosphorylation by src facilitates the integration of pyk2 to psd-95 signal complex, the activation of pyk2/src, as well as the subsequent tyrosine phosphorylation of nr2a, which ultimately results in the upregulation of nmda receptor function and synaptic transmission.	SIGNOR-205120	0.583
CDK1	protein	P06493	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser315	LPNNTSSsPQPKKKP	9606									24173284	t		lperfetto	The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A	SIGNOR-84256	0.598
AKT1	protein	P31749	UNIPROT	NUAK1	protein	O60285	UNIPROT	up-regulates	phosphorylation	Ser600	PARQRIRsCVSAENF	9606									12409306	t		esanto	Ser(600) in ark5 was found to be phosphorylated by active akt resulting in the activation of kinase activity.	SIGNOR-252591	0.266
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr522	SSPGSPGtPGSRSRT	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-251593	0.695
BCL2L11	protein	O43521	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								18498746	t		lperfetto	Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly.	SIGNOR-178679	0.955
RHOH	protein	Q15669	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	relocalization			10090	BTO:0004850								18089848	t		irozzo	Therefore, RhoH functions as a Rac1 antagonist by inhibiting Rac1 translocation to the cell plasma membrane in the regulation of cell migration and F-actin assembly of HPCs	SIGNOR-259085	0.384
COX5B	protein	P10606	UNIPROT	Cell_cycle_exit	phenotype	SIGNOR-PH41	SIGNOR	down-regulates				10090	BTO:0000165								18701479	f		lperfetto	Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS.|R-cadherin expression inhibits myoblast cell cycle exit	SIGNOR-253105	0.7
PTPN1	protein	P18031	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates activity	dephosphorylation	Tyr421	RLPSSPVyEDAASFK	9606									27824079	t		lperfetto	We conclude that Mena INV promotes invadopodium maturation by inhibiting normal dephosphorylation of cortactin at tyrosine 421 by the phosphatase PTP1B.	SIGNOR-277027	0.532
MAP4K1	protein	Q92918	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates				9606									8824585	f		gcesareni	These results demonstrated that the observed jnk1 activation was from hpk1 and not from other hpkl-associated kinases or from cross-reactive kinases precipitated by anti-hpk1 antibody.	SIGNOR-43999	0.325
KAT2A	protein	Q92830	UNIPROT	SLC44A2	protein	Q8IWA5	UNIPROT	up-regulates quantity				9606	BTO:0003065								21367571	f		lperfetto	Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it 	SIGNOR-260408	0.2
CSNK2A1	protein	P68400	UNIPROT	FOSB	protein	P53539	UNIPROT	up-regulates	phosphorylation	Ser27	SAESQYLsSVDSFGS	9606									17241283	t		lperfetto	Our findings indicate that ck2 activation increases deltafosb's transactivation potential, while ck2 inhibition decreases it. Further, we show that preventing ser27 phosphorylation by mutating the site to ala results in a significant decrease in deltafosb transactivation	SIGNOR-152403	0.2
LCMT1	protein	Q9UIC8	UNIPROT	PPP2CA	protein	P67775	UNIPROT	up-regulates activity	methylation	Leu309	RRTPDYFl	-1									18394995	t		lperfetto	Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1)	SIGNOR-265749	0.906
GSK3B	protein	P49841	UNIPROT	SCN2A	protein	Q99250	UNIPROT	down-regulates activity	phosphorylation	Thr1966	TPEKTDMtPSTTSPP	9606	BTO:0000938								32599005	t		lperfetto	Glycogen synthase kinase 3β (GSK3beta) phosphorylates the Nav1.2C-terminal tail at T1966, suppressing Na+ currents and channel trafficking to the plasma membrane	SIGNOR-275748	0.2
3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one	chemical	CHEBI:91346	ChEBI	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	chemical inhibition												25309440	t	inferred from 70% of family members	lperfetto	Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway.	SIGNOR-269849	0.8
COL4A2	protein	P08572	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	up-regulates activity	binding			9606	BTO:0000664								12123670	t		lperfetto	We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1.	SIGNOR-253243	0.468
TSPO2	protein	Q5TGU0	UNIPROT	SLC25A4	protein	P12235	UNIPROT	up-regulates activity	binding			9606	BTO:0000424								30061676	t		miannu	Our results demonstrate the existence of a VDAC-TSPO2-ANT complex that mediates ATP release from RBCs. We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transport complex in human red blood cells (RBCs). . The present results show that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by a supramolecular complex involving VDAC, TSPO2 and ANT.	SIGNOR-261825	0.282
CSF1	protein	P09603	UNIPROT	CSF2RA	protein	P15509	UNIPROT	up-regulates	binding			9606									10572088	t		gcesareni	Granulocyte-macrophage colony-stimulating factor (gm-csf) is an important hematopoietic cytokine that exerts its effects by interaction with the gm-csf receptor (gmr) on the surface of responsive cells. The gm-csf receptor consists of two subunits: gmralpha, which binds gm-csf with low affinity, and gmrbeta, which lacks intrinsic ligand-binding capability but complexes with gmralpha to form a high-affinity receptor (gmralpha/beta).	SIGNOR-72455	0.344
malonyl-CoA	smallmolecule	CHEBI:15531	ChEBI	CPT1A	protein	P50416	UNIPROT	down-regulates activity	binding			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267114	0.8
EEF1A1P5	protein	Q5VTE0	UNIPROT	Gly-tRNA(Gly)	smallmolecule	CHEBI:29156	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269561	0.8
PTPN1	protein	P18031	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates activity	dephosphorylation	Tyr487	SLSNIDFyAQVSDIT	10029									12907755	t			PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 	SIGNOR-248419	0.478
AREG	protein	P15514	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates	phosphorylation			9606									7679104	t		gcesareni	Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor	SIGNOR-31199	0.614
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	FBXO32	protein	Q969P5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									18612045	t		areggio	These findings present new insights into the role of the GR and FOXO family of transcription factors in the transcriptional regulation of the MuRF1 gene, a direct target of the GR in skeletal muscle.	SIGNOR-254991	0.2
SLC46A1	protein	Q96NT5	UNIPROT	dihydrofolate(2-)	smallmolecule	CHEBI:57451	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000575								17129779	t		lperfetto	However, the current study establishes that a major function of this gene product is proton-coupled folate transport required for folate homeostasis in man, and we have thus amended the name to PCFT/HCP1.	SIGNOR-268264	0.8
1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone	chemical	CHEBI:93753	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192601	0.8
LYN	protein	P07948	UNIPROT	HCLS1	protein	P14317	UNIPROT	up-regulates activity	phosphorylation	Tyr378	EPEPENDyEDVEEMD	9606									9104825	t			Lyn and Syk synergistically phosphorylate HS1, and that Tyr-378 and Tyr-397 of HS1 are the critical residues for its BCR-induced phosphorylation. tyrosine phosphorylation of HS1 is required for BCR-induced apoptosis and nuclear translocation of HS1 may be a prerequisite for B cell apoptosis. PMID: 9104825 PMCID: PMC2196252	SIGNOR-251400	0.702
AURKA	protein	O14965	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser98	RSSSGYFsFDTDRSP	9606	BTO:0002181								23912711	t		miannu	 We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL. 	SIGNOR-276246	0.384
metaproterenol	chemical	CHEBI:6792	ChEBI	ADRB3	protein	P13945	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)	SIGNOR-257874	0.8
ABL1	protein	P00519	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000938								22590567	t	inferred from 70% of family members	llicata	We demonstrate that c-abl kinase phosphorylates mst2 at an evolutionarily conserved site, y81, within the kinase domain. We further show that the phosphorylation of mst2 by c-abl leads to the disruption of the interaction with raf-1 proteins and the enhancement of homodimerization of mst2 proteins. It thereby enhances the mst2 activation and induces neuronal cell death.	SIGNOR-269946	0.348
PTGER1	protein	P34995	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257278	0.265
TIMM17A	protein	Q99595	UNIPROT	TIM23 complex	complex	SIGNOR-C423	SIGNOR	form complex	binding												32074073	t		lperfetto	The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE.	SIGNOR-267695	0.702
GPR183	protein	P32249	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256858	0.406
CAMK2A	protein	Q9UQM7	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Ser1120	QPLNPAPsRDPHYQD	9606	BTO:0000007								10347170	t		llicata	 We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. 	SIGNOR-250623	0.378
PRKACG	protein	P22612	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser304	SLLKKRDsFRTPRDS	9606		BTO:0000887							20151718	t		miannu	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163792	0.278
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PDE4C	protein	Q08493	UNIPROT	up-regulates activity	phosphorylation	Ser14	GEGAEACsRLSRSRG	9534									12023945	t		miannu	Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms.	SIGNOR-275987	0.2
PRKCA	protein	P17252	UNIPROT	IQGAP1	protein	P46940	UNIPROT	up-regulates	phosphorylation	Ser1443	DKMKKSKsVKEDSNL	9606									15355962	t		gcesareni	Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth.	SIGNOR-128714	0.261
MAPK1	protein	P28482	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Ser447	GSPRTPVsPVKFSPG	9606									7545671	t		gcesareni	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-28800	0.578
NCF1	protein	P14598	UNIPROT	CYBA	protein	P13498	UNIPROT	up-regulates activity	binding			9606									12672956	t		miannu	Stimulus-induced phosphorylation of p47phox causes a conformational change, by which both PX and SH3 domains become accessible to their membranous targets, phosphoinositides and p22phox, respectively. Cooperation of these two interactions, each being indispensable, enables p47phox to form a stable complex with cytochrome b558 (composed of the two subunit gp91phox and p22phox), leading to activation of the phagocyte NADPH oxidase.	SIGNOR-276625	0.783
PRKDC	protein	P78527	UNIPROT	MCC	protein	P23508	UNIPROT	up-regulates activity	phosphorylation	Ser118	SELRSELsQSQHEVN	9606	BTO:0001109								21779472	t		miannu	MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. 	SIGNOR-273530	0.2
POU4F2	protein	Q12837	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates activity	binding			9606	BTO:0000093								9448000	t	2	miannu	the POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect.	SIGNOR-241208	0.552
MMP25	protein	Q9NPA2	UNIPROT	MMP2	protein	P08253	UNIPROT	up-regulates activity	cleavage	Asn109	CGNPDVAnYNFFPRK	-1									14583471	t		miannu	Direct activation of pro-matrix metalloproteinase-2 by leukolysin/membrane-type 6 matrix metalloproteinase/matrix metalloproteinase 25 at the asn(109)-Tyr bond. Leukolysin Cleaves ProMMP-2 at Asn66-Leu and Asn109-Tyr.	SIGNOR-256345	0.383
RHOA	protein	P61586	UNIPROT	ROCK1	protein	Q13464	UNIPROT	up-regulates activity	binding			9606									23151663	t		gcesareni	Planar cell polarity (pcp) signalling triggers activation of the small gtpases rhoa and rac1, which in turn activate rho kinase (rock) and jun-n-terminal kinase (jnk), respectively, leading to actin polymerization and microtubule stabilization.	SIGNOR-199542	0.804
IRAK1	protein	P51617	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Thr80	DQHSISYtLSRAQTV	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276138	0.758
hexestrol	chemical	CHEBI:31669	ChEBI	AKR1C2	protein	P52895	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193300	0.8
oxybutynin	chemical	CHEBI:7856	ChEBI	CHRM2	protein	P08172	UNIPROT	down-regulates activity	chemical inhibition			10030	BTO:0000246								22243489	t		Luana	 Compared to the reference compound oxybutynin, an antagonist used for the treatment of OAB,(5) the newly synthesized 1,4-dioxane derivatives exhibit a higher potency.	SIGNOR-258329	0.8
SREBF2	protein	Q12772	UNIPROT	PCSK9	protein	Q8NBP7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17921436	t		miannu	 Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9.	SIGNOR-255223	0.48
NR3C1	protein	P04150	UNIPROT	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity	transcriptional regulation			9606									26652733	t	inferred from family member		Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-267792	0.2
FLT4	protein	P35916	UNIPROT	SHC1	protein	P29353	UNIPROT	unknown	phosphorylation	Tyr349	EEPPDHQyYNDFPGK	9606									9927207	t		llicata	We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites.	SIGNOR-64186	0.574
SP3	protein	Q02447	UNIPROT	IFITM5	protein	A6NNB3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23530031	f	 	miannu	Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation.	SIGNOR-254220	0.2
NEUROG3	protein	Q9Y4Z2	UNIPROT	INSM1	protein	Q01101	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000944								17300785	f		miannu	 The ngn3/E47 heterodimer selectively binds and activates the E-box3 of the INSM1 promoter. The endogenous ngn3 and CREB-binding protein (CBP) co-activator occupy the INSM1 promoter, resulting in hyper-acetylation of histone H3/H4 chromatin in a human neuroblastoma cell line, IMR-32.	SIGNOR-253814	0.58
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	KDM4C	protein	Q9H3R0	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273474	0.8
UNC80	protein	Q8N2C7	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								19535918	t		miannu	UNC80 is a protein that is associated with the NALCN Na(+) leak cation channel, and is required for the activation of this channel by the neuropeptide substance P through GPCRs in a G-protein-independent fashion. Here, we show that UNC80 binds Src kinases and recruits Src into the channel complex. 	SIGNOR-265179	0.359
TFEB	protein	P19484	UNIPROT	CYP7A1	protein	P22680	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2)	SIGNOR-276787	0.2
LYN	protein	P07948	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates activity	phosphorylation	Tyr783	EGRNPGFyVEANPMP	-1									7682059	t		lperfetto	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249382	0.642
PAK5	protein	Q9P286	UNIPROT	PACSIN1	protein	Q9BY11	UNIPROT	up-regulates activity	phosphorylation	Ser346	SQAGDRGsVSSYDRG	-1									22371566	t		miannu	We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. 	SIGNOR-263025	0.2
PRKD1	protein	Q15139	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	unknown	phosphorylation	Ser358	WPLSRTRsEPLPPSA	-1									15738054	t		lperfetto	We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro.	SIGNOR-249274	0.492
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	SLC2A4	protein	P14672	UNIPROT	up-regulates				9606									8940145	f	Translocation from intracellular compartment to cell surface in muscle and adipose tissue	gcesareni	The constitutively active Akt induced glucose uptake into adipocytes in the absence of insulin by stimulating translocation of the insulin-responsive glucose transporter 4 to the plasma membrane.	SIGNOR-45117	0.2
PRKAR1A	protein	P10644	UNIPROT	PRKACB	protein	P22694	UNIPROT	down-regulates activity	binding			9606									26687711	t			Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 	SIGNOR-258755	0.858
DISC1	protein	Q9NRI5	UNIPROT	NDEL1	protein	Q9GZM8	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								17202468	t		miannu	Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3ε. 14-3-3ε is involved in the proper localization of NUDEL and LIS1 in axons. the association with NUDEL and LIS1 supports the notion that DISC1 contributes to the neuronal development and morphology 	SIGNOR-252162	0.6
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	HMOX1	protein	P09601	UNIPROT	unknown	phosphorylation	Ser188	LYRSRMNsLEMTPAV	9606	BTO:0000007								15581622	t		llicata	We have identified a putative consensus sequence for phosphorylation by akt/pkb of ho-1 at ser188. although the changes in activity are small, this study provides the first evidence for a role of the survival kinase akt in the regulation of ho-1.	SIGNOR-161283	0.2
CDH11	protein	P55287	UNIPROT	CTNNB1	protein	P35222	UNIPROT	unknown	binding			9606	BTO:0000150								10029089	t		miannu	Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin	SIGNOR-64862	0.639
MAX	protein	P61244	UNIPROT	MXI1	protein	P50539	UNIPROT	up-regulates activity	binding			9606									7954804	t	2	miannu	The role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences.	SIGNOR-240314	0.575
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000150								10931950	t	inferred from 70% family members	gcesareni	These data suggest that increased signaling by erbb receptors up-regulates mapk activity, which, in turn, phosphorylates and destabilizes p27, thus contributing to dysregulated cell cycle progression.	SIGNOR-270087	0.2
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	EIF4B	protein	P23588	UNIPROT	up-regulates activity	phosphorylation	Ser422	RERSRTGsESSQTGT	9606	BTO:0001109								36882522	t		lperfetto	CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. 	SIGNOR-273116	0.279
PRKCB	protein	P05771	UNIPROT	SLC6A9	protein	P48067-2	UNIPROT	down-regulates activity	phosphorylation	Ser625	PIVGSNGsSRLQDSR	9823									21864610	t		miannu	We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 	SIGNOR-262924	0.2
CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	RC3H2	protein	Q9HBD1	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			9606									31320642	t		lperfetto	In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins	SIGNOR-268353	0.321
CSNK2A1	protein	P68400	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates	phosphorylation	Thr291	EDEESYDtESEFTEF	9606	BTO:0000782								8622692	t		llicata	Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation.	SIGNOR-40514	0.566
CDK1	protein	P06493	UNIPROT	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr199	VKKSIRDtPAKNAQK	9606			SIGNOR-C17						12058066	t		llicata	However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation.	SIGNOR-89605	0.534
ABL1	protein	P00519	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity	phosphorylation	Tyr102	YDLKLQEyQSAIKVE	10090	BTO:0000007;BTO:0000011								25368164	t			We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ.	SIGNOR-262297	0.347
KLF15	protein	Q9UIH9	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates	transcriptional regulation			10090	BTO:0002572								20956975	f		lperfetto	Our results provide a new mechanism for understanding glucocorticoids-dependent adipogenesis and that GR promotes adipogenesis via KLF15 gene expression as a transcriptional direct target.	SIGNOR-236230	0.7
β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	beta-D-fructofuranose 2,6-bisphosphate	smallmolecule	CHEBI:28602	ChEBI	up-regulates quantity	precursor of			9606									15170386	t			Fru-2,6-P2 (fructose 2,6-bisphosphate) is a signal molecule that controls glycolysis. Since its discovery more than 20 years ago, inroads have been made towards the understanding of the structure‚Äì function relationships in PFK-2 (6-phosphofructo-2-kinase)/ FBPase-2 (fructose-2,6-bisphosphatase), the homodimeric bifunctional enzyme that catalyses the synthesis and degradation of Fru-2,6-P2	SIGNOR-267265	0.8
ROCK1	protein	Q13464	UNIPROT	ARHGAP24	protein	Q8N264	UNIPROT	up-regulates activity	phosphorylation	Ser415	HKLDVSRsPPLMVKK	9606									16862148	t		lperfetto	ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS‚‚PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573‚‚577 (see Supplementary Information, Table S2).	SIGNOR-249307	0.444
MYF5	protein	P13349	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates activity						BTO:0001103							17495111	f		Simone Vumbaca	In summary, the absence of Myf5 clearly reduced the initial expansion of satellite cell-derived transient amplifying cells and resulted in a shift of the ratio of satellite cell subpopulations but did not affect the specification and generation of specific subpopulations of satellite cell-derived cells such as reserve cells, amplifying cells, and differentiating mature myogenic cells.	SIGNOR-255643	0.7
NR3C1	protein	P04150	UNIPROT	ATP1B1	protein	P05026	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									9694812	t		miannu	 Together these data indicate that the 21-base pair sequence represents a true MRE/GRE and that optimal activation of the human Na/K-ATPase beta1 promoter is controlled by mineralocorticoid and glucocorticoid hormones. It appears that an interaction of MR with GR on the beta1 promoter effectively down-regulates transcription.	SIGNOR-254864	0.2
ALDOC	protein	P09972	UNIPROT	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266481	0.8
HCK	protein	P08631	UNIPROT	CBL	protein	P22681	UNIPROT	unknown	phosphorylation			10090									10092522	t			Hck is one member of the Src-family PTKs that is able to phosphorylate Cbl. Upon enzymatic activation of Hck either by pharmacological agents or genetic mutation, Cbl becomes tyrosine phosphorylated. 	SIGNOR-251262	0.653
FLT3	protein	P36888	UNIPROT	FZD4	protein	Q9ULV1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002882								15650056	f			AML-typical Flt3 mutations induce the expression of Frizzled-4 on the mRNA and protein level, mimicking the effects of IL-3.	SIGNOR-261533	0.2
CSNK2A1	protein	P68400	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	unknown	phosphorylation	Ser231	KERDKEVsDDEAEEK	9606	BTO:0000567								2492519	t		llicata	Both hsp 90 proteins are phosphorylated at two homologous sites. For the alpha protein, these sites correspond to serine 231 and serine 263. | Dephosphorylated hsp 90 is phosphorylated at both sites by casein kinase II from HeLa cells, calf thymus, or rabbit reticulocytes; no other hsp 90 residues were phosphorylated by casein kinase II in vitro.	SIGNOR-250899	0.547
NMBR	protein	P28336	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606									8026589	t		fspada	G-proteins of the q family have been implicated as mediators of bombesin receptors action. This suggests that nmb-r couples to g?q, and that grp-r and nmb-r show distinct g-protein coupling preferences in the xenopus oocyte.	SIGNOR-35864	0.448
1D-myo-inositol 1,4,5-trisphosphate	smallmolecule	CHEBI:16595	ChEBI	ITPR1	protein	Q14643	UNIPROT	up-regulates activity	chemical activation			9606									24646566	t		miannu	The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell.	SIGNOR-256239	0.8
PPARG	protein	P37231	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20303941	f		gcesareni	The results from mammalian one-hybrid experiments showed that functional ppar gamma was necessary for ligand-dependent inhibition of beta-catenin transactivation.	SIGNOR-164516	0.555
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Ser122	DQHLMKCsPAQLLCS	9606									10864927	t		lperfetto	Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b.	SIGNOR-216741	0.839
N-(2-(4-(7-Methoxy-1-naphthalenyl)-1-piperazinyl)ethyl)-2-thiophenecarboxamide	chemical	CID:131907	PUBCHEM	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258866	0.8
alvocidib	chemical	CHEBI:47344	ChEBI	CDK2	protein	P24941	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258171	0.8
GALR3	protein	O60755	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256719	0.425
CSNK2A1	protein	P68400	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates	phosphorylation	Thr387	LPWDLWTtSTDLVQP	9606	BTO:0000567								16945112	t		lperfetto	Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin.	SIGNOR-149318	0.2
ERBB3	protein	P21860	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									16729043	t		gcesareni	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-252673	0.708
NDUFS7	protein	O75251	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46].	SIGNOR-262181	0.857
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	HK2	protein	P52789	UNIPROT	up-regulates activity	phosphorylation	Thr473	QHRARQKtLEHLQLS	9606	BTO:0003324								25323588	t		miannu	Hexokinase II is phosphorylated by Akt leading to increased mitochondrial binding and mitochondrial protection.We found that Akt, activated by receptor agonists, translocates to mitochondria and phosphorylates HK-II at Thr473, a critical step in Akt-mediated mitoHK-II increase and protection in cardiomyocytes	SIGNOR-267576	0.2
ADSS1	protein	Q8N142	UNIPROT	IMP	smallmolecule	CHEBI:17202	ChEBI	down-regulates quantity	chemical modification			9606									10496970	t		miannu	Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 	SIGNOR-267344	0.8
PTBP1	protein	P26599	UNIPROT	Alternative_Splicing_Regulation	phenotype	SIGNOR-PH204	SIGNOR	up-regulates				9606									20010808	f			We show that three heterogeneous nuclear ribonucleoprotein (hnRNP) proteins, polypyrimidine tract binding protein (PTB, also known as hnRNPI), hnRNPA1 and hnRNPA2, bind repressively to sequences flanking exon 9, resulting in exon 10 inclusion.	SIGNOR-268688	0.7
UVRAG	protein	Q9P2Y5	UNIPROT	Vps34 Complex II	complex	SIGNOR-C241	SIGNOR	form complex	binding			-1									30397185	t		lperfetto	PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively.	SIGNOR-260322	0.815
atropine	chemical	CHEBI:16684	ChEBI	CHRM5	protein	P08912	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								2704370	t		miannu	In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 	SIGNOR-258393	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CCR3	protein	P51677	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16604092	f		miannu	Rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling.	SIGNOR-254660	0.261
MRPL57	protein	Q9BQC6	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262341	0.618
SRC	protein	P12931	UNIPROT	GRK2	protein	P25098	UNIPROT	up-regulates activity	phosphorylation	Tyr92	FYEEIKKyEKLETEE	9606	BTO:0000007								16725308	t		miannu	Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq. 	SIGNOR-266305	0.2
NRG3	protein	P56975	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606		BTO:0000887							9275162	t		gcesareni	The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4.	SIGNOR-50614	0.738
CDK2	protein	P24941	UNIPROT	LIG1	protein	P18858	UNIPROT	up-regulates activity	phosphorylation	Ser76	EEEDEALsPAKGQKP	9606	BTO:0000567								12851383	t		lperfetto	We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner.	SIGNOR-103250	0.468
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	EP300	protein	Q09472	UNIPROT	up-regulates	phosphorylation	Ser2279	PVQPNPMsPQQHMLP	9606									17623675	t		lperfetto	Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo.	SIGNOR-244533	0.2
PHF3	protein	Q92576	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	down-regulates activity	binding			9606	BTO:0000007								34667177	t		miannu	PHF3 interacts with RNA polymerase II through the SPOC domain. PHF3 negatively regulates mRNA levels. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay. PHF3 SPOC preferentially binds RNA Pol II CTD phosphorylated on Serine-2	SIGNOR-266964	0.346
RPS6KA1	protein	Q15418	UNIPROT	MITF	protein	O75030	UNIPROT	down-regulates	phosphorylation	Ser409	HGLSLIPsTGLCSPD	9606									21749389	t	The effect has been demonstrated using O75030-9	gcesareni	The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert.	SIGNOR-174760	0.419
ADSS2	protein	P30520	UNIPROT	GDP	smallmolecule	CHEBI:17552	ChEBI	up-regulates quantity	chemical modification			9606									10496970	t		miannu	Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 	SIGNOR-267349	0.8
CSNK2A1	protein	P68400	UNIPROT	EIF5	protein	P55010	UNIPROT	up-regulates	phosphorylation	Ser389	LKEAEEEsSGGEEED	9606									18649047	t		gcesareni	We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2.	SIGNOR-179542	0.402
SMARCC2	protein	Q8TAQ2	UNIPROT	Brain-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C486	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270754	0.843
SMO	protein	Q99835	UNIPROT	GNAT2	protein	P19087	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-199171	0.264
KDM4B	protein	O94953	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									30759871	t		miannu	The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. The majority of studies regarding its function describe it as an activator that removes repressive H3K9me3 and H3K9me2 at or near regulated promoters in order to facilitate expression of the indicated pathways. 	SIGNOR-263734	0.2
PRKCD	protein	Q05655	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser715	GYRQDDPsYRSFHSG	9606									25639486	t		Manara	 Moreover, protein kinase Cδ, which directly phosphorylates β-catenin at Ser715, is required for the TRIM33–β-catenin interaction. | Phosphorylation of β-catenin Ser715 is critical for TRIM33-induced β-catenin degradation	SIGNOR-260897	0.273
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	CHKB	protein	Q9Y259	UNIPROT	up-regulates activity	phosphorylation	Ser39	TPKRRRAsSLSRDAE										27149373	t		lperfetto	Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. 	SIGNOR-275632	0.2
LAMA1	protein	P25391	UNIPROT	Laminin-1	complex	SIGNOR-C183	SIGNOR	form complex	binding												7496033	t		lperfetto	Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1.	SIGNOR-253232	0.549
RPS6KA5	protein	O75582	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser118	GRELRRMsDEFVDSF										12213813	t		lperfetto	Phosphorylation of Bad at Ser112 in response to growth factors or cytokines is generally linked to cell survival. Knockdown of MSK1 suppressed Bad phosphorylation after calcium ionophore A23187 treatment in neuronal cells	SIGNOR-262990	0.35
KAT2B	protein	Q92831	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	acetylation			9606			SIGNOR-C465						34811519	t		lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269610	0.2
NOTCH1	protein	P46531	UNIPROT	FABP7	protein	O15540	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16554461	f		gcesareni	Here we demonstrate that neuronal induction of radial glia formation is the result of sequential signaling through notch1 and erbb receptors. First, notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (blbp) and erbb2 genes.	SIGNOR-145365	0.529
RUNX3	protein	Q13761	UNIPROT	CASP2	protein	P42575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002384								17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255094	0.2
D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	5-phospho-α-D-ribose 1-diphosphate	smallmolecule	CHEBI:58017	ChEBI	up-regulates quantity	precursor of			9606									16939420	t		miannu	PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP.	SIGNOR-267077	0.8
PTPA	protein	Q15257	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606									21159657	t		gcesareni	Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473)	SIGNOR-252607	0.2
MRPS7	protein	Q9Y2R9	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-267730	0.753
CHD8	protein	Q9HCK8	UNIPROT	SOX3	protein	P41225	UNIPROT	down-regulates quantity	transcriptional regulation			10090									32839322	t		Gianni	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268920	0.2
mTORC1	complex	SIGNOR-C3	SIGNOR	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression				10090									19593385	f		lperfetto	Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master transcriptional regulator of adipocyte differentiation.	SIGNOR-235343	0.427
CDK5	protein	Q00535	UNIPROT	AMPH	protein	P49418	UNIPROT	unknown	phosphorylation	Ser276	PLPSPTAsPNHTLAP	-1									11113134	t		llicata	Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. 	SIGNOR-250649	0.537
KRAS	protein	P01116	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									21779497	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism.	SIGNOR-252698	0.729
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1654	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-119366	0.316
TRAF2	protein	Q12933	UNIPROT	UBE2N	protein	P61088	UNIPROT	up-regulates activity	binding			9606	BTO:0000459								18635759	t		lperfetto	Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades.	SIGNOR-179479	0.439
LCK	protein	P06239	UNIPROT	CCDC50	protein	Q8IVM0	UNIPROT	down-regulates activity	phosphorylation	Tyr217	MAEEKKAyKKAKERE	9606									19059208	t		miannu	We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling.	SIGNOR-262853	0.2
EGFR	protein	P00533	UNIPROT	NCK1	protein	P16333	UNIPROT	up-regulates				9606									9362449	f	Nck interacts witn ErbB1 through SH2 and SH3 domains	gcesareni	We found that nck does not directly bind to egf receptor, instead it binds via its sh2 domain to a 62 kda phosphotyrosine protein	SIGNOR-52954	0.592
SRC	protein	P12931	UNIPROT	CHKA	protein	P35790	UNIPROT	up-regulates activity	phosphorylation	Tyr197	RSLGPKLyGIFPQGR	9606	BTO:0000093								21822308	t		miannu	We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333.	SIGNOR-266351	0.343
ELOVL5	protein	Q9NYP7	UNIPROT	palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	down-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267891	0.8
ACP1	protein	P24666	UNIPROT	AKT2	protein	P31751	UNIPROT	down-regulates activity	dephosphorylation	Ser474	RTHFPQFsYSASIRE	10090									17353188	t			Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3	SIGNOR-248456	0.2
PPP2CB	protein	P62714	UNIPROT	CHEK1	protein	O14757	UNIPROT	down-regulates activity	dephosphorylation	Ser345	LVQGISFsQPTCPDH	9606									17015476	t			Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo.	SIGNOR-248578	0.269
LAMB1	protein	P07942	UNIPROT	Laminin-8	complex	SIGNOR-C181	SIGNOR	form complex	binding												10809728	t		lperfetto	Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. 	SIGNOR-253227	0.6
IRAK1	protein	P51617	UNIPROT	PELI3	protein	Q8N2H9	UNIPROT	up-regulates	phosphorylation			9606									12874243	t		gcesareni	Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity.	SIGNOR-103983	0.717
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates	phosphorylation	Tyr317	TEQDLQLyCDFPNII	9606	BTO:0000007								19364823	t	16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling.	lperfetto	Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2.	SIGNOR-236502	0.2
mepyramine	chemical	CHEBI:6762	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7925364	t		miannu	The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum.	SIGNOR-258748	0.8
CCKBR	protein	P32239	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257238	0.256
TOP2B	protein	Q02880	UNIPROT	DAB1	protein	O75553	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24463367	f		lperfetto	While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development	SIGNOR-242210	0.2
NMDA receptor_2D	complex	SIGNOR-C350	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264135	0.7
CDK9	protein	P50750	UNIPROT	NCOA2	protein	Q15596	UNIPROT	up-regulates activity	phosphorylation	Ser469	NYALKMNsPSQSSPG	9606	BTO:0000801								29170386	t			Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties.	SIGNOR-256096	0.248
DERA	protein	Q9Y315	UNIPROT	acetaldehyde	smallmolecule	CHEBI:15343	ChEBI	up-regulates quantity	chemical modification			9606									25229427	t		miannu	Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase.	SIGNOR-267099	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BCL2	protein	P10415	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser70	RDPVARTsPLQTPAA	9534	BTO:0004055								10677502	t		lperfetto	Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70.	SIGNOR-244501	0.2
lenalidomide	chemical	CHEBI:63791	ChEBI	IKZF3	protein	Q9UKT9	UNIPROT	down-regulates quantity by destabilization	chemical inhibition			9606									24328678	t		gcesareni	Members of the Ikaros family of transcription factors, specifically Ikaros and Aiolos (encoded by the genes IKZF1 and IKZF3 respectively), are recruited as protein substrates for CRL4CRBN in T cells in response to lenalidomide or pomalidomide treatment.	SIGNOR-236925	0.8
ATP1A3	protein	P13637	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	up-regulates quantity	relocalization			9606									22797008	t		miannu	The sodium/potassium transporting ATPase subunit alpha-3 (AT1A3; syn.: sodium pump subunit alpha-3; E.C. 3.6.3.9; UniProtKB ID: Q6PIC6) belongs to the cation transport ATPase (P-type) 3.A.3 family catalyzing hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action generates the electrochemical gradient of sodium and potassium ions thus providing energy for active transport of various nutrients. Three sodium/potassium transporting ATPase isoforms are expressed in the brain but AT1A3 is detectable in neurons exclusively.	SIGNOR-265793	0.8
WEE1	protein	P30291	UNIPROT	ERG	protein	P11308	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr183	FQRLTPSyNADILLS	9606	BTO:0001033								32871104	t		miannu	Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3β and WEE1, respectively.	SIGNOR-277529	0.2
LYPLA2	protein	O95372	UNIPROT	GAP43	protein	P17677	UNIPROT	down-regulates quantity by destabilization	deacetylation	Cys4	cMRRTKQV	9606	BTO:0000567								21152083	t		miannu	Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution.we demonstrated that the reduction in the protein level was abrogated when cells were also treated with proteasome inhibitors (chloroquine, MG132 and lactacystin) which strongly suggest that GAP-43 deacylation is an early and necessary step for its later ubiquitination and degradation by the proteasome. In addition, it also suggests that acyl-protein thioesterase levels not only regulate palmitate turnover but also global protein turnover of GAP-43.	SIGNOR-266768	0.455
PIM1	protein	P11309	UNIPROT	HBP1	protein	O60381	UNIPROT	up-regulates activity	phosphorylation	Ser380	MARQRRAsLSCGGPG	9606	BTO:0002181								28348080	t		miannu	 Pim-1 binds to and phosphorylates the transcription factor high mobility group box transcription factor 1 (HBP1), activating it.	SIGNOR-277347	0.2
LCK	protein	P06239	UNIPROT	CCDC50	protein	Q8IVM0	UNIPROT	down-regulates activity	phosphorylation	Tyr279	TDGEDADyTHFTNQQ	9606	BTO:0000567								19059208	t		miannu	We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling.	SIGNOR-262854	0.2
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	MAPK3	protein	P27361	UNIPROT	up-regulates activity	phosphorylation			10090									11730323	t			Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs	SIGNOR-258991	0.2
CDC7	protein	O00311	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates	phosphorylation	Ser139	RRGLLYDsDEEDEER	9606	BTO:0000567								16899510	t		gcesareni	In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells.	SIGNOR-148709	0.961
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	TSC2	protein	P49815	UNIPROT	down-regulates	phosphorylation	Ser664	KKTSGPLsPPTGPPG	9606									15851026	t		lperfetto	Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. s664 is the primary erk phosphorylation site on tsc2 in vitro and in vivo	SIGNOR-244765	0.2
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	JUN	protein	P05412	UNIPROT	up-regulates	dephosphorylation	Ser243	PGETPPLsPIDMESQ	9606	BTO:0000938;BTO:0000017								17215518	t		lperfetto	Importantly, pp2b not only dephosphorylates the c-jun at ser-243 but also interacts with c-jun in pma-treated cells. Pma stimulates the association of the pp2b/c-jun/sp1 complex with the promoter. These findings indicate the dephosphorylation of c-jun c terminus is required for the c-jun/sp1 interaction	SIGNOR-152006	0.2
bremazocine	chemical	CHEBI:3171	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258777	0.8
DLGAP1	protein	O14490	UNIPROT	SHANK2	protein	Q9UPX8	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264587	0.82
DYRK2	protein	Q92630	UNIPROT	KATNA1	protein	O75449	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser42	QMNKYLYsVKDTYLQ	9606	BTO:0000007								19287380	t		miannu	DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d). 	SIGNOR-262848	0.524
TAOK1	protein	Q7L7X3	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	up-regulates	phosphorylation			9606									23431053	t	inferred from 70% of family members	gcesareni	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.	SIGNOR-269938	0.378
SLC2A4	protein	P14672	UNIPROT	glucose	chemical	CHEBI:17234	ChEBI	up-regulates quantity	relocalization			9606									17403369	t			Skeletal muscle both stores glucose as glycogen and oxidizes it to produce energy following the transport step. The principal glucose transporter protein that mediates this uptake is GLUT4, which plays a key role in regulating whole body glucose homeostasis	SIGNOR-267288	0.8
MYC	protein	P01106	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606		BTO:0001103							21408055	f		andrea cerquone perpetuini	We have demonstrated that following muscle damage, phosphorylated STAT3 (p-STAT3) in SCs increases early (within one hour), inducing downstream target genes (i.e. GP130 and SOCS3), which further regulate the increase in STAT3 production and response (as induced via IL-6), leading to increased cMyc expression, which drives cell proliferation	SIGNOR-255414	0.7
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates activity	phosphorylation	Ser162	FDIVSRGsTADLDGL	-1									19661060	t		miannu	 We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.	SIGNOR-276232	0.2
CHMP7	protein	Q8WUX9	UNIPROT	ESCRT-III	complex	SIGNOR-C379	SIGNOR	form complex	binding			-1									26775243	t		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission.	SIGNOR-265525	0.605
PRKCA	protein	P17252	UNIPROT	ADD2	protein	P35612	UNIPROT	down-regulates	phosphorylation	Ser713	KKKFRTPsFLKKSKK	9606									16116087	t		gcesareni	We now demonstrate that ptn stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (pk) c substrate domain of beta-adducin through activation of either pkc alpha or beta.	SIGNOR-139870	0.2
BMPR1A	protein	P36894	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates	phosphorylation	Ser463	SPHNPISsVS	9606									9136927	t		fspada	Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro	SIGNOR-210084	0.721
ESRRA	protein	P11474	UNIPROT	NR2F1	protein	P10589	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000155								15955695	f		miannu	 In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro.	SIGNOR-253795	0.248
UTP(4-)	smallmolecule	CHEBI:46398	ChEBI	UDP-alpha-D-glucose(2-)	chemical	CHEBI:58885	ChEBI	up-regulates quantity	precursor of			9606									8631325	t		miannu	UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi.	SIGNOR-267925	0.8
MARCHF9	protein	Q86YJ5	UNIPROT	PLXNC1	protein	O60486	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001522								19457934	t		miannu	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. 	SIGNOR-271532	0.2
CSNK1D	protein	P48730	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	phosphorylation	Ser403	ESTDSGLsMSSYSVP	9606							phosphorylation:Ser127	PQHVRAHsSPASLQL	23431053	t		milica	Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ	SIGNOR-201154	0.4
CYP27B1	protein	O15528	UNIPROT	calcidiol	smallmolecule	CHEBI:17933	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000671							12050193	t		lperfetto	The rate-limiting, hormonally regulated step in the biological activation of vitamin D is its 1alpha-hydroxylation to 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] in the kidney, catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha. 	SIGNOR-270560	0.8
TNC	protein	P24821	UNIPROT	A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								7559467	t		lperfetto	The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin.	SIGNOR-253306	0.414
FNIP2	protein	Q9P278	UNIPROT	HSP90AB1	protein	P08238	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								27353360	t		miannu	FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle. 	SIGNOR-261416	0.267
CSNK2A1	protein	P68400	UNIPROT	CORO1C	protein	Q9ULV4	UNIPROT	up-regulates	phosphorylation	Ser463	CNQDERIsKLEQQMA	9606									22355754	t		lperfetto	We demonstrate that crn2 is a binding partner and substrate of protein kinase ck2, which phosphorylates crn2 at s463 in its c-terminal coiled coil domain	SIGNOR-196193	0.2
MYLK	protein	Q15746	UNIPROT	MYL6B	protein	P14649	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000567	BTO:0000671							10092231	t		gcesareni	Cytoskeletal dynamics are primarily modulated by interactions of actin and myosin ii that are regulated by myosin light chain kinase (mlck)-mediated phosphorylation of the regulatory myosin light chain (mlc).	SIGNOR-65865	0.71
BMX	protein	P51813	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr577	YMEDSTYyKASKGKL	9606									23716717	t		llicata	Bmx phosphorylated focal adhesion kinase (fak) at tyr577 subsequent to its src-mediated phosphorylation at tyr576. Loss of bmx by rna interference or by genetic deletion in mouse embryonic fibroblasts (mefs) markedly impaired fak activity.	SIGNOR-202139	0.53
MAPK1	protein	P28482	UNIPROT	TH	protein	P07101	UNIPROT	up-regulates	phosphorylation	Ser62	SYTPTPRsPRFIGRR	9606									7901013	t	The effect has been demonstrated using P07101-2	gcesareni	Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylase in vitro at comparable rates to other proteins thought to be physiological substrates of these protein kinases.The effect on activity of phosphorylating both ser31 and ser40 was not additive. The possible roles of mapkap kinase-1, mapkap kinase-2 and map kinase in the regulation of tyrosine hydroxylase in vivo are discussed.	SIGNOR-34674	0.452
KANSL3	protein	Q9P2N6	UNIPROT	Chromosome_segregation	phenotype	SIGNOR-PH44	SIGNOR	up-regulates				9606	BTO:0000567								26243146	f		miannu	Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. 	SIGNOR-267171	0.7
NTF3	protein	P20783	UNIPROT	NTRK3	protein	Q16288	UNIPROT	up-regulates	binding			9606									1653651	t		gcesareni	Trkc, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3.	SIGNOR-20699	0.844
SMARCB1	protein	Q12824	UNIPROT	SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270607	0.814
CASP6	protein	P55212	UNIPROT	Caspase 6 complex	complex	SIGNOR-C228	SIGNOR	form complex	binding								cleavage:Asp193	DTNITEVdAASVYTL			21621544	t		lperfetto	It is generally recognized that effector caspases undergo proteolytic cleavage of the inactive zymogen at a specific aspartate residue, resulting in a large N-terminal p20 polypeptide chain and a small C-terminal p10 polypeptide chain, leading to a p202/p102 tetramer.	SIGNOR-256392	0.2
AKT1	protein	P31749	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation	Ser259	SQRQRSTsTPNVHMV	9606	BTO:0000150;BTO:0001130								16854453	t		gcesareni	Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity.	SIGNOR-147963	0.687
MARK1	protein	Q9P0L2	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser673	RVQSKIGsLDNITHV	9606									21215781	t	The effect has been demonstrated using P10636-8	lperfetto	Mark and pka phosphorylate several sites within the repeats (notably the kxgs motifs including ser262, ser324, and ser356, plus ser320)tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process	SIGNOR-171058	0.44
RZZ complex	complex	SIGNOR-C357	SIGNOR	DCTN2	protein	Q13561	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								20462495	t		lperfetto	ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores	SIGNOR-265017	0.436
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	MCM4	protein	P33991	UNIPROT	down-regulates	phosphorylation	Ser54	ELQPMPTsPGVDLQS	9606	BTO:0000567								12714602	t		lperfetto	We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a.	SIGNOR-217348	0.687
PHACTR1	protein	Q9C0D0	UNIPROT	PPP1CA	protein	P62136	UNIPROT	up-regulates activity	binding			9606	BTO:0001949								21939755	t		miannu	Phactr-1 was previously identified as protein phosphatase 1 (PP1) α-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process.	SIGNOR-260062	0.553
SGK1	protein	O00141	UNIPROT	NDRG1	protein	Q92597	UNIPROT	up-regulates	phosphorylation	Thr346	GTRSRSHtSEGTRSR	9606									18787837	t		llicata	Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1.	SIGNOR-180821	0.588
POLR2M	protein	P0CAP2	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606									9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266169	0.463
FGFR3	protein	P22607	UNIPROT	TET2	protein	Q6N021	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr1902	TRISLVFyQHKSMNE	9606	BTO:0000976								33097695	t		miannu	FGFR3∆7-9, but not wild-type FGFR3, directly interacts with TET2 and phosphorylates TET2 at Y1902 site, leading to the ubiquitination and proteasome-mediated degradation of TET2.	SIGNOR-277535	0.253
ZMYND8	protein	Q9ULU4	UNIPROT	NAV2	protein	Q8IVL1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								21620140	t		Luana	We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8. 	SIGNOR-266209	0.2
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT10A	protein	Q9GZT5	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242695	0.338
RIMBP3C	protein	A6NJZ7	UNIPROT	RIMS3	protein	Q9UJD0	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264372	0.267
ERBB2	protein	P04626	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	binding			9606									10085134	t		gcesareni	Shc interacts with and is an excellent substrate for erbb2 and appears to play an important role in mitogenic signaling through this receptor tyrosine kinase	SIGNOR-65579	0.799
CSNK2B	protein	P67870	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates activity	phosphorylation	Ser1124	LNTEEFSsESDMEES	9606	BTO:0000938								19064667	t		lperfetto	 We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275756	0.2
PDPK1	protein	O15530	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Thr308	KDGATMKtFCGTPEY	9606									15718470	t		gcesareni	Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase.	SIGNOR-243203	0.736
INO80C	protein	Q6PI98	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270851	0.641
RXRB	protein	P28702	UNIPROT	RAR	proteinfamily	SIGNOR-PF45	SIGNOR	up-regulates	binding			9606									1310351	t	inferred from 70% of family members	gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-269852	0.708
CDK1	protein	P06493	UNIPROT	NDUFS2	protein	O75306	UNIPROT	up-regulates activity	phosphorylation	Ser364	KVDDAKVsPPKRAEM										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275592	0.2
IL5RA	protein	Q01344	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation			9606									7602114	t			Jak 2 is physically associated with the IL-5b receptor. The binding of IL-5 to its receptor results in tyrosine phosphorylation and activation of Jak 2 tyrosine kinase within 1 to 3 min.	SIGNOR-254352	0.585
LRFN4	protein	Q6PJG9	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								21736948	t		miannu	 SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. One possibility is that SALM3, which is capable of inducing presynaptic differentiation in contacting axons [19], recruits PSD-95 or SAP102 to the sites of early synaptic adhesion.	SIGNOR-264096	0.67
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1861	TPTSPKYsPTSPKYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273080	0.636
HRAS	protein	P01112	UNIPROT	BRAF	protein	P15056	UNIPROT	up-regulates activity	binding			9606									21779497	t		lperfetto	The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.	SIGNOR-147327	0.873
DRD4	protein	P21917	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257098	0.282
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259001	0.474
BIRC3	protein	Q13489	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	binding			9606									9545235	t		gcesareni	Xiap, birc2 and birc3 were shown to bind pro-casp9. Iaps may suppress casp9 by direct auto-activation of pro-caspase-11	SIGNOR-56481	0.75
JAK1	protein	P23458	UNIPROT	STAT2	protein	P52630	UNIPROT	up-regulates activity	phosphorylation			9606									9020188	t		lperfetto	The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-?, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases.	SIGNOR-88285	0.76
VX-745	chemical	CHEBI:90528	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258310	0.8
TP53	protein	P04637	UNIPROT	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	down-regulates				9606									27692180	f		miannu	P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.	SIGNOR-267467	0.7
LBX1	protein	P52954	UNIPROT	SNAI1	protein	O95863	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002181								19651985	t		Luana	Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively 	SIGNOR-266053	0.326
SETD1B	protein	Q9UPS6	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606									32546566	t		miannu	SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks.	SIGNOR-265576	0.2
SYN3	protein	O14994	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates activity	binding			9606	BTO:0000938								15265865	t		miannu	Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. 	SIGNOR-269186	0.7
NR3C1	protein	P04150	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000011								10649448	f		gcesareni	The dose of DEX required to promote maximal expression of PPARg mRNA is approximately 10 nM, which is within the range of the Kd for the association of DEX with the glucocorticoid receptor in 3T3-L1 cells	SIGNOR-255753	0.401
HDAC5	protein	Q9UQL6	UNIPROT	MEF2A	protein	Q02078	UNIPROT	down-regulates	binding			9606									11062529	t		gcesareni	The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis.	SIGNOR-84023	0.694
MASP2	protein	O00187	UNIPROT	C2	protein	P06681	UNIPROT	up-regulates activity	cleavage	Arg243	KTKESLGrKIQIQRS	9606	BTO:0000392								11907111	t		lperfetto	The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase	SIGNOR-263416	0.415
ZMYND8	protein	Q9ULU4	UNIPROT	ZMYND8	protein	Q9ULU4	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								27477906	t		lperfetto	We identified ZMYND8 as a transcriptional corepressor of the H3K4 demethylase JARID1D|Co-immunoprecipitation between ectopically expressed FLAG-tagged JARID1D and endogenous ZMYND8 protein. 	SIGNOR-262037	0.2
PTPN2	protein	P17706	UNIPROT	GJA1	protein	P17302	UNIPROT	up-regulates	dephosphorylation	Tyr265	KDCGSQKyAYFNGCS	9606		BTO:0000671							24849651	t		lperfetto	Tc-ptp dephosphorylates cx43 residues y247 and y265, dephosphorylation maintained cx43 gap junctions at the plaque and partially reversed the channel closure caused by v-src-mediated phosphorylation of cx43.	SIGNOR-205101	0.331
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Ser65	FLMECRNsPVTKTPP	9606	BTO:0000007		SIGNOR-C3						12747827	t		lperfetto	Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo.	SIGNOR-101115	0.924
ADSL	protein	P30566	UNIPROT	N(6)-(1,2-dicarboxylatoethyl)-AMP(4-)	smallmolecule	CHEBI:57567	ChEBI	down-regulates quantity	chemical modification			9606									22812634	t		miannu	ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case	SIGNOR-266612	0.8
PGAM2	protein	P15259	UNIPROT	3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	down-regulates quantity	chemical modification			9606									24786789	t		miannu	Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle.	SIGNOR-266512	0.8
INSR	protein	P06213	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	phosphorylation	Tyr465	GEEELSNyICMGGKG	10116									7651388	t		lperfetto	All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10).	SIGNOR-236713	0.911
NOTCH1	protein	P46531	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000938								16554461	f		gcesareni	Notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (blbp) and erbb2 genes.	SIGNOR-145322	0.511
USF2	protein	Q15853	UNIPROT	B2M	protein	P61769	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12480693	f		miannu	 Here we show that upstream stimulatory factor 1 (USF1) and USF2 bind to the E box and regulate beta(2)m transactivation.	SIGNOR-254656	0.2
CAMKK2	protein	Q96RR4	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000567								15980064	t		lperfetto	These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo.	SIGNOR-217496	0.589
fingolimod	chemical	CHEBI:63115	ChEBI	S1PR1	protein	P21453	UNIPROT	down-regulates	chemical inhibition			9606									22225501	t		gcesareni	Sphingosine-1-phosphate (s1p(1)) receptor agonists such as fingolimod (fty-720) are a novel class of immunomodulators that have clinical utility in the treatment of remitting relapsing multiples sclerosis.	SIGNOR-195343	0.8
PTCH1	protein	Q13635	UNIPROT	SMO	protein	Q99835	UNIPROT	down-regulates activity	binding			9606									14556242	t		lperfetto	In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other.	SIGNOR-118609	0.779
AURKB	protein	Q96GD4	UNIPROT	HASPIN	protein	Q8TF76	UNIPROT	up-regulates activity	phosphorylation	Ser143	PPFPSRDsGRLSPDL	9606	BTO:0000567								21658950	t		miannu	Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis.	SIGNOR-263138	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PTTG1	protein	O95997	UNIPROT	up-regulates	phosphorylation			9606									10906323	t	inferred from 70% family members	gcesareni	Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function.	SIGNOR-270038	0.2
JMJD1C	protein	Q15652	UNIPROT	H3-4	protein	Q16695	UNIPROT	down-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									32034158	t		miannu	We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state.	SIGNOR-265170	0.2
PRKCE	protein	Q02156	UNIPROT	GABRG2	protein	P18507	UNIPROT	down-regulates activity	phosphorylation	Ser366	FVSNRKPsKDKDKKK	-1									17875639	t		miannu	Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2 subunits. Our findings indicate that PKCepsilon phosphorylation of gamma2 regulates the response of GABA(A) receptors to specific allosteric modulators, and, in particular, PKCepsilon inhibition renders these receptors sensitive to low intoxicating concentrations of ethanol. 	SIGNOR-263174	0.235
PRKCB	protein	P05771	UNIPROT	TYR	protein	P14679	UNIPROT	up-regulates	phosphorylation	Ser523	MEKEDYHsLYQSHL	9606									10347209	t		llicata	We conclude that pkc-beta activates tyrosinase directly by phosphorylating serine residues at positions 505 and 509 in the cytoplasmic domain of this melanosome-associated protein. our results strongly suggest that direct phosphorylation of tyrosinase by pkc-_ leads to its activation.	SIGNOR-67866	0.421
CDC25A	protein	P30304	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates	dephosphorylation	Thr14	VEKIGEGtYGVVYKA	9606									22263797	t		gcesareni	Cell division cycle 25 a (cdc25a), a dual-specificity protein phosphatase, is one of the most crucial cell cycle regulators, which removes the inhibitory phosphorylation in cyclin-dependent kinases (cdks), such as cdk2, cdk4, and cdk6, and positively regulates the activities of cdks that lead to cell cycle progression.	SIGNOR-195521	0.824
GRM3	protein	Q14832	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264353	0.7
dexamethasone	chemical	CHEBI:41879	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									27660409	t	diabetic macular edema	gcesareni	They differ according to their glucocorticoid-receptor binding affinities (dexamethasone > triamcinolone > fluocinolone) and their lipophilicity (triamcinolone > fluocinolone > dexamethasone), characteristics that may partially explain their relative potencies	SIGNOR-251694	0.8
CSNK2A1	protein	P68400	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates	phosphorylation	Ser559	PTSRGGAsVEETDQS	9606	BTO:0000150;BTO:0000567								20043841	t		lperfetto	Additionally protein kinase ck2 was identified as a kinase that phosphorylated eralpha at s282 and s559 s282 and s559 represent the second and third sites of er_ regulation by ck2. Remarkably, mutation of s282 or s559 to alanine resulted in near opposite functional effects on er_ as compared to mutation of s167 to alanine. Er_ ligand independent transcriptional activity was markedly enhanced upon mutation of s282 and s559 to alanine	SIGNOR-162657	0.248
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Thr359	DTEFTSRtPKDSPGI	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252745	0.754
MED7	protein	O43513	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266657	0.847
MOV10	protein	Q9HCE1	UNIPROT	IKBKE	protein	Q14164	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								27016603	t		miannu	 MOV10 enhances IRF3 activation and IRF3-mediated gene induction. This indicated that MOV10-mediated antiviral activity is most likely mediated through IKKε and not through TBK1. Involvement of IKKε was further established by examining the physical interaction of MOV10 and IKKε.	SIGNOR-261138	0.2
CUL5	protein	Q93034	UNIPROT	ARIH2	protein	O95376	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								24076655	t		miannu	Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin.	SIGNOR-268843	0.514
ELP6	protein	Q0PNE2	UNIPROT	Elongator complex	complex	SIGNOR-C466	SIGNOR	form complex	binding			9606									28601220	t		miannu	Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer.	SIGNOR-269713	0.762
PRKCA	protein	P17252	UNIPROT	PLD1	protein	Q13393	UNIPROT	up-regulates	phosphorylation	Thr147	PIPTRRHtFRRQNVR	9606		BTO:0000142							10441128	t		gcesareni	Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells.	SIGNOR-69938	0.703
CD226	protein	Q15762	UNIPROT	AL/b2 integrin	complex	SIGNOR-C169	SIGNOR	up-regulates				9606	BTO:0000914								15039383	f		lperfetto	CD226 and LFA-1 cooperate in cytotoxicity and cytokine secretion mediated by T and NK cells|These results were consistent with our observation that cross-linking CD226 with anti- CD226 mAb did not induce re-directed cytotoxicity against P815 by LFA-1-deficient LAD NK clones (Fig. 4D), suggesting a requirement for LFA-1 for CD226-mediated cytotoxicity.	SIGNOR-261427	0.527
HCK	protein	P08631	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	-1									12244095	t			Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. Direct Phosphorylation of STAT3 on Tyr-705 by Src Family Kinases	SIGNOR-251267	0.601
PPARA	protein	Q07869	UNIPROT	Fatty_acid_oxidation	phenotype	SIGNOR-PH129	SIGNOR	up-regulates				9606		BTO:0001103;BTO:0000671							18836859	f		miannu	 PPAR-α is predominantly expressed in the liver and skeletal muscles, participating in fatty-acids catabolism. PPAR-α also activates fatty-acid oxidation in the kidney, skeletal muscles, and heart 	SIGNOR-268027	0.7
PTPN1	protein	P18031	UNIPROT	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	down-regulates	dephosphorylation			9606							phosphorylation:Tyr177		9566916	t		gcesareni	We have observed association and dephosphorylation of p210 bcr-abl, but not v-abl, by ptp1b in vivo.	SIGNOR-56822	0.2
HOXB6	protein	P17509	UNIPROT	HBA1	protein	P69905	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000664								15269212	t		Luana	HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion.	SIGNOR-261637	0.2
OXSR1	protein	O95747	UNIPROT	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation	Thr100	TNTYYLQtFGHNTMD	9606	BTO:0000007								21321328	t		miannu	 We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A).	SIGNOR-276311	0.517
NFIA	protein	Q12857	UNIPROT	RBFOX3	protein	A6NFN3	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268911	0.264
SYK	protein	P43405	UNIPROT	LAT2	protein	Q9GZY6	UNIPROT	up-regulates activity	phosphorylation	Tyr193	EDEESEDyQNSASIH	10090	BTO:0001930								14722116	t		miannu	Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases.	SIGNOR-273575	0.576
MARCHF9	protein	Q86YJ5	UNIPROT	PTPRF	protein	P10586	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001522								19457934	t		miannu	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. 	SIGNOR-271536	0.2
PTPN1	protein	P18031	UNIPROT	LAT	protein	O43561	UNIPROT	down-regulates activity	dephosphorylation			9606									12857726	t			Using a pharmacological inhibitor, we provide evidence that PTP1B activation and LAT dephosphorylation processes were required for irreversible platelet aggregation.|In collagen-stimulated platelets, the signaling complexes recruited by tyrosine-phosphorylated LAT are essential for PLCgamma2 activation	SIGNOR-248403	0.481
WNT5A	protein	P41221	UNIPROT	FZD6	protein	O60353	UNIPROT	up-regulates activity	binding			9606	BTO:0000551;BTO:0000848								16273260	t		gcesareni	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-141437	0.686
AURKB	protein	Q96GD4	UNIPROT	CKAP2	protein	Q8WWK9	UNIPROT	up-regulates	phosphorylation	Ser628	FLTPVRRsRRLQEKT	9606									20458174	t		lperfetto	Here, we report that tmap is a novel substrate of the aurora b kinase. Ser627 of tmap was specifically phosphorylated by aurora b both in vitro and in vivo. Nearly all mutations at the phosphorylation motif had dramatic effects on the subcellular localization of tmap.	SIGNOR-165410	0.3
HNF4G	protein	Q14541	UNIPROT	AFP	protein	P02771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								9792724	f	 	miannu	 AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP.	SIGNOR-254442	0.2
NR2E3	protein	Q9Y5X4	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								22174013	t		Luana	NR2E3 directly regulates expression of ESR1 | Furthermore, overexpression of exogenous NR2E3 further increased expression of ESR1 and its downstream targets as well as its transcriptional activity in MCF-7 cells (Fig S1 of Supporting Information), strongly demonstrating that NR2E3 regulates ESR1 expression and subsequent ESR1-mediated induction of target genes.	SIGNOR-266207	0.253
CDC7	protein	O00311	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates	phosphorylation	Ser53	LPPFEDEsEGLLGTE	9606									19647517	t		lperfetto	Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry	SIGNOR-187400	0.961
PRKCE	protein	Q02156	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates activity	phosphorylation	Ser185	SAYVGRLsARPKLKA	-1									15604283	t		miannu	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276021	0.2
PAK1	protein	Q13153	UNIPROT	PLK1	protein	P53350	UNIPROT	up-regulates	phosphorylation	Ser49	EVLVDPRsRRRYVRG	9606									18427546	t		llicata	We show here that pak1 is required for cell proliferation, mitotic progression and plk1 activity in hela cells. phosphorylation of plk1 on ser 49 is important for metaphase-associated events.	SIGNOR-178353	0.532
SRC	protein	P12931	UNIPROT	HK1	protein	P19367	UNIPROT	up-regulates activity	phosphorylation	Tyr732	YDRLVDEySLNAGKQ	9606	BTO:0002181								28054552	t		miannu	Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its Km and increases its Vmax by disrupting its dimer formation. 	SIGNOR-277335	0.506
MC5R	protein	P33032	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256798	0.435
PPARGC1A	protein	Q9UBK2	UNIPROT	NR1D1	protein	P20393	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								17476214	t		miannu	Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Chromatin immunoprecipitation (ChIP) assays in HepG2 cells indicate that PGC-1α is present near RORE on the proximal Bmal1 promoter.These results indicate that PGC-1α activates Bmal1 transcription by altering the local chromatin environment from a repressive to an active state.	SIGNOR-268030	0.503
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRM6	protein	O15303	UNIPROT	up-regulates activity	chemical activation			9606									25042998	t		miannu	Glutamate is the major excitatory neurotransmitter in the central nervous system. Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate.	SIGNOR-264076	0.8
FLT1	protein	P17948	UNIPROT	FLT1	protein	P17948	UNIPROT	up-regulates	phosphorylation	Tyr1169	VQQDGKDyIPINAIL	9606									9299537	t		lperfetto	Tyr-1169 and tyr-1213 on flt-1 were found to be auto-phosphorylated these results strongly suggest that tyr-1169 on flt-1 is a major binding site for plcgamma and important for flt-1 signal transduction within the cell	SIGNOR-50834	0.2
PRKACA	protein	P17612	UNIPROT	LRRK2	protein	Q5S007	UNIPROT	down-regulates activity	phosphorylation	Ser1444	NIKARASsSPVILVG	-1									24351927	t		gcesareni	Furthermore, our work establishes S1444 as a PKA-regulated 14-3-3 docking site€.Strikingly, 14-3-3 binding to phospho-S1444 decreased LRRK2 kinase activity in vitro.	SIGNOR-237444	0.415
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1868	SPTSPKYsPTSPKYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203564	0.77
CDK2	protein	P24941	UNIPROT	ORC2	protein	Q13416	UNIPROT	up-regulates	phosphorylation	Thr226	SAPVGKEtPSKRMKR	9606									22334659	t		gcesareni	Phosphorylation at thr-116 and thr-226 of orc2 occurs by cyclin-dependent kinase during the s phase and is maintained until the m phase. Phosphorylation of orc2 at thr-116 and thr-226 dissociated the orc2-5 from chromatin.	SIGNOR-196048	0.744
VXJPSOQJNUZHDN-YJFQKBDPSA-N	smallmolecule	CID:118708139	PUBCHEM	NMUR1	protein	Q9HB89	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257591	0.8
RNF111	protein	Q6ZNA4	UNIPROT	SMAD7	protein	O15105	UNIPROT	down-regulates	ubiquitination			9606									14657019	t		gcesareni	Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia	SIGNOR-119666	0.725
EEF1A1P5	protein	Q5VTE0	UNIPROT	Gln-tRNA(Gln)	smallmolecule	CHEBI:29166	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269550	0.8
DDX3X	protein	O00571	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates activity	binding			9606									33627125	t		miannu	DDX3X enhances transcription by interacting with transcription factors to promote their binding to the promoter of the target gene. The best characterized mechanism is its cooperation with the transcription factor SP1. The downstream genes of DDX3X-SP1-mediated transactivation include P21, KRAS, and MDM2	SIGNOR-269195	0.36
INS	protein	P01308	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates				10090	BTO:0000011								11279134	f		lperfetto	The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin	SIGNOR-250565	0.439
CSNK1D	protein	P48730	UNIPROT	GJA1	protein	P17302	UNIPROT	up-regulates activity	phosphorylation	Ser325	NRMGQAGsTISNSHA	10116	BTO:0000067								12270943	t		lperfetto	We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation).	SIGNOR-249329	0.587
MYOCD	protein	Q8IZQ8	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001260							21673106	t		gcesareni	A coactivator of srf, myocd, interacts with srf and activates vsmc expression of contractile genes.	SIGNOR-174322	0.79
IL5	protein	P05113	UNIPROT	IL5RA	protein	Q01344	UNIPROT	up-regulates	binding			-1									8567620	t		fspada	Single chain and wt il5 also had similar binding affinity for soluble il5 receptor alpha chain, the specificity subunit of the il5 receptor, as measured kinetically with an optical biosensor.	SIGNOR-40039	0.879
4-[4-(6-methoxy-2-naphthalenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine	chemical	CHEBI:91442	ChEBI	TEK	protein	Q02763	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207287	0.8
CS	protein	O75390	UNIPROT	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	down-regulates quantity	chemical modification			9606									3013232	t		miannu	Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond.	SIGNOR-266549	0.8
lysophosphatidic acids	smallmolecule	CHEBI:32957	ChEBI	LPAR1	protein	Q92633	UNIPROT	up-regulates	chemical activation			9606									22863277	t		gcesareni	Lpa binds to a family of gpcrs known as lpa receptors (lpa1-6) to initiate intracellular signaling. Lpa1 was highly expressed and lpa3 was detectable in hek293a cells compared to other lpa receptors.	SIGNOR-198523	0.8
yohimbine	chemical	CHEBI:10093	ChEBI	HTR2B	protein	P41595	UNIPROT	down-regulates activity	chemical inhibition			10036									9459568	t		miannu	The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-	SIGNOR-258682	0.8
PLK1	protein	P53350	UNIPROT	NINL	protein	Q9Y2I6	UNIPROT	down-regulates activity	phosphorylation	Ser88	RPSDEDSsSLESAAS	-1									12852856	t		lperfetto	Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction	SIGNOR-103356	0.688
PTPN11	protein	Q06124	UNIPROT	NEDD9	protein	Q14511	UNIPROT	down-regulates activity	dephosphorylation			9606									19275884	t		miannu	In this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L.|These results show that both SH2 domains of SHP-2 are necessary for the interaction with Cas-L.\nIn this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L. Furthermore, our data raise the possibility that Cas-L is a direct substrate for SHP-2, although SHP-2 may inhibit Cas-L phosphorylation indirectly by regulating kinase activity.	SIGNOR-277083	0.502
3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine	smallmolecule	CHEBI:15786	ChEBI	glycine zwitterion	smallmolecule	CHEBI:57305	ChEBI	up-regulates quantity	precursor of			9606									11802770	t		miannu	 HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine.	SIGNOR-269691	0.8
EXOSC3	protein	Q9NQT5	UNIPROT	Exosome_Complex	complex	SIGNOR-C255	SIGNOR	form complex	binding			-1									24189234	t		miannu	The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 	SIGNOR-261382	0.967
PRKG1	protein	Q13976	UNIPROT	VASP	protein	P50552	UNIPROT	unknown	phosphorylation	Ser157	EHIERRVsNAGGPPA	9606									14679200	t		lperfetto	Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro	SIGNOR-120347	0.73
AKT1	protein	P31749	UNIPROT	ADRB2	protein	P07550	UNIPROT	down-regulates	phosphorylation	Ser346	LLCLRRSsLKAYGNG	9606									11809767	t		lperfetto	Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation.	SIGNOR-252470	0.362
LRRK2	protein	Q5S007	UNIPROT	ARHGEF7	protein	Q14155	UNIPROT	up-regulates	phosphorylation	Thr164	LGSQSLHtRTSKLFQ	9606									21048939	t		gcesareni	Arhgef7 is interacting with lrrk2 in vitro and in vivo. Lrrk2 phosphorylates arhgef7 in vitro.Two Threonine residues, t107 and t143, within the arhgef7 n-terminus were identified with high confidence	SIGNOR-169225	0.468
PAK1	protein	Q13153	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser298	RTPGRPLsSYGMDSR	9606	BTO:0001955								12876277	t		lperfetto	We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation.	SIGNOR-236002	0.563
TGFBR1	protein	P36897	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates	binding			9606	BTO:0001660								9435577	t		lperfetto	These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells.	SIGNOR-227525	0.389
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	LTB4R2	protein	Q9NPC1	UNIPROT	unknown	phosphorylation	Thr324	GGRSREGtMELRTTP	9606									22044535	t		llicata	Blt2 phosphorylation at thr355 by akt is necessary for blt2-mediated chemotaxis.	SIGNOR-177019	0.2
denileukin diftitox	smallmolecule	SID:125240988	ChEBI	IL2RB	protein	P14784	UNIPROT	up-regulates activity	chemical activation			9606									15757436	t		miannu	Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells. 	SIGNOR-259393	0.8
ABL1	protein	P00519	UNIPROT	PRDX1	protein	Q06830	UNIPROT	down-regulates activity	phosphorylation	Tyr194	DVQKSKEyFSKQK	-1									20178744	t		miannu	Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.	SIGNOR-276278	0.396
STON2	protein	Q8WXE9	UNIPROT	VAMP2	protein	P63027	UNIPROT	up-regulates quantity	binding			9606									26903854	t		miannu	 the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. Furthermore, recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval.	SIGNOR-264113	0.546
vorinostat	chemical	CHEBI:45716	ChEBI	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257919	0.8
GSK3B	protein	P49841	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606									16076840	t		gcesareni	The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex.	SIGNOR-139324	0.347
PAK2	protein	Q13177	UNIPROT	RPS6	protein	P62753	UNIPROT	unknown	phosphorylation	Ser240	RLSSLRAsTSKSESS	-1									1985906	t		miannu	The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide.	SIGNOR-250233	0.313
FYN	protein	P06241	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	unknown	phosphorylation	Tyr1252	CKKAGNLyDISEDNS	9606	BTO:0000007								11024032	t			Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed.	SIGNOR-251172	0.76
MKRN1	protein	Q9UHC7	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys291	TEEENLRkKGEPHHE	9606	BTO:0002552								19536131	t		miannu	Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. K291 and K292 of p53 are required for MKRN1-mediated degradation and ubiquitination of p53	SIGNOR-271846	0.443
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257908	0.8
SRC	protein	P12931	UNIPROT	TGFA	protein	P01135	UNIPROT	up-regulates activity				9606									17251915	f		lperfetto	Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network.	SIGNOR-236534	0.305
PB28 dihydrochloride	chemical	CID:46861545	PUBCHEM	SIGMAR1	protein	Q99720	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000093								16891467	t		Federica	Cyclohexylpiperazine derivative PB28, a σ2 agonist and σ1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer	SIGNOR-261111	0.8
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	up-regulates				9606									24877152	f			Conversely, a reduced amount of IGF-1R diminished the levels of P-AKT, allowing dissociation and nuclear translocation of Smad3 and enhancement of the TGFβ1 signaling pathway and fibrosis 	SIGNOR-254375	0.7
MMP11	protein	P24347	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272379	0.7
ASXL1	protein	Q8IXJ9	UNIPROT	RXRA	protein	P19793	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								16606617	t		irozzo	In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells.	SIGNOR-255911	0.287
CDK1	protein	P06493	UNIPROT	CEP55	protein	Q53EZ4	UNIPROT	down-regulates	phosphorylation	Ser428	KVAASPKsPTAALNE	9606									16198290	t		lperfetto	Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis.	SIGNOR-140886	0.461
perfluorooctanoic acid	chemical	CHEBI:35549	ChEBI	PPARA	protein	Q07869	UNIPROT	up-regulates activity	chemical activation			10090	BTO:0000011								16731579	t		miannu	Human, mouse, and rat PPARα were activated by PFOA isomers and PFOS.	SIGNOR-268790	0.8
UIMC1	protein	Q96RL1	UNIPROT	BRCA1-A complex	complex	SIGNOR-C296	SIGNOR	form complex	binding			9606	BTO:0000007								20656690	t		lperfetto	We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1. 	SIGNOR-263211	0.923
CDK5	protein	Q00535	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates activity	phosphorylation	Ser211	PGKETNEsPWRSDLL	9606									17440046	t		llicata	Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue 	SIGNOR-154405	0.459
SNCA	protein	P37840	UNIPROT	Lewy_body_formation	phenotype	SIGNOR-PH56	SIGNOR	up-regulates				9606									12666095	f		lperfetto	A key observation linking alpha-synuclein to PD was the demonstration that it is one of the principal components of Lewy bodies. Furthermore, mutant isoforms of alpha-synuclein more readily oligomerize, and it has been suggested that its tendency to aggregate into misfolded structures may confer toxic properties to the protein. 	SIGNOR-249700	0.7
JAK2	protein	O60674	UNIPROT	LEPR	protein	P48357	UNIPROT	up-regulates activity	phosphorylation	Tyr986	QRQPFVKyATLISNS	9606	BTO:0000007								11018044	t		miannu	LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. 	SIGNOR-263493	0.766
EXOC6	protein	Q8TAG9	UNIPROT	Exocyst_EXOC6 variant	complex	SIGNOR-C492	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270789	0.94
CSNK1D	protein	P48730	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser396	DDKKAKTsTRSSAKT	9606	BTO:0000007								14761950	t		lperfetto	Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells.	SIGNOR-121709	0.381
PPM1E	protein	Q8WY54	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	dephosphorylation	Ser57	KKDRFYRsILPGDKT	10116									11864573	t			The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX.	SIGNOR-248760	0.308
PRKD1	protein	Q15139	UNIPROT	RIN1	protein	Q13671	UNIPROT	unknown	phosphorylation	Ser351	RPLLRSMsAAFCSLL	9606									11784866	t		llicata	Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation.	SIGNOR-113964	0.413
KRAS	protein	P01116	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates	binding			9606									7744823	t		fstefani	Mitogen-activated protein kinase kinase kinase (mekk1) is a serine-threonine kinase that regulates sequential protein kinase pathways involving stress-activated protein kinases and mitogen-activated protein kinases. Mekk1 is activated in response to growth factor stimulation of cells and by expression of activated ras. mekk1 directly binds ras.GTP. Thus, ras interacts with protein kinases of both the raf and mekk families.	SIGNOR-32620	0.374
CD19	protein	P15391	UNIPROT	B_cell_maturation	phenotype	SIGNOR-PH15	SIGNOR	up-regulates				10090	BTO:0000776								25673924	f		lperfetto	CD19 is a crucial regulator of B cell activation.	SIGNOR-242888	0.7
BZW2	protein	Q9Y6E2	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates				9606	BTO:0003897								30805927	f		francesca	Overexpression (or silence) of BZW2 in HCC cells significantly stimulates (or decreases) the activation of the PI3K/AKT/mTOR signaling pathway	SIGNOR-261218	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser155	GRLKRERsMSENAVR	9606	BTO:0001938								26816379	t		gcesareni	A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission.	SIGNOR-245948	0.2
vorinostat	chemical	CHEBI:45716	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257921	0.8
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	DCX	protein	O43602	UNIPROT	unknown	phosphorylation	Ser287	ATAGPKAsPTPQKTS	9606	BTO:0000007								14741103	t		llicata	In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35.	SIGNOR-250655	0.415
mTORC1	complex	SIGNOR-C3	SIGNOR	HIF1A	protein	Q16665	UNIPROT	up-regulates				9606									20670887	f		gcesareni	Hif1alfa is the transcription factor downstream of mtorc1 in the control of glycolytic genes.	SIGNOR-167187	0.369
MAPK8	protein	P45983	UNIPROT	BCL2L11	protein	O43521	UNIPROT	up-regulates	phosphorylation			9606									12591950	t		gcesareni	Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf).	SIGNOR-98399	0.751
EZH2	protein	Q15910	UNIPROT	TWIST1	protein	Q15672	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001939								23836662	f	 	miannu	 We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes.	SIGNOR-254151	0.337
MAPK8	protein	P45983	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	down-regulates	phosphorylation	Ser62	PSWHLADsPAVNGAT	9606	BTO:0001130								12633850	t		gcesareni	By site-directed mutagenesis studies, we have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation in prostate cancer cells. Further studies with the inhibitor of jun kinase (jnk) and phosphorylation mutant of bcl-xl reveal the augmentative role of jnk-mediated bcl-xl phosphorylation in apoptosis of prostate cancer cells. In summary, our studies suggest that the phosphorylation of bcl-xl by stress response kinase signaling might oppose the anti-apoptotic function of bcl-xl to permit prostate cancer cells to die by apoptosis	SIGNOR-99219	0.771
TRIM13	protein	O60858	UNIPROT	TRIM13	protein	O60858	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									31744379	t		miannu	 In this study, we showed that the N-degron pathway mediates ubiquitin (Ub)-dependent reticulophagy. During this 2-step process, the ER transmembrane E3 ligase TRIM13 undergoes auto-ubiquitination via lysine 63 (K63) linkage chains and acts as a ligand for the autophagic receptor SQSTM1/p62 (sequestosome 1). 	SIGNOR-272219	0.2
gefitinib	chemical	CHEBI:49668	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258218	0.8
OXGR1	protein	Q96P68	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257243	0.2
DNMT3A	protein	Q9Y6K1	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19786833	f		irozzo	Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. 	SIGNOR-255808	0.485
PRKCG	protein	P05129	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser465	LKHVTQSsRKLIRAD	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-129320	0.326
Laminin-8	complex	SIGNOR-C181	SIGNOR	A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	up-regulates activity	binding												12123670	t		lperfetto	We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1.	SIGNOR-253220	0.519
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	AMBRA1	protein	Q9C0C7	UNIPROT	up-regulates activity	phosphorylation	Thr1238	ASWDQPGtPGREPTQ	9606	BTO:0000567								37584777	t	phosphorylation site remapping based on mass spec table	lperfetto	CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects.	SIGNOR-272967	0.259
H2AC4	protein	P04908	UNIPROT	Nucleosome_H3.1t variant	complex	SIGNOR-C325	SIGNOR	form complex	binding			-1									20498094	t		miannu	A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. 	SIGNOR-263724	0.2
LRRK2	protein	Q5S007	UNIPROT	LRRK2	protein	Q5S007	UNIPROT	unknown	phosphorylation	Thr1410	STHPHFMtQRALYLA	9606	BTO:0000938								19824698	t		lperfetto	We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites.	SIGNOR-188437	0.2
NOTCH1	protein	P46531	UNIPROT	LFNG	protein	Q8NES3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22298955	f		gcesareni	Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta.	SIGNOR-195621	0.748
CAMK2A	protein	Q9UQM7	UNIPROT	ETS1	protein	P14921	UNIPROT	down-regulates	phosphorylation	Ser285	QRVPSYDsFDSEDYP	9606	BTO:0000782								12475968	t		lperfetto	Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition	SIGNOR-96342	0.313
GRK2	protein	P25098	UNIPROT	ADIPOR1	protein	Q96A54	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser205	EKVSRTFsKLDYSGI	10090	BTO:0003324								35611695	t		miannu	. GRK2-induced AdipoR1 endocytosis and degradation were blocked by AdipoR1S205A overexpression. Moreover, AdipoR1S205E (pseudophosphorylation) phenocopied GRK2 effects, promoted AdipoR1 endocytosis and degradation, and inhibited AdipoR1 biological function.	SIGNOR-277594	0.2
AR	protein	P10275	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000938								11916967	f		lperfetto	Transcription assays demonstrated that liganded ar repressed beta-catenin/t cell factor-responsive reporter gene activity	SIGNOR-116260	0.719
AVPR1B	protein	P47901	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256791	0.428
EIF3E	protein	P60228	UNIPROT	MAD2L1	protein	Q13257	UNIPROT	down-regulates quantity	translation regulation			9606	BTO:0000815; BTO:0001938								20453879	f		irozzo	Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression.	SIGNOR-259157	0.266
FUS	protein	P35637	UNIPROT	PA2G4	protein	Q9UQ80	UNIPROT	up-regulates activity	sumoylation	Lys298	MGVVECAkHELLQPF	9606	BTO:0000007								19946338	t		gcesareni	Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity €.. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity.	SIGNOR-249657	0.342
BMP7	protein	P18075	UNIPROT	PRDM16	protein	Q9HAZ2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18719589	f		fspada	Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways	SIGNOR-180317	0.414
CDK4	protein	P11802	UNIPROT	SMAD3	protein	P84022	UNIPROT	unknown	phosphorylation	Ser208	DAGSPNLsPNPMSPA	-1									15241418	t		llicata	Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo.	SIGNOR-250767	0.748
CDKN2A	protein	P42771	UNIPROT	CyclinD1/CDK6	complex	SIGNOR-C143	SIGNOR	down-regulates	binding			9606									8891723	t		luana	The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb.	SIGNOR-259810	0.803
ROCK1	protein	Q13464	UNIPROT	MSN	protein	P26038	UNIPROT	up-regulates activity	phosphorylation	Thr558	LGRDKYKtLRQIRQG	9534	BTO:0000298								9856983	t		lperfetto	Rho-associated kinase (Rho-kinase), which is activated by the small GTPase Rho, phosphorylates moesin at Thr558 in vitro. Here, using a site- and phosphorylation state-specific antibody, we found that the expression of dominant active RhoA in COS7 cells induced moesin phosphorylation and the formation of microvilli-like structures at apical membranes where the Thr558-phosphorylated moesin accumulated, whereas the expression of dominant negative Rho-kinase inhibited both of these processes.	SIGNOR-249014	0.675
letrozole	chemical	CHEBI:6413	ChEBI	CYP19A1	protein	P11511	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193651	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									11359934	f		gcesareni	The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types.	SIGNOR-245043	0.7
MAPK10	protein	P53779	UNIPROT	STMN2	protein	Q93045	UNIPROT	down-regulates	phosphorylation	Ser73	EAPRTLAsPKKKDLS	9606									11718727	t		gcesareni	We demonstrate that purified scg10 can be phosphorylated by two subclasses of mitogen-activated protein (map) kinases, c-jun n-terminal/stress-activated protein kinase (jnk/sapk) and p38 map kinase;jnk3/sapkbeta phosphorylation occurs at ser-62 and ser-73, residues that result in reduced microtubule-destabilizing activity for scg10.	SIGNOR-112114	0.455
M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	TGFb	proteinfamily	SIGNOR-PF5	SIGNOR	up-regulates				9606	BTO:0000801								32454942	f		miannu	Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation	SIGNOR-263824	0.7
ZNRF3	protein	Q9ULT6	UNIPROT	FZD2	protein	Q14332	UNIPROT	down-regulates	ubiquitination			9606									22575959	t		gcesareni	Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6.	SIGNOR-197417	0.297
GNA12	protein	Q03113	UNIPROT	ARHGEF11	protein	O15085	UNIPROT	up-regulates activity	binding			9606									11799111	t			This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho	SIGNOR-256516	0.619
metyrapone	chemical	CHEBI:44241	ChEBI	CYP11B1	protein	P15538	UNIPROT	down-regulates activity	chemical inhibition			-1									21129965	t		Luana	In an effort to develop and evaluate new classes of compounds as CYP inhibitors, we based our investigations on the structure of the well-known CYP inhibitor Metyrapone 2, which has been used for the treatment of hypercortisolism and Cushing’ssyndrome for several decades.	SIGNOR-257884	0.8
WNT10B	protein	O00744	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				9606									12055200	f		fspada	We have identified wnt10b as a potent inhibitor of adipogenesis that must be suppressed for preadipocytes to differentiate in vitro	SIGNOR-89131	0.7
AKT2	protein	P31751	UNIPROT	AKT1S1	protein	Q96B36	UNIPROT	down-regulates	phosphorylation			9606				SIGNOR-C3					17277771	t		gcesareni	Furthermore, pras40 phosphorylation by akt and association with 14-3-3, a cytosolic anchor protein, are crucial for insulin to stimulate mtor. These findings identify pras40 as an important regulator of insulin sensitivity of the akt-mtor pathway and a potential target for the treatment of cancers, insulin resistance and hamartoma syndromes.	SIGNOR-152936	0.66
LPAR2	protein	Q9HBW0	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates	binding			9606									15856019	t		gcesareni	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. lpa2 also can couple to the gi/o, g12/13, and gqfamilies.	SIGNOR-135834	0.469
MAP4K2	protein	Q12851	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates	binding			9606									9712898	t		gcesareni	The mekk1 associated with the gck carboxyl terminus is catalytically active.	SIGNOR-59682	0.546
MECP2	protein	P51608	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	up-regulates				10090	BTO:0002881								19427855	f		Luana	Neuronal differentiation of neural precursor cells is promoted by the methyl-CpG-binding protein MeCP2	SIGNOR-264966	0.7
CPSF7	protein	Q8N684	UNIPROT	CFI complex	complex	SIGNOR-C388	SIGNOR	form complex	binding			9606	BTO:0000567								8626397	t		lperfetto	We report here the purification of CF Im from HeLa cell nuclear extracts. Three polypeptides of 68, 59, and 25 kDa copurified with CF Im activity.	SIGNOR-266124	0.78
GCK	protein	P35557	UNIPROT	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor.	SIGNOR-266458	0.8
PRKAA2	protein	P54646	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates	phosphorylation	Ser181	DQGSLCTsFVGTLQY	9606				SIGNOR-C14					21673972	t		lperfetto	These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes	SIGNOR-174405	0.259
ESCRT-III	complex	SIGNOR-C379	SIGNOR	Membrane_fusion	phenotype	SIGNOR-PH122	SIGNOR	up-regulates				9606									26775243	f		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit.	SIGNOR-265536	0.7
WNK3	protein	Q9BYP7	UNIPROT	WNK1	protein	Q9H4A3	UNIPROT	up-regulates activity	phosphorylation	Ser382	KRASFAKsVIGTPEF	9606									22032326	t		Manara	We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro.	SIGNOR-260789	0.287
MRPL51	protein	Q4U2R6	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262337	0.648
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MARS1	protein	P56192	UNIPROT	up-regulates activity	phosphorylation	Ser209	LQKQPQPsPAEGRAV	9606	BTO:0000567								25097229	t		miannu	Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins. 	SIGNOR-276671	0.2
LRFN5	protein	Q96NI6	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606	BTO:0000938								21736948	f		miannu	This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments.	SIGNOR-264098	0.7
BCR-Ml	complex	SIGNOR-C434	SIGNOR	SYK	protein	P43405	UNIPROT	up-regulates activity	binding			9606									32323266	t		scontino	The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK).	SIGNOR-268440	0.703
P2RY11	protein	Q96G91	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257261	0.2
DOCK1	protein	Q14185	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			10090	BTO:0001909								25533347	t		miannu	We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth.	SIGNOR-266822	0.724
SCF-SKP2	complex	SIGNOR-C136	SIGNOR	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000552								9736735	t		lperfetto	Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21CIP1/WAF1 and cyclin D proteins|These data suggest that the human p19(SKP1)/p45(SKP2)/CUL-1 complex is likely to function as an E3 ligase to selectively target cyclin D and p21 for the ubiquitin-dependent protein degradation.	SIGNOR-267556	0.667
TP53	protein	P04637	UNIPROT	NOXA1	protein	Q86UR1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19879762	t		lperfetto	As a transcription factor, p53 induces several pro-apoptotic Bcl-2 members including Bax, Puma, Noxa and Bid, and represses the transcription of certain anti-apoptotic genes, including those encoding Bcl-2, Bcl-xL and survivin 3_and_5.	SIGNOR-209687	0.263
5-(2-propoxyphenyl)-2,3-dihydrotriazolo[4,5-d]pyrimidin-7-one	chemical	CHEBI:92215	ChEBI	GPR35	protein	Q9HC97	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257506	0.8
PRKACA	protein	P17612	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser233	VSSQHRYsTPHAFTF	9534									12801936	t		miannu	Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259).	SIGNOR-250040	0.481
vandetanib	chemical	CHEBI:49960	ChEBI	RET	protein	P07949	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258307	0.8
GATA3	protein	P23771	UNIPROT	CD8A	protein	P01732	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8413295	f	 	miannu	Taken together, these results suggest that the human CD8 alpha gene is regulated by the interaction of multiple T-cell nuclear proteins with a transcriptional enhancer located in the last intron of the gene. Site-directed mutation of the Ets-1 and GATA-3 sites dramatically reduced enhancer activity. 	SIGNOR-254079	0.312
PRKCB	protein	P05771	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates activity	phosphorylation	Ser368	QRPSSRAsSRASSRP	10116									10871288	t		lperfetto	Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.	SIGNOR-249049	0.395
RANBP2	protein	P49792	UNIPROT	BICD2	protein	Q8TD16	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000567								20386726	t		irozzo	We show that the dynein/dynactin adaptor BICD2 is specifically recruited to the NPC in G2phase through a direct interaction with the NPC componentRanBP2.	SIGNOR-259122	0.52
SIRT2	protein	Q8IXJ6	UNIPROT	PCK1	protein	P35558	UNIPROT	up-regulates quantity by stabilization	deacetylation	Lys594	KEVEDIEkYLEDQVN	9606	BTO:0000007								21726808	t		lperfetto	Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 	SIGNOR-267602	0.438
MAPK1	protein	P28482	UNIPROT	POU5F1	protein	Q01860	UNIPROT	down-regulates	phosphorylation	Ser111	ESNSDGAsPEPCTVT	9606									23024368	t		miannu	We demonstrate that oct4a interacts with erk1/2 by using both in vitro gst pulldown and in vivo co-immunoprecipitation assays. Ms analysis identified phosphorylation of oct4a at ser-111. / serine 111 phosphorylation regulates oct4a protein subcellular distribution and degradation.	SIGNOR-192097	0.39
H4C1	protein	P62805	UNIPROT	BRDT	protein	Q58F21	UNIPROT	up-regulates activity	relocalization			9606					acetylation:Lys6;Lys9	kGGKGLGK;SGRGKGGkGLGKGGA			27991587	t		lperfetto	BRDT interacts with acetylated nucleosomes via its BD1 domain. Binding may be initiated through non-specific interactions with DNA, which allow BRDT to localize to chromatin. Specificity is generated through recognition of tandem acetylated lysine residues (K5ac/K8ac) on the histone H4 tail,	SIGNOR-262066	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TERT	protein	O14746	UNIPROT	up-regulates	phosphorylation	Ser824	AVRIRGKsYVQCQGI	9606									10224060	t		lperfetto	Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins.	SIGNOR-244357	0.2
ZBTB7A	protein	O95365	UNIPROT	CDKN2A	protein	Q8N726	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15662416	f		miannu	Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding.	SIGNOR-225900	0.375
PRKCD	protein	Q05655	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser328	QDAYRRNsVRFLQQR	9606	BTO:0000130								12056906	t		esanto	Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?.	SIGNOR-89233	0.459
PPP4C	protein	P60510	UNIPROT	BANF1	protein	O75531	UNIPROT	up-regulates	dephosphorylation	Ser4	sQKHRDFV	9606									16495336	t		lperfetto	Herein, we demonstrate we demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. We have identified the major phosphatase responsible for dephosphorylation of ser-4 to be protein phosphatase 4 catalytic subunit.	SIGNOR-144779	0.2
D-glucitol	smallmolecule	CHEBI:17924	ChEBI	HNRNPA1	protein	P09651	UNIPROT	down-regulates activity	relocalization			9606	BTO:0000312								33172210	f			We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne	SIGNOR-262814	0.8
FBXW7	protein	Q969H0	UNIPROT	CCDC6	protein	Q16204	UNIPROT	down-regulates	binding			9606	BTO:0000551								23108047	t		miannu	Fbxw7 interacts with and targets ccdc6 for ubiquitin-mediated proteasomal degradation	SIGNOR-199279	0.374
FGFR1	protein	P11362	UNIPROT	LDHA	protein	P00338	UNIPROT	up-regulates	phosphorylation	Tyr83	KIVSGKDyNVTANSK	9606									21969607	t		gcesareni	We found that the oncogenic receptor tyrosine kinase fgfr1 directly phosphorylates ldh-a. Phosphorylation at y10 and y83 enhances ldh-a activity by enhancing the formation of active, tetrameric ldh-a and the binding of ldh-a substrate nadh, respectively.	SIGNOR-176734	0.376
BCL2L11	protein	O43521	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates	binding			9606									15694340	t		gcesareni	Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.. Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1	SIGNOR-133823	0.811
CDK2	protein	P24941	UNIPROT	FOXM1	protein	Q08050	UNIPROT	up-regulates activity	phosphorylation	Thr611	ETLPISStPSKSVLP		BTO:0001938								15024056	t		llicata	We demonstrated that FoxM1B transcriptional activity requires binding of either S-phase or M-phase Cdk-cyclin complexes to mediate efficient Cdk phosphorylation of the FoxM1B Thr 596 residue, which is essential for recruitment of p300/CBP coactivator proteins.	SIGNOR-250731	0.74
FGF2	protein	P09038	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates				9606									20974802	f		gcesareni	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription.	SIGNOR-168995	0.587
EEF1A2	protein	Q05639	UNIPROT	Ser-tRNA(Ser)	smallmolecule	CHEBI:29162	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269535	0.8
CDK12	protein	Q9NYV4	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1861	TPTSPKYsPTSPKYS	9606									22012619	t		miannu	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176793	0.775
PAK2	protein	Q13177	UNIPROT	MYLK	protein	Q15746	UNIPROT	down-regulates activity	phosphorylation	Ser1208	MKSRRPKsSLPPVLG	-1									10748018	t		miannu	PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991.	SIGNOR-250222	0.512
CSNK1A1	protein	P48729	UNIPROT	RAPGEF2	protein	Q9Y4G8	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1244	ASLDAADsGRGSWTS	9606	BTO:0002181								24290981	t		miannu	Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase.	SIGNOR-276605	0.2
SHMT1	protein	P34896	UNIPROT	4-trimethylammoniobutanal	smallmolecule	CHEBI:18020	ChEBI	up-regulates quantity	chemical modification			9606									11802770	t		miannu	 HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine.	SIGNOR-269688	0.8
TBK1	protein	Q9UHD2	UNIPROT	REL	protein	Q04864	UNIPROT	up-regulates	phosphorylation			9606				SIGNOR-C68					16888014	t		miannu	The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel.	SIGNOR-148623	0.565
SRC	protein	P12931	UNIPROT	HDAC3	protein	O15379	UNIPROT	up-regulates activity	phosphorylation	Tyr325	AISEELPySEYFEYF	-1									30317579	t		miannu	C-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form). 	SIGNOR-277484	0.394
MAP3K11	protein	Q16584	UNIPROT	MAP3K11	protein	Q16584	UNIPROT	up-regulates	phosphorylation	Thr277	LAREWHKtTQMSAAG	9606									11053428	t		gcesareni	These residues within the activation loop are critical for mlk-3 autophosphorylation and activation. In addition, when the thr277 and ser281 residues were mutated to negatively charged glutamic acid to mimic phosphorylated serine/threonine residues, the resulting mutants were fully functional, implying that these two residues may serve as the autophosphorylation sites.	SIGNOR-83411	0.2
INS	protein	P01308	UNIPROT	APOB	protein	P04114	UNIPROT	down-regulates quantity by destabilization				9606									23721961	f		miannu	Insulin decreases ApoB secretion by promoting ApoB degradation in the hepatocyte. Though insulin does not alter ApoB mRNA levels, it inhibits ApoB translation by promoting the trafficking of ApoB mRNA into P-bodies, aggregates of translationally repressed mRNAs	SIGNOR-252114	0.489
UHMK1	protein	Q8TAS1	UNIPROT	MBP	protein	P02686	UNIPROT	down-regulates	phosphorylation	Ser299	GRDSRSGsPMARR	9606									10880969	t		lperfetto	Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of mbp as the unique site phosphorylated by kis. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1.	SIGNOR-78895	0.2
ALDOB	protein	P05062	UNIPROT	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266480	0.8
CDX2	protein	Q99626	UNIPROT	VIL1	protein	P09327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19371634	f		miannu	We concluded that cdx2 regulates intestinal villin expression through recruiting brm-type swi/snf complex to the villin promoter.	SIGNOR-185486	0.348
GSN	protein	P06396	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	down-regulates quantity	binding			9606	BTO:0000132								27871158	t		lperfetto	Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. 	SIGNOR-261835	0.7
MAPK8IP1	protein	Q9UQF2	UNIPROT	MAP3K12	protein	Q12852	UNIPROT	down-regulates	binding			9606									11432832	t		gcesareni	Jip inhibits dlk dimerization.	SIGNOR-109046	0.53
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	MITF	protein	O75030	UNIPROT	down-regulates	phosphorylation	Ser409	HGLSLIPsTGLCSPD	9606									21749389	t	The effect has been demonstrated using O75030-9	gcesareni	The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert.	SIGNOR-252795	0.2
CARM1	protein	Q86X55	UNIPROT	MEF2A	protein	Q02078	UNIPROT	up-regulates	methylation			10090		BTO:0001103							29163212	t		FFerrentino	The first evidence alluding to a role of PRMTs in mediating skeletal muscle plasticity, specifically myogenesis, arose from the identification of CARM1 as a glucocorticoid receptor-interacting protein 1 (GRIP1) binding protein. (Chen et al., 2000). Here, GRIP1 and MEF2 were co-expressed in the nucleus during skeletal muscle differentiation. These initial findings led to an investigation that revealed that this methyltransferase was responsible for coactivating the transcription of myocyte enhancer factor-2C (MEF2C) via GRIP1 	SIGNOR-255964	0.397
SKOR1	protein	P84550	UNIPROT	LBX1	protein	P52954	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								15528197	t		llicata	Furthermore, Corl1 interacted with Lbx1 and cooperatively repressed transcription, suggesting that it acts as a transcriptional corepressor for Lbx1 in regulating cell fate determination in the dorsal spinal cord.	SIGNOR-238004	0.576
RAF1	protein	P04049	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser222	LIDSMANsFVGTRSY	9606		BTO:0000975							10359597	t		lperfetto	Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 ras activation leads to raf and subsequently mek activation. Phospholipide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf.	SIGNOR-235991	0.737
AMPK	complex	SIGNOR-C15	SIGNOR	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606									20640476	t		lperfetto	The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes.	SIGNOR-209947	0.391
MAPK1	protein	P28482	UNIPROT	NDE1	protein	Q9NXR1	UNIPROT	up-regulates activity	phosphorylation			-1									12556484	t	done	miannu	We found that Nudel and NudE were also phosphorylated in M phase (Fig. ​(Fig.22 and ​and3).3). First, Nudel and NudE were specifically phosphorylated in M phase. Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro.Due to conservation of the S/TP motifs, NudE may also be phosphorylated at similar sites by these kinases, though it contains an additional potential Cdk site at S282 (SPNR).	SIGNOR-274078	0.382
PTPRO	protein	Q16827	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Tyr1248	PTAENPEyLGLDVPV	9606									27345410	t		lperfetto	In this study, our co-immunoprecipitation experiment along with the results derived from in vivo , cultured cells and clinical specimen confirm that PTPRO dephosphorylates ERBB2 at Y1248.|PTPRO overexpression remarkably accelerated degradation of ERBB2 (XREF_FIG).	SIGNOR-276979	0.413
PPP2R2A	protein	P63151	UNIPROT	PPP2CA	protein	P67775	UNIPROT	down-regulates activity	binding			9606									19114990	t		lperfetto	Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity	SIGNOR-217875	0.909
ixazomib	chemical	CHEBI:90942	ChEBI	PSMB5	protein	P28074	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194509	0.8
HK3	protein	P52790	UNIPROT	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor.	SIGNOR-266457	0.8
ANAPC2	protein	Q9UJX6	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	form complex	binding												16896351	t		lperfetto	The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex.	SIGNOR-252002	0.87
YAP1	protein	P46937	UNIPROT	TOP2A	protein	P11388	UNIPROT	up-regulates quantity by expression	transcriptional regulation					BTO:0001939							30224758	f		lperfetto	 By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 	SIGNOR-276570	0.2
AURKA	protein	O14965	UNIPROT	H3C1	protein	P68431	UNIPROT	unknown	phosphorylation	Ser11	TKQTARKsTGGKAPR	10090									12234980	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	In the present study, chromosome number instability and increased tumor invasiveness were noted in constitutively AIM-1-overexpressing cells in vivo. Increased mitotic Ser-10 phosphorylation was also observed in various colorectal tumor cells with high AIM-1 expression levels. These data suggest that increased H3 histone phosphorylation as a result of AIM-1 overexpression is a major precipitating factor of chromosome instability and, thus, may play a role in carcinogenesis.	SIGNOR-118886	0.2
C1QBP	protein	Q07021	UNIPROT	Complement C1q	complex	SIGNOR-C308	SIGNOR	down-regulates activity	binding												28018340	t		lperfetto	Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping.	SIGNOR-263401	0.382
TNF	protein	P01375	UNIPROT	SCN1A	protein	P35498	UNIPROT	up-regulates activity				10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253487	0.261
PRKCA	protein	P17252	UNIPROT	HMGN1	protein	P05114	UNIPROT	down-regulates	phosphorylation	Ser21	KEEPKRRsARLSAKP	9606									10739259	t		lperfetto	Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.	SIGNOR-76282	0.311
Calcineurin	complex	SIGNOR-C155	SIGNOR	DNM2	protein	P50570	UNIPROT	unknown	dephosphorylation	Ser764	LQSASSHsPTPQRRP	10116									20496096	t			CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII).	SIGNOR-252317	0.269
CNR2	protein	P34972	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257095	0.252
CDK14	protein	O94921	UNIPROT	CCNY	protein	Q8ND76	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser71	RASTIFLsKSQTDVR	9606	BTO:0000599								24794231	t		lperfetto	Phosphorylation of cyclin Y by CDK14 induces its ubiquitination and degradation|Phosphorylation of CCNY at Serines 71 and 73 creates a putative phospho-degron that controls its association with an SCF complex	SIGNOR-273008	0.824
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1626	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269348	0.718
linifanib	chemical	CHEBI:91435	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258243	0.8
CAK complex	complex	SIGNOR-C456	SIGNOR	TFIIH	complex	SIGNOR-C457	SIGNOR	form complex	binding			9606									30860024	t		lperfetto	Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 	SIGNOR-269318	0.85
AURKA	protein	O14965	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	unknown	phosphorylation			10090									12234980	t		gcesareni	In the present study, chromosome number instability and increased tumor invasiveness were noted in constitutively AIM-1-overexpressing cells in vivo. Increased mitotic Ser-10 phosphorylation was also observed in various colorectal tumor cells with high AIM-1 expression levels. These data suggest that increased H3 histone phosphorylation as a result of AIM-1 overexpression is a major precipitating factor of chromosome instability and, thus, may play a role in carcinogenesis.	SIGNOR-265356	0.2
SMAD3	protein	P84022	UNIPROT	CEBPB	protein	P17676	UNIPROT	down-regulates activity	binding			10090									12524424	t		gcesareni	Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters	SIGNOR-250567	0.58
TAF1	protein	P21675	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263932	0.877
CHUK	protein	O15111	UNIPROT	TAX1BP1	protein	Q86VP1	UNIPROT	up-regulates activity	phosphorylation	Ser666	RPPVRVPsWGLEDNV	10090	BTO:0002572								21765415	t	The effect has been demonstrated using Q86VP1-2	lperfetto	Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, but not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1).	SIGNOR-175062	0.39
RAB6B	protein	Q9NRW1	UNIPROT	VPS13B	protein	Q7Z7G8	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								25492866	t		miannu	Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 Golgi Localization Is Mediated by Active RAB6 . COH1 Interacts with All Three Mammalian RAB6 Homologues	SIGNOR-269205	0.2
SYP	protein	P08247	UNIPROT	VAMP2	protein	P63027	UNIPROT	up-regulates quantity	binding			9606									17331077	t		miannu	Synaptophysin I interacts with VAMP2 and controls its subcellular distribution. On the SV membrane, VAMP2 is engaged in a complex with synaptophysin I, which is mutually exclusive with the formation of fusogenic SNARE complexes. This model implicates synaptophysin I in escorting VAMP2 to the sites where exocytosis must take place exclusively after the arrival of the appropriate stimulus. We show that, at early stages along the secretory pathway, synaptophysin I directs sorting of VAMP2 to vesicles exhibiting limited availability for constitutive exocytosis.	SIGNOR-264102	0.619
INSR	protein	P06213	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates activity	phosphorylation	Tyr371	TQEQYELyCEMGSTF	10090	BTO:0000944								11997497	t			Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation.	SIGNOR-251304	0.506
SIRT6	protein	Q8N6T7	UNIPROT	TNF	protein	P01375	UNIPROT	up-regulates	deacetylation	Lys19	LAEEALPkKTGGPQG	9606									23552949	t		gcesareni	Sirt6 regulates tnf-alfa secretion through hydrolysis of long-chain fatty acyl lysine	SIGNOR-201658	0.321
Laminin-10	complex	SIGNOR-C182	SIGNOR	Laminin-10	complex	SIGNOR-C182	SIGNOR	up-regulates activity	binding			10090	BTO:0001086								18757303	t		lperfetto	Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. 	SIGNOR-253277	0.713
PRKACA	protein	P17612	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates activity	phosphorylation	Ser700	FGEKRKNsILNPINS	-1									1377674	t		miannu	CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795. 	SIGNOR-250348	0.466
WNT5A	protein	P41221	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates activity	binding			9606	BTO:0000551;BTO:0000848								16273260	t		gcesareni	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-141434	0.697
Obatoclax mesylate	chemical	CID:46930996	PUBCHEM	BCL2	protein	P10415	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194952	0.8
IKK-complex	complex	SIGNOR-C14	SIGNOR	NFKBIA	protein	P25963	UNIPROT	down-regulates	phosphorylation	Ser36	RHDSGLDsMKDEEYE	9606									9346241	t		lperfetto	We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation	SIGNOR-216389	0.885
beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266477	0.8
XL-647	chemical	CID:10458325	PUBCHEM	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207857	0.8
RPL8	protein	P62917	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262453	0.852
USP39	protein	Q53GS9	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270640	0.7
RIPK3	protein	Q9Y572	UNIPROT	MLKL	protein	Q8NB16	UNIPROT	up-regulates activity	phosphorylation	Thr357	FELRKTQtSMSLGTT	10090									24012422	t		gianni	MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays	SIGNOR-266429	0.742
CSNK2A1	protein	P68400	UNIPROT	CD5	protein	P06127	UNIPROT	up-regulates	phosphorylation	Ser482	SSMQPDNsSDSDYDL	9606									9834084	t		lperfetto	In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461)	SIGNOR-62303	0.348
SMURF	proteinfamily	SIGNOR-PF29	SIGNOR	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	ubiquitination			9606		BTO:0000007							11016919	t		lperfetto	The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway.	SIGNOR-253263	0.2
FYN	protein	P06241	UNIPROT	CNN3	protein	Q15417	UNIPROT	down-regulates activity	phosphorylation	Tyr261	SQKGMSVyGLGRQVY	9534	BTO:0000298								15206927	t			We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin	SIGNOR-251159	0.338
L-isoprenaline	chemical	CHEBI:6257	ChEBI	ADRB1	protein	P08588	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257456	0.8
Helicase	protein	P0DTD1-PRO_0000449630	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								32979938	t		miannu	We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F).	SIGNOR-262511	0.2
LCK	protein	P06239	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	phosphorylation	Tyr474	VLLVNRHyAKISDFG	9606	BTO:0000661								9685404	t		lperfetto	We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck	SIGNOR-249375	0.601
PRKCD	protein	Q05655	UNIPROT	CYBA	protein	P13498	UNIPROT	up-regulates	phosphorylation	Thr147	ERPQIGGtIKQPPSN	-1									19948736	t		Manara	Phosphorylation of p22phox on threonine 147 enhances NADPH oxidase activity by promoting p47phox binding. | Threonine 147 of p22phox Is Phosphorylated by PKC-α and PKC-δ in Vitro	SIGNOR-260892	0.2
RAC1	protein	P63000	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates activity	binding			10090	BTO:0000142								8107774	t		gcesareni	A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways.	SIGNOR-248250	0.739
MKX	protein	Q8IYA7	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001592							33115953	t		miannu	MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2). 	SIGNOR-267215	0.307
hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	GABA-A (a4-b3-d) receptor	complex	SIGNOR-C327	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000938								26136660	t		miannu	The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 	SIGNOR-264925	0.8
MAD2L1	protein	Q13257	UNIPROT	MCC	complex	SIGNOR-C382	SIGNOR	form complex	binding			9606	BTO:0000567								25092294	t		miannu	The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. 	SIGNOR-265973	0.963
GlyR	proteinfamily	SIGNOR-PF62	SIGNOR	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	relocalization			9606									18721822	t		miannu	The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. 	SIGNOR-264984	0.8
NR2F2	protein	P24468	UNIPROT	NR3C1	protein	P04150	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14739255	f		gcesareni	Gralpha, but not grbeta, enhanced coup-tfii-induced transactivation of the simple coup-tfii-responsive 7alpha-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas coup-tfii repressed gralpha-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors.	SIGNOR-121419	0.357
HTRA2	protein	O43464	UNIPROT	PEA15	protein	Q15121	UNIPROT	down-regulates	binding			9606									15328349	t		gcesareni	Htra2 promotes cell death by binding and degrading the anti-apoptotic protein pea15	SIGNOR-126966	0.499
(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	ADRA1D	protein	P25100	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257452	0.8
NFIA	protein	Q12857	UNIPROT	EPHA8	protein	P29322	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268896	0.2
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	succinyl-CoA(5-)	smallmolecule	CHEBI:57292	ChEBI	up-regulates quantity	precursor of			9606									15953811	t		miannu	The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH.	SIGNOR-266253	0.8
GRK6	protein	P43250	UNIPROT	GRK6	protein	P43250	UNIPROT	unknown	phosphorylation	Ser484	VLDIEQFsTVKGVEL	9534	BTO:0000298								10334944	t			GRK6 Is Autophosphorylated in COS-7 Cells. GRK6, like GRK5, is autophosphorylated on Ser484 and Thr485. Whether the autophosphorylation of GRK6 modulates its activity remains however to be established.	SIGNOR-251211	0.2
FIZ1	protein	Q96SL8	UNIPROT	NRL	protein	P54845	UNIPROT	up-regulates activity	binding			9913									12566383	t		miannu	Interaction of Fiz1 and NRL-leucine zipper was validated by GST pulldown assays and co-immunoprecipitation from bovine retinal nuclear extracts. Fiz1 suppressed NRL- but not CRX-mediated transactivation of rhodopsin promoter activity in transiently transfected CV1 cells.	SIGNOR-223796	0.568
SMAD3	protein	P84022	UNIPROT	SMAD3/JUN	complex	SIGNOR-C86	SIGNOR	form complex	binding			9606									9732876	t		gcesareni	These results show a ligand-dependent association of smad3 with c-jun	SIGNOR-59873	0.741
PASK	protein	Q96RG2	UNIPROT	PASK	protein	Q96RG2	UNIPROT	up-regulates activity	phosphorylation	Thr1165	LFYTFCGtIEYCAPE	-1									11459942	t		lperfetto	We present evidence that the activity of pask is regulated by two mechanisms. Autophosphorylation at two threonine residues located within the activation loop significantly increases catalytic activity.	SIGNOR-109485	0.2
GLI3	protein	P10071	UNIPROT	MED12	protein	Q93074	UNIPROT	down-regulates	binding			9606									17000779	t		gcesareni	We propose that activated gli3 physically targets med12 in mediator to reverse mediator-dependent suppression of shh target gene (i.e., Gli1 or cyclin d1) transcription.	SIGNOR-149876	0.519
TCL1B	protein	O95988	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	binding			9606	BTO:0000782;BTO:0001271								10983986	t		lperfetto	In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation.	SIGNOR-244452	0.663
TNFRSF17	protein	Q02223	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates				9606									10903733	f		miannu	Overexpression of bcma activates the p38 mapk	SIGNOR-79504	0.268
BACH1	protein	O14867	UNIPROT	HMOX1	protein	P09601	UNIPROT	down-regulates quantity	transcriptional regulation			9606									14747657	t			These results indicate that ho-1 regulation involves a competition between the activator Nrf2 and the Bach1 repressor for interactions with the small Maf proteins.	SIGNOR-259336	0.37
CDK9	protein	P50750	UNIPROT	SUPT5H	protein	O00267	UNIPROT	up-regulates	phosphorylation	Thr784	MYGSGSRtPMYGSQT	9606									16427012	t		lperfetto	We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif	SIGNOR-143927	0.769
CSTF complex	complex	SIGNOR-C441	SIGNOR	mRNA_polyadenylation	phenotype	SIGNOR-PH200	SIGNOR	up-regulates				9606									10669729	f		lperfetto	Polyadenylation of mRNA precursors is a two-step reaction requiring multiple protein factors. Cleavage stimulation factor (CstF) is a heterotrimer necessary for the first step, endonucleolytic cleavage, and it plays an important role in determining the efficiency of polyadenylation. 	SIGNOR-268369	0.7
DYRK1A	protein	Q13627	UNIPROT	CCNL2	protein	Q96S94	UNIPROT	unknown	phosphorylation	Ser369	AKKAKADsPVNGLPK	9534	BTO:0000298								14623875	t		llicata	DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase. 	SIGNOR-251089	0.591
RAPGEF6	protein	Q8TEU7	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183796	0.342
TACR3	protein	P29371	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257179	0.2
ZAP70	protein	P43403	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates activity	phosphorylation	Tyr128	DGEDDGDyESPNEEE	9606	BTO:0000782								12817019	t		lperfetto	Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase.	SIGNOR-102511	0.798
CDK5	protein	Q00535	UNIPROT	PLD2	protein	O14939	UNIPROT	down-regulates activity	phosphorylation	Ser134	ARFAVAYsPARDAGN	9606	BTO:0000007								18625302	t		miannu	In this study, we suggest that the phosphorylation and activation of PLD2 by cyclin-dependent kinase 5 (Cdk5) is critical for EGF-dependent insulin secretion. We determined that the phosphorylation site of PLD2 was located at Ser(134). 	SIGNOR-276168	0.377
NMBR	protein	P28336	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257315	0.252
RAD21	protein	O60216	UNIPROT	RUNX1	protein	Q01196	UNIPROT	down-regulates activity	relocalization			9606	BTO:0001545								26607380	t		miannu	Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity.	SIGNOR-261514	0.288
TEC	protein	P42680	UNIPROT	BMX	protein	P51813	UNIPROT	up-regulates	phosphorylation	Tyr224	DSNSKKIyGSQPNFN	9606									12573241	t		lperfetto	Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. For bmx, we obtained two phosphorylated sites, y215 and y223 (fig. 6c). The bmx-y215 is a conserved tyrosine, which is homologous to btk-y223 and itk-y180	SIGNOR-98094	0.337
CIITA	protein	P33076	UNIPROT	HLA-DOA	protein	P06340	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								11823510	f	 	 	Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA. 	SIGNOR-254005	0.343
ATM	protein	Q13315	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	up-regulates	phosphorylation			9606									22621922	t		gcesareni	The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells.	SIGNOR-197622	0.869
CUL3	protein	Q13618	UNIPROT	HSF2	protein	Q03933	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0002572								19768582	t	1	miannu	Here we show that the PEST sequences of a short-lived protein called HSF2 interact with Cullin3, a subunit of a Cullin-RING E3 ubiquitin ligase, and that this interaction mediates the Cul3-dependent ubiquitination and degradation of HSF2	SIGNOR-239129	0.331
CCND3	protein	P30281	UNIPROT	CyclinD3/CDK6	complex	SIGNOR-C234	SIGNOR	form complex	binding												8114739	t		lperfetto	Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells.	SIGNOR-273027	0.933
PRKAG1	protein	P54619	UNIPROT	PRKAA2	protein	P54646	UNIPROT	up-regulates	binding			9606									16054041	t		gcesareni	Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits.	SIGNOR-139173	0.893
MTOR	protein	P42345	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0000182;BTO:0000018		SIGNOR-C2						15718470	t		lperfetto	The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1	SIGNOR-252599	0.928
EXOC2	protein	Q96KP1	UNIPROT	Exocyst_EXOC6B variant	complex	SIGNOR-C491	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270777	0.928
RPS6KA3	protein	P51812	UNIPROT	NFATC4	protein	Q14934	UNIPROT	up-regulates	phosphorylation	Ser676	SNGRRKRsPTQSFRF	9606									15657420	t		esanto	We demonstrate that p90 ribosomal s6 kinase (rsk) is recruited to the nfat-dna transcription complex upon activation.Bound Rsk phosphorylates ser(676) and potentiates nfatc4 dna binding. Ser(676) is also targeted by the erk map kinase.	SIGNOR-133283	0.395
CDK1	protein	P06493	UNIPROT	PITPNM1	protein	O00562	UNIPROT	up-regulates	phosphorylation	Thr287	SAASNTGtPDGPEAP	9606									15125835	t		lperfetto	T287 is phosphorylated by cdk1 during mitosis. Phosphorylation of nir2 by cdk1 facilitates its dissociation from the golgi apparatus, and phospho-nir2(ps382) is localized in the cleavage furrow and midbody during cytokinesis.	SIGNOR-124642	0.477
ATM	protein	Q13315	UNIPROT	H2AX	protein	P16104	UNIPROT	up-regulates	phosphorylation	Ser140	GKKATQAsQEY	9606									18158901	t		gcesareni	H2ax interacts with numerous proteins required for dna damage signaling and repair when phosphorylated on ser-140. Phosphorylation of ser-140 (h2ax139ph) in response to ionizing radiation is mediated by both atm and prkdc. Our data showed that h2ax is phosphorylated by uva-activated jnk.	SIGNOR-160206	0.2
MAPK14	protein	Q16539	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr46	GGTLFSTtPGGTRII	9606	BTO:0003316								11777913	t		miannu	4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E. 	SIGNOR-250099	0.444
LCK	protein	P06239	UNIPROT	ADAM15	protein	Q13444	UNIPROT	up-regulates	phosphorylation	Tyr715	LVMLGASyWYRARLH	9606	BTO:0000661								11741929	t		lperfetto	Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling.	SIGNOR-112931	0.356
ETS2	protein	P15036	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606									11175361	f		miannu	Ets1 and Ets2 seem to play opposing roles in apoptosis. While Ets1 seems to activate pro-apoptotic pathways, Ets2 seems to inhibit apoptosis	SIGNOR-259870	0.7
MAP2K4	protein	P45985	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates activity	phosphorylation	Thr183	AGTSFMMtPYVVTRY	9606	BTO:0000007								9724739	t		gcesareni	MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53	SIGNOR-244982	0.74
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR3E	protein	A5X5Y0	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264291	0.8
veliparib	chemical	CHEBI:62880	ChEBI	PARP1	protein	P09874	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189183	0.8
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1626	SPSYSPTsPSYSPTS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248805	0.849
PRKCG	protein	P05129	UNIPROT	CD5	protein	P06127	UNIPROT	unknown	phosphorylation	Thr436	FHRNHTAtVRSHAEN	9606									11123317	t		lperfetto	Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. 	SIGNOR-249074	0.348
AKT1	protein	P31749	UNIPROT	IMPDH2	protein	P12268	UNIPROT	up-regulates activity	phosphorylation			9534	BTO:0004055								10930578	t		Federica	Further, we have demonstrated an in vivo association of IMPDH and PKB/Akt by co‐immunoprecipitation from COS cells expressing a constitutively active form of PKB/Akt. Finally, we were able to show that this constitutively active PKB/Akt could phosphorylate IMPDH in vitro. Thus, the interplay between PKB/Akt and IMPDH reported here could suggest that PKB/Akt activation leads to IMPDH type II activation which in turn prepares the cell for entry into S phase. 	SIGNOR-261262	0.394
KCNC4	protein	Q03721	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			9606									11506885	t		miannu	Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height	SIGNOR-265588	0.8
PRKCQ	protein	Q04759	UNIPROT	RASGRP3	protein	Q8IV61	UNIPROT	up-regulates	phosphorylation	Thr133	YDWMRRVtQRKKVSK	9606	BTO:0000776								15545601	t		lperfetto	Activation of rasgrp3 by phosphorylation of thr-133 is required for b cell receptor-mediated ras activation. our data suggest that pkc, after being activated by diacylglycerol, phosphorylates rasgrp3, thereby contributing to its full activation.	SIGNOR-130490	0.333
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SCNN1B	protein	P51168	UNIPROT	down-regulates quantity by destabilization	phosphorylation			-1									11805112	t	inferred from 70% family members	lperfetto	Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.	SIGNOR-270163	0.2
HSPA1A	protein	P0DMV8	UNIPROT	MAPK8	protein	P45983	UNIPROT	down-regulates				9606									16172114	f		gcesareni	Hsp70 inhibited stress-induced jnk activation and jnk with sp600125 or by expression of a dominant negative mutant of jnk-blocked bax translocation as effectively as hsp70 overexpression	SIGNOR-140553	0.495
CSNK2A1	protein	P68400	UNIPROT	CERS6	protein	Q6ZMG9	UNIPROT	up-regulates activity	phosphorylation	Ser345	DDRSDIEsSSDEEDS	9606	BTO:0000007								26887952	t		miannu	Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue. 	SIGNOR-273991	0.2
ponatinib	chemical	CHEBI:78543	ChEBI	RET	protein	P07949	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001271;BTO:0000184								23526464	t		miannu	The RET tyrosine kinase encoding gene acts as a dominantly transforming oncogene in thyroid carcinoma and other malignancies. Ponatinib (AP24534) is an oral ATP-competitive tyrosine kinase inhibitor that is in advanced clinical experimentation in leukemia.Ponatinib is a potent inhibitor of RET kinase and has promising preclinical activity in models of RET-driven medullary thyroid carcinoma.	SIGNOR-259275	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	JUND	protein	P17535	UNIPROT	up-regulates	phosphorylation			9606									22327296	t	inferred from 70% family members	gcesareni	Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase.	SIGNOR-270083	0.2
MTMR1	protein	Q13613	UNIPROT	1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate(5-)	smallmolecule	CHEBI:57923	ChEBI	down-regulates quantity	chemical modification			9606									18429927	t		miannu	PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 	SIGNOR-269804	0.8
CDK1	protein	P06493	UNIPROT	KAT5	protein	Q92993	UNIPROT	up-regulates	phosphorylation	Ser86	TKNGLPGsRPGSPER	9606									16103124	t		gcesareni	Moreover, app stabilized tip60 through cdk-dependent phosphorylation	SIGNOR-139649	0.491
ANXA3	protein	P12429	UNIPROT	NFKBIA	protein	P25963	UNIPROT	up-regulates activity				9606	BTO:0000018								27995049	f		miannu	We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells. 	SIGNOR-262213	0.2
PRKCA	protein	P17252	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates	phosphorylation	Ser44	KKSKISAsRKLQLKT	9606									15769444	t		lperfetto	Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.	SIGNOR-134617	0.349
ARHGAP27	protein	Q6ZUM4	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260482	0.571
ELANE	protein	P08246	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates activity	cleavage	Ala86	PLQKQLPaFISEDAS	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263566	0.441
TM9SF4	protein	Q92544	UNIPROT	ATP6V1H	protein	Q9UI12	UNIPROT	up-regulates activity	binding			9606	BTO:0001109;BTO:0000038								25659576	t		miannu	Here, we demonstrate that TM9SF4 represents a novel V-ATPase-associated protein involved in V-ATPase activation. We have observed in HCT116 and SW480 colon cancer cell lines that TM9SF4 interacts with the ATP6V1H subunit of the V-ATPase V1 sector. Suppression of TM9SF4 with small interfering RNAs strongly reduces assembly of V-ATPase V0/V1 sectors, thus reversing tumor pH gradient with a decrease of cytosolic pH, alkalization of intracellular vesicles and a reduction of extracellular acidity. 	SIGNOR-266885	0.275
FGF9	protein	P31371	UNIPROT	BMP2	protein	P12643	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22298955	f	FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1.	gcesareni	Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts.	SIGNOR-195591	0.384
POLG2	protein	Q9UHN1	UNIPROT	DNA polymerase gamma	complex	SIGNOR-C378	SIGNOR	form complex	binding			-1									19837034	t		lperfetto	Here, we report a crystal structure of human DNA Pol gamma holoenzyme. The holoenzyme is a heterotrimer containing one Pol gammaA subunit and a dimeric Pol gammaB subunit.	SIGNOR-265718	0.739
SRPK2	protein	P78362	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19592491	f		lperfetto	Compared with control, srpk2 wild type evidently elevated cyclin d1 transcription, and the catalytic activity was lost in srpk2 kd, suggesting that kinase activity of srpk2 is required for this effect.	SIGNOR-186763	0.2
EIF2S1	protein	P05198	UNIPROT	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	up-regulates				9606									31226023	f		miannu	Activated PERK phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), which inhibits the conversion of inactive GDP-bound eIF2α back to the active GTP-bound form, thereby suppressing translation initiation.The resulting global attenuation of protein synthesis reduces the ER protein influx and allows the ER to reprogram for preferential expression of UPR genes.	SIGNOR-260166	0.7
PRKN	protein	O60260	UNIPROT	EPS15	protein	P42566	UNIPROT	up-regulates	ubiquitination			9606	BTO:0000938	BTO:0000142							16862145	t		gcesareni	Treatment of cells with egf stimulates parkin binding to both eps15 and the egfr and promotes parkin-mediated ubiquitination of eps15	SIGNOR-148218	0.2
CDK1	protein	P06493	UNIPROT	PKN1	protein	Q16512	UNIPROT	up-regulates activity	phosphorylation	Ser533	ATGTGTFsPGASPGS	9606	BTO:0000567								31981797	t		miannu	CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines.	SIGNOR-276834	0.411
SP3	protein	Q02447	UNIPROT	FMR1	protein	Q06787	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15479157	f		miannu	 we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity.	SIGNOR-255203	0.2
USP15	protein	Q9Y4E8	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	down-regulates activity	deubiquitination			9606	BTO:0000567								27368102	t		miannu	SQSTM1 Is a Substrate for RNF26 and the DUB USP15. Catalytically competent RNF26 (light red) recruits SQSTM1 (blue) and mediates ubiquitin ligation (red), which serves to attract UBDs of specific vesicle-associated adaptors. Dissociation of the RNF26/SQSTM1 complex, promoted by the DUB USP15 (yellow), releases target vesicles for (4) fast transport into the cell periphery.	SIGNOR-269829	0.263
RAPH1	protein	Q70E73	UNIPROT	ENAH	protein	Q8N8S7	UNIPROT	up-regulates activity	binding			9606									20417104	t		miannu	 Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins.	SIGNOR-268425	0.56
adenosine	smallmolecule	CHEBI:16335	ChEBI	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000142							18957298	t		miannu	Adenosine is an endogenous inhibitor of excitatory synaptic transmission with potent anticonvulsant properties in the mammalian brain. 	SIGNOR-265464	0.7
MAP2K7	protein	O14733	UNIPROT	FADD	protein	Q13158	UNIPROT	down-regulates activity	phosphorylation	Ser194	QNRSGAMsPMSWNSD	9606									15001534	t		gcesareni	The results clearly show that fadd phosphorylation at ser194 affects functions both upstream and downstream of the mekk1/mkk7/jnk1 pathway and is closely associated with chemosensitivity in prostate cancer cells	SIGNOR-123164	0.476
CHD1	protein	O14646	UNIPROT	SF3a	complex	SIGNOR-C345	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								18042460	t		miannu	CHD1 was found to bridge core spliceosomal components to H3K4me3 via specific interactions with the SF3a sub-complex of U2 snRNP. The recruitment of SF3a and the efficiency of pre-mRNA splicing were perturbed upon reduction of CHD1 and H3K4me3.	SIGNOR-263951	0.251
6-(7-hydroxy-5,6-dihydropyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthalenecarboxamide	chemical	CHEBI:94965	ChEBI	CYP17A1	protein	P05093	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207141	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MCRIP1	protein	C9JLW8	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000007								25728771	t	inferred from 70% family members	lperfetto	When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation	SIGNOR-270188	0.2
PPP1CA	protein	P62136	UNIPROT	PREX1	protein	Q8TCU6	UNIPROT	up-regulates activity	dephosphorylation	Ser1001	IRFGRKPsLIGLDPE	9606									22242915	t		lperfetto	MS analysis of wild-type P-Rex1 and a PP1\u03b1-binding-deficient mutant revealed that endogenous PP1\u03b1 dephosphorylates P-Rex1 on at least three residues, Ser834, Ser1001 and Ser1165.|The phosphatase activity of PP1\u03b1 is required for P-Rex1 activation.	SIGNOR-277024	0.2
TFEB	protein	P19484	UNIPROT	ATP6V0E1	protein	O15342	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19556463	f	Figure 1	lperfetto	Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 	SIGNOR-276534	0.316
CASP3	protein	P42574	UNIPROT	ACIN1	protein	Q9UKV3	UNIPROT	up-regulates	cleavage			9606									10490026	t		amattioni	Induces apoptotic chromatin condensation after activation by casp3	SIGNOR-70800	0.612
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GRK7	protein	Q8WTQ7	UNIPROT	down-regulates activity	phosphorylation	Ser23	YLQARKPsDCDSKEL	9606									15946941	t		Luana	Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA. 	SIGNOR-260839	0.2
IGF1	protein	P05019	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity	binding			9606	BTO:0000150;BTO:0000680								16039586	t		lperfetto	Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin. This pathway is a general signal, as it was also observed in cell lines in which erk-primed inactivation of gsk-3beta was regulated by igf-1, tgf-beta, and receptor tyrosine kinase her2	SIGNOR-227948	0.343
CSNK2A1	protein	P68400	UNIPROT	VTN	protein	P04004	UNIPROT	up-regulates activity	phosphorylation	Thr76	TMPEDEYtVYDDGEE	10090									9733784	t		llicata	 Therefore, we expressed Vn in a baculovirus system and show (i) that the CKII phosphorylation of wt-Vn enhances the adhesion of bovine aorta endothelial cells; (ii) that the double mutant T50E/T57E (in which the neutral Thr residues are replaced by the negatively charged Glu residues considered analogs of Thr-P) has a significantly enhanced capacity to promote cell adhesion and to accelerate cell spreading when compared with either wild-type Vn or to the neutral T50A/T57A mutant	SIGNOR-250971	0.333
ECM	stimulus	SIGNOR-ST20	SIGNOR	A4/b7 integrin	complex	SIGNOR-C187	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259041	0.7
VCP	protein	P55072	UNIPROT	NGLY1	protein	Q96IV0	UNIPROT	up-regulates activity	binding			9606									15362974	t		simone	PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome.	SIGNOR-261058	0.683
PPP2CB	protein	P62714	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates activity	dephosphorylation	Ser87	AAAGPALsPVPPVVH	9606									15225643	t			The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A.	SIGNOR-248589	0.369
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	GJA1	protein	P17302	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000567								9535909	t	inferred from 70% family members	lperfetto	These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.	SIGNOR-270025	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	TSC2	protein	P49815	UNIPROT	up-regulates	phosphorylation	Ser1387	QPLSKSSsSPELQTL	9606									16959574	t		lperfetto	We have observed that ampk directly phosphorylates tsc2, and the ampk-dependent phosphorylation of tsc2 is critical for the coordination between cell growth and cellular energy levels. Phosphorylation of tsc2 by ampk is required for translation regulation and cell size control in response to energy deprivation.	SIGNOR-216438	0.516
CNR1	protein	P21554	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257285	0.366
LSM8	protein	O95777	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270626	0.823
DZIP3	protein	Q86Y13	UNIPROT	H2AC12	protein	Q96KK5	UNIPROT	up-regulates activity	monoubiquitination	Lys119	IQAVLLPkKTESHHK	9606	BTO:0000007								18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271760	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Thr60	AGQEEPGtPPSSPLS	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276095	0.275
ULK1	protein	O75385	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	down-regulates	phosphorylation			9606									21460634	t		lperfetto	Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity.	SIGNOR-217484	0.469
17beta-hydroxy-5alpha-androstan-3-one	smallmolecule	CHEBI:16330	ChEBI	AR	protein	P10275	UNIPROT	up-regulates	chemical activation			9606									15861399	t		miannu	Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. 	SIGNOR-251533	0.8
CDK11A	protein	Q9UQ88	UNIPROT	SPDEF	protein	O95238	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser238	SEESWTDsEVDSSCS	9606	BTO:0000007								26885618	t		lperfetto	In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|	SIGNOR-273020	0.364
ABL1	protein	P00519	UNIPROT	RBM39	protein	Q14498	UNIPROT	up-regulates activity	phosphorylation	Tyr95	DRRFRGRyRSPYSGP	9606	BTO:0000007								27018250	t		miannu	In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner.	SIGNOR-262609	0.329
EXOSC6	protein	Q5RKV6	UNIPROT	Exosome_Complex	complex	SIGNOR-C255	SIGNOR	form complex	binding			-1									24189234	t		miannu	The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 	SIGNOR-261389	0.913
Reduced Vitamin K	smallmolecule	CHEBI:8784	ChEBI	vitamin K epoxide	smallmolecule	CHEBI:28371	ChEBI	up-regulates quantity	precursor of			9606									31226734	t		lperfetto	GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form.	SIGNOR-265909	0.8
NANOG	protein	Q9H9S0	UNIPROT	GATA4	protein	P43694	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086;BTO:0005511								15983365	f		miannu	 Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 	SIGNOR-254626	0.455
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1934	SPTYSPTsPKGSTYS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269386	0.718
SREBF2	protein	Q12772	UNIPROT	SND1	protein	Q7KZF4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									29296233	t		irozzo	These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression.	SIGNOR-259136	0.349
PRKAA1	protein	Q13131	UNIPROT	GFPT1	protein	Q06210	UNIPROT	down-regulates	phosphorylation	Ser242	SKFTRWGsQGERGKD	9606									19170765	t		lperfetto	Amp-activated protein kinase phosphorylates glutamine : fructose-6-phosphate amidotransferase 1 at ser243 to modulate its enzymatic activityhe 2-dg induced phosphorylation of gfat1 . The assay of the gfat enzymatic activity in the cell lysates indicated that the 2-dg-treatment inhibited the enzymatic activity	SIGNOR-183528	0.2
MAPK1	protein	P28482	UNIPROT	PDXDC1	protein	Q6P996	UNIPROT	unknown	phosphorylation	Thr691	AGVTLPPtPSGSRTK	10090	BTO:0000944								22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262759	0.2
CYCS	protein	P99999	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								9390557	t		lperfetto	Caspase-9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cytochrome c and datp, an event that leads to caspase-9 activation.	SIGNOR-53585	0.876
TPR	protein	P12270	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262070	0.592
PPP3R1	protein	P63098	UNIPROT	Calcineurin	complex	SIGNOR-C155	SIGNOR	form complex	binding			9606									14623295	t		miannu	Calcineurin is a heterodimer consisting of a catalytic subunit with a molecular mass of about 59 kDa (calcienurin A or CNA) and a regulatory subunit with a molecular mass of 19 kDa (calcineurin B or CNB). 	SIGNOR-255289	0.953
UBA3	protein	Q8TBC4	UNIPROT	NAE	complex	SIGNOR-C131	SIGNOR	form complex	binding			9606									25504797	t		lperfetto	the NEDD8 E1-activating enzyme (NAE) is a heterodimer of APPBP1 and UBA3 corresponding to the N-terminal and C-terminal of the single polypeptide of the ubiquitin E1 respectively	SIGNOR-242904	0.965
HCK	protein	P08631	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates activity	phosphorylation	Tyr783	EGRNPGFyVEANPMP	-1									7682059	t		lperfetto	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249362	0.666
CAMK2B	protein	Q13554	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity	phosphorylation	Ser561	PFLSRHNsKSSIFSF	9606	BTO:0000938								32611770	t		lperfetto	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275787	0.275
CD40	protein	P25942	UNIPROT	TRAF3	protein	Q13114	UNIPROT	up-regulates activity	binding			9606									18635759	t		lperfetto	Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3.	SIGNOR-250560	0.916
SMARCA1	protein	P28370	UNIPROT	ST7	protein	Q9NRC1	UNIPROT	down-regulates quantity by repression	transcriptional regulation												15485929	t		lperfetto	Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes.	SIGNOR-268991	0.2
GATAD2A	protein	Q86YP4	UNIPROT	MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes.	SIGNOR-263858	0.824
PGAM1	protein	P18669	UNIPROT	2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	up-regulates quantity	chemical modification			9606									24786789	t		miannu	Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle.	SIGNOR-266514	0.8
prostaglandin E2(1-)	smallmolecule	CHEBI:606564	ChEBI	prostaglandin H2(1-)	smallmolecule	CHEBI:57405	ChEBI	up-regulates quantity	precursor of			-1									10922363	t		Luana	Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently.	SIGNOR-269767	0.8
PRKACA	protein	P17612	UNIPROT	CFTR	protein	P13569	UNIPROT	down-regulates activity	phosphorylation	Ser768	EPLERRLsLVPDSEQ	9606									19095655	t		Luana	AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.	SIGNOR-18141	0.466
CDK1	protein	P06493	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Thr67	LSILSGGtPKRCLDL	9606									8119945	t		gcesareni	Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity.	SIGNOR-36275	0.853
DUSP22	protein	Q9NRW4	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates activity	dephosphorylation	Ser118	LHPPPQLsPFLQPHG	9606									17384676	t			These results strongly suggest that DUSP22 acts as a negative regulator of the ERalpha-mediated signaling pathway|whereas E2-induced phosphorylation and activation of ERalpha was suppressed by overexpression of DUSP22 but not catalytically inactive mutants. 	SIGNOR-248827	0.264
PINK1	protein	Q9BXM7	UNIPROT	RAB8A	protein	P61006	UNIPROT	down-regulates activity	phosphorylation	Ser111	RNIEEHAsADVEKMI	-1									31361120	t		lperfetto	For Rab8a, it was shown that serine 111 phosphorylation (pS111) is dependent on the protein kinase PINK1 and that mimicking the phosphorylation at S111 by a serine/glutamate substitution (S111E) impaired Rab8a activation by its cognate nucleotide exchange factor (GEF) Rabin8. 	SIGNOR-260268	0.275
spiperone	chemical	CHEBI:9233	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258859	0.8
NFASC	protein	O94856	UNIPROT	ANK2	protein	Q01484	UNIPROT	up-regulates quantity	relocalization			10116		BTO:0000227							7961622	t		miannu	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266716	0.682
EIF4E2	protein	O60573	UNIPROT	EIF4E2/GIGYF2 complex	complex	SIGNOR-C257	SIGNOR	form complex	binding			9606	BTO:0000568								22751931	t		SARA	A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|GIGYF2 interacts specifically with m4EHP. The stabilities of m4EHP and GIGYF2 proteins are coregulated.	SIGNOR-261008	0.713
amitriptyline	chemical	CHEBI:2666	ChEBI	CHRM1	protein	P11229	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8100134	t		miannu	Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 	SIGNOR-258703	0.8
MAPK3	protein	P27361	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser289	RSHSESAsPSALSSS	10090									15664191	t		lperfetto	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-143688	0.622
MAPKAPK2	protein	P49137	UNIPROT	HNRNPA0	protein	Q13151	UNIPROT	up-regulates activity	phosphorylation	Ser84	VELKRAVsREDSARP	10090	BTO:0000801								12456657	t		miannu	MAPKAP-K2 phosphorylated hnRNP A0 at Ser84 in vitro and this residue became phosphorylated in LPS-stimulated cells. The simplest explanation for these findings is that the phosphorylation of hnRNP A0 at Ser84 by MAPKAP-K2 enhances binding to the AREs of these mRNAs or allows hnRNP A0 to displace another protein(s) from the AREs.	SIGNOR-262951	0.548
SRC	protein	P12931	UNIPROT	KLF16	protein	Q9BXK1	UNIPROT	up-regulates activity	phosphorylation	Tyr10	AAVACVDyFAADVLM	9606	BTO:0003041								22203677	t		miannu	We further confirmed that the Tyr-10 residue of KLF16 is phosphorylated in uterine cells (Fig. 7c). Additional experiments using both pharmacological and dominant negative inhibitors of Src further supported a role for this tyrosine kinase in modulating the activity of KLF16 (Fig. 7, d and f). 	SIGNOR-276398	0.246
BIRC3	protein	Q13489	UNIPROT	RIPK2	protein	O43353	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0000007								21931591	t		miannu	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.	SIGNOR-272715	0.78
SOD3	protein	P08294	UNIPROT	dioxygen	smallmolecule	CHEBI:15379	ChEBI	up-regulates quantity	chemical modification			9606									29301787	t		lperfetto	Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD).	SIGNOR-272272	0.8
AKT1	protein	P31749	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	phosphorylation	Ser615	SYKIRFNsISCSDPL	9606	BTO:0001853								24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251622	0.874
TNF	protein	P01375	UNIPROT	SCN1A	protein	P35498	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253478	0.261
STK4	protein	Q13043	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	phosphorylation	Ser872	HQRCLAHsLVGTPNY	9606									23431053	t		milica	MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation	SIGNOR-201298	0.62
ITCH	protein	Q96J02	UNIPROT	ERBB4	protein	Q15303	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9534	BTO:0000298								18334649	t		miannu	 Itch catalyzed ubiquitination of ErbB4 CYT-1, promoted its localization into intracellular vesicles, and stimulated degradation of ErbB4 CYT-1	SIGNOR-271416	0.589
FER	protein	P16591	UNIPROT	FER	protein	P16591	UNIPROT	up-regulates activity	phosphorylation	Tyr714	RQEDGGVySSSGLKQ	-1									19159681	t		miannu	 Mutation analysis unveiled a tyrosine (Tyr(616)) embedded in the Hsp90 recognition loop, which is required for the kinase activity of Fer. Replacement of this tyrosine by phenylalanine (Y616F) disabled the auto-phosphorylation activity of Fer and abolished its ability to phosphorylate Stat3. 	SIGNOR-276236	0.2
IKBKB	protein	O14920	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	unknown	phosphorylation	Ser376	PPAPAYLsSPLALPS	9606			SIGNOR-C14	SIGNOR-C14					12657630	t			IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376. IKKβ mediates IKKγ phosphorylation under physiologic signaling conditions. IKKγ is chronically phosphorylated in cells expressing the HTLV1 Tax oncoprotein, which interfaces directly with the IκB kinase complex.both Tax and TNF induce phosphorylation of human IKKγ at Ser-31, Ser-43, and Ser-376.	SIGNOR-251286	0.962
FASN	protein	P49327	UNIPROT	acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	down-regulates quantity	chemical modification			9606									15507492	t			Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the de novo biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH. 	SIGNOR-267211	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	HIF1A	protein	Q16665	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000567								18519666	t	inferred from 70% family members	lperfetto	We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_	SIGNOR-270095	0.2
KRAS	protein	P01116	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	binding			9606									16293107	t		gcesareni	Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade.	SIGNOR-141641	0.841
MAP3K4	protein	Q9Y6R4	UNIPROT	MAP2K6	protein	P52564	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								9841871	t		lperfetto	When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro.	SIGNOR-62372	0.641
GAS6	protein	Q14393	UNIPROT	AXL	protein	P30530	UNIPROT	up-regulates	binding			9606									7867073	t		gcesareni	Receptor tyrosine kinases of the axl family are activated by the vitamin k-dependent protein gas6. We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function.	SIGNOR-34339	0.906
CAMK2A	protein	Q9UQM7	UNIPROT	GRIA4	protein	P48058	UNIPROT	up-regulates	phosphorylation	Ser862	IRNKARLsITGSVGE	9606									12536214	t		gcesareni	Receptor internalization, altered;intracellular localization	SIGNOR-97546	0.574
CDK2	protein	P24941	UNIPROT	FOXK2	protein	Q01167	UNIPROT	up-regulates	phosphorylation	Ser373	SSRSAPAsPNHAGVL	9606									20810654	t		gcesareni	We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis.	SIGNOR-167830	0.376
PTPRG	protein	P23470	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254704	0.373
2-deoxy-D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:62877	ChEBI	acetaldehyde	smallmolecule	CHEBI:15343	ChEBI	up-regulates quantity	precursor of			9606									25229427	t		miannu	Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase.	SIGNOR-268076	0.8
GRK6	protein	P43250	UNIPROT	IGF1R	protein	P08069	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1321	LPLPDRHsGHKAENG	-1									22509025	t		miannu	GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation	SIGNOR-276412	0.311
PPP3CB	protein	P16298	UNIPROT	KSR2	protein	Q6VAB6	UNIPROT	up-regulates activity	dephosphorylation	Ser198	IRTHLSQsPRVPSKC	10090									19560418	t			These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3	SIGNOR-248380	0.262
G3BP2	protein	Q9UN86	UNIPROT	G3BP1	protein	Q13283	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								23279204	t		miannu	Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli.	SIGNOR-260863	0.469
SPI1	protein	P17947	UNIPROT	Monocyte_differentiation 	phenotype	SIGNOR-PH101	SIGNOR	up-regulates				9606									20861919	f		irozzo	In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation.	SIGNOR-256085	0.7
BCL7B	protein	Q9BQE9	UNIPROT	GBAF	complex	SIGNOR-C467	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269783	0.435
OAT	protein	P04181	UNIPROT	L-ornithine	smallmolecule	CHEBI:15729	ChEBI	down-regulates quantity	chemical modification			9606									14617280	t		miannu	Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC)	SIGNOR-256032	0.8
PAK1	protein	Q13153	UNIPROT	ITGB3BP	protein	Q13352	UNIPROT	up-regulates	phosphorylation	Ser28	SKITRKKsVITYSPT	9606	BTO:0000150								18521086	t		lperfetto	Serine 28 phosphorylation of nrif3 confers its co-activator function for estrogen receptor-alpha transactivation. p21-activated protein kinase 1 (pak1) phosphorylates eralpha at ser305 and this modification is important in eralpha transactivation function.	SIGNOR-178795	0.2
FASN	protein	P49327	UNIPROT	Fatty_Acid_Biosynthesis	phenotype	SIGNOR-PH190	SIGNOR	up-regulates				9606									9356448	f		miannu	Our model of the native fatty acid synthase (FAS) depicts it as a dimer of two identical multifunctional proteins (Mr approximately 272,000) arranged in an antiparallel configuration so that the active Cys-SH of the beta-ketoacyl synthase of one subunit (where the acyl group is attached) is juxtaposed within 2 A of the pantetheinyl-SH of the second subunit (where the malonyl group is bound). This arrangement generates two active centers for fatty acid synthesis and predicts that if we have two appropriate halves of the monomer, we should be able to reconstitute an active fatty acid-synthesizing site	SIGNOR-268159	0.7
4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[4-methyl-6-(4-morpholinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-pyridinone	chemical	CHEBI:91454	ChEBI	IGF1R	protein	P08069	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190443	0.8
CDK1	protein	P06493	UNIPROT	TOP2A	protein	P11388	UNIPROT	unknown	phosphorylation	Ser1393	GSVPLSSsPPATHFP	9606									7635160	t		llicata	We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. phosphopeptide 1 was eliminated by replacement of ser1392	SIGNOR-30256	0.54
1-acyl-sn-glycerol 3-phosphate(2-)	smallmolecule	CHEBI:57970	ChEBI	phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	up-regulates quantity	precursor of			9606									21173190	t		lperfetto	The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA). 	SIGNOR-267013	0.8
AKT1	protein	P31749	UNIPROT	PDCD4	protein	Q53EL6	UNIPROT	down-regulates	phosphorylation	Ser457	RGRKRFVsEGDGGRL	9606									16357133	t		gcesareni	Our results show that akt specifically phosphorylates ser(67) and ser(457) residues of pdcd4 in vitro and in vivo. We further show that phosphorylation of pdcd4 by akt causes nuclear translocation of pdcd4.	SIGNOR-252488	0.448
AURKB	protein	Q96GD4	UNIPROT	CDCA2	protein	Q69YH5	UNIPROT	down-regulates activity	phosphorylation	Ser542	KKINRRKsQETKCTK	9606	BTO:0000567								32938714	t	done	miannu	This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin.	SIGNOR-274002	0.459
POLA2	protein	Q14181	UNIPROT	DNA polymerase alpha:primase complex	complex	SIGNOR-C262	SIGNOR	form complex	binding			-1									24043831	t		lperfetto	At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation 	SIGNOR-261342	0.979
RET	protein	P07949	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	up-regulates	phosphorylation			9606									16153436	t	inferred from 70% of family members	gcesareni	We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).	SIGNOR-269894	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	GLI1	protein	P08151	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser102	LQTVIRTsPSSLVAF										26190112	t			Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency.	SIGNOR-253542	0.3
MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606									27098840	f		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes.	SIGNOR-263860	0.7
PTPN1	protein	P18031	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	dephosphorylation	Tyr530	FTSTEPQyQPGENL	9606									17974954	t			Overexpression of PTP1B increased Src specific activity in colon cancer cells by reducing phosphorylation at Y530 of Src.	SIGNOR-248422	0.773
AURKB	protein	Q96GD4	UNIPROT	HASPIN	protein	Q8TF76	UNIPROT	up-regulates activity	phosphorylation	Ser93	RVPKDRPsLTVTPKR	9606	BTO:0000567								21658950	t		miannu	Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis.	SIGNOR-263139	0.2
FLT3	protein	P36888	UNIPROT	USP22	protein	Q9UPT9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26049753	f			USP22 deubiquitinase was overexpressed in FLT3-ITD positive AML CD34+ cells.USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells.	SIGNOR-261559	0.2
FGF13	protein	Q92913	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253411	0.416
PPP2CA	protein	P67775	UNIPROT	TFCP2	protein	Q12800	UNIPROT	up-regulates	dephosphorylation	Ser309	SLGEGNGsPNHQPEP	9606									20682773	t		lperfetto	We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a	SIGNOR-167389	0.2
NDUFS1	protein	P28331	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24].	SIGNOR-262175	0.851
KAT2A	protein	Q92830	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269603	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates	phosphorylation	Ser100	HLSGRKLsLQERSQG	9606									22778263	t		lperfetto	Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity	SIGNOR-198146	0.2
MYOD1	protein	P15172	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates				9606									8288123	f		lperfetto	The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers.	SIGNOR-37458	0.7
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser380	HQLFRGFsFVATGLM	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252746	0.754
FOXO1	protein	Q12778	UNIPROT	TCF4	protein	P15884	UNIPROT	down-regulates activity	binding			9606	BTO:0000797								18250171	t		Gianni	Here we show that the beta-catenin binding to FOXO serves a dual effect. beta-catenin, through binding, enhances FOXO transcriptional activity. In addition, FOXO competes with TCF for interaction with beta-catenin, thereby inhibiting TCF transcriptional activity.	SIGNOR-262529	0.271
GDNF	protein	P39905	UNIPROT	ID1	protein	P41134	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252179	0.2
RAPGEF5	protein	Q92565	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183732	0.491
WNT5A	protein	P41221	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates				9606									21078818	f		lperfetto	We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3).	SIGNOR-227958	0.435
SRC	protein	P12931	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	up-regulates	phosphorylation	Tyr529	TITKTVEyLHAQGVV	9606	BTO:0000007								18156174	t		llicata	Together, our findings suggest that src-dependent phosphorylation at tyr-529 facilitates inactive erk binding to rsk2, which might be a general requirement for rsk2 activation by egf through the mek/erk pathway.	SIGNOR-160052	0.362
FOXO1	protein	Q12778	UNIPROT	CDKN2B	protein	P42772	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17873901	f		gcesareni	Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity	SIGNOR-157794	0.308
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	(R)-2-hydroxyglutarate(2-)	smallmolecule	CHEBI:15801	ChEBI	up-regulates quantity	precursor of												25406093	t		lperfetto	Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of alpha-ketoglutarate (AKG) to the oncometabolite d-2-hydroxyglutarate (d-2HG). 	SIGNOR-268573	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation	Ser119	EILSRRPsYRKILND	9606	BTO:0000007								9829964	t		gcesareni	When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner.	SIGNOR-247992	0.2
PTPRG	protein	P23470	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	dephosphorylation	Tyr705	DPGSAAPyLKTKFIC	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254729	0.262
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Thr548	KKVAVVRtPPKSPSS	9606									21215781	t	The effect has been demonstrated using P10636-8	lperfetto	Gsk3b phosphorylates tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules	SIGNOR-171046	0.729
COL1A1	protein	P02452	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates activity	binding			9606	BTO:0000664								12123670	t		lperfetto	We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1.	SIGNOR-253247	0.55
PRKACA	protein	P17612	UNIPROT	VTN	protein	P04004	UNIPROT	unknown	phosphorylation	Ser397	NQNSRRPsRATWLSL	-1									1706595	t		miannu	Phosphorylation of vitronectin by protein kinase A is stoichiometric (approx. 1 mol/mol), that it is targeted to one site (Ser-378) at the C-terminal edge of the heparin-binding domain. gh the role of phosphorylation by PKA remains to be established, the identification of Ser-378 as the sole site for PKA action, and the proximity of the phosphorylation site to the point of cleavage that converts V75 into V65 10' focuses attention on a putative role for PKA in the modulation of this cleavage. 	SIGNOR-250072	0.311
PRKCE	protein	Q02156	UNIPROT	PPP1R14A	protein	Q96A00	UNIPROT	up-regulates activity	phosphorylation	Thr38	QKRHARVtVKYDRRE	9606									32471307	t		lperfetto	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.	SIGNOR-249258	0.263
PRKACA	protein	P17612	UNIPROT	MCOLN1	protein	Q9GZU1	UNIPROT	down-regulates	phosphorylation	Ser557	SGKFRRGsGSACSLL	9606									17988215	t		llicata	The stimulatory effect of h89 on mcoln1 function was not observed when ser(557) and ser(559) were mutated to alanine residues, indicating that these two residues are essential for pka-mediated negative regulation of mcoln1.	SIGNOR-158946	0.2
reserpine	chemical	CHEBI:28487	ChEBI	SLC18A1	protein	P54219	UNIPROT	down-regulates activity	chemical inhibition			9606									8643547	t		miannu	Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2.	SIGNOR-258492	0.8
CASP3	protein	P42574	UNIPROT	GSN	protein	P06396	UNIPROT	down-regulates	cleavage			9606	BTO:0000130								9323209	t		amattioni	Caspase-3 mediates cleavage of gelsolin, generating a fragment that severs actin filaments in an unregulated fashion. The cleavage of gelsolin causes cells to round up, detach and undergo nuclear fragmentation.	SIGNOR-51652	0.624
NR3C1	protein	P04150	UNIPROT	NR2F2	protein	P24468	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14739255	f		gcesareni	Gralpha, but not grbeta, enhanced coup-tfii-induced transactivation of the simple coup-tfii-responsive 7alpha-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas coup-tfii repressed gralpha-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors.	SIGNOR-121422	0.357
SLA2	protein	Q9H6Q3	UNIPROT	FLT3	protein	P36888	UNIPROT	down-regulates activity	binding			10090	BTO:0000740								27458164	t		miannu	We screened a panel of SH2 domain-containing proteins and identified SLAP2 as a potent interacting partner of FLT3. We demonstrated that interaction occurs when FLT3 is activated, and also, an intact SH2 domain of SLAP2 is required for binding. Expression of SLAP2 blocked FLT3 downstream signaling cascades including AKT, ERK, p38 and STAT5.	SIGNOR-256155	0.251
NLGN1	protein	Q8N2Q7	UNIPROT	NRXN2	protein	Q9P2S2	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264154	0.824
dexmedetomidine	chemical	CHEBI:4466	ChEBI	ADRA2B	protein	P18089	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258907	0.8
ivacaftor	chemical	CHEBI:66901	ChEBI	CFTR	protein	P13569	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck;potentiator	gcesareni		SIGNOR-193495	0.8
RAF1	protein	P04049	UNIPROT	KLF10	protein	Q13118	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr93	TIPAFCLtPPYSPSD	9606	BTO:0000018								23994618	t		miannu	RAF1 phosphorylates the Thr93 site of KLF10 in vivo. Since the phosphorylation of Thr93 enables KLF10 and PIN1 to bind, it seems likely that RAF-1 will have an effect on KLF10 stability that is similar to that of PIN1.PIN1 facilitates KLF10 protein degradation. (	SIGNOR-276502	0.2
N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide	chemical	CHEBI:47322	ChEBI	CSNK1E	protein	P49674	UNIPROT	down-regulates	chemical inhibition			9606									11524435	t		amattioni	Cki-7, an inhibitor of ck1epsilon	SIGNOR-110053	0.8
AKT2	protein	P31751	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Thr32	QSRPRSCtWPLQRPE										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-252865	0.757
PRKCE	protein	Q02156	UNIPROT	GJA1	protein	P17302	UNIPROT	up-regulates	phosphorylation	Ser373	RASSRASsRPRPDDL	9606									16474210	t		lperfetto	We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity.	SIGNOR-144473	0.451
AKT1	protein	P31749	UNIPROT	LARP1	protein	Q6PKG0	UNIPROT	down-regulates activity	phosphorylation	Ser847	EHRPRTAsISSSPSE	9606	BTO:0002181								28650797	t		SARA	LARP1 is a direct substrate of Akt/S6K1 and mTORC1. Akt is a physiologically relevant primary kinase for S770/S979 phosphorylation of LARP1|Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation.	SIGNOR-260991	0.292
FLT3	protein	P36888	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									14592841	f			Thus, induction of C/EBPα and PU.1 expression is inhibited in 32D cells due to the expression of FLT3/ITD	SIGNOR-261529	0.623
SMC5/6 	complex	SIGNOR-C374	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									27427983	f		miannu	The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks	SIGNOR-265487	0.7
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	WWC1	protein	Q8IX03	UNIPROT	up-regulates	phosphorylation	Ser947	CRLNRSDsDSSTLSK	9606		BTO:0000149							24269383	t		llicata	Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. erk_rsk phosphorylation of kibra is required for proper cell proliferation and rsk-mediated phosphorylation also positively modulates kibra's migratory activity.	SIGNOR-252809	0.2
TTC19	protein	Q6DKK2	UNIPROT	CHMP4B	protein	Q9H444	UNIPROT	up-regulates activity	binding			9606	BTO:0000567			SIGNOR-C379					20208530	t		miannu	We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B.	SIGNOR-265541	0.429
MAPKAPK2	protein	P49137	UNIPROT	LIMK1	protein	P53667	UNIPROT	up-regulates	phosphorylation	Ser323	KDLGRSEsLRVVCRP	9606									16456544	t		lperfetto	Mk2 activated limk1 by phosphorylation at ser-323.	SIGNOR-144333	0.366
PAK1	protein	Q13153	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606									10611223	t		lperfetto	Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau.	SIGNOR-73533	0.341
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser104	FPPLNSVsPSPLMLL	9606									10428798	t		lperfetto	Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity.	SIGNOR-217284	0.43
SRC	protein	P12931	UNIPROT	SDHA	protein	P31040	UNIPROT	up-regulates activity	phosphorylation	Tyr215	SLRYDTSyFVEYFAL	9606	BTO:0001583								22823520	t		miannu	Phosphorylation-site analysis selects c-Src targets, including NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) at Tyr(193) of respiratory complex I and SDHA (succinate dehydrogenase A) at Tyr(215) of complex II. The phosphorylation of these sites by c-Src is supported by an in vivo assay using cells expressing their phosphorylation-defective mutants. 	SIGNOR-276420	0.271
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Ser65	FLMECRNsPVTKTPP	9823	BTO:0001840		SIGNOR-C3						23486913	t		lperfetto	These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation	SIGNOR-219257	0.924
GABA-A (a6-b3-d) receptor	complex	SIGNOR-C329	SIGNOR	CRHR1	protein	P34998	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268609	0.276
SRC	protein	P12931	UNIPROT	CYP19A1	protein	P11511	UNIPROT	up-regulates	phosphorylation	Tyr361	KVMENFIyESMRYQP	9606	BTO:0000150								19556341	t		amattioni	Phosphorylation of the 361-tyrosine residue is crucial in the up-regulation of aromatase activity. c-src protein directly phosphorylates aromatase on tyrosine 361.	SIGNOR-186284	0.358
CDK1	protein	P06493	UNIPROT	ORC1	protein	Q13415	UNIPROT	up-regulates	phosphorylation	Ser258	TSCASLDsPGRIKRK	9606									11931757	t		lperfetto	Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.	SIGNOR-116321	0.621
TPO	protein	P07202	UNIPROT	TG	protein	P01266	UNIPROT	up-regulates activity	catalytic activity			9606									23349248	t		miannu	After transport through the apical membrane, I− is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO).	SIGNOR-259914	0.521
9-cis-retinoic acid	chemical	CHEBI:50648	ChEBI	RARG	protein	P13631	UNIPROT	up-regulates activity	chemical activation			9606									18321241	t		miannu	Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma).	SIGNOR-259236	0.8
SGK1	protein	O00141	UNIPROT	HTT	protein	P42858	UNIPROT	down-regulates	phosphorylation	Ser419	GGRSRSGsIVELIAG	9606									14725621	t		llicata	The serum- and glucocorticoid-induced kinase sgk inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin.	SIGNOR-121349	0.382
PPARA	protein	Q07869	UNIPROT	LPL	protein	P06858	UNIPROT	up-regulates activity				9606									16511610	f	Regulation	miannu	The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha-dependent stimulation of lipoprotein lipase and of apolipoprotein (apo)A-V and to an inhibition of apoC-III expression, whereas the increase in plasma HDL-cholesterol depends partly on an overexpression of apoA-I and apoA-II. 	SIGNOR-251849	0.576
PRKCD	protein	Q05655	UNIPROT	ADRB2	protein	P07550	UNIPROT	down-regulates activity	phosphorylation	Ser346	LLCLRRSsLKAYGNG	-1									1848190	t		lperfetto	We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling.	SIGNOR-248856	0.358
GNAS	protein	P63092	UNIPROT	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	up-regulates activity	binding			-1									10224115	t			G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics.	SIGNOR-256539	0.2
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	DPPA4	protein	Q7L190	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269243	0.471
KAT2B	protein	Q92831	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	acetylation			9606	BTO:0000782;BTO:0001271								23029358	t		gcesareni	In earlier studies, we demonstrated that maml1 enhanced p300 acetyltransferase activity, which increased the acetylation of notch by p300.Acetylation controls notch stability and function in t-cell leukemia.	SIGNOR-199024	0.584
DVL3	protein	Q92997	UNIPROT	PIP5K1A	protein	Q99755	UNIPROT	up-regulates	binding			9606									18772438	t		gcesareni	Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki.	SIGNOR-180788	0.2
SRPK1	protein	Q96SB4	UNIPROT	SRPK1	protein	Q96SB4	UNIPROT	up-regulates	phosphorylation	Ser33	SETQHRGsAPHSESD	9606									22727668	t		llicata	We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1	SIGNOR-197989	0.2
ELANE	protein	P08246	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Val42	GRSLIGKvDGTSHVT	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263588	0.404
FZD3	protein	Q9NPG1	UNIPROT	GNB1	protein	P62873	UNIPROT	up-regulates	binding			9606									17251915	t		gcesareni	In the non-canonical wnt signalling pathway, frizzled uses galphaq or galphai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat.	SIGNOR-152600	0.357
GABBR2	protein	O75899	UNIPROT	GABA-B receptor	complex	SIGNOR-C336	SIGNOR	form complex	binding			9606	BTO:0000007								9872316	t	brain	lperfetto	Heterodimerization is required for the formation of a functional GABA(B) receptor.|These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2. 	SIGNOR-263743	0.678
GNAI1	protein	P63096	UNIPROT	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	up-regulates activity	binding			-1									10224115	t			G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics.	SIGNOR-256538	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	RPS6KA2	protein	Q15349	UNIPROT	up-regulates	phosphorylation			9606									8939914	t	inferred from 70% family members	gcesareni	Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms	SIGNOR-270018	0.2
SHMT1	protein	P34896	UNIPROT	(6R)-5,10-methylenetetrahydrofolate(2-)	smallmolecule	CHEBI:15636	ChEBI	up-regulates quantity	chemical modification			9606									32439610	t		lperfetto	Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. 	SIGNOR-268226	0.8
PTPN9	protein	P43378	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates activity	dephosphorylation			9606									20335174	t		miannu	Conversely, increasing expression of PTPN9 wild type (WT) inhibits tyrosyl phosphorylation of ErbB2 and EGFR.|Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells.	SIGNOR-277170	0.309
ATM	protein	Q13315	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity				9606		BTO:0000887							18534819	f		gcesareni	The decreased atm expression suggests that atm is involved in the development of insulin resistance through down-regulation of akt activity.	SIGNOR-161434	0.462
MAPK8	protein	P45983	UNIPROT	MAPK8IP1	protein	Q9UQF2	UNIPROT	unknown	phosphorylation	Ser421	DNCASVSsPYESAIG	9534	BTO:0000298								12756254	t		miannu	After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1.	SIGNOR-250126	0.879
PRKCA	protein	P17252	UNIPROT	OPRD1	protein	P41143	UNIPROT	unknown	phosphorylation	Ser344	CGRPDPSsFSRAREA	9606	BTO:0000007								11085981	t		lperfetto	In the current study, we identified a PKC-mediated phosphorylation site in the delta-opioid receptor (DOR) and demonstrated that activation of PKC by stimulation of other types of GPCR or increase in intracellular Ca2+concentration in HEK 293 cells induces heterologous phosphorylation of DOR. Our results further established that DOR phosphorylation at Ser-344 by PKC results in internalization of DOR in HEK 293 cells through a beta-arrestin- and clathrin-mediated mechanism.	SIGNOR-249062	0.355
CAV1	protein	Q03135	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264454	0.7
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252848	0.908
Angiotensin 1-7	protein	P01019-PRO_0000420660	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates activity				9606									24168260	f		miannu	We hypothesized that the ACE2/Ang-(1-7)/Mas axis protects against pulmonary fibrosis by inhibiting the MAPK/NF-κB pathway.In summary, our study demonstrate that exogenous Ang-(1-7) and ACE2 overexpression protect against BLM- or AngII-induced pulmonary fibrosis by down-regulating the MAPK/NF-κB pathway. However, constant infusion of Ang-(1-7) paradoxically initiates an inflammatory response in the lungs. The antifibrotic effects of Ang-(1-7) noted here make the heptapeptide a strong candidate for a therapeutic target in humans with pulmonary fibrosis.	SIGNOR-260447	0.2
STK39	protein	Q9UEW8	UNIPROT	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation	Thr95	AYDSHTNtYYLQTFG	9606	BTO:0000007								21321328	t		miannu	We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity.	SIGNOR-263132	0.596
PRKCA	protein	P17252	UNIPROT	NFATC1	protein	O95644	UNIPROT	down-regulates activity	phosphorylation	Ser294	PHGSPRVsVTDDSWL	9606									12351631	t		lperfetto	Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1. | Here we show that overexpression of PKA causes phosphorylation and cytoplasmic accumulation of NF-ATc1 in direct opposition to calcineurin by phosphorylating Ser-245, Ser-269, and Ser-294 in the conserved serine-proline repeat domain, and that mutation of these serines blocks the effect of PKA. Activation of endogenous PKA is similarly able to promote phosphorylation of these sites on NF-ATc1 in two lymphoid cell lines.	SIGNOR-249175	0.392
GSK3A	protein	P49840	UNIPROT	SFPQ	protein	P23246	UNIPROT	down-regulates	phosphorylation	Thr687	PRGMGPGtPAGYGRG	9606									20932480	t		miannu	Here we demonstrate that in resting tcells psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. Upon tcell activation, reduced gsk3 activity leads to reduced psf phosphorylation, releasing psf from trap150 and allowing it to bind cd45 splicing regulatory elements and repress exon inclusion.	SIGNOR-168382	0.2
AURKB	protein	Q96GD4	UNIPROT	HASPIN	protein	Q8TF76	UNIPROT	up-regulates activity	phosphorylation	Ser108	WKLRARPsLTVTPRR	9606	BTO:0000567								21658950	t		miannu	Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis.	SIGNOR-263137	0.2
SCAP	protein	Q12770	UNIPROT	SREBF2	protein	Q12772	UNIPROT	up-regulates activity	relocalization			10029	BTO:0000246								12202038	t			SCAP contains two domains: an NH2-terminal membrane attachment domain with eight membrane-spanning helices (Nohturfft et al., 1998b) and a long COOH-terminal extension that contains multiple copies of a WD40 repeat sequence, which forms a propeller-like structure that binds to the COOH-terminal domains of the SREBPs, thereby permitting the escort function	SIGNOR-267502	0.898
PPARG	protein	P37231	UNIPROT	HDAC1	protein	Q13547	UNIPROT	down-regulates	relocalization			9606									16431920	t		fspada	These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome	SIGNOR-143961	0.6
DNA polymerase gamma	complex	SIGNOR-C378	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									19837034	f		lperfetto	DNA Pol gamma, in contrast to the many nuclear DNA polymerases (DNAPs) that have specialized functions, is solely responsible for DNA replication and repair in mitochondria. 	SIGNOR-265723	0.7
BMPR2	protein	Q13873	UNIPROT	BMPR1B	protein	O00238	UNIPROT	up-regulates activity	binding			9534									10712517	t		lperfetto	Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii).	SIGNOR-219291	0.608
DYRK1A	protein	Q13627	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser721	PVVSGDTsPRHLSNV	9606									21215781	t	The effect has been demonstrated using P10636-8	lperfetto	Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna	SIGNOR-171034	0.44
MAPK9	protein	P45984	UNIPROT	PPM1J	protein	Q5JR12	UNIPROT	down-regulates	phosphorylation	Ser93	HAGRAVQsPPDTGRR	9606									18553930	t		gcesareni	Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells.	SIGNOR-178934	0.2
POU5F1	protein	Q01860	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004180								23041284	t		flangone	Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription.	SIGNOR-252635	0.471
RPS6KA1	protein	Q15418	UNIPROT	MAGI1	protein	Q96QZ7	UNIPROT	up-regulates activity	phosphorylation	Ser741	QPLERKDsQNSSQHS	9606	BTO:0001949								30944250	t	done	miannu	 We report herein that p90RSK associates with MAGI1 in ECs and executes 2 independently regulated PTMs of MAGI1: S741 phosphorylation and K931 deSUMOylation. MAGI1-S741 phosphorylation is vital for Rap1 activation.	SIGNOR-273837	0.289
AURKB	protein	Q96GD4	UNIPROT	SKA1	protein	Q96BD8	UNIPROT	up-regulates activity	phosphorylation			-1									22371557	t		miannu	Aurora B directly phosphorylated Ska1 and Ska3 in vitro, and expression of phosphomimetic mutants of Ska1 and Ska3 impaired Ska KT recruitment and formation of stable KT-MT fibers (K-fibers), disrupting mitotic progression. We propose that Aurora B phosphorylation antagonizes the interaction between the Ska complex and the KMN network, thereby controlling Ska recruitment to KTs and stabilization of KT-MT attachments.	SIGNOR-262662	0.725
Blood vessel damage	stimulus	SIGNOR-ST26	SIGNOR	F12	protein	P00748	UNIPROT	up-regulates													NBK482253	f		lperfetto	It begins with the activation of Factor XII (a zymogen, inactivated serine protease) which becomes Factor XIIA (activated serine protease) after exposure to endothelial collagen. Endothelial collagen is only exposed when endothelial damage occurs.	SIGNOR-263514	0.7
NLGN4Y	protein	Q8NFZ3	UNIPROT	NRXN3	protein	Q9HDB5	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264168	0.2
FZD4	protein	Q9ULV1	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates activity	binding			9606									27096005	t		areggio	Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin.	SIGNOR-258955	0.593
RBMX2	protein	Q9Y388	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270674	0.563
acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	citrate(3-)	smallmolecule	CHEBI:16947	ChEBI	up-regulates quantity	precursor of			9606									3013232	t		miannu	Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond.	SIGNOR-266236	0.8
CHL1	protein	O00533	UNIPROT	ANK3	protein	Q12955	UNIPROT	up-regulates quantity	relocalization			10116		BTO:0000227							7961622	t		miannu	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266723	0.422
CDK5	protein	Q00535	UNIPROT	AGAP2	protein	Q99490	UNIPROT	up-regulates	phosphorylation	Ser279	KSKTLDNsDLHPGPP	9606	BTO:0000938;BTO:0000527								18487454	t		lperfetto	Here, we demonstrate that cyclin dependent kinase 5 (cdk5), a protein known to function mainly in postmitotic neurons, directly phosphorylates pike-a at ser-279 in its gtpase domain in glioblastoma cells. This phosphorylation event stimulates pike-a gtpase activity and the activity of its downstream effector akt.	SIGNOR-178660	0.265
IGF1	protein	P05019	UNIPROT	PPP3CA	protein	Q08209	UNIPROT	up-regulates				10090	BTO:0000165;BTO:0002314	BTO:0000887;BTO:0001103;BTO:0001760							10448861	f		lperfetto	Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1.	SIGNOR-235645	0.279
INS	protein	P01308	UNIPROT	CEBPA	protein	P49715	UNIPROT	up-regulates				9606									11279134	f		fspada	The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin	SIGNOR-250570	0.448
PDPK1	protein	O15530	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Thr308	KDGATMKtFCGTPEY	9606		BTO:0000887;BTO:0001103;BTO:0001760							9512493	t		lperfetto	The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma)	SIGNOR-244480	0.736
H3C1	protein	P68431	UNIPROT	Transcritpional_activation	phenotype	SIGNOR-PH205	SIGNOR	up-regulates activity				9606									22266761	f		Gianni	Widely described to be associated with active chromatin, H3K36 methylation has also been implicated in transcriptional repression, alternative splicing, dosage compensation, DNA replication and repair	SIGNOR-269072	0.7
WWTR1	protein	Q9GZV5	UNIPROT	TTF1	protein	Q15361	UNIPROT	up-regulates	binding			9606		BTO:0000763							19010321	t		miannu	Taz is a coactivator for pax8 and ttf-1, two transcription factors involved in thyroid differentiation. / we show that this interaction leads to a significant enhancement of the transcriptional activity of pax8 and ttf-1 on the thyroglobulin promoter thus suggesting a role of taz in the control of genes involved in thyroid development and differentiation.	SIGNOR-182296	0.318
CAMK2A	protein	Q9UQM7	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser579	NVKSKIGsTENLKHQ	9606	BTO:0000590								10090741	t		lperfetto	We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II.	SIGNOR-249314	0.578
PIAS4	protein	Q8N2W9	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	binding			9606				SIGNOR-C9					12904571	t		gcesareni	Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity.	SIGNOR-104538	0.633
IRAK1	protein	P51617	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Ser293	FNTLAFPsMKRKDVV	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276137	0.758
NRF1	protein	Q16656	UNIPROT	FMR1	protein	Q06787	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001363; BTO:0000142							11058604	f		miannu	 We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs.	SIGNOR-254881	0.294
SCNN1A	protein	P37088	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606									26772908	t		miannu	The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity.	SIGNOR-269275	0.8
MAPK14	protein	Q16539	UNIPROT	MAPKAPK2	protein	P49137	UNIPROT	up-regulates activity	phosphorylation	Thr222	TSHNSLTtPCYTPYY	9606	BTO:0000130								14499342	t		lperfetto	Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils.	SIGNOR-118040	0.758
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1875	SPTSPKYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273039	0.556
TCF12	protein	Q99081	UNIPROT	PTCRA	protein	Q6ISU1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22577461	f		miannu	Hebalt positively regulates t-cell genes, such as pt_ and notch3	SIGNOR-197520	0.332
MYC	protein	P01106	UNIPROT	ST3GAL4	protein	Q11206	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22547830	f	 	 	We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. 	SIGNOR-253959	0.2
CTBP1	protein	Q13363	UNIPROT	BHLHE41	protein	Q9C0J9	UNIPROT	up-regulates	binding			9606									16287852	t		gcesareni	We identify the ctip and ctbp corepressors as novel components of the human rbp-jkappa/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain. Functionally, ctip and ctbp augment sharp-mediated repression.	SIGNOR-141613	0.268
PIM1	protein	P11309	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates	phosphorylation	Ser186	RQRKRHKsDSISLSF	9606	BTO:0000785								18467333	t		gcesareni	Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt.	SIGNOR-178619	0.397
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	Synaptic_vesicle_exocytosis	phenotype	SIGNOR-PH160	SIGNOR	up-regulates				9606	BTO:0000938								29953871	f		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. 	SIGNOR-264954	0.7
HOOK1	protein	Q9UJC3	UNIPROT	Epithelial-mesenchymal_transition	phenotype	SIGNOR-PH45	SIGNOR	down-regulates				9606	BTO:0000018								25331952	f		miannu	The epithelial-mesenchymal transition (EMT) is an essential process for embryogenesis. It also plays a critical role in the initiation of tumor metastasis.Overexpression of Hook1 inhibited EMT while knockdown of Hook1 promoted EMT. 	SIGNOR-260643	0.7
SRC	protein	P12931	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1172	ISLDNPDyQQDFFPK	9606									8845374	t		lperfetto	Revealed that peptides derived from egfr residues y992, y1086, y1101, and y1148 bound directly to the sh2 domain of c-src (figure 8c). These experiments demonstrate that a specific subset of egfr receptor c-src phosphorylation sites are also ligands for the sh2 domain of c-src.Cellular src functions as a co-transducer of transmembrane signals emanating from a variety of growth factor receptors, including egfr	SIGNOR-44251	0.609
GATA2	protein	P23769	UNIPROT	TRH	protein	P20396	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534	BTO:0000318								33201916	t		scontino	The rat prepro-TRH gene is activated by GATA2.	SIGNOR-267259	0.267
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates quantity by destabilization	cleavage	Phe619	EVKMDAEfRHDSGYE	-1									8943232	t		lperfetto	FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261769	0.502
tamoxifen	chemical	CHEBI:41774	ChEBI	ESR2	protein	Q92731	UNIPROT	down-regulates activity	chemical inhibition			9606									20512796	t		miannu	Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth. 	SIGNOR-258588	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RHOA	protein	P61586	UNIPROT	up-regulates activity	phosphorylation	Thr100	ENIPEKWtPEVKHFC	9534	BTO:0000298								26816343	t		miannu	We have recently reported that Rac1 is phosphorylated on threonine 108 (108T) by extracellular signal-regulated kinases (ERK) in response to epidermal growth factor (EGF) stimulation. Here, we provide evidence that RhoA is phosphorylated by ERK on 88S and 100T in response to EGF stimulation.	SIGNOR-277203	0.2
FHIT	protein	P49789	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates				9606	BTO:0000551								15313915	f		miannu	We found that this synergistic inhibition of tumor cell growth corresponded with the fhit-mediated inactivation of mdm2, which thereby blocked the association of mdm2 with p53, thus stabilizing the p53 protein.	SIGNOR-127610	0.439
GSK3B	protein	P49841	UNIPROT	IL17RA	protein	Q96F46	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr780	MVLTDPHtPYEEEQR	9606	BTO:0000007								26871944	t		miannu	Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation. 	SIGNOR-277205	0.2
GREB1	protein	Q4ZG55	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	binding			9606	BTO:0000599								31462641	t		miannu	GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Binding of GREB1 to Smad2/3 inhibits transcription	SIGNOR-265885	0.2
CC2D1B	protein	Q5T0F9	UNIPROT	HTR1A	protein	P08908	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007;BTO:0000938								19423080	t	nucleus	lperfetto	Human Freud-2/CC2D1B: a novel repressor of postsynaptic serotonin-1A receptor expression|Human Freud-2 showed strong repressor activity at the human 5-HT1A or heterologous promoter in human HEK-293 5-HT1A-negative cells and neuronal SK-N-SH cells, a model of postsynaptic 5-HT1A receptor-positive cells. 	SIGNOR-268298	0.342
FLT3	protein	P36888	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity				9606									16266983	f		gcesareni	We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway.	SIGNOR-245064	0.443
L-selenocystathionine zwitterion	smallmolecule	CHEBI:62226	ChEBI	L-selenocysteine zwitterion	smallmolecule	CHEBI:57843	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000671;BTO:0000759;BTO:0002688							19961860	t		lperfetto	 the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production.	SIGNOR-275817	0.8
GRK4	protein	P32298	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser375	GTLRTSIsVERQIHK	9606	BTO:0000007								11517230	t		gcesareni	...expression of GRK4ƒŽ‚ drastically increased the basal level of32P incorporation into B2R.[ƒ‚€‚]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation.	SIGNOR-249674	0.292
PIGF	protein	Q07326	UNIPROT	PIGO	protein	Q8TEQ8	UNIPROT	down-regulates quantity by destabilization				10029	BTO:0000246								15632136	f		miannu	We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O.	SIGNOR-261360	0.698
PIM1	protein	P11309	UNIPROT	SKP2	protein	Q13309	UNIPROT	up-regulates activity	phosphorylation	Ser72	PPRKRLKsKGSDKDF	9606									20663873	t		miannu	We found that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser(64) and Ser(72), we have identified Thr(417) as a unique Pim-1 phosphorylation target. Phosphorylation of Thr(417) controls the stability of Skp2 and its ability to degrade p27. 	SIGNOR-259819	0.346
PDGFRB	protein	P09619	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates activity	phosphorylation	Tyr28	SLNQSSGyRYGTDPT	-1									9425276	t		miannu	PDGF-induced phosphorylation of Tyr28 in the N-terminus of Fyn affects Fyn activation. We show here that Fyn, a member of the Src family, is phosphorylated on Tyr28 in the unique N-terminal part of the molecule after interaction with the intracellular domain of the PDGF beta-receptor. Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn.	SIGNOR-250253	0.562
POU5F1	protein	Q01860	UNIPROT	THY1	protein	P04216	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001086								17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254931	0.433
tRNA(Asp)	smallmolecule	CHEBI:29186	ChEBI	Asp-tRNA(Asp)	smallmolecule	CHEBI:29158	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270377	0.8
RABEPK	protein	Q7Z6M1	UNIPROT	IGF2R	protein	P11717	UNIPROT	up-regulates activity	relocalization												9230071	t		lperfetto	P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking.	SIGNOR-253090	0.357
MAP2K1	protein	Q02750	UNIPROT	TAL1	protein	P17542	UNIPROT	down-regulates	phosphorylation	Ser122	DGRMVQLsPPALAAP	9606									11904294	t		gcesareni	We found that hypoxia greatly accelerated tal1 turnover in these cells through mitogen-activated protein kinase (mapk)2-mediated phosphorylation, ubiquitination, and proteasomal degradation.	SIGNOR-116149	0.2
N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide	chemical	CHEBI:91408	ChEBI	JAK2	protein	O60674	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207239	0.8
FLT4	protein	P35916	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates activity	phosphorylation	Tyr1265	FPMTPTTyKGSVDNQ	9606	BTO:0000394								12881528	t		lperfetto	Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail.	SIGNOR-104080	0.2
CDKN1A	protein	P38936	UNIPROT	CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	down-regulates activity	binding			9606	BTO:0000093								11154267	t		lperfetto	Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity	SIGNOR-245462	0.887
TNF	protein	P01375	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				9606									21514273	f	via a ?-catenin-dependent pathway	fspada	Tumor necrosis factor-? (TNF-alpha) Is known to suppress adipocyte differentiation via a Beta-catenin-dependent pathway.	SIGNOR-173421	0.7
isoprenaline	chemical	CHEBI:64317	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								8982677	t		miannu	K i values of the agonists for [~25I]iodocyanopindolol binding to the COS-7 cell membranes are shown in Table 1. In the membranes expressing one of the 13-adrenoceptor subtypes, both isoproterenol and T-0509 caused monophasic dis- placement of [~25I]iodocyanopindolol, suggesting a single binding site of the agonists.	SIGNOR-258576	0.8
MSL3	protein	Q8N5Y2	UNIPROT	MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	form complex	binding			9606		BTO:0000567							16227571	t		miannu	We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. 	SIGNOR-263940	0.815
PTPN2	protein	P17706	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates activity	dephosphorylation	Tyr534	NFLMDNAyFCEADAK	10029	BTO:0000246								12907755	t			PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 	SIGNOR-248393	0.298
TEK	protein	Q02763	UNIPROT	TEK	protein	Q02763	UNIPROT	up-regulates activity	phosphorylation	Tyr1048	GMTCAELyEKLPQGY	-1									11513602	t		lperfetto	Isoelectric focusing electrophoresis and mass spectrometric analysis of a tie2 autophosphorylation time course showed that tyr992 on the putative activation loop was phosphorylated first followed by tyr1108 in the c-terminal tail autophosphorylation of tie2 to produce ptie2 resulted in a 100-fold increase in kcat and a 460-fold increase in kcat/km.	SIGNOR-109786	0.2
PTPRG	protein	P23470	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	dephosphorylation	Tyr1474	GSSNGHVyEKLSSIE	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254702	0.28
POU5F1	protein	Q01860	UNIPROT	TBX18	protein	O95935	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086								17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254945	0.33
IL1B	protein	P01584	UNIPROT	ITGA3	protein	P26006	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001596								1744142	f		lperfetto	TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way.	SIGNOR-253355	0.2
ILK	protein	Q13418	UNIPROT	IPP complex	complex	SIGNOR-C380	SIGNOR	form complex	binding												16493410	t		lperfetto	Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton.	SIGNOR-265762	0.894
G3BP1	protein	Q13283	UNIPROT	Stress_granules	phenotype	SIGNOR-PH124	SIGNOR	up-regulates				9606									25520508	f		miannu	Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) is a stress granule-resident protein that nucleates stress granule assembly and is also inactivated or coopted by many viruses to promote productive infection	SIGNOR-260747	0.7
LHX2	protein	P50458	UNIPROT	MSX1	protein	P28360	UNIPROT	down-regulates activity	binding			-1									9697309	t	2	miannu	Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity	SIGNOR-241327	0.49
TNFRSF17	protein	Q02223	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates				9606									10903733	f		miannu	Bcma overexpression activates elk-1 nuclear factor	SIGNOR-79486	0.2
PP121	chemical	CHEBI:50915	ChEBI	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206298	0.8
FYN	protein	P06241	UNIPROT	VAV1	protein	P15498	UNIPROT	up-regulates	phosphorylation			9606									11005864	t		lperfetto	Study of t cells from a fyn-deficient tcr transgenic mouse also showed that fyn was required for tyrosine phosphorylation and activation of vav induced by both antagonist and agonist peptides.	SIGNOR-82287	0.62
bortezomib	chemical	CHEBI:52717	ChEBI	PSMB2	protein	P49721	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000898								21504411	t		miannu	Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma.	SIGNOR-259309	0.8
KCNQ2	protein	O43526	UNIPROT	KCNQ3	protein	O43525	UNIPROT	up-regulates activity	binding			10116	BTO:0000938								9836639	t			The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current.	SIGNOR-268833	0.497
LYN	protein	P07948	UNIPROT	CD79A	protein	P11912	UNIPROT	up-regulates activity	phosphorylation	Tyr188	EYEDENLyEGLNLDD	-1									9531288	t			Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b. phosphorylation of Y182 alone can lead to further kinase activation and/or effector focusing necessary for phosphorylation of certain downstream targets, such as p62, p110, and Shc, but not others, such as Vav.	SIGNOR-251397	0.729
LRRK2	protein	Q5S007	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates activity	phosphorylation	Ser129	NEAYEMPsEEGYQDY	9606									19576176	t		lperfetto	Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD.	SIGNOR-249690	0.645
CDK1	protein	P06493	UNIPROT	ERCC6L	protein	Q2NKX8	UNIPROT	up-regulates	phosphorylation	Thr1063	VKQFDAStPKNDISP	9606									17218258	t		lperfetto	Following phosphorylation of pich on the cdk1 site t1063, plk1 is recruited to pich and controls its localization. Starting in prometaphase, pich accumulates at kinetochores and inner centromeres.	SIGNOR-152133	0.56
GSK3B	protein	P49841	UNIPROT	CABYR	protein	O75952	UNIPROT	unknown	phosphorylation	Ser155	KTTTPPSsPPPTAVS	-1									15752768	t			GSK3β interacts with and phosphorylates CABYR in vitro. GSK3β interacts with and phosphorylates CABYR in vitro. the functional extent of the CABYR phosphorylation sites to participate in cellular processes through GSK3β remains to be investigated.	SIGNOR-251223	0.41
TUT7	protein	Q5VYS8	UNIPROT	mRNA_polyadenylation	phenotype	SIGNOR-PH200	SIGNOR	down-regulates													25480299	f		lperfetto	Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. Consistently, purified TUT4/7 selectively recognize and uridylate RNAs with short A-tails (less than ∼ 25 nt) in vitro. PABPC1 antagonizes uridylation of polyadenylated mRNAs, contributing to the specificity for short A-tails. 	SIGNOR-268354	0.7
CSNK2A1	protein	P68400	UNIPROT	HDAC2	protein	Q92769	UNIPROT	up-regulates activity	phosphorylation	Ser424	CDEEFSDsEDEGEGG	9606	BTO:0000567								12082111	t		llicata	HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2.	SIGNOR-250888	0.608
TACR1	protein	P25103	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257316	0.294
CSNK2A1	protein	P68400	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser121	WEEEGFGsSSPVKSP	9606	BTO:0000567								16085715	t		miannu	 In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms.  S123 phosphorylation creates a PBD-binding motif and accelerates S53 phosphorylation by Plk1.	SIGNOR-276038	0.418
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	SP1	protein	P08047	UNIPROT	down-regulates activity	dephosphorylation			9606									12684058	t		lperfetto	Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression.	SIGNOR-264669	0.2
FCGR3A	protein	P08637	UNIPROT	TNF	protein	P01375	UNIPROT	up-regulates quantity by expression				9606	BTO:0000801								10728755	f		lperfetto	This study suggests a dominant role for FcgammaRIIIA in the induction of both TNFalpha and IL-1alpha production by human macrophages in rheumatoid arthritis following receptor ligation by small immune complexes. The signaling of TNFalpha production may require the ligation of either 3 FcgammaRIIIA receptors or only 2 FcgammaRIIIA receptors, where one interaction must involve binding via an Fc domain.	SIGNOR-249526	0.339
ANKRD11	protein	Q6UB99	UNIPROT	Dendritic_spine_morphogenesis	phenotype	SIGNOR-PH183	SIGNOR	up-regulates				10090		BTO:0000142							29274743	f		miannu	We found that Ankrd11 knockdown disrupted dendrite and spine formation in developing pyramidal neurons.	SIGNOR-266730	0.7
Papain-like proteinase	protein	P0C6X7-PRO_0000037311	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	down-regulates activity	deubiquitination			9606									31226023	t		miannu	Also, SARS-CoVPLPro catalyzed deubiquitination ofTNF-receptor-associatedfactor3(TRAF3)and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist	SIGNOR-260248	0.2
SGK1	protein	O00141	UNIPROT	MAP3K3	protein	Q99759	UNIPROT	down-regulates activity	phosphorylation	Ser337	DPRGRLRsADSENAL	9534	BTO:0001538								12392720	t		miannu	It was shown that the recombinant MEKK3 protein and fluorescein-labeled MEKK3 peptides (FITC-(159)epRsRhlSVi(168) and FITC-(330)dpRgRlpSAd(339)) are phosphorylated by SGK1 in vitro. It was also observed that the intrinsic kinase activity of MEKK3 on Ser(189) of MKK3 (equivalent to Ser(207) of MKK6) decreased along with phosphorylation of Ser(166) and Ser(337) in MEKK3 in vitro and in vivo. Therefore, it is suggested that SGK1 inhibits MEKK3-MKK3/6 signal transduction by phosphorylation of MEKK3.	SIGNOR-250005	0.2
A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257701	0.561
AXIN2	protein	Q9Y2T1	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9606		BTO:0000142;BTO:0000671;BTO:0000763							10911903	t		gcesareni	It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains.	SIGNOR-79947	0.843
SARM1	protein	Q6SZW1	UNIPROT	TICAM1	protein	Q8IUC6	UNIPROT	down-regulates	binding			10090									17667936	t		gcesareni	SARM utilizes its TIR domain to negatively regulate TRIF	SIGNOR-252068	0.546
MRE11/RAD50/NBS1	complex	SIGNOR-C147	SIGNOR	UFL1	protein	O94874	UNIPROT	up-regulates activity	relocalization			9606	BTO:0001938								30886146	t		lperfetto	UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. UFL1 is recruited to double strand breaks by the MRE11/RAD50/NBS1 complex, and monoufmylates histone H4 following DNA damage.	SIGNOR-265074	0.2
CDK6	protein	Q00534	UNIPROT	CyclinD1/CDK6	complex	SIGNOR-C143	SIGNOR	form complex	binding			9606									8114739	t		lperfetto	Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells.	SIGNOR-250681	0.95
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1696	SPSYSPTsPSYSPTS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248810	0.849
SGK1	protein	O00141	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates activity	phosphorylation	Ser29	GPRYTNLsYIGEGAY	9606	BTO:0000599								19447520	t		miannu	SGK1 was found to physically interact with ERK1/2 as well as MEK1/2. Furthermore, SGK1 mediated the phosphorylation of ERK2 on Ser(29) in a serum-dependent manner. Replacement of Ser(29) to aspartic acid, which mimics the phosphorylation of Ser(29), enhanced the ERK2 activity as well as the MEK/ERK complexes formation.	SIGNOR-276223	0.314
EFNA1	protein	P20827	UNIPROT	EPHA4	protein	P54764	UNIPROT	up-regulates	binding			9606									9330863	t		tpavlidou	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52087	0.817
SMO	protein	Q99835	UNIPROT	GNB2	protein	P62879	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-199177	0.2
PLIN3	protein	O60664	UNIPROT	M6PR	protein	P20645	UNIPROT	up-regulates activity	relocalization			9534	BTO:0004055								9590177	t		lperfetto	TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi.	SIGNOR-253093	0.72
ABL2	protein	P42684	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates activity	phosphorylation	Tyr231	NANGEAVyCKFHYKT	9606	BTO:0000093								12777400	t		lperfetto	C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases	SIGNOR-101306	0.345
INSR	protein	P06213	UNIPROT	IRS2	protein	Q9Y4H2	UNIPROT	up-regulates	binding			9534									7629118	t			Tyrosine phosphorylation of insulin receptor substrate-1 in vivo depends upon the presence of its pleckstrin homology region.	SIGNOR-253604	0.748
IKBKB	protein	O14920	UNIPROT	BCL10	protein	O95999	UNIPROT	up-regulates activity	phosphorylation	Ser134	DGATNNLsRSNSDES	9606	BTO:0000007								16818229	t		miannu	Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling.	SIGNOR-276291	0.765
PIP3	smallmolecule	CHEBI:16618	ChEBI	AKT1	protein	P31749	UNIPROT	up-regulates activity	relocalization			9606									21798082	t		lperfetto	Pip3 acts in turn as a docking site for two kinases, phosphoinositidedependent kinase 1 pdk1) and akt, and the subsequent phosphorylation of akt at serine 308 by pdk1, leading to akt activation.	SIGNOR-236349	0.8
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	PPP1R3A	protein	Q16821	UNIPROT	up-regulates activity	phosphorylation	Ser46	PQPSRRGsDSSEDIY	-1									10648825	t		lperfetto	The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates. 	SIGNOR-252777	0.2
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DRB4	protein	P13762	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-254002	0.2
FGFR1	protein	P11362	UNIPROT	PDK1	protein	Q15118	UNIPROT	up-regulates	phosphorylation	Tyr244	RRLCDLYyINSPELE	9606									22195962	t		llicata	Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1	SIGNOR-193454	0.355
SNAI2	protein	O43623	UNIPROT	CXCR4	protein	P61073	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001033								22074556	f		miannu	 We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. 	SIGNOR-255171	0.414
PTPN6	protein	P29350	UNIPROT	CD72	protein	P21854	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000776								9740800	t		gcesareni	Our work clearly identifies cd72 as both an shp-1 binding protein (figure 1,figure 2) and a direct substrate for shp-1 in vivo (figure 3). As tyrosine phosphorylation of cd72 strongly correlates with the ability of the bcr to deliver growth-inhibitory/apoptosis-inducing signals (figure 4), our results suggest that shp-1-catalyzed dephosphorylation of cd72 may antagonize these signals.	SIGNOR-60155	0.607
CAMK2A	protein	Q9UQM7	UNIPROT	SYNGAP1	protein	Q96PV0	UNIPROT	up-regulates activity	phosphorylation	Ser1138	PSITKQHsQTPSTLN	-1									14970204	t		miannu	Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. We identify four major sites of phosphorylation, serines 1123, 1058, 750/751/756, and 764/765. 	SIGNOR-262688	0.439
CHEK1	protein	O14757	UNIPROT	TP73	protein	O15350	UNIPROT	up-regulates	phosphorylation	Ser47	EVVGGTDsSMDVFHL	9606									14585975	t		llicata	We found that endogenous p73alpha is serine phosphorylated by endogenous chk1 upon dna damage, which is a mechanism required for the apoptotic-inducing function of p73alpha.	SIGNOR-118913	0.517
adenosine	smallmolecule	CHEBI:16335	ChEBI	inosine	smallmolecule	CHEBI:17596	ChEBI	up-regulates quantity	precursor of			-1									15926889	t		Luana	Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates	SIGNOR-269736	0.8
PRPS2	protein	P11908	UNIPROT	Nucleotide_synthesis	phenotype	SIGNOR-PH179	SIGNOR	up-regulates				9606	BTO:0006038								29074724	f		lperfetto	We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production.	SIGNOR-265734	0.7
BAK1	protein	Q16611	UNIPROT	CYCS	protein	P99999	UNIPROT	up-regulates	relocalization			9606									11175253	t	Translocation from Mitochondria to Cytosol	amattioni	Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux	SIGNOR-105206	0.549
AMPK	complex	SIGNOR-C15	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									15866171	t		lperfetto	Ampk activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate ampk-dependent cell-cycle arrest	SIGNOR-216475	0.421
APBA1	protein	Q02410	UNIPROT	Exocytosis	phenotype	SIGNOR-PH157	SIGNOR	up-regulates				9606	BTO:0000938								11036064	f		miannu	As neurexins have been proposed to function in neuronal cell adhesion, it is possible that they define specific sites at the plasma membrane and that Mint complexes and Mint1-CASK complexes on neurexin are involved in the localized recruitment of Munc18 to the sites of exocytosis. In support of this hypothesis, both CASK and Mint1 have been reported to be localized at synapses	SIGNOR-264043	0.7
CBL	protein	P22681	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									10514377	t		miannu	Ubiquitination of the PDGF β-receptor (Rβ) by the c-Cbl RING in an SH2-dependent manner.	SIGNOR-272553	0.612
MEF2C	protein	Q06413	UNIPROT	MYH10	protein	P35580	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0001103							15728583	t		lperfetto	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238769	0.352
PSEN1	protein	P49768	UNIPROT	gamma-secretase	complex	SIGNOR-C98	SIGNOR	form complex	binding			9606									25610395	t		lperfetto	-Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2)	SIGNOR-209705	0.956
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRM4	protein	Q14833	UNIPROT	up-regulates activity	chemical activation			9606									25042998	t		miannu	Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate	SIGNOR-264074	0.8
SIX1	protein	Q15475	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates quantity	transcriptional regulation			9606									16488997	t			We now show that the gene encoding Ezrin is a direct transcriptional target of Six1.	SIGNOR-259374	0.35
HTR4	protein	Q13639	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257154	0.252
CSF2	protein	P04141	UNIPROT	CSF3R	protein	Q99062	UNIPROT	up-regulates	binding			9606	BTO:0000130								16492764	t		gcesareni	A g-csfr expression plasmid was introduced into interleukin-3 (il-3)-dependent mouse myeloid precursor fdc-p1 cells that normally do not respond to g-csf. G-csf stimulated proliferation of the transformants. These results suggested that the g-csfr, but not the il-3/gm-csf receptors, transduced the neutrophilic differentiation signal into cells	SIGNOR-144740	0.586
PLK2	protein	Q9NYY3	UNIPROT	NPM1	protein	P06748	UNIPROT	up-regulates	phosphorylation	Ser4	sMDMDMSP	9606	BTO:0000567								15190079	t		gcesareni	Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.	SIGNOR-125720	0.517
DYRK1A	protein	Q13627	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity.	SIGNOR-183670	0.521
ZM447439	chemical	CHEBI:91376	ChEBI	AURKC	protein	Q9UQB9	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207926	0.8
DAAM1	protein	Q9Y4D1	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity				9606									23151663	f		gcesareni	In pcp, dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58.	SIGNOR-199381	0.417
ERG	protein	P11308	UNIPROT	CXCR4	protein	P61073	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19396168	f	 	miannu	ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression. 	SIGNOR-253911	0.2
EGFR	protein	P00533	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates	binding			9606	BTO:0000093	BTO:0000150							26918608	t		lperfetto	p85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation. 	SIGNOR-33633	0.802
POLR1G	protein	O15446	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding												22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266155	0.2
L-serine	chemical	CHEBI:17115	ChEBI	PKM	protein	P14618	UNIPROT	up-regulates activity	chemical activation			9606									23064226	t			We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation.	SIGNOR-251557	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	GTF2I	protein	P78347	UNIPROT	up-regulates	phosphorylation			9606									10648599	t	inferred from 70% family members	lperfetto	Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation.	SIGNOR-270057	0.2
GTF2I	protein	P78347	UNIPROT	PRRX1	protein	P54821	UNIPROT	up-regulates	binding			9606									9334314	t		miannu	Spin binds specifically to multiple sequences in the c-fos promoter and interacts cooperatively withphox1to promote serum-inducible transcription of a reporter gene driven by the c-fos serum response element (sre).	SIGNOR-52654	0.351
MAP3K11	protein	Q16584	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	phosphorylation	Ser257	ISGQLVDsIAKTRDA	9606	BTO:0001538								9003778	t		lperfetto	These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo.	SIGNOR-48574	0.608
AKAP12	protein	Q02952	UNIPROT	PRKACA	protein	P17612	UNIPROT	up-regulates activity	relocalization												14657015	t		lperfetto	A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. 	SIGNOR-271835	0.2
TGFBR2	protein	P37173	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates activity	phosphorylation	Thr204	VQRTIARtIVLQESI	452646									7774578	t		lperfetto	The TGF-beta type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, T beta R-I, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling.	SIGNOR-32748	0.709
NR0B2	protein	Q15466	UNIPROT	NR1I3	protein	Q14994	UNIPROT	down-regulates	binding			9606									15000748	t		gcesareni	The short heterodimer partner (shp), an orphan nuclear receptor that lacks a conventional dna binding domain, was initially identified by its interaction with car. We have examined the role of shp in car-mediated transactivation of the cyp2b gene. Coexpression of shp inhibited the transactivation of the cyp2b gene by car in cultured hepatoma cells and the p160 coactivator grip1 reversed the inhibition.	SIGNOR-123154	0.523
pimozide	chemical	CHEBI:8212	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258378	0.8
IKBKB	protein	O14920	UNIPROT	DOK1	protein	Q99704	UNIPROT	up-regulates	phosphorylation	Ser443	ATGSGIKsHNSALYS	9606									15574499	t		amattioni	Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility.	SIGNOR-131451	0.255
PRKCZ	protein	Q05513	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser558	VPTYESAsIRRFQEG	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	Finally, basal chat phosphorylation in neurons is mediated predominantly by pkc at ser-476, with pkc activation increasing phosphorylation at ser-440 and enhancing chat activity.	SIGNOR-129336	0.291
AXIN1	protein	O15169	UNIPROT	APC	protein	P25054	UNIPROT	up-regulates activity	binding			9606	BTO:0000038								9734785	t		amattioni	Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level.	SIGNOR-60043	0.943
PPM1A	protein	P35813	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	dephosphorylation			9606									16751101	t		lperfetto	Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.	SIGNOR-232110	0.606
RDH10	protein	Q8IZV5	UNIPROT	retinal	smallmolecule	CHEBI:15035	ChEBI	up-regulates quantity	chemical modification			9606									21621639	t		lperfetto	Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11	SIGNOR-265120	0.8
IMPDH2	protein	P12268	UNIPROT	IMP	smallmolecule	CHEBI:17202	ChEBI	down-regulates quantity	chemical modification			9606									19480389	t		miannu	IMPDH controls the gateway to guanine nucleotides, making it an “enzyme of consequence” for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS).	SIGNOR-267334	0.8
MUC1	protein	P15941	UNIPROT	KLF4	protein	O43474	UNIPROT	up-regulates activity	binding												17308127	t		lperfetto	Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element. Our results show that MUC1-C binds constitutively to KLF4, occupies PE21 with KLF4, and enhances the KLF4 occupancy of PE21. 	SIGNOR-270543	0.285
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	DCX	protein	O43602	UNIPROT	unknown	phosphorylation	Thr336	SKQSPIStPTSPGSL	9606									14741103	t		llicata	In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35.	SIGNOR-250660	0.415
CDK1	protein	P06493	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0003918								19917720	t		lperfetto	Cyclin-Dependent Kinase 1-Mediated Bcl-xL/Bcl-2 Phosphorylation Acts as a Functional Link Coupling Mitotic Arrest and Apoptosis|These findings suggest a model whereby a switch in the duration of CDK1 activation, from transient during mitosis to sustained during mitotic arrest, dramatically increases the extent of Bcl-xL/Bcl-2 phosphorylation, resulting in inactivation of their antiapoptotic function. Thus, phosphorylation of antiapoptotic Bcl-2 proteins acts as a sensor for CDK1 signal duration and as a functional link coupling mitotic arrest to apoptosis.	SIGNOR-267987	0.351
SUCLG1	protein	P53597	UNIPROT	Succinyl-CoA GTP variant	complex	SIGNOR-C399	SIGNOR	form complex	binding			9606									32627745	t		miannu	Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS). 	SIGNOR-266263	0.927
RPS27	protein	P42677	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262444	0.863
PRKG1	protein	Q13976	UNIPROT	TNNI3	protein	P19429	UNIPROT	up-regulates activity	phosphorylation	Ser23	PAPIRRRsSNYRAYA	9606									15769444	t		lperfetto	Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.	SIGNOR-134640	0.366
CSNK1A1	protein	P48729	UNIPROT	TIAM1	protein	Q13009	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser329	DVNAGEGsEFADSGI	9606	BTO:0002181								25124033	t		miannu	Phosphorylation of Ser329, Ser334, and Thr340 in Tiam1 is required for its interaction with βTrCP1. The proteolysis of Tiam1 is prevented by βTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site.	SIGNOR-276673	0.313
ERCC1	protein	P07992	UNIPROT	Nucleotide-excision_repair	phenotype	SIGNOR-PH209	SIGNOR	up-regulates													24086043	f		lperfetto	The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275710	0.7
ziprasidone	chemical	CHEBI:10119	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258504	0.8
PRKCA	protein	P17252	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates activity	phosphorylation	Ser876	QGLAERIsVL										12058027	t		lperfetto	Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.	SIGNOR-275953	0.371
PPARGC1A	protein	Q9UBK2	UNIPROT	CYCS	protein	P99999	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000443								23021218	f		lperfetto	PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). 	SIGNOR-253097	0.391
NOX4	protein	Q9NPH5	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	up-regulates quantity	chemical modification			9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264724	0.8
MCF2	protein	P10911	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260558	0.769
L3MBTL2	protein	Q969R5	UNIPROT	MDC1	protein	Q14676	UNIPROT	up-regulates activity	binding			9606									31225475	t		miannu	L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.	SIGNOR-266786	0.2
NEK2	protein	P51955	UNIPROT	CEP250	protein	Q9BV73	UNIPROT	down-regulates	phosphorylation	Ser2392	AGLHHSLsHSLLAVA	9606									24695856	t		lperfetto	Our data support a model in which centrosome disjunction is triggered by the hyperphosphorylation of c-nap1, a major linker component. This occurs in response to a shift in the balance of activities of the nek2?_Pp1 bi-stable switch. C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro.	SIGNOR-204833	0.766
PRKACA	protein	P17612	UNIPROT	RET	protein	P07949	UNIPROT	down-regulates	phosphorylation	Ser696	SSGARRPsLDSMENQ	9606	BTO:0000938								20682772	t		llicata	Furthermore, we find that activation of protein kinase a (pka) by forskolin reduces the recruitment of shp2 to ret and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of ser(696), a known pka phosphorylation site in ret, enhances shp2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth.	SIGNOR-167349	0.374
IKBKE	protein	Q14164	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Thr404	NSHPLSLtSDQYKAY	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178387	0.732
perfluorooctanoic acid	chemical	CHEBI:35549	ChEBI	AR	protein	P10275	UNIPROT	down-regulates activity	chemical inhibition			-1									23764977	t		miannu	Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. 	SIGNOR-268768	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	NUP50	protein	Q9UKX7	UNIPROT	down-regulates activity	phosphorylation	Ser315	TQSKPVSsPFPTKPL	9606									19767751	t		llicata	Erk phosphorylates nup50 at ser221 and ser315 phosphorylation of nup50 reduces affinity for importin-beta	SIGNOR-263043	0.2
CHUK	protein	O15111	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								15808510	t		gcesareni	Ikkalpha phosphorylates eralpha, aib1/src-3, and histone h3.	SIGNOR-135050	0.403
FZD4	protein	Q9ULV1	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates activity	binding			9606									27096005	t		areggio	Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin.	SIGNOR-258958	0.741
adenosine	smallmolecule	CHEBI:16335	ChEBI	ADORA2A	protein	P29274	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257447	0.8
CDK1	protein	P06493	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates	phosphorylation	Ser5	sPPLRDVD	9606			SIGNOR-C17						14749395	t		lperfetto	Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21.	SIGNOR-121605	0.372
M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	IL4	protein	P05112	UNIPROT	up-regulates				9606	BTO:0000801								32454942	f		miannu	Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation	SIGNOR-263822	0.7
PTPRD	protein	P23468	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates	dephosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606	BTO:0000551;BTO:0000527	BTO:0000142							19478061	t		miannu	Transfection of wild-type ptprd resulted in the specific dephosphorylation of stat3 at tyrosine 705, a residue that must be phosphorylated for stat3 to be active	SIGNOR-185933	0.533
MAPK1	protein	P28482	UNIPROT	NR3C2	protein	P08235	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser227	FGSFPVHsPITQGTP	9606	BTO:0005043								22798426	t		miannu	 Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276103	0.291
NKX6-3	protein	A6NJ46	UNIPROT	GKN1	protein	Q9NS71	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001007								26314965	t		Luana	 In particular, NKX6.3 transcriptional factor was found to bind specifically to the upstream sequences of GKN1, a gastric-specific tumor suppressor, and dramatically increase expression of the latter. 	SIGNOR-266096	0.38
PFK	proteinfamily	SIGNOR-PF79	SIGNOR	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35.	SIGNOR-266474	0.8
WAC	protein	Q9BTA9	UNIPROT	PLK1	protein	P53350	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								30021153	t		lperfetto	Here, we report that the activation of Plk1 requires WAC, a WW domain-containing adaptor protein with a coiled-coil region that predominantly localizes to the nucleus in interphase. Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. 	SIGNOR-265036	0.2
JAK1	protein	P23458	UNIPROT	JAK1/STAT1/STAT3	complex	SIGNOR-C120	SIGNOR	form complex	binding			10090									15284024	t		lperfetto	Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min.	SIGNOR-235608	0.2
CD40	protein	P25942	UNIPROT	TRAF2	protein	Q12933	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								18635759	t		lperfetto	Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3.	SIGNOR-179473	0.838
TRAF2	protein	Q12933	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates				9606									10795740	t			We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation	SIGNOR-256252	0.891
MAPK3	protein	P27361	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation	Ser664	KKTSGPLsPPTGPPG	10090	BTO:0000944								15851026	t		lperfetto	Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation.	SIGNOR-249457	0.682
SPOP	protein	O43791	UNIPROT	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								28599312	t		Gianni	Cullin3 SPOP ubiquitin E3 ligase promotes the poly-ubiquitination and degradation of HDAC6	SIGNOR-268862	0.2
AKT2	protein	P31751	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	phosphorylation	Ser615	SYKIRFNsISCSDPL	9606	BTO:0001853								24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251624	0.483
AKT1	protein	P31749	UNIPROT	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606	BTO:0000567								12853467	t		gcesareni	These findings suggest that PKB-dependent binding of 14-3-3s to phospho-Ser483 of cardiac PFK-2 mediates the stimulation of glycolysis by growth factor.	SIGNOR-252555	0.643
PTPRJ	protein	Q12913	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	9606									10734133	t		gcesareni	These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase.	SIGNOR-76088	0.309
FYN	protein	P06241	UNIPROT	CDK5	protein	Q00535	UNIPROT	up-regulates activity	phosphorylation	Tyr15	EKIGEGTyGTVFKAK	9606									14757045	t			Constitutively active Fyn phosphorylated Tyr15 of Cdk5. Fyn Facilitates Kinase Activity of Cdk5 Via Tyr15 Phosphorylation	SIGNOR-251156	0.59
HSP90AA1	protein	P07900	UNIPROT	CBLL1	protein	Q75N03	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								31952268	t		miannu	By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. 	SIGNOR-271474	0.2
PDGFRB	protein	P09619	UNIPROT	PDGFRB	protein	P09619	UNIPROT	unknown	phosphorylation	Tyr857	DIMRDSNyISKGSTF	9606									2550144	t		llicata	We have identified two platelet-derived growth factor (pdgf)-dependent autophosphorylation sites in the beta subunit of the human pdgf receptor (pdgf-r). The major site of phosphorylation (tyr-857) corresponds to the major autophosphorylation site in many other tyrosine kinases. Tyr-751, which lies within the kinase insert region, is a second in vivo site and the major in vitro site.	SIGNOR-22997	0.2
NOTCH1	protein	P46531	UNIPROT	LFNG	protein	Q8NES3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								15207708	f		gcesareni	Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta.	SIGNOR-236845	0.748
vorinostat	chemical	CHEBI:45716	ChEBI	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257947	0.8
PRKCA	protein	P17252	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	phosphorylation	Ser1323	ALAPRSVsLKDKGRF	-1									11306676	t		lperfetto	These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels.	SIGNOR-249086	0.482
AMPK	complex	SIGNOR-C15	SIGNOR	RPTOR	protein	Q8N122	UNIPROT	down-regulates	phosphorylation	Ser792	LTQSAPAsPTNKGVH	10090			SIGNOR-C15	SIGNOR-C3					18439900	t		lperfetto	These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK	SIGNOR-263044	0.501
RASGRF2	protein	O14827	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260574	0.476
RFX3	protein	P48380	UNIPROT	FOXJ1	protein	Q92949	UNIPROT	up-regulates activity	binding			9606	BTO:0000939								23822649	t		miannu	 RFX3 acts as a transcriptional co-activator to FOXJ1 that enhances the expression of cilia-associated genes. FOXJ1 is an important regulator of cilia gene expression during ciliated cell differentiation, with RFX3 as a transcriptional co-activator to FOXJ1, helping to induce the expression of cilia genes in the process of ciliated cell differentiation of basal/progenitor cells.	SIGNOR-266929	0.566
SRC	protein	P12931	UNIPROT	FBXO5	protein	Q9UKT4	UNIPROT	up-regulates	phosphorylation	Tyr142	ALETSRLyEDSGYSS	9606									20717963	t		lperfetto	We found that emi1 stability was regulated by phosphorylation and mutation of tyrosine 142 reduced the stability. Our data suggested bcr-abl-induced emi1 phosphorylation might be mediated by src kinase.	SIGNOR-167529	0.329
CLASP1	protein	Q7Z460	UNIPROT	CLIP2	protein	Q9UDT6	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								15631994	t		lperfetto	CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. 	SIGNOR-265092	0.613
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	ALOX5	protein	P09917	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000567								12670876	t	inferred from 70% family members	lperfetto	Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells.	SIGNOR-270088	0.2
CBL	protein	P22681	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	ubiquitination			9606	BTO:0000782								11526404	t		lperfetto	Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner.	SIGNOR-252668	0.594
MAPK9	protein	P45984	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	binding			9606									9405416	t	Inactive c-Jun NH2-terminal kinase (JNK).	gcesareni	C-jun is targeted for ubiquitination by its association with inactive c-jun nh2-terminal kinase (jnk).Phosphorylation By activated jnk protects c-jun from ubiquitination.	SIGNOR-53791	0.881
PTPRJ	protein	Q12913	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606									10734133	t		gcesareni	These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase.	SIGNOR-76092	0.309
ABL1	protein	P00519	UNIPROT	LGALS3	protein	P17931	UNIPROT	unknown	phosphorylation	Tyr79	GAPAPGVyPGPPSGP	9606									20600357	t		llicata	In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility.	SIGNOR-166501	0.364
CSNK1A1	protein	P48729	UNIPROT	PSEN2	protein	P49810	UNIPROT	unknown	phosphorylation	Ser19	EVCDERTsLMSAESP	-1									8972483	t		llicata	In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. 	SIGNOR-250790	0.4
P2RY6	protein	Q15077	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257343	0.2
PIM1	protein	P11309	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation	Ser153	PSSKRSPsTATLSLP	9606	BTO:0001061								31730483	t		miannu	Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 	SIGNOR-276774	0.629
ABL1	protein	P00519	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates	phosphorylation	Tyr407	SGLSMSSySVPRTPD	9606									18280240	t		llicata	In this study, we show that c-abl directly phosphorylates yap1 at position y357 in response to dna damage. Tyrosine-phosphorylated yap1 is a more stable protein that displays higher affinity to p73 and selectively coactivates p73 proapoptotic target genes.	SIGNOR-160860	0.707
FOXA1	protein	P55317	UNIPROT	HSPA1A	protein	P0DMV8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19486887	f	 	miannu	 The results showed overexpression of Foxa1 promoted the expression of HSP72, while Foxa1 depletion, induced by antisense oligonucleotides, decreased the expression of HSP72 in MCF-7 cells under normal and heat stress condition. 	SIGNOR-254164	0.2
TRRAP	protein	Q9Y4A5	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269589	0.73
DLX2	protein	Q07687	UNIPROT	MSX1	protein	P28360	UNIPROT	down-regulates activity	binding			10090	BTO:0000944								9111364	t	2	miannu	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240918	0.408
TRIM9	protein	Q9C026	UNIPROT	TRIM9	protein	Q9C026	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606		BTO:0000142							20085810	t		miannu	Collectively, these results indicated that TRIM9 is an E3 ligase for its self-ubiquitination and that the ubiquitination of TRIM9 likely serves as a signal for proteasomal degradation. As shown in Fig. 1A, TRIM9 was ubiquitinated by itself when incubated with UbcH5b. In contrast, ubiquitination was observed when incubated with other E2 enzymes. These results suggest that TRIM9 cooperates with UbcH5b for its self-ubiquitination. N	SIGNOR-271419	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation			9606									14699954	t	inferred from 70% family members	amattioni	The targets of jnk include the transcription factors p53. P75ntr-mediated apoptosis was shown to be dependent of p53	SIGNOR-269985	0.2
OTUB1	protein	Q96FW1	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	deubiquitination												34785775	t		lperfetto	Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec	SIGNOR-276528	0.546
HTR7	protein	P34969	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257323	0.252
PTPN7	protein	P35236	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Tyr187	HTGFLTEyVATRWYR	9606									16226275	t			First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185	SIGNOR-248483	0.805
MDM4	protein	O15151	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1									12393902	t		miannu	Here we demonstrate that MdmX acts as a ubiquitin ligase in vitro, being capable of autoubiquitination, as well as mediating the ubiquitination of p53. 	SIGNOR-271389	0.947
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	S100A6	protein	P06703	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12859951	f		miannu	NF-kappaB transcription factor contributes to the activation of S100A6 gene expression in response to TNFalpha in HepG2 cells.	SIGNOR-254803	0.2
AKT1	protein	P31749	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates	phosphorylation	Ser319	TFRPRTSsNASTISG	9606									11237865	t		lperfetto	The transcription factor, forkhead in rhabdomyosarcoma (FKHR), is phosphorylated at three amino acid residues (Thr-24, Ser-256 and Ser-319) by protein kinase b (PKB)alpha. FKHR (forkhead in rhabdomyosarcoma), AFX (all1 fused gene from chromosome x) and FKHRL1 (FKHR-like 1) are phosphorylated directly by PKB in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus.	SIGNOR-105459	0.866
FOXO1	protein	Q12778	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								25510553	t		miannu	FoxO1, which is up-regulated during early stages of diet-induced leptin resistance, directly interacts with STAT3 and prevents STAT3 from binding to specificity protein 1 (SP1)-pro-opiomelanocortin (POMC) promoter complex, and thereby inhibits STAT3-mediated regulation of POMC transcription.	SIGNOR-263496	0.58
PGM1	protein	P36871	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	down-regulates quantity	chemical modification			9606									32898648	t		miannu	Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P).	SIGNOR-267932	0.8
RAD21	protein	O60216	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates activity				10090									20711430	f			Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice	SIGNOR-259975	0.7
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	ENAH	protein	Q8N8S7	UNIPROT	up-regulates activity	phosphorylation			9606									15066263	t		miannu	 Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts	SIGNOR-268285	0.2
F2RL3	protein	Q96RI0	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257370	0.357
GATA6	protein	Q92908	UNIPROT	CYP17A1	protein	P05093	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002850	 BTO:0000975							15284005	f	 	miannu	The transcription factor GATA6, which regulates the promoter activity of CYP17 and CYP11A, was increased in the PCOS compared to normal theca cells. 	SIGNOR-254198	0.353
AURKA	protein	O14965	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	phosphorylation	Ser83	ALREIRYsLLPFANE	9606									15147269	t		lperfetto	On the basis of these observations, we conclude that s83 of lats2 is a phosphorylation target of aurora-a and this phosphorylation plays a role of the centrosomal localization of lats2.	SIGNOR-124830	0.388
LRRC4	protein	Q9HBW1	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		BTO:0000142							25526788	f		miannu	LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway.	SIGNOR-264056	0.2
RBPJ	protein	Q06330	UNIPROT	DUSP1	protein	P28562	UNIPROT	up-regulates	binding			10090									17158101	t		gcesareni	Notch induction of mkp-1 depends on an rbp-j-dependent mechanism.	SIGNOR-236851	0.252
4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide	chemical	CHEBI:94506	ChEBI	CDK1	protein	P06493	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193546	0.8
CPT1A	protein	P50416	UNIPROT	O-palmitoyl-L-carnitine	smallmolecule	CHEBI:17490	ChEBI	up-regulates quantity	chemical modification			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267129	0.8
CSNK2B	protein	P67870	UNIPROT	EIF5	protein	P55010	UNIPROT	up-regulates activity	phosphorylation	Ser389	LKEAEEEsSGGEEED	9606	BTO:0001938								11861906	t		llicata	Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis.	SIGNOR-251069	0.387
PPFIA1	protein	Q13136	UNIPROT	PTPRF	protein	P10586	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000093								7796809	t	brain	lperfetto	We have identified a novel cytoplasmic 160 kDa phosphoserine protein termed LAR-interacting protein 1 (LIP.1), which binds to the LAR membrane-distal D2 protein tyrosine phosphatase domain and appears to localize LAR to focal adhesions.	SIGNOR-264141	0.793
NPRL3	protein	Q12980	UNIPROT	GATOR1	complex	SIGNOR-C192	SIGNOR	form complex	binding			9606									23723238	t		miannu	Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5	SIGNOR-255282	0.952
BBOX1	protein	O75936	UNIPROT	4-(trimethylammonio)butanoate	smallmolecule	CHEBI:16244	ChEBI	down-regulates quantity	chemical modification			9606									11802770	t		miannu	In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine.	SIGNOR-269697	0.8
MAPKAPK2	protein	P49137	UNIPROT	HSPA1L	protein	P34931	UNIPROT	up-regulates activity	phosphorylation	Ser241	DFDNRLVsHFVEEFK	-1									31642047	t	done	miannu	 We demonstrate that MK2 phosphorylates HspA1L solely on Ser241, a residue within the N-terminal nucleotide-binding domain of the enzyme. This phosphorylation event enhances the chaperone activity of HspA1L in vitro and renders male germ cells more resistant to heat stress-induced apoptosis.	SIGNOR-273674	0.2
PPARD	protein	Q03181	UNIPROT	SOD1	protein	P00441	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001951								18048767	f		miannu	 Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs. 	SIGNOR-255053	0.27
GHR	protein	P10912	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates				9606									23612709	f		miannu	Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin. Possible stimuli for NFATc2 activation are PGF2α and GH.	SIGNOR-255459	0.2
WNT5A	protein	P41221	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates activity				9606									21078818	f		gcesareni	Common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3).	SIGNOR-169666	0.706
MYOD1	protein	P15172	UNIPROT	MYOG	protein	P15173	UNIPROT	up-regulates quantity by expression	transcriptional regulation					BTO:0001103							15870273	t		Simone Vumbaca	We suggest that the interaction between MyoD and Pbx is necessary to initially target MyoD to the myogenin promoter	SIGNOR-255639	0.436
ERO1A	protein	Q96HE7	UNIPROT	ERP44	protein	Q9BS26	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000567								11847130	t		Simone	Here, we report the functional characterization of a novel UPR-induced ER resident protein (ERp44) that forms mixed disulfides with both hEROs, as well as with partially unfolded Ig subunits.	SIGNOR-261049	0.2
NOTCH4	protein	Q99466	UNIPROT	MAML2	protein	Q8IZL2	UNIPROT	up-regulates	binding			9606									12386158	t		gcesareni	We show here identification of two new members of human mam family (human mastermind-2 (hmam-2) and human mastermind-3 (hmam-3)), which retain characteristics similar to human mastermind-1 (hmam-1) and drosophila mastermind. Both hmam-2 and hmam-3 stabilize and participate in the dna-binding complex rbp-j/cbf-1 protein and the notch intracellular domains that serve as intermediates of the signaling. Both hmam-2 and hmam-3 enhanced the activation of transcription from a target promoter by notch signaling. However, we also show evidence that the activation of the target promoter by notch3 and notch4 is more efficiently potentiated by hmam-2 than by hmam-1 or -3.	SIGNOR-94279	0.854
MAPK1	protein	P28482	UNIPROT	PGR	protein	P06401	UNIPROT	down-regulates	phosphorylation	Ser294	APMAPGRsPLATTVM	9606	BTO:0000150								10655479	t		miannu	Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26s proteasome	SIGNOR-74712	0.588
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1892	TPKYSPTsPTYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120140	0.316
PPM1B	protein	O75688	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	down-regulates activity	dephosphorylation			-1									22750291	t		lperfetto	PPM1B dephosphorylates TBK1 in vivo and in vitro.|These results demonstrate that PPM1B inhibits TBK1 mediated antiviral signaling by directly dephosphorylating TBK1 at Ser172.	SIGNOR-276985	0.36
NEUROG3	protein	Q9Y4Z2	UNIPROT	ASH1L	protein	Q9NR48	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19028584	f		miannu	Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated.	SIGNOR-254629	0.2
RPS6KA5	protein	O75582	UNIPROT	ETV1	protein	P50549	UNIPROT	up-regulates activity	phosphorylation	Ser216	PMYQRQMsEPNIPFP	9606	BTO:0002181								12213813	t		lperfetto	Activated, overexpressed MSK1 was able to phosphorylate ER81 at Ser191 and Ser216. Mutation of these residues strongly impairs ER81-responsive promoter activity.	SIGNOR-262987	0.476
BIRC6	protein	Q9NR09	UNIPROT	CASP3	protein	P42574	UNIPROT	down-regulates	binding			9606									15200957	t		gcesareni	Bruce binds and thereby inhibits caspases, in particular effector caspase-3.	SIGNOR-125956	0.477
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1892	TPKYSPTsPTYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120052	0.781
FZR1	protein	Q9UM11	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								12234927	t		miannu	We found that Cdc25 A degradation during mitotic exit and in early G(1) is mediated by the anaphase-promoting complex or cyclosome (APC/C)(Cdh1) ligase, and that a KEN-box motif in the N-terminus of the protein is required for its targeted degradation.	SIGNOR-271388	0.476
RPS6KA1	protein	Q15418	UNIPROT	RANBP3	protein	Q9H6Z4	UNIPROT	unknown	phosphorylation	Ser126	VKRERTSsLTQFPPS	9606									18280241	t		llicata	Rsk phosphorylates serine 58 of ranbp3 in vitro and in vivo	SIGNOR-160904	0.326
glucose	chemical	CHEBI:17234	ChEBI	AMPK	complex	SIGNOR-C15	SIGNOR	down-regulates activity				10090	BTO:0000222								18477450	f			Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK).	SIGNOR-256137	0.8
RRAGB	protein	Q5VZM2	UNIPROT	RAGBD	complex	SIGNOR-C116	SIGNOR	form complex	binding			9606									20381137	t		gcesareni	Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant	SIGNOR-228179	0.77
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates	phosphorylation	Ser495	KTMIRKRsFGNPFEG	9606									22778263	t		lperfetto	Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity	SIGNOR-198150	0.2
PRKACA	protein	P17612	UNIPROT	STMN2	protein	Q93045	UNIPROT	down-regulates activity	phosphorylation	Ser97	AAEERRKsQEAQVLK	9534	BTO:0000298								9525956	t		miannu	Using in vitro phosphorylated recombinant protein, four phosphorylation sites were identified in the SCG10 sequence. Ser-50 and Ser-97 were the target sites for protein kinase A. phosphorylation negatively regulates the microtubule-depolymerizing activity of SCG10 and that all four sites participate in this regulation	SIGNOR-250057	0.313
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	TDGF1	protein	P13385	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269244	0.519
DLL1	protein	O00548	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								16140393	t		lperfetto	Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate.	SIGNOR-209732	0.61
BAZ1B	protein	Q9UIG0	UNIPROT	MDC1	protein	Q14676	UNIPROT	down-regulates				9606									20965415	f		gcesareni	H2ax tyr142 is constitutively phosphorylated by the kinase wstf, a member of the baz/wal family of chromatin remodelling enzymes, and blocks mdc1 recruitment	SIGNOR-168831	0.371
DIO2	protein	Q92813	UNIPROT	iodide	smallmolecule	CHEBI:16382	ChEBI	up-regulates quantity	chemical modification			9606									34674502	t		scontino	Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3.	SIGNOR-266953	0.8
PDP1	protein	Q9P0J1	UNIPROT	PDHA1	protein	P08559	UNIPROT	up-regulates activity	dephosphorylation	Ser232	NRYGMGTsVERAAAS	-1									7782287	t			Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism	SIGNOR-252055	0.722
UQCRC1	protein	P31930	UNIPROT	Mitochondrial respiratory chain complex III	complex	SIGNOR-C279	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits	SIGNOR-262198	0.889
EXT1	protein	Q16394	UNIPROT	BMP4	protein	P12644	UNIPROT	up-regulates activity				9606									24860992	f		miannu	Decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern.	SIGNOR-264018	0.365
GRIPAP1	protein	Q4V328	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates activity	binding			9606	BTO:0002181;BTO:0000142								17761173	t		Giorgia	To examine whether GRASP‐1 interacts with MEKK1 and JNK1 in neurons, co‐immunoprecipitation experiments were performed with detergent‐solubilized extracts from cultured cortical neurons. Both antiJNK1 and anti‐MEKK1 antibodies immunoprecipitated GRASP‐1 from neuronal lysates. These results suggest that GRASP‐1 interacts with MEKK1 and JNK1 in neurons.	SIGNOR-260640	0.316
MAPK3	protein	P27361	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser69	GPLAPPAsPGPFATR	9606									15486195	t		lperfetto	In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel	SIGNOR-129878	0.721
DOK1	protein	Q99704	UNIPROT	AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257686	0.34
F2R	protein	P25116	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256732	0.376
EPAS1	protein	Q99814	UNIPROT	KDM5B	protein	Q9UGL1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271578	0.288
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser705	LPEPAKKsEELVAEA	9606									10195894	t			Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.	SIGNOR-251283	0.2
HNRNPU	protein	Q00839	UNIPROT	HOXA2	protein	O43364	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation												17174306	f		lperfetto	In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs.	SIGNOR-262284	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates activity	phosphorylation	Ser325	EQLSRELsTLRNLFK	-1									1314426	t		llicata	These studies implicate Ser276 of CIEBPP as the major in vim phosphorylation site for CaMKII. | Phosphorylation of serine at position 276 within the leucine zipper of C/EBP beta appeared to confer calcium-regulated transcriptional stimulation of a promoter that contained binding sites for C/EBP beta.	SIGNOR-250617	0.331
Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606									28347630	f		miannu	Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation	SIGNOR-266830	0.7
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1875	SPTSPKYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273089	0.745
FLT3	protein	P36888	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity				10090	BTO:0001516								23246379	f		miannu	Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells.	SIGNOR-260083	0.54
BMAL1/NPAS2	complex	SIGNOR-C431	SIGNOR	PER2	protein	O15055	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements.	SIGNOR-267969	0.739
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser174	LSPASSGsSASFISD	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248367	0.598
NLGN2	protein	Q8NFZ4	UNIPROT	NRXN3	protein	Q9Y4C0	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264166	0.82
A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257721	0.496
CDK1	protein	P06493	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr285	AVNPPTMtPDMRSIT	9606	BTO:0000567								26183396	t		miannu	In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system.	SIGNOR-276925	0.261
CyclinD3/CDK6	complex	SIGNOR-C234	SIGNOR	PKM	protein	P14618	UNIPROT	down-regulates activity	phosphorylation	Ser37	MCRLDIDsPPITARN	9606									28607489	t		miannu	We show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity, which was not further affected by pre-incubation with cyclin D3-CDK6 (Extended Data Fig. 3a, b). 	SIGNOR-276454	0.263
CASP8	protein	Q14790	UNIPROT	CASP8AP2	protein	Q9UKL3	UNIPROT	up-regulates	binding			9606									17245429	t		gcesareni	The caspase-8-binding protein flice-associated huge protein (flash) would form a molecular complex with caspase-8, thereby presumably activating the mitochondrial apoptosis pathway by regulating caspase-8 activity.	SIGNOR-152473	0.459
ERBB2	protein	P04626	UNIPROT	NOTCH3	protein	Q9UM47	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								21743488	f		gcesareni	We demonstrate that her2 overexpression in this cellular model of dcis drives transcriptional upregulation of multiple components of the notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising notch3, its cleaved intracellular domain and the transcriptional regulator hes1.	SIGNOR-174747	0.413
PKI-587	chemical	CID:44516953	PUBCHEM	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205992	0.8
E4F1	protein	Q66K89	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	ubiquitination	Lys319	TSSSPQPkKKPLDGE	9606	BTO:0001938								17110336	t		miannu	E4F1 Has an Intrinsic Ubiquitin E3 Ligase Activity that Drives K48-type Ubiquitylation of p53. These data demonstrate that E4F1 stimulates the ubiquitylation of p53 on the lysine cluster K319–K321, i.e., at sites distinct from those targeted by Hdm2. p53 forms Ubiquitylated by E4F1 Are Localized on Chromatin. In striking contrast with Ub-p53 forms stimulated by Hdm2, which are mainly cytosoluble and targeted to the proteasome, we found that E4F1-stimulated Ub-p53 forms are tightly associated with chromatin, suggesting that they could be involved in transcription.	SIGNOR-271394	0.591
GRK2	protein	P25098	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser366	EPIQMENsMGTLRTS	9606	BTO:0000007								11517230	t			Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251444	0.2
VDR	protein	P11473	UNIPROT	CYP24A1	protein	Q07973	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000067								9687155	f		miannu	 Repression of basal transcription of a 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) responsive 25-hydroxyvitamin D3-24-hydroxylase (CYP24) promoter construct as observed in kidney cells in the absence of ligand and this repression was dependent on a functional vitamin D response element (VDRE). Basal repression was also seen with a construct where a consensus DR-3-type VDRE was fused to the thymidine kinase promoter. Expression of a dominant negative vitamin D receptor (VDR) isoform that strongly bound to the VDRE motif in the CYP24 promoter ablated basal repression.	SIGNOR-255599	0.584
PPM1A	protein	P35813	UNIPROT	RELA	protein	Q04206	UNIPROT	down-regulates activity	dephosphorylation	Ser536	SGDEDFSsIADMDFS	9606									23812431	t		lperfetto	We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited NF-kappaB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1 and chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis.|18 Wild-type, but not phosphatase-dead, PPM1A dephosphorylated the pS536 peptide with equivalent efficacy as the known RelA S536 phosphatase, Wip1 (XREF_FIG, compare lanes 4 and 7).|Taken together, these data suggest that dephosphorylation of S276 by PPM1A may contribute to inhibit RelA transcriptional activity, but the majority of PPM1A activity to inhibit RelA transcription relies on dephos phorylation of S536 of RelA.	SIGNOR-276964	0.361
clobetasol	chemical	CHEBI:205919	ChEBI	SMO	protein	Q99835	UNIPROT	up-regulates activity	chemical activation			9606									26658258	t	Non-canonical SMO pathway	SimoneGraziosi	Two of the top ranking compounds, Halcinonide and Clobetasol, act as Smoothened (Smo) agonists to up-regulate myelin gene expression in the Oli-neuM cell line. 	SIGNOR-269216	0.8
PPM1A	protein	P35813	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	dephosphorylation	Ser181	DQGSLCTsFVGTLQY	9606									18930133	t			PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation.	SIGNOR-248487	0.313
BRCA1-BARD1 complex	complex	SIGNOR-C297	SIGNOR	BRCA1-C complex	complex	SIGNOR-C299	SIGNOR	form complex	binding												25400280	t		lperfetto	The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2	SIGNOR-263222	0.805
FFAR2	protein	O15552	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257397	0.2
ITGAV	protein	P06756	UNIPROT	Av/b8 integrin	complex	SIGNOR-C185	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253289	0.828
HMGA1	protein	P17096	UNIPROT	SLC2A3	protein	P11169	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22706202	f		miannu	CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization.	SIGNOR-254427	0.2
NFIL3	protein	Q16649	UNIPROT	IL3	protein	P08700	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9580									7565758	t		Luana	NF-IL3A transactivates the IL-3 promoter through the A region sequences.	SIGNOR-266222	0.543
PRKCB	protein	P05771	UNIPROT	CASR	protein	P41180	UNIPROT	down-regulates activity	phosphorylation	Thr888	FKVAARAtLRRSNVS	9606	BTO:0000007								12356761	t		lperfetto	Expression of a mutant CaR in which the major PKC phosphorylation site is altered by substitution of alanine for threonine (T888A) eliminated oscillatory behavior, producing [Ca(2+)](i) responses almost identical to those produced by the wild type CaR exposed to PKC inhibitors. These results support a model in which phosphorylation of the CaR at the inhibitory threonine 888 by PKC provides the negative feedback needed to cause [Ca(2+)](i) oscillations mediated by this receptor.	SIGNOR-249176	0.323
Scribble_complex_DLG3-LLGL2_variant	complex	SIGNOR-C504	SIGNOR	Cell_polarity	phenotype	SIGNOR-PH213	SIGNOR	up-regulates				9606									23397623	f		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270886	0.7
MC1R	protein	Q01726	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257085	0.252
PRKACB	protein	P22694	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606									10949026	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136.	SIGNOR-81149	0.403
EZR	protein	P15311	UNIPROT	Metastasis	phenotype	SIGNOR-PH107	SIGNOR	up-regulates				9606	BTO:0001802								16488997	f			Ezrin is indispensable for Six1-induced metastasis and highly expressed in a panel of representative pediatric cancers.	SIGNOR-259375	0.7
BCR-Dk	complex	SIGNOR-C435	SIGNOR	SYK	protein	P43405	UNIPROT	up-regulates activity	binding			9606									32323266	t		scontino	The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK).	SIGNOR-268441	0.703
CSNK2A1	protein	P68400	UNIPROT	MS4A1	protein	P11836	UNIPROT	unknown	phosphorylation	Ser231	KSNIVLLsAEEKKEQ	9606									7678037	t		llicata	These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells.	SIGNOR-250915	0.311
TLK1	protein	Q9UKI8	UNIPROT	RAD9A	protein	Q99638	UNIPROT	unknown	phosphorylation	Thr355	EPSTVPGtPPPKKFR	9606									24376897	t	The effect has been demonstrated using Q9UKI8-2	llicata	Here we show that rad9 is phosphorylated in a tlk-dependent manner in vitro and in vivo, and that t355 within the c-terminal tail is the primary targeted residue.	SIGNOR-203503	0.462
KDM5C	protein	P41229	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30921702	f		miannu	KDM5C performs its oncogenic function by suppressing PTEN epigenetically.	SIGNOR-264312	0.343
6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide	chemical	CHEBI:92401	ChEBI	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258005	0.8
PRKAA1	protein	Q13131	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Ser811	IYISPLKsPYKISEG	9606			SIGNOR-C15						19217427	t		gcesareni	Amp-activated protein kinase phosphorylates retinoblastoma protein. Rb phosphorylation sites, ser804 (ser811 in human), resembled the ampk consensus phosphorylation site.	SIGNOR-184052	0.2
INSR	protein	P06213	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr472	EPIQEANyVPMTPGT	10090									10978177	t			HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin	SIGNOR-251314	0.492
PRKCZ	protein	Q05513	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser552	QDTQRRTsMGGTQQQ	9606	BTO:0002181								25660024	t		miannu	 Yap and β-catenin are direct substrates of PKCζ. Similar MS/MS analysis to map the sites phosphorylated in β-catenin by PKCζ identified S45 and several sites of low abundance that included S552 and S675 (Figure S3C). 	SIGNOR-276879	0.582
vatalanib	chemical	CHEBI:90620	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258309	0.8
JAK2	protein	O60674	UNIPROT	CSF2RA	protein	P15509	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000801								8977526	t		lperfetto	JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.	SIGNOR-249503	0.513
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser319	TFRPRTSsNASTISG	9606									11237865	t		lperfetto	The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus	SIGNOR-252860	0.908
SRC	protein	P12931	UNIPROT	PROM1	protein	O43490	UNIPROT	unknown	phosphorylation	Tyr828	RMDSEDVyDDVETIP	9606									19296573	t		llicata	Cd133 (prominin-1) is phosphorylated on cytoplasmic tyrosine-828 and tyrosine-852 by src	SIGNOR-184772	0.515
MAPK1	protein	P28482	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	up-regulates activity	phosphorylation	Ser14	MGAELPSsPLAIEYV	9606	BTO:0000567								11416124	t		miannu	In the present study, we provide the first evidence that MafA is phosphorylated and that its biological properties strongly rely upon phosphorylation of serines 14 and 65, two residues located in the transcriptional activating domain within a consensus for phosphorylation by mitogen-activated protein kinases and which are conserved among Maf proteins. These residues are phosphorylated by ERK2 but not by p38, JNK, and ERK5 in vitro. 	SIGNOR-275976	0.34
TLN1	protein	Q9Y490	UNIPROT	A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257615	0.638
SEPTIN9	protein	Q9UHD8	UNIPROT	ARHGEF18	protein	Q6ZSZ5	UNIPROT	down-regulates	binding			9606									15558029	t		miannu	In transient expression analyses, sept9b inhibited sa-rhogef-dependent rho activation in cos7 and hela cells.	SIGNOR-131184	0.2
CASP3	protein	P42574	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	cleavage			-1									10579725	t		lperfetto	P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro	SIGNOR-72677	0.662
ATR	protein	Q13535	UNIPROT	CHEK1	protein	O14757	UNIPROT	up-regulates	phosphorylation	Ser317	ENVKYSSsQPEPRTG	9606									15775976	t		gcesareni	Atr activation typically leads to chk1 phosphorylation and activation. In response to genotoxic stress, chk1 is phosphorylated on serines 317 (s317) and 345 (s345) by the ataxia-telangiectasia-related (atr) protein kinase.	SIGNOR-134712	0.923
BRCC3	protein	P46736	UNIPROT	BRCC ubiquitin ligase complex	complex	SIGNOR-C295	SIGNOR	form complex	binding			9606	BTO:0000007								14636569	t		lperfetto	These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer	SIGNOR-263205	0.559
NPBWR1	protein	P48145	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256818	0.409
MAPK1	protein	P28482	UNIPROT	KCND2	protein	Q9NZV8	UNIPROT	up-regulates activity	phosphorylation	Thr607	IPTPPVTtPEGDDRP	10116	BTO:0000601								11080179	t		miannu	We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP.	SIGNOR-262936	0.376
PDGFRB	protein	P09619	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates activity	phosphorylation	Tyr581	SDGHEYIyVDPMQLP	9606	BTO:0000599								9642269	t		miannu	We used two platelet-derived growth factor beta-receptor (beta-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the beta-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain-containing proteins.	SIGNOR-250255	0.2
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									10837473	t		gcesareni	Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax	SIGNOR-259418	0.2
pazopanib hydrochloride	chemical	CHEBI:71217	ChEBI	ITK	protein	Q08881	UNIPROT	down-regulates activity	chemical inhibition			-1									17620431	t		miannu	Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. 	SIGNOR-259164	0.8
MITF	protein	O75030	UNIPROT	SERPINF1	protein	P36955	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001177								22115973	f		miannu	 Here we show that the basic-helix-loop-helix-leucine zipper microphthalmia-associated transcription factor (MITF), which plays central roles in the development and function of a variety of cell types including RPE cells, upregulates the expression of a multifunctional factor PEDF in RPE cells. 	SIGNOR-254587	0.312
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	NCOA1	protein	Q15788	UNIPROT	up-regulates	phosphorylation			9606	BTO:0001130								12163482	t	inferred from 70% family members	lperfetto	Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein	SIGNOR-270194	0.2
PRKACA	protein	P17612	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	phosphorylation	Ser183	GLRTRTGsNIDCEKL	9606									15703181	t		lperfetto	We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195.	SIGNOR-133880	0.2
FOXO1	protein	Q12778	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	down-regulates				9606									20577053	f		gcesareni	Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner.	SIGNOR-166352	0.568
lysophosphatidylserine 14:0(1-)	chemical	CHEBI:72402	ChEBI	P2RY10	protein	O00398	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257558	0.8
RRAGA	protein	Q7L523	UNIPROT	RAGAD	complex	SIGNOR-C114	SIGNOR	form complex	binding			9606									20381137	t		gcesareni	Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant	SIGNOR-228167	0.767
gamma-secretase	complex	SIGNOR-C98	SIGNOR	NOTCH4	protein	Q99466	UNIPROT	up-regulates activity	cleavage			9606									25610395	t		lperfetto	The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins.	SIGNOR-209729	0.515
ACP1	protein	P24666	UNIPROT	PKM	protein	P14618	UNIPROT	up-regulates activity	dephosphorylation			9606									30251652	t		miannu	Indeed, it is evident that LMW-PTP, hydrolyzing phosphotyrosine residues, contributes to maintain PKM2 in its active form.|We speculate that this effect is in large part due to LMW-PTP inhibition, which leads a fast PKM2 phosphorylation and inactivation.|we demonstrate that in melanoma cells the overexpression of LMW-PTP is functional to maintain PKM2 in its dephosphorylate status – the tetrameric, “full active” form - which is retained in the cytoplasm	SIGNOR-277134	0.283
AKT3	protein	Q9Y243	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser315	DFRSRTNsNASTVSG										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-252875	0.697
P2RY13	protein	Q9BPV8	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257027	0.2
SRC	protein	P12931	UNIPROT	CDH2	protein	P19022	UNIPROT	down-regulates	phosphorylation	Tyr852	NDPTAPPyDSLLVFD	9606									16371504	t		lperfetto	Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated.	SIGNOR-143234	0.408
IL2	protein	P60568	UNIPROT	IL2RB	protein	P14784	UNIPROT	up-regulates	binding			9606									16477002	t		miannu	Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c).	SIGNOR-144540	0.864
PPM1A	protein	P35813	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates	dephosphorylation	Ser177	AKELDQGsLCTSFVG	9606									18930133	t		lperfetto	Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation	SIGNOR-181655	0.313
GLS2	protein	Q9UI32	UNIPROT	glutamine	smallmolecule	CHEBI:28300	ChEBI	down-regulates quantity	chemical modification			9606									22049910	t			Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia.	SIGNOR-266909	0.8
APC-c	complex	SIGNOR-C150	SIGNOR	TK1	protein	P04183	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									14701726	t		miannu	We show that hTK1 is degraded via a ubiquitin-proteasome pathway in mammalian cells and that anaphase-promoting complex/cyclosome (APC/C) activator Cdh1 is not only a necessary but also a rate-limiting factor for mitotic degradation of hTK1. By in vitro ubiquitinylation assays, we demonstrated that hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif. 	SIGNOR-272946	0.251
CCKBR	protein	P32239	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257363	0.428
ETS1	protein	P14921	UNIPROT	VWF	protein	P04275	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9444957	f	 	miannu	 Cotransfection of Ets-1 and Erg expression plasmids is sufficient to induce the -60/+19 vWF promoter activity in HeLa cells.	SIGNOR-253915	0.299
MAPK8	protein	P45983	UNIPROT	JUNB	protein	P17275	UNIPROT	up-regulates activity	phosphorylation	Thr102	SNGVITTtPTPPGQY	10090									9889198	t		miannu	JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation. 	SIGNOR-250120	0.72
KISS1	protein	Q15726	UNIPROT	KISS1R	protein	Q969F8	UNIPROT	up-regulates	binding			9606									11385580	t		gcesareni	Here we show that kiss-1 (refs 1, 4) encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which we have isolated from human placenta as the endogenous ligand of an orphan g-protein-coupled receptor (hot7t175) and have named 'metastin'	SIGNOR-108480	0.8
CAMKK1	protein	Q8N5S9	UNIPROT	CAMK4	protein	Q16566	UNIPROT	up-regulates	phosphorylation			9606									10770941	t		lperfetto	Ca(2+)/calmodulin-dependent protein kinase kinase (CaM-KK) is a novel member of the CaM kinase family, which specifically phosphorylates and activates CaM kinase I and IV	SIGNOR-232181	0.603
CIB2	protein	O75838	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	down-regulates activity	binding			10090									34162842	t		miannu	Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to 'nucleotide empty' or inactive GDP-loaded Rheb. 	SIGNOR-269663	0.266
MAPK1	protein	P28482	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser104	FPPLNSVsPSPLMLL	9606	BTO:0000150								18372406	t		gcesareni	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity	SIGNOR-178133	0.657
NOD1	protein	Q9Y239	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates				9606									18079694	f		miannu	Nod1 and Nod2 stimulation activates NF-kappaB through RICK, a caspase-recruitment domain-containing kinase.	SIGNOR-252411	0.299
chlorpromazine	chemical	CHEBI:3647	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258836	0.8
long-chain fatty acyl-CoA(4-)	smallmolecule	CHEBI:83139	ChEBI	arachidonoyl-CoA	smallmolecule	CHEBI:15514	ChEBI	up-regulates quantity	precursor of			9606									15189125	t		miannu	Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity.	SIGNOR-267906	0.8
DAPK3	protein	O43293	UNIPROT	MYL12B	protein	O14950	UNIPROT	up-regulates	phosphorylation	Ser20	KRPQRATsNVFAMFD	9606									1178183	t		lperfetto	Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge.	SIGNOR-16043	0.526
GRK2	protein	P25098	UNIPROT	ADRA2A	protein	P08913	UNIPROT	down-regulates activity	phosphorylation	Ser313	LDLEESSsSDHAERP	10029	BTO:0000246								7876239	t			The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization.	SIGNOR-251442	0.2
MAPK1	protein	P28482	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser38	SVPEFPLsPPKKKDL	9606									20630875	t		gcesareni	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. The kinases involved in phosphorylating stmn ser-16 and ser-63 include camp-dependent protein kinase (pka) and pak1, whereas stmn ser-25 and ser-38 have been shown to be targets for proline-directed serine/threonine kinases such as cyclin-dependent kinases, erk1/2, and members of the p38 mapk subfamily.	SIGNOR-166686	0.432
ATM	protein	Q13315	UNIPROT	ABRAXAS1	protein	Q6UWZ7	UNIPROT	up-regulates activity	phosphorylation	Ser406	GPGEYSRsPTF	9606									26778126	t			IR-Induced Double Phosphorylation of Abraxas C Terminus S404 and S406 Is ATM Dependent	SIGNOR-255588	0.2
CDK4	protein	P11802	UNIPROT	KAT2A	protein	Q92830	UNIPROT	up-regulates activity	phosphorylation	Thr272	LNYWKLEtPAQFRQR										24870244	t		lperfetto	Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT)	SIGNOR-275495	0.367
PRKCZ	protein	Q05513	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates activity	phosphorylation	Ser346	EWEAQRDsHLGPHRS	9606									14576165	t		lperfetto	A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis.	SIGNOR-249239	0.342
FYN	protein	P06241	UNIPROT	PTPRJ	protein	Q12913	UNIPROT	up-regulates activity	phosphorylation	Tyr1311	DSKVDLIyQNTTAMT	9606	BTO:0000007								22898603	t		miannu	 We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin.	SIGNOR-276372	0.374
MMP8	protein	P22894	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272398	0.7
Corticotropin	protein	P01189-PRO_0000024969	UNIPROT	MC3R	protein	P41968	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268706	0.2
BCL2L11	protein	O43521	UNIPROT	BCL2L2	protein	Q92843	UNIPROT	down-regulates	binding			9606									15694340	t		gcesareni	Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.	SIGNOR-133832	0.789
BRAF	protein	P15056	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates	phosphorylation			9606									8668348	t		lperfetto	We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l.	SIGNOR-244843	0.779
LYN	protein	P07948	UNIPROT	CD19	protein	P15391	UNIPROT	up-regulates activity	phosphorylation	Tyr531	HEEDADSyENMDNPD	10090	BTO:0000776								10933394	t		lperfetto	Experiments with purified proteins demonstrated that CD19-Y513 was Lyn's initial phosphorylation and binding site. This led to processive phosphorylation of CD19-Y482, which recruited a second Lyn molecule, allowing for transphosphorylation and amplification of Lyn activation|Tyrosine phosphorylation of CD19 following BCR and/or CD19 ligation provides Src homology 2 (SH2) recognition motifs that recruit regulatory molecules to the cell surface. CD19 dually phosphorylated at CD19€“Y482 and CD19€“Y513 binds the tandem SH2 domains of phosphatidylinositol 3-kinase (PI 3-kinase) p85 subuni	SIGNOR-249377	0.765
ponatinib	chemical	CHEBI:78543	ChEBI	RIPK1	protein	Q13546	UNIPROT	down-regulates activity	chemical inhibition			9606									25801024	t		Federica	Discovery of ponatinib as the first-in-class dual inhibitor of RIPK1 and RIPK3	SIGNOR-261082	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	SMAD3	protein	P84022	UNIPROT	down-regulates	binding			9606									15048128	t		gcesareni	Pkb inhibits smad3 by preventing its phosphorylation, binding to smad4 and nuclear translocation. [...] Regulation of smad3 by pkb occurs through a kinase-activity-independent mechanism, resulting in a decrease in smad3-mediated transcription and protection of cells against tgf-beta-induced apoptosis.	SIGNOR-252345	0.2
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2C	protein	O00762	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271322	0.716
YES1	protein	P07947	UNIPROT	SOCS1	protein	O15524	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr80	LLDACGFyWGPLSVH	9606	BTO:0000104								31101761	t		miannu	 Samples from human lymphomas that often overexpress SOCS1 also displayed SRC family kinase activation, constitutive phosphorylation of SOCS1 on Y80, and SOCS1 cytoplasmic localization. 	SIGNOR-277453	0.2
YAP1	protein	P46937	UNIPROT	TEAD4	protein	Q15561	UNIPROT	up-regulates	binding			9606									23431053	t	Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4	gcesareni	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.	SIGNOR-201474	0.925
Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	H3C1	protein	P68431	UNIPROT	up-regulates activity	methylation	Lys28	LATKAARkSAPATGG	9606									24987060	t		miannu	The presence of trimethylation of H3K27 (H3K27me3) at promoter regions is associated with gene repression. This modification is generated by the Polycomb repressive complex 2 (PRC2), composed of the SET domain-containing histone methyltransferase (HMT) EZH2 (enhancer of zeste homolog 2) or its functional homologue EZH1, and core accessory proteins (EED, SUZ12, and RbAp48) (Fig. 1A).	SIGNOR-260449	0.2
IDH	complex	SIGNOR-C396	SIGNOR	NADH	smallmolecule	CHEBI:16908	ChEBI	down-regulates quantity	chemical modification			9606									28139779	t		miannu	Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP.	SIGNOR-268114	0.8
SDHB	protein	P21912	UNIPROT	Mitochondrial respiratory chain complex II	complex	SIGNOR-C278	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites	SIGNOR-262189	0.965
canertinib	chemical	CHEBI:61399	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258094	0.8
SET	protein	Q01105	UNIPROT	PPP2CB	protein	P62714	UNIPROT	down-regulates	binding			9606									21806989	t		miannu	Here we report that both the amino terminal fragment (i(2ntf);aa 1-175) and the carboxy terminal fragment (i(2ctf);aa 176-277) of i(2)(pp2a) inhibit pp2a by binding to its catalytic subunit pp2ac	SIGNOR-175722	0.286
NCOA4	protein	Q13772	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates	binding			9606									10347167	t		miannu	We demonstrated that ara70 and ar physically interact and that ara70 can function as an androgen-dependent coactivator for ar.	SIGNOR-67684	0.854
ZFX	protein	P17010	UNIPROT	FBP1	protein	P09467	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003081;BTO:0000849								30616754	t		lperfetto	For instance, nucleophosmin (NPM1) and zinc-finger protein X-linked (ZFX) bind to the E-box and ZFX binding site on the FBP1 promoter, respectively, and restrain FBP1 expression to facilitate aerobic glycolysis in PDAC and melanoma	SIGNOR-267595	0.2
COL4A1	protein	P02462	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates activity	binding												35267698	t		lperfetto	Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23].	SIGNOR-272353	0.512
CDK2	protein	P24941	UNIPROT	COIL	protein	P38432	UNIPROT	up-regulates	phosphorylation	Ser184	NEEAKRKsPKKKEKC	9606			SIGNOR-C16						11102515	t		lperfetto	In particular, we have recently found that the cdk2/cyclin e complex can phosphorylate coilin in vitro . there is but a single consensus cdk2/cyclin e phosphorylation site in coilin, located at serine 184. when serine 184 was mutated to an alanine (s184a), mimicking a dephosphorylated state, a nucleolar mislocalization similar to that of gfp-coilin(1_248) was observed	SIGNOR-84949	0.389
TWIST2	protein	Q8WVJ9	UNIPROT	MYB	protein	P10242	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f	 	miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255495	0.2
HDAC1	protein	Q13547	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates	transcriptional regulation			9606									16431920	t		fspada	These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome	SIGNOR-210013	0.446
HOXB4	protein	P17483	UNIPROT	IGFBP1	protein	P08833	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12489992	t		Luana	These data showed that Hox genes selectively activate the transcription of theIGFBP-1 	SIGNOR-261636	0.2
GSK3B	protein	P49841	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Thr41	GIHSGATtTAPSLSG	9606			SIGNOR-C110						11955436	t		gcesareni	Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC).	SIGNOR-116528	0.856
CAMK2G	protein	Q13555	UNIPROT	PLCB3	protein	Q01970	UNIPROT	unknown	phosphorylation	Ser537	PSLEPQKsLGDEGLN										11325525	t		llicata	CaMK II phosphorylated PLCbeta3 but not PLCbeta1 in vitro. Phosphorylation occurred exclusively on 537Ser in the X-Y linker region of PLCbeta3. 537Ser was also phosphorylated in the basal state in cells and phosphorylation was enhanced by ionomycin treatment	SIGNOR-250702	0.385
RHOA	protein	P61586	UNIPROT	MSN	protein	P26038	UNIPROT	up-regulates activity	phosphorylation	Thr558	LGRDKYKtLRQIRQG	9606	BTO:0000132								35267019	t		miannu	Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. 	SIGNOR-268431	0.63
MAPK3	protein	P27361	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation	Ser540	KVMARSLsPPPELEE	10090									15851026	t		lperfetto	Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation.	SIGNOR-249458	0.682
RET	protein	P07949	UNIPROT	RET	protein	P07949	UNIPROT	up-regulates	phosphorylation	Tyr1015	MMVKRRDyLDLAAST	9606									14981541	t		llicata	Opn upregulation depended on the integrity of the ret/ptc kinase and tyrosines y1015 and y1062, two major ret/ptc autophosphorylation sites. ret signalling mainly depends on three key tyrosine residues: tyrosine 905, in the activation loop, whose phosphorylation stabilizes the active conformation of the catalytic domain , tyrosine 1015, a docking site for phospholipase citalic gamma and tyrosine 1062.	SIGNOR-122915	0.2
CAMK2G	protein	Q13555	UNIPROT	Adenylate_cyclase	proteinfamily	SIGNOR-PF92	SIGNOR	down-regulates activity	phosphorylation	Ser1076	NVASRMEsTGVMGNI	9606	BTO:0000007								8798667	t		llicata	Phosphorylation and inhibition of type III adenylyl cyclase by calmodulin-dependent protein kinase II in vivo. | Site-directed mutagenesis of a CaM kinase II consensus site (Ser-1076 to Ala-1076) in III-AC greatly reduced Ca2+-stimulated phosphorylation and inhibition of III-AC in vivo.	SIGNOR-267845	0.571
sapitinib	chemical	CHEBI:132986	ChEBI	ERBB3	protein	P21860	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190155	0.8
WNT10B	protein	O00744	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131625	0.601
SOHLH1	protein	Q5JUK2	UNIPROT	LHX8	protein	Q68G74	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								16690745	t		Luana	Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.	SIGNOR-266076	0.502
CNKSR1	protein	Q969H4	UNIPROT	EPHB1	protein	P54762	UNIPROT	up-regulates activity	binding												26319181	t		lperfetto	The phosphorylated CNK1 interacts with ephrinB1. The binding of ephrinB1 to CNK1 connects RhoA and p115RhoGEF with ephrinB1-associated MKK4, promoting JNK activation and cell migration.	SIGNOR-275921	0.297
CEBPB	protein	P17676	UNIPROT	CSRP1	protein	P21291	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14522018	t	 	 	We conclude that c-Rel regulates CRP expression without the requirement of binding to a kappaB site, and binds directly to C/EBPbeta to facilitate the binding of C/EBPbeta to the CRP promoter	SIGNOR-254049	0.2
oxytocin	smallmolecule	CHEBI:7872	ChEBI	OXTR	protein	P30559	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257556	0.8
NUMA1	protein	Q14980	UNIPROT	TUBA1C	protein	Q9BQE3	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116677	0.262
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	RAD23A	protein	P54725	UNIPROT	up-regulates													24086043	f		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein).	SIGNOR-275686	0.7
CUDC-907	chemical	CID:54575456	PUBCHEM	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252661	0.8
KIT	protein	P10721	UNIPROT	SLA	protein	Q13239	UNIPROT	down-regulates activity	phosphorylation	Tyr273	SFFSSPPyFED	9534	BTO:0001538								24284075	t		miannu	Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity	SIGNOR-263142	0.2
DAPK1	protein	P53355	UNIPROT	STX1A	protein	Q16623	UNIPROT	down-regulates activity	phosphorylation	Ser188	IIMDSSIsKQALSEI	9606	BTO:0000007;BTO:0000356								12730201	t		llicata	Syntaxin-1A phosphorylation by DAP kinase or its S188D mutant, which mimics a state of complete phosphorylation, significantly decreases syntaxin binding to Munc18-1, a syntaxin-binding protein that regulates SNARE complex formation and is required for synaptic vesicle docking.	SIGNOR-251083	0.345
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PCBP2	protein	Q15366	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser173	MLETLSQsPPKGVTI	10090	BTO:0000664								17475908	t		miannu	All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells.	SIGNOR-262668	0.2
NAE	complex	SIGNOR-C131	SIGNOR	CUL4A	protein	Q13619	UNIPROT	up-regulates activity	neddylation			9606									25504797	t		lperfetto	The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates.	SIGNOR-243160	0.611
TMC1	protein	Q8TDI8	UNIPROT	Hair cells mechanotransduction channel	complex	SIGNOR-C290	SIGNOR	form complex	binding			10090		BTO:0000630							23217710	t		lperfetto	The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012).	SIGNOR-262569	0.402
DYRK1A	protein	Q13627	UNIPROT	SPRY2	protein	O43597	UNIPROT	down-regulates	phosphorylation	Thr75	KPAPRPStQHKHERL	9606									18678649	t		gcesareni	We identify dyrk1a as one of the protein kinases of sprouty2. We show that dyrk1a interacts with and regulates the phosphorylation status of sprouty2. Moreover, we identify thr75 on sprouty2 as a dyrk1a phosphorylation site in vitro and in vivo.	SIGNOR-179828	0.31
CHD8	protein	Q9HCK8	UNIPROT	ASCL1	protein	P50553	UNIPROT	down-regulates quantity	transcriptional regulation			10090									32839322	t		Gianni	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268914	0.2
PROC	protein	P04070	UNIPROT	F5	protein	P12259	UNIPROT	down-regulates activity	cleavage	Lys1022	GGKSRLKkSQFLIKT	-1									7989361	t		lperfetto	The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. 	SIGNOR-263627	0.583
SRC	protein	P12931	UNIPROT	TNS3	protein	Q68CZ2	UNIPROT	up-regulates	phosphorylation	Tyr1173	QDTSKFWyKADISRE	9606	BTO:0000150;BTO:0000551;BTO:0000848								19732724	t		llicata	Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate	SIGNOR-187843	0.417
WT1	protein	P19544	UNIPROT	SRY	protein	Q05066	UNIPROT	up-regulates	binding			9606									12970737	t		miannu	Here we report that wt1 binds to and acts synergistically with sry to activate transcription from a promoter containing sry-binding sites	SIGNOR-100345	0.2
CENPX	protein	A8MT69	UNIPROT	FANCM	protein	Q8IYD8	UNIPROT	up-regulates	binding			9606									20347429	t		gcesareni	We also provide biochemical evidence that mhf1 and mhf2 assemble into a heterodimer that binds dna and enhances the dna branch migration activity of fancm. These findings reveal critical roles of the mhf1-mhf2 dimer in dna damage repair and genome maintenance through fancm.	SIGNOR-164729	0.2
SRC	protein	P12931	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Tyr315	TFCGTPEyLAPEVLE	9606	BTO:0000007								12600984	t		lperfetto	We also showed that phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this proline motif fails to block the transcription activity of Forkhead in 293 cells and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken together, our data suggest that the interaction between the SH3 domain of Src family kinases and the proline-rich motif in the C-terminal regulatory region of Akt is required for tyrosine phosphorylation of Akt and its subsequent activation.	SIGNOR-246373	0.663
erlotinib	chemical	CHEBI:114785	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258212	0.8
vorinostat	chemical	CHEBI:45716	ChEBI	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257920	0.8
PTPRF	protein	P10586	UNIPROT	PLCG1	protein	P19174	UNIPROT	down-regulates	dephosphorylation			9606									11121408	t		gcesareni	Here we show that lar reduces the constitutive tyrosine autophosphorylation and kinase activity of ret-men2a but not ret-men2b, accompanying a significant decrease of phosphorylation of phospholipase cgamma, akt, and erk1/2.	SIGNOR-85166	0.2
RELA	protein	Q04206	UNIPROT	MET	protein	P08581	UNIPROT	up-regulates quantity	transcriptional regulation			10090	BTO:0002895								19530226	t		gcesareni	Together, these results indicate that the Met gene is a direct target of NFkappaB and that Met participates in NFkappaB-mediated cell survival.	SIGNOR-241929	0.253
RAN	protein	P62826	UNIPROT	XPOT	protein	O43592	UNIPROT	up-regulates activity	binding			9606									9660920	t		miannu	The first step in export appears to be the formation of a trimeric tRNA/exportin-t/RanGTP complex. tRNA and RanGTP bind to exportin-t in a highly cooperative manner: tRNA increases the affinity of exportin-t for RanGTP apparently 300-fold (Figure 5A); conversely, RanGTP has to increase the affinity of exportin-t for tRNA by the same factor. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus 	SIGNOR-261392	0.808
TGFBR1	protein	P36897	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	phosphorylation	Ser425	SIRCSSVs	10090	BTO:0005493;BTO:0000165								19458083	t		lperfetto	A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus	SIGNOR-235380	0.806
HTR2B	protein	P41595	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257022	0.252
RPS6KA1	protein	Q15418	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	phosphorylation			9606									14625384	t		gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-265346	0.2
VAC14	protein	Q08AM6	UNIPROT	PAS complex	complex	SIGNOR-C190	SIGNOR	form complex	binding			9606	BTO:0000007								17556371	t		miannu	Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels.	SIGNOR-253530	0.922
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	NOXA1	protein	Q86UR1	UNIPROT	down-regulates activity	phosphorylation	Ser172	DQVQRRGsLPPRQVP	9606	BTO:0003250								20943948	t		lperfetto	On the other hand, our group has shown that protein kinase A (PKA) inhibits Nox1 activity in colon epithelial cells by phosphorylating NoxA1 at two distinct sites, Ser172 and Ser461	SIGNOR-264712	0.2
COX5B	protein	P10606	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	down-regulates				10090	BTO:0000165								18701479	f		lperfetto	Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS.	SIGNOR-253104	0.7
ABL1	protein	P00519	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates activity	phosphorylation	Tyr536	QKGQESEyGNITYPP	9606	BTO:0001412								8692915	t		gcesareni	Treatment with ionizing radiation is associated with c-Abl-dependent tyrosine phosphorylation of SHPTP1. The results demonstrate that the SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites.	SIGNOR-246227	0.423
SRC	protein	P12931	UNIPROT	PTPRJ	protein	Q12913	UNIPROT	up-regulates activity	phosphorylation	Tyr1320	NTTAMTIyENLAPVT	9606	BTO:0000007								22898603	t		miannu	 We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin.	SIGNOR-276375	0.622
MAPK8	protein	P45983	UNIPROT	H2AX	protein	P16104	UNIPROT	up-regulates	phosphorylation	Ser140	GKKATQAsQEY	9606		BTO:0000671							19234442	t		gcesareni	The stress-response kinase jnk1, activated by dna damage and initiating a pro-apoptotic program, has been recently shown to translocate into the nucleus upon activation where it phosphorylates substrates including h2ax s139, an event critical for dna degradation mediated by caspase-activated dnase (cad) in apoptotic cells	SIGNOR-184146	0.2
RPS5	protein	P46782	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262419	0.883
PRTN3	protein	P24158	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Lys72	SASVLTGkLTTVFLP	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263594	0.381
ARRB2	protein	P32121	UNIPROT	KIF3A	protein	Q9Y496	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Betaarrestin 2 was subsequentialy shown to bridge smo to the kinestesin motor kif3 to promote ciliary accumulation of smo in mammalian cells	SIGNOR-199107	0.623
ZFHX3	protein	Q15911	UNIPROT	AFP	protein	P02771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									14654895	f		miannu	 these results corroborated the previous reports that ATBF1 regulated AFP expression and inhibited transcription.	SIGNOR-255625	0.428
CDC14B	protein	O60729	UNIPROT	TAF1C	protein	Q15572	UNIPROT	up-regulates activity	dephosphorylation			9606									26023773	t		miannu	Consistent with prior studies showing that the phosphatase hCdc14B regulates progression through mitosis by counteracting mitotic phosphorylation by Cdk1/cyclin B [ ], hCdc14B dephosphorylates TAFI110, thus promoting its reactivation as cells exit mitosis.|Here we show that hCdc14B, the phosphatase that regulates Cdk1/cyclin B activity and progression through mitosis, promotes reactivation of rDNA transcription by dephosphorylating TAFI110.	SIGNOR-277135	0.2
PRKACA	protein	P17612	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates activity	phosphorylation	Ser47	LGSALRPsTSRSLYA	-1									2500966	t		miannu	Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure.	SIGNOR-250070	0.313
PTGS1	protein	P23219	UNIPROT	prostaglandin H2(1-)	smallmolecule	CHEBI:57405	ChEBI	up-regulates quantity	chemical modification			-1									7592599	t		Luana	[14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2,	SIGNOR-269778	0.8
GPIb-IX-V complex	complex	SIGNOR-C270	SIGNOR	Platelet_aggregation	phenotype	SIGNOR-PH81	SIGNOR	up-regulates				9606									32644488	f		lperfetto	Therefore, VWF cannot bind to the GpIb receptors on platelets via the A1 domain to induce platelet aggregation and further hemostasis. 	SIGNOR-261866	0.7
nilotinib	chemical	CHEBI:52172	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258259	0.8
PLK3	protein	Q9H4B4	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									21098032	t		gcesareni	Kinase activity of plk3 was significantly activated by hyperosmotic stimulation. Further downstream, active plk3 phosphorylated atf-2 at the thr-71 site in vivo and in vitro.	SIGNOR-170008	0.2
AVPR1B	protein	P47901	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256934	0.252
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	AHCYL1	protein	O43865	UNIPROT	unknown	dephosphorylation	Ser68	RSLSRSIsQSSTDSY	10090									17635105	t		lperfetto	Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1.	SIGNOR-264657	0.2
GRID2	protein	O43424	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial.	SIGNOR-264952	0.8
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	MAPK6	protein	Q16659	UNIPROT	up-regulates	phosphorylation	Ser684	IGIPQFHsPVGSPLK	9606									20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.	SIGNOR-216797	0.373
SRC	protein	P12931	UNIPROT	RACK1	protein	P63244	UNIPROT	up-regulates	phosphorylation	Tyr246	LCFSPNRyWLCAATG	9606									12400005	t		gcesareni	We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246	SIGNOR-94800	0.2
MAPK1	protein	P28482	UNIPROT	RSPH3	protein	Q86UC2	UNIPROT	up-regulates activity	phosphorylation	Thr243	QEQLRPQtPEPVEGR	9606									19684019	t		miannu	ERK1/2 phosphorylate RSPH3. the extent of radiolabeled phosphate incorporation into RSPH3 T286A was much less than that into wild-type RSPH3, suggesting that threonine 286 is the major ERK1/2 phosphorylation site in cells. ERK2 also phosphorylates RSPH3 on threonine 243 to a lesser extent. Phosphorylation of the double mutant T243V/T286A RSPH3 was no more than 20% that of wild-type RSPH3 (Fig. 4, C and D). inhibiting ERK1/2 activity appears to negatively regulate the AKAP function of RSPH3.	SIGNOR-262839	0.2
RNF11	protein	Q9Y3C5	UNIPROT	ITCH	protein	Q96J02	UNIPROT	up-regulates activity	binding			9606	BTO:0000150								19131965	t		lperfetto	Rnf11, together with tax1bp1 and itch, is an essential component of an a20 ubiquitin-editing protein complex; rnf11 is required for a20 to interact with and inactivate rip1 to inhibit tnf-mediated nf-_kb activation.	SIGNOR-183188	0.57
RNF8	protein	O76064	UNIPROT	RAD18	protein	Q9NS91	UNIPROT	up-regulates	binding			9606									19396164	t		gcesareni	Rnf8 depletion also significantly reduced the accumulation of rad18 to chromatin fraction after ir	SIGNOR-185593	0.427
NFYA	protein	P23511	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates activity	binding			9606									12427542	t		miannu	Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response.	SIGNOR-254816	0.6
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser286	SSMSSCGsSGYFSSS	9606									22017877	t		lperfetto	We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1	SIGNOR-252797	0.2
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	DFFB	protein	O76075	UNIPROT	up-regulates	cleavage			9606									9108473	t		gcesareni	Casp3_ cleaves the 45 kda subunit at two sites to generate an active factor that produces_ dna_ fragmentation	SIGNOR-256463	0.672
TRIM33	protein	Q9UPN9	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity by destabilization	binding			9606									25639486	t		Luana	Tumour suppressor TRIM33 targets nuclear β-catenin degradation	SIGNOR-260896	0.469
SRCAP	protein	Q6ZRS2	UNIPROT	KLK3	protein	P07288	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003160								20432434	f		miannu	 ShRNA mediated knockdown of SRCAP resulted in decreased H2A.Z binding at the enhancer region of the PSA promoter and decreased expression of PSA in prostate cancer cells.	SIGNOR-255220	0.2
SRC	protein	P12931	UNIPROT	GRK2	protein	P25098	UNIPROT	up-regulates activity	phosphorylation	Tyr92	FYEEIKKyEKLETEE										16725308	t		miannu	Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq. 	SIGNOR-266293	0.2
MAP2K2	protein	P36507	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates	phosphorylation			9606									11971971	t		lperfetto	Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.	SIGNOR-244637	0.735
RAGAC	complex	SIGNOR-C113	SIGNOR	MTOR	protein	P42345	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000007			SIGNOR-C3					20381137	t		lperfetto	The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb	SIGNOR-228657	0.804
MAPKAPK5	protein	Q8IW41	UNIPROT	PLA2G4A	protein	P47712	UNIPROT	up-regulates activity	phosphorylation	Ser727	RQNPSRCsVSLSNVE	9606	BTO:0000007;BTO:0000567								10978317	t		miannu	The p38-activated protein kinases MNK1, MSK1, and PRAK1 phosphorylate cPLA2 in vitro uniquely on Ser-727. By using Chinese hamster ovary, HeLa, and HEK293 cells stably transfected with wild type and phosphorylation site mutant forms of cPLA2, we show that phosphorylation of cPLA2 at both Ser-505 and Ser-727 and elevation of Ca(2+) leads to its activation in agonist-stimulated cells.	SIGNOR-250162	0.339
PSMA4	protein	P25789	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263366	0.834
TNFRSF17	protein	Q02223	UNIPROT	MAPK13	protein	O15264	UNIPROT	up-regulates				9606									10903733	f		miannu	Overexpression of bcma activates the p38 mapk	SIGNOR-79501	0.2
MTHFD1L	protein	Q6UB35	UNIPROT	formate	smallmolecule	CHEBI:15740	ChEBI	up-regulates quantity	chemical modification			9606									16171773	t		lperfetto	A human mitochondrial isozyme of C1-tetrahydrofolate (THF) synthase was previously identified by its similarity to the human cytoplasmic C1-THF synthase. All C1-THF synthases characterized to date, from yeast to human, are trifunctional, containing the activities of 5,10-methylene-THF dehydrogenase, 5,10-methenyl-THF cyclohydrolase, and 10-formyl-THF synthetase. Here we report on the enzymatic characterization of the recombinant human mitochondrial isozyme. Enzyme assays of purified human mitochondrial C1-THF synthase protein revealed only the presence of 10-formyl-THF synthetase activity. 	SIGNOR-268254	0.8
NCOA2	protein	Q15596	UNIPROT	RARA	protein	P10276	UNIPROT	up-regulates	binding			9606									12503607	t		gcesareni	Transcriptional coactivator for steroid receptors and nuclear receptors.nteracts with casp8ap2 and ttll5/stamp. Interacts with esr1, rara and rxra.	SIGNOR-96827	0.615
CLIP2	protein	Q9UDT6	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates				9606	BTO:0000567								15631994	f		lperfetto	CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. 	SIGNOR-265095	0.7
DDX3X	protein	O00571	UNIPROT	EIF4E	protein	P06730	UNIPROT	down-regulates activity	binding			9606	BTO:0001950								17667941	t		miannu	DDX3 is a human RNA helicase with plethoric functions. we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G.	SIGNOR-269193	0.649
PTPN2	protein	P17706	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									12612081	t			In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A substrate-trapping mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR beta-subunit in 293 cells.|IR β-subunit phosphorylated on tyrosine and specifically on tyrosines 1162 and 1163 could be coimmunoprecipitated with the TC48-D182A and TC45-D182A mutants but not the wild-type TC48 or TC45 in response to insulin	SIGNOR-248386	0.604
vorinostat	chemical	CHEBI:45716	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257951	0.8
EIF2B1	protein	Q14232	UNIPROT	EIF2S2	protein	P20042	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269129	0.77
carvedilol	chemical	CHEBI:3441	ChEBI	UGT1A1	protein	P22309	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								21030469	t		Luana	Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation.	SIGNOR-258165	0.8
5'-xanthylic acid	smallmolecule	CHEBI:15652	ChEBI	guanosine 5'-monophosphate	smallmolecule	CHEBI:17345	ChEBI	up-regulates quantity	precursor of			9606									6698284	t		miannu	The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2).	SIGNOR-267336	0.8
CDK2	protein	P24941	UNIPROT	ZC3HC1	protein	Q86WB0	UNIPROT	down-regulates	phosphorylation	Ser395	PGLEVPSsPLRKAKR	9606									17389604	t		gcesareni	Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1	SIGNOR-154051	0.2
PDGFB	protein	P01127	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates	binding			9606									11331882	t		miannu	Pdgf-b activates both pdgfr-alpha and pdgfr-beta	SIGNOR-107400	0.903
CXCL8	protein	P10145	UNIPROT	CXCR2	protein	P25025	UNIPROT	up-regulates	binding			9606									11350788	t		gcesareni	Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades.	SIGNOR-107983	0.856
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	CD4	protein	P01730	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									11893391	t		miannu	Degradation of the HIV receptor CD4 by the proteasome, mediated by the HIV-1 protein Vpu, is crucial for the release of fully infectious virions. To promote CD4 degradation Vpu has to be phosphorylated on a motif DSGXXS, which is conserved in several signalling proteins known to be degraded by the proteasome upon phosphorylation. Such phosphorylation is required for the interaction of Vpu with the ubiquitin ligase SCF-beta-TrCP that triggers CD4 degradation by the proteasome.	SIGNOR-272615	0.255
KMN network	complex	SIGNOR-C366	SIGNOR	Spindle_assembly	phenotype	SIGNOR-PH60	SIGNOR	up-regulates				9606									18007590	f		lperfetto	Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis.	SIGNOR-265215	0.7
pazopanib hydrochloride	chemical	CHEBI:71217	ChEBI	FGFR3	protein	P22607	UNIPROT	down-regulates activity	chemical inhibition			-1									17620431	t		miannu	Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. 	SIGNOR-259165	0.8
PPP1CA	protein	P62136	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser370	KKTIVNDsRESCVEE	9606	BTO:0001938								23277204	t			Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity.	SIGNOR-248566	0.363
3-isobutyl-1-methyl-7H-xanthine	smallmolecule	CHEBI:34795	ChEBI	CEBPB	protein	P17676	UNIPROT	up-regulates				9606									11279134	f		fspada	The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin	SIGNOR-209986	0.8
CASP8	protein	Q14790	UNIPROT	RIPK1	protein	Q13546	UNIPROT	down-regulates activity	cleavage	Asp324	RMQSLQLdCVAVPSS	9606	BTO:0000007;BTO:0000093;BTO:0000567								10521396	t		amattioni	These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability.	SIGNOR-71265	0.907
CSNK2A1	protein	P68400	UNIPROT	BRMS1	protein	Q9HCU9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser30	MNGEEEEsEEERSGS	-1									26980766	t		miannu	 We show that BRMS1 is posttranslationally regulated by TNF-induced casein kinase 2 catalytic subunit (CK2α') phosphorylation of nuclear BRMS1 on serine 30 (S30), resulting in 14-3-3ε-mediated nuclear exportation, increased BRMS1 cytosolic expression, and ubiquitin-proteasome-induced BRMS1 degradation. 	SIGNOR-266407	0.463
TADA3	protein	O75528	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269584	0.75
CHD8	protein	Q9HCK8	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								19255092	t		miannu	 We also show that CHD8 associates with the elongating form of RNAPII, which is phosphorylated in its carboxy-terminal domain (CTD). Furthermore, CHD8-depleted cells are hypersensitive to drugs that inhibit RNAPII phosphorylation at serine 2, suggesting that CHD8 is required for an early step of the RNAPII transcription cycle.	SIGNOR-268806	0.28
RNGTT	protein	O60942	UNIPROT	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates quantity	chemical modification			9606									9512541	t		lperfetto	The human mRNA 5'-capping enzyme cDNA was identified. Three highly related cDNAs, HCE1 (human mRNAcappingenzyme1), HCE1A and HCE1B , were isolated from a HeLa cDNA library. The HCE1 cDNA has the longest ORF, which can encode a 69 kDa protein. A short region of 69 bp in the 3'-half of the HCE1 ORF was missing in HCE1A and HCE1B , and, additionally, HCE1B has an early translation termi	SIGNOR-268357	0.8
MECP2	protein	P51608	UNIPROT	BDNF	protein	P23560	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									14593183	t		Luana	We find that MeCP2 binds selectively to BDNF promoter III and functions to repress expression of the BDNF gene.	SIGNOR-264540	0.486
RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	NRARP	protein	Q7Z6K4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000222;BTO:0000782								11783997	t		gcesareni	These observations demonstrate that the nrarp gene is an evolutionarily conserved transcriptional target of the notch signaling pathway.	SIGNOR-113786	0.419
CAMK2B	protein	Q13554	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	phosphorylation	Thr332	VNIMRTYtYEKLLWT	9606	BTO:0000938								24117889	t		lperfetto	Camkii represses transcriptionally active _-catenin to mediate acute ethanol neurodegeneration and can phosphorylate _-catenincamkii can directly phosphorylate _-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human _-catenin at t332, t472, and s552.	SIGNOR-202829	0.294
BMP1	protein	P13497	UNIPROT	COL5A1	protein	P20908	UNIPROT	up-regulates activity	cleavage	Asp1549	IKTEEISeVKMDAEF	9606	BTO:0002974								11741999	t		miannu	BMP-1 Can Efficiently Cleave Pro-α1(V) N-propeptides and Pro-α2(V) C-propeptides and Less Efficiently Cleave Pro-α1(V) C-propeptides in Vitro.NH2-terminal sequencing of an ∼35-kDa band in the BMP-1-treated material (N-α1(V), Fig. 3 B,lanes 2 and 3) showed it to correspond to the NH2-terminal portion of the pro-α1(V) N-propeptide previously shown to be cleaved in pro-α1(V)3 homotrimers by BMP-1 (39), whereas NH2-terminal sequencing of an ∼38-kDa band (C-α1(V)BMP-1, Fig. 3 B,lanes 2 and 3) showed it to correspond to pro-α1(V) C-propeptides cleaved between Asp-1594 and Asp-1595.	SIGNOR-256344	0.607
STX17-VAMP8 SNARE complex	complex	SIGNOR-C551	SIGNOR	Membrane_fusion	phenotype	SIGNOR-PH122	SIGNOR	up-regulates activity				9606	BTO:0000007								23217709	f		miannu	Here, we identify syntaxin 17 (Stx17) as the autophagosomal SNARE required for fusion with the endosome/lysosome. Stx17 localizes to the outer membrane of completed autophagosomes but not to the isolation membrane (unclosed intermediate structures); for this reason, the lysosome does not fuse with the isolation membrane. Stx17 interacts with SNAP-29 and the endosomal/lysosomal SNARE VAMP8. 	SIGNOR-273712	0.7
GNB1	protein	P62873	UNIPROT	GNG2	protein	P59768	UNIPROT	up-regulates activity	binding												10696571	t			GNB1 dissociates from the receptor, bound with GNG2 as stable dimer	SIGNOR-251105	0.938
GSK3B	protein	P49841	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates activity	phosphorylation	Ser486	LRTPGRQsPGPGHRS	9606									10581160	t			Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP	SIGNOR-251221	0.917
ARHGEF9	protein	O43307	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606	BTO:0000938								25882190	f		miannu	Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses.	SIGNOR-264976	0.7
CDH1	protein	P12830	UNIPROT	FBXO31	protein	Q5XUX0	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0002181								29343641	t		miannu	Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT.	SIGNOR-277377	0.2
CBP/p300	complex	SIGNOR-C6	SIGNOR	EPCAM	protein	P16422	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11505407	f	 	miannu	 The current results provide the first insights into the regulation of EpCAM expression, which is regulated negatively by TNFalpha and TPA through the activation of NF-kappaB. The repression may rely on the competition of NF-kappaB for p300/CBP histone acetyl transferase activity, because the overexpression of p300 reverts TNFalpha effects.	SIGNOR-254791	0.257
AURKC	protein	Q9UQB9	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates	phosphorylation			9606									12588998	t		gcesareni	Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.	SIGNOR-265357	0.2
BMPR1A	protein	P36894	UNIPROT	SMAD5	protein	Q99717	UNIPROT	up-regulates	phosphorylation			9606									19620713	t		gcesareni	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-187184	0.676
LEF1	protein	Q9UJU2	UNIPROT	CLDN2	protein	P57739	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0003569								14751232	f	 	lperfetto	Activity of the claudin-2 promoter was elevated in mouse mammary epithelial C57 cells expressing Wnt-1. LEF-1, a nuclear effector of the Wnt signaling pathway which is involved in the regulation of cell differentiation and polarization, was found to bind directly to the claudin-2 promoter as revealed by electrophoretic mobility shift assays. Expression of LEF-1 and beta-catenin both enhanced claudin-2 promoter activity.	SIGNOR-254120	0.2
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	ESR2	protein	Q92731	UNIPROT	up-regulates	chemical activation			9606	BTO:0000150								17478088	t		gcesareni	Oestrogen receptors (er)alpha and beta modify the expression of genes involved in cell growth, proliferation and differentiation through binding to oestrogen response elements (eres) located in a number of gene promoters.	SIGNOR-154663	0.8
TACR1	protein	P25103	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257249	0.2
Stress_granules	phenotype	SIGNOR-PH124	SIGNOR	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	down-regulates				9606									27920254	f		miannu	Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis.	SIGNOR-260866	0.7
IKBKE	protein	Q14164	UNIPROT	IKBKE	protein	Q14164	UNIPROT	up-regulates activity	phosphorylation	Thr501	ELRSRLRtLAEVLSR	9606	BTO:0000018								24882218	t		miannu	As previously reported, IKKε underwent rapid activation by auto-phosphorylation on T501 upon IFNβ treatment of control A549 cells, which was impaired by TRIM6si (Figure 4D)	SIGNOR-276637	0.2
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR3B	protein	O95264	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264290	0.8
ATM	protein	Q13315	UNIPROT	DYRK2	protein	Q92630	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser442	IELLGMPsQKLLDAS										19965871	t	Phosphosites were derived from Figure 3	lperfetto	ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. 	SIGNOR-275577	0.538
PTPN2	protein	P17706	UNIPROT	BCL2L11	protein	O43521	UNIPROT	up-regulates activity	dephosphorylation			9606									21984578	f		miannu	Moreover, it indicates that PTPN2 modulates the apoptotic activity of Bim via regulation of the protein kinase JNK1.|PTPN2 inhibition increased Bim phosphorylation at residue 65 in untreated INS-1E cells, and this effect was prolonged until 4 h of treatment with IFNalpha or 8 h after treatment with IFNgamma (XREF_FIG).	SIGNOR-277055	0.272
PRKCA	protein	P17252	UNIPROT	TNNI3	protein	P19429	UNIPROT	up-regulates activity	phosphorylation	Ser23	PAPIRRRsSNYRAYA	-1									11121119	t		lperfetto	In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation.	SIGNOR-249066	0.349
VCPIP1	protein	Q96JH7	UNIPROT	VCP	protein	P55072	UNIPROT	up-regulates activity	binding												23500464	t		lperfetto	Golgi biogenesis requires two distinct p97ATPase-mediated membrane fusion, the p97/p47 and p97/p37 pathways. |We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97. 	SIGNOR-265039	0.568
PK	proteinfamily	SIGNOR-PF80	SIGNOR	HIF-1 complex	complex	SIGNOR-C418	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								21620138	t			PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements,	SIGNOR-268150	0.399
CTDSP2	protein	O14595	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation	Ser245	NQSMDTGsPAELSPT	9606									17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248297	0.421
HASPIN	protein	Q8TF76	UNIPROT	PLK1	protein	P53350	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								24413556	t		miannu	Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis.	SIGNOR-275420	0.2
MMP23B	protein	O75900	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272390	0.7
OGT	protein	O15294	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates activity	glycosylation	Ser109	KSHSRQAsTDAGTAG										34155345	t		lperfetto	Mass spectrometry analysis showed that YAP was the effector protein modified by OGT. In details, YAP Ser109 O-GlcNAcylation promoted the malignant phenotypes in PTC cells by inducing YAP Ser127 dephosphorylation and activation.	SIGNOR-276942	0.287
POLR3D	protein	P05423	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266130	0.872
Interferon-type-I	proteinfamily	SIGNOR-PF50	SIGNOR	RAE1	protein	P78406	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16036565	f		miannu	Nup98/Nup96 (41) and Rae1 (17)are up regulated by interferons, which revert the mRNAexport block induced by VSV M protein	SIGNOR-260869	0.2
ACD	protein	Q96AP0	UNIPROT	TERT	protein	O14746	UNIPROT	up-regulates	binding			9606									17237768	t		miannu	We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme.	SIGNOR-152321	0.553
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	CASP9	protein	P55211	UNIPROT	down-regulates activity	phosphorylation												12792650	t	inferred from 70% family members	lperfetto	Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2	SIGNOR-270222	0.2
CSNK1D	protein	P48730	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser519	SGYSSPGsPGTPGSR	9606	BTO:0000007								14761950	t	The effect has been demonstrated using P10636-8	lperfetto	Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells.	SIGNOR-121705	0.381
Phenylalanyl-tRNA synthetase	complex	SIGNOR-C473	SIGNOR	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									20223217	t		miannu	Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers.	SIGNOR-270441	0.8
CSNK1A1	protein	P48729	UNIPROT	SMO	protein	Q99835	UNIPROT	up-regulates	phosphorylation			9606									21695114	t		gcesareni	We demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1α and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation.	SIGNOR-174542	0.5
PRKCA	protein	P17252	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates activity	phosphorylation	Ser39	EPHAKKKsKISASRK	-1									11121119	t		lperfetto	In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Overphosphorylation of troponin I reduced its affinity for troponin C, as measured by isothermal titration microcalorimetry. Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation.	SIGNOR-249068	0.349
CSNK1D	protein	P48730	UNIPROT	UHRF1	protein	Q96T88	UNIPROT	up-regulates	phosphorylation	Ser95	SELSDTDsGCCLGQS	9606									23297342	t		llicata	We further show that uhrf1 physically interacts with _-trcp1 in a manner dependent on phosphorylation of serine 108 (s108(uhrf1)) within the dsg degron. Furthermore, we demonstrate that s108(uhrf1) phosphorylation is catalyzed by casein kinase 1 delta (ck1_) and is important for the recognition of uhrf1 by scf(_-trcp).	SIGNOR-200349	0.247
T_cell_activation	phenotype	SIGNOR-PH73	SIGNOR	ARDS	phenotype	SIGNOR-PH128	SIGNOR	up-regulates				9606									32446778	f		miannu	The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm.	SIGNOR-261022	0.7
PLEKHF2	protein	Q9H8W4	UNIPROT	EEA1	protein	Q15075	UNIPROT	up-regulates activity	binding			-1									22816767	t		Giulio	In yeast two-hybrid analysis we identified Phafin2 as a novel interactor of the endosomal-tethering protein EEA1, and Phafin2 colocalized strongly with EEA1 in microdomains of the endosome membrane. Our results suggest that Phafin2 controls receptor trafficking and fluid-phase transport through early endosomes by facilitating endosome fusion in concert with EEA1.	SIGNOR-261276	0.251
DTX3L	protein	Q8TDB6	UNIPROT	H4C1	protein	P62805	UNIPROT	down-regulates activity	monoubiquitination	Lys92	MDVVYALkRQGRTLY	9606	BTO:0000007								19818714	t		miannu	Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA-damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage.  In response to DNA damage, BBAP expression increases and the E3 ligase selectively monoubiquitylates H4K91. Disruption of BBAP-mediated monoubiquitylation of H4K91 is associated with loss of chromatin-associated PR-Set7/Set8 and mono- and dimethyl H4K20, delayed kinetics of 53BP1 foci formation and increased sensitivity to DNA damage.	SIGNOR-271897	0.2
N-[5-[(2R)-2-methoxy-1-oxo-2-phenylethyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-1-piperazinyl)benzamide	chemical	CHEBI:94490	ChEBI	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191274	0.8
PRKAA1	protein	Q13131	UNIPROT	KIF4A	protein	O95239	UNIPROT	up-regulates activity	phosphorylation	Ser801	KLRRRTFsLTEVRGQ	-1									28992084	t		miannu	We found that the strong direct substrate KIF4A is phosphorylated by AMPK at Ser801.Using in vitro kinase assays, we found that active AMPK and Aurora B phosphorylated KIF4A at Ser801 and Thr799 respectively in a time-dependent manner (Figure 5D). KIF4A is phosphoregulated by AMPK and Aurora B. Although AMPK phosphorylation increased the ATPase activity of KIF4A, Aurora B phosphorylation resulted in a stronger increase (Figure 5I), which might be consistent with the more powerful kinase function of Aurora B during mitosis. 	SIGNOR-265991	0.2
STAT3	protein	P40763	UNIPROT	BIRC5	protein	O15392	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26512963	f		miannu	DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. 	SIGNOR-254762	0.61
CARS1	protein	P49589	UNIPROT	cysteine	smallmolecule	CHEBI:15356	ChEBI	down-regulates quantity	chemical modification			9606									11347887	t		miannu	Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine.	SIGNOR-270470	0.8
ITGAV	protein	P06756	UNIPROT	Av/b2 integrin	complex	SIGNOR-C176	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253203	0.651
SOS1	protein	Q07889	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									25624485	t	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.	gcesareni	Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts 	SIGNOR-141647	0.821
CPS1	protein	P31327	UNIPROT	Pyrimidine biosynthesis	phenotype	SIGNOR-PH187	SIGNOR	up-regulates activity				9606									15096496	f			CPSase catalyzes the rate-limiting step in de novo pyrimidine biosynthesis and, as discussed below, controls the flux through the pathway	SIGNOR-267195	0.7
TGFBR1	protein	P36897	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606	BTO:0001660								9435577	t		lperfetto	These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells.	SIGNOR-252730	0.354
GOT1	protein	P17174	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	chemical modification			9606									26003525	t		miannu	Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and α-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer.	SIGNOR-267510	0.8
ATM	protein	Q13315	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Ser28	PHGSVTQsQGSSSQS	9606	BTO:0000007								10973490	t		lperfetto	Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to irser28 was also found to be phosphorylated in an atm-dependent manner	SIGNOR-81395	0.83
CTSG	protein	P08311	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Phe64	TVFSVDEfSASVLTG	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263586	0.518
GMPS	protein	P49915	UNIPROT	L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	down-regulates quantity	chemical modification			9606									6698284	t		miannu	The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2).	SIGNOR-267340	0.8
CDK1	protein	P06493	UNIPROT	TOP1	protein	P11387	UNIPROT	up-regulates activity	phosphorylation	Ser112	EKENGFSsPPQIKDE	-1									18408216	t		miannu	In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells.	SIGNOR-276156	0.358
DNMT3A	protein	Q9Y6K1	UNIPROT	DPP6	protein	P42658	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000596								23409053	t		lperfetto	In the absence of Dnmt3b, Dnmt3a was associated with Dpp6 gene promoter and regulated its expression and methylation in P19 cells.	SIGNOR-268962	0.2
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser333	NLKSVQNsHFKEPLV	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276197	0.389
EPHA5	protein	P54756	UNIPROT	GLO1	protein	Q04760	UNIPROT	up-regulates activity	phosphorylation	Tyr136	GIAVPDVySACKRFE	-1									34838714	t		miannu	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276183	0.2
PTEN	protein	P60484	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity				9606	BTO:0001332								19903340	f		lperfetto	PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression	SIGNOR-189105	0.656
COL1A1	protein	P02452	UNIPROT	A11/b1 integrin	complex	SIGNOR-C168	SIGNOR	up-regulates activity	binding			10090	BTO:0000165								12496264	t		lperfetto	Modeling of the alpha I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar collagens is a common recognition motif used by alpha(1)beta(1), alpha(2)beta(1), and also alpha(11)beta(1) integrins.	SIGNOR-253345	0.565
MAPK1	protein	P28482	UNIPROT	NDE1	protein	Q9NXR1	UNIPROT	up-regulates activity	phosphorylation	Thr215	ATGSVPStPIAHRGP	9606	BTO:0000007								12556484	t		lperfetto	Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro. In the case of Nudel, the phosphorylation sites were also located in the S/TP motifs. Detailed mutagenesis study indicated that T219, S242, and T245 were phosphorylated by Cdc2, while T219 and T245 were phosphorylated by Erk2.|Phosphorylation of Nudel in M phase appears to positively modulate dynein motor activity. Both phosphorylated and unphosphorylated forms of Nudel were transported by dynein (Fig. 7 and 9 and data not shown), indicating that neither of them inactivated the dynein motor. On the other hand, both phospho-Nudel and Nudelpmt5 bound Lis1 more strongly than Nudel or Nudelmt5 did 	SIGNOR-249422	0.382
WNT7B	protein	P56706	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131981	0.661
ABL1	protein	P00519	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates	phosphorylation	Tyr463	NDTGSRYyKEIPLSE	9606									12637538	t		llicata	By using a phospho-specific antibody, we show that abl directly phosphorylates pkd at tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of pkd	SIGNOR-99255	0.345
NR5A1	protein	Q13285	UNIPROT	CYP19A1	protein	P11511	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001555								19022561	f		miannu	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 	SIGNOR-254871	0.494
SATB1	protein	Q01826	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000725								23563689	f		miannu	Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc	SIGNOR-224831	0.407
ROCK2	protein	O75116	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates activity	phosphorylation	Thr19	KKRPQRAtSNVFAMF	9606									8702756	t		miannu	 Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. 	SIGNOR-261708	0.633
diphenhydramine	chemical	CHEBI:4636	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002126								18446005	t		Luana	We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells	SIGNOR-257787	0.8
PPAT	protein	Q06203	UNIPROT	5-phospho-beta-D-ribosylaminium(1-)	smallmolecule	CHEBI:58681	ChEBI	up-regulates quantity	chemical modification			9606									9914248	t		miannu	Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine.	SIGNOR-267295	0.8
mTORC2	complex	SIGNOR-C2	SIGNOR	FUS	protein	P35637	UNIPROT	down-regulates activity				9606	BTO:0000007								33082139	f			When mTORC2 is inhibited, FUS is recruited to polyribosomes to promote translation inhibition and polyribosome stalling. Panel iv, ALS-FUS R521G and P525L mutants that localize more prominently to the cytoplasm also associate more abundantly with polyribosomes to inhibit translation and protein synthesis.	SIGNOR-262819	0.298
2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid	chemical	CID:135461425	PUBCHEM	FGFR2	protein	P21802	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258080	0.8
TAF12	protein	Q16514	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263924	0.885
CDK11A	protein	Q9UQ88	UNIPROT	SPDEF	protein	O95238	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser243	TDSEVDSsCSGQPIH	9606	BTO:0000007								26885618	t		lperfetto	In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|	SIGNOR-273022	0.364
MYC	protein	P01106	UNIPROT	ITGA7	protein	Q13683	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									14525975	f		lperfetto	This report provides evidence that alpha7 gene expression during muscle differentiation is regulated by the c-Myc transcription factor. In myoblasts, alpha7 is expressed at basal levels, but following conversion to myotubes the expression of the integrin is strongly elevated. The increased alpha7 mRNA and protein levels following myogenic differentiation are inversely correlated with c-Myc expression. Transfection of myoblasts with the c-Myc transcription factor down-regulated alpha7 expression	SIGNOR-241769	0.2
mono(2-ethylhexyl) phthalate	chemical	CHEBI:17243	ChEBI	PPARA	protein	Q07869	UNIPROT	up-regulates activity	chemical activation			9606									19433246	t		miannu	Phthalates are true ligands of PPARs. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic.	SIGNOR-268745	0.8
GDNF	protein	P39905	UNIPROT	ID3	protein	Q02535	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252181	0.2
CSNK2A1	protein	P68400	UNIPROT	HSPH1	protein	Q92598	UNIPROT	down-regulates activity	phosphorylation	Ser509	PTEENEMsSEADMEC	-1									12558502	t		llicata	Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. | the phosphorylation of Hsp105 alpha at Ser(509) abolished the inhibitory activity of Hsp105 alpha in vitro.	SIGNOR-250901	0.334
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser221	PRTSPIMsPRTSLAE	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252331	0.635
DRD5	protein	P21918	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256914	0.492
hexadecanoic acid	smallmolecule	CHEBI:15756	ChEBI	FFAR1	protein	O14842	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257488	0.8
PRKCA	protein	P17252	UNIPROT	GABRR1	protein	P24046	UNIPROT	unknown	phosphorylation	Ser443	PQRKSQRsSYVSMRI	-1									12175859	t		miannu	Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation	SIGNOR-262752	0.341
CREB1	protein	P16220	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity by expression	transcriptional regulation			8355									10775268	f		lperfetto	Here we demonstrate that the closely related acetyltransferases p300 and cbp potentiate beta-catenin-mediated activation of the siamois promoter	SIGNOR-76984	0.468
TAF13	protein	Q15543	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263923	0.869
CPN1	protein	P15169	UNIPROT	HBA1	protein	P69905	UNIPROT	down-regulates activity	cleavage	Tyr141	STVLTSKyR	-1									8635221	t		miannu	Both human plasma carboxypeptidase N (CPN) and membrane-bound carboxypeptidase M (CPM) released the C-terminal arginine (alpha-Arg141) of the alpha chain of human adult hemoglobin. Thus, the hydrolysis of hemoglobin by CPM and CPN demonstrated the contribution of the alpha-Arg141 residue to sustaining the tetrameric structure of hemoglobin and its normal oxygen affinity and vasoactivity.	SIGNOR-256508	0.2
HES1	protein	Q14469	UNIPROT	FLT3	protein	P36888	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									25234168	t			We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity.	SIGNOR-261563	0.2
SSTR2	protein	P30874	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256827	0.425
CDK1	protein	P06493	UNIPROT	RAD9A	protein	Q99638	UNIPROT	up-regulates activity	phosphorylation	Thr292	PQLQAHStPHPDDFA	9606									12734188	t		lperfetto	Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9.	SIGNOR-101055	0.37
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BW2	protein	P0C1H6	UNIPROT	down-regulates activity	monoubiquitination	Lys35	ANSTKAQkQKRRGCR	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271981	0.2
MAPK1	protein	P28482	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation			9606									12832467	t		lperfetto	Efficient rsk activation by erk requires its interaction through a docking site located near the c terminus of rsk	SIGNOR-252749	0.751
GNRHR	protein	P30968	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257177	0.252
LPAR3	protein	Q9UBY5	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			9606									15856019	t		gcesareni	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13.	SIGNOR-135846	0.385
DTNBP1	protein	Q96EV8	UNIPROT	WASF2	protein	Q9Y6W5	UNIPROT	up-regulates activity	binding			10116		BTO:0000601							20531346	t		miannu	Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1. 	SIGNOR-265659	0.35
CSNK2A1	protein	P68400	UNIPROT	HCLS1	protein	P14317	UNIPROT	unknown	phosphorylation	Thr23	TQGDDWDtDPDFVND	9606									10806407	t		llicata	 The in vivo Ser/Thr phosphorylation of HS1 is enhanced by okadaic acid and reduced by specific inhibitors of casein kinase (CK)2. In vitro, HS1 is an excellent substrate for either CK2 alpha subunit alone (Km = 47 nM) or CK2 holoenzyme | It is likely therefore that Thr16 and/or Thr23 account for the phosphate incorporated into HS1 threonyl residue(s) upon incubation with CK2.	SIGNOR-250886	0.311
SUPT3H	protein	O75486	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269590	0.758
ARHGAP31	protein	Q2M1Z3	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260488	0.509
COL14A1	protein	Q05707	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									21949456	t			Types XII and XIV collagen are fibril-associated collagens with interrupted triple helices (FACITs) localized primarily to perimysium.23 While they appear to link fibrillar collagen to other ECM components, their precise function is not known	SIGNOR-254672	0.7
fumarate(2-)	smallmolecule	CHEBI:29806	ChEBI	Citric_Acid_Cycle	phenotype	SIGNOR-PH191	SIGNOR	up-regulates				9606									30090811	f		miannu	Fumarase is a TCA cycle enzyme which catalyzes the conversion of fumarate to L-malate in the mitochondria. Upon DNA damage the cytosolic echoform of fumarase is localized to the nucleus, there, its enzymatic activity catalyzes the reverse conversion of malate to fumarate, so causing local accumulation of fumarate.	SIGNOR-267989	0.7
ABL1	protein	P00519	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	phosphorylation	Tyr1172	ISLDNPDyQQDFFPK	9606									16943190	t		gcesareni	We show that activated abl phosphorylates the egfr primarily on tyrosine 1173.	SIGNOR-149273	0.429
ITGB1BP1	protein	O14713	UNIPROT	A4/b7 integrin	complex	SIGNOR-C187	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257666	0.29
TPI1	protein	P60174	UNIPROT	glycerone phosphate(2-)	smallmolecule	CHEBI:57642	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa).	SIGNOR-266491	0.8
CDK1	protein	P06493	UNIPROT	RANBP2	protein	P49792	UNIPROT	up-regulates activity	phosphorylation	Ser2276	SFKSALSerPSKSPA	-1									26051540	t		irozzo	Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment.	SIGNOR-259120	0.452
STAT5A	protein	P42229	UNIPROT	SOCS2	protein	O14508	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									12468433	t			We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling	SIGNOR-261547	0.656
TRIM25	protein	Q14258	UNIPROT	MAVS	protein	Q7Z434	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys10	FAEDKTYkYICRNFS	9606	BTO:0000007								22626058	t	k48	miannu	We report here that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling. 	SIGNOR-272042	0.762
LRRC4	protein	Q9HBW1	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	down-regulates				9606		BTO:0000142							25526788	f		miannu	The overexpression of LRRC4/NGL-2 suppresses glioma cell growth, angiogenesis and invasion through complicated signaling regulation networks. 	SIGNOR-264060	0.7
JUN	protein	P05412	UNIPROT	TNFAIP6	protein	P98066	UNIPROT	up-regulates quantity by expression	transcriptional regulation												8454627	t	 	 	Tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6) encodes a protein expressed during inflammation. We have previously shown that transcription factors of the NF-IL6 and AP-1 families cooperatively modulate activation of the TSG-6 gene by TNF or interleukin 1 (IL-1) through a promoter region that contains an NF-IL6 site (-106 to -114) and an AP-1 element	SIGNOR-254052	0.314
PPP6C	protein	O00743	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates activity	dephosphorylation			9606									19198648	t		miannu	In addition, siRNA knockdown of either PP6R1 or PP6 significantly decreased IR activation of DNA-PK, suggesting that PP6 activates DNA-PK by association and dephosphorylation.|PP6 may dephosphorylate sites in DNA-PKcs to reduce binding with heterodimer Ku proteins, because DNA-PK activation completely depends on Ku-mediated complex formation with DNA.	SIGNOR-277164	0.555
MAPK3	protein	P27361	UNIPROT	MAZ	protein	P56270	UNIPROT	up-regulates	phosphorylation	Thr72	AAPAPPPtPQAPAAE	9606									11809795	t		lperfetto	Together, these results show that activation of saf-1 in response to il-1 and -6 is mediated via map kinase-regulated phosphorylation.	SIGNOR-114475	0.304
PI3K	complex	SIGNOR-C156	SIGNOR	AKT2	protein	P31751	UNIPROT	up-regulates				9606	BTO:0000586								16293724	f		gcesareni	We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin.	SIGNOR-252716	0.631
SIRT1	protein	Q96EB6	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21633182	t		miannu	 Interestingly, SIRT1 suppresses PPARγ but activates PGC-1α , and thus affects the clock network through multiple mechanisms.	SIGNOR-268033	0.792
PABPC1	protein	P11940	UNIPROT	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates quantity by stabilization	binding			9606									25480299	t		lperfetto	As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length.	SIGNOR-268318	0.8
PICK1	protein	Q9NRD5	UNIPROT	BNC1	protein	Q01954	UNIPROT	up-regulates activity	relocalization			10116	BTO:0000938								11802773	t		miannu	we found that the PDZ domain-containing protein PICK1 (protein interacting with C kinase) interacts specifically with the C-termini of BNC1 and ASIC. Our studies showing association of recombinant PICK1 with ASIC and BNC1, and the presence of both PICK1 and ASIC in the synaptosomal fraction	SIGNOR-223414	0.311
MAPK3	protein	P27361	UNIPROT	TFCP2	protein	Q12800	UNIPROT	down-regulates	phosphorylation	Ser291	TYVNNSPsPGFNSSH	9606									19237534	t		lperfetto	We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309.	SIGNOR-184176	0.2
HTR2A	protein	P28223	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256885	0.271
SERPINC1	protein	P01008	UNIPROT	F9	protein	P00740	UNIPROT	down-regulates activity	cleavage												31030036	t		lperfetto	Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1	SIGNOR-264140	0.892
LRRK2	protein	Q5S007	UNIPROT	LARS1	protein	Q9P2J5	UNIPROT	down-regulates activity	phosphorylation	Thr293	NIFLVAAtLRPETMF	-1									30411383	t		miannu	In this study, we elucidated that leucyl-tRNA synthetase (LRS) was an LRRK2 kinase substrate and identified T293 as an LRRK2 phosphorylation site. LRRK2-meidated LRS phosphorylation or G2019S can lead to impairment of LRS editing, increased ER stress, and accumulation of autophagy markers.	SIGNOR-277417	0.2
dopamine	smallmolecule	CHEBI:18243	ChEBI	DRD4	protein	P21917	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257480	0.8
PRKACA	protein	P17612	UNIPROT	AKAP13	protein	Q12802	UNIPROT	up-regulates	phosphorylation	Ser2733	SVSPKRNsISRTHKD	9606									15383279	t		llicata	Using a combination of biochemical, enzymatic, and immunofluorescence techniques, we show that the anchoring protein contributes to pkd activation in two ways: it recruits an upstream kinase pkceta and coordinates pka phosphorylation events that release activated protein kinase d. Thus, akap-lbc synchronizes pka and pkc activities in a manner that leads to the activation of a third kinase.	SIGNOR-129345	0.337
MAPK3	protein	P27361	UNIPROT	TRPV3	protein	Q8NET8	UNIPROT	up-regulates activity	phosphorylation	Thr264	EGFYFGEtPLALAAC	9606	BTO:0000552								29084846	t	done	miannu	We observed that ERK-mediated phosphorylation of TRPV3 alters its responsiveness to repeated chemical stimuli. Among several putative ERK phosphorylation sites, we identified threonine 264 in the N-terminal ankyrin repeat domain as the most critical site for the ERK-dependent modulation of TRPV3 channel activity. Of note, Thr264 is in close vicinity to a structurally and functionally important TRPV3 region comprising an atypical finger 3 and oxygen-dependent hydroxylation site. In summary, our findings indicate that Thr264 in TRPV3 is a key ERK phosphorylation site mediating EGFR-induced sensitization of the channel to stimulate signaling pathways involved in regulating skin homeostasis.	SIGNOR-273672	0.2
PRKCA	protein	P17252	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser159	KKKKKRFsFKKSFKL	9606									16116087	t		llicata	The present experiments demonstrate that ptn stimulates phosphorylation of serines 713 and 726 in the marcks domain of _-adducin (and serine 724 in _-adducin) and serines 152 and 156 in the marcks protein itself through the activation of either pkc _ or _ and perhaps other pkc(s) isoforms.	SIGNOR-139906	0.72
MAPK3	protein	P27361	UNIPROT	MYB	protein	P10242	UNIPROT	down-regulates	phosphorylation	Ser532	KIKQEVEsPTDKSGN	9606	BTO:0000661								8960373	t		lperfetto	Functional analysis of phosphorylation at serine 532 of human c-myb by map kinase. expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532. Our data suggest that the mapk-dependent state of phosphorylation modifies the cellular function of c-myb by modulating its interaction with a putative inhibitory factor	SIGNOR-45348	0.306
MAP2K6	protein	P52564	UNIPROT	HSF4	protein	Q9ULV5	UNIPROT	up-regulates activity	phosphorylation	Thr471	LGLPGALtIYSTPES										24361130	t		lperfetto	Regulation of Hsf4b nuclear translocation and transcription activity by phosphorylation at threonine 472| At the upstream, MEK6 was found to interact with Hsf4b and enhance Hsf4b's nuclear translocation and transcription activity, probably by phosphorylation at sites such as T472. Taken together, our results suggest that phosphotylation of Hsf4b at T472 by protein kinases such as MEI	SIGNOR-275493	0.2
PPM1B	protein	O75688	UNIPROT	MAP3K7	protein	O43318	UNIPROT	down-regulates activity	dephosphorylation			-1									11104763	t		miannu	In vitro, PP2Cbeta-1 dephosphorylated and inactivated TAK1.	SIGNOR-277154	0.534
ADD1	protein	P35611	UNIPROT	4.1 complex	complex	SIGNOR-C386	SIGNOR	form complex	binding			9606	BTO:0000424								33187473	t		lperfetto	The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]	SIGNOR-266037	0.341
WWTR1	protein	Q9GZV5	UNIPROT	TEAD2	protein	Q15562	UNIPROT	up-regulates	binding			9606									23431053	t	YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death.	gcesareni	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.	SIGNOR-201382	0.8
BAK1	protein	Q16611	UNIPROT	CYCS	protein	P99999	UNIPROT	up-regulates				9606									18097445	f		gcesareni	This process of mitochondrial outer membrane permeabilization (momp) results in the release of cycs. It is commonly thought that bax and bak form pores in membranes	SIGNOR-160036	0.549
PPP1CA	protein	P62136	UNIPROT	SP1	protein	P08047	UNIPROT	down-regulates activity	dephosphorylation			9606									12684058	t		miannu	Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression.	SIGNOR-251952	0.269
TGFB1	protein	P01137	UNIPROT	OMD	protein	Q99983	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16970923	f		miannu	We found tgf-beta1 to down regulate osad	SIGNOR-149565	0.272
PRKCD	protein	Q05655	UNIPROT	RPS3	protein	P23396	UNIPROT	up-regulates activity	phosphorylation	Ser6	sKKRKFVA	9606									19059439	t		Manara	Here we show that PKCδ phosphorylates rpS3 resulting in its mobilization in the nucleus to repair damaged DNA	SIGNOR-260894	0.2
p38	proteinfamily	SIGNOR-PF16	SIGNOR	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser69	GPLAPPAsPGPFATR	10116									15486195	t		miannu	Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. 	SIGNOR-260443	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser732	RRVRKLPsTTL	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252744	0.754
PTCRA	protein	Q6ISU1	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	binding			9606	BTO:0000782								1717999	t		lperfetto	Stimulation of the T-cell antigen receptor (TCR) leads to tyrosine phosphorylation of a number of cellular proteins, including phospholipase C (PLC) gamma 1 and the TCR zeta chain. We describe here a 70-kDa tyrosine phosphoprotein (ZAP-70) that associates with zeta within 15 sec following TCR stimulation. The phosphorylation of ZAP-70 and its association with zeta is independent of the other TCR chains	SIGNOR-134325	0.289
ITK	protein	Q08881	UNIPROT	ITK	protein	Q08881	UNIPROT	up-regulates activity	phosphorylation	Tyr180	ETVVIALyDYQTNDP	9606	BTO:0000782								12842872	t		lperfetto	In this study, we present evidence for another mode of regulation for itk, the autophosphorylation of tyr-180 in the src homology 3 (sh3) domain.	SIGNOR-103170	0.2
EXOC8	protein	Q8IYI6	UNIPROT	Exocyst_EXOC6B variant	complex	SIGNOR-C491	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270783	0.914
LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	YAP1	protein	P46937	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser397	TYHSRDEsTDSGLSM	9606	BTO:0000007								20048001	t		miannu	We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition	SIGNOR-277636	0.2
YES1	protein	P07947	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Tyr391	PFLNSGTyHSRDEST	9606	BTO:0000578								35041461	t		miannu	Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C). 	SIGNOR-277652	0.71
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	EP300	protein	Q09472	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1038	STSATQSsPAPGQSK	9606	BTO:0000551								24530506	t		miannu	In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels. 	SIGNOR-276455	0.2
XPO1	protein	O14980	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates	relocalization			9606									11074002	t		gcesareni	We demonstrate that inhibition of crm1-mediated nuclear export by treatment of cells with leptomycin b results in endogenous smad4 accumulating very rapidly in the nucleus.	SIGNOR-84247	0.306
sorafenib tosylate	chemical	CHEBI:50928	ChEBI	FGFR1	protein	P11362	UNIPROT	down-regulates activity	chemical inhibition			-1									16757355	t		miannu	Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 	SIGNOR-259221	0.8
KIF5B	protein	P33176	UNIPROT	JAKMIP1	protein	Q96N16	UNIPROT	up-regulates activity	relocalization			10090									17532644	t		SARA	Marlin-1 is associated with kinesin-I and suggest that the movement of Marlin-1 is mediated by plus end microtubuledependent molecular motors	SIGNOR-260989	0.2
hydromorphone	chemical	CHEBI:5790	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000246								19282177	t		Luana	A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 	SIGNOR-258037	0.8
PPAT	protein	Q06203	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	chemical modification			9606									9914248	t		miannu	Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine.	SIGNOR-267294	0.8
PPP2CA	protein	P67775	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	up-regulates activity	dephosphorylation	Ser181	NPLLRKEsAPPSLRR	9606									18339811	t			Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. 	SIGNOR-248647	0.322
Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	CTNNB1	protein	P35222	UNIPROT	up-regulates						BTO:0001103							23209147	f		apalma	The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization.	SIGNOR-255687	0.2
YAP1	protein	P46937	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates	binding			9606									22153608	t	Regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation.	gcesareni	Here we show that the endogenous yes-associated protein (yap), a mediator of src/yes signaling, interacts with the native runx2 protein, an osteoblast-related transcription factor, and suppresses runx2 transcriptional activity in a dose-dependent manner.	SIGNOR-195221	0.461
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser389	LSPIAPRsPAKLSFQ	9606									7889942	t		gcesareni	Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-252086	0.2
ATM	protein	Q13315	UNIPROT	NABP2	protein	Q9BQ15	UNIPROT	up-regulates activity	phosphorylation	Thr117	EPNPEYStQQAPNKA	10090	BTO:0002245								18449195	t		miannu	 Ataxia telangiectasia mutated (ATM) kinase phosphorylates hSSB1 in response to DNA double-strand breaks (DSBs). This phosphorylation event is required for DNA damage-induced stabilization of hSSB1. 	SIGNOR-262639	0.516
FOS	protein	P01100	UNIPROT	AP1	complex	SIGNOR-C154	SIGNOR	form complex	binding			9606									1904542	t		irozzo	The proteins encoded by the proto-oncogenes c-fos and c-jun (Fos and Jun, respectively) form a heterodimeric complex that regulates transcription by interacting with the DNA-regulatory element known as the activator protein 1 (AP-1) binding site.	SIGNOR-256364	0.951
HES1	protein	Q14469	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				10090	BTO:0000011								16282371	f			Notch signaling blocks differentiation of 3T3-L1 preadipocytes, and this can be mimicked by constitutive expression of the Notch target gene Hes-1	SIGNOR-253058	0.7
PLCG1	protein	P19174	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser146	GRKRRQTsMTDFYHS	9606									31575057	t		gcesareni	Phosphorylation at Ser-146 by PKCδ increases p21 stability	SIGNOR-262962	0.266
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1787	SPNYSPTsPSYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269367	0.718
UNC13B	protein	O14795	UNIPROT	SNARE_complex 	complex	SIGNOR-C346	SIGNOR	up-regulates activity	transcriptional regulation			9606	BTO:0000938								30267828	t		miannu	 In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2.	SIGNOR-263972	0.707
NCSTN	protein	Q92542	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates	binding			9606									12603837	t	Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation	gcesareni	Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2.	SIGNOR-98724	0.964
CASP3	protein	P42574	UNIPROT	GORASP1	protein	Q9BQQ3	UNIPROT	down-regulates quantity by destabilization	cleavage	Asp390	LPQLTLPdSLTSAAS	9606									11815631	t		Giulio	Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage	SIGNOR-260604	0.405
GSK3B	protein	P49841	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	down-regulates activity	phosphorylation	Ser2093	GPNRSFLsLKHTPMG	9606	BTO:0000007								12794074	t			Ser-2093 is efficiently phosphorylated by GSK-3β and, to a minor extent, residues Thr-2068 and/or Ser-2070 and Thr-2074 of Notch2 are also targets for GSK-3β-dependent phosphorylation. We also find that GSK-3β-dependent phosphorylation of Notch2 is inhibiting transcriptional activation of different Notch target genes. 	SIGNOR-251253	0.495
ATM	protein	Q13315	UNIPROT	USP10	protein	Q14694	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr42	SGTVLCGtQAVDKLP	9606	BTO:0001109								20096447	t		miannu	The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337. 	SIGNOR-276275	0.254
RF-C complex	complex	SIGNOR-C375	SIGNOR	PCNA	protein	P12004	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								12930972	t		lperfetto	Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases.	SIGNOR-265510	0.809
ETV4	protein	P43268	UNIPROT	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24983502	f		miannu	Transcriptional activation of oct4 by the ets transcription factor pea3 in nccit human embryonic carcinoma cells	SIGNOR-205173	0.387
FBXO11	protein	Q86XK2	UNIPROT	BCL6	protein	P41182	UNIPROT	down-regulates	binding			9606	BTO:0000785								22113614	t		miannu	Fbxo11 targets bcl6 for degradation	SIGNOR-177652	0.504
Ast-487	chemical	CID:11409972	PUBCHEM	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258173	0.8
PSPN	protein	O60542	UNIPROT	GFRA4	protein	Q9GZZ7	UNIPROT	up-regulates	binding			9606	BTO:0000938								11116144	t		gcesareni	Glial cell line-derived neurotrophic factor (gdnf) family ligands signal through receptor complex consisting of a glycosylphosphatidylinositol-linked gdnf family receptor (gfr) alpha subunit and the transmembrane receptor tyrosine kinase ret.	SIGNOR-85162	0.737
CSF2RA	protein	P15509	UNIPROT	CSF2RA/CSF2RB	complex	SIGNOR-C212	SIGNOR	form complex	binding			9606									9680354	t		apalma	The high-affinity GMR is known to be composed of a specific ligand-binding alpha subunit (GMRα) and a common beta subunit (βc), which is also a component of the interleukins-3 (IL-3) and -5 (IL-5) receptors.	SIGNOR-255582	0.864
PTPN1	protein	P18031	UNIPROT	STAT5A	protein	P42229	UNIPROT	down-regulates activity	dephosphorylation	Tyr694	LAKAVDGyVKPQIKQ	9534									10993888	t			A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b	SIGNOR-248428	0.662
ACTB	protein	P60709	UNIPROT	Endocytosis	phenotype	SIGNOR-PH123	SIGNOR	up-regulates				9606	BTO:0000007								19121306	f		lperfetto	However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin.	SIGNOR-260608	0.7
YAP1	protein	P46937	UNIPROT	KIF23	protein	Q02241	UNIPROT	up-regulates quantity by expression	transcriptional regulation					BTO:0001939							30224758	f		lperfetto	 By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 	SIGNOR-276567	0.2
SMAD9	protein	O15198	UNIPROT	SMAD8/SMAD4	complex	SIGNOR-C206	SIGNOR	form complex	binding			10116									9371779	t		ggiuliani	As shown in Fig. 2, immunoprecipitation of Smad8 with an anti-myc antibody could bring down the Flag-tagged Smad4 only in the presence of CA-ALK-2, indicating that only activation of ALK-2 but not ALK-4 could induce the heteromerization of Smad8 with Smad4.	SIGNOR-255776	0.67
PLK1	protein	P53350	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by destabilization	phosphorylation												23972993	t	For phosphorylated residues see Figure 7	lperfetto	Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP	SIGNOR-274053	0.302
HOXC11	protein	O43248	UNIPROT	HNF1A	protein	P20823	UNIPROT	up-regulates				9606									9582375	f		miannu	The observed stimulatory effect of hoxc11 on hnf1_ may be due to a similar stabilizing effect on hnf1_ dna binding and/or an increase in transcriptional activity of hnf1_.	SIGNOR-57484	0.313
EPHA2	protein	P29317	UNIPROT	PIK3R2	protein	O00459	UNIPROT	up-regulates				9606	BTO:0000782								7982920	f		gcesareni	In keeping with the above observations, activation of eck by its ligand, b61, increased phosphatidylinositol 3-kinase activity	SIGNOR-35418	0.37
KSR2	protein	Q6VAB6	UNIPROT	BRAF	protein	P15056	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								29433126	t		miannu	 In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. 	SIGNOR-273877	0.6
Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	GABA-A (a3-b1-g2) receptor	complex	SIGNOR-C332	SIGNOR	up-regulates				9606									33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors	SIGNOR-268581	0.2
ITGB2	protein	P05107	UNIPROT	AD/b2 integrin	complex	SIGNOR-C172	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253196	0.73
CBX4	protein	O00257	UNIPROT	ZEB2	protein	O60315	UNIPROT	down-regulates activity	sumoylation			9606	BTO:0000007								16061479	t		miannu	Polycomb protein Pc2 acts as an SUMO E3 ligase for SIP1. SIP1 is an active transcription repressor for many transcription factors and target genes. SIP1 Sumoylation Disrupts the Recruitment of the Corepressor CtBP	SIGNOR-225481	0.336
afatinib	chemical	CHEBI:61390	ChEBI	ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	down-regulates activity	chemical inhibition			9606	BTO:0000551								22452896	t	Like lapatinib and neratinib, afatinib is a next generation tyrosine kinase inhibitor (TKI) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases.	gcesareni	Afatinib, an irreversible erbb-family blocker, has shown preclinical activity when tested in egfr mutant models with mutations that confer resistance to egfr tyrosine-kinase inhibitors.	SIGNOR-259440	0.8
KIT	protein	P10721	UNIPROT	PTPN11	protein	Q06124	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0002882								22806893	t		irozzo	SHP2 can be phosphorylated at 2 C-terminal tyrosyl residues by receptor tyrosine kinases, including KIT as well as cytosolic tyrosine kinases, including Src and Abl. The level of tyrosyl phosphorylation of SHP2 has been associated with its recruitment to the receptor.Thus, pharmacologic inhibition of SHP2 phosphatase function might permit SHP2 to return to its inactive conformation resulting in reduced tyrosine phosphorylation. 	SIGNOR-256140	0.671
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000017								28192398	t		miannu	We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation. 	SIGNOR-277344	0.493
CSNK1D	protein	P48730	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Thr522	SSPGSPGtPGSRSRT	9606	BTO:0000007								14761950	t	The effect has been demonstrated using P10636-8	lperfetto	Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells.	SIGNOR-121717	0.381
PIK3R4	protein	Q99570	UNIPROT	Vps34 Complex I	complex	SIGNOR-C242	SIGNOR	form complex	binding			-1									30397185	t		lperfetto	PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively.	SIGNOR-260317	0.917
STK39	protein	Q9UEW8	UNIPROT	SLC4A4	protein	Q9Y6R1	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000007								21317537	t		miannu	SPAK phosphorylates the transporters to reduce their surface expression and thus their activity and consequently inhibits ductal secretion to stabilize the resting state. PP1 reverses the effect of SPAK. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression.	SIGNOR-263133	0.356
PRKCA	protein	P17252	UNIPROT	CD163	protein	Q86VB7	UNIPROT	unknown	phosphorylation	Ser1084	QRQRLAVsSRGENLV	9606	BTO:0000801								11298324	t		lperfetto	Furthermore, we demonstrated that the cytoplasmic domains of CD163 variants are phosphorylated by PKC-alpha in vitro. Inhibition studies using specific kinase inhibitors reveal that both CKII and PKC are involved in the CD163 signaling mechanism resulting in the secretion of proinflammatory cytokines.	SIGNOR-249082	0.328
arformoterol	chemical	CHEBI:408174	ChEBI	ADRB1	protein	P08588	UNIPROT	up-regulates activity	chemical activation			-1									20655218	t		Luana	Table 1. Human β2- and β1-adrenoceptor binding and calculated log D7.4 values for formoterol, indacaterol, salmeterol, S1319 and the representative library members 11–41	SIGNOR-257881	0.8
NME1	protein	P15531	UNIPROT	PTN	protein	P21246	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001567								17671192	f		miannu	To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 	SIGNOR-255167	0.2
SREBF1	protein	P36956	UNIPROT	PCSK9	protein	Q8NBP7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17921436	t		miannu	 Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9.	SIGNOR-255222	0.44
AMPK	complex	SIGNOR-C15	SIGNOR	PRPS2	protein	P11908	UNIPROT	down-regulates activity	phosphorylation	Ser180	GGAKRVTsIADRLNV	9606	BTO:0006038								29074724	t		lperfetto	We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production.	SIGNOR-265732	0.244
YWHAG	protein	P61981	UNIPROT	GEM	protein	P55040	UNIPROT	up-regulates quantity by stabilization	binding			9534	BTO:0000298								14701738	t		miannu	In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase	SIGNOR-261723	0.269
HDAC4	protein	P56524	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000150								25726523	t		lperfetto	GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. 	SIGNOR-275663	0.292
STK4	protein	Q13043	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation	Ser212	SSAGWKNsIRHNLSL	9606									18394876	t		gcesareni	Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1.	SIGNOR-252999	0.673
RALGDS	protein	Q12967	UNIPROT	RIT1	protein	Q92963	UNIPROT	up-regulates activity	binding			9606									10545207	t		miannu	Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors.	SIGNOR-220859	0.55
SEC62	protein	Q99442	UNIPROT	Protein_translocation	phenotype	SIGNOR-PH176	SIGNOR	up-regulates													22375059	f		lperfetto	We demonstrated, with a similar knockdown approach, a precursor-specific involvement of mammalian Sec63 in the initial phase of co-translational protein transport into the ER.	SIGNOR-265281	0.7
MAPK9	protein	P45984	UNIPROT	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation	Ser154	SSVSSSPsPPFGHSA	9606									12151396	t		gcesareni	Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro.	SIGNOR-91071	0.346
Fibrin	complex	SIGNOR-C317	SIGNOR	Fibrin_clot_formation	phenotype	SIGNOR-PH153	SIGNOR	up-regulates	binding			9606		BTO:0000131							18544683	t		lperfetto	A fibrin clot is the final product of the blood clotting cascade. Thrombin catalyzes release of fibrinopeptide A from fibrinogen to create fibrin monomers, which then aggregate to protofibrils. Proteolytic release of fibrinopeptide B by thrombin permits lateral protofibril aggregation, resulting in a three-dimensional fibrin gel.|Fibrin clots were formed as described for turbidity experiments, in which the fibrinogen, calcium, and polyP (when included) were preincubated for 15 minutes before adding thrombin. 	SIGNOR-263531	0.7
estrone	smallmolecule	CHEBI:17263	ChEBI	17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	up-regulates quantity	precursor of			-1									8994190	t		Luana	Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues. 	SIGNOR-269759	0.8
KDM6A	protein	O15550	UNIPROT	ETS2	protein	P15036	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									29736013	t		miannu	Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase	SIGNOR-260035	0.2
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	DCX	protein	O43602	UNIPROT	up-regulates activity	phosphorylation	Ser297	PQKTSAKsPGPMRRS	9606									14741103	t		llicata	We identified that Ser297 is the major phosphorylation site by Cdk5. Phosphorylation of this site occurs in human. | Mutation of Ser297 blocks the effect of Dcx on migration in a fashion similar to pharmacological inhibition of Cdk5 activity.	SIGNOR-250657	0.415
ceramide	smallmolecule	CHEBI:17761	ChEBI	ceramide 1-phosphate(2-)	smallmolecule	CHEBI:84404	ChEBI	up-regulates quantity	precursor of			9606									34202192	t		miannu	Another relevant enzyme is Ceramide kinase (CerK), which phosphorylates Cer to produce Ceramide 1-phosphate (C1P). 	SIGNOR-268501	0.8
SMURF2	protein	Q9HAU4	UNIPROT	SMAD9	protein	O15198	UNIPROT	down-regulates	ubiquitination			9606									22298955	t		gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-193390	0.63
MAPK14	protein	Q16539	UNIPROT	GATA2	protein	P23769	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								25056917	t			P38α promotes multi‐site GATA‐2 phosphorylation, increasing its localization in nuclear foci enriched in an active form of RNA polymerase II and its capacity to regulate endogenous target genes.	SIGNOR-259946	0.273
MN1	protein	Q10571	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				10090									17494859	f		irozzo	MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment.	SIGNOR-256015	0.7
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser245	NQSMDTGsPAELSPT	9606									19115199	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-182988	0.739
CDK1	protein	P06493	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Thr187	NAGSVEQtPKKPGLR	9606									10931950	t		gcesareni	Phosphorylation of kip1 on thr-187, by cdk1 and cdk2 leads to protein ubiquitination and proteasomal degradation.	SIGNOR-80230	0.676
AP3S2	protein	P59780	UNIPROT	Neuronal AP-3	complex	SIGNOR-C445	SIGNOR	form complex	binding			9606	BTO:0000938								19497727	t		miannu	Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) 	SIGNOR-268518	0.7
AREL1	protein	O15033	UNIPROT	HTRA2	protein	O43464	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									23479728	t		lperfetto	Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists	SIGNOR-267669	0.416
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	GSK3B	protein	P49841	UNIPROT	down-regulates	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606									11584304	t		lperfetto	S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity.	SIGNOR-252788	0.2
FYN	protein	P06241	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates activity	phosphorylation	Tyr30	NQSSGYRyGTDPTPQ	-1									9425276	t			Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn.	SIGNOR-251165	0.2
PURA	protein	Q00577	UNIPROT	MYH6	protein	P13533	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12933792	f	 	miannu	In functional assays, PURalpha and PURbeta repressed alpha-myosin heavy chain (alpha-MHC) gene expression in the presence of upstream regulatory sequences of the gene.	SIGNOR-253902	0.2
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2V2	protein	Q15819	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271335	0.544
MAPK1	protein	P28482	UNIPROT	GABRR1	protein	P24046	UNIPROT	unknown	phosphorylation	Ser435	TLASERSsPQRKSQR	-1									12175859	t		miannu	Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414. An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation	SIGNOR-262747	0.289
SHANK3	protein	Q9BYB0	UNIPROT	ACTN1	protein	P12814	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264585	0.2
WNT8A	protein	Q9H1J5	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131987	0.619
ARF4	protein	P18085	UNIPROT	Vesicle_transport	phenotype	SIGNOR-PH172	SIGNOR	up-regulates													14973189	f		lperfetto	ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface	SIGNOR-272151	0.7
CASP8	protein	Q14790	UNIPROT	CYCS	protein	P99999	UNIPROT	up-regulates activity				9606	BTO:0000661								10364179	f	Translocation from Mitochondria to Cytosol	lperfetto	Caspase-8 triggered rapid cytochrome c release from mitochondria. The effect was indirect.	SIGNOR-68225	0.495
EGFR	protein	P00533	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	phosphorylation	Tyr155	LNDSAAYyLNDLDRI	-1									33139573	t		miannu	RTKs directly phosphorylate Gαi on Y154, 155, and Y320.	SIGNOR-277226	0.44
ATR	protein	Q13535	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates activity	phosphorylation	Ser1981	SLAFEEGsQSTTISS	9606									17124492	t		lperfetto	Atr-dependent phosphorylation and activation of atm in response to uv treatment or replication fork stalling. Here, we show that atm phosphorylation at ser1981, a characterised autophosphorylation site, is atr-dependent and atm-independent following replication fork stalling or uv treatment	SIGNOR-150870	0.735
NUP214	protein	P35658	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262075	0.655
MAPK3	protein	P27361	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates activity	phosphorylation	Ser376	EKLFQGYsFVAPSIL										15568999	t		lperfetto	In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1	SIGNOR-249479	0.567
JAK1	protein	P23458	UNIPROT	ISGF3 complex	complex	SIGNOR-C124	SIGNOR	up-regulates activity	phosphorylation			9606									15120645	t		miannu	Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48).	SIGNOR-260149	0.715
AKT1	protein	P31749	UNIPROT	PDCD4	protein	Q53EL6	UNIPROT	down-regulates	phosphorylation	Ser67	KRRLRKNsSRDSGRG	9606	BTO:0000007	BTO:0001253							18296647	t		gcesareni	Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.	SIGNOR-252505	0.448
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	isoleucine	smallmolecule	CHEBI:24898	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270421	0.8
PLK1	protein	P53350	UNIPROT	KIF2C	protein	Q99661	UNIPROT	up-regulates activity	phosphorylation	Ser633	ELSSQMSsFNEAMTQ	9606	BTO:0000567								25504441	t		miannu	Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. 	SIGNOR-276861	0.804
SRC	protein	P12931	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000944								9566874	t		lperfetto	Previous studies have demonstrated that one STAT family member, Stat3, possesses constitutively elevated tyrosine phosphorylation and DNA-binding activity in fibroblasts stably transformed by the Src oncoprotein.We conclude that Stat3 activation by the Src oncoprotein leads to specific gene regulation and that Stat3 is one of the critical signaling pathways involved in Src oncogenesis.	SIGNOR-235445	0.782
CAMK2A	protein	Q9UQM7	UNIPROT	ITGB1BP1	protein	O14713	UNIPROT	up-regulates activity	phosphorylation	Thr38	GGLSRSStVASLDTD										9813144	t		llicata	The point mutation T38D localized within the optimal CaMKII recognition motif of ICAP-1alpha results in a strong defect in cell spreading which cannot be overcome by the inhibition of the endogenous CaMKII. This fact strongly suggests that the phosphorylation of Threonine 38 by CaMKII modulates the alpha5beta1 integrin function. Conversely, the mutation T38A produces an analog of ICAP-1alpha that cannot be phosphorylated and that stimulates cell spreading on fibronectin to a similar extent when CaMKII is inhibited.	SIGNOR-250632	0.311
FUS	protein	P35637	UNIPROT	Protein_aggregates	phenotype	SIGNOR-PH142	SIGNOR	up-regulates quantity				9606	BTO:0000312								22051914	f		lperfetto	Similarly, cytoplasmic inclu- sions containing mutant fused in sarcoma (FUS) protein have been observed in some patients with FUS-related FALS. 	SIGNOR-262277	0.7
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser531	GSRSRTPsLPTPPTR	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249318	0.754
Uridylate-specific endoribonuclease	protein	P0C6X7-PRO_0000037321	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	down-regulates activity				9606									28158275	f		miannu	Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation. 	SIGNOR-260348	0.2
BMPR1A	protein	P36894	UNIPROT	SMAD1/4	complex	SIGNOR-C85	SIGNOR	up-regulates activity	phosphorylation			9606									8893010	t		ggiuliani	Conversely, Smad1 and DPC4 formed a complex when the cells were stimulated with BMP4 but not with activin of TGF-beta.	SIGNOR-255778	0.702
ATM	protein	Q13315	UNIPROT	KHDC3L	protein	Q587J8	UNIPROT	up-regulates activity	phosphorylation	Thr145	IEVREAGtQRSVEVR	9606	BTO:0001086								31609975	t		miannu	Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions. 	SIGNOR-273505	0.2
LRRK2	protein	Q5S007	UNIPROT	LRRK2	protein	Q5S007	UNIPROT	unknown	phosphorylation	Thr1404	GREEFYStHPHFMTQ	9606	BTO:0000938								19824698	t		lperfetto	We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites.	SIGNOR-188433	0.2
NR0B2	protein	Q15466	UNIPROT	G6PC1	protein	P35575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17909097	f		gcesareni	As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells	SIGNOR-158065	0.2
GATA1	protein	P15976	UNIPROT	MPL	protein	P40238	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15466856	f	 	miannu	Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. 	SIGNOR-254162	0.454
PRKAA2	protein	P54646	UNIPROT	ACACB	protein	O00763	UNIPROT	down-regulates activity	phosphorylation	Ser222	PTMRPSMsGLHLVKR	9606									9148944	t		miannu	The results suggest that the decrease in ACC activity during muscle contraction is caused by an increase in its phosphorylation, most probably due, at least in part, to activation of the alpha2 isoform of AMPK.	SIGNOR-250318	0.638
MAPK1	protein	P28482	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser344	QDDDAPLsPMLYSSS	9606	BTO:0000007								18204439	t		lperfetto	Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation.	SIGNOR-252958	0.71
HIRA	protein	P54198	UNIPROT	HIRA complex 2	complex	SIGNOR-C462	SIGNOR	form complex	binding			9606									30285846	t		miannu	H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex.	SIGNOR-269437	0.52
ABL1	protein	P00519	UNIPROT	BTK	protein	Q06187	UNIPROT	down-regulates activity	phosphorylation	Tyr223	LKKVVALyDYMPMNA	9606									12445832	t		Manara	In this report we describe for the first time that ABL1 and Btk physically interact and that ABL1 can phosphorylate tyrosine 223 in the SH3 domain of Btk. | This is presumably due to the negative regulatory effectof Btk SH3 domain phosphorylation caused by ABL1,which would result in a decreased catalytic activity ofBtk resulting in impaired autophosphorylation. 	SIGNOR-260801	0.342
POU2F1	protein	P14859	UNIPROT	MYH10	protein	P35580	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15728583	t		lperfetto	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238772	0.2
MAPK1	protein	P28482	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									20068231	t		gcesareni	Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.	SIGNOR-163242	0.723
TFE3	protein	P19532	UNIPROT	CTSS	protein	P25774	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276818	0.273
PNPLA6	protein	Q8IY17	UNIPROT	2-(((R)-2,3-Dihydroxypropyl)phosphoryloxy)-N,N,N-trimethylethanaminium	smallmolecule	CID:439285	PUBCHEM	up-regulates quantity	chemical modification			9606									25033069	t			PNPLA6 encodes NTE, a lysophospholipase that converts lysophosphatidylcholine (LPC) to glycerophosphocholine. PNPLA6 is expressed in neurons throughout the brain, particularly in the cortex, Purkinje cells of the cerebellum, and hippocampus	SIGNOR-253611	0.8
PCDH19	protein	Q8TAB3	UNIPROT	GABRA3	protein	P34903	UNIPROT	up-regulates quantity by stabilization	binding			10116	BTO:0003102			SIGNOR-C334					29360992	t		miannu	Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons. 	SIGNOR-267222	0.2
HNRNPU	protein	Q00839	UNIPROT	IER3	protein	P46695	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation												17174306	f		lperfetto	In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs.	SIGNOR-262285	0.2
GTP	smallmolecule	CHEBI:15996	ChEBI	GNAS	protein	Q5JWF2	UNIPROT	up-regulates	chemical activation			9606									17095603	t		gcesareni	Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis.	SIGNOR-253071	0.8
MTCH2	protein	Q9Y6C9	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates	relocalization			9606									20436477	t	In the experiment they use a truncated BID (tBID)-interacting protein.	gcesareni	Mtch2/mimp (mitochondrial carrier homologue 2/met-induced mitochondrial protein), a novel truncated bid (tbid)-interacting protein, is a surface-exposed outer mitochondrial membrane protein that facilitates the recruitment of tbid to mitochondria	SIGNOR-165081	0.309
SPRY4	protein	Q9C004	UNIPROT	Epithelial-mesenchymal_transition	phenotype	SIGNOR-PH45	SIGNOR	down-regulates				9606	BTO:0002058								20501643	f		miannu	 Spry4 expression induces a reversal of the epithelial to mesenchymal transition characteristic of tumor cells. Treatment of a non-transformed lung epithelial cell line with shRNA to Spry4 led to decreased expression of epithelial markers and increased cell growth, supporting the concept of Spry4 acting as a tumor suppressor.	SIGNOR-253036	0.7
RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11486031	t		lperfetto	Using this inducible system, we show that Notchic activates transcription of the cyclin D1 gene with rapid kinetics.	SIGNOR-209753	0.597
long-chain fatty acid anion	smallmolecule	CHEBI:57560	ChEBI	long-chain fatty acyl-CoA(4-)	smallmolecule	CHEBI:83139	ChEBI	up-regulates quantity	precursor of			9606									24269233	t			ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity	SIGNOR-267711	0.8
USP6	protein	P35125	UNIPROT	ARF6	protein	P62330	UNIPROT	up-regulates	relocalization			9606									15509780	t		miannu	Here we show that tre17 (also called tre-2 and usp6), a founding member of the tbc family, targets the arf family gtpase arf6, which regulates plasma membrane-endosome trafficking. Surprisingly, tre17 does not function as a gap for arf6 but rather promotes its activation in vivo. Forced expression of tre17 promotes the localization of arf6 to the plasma membrane, leading to arf6 activation, presumably due to facilitated access to membrane-associated guanine nucleotide exchange factors (gefs).	SIGNOR-130019	0.645
TAB3	protein	Q8N5C8	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates	binding			9606									25290089	t		lperfetto	The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.	SIGNOR-205452	0.439
CDK1	protein	P06493	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Thr143	AVSPGTLtPTGVVSG										26933062	t		lperfetto	Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis.	SIGNOR-276588	0.437
PRKCH	protein	P24723	UNIPROT	ITGB2	protein	P05107	UNIPROT	unknown	phosphorylation	Thr758	NPLFKSAtTTVMNPK	9606	BTO:0000751								11700305	t		lperfetto	Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |	SIGNOR-249123	0.35
SRC	protein	P12931	UNIPROT	HCN2	protein	Q9UL51	UNIPROT	up-regulates activity	phosphorylation	Tyr476	LDSSRRQyQEKYKQV	9606	BTO:0000007								26280531	t		miannu	We identified a highly conserved tyrosine residue in the C-linker of HCN channels (Tyr476 in HCN2) that confers modulation by Src. Replacement of this tyrosine by phenylalanine in HCN2 or HCN4 abolished sensitivity to Src inhibitors. Mass spectrometry confirmed that Tyr476 is phosphorylated by Src. Our results have functional implications for HCN channel gating. Furthermore, they indicate that tyrosine phosphorylation contributes in vivo to the fine tuning of HCN channel activity.	SIGNOR-263199	0.27
SRC	protein	P12931	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	phosphorylation	Tyr1125	APSRDPHyQDPHSTA	9606									8845374	t		lperfetto	The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site	SIGNOR-44247	0.609
RNF167	protein	Q9H6Y7	UNIPROT	VAMP3	protein	Q15836	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys68	ETSAAKLkRKYWWKN	9606	BTO:0000007								23353890	t		miannu	Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains.	SIGNOR-272094	0.335
ZMYND8	protein	Q9ULU4	UNIPROT	MMP3	protein	P08254	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001033								27477906	t		lperfetto	Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported	SIGNOR-262043	0.2
IFNAR2	protein	P48551	UNIPROT	IFNAR	complex	SIGNOR-C243	SIGNOR	form complex	binding			9606									11278538	t		miannu	The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. 	SIGNOR-260333	0.903
D-ribofuranose	smallmolecule	CHEBI:47013	ChEBI	D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	up-regulates quantity	precursor of			9606									25749547	t		miannu	Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds.	SIGNOR-267071	0.8
OPTN	protein	Q96CV9	UNIPROT	Protein_aggregates	phenotype	SIGNOR-PH142	SIGNOR	up-regulates													27181519	f		lperfetto	Optineurin and TBK1 have also been discovered co-localizing in protein aggregates, and the phosphorylation of optineurin at serine 177 has been shown to be critical to its function in mediating clearance of aggregated proteins via autophagy	SIGNOR-262275	0.7
iron-sulfur cluster	smallmolecule	CHEBI:30408	ChEBI	Mitochondrial respiratory chain complex II	complex	SIGNOR-C278	SIGNOR	up-regulates activity	chemical activation												26083061	t		lperfetto	Respiratory chain complexes I–III depend on Fe-S clusters for function	SIGNOR-262136	0.8
PML	protein	P29590	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	binding			9606									15356634	t		lperfetto	Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome.	SIGNOR-128738	0.529
RNF128	protein	Q8TEB7	UNIPROT	CD83	protein	Q01151	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys177	SIFPDFSkAGMERAF	9606	BTO:0000007								19542455	t		miannu	In this study, we show that GRAIL can down-modulate the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. GRAIL-mediated down-modulation of CD83 is dependent on an intact GRAIL extracellular protease-associated domain and an enzymatically active cytosolic RING domain, and proceeds via the ubiquitin-dependent 26S proteosome pathway. Ubiquitin modification of lysine residues K168 and K183, but not K192, in the cytoplasmic domain of CD83 was shown to be necessary for GRAIL-mediated degradation of CD83.	SIGNOR-271850	0.359
CDK2	protein	P24941	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Ser249	DTRQIQPsPPWSYDQ	9606									16046550	t	The effect has been demonstrated using Q01196-8	gcesareni	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-138928	0.2
CDK1	protein	P06493	UNIPROT	PPM1D	protein	O15297	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser40	PTAEEKPsPRRSLSQ										33309518	t		lperfetto	Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20)	SIGNOR-275489	0.355
GABRB1	protein	P18505	UNIPROT	GABA-A (a2-b1-g2) receptor	complex	SIGNOR-C331	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263754	0.603
FGF11	protein	Q92914	UNIPROT	SCN10A	protein	Q9Y5Y9	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253442	0.2
AIM2 inflammasome	complex	SIGNOR-C222	SIGNOR	Pyroptosis	phenotype	SIGNOR-PH105	SIGNOR	up-regulates				9606									30166988	f		miannu	Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma.	SIGNOR-263123	0.7
TLR2	protein	O60603	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates activity				9606	BTO:0001025								19185596	f		miannu	S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. we have provided evidence that S protein induces IL-8 in PBMC in vitro and in THP-1 cells. The ability of S protein to increase IL-8 mRNA was mediated by activation of NF-κB possibly via TLR2 ligand and could be inhibited by the NF-κB inhibitor TPCK. The ability to detect elevated NF-κB transcription factor activity in the nucleus in response to S protein suggests that this most likely occurs by the mechanism of induction. Moreover increased secretion of IL-8 and IL-6 cytokines indicated that levels of proinflammatory mediators could be enhanced by S protein interaction with monocyte macrophages and could stimulate NK, neutrophil and monocyte migration to the site of infection.	SIGNOR-260973	0.547
FYN	protein	P06241	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	unknown	phosphorylation	Tyr932	IRRESSVyDISEHRR	-1									11024032	t			Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro.	SIGNOR-251174	0.76
GNAI1	protein	P63096	UNIPROT	TNFAIP8	protein	O95379	UNIPROT	up-regulates activity	binding			9606									20607800	t			TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation	SIGNOR-256491	0.2
FHIT	protein	P49789	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9606									18077326	t		miannu	Fhit interacts with _-catenin in vitro and in vivo / the tumor suppressor fhit acts as a repressor of _-catenin transcriptional activity	SIGNOR-159873	0.524
GABA-A (a3-b1-g2) receptor	complex	SIGNOR-C332	SIGNOR	CRHR2	protein	Q13324	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268591	0.2
ALDH9A1	protein	P49189	UNIPROT	NAD(1-)	smallmolecule	CHEBI:57540	ChEBI	down-regulates quantity	chemical modification			9606									11802770	t		miannu	Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). 	SIGNOR-269694	0.8
PRKCQ	protein	Q04759	UNIPROT	CARD11	protein	Q9BXL7	UNIPROT	up-regulates activity	phosphorylation	Ser644	NLMFRKFsLERPFRP	9606	BTO:0000782								21157432	t		lperfetto	NF-kappaB activation is triggered by PKCteta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCteta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCteta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation.	SIGNOR-249193	0.767
CSNK2A2	protein	P19784	UNIPROT	GTF2A1	protein	P52655	UNIPROT	up-regulates activity	phosphorylation	Ser321	LNSEDDVsDEEGQEL	-1									11278496	t		llicata	We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function.	SIGNOR-250998	0.382
GABA-A (a4-b3-d) receptor	complex	SIGNOR-C327	SIGNOR	CRHR2	protein	Q13324	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268594	0.2
TAL1	protein	P17542	UNIPROT	ANGPT2	protein	O15123	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22792348	f		miannu	Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation.	SIGNOR-198279	0.2
1-(4-fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-butanol	chemical	CHEBI:91549	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3).	SIGNOR-258849	0.8
MRPL47	protein	Q9HD33	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262349	0.714
EIF6	protein	P56537	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	down-regulates activity	binding			9606									14654845	t		lperfetto	The assembly of 80S ribosomes requires joining of the 40S and 60S subunits, which is triggered by the formation of an initiation complex on the 40S subunit. This event is rate-limiting for translation, and depends on external stimuli and the status of the cell. Here we show that 60S subunits are activated by release of eIF6 (also termed p27BBP). | Loading 60S subunits with eIF6 caused a dose-dependent translational block and impairment of 80S formation, which were reversed by expression of RACK1 and stimulation of PKC in vivo and in vitro. PKC stimulation led to eIF6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eIF6 impaired RACK1/PKC-mediated translational rescue. 	SIGNOR-269150	0.504
CHEK2	protein	O96017	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser124	PALKRSHsDSLDHDI	9606									11298456	t	Phosphorylation is the signal for ubiquitination	lperfetto	We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123.	SIGNOR-106808	0.837
perfluorooctane-1-sulfonic acid	chemical	CHEBI:39421	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			-1									23764977	t		miannu	Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. 	SIGNOR-268760	0.8
gefitinib	chemical	CHEBI:49668	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000551								15329413	t		gcesareni	Egfr is a tk of the erbb family that is the presumptive target of the tk inhibitor (tki) gefitinib.	SIGNOR-126976	0.8
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2R2	protein	Q712K3	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271324	0.755
HTR2C	protein	P28335	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257405	0.28
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MDM4	protein	O15151	UNIPROT	up-regulates activity	phosphorylation	Ser367	PDCRRTIsAPVVRPK	9606									18356162	t		lperfetto	We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2.	SIGNOR-178063	0.2
Vps34 Complex II	complex	SIGNOR-C241	SIGNOR	Autophagy	phenotype	SIGNOR-PH31	SIGNOR	up-regulates													30397185	f		lperfetto	PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively.	SIGNOR-260326	0.7
MAPKAPK2	protein	P49137	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	up-regulates	phosphorylation	Ser387	SKLMRSAsFNTDPYV	9606									20626350	t		gcesareni	Mk2 was found to phopsphorylate in vitro the ago2 protein in ser387, which was identified as the major ago2 phosphorylation site in cells.and mutation of ser387 to alanineimpairsago2 localization to therna-containing granules termedprocessing bodies	SIGNOR-166615	0.447
PTPRG	protein	P23470	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates activity	dephosphorylation	Tyr1003	VSNESVDyRATFPED	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254712	0.321
MAPK14	protein	Q16539	UNIPROT	RBPJ	protein	Q06330	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr339	STDKAEYtFYEGMGP	9606	BTO:0000007								22302987	t		miannu	P38 MAPK phosphorylates RBP-Jk at Thr339 by physical binding, which subsequently induces the degradation and ubiquitylation of the RBP-Jk protein. 	SIGNOR-276403	0.25
PRKCD	protein	Q05655	UNIPROT	PEBP1	protein	P30086	UNIPROT	up-regulates	phosphorylation	Ser153	RGKFKVAsFRKKYEL	9606									14654844	t		miannu	Here we show that the raf kinase inhibitor protein (rkip) is a physiological inhibitor of grk-2. After stimulation of gpcr, rkip dissociates from its known target, raf-1 (refs 6-8), to associate with grk-2 and block its activity. This switch is triggered by protein kinase c (pkc)-dependent phosphorylation of the rkip on serine 153.	SIGNOR-119551	0.305
PTK6	protein	Q13882	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	phosphorylation	Tyr326	EVLEDNDyGRAVDWW	9606	BTO:0000150	BTO:0001129							20606012	t		gcesareni	Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6.	SIGNOR-166510	0.454
MAPK10	protein	P53779	UNIPROT	SFN	protein	P31947	UNIPROT	down-regulates	phosphorylation	Ser186	FHYEIANsPEEAISL	9606									15071501	t	Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons	gcesareni	Here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein.Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-191	SIGNOR-124005	0.2
dabrafenib	chemical	CHEBI:75045	ChEBI	BRAF	protein	P15056	UNIPROT	down-regulates activity	chemical inhibition			-1									24720932	t		miannu	Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations	SIGNOR-259215	0.8
IL6ST	protein	P40189	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation	Tyr1007	VLPQDKEyYKVKEPG	9606									9716487	t		lperfetto	All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59].	SIGNOR-238630	0.624
XRCC3	protein	O43542	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity				9606	BTO:0000567								23438602	f		lperfetto	Interestingly, as with ATM (40, 41), XRCC3-deficient cells exhibited RDS and impaired CHK2 activation|Notably, early activation of CHK2 in S/G2 phase was downstream of XRCC3 recruitment as well as its phosphorylation at the sites of DSBs. NBS1 also has been shown to be involved in the early activation of CHK2 in response to IR (42). It is likely that NBS1-dependent CHK2 phosphorylation is mediated through XRCC3 activation.	SIGNOR-263261	0.527
PRKACA	protein	P17612	UNIPROT	LIPE	protein	Q05469	UNIPROT	up-regulates activity	phosphorylation	Ser950	EGFHPRRsSQGATQM	10090	BTO:0000944								11581251	t		lperfetto	HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme	SIGNOR-249203	0.585
CARM1	protein	Q86X55	UNIPROT	MAPK12/CARM1	complex	SIGNOR-C218	SIGNOR	form complex	binding					BTO:0001103							29681515	t		apalma	Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated	SIGNOR-255980	0.346
PPP1CB	protein	P62140	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	dephosphorylation	Thr495	TGITRKKtFKEVANA	9606	BTO:0001176								19036824	t			The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation	SIGNOR-248574	0.2
C5 convertase complex	complex	SIGNOR-C312	SIGNOR	C5	protein	P01031	UNIPROT	up-regulates activity	cleavage	Arg751	HKDMQLGrLHMKTLL										31331124	t		lperfetto	 Association of C3b with C3 convertases (C3bBb or C4b2a) results in formation of C5 convertases, C3bBbC3b and C4b2aC3b, which initiate the lytic pathway by cleavage of C5 to C5a and C5b	SIGNOR-263453	0.538
IKBKE	protein	Q14164	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	phosphorylation	Ser536	SGDEDFSsIADMDFS	9606				SIGNOR-C13					15489227	t		gcesareni	Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro.	SIGNOR-129943	0.45
dUMP(2-)	smallmolecule	CHEBI:246422	ChEBI	dTMP(2-)	smallmolecule	CHEBI:63528	ChEBI	up-regulates quantity	precursor of			9606									21876188	t		lperfetto	In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR.	SIGNOR-268236	0.8
PTPN2	protein	P17706	UNIPROT	JAK1	protein	P23458	UNIPROT	down-regulates activity	dephosphorylation	Tyr1035	IETDKEYyTVKDDRD	10090									11909529	t			The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3|We have identified JAK1 and JAK3 as physiological substrates of TCPTP.| Using a site-specific antibody directed against the activation loop phosphotyrosines in JAK1 (pY1022/pY1023), we found that these sites were in fact dephosphorylated by TCPTP	SIGNOR-248396	0.758
HHIP	protein	Q96QV1	UNIPROT	IHH	protein	Q14623	UNIPROT	down-regulates activity	binding			10090									10050855	t		lperfetto	Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal.	SIGNOR-65075	0.702
MOB1B	protein	Q7L9L4	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	binding			9606									21084559	t	Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases.	gcesareni	Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1.	SIGNOR-169798	0.872
Hexocyclium	chemical	CHEBI:5707	ChEBI	CHRM5	protein	P08912	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								2704370	t		miannu	In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 	SIGNOR-258399	0.8
PTPN1	protein	P18031	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	dephosphorylation	Tyr1008	LPQDKEYyKVKEPGE	9606									11970898	t			Immunoblots with phospho-specific antibodies confirmed that PTP1B suppresses phosphorylation of the Jak2 activation site tyrosines (Y1007/Y1008) and Stat3 in a dose-dependent manner	SIGNOR-248405	0.79
CTDSP1	protein	Q9GZU7	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	dephosphorylation	Ser204	NHSMDAGsPNLSPNP	9606									17035229	t			SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248791	0.408
OXTR	protein	P30559	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257065	0.429
LLGL2	protein	Q6P1M3	UNIPROT	Scribble_complex_DLG4-LLGL2_variant	complex	SIGNOR-C505	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270887	0.526
DENR	protein	O43583	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004163								35440133	t		miannu	DENR directly regulates JAK2 expression. 	SIGNOR-269675	0.2
SIK2	protein	Q9H0K1	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	phosphorylation	Ser154	STLYRTQsSSNLAEL	-1									27478041	t		miannu	The Regulatory Subunit of PI3K Is a Direct Catalytic Target of SIK2. These data confirm that p85α is a direct catalytic substrate of SIK2 and that SIK2 S154 phosphorylation significantly increases the activity of the PI3K/AKT pathway in ovarian cancer cells.	SIGNOR-277269	0.327
TAF6	protein	P49848	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263922	0.909
SLBP	protein	Q14493	UNIPROT	H2BW1	protein	Q7Z2G1	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265387	0.2
CPT1C	protein	Q8TCG5	UNIPROT	palmitoyl-CoA(4-)	smallmolecule	CHEBI:57379	ChEBI	down-regulates quantity	chemical modification			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267128	0.8
PRKAA1	protein	Q13131	UNIPROT	GAPDH	protein	P04406	UNIPROT	up-regulates activity	phosphorylation	Ser122	GAKRVIIsAPSADAP	10090									26626483	t		Luana	 Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated. 	SIGNOR-259857	0.298
PRKCD	protein	Q05655	UNIPROT	PTPN22	protein	Q9Y2R2	UNIPROT	down-regulates	phosphorylation	Ser35	FLKLKRQsTKYKADK	9606	BTO:0000782								18056643	t		llicata	We show that lyp is phosphorylated exclusively at ser-35 by pkc both in vitro and in vivo. our data establish a mechanism by which pkc could attenuate the cellular function of lyp, thereby augmenting t cell activation.	SIGNOR-159591	0.318
PPP1CC	protein	P36873	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates	dephosphorylation			9606									14718519	t		lpetrilli	We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI.	SIGNOR-121277	0.445
EXOC4	protein	Q96A65	UNIPROT	Exocyst_EXOC6 variant	complex	SIGNOR-C492	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270787	0.959
RBBP8	protein	Q99708	UNIPROT	SPEN	protein	Q96T58	UNIPROT	down-regulates	binding			9606									16287852	t		gcesareni	We identify the ctip and ctbp corepressors as novel components of the human rbp-jk/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain.	SIGNOR-141616	0.522
COX6B1	protein	P14854	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267742	0.748
C9	protein	P02748	UNIPROT	Membrane attack complex	complex	SIGNOR-C313	SIGNOR	form complex	binding			-1									30552328	t		lperfetto	The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer	SIGNOR-263441	0.468
RELA	protein	Q04206	UNIPROT	CITED1	protein	Q99966	UNIPROT	up-regulates	binding			9606			SIGNOR-C13						9660950	t		gcesareni	The transcriptional coactivator cpb/p300 associates with nf-kappa b p65 through two sites, an n-terminal domain that interacts with the c-terminal region of unphosphorylated p65, and a second domain that only interacts with p65 phosphorylated on serine 276.	SIGNOR-59054	0.2
NUMB	protein	P49757	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								12682059	t		lperfetto	Mammalian numb proteins promote notch1 receptor ubiquitination and degradation of the notch1 intracellular domain	SIGNOR-99762	0.791
CX3CL1	protein	P78423	UNIPROT	CX3CR1	protein	P49238	UNIPROT	up-regulates	binding			9606									11432858	t		gcesareni	Fractalkine/cx3cl1 is a membrane-tethered chemokine that functions as a chemoattractant and adhesion protein by interacting with the receptor cx3cr1.	SIGNOR-109135	0.778
MC1R	protein	Q01726	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268697	0.458
CDK1	protein	P06493	UNIPROT	RPA2	protein	P15927	UNIPROT	up-regulates activity	phosphorylation	Ser29	QSPGGFGsPAPSQAE	9606									1318195	t		llicata	Cdc2 family kinases phosphorylate a human cell dna replication factor, rpa, and activate dna replication. therefore, the serines on rpa p34 that were necessary for phosphorylation by cdc2 kinase were also necessary for phosphorylation in the cell	SIGNOR-16975	0.52
MTMR4	protein	Q9NYA4	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates	dephosphorylation			9606									20061380	t		gcesareni	Here we demonstrate that myotubularin-related protein 4 (mtmr4), a fyve domain-containing dual-specificity protein phosphatase (dsp), attenuates tgfbeta signaling by reducing the phosphorylation level of r-smads in early endosomes.	SIGNOR-163031	0.509
SCRIB	protein	Q14160	UNIPROT	Scribble_complex_DLG5-LLGL2_variant	complex	SIGNOR-C506	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270892	0.45
PLK1	protein	P53350	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates	phosphorylation	Ser260	SLDSEDYsLSEEGQE	9606									12383858	t		gcesareni	Here we show that the oncogenic and cell cycle-regulatory protein kinase, polo-like kinase-1 (plk1), phosphorylates mdm2 at one of these residues, ser260, and stimulates mdm2-mediated turnover of p53. These data are consistent with the idea that deregulation of plk1 during tumourigenesis may help suppress p53 function.	SIGNOR-94272	0.478
PRKAA2	protein	P54646	UNIPROT	HIPK2	protein	Q9H2X6	UNIPROT	down-regulates activity	phosphorylation	Ser121	LMRRSTVsLLDTYQK										23871434	t	Phosphosite positions are derived from Figure S5	lperfetto	AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro	SIGNOR-275486	0.2
CTSG	protein	P08311	UNIPROT	F2R	protein	P25116	UNIPROT	up-regulates activity	cleavage	Arg41	TNATLDPrSFLLRNP	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Arg41-Ser42 activation site	SIGNOR-263561	0.577
NARS1	protein	O43776	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270455	0.8
ROCK2	protein	O75116	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates activity	phosphorylation	Thr19	KKRPQRAtSNVFAMF	9606									8702756	t		miannu	 Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. 	SIGNOR-261718	0.633
TACR3	protein	P29371	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256937	0.2
MECOM	protein	Q03112	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	binding			9606									9665135	t		miannu	Evi-1 interacts with smad3, an intracellular mediator of tgf-beta signalling, thereby suppressing the transcriptional activity of smad3.	SIGNOR-59132	0.505
NCBP2	protein	P52298	UNIPROT	Cap-binding complex	complex	SIGNOR-C440	SIGNOR	form complex	binding			9606									26382858	t		lperfetto	The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. 	SIGNOR-268358	0.969
CDC42BPA	protein	Q5VT25	UNIPROT	LIMK1	protein	P53667	UNIPROT	up-regulates activity	phosphorylation	Thr508	PDRKKRYtVVGNPYW		BTO:0000567								11340065	t		llicata	Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. \ In vitro, MRCKalpha phosphorylated the protein kinase domain of LIM kinases, and the site in LIMK2 phosphorylated by MRCKalpha proved to be threonine 505 within the activation segment. 	SIGNOR-250721	0.413
CBP/p300	complex	SIGNOR-C6	SIGNOR	MYOD1	protein	P15172	UNIPROT	up-regulates	binding			9606		BTO:0000887							10944526	t		gcesareni	Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.	SIGNOR-81047	0.633
AKT1	protein	P31749	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Ser315	DFRSRTNsNASTVSG	9606									19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252523	0.908
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	NOS3	protein	P29474	UNIPROT	up-regulates	phosphorylation	Ser1177	TSRIRTQsFSLQERQ	9606									11729179	t		lperfetto	Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.	SIGNOR-244322	0.2
TTK	protein	P33981	UNIPROT	MAP4	protein	P27816	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser928	SRLATNTsAPDLKNV	9606	BTO:0000567								31253867	t		miannu	We further uncovered that Mps1 is a kinase of MAP4, and E7-MAP4 binding blocks Mps1 phosphorylation of MAP4, thereby interrupting phosphorylation-dependent MAP4 degradation. 	SIGNOR-277458	0.2
SRC	protein	P12931	UNIPROT	ENO1	protein	P06733	UNIPROT	up-regulates	phosphorylation	Tyr44	SGASTGIyEALELRD	9606									7629021	t		lperfetto	The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways	SIGNOR-30126	0.419
PPM1D	protein	O15297	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	dephosphorylation	Ser15	PSVEPPLsQETFSDL	9606									15870257	t		lperfetto	PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair.	SIGNOR-135980	0.576
PPM1D	protein	O15297	UNIPROT	CHEK1	protein	O14757	UNIPROT	down-regulates activity	dephosphorylation	Ser345	LVQGISFsQPTCPDH	9606									15870257	t			Here we show that the oncogenic p53-induced serine/threonine phosphatase, PPM1D (or Wip1), dephosphorylates two ATM/ATR targets, Chk1 and p53. PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity.	SIGNOR-248317	0.487
KCNMA1	protein	Q12791	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			9606	BTO:0000938								31152168	t		miannu	The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. 	SIGNOR-269198	0.8
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	Membrane_blebbing	phenotype	SIGNOR-PH24	SIGNOR	up-regulates				9606		BTO:0000142							10200555	f		amattioni	Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation	SIGNOR-256481	0.7
DUSP1	protein	P28562	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates activity	dephosphorylation	Tyr204	HTGFLTEyVATRWYR	10116									7535768	t			We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively	SIGNOR-248463	0.778
PLK1	protein	P53350	UNIPROT	KLF4	protein	O43474	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser234	GKFVLKAsLSAPGSE	9606	BTO:0002181								31281496	t		miannu	We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization.	SIGNOR-277463	0.252
PRKCB	protein	P05771	UNIPROT	SLC6A9	protein	P48067-2	UNIPROT	down-regulates activity	phosphorylation	Ser239	LIRGVKSsGKVVYFT	9823									21864610	t		miannu	We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 	SIGNOR-262922	0.2
GPHN	protein	Q9NQX3	UNIPROT	ARHGEF9	protein	O43307	UNIPROT	up-regulates activity	binding			9606									25882190	t		miannu	Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses.	SIGNOR-264973	0.625
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	USP7	protein	Q93009	UNIPROT	up-regulates activity	phosphorylation	Tyr243	NQLRKAVyMMPTEGD										24317448	t		lperfetto	In this study, we show that BCR-ABL enhances HAUSP-induced de-ubiquitination of PTEN in turn favoring its nuclear exclusion. We further demonstrate that BCR-ABL physically interacts with and phosphorylates HAUSP on tyrosine residues to trigger its activity.|The HAUSP Y243F mutant showed significantly reduced BCR-ABL-induced HAUSP phosphorylation, which in turn was completely abrogated by imatinib treatment	SIGNOR-276532	0.2
MAPK3	protein	P27361	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser294	QLSKWPGsPTSRSSD	9606									19282669	t		lperfetto	Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway	SIGNOR-252961	0.583
TRAF6	protein	Q9Y4K3	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	ubiquitination	Lys34	NFEEIDYkEIEVEEV	9606									18758450	t		lperfetto	Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.	SIGNOR-236071	0.889
AHR	protein	P35869	UNIPROT	CYP1A1	protein	P04798	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									9865727	t	 	 	Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor|These data demonstrate that resveratrol inhibits CYP1A1 expression in vitro, and that it does this by preventing the binding of the AHR to promoter sequences that regulate CYP1A1 transcription. 	SIGNOR-253639	0.673
PPARG	protein	P37231	UNIPROT	CEBPA	protein	P49715	UNIPROT	up-regulates activity	transcriptional regulation			10090	BTO:0002572;BTO:0000011;BTO:0005065								16431920	f	Dislodging hdac1 from the promoter	lperfetto	These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome	SIGNOR-235358	0.641
MAD2L2	protein	Q9UI95	UNIPROT	FZR1	protein	Q9UM11	UNIPROT	down-regulates activity	binding			-1									11459826	t		miannu	 The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20. We show here that a MAD2 homolog MAD2B also inhibits APC. MAD2B directly inhibits activation of APC by CDC20 and CDH1	SIGNOR-264902	0.528
RPS16	protein	P62249	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262435	0.87
SLC38A9	protein	Q8NBW4	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				9606									25567906	f		Luana	SLC38A9 is a Lysosomal Membrane Protein Required for mTORC1 Activation	SIGNOR-268014	0.469
ARHGAP44	protein	Q17R89	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260498	0.571
AKT3	protein	Q9Y243	UNIPROT	TBX3	protein	O15119	UNIPROT	up-regulates activity	phosphorylation	Ser719	AEKEAATsELQSIQR	9606									25595898	t		miannu	We have identified TBX3 as a key substrate of AKT3 in melanomagenesis. we have identified the AKT3 target site at serine residue 720 in the TBX3 protein and show that this site is phosphorylated in vivo. the phosphorylation at S720 promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion.	SIGNOR-223534	0.363
MTOR	protein	P42345	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606	BTO:0000527								16740698	t		miannu	Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor	SIGNOR-146915	0.738
MFGE8	protein	Q08431	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	down-regulates activity				10116									19020771	f		Giorgia	In our current study, we have shown that after LPS-stimulation, MFG-E8-mediated apoptotic cell phagocytosis suppresses various ERK1/2, p38, JNK, and NFκB activation, resulting in a lower TNF-α release. We also explored whether MFG-E8 helps to suppress the proinflammatory pathway within RPMs. We hence incubated the macrophages with apoptotic cells and stimulated them with LPS and examined the activation of MAP kinase and NFkB pathways after the exogenous addition of recombinant MFG-E8 (rMFG-E8). While apoptotic cells alone had no effect on these pathways, the addition of rMFG-E8 to apoptotic cells prior to phagocytosis and LPS stimulation had a marked suppressive effect on all of the investigated pathways, particularly on the p38 and NFκB pathways that play a key role in the cytokine response of macrophages	SIGNOR-260651	0.248
MAP3K7	protein	O43318	UNIPROT	TAB1	protein	Q15750	UNIPROT	up-regulates activity	phosphorylation	Ser453	TNTHTQSsSSSSDGG	9606	BTO:0000007								22216226	t		miannu	We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro. 	SIGNOR-276366	0.927
RPS6KB2	protein	Q9UBS0	UNIPROT	TARBP2	protein	Q15633	UNIPROT	up-regulates activity	phosphorylation	Ser283	ILSLRSCsLGSLGAL	-1									27407113	t		miannu	We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. 	SIGNOR-274066	0.341
LRRK2	protein	Q5S007	UNIPROT	LRRK2	protein	Q5S007	UNIPROT	unknown	phosphorylation	Ser1403	AGREEFYsTHPHFMT	9606	BTO:0000938								19824698	t		lperfetto	We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites.	SIGNOR-188429	0.2
GSK3B	protein	P49841	UNIPROT	RXRA	protein	P19793	UNIPROT	up-regulates activity	phosphorylation	Ser49	GSPGQLHsPISTLSS	9606	BTO:0000007								29137318	t		miannu	GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis. 	SIGNOR-277372	0.279
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	YWHAZ	protein	P63104	UNIPROT	down-regulates	phosphorylation			9606									15071501	t	Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons	gcesareni	Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-190	SIGNOR-269980	0.2
ETS1	protein	P14921	UNIPROT	MMP13	protein	P45452	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000948								22270366	f	 	miannu	 VEGF-induced MMP-9 and MMP-13 promoter activities were down-regulated in ETS-1 siRNA-transfected cells. it is hypothesized that the activation of PI3K/AKT and p38 MAPK by VEGF results in ETS-1 gene expression, which activates MMP-9 and MMP-13, leading to the invasion and scattering of SKOV-3 cells. 	SIGNOR-254084	0.312
CAMK2G	protein	Q13555	UNIPROT	MYLK	protein	Q15746	UNIPROT	down-regulates activity	phosphorylation	Ser1760	RAIGRLSsMAMISGL										2160950	t		llicata	Phosphorylation of MLC kinase by CaM protein kinase II increased the dissociation constant of MLC kinase for calmodulin about 10 times without changing the Vmax. The location of the phosphorylation sites was identified by isolating and sequencing the tryptic phosphopeptides of MLC kinase. The preferred site was identified as serine 512 and the second site as serine 525. These sites are the same as the sites phosphorylated by cAMP-dependent protein kinase.	SIGNOR-250700	0.336
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	BNIP3L	protein	O60238	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27692180	t		miannu	HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 	SIGNOR-267455	0.306
GGCX	protein	P38435	UNIPROT	BGLAP	protein	P02818	UNIPROT	up-regulates activity	carboxylation			9606									31226734	t		lperfetto	Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.	SIGNOR-265922	0.674
SRC	protein	P12931	UNIPROT	DNM2	protein	P50570	UNIPROT	down-regulates activity	phosphorylation	Tyr597	NTEQRNVyKDLRQIE	10090	BTO:0000944								33113375	t		miannu	We used cSrc-transformed NIH 3T3 fibroblasts to examine the effect of mutant Dyn2Y597. Similar to its effect in myotubes, Dyn2Y597F presented reduced enrichment at podosomes, whereas Dyn2Y597E clearly targeted podosome rosettes (Figures S9B and S9C). Moreover, Dyn2Y597F significantly reduced the podosome area, ECM degradation ability, and lifespan of the podosome in cSrc-transformed NIH 3T3 fibroblasts, whereas Dyn2Y597E displayed contradictory effects (Figures S9D–S9G).	SIGNOR-277539	0.575
GSK3B	protein	P49841	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates	phosphorylation	Thr286	EEVDLACtPTDVRDV	9606	BTO:0000150								16504004	t		gcesareni	Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover.	SIGNOR-144818	0.776
WNT10A	protein	Q9GZT5	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131619	0.566
SRC	protein	P12931	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates activity	phosphorylation	Tyr240	RREDKFMyFEFPQPL	9606	BTO:0002035								11948419	t		miannu	MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e).	SIGNOR-275982	0.554
PRKG1	protein	Q13976	UNIPROT	GTF2I	protein	P78347	UNIPROT	up-regulates	phosphorylation	Ser412	GIPFRRPsTYGIPRL	9606		BTO:0000671							12082086	t		lperfetto	G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells	SIGNOR-89849	0.554
FCGR1A	protein	P12314	UNIPROT	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606									24445665	f		lperfetto	Although crosslinking of activating FcgammaRs on monocytes and macrophages induces the production of several pro-inflammatory cytokines and chemokines, immune complex-mediated signalling via activating FcgammaRs together with Toll-like receptor (TLR) triggering induces a specific M2 activation state in macrophages macrophages in this state were termed M2b or regulatory macrophages.	SIGNOR-249524	0.7
KCNQ4	protein	P56696	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	up-regulates quantity	relocalization			9606									19298256	t		miannu	KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations.	SIGNOR-265985	0.8
PRKAA1	protein	Q13131	UNIPROT	FANCA	protein	O15360	UNIPROT	up-regulates activity	phosphorylation	Ser347	VQMQREWsFARTHPL	9606	BTO:0001938								27449087	t		miannu	FANCA was phosphorylated by AMPK at S347 and phosphorylation increased with MMC treatment. MMC-induced FANCD2 monoubiquitination and nuclear foci formation were compromised in a U2OS cell line that stably overexpressed the S347A mutant form of FANCA compared to wild-type FANCA-overexpressing cells, indicating a requirement for FANCA phosphorylation at S347 for proper activation of the FA/BRCA pathway. 	SIGNOR-277264	0.338
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDUFB6	protein	O95139	UNIPROT	up-regulates activity	phosphorylation	Ser55	NKFLENKsPWRKMVH										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275598	0.251
CNTRL	protein	Q7Z7A1	UNIPROT	CEP290	protein	O15078	UNIPROT	down-regulates activity	binding			9606									18694559	t		miannu	CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CP110 in this complex is to keep CEP290 inactive in growing cells until cells are ready to undergo ciliogenesis as they transit into the quiescent state	SIGNOR-252149	0.447
tacrolimus (anhydrous)	chemical	CHEBI:61049	ChEBI	PPP3CC	protein	P48454	UNIPROT	down-regulates	chemical inhibition			9606									15276472	t		gcesareni	Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins.	SIGNOR-127245	0.8
HRH3	protein	Q9Y5N1	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256968	0.263
PRKACA	protein	P17612	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates	phosphorylation	Ser660	FSAERRNsILTETLH	9606									1716180	t		lperfetto	Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response.	SIGNOR-21312	0.466
PTPRJ	protein	Q12913	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates	dephosphorylation			9606									12771128	t	inferred from 70% of family members	gcesareni	A dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation.	SIGNOR-269919	0.47
JUNB	protein	P17275	UNIPROT	IL4	protein	P05112	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								21799768	f			Our results suggest that the prolonged IL-4 expression in NFAT1 deficient Th2 cells is mediated by preferential binding of JUNB/SATB1 to the IL-4 promoter with permissive chromatin architecture	SIGNOR-254503	0.47
CTSG	protein	P08311	UNIPROT	AGT	protein	P01019	UNIPROT	up-regulates activity	cleavage	Phe41	DRVYIHPfHLVIHNE	-1									11747312	t		miannu	Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.	SIGNOR-256312	0.627
PRKACA	protein	P17612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser118	GRELRRMsDEFVDSF	9534	BTO:0000298								10880354	t		miannu	Ser(155) is phosphorylated preferentially by PKA in vitro and is the only residue in BAD that becomes phosphorylated when cells are exposed to cAMP-elevating agents. The phosphorylation of BAD at Ser(155) prevents it from binding to Bcl-X(L) and promotes its interaction with 14-3-3 proteins.	SIGNOR-250338	0.521
MLL-AF9	fusion protein	SIGNOR-FP5	SIGNOR	AEP complex	complex	SIGNOR-C117	SIGNOR	up-regulates activity	binding			9606	BTO:0005261								19956800	t		irozzo	Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription.	SIGNOR-255876	0.2
Microprocessor complex	complex	SIGNOR-C356	SIGNOR	NcRNA_processing	phenotype	SIGNOR-PH95	SIGNOR	up-regulates													24581491	f		lperfetto	Microprocessor minimally comprises the ribonuclease DROSHA and its double-stranded RNA-binding partner DGCR8 (Denli et al., 2004; Gregory et al., 2004). Microprocessor recognizes pri-miRNA through the stem-loop (Zeng et al., 2005) and the stem-loop-ssRNA junction (Han et al., 2006), and cleaves both the 5′ and 3′ flanking segments to generate pre-miRNA.	SIGNOR-264850	0.7
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	NFATC4	protein	Q14934	UNIPROT	up-regulates	phosphorylation			9606									15657420	t	inferred from 70% family members	lperfetto	The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity.	SIGNOR-270047	0.2
TFAP2C	protein	Q92754	UNIPROT	SULT1E1	protein	P49888	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002828								17187826	f	 	miannu	 Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. 	SIGNOR-255399	0.2
C3 convertase complex (C3bBb)	complex	SIGNOR-C314	SIGNOR	C5 convertase complex (C3bBbC3b)	complex	SIGNOR-C315	SIGNOR	form complex	binding			9606		BTO:0000089							26489954	t		lperfetto	In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC).	SIGNOR-263479	0.2
COL4A2	protein	P08572	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates activity	binding												35267698	t		lperfetto	Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23].	SIGNOR-272348	0.467
GLI1	protein	P08151	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150;BTO:0000551								19860666	f		gcesareni	GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin	SIGNOR-188869	0.563
HIF1A	protein	Q16665	UNIPROT	KDM4B	protein	O94953	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001248								20682797	f		miannu	Here, we show the histone demethylase JMJD2B is regulated by both ERalpha and HIF-1alpha, drives breast cancer cell proliferation in normoxia and hypoxia, and epigenetically regulates the expression of cell cycle genes such as CCND1, CCNA1, and WEE1. 	SIGNOR-263738	0.265
UBE2I	protein	P63279	UNIPROT	MBD4	protein	O95243	UNIPROT	up-regulates activity	sumoylation	Lys137	KNGETSLkPEDFDFT										31476572	t		lperfetto	MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro.	SIGNOR-275676	0.2
PRKCD	protein	Q05655	UNIPROT	MUC1	protein	P15941	UNIPROT	up-regulates	phosphorylation	Thr1224	RYVPPSStDRSPYEK	9606									11877440	t		gcesareni	We show that phosphorylation of muc1 by pkcdelta increases binding of muc1 and beta-catenin in vitro and in vivo. The functional significance of the muc1-pkcdelta interaction is further supported by the demonstration that mutation of the pkcdelta phosphorylation site abrogates muc1-mediated decreases in binding of beta-catenin to e-cadherin	SIGNOR-115501	0.342
CDK5	protein	Q00535	UNIPROT	CRMP1	protein	Q14194	UNIPROT	up-regulates	phosphorylation	Thr509	PVYEVPAtPKYATPA	9606	BTO:0000938								16611631	t		lperfetto	In summary, phosphorylation of thr509 of human crmp1 appears to be regulated by two mechanisms; direct phosphorylation by cdk5, or by priming of ser522 by cdk5 followed by sequential phosphorylation of ser518, thr514, and thr509 by gsk3.	SIGNOR-145912	0.608
SMURF2	protein	Q9HAU4	UNIPROT	SMAD7	protein	O15105	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0001538								11163210	t		miannu	Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways. 	SIGNOR-272940	0.865
PRKACA	protein	P17612	UNIPROT	PTPRR	protein	Q15256	UNIPROT	down-regulates activity	phosphorylation	Ser339	GLQERRGsNVSLTLD	9534									10601328	t		miannu	 The PKA phosphorylation site on PTP-SL was identified as the Ser(231) residue. treatment of COS-7 cells with PKA activators, or overexpression of the Calpha catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild-type PTP-SL, but not by a PTP-SL S231A mutant.‚ 	SIGNOR-250038	0.349
EGLN2	protein	Q96KS0	UNIPROT	HIF1A	protein	Q16665	UNIPROT	down-regulates quantity by destabilization	hydroxylation			9606									24990963	t		lperfetto	There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization	SIGNOR-261999	0.851
NOS1	protein	P29475	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255996	0.369
MAPK3	protein	P27361	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	down-regulates activity	phosphorylation			9606									12809513	t	inferred from family member	llicata	We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay.	SIGNOR-270301	0.424
Cell-Cell_contact	stimulus	SIGNOR-ST13	SIGNOR	STK4	protein	Q13043	UNIPROT	up-regulates				9606									22683405	f		milica	In response to growth inhibitory signal (e.g. cell–cell contact), MST1/2 in active form phosphorylates LATS1/2 that sequentially phosphorylates YAP at Ser-127.	SIGNOR-230693	0.7
WDR61	protein	Q9GZS3	UNIPROT	PAF1C	complex	SIGNOR-C471	SIGNOR	form complex	binding			9606	BTO:0000567								20178742	t		miannu	Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A). 	SIGNOR-269831	0.845
AKT2	protein	P31751	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser253	APRRRAVsMDNSNKY										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-252863	0.757
PICK1	protein	Q9NRD5	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates activity	binding			10116	BTO:0003036								16554470	t		miannu	We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. 	SIGNOR-268178	0.796
PTPN2	protein	P17706	UNIPROT	STAT1	protein	P42224	UNIPROT	down-regulates	dephosphorylation	Tyr701	DGPKGTGyIKTELIS	9606									12138178	t		miannu	Stat1 becomes tyrosine phosphorylated and translocates into the nucleus, where it binds to dna to activate transcription. The activity of stat1 is dependent on tyrosine phosphorylation, and its inactivation in the nucleus is accomplished by a previously unknown protein tyrosine phosphatase (ptp). We have now purified a stat1 ptp activity from hela cell nuclear extract and identified it as tc45, the nuclear isoform of the t-cell ptp (tc-ptp). Tc45 can dephosphorylate stat1 both in vitro and in vivo.	SIGNOR-90814	0.724
MAP3K7	protein	O43318	UNIPROT	TAB1	protein	Q15750	UNIPROT	up-regulates activity	phosphorylation	Ser457	TQSSSSSsDGGLFRS	9606	BTO:0000007								22216226	t		miannu	We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro. 	SIGNOR-276367	0.927
LRRK2	protein	Q5S007	UNIPROT	LRRK2	protein	Q5S007	UNIPROT	up-regulates	phosphorylation	Thr1969	DKASLTRtLQHRIAL	9606	BTO:0000938								19824698	t		lperfetto	We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. Substitution of thr1967, an autophosphorylation site located within the kinase domain, to ala caused a significant decrease in the kinase activity	SIGNOR-188421	0.2
MAPK3	protein	P27361	UNIPROT	THRB	protein	P10828	UNIPROT	down-regulates activity	phosphorylation	Ser142	IQKNLHPsYSCKYEG	9606									12809513	t		llicata	We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay.	SIGNOR-102224	0.407
MAP2K2	protein	P36507	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates activity	phosphorylation	Thr125	PEVLRPEtPRPVDIG										12792650	t		lperfetto	Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2	SIGNOR-249386	0.354
SMO	protein	Q99835	UNIPROT	CXCL1	protein	P09341	UNIPROT	up-regulates	binding			9606									16885213	t		gcesareni	We found that smo, by virtue of what appears to be constitutive activity, activates all members of the g(i) family but does not activate members of the g(s), g(q), and g(12) families.	SIGNOR-148484	0.2
ITGAV	protein	P06756	UNIPROT	Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253205	0.912
CLU	protein	P10909	UNIPROT	LRP2	protein	P98164	UNIPROT	up-regulates quantity	binding			10090									32332780	t		miannu	 Our results demonstrate that circulating ApoJ is retained in muscle via LRP2 and that LRP2 signaling could play a role in the maintenance of ApoJ homeostasis in circulation, at least in part.	SIGNOR-265256	0.578
NFKBIZ	protein	Q9BYH8	UNIPROT	IL17A	protein	Q16552	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000782								20383124	t		Luana	In cooperation with RORγt and RORα, IκBζ enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. 	SIGNOR-266210	0.391
GSK3B	protein	P49841	UNIPROT	CHEK1	protein	O14757	UNIPROT	down-regulates activity				10090									24260231	f		miannu	Involvement of GSK3 Inhibition by the PI3K/Akt Pathway in Regulation of Etoposide-induced Chk1 Activation. GSK3ß regulates etoposide-induced Chk1 activation. GSK3 inhibitors, including LiCl and SB216763, restored the sustained Chk1 activation and mitigated apoptosis in cells treated with etoposide and the inhibitors for aberrant kinases, PI3K, or Akt. Thus, proteasomal degradation of Chk1 as well as GSK3 activation may be involved in negative regulation of etoposide-induced Chk1 by imatinib in these cells.	SIGNOR-263050	0.302
PRKACA	protein	P17612	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates activity	phosphorylation	Ser813	DIYSRRLsQETGLEI	-1									1377674	t		miannu	CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795. 	SIGNOR-250351	0.466
PAK3	protein	O75914	UNIPROT	SORT1	protein	Q99523	UNIPROT	down-regulates activity	phosphorylation	Ser793	RFLVHRYsVLQQHAE	9606	BTO:0000007								31767632	t		miannu	PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction. 	SIGNOR-273719	0.2
PRKD1	protein	Q15139	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	phosphorylation	Thr120	QFDAAHPtNVQRLAE	9606	BTO:0001130								19141652	t		lperfetto	This study provides evidence that pkd1 interacts with and phosphorylates beta-catenin at thr(112) and thr(120) we postulate that pkd1 phosphorylation is required to maintain _-catenin transcription activity.	SIGNOR-183388	0.398
DGC	complex	SIGNOR-C217	SIGNOR	NRXN3	protein	Q9Y4C0	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							11470830	t		miannu	In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan.	SIGNOR-265451	0.306
MAX	protein	P61244	UNIPROT	MXD4	protein	Q14582	UNIPROT	up-regulates activity	binding			9606									7954804	t	2	miannu	the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences.	SIGNOR-240224	0.496
L-serine	chemical	CHEBI:17115	ChEBI	pyruvate	smallmolecule	CHEBI:15361	ChEBI	up-regulates quantity	precursor of			10090		BTO:0000142							12393813	t		lperfetto	High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media.	SIGNOR-268269	0.8
MYC	protein	P01106	UNIPROT	IMPDH2	protein	P12268	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18677108	t		miannu	Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.	SIGNOR-267375	0.299
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	KDM3A	protein	Q9Y4C1	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273479	0.8
PRKAA2	protein	P54646	UNIPROT	PDHA1	protein	P08559	UNIPROT	up-regulates activity	phosphorylation	Ser295	RYHGHSMsDPGVSYR	-1									33022274	t		miannu	AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex	SIGNOR-276840	0.2
MAPK3	protein	P27361	UNIPROT	SREBF2	protein	Q12772	UNIPROT	up-regulates	phosphorylation	Ser455	SIDSEPGsPLLDDAK	9606									14988395	t		lperfetto	Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity.	SIGNOR-123053	0.4
MAPK1	protein	P28482	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Thr312	ISYDIPPtPGNTYQI	10029	BTO:0000246								15379552	t		lperfetto	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-249399	0.584
SOX9	protein	P48436	UNIPROT	CEBPB	protein	P17676	UNIPROT	down-regulates	transcriptional regulation			9606									19254573	f		fspada	Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation	SIGNOR-210037	0.332
SEC13	protein	P55735	UNIPROT	COPII vesicle	complex	SIGNOR-C370	SIGNOR	form complex	binding			9606									30605680	t		lperfetto	The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat	SIGNOR-265296	0.842
ATR	protein	Q13535	UNIPROT	MCM2	protein	P49736	UNIPROT	unknown	phosphorylation	Ser108	DVEELTAsQREAAER	9606									15210935	t		lperfetto	Atm phosphorylates mcm3 on s535 in response to ionizing radiation. Second, atr phosphorylates mcm2 on s108 in response to multiple forms of dna damage and stalling of replication forksthe functional consequences of mcm2 s108 and mcm3 s535 phosphorylation are not clear	SIGNOR-126363	0.697
WNK1	protein	Q9H4A3	UNIPROT	OXSR1	protein	O95747	UNIPROT	up-regulates	phosphorylation	Ser325	VRRVPGSsGRLHKTE	9606									17190791	t		gcesareni	Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1)	SIGNOR-151659	0.496
PIM2	protein	Q9P1W9	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606	BTO:0000007								16403219	t		lperfetto	All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death.	SIGNOR-249604	0.4
GATA1	protein	P15976	UNIPROT	FLI1	protein	Q01543	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10523830	f		irozzo	Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression.	SIGNOR-256053	0.534
Phenylalanyl-tRNA synthetase	complex	SIGNOR-C473	SIGNOR	phenylalanine	smallmolecule	CHEBI:28044	ChEBI	down-regulates quantity	chemical modification			9606									20223217	t		miannu	Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers.	SIGNOR-270439	0.8
IKBKE	protein	Q14164	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser167	GGRERLAsTNDKGSM	9606	BTO:0000150								19940156	t		lperfetto	Here, we show that ikkepsilon interacts with and phosphorylates estrogen receptor alpha (eralpha) on serine 167 in vitro and in vivo. As a result, ikkepsilon induces eralpha transactivation activity and enhances eralpha binding to dna.	SIGNOR-161834	0.346
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1917	SPTSPTYsPTSPKYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273075	0.636
MRGPRX1	protein	Q96LB2	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257384	0.348
CUL3	protein	Q13618	UNIPROT	MAP1S	protein	Q66K74	UNIPROT	down-regulates quantity	ubiquitination			10090	BTO:0000142								18680552	t		miannu	Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. 	SIGNOR-268947	0.245
PPP3CC	protein	P48454	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates	relocalization			9606		BTO:0001103							11062529	t		gcesareni	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-84053	0.69
Aldolase	proteinfamily	SIGNOR-PF75	SIGNOR	glycerone phosphate(2-)	smallmolecule	CHEBI:57642	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266486	0.8
ZAP70	protein	P43403	UNIPROT	LAT	protein	O43561	UNIPROT	up-regulates activity	phosphorylation	Tyr161	DDYHNPGyLVVLPDS	9606									11368773	t		lperfetto	In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127.	SIGNOR-247022	0.762
ibrutinib	chemical	CHEBI:76612	ChEBI	BTK	protein	Q06187	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189641	0.8
SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	LEFTY2	protein	O00292	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269251	0.431
long-chain fatty acyl-CoA(4-)	smallmolecule	CHEBI:83139	ChEBI	arachidonoyl-CoA	smallmolecule	CHEBI:15514	ChEBI	up-regulates quantity	precursor of			9606									15189125	t		miannu	Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity.	SIGNOR-267904	0.8
CASP3	protein	P42574	UNIPROT	GRIPAP1	protein	Q4V328	UNIPROT	up-regulates activity	cleavage			9606									17761173	t		Giorgia	These results suggest that the region of GRASP‐1 downstream of the Caspase‐3‐cleavage site is capable of activating the JNK signaling pathway by enhancing the phosphorylation of JNK. these results suggest that full length GRASP‐1 does not enhance JNK pathway activity, possibly due to the inhibitory effect of the N‐terminal fragment on the C‐terminal fragment. In contrast, Caspase‐3 cleavage of GRASP‐1 releases the C‐terminal fragment, which in turn activates JNK signaling by serving as a scaffold protein.	SIGNOR-260641	0.424
GOLPH3	protein	Q9H4A6	UNIPROT	mTORC2	complex	SIGNOR-C2	SIGNOR	up-regulates activity				9606	BTO:0000018;BTO:0005011								19553991	f			Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo.	SIGNOR-253556	0.297
CYTH2	protein	Q99418	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				10116	BTO:0003102								14565977	f		miannu	ARNO and ARF6 regulate axonal elongation and branching through downstream activation of phosphatidylinositol 4-phosphate 5-kinase alpha	SIGNOR-264909	0.7
ASNS	protein	P08243	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									29084849	t		miannu	Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7.	SIGNOR-267534	0.8
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT5A	protein	P41221	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242736	0.308
CAD	protein	P27708	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	down-regulates quantity	chemical modification			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-267424	0.8
CHEK1	protein	O14757	UNIPROT	NEK11	protein	Q8NG66	UNIPROT	up-regulates	phosphorylation	Ser273	SMLNKNPsLRPSAIE	9606									19734889	t		lperfetto	We demonstrate that chk1 (checkpoint kinase 1) directly activates nek11 by phosphorylating it on ser 273	SIGNOR-187863	0.267
POU5F1	protein	Q01860	UNIPROT	SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	form complex	binding												23474895	t		SimoneGraziosi	Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm|We show that Sox17 partners with Oct4 and binds to a unique ‘compressed' Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at ‘canonical' binding sites. 	SIGNOR-269221	0.628
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Glu)	smallmolecule	CHEBI:29175	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269486	0.8
GSTA1	protein	P08263	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0000018								29928434	f		irozzo	In addition, the downregulation of GSTA1 in A549 cells significantly induced cell apoptosis in vitro. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line.	SIGNOR-256297	0.7
POU5F1	protein	Q01860	UNIPROT	SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	form complex	binding			9606									7590241	t		miannu	Sox2 can form a ternary complex with either the ubiquitous oct-1 or the embryonic-specific oct-3 protein on fgf-4 enhancer dna sequences. However, only the sox2/oct-3 complex is able to promote transcriptional activation.	SIGNOR-29509	0.834
DVL1P1	protein	P54792	UNIPROT	DAAM1	protein	Q9Y4D1	UNIPROT	up-regulates	binding			9606									23151663	t		gcesareni	Importantly, daam1 binds to disheveled (dvl) and thus functions downstream of the frizzled receptors. Little is known of how daam1 is localized and functions in mammalian cells.	SIGNOR-199451	0.2
MAP4K5	protein	Q9Y4K4	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606	BTO:0000776								16914735	t		lperfetto	Gckr can phosphorylate an n-terminal recombinant fusion protein of gsk3_ and enhance the in vivo phosphorylation of gsk3_ on serine 9reduction of gckr expression inhibits wnt3a-induced phosphorylation of gsk3_ at serine 9 and decreases the accumulation of cytosolic _-catenin.	SIGNOR-148908	0.2
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	MLXIPL	protein	Q9NP71	UNIPROT	down-regulates activity	relocalization			10116									26984404	t			AMP inhibits the nuclear localization of ChREBP through an allosteric activation of ChREBP/14-3-3 interactions	SIGNOR-255667	0.2
COL4A6	protein	Q14031	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									12778132	t			Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6)	SIGNOR-254670	0.7
IL4	protein	P05112	UNIPROT	IL4R	protein	P24394	UNIPROT	up-regulates	binding			-1									10219247	t		gcesareni	Nterleukin-4 (il-4) is a principal regulatory cytokine during an immune response and a crucial determinant for allergy and asthma. Il-4 binds with high affinity and specificity to the ectodomain of the il-4 receptor alpha chain (il4-bp).	SIGNOR-67217	0.941
EGFR	protein	P00533	UNIPROT	EZR	protein	P15311	UNIPROT	unknown	phosphorylation	Tyr146	KEVHKSGyLSSERLI	9606	BTO:0000017								15647376	t		lperfetto	Here we report the identification of the tyrosine phosphorylation sites in ezrin using bacterially expressed protein as a substrate for in vitro phosphorylation with the egf receptor. tyrosines 145 and 353 were identified as the sites of phosphorylation. but as of yet the role of ezrin phosphorylation at y145 is unknown.	SIGNOR-133219	0.546
MALT1	protein	Q9UDY8	UNIPROT	CBM	complex	SIGNOR-C555	SIGNOR	form complex	binding			9606									15122200	t		miannu	CARMA1, the adaptor protein BCL-10 (B-cell lymphoma 10) and the caspase-like protein MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) form a signalling complex that has a key role in antigen-receptor-mediated activation of the nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK) pathways.	SIGNOR-276295	0.806
GLI3	protein	P10071	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17419683	f		gcesareni	Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin.	SIGNOR-154234	0.575
SATB1	protein	Q01826	UNIPROT	IGFBP2	protein	P18065	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000664								17343824	f		miannu	We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 	SIGNOR-255129	0.2
Calcineurin	complex	SIGNOR-C155	SIGNOR	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression				10090									18177723	f		lperfetto	Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy	SIGNOR-252340	0.256
SMURF1	protein	Q9HCE7	UNIPROT	CTNND1	protein	O60716	UNIPROT	down-regulates activity	monoubiquitination			9615	BTO:0000837								32010791	t		miannu	 Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation. 	SIGNOR-277507	0.2
CCND1	protein	P24385	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0000575								11731443	f			Cyclin D1 regulates mitogen-dependent progression through G1 phase in cultured cells, and its overexpression in malignant cells is thought to contribute to autonomous proliferation in vivo.	SIGNOR-260014	0.7
ARPP19	protein	P56211	UNIPROT	PPP2R2D	protein	Q66LE6	UNIPROT	down-regulates activity	binding			-1					phosphorylation:Ser62	KGQKYFDsGDYNMAK			21164014	t		gcesareni	We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry.	SIGNOR-243731	0.683
NOG	protein	Q13253	UNIPROT	GDF5	protein	P43026	UNIPROT	down-regulates activity	binding			9606									19956691	t	Regulation	miannu	We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP–related ligand GDF5. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. 	SIGNOR-251865	0.688
GSK3B	protein	P49841	UNIPROT	APP	protein	P05067	UNIPROT	unknown	phosphorylation	Thr743	VEVDAAVtPEERHLS	-1									8764598	t			The sole site of phosphorylation in APPcyt by GSK-3beta was determined by phosphoamino acid analysis and phosphorylation of APPcyt mutant peptides to be Thr743 (numbering as for APP770).	SIGNOR-251220	0.559
Diprenorphine	chemical	CHEBI:4650	ChEBI	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258789	0.8
MMP2	protein	P08253	UNIPROT	HAPLN1	protein	P10915	UNIPROT	down-regulates quantity by destabilization	cleavage	Leu40	QAENGPHlLVEAEQA	-1									7694569	t		miannu	Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.	SIGNOR-256333	0.345
RIPK3	protein	Q9Y572	UNIPROT	DLD	protein	P09622	UNIPROT	up-regulates activity	phosphorylation	Thr135	STAVKALtGGIAHLF	-1									29358703	t		miannu	Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135.	SIGNOR-266372	0.2
CHUK	protein	O15111	UNIPROT	IRF7	protein	Q92985	UNIPROT	up-regulates	phosphorylation			9606									16612387	t		gcesareni	Ikkalfa associated with and phosphorylated and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production.	SIGNOR-146116	0.68
Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	CTNNB1	protein	P35222	UNIPROT	up-regulates activity													18697834	f		Simone Vumbaca	[…] we suggest that Wnt1, Wnt3a and Wnt5a result in the accumulation of Act-β-Cat	SIGNOR-255652	0.2
PTPN6	protein	P29350	UNIPROT	SH3BP2	protein	P78314	UNIPROT	down-regulates activity	dephosphorylation	Tyr448	GDDSDEDyEKVPLPN	9606									16649996	t		miannu	Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling|adaptor protein 3BP2 serves as a binding protein and a physiological substrate of SHP-1. 3BP2 is phosphorylated on tyrosyl residue 448 in response to TCR activation, and the phosphorylation is required for T c	SIGNOR-277172	0.551
SRC	protein	P12931	UNIPROT	TNS3	protein	Q68CZ2	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150;BTO:0000551;BTO:0000848								19732724	t		gcesareni	Although sh2 domains have not been reported previously to be phosphorylated, the tensin-3 sh2 domain is a physiologic substrate for src. Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding.	SIGNOR-187854	0.417
RPLP2	protein	P05387	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262449	0.809
CDK1	protein	P06493	UNIPROT	MAP4	protein	P27816	UNIPROT	down-regulates	phosphorylation	Ser696	PNKELPPsPEKKTKP	9606	BTO:0000567								9398320	t		lperfetto	Map4 is phosphorylated by cdc2 kinase in mitotic hela/ phosphorylation by cdc2 kinase decreased the microtubule-stabilizing ability of map4, suggesting that there are critical phosphorylation sites among the five major cdc2 kinase-dependent phosphorylation sites [spots 4 (ser-696), 5, 6, 9, and 10 (ser-787)].	SIGNOR-53735	0.512
DEF6	protein	Q9H4E7	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									18976935	t		lperfetto	Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner. 	SIGNOR-253369	0.401
PRKCB	protein	P05771	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser159	KKKKKRFsFKKSFKL	-1									8422248	t		lperfetto	These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III.	SIGNOR-248923	0.663
CAMK2A	protein	Q9UQM7	UNIPROT	CAMK2A	protein	Q9UQM7	UNIPROT	down-regulates	phosphorylation	Thr305	KLKGAILtTMLATRN	9606									1324926	t		lperfetto	After removal of ca2+/calmodulin, the autonomous kinase undergoes a burst of inhibitory autophosphorylation at sites distinct from the autonomy site. Ca(2+)-independent autophosphorylation occurs within the calmodulin binding domain at thr305, thr306, and ser314	SIGNOR-17312	0.2
PRKACA	protein	P17612	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	phosphorylation	Ser99	NRQAAKLsKPTLENL	9606									15703181	t		lperfetto	We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195.	SIGNOR-133888	0.2
IRX1	protein	P78414	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002392								20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 	SIGNOR-261651	0.2
DDIT3	protein	P35638	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									31226023	f		miannu	ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress.	SIGNOR-260171	0.7
ATR	protein	Q13535	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates activity	phosphorylation	Ser407	SSSIIYSsQEDVKEF	9606	BTO:0002552								14654783	t		lperfetto	We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm.	SIGNOR-119546	0.502
LRP6	protein	O75581	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates activity	binding			9606									23209147	t		Gianni	The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization.	SIGNOR-262526	0.697
MAPK14	protein	Q16539	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates activity	phosphorylation	Ser860	NRAVSLDsPVSVGSS	9606	BTO:0000093								15383283	t		miannu	P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators.	SIGNOR-250105	0.505
ZNF804A	protein	Q7Z570	UNIPROT	ANKRD1	protein	Q15327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								23434502	t		miannu	ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 	SIGNOR-269461	0.2
NPFFR1	protein	Q9GZQ6	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256851	0.252
ADSL	protein	P30566	UNIPROT	SAICAR(4-)	smallmolecule	CHEBI:58443	ChEBI	down-regulates quantity	chemical modification			9606									22812634	t		miannu	ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case	SIGNOR-266611	0.8
SFN	protein	P31947	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	relocalization			9606									20940406	t		lperfetto	Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding	SIGNOR-168540	0.2
ANXA3	protein	P12429	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity				9606									27995049	f		miannu	We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells. 	SIGNOR-262212	0.286
DVL3	protein	Q92997	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates	binding			9606									12533515	t		gcesareni	Wnt/fz activation of rac and rho is inhibited by rac-n17 and rho-n19, respectively (figs. _(figs.1d,1d, _d,5c,d;5c,d;habas et al. 2001), and requires different dvl domains wnt signaling induces complex formation between dvl and rac.	SIGNOR-97409	0.444
2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine	smallmolecule	CHEBI:147287	ChEBI	5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium	smallmolecule	CHEBI:137981	ChEBI	up-regulates quantity	precursor of			9606									33179964	t		miannu	The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner.	SIGNOR-267313	0.8
MAPK12	protein	P53778	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr548	KKVAVVRtPPKSPSS	-1									9199504	t		miannu	Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective.	SIGNOR-250088	0.504
FGF13	protein	Q92913	UNIPROT	SCN5A	protein	Q14524	UNIPROT	down-regulates activity	binding			9606		BTO:0000199							20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253415	0.42
CXCL10	protein	P02778	UNIPROT	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates				9606									32283152	f		miannu	High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity.	SIGNOR-261025	0.7
ZFYVE26	protein	Q68DK2	UNIPROT	TTC19	protein	Q6DKK2	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								20208530	t		miannu	We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. FYVE-CENT interacts with KIF13A and TTC19	SIGNOR-265538	0.477
CSNK1A1	protein	P48729	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	down-regulates activity	phosphorylation	Ser828	EHDSAEGsHTSGQSN	9606	BTO:0001109								28114302	t		miannu	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276512	0.378
DLL4	protein	Q9NR61	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	binding			9606	BTO:0000574								11739188	t		lperfetto	Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology	SIGNOR-112649	0.628
TGFB1	protein	P01137	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates activity	binding			9606									22326956	t		lperfetto	TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family.	SIGNOR-196022	0.84
YAP1	protein	P46937	UNIPROT	WWC1	protein	Q8IX03	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21233212	f		miannu	We also found that KIBRA mRNA is induced by YAP overexpression in both murine and human cells, suggesting the evolutionary conservation of KIBRA as a transcriptional target of the Hippo signaling pathway. Thus, our study revealed a new connection between KIBRA and mammalian Hippo signaling.	SIGNOR-263660	0.373
CAMK2A	protein	Q9UQM7	UNIPROT	OPRM1	protein	P35372	UNIPROT	down-regulates	phosphorylation	Thr372	STRIRQNtRDHPSTA	9606		BTO:0000671							10908300	t		gcesareni	The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization.	SIGNOR-79686	0.2
ITGB3	protein	P05106	UNIPROT	AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253198	0.946
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser399	DNITLPPsQPSPTGG	-1									17711846	t	done	miannu	Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626).	SIGNOR-274095	0.397
SLC9A7	protein	Q96T83	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265606	0.8
DYRK2	protein	Q92630	UNIPROT	DPYSL3	protein	Q14195	UNIPROT	up-regulates activity	phosphorylation	Ser518	KGGTPAGsARGSPTR	9606									16611631	t		lperfetto	Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-145975	0.373
AKT1	protein	P31749	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates activity	phosphorylation	Ser83	ATRGRGSsVGGGSRR	9606	BTO:0000007								11154276	t		lperfetto	Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1.	SIGNOR-252465	0.716
EN1	protein	Q05925	UNIPROT	FGF8	protein	P55075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003560								10026229	t		miannu	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 	SIGNOR-265776	0.466
clozapine	chemical	CHEBI:3766	ChEBI	HTR2A	protein	P28223	UNIPROT	down-regulates activity	chemical inhibition			10090	BTO:0000331								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258516	0.8
MAF	protein	O75444	UNIPROT	MYB	protein	P10242	UNIPROT	down-regulates	binding			9606									9566892	t		miannu	Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity.	SIGNOR-56811	0.646
MAPK1	protein	P28482	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser374	PSSDSLSsPTLLAL	9606									12972619	t		lperfetto	We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2.	SIGNOR-235671	0.784
ERBB4	protein	Q15303	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606									16729043	t		gcesareni	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146879	0.594
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1927	SPKYSPTsPTYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120156	0.316
ZRSR2/U2AF2	complex	SIGNOR-C81	SIGNOR	Spliceosomal_snRNP_assembly	phenotype	SIGNOR-PH79	SIGNOR	up-regulates				9606									11739736	f		miannu	The essential splicing factor U2AF (U2 auxiliary factor) is a heterodimer composed of 65-kDa (U2AF(65)) and 35-kDa (U2AF(35)) subunits. U2AF(35) has multiple functions in pre-mRNA splicing. First, U2AF(35) has been shown to function by directly interacting with the AG at the 3' splice site. Second, U2AF(35) is thought to play a role in the recruitment of U2AF(65) by serine-arginine-rich (SR) proteins in enhancer-dependent splicing. 	SIGNOR-263946	0.7
PKN1	protein	Q16512	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Ser338	RPRGQRDsSYYWEIE	9606									11733498	t		lperfetto	Interaction between active pak1 and raf-1 is necessary for phosphorylation and activation of raf-1.	SIGNOR-112549	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	AMPK	complex	SIGNOR-C15	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000007								17728241	t		lperfetto	Mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of ampk by a-769662 in cells and in vitro, while only partially reducing activation by ampk	SIGNOR-216411	0.795
RAD21	protein	O60216	UNIPROT	GATA2	protein	P23769	UNIPROT	down-regulates activity	relocalization			9606	BTO:0001545								26607380	t		miannu	Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity.	SIGNOR-261513	0.332
PSMB5	protein	P28074	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606									29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263357	0.853
CDK2	protein	P24941	UNIPROT	CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	form complex	binding			9606									19056339	t		lperfetto	We therefore compared human cyclin a1- and cyclin a2-containing cdk complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate prb and p53. Differences in biochemical activity were observed in cdk2 but not cdk1 when complexed with cyclin a1 versus cyclin a2. Further, cdk1/cyclin a1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates prb and p53 than cdk2/cyclin a2.	SIGNOR-182569	0.976
SEPTIN2	protein	Q15019	UNIPROT	SEPT6/SEPT2	complex	SIGNOR-C71	SIGNOR	form complex	binding			9606									16914550	t		miannu	We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains.	SIGNOR-148889	0.2
SEPTIN7	protein	Q16181	UNIPROT	SEPT6/SEPT7	complex	SIGNOR-C72	SIGNOR	form complex	binding			9606									16914550	t		miannu	We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains.	SIGNOR-148898	0.2
ESR2	protein	Q92731	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000356								11517191	f	 	 	ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression	SIGNOR-253943	0.295
PRKCB	protein	P05771	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates	phosphorylation	Ser44	KKSKISAsRKLQLKT	9606									15769444	t		lperfetto	Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.	SIGNOR-134628	0.2
LPAR5	protein	Q9H1C0	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256997	0.2
WNK1	protein	Q9H4A3	UNIPROT	WNK1	protein	Q9H4A3	UNIPROT	up-regulates activity	phosphorylation	Ser382	LKRASFAkSVIGTPE	9606									12374799	t		Manara	Activation of WNKs requires autophosphorylation of at least one serine residue, serine 382 in WNK1, within the WNK activation loop.	SIGNOR-260826	0.2
PIP3	smallmolecule	CHEBI:16618	ChEBI	WIPI2	protein	Q9Y4P8	UNIPROT	up-regulates	chemical activation			9606									22082875	t		gcesareni	We identified the human wipi protein family and found that wipi-1 specifically binds ptdins(3)p, accumulates at the phagophore and becomes a membrane protein of generated autophagosomes.	SIGNOR-177226	0.8
DDX5	protein	P17844	UNIPROT	RNA helicases DDX5/DDX17	complex	SIGNOR-C34	SIGNOR	form complex	binding			9606		BTO:0000887;BTO:0001103							17011493	t		lperfetto	We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod.	SIGNOR-149964	0.434
ITCH	protein	Q96J02	UNIPROT	BCL10	protein	O95999	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000661								15082780	t		miannu	The HECT domain ubiquitin ligases NEDD4 and Itch promote ubiquitination and degradation of Bcl10, thus downmodulating NF-kappa B activation. 	SIGNOR-271413	0.28
PDGFRB	protein	P09619	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr5	yLDPNLNH	9606									20802513	t		llicata	In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.	SIGNOR-167662	0.537
PAX7	protein	P23759	UNIPROT	PAX7/MLL2 complex	complex	SIGNOR-C91	SIGNOR	form complex	binding			9606	BTO:0002314	BTO:0000887;BTO:0001103							22863532	t		miannu	Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5.	SIGNOR-198635	0.31
CSNK2A1	protein	P68400	UNIPROT	MRE11	protein	P49959	UNIPROT	up-regulates activity	phosphorylation	Ser688	SKGVDFEsSEDDDDD	-1									28436950	t		miannu	Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689.	SIGNOR-265893	0.2
IGF1	protein	P05019	UNIPROT	FBN1	protein	P35555	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									17200203	f	Regulation of expression	miannu	Decorin and IGF-I induce fibrillin-1 protein synthesis in normal rat kidney fibroblasts 	SIGNOR-251862	0.296
CENPH	protein	Q9H3R5	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265198	0.756
JAK2	protein	O60674	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates	phosphorylation	Tyr701	DGPKGTGyIKTELIS	9606	BTO:0000567								15322115	t		lperfetto	Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation.	SIGNOR-235709	0.8
Macrophage_activation	phenotype	SIGNOR-PH126	SIGNOR	CCL7	protein	P80098	UNIPROT	up-regulates quantity				10090									32283152	f		miannu	The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages.	SIGNOR-260963	0.7
PRKCB	protein	P05771	UNIPROT	TOP2A	protein	P11388	UNIPROT	up-regulates activity	phosphorylation	Ser29	EDAKKRLsVERIYQK	9606	BTO:0000567								12569090	t		lperfetto	Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. | Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides. 	SIGNOR-249195	0.365
MAPK3	protein	P27361	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation			9606									15664191	t		gcesareni	Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity. previous studies have shown that phosphorylation is required for raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated erk	SIGNOR-133345	0.622
PRKCA	protein	P17252	UNIPROT	RALBP1	protein	Q15311	UNIPROT	up-regulates activity	phosphorylation	Thr297	ACGRTTEtEKVQEFQ	-1									16087181	t		miannu	In deletion mutant analyses of potential phosphorylation sites in RLIP76, we identified T297 and S509 as targets for phosphorylation by PKCalpha. Phosphorylation at T297 increased doxorubicin (DOX)-transport activity approximately 2-fold for RLIP76 purified from recombinant source	SIGNOR-263164	0.398
NPY	protein	P01303	UNIPROT	NPY5R	protein	Q15761	UNIPROT	up-regulates	binding			9606									11825645	t		gcesareni	Npy expression significantly increases whereas the gene expression of its receptors npy1r, npy2r, and npy5r initially decreases.	SIGNOR-114746	0.731
ATRX	protein	P46100	UNIPROT	ZBED1	protein	O96006	UNIPROT	up-regulates activity	binding			7227	BTO:0001138								22021382	t	1	miannu	XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression.	SIGNOR-239729	0.422
GSK3A	protein	P49840	UNIPROT	STAT2	protein	P52630	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser393	LTPEKGQsQGLIWDF	9606	BTO:0002181								31843895	t		miannu	GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation.	SIGNOR-276762	0.266
MAPK3	protein	P27361	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Thr325	TELEPLCtPVVTCTP	9606									12972619	t		lperfetto	In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity.	SIGNOR-118027	0.707
AKT1	protein	P31749	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates activity	phosphorylation	Ser215	SGRAREAsGAPTSSK	9534	BTO:0001538								11404460	t		lperfetto	Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790	SIGNOR-108504	0.605
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Phe709	ENPTYKFfEQMQN	-1									10605825	t		lperfetto	In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D.	SIGNOR-261778	0.502
PTPRJ	protein	Q12913	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606									12771128	t		gcesareni	A dominant-negative mutant of high cell density-enhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation.	SIGNOR-101279	0.415
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CDK9	protein	P50750	UNIPROT	down-regulates activity	chemical inhibition			-1									29901072	t		miannu	AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9.	SIGNOR-262217	0.8
MYOG	protein	P15173	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									25211658	t			P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells	SIGNOR-251575	0.338
CTDSPL	protein	O15194	UNIPROT	RB1	protein	P06400	UNIPROT	up-regulates activity	dephosphorylation	Ser807	PGGNIYIsPLKSPYK	9606									15051889	t			ppRB (RB phosphorylated at Ser-807/811|Possible Mechanisms of HYA22 Action in Tumorigenesis: Dephosphorylation of RB by Transient Expression of HYA22 Isoforms.	SIGNOR-248304	0.303
CDKN2A	protein	P42771	UNIPROT	Immortality	phenotype	SIGNOR-PH47	SIGNOR	down-regulates				9606									10648628	f			Human keratinocytes that express hTERT and also bypass a p16(INK4a)-enforced mechanism that limits life span become immortal yet retain normal growth and differentiation characteristics	SIGNOR-259286	0.7
RNF139	protein	Q8WU17	UNIPROT	INSIG1	protein	O15503	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								20068067	t		miannu	TRC8/RNF139 encodes an endoplasmic reticulum-resident E3 ubiquitin ligase that inhibits growth in a RING- and ubiquitylation-dependent manner. TRC8 also contains a predicted sterol-sensing domain. Here, we report that TRC8 protein levels are sterol responsive and that it binds and stimulates ubiquitylation of the endoplasmic reticulum anchor protein INSIG. Thus, we conclude that INSIG-1 and 2 physically interact with TRC8, and that TRC8 enhances ubiquitylation of INSIG-1 in a RING-dependent manner	SIGNOR-271955	0.49
CSNK2A1	protein	P68400	UNIPROT	CDC34	protein	P49427	UNIPROT	down-regulates activity	phosphorylation	Ser231	FGDDEDDsGTEES	9606	BTO:0000567								11546811	t		lperfetto	The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm.	SIGNOR-110399	0.403
PTPRJ	protein	Q12913	UNIPROT	FLT1	protein	P17948	UNIPROT	down-regulates	dephosphorylation			9606									12771128	t		gcesareni	Vegf acts by binding to two high affinity receptor tyrosine kinases: vegf receptor (vegfr)* 1 also called flt-1, and vegfr-2, also called flk-1/kdr a dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation.	SIGNOR-101272	0.369
GSK3B	protein	P49841	UNIPROT	FCAR	protein	P24071	UNIPROT	down-regulates activity	phosphorylation	Ser284	LTFARTPsVCK	10090	BTO:0001516								30766540	t		lperfetto	GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state. 	SIGNOR-264857	0.2
CUL3	protein	Q13618	UNIPROT	MAP1B	protein	P46821	UNIPROT	down-regulates quantity	ubiquitination			10090	BTO:0000142								18680552	t		miannu	Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. 	SIGNOR-268946	0.257
SARS1	protein	P49591	UNIPROT	alpha-aminoacyl-tRNA	smallmolecule	CHEBI:2651	ChEBI	up-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 	SIGNOR-270800	0.8
CDK3	protein	Q00526	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9606									19118012	t		gcesareni	Egf-induced cdk3 activation caused c-jun phosphorylation at ser63 and ser73, resulting in increased ap-1 transactivation.	SIGNOR-183009	0.455
MTARC1	protein	Q5VT66	UNIPROT	nitric oxide	smallmolecule	CHEBI:16480	ChEBI	up-regulates quantity	chemical modification			9606									24500710	t		miannu	 our results indicate that mARC can generate nitric oxide (NO) from nitrite when forming an electron transfer chain with NADH, cytochrome b5, and NADH-dependent cytochrome b5 reductase. expression of mARC-1 in HEK cells using a lentivirus vector was used to confirm cellular nitrite reduction to NO.	SIGNOR-261419	0.8
CSNK2A1	protein	P68400	UNIPROT	OTUB1	protein	Q96FW1	UNIPROT	up-regulates activity	phosphorylation	Ser16	QKQEPLGsDSEGVNC										34785775	t		lperfetto	Casein kinase 2 (CK2)-dependent phosphorylation of OTUB1 at Ser16 played a critical role in ODN- and cathepsin K siRNA-mediated p53 stabilization. |Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec	SIGNOR-276527	0.324
MAML2	protein	Q8IZL2	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									12370315	f		gcesareni	We recently cloned a mammalian homologue of the mastermind gene of drosophila melanogaster, maml1 (mastermind-like-1 molecule) and determined that it functions as a transcriptional coactivator for notch receptors.	SIGNOR-254307	0.857
PURB	protein	Q96QR8	UNIPROT	MYH6	protein	P13533	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12933792	f	 	miannu	In functional assays, PURalpha and PURbeta repressed alpha-myosin heavy chain (alpha-MHC) gene expression in the presence of upstream regulatory sequences of the gene.	SIGNOR-253901	0.373
INS	protein	P01308	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates				9606									15209375	f		gcesareni	The interaction ofinsulin and growth factors with their receptors on the outside surface of a cell, leads to the activation of phosphatidylinositol 3-kinase (pi 3-kinase) and generation of the phosphatidylinositol 3,4,5-trisphosphate (ptdins(3,4,5)p3) second messenger at the inner surface of the cell membrane.	SIGNOR-126063	0.342
GSK3B	protein	P49841	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr265	ATYHHNStTTWTGSR	10090	BTO:0000944								25373906	t		miannu	In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region. 	SIGNOR-276442	0.408
SRC	protein	P12931	UNIPROT	AFAP1	protein	Q8N556	UNIPROT	unknown	phosphorylation	Tyr94	SSLPEGYyEEAVPLS	9534									9655255	t		lperfetto	In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110.	SIGNOR-246363	0.589
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	POU5F1	protein	Q01860	UNIPROT	down-regulates	phosphorylation			9606									23024368	t	inferred from 70% family members	gcesareni	Phosphorylation of this site downregulates nanog, sox2, rex1 and upregulates bmp4, gata6, ddlx5.	SIGNOR-270085	0.2
Papain-like proteinase	protein	P0C6X7-PRO_0000037311	UNIPROT	TRAF3	protein	Q13114	UNIPROT	down-regulates activity	deubiquitination			9606									31226023	t		miannu	Overexpressing PLPro of SARS-CoV or MERS-CoV significantly reduced the expression of IFN-β and proinflammatory cytokines in MDA5-stimulated 293T cells (83).Also, SARS-CoVPLPro catalyzed deubiquitination of TNF-receptor-associated factor3 (TRAF3) and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist (63). The deubiquitinating activity of SARS-CoV PLPro also suppressed a constitutively active phosphomimetic IRF3, suggesting its involvement in the postactivation signaling of IRF3	SIGNOR-260246	0.2
retinol	smallmolecule	CHEBI:50211	ChEBI	all-trans-retinyl ester	smallmolecule	CHEBI:63410	ChEBI	up-regulates quantity	precursor of			10090									18093970	t		lperfetto	We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis	SIGNOR-265109	0.8
HIPK1	protein	Q86Z02	UNIPROT	DAXX	protein	Q9UER7	UNIPROT	down-regulates activity	phosphorylation	Ser668	KKICTLPsPPSPLAS	9606									12529400	t		Manara	HIPK1 phosphorylates Daxx on Ser 669, and phosphorylation of this site is important in modulating the ability of Daxx to function as a transcriptional repressor. | Therefore, phosphorylation at Ser 669 by HIPK1 diminishes the ability of Daxx to repress transcription.	SIGNOR-260842	0.631
SPAG1	protein	Q07617	UNIPROT	R2SP co-chaperone	complex	SIGNOR-C517	SIGNOR	form complex	binding			9606									29844425	t		miannu	Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes.	SIGNOR-270938	0.393
ANGPT1	protein	Q15389	UNIPROT	MYH1	protein	P12882	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000222								26042050	f		lperfetto	Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein.	SIGNOR-241560	0.2
PRKCB	protein	P05771	UNIPROT	PRKCB	protein	P05771	UNIPROT	up-regulates activity	phosphorylation	Ser661	QNEFAGFsYTNPEFV	9606									10828076	t	The effect has been demonstrated using P05771-2	llicata	We found in preliminary studies that autophosphorylation at ser660 was enhanced in response to angiotensin ii and phorbol esters|However, it was apparent that the return of the mutant GFP-S660A from the membrane to the cytoplasm was impaired, suggesting a specific role for this autophosphorylation site in the regulation of reverse translocation.	SIGNOR-77583	0.2
MSH release-inhibiting hormone	smallmolecule	CID:56842142	PUBCHEM	MC1R	protein	Q01726	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257536	0.8
RLF	protein	Q13129	UNIPROT	RIN1	protein	Q13671	UNIPROT	up-regulates activity	binding			9606									10545207	t		miannu	Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors.	SIGNOR-220920	0.2
PTPN11	protein	Q06124	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	dephosphorylation	Tyr1016	DVVDADEyLIPQQGF	9534	BTO:0004055								12582165	t		lperfetto	Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not	SIGNOR-236424	0.865
PELI1	protein	Q96FA3	UNIPROT	HPD	protein	P32754	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0003036								31537781	t		lperfetto	Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. 	SIGNOR-272959	0.2
NUP98-HOXA9	fusion protein	SIGNOR-FP15	SIGNOR	CD44	protein	P16070	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17442773	f		miannu	Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. CD44 is also upregulated by NUP98‐HOXA9.	SIGNOR-261502	0.2
SMOC1	protein	Q9H4F8	UNIPROT	SPP1	protein	P10451	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20359165	f		Giorgia	The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells	SIGNOR-260385	0.2
LPAR6	protein	P43657	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257286	0.343
FIG4	protein	Q92562	UNIPROT	1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate)(5-)	smallmolecule	CHEBI:85342	ChEBI	down-regulates quantity	chemical modification			-1									23165282	t		miannu	Fig4/Sac3 can decrease PI(3,5)P2 levels via its phosphatase function and also promote PI3,5P2 synthesis by acting as a secondary scaffold for the Fab1/Vac14 interaction. However, the later function appears dominant.	SIGNOR-253535	0.8
PCSK2	protein	P16519	UNIPROT	OXT	protein	P01178	UNIPROT	down-regulates quantity	cleavage			9606	BTO:0001073								11690596	t		miannu	Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension.	SIGNOR-270328	0.269
MAPK1	protein	P28482	UNIPROT	NEFH	protein	P12036	UNIPROT	up-regulates activity	phosphorylation	Ser532	KSPAEAKsPEKEEAK	10116									9592082	t		lperfetto	The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation. 	SIGNOR-249425	0.375
SRC	protein	P12931	UNIPROT	RRAS	protein	P10301	UNIPROT	down-regulates activity	phosphorylation	Tyr66	DPTIEDSyTKICSVD	9606	BTO:0000007								11682467	t		lperfetto	The small gtpase, r-ras, affects cell adhesion by maintaining integrin activity. Activated src oncogene phosphorylates r-ras and suppresses integrin activity. the src phosphorylation site in r-ras was tyrosine 66	SIGNOR-111189	0.562
MTA1	protein	Q13330	UNIPROT	MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263842	0.8
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	WEE1	protein	P30291	UNIPROT	down-regulates	binding			9606									15340381	t		lperfetto	Scfb-trcp continues to have a role in this phase, however, through its induced degradation of the cdk1 inhibitor, wee1.	SIGNOR-217184	0.396
LAMTOR5	protein	O43504	UNIPROT	LIN28B	protein	Q6ZN17	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23494474	f		miannu	We found that HBXIP was able to upregulate Lin28B in breast cancer MCF-7 cells.	SIGNOR-255251	0.253
TAOK3	protein	Q9H2K8	UNIPROT	TAOK3	protein	Q9H2K8	UNIPROT	up-regulates activity	phosphorylation	Tyr183	NSFVGTPyWMAPEVI	9534	BTO:0004055								10559204	t		lperfetto	These data indicate that JIK is indeed the protein kinase present in the immune complex responsible for autophosphorylation and for the phosphorylation of the exogenous substrate. Moreover, our observations suggest that JIK (A181F183) acts as the catalytically inactive mutant of JIK, which is no longer able to potently undergo autophosphorylation and dramatically phosphorylate MBP, as compared with the wild type JIK.	SIGNOR-246302	0.2
GALR2	protein	O43603	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257226	0.292
RUNX2	protein	Q13950	UNIPROT	TWIST1	protein	Q15672	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001610								22641097	f		miannu	 Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells.	SIGNOR-255085	0.461
KISS1R	protein	Q969F8	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256750	0.477
NR1D1	protein	P20393	UNIPROT	ARNTL	protein	O00327	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20817722	t		miannu	In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.	SIGNOR-267983	0.659
STAT5A	protein	P42229	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15626738	t			FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells	SIGNOR-261551	0.64
GSK3B	protein	P49841	UNIPROT	ZNF281	protein	Q9Y2X9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser638	PRVDLHTsGEHSELV	9606	BTO:0001615								29179460	t		lperfetto	GSK-3beta phosphorylation-dependent degradation of ZNF281 by beta-TrCP2 suppresses colorectal cancer progression|	SIGNOR-264890	0.2
MAPK3	protein	P27361	UNIPROT	PCBP2	protein	Q15366	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser272	FSGIESSsPEVKGYW	9606									17475908	t		miannu	We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 	SIGNOR-262916	0.329
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates	phosphorylation	Ser374	PSSDSLSsPTLLAL	9606									12972619	t		lperfetto	In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity.	SIGNOR-252358	0.784
RIMS2	protein	Q9UQ26	UNIPROT	UNC13B	protein	O14795	UNIPROT	up-regulates activity	relocalization			9606									31679900	t		miannu	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264383	0.365
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	DDX3X	protein	O00571	UNIPROT	down-regulates	phosphorylation	Thr204	LTRYTRPtPVQKHAI	9606									16280325	t		lperfetto	Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis.	SIGNOR-216868	0.345
LRIG1	protein	Q96JA1	UNIPROT	ERBB4	protein	Q15303	UNIPROT	down-regulates	ubiquitination			9606									16123311	t		gcesareni	We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.	SIGNOR-139954	0.591
N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide	chemical	CHEBI:91393	ChEBI	MST1R	protein	Q04912	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194346	0.8
TAB2	protein	Q9NYJ8	UNIPROT	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	up-regulates	binding			9606									25290089	t		lperfetto	The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.	SIGNOR-205443	0.426
PRKAA2	protein	P54646	UNIPROT	BAIAP2	protein	Q9UQB8	UNIPROT	down-regulates	phosphorylation	Ser366	KTLPRSSsMAAGLER	9606			SIGNOR-C15						22137581	t		lperfetto	Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction	SIGNOR-195102	0.2
3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	up-regulates quantity	precursor of			9606									24786789	t		miannu	Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle.	SIGNOR-266510	0.8
WHAMM	protein	Q8TF30	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								20498093	t		lperfetto	Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes.	SIGNOR-261004	0.357
PPP1R2	protein	P41236	UNIPROT	PP1	proteinfamily	SIGNOR-PF54	SIGNOR	down-regulates	binding			9606									18250156	t		lperfetto	Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1.	SIGNOR-264672	0.807
EFNA1	protein	P20827	UNIPROT	EPHA6	protein	Q9UF33	UNIPROT	up-regulates	binding			9606									9576626	t		tpavlidou	Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity	SIGNOR-56962	0.804
RPS6KA1	protein	Q15418	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser291	CGSSGYFsSSPTLSS	9606									22017877	t		lperfetto	We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1	SIGNOR-176891	0.507
TTC8	protein	Q8TAM2	UNIPROT	BBsome complex	complex	SIGNOR-C288	SIGNOR	form complex	binding			9606	BTO:0004910								19081074	t		lperfetto	We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 	SIGNOR-262554	0.751
ATF4	protein	P18848	UNIPROT	NUPR1	protein	O60356	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								19946894	f	 	lperfetto	Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4.	SIGNOR-253730	0.396
NR4A1	protein	P22736	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15591535	f		gcesareni	Our data suggest a mechanism for transrepression between two nuclear receptors, gr and ngfi-b.	SIGNOR-132312	0.329
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CDK4	protein	P11802	UNIPROT	down-regulates activity	chemical inhibition			-1									29901072	t		miannu	AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9.	SIGNOR-262220	0.8
isoprenaline	chemical	CHEBI:64317	ChEBI	ADRB1	protein	P08588	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								8982677	t		miannu	K i values of the agonists for [~25I]iodocyanopindolol binding to the COS-7 cell membranes are shown in Table 1. In the membranes expressing one of the 13-adrenoceptor subtypes, both isoproterenol and T-0509 caused monophasic dis- placement of [~25I]iodocyanopindolol, suggesting a single binding site of the agonists.	SIGNOR-258578	0.8
STK3	protein	Q13188	UNIPROT	MOB1A	protein	Q9H8S9	UNIPROT	up-regulates	phosphorylation	Thr12	FSSRSSKtFKPKKNI	9606									23431053	t		milica	Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity	SIGNOR-201282	0.844
CDK1	protein	P06493	UNIPROT	CASP8	protein	Q14790	UNIPROT	down-regulates	phosphorylation	Ser387	YLEMDLSsPQTRYIP	9606		BTO:0000149	SIGNOR-C17						20937773	t		lperfetto	In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by cdk1na interference-mediated silencing of cyclin b1 or treatment with the cdk1 inhibitor ro-3306 enhances the fas-mediated activation and processing of procaspase-8 in mitotic cells/cyclin b1 on ser-387	SIGNOR-168446	0.37
LMO3	protein	Q8TAP4	UNIPROT	HES1	protein	Q14469	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21573214	f		miannu	 Luciferase reporter assay demonstrated that the co-expression of LMO3 and HEN2 attenuates HES1 (a negative regulator for Mash1)-dependent reduction of luciferase activity driven by the Mash1 promoter. 	SIGNOR-254826	0.348
MAS1	protein	P04201	UNIPROT	AGTR1	protein	P30556	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								15809376	t		miannu	 our findings demonstrate that the protein encoded by the Mas proto-oncogene exhibits direct antagonistic properties on the AT1 receptor in vitro and that this oligomeric interaction may represent a natural state for these receptors in vivo in some tissues. the present findings in native tissues suggest that the Mas receptor can act as an in vivo functional antagonist of the AT1 receptor owing to formation of a hetero-oligomeric complex	SIGNOR-260626	0.28
AP3B1	protein	O00203	UNIPROT	KIF3A	protein	Q9Y496	UNIPROT	up-regulates activity	binding			10090	BTO:0002572								19934039	t		Giorgia	Here, we show that the beta subunit of AP-3, a clathrin-associated protein complex required for HIV-1 release, is a target of IP(7)-mediated pyrophosphorylation. We have identified Kif3A, a motor protein of the kinesin superfamily, as an AP3B1-binding partner and demonstrate that Kif3A, like the AP-3 complex, is involved in an intracellular process required for HIV-1 Gag release.	SIGNOR-260398	0.378
YAP1	protein	P46937	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates				9606									23075495	f		gcesareni	Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis.	SIGNOR-256669	0.7
HLX	protein	Q14774	UNIPROT	CCNB1	protein	P14635	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003980								20008130	t		Luana	In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.	SIGNOR-261619	0.2
IL17A	protein	Q16552	UNIPROT	KLF3	protein	P57682	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23332504	f		fspada	Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic.	SIGNOR-192610	0.2
SIL1	protein	Q9H173	UNIPROT	HSPA5	protein	P11021	UNIPROT	up-regulates activity	binding			9534	BTO:0001538								12356756	t		Simone	BAP, a Mammalian BiP-associated Protein, Is a Nucleotide Exchange Factor That Regulates the ATPase Activity of BiP. In addition,BAP was associated with BiP in mammalian cells and inter-acted with BiP functionallyin vitro. BAP stimulated the ATPase activity of BiP when added alone or together with the ER DnaJ protein, ERdj4, by promoting the release of ADP from BiP. Together, these data demonstrate that BAP serves as a nucleotide exchange factor for BiP and provide insights into the mechanisms that control protein folding in the mammalian ER.	SIGNOR-261045	0.595
ADAM17	protein	P78536	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	cleavage			9606									10882063	t		gcesareni	... here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to tace (tnfalpha-converting enzyme), a member of the adam (a disintegrin and metalloprotease domain) family of metalloproteases.	SIGNOR-78903	0.729
CSNK2A1	protein	P68400	UNIPROT	PTPRC	protein	P08575	UNIPROT	up-regulates	phosphorylation	Ser1005	EHDSDESsDDDSDSE	9606									10066810	t		gcesareni	Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein,	SIGNOR-65273	0.453
HBA1	protein	P69905	UNIPROT	APOB	protein	P04114	UNIPROT	up-regulates quantity by stabilization				9606									8611031	f	Regulation of binding	miannu	Hemoglobin induced apolipoprotein B crosslinking in low-density lipoprotein peroxidation. Crosslinked apo B was shown to resist lysosomal degradation, thereby causing accumulation of oxidized LDL in macrophages	SIGNOR-251755	0.326
WNT11	protein	O96014	UNIPROT	Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	up-regulates activity	binding			9606	BTO:0000551;BTO:0000848								16273260	t		gcesareni	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-253127	0.701
CDK1	protein	P06493	UNIPROT	ABI1	protein	Q8IZP0	UNIPROT	down-regulates activity	phosphorylation	Ser216	VPNDYMTsPARLGSQ	9606	BTO:0000567								21900237	t		lperfetto	We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis.|Bcr-Abl-induced actin polymerization requires the Abi1 pathway, as the blockade of the signal transduction from Bcr-Abl to Abi1 abolishes the F-actin assembly|serine phosphorylation of Abi1 by CDK1/cyclin B serves as a cell cycle-dependent regulatory mechanism that inhibits actin assembly	SIGNOR-264421	0.43
MAPK14	protein	Q16539	UNIPROT	FGFR1	protein	P11362	UNIPROT	down-regulates	phosphorylation	Ser777	SMPLDQYsPSFPDTR	9606									20626350	t		gcesareni	Fgfr1 translocation requires p38 mapk activation which phosphorylates the c-term tail of fgfr1 on ser777	SIGNOR-166598	0.278
FCRL3	protein	Q96P31	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates activity	binding			-1									12051764	t		miannu	Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2.	SIGNOR-274013	0.399
RNF26	protein	Q9BY78	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0000567								27368102	t		miannu	SQSTM1 Is a Substrate for RNF26 and the DUB USP15. Catalytically competent RNF26 (light red) recruits SQSTM1 (blue) and mediates ubiquitin ligation (red), which serves to attract UBDs of specific vesicle-associated adaptors. 	SIGNOR-269830	0.365
GSK3B	protein	P49841	UNIPROT	PPIF	protein	P30405	UNIPROT	up-regulates activity	phosphorylation	Ser191	IESFGSKsGRTSKKI	9606	BTO:0000007								32814770	t		lperfetto	Phosphorylation of cyclophilin D at serine 191 regulates mitochondrial permeability transition pore opening and cell death after ischemia-reperfusion|We conclude that CypD phosphorylation at S191 residue leads to its binding to OSCP and thus sensitizes mPTP opening for the subsequent cell death.|Under baseline condition (WT group), the phosphorylation of CypD by a kinase (e.g. GSK3beta) at S191 induces its translocation to the OSCP, to favor mPTP opening and subsequent cell death at reperfusion.	SIGNOR-264880	0.387
MAPK1	protein	P28482	UNIPROT	DAPK1	protein	P53355	UNIPROT	up-regulates	phosphorylation	Ser734	NSSRFPPsPLASKPT	9606									15616583	t		gcesareni	Dapk interacts with erk through a docking sequence within its death domain and is a substrate of erk. Phosphorylation of dapk at ser 735 by erk increases the catalytic activity of dapk both in vitro and in vivo	SIGNOR-132614	0.55
TP53	protein	P04637	UNIPROT	GLS2	protein	Q9UI32	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22307140	t		Luana	Glutaminase 2 (GLS2) can be directly transactivated by p53 and can therefore mediate p53-dependent regulation of cellular energy metabolism. G	SIGNOR-268041	0.618
AKT1	protein	P31749	UNIPROT	ITCH	protein	Q96J02	UNIPROT	up-regulates quantity	phosphorylation	Ser257	PSRPPRPsRPPPPTP	9606	BTO:0000815								30517763	t		miannu	AKT1-mediated phosphorylation of ITCH at Ser257 drives its nuclear translocation	SIGNOR-272922	0.325
OPRK1	protein	P41145	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256710	0.452
CDC7	protein	O00311	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates	phosphorylation	Ser139	RRGLLYDsDEEDEER	9606									16446360	t		gcesareni	In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells.	SIGNOR-143988	0.961
ponatinib	chemical	CHEBI:78543	ChEBI	FGFR4	protein	P22455	UNIPROT	down-regulates activity	chemical inhibition			9606									23468082	t		miannu	Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. 	SIGNOR-259280	0.8
CDK1	protein	P06493	UNIPROT	RUNX1	protein	Q01196	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser276	VHPATPIsPGRASGM	9606									17015473	t	The effect has been demonstrated using Q01196-8.	gcesareni	Aml1/runx1 phosphorylation by cyclin-dependent kinases regulates the degradation of aml1/runx1 by the anaphase-promoting complex.	SIGNOR-149972	0.347
KAT2B	protein	Q92831	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates activity	acetylation												32917954	t		SimoneGraziosi	NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase 	SIGNOR-269270	0.482
PPP2CA	protein	P67775	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	up-regulates activity	dephosphorylation	Ser155	FPLRKTVsEPNLKLR	9606									18339811	t			Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. 	SIGNOR-248646	0.322
MYC	protein	P01106	UNIPROT	ST3GAL3	protein	Q11203	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22547830	f	 	 	We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. 	SIGNOR-253962	0.2
AKT2	protein	P31751	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites.	SIGNOR-252869	0.757
FOXA1	protein	P55317	UNIPROT	SFTPB	protein	P07988	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004299								18003659	f	 	miannu	TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription.	SIGNOR-254171	0.287
SPI1	protein	P17947	UNIPROT	Lymphopoiesis	phenotype	SIGNOR-PH111	SIGNOR	up-regulates activity				10090	BTO:0000725								8079170	f			Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. [...]An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor.	SIGNOR-259956	0.7
F2RL1	protein	P55085	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256895	0.2
PTPRA	protein	P18433	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates	dephosphorylation	Tyr531	FTATEPQyQPGENL	9606	BTO:0000782								17507376	t		gcesareni	Ptpalpha is a more widely expressed transmembrane ptp that has been shown to regulate the src family kinases, src and fyn, and is also present in t cells.	SIGNOR-154796	0.644
FGF14	protein	Q92915	UNIPROT	SCN3A	protein	Q9NY46	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253445	0.246
VRK1	protein	Q99986	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Ser62	FGPARNDsVIVADQT	9606									15105425	t		gcesareni	Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level.	SIGNOR-124330	0.379
CCL3	protein	P10147	UNIPROT	CCR1	protein	P32246	UNIPROT	up-regulates	binding			9606									10734056	t			CCR1 is also activated by MIP-1α, MCP-2, and MCP-3, although maximum responses are only obtained with RANTES and MIP-1α.	SIGNOR-254366	0.711
CDK1	protein	P06493	UNIPROT	RANGAP1	protein	P46060	UNIPROT	up-regulates	phosphorylation	Thr409	GQGEKSAtPSRKILD	9606			SIGNOR-C17						15037602	t		lperfetto	Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis. The m-phase kinase cyclin b/cdk1 phosphorylates rangap1 efficiently in vitro, and t409 phosphorylation correlates with nuclear accumulation of cyclin b1 in vivo.	SIGNOR-123524	0.472
EPHB2	protein	P29323	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates	binding			9606									9632142	t		lperfetto	We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation	SIGNOR-58142	0.546
HSF1	protein	Q00613	UNIPROT	HSPA6	protein	P17066	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12813038	f	 	miannu	These experiments suggest that HSF2 is involved in the stress response, but unlike the ubiquitous HSF1 operates in a cell-line specific manner through differential expression of alternatively spliced isoforms. Curiously, HSF2A could not be activated by heat shock in cells deficient in functional HSF1 and required the expression of HSF1 for heat induction of the hsp70B gene in cells. 	SIGNOR-254477	0.44
SB 505124	chemical	CHEBI:100922	ChEBI	TGFBR1	protein	P36897	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206742	0.8
CTNNB1	protein	P35222	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity				9606									16510874	f		Luana	Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro. Chromatin immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp.	SIGNOR-265358	0.2
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	RAPGEF2	protein	Q9Y4G8	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002181								24290981	t		miannu	Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase.	SIGNOR-276607	0.2
NOTCH1	protein	P46531	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								16256737	t		lperfetto	The notch intracellular domain interacts with hif-1alpha and hif-1alpha is recruited to notch-responsive promoters upon notch activation under hypoxic conditions.	SIGNOR-141315	0.634
PTPRG	protein	P23470	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	dephosphorylation	Tyr315	MPMDTSVyESPYSDP	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254733	0.263
SRC	protein	P12931	UNIPROT	KCNA3	protein	P22001	UNIPROT	up-regulates	phosphorylation	Tyr187	FSEEIRFyQLGEEAM	9606									11812778	t		gcesareni	The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties.	SIGNOR-114641	0.316
AMPK	complex	SIGNOR-C15	SIGNOR	MLXIPL	protein	Q9NP71	UNIPROT	down-regulates	phosphorylation	Ser556	LLRSPGsPQETVPE	10116									11724780	t		lperfetto	These results strongly suggested that the fatty acid inhibition of glucose-induced l-PK transcription resulted from AMPK phosphorylation of ChREBP at Ser568, which inactivated the DNA binding activity.	SIGNOR-216526	0.406
CAMK4	protein	Q16566	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation	Ser119	EILSRRPsYRKILND	9606	BTO:0001271								12835716	t		lperfetto	Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. All these kinases target CREB on S133 to activate CREB.	SIGNOR-102722	0.698
HNF4A	protein	P41235	UNIPROT	AKR1C4	protein	P17516	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003846								2044952	f	2	miannu	Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-4_ is a necessary factor for the activation of the human DD4 gene. is much higher than that of vHNF-1-C.	SIGNOR-240016	0.258
CRTC2	protein	Q53ET0	UNIPROT	PCK1	protein	P35558	UNIPROT	up-regulates quantity	transcriptional regulation			9606									26652733	t			These results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK.	SIGNOR-256106	0.396
Unfolded_Proteins	stimulus	SIGNOR-ST22	SIGNOR	HERPUD1	protein	Q15011	UNIPROT	up-regulates quantity by expression				9606									10922362	f		miannu	We demonstrate a new target gene for upr-induced transcription, herp.	SIGNOR-80156	0.7
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	BCL2L11	protein	O43521	UNIPROT	down-regulates	binding			9606									16282323	t		gcesareni	Cytokine stimulation promotes bim(el) binding to 14-3-3 proteins. Akt could directly phosphorylate a gst-bim(el) fusion protein and identified the akt phosphorylation site in the bim(el) domain as ser(87). we propose that ser87 of bimel is an important regulatory site that is targeted byakt to attenuate thepro-apoptotic function of bim el, thereby promoting cell survival.	SIGNOR-141577	0.2
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606									18593906	t		tpavlidou	Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene.	SIGNOR-259429	0.2
PCSK7	protein	Q16549	UNIPROT	ELK4	protein	P28324	UNIPROT	up-regulates	phosphorylation			9606									9130707	t		gcesareni	In contrast, the tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387	SIGNOR-47771	0.2
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Thr658	VGGVVIAtVIVITLV	-1									10605825	t		lperfetto	In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D.	SIGNOR-261792	0.502
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT7A	protein	O00755	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242710	0.274
FLT3	protein	P36888	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates activity	phosphorylation	Tyr694	LAKAVDGyVKPQIKQ	10090	BTO:0002882								17356133	t		gcesareni	in vitro kinase assays revealed that STAT5 is a direct target of Flt3	SIGNOR-245069	0.594
TP53	protein	P04637	UNIPROT	SLC2A1	protein	P11166	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									27692180	t		miannu	P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.	SIGNOR-267464	0.585
NOTCH4	protein	Q99466	UNIPROT	MAML3	protein	Q96JK9	UNIPROT	up-regulates	binding			9606									12370315	t		gcesareni	Moreover, as determined by using coimmunoprecipitation assays, each maml protein was found to be capable of forming a multiprotein complex with the intracellular domain of each notch receptor (icn1 to -4) and csl in vivo	SIGNOR-94109	0.862
(8R)-7-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-13,14-diol	chemical	CHEBI:92234	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258730	0.8
p38	proteinfamily	SIGNOR-PF16	SIGNOR	CDT1	protein	Q9H211	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser391	LRSAAPSsPGSPRPA	9606	BTO:0000567								21930785	t		miannu	 We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2. 	SIGNOR-276362	0.2
ABL1	protein	P00519	UNIPROT	RAD51	protein	Q06609	UNIPROT	down-regulates	phosphorylation	Tyr54	HTVEAVAyAPKKELI	9606									9461559	t		llicata	Here we demonstrate that c-abl interacts constitutively with rad51. We show that c-abl phosphorylates rad51 on tyr-54 in vitro. The results also show that treatment of cells with ionizing radiation induces c-abl-dependent phosphorylation of rad51. Phosphorylation of rad51 by c-abl inhibits the binding of rad51 to dna and the function of rad51 in atp-dependent dna strand exchange reactions.	SIGNOR-55482	0.764
NPTX1	protein	Q15818	UNIPROT	MCL1	protein	Q07820	UNIPROT	down-regulates quantity				9606	BTO:0004168;BTO:0003227								31113871	f		lperfetto	We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control	SIGNOR-260413	0.2
IL1B	protein	P01584	UNIPROT	ITGA2	protein	P17301	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001596								1744142	f		lperfetto	TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way.	SIGNOR-253356	0.278
FBXO21	protein	O94952	UNIPROT	ABCB1	protein	P08183	UNIPROT	down-regulates quantity by destabilization	binding			-1									26299618	t		miannu	Here we demonstrate that a ubiquitin E3-ligase, FBXO21, targets the multidrug resistance transporter, ABCB1, also known as P-glycoprotein (P-gp), for proteasomal degradation.Purified in vitro translated FLAG-tagged P-gp along with E2 (UbcH5c), E3 ligase FBXO21, Cul1, Skp1, Roc1 purified from Sf-9 insect cells were incubated in vitro. 	SIGNOR-272422	0.332
DBP	protein	Q10586	UNIPROT	Gluconeogenesis	phenotype	SIGNOR-PH35	SIGNOR	up-regulates				9606									21633182	f		miannu	In addition to NHRs, Dbp, a known clock target gene, regulates expression of key metabolic genes involved in gluconeogenesis and lipogenesis (60). Because DBP levels change 100-fold in response to CLOCK/BMAL1 activation, it is conceivable that DBP generates circadian oscillation in metabolic processes such as gluconeogenesis.	SIGNOR-268028	0.7
Jervine	chemical	CHEBI:6088	ChEBI	SMO	protein	Q99835	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150	BTO:0000149							16112412	t		gcesareni	Here, we demonstrate that cyclopamine and jervine, two structurally related inhibitors of smo, force ciliary translocation of smo.	SIGNOR-139865	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	Interferon-type-I	proteinfamily	SIGNOR-PF50	SIGNOR	up-regulates quantity by expression	transcriptional regulation			10090									20610653	f		miannu	Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors.	SIGNOR-260329	0.2
lenvatinib	chemical	CHEBI:85994	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191457	0.8
PORCN	protein	Q9H237	UNIPROT	WNT3A	protein	P56704	UNIPROT	up-regulates activity	palmitoylation	Ser209	KCKCHGLsGSCEVKTC	9606	BTO:0000007								20826466	t			And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane.	SIGNOR-256598	0.688
Caspase 1 complex	complex	SIGNOR-C220	SIGNOR	IL18	protein	Q14116	UNIPROT	up-regulates activity	cleavage	Asp36	DDENLESdYFGKLES	9606	BTO:0001370								9334240	t		lperfetto	We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products.	SIGNOR-256377	0.784
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser36	AEKQARGsTTLQESR	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275765	0.2
CyclinE1/CDK3	complex	SIGNOR-C546	SIGNOR	G1/S_transition	phenotype	SIGNOR-PH50	SIGNOR	up-regulates													37104883	f		lperfetto	Among them, CDK3 is critically important because it triggers the transitions of G0 to G1 and G1 to S phase through binding to cyclin C and cyclin E1, respectively. 	SIGNOR-273191	0.7
AKT1	protein	P31749	UNIPROT	COPS6	protein	Q7L5N1	UNIPROT	up-regulates	phosphorylation	Ser60	DHWIRMRsQEGRPVQ	9606									23095642	t		llicata	Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6.	SIGNOR-252532	0.287
DYRK1B	protein	Q9Y463	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation	Ser641	YRYPRPAsVPPSPSL	9534	BTO:0000298								14593110	t		miannu	DYRK Family Protein Kinases Phosphorylate and Inactivate Glycogen Synthase. both protein kinases phosphorylate site 3a but no other sites that affect glycogen synthase activity.	SIGNOR-260633	0.261
HIF1A	protein	Q16665	UNIPROT	VEGFA	protein	P15692	UNIPROT	up-regulates quantity	transcriptional regulation			9606									8387214	t			Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription.	SIGNOR-256592	0.766
GNRHR	protein	P30968	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257265	0.451
SDH	complex	SIGNOR-C400	SIGNOR	succinate(2-)	smallmolecule	CHEBI:30031	ChEBI	down-regulates quantity	chemical modification			9606									16143825	t		miannu	Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions.	SIGNOR-266276	0.8
GRK2	protein	P25098	UNIPROT	CXCR2	protein	P25025	UNIPROT	down-regulates activity	phosphorylation			10090	BTO:0000763								22634615	t		miannu	Upon activation, GRK2 phosphorylates CXCR2 and causes receptor desensitization and internalization, leading to down-regulation of neutrophil chemotaxis 	SIGNOR-260647	0.2
POU2F1	protein	P14859	UNIPROT	TWIST1	protein	Q15672	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001939								23836662	f	 	miannu	 This PER2-OCT1 interaction effectively converted OCT1 sites, which normally activate expression, into repressor sites by recruitment of a polycomb repressor complex including EZH2 and SUZ12, as well as HDAC2. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes.	SIGNOR-254152	0.26
MAP3K11	protein	Q16584	UNIPROT	MAP3K11	protein	Q16584	UNIPROT	up-regulates	phosphorylation	Ser281	WHKTTQMsAAGTYAW	9606									11053428	t		gcesareni	These residues within the activation loop are critical for mlk-3 autophosphorylation and activation. In addition, when the thr277 and ser281 residues were mutated to negatively charged glutamic acid to mimic phosphorylated serine/threonine residues, the resulting mutants were fully functional, implying that these two residues may serve as the autophosphorylation sites.	SIGNOR-83407	0.2
SPAG9	protein	O60271	UNIPROT	MAP3K7	protein	O43318	UNIPROT	unknown	binding			10090	BTO:0000165;BTO:0000222;BTO:0002181		SIGNOR-C21						22337877	t		lperfetto	Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts	SIGNOR-235548	0.2
GDF5	protein	P43026	UNIPROT	Cartilage_development	phenotype	SIGNOR-PH75	SIGNOR	up-regulates				9606									21976273	f		miannu	Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. 	SIGNOR-252418	0.7
PPM1D	protein	O15297	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	down-regulates activity	dephosphorylation	Thr577	AENGLLMtPCYTANF	10090									15206906	t			RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity	SIGNOR-248323	0.369
(E)-3-tosylacrylonitrile	chemical	CHEBI:85928	ChEBI	PTPN1	protein	P18031	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	The anti-inflammatory compound BAY 11-7082 is a potent inhibitor of Protein Tyrosine Phosphatases.	gcesareni		SIGNOR-190254	0.8
CDK2	protein	P24941	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates activity	phosphorylation	Ser452	PVKTLPFsPSQFLNF		BTO:0000007								10593981	t		llicata	Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. 	SIGNOR-250735	0.711
BRCA1	protein	P38398	UNIPROT	CTSD	protein	P07339	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000150								11244506	f		miannu	 BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D.	SIGNOR-253759	0.28
NTRK1	protein	P04629	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	binding			9606	BTO:0000938								10708759	t		esanto	Autophosphorylated trka binds directly to plc?, Abl, and shc.	SIGNOR-75405	0.637
CDK1	protein	P06493	UNIPROT	DDX3X	protein	O00571	UNIPROT	down-regulates	phosphorylation	Thr204	LTRYTRPtPVQKHAI	9606			SIGNOR-C17						16280325	t		lperfetto	Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis.	SIGNOR-141565	0.301
PIK3CB	protein	P42338	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9534	BTO:0004055								14665640	f		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242652	0.7
RFXANK	protein	O14593	UNIPROT	RFX complex	complex	SIGNOR-C104	SIGNOR	form complex	binding			-1									10825209	t		miannu	RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes	SIGNOR-221571	0.809
MAPK1	protein	P28482	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Thr444	RFIGSPRtPVSPVKF	9606									15774499	t		gcesareni	The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain.	SIGNOR-134658	0.578
NUMA1	protein	Q14980	UNIPROT	TUBB4A	protein	P04350	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-117025	0.375
CSNK2A1	protein	P68400	UNIPROT	HDAC1	protein	Q13547	UNIPROT	up-regulates	phosphorylation	Ser423	CEEEFSDsEEEGEGG	9606									11602581	t		gcesareni	Human hdac1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, ser(421) and ser(423), were unambiguously identified. Loss of phosphorylation at ser(421) and ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of hdac1.	SIGNOR-111015	0.61
BIRC5	protein	O15392	UNIPROT	CASP3	protein	P42574	UNIPROT	down-regulates	binding			9606									10587640	t		gcesareni	Use of a dominant-negative survivin mutant or antisense survivin complementary dna disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21waf1/cip1 within centrosomes, and results in caspase-dependent cleavage of p21.	SIGNOR-72882	0.502
SYK	protein	P43405	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Tyr18	MEDHAGTyGLGDRKD	9606	BTO:0000938								18070606	t		lperfetto	We established that tyrosine 18 was the primary residue in tau phosphorylated by sykphosphorylation of tau by syk could be involved in neurite outgrowth.	SIGNOR-159648	0.479
3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea	chemical	CHEBI:91362	ChEBI	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192811	0.8
pemetrexed disodium	chemical	CHEBI:63722	ChEBI	TYMS	protein	P04818	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002058								14596699	t		miannu	Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). 	SIGNOR-259289	0.8
RELA	protein	Q04206	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	binding			9606			SIGNOR-C13						10671503	t		gcesareni	Rela (p65) nf-kappab subunit interacts with the zinc finger dna-binding domain of sp1.	SIGNOR-75004	0.614
CSNK2A1	protein	P68400	UNIPROT	EXOSC9	protein	Q06265	UNIPROT	up-regulates	phosphorylation	Ser394	APIILSDsEEEEMII	9606									19217413	t		lperfetto	Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay	SIGNOR-184035	0.2
MAP2K4	protein	P45985	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation			9606									7839144	t		lperfetto	Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase.	SIGNOR-34121	0.574
SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	up-regulates				9606									30397315	f		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270609	0.7
PRKAA2	protein	P54646	UNIPROT	TSC2	protein	P49815	UNIPROT	up-regulates	phosphorylation	Ser1387	QPLSKSSsSPELQTL	9606			SIGNOR-C15						16959574	t		gcesareni	We have observed that ampk directly phosphorylates tsc2, and the ampk-dependent phosphorylation of tsc2 is critical for the coordination between cell growth and cellular energy levels.	SIGNOR-149388	0.56
CSNK2A1	protein	P68400	UNIPROT	SLC29A1	protein	Q99808	UNIPROT	up-regulates activity	phosphorylation	Ser254	ETKLDLIsKGEEPRA	-1									17520485	t		miannu	These data suggest that inhibition of CK2-mediated phosphorylation at Ser254 had the same effect on transporter function as the actual loss of Ser254 in mENT1a, implying that this site is constitutively phosphorylated by CK2. 	SIGNOR-276063	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	DLG1	protein	Q12959	UNIPROT	down-regulates activity	phosphorylation	Ser232	ITLERGNsGLGFSIA	9534	BTO:0000298								12933808	t		llicata	Synapse-associated protein 97 (SAP97), a member of membrane-associated guanylate kinase protein family, has been implicated in the processes of targeting ionotropic glutamate receptors at postsynaptic sites. | We show here that SAP97 is directly associated with NR2A through its PDZ1 domain, and CaMKII-dependent phosphorylation of SAP97-Ser-232 disrupts NR2A interaction both in an in vitro pull-out assay and in transfected COS-7 cells. Moreover, expression of SAP97(S232D) mutant has effects similar to those observed upon constitutively activating CaMKII.	SIGNOR-250618	0.633
NMDA receptor_2D	complex	SIGNOR-C350	SIGNOR	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								11052931	t		miannu	Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor	SIGNOR-264225	0.731
ABL2	protein	P42684	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates activity	phosphorylation	Tyr386	YRARVANyQRDGPMC	9606									12777400	t		Manara	These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386	SIGNOR-260772	0.345
SNAI2	protein	O43623	UNIPROT	JAG1	protein	P78504	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								20509143	f		miannu	 SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. 	SIGNOR-255151	0.428
CSNK2A2	protein	P19784	UNIPROT	CTDP1	protein	Q9Y5B0	UNIPROT	down-regulates activity	phosphorylation	Ser740	TKAQRENsPAAFPDR	9606	BTO:0000567								12591939	t		llicata	We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified 	SIGNOR-250986	0.381
SLC36A4	protein	Q6YBV0	UNIPROT	tryptophan	smallmolecule	CHEBI:27897	ChEBI	up-regulates quantity	relocalization			8355									21097500	t		lperfetto	HPAT4 in Xenopus oocytes mediated sodium-independent, electroneutral uptake of [(3)H]proline, with the highest rate of uptake when the uptake medium pH was 7.4 and an affinity of 3.13 μM. Tryptophan was also an excellently transported substrate with a similarly high affinity (1.72 μM). 	SIGNOR-264735	0.8
TLN1	protein	Q9Y490	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257607	0.79
PDPK1	protein	O15530	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates	phosphorylation	Thr256	EHNSTTStFCGTPEY	9606									15209375	t		lperfetto	Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.	SIGNOR-236637	0.634
2-cyclopentyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid	chemical	CHEBI:95066	ChEBI	SGK3	protein	Q96BR1	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0003136								25458846	t		lperfetto	A catalytic small molecule pan-SGK inhibitor, GSK650394 (Sherk et al., 2008) also significantly blocks MCF7, ZR-75-1, and T47D cell migration (Figure 5C, Figures S4B–C). Finally, ectopic expression of SGK3 also promotes invasive migration through Matrigel (Figure 5D). Therefore, SGK3 protein kinase activity promotes migration of breast cancer cells that display elevated levels of INPP4B.	SIGNOR-262019	0.8
BTG1	protein	P62324	UNIPROT	HOXB9	protein	P17482	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								10617598	t		miannu	The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation.	SIGNOR-221019	0.454
SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	LIN28A	protein	Q9H9Z2	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269238	0.705
RASSF1	protein	Q9NS23	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	up-regulates	binding			9606									21808241	t	Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage	milica	Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization.	SIGNOR-269950	0.801
UBIAD1	protein	Q9Y5Z9	UNIPROT	HRAS	protein	P01112	UNIPROT	down-regulates activity	binding			9606	BTO:0000362								30518913	t		miannu	This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells. 	SIGNOR-256206	0.2
PRKCQ	protein	Q04759	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000782								26284074	t		Barakat	PKC-θ-mediated phosphorylation of serine and tyrosine residues of c-Cbl prevents its inhibitory effect. Phosphorylation of c-Cbl by PKC-θ inhibits the recruitment of Sh2-containing proteins and subsequent association of cbl E3 ubiquitin ligase with its target proteins	SIGNOR-274144	0.361
MAPK1	protein	P28482	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser106	PLNSVSPsPLMLLHP	9606	BTO:0000150								18372406	t		gcesareni	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity	SIGNOR-178137	0.657
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									18931691	f		miannu	JNKs activate apoptotic signaling by the upregulation pro-apoptotic genes via the transactivation of specific transcription factors or by directly modulating the activities of mitochondrial pro- and anti-apoptotic proteins through distinct phosphorylation events. 	SIGNOR-260178	0.7
PPARG	protein	P37231	UNIPROT	ABCG2	protein	Q9UNQ0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002042								16785230	f		miannu	 these results uncovered a mechanism by which up-regulation of functional ABCG2 expression can be achieved via exogenous or endogenous activation of the lipid-activated transcription factor, PPARgamma. 	SIGNOR-255054	0.406
AKT1	protein	P31749	UNIPROT	PDE3B	protein	Q13370	UNIPROT	up-regulates activity	phosphorylation	Ser295	VIRPRRRsSCVSLGE	10090	BTO:0000944								10454575	t			PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B	SIGNOR-252573	0.679
HNF4A	protein	P41235	UNIPROT	PCSK9	protein	Q8NBP7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000398								21123766	f		miannu	 Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes.	SIGNOR-254451	0.271
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Thr60	AGQEEPGtPPSSPLS	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276099	0.267
MAP2K7	protein	O14733	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser312	TESITATsPASMVGG	9606		BTO:0000975							17360977	t		lperfetto	Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 Ser312 can be phosphorylated by kinases, such as c-jun NH2-terminal kinase and inhibitor of _B kinase	SIGNOR-217920	0.378
EGFR	protein	P00533	UNIPROT	STAT5B	protein	P51692	UNIPROT	up-regulates activity	phosphorylation	Tyr699	TAKAVDGyVKPQIKQ	9606	BTO:0000007;BTO:0000356								11751923	t		llicata	We have shown that EGF activates STAT5b not only in a HEK293 cell model in which the EGFR is stably overexpressed but also in the MDA-MB468 breast cancer cell line. Furthermore, EGF (but not GH) is able to activate tyrosine phosphorylation of a Tyr-699 mutant of STAT5b. | Fig. 2 A (bottom panels) demonstrates that EGF-induced phosphorylation of tyrosine 699 (the well-described site of STAT5b phosphorylation) is detected only in the EGFR-overexpressing MDA-MB468 cells and not the MCF-7 cells.	SIGNOR-251098	0.827
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	TH	protein	P07101	UNIPROT	up-regulates	phosphorylation			9606									7901013	t	inferred from 70% family members	gcesareni	In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11	SIGNOR-270167	0.2
TWIST2	protein	Q8WVJ9	UNIPROT	RBL2	protein	Q08999	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255509	0.2
ATM	protein	Q13315	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates activity	phosphorylation	Ser367	DTRSLEIsQSYTTTQ	9606									21149446	t		gcesareni	In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible.	SIGNOR-170477	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation			9606									10230396	t	inferred from 70% family members	gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.	SIGNOR-270129	0.2
EZH2	protein	Q15910	UNIPROT	HOXA10	protein	P31260	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20565746	t		miannu	These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression.	SIGNOR-260070	0.449
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Thr371	LLAKLEEtKEYQEPE	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276211	0.2
EGR2	protein	P11161	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606									11494141	f		miannu	Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G1/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated.	SIGNOR-260048	0.7
CEBPB	protein	P17676	UNIPROT	SLC19A1	protein	P41440	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15652157	t	 	 	Collectively, these results identify transcriptionally important regions in the hRFC-C minimal promoter that include a GC-box and CCAAT-box, and suggest that cooperative interactions between Sp1 and C/EBP beta are essential for hRFC-C transactivation.	SIGNOR-254053	0.2
PPP2R1A	protein	P30153	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	dephosphorylation			9606									15525651	t		gcesareni	Galpha12 directly interacts with pp2a: evidence for galpha12-stimulated pp2a phosphatase activity and dephosphorylation of microtubule-associated protein, tau.	SIGNOR-130136	0.2
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2A	protein	P49459	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271361	0.66
Immune complexes	stimulus	SIGNOR-ST15	SIGNOR	Complement C1q	complex	SIGNOR-C308	SIGNOR	up-regulates activity	binding			-1									29449492	t		lperfetto	We used IgG monoclonal antibodies (mAbs) oligomerized through antigen-binding on liposomes or preformed antibody complexes in solution and applied tomography and single-particle cryo–electron microscopy (cryo-EM) to resolve the mechanisms of C1 binding and activation.|Binding of C1 through its gC1q modules to mediators of inflammation, such as immunoglobulin G (IgG) or IgM antibodies (fig. S1, C and D), on cell surfaces activates the associated proteases and initiates the proteolytic cascade of complement	SIGNOR-263397	0.7
STAT1	protein	P42224	UNIPROT	CIITA	protein	P33076	UNIPROT	up-regulates	transcriptional regulation			9606		BTO:0001103							21576360	t			When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita	SIGNOR-256249	0.524
serine	smallmolecule	CHEBI:17822	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264760	0.7
PRKCE	protein	Q02156	UNIPROT	TRPV1	protein	Q8NER1	UNIPROT	up-regulates activity	phosphorylation	Ser775	EGVKRTLsFSLRSSR	9534	BTO:0000298								14523239	t		lperfetto	We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. 	SIGNOR-249231	0.2
PRKACA	protein	P17612	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser579	NVKSKIGsTENLKHQ	9606	BTO:0000938								9771888	t	The effect has been demonstrated using P10636-8	gcesareni	Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase.	SIGNOR-60659	0.442
metformin	chemical	CHEBI:6801	ChEBI	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity by expression				9606									17909097	f	inferred from family member	gcesareni	In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp.	SIGNOR-270254	0.8
SLC6A8	protein	P48029	UNIPROT	creatine	smallmolecule	CHEBI:16919	ChEBI	up-regulates quantity	relocalization			9606									18652074	t		miannu	CRT is essential for normal brain function as mutations in the CRT gene (SLC6A8) result in X-linked mental retardation, associated with the almost complete lack of creatine in the brain, severe speech and language delay, epilepsy, and autistic behaviour.	SIGNOR-265808	0.8
RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									7566092	t		lperfetto	Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-J kappa (refs 8,9) and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter.	SIGNOR-209590	0.674
GATA2	protein	P23769	UNIPROT	SPI1	protein	P17947	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									24583263	f		irozzo	We also identify Spi1 as a common downstream target gene of Etv2 and Gata2. We provide evidence that Etv2 and Gata2 bind to the Spi1 promoter in vitro and in vivo. Etv2 and Gata2 synergistically transactivate Spi1 gene expression.	SIGNOR-256007	0.596
Immunoglobulin mu heavy chain	protein	P0DOX6	UNIPROT	BCR-Ml	complex	SIGNOR-C434	SIGNOR	form complex	binding			9606	BTO:0000776								32323265	t		scontino	An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs.	SIGNOR-268191	0.2
JAK2	protein	O60674	UNIPROT	ITGAL	protein	P20701	UNIPROT	up-regulates activity	phosphorylation			9606									25624455	t		miannu	PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.	SIGNOR-254739	0.272
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1951	SPGYSPTsPTYSLTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120260	0.321
SRC	protein	P12931	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates activity	phosphorylation	Tyr432	KEGWMVHyTSKDTLR	9606	BTO:0000567								12637538	t		lperfetto	Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation.	SIGNOR-247320	0.421
AMPK	complex	SIGNOR-C15	SIGNOR	CRY1	protein	Q16526	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser280	YKKVKKNsSPPLSLY	9606									19833968	t		miannu	We demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Phosphorylation of S71 or S280 by AMPK destabilizes CRY1	SIGNOR-268047	0.349
MAP2K4	protein	P45985	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates	phosphorylation			9606									11242034	t	Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif.	gcesareni	A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1).	SIGNOR-105692	0.732
ROCK1	protein	Q13464	UNIPROT	PPP1R12A	protein	O14974	UNIPROT	down-regulates activity	phosphorylation	Thr853	PREKRRStGVSFWTQ	10090									10601309	t		lperfetto	Phosphorylation by Rho-kinase inhibited MP activity and this reflected a decrease in V(max). Activity of MP with different substrates also was inhibited by phosphorylation. Two major sites of phosphorylation on MYPT1 were Thr(695) and Thr(850).	SIGNOR-249034	0.766
DRD4	protein	P21917	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256846	0.423
CDK8	protein	P49336	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2513	EHPFLTPsPESPDQW	-1									25344755	t		lperfetto	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273176	0.534
HTR1B	protein	P28222	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256720	0.443
PRTN3	protein	P24158	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates activity	cleavage	Pro54	NPNDKYEpFWEDEEK	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263578	0.43
CASP8	protein	Q14790	UNIPROT	RNF31	protein	Q96EP0	UNIPROT	down-regulates activity	cleavage	Asp348	GTGGLEPdLARGRWA	9606	BTO:0005111								32122970	t		miannu	We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death.	SIGNOR-272194	0.321
p38	proteinfamily	SIGNOR-PF16	SIGNOR	BCL2	protein	P10415	UNIPROT	down-regulates activity	phosphorylation	Ser87	AAAGPALsPVPPVVH	9606									19336399	t		gcesareni	The protein's reduced antiapoptotic capacity was related to phosphorylation of its threonine 56 and serine 87 residues by virally activated p38mapk	SIGNOR-260450	0.2
MYC	protein	P01106	UNIPROT	SLC2A1	protein	P11166	UNIPROT	up-regulates quantity	transcriptional regulation			10116									10823814	t			C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.	SIGNOR-259987	0.442
Integrator complex	complex	SIGNOR-C265	SIGNOR	H4C1	protein	P62805	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								25675981	f		lperfetto	Integrator-dependent function at promoter proximal sites that is unrelated to NELF-regulated pausing. Given its termination function at both the U2 snRNA and Histone H4 genes, we favor a model in which Integrator also has a termination function at promoter proximal sites.	SIGNOR-261481	0.2
CSNK1A1	protein	P48729	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation	Ser318	SRTNSNAsTVSGRLS	9606									20110348	t		lperfetto	Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export	SIGNOR-163672	0.2
NCL	protein	P19338	UNIPROT	MYB	protein	P10242	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								10660576	t		miannu	We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity.	SIGNOR-221236	0.41
SPDEF	protein	O95238	UNIPROT	MMP13	protein	P45452	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003160								22761428	f		miannu	 Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. 	SIGNOR-255219	0.2
CHUK	protein	O15111	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser927	DSDSVCDsGVETSFR	10090	BTO:0000944		SIGNOR-C14	SIGNOR-C13					11297557	t		lperfetto	The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk.	SIGNOR-235438	0.737
PTEN	protein	P60484	UNIPROT	DVL2	protein	O14641	UNIPROT	down-regulates activity	dephosphorylation	Ser143	FHPNVSSsHENLEPE	9606									26399523	t		miannu	This showed that while both PTEN WT and the lipid phosphatase-inactive G129E mutant suppressed phosphorylation of DVL2 on serine 143 that accumulated upon PTEN knockdown, the C124S and Y138L mutants did not .|Finally, it is important to point out that while our studies show that PTEN can directly dephosphorylate DVL2 in vitro, it is possible that regulation of serine 143 phosphorylation of DVL2 by PTEN in cells may require additional protein factors, or post-translational modifications.	SIGNOR-277035	0.324
JARID2	protein	Q92833	UNIPROT	NPPA	protein	P01160	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0003324								15542826	f		miannu	JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4.	SIGNOR-224790	0.2
CSNK2A1	protein	P68400	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates	phosphorylation	Ser283	NLQMLPEsEDEESYD	9606	BTO:0000782								8622692	t		llicata	Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation.	SIGNOR-40502	0.566
metaproterenol	chemical	CHEBI:6792	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			-1									19168263	t		Luana	Synthesis, pharmacological and in silico evaluation of 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, a compound designed to act as a β2 adrenoceptor agonist | After that, in vitro assays were carried out and the Kd value obtained for BR-AEA was compared with reported in vitro data for salbutamol and other well-known ligands.	SIGNOR-257814	0.8
KAT2B	protein	Q92831	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269620	0.2
GNG12	protein	Q9UBI6	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606	BTO:0000586								16293724	t		gcesareni	We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin.	SIGNOR-252681	0.373
Pituitary adenylate cyclase-activating peptide-27	smallmolecule	CHEBI:80303	ChEBI	ADCYAP1R1	protein	P41586	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257445	0.8
CLN8	protein	Q9UBY8	UNIPROT	SET	protein	Q01105	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								30453012	t		miannu	CLN8 interacts with ceramide binding proteins PP2A and I2PP2A. We showed that the phosphorylation levels of several substrates of PP2A, namely Akt, S6 kinase, and GSK3β, were decreased in CLN8 disease patient fibroblasts. This reduction can be reversed by inhibiting PP2A phosphatase activity with cantharidin, suggesting a higher PP2A activity in CLN8-deficient cells. The phosphorylation levels of PP2A substrates are decreased in the absence of CLN8.	SIGNOR-265584	0.2
SREBF1	protein	P36956	UNIPROT	FASN	protein	P49327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16308421	t		gcesareni	Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk)	SIGNOR-142294	0.511
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	EGFR	protein	P00533	UNIPROT	down-regulates	phosphorylation			9606									1651322	t	inferred from 70% family members	lperfetto	It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation.	SIGNOR-270017	0.2
PRKCG	protein	P05129	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates	phosphorylation	Ser44	KKSKISAsRKLQLKT	9606		BTO:0000887							15769444	t		lperfetto	Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.	SIGNOR-134636	0.2
CCL2	protein	P13500	UNIPROT	Macrophage_activation	phenotype	SIGNOR-PH126	SIGNOR	up-regulates				10090									32283152	f		miannu	The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages.	SIGNOR-260849	0.7
FBXO32	protein	Q969P5	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606		BTO:0001103							19319192	t		gcesareni	Here we present evidence that mafbx targets myod for degradation in several models of skeletal muscle atrophy.	SIGNOR-184861	0.577
NEDD4L	protein	Q96PU5	UNIPROT	SCN4A	protein	P35499	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000938								23778145	t		miannu	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 	SIGNOR-253460	0.283
RUNX2	protein	Q13950	UNIPROT	TNFSF11	protein	O14788	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11331591	f		gcesareni	In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast	SIGNOR-107242	0.49
CSNK1A1	protein	P48729	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	phosphorylation	Ser316	FKSIMKKsPFSGPTD	-1									26082493	t		miannu	 These data strongly suggested that CKI phosphorylated Ser-316 of p65. Our data suggested that phosphorylation of p65 on Ser-316 controls the activity and function of NF-κB. Importantly, we found that phosphorylation at the novel Ser-316 site and other two known phosphorylation sites, Ser-529 and Ser-536, either individually or cooperatively, regulated distinct groups of NF-κB-dependent genes, suggesting the unique role of each individual phosphorylation site on NF-κB-dependent gene regulation. 	SIGNOR-276916	0.2
SMARCC2	protein	Q8TAQ2	UNIPROT	Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270695	0.829
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	SQSTM1	protein	Q13501	UNIPROT	up-regulates	phosphorylation	Ser272	RSRLTPVsPESSSTE	9606	BTO:0000551								20974803	t		lperfetto	Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis.	SIGNOR-216932	0.355
EIF3E	protein	P60228	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	up-regulates quantity	translation regulation			9606	BTO:0000815; BTO:0001938								20453879	f		irozzo	Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression.	SIGNOR-259156	0.2
CCKAR	protein	P32238	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606	BTO:0001130;BTO:0000551								11313903	t		gcesareni	These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways.	SIGNOR-106998	0.441
NPTX1	protein	Q15818	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates quantity				9606	BTO:0004168;BTO:0003227								31113871	f		lperfetto	We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control	SIGNOR-260411	0.2
PTPN2	protein	P17706	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr999	YASSNPEyLSASDVF	9606									10734133	t		flangone	Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1.	SIGNOR-75922	0.604
MMP14	protein	P50281	UNIPROT	FGG	protein	P02679	UNIPROT	down-regulates quantity by destabilization	cleavage	Ile105	ESSKPNMiDAATLKS	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain	SIGNOR-263618	0.2
IKBKE	protein	Q14164	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser36	RHDSGLDsMKDEEYE										11815618	t		lperfetto	Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. |TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha.	SIGNOR-249367	0.498
NR1D1	protein	P20393	UNIPROT	ARNTL	protein	O00327	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24577401	t		miannu	A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription.	SIGNOR-268005	0.659
PSENEN	protein	Q9NZ42	UNIPROT	gamma-secretase	complex	SIGNOR-C98	SIGNOR	form complex	binding			9606									25610395	t		lperfetto	-Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2)	SIGNOR-209708	0.96
Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	down-regulates				9606									22303254	f			Polycomb group (PcG) and Trithorax group (TrxG) proteins are epigenetic regulators that control gene expression through modulating chromatin structure and addition of posttranslational modifications (PTMs) on histones	SIGNOR-268625	0.7
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	NAIP	protein	Q13075	UNIPROT	up-regulates activity													16037825	f		lperfetto	Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage	SIGNOR-256424	0.7
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1882	SPTSPTYsPTTPKYS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269349	0.718
DRD5	protein	P21918	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257043	0.293
SMARCA2	protein	P51531	UNIPROT	GBAF	complex	SIGNOR-C467	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269779	0.639
GABRA6	protein	Q16445	UNIPROT	GABA-A (a6-b1-g2) receptor	complex	SIGNOR-C334	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263762	0.593
CDK1	protein	P06493	UNIPROT	BIRC5	protein	O15392	UNIPROT	up-regulates	phosphorylation	Thr34	FLEGCACtPERMAEA	9606									11861764	t		gcesareni	Survivin is a member of the inhibitor of apoptosis gene family that has been implicated in both apoptosis inhibition and regulation of mitosisin synchronized cultures, cytosolic survivin abruptly increased at mitosis, physically associated with p34(cdc2), and was phosphorylated by p34(cdc2) on thr(34), in vivo	SIGNOR-115129	0.672
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	PRDM14	protein	Q9GZV8	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269242	0.513
CHRM3	protein	P20309	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256739	0.282
PRKACA	protein	P17612	UNIPROT	ADD1	protein	P35611	UNIPROT	down-regulates activity	phosphorylation	Ser436	TCSPLRHsFQKQQRE	-1									8810272	t		miannu	Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin.	SIGNOR-250330	0.316
GSK3B	protein	P49841	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation	Ser641	YRYPRPAsVPPSPSL	9606		BTO:0000887;BTO:0001103							14593110	t		lperfetto	Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase	SIGNOR-235793	0.673
Factor FVIIa:TF	complex	SIGNOR-C319	SIGNOR	F5	protein	P12259	UNIPROT	down-regulates activity	cleavage	Arg1220	LSPELIQrNLSPALG	-1									10026263	t		lperfetto	Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 	SIGNOR-263648	0.496
PRKCA	protein	P17252	UNIPROT	EGLN2	protein	Q96KS0	UNIPROT	down-regulates	phosphorylation	Ser234	QRAIPPRsIRGDQIA	9606									18710826	t		tpavlidou	Thus, recombinant phd1 was examined for in vitro phosphorylation using protein kinase a, protein kinase calpha, casein kinase i and ii and erk2. The protein was most strongly phosphorylated by protein kinase calpha, and the phosphorylation sites were found to be ser-132, ser-226 and ser-234.Mutation Of ser-132 or ser-234 to asp or glu diminished the enzymatic activity to 25-60%, while mutation of ser-226 scarcely influenced the activity.	SIGNOR-180203	0.34
sunitinib	chemical	CHEBI:38940	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates	chemical inhibition			9606									21423276	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-172926	0.8
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	tRNA(Gln)	smallmolecule	CHEBI:29168	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270387	0.8
MAPK1	protein	P28482	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	down-regulates activity	phosphorylation	Thr386	IGLNQPStPTHAAGV	9606									10567369	t		lperfetto	An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2	SIGNOR-236498	0.739
SUPT7L	protein	O94864	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269585	0.655
NFATC1	protein	O95644	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606	BTO:0000776								11163226	f		scontino	In this study, the roles of NFATc1 and NFATc2 in T and B cells were examined. These results further characterize NFAT as a transcription factor family that plays a critical role in the regulation of lymphocyte effector differentiation.	SIGNOR-270537	0.7
SHMT1	protein	P34896	UNIPROT	3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine	smallmolecule	CHEBI:15786	ChEBI	down-regulates quantity	chemical modification			9606									11802770	t		miannu	 HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine.	SIGNOR-269687	0.8
ABL1	protein	P00519	UNIPROT	WASL	protein	O00401	UNIPROT	up-regulates activity	phosphorylation	Tyr256	RETSKVIyDFIEKTG	-1									16199863	t			Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation.	SIGNOR-251437	0.566
GRK5	protein	P34947	UNIPROT	GRK5	protein	P34947	UNIPROT	up-regulates activity	phosphorylation	Thr485	LDIEQFStVKGVNLD	-1									8144599	t			Autophosphorylation of GRK5 occurs primarily at residues Ser-484 and Thr-485. Phospholipid-stimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5.	SIGNOR-251202	0.2
heme	smallmolecule	CHEBI:30413	ChEBI	HBA1	protein	P69905	UNIPROT	up-regulates activity	chemical activation			9606									26557657	t		miannu	Heme is a prosthetic group comprising ferrous iron (Fe2+) and protoporphyrin IX and is an essential cofactor in various biological processes such as oxygen transport (hemoglobin) and storage (myoglobin) and electron transfer (respiratory cytochromes) in addition to its role as a structural component of hemoproteins.	SIGNOR-251909	0.8
ABCC4	protein	O15439	UNIPROT	sphingosine 1-phosphate	smallmolecule	CHEBI:37550	ChEBI	up-regulates quantity	relocalization			9606									29304533	t		lperfetto	Release of Platelet-Derived Sphingosine-1-Phosphate Involves Multidrug Resistance Protein 4 (MRP4/ABCC4) and Is Inhibited by Statins	SIGNOR-265912	0.8
GGCX	protein	P38435	UNIPROT	F2	protein	P00734	UNIPROT	up-regulates activity	carboxylation	Glu62	NLERECVeETCSYEE	-1									10556651	t		lperfetto	We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 	SIGNOR-263679	0.655
MAPK14	protein	Q16539	UNIPROT	TAB1	protein	Q15750	UNIPROT	down-regulates activity	phosphorylation	Ser438	TPTLTNQsPTLTLQS	9606	BTO:0000801								14592977	t		lperfetto	Tab1, a subunit of the kinase tak1, was phosphorylated by sapk2a/p38alpha at ser423, thr431 and ser438 in vitro. the results presented here also show that sapk2a/p38? Suppresses the activity of tak1 in cells, because the activation of tak1 by proinflammatory cytokines and lps is enhanced if cells are first pre?incubated With sb 203580 or in cells that do not express sapk2a/p38?.	SIGNOR-118922	0.817
SRC	protein	P12931	UNIPROT	FERMT2	protein	Q96AC1	UNIPROT	up-regulates activity	phosphorylation	Tyr193	SKTMTPTyDAHDGSP	9606	BTO:0000007								26037143	t		miannu	Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. 	SIGNOR-266100	0.379
Goserelin	chemical	CHEBI:5523	ChEBI	GNRHR	protein	P30968	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0001033								22416801	t		miannu	The efficacy of degarelix compared with a GnRH agonist (goserelin, plus flare protection with bicalutamide) was evaluated in a 12‐week trial in men with lower urinary tract symptoms secondary to prostate cancer.	SIGNOR-259161	0.8
MARK2	protein	Q7KZI7	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates	phosphorylation	Ser155	FPLRKTVsEPNLKLR	9606									16980613	t		lperfetto	We further show that emk and c-tak1 phosphorylate class iia hdacs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function	SIGNOR-149583	0.35
MAPK3	protein	P27361	UNIPROT	IL16	protein	Q14005	UNIPROT	up-regulates	phosphorylation	Ser845	SIRQRISsFETFGSS	9606									14768064	t		lperfetto	The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 in antigen receptor-, sdf1alpha- and il-2-activated t cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response.	SIGNOR-121856	0.269
AKT1	protein	P31749	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates	phosphorylation	Ser262	TFRPRSSsNASSVST	9606									16272144	t		lperfetto	Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression	SIGNOR-252485	0.755
5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-)	smallmolecule	CHEBI:77657	ChEBI	SAICAR(4-)	smallmolecule	CHEBI:58443	ChEBI	up-regulates quantity	precursor of			9606									33179964	t		miannu	The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS).	SIGNOR-268109	0.8
CELF4	protein	Q9BZC1	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606		BTO:0000227							23209433	f		miannu	CELF4 (CUGBP, ELAV-like family member 4) is one of six mammalian CELF proteins that function in mRNA metabolism. CELF4 is expressed predominantly in excitatory neurons, with highest expression in pyramidal neurons of the hippocampus and the cerebral cortex. we suggest that CELF4 deficiency leads to abnormal neuronal function by combining a specific effect on neuronal excitation with a general impairment of synaptic transmission.	SIGNOR-264257	0.7
RORA	protein	P35398	UNIPROT	ARNTL	protein	O00327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20817722	t		miannu	Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.	SIGNOR-267982	0.677
PRKDC	protein	P78527	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates	phosphorylation	Thr68	SSLETVStQELYSIP	9606									15668230	t		gcesareni	We have found that dna-pk is the major constituent of an activity present in extracts of mammalian cells that phosphorylates chk2. Our results suggest that hypophosphorylated chk2 can be phosphorylated at thr68 by dna-pk in vitro.	SIGNOR-133384	0.609
PRKCE	protein	Q02156	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	unknown	phosphorylation	Ser473	PPSGTKKsKRGRGRP	9606									12529391	t		llicata	Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm.	SIGNOR-97291	0.478
SETD2	protein	Q9BYW2	UNIPROT	TUBA1B	protein	P68363	UNIPROT	up-regulates activity	methylation	Lys40	DGQMPSDkTIGGGDD	9606	BTO:0000007								27518565	t		Gianni	The histone methyltransferase SET-domain-containing 2 (SETD2), which is responsible for H3 lysine 36 trimethylation (H3K36me3) of histones, also methylates α-tubulin at lysine 40, the same lysine that is marked by acetylation on microtubules. Methylation of microtubules occurs during mitosis and cytokinesis and can be ablated by SETD2 deletion, which causes mitotic spindle and cytokinesis defects, micronuclei, and polyploidy	SIGNOR-269090	0.246
EPHA2	protein	P29317	UNIPROT	CLDN4	protein	O14493	UNIPROT	down-regulates activity	phosphorylation	Tyr208	RSAAASNyV	9534									16236711	t		miannu	EphA2 associates with claudin-4 via their extracellular domains. This association, in turn, leads to phosphorylation of the cytoplasmic carboxyl terminus of claudin-4 at Tyr-208. The tyrosine phosphorylation of claudin-4 attenuates association of claudin-4 with ZO-1, decreasing integration of claudin-4 into sites of cell-cell contact and enhancing paracellular permeability. These results indicate that EphA2 moderates the function of tight junctions via phosphorylation of claudin-4.	SIGNOR-262859	0.491
DAMPS	stimulus	SIGNOR-ST18	SIGNOR	NLRP1	protein	Q9C000	UNIPROT	up-regulates activity													16037825	f		lperfetto	Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage	SIGNOR-256421	0.7
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	KDM4C	protein	Q9H3R0	UNIPROT	down-regulates activity	cleavage			9606									29207681	t		miannu	JMJD2C as a novel substrate for caspase-3 (cysteine-aspartic acid protease-3), and cleavage of JMJD2C by caspase-3 led to inactivation of JMJD2C demethylase activity and elevation of H3K9 methylation levels.	SIGNOR-263871	0.2
G6PD	protein	P11413	UNIPROT	6-O-phosphono-D-glucono-1,5-lactone	smallmolecule	CHEBI:16938	ChEBI	up-regulates quantity	chemical modification			9606									24769394	t		miannu	G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress	SIGNOR-267051	0.8
AKT2	protein	P31751	UNIPROT	PKP1	protein	Q13835	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr179	LGSKGQKtTQNRYSF	-1									23444369	t		miannu	Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry.	SIGNOR-273489	0.27
PDIA6	protein	Q15084	UNIPROT	EIF2AK3	protein	Q9NZJ5	UNIPROT	down-regulates activity				10116	BTO:0003318								26487694	t			Protein disulfide isomerase A6 (PDIA6) interacts with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme (IRE)-1 and inhibits their unfolded protein response signaling.	SIGNOR-256537	0.2
TACR1	protein	P25103	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257374	0.477
PCDH15	protein	Q96QU1	UNIPROT	TIP-LINK complex	complex	SIGNOR-C291	SIGNOR	form complex	binding			10090		BTO:0000630							23217710	t		lperfetto	The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction.	SIGNOR-262575	0.567
ELOVL2	protein	Q9NXB9	UNIPROT	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267897	0.8
PRKACA	protein	P17612	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser311	SFRTPRDsKLEAPAE	9606		BTO:0000887							20151718	t		miannu	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163764	0.278
glucose	chemical	CHEBI:17234	ChEBI	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	up-regulates quantity by stabilization				9606	BTO:0004424								26323688	t	inferred from family member		Consistently, treatment of cells with 2-deoxy-d-glucose (2DG), which completely inhibits glucose metabolism, leads to HK2 degradation and cell death in combination with C43	SIGNOR-270265	0.8
GSK3B	protein	P49841	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates activity	phosphorylation	Thr239	VPEMPGEtPPLSPID	9606	BTO:0000007								16023596	t		lperfetto	The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance	SIGNOR-236717	0.7
TNFRSF10B	protein	O14763	UNIPROT	FADD	protein	Q13158	UNIPROT	up-regulates	binding			9606									14585074	t		amattioni	Fadd binds to ligated trailr1 or trail-r2	SIGNOR-98565	0.844
PLK1	protein	P53350	UNIPROT	STAG2	protein	Q8N3U4	UNIPROT	down-regulates activity	dephosphorylation	Ser1224	PASIMDEsVLGVSMF	9606	BTO:0000567								15737063	t		lperfetto	Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase	SIGNOR-275532	0.727
PSMF1	protein	Q92530	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	down-regulates activity	binding			9606	BTO:0000007								23622245	t		lperfetto	We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31.	SIGNOR-263341	0.506
TTL	protein	Q8NG68	UNIPROT	TUBA1B	protein	P68363	UNIPROT	down-regulates	tyrosination			9606									22020298	t		miannu	Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization	SIGNOR-176915	0.435
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CD40	protein	P25942	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19164127	f	 	miannu	 We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. 	SIGNOR-254785	0.555
PK	proteinfamily	SIGNOR-PF80	SIGNOR	pyruvate	smallmolecule	CHEBI:15361	ChEBI	up-regulates quantity	chemical modification			9606									15996096	t		miannu	Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A).	SIGNOR-266540	0.8
ATM	protein	Q13315	UNIPROT	MRE11	protein	P49959	UNIPROT	up-regulates	phosphorylation	Ser264	EQQLFYIsQPGSSVV	9606									10608806	t		lperfetto	In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage.	SIGNOR-73366	0.2
Cell-Cell_contact	stimulus	SIGNOR-ST13	SIGNOR	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	up-regulates				9606									22683405	f	inferred from 70% of family members	milica	In response to growth inhibitory signal (e.g. cell–cell contact), MST1/2 in active form phosphorylates LATS1/2 that sequentially phosphorylates YAP at Ser-127.	SIGNOR-269943	0.7
PTPN6	protein	P29350	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates activity	dephosphorylation	Tyr1059	DIYKDPDyVRKGDAR	9606									18377662	t			Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175	SIGNOR-248474	0.654
MAPK3	protein	P27361	UNIPROT	METTL3	protein	Q86U44	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser43	RNPEAALsPTFRSDS	9606	BTO:0000007								33217317	t		miannu	 Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.	SIGNOR-265949	0.274
NEK1	protein	Q96PY6	UNIPROT	ME1	protein	P48163	UNIPROT	down-regulates activity	phosphorylation	Ser336	KKIWLVDsKGLIVKG										31735643	t		lperfetto	PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. 	SIGNOR-275570	0.2
ID1	protein	P41134	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates activity	binding			10090	BTO:0004058			SIGNOR-C127					9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241107	0.653
CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	NANOS1	protein	Q8WY41	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			9606									31320642	t		lperfetto	In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins	SIGNOR-268346	0.356
PRKCQ	protein	Q04759	UNIPROT	PRKCQ	protein	Q04759	UNIPROT	up-regulates activity	phosphorylation	Thr219	SAINSREtMFHKERF	9606									16252004	t		lperfetto	Critical role of novel Thr-219 autophosphorylation for the cellular function of PKCtheta in T lymphocytes.	SIGNOR-249298	0.2
HEY1	protein	Q9Y5J3	UNIPROT	MEF2C	protein	Q06413	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									19917614	f		lperfetto	Our results indicate instead that hey1 is recruited to the promoter regions of myogenin and mef2c, two genes whose induction is critical for myogenesis.	SIGNOR-235819	0.313
BCL2L2	protein	Q92843	UNIPROT	BAK1	protein	Q16611	UNIPROT	down-regulates	binding			9606									17289999	t		gcesareni	Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax.	SIGNOR-152989	0.458
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH4	protein	P55283	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265844	0.8
CGA	protein	P01215	UNIPROT	TSH	complex	SIGNOR-C412	SIGNOR	form complex	binding			9606		BTO:0001379							8196184	t		scontino	TSH is a heterodimer composed of common alpha subunit and unique beta subunit encoded by genes located on different chromosomes. It is known that the expression of these subunit genes is regulated in different mechanism by several extracellular factors.	SIGNOR-267046	0.667
glycine	smallmolecule	CHEBI:15428	ChEBI	Gly-tRNA(Gly)	smallmolecule	CHEBI:29156	ChEBI	up-regulates quantity	precursor of			9606									24898252	t		miannu	Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 	SIGNOR-270484	0.8
TP63	protein	Q9H3D4	UNIPROT	PERP	protein	Q96FX8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21965674	f		miannu	 SATB2 attenuates p63-mediated gene expression of perp (p53 apoptosis effector related to PMP-22), a critical downstream target gene during development, and specifically decreases p63 perp promoter binding.	SIGNOR-255136	0.609
PTK2	protein	Q05397	UNIPROT	ACTN4	protein	O43707	UNIPROT	down-regulates	phosphorylation	Tyr4	yHAANQSY	9606									23454549	t		lperfetto	Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin	SIGNOR-192199	0.54
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CCNF	protein	P41002	UNIPROT	up-regulates activity	phosphorylation	Thr31	RRRPRNLtILSLPED	9606	BTO:0001938								28954236	t		miannu	AKT phosphorylation of cyclin F enhances its stability and promotes assembly into productive E3 ligase complexes. 	SIGNOR-266360	0.2
NPC	complex	SIGNOR-C263	SIGNOR	Nuclear_pore_function	phenotype	SIGNOR-PH130	SIGNOR	up-regulates				9606	BTO:0000007								9660920	f		miannu	Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus.	SIGNOR-261395	0.7
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	MEF2C	protein	Q06413	UNIPROT	up-regulates				9606		BTO:0001103							11062529	f	inferred from 70% family members	gcesareni	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-269993	0.2
FOS	protein	P01100	UNIPROT	CYP19A1	protein	P11511	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19022561	t		miannu	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 	SIGNOR-254879	0.354
RXRA	protein	P19793	UNIPROT	NR1H2	protein	P55055	UNIPROT	up-regulates	binding			9606									14993927	t		lperfetto	We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active.	SIGNOR-123091	0.68
CDK8	protein	P49336	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Ser128	QHVRAHSsPASLQLG	-1									29967145	t		miannu	CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro.	SIGNOR-277649	0.327
NSL histone acetyltransferase	complex	SIGNOR-C413	SIGNOR	H4C1	protein	P62805	UNIPROT	down-regulates activity	acetylation	Lys17	GLGKGGAkRHRKVLR	9606									20018852	t		miannu	Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8.	SIGNOR-267166	0.2
PRKACA	protein	P17612	UNIPROT	STK24	protein	Q9Y6E0	UNIPROT	unknown	phosphorylation	Thr18	ALNKRRAtLPHPGGS	9606	BTO:0000007	BTO:0000142;BTO:0000671							10644707	t		llicata	Further experiments demonstrated that mst3b, but not mst3, was effectively phosphorylated by activation of cyclic amp-dependent protein kinase (pka) in both in vivo and in vitro assays. The mutation of thr-18 into ala in mst3b (t18a), a putative pka phosphorylation site that is absent in mst3, abolished its phosphorylation by pka.	SIGNOR-74284	0.219
TLN1	protein	Q9Y490	UNIPROT	AD/b2 integrin	complex	SIGNOR-C172	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257623	0.484
ARID1A	protein	O14497	UNIPROT	Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270689	0.799
STAT3	protein	P40763	UNIPROT	CD46	protein	P15529	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17699108	f		miannu	 The CD46 promoter contains two binding sites for activated STAT3 and mutations introduced into the major site abolished STAT3 binding. Chromatin immunoprecipitation confirms binding of STAT3 to the CD46 promoter. CD46 promoter activity is induced by activation of STAT3 and blocked by a dominant-negative form of STAT3 in luciferase reporter assays. 	SIGNOR-255238	0.271
CARS1	protein	P49589	UNIPROT	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									11347887	t		miannu	Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine.	SIGNOR-270472	0.8
UBQLN2	protein	Q9UHD9	UNIPROT	TARDBP	protein	Q13148	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0003704								23541532	t		lperfetto	Here, we describe a high affinity interaction between UBQLN2 and TDP-43 and demonstrate that overexpression of both UBQLN2 and TDP-43 reduces levels of both exogenous and endogenous TDP-43 in human H4 cells.|Consequently, these data suggest that UBQLN2 enhances the clearance of TDP-43	SIGNOR-262112	0.602
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	GRB2	protein	P62993	UNIPROT	down-regulates activity	phosphorylation	Tyr37	EECDQNWyKAELNGK	9606									20554525	t		lperfetto	More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway.	SIGNOR-246289	0.2
LPAR3	protein	Q9UBY5	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257229	0.252
HTR6	protein	P50406	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257186	0.254
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BRAF	protein	P15056	UNIPROT	down-regulates activity	phosphorylation	Ser151	VARSNPKsPQKPIVR	9606	BTO:0000848								21478863	t			We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction	SIGNOR-259919	0.2
A4/b7 integrin	complex	SIGNOR-C187	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269031	0.7
TBK1	protein	Q9UHD2	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606									21329883	t		lperfetto	Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling.	SIGNOR-172132	0.417
dasatinib (anhydrous)	chemical	CHEBI:49375	ChEBI	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	down-regulates activity	chemical inhibition			9606	BTO:0001056								23409026	t		miannu	Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. 	SIGNOR-259270	0.8
CSNK2A2	protein	P19784	UNIPROT	SPIB	protein	Q01892	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser37	KHSSYPDsEGAPDSL	9606	BTO:0000567								10618498	t		llicata	Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo	SIGNOR-251042	0.311
CDK4	protein	P11802	UNIPROT	TOB2	protein	Q14106	UNIPROT	up-regulates activity	phosphorylation	Ser254	PAPQSQLsPNAKEFV	-1									32404348	t		miannu	Taken together, these observations strongly support the notion that several different CDK-cyclin complexes are involved in the phosphorylation of Tob2 at S254.A more detailed regulatory context of Tob2 phosphorylation at S254 is provided by our findings from mass-spec and in vitro kinase analyses that suggest connections to PP2B and PP2C phosphatases and CDK-cyclin complexes, particularly CDK1, CDK2, and CDK4 (Table 1; Supplemental Table S2).One possibility is that the phosphorylation of S254 helps stabilize the interaction of Tob2 with the Ccr4–Not complex, which could contribute to Tob2's ability to recruit the entire Ccr4–Not complex and thus further enhances deadenylation. 	SIGNOR-273602	0.2
asparagine	smallmolecule	CHEBI:22653	ChEBI	Asn-tRNA(Asn)	smallmolecule	CHEBI:29265	ChEBI	up-regulates quantity	precursor of			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270460	0.8
TLK2	protein	Q86UE8	UNIPROT	ASF1A	protein	Q9Y294	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser192	GWSTSENsLNVMLES	9606									20016786	t		Manara	We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 | Consistent	SIGNOR-260787	0.689
ARHGAP40	protein	Q5TG30	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260496	0.407
TCF12	protein	Q99081	UNIPROT	MYOD/HEB	complex	SIGNOR-C128	SIGNOR	form complex	binding			9606									16847330	t	2	miannu	The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation.	SIGNOR-241119	0.66
PRKDC	protein	P78527	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0001949								18439899	t		gcesareni	DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform	SIGNOR-252431	0.745
GRK2	protein	P25098	UNIPROT	PDE6G	protein	P18545	UNIPROT	up-regulates activity	phosphorylation	Thr62	PGMEGLGtDITVICP	9606	BTO:0000007								11502744	t			Rod PDEγ is predominantly phosphorylated by GRK2 at the Thr-62. GRK2 is required for the stimulatory effect of rod PDEγ on both the EGF- and thrombin-dependent activation of p42/p44 MAPK	SIGNOR-251459	0.2
4,4'-sulfonyldiphenol	chemical	CHEBI:34372	ChEBI	AHR	protein	P35869	UNIPROT	up-regulates activity	chemical activation			-1									31995776	t		miannu	This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity.In our study, BPs showed AhR agonist activity only at the highest concentrations, and the mixture did not differ from the single BPs.	SIGNOR-268736	0.8
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	MTSS1	protein	O43312	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								24318128	t		miannu	Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation. 	SIGNOR-276610	0.324
PRKDC	protein	P78527	UNIPROT	XRCC4	protein	Q13426	UNIPROT	up-regulates activity	phosphorylation	Ser328	LETLRNSsPEDLFDE	9606	BTO:0002137								26774286	t		miannu	In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair. 	SIGNOR-277199	0.905
D-ribulose 5-phosphate	smallmolecule	CHEBI:17363	ChEBI	D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	up-regulates quantity	precursor of			9606									34775382	t		miannu	The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux.	SIGNOR-267064	0.8
AR	protein	P10275	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606									15861399	f		miannu	AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation	SIGNOR-251538	0.7
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser23	ARKRHAPsPEPAVQG	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276084	0.283
CHFR	protein	Q96EP1	UNIPROT	SMARCD1	protein	Q96GM5	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0000298								22285184	t		miannu	Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination.	SIGNOR-271459	0.311
IRX1	protein	P78414	UNIPROT	INHBA	protein	P08476	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed.	SIGNOR-261666	0.2
SMARCA4	protein	P51532	UNIPROT	ABCG2	protein	Q9UNQ0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18234970	f		miannu	An increased association of the chromatin remodeling factor, Brg-1, to the ABCG2 promoter was observed consistently in S1 and H460 cells where ABCG2 expression was activated by romidepsin treatment	SIGNOR-255150	0.309
TLX1	protein	P31314	UNIPROT	PPP2CA	protein	P67775	UNIPROT	down-regulates activity	binding			9606	BTO:0000661								15897879	t	2	miannu	HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade.	SIGNOR-240719	0.313
CALM2	protein	P0DP24	UNIPROT	PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	up-regulates	binding			9606									11796223	t	inferred from 70% of family members	miannu	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-269888	0.603
LCK	protein	P06239	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Tyr537	CKNVVPLyDLLLEML	9606									10571988	t		gcesareni	On the basis of these data and other reports describing the structure and activity of y537 mutations, as well as knowledge of the three-dimensional structure of the her ligand binding domain, we propose an alternate model wherein y537f mutation favors an open pocket conformation, affecting the estrogen binding kinetics and stability of the hormone-bound, transcriptionally active closed pocket conformation.	SIGNOR-72373	0.391
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr534	SRTPSLPtPPTREPK	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-251595	0.695
CAMK2A	protein	Q9UQM7	UNIPROT	CACNA1S	protein	Q13698	UNIPROT	up-regulates activity	phosphorylation	Ser1575	PEICRTVsGDLAAEE	-1									20937870	t		miannu	 To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2. 	SIGNOR-263113	0.437
PAC-1	chemical	CID:6851947	PUBCHEM	CASP3	protein	P42574	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-198535	0.8
S1PR3	protein	Q99500	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates	binding			9606									10488065	t		gcesareni	Edg-3 and edg-5 couple not only to gibut also to gqand g13	SIGNOR-70713	0.47
SNRPF	protein	P62306	UNIPROT	U1 snRNP complex	complex	SIGNOR-C480	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270682	0.917
SIRT1	protein	Q96EB6	UNIPROT	nicotinamide	smallmolecule	CHEBI:17154	ChEBI	up-regulates quantity	chemical modification			9606									18662546	t		miannu	The SIRT1 catalytic reaction involves the breakdown of one NAD+ molecule for each deacetylated acetyl lysine and the generation of nicotinamide and O-acetyl-ADP-ribose. 	SIGNOR-267964	0.8
TAF1B	protein	Q53T94	UNIPROT	SL1 complex	complex	SIGNOR-C464	SIGNOR	form complex	binding			9606									30693017	t		lperfetto	SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation.	SIGNOR-269565	0.838
PTPN6	protein	P29350	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates activity	dephosphorylation	Tyr1175	AQQDGKDyIVLPISE	9606									18377662	t			Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175	SIGNOR-248475	0.654
SRC	protein	P12931	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	phosphorylation	Tyr349	EEPPDHQyYNDFPGK	9606									8939605	t		lperfetto	Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway.	SIGNOR-44866	0.651
SOX6	protein	P35712	UNIPROT	MEST	protein	Q5EB52	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003298								26893351	f			 We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST.	SIGNOR-255823	0.2
GSK3B	protein	P49841	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates	phosphorylation	Ser133	LPYSPVSsPQSSPRL	9606									22778263	t		lperfetto	Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity.	SIGNOR-198138	0.276
GABRA4	protein	P48169	UNIPROT	GABA-A (a4-b3-d) receptor	complex	SIGNOR-C327	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263748	0.507
VRK2	protein	Q86Y07	UNIPROT	TRiC	complex	SIGNOR-C539	SIGNOR	down-regulates quantity by destabilization	binding			9606	BTO:0000007								24298020	t		miannu	Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not.The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.COP1 functions as an E3 ligase by forming a supercomplex that also includes heterodimeric substrate receptor DET1, adaptor DDB1, scaffold Cul4A, and RBX1 to recruit the E2 enzyme.The results suggest that VRK2 enables the COP1 complex to efficiently attach ubiquitin on the CCT4 by providing a close interaction between CCT4 and the COP1 complex.	SIGNOR-272875	0.305
SHH	protein	Q15465	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates				9606	BTO:0002314								18662193	f		gcesareni	Shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors myf-5 and myod, decreases the up-regulation of insulin-like growth factor (igf)-1 and reduces the number of myogenic satellite cells at injured site.	SIGNOR-179629	0.42
RAC1	protein	P63000	UNIPROT	PAK1	protein	Q13153	UNIPROT	up-regulates activity	binding			10090	BTO:0000142								8107774	t		gcesareni	A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways.	SIGNOR-248236	0.781
CDK1	protein	P06493	UNIPROT	ZC3HC1	protein	Q86WB0	UNIPROT	down-regulates	phosphorylation	Ser395	PGLEVPSsPLRKAKR	9606			SIGNOR-C17						17389604	t		gcesareni	Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1	SIGNOR-154047	0.256
CDK1	protein	P06493	UNIPROT	UBXN2B	protein	Q14CS0	UNIPROT	down-regulates activity	phosphorylation	Thr59	TVFKSPRtPPQRFYS										23500464	t		lperfetto	At mitosis, Cdc2 kinase phosphorylates p47 on Serine-140 and p37 on Serine-56 and Threonine-59, respectively. The phosphorylated p47 and p37 are unable to bind to Golgi membranes, resulting in mitotic inhibition of the p97/p47 and the p97/p37 pathways, respectively.	SIGNOR-265041	0.2
GDF5	protein	P43026	UNIPROT	BMPR1B	protein	O00238	UNIPROT	up-regulates activity	binding			10090									15890363	t			In contrast to other members of the TGF-beta superfamily, GDF-5 shows a pronounced specificity in type I receptor interaction in cross-link experiments binding only to BMP receptor IB (BMPR-IB). In mice, deletion of either GDF-5 or BMPR-IB results in a similar phenotype, indicating that GDF-5 signaling is highly dependent on BMPR-IB.	SIGNOR-256483	0.777
ATR	protein	Q13535	UNIPROT	MCM4	protein	P33991	UNIPROT	up-regulates	phosphorylation			9606									21070963	t		gcesareni	Together these data strongly support the conclusion that mec1 directly targets the s/tq sites in mcm4 and mcm6, although it is formally possible that mec1 and mrc1 activate a different s/tq-directed kinase to target mcm4 and mcm6.	SIGNOR-169412	0.714
MATK	protein	P42679	UNIPROT	LYN	protein	P07948	UNIPROT	down-regulates activity	phosphorylation	Tyr508	YTATEGQyQQQP	-1									9171348	t		miannu	 In vitro phosphorylation assays showed that Chk suppressed Lyn activity by phosphorylating its C-terminal negative regulatory tyrosine. 	SIGNOR-250177	0.339
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1738	SPSYSPTsPSYSPTS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248744	0.727
AMPK	complex	SIGNOR-C15	SIGNOR	HIPK2	protein	Q9H2X6	UNIPROT	down-regulates activity	phosphorylation	Ser121	LMRRSTVsLLDTYQK										23871434	t	Phosphosite positions are derived from Figure S5	lperfetto	AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro	SIGNOR-275483	0.251
CDK2	protein	P24941	UNIPROT	PTHLH	protein	P12272	UNIPROT	down-regulates	phosphorylation	Thr121	YKEQPLKtPGKKKKG	9606									10373465	t		llicata	Phosphorylation at the cyclin-dependent kinases site (thr85) of parathyroid hormone-related protein negatively regulates its nuclear localization	SIGNOR-68548	0.38
ETS1	protein	P14921	UNIPROT	ECE1	protein	P42892	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000396								9595399	f	 	miannu	 Endothelial expression of endothelin-converting enzyme-1 beta mRNA is regulated by the transcription factor Ets-1. We conclude that Ets-1 is involved in transcriptional upregulation of ECE-1 beta mRNA in E.A. hy 926 cells induced by phorbol ester.	SIGNOR-254080	0.266
Ethylketocyclazocine	chemical	CHEBI:4901	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258780	0.8
Viral_dsRNA	stimulus	SIGNOR-ST21	SIGNOR	IFIH1	protein	Q9BYX4	UNIPROT	up-regulates				9606									19052324	t		miannu	Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ.	SIGNOR-260142	0.7
C5 convertase complex (C3bBbC3b)	complex	SIGNOR-C315	SIGNOR	C5	protein	P01031	UNIPROT	up-regulates activity	cleavage	Arg677	KEILRPRrTLQKKIE	9606		BTO:0000089							26489954	t		lperfetto	In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC).	SIGNOR-263481	0.538
PRKDC	protein	P78527	UNIPROT	PNKP	protein	Q96T60	UNIPROT	up-regulates	phosphorylation	Ser126	PPGTPLVsQDEKRDA	9606									21824916	t		lperfetto	We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro.	SIGNOR-176020	0.636
ANKRD11	protein	Q6UB99	UNIPROT	RAB13	protein	P51153	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000142							29274743	t		miannu	Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons. 	SIGNOR-266738	0.2
verapamil	chemical	CHEBI:9948	ChEBI	SCN2A	protein	Q99250	UNIPROT	down-regulates activity	chemical inhibition			10116									1658608	t		miannu	This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. 	SIGNOR-258355	0.8
PABPC4	protein	Q13310	UNIPROT	NFX1	protein	Q12986	UNIPROT	up-regulates activity	binding			9606	BTO:0000008								17267499	t		Simone	We identifiednew protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) thatinteracted with NFX1-123 through its N-terminal PAM2 motif. Central to our findings were our observations that PABPCs copurify with NFX1-123, that a PAM2 motif is present in NFX1, and this motif and the PABPCs are important in the enhancement of hTERT activity by NFX1-123. 	SIGNOR-261051	0.248
CDK9	protein	P50750	UNIPROT	RCHY1	protein	Q96PM5	UNIPROT	down-regulates	phosphorylation	Thr217	PSEYQNMtVDILCND	9606									23603988	t		lperfetto	We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr.	SIGNOR-201927	0.473
MELK	protein	Q14680	UNIPROT	MELK	protein	Q14680	UNIPROT	up-regulates	phosphorylation	Thr539	RGLDKVItVLTRSKR	9606									16216881	t		lperfetto	We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase.	SIGNOR-141034	0.2
MAPK1	protein	P28482	UNIPROT	NUP50	protein	Q9UKX7	UNIPROT	down-regulates activity	phosphorylation	Ser315	TQSKPVSsPFPTKPL	9606									19767751	t		llicata	Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin.	SIGNOR-188135	0.2
MAP4K4	protein	O95819	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	phosphorylation	Thr322	SNVNRNStIENTRRH	9606	BTO:0002181								21690388	t		miannu	Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation. 	SIGNOR-276335	0.2
KDM6A	protein	O15550	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	demethylation			9606									24561908	t	This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions.	miannu	Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation.	SIGNOR-265360	0.2
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	TNNT2	protein	P45379	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136870	0.34
MTOR	protein	P42345	UNIPROT	DAP	protein	P51397	UNIPROT	down-regulates activity	phosphorylation	Ser51	DQEWESPsPPKPTVF	9606									20537536	t		miannu	 A critical step in autophagy induction comprises the inactivation of a key negative regulator of the process, the Ser/Thr kinase mammalian target of rapamycin (mTOR). Here we identify death-associated protein 1 (DAP1) as a novel substrate of mTOR that negatively regulates autophagy. Mapping of the phosphorylation sites and analysis of phosphorylation mutants indicated that DAP1 is functionally silenced in growing cells through mTOR-dependent phosphorylations on Ser3 and Ser51. 	SIGNOR-259812	0.405
Monobutylphthalate	chemical	CHEBI:88522	ChEBI	PPARG	protein	P37231	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000816								16326050	t		miannu	Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast	SIGNOR-268752	0.8
SMAD2/SMAD4	complex	SIGNOR-C8	SIGNOR	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606									27418133	f			The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines	SIGNOR-253588	0.7
CDK1	protein	P06493	UNIPROT	PP1	proteinfamily	SIGNOR-PF54	SIGNOR	down-regulates activity	phosphorylation			9606									12202491	t		lperfetto	Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity.	SIGNOR-264648	0.557
SP1	protein	P08047	UNIPROT	FMR1	protein	Q06787	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15479157	f		miannu	 we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity.	SIGNOR-255204	0.2
CDK5	protein	Q00535	UNIPROT	LMTK2	protein	Q8IWU2	UNIPROT	down-regulates	phosphorylation			9606									12832520	t		gcesareni	Cprk displays catalytic activity in in vitro kinase assays and is itself phosphorylated by cdk5/p35. Cdk5/p35 inhibits cprk activity.	SIGNOR-102652	0.512
PRKACA	protein	P17612	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation			10090		BTO:0000742							15568017	t		gcesareni	We demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for Wnt-directed myogenic gene expression.	SIGNOR-255799	0.563
CREB5	protein	Q02930	UNIPROT	MX1	protein	P20591	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		 BTO:0002807							21132541	f		miannu	 Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition),	SIGNOR-253800	0.2
pictrelisib	chemical	CHEBI:65326	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606		BTO:0000149							21876152	t		gcesareni	Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed	SIGNOR-252664	0.8
CAPZA1	protein	P52907	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates quantity	binding			9606	BTO:0000132								27871158	t		lperfetto	Finally, the capZ protein recaps the barbed filament ends to complete the assembly and these actin cytoskeletons can be used for cellular contraction, resulting in the final activated platelet shape	SIGNOR-261855	0.7
GSK3A	protein	P49840	UNIPROT	OSBP2	protein	Q969R2	UNIPROT	up-regulates activity	phosphorylation												30925160	t		lperfetto	CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.	SIGNOR-264875	0.2
MAPK3	protein	P27361	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Thr331	CTPVVTCtPSCTAYT	9606									12972619	t		lperfetto	In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity.	SIGNOR-118031	0.707
glycerone phosphate(2-)	smallmolecule	CHEBI:57642	ChEBI	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa).	SIGNOR-268136	0.8
IRX1	protein	P78414	UNIPROT	SPON1	protein	Q9HCB6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002392								20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed.	SIGNOR-261669	0.2
CSNK2A1	protein	P68400	UNIPROT	GYS1	protein	P13807	UNIPROT	unknown	phosphorylation	Ser10	LNRTLSMsSLPGLED	-1									2117608	t		llicata	With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. | From analysis of 32P release during Edman degradation, no radioactively labeled phosphate was associated with Thr3 or Ser7, but could be accounted for by phosphorylation at Ser10	SIGNOR-250878	0.334
panobinostat	chemical	CHEBI:85990	ChEBI	HDAC4	protein	P56524	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257755	0.8
EEF1D	protein	P29692	UNIPROT	EEF1B complex	complex	SIGNOR-C460	SIGNOR	form complex	binding			9606									23699257	t		lperfetto	An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. The requirement for a guanine nucleotide exchange factor, the eEF1B complex, which in metazoans is composed of the subunits α, δ, and γ (also called eEF1B, eEF1D, and eEF1G, respectively)	SIGNOR-269392	0.814
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser100	DEDSGKGsQPPSPPS	9606									15448698	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-129398	0.575
LCK	protein	P06239	UNIPROT	MUC1	protein	P15941	UNIPROT	up-regulates activity	phosphorylation	Tyr1229	SSTDRSPyEKVSAGN	9606									14766232	t		lperfetto	The present results demonstrate that Lck phosphorylation of MUC1 on Y-46 also increases binding of MUC1 and _-catenin. The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 and _-catenin	SIGNOR-247058	0.473
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	SIRT3	protein	Q9NTG7	UNIPROT	up-regulates activity	phosphorylation	Ser159	SGIPDFRsPGSGLYS	9606	BTO:0001109								26141949	t		miannu	 Posttranscriptionally, SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by cyclin B1-CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3. 	SIGNOR-276921	0.295
INPP4B	protein	O15327	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	dephosphorylation			9606									24070612	t		miannu	Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and PTP activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation.|Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and protein tyrosine phosphatase activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation.	SIGNOR-277106	0.383
RPL13	protein	P26373	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262486	0.784
RBM10	protein	P98175	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0001938								30403180	f		irozzo	Osteosarcoma is the most common malignant bone tumor with high incidence in adolescence and poor prognosis. RBM10, a member of RBPs, was reported to be a tumor suppressor in many kinds of cancers. The results showed that U2OS cell growth was significantly inhibited when RBM10 is overexpressed as compared with negative control cells. 	SIGNOR-259149	0.7
ASCL1	protein	P50553	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	up-regulates				10090	BTO:0000938	BTO:0000142							24243019	f		lperfetto	Here we reveal a hierarchical mechanism in the direct conversion of fibroblasts into induced neuronal (iN) cells mediated by the transcription factors Ascl1|Accordingly, Ascl1-mutant mice show severe defects in neurogenesis	SIGNOR-265174	0.7
PTPN2	protein	P17706	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	dephosphorylation			9606									33603165	t		lperfetto	Since PTPN2 dephosphorylates and inactivates Src [ xref ], the increase of pY439 might have resulted from reduced dephosphorylation or elevated Src activity or both.	SIGNOR-276996	0.709
VEZF1	protein	Q14119	UNIPROT	CITED2	protein	Q99967	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0001086								29794136	t		miannu	The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells	SIGNOR-266883	0.2
NFYA	protein	P23511	UNIPROT	CBS	protein	P35520	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12427542	f		miannu	Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response.	SIGNOR-254815	0.2
P2RY4	protein	P51582	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256870	0.357
MICU1	protein	Q9BPX6	UNIPROT	MCU_MICU2_variant	complex	SIGNOR-C502	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270876	0.679
ATF6	protein	P18850	UNIPROT	NUCB1	protein	Q02818	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17686766	f		miannu	 we identified nucleobindin 1 (NUCB1) as a novel repressor of the S1P-mediated ATF6 activation. NUCB1 is an ER stress-inducible gene with the promoter region having functional cis-elements for transcriptional activation by ATF6. 	SIGNOR-253753	0.361
IL1A	protein	P01583	UNIPROT	SERPINA3	protein	P01011	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002600								11027208	f		miannu	We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. 	SIGNOR-254807	0.2
PRSS3	protein	P35030	UNIPROT	F2RL1	protein	P55085	UNIPROT	up-regulates activity	cleavage	Lys34	QGTNRSSkGRSLIGK	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263607	0.373
RAB32	protein	Q13637	UNIPROT	Neuronal AP-3	complex	SIGNOR-C445	SIGNOR	up-regulates activity	relocalization			9606									23247405	t		miannu	Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes.	SIGNOR-268524	0.277
paliperidone	chemical	CHEBI:82978	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258563	0.8
PPM1D	protein	O15297	UNIPROT	KDM1A	protein	O60341	UNIPROT	down-regulates activity	dephosphorylation	Ser131	DESLANLsEDEYYSE	9606	BTO:0002181								25999347	t		miannu	We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites.	SIGNOR-276904	0.478
carfilzomib	chemical	CHEBI:65347	ChEBI	PSMB9	protein	P28065	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000898								17591945	t		miannu	Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM.	SIGNOR-259311	0.8
CSNK2A1	protein	P68400	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates	phosphorylation	Ser112	KRAGGEEsQFEMDI	9606									12588975	t		gcesareni	Phosphorylation at s112 directly affects binding of 4e-bp1 to eif4e without influencing phosphorylation of other sites.	SIGNOR-98280	0.346
ATP	smallmolecule	CHEBI:15422	ChEBI	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates quantity	precursor of			9606									11376933	t		miannu	To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis.	SIGNOR-267842	0.8
CLOCK/BMAL2	complex	SIGNOR-C196	SIGNOR	SERPINE1	protein	P05121	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001615								22198637	t		lperfetto	Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1	SIGNOR-253713	0.498
ELAVL2	protein	Q12926	UNIPROT	ADAM10	protein	O14672	UNIPROT	up-regulates quantity	post transcriptional regulation			9606									19221430	t		miannu	Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure	SIGNOR-266863	0.2
MET	protein	P08581	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr194	ALEKKSNyEVLEKDV	9606									20802513	t		gcesareni	In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain (band 4.1 and ezrin/radixin/moesin homology domain).	SIGNOR-167654	0.475
S1PR5	protein	Q9H228	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256819	0.357
YARS1	protein	P54577	UNIPROT	tyrosine	smallmolecule	CHEBI:18186	ChEBI	down-regulates quantity	chemical modification			9606									16429158	t		miannu	YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr	SIGNOR-270518	0.8
ROCK1	protein	Q13464	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates	phosphorylation	Ser229	VKIYSSNsGPTRRED	9606		BTO:0000672							15793569	t		llicata	In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues.	SIGNOR-134851	0.643
TNFRSF13C	protein	Q96RJ3	UNIPROT	Lymphoma	phenotype	SIGNOR-PH14	SIGNOR	up-regulates				9606	BTO:0000776								24432023	f		lperfetto	Non-canonical nf-kb signaling initiated by baff influences b cell biology at multiple junctures.	SIGNOR-204364	0.7
RBBP8	protein	Q99708	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001130								22832221	f		gcesareni	Brca1/e2f1/ctipbinding to atm promoter activates atm transcription.	SIGNOR-198473	0.823
PRKACA	protein	P17612	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Ser38	LGPGTRLsLARMPPP	-1									2155236	t		miannu	GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments.	SIGNOR-249713	0.286
LY2784544	chemical	CID:46213929	PUBCHEM	JAK2	protein	O60674	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193796	0.8
AURKB	protein	Q96GD4	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									12588998	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.	SIGNOR-98297	0.2
PIK3C3	protein	Q8NEB9	UNIPROT	Vps34 Complex II	complex	SIGNOR-C241	SIGNOR	form complex	binding			-1									30397185	t		lperfetto	PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively.	SIGNOR-260320	0.892
PTGS2	protein	P35354	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates				9606	BTO:0001103								20219869	t		apalma	Furthermore, COX-2 inhibition reduced MyoD expression in regenerating muscle, suggesting a role for COX-2 in modulating muscle differentiation, as well as growth	SIGNOR-256214	0.267
CUDC-101	chemical	CID:24756910	PUBCHEM	HDAC10	protein	Q969S8	UNIPROT	down-regulates activity	chemical inhibition			-1									20143778	t		miannu	By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively.	SIGNOR-262257	0.8
FGF13	protein	Q92913	UNIPROT	SCN3A	protein	Q9NY46	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253443	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	phosphorylation			9606									10464286	t		gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-265345	0.2
bethanechol	chemical	CHEBI:3084	ChEBI	CHRM1	protein	P11229	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258622	0.8
Membrane_blebbing	phenotype	SIGNOR-PH24	SIGNOR	BMI1	protein	P35226	UNIPROT	up-regulates activity	phosphorylation	Ser316	ANRPRKSsVNGSSAT										22505453	t		lperfetto	The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate	SIGNOR-249584	0.7
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ALOX5	protein	P09917	UNIPROT	up-regulates activity	phosphorylation	Ser272	CSLERQLsLEQEVQQ	9606	BTO:0000567								12670876	t		lperfetto	Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells.	SIGNOR-264443	0.2
NRG1	protein	Q02297	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates	binding			9606	BTO:0000150								7514177	t		gcesareni	Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.	SIGNOR-26875	0.784
MAPK14	protein	Q16539	UNIPROT	PTPN7	protein	P35236	UNIPROT	down-regulates activity	phosphorylation	Thr66	EPICSVNtPREVTLH	-1									10206983	t		miannu	The noncatalytic N terminus of HePTP binds Erk and p38 and is phosphorylated at Ser-72 and Thr-45 by these kinases. the N terminus of HePTP binds Erk and p38 but may release them upon phosphorylation.it is clear that phosphorylation of HePTP at Thr-45 and/or Ser-72 is not required for inhibition of MAP kinase. Rather, it seems that phosphorylation has the opposite effect, namely to lessen the inhibitory effect of HePTP. 	SIGNOR-250110	0.584
SATB1	protein	Q01826	UNIPROT	IL23A	protein	Q9NPF7	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000664								17343824	f		miannu	We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 	SIGNOR-255132	0.2
SRC	protein	P12931	UNIPROT	MAPK7	protein	Q13164	UNIPROT	up-regulates				9606		BTO:0000142							11782488	f		gcesareni	C-src was suggested to be involved in bmk1 activation from the experiments with herbimycin a and pp2, specific inhibitors of src family kinases.	SIGNOR-113779	0.351
PAK2	protein	Q13177	UNIPROT	SORT1	protein	Q99523	UNIPROT	down-regulates activity	phosphorylation	Ser793	RFLVHRYsVLQQHAE	9606	BTO:0000007								31767632	t		miannu	PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction. 	SIGNOR-273717	0.2
PLAGL2	protein	Q9UPG8	UNIPROT	SFTPC	protein	P11686	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000353								17618602	f		miannu	 nuclear PLAGL2 occupied and transactivated the endogenous SP-C promoter in lung cells. 	SIGNOR-254927	0.304
MTOR	protein	P42345	UNIPROT	AKT1S1	protein	Q96B36	UNIPROT	down-regulates activity	phosphorylation	Ser183	PTQQYAKsLPVSVPV	-1			SIGNOR-C3	SIGNOR-C3					18372248	t		lperfetto	Pras40 functions as a negative regulator when bound to mtorc1, and it dissociates from mtorc1 in response to insulin. Pras40 has been demonstrated to be a substrate of mtorc1, and one phosphorylation site, ser-183, has been identified.	SIGNOR-178120	0.901
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	MAP3K5	protein	Q99683	UNIPROT	down-regulates	phosphorylation	Ser83	ATRGRGSsVGGGSRR	9606	BTO:0002552								19749799	t		lperfetto	Pim1 phosphorylates and negatively regulates ask1-mediated apoptosispim1 phosphorylation of ask1 on ser83 inhibited ask1-mediated c-jun n-terminal kinase phosphorylation	SIGNOR-259410	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	HOMER3	protein	Q9NSC5	UNIPROT	down-regulates activity	phosphorylation	Ser159	EKLFRSQsADAPGPT	-1									18480293	t		miannu	Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation	SIGNOR-262685	0.2
PRKCA	protein	P17252	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates	phosphorylation	Ser746	RRSVRIGsYIERDVT	9606									7539802	t		miannu	Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity	SIGNOR-28605	0.51
FGR	protein	P09769	UNIPROT	ACO2	protein	Q99798	UNIPROT	unknown	phosphorylation	Tyr665	VVIGDENyGEGSSRE	-1									17997986	t		miannu	Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations.	SIGNOR-262870	0.2
CHEK2	protein	O96017	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Thr387	LMRTLCGtPTYLAPE	9606	BTO:0000007								11901158	t		gcesareni	Phosphorylation of thr-68 by the ataxia telangiectasia-mutated is necessary for efficient activation of chk2 when cells are exposed to ionizing radiation. By an unknown mechanism, this initial event promotes additional autophosphorylation events including modifications of thr-383 and thr-387	SIGNOR-116131	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	SLC9A1	protein	P19634	UNIPROT	up-regulates	phosphorylation	Ser703	MSRARIGsDPLAYEP	9606									10400637	t		gcesareni	The results indicate that p90rsk phosphorylates serine 703 of nhe-1, and this phosphorylation is required for growth factor stimulation of na+/h+ exchange.	SIGNOR-252792	0.2
ACE	protein	P12821	UNIPROT	AGT	protein	P01019	UNIPROT	up-regulates activity	cleavage			9606									11076943	t		gcesareni	Angiotensin I-converting enzyme is a zinc metallopeptidase that plays an important role in blood pressure regulation by cleaving the inactive decapeptide angiotensin I to angiotensin II, a potent vasopressor octapeptide. 	SIGNOR-253326	0.775
PRKCA	protein	P17252	UNIPROT	MARCKS	protein	P29966	UNIPROT	down-regulates activity	phosphorylation	Ser159	KKKKKRFsFKKSFKL	-1									1560845	t		gcesareni	Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin	SIGNOR-243192	0.72
CIB2	protein	O75838	UNIPROT	a7/b1 integrin	complex	SIGNOR-C126	SIGNOR	up-regulates activity	binding			9606									35408910	t		miannu	So far, two integrins have been found to interact with CIB2: αIIbβ3 is expressed by platelets and megakaryocytes and, apparently, a common target for all CIB family members, at odds with α7Bβ1D, which seems to be CIB2-specific and is expressed in skeletal muscles.	SIGNOR-269668	0.2
ELANE	protein	P08246	UNIPROT	SERPIND1	protein	P05546	UNIPROT	down-regulates activity	cleavage	Val458	QATTVTTvGFMPLST	-1									2318847	t		miannu	Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC.	SIGNOR-256510	0.462
NDUFA10	protein	O95299	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 	SIGNOR-262151	0.818
EGFR	protein	P00533	UNIPROT	STAM2	protein	O75886	UNIPROT	unknown	phosphorylation	Tyr192	HTETKSLyPSSEIQL	-1									11687594	t		llicata	Another major tyrosine phosphorylation site of STAM2 was identified as Tyr-192	SIGNOR-251097	0.589
IRF2BP1	protein	Q8IU81	UNIPROT	IRF2	protein	P14316	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								12799427	t		miannu	We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation.	SIGNOR-224045	0.715
PTPRT	protein	O14522	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation			9606									17360477	t		miannu	Here, we report identification of signal transducer and activator of transcription 3 (STAT3) as a substrate of PTPRT. Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position. Accordingly, overexpression of normal PTPRT in colorectal cancer cells reduced the expression of STAT3 target genes.|Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position.	SIGNOR-277043	0.531
ANXA3	protein	P12429	UNIPROT	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	up-regulates activity				9606									26095609	f		miannu	ANXA3 Induces a Feed-Forward Loop that Is Mediated by the MKK4/JNK Signaling Cascade. To substantiate the importance of the JNK/AP-1 pathway in ANXA3-driven HCC, we performed rescue experiments using the JNK-specific inhibitor (JNKi) SP600125. JNKi suppressed the oncogenic properties conferred by ANXA3 overexpression, as evidenced by the diminished abilities of HCC cells to form colonies, migrate, invade, induce angiogenesis, form hepatospheres, and resist apoptosis and chemotherapy (Figures 6F–6J). Interestingly, treatment of parental HCC cells or HCC cells overexpressing ANXA3 with JNKi resulted in not only a reduction in JNK activity and modulation of downstream target genes (c-MYC and p21) but also a marked decrease in ANXA3 expression, suggesting that ANXA3 induces a feed-forward loop that is mediated by MKK4/JNK signaling (Figures 6K–6L).	SIGNOR-262214	0.282
PRKCI	protein	P41743	UNIPROT	FBXW7	protein	Q969H0	UNIPROT	down-regulates activity	phosphorylation	Ser18	KRRRTGGsLRGNPSS	9606	BTO:0000567								28850619	t		miannu	Here, we report that Fbw7α, the only Fbw7 isoform detected in eggs, is phosphorylated by PKC (protein kinase C) at a key residue (S18) in a manner coincident with Fbw7α inactivation.	SIGNOR-277250	0.27
PRRX1	protein	P54821	UNIPROT	MAFF	protein	Q9ULX9	UNIPROT	down-regulates activity	binding			-1									11036080	t		miannu	Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.	SIGNOR-221890	0.36
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates	binding			9606									10949026	t		gcesareni	14-3-3 blocks bad activity by promoting ser-155 phosphorylation, which induces the dissociation of bad and bcl-xl. in the presence of survival factor il-3, cells phosphorylated bad on two serine residues embedded in 14-3-3 consensus binding sites. Only the nonphosphorylated bad heterodimerized with bcl-x(l) at membrane sites to promote cell death.	SIGNOR-81106	0.2
Cyclopamine	chemical	CHEBI:4021	ChEBI	SMO	protein	Q99835	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191227	0.8
RIPK1	protein	Q13546	UNIPROT	DAB2IP	protein	Q5VWQ8	UNIPROT	up-regulates activity	phosphorylation	Ser728	PSPARSSsYSEANEP	9606									27858941	t		miannu	Upon TNF stimulation, RIP1 phosphorylates DAB2IP on Serine 604, inducing a conformational switch that allows formation of the complex.	SIGNOR-254763	0.437
PRKG1	protein	Q13976	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates	phosphorylation	Ser660	FSAERRNsILTETLH	9606									10581361	t		lperfetto	Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function	SIGNOR-72712	0.521
PTPRB	protein	P23467	UNIPROT	TEK	protein	Q02763	UNIPROT	down-regulates activity	dephosphorylation			9606									34417472	t		miannu	Simultaneous inhibition of Tie2 cleavage and VE-PTP synergistically enhances Tie2 activation by up to 10-fold (Fig. 7A).|Tie2 activation is also importantly regulated by vascular endothelial protein tyrosine phosphatase (VE-PTP), which dephosphorylates Tie2 to inhibit its vascular stabilizing effects  .|Tie2 activation is also importantly regulated by vascular endothelial protein tyrosine phosphatase (VE-PTP), which dephosphorylates Tie2 to inhibit its vascular stabilizing effects.	SIGNOR-277059	0.572
CDK5	protein	Q00535	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates activity	phosphorylation	Thr235	YEKDDKLtPKIGFPW	9606	BTO:0000971								12769842	t		llicata	Increased ezrin expression and activation by CDK5 coincident with acquisition of the senescent phenotype.	SIGNOR-250665	0.477
TAF6L	protein	Q9Y6J9	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269587	0.71
ACP1	protein	P24666	UNIPROT	PTK2	protein	Q05397	UNIPROT	down-regulates activity	dephosphorylation			9606									12815062	t		miannu	Lymphocyte function-associated antigen-1-mediated T cell adhesion is impaired by low molecular weight phosphotyrosine phosphatase-dependent inhibition of FAK activity.  4000254={CellProcess=4107155 CellType=10000184}}|Moreover, in these conditions LMW-PTP causes FAK dephosphorylation, thus preventing the activation of FAK downstream pathways.	SIGNOR-277064	0.28
GSDMD	protein	P57764	UNIPROT	Pyroptosis	phenotype	SIGNOR-PH105	SIGNOR	up-regulates									cleavage:Asp275	CLHNFLTdGVPAEGA			26375003	f		lperfetto	These results establish that proteolytic cleavage at Asp275 in GSDMDis sufficient to instructmammalian cells to undergo pyroptosis	SIGNOR-256416	0.7
GATA4	protein	P43694	UNIPROT	CTNNA3	protein	Q9UI47	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002320								21598020	t		miannu	 GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter	SIGNOR-265490	0.253
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	CDKN2D	protein	P55273	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17873901	f		gcesareni	Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity	SIGNOR-252918	0.2
PTPRJ	protein	Q12913	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Tyr1197	STAENAEyLRVAPQS	9606	BTO:0000567								19836242	t			We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173	SIGNOR-248699	0.504
CSNK2A1	protein	P68400	UNIPROT	PACS1	protein	Q6VY07	UNIPROT	up-regulates activity	phosphorylation	Ser278	SPDIDNYsEEEEESF	10090	BTO:0003532								14633983	t		llicata	Phosphorylation of Ser278 by CK2 or a Ser278-->Asp mutation increased the interaction between PACS-1 and cargo, whereas a Ser278-->Ala substitution decreased this interaction. Moreover, the Ser278-->Ala mutation yields a dominant-negative PACS-1 molecule that selectively blocks retrieval of PACS-1-regulated cargo molecules to the TGN.	SIGNOR-250925	0.562
SGK1	protein	O00141	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation	Ser1130	GARDRVRsMSGGHGL	-1									27451907	t		miannu	SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2. 	SIGNOR-277266	0.597
CKM complex	complex	SIGNOR-C406	SIGNOR	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates quantity by destabilization	phosphorylation			9606									15546612	t		gcesareni	Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.	SIGNOR-273153	0.379
POU5F1	protein	Q01860	UNIPROT	DNMT1	protein	P26358	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22795133	t		lperfetto	Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation	SIGNOR-253158	0.45
MYBBP1A	protein	Q9BQG0	UNIPROT	B-WICH complex	complex	SIGNOR-C447	SIGNOR	form complex	binding			9606									21559432	t		miannu	The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 	SIGNOR-268821	0.468
MTMR3	protein	Q13615	UNIPROT	1-phosphatidyl-1D-myo-inositol(1-)	smallmolecule	CHEBI:57880	ChEBI	up-regulates quantity	chemical modification			9606									18429927	t		miannu	PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 	SIGNOR-269811	0.8
MDM2	protein	Q00987	UNIPROT	POLQ	protein	O75417	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0001890								22056306	t		miannu	DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation	SIGNOR-272729	0.2
CAMK2D	protein	Q13557	UNIPROT	ANKRD28	protein	O15084	UNIPROT	down-regulates activity	phosphorylation	Ser1011	TNTSKTVsFEALPIM	-1									17023142	t		lperfetto	We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K	SIGNOR-264793	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates	phosphorylation	Thr41	GIHSGATtTAPSLSG	9606									19667122	t		lperfetto	Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta.	SIGNOR-187582	0.2
CDK2	protein	P24941	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation			9606			SIGNOR-C16						21902831	t		gcesareni	Cycline/cdk2 blocks myod-induced gene expression through the phosphorylation of rb, preventing rb from binding and transactivating myod, and triggering s phase entry instead of differentiation.	SIGNOR-176512	0.879
LYN	protein	P07948	UNIPROT	PDIA3	protein	P30101	UNIPROT	unknown	phosphorylation	Tyr445	ANDVPSPyEVRGFPT	-1									8631326	t		miannu	Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s).	SIGNOR-262894	0.2
MITF	protein	O75030	UNIPROT	TYRP1	protein	P17643	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000847								22371403	f		miannu	 MITF transcription factor regulates melanogenesis by activation of tyrosinase, TRP1 and TRP2 transcription.	SIGNOR-254591	0.503
KDM1A	protein	O60341	UNIPROT	CoREST-HDAC complex	complex	SIGNOR-C105	SIGNOR	form complex	binding			9606	BTO:0000567								11171972	t		miannu	Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function.	SIGNOR-222121	0.74
ENO1	protein	P06733	UNIPROT	2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	down-regulates quantity	chemical modification			9606									29767008	t		miannu	Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits.	SIGNOR-266528	0.8
TNF	protein	P01375	UNIPROT	TNFRSF1B	protein	P20333	UNIPROT	up-regulates activity	binding												17151142	t			These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling	SIGNOR-253592	0.928
PRKCA	protein	P17252	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser7	sSSSYRRM	-1									2500966	t		lperfetto	We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65.	SIGNOR-248886	0.289
USP37	protein	Q86T82	UNIPROT	CCNA2	protein	P20248	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0000007								21596315	t		lperfetto	USP37 Binds, Deubiquitinates, and Stabilizes Cyclin A	SIGNOR-265052	0.562
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270368	0.8
CAMK2B	protein	Q13554	UNIPROT	ETS1	protein	P14921	UNIPROT	down-regulates activity	phosphorylation	Ser282	NSLQRVPsYDSFDSE		BTO:0003637								12475968	t		llicata	Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1 	SIGNOR-250686	0.313
SRC	protein	P12931	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	down-regulates activity	phosphorylation	Tyr374	PLPPAPAyLSSPLAL	9606	BTO:0000007								23131831	t		miannu	Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation. 	SIGNOR-276370	0.426
PFKFB2	protein	O60825	UNIPROT	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	up-regulates				9606									20640476	f		lperfetto	The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes.	SIGNOR-209950	0.7
PRKCA	protein	P17252	UNIPROT	RAB37	protein	Q96AX2	UNIPROT	down-regulates activity	phosphorylation	Thr172	YGVPFLEtSAKTGMN	9606	BTO:0002877								29312551	t	done	miannu	We also show that Rab37 is phosphorylated by protein kinase Cα (PKCα) at threonine 172 (T172), leading to attenuation of its GTP-bound state, and impairment of the Rab37-mediated exocytosis of TIMP1, and thus reduces its suppression activity on lung cancer cell motility. 	SIGNOR-273803	0.2
SMO	protein	Q99835	UNIPROT	GNG2	protein	P59768	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-199183	0.357
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	SREBF1	protein	P36956	UNIPROT	up-regulates	phosphorylation	Ser439	AGSPFQSsPLSLGSR	9606									16880739	t		lperfetto	Cdk1/cyclin b-mediated phosphorylation stabilizes srebp1 during mitosis.	SIGNOR-216821	0.281
FASTKD5	protein	Q7L8L6	UNIPROT	Stress_granules	phenotype	SIGNOR-PH124	SIGNOR	up-regulates				9606									25683715	f		miannu	DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. 	SIGNOR-261226	0.7
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr37	PPGDYSTtPGGTLFS	9606									23486913	t		lperfetto	These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation	SIGNOR-217110	0.753
MAPK1	protein	P28482	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Ser381	CIPTAGMsPSRSNTI	10029	BTO:0000246								15379552	t		lperfetto	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-249395	0.584
PRKCB	protein	P05771	UNIPROT	CD5	protein	P06127	UNIPROT	unknown	phosphorylation	Thr436	FHRNHTAtVRSHAEN	9606	BTO:0000661								11123317	t		lperfetto	Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. 	SIGNOR-249075	0.364
BRSK1	protein	Q8TDC3	UNIPROT	TUBG1	protein	P23258	UNIPROT	up-regulates	phosphorylation	Ser131	READGSDsLEGFVLC	9606									19648910	t	The effect has been demonstrated using Q8TDC3-2	llicata	Sadb kinases associate and phosphorylate gamma-tubulin on ser 131 s131d gamma-tubulin expression amplifies centrosome duplication	SIGNOR-187405	0.251
MTOR	protein	P42345	UNIPROT	AKT1S1	protein	Q96B36	UNIPROT	down-regulates activity	phosphorylation	Ser221	DLDRIAAsMRALVLR	-1			SIGNOR-C3	SIGNOR-C3					18372248	t		lperfetto	We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competitionwe also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1.	SIGNOR-178128	0.901
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270384	0.8
veliparib	chemical	CHEBI:62880	ChEBI	PARP2	protein	Q9UGN5	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189224	0.8
CSNK2A1	protein	P68400	UNIPROT	ATF1	protein	P18846	UNIPROT	down-regulates	phosphorylation	Ser38	QVSSLSEsEESQDSS	9606									20730097	t		lperfetto	These data suggested that atf1 is always hyperphosphorylated on the ck sites in vivo. Also, the antibody reactivity suggested that in addition to ser-36 and ser-41, ser-38 and ser-44 were phosphorylated in vivo. To accommodate these findings, we propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression.	SIGNOR-167548	0.3
CTDSP2	protein	O14595	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	dephosphorylation			9606									16882717	t		lpetrilli	In human cells, rnai-mediated depletion of scp1 and scp2 increases the extent and duration of smad1 phosphorylation in response to bmp, the transcriptional action of smad1, and the strength of endogenous bmp gene responses. The present identification of the scp family as smad c-terminal phosphatases sheds light on the events that attenuate smad signaling and reveals unexpected links to the essential phosphatases that control rna polymerase ii in eukaryotes.	SIGNOR-148434	0.477
TFDP1	protein	Q14186	UNIPROT	PCNA	protein	P12004	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253858	0.462
LYN	protein	P07948	UNIPROT	PDIA3	protein	P30101	UNIPROT	unknown	phosphorylation	Tyr467	KKLNPKKyEGGRELS	-1									8631326	t		miannu	Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s).	SIGNOR-262896	0.2
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1672	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273046	0.556
WNT5B	protein	Q9H1J7	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131888	0.622
AP-1 complex	complex	SIGNOR-C248	SIGNOR	AP-1/clathrin vescicle	complex	SIGNOR-C251	SIGNOR	form complex	binding			9606									23103167	t		lperfetto	Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors	SIGNOR-260674	0.559
PTPN11	protein	Q06124	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	down-regulates activity	dephosphorylation	Tyr1474	GSSNGHVyEKLSSIE	9606									32140036	t		lperfetto	In addition, surface expression of GluN2B was not reduced in mutant mice and it remains to be investigated how the direct dephosphorylation of GluN2B Y1252 by Shp2 reduces GluN2B function.|The increased GluN2B Y1472 phosphorylation was reversed by a Src family kinase inhibitor, suggesting that Shp2 may negatively regulate GluN2B Y1472 phosphorylation through suppressing Src activity .	SIGNOR-276950	0.481
CDK1	protein	P06493	UNIPROT	RRM2	protein	P31350	UNIPROT	unknown	phosphorylation	Ser20	DPQQLQLsPLKGLSL	9606									9990288	t		llicata	Ribonucleotide reductase r2 protein is phosphorylated at serine-20 by p34cdc2 kinase. comparison of ribonucleotide reductase activities between wild type and mutated forms of the r2 proteins suggested that mutation at serine-20 did not significantly affect enzyme activity.	SIGNOR-64312	0.518
PCGF2	protein	P35227	UNIPROT	HSF2	protein	Q03933	UNIPROT	down-regulates activity	sumoylation			9606	BTO:0000007								18211895	t		miannu	MEL-18, in contrast to the polycomb protein PC2/CBX4, in which SUMO E3 activity stimulates sumoylation of certain proteins, actually functions like an anti-SUMO E3 protein, interacting with both HSF2 and the SUMO E2 UBC9 but acting to inhibit UBC9 activity and thereby decreasing sumoylation of a target protein, in this case that of HSF2. sumoylation of HSF2 is up-regulated during mitosis and is important for the interaction of this factor with a subunit of the condensin complex during the bookmarking process	SIGNOR-226245	0.33
CDKN1B	protein	P46527	UNIPROT	Cell_cycle_block	phenotype	SIGNOR-PH10	SIGNOR	up-regulates				9606									18423396	f		fspada	Moreover, expression of p27(kip1), an inhibitor of the cell cycle, was down regulated in an akt1/pkbalpha-specific manner during adipocytedifferentiation.	SIGNOR-178278	0.7
GLI1	protein	P08151	UNIPROT	GLI1/GLI2	complex	SIGNOR-C450	SIGNOR	form complex	binding			9606	BTO:0000304								32766732	t	GLI2 and GLI1 heterodimerize via the Zn-finger domain	SimoneGraziosi	GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. 	SIGNOR-269209	0.434
EGLN3	protein	Q9H6Z9	UNIPROT	BCL2L11	protein	O43521-1	UNIPROT	up-regulates quantity by stabilization	hydroxylation	Pro70	PLAPPASpGPFATRS	9606									31375625	t		lperfetto	EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance|EglN3 Hydroxylates BIM-EL at the Proline67/70 Residues	SIGNOR-262004	0.257
MAPK1	protein	P28482	UNIPROT	SOS1	protein	Q07889	UNIPROT	down-regulates activity	phosphorylation	Ser1197	KAYSPRYsISDRTSI	9534									8816480	t		lperfetto	In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1	SIGNOR-235929	0.702
NRG1	protein	Q02297	UNIPROT	ERBB3	protein	P21860	UNIPROT	up-regulates	binding			9606	BTO:0000150								7514177	t		gcesareni	The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4 direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.	SIGNOR-26878	0.868
N-(6-Chloro-7-methoxy-9H-pyrido[3,4-b]indol-8-yl)-2-methylnicotinamide	chemical	CID:9929127	PUBCHEM	IKBKB	protein	O14920	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258249	0.8
TG101209	chemical	CHEBI:90304	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207260	0.8
sirolimus	chemical	CHEBI:9168	ChEBI	CD86	protein	P42081	UNIPROT	down-regulates quantity by repression				9606									18652845	f		miannu	Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells.	SIGNOR-255479	0.8
SRC	protein	P12931	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates	phosphorylation	Tyr265	KDCGSQKyAYFNGCS	9606									16916748	t		lperfetto	The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites.	SIGNOR-148917	0.608
KAT5	protein	Q92993	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269297	0.775
VBP1	protein	P61758	UNIPROT	Prefoldin co-chaperone	complex	SIGNOR-C513	SIGNOR	form complex	binding			9606									32699605	t		miannu	The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6)	SIGNOR-270935	0.952
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	TET2	protein	Q6N021	UNIPROT	up-regulates activity	binding			9606									25699704	t		irozzo	A second group of AML patients (15%–33% of all cases) harbor mutations in either the isocitrate dehydrogenase (IDH) 1 or 2 gene (Shih et al., 2012). These enzymes produce α-ketoglutarate (α-KG), which is required for TET activity.	SIGNOR-255706	0.8
3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide	chemical	CHEBI:92223	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-202807	0.8
DAB2IP	protein	Q5VWQ8	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	binding			9606	BTO:0001033								26512963	t		miannu	DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. 	SIGNOR-254761	0.354
hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	GABA-A (a4-b1-g2) receptor	complex	SIGNOR-C333	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000938								26136660	t		miannu	The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 	SIGNOR-264923	0.8
tolazoline	chemical	CHEBI:28502	ChEBI	ADRA2A	protein	P08913	UNIPROT	down-regulates activity	chemical inhibition			9606									9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258912	0.8
ROCK1	protein	Q13464	UNIPROT	ARHGAP35	protein	Q9NRY4	UNIPROT	down-regulates activity	phosphorylation	Thr1226	LRSLRRNtKKPKPKP	9534	BTO:0000298								19103606	t		miannu	 these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells 	SIGNOR-276178	0.425
A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257705	0.595
PAK4	protein	O96013	UNIPROT	FH	protein	P07954	UNIPROT	down-regulates quantity	phosphorylation	Ser46	PNAARMAsQNSFRIE	9606	BTO:0002058								30683654	t		miannu	 FH is massively phosphorylated at the Ser 46 by PAK4 in non-small cell lung cancer (NSCLC) cells, and PAK4-phosphorylated FH binds to 14-3-3, resulting in cytosolic detention of FH and prohibition of FH/CSL/p53 complex formation. 	SIGNOR-266315	0.2
SMAD7	protein	O15105	UNIPROT	PPP1CA	protein	P62136	UNIPROT	up-regulates	binding			9606									16571110	t		gcesareni	Smad7, induced by alk1 activation, recruits pp1? To alk1 and thereby inhibits tgf-?/Alk1-induced smad1/5 phosphorylation in ecs	SIGNOR-145389	0.405
TFEB	protein	P19484	UNIPROT	NDUFA8	protein	P51970	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4).	SIGNOR-276702	0.2
CREB5	protein	Q02930	UNIPROT	MAPKAPK3	protein	Q16644	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		 BTO:0002814							21132541	f		miannu	 Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition),	SIGNOR-253807	0.253
PPP1CA	protein	P62136	UNIPROT	MECOM	protein	Q03112	UNIPROT	down-regulates activity	dephosphorylation	Ser1037	IGNSNHGsQSPRNVE										23858473	t	phosphorylation site remapping based on Fig 5	lperfetto	We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. 	SIGNOR-273429	0.2
serotonin	smallmolecule	CHEBI:28790	ChEBI	AANAT	protein	Q16613	UNIPROT	up-regulates activity	chemical activation			-1									22775292	t		miannu	Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS.	SIGNOR-265477	0.8
RET	protein	P07949	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	phosphorylation	Tyr315	TFCGTPEyLAPEVLE	9606									15994200	t		lperfetto	The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity	SIGNOR-166514	0.329
GSK2126458	chemical	CID:25167777	PUBCHEM	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252645	0.8
BTK	protein	Q06187	UNIPROT	GTF2I	protein	P78347	UNIPROT	up-regulates activity	phosphorylation	Tyr503	EAHPNDLyVEGLPEN	9534									11373296	t		lperfetto	These residues, tyr248, tyr357, and tyr462, were also found to be the major sites for btk-dependent phosphorylation of bap/tfii-i in vivo. Residues tyr357 and tyr462 are contained within the loop regions of adjacent helix-loop-helix-like repeats within bap/tfii-i. Mutation of either tyr248, tyr357, or tyr462 to phenylalanine reduced transcription from a c-fos promoter relative to wild-type bap/tfii-i in transfected cos-7 cells, consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation.	SIGNOR-108346	0.532
BMPR1A	protein	P36894	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates	phosphorylation	Ser465	HNPISSVs	9606									9136927	t		fspada	Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro	SIGNOR-249649	0.721
GSK3B	protein	P49841	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	phosphorylation	Ser468	AVFTDLAsVDNSEFQ	9606	BTO:0000782			SIGNOR-C13					16407239	t		gcesareni	Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) .	SIGNOR-143581	0.364
JUN	protein	P05412	UNIPROT	Brown_adipogenesis	phenotype	SIGNOR-PH27	SIGNOR	up-regulates				9606		BTO:0000887;BTO:0001103							22944199	f		gcesareni	Other g protein-mediated pathways are the planar cell polarity (pcp) pathway (shown in blue) leading to the activation of rac/rho, c-jun n-terminal kinase (jnk), and/or rho-associated kinase (rock). Jnk can induce jun, which, together with fos, forms the ap-1 early response transcription factor. Both pcp pathways have been implicated in cytoskeletal rearrangements	SIGNOR-198834	0.7
PRKDC	protein	P78527	UNIPROT	PNKP	protein	Q96T60	UNIPROT	up-regulates	phosphorylation	Ser114	EETRTPEsQPDTPPG	9606									21824916	t		lperfetto	We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro.	SIGNOR-176016	0.636
FPR2	protein	P25090	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256888	0.409
Ionizing radiation	stimulus	SIGNOR-ST16	SIGNOR	TRIM13	protein	O60858	UNIPROT	up-regulates				9606	BTO:0000007								21333377	f		miannu	These data suggest that irradiation causes RFP2 overexpression, which enhances ionizing radiation-induced apoptosis by increasing p53 stability and decreasing AKT kinase activity through MDM2 and AKT degradation.	SIGNOR-271854	0.7
MAP3K8	protein	P41279	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates	phosphorylation	Ser222	LIDSMANsFVGTRSY	9606									8131746	t		gcesareni	Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf	SIGNOR-36449	0.556
SYK	protein	P43405	UNIPROT	LCK	protein	P06239	UNIPROT	down-regulates activity	phosphorylation	Tyr192	NLDNGGFyISPRITF	9606	BTO:0000782								8798764	t		lperfetto	Our experiments indicate that the TCR-induced activation of Erk2 depends on the function of SH2 domain of Lck and is reduced by phosphorylation of wild type Lck at Tyr192 or by mutation of this site to a negatively charged amino acid. Such dependence on the SH2 domain has also been reported for the bulk of TCR-induced tyrosine phosphorylation and activation of the interleukin 2 gene (26). Thus, phosphorylation of Lck at Tyr192 may represent a negative feedback mechanism in the interplay between Src and Syk family PTKs in TCR signaling	SIGNOR-246562	0.573
BRCA1	protein	P38398	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0002572								19074868	t		gcesareni	The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation	SIGNOR-252458	0.521
MAPK1	protein	P28482	UNIPROT	PARVA	protein	Q9NVD7	UNIPROT	up-regulates activity	phosphorylation	Ser8	MATSPQKsPSVPKSP	9606	BTO:0001938								22955285	t		lperfetto	Actopaxin (alpha-parvin) is a paxillin, integrin-linked kinase, and F-actin binding focal adhesion protein with several serine phosphorylation sites in the amino terminus that contribute to the regulation of cell spreading and migration.|Actopaxin phosphorylation of Ser4/8 enhances cell migration whereas a nonphosphorylatable (Quint) mutant suppresses migration in U2OS osteosarcoma cells (7).	SIGNOR-265759	0.262
MARK3	protein	P27448	UNIPROT	ARHGEF2	protein	Q92974	UNIPROT	up-regulates activity	phosphorylation	Ser151	LSLAKSVsTTNIAGH	9606	BTO:0002181								29089450	t		miannu	Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser151 This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules.	SIGNOR-277368	0.392
RXRB	protein	P28702	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates	binding			9606									10976919	t	inferred from family member	gcesareni	Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr	SIGNOR-270297	0.641
PPP3CB	protein	P16298	UNIPROT	KSR2	protein	Q6VAB6	UNIPROT	up-regulates activity	dephosphorylation	Thr290	NKLKPPGtPPPSSRK	10090									19560418	t			These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3	SIGNOR-248381	0.262
CUL9	protein	Q8IWT3	UNIPROT	FERMT2	protein	Q96AC1	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								35469017	t		miannu	M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2.	SIGNOR-276717	0.2
NFE2L2	protein	Q16236	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0000599								26194347	f		irozzo	Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes.	SIGNOR-256263	0.7
DDX3X	protein	O00571	UNIPROT	PABPC1	protein	P11940	UNIPROT	up-regulates activity	binding			9606									21883093	t		miannu	In the present study, we indentified the SG marker PABP1 [poly(A)-binding protein 1] as another direct interaction partner of DDX3. Interestingly, down-regulation of DDX3 interfered with SG assembly, led to nuclear accumulation of PABP1 and reduced cell viability following stress. Conversely, supplementation with a shRNA (short hairpin RNA)-resistant DDX3 restored SG formation, the translocation of PABP1 into SGs and cell survival. 	SIGNOR-269201	0.588
HOXA9	protein	P31269	UNIPROT	MEIS1	protein	O00470	UNIPROT	up-regulates activity	binding			-1									9343407	t	2	miannu	We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets.	SIGNOR-241162	0.641
ADAM10	protein	O14672	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates activity	cleavage			9606									28624438	t		miannu	One of the most important and best characterized ADAM10 substrates is the Notch receptor [16]. After ligand binding to the Notch receptor, ADAM10 liberates the ectodomain and the membrane remaining part is processed by the γ-secretase complex, which releases a Notch Intracellular Domain (NICD). 	SIGNOR-259836	0.773
MAPK3	protein	P27361	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates	phosphorylation	Ser360	TEMDPTYsPAALPQS	9606									15568999	t		gcesareni	In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758.	SIGNOR-131379	0.567
SOX6	protein	P35712	UNIPROT	COL2A1	protein	P02458	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10980415	f		miannu	Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Two other members of the Sox family, L-Sox5 and Sox6, also bind to the 48-bp Col2a1 enhancer and together with Sox9 activate this enhancer as well as the endogenous Col2a1 	SIGNOR-251760	0.431
KLF3	protein	P57682	UNIPROT	KLF8	protein	O95600	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090		BTO:0000759							18687676	t		Luana	Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly. 	SIGNOR-266049	0.258
UBA52	protein	P62987	UNIPROT	PRKN	protein	O60260	UNIPROT	up-regulates activity	binding			10090	BTO:0002572				phosphorylation: ser65	DYNIQKEsTLHLVLR			24784582	t			The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator.	SIGNOR-270344	0.2
MECP2	protein	P51608	UNIPROT	DLL1	protein	O00548	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									25420914	t		Luana	As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1 	SIGNOR-264674	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PPARG	protein	P37231	UNIPROT	up-regulates activity	phosphorylation	Ser112	AIKVEPAsPPYYSEK	9606									11733495	t		gcesareni	Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells.	SIGNOR-232236	0.2
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1766	SPSYSPTsPSYSPTS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248814	0.849
NOX5	protein	Q96PH1	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	up-regulates quantity	chemical modification			9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264725	0.8
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	MAPK1	protein	P28482	UNIPROT	up-regulates activity	phosphorylation			10090									11730323	t			Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs	SIGNOR-258990	0.2
HLA-G	protein	P17693	UNIPROT	KIR2DL4	protein	Q99706	UNIPROT	up-regulates	binding			9606									10190900	t		gcesareni	Recombinant soluble kir2dl4 binds to cells expressing hla-g but not to cells expressing other hla class i molecules.	SIGNOR-66132	0.756
FGF9	protein	P31371	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22298955	f	FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1	gcesareni	Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts	SIGNOR-195594	0.313
PSMD12	protein	O00232	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263352	0.914
KAT2A	protein	Q92830	UNIPROT	H3-4	protein	Q16695	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269604	0.2
CIITA	protein	P33076	UNIPROT	HLA-F	protein	P30511	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								11137213	f	 	 	HLA-E is inducible by CIITA through the SXY regulatory module. HLA-F is inducible by NF-kappaB through the kappaB1 site of enhancer A, is responsive to IFN-gamma through the ISRE, and is inducible by CIITA	SIGNOR-254018	0.453
(S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide	chemical	CID:6918848	PUBCHEM	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			9606									31908417	t		miannu	The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs.	SIGNOR-262250	0.8
GSK3B	protein	P49841	UNIPROT	SPAG5	protein	Q96R06	UNIPROT	up-regulates	phosphorylation	Thr978	AEMSIMTtELQSLCS	9606									18055457	t		lperfetto	Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta	SIGNOR-159586	0.274
MAPK15	protein	Q8TD08	UNIPROT	MAPK15	protein	Q8TD08	UNIPROT	up-regulates	phosphorylation	Thr175	GPEDQAVtEYVATRW	9606									16336213	t		lperfetto	Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif.Our results suggest that the activity of erk8 in transfected hek-293 cells depends on the relative rates of erk8 autophosphorylation	SIGNOR-142969	0.2
PTPRF	protein	P10586	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates	dephosphorylation	Tyr531	FTATEPQyQPGENL	9606									12496362	t		gcesareni	Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule.	SIGNOR-96764	0.405
entinostat	chemical	CHEBI:132082	ChEBI	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257905	0.8
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1696	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120104	0.316
PRKACB	protein	P22694	UNIPROT	GPKOW	protein	Q92917	UNIPROT	up-regulates activity	phosphorylation	Thr316	GTASSRKtLWNQELY										21880142	t		miannu	Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2.PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites.	SIGNOR-266298	0.311
KIFC1	protein	Q9BW19	UNIPROT	CENPE	protein	Q02224	UNIPROT	up-regulates activity	binding			9606	BTO:0000948								33361741	t		miannu	We found that KIFC1 could directly bind to CENPE in SKOV3 cells (Figure 4C, 4D).	SIGNOR-266116	0.554
PRKACA	protein	P17612	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606	BTO:0000782								19836308	t		lperfetto	Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3alpha or ser9 in gsk3beta. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).	SIGNOR-188577	0.54
NIN	protein	Q8N4C6	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates	binding			9606									25332239	t		miannu	We showed that jak2 directly phosphorylates the n-terminus ofnineinwhile the c-terminus ofnineininhibits jak2 kinase activity in vitro.	SIGNOR-205581	0.244
RRM1	protein	P23921	UNIPROT	Ribonucleotide reductase	complex	SIGNOR-C233	SIGNOR	form complex	binding			9606									14583450	t		miannu	Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2.	SIGNOR-259363	0.93
BAK1	protein	Q16611	UNIPROT	HTRA2	protein	O43464	UNIPROT	up-regulates	relocalization			9606									14585074	t	Translocation from Mitochondria to Cytosol	amattioni	Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi	SIGNOR-118908	0.3
docetaxel anhydrous	chemical	CHEBI:4672	ChEBI	TUBA4A	protein	P68366	UNIPROT	down-regulates activity	chemical inhibition			9606									23337758	t		miannu	Tubulin exists in the cell as dimers of α and β subunits, which complexes with a variety of regulatory proteins. There is a dynamic equilibrium between free and polymerized tubulin causing a state called "dynamic instability," which is a target of anticancer drugs, which inhibit tubulin through polymerization (taxanes, epothilones) or depolymerization (vinca alkaloids). Docetaxel-based therapy was the first such treatment to demonstrate a survival benefit in men with castration-resistant prostate cancer. 	SIGNOR-259342	0.8
MAP2K1	protein	Q02750	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates activity	phosphorylation			10090									11730323	t			Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs	SIGNOR-258994	0.741
CHEK1	protein	O14757	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser178	LFTQRQNsAPARMLS	9606									20068082	t		gcesareni	The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts);	SIGNOR-163138	0.852
RPS20	protein	P60866	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262430	0.872
M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	IL10	protein	P22301	UNIPROT	up-regulates				9606	BTO:0000801								32454942	f		miannu	Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation	SIGNOR-263823	0.7
SRC	protein	P12931	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates	phosphorylation	Tyr199	ELLEQQKyTVTVDYW	9606				SIGNOR-C14					12645577	t		gcesareni	These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation.	SIGNOR-99318	0.369
MAPK1	protein	P28482	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Thr444	RFIGSPRtPVSPVKF	9606		BTO:0000887;BTO:0001103							11705993	t		gcesareni	The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain.	SIGNOR-111511	0.578
YBX1	protein	P67809	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001023								17072343	f		miannu	 YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. 	SIGNOR-255610	0.329
GNRH1	protein	P01148	UNIPROT	EGR1	protein	P18146	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									19106114	f		miannu	GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. 	SIGNOR-254917	0.456
GATA1	protein	P15976	UNIPROT	GP9	protein	P14770	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002581								15466856	f	 	miannu	Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. 	SIGNOR-254161	0.363
SRC	protein	P12931	UNIPROT	ARHGDIB	protein	P52566	UNIPROT	unknown	phosphorylation	Tyr153	YGPRPEEyEFLTPVE	9606									19321744	t		llicata	Studies confirmed that activated src kinase binds and phosphorylates rhogdi2 in vitro and vivo. Mutagenesis revealed that tyr-153 and, to a lesser degree, tyr-24 were the primary src phosphorylation sites. Phosphorylation decreased the amount of rac1 in rhogdi2 complexes and increased rhogdi2 association with cell membranes.	SIGNOR-184908	0.405
AREL1	protein	O15033	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys191	RNHIQLVkLQVEEVH	9606	BTO:0002552								31732561	t		lperfetto	AREL1 ubiquitinated SMAC, primarily on Lys62 and Lys191 |E701A substitution in the AREL1 HECT domain substantially increased its autopolyubiquitination and SMAC ubiquitination activity, whereas deletion of the last three amino acids at the C terminus completely abrogated AREL1 autoubiquitination and reduced SMAC ubiquitination.	SIGNOR-267672	0.386
ASIP	protein	P42127	UNIPROT	MC4R	protein	P32245	UNIPROT	down-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268708	0.515
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	LRP6	protein	O75581	UNIPROT	up-regulates activity	phosphorylation	Ser1490	AILNPPPsPATERSH	10090	BTO:0002572								16341017	t		gcesareni	Glycogen synthase kinase 3 (gsk3), which is known for its inhibitory role in wnt through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of lrp6. We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.	SIGNOR-228014	0.723
AKT2	protein	P31751	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity	phosphorylation			9606									17277771	t		lperfetto	Furthermore, pras40 phosphorylation by akt and association with 14-3-3, a cytosolic anchor protein, are crucial for insulin to stimulate mtor. These findings identify pras40 as an important regulator of insulin sensitivity of the akt-mtor pathway and a potential target for the treatment of cancers, insulin resistance and hamartoma syndromes.	SIGNOR-235967	0.568
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	FLNA	protein	P21333	UNIPROT	up-regulates	phosphorylation	Ser2152	TRRRRAPsVANVGSH	9606	BTO:0000848								15024089	t		gcesareni	We show that the n-terminal kinase domain of rsk phosphorylates flna on ser(2152) in response to mitogens	SIGNOR-252790	0.2
GPHN	protein	Q9NQX3	UNIPROT	NLGN2	protein	Q8NFZ4	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								25882190	t		miannu	Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses.	SIGNOR-264974	0.488
ABL1	protein	P00519	UNIPROT	STX17	protein	P56962	UNIPROT	down-regulates activity	phosphorylation	Tyr157	SQSLTQIyALPEIPQ	9534	BTO:0001538								23006999	t		miannu	C-Abl was identified as one of the kinases, which phosphorylates syntaxin 17.Western blot shows phosphorylation of syntaxin 17 on Tyr-156 by overexpression and activation of c-Abl. A phospho-mimicking mutant (Y156E) of syntaxin 17 showed reduced interaction with COPI vesicles. These results suggest that tyrosine phosphorylation of syntaxin 17 is likely to have a role in regulating syntaxin 17 dependent membrane trafficking in the early secretory pathway.	SIGNOR-273538	0.2
PIP5K1A	protein	Q99755	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates				9606									18772438	f		gcesareni	Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. In turn, ptdins (4,5)p2 regulated phosphorylation of lrp6 at thr1479 and ser1490	SIGNOR-180800	0.276
NFIX	protein	Q14938	UNIPROT	NEUROD1	protein	Q13562	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268904	0.268
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	MEF2D	protein	Q14814	UNIPROT	down-regulates	binding			9606									21902831	t		lperfetto	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-216966	0.268
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	Synaptic_vesicle_exocytosis	phenotype	SIGNOR-PH160	SIGNOR	up-regulates				9606	BTO:0000938								11988172	f		miannu	Ca(2+) influx through voltage-gated channels initiates the exocytotic fusion of synaptic vesicles to the plasma membrane. 	SIGNOR-264355	0.7
MAPKAPK2	protein	P49137	UNIPROT	ETV1	protein	P50549	UNIPROT	down-regulates activity	phosphorylation	Ser191	HRFRRQLsEPCNSFP	452646									11551945	t		miannu	MK2 phosphorylates ER81 in vitro within its central inhibitory domain, and overexpression of MK2 leads to increased in vivo phosphorylation of ER81. Two serine residues, ER81 amino acids 191 and 216, were identified as MK2 phosphorylation sites. MK2 suppresses basal ER81-dependent transcription	SIGNOR-250145	0.595
PRKCE	protein	Q02156	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates activity	phosphorylation	Ser706	ARIIGEKsFRRSVVG										12058027	t		lperfetto	Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.	SIGNOR-275961	0.2
PAK5	protein	Q9P286	UNIPROT	TCF3	protein	P15923	UNIPROT	up-regulates activity	phosphorylation	Ser39	NGKGRPAsLAGAQFG	9606	BTO:0000150								26212009	t		lperfetto	The p21-activated kinase 5 (PAK5) is overexpressed in advanced cancer and the transcription factor E47 is a direct repressor of E-cadherin and inducer of epithelial-mesenchymal transition (EMT). |In this study, we found that PAK5-mediated E47 phosphorylation promoted EMT in advanced colon cancer. PAK5 interacted with E47 and phosphorylated E47 on Ser39 under hepatocyte growth factor (HGF) stimulation	SIGNOR-275653	0.2
TRAC	protein	P01848	UNIPROT	TCR	complex	SIGNOR-C153	SIGNOR	form complex	binding			9606									12507424	t		miannu	The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ	SIGNOR-255297	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	YBX1	protein	P67809	UNIPROT	up-regulates	phosphorylation	Ser102	NPRKYLRsVGDGETV	9606	BTO:0000150								19036157	t		lperfetto	Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102	SIGNOR-182493	0.2
SPOP	protein	O43791	UNIPROT	TRIM24	protein	O15164	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								25278611	t		miannu	Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. 	SIGNOR-272825	0.345
HOXD3	protein	P31249	UNIPROT	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002828								14610084	t		Luana	The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis.	SIGNOR-261650	0.253
MARCHF9	protein	Q86YJ5	UNIPROT	HLA-DQB1	protein	P01920	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001522								19457934	t		miannu	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. 	SIGNOR-271539	0.2
precursor messenger RNA	smallmolecule	CHEBI:139356	ChEBI	SF3b	complex	SIGNOR-C442	SIGNOR	up-regulates activity	relocalization			9606									32140746	t		lperfetto	The SF3b complex is an intrinsic component of the functional U2 small nuclear ribonucleoprotein (snRNP). As U2 snRNP enters nuclear pre-mRNA splicing, SF3b plays key roles in recognizing the branch point sequence (BPS) and facilitating spliceosome assembly and activation. 	SIGNOR-268413	0.8
EFNA2	protein	O43921	UNIPROT	EPHA4	protein	P54764	UNIPROT	up-regulates	binding			9606									9330863	t		tpavlidou	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52203	0.921
CDK1	protein	P06493	UNIPROT	MPLKIP	protein	Q8TAP9	UNIPROT	up-regulates	phosphorylation	Ser104	SQQQFGYsPGQQQTH	9606									17310276	t		lperfetto	Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1	SIGNOR-153300	0.348
PRKD1	protein	Q15139	UNIPROT	ATP7B	protein	P35670	UNIPROT	up-regulates activity	phosphorylation	Ser478	APDILAKsPQSTRAV	9606	BTO:0000599								21189263	t		lperfetto	ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking.	SIGNOR-272296	0.302
INSR	protein	P06213	UNIPROT	PIK3R3	protein	Q92569	UNIPROT	unknown	phosphorylation	Tyr341	NEDADENyFINEEDE	9606		BTO:0000142;BTO:0000671							7542745	t		llicata	This pattern of 32p-tyr release unambiguously identified tyr-341 in p55pik as a major in vitro phosphorylation site.	SIGNOR-28791	0.61
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates quantity by destabilization	cleavage	Leu664	ATVIVITlVMLKKKQ	-1									8943232	t		lperfetto	The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261784	0.502
Z-RNA	stimulus	SIGNOR-ST29	SIGNOR	ZBP1	protein	Q9H171	UNIPROT	up-regulates activity	binding			10090									32200799	t		gianni	Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis.	SIGNOR-266432	0.7
AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								15919192	f		miannu	Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1–4); five kainate receptor genes (GluR5–7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits.	SIGNOR-264695	0.7
GPR35	protein	Q9HC97	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257283	0.2
IRAK4	protein	Q9NWZ3	UNIPROT	IRAK4	protein	Q9NWZ3	UNIPROT	up-regulates activity	phosphorylation	Thr342	ASEKFAQtVMTSRIV	9606	BTO:0000876								24567333	t		lperfetto	We show irak4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues thr-342, thr-345, and ser-346 is required for full activity	SIGNOR-204657	0.2
PPARG	protein	P37231	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates				10090									16150867	f		lperfetto	Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor	SIGNOR-228622	0.7
MAPK1	protein	P28482	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	unknown	phosphorylation	Ser696	EKNYALPsPATTEGG	9606				SIGNOR-C3					21071439	t		llicata	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-169514	0.533
PCSK7	protein	Q16549	UNIPROT	PPP2CA	protein	P67775	UNIPROT	up-regulates	phosphorylation			9606									11259586	t		gcesareni	This together with the rapid kinetics of pp1-pp2a activation following p38 activation suggests that pp1 and/or pp2a complexes are direct targets for p38-mediated phosphorylation	SIGNOR-105783	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	FBXO43	protein	Q4G163	UNIPROT	up-regulates activity	phosphorylation	Ser192	NLEKNIPsSASGFSR	-1									16407128	t		Manara	CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. | these results implicate the 192RSST motif of Emi2 as a critical molecular target of CaMKII during CSF release	SIGNOR-260907	0.381
PIM1	protein	P11309	UNIPROT	PSMD2	protein	Q13200	UNIPROT	up-regulates activity	phosphorylation	Ser361	ENNRFGGsGSQVDSA	-1									31843888	t	done	miannu	Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B). 	SIGNOR-273895	0.2
CDK1	protein	P06493	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates	phosphorylation	Ser123	EEGFGSSsPVKSPAA	9606									15070733	t		gcesareni	We have found also that the major M-phase kinases polo-like kinase 1 (Plk1) and Cdc2 are responsible for the phosphorylation of S53 and S123, respectively, and that in each case phosphorylation generates an unconventional phospho-degron (signal for degradation) that can be recognized by beta-TrCP	SIGNOR-123824	0.854
phosphatidylinositol bisphosphate	smallmolecule	CHEBI:37328	ChEBI	CADPS2	protein	Q86UW7	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								24363652	t		miannu	CAPS exhibits low affinity but functionally significant interactions with plasma membrane PIP2 via its central PH (pleckstrin homology) domain (82, 111). PIP2 enhanced CAPS stimulation of SNARE-dependent liposome fusion with wild-type but not with mutant PH domain CAPS proteins	SIGNOR-264335	0.8
HDAC2	protein	Q92769	UNIPROT	CIITA	protein	P33076	UNIPROT	down-regulates quantity by repression	deacetylation			9606	BTO:0000801;BTO:0004576								19041327	t		miannu	We report that CIITA and histone deacetylase 2 (HDAC2) interact in smooth muscle cells and macrophages as assayed by co-immunoprecipitations. HDAC2 deacetylates CIITA whereas both the HDAC inhibitor trichostatin A (TSA) and over-expression of HDAC2 interfering RNA increase CIITA acetylation. HDAC2 down-regulates CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays, and suppresses MHC II activation and collagen repression mediated by CIITA in luciferase reporter assays.	SIGNOR-254231	0.423
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates activity	chemical activation			10116	BTO:0000759								2158622	t	inferred from family member	miannu	We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 	SIGNOR-270300	0.8
NLGN4X	protein	Q8N0W4	UNIPROT	NRXN3	protein	Q9HDB5	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264170	0.76
CDKL5	protein	O76039	UNIPROT	CDKL5	protein	O76039	UNIPROT	up-regulates activity	phosphorylation	Thr169	EGNNANYtEYVATRW	-1									16935860	t		gcesareni	Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif.	SIGNOR-262289	0.2
MAPK3	protein	P27361	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates activity	phosphorylation	Thr739	SEGSGTAtPSALITT	9606									14744793	t		lperfetto	Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.|this activation promotes the phosphorylation of Sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased Sp1 binding and enhanced p21(waf1/cip1) transcription. 	SIGNOR-249481	0.638
AKT1	protein	P31749	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation	Ser939	SFRARSTsLNERPKS	10090	BTO:0000944								12150915	t		lperfetto	We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines.	SIGNOR-235511	0.811
RPL10	protein	P27635	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates	binding			9606									12138090	t		miannu	The qm gene encodes a 24.5 kda ribosomal protein l10 known to be highly homologous to a jun-binding protein (jif-1), which inhibits the formation of jun-jun dimers.	SIGNOR-90750	0.397
A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	TNF	protein	P01375	UNIPROT	up-regulates quantity by expression				9606									24241034	f		lperfetto	Importantly, autocrine and paracrine interactions of alpha9beta1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-alpha± and IL-1beta in synovial macrophages.	SIGNOR-253315	0.317
NEUROG3	protein	Q9Y4Z2	UNIPROT	VSX2	protein	P58304	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19028584	f		miannu	Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated.	SIGNOR-254635	0.277
PRKD3	protein	O94806	UNIPROT	PAK4	protein	O96013	UNIPROT	up-regulates activity	phosphorylation	Ser474	KEVPRRKsLVGTPYW										23841590	t		lperfetto	PAK4 activity is regulated by an autoinhibitory domain that is released upon RhoGTPase binding as well as phosphorylation at Ser474 in the activation loop of the kinase domain. In the present study, we add another level of complexity to PAK4 regulation by showing that phosphorylation at Ser99 is required for its targeting to the leading edge. This phosphorylation is mediated by PKD1 (protein kinase D1)	SIGNOR-275931	0.255
UNC5A	protein	Q6ZN44	UNIPROT	PICK1	protein	Q9NRD5	UNIPROT	up-regulates activity	binding			10116	BTO:0003036								16554470	t		miannu	Recently, our laboratory showed that UNC5A is coimmunoprecipitated with PICK1 and PKCα. Moreover, we demonstrated that the association of PKCα with UNC5A depends on the activation of PKCα and the ability of UNC5A to bind PICK1 	SIGNOR-268181	0.293
SLC24A3	protein	Q9HC58	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	down-regulates quantity	relocalization			9606									30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264391	0.8
ADRA1B	protein	P35368	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256807	0.484
CSNK1D	protein	P48730	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	phosphorylation	Ser335	YDSFGEPsYPEVFEP	-1									9558331	t		llicata	In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites.	SIGNOR-250802	0.371
MSH2	protein	P43246	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates activity				10090									9500552	f			Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer	SIGNOR-257594	0.7
NR3C1	protein	P04150	UNIPROT	KLF15	protein	Q9UIH9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002572								20956975	f		lperfetto	We identified glucocorticoid response element sites in the first intron of KLF15 by bioinformatical promoter analysis and confirmed their functional relevance by demonstrating GR interaction by chromatin immunoprecipitation	SIGNOR-236212	0.385
YY1	protein	P25490	UNIPROT	COX7C	protein	P15954	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9092564	f		miannu	 Mutation of both YY1 sites eliminates most of the promoter activity. Mutation at the upstream YY1 site significantly reduces the efficiency of transcript initiation at the major start site and thus plays the dominant role in COX7C regulation.	SIGNOR-255617	0.26
SMDT1	protein	Q9H4I9	UNIPROT	MCU_MICUB_variant	complex	SIGNOR-C499	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270861	0.619
FFAR2	protein	O15552	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256946	0.2
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	up-regulates activity	phosphorylation	Thr46	GGTLFSTtPGGTRII	9606	BTO:0001109								36882522	t		lperfetto	CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. 	SIGNOR-273114	0.2
SIRT1	protein	Q96EB6	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								20713551	f		miannu	Overexpression of SIRT1 enhanced both FoxO reporter activity and nuclear levels of FoxO1. Protein expression of MDR1 and gene transcriptional activity were also up-regulated by SIRT1 overexpression. 	SIGNOR-255139	0.26
COP1	protein	Q8NHY2	UNIPROT	MTA1	protein	Q13330	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0001938								19805145	t		miannu	Here we report that MTA1 is an ubiquitinated protein and targeted by the RING-finger E3 ubiquitin-protein ligase constitutive photomorphogenesis protein 1 (COP1) for degradation via the ubiquitin-proteasome pathway.	SIGNOR-271891	0.2
regorafenib	chemical	CHEBI:68647	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			9606									26254357	t		miannu	A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF	SIGNOR-259180	0.8
MTMR2	protein	Q13614	UNIPROT	1-phosphatidyl-1D-myo-inositol(1-)	smallmolecule	CHEBI:57880	ChEBI	up-regulates quantity	chemical modification			9606									18429927	t		miannu	PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 	SIGNOR-269808	0.8
CXCL1	protein	P09341	UNIPROT	PLCE1	protein	Q9P212	UNIPROT	up-regulates	binding			9606									17251915	t		gcesareni	In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor.	SIGNOR-152591	0.2
CEBPB	protein	P17676	UNIPROT	PCK2	protein	Q16822	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000608								8093246	f		miannu	C/EBP beta can regulate PEPCK gene transcription by acting through the CRE and that C/EBP beta, together with CREB, may contribute to the cAMP responsiveness of the PEPCK promoter.	SIGNOR-253773	0.334
CYFIP1	protein	Q7L576	UNIPROT	WAVE complex	complex	SIGNOR-C271	SIGNOR	form complex	binding			9606	BTO:0000567								15070726	t		lperfetto	Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex. 	SIGNOR-261873	0.903
MAPK1	protein	P28482	UNIPROT	PCBP2	protein	Q15366	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser189	YRPKPSSsPVIFAGG	9606	BTO:0000664								17475908	t		miannu	We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 	SIGNOR-262911	0.324
CHD2	protein	O14647	UNIPROT	XRCC4	protein	Q13426	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0001938								26895424	t		miannu	CHD2 Promotes the Recruitment of Core NHEJ Factors. overexpression of ATPase-dead CHD2 (K515R; Figure S5F), but not wild-type CHD2, also reduced the recruitment of XRCC4 (Figure 5E). Together, these findings suggest that the chromatin remodeling activity of CHD2 promotes the efficient assembly of NHEJ complexes at DSBs.	SIGNOR-264528	0.2
SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	Myog/SWI/SNF complex	complex	SIGNOR-C94	SIGNOR	form complex	binding			9606		BTO:0001103							17194702	t		miannu	Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle	SIGNOR-151706	0.541
PRKACG	protein	P22612	UNIPROT	PHKA1	protein	P46020	UNIPROT	down-regulates activity	phosphorylation			9606									10487978	t			Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.	SIGNOR-267415	0.307
PRKN	protein	O60260	UNIPROT	HSD17B10	protein	Q99714	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9534	BTO:0000298								25591737	t		miannu	 This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-β hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate.	SIGNOR-272823	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	NLRP3 inflammasome	complex	SIGNOR-C225	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									28531279	f		miannu	The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3	SIGNOR-260328	0.361
nintedanib	chemical	CHEBI:85164	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									18559524	t		Luana	In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers.	SIGNOR-257802	0.8
(S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide	chemical	CID:6918848	PUBCHEM	HDAC10	protein	Q969S8	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002428								31908417	t		miannu	The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs.	SIGNOR-262252	0.8
JMJD1C	protein	Q15652	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	demethylation			9606	BTO:0000007								32034158	t		miannu	We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state.	SIGNOR-265331	0.2
MASP1	protein	P48740	UNIPROT	C2	protein	P06681	UNIPROT	up-regulates activity	cleavage	Ser20	LYPGLADsAPSCPQN	9606	BTO:0000392								11907111	t		lperfetto	The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase	SIGNOR-263420	0.516
RAPGEF2	protein	Q9Y4G8	UNIPROT	RAP1A	protein	P62834	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0002181								24290981	t		miannu	Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity.Increased intracellular concentrations of cAMP enhanced the Rapgef2-dependent activation of Rap1, which in turn associated with B-Raf to enable the activation of ERK and subsequent neuronal- and endocrine-specific cellular outcomes, such as induction of neuroendocrine-specific genes and extension of neuritic processes (neuritogenesis).	SIGNOR-276609	0.786
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SP3	protein	Q02447	UNIPROT	up-regulates	phosphorylation			9606									17685427	t	inferred from 70% family members	gcesareni	Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73.	SIGNOR-270165	0.2
SNTB2	protein	Q13425	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255993	0.474
CDC25B	protein	P30305	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates activity	dephosphorylation	Thr14	IEKIGEGtYGVVYKG	9606									25384584	t		lperfetto	CDC25B facilitates dephosphorylation of the key cell cycle regulator CDC2 (also called CDK1) at Tyr15 or Thr14, thereby initiating the G 2 /M transition ( xref ).|CDC25B facilitates dephosphorylation of the key cell cycle regulator CDC2 (also called CDK1) at Tyr15 or Thr14, thereby initiating the G2/M transition ( ).	SIGNOR-276969	0.823
USP22	protein	Q9UPT9	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606									26049753	t			USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells.	SIGNOR-261561	0.551
MT-CO3	protein	P00414	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267743	0.673
CHD8	protein	Q9HCK8	UNIPROT	MLL/SET subcomplex	complex	SIGNOR-C87	SIGNOR	up-regulates activity	binding			9606	BTO:0000946								20085832	t		miannu	Chromodomain, helicase, DNA-binding protein 8 (CHD8) is an ATP-dependent chromatin remodeling enzyme that has been demonstrated to exist within a large protein complex which includes WDR5, Ash2L, and RbBP5, members of the Mixed Lineage Leukemia (MLL) histone modifying complexes. CHD8 forms a complex with the core WDR5/Ash2L/RbBP5 complex. CHD8 is required for recruitment of the WAR complex	SIGNOR-268807	0.427
FLT3	protein	P36888	UNIPROT	PIM2	protein	Q9P1W9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15769897	f			The serine-threonine kinase Pim-2 is a functionally relevant downstream target of STAT5.24 Here, we observed only a weak induction of Pim-2 by Flt3-D835Y compared to the effects of Flt3-ITD.	SIGNOR-261541	0.344
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CDC25B	protein	P30305	UNIPROT	up-regulates	phosphorylation	Ser160	PVRLLGHsPVLRNIT	9606									12107172	t		lperfetto	We demonstrate that serine 146 is required for two crucial features of cdc25b1. It is essential for cdc25b1 to function as a mitotic inducer and to prevent cdc25b1 export from the nucleus. We also show that serine 146 is phosphorylated in vitro by cdk1-cyclin b. Serine 146 phosphorylation is proposed to be a key event in the regulation of the cdc25b function	SIGNOR-216753	0.759
BMPR1B	protein	O00238	UNIPROT	STAMBP	protein	O95630	UNIPROT	up-regulates activity	phosphorylation	Ser48	VEIIRMAsIYSEEGN	9534	BTO:0000298								11483516	t		llicata	BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads.	SIGNOR-250600	0.294
MAPK9	protein	P45984	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9606	BTO:0000938								12040039	t		gcesareni	Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Jnk2/3 activity selectively targets c-jun.	SIGNOR-88208	0.881
PTEN	protein	P60484	UNIPROT	NFIL3	protein	Q16649	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11494141	f		miannu	Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 	SIGNOR-260055	0.2
APLNR	protein	P35414	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256681	0.412
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PGR	protein	P06401	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000150								10655479	t	inferred from 70% family members	gcesareni	Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation.	SIGNOR-270040	0.2
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	HNF4A	protein	P41235	UNIPROT	down-regulates quantity by repression				9606									9792724	f		miannu	Retinoic acid mediates down-regulation of the alpha-fetoprotein gene through decreased expression of hepatocyte nuclear factors. The levels of HNF1 and HNF4 mRNA were also decreased following RA treatment.	SIGNOR-254445	0.8
SIRT2	protein	Q8IXJ6	UNIPROT	MYCN	protein	P04198	UNIPROT	up-regulates quantity by stabilization				9606									23175188	f		miannu	Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation.	SIGNOR-255147	0.385
RET	protein	P07949	UNIPROT	RET	protein	P07949	UNIPROT	up-regulates	phosphorylation	Tyr1096	RYPNDSVyANWMLSP	9606									14711813	t		llicata	Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites.	SIGNOR-121149	0.2
LCK	protein	P06239	UNIPROT	ADAM15	protein	Q13444	UNIPROT	up-regulates	phosphorylation	Tyr735	LKGPTCQyRAAQSGP	9606									11741929	t		lperfetto	Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling.	SIGNOR-112935	0.356
PRKG1	protein	Q13976	UNIPROT	RGS2	protein	P41220	UNIPROT	up-regulates activity	phosphorylation	Ser46	KDWKTRLsYFLQNSS	-1									14608379	t		lperfetto	Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction. 	SIGNOR-249240	0.671
SRC	protein	P12931	UNIPROT	GRK2	protein	P25098	UNIPROT	up-regulates activity	phosphorylation	Tyr13	AVLADVSyLMAMEKS	9606	BTO:0000007								16725308	t		miannu	Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq. 	SIGNOR-266307	0.2
TGFB1	protein	P01137	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates activity	binding			9606									22326956	t		giulio giuliani	In Tgfbr2fl/fl control MEPM cells, radioactive TGF-β2 ligands (12.5 kDa) bind to TβRI (53 kDa), TβRII (70 kDa), and TβRIII (100–200 kDa, highly glycosylated molecule) and form the ligand-receptor complexes of TβRI::TGF-β2 (65.5 kDa), TβRII::TGF-β2 (82.5 kDa), and TβRIII::TGF-β2 (112.5–212.5 kDa)	SIGNOR-255960	0.84
AXIN1	protein	O15169	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	form complex	binding			9606	BTO:0000586								9734785	t		lperfetto	Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level.	SIGNOR-227292	0.93
CASP8	protein	Q14790	UNIPROT	CASP7	protein	P55210	UNIPROT	up-regulates	cleavage			9606									18073771	t		amattioni	Active caspase-8 then proteolytically processes and activates caspase-7	SIGNOR-159853	0.729
H4C1	protein	P62805	UNIPROT	Nucleosome_H2A.Z.1 variant	complex	SIGNOR-C322	SIGNOR	form complex	binding			-1									24311584	t		miannu	In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined.	SIGNOR-263718	0.2
PRPS1	protein	P60891	UNIPROT	Nucleotide_synthesis	phenotype	SIGNOR-PH179	SIGNOR	up-regulates				9606	BTO:0006038								29074724	f		lperfetto	We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production.	SIGNOR-265733	0.7
CSNK1G2	protein	P78368	UNIPROT	LYN	protein	P07948	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser13	SKGKDSLsDDGVDLK	9606	BTO:0000007								33004926	t		miannu	Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane.	SIGNOR-275397	0.2
NSD3	protein	Q9BZ95	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	methylation	Lys366	RLVMVLysVVPTC	9606	BTO:0002181								29101251	t		irozzo	We found that lysine methyltransferase NSD3 interacts with and directly monomethylates IRF3 in the nucleus, leading to the enhanced IRF3 transcriptional activity and antiviral immune responses. 	SIGNOR-259198	0.2
GOLGB1	protein	Q14789	UNIPROT	GOLGA2	protein	Q08379	UNIPROT	up-regulates activity	binding			9606									23555793	t		miannu	The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane.	SIGNOR-261238	0.761
TP53	protein	P04637	UNIPROT	CYCS	protein	P99999	UNIPROT	up-regulates				9606									19007744	f	Translocation from Mitochondria to Cytosol	lperfetto	P53 translocation precedes changes of mitochondrial membrane potential, cytochrome c release and caspase activation	SIGNOR-140251	0.47
GABPB1	protein	Q06547	UNIPROT	HCFC1	protein	P51610	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								10675337	t		miannu	The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1–GABP interaction can inhibit GABP_dependent transcriptional activation	SIGNOR-221377	0.334
FYN	protein	P06241	UNIPROT	BCR-Ml	complex	SIGNOR-C434	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000776								32323266	t		scontino	The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases.	SIGNOR-268210	0.619
TFEB	protein	P19484	UNIPROT	CLCN7	protein	P51798	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19556463	f	Figure 1	lperfetto	Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 	SIGNOR-276536	0.335
beta-carboline	chemical	CHEBI:109895	ChEBI	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	up-regulates activity	chemical activation			9606		BTO:0000227							18790874	t	brain	lperfetto	The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005).	SIGNOR-263805	0.8
FOXO1	protein	Q12778	UNIPROT	NPY	protein	P01303	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000614								28270795	f		miannu	 Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations. 	SIGNOR-263502	0.411
PPP3CA	protein	Q08209	UNIPROT	PPP1R1A	protein	Q13522	UNIPROT	unknown	dephosphorylation	Ser67	LKSTLAMsPRQRKKM	10116									11278334	t			In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation.	SIGNOR-248693	0.392
quizartinib	chemical	CHEBI:90217	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258271	0.8
MELK	protein	Q14680	UNIPROT	CDC25B	protein	P30305	UNIPROT	down-regulates activity	phosphorylation	Ser219	HALAEWAsRREAFAQ	9606	BTO:0001938								12400006	t			In the present study we show that the human pEg3 kinase is able to specifically phosphorylate CDC25B in vitro. One phosphorylation site was identified and corresponded to serine 323[Ä] Taken together these results suggest that pEg3 is a potential regulator of the G2/M progression and may act antagonistically to the CDC25B phosphatase	SIGNOR-255655	0.549
FBN1	protein	P35555	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates quantity	binding			9606									17242066	t	Regulation of localization	miannu	We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFbeta signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling.	SIGNOR-251888	0.504
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	RANBP3	protein	Q9H6Z4	UNIPROT	up-regulates quantity	phosphorylation	Ser57	HGTGHPEsAGEHALE	9606	BTO:0000007								18280241	t		miannu	Akt phosphorylates RanBP3 at Serine 58 residue in vitro and in vivo. RanBP3 phosphorylation increases its affinity towards Ran	SIGNOR-276150	0.2
CARD9	protein	Q9H257	UNIPROT	BCL10	protein	O95999	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								11053425	t			To identify upstream signaling partners of BCL10, we performed a mammalian two-hybrid analysis and identified CARD9 as a novel CARD-containing protein that interacts selectively with the CARD activation domain of BCL10. When expressed in cells, CARD9 binds to BCL10 and activates NF-kappaB.	SIGNOR-257602	0.751
3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	THRA	protein	P10827	UNIPROT	up-regulates activity	binding			9606		BTO:0001073							29407449	t		scontino	T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb.	SIGNOR-267255	0.8
SRC	protein	P12931	UNIPROT	STAT5B	protein	P51692	UNIPROT	up-regulates	phosphorylation	Tyr679	DRPKDEVySKYYTPV	9606									12621061	t		llicata	Stat5 is activated by a broad spectrum of cytokines, as well as non-receptor tyrosine kinases, such as src. these conformational differences may in part be due to differential effects of prl and src on stat5b tyrosine phosphorylation, since src induced several additional sites of tyrosine phosphorylation of stat5b at residues other than tyr-699, including tyr-724 and tyr-679.	SIGNOR-99002	0.597
CAMKK2	protein	Q96RR4	UNIPROT	CAMK1	protein	Q14012	UNIPROT	up-regulates activity	phosphorylation	Thr177	DPGSVLStACGTPGY										7641687	t		llicata	Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase.	SIGNOR-250716	0.422
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	CAPN2	protein	P17655	UNIPROT	up-regulates	phosphorylation			9606									14993287	t	inferred from 70% family members	lperfetto	Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo.	SIGNOR-270078	0.2
MAPK8IP2	protein	Q13387	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates	binding			9606									10490659	t		gcesareni	Both jip1 and jip2 selectively bind the mapkk isoform mkk7.	SIGNOR-70857	0.668
APP	protein	P05067	UNIPROT	GSK3A	protein	P49840	UNIPROT	up-regulates				9606	BTO:0000938								16446437	f		gcesareni	These results suggest a direct relationship between app proteolytic processing, but not amyloid-_, in gsk-3_ activation and tau phosphorylation in human neurons.	SIGNOR-144057	0.419
CAMK2A	protein	Q9UQM7	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Ser38	LGPGTRLsLARMPPP	-1									7822264	t		llicata	On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II.	SIGNOR-250628	0.438
thiocyanate	smallmolecule	CHEBI:18022	ChEBI	Cell_killing	phenotype	SIGNOR-PH149	SIGNOR	up-regulates				9606		BTO:0000133							9922160	f		lperfetto	Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. The enzyme uses hydrogen peroxide to oxidize chloride (Cl-), bromide (Br-), iodide (I-), and the pseudohalide thiocyanate (SCN-) to their respective hypohalous acids.| Our results show that thiocyanate is an important substrate of myeloperoxidase in most environments and that hypothiocyanate is likely to contribute to leukocyte antimicrobial activity.	SIGNOR-270592	0.7
PPP2CB	protein	P62714	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Thr185	HDHTGFLtEYVATRW	10116									7780739	t			Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts. 	SIGNOR-248590	0.456
LYN	protein	P07948	UNIPROT	FCGR2C	protein	P31995	UNIPROT	up-regulates activity	phosphorylation	Tyr310	TDDDKNIyLTLPPND	-1									8756631	t		miannu	Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation	SIGNOR-262676	0.2
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	down-regulates				9606									20966922	f			 APL cells closely resemble normal promyelocytes, a specific stage of the granulocytic differentiation pathway, suggesting that PML–RARα blocks the normal myeloid differentiation programme.	SIGNOR-255724	0.7
MIF	protein	P14174	UNIPROT	CXCR2	protein	P25025	UNIPROT	up-regulates activity	binding			10090									17435771	t		gcesareni	We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF [] By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis.	SIGNOR-252061	0.392
EEF1A2	protein	Q05639	UNIPROT	Cys-tRNA(Cys)	smallmolecule	CHEBI:29152	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269528	0.8
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1616	TPQSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273104	0.745
PRKACA	protein	P17612	UNIPROT	IMMT	protein	Q16891	UNIPROT	down-regulates activity	phosphorylation	Ser528	ELQFRRLsQEQVDNF	-1									27153535	t		miannu	PKA directly phosphorylated the Ser528 residue of MIC60. Phosphorylation of MIC60 Interrupts Parkin Recruitment and Formation of the MICOS Complex	SIGNOR-266302	0.2
HMG20B	protein	Q9P0W2	UNIPROT	BHC complex	complex	SIGNOR-C353	SIGNOR	form complex	binding			9606	BTO:0000567; BTO:0000007								15325272	t		miannu	BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells	SIGNOR-264503	0.764
PRKCA	protein	P17252	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates activity	phosphorylation	Ser346	EWEAQRDsHLGPHRS	9606									14576165	t		lperfetto	A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis.	SIGNOR-249236	0.267
gamma-secretase	complex	SIGNOR-C98	SIGNOR	DSCAML1	protein	Q8TD84	UNIPROT	down-regulates quantity	cleavage			9606	BTO:0000938								30745319	t		miannu	γ‐secretase‐mediated intra‐membrane cleavage of DSCAM receptors results in the release of the DSCAM ICD, which is likely proceeded by shedding of the DSCAM ectodomain. Interaction of IPO5 with the NLS of DSCAM then leads to importin‐mediated nuclear import of the DSCAM ICD. In the nucleus, the DSCAM ICD may regulate the transcription of genes involved in neuronal development and function, thereby regulating processes such as neurite outgrowth, branching, and repulsion, as well as synapse formation, axon guidance, and neuronal cell death and survival.	SIGNOR-264272	0.2
DUSP23	protein	Q9BVJ7	UNIPROT	GCM1	protein	Q9NP62	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser322	NYPFPLTsWPCSFSP	9606									20855292	t		lperfetto	DUSP23 prevents GCM1 from ubiquitination and prolongs the half-life of GCM1.|Second, DUSP23 is able to dephosphorylate Ser322 in GCM1 in vitro and in a stable cell line expressing HA-GCM1.	SIGNOR-276982	0.477
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser291	CGSSGYFsSSPTLSS	9606									22017877	t		lperfetto	We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1	SIGNOR-252799	0.2
GSK1016790A	chemical	CID:23630211	PUBCHEM	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates activity	binding												23021218	t		lperfetto	We next examined whether chemical activation of TRPV4 would have the opposite impact on these pathways. When added to 3T3-F442A adipocytes, the TRPV4 agonist GSK1016790A repressed the expression of mRNAs encoding Pgc1a, Ucp1, and Cox8b in a TRPV4-dependent manner (Fig- ure 2I). Taken together, these data strongly suggest that TRPV4 functions as a negative regulator of PGC1a and oxidative metabolism in white adipocytes.	SIGNOR-253094	0.8
STAT3	protein	P40763	UNIPROT	CEBPD	protein	P49716	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									24011072	f		miannu	To assess whether Stat3 affects C/EBPδ expression, we co-transfected C2C12 myoblasts with a plasmid expressing a C/EBPδpromoter-driven luciferase plus a lentivirus expressing the constitutively active Stat3C-GFP. Overexpression of Stat3C increased C/EBPδpromoter activity compared to that in lentivirus expressing GFP control	SIGNOR-255333	0.596
mTORC2	complex	SIGNOR-C2	SIGNOR	mTORC2	complex	SIGNOR-C2	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000782								10702316	t		lperfetto	We report here the identification of a FRAP autophosphorylation site. This site, Ser-2481, is located in a hydrophobic region near the conserved carboxyl-terminal FRAP tail. We demonstrate that the COOH-terminal tail is required for FRAP kinase activity and for signaling to the translational regulator p70(s6k) (ribosomal subunit S6 kinase).	SIGNOR-217000	0.678
MAPK14	protein	Q16539	UNIPROT	USF1	protein	P22415	UNIPROT	up-regulates activity	phosphorylation	Thr153	EALLGQAtPPGTGQF	9606									19389701	t		lperfetto	Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes	SIGNOR-185572	0.533
AKT1	protein	P31749	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates activity	phosphorylation	Ser196	KLRRRFSsLHFMVEV	9606	BTO:0000938								10529400	t		lperfetto	Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9BAD phosphorylation by Akt is an essential step for growth factor-mediated inhibition of caspase activation	SIGNOR-252585	0.768
MAP3K7	protein	O43318	UNIPROT	MAP2K6	protein	P52564	UNIPROT	up-regulates activity	phosphorylation			9606									11460167	t		lperfetto	The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination	SIGNOR-109497	0.753
DDIT3	protein	P35638	UNIPROT	CEBPB	protein	P17676	UNIPROT	down-regulates quantity	transcriptional regulation			10090									7588595	t			We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process.	SIGNOR-255914	0.669
MAP2K7	protein	O14733	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates	phosphorylation	Tyr185	TSFMMTPyVVTRYYR	9606									9312068	t		gcesareni	Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues.	SIGNOR-51203	0.686
USP5	protein	P45974	UNIPROT	Ubiquitin	proteinfamily	SIGNOR-PF89	SIGNOR	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270830	0.84
ITGAE	protein	P38570	UNIPROT	AE/b7 integrin	complex	SIGNOR-C186	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253291	0.676
2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-4-quinazolinyl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide	chemical	CHEBI:91367	ChEBI	AURKB	protein	Q96GD4	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258181	0.8
ritonavir	chemical	CHEBI:45409	ChEBI	UGT1A1	protein	P22309	UNIPROT	down-regulates activity	chemical inhibition			9606									21030469	t		Luana	Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation.	SIGNOR-258154	0.8
GABA-A	proteinfamily	SIGNOR-PF61	SIGNOR	CRHR1	protein	P34998	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268610	0.2
CBP/p300	complex	SIGNOR-C6	SIGNOR	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	acetylation	Lys19	VKRLLGWkKSAGGSG	9606	BTO:0000567;BTO:0002181;BTO:0000552								17074756	t		lperfetto	We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfbeta-dependent manner. To identify the specific lysine residue acetylated by p300, lys19, and lys20 in smad2(fl) were mutated individually and subjected to p300-mediated acetylation following expression in 293t cells. Mutation of lys19 blocked the p300-mediated acetylation of smad2(fl), whereas mutation of lys20 had no effect (fig. 2b), suggesting that lys19 is the preferred site for p300-mediated acetylation of smad2(fl).	SIGNOR-235899	0.646
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser695	MSQPSTAsNSLPEPA	9606									10195894	t			Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.	SIGNOR-251281	0.2
CSNK1A1	protein	P48729	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation			9606									19188143	t		gcesareni	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity.	SIGNOR-252898	0.392
URI1 prefoldin co-chaperone	complex	SIGNOR-C514	SIGNOR	PAQosome co-chaperone complex	complex	SIGNOR-C516	SIGNOR	form complex	binding			9606									30484152	t		miannu	The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92. 	SIGNOR-270924	0.565
NRAS	protein	P01111	UNIPROT	PIK3CB	protein	P42338	UNIPROT	up-regulates	binding			9606									21779497	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k	SIGNOR-175225	0.653
MAP3K5	protein	Q99683	UNIPROT	DAXX	protein	Q9UER7	UNIPROT	up-regulates	phosphorylation	Ser184	QSPRTRGsRRQIQRL	9606									19789335	t		gcesareni	Our data demonstrated that ask1 controls the cytoplasmic localization of daxx (fig.1). our results indicate that daxx not only activates ask1 but also is a downstream target of ask1 and that accumulated daxx further activates ask1. Thus, the daxx-ask1 positive feedback loop amplifying jnk/p38 signaling plays an important role in the cell-killing effects of stressors, such as tnfalpha.	SIGNOR-188325	0.835
OPRD1	protein	P41143	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256826	0.437
PRKCB	protein	P05771	UNIPROT	ITGB2	protein	P05107	UNIPROT	unknown	phosphorylation	Thr758	NPLFKSAtTTVMNPK	9606									11700305	t		lperfetto	Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |	SIGNOR-249122	0.359
TP53	protein	P04637	UNIPROT	BAK1	protein	Q16611	UNIPROT	up-regulates	binding			9606									15077116	t		gcesareni	P53 interacts with the pro-apoptotic mitochondrial membrane protein bak	SIGNOR-124122	0.678
471905-41-6	chemical	CID:9803433	PUBCHEM	APP	protein	P05067	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194358	0.8
TNFRSF1A	protein	P19438	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization				10090	BTO:0002572;BTO:0000801								21232017	f		lperfetto	Tnfr1-induced phosforylation and degradarionn of ikb are almost completely abolished in tradd-deficient mefs,these hallmarks of classical nf-kn signaling are only attenuated in tradd-deficient macrophage.	SIGNOR-235789	0.54
budesonide	chemical	CHEBI:3207	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates activity	chemical activation			-1									9793625	t			Mometasone furoate (MF, CAS 83919-23-7, Sch 32088), budesonide (BUD, CAS 51372-29-3), fluticasone propionate (FP, CAS 80474-14-2), and triamcinolone acetonide (TA, CAS-76-25-5) are corticosteroids. All of the test compounds had a higher affinity for the recombinant glucocorticoid receptor than the reference glucocorticoid receptor ligand, dexamethasone (DEX, CAS 50-02-2). All compounds showed greater potency than dexamethasone in stimulating transcription of a synthetic target gene regulated by a glucocorticoid response element. 	SIGNOR-253053	0.8
CHRM3	protein	P20309	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257134	0.385
SYK	protein	P43405	UNIPROT	SLC4A1	protein	P02730	UNIPROT	unknown	phosphorylation	Tyr21	ENLEQEEyEDPDIPE	-1									10942405	t			The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton 	SIGNOR-251411	0.462
IKBKE	protein	Q14164	UNIPROT	TANK	protein	Q92844	UNIPROT	down-regulates activity	phosphorylation	Ser100	QPQDKVIsGIAREKL	9534	BTO:0000298								10759890	t		miannu	IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex	SIGNOR-262713	0.734
WDR83	protein	Q9BRX9	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates	binding			9606									15118098	t		gcesareni	Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex.	SIGNOR-124473	0.486
RBBP4	protein	Q09028	UNIPROT	Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	form complex	binding			9606									23110252	t		lperfetto	The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48).	SIGNOR-241906	0.886
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	PARP1	protein	P09874	UNIPROT	up-regulates				9606									17891139	f		miannu	We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus.	SIGNOR-260065	0.7
TFEB	protein	P19484	UNIPROT	GLA	protein	P06280	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19556463	f	Figure 1	lperfetto	Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 	SIGNOR-276539	0.29
LMO2	protein	P25791	UNIPROT	ERG	protein	P11308	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001106								21536859	f	 	miannu	 We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer.	SIGNOR-253922	0.39
FZD2	protein	Q14332	UNIPROT	DVL3	protein	Q92997	UNIPROT	up-regulates activity	binding			9606									23151663	t		areggio	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. 	SIGNOR-258962	0.626
ITK	protein	Q08881	UNIPROT	BMX	protein	P51813	UNIPROT	up-regulates activity	phosphorylation	Tyr216	SSTSLAQyDSNSKKI	-1									12573241	t			Itk phosphorylated Bmx-SH3 to a low extent. pY positions correspond to the residues Y215 and Y223 in Bmx. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.	SIGNOR-251331	0.339
PTK2	protein	Q05397	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr397	SVSETDDyAEIIDEE	9606									10816598	t		miannu	Fak autophosphorylation site, tyr397. / extracellular matrix (ecm)-induced autophosphorylation of fak on tyr397 creates a high affinity binding site for the sh2 domain of c-src, and mutation (tyr to phe) of this residue inhibits association	SIGNOR-77434	0.2
NFE2L2	protein	Q16236	UNIPROT	GCLC	protein	P48506	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22459801	f		miannu	 Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed. 	SIGNOR-254643	0.485
CDK8	protein	P49336	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR										18418385	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	lperfetto	However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo.	SIGNOR-273171	0.2
ANK3	protein	Q12955	UNIPROT	SPTBN1	protein	Q01082	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								17620337	t		miannu	Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. Ankyrin-G also recruits beta-2-spectrin to E-cadherin-beta-catenin complexes, thus providing a direct connection between E-cadherin and the spectrin/actin skeleton. 	SIGNOR-266711	0.63
CHEK1	protein	O14757	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates activity	phosphorylation	Ser331	KSKGRASsSGNQESS	9606	BTO:0000567								19861535	t		lperfetto	In vitro and in vivo experiments show that phosphorylation of s331 is mediated by chk1, the s-phase checkpoint kinase implicated in the fanconi anemia dna repair pathway. phosphorylation at this site is dependent on chk1, signifying the importance of the s-phase checkpoint in the activation of fanconi anemia pathway.	SIGNOR-107042	0.604
Stress_granules	phenotype	SIGNOR-PH124	SIGNOR	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates				9606									27920254	f		miannu	Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis.	SIGNOR-260867	0.7
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258015	0.8
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258013	0.8
CCAR2	protein	Q8N163	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	down-regulates activity	binding			9606									22735644	t		lperfetto	 Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death. 	SIGNOR-267663	0.735
CSNK2A1	protein	P68400	UNIPROT	NPHP1	protein	O15259	UNIPROT	up-regulates	phosphorylation	Ser126	EESESEDsEDSGGEE	9606									16308564	t		lperfetto	Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting.	SIGNOR-142351	0.2
RCHY1	protein	Q96PM5	UNIPROT	POLH	protein	Q9Y253	UNIPROT	down-regulates activity	monoubiquitination	Lys709	QTLESFFkPLTH	9606									21791603	t		miannu	Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709).	SIGNOR-272733	0.563
ziprasidone	chemical	CHEBI:10119	ChEBI	HTR1B	protein	P28222	UNIPROT	up-regulates activity	chemical activation			10116		BTO:0001311							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258501	0.8
ERG	protein	P11308	UNIPROT	VIM	protein	P08670	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093;BTO:0000815								8895512	f	 	miannu	 Our results suggest that PEA3 specifically transactivates vimentin promoter through PEA3 site. Among members of the ETS transcription factor family only Erg showed ability to transactivate vimentin promoter besides PEA3.	SIGNOR-254069	0.2
CASP3	protein	P42574	UNIPROT	MYL3	protein	P08590	UNIPROT	down-regulates quantity by destabilization	cleavage	Glu135	GTYEDFVeGLRVFDK	9986	BTO:0003324								12186978	t		lperfetto	By sequencing and site-directed mutagenesis, a noncanonical cleavage site for caspase-3 was mapped to the C-terminal DFVE(135)G motif. We demonstrated that vMLC1 cleavage in failing myocardium in vivo is associated with a morphological disruption of the organized vMLC1 staining of sarcomeres, and with a reduction in myocyte contractile performance.	SIGNOR-270593	0.385
DLL4	protein	Q9NR61	UNIPROT	NRP1	protein	O14786	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18339870	f		gcesareni	Dll4 down-regulates vascular endothelial growth factor (vegf)_ receptor_ 2 and nrp1 expression and inhibits vegf function	SIGNOR-178029	0.37
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	MYL4	protein	P12829	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136697	0.305
BMP7	protein	P18075	UNIPROT	Brown_adipogenesis	phenotype	SIGNOR-PH27	SIGNOR	up-regulates				9606									18719589	f		fspada	Here we demonstrate that whereas some members of the family of bone morphogenetic proteins (bmps) support white adipocyte differentiation, bmp7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail.	SIGNOR-180305	0.7
CHUK	protein	O15111	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates	phosphorylation	Ser857	PPYNRAVsLDSPVSV	9606									15383283	t		gcesareni	Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites.	SIGNOR-127064	0.403
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	FRAT1	protein	Q92837	UNIPROT	down-regulates activity	phosphorylation	Ser188	RLQQRRGsQPETRTG	9606	BTO:0002181								16982607	t		miannu	Protein kinase A (PKA) was found to phosphorylate Ser188 in vitro as well as in intact cells. Importantly, activation of endogenous cAMP-coupled beta-adrenergic receptors with norepinephrine stimulated the phosphorylation of FRAT1 at Ser188. GSK-3 was also able to phosphorylate FRAT1 at Ser188 and other residues in vitro or when overexpressed in intact cells.  Phosphorylation of Ser188 by PKA inhibited the ability of FRAT1 to activate beta-catenin-dependent transcription.	SIGNOR-276058	0.2
EGFR	protein	P00533	UNIPROT	KCND3	protein	Q9UK17	UNIPROT	up-regulates activity	phosphorylation	Tyr136	GDCCYEEyKDRKREN										22198508	t		lperfetto	Our results demonstrate that human atrial I(to) and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue|We found that human atrial I(to) was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2.	SIGNOR-275549	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Thr273	SPSVHPAtPISPGRA	9606	BTO:0002181								16046550	t	The effect has been demonstrated using Q01196-8	lperfetto	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-244715	0.2
STAT3	protein	P40763	UNIPROT	HAMP	protein	P81172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001950								18671304	f		miannu	 HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter.	SIGNOR-255239	0.439
PDPK1	protein	O15530	UNIPROT	ITGB3	protein	P05106	UNIPROT	down-regulates activity	phosphorylation	Thr779	LYKEATStFTNITYR	-1									10896934	t		miannu	PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3.	SIGNOR-250266	0.449
NOTCH1	protein	P46531	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	down-regulates				10090									9601631	f		Luana	Signalling through activated Notch is known both to control multiple cell fate determinations (in both invertebrates and vertebrates) and to inhibit developmental processes, such as neurogenesis	SIGNOR-265769	0.7
PRKCA	protein	P17252	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser379	DLILNRCsESTKRKL	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89178	0.538
S1PR3	protein	Q99500	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257175	0.4
N-acetyl-L-aspartate(2-)	smallmolecule	CHEBI:16953	ChEBI	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	up-regulates quantity	precursor of			9606									17194761	t		miannu	N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain.	SIGNOR-267525	0.8
IFNG	protein	P01579	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606									18231581	f		lperfetto	Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS	SIGNOR-260259	0.7
CDK1	protein	P06493	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates	phosphorylation	Ser123	EEGFGSSsPVKSPAA	9606									16085715	t		gcesareni	We show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms. The pS123 not only directly interacted with basic residues in the WD40 repeat domain of beta-TrCP but also primed phosphorylation by two independent protein kinases, Plk1 and CK2 (formerly casein kinase 2)	SIGNOR-139465	0.854
hexestrol	chemical	CHEBI:31669	ChEBI	ESR1	protein	P03372	UNIPROT	down-regulates activity	chemical inhibition			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258593	0.8
CLASP2	protein	O75122	UNIPROT	CLIP1	protein	P30622	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								19638411	t		lperfetto	CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells|the C-terminal region of CLASP2 is known to interact with CLIP-170	SIGNOR-264827	0.763
NBEA	protein	Q8NFP9	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates activity	binding			9606	BTO:0000007	BTO:0000227							26999814	t		lperfetto	Yeast two-hybrid identified the Notch1 intracellular domain as a physical interactor of the PBW domain and a role for NBEA as a negative regulator in Notch-mediated transcription was demonstrated.|Defining novel interaction partners of conserved NBEA domain modules identified a role for NBEA as transcriptional regulator in the nucleus. The physical interaction of NBEA with NOTCH1 is most relevant for ASD pathogenesis because NOTCH signaling is essential for neural development.	SIGNOR-266010	0.31
PLK1	protein	P53350	UNIPROT	NEDD1	protein	Q8NHV4	UNIPROT	up-regulates activity	phosphorylation	Ser397	GKNQDFSsFDDTGKS	9606	BTO:0000567								19509060	t		lperfetto	Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation.	SIGNOR-272994	0.604
PRKACA	protein	P17612	UNIPROT	STK11	protein	Q15831	UNIPROT	up-regulates activity	phosphorylation	Ser428	SSKIRRLsACKQQ	10116									11297520	t		miannu	Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth.	SIGNOR-250055	0.479
Integrator complex	complex	SIGNOR-C265	SIGNOR	SDC4	protein	P31431	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								25675981	f		lperfetto	The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes.	SIGNOR-261480	0.2
SMAD5	protein	Q99717	UNIPROT	SMAD6	protein	O43541	UNIPROT	up-regulates quantity	transcriptional regulation			10090									22219353	t		Gianni	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268940	0.582
MECP2	protein	P51608	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			9606	BTO:0000007								24150225	t		Luana	MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2	SIGNOR-264683	0.274
MYC	protein	P01106	UNIPROT	VEGFA	protein	P15692	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									12368264	f			These defects are intrinsic to c-Myc, and are in part associated with a requirement for c-Myc for the expression of vascular endothelial growth factor (VEGF), as VEGF can partially rescue these defects.	SIGNOR-259369	0.475
TARDBP	protein	Q13148	UNIPROT	Protein_aggregates	phenotype	SIGNOR-PH142	SIGNOR	up-regulates quantity				9606	BTO:0000312								22051914	f		lperfetto	Pathological protein aggregates, identified as compact or skein-like ubiquitinated inclusions, are a cardinal feature of ALS.4–6 The identification of TDP-43 as the major protein constituent of these inclusions initi- ated a major shift in our understanding of the patho- biology of ALS	SIGNOR-262278	0.7
PRKCZ	protein	Q05513	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser307	TRRSRTEsITATSPA	10029									15069075	t		lperfetto	Extensive studies have provided evidence that phosphorylation of Ser307 in IRS-1 inhibits IR/IRS-1 complex formation and IRS-1 tyrosine phosphorylation after prolonged insulin-stimulation similar to our results.	SIGNOR-236760	0.716
KAT2B	protein	Q92831	UNIPROT	H3-4	protein	Q16695	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269613	0.2
FRAT1	protein	Q92837	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates	binding			9606				SIGNOR-C110					9635432	t		gcesareni	The frat family consists of three members: frat-1, -2, and -3. It has been shown that different sites of frat-1 interact with gsk-3 and dvl-1 and that wnt-1 disintegrates the complex formation of frat-1, dvl-1, and axin, resulting in the activation of the wnt signaling pathway	SIGNOR-58219	0.765
CSNK1D	protein	P48730	UNIPROT	SMARCA4	protein	P51532	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser31	PGAMLGPsPGPSPGS	9606	BTO:0001225								30177679	t		miannu	 We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation. 	SIGNOR-277408	0.2
SYVN1	protein	Q86TM6	UNIPROT	HERPUD1	protein	Q15011	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								28827405	t		miannu	FAM8A1 enhances binding of Herp to Hrd1, an interaction that is required for ERAD. Our findings support a model of Hrd1 complex formation, where the Hrd1 cytoplasmic domain and FAM8A1 have a central role in the assembly and activity of this ERAD machinery. A conserved Hrd1 cytoplasmic domain interacts with FAM8A1 and Herp	SIGNOR-261349	0.592
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1721	SPTSPSYsPTSPSYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203540	0.77
PPP2CA	protein	P67775	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	dephosphorylation	Thr308	KDGATMKtFCGTPEY	9606									18160256	t			Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248626	0.889
XPO1	protein	O14980	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	relocalization			9606									17891139	t		miannu	We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus.	SIGNOR-260067	0.566
FCRL3	protein	Q96P31	UNIPROT	SYK	protein	P43405	UNIPROT	up-regulates activity	binding			-1									12051764	t		miannu	Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2.	SIGNOR-274011	0.359
NEDD4	protein	P46934	UNIPROT	SYK	protein	P43405	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									11046148	t		miannu	The latent membrane protein (LMP) 2A of Epstein-Barr virus (EBV) is implicated in the maintenance of viral latency and appears to function in part by inhibiting B-cell receptor (BCR) signaling. LMP2A enhances Lyn and Syk ubiquitination in vivo in a fashion that depends on the activity of Nedd4 family members and correlates with destabilization of the Lyn tyrosine kinase. These results suggest that LMP2A serves as a molecular scaffold to recruit both B-cell tyrosine kinases and C2/WW/Hect domain E3 protein-ubiquitin ligases. 	SIGNOR-272581	0.296
NOD1	protein	Q9Y239	UNIPROT	Autophagy	phenotype	SIGNOR-PH31	SIGNOR	up-regulates				9606	BTO:0000567								19898471	f		miannu	Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria.	SIGNOR-252404	0.7
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser217	AHYSPRTsPIMSPRT	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248686	0.613
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC4	protein	P56524	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257968	0.8
MAPK8	protein	P45983	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									7824938	t		gcesareni	Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain.	SIGNOR-33918	0.772
CSDE1	protein	O75534	UNIPROT	FOS	protein	P01100	UNIPROT	down-regulates quantity	post transcriptional regulation			10090	BTO:0000944								15314026	t			By testing different classes of mammalian poly(A) nucleases, we identified CCR4 as a poly(A) nuclease involved in the mCRD-mediated rapid deadenylation in viv	SIGNOR-261145	0.3
GSK3B	protein	P49841	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates	binding			9606			SIGNOR-C110	SIGNOR-C110					10318824	t		lperfetto	From the binding experiments, we defined the domains of Axin that bind glycogen synthase kinase-3beta (GSK-3beta) and beta-catenin. We also examined the ability of each Axin mutant to inhibit lymphoid enhancer factor-1 (Lef-1) reporter activity in a cell line expressing high levels of beta-catenin.	SIGNOR-67438	0.917
TFE3	protein	P19532	UNIPROT	CD63	protein	P08962	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276812	0.2
CSNK2A1	protein	P68400	UNIPROT	TCF7L2	protein	Q9NQB0	UNIPROT	up-regulates activity	phosphorylation	Ser59	SETNQNSsSDSEAER	-1									11711551	t		llicata	We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. 	SIGNOR-250963	0.365
TCF3	protein	P15923	UNIPROT	BBC3	protein	Q96PG8	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									23684607	f	 	miannu	 The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins.	SIGNOR-255386	0.276
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser315	DFRSRTNsNASTVSG										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249647	0.2
APEX1	protein	P27695	UNIPROT	TG	protein	P01266	UNIPROT	up-regulates quantity by expression	transcriptional regulation												9813166	t		lperfetto	In co-transfection experiments, Ref-1 increases the Pax-8 activating effect on thyroglobulin promoter.	SIGNOR-271694	0.2
BACH1	protein	O14867	UNIPROT	MAFK	protein	O60675	UNIPROT	up-regulates activity	binding			10090	BTO:0004475								19011633	t		miannu	Bach1 forms a heterodimer with the small Maf oncoproteins and binds to the Maf-recognition element (MARE) to inhibit target genes	SIGNOR-226409	0.486
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	Pr3-ANCA	complex	SIGNOR-C475	SIGNOR	up-regulates quantity				9606		BTO:0000133							15972951	f		lperfetto	In the early phase, LPS enhanced anti-MPO IgG-induced glomerular neutrophil accumulation. |using bacterial lipopolysaccharide (LPS) as the proinflammatory stimulus.	SIGNOR-270587	0.7
CHEK2	protein	O96017	UNIPROT	VHL	protein	P40337	UNIPROT	up-regulates	phosphorylation	Ser111	GTGRRIHsYRGHLWL	9606	BTO:0000680								22071692	t		llicata	We demonstrated that checkpoint kinase-2 (chk2) binds to the beta-domain of pvhl and phosphorylates ser 111 on dna damage. Notably, this modification enhances pvhl-mediated transactivation of p53 by recruiting p300 and tip60 to the chromatin of p53 target gene	SIGNOR-177091	0.467
KRAS	protein	P01116	UNIPROT	NFIL3	protein	Q16649	UNIPROT	up-regulates				10090	BTO:0003104								10082541	f		lperfetto	A constitutively active Ras protein [Ras(G12V)] regulates the stable expression of the NFIL3 transcription factor through both the Raf-MAPK and PI3-K pathways.	SIGNOR-242757	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		lperfetto	Phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression	SIGNOR-244602	0.2
MARK2	protein	Q7KZI7	UNIPROT	UTRN	protein	P46939	UNIPROT	up-regulates	phosphorylation	Ser1258	TLEERMKsTEVLPEK	9606		BTO:0000887;BTO:0001103							19945424	t		lperfetto	Par-1b, interacts with the utrophin-dg complex, and positively regulates the interaction between utrophin and dg. Ser1258 within r9 is specifically phosphorylated by par-1b.	SIGNOR-161915	0.433
EPAS1	protein	Q99814	UNIPROT	KDM1A	protein	O60341	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271588	0.283
CTTNBP2	protein	Q8WZ74	UNIPROT	SHANK3	protein	Q9BYB0	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								35562389	t		miannu	Synaptopathy, a key feature of autism spectrum disorders (ASD), is likely relevant to the impaired phase separation and/or transition of ASD-linked synaptic proteins. Here, we report that LLPS and zinc-induced liquid-to-gel phase transition regulate the synaptic distribution and protein-protein interaction of cortactin-binding protein 2 (CTTNBP2), an ASD-linked protein. CTTNBP2 forms self-assembled condensates through its C-terminal intrinsically disordered region and facilitates SHANK3 co-condensation at dendritic spines.	SIGNOR-269702	0.2
NARS1	protein	O43776	UNIPROT	Asn-tRNA(Asn)	smallmolecule	CHEBI:29265	ChEBI	up-regulates quantity	chemical modification			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270456	0.8
TDGF1	protein	P13385	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates				9606	BTO:0002314	BTO:0000887;BTO:0001103							23129614	f		miannu	Cripto, a regulator of early embryogenesis, is a novel regulator of muscle regeneration and satellite cell progression toward the myogenic lineage.	SIGNOR-192439	0.7
PRKAA1	protein	Q13131	UNIPROT	SNAI1	protein	O95863	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser92	SFLVRKPsDPNRKPN	9606									19923321	t		lperfetto	Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively.	SIGNOR-161779	0.2
BMPR1B	protein	O00238	UNIPROT	STAMBP	protein	O95630	UNIPROT	up-regulates activity	phosphorylation	Ser2	sDHGDVSL	9534	BTO:0000298								11483516	t		llicata	BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads.	SIGNOR-250596	0.294
BDKRB2	protein	P30411	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256974	0.2
SNRPB	protein	P14678	UNIPROT	U1 snRNP complex	complex	SIGNOR-C480	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270680	0.918
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	IKBKB	protein	O14920	UNIPROT	down-regulates	cleavage	Asp78	PNVVAARdVPEGMQN	9606									11741536	t		gcesareni	Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis.	SIGNOR-256434	0.373
U0126	chemical	CHEBI:90693	ChEBI	MAP2K1	protein	Q02750	UNIPROT	down-regulates	chemical inhibition			9606									9873633	t		gcesareni	The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2.	SIGNOR-62892	0.8
TLN1	protein	Q9Y490	UNIPROT	AL/b2 integrin	complex	SIGNOR-C169	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257619	0.589
SHOC2	protein	Q9UQ13	UNIPROT	PPP1CA	protein	P62136	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16630891	t			Using a proteomics approach, we have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site	SIGNOR-251647	0.577
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr36	LPPGDYStTPGGTLF	9606	BTO:0000007		SIGNOR-C3						9465032	t		lperfetto	Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size.	SIGNOR-55697	0.924
G6P	proteinfamily	SIGNOR-PF81	SIGNOR	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	up-regulates quantity	chemical modification			9606									12093795	t		miannu	Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis	SIGNOR-266567	0.8
chloroquine	chemical	CHEBI:3638	ChEBI	TNF	protein	P01375	UNIPROT	down-regulates quantity				9606									32283152	f		miannu	Chloroquine inhibits the production and release of TNF and IL-6, which indicates that chloroquine may suppress the cytokine storm in patients infected with COVID-19.	SIGNOR-260853	0.8
BMPR1B	protein	O00238	UNIPROT	STAMBP	protein	O95630	UNIPROT	up-regulates activity	phosphorylation	Ser245	KPGALSNsESIPTID	9534	BTO:0000298								11483516	t		llicata	BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads.	SIGNOR-250598	0.294
NCS1	protein	P62166	UNIPROT	DRD2	protein	P14416	UNIPROT	down-regulates activity	binding			9606	BTO:0000007;BTO:0000938								12351722	t		miannu	Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization.	SIGNOR-263964	0.668
NFIA	protein	Q12857	UNIPROT	ROBO1	protein	Q9Y6N7	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268893	0.2
p38	proteinfamily	SIGNOR-PF16	SIGNOR	DDIT3	protein	P35638	UNIPROT	up-regulates activity	phosphorylation			-1									8650547	t		Luana	Stress-Induced Phosphorylation and Activation of the Transcription Factor CHOP (GADD153) by p38 MAP Kinase	SIGNOR-260724	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	HNRNPK	protein	P61978	UNIPROT	up-regulates	phosphorylation	Ser353	DSAIDTWsPSEWQMA	9606									11259409	t		lperfetto	Using modified jnk and its atp analogue enables the detection of novel jnk substrates. Among substrates identified using this approach is heterogeneous nuclear ribonucleoprotein k, which is involved in transcription and post-transcriptional mrna metabolism. The newly identified substrate can be phosphorylated by jnk on amino acids 216 and 353, which contribute to heterogeneous nuclear ribonucleoprotein k mediated transcriptional activities.	SIGNOR-105762	0.2
PAX7	protein	P23759	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates quantity by expression	transcriptional regulation												18066051	t		Simone Vumbaca	Together, these experiments indicate that Pax7 enforces satellite cell commitment by recruiting a HMT complex to Myf5, resulting in transcriptional activation. 	SIGNOR-255641	0.508
CSNK2A3	protein	Q8NEV1	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates activity	phosphorylation	Ser1126	TEEFSSEsDMEESKE	9606	BTO:0000938								19064667	t		lperfetto	 We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275759	0.2
UHRF1	protein	Q96T88	UNIPROT	RIF1	protein	Q5UIP0	UNIPROT	down-regulates activity	polyubiquitination			9606	BTO:0002181								26727879	t		miannu	UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation. 	SIGNOR-277193	0.2
CASP8AP2	protein	Q9UKL3	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates	binding			9606									22075988	t		lperfetto	In addition, both cleavage products of c-flip turned out to be inducers of nf-kb activity by binding to the ikk complex.	SIGNOR-217385	0.248
ROCK1	protein	Q13464	UNIPROT	LIMK2	protein	P53671	UNIPROT	up-regulates	phosphorylation	Thr505	NDRKKRYtVVGNPYW	9606									11018042	t		lperfetto	Specific activation of lim kinase 2 via phosphorylation of threonine 505 by rock, a rho-dependent protein kinase	SIGNOR-82755	0.616
MAPK1	protein	P28482	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates activity	phosphorylation	Thr185	HDHTGFLtEYVATRW										1712480	t		lperfetto	Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.|	SIGNOR-249414	0.2
EPHA3	protein	P29320	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates	binding			9606	BTO:0000938								9632142	t		gcesareni	We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation.	SIGNOR-58139	0.507
HAP1	protein	P54257	UNIPROT	AHI1	protein	Q8N157	UNIPROT	up-regulates activity	binding			9606	BTO:0000452								23532844	t		miannu	Huntingtin-associated protein-1 (Hap1) is a regulatory protein that binds Ahi1, and Hap1 knock-out mice have been reported to have JBTS-like phenotypes, suggesting a role for Hap1 in ciliogenesis. 	SIGNOR-269081	0.566
MCU	protein	Q8NE86	UNIPROT	MCU_MICU2_variant	complex	SIGNOR-C502	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270874	0.696
RNF208	protein	Q9H0X6	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys97	DAINTEFkNTRTNEK	9606	BTO:0000815								31862882	t		Gianni	Here, we show that RING finger protein 208 (RNF208) decreases the stability of soluble Vimentin protein through a polyubiquitin-mediated proteasomal degradation pathway, thereby suppressing metastasis of TNBC cells	SIGNOR-269051	0.2
PRKAA1	protein	Q13131	UNIPROT	HIPK2	protein	Q9H2X6	UNIPROT	up-regulates activity	phosphorylation	Thr119	HNLMRRStVSLLDTY	-1									23871434	t		miannu	These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J).	SIGNOR-276468	0.2
CSNK1A1	protein	P48729	UNIPROT	PHLPP1	protein	O60346	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr1363	HVQSVLLtPQDEFFI	9606	BTO:0002181								19797085	t		miannu	We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity. 	SIGNOR-276262	0.313
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	MKNK2	protein	Q9HBH9	UNIPROT	up-regulates	phosphorylation			9606									9155017	t	inferred from 70% family members	gcesareni	Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity.	SIGNOR-270115	0.2
MEF2C	protein	Q06413	UNIPROT	MYH1	protein	P12882	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15728583	t		lperfetto	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238754	0.392
histamine	smallmolecule	CHEBI:18295	ChEBI	HRH2	protein	P25021	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257513	0.8
CyclinA2/CDK1	complex	SIGNOR-C420	SIGNOR	BORA	protein	Q6PGQ7	UNIPROT	up-regulates activity	phosphorylation			9606									29870721	t		lperfetto	The active cyclin A/cdk1 complex phosphorylates Bora and promotes Plx1 activation	SIGNOR-267573	0.438
SMAD7	protein	O15105	UNIPROT	PPP1R15A	protein	O75807	UNIPROT	up-regulates	binding			9606									14718519	t		lpetrilli	We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI.	SIGNOR-121280	0.667
NYYJKMXNVNFOFQ-MHZLTWQESA-N	chemical	CID:9829836	PUBCHEM	ADRB3	protein	P13945	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	There were several β3-selective compounds (e.g. AZ 40140d, L 755507, L 748337 and TAK 677)	SIGNOR-257856	0.8
EDNRB	protein	P24530	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256924	0.27
FBXO22	protein	Q8NEZ5	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0003031								26868148	t	methylated tp53	lperfetto	We demonstrate here that SCFFbxo22-KDM4A is a senescence-associated E3 ligase targeting methylated p53 for degradation. We find that Fbxo22 is highly expressed in senescent cells in a p53-dependent manner, and that SCFFbxo22 ubiquitylated p53 and formed a complex with a lysine demethylase, KDM4A. |SCFFbxo22 forms a ternary complex with p53 and KDM4A that targets methylated p53 for degradation.	SIGNOR-273448	0.346
GNAS	protein	P63092	UNIPROT	Adenylate_cyclase	proteinfamily	SIGNOR-PF92	SIGNOR	up-regulates activity	binding			9606									17652154	t		gcesareni	Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR	SIGNOR-267848	0.731
VAV1	protein	P15498	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates				9606									9013873	f		gcesareni	Vav may link gp130 activation to downstream mapk activation in hematopoietic cells.	SIGNOR-46064	0.524
PRKACG	protein	P22612	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser311	SFRTPRDsKLEAPAE	9606		BTO:0000887							20151718	t		miannu	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163796	0.278
XAV939	chemical	CHEBI:62878	ChEBI	TNKS2	protein	Q9H2K2	UNIPROT	down-regulates	chemical inhibition			9606									19759537	t		gcesareni	Xav939 inhibits the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2.	SIGNOR-188057	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	GADD45B	protein	O75293	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11713530	f		gcesareni	Here we report that nf-kappab complexes downregulate the c-jun amino-terminal kinase (jnk) cascade, thus establishing a link between the nf-kappab and the jnk pathways. This link involves the transcriptional upregulation of gadd45beta/myd118, which downregulates jnk induced by the tnf receptor (tnf-r).	SIGNOR-111963	0.296
PTPRA	protein	P18433	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates activity	dephosphorylation	Tyr531	FTATEPQyQPGENL	10090	BTO:0000255								9535845	t			In a coexpression system, PTPalpha effected a dose-dependent tyrosine dephosphorylation and activation of p59(fyn), where maximal dephosphorylation correlated with a 5-fold increase in kinase activity.|the increased p59fyn catalytic activity and SH2 availability for binding are consistent with a PTPα-mediated dephosphorylation of the C-terminal Tyr-531 of p59fyn. 	SIGNOR-248435	0.644
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	CEBPA	protein	P49715	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19797526	f			We therefore conclude that PML-RARα–mediated repression of C/EBPα is driven through a DNA methylation pathway. In accordance with this finding, a recent study in human APL samples described increased C/EBPα promoter methylation, consistent with the ability of PML-RARα to recruit corepressor complexes. Moreover, the PML-RARα effect on C/EBPα repression does not seem to be mediated via direct binding.	SIGNOR-255726	0.2
Obatoclax mesylate	chemical	CID:46930996	PUBCHEM	MCL1	protein	Q07820	UNIPROT	down-regulates activity	chemical inhibition			-1									23515850	t		lperfetto	Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro|The ability of obatoclax to inhibit MCL-1 may be particularly important, given that several hematological malignancies appear to depend on this protein for survival, such as acute lymphoblastic leukemia (ALL),44 CLL,44 multiple myeloma,45 and diffuse large B-cell lymphoma (DLBCL)	SIGNOR-262025	0.8
FGF14	protein	Q92915	UNIPROT	SCN5A	protein	Q14524	UNIPROT	down-regulates activity	binding			9606		BTO:0000199							20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253417	0.286
NR3C1	protein	P04150	UNIPROT	NR4A2	protein	P43354	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15591535	f		gcesareni	We now show that the other nur factors, nurr1 and nor-1, are also subject to antagonism by gr and that this transrepression appears to involve direct protein-protein interactions between the dbds of gr and nur factors.	SIGNOR-132254	0.311
PTPN9	protein	P43378	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									16679294	t		gcesareni	Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action	SIGNOR-146676	0.263
CDK5	protein	Q00535	UNIPROT	CABLES1	protein	Q8TDN4	UNIPROT	unknown	phosphorylation	Ser313	RCRTLSGsPRPKNFK	9534									11733001	t		miannu	P70ik3-1 is phosphorylated by either cyclin A/cdk3 or cyclin E/cdk3 reconstituted in COS7 cells. Accordingly, we can conclude that in COS7 cells, Ser274 in p70ik3-1 is phosphorylated by endogenous kinases other than cdk5 (Fig. 4), at least one of which is cdk3 as shown in this work. Currently, however, the question of how ik3-1 function is modified by its cdk3-mediated phosphorylation of Ser274 remains to be adressed.	SIGNOR-112418	0.73
Food intake	phenotype	SIGNOR-PH152	SIGNOR	vitamin K	smallmolecule	CHEBI:28384	ChEBI	up-regulates quantity													31226734	f		lperfetto	Vitamin K obtained from the diet is considered to reach the target tissues via lipid absorption and the transport system 	SIGNOR-265899	0.7
8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	chemical	CHEBI:93369	ChEBI	HTR2A	protein	P28223	UNIPROT	down-regulates activity	chemical inhibition			10090	BTO:0000331								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258537	0.8
MAPK4	protein	P31152	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Thr308	KDGATMKtFCGTPEY	9606	BTO:0001109								30688659	t		miannu	 Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308. 	SIGNOR-275450	0.274
AURKB	protein	Q96GD4	UNIPROT	CHMP4C	protein	Q96CF2	UNIPROT	up-regulates	phosphorylation	Ser215	RRSRAASsQRAEEED	9606									22422861	t		lperfetto	Chmp4c functioned in the aurora b-dependent abscission checkpoint to prevent both premature resolution of intercellular chromosome bridges and accumulation of dna damage. Chmp4c engaged the chromosomal passenger complex (cpc) via interaction with borealin, which suggested a model whereby chmp4c inhibits abscission upon phosphorylation by aurora b	SIGNOR-196728	0.483
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr145	QGRKRRQtSMTDFYH	9606									16982699	t		gcesareni	Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.[...] We next investigated if phosphorylation of p21-t145 interfered with akt2 binding. As shown in fig. ?Fig.8e8e (right lane), phosphorylation of p21 on t145 effectively prevented akt2 interaction.	SIGNOR-244180	0.2
OGA	protein	O60502	UNIPROT	G6PD	protein	P11413	UNIPROT	down-regulates activity	deglycosylation	Ser84	VADIRKQsEPFFKAT	9606									26399441	t		lperfetto	O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth|O-GlcNAcylation of G6PD activates enzyme activity|G6PD is dynamically modified by O-GlcNAc at serine 84|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 	SIGNOR-267605	0.2
MAPK8IP1	protein	Q9UQF2	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	binding			9606									20508646	t	Interferes with binding to RBP-J	gcesareni	Here, we show that jip1 suppresses notch1 activity. Jip1 was found to physically associate with either intracellular domain of notch1 or rbp-jk and interfere with the interaction between them.	SIGNOR-165710	0.269
MAPK1	protein	P28482	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates	phosphorylation	Thr160	GVPVRTYtHEVVTLW	9606				SIGNOR-C16					12359725	t		gcesareni	In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e.	SIGNOR-94003	0.475
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									21524151	f		miannu	In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F	SIGNOR-262532	0.7
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGB4	protein	Q9UN71	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265701	0.2
MFGE8	protein	Q08431	UNIPROT	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	down-regulates				10116									31958465	f		miannu	We demonstrated that Milk fat globule-EGF factor8 (MFGE8) is protective against Ang-II-induced atrial fibrosis and atrial fibrillation. In vitro, silencing of MFGE8 by small interfering RNA significantly increased Ang-II-induced atrial fibrosis, whereas administration of recombinant human MFGE8 (rhMFGE8) attenuated the atrial fibrosis. 	SIGNOR-260646	0.7
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270431	0.8
NMDA receptor_2C	complex	SIGNOR-C349	SIGNOR	CTTN	protein	Q14247	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000142								14684878	t		miannu	Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors.	SIGNOR-266601	0.292
MAPK7	protein	Q13164	UNIPROT	MAPK7	protein	Q13164	UNIPROT	up-regulates activity	phosphorylation	Ser803	QREIQMDsPMLLADL	9606	BTO:0000567								20667468	t		miannu	Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803.	SIGNOR-259826	0.2
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile	chemical	CHEBI:77397	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606									18487050	t		Luana	For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428. 	SIGNOR-257794	0.8
USF1	protein	P22415	UNIPROT	GATA5	protein	Q9BWX5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22625849	f		miannu	 The present study provides the first evidence that USF1 activates GATA5 gene expression through the E-box motif and suggests a potential mechanism (disruption of the E-box) by which GATA5 promoter methylation reduces GATA5 expression in cancer.	SIGNOR-255596	0.341
FER	protein	P16591	UNIPROT	JUP	protein	P14923	UNIPROT	down-regulates activity	phosphorylation	Tyr550	AAGTQQPyTDGVRME	10116	BTO:0004604								14517306	t			The tyrosine kinase Fer, which modifies beta-catenin Tyr142, lessening its association with alpha-catenin, phosphorylates plakoglobin Tyr549 and exerts the contrary effect: it raises the binding of plakoglobin to alpha-catenin. Fer stimulation, through modification of Tyr549, causes diminished binding of plakoglobin to components of desmosomes (desmoplakin) and increased interaction with adherens junction proteins (α-catenin)	SIGNOR-251135	0.504
CHEK2	protein	O96017	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity	phosphorylation	Ser279	VLKRPERsQEESPPG	9606									12676583	t		Manara	Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A	SIGNOR-260834	0.837
anthra[1,9-cd]pyrazol-6(2H)-one	chemical	CHEBI:90695	ChEBI	MAPK10	protein	P53779	UNIPROT	down-regulates	chemical inhibition			9606									15071501	t		gcesareni	We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). To determine whether jnk activity is required for stress-induced translocation of bax to the mitochondria, we examined the effect of sp600125, a jnk inhibitor.	SIGNOR-124034	0.8
CUDC-101	chemical	CID:24756910	PUBCHEM	ERBB2	protein	P04626	UNIPROT	down-regulates activity	chemical inhibition			-1									20143778	t		miannu	By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively.	SIGNOR-262255	0.8
Caspase 8 complex	complex	SIGNOR-C231	SIGNOR	RIPK1	protein	Q13546	UNIPROT	down-regulates activity	cleavage	Asp324	RMQSLQLdCVAVPSS	9606	BTO:0000007;BTO:0000093;BTO:0000567								10521396	t		amattioni	These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability.	SIGNOR-256442	0.907
PRKACA	protein	P17612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									10949026	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.	SIGNOR-81129	0.521
MEIS1	protein	O00470	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0001271								19109563	f		irozzo	To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells.	SIGNOR-255860	0.7
GSK3B	protein	P49841	UNIPROT	ETS1	protein	P14921	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser269	DRLTQSWsSQSSFNS	9606	BTO:0000007								34023818	t		miannu	Here, we show that ETS1 forms a complex with glycogen synthase kinase-3β (GSK3β). Specifically, GSK3β-mediated phosphorylation of ETS1 at threonine 265 and serine 269 promoted protein stability, induced the transcriptional activation of matrix metalloproteinase (MMP)-9, and increased cell migration.	SIGNOR-277561	0.2
CSNK1E	protein	P49674	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates activity	phosphorylation	Ser139	DNETGTEsMVSHRRE	9606									16965538	t		lperfetto	Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development.	SIGNOR-217845	0.621
STK24	protein	Q9Y6E0	UNIPROT	STK38L	protein	Q9Y2H1	UNIPROT	up-regulates	phosphorylation	Thr442	DWVFLNYtYKRFEGL	9606	BTO:0000007								16314523	t		lperfetto	Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity.	SIGNOR-142510	0.451
LHX3	protein	Q9UBR4	UNIPROT	FSHB	protein	P01225	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23766128	f		miannu	 we also demonstrated that LHX3 bound with greater affinity to the wild-type human FSHB promoter compared with the -211 G/T mutation and that LHX3 binding was more effectively competed with excess wild-type oligonucleotide than with the SNP. Finally, we showed that FSHB transcription was decreased in gonadotrope cells with the -211 G/T mutation compared with the wild-type FSHB promoter.	SIGNOR-254557	0.378
AMPK	complex	SIGNOR-C15	SIGNOR	PPP1R12C	protein	Q9BZL4	UNIPROT	down-regulates	phosphorylation	Ser452	AGLQRSAsSSWLEGT	9606									22137581	t		lperfetto	Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo.	SIGNOR-216600	0.259
Netrin	proteinfamily	SIGNOR-PF97	SIGNOR	DSCAM	protein	O60469	UNIPROT	up-regulates activity	binding			10090	BTO:0001279								18585357	t		miannu	 Here, we report that the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons, binds netrin-1, and is necessary for commissural axons to grow toward and across the midline. DSCAM and DCC can each mediate a turning response of these neurons to netrin-1. 	SIGNOR-268173	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	up-regulates activity	phosphorylation	Ser362	FYTLNGSsVDSQPQS	9606	BTO:0004553								24614225	t		gianni	NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity.	SIGNOR-266434	0.311
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Val)	smallmolecule	CHEBI:29183	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269500	0.8
SLBP	protein	Q14493	UNIPROT	H2AC18	protein	Q6FI13	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265396	0.2
PRKN	protein	O60260	UNIPROT	MFN1	protein	Q8IWA4	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000793								20871098	t		miannu	Parkin and PINK1 are required for ubiquitination of MFN-1 and MFN-2.  Decreases in MFN-1 and MFN-2 protein levels seen at later timepoints are difficult to interpret as it is unclear whether this is due to degradation by the proteasome and/or loss of whole mitochondria by mitophagy.	SIGNOR-272779	0.2
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser37	NVLSPLPsQAMDDLM	9606	BTO:0000567								10673501	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-75017	0.784
PRKCA	protein	P17252	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0000599								15730925	f		irozzo	PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC.	SIGNOR-256266	0.7
SRC	protein	P12931	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates activity	phosphorylation	Tyr783	EGRNPGFyVEANPMP	-1									7682059	t		lperfetto	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-247316	0.62
PTPN6	protein	P29350	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606									10734133	t		flangone	Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1.	SIGNOR-75930	0.365
XBP1	protein	P17861	UNIPROT	B-Lymphocyte_diff	phenotype	SIGNOR-PH113	SIGNOR	up-regulates activity				9606	BTO:0000392								11460154	f			XBP-1 is the only transcription factor known to be selectively and specifically required for the terminal differentiation of B lymphocytes to plasma cells.	SIGNOR-259957	0.7
MTOR	protein	P42345	UNIPROT	AMBRA1	protein	Q9C0C7	UNIPROT	down-regulates activity	phosphorylation	Ser52	KRVELPDsPRSTFLL										23524951	t		lperfetto	We show that under non-autophagic conditions, mTOR inhibits AMBRA1 by phosphorylation, whereas on autophagy induction, AMBRA1 is dephosphorylated. In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. As ULK1 has been shown to activate AMBRA1 by phosphorylation, the proposed pathway may act as a positive regulation loop, which may be targeted in human disorders linked to impaired autophagy.|mTOR phosphorylates AMBRA1 at Ser 52, inhibiting its role in ULK1 modification	SIGNOR-272986	0.484
GLI2	protein	P10070	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002572								16571352	f		lperfetto	Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1.	SIGNOR-209629	0.434
pazopanib hydrochloride	chemical	CHEBI:71217	ChEBI	RTKs	proteinfamily	SIGNOR-PF38	SIGNOR	down-regulates activity	chemical inhibition			-1									17620431	t		miannu	The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases.	SIGNOR-259451	0.8
IDH3G	protein	P51553	UNIPROT	IDH	complex	SIGNOR-C396	SIGNOR	form complex	binding			9606									28139779	t		miannu	Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. 	SIGNOR-266247	0.687
PDPK1	protein	O15530	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates activity	phosphorylation	Ser422	AEAFLGFsYAPPTDS	-1									10191262	t		miannu	The activation of SGK by PDK1 in vitro is unaffected by PtdIns(3,4,5)P3, abolished by the mutation of Ser422 to Ala, and greatly potentiated by mutation of Ser422 to Asp	SIGNOR-250274	0.634
dopamine	smallmolecule	CHEBI:18243	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257478	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	BAIAP2	protein	Q9UQB8	UNIPROT	down-regulates	phosphorylation	Ser366	KTLPRSSsMAAGLER	9606									19933840	t		lperfetto	Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction	SIGNOR-216572	0.2
CTSL	protein	P07711	UNIPROT	BGLAP	protein	P02818	UNIPROT	down-regulates quantity by destabilization	cleavage	Arg94	IGFQEAYrRFYGPV	-1									9076588	t		miannu	This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 	SIGNOR-256322	0.2
LCK	protein	P06239	UNIPROT	DOK1	protein	Q99704	UNIPROT	up-regulates activity	phosphorylation			9606									10799545	t			Phosphorylation of p56 dok and p62 dok is increased following CD2 stimulation and requires Lck. Phosphorylation of Dok proteins by Lck might provide a mechanism by which SH2-containing proteins can be recruited and co-localized with their substrates.	SIGNOR-251373	0.582
MECP2	protein	P51608	UNIPROT	OPRK1	protein	P41145	UNIPROT	up-regulates quantity by expression	post transcriptional regulation			10090	BTO:0000614								18511691	t		Luana	MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.	SIGNOR-264677	0.276
BUD13	protein	Q9BRD0	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270672	0.535
PTPRJ	protein	Q12913	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Tyr205	IMLNSKGyTKSIDIW	9606	BTO:0000007								19494114	t		lperfetto	In this study we show that one of these potential targets, the erk1/2, is indeed a direct dep-1 substrate in vivo.	SIGNOR-101276	0.415
AKT2	protein	P31751	UNIPROT	JAG1	protein	P78504	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									38402584	f		miannu	Jagged1 is upregulated by Akt upon activation by R-Ras. All three Akt isoforms influence Jagged1 expression in ECs, but Akt3 is the most prominent Akt isoform in this role, despite its low expression level compared with Akt1. Jagged1 then activates Notch to upregulate Hey1, Hes1, p21, p53, and Unc5b in adjacent cells. 	SIGNOR-277223	0.312
P2RY12	protein	Q9H244	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257107	0.2
UBA1	protein	P22314	UNIPROT	Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	form complex	binding			9606									24816100	t		miannu	The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin.	SIGNOR-270833	0.2
CDK1	protein	P06493	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates	phosphorylation	Ser465	MVPGGDRsPSRMLPP	9606	BTO:0000150;BTO:0001130								16407259	t		llicata	In vitro kinase assays using recombinant cdc2 kinase showed that runx2 was phosphorylated at ser(451) the cdc2 inhibitor roscovitine dose dependently inhibited in vivo runx2 dna-binding activity during mitosis and the runx2 mutant s451a exhibited lower dna-binding activity and reduced stimulation of anchorage-independent growth relative to wild type runx2.	SIGNOR-143586	0.492
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation			9606									12510059	t	inferred from 70% family members	gcesareni	Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1.	SIGNOR-269997	0.2
UBE2L3	protein	P68036	UNIPROT	PRKN	protein	O60260	UNIPROT	up-regulates activity	ubiquitination			-1									19240029	t		miannu	Only UbcH5 and Related Class I E2s Support Ubiquitination of S5a—UbcH5 belongs to the Class I family of E2s which contains a catalytic core (UBC domain) without a distinct Ub binding domain (38). To test whether other Class I E2s can also support ubiquitination of S5a, we assayed the ubiquitination of S5a with UbcH7 and the E3s, Nedd4, or Parkin. With either of these E3s, UbcH7 supported ubiquitination of S5a (Fig. 8, A and B). In addition, another Class I E2, Ubc4, a close homolog of UbcH5, supported ubiquitination of S5a by the APC, a multimeric Ring finger E3 responsible for cell cycle progression through mitosis (39) (Fig. 8C). Thus, multiple Class I E2s can support ubiquitination of S5a by various types of E3s (Table 1).	SIGNOR-272734	0.2
PLK1	protein	P53350	UNIPROT	TRIOBP	protein	Q9H2D6	UNIPROT	up-regulates	phosphorylation	Thr2229	QAEEREHtLRRCQQE	9606									22820163	t		lperfetto	Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1	SIGNOR-198353	0.34
GDNF	protein	P39905	UNIPROT	GFRA1	protein	P56159	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000142							9182803	t		gcesareni	A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling	SIGNOR-49091	0.793
RARA	protein	P10276	UNIPROT	RXRA	protein	P19793	UNIPROT	up-regulates	binding			9606									1310351	t		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16433	0.711
STAT6	protein	P42226	UNIPROT	STAT1	protein	P42224	UNIPROT	down-regulates activity	binding			9606	BTO:0000801								10982806	t		lperfetto	STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site	SIGNOR-249552	0.466
ADCY1	protein	Q08828	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates	chemical modification			9606									22863277	t		milica	To further explore the role of camp signaling in the hippo pathway, we treated cells with forskolin, an activator of adenylyl cyclase that results in cAMP production.	SIGNOR-198486	0.8
CDK1	protein	P06493	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates activity	phosphorylation	Thr326	GCYSVPTtPEDFLSN										26375055	t		lperfetto	We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity	SIGNOR-276519	0.261
AFDN	protein	P55196	UNIPROT	RIT1	protein	Q92963	UNIPROT	up-regulates activity	binding			9606									10545207	t		miannu	Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors.	SIGNOR-220917	0.2
CSNK2A1	protein	P68400	UNIPROT	IGFBP3	protein	P17936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser138	PPAPGNAsESEEDRS	9606	BTO:0000093								10650937	t		llicata	The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro | These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment.	SIGNOR-250903	0.344
NARS1	protein	O43776	UNIPROT	asparagine	smallmolecule	CHEBI:22653	ChEBI	down-regulates quantity	chemical modification			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270454	0.8
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2Q2	protein	Q8WVN8	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271363	0.401
PRKCZ	protein	Q05513	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Ser641	GKVYGKTsHLRAHLR	9606									19464346	t		gcesareni	The hdac inhibitor tsa-induced cell-specific phosphatase release from the promoter, which serves as an 'on' mechanism for sp1 phosphorylation by phosphatidylinositol 3-kinase/protein kinase czeta (pi3k/pkczeta) at ser641, leading to p107 repressor derecruitment and lhr transcriptional activation.	SIGNOR-185741	0.498
ME1	protein	P48163	UNIPROT	NADP(3-)	smallmolecule	CHEBI:58349	ChEBI	down-regulates quantity	chemical modification			9606									33064660	t		miannu	Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP.	SIGNOR-267722	0.8
TNKS2	protein	Q9H2K2	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates quantity by destabilization				9606	BTO:0000007								19759537	t			Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway.	SIGNOR-261248	0.451
AKT2	protein	P31751	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates activity	phosphorylation			9606									21620960	t		lperfetto	Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity.	SIGNOR-233529	0.593
NHP2	protein	Q9NX24	UNIPROT	TERT	protein	O14746	UNIPROT	up-regulates activity	binding												18680434	t		lperfetto	A complex of four proteins (GAR1, NHP2, NOP10, and the putative pseudouridine synthase dyskerin) associates with snoRNAs to form small nucleolar ribonucleoprotein particles (snoRNPs), and the binding of this complex to the H/ACA domain of TERC may have a role in the biogenesis of the telomerase RNP	SIGNOR-263330	0.644
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	ADAM19	protein	Q9H013	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10933396	f		gcesareni	Interestingly, in absence of delta signal, both hes-1 and tcfl5 decreased, and further decreased by incubation with dapt. (figure 4). This pharmacological approach therefore provides additional evidence that tcfl5, similar to hes1, is a true notch target gene.	SIGNOR-254340	0.2
SPI1	protein	P17947	UNIPROT	GATA2	protein	P23769	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12433372	f		irozzo	Using these progenitors and a conditionally activatable PU.1 protein, we show that PU.1 can negatively regulate expression of the GATA-2 gene.The above experiments suggested that PU.1 may physiologically downregulate the expression of the GATA-2 gene during the differentiation of myeloid progenitors into macrophages. 	SIGNOR-256069	0.596
UBE2N	protein	P61088	UNIPROT	TRAF2	protein	Q12933	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0000785								14713952	t		lperfetto	Intact ring and zinc finger domains are required for tnfalfa-induced traf2 ubiquitination, which is also dependent on ubc13. Traf2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of jnk. Ubc13 expression by rnai resulted in tnfalfa-induced traf2 translocation and impaired activation of jnk but not of ikk or p38.	SIGNOR-121274	0.439
EDNRB	protein	P24530	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257321	0.409
TNFRSF1A	protein	P19438	UNIPROT	TRADD	protein	Q15628	UNIPROT	up-regulates activity	binding			9606									11502070	t		lperfetto	The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd.	SIGNOR-109719	0.799
AURKA	protein	O14965	UNIPROT	ARHGEF2	protein	Q92974	UNIPROT	down-regulates activity	phosphorylation	Ser960	SRLSPPHsPRDFTRM	9606	BTO:0000567								17488622	t		miannu	The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity.	SIGNOR-276061	0.339
PRKCZ	protein	Q05513	UNIPROT	ADARB1	protein	P78563	UNIPROT	up-regulates activity	phosphorylation	Ser211	GDLSLSAsPVPASLA	9606	BTO:0001615								29694894	t		miannu	 Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing. 	SIGNOR-277392	0.2
CDK8	protein	P49336	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser206	SSSTYPHsPTSSDPG	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-189137	0.392
AURKB	protein	Q96GD4	UNIPROT	DSN1	protein	Q9H410	UNIPROT	down-regulates	phosphorylation	Ser109	KETNRRKsLHPIHQG	9606									20471944	t		lperfetto	To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant).	SIGNOR-165550	0.64
MT-ATP8	protein	P03928	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261406	0.2
TXNL4A	protein	P83876	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270638	0.74
NPFFR2	protein	Q9Y5X5	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257104	0.254
ITK	protein	Q08881	UNIPROT	CD28	protein	P10747	UNIPROT	up-regulates	phosphorylation	Tyr209	TRKHYQPyAPPRDFA	9606	BTO:0000782;BTO:0001271								8992971	t		lperfetto	We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tailother studies demonstrated that tyr191 within the p190yap motif is one of two major phosphorylation sites in cd28-stimulated jurkat t cells, and the only tyrosine residue within the cd28 cytoplasmic tail that is essential for delivery of costimulatory signals	SIGNOR-45516	0.677
CHMP4B	protein	Q9H444	UNIPROT	ESCRT-III	complex	SIGNOR-C379	SIGNOR	form complex	binding			-1									26775243	t		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission.	SIGNOR-265533	0.721
GRID2IP	protein	A4D2P6	UNIPROT	GRID2	protein	O43424	UNIPROT	up-regulates quantity	binding			9606									11826110	t		miannu	We identified a novel GluRdelta2-interacting protein, named Delphilin, that contains a single PDZ domain and formin homology (FH) domains FH1 and FH2 plus coiled-coil structure. Delphilin is selectively localized at the postsynaptic junction site of the parallel fiber-Purkinje cell synapse and colocalized with GluRdelta2. Thus, Delphilin is a postsynaptic scaffolding protein at the parallel fiber-Purkinje cell synapse, where it may serve to link GluRdelta2 with actin cytoskeleton and various signaling molecules.	SIGNOR-264475	0.629
GTF2I	protein	P78347	UNIPROT	HSPA5	protein	P11021	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19097122	f	 	miannu	Transcription factor TFII-I causes transcriptional upregulation of GRP78 synthesis in prostate cancer cells.	SIGNOR-254221	0.381
PDZD8	protein	Q8NEN9	UNIPROT	MSN/PDZD8	complex	SIGNOR-C61	SIGNOR	form complex	binding			9606									21549406	t		miannu	These results demonstrated that both human moesin and its newly identified binding partner, pdzd8 had similar effects on host mt networks, suggesting that they are likely to function as part of a stable mt regulatory complex.	SIGNOR-173650	0.324
GSK3B	protein	P49841	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	down-regulates activity	phosphorylation	Ser2070	DEYNVTPsPPGTVLT	9606	BTO:0000007								12794074	t			Ser-2093 is efficiently phosphorylated by GSK-3β and, to a minor extent, residues Thr-2068 and/or Ser-2070 and Thr-2074 of Notch2 are also targets for GSK-3β-dependent phosphorylation. We also find that GSK-3β-dependent phosphorylation of Notch2 is inhibiting transcriptional activation of different Notch target genes. 	SIGNOR-251254	0.495
PP121	chemical	CHEBI:50915	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206289	0.8
PITRM1	protein	Q5JRX3	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates activity	cleavage			9606	BTO:0000142								16849325	t		Giorgia	In the present study we have identified and characterized the human PreP homologue, hPreP, in brain mitochondria, and we show its capacity to degrade the amyloid beta-protein (Abeta). PreP belongs to the pitrilysin oligopeptidase family M16C containing an inverted zinc-binding motif. We show that hPreP is localized to the mitochondrial matrix. In situ immuno-inactivation studies in human brain mitochondria using anti-hPreP antibodies showed complete inhibition of proteolytic activity against Abeta.	SIGNOR-260661	0.381
CASP3	protein	P42574	UNIPROT	BRCA1	protein	P38398	UNIPROT	down-regulates quantity by destabilization	cleavage	Asp1155	ETPDDLLdDGEIKED	9606									12149654	t		miannu	We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable.	SIGNOR-256326	0.486
AKT2	protein	P31751	UNIPROT	SH3RF1	protein	Q7Z6J0	UNIPROT	down-regulates	phosphorylation	Ser304	KNTKKRHsFTSLTMA	9606									17535800	t		gcesareni	Overexpression of posh induces apoptosis in a variety of cell types, but apoptosis can be prevented by co-expressing the pro-survival protein kinase akt. We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac	SIGNOR-155233	0.397
IC-87114	chemical	CHEBI:90686	ChEBI	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206190	0.8
PLK1	protein	P53350	UNIPROT	KAT7	protein	O95251	UNIPROT	up-regulates	phosphorylation	Ser57	SQSSQDSsPVRNLQS	9606									18250300	t		lperfetto	Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate.	SIGNOR-160751	0.518
SRC	protein	P12931	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	unknown	phosphorylation	Tyr488	DVYDDGKyVYVVTEL	9606	BTO:0000007								18156174	t		llicata	The results showed that tyr-488 is a major site of src but mutations at tyr-529 or tyr-707 did not significantly decrease src-dependent tyrosine phosphorylation of rsk2 (fig. 4c). However, we have previously characterized the tyr-488 site that is also phosphorylated by fgfr3 (14), and substitution of tyr-488 did not affect rsk2 activation.	SIGNOR-160056	0.362
NR2F6	protein	P10588	UNIPROT	LHCGR	protein	P22888	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9534	BTO:0000318								10644740	t		Luana	Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription.	SIGNOR-266216	0.308
NVP-BVU972	chemical	CID:44206063	PUBCHEM	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194943	0.8
TRIM21	protein	P19474	UNIPROT	GMPS	protein	P49915	UNIPROT	down-regulates	ubiquitination			9606									24462112	t		miannu	Cytoplasmic sequestration of gmps requires ubiquitylation by trim21, a ubiquitin ligase associated with autoimmune disease.	SIGNOR-204478	0.331
LRRK2	protein	Q5S007	UNIPROT	Autophagy	phenotype	SIGNOR-PH31	SIGNOR	up-regulates				9606	BTO:0000007								22012985	f		gcesareni	We report that LRRK2 activates a calcium-dependent protein kinase kinase-² (CaMKK-²)/adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway which is followed by a persistent increase in autophagosome formation.	SIGNOR-237005	0.7
PIK3CG	protein	P48736	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9534	BTO:0004055								14665640	f		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242658	0.7
MTOR	protein	P42345	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser315	ITATSPAsMVGGKPG	10116	BTO:0000452								11287630	t		lperfetto	Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten	SIGNOR-106578	0.758
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1738	SPSYSPTsPSYSPTS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248777	0.441
PRKAA1	protein	Q13131	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates activity	phosphorylation	Thr1074	QRGSSGHtPPPSGPP	9606									26190112	t		Luana	AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency.	SIGNOR-259862	0.339
CDC25A	protein	P30304	UNIPROT	CDK4	protein	P11802	UNIPROT	up-regulates activity	dephosphorylation	Tyr17	AEIGVGAyGTVYKAR	9606	BTO:0000007								23429262	t		lperfetto	Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs.	SIGNOR-267568	0.694
metyrapone	chemical	CHEBI:44241	ChEBI	CYP11B2	protein	P19099	UNIPROT	down-regulates activity	chemical inhibition			-1									21129965	t		Luana	In an effort to develop and evaluate new classes of compounds as CYP inhibitors, we based our investigations on the structure of the well-known CYP inhibitor Metyrapone 2, which has been used for the treatment of hypercortisolism and Cushing’ssyndrome for several decades.	SIGNOR-257885	0.8
MLKL	protein	Q8NB16	UNIPROT	Necroptosis	phenotype	SIGNOR-PH174	SIGNOR	up-regulates activity				9606									24316671	t		gianni	Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca(2+) influx, which is an early event of TNF-induced necroptosis.	SIGNOR-266431	0.7
N-[2-(4-bromocinnamylamino)ethyl]isoquinoline-5-sulfonamide	chemical	CHEBI:47495	ChEBI	PRKACA	protein	P17612	UNIPROT	down-regulates activity	chemical inhibition			10116									2156866	t		Simone Vumbaca	Kinetic analysis indicated that H-89 inhibits protein kinase A, in competitive fashion against ATP.	SIGNOR-261087	0.8
NOS1	protein	P29475	UNIPROT	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	s-nitrosylation			10090		BTO:0001103							19047631	t		gcesareni	we found that restoration of NO signaling in vivo, by adenoviral-mediated expression of a constitutively active endothelial NOS mutant in MDX muscles, and in vitro, by exposing MDX-derived satellite cells to NO donors, resulted in HDAC2 blockade by cysteine S-nitrosylation	SIGNOR-236919	0.268
TP53	protein	P04637	UNIPROT	BIRC5	protein	O15392	UNIPROT	down-regulates	binding			9606									11714700	t		gcesareni	This study identifies the anti-apoptotic survivin gene as a p53-repressed gene;notably, survivin repression by p53 is shown to be distinct from p53-dependent growth arrest.	SIGNOR-111971	0.544
SMURF1	protein	Q9HCE7	UNIPROT	SLAIN2	protein	Q9P270	UNIPROT	unknown	ubiquitination			-1									20804422	t		miannu	Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay.	SIGNOR-272696	0.2
FGF2	protein	P09038	UNIPROT	BMP2	protein	P12643	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15780951	f		lperfetto	Furthermore, FGF-2 and FGF-9 increased expression of other osteogenic factors BMP-2 and TGFbeta-1. Meanwhile, blocking endogenous FGF signaling, using a virally transduced dominant-negative FGF receptor (FgfR), resulted in drastically reduced expression of the BMP-2 gene, demonstrating for the first time that endogenous FGF/FgfR signaling is a positive upstream regulator of the BMP-2 gene in calvarial osteoblasts	SIGNOR-134785	0.486
ITGB1BP1	protein	O14713	UNIPROT	ITGB5	protein	P18084	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257660	0.323
TPR	protein	P12270	UNIPROT	MAD1L1	protein	Q9Y6D9	UNIPROT	up-regulates	binding			9606	BTO:0000567								18981471	t		miannu	Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20).	SIGNOR-181918	0.498
GRK5	protein	P34947	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	phosphorylation	Thr55	DDIEQWFtEDPGPDE	9606									20124405	t		llicata	Grk5, but not grk2 or grk6, phosphorylates p53 at thr-55, which promotes the degradation of p53, leading to inhibition of p53-dependent apoptotic response to genotoxic damage.	SIGNOR-163707	0.379
ATF1	protein	P18846	UNIPROT	IL10	protein	P22301	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10540320	f		miannu	Our data suggest that intracellular cAMP may directly affect expression of the immunoregulatory cytokine IL-10 in monocytic cells via activation of the eukaryotic transcription factors CREB-1 and ATF-1 and their binding to CRE1 and CRE4 in the upstream enhancer of the IL-10 promoter	SIGNOR-254521	0.252
AMPK	complex	SIGNOR-C15	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	down-regulates activity	phosphorylation			9606	BTO:0000007								18439900	t		lperfetto	The phosphorylation of raptor by ampk is required for the inhibition of mtorc1 and cell-cycle arrest induced by energy stress.	SIGNOR-216430	0.449
PRKCA	protein	P17252	UNIPROT	EWSR1	protein	Q01844	UNIPROT	down-regulates activity	phosphorylation	Ser266	SSYGQQSsFRQDHPS	9606									9341188	t		miannu	Here we report thatews, a nuclearrna-bindingprooncoprotein, contains an iq domain, is phosphorylated byproteinkinase c, and interacts with calmodulin. Interestingly, pkc phosphorylation of ews inhibits its binding to rna homopolymers, and conversely,rna binding to ews interferes with pkc phosphorylation./ these data indicate that ews contains an iq domain with ser266 acting as the primary site for pkc phosphorylation.	SIGNOR-52850	0.337
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	TSC1	protein	Q92574	UNIPROT	down-regulates	phosphorylation	Ser584	ETSIFTPsPCKIPPP	9606	BTO:0000680;BTO:0001573;BTO:0001286								14551205	t		lperfetto	Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex	SIGNOR-216944	0.426
MAPK8	protein	P45983	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr81	APAPAAPtPAAPAPA	9606	BTO:0000007								11283254	t		lperfetto	Jnk phosphorylated p53 at t81 in response to dna damage and stress-inducing agents, as determined by phospho-specific antibodies to t81 . Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress.	SIGNOR-106542	0.79
CTNNB1	protein	P35222	UNIPROT	POU5F1	protein	Q01860	UNIPROT	up-regulates activity	binding			10090	BTO:0001086								21295277	t		flangone	We provide evidence suggesting that Beta-catenin’s interaction with the pluripotency regulator Oct-4 at least partially underlies its effects on sustaining pluripotency.	SIGNOR-241981	0.593
BMX	protein	P51813	UNIPROT	RUFY1	protein	Q96T51	UNIPROT	up-regulates activity	phosphorylation	Tyr400	RQGLDEMySDVWKQL	9534									11877430	t		miannu	 Etk interacts with RUFY1 through its SH3 and SH2 domains. RUFY1 is tyrosine-phosphorylated and appears to be a substrate of Etk. Phosphorylation of the two tyrosine residues, Tyr-281 and Tyr-292, located in the linker region of the two coiled-coil domains by Etk seems to be critical for RUFY1 targeting to the endosomes.	SIGNOR-262679	0.619
BUB1	protein	O43683	UNIPROT	CDC20	protein	Q12834	UNIPROT	down-regulates activity	phosphorylation	Ser92	AAQMEVAsFLLSKEN	9606	BTO:0000567								15525512	t		llicata	Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. 	SIGNOR-250608	0.992
BTF3	protein	P20290	UNIPROT	ABL2	protein	P42684	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000584								17312387	f	 	 	In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis.	SIGNOR-253947	0.2
WNT16	protein	Q9UBV4	UNIPROT	CHRNA1	protein	P02708	UNIPROT	up-regulates				9606	BTO:0000938	BTO:0000887							22309736	f		gcesareni	We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles.	SIGNOR-195969	0.2
GSK3B	protein	P49841	UNIPROT	CLASP2	protein	O75122	UNIPROT	down-regulates activity	phosphorylation	Ser537	REASRESsRDTSPVR	9534	BTO:0004055								19638411	t		lperfetto	GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells	SIGNOR-264826	0.529
HTR2C	protein	P28335	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257221	0.549
COL4A3	protein	Q01955	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	up-regulates activity	binding			9606	BTO:0000664								12123670	t		lperfetto	We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1.	SIGNOR-253244	0.431
CASP2	protein	P42575	UNIPROT	Caspase 2 complex	complex	SIGNOR-C227	SIGNOR	form complex	binding								cleavage:Asp347	SPGCEESdAGKEKLP			21828056	t		lperfetto	Like other caspases, caspase-2 is synthesized as an inactive zymogen. The zymogen sequence includes a long prodomain containing a CARD followed by a large domain, a linker, and a small domain. Caspase-2 undergoes autocatalytic activation to remove the prodomain and linker region to generate a stable dimer consisting of the large subunit (p19) and the small subunit (p12). This p19/p12 dimer self-associates to form the active caspase-2	SIGNOR-256389	0.2
PRKACA	protein	P17612	UNIPROT	ALOX5	protein	P09917	UNIPROT	down-regulates activity	phosphorylation	Ser524	GMRGRKSsGFPKSVK	-1									15280375	t		lperfetto	These results indicate that PKA phosphorylates 5-LO on Ser-523, which inhibits the catalytic activity of 5-LO and reduces cellular LT generation.	SIGNOR-264410	0.341
SYK	protein	P43405	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation	Tyr350	EPPDHQYyNDFPGKE	9606	BTO:0000782								9710204	t		gcesareni	The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2).	SIGNOR-59639	0.753
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1934	SPTYSPTsPKGSTYS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120072	0.781
PRKACA	protein	P17612	UNIPROT	GRIA4	protein	P48058	UNIPROT	up-regulates	phosphorylation	Ser862	IRNKARLsITGSVGE	9606									12536214	t		gcesareni	We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus.	SIGNOR-97550	0.415
MAPK1	protein	P28482	UNIPROT	RAI14	protein	Q9P0K7	UNIPROT	unknown	phosphorylation	Thr249	SQDADLKtPTKPKQH	10090	BTO:0000944								22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262760	0.269
RALA	protein	P11233	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Thr455	ALGTPVLtPPTEAAS	10090	BTO:0000944								11689711	t		gcesareni	We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT.	SIGNOR-252985	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	PPM1D	protein	O15297	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser40	PTAEEKPsPRRSLSQ										33309518	t		lperfetto	Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20)	SIGNOR-275490	0.341
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	IKZF1	protein	Q13422	UNIPROT	up-regulates	dephosphorylation			9606									21750978	t		lperfetto	Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway	SIGNOR-264663	0.2
2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide	chemical	CHEBI:91426	ChEBI	SYK	protein	P43405	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000793								30744170	t		lperfetto	The Selective SYK Inhibitor BAY 61-3606 Enhances the Effect of Chemotherapeutic Drugs on Neuroblastoma Cells	SIGNOR-262020	0.8
PRKACA	protein	P17612	UNIPROT	RXRA	protein	P19793	UNIPROT	down-regulates	phosphorylation	Ser27	TSPTGRGsMAAPSLH	9606									11162439	t		llicata	Serine 27, a human retinoid x receptor alpha residue, phosphorylated by protein kinase a is essential for cyclicamp-mediated downregulation of rxralpha function.	SIGNOR-104954	0.2
CENPC	protein	Q03188	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265200	0.651
CNTFR	protein	P26992	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates				9606									10582086	f		gcesareni	Clc/clf activates stat1 and stat3.	SIGNOR-72774	0.346
HTR7	protein	P34969	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257055	0.284
PLK4	protein	O00444	UNIPROT	PLK4	protein	O00444	UNIPROT	up-regulates	phosphorylation	Ser305	SSTSISGsLFDKRRL	9606									20032307	t		llicata	Autophosphorylation probably plays a role in the process of centriole duplication, because mimicking s305 phosphorylation enhances the ability of overexpressed plk4 to induce centriole amplification. Importantly, we show that s305-phosphorylated plk4 is specifically sequestered at the centrosome contrary to the nonphosphorylated form.	SIGNOR-162559	0.2
ponatinib	chemical	CHEBI:78543	ChEBI	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	down-regulates activity	chemical inhibition			9606	BTO:0001056								23409026	t		miannu	Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. 	SIGNOR-259268	0.8
RPL22	protein	P35268	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262499	0.849
ETV6	protein	P41212	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002883								16828711	f	 	miannu	 Forced expression of TEL stimulated transcription via the p53-responsive element and increased the expression of cellular target genes for p53 such as cell cycle regulator p21 and apoptosis inducer Puma.	SIGNOR-254138	0.344
ATM	protein	Q13315	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	down-regulates	phosphorylation	Thr491	PQQRNALtPTTIPDG	9606									18769144	t		lperfetto	Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively	SIGNOR-180755	0.413
IRF4	protein	Q15306	UNIPROT	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606									22378047	f		lperfetto	IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization.	SIGNOR-249559	0.7
HCRTR1	protein	O43613	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257354	0.425
HBA1	protein	P69905	UNIPROT	EDN1	protein	P05305	UNIPROT	down-regulates activity				9606									8573884	f	Regulation of localization	miannu	Hb inhibitory activity toward ET-1 production might be related to Hb mediated endothelial oxidative injury.	SIGNOR-251767	0.264
SARS1	protein	P49591	UNIPROT	tRNA(Ser)	smallmolecule	CHEBI:29179	ChEBI	down-regulates quantity	chemical modification			9606									24095058	t		miannu	As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis	SIGNOR-270493	0.8
LRRK2	protein	Q5S007	UNIPROT	SNAPIN	protein	O95295	UNIPROT	down-regulates	phosphorylation	Thr117	NHSVAKEtARRRAML	9606	BTO:0000938	BTO:0000142							23949442	t		lperfetto	Lrrk2 phosphorylates snapin and inhibits interaction of snapin with snap-25. these data suggest that lrrk2 may regulate neurotransmitter release via control of snapin function by inhibitory phosphorylation. hreonine 117 of snapin is one of the sites phosphorylated by lrrk2	SIGNOR-202436	0.53
EIF2B1	protein	Q14232	UNIPROT	EIF2S3	protein	P41091	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269134	0.681
LAMC1	protein	P11047	UNIPROT	Laminin-10	complex	SIGNOR-C182	SIGNOR	form complex	binding												11821406	t		lperfetto	The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia.	SIGNOR-253231	0.694
BRCA1	protein	P38398	UNIPROT	FOXC2	protein	Q99958	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000150								22120723	f		miannu	 We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner.	SIGNOR-253760	0.263
Av/b2 integrin	complex	SIGNOR-C176	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269025	0.7
AMPK	complex	SIGNOR-C15	SIGNOR	GLI1	protein	P08151	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser408	GPLPRAPsISTVEPK										26843621	t			Indeed we show that AMPK phosphorylates Gli1 at the unique residue Ser408, which is conserved only in primates but not in other species. Once phosphorylated, Gli1 is targeted for proteasomal degradation.	SIGNOR-253540	0.3
PTPRA	protein	P18433	UNIPROT	LYN	protein	P07948	UNIPROT	down-regulates activity	dephosphorylation	Tyr397	RVIEDNEyTAREGAK	10116									15537644	t			We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397|Lyn expressed in CHO cells has a substantially higher specific activity than Lyn in RBL cells because of high levels of phosphorylation at its active site Tyr-397 (Fig. 1). Enhanced Lyn kinase activity in the CHO cells leads to spontaneous phosphorylation of multiple cellular proteins, including FcϵRI	SIGNOR-248436	0.305
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	HIF1A	protein	Q16665	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000567								18519666	t	inferred from 70% family members	lperfetto	We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_	SIGNOR-270191	0.2
sorafenib tosylate	chemical	CHEBI:50928	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates activity	chemical inhibition			-1									16757355	t		miannu	Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 	SIGNOR-259222	0.8
phenformin	chemical	CHEBI:8064	ChEBI	KCNJ11	protein	Q14654	UNIPROT	down-regulates activity	chemical inhibition			9606									20188727	t		lperfetto	Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel |Phenformin but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1).	SIGNOR-262031	0.8
ATM	protein	Q13315	UNIPROT	TAOK1	protein	Q7L7X3	UNIPROT	up-regulates	phosphorylation	Ser990	SRSTSVTsQISNGSH	9606									17396146	t		gcesareni	The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells.	SIGNOR-154167	0.394
FANCG	protein	O15287	UNIPROT	D1-D2-G-X3 complex	complex	SIGNOR-C301	SIGNOR	form complex	binding			9606	BTO:0000567								18212739	t		lperfetto	These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). 	SIGNOR-263254	0.727
PRKACA	protein	P17612	UNIPROT	SCRIB	protein	Q14160	UNIPROT	unknown	phosphorylation	Ser1445	PSPTSRQsPASPPPL	9606	BTO:0000007								20622900	t		miannu	HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further.	SIGNOR-263066	0.252
GRK2	protein	P25098	UNIPROT	SMO	protein	Q99835	UNIPROT	up-regulates	phosphorylation			9606									15618519	t		gcesareni	We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins	SIGNOR-132669	0.2
ARID5B	protein	Q14865	UNIPROT	TAL1	protein	P17542	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									29326336	f		miannu	ARID5B positively regulates the expression of TAL1 and its regulatory partners. we also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F).	SIGNOR-256157	0.269
AMPK	complex	SIGNOR-C15	SIGNOR	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation	Ser317	SHLASPPsLGEMQQL	9606									21205641	t		lperfetto	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-216453	0.469
GSK3B	protein	P49841	UNIPROT	FGF14	protein	Q92915	UNIPROT	up-regulates activity	phosphorylation	Ser226	PKPGVTPsKSTSASA	9606	BTO:0000938								32599005	t		lperfetto	Our laboratory has also demonstrated that FGF14 is a key accessory protein that binds to the intracellular Nav1.6 C-terminal tail, and that GSK3β can phosphorylate FGF14 both in vitro and in vivo at S226 [20] in an experimental model of Alzheimer's disease	SIGNOR-275746	0.262
SNRPE	protein	P62304	UNIPROT	U1 snRNP complex	complex	SIGNOR-C480	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270681	0.941
RPS6KB1	protein	P23443	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser291	CGSSGYFsSSPTLSS	9606									22017876	t		llicata	Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation.	SIGNOR-176866	0.659
SGK1	protein	O00141	UNIPROT	KMT2D	protein	O14686	UNIPROT	down-regulates activity	phosphorylation	Ser1331	RGRARLKsTASSIET	9606	BTO:0002181								30943409	t		miannu	 Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity. 	SIGNOR-277447	0.287
CCL3	protein	P10147	UNIPROT	CCR2	protein	P41597	UNIPROT	up-regulates activity	binding			10090									15075201	t		lperfetto	The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days. 	SIGNOR-251723	0.55
ABL1	protein	P00519	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates	phosphorylation	Tyr153	RGNADLAyILSMEPC	9606									15657060	t		gcesareni	C-abl phosphorylates casp9 on tyr-153 in vitro and in vivo in response to dna damage.The Present results demonstrate that c-abl binds directly to casp9.	SIGNOR-133260	0.528
CTDSP1	protein	Q9GZU7	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation	Ser250	TGSPAELsPTTLSPV	9606	BTO:0000007								17035229	t			SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248796	0.493
MTOR	protein	P42345	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates activity	phosphorylation	Ser859	DTSSLTQsAPASPTN	9606	BTO:0000007								19864431	t		lperfetto	Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855))	SIGNOR-188920	0.989
bis(2-ethylhexyl) phthalate	chemical	CHEBI:17747	ChEBI	SLC5A5	protein	Q92911	UNIPROT	up-regulates quantity by expression				10116									16257484	f		miannu	DIDP, BBP and DOP stimulate NIS mRNA expression. Here, hNIS promoter construct (N3) was up-regulated 2.5-fold by DIDP, 2.6-fold by BBP and 2.4-fold by DOP in the presence of TSH. Likewise, these phthalates also enhanced rNIS endogenous mRNA expression, which increased ca. 2-fold after 48 h of treatment compared with the expression level generated by TSH only. At 72 h, mRNA content was unchanged.	SIGNOR-268744	0.8
SCRIB	protein	Q14160	UNIPROT	Scribble_complex_DLG2-LLGL2_variant	complex	SIGNOR-C503	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270880	0.538
LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	VEPH1	protein	Q14D04	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000938								22055343	f	In the neuronal differentiation	lperfetto	Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9	SIGNOR-269959	0.2
DYRK1A	protein	Q13627	UNIPROT	DYRK1A	protein	Q13627	UNIPROT	up-regulates	phosphorylation	Tyr321	LGQRIYQyIQSRFYR	9606									10910078	t		lperfetto	Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site	SIGNOR-79764	0.2
PLK1	protein	P53350	UNIPROT	PINX1	protein	Q96BK5	UNIPROT	down-regulates	phosphorylation	Thr317	EDATLEEtLVKKKKK	9606									20573420	t		lperfetto	Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation.	SIGNOR-166333	0.37
CDK5	protein	Q00535	UNIPROT	PPP1R1B	protein	Q9UD71	UNIPROT	up-regulates activity	phosphorylation	Thr75	RPNPCAYtPPSLKAV	10116	BTO:0000142								10604473	t		llicata	We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism.	SIGNOR-250671	0.769
PPP2CB	protein	P62714	UNIPROT	PRKCB	protein	P05771-2	UNIPROT	down-regulates activity	dephosphorylation	Ser660	QSEFEGFsFVNSEFL	10116									15880462	t			Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform	SIGNOR-248586	0.457
Ile(5)-angiotensin II	smallmolecule	CHEBI:2719	ChEBI	AGTR1	protein	P30556	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257459	0.8
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	PSEN1	protein	P49768	UNIPROT	down-regulates activity	phosphorylation	Ser353	SHLGPHRsTPESRAA	9606	BTO:0000007								17360711	t		gcesareni	We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin.	SIGNOR-228018	0.404
CSNK2A1	protein	P68400	UNIPROT	EIF2B5	protein	Q13144	UNIPROT	up-regulates activity	phosphorylation	Ser718	KEAEEESsEDD	9606	BTO:0000007								11500362	t		llicata	Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro. 	SIGNOR-250860	0.394
SAMM50	protein	Q9Y512	UNIPROT	SAM complex	complex	SIGNOR-C422	SIGNOR	form complex	binding												31387448	t		lperfetto	The SAM complex of the outer membrane mediates insertion of β-barrel proteins into the outer membrane. hSam50 associates with MTX1 and MTX2. 	SIGNOR-267683	0.8
NEFM	protein	P07197	UNIPROT	Neurofilament bundle assembly	phenotype	SIGNOR-PH72	SIGNOR	up-regulates				9606									8376466	f		miannu	Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons.	SIGNOR-252391	0.7
glycine	smallmolecule	CHEBI:15428	ChEBI	GLRA1	protein	P23415	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9009272	t		miannu	For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system.	SIGNOR-258580	0.8
mTORC2	complex	SIGNOR-C2	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Thr450	TAQMITItPPDQDDS	10090	BTO:0002572								18566586	t		gcesareni	MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt	SIGNOR-252448	0.634
BZW2	protein	Q9Y6E2	UNIPROT	EIF3A	protein	Q14152	UNIPROT	up-regulates activity	binding			9606									31643092	t		miannu	BZW2, as an evolutionary highly conserved protein, interacts with eIF2 and eIF3 and promotes ternary complex formation in vitro	SIGNOR-261221	0.329
TRIM27	protein	P14373	UNIPROT	PIK3C2B	protein	O00750	UNIPROT	down-regulates	ubiquitination			9606									22128329	t		miannu	We now show that trim27 functions as an e3 ligase and mediates lysine 48 polyubiquitination of pi3kc2_, leading to a decrease in pi3k enzyme activity.	SIGNOR-177935	0.411
MAPK8	protein	P45983	UNIPROT	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates activity	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9534	BTO:0004055								8137421	t		lperfetto	The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity.	SIGNOR-252354	0.811
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	G2/M_transition	phenotype	SIGNOR-PH52	SIGNOR	up-regulates													15549093	f		lperfetto	The critical target of the G2 checkpoint is the mitosis-promoting activity of the cyclin B/CDK1 kinase, whose activation after various stresses is inhibited by ATM/ATR, CHK1/CHK2 and/or p38-kinase-mediated subcellular sequestration, degradation and/or inhibition of the CDC25 family of phosphatases that normally activate CDK1 at the G2/M boundary	SIGNOR-251497	0.7
LEF1	protein	Q9UJU2	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606									17081971	f		amattioni	The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells.	SIGNOR-229770	0.7
CSNK2A1	protein	P68400	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	phosphorylation	Thr102	RAAMFPEtLDEGMQI	9606	BTO:0000007								12432063	t		llicata	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin	SIGNOR-250847	0.54
CCKAR	protein	P32238	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257236	0.254
3-isobutyl-1-methyl-7H-xanthine	smallmolecule	CHEBI:34795	ChEBI	PDE1A	protein	P54750	UNIPROT	down-regulates activity	chemical inhibition			9606									22014080	t			Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors.	SIGNOR-256274	0.8
RXRB	protein	P28702	UNIPROT	RARA	protein	P10276	UNIPROT	up-regulates	binding			9606									1310351	t		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16674	0.708
RARG	protein	P13631	UNIPROT	THRA	protein	P10827	UNIPROT	up-regulates	binding			9606									15650024	t		lperfetto	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs	SIGNOR-133237	0.393
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	A4/b7 integrin	complex	SIGNOR-C187	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259011	0.325
DCX DET1-COP1	complex	SIGNOR-C24	SIGNOR	JUN	protein	P05412	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								14739464	t		miannu	We report that human DET1 (hDET1) promotes ubiquitination and degradation of the proto-oncogenic transcription factor c-Jun by assembling a multisubunit ubiquitin ligase containing DNA Damage Binding Protein-1 (DDB1), cullin 4A (CUL4A), Regulator of Cullins-1 (ROC1), and constitutively photomorphogenic-1.  Ablation of any subunit by RNA interference stabilized c-Jun and increased c-Jun-activated transcription. 	SIGNOR-271500	0.379
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates activity	phosphorylation	Thr175	GLLPFLLtHKKRLTD	9606									19661060	t		Manara	We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.	SIGNOR-260881	0.2
PCNA	protein	P12004	UNIPROT	DNA polymerase epsilon	complex	SIGNOR-C377	SIGNOR	up-regulates activity	binding			9534	BTO:0004055								12930972	t		lperfetto	Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA).	SIGNOR-265512	0.557
MYC	protein	P01106	UNIPROT	HLA-A	protein	P04439	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									8206526	f		miannu	 In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene.	SIGNOR-254603	0.272
PRKCH	protein	P24723	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates activity	phosphorylation	Ser876	QGLAERIsVL										12058027	t		lperfetto	Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.	SIGNOR-275956	0.2
4-fluoro-N-{2-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]ethyl}benzamide	chemical	CHEBI:64101	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9550290	t		miannu	Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists.	SIGNOR-258893	0.8
MICU1	protein	Q9BPX6	UNIPROT	MCU_MICU1_variant	complex	SIGNOR-C500	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270867	0.686
CLOCK	protein	O15516	UNIPROT	CRY2	protein	Q49AN0	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f			Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253632	0.923
FBLIM1	protein	Q8WUP2	UNIPROT	FLNB	protein	O75369	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								24165133	t		miannu	Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 	SIGNOR-266106	0.746
cholesta-5,7-dien-3beta-ol	smallmolecule	CHEBI:17759	ChEBI	calciol	smallmolecule	CHEBI:28940	ChEBI	up-regulates quantity	precursor of			9606		BTO:0001253							30080183	t		lperfetto	Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin	SIGNOR-270561	0.8
SMAD3	protein	P84022	UNIPROT	PAX8	protein	Q06710	UNIPROT	down-regulates activity	binding			9606									14623893	t		miannu	DNA Binding Activity of Pax8 to the NIS Promoter Is Reduced by Smad3. TGF-β decreases Pax8 DNA binding to the NIS promoter and also found a physical interaction between Pax8 and Smad3.	SIGNOR-251992	0.373
PPARG	protein	P37231	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								32991581	t	brain	lperfetto	NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,	SIGNOR-263984	0.899
methionine	smallmolecule	CHEBI:16811	ChEBI	Met-tRNA(Met)	chemical	CHEBI:16635	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270402	0.8
BRCA1-C complex	complex	SIGNOR-C299	SIGNOR	G2/M_transition-checkpoint	phenotype	SIGNOR-PH146	SIGNOR	up-regulates				9606	BTO:0000567								16391231	f		lperfetto	This result implies that the BRCA1/BARD1–RMN–CtIP complex is required for activation of the G2/M checkpoint.	SIGNOR-263229	0.7
NFIA	protein	Q12857	UNIPROT	NFIX	protein	Q14938	UNIPROT	up-regulates quantity	transcriptional regulation			10090									29106906	t		Gianni	We report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord.	SIGNOR-268871	0.2
GLS	protein	O94925	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	chemical modification			9606									22049910	t		miannu	Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia.	SIGNOR-266910	0.8
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CEBPB	protein	P17676	UNIPROT	up-regulates	phosphorylation	Thr235	SSSSPPGtPSPADAK	9606									22369944	t		lperfetto	Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity.	SIGNOR-217316	0.345
ASH2L	protein	Q9UBL3	UNIPROT	TBX1	protein	O43435	UNIPROT	up-regulates activity	binding			9606									20463296	t	Regulation	miannu	 Tbx1 interacts with Ash2l in both yeast and mammalian cells and Ash2l acts as a transcriptional co-activator in luciferase reporter assays.	SIGNOR-251868	0.313
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	USP24	protein	Q9UPU5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1616	NSHSPAGsAAISQQD	9606	BTO:0000018								27991932	t		lperfetto	 Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604.	SIGNOR-275611	0.26
RAP1GDS1	protein	P52306	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates	binding			9606									21242305	t		miannu	Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob	SIGNOR-171418	0.461
APOC2	protein	P02655	UNIPROT	LPL	protein	P06858	UNIPROT	up-regulates activity				9606									19956660	f	Regulation	miannu	Triglycerides in VLDL are hydrolyzed by lipoprotein lipase, which in turn is activated by apolipoprotein CII on the surface but inhibited by apolipoprotein CIII.	SIGNOR-251846	0.755
7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-2-ol	chemical	CHEBI:111176	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258724	0.8
AKT1	protein	P31749	UNIPROT	ZFP36L1	protein	Q07352	UNIPROT	down-regulates	phosphorylation	Ser92	RFRDRSFsEGGERLL	9606									15538381	t		llicata	Here we report that protein kinase b (pkb/akt) stabilizes are transcripts by phosphorylating brf1 at serine 92 (s92). Recombinant brf1 promoted in vitro decay of are-containing mrna (are-mrna), yet phosphorylation by pkb impaired this activity.	SIGNOR-130376	0.643
DYRK1A	protein	Q13627	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser519	SGYSSPGsPGTPGSR	9606									21215781	t	The effect has been demonstrated using P10636-8	lperfetto	Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna	SIGNOR-171030	0.44
SALL4	protein	Q9UJQ4	UNIPROT	SALL1	protein	Q9NSC2	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19440552	f		miannu	 Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex.	SIGNOR-255127	0.432
SRC	protein	P12931	UNIPROT	WNK4	protein	Q96J92	UNIPROT	down-regulates activity	phosphorylation	Tyr1164	KKEIEDLySRLGKQP	9606	BTO:0002181								25805816	t		miannu	Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4. 	SIGNOR-276896	0.2
SLBP	protein	Q14493	UNIPROT	H2BC18	protein	Q5QNW6	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265394	0.2
WWTR1	protein	Q9GZV5	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates	binding			9606									22153608	t	Runx family members play key roles in regulating mesenchymal stem cell differentiation during bone formation, and therefore the regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation.	gcesareni	Taz binding to the transcription factor runx2 promotes osteoblast lineage specification, whereas taz binding to the transcription factor ppargamma inhibits adipogenesis.	SIGNOR-195218	0.521
TALDO1	protein	P37837	UNIPROT	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	down-regulates quantity	chemical modification			9606									19401148	t		miannu	Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 	SIGNOR-267090	0.8
CAD	protein	P27708	UNIPROT	carbamoyl phosphate(2-)	smallmolecule	CHEBI:58228	ChEBI	up-regulates quantity	chemical modification			9606									24332717	t			In animals, the first three reactions of the pathway are catalyzed by CAD, an 
240 kDa multifunctional protein that combines glutamine-dependent carbamyl phosphate synthetase (GLNCPSase), aspartate transcarbamylase (ATCase), and dihydroorotase (DHOase) activities	SIGNOR-267194	0.8
SOCS5	protein	O75159	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates quantity	binding			9606	BTO:0000007								15590694	t		miannu	SOCS5 Can Physically Associate with the EGFR. The complex recruited by SOCS proteins is composed of ElonginBC, Cullin, and Roc1 (15, 16). Together, this complex has E3 ubiquitin ligase activity. We suspect that the role of the SB domain is to mediate coupling of EGFR with the Elongin-Cullin-Roc E3 ubiquitin ligase complex, resulting in enhanced EGFR degradation. 	SIGNOR-271516	0.458
sphingosine 1-phosphate	smallmolecule	CHEBI:37550	ChEBI	S1PR3	protein	Q99500	UNIPROT	up-regulates activity	chemical activation			10116									10617617	t			We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation.	SIGNOR-261142	0.8
KDM6B	protein	O15054	UNIPROT	M1_polarization	phenotype	SIGNOR-PH54	SIGNOR	down-regulates				9606									22378047	f		lperfetto	IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization.	SIGNOR-249563	0.7
LATS2	protein	Q9NRM7	UNIPROT	SNAI1	protein	O95863	UNIPROT	up-regulates quantity by stabilization	phosphorylation			-1									24157836	t		miannu	FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. 	SIGNOR-272138	0.543
CDH1	protein	P12830	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265863	0.959
PPP2CB	protein	P62714	UNIPROT	AKT2	protein	P31751	UNIPROT	down-regulates	dephosphorylation			9606									8650155	t		gcesareni	These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity	SIGNOR-42123	0.458
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser276	PQRSRSPsPQPSSHV	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248690	0.613
BTRC	protein	Q9Y297	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000944								16421275	t		lperfetto	Here we show that Gli is rapidly destroyed by the proteasome and that mouse basal cell carcinoma induction correlates with Gli protein accumulation. We identify two independent destruction signals in Gli1, D(N) and D(C), and show that removal of these signals stabilizes Gli1 protein and rapidly accelerates tumor formation in transgenic animals.Levels of _TrCP appeared to be limiting for Gli1 degradation, as increasing the levels of _TrCP protein significantly decreased steady-state levels of Gli1 protein	SIGNOR-235631	0.649
PRKD1	protein	Q15139	UNIPROT	PRKD1	protein	Q15139	UNIPROT	unknown	phosphorylation	Ser738	ARIIGEKsFRRSVVG	-1									10867018	t		lperfetto	The last two autophosphorylation sites (Ser(744) and Ser(748)) are located in the activation loop but are only phosphorylated in the isolated PKD-catalytic domain and not in the full-length PKD; they may affect enzyme catalysis but are not involved in the activation of wild-type PKD by phorbol ester. | These results indicate that neither of the activation loop serines is involved in PDBu-induced activation but that they may be involved in catalysis or in maintaining the conformation of the enzyme prot	SIGNOR-249046	0.2
GAS6	protein	Q14393	UNIPROT	MERTK	protein	Q12866	UNIPROT	up-regulates	binding			9606		BTO:0000975							8939948	t		gcesareni	We also found that gas6 stimulated tyrosine phosphorylation of axl, sky, and mer receptors ectopically expressed in chinese hamster ovary cells. Taken together, these findings suggest that gas6 is a common ligand for axl, sky, and mer, all known members of an axl/sky receptor subfamily.	SIGNOR-44953	0.754
CUL4A	protein	Q13619	UNIPROT	Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	form complex	binding			9606									22649780	t		gcesareni	The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors	SIGNOR-234793	0.899
MYO9B	protein	Q13459	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260510	0.521
GSK3B	protein	P49841	UNIPROT	ACLY	protein	P53396	UNIPROT	up-regulates activity	phosphorylation	Ser451	STSTPAPsRTASFSE										10653665	t			Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3)	SIGNOR-251218	0.371
CNOT8	protein	Q9UFF9	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	form complex	binding			9606									19558367	t		lperfetto	In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules.	SIGNOR-268310	0.784
IKBKE	protein	Q14164	UNIPROT	TANK	protein	Q92844	UNIPROT	down-regulates activity	phosphorylation	Ser126	RKETSARsLGSPLLH	9534	BTO:0000298								10759890	t		miannu	IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex	SIGNOR-262715	0.734
gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	GABA-A (a3-b1-g2) receptor	complex	SIGNOR-C332	SIGNOR	up-regulates activity	chemical activation			9606									18790874	t	brain	lperfetto	Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS).	SIGNOR-263788	0.8
8-oxo-7-[(6-sulfo-2-naphthalenyl)hydrazinylidene]-5-quinolinesulfonic acid	chemical	CHEBI:95064	ChEBI	PTPN11	protein	Q06124	UNIPROT	down-regulates activity	chemical inhibition			9606									16717135	t			These results identified NSC-87877 as the first PTP inhibitor capable of inhibiting Shp2 PTP in cell cultures without a detectable off-target effect.	SIGNOR-261912	0.8
PTPN12	protein	Q05209	UNIPROT	GIT2	protein	Q14161	UNIPROT	down-regulates	dephosphorylation	Tyr392	QDNDQPDyDSVASDE	9606									16317044	t		fspada	Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest.	SIGNOR-142715	0.352
BMP7	protein	P18075	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18719589	f	induction of mitochondrial biogenesis	fspada	Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways	SIGNOR-180314	0.294
DAG1	protein	Q14118	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255983	0.574
KMT2A	protein	Q03164	UNIPROT	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	up-regulates				9606									22303254	f			Polycomb group (PcG) and Trithorax group (TrxG) proteins are epigenetic regulators that control gene expression through modulating chromatin structure and addition of posttranslational modifications (PTMs) on histones	SIGNOR-268626	0.7
DLL3	protein	Q9NYJ7	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates activity	binding			9606	BTO:0000776								16140393	t		lperfetto	Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate.	SIGNOR-254316	0.47
dimethyloxalylglycine	chemical	CHEBI:102218	ChEBI	EGLN2	protein	Q96KS0	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000018								28900510	t		lperfetto	We treated the A549 cells with the following EGLN/PHD inhibitors: dimethyloxalyglycine (DMOG), CoCl2, inhibitors of dioxygenases, and BAY 85-3494 (BAY), a specific inhibitor of EGLNs with highest potency against EGLN1.	SIGNOR-261992	0.8
CREB5	protein	Q02930	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity	binding			-1									8440710	t	2	miannu	CRE-BPa binds to CRE with higher affinity than to the 12-O-tetradecanoylphorbol-13-acetate response element as a homodimer or a CRE-BPa/c-Jun or CRE-BPa/CRE-BP1 heterodimer.	SIGNOR-240397	0.522
EEF1A1	protein	P68104	UNIPROT	Leu-tRNA(Leu)	smallmolecule	CHEBI:16624	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269513	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MKNK1	protein	Q9BUB5	UNIPROT	up-regulates activity	phosphorylation	Thr250	NSCTPITtPELTTPC	9606	BTO:0000093								17130135	t			We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation	SIGNOR-253014	0.2
PTPN1	protein	P18031	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	dephosphorylation			9606									12377785	t		miannu	PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site.|The nonreceptor tyrosine phosphatase PTP1B associates with the cytoplasmic domain of N-cadherin and may regulate cadherin function through dephosphorylation of beta-catenin.|Thus, interaction of PTP1B with N-cadherin is essential for its association with beta-catenin, stable expression at the cell surface, and consequently, cadherin function.	SIGNOR-277121	0.646
SMARCAD1	protein	Q9H4L7	UNIPROT	HDAC1	protein	Q13547	UNIPROT	up-regulates activity	binding			9606									21549307	t	1	miannu	SMARCAD1 interacts with HDAC1 and KAP1 and is required for their binding to heterochromatin	SIGNOR-239835	0.324
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	FOXO4	protein	P98177	UNIPROT	up-regulates	phosphorylation	Thr451	PIPKALGtPVLTPPT	9606	BTO:0000848	BTO:0001253							20959475	t		lperfetto	Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451).	SIGNOR-168762	0.2
CNP	protein	P09543	UNIPROT	MBP	protein	P02686	UNIPROT	down-regulates activity													28076777	t		SimoneGraziosi	We provide evidence that CNP directly associates with and organizes the actin cytoskeleton, thereby providing an intracellular strut that counteracts membrane compaction by myelin basic protein (MBP).	SIGNOR-269269	0.469
JAK3	protein	P52333	UNIPROT	SIGLEC10	protein	Q96LC7	UNIPROT	up-regulates	phosphorylation	Tyr597	RHSTILDyINVVPTA	9606									11733002	t		lperfetto	These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling	SIGNOR-112479	0.2
ITK	protein	Q08881	UNIPROT	BTK	protein	Q06187	UNIPROT	down-regulates activity	phosphorylation	Tyr223	LKKVVALyDYMPMNA	-1									12573241	t			Btk-SH3 mutant Y223A was not phosphorylated by Itk. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role	SIGNOR-251333	0.474
CSNK2A1	protein	P68400	UNIPROT	KLF1	protein	Q13351	UNIPROT	up-regulates activity	phosphorylation	Thr23	ALGPFPDtQDDFLKW	10090	BTO:0004475								9722526	t	2	miannu	Regulation of erythroid Krƒppel-like factor (EKLF) transcriptional activity by phosphorylation of a protein kinase casein kinase II site within its interaction domain. the transactivation capability of EKLF is augmented by co-transfection of CKIIalpha. in vitro assays demonstrate that CKIIalpha interacts with EKLF, and that the EKLF interaction domain is phosphorylated by CKII only at Thr-41	SIGNOR-241361	0.349
TNFSF13B	protein	Q9Y275	UNIPROT	TNFRSF13C	protein	Q96RJ3	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								15644327	t		lperfetto	Baff interacts with baff receptor (baffr).	SIGNOR-133210	0.778
AURKB	protein	Q96GD4	UNIPROT	YY1	protein	P25490	UNIPROT	up-regulates	phosphorylation	Ser184	GKKSGKKsYLSGGAG	9606									23226345	t		lperfetto	Aurora b kinase phosphorylates yy1 on serine 184 and to a lesser extent serine 180 at the g2/m stage of the cell cycle (fig. 7). We show that yy1 is rapidly dephosphorylated as the cells exit mitosis, likely by pp1. Also, our data indicates that phosphorylation at serine 180 and serine 184 can affect the dna binding activity of yy1	SIGNOR-200079	0.377
PRSS3	protein	P35030	UNIPROT	F2RL1	protein	P55085	UNIPROT	up-regulates activity	cleavage	Arg36	TNRSSKGrSLIGKVD	-1									10978167	t		lperfetto	Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3. 	SIGNOR-263604	0.373
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser363	TSRTPKDsPGIPPSA	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252742	0.754
CAMK2A	protein	Q9UQM7	UNIPROT	NOX5	protein	Q96PH1	UNIPROT	unknown	phosphorylation	Ser548	MRKSQRSsKGSEILL	-1									21642394	t		miannu	In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475.	SIGNOR-276333	0.2
AKT2	protein	P31751	UNIPROT	AKT1S1	protein	Q96B36	UNIPROT	down-regulates	phosphorylation			9606				SIGNOR-C3					17386266	t		gcesareni	Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity.	SIGNOR-153931	0.66
beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	up-regulates quantity	precursor of			9606									30616754	t		lperfetto	FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle	SIGNOR-267589	0.8
RUNX3	protein	Q13761	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255089	0.2
BAK1	protein	Q16611	UNIPROT	ENDOG	protein	Q14249	UNIPROT	up-regulates				9606									12941691	f		gcesareni	We show that the mitochondrial outer-membrane permeabilization induced by bax-, tbid- or bax/bak-dependent pro-apoptotic drugs results in the release of cytochrome c, smac/diablo and htra2/omi, but that subsequent caspase activation is required to induce the translocation of endog in addition to aif into the cytosol.	SIGNOR-86406	0.297
MAPK8	protein	P45983	UNIPROT	MAPK8IP1	protein	Q9UQF2	UNIPROT	unknown	phosphorylation	Ser197	DRVSRSSsPLKTGEQ	9534	BTO:0000298								12756254	t		miannu	After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1.	SIGNOR-250124	0.879
PTPRJ	protein	Q12913	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates activity	dephosphorylation	Tyr1059	DIYKDPDyVRKGDAR	9606									18936167	t			These results therefore suggest that the autoactivation residues Y1054 and Y1059 are targeted by DEP-1 and that this results in the inhibition of kinase activity and the consequent general dephosphorylation of VEGFR2.	SIGNOR-248710	0.687
GSK3A	protein	P49840	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	up-regulates activity	phosphorylation	Ser49	CHRLPPGsLSSTPLS	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159365	0.2
SKP2	protein	Q13309	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	ubiquitination			9606									17409098	t		gcesareni	Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3).	SIGNOR-154194	0.758
PRKCA	protein	P17252	UNIPROT	GSK3A	protein	P49840	UNIPROT	down-regulates	phosphorylation	Ser21	SGRARTSsFAEPGGG	9606									11884598	t		lperfetto	Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway.	SIGNOR-115714	0.352
regorafenib	chemical	CHEBI:68647	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates activity	chemical inhibition			9606									24756792	t		miannu	In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically.	SIGNOR-259205	0.8
F2R	protein	P25116	UNIPROT	KLF6	protein	Q99612	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254849	0.2
KSR1	protein	Q8IVT5	UNIPROT	ARAF	protein	P10398	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								29433126	t		miannu	 In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. 	SIGNOR-273876	0.548
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	tRNA(Asp)	smallmolecule	CHEBI:29186	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270371	0.8
MAP2K6	protein	P52564	UNIPROT	MAPK13	protein	O15264	UNIPROT	up-regulates activity	phosphorylation	Tyr182	ADAEMTGyVVTRWYR	9606	BTO:0000007								10066767	t	done	miannu	 p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.	SIGNOR-273951	0.645
MAFA	protein	Q8NHW3	UNIPROT	PDX1	protein	P52945	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17149590	f		miannu	 the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA.	SIGNOR-254562	0.737
FLT3	protein	P36888	UNIPROT	PARP1	protein	P09874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									21228325	f			Interestingly, quantitative RT-PCR analysis demonstrated a 2-fold increase in PARP-1 expression. Western blotting analysis of protein nuclear extracts from FLT3/ITD B-cells confirmed that PARP1 was up-regulated, compared with wild-type controls 	SIGNOR-261554	0.253
dopamine	smallmolecule	CHEBI:18243	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258376	0.8
MECP2	protein	P51608	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	up-regulates				10090		BTO:0000601							25420914	f		Luana	Our current study highlights the phosphorylation, but not the overall expression level, of MeCP2 as a significant regulatory mechanism in regulating adult neurogenesis in the hippocampus. 	SIGNOR-264967	0.7
SPTB	proteinfamily	SIGNOR-PF73	SIGNOR	Non-erythrocytic spectrin	complex	SIGNOR-C385	SIGNOR	form complex	binding			9606									24302288	t		lperfetto	Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell	SIGNOR-266027	0.2
NMUR2	protein	Q9GZQ4	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257218	0.44
TGFB2	protein	P61812	UNIPROT	TGFB2	protein	P61812	UNIPROT	up-regulates	binding			9606									16885528	t		gcesareni	The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge	SIGNOR-148608	0.2
PLCB3	protein	Q01970	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	up-regulates quantity													23994464	f		apalma	The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release	SIGNOR-255014	0.8
Apoptosome	complex	SIGNOR-C230	SIGNOR	CASP3	protein	P42574	UNIPROT	up-regulates activity	cleavage			9606									15657060	t		lperfetto	Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3.	SIGNOR-256471	0.731
HOXD13	protein	P35453	UNIPROT	EPHA7	protein	Q15375	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16314414	f		miannu	We show that hoxd13 andhoxa13activate transcription from the epha7 promoter and that a mutation of thehoxa13/hoxd13 binding site was sufficient to abolish activation.	SIGNOR-142453	0.275
MAPK8IP1	protein	Q9UQF2	UNIPROT	MAP3K10	protein	Q02779	UNIPROT	up-regulates	binding			9606									15767678	t		gcesareni	The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.	SIGNOR-134552	0.519
FANCI	protein	Q9NVI1	UNIPROT	Fanconi anemia ID complex	complex	SIGNOR-C302	SIGNOR	form complex	binding			9606	BTO:0000007								17412408	t		lperfetto	Immunoprecipitation of HA-FLAG-tagged FANCI expressed in 293T cells with antibodies against either HA or FLAG, but not MYC, resulted in coimmunoprecipitation of endogenous FANCD2|The FANCI protein associates with FANCD2 and, together, as the FANCI-FANCD2 (ID) complex, localize to chromatin in response to DNA damage.	SIGNOR-263269	0.955
SETD2	protein	Q9BYW2	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18158893	f		gcesareni	In response to hypoxia, foxo3a transcript levels accumulate in an hif1-dependent way, resulting in enhanced foxo3a activity.	SIGNOR-160201	0.2
IRX1	protein	P78414	UNIPROT	PTGS2	protein	P35354	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002392								20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed.	SIGNOR-261662	0.2
HTR1E	protein	P28566	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257100	0.255
CDKN1A	protein	P38936	UNIPROT	CDK4	protein	P11802	UNIPROT	down-regulates	binding			9606									7626805	t		gcesareni	P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases.	SIGNOR-29957	0.939
DAPK1	protein	P53355	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Thr18	EPPLSQEtFSDLWKL	9606	BTO:0000776								17339337	t		gcesareni	Dna damage-activated protein kinases like chk1/2 modify the box-i domain of p53 at thr18 and ser20 (46) by an allosteric mechanism (10).	SIGNOR-153491	0.575
CEBPD	protein	P49716	UNIPROT	CCL20	protein	P78556	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000801								23028973	f	 	 	CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions.	SIGNOR-254056	0.253
MAPK1	protein	P28482	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									12110590	t		gcesareni	Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway.	SIGNOR-90517	0.723
LCK	protein	P06239	UNIPROT	IL2RB	protein	P14784	UNIPROT	unknown	phosphorylation	Tyr384	ACQVYFTyDPYSEED	-1									10214954	t			Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510.	SIGNOR-251376	0.629
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Ser65	FLMECRNsPVTKTPP	9606	BTO:0002181			SIGNOR-C3					10942774	t		lperfetto	PHAS-I in adipocytes and HEK293 cells is phosphorylated in the following five sites, all of which conform to a (S/T)P motif (9, 10): Thr-36, Thr-45, Ser-64, Thr-69, and Ser-82. Thr-45 and Ser-64 flank the eIF4E-binding motif (7, 8), and phosphorylation of either site blocks eIF4E binding in vitro (10, 11). Insulin stimulates the phosphorylation of Thr-36, Thr-45, Ser-64, and Thr-69 in both fat cells and HEK293 cells, and incubating cells with rapamycin decreases the phosphorylation of these sites.Immunoprecipitated epitope-tagged mammalian target of rapamycin (mTOR) phosphorylated Thr-36/45. mTOR also phosphorylated Thr-69 and Ser-64 but only when purified immune complexes were incubated with the activating antibody, mTAb1.	SIGNOR-226714	0.924
SKI	protein	P12755	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	binding			9606	BTO:0000848								12793438	t		lperfetto	The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway	SIGNOR-236077	0.716
LCK	protein	P06239	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000782								17998336	t	inferred from 70% of family members	gcesareni	The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1.	SIGNOR-269921	0.569
KIF5B	protein	P33176	UNIPROT	Organelle_transport	phenotype	SIGNOR-PH159	SIGNOR	up-regulates				9606	BTO:0000938								9438838	f		miannu	The kinesin superfamily of proteins plays a major role in this complex organelle transport. Kinesin is primarily associated with anterogradely transported membranous organelles in nerve axons. KIF5B and HsuKHC are expressed ubiquitously in many tissues, whereas KIF5A, KIF5C, and HsnKHC are specific to nerve tissue.	SIGNOR-264068	0.7
EID1	protein	Q9Y6B2	UNIPROT	EP300	protein	Q09472	UNIPROT	down-regulates activity	binding												11073990	t		lperfetto	Inhibition of MyoD may be explained by EID-1's ability to bind and inhibit p300's histone acetylase activity, an essential MyoD coactivator. 	SIGNOR-253377	0.431
NCK1	protein	P16333	UNIPROT	PAK1	protein	Q13153	UNIPROT	up-regulates	binding			9534									8824201	t		lperfetto	We describe here a specific interaction of the Nck adapter molecule with PAK1 both in vitro and in vivo. Association of Nck with PAK1 may serve to link this important regulatory kinase to cell activation by growth factor receptors.	SIGNOR-236324	0.697
PRKCA	protein	P17252	UNIPROT	UNC5A	protein	Q6ZN44	UNIPROT	down-regulates quantity	phosphorylation	Ser352	TSGFQPVsIKPSKAD	10116	BTO:0003036								16554470	t		miannu	We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. 	SIGNOR-268180	0.2
FZD2	protein	Q14332	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates				9606	BTO:0000222								10937998	f		fspada	Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma)	SIGNOR-80601	0.2
BDKRB1	protein	P46663	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257304	0.571
NOTCH1	protein	P46531	UNIPROT	IL2RA	protein	P01589	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001454								10933396	f		gcesareni	Activation of notch1 signaling in dp thymocytes and thymoma cell lines results in the upregulation of cd25 and cd44 expression.	SIGNOR-80336	0.3
CCL3	protein	P10147	UNIPROT	CCR1	protein	P32246	UNIPROT	up-regulates activity	binding			9606									20219869	t		areggio	The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. 	SIGNOR-255114	0.711
ACAN	protein	P16112	UNIPROT	Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	up-regulates activity	binding			9606	BTO:0003858								16051604	t		lperfetto	Cartilage Oligomeric Matrix Protein/Thrombospondin 5 Supports Chondrocyte Attachment through Interaction with Integrins|We show that COMP/TSP5 can support chondrocyte attachment and that the RGD sequence in COMP/TSP5 and the integrin receptors alpha5beta1 and alphaVbeta3 on the chondrocytes are involved in mediating this attachment. The interactions of COMP/TSP5 with the integrins are dependent on COMP/TSP5 conformation.	SIGNOR-266987	0.267
SP1	protein	P08047	UNIPROT	NDUFV2	protein	P19404	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000931								17786189	f		miannu	 Sp1 role in the regulation of complex I subunits, was demonstrated by the ability of the Sp1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, Sp1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin.	SIGNOR-255207	0.352
HMOX1	protein	P09601	UNIPROT	HBA1	protein	P69905	UNIPROT	down-regulates activity				9606									10490932	t	Regulation	miannu	Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme	SIGNOR-251813	0.256
SKIL	protein	P12757	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates activity	binding			9606									10531062	t		lperfetto	Thus, SnoN can interact with Smad4 and Smad2 and inhibit their abilities to activate transcription.	SIGNOR-71633	0.882
DYRK2	protein	Q92630	UNIPROT	CARHSP1	protein	Q9Y2V2	UNIPROT	unknown	phosphorylation	Ser41	LRGNVVPsPLPTRRT	9606									21177848	t		gcesareni	Ser41 is known to be phosphorylated by a dyrk isoform in serum-fed or -starved cells (21). A phosphomimetic mutation of ser41 to asp resulted in complete loss of human crhsp-24 binding ability whether in the oxidative state or not	SIGNOR-170781	0.263
NOS2	protein	P35228	UNIPROT	nitric oxide	smallmolecule	CHEBI:16480	ChEBI	up-regulates				9606									7537672	f		apalma	Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the ammino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline	SIGNOR-255381	0.8
ACO2	protein	Q99798	UNIPROT	citrate(3-)	smallmolecule	CHEBI:16947	ChEBI	down-regulates quantity	chemical modification			9606									24068518	t		miannu	Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained.	SIGNOR-266244	0.8
AKAP13	protein	Q12802	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260527	0.735
TUBB	protein	P07437	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	binding			9606									17429065	t		lperfetto	Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin.	SIGNOR-217631	0.2
IRX1	protein	P78414	UNIPROT	CELF2	protein	O95319	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 	SIGNOR-261657	0.2
CREBBP	protein	Q92793	UNIPROT	LHX3	protein	Q9UBR4	UNIPROT	up-regulates activity	binding			9606									10931853	t		scontino	Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). P-Lim and CBP Act Synergistically in TRH Stimulation of the Human α-GSU Promoter. 	SIGNOR-267206	0.2
EEF1A1P5	protein	Q5VTE0	UNIPROT	Translational_elongation	phenotype	SIGNOR-PH210	SIGNOR	up-regulates				9606									23699257	f		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269395	0.7
FKBP5	protein	Q13451	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	up-regulates quantity by expression	catalytic activity			9606	BTO:0002035								28978117	t		Barakat	FKBP51s upregulated PD-L1 expression on the plasma membrane by catalysing the protein folding required for subsequent glycosylation. Inhibition of FKBP51s isomerase activity by SAFit decreased PD-L1 levels	SIGNOR-274973	0.2
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606		BTO:0000142							10200555	f		amattioni	Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation	SIGNOR-256477	0.7
2-(6-Bromo-1,3-benzodioxol-5-yl)-N-(4-cyanophenyl)-1-[(1S)-1-cyclohexylethyl]benzimidazole-5-carboxamide	chemical	CID:126961335	PUBCHEM	F2RL1	protein	P55085	UNIPROT	down-regulates activity	chemical inhibition			-1									28445455	t		Simone Vumbaca	The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. | Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling.	SIGNOR-261119	0.8
MICU2	protein	Q8IYU8	UNIPROT	MCU_MICU2_variant	complex	SIGNOR-C502	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270877	0.645
PRKDC	protein	P78527	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	down-regulates activity	phosphorylation	Ser43	PAMLHLPsEQGAPET	-1									31932854	t		miannu	Here, we show that DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA double-strand break (DSB) repair, triggers the phosphorylation of NEMO by genotoxic stress, thereby enabling shuttling of NEMO through the nucleus with subsequent NF-κB activation. We identified serine 43 of NEMO as a DNA-PK phosphorylation site and point mutation of this serine to alanine led to a complete block of NF-κB activation by ionizing radiation (IR).	SIGNOR-277508	0.301
ATM	protein	Q13315	UNIPROT	BLM	protein	P54132	UNIPROT	up-regulates	phosphorylation	Thr99	NAPAGQEtQRGGSKS	9606									12034743	t		lperfetto	Mitotic phosphorylation of blm was partially dependent on atm, and phosphorylation sites on blm were identified. A phosphospecific antibody against one of these sites (thr-99) revealed radiation-induced phosphorylation, which was defective in ataxia-telangiectasia cells. These data suggest that atm and blm function together in recognizing abnormal dna structures by direct interaction and that these phosphorylation sites in blm are important for radiosensitivity status but not for sce frequency.	SIGNOR-88010	0.767
PPP2CB	protein	P62714	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates	dephosphorylation			9606									8650155	t		gcesareni	These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity	SIGNOR-42050	0.487
HES1	protein	Q14469	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		BTO:0000759							14614508	t			CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo	SIGNOR-253584	0.251
MRAP	protein	Q8TCY5	UNIPROT	MC1R	protein	Q01726	UNIPROT	down-regulates activity	binding			10029	BTO:0000246								19329486	t		miannu	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252364	0.356
GDNF	protein	P39905	UNIPROT	TUBA1A	protein	Q71U36	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization.	SIGNOR-252174	0.2
GSK3B	protein	P49841	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation	Ser649	VPPSPSLsRHSSPHQ										11427888	t			Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. 	SIGNOR-251240	0.673
MRTFA	protein	Q969V6	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001260							21673106	t		gcesareni	Similarly, the myocd-related transcription factor (mrtf) family of proteins, mrtf-a and mrtf-b, are also involved in the transcriptional regulation of contractile gene markers as coactivators of srf.	SIGNOR-174264	0.2
DNAJC15	protein	Q9Y5T4	UNIPROT	TIM23 complex	complex	SIGNOR-C423	SIGNOR	form complex	binding												32074073	t		lperfetto	The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE.	SIGNOR-267692	0.445
TGFB2	protein	P61812	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates	binding			9606									22326956	t		miannu	Tgf-? Signaling mediates a wide range of biological activities in development and disease. Tgf-? Ligands signal through heterodimeric type i and type ii receptors (tgf-? Receptor type i [t?RI, also known as alk5 and tgfbr1] and t?RII) that are members of the serine/threonine kinase family.	SIGNOR-196025	0.735
RGS6	protein	P49758	UNIPROT	ITGB3	protein	P05106	UNIPROT	down-regulates	binding			9606									17609107	t		flangone	Numb binds to integrin-betas and localizes to clathrin-coated structures	SIGNOR-156762	0.2
GSK3B	protein	P49841	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser37	YLDSGIHsGATTTAP	9606	BTO:0000938	BTO:0000142	SIGNOR-C110						19303846	t		gcesareni	DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin.	SIGNOR-184785	0.856
PRKAG2	protein	Q9UGJ0	UNIPROT	STIM1	protein	Q13586	UNIPROT	down-regulates activity	phosphorylation	Ser257	GLHRAEQsLHDLQER	10090	BTO:0000452								31381180	t		miannu	STIM1 is a novel exercise‐regulated AMPK substrate. Phosphorylation of STIM1 by AMPK suppresses SOCE	SIGNOR-277297	0.2
CDKAL1	protein	Q5VV42	UNIPROT	tRNA(Lys)	smallmolecule	CHEBI:29185	ChEBI	up-regulates quantity	chemical modification			9606									21841312	t			We show that Cdkal1 is a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) in tRNA(Lys)(UUU) and that it is required for the accurate translation of AAA and AAG codons	SIGNOR-272474	0.8
CDK2	protein	P24941	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	down-regulates	phosphorylation	Ser560	LARLGCSsCLDYFTT	9606									18769144	t		lperfetto	Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively	SIGNOR-180763	0.249
ROCK1	protein	Q13464	UNIPROT	MYLK	protein	Q15746	UNIPROT	up-regulates	binding			9606									11283607	t		gcesareni	Rock proteins are known to regulate mlc-phosphorylation, and apoptotic cells exhibit a gradual increase in levels of phosphorylated mlc concomitant with rock i cleavage.	SIGNOR-106552	0.321
PRKCG	protein	P05129	UNIPROT	SDC2	protein	P34741	UNIPROT	unknown	phosphorylation	Ser188	LGERKPSsAAYQKAP	-1									9244383	t		lperfetto	We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198.	SIGNOR-248978	0.359
4'-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile	chemical	CID:9843116	PUBCHEM	ACHE	protein	P22303	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001239								17888667	t		Luana	AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE.	SIGNOR-257759	0.8
PAX7	protein	P23759	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	down-regulates						BTO:0001103							15501225	f		svumbaca	We found that ectopic expression of Pax-7 prevented myogenic differentiation and the induction of myogenin protein.	SIGNOR-255367	0.7
EFR3B	protein	Q9Y2G0	UNIPROT	PI4KA	protein	P42356	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								34504076	t		miannu	PI4KA is recruited to plasma membrane by the adapter protein EFR3, which has two isoforms, EFR3A and EFR3B	SIGNOR-269093	0.525
AKT1	protein	P31749	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Thr72	TERPRPNtFIIRCLQ	-1									16549426	t		miannu	Autophosphorylation of Akt on Thr-72 and Ser-246 appeared to require prior phosphorylation of Akt on Thr-308 and Ser-473. Compared with wild-type Akt, Akt/T72A/S246A mutant exhibited markedly reduced basal Akt kinase activity and response to cellular stimulation by insulin-like growth factor-1, and also conferred less cellular resistance to doxorubicin-induced apoptosis.	SIGNOR-276054	0.2
INSIG2	protein	Q9Y5U4	UNIPROT	SCAP	protein	Q12770	UNIPROT	down-regulates activity	binding			10029	BTO:0000246								12242332	t			 insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. 	SIGNOR-256209	0.706
TNKS2	protein	Q9H2K2	UNIPROT	AXIN2	protein	Q9Y2T1	UNIPROT	down-regulates	ubiquitination			9606									19759537	t		gcesareni	Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway.	SIGNOR-188036	0.684
ETS1	protein	P14921	UNIPROT	ITGA11	protein	Q9UKX5	UNIPROT	up-regulates quantity by expression				9606	BTO:0001282								16300938	t		lperfetto	We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors.	SIGNOR-253352	0.286
TGFB1	protein	P01137	UNIPROT	COL1A2	protein	P08123	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8182090	f		gcesareni	Tgf-beta stimulates transcription of the human alpha 2(i) collagen gene (col1a2) promoter by increasing the affinity of an sp1-containing protein complex for its cognate dna-binding site	SIGNOR-36783	0.405
MYLK3	protein	Q32MK0	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates activity	phosphorylation	Thr80	NEPHESRtNSDIVET	9606	BTO:0000007								21556048	t		lperfetto	Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis.|Here, we show that skMLCK directly phosphorylates MEF2C, leading to p300/PCAF recruitment, increased acetylation of skeletal muscle-specific genes, and enhanced skeletal myogenesis 	SIGNOR-264565	0.272
CAMK4	protein	Q16566	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser259	FPLRKTAsEPNLKVR	9606		BTO:0000887							11114197	t		gcesareni	Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs.	SIGNOR-85106	0.49
UBE2I	protein	P63279	UNIPROT	MBD4	protein	O95243	UNIPROT	up-regulates activity	sumoylation	Lys215	TSTHLLLkEDEGVDD										31476572	t		lperfetto	MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro.	SIGNOR-275677	0.2
ITCH	protein	Q96J02	UNIPROT	BID	protein	P55957	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								20392206	t		miannu	The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal growth factor by promoting the ubiquitylation and degradation of the truncated C-terminal portion of Bid	SIGNOR-271415	0.359
PRKACA	protein	P17612	UNIPROT	NF2	protein	P35240	UNIPROT	up-regulates	phosphorylation	Ser10	GAIASRMsFSSLKRK	9606									18071304	t		lperfetto	Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth,	SIGNOR-159840	0.379
DIDO1	protein	Q9BTC0	UNIPROT	ITGA5	protein	P08648	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001673								22469980	t		Luana	Dido1 upregulates the expression of Integrin αV, thereby influencing the attachment, apoptosis and migration of melanoma cells.	SIGNOR-261580	0.2
JUN	protein	P05412	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									23936544	t		lperfetto	MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-beta mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-beta production	SIGNOR-251713	0.524
RARG	protein	P13631	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates	binding			9606									15650024	t	inferred from family member	lperfetto	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs	SIGNOR-270296	0.393
RARB	protein	P10826	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates	binding			9606									15650024	t	inferred from family member	gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs	SIGNOR-270299	0.398
CDX2	protein	Q99626	UNIPROT	INS	protein	P01308	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000120								12783165	f		miannu	In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3.	SIGNOR-254906	0.314
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PHF2	protein	O75151	UNIPROT	up-regulates activity	phosphorylation	Ser1056	FLTQRRPsASSPNNN	9606	BTO:0000007								21532585	t		miannu	PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h).	SIGNOR-264513	0.2
GRIA2	protein	P42262	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial.	SIGNOR-264948	0.8
2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide	chemical	CHEBI:91353	ChEBI	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	lperfetto		SIGNOR-244854	0.8
PAK1	protein	Q13153	UNIPROT	SORT1	protein	Q99523	UNIPROT	down-regulates activity	phosphorylation	Ser793	RFLVHRYsVLQQHAE	9606	BTO:0000007								31767632	t		miannu	PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction. 	SIGNOR-273718	0.2
PDGFRB	protein	P09619	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates activity	phosphorylation	Tyr740	TGESDGGyMDMSKDE	-1									8195171	t		miannu	Synthetic peptide analysis revealed that certain autophosphorylation sites in the PDGF beta-receptor (Tyr-579, Tyr-740, Tyr-751, and Tyr-771) were able to mediate the specific binding of the Shc SH2 domain as well as intact Shc proteins.	SIGNOR-250257	0.2
CSMD1	protein	Q96PZ7	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	down-regulates				9606									22538441	f		miannu	CSMD1 inhibits tumor growth, angiogenesis, and survival rate in vivo	SIGNOR-265150	0.7
GNRHR	protein	P30968	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256935	0.277
CTSG	protein	P08311	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates activity	cleavage	Tyr69	NESGLTEyRLVSINK	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263564	0.577
NF1	protein	P21359	UNIPROT	AFP	protein	P02771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								7549116	f		miannu	Our results pointed to a key role that NF1 might play in the functioning of the AFP promoter. Indeed, overexpression of NF1 induced a specific decrease in the activity of the AFP promoter. Competition between NF1 and HNF-1 for binding to their overlapping binding sites on the AFP promoter would be critical for modulating its activity.	SIGNOR-254636	0.275
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1927	SPKYSPTsPTYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120068	0.781
MAPK8	protein	P45983	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	up-regulates	phosphorylation	Ser47	DGPGLERsPGEPGGA	9606									20027304	t	This phosphorylation increased sirt1 nuclear localization	gcesareni	Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53.	SIGNOR-162318	0.621
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	EIF4B	protein	P23588	UNIPROT	up-regulates	phosphorylation	Ser422	RERSRTGsESSQTGT	9606									18836482	t		gcesareni	Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b.	SIGNOR-181536	0.2
SRC	protein	P12931	UNIPROT	HNRNPK	protein	P61978	UNIPROT	down-regulates	phosphorylation	Tyr72	IKALRTDyNASVSVP	9606									12052863	t		lperfetto	We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown).	SIGNOR-88919	0.609
EMSY	protein	Q7Z589	UNIPROT	CBX1	protein	P83916	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								14651845	t		miannu	The binding sites for HP1β and BS69 with EMSY abut each other, and are found directly adjacent to the ENT domain of EMSY. This demonstrates that EMSY has the capacity to contact directly at least two proteins which contain a Royal Family domain. Since this domain is found in proteins with a chromatin connection, we assume that EMSY functions, at least partly, in the regulation of chromatin.	SIGNOR-263917	0.2
alvocidib	chemical	CHEBI:47344	ChEBI	CDK5	protein	Q00535	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192104	0.8
BBC3	protein	Q9BXH1	UNIPROT	BAK1	protein	Q16611	UNIPROT	up-regulates	binding			9606									17289999	t		gcesareni	Bh3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding bax and bak enabler bh3-only proteins such as puma promote momp more indirectly. They activate bax and bak by forming inhibitory complexes with the anti-apoptotic bh1-4 proteins such as bcl2, bclxl and mcl1 that normally stabilize the outer membrane.	SIGNOR-152974	0.392
FUS	protein	P35637	UNIPROT	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	down-regulates				9606	BTO:0000007								33082139	f	P35637:p.Pro525Leu (mutation increasing interaction); P35637:p.Pro521Gly (mutation increasing interaction)		When mTORC2 is inhibited, FUS is recruited to polyribosomes to promote translation inhibition and polyribosome stalling. Panel iv, ALS-FUS R521G and P525L mutants that localize more prominently to the cytoplasm also associate more abundantly with polyribosomes to inhibit translation and protein synthesis.	SIGNOR-262820	0.7
SNRPA	protein	P09012	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270627	0.666
BCOR	protein	Q6W2J9	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								10898795	t		miannu	BCoR can interact w Because HDACs appear to be involved in repression by an increasing number of transcriptional repressors, we tested whether BCoR can associate with HDACs. BCoR can interact with HDAC1, HDAC3, and HDAC-B/5 more strongly than with HDAC-A/4, HDAC-C, HDAC-D, and HDAC-E. 	SIGNOR-252238	0.53
PRKD1	protein	Q15139	UNIPROT	PKD2	protein	Q13563	UNIPROT	up-regulates activity	phosphorylation	Ser801	SSLPRPMsSRSFPRS	9606	BTO:0000007								20881056	t		miannu	Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. Phosphorylation at this site was significantly increased in response to serum and epidermal growth factor stimulation.We confirmed previous studies showing that PC2 mediated Ca2+ release from the ER can be stimulated by ATP.Phosphorylation at Ser801 seems to be permissive for this activity without altering the subcellular localization nor homophilic and heterophilic (with PC1) interactions of wild-type PC2. 	SIGNOR-259829	0.472
PPP2CB	protein	P62714	UNIPROT	CHEK1	protein	O14757	UNIPROT	down-regulates activity	dephosphorylation	Ser317	ENVKYSSsQPEPRTG	9606									17015476	t			Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo.	SIGNOR-248579	0.269
BLM	protein	P54132	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									28912125	f		miannu	The BLM gene product, BLM, is a RECQ helicase that is involved in DNA replication and repair of DNA double-strand breaks by the homologous recombination (HR) pathway. During HR, BLM has both pro- and anti-recombinogenic activities, either of which may contribute to maintenance of genomic integrity. 	SIGNOR-261824	0.7
SGK1	protein	O00141	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606									11154281	t		lperfetto	Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 	SIGNOR-249133	0.787
BMP7	protein	P18075	UNIPROT	UCP1	protein	P25874	UNIPROT	up-regulates	transcriptional regulation			9606									18719589	f		fspada	Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16; ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways	SIGNOR-210059	0.44
PRL	protein	P01236	UNIPROT	PRLR	protein	P16471	UNIPROT	up-regulates	binding			9606									10585417	t		gcesareni	Prolactin-dependent signaling occurs as the result of ligand-induced dimerization of the prolactin receptor (prlr).	SIGNOR-72810	0.922
MLL Fusion	fusion protein	SIGNOR-FP14	SIGNOR	DOT1L	protein	Q8TEK3	UNIPROT	up-regulates activity	binding			9606	BTO:0001133								18977325	t		miannu	Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed.	SIGNOR-260095	0.2
TFE3	protein	P19532	UNIPROT	GABARAPL1	protein	Q9H0R8	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells	SIGNOR-276821	0.331
CDK1	protein	P06493	UNIPROT	ATAD5	protein	Q96QE3	UNIPROT	down-regulates activity	phosphorylation	Ser653	TVPFDSEsPIRMKFT	9606	BTO:0000007								31875566	t		miannu	To determine whether mitotic CDK phosphorylates ATAD5, a CDK1 inhibitor (RO3306) was applied to nocodazole-arrested cells (Figure S3F). CDK1 inhibition resulted in a loss of S653 phosphorylation (Figure S3F). These data meant that the S653 residue in the BET BD of ATAD5 is phosphorylated by mitotic CDK. This result suggested that the BRD4-ATAD5 interaction is inhibited during mitosis. 	SIGNOR-266410	0.241
PRKACA	protein	P17612	UNIPROT	PTPN7	protein	P35236	UNIPROT	down-regulates	phosphorylation	Ser44	RLQERRGsNVALMLD	9606									10559944	t		llicata	Here we show that cyclic-amp-dependent protein kinase (pka) phosphorylates serine residue 23 in the kim of heptp in vitro and in intact cells. This modification reduces binding of map kinases to the kim, an effect that is prevented by mutation of serine 23 to alanine.	SIGNOR-72147	0.367
CSNK2A1	protein	P68400	UNIPROT	TCF7L2	protein	Q9NQB0	UNIPROT	up-regulates activity	phosphorylation	Ser60	ETNQNSSsDSEAERR	-1									11711551	t		llicata	We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. 	SIGNOR-250964	0.365
CPSF4	protein	O95639	UNIPROT	CPSF complex	complex	SIGNOR-C53	SIGNOR	form complex	binding			9606	BTO:0000007								19224921	t		lperfetto	The CPSF complex consists of five subunits, named CPSF160, CPSF100, Fip1, CPSF73, and CPSF30.	SIGNOR-268334	0.914
STAT6	protein	P42226	UNIPROT	PPARA	protein	Q07869	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000801								20508200	f		lperfetto	Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation.	SIGNOR-249534	0.358
PRKACA	protein	P17612	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	phosphorylation	Ser195	EKLRRRFsSLHFMVE	9606									15703181	t		lperfetto	We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195.	SIGNOR-133884	0.2
MBTPS2	protein	O43462	UNIPROT	CREB3L1	protein	Q96BA8	UNIPROT	up-regulates	cleavage			9606									16417584	t		miannu	Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes	SIGNOR-143820	0.551
AURKB	protein	Q96GD4	UNIPROT	RACGAP1	protein	Q9H0H5	UNIPROT	up-regulates activity	phosphorylation	Ser144	NAGNKRLsTIDESGS	9606	BTO:0000567								14744859	t		llicata	It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1	SIGNOR-250586	0.772
CREBBP	protein	Q92793	UNIPROT	KLF1	protein	Q13351	UNIPROT	up-regulates activity	acetylation	Lys288	CAHPGCGkSYTKSSH	9606									11259590	t	Regulation	miannu	EKLF residues acetylated by CREB binding protein (CBP) in vitro map to Lys-288 in its transactivation domain and Lys-302 in its zinc finger domain.	SIGNOR-251826	0.504
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Thr476	EANYVPMtPGTFDFS	9606									15379552	t		lperfetto	Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597)	SIGNOR-129200	0.2
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270381	0.8
IL6	protein	P05231	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates activity				-1									8511589	f		lperfetto	The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130.	SIGNOR-238617	0.864
LATS1	protein	O95835	UNIPROT	MTF1	protein	Q14872	UNIPROT	down-regulates activity	phosphorylation	Ser152	EGCPRTYsTAGNLRT										35027733	t		lperfetto	The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1|the Hippo pathway kinase LATS phosphorylates and inhibits MTF1|LATS phosphorylates MTF1 at S152 and disrupts its association with the promoters of heavy metal response genes, resulting in the loss of heavy metal response gene expression	SIGNOR-275473	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	MKNK1	protein	Q9BUB5	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000567								9155018	t	inferred from 70% family members	lperfetto	Mnk1 was phosphorylated and activated in vitro by erk1 and p38 map kinasespreliminary results showed that thr344 at least was one of the major sites phosphorylated by erk1	SIGNOR-270022	0.2
CDH19	protein	Q9H159	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265858	0.32
RUNX1	protein	Q01196	UNIPROT	CCL3	protein	P10147	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000661								12771199	t		lperfetto	We show that RUNX1 can specifically bind to both RUNX sites but that only the proximal RUNX site is essential for PMA/ PHA stimulation of the MIP-1a promoter in Jurkat T-cells. We also show that the endogenous MIP-1a promoter is constitutively bound by RUNX1.	SIGNOR-251738	0.2
IL23A	protein	Q9NPF7	UNIPROT	IL23R	protein	Q5VWK5	UNIPROT	up-regulates	binding			9606	BTO:0000782								12023369	t		gcesareni	We identify a novel member of the hemopoietin receptor family as a subunit of the receptor for il-23, il-23r.	SIGNOR-87805	0.856
ZNF143	protein	P52747	UNIPROT	TCP1	protein	P17987	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10893243	t		Luana	The transcription from the minimalCcta promoter was up-regulated 3-fold by ZNF143 and 6-fold by ZNF76 when full-length proteins were co-expressed, indicating that both ZNF143 and ZNF76 can enhance Ccta transcription.	SIGNOR-266220	0.283
GSK3B	protein	P49841	UNIPROT	CCNE1	protein	P24864	UNIPROT	down-regulates	phosphorylation	Thr77	DPCSLIPtPDKEDDD	9606									14536078	t		gcesareni	Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380	SIGNOR-118563	0.456
5-chloro-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	chemical	CHEBI:91338	ChEBI	ALK	protein	Q9UM73	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258293	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	PTTG1	protein	O95997	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr66	ATRKALGtVNRATEK	9606	BTO:0000567								24781523	t		miannu	CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase	SIGNOR-276377	0.314
SND1	protein	Q7KZF4	UNIPROT	MGLL	protein	Q99685	UNIPROT	down-regulates quantity by destabilization	binding			9606									26997225	t		irozzo	Interaction of SND1 with MGLL resulted in ubiquitination and proteosomal degradation of MGLL. We demonstrate that interaction of SND1 with MGLL results in increased ubiquitination and subsequent proteosomal degradation of MGLL. This down-regulation of MGLL is required for SND1 to exert its pro-tumorigenic activity because forced overexpression of MGLL markedly abrogates cell proliferation.	SIGNOR-259138	0.2
SYK	protein	P43405	UNIPROT	DUSP3	protein	P51452	UNIPROT	up-regulates activity	phosphorylation	Tyr138	SPTLVIAyLMMRQKM	9534	BTO:0001538								12447358	t		miannu	ZAP-70 and Syk also tyrosine-phosphorylated VHR in COS-1 cells (Fig. 2d), whereas other kinases (Csk, Lck, Fyn, Jak2, Bcr-Abl and Itk) had little effect. Finally, recombinant ZAP-70 readily phosphorylated VHR in vitro (Fig. 2f). 	SIGNOR-275999	0.37
BIRC2	protein	Q13490	UNIPROT	RIPK3	protein	Q9Y572	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0000007								21931591	t		miannu	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.	SIGNOR-272711	0.664
DIO	proteinfamily	SIGNOR-PF83	SIGNOR	3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	up-regulates quantity	chemical modification			9606									20978344	t	inferred from family member	miannu	The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4)	SIGNOR-267809	0.8
FBP1	protein	P09467	UNIPROT	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	up-regulates quantity	chemical modification			9606									30616754	t		lperfetto	FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle	SIGNOR-267611	0.8
PIM2	protein	Q9P1W9	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	down-regulates activity	phosphorylation	Ser467	LQLYQVDsRTYLLDF	9606	BTO:0001555								31358902	t		miannu	Specifically, we found that PIM2 bound to AMPKα1, and directly phosphorylated it on Thr467. Phosphorylation of AMPKα1 by PIM2 led to decreasing AMPKα1 kinase activity, which in turn promoted aerobic glycolysis and tumor growth.	SIGNOR-277471	0.2
pyruvate	smallmolecule	CHEBI:15361	ChEBI	acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	up-regulates quantity	precursor of			9606									29059435	t		miannu	The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics.	SIGNOR-266542	0.8
TNF	protein	P01375	UNIPROT	NOTCH4	protein	Q99466	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004914								14586405	f			We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues.	SIGNOR-253607	0.317
SP1	protein	P08047	UNIPROT	TINF2	protein	Q9BSI4	UNIPROT	up-regulates quantity by expression	transcriptional regulation												21731707	t		lperfetto	Transfection of a plasmid carrying the Sp1 transcription factor into Sp-deficient SL2 cells strongly activated TIN2 promoter-driven luciferase reporter expression.	SIGNOR-271698	0.2
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser23	ARKRHAPsPEPAVQG	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276097	0.267
monoisononyl phthalate	chemical	CHEBI:132593	ChEBI	PPARG	protein	P37231	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 	SIGNOR-268782	0.8
CGAS	protein	Q8N884	UNIPROT	2'-3'-cGAMP(2-)	smallmolecule	CHEBI:143093	ChEBI	up-regulates quantity	chemical modification												23258413	t		lperfetto	Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family.	SIGNOR-276593	0.8
CSNK1E	protein	P49674	UNIPROT	PER1	protein	O15534	UNIPROT	down-regulates	phosphorylation			9606									15917222	t		miannu	Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1.	SIGNOR-137706	0.835
CDC14A	protein	Q9UNH5	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates	dephosphorylation	Ser688	QFHSPVGsPLKSIQA	9606									20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis.	SIGNOR-164408	0.627
EXOC3	protein	O60645	UNIPROT	Exocyst_EXOC6 variant	complex	SIGNOR-C492	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270786	0.958
SIAH2	protein	O43255	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. 	SIGNOR-272748	0.443
CDK1	protein	P06493	UNIPROT	CyclinA2/CDK1	complex	SIGNOR-C420	SIGNOR	form complex	binding			9606									29870721	t		lperfetto	Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis. 	SIGNOR-267570	0.919
BRCA1	protein	P38398	UNIPROT	Cell_cycle_block	phenotype	SIGNOR-PH10	SIGNOR	up-regulates													15549093	f		lperfetto	The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination	SIGNOR-251499	0.7
FLI1	protein	Q01543	UNIPROT	COL1A2	protein	P08123	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24058639	f		miannu	Fli1 functions as a potent transcriptional repressor of the col1a2 gene	SIGNOR-202685	0.249
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr249	APGPQDIyDVPPVRG	9606									12972425	t		lperfetto	We tested synthetic peptides modeled on cas phosphorylation sites, and found that the sequence containing tyrosine 253 was phosphorylated by src most efficiently. Using cells derived from cas-deficient mice, we confirmed that cas greatly enhanced the ability of src to transform cells.	SIGNOR-100363	0.797
CBFA2T3	protein	O75081	UNIPROT	ZNF652	protein	Q9Y2D9	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								20116376	t	 	 	Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes.	SIGNOR-253954	0.525
PRKCQ	protein	Q04759	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Ser840	VRSAFTTsTVVRMHV	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249283	0.294
TLR4	protein	O00206	UNIPROT	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	up-regulates activity	phosphorylation			9606									28137827	t		miannu	Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation.	SIGNOR-261929	0.501
MAPK14	protein	Q16539	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	phosphorylation			10116									14512875	t		lperfetto	P38 mapk mediates fibrogenic signal through smad3 phosphorylation in rat myofibroblasts. the phosphorylation promoted hetero-complex formation and nuclear translocation of smad3 and smad4.	SIGNOR-236136	0.553
Nalorphine	chemical	CHEBI:7458	ChEBI	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258813	0.8
MELK	protein	Q14680	UNIPROT	CDC25B	protein	P30305	UNIPROT	up-regulates	phosphorylation	Ser169	VLRNITNsQAPDGRR	9606									15908796	t		lperfetto	We demonstrate that cdc25b is phosphorylated in vitro by peg3 on serine 169this phosphorylated form of cdc25b accumulates during mitosis, and is localized to the centrosomes	SIGNOR-137378	0.549
MPO-ANCA	complex	SIGNOR-C474	SIGNOR	Neutrophil_activation	phenotype	SIGNOR-PH211	SIGNOR	up-regulates				9606		BTO:0000133							2161532	f		lperfetto	ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation. 	SIGNOR-270583	0.7
SRC	protein	P12931	UNIPROT	BAIAP2L1	protein	Q9UHR4	UNIPROT	up-regulates activity	phosphorylation	Tyr439	VVIPPPDyLECLSMG	-1									21840312	t		miannu	Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility.	SIGNOR-263042	0.399
CCNH	protein	P51946	UNIPROT	CAK complex	complex	SIGNOR-C456	SIGNOR	form complex	binding			9606									30860024	t		lperfetto	CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 	SIGNOR-269321	0.96
HSPA1B	protein	P0DMV9	UNIPROT	GSTA4	protein	O15217	UNIPROT	up-regulates activity	relocalization										phosphorylation:Thr193;Ser189	VKLSNIPtIKRFLEP;QEYTVKLsNIPTIKR	21929724	t		lperfetto	Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. |Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation	SIGNOR-264800	0.2
OXSR1	protein	O95747	UNIPROT	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation	Thr105	LQTFGHNtMDAVPKI	9606	BTO:0000007								21321328	t		miannu	 We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A).	SIGNOR-276310	0.517
S100A8	protein	P05109	UNIPROT	TLR4	protein	O00206	UNIPROT	down-regulates activity	binding			9606									28137827	t		miannu	Interestingly, in the present study, we report that extracellular S100A9 induces terminal differentiation of myeloid leukemia cells in human and murine AMLs after TLR4 activation, which is highly expressed by primary myelomonocytic and monocytic leukemia cells. In contrast, anti-S100A8 induced the differentiation of AML cells, suggesting that the differentiation-promoting effect of S100A9 is inhibited by S100A8. ) S100A8 could bind to TLR4 and activate different signaling pathways, leading to the inhibition of cellular differentiation induced by S100A9. 	SIGNOR-261921	0.515
PRDM16	protein	Q9HAZ2	UNIPROT	Brown_adipogenesis	phenotype	SIGNOR-PH27	SIGNOR	up-regulates				9606	BTO:0000222	BTO:0000887;BTO:0001103							18719582	f		fspada	Loss of prdm16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of prdm16 in myoblasts induces their differentiation into brown fat cells.	SIGNOR-180295	0.7
BIRC2	protein	Q13490	UNIPROT	TRAF2	protein	Q12933	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								18997794	t		lperfetto	Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3.	SIGNOR-182128	0.868
MMP20	protein	O60882	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272388	0.7
RAPGEF3	protein	O95398	UNIPROT	RAP1A	protein	P62834	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9534	BTO:0000298								10777494	t		miannu	Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.	SIGNOR-263956	0.699
TNKS2	protein	Q9H2K2	UNIPROT	AXIN2	protein	Q9Y2T1	UNIPROT	down-regulates quantity by destabilization	ADP-ribosylation			9606	BTO:0000007								19759537	t		lperfetto	Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin.	SIGNOR-263380	0.684
LLGL1	protein	Q15334	UNIPROT	Scribble_complex_DLG5-LLGL1_variant	complex	SIGNOR-C508	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270899	0.461
RPS15	protein	P62841	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262437	0.899
ATM	protein	Q13315	UNIPROT	TAOK1	protein	Q7L7X3	UNIPROT	up-regulates	phosphorylation	Thr785	SINEMLStQALRLDE	9606									17396146	t		gcesareni	The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells.	SIGNOR-154175	0.394
eIF4F_complex	complex	SIGNOR-C44	SIGNOR	48S_initiation_complex	complex	SIGNOR-C454	SIGNOR	form complex	binding			9606									35489072	t		lperfetto	In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 	SIGNOR-269166	0.846
RPS6KA1	protein	Q15418	UNIPROT	SLC9A1	protein	P19634	UNIPROT	up-regulates	phosphorylation	Ser703	MSRARIGsDPLAYEP	9606									10400637	t		gcesareni	The results indicate that p90rsk phosphorylates serine 703 of nhe-1, and this phosphorylation is required for growth factor stimulation of na+/h+ exchange.	SIGNOR-69171	0.466
DLL4	protein	Q9NR61	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	binding			9606	BTO:0000574								10837024	t		lperfetto	Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology	SIGNOR-77973	0.628
TTK	protein	P33981	UNIPROT	USP16	protein	Q9Y5T5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser415	VEDEDQDsEEEKDND	9606	BTO:0002181								28380042	t		miannu	 Usp16 is a TTK phosphorylation substrate. 	SIGNOR-277350	0.378
HTR4	protein	Q13639	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256769	0.475
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	BAD	protein	Q92934	UNIPROT	up-regulates activity	dephosphorylation			9606	BTO:0000007								10195903	t	inferred from 70% family members		Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 	SIGNOR-269992	0.2
HTR6	protein	P50406	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257073	0.252
SIRT1	protein	Q96EB6	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates activity	deacetylation			9606									20640476	t		lperfetto	AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1	SIGNOR-209962	0.792
AKT2	protein	P31751	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates	phosphorylation	Thr1462	GLRPRGYtISDSAPS	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex.	SIGNOR-183640	0.719
RFX2	protein	P48378	UNIPROT	Cilium_assembly	phenotype	SIGNOR-PH64	SIGNOR	up-regulates				10090									32725242	f		miannu	RFX2 and RFX3 are key regulators of ependymal cell ciliogenesis in vitro and in vivo. We show here that RFX2 and RFX3 have both redundant and specific functions in the biogenesis of motile cilia on mouse ependymal cells, whereas RFX1 does not seem to play a key regulatory role in this process.	SIGNOR-266928	0.7
PRKCA	protein	P17252	UNIPROT	CDKN2D	protein	P55273	UNIPROT	up-regulates	phosphorylation	Ser76	VQDTSGTsPVHDAAR	9606									22558186	t		lperfetto	Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively. Nuclear translocation of p19ink4d induced by dna damage was shown to be dependent on serine 76 phosphorylation.	SIGNOR-197285	0.2
GRB10	protein	Q13322	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	binding			9606									21659604	t		gcesareni	Grb10 negatively regulates growth factor signaling. It binds the insulin and insulin-like growth factor 1 (igf-1) receptors;mice without grb10 are larger and exhibit enhanced insulin sensitivity.	SIGNOR-174065	0.646
TMOD1	protein	P28289	UNIPROT	TPM3	protein	P06753	UNIPROT	down-regulates activity	binding			9606									8002995	t		irozzo	Tropomodulin is a 40.6-kDa protein that binds to one end of the rod-like tropomyosin and inhibits its cooperativity and binding to actin. [.] we demonstrate that it is the N-terminus of tropomyosin that interacts with tropomodulin. Among several tropomyosin isoforms tested, hTM5 encoded by the human gamma-tropomyosin gene has the highest affinity toward human erythrocyte tropomodulin. 	SIGNOR-259111	0.721
CLK4	protein	Q9HAZ1	UNIPROT	SRSF1	protein	Q07955	UNIPROT	up-regulates activity	phosphorylation			-1									8617202	t		miannu	 In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors.	SIGNOR-273860	0.365
SEC31A	protein	O94979	UNIPROT	COPII vesicle	complex	SIGNOR-C370	SIGNOR	form complex	binding			9606	BTO:0000567								30605680	t		lperfetto	The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat	SIGNOR-265292	0.755
LRP5	protein	O75197	UNIPROT	LPR5/6	complex	SIGNOR-C219	SIGNOR	form complex	binding			9606									27821587	t		miannu	Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are co-receptors for Wnt ligands.	SIGNOR-256176	0.38
FOXO1	protein	Q12778	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									16670091	f		lperfetto	FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect.	SIGNOR-218013	0.561
TARS1	protein	P26639	UNIPROT	tRNA(Thr)	smallmolecule	CHEBI:29180	ChEBI	down-regulates quantity	chemical modification			9606									25824639	t		miannu	Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 	SIGNOR-270501	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CDCA5	protein	Q96FF9	UNIPROT	up-regulates activity	phosphorylation	Ser209	DMTLPGIsPPPEKQK	9606	BTO:0000567								20551060	t		miannu	Phosphorylation and activation of cell division cycle associated 5 by mitogen-activated protein kinase play a crucial role in human lung carcinogenesis. Our data suggest that transactivation of CDCA5 and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation, and that the selective suppression of the ERK-CDCA5 pathway could be a promising strategy for cancer therapy.	SIGNOR-262968	0.2
NRXN2	protein	P58401	UNIPROT	NLGN2	protein	Q8NFZ4	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							22626545	t		miannu	 The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites	SIGNOR-265455	0.824
MAP2K3	protein	P46734	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation			9606									8622669	t		lperfetto	Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. MKK3 is therefore a specific activator of p38 MAP kinase that is independent of the JNK and ERK signaling pathways. 	SIGNOR-40356	0.715
PRKCZ	protein	Q05513	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Thr681	QRHKRTHtGEKKFAC	9606		BTO:0000887;BTO:0001260							18258854	t		llicata	Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter.	SIGNOR-160774	0.498
SMO	protein	Q99835	UNIPROT	GNGT1	protein	P63211	UNIPROT	up-regulates	binding			9606									16885213	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-148601	0.2
TRIB2	protein	Q92519	UNIPROT	PKM	protein	P14618	UNIPROT	up-regulates activity	phosphorylation	Ser37	MCRLDIDsPPITARN	9606	BTO:0000018								35790734	t		miannu	 This study demonstrated that TRIB2, not a "pseudokinase", has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells. 	SIGNOR-275431	0.2
KDM5D	protein	Q9BY66	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264310	0.2
SMARCB1	protein	Q12824	UNIPROT	CCNA1	protein	P78396	UNIPROT	down-regulates				9606									12226744	f		miannu	We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6.	SIGNOR-92779	0.342
DYRK1A	protein	Q13627	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser330	RLSPIMAsTELDEVQ	9606									19188143	t		lperfetto	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition.	SIGNOR-252906	0.521
SRC	protein	P12931	UNIPROT	AFAP1	protein	Q8N556	UNIPROT	unknown	phosphorylation	Tyr451	TDPEALHyDYIDVEM	9534	BTO:0004055								9655255	t		lperfetto	In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110.	SIGNOR-246351	0.589
RalGAP2	complex	SIGNOR-C469	SIGNOR	RALA	protein	P11233	UNIPROT	down-regulates activity	guanine nucleotide exchange factor			10090	BTO:0000011								21148297	t		miannu	 Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. RGC2 negatively regulates RalA activity in adipocytes. When immunoprecipitated from cell lysates of 3T3-L1 adipocytes by an anti-RGC2 antibody, RGC proteins efficiently enhanced GTP hydrolysis of recombinant RalA in vitro, compared with RalA alone or RalA incubated with various control immunoprecipitates (Figure 2C).	SIGNOR-269796	0.497
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser396	DDKKAKTsTRSSAKT	9606	BTO:0000590								20679343	t		lperfetto	Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3?	SIGNOR-167286	0.729
NOTCH1	protein	P46531	UNIPROT	HEYL	protein	Q9NQ87	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887;BTO:0001260							11044625	f		gcesareni	These data confirm heyl as a notch1 target gene that is likely involved in somite formation and patterning.	SIGNOR-83399	0.595
MAPK3	protein	P27361	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates	phosphorylation			9606									14967450	t		gcesareni	Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1	SIGNOR-121991	0.297
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	JUN	protein	P05412	UNIPROT	up-regulates	binding			9606									18174238	t		lperfetto	Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment	SIGNOR-216337	0.578
RRAGD	protein	Q9NQL2	UNIPROT	RAGAD	complex	SIGNOR-C114	SIGNOR	form complex	binding			9606									20381137	t		gcesareni	Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant	SIGNOR-228170	0.767
MAPK7	protein	Q13164	UNIPROT	ETS1	protein	P14921	UNIPROT	up-regulates	phosphorylation	Thr38	CADVPLLtPSSKEMM	9606									12048211	t		gcesareni	9-cis retinoid x receptor alpha (rxr alpha) interacted with erk2 but not erk5 in intact cells, whereas ets-1 interacted preferentially with erk5. Increased phosphorylation of rxr alpha and ets-1 was detected in response to 1,25d. Activated erk2 and erk5 specifically phosphorylated rxr alpha and ets-1, respectively.Mutagenesis of ets-1 (t38a) reduced cyp24 promoter activity to levels observed with the dominant-negative mek5(a) and inhibited erk5-directed phosphorylation. Mutated rxr alpha (s260a) inhibited 1,25d-induced cyp24 promoter activity and abolished phosphorylation by activated erk2.	SIGNOR-88666	0.43
WAPL	protein	Q7Z5K2	UNIPROT	Cohesin complex	complex	SIGNOR-C304	SIGNOR	down-regulates activity				9606	BTO:0000567								17113138	t		lperfetto	We show that human Wapl interacts with cohesin throughout the cell cycle via cohesin's Scc1 and SA1/SA2 subunits and that Wapl forms a subcomplex with Pds5A|These results indicate that Wapl is required for the release of cohesin from both interphase chromatin and mitotic chromosomes, perhaps by facilitating opening of the cohesin ring or by modulating direct interactions between cohesin and DNA. 	SIGNOR-265265	0.2
PTK6	protein	Q13882	UNIPROT	STAP2	protein	Q9UGK3	UNIPROT	up-regulates activity	phosphorylation	Tyr250	PFLLDEDyEKVLGYV	9606									19393627	t		lperfetto	Our previous studies revealed that STAP-2 binds to signal transducer and activator of transcription 3 (STAT3) and STAT5, and regulates the signaling pathways downstream of them. In the present study, we identified tyrosine-250 (Tyr250) in STAP-2 as a major site of phosphorylation by Brk, using a series of STAP-2 YF mutants and anti-phospho-STAP-2 Tyr250 antibody. Furthermore, overexpression of the STAP-2 Y250F mutant protein affected Brk-mediated STAT3 activation.	SIGNOR-247067	0.714
MAPK14	protein	Q16539	UNIPROT	PIAS2	protein	O75928	UNIPROT	up-regulates activity	phosphorylation	Ser116	VTPHSPSsPVGSVLL	9606	BTO:0000007								16713578	t		miannu	The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles	SIGNOR-262949	0.322
MAPK14	protein	Q16539	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates activity	phosphorylation			10090									20551513	t		ggiuliani	Mechanistic analysis revealed that the TAK1–MKK3/6–p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo.	SIGNOR-255777	0.377
HARS1	protein	P12081	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									10430027	t		miannu	Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 	SIGNOR-270489	0.8
GRIK5	protein	Q16478	UNIPROT	D-serine	smallmolecule	CHEBI:16523	ChEBI	up-regulates quantity	relocalization			9606	BTO:0002609								12393813	t		lperfetto	Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine	SIGNOR-268276	0.8
DLG4	protein	P78352	UNIPROT	TANC2	protein	Q9HCD6	UNIPROT	up-regulates activity	binding			10116		BTO:0000142							21068316	t		miannu	 In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses.	SIGNOR-266895	0.317
gefitinib	chemical	CHEBI:49668	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates activity	chemical inhibition			9606									15284455	t		SimoneGraziosi	Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain. 	SIGNOR-269264	0.8
DIO	proteinfamily	SIGNOR-PF83	SIGNOR	MYOD1	protein	P15172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20978344	f	inferred from family member	miannu	The active thyroid hormone 3,5,3' triiodothyronine (T3) is a major regulator of skeletal muscle function. The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4). Here we show that type 2 deiodinase (D2) is essential for normal mouse myogenesis and muscle regeneration. Indeed, D2-mediated increases in T3 were essential for the enhanced transcription of myogenic differentiation 1 (MyoD) and for execution of the myogenic program. 	SIGNOR-270306	0.2
CDK5	protein	Q00535	UNIPROT	TPPP	protein	O94811	UNIPROT	down-regulates activity	phosphorylation	Ser18	ANRTPPKsPGDPSKD	-1									17693641	t		miannu	 Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP.	SIGNOR-262932	0.414
PDRG1	protein	Q9NUG6	UNIPROT	URI1 prefoldin co-chaperone	complex	SIGNOR-C514	SIGNOR	form complex	binding			9606									30484151	t		miannu	In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR92	SIGNOR-270915	0.577
RIN1	protein	Q13671	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606									12783862	t		gcesareni	The interaction between egfr and rin1 delineates a novel signal transduction pathway between egfr and its effectors, rin1, rab5a, and ras, which together coordinate and regulate both signaling and membrane trafficking.	SIGNOR-101530	0.413
Ubiquitin	proteinfamily	SIGNOR-PF89	SIGNOR	Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	form complex	binding			9606									24816100	t		miannu	The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin.	SIGNOR-270836	0.728
gemcitabine	chemical	CHEBI:175901	ChEBI	RRM1	protein	P23921	UNIPROT	down-regulates activity	chemical inhibition			-1									2233693	t		miannu	Direct assays of partially purified ribonucleoside diphosphate reductase (EC 1.17.4.1) demonstrated 50% inhibition by 4 microM dFdC 5'-diphosphate; dFdC 5'-triphosphate was much less inhibitory. We conclude that dFdC 5'-diphosphate acts as an inhibitor of ribonucleoside diphosphate reductase.	SIGNOR-258386	0.8
CSNK1E	protein	P49674	UNIPROT	PER2	protein	O15055	UNIPROT	down-regulates quantity by destabilization	phosphorylation			10090									15767683	t		miannu	The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation. CKIepsilon-mediated phosphorylation of PER2 recruits the ubiquitin ligase adapter protein beta-TrCP to a specific site, and dominant negative beta-TrCP blocks phosphorylation-dependent degradation of mPER2. These results provide a biochemical mechanism and functional relevance for the observed phosphorylation-degradation cycle of mammalian PER2.	SIGNOR-267995	0.898
MLL Fusion	fusion protein	SIGNOR-FP14	SIGNOR	RUNX1	protein	Q01196	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24449215	f		miannu	However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions.	SIGNOR-260129	0.2
WWC1	protein	Q8IX03	UNIPROT	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								21233212	t		miannu	Here, we show that KIBRA associates with and activates Lats (large tumor suppressor) 1 and 2 kinases by stimulating their phosphorylation on the hydrophobic motif. KIBRA overexpression stimulates the phosphorylation of Yes-associated protein (YAP), the Hippo pathway effector. 	SIGNOR-263659	0.782
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SYN1	protein	P17600	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000938								10571231	t		miannu	 Synapsins are exclusively localized to synaptic vesicles, which they coat as peripheral membrane proteins; they probably constitute one of the most abundant neuronal PKA substrates. Our study reveals an unexpectedly dynamic state of synapsins in nerve terminals: any changes in PKA or CaM Kinase I activity will modulate the amount of synapsin on synaptic vesicles. PKA Activation Triggers Synapsin Dissociation	SIGNOR-264108	0.2
ERBB2	protein	P04626	UNIPROT	SHC3	protein	Q92529	UNIPROT	up-regulates	relocalization			9606									16729043	t		gcesareni	Erbb3 is characterized by a large number of binding sites for phosphatidylinositol-3-kinase (pi3k), while erbb2 has only few interaction partners with shc as the most frequent one.	SIGNOR-146855	0.533
PIM1	protein	P11309	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation	Thr339	PVKSRKTtLEQPPSV	9606	BTO:0001061								31730483	t		miannu	Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 	SIGNOR-276771	0.629
trametinib	chemical	CHEBI:75998	ChEBI	MAP2K2	protein	P36507	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192826	0.8
10-formyltetrahydrofolate(2-)	smallmolecule	CHEBI:57454	ChEBI	N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-)	smallmolecule	CHEBI:147286	ChEBI	up-regulates quantity	precursor of			9606									11381136	t		miannu	The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR.	SIGNOR-268104	0.8
GTF2B	protein	Q00403	UNIPROT	TFIIF	complex	SIGNOR-C394	SIGNOR	up-regulates activity	relocalization			9606									27096372	t		lperfetto	Our structures suggest that a primary function of TFIID during PIC assembly is the proper positioning of TBP on the upstream promoter, which ultimately determines the placement of Pol II relative to the TSS. The structures presented here offer a structural framework for understanding the complex mechanism underlying TFIID function, shedding new light into the overlapping roles of TFIID as both a coactivator and a general platform for PIC assembly in the coordination of transcription initiation.	SIGNOR-266193	0.928
INSR	protein	P06213	UNIPROT	BLVRA	protein	P53004	UNIPROT	up-regulates activity	phosphorylation	Tyr228	PGLKRNRyLSFHFKS										15870194	t		lperfetto	Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK 	SIGNOR-275515	0.494
CDK18	protein	Q07002	UNIPROT	AQP2	protein	P41181	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser261	RQSVELHsPQSLPRG	9606	BTO:0000007								32164329	t		lperfetto	CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. |We had previously observed that a decrease in the phosphorylation of AQP2 at S261 is associated with a decrease in its poly-ubiquitination and an increase in its abundance 	SIGNOR-264562	0.263
DIO3	protein	P55073	UNIPROT	3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	up-regulates quantity	chemical modification			9606									12746313	t		scontino	Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144.	SIGNOR-266942	0.8
CDK2	protein	P24941	UNIPROT	CDK7	protein	P50613	UNIPROT	unknown	phosphorylation	Ser164	GLAKSFGsPNRAYTH	9606									11113184	t		amattioni	Cdk2 phosphorylates serine-164 in the cdk7 t loop.	SIGNOR-84832	0.551
HDAC1	protein	Q13547	UNIPROT	MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263851	0.817
Immunoglobulin delta heavy chain	protein	P0DOX3	UNIPROT	BCR-Dk	complex	SIGNOR-C435	SIGNOR	form complex	binding			9606	BTO:0000776								20176268	t		scontino	Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes.	SIGNOR-268195	0.2
Tomivosertib	chemical	CID:118598754	PUBCHEM	MKNK1	protein	Q9BUB5	UNIPROT	down-regulates activity	chemical inhibition			9606									29526098	t		Simone Vumbaca	Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation.	SIGNOR-261116	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates activity	phosphorylation	Ser539	SLFNVSPsCSSFNSP	10090		BTO:0001103							17609368	t		gcesareni	AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter	SIGNOR-228646	0.483
MAP3K7	protein	O43318	UNIPROT	TAB1	protein	Q15750	UNIPROT	up-regulates activity	phosphorylation	Ser452	STNTHTQsSSSSSDG	9606	BTO:0000007								22216226	t		miannu	We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro. 	SIGNOR-276364	0.927
MAPK1	protein	P28482	UNIPROT	CSNK2A1	protein	P68400	UNIPROT	up-regulates	phosphorylation	Thr360	SGISSVPtPSPLGPL	9606	BTO:0000527								19941816	t		lperfetto	Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity	SIGNOR-161855	0.376
HDAC1	protein	Q13547	UNIPROT	CoREST-HDAC complex	complex	SIGNOR-C105	SIGNOR	form complex	binding			9606									11171972	t		miannu	Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function.	SIGNOR-222124	0.699
DLX5	protein	P56178	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17335796	f		gcesareni	Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme.	SIGNOR-153454	0.5
NLGN1	protein	Q8N2Q7	UNIPROT	NRXN1	protein	P58400	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264149	0.835
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CDC7	protein	O00311	UNIPROT	up-regulates activity	phosphorylation	Thr376	QVAPRAGtPGFRAPE	-1									10846177	t		llicata	Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks.	SIGNOR-250643	0.481
ELOC	protein	Q15369	UNIPROT	NOTCH4	protein	Q99466	UNIPROT	down-regulates	ubiquitination			9606		BTO:0000672							22001063	t		gcesareni	Using proteomic techniques, several components of the elongin c complex were identified as candidate notch4(icd) interactors. Elongin c complexes can function as ubiquitin ligases capable of regulating proteasomal degradation of specific protein substrates. Our studies indicate that ectopic elongin c expression stimulates notch4(icd) degradation and inhibits its transcriptional activity in human kidney tubule hk11 cells.	SIGNOR-176779	0.2
PRKACA	protein	P17612	UNIPROT	VASP	protein	P50552	UNIPROT	unknown	phosphorylation	Ser157	EHIERRVsNAGGPPA	9606									12576312	t		miannu	Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro	SIGNOR-250064	0.487
MAP1LC3B	protein	Q9GZQ8	UNIPROT	Autophagosome_formation	phenotype	SIGNOR-PH36	SIGNOR	up-regulates				9606									20921139	f		lperfetto	We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation	SIGNOR-219403	0.7
GGCX	protein	P38435	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	carboxylation	Glu66	NLERECMeEKCSFEE	10090		BTO:0001103							11133752	t		lperfetto	The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.	SIGNOR-263690	0.67
MYC	protein	P01106	UNIPROT	YY1	protein	P25490	UNIPROT	down-regulates activity	binding			10090	BTO:0000944								8266081	t		miannu	Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1.	SIGNOR-268795	0.562
EGFR	protein	P00533	UNIPROT	TRIP13	protein	Q15645	UNIPROT	up-regulates quantity	phosphorylation	Tyr56	HNIVFGDyTWTEFDE	9606	BTO:0000007								32860853	t		lperfetto	Reciprocally, TRIP13 was phosphorylated at tyrosine(Y) 56 by EGFRvIII and EGF-activated EGFR. Abrogating TRIP13 Y56 phosphorylation dramatically attenuated TRIP13 expression-enhanced EGFR signaling and GBM cell growth.	SIGNOR-265083	0.2
LRRC4	protein	Q9HBW1	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000142							25526788	f		miannu	LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway.	SIGNOR-264055	0.2
EXOSC9	protein	Q06265	UNIPROT	Exosome_Complex	complex	SIGNOR-C255	SIGNOR	form complex	binding			-1									24189234	t		miannu	The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 	SIGNOR-261388	0.918
PIM1	protein	P11309	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation	Ser269	PCNKRKYsLNGRQPP	9606	BTO:0001061								31730483	t		miannu	Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 	SIGNOR-276769	0.629
MAPK1	protein	P28482	UNIPROT	PCYT1A	protein	P49585	UNIPROT	down-regulates	phosphorylation	Ser315	GRMLQAIsPKQSPSS	9606		BTO:0000763							15788406	t		gcesareni	Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis.	SIGNOR-134837	0.429
ITGB1	protein	P05556	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257700	0.698
MAPK3	protein	P27361	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates activity	phosphorylation	Thr207	FLTEYVAtRWYRAPE	9606		BTO:0000562							19060905	t		lperfetto	Here we show that autophosphorylation of erk1/2 on thr188 directs erk1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy.	SIGNOR-182628	0.2
GLI3	protein	P10071	UNIPROT	PTCH1	protein	Q13635	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002572								16571352	f		lperfetto	Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1.	SIGNOR-209641	0.699
RFNG	protein	Q9Y644	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606		BTO:0000975							12486116	t		gcesareni	We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1.	SIGNOR-96561	0.633
PRKCD	protein	Q05655	UNIPROT	DBI	protein	P07108	UNIPROT	up-regulates	phosphorylation	Thr42	ATVGDINtERPGMLD	9606									18194441	t		gcesareni	Acyl coenzyme a-binding protein (acbp) is phosphorylated following protein kinase c activation.	SIGNOR-160393	0.2
KLKB1	protein	P03952	UNIPROT	F12	protein	P00748	UNIPROT	up-regulates activity	cleavage	Arg353	EQPPSLTrNGPLSCG	9606		BTO:0000131							28966616	t		lperfetto	FXIIa converts PK to the active protease PKa, which reciprocally activates more FXII|In addition, PKa can initiate a further proteolysis of FXIIa into a ~30 kDa light chain fragment, termed β-FXIIa. The cleavage takes place at the peptide bond Arg353–Val354 and consequently, the active site released from the heavy chain and thus from surfaces.	SIGNOR-263520	0.588
NEK6	protein	Q9HC98	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates activity	phosphorylation	Ser422	AEAFLGFsYAPPTDS	-1									12023960	t		miannu	The present study is the first report of a protein kinase (NEK6) capable of phosphorylating the hydrophobic motif of SGK1, although our data suggest that NEK6 may not mediate this reaction in cells. Nevertheless, the phosphorylation of the hydrophobic motif of SGK1in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1. Ser377 and Ser422of SGK1, and the CDK7 T-loop peptide, which are phosphorylated by NEK6.	SIGNOR-250297	0.344
AVPR1A	protein	P37288	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257077	0.439
JNJ-28312141 free base	chemical	CID:11676971	PUBCHEM	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259749	0.8
SIRT5	protein	Q9NXA8	UNIPROT	G6PD	protein	P11413	UNIPROT	up-regulates activity	catalytic activity			9606									27113762	t		Monia	Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes.	SIGNOR-261211	0.282
ID2	protein	Q02363	UNIPROT	MYOD/E12E47	complex	SIGNOR-C127	SIGNOR	down-regulates activity	binding			10090	BTO:0004058								9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241149	0.58
2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid	chemical	CID:135461425	PUBCHEM	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259708	0.8
DOK1	protein	Q99704	UNIPROT	A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257677	0.32
RPS6KA1	protein	Q15418	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser295	TKRRKSMsGASPKES	9606									23708659	t		lperfetto	Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.	SIGNOR-202117	0.375
CDK5	protein	Q00535	UNIPROT	PARP1	protein	P09874	UNIPROT	down-regulates activity	phosphorylation	Ser786	RGGSDDSsKDPIDVN	-1									21922195	t		miannu	These results would suggest that the phosphorylation of PARP-1 via Cdk5's kinase activity is necessary for its persistence at damage sites.Based on these results and the recruitment data, we hypothesize that the phosphorylation of the PARP-1 protein by Cdk5 on one or more of the serines 782, 785, and 786 results in an attenuation of its ribosylating activity facilitating its persistence at the sites of DNA damage.	SIGNOR-276359	0.261
AP1	complex	SIGNOR-C154	SIGNOR	CCND1	protein	P24385	UNIPROT	up-regulates	transcriptional regulation			9606	BTO:0000762								12509763	f		lperfetto	Substrates for ERK1/2 include nuclear proteins such as C-JUN, this leads to activation of the AP-1 transcription factor, which is made up of FOS-JUN heterodimers.|As a result of stimulating these transcriptional regulators, key cell-cycle regulatory proteins, such as D-type cyclins, are expressed, which enables the cell to progress through the G1 phase of the cell-cycle. 	SIGNOR-253215	0.606
TTK	protein	P33981	UNIPROT	CDCA8	protein	Q53HL2	UNIPROT	up-regulates	phosphorylation	Thr169	KRSSRANtVTPAVGR	9606									19530738	t		lperfetto	First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form.	SIGNOR-186143	0.472
CDKN1A	protein	P38936	UNIPROT	CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	down-regulates activity	binding												10913154	t		lperfetto	P21 Inhibits Thr161 Phosphorylation of Cdc2 to Enforce the G2 DNA Damage Checkpoint|The cyclin-dependent kinase inhibitor p21 is required for a sustained G2 arrest after activation of the DNA damage checkpoint. Here we have addressed the mechanism by which p21 can contribute to this arrest in G2. We show that p21 blocks the activating phosphorylation of Cdc2 on Thr161	SIGNOR-251498	0.85
CyclinD1/CDK6	complex	SIGNOR-C143	SIGNOR	G0/G1_transition	phenotype	SIGNOR-PH219	SIGNOR	up-regulates													12640120	f		lperfetto	Transition through this point requires cdk6/4-cyclin D, since inhibition with TAT-p16INK4A during the first 3 to 5 h prevents cell cycle entry and maintains both naive and memory T cells in G0.	SIGNOR-273192	0.7
IL1B	protein	P01584	UNIPROT	SERPINA3	protein	P01011	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002600								11027208	f		miannu	We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. 	SIGNOR-254806	0.2
PRL	protein	P01236	UNIPROT	KRT15	protein	P19012	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000667								20103718	f	Regulation	miannu	PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes.	SIGNOR-251904	0.2
CAMK2B	protein	Q13554	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity	phosphorylation	Ser641	RRSVKRNsTVDCNGV	9606	BTO:0000938								32611770	t		lperfetto	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275788	0.275
EIF2AK1	protein	Q9BQI3	UNIPROT	EIF2S1	protein	P05198	UNIPROT	down-regulates	phosphorylation	Ser52	MILLSELsRRRIRSI	9606									11041858	t		lperfetto	The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases . The ser-51 mutant showed little covalent modification by the endogenous enzymes. Phosphorylation of the serine 51 residue in the alpha-subunit of translational initiation factor 2 in eukaryotes (eif2 alpha) impairs protein synthesis presumably by sequestering eif2b, a rate-limiting pentameric guanine nucleotide exchange protein which catalyzes the exchange of gtp for gdp in the eif2-gdp binary complex	SIGNOR-83226	0.886
MAPK3	protein	P27361	UNIPROT	SOS1	protein	Q07889	UNIPROT	down-regulates	phosphorylation	Ser1132	TLPHGPRsASVSSIS	9606									8816480	t		lperfetto	In this report, we describe the identification of five MAP kinase sites (S-1137, S-1167, S-1178, S-1193, and S-1197) on hSos1.Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1	SIGNOR-43939	0.621
ULK1	protein	O75385	UNIPROT	DENND3	protein	A2RUS2	UNIPROT	up-regulates activity	phosphorylation	Ser472	THRRMVVsMPNLQDI	9606									25925668	t		lperfetto	ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12.	SIGNOR-264730	0.41
FAD(3-)	chemical	CHEBI:57692	ChEBI	ETF	complex	SIGNOR-C463	SIGNOR	form complex	binding			9606									33450351	t		miannu	Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors.	SIGNOR-269469	0.8
PRKCA	protein	P17252	UNIPROT	PPP2R5A	protein	Q15172	UNIPROT	down-regulates activity	phosphorylation	Ser41	RQKRSQGsSQFRSQG	-1									24225947	t		miannu	 In this study, we identified a novel phosphorylation site at Ser(41) of B56α. This phosphoamino acid residue was efficiently phosphorylated in vitro by PKCα. 	SIGNOR-276603	0.349
MAPK14	protein	Q16539	UNIPROT	MAPKAPK5	protein	Q8IW41	UNIPROT	up-regulates activity	phosphorylation	Thr182	IDQGDLMtPQFTPYY	9606	BTO:0000567								9628874	t		lperfetto	In hela cells, prak was activated in response to cellular stress and proinflammatory cytokines. Prak activity was regulated by p38alpha and p38beta both in vitro and in vivo and thr182 was shown to be the regulatory phosphorylation site.	SIGNOR-58135	0.621
TRHR	protein	P34981	UNIPROT	GNA11	protein	P29992	UNIPROT	up-regulates activity	binding			9606		BTO:0001379							27515033	t		scontino	Binding of TRH to TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C.	SIGNOR-267201	0.462
TACR1	protein	P25103	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257161	0.2
IMPDH2	protein	P12268	UNIPROT	MKI67	protein	P46013	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30518405	f		miannu	We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. 	SIGNOR-260958	0.2
CDK2	protein	P24941	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation			9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity	SIGNOR-252891	0.638
CDK14	protein	O94921	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity													24794231	t		lperfetto	Compared with the wild-type CDK14, CDK14D256A mutant showed 2-fold reduced phosphorylation of LRP6 at Ser-1490, a known substrate of the CDK14/CCNY complex| It is also reported to be required for maximal phosphorylation of LRP6 on Ser 1490 and activation of Wnt signaling 	SIGNOR-273019	0.34
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	LCN2	protein	P80188	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15536164	f	 	miannu	 Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG. 	SIGNOR-254796	0.34
MCM10	protein	Q7L590	UNIPROT	RECQL4	protein	O94761	UNIPROT	down-regulates	binding			9606									19696745	t		miannu	Mcm10 inhibits recq4 helicase activity.	SIGNOR-187701	0.525
TCF3	protein	P15923	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity	binding			9606		BTO:0000887							1649701	t	E12/E47-like proteins interact in vivo with the myogenic HLH proteins MyoD and myogenin	lperfetto	In addition we demonstrate that myod, in conjunction with e12/e47-like proteins, is functioning as a regulatory nodal point for activation of several other downstream muscle regulators.	SIGNOR-20540	0.799
ADORA3	protein	P0DMS8	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256671	0.437
CCAR2	protein	Q8N163	UNIPROT	HDAC3	protein	O15379	UNIPROT	down-regulates activity	binding												26158765	t		lperfetto	Besides SIRT1, CCAR2 inhibits the activity of the histone-modifying enzymes SUV39H1 and HDAC3 [9, 10], thus playing an important role in chromatin structure regulation.	SIGNOR-267665	0.257
PEX12	protein	O00623	UNIPROT	UBE2D1	protein	P51668	UNIPROT	up-regulates activity	binding			-1									19687296	t		miannu	Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. 	SIGNOR-253024	0.611
CDK1	protein	P06493	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates activity	phosphorylation	Thr56	FSSQPGHtPHPAASR	9606									10766756	t		gcesareni	Using synthetic peptides and mutant cell lines, we identified threonine 56, one of two consensus sites for cdc2 within the bcl-2 sequence, as a residue phosphorylated by cdc2. Mutation at threonine 56 abrogated the cell cycle inhibitory effect of bcl-2 without affecting anti-apoptotic function.Taken together, our present findings indicate that phosphorylation of bcl-2 at threonine 56 by cdc2 is required for bcl-2-mediated cell cycle inhibition, which may have some roles during mitosis in the normal cell cycle.	SIGNOR-76837	0.351
NAALAD2	protein	Q9Y3Q0	UNIPROT	Ac-Asp-Glu(3-)	smallmolecule	CHEBI:76931	ChEBI	down-regulates quantity	chemical modification			9606									10085079	t		miannu	The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated.	SIGNOR-267541	0.8
PPP2CA	protein	P67775	UNIPROT	PTTG1	protein	O95997	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser31	LKLGSGPsIKALDGR	9606	BTO:0000567								24781523	t		miannu	CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase	SIGNOR-276379	0.301
MAPK1	protein	P28482	UNIPROT	TPR	protein	P12270	UNIPROT	up-regulates	phosphorylation	Thr2137	EDRTVPStPTLVVPH	9606									18794356	t		miannu	Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore.	SIGNOR-181022	0.382
GSK3B	protein	P49841	UNIPROT	NEB	protein	P20929	UNIPROT	down-regulates	phosphorylation			9606									21798082	t		gcesareni	Gsk3b is able to phosphorylate nebulin at two ser sites in the c-terminal region of nebulin localized to the z-disk, thus preventing the interaction of nebulin with neuronal wiscott-aldrich syndrome protein (nwasp), a ubiquitously expressed member of the wasp family, which is involved in actin assembly.	SIGNOR-175659	0.312
PTPRG	protein	P23470	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity	dephosphorylation	Tyr576	RYMEDSTyYKASKGK	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254719	0.245
YAP1	protein	P46937	UNIPROT	SLC2A1	protein	P11166	UNIPROT	up-regulates quantity by expression	transcriptional regulation												30348863	f		lperfetto	Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap-/- mutants, and impaired glucose tolerance in adults.	SIGNOR-276584	0.263
UNC80	protein	Q8N2C7	UNIPROT	NALCN	protein	Q8IZF0	UNIPROT	up-regulates activity	binding			9606	BTO:0000142								22196327	t		miannu	The NALCN complex in the brain consists of NALCN, UNC80 and UNC79. UNC80 directly associates with NALCN and UNC79 forms part of the complex by its interaction with UNC80. 	SIGNOR-265184	0.803
pemetrexed	chemical	CHEBI:63616	ChEBI	TYMS	protein	P04818	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205933	0.8
H3C1	protein	P68431	UNIPROT	Nucleosome_H3.1 variant	complex	SIGNOR-C324	SIGNOR	form complex	binding			-1									21812398	t		miannu	The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 	SIGNOR-263721	0.2
PRKACA	protein	P17612	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates activity	phosphorylation	Ser364	PLLSRMGsLRAPVDE	9606	BTO:0000007								33110360	t		miannu	We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence.	SIGNOR-277537	0.2
anastrozole	chemical	CHEBI:2704	ChEBI	CYP19A1	protein	P11511	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189614	0.8
MRGPRX2	protein	Q96LB1	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256930	0.2
(+)-pilocarpine	chemical	CHEBI:8207	ChEBI	CHRM3	protein	P20309	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258626	0.8
IL6	protein	P05231	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606									18231581	f		lperfetto	Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS	SIGNOR-260256	0.7
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2H	protein	P62256	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271362	0.489
RAF1	protein	P04049	UNIPROT	MAP2K2	protein	P36507	UNIPROT	up-regulates	phosphorylation	Ser226	LIDSMANsFVGTRSY	9606									8157000	t	Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases.	gcesareni	To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1.	SIGNOR-36553	0.72
PLK1	protein	P53350	UNIPROT	STAG2	protein	Q8N3U4	UNIPROT	down-regulates activity	dephosphorylation	Ser1137	KRLRPEDsFMSVYPM	9606	BTO:0000567								15737063	t		lperfetto	Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase	SIGNOR-275534	0.727
PAX7-FOXO1	fusion protein	SIGNOR-FP11	SIGNOR	IGF1R	protein	P08069	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20663909	t		lperfetto	We also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The map of PAX3-FKHR binding sites provides a framework for understanding the pathogenic roles of PAX3-FKHR, as well as its molecular targets to allow a systematic evaluation of agents against this aggressive rhabdomyosarcoma.	SIGNOR-249595	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	MYOD1	protein	P15172	UNIPROT	down-regulates	phosphorylation	Ser200	YSGDSDAsSPRSNCS	9606	BTO:0000222								14749395	t		lperfetto	Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21.	SIGNOR-216920	0.325
BGJ-398	chemical	CHEBI:63451	ChEBI	FGFR2	protein	P21802	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190266	0.8
THRA	protein	P10827	UNIPROT	RARA	protein	P10276	UNIPROT	up-regulates	binding			9606									15650024	t		gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-133240	0.407
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SCNN1G	protein	P51170	UNIPROT	down-regulates quantity by destabilization	phosphorylation			-1									11805112	t	inferred from 70% family members	lperfetto	Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.	SIGNOR-270171	0.2
PRKCE	protein	Q02156	UNIPROT	CTNND1	protein	O60716	UNIPROT	down-regulates	phosphorylation	Ser268	PQVRVGGsSVDLHRF	9606	BTO:0000150;BTO:0001130;BTO:0000551								23542175	t		lperfetto	We find that ctnnd1/p120ctn phosphorylation at serine 268 (p-s268) occurs in a strictly pkc_-dependent manner,serine/threonine phosphorylation of p120-ctn has been reported to affect the integrity of ajs [12], [24] and [25]. Xia et al. (2003) reported that several residues (ser122, ser252, ser268, ser288, thr310, ser312, ser873, and thr910) in p120ctn can be either phosphorylated or dephosphorylated upon pkc activation	SIGNOR-201600	0.2
CSNK2A1	protein	P68400	UNIPROT	YY1	protein	P25490	UNIPROT	up-regulates	phosphorylation	Ser118	EVVGGDDsDGLRAED	9606									23226345	t		lperfetto	More recently, we identified and mapped multiple phosphorylation sites in yy1, including, threonine 39, serine 118, serine 247, threonine 348 and threonine 378. The first kinase proven to phosphorylate yy1 in vivo was plk1, which phosphorylates threonine 39 during g2/m stage of the cell cycle [25]. Ck2_ is another kinase identified as constitutively phosphorylating yy1 at serine 118. This modification protects yy1 cleavage by caspase 7 during apoptosis	SIGNOR-200083	0.29
BMP4	protein	P12644	UNIPROT	BMPR2	protein	Q13873	UNIPROT	up-regulates	binding			9606									8006002	t		fspada	Bmp-4 bound to alk-3 and alk-6 efficiently	SIGNOR-35763	0.772
SMO	protein	Q99835	UNIPROT	GNB3	protein	P16520	UNIPROT	up-regulates	binding			9606									17251915	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp	SIGNOR-152814	0.2
TWIST2	protein	Q8WVJ9	UNIPROT	CD44	protein	P16070	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002590								17487558	f		miannu	 Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells	SIGNOR-255517	0.455
RB1	protein	P06400	UNIPROT	HDAC3	protein	O15379	UNIPROT	up-regulates				9606									14560017	f		gcesareni	We find that active rb mediates histone deacetylation on cyclin a, cdc2, topoisomerase iialfa, and thymidylate synthase promoters. We also demonstrate that this deacetylation is hdac dependent, since the hdac inhibitor trichostatin a (tsa) prevented histone deacetylation at each promoter.	SIGNOR-118839	0.608
CSNK2A1	protein	P68400	UNIPROT	TOP1	protein	P11387	UNIPROT	up-regulates activity	phosphorylation	Ser10	GDHLHNDsQIEADFR	-1									18408216	t		miannu	In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells.	SIGNOR-276155	0.391
DLX5	protein	P56178	UNIPROT	Osteoblast_differentiation	phenotype	SIGNOR-PH9	SIGNOR	up-regulates				10090									12000792	f		Giulio Giuliani	In conclusion, Dlx5 and Dlx6 are dynamic regulators of mammalian development, which are absolutely required for proper craniofacial and skeletal development and which display overlapping genetic functions in all tissues in which they are expressed. In addition, they appear to act as essential regulators of chondrogenesis and osteogenesis.	SIGNOR-255450	0.7
Alamandine	chemical	CID:44192273	PUBCHEM	MRGPRD	protein	Q8TDS7	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								23446738	t		Luana	Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D.	SIGNOR-262308	0.8
CDK2	protein	P24941	UNIPROT	DNMT1	protein	P26358	UNIPROT	up-regulates	phosphorylation	Ser154	AKPEPSPsPRITRKS	9606									21565170	t		gcesareni	We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5	SIGNOR-173681	0.349
FNTB	protein	P49356	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates activity				9606									24294527	t		lperfetto	Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials.	SIGNOR-242556	0.428
PCSK2	protein	P16519	UNIPROT	Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0001073								11690596	t		miannu	Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension.	SIGNOR-270335	0.2
GNG3	protein	P63215	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606									16537363	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt	SIGNOR-145125	0.357
SMARCB1	protein	Q12824	UNIPROT	CDC6	protein	Q99741	UNIPROT	down-regulates				9606									12226744	f		miannu	We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6.	SIGNOR-92785	0.319
RPS6KA5	protein	O75582	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr45	PGGTLFStTPGGTRI	-1									11777913	t		lperfetto	Here, using mass spectrometry, we identify the serum-responsive, rapamycin-sensitive sites as Ser 65 and Thr 70. | Phosphorylation of Thr 37/Thr 46 is followed by Thr 70 phosphorylation, and Ser 65 is phosphorylated last. Finally, we show that phosphorylation of Ser 65 and Thr 70 alone is insufficient to block binding to eIF4E, indicating that a combination of phosphorylation events is necessary to dissociate 4E-BP1 from eIF4E.	SIGNOR-249131	0.658
NFIL3	protein	Q16649	UNIPROT	CYP3A4	protein	P08684	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								18004209	f		miannu	 The oscillation in the expression of the CYP3A4 gene seemed to be the underlying cause of the rhythmic change in its metabolic activity. Luciferase reporter gene analysis and electrophoretic mobility shift assay revealed that the circadian transcriptional factor, D-site-binding protein (DBP), activated the transcription of the CYP3A4 gene by binding to the DNA sequence near the upstream of the transcriptional start site. The transactivation of the CYP3A4 gene by DBP was repressed by the E4 promoter-binding protein-4 (E4BP4), a negative component of the circadian clock.	SIGNOR-253836	0.2
CHD8	protein	Q9HCK8	UNIPROT	SOX7	protein	Q9BT81	UNIPROT	down-regulates quantity	transcriptional regulation			10090									32839322	t		Gianni	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268922	0.2
Hemoglobin	complex	SIGNOR-C209	SIGNOR	hb:hp	complex	SIGNOR-C149	SIGNOR	form complex	binding			9606									11854029	t		miannu	CD163 was identified as the endocytic receptor binding hemoglobin (Hb) in complex with the plasma protein haptoglobin (Hp). This specific receptor-ligand interaction leading to removal from plasma of the Hp-Hb complex-but not free Hp or Hb-now explains the depletion of circulating Hp in individuals with increased intravascular hemolysis.	SIGNOR-255284	0.723
Diprenorphine	chemical	CHEBI:4650	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258791	0.8
HNF4A	protein	P41235	UNIPROT	G6PC1	protein	P35575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16308421	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-142153	0.2
CDK1	protein	P06493	UNIPROT	MPLKIP	protein	Q8TAP9	UNIPROT	up-regulates	phosphorylation	Thr120	QGSPRTStPFGSGRV	9606									17310276	t		lperfetto	Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1	SIGNOR-153308	0.348
PLK1	protein	P53350	UNIPROT	ZMYM2	protein	Q9UBW7	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser305	QPGVDSLsPVASLPK										25855382	t		lperfetto	PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant	SIGNOR-275558	0.386
NR0B2	protein	Q15466	UNIPROT	THRA	protein	P10827	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11368516	f		gcesareni	Shp (short heterodimer partner) is an orphan nuclear receptor lacking a dna binding domain that interacts with nuclear receptors (nr) including thyroid receptor (tr), retinoic acid receptors (rar and rxr), and estrogen receptors alpha and beta (eralpha and erbeta). Shp acts as a negative regulator of these receptors by inhibiting dna binding and transcriptional activation.	SIGNOR-108248	0.378
DLG4	protein	P78352	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606	BTO:0000938								19075115	f		miannu	Postsynaptic density 95 (PSD-95) is an important regulator of synaptic structure and plasticity.	SIGNOR-264053	0.7
PRKCZ	protein	Q05513	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr110	SHSRQAStDAGTAGA	9606	BTO:0002181								25660024	t		miannu	 Yap and β-catenin are direct substrates of PKCζ.We show here that PKCζ suppresses intestinal stem cell function by promoting the downregulation of β-catenin and Yap through direct phosphorylation.Consistent with MS/MS analysis, mutation to alanine of these two sites completely abolished Yap phosphorylation by PKCζ. Interestingly, S109 and T110 sites were highly conserved among species (Figure S3B), which suggested an important role in Yap regulation. 	SIGNOR-276877	0.28
ELOVL5	protein	Q9NYP7	UNIPROT	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267898	0.8
TIAM1	protein	Q13009	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates				9606	BTO:0000938	BTO:0000142							20654717	f		gcesareni	This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1.	SIGNOR-167073	0.74
TGFA	protein	P01135	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	binding			9606	BTO:0000584								16585207	t	Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines	gcesareni	Our data indicate that a subset of cell lines is dependent on TGF-_-mediated activation of the EGFR for cell proliferation and strongly suggest that pancreatic tumors expressing high levels of TGF-_ and phosphorylated (activated) EGFR are EGFR-dependent in vitro and in vivo.	SIGNOR-93199	0.896
MAPK3	protein	P27361	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser363	TSRTPKDsPGIPPSA	9534	BTO:0001538								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252759	0.718
ZDHHC2	protein	Q9UIJ5	UNIPROT	AKAP5	protein	P24588	UNIPROT	up-regulates activity	palmitoylation	Cys129	KSRLKIPcIKFPRGP	10116									25589740	t			Here, we report that the recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms	SIGNOR-261289	0.338
DYRK1B	protein	Q9Y463	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				10090	BTO:0000165;BTO:0000222;BTO:0001946	BTO:0000887;BTO:0001760							15851482	f		lperfetto	Mirk diminishes the extent of myoblast apoptosis during the differentiation process, at least in part by direct modulation of p21cip1 localization.	SIGNOR-235731	0.7
MASP1	protein	P48740	UNIPROT	C4B	protein	P0C0L5	UNIPROT	up-regulates activity	cleavage	Arg679	EKTTRKKrNVNFQKA	-1									9087411	t		lperfetto	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263423	0.663
imatinib	chemical	CHEBI:45783	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258227	0.8
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BC12	protein	O60814	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSVYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271979	0.2
MAPK14	protein	Q16539	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606	BTO:0000093								10581258	t		lperfetto	P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.	SIGNOR-72695	0.765
KDM5A	protein	P29375	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	demethylation			9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-265334	0.2
PINK1	protein	Q9BXM7	UNIPROT	UBC	protein	P0CG48	UNIPROT	up-regulates activity	phosphorylation	Ser65	DYNIQKEsTLHLVLR	9606	BTO:0000938								24784582	t		lperfetto	Ubiquitin is phosphorylated by PINK1 to activate parkin|PINK1 phosphorylated ubiquitin at Ser65 both in vitro and in cells	SIGNOR-249691	0.587
HTR1B	protein	P28222	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256863	0.411
STK4	protein	Q13043	UNIPROT	MOB1A	protein	Q9H8S9	UNIPROT	up-regulates	phosphorylation	Thr12	FSSRSSKtFKPKKNI	9606									21808241	t	MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors.	gcesareni	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction.	SIGNOR-175829	0.896
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	LDHA	protein	P00338	UNIPROT	up-regulates quantity	transcriptional regulation			9606									7673128	t			Deletional and mutational analysis of the function of mouse LDH-reporter fusion gene constructs in transient transfection assays defined three domains, between -41 and -84 base pairs upstream of the transcription initiation site, which were crucial for oxygen-regulated expression. The most important of these, although not capable of driving hypoxic induction in isolation, had the consensus of a hypoxia-inducible factor 1 (HIF-1) site, and cross-competed for the binding of HIF-1 with functionally active Epo and phosphoglycerate kinase-1 sequences	SIGNOR-267479	0.644
SB 505124	chemical	CHEBI:100922	ChEBI	TGFBR1	protein	P36897	UNIPROT	down-regulates	chemical inhibition			9606									14978253	t		gcesareni	Sb-505124 is a selective inhibitor of transforming growth factor-beta type i receptors alk4, alk5, and alk7.	SIGNOR-122910	0.8
FGFR4	protein	P22455	UNIPROT	FGFR4	protein	P22455	UNIPROT	up-regulates	phosphorylation	Tyr643	GVHHIDYyKKTSNGR	9606	BTO:0001130								18670643	t		lperfetto	Binding of fgf to fgf receptors leads to receptor dimerization and subsequent tyrosine autophosphorylation and phosphorylation of target substrates. Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanismthis antibody specifically recognizes tyr642/643 in fgfr-4.	SIGNOR-179780	0.2
SMARCC1	protein	Q92922	UNIPROT	SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270606	0.792
SATB2	protein	Q9UPW6	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	down-regulates activity	binding			9606									21965674	t		miannu	 SATB2 attenuates p63-mediated gene expression of perp (p53 apoptosis effector related to PMP-22), a critical downstream target gene during development, and specifically decreases p63 perp promoter binding.	SIGNOR-255149	0.379
CSNK2A1	protein	P68400	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	down-regulates activity	phosphorylation	Ser898	SECDPTPsHRGQLNK	9606	BTO:0000567								31167143	t		miannu	Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations. 	SIGNOR-276729	0.2
DNMT1	protein	P26358	UNIPROT	BAG1	protein	Q99933	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18413740	f	 	lperfetto	DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation 	SIGNOR-254108	0.2
CDK11B	protein	P21127	UNIPROT	EIF3F	protein	O00303	UNIPROT	up-regulates activity	phosphorylation	Thr119	GAARVIGtLLGTVDK										19245811	t		lperfetto	Here, we identified a second eIF3f phosphorylation site (Thr119) by CDK11(p46) during apoptosis. We demonstrated that eIF3f is directly phosphorylated by CDK11(p46) in vivo. Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis. 	SIGNOR-273131	0.531
PTEN	protein	P60484	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity				9606	BTO:0001271								20596030	f		lperfetto	Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfralpha was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib.	SIGNOR-166478	0.656
PFDN2	protein	Q9UHV9	UNIPROT	Prefoldin co-chaperone	complex	SIGNOR-C513	SIGNOR	form complex	binding			9606									32699605	t		miannu	The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6)	SIGNOR-270931	0.949
COL1A1	protein	P02452	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	up-regulates	binding			9606									7688313	t		gcesareni	Both a2b1- and a1b1- inegrins are implicated in chondrocyte adhesion to native collagene i and ii	SIGNOR-31787	0.623
MAPK8	protein	P45983	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser69	GPLAPPAsPGPFATR	10090									15486195	t		miannu	Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. 	SIGNOR-250132	0.751
TAB1	protein	Q15750	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates	binding			9606									25290089	t		lperfetto	The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.	SIGNOR-205440	0.821
COL1A2	protein	P08123	UNIPROT	A11/b1 integrin	complex	SIGNOR-C168	SIGNOR	up-regulates activity	binding			10090	BTO:0000165								12496264	t		lperfetto	Modeling of the alpha I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar collagens is a common recognition motif used by alpha(1)beta(1), alpha(2)beta(1), and also alpha(11)beta(1) integrins.	SIGNOR-253346	0.455
ACE	protein	P12821	UNIPROT	bradykinin	smallmolecule	CHEBI:3165	ChEBI	down-regulates quantity by destabilization	binding			9606									16219810	t			The angiotensin-converting enzyme (ACE) is a membrane-bound peptidyl dipeptidase known to act on a variety of peptide substrates in the extracellular space. Its most notable functions are the formation of angiotensin II and the degradation of bradykinin.	SIGNOR-253341	0.8
TOP1	protein	P11387	UNIPROT	ARNTL	protein	O00327	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000944								22904072	t		miannu	We examined the mechanism of topoisomerase I (Top1) to understand the role of the unique chromatin structure in Bmal1 gene regulation.  Promoter assays showed that the Top1-binding site is required for transcriptional suppression and that it functions cooperatively with the distal RORE, supporting that Bmal1 transcription is upregulated by Top1 inhibition. 	SIGNOR-277354	0.349
RTKN	protein	Q9BST9	UNIPROT	SEPTIN9	protein	Q9UHD8	UNIPROT	down-regulates				9606									16007136	f		miannu	We identified rhotekin, a downstream effector for rho, as a candidate regulator organizing septin structures through filament disruption.	SIGNOR-138578	0.2
AGTR1	protein	P30556	UNIPROT	NPHS1	protein	O60500	UNIPROT	down-regulates activity				10116									21982880	f		miannu	Ang II-receiving rats displayed diminished phosphorylation of nephrin but enhanced glomerular/podocyte injury and proteinuria when compared to control rats. These findings indicate that Ang II induces nephrin dephosphorylation and podocyte injury through a caveolin-1-dependent mechanism.	SIGNOR-253342	0.372
TUBG1	protein	P23258	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates				9606	BTO:0000567								19029337	f		miannu	It has been reported that NEDD1 directly interacts with and recruits the γ-tubulin ring complex to centrosomes and to spindle MTs to promote MT nucleation and spindle assembly 	SIGNOR-261423	0.7
KLK3	protein	P07288	UNIPROT	PTHLH	protein	P12272	UNIPROT	down-regulates activity	cleavage	Pro21	FLLSYAVpSCGRSVE	-1									8753751	t		lperfetto	Our study demonstrates that PTHrP is a substrate for PSA. The cleavage of the amino-terminal portion of PTHrP completely disrupts its ability to interact with the PTH/PTHrP receptor and thus inhibits its PTH-like activity. | Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments.	SIGNOR-270546	0.432
EIF5B	protein	O60841	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	down-regulates activity	binding			9606									30211544	t		lperfetto	 eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC.	SIGNOR-269120	0.661
CDK6	protein	Q00534	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Ser1035	NMDAPPLsPYPFVRT	9606	BTO:0001938								11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus)	SIGNOR-104711	0.667
Non-structural protein 6	protein	P0DTD1-PRO_0000449624	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	down-regulates activity	binding			9606									32979938	t		miannu	We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F).	SIGNOR-262510	0.2
ATM	protein	Q13315	UNIPROT	H2AX	protein	P16104	UNIPROT	up-regulates	phosphorylation	Ser140	GKKATQAsQEY	9606									21690091	t		gcesareni	Upon dna damage, h2ax is phosphorylated by ataxia telangiectasia mutated (atm) and atm-related kinases at serine 139, known as ?_?_?_-H2ax, which serves as a docking site to recruit the mediator of dna damage checkpoint protein 1 (mdc1) to sites of dna damage, named dna damage foci	SIGNOR-174442	0.2
TNF	protein	P01375	UNIPROT	REL	protein	Q04864	UNIPROT	up-regulates				9606	BTO:0000782								10823840	f		miannu	C-rel emerges as the main nf-kb family member stimulated by tnf_ in the context of physiologic activation of resting t cells.	SIGNOR-77547	0.425
BMI1	protein	P35226	UNIPROT	CDKN2A	protein	P42771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20551323	f		gcesareni	One important pathway in which bmi-1 acts to promote the overall growth of mice and cellular proliferation includes cdkn2a;bmi-1 represses the expression of cdkn2a, which encodes two cyclin-dependent kinase inhibitors, p16ink4a (p16) and p19arf	SIGNOR-166163	0.47
DRD5	protein	P21918	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257418	0.267
MAPK14	protein	Q16539	UNIPROT	CDX2	protein	Q99626	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser283	RSVPEPLsPVSSLQA	9606									16027724	t		miannu	ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation	SIGNOR-250092	0.425
CDK1	protein	P06493	UNIPROT	FOXM1	protein	Q08050	UNIPROT	up-regulates	phosphorylation	Ser251	MIQFAINsTERKRMT	9606			SIGNOR-C17						19737929	t		lperfetto	A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1the phosphorylation at ser-251 is critical for the activation of foxm1.	SIGNOR-187876	0.752
SMO	protein	Q99835	UNIPROT	MAL	protein	P21145	UNIPROT	up-regulates quantity	transcriptional regulation			10090									35082605	f	Non-canonical pathway (Gli1-indipendent): SMO/AMPK	SimoneGraziosi	We show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMPactivated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell.	SIGNOR-269224	0.2
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	CFTR	protein	P13569	UNIPROT	up-regulates activity	dephosphorylation			10090		BTO:0000988							21317537	t		lperfetto	WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression,	SIGNOR-264646	0.2
F2RL1	protein	P55085	UNIPROT	F2RL1	protein	P55085	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	PAR2 expression is up-regulated following PAR2 activation. This is logical for PAR2, as endogenous activators for the receptor are serine proteases, which irreversibly activate PAR2 through N-terminal cleavage. 	SIGNOR-254840	0.2
SGK1	protein	O00141	UNIPROT	NEDD4L	protein	Q96PU5	UNIPROT	down-regulates	phosphorylation	Ser448	IRRPRSLsSPTVTLS	9606									15677482	t		gcesareni	Nedd4-2 function is negatively regulated by phosphorylation via a serum- and glucocorticoid-inducible protein kinase (sgk1), which serves as a mechanism to inhibit the ubiquitination-dependent degradation of enac. Sgk1 catalyzed phosphorylation of hnedd4-2 at ser-468 maintaining hnedd4-2 in an inactive phosphorylated state.	SIGNOR-133438	0.78
SNAI1	protein	O95863	UNIPROT	SERPINE1	protein	P05121	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19055748	f		lperfetto	We demonstrated by both cDNA microarrays and real-time quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts.	SIGNOR-252262	0.428
SRC	protein	P12931	UNIPROT	ABL1	protein	P00519	UNIPROT	up-regulates activity	phosphorylation	Tyr226	KRNKPTVyGVSPNYD	9606									11847100	t		lperfetto	c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function.	SIGNOR-246307	0.517
Yellow AB	chemical	CHEBI:82554	ChEBI	PTCH1	protein	Q13635	UNIPROT	down-regulates	chemical inhibition			9606									17970037	t		gcesareni	Anti-patched-1 antibodies suppress hedgehog signaling pathway and pancreatic cancer proliferation.	SIGNOR-158650	0.8
CDC20	protein	Q12834	UNIPROT	FBXO31	protein	Q5XUX0	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0002181								29343641	t		miannu	Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT.	SIGNOR-277378	0.371
ceramide	smallmolecule	CHEBI:17761	ChEBI	glycosphingolipid	smallmolecule	CHEBI:24402	ChEBI	up-regulates quantity	precursor of			9606									18184806	t		miannu	Ceramide is a common precursor for both sphingomyelin and glycosphingolipids, which are ubiquitous components of membranes in mammalian cells and play important roles in cell growth, differentiation, and apoptosis 	SIGNOR-268498	0.8
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	down-regulates	binding			9606									20006481	t		lperfetto	Akt can phosphorylate pras40, a raptor binding protein that also acts as an inhibitor of torc1. Akt-mediated phosphorylation of pras40 again promotes 14-3-3 binding, in this case leading to relief from pras40-mediated inhibition.	SIGNOR-217565	0.511
SRC	protein	P12931	UNIPROT	CASP8	protein	Q14790	UNIPROT	down-regulates	phosphorylation	Tyr380	TDSEEQPyLEMDLSS	9606									16619028	t		lperfetto	Src kinase phosphorylates caspase-8 on tyr380: a novel mechanism of apoptosis suppressionwe identified caspase-8 as a new substrate for src kinase. Phosphorylation occurs on tyr380, situated in the linker region between the large and the small subunits of human procaspase-8, and results in downregulation of caspase-8 proapoptotic function	SIGNOR-146127	0.467
PPBP	protein	P02775	UNIPROT	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029									9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258413	0.357
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RRAS	protein	P10301	UNIPROT	up-regulates activity	phosphorylation	Ser201	QEQELPPsPPSAPRK	9606	BTO:0002181								27086924	t		miannu	 In this study, we report that TC21 and R-Ras are phosphorylated on a conserved serine, Ser186 and Ser201, respectively, in intact cells. This residue is located in the C-terminal hypervariable region of the proteins and is not conserved in M-Ras. We show that the MAP kinases ERK1/2 phosphorylate TC21 and R-Ras on this C-terminal serine residue both in vitro and in vivo. 	SIGNOR-277219	0.2
MAPK12	protein	P53778	UNIPROT	NUP62	protein	P37198	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr269	GAASGTStTTSTAAT	9606	BTO:0000007								30401435	t		miannu	We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). 	SIGNOR-277415	0.2
PTPRG	protein	P23470	UNIPROT	VCL	protein	P18206	UNIPROT	down-regulates activity	dephosphorylation	Tyr822	KSFLDSGyRILGAVA	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254731	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606		BTO:0001103							20219869	f		apalma	ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation	SIGNOR-256216	0.7
PRKD2	protein	Q9BZL6	UNIPROT	PI4KB	protein	Q9UBF8	UNIPROT	up-regulates	phosphorylation	Ser294	SNLKRTAsNPKVENE	9606									16912074	t	The effect has been demonstrated using Q9UBF8-2	gcesareni	Binding of 14-3-3 proteins to pi4kiiibeta involved the pkd phosphorylation site ser294, evident from reduced 14-3-3 binding to a s294a pi4kiiibeta mutant. Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase iii beta protects from dephosphorylation and stabilizes lipid kinase activity.	SIGNOR-148880	0.2
DUSP5	protein	Q16690	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606									10224087	t		gcesareni	Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway	SIGNOR-67355	0.773
ABL1	protein	P00519	UNIPROT	AHSA1	protein	O95433	UNIPROT	up-regulates activity	phosphorylation	Tyr223	LTSPEELyRVFTTQE	9606									26235616	t		Manara	Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity	SIGNOR-260938	0.254
WDR62	protein	O43379	UNIPROT	MAP3K3	protein	Q99759	UNIPROT	up-regulates activity	relocalization			10090									30566428	t		lperfetto	In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis	SIGNOR-271717	0.2
MAPK8IP3	protein	Q9UPT6	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates	binding			9606									10523642	t		gcesareni	Overexpression of full-length jsap1 in cos-7 cells led to a considerable enhancement of jnk3 activation, and modest enhancement of jnk1 and jnk2 activation, by the mekk1-sek1 pathwaythe regions of jsap1 that bound jnk, sek1, and mekk1 were distinct from one another. Jnk and mekk1 also bound jsap1 in vitro, suggesting that these interactions are direct.	SIGNOR-71468	0.617
CELF6	protein	Q96J87	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation			9606	BTO:0001109								31534127	t		miannu	CELF6 binds to the 3'UTR of p21 transcript and increases its mRNA stability. Depletion of CELF6 promotes cell cycle progression, cell proliferation and colony formation whereas overexpression of CELF6 induces G1 phase arrest. 	SIGNOR-269044	0.2
GRIK3	protein	Q13003	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264344	0.7
S1RA	chemical	CID:44247568	PUBCHEM	SIGMAR1	protein	Q99720	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000195								22784008	t		Simone Vumbaca	The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862) emerged as the most interesting candidate. Compound 28 is a highly selective σ1R antagonist and has successfully completed phase I safety and pharmacokinetic evaluation in humans.	SIGNOR-261122	0.8
5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide	chemical	CID:73755145	PUBCHEM	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259809	0.8
abiraterone	chemical	CHEBI:68642	ChEBI	CYP17A1	protein	P05093	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-204810	0.8
ERBB2	protein	P04626	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates	phosphorylation	Tyr1221	SPAFDNLyYWDQDPP	9606		BTO:0000149							1706616	t		gcesareni	However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2.	SIGNOR-21199	0.2
NDRG1	protein	Q92597	UNIPROT	RAB4A	protein	P20338	UNIPROT	up-regulates	binding			9606	BTO:0000150;BTO:0001130								17786215	t		miannu	In this report evidence is provided that ndrg1 is a rab4a effector protein that localizes to perinuclear recycling/sorting vesicles in the trans golgi network by binding to phophatidylinositol 4-phosphate and is involved in recycling of e-cadherin. This is the first demonstration providing evidence that ndrg1 is a rab4a effector recruiting to recycling/sorting endosomes.	SIGNOR-157697	0.328
PTGER3	protein	P43115	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256995	0.283
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	NR3C1	protein	P04150	UNIPROT	down-regulates	phosphorylation			-1									9199329	t	inferred from 70% family members	lperfetto	Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.	SIGNOR-270098	0.2
PTK2	protein	Q05397	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding												15688067	t		miannu	Src-mediated phosphorylation of FAK at Tyr925 creates an SH2 binding site for the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which leads to the activation of Ras and the extracellular signal-regulated kinase-2 (ERK2) cascade.	SIGNOR-257733	0.694
TRIB3	protein	Q96RU7	UNIPROT	COP1	protein	Q8NHY2	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16794074	t		miannu	TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).	SIGNOR-271602	0.2
MRPL44	protein	Q9H9J2	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262352	0.688
IKBKB	protein	O14920	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser272	RPRSKSQsSSNCSNP	-1									12351658	t			IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.	SIGNOR-251290	0.644
NR3C1	protein	P04150	UNIPROT	CEBPA	protein	P49715	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000011								11279134	f		lperfetto	The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin	SIGNOR-235346	0.467
MAPK1	protein	P28482	UNIPROT	SLC9A1	protein	P19634	UNIPROT	up-regulates	phosphorylation	Ser770	MMRSKETsSPGTDDV	9606									17209041	t		miannu	We have demonstrated that the map kinases extracellular signal-regulated kinases 1 and 2 (erk1/2) are implicated in growth factor activation of nhe1. / our results suggest that amino acids ser770 and ser771 mediate erk-dependent activation of the na+/h+ exchanger in vivo.	SIGNOR-151925	0.659
SMAD2	protein	Q15796	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates	binding			9606			SIGNOR-C8						9689110	t		gcesareni	We demonstrate that human smad2 and smad4, two essential smad proteins involved in mediating tgf-beta transcriptional responses in endothelial and other cell types, can functionally interact with the transcriptional coactivator creb binding protein (cbp). This interaction is specific in that it requires ligand (tgf-beta) activation and is mediated by the transcriptional activation domains of the smad proteins.	SIGNOR-59462	0.332
UBE2S	protein	Q16763	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								19822757	t		lperfetto	Here, we identify the highly conserved Ube2S as a regulator of human and Drosophila APC/C. Ube2S functions as a K11-specific chain elongating E2 of APC/C, which depends on chain initiation by UbcH10. Together, UbcH10 and Ube2S are required for the degradation of all APC/C substrates tested so far, spindle formation, and progression of cells through mitosis. 	SIGNOR-265080	0.655
G3BP2	protein	Q9UN86	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates activity	relocalization			9606	BTO:0000567								10969074	t		SARA	IkappaBalpha interacts with G3BP2 both in vivo and in vitrothrough the IkappaBalpha CRS. Overexpression of G3BP2 directly promotes retention of IkappaBalpha in the cytoplasm.	SIGNOR-260985	0.348
SMAD4	protein	Q13485	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	up-regulates activity				9606	BTO:0000599								10890911	f		lperfetto	Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity	SIGNOR-229311	0.677
CBL	protein	P22681	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									20332299	t		lperfetto	Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface.	SIGNOR-65642	0.882
MGLL	protein	Q99685	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606									26997225	f		irozzo	Overexpression of MGLL inhibits proliferation and delays cell cycle progression in QGY-7703 cells. Forced overexpression of MGLL in human HCC cells resulted in marked inhibition in cell proliferation with a significant delay in cell cycle progression [.]	SIGNOR-259139	0.7
CPSF complex	complex	SIGNOR-C53	SIGNOR	PAPOLB	protein	Q9NRJ5	UNIPROT	up-regulates activity	relocalization			9606									14749727	t		lperfetto	Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna.	SIGNOR-268324	0.565
TLR4	protein	O00206	UNIPROT	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates				9606									20596954	f		fstefani	Regulation of toll-like receptor signaling in the innate immunity.	SIGNOR-166485	0.7
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PML	protein	P29590	UNIPROT	up-regulates	phosphorylation			9606	BTO:0001271								15093545	t	The effect has been demonstrated using P29590-4	gcesareni	Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis.	SIGNOR-270034	0.2
SMOC1	protein	Q9H4F8	UNIPROT	COL1A1	protein	P02452	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20359165	f		lperfetto	The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells	SIGNOR-260402	0.2
GATA1	protein	P15976	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	binding			9606									17725493	t		miannu	 We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. In particular, we will elaborate on recent data which suggest that GATA-1 targets RUNX1 for modification, in particular phosphorylation by cyclin-dependent kinases. Furthermore, targeting of RUNX1 by GATA-1 for phosphorylation may convert RUNX1 from a repressor to an activator. This is a potential mechanism of transcriptional cooperation and may be an essential step in megakaryocytic differentiation.	SIGNOR-254194	0.629
BMPR1A	protein	P36894	UNIPROT	FAM83G	protein	A6ND36	UNIPROT	up-regulates activity	phosphorylation	Ser614	RRPSVASsVSEEYFE	-1									24554596	t		lperfetto	These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway.	SIGNOR-264766	0.383
ALK	protein	Q9UM73	UNIPROT	SFPQ	protein	P23246	UNIPROT	down-regulates	phosphorylation	Tyr293	RRPGEKTyTQRCRLF	9606	BTO:0000785								17537995	t		lperfetto	Furthermore, psf was shown to be a direct substrate of purified alk kinase domain in vitro, and psf tyr293 was identified as the site of phosphorylation. Psf phosphorylation also increased its binding to rna and decreased the psf-mediated suppression of gage6 expression.	SIGNOR-155298	0.2
GCG	protein	P01275	UNIPROT	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	up-regulates				9606									23075495	f	inferred from 70% of family members	gcesareni	On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz.	SIGNOR-269857	0.276
PTK6	protein	Q13882	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	phosphorylation	Tyr315	TFCGTPEyLAPEVLE	9606									15994200	t		gcesareni	These observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis.	SIGNOR-138437	0.454
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PRPH	protein	P41219	UNIPROT	up-regulates activity	phosphorylation	Ser59	SSSVRLGsFRSPRAG	9606	BTO:0000007								17569669	t		miannu	Here we demonstrate that peripherin, which is a peripheral nervous system neuron-specific intermediate filament protein, is a novel Akt substrate, and that Ser66 of peripherin is the phosphorylation site. Peripherin phosphorylation is apparently induced in motor neurons after nerve injury, suggesting that the Akt-mediated peripherin phosphorylation may play a role in motor nerve regeneration.	SIGNOR-262627	0.2
CSNK2A1	protein	P68400	UNIPROT	CALM1	protein	P0DP23	UNIPROT	down-regulates activity	phosphorylation	Ser82	RKMKDTDsEEEIREA	-1									26675311	t		miannu	Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. We found that in the complex between CaM and CaMKII, residue E115 of CaM is strongly interacting with K299 of the kinase through forming a salt-bridge (PDB entry 1WEL), it is quite likely that the phosphorylation induced structural change can disrupt this interaction and negatively affect the binding between the two proteins	SIGNOR-266353	0.432
SIRT5	protein	Q9NXA8	UNIPROT	ACOX1	protein	Q15067	UNIPROT	down-regulates activity	catalytic activity			9606	BTO:0000007								29491006	t		Monia	SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation.	SIGNOR-261210	0.263
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CASP8	protein	Q14790	UNIPROT	down-regulates	phosphorylation	Ser387	YLEMDLSsPQTRYIP	9606		BTO:0000149							24342355	t		lperfetto	We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity	SIGNOR-244509	0.2
TAOK	proteinfamily	SIGNOR-PF21	SIGNOR	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	up-regulates activity	phosphorylation			9606									23431053	t		miannu	The thousand-and-one (TAO) amino acids kinase or TAOK1 – 3 has been shown to directly phosphorylate and activate Hpo or MST1/2.	SIGNOR-256182	0.378
MAPK1	protein	P28482	UNIPROT	PPARA	protein	Q07869	UNIPROT	up-regulates activity	phosphorylation	Ser21	LEAGDLEsPLSEEFL	9606	BTO:0000599								10187842	t		lperfetto	We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution.	SIGNOR-249434	0.559
MAPK9	protein	P45984	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates	phosphorylation	Ser71	SRRSGLCsPSYVAVT	9606									10551811	t		gcesareni	The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71.	SIGNOR-72108	0.368
PPP3CB	protein	P16298	UNIPROT	TFEB	protein	P19484	UNIPROT	up-regulates activity	dephosphorylation	Ser211	LVGVTSSsCPADLTQ	9606	BTO:0000007								26000950	t			Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation.	SIGNOR-255306	0.384
DLGAP1	protein	O14490	UNIPROT	SHANK1	protein	Q9Y566	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264586	0.851
CUDC-101	chemical	CID:24756910	PUBCHEM	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	chemical inhibition			-1									20143778	t		miannu	By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively.	SIGNOR-262261	0.8
TYSND1	protein	Q2T9J0	UNIPROT	SCP2	protein	P22307	UNIPROT	up-regulates activity	cleavage			-1									17255948	t		miannu	 Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1.	SIGNOR-261055	0.481
RPS6KB1	protein	P23443	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser1101	GCRRRHSsETFSSTP	10090									15306821	t		lperfetto	Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulates insulin.	SIGNOR-127904	0.781
JWOGUUIOCYMBPV-GMFLJSBRSA-N	chemical	CID:6918328	PUBCHEM	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			9606									17868033	t		Simone Vumbaca	Apicidin inhibited rhHDACs 2 and 3 in the nanomolar range.	SIGNOR-261128	0.8
FCER1G/FCER1G	complex	SIGNOR-C199	SIGNOR	FCER1	complex	SIGNOR-C200	SIGNOR	form complex	binding			9606	BTO:0000830								16470226	t		Alessandro Palma	FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling.	SIGNOR-254962	0.595
NUP98-HOXA9	fusion protein	SIGNOR-FP15	SIGNOR	RUNX1	protein	Q01196	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17442773	f		miannu	Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. Runx1 is also upregulated in the NUP98‐HOXA9 transcriptosome and is a critical regulator of hematopoietic development and a frequent target for chromosomal translocation in leukemia	SIGNOR-261499	0.2
PPP1CA	protein	P62136	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	up-regulates activity	dephosphorylation	Ser311	PYHSREQsTDSGLGL	9606									21189257	t		miannu	PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase.	SIGNOR-277115	0.526
prednisolone	chemical	CHEBI:8378	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									8342904	t	ashma	gcesareni		SIGNOR-251698	0.8
BKM120	chemical	CHEBI:71954	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190392	0.8
SOX9	protein	P48436	UNIPROT	OTX2	protein	P32243	UNIPROT	up-regulates activity	binding			10090									20530484	t		miannu	BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles.	SIGNOR-255184	0.358
PRKACA	protein	P17612	UNIPROT	CBX3	protein	Q13185	UNIPROT	up-regulates	phosphorylation	Ser93	KDGTKRKsLSDSESD	9606									16531993	t		gcesareni	We demonstrate that p-ser 83-hp1gamma has an exclusively euchromatic localization, interacts with ku70 (a regulatory protein involved in multiple nuclear procesess), has impaired silencing activity and serves as a marker for transcription elongation.	SIGNOR-145109	0.2
N-(6-fluoro-1H-indazol-5-yl)-6-methyl-2-oxo-4-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyridine-5-carboxamide	chemical	CHEBI:91332	ChEBI	ROCK1	protein	Q13464	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								19740074	t		miannu	We also observed that several ROCK (Rho kinase) inhibitors such as Y-27632 and H-1152, suppressed LRRK2 with similar potency to which they inhibited ROCK2. In contrast, GSK429286A, a selective ROCK inhibitor, did not significantly inhibit LRRK2.	SIGNOR-262229	0.8
IL23R	protein	Q5VWK5	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates	binding			9606	BTO:0000782								12023369	t		gcesareni	Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12.	SIGNOR-87808	0.689
CDC14A	protein	Q9UNH5	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser705	TPSAMKSsPQIPHQT	9606									20236090	t			Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3.	SIGNOR-248833	0.627
FCER1	complex	SIGNOR-C200	SIGNOR	SRC_kinase_family	proteinfamily	SIGNOR-PF32	SIGNOR	up-regulates				9606	BTO:0000830								16470226	f		Alessandro Palma	It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits	SIGNOR-254955	0.593
CDH9	protein	Q9ULB4	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265871	0.568
SMO	protein	Q99835	UNIPROT	GNB3	protein	P16520	UNIPROT	up-regulates	binding			9606									16885213	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp	SIGNOR-148592	0.2
PCDH19	protein	Q8TAB3	UNIPROT	GABRA1	protein	P14867	UNIPROT	up-regulates quantity by stabilization	binding			10116	BTO:0003102			SIGNOR-C330					29360992	t		miannu	Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons. 	SIGNOR-267217	0.373
PRKG1	protein	Q13976	UNIPROT	PRKAR1A	protein	P10644	UNIPROT	up-regulates activity	phosphorylation	Ser101	RRRRGAIsAEVYTEE	9606	BTO:0002181								29378851	t		miannu	 In this study, we further examined the potential of RIα phosphorylation to regulate physiologically relevant "desensitization" of PKAc activity. First, the serine 101 site of RIα was validated as a target of PKGIα phosphorylation both in vitro and in cells.These findings suggest that RIα phosphorylation may be a novel mechanism to circumvent the requirement of cAMP stimulus to activate type I PKA in cells.	SIGNOR-277383	0.236
MEF2C	protein	Q06413	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity	binding			9606									9418854	t		lperfetto	Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis.	SIGNOR-54089	0.733
CASP6	protein	P55212	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Asp616	EISEVKMdAEFRHDS	-1									10438520	t		lperfetto	Inhibition of caspase-6 activity prevents serum deprivation-mediated increase of Ab. Caspase-6 directly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an Ab-containing 6.5-kDa fragment, Capp6.5, that increases in serum-deprived neurons	SIGNOR-261762	0.712
GSK3B	protein	P49841	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates	phosphorylation			9606			SIGNOR-C110	SIGNOR-C110					23579495	t		lperfetto	Phosphorylation by GSK3 kept Axin activated (open) for _-catenin interaction and poised for engagement of LRP6.	SIGNOR-201683	0.917
C4A	protein	P0C0L4	UNIPROT	C3 convertase complex	complex	SIGNOR-C310	SIGNOR	form complex	binding			-1					cleavage:Arg756;Gly1446	KGQAGLQrALEILQE;TPLQLFEgRRNRRRR			17204478	t	complement C4b fragment: PRO_0000005970	lperfetto	 However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex	SIGNOR-263400	0.607
MAP3K14	protein	Q99558	UNIPROT	NFKB2	protein	Q00653	UNIPROT	up-regulates activity	phosphorylation	Ser866	TAEVKEDsAYGSQSV	9606	BTO:0000007								11239468	t		lperfetto	NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870	SIGNOR-105553	0.664
MAPK1	protein	P28482	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser289	RSHSESAsPSALSSS	10090									15664191	t		lperfetto	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-249440	0.616
MFNG	protein	O00587	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606									10935626	t	Fucosylation	gcesareni	Manic fringe elongates the o-linked fucose saccharides on full-length notch1 and notch1 egf repeats 1923.	SIGNOR-80555	0.709
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	MYOD1	protein	P15172	UNIPROT	down-regulates	binding			9606									21902831	t		lperfetto	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-216969	0.444
CDK5	protein	Q00535	UNIPROT	APEX1	protein	P27695	UNIPROT	up-regulates activity	phosphorylation	Thr233	NKKNAGFtPQERQGF	9606									21727086	t		miannu	Apurinic/apyrimidinic endonuclease-1 (APE1) is a multifunctional DNA repair/gene regulatory protein in mammalian cells, and was recently reported to be phosphorylated at Thr233 by CDK5.	SIGNOR-276337	0.387
PPP5C	protein	P53041	UNIPROT	ABCB1	protein	P08183	UNIPROT	down-regulates activity	dephosphorylation	Ser671	RKRSTRRsVRGSQAQ	9606	BTO:0000007								24333728	t			Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp	SIGNOR-272507	0.2
MAPK14	protein	Q16539	UNIPROT	ZAP70	protein	P43403	UNIPROT	down-regulates activity	phosphorylation	Thr293	TLNSDGYtPEPARIT	9606	BTO:0000782								29440413	t		miannu	We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. These results identify a tight negative feedback loop in which ZAP-70-activated p38 reciprocally phosphorylates ZAP-70 and destabilizes the signaling complex.	SIGNOR-277384	0.457
ZWINT	protein	O95229	UNIPROT	RZZ complex	complex	SIGNOR-C357	SIGNOR	form complex	binding			9606	BTO:0000567								20462495	t		lperfetto	The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico.	SIGNOR-265013	0.639
mono(2-ethylhexyl) phthalate	chemical	CHEBI:17243	ChEBI	PPARA	protein	Q07869	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 	SIGNOR-268783	0.8
PPP2CB	protein	P62714	UNIPROT	CARD11	protein	Q9BXL7	UNIPROT	down-regulates activity	dephosphorylation	Ser644	NLMFRKFsLERPFRP	9606									21157432	t			NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation.	SIGNOR-248607	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	TENT2	protein	Q6PIY7	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000007								31057087	t	inferred from 70% family members	miannu	We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. 	SIGNOR-270130	0.2
CCND1	protein	P24385	UNIPROT	MSI1	protein	O43347	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20443831	f		gcesareni	We hypothesized that cyclin d1 may induce notch1 activity either by repressing numb or by inducing musashi 1 expression	SIGNOR-165186	0.288
MAP3K5	protein	Q99683	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates activity	phosphorylation	Thr838	GINPCTEtFTGTLQY	9606									17937911	t		lperfetto	Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling.	SIGNOR-158427	0.2
ABL1	protein	P00519	UNIPROT	ABL2	protein	P42684	UNIPROT	up-regulates	phosphorylation	Tyr261	GLVTTLHyPAPKCNK	9606									15735735	t		lperfetto	The results show that arg is stabilized in response to 0.1 mm h2o2 by autophosphorylation of y-261, consistent with involvement of the arg kinase function in regulating arg levels. The results further demonstrate that c-abl-mediated phosphorylation of arg on y-261 similarly confers arg stabilization	SIGNOR-134396	0.495
PTPRG	protein	P23470	UNIPROT	ITGB1	protein	P05556	UNIPROT	down-regulates activity	dephosphorylation	Tyr783	DTGENPIyKSAVTTV	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254706	0.268
SUPT20H	protein	Q8NEM7	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269575	0.74
PDPK1	protein	O15530	UNIPROT	PRKCZ	protein	Q05513	UNIPROT	up-regulates	phosphorylation	Thr410	GPGDTTStFCGTPNY	9606									11141077	t		gcesareni	Our findings suggest that insulin, via pip(3), provokes increases in pkc-zeta enzyme activity through (a) pdk-1-dependent t410 loop phosphorylation, (b) t560 autophosphorylationcytoskeletal reorganization;tnni1(induces);desmin(induces);tpm1(induces);myo1c(induces);tnnt1(induces);	SIGNOR-85501	0.558
SEMA3C	protein	Q99985	UNIPROT	PLXNA2	protein	O75051	UNIPROT	up-regulates activity	binding												19666519	t		lperfetto	Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes.	SIGNOR-253151	0.501
MET	protein	P08581	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr627	KGDKQVEyLDLDLDS	9606	BTO:0000018								10734310	t		miannu	Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF.	SIGNOR-250289	0.661
PBK	protein	Q96KB5	UNIPROT	GPSM2	protein	P81274	UNIPROT	up-regulates	phosphorylation	Thr457	LKGKKYKtNSSTKVL	9606	BTO:0000150								20589935	t		lperfetto	We found that the 450th threonine (thr450) of lgn/gpsm2 was phosphorylated by the serine/threonine kinase pbk/topk during mitosis. Western blot analysis indicated the highest expression and the phosphorylated form of lgn/gpsm2 protein in g2/m phase.	SIGNOR-166461	0.273
CDK5	protein	Q00535	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606	BTO:0000938	BTO:0000887;BTO:0001760;BTO:0000142							15096606	t		gcesareni	We report here that the cdk5/p35 complex associates with stat3 and phosphorylates stat3 on the ser-727 residue in vitro and in vivo. Ser phosphorylation of stat3 and transcription of stat3 target genes, such as c-fos and junb, in a cdk5-dependent manner.	SIGNOR-124325	0.413
P2RY2	protein	P41231	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264307	0.2
TFEB	protein	P19484	UNIPROT	GALNS	protein	P34059	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19556463	f	Figure 1	lperfetto	Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 	SIGNOR-276538	0.293
metformin	chemical	CHEBI:6801	ChEBI	NR0B2	protein	Q15466	UNIPROT	up-regulates quantity by expression				9606									17909097	f		gcesareni	In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp.	SIGNOR-158059	0.8
PHKA2	protein	P46019	UNIPROT	PHKG2	protein	P15735	UNIPROT	down-regulates activity	binding			9606									10487978	t			Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.	SIGNOR-267406	0.914
SOCS3	protein	O14543	UNIPROT	IL6ST	protein	P40189	UNIPROT	down-regulates activity	binding			9606		BTO:0000887;BTO:0001103							19620279	t		miannu	We now show that SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by specifically inhibiting the LIF-induced JAK1/STAT1/STAT3 pathway via distinct targets; whereas SOCS1 and SOCS3 selectively bind and inhibit JAK1 and gp130, respectively, PIAS1 targets mainly the activated STAT1 and prevents its binding to DNA.	SIGNOR-202045	0.637
AP2M1	protein	Q96CW1	UNIPROT	AP-2 complex	complex	SIGNOR-C245	SIGNOR	form complex	binding												31671891	t		lperfetto	 The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit	SIGNOR-260420	0.915
GSK3B	protein	P49841	UNIPROT	CTNND1	protein	O60716	UNIPROT	unknown	phosphorylation	Thr310	GTARRTGtPSDPRRR	-1									12885254	t			GSK3beta selectively phosphorylates p120 on S252 and T310 in Vitro	SIGNOR-251235	0.395
MAPK3	protein	P27361	UNIPROT	DUSP1	protein	P28562	UNIPROT	down-regulates	phosphorylation	Ser323	HCSAEAGsPAMAVLD	9606									16286470	t		lperfetto	The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain	SIGNOR-141609	0.778
MAP3K13	protein	O43283	UNIPROT	TRIM25	protein	Q14258	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser12	CPLAEELsCSICLEP	9606	BTO:0002181								31186535	t		miannu	Mechanistically, MAP3K13 phosphorylates the E3 ubiquitin ligase TRIM25 at Ser12 to decrease its polyubiquitination and proteasomal degradation.	SIGNOR-277456	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Ser1070	DSFLQRYsSDPTGAL	9606	BTO:0000007								10347170	t		llicata	 We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. 	SIGNOR-250620	0.378
TERB2	protein	Q8NHR7	UNIPROT	TTM complex	complex	SIGNOR-C305	SIGNOR	form complex	binding			9606	BTO:0000007								30718482	t		lperfetto	Meiotic specific proteins TERB1, TERB2, and MAJIN form a stable complex that plays a critical role in regulating the recruitment of telomeres to the NE	SIGNOR-263304	0.2
MMP1	protein	P03956	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates				9606	BTO:0005387								19584257	f		lperfetto	However, we show that soluble factors secreted by SUM102 breast cancer cells stimulated the expression of MMP-1 and CXCR4 in HMFs. As a result, these stromal cells acquired an invasive and migratory phenotype	SIGNOR-252265	0.7
LAMC1	protein	P11047	UNIPROT	Laminin-8	complex	SIGNOR-C181	SIGNOR	form complex	binding												10809728	t		lperfetto	Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. 	SIGNOR-253228	0.568
PRKCA	protein	P17252	UNIPROT	HABP4	protein	Q5JVS0	UNIPROT	down-regulates activity	phosphorylation	Thr354	RKPANDItSQLEINF	9606	BTO:0004974								14699138	t		lperfetto	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249246	0.293
MECP2	protein	P51608	UNIPROT	ALOX5	protein	P09917	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001412								19781662	f	 	 	Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene.	SIGNOR-254062	0.2
ROCK1	protein	Q13464	UNIPROT	PPP1R12A	protein	O14974	UNIPROT	down-regulates	phosphorylation	Thr696	ARQSRRStQGVTLTD	9606									8662509	t	Rho-associated kinase (Rho-kinase) is activated by GTP-RhoA	gcesareni	Rho-associated kinase (rho-kinase) phosphorylated mbs and consequently inactivated myosin phosphatase. Rho appears to inhibit myosin phosphatase through the action of rho-kinase.	SIGNOR-42354	0.766
3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione	chemical	CHEBI:91368	ChEBI	PRKCG	protein	P05129	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191499	0.8
HNF1A	protein	P20823	UNIPROT	SLC22A10	protein	Q63ZE4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								20829431	t		lperfetto	Luciferase reporter gene constructs containing the OAT5 (SLC22A10) and OAT7 (SLC22A9) promoter regions were transactivated by HNF-1 in HepG2 cells.	SIGNOR-268983	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BCL2	protein	P10415	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser87	AAAGPALsPVPPVVH	9606	BTO:0000567								10669763	t		lperfetto	The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro.	SIGNOR-244505	0.2
JUNB	protein	P17275	UNIPROT	LORICRIN	protein	P23490	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000667								12200429	f		miannu	Loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins.	SIGNOR-254535	0.2
RPS6KA3	protein	P51812	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates activity	phosphorylation	Ser83	ATRGRGSsVGGGSRR	9606	BTO:0002181								23608533	t		miannu	We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding.	SIGNOR-276464	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	RCHY1	protein	Q96PM5	UNIPROT	down-regulates	phosphorylation	Ser155	CLEDIHTsRVVAHVL	9606									17568776	t		lperfetto	Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53	SIGNOR-156064	0.3
GSK3B	protein	P49841	UNIPROT	UNG	protein	P13051	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr60	AGQEEPGtPPSSPLS	9606	BTO:0000812						phosphorylation:Ser64	EPGTPPSsPLSAEQL	27875297	t		lperfetto	Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation 	SIGNOR-264885	0.2
PTPRG	protein	P23470	UNIPROT	PXN	protein	P49023	UNIPROT	up-regulates activity	dephosphorylation			-1									25624455	t		miannu	 a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254722	0.262
SHC3	protein	Q92529	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	relocalization			9606									16729043	t		gcesareni	In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation.	SIGNOR-146897	0.811
ELOVL3	protein	Q9HB03	UNIPROT	palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	down-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267886	0.8
SYK	protein	P43405	UNIPROT	VAV1	protein	P15498	UNIPROT	up-regulates	phosphorylation			9606									11331248	t		gcesareni	Vav interacts with the tyrosine kinase syk. inhibition of syk kinase activity prevents tyrosine phosphorylation of vav and its interaction with pi 3-k.	SIGNOR-107046	0.918
CHEK1	protein	O14757	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates activity				9606									28138032	f		miannu	Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Ras–MEK signaling transcriptionally activates Chk1, which appears to sustain cancer cell growth by maintaining DNA damage levels below a threshold that would otherwise drive apoptosis.	SIGNOR-263059	0.329
MAPK3	protein	P27361	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Thr359	DTEFTSRtPKDSPGI	9534									9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-219349	0.705
SOX9	protein	P48436	UNIPROT	COL11A2	protein	P13942	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10980415	f		miannu	Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan. 	SIGNOR-251758	0.398
AHCYL1	protein	O43865	UNIPROT	PAPOLA	protein	P51003	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								19224921	t		lperfetto	Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner.	SIGNOR-268329	0.248
alpha-aminoacyl-tRNA	smallmolecule	CHEBI:2651	ChEBI	EEF1A:GTP:aa-tRNA	complex	SIGNOR-C493	SIGNOR	form complex	binding			9606									8722040	t		miannu	The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. 	SIGNOR-270808	0.8
TGFBR2	protein	P37173	UNIPROT	PARD6A	protein	Q9NPB6	UNIPROT	up-regulates	phosphorylation	Ser345	RGDGSGFsL	9606	BTO:0000551								23249950	t		lpetrilli	Transforming growth factor ? (tgf-?) Has been shown to regulate cell plasticity through the phosphorylation of par6 on a conserved serine residue (s345) by the type ii tgf-? Receptor.	SIGNOR-200193	0.443
ABL1	protein	P00519	UNIPROT	LGALS3	protein	P17931	UNIPROT	unknown	phosphorylation	Tyr118	AGPLIVPyNLPLPGG	9606									20600357	t		llicata	In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility.	SIGNOR-166497	0.364
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	GBF1	protein	Q92538	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002181								29898406	t		miannu	We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation.	SIGNOR-277399	0.253
QOCYWLABLBUJOR-UHFFFAOYSA-N	chemical	CID:53299324	PUBCHEM	SLC6A3	protein	Q01959	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								18487050	t		Luana	For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428. 	SIGNOR-257796	0.8
AKT3	protein	Q9Y243	UNIPROT	CYCS	protein	P99999	UNIPROT	down-regulates activity	phosphorylation	Tyr47	KTGQAPGySYTAANK	-1									32781572	t		miannu	Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.	SIGNOR-277235	0.268
TPR	protein	P12270	UNIPROT	MAD2L1	protein	Q13257	UNIPROT	up-regulates	binding			9606									18981471	t		miannu	Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20).	SIGNOR-181975	0.315
DPM2	protein	O94777	UNIPROT	DPM complex	complex	SIGNOR-C289	SIGNOR	form complex	binding			9606									10835346	t		lperfetto	Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3.	SIGNOR-262564	0.779
LYN	protein	P07948	UNIPROT	IRF5	protein	Q13568	UNIPROT	down-regulates activity	phosphorylation	Tyr313	PSDKQRFyTNQLLDV	9606	BTO:0002181								27521268	t		miannu	Lyn Kinase Suppresses the Transcriptional Activity of IRF5. Here, we found that Lyn physically interacted with IRF5 to inhibit ubiquitination and phosphorylation of IRF5 in the TLR-MyD88 pathway, thereby suppressing the transcriptional activity of IRF5 in a manner independent of Lyn's kinase activity.	SIGNOR-277247	0.335
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1878	SPKYSPTsPTYSPTT	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273060	0.636
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	NLRP1 inflammasome	complex	SIGNOR-C224	SIGNOR	up-regulates activity													16037825	f		miannu	Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage	SIGNOR-263125	0.7
EIF3_complex	complex	SIGNOR-C401	SIGNOR	EIF5	protein	P55010	UNIPROT	up-regulates activity	stabilization			9606									17581632	t		lperfetto	EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 	SIGNOR-269153	0.684
PYGL	protein	P06737	UNIPROT	glycogen	smallmolecule	CHEBI:28087	ChEBI	down-regulates quantity	chemical modification			9606									3346228	t			Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267949	0.8
IGF1R	protein	P08069	UNIPROT	PCNA	protein	P12004	UNIPROT	up-regulates activity	phosphorylation	Tyr60	RSEGFDTyRCDRNLA	-1									28924044	t		miannu	In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination.	SIGNOR-277253	0.2
PRKCD	protein	Q05655	UNIPROT	FLI1	protein	Q01543	UNIPROT	down-regulates	phosphorylation	Thr312	TNGEFKMtDPDEVAR	9606									21321929	t		lperfetto	We have previously demonstrated that in response to transforming growth factor _ (tgf_), fli-1 activity is repressed through a series of sequential posttranslational modifications, consisting of protein kinase c_ (pkc_)-induced thr312 phosphorylation, acetylation by p300/creb binding protein-associated factor, and detachment from the collagen promoter.	SIGNOR-172113	0.353
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MAP2K4	protein	P45985	UNIPROT	down-regulates	phosphorylation	Ser80	IERLRTHsIESSGKL	9606	BTO:0000007								11707464	t		lperfetto	Akt phosphorylated sek1 on serine 78.	SIGNOR-244285	0.2
Sin3B_complex	complex	SIGNOR-C409	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	binding			9606									21041482	t		miannu	We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin.	SIGNOR-266970	0.2
MLF1	protein	P58340	UNIPROT	COP1	protein	Q8NHY2	UNIPROT	up-regulates				9606									15861129	f		miannu	As downstream elements of mlf1 leading to cell growth arrest due to p53 accumulation, we identified two factors, csn3, the third component of the cop9 signalosome (csn), and cop1, a recently characterized e3 ubiquitin ligase for p53	SIGNOR-135940	0.2
PTPRJ	protein	Q12913	UNIPROT	PIK3R1	protein	P27986	UNIPROT	down-regulates	dephosphorylation			9606									18348712	t		gcesareni	As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors.	SIGNOR-178049	0.264
FIG4	protein	Q92562	UNIPROT	PAS complex	complex	SIGNOR-C190	SIGNOR	form complex	binding			9606	BTO:0000007								17556371	t		miannu	Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels.	SIGNOR-253528	0.929
SRC	protein	P12931	UNIPROT	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	down-regulates activity	phosphorylation			9606									30889378	t		miannu	SRC can directly phosphorylate and inhibit LATS	SIGNOR-259056	0.391
FLI1	protein	Q01543	UNIPROT	GP9	protein	P14770	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002581								15466856	f	 	miannu	Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. 	SIGNOR-254160	0.25
cyclosporin A	chemical	CHEBI:4031	ChEBI	PPP3CC	protein	P48454	UNIPROT	down-regulates	chemical inhibition			9606									15276472	t		gcesareni	Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins.	SIGNOR-127231	0.8
retinol	smallmolecule	CHEBI:50211	ChEBI	retinal	smallmolecule	CHEBI:15035	ChEBI	up-regulates quantity	precursor of			9606									21621639	t		lperfetto	Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9	SIGNOR-265115	0.8
ABL2	protein	P42684	UNIPROT	CRK	protein	P46108	UNIPROT	down-regulates	phosphorylation	Tyr221	GGPEPGPyAQPSVNT	10090									15886098	t		gcesareni	Rin1 binds to the abl sh3 and sh2 domains, and these interactions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl, inhibiting these cytoskeletal regulators by promoting intramolecular over intermolecular associations. the ability of crk to function as an adaptor protein is negatively regulated and terminated by phosphorylation on y221, which results in an intramolecular sh2-ptyr clamp, thereby resulting in the disassembly of crk-mediated signaling complexes	SIGNOR-136955	0.684
TGFB1	protein	P01137	UNIPROT	SALL2	protein	Q9Y467	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000452								21228219	f		miannu	TGFβ effectively inhibits expression of SALL2 and its regulator AP4 when added to quiescent fibroblasts. 	SIGNOR-255427	0.2
RRAGC	protein	Q9HB90	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates	binding			9606									20006481	t		lperfetto	Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor.	SIGNOR-217547	0.687
ANKRD6	protein	Q9Y2G4	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates	binding			9606									20006983	t		gcesareni	Our data thus demonstrate that diversin and dishevelled function together in a mutually dependent fashion in zebrafish gastrulation and organ formation	SIGNOR-162142	0.487
RAP1GDS1	protein	P52306	UNIPROT	RHOB	protein	P62745	UNIPROT	up-regulates	binding			9606									21242305	t		miannu	Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob	SIGNOR-171615	0.283
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270392	0.8
PRKACA	protein	P17612	UNIPROT	GMFB	protein	P60983	UNIPROT	up-regulates activity	phosphorylation	Thr27	KFRFRKEtNNAAIIM	-1									9030586	t		miannu	Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82.	SIGNOR-249984	0.311
ESCRT-III	complex	SIGNOR-C379	SIGNOR	Viral_budding	phenotype	SIGNOR-PH125	SIGNOR	up-regulates				9606									26775243	f		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit.	SIGNOR-265534	0.7
CSNK1E	protein	P49674	UNIPROT	PER2	protein	O15055	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser480	PVPHSGSsGYGSLGS	-1									30425162	t		miannu	Priming-independent clusters located in the C-terminal portion of PER2’s PAS domains are targeted by CK1ε/δ and are required for ubiquitin ligase–mediated degradation of PER2	SIGNOR-277419	0.898
CSNK1D	protein	P48730	UNIPROT	PER2	protein	O15055	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser480	PVPHSGSsGYGSLGS	-1									30425162	t		miannu	Priming-independent clusters located in the C-terminal portion of PER2’s PAS domains are targeted by CK1ε/δ and are required for ubiquitin ligase–mediated degradation of PER2	SIGNOR-277420	0.864
SPI1	protein	P17947	UNIPROT	FCER1A	protein	P12319	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11971001	f			Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells	SIGNOR-254289	0.278
ABL1	protein	P00519	UNIPROT	MYLK	protein	Q15746	UNIPROT	up-regulates	phosphorylation	Tyr231	NQDDVGVyTCLVVNG	9606		BTO:0000763							20861316	t		lperfetto	Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity	SIGNOR-167989	0.305
GNG2	protein	P59768	UNIPROT	GNB/GNG	complex	SIGNOR-C202	SIGNOR	form complex	binding			9606									23994464	t		apalma	Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the Gβγ subunit	SIGNOR-255005	0.938
FLT4	protein	P35916	UNIPROT	SHC1	protein	P29353	UNIPROT	unknown	phosphorylation	Tyr350	EPPDHQYyNDFPGKE	9606									9927207	t		llicata	We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites.	SIGNOR-64076	0.574
BTC	protein	P35070	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606									10209155	t		gcesareni	Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4.	SIGNOR-67003	0.737
STAT5A	protein	P42229	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9606	BTO:0000876	BTO:0001103							19436055	f		miannu	 The alternative survival and proliferation pathway triggered by higher concentrations of GM-CSF is dependent on the dodecamer assembly and involves the Jak/STAT, Ras/mitogen-activated protein kinase, and PI-3 kinase pathways	SIGNOR-255578	0.7
ZBP1	protein	Q9H171	UNIPROT	RIPK3	protein	Q9Y572	UNIPROT	up-regulates activity	binding			10090	BTO:0002572								32200799	t		gianni	ZBP1 initiates RIPK3-driven cell death by sensing IAV RNA and activating RIPK3. Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis.	SIGNOR-266430	0.622
GNAO1	protein	P09471	UNIPROT	TAOK1	protein	Q7L7X3	UNIPROT	up-regulates				9606									12665513	f		lperfetto	These results suggest that go alpha q205l activates p38 through taos and mek3/6.	SIGNOR-235539	0.2
mTORC2	complex	SIGNOR-C2	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Ser477	PQFSYSAsGTA	9606	BTO:0000093								24670654	t		gcesareni	Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation	SIGNOR-252451	0.634
PTTG1	protein	O95997	UNIPROT	S100A4	protein	P26447	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002430								19351864	f		miannu	PTTG induced S100A4 and galectin-1 mRNA and protein expression as assessed by Western blot and reverse transcription-PCR. 	SIGNOR-255070	0.275
CDK9	protein	P50750	UNIPROT	SUPT5H	protein	O00267	UNIPROT	up-regulates	phosphorylation	Thr791	TPMYGSQtPLQDGSR	9606									16427012	t		lperfetto	We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif	SIGNOR-143931	0.769
morphine	chemical	CHEBI:17303	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258765	0.8
P2RY4	protein	P51582	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257214	0.2
PRKCD	protein	Q05655	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation	Ser932	DDTPEKDsFRARSTS	9606	BTO:0002181								30684133	t		miannu	In vivo kinase analysis further indicated that both S932 and S939 are phosphorylated in response to translation inhibitors. Finally, phosphorylation defective TSC2 mutants (S932A and S939A single mutants and a S932A/S939A double mutant) failed to upregulate mTORC1 activity in the presence of translation inhibitors, suggesting that activation of mTORC1 by translation inhibitors is mediated by PKC-δ phosphorylation of TSC2 at S932/S939, which inactivates TSC.	SIGNOR-277426	0.2
SRC	protein	P12931	UNIPROT	PRMT5	protein	O14744	UNIPROT	down-regulates activity	phosphorylation	Tyr324	DNLESQTyEVFEKDP	9606	BTO:0002181								32759981	t		miannu	Here, we demonstrate that PRMT5 is phosphorylated at residue Y324 by Src kinase, a negative regulator of its activity.	SIGNOR-277523	0.265
PTGS2	protein	P35354	UNIPROT	prostaglandin D2	smallmolecule	CHEBI:15555	ChEBI	up-regulates	chemical modification			9606									11751058	t		gcesareni	Cox catalyzes two enzymatic activities;namely, the conversion of aa to the hydroperoxy endoperoxide pgg2, followed by its subsequent reduction to the labile product pgh2. Pgh2_ is the common substrate for a number of different cell-specific synthases, which convert pgh2_ to the individual pgs or tx, including pge2, pgi2_ (prostacyclin), pgd2, pgf2alfa, and txa2	SIGNOR-113282	0.8
NFE2L2	protein	Q16236	UNIPROT	HMOX1	protein	P09601	UNIPROT	up-regulates quantity	transcriptional regulation			9606									31257023	f			Nrf2 accumulation in lung cancers causes the stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme.	SIGNOR-259334	0.669
FERMT2	protein	Q96AC1	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								26037143	t		miannu	Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. 	SIGNOR-266101	0.379
GSK3B	protein	P49841	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates activity													25309941	f			Following GSK3β activation, NF-κB is translocated from the cytoplasm to the nucleus and binds transcriptional sites with CBP leading to an increase in the transcription of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6). 	SIGNOR-255485	0.38
tacedinaline	chemical	CHEBI:90195	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258009	0.8
CKM complex	complex	SIGNOR-C406	SIGNOR	SMAD3	protein	P84022	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									19914168	t		lpetrilli	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-273146	0.421
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2L3	protein	P68036	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271360	0.486
PRKCD	protein	Q05655	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation	Ser939	SFRARSTsLNERPKS	9606	BTO:0002181								30684133	t		miannu	In vivo kinase analysis further indicated that both S932 and S939 are phosphorylated in response to translation inhibitors. Finally, phosphorylation defective TSC2 mutants (S932A and S939A single mutants and a S932A/S939A double mutant) failed to upregulate mTORC1 activity in the presence of translation inhibitors, suggesting that activation of mTORC1 by translation inhibitors is mediated by PKC-δ phosphorylation of TSC2 at S932/S939, which inactivates TSC.	SIGNOR-277427	0.2
PRKCA	protein	P17252	UNIPROT	TWIST1	protein	Q15672	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser144	TLPSDKLsKIQTLKL	9606	BTO:0002181								30733340	t		miannu	Because most of these sites were predicted to be phosphorylated by protein kinase C (PKC), we overexpressed PKCα in several cell lines and found that it phosphorylates Twist1 on Ser-144. we observed that PKCα-mediated Twist1 phosphorylation at Ser-144 inhibits Twist1 ubiquitination and consequently stabilizes it. 	SIGNOR-277429	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PPP2R5C	protein	Q13362	UNIPROT	down-regulates	phosphorylation			9606									16456541	t	inferred from 70% family members	gcesareni	Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit.	SIGNOR-270196	0.2
DAPK3	protein	O43293	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606	BTO:0000776								17339337	t		gcesareni	A cell-free ser(20) phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser(20) kinases.Evaluation of these calcium calmodulin kinase superfamily members as candidate ser(20) kinases in vivo has shown that only chk1 or dapk-1 can stimulate p53 transactivation and induce ser(20) phosphorylation of p53.	SIGNOR-153495	0.415
COL6A3	protein	P12111	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									21949456	t			Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present.	SIGNOR-254675	0.7
CSNK1A1	protein	P48729	UNIPROT	PHLPP1	protein	O60346	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1359	VPRPHVQsVLLTPQD	9606	BTO:0002181								19797085	t		miannu	We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity. 	SIGNOR-276261	0.313
WASF1	protein	Q92558	UNIPROT	WRC complex	complex	SIGNOR-C191	SIGNOR	form complex	binding			9606									21107423	t		miannu	WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems.	SIGNOR-253572	0.893
CASP3	protein	P42574	UNIPROT	Membrane_blebbing	phenotype	SIGNOR-PH24	SIGNOR	up-regulates				9606		BTO:0000142							10200555	f		amattioni	Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation	SIGNOR-66866	0.7
ATM	protein	Q13315	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates	phosphorylation	Ser222	LPEILGDsQHADVGK	9606									12086603	t		lperfetto	Atm phosphorylates fancd2 on serine 222 in vitro. This site is also phosphorylated in vivo in an atm-dependent manner following ir. Phosphorylation of fancd2 is required for activation of an s phase checkpoint. The atm-dependent phosphorylation of fancd2 on s222 and the fa pathway-dependent monoubiquitination of fancd2 on k561 are independent posttranslational modifications regulating discrete cellular signaling pathways.	SIGNOR-90121	0.782
AS-605240	chemical	CID:5289247	PUBCHEM	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189921	0.8
TESK1	protein	Q15569	UNIPROT	CFL1	protein	P23528	UNIPROT	down-regulates activity	phosphorylation	Ser3	sGVAVSDG	9606	BTO:0001363								11418599	t		lperfetto	Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin	SIGNOR-246723	0.545
ATR	protein	Q13535	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates	phosphorylation	Ser717	KDGGPVTsQESGQKL	9606									16943440	t		lperfetto	In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents	SIGNOR-149305	0.66
MAPK8	protein	P45983	UNIPROT	GRB7	protein	Q14451	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser194	KYELFKSsPHSLFPE	9606	BTO:0000017								27658202	t		miannu	Our data show that phosphorylation of Grb7 protein on the Ser194-Pro motif by c-Jun N-terminal kinase facilitates its binding with the WW domain of Pin1. Subsequently, Grb7 is degraded by the ubiquitin- and proteasome-dependent proteolytic pathway. I	SIGNOR-277280	0.265
OPRL1	protein	P41146	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256865	0.434
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CD80	protein	P33681	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12860928	f	 	miannu	Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. 	SIGNOR-254783	0.302
CASP3	protein	P42574	UNIPROT	GAS2	protein	O43903	UNIPROT	up-regulates	cleavage	Asp278	MLQISRVdGKTSPIQ	9606									10564664	t		gcesareni	We now demonstrate that gas2 is a substrate of caspase-3 but not of caspase-6. Proteolytic processing both in vitro and in vivo is dependent on aspartic residue 279.	SIGNOR-72347	0.428
AKT3	protein	Q9Y243	UNIPROT	JAG1	protein	P78504	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									38402584	f		miannu	Jagged1 is upregulated by Akt upon activation by R-Ras. All three Akt isoforms influence Jagged1 expression in ECs, but Akt3 is the most prominent Akt isoform in this role, despite its low expression level compared with Akt1. Jagged1 then activates Notch to upregulate Hey1, Hes1, p21, p53, and Unc5b in adjacent cells. 	SIGNOR-277224	0.292
FLT4	protein	P35916	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates activity	phosphorylation	Tyr1231	HSLAARYyNWVSFPG	9606									12881528	t		lperfetto	Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail.	SIGNOR-104076	0.2
EZH2	protein	Q15910	UNIPROT	ALDH1A1	protein	P00352	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004094								22144423	f	 	miannu	 For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci.	SIGNOR-254141	0.401
ITCH	protein	Q96J02	UNIPROT	MAVS	protein	Q7Z434	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys420	GLGSELSkPGVLASQ	9606	BTO:0002181								19881509	t		Giorgia	These data collectively indicate that AIP4 is the E3 ligase for MAVS.|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation	SIGNOR-260363	0.631
HARS1	protein	P12081	UNIPROT	tRNA(His)	smallmolecule	CHEBI:29178	ChEBI	down-regulates quantity	chemical modification			9606									10430027	t		miannu	Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 	SIGNOR-270485	0.8
PRKCE	protein	Q02156	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates activity	phosphorylation	Ser368	QRPSSRAsSRASSRP	10116									10871288	t		lperfetto	Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.	SIGNOR-144465	0.451
TNPO1	protein	Q92973	UNIPROT	HNRNPA1	protein	P09651	UNIPROT	up-regulates activity	relocalization												29970603	t		lperfetto	TNPO1 only mediates the nuclear import of a subset of proteins.|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import	SIGNOR-262099	0.59
CSNK2A3	protein	Q8NEV1	UNIPROT	F8	protein	P00451	UNIPROT	down-regulates activity	phosphorylation	Ser1656	GRTERLCsQNPPVLK	-1									8427963	t		lperfetto	Our findings suggest that phosphorylation of factors Va and VIIIa by a platelet casein kinase II-like kinase may downregulate the activity of the two cofactors.| Recombinant human factor VIII also showed incorporation of radioactivity in the presence of purified casein kinase II at the acidic NH2-terminal portion of factor VIII light chain (residues 1648 through 1689). Based on all the considerations reported above Se1657 is the most likely candidate within this region capable of incorporation of radioactivity	SIGNOR-263649	0.2
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	KDM4B	protein	O94953	UNIPROT	up-regulates				9606									30759871	f		miannu	The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. KDM4 enzymes are generally over-expressed in cancers, making them compelling targets for study and therapeutic inhibition. One of these family members, KDM4B, is especially interesting due to its regulation by multiple cellular stimuli, including DNA damage, steroid hormones, and hypoxia.	SIGNOR-263736	0.7
PRKDC	protein	P78527	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates	phosphorylation	Thr135	GGGSTSDtQEDILDE	9606									11867762	t		lperfetto	Phosphorylation of irf-3 by dna-pk after virus infection results in its nuclear retention and delayed proteolysis	SIGNOR-115331	0.406
ENO1	protein	P06733	UNIPROT	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	up-regulates quantity	chemical modification			9606									29767008	t		miannu	Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits.	SIGNOR-266524	0.8
JAK2	protein	O60674	UNIPROT	TET2	protein	Q6N021	UNIPROT	up-regulates activity	phosphorylation	Tyr1939	CEKYGPDyVPQKSHG	-1									30944118	t		miannu	Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin. 	SIGNOR-277290	0.43
SRC	protein	P12931	UNIPROT	LPIN1	protein	Q14693	UNIPROT	up-regulates activity	phosphorylation	Tyr795	FPNTEPFyAAFGNRP	9606	BTO:0002181								33203880	t		miannu	Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride.	SIGNOR-277291	0.2
SRC	protein	P12931	UNIPROT	LPIN1	protein	Q14693	UNIPROT	up-regulates activity	phosphorylation	Tyr398	HLGADGVyLDDLTDM	9606	BTO:0002181								33203880	t		miannu	Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride.	SIGNOR-277292	0.2
SNAI2	protein	O43623	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15311212	f		miannu	 known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT.	SIGNOR-255155	0.669
TLR4	protein	O00206	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates activity				9606	BTO:0000801								7635431	f		lperfetto	The activation of NF-kB is triggered by different stimuli, eg., lipopolysaccharides (LPSs), muramyl peptides, viruses,e inflammatory cytokines tumor necrosis factor-alpha(TNF-a) and interleukin (IL)-1b, irradiation, and reactive xygen intermediates (H2O2).	SIGNOR-249517	0.564
MITF	protein	O75030	UNIPROT	DCT	protein	P40126	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22371403	f		miannu	 MITF transcription factor regulates melanogenesis by activation of tyrosinase, TRP1 and TRP2 transcription.	SIGNOR-254592	0.475
FLT3	protein	P36888	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0002882								15769897	t			 we observed constitutive activation of Erk-1 and Erk-2, Akt, and of Shc by both Flt3-ITD and Flt3-D835Y	SIGNOR-261540	0.434
BMP7	protein	P18075	UNIPROT	BMP7	protein	P18075	UNIPROT	up-regulates	binding			9606		BTO:0000887							11178121	t		lperfetto	Bmps are dimeric proteins with a single inter-chain disulfide bond. The dimeric conformation is an absolute requirement for the biological action and interac- tion with receptors	SIGNOR-236172	0.2
PRKCA	protein	P17252	UNIPROT	CSNK1D	protein	P48730	UNIPROT	up-regulates activity	phosphorylation	Ser181	TGTARYAsINTHLGI	-1									31096047	t		miannu	In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity.	SIGNOR-277452	0.2
SMAD1/5/8/SMAD4	complex	SIGNOR-C215	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				10090		BTO:0000887							24145169	f			The BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling	SIGNOR-256487	0.2
TRIM13	protein	O60858	UNIPROT	AKT2	protein	P31751	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								21333377	t		miannu	Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT.  We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro. 	SIGNOR-271853	0.2
nalbuphine	chemical	CHEBI:7454	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000246								19282177	t		Luana	A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 	SIGNOR-258144	0.8
8-Hydroxy-7-(6-sulfo-naphthalen-2-ylazo)-quinoline-5-sulfonic acid	chemical	CID:92577	PUBCHEM	PTPN11	protein	Q06124	UNIPROT	down-regulates activity	chemical inhibition			-1									19233143	t		lperfetto	In this study, we screened protein tyrosine phosphatases (PTPs) by in vitro phosphatase assays to identify PTPs that are inhibited by 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877), a potent inhibitor of SHP-1 and SHP-2 PTPs.	SIGNOR-261977	0.8
MAPK1	protein	P28482	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser187	NSHPFPHsPNSSYPN	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3	SIGNOR-161593	0.59
pemetrexed	chemical	CHEBI:63616	ChEBI	GART	protein	P22102	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205883	0.8
MAP4	protein	P27816	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates				9606									10791892	f		miannu	We have shown that MAP4 is phosphorylated in vivo in mitotic HeLa cells at eight sites. Five of these were phosphorylated by p34cdc2 kinase. Two of the five p34cdc2 kinase phosphorylation sites were shown to be Ser696 and Ser787 in the proline-rich region. Mutation of Ser787 to Glu strikingly reduced the MAP4's MT-polymerization activity, while Glu-mutation at Ser696 did not. These results suggest that Ser787 could be the critical phosphorylation site causing MTs to be dynamic at mitosis.	SIGNOR-277460	0.7
PTPRG	protein	P23470	UNIPROT	SHC1	protein	P29353	UNIPROT	down-regulates activity	dephosphorylation	Tyr350	EPPDHQYyNDFPGKE	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254724	0.2
KDM5A	protein	P29375	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates quantity by destabilization	transcriptional regulation			9606									31374292	t		miannu	The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL.	SIGNOR-260079	0.294
XL765	chemical	CHEBI:71958	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252660	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ADAM17	protein	P78536	UNIPROT	up-regulates	phosphorylation	Thr735	KPFPAPQtPGRLQPA	9606									12058067	t		lperfetto	We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (tace) is phosphorylated by erk at threonine 735.These results demonstrate that secretases are able to discriminate between the different stimuli that trigger membrane protein ectodomain cleavage and indicate that phosphorylation by mapks may regulate the proteolytic function of membrane secretases.	SIGNOR-89614	0.2
ABL2	protein	P42684	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				10090									33622779	f		miannu	Here, using cultured hippocampal neurons pooled from both sexes of mice, we provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability.	SIGNOR-266594	0.7
CHEK2	protein	O96017	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Ser516	PQVLAQPsTSRKRPR	9606	BTO:0002201								12855706	t		lperfetto	Chk2 is also autophosphorylated following dna damage. It is proposed that autophosphorylation of chk2 may contribute to chk2 activation. To fully understand the regulation of chk2, we mapped an in vitro chk2 autophosphorylation site at c-terminal serine 516 site (ser-516). Ser-516 of chk2 is phosphorylated following radiation in vivo, and this phosphorylation depends on the kinase activity of chk2.	SIGNOR-103544	0.2
tyrosine	smallmolecule	CHEBI:18186	ChEBI	L-dopa	smallmolecule	CHEBI:15765	ChEBI	up-regulates quantity	precursor of			9606									NBK536726	t	brain	lperfetto	Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH).	SIGNOR-264173	0.8
CDK5	protein	Q00535	UNIPROT	DNM1	protein	Q05193	UNIPROT	up-regulates activity	phosphorylation	Ser778	GRRSPTSsPTPQRRA	-1									12855954	t		llicata	Here, we show that cyclin-dependent kinase 5 (Cdk5) phosphorylates dynamin I on Ser 774 and Ser 778 in vitro, which are identical to its endogenous phosphorylation sites in vivo. Cdk5 antagonists and expression of dominant-negative Cdk5 block phosphorylation of dynamin I, but not of amphiphysin or AP180, in nerve terminals and inhibit SVE. 	SIGNOR-250662	0.531
MAPK1	protein	P28482	UNIPROT	APBB1	protein	O00213	UNIPROT	unknown	phosphorylation	Ser175	EEEEDLSsPPGLPEP	9606									14697653	t		lperfetto	Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved.	SIGNOR-120451	0.262
NFIB	protein	O00712	UNIPROT	NFIX	protein	Q14938	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								9099724	t	2	miannu	Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function.	SIGNOR-240915	0.429
MDGA2	protein	Q7Z553	UNIPROT	DMAP1	protein	Q9NPF5	UNIPROT	up-regulates quantity by stabilization	binding			9606									26206665	t		miannu	The anti-tumorigenic effect of MDGA2 was mediated through direct stabilising of DNA methyltransferase 1 associated protein 1 (DMAP1), which played a tumour suppressive role in gastric cancer. MDGA2 expression and MG132 treatment increased the level of DMAP1, suggesting that the MDGA2–DMAP1 interaction stabilises DMAP1 by inhibiting its ubiquitin-mediated degradation.	SIGNOR-264240	0.356
TBK1	protein	Q9UHD2	UNIPROT	PRPS1	protein	P60891	UNIPROT	up-regulates activity	phosphorylation	Thr228	DMADTCGtICHAADK	-1									34343500	t		miannu	Here, we show that ionizing radiation results in TBK1-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2 at T228, thereby enhancing PRPS1/2 catalytic activity and promoting deoxyribonucleotide synthesis. 	SIGNOR-277316	0.2
DRD5	protein	P21918	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257369	0.484
PTGDR	protein	Q13258	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256755	0.575
NUP37	protein	Q8NFH4	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262085	0.676
MLL-AF9	fusion protein	SIGNOR-FP5	SIGNOR	BCOR	protein	Q6W2J9	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								12776190	t		irozzo	As BCoR binds the C-terminus of AF9, it seems likely that BCoR will also bind chimeric MLL–AF9 proteins. As transcriptional repressors, BCoR or Pc3 bound to MLL–AF9 might interfere with the expression of genes required for normal hematopoiesis.	SIGNOR-256142	0.2
F2	protein	P00734	UNIPROT	F8	protein	P00451	UNIPROT	up-regulates activity	cleavage	Arg1708	EDENQSPrSFQKKTR	-1									10350471	t		lperfetto	Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689.	SIGNOR-263639	0.746
RRAGC	protein	Q9HB90	UNIPROT	RAGAC	complex	SIGNOR-C113	SIGNOR	form complex	binding			9606									20381137	t		gcesareni	Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant	SIGNOR-228161	0.77
ADA	protein	P00813	UNIPROT	adenosine	smallmolecule	CHEBI:16335	ChEBI	up-regulates quantity	chemical modification			-1									15926889	t		Luana	Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates	SIGNOR-269735	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	TCF3	protein	P15923	UNIPROT	down-regulates quantity by destabilization	phosphorylation			10090	BTO:0000944								14592976	t	inferred from 70% family members	lperfetto	Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG)	SIGNOR-270139	0.2
DHFR2	protein	Q86XF0	UNIPROT	(6S)-5,6,7,8-tetrahydrofolate(2-)	smallmolecule	CHEBI:57453	ChEBI	up-regulates quantity	chemical modification			9606									21876184	t		lperfetto	Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. |We demonstrate that the DHFRP4, or dihydrofolate reductase-like 1 (DHFRL1), gene is expressed and shares some commonalities with DHFR.	SIGNOR-268261	0.8
CREB5	protein	Q02930	UNIPROT	CREB5	protein	Q02930	UNIPROT	up-regulates activity	binding			9534	BTO:0000318								8378084	t		miannu	CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription	SIGNOR-219602	0.2
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1616	TPQSPSYsPTSPSYS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248803	0.849
CD27	protein	P26842	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12324477	f		gcesareni	Cd40 ligation up-regulated bcl-2 and bcl-xl as much as 9.7- (p < 0.01) and 6.8-fold (p < 0.01), respectively (fig. 2, b and c). Under similar conditions, cd27 ligation also up-regulated bcl-2 and bcl-xl as much as 5.0- (p < 0.01) and 3.9-fold (p < 0.01), respectively.	SIGNOR-93317	0.2
GRM7	protein	Q14831	UNIPROT	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							20055706	t		miannu	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264080	0.341
EGFR	protein	P00533	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates	binding			9606									11279155	t		gcesareni	These results demonstrate that egfr-erbb2 oligomers are potent activators of mapk and akt, and this signaling does not require egfr kinase activity	SIGNOR-106500	0.595
PRKN	protein	O60260	UNIPROT	EPS15	protein	P42566	UNIPROT	down-regulates activity	ubiquitination			10090									16862145	t		gcesareni	Treatment of cells with EGF stimulates parkin binding to both Eps15 and the EGFR and promotes parkin-mediated ubiquitination of Eps15.	SIGNOR-243282	0.2
MED24	protein	O75448	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266666	0.772
BMP7	protein	P18075	UNIPROT	ACVR1/BMPR2	complex	SIGNOR-C30	SIGNOR	up-regulates	binding			10090	BTO:0000165								11282024	t		lperfetto	Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2	SIGNOR-235364	0.799
PRKCE	protein	Q02156	UNIPROT	IQGAP1	protein	P46940	UNIPROT	up-regulates	phosphorylation	Ser1443	DKMKKSKsVKEDSNL	9606									15695813	t		gcesareni	Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth.	SIGNOR-133865	0.2
80S_cytosolic_ribosome	complex	SIGNOR-C455	SIGNOR	peptide	smallmolecule	CHEBI:16670	ChEBI	up-regulates quantity	chemical modification			9606									20025795	t		miannu	In the initial binding state, referred to as A/T state, this aa-tRNA is in a ternary complex with the GTPase EF-Tu (eEF1A in eukaryotes) and GTP. When a Watson–Crick codon–anticodon match is recognized by the ribosome, a signal is transmitted to EF-Tu that triggers GTP hydrolysis and thereby causes the dissociation of EF-Tu from the ribosome. The subsequent accommodation of the 3′ acceptor arm of the tRNA in the PTC of the large subunit leads to a rapid peptide bond transfer	SIGNOR-270811	0.8
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	STX5	protein	Q13190	UNIPROT	down-regulates activity	cleavage			9606									14970262	t		miannu	Giantin and syntaxin 5 are cleaved by caspase-3. Given that both giantin and syntaxin 5 are cleaved at an early stage during apoptosis, we anticipated that, at the very least, the delivery of ER-derived transport intermediates to the Golgi would be impaired in apoptotic cells.	SIGNOR-261236	0.2
RAB2A	protein	P61019	UNIPROT	PRKCI	protein	P41743	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								14570876	t		Sara	Rab2 Binds to the PKCι/λ Regulatory Domain and Inhibits PKCι/λ-dependent GAPDH Phosphorylation	SIGNOR-261301	0.468
DDB1	protein	Q16531	UNIPROT	RAD23A	protein	P54725	UNIPROT	up-regulates													24086044	f		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein).	SIGNOR-275687	0.587
PIAS4	protein	Q8N2W9	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	up-regulates	sumoylation			9606									20016603	t		gcesareni	Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation	SIGNOR-162167	0.621
oxymetazoline	chemical	CHEBI:7862	ChEBI	ADRA2B	protein	P18089	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258916	0.8
SF3B2	protein	Q13435	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270664	0.778
lofexidine	chemical	CHEBI:51368	ChEBI	ADRA2A	protein	P08913	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000246								22341244	t		Luana	Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism. 	SIGNOR-258332	0.8
CHUK	protein	O15111	UNIPROT	ELAVL1	protein	Q15717	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser304	EAAMAIAsLNGYRLG	9606	BTO:0001321								23115237	t		miannu	Furthermore, mutational analysis indicates that IKKα-dependent phosphorylation at Ser-304 is crucial to the binding of HuR to β-TrCP1. Mechanistically, this HuR degradation pathway differs from that reported for heat shock and hypoxia, which underlies the complexity in the regulation of HuR turnover under different stress stimuli. 	SIGNOR-276422	0.328
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	METTL3	protein	Q86U44	UNIPROT	up-regulates quantity by stabilization	phosphorylation			9606	BTO:0000007								33217317	t	inferred from 70% family members	miannu	 Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.	SIGNOR-270035	0.2
EFNA3	protein	P52797	UNIPROT	EPHA2	protein	P29317	UNIPROT	up-regulates	binding			9606									9330863	t		gcesareni	The eph family of receptors.	SIGNOR-52309	0.807
CREB5	protein	Q02930	UNIPROT	ATP6V0E1	protein	O15342	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21132541	f		miannu	 Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition),	SIGNOR-253801	0.2
BCOR	protein	Q6W2J9	UNIPROT	RNF2	protein	Q99496	UNIPROT	up-regulates activity	binding			9606									17296600	t		miannu	BcoR and Fbxl10/Jhdm1B are among the most abundant Ring1B/Rnf2 interactors identified with the highest confidence, and their association has been validated by coimmunoprecipitation studies; hence we call this the Fbxl10-BcoR complex. In summary, we have widened the set of multiprotein complexes containing the Polycomb group protein Ring1B/Rnf2. The new interactors contain protein motifs whose enzymatic activities and binding properties would expand the regulatory potential and gene target diversity of Ring1B/Rnf2 complexes in terms of recruitment to and modification of chromatin	SIGNOR-252241	0.561
WWP1	protein	Q9H0M0	UNIPROT	AMOT	protein	Q4VCS5	UNIPROT	up-regulates quantity by stabilization	ubiquitination												24101513	t		lperfetto	Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130	SIGNOR-275847	0.279
PRKCD	protein	Q05655	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	phosphorylation	Ser259	FPLRKTAsEPNLKVR	9606									18332134	t		Manara	In this report, we show that VEGF stimulates PKD-dependent phosphorylation of HDAC5 at Ser259/498residues in ECs, which leads to HDAC5 nuclear exclusion and myocyte enhancer factor-2 (MEF2) transcriptional activation.	SIGNOR-260875	0.359
MTOR	protein	P42345	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606		BTO:0000007							20508131	f			The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size.	SIGNOR-255944	0.7
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser107	SQPPSPPsPAPSSFS	9606									20305697	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-164621	0.575
EGFR	protein	P00533	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1092	TFLPVPEyINQSVPK	9606	BTO:0000567								10653583	t	Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer	lperfetto	After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine.	SIGNOR-236479	0.2
beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266478	0.8
LAMB2	protein	P55268	UNIPROT	Laminin-9	complex	SIGNOR-C180	SIGNOR	form complex	binding												10809728	t		lperfetto	Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. 	SIGNOR-253224	0.54
ABCA7	protein	Q8IZY2	UNIPROT	HDL_assembly	phenotype	SIGNOR-PH61	SIGNOR	up-regulates				10090									14570867	f		miannu	Transfected ABCA7-GFP induced apolipoprotein-mediated assembly of cholesterol-containing HDL also in L929 cells, which otherwise generate only cholesterol-deficient HDL with their endogenous ABCA1.	SIGNOR-265177	0.7
AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	Platelet_aggregation	phenotype	SIGNOR-PH81	SIGNOR	up-regulates				10090									18278053	f		lperfetto	Activated alphaIIbbeta3 integrins bind fibrinogen, vWF and fibronectin, thus allowing firm platelet adhesion and platelet aggregation. 	SIGNOR-266067	0.7
STAT1	protein	P42224	UNIPROT	IRF7	protein	Q92985	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000667								16628196	f		miannu	The activation of STAT1 by IFNs not only induces chemokine production, but also results in the expression of IRF-7 and TLR3, thus amplifying the dsRNA-provoked reaction in a positive-feedback manner during viral infection.	SIGNOR-255231	0.497
regorafenib	chemical	CHEBI:68647	ChEBI	FGFR1	protein	P11362	UNIPROT	down-regulates activity	chemical inhibition			9606									26254357	t		miannu	A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF	SIGNOR-259177	0.8
MMP20	protein	O60882	UNIPROT	ACAN	protein	P16112	UNIPROT	down-regulates quantity by destabilization	cleavage	Asn360	DFVDIPEnFFGVGGE	-1									10922468	t		lperfetto	Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development.	SIGNOR-266979	0.491
ANXA3	protein	P12429	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0001109;BTO:0000038								30998268	f		miannu	ANXA3 downregulation evidently increased the apoptosis of HCT116 (Figure 2C) and SW480 (Figure 2D) cells, and Ox‐induced cell apoptosis was further aggravated by ANXA3 suppression.	SIGNOR-262208	0.7
H3C1	protein	P68431	UNIPROT	Nucleosome_H2A.Z.2 variant	complex	SIGNOR-C323	SIGNOR	form complex	binding			-1									24311584	t		miannu	In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined.	SIGNOR-263711	0.2
CTNNB1	protein	P35222	UNIPROT	FOXA2	protein	Q9Y261	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22945641	f		gcesareni	Our study indicates that beta-catenin regulates foxa2 expression, and this interaction is possibly essential to control cell cycle progression during endometrial hyperplasia formation	SIGNOR-198929	0.456
WIPF1	protein	O43516	UNIPROT	Endocytosis	phenotype	SIGNOR-PH123	SIGNOR	up-regulates				9606									19121306	f		lperfetto	However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin.	SIGNOR-260609	0.7
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2M	protein	P61081	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271332	0.716
3,5-diiodo-L-tyrosine	smallmolecule	CHEBI:15768	ChEBI	L-tyrosine zwitterion	smallmolecule	CHEBI:58315	ChEBI	up-regulates quantity	precursor of			9606									28153798	t		scontino	MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide.	SIGNOR-267035	0.8
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation			9606									21440011	t		lperfetto	Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs	SIGNOR-252858	0.908
BDKRB1	protein	P46663	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256907	0.252
PTPRC	protein	P08575	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	dephosphorylation			10090	BTO:0003620								11201744	t			CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling	SIGNOR-248347	0.484
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1913	SPKYSPTsPTYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269345	0.718
indometacin	chemical	CHEBI:49662	ChEBI	PTGS1	protein	P23219	UNIPROT	down-regulates activity	chemical inhibition			-1									9057869	t		miannu	Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). 	SIGNOR-258607	0.8
ZNF165	protein	P49910	UNIPROT	SMAD7	protein	O15105	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									26567849	t		Luana	ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1.	SIGNOR-266093	0.2
PRKACA	protein	P17612	UNIPROT	GRIA1	protein	P42261	UNIPROT	up-regulates activity	phosphorylation	Ser863	TSTLPRNsGAGASSG	9606									8663994	t		miannu	Phosphorylation of Ser-845 on GluR1 by PKA potentiates its response to glutamate.	SIGNOR-249987	0.475
DIABLO	protein	Q9NR28	UNIPROT	BIRC2	protein	Q13490	UNIPROT	down-regulates activity	binding			9606	BTO:0000007;BTO:0000891								10929712	t		amattioni	Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria.	SIGNOR-80222	0.891
LE-TGN SNARE	complex	SIGNOR-C157	SIGNOR	M6PR	protein	P20645	UNIPROT	up-regulates activity	relocalization			9606									18195106	t		lperfetto	These findings place the retromer complex upstream of both STX10 function and the GCC185 tethering complex in MPR transport. Together, our data suggest that STX10, STX16, Vti1a, and VAMP3 are important for the trafficking of both CD- and CI-MPRs.|Thus, MPRs must pass through a compartment of pH ≤ 5.5 before returning to the Golgi to carry out their biological function.	SIGNOR-253084	0.516
SIRT5	protein	Q9NXA8	UNIPROT	IDH2	protein	P48735	UNIPROT	up-regulates activity	catalytic activity			9606									27113762	t		Monia	Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes.	SIGNOR-261212	0.42
RWDD3	protein	Q9Y3V2	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates	sumoylation			9606									17956732	t		lperfetto	Rsume,_a small_rwd-containing protein, enhances sumo conjugation and stabilizes hif-1alpha during hypoxia	SIGNOR-158590	0.47
MAPK14	protein	Q16539	UNIPROT	ZNHIT1	protein	O43257	UNIPROT	up-regulates	phosphorylation			9606									20473270	t		gcesareni	We show that the srcap subunit named znhit1 or p18(hamlet), which is a substrate of p38 mapk, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 mapk-dependent manner. Furthermore, p18hamlet was phosphorylated during myoblast differentiation in a p38 mapk-dependent manner (dal testo pmc)	SIGNOR-165571	0.319
IL6ST	protein	P40189	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates	binding			9606									24710148	t		milica	The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3).	SIGNOR-204841	0.662
Naltriben	chemical	CID:5486827	PUBCHEM	OPRD1	protein	P41143	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258425	0.8
MED15	protein	Q96RN5	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266660	0.793
GSK3B	protein	P49841	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser61	PLSTPCSsVPSSPSF	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159462	0.26
DAB2	protein	P98082	UNIPROT	DAB2IP	protein	Q5VWQ8	UNIPROT	up-regulates activity	binding			9606									27858941	t		miannu	In prostate cancer cells, DAB2IP was shown to be recruited by the adaptor protein DAB2/DOC2 to promote Ras inactivation and inhibition of MAPK signaling upon receptor stimulation.	SIGNOR-254744	0.537
DYRK2	protein	Q92630	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser156	KKPVRPVsRGCLHSH	9606	BTO:0002181								34363019	t		miannu	Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. 	SIGNOR-276740	0.2
VKORC1L1	protein	Q8N0U8	UNIPROT	vitamin K	smallmolecule	CHEBI:28384	ChEBI	up-regulates quantity	chemical modification			9606									31226734	t		lperfetto	The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form	SIGNOR-265903	0.8
PTPRR	protein	Q15256	UNIPROT	MAPK7	protein	Q13164	UNIPROT	down-regulates activity	dephosphorylation	Tyr221	HQYFMTEyVATRWYR	9534									12042304	t			In this study we concentrated on whether and how PTP-SL, a kinase-interacting motif-containing PTP, might be involved in the down-regulation of the ERK5 signal|Whereas inactivation of ERK5 by PTP-SL monitored in vitro is most probably simply due to the dephosphorylation of tyrosine 220 in the activating TEY motif	SIGNOR-248721	0.461
GATA1	protein	P15976	UNIPROT	CYBB	protein	P04839	UNIPROT	up-regulates quantity	transcriptional regulation			9606									10734088	t			These results suggest that GATA-1 is an activator and that GATA-2 is a relative competitive inhibitor of GATA-1 in the expression of the gp91(phox) gene in human eosinophils.	SIGNOR-259947	0.283
UVB radiation	stimulus	SIGNOR-ST17	SIGNOR	IL1B	protein	P01584	UNIPROT	up-regulates				9606									9767234	f		miannu	UVB can stimulate the synthesis of IL-1, TNF-a and ET-1, and other cytokines by keratinocytes.	SIGNOR-252382	0.7
PAXIP1	protein	Q6ZW49	UNIPROT	PAX2	protein	Q02962	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								10908331	t		miannu	PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin. The degree of interaction with the Pax2 C-terminal polypeptides correlates with their transcription transactivation potential and we have therefore designated this factor PTIP for Pax transactivation-domain interacting protein.	SIGNOR-236965	0.589
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CDKN1C	protein	P49918	UNIPROT	down-regulates	phosphorylation	Thr310	GVGSVEQtPRKRLR	9606	BTO:0000150								23421998	t		lperfetto	Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination	SIGNOR-201046	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ETV6	protein	P41212	UNIPROT	down-regulates	phosphorylation	Ser213	DNMIRRLsPAERAQG	10090	BTO:0000944								15060146	t		miannu	Leukemia-related transcription factor TEL is negatively regulated through extracellular signal-regulated kinase-induced phosphorylation. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser(213) and Ser(257).	SIGNOR-260084	0.2
MAPK14	protein	Q16539	UNIPROT	MAPKAPK2	protein	P49137	UNIPROT	up-regulates activity	phosphorylation	Thr317	PTQRMTItEFMNHPW	-1									7592979	t		miannu	In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction	SIGNOR-250102	0.758
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270404	0.8
TRAF6	protein	Q9Y4K3	UNIPROT	TNFRSF11A	protein	Q9Y6Q6	UNIPROT	up-regulates activity	binding			9606									10075662	t		miannu	TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappaB activation. 	SIGNOR-253045	0.717
CDK8	protein	P49336	UNIPROT	CCNH	protein	P51946	UNIPROT	down-regulates	phosphorylation	Ser304	YEDDDYVsKKSKHEE	9606									10993082	t		lperfetto	Cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity	SIGNOR-82033	0.667
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	EGR1	protein	P18146	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								21983014	f	 	 	In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression.	SIGNOR-254258	0.407
PRKACA	protein	P17612	UNIPROT	LCP1	protein	P13796	UNIPROT	up-regulates	phosphorylation	Ser5	sVSDEEMM	9606	BTO:0000007								16636079	t		gcesareni	Phosphorylation on ser5 increases the f-actin-binding activity of l-plastin and promotes its targeting to sites of actin assembly in cells. L-plastin phosphorylation require protein kinase a.	SIGNOR-146287	0.332
GSK3B	protein	P49841	UNIPROT	SREBF1	protein	P36956	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser430	DTLTPPPsDAGSPFQ	9606	BTO:0000567								16825193	t		lperfetto	The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding	SIGNOR-236645	0.499
FLT3	protein	P36888	UNIPROT	SOCS3	protein	O14543	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									12468433	f			We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling	SIGNOR-261546	0.285
SH3GLB1	protein	Q9Y371	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates	binding			9606									21311563	t		gcesareni	Bif-1 forms a complex with beclin1 through uvrag and promotes the activation of the class iii pi3 kinase, vps34, in mammalian cells.	SIGNOR-171899	0.56
ARHGEF1	protein	Q92888	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260528	0.825
LRRC4	protein	Q9HBW1	UNIPROT	CDK2	protein	P24941	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		BTO:0000142							25526788	f		miannu	LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway.	SIGNOR-264058	0.355
RB1	protein	P06400	UNIPROT	E2F2	protein	Q14209	UNIPROT	down-regulates	binding			9606									22569856	t		gcesareni	Cyclin-dependent kinase (cdk) phosphorylation of the retinoblastoma protein (rb) drives cell proliferation through rb complexes with e2f transcription factors and other regulatory proteins.	SIGNOR-197328	0.911
RELA	protein	Q04206	UNIPROT	CREBBP	protein	Q92793	UNIPROT	up-regulates	binding			9606				SIGNOR-C6					10207072	t		gcesareni	Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo.	SIGNOR-66953	0.874
IKK-complex	complex	SIGNOR-C14	SIGNOR	NCOR2	protein	Q9Y618	UNIPROT	down-regulates	phosphorylation	Ser2407	AKVSGRPsSRKAKSP	9606									15494311	t	Translocation from Nucleus to Cytoplasm	lperfetto	Nf-kappab transcription requires ikkalpha to phosphorylate smrt on chromatin, stimulating the exchange of corepressor for coactivator complexes. Ikk directly phosphorylates smrt to stimulate nuclear export. Ikkalpha orchestrates smrt derepression, a prerequisite for nf-kappab transcription and survival.	SIGNOR-216393	0.418
INS	protein	P01308	UNIPROT	LPL	protein	P06858	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001487							21966368	f	Regulation	miannu	Insulin has a major effect on LPL regulation in adipose tissue since in mature adipocytes insulin not only increases the level of LPL mRNA but also regulates LPL activity through both posttranscriptional and posttranslational mechanisms 	SIGNOR-251857	0.478
N-carbamoyl-L-aspartate(2-)	smallmolecule	CHEBI:32814	ChEBI	(S)-dihydroorotate	smallmolecule	CHEBI:30864	ChEBI	up-regulates quantity	precursor of			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-268091	0.8
POLR3K	protein	Q9Y2Y1	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266135	0.819
IRS1	protein	P35568	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			9606	BTO:0000156								11259577	t		lperfetto	Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis.	SIGNOR-236614	0.796
CDK1	protein	P06493	UNIPROT	CDC25B	protein	P30305	UNIPROT	up-regulates	phosphorylation	Ser160	PVRLLGHsPVLRNIT	9606			SIGNOR-C17						12107172	t		lperfetto	We demonstrate that serine 146 is required for two crucial features of cdc25b1. It is essential for cdc25b1 to function as a mitotic inducer and to prevent cdc25b1 export from the nucleus. We also show that serine 146 is phosphorylated in vitro by cdk1-cyclin b. Serine 146 phosphorylation is proposed to be a key event in the regulation of the cdc25b function	SIGNOR-90451	0.823
pimozide	chemical	CHEBI:8212	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258719	0.8
CCN2	protein	P29279	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									33358571	f		miannu	As a matricellular protein, connective tissue growth factor (CTGF) functions beyond its classical role in extracellular matrix (ECM) remolding. Increasing evidence emphasizes the notion that CTGF is pivotal in cancer initiation and progression. 	SIGNOR-277683	0.7
ATR	protein	Q13535	UNIPROT	WDHD1	protein	O75717	UNIPROT	up-regulates activity	phosphorylation	Thr826	KAAELTAtQVEEEEE	9606	BTO:0001109								26082189	t		miannu	 And-1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And-1 to accumulate at the damage sites, where And-1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR. 	SIGNOR-262664	0.555
TTK	protein	P33981	UNIPROT	MAP4	protein	P27816	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr927	LSRLATNtSAPDLKN	9606	BTO:0000567								31253867	t		miannu	We further uncovered that Mps1 is a kinase of MAP4, and E7-MAP4 binding blocks Mps1 phosphorylation of MAP4, thereby interrupting phosphorylation-dependent MAP4 degradation. 	SIGNOR-277462	0.2
PTK6	protein	Q13882	UNIPROT	STAT5B	protein	P51692	UNIPROT	up-regulates	phosphorylation	Tyr699	TAKAVDGyVKPQIKQ	9606	BTO:0000150								17997837	t		llicata	Phosphospecific antibodies, mutational analysis, and in vitro kinase assays demonstrated that brk specifically mediated stat5b phosphorylation at the activating tyrosine, y699.	SIGNOR-159066	0.441
SERPINE1	protein	P05121	UNIPROT	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									10368279	f		gcesareni	Pai-1 is now being identified as a key player in the link between coagulation and the cell adhesion pathways involved in tissue remodeling and metastasis. Active pai-1 (but not its latent or cleaved forms) binds tightly to the adhesive glycoprotein vitronectin in the extracellular matrix.	SIGNOR-68478	0.7
NEK2	protein	P51955	UNIPROT	SGO1	protein	Q5FBB7	UNIPROT	up-regulates	phosphorylation	Ser14	LKKSFQDsLEDIKKR	9606									17621308	t		lperfetto	Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507)	SIGNOR-156878	0.2
HNF1A	protein	P20823	UNIPROT	UGT1A1	protein	P22309	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18172616	f	 	miannu	 This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities.	SIGNOR-254437	0.285
PPARG	protein	P37231	UNIPROT	FABP4	protein	P15090	UNIPROT	up-regulates	transcriptional regulation			10116									8943212	f		fspada	We report that insulin and a ppargamma ligand (thiazolidinedione (tzd)) stimulate in a synergistic manner the expression of an adipocyte-specific gene (ap2) in rat adipocytes and 3t3-l1 cells	SIGNOR-210149	0.673
SREBF2	protein	Q12772	UNIPROT	PON2	protein	Q15165	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19497963	f		miannu	UPA upregulated PON2 expression in a sterol regulatory binding protein-2 (SREBP-2)-dependent manner, since blocking SREBP-2 maturation by 4-(2-aminoethyl)-benzenesulfonyl fluoride abolished uPA-stimulation of PON2, whereas inhibition of SREBP-2 catabolism by N-acetyl-leucyl-norleucinal had an opposite effect.	SIGNOR-255225	0.28
Macrophage_activation	phenotype	SIGNOR-PH126	SIGNOR	CCL2	protein	P13500	UNIPROT	up-regulates quantity				10090									32283152	f		miannu	The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages.	SIGNOR-260962	0.7
adenosine	smallmolecule	CHEBI:16335	ChEBI	ADORA2B	protein	P29275	UNIPROT	up-regulates activity	binding			-1									14662005	t		Luana	Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3.	SIGNOR-268421	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	PTTG1	protein	O95997	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser89	KQKQPSFsAKKMTEK	9606	BTO:0000567								24781523	t		miannu	CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase	SIGNOR-276383	0.314
FZD2	protein	Q14332	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates activity	binding			9606									23151663	t		areggio	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. 	SIGNOR-258956	0.654
SNAI2	protein	O43623	UNIPROT	CD44	protein	P16070	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								20509143	f		miannu	 SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. 	SIGNOR-255153	0.419
WNT1	protein	P04628	UNIPROT	RYK	protein	P34925	UNIPROT	up-regulates	binding			9606									15454084	t		lperfetto	Mammalian ryk is a wnt coreceptor required for stimulation of neurite outgrowth	SIGNOR-129577	0.697
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Thr24	LPRPRSCtWPLPRPE	-1	BTO:0000318								10377430	t		lperfetto	Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export.	SIGNOR-252832	0.908
AKT1	protein	P31749	UNIPROT	CHEK1	protein	O14757	UNIPROT	down-regulates	phosphorylation	Ser280	AKRPRVTsGGVSESP	9606									15107605	t		gcesareni	The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1.	SIGNOR-124365	0.441
UBE3A	protein	Q05086	UNIPROT	LAMTOR1	protein	Q6IAA8	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090									30020076	t			Ube3a regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator. Ube3a ubiquinates p18, resulting in its proteasomal degradation, and Ube3a deficiency in the hippocampus of AS mice induces increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity	SIGNOR-256145	0.2
STRN	protein	O43815	UNIPROT	PPP2CB	protein	P62714	UNIPROT	up-regulates activity	binding			10090	BTO:0000938								29802198	t		miannu	The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms	SIGNOR-261700	0.612
DLGAP4	protein	Q9Y2H0	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								9115257	t		miannu	SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.	SIGNOR-264212	0.794
SUFU	protein	Q9UMX1	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates	relocalization			9606	BTO:0001130;BTO:0000848;BTO:0000527								10564661	t		gcesareni	Su(fu) is a negative regulator of shh that interacts with all three gli proteins to retain them in the cytosol.	SIGNOR-72308	0.885
PRKCA	protein	P17252	UNIPROT	KCNE1	protein	P15382	UNIPROT	down-regulates activity	phosphorylation	Ser102	VQARVLEsYRSCYVV	-1									1553557	t		lperfetto	Inhibition of the current was not seen in channels in which Ser103 was replaced by Ala, although other properties of the current were unchanged. These results indicate that inhibition of the potassium current results from direct phosphorylation of the channel subunit protein at Ser103.	SIGNOR-248852	0.311
CSNK2A1	protein	P68400	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	phosphorylation	Ser335	YDSFGEPsYPEVFEP	-1									9558331	t		llicata	In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites.	SIGNOR-250935	0.311
risperidone	chemical	CHEBI:8871	ChEBI	HTR1E	protein	P28566	UNIPROT	down-regulates activity	chemical inhibition			9534	BTO:0000298								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258528	0.8
ECM	stimulus	SIGNOR-ST20	SIGNOR	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259035	0.7
AKT1	protein	P31749	UNIPROT	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606		BTO:0000562							10521487	t		gcesareni	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-252584	0.643
CDK10	protein	Q15131	UNIPROT	ETS2	protein	P15036	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser220	PKGGLLDsMCPASTP	9606									24218572	t		Manara	Altogether, these results suggest that CDK10/cyclin M directly controls ETS2 degradation through the phosphorylation of these two serines.	SIGNOR-260913	0.544
CREBL2	protein	O60519	UNIPROT	CEBPA	protein	P49715	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000011								21728997	f		Luana	 Accordingly, the results of QPCR and immunoblot analysis showed that during adipogenesis, both the mRNA (Figures 4D and 4E) and protein (Figure 4F) levels of PPARγ , as well as C/EBPα, in 3T3-L1 preadipocytes transfected with either siCREBL2-1 or siCREBL2-2 were significantly decreased compared with the control (P < 0.05), suggesting that knockdown of CREBL2 protein suppress 3T3-L1 preadipocyte differentiation via inhibition of PPARγ and C/EBPα expression.	SIGNOR-261574	0.2
RPA2	protein	P15927	UNIPROT	ATRIP	protein	Q8WXE1	UNIPROT	up-regulates	binding			9606									20068082	t		gcesareni	Ssdna lesions are then coated by replication protein a (rpa), recruiting atr/atrip (atr-interacting protein) complexes via recognition and association of rpa-ssdna by atrip.	SIGNOR-163176	0.674
PRKDC	protein	P78527	UNIPROT	PNPT1	protein	Q8TCS8	UNIPROT	up-regulates activity	phosphorylation	Ser776	IVMGEPIsQSSSNSQ	9606									22815474	t		miannu	We also demonstrated that DNAPK phosphorylates PNPase at Ser-776, which is critical for its ribonuclease activity. 	SIGNOR-263182	0.2
F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	LATS2	protein	Q9NRM7	UNIPROT	down-regulates				9606									23450633	f		gcesareni	Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism.	SIGNOR-192783	0.7
SMO	protein	Q99835	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates	phosphorylation			9606									18455992	t		gcesareni	Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion.	SIGNOR-178610	0.415
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	PSIP1	protein	O75475	UNIPROT	down-regulates	cleavage			9606	BTO:0001130								18708362	t		miannu	Ledgf/ p75 has a cooh-terminally truncated splice variant, p52 / during apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the nh2-terminal pwwp domain and failed to transactivate the hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of ledgf/p75	SIGNOR-256469	0.354
DUSP26	protein	Q9BV47	UNIPROT	FADD	protein	Q13158	UNIPROT	down-regulates activity	dephosphorylation	Ser194	QNRSGAMsPMSWNSD	9606									24548998	t		lperfetto	This multi-functionality of fadd may depend primarily on its subcellular location. Fadd shuttles between the cytosol and the nucleus and this signal is unclear;however, fadd trafficking requires phosphorylation of the protein on ser194dusp26 suppresses cell proliferation by fadd dephosphorylation	SIGNOR-204559	0.376
PCDH19	protein	Q8TAB3	UNIPROT	GABRA2	protein	P47869	UNIPROT	up-regulates quantity by stabilization	binding			10116	BTO:0003102			SIGNOR-C331					29360992	t		miannu	Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons. 	SIGNOR-267218	0.2
MAPK1	protein	P28482	UNIPROT	NUP153	protein	P49790	UNIPROT	unknown	phosphorylation	Thr388	VYFKPSLtPSGEFRK	9606									19767751	t		llicata	These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport.	SIGNOR-188127	0.397
FBXW5	protein	Q969U6	UNIPROT	SEC23B	protein	Q15437	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									30596474	t		lperfetto	SCFFBXW5 interacts with SEC23B and targets it for ubiquitylation and proteasome-mediated degradation.	SIGNOR-265286	0.2
SATB1	protein	Q01826	UNIPROT	HSPA6	protein	P17066	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000664								17343824	f		miannu	We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 	SIGNOR-255134	0.2
NFIX	protein	Q14938	UNIPROT	RBFOX3	protein	A6NFN3	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268913	0.2
PRKACA	protein	P17612	UNIPROT	PIM	proteinfamily	SIGNOR-PF34	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000007								30017192	t		miannu	In this study, we found that PKCα stabilized and activated PIM-1L by phosphorylation at Ser65. The PIM-1L phosphorylation suppressed sotrastaurin-induced apoptosis. These findings suggest that PKCα promotes cell survival and proliferation by upregulating PIM-1L in acute myeloid leukemia.	SIGNOR-259413	0.269
PRKCB	protein	P05771	UNIPROT	LMNB1	protein	P20700	UNIPROT	unknown	phosphorylation	Ser405	VTVSRASsSRSVRTT	9606	BTO:0001271								8034666	t		lperfetto	Beta II PKC-mediated phosphorylation of lamin B is confined to two sites, Ser395 and Ser405 | Comparative tryptic phosphopeptide mapping demonstrates that the beta II PKC site, Ser405, is a prominent target of mitotic lamin B phosphorylation in vivo. beta II PKC translocates to the nucleus during the G2/M phase of cell cycle concomitant with phosphorylation of Ser405, indicating a physiologic role for nuclear beta II PKC activation in mitotic lamin B phosphorylation in vivo. 	SIGNOR-248912	0.476
CHRM3	protein	P20309	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256882	0.2
U0126	chemical	CHEBI:90693	ChEBI	MAP2K1	protein	Q02750	UNIPROT	down-regulates	chemical inhibition			9606									11160424	t		gcesareni	The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2.	SIGNOR-104939	0.8
MAPK1	protein	P28482	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser363	TSRTPKDsPGIPPSA	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-219312	0.748
STK11	protein	Q15831	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	up-regulates activity	phosphorylation	Ser615	GEKNERTsVAGTVRK	9606	BTO:0002181								34216621	t		miannu	 Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction. 	SIGNOR-277322	0.591
MAPK3	protein	P27361	UNIPROT	SOX9	protein	P48436	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20457810	f		fspada	Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression.	SIGNOR-165353	0.391
NEK9	protein	Q8TD19	UNIPROT	NEK7	protein	Q8TDX7	UNIPROT	up-regulates activity	phosphorylation	Ser195	SKTTAAHsLVGTPYY	9606	BTO:0000007								12840024	t		lperfetto	Nercc1 catalyzes the phosphorylation of nek6 (ser206) and the equivalent site on nek7 (ser195), resulting in a 20-25-fold activation of nek6/7 kinase activity	SIGNOR-103030	0.701
FABP2	protein	P12104	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264456	0.7
PRKCA	protein	P17252	UNIPROT	PDE3A	protein	Q14432	UNIPROT	up-regulates	phosphorylation	Ser492	MTLTKSRsFTSSYAI	9606									19261611	t		llicata	Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding.	SIGNOR-184464	0.2
AKT1	protein	P31749	UNIPROT	MAP3K8	protein	P41279	UNIPROT	up-regulates activity	phosphorylation	Ser413	LERKRLLsRKELELP	9606	BTO:0000007								12138205	t			Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator.	SIGNOR-252572	0.538
INHBA	protein	P08476	UNIPROT	ACVR2A	protein	P27037	UNIPROT	up-regulates activity	binding			9606									1646080	t		gcesareni	A protein of 494 amino acids comprising a ligand-binding extracellular domain, a single membrane-spanning domain, and an intracellular kinase domain with predicted serine/threonine specificity. 125I-activin A binds to transfected COS cells with an affinity of 180 pM and can be competed by activin A, activin B, and inhibin A, but not by transforming growth factor beta 1.	SIGNOR-235138	0.807
PLK1	protein	P53350	UNIPROT	BRCA2	protein	P51587	UNIPROT	unknown	phosphorylation	Ser193	AEVDPDMsWSSSLAT	9606	BTO:0001938								12815053	t		lperfetto	Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation.	SIGNOR-249217	0.556
ABL1	protein	P00519	UNIPROT	LASP1	protein	Q14847	UNIPROT	up-regulates	phosphorylation	Tyr171	IPTSAPVyQQPQQQP	9606	BTO:0000150								15138294	t		llicata	C-abl activation by apoptotic agents specifically promotes phosphorylation of lasp-1 at tyrosine 171, which is associated with the loss of lasp-1 localization to focal adhesions and induction of cell death. Thus, lasp-1 is a dynamic focal adhesion protein necessary for cell migration and survival in response to growth factors and ecm proteins.	SIGNOR-124719	0.351
ZNF224	protein	Q9NZL3	UNIPROT	ALDOA	protein	P04075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17900823	f		miannu	 We previously reported that ZNF224, a novel Krüppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. 	SIGNOR-255627	0.505
IMPDH2	protein	P12268	UNIPROT	5'-xanthylic acid	smallmolecule	CHEBI:15652	ChEBI	up-regulates quantity	chemical modification			9606									19480389	t		miannu	IMPDH controls the gateway to guanine nucleotides, making it an “enzyme of consequence” for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS).	SIGNOR-267335	0.8
GATA6	protein	Q92908	UNIPROT	SEMA3C	protein	Q99985	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19666519	f		lperfetto	Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes.	SIGNOR-253150	0.409
PPP1CA	protein	P62136	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	dephosphorylation	Ser75	LGYEPEGsASPTPPY	9606									17318175	t			The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 	SIGNOR-248551	0.338
IYD	protein	Q6PHW0	UNIPROT	L-tyrosine zwitterion	smallmolecule	CHEBI:58315	ChEBI	up-regulates quantity	chemical modification			9606									28153798	t		scontino	MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide.	SIGNOR-267033	0.8
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	MYOG	protein	P15173	UNIPROT	down-regulates	binding			9606									21902831	t		lperfetto	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-216972	0.346
SGK1	protein	O00141	UNIPROT	FBXW7	protein	Q969H0	UNIPROT	up-regulates	phosphorylation	Ser227	QQRRRITsVQPPTGL	9606	BTO:0001271								21147854	t		lperfetto	Here, we report that the serum- and glucocorticoid-inducible protein kinase sgk1 remarkably reduced the protein stability of the active form of notch1 through fbw7activated sgk1 phosphorylated fbw7 at serine 227	SIGNOR-170404	0.296
PRKCB	protein	P05771	UNIPROT	EIF6	protein	P56537	UNIPROT	down-regulates activity	phosphorylation	Ser235	QPSTIATsMRDSLID	9606									14654845	t		lperfetto	Our results show that release of eIF6 from 60S subunits may operate, in mammalian cells, through a RACK1–PKC betaII pathway. |Loading 60S subunits with eIF6 caused a dose-dependent translational block and impairment of 80S formation, which were reversed by expression of RACK1 and stimulation of PKC in vivo and in vitro. PKC stimulation led to eIF6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eIF6 impaired RACK1/PKC-mediated translational rescue. |S235A eIF6 inhibits ribosomal joining in the presence of RACK1–PKCbetaII	SIGNOR-249245	0.311
KDM6A	protein	O15550	UNIPROT	HOXC8	protein	P31273	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24561908	t		miannu	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260029	0.312
RPS6KB1	protein	P23443	UNIPROT	MRE11	protein	P49959	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr597	SQRGRADtGLETSTR	-1									28967905	t		miannu	MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro.	SIGNOR-265944	0.2
PPP2CB	protein	P62714	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	dephosphorylation	Thr68	SSLETVStQELYSIP	9606									16596250	t			Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation. 	SIGNOR-248582	0.314
(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	ADRA1B	protein	P35368	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257451	0.8
LATS2	protein	Q9NRM7	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates	phosphorylation	Ser89	AQHVRSHsSPASLQL	9606									21808241	t	Together the YAP/TAZ-TEAD complex promotes proliferative and survival programs.	gcesareni	Activated lats1/2 in turn phosphorylate and inhibit yap/taz transcription co-activators	SIGNOR-175787	0.686
SP1	protein	P08047	UNIPROT	CHGA	protein	P10645	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12456801	t	 	 	Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation.	SIGNOR-254273	0.2
NRXN1	protein	P58400	UNIPROT	NLGN2	protein	Q8NFZ4	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							22626543	t		miannu	 The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites	SIGNOR-265453	0.819
CSNK2A1	protein	P68400	UNIPROT	HDAC2	protein	Q92769	UNIPROT	up-regulates	phosphorylation	Ser394	EDAVHEDsGDEDGED	9606									12082111	t		gcesareni	Protein kinase ck2-mediated phosphorylation of hdac2 regulates co-repressor formation, deacetylase activity and acetylation of hdac2 by cigarette smoke and aldehydesstudies using unfractionated cell extracts with ck2 inhibitors suggest that protein kinase ck2 is the major source of hdac2 kinase. Finally, and perhaps most interesting, hdac2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. Together, our data indicate that like many hdacs, hdac2 is regulated by post-translational modification, particularly phosphorylation.	SIGNOR-89937	0.608
STARD8	protein	Q92502	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260519	0.538
KLF4	protein	O43474	UNIPROT	SOD1	protein	P00441	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002104								23370975	f		miannu	 The expression of superoxide dismutase (SOD) 1 in both mRNA and protein levels was found to be decreased by overexpressing KLF4, while increased by knockdown of KLF4	SIGNOR-254545	0.296
LCK	protein	P06239	UNIPROT	MUC1	protein	P15941	UNIPROT	up-regulates activity	phosphorylation	Tyr1229	SSTDRSPyEKVSAGN		BTO:0000661								14766232	t		lperfetto	The present results demonstrate that Lck phosphorylation of MUC1 on Y-46 also increases binding of MUC1 and beta-catenin. The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 and beta-catenin	SIGNOR-249358	0.473
CSNK1E	protein	P49674	UNIPROT	PER3	protein	P56645	UNIPROT	down-regulates activity	phosphorylation	Ser633	GISQCGYsSTIVHVP	9534	BTO:0000298								11865049	t		llicata	The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. 	SIGNOR-250818	0.734
ELOVL1	protein	Q9BW60	UNIPROT	palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	down-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267889	0.8
CD38	protein	P28907	UNIPROT	nicotinamide	smallmolecule	CHEBI:17154	ChEBI	up-regulates quantity	chemical modification			9606									18626062	t		miannu	CD38 is also able to catalyze the degradation of the NAD precursor nicotinamide mono-nucleotide (NMN) into nicotinamide	SIGNOR-264253	0.8
CDK1	protein	P06493	UNIPROT	DCTN6	protein	O00399	UNIPROT	up-regulates activity	phosphorylation	Thr186	KTMKGSStPVKN	-1									23455152	t		lperfetto	Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin‐dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo‐like kinase 1 (Plk1) at kinetochores. 	SIGNOR-264777	0.311
1,2-diacyl-sn-glycero-3-phosphocholine	chemical	CHEBI:57643	ChEBI	1-O-acyl-sn-glycero-3-phosphocholine	chemical	CHEBI:58168	ChEBI	up-regulates quantity	precursor of			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272768	0.8
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270412	0.8
USP16	protein	Q9Y5T5	UNIPROT	Histone H2A	proteinfamily	SIGNOR-PF70	SIGNOR	down-regulates activity	deubiquitination			9606									17914355	t		miannu	 Here we report the identification and functional characterization of the major deubiquitinase for histone H2A, Ubp-M (also called USP16). Ubp-M prefers nucleosomal substrates in vitro, and specifically deubiquitinates histone H2A but not H2B in vitro and in vivo.  This study identifies the major deubiquitinase for histone H2A and demonstrates that H2A deubiquitination is critically involved in cell cycle progression and gene expression.	SIGNOR-277348	0.2
RCAN1	protein	P53805	UNIPROT	Calcineurin	complex	SIGNOR-C155	SIGNOR	down-regulates activity	binding			9606									12554096	t			MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure	SIGNOR-252341	0.623
MRPS18C	protein	Q9Y3D5	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261450	0.687
MYBL2	protein	P10244	UNIPROT	CLU	protein	P10909	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534	BTO:0000298								10770937	t		miannu	Here we show that the human ApoJ/Clusterin gene contains a Myb binding site in its 5' flanking region, which interacts with bacterially synthesized B-MYB protein and mediates B-MYB-dependent transactivation of the ApoJ/Clusterin promoter in transient transfection assays. Endogenous ApoJ/Clusterin expression is induced in mammalian cell lines following transient transfection of a B-MYB cDNA.	SIGNOR-269800	0.278
CDK2	protein	P24941	UNIPROT	ORC2	protein	Q13416	UNIPROT	up-regulates	phosphorylation	Thr226	SAPVGKEtPSKRMKR	9606			SIGNOR-C83						11931757	t		lperfetto	We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.	SIGNOR-116476	0.744
NLK	protein	Q9UBE8	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	down-regulates	phosphorylation	Thr155	SHAVHPLtPLITYSD	9606									12556497	t		gcesareni	Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk.	SIGNOR-97812	0.751
MECP2	protein	P51608	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									25420914	t		Luana	As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1 	SIGNOR-264675	0.295
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	ID2	protein	Q02363	UNIPROT	down-regulates	phosphorylation	Ser5	sPVRSVRK	9606									9029153	t		lperfetto	Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_	SIGNOR-217320	0.37
TNF	protein	P01375	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates activity				9606									8530143	f		andrea cerquone perpetuini	Data from our laboratory demonstrate that the TNF signal transduction pathway-mediating NF-kappa B activation involves two phospholipases, a phosphatidylcholine-specific phospholipase C (PC-PLC) and an endosomal acidic sphingomyelinase (aSMase). The aSMase activation by TNF is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-PLC. SMase and its product ceramide induce degradation of the NF-kappa B inhibitor I kappa B as well as NF-kappa B activation.	SIGNOR-255689	0.666
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	RPTOR	protein	Q8N122	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007			SIGNOR-C3					21071439	t	inferred from 70% family members	lperfetto	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-270032	0.2
ATM	protein	Q13315	UNIPROT	PRKAA2	protein	P54646	UNIPROT	up-regulates activity	phosphorylation	Thr172	SDGEFLRtSCGSPNY										23871434	t		lperfetto	ATM phosphorylates AMPKalpha2 to induce inhibitory phosphorylation of HIPK2|	SIGNOR-275488	0.267
KDM6A	protein	O15550	UNIPROT	HOXA11	protein	P31270	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24561908	t		miannu	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260021	0.266
ICE2	protein	Q659A1	UNIPROT	ELL/ICE2	complex	SIGNOR-C49	SIGNOR	form complex	binding			9606	BTO:0001271								22195968	t		miannu	The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes.	SIGNOR-193603	0.63
XAV939	chemical	CHEBI:62878	ChEBI	TNKS	protein	O95271	UNIPROT	down-regulates activity	chemical inhibition			-1									19759537	t			In biochemical activity assays, XAV939 strongly inhibited TNKS1 and TNKS2, with half-maximal inhibitory concentration values of 0.011 and 0.004 μM, respectively, but displayed much weaker effects on PARP1 and PARP2	SIGNOR-259994	0.8
AKT1	protein	P31749	UNIPROT	PHF20	protein	Q9BVI0	UNIPROT	down-regulates	phosphorylation	Ser291	ELRRRKIsKGCEVPL	9606									22334668	t		llicata	Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function.	SIGNOR-252529	0.533
HTR6	protein	P50406	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257395	0.252
NF2	protein	P35240	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates activity	binding			10090	BTO:0003324								27402866	t	Hippo pathway	Gianni	NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart.	SIGNOR-261956	0.422
NAA20	protein	P61599	UNIPROT	NatB 	complex	SIGNOR-C416	SIGNOR	form complex	binding			9606									18570629	t		miannu	In the present study we present the components of hNatB (human NatB complex). It consists of the Nat3p homologue hNAT3 (human N-acetyltransferase 3) and the Mdm20p homologue hMDM20 (human mitochondrial distribution and morphology 20). They form a stable complex and in vitro display sequence-specific N(alpha)-acetyltransferase activity on a peptide with the N-terminus Met-Asp-. 	SIGNOR-267230	0.9
CDK1	protein	P06493	UNIPROT	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr234	SFKKQEKtPKTPKGP	9606			SIGNOR-C17						12058066	t		gcesareni	Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association.	SIGNOR-89597	0.534
ATM	protein	Q13315	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates activity	phosphorylation	Ser386	DDKITQAsQSQESED	9606	BTO:0000007								19816404	t		lperfetto	These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination	SIGNOR-188408	0.747
2-[4-[3-[2-(trifluoromethyl)-9-thioxanthenylidene]propyl]-1-piperazinyl]ethanol	chemical	CHEBI:93235	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258728	0.8
FBXL17	protein	Q9UF56	UNIPROT	SUFU	protein	Q9UMX1	UNIPROT	down-regulates quantity by destabilization	ubiquitination												27234298	t			Here, we show that Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction	SIGNOR-253545	0.43
MECP2	protein	P51608	UNIPROT	PRPF3	protein	O43395	UNIPROT	up-regulates activity	binding			10090		BTO:0000142							21070191	t		lperfetto	MeCP2 interacts directly with Prpf3 and Sdccag1|Notably, Mecp2308/Y mice, which produce a truncated form of MeCP2 and reproduce many of the classical features of RTT [43], have been shown to have multiple genes that are abnormally spliced in the brain [23]. This suggests the C-terminal portion of MeCP2, which we have identified as the putative Sdccag1 interaction domain, plays a critical role in regulating alternative splicing.	SIGNOR-277691	0.271
PRKCB	protein	P05771	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser273	AGTRRREsLGKKAKR	-1									9677319	t		lperfetto	Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases.	SIGNOR-249005	0.308
STUB1	protein	Q9UNE7	UNIPROT	TAL1	protein	P17542	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000944								17962192	t		miannu	Ubiquitination and degradation of Tal1/SCL are induced by notch signaling and depend on Skp2 and CHIP. CHIP promoted Tal1 degradation with both chaperone binding and ubiquitin ligase activities, which are mediated by its TPR domain and U box, respectively. 	SIGNOR-271393	0.362
OXGR1	protein	Q96P68	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256770	0.2
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	CABLES1	protein	Q8TDN4	UNIPROT	down-regulates activity	binding			-1									25361894	t		miannu	Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex.Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis.	SIGNOR-276758	0.2
EFNB2	protein	P52799	UNIPROT	EPHB3	protein	P54753	UNIPROT	up-regulates	binding			9606									8559144	t		gcesareni	Lerk-5 is a ligand for both elk and hek and induces receptor phosphorylation	SIGNOR-39862	0.879
LPAR6	protein	P43657	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256868	0.2
PFKP	protein	Q01813	UNIPROT	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35.	SIGNOR-266469	0.8
EIF2B2	protein	P49770	UNIPROT	EIF2S2	protein	P20042	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269130	0.74
STOX1	protein	Q6ZVD7	UNIPROT	CNTNAP2	protein	Q9UHC6	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000601								22728895	t		Gianni	In this study we performed chromatin immunoprecipitation coupled to shotgun cloning to discover novel STOX1A target genes. Our results show that CNTNAP2, a member of the neurexin family, is directly downregulated by STOX1A.	SIGNOR-269065	0.2
CAMK2B	protein	Q13554	UNIPROT	GSK3A	protein	P49840	UNIPROT	down-regulates	phosphorylation	Ser21	SGRARTSsFAEPGGG	9606	BTO:0000938								20841359	t		gcesareni	Inhibitory phosphorylation of gsk-3 by camkii couples depolarization to neuronal survival.	SIGNOR-167962	0.295
KIF1C	protein	O43896	UNIPROT	RAB6A	protein	P20340	UNIPROT	up-regulates quantity	relocalization			-1									20360680	t		miannu	Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation.	SIGNOR-266877	0.421
EGFR	protein	P00533	UNIPROT	ERRFI1	protein	Q9UJM3	UNIPROT	up-regulates activity	phosphorylation	Tyr394	KKVSSTHyYLLPERP	10090	BTO:0000944						phosphorylation:Tyr395	KVSSTHYyLLPERPP	26280531	t			"here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src."	SIGNOR-252091	0.66
JAK3	protein	P52333	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation			9606									30029643	t			Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated	SIGNOR-256254	0.785
CHEK1	protein	O14757	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates	phosphorylation	Ser328	INITKPAsVFVQLRR	9606									22152481	t		llicata	Taken together, the above findings suggest that chk1 phosphorylates p50 at s329 and further, that this phosphorylation blocks p50 dna binding.	SIGNOR-195208	0.279
PTPRH	protein	Q9HD43	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	dephosphorylation			9606									28065597	t		miannu	We further found that PTPRH and PTPRB directly dephosphorylate EGFR and repress its downstream signaling.	SIGNOR-277090	0.292
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CACNA1B	protein	Q00975	UNIPROT	up-regulates activity	phosphorylation	Ser446	ADLCAVGsPFARASL	9534									16406008	t		miannu	Thus, Ser-447 on Ca(v)2.2 and Ser-161 and Ser-348 of Ca(v)beta1b appear to be both necessary and sufficient for ERK-dependent modulation of these channels. Together, our data strongly suggest that modulation of neuronal N-type VDCCs by ERK involves phosphorylation of Ca(v)2.2alpha1 and to a lesser extent possibly also Ca(v)beta subunits. On the basis of the evidence presented here, it is therefore suggested that ERK-dependent up-regulation of Cav2.2 channels is primarily mediated by phosphorylation of Ser-447 on the I–II loop of Cav2.2 and possibly also the two SP sites conserved on Cavβs.	SIGNOR-262967	0.2
CERS6	protein	Q6ZMG9	UNIPROT	ceramide	smallmolecule	CHEBI:17761	ChEBI	up-regulates quantity	chemical modification			9606									26887952	t	done	miannu	 Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity. 	SIGNOR-273997	0.8
ARNTL	protein	O00327	UNIPROT	PER3	protein	P56645	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f			Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253630	0.587
CCT6A	protein	P40227	UNIPROT	TRiC	complex	SIGNOR-C539	SIGNOR	form complex	binding			9606									36185250	t		miannu	Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC).	SIGNOR-272865	0.749
PTPRG	protein	P23470	UNIPROT	PDGFRA	protein	P16234	UNIPROT	up-regulates activity	dephosphorylation	Tyr742	KQADTTQyVPMLERK	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254713	0.251
CSNK2A1	protein	P68400	UNIPROT	APEX1	protein	P27695	UNIPROT	up-regulates activity	phosphorylation	Ser123	HQYWSAPsDKEGYSG	9534	BTO:0004055								10023679	t		llicata	Here we demonstrate that APE/Ref-1 is phosphorylated by casein kinase II (CKII). This was shown for both the recombinant APE/Ref-1 protein (Km=0.55 mM) and for APE/Ref-1 expressed in COS cells. Phosphorylation of APE/Ref-1 did not alter the repair activity of the enzyme, whereas it stimulated its redox capability towards AP-1, thus promoting DNA binding activity of AP-1.	SIGNOR-250825	0.499
DOK4	protein	Q8TEW6	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001103;BTO:0000671							12730241	t		gcesareni	Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells.	SIGNOR-101002	0.429
WNT1	protein	P04628	UNIPROT	FZD1	protein	Q9UP38	UNIPROT	up-regulates activity	binding			9606		BTO:0000887;BTO:0001103							22944199	t		gcesareni	Distinctly, wnt1 signals through fzd receptors 1 and 6 in the epaxial domain of the somite, to regulate myf5 expression via the canonical _-catenin pathway	SIGNOR-198843	0.69
AKT2	protein	P31751	UNIPROT	ATP7A	protein	Q04656	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser1466	YSRASINsLLSDKRS	10090									29301787	t		lperfetto	Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466	SIGNOR-272270	0.263
NFATC1	protein	O95644	UNIPROT	PLAUR	protein	Q03405	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23015147	t			Inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays.	SIGNOR-253336	0.2
NLRP1 inflammasome	complex	SIGNOR-C224	SIGNOR	Pyroptosis	phenotype	SIGNOR-PH105	SIGNOR	up-regulates				9606									30166988	f		miannu	Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma.	SIGNOR-260355	0.7
PAX3	protein	P23760	UNIPROT	PITX2	protein	Q99697	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21143873	f		gcesareni	Pitx genes, such as pitx2, which is positively regulated by pax3, have been implicated in myogenesis.	SIGNOR-170343	0.28
TBK1	protein	Q9UHD2	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Ser402	ISNSHPLsLTSDQYK	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178407	0.817
GSK3B	protein	P49841	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates	phosphorylation			9606									17183360	t		lperfetto	Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) .	SIGNOR-217367	0.38
NARS2	protein	Q96I59	UNIPROT	Asn-tRNA(Asn)	smallmolecule	CHEBI:29265	ChEBI	up-regulates quantity	chemical modification			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270464	0.8
GSK3B	protein	P49841	UNIPROT	ARNTL	protein	O00327	UNIPROT	down-regulates	phosphorylation	Ser17	STISDFMsPGPTDLL	9606									20049328	t		lperfetto	Gsk3beta phosphorylates bmal1 specifically on ser 17 and thr 21 and primes it for ubiquitylation. In the absence of gsk3beta-mediated phosphorylation, bmal1 becomes stabilized and bmal1 dependent circadian gene expression is dampened.	SIGNOR-162786	0.392
PLG	protein	P00747	UNIPROT	PLAT	protein	P00750	UNIPROT	up-regulates activity	cleavage	Arg310	QYSQPQFrIKGGLFA	9606		BTO:0000131							1447176	t		lperfetto	The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme 	SIGNOR-263534	0.555
ATP5MC1	protein	P05496	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261409	0.2
EGFR	protein	P00533	UNIPROT	ANXA1	protein	P04083	UNIPROT	up-regulates	phosphorylation	Tyr21	IENEEQEyVQTVKSS	9606									24103589	t		lperfetto	The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf	SIGNOR-202776	0.523
ERN1	protein	O75460	UNIPROT	ERN1	protein	O75460	UNIPROT	up-regulates activity	phosphorylation	Tyr628	EHPNVIRyFCTEKDR	-1									25968568	t		miannu	IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although the conservation of the underlying molecular mechanism is not clear from existing structures. 	SIGNOR-275417	0.2
TGFB1	protein	P01137	UNIPROT	HBA1	protein	P69905	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8142649	f	Regulation	miannu	Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production.	SIGNOR-251798	0.2
AVPR1A	protein	P37288	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256948	0.274
Elongator complex	complex	SIGNOR-C466	SIGNOR	TUBA1C	protein	Q9BQE3	UNIPROT	up-regulates activity	acetylation			9606	BTO:0000007								19185337	t		miannu	Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. 	SIGNOR-269720	0.257
SRF	protein	P11831	UNIPROT	PLAU	protein	P00749	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000161								15514113	f		miannu	 We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1. 	SIGNOR-255227	0.26
ARHGAP23	protein	Q9P227	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260480	0.404
MTOR	protein	P42345	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0000182;BTO:0000018		SIGNOR-C2						15718470	t		lperfetto	The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1	SIGNOR-134185	0.928
IFNW1	protein	P05000	UNIPROT	IFNAR	complex	SIGNOR-C243	SIGNOR	up-regulates activity	binding			9606									11278538	t		miannu	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-260336	0.735
CHEK2	protein	O96017	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity	phosphorylation	Ser293	GSTKRRKsMSGASPK	9606									12676583	t		Manara	Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A	SIGNOR-260836	0.837
COL4A2	protein	P08572	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									12778132	t			Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6)	SIGNOR-254666	0.7
FOXP2	protein	O15409	UNIPROT	RELN	protein	P78509	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000142							25232744	t		miannu	By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets.	SIGNOR-266833	0.374
ARHGAP30	protein	Q7Z6I6	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606									32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260485	0.425
PER2	protein	O15055	UNIPROT	TWIST1	protein	Q15672	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001939								23836662	f	 	miannu	 We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes.	SIGNOR-254153	0.2
PRKCA	protein	P17252	UNIPROT	CTPS1	protein	P17812	UNIPROT	down-regulates	phosphorylation	Thr455	MRLGKRRtLFQTKNS	9606									17463002	t		llicata	These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity.	SIGNOR-154621	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	Translational_regulation	phenotype	SIGNOR-PH202	SIGNOR	up-regulates				9606									17360704	f		gianni	Mutation of rpS6 at Ser(235/236) reveals that phosphorylation of these sites promotes its recruitment to the 7-methylguanosine cap complex, suggesting that Ras/ERK signaling regulates assembly of the translation preinitiation complex. These data demonstrate that RSK provides an mTOR-independent pathway linking the Ras/ERK signaling cascade to the translational machinery.	SIGNOR-268527	0.7
GABA-B receptor	complex	SIGNOR-C336	SIGNOR	GNB/GNG	complex	SIGNOR-C202	SIGNOR	up-regulates activity	binding			9606	BTO:0000938								20655485	t		miannu	The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release.	SIGNOR-265068	0.386
GRK2	protein	P25098	UNIPROT	OPRD1	protein	P41143	UNIPROT	down-regulates activity	phosphorylation	Thr358	ATARERVtACTPSDG	9606	BTO:0000007								11040053	t			GRK2 strongly enhanced agonist-stimulated phosphorylation of the wild-type DOR (WT), but Delta15 or mutant DOR (T358A/T361A/S363G) failed to show any detectable phosphorylation under these conditions. agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus. GRKs are important mediators in agonist-induced opioid receptor phosphorylation and desensitization.	SIGNOR-251457	0.2
USP10	protein	Q14694	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0002181			SIGNOR-C242					21962518	t		lperfetto	Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E)	SIGNOR-260299	0.488
AD/b2 integrin	complex	SIGNOR-C172	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269021	0.7
FSTL1	protein	Q12841	UNIPROT	DIP2A	protein	Q14689	UNIPROT	up-regulates activity	binding			9606	BTO:0005562								20054002	t		miannu	We identified DIP2A as a novel FSTL1-binding partner from the membrane fraction of endothelial cells. Co-immunoprecipitation assays revealed a direct physical interaction between FSTL1 and DIP2A. The work in the current study identifies DIP2A as a novel receptor for FSTL1 that mediates Akt activation and cell survival and function in cardiovascular cells in vitro. 	SIGNOR-266603	0.494
PTMA	protein	P06454	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	binding			9606	BTO:0000567								12522243	t			PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation.	SIGNOR-259079	0.374
IER3	protein	P46695	UNIPROT	PPP2R5C	protein	Q13362	UNIPROT	down-regulates	binding			9606									16456541	t		gcesareni	Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit.	SIGNOR-144309	0.521
MAPK3	protein	P27361	UNIPROT	RRN3	protein	Q9NYV6	UNIPROT	up-regulates	phosphorylation	Ser633	SFDTHFRsPSSSVGS	9606									12620228	t		llicata	Erk-dependent phosphorylation of the transcription initiation factor tif-ia is required for rna polymerase i transcription and cell growth. phosphopeptide mapping and mutational analysis reveals two serine residues (s633 and s649) that are phosphorylated by erk and rsk kinases. Replacement of s649 by alanine inactivates tif-ia, inhibits pre-rrna synthesis, and retards cell growth.	SIGNOR-98980	0.2
SMARCA4	protein	P51532	UNIPROT	Brain-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C486	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270756	0.857
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000567								17615152	t	inferred from 70% family members	gcesareni	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity	SIGNOR-270023	0.2
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1654	SPSYSPTsPSYSPTS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248807	0.849
1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	PRKCE	protein	Q02156	UNIPROT	up-regulates activity	binding			9606									14967450	t	PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine.	lperfetto	The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified.	SIGNOR-242590	0.8
R547	chemical	CID:6918852	PUBCHEM	CDK4	protein	P11802	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259794	0.8
A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269015	0.7
VEGFC	protein	P49767	UNIPROT	NRP2	protein	O60462	UNIPROT	up-regulates	binding			9606	BTO:0000938								16816121	t		gcesareni	The functional importance of the interaction of np2 with the lymphangiogenic growth factors was demonstrated by cointernalization of np2 along with vegfr-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with vegf-c or vegf-d.	SIGNOR-147611	0.739
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser697	QPSTASNsLPEPAKK	9606									10195894	t			Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.	SIGNOR-251282	0.2
KIT	protein	P10721	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity				9606	BTO:0000830								15526160	f		miannu	A number of studies have demonstrated the ability of SCF to activate the Ras-Erk pathway. The adapter protein Grb2 can directly associate with phosphorylated Y703 and Y936 in c-Kit	SIGNOR-254947	0.31
PLK1	protein	P53350	UNIPROT	BRCA2	protein	P51587	UNIPROT	down-regulates activity	phosphorylation	Thr207	TPPTLSStVLIVRNE	9606	BTO:0001938								12815053	t		lperfetto	M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1	SIGNOR-102502	0.556
lisuride	chemical	CHEBI:51164	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9205951	t		miannu	The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively.	SIGNOR-258615	0.8
D-glucitol	smallmolecule	CHEBI:17924	ChEBI	FUS	protein	P35637	UNIPROT	down-regulates activity	relocalization			9606	BTO:0000312								33172210	f			We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne	SIGNOR-262813	0.8
ATG10	protein	Q9H0Y0	UNIPROT	ATG12/5/16L1	complex	SIGNOR-C109	SIGNOR	up-regulates	binding			9606									18704115	t		lperfetto	Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein.	SIGNOR-226699	0.777
STAT3	protein	P40763	UNIPROT	HSPA1A	protein	P0DMV8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19754877	f		miannu	 Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress.	SIGNOR-255240	0.323
PTPN1	protein	P18031	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606									15821101	t			PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3.	SIGNOR-248427	0.569
FYN	protein	P06241	UNIPROT	CTLA4	protein	P16410	UNIPROT	unknown	phosphorylation	Tyr218	CEKQFQPyFIPIN	9606									9973379	t			CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.  Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4. 	SIGNOR-251160	0.762
SMAD1	protein	Q15797	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates	binding			9606									16621789	t		gcesareni	These results identify a potential mechanism whereby bmp-2 antagonizes wnt signaling in osteoblast progenitors by promoting an interaction between smad1 and dvl-1 that restricts beta-catenin activation.	SIGNOR-146131	0.353
PIM2	protein	Q9P1W9	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606	BTO:0000007								16403219	t		miannu	Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.	SIGNOR-250395	0.4
DDX23	protein	Q9BUQ8	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270646	0.717
FOXO1	protein	Q12778	UNIPROT	FBXO32	protein	Q969P5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								15109499	f		miannu	The activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression.	SIGNOR-252069	0.44
AAK1	protein	Q2M2I8	UNIPROT	NUMB	protein	P49757	UNIPROT	up-regulates	phosphorylation	Thr102	LRVVDEKtKDLIVDQ	9606									18657069	t		llicata	Collectively, these observations demonstrate that numb endocytic activity is regulated by aak1 and that phosphorylation may be a critical step in promoting coated pit maturation.	SIGNOR-179606	0.472
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	HK2	protein	P52789	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000192								31435020	t			K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization	SIGNOR-259985	0.2
VCP	protein	P55072	UNIPROT	NPLOC4	protein	Q8TAT6	UNIPROT	up-regulates activity	binding			9606									20442859	t		miannu	These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes.	SIGNOR-252423	0.945
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	IDH1	protein	O75874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25648147	t		miannu	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260088	0.2
PPP3CA	protein	Q08209	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates activity	dephosphorylation	Ser99	PFRGRSRsAPPNLWA	-1									10195903	t		lperfetto	Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.| Bcl-xL did not coimmunoprecipitate with BAD(S75E, S99E) protein (Fig. 2A), regardless of whether it was coexpressed with DCnA/B 	SIGNOR-263740	0.451
SMARCC2	protein	Q8TAQ2	UNIPROT	Muscle cell-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C483	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex.	SIGNOR-270735	0.83
AMFR	protein	Q9UKV5	UNIPROT	MFN2	protein	O95140	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0000298								23427266	t		miannu	Gp78 induces ubiquitylation and proteasomal degradation of Mfn1 and Mfn2.	SIGNOR-272887	0.305
SULT1E1	protein	P49888	UNIPROT	17beta-estradiol 3-sulfate(1-)	smallmolecule	CHEBI:136582	ChEBI	up-regulates quantity	chemical modification			-1									7779757	t		Luana	HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM.	SIGNOR-269751	0.8
CCN2	protein	P29279	UNIPROT	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	up-regulates activity	binding			9606									32928643	t		miannu	CTGF is highly expressed in PDAC tissues, especially in tumor stroma (as shown by immunohistochemistry, CTGF: brown stain). The tumor cell-secreted CTGF promotes pancreatic stellate cell (PSC) proliferation, adhesion, and migration via integrin α5β1, leading to extracellular matrix (ECM) deposition.Pancreatic cancer cells secrete high levels of CTGF that binds to integrin α5β1, promoting PSC proliferation, adhesion, and migration	SIGNOR-277687	0.2
FZD5	protein	Q13467	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates activity	binding			9606									23151663	t		areggio	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. 	SIGNOR-258960	0.692
YY1	protein	P25490	UNIPROT	GDAP1	protein	Q8TB36	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19720140	f		miannu	 Overexpression of YY1 activated the GDAP1 promoter in a reporter gene system as well as increased the level of endogenous mRNA. 	SIGNOR-255618	0.2
NRG3	protein	P56975	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606		BTO:0000887							7477375	t		gcesareni	The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4.	SIGNOR-26251	0.738
CHEK1	protein	O14757	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser216	SGLYRSPsMPENLNR	9606									20068082	t		gcesareni	The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216).	SIGNOR-163158	0.845
VAV1	protein	P15498	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260580	0.74
DCC	protein	P43146	UNIPROT	CACNA1D	protein	Q01668	UNIPROT	up-regulates activity				9606									12827203	t		miannu	DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER.	SIGNOR-268292	0.302
CTDSPL	protein	O15194	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation	Ser250	TGSPAELsPTTLSPV	9606	BTO:0000007								17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248311	0.475
PTPN2	protein	P17706	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates	dephosphorylation	Tyr1235	DMYDKEYySVHNKTG	9606									18819921	t		gcesareni	We have identified ptp1b and tcptp as negative regulators of the hepatocyte growth factor receptor, the met receptor-tyrosine kinase. In vivo, loss of ptp1b or tcptp enhances hepatocyte growth factor-mediated phosphorylation of met.	SIGNOR-181335	0.479
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Thr509	LKRKRRPtSGLHPED	9606	BTO:0000150								17428466	t		lperfetto	Phosphatidylinositol 3-kinase/akt signaling enhances nuclear localization and transcriptional activity of brca1. mutation of threonine 509 in brca1, the site of akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce brca1 nuclear accumulation	SIGNOR-244168	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser528	KPRSSRGsIFTFRRR	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275764	0.2
GNAI1	protein	P63096	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								11099498	t			These findings indicate that both G alpha(i) and G beta gamma stimulate Rac and Cdc42 pathways with lysophosphatidic acid-induced cell spreading on fibronectin	SIGNOR-256531	0.502
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	KDM4B	protein	O94953	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273466	0.8
CBX5	protein	P45973	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	binding			9606							methylation:Lys10	RTKQTARkSTGGKAP	19111658	t		miannu	 A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 	SIGNOR-264489	0.2
NPTX1	protein	Q15818	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates quantity				9606	BTO:0004168;BTO:0003227								31113871	f		lperfetto	We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control	SIGNOR-260410	0.2
PPP2R5B	protein	Q15173	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates	dephosphorylation	Thr308	KDGATMKtFCGTPEY	9606									16495456	t		gcesareni	Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt.	SIGNOR-252615	0.647
PTPN11	protein	Q06124	UNIPROT	CTNNA1	protein	P35221	UNIPROT	down-regulates	dephosphorylation	Tyr148	LADMADVyKLLVQLK	9606									16767162	t		gcesareni	Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals.	SIGNOR-147075	0.41
SIRT7	protein	Q9NRC8	UNIPROT	H3-5	protein	Q6NXT2	UNIPROT	up-regulates activity	deacetylation	Lys38	K-->P										30653310	t		lperfetto	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 	SIGNOR-275885	0.2
1,1-dioxo-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3-one	chemical	CHEBI:93578	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9550290	t		miannu	Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists.	SIGNOR-258891	0.8
EEF2	protein	P13639	UNIPROT	Translational_elongation	phenotype	SIGNOR-PH210	SIGNOR	up-regulates				9606									14709557	f		lperfetto	In mammalian cells, peptide chain elongation requires two main elongation factors, eEF1A and eEF2. 	SIGNOR-269396	0.7
CSNK2A2	protein	P19784	UNIPROT	MS4A1	protein	P11836	UNIPROT	unknown	phosphorylation	Thr250	KEEVVGLtETSSQPK	9606	BTO:0000776								7678037	t		llicata	These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells.	SIGNOR-251013	0.311
ABCA1	protein	O95477	UNIPROT	HDL_assembly	phenotype	SIGNOR-PH61	SIGNOR	up-regulates				9606									23077142	f		miannu	Cholesterol efflux is the first step in the formation of HDL, which is initiated through the action of ATP binding cassette transporter (ABC) A1 on apolipoprotein (apo) A-I that produces nascent HDL (nHDL).	SIGNOR-252109	0.7
OXGR1	protein	Q96P68	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257417	0.2
MEIS2	protein	O14770	UNIPROT	CDKN2A	protein	P42771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								21746878	t		miannu	We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.	SIGNOR-267240	0.2
olanzapine	chemical	CHEBI:7735	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3).	SIGNOR-258834	0.8
AKT1	protein	P31749	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates	phosphorylation			9606		BTO:0000887		SIGNOR-C7					17964260	t		gcesareni	Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300.	SIGNOR-158624	0.685
NODAL	protein	Q96S42	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606	BTO:0004094								15531507	f	Regulation	miannu	Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7.	SIGNOR-256656	0.7
DYRK2	protein	Q92630	UNIPROT	KATNA1	protein	O75449	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser109	VPVERRPsPGPRKRQ	9606	BTO:0000007								19287380	t		miannu	DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d). 	SIGNOR-262847	0.524
BDKRB1	protein	P46663	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257237	0.252
3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine	smallmolecule	CHEBI:15786	ChEBI	4-trimethylammoniobutanal	smallmolecule	CHEBI:18020	ChEBI	up-regulates quantity	precursor of			9606									11802770	t		miannu	 HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine.	SIGNOR-269690	0.8
FAM83G	protein	A6ND36	UNIPROT	CD2AP	protein	Q9Y5K6	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								29175910	t		lperfetto	PAWS1 interacts in a dynamic fashion with the actin/cytoskeletal regulator CD2AP at lamellae|Loss of PAWS1 causes severe defects in F-actin organization and distribution as well as in lamellipodial organization, resulting in impaired cell migration.	SIGNOR-264768	0.354
MYOG	protein	P15173	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	up-regulates	binding			9606		BTO:0001103							17194702	t		lperfetto	Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle	SIGNOR-217740	0.327
ATM	protein	Q13315	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates activity	phosphorylation	Ser395	SQESEDYsQPSTSSS	9606	BTO:0002552								11331603	t		lperfetto	Atm phosphorylates mdm2 on s395 in vitro. Moreover, s395 appears to be phosphorylated in an atm-dependent manner in vivo the precise mechanism through which s395 phosphorylation attenuates mdm2 function is unclear.	SIGNOR-107256	0.747
LY-2157299	chemical	CHEBI:137064	ChEBI	TGFBR1	protein	P36897	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193775	0.8
FURIN	protein	P09958	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000666								25527501	t		Giorgia	Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation.	SIGNOR-260365	0.287
PTPRC	protein	P08575	UNIPROT	TYK2	protein	P29597	UNIPROT	down-regulates activity	dephosphorylation	Tyr1055	VPEGHEYyRVREDGD	10090									11201744	t			CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells 	SIGNOR-248358	0.416
ASH2L	protein	Q9UBL3	UNIPROT	GATA3	protein	P23771	UNIPROT	up-regulates	binding			9606	BTO:0000150								25258321	t		miannu	We identifiedgata3as the binding protein of ash2l. Ash2l was shown to potentiate the transcriptional activity ofgata3.	SIGNOR-205312	0.252
adrenaline	smallmolecule	CHEBI:33568	ChEBI	ADRB1	protein	P08588	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)	SIGNOR-257876	0.8
MAFA	protein	Q8NHW3	UNIPROT	PCSK1	protein	P29120	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17149590	f		miannu	 the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA.	SIGNOR-254566	0.291
COX7C	protein	P15954	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267754	0.772
PHLPP2	protein	Q6ZVD8	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates activity	dephosphorylation	Thr387	TMKRRDEtMQPAKPS	9606									20513427	t			PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis.	SIGNOR-248730	0.2
ROCK1	protein	Q13464	UNIPROT	ARHGAP35	protein	Q9NRY4	UNIPROT	down-regulates	phosphorylation	Ser1236	PKPKPRPsITKATWE	9606		BTO:0000887;BTO:0001260							19103606	t		acerquone	Here we show that rho-kinase, an effector of rhoa, phosphorylated p190a rhogap at ser1150 and attenuated p190a rhogap activity in cos7 cells	SIGNOR-182853	0.425
RPS6KA4	protein	O75676	UNIPROT	RPS6KA4	protein	O75676	UNIPROT	up-regulates activity	phosphorylation	Ser196	EEKERTFsFCGTIEY	9606	BTO:0002181								19933278	t		miannu	Here we report that the CK2 protein kinase, which contributes to NF-kappaB activation following UV radiation in a p38-dependent manner, physically interacts with MSK2 but not MSK1 and that CK2 inhibition specifically impairs UV-induced MSK2 kinase activation. A putative site of CK2 phosphorylation was mapped to MSK2 residue Ser(324) and when substituted to alanine (S324A) also compromised MSK2 activity.Serine 324 is required for UV-induced MSK2 activation and for autophosphorylation at MSK2-Ser196. 	SIGNOR-276269	0.2
YWHAQ	protein	P27348	UNIPROT	MEF2D	protein	Q14814	UNIPROT	up-regulates	binding			9606									11433030	t		gcesareni	14-3-3tau associates with and activates the mef2d transcription factor during muscle cell differentiation.	SIGNOR-109139	0.565
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser111	SPPSPAPsSFSSTSV	9606									20305697	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-164625	0.575
PRKCG	protein	P05129	UNIPROT	ARHGEF7	protein	Q14155	UNIPROT	up-regulates	phosphorylation	Ser518	LSASPRMsGFIYQGK	9606									25009260	t		lperfetto	Pkc_ directly phosphorylates _pix at ser583 and indirectly at ser340 in cells. herefore, we propose that pkc_ positively modulates dopamine release through _2pix phosphorylation. The pkc_-_pix-cdc42/rac1 phosphorylation axis may provide a new therapeutic target for the treatment of parkinsonian syndrome	SIGNOR-205234	0.2
ACLY	protein	P53396	UNIPROT	ADP(3-)	smallmolecule	CHEBI:456216	ChEBI	up-regulates quantity	chemical modification			9606									19286649	t		miannu	ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor.	SIGNOR-268080	0.8
OSBP2	protein	Q969R2	UNIPROT	cholesterol	smallmolecule	CHEBI:16113	ChEBI	up-regulates quantity	relocalization												30925160	t		lperfetto	CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.	SIGNOR-264879	0.8
SLC4A1	protein	P02730	UNIPROT	4.1 complex	complex	SIGNOR-C386	SIGNOR	form complex	binding			9606	BTO:0000424								33187473	t		lperfetto	The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]	SIGNOR-266036	0.386
APC-c	complex	SIGNOR-C150	SIGNOR	USP37	protein	Q86T82	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								21596315	t		lperfetto	USP37 is ubiquitinated by APCCDH1 in late mitosis and early G1 phase||Inactive USP37 now becomes a substrate for APCCDH1, undergoing K11-linked polyubiquitination and proteasomal degradation. Elimination of USP37 ensures that it does not antagonize APC/C substrate degradation during mitosis.	SIGNOR-265048	0.294
TRIM41	protein	Q8WV44	UNIPROT	PRKCB	protein	P05771	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								17893151	t		miannu	RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. The RINCK-mediated ubiquitination is likely to be polyubiquitination, because the ubiquitinated PKCβII was detected as a high molecular weight smear. 	SIGNOR-271667	0.322
GATA4	protein	P43694	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606	BTO:0001086								32376282	f		miannu	HYDIN promotes expression of Gata4 in cardiomyocyte differentiation. HYDIN functions as a positive regulator of human cardiomyocyte differentiation and promotes expression of cardiac contractile genes in hESC cells. This is mediated through GATA4, a critical transcription factor in heart development. Cardiac-specific Hydin knockdown in vivo leads to Gata4 downregulation and enhanced atrial septal defect (ASD) risk in mice. GATA4 is a fundamental TF in embryonic heart development and cardiac differentiation, and reduction in GATA4 function results in a diverse range of CHDs	SIGNOR-265480	0.7
TXK	protein	P42681	UNIPROT	TXK	protein	P42681	UNIPROT	up-regulates	phosphorylation	Tyr91	KIQVKALyDFLPREP	9606									12081135	t		lperfetto	Evidence of autophosphorylation in txk: y91 is an autophosphorylation site. the results suggest that phosphorylated txk is an active form to promote ifn-gamma synthesis	SIGNOR-89844	0.2
PIM1	protein	P11309	UNIPROT	SKP2	protein	Q13309	UNIPROT	up-regulates activity	phosphorylation	Thr417	WGIKCRLtLQKPSCL	9606									20663873	t		miannu	We found that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser(64) and Ser(72), we have identified Thr(417) as a unique Pim-1 phosphorylation target. Phosphorylation of Thr(417) controls the stability of Skp2 and its ability to degrade p27. 	SIGNOR-259817	0.346
Ethylketocyclazocine	chemical	CHEBI:4901	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258782	0.8
PAK1	protein	Q13153	UNIPROT	PREX2	protein	Q70Z35	UNIPROT	down-regulates activity	phosphorylation	Ser1107	DTISNRDsYSDCNSN	9606	BTO:0000007								26438819	t		miannu	P21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. 	SIGNOR-277181	0.375
HDAC3	protein	O15379	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates	binding			9606									23213415	t		gcesareni	Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes.	SIGNOR-199961	0.474
TP63	protein	Q9H3D4	UNIPROT	PLEC	protein	Q15149	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									28595999	t		lperfetto	Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets.	SIGNOR-263279	0.2
androsta-1,4,6-triene-3,17-dione	chemical	CHEBI:131190	ChEBI	CYP19A1	protein	P11511	UNIPROT	down-regulates activity	chemical inhibition			-1									7083195	t		miannu	Recently, it was discovered that 4-hydroxy-4-androstene-3,17-dione, 4-androstene-3,6,17-trione, and 1,4,6-androstatriene-3,17-dione, compounds previously reported to be competitive inhibitors of aromatase, cause a time-dependent loss of aromatase activity in human placental microsomes.	SIGNOR-258408	0.8
4,4'-sulfonyldiphenol	chemical	CHEBI:34372	ChEBI	AR	protein	P10275	UNIPROT	down-regulates activity	chemical inhibition			-1									31995776	t		miannu	This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . 	SIGNOR-268733	0.8
STAT5A	protein	P42229	UNIPROT	PIM2	protein	Q9P1W9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15769897	t			The serine-threonine kinase Pim-2 is a functionally relevant downstream target of STAT5. Here, we observed only a weak induction of Pim-2 by Flt3-D835Y compared to the effects of Flt3-ITD.	SIGNOR-261543	0.422
CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	DBP	protein	Q10586	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000759							30100984	t		miannu	The albumin D-box binding protein (DBP) is a member of the PAR bZip (proline and acidic amino acid-rich basic leucine zipper) transcription factor family and functions as important regulator of circadian core and output gene expression. Gene expression of DBP itself is under the control of E-box-dependent binding by the Bmal1-Clock heterodimer and CRE-dependent binding by the cAMP responsive element binding protein (CREB).	SIGNOR-268029	0.701
CRY1	protein	Q16526	UNIPROT	BMAL1/NPAS2	complex	SIGNOR-C431	SIGNOR	down-regulates activity	binding			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop.	SIGNOR-267971	0.891
PTPN11	protein	Q06124	UNIPROT	SPRY1	protein	O43609	UNIPROT	down-regulates	dephosphorylation			9606									16481357	t		gcesareni	These results identify sprouty proteins as in vivo targets of corkscrew/shp-2 tyrosine phosphatases and show how corkscrew/shp-2 proteins can promote rtk signaling by inactivating a feedback inhibitor.	SIGNOR-144547	0.419
gemfibrozil	chemical	CHEBI:5296	ChEBI	PPARA	protein	Q07869	UNIPROT	up-regulates activity	chemical activation			9606									21889235	t		Luana	 The combination of stilbene scaffold and gemfibrozil enhances the PPARα agonistic activity.	SIGNOR-258318	0.8
PIK3CG	protein	P48736	UNIPROT	PIP3	smallmolecule	CHEBI:16618	ChEBI	up-regulates	chemical modification			9606									16847462	t		gcesareni	The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2)	SIGNOR-147954	0.8
GNAI2	protein	P04899	UNIPROT	ADCY1	protein	Q08828	UNIPROT	down-regulates activity	binding			9606									19703466	t			Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma)	SIGNOR-256499	0.579
PRKCA	protein	P17252	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	phosphorylation	Ser498	RPLSRTQsSPLPQSP	10116	BTO:0002320								15367659	t		lperfetto	We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. | Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E	SIGNOR-249269	0.2
CDH2	protein	P19022	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265864	0.812
AMPK	complex	SIGNOR-C15	SIGNOR	KPNA2	protein	P52292	UNIPROT	up-regulates	phosphorylation	Ser105	QAARKLLsREKQPPI	9606									15342649	t		lperfetto	Ampk phosphorylated importin alpha1 on ser(105). Accordingly, expression of importin alpha1 proteins bearing k22r or s105a mutations failed to mediate the nuclear import of hur in intact cells. Our results point to importin alpha1 as a critical downstream target of ampk and key mediator of ampk-triggered hur nuclear import.	SIGNOR-216449	0.2
PAX3-FOXO1	fusion protein	SIGNOR-FP12	SIGNOR	MET	protein	P08581	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25211658	t		miannu	Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA.	SIGNOR-251570	0.2
PRKCD	protein	Q05655	UNIPROT	ITGB2	protein	P05107	UNIPROT	unknown	phosphorylation	Thr758	NPLFKSAtTTVMNPK	9606	BTO:0000751								11700305	t		lperfetto	Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |	SIGNOR-249124	0.334
BPTF	protein	Q12830	UNIPROT	HNuRF	complex	SIGNOR-C448	SIGNOR	form complex	binding			9606	BTO:0000007								14609955	t		miannu	 hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays.	SIGNOR-268817	0.689
SRC	protein	P12931	UNIPROT	INPPL1	protein	O15357	UNIPROT	up-regulates	phosphorylation	Tyr987	SFNNPAYyVLEGVPH	9606									12235291	t		lperfetto	Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo.	SIGNOR-92935	0.551
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	ITGB3	protein	P05106	UNIPROT	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259002	0.2
HOXD3	protein	P31249	UNIPROT	ITGA5	protein	P08648	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14610084	t		Luana	The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis.	SIGNOR-261649	0.253
SMURF1	protein	Q9HCE7	UNIPROT	ILRUN	protein	Q9H6K1	UNIPROT	unknown	ubiquitination			-1									20804422	t		miannu	Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay.	SIGNOR-272697	0.2
ABL1	protein	P00519	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates activity	phosphorylation	Tyr564	SKHKEDVyENLHTKN	9606									8692915	t		Manara	The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites.	SIGNOR-260821	0.423
PAK2	protein	Q13177	UNIPROT	MYLK	protein	Q15746	UNIPROT	down-regulates activity	phosphorylation	Ser1760	RAIGRLSsMAMISGL	-1									10748018	t		miannu	PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991.	SIGNOR-250223	0.512
P2RY14	protein	Q15391	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257002	0.25
BCL2L11	protein	O43521	UNIPROT	BAK1	protein	Q16611	UNIPROT	up-regulates	binding			9606									22492984	t		gcesareni	Bim, and puma bind with high affinity to all pro-survival proteins	SIGNOR-196932	0.83
DYRK1A	protein	Q13627	UNIPROT	SNCA	protein	P37840	UNIPROT	up-regulates	phosphorylation	Ser87	KTVEGAGsIAAATGF	9606	BTO:0000938								16959772	t		lperfetto	In vitro kinase assay of anti-dyrk1a immunocomplexes demonstrated that dyrk1a could phosphorylate alpha-synuclein at ser-87. Furthermore, aggregates formed by phosphorylated alpha-synuclein have a distinct morphology and are more neurotoxic compared with aggregates composed of unmodified wild type alpha-synuclein. These findings suggest alpha-synuclein inclusion formation regulated by dyrk1a, potentially affecting neuronal cell viability.	SIGNOR-149393	0.579
MAPK8	protein	P45983	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates	phosphorylation	Ser82	SIMQQCDsPHVVKYY	9606									20028971	t		llicata	C-jun n-terminal kinase enhances mst1-mediated pro-apoptotic signaling through phosphorylation at serine 82.	SIGNOR-162327	0.271
TLR2	protein	O60603	UNIPROT	TIRAP	protein	P58753	UNIPROT	up-regulates activity	binding			10090									22664090	t		scontino	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266745	0.716
4-(trimethylammonio)butanoate	smallmolecule	CHEBI:16244	ChEBI	carnitine	smallmolecule	CHEBI:17126	ChEBI	up-regulates quantity	precursor of			9606									11802770	t		miannu	In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine.	SIGNOR-269701	0.8
ROS	stimulus	SIGNOR-ST2	SIGNOR	FOXL2	protein	P58012	UNIPROT	up-regulates quantity by expression				9606									19010791	f		miannu	Transcriptional upregulation of foxl2 during oxidative and heat stress	SIGNOR-182303	0.7
MTTP	protein	P55157	UNIPROT	APOB	protein	P04114	UNIPROT	up-regulates activity	lipidation			9606									23721961	t		miannu	As ApoB is translated, it is lipidated by microsomal triglyceride transfer protein (MTP). MTP adds triglycerides to the nascent ApoB during its co-translational translocation into the lumen of the endoplasmic reticulum.	SIGNOR-252118	0.786
AFF1	protein	P51825	UNIPROT	AEP complex	complex	SIGNOR-C117	SIGNOR	form complex	binding			9606	BTO:0000664								20153263	t	1	miannu	These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells.	SIGNOR-239231	0.471
LAS1L	protein	Q9Y4W2	UNIPROT	Rix1 complex	complex	SIGNOR-C373	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								22190735	t		miannu	LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes.	SIGNOR-265467	0.843
E2F1	protein	Q01094	UNIPROT	USP37	protein	Q86T82	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21596315	t		lperfetto	USP37 was induced by E2F transcription factors in G1|Ectopic E2F1 activated the wild-type promoter, but not the mutant promoter, 3-fold over basal levels in 293T cells (Figure 4F), confirming the functionality of the E2F binding sites in the USP37 promoter.	SIGNOR-265047	0.2
PBX1	protein	P40424	UNIPROT	CDKN2A	protein	P42771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								21746878	t		miannu	We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.	SIGNOR-267239	0.314
BVES	protein	Q8NE79	UNIPROT	VAMP3	protein	Q15836	UNIPROT	up-regulates activity	binding			-1									20057356	t		llicata	Taken together, these data demonstrate that Bves interacts with VAMP3 and facilitates receptor recycling both in vitro and during early development.	SIGNOR-237771	0.432
PHLPP1	protein	O60346	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0001544								19261608	t			The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.	SIGNOR-248327	0.752
GRK2	protein	P25098	UNIPROT	RPLP2	protein	P05387	UNIPROT	up-regulates	phosphorylation	Ser105	KKEESEEsDDDMGFG	9606									12379128	t		gcesareni	The phosphorylation sites in grk2-phosphorylated p2 are identified (s102 and s105) and are identical to the sites known to regulate p2 activity.	SIGNOR-94258	0.2
NFKB1	protein	P19838	UNIPROT	NPPB	protein	P16860	UNIPROT	unknown	transcriptional regulation												15837525	f	 	 	In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription.	SIGNOR-253648	0.2
CDK2	protein	P24941	UNIPROT	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr234	SFKKQEKtPKTPKGP	10090			SIGNOR-C16						11278991	t		lperfetto	We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. Upon phosphorylation by CDK2-cyclin E, NPM/B23 dissociates from centrosomes, which is a prerequisite step for centrosomes to initiate duplication.	SIGNOR-235725	0.578
EGFR	protein	P00533	UNIPROT	CRK	protein	P46108	UNIPROT	down-regulates activity	phosphorylation	Tyr221	GGPEPGPyAQPSVNT	9606	BTO:0000007								9642287	t		llicata	To address these questions, we have developed an antibody that specifically recognizes the CrkII protein phosphorylated on Tyr221, and we found that the EGF receptor directly phosphorylates CrkII on Tyr221. Furthermore, we observed that the phosphorylation of Tyr221 of CrkII correlated with its dissociation from the EGF receptor, implicating the phosphorylation of Tyr221 in the negative feedback of binding to the EGF receptor.	SIGNOR-251091	0.732
CAPN2	protein	P17655	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Val58	KGVTVETvFSVDEFS	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263583	0.301
MTOR	protein	P42345	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	phosphorylation	Ser616	PIPIMPAsPQKGHAV	9606	BTO:0000661								34535949	t		Barakat	Furthermore, we confirmed also in Jurkat cells that the specific silencing of both ERK1/2 and mTOR by siRNA downregulates Drp1 phosphorylation on Ser616	SIGNOR-275430	0.352
STK11	protein	Q15831	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	up-regulates	phosphorylation			-1									14614828	t		lperfetto	We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli	SIGNOR-217469	0.595
FASTKD5	protein	Q7L8L6	UNIPROT	COX4I1	protein	P13073	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25683715	f		miannu	FASTKD5 is required for maturing precursor mRNAs that are not flanked by tRNAs and that therefore cannot be processed by the canonical mRNA maturation pathway. Silencing FASTKD5 rendered mature COX I mRNA almost undetectable, which severely reduced the synthesis of COX I, resulting in a complex IV assembly defect. 	SIGNOR-261223	0.2
CSNK2A1	protein	P68400	UNIPROT	SNAI1	protein	O95863	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser11	SFLVRKPsDPNRKPN	9606									19923321	t		lperfetto	Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively.	SIGNOR-161771	0.354
ROCK1	protein	Q13464	UNIPROT	ARHGAP24	protein	Q8N264	UNIPROT	up-regulates activity	phosphorylation	Thr576	NSCRSSTtTCPEQDF	9606	BTO:0000007								16862148	t		lperfetto	ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2).	SIGNOR-249300	0.444
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MTOR	protein	P42345	UNIPROT	unknown	phosphorylation	Ser2448	RSRTRTDsYSAGQSV	9606									10910062	t		lperfetto	AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR. 	SIGNOR-244311	0.2
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGB2	protein	Q9Y5G2	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265710	0.2
DHFR	protein	P00374	UNIPROT	(6S)-5,6,7,8-tetrahydrofolate(2-)	smallmolecule	CHEBI:57453	ChEBI	up-regulates quantity	chemical modification			9606									21876184	t		lperfetto	Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. 	SIGNOR-268258	0.8
D-glucopyranose	smallmolecule	CHEBI:4167	ChEBI	UDP(3-)	smallmolecule	CHEBI:58223	ChEBI	up-regulates quantity	precursor of			9606									16157350	t		miannu	Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 	SIGNOR-268472	0.8
FUS	protein	P35637	UNIPROT	DDX3X	protein	O00571	UNIPROT	down-regulates activity	relocalization			9606									27460707	t	P35637:p.Pro525Leu (mutation causing interaction)		We found that ALS mutants of FUS co-localized with Caprin-1, DDX3X, and DHX9 in cytoplasmic inclusions that could lead to the mis-regulation of their respective pathways, providing further clues to the mechanism of ALS pathogenesis.|FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. | We also demonstrated the co-localization of DHX9, DDX3X and Caprin-1 with cytoplasmic EGFP-P525L mutant FUS inclusions in primary cortical neurons	SIGNOR-262811	0.259
PLAG1	protein	Q6DJT9	UNIPROT	ABCC6	protein	O95255	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007;BTO:0000599								18850323	f		miannu	We identified ABCC6 as a target gene for transcriptional induction by PLAG1 and PLAGL1, transcription factors from the PLAG family of cell cycle progression-related DNA-binding proteins. Both these factors are shown to bind to the same single consensus-binding element in the ABCC6 proximal promoter in cell lines of hepatic and renal origin by reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation. PLAG-mediated ABCC6 transactivation may play an important role in determining the level of tissue-specific expression of this gene. The described mechanism can also find potential application in therapeutic interventions in forms of PXE related to impaired ABCC6 expression.	SIGNOR-254925	0.39
NCOR2	protein	Q9Y618	UNIPROT	SPEN	protein	Q96T58	UNIPROT	up-regulates	binding			9606									11331609	t		gcesareni	Sharp is a potent transcriptional repressor whose repression domain (rd) interacts directly with smrt	SIGNOR-107260	0.48
IL6ST	protein	P40189	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation	Tyr1008	LPQDKEYyKVKEPGE	9606									9716487	t		lperfetto	All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59].	SIGNOR-238634	0.624
TGFB1	protein	P01137	UNIPROT	CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	down-regulates activity				9606									10611320	f		lperfetto	Tgf-beta treatment resulted in the specific inactivation of cyclin cdk2 complexes caused by absence of the activating thr(160) phosphorylation on cdk2.	SIGNOR-217502	0.279
EEF1A1	protein	P68104	UNIPROT	Val-tRNA(Val)	smallmolecule	CHEBI:29164	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269519	0.8
Calcineurin	complex	SIGNOR-C155	SIGNOR	BAD	protein	Q92934	UNIPROT	up-regulates activity	dephosphorylation	Ser75	EIRSRHSsYPAGTED	9606	BTO:0000007								10195903	t			Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.	SIGNOR-252324	0.412
WNT7A	protein	O00755	UNIPROT	SPRY4	protein	Q9C004	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002058								15705594	f		miannu	In NSCLC cells, Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not beta-catenin/T cell factor activity.	SIGNOR-253034	0.279
UBE2J1	protein	Q9Y385	UNIPROT	DIO2	protein	Q92813	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys244	KIAYLGGkGPFSYNL	9606		BTO:0001379							29892818	t		scontino	ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244.	SIGNOR-267482	0.387
INSR	protein	P06213	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr447	SEELDENyVPMNPNS	10090									10978177	t			HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin	SIGNOR-251313	0.492
CASP8	protein	Q14790	UNIPROT	Caspase 8 complex	complex	SIGNOR-C231	SIGNOR	form complex	binding								cleavage:Asp216	SDSPREQdSESQTLD			10508785	t		lperfetto	Activated caspase-8 (an alpha2beta2 heterotetramer) activates other downstream caspases that are incapable of autocatalytic processing and activation. |The alphabeta dimeric protein associates further to form an alpha2beta2 heterotetramer that appears to be required for catalytic activity.	SIGNOR-256395	0.2
SRPK1	protein	Q96SB4	UNIPROT	RBM8A	protein	Q9Y5S9	UNIPROT	down-regulates	phosphorylation	Ser166	RRGGRRRsRSPDRRR	9606									16100109	t		gcesareni	We demonstrate that y14 is phosphorylated at its repeated arginine/serine (rs) dipeptides, likely by sr protein-specific kinases. Phosphorylation of y14 abolished its interaction with ejc components as well as factors that function downstream of the ejc.	SIGNOR-139551	0.264
TNF	protein	P01375	UNIPROT	TNFRSF1A	protein	P19438	UNIPROT	up-regulates activity	binding			9606									23070005	t		miannu	For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. 	SIGNOR-199091	0.923
MAPK1	protein	P28482	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606		BTO:0000763;BTO:0000149							10197981	t		llicata	Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain.	SIGNOR-66742	0.736
CDK5	protein	Q00535	UNIPROT	PP1	proteinfamily	SIGNOR-PF54	SIGNOR	down-regulates activity	phosphorylation			9606									12202491	t		lperfetto	Pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. Increasing doses of cdk2 resulted in increased phosphorylation of the thr-320 site. Phosphorylation of this site in pp1 corresponded to decreased pp1 activity.	SIGNOR-264649	0.484
SMURF1	protein	Q9HCE7	UNIPROT	TGFBR2	protein	P37173	UNIPROT	down-regulates activity	ubiquitination			9606									22298955	t		lperfetto	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-195672	0.598
MAPK8IP2	protein	Q13387	UNIPROT	MAPK8IP1	protein	Q9UQF2	UNIPROT	up-regulates	binding			9606									10490659	t		gcesareni	Deletion analysis demonstrated that the cooh-terminal regions of jip1 and jip2 were sufficient for the formation of hetero-oligomeric complexes	SIGNOR-70863	0.643
vismodegib	chemical	CHEBI:66903	ChEBI	SMO	protein	Q99835	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001271								21041712	t		gcesareni	Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date.	SIGNOR-169194	0.8
KHK	protein	P50053	UNIPROT	PRPS1	protein	P60891	UNIPROT	up-regulates activity	phosphorylation	Thr225	LVDDMADtCGTICHA										29074724	t		lperfetto	Ketohexokinase-A (KHK-A; also known as fructokinase-A) phosphorylates PRPS1 T225 and activates PRPS1 by blocking the binding of ADP, AMP, and GDP, which is required for hepatocellular carcinoma development	SIGNOR-265735	0.355
ABL1	protein	P00519	UNIPROT	RBM39	protein	Q14498	UNIPROT	up-regulates activity	phosphorylation	Tyr99	RGRYRSPySGPKFNS	9606	BTO:0000007								27018250	t		miannu	In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner.	SIGNOR-262610	0.329
SNTB1	protein	Q13884	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255992	0.497
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1654	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269338	0.718
PRKCD	protein	Q05655	UNIPROT	RPS3	protein	P23396	UNIPROT	up-regulates	phosphorylation	Ser6	sKKRKFVA	9606									15950189	t		lperfetto	It has been shown previously that ribosomal protein s3 (rps3)	SIGNOR-137967	0.2
3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea	chemical	CHEBI:91362	ChEBI	AURKA	protein	O14965	UNIPROT	down-regulates activity	chemical inhibition			9606									19567821	t		miannu	The protein kinases, Aurora A, B, and C have critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. GSK1070916, is a novel ATP competitive inhibitor that is highly potent and selective for Aurora B/C kinases. 	SIGNOR-262225	0.8
BCL9	protein	O00512	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	binding			9606	BTO:0000776								11955446	t		amattioni	Bcl9 exert its function by physically linking pygo to beta-catenin. The recruitment of pygo permits beta-catenin to transcriptionally activate wnt target genes.	SIGNOR-116552	0.936
RERE	protein	Q9P2R6	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	binding			9606	BTO:0000932								28144959	t		miannu	In mammalian cells, RERE co‐immunoprecipitates with CBF1 and Notch intracellular domain (NICD), and is recruited to nuclear foci formed by over‐expressed NICD1. RERE is also necessary for NICD to activate the expression of Notch target genes. 	SIGNOR-264486	0.324
sedoheptulose 7-phosphate	smallmolecule	CHEBI:15721	ChEBI	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	up-regulates quantity	precursor of			9606									19401148	t		miannu	Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 	SIGNOR-268133	0.8
haloperidol	chemical	CHEBI:5613	ChEBI	HTR2A	protein	P28223	UNIPROT	down-regulates activity	chemical inhibition			10090	BTO:0000331								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258520	0.8
LNX1	protein	Q8TBB1	UNIPROT	NUMB	protein	P49757	UNIPROT	down-regulates	ubiquitination			9606									11782429	t		esanto	Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation.	SIGNOR-112201	0.73
axitinib	chemical	CHEBI:66910	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150								21297102	t		gcesareni	Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (rcc) after failure of prior treatment with sunitinib or a cytokine.	SIGNOR-171863	0.8
NUMB	protein	P49757	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates	binding			9606									20818436	t		gcesareni	The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation.	SIGNOR-167841	0.607
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	RARG	protein	P13631	UNIPROT	up-regulates activity	chemical activation			9606									17132853	t		miannu	The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 	SIGNOR-256196	0.8
CTSL	protein	P07711	UNIPROT	BGLAP	protein	P02818	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly58	RYLYQWLgAPVPYPD	-1									9076588	t		miannu	This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 	SIGNOR-256321	0.2
SMURF2	protein	Q9HAU4	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0001538								11158580	t		miannu	Here, we report the identification of Smurf2, a new member of the Hect family of E3 ubiquitin ligases. Smurf2 selectively interacts with receptor-regulated Smads and preferentially targets Smad1 for ubiquitination and proteasome-mediated degradation. At higher expression levels, Smurf2 also decreases the protein levels of Smad2, but not Smad3. 	SIGNOR-272936	0.713
PDGFRB	protein	P09619	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr194	ALEKKSNyEVLEKDV	9606									20802513	t		llicata	In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.	SIGNOR-167658	0.537
NMDA	proteinfamily	SIGNOR-PF56	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). In contrast, group I mGluRs increase the intracellular Ca2+ concentration via a classical Gq-mediated mechanism that triggers release from intracellular stores through IP3 receptors 	SIGNOR-264931	0.8
SIK2	protein	Q9H0K1	UNIPROT	CEP250	protein	Q9BV73	UNIPROT	unknown	phosphorylation	Ser2394	LHHSLSHsLLAVAQA	9606									20708153	t		lperfetto	Remarkably, lc-ms confirmed that the predominant serine phosphorylation site of the recombinant carboxy-terminal domain of c-nap1 is s2392 at the predicted consensus phosphorylation sequence and to a lesser extent s2394.	SIGNOR-167492	0.326
Obatoclax mesylate	chemical	CID:46930996	PUBCHEM	BCL2	protein	P10415	UNIPROT	down-regulates activity	chemical inhibition			-1									23515850	t		lperfetto	Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro	SIGNOR-262022	0.8
TERB1	protein	Q8NA31	UNIPROT	TERF1	protein	P54274	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000007		SIGNOR-C305	SIGNOR-C306					33015044	t		lperfetto	The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1	SIGNOR-263315	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	WEE1	protein	P30291	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser123	EEGFGSSsPVKSPAA										23051732	t		lperfetto	Cdk1 phosphorylates Wee1 on Ser-123, which primes additional phosphorylation by other kinases, leading to the formation of phosphodegrons responsible for SCF (Skp1/cullin/F-box) ubiquitin-mediated degradation of Wee1 	SIGNOR-267471	0.777
STK3	protein	Q13188	UNIPROT	SAV1	protein	Q9H4B6	UNIPROT	up-regulates	phosphorylation			-1	BTO:0000007								16930133	t		milica	In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav	SIGNOR-230716	0.827
GSK3A	protein	P49840	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	phosphorylation	Thr254	RQVAIVFRtPPYADPS	10090	BTO:0000249								22761446	t			Redundant functions of GSK-3_ and GSK-3_ through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation	SIGNOR-255827	0.2
FLI1	protein	Q01543	UNIPROT	HOXA10	protein	P31260	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001549								17688409	f		miannu	Transcription factors GATA-1 and Fli-1 regulate human HOXA10 expression in megakaryocytic cells. Mutation of the GATA-1 and the Ets-1 motifs amplified the expression of HOXA10 in HEL and K562 cells, confirming the importance of these cis-acting elements in regulating HOXA10 expression in megakaryocytic cells. Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression. 	SIGNOR-254471	0.2
CSNK1G1	protein	Q9HCP0	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation	Thr1479	SSSSTKGtYFPAILN	9606									16341016	t		gcesareni	Ck1gamma is associated with lrp6, which has multiple, modular ck1 phosphorylation sites. Wnt treatment induces the rapid ck1gamma-mediated phosphorylation of these sites within lrp6	SIGNOR-143029	0.527
BID	protein	P55957	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates	binding			9606									15574335	t		gcesareni	We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma	SIGNOR-131442	0.818
IDE	protein	P14735	UNIPROT	INS	protein	P01308	UNIPROT	down-regulates quantity by destabilization	cleavage			-1									29596046	t		SARA	IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds	SIGNOR-260986	0.743
MMP2	protein	P08253	UNIPROT	LRP2	protein	P98164	UNIPROT	up-regulates quantity	binding			10116									28659595	t		miannu	We show that megalin/LRP-2 acts as an endocytic receptor for proMMP-2:TIMP-2 complex. We found that RAP, an antagonist of the LDL receptor family18, competed with binding of proMMP-2:TIMP-2 complex onto rat BN16 epithelial cells.	SIGNOR-265255	0.35
PRKCB	protein	P05771	UNIPROT	KIR3DL1	protein	P43629	UNIPROT	down-regulates activity	phosphorylation	Ser415	QRKITRPsQRPKTPP	-1									17911614	t		miannu	Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII.	SIGNOR-276079	0.2
EPO	protein	P01588	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000574								9168989	f	Regulation	miannu	We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin.	SIGNOR-251783	0.358
bexarotene	chemical	CHEBI:50859	ChEBI	RXRA	protein	P19793	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002058								17483357	t		miannu	Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification.	SIGNOR-259230	0.8
MMP28	protein	Q9H239	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272372	0.7
ATP6AP1	protein	Q15904	UNIPROT	HIF1A	protein	Q16665	UNIPROT	down-regulates quantity by destabilization				9606									28296633	f		miannu	Depletion or inhibition of the V-ATPase stabilises HIF1α in aerobic conditions. 	SIGNOR-261347	0.2
UBE2I	protein	P63279	UNIPROT	ETV5	protein	P41161	UNIPROT	down-regulates	sumoylation			9606									15857832	t		miannu	Here we show that erm interacts with the sumo-conjugating enzyme ubc9 and is modified by sumo. We further show that sumo modification of this ets transcription factor affects its ability to activate transcription.	SIGNOR-135850	0.269
VAV2	protein	P52735	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260583	0.752
NFS1	protein	Q9Y697	UNIPROT	Mitochondrial Fe-S Cluster Assembly Complex	complex	SIGNOR-C276	SIGNOR	form complex	binding			-1									27519411	t		lperfetto	As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry.	SIGNOR-262127	0.787
CWC27	protein	Q6UX04	UNIPROT	Spliceosomal_snRNP_assembly	phenotype	SIGNOR-PH79	SIGNOR	up-regulates				9606									11991638	f			Purification and characterization of native pliceosomes suitable for three-dimensional structural analysis 	SIGNOR-261148	0.7
DAB2IP	protein	Q5VWQ8	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								20080667	t		miannu	DAB2IP activates GSK-3β and antagonizes Wnt-mediated EMT. GSK-3β appears to directly associate with DAB2IP. Because DAB2IP is not a phosphatase, the mechanism of GSK-3β activation by DAB2IP is likely mediated by a separate phosphatase associated within this complex. PP2A is critical for DAB2IP-mediated GSK-3β activation and MET responses.	SIGNOR-254752	0.315
PRKCB	protein	P05771	UNIPROT	NRGN	protein	Q92686	UNIPROT	up-regulates activity	phosphorylation	Ser36	AAAKIQAsFRGHMAR	-1									8080473	t		lperfetto	Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM.	SIGNOR-248914	0.368
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PFKFB3	protein	Q16875	UNIPROT	up-regulates	phosphorylation	Ser461	NPLMRRNsVTPLASP	9606									15896703	t		gcesareni	We also found that AMP activated protein kinase and protein kinases A, B, and C catalyzed the phosphorylation of Ser-460 of HBP1, and that in addition both isoforms are phosphorylated at a second, as yet undetermined site by protein kinase C. However, none of the phosphorylations had any effect on the intrinsic kinetic characteristics of either enzymatic activity, and neither did point mutation (mimicking phosphorylation), deletion, and alternative-splice modification of the HBP1 carboxy-terminal region. Instead, these phosphorylations and mutations decreased the sensitivity of the 6PF2K to a potent allosteric inhibitor, phosphoenolpyruvate, which appears to be the major regulatory mechanism.	SIGNOR-137241	0.2
CUX2	protein	O14529	UNIPROT	OGG1	protein	O15527	UNIPROT	up-regulates activity	binding			10090									26221032	t		miannu	CUX2 Interacts Directly with OGG1 and Stimulate Its Binding to DNA Containing 8-OxoG	SIGNOR-263960	0.2
DNMT1	protein	P26358	UNIPROT	DNMT1/DNMT3A	complex	SIGNOR-C42	SIGNOR	form complex	binding			9606									12145218	t		miannu	We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation	SIGNOR-90836	0.775
MAPKAPK3	protein	Q16644	UNIPROT	RCSD1	protein	Q6JBY9	UNIPROT	down-regulates activity	phosphorylation	Ser179	RRFRRSQsDCGELGD	-1									15850461	t		miannu	Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263081	0.496
SF3A2	protein	Q15428	UNIPROT	SF3a	complex	SIGNOR-C345	SIGNOR	form complex	binding			9606	BTO:0000567								8349644	t		miannu	Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. 	SIGNOR-263947	0.96
VRK1	protein	Q99986	UNIPROT	BANF1	protein	O75531	UNIPROT	down-regulates	phosphorylation	Ser4	sQKHRDFV	9606									16495336	t		gcesareni	We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell	SIGNOR-144783	0.873
SNTB1	protein	Q13884	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding					BTO:0001103							29681515	t		apalma	Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated	SIGNOR-255979	0.497
UNC80	protein	Q8N2C7	UNIPROT	UNC79	protein	Q9P2D8	UNIPROT	up-regulates activity	binding			9606	BTO:0000142								22196327	t		miannu	The NALCN complex in the brain consists of NALCN, UNC80 and UNC79. UNC80 directly associates with NALCN and UNC79 forms part of the complex by its interaction with UNC80. 	SIGNOR-265183	0.797
FZD2	protein	Q14332	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates activity	binding			9606									25902418	t		areggio	Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain.	SIGNOR-258968	0.675
gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	GABA-A	proteinfamily	SIGNOR-PF61	SIGNOR	up-regulates activity	chemical activation			9606		BTO:0000227							18790874	t		miannu	Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS).	SIGNOR-264963	0.8
eprosartan	chemical	CHEBI:4814	ChEBI	AGTR1	protein	P30556	UNIPROT	down-regulates activity	chemical inhibition			9606									1309870	t		miannu	The angiotensin II (AII) antagonist activity of (E)-alpha-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5- yl]methylene]-2-thiophenepropanoic acid (SK&F 108566), was examined in a number of in vitro and in vivo assays. 	SIGNOR-258347	0.8
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser12	LASDFAFsPPPGGGG	-1									31306665	t		lperfetto	Recent work found that CyclinE/CDK2 can phosphorylate OCT4 on serine 12 (S12), serine 355 (S355) and threonine 322 (T322) in vitro|Phosphorylation of OCT4 on S12 has been previously implicated to stabilize OCT4 by binding to PIN1, thereby preventing ubiquitinylation by WWP2.	SIGNOR-264436	0.325
CDK14	protein	O94921	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation	Ser1490	AILNPPPsPATERSH	9606									20059949	t		gcesareni	Low-density lipoprotein receptor related proteins 5 and 6 (lrp5/6) are transmembrane receptors that initiate wnt/beta-catenin signaling. Phosphorylation of pppsp motifs in the lrp6 cytoplasmic domain is crucial for signal transduction. Using a kinome-wide rnai screen, we show that pppsp phosphorylation requires the drosophila cyclin-dependent kinase (cdk) l63. L63 and its vertebrate homolog pftk are regulated by the membrane tethered g2/m cyclin, cyclin y, which mediates binding to and phosphorylation of lrp6.	SIGNOR-162924	0.34
MAPK12	protein	P53778	UNIPROT	CARM1	protein	Q86X55	UNIPROT	down-regulates activity	phosphorylation	Ser595	GPAISMAsPMSIPTN	10090									29681515	t		apalma	Here, we identify a role for the mitogen-activated protein kinase (MAPK) p38g/MAPK12 as a critical regulator of satellite stem cell fate through phosphorylation of Carm1.	SIGNOR-255897	0.346
PAK2	protein	Q13177	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates activity	phosphorylation	Ser192	PRPDHTKsIYTRSVI	-1									10075701	t		miannu	Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites	SIGNOR-250225	0.2
HDAC4	protein	P56524	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates activity	deacetylation			9606									16613856	t		lperfetto	HDAC4 and HDAC5 deacetylate Runx2, allowing the protein to undergo Smurf-mediated degradation	SIGNOR-227547	0.54
HNRNPU	protein	Q00839	UNIPROT	GADD45A	protein	P24522	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation												17174306	f		lperfetto	In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs.	SIGNOR-262282	0.344
EIF3I	protein	Q13347	UNIPROT	EIF3_complex	complex	SIGNOR-C401	SIGNOR	form complex	binding			-1									16920360	t		miannu	Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 	SIGNOR-266392	0.932
PTPN2	protein	P17706	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates activity	dephosphorylation	Tyr1235	DMYDKEYySVHNKTG	9606									18819921	t			Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases.	SIGNOR-248388	0.479
PRKACA	protein	P17612	UNIPROT	ASIC1	protein	P78348	UNIPROT	unknown	phosphorylation	Ser479	QKEAKRSsADKGVAL	9606		BTO:0000142							12578970	t		llicata	We found that protein kinase a phosphorylation of ser-479 in the asic1 c terminus interfered with pick1 binding.	SIGNOR-98196	0.331
CSNK1D	protein	P48730	UNIPROT	CDK5	protein	Q00535	UNIPROT	up-regulates activity	phosphorylation	Ser159	GIPVRCYsAEVVTLW	-1									10500146	t		llicata	We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro.	SIGNOR-250798	0.535
ADIPOQ	protein	Q15848	UNIPROT	ADIPOR2	protein	Q86V24	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001103							12802337	t		acerquone	Expression of adipor1/r2 or suppression of adipor1/r2 expression by small-interfering rna supports our conclusion that they serve as receptors for globular and full-length adiponectin,	SIGNOR-101809	0.765
BCL2L1	protein	Q07817	UNIPROT	APAF1	protein	O14727	UNIPROT	down-regulates activity	binding			9606									9539746	t		lperfetto	These experiments demonstrate that bcl-xl associates with caspase-9 and apaf-1, and show that bcl-xl inhibits the maturation of caspase-9 mediated by apaf-1.	SIGNOR-56399	0.836
SMAD4	protein	Q13485	UNIPROT	SMAD2/SMAD4	complex	SIGNOR-C8	SIGNOR	form complex	binding			9606									11274206	t		gcesareni	the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4	SIGNOR-235178	0.708
PRKCE	protein	Q02156	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser594	HKAAVPAsEKLLLLK	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation	SIGNOR-129312	0.316
NME1	protein	P15531	UNIPROT	NME1	protein	P15531	UNIPROT	up-regulates	phosphorylation	His118	QVGRNIIhGSDSVES	9606		BTO:0000763							22869372	t		llicata	Ndpk catalytic function requires autophosphorylation at the catalytic his-118 residue. the simplest interpretation of these data is that ampk does not directly phosphorylate ndpk-a at ser-120 or ser-122 (or at any other site) but rather enhances ndpk-a autophosphorylation at his-118.	SIGNOR-198667	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Ser555	RALSNSVsNMGLSES	9606	BTO:0000007								17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-252882	0.398
GSK3A	protein	P49840	UNIPROT	STAT2	protein	P52630	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr385	ILTSNQKtLTPEKGQ	9606	BTO:0002181								31843895	t		miannu	GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation.	SIGNOR-276761	0.266
ELOVL4	protein	Q9GZR5	UNIPROT	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267899	0.8
IL1B	protein	P01584	UNIPROT	KRT1	protein	P04264	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17982242	f	Regulation of expression	miannu	IL-1β alone decreased the expression of E-cadherin and cytokeratin	SIGNOR-251883	0.251
acetylcholine	smallmolecule	CHEBI:15355	ChEBI	CHRNA7	protein	P36544	UNIPROT	up-regulates activity	chemical activation												27167578	t			Here, we demonstrate a role for α7 nAChR/G protein interaction in the activation of the small (monomeric) RhoA GTPase leading to cytoskeletal changes during neurite growth. Treatment of PC12 cells with the α7 nAChR agonist choline or PNU-282987 was associated with an increase in RhoA activity and an inhibition in neurite growth.	SIGNOR-253984	0.8
PLK3	protein	Q9H4B4	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9606									17804415	t		gcesareni	Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun.	SIGNOR-157721	0.379
PTPRB	protein	P23467	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates	dephosphorylation			9606									12907755	t		gcesareni	Inally, mrna tissue distribution of these ptps by rt-pcr analysis and coexpression of the wild-type ptps to test their ability to dephosphorylate ligand-activated ghr suggest ptp-h1 and ptp1b as potential candidates involved in ghr signaling.	SIGNOR-104580	0.298
BRSK1	protein	Q8TDC3	UNIPROT	CDC25B	protein	P30305	UNIPROT	down-regulates	phosphorylation	Ser375	ARVLRSKsLCHDEIE	9606	BTO:0000567;BTO:0000938	BTO:0000142							15150265	t		lperfetto	Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectivelyphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3	SIGNOR-124839	0.521
CSNK2A1	protein	P68400	UNIPROT	MDC1	protein	Q14676	UNIPROT	up-regulates	phosphorylation			9606									19230643	t		gcesareni	Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1.	SIGNOR-184130	0.353
MAPK3	protein	P27361	UNIPROT	PPP2R5C	protein	Q13362	UNIPROT	down-regulates	phosphorylation	Ser337	QLAKCVSsPHFQVAE	9606									16456541	t		gcesareni	Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit.	SIGNOR-144317	0.395
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PARP1	protein	P09874	UNIPROT	up-regulates	phosphorylation	Thr373	AATPPPStASAPAAV	9606	BTO:0000938	BTO:0000142							16627622	t		lperfetto	Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation.	SIGNOR-244673	0.2
LAMTOR3	protein	Q9UHA4	UNIPROT	LAMTOR	complex	SIGNOR-C26	SIGNOR	form complex	binding			9606									20381137	t		lperfetto	Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant	SIGNOR-164775	0.929
TGFB1	protein	P01137	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates activity	binding			9606									22703233	t		lperfetto	TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex.	SIGNOR-249548	0.84
YWHAZ	protein	P63104	UNIPROT	NEFL	protein	P07196	UNIPROT	down-regulates activity	binding			9606									23230147	t		miannu	These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments.	SIGNOR-252397	0.281
AKAP8L	protein	Q9ULX6	UNIPROT	DHX9	protein	Q08211	UNIPROT	up-regulates activity	binding			9606									11402034	t		miannu	We report evidence for a novel nuclear export signal in HAP95 and showed that the domains involved in RHA binding and nuclear localization are required for CTE activation. Finally, we showed that HAP95 synergizes significantly with RHA on CTE-mediated reporter gene expression and promotes nuclear export of unspliced mRNA in transfected cells. Taken together, these data support the proposal that HAP95 specifically facilitates CTE-mediated gene expression by directly binding to RHA.	SIGNOR-260950	0.561
BDKRB2	protein	P30411	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257281	0.401
RXRB	protein	P28702	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates	binding			9606									11237216	t		lperfetto	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-105454	0.652
D-thyroxine	smallmolecule	CHEBI:30659	ChEBI	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0003736								6777394	t	inferred from family member	miannu	 The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response.	SIGNOR-270294	0.8
HTR1E	protein	P28566	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256984	0.362
GCG	protein	P01275	UNIPROT	GCGR	protein	P47871	UNIPROT	up-regulates	binding			9606									12529935	t		fspada	Mutation of a highly conserved d64 residue in the n-terminal portion of the rat glucagon receptor completely eliminates glucagon binding. This residue corresponds to a mutated asp residue at amino acid 60 in the growth hormone releasing hormone receptor that gives rise to the little mouse phenotype (lin et al.1993). Antisera directed against amino acid sequences 126_137 of the n-terminal region, and agai residues 206_219 of the first extracellular loop block [125i]-glucagon binding and interfere with glucagon-induced adenylyl cyclase generation in rat liver membranes.	SIGNOR-97338	0.769
SUMO1	protein	P63165	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates	sumoylation	Lys160	EAHQWFLkHEARPLA	9534									9756909	t		lperfetto	We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation.	SIGNOR-261786	0.771
KLF14	protein	Q8TD94	UNIPROT	SPHK1	protein	Q9NYA1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								24759103	t		Luana	KLF14 Is a Transcriptional Activator of SK1 Gene Expression in Endothelial Cells	SIGNOR-266047	0.2
α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor.	SIGNOR-266450	0.8
TAF11	protein	Q15544	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263925	0.899
β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35 Three different subunits have been identified in humans: PFK-M (muscle), PFK-L (liver), and PFK-P (platelet).The subunits are expressed in a tissue-specific manner and, in erythrocytes, 5 isoenzymes of varying subunit composition (M4, M3L1, M2L2, ML3, and L4) can be identified.	SIGNOR-266464	0.8
ACP1	protein	P24666	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	dephosphorylation	Tyr857	DIMRDSNyISKGSTF	9606									12149261	t			Insight into the role of low molecular weight phosphotyrosine phosphatase (LMW-PTP) on platelet-derived growth factor receptor (PDGF-r) signaling. LMW-PTP controls PDGF-r kinase activity through TYR-857 dephosphorylation|On the basis of these results, we propose a key role for LMW-PTP in PDGF-r down-regulation through the dephosphorylation of the activation loop Tyr-857, thus determining a general negative regulation of all downstream signals, with the exception of those elicited by internalized receptors.	SIGNOR-248452	0.314
AREL1	protein	O15033	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys62	CAVPIAQkSEPHSLS	9606	BTO:0002552								31732561	t		lperfetto	AREL1 ubiquitinated SMAC, primarily on Lys62 and Lys191 |E701A substitution in the AREL1 HECT domain substantially increased its autopolyubiquitination and SMAC ubiquitination activity, whereas deletion of the last three amino acids at the C terminus completely abrogated AREL1 autoubiquitination and reduced SMAC ubiquitination.	SIGNOR-267673	0.386
MAPK3	protein	P27361	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates activity	phosphorylation	Ser696	EKNYALPsPATTEGG	9606	BTO:0000007			SIGNOR-C3					21071439	t		lperfetto	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-169526	0.482
TUBD1	protein	Q9UJT1	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates				9606									28347630	f		miannu	Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation	SIGNOR-267177	0.7
TBXA2R	protein	P21731	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256887	0.639
Mob1	proteinfamily	SIGNOR-PF42	SIGNOR	LATS1	protein	O95835	UNIPROT	up-regulates	binding			9606									21084559	t	Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases.	gcesareni	Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1.	SIGNOR-269958	0.2
ITGB1BP1	protein	O14713	UNIPROT	A10/b1 integrin	complex	SIGNOR-C167	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257647	0.757
IMPDH1	protein	P20839	UNIPROT	IMP	smallmolecule	CHEBI:17202	ChEBI	down-regulates quantity	chemical modification			9606									19480389	t		miannu	IMPDH controls the gateway to guanine nucleotides, making it an “enzyme of consequence” for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS).	SIGNOR-267331	0.8
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269637	0.2
MAPK1	protein	P28482	UNIPROT	NCOA1	protein	Q15788	UNIPROT	up-regulates	phosphorylation	Thr1179	NYGTNPGtPPASTSP	9606									10660621	t		lperfetto	Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene.	SIGNOR-74880	0.371
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDE1	protein	Q9NXR1	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr228	GPSSSLNtPGSFRRG	9606	BTO:0000007								16682949	t	done	miannu	Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. 	SIGNOR-274085	0.525
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1878	SPKYSPTsPTYSPTT	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273035	0.556
diisononyl phthalate	chemical	CHEBI:35459	ChEBI	NR1I2	protein	O75469	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). 	SIGNOR-268775	0.8
RUNX2	protein	Q13950	UNIPROT	BMP2	protein	P12643	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15765505	f		gcesareni	Runx2 is an important mediator of the expression of bmp-2 in response to fgf stimulation in cranial bone development	SIGNOR-134515	0.51
PIK3C3	protein	Q8NEB9	UNIPROT	Vps34 Complex I	complex	SIGNOR-C242	SIGNOR	form complex	binding			-1									30397185	t		lperfetto	PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively.	SIGNOR-260316	0.917
PTPN12	protein	Q05209	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr999	YASSNPEyLSASDVF	9606									10734133	t		gcesareni	Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190.	SIGNOR-75906	0.384
BCL2L1	protein	Q07817	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates activity	binding			-1									10949026	t		lperfetto	Bad dimerizes with bcl-xl at the mitochondrial membrane where it exert its killing effects. Phosphorylation of bad promotes its binding to 14-3-3 protein, which may sequester bad from bcl-xl, thus promoting cell cells survival.	SIGNOR-81125	0.841
CDK1	protein	P06493	UNIPROT	WAC	protein	Q9BTA9	UNIPROT	up-regulates activity	phosphorylation	Thr457	YVSPRIStPQTNTVP	9606	BTO:0000567								30021153	t		lperfetto	Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. 	SIGNOR-265035	0.2
PRKCA	protein	P17252	UNIPROT	DLX3	protein	O60479	UNIPROT	unknown	phosphorylation	Ser138	KPRTIYSsYQLAALQ	10090									11343707	t		lperfetto	Dlx3 is primarily phosphorylated by PKCalpha. By deletion and mutational analysis, we show that the serine residue S138, located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3. | Since DNA binding may reveal only a part of Dlx3 protein function, we cannot rule out the influence of phosphorylation on other biological functions. Thus, the characterization of the full biological function of PKC phosphorylation of Dlx3 protein will require further studies. 	SIGNOR-249095	0.311
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	LIMA1	protein	Q9UHB6	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser362	PVHPKPLsPDSRASS	9606	BTO:0001033								23188829	t		miannu	Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover.	SIGNOR-263062	0.2
PDGFRB	protein	P09619	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	phosphorylation	Tyr155	LNDSAAYyLNDLDRI	-1									33139573	t		miannu	RTKs directly phosphorylate Gαi on Y154, 155, and Y320.	SIGNOR-277232	0.2
WARS1	protein	P23381	UNIPROT	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 	SIGNOR-270512	0.8
2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid	chemical	CID:135461425	PUBCHEM	FGFR3	protein	P22607	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258081	0.8
CSNK1A1	protein	P48729	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser321	NSNASTVsGRLSPIM	9606									20110348	t		lperfetto	Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export	SIGNOR-252900	0.392
heme	smallmolecule	CHEBI:30413	ChEBI	HBB	protein	P68871	UNIPROT	up-regulates activity	chemical activation			9606									26557657	t		miannu	Heme is a prosthetic group comprising ferrous iron (Fe2+) and protoporphyrin IX and is an essential cofactor in various biological processes such as oxygen transport (hemoglobin) and storage (myoglobin) and electron transfer (respiratory cytochromes) in addition to its role as a structural component of hemoproteins.	SIGNOR-251908	0.8
PCDHAC2	protein	Q9Y5I4	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-269033	0.2
FZD3	protein	Q9NPG1	UNIPROT	GNGT1	protein	P63211	UNIPROT	up-regulates	binding			9606									17251915	t		gcesareni	In the non-canonical wnt signalling pathway, frizzled uses galphaq or galphai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat.	SIGNOR-152606	0.372
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TSC	complex	SIGNOR-C101	SIGNOR	down-regulates activity	phosphorylation			10090	BTO:0000011								19593385	t		lperfetto	In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis	SIGNOR-251526	0.778
AKT2	protein	P31751	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Ser315	DFRSRTNsNASTVSG	9606									19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites.	SIGNOR-235960	0.742
SRC	protein	P12931	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates	phosphorylation	Tyr1166	DIYETDYyRKGGKGL	9606									8940173	t		lperfetto	Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor	SIGNOR-45130	0.564
CDK2	protein	P24941	UNIPROT	CDX2	protein	Q99626	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser295	LQASVPGsVPGVLGP	9606									16027724	t		llicata	Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. 	SIGNOR-250730	0.489
SMURF1	protein	Q9HCE7	UNIPROT	BMPR1A	protein	P36894	UNIPROT	down-regulates	ubiquitination			9606									22298955	t		gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-195651	0.645
GNG12	protein	Q9UBI6	UNIPROT	PRKACA	protein	P17612	UNIPROT	down-regulates	binding			9606									17251915	t		gcesareni	As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp.	SIGNOR-152615	0.385
FGF1	protein	P05230	UNIPROT	FGFR2	protein	P21802	UNIPROT	up-regulates	binding			9606									10618369	t		lperfetto	We have crystallized a complex between human FGF1 and a two-domain extracellular fragment of human FGFR2.	SIGNOR-73811	0.906
ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	P2RY2	protein	P41231	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257563	0.8
SIK2	protein	Q9H0K1	UNIPROT	CRTC2	protein	Q53ET0	UNIPROT	down-regulates	phosphorylation	Ser171	SALNRTSsDSALHTS	9606									16308421	t		gcesareni	Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2	SIGNOR-142218	0.734
MELK	protein	Q14680	UNIPROT	MELK	protein	Q14680	UNIPROT	up-regulates	phosphorylation	Ser505	SPERRCRsVELDLNQ	9606									16216881	t		lperfetto	We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase.	SIGNOR-141014	0.2
MLL-AF4	fusion protein	SIGNOR-FP4	SIGNOR	 Core Binding Factor complex	complex	SIGNOR-C214	SIGNOR	down-regulates quantity by repression	transcriptional regulation			9606									24449215	f		miannu	However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. 	SIGNOR-255972	0.2
IST1	protein	P53990	UNIPROT	SPAST	protein	Q9UBP0	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								23897888	t		Gianni	Our results suggest that inclusion of IST1 into the ESCRT complex allows recruitment of spastin to promote fission of recycling tubules from the endosome. Thus, we reveal a novel cellular role for MT severing and identify a mechanism by which endosomal recycling can be coordinated with the degradative machinery.	SIGNOR-269047	0.535
dothiepin	chemical	CHEBI:36798	ChEBI	CHRM4	protein	P08173	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8100134	t		miannu	Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 	SIGNOR-258698	0.8
LSM-20934	chemical	CHEBI:109533	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			10029									8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258726	0.8
ATR	protein	Q13535	UNIPROT	ZDHHC13	protein	Q8IUH4	UNIPROT	up-regulates activity	phosphorylation	Ser8	MEGPGLGsQCRNHSH	10090	BTO:0000847								28869973	t		miannu	Collectively these results suggest that ZDHHC13 phosphorylation by ATR following UVB irradiation promotes its interaction with MC1R to stimulate MC1R palmitoylation.	SIGNOR-273517	0.2
MBD3	protein	O95983	UNIPROT	MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263847	0.8
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	PSEN1	protein	P49768	UNIPROT	down-regulates activity	phosphorylation	Ser357	PHRSTPEsRAAVQEL	9606	BTO:0000007								17360711	t		gcesareni	We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin.	SIGNOR-228022	0.404
TFIIH	complex	SIGNOR-C457	SIGNOR	AR	protein	P10275	UNIPROT	down-regulates	phosphorylation	Ser516	VSRVPYPsPTCVKSE	9606									21157430	t		acerquone	Here, we show that the transcription factor tfiih, via its cdk7 kinase, phosphorylates the androgen receptor (ar) at position ar/s515. Strikingly, this phosphorylation is a key step for an accurate transactivation that includes the cyclic recruitment of the transcription machinery, the mdm2 e3 ligase, the subsequent ubiquitination of ar at the promoter of target genes and its degradation by the proteasome machinery	SIGNOR-269331	0.324
SRC	protein	P12931	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1016	DVVDADEyLIPQQGF	9606									8845374	t		lperfetto	The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site	SIGNOR-44239	0.609
BABAM1	protein	Q9NWV8	UNIPROT	BRCA1-A complex	complex	SIGNOR-C296	SIGNOR	form complex	binding			9606	BTO:0000007								20656690	t		lperfetto	We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1. 	SIGNOR-263215	0.924
P2RY1	protein	P47900	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257442	0.2
MAPK3	protein	P27361	UNIPROT	HSF1	protein	Q00613	UNIPROT	down-regulates	phosphorylation	Ser307	EPPSPPQsPRVEEAS	9606									8940068	t		gcesareni	Sequential phosphorylation of hsf1 by mitogen-activated protein kinase and glycogen synthase kinase 3 at ser-303 and ser-307 represses transcriptional activation by heat shock factor-1.	SIGNOR-44999	0.615
TFEB	protein	P19484	UNIPROT	ATP6V1H	protein	Q9UI12	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19556463	f	Figure 1	lperfetto	Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 	SIGNOR-276535	0.31
FLNA	protein	P21333	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	binding			9606									20156194	t		miannu	We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself	SIGNOR-260629	0.507
PTK2	protein	Q05397	UNIPROT	BCAR1	protein	P56945	UNIPROT	unknown	phosphorylation	Tyr666	GWMEDYDyVHLQGKE										11604500	t		lperfetto	FAK phosphorylates CAS-SBD tyrosines 668 and/or 670, driving an SH2-mediated recruitment of Src which then phosphorylates CAS-SD.	SIGNOR-249112	0.805
PRKCE	protein	Q02156	UNIPROT	FGFR2	protein	P21802	UNIPROT	up-regulates	phosphorylation	Ser782	PLEQYSPsYPDTRSS	9606	BTO:0000938								23564461	t		lperfetto	Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiation	SIGNOR-201675	0.2
TBR1	protein	Q16650	UNIPROT	FEZF2	protein	Q8TBJ5	UNIPROT	down-regulates quantity by repression	transcriptional regulation				BTO:0000938								21228164	t		lperfetto	We found that TBR1 promotes the identity of corticothalamic neurons and represses subcerebral fates through reducing expression of Fezf2 and CTIP2.|(3) Chromatin immunoprecipitation analysis using TBR1 antibodies showed that TBR1 bound to a conserved region in the Fezf2 gene.	SIGNOR-268967	0.501
NUP98-HOXA9	fusion protein	SIGNOR-FP15	SIGNOR	RBPMS	protein	Q93062	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17442773	f		miannu	Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The gene for the RNA‐binding protein with multiple splicing (RBPMS) was upregulated in NUP98‐HOXA9–transduced cord blood CD34+ cells and also in the transcriptosomes of normal CD34+ and CD133+ cells.	SIGNOR-261503	0.2
TP53	protein	P04637	UNIPROT	TNFRSF10B	protein	O14763	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15964798	f		gcesareni	Reduction in p53 expression also blocks p65 binding to the intronic region of the dr5 gene, indicating cooperation between p53 and p65 in dr5 expression. (articolo-abstract)	SIGNOR-138293	0.635
PTPRJ	protein	Q12913	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Tyr1069	EDSFLQRySSDPTGA	9606	BTO:0000567								19836242	t			We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173	SIGNOR-248697	0.504
PLCG1	protein	P19174	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates	phosphorylation			9606									12645577	t		gcesareni	Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199.	SIGNOR-99310	0.538
MAP3K7	protein	O43318	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	up-regulates activity	binding			9606				SIGNOR-C14					20038579	t		lperfetto	This result suggests that ikkgamma/nemo binds to the polyubiquitinated tak1.	SIGNOR-162634	0.807
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr548	KKVAVVRtPPKSPSS	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249350	0.729
CDK9	protein	P50750	UNIPROT	SUPT5H	protein	O00267	UNIPROT	up-regulates	phosphorylation	Thr775	TPMYGSQtPMYGSGS	9606									16427012	t		lperfetto	We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif	SIGNOR-143923	0.769
MAPK3	protein	P27361	UNIPROT	XPO5	protein	Q9HAV4	UNIPROT	down-regulates activity	phosphorylation	Ser416	GFPSKTDsPSCEYSR	9606	BTO:0000007								27846390	t		lperfetto	Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. 	SIGNOR-262979	0.317
CDC42BPA	protein	Q5VT25	UNIPROT	PPP1R12C	protein	Q9BZL4	UNIPROT	down-regulates activity	phosphorylation	Thr560	MRQSRRStQGVTLTD		BTO:0000298								11399775	t		llicata	Identification of the Phosphorylation Site of p85 on Threonine 560 by MRCKα-CAT | Wild-type p85 but not the mutant p85AA, when phosphorylated in vitro with MRCKα-CAT, showed significant reduction in the rate of MLC2 dephosphorylation. These results confirm a similar observation with MBS130 where phosphorylation of a conserved threonine 695 within a highly conserved motif was essential for the inhibition of phosphatase catalytic activity 	SIGNOR-250724	0.576
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	USP24	protein	Q9UPU5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2047	QRVSDQNsPVLPKKS	9606	BTO:0000018								27991932	t		lperfetto	 Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604.	SIGNOR-275610	0.26
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	FBXO32	protein	Q969P5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15109499	t			Constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers	SIGNOR-252929	0.2
CSF2RA	protein	P15509	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	binding			9606									8977526	t		lperfetto	JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.	SIGNOR-249502	0.513
USF1	protein	P22415	UNIPROT	ADAM10	protein	O14672	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									28624438	t		miannu	The promoter region of ADAM10 contains several transcription factor binding sites that can stimulate its transcription. These include binding sites for transcription factors SP1 and USF, and the spliced form of the X-box binding protein (XBP)-1 as well as a retinoic acid-responsive element	SIGNOR-259837	0.274
MAPK3	protein	P27361	UNIPROT	METTL3	protein	Q86U44	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser50	SPTFRSDsPVPTAPT	9606	BTO:0000007								33217317	t		miannu	 Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.	SIGNOR-265945	0.274
PIK3CA	protein	P42336	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation			9606									12167717	t		lperfetto	PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473,	SIGNOR-244429	0.811
PRKAA1	protein	Q13131	UNIPROT	HAT1	protein	O14929	UNIPROT	up-regulates activity	phosphorylation	Ser190	MWFIETAsFIDVDDE	-1									28143904	t		lperfetto	Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314	SIGNOR-264782	0.2
PRKCD	protein	Q05655	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Thr841	RSAFTTStVVRMHVG	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249287	0.353
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1784	TPTSPNYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273107	0.745
POLE2	protein	P56282	UNIPROT	DNA polymerase epsilon	complex	SIGNOR-C377	SIGNOR	form complex	binding			9606	BTO:0000567								10801849	t		lperfetto	Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon.	SIGNOR-265519	0.919
TLR7	protein	Q9NYK1	UNIPROT	IFNA1	protein	P01562	UNIPROT	up-regulates quantity				9606	BTO:0004625								15661881	f		miannu	TLR7 in pDC is functionally associated with the production of IFN-α- and IFN-regulated cytokines, similar to the role of TLR9.	SIGNOR-259248	0.415
PTPN2	protein	P17706	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates	dephosphorylation			9606									22080863	t		gcesareni	We found that tcptp dephosphorylates and inactivates src family kinases to regulate t cell responses._	SIGNOR-177116	0.709
SIAH2	protein	O43255	UNIPROT	SNCAIP	protein	Q9Y6H5	UNIPROT	down-regulates	ubiquitination			9606									16174773	t		lperfetto	Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system	SIGNOR-140651	0.604
TGFB1	protein	P01137	UNIPROT	ENPP1	protein	P22413	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000249								20930330	f		miannu	TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line.	SIGNOR-252200	0.271
FANCL	protein	Q9NW38	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates activity	ubiquitination						SIGNOR-C300						18985065	t		lperfetto	Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding	SIGNOR-263264	0.897
PRKCB	protein	P05771	UNIPROT	EWSR1	protein	Q01844	UNIPROT	down-regulates activity	phosphorylation	Ser266	SSYGQQSsFRQDHPS	9606									9341188	t		miannu	Here we report thatews, a nuclearrna-bindingprooncoprotein, contains an iq domain, is phosphorylated byproteinkinase c, and interacts with calmodulin. Interestingly, pkc phosphorylation of ews inhibits its binding to rna homopolymers, and conversely,rna binding to ews interferes with pkc phosphorylation./ these data indicate that ews contains an iq domain with ser266 acting as the primary site for pkc phosphorylation.	SIGNOR-52854	0.28
TSC1	protein	Q92574	UNIPROT	TSC	complex	SIGNOR-C101	SIGNOR	form complex	binding			9606									12172553	t		lperfetto	TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR).	SIGNOR-217910	0.933
MDM2	protein	Q00987	UNIPROT	EP300	protein	Q09472	UNIPROT	down-regulates	binding			9606	BTO:0000567								11070080	t		gcesareni	Mdm2, a negative-feedback regulator of p53, inhibited p300-mediated p53 acetylation by complexing with these two proteins.	SIGNOR-84077	0.675
PRKAR1B	protein	P31321	UNIPROT	PRKACA	protein	P17612	UNIPROT	down-regulates activity	binding			9606									26687711	t			Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 	SIGNOR-258753	0.851
CSNK1A1	protein	P48729	UNIPROT	HNRNPC	protein	P07910	UNIPROT	down-regulates	phosphorylation	Ser253	ETNVKMEsEGGADDS	9606									15687492	t		gcesareni	A kinase activity was identified in mouse liver that phosphorylates the acd of hnrnp-c at ser(240) and at two sites at ser(225)-ser(228). The kinase was purified and identified by tandem mass spectrometry as protein kinase ck1alpha (formerly casein kinase 1alpha).hnrnp-c1 that was also modified at the ck1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that ck1alpha-mediated phosphorylation modulates the mrna binding ability of hnrnp-c.	SIGNOR-133528	0.361
histamine	smallmolecule	CHEBI:18295	ChEBI	HRH4	protein	Q9H3N8	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257515	0.8
SYK	protein	P43405	UNIPROT	BLNK	protein	Q8WV28	UNIPROT	up-regulates	phosphorylation	Tyr72	SDDFDSDyENPDEHS	9606	BTO:0000776								12456653	t		llicata	The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex.	SIGNOR-96044	0.799
RPL23A	protein	P62750	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262476	0.851
CASP8	protein	Q14790	UNIPROT	CASP3	protein	P42574	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000007								16964285	t		amattioni	Casp8 induces apoptosis by directly activating casp3.	SIGNOR-149420	0.713
FRK	protein	P42685	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr336	NKDKANRyFSPNFKV	9606	BTO:0000093								19345329	t		miannu	Rak phosphorylates PTEN on Tyr 336 to prevent its protein degradation. In this study, we demonstrate that the Rak tyrosine kinase physically interacts with PTEN and phosphorylates PTEN on Tyr336. Knockdown of Rak enhanced the binding of PTEN to its E3 ligase NEDD4-1 and promoted PTEN polyubiquitination, leading to PTEN protein degradation. 	SIGNOR-275458	0.581
SIN3A	protein	Q96ST3	UNIPROT	KLK3	protein	P07288	UNIPROT	down-regulates quantity by repression	transcriptional regulation												16254079	t	 	 	Chromatin immunoprecipitation (ChIP) and DNA affinity precipitation analysis demonstrated that Ebp1 and Sin3A associate at the PSA and E2F1 promoters. Functionally, Sin3A enhanced the ability of Ebp1 to repress transcription of androgen receptor (AR) and E2F1 regulated genes.	SIGNOR-253663	0.2
CSNK2A1	protein	P68400	UNIPROT	HSF1	protein	Q00613	UNIPROT	up-regulates activity	phosphorylation	Thr142	DSVTKLLtDVQLMKG	-1									12659875	t		llicata	Transcriptional activity and DNA binding of heat shock factor-1 involve phosphorylation on threonine 142 by CK2.	SIGNOR-250898	0.377
lysophosphatidic acids	smallmolecule	CHEBI:32957	ChEBI	LPAR3	protein	Q9UBY5	UNIPROT	up-regulates	chemical activation			9606									22863277	t		gcesareni	Lpa binds to a family of gpcrs known as lpa receptors (lpa1-6) to initiate intracellular signaling. Lpa1 was highly expressed and lpa3 was detectable in hek293a cells compared to other lpa receptors.	SIGNOR-198526	0.8
YAP1	protein	P46937	UNIPROT	TEAD1	protein	P28347	UNIPROT	up-regulates	binding			9606									23431053	t	Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4	gcesareni	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.	SIGNOR-201465	0.902
FIS1	protein	Q9Y3D6	UNIPROT	Mitochondrial_fission	phenotype	SIGNOR-PH143	SIGNOR	up-regulates				9606									25486875	f		lperfetto	During fission, DRP1 is recruited from the cytosol to the outer mitochondrial membrane, where it assembles with FIS1 to constrict the mitochondrial tubule (2)	SIGNOR-272976	0.7
CAK complex	complex	SIGNOR-C456	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser392	FKTEGPDsD	9606									9315650	t		llicata	The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase.	SIGNOR-269324	0.446
KAT2A	protein	Q92830	UNIPROT	H3-2	protein	Q5TEC6	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269607	0.2
SRC	protein	P12931	UNIPROT	HNRNPK	protein	P61978	UNIPROT	down-regulates	phosphorylation	Tyr225	IKGRAQPyDPNFYDE	9606									12052863	t		lperfetto	We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown).	SIGNOR-88899	0.609
PRCP	protein	P42785	UNIPROT	POMC	protein	P01189	UNIPROT	down-regulates activity				10090									20694162	f		miannu	Prolylcarboxypeptidase (PRCP) was found to be responsible for the control of food intake and energy expenditure at a central level. The molecular mechanisms underlying the suppression of food intake in PRCP-deficient mice or by the inhibitor of PRCP clearly provide physiological evidence that PRCP is an inactivator of α-MSH	SIGNOR-252372	0.304
RPS6KA1	protein	Q15418	UNIPROT	WWC1	protein	Q8IX03	UNIPROT	up-regulates	phosphorylation	Ser947	CRLNRSDsDSSTLSK	9606		BTO:0000149							24269383	t		llicata	Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. erk_rsk phosphorylation of kibra is required for proper cell proliferation and rsk-mediated phosphorylation also positively modulates kibra's migratory activity.	SIGNOR-203294	0.342
GATA2	protein	P23769	UNIPROT	Mast-Cell_diff	phenotype	SIGNOR-PH117	SIGNOR	up-regulates activity				10090	BTO:0000830								25801432	f			We have identified GATA2 as an essential transcription factor in differentiation of newly identified common basophil and mast cell progenitors into basophils and mast cells. ll differentiation and maintenance	SIGNOR-259959	0.7
9-cis-retinoic acid	chemical	CHEBI:50648	ChEBI	RXRA	protein	P19793	UNIPROT	up-regulates activity	chemical activation			9606									18321241	t		miannu	Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma).	SIGNOR-259237	0.8
PRKCA	protein	P17252	UNIPROT	TNNI3	protein	P19429	UNIPROT	unknown	phosphorylation	Ser77	GEKGRALsTRCQPLE	-1									2584239	t		lperfetto	We have now determined that PKC phosphorylated serine 43 (and/or serine 45), serine 78, and threonine 144 in the free Tn-I subunit	SIGNOR-248890	0.349
MAPK3	protein	P27361	UNIPROT	EPS8	protein	Q12929	UNIPROT	down-regulates activity	phosphorylation	Ser625	ADTPPAPsPPPTPAP	-1									19564905	t		miannu	We further show that the actin barbed-end capping activity of Eps8 is inhibited by brain-derived neurotrophic factor (BDNF) treatment through MAPK-dependent phosphorylation of Eps8 residues S624 and T628. Additionally, an Eps8 mutant, impaired in the MAPK target sites (S624A/T628A), displays increased association to actin-rich structures, is resistant to BDNF-mediated release from microfilaments, and inhibits BDNF-induced filopodia. The opposite is observed for a phosphomimetic Eps8 (S624E/T628E) mutant. Thus, collectively, our data identify Eps8 as a critical capping protein in the regulation of axonal filopodia and delineate a molecular pathway by which BDNF, through MAPK-dependent phosphorylation of Eps8, stimulates axonal filopodia formation, a process with crucial impacts on neuronal development and synapse formation.	SIGNOR-263058	0.329
Camostat	chemical	CID:2536	PUBCHEM	TMPRSS2	protein	O15393	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000195								32142651	t		miannu	Indeed, the clinically proven serine protease inhibitor camostat mesylate, which is active against TMPRSS2 (Kawase et al., 2012), partially blocked SARS-2-S-driven entry into Caco-2 (Figure S3 B) and Vero-TMPRSS2 cells (Figure 4 A). Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines.	SIGNOR-260284	0.8
CNOT7	protein	Q9UIV1	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	form complex	binding			9606									19558367	t		lperfetto	In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules.	SIGNOR-268307	0.83
VKORC1L1	protein	Q8N0U8	UNIPROT	vitamin K epoxide	smallmolecule	CHEBI:28371	ChEBI	down-regulates quantity	chemical modification			9606									31226734	t		lperfetto	The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form	SIGNOR-265902	0.8
KMT5B	protein	Q4FZB7	UNIPROT	EID3	protein	Q8N140	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								23720823	t		miannu	Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. The novel inhibitor of differentiation Eid3 is an FRG1/Suv4-20h1 target involved in the myogenic defects caused by FRG1 over-expression. Eid3 is down-regulated upon muscle differentiation and behaves as a myogenic inhibitor gene. 	SIGNOR-266640	0.2
WDR45B	protein	Q5MNZ6	UNIPROT	TSC	complex	SIGNOR-C101	SIGNOR	up-regulates quantity	binding			9606	BTO:0001938								28561066	t		miannu	WIPI3 associates with the TSC complex and FIP200. The specific interaction between WIPI3 and the TSC complex was demonstrated by immunopurification of both endogenous TSC1 and TSC2 with GFP-WIPI3 (Fig. 5a). These data suggest that WIPI3 functions in association with the TSC complex to regulate mTOR activity in the lysosomal compartment.	SIGNOR-268479	0.2
KIF16B	protein	Q96L93	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272527	0.7
BRCC ubiquitin ligase complex	complex	SIGNOR-C295	SIGNOR	TP53	protein	P04637	UNIPROT	unknown	ubiquitination			9606	BTO:0000007								14636569	t		lperfetto	 However, since the same domain of p53 is also the target of ubiquitination by MDM2 protein, further in vivo experiments are required to demonstrate the biological relevance of p53 ubiquitination by BRCC.|The Extreme C Terminus of p53 Is Ubiquitinated by BRCC	SIGNOR-263210	0.616
PIP3	smallmolecule	CHEBI:16618	ChEBI	ZFYVE26	protein	Q68DK2	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000567								20208530	t		miannu	We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. 	SIGNOR-265537	0.8
PDPK1	protein	O15530	UNIPROT	PRKCB	protein	P05771	UNIPROT	up-regulates	phosphorylation	Thr500	WDGVTTKtFCGTPDY	9606									17115692	t		lperfetto	The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif	SIGNOR-150857	0.5
IRAK1	protein	P51617	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity	phosphorylation	Ser376	GSSPSQSsMVARTQT	-1									11960013	t			In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4.	SIGNOR-251326	0.2
ROS	stimulus	SIGNOR-ST2	SIGNOR	SNCA	protein	P37840	UNIPROT	up-regulates quantity				9606									16000336	f		lperfetto	The increased concentration of neuronal alpha-synuclein and pigment in normal A9 neurons may already predispose these neurons to precipitate alpha-synuclein around pigment-associated lipid under oxidative conditions.	SIGNOR-249699	0.7
MAPK9	protein	P45984	UNIPROT	MFN2	protein	O95140	UNIPROT	down-regulates	phosphorylation	Ser27	HMAEVNAsPLKHFVT	9606									22748923	t		lperfetto	Jnk phosphorylation of mitofusin 2 in response to cellular stress leads to recruitment of the ubiquitin ligase (e3) huwe1/mule/arf-bp1/hecth9/e3histone/lasu1 to mitofusin 2, with the bh3 domain of huwe1 implicated in this interaction. This results in ubiquitin-mediated proteasomal degradation of mitofusin 2these data establish that mfn2 is phosphorylated on ser27 in response to a variety of cellular stresses and implicate jnk in this process	SIGNOR-198054	0.358
MAP2K6	protein	P52564	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates	phosphorylation			9606									8974401	t		gcesareni	A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase)	SIGNOR-45369	0.451
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1738	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120116	0.316
MAML1	protein	Q92585	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates	relocalization			9606									19304754	t		gcesareni	We show that maml1 potentiates p300 autoacetylation and p300 transcriptional activation. Maml1 directly enhances p300 hat activity, and this coincides with the translocation of maml1, p300 and acetylated histones to nuclear bodies.	SIGNOR-184853	0.635
SRC	protein	P12931	UNIPROT	DNM1	protein	Q05193	UNIPROT	up-regulates activity	phosphorylation	Tyr597	NTEQRNVyKDYRQLE	9534	BTO:0004055								12011079	t		lperfetto	Endocytosis of ligand-activated receptors requires dynamin-mediated GTP hydrolysis, which is regulated by dynamin self-assembly. Here, we demonstrate that phosphorylation of dynamin I by c-Src induces its self-assembly and increases its GTPase activity. Electron microscopic analyses reveal that tyrosine-phosphorylated dynamin I spontaneously self-assembles into large stacks of rings. Tyrosine 597 was identified as being phosphorylated both in vitro and in cultured cells following epidermal growth factor receptor stimulation.	SIGNOR-247129	0.621
DUSP6	protein	Q16828	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates	dephosphorylation			9606									12840032	t		gcesareni	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).	SIGNOR-103149	0.849
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser280	RSPSPQPsSHVAPQD	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248691	0.613
Immunoglobulin kappa light chain	protein	P0DOX7	UNIPROT	BCR-Mk	complex	SIGNOR-C433	SIGNOR	form complex	binding			9606	BTO:0000776								32323265	t		scontino	An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs.	SIGNOR-268186	0.2
fluoxetine	chemical	CHEBI:5118	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606									9537821	t		miannu	Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 	SIGNOR-258738	0.8
FASN	protein	P49327	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity by stabilization				9606	BTO:0001130								18838960	f		lperfetto	Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer	SIGNOR-242878	0.272
CDK1	protein	P06493	UNIPROT	MAPK6	protein	Q16659	UNIPROT	up-regulates	phosphorylation	Ser688	QFHSPVGsPLKSIQA	9606			SIGNOR-C17						20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.	SIGNOR-164491	0.461
VRK1	protein	Q99986	UNIPROT	BANF1	protein	O75531	UNIPROT	down-regulates	phosphorylation	Ser4	sQKHRDFV	9606	BTO:0000567								16371512	t		gcesareni	We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell	SIGNOR-143285	0.873
F2	protein	P00734	UNIPROT	F2R	protein	P25116	UNIPROT	up-regulates activity	cleavage			-1									10978167	t		lperfetto	Thrombin selectively cleaves PAR1, PAR3, and PAR4 to induce activation of platelets and vascular cells,	SIGNOR-263608	0.883
mTORC1	complex	SIGNOR-C3	SIGNOR	MYC	protein	P01106	UNIPROT	up-regulates				9606									24856037	f		miannu	MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity 	SIGNOR-256172	0.349
FGR	protein	P09769	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr925	DRSNDKVyENVTGLV	9606									12387730	t		gcesareni	Phosphorylated on tyrosine residues upon activation. Phosphorylation at tyr-925 is important for interaction with grb2 and depends on the complex formation between fak and the src-kinase fgr.	SIGNOR-94405	0.532
DVL2	protein	O14641	UNIPROT	PARD6A	protein	Q9NPB6	UNIPROT	up-regulates	binding			9606									23151663	t		gcesareni	In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl-associated activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58.	SIGNOR-199500	0.628
PRKCE	protein	Q02156	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates	phosphorylation	Ser706	ARIIGEKsFRRSVVG	9606									12058027	t		gcesareni	Furthermore, we show that pkd2 can be activated by classical and novel members of the protein kinase c (pkc) family such as pkc alpha, pkc epsilon, and pkc eta. These pkcs are activated by gastrin in ags-b cells. Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin.	SIGNOR-89411	0.2
PRKCA	protein	P17252	UNIPROT	AQP1	protein	P29972	UNIPROT	up-regulates	phosphorylation	Thr239	APRSSDLtDRVKVWT	9606		BTO:0000671							17522053	t		llicata	Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc).	SIGNOR-155106	0.2
MAPK9	protein	P45984	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606									18691976	t	The effect has been demonstrated using P45984-2	gcesareni	Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle.	SIGNOR-179275	0.495
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	iodide	smallmolecule	CHEBI:16382	ChEBI	up-regulates quantity	precursor of			9606									34674502	t		scontino	Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule. 	SIGNOR-268126	0.8
PTEN	protein	P60484	UNIPROT	NKX3-1	protein	Q99801	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Thr179	FQNRRYKtKRKQLSS	9606									31213464	t		lperfetto	Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression.|PTEN was also able to dephosphorylate NKX3.1 at threonine 179, a target of protein kinase C, but not threonine residues 89 and 93, targeted by casein kinase 2 .	SIGNOR-277026	0.455
SKA complex	complex	SIGNOR-C364	SIGNOR	Ndc80 complex	complex	SIGNOR-C361	SIGNOR	up-regulates activity	relocalization			-1									22483620	t		lperfetto	The Ska complex is an essential mitotic component required for accurate cell division in human cells. It is composed of three subunits that function together to establish stable kinetochore-microtubule interactions in concert with the Ndc80 network. |We discuss how this symmetric architecture might complement and stabilize the Ndc80-microtubule attachments 	SIGNOR-265225	0.546
GZMA	protein	P12544	UNIPROT	SET	protein	Q01105	UNIPROT	down-regulates	cleavage			9606									11555662	t		miannu	Gzma cleaved the nucleosome assembly protein set after lys176 and disrupted its nucleosome assembly activity.	SIGNOR-110462	0.7
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	A3/b1 integrin	complex	SIGNOR-C161	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259015	0.41
CDK5	protein	Q00535	UNIPROT	PPP1CA	protein	P62136	UNIPROT	down-regulates activity	phosphorylation	Thr320	NPGGRPItPPRNSAK	9606									12202491	t		gcesareni	Pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. Increasing doses of cdk2 resulted in increased phosphorylation of the thr-320 site. Phosphorylation of this site in pp1 corresponded to decreased pp1 activity.	SIGNOR-92269	0.403
NAE	complex	SIGNOR-C131	SIGNOR	CUL1	protein	Q13616	UNIPROT	up-regulates activity	neddylation			9606									25504797	t		lperfetto	The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates.	SIGNOR-243151	0.736
DBP	protein	Q10586	UNIPROT	CYP3A4	protein	P08684	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								18004209	f		miannu	 The oscillation in the expression of the CYP3A4 gene seemed to be the underlying cause of the rhythmic change in its metabolic activity. Luciferase reporter gene analysis and electrophoretic mobility shift assay revealed that the circadian transcriptional factor, D-site-binding protein (DBP), activated the transcription of the CYP3A4 gene by binding to the DNA sequence near the upstream of the transcriptional start site. The transactivation of the CYP3A4 gene by DBP was repressed by the E4 promoter-binding protein-4 (E4BP4), a negative component of the circadian clock.	SIGNOR-253835	0.2
WWTR1	protein	Q9GZV5	UNIPROT	ASNS	protein	P08243	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001615								22470139	f		miannu	Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation.	SIGNOR-255608	0.2
NR3C1	protein	P04150	UNIPROT	NR3C1/STAT5A	complex	SIGNOR-C84	SIGNOR	form complex	binding			9606									8878484	t		fspada	We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter.	SIGNOR-44373	0.546
3-methyladenine	chemical	CHEBI:38635	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205639	0.8
AKT1	protein	P31749	UNIPROT	FOXO6	protein	A8MYZ6	UNIPROT	down-regulates	phosphorylation			9606									21798082	t		gcesareni	Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b).	SIGNOR-175294	0.635
SPOP	protein	O43791	UNIPROT	BMI1	protein	P35226	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								15897469	t		miannu	Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. To investigate whether BMI1 can form a complex with SPOP and CULLIN3 in vivo, we reconstituted the complex in 293HEK cells. We find that BMI1 readily immunoprecipitates both hemagglutinin (HA)-SPOP and CULLIN3, and, conversely, CULLIN3 immunoprecipitates BMI1 (Fig. 2a). Complex formation depends on the presence of SPOP, in accordance with BMI1 binding to the MATH domain of SPOP (Fig. 1b) and previously published data showing SPOP–CULLIN interaction by means of the BTB/POZ domain of SPOP (30).	SIGNOR-272658	0.409
CRTC3	protein	Q6UUV7	UNIPROT	BCL3	protein	P20749	UNIPROT	up-regulates	binding			9606	BTO:0001271;BTO:0000776;BTO:0000786								17644518	t		miannu	The ankyrin repeat domain of bcl3 interacted with torc3 / we determined that bcl3 inhibited transcription from the htlv-1 ltr in a manner dependent on torc3	SIGNOR-156950	0.369
PFKFB4	protein	Q16877	UNIPROT	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	down-regulates quantity	chemical modification			9606									15170386	t		miannu	Fru-2,6-P2 (fructose 2,6-bisphosphate) is a signal molecule that controls glycolysis. Since its discovery more than 20 years ago, inroads have been made towards the understanding of the structure‚Äì function relationships in PFK-2 (6-phosphofructo-2-kinase)/ FBPase-2 (fructose-2,6-bisphosphatase), the homodimeric bifunctional enzyme that catalyses the synthesis and degradation of Fru-2,6-P2	SIGNOR-268117	0.8
452342-67-5	chemical	CID:10202642	PUBCHEM	TGFBR1	protein	P36897	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0000671							18075500	t		gcesareni	Gw788388 is a new tgf-beta type i receptor inhibitor with a much improved pharmacokinetic profile compared with sb431542.	SIGNOR-159863	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SP1	protein	P08047	UNIPROT	up-regulates activity	phosphorylation			9606									23616010	t		lperfetto	Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1.	SIGNOR-233523	0.2
GSK3B	protein	P49841	UNIPROT	CRMP1	protein	Q14194	UNIPROT	up-regulates	phosphorylation	Thr514	PATPKYAtPAPSAKS	9606	BTO:0000938								16611631	t		lperfetto	Using in vitro kinase assays and pharmacological inhibition of gsk3 as described above for crmp2 and crmp4, it was found that thr509 (and presumably ser518 and thr514) of human crmp1 is phosphorylated by gsk3, following priming of ser522 by cdk5	SIGNOR-145999	0.447
MRGPRD	protein	Q8TDS7	UNIPROT	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	down-regulates				10116									23446738	f		Luana	Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D.	SIGNOR-262309	0.7
RAF1	protein	P04049	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates activity	phosphorylation			9606		BTO:0000975							11018021	t		lperfetto	The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins.	SIGNOR-244945	0.737
FBXO22	protein	Q8NEZ5	UNIPROT	KLF4	protein	O43474	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000594								26087183	t		lperfetto	F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression	SIGNOR-273444	0.372
PRKACA	protein	P17612	UNIPROT	AQP5	protein	P55064	UNIPROT	up-regulates activity	phosphorylation	Ser156	STDSRRTsPVGSPAL	9606	BTO:0000007								26569106	t		lperfetto	 AQP5 can be directly phosphorylated by PKA at Ser 156 |Our data hint at a mechanism whereby phosphorylation of Ser 156 in AQP5 increases its membrane localization, thereby enhancing cancer cell proliferation.	SIGNOR-272088	0.2
MAPK1	protein	P28482	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Ser266	QYLGSIAsPSVHPAT	9606									16046550	t	The effect has been demonstrated using Q01196-8	miannu	We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 	SIGNOR-138973	0.2
CPT1B	protein	Q92523	UNIPROT	(R)-carnitine	smallmolecule	CHEBI:16347	ChEBI	down-regulates quantity	chemical modification			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267121	0.8
MTSS1	protein	O43312	UNIPROT	SUFU	protein	Q9UMX1	UNIPROT	up-regulates	binding			9606		BTO:0001253							15545630	t		miannu	We found that in vitro translated gli1 and sufu bind to gst-mim, but not gst-mim?N399 Or gst columns (fig. 4f). Indicative of the importance of the mim/gli complex interactions, the mim?N399 Mutant that fails to interact with gli and sufu showed a markedly reduced capacity to potentiate gli-dependent transcription (fig. 4g). Although these results indicate that a mim/gli/sufu complex is important for mim-mediated transcriptional potentiation	SIGNOR-130545	0.451
C5AR1	protein	P21730	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	up-regulates quantity by expression													1847994	f		lperfetto	The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 	SIGNOR-263469	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PDE4C	protein	Q08493	UNIPROT	up-regulates activity	phosphorylation	Ser14	GEGAEACsRLSRSRG	9534									12023945	t		miannu	Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5.	SIGNOR-273938	0.2
CSNK2A1	protein	P68400	UNIPROT	GMFB	protein	P60983	UNIPROT	unknown	phosphorylation	Ser53	DEELEGIsPDELKDE	-1									7598724	t		llicata	We report that recombinant glia maturation factor (GMF), a 17-kD brain protein, can be phosphorylated in vitro at the serine residue by protein kinase C (PKC), protein kinase A (PKA), and casein kinase II (CKII), and at the threonine residue by p90 ribosomal S6 kinase (RSK). 	SIGNOR-250868	0.336
MAPK3	protein	P27361	UNIPROT	SYN3	protein	O14994	UNIPROT	up-regulates	phosphorylation	Ser470	PQGQQPLsPQSGSPQ	9606									14732590	t		lperfetto	A rare, missense polymorphism, s470n, was identified in the synapsin iii gene and appeared more frequently in individuals with schizophrenia than in controls. Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action.	SIGNOR-121402	0.2
SNAI2	protein	O43623	UNIPROT	CXCL12	protein	P48061	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001033								22074556	f		miannu	 We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. 	SIGNOR-255169	0.419
ITCH	protein	Q96J02	UNIPROT	DTX1	protein	Q86Y01	UNIPROT	down-regulates	ubiquitination			9606									17028573	t		gcesareni	Itch/aip4 mediates deltex degradation through the formation of k29-linked polyubiquitin chains.	SIGNOR-150002	0.688
PRKACA	protein	P17612	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	down-regulates activity	phosphorylation	Ser486	DDEITEAKsGTATPQRS	10116	BTO:0002135								17023420	t			These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine.	SIGNOR-256110	0.401
CBX1	protein	P83916	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	binding			9606							methylation:Lys10	RTKQTARkSTGGKAP	19111658	t		miannu	 A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 	SIGNOR-264493	0.2
HMOX1	protein	P09601	UNIPROT	heme	smallmolecule	CHEBI:30413	ChEBI	down-regulates quantity	chemical modification			9606									10490932	t	Regulation	miannu	Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme	SIGNOR-251911	0.8
HIC1	protein	Q14526	UNIPROT	E2F1	protein	Q01094	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000452								19486893	f	 	miannu	 HIC1 is also implicated in growth control since it recruits BRG1, one of the two alternative ATPases (BRM or BRG1) of SWI/SNF chromatin-remodeling complexes to repress transcription of E2F1 in quiescent fibroblasts.	SIGNOR-254239	0.293
ZNF521	protein	Q96K83	UNIPROT	EBF1	protein	Q9UH73	UNIPROT	down-regulates	binding			9606	BTO:0000776								14630787	t		miannu	Ehzf inhibits the transcriptional activity of early b-cell factor (ebf), a transcription factor essential for specification of the b-cell lineage /ability to interact with the neural and hematopoietic transcription factor olf1/ebf1 and inhibit its binding to dna	SIGNOR-119300	0.515
CD38	protein	P28907	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0000078								18626062	f		miannu	CD38 knockdown was found to increase apoptosis in normal microglia, but played a protective role in LPS-stimulated microglia and reduced proinflammatory cytokine secretion (Figure 1)	SIGNOR-264255	0.7
GABA-A	proteinfamily	SIGNOR-PF61	SIGNOR	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	relocalization			9606									18790874	t		miannu	GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-264988	0.8
MC3R	protein	P41968	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256891	0.252
RAB38	protein	P57729	UNIPROT	Neuronal AP-3	complex	SIGNOR-C445	SIGNOR	up-regulates activity	relocalization			9606									23247405	t		miannu	Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes.	SIGNOR-268526	0.282
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRM2	protein	Q14416	UNIPROT	up-regulates activity	chemical activation			9606									25042998	t		miannu	Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate	SIGNOR-264071	0.8
FYN	protein	P06241	UNIPROT	BCR-Dk	complex	SIGNOR-C435	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000776								32323266	t		scontino	The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases.	SIGNOR-268213	0.619
NF2	protein	P35240	UNIPROT	LATS1	protein	O95835	UNIPROT	up-regulates	binding			9606									24012335	t	The opposite changes in Lats/YAP and Mst1/2 phosphorylation upon loss of NF2 therefore argue against the generally assumed linear model in which NF2 signals through activation of Mst1/3	flangone	As expected, the nf2-/- fc-912 cells were defective in lats1/2 phosphorylation (figure s2e-f). Subcellular fractionation revealed a significant increase of endogenous lats1/2 in the cytoplasmic relative to the membrane fraction in the nf2-/- fc-912 schwann cells compared to the nf2+/+ fh-912 schwann cells (figure 2e). This localization defect was rescued by re-expression of nf2	SIGNOR-202604	0.712
INTS1	protein	Q8N201	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261468	0.889
CSRP3	protein	P50461	UNIPROT	MYF6	protein	P23409	UNIPROT	up-regulates activity	binding			10090	BTO:0004058								9234731	t	2	miannu	we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements.	SIGNOR-241096	0.457
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20921405	f		gcesareni	Nf-kb activation following t-cell receptor engagement induces the expression of mdm2 through interaction with nf-kb sites in its p1 promoter	SIGNOR-168296	0.38
C5AR2	protein	Q9P296	UNIPROT	Chemotaxis	phenotype	SIGNOR-PH93	SIGNOR	up-regulates				9606									9108406	f		lperfetto	We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro.	SIGNOR-263459	0.7
RPS6KA1	protein	Q15418	UNIPROT	FLNA	protein	P21333	UNIPROT	up-regulates	phosphorylation	Ser2152	TRRRRAPsVANVGSH	9606	BTO:0000848								15024089	t		gcesareni	We show that the n-terminal kinase domain of rsk phosphorylates flna on ser(2152) in response to mitogens	SIGNOR-123458	0.393
pyruvate	smallmolecule	CHEBI:15361	ChEBI	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	up-regulates quantity	precursor of			9606									24363178	t		miannu	As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2)	SIGNOR-266553	0.8
CSK	protein	P41240	UNIPROT	FGR	protein	P09769	UNIPROT	down-regulates activity	phosphorylation	Tyr523	FTSAEPQyQPGDQT	-1									7515063	t		llicata	CSK catalyzed phosphorylation affects Tyr-511 of c-Fgr, homologous to Tyr-527 of c-Src and it prevents the autophosphorylation normally occurring at c-Fgr Tyr-400, homologous to c-Src Tyr-416. | Once phosphorylated at Tyr-511 and down-regulated by CSK, c-Fgr is no more susceptible to polylysine stimulation. 	SIGNOR-250779	0.516
MYC	protein	P01106	UNIPROT	HLA-E	protein	P13747	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000848								8206526	f		miannu	 In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene.	SIGNOR-254604	0.2
oxaprozin	chemical	CHEBI:7822	ChEBI	PTGS1	protein	P23219	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000132;BTO:0003652								9650852	t		miannu	We used human platelets cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 for measuring cyclooxygenase selectivity. The presence of the enzymes was confirmed by immunoblotting and immunoprecipitation analysis, and by the reverse transcriptase-polymerase chain reaction. Mean IC50 values (microM) for human platelet cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 and cyclooxygenase-1/-2 IC50 ratio of various NSAIDs were as follows: aspirin, 3.2, 26, 0.12; diclofenac, 0.037, 0.00097, 38; etodolac, 122, 0.68, 179; ibuprofen, 3.0, 3.5, 0.86; indomethacin, 0.013, 0.044, 0.30; loxoprofen (active metabolite), 0.38, 0.12, 3.2; NS-398, 12, 0.0095, 1263; oxaprozin, 2.2, 36, 0.061; zaltoprofen, 1.3, 0.34, 3.8; respectively.	SIGNOR-258929	0.8
APC2	protein	O95996	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates	binding			9606				SIGNOR-C110					9601641	t		acerquone	Human axin (haxin) binds directly to beta-catenin, gsk3 beta, and apc in vitro, and the endogenous proteins are found in a complex in cells.	SIGNOR-57673	0.765
SNU13	protein	P55769	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270629	0.2
PAK1	protein	Q13153	UNIPROT	PAK1	protein	Q13153	UNIPROT	up-regulates activity	phosphorylation	Ser57	KKDRFYRsILPGDKT	9534	BTO:0000298								9032240	t		miannu	Cdc42 and Rac1 cause alpha-PAK autophosphorylation and kinase activation.	SIGNOR-250219	0.2
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates	phosphorylation	Thr89	VSPLLLTtTNSSEGL	9606									11152499	t		tpavlidou	Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites.	SIGNOR-85785	0.2
S1PR3	protein	Q99500	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			9606	BTO:0000007								10488065	t		gcesareni	Edg-3 and edg-5 couple not only to gibut also to gqand g13.	SIGNOR-70710	0.508
CEP72	protein	Q9P209	UNIPROT	CDK5RAP2	protein	Q96SN8	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								26297806	t		lperfetto	By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically.	SIGNOR-271720	0.65
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	PBK	protein	Q96KB5	UNIPROT	up-regulates activity	phosphorylation	Thr9	EGISNFKtPSKLSEK										15541388	t		llicata	During mitosis, TOPK-Thr-9 was phosphorylated by cdk1/cyclin B and TOPK significantly associates with mitotic spindles. When TOPK expression was suppressed, formation of spindle midzone was thinned and dimmed and cytokinesis was disturbed.	SIGNOR-250720	0.568
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	SPHK2	protein	Q9NRA0	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								17311928	t	inferred from 70% family members	llicata	Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1	SIGNOR-270036	0.2
MCM2	protein	P49736	UNIPROT	MCM	complex	SIGNOR-C268	SIGNOR	form complex	binding			9606									19946136	t			The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication.	SIGNOR-198428	0.766
PRKCG	protein	P05129	UNIPROT	STK17B	protein	O94768	UNIPROT	down-regulates activity	phosphorylation	Ser351	PEDSSMVsKRFRFDD	10090	BTO:0000944								18084041	t		miannu	These results suggest that phosphorylation of Ser350 plays an essential role in regulating translocation of DRAK2 to the nucleus from the cytoplasm, possibly by affecting the activity of the NLS. Ectopic expression of PKC-gamma induced cytoplasmic localization of DRAK2 and PKC-gamma phosphorylated Ser350 flanking the NLS. 	SIGNOR-263178	0.2
CTNND1	protein	O60716	UNIPROT	CDH5	protein	P33151	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0003564								14610055	t		miannu	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 	SIGNOR-252126	0.768
DEPTOR	protein	Q8TB45	UNIPROT	mTORC2	complex	SIGNOR-C2	SIGNOR	form complex	binding			9606									25628925	t		lperfetto	Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)	SIGNOR-205603	0.715
RNF5	protein	Q99942	UNIPROT	PXN	protein	P49023	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								12861019	t		miannu	Here we demonstrate that the human homologue of RNF5 associates with the amino-terminal domain of paxillin, resulting in its ubiquitination. RNF5 requires intact RING and C-terminal domains to mediate paxillin ubiquitination.  Concomitantly, RNF5 expression results in inhibition of cell motility. Via targeting of paxillin ubiquitination, which alters its localization, RNF5 emerges as a novel regulator of cell motility.	SIGNOR-271479	0.416
MAOB	protein	P27338	UNIPROT	serotonin	smallmolecule	CHEBI:28790	ChEBI	down-regulates quantity	chemical modification			9606									31024440	t	brain	lperfetto	Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA).	SIGNOR-264015	0.8
PLK1	protein	P53350	UNIPROT	BUB1B	protein	O60566	UNIPROT	up-regulates	phosphorylation	Thr1008	LNANDEAtVSVLGEL	9606									17376779	t		gcesareni	Bubr1 was phosphorylated by plk1 in vitro at two plk1 consensus sites in the kinase domain of bubr1	SIGNOR-153863	0.834
CSNK2A2	protein	P19784	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates activity	phosphorylation	Ser64	LQTDGNRsSHSRLGR	9606									11583622	t		llicata	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250978	0.289
Dacinostat	chemical	CID:6445533	PUBCHEM	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									15171259	t		lperfetto	We have developed a cinnamic hydroxamic class of histone deacetylase inhibitors of which a prototype was designated as NVP-LAQ824. NVP-LAQ824, inhibits histone deacetylase enzymatic activities in vitro and transcriptionally activated the p21 promoter in reporter gene assays.	SIGNOR-262032	0.8
MAP3K14	protein	Q99558	UNIPROT	NFKB2	protein	Q00653	UNIPROT	up-regulates activity	phosphorylation	Ser870	KEDSAYGsQSVEQEA	9606	BTO:0000007								11239468	t		lperfetto	NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870	SIGNOR-105557	0.664
HIPK2	protein	Q9H2X6	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates	phosphorylation	Ser38	EGRQPSPsPSPTERA	9606									19015637	t		llicata	In response to dna damage, hipk2 phosphorylates pml at serines 8 and 38. he n-terminal phosphorylation sites contribute to the dna damage-induced pml sumoylation and are required for the ability of pml to cooperate with hipk2 for the induction of cell death.	SIGNOR-182428	0.45
LATS2	protein	Q9NRM7	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	phosphorylation	Ser127	PQHVRAHsSPASLQL	9606									22658639	t	Uninhibited YAP/TAZ localize to the nucleus where they serve as coactivators for the TEA-domain family member (TEAD) of DNA-binding transcription factors.	milica	In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus.	SIGNOR-197655	0.815
JNJ-28312141 free base	chemical	CID:11676971	PUBCHEM	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258125	0.8
CDK1	protein	P06493	UNIPROT	PML	protein	P29590	UNIPROT	down-regulates	phosphorylation			9606									21840486	t		gcesareni	Here, we show that klhl20, a cullin3 (cul3) substrate adaptor induced by hif-1, coordinates with the actions of cdk1/2 and pin1 to mediate hypoxia-induced pml proteasomal degradation.	SIGNOR-176033	0.351
MAPK1	protein	P28482	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser130	SGEQAEGsPGGPGDS	9606									19364816	t		gcesareni	Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1.|Phosphopeptide analysis of in vitro ERK2-phosphorylated p21(Cip1) revealed two phosphorylation sites, Thr57 and Ser130. 	SIGNOR-185215	0.373
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	LATS1	protein	O95835	UNIPROT	up-regulates	phosphorylation	Ser613	EKKQITTsPITVRKN	9606									12372621	t		lperfetto	Warts is a serine/threonine kinase and a dynamic component of the mitotic apparatus. We have found that cdc2/cyclin b forms a complex with a fraction of warts in the centrosome and phosphorylates the ser613 site of warts during mitosisit can be speculated that phosphorylation of warts by cdc2/cyclin b promotes a protein complex formation on the mitotic apparatus at early mitosis, which may be required for subsequent activation of warts kinase at the metaphase-anaphase transition.	SIGNOR-216757	0.358
BRF1	protein	Q92994	UNIPROT	TFIIIB	complex	SIGNOR-C393	SIGNOR	form complex	binding												29378333	t		lperfetto	Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1).	SIGNOR-266190	0.703
SRC	protein	P12931	UNIPROT	BMX	protein	P51813	UNIPROT	up-regulates	phosphorylation	Tyr566	RYVLDDQyVSSVGTK	9606									10688651	t		lperfetto	Coexpression of v-src and etk led to a transphosphorylation on tyrosine 566 of etk and subsequent autophosphorylation. These events correlated with a substantial increase in the kinase activity of etk.	SIGNOR-75330	0.515
CDK1	protein	P06493	UNIPROT	PLEC	protein	Q15149	UNIPROT	down-regulates	phosphorylation	Thr4539	GGLIEPDtPGRVPLD	9606			SIGNOR-C17						19709076	t		lperfetto	Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane.	SIGNOR-187766	0.396
MAPK1	protein	P28482	UNIPROT	PDE4C	protein	Q08493	UNIPROT	down-regulates	phosphorylation	Ser641	YQSKIPRsPSDLTNP	9606									11030732	t	The effect has been demonstrated using Q08493-2	gcesareni	The short-form pde4b2 isoenzyme was activated by erk2 phosphorylation. sub-family selective actions in the ability of erk2 map kinase to phosphorylate and regulate the activity of pde4 cyclic amp-specific phosphodiesterases	SIGNOR-83187	0.259
TDGF1	protein	P13385	UNIPROT	ACVR2A	protein	P27037	UNIPROT	down-regulates	binding			9606	BTO:0000007								12682303	t		acerquone	Here we show that cripto can form a complex with activin and actrii/iib cripto inhibited crosslinking of activin to alk4 and the association of alk4 with actrii/iib.	SIGNOR-100052	0.627
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				9606	BTO:0000567								22749528	f		Luana	Leucine and Glutamine Activate Glutaminolysis and mTORC1	SIGNOR-268015	0.8
ABL1	protein	P00519	UNIPROT	ABL1	protein	P00519	UNIPROT	up-regulates activity	phosphorylation	Tyr393	RLMTGDTyTAHAGAK	9606	BTO:0001271								8441409	t		lperfetto	Sh1 domain autophosphorylation of p210 bcr/abl is required for transformation but not growth factor independence.	SIGNOR-39142	0.2
EXOSC10	protein	Q01780	UNIPROT	Exosome_Complex	complex	SIGNOR-C255	SIGNOR	form complex	binding			-1									24189234	t		miannu	The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 	SIGNOR-261390	0.943
JUN	protein	P05412	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	binding			9606									10871633	t		irozzo	These results indicate that interaction between Smad3 and c-Jun may repress Smad3 transcriptional activity.	SIGNOR-256284	0.741
AMER1	protein	Q5JTC6	UNIPROT	CSNK1G1	protein	Q9HCP0	UNIPROT	up-regulates	binding			9606									21304492	t		gcesareni	Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6.	SIGNOR-171889	0.2
HDLBP	protein	Q00341	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates activity	binding			9606	BTO:0000150								33941620	t		miannu	We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites.	SIGNOR-266697	0.2
FZR1	protein	Q9UM11	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	up-regulates activity	binding												16896351	t		lperfetto	In addition to E2 enzymes, APC/C activity is also strictly dependent on one of several co-activator proteins that associate with APC/C during specific periods of the cell cycle. The best studied of these are Cdc20 and Cdh1	SIGNOR-252015	0.845
arginine	smallmolecule	CHEBI:29016	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264756	0.7
oxymetazoline	chemical	CHEBI:7862	ChEBI	HTR1B	protein	P28222	UNIPROT	up-regulates activity	chemical activation			9913		BTO:0000142							9632357	t		miannu	Benzylimidazolines may represent a class of 5-HT1D ligands that has yet to be exploited. On the basis of a previous report that the 2-(substituted-benzyl)imidazoline alpha-adrenergic agonist oxymetazoline (8) binds with high affinity at calf brain 5-HT1D receptors, we explored the structure-affinity relationships of a series of related derivatives.	SIGNOR-258928	0.8
ANAPC13	protein	Q9BS18	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	form complex	binding												16896351	t		lperfetto	The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex.	SIGNOR-252012	0.828
SIRT1	protein	Q96EB6	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	deacetylation	Lys382	QSTSRHKkLMFKTEG	9606	BTO:0000150								19047049	t		gcesareni	Sirt1 has been shown to regulate cell fate in part by deacetylating the p53 protein at lysine 382 and inhibiting p53-mediated transcriptional activation and apoptosis.	SIGNOR-182515	0.797
LAMC1	protein	P11047	UNIPROT	Laminin-1	complex	SIGNOR-C183	SIGNOR	form complex	binding												7496033	t		lperfetto	Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1.	SIGNOR-253234	0.601
SMAD7	protein	O15105	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	binding			9606									9892110	t		lperfetto	Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3.	SIGNOR-64085	0.596
estriol	smallmolecule	CHEBI:27974	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258586	0.8
PTPN11	protein	Q06124	UNIPROT	STAT1	protein	P42224	UNIPROT	down-regulates activity	dephosphorylation	Ser727	TDNLLPMsPEEFDEV	9606	BTO:0000007								12270932	t			SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei|In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) |Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity.	SIGNOR-248673	0.733
CTBP1	protein	Q13363	UNIPROT	ZEB2	protein	O60315	UNIPROT	up-regulates activity	binding			9606									16061479	t		miannu	Polycomb protein Pc2 acts as an SUMO E3 ligase for SIP1. SIP1 is an active transcription repressor for many transcription factors and target genes. SIP1 Sumoylation Disrupts the Recruitment of the Corepressor CtBP	SIGNOR-225484	0.487
FUS	protein	P35637	UNIPROT	DUSP22	protein	Q9NRW4	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			10090									28515487	f			This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease	SIGNOR-262803	0.2
Ruboxistaurin	chemical	CID:153999	PUBCHEM	PRKACB	protein	P22694	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258275	0.8
MAPK8	protein	P45983	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser616	DDGYMPMsPGVAPVP	9606									12510059	t		gcesareni	Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1.	SIGNOR-96944	0.767
HCK	protein	P08631	UNIPROT	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	up-regulates activity	phosphorylation	Tyr832	LRYEGRVyHYRINTA	9606									16912036	t		Manara	Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 	SIGNOR-260814	0.2
PTPN12	protein	Q05209	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates activity	dephosphorylation	Tyr1196	GAVENPEyLTPQGGA	9606									29330094	t		miannu	In MDA-MB-231 cells, a human triple negative breast cancer cell line, phosphorylation of PTPN12 on Ser 19 was increased in response to cyclin dependent kinase 2 (CDK2), and this impaired PTPN12 's ability to dephosphorylate HER2 on Y1196.|PTPN12 negatively regulates Her2, by dephosphorylation on Tyr 1196 on Her2.	SIGNOR-277038	0.602
α-D-glucosyl-glycogenin	complex	SIGNOR-C430	SIGNOR	glycogen	smallmolecule	CHEBI:28087	ChEBI	up-regulates quantity	precursor of			9606									26199317	t		miannu	Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked glucose chains, to increase solubility of the glycogen polymer. In eukaryotes, glycogenin (EC 2.4.1.186) initiates the synthesis of the linear glucan chain (2), which is elongated by glycogen synthase (GYS, EC 2.4.1.11) (3), functioning in concert with glycogen branching enzyme (GBE, EC 2.4.1.18) to introduce side chains	SIGNOR-268138	0.8
LHX1	protein	P48742	UNIPROT	OTX2	protein	P32243	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								10623575	t		miannu	Here we show that OTX2 directly associates with LIM1 and HNF-3beta. The luciferase assay with the P3C sequence, a specific DNA binding sequence for paired-class homeobox genes, has demonstrated that LIM1 enhances, but HNF-3beta represses, OTX2-directed gene expression.	SIGNOR-221161	0.445
MYC	protein	P01106	UNIPROT	SHMT1	protein	P34896	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003291								18628958	t		miannu	Myc regulates the de novo purine and pyrimidine synthetic genes in multiple biological systems. Intriguingly, MYC was found to directly activate the expression of SHMT1, and SHMT2, which are enzymes involved in single carbon metabolism and are essential for dNTP synthesis	SIGNOR-267379	0.28
FZD7	protein	O75084	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity													23290138	f		Simone Vumbaca	We observed that overexpression of Fzd7 or stimulation with FN resulted in increased levels of active Rac1 in primary myoblasts	SIGNOR-255647	0.43
BCL7C	protein	Q8WUZ0	UNIPROT	Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	form complex	binding			10090	BTO:0001086								19279220	t		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270715	0.516
WNT5A	protein	P41221	UNIPROT	Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	up-regulates activity	binding			9606									16273260	t		gcesareni	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-253129	0.828
FAM13A	protein	O94988	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260502	0.409
FH	protein	P07954	UNIPROT	(S)-malate(2-)	smallmolecule	CHEBI:15589	ChEBI	up-regulates quantity	chemical modification			9606									30761759	t		miannu	Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors.	SIGNOR-266280	0.8
RPL14	protein	P50914	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262484	0.866
TNF	protein	P01375	UNIPROT	DIO	proteinfamily	SIGNOR-PF83	SIGNOR	down-regulates quantity by repression	transcriptional regulation			10116									9397972	f	inferred from family member	scontino	From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells grown in TSH-containing medium. These include TNF-a, IL-lb and INF-g but not TGF-b.	SIGNOR-267811	0.261
exemestane	chemical	CHEBI:4953	ChEBI	CYP19A1	protein	P11511	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191520	0.8
ATM	protein	Q13315	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser9	EEPQSDPsVEPPLSQ	9606									11875057	t		gcesareni	In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization.	SIGNOR-115348	0.838
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	SRPK2	protein	P78362	UNIPROT	up-regulates	phosphorylation	Thr492	PSHDRSRtVSASSTG	9606	BTO:0000938	BTO:0000142							19592491	t		lperfetto	Here we show that srpk2, a protein kinase specific for the serine/arginine (sr) family of splicing factors, triggers cell cycle progression in neurons and induces apoptosis through regulation of nuclear cyclin d1. Akt phosphorylates srpk2 on thr-492 and promotes its nuclear translocation leading to cyclin d1 up-regulation, cell cycle reentry, and neuronal apoptosis.	SIGNOR-244341	0.2
KRAS	protein	P01116	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates	phosphorylation	Ser67	RQLRKVRsVELDQLP	9606	BTO:0000776;BTO:0000785								8649450	t		gcesareni	Activation of ras may lead to two distinct ras-dependent pathways involving either a raf1/mek/mapk module or a mekk/sek/sapk module; jnk/sapk binds to the d domain near the nh2 terminus of mekk1 from approximately residues 6270 (9, 10). Pak1 can phosphorylate mekk1 on serine 67 within its jnk/sapk-binding d domain. Phosphorylation of mekk1 on serine 67 alters the state of the d domain, thereby decreasing its affinity for jnk/sapk. Under these conditions jnk/sapk is not recruited into the mekk1 signaling module.	SIGNOR-41953	0.374
MAPK9	protein	P45984	UNIPROT	BCL2L11	protein	O43521	UNIPROT	up-regulates activity	phosphorylation	Ser77	PGPFATRsPLFIFMR										12818176	t		miannu	JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity. 	SIGNOR-250135	0.622
ERBB2	protein	P04626	UNIPROT	ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	up-regulates activity	phosphorylation			-1									1706616	t	inferred from 70% of family members		 Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2.	SIGNOR-269875	0.61
EGFR	protein	P00533	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr194	ALEKKSNyEVLEKDV	9606									20802513	t		llicata	In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.	SIGNOR-167646	0.581
lenalidomide	chemical	CHEBI:63791	ChEBI	CSNK1A1	protein	P48729	UNIPROT	down-regulates quantity by destabilization				9606	BTO:0000670								26131937	f		gcesareni	We demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1a) by the E3 ubiquitin ligase CUL4€“RBX1€“DDB1€“CRBN (known as CRL4CRBN)	SIGNOR-236895	0.8
NCOA1	protein	Q15788	UNIPROT	APOC3	protein	P02656	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f		miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-255065	0.2
AKT3	protein	Q9Y243	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606									23552696	t		lperfetto	Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1	SIGNOR-245424	0.724
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr280	VEFMCKVySDPQPHI	9606									12601080	t		lperfetto	Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways.	SIGNOR-98626	0.2
A4/b1 integrin	complex	SIGNOR-C162	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257704	0.621
R2TP core co-chaperone	complex	SIGNOR-C515	SIGNOR	PAQosome co-chaperone complex	complex	SIGNOR-C516	SIGNOR	form complex	binding			9606									30484152	t		miannu	The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92. 	SIGNOR-270925	0.552
PSMA3	protein	P25788	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263362	0.846
CTNNB1	protein	P35222	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates				9606									22298955	f		gcesareni	In-teractions between beta-catenin and runx2 play an im-portant role in bmp-9-induced osteogenic differentia-tion of mscs.	SIGNOR-195570	0.455
LAMB1	protein	P07942	UNIPROT	Laminin-1	complex	SIGNOR-C183	SIGNOR	form complex	binding												7496033	t		lperfetto	Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1.	SIGNOR-253233	0.613
MAP4K1	protein	Q92918	UNIPROT	CARD11	protein	Q9BXL7	UNIPROT	up-regulates activity	phosphorylation	Ser558	MQPPRSRsSIMSITA	-1									19706536	t		miannu	HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro.	SIGNOR-276257	0.507
CSNK2A1	protein	P68400	UNIPROT	DEK	protein	P35659	UNIPROT	up-regulates	phosphorylation	Ser32	MPGPREEsEEEEDED	9606									16809543	t		amattioni	Dek phosphorylated at serines 19 and 32. Dek and its phosphorylation are required for intron removal	SIGNOR-147365	0.356
IKBKB	protein	O14920	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000567								11971985	t			We demonstrated the in vitro phosphorylation of SRC-3 by the two catalytic subunits of the IKK complex, IKKα and IKKβ.  IKK kinase activity is required for synergistic activation with SRC-3	SIGNOR-251298	0.385
NFE2L2	protein	Q16236	UNIPROT	TALDO1	protein	P37837	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22789539	f		miannu	We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). 	SIGNOR-267357	0.376
CLK2	protein	P49760	UNIPROT	PTPN1	protein	P18031	UNIPROT	up-regulates activity	phosphorylation	Ser243	DKRKDPSsVDIKKVL	-1									10480872	t		llicata	The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. 	SIGNOR-250776	0.327
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGA2	protein	Q9Y5H1	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265691	0.2
clonidine	chemical	CHEBI:46631	ChEBI	ADRA2C	protein	P18825	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258903	0.8
SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates activity	binding			9606	BTO:0002181								11950834	t		irozzo	Using genetic and biochemical approaches, we show that several subunits of the human SWI/SNF complex bind to the tumor suppressor protein p53 in vivo and in vitro.Molecular connection between p53 and the SWI/SNF complex implicates that (i) the SWI/SNF complex is necessary for p53-driven transcriptional activation, and (ii) the SWI/SNF complex plays an important role in p53-mediated cell cycle control.	SIGNOR-256285	0.444
DSCAM	protein	O60469	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								30745319	t		miannu	Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels.	SIGNOR-264277	0.2
TFIIE	complex	SIGNOR-C458	SIGNOR	TFIIH	complex	SIGNOR-C457	SIGNOR	up-regulates activity	relocalization			9606									31064989	t		lperfetto	The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur.	SIGNOR-269363	0.729
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	MARK3	protein	P27448	UNIPROT	down-regulates	phosphorylation	Thr90	AIKIIDKtQLNPTSL	9606									15319445	t		gcesareni	Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1.	SIGNOR-259431	0.2
PELI1	protein	Q96FA3	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates quantity by expression	ubiquitination			9606									17997719	t		lperfetto	These results were consistent with the observations made in vitro, namely that pellino isoforms are activated by irak1-catalysed phosphorylation and that, once activated, can ubiquitinate irak1 in cells.	SIGNOR-159055	0.758
PIK3R1	protein	P27986	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								14665640	t		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242637	0.934
TRIB3	protein	Q96RU7	UNIPROT	ACACB	protein	O00763	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								16794074	t		miannu	TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).	SIGNOR-271601	0.261
MLL1 complex	complex	SIGNOR-C89	SIGNOR	H3-4	protein	Q16695	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606									24680668	t		miannu	Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation.	SIGNOR-268803	0.2
Lig4-Xrcc4 complex	complex	SIGNOR-C354	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				-1									19837014	t		miannu	The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals. 	SIGNOR-264534	0.7
PRKCE	protein	Q02156	UNIPROT	KCNK3	protein	O14649	UNIPROT	down-regulates activity	phosphorylation	Thr383	TGLHSLStFRGLMKR	-1									23229553	t		miannu	We have previously shown that carbamylated PAF-induced repolarization abnormalities result from the protein kinase C (PKC) ε-dependent phosphorylation of the two-pore domain potassium channel TASK-1. Further studies identified threonine 383 in the C terminus of human and canine TASK-1 as the phosphorylation site required for PAF-dependent inhibition of the channel.	SIGNOR-276431	0.2
DOK1	protein	Q99704	UNIPROT	A11/b1 integrin	complex	SIGNOR-C168	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257679	0.32
ALG11	protein	Q2TAA5	UNIPROT	alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol)	smallmolecule	CHEBI:133994	ChEBI	up-regulates quantity	chemical modification			9606									28575298	t		lperfetto	The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum.	SIGNOR-260417	0.8
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	TAL1	protein	P17542	UNIPROT	down-regulates	phosphorylation	Ser122	DGRMVQLsPPALAAP	9606									11904294	t		lperfetto	We found that hypoxia greatly accelerated tal1 turnover in these cells through mitogen-activated protein kinase (mapk)2-mediated phosphorylation, ubiquitination, and proteasomal degradation.	SIGNOR-244975	0.2
DVL1	protein	O14640	UNIPROT	RND1	protein	Q92730	UNIPROT	up-regulates				9606									23151663	f		gcesareni	In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58.	SIGNOR-199387	0.276
DUSP16	protein	Q9BY84	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	dephosphorylation			9606									11359773	t		gcesareni	Mkp-7 binds to and inactivates p38 mapk and jnk/sapk, but not erk inhibited by dual specificity phosphatases, such as dusp1, dusp10, and dusp16(uniprot)	SIGNOR-108233	0.798
EIF2AK2	protein	P19525	UNIPROT	PPP2R5A	protein	Q15172	UNIPROT	up-regulates	phosphorylation	Ser28	VDGFTRKsVRKAQRQ	9606									18957415	t		llicata	Phosphorylation of serine 28 by pkr promotes mitochondrial localization of b56alpha, because wild-type but not mutant s28a b56alpha promoted mitochondrial pp2a activity.	SIGNOR-181793	0.333
EEF1A1	protein	P68104	UNIPROT	Asp-tRNA(Asp)	smallmolecule	CHEBI:29158	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269507	0.8
PRKCD	protein	Q05655	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	phosphorylation	Ser12	KSKPKDAsQRRRSLE	9606	BTO:0001938								18069897	t		gcesareni	We conclude that treatment with either UV or PMA induces the phosphorylation of the PKC site Ser12 on c-SRC and that this specific phosphorylation event is significantly diminished in cells overexpressing PR55	SIGNOR-247974	0.584
NRXN2	protein	Q9P2S2	UNIPROT	DAG1	protein	Q14118	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							22626542	t		miannu	 The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 	SIGNOR-265460	0.265
WNT3A	protein	P56704	UNIPROT	RYK	protein	P34925	UNIPROT	up-regulates	binding			9606									15454084	t		gcesareni	Here, we report that ryk directly binds wnt-1 and wnt-3a via its wif domain and is required for the tcf.	SIGNOR-129580	0.754
MAPK3	protein	P27361	UNIPROT	RPS3	protein	P23396	UNIPROT	unknown	phosphorylation	Thr42	SGVEVRVtPTRTEII	9606									15950189	t		llicata	Erk phosphorylates threonine 42 residue of ribosomal protein s3.	SIGNOR-137959	0.359
KIF14	protein	Q15058	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272524	0.7
phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	CDP-diacylglycerol(2-)	smallmolecule	CHEBI:58332	ChEBI	up-regulates quantity	precursor of			9606									25375833	t		lperfetto	CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA).	SIGNOR-267019	0.8
SRC	protein	P12931	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Tyr340	RGQRDSSyYWEIEAS	9606									12551923	t		gcesareni	We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain.	SIGNOR-97635	0.588
PTPRJ	protein	Q12913	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates activity	dephosphorylation	Tyr1054	FGLARDIyKDPDYVR	9606									18936167	t			These results therefore suggest that the autoactivation residues Y1054 and Y1059 are targeted by DEP-1 and that this results in the inhibition of kinase activity and the consequent general dephosphorylation of VEGFR2.	SIGNOR-248709	0.687
AKT2	protein	P31751	UNIPROT	PKP1	protein	Q13835	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser188	QNRYSFYsTCSGQKA	-1									23444369	t		miannu	Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry.	SIGNOR-273490	0.27
MAPK3	protein	P27361	UNIPROT	SOS1	protein	Q07889	UNIPROT	down-regulates	phosphorylation	Ser1193	QPTSKAYsPRYSISD	9606									8816480	t		gcesareni	In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1	SIGNOR-43951	0.621
RAF1	protein	P04049	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates activity	phosphorylation	Ser621	PKINRSAsEPSLHRA	9534									19595761	t		lperfetto	We show that phosphorylation of s621 turns over rapidly and is enriched in the activated pool of endogenous raf-1. The phosphorylation on this site can be mediated by raf-1 itself but also by other kinase(s)	SIGNOR-235770	0.2
HK2	protein	P52789	UNIPROT	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	up-regulates activity				9606									18350175	f			The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase.	SIGNOR-259980	0.7
CSNK2A1	protein	P68400	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates activity	phosphorylation	Ser83	YSGSEGDsESGEEEE	-1									2046671	t		llicata	Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro. We report here that serine 83 appears to be the residue phosphorylated by CKII but that three other serines in this region can also be involved in phosphorylation and the enhancement of DNA-binding activity.	SIGNOR-250958	0.532
CBL	protein	P22681	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates activity	ubiquitination			9606									15315962	t		miannu	KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. 	SIGNOR-260104	0.601
FLT3	protein	P36888	UNIPROT	IDH1	protein	O75874	UNIPROT	up-regulates activity	phosphorylation	Tyr391	PNVQRSDyLNTFEFM	-1									34289383	t		lperfetto	Moreover, in an in vitro kinase assay, purified recombinant FLT3 (rFLT3) phosphorylated recombinant IDH2 R140Q mutant but did not alter its catalytic activity (Figure 1C), whereas rFLT3 phosphorylated mIDH1 protein and enhanced its catalytic activity	SIGNOR-267630	0.437
creatine	smallmolecule	CHEBI:16919	ChEBI	CKM	protein	P06732	UNIPROT	up-regulates activity	chemical activation			9606									18502307	t		miannu	Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 	SIGNOR-265784	0.8
3-methoxytyramine	smallmolecule	CHEBI:1582	ChEBI	3,4-dihydroxyphenylacetaldehyde	smallmolecule	CHEBI:27978	ChEBI	up-regulates quantity	precursor of			9606									NBK536726	t	brain	lperfetto	Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO.	SIGNOR-264178	0.8
TGFB1	protein	P01137	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity				10090	BTO:0000944								17673906	f		lperfetto	We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases.	SIGNOR-242631	0.431
IGFBP3	protein	P17936	UNIPROT	Neuron_maturation	phenotype	SIGNOR-PH169	SIGNOR	down-regulates				10090		BTO:0000142							17278996	f		Luana	IGFBP3 overexpression due to lack of MeCP2 may lead to delayed brain maturation.	SIGNOR-265774	0.7
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3-5	protein	Q6NXT2	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269642	0.2
PIM1	protein	P11309	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									17643117	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation.	SIGNOR-156946	0.2
ITK	protein	Q08881	UNIPROT	CD28	protein	P10747	UNIPROT	up-regulates activity	phosphorylation	Tyr218	PPRDFAAyRS										8992971	t			EMT can phosphorylate all four tyrosines of the CD28 tail. in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor.	SIGNOR-251337	0.677
ERCC5	protein	P28715	UNIPROT	ERCC2	protein	P18074	UNIPROT	up-regulates quantity by stabilization	binding			9606									20840796	t	Regulation of binding		The NER protein XPG was also found to associate with the TFIIH complex by interacting directly with XPD stabilizing the interaction between TFIIH and the CAK-XPD complex	SIGNOR-251974	0.946
LAMTOR2	protein	Q9Y2Q5	UNIPROT	LAMTOR	complex	SIGNOR-C26	SIGNOR	form complex	binding			9606									20381137	t		lperfetto	Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant	SIGNOR-164772	0.924
MAPK13	protein	O15264	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser46	AMDDLMLsPDDIEQW	9606									10581258	t		gcesareni	In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.	SIGNOR-72691	0.443
CSNK2A1	protein	P68400	UNIPROT	MYH9	protein	P35579	UNIPROT	up-regulates	phosphorylation	Ser1943	RKGAGDGsDEEVDGK	9606									18971378	t		gcesareni	In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)	SIGNOR-181811	0.347
LRIG1	protein	Q96JA1	UNIPROT	CBLC	protein	Q9ULV8	UNIPROT	up-regulates	binding			9606		BTO:0001253							15282549	t		gcesareni	Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation	SIGNOR-127301	0.2
bisphenol F	chemical	CHEBI:34575	ChEBI	AR	protein	P10275	UNIPROT	down-regulates activity	chemical inhibition			-1									31995776	t		miannu	This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . 	SIGNOR-268734	0.8
amisulpride	chemical	CHEBI:64045	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258364	0.8
carbachol	chemical	CHEBI:3385	ChEBI	CHRM3	protein	P20309	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258618	0.8
PAM	protein	P19021	UNIPROT	Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	up-regulates activity	cleavage			9606									23084901	t		lperfetto	Nevertheless, overall the results of this study show that peptide sequence recognition is an important aspect of the interactions of the prohormone substrates prooxytocin (3d) and procalcitonin (7e) with PAM, which is mirrored in the potency of analogous peptidomimetic glycolate inhibitors of the enzyme.	SIGNOR-268551	0.2
TERT	protein	O14746	UNIPROT	Telomere_maintenance	phenotype	SIGNOR-PH148	SIGNOR	up-regulates													18680434	t		lperfetto	 Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity 	SIGNOR-263334	0.7
PD318088	chemical	CID:10231331	PUBCHEM	MAP2K2	protein	P36507	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205740	0.8
MAS1	protein	P04201	UNIPROT	FLNA	protein	P21333	UNIPROT	up-regulates activity	binding			9606									26460884	t		miannu	We further determined that GPCRs, AT1R, and MAS directly recruited FLNa and promoted its phosphorylation by cellular S/T kinases in an agonist-dependent manner. Our studies thus provide a structural framework for filamin in GPCR signaling, potentially regulating a variety of cellular responses. MAS likely binds filamin constitutively and hence leads to constitutive filamin phosphorylation. These results emphasize that it is the active receptor that mediates filamin phosphorylation by PKA or other cellular S/T kinases	SIGNOR-260627	0.2
SYK	protein	P43405	UNIPROT	SYK	protein	P43405	UNIPROT	up-regulates activity	phosphorylation	Tyr131	KENLIREyVKQTWNL	9606	BTO:0000776								9820500	t		lperfetto	These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520	SIGNOR-246601	0.2
NTRK1	protein	P04629	UNIPROT	ABL1	protein	P00519	UNIPROT	up-regulates	binding			9606									10708759	t		esanto	Autophosphorylated trka binds directly to plc?, Abl, and shc.	SIGNOR-75402	0.515
MCM10	protein	Q7L590	UNIPROT	POLA1	protein	P09884	UNIPROT	up-regulates quantity by stabilization	relocalization			-1									19608746	t		Federica	Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase alpha (pol alpha), with chromatin.	SIGNOR-261271	0.857
DPF3	protein	Q92784	UNIPROT	Muscle cell-specific SWI/SNF ARID1B variant	complex	SIGNOR-C482	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270703	0.739
PFKFB3	protein	Q16875	UNIPROT	beta-D-fructofuranose 2,6-bisphosphate	smallmolecule	CHEBI:28602	ChEBI	up-regulates quantity	chemical modification			9606									9404080	t			A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in Escherichia coli. [...]The expressed enzyme was bifunctional with Vmax values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively.	SIGNOR-267260	0.8
LCK	protein	P06239	UNIPROT	LCK	protein	P06239	UNIPROT	up-regulates activity	phosphorylation	Tyr394	RLIEDNEyTAREGAK	9606									2250907	t		lperfetto	They also demonstrate that replacement of the major site of autophosphorylation of p56lck (tyrosine 394) by a phenylalanine residue abolishes the ability to activate p56lck by CD4 cross-linking, implying that this residue is critical for the positive regulation of the Lck tyrosine kinase activity by CD4.	SIGNOR-81372	0.2
GAL	protein	P22466	UNIPROT	GALR2	protein	O43603	UNIPROT	up-regulates	binding			9606									10601261	t		gcesareni	Galanin showed high affinity for the galr1 (ic(50) = 0.097 nm) and galr2 receptors (ic(50) = 0.48 nm).	SIGNOR-73125	0.858
PIM1	protein	P11309	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates													16146838	f		lperfetto	The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells.	SIGNOR-249623	0.7
MAPK14	protein	Q16539	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606									17502367	t		gcesareni	All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).	SIGNOR-154783	0.606
PLAG1	protein	Q6DJT9	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									11888928	f		miannu	Plagl1 has been shown to prevent the proliferation of tumor cells by inducing cell cycle arrest and apoptosis	SIGNOR-115772	0.7
EGFR	protein	P00533	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates	phosphorylation	Tyr285	TEADGELyVFNTPSG	9606	BTO:0000527;BTO:0000017								9890893	t		lperfetto	Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689).	SIGNOR-236400	0.751
PRKACA	protein	P17612	UNIPROT	CHKB	protein	Q9Y259	UNIPROT	up-regulates activity	phosphorylation	Ser40	PKRRRASsLSRDAER										27149373	t		lperfetto	Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. 	SIGNOR-275629	0.255
TAF1D	protein	Q9H5J8	UNIPROT	SL1 complex	complex	SIGNOR-C464	SIGNOR	form complex	binding			9606									30693017	t		lperfetto	SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation.	SIGNOR-269563	0.805
JAK3	protein	P52333	UNIPROT	JAK3	protein	P52333	UNIPROT	up-regulates	phosphorylation	Tyr939	QICKGMEyLGSRRCV	9606									18250158	t		lperfetto	Y904 and y939 are required for optimal jak3 autophosphorylation and kinase activity in vitro	SIGNOR-160668	0.2
LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	YAP1	protein	P46937	UNIPROT	down-regulates activity	phosphorylation	Ser127	PQHVRAHsSPASLQL	9606									22658639	t		miannu	In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus.	SIGNOR-256188	0.2
IL10	protein	P22301	UNIPROT	SCN9A	protein	Q15858	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									23357618	f		miannu	Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α.	SIGNOR-253498	0.2
SHH	protein	Q15465	UNIPROT	PTCH1	protein	Q13635	UNIPROT	down-regulates activity	binding			9606		BTO:0001253							9811851	t		lperfetto	Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH.	SIGNOR-61552	0.941
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1910	TPTSPKYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273106	0.745
USP7	protein	Q93009	UNIPROT	Ubiquitin	proteinfamily	SIGNOR-PF89	SIGNOR	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270837	0.777
SRC	protein	P12931	UNIPROT	PTPRJ	protein	Q12913	UNIPROT	up-regulates activity	phosphorylation	Tyr1311	DSKVDLIyQNTTAMT	9606	BTO:0000007								22898603	t		miannu	 We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin.	SIGNOR-276373	0.622
PRKACA	protein	P17612	UNIPROT	EEF2K	protein	O00418	UNIPROT	up-regulates activity	phosphorylation	Ser500	RLHLPRAsAVALEVQ	-1									11171059	t		miannu	EEF-2K can be phosphorylated in vitro by cAMP-dependent protein kinase (PKA) and that this induces significant Ca(2+)/calmodulin (CaM)-independent eEF-2K activity. sites of phosphorylation were Ser-365 and Ser-499	SIGNOR-250444	0.31
MUSK	protein	O15146	UNIPROT	DOK7	protein	Q18PE1	UNIPROT	up-regulates activity	phosphorylation	Tyr395	CLPGTVEyQVPTSLR	10090									20603078	t		miannu	Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes. 	SIGNOR-273845	0.746
MAPKAPK2	protein	P49137	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser78	PAYSRALsRQLSSGV	9606									20626350	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	gcesareni	Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27.	SIGNOR-166633	0.803
NR3C1	protein	P04150	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates activity	binding			10090	BTO:0000011								11279134	t		lperfetto	The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin	SIGNOR-250566	0.472
SCAND1	protein	P57086	UNIPROT	MZF1	protein	P28698	UNIPROT	up-regulates activity	binding			-1									10777584	t		miannu	Co-immunoprecipitation and yeast two-hybrid analyses demonstrate that MZF1B and RAZ1 associate in vitro via a SCAN box-dependent mechanism. The interaction between MZF1B and RAZ1 might be necessary for mediating MZF1B function	SIGNOR-221561	0.372
HACD4	protein	Q5VWC8	UNIPROT	FASN	protein	P49327	UNIPROT	up-regulates activity	chemical activation			9606									18554506	t			Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases,	SIGNOR-267763	0.2
PRKACG	protein	P22612	UNIPROT	TENT2	protein	Q6PIY7	UNIPROT	down-regulates activity	phosphorylation	Ser116	LSGERRYsMPPLFHT	9606	BTO:0000007								31057087	t		miannu	We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. 	SIGNOR-259404	0.2
BACE1	protein	P56817	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Asp616	EISEVKMdAEFRHDS	9606									10931940	t		lperfetto	Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating α- and β-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform.	SIGNOR-261763	0.787
LIMS3	protein	P0CW19	UNIPROT	IPP complex	complex	SIGNOR-C380	SIGNOR	form complex	binding												16493410	t		lperfetto	Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton.	SIGNOR-265765	0.58
MAP3K7	protein	O43318	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	up-regulates activity	phosphorylation			9606									21133840	t		miannu	RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of κB kinase) complex	SIGNOR-256024	0.717
DAPK1	protein	P53355	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates	phosphorylation	Ser511	RREERSLsAPGNLLT	9606	BTO:0000938	BTO:0000142							15209507	t		lperfetto	Dapk phosphorylates camkk. S511 was identified as the phosphorylation site . a potential mechanism of action was identified on the basis of the location of s511 near the cam recognition domain of camkk and demonstrated by attenuation of cam-stimulated camkk autophosphorylation after dapk phosphorylation.	SIGNOR-126241	0.287
MAP2K1	protein	Q02750	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates	phosphorylation			9606									12270934	t		lbriganti	Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis.	SIGNOR-210176	0.741
HIF3A	protein	Q9Y2N7	UNIPROT	HIF1A	protein	Q16665	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000972								21479871	t		Luana	None of the long HIF-3α variants was capable of efficient induction of an HRE reporter in overexpression experiments, but instead inhibited the transcriptional activation of the reporter by HIF-1 and HIF-2. 	SIGNOR-261615	0.503
ZFPM2	protein	Q8WW38	UNIPROT	GATA4	protein	P43694	UNIPROT	down-regulates activity	binding			10090	BTO:0000944								9927675	t		miannu	FOG-2 associates physically with the N-terminal zinc finger of GATA-4 both in vitro and in vivo. This interaction appears to modulate specifically the transcriptional activity of GATA-4 because overexpression of FOG-2 in both NIH 3T3 cells and primary rat cardiomyocytes represses GATA-4-dependent transcription from multiple cardiac-restricted promoters.	SIGNOR-236959	0.775
AR	protein	P10275	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16281084	f	 	 	 After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes.	SIGNOR-253678	0.263
AGRP	protein	O00253	UNIPROT	MC3R	protein	P41968	UNIPROT	down-regulates activity	binding			9606									10318826	t		miannu	AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor.	SIGNOR-252380	0.612
FGF14	protein	Q92915	UNIPROT	SCN4A	protein	P35499	UNIPROT	down-regulates activity	binding			9606		BTO:0001103							20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253433	0.264
SYNE1	protein	Q8NF91	UNIPROT	MSH2/MSH6	complex	SIGNOR-C60	SIGNOR	up-regulates activity	binding			9606	BTO:0001950								24781983	t		miannu	Nesprin-1 is involved in the DNA Damage Response network. The Nesprin-1 interaction with MSH2 and MSH6 (MutSα complex) is a constitutive cellular event required for proper DNA repair. 	SIGNOR-261823	0.254
ROS	stimulus	SIGNOR-ST2	SIGNOR	NLRP3	protein	Q96P20	UNIPROT	up-regulates activity													28531279	f		lperfetto	Different mechanisms have been proposed for NLRP3 activation, including potassium efflux, calcium influx, reactive oxygen species (ROS), oxidized mitochondrial DNA, translocation of cardiolipin from the inner mitochondrial membrane, phagosome destabilization, perturbation in cell volume and pore-formation mechanisms driven by the host or bacteria	SIGNOR-256427	0.7
MAPK8	protein	P45983	UNIPROT	KRT8	protein	P05787	UNIPROT	up-regulates	phosphorylation	Ser74	TVNQSLLsPLVLEVD	9606									11781324	t		lperfetto	Kinase assays showed that c-jun n-terminal kinase (jnk) was also activated with activation kinetics corresponding to that of k8 phosphorylation. Furthermore, k8 was also phosphorylated on ser-73 by jnk in vitro. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.	SIGNOR-113645	0.383
SRC	protein	P12931	UNIPROT	PIP5K1C	protein	O60331	UNIPROT	up-regulates	phosphorylation	Tyr649	TDERSWVySPLHYSA	9606									15738269	t		lperfetto	Phosphorylation by src of the tyrosine adjacent to s650 (y649 in human pipki gamma) was shown to enhance pipki gamma targeting to focal adhesions. We find that y649 phosphorylation does not stimulate directly pipki gamma binding to talin, but may do so indirectly by inhibiting s650 phosphorylation.	SIGNOR-134459	0.289
rauwolscine	chemical	CHEBI:48562	ChEBI	HTR2B	protein	P41595	UNIPROT	down-regulates activity	chemical inhibition			10036									9459568	t		miannu	These studies display the usefulness of [3H]rauwolscine as an antagonist radioligand for the cloned human 5-HT2B receptor. The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor	SIGNOR-258690	0.8
RAB9A	protein	P51151	UNIPROT	RABEPK	protein	Q7Z6M1	UNIPROT	up-regulates activity													9230071	t		lperfetto	P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking.	SIGNOR-253088	0.563
PAFAH1B1	protein	P43034	UNIPROT	CLIP1	protein	P30622	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								11940666	t		miannu	Here we demonstrate colocalization and direct interaction between CLIP-170 and LIS1. In mammalian cells, LIS1 recruitment to kinetochores is dynein/dynactin dependent, and recruitment there of CLIP-170 is dependent on its site of binding to LIS1, located in the distal zinc finger motif.	SIGNOR-252166	0.785
CAMK2G	protein	Q13555	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser273	AGTRRREsLGKKAKR										9677319	t		llicata	Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. By deletion and point mutation analysis we show that phosphorylation by CaMKII and PKA occurs on a single serine residue at position 273	SIGNOR-250703	0.342
AD/b2 integrin	complex	SIGNOR-C172	SIGNOR	VCAM1	protein	P19320	UNIPROT	up-regulates activity	binding			9606	BTO:0000751								10438935	t		lperfetto	These results indicate that VCAM-1 can bind to an I domain and that the binding of alpha D beta 2 to VCAM-1 may contribute to the trafficking of a subpopulation of leukocytes that express alpha D beta 2.	SIGNOR-253375	0.573
GOT2	protein	P00505	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	down-regulates quantity	chemical modification			9606									31422819	t		miannu	This is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1).	SIGNOR-268059	0.8
MLN	protein	P12872	UNIPROT	MLNR	protein	O43193	UNIPROT	up-regulates	binding			9606	BTO:0000938								10381885	t		gcesareni	A heterotrimeric guanosine triphosphate-binding protein (g protein)-coupled receptor for motilin was isolated from human stomach	SIGNOR-68721	0.762
p38	proteinfamily	SIGNOR-PF16	SIGNOR	DROSHA	protein	Q9NRR4	UNIPROT	down-regulates activity	phosphorylation	Ser300	RHRDNRRsPSLERSY	9606	BTO:0000007								25699712	t		lperfetto	Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes. 	SIGNOR-264847	0.2
MIPOL1	protein	Q8TD10	UNIPROT	RHOB	protein	P62745	UNIPROT	up-regulates activity	binding			9606									31609475	t		miannu	MIPOL1 protein interacts with tumor suppressor RhoB and enhances its cellular activity	SIGNOR-261134	0.2
BRCA1	protein	P38398	UNIPROT	RBBP8	protein	Q99708	UNIPROT	up-regulates	ubiquitination			9606									16818604	t		gcesareni	In conclusion, our data show that ctip is a physiological substrate of the brca1 e3 ligase. Brca1 recruits ctip through its c-terminal brct domains and promotes ctip ubiquitination through its n-terminal ring domain. The ubiquitinated ctip is not targeted for degradation. Instead, ubiquitinated ctip binds to chromatin following dna damage and is likely to be involved in dna damage checkpoint control.	SIGNOR-147711	0.836
NFE2L2	protein	Q16236	UNIPROT	TXN	protein	P10599	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000552								18629308	f		miannu	 When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression.	SIGNOR-254646	0.415
MED21	protein	Q13503	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266678	0.806
APC-c	complex	SIGNOR-C150	SIGNOR	KIF4A	protein	O95239	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1									24510915	t		miannu	Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A). 	SIGNOR-266112	0.291
FASN	protein	P49327	UNIPROT	hexadecanoic acid	smallmolecule	CHEBI:15756	ChEBI	up-regulates quantity	chemical modification			9606									12689621	t			An organizational model for animal FAS was proposed in which the two subunits depicted in domains I, II, and III were arranged in an antiparallel fashion, thereby generating two sites for palmitate synthesis. Initiation of the series of condensation reactions leading to the production of palmitic acid requires the translocation of one acetyl and seven malonyl moieties, from CoA thioester to the phosphopantetheine thiol of the ACP domain.	SIGNOR-267373	0.8
PRKCA	protein	P17252	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser81	AAGSGAAsPSAAEKG	-1									8034575	t		lperfetto	Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites.	SIGNOR-248910	0.72
PRKCD	protein	Q05655	UNIPROT	KLF5	protein	Q13887	UNIPROT	up-regulates activity	phosphorylation	Ser153	LRTGLYKsQRPCVTH	9606	BTO:0003038								12682370	t		lperfetto	Phosphorylation of Kruppel-like factor 5 (KLF5/IKLF) at the CBP interaction region enhances its transactivation function. | Inhibition of protein kinase activity by H7 or calphostin C blocked both full-length and N-terminal fragment (amino acids 1-238) KLF5 activities. Mutation at a potential protein kinase C phosphorylation site within the CBP interaction domain of KLF5 reduces its transactivation function. Furthermore, using the GST pull-down approach, we showed that phosphorylation of KLF5 enhances its interaction with CBP. The results of the present study provide a mechanism for KLF5 transactivation function. | We found that KLF5€™s activity was reduced to half when the serine in the potential PKC phosphorylation site was mutated to alanine (Fig. 6B, S153A) Nonetheless, the S153A mutant still retains significant transactivation activity.	SIGNOR-249206	0.341
MAP2K2	protein	P36507	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates	phosphorylation	Tyr187	HTGFLTEyVATRWYR	9606									11971971	t		gcesareni	Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.	SIGNOR-86713	0.733
DVL2	protein	O14641	UNIPROT	RBPJ	protein	Q06330	UNIPROT	down-regulates activity	binding			10029	BTO:0000457								23132247	t		gcesareni	Mechanistically, Dishevelled binds and directly inhibits CSL transcription factors downstream of Notch receptors, reducing their activity. Furthermore, our data suggest that this crosstalk mechanism is conserved between vertebrate and invertebrate homologues. Thus, we identify a dual function for Dishevelled as an inhibitor of Notch signalling and an activator of the Wnt pathway that sharpens the distinction between opposing Wnt and Notch responses, allowing for robust cell-fate decisions.	SIGNOR-243999	0.272
PRMT1	protein	Q99873	UNIPROT	TAF15	protein	Q92804	UNIPROT	up-regulates	methylation			9606									19124016	t		miannu	The methylation of taf15 by prmt1 is required for the ability of taf15 to positively regulate the expression of the studied endogenous taf15-target genes.	SIGNOR-183137	0.44
CSNK2B	protein	P67870	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Thr502	TPGTGLGtSPALAGD	-1									8349691	t		llicata	These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1.	SIGNOR-251077	0.324
PRKCG	protein	P05129	UNIPROT	DAB2	protein	P98082	UNIPROT	unknown	phosphorylation	Ser24	QAAPKAPsKKEKKKG	9534	BTO:0004055								10542228	t		lperfetto	We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function.	SIGNOR-249027	0.303
A2M	protein	P01023	UNIPROT	MMP9	protein	P14780	UNIPROT	down-regulates activity	binding			-1									9344465	t		lperfetto	Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261801	0.471
F11	protein	P03951	UNIPROT	HGF	protein	P14210	UNIPROT	up-regulates activity	cleavage	Arg424	KNMEDLHrHIFWEPD	-1									12372819	t		miannu	 the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. 	SIGNOR-256515	0.317
USP13	protein	Q92995	UNIPROT	ATG5	protein	Q9H1Y0	UNIPROT	up-regulates quantity by stabilization	deubiquitination												36528756	t		lperfetto	Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. 	SIGNOR-275838	0.278
Degranulation	phenotype	SIGNOR-PH92	SIGNOR	IL6	protein	P05231	UNIPROT	up-regulates quantity				9606	BTO:0000830								24232182	f		apalma	Particularly, damage-activated mast cells almost instantly begin to secrete TNFa, histamine and tryptase and then initiate the de novo synthesis of other cytokines, such as interleukin (IL)6	SIGNOR-255349	0.7
SEMA7A	protein	O75326	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates activity	binding			10090									17377534	t		lperfetto	Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin.	SIGNOR-253249	0.528
TFAP2A	protein	P05549	UNIPROT	SULT1E1	protein	P49888	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17187826	f	 	miannu	 Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. 	SIGNOR-255397	0.2
NCSTN	protein	Q92542	UNIPROT	APH1A	protein	Q96BI3	UNIPROT	up-regulates	binding			9606		BTO:0000142							12857757	t		gcesareni	We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch).	SIGNOR-103611	0.967
MMP14	protein	P50281	UNIPROT	FGA	protein	P02671	UNIPROT	down-regulates quantity by destabilization	cleavage	Phe117	MEILRGDfSSANNRD	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain	SIGNOR-263621	0.2
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	ENO3	protein	P13929	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136550	0.27
FAM20C	protein	Q8IXL6	UNIPROT	P4HB	protein	P07237	UNIPROT	up-regulates activity	phosphorylation	Ser357	KIKPHLMsQELPEDW										32149426	t		lperfetto	The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity. 	SIGNOR-275574	0.36
PPARA	protein	Q07869	UNIPROT	PLIN2	protein	Q99541	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003204								17150915	f		miannu	 To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA.	SIGNOR-255046	0.529
LATS1	protein	O95835	UNIPROT	VEPH1	protein	Q14D04	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000938								22055343	f	In the neuronal differentiation	lperfetto	Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r8	SIGNOR-177068	0.2
BIRC2	protein	Q13490	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0000007								21931591	t		miannu	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.	SIGNOR-272710	0.76
SNAI1	protein	O95863	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity	transcriptional regulation			9606									19055748	f		lperfetto	Taken together these results suggest that SNAI1 functional blockade is leading to partial re-expression of E-cadherin (i.e. at the level of transcription), to a decrease in PAI-1 and to a more collective migration, while the parental cells expressing SNAI1 have less E-cadherin, more PAI 1, and migrate individually. We suggest that the present study establishes a relation between SNAI1 function, PAI-1 distribution and EMT status.	SIGNOR-252260	0.75
JUN	protein	P05412	UNIPROT	LORICRIN	protein	P23490	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000667								12200429	f		miannu	Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity. 	SIGNOR-254536	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606	BTO:0000007								10837486	t		lperfetto	Rsk1, and survival factor signaling stimulate phosphorylation of bad at ser-155, blocking the binding of bad to bcl-xl.	SIGNOR-252786	0.2
MAPK8	protein	P45983	UNIPROT	HNRNPK	protein	P61978	UNIPROT	up-regulates	phosphorylation	Ser216	ILDLISEsPIKGRAQ	9606									11259409	t		gcesareni	The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein.	SIGNOR-105766	0.381
PTPRB	protein	P23467	UNIPROT	CDH5	protein	P33151	UNIPROT	up-regulates activity	dephosphorylation			9606									19015309	t		miannu	Because we had shown previously that VE-PTP supports VE-cadherin function when exogenously expressed in transfected cells, we expected it to be expressed at endothelial cell contacts.|Indeed, tyrosine phosphorylation of VE-cadherin is reduced by VE-PTP in COS-7 and CHO cells.	SIGNOR-277131	0.6
PRKG1	protein	Q13976	UNIPROT	ITPR1	protein	Q14643	UNIPROT	unknown	phosphorylation	Ser1764	RPSGRREsLTSFGNG	10116	BTO:0004578								8132598	t		lperfetto	Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic GMP-dependent protein kinase. | The synthetic peptide corresponding to serine 1755 (GRRESLTSFG) was phosphorylated with aKm in the range of 30-40 microM by both kinases. The kinetic analysis revealed that this peptide substrate is the best substrate described for cGMP kinase to date. Vascular smooth muscle cells prelabeled with [32P]orthophosphate and treated with atrial natriuretic peptide or sodium nitroprusside to elevate cGMP also resulted in increased labeling of the IP3 receptor. Phosphorylation of IP3 receptor by cGMP kinase may regulate the function of IP3 receptor in vascular smooth muscle cells and contribute to the effect of cGMP to regulate intracellular calcium levels.	SIGNOR-248916	0.473
ATR	protein	Q13535	UNIPROT	XPA	protein	P23025	UNIPROT	up-regulates activity	phosphorylation	Ser173	VKKNPHHsQWGDMKL	9606	BTO:0000018								16540648	t		llicata	Defects in ATR-dependent XPA phosphorylation increases the cell sensitivity to UV irradiation. | The XPA-deficient cells complemented with XPA-S196A mutant, in which Ser196 was substituted with an alanine, displayed significantly higher UV sensitivity compared with the XPA cells complemented with wild-type XPA. Moreover, substitution of Ser196 with aspartic acid for mimicking the phosphorylation of XPA increased the cell survival to UV irradiation.	SIGNOR-250584	0.505
PSMC3	protein	P17980	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263369	0.871
CDK1	protein	P06493	UNIPROT	STIP1	protein	P31948	UNIPROT	down-regulates activity	phosphorylation	Thr332	KSLAEHRtPDVLKKC	10090	BTO:0000944								14754904	t		miannu	Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions. A lower level of phosphorylation was observed for the double mutant, suggesting that T332 might also be phosphorylated by cdc2 kinase.	SIGNOR-262728	0.267
PRKCE	protein	Q02156	UNIPROT	TRPV1	protein	Q8NER1	UNIPROT	up-regulates activity	phosphorylation	Thr145	QKSKKHLtDNEFKDP	-1									14523239	t		lperfetto	We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. | Edman sequencing and scintillation counting delineated T144 as the in vitro PKC phosphorylation site	SIGNOR-249234	0.2
(S,S)-asenapine	chemical	CHEBI:71257	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10116									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258570	0.8
FOXO3	protein	O43524	UNIPROT	IDH1	protein	O75874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25648147	t		miannu	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260089	0.251
PRKAA1	protein	Q13131	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Ser626	SLECDMEsIIRSELM	9606	BTO:0000007								17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-252979	0.509
KHSRP	protein	Q92945	UNIPROT	DVL3	protein	Q92997	UNIPROT	down-regulates	binding			9606	BTO:0000130;BTO:0000876								2848118	t		gcesareni	Ksrp was shown to interact with the c-terminus of dvl3. We show that ksrp negatively regulates wnt/beta-catenin signaling at the level of post-transcriptional ctnnb1 (beta-catenin) mrna stability.	SIGNOR-23800	0.2
UNG	protein	P13051	UNIPROT	Base-excision_repair	phenotype	SIGNOR-PH222	SIGNOR	up-regulates													23545420	f		lperfetto	The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1).	SIGNOR-275711	0.7
TNKS	protein	O95271	UNIPROT	TERF1	protein	P54274	UNIPROT	down-regulates activity	ADP-ribosylation			-1									11739745	t		lperfetto	Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA.	SIGNOR-263377	0.796
PLK1	protein	P53350	UNIPROT	KIF2B	protein	Q8N4N8	UNIPROT	up-regulates activity	phosphorylation	Thr125	MIPQKNQtASGDSLD	9606	BTO:0001938								22535524	t		lperfetto	We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors.	SIGNOR-252049	0.647
PNPLA6	protein	Q8IY17	UNIPROT	Lysophosphatidylcholine	smallmolecule	CID:5311264	PUBCHEM	down-regulates quantity	chemical modification			9606									25033069	t			PNPLA6 encodes NTE, a lysophospholipase that converts lysophosphatidylcholine (LPC) to glycerophosphocholine. PNPLA6 is expressed in neurons throughout the brain, particularly in the cortex, Purkinje cells of the cerebellum, and hippocampus	SIGNOR-253610	0.8
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	NLRP3 inflammasome	complex	SIGNOR-C225	SIGNOR	up-regulates activity													16037825	f		miannu	Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage	SIGNOR-263127	0.7
XIAP	protein	P98170	UNIPROT	CASP3	protein	P42574	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									11447297	t		lperfetto	Xiap promotes the degradation of active-form caspase-3, but not procaspase-3, in living cells. Both the association of XIAP with caspase-3 and the RING finger domain of XIAP were essential for ubiquitination. XIAP promotes the degradation of caspase-3, which enhances its anti-apoptotic effect.	SIGNOR-109243	0.938
ODC1	protein	P11926	UNIPROT	spermidine	smallmolecule	CHEBI:16610	ChEBI	up-regulates quantity	chemical modification			9606									14617280	t		miannu	Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC)	SIGNOR-256038	0.8
CSNK1A1	protein	P48729	UNIPROT	RHOB	protein	P62745	UNIPROT	down-regulates	phosphorylation	Ser185	ALQKRYGsQNGCINC	9606	BTO:0000567								18590726	t		llicata	Mass spectrometry analysis demonstrates that rhob is monophosphorylated by ck1, in its c-terminal end, on serine 185. lastly we show that the inhibition of ck1 activates rhob and promotes rhob dependent actin fiber formation and egf-r level.	SIGNOR-179255	0.2
UHRF2	protein	Q96PU4	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9534	BTO:0000298								21952639	t		miannu	We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1.	SIGNOR-271885	0.298
ZC3HAV1	protein	Q7Z2W4	UNIPROT	PARN	protein	O95453	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								21876179	t			We provide evidence indicating that ZAP selectively recruits cellular poly(A)-specific ribonuclease (PARN) to shorten the poly(A) tail of target viral mRNA and recruits the RNA exosome to degrade the RNA body from the 3′ end.	SIGNOR-261296	0.424
C1QBP	protein	Q07021	UNIPROT	C1QA	protein	P02745	UNIPROT	down-regulates activity	binding							SIGNOR-C308					28018340	t		lperfetto	Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping.	SIGNOR-263402	0.392
MAPK3	protein	P27361	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser732	RRVRKLPsTTL	9534	BTO:0001538								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252761	0.718
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BC14	protein	Q99879	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSVYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271994	0.2
NAMPT	protein	P43490	UNIPROT	NAD(1-)	smallmolecule	CHEBI:57540	ChEBI	up-regulates quantity	chemical modification			9606									12555668	t		gcesareni	Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesi	SIGNOR-238602	0.8
PDP1	protein	Q9P0J1	UNIPROT	PDHA1	protein	P08559	UNIPROT	up-regulates activity	dephosphorylation	Ser293	TYRYHGHsMSDPGVS	-1									7782287	t			Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism	SIGNOR-252054	0.722
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1665	SPTSPSYsPTSPSYS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248819	0.849
A3/b1 integrin	complex	SIGNOR-C161	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269010	0.7
AKT2	protein	P31751	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser315	DFRSRTNsNASTVSG										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249641	0.742
MAPK8	protein	P45983	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates	phosphorylation	Ser70	RDPVARTsPLQTPAA	9606									18570871	t		gcesareni	Together, our findings demonstrate that jnk1-mediated multisite phosphorylation of bcl-2 stimulates starvation-induced autophagy by disrupting the bcl-2/beclin 1 complex.	SIGNOR-179088	0.564
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PLCB1	protein	Q9NQ66	UNIPROT	up-regulates activity	phosphorylation			-1									11287604	t	inferred from 70% family members	lperfetto	Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982	SIGNOR-270109	0.2
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	Av/b8 integrin	complex	SIGNOR-C185	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259013	0.333
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	Postsynaptic density assembly	phenotype	SIGNOR-PH163	SIGNOR	up-regulates				9606	BTO:0000938	BTO:0004249							23125836	f		miannu	PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex	SIGNOR-264960	0.7
DUOX1	protein	Q9NRD9	UNIPROT	ROS	stimulus	SIGNOR-ST2	SIGNOR	up-regulates				9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264719	0.7
RBBP7	protein	Q16576	UNIPROT	HAT1	protein	O14929	UNIPROT	up-regulates activity	binding			-1									28143904	t		lperfetto	AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity	SIGNOR-264786	0.893
KPNA6	protein	O60684	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	relocalization			9606									20454918	t		gcesareni	Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling.	SIGNOR-254332	0.2
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	UBTF	protein	P17480	UNIPROT	up-regulates activity	phosphorylation	Ser484	ERGKLPEsPKRAEEI	10090	BTO:0000944								10202152	t		llicata	We have identified Ser484 as a direct target for cyclin-dependent kinase 4 (cdk4)-cyclin D1- and cdk2-cyclin E-directed phosphorylation. Mutation of Ser484 impairs rDNA transcription in vivo and in vitro. 	SIGNOR-250754	0.345
PRKAA2	protein	P54646	UNIPROT	SREBF1	protein	P36956	UNIPROT	down-regulates	phosphorylation	Ser396	TAVHKSKsLKDLVSA	9606			SIGNOR-C15						21459323	t		gcesareni	Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372	SIGNOR-173031	0.335
MRPL52	protein	Q86TS9	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262346	0.667
SOS1	protein	Q07889	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									23132018	t		lperfetto	The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras.	SIGNOR-59472	0.888
GLDC	protein	P23378	UNIPROT	Glycine cleavage system	complex	SIGNOR-C437	SIGNOR	form complex	binding			9606									16051266	t		lperfetto	The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide.	SIGNOR-268240	0.688
HDLBP	protein	Q00341	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates activity	binding			9606	BTO:0000150								33941620	t		miannu	We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites.	SIGNOR-266698	0.2
S1PR2	protein	O95136	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256871	0.359
TBX5	protein	Q99593	UNIPROT	CDKN2A	protein	P42771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20802524	f		miannu	TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2.	SIGNOR-255253	0.271
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	AKAP12	protein	Q02952	UNIPROT	up-regulates activity	phosphorylation	Thr767	ESFKRLVtPRKKSKS	9606	BTO:0000007								23063527	t		lperfetto	Mass spectrometry, molecular, and cellular approaches show that CDK1/Cyclin B1 phosphorylates Gravin on threonine 766 to prime the recruitment of the polo-like kinase Plk1 at defined phases of mitosis. 	SIGNOR-271840	0.289
SMARCE1	protein	Q969G3	UNIPROT	Neural progenitor-specific SWI/SNF	complex	SIGNOR-C477	SIGNOR	form complex	binding			9606									25195934	t		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270612	0.83
HEXIM1	protein	O94992	UNIPROT	P-TEFb	complex	SIGNOR-C238	SIGNOR	down-regulates activity	binding			9606									18371977	t		miannu	Studies show that more than half of P-TEFb in cells is associated with HEXIM1, which results in the inactivation of P-TEFb. The mislocalization of HEXIM1 and the increased P-TEFb-dependent transcription caused by NPMc+ suggests that the misregulated activity of PTEFb may contribute to the tumorigenesis of NPMc+ AML.	SIGNOR-260135	0.743
CPSF2	protein	Q9P2I0	UNIPROT	CPSF complex	complex	SIGNOR-C53	SIGNOR	form complex	binding			9606	BTO:0000007								19224921	t		lperfetto	The CPSF complex consists of five subunits, named CPSF160, CPSF100, Fip1, CPSF73, and CPSF30.	SIGNOR-268335	0.893
MC3R	protein	P41968	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268702	0.528
protriptyline	chemical	CHEBI:8597	ChEBI	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			9606									9537821	t		miannu	At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. 	SIGNOR-258736	0.8
UBA6	protein	A0AVT1	UNIPROT	Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	form complex	binding			9606									24816100	t		miannu	The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin.	SIGNOR-270835	0.2
PRKACA	protein	P17612	UNIPROT	SNAP25	protein	P60880	UNIPROT	unknown	phosphorylation	Thr138	GGFIRRVtNDARENE	10116	BTO:0001009								12459461	t		miannu	Thr138 as the exclusive site of SNAP-25 phosphorylation by protein kinase A in vivo. PMA or forskolin treatment alone resulted in dramatic phosphorylation of SNAP-25 Ser187 and/or Thr138 without appreciable neurotransmitter release.	SIGNOR-250052	0.331
DAPK1	protein	P53355	UNIPROT	MCM3	protein	P25205	UNIPROT	unknown	phosphorylation	Ser160	KTIERRYsDLTTLVA	9606									18283219	t		lperfetto	Mcm3 was efficiently and specifically phosphorylated by dapk on a unique site, ser160 / the functional effects of dapk-mediated phosphorylation and any connection to these functions remain to be determined	SIGNOR-160958	0.335
coenzyme Q10	smallmolecule	CHEBI:46245	ChEBI	ubiquinol	smallmolecule	CHEBI:17976	ChEBI	up-regulates quantity	precursor of			9606									30449682	t		miannu	OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway	SIGNOR-267429	0.8
ACTL6A	protein	O96019	UNIPROT	Muscle cell-specific SWI/SNF ARID1B variant	complex	SIGNOR-C482	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270712	0.821
Mitochondrial respiratory chain complex II	complex	SIGNOR-C278	SIGNOR	Respiratory electron transport chain	phenotype	SIGNOR-PH141	SIGNOR	up-regulates													30030361	f		lperfetto	The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA).	SIGNOR-262138	0.7
NIPBL	protein	Q6KC79	UNIPROT	Cohesin complex	complex	SIGNOR-C304	SIGNOR	up-regulates activity	binding			9606									28914604	t		miannu	Scc2 (Nipbl) stimulates cohesin’s ABC-like ATPase and is essential for loading cohesin onto chromosomes. However, it is possible that the stimulation of cohesin’s ATPase by Scc2 also has a post-loading function, for example driving loop extrusion. Using fluorescence recovery after photobleaching (FRAP) and single-molecule tracking in human cells, we show that Scc2 binds dynamically to chromatin, principally through an association with cohesin.	SIGNOR-264522	0.841
E2F1	protein	Q01094	UNIPROT	PCNA	protein	P12004	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253856	0.474
TACR3	protein	P29371	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257389	0.287
PPP2CB	protein	P62714	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	dephosphorylation	Ser199	PRPEHTKsVYTRSVI	10116									18586681	t			Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation.	SIGNOR-248599	0.2
L-cysteine zwitterion	smallmolecule	CHEBI:35235	ChEBI	hydrosulfide	smallmolecule	CHEBI:29919	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000671;BTO:0000759;BTO:0002688							19961860	t		lperfetto	 the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production.	SIGNOR-275814	0.8
RIMBP2	protein	O15034	UNIPROT	RIMS3	protein	Q9UJD0	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264371	0.285
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Ser662	GLGRSITsPTTLYDR	9606	BTO:0001938								11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130.	SIGNOR-104683	0.843
MAPK9	protein	P45984	UNIPROT	MAPK8IP3	protein	Q9UPT6	UNIPROT	up-regulates	phosphorylation	Thr275	TTGTKSNtPTSSVPS	9606									15767678	t		gcesareni	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134572	0.652
SGK1	protein	O00141	UNIPROT	MKNK1	protein	Q9BUB5	UNIPROT	down-regulates activity	phosphorylation	Ser353	S-->K	-1									28545025	t		miannu	We show that SGK1 phosphorylates MNK1 at a conserved site, which represses its activity. 	SIGNOR-277357	0.2
TGFB1	protein	P01137	UNIPROT	CDKN2B	protein	P42772	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									7592908	f		gcesareni	The steadystate level of p15ink4b mrna was induced 30-fold upon tgf-beta treatment, implicating p15ink4b as a primary effector of the tgf-beta-mediated cell cycle arrest	SIGNOR-29582	0.286
SMAD6	protein	O43541	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	binding			9606									9892110	t		lperfetto	Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3	SIGNOR-64071	0.479
CHEK2	protein	O96017	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates activity	phosphorylation	Ser90	IPPARMMsTESANSF	9606	BTO:0002552								32187724	t		lperfetto	We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion.|CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, promoting autophagy via Beclin 1 release from Bcl‐2 sequestration	SIGNOR-264557	0.303
AKT2	protein	P31751	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser82	RALSRQLsSGVSEIR	9606									19593530	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	lperfetto	First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.	SIGNOR-186776	0.293
PRKD1	protein	Q15139	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser172	GQLVRNDsLWHRSDS										34010649	t		lperfetto	The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-275942	0.2
STX11-SNAP23 SNARE complex	complex	SIGNOR-C272	SIGNOR	Membrane_fusion	phenotype	SIGNOR-PH122	SIGNOR	up-regulates				9606	BTO:0000782								22767500	f		lperfetto	Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. 	SIGNOR-261899	0.7
PRKACA	protein	P17612	UNIPROT	MC4R	protein	P32245	UNIPROT	down-regulates activity	phosphorylation	Ser329	LGGLCDLsSRY	9606									12639913	t		miannu	Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA 	SIGNOR-250016	0.312
NR3C1	protein	P04150	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	down-regulates				9606									25910399	f			Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases [.. }The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged.	SIGNOR-257599	0.7
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	PTCH1	protein	Q13635	UNIPROT	down-regulates	cleavage	Asp1405	CPGYPETdHGLFEDP	9606									23074268	t		gcesareni	Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain.	SIGNOR-256437	0.327
LPAR4	protein	Q99677	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257057	0.2
TOPBP1	protein	Q92547	UNIPROT	ATR	protein	Q13535	UNIPROT	up-regulates activity	binding			9606	BTO:0001938		SIGNOR-C298						16530042	t		lperfetto	These results establish that TopBP1 can activate both Xenopus and human ATR. Furthermore, these experiments provide conclusive evidence that the kinase activity that is induced by TopBP1 is intrinsic to the ATR protein itself and is not due to a kinase that associates with ATR.	SIGNOR-263232	0.807
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	Corticotropin	protein	P01189-PRO_0000024969	UNIPROT	up-regulates													24631756	f		lperfetto	ACTH and corticosterone responses to the same acute stress stimulus are higher in the pro-estrus phase of the cycle, when the serum concentrations of estrogen are the highest |Moreover, Kirschbaum et al. conducted a double blind study of 32 men, showing that 100 mcg of estradiol/day for two days was sufficient to produce statistically significant increases in ACTH	SIGNOR-268726	0.8
ITGB1BP1	protein	O14713	UNIPROT	AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257655	0.282
BACH1	protein	O14867	UNIPROT	Metastasis	phenotype	SIGNOR-PH107	SIGNOR	up-regulates				9606	BTO:0000150								22875853	f			Transcriptional network analysis identifies BACH1 as a master regulator of breast cancer bone metastasis	SIGNOR-259337	0.7
NFKB1	protein	P19838	UNIPROT	MAP3K8	protein	P41279	UNIPROT	down-regulates	binding			9606			SIGNOR-C13						22435554	t		gcesareni	Tpl-2 is stoichiometrically complexed with the nf-kb inhibitory protein, nf-kb1 p105, and the ubiquitin-binding protein abin-2, both of which are required to maintain tpl-2 protein stability. Binding to p105 also prevents tpl-2 from phosphorylating mek	SIGNOR-196747	0.675
CSNK2A1	protein	P68400	UNIPROT	KDM1A	protein	O60341	UNIPROT	up-regulates activity	phosphorylation	Ser137	LSEDEYYsEEERNAK	9606	BTO:0002181								25999347	t		miannu	We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites.	SIGNOR-276903	0.323
PDPK1	protein	O15530	UNIPROT	PDPK1	protein	O15530	UNIPROT	unknown	phosphorylation	Ser393	MQVSSSSsSHSLSAS	9606									10455013	t		lperfetto	3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity	SIGNOR-235782	0.2
SERPINC1	protein	P01008	UNIPROT	F2	protein	P00734	UNIPROT	down-regulates activity	cleavage												31030036	t		lperfetto	Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1	SIGNOR-264136	0.946
VX-765	chemical	CID:53245642	PUBCHEM	CASP1	protein	P29466	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207770	0.8
STAT6	protein	P42226	UNIPROT	RETN	protein	Q9HD89	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000801								20508200	f		lperfetto	Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation.	SIGNOR-249536	0.319
SRC	protein	P12931	UNIPROT	DAPP1	protein	Q9UN19	UNIPROT	up-regulates activity	phosphorylation	Tyr139	KVEEPSIyESVRVHT	9606	BTO:0000776								10880360	t		lperfetto	Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell linesyrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins.	SIGNOR-247119	0.568
PTPN1	protein	P18031	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates activity	dephosphorylation			9606									29920310	t		lperfetto	It has been reported that the protein tyrosine phosphatase PTP1B could inactivate MET by direct dephosphorylation of Tyr 1234 and 1235 in its activation loop, and that this dephosphorylation takes place in peri-nuclear region of the cell [ xref ].	SIGNOR-277001	0.621
PTPN12	protein	Q05209	UNIPROT	BCAR1	protein	P56945	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000782								11432829	t		gcesareni	Ptp-pest is an efficient negative regulator of lymphocyte activation. This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway.	SIGNOR-109032	0.564
PLK1	protein	P53350	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates				9606									19473992	f		lperfetto	Plk1-mediated phosphorylation of topors regulates p53 stability. Herein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation.	SIGNOR-185841	0.595
PSTPIP1	protein	O43586	UNIPROT	DNM2	protein	P50570	UNIPROT	down-regulates	binding			9606									18480402	t		miannu	We show that pstpip1 associates with the regulator of endocytosis, dynamin 2, and pstpip1 expression impairs transferrin uptake and endocytosis	SIGNOR-178628	0.382
BCR-Dl	complex	SIGNOR-C436	SIGNOR	SYK	protein	P43405	UNIPROT	up-regulates activity	binding			9606									32323266	t		scontino	The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK).	SIGNOR-268442	0.703
SPI1	protein	P17947	UNIPROT	FLI1	protein	Q01543	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10523830	f		irozzo	Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression.	SIGNOR-256054	0.271
1-phosphatidyl-1D-myo-inositol 4-phosphate	smallmolecule	CHEBI:17526	ChEBI	AP-1/clathrin vescicle	complex	SIGNOR-C251	SIGNOR	form complex	binding			9606									23103167	t		lperfetto	Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors	SIGNOR-260675	0.8
MARK1	protein	Q9P0L2	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser579	NVKSKIGsTENLKHQ	9606									21215781	t	The effect has been demonstrated using P10636-8	lperfetto	Mark and pka phosphorylate several sites within the repeats (notably the kxgs motifs including ser262, ser324, and ser356, plus ser320)tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process	SIGNOR-171050	0.44
VEGFC	protein	P49767	UNIPROT	KDR	protein	P35968	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001103;BTO:0000763							9435229	t		gcesareni	Vegf-c is also a ligand for vegfr-2 (12), but the functional significance of this potential interaction in vivo is unknown	SIGNOR-55208	0.913
sertindole	chemical	CHEBI:9122	ChEBI	HTR1B	protein	P28222	UNIPROT	down-regulates activity	chemical inhibition			10116		BTO:0001311							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258545	0.8
MED1	protein	Q15648	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266667	0.803
ABTB1	protein	Q969K4	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606									11494141	f		miannu	Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G1/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated.	SIGNOR-260046	0.7
SPOP	protein	O43791	UNIPROT	EGLN2	protein	Q96KS0	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001033								28089830	t		lperfetto	Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells	SIGNOR-261996	0.353
WIPF1	protein	O43516	UNIPROT	WASL	protein	O00401	UNIPROT	up-regulates activity	binding			9606									10878810	t		lperfetto	Recruitment of N-WASP to vaccinia is mediated by WASP-interacting protein (WIP), whereas in Shigella WIP is recruited by N-WASP. Our observations show that vaccinia and Shigella activate the Arp2/3 complex to achieve actin-based motility, by mimicking either the SH2/SH3-containing adaptor or Cdc42 signalling pathways to recruit the N-WASP-WIP complex.	SIGNOR-261880	0.931
ERAP2	protein	Q6P179	UNIPROT	peptide antigen	smallmolecule	CHEBI:166824	ChEBI	up-regulates quantity	chemical modification			9606									15908954	t			The generation of many HLA class I peptides entails a final trimming step in the endoplasmic reticulum that, in humans, is accomplished by two 'candidate' aminopeptidases | We show here that one of these, ERAP1, was unable to remove several N-terminal amino acids that were trimmed efficiently by the second enzyme, ERAP2.	SIGNOR-272496	0.8
vismodegib	chemical	CHEBI:66903	ChEBI	SMO	protein	Q99835	UNIPROT	down-regulates	chemical inhibition			9606									21679342	t		gcesareni	Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date.	SIGNOR-174417	0.8
PPP2CA	protein	P67775	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates	dephosphorylation			9606	BTO:0000848								11591705	t		lperfetto	Rela was dephosphorylated by a purified pp2a core enzyme, a heterodimer formed by the catalytic subunit of pp2a (pp2ac) and pr65, in a concentration-dependent manner.These data suggest that the constitutive activation of rela in melanoma cells could be due, at least in part, to the deficiency of pp2a, which exhibits decreased dephosphorylation of nf-kappa b/rela.	SIGNOR-217421	0.439
POU5F1	protein	Q01860	UNIPROT	DPPA4	protein	Q7L190	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001086								17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254941	0.615
IL1R1	protein	P14778	UNIPROT	MYD88	protein	Q99836	UNIPROT	up-regulates activity	binding			9606	BTO:0003432								10217414	t		lperfetto	Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88.	SIGNOR-67140	0.944
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Ser454	YVPMNPNsPPRQHSS	9606									15379552	t		lperfetto	Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597)	SIGNOR-129188	0.2
PRKDC	protein	P78527	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates activity	phosphorylation	Ser446	STMQVSHsQVQEPGG	-1									8407951	t		lperfetto	 The carboxyl-terminal transcription activation domain was mapped within a 71-amino acid region that contains both DNA-PK phosphorylation sites. Amino acid substitutions that interfered with phosphorylation by DNA-PK at Ser-435/446 in GAL4-SRF fusion proteins were reduced in transactivation potency. From these data we suggest that DNA-PK phosphorylation may modulate SRF activity in vivo.	SIGNOR-248922	0.415
RAD50	protein	Q92878	UNIPROT	MRE11	protein	P49959	UNIPROT	up-regulates	binding			9606									17713585	t		fstefani	To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50.	SIGNOR-157478	0.2
TLN1	protein	Q9Y490	UNIPROT	A4/b7 integrin	complex	SIGNOR-C187	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257635	0.538
PRKCA	protein	P17252	UNIPROT	RAB11A	protein	P62491	UNIPROT	unknown	phosphorylation	Ser177	TEIYRIVsQKQMSDR	-1									22188018	t		miannu	 This report shows for the first time that Rab11 is differentially phosphorylated by distinct PKC isoenzymes and that this post-translational modification might be a regulatory mechanism of intracellular trafficking.Our results demonstrate that classical PKC (PKCα and PKCβII but not PKCβI) directly phosphorylate Rab11 in vitro. In addition, novel PKCε and PKCη but not PKCδ isoenzymes also phosphorylate Rab11. Mass spectrometry analysis revealed that Ser 177 is the Rab11 residue to be phosphorylated in vitro by either PKCβII or PKCε. 	SIGNOR-263168	0.2
COLGALT2	protein	Q8IYK4	UNIPROT	COL4A1	protein	P02462	UNIPROT	up-regulates activity	glycosylation			-1									19075007	t			Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261159	0.427
PRKCD	protein	Q05655	UNIPROT	GRK2	protein	P25098	UNIPROT	up-regulates activity	phosphorylation	Ser29	ATPAARAsKKILLPE	9606	BTO:0000007								11042191	t		lperfetto	Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells. 	SIGNOR-249059	0.2
PTPN1	protein	P18031	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates	dephosphorylation	Tyr1235	DMYDKEYySVHNKTG	9606									16537444	t		gcesareni	Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion.	SIGNOR-145145	0.621
GSK3B	protein	P49841	UNIPROT	SFPQ	protein	P23246	UNIPROT	down-regulates	phosphorylation			9606									20932480	t		miannu	Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687	SIGNOR-168392	0.351
CPC	complex	SIGNOR-C554	SIGNOR	Chromosome_segregation	phenotype	SIGNOR-PH44	SIGNOR	up-regulates				9606									37292983	f		miannu	Here, we focus on the chromosome passenger complex (CPC), that forms a chromatin body that regulates chromosome segregation in mitosis.	SIGNOR-275427	0.7
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	SPHK1	protein	Q9NYA1	UNIPROT	up-regulates	phosphorylation			9606									14532121	t	inferred from 70% family members	gcesareni	Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation.	SIGNOR-270063	0.2
MAPK1	protein	P28482	UNIPROT	SCNN1B	protein	P51168	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr615	QALPIPGtPPPNYDS	-1									11805112	t		lperfetto	Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.	SIGNOR-249446	0.294
AP1	complex	SIGNOR-C154	SIGNOR	GLIS1	protein	Q8NBF1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								24383088	t		miannu	 Co-transfection experiments revealed that HIF-2α had greater potency on the GLIS1 promoter activation than HIF-1α. Subsequent studies using wild-type and mutant HIF-2α demonstrated that DNA binding activity was not necessary but TADs were critical for GLIS1 induction. Finally, co-transfection experiments indicated that HIF-2α cooperated with AP-1 family members in upregulating GLIS1 transcription. These results suggest that the hypoxic signaling pathway may play a pivotal role in regulating the reprogramming factor GLIS1, via non-canonical mechanisms involving partner transcription factor rather than by direct HIF transactivation.	SIGNOR-269041	0.2
sunitinib	chemical	CHEBI:38940	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									21993628	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-176757	0.8
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1784	TPTSPNYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273057	0.556
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PARP1	protein	P09874	UNIPROT	up-regulates	phosphorylation	Ser372	VAATPPPsTASAPAA	9606	BTO:0000938	BTO:0000142							16627622	t		lperfetto	Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation.	SIGNOR-244669	0.2
SLC19A1	protein	P41440	UNIPROT	(6S)-5-methyltetrahydrofolate(2-)	smallmolecule	CHEBI:18608	ChEBI	up-regulates quantity	relocalization			9606									10787414	t		lperfetto	The differential polarized distribution of the reduced-folate transporter (RFT-1) and folate receptor alpha (FRalpha), the two proteins involved in the transport of folate, has been characterized in normal mouse retinal pigment epithelium (RPE) and in cultured human RPE cells.	SIGNOR-268266	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Thr32	QSRPRSCtWPLPRPE	9606									16272144	t		lperfetto	Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression	SIGNOR-252830	0.908
CD79B	protein	P40259	UNIPROT	BCR-Ml	complex	SIGNOR-C434	SIGNOR	form complex	binding			9606	BTO:0000776								32323266	t		scontino	BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition.	SIGNOR-268193	0.641
CAMK2A	protein	Q9UQM7	UNIPROT	CAMK2A	protein	Q9UQM7	UNIPROT	up-regulates	phosphorylation	Thr286	SCMHRQEtVDCLKKF	9606		BTO:0000975							1849884	t		lperfetto	Role of threonine-286 as autophosphorylation site for appearance of ca2(+)-independent activity of calmodulin-dependent protein kinase ii alpha subunit	SIGNOR-21797	0.2
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606									17339337	t		Manara	Evaluation of these calcium calmodulin kinase superfamily members as candidate Ser(20) kinases in vivo has shown that only CHK1 or DAPK-1 can stimulate p53 transactivation and induce Ser(20) phosphorylation of p53.| Thus, endogenous CHK1 is required for the majority of Ser20 site phosphorylation of ectopically expressed p53 in H1299 cells.	SIGNOR-260776	0.784
GART	protein	P22102	UNIPROT	N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-)	smallmolecule	CHEBI:143788	ChEBI	down-regulates quantity	chemical modification			9606									34283828	t		miannu	In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR).	SIGNOR-268101	0.8
1-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-2-methoxyphenyl)-3-(1-(thiazol-2-yl)ethyl)urea	chemical	CID:9869779	PUBCHEM	CSF1R	protein	P07333	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259750	0.8
LATS2	protein	Q9NRM7	UNIPROT	YWHAG	protein	P61981	UNIPROT	up-regulates	phosphorylation	Ser59	VVGARRSsWRVISSI	9606									25086053	t		lperfetto	Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions,	SIGNOR-205247	0.336
HARS1	protein	P12081	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									10430027	t		miannu	Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 	SIGNOR-270487	0.8
PRKD1	protein	Q15139	UNIPROT	CACNA1C	protein	Q13936	UNIPROT	up-regulates	phosphorylation	Ser1981	ASLGRRAsFHLECLK	9606									22100296	t		gcesareni	Both the expression of a dominant-negative mutant of pkd and the mutation of serine 1884 but not serine 1930, putative targets of pkd, strongly reduced l-type calcium currents and single channel activity without affecting the channel's expression at the plasma membrane. Our results suggest that serine 1884 is essential for the regulation of hcav1.2 by pkd.	SIGNOR-177481	0.258
PRKCB	protein	P05771	UNIPROT	PA2G4	protein	Q9UQ80	UNIPROT	unknown	phosphorylation	Ser363	ALLQSSAsRKTQKKK	9606	BTO:0004737								11325528	t		lperfetto	We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC.	SIGNOR-249090	0.286
SORT1	protein	Q99523	UNIPROT	APOA1	protein	P02647	UNIPROT	up-regulates quantity	binding			10029	BTO:0000246								23283348	t		miannu	Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms.	SIGNOR-273722	0.338
SAR1A	protein	Q9NR31	UNIPROT	COPII vesicle	complex	SIGNOR-C370	SIGNOR	up-regulates quantity	binding												30605680	t		lperfetto	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 	SIGNOR-265304	0.711
PRKD1	protein	Q15139	UNIPROT	PTPN7	protein	P35236	UNIPROT	up-regulates activity	phosphorylation	Ser246	QYQEERRsVKHILFS	-1									16479000	t		miannu	HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. 	SIGNOR-276046	0.2
MTNR1A	protein	P48039	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256706	0.453
POGZ	protein	Q7Z3K3	UNIPROT	CBX5	protein	P45973	UNIPROT	down-regulates activity	binding			9606	BTO:0000932								20562864	t		miannu	 POGZ was found to bind to HP1alpha through a zinc-finger-like motif. Binding by POGZ, mediated through its zinc-finger-like motif, competed with PxVxL proteins and destabilized the HP1alpha-chromatin interaction.	SIGNOR-264487	0.443
STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	Mob1	proteinfamily	SIGNOR-PF42	SIGNOR	up-regulates activity	phosphorylation			9606									23431053	t		miannu	Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity	SIGNOR-256185	0.897
CSNK2A1	protein	P68400	UNIPROT	CARD9	protein	Q9H257	UNIPROT	down-regulates	phosphorylation	Thr533	TGSDNTDtEGS	9606									17936701	t		lperfetto	Pvhl acts as an adaptor to promote the inhibitory phosphorylation of the nf-kappab agonist card9 by ck2. The card9 c terminus contains multiple serine and threonine residues that resemble ck2 phosphorylation sites. Mass spectrometry analysis of myc-card9 recovered from hela cells revealed that these sites, including t531 and t533, were phosphorylated in vivo	SIGNOR-158418	0.352
IL10	protein	P22301	UNIPROT	IL10RB	protein	Q08334	UNIPROT	up-regulates	binding			9606		BTO:0000671							11035029	t		fspada	The il-10r2 chain is ubiquitously expressed, whereas the il-10 activity is restricted mainly to cells of hematopoietic origin (35, 36). This raised the question of why the second chain of the il-10 receptor complex is widely expressed when its function was required only in limited cellular subsets. One hypothesis is that the il-10r2 chain is shared by receptors for ligands other than il-10	SIGNOR-83191	0.704
canertinib	chemical	CHEBI:61399	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258095	0.8
GFAP	protein	P14136	UNIPROT	ACTB	protein	P60709	UNIPROT	up-regulates quantity	binding			9606	BTO:0000099								31626364	t		miannu	GFAP is the major cytoskeletal element and scaffold of astrocytes In astrocytes, GFAP has close interaction with F-actin molecularly and functionally.	SIGNOR-269271	0.384
PRKG1	protein	Q13976	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates	phosphorylation	Ser660	FSAERRNsILTETLH	9606									1377674	t		lperfetto	Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function	SIGNOR-18237	0.521
RNF7	protein	Q9UBF6	UNIPROT	CDC34	protein	P49427	UNIPROT	down-regulates activity	polyubiquitination			9606									10851089	t		miannu	SAG was found to be the second family member of Rbx (RING box protein) or ROC (Regulator of cullins) or Hrt that is a component of SCF E3 ubiquitin ligase. Indeed, like ROC1/Rbx1/Hrt1, SAG binds to Cul1 and SAG-Cul1 complex has ubiquitin ligase activity to promote poly-ubiquitination of E2/Cdc34. 	SIGNOR-271443	0.737
MLH1	protein	P40692	UNIPROT	MLH1/PMS1	complex	SIGNOR-C58	SIGNOR	form complex	binding			9606									10542278	t		miannu	We now show that hpms1 is expressed in human cells and that it interacts with hmlh1 with high affinity to form the heterodimer hmutl_.	SIGNOR-71768	0.694
mTORC2	complex	SIGNOR-C2	SIGNOR	SLC7A11	protein	Q9UPY5	UNIPROT	down-regulates activity	phosphorylation	Ser26	NVNGRLPsLGNKEPP	9606	BTO:0002036								28648777	t		miannu	MTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity. 	SIGNOR-273682	0.279
GNAS	protein	P63092	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates	binding			9606				SIGNOR-C110					16293724	t		gcesareni	We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin.	SIGNOR-141789	0.389
P2RY14	protein	Q15391	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256866	0.376
RIMS3	protein	Q9UJD0	UNIPROT	UNC13B	protein	O14795	UNIPROT	up-regulates activity	relocalization			9606									31679900	t		miannu	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264384	0.269
VDR	protein	P11473	UNIPROT	HLA-DRB1	protein	P01911	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									19956544	f	 	 	The promoter sequence analysis of HLA-DRB1 0301 showed presence of VDRE involved in higher expression of HLA-DRB1 030, which was confirmed by flow cytometry and real time PCR analysis| The data shows an average of 1.79±0.28 (mean±S.D. of three independent experiments) fold increase in the HLA-DRB1 transcripts from B-LCL treated with calcitriol as compared to the vehicle control.	SIGNOR-253978	0.31
KDM2A	protein	Q9Y2K7	UNIPROT	RELA	protein	Q04206	UNIPROT	down-regulates	demethylation	Lys218	EIFLLCDkVQKEDIE	9606				SIGNOR-C13					20080798	t		miannu	Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation.	SIGNOR-163384	0.471
EP300	protein	Q09472	UNIPROT	CAV3	protein	P56539	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534	BTO:0001538								15199055	f	 	 	Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle.	SIGNOR-254259	0.2
CSNK1E	protein	P49674	UNIPROT	PER1	protein	O15534	UNIPROT	down-regulates quantity by destabilization	phosphorylation			10090									11865049	t		miannu	We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. 	SIGNOR-267997	0.835
PBX2	protein	P40425	UNIPROT	EMX2	protein	Q04743	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15494461	f		miannu	EMSA demonstrated HOXA10-Pbx2 binding as a heterodimer to an enhancer of the EMX2 gene, a known target of HOXA10 regulation.	SIGNOR-254466	0.4
PLAT	protein	P00750	UNIPROT	PLG	protein	P00747	UNIPROT	up-regulates activity	binding			9606		BTO:0000131							1447176	t		lperfetto	The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme 	SIGNOR-263533	0.555
RPS6KA1	protein	Q15418	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation	Ser119	EILSRRPsYRKILND	9606									10558990	t		lperfetto	The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival.	SIGNOR-72117	0.738
CTNND2	protein	Q9UQB3	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0001109								14610055	t		miannu	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 	SIGNOR-252134	0.459
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser33	QQQSYLDsGIHSGAT	9606	BTO:0000938	BTO:0000142							19303846	t		lperfetto	GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation	SIGNOR-227870	0.892
perfluorododecanoic acid	chemical	CHEBI:90633	ChEBI	PPARD	protein	Q03181	UNIPROT	up-regulates activity	chemical activation			-1									31332417	t		miannu	In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group.	SIGNOR-268759	0.8
MAPK14	protein	Q16539	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates				9606									11777913	f		gcesareni	Phosphorylation of 4e-bp1 is mediated by the p38/msk1 pathway in response to uvb irradiation. In the present study we demonstrated that uvb induced 4e-bp1 phosphorylation at multiple sites, thr-36, thr-45, ser-64, and thr-69, leading to dissociation of 4e-bp1 from eif-4e. Uvb-induced phosphorylation of 4e-bp1 was blocked by p38 kinase inhibitors, pd169316 and sb202190, and msk1 inhibitor, h89, but not by mitogen-activated protein kinase kinase inhibitors, pd98059 or u0126.	SIGNOR-113566	0.444
NR4A3	protein	Q92570	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30455429	t		miannu	Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax.	SIGNOR-259397	0.2
IL26	protein	Q9NPH9	UNIPROT	IL20RA	protein	Q9UHF4	UNIPROT	up-regulates	binding			9606		BTO:0001253							17208301	t		gcesareni	The mrna expression level of il10, il19, il20, il22, il24, il26, il28b, il29 and their receptors il10ra, il10rb, il20ra, il20rb, il22ra1, il22ra2, il28ra was compared in skin biopsies of children and adults and in childrens' skin cells by quantitative real-time pcr (qrt-pcr).	SIGNOR-151920	0.586
CAMK1	protein	Q14012	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates activity	phosphorylation	Thr198	PGLRRRQt	10090									23707388	t		Monia	We also demonstrate that i) CaMKI phosphorylates p27 at Thr157and Thr198 in human cells and at Thr170and Thr197in mouse cells to modulate its subcellular localization;|Collectively, these results suggest that CaMKI is involved in mediating G1 progression by promoting cyclin D1/cdk4 complex formation through site-specific p27 phosphorylation in human lung epithelia.	SIGNOR-261194	0.309
ABL1	protein	P00519	UNIPROT	TP73	protein	O15350	UNIPROT	up-regulates	phosphorylation	Tyr99	SVPTHSPyAQPSSTF	9606									10391251	t		gcesareni	C-abl phosphorylates p73 on a tyrosine residue at position 99 both in vitro and in cells that have been exposed to ionizing radiation. Our results show that c-abl stimulates p73-mediated transactivation and apoptosis.	SIGNOR-68931	0.745
ETS1	protein	P14921	UNIPROT	TNC	protein	P24821	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15001984	t		Luana	Sp1 and Ets1 are potent transactivators of the TN-C promoter.	SIGNOR-261599	0.2
GSK3A	protein	P49840	UNIPROT	GATA6	protein	Q92908	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser37	REPSTPPsPISSSSS	9606	BTO:0000182								27273097	t		lperfetto	Through bioinformatics and cell-based experiments, we identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin	SIGNOR-253156	0.268
TARS1	protein	P26639	UNIPROT	alpha-aminoacyl-tRNA	smallmolecule	CHEBI:2651	ChEBI	up-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 	SIGNOR-270799	0.8
PAK4	protein	O96013	UNIPROT	SNAI2	protein	O43623	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser158	CDAQSRKsFSCKYCD	-1									29849120	t		miannu	PAK4 bound and directly phosphorylated Slug at two previously unknown sites, S158 and S254, which resulted in its stabilization. 	SIGNOR-277393	0.2
GSK3B	protein	P49841	UNIPROT	MITF	protein	O75030	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser405	QARAHGLsLIPSTGL	9606	BTO:0005451								25605940	t		miannu	We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here.	SIGNOR-276477	0.446
bethanechol	chemical	CHEBI:3084	ChEBI	CHRM4	protein	P08173	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258624	0.8
SRC	protein	P12931	UNIPROT	SLC6A4	protein	P31645	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr142	MELALGQyHRNGCIS	10116	BTO:0000132								21992875	t		miannu	We found that 1) SERT exists in a tyrosine-phosphorylated form, 2) inhibition of tyrosine kinase(s) reduces SERT expression levels by facilitating SERT protein degradation, 3) Src-kinase activity up-regulates SERT protein expression with a concomitant increase in 5-HT uptake and tyrosine phosphorylation, and 4) mutation of Tyr47 or Tyr142 abolishes src-induced increases in transport function and phosphorylation of SERT. 	SIGNOR-276386	0.262
MAPK1	protein	P28482	UNIPROT	DUSP1	protein	P28562	UNIPROT	up-regulates	phosphorylation	Ser364	LQSPITTsPSC	9606									10617468	t		lperfetto	Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein.	SIGNOR-73625	0.799
CDK1	protein	P06493	UNIPROT	PIK3C2A	protein	O00443	UNIPROT	down-regulates activity	phosphorylation	Ser259	KVSNLQVsPKSEDIS	9606									12719431	t		lperfetto	Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. Stress-dependent and mitotic phosphorylation of hspik3-c2alpha occurs on the same serine residue (ser259) within a recognition motif for proline-directed kinases. Mitotic phosphorylation of hspik3-c2alpha can be attributed to cdc2 activity, and stress-induced phosphorylation of hspik3-c2alpha is mediated by jnk/sapk	SIGNOR-100903	0.285
Ankyrin complex	complex	SIGNOR-C383	SIGNOR	SPTB	protein	P11277	UNIPROT	up-regulates activity	binding			9606	BTO:0000424								22465511	t		lperfetto	The junctional complex is focused around a hub or ‘junction’ arising from lateral connections between protein 4.1, actin and beta spectrin (the first of which stabilises the actin spectrin association via direct binding to both proteins [8]).	SIGNOR-266023	0.436
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	METTL3	protein	Q86U44	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser525	YGMIERLsPGTRKIE	9606	BTO:0000007								33217317	t		miannu	 Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.	SIGNOR-265952	0.2
PAK1	protein	Q13153	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates activity	phosphorylation	Ser67	RQLRKVRsVELDQLP	9606	BTO:0000007								12228228	t		lperfetto	We found that pak1 phosphorylated mekk1 on serine 67 of its amino-terminal regulatory domain. mekk1 activity was increased modestly following pak phosphorylation.	SIGNOR-236006	0.517
CHD7	protein	Q9P2D1	UNIPROT	SETDB1/NLK/CHD7	complex	SIGNOR-C189	SIGNOR	form complex	binding			10090									21952300	t		FFerrentino	The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43.	SIGNOR-253526	0.479
MKNK1	protein	Q9BUB5	UNIPROT	EIF4E	protein	P06730	UNIPROT	up-regulates	phosphorylation	Ser209	DTATKSGsTTKNRFV	9606									17724079	t		lperfetto	Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes.	SIGNOR-157533	0.771
AML1-ETO	fusion protein	SIGNOR-FP1	SIGNOR	KIT	protein	P10721	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									29236325	f		irozzo	 We report here that AML1/ETO transactivates c-KIT expression through directly binding to and mediating the long-range interaction between the promoter and intronic enhancer regions of c-KIT.	SIGNOR-255699	0.2
SRC	protein	P12931	UNIPROT	CHN2	protein	P52757	UNIPROT	down-regulates	phosphorylation	Tyr21	VSSDAEEyQPPIWKS	9606									17560670	t		llicata	Here we report that beta2-chimaerin is tyrosine-phosphorylated by src-family kinases (sfks) upon cell stimulation with epidermal growth factor (egf). Mutational analysis identified tyr-21 in the n-terminal regulatory region as a major phosphorylation site. these results suggest tyr-21 phosphorylation as a novel, sfk-dependent mechanism that negatively regulates beta2-chimaerin rac-gap activity.	SIGNOR-155713	0.2
IKBKE	protein	Q14164	UNIPROT	REL/RELA	complex	SIGNOR-C68	SIGNOR	up-regulates	phosphorylation			9606									16888014	t		lperfetto	The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel.	SIGNOR-217664	0.406
ATM	protein	Q13315	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1387	EDCSGLSsQSDILTT	9606	BTO:0000150								12183412	t		gcesareni	Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint.	SIGNOR-91482	0.813
AKT1	protein	P31749	UNIPROT	RPS3	protein	P23396	UNIPROT	up-regulates activity	phosphorylation	Thr70	GRRIRELtAVVQKRF	10116	BTO:0003060								20605787	t		miannu	Here, we show that human RPS3 is a physiological target of Akt kinase and a novel mediator of neuronal apoptosis. NGF stimulation resulted in phosphorylation of threonine 70 of RPS3 by Akt, and this phosphorylation was required for Akt binding to RPS3.our experiment demonstrated that Akt up-regulates the endonuclease activity of RPS3 via phosphorylation and led us to believe that Akt phosphorylation of RPS3 after DNA damage is an antiapoptotic signal or a molecular switch that extends the life of a cell after DNA damage.	SIGNOR-259815	0.377
WNT9A	protein	O14904	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-132070	0.607
FBXO32	protein	Q969P5	UNIPROT	Muscle_atrophy	phenotype	SIGNOR-PH40	SIGNOR	up-regulates activity				10090									25549588	f		areggio	Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX)8, are markedly induced in almost all types of atrophy. 	SIGNOR-254994	0.7
PRKCQ	protein	Q04759	UNIPROT	HABP4	protein	Q5JVS0	UNIPROT	down-regulates activity	phosphorylation	Thr354	RKPANDItSQLEINF	9606									14699138	t		lperfetto	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249250	0.307
RET	protein	P07949	UNIPROT	RET	protein	P07949	UNIPROT	up-regulates	phosphorylation	Tyr900	FGLSRDVyEEDSYVK	9606									14711813	t		gcesareni	Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation	SIGNOR-121161	0.2
HTR4	protein	Q13639	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256912	0.359
CLK3	protein	P49761	UNIPROT	SRSF1	protein	Q07955	UNIPROT	up-regulates activity	phosphorylation			-1									8617202	t		miannu	 In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors.	SIGNOR-273859	0.545
AGTR2	protein	P50052	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									32201502	f		MIANNU	 AT2 receptor stimulation has been associated, for instance, with protection of the brain against ischemia [94]. In essence, AT2 receptors are linked to vasodilatation, release of nitric oxide, tissue development and remodeling, by stimulating apoptosis and inhibition of cell growth 	SIGNOR-260232	0.7
PRKCA	protein	P17252	UNIPROT	TRPM4	protein	Q8TD43	UNIPROT	up-regulates	phosphorylation	Ser1145	RDKRESDsERLKRTS	9606									15590641	t		gcesareni	Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites.	SIGNOR-132243	0.2
TGFB1	protein	P01137	UNIPROT	Activated PSC	phenotype	SIGNOR-PH224	SIGNOR	up-regulates				9606		BTO:0000988							38540204	t		miannu	Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction	SIGNOR-277679	0.7
TGFB1	protein	P01137	UNIPROT	ACTA2	protein	P62736	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000452							11988769	t		miannu	A TGF-β1 response element that has a sequence different to that known for Smad binding has been identified in the α- SM actin promoter and seems to be essential for expression of α-SM actin in both SM cells 72 and myofibroblasts73 . How TGF-β1 activates expression of α-SM actin through this TGF-β1 control element is, as yet, unknown	SIGNOR-277681	0.431
SRC	protein	P12931	UNIPROT	RASA1	protein	P20936	UNIPROT	down-regulates	phosphorylation			9606									11389730	t		lperfetto	The phosphorylation of p120-gap by p60c-src inhibited its ability to stimulate the ha-ras-gtpase activity	SIGNOR-86008	0.598
RELA	protein	Q04206	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	form complex	binding			9606									9450761	t		gcesareni	Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna	SIGNOR-55381	0.699
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	methionine	smallmolecule	CHEBI:16811	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270397	0.8
CYP2D6	protein	P10635	UNIPROT	tyramine	smallmolecule	CHEBI:15760	ChEBI	down-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain 	SIGNOR-263995	0.8
ROCK2	protein	O75116	UNIPROT	PPP1R14A	protein	Q96A00	UNIPROT	up-regulates activity	phosphorylation	Thr38	QKRHARVtVKYDRRE	9606									32471307	t		lperfetto	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225].	SIGNOR-96696	0.424
PITX1	protein	P78337	UNIPROT	LHB	protein	P01229	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									19106114	f		miannu	 GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. 	SIGNOR-254920	0.357
SUCLG1	protein	P53597	UNIPROT	Succinyl-CoA ATP variant	complex	SIGNOR-C398	SIGNOR	form complex	binding			9606									32627745	t		miannu	Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS). 	SIGNOR-266261	0.986
PTGES2	protein	Q9H7Z7	UNIPROT	prostaglandin H2(1-)	smallmolecule	CHEBI:57405	ChEBI	up-regulates quantity	chemical modification			-1									10922363	t		Luana	Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently.	SIGNOR-269768	0.8
orantinib	chemical	CHEBI:91088	ChEBI	FGFR1	protein	P11362	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207435	0.8
2,5-dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide	chemical	CHEBI:125569	ChEBI	PPARG	protein	P37231	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001950								27489280	t		lperfetto	We performed reporter assays to examine the effect of NeoB on the transcriptional activity of specific nuclear hormone receptors, including PPARs, retinoic acid receptor (RAR), ER, and LXR, in uninfected Huh7-25 cells (Fig. 3A). NeoB did not have a significant effect [...] in contrast to the transcriptional repression by known antagonists as positive controls (GW6471, GSK0660, FH535, Ro41-5253, and 4-hydroxytamoxifen) (Fig. 3A)	SIGNOR-262015	0.8
CSNK1D	protein	P48730	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	phosphorylation	Ser400	SRDESTDsGLSMSSY	9606							phosphorylation:Ser127	PQHVRAHsSPASLQL	23431053	t		milica	Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ	SIGNOR-201143	0.4
SRPK1	protein	Q96SB4	UNIPROT	SRPK1	protein	Q96SB4	UNIPROT	up-regulates	phosphorylation	Thr326	ENPPNKMtQEKLEES	9606									22727668	t		llicata	We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1	SIGNOR-197993	0.2
SYK	protein	P43405	UNIPROT	FCGR2C	protein	P31995	UNIPROT	up-regulates activity	phosphorylation	Tyr310	TDDDKNIyLTLPPND	-1									8756631	t		miannu	Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation	SIGNOR-262675	0.2
SREBF1	protein	P36956	UNIPROT	PK	proteinfamily	SIGNOR-PF80	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									16308421	t	inferred from family member	gcesareni	Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk)	SIGNOR-267799	0.34
TFPT	protein	P0C1Z6	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270857	0.437
melatonin	smallmolecule	CHEBI:16796	ChEBI	MTNR1A	protein	P48039	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257545	0.8
PRKCA	protein	P17252	UNIPROT	CDC42EP4	protein	Q9H3Q1	UNIPROT	down-regulates activity	phosphorylation	Ser80	SSKRSLLsRKFRGSK	9606	BTO:0001939								25086031	t		miannu	Cdc42 effector protein-4 (CEP4) was recently identified by our laboratory to be a substrate of multiple PKC isoforms in non-transformed MCF-10A human breast cells. MS/MS analysis verified that Ser(18) and Ser(80) were directly phosphorylated by PKCα in vitro. Phosphorylation of CEP4 severely diminished its affinity for Cdc42 while promoting Rac activation and formation of filopodia (microspikes). 	SIGNOR-263161	0.2
MAPK1	protein	P28482	UNIPROT	IRX2	protein	Q9BZI1	UNIPROT	up-regulates activity	phosphorylation	Ser46	SASGSAFsPYPGSAA	-1									15133517	t		miannu	We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation.	SIGNOR-263052	0.2
sunitinib	chemical	CHEBI:38940	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates	chemical inhibition			9606									21993628	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-176754	0.8
mono(2-ethylhexyl) phthalate	chemical	CHEBI:17243	ChEBI	NR1I2	protein	O75469	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 	SIGNOR-268777	0.8
8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	chemical	CHEBI:93369	ChEBI	HTR1D	protein	P28221	UNIPROT	down-regulates activity	chemical inhibition			10116	BTO:0000529								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258539	0.8
DCK	protein	P27707	UNIPROT	2'-deoxycytosine 5'-monophosphate(2-)	smallmolecule	CHEBI:57566	ChEBI	up-regulates quantity	chemical modification												20637175	t		lperfetto	Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis	SIGNOR-275807	0.8
WNT3	protein	P56703	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131820	0.617
GLI2	protein	P10070	UNIPROT	GLI1/GLI2	complex	SIGNOR-C450	SIGNOR	form complex	binding			9606	BTO:0000304								32766732	t	GLI2 and GLI1 heterodimerize via the Zn-finger domain	SimoneGraziosi	GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. 	SIGNOR-269210	0.434
TARS1	protein	P26639	UNIPROT	Thr-tRNA(Thr)	smallmolecule	CHEBI:29163	ChEBI	up-regulates quantity	chemical modification			9606									25824639	t		miannu	Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 	SIGNOR-270506	0.8
VCP	protein	P55072	UNIPROT	AURKA	protein	O14965	UNIPROT	down-regulates activity	binding			6239									23649807	t		lperfetto	The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.|We found that UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 from embryonic extracts	SIGNOR-265044	0.319
PRKACA	protein	P17612	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser16	KELEKRAsGQAFELI	9606									8376365	t		gcesareni	Phosphorylation at either ser(16) or ser(63) strongly reduced or abolished the ability of stathmin to bind to and sequester soluble tubulin and its ability to act as a catastrophe factor by directly binding to the microtubules. The known in vivo phosphorylation sites of stathmin are ser-16 and ser-63 for cyclic amp-dependent protein kinase (pka).	SIGNOR-38318	0.313
STK4	protein	Q13043	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	phosphorylation	Thr1041	EHAFYEFtFRRFFDD	9606									21808241	t		gcesareni	Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2.	SIGNOR-175825	0.62
KAT6A/KAT6B	complex	SIGNOR-C54	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates	acetylation	Lys382	QSTSRHKkLMFKTEG	9606	BTO:0001271								23431171	t		lperfetto	We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression	SIGNOR-217198	0.492
PTEN	protein	P60484	UNIPROT	CFL1	protein	P23528	UNIPROT	up-regulates activity	dephosphorylation			9606									22317922	t		lperfetto	Unexpectedly, cofilin-1 activation by PGE 2 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated.|Unexpectedly, cofilin-1 dephosphorylation and activation in our model was mediated by the protein phosphatase activity of PTEN.	SIGNOR-276980	0.453
propionyl-CoA(4-)	smallmolecule	CHEBI:57392	ChEBI	(S)-methylmalonyl-CoA(5-)	smallmolecule	CHEBI:57327	ChEBI	up-regulates quantity	precursor of			9606									15890657	t		miannu	Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively.	SIGNOR-267185	0.8
PDPK1	protein	O15530	UNIPROT	PDPK1	protein	O15530	UNIPROT	up-regulates activity	phosphorylation	Ser241	SKQARANsFVGTAQY	9606									10455013	t		lperfetto	Pdk1 is itself phosphorylated in vivo and whether phosphorylation plays a role in regulating its activity/ phosphorylation of ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1	SIGNOR-236789	0.2
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	phosphorylation	Tyr570	VRREVGDyGQLHETE	9606	BTO:0000007								15143187	t			JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity	SIGNOR-251359	0.2
CAMK4	protein	Q16566	UNIPROT	HNRNPL	protein	P14866	UNIPROT	up-regulates	phosphorylation	Ser544	GKSERSSsGLLEWES	9606									22570490	t		lperfetto	Here we show that the regulation of the stress axis-regulated exon of the slo1 potassium channel transcripts by membrane depolarization requires a highly conserved camkiv target serine (ser-513) of the heterogeneous ribonucleoprotein l. Ser-513 phosphorylation within the rna recognition motif 4 enhanced heterogeneous ribonucleoprotein l interaction with the camkiv-responsive rna element 1 of stress axis-regulated exon and inhibited binding of the large subunit of the u2 auxiliary factor u2af65.	SIGNOR-197367	0.389
CHEK1	protein	O14757	UNIPROT	PABIR1	protein	Q96E09	UNIPROT	down-regulates activity	phosphorylation	Ser37	GGLRRSNsAPLIHGL	9606	BTO:0000018								33108758	t		miannu	Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression.	SIGNOR-266380	0.2
HMGB2	protein	P26583	UNIPROT	POU3F1	protein	Q03052	UNIPROT	up-regulates activity	binding			10090	BTO:0002910								7720710	t	2	miannu	HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins	SIGNOR-240148	0.311
C3AR1	protein	Q16581	UNIPROT	Vascular_Permeability	phenotype	SIGNOR-PH140	SIGNOR	up-regulates													10984054	f		lperfetto	The anaphylatoxins C3a and C5a are liberated as activation byproducts and are potent pro-inflammatory mediators that bind to specific cell surface receptors and cause leukocyte activation, smooth muscle contraction and vascular permeability	SIGNOR-263458	0.7
NCOA3	protein	Q9Y6Q9	UNIPROT	ATF4	protein	P18848	UNIPROT	up-regulates activity	binding			9606	BTO:0000578								31066068	t		miannu	Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity.	SIGNOR-275452	0.2
BCL11A	protein	Q9H165	UNIPROT	HBG1	protein	P69891	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004408								29606353	t		Gianni	Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching.	SIGNOR-269067	0.46
PPARGC1A	protein	Q9UBK2	UNIPROT	Gluconeogenesis	phenotype	SIGNOR-PH35	SIGNOR	up-regulates				9606									20640476	f		Gianni	However, in contrast to the role of AMPK, most reports to date indicate that PGC-1a induces gluconeogenesis	SIGNOR-209932	0.7
MITF	protein	O75030	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by expression	transcriptional regulation												12086670	t		lperfetto	MITF directly occupies the BCL2 promoter in vivo and this suggest that BCL2 may be a direct transcriptional target of MITF	SIGNOR-249618	0.453
PPP2CA	protein	P67775	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	down-regulates activity	dephosphorylation	Thr305	TDAATMKtFCGTPEY	9606									18160256	t			Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248651	0.725
SDH	complex	SIGNOR-C400	SIGNOR	fumarate(2-)	smallmolecule	CHEBI:29806	ChEBI	up-regulates quantity	chemical modification			9606									16143825	t		miannu	Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions.	SIGNOR-266277	0.8
LYN	protein	P07948	UNIPROT	PRKCD	protein	Q05655	UNIPROT	down-regulates activity	phosphorylation	Tyr567	IRVDTPHyPRWITKE	-1									11812791	t			Src, Fyn, or Lyn are the essential kinases that tyrosine phosphorylate and inactivate PKC δ. Lyn phosphorylates tyrosine residue 565 in vitro	SIGNOR-251407	0.537
TP73	protein	O15350	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									17700533	f		miannu	Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death.	SIGNOR-256665	0.7
RNF7	protein	Q9UBF6	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates activity	ubiquitination			9606									23136067	t		miannu	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 	SIGNOR-271452	0.331
NAB2	protein	Q15742	UNIPROT	GFI1	protein	Q99684	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									16923394	f		miannu	Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene.	SIGNOR-256042	0.403
STK38	protein	Q15208	UNIPROT	PI4KB	protein	Q9UBF8	UNIPROT	up-regulates activity	phosphorylation	Ser277	RTHQRSKsDATASIS	10090		BTO:0000142							22445341	t		miannu	We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. 	SIGNOR-263033	0.27
LAG3	protein	P18627	UNIPROT	T cell exhaustion 	phenotype	SIGNOR-PH221	SIGNOR	up-regulates				9606	BTO:0000782								27192565	f		Barakat	Lag-3, Tim-3, and TIGIT are highly expressed on dysfunctional or exhausted T cells in chronic diseases such as chronic viral infection and cancer. 	SIGNOR-275414	0.7
TWIST1	protein	Q15672	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003298								21931630	f		miannu	Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2.	SIGNOR-255593	0.461
ACTB	protein	P60709	UNIPROT	GBAF	complex	SIGNOR-C467	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269788	0.425
methionine	smallmolecule	CHEBI:16811	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264750	0.7
AMPK	complex	SIGNOR-C15	SIGNOR	NEDD4L	protein	Q96PU5	UNIPROT	up-regulates activity	phosphorylation	Ser795	VDLKPNGsEIMVTNE	-1									21501591	t		miannu	The AMP-activated protein kinase (AMPK) down-regulates the inward rectifier K+ channel Kir2.1. Expression of wild type Nedd4-2 or of Nedd4-2S795A lacking an AMPK phosphorylation consensus sequence downregulated Kir2.1 currents. The effect of wild type Nedd4-2 but not of Nedd4-2S795A was significantly augmented by additional coexpression of AMPK.	SIGNOR-276324	0.258
KSR2	protein	Q6VAB6	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								29433126	t		miannu	 In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. 	SIGNOR-273879	0.588
HTR2B	protein	P41595	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256743	0.28
MKRN1	protein	Q9UHC7	UNIPROT	RPS10	protein	P46783	UNIPROT	up-regulates activity	ubiquitination	Lys107	ETGRPRPkGLEGERP	9606	BTO:0000007								31640799	t		miannu	We show that MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) and associates with polysomes. MKRN1 is positioned upstream of poly(A) tails in mRNAs in a PABPC1-dependent manner. Ubiquitin remnant profiling and in vitro ubiquitylation assays uncover PABPC1 and ribosomal protein RPS10 as direct ubiquitylation substrates of MKRN1.Our data show that MKRN1 associates with polysomes and ubiquitylates RPS10, indicating a role in translational control. We hypothesize that ribosomes encountering the MKRN1-PABPC1 complex are stalled, possibly via ubiquitylation of RPS10 on K107 and other MKRN1 substrates.	SIGNOR-272216	0.2
TGFB2	protein	P61812	UNIPROT	Activated PSC	phenotype	SIGNOR-PH224	SIGNOR	up-regulates				9606		BTO:0000988							38540204	t		miannu	Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction	SIGNOR-277680	0.7
SGK1	protein	O00141	UNIPROT	NEDD4L	protein	Q96PU5	UNIPROT	down-regulates activity	phosphorylation	Thr383	PSVAYVHtTPGLPSG	-1									12911626	t		miannu	 Site‐directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4‐2 protein (S382A,S468ANedd4‐2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Introduction of a negative charge at the SGK phosphorylation site in the EAAT1 protein leads to a strong stimulation of the carrier, whereas replacement with alanine markedly decreases the EAAT1‐mediated current. These observations suggest that SGK1 exerts its effect not only by phosphorylation of Nedd4‐2 but also by phosphorylation of EAAT1.	SIGNOR-263076	0.78
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									10464286	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-252815	0.2
NFE2L2	protein	Q16236	UNIPROT	PXDN	protein	Q92626	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567; BTO:0000007								29953917	t		miannu	PXDN expression in response to H2O2 and the Nrf2-specific inducers, tert-butylhydroquinone (tBHQ) and sulforaphane (SFN), was determined by western blotting and immunofluorescence microscopy, in HeLa and HEK293 cells.We found that Nrf2 binds to and increases luciferase reporter gene expression from the PXDN promoter via a putative Nrf2-binding site. In summary, we show that PXDN is a novel target of the redox sensitive transcription factor Nrf2. 	SIGNOR-265248	0.2
RAPH1	protein	Q70E73	UNIPROT	EVL	protein	Q9UI08	UNIPROT	up-regulates activity	binding			9606									20417104	t		miannu	 Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins.	SIGNOR-268427	0.353
(-)-anisomycin	chemical	CHEBI:338412	ChEBI	MAPK14	protein	Q16539	UNIPROT	up-regulates	chemical activation			9606									Other	t	CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb	gcesareni		SIGNOR-189699	0.8
NADPH(4-)	smallmolecule	CHEBI:57783	ChEBI	FASN	protein	P49327	UNIPROT	up-regulates activity	binding			9606									34765544	t		miannu	We determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH.	SIGNOR-267371	0.8
SH2B1	protein	Q9NRF2	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	binding												27154742	t		lperfetto	The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex	SIGNOR-253078	0.679
MAPK8	protein	P45983	UNIPROT	SYT4	protein	Q9H2B2	UNIPROT	up-regulates activity	phosphorylation	Ser135	EGEKESVsPESLKSS	10116	BTO:0001009								18046461	t	done	miannu	JNK phosphorylates Syt 4 at Ser135 in vitro and in vivo.	SIGNOR-273673	0.421
FGR	protein	P09769	UNIPROT	FGR	protein	P09769	UNIPROT	up-regulates activity	phosphorylation	Tyr412	RLIKDDEyNPCQGSK	-1									8612628	t			Autophosphorylation of c-Fgr under basal conditions involves Tyr-400 (homologous of c-Src Tyr-416) but not, to any appreciable extent, Tyr-511. Both Tyr-511 and Tyr-400, however, incorporate phosphate if autophosphorylation is performed in the presence of polycationic peptides, such as polylysine, histones H1 and protamines. Such a double phosphorylation induced by polylysine gives rise to an upshifted form of c-Fgr on SDS-PAGE and correlates with a stimulation of catalytic activity instead of a down-regulation	SIGNOR-251143	0.2
CAMK4	protein	Q16566	UNIPROT	NOS1	protein	P29475	UNIPROT	down-regulates activity	phosphorylation	Ser852	SYKVRFNsVSSYSDS										10400690	t		llicata	It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation.	SIGNOR-250713	0.364
EEF1A1P5	protein	Q5VTE0	UNIPROT	Ile-tRNA(Ile)	smallmolecule	CHEBI:29160	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269552	0.8
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	MYC	protein	P01106	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								20551172	t		miannu	We characterize a new Myc-interacting factor, TRPC4AP (transient receptor potential cation channel, subfamily C, member 4-associated protein)/TRUSS (tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein), which is the receptor for a DDB1 (damage-specific DNA-binding protein 1)-CUL4 (Cullin 4) E3 ligase complex for selective Myc degradation through the proteasome. TRPC4AP/TRUSS binds specifically to the Myc C terminus and promotes its ubiquitination and destruction through the recognition of evolutionarily conserved domains in the Myc N terminus. 	SIGNOR-271965	0.386
ATF3	protein	P18847	UNIPROT	ASNS	protein	P08243	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12881527	f		miannu	Transcription from the ASNS (asparagine synthetase) gene is increased in response to either amino acid (amino acid response) or glucose (endoplasmic reticulum stress response) deprivation. the results provide evidence for a potential role of multiple predicted ATF3 isoforms in the transcriptional regulation of the ASNS gene in response to nutrient deprivation.	SIGNOR-253746	0.42
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270364	0.8
PAK2	protein	Q13177	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Thr2	tAKMETTF	9606	BTO:0000848								21177766	t		lperfetto	P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)	SIGNOR-170760	0.272
ATM	protein	Q13315	UNIPROT	MECOM	protein	Q03112	UNIPROT	up-regulates activity	phosphorylation	Ser1037	IGNSNHGsQSPRNVE										29939287	t	phosphorylation site remapping based on Fig 1	lperfetto	To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif. 	SIGNOR-273433	0.2
OXTR	protein	P30559	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256793	0.409
MRGPRX1	protein	Q96LB2	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257433	0.2
A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	Activated PSC	phenotype	SIGNOR-PH224	SIGNOR	up-regulates				9606									32928643	t		miannu	CTGF is highly expressed in PDAC tissues, especially in tumor stroma (as shown by immunohistochemistry, CTGF: brown stain). The tumor cell-secreted CTGF promotes pancreatic stellate cell (PSC) proliferation, adhesion, and migration via integrin α5β1, leading to extracellular matrix (ECM) deposition.Pancreatic cancer cells secrete high levels of CTGF that binds to integrin α5β1, promoting PSC proliferation, adhesion, and migration	SIGNOR-277688	0.7
SCF-SKP2	complex	SIGNOR-C136	SIGNOR	CCNE2	protein	O96020	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1							phosphorylation:Ser383;Thr392	FRKGGQLsPVCNGGI;VCNGGIMtPPKSTEK	11533444	t		lperfetto	The amount of cyclin E protein present in the cell is tightly controlled by ubiquitin-mediated proteolysis. Here we identify the ubiquitin ligase responsible for cyclin E ubiquitination as SCFFbw7 and demonstrate that it is functionally conserved in yeast, flies, and mammals. Fbw7 associates specifically with phosphorylated cyclin E, and SCFFbw7 catalyzes cyclin E ubiquitination in vitro	SIGNOR-267559	0.558
ADSL	protein	P30566	UNIPROT	5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-)	smallmolecule	CHEBI:58475	ChEBI	up-regulates quantity	chemical modification			9606									22812634	t		miannu	ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case	SIGNOR-266608	0.8
TNF	protein	P01375	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity				10090									10485710	f		lperfetto	Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k).	SIGNOR-252733	0.324
CSNK2A2	protein	P19784	UNIPROT	HSF1	protein	Q00613	UNIPROT	up-regulates	phosphorylation	Thr142	DSVTKLLtDVQLMKG	9606									12659875	t		lperfetto	Transcriptional activity and dna binding of heat shock factor-1 involve phosphorylation on threonine 142 by ck2.As hsf1 is activated by heat shock simultaneously with the nuclear translocation of the protein kinase ck2, we have investigated the role of ck2 in hsf1 activatio	SIGNOR-99606	0.355
GSK3B	protein	P49841	UNIPROT	CRMP1	protein	Q14194	UNIPROT	up-regulates	phosphorylation	Ser518	KYATPAPsAKSSPSK	9606	BTO:0000938								16611631	t		lperfetto	Using in vitro kinase assays and pharmacological inhibition of gsk3 as described above for crmp2 and crmp4, it was found that thr509 (and presumably ser518 and thr514) of human crmp1 is phosphorylated by gsk3, following priming of ser522 by cdk5	SIGNOR-145991	0.447
SGK1	protein	O00141	UNIPROT	NDRG2	protein	Q9UN36	UNIPROT	up-regulates	phosphorylation	Ser332	LSRSRTAsLTSAASV	9606	BTO:0000567	BTO:0000887;BTO:0001103;BTO:0000763							15461589	t		llicata	Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344	SIGNOR-129672	0.405
CDX2	protein	Q99626	UNIPROT	CDH17	protein	Q12864	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972;BTO:0004168								20568120	t	 	 	The present study aims to identify the transcription factors which interact and regulate CDH17 promoter activity that might contribute to the up-regulation of CDH17 gene in human HCC|we identified hepatic nuclear factor 1α (HNF1α) and caudal-related homeobox 2 (CDX2) binding sites at the proximal promoter region which modulate the CDH17 promoter activities in two HCC cell lines (Hep3B and MHCC97L)	SIGNOR-253963	0.417
SAGA complex	complex	SIGNOR-C465	SIGNOR	Transcritpional_activation	phenotype	SIGNOR-PH205	SIGNOR	up-regulates				9606									15970593	f		lperfetto	Transcription initiation is a major regulatory step in eukaryotic gene expression. Co-activators establish transcriptionally competent promoter architectures and chromatin signatures to allow the formation of the pre-initiation complex (PIC), comprising RNA polymerase II (Pol II) and general transcription factors (GTFs).|this observation appears remarkably prevalent for chromatin-modifying and remodeling complexes. Here, we use the modular organization of the evolutionary conserved Spt-Ada-Gcn5 acetyltransferase (SAGA) complex as a paradigm to illustrate how co-activators share and combine a relatively limited set of functional tools.	SIGNOR-269570	0.7
SOX2	protein	P48431	UNIPROT	SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	form complex	binding			9606									7590241	t		miannu	Sox2 can form a ternary complex with either the ubiquitous oct-1 or the embryonic-specific oct-3 protein on fgf-4 enhancer dna sequences. However, only the sox2/oct-3 complex is able to promote transcriptional activation.	SIGNOR-29512	0.834
(6S)-5-methyltetrahydrofolate(2-)	smallmolecule	CHEBI:18608	ChEBI	methionine	smallmolecule	CHEBI:16811	ChEBI	up-regulates quantity	precursor of			9606									10720211	t		lperfetto	Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine.	SIGNOR-253141	0.8
KRAS	protein	P01116	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606									9727023	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner.	SIGNOR-59819	0.768
PRKCG	protein	P05129	UNIPROT	SDC2	protein	P34741	UNIPROT	unknown	phosphorylation	Ser187	DLGERKPsSAAYQKA	-1									9244383	t		lperfetto	We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198.	SIGNOR-248975	0.359
WRC complex	complex	SIGNOR-C191	SIGNOR	ARP2/3	complex	SIGNOR-C146	SIGNOR	up-regulates activity	binding			9606									20332100	t		miannu	The activated WAVE complex at the leading edge of lamellipodia promotes actin polymerization at the plasma membrane by activating the Arp2/3 complex	SIGNOR-253573	0.526
HBA1	protein	P69905	UNIPROT	CD163	protein	Q86VB7	UNIPROT	up-regulates activity	binding			9606									16522161	t	Regulation	miannu	These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells.	SIGNOR-251747	0.262
HMOX2	protein	P30519	UNIPROT	HBA1	protein	P69905	UNIPROT	down-regulates activity				9606									10490932	t	Regulation	miannu	Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme	SIGNOR-251814	0.258
PDPK1	protein	O15530	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser221	DHEKKAYsFCGTVEY	9534	BTO:0000298								10480933	t		miannu	Full-length RSK1, RSK2, and RSK3 Are Activated when Coexpressed with PDK1 in COS7 Cells. Ser221 phosphorylation is increased 2–3-fold during ERK-mediated activation of RSK1 in COS1 cells	SIGNOR-250270	0.613
KIT	protein	P10721	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000830								15526160	t		miannu	Activation of PI3-kinase by c-Kit has been linked to mitogenesis, differentiation, survival, adhesion, secretion and actin cytoskeletal reorganization. In c-Kit, Y721 has been found to directly interact with PI3-kinase	SIGNOR-254949	0.709
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029									9550290	t		miannu	Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists.	SIGNOR-258889	0.8
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser214	TVLTAQEsFSGSLGH	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276216	0.389
MAPK8	protein	P45983	UNIPROT	HNRNPK	protein	P61978	UNIPROT	up-regulates activity	phosphorylation	Ser216	ILDLISEsPIKGRAQ	9606									11259409	t		lperfetto	The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein.	SIGNOR-105247	0.381
NR3C1/STAT5A	complex	SIGNOR-C84	SIGNOR	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates				9606									12540601	f		fspada	We have shown that stat5a is associated with the glucocorticoid receptor during adipogenesis in a highly regulated manner.	SIGNOR-97562	0.7
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	FERMT1	protein	Q9BQL6	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser176	SSPTASGsSVSPGLY	9606	BTO:0000567								35469017	t		miannu	 CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry.	SIGNOR-276720	0.2
CDK1	protein	P06493	UNIPROT	NEDD1	protein	Q8NHV4	UNIPROT	up-regulates activity	phosphorylation	Ser460	STSVLHSsPLNVFMG										21690413	t		lperfetto	Mechanistically, we demonstrated that Cdc2-dependent phosphorylation on a γ-tubulin ring complex (γ-TuRC) recruitment protein, Nedd1/GCP-WD, at the previously uncharacterized S460 residue induces the Nedd1-Plk1 interaction	SIGNOR-272972	0.568
PARP1	protein	P09874	UNIPROT	THBD	protein	P07204	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002423								21489980	f		miannu	Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells.	SIGNOR-254892	0.2
PPARG	protein	P37231	UNIPROT	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606									17681149	f		lperfetto	This mechanism is mainly operative in native monocytes that, in the presence of an appropriate M2 stimulus such as IL-4, can be primed by PPARg ligands to an enhanced M2 phenotype.	SIGNOR-249542	0.7
HSPA9	protein	P38646	UNIPROT	TIM23 complex	complex	SIGNOR-C423	SIGNOR	form complex	binding												32074073	t		lperfetto	The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE.	SIGNOR-267693	0.679
FGFR1	protein	P11362	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates				9606									12270934	f		lperfetto	 Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors	SIGNOR-218010	0.315
FOXO1	protein	Q12778	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	down-regulates				9606									16308421	f		gcesareni	Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner.	SIGNOR-142150	0.568
NARS1	protein	O43776	UNIPROT	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270457	0.8
MEF2C	protein	Q06413	UNIPROT	CTNNA3	protein	Q9UI47	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002320								21598020	t		miannu	 GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter	SIGNOR-265491	0.243
p38	proteinfamily	SIGNOR-PF16	SIGNOR	KRT8	protein	P05787	UNIPROT	up-regulates	phosphorylation			9606									11788583	t	inferred from 70% family members	lperfetto	Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.	SIGNOR-270125	0.2
GUCY1A2-B2	complex	SIGNOR-C137	SIGNOR	IDH2	protein	P48735	UNIPROT	down-regulates quantity by destabilization	ubiquitination										phosphorylation:Thr197	GTFKMVFtPKDGSGV	34929314	t		lperfetto	During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome	SIGNOR-267624	0.2
alvocidib	chemical	CHEBI:47344	ChEBI	CDK9	protein	P50750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192449	0.8
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	PRC1	protein	O43663	UNIPROT	unknown	phosphorylation	Thr470	LYGSAPRtPSKRRGL										9885575	t		llicata	We have shown that PRC1 is a good in vitro substrate for several CDKs, and that it is also phosphorylated in a cell cycle–dependent manner in vivo at Thr-481 (major mitosis. and Thr-470 (minor site), which are the in vitro phosphorylation sites.	SIGNOR-250745	0.351
CNR1	protein	P21554	UNIPROT	HCRTR1	protein	O43613	UNIPROT	up-regulates activity	binding			9606									29751001	t		miannu	Another example is the heteromer between CB1 and orexin 1 receptor (OX1R). The CB1 activation potentiated the OX1R signaling (218), suggesting the interaction of these two receptors. Interaction of their surface distribution was also reported. 	SIGNOR-264269	0.397
2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	chemical	CHEBI:93768	ChEBI	ALK	protein	Q9UM73	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258219	0.8
MAPK1	protein	P28482	UNIPROT	ARHGAP26	protein	Q9UNA1	UNIPROT	unknown	phosphorylation	Ser685	PMFSAPSsPMPTSST	-1									9525907	t		miannu	In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling.	SIGNOR-262944	0.2
TSPO2	protein	Q5TGU0	UNIPROT	VDAC1	protein	P21796	UNIPROT	up-regulates activity	binding			9606	BTO:0000424								30061676	t		miannu	Our results demonstrate the existence of a VDAC-TSPO2-ANT complex that mediates ATP release from RBCs. We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transport complex in human red blood cells (RBCs). . The present results show that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by a supramolecular complex involving VDAC, TSPO2 and ANT.	SIGNOR-261826	0.315
IFNA1	protein	P01562	UNIPROT	ISGF3 complex	complex	SIGNOR-C124	SIGNOR	up-regulates quantity by stabilization				9606									22171011	f	2	miannu	IFN-I (IFN-_ and IFN-_) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9.	SIGNOR-240610	0.464
FYN	protein	P06241	UNIPROT	KIRREL1	protein	Q96J84	UNIPROT	up-regulates activity	phosphorylation	Tyr606	KDPTNGYyNVRAHED	9606	BTO:0000007								18258597	t		miannu	Here we have characterized Neph1, another SD component, as a novel substrate of SFK. Fyn interacts with and phosphorylates the cytoplasmic domain of Neph1 in vitro and in intact cells. Both tyrosine 637 and 638 of Neph1 are crucial for Neph1-Grb2 binding.	SIGNOR-262746	0.2
RORA	protein	P35398	UNIPROT	SLC1A6	protein	P48664	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001011								19381306	t		miannu	RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. 	SIGNOR-266850	0.254
GSK3B	protein	P49841	UNIPROT	OGT	protein	O15294	UNIPROT	up-regulates activity	phosphorylation	Ser3	sSVGNVAD	10090	BTO:0000142								23395175	t		miannu	We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3β-dependent pathways and identified O-GlcNAc transferase (OGT) as a substrate of GSK3β. Interestingly, OGT activity is regulated by GSK3β; hence, OGT and GSK3β exhibit reciprocal regulation.	SIGNOR-276482	0.5
PRKCA	protein	P17252	UNIPROT	RAF1	protein	P04049	UNIPROT	unknown	phosphorylation	Ser233	VSSQHRYsTPHAFTF	9606									12551925	t		gcesareni	For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1.	SIGNOR-37466	0.538
MC5R	protein	P33032	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257393	0.271
PRKCE	protein	Q02156	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Ser779	PLDQYSPsFPDTRSS	9606	BTO:0000938								23564461	t		lperfetto	Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiationour findings show that in addition to fgfr tyrosine phosphorylation, the phosphorylation of a conserved serine residue, ser(779), can quantitatively control ras/mapk signaling to promote specific cellular responses.	SIGNOR-201671	0.2
FOXA1	protein	P55317	UNIPROT	NFIB	protein	O00712	UNIPROT	up-regulates	binding			9606									24801505	t		miannu	Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex.	SIGNOR-205027	0.32
PXDN	protein	Q92626	UNIPROT	COL4A4	protein	P53420	UNIPROT	up-regulates quantity by stabilization	catalytic activity			9606	BTO:0000567								29305973	t		miannu	Peroxidasin (PXDN), an ECM protein with peroxidase activity, is integral to basement membrane consolidation through catalysis of sulfilimine bonds in collagen IV. PXDN has been shown to form dityrosine crosslinks and also catalyses sulfilimine bonds, in the presence of hypohalous acids, to connect collagen IV protomers, which are an integral component of the basement membrane	SIGNOR-265250	0.259
NEK2	protein	P51955	UNIPROT	NEK2	protein	P51955	UNIPROT	up-regulates	phosphorylation	Ser171	RILNHDTsFAKTFVG	9606									17197699	t		gcesareni	Enzymatic activity, induced;	SIGNOR-151755	0.2
SLBP	protein	Q14493	UNIPROT	H4C1	protein	P62805	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265376	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Ser138	SLQLGAVsPGTLTPT	9606	BTO:0001938								21364637	t		miannu	JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells	SIGNOR-277642	0.2
PAK1	protein	Q13153	UNIPROT	KIF2C	protein	Q99661	UNIPROT	down-regulates	phosphorylation	Ser111	KESLRSRsTRMSTVS	9606									23055517	t		lperfetto	Here we found that mcak is a cognate substrate of pak1 wherein pak1 phosphorylates mcak on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that pak1 phosphorylation of mcak on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes	SIGNOR-199080	0.394
TMLHE	protein	Q9NVH6	UNIPROT	succinate(2-)	smallmolecule	CHEBI:30031	ChEBI	up-regulates quantity	chemical modification			9606									11431483	t		miannu	Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. 	SIGNOR-269683	0.8
PKN1	protein	Q16512	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Thr678	RHIVRKRtLRRLLQE	9606									21749319	t		lperfetto	This identified thr654 in egfr as the pkn1 phosphorylation siteit has been shown that the phosphorylation of egfr at thr654 by pkc reduces the tyrosine kinase activity of the receptor	SIGNOR-174755	0.2
NDUFV2	protein	P19404	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24].	SIGNOR-262184	0.853
S1PR2	protein	O95136	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates	binding			9606									10488065	t		gcesareni	Edg-3 and edg-5 couple not only to gibut also to gqand g13.	SIGNOR-70664	0.451
ETV3	protein	P41162	UNIPROT	DUSP6	protein	Q16828	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000944								22028473	t		miannu	ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation.	SIGNOR-262780	0.2
HBP1	protein	O60381	UNIPROT	NCF1	protein	P14598	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002181								15024088	t		Luana	Together, these results indicate that HBP1 may contribute to the regulation of NADPH oxidase-dependent superoxide production through transcriptional repression of the p47phox gene. 	SIGNOR-261614	0.268
TAOK2	protein	Q9UL54	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates	binding			9606									10660600	t		gcesareni	Immunoprecipitated psk phosphorylates myelin basic protein and transfected psk stimulates mkk4 and mkk7 and activates the c-jun n-terminal kinase mitogen-activated protein kinase pathway.	SIGNOR-74867	0.2
GSK3B	protein	P49841	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser58	SFFKEPDsGSHSRQS	9606	BTO:0002181								22692215	t		miannu	GSK3 destabilizes TAZ. TAZS58A/S62A but not the TAZ S66A mutant diminished phos- phorylation by GSK3 
, suggesting that Ser-58 and Ser-62 are important for GSK3 
 phosphorylation, whereas the Ser-66 is not (Fig. 4D).	SIGNOR-277646	0.2
PRKACA	protein	P17612	UNIPROT	MIP	protein	P30301	UNIPROT	down-regulates activity	phosphorylation	Ser229	LLFPRLKsISERLSV	-1									2176601	t		miannu	Phosphorylation at one of these sites (serine 243) could be increased by A kinase in vitro. phosphorylation of MIP reconstituted into single bilayers increased the voltage dependence and long-term closures of the channels observed.	SIGNOR-250018	0.316
N'-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine	chemical	CHEBI:91340	ChEBI	IKBKB	protein	O14920	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258190	0.8
WNT7B	protein	P56706	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131978	0.633
CSNK2A1	protein	P68400	UNIPROT	PTGES3	protein	Q15185	UNIPROT	up-regulates	phosphorylation	Ser118	DDSDEDMsNFDRFSE	9606									15040786	t		gcesareni	Cpges-activating protein kinase is ck-ii (casein kinase ii). Mutations of either of two predicted ck-ii phosphorylation sites on cpges (ser113 and ser118) abrogated its phosphorylation and activation both in vitro and in vivo. Hypoxia induced the mitogen-activated protein kinase-mediated phosphorylation of a single serine residue, ser(122), in the protein, and site-directed mutagenesis demonstrated that ser(122) phosphorylation was necessary for hypoxic acceleration of tal1 turnover.	SIGNOR-123598	0.36
KDM4B	protein	O94953	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001109								28073943	f		miannu	 JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. 	SIGNOR-263730	0.2
RRAGD	protein	Q9NQL2	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates	binding			9606				SIGNOR-C3					20006481	t		gcesareni	Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor	SIGNOR-162093	0.902
PLK1	protein	P53350	UNIPROT	PKMYT1	protein	Q99640	UNIPROT	unknown	phosphorylation	Thr495	LLSLFEDtLDPT	9606									12738781	t		lperfetto	These results suggest that Ser-426 is a major phosphorylation site by Plk1, and Thr-495 is a second major site. 	SIGNOR-249208	0.707
HACD	proteinfamily	SIGNOR-PF86	SIGNOR	very long-chain (R)-3-hydroxyacyl-CoA(4-)	smallmolecule	CHEBI:85440	ChEBI	down-regulates quantity	chemical modification			9606									18554507	t		miannu	Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle.	SIGNOR-267917	0.8
PPP2R2A	protein	P63151	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	binding			10090									18042541	t		gcesareni	Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural |Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells.subunit (A), catalytic subunit (C), and a variable regulatory subunit (B).	SIGNOR-252637	0.474
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity	phosphorylation			10090	BTO:0000011								19593385	t		lperfetto	In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis	SIGNOR-252817	0.72
DNM1	protein	Q05193	UNIPROT	MYO1E	protein	Q12965	UNIPROT	up-regulates activity	binding			10116		BTO:0000142							17257598	t		miannu	We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. 	SIGNOR-265424	0.338
DYRK1A	protein	Q13627	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates	phosphorylation			9606									12138125	t	Dyrk1 acts synergistically with Shh to induce transcription of a Gli-promoter-driven luciferase reporter gene and of endogenous alkaline phosphatase.	gcesareni	Dyrk1 phosphorylates gli1 on more than one domain.	SIGNOR-90809	0.529
PRKCA	protein	P17252	UNIPROT	RPL10	protein	P27635	UNIPROT	unknown				-1									9016777	t		lperfetto	QM is phosphorylated by PKC and the extent of phosphorylation by PKC is correlated with the extent of inhibition of binding of QM to c-Jun.	SIGNOR-248957	0.311
SMARCA4	protein	P51532	UNIPROT	TERT	protein	O14746	UNIPROT	up-regulates	binding			9606									19571879	t		miannu	Tert activates wnt reporter plasmids in a brg1-dependent manner.	SIGNOR-186607	0.768
AKT1	protein	P31749	UNIPROT	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	up-regulates				9606									18483217	f			PDGF signaling has been implicated in several fibrotic conditions and is assumed to play a role in driving proliferation of cells with a myofibroblast phenotype.	SIGNOR-254371	0.7
MARK1	protein	Q9P0L2	UNIPROT	MAP4	protein	P27816	UNIPROT	down-regulates activity	phosphorylation	Ser928	SRLATNTsAPDLKNV	-1									8631898	t		miannu	Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 	SIGNOR-250170	0.449
PPME1	protein	Q9Y570	UNIPROT	PPP2CB	protein	P62714	UNIPROT	down-regulates activity	demethylation	Leu309	RRTPDYFl	-1									18394995	t		lperfetto	Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans.	SIGNOR-265750	0.703
CHEK1	protein	O14757	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser76	SNLQRMGsSESTDSG	9606									20068082	t		gcesareni	The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts);	SIGNOR-163150	0.852
CRABP2	protein	P29373	UNIPROT	Metastasis	phenotype	SIGNOR-PH107	SIGNOR	up-regulates				9606	BTO:0000551								30696915	f			Analysis of clinical samples revealed that high CRABP2 levels were correlated with lymph node metastases, poor overall survival, and increased recurrence. Knockdown of Crabp2 decreased migration, invasion, anoikis resistance, and in vivo metastasis. 	SIGNOR-259371	0.7
Caspase 8 complex	complex	SIGNOR-C231	SIGNOR	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									14585074	f		amattioni	Downstream of caspase-8 activation, apoptosis induction takes place	SIGNOR-256641	0.7
CHUK	protein	O15111	UNIPROT	MTOR	protein	P42345	UNIPROT	up-regulates activity	phosphorylation	Ser1415	PTPAILEsLISINNK	9606	BTO:0002181								24990947	t		miannu	 Importantly, IKKα is shown to phosphorylate mTOR at serine 1415 in a manner dependent on Akt to promote mTORC1 activity. These results demonstrate that IKKα is an effector of Akt in promoting mTORC1 activity.	SIGNOR-276646	0.523
PTAFR	protein	P25105	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257061	0.2
MBOAT7	protein	Q96N66	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	chemical modification			-1									18772128	t		miannu	The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils.	SIGNOR-267247	0.8
PRKCA	protein	P17252	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates	phosphorylation	Ser70	RDPVARTsPLQTPAA	9606	BTO:0001271								9738012	t		gcesareni	Purified pkca can efficiently and directly phosphorylate bcl2 at serine 70	SIGNOR-60120	0.355
carbachol	chemical	CHEBI:3385	ChEBI	CHRM2	protein	P08172	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258619	0.8
MAPK14	protein	Q16539	UNIPROT	MKNK2	protein	Q9HBH9	UNIPROT	up-regulates	phosphorylation			9606									9155017	t		gcesareni	Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity	SIGNOR-48349	0.423
A11/b1 integrin	complex	SIGNOR-C168	SIGNOR	Cell_migration	phenotype	SIGNOR-PH38	SIGNOR	up-regulates				10090	BTO:0000165								11518510	f		lperfetto	In addition, alpha11beta1 mediated contraction of fibrillar collagen gels in a manner similar to alpha2beta1, and supported migration on collagen I in response to chemotactic stimuli. Our data support a role for alpha11beta1 as a receptor for interstitial collagens on mesenchymally derived cells and suggest a multifunctional role of alpha11beta1 in the recognition and organization of interstitial collagen matrices during development.	SIGNOR-253349	0.7
EDN1	protein	P05305	UNIPROT	MYH7	protein	P12883	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12847114	f	Regulation of expression	miannu	βMHC expression was markedly augmented by PE and ET, suggesting the transformation of myosin. endothelin-1 (ET)	SIGNOR-251955	0.284
TGFBR2	protein	P37173	UNIPROT	PIK3R2	protein	O00459	UNIPROT	up-regulates	binding			9606									9435577	t		lperfetto	These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells.	SIGNOR-227528	0.443
ADRA1D	protein	P25100	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256808	0.295
RPL35A	protein	P18077	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262465	0.848
IFNG	protein	P01579	UNIPROT	DIO	proteinfamily	SIGNOR-PF83	SIGNOR	down-regulates quantity by repression	transcriptional regulation			10116									9397972	f	inferred from family member	scontino	From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y.	SIGNOR-270238	0.2
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1787	SPNYSPTsPSYSPTS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248815	0.849
GNAS	protein	P63092	UNIPROT	HCK	protein	P08631	UNIPROT	up-regulates activity	binding			-1									11007482	t			Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases.	SIGNOR-256529	0.2
F2RL1	protein	P55085	UNIPROT	MSC	protein	O60682	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21072196	f		miannu	 PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 	SIGNOR-254861	0.2
CDK8	protein	P49336	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser195	PNSSYPNsPGSSSST	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-189133	0.392
JAK2	protein	O60674	UNIPROT	PTPN11	protein	Q06124	UNIPROT	up-regulates activity	phosphorylation	Tyr304	PNEPVSDyINANIIM	9534	BTO:0004055								8995399	t		lperfetto	Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2	SIGNOR-236266	0.786
PPP2CA	protein	P67775	UNIPROT	RBL2	protein	Q08999	UNIPROT	up-regulates	dephosphorylation			9606									15467457	t		miannu	Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation.	SIGNOR-129752	0.561
PKN3	protein	Q6P5Z2	UNIPROT	BCAR1	protein	P56945	UNIPROT	unknown	phosphorylation	Ser428	PAEGKRLsASSTGST	-1									30422386	t		lperfetto	These results verified the presence of a PKN3 phosphorylation motif in the sequence surrounding Ser432 and indicated that PKN3 phosphorylates p130Cas on Ser432 in vitro.|Human Ser428 of p130Cas corresponds to mouse p130Cas Ser432|	SIGNOR-264574	0.2
PTPN1	protein	P18031	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates	dephosphorylation	Tyr1009	LDTSSVLyTAVQPNE	9606									18567737	t		gcesareni	Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr.	SIGNOR-179064	0.679
AKT2	protein	P31751	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates activity	phosphorylation	Ser83	ATRGRGSsVGGGSRR	9606	BTO:0000150								12697749	t		lperfetto	Akt2 interacts with and phosphorylates ask1 at ser-83 resulting in inhibition of its kinase activity	SIGNOR-100588	0.633
PLXNB3	protein	Q9ULL4	UNIPROT	ARHGDIA	protein	P52565	UNIPROT	up-regulates activity	binding			10116	BTO:0000526								20696765	t		miannu	Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays.	SIGNOR-268435	0.253
PIK3R3	protein	Q92569	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606									9415396	t		gcesareni	The region between the src homology 2 (sh2) domains of p55pik bound to the nh2 terminus region of p110alpha	SIGNOR-53597	0.84
BMP2	protein	P12643	UNIPROT	BMPR1A	protein	P36894	UNIPROT	up-regulates	binding												26330344	t		fferrentino	BMP interacts with specific receptors on the cell surface, BMP receptor types 1 and 2 (BMPr1 and BMPr2).	SIGNOR-253547	0.927
SHC1	protein	P29353	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates activity				10090	BTO:0000944								17673906	f		lperfetto	We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases.	SIGNOR-242622	0.702
LYN	protein	P07948	UNIPROT	SLC4A1	protein	P02730	UNIPROT	unknown	phosphorylation	Tyr359	AKPDSSFyKGLDLNG	-1									10942405	t			Lyn phosphorylates Y904 and Y359 of band 3. The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton movements, and anion transport.	SIGNOR-251412	0.343
GDNF	protein	P39905	UNIPROT	MAP1LC3B	protein	Q9GZQ8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252176	0.2
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1616	TPQSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273054	0.556
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1941	SPKGSTYsPTSPGYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273059	0.636
PIM1	protein	P11309	UNIPROT	MARK3	protein	P27448	UNIPROT	down-regulates	phosphorylation	Thr95	DKTQLNPtSLQKLFR	9606									15319445	t		gcesareni	Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1.	SIGNOR-128268	0.427
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	TSC1	protein	Q92574	UNIPROT	down-regulates	phosphorylation	Thr1047	SSSSELStPEKPPHQ	9606	BTO:0000680;BTO:0001573;BTO:0001286								14551205	t		lperfetto	Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex	SIGNOR-216949	0.426
PRKCG	protein	P05129	UNIPROT	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	up-regulates	phosphorylation			9606									12536214	t	inferred from family member	gcesareni	We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus.	SIGNOR-270233	0.693
MXI1	protein	P50539	UNIPROT	CCNB1	protein	P14635	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002036								11875718	t		Luana	Mxi1 inhibits the proliferation of U87 glioma cells through down-regulation of cyclin B1 gene expression | Mxi1 inhibits the promoter activity of the cyclin B1 gene. 	SIGNOR-266064	0.269
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates quantity by destabilization	cleavage	Asp638	KLVFFAEdVGSNKGA	-1									8943232	t		lperfetto	FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261764	0.502
ZNRF3	protein	Q9ULT6	UNIPROT	FZD4	protein	Q9ULV1	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								22575959	t			Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.	SIGNOR-260115	0.547
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	A4/b1 integrin	complex	SIGNOR-C162	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259016	0.359
ROCK1	protein	Q13464	UNIPROT	DES	protein	P17661	UNIPROT	unknown	phosphorylation	Thr17	RVSSYRRtFGGAPGF	9606	BTO:0000971								10574968	t		lperfetto	We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin	SIGNOR-249032	0.321
TELO2	protein	Q9Y4R8	UNIPROT	mTORC2	complex	SIGNOR-C2	SIGNOR	up-regulates quantity by stabilization	binding			9606	BTO:0000007								20427287	t		miannu	MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. 	SIGNOR-272003	0.569
RRN3	protein	Q9NYV6	UNIPROT	SL1 complex	complex	SIGNOR-C464	SIGNOR	up-regulates activity	relocalization			9606	BTO:0000567								11250903	t		lperfetto	HRRN3 is essential in the SL1-mediated recruitment of RNA Polymerase I to rRNA gene promoters|We conclude that hRRN3 functions to recruit initiation-competent Pol I to rRNA gene promoters. The essential role for hRRN3 in linking Pol I to SL1 suggests a mechanism for growth control of Pol I transcription.	SIGNOR-269647	0.649
TP53	protein	P04637	UNIPROT	VCAN	protein	P13611	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12438652	t		miannu	 By using in vitro and in vivo assays, we showed CSPG2 to be directly transactivated by p53.	SIGNOR-255441	0.295
PTPN1	protein	P18031	UNIPROT	KRT8	protein	P05787	UNIPROT	down-regulates activity	dephosphorylation	Tyr267	IAEVKAQyEDIANRS	9606	BTO:0000182								24003221	t		lperfetto	Keratin 8 phospho-Tyr-267 is dephosphorylated by PTP1B and promotes insolubility and filament organization, as does the paralogous GFAP tyrosine.	SIGNOR-265495	0.2
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	MEFV	protein	O15553	UNIPROT	up-regulates activity													16037825	f		lperfetto	Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage	SIGNOR-256426	0.7
MAP2K6	protein	P52564	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates	phosphorylation			9606									8974401	t		gcesareni	A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subgroups of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase)	SIGNOR-45363	0.441
CXCL10	protein	P02778	UNIPROT	CXCR3	protein	P49682	UNIPROT	up-regulates activity	binding			9606	BTO:0000782								12750173	t		miannu	The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells.	SIGNOR-260969	0.78
GGNBP2	protein	Q9H3C7	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates activity	binding			9606	BTO:0001248								27357812	t		miannu	We further demonstrate that GGNBP2 protein physically interacts with ERα, inhibits E2-induced activation of estrogen response element-driven reporter activity, and attenuates ER target gene expression in T47D cells. 	SIGNOR-269076	0.2
STK26	protein	Q9P289	UNIPROT	ATG4B	protein	Q9Y4P1	UNIPROT	up-regulates activity	phosphorylation	Ser383	RLERFFDsEDEDFEI										29232556	t		lperfetto	ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux.	SIGNOR-275833	0.2
MAPK3	protein	P27361	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr56	FSSQPGHtPHPAASR	9606									10669763	t		gcesareni	Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo.	SIGNOR-74939	0.541
PRKDC	protein	P78527	UNIPROT	H1-2	protein	P16403	UNIPROT	down-regulates activity	phosphorylation	Thr146	KKAAGGAtPKKSAKK	9606	BTO:0001938								22249259	t	done	miannu	Similarly, DNA-PK-mediated phosphorylation of H1.2 at T146 enhances p53 transcriptional activity by impeding H1.2 binding to p53 and thereby attenuating its suppressive effects on p53 transactivation. 	SIGNOR-273834	0.2
PGM2	protein	Q96G03	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	down-regulates quantity	chemical modification			9606									32898648	t		miannu	Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P).	SIGNOR-268116	0.8
BMP10	protein	O95393	UNIPROT	BMPR1A	protein	P36894	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000562							16049014	t		acerquone	We showed that three orphan ligands known to be important for joint and cartilage formation (gdf6) (10), interneuron, sensory neurons, and seminal vesicle formation (gdf7) (11_13), and heart development (bmp10) (14) used the type i receptors alk3 or alk6 and the type ii receptors bmprii or actriia to activate the smad1/5/8 proteins.	SIGNOR-139052	0.617
RALA	protein	P11233	UNIPROT	FOXO4	protein	P98177	UNIPROT	up-regulates activity	phosphorylation	Thr455	ALGTPVLtPPTEAAS	10090									11689711	t		gcesareni	We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT.	SIGNOR-249665	0.2
PRKCD	protein	Q05655	UNIPROT	PRKCD	protein	Q05655	UNIPROT	up-regulates	phosphorylation	Thr507	FGESRAStFCGTPDY	9606									19366211	t		llicata	This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. studies reported herein show that a t505a substitution reduces pkcdelta-thr(295) autophosphorylation	SIGNOR-185287	0.2
DMTF1	protein	Q9Y222	UNIPROT	MBD1	protein	Q9UIS9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004532								19816943	f		Luana	 Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. 	SIGNOR-261586	0.2
POT1	protein	Q9NUX5	UNIPROT	RPA3	protein	P35244	UNIPROT	down-regulates activity	binding						SIGNOR-C306						18680434	t		lperfetto	The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA	SIGNOR-263326	0.267
DAPK3	protein	O43293	UNIPROT	RPL13A	protein	P40429	UNIPROT	up-regulates	phosphorylation	Ser77	PYHFRAPsRIFWRTV	9606	BTO:0000801								18995835	t		lperfetto	Zipk phosphorylates l13a in vitro / l13a is phosphorylated on ser77 in vitro	SIGNOR-182117	0.413
adenosine	smallmolecule	CHEBI:16335	ChEBI	ADP(3-)	smallmolecule	CHEBI:456216	ChEBI	up-regulates quantity	precursor of			9606									33961946	t		miannu	Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5′-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). 	SIGNOR-267836	0.8
CUL2	protein	Q13617	UNIPROT	ARIH1	protein	Q9Y4X5	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								24076655	t		miannu	Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin.	SIGNOR-268845	0.315
CPSF1	protein	Q10570	UNIPROT	CPSF complex	complex	SIGNOR-C53	SIGNOR	form complex	binding			9606									14749727	t		miannu	Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna.	SIGNOR-121646	0.939
ELF4	protein	Q99607	UNIPROT	ELF4/RUNX1	complex	SIGNOR-C47	SIGNOR	form complex	binding			9606	BTO:0001271								10207087	t		miannu	We readily detected an in vivo physical interaction between mef and aml1 proteins in kasumi-1 cells/ coexpression of mef and aml1b synergistically activates promoter function	SIGNOR-66960	0.357
WARS1	protein	P23381	UNIPROT	Trp-tRNA(Trp)	smallmolecule	CHEBI:29159	ChEBI	up-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 	SIGNOR-270514	0.8
ERBB3	protein	P21860	UNIPROT	PIK3CD	protein	O00329	UNIPROT	up-regulates	binding			9606									16729043	t		gcesareni	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146867	0.394
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	THRB	protein	P10828	UNIPROT	up-regulates activity	chemical activation			10116	BTO:0000759								2158622	t		miannu	We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 	SIGNOR-258383	0.8
FANCC	protein	Q00597	UNIPROT	Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	form complex	binding			9606	BTO:0000567								17396147	t		lperfetto	This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo 	SIGNOR-263246	0.921
PIM3	protein	Q86V86	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation			-1									31730483	t		miannu	In addition to PIM1, also PIM2 and PIM3 were able to phosphorylate WT, but not MM NFATC1 in vitro (Fig. ​(Fig.22c).	SIGNOR-276773	0.248
DEAF1	protein	O75398	UNIPROT	HTR1A	protein	P08908	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000142								29636529	t		Gianni	The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription	SIGNOR-269064	0.45
ZRSR2	protein	Q15696	UNIPROT	ZRSR2/U2AF2	complex	SIGNOR-C81	SIGNOR	form complex	binding			9606									9237760	t		miannu	Recognition of a functional 3' splice site in pre-mrna splicing requires a heterodimer of the proteins u2af65/u2af35.	SIGNOR-50176	0.77
NCOA1	protein	Q15788	UNIPROT	STAT5B	protein	P51692	UNIPROT	up-regulates	binding			9606		BTO:0000149							12954634	t		miannu	Ncoa-1/src-1 is an essential coactivator of stat5 that binds to the fdl motif in the alpha-helical region of the stat5 transactivation domain.	SIGNOR-100261	0.329
RNA_splicing	phenotype	SIGNOR-PH201	SIGNOR	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates				9606									32140746	f		lperfetto	The splicing of introns from nuclear precursors of message RNA (pre-mRNA) is executed by the spliceosome, a ribonucleoprotein (RNP) apparatus that first surfaced in the literature in 1985 	SIGNOR-268402	0.7
IRAK1	protein	P51617	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Ser78	NKDQHSIsYTLSRAQ	9606	BTO:0000007								12496252	t		lperfetto	In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation	SIGNOR-96743	0.758
Apelin	smallmolecule	CID:56841713	PUBCHEM	APLNR	protein	P35414	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257460	0.8
JUN	protein	P05412	UNIPROT	CYP19A1	protein	P11511	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001555								19022561	f		miannu	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 	SIGNOR-254876	0.35
KAT2A	protein	Q92830	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates	binding			9606	BTO:0000150		SIGNOR-C7						15009097	t		gcesareni	Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo.	SIGNOR-123318	0.505
DICER1	protein	Q9UPY3	UNIPROT	RISC(DICER1/AGO2/TARBP2)	complex	SIGNOR-C32	SIGNOR	form complex	binding			9606									16142218	t		lperfetto	Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si_ or mi_riscs in mammalian cells, but it may also facilitate the cleavage of pre_mirnas by dicer.	SIGNOR-140223	0.939
PRKACG	protein	P22612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606									10230396	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.	SIGNOR-67396	0.409
SS18	protein	Q15532	UNIPROT	SS18/MLLT10	complex	SIGNOR-C75	SIGNOR	form complex	binding			9606	BTO:0001271								11423977	t		miannu	Based on these results, a model is proposed in which the syt and af10 proteins act in concert as bipartite transcription factors	SIGNOR-108927	0.437
CEBPA	protein	P49715	UNIPROT	ELANE	protein	P08246	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004408								19620402	f		miannu	 The ELA2 gene promoter is positively regulated by the direct binding of LEF-1 or C/EBPalpha, documenting the role of LEF1 in the diminished ELA2 expression. 	SIGNOR-253769	0.313
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	STK4	protein	Q13043	UNIPROT	down-regulates	phosphorylation	Thr387	TMKRRDEtMQPAKPS	9606									23431053	t		gcesareni	Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt.	SIGNOR-201121	0.2
1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	PRKCA	protein	P17252	UNIPROT	up-regulates	chemical activation			9606									18593525	t		gcesareni	The increases in the membrane levels of nacholeate itself and of dag induce a translocation and overexpression of protein kinase c (pkc) and subsequent reductions of cyclin d, cyclin-dependent kinases 4 and 6 (cdks 4 and 6), hypophosphorylation of the retinoblastoma protein, inhibition of e2f1 and knockdown of dihydrofolate reductase (dhfr) impairing dna synthesis.	SIGNOR-179279	0.8
iron-sulfur cluster	smallmolecule	CHEBI:30408	ChEBI	SDHB	protein	P21912	UNIPROT	up-regulates activity	chemical activation												26083061	t		lperfetto	Succinate dehydrogenase subunit B contains three Fe-S clusters |The enzymatic activity of both proteins depends on the presence of intact Fe-S clusters	SIGNOR-262133	0.8
methylnaltrexone	chemical	CHEBI:136007	ChEBI	OPRD1	protein	P41143	UNIPROT	down-regulates activity	chemical inhibition			10030	BTO:0000246								19282177	t		Luana	A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 	SIGNOR-258147	0.8
DDC	protein	P20711	UNIPROT	tyrosine	smallmolecule	CHEBI:18186	ChEBI	down-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain 	SIGNOR-263993	0.8
SMURF1	protein	Q9HCE7	UNIPROT	SMAD1/5/8	proteinfamily	SIGNOR-PF35	SIGNOR	down-regulates	ubiquitination			9606									22298955	t	Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes	gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps	SIGNOR-269847	0.76
GSK3A	protein	P49840	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser641	KVTSKCGsLGNIHHK	9606	BTO:0000590								7706316	t		lperfetto	Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262.	SIGNOR-249342	0.44
glycogen	smallmolecule	CHEBI:28087	ChEBI	PYGB	protein	P11216	UNIPROT	up-regulates activity	chemical activation			9606									3346228	t			Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267951	0.8
TLK1	protein	Q9UKI8	UNIPROT	NEK1	protein	Q96PY6	UNIPROT	up-regulates activity	phosphorylation	Thr141	IFLTKDGtVQLGDFG										28426283	t		lperfetto	TLK1 phosphorylated NEK1 at T141, which lies in the kinase domain, and caused an increase in its activity. 	SIGNOR-275840	0.295
MYC	protein	P01106	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12835716	t		gcesareni	C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a	SIGNOR-102740	0.772
alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P.	SIGNOR-266460	0.8
MC5R	protein	P33032	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257070	0.252
FOXO1	protein	Q12778	UNIPROT	GK	protein	P32189	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18805788	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription foxo1 localizes to the nucleus, where it represses hnf-4-dependent activity of the gk promoter as a corepressor.	SIGNOR-181268	0.253
GTF2I	protein	P78347	UNIPROT	GSC	protein	P56915	UNIPROT	up-regulates quantity by expression	transcriptional regulation												16611241	f		lperfetto	For example, TFII-I binds to the Inr element of the T cell receptor Vbeta gene and activates its transcription in reporter gene assays (Cheriyath et al. 1998). TFII-I also activates transcription of c-fos and Goosecoid through binding to the serum response element and the distal element, respectively (Grueneberg et al. 1997; Ku et al. 2005).	SIGNOR-268536	0.2
IL21	protein	Q9HBE4	UNIPROT	IL2RG	protein	P31785	UNIPROT	up-regulates	binding			9606									11418623	t		gcesareni	The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex	SIGNOR-108858	0.593
SMAD5	protein	Q99717	UNIPROT	GADD45G	protein	O95257	UNIPROT	up-regulates quantity	transcriptional regulation			10090									22219353	t		Gianni	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268942	0.2
IL15RA	protein	Q13261	UNIPROT	JAK3	protein	P52333	UNIPROT	up-regulates				9606									30029643	t			Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated	SIGNOR-256226	0.481
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates	dephosphorylation			9606									21880741	t		gcesareni	Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.	SIGNOR-252311	0.635
PAX3-FOXO1	fusion protein	SIGNOR-FP12	SIGNOR	PDGFA	protein	P04085	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25211658	t		miannu	Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA.	SIGNOR-251571	0.2
STARD13	protein	Q9Y3M8	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260521	0.631
IFI30	protein	P13284	UNIPROT	peptide antigen	smallmolecule	CHEBI:166824	ChEBI	up-regulates quantity	chemical modification			9606									31810556	t		scontino	Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol.	SIGNOR-267864	0.8
P2RY11	protein	Q96G91	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257173	0.2
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1944	GSTYSPTsPGYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120076	0.781
PRPF19	protein	Q9UMS4	UNIPROT	RPA1	protein	P27694	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0000567								24332808	t		miannu	PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). PRP19 ubiquitylates RPA and promotes ATRIP recruitment.	SIGNOR-272076	0.486
RPS6KA1	protein	Q15418	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates	phosphorylation	Ser719	PCTPRLRsVSSYGNI	9606				SIGNOR-C3					18722121	t		llicata	Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity	SIGNOR-180458	0.564
SOSTDC1	protein	Q6X4U4	UNIPROT	BMP2	protein	P12643	UNIPROT	down-regulates activity				10090									18032587	f		lperfetto	SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7	SIGNOR-242746	0.582
CYP11B2	protein	P19099	UNIPROT	corticosterone	smallmolecule	CHEBI:16827	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000048							33117906	t		lperfetto	The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone	SIGNOR-268680	0.8
NOD1	protein	Q9Y239	UNIPROT	ATG16L1	protein	Q676U5	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								19898471	t		miannu	By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease.	SIGNOR-252406	0.672
P2RY10	protein	O00398	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257213	0.357
RHOQ	protein	P17081	UNIPROT	EXOC7	protein	Q9UPT5	UNIPROT	up-regulates	binding			9606									12687004	t		gcesareni	Here we show that tc10 interacts with one of the components of the exocyst complex, exo70.	SIGNOR-100486	0.62
MARCHF9	protein	Q86YJ5	UNIPROT	VAMP8	protein	Q9BV40	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001522								19457934	t		miannu	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. 	SIGNOR-271531	0.2
HNF1A	protein	P20823	UNIPROT	AFP	protein	P02771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								9792724	f	 	miannu	 AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP.	SIGNOR-254447	0.336
SMARCB1	protein	Q12824	UNIPROT	CSF1	protein	P09603	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								16267391	f		miannu	Ini1/hsnf5/baf47 is involved in activation of the csf1 promoter.	SIGNOR-141047	0.2
BTRC	protein	Q9Y297	UNIPROT	CDC25A	protein	P30304	UNIPROT	up-regulates	ubiquitination			9606			SIGNOR-C5						15340381	t		gcesareni	Scfb-trcp has recently been shown to degrade phosphorylated cdc25a in the s and g2 phases.	SIGNOR-128436	0.508
CYSLTR1	protein	Q9Y271	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257135	0.357
Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	GABA-A (a6-b3-d) receptor	complex	SIGNOR-C329	SIGNOR	up-regulates				9606									33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors	SIGNOR-268588	0.2
SAV1	protein	Q9H4B6	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	up-regulates activity	binding			9606									21084559	t		miannu	 Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst.	SIGNOR-256183	0.891
CSNK1G1	protein	Q9HCP0	UNIPROT	LYN	protein	P07948	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser13	SKGKDSLsDDGVDLK	9606	BTO:0000007								33004926	t		miannu	Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane.	SIGNOR-275396	0.2
YY1	protein	P25490	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates activity	binding			9606	BTO:0000664								12913000	t			Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex [..] both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling.	SIGNOR-251654	0.607
PAK	proteinfamily	SIGNOR-PF13	SIGNOR	SYN1	protein	P17600	UNIPROT	unknown	phosphorylation			10116									12237306	t	inferred from 70% family members	miannu	Recombinant PAK2 could also phosphorylate the Ser9 and Ser551 residues. 	SIGNOR-269974	0.2
RPS17	protein	P08708	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262434	0.899
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	RASSF1	protein	Q9NS23	UNIPROT	down-regulates	phosphorylation	Ser207	TSVRRRTsFYLPKDA	9606									18071316	t		llicata	This skp2-dependent destruction of rassf1a requires phosphorylation of the latter on serine-203 by cyclin d-cyclin-dependent kinase 4.	SIGNOR-216976	0.489
AP1	complex	SIGNOR-C154	SIGNOR	SPI1	protein	P17947	UNIPROT	up-regulates activity	binding			9606	BTO:0004136								12393465	t		miannu	These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1.	SIGNOR-260098	0.525
CBP/p300	complex	SIGNOR-C6	SIGNOR	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	acetylation			9606									21131905	t		lperfetto	These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription.	SIGNOR-265322	0.2
CSNK2A1	protein	P68400	UNIPROT	MAX	protein	P61244	UNIPROT	down-regulates	phosphorylation	Ser11	NDDIEVEsDEEQPRF	9606									8018564	t		gcesareni	Max activity is affected by phosphorylation at two nh2-terminal sites, ser2 and ser11.	SIGNOR-35768	0.368
LIF	protein	P15018	UNIPROT	LIFR	protein	P42702	UNIPROT	up-regulates	binding			9606									24710148	t		milica	The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3).	SIGNOR-204847	0.751
SOX9	protein	P48436	UNIPROT	COL9A2	protein	Q14055	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10980415	f		miannu	Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan. 	SIGNOR-251757	0.363
DUSP10	protein	Q9Y6W6	UNIPROT	MAPK8	protein	P45983	UNIPROT	down-regulates	dephosphorylation			9606									10391943	t		gcesareni	Mkp-5 directly dephosphorylates sapk/jnk and p38 in vitromkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk	SIGNOR-68986	0.705
MAPK14	protein	Q16539	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									12110590	t		gcesareni	Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway.	SIGNOR-90521	0.786
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser175	SPASSGSsASFISDT	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248513	0.386
AXIN2	protein	Q9Y2T1	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates				9606		BTO:0000149							11940574	f		gcesareni	Although wnts act to stabilize _-catenin levels in the cytosol and nucleus, a multiprotein complex containing adenomatous polyposis coli, glycogen synthase kinase 3_, and axin1 or its homolog axin2/axil/conductin promotes _-catenin phosphorylation and subsequent proteasomal degradation.	SIGNOR-116480	0.843
CDC5L	protein	Q99459	UNIPROT	HNRNPM	protein	P52272	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								20467437	t	1	miannu	hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay.	SIGNOR-239410	0.618
ATM	protein	Q13315	UNIPROT	STK11	protein	Q15831	UNIPROT	unknown	phosphorylation	Thr363	IEDDIIYtQDFTVPG	9606	BTO:0000848								12234250	t		llicata	We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo. however, phosphorylation of lkb1 at thr-366 may have some role in enabling lkb1 to suppress cell growth	SIGNOR-92877	0.59
FBXW7	protein	Q969H0	UNIPROT	CCNE2	protein	O96020	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0002524								17298674	t		miannu	Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme	SIGNOR-271642	0.447
CSNK2A1	protein	P68400	UNIPROT	PDCL	protein	Q13371	UNIPROT	up-regulates	phosphorylation	Ser20	LQYYYSSsEDEDSDH	9606									16717095	t		lperfetto	Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2.	SIGNOR-146833	0.36
MAPK3	protein	P27361	UNIPROT	GRK2	protein	P25098	UNIPROT	down-regulates	phosphorylation	Ser670	KMKNKPRsPVVELSK	9606	BTO:0000007								10574913	t		gcesareni	Erk1 phosphorylates grk2 at ser(670). Inhibition of erk activity in hek293 cells potentiates grk2 activity, whereas, conversely, erk activation inhibits grk2 activity.	SIGNOR-72582	0.2
EXT2	protein	Q93063	UNIPROT	EXT1/EXT2	complex	SIGNOR-C51	SIGNOR	form complex	binding			9606									11518722	t		miannu	Biochemical analysis shows that ext1 and ext2 are type ii transmembrane glycoproteins and form a golgi-localized hetero-oligomeric complex that catalyzes the polymerization of hs	SIGNOR-109941	0.563
GTP	smallmolecule	CHEBI:15996	ChEBI	EEF1A:GTP:aa-tRNA	complex	SIGNOR-C493	SIGNOR	form complex	binding			9606									8722040	t		miannu	The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. 	SIGNOR-270812	0.8
GPER1	protein	Q99527	UNIPROT	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding												10696571	t			GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; the activated receptor induces a conformational change in the associated G protein α-subunit leading to release of GDP followed by binding of GTP and α-subunit dissociation from the receptor.	SIGNOR-251102	0.353
2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid	chemical	CID:135461425	PUBCHEM	PDGFRA	protein	P16234	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259706	0.8
EIF2AK3	protein	Q9NZJ5	UNIPROT	EIF2S1	protein	P05198	UNIPROT	down-regulates activity	phosphorylation			9606									31226023	t		miannu	Activated PERK phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), which inhibits the conversion of inactive GDP-bound eIF2α back to the active GTP-bound form, thereby suppressing translation initiation.	SIGNOR-260165	0.757
PHF2	protein	O75151	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606	BTO:0000007								21532585	t		miannu	PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark.	SIGNOR-264518	0.2
CTBP2	protein	P56545	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002181								21315774	t		Luana	Overexpression of the CtBP2 protein enhanced the repression activity of the E-cadherin promoter in a dose-dependent manner, whereas overexpression of ataxin-1 increased the activity of the E-cadherin promoter in a dose-dependent manner 	SIGNOR-261578	0.391
TNFRSF21	protein	O75509	UNIPROT	Demyelination	phenotype	SIGNOR-PH155	SIGNOR	down-regulates				9606									32454942	f		miannu	Next to inhibition of sTNF/TNFR1 signaling, specific activation of TNFR2 may hold promise as a new MS therapy. Indeed, TNF promotes proliferation of oligodendrocyte progenitors and remyelination via TNFR2	SIGNOR-263832	0.7
PRKCB	protein	P05771	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser163	KRFSFKKsFKLSGFS	-1									8422248	t		lperfetto	These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III	SIGNOR-248926	0.663
sphingosine 1-phosphate	smallmolecule	CHEBI:37550	ChEBI	S1PR2	protein	O95136	UNIPROT	up-regulates activity	chemical activation			10116									10617617	t			We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation.	SIGNOR-261141	0.8
NKX3-1	protein	Q99801	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization				9606									16697957	f		miannu	NKX3.1 stabilizes p53.NKX3.1 can physically associate with HDAC1 and promotes p53 acetylation by recruiting HDAC1 from p53-MDM2-HDAC1 complex	SIGNOR-251548	0.364
MMP13	protein	P45452	UNIPROT	F12	protein	P00748	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly376	SMTRVVGgLVALRGA	-1									10930399	t		lperfetto	The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage.	SIGNOR-263609	0.317
CDK2	protein	P24941	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates	phosphorylation	Thr235	SSSSPPGtPSPADAK	9606			SIGNOR-C83						17601773	t		fspada	Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity.	SIGNOR-156509	0.406
ASNS	protein	P08243	UNIPROT	L-asparagine zwitterion	smallmolecule	CHEBI:58048	ChEBI	up-regulates quantity	chemical modification			9606									29084849	t		miannu	Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7.	SIGNOR-267533	0.8
TBL1XR1	protein	Q9BZK7	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates	binding			9606	BTO:0001130								24243687	t		miannu	We showed that tblr1 physically interacts with ar and directly occupies the androgen-response elements of the affected ar target genes in an androgen-dependent manner. / we characterized tblr1 as a coactivator of ar	SIGNOR-203235	0.403
GRK2	protein	P25098	UNIPROT	FPR1	protein	P21462	UNIPROT	down-regulates activity	phosphorylation	Thr329	RALTEDStQTSDTAT	-1									7836371	t		gcesareni	Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation.	SIGNOR-249664	0.2
PIK3R1	protein	P27986	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								14665640	t		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242646	0.712
GSK3B	protein	P49841	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates activity	phosphorylation	Thr235	SSSSPPGtPSPADAK	10090	BTO:0001169								22355693	t			We found that expression of srebf1a depended on GSK3β activity and that GSK3β activity was necessary for C/EBPβ phosphorylation at Thr188	SIGNOR-251644	0.469
serotonin(1+)	smallmolecule	CHEBI:350546	ChEBI	HTR2A	protein	P28223	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257521	0.8
PPP6C	protein	O00743	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	up-regulates activity	dephosphorylation	Ser824	LVDKEHDsAEGSHTS	9606	BTO:0001109								28114302	t		miannu	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276516	0.335
CREBBP	protein	Q92793	UNIPROT	IFNAR2	protein	P48551	UNIPROT	up-regulates activity	acetylation	Lys399	SGPCERRkSPLQDPF	9606	BTO:0000007								17923090	t		lperfetto	By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2.	SIGNOR-217783	0.352
CREB1	protein	P16220	UNIPROT	UXT	protein	Q9UBK9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001033								17761951	f	 	lperfetto	The DNA response elements that control the induction of ART-27 gene expression were also characterized. The major cis-acting element corresponds to a consensus cAMP-responsive element (CRE) and binds the CRE-binding protein (CREB) as shown by EMSA and chromatin immunoprecipitation assays. Furthermore, ART-27 promoter activity is induced upon CREB overexpression. Epidermal growth factor, which activates CREB via phosphorylation, also induces ART-27 expression, whereas a reduction in CREB phosphorylation or expression blocks this induction in prostate cells.	SIGNOR-254092	0.2
PRKCA	protein	P17252	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation	Ser518	VFRTNGVsDVPTSPT	-1									27368100	t		miannu	These results suggest that PKC activates JAK2 and thereby STAT3 by directly phosphorylating T174 and S518. 	SIGNOR-277261	0.262
FOXN1	protein	O15353	UNIPROT	DSG4	protein	Q86SJ6	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000552								19683850	f	 	miannu	 we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle.	SIGNOR-254182	0.391
NTN1	protein	O95631	UNIPROT	UNC5C	protein	O95185	UNIPROT	up-regulates	binding			9606									10399920	t		gcesareni	We provide evidence that netrin-1 triggers the formation of a receptor complex of dcc and unc5 proteins and simultaneously derepresses the interaction between their cytoplasmic domains, thereby converting dcc-mediated attraction to unc5/dcc-mediated repulsion.	SIGNOR-69047	0.826
SNIP1	protein	Q8TAD8	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270671	0.444
MAPK3	protein	P27361	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser221	DHEKKAYsFCGTVEY	9534	BTO:0001538								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-219332	0.705
HASPIN	protein	Q8TF76	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	phosphorylation	Thr3	T-->R	9606									20705812	t		miannu	Here we show that phosphorylation of histone H3 threonine 3 (H3T3ph) by Haspin is necessary for CPC accumulation at centromeres and that the CPC subunit Survivin binds directly to H3T3ph.	SIGNOR-275418	0.2
CTCFL	protein	Q8NI51	UNIPROT	BAG1	protein	Q99933	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0003293								18413740	t	 	lperfetto	DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation 	SIGNOR-254107	0.285
SMC5	protein	Q8IY18	UNIPROT	SMC5/6 	complex	SIGNOR-C374	SIGNOR	form complex	binding			-1									27427983	t		miannu	The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks	SIGNOR-265481	0.891
FUS	protein	P35637	UNIPROT	GRIA4	protein	P48058	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			10090		BTO:0001279							28515487	f			This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease	SIGNOR-262806	0.2
GRIK4	protein	Q16099	UNIPROT	D-serine	smallmolecule	CHEBI:16523	ChEBI	up-regulates quantity	relocalization			9606	BTO:0002609								12393813	t		lperfetto	Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine	SIGNOR-268275	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PTPN1	protein	P18031	UNIPROT	down-regulates activity	phosphorylation	Ser50	RNRYRDVsPFDHSRI	10090	BTO:0000944								11579209	t		lperfetto	Phosphorylation of ptp1b at ser(50) by akt impairs its ability to dephosphorylate the insulin receptor.	SIGNOR-235411	0.2
TBX21	protein	Q9UL17	UNIPROT	IL2	protein	P60568	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003432								10761931	t		Luana	T-bet Transactivates the IFNγ Gene and Represses the IL-2 Gene in EL4 Cells	SIGNOR-266233	0.488
DDX3X	protein	O00571	UNIPROT	EIF4E	protein	P06730	UNIPROT	down-regulates activity	binding			9606	BTO:0001950								17667941	t		miannu	DDX3 is a human RNA helicase with plethoric functions. we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G.	SIGNOR-269200	0.649
TWIST1	protein	Q15672	UNIPROT	FAP	protein	Q12884	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20646316	f		miannu	Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1.	SIGNOR-255523	0.244
BRD9	protein	Q9H8M2	UNIPROT	GBAF	complex	SIGNOR-C467	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269787	0.487
pyruvate	smallmolecule	CHEBI:15361	ChEBI	Citric_Acid_Cycle	phenotype	SIGNOR-PH191	SIGNOR	up-regulates activity				9606									18613815	f			Pyruvate carboxylase (PC) is a biotin-containing enzyme that catalyses the HCO3−- and MgATP-dependent carboxylation of pyruvate to form oxaloacetate. This is a very important anaplerotic reaction, replenishing oxaloacetate withdrawn from the Krebs cycle for various pivotal biochemical pathways.	SIGNOR-267384	0.7
EGFR	protein	P00533	UNIPROT	VAV2	protein	P52735	UNIPROT	up-regulates	phosphorylation	Tyr172	EDGGDDIyEDIIKVE	9606									12454019	t		miannu	To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor.	SIGNOR-95980	0.61
PPP3CA	protein	Q08209	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates	dephosphorylation			9606	BTO:0000782								14722106	t		gcesareni	Once activated, calcineurin directly dephosphorylates NFAT proteins that are present in a hyperphosphorylated latent form in the cytoplasm and induces their rapid translocation into the nucleus, where in concert with nuclear partner proteins such as the AP-1 transcription factor complex, they are able to bind cooperatively to their target promoter elements and activate the transcription of specific NFAT target genes	SIGNOR-84038	0.817
CFB	protein	P00751	UNIPROT	C3 convertase complex (C3bBb)	complex	SIGNOR-C314	SIGNOR	form complex	binding			9606		BTO:0000089			cleavage:Arg259	GPGEQQKrKIVLDPS			26489954	t	complement factor B, b fragment: PRO_0000027547	lperfetto	Surface‐associated C3b recruits FB, which leads to FB activation and the formation of C3bBb, the AP C3 convertase, which cleaves more C3 and amplifies complement activation. In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over)	SIGNOR-263486	0.903
PRKCB	protein	P05771	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	down-regulates activity	phosphorylation	Ser496	ATPQRSGsVSNYRSC	-1									27784766	t		miannu	Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle.	SIGNOR-276460	0.2
PLK1	protein	P53350	UNIPROT	NEK9	protein	Q8TD19	UNIPROT	up-regulates activity	phosphorylation	Thr210	SEYSMAEtLVGTPYY	9606	BTO:0000567								21642957	t	done	miannu	We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. while CDK1 activity is necessary for Nek9 phosphorylation in mitosis and the resulting change in electrophoretical mobility, Nek9 Thr210 phosphorylation and mitotic activation requires both CDK1 and Plk1.	SIGNOR-273888	0.593
KLF11	protein	O14901	UNIPROT	HBG2	protein	P69892	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000664								10207080	f	Regulation	miannu	Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression. 	SIGNOR-251827	0.2
(-)-anisomycin	chemical	CHEBI:338412	ChEBI	JUN	protein	P05412	UNIPROT	up-regulates	chemical activation			9606									Other	t	CellSignaling	gcesareni		SIGNOR-189632	0.8
chelerythrine	chemical	CHEBI:78373	ChEBI	MAPK8	protein	P45983	UNIPROT	up-regulates	chemical activation			9606									Other	t	CellSignaling	gcesareni		SIGNOR-190964	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ADRB2	protein	P07550	UNIPROT	down-regulates	phosphorylation	Ser345	ELLCLRRsSLKAYGN	9606									11809767	t		lperfetto	Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation.	SIGNOR-114466	0.2
PRKACA	protein	P17612	UNIPROT	NFATC1	protein	O95644	UNIPROT	down-regulates	phosphorylation	Ser294	PHGSPRVsVTDDSWL	9606									12351631	t		lperfetto	Here we show that overexpression of pka causes phosphorylation and cytoplasmic accumulation of nf-atc1 in direct opposition to calcineurin by phosphorylating ser-245, ser-269, and ser-294 in the conserved serine-proline repeat domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3)	SIGNOR-93539	0.357
corticosterone	smallmolecule	CHEBI:16827	ChEBI	18-hydroxycorticosterone	smallmolecule	CHEBI:16485	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000048							33117906	t		lperfetto	The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone	SIGNOR-268674	0.8
PRKCA	protein	P17252	UNIPROT	ITPKB	protein	P27987	UNIPROT	down-regulates activity				-1									9374536	t		lperfetto	However, when assayed in the presence of calcium/calmodulin, the activity of the B isoform was decreased following phosphorylation by either protein kinase.	SIGNOR-248990	0.366
DUSP4	protein	Q13115	UNIPROT	MAPK8	protein	P45983	UNIPROT	down-regulates	dephosphorylation			9606									9020184	t		lperfetto	Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2	SIGNOR-27756	0.702
SMARCD3	protein	Q6STE5	UNIPROT	Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270692	0.752
mTORC1	complex	SIGNOR-C3	SIGNOR	TFEB	protein	P19484	UNIPROT	down-regulates activity	phosphorylation	Ser142	AGNSAPNsPMAMLHI	9606	BTO:0000007								22343943	t			Here, we have used an mTORC1 in-vitro kinase assay and a phosphoantibody to demonstrate that serine S142, which we previously found to be phosphorylated by ERK2, is also phosphorylated by mTOR and that this phosphorylation has a crucial role in controlling TFEB subcellular localization and activity.	SIGNOR-255309	0.371
ORC6	protein	Q9Y5N6	UNIPROT	ORC	complex	SIGNOR-C419	SIGNOR	form complex	binding			9606									32808929	t		lperfetto	The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA	SIGNOR-267562	0.943
USF1	protein	P22415	UNIPROT	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								9677331	f	inferred from family member	miannu	Cotransfection of an expression plasmid encoding USF1 into HepG2 hepatoma cells resulted in the activation of the glucokinase promoter, dependent on the integrity of the P2 element	SIGNOR-267797	0.294
TRIM17	protein	Q9Y577	UNIPROT	MCL1	protein	Q07820	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			10090	BTO:0001976								22976837	t		miannu	Here, we identified Trim17 as a novel E3 ubiquitin-ligase for Mcl-1. Indeed, Trim17 co-immunoprecipitated with Mcl-1. Trim17 ubiquitinated Mcl-1 in vitro. Overexpression of Trim17 decreased the protein level of Mcl-1 in a phosphorylation- and proteasome-dependent manner. Finally, knock down of Trim17 expression reduced both ubiquitination and degradation of Mcl-1 in neurons.	SIGNOR-272032	0.456
CDC25C	protein	P30307	UNIPROT	CCNB1	protein	P14635	UNIPROT	up-regulates activity	dephosphorylation			9606									25949173	t		miannu	Cdc25C is an activator of Cdc2 kinase and dephosphorylates and activates the CyclinB-Cdc2 complex shortly before the entry into the mitosis.	SIGNOR-277099	0.826
IFNG	protein	P01579	UNIPROT	ARDS	phenotype	SIGNOR-PH128	SIGNOR	up-regulates				9606									32446778	f		miannu	Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection	SIGNOR-261033	0.7
ziprasidone	chemical	CHEBI:10119	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10116									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258505	0.8
TMPRSS2	protein	O15393	UNIPROT	HGF	protein	P14210	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25122198	t		miannu	 we identified pro-hepatocyte growth factor (HGF) as a TMPRSS2 substrate and confirmed that HGF and it’s cognate receptor c-Met are activated in prostate cancers expressing TMPRSS2, a finding that also associated with the acquisition of a pro-invasive mesenchymal gene expression program.	SIGNOR-263657	0.2
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257924	0.8
PRKACA	protein	P17612	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates	phosphorylation			9606									9660950	t		lperfetto	The transcriptional activity of nf-kappa b is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase a (pka).	SIGNOR-217364	0.49
VRK2	protein	Q86Y07	UNIPROT	BANF1	protein	O75531	UNIPROT	down-regulates	phosphorylation	Ser4	sQKHRDFV	9606	BTO:0000567								16371512	t		gcesareni	We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell	SIGNOR-143368	0.517
PLK3	protein	Q9H4B4	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Thr366	ASSSTSVtPDVSDNE	9606									20940307	t		gcesareni	Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis	SIGNOR-168473	0.342
PKN1	protein	Q16512	UNIPROT	MEFV	protein	O15553	UNIPROT	down-regulates activity	phosphorylation	Ser242	SGKMRPRsLEVTIST	10090	BTO:0004732								27270401	t	no	miannu	PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. 	SIGNOR-275461	0.394
CDCA2	protein	Q69YH5	UNIPROT	PPP1CC	protein	P36873	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								32938714	t	done	miannu	This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin.	SIGNOR-274003	0.38
Nutlin-3	smallmolecule	CID:216345	PUBCHEM	TP53	protein	P04637	UNIPROT	up-regulates				9606									17700533	t		miannu	Nutlin, a class of small molecule antagonist of HDM2, binds to the p53-binding pocket of HDM2, preventing p53 from binding to HDM2 and thus, resulting in stabilization and activation of p53 	SIGNOR-255471	0.8
MAPK1	protein	P28482	UNIPROT	KCND2	protein	Q9NZV8	UNIPROT	up-regulates activity	phosphorylation	Ser616	EGDDRPEsPEYSGGN	10116	BTO:0000601								11080179	t		miannu	We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP.	SIGNOR-262934	0.376
TNKS	protein	O95271	UNIPROT	BLZF1	protein	Q9H2G9	UNIPROT	down-regulates quantity by destabilization	ADP-ribosylation			9606	BTO:0000007								21478859	t		lperfetto	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 	SIGNOR-263385	0.357
EGR1	protein	P18146	UNIPROT	SLC9A3	protein	P48764	UNIPROT	up-regulates quantity by expression	transcriptional regulation			7227	BTO:0001677								16464174	f	 	 	Transcriptional stimulation of the human NHE3 promoter activity by PMA: PKC independence and involvement of the transcription factor EGR-1|Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity	SIGNOR-254269	0.248
SRC	protein	P12931	UNIPROT	CTNND1	protein	O60716	UNIPROT	up-regulates activity	phosphorylation	Tyr257	APSRQDVyGPQPQVR	-1									11382764	t		lperfetto	Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302	SIGNOR-246488	0.92
Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	KDM5B	protein	Q9UGL1	UNIPROT	down-regulates activity				9606									35217626	t		SaraGualdi	Our transcriptomic profiling in AML further identified Kdm5b (also known as Jarid1b, Plu-1, or RBP2-H1), a multifunctional demethylase that can remove histone H3 lysine 4 tri/di-methylation (H3K4me3/2), to be a critical downstream target repressed by PRC2. 	SIGNOR-271577	0.37
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PPARA	protein	Q07869	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000599								10187842	t	inferred from 70% family members	lperfetto	We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution.	SIGNOR-270180	0.2
CCND1	protein	P24385	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates				9606	BTO:0000150	BTO:0000149							20443831	f		gcesareni	The mechanism by which cyclin d1 enhances notch1 activity in different cell types remains to be determined;the current studies demonstrate for the first time that notch1 activity is induced by cyclin d1. The expression of cyclin d1 sirna reduced notch1 activity.	SIGNOR-165189	0.624
SUFU	protein	Q9UMX1	UNIPROT	SUFU	protein	Q9UMX1	UNIPROT	up-regulates	binding			9606	BTO:0001130;BTO:0000848;BTO:0000527								10564661	t		miannu	Hsu(fu) associated with itself / homo- or heterodimers of hsu(fu) might function to bring together other effector proteins	SIGNOR-72311	0.2
HPS3	protein	Q969F9	UNIPROT	BLOC-2	complex	SIGNOR-C252	SIGNOR	form complex	binding			9606									15030569	t		lperfetto	Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6	SIGNOR-260688	0.705
NECAP1	protein	Q8NC96	UNIPROT	AP-2 complex	complex	SIGNOR-C245	SIGNOR	up-regulates activity	binding			9606									24130457	t		lperfetto	Knockdown and functional rescue studies demonstrate that through these interactions, NECAP 1 and AP-2 cooperate to increase the probability of clathrin-coated vesicle formation and to control the number, size, and cargo content of the vesicles. 	SIGNOR-260710	0.463
ADORA2A	protein	P29274	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257364	0.304
PRKCA	protein	P17252	UNIPROT	TRPC3	protein	Q13507	UNIPROT	down-regulates	phosphorylation	Ser703	SLVPSPKsFVYFIMR	9606									16331690	t		gcesareni	There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712.	SIGNOR-142945	0.354
ABL1	protein	P00519	UNIPROT	PLSCR1	protein	O15162	UNIPROT	unknown	phosphorylation	Tyr69	PVPNQPVyNQPVYNQ	9606									11390389	t		Manara	Our data establish that the Abl SH3 domain binds to the N-terminal proline-rich segment of PLSCR1 and that ABL1 phosphorylates Tyr residues of the PLSCR1 polypeptide, most likely Tyr69 and Tyr74 within the tandem repeat sequence 	SIGNOR-260807	0.393
INPP4B	protein	O15327	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	dephosphorylation			9606									26411369	t		lperfetto	In support, the increase in PTEN caused by INPP4B knockdown was associated with increased phosphorylation of the Ser380, Thr382, Thr383 and Ser385 cluster of the protein (XREF_FIG), which is known to increase PTEN half-life, in colon cancer cells.|Exogenous INPP4B could pull down and dephosphorylate endogenous PTEN, suggesting that effect of INPP4B on PTEN in colon cancer cells is not due to cell-type-specific characteristics of INPP4B per se.|INPP4B downregulates PTEN in colon cancer cells.	SIGNOR-277018	0.618
HSPH1	protein	Q92598	UNIPROT	HSPA1A	protein	P0DMV8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19754877	f		miannu	 Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress.	SIGNOR-255242	0.479
PPP2R5C	protein	Q13362	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates	dephosphorylation	Ser36	AQQVSSLsESEESQD	9606									20730097	t		lperfetto	We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf1	SIGNOR-167560	0.2
MED13L	protein	Q71F56	UNIPROT	CKM complex	complex	SIGNOR-C406	SIGNOR	form complex	binding			9606									23563140	t		miannu	The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation.	SIGNOR-266702	0.761
AKT1	protein	P31749	UNIPROT	CCDC88A	protein	Q3V6T2	UNIPROT	unknown	phosphorylation	Ser1417	INRERQKsLTLTPTR	9606									16139227	t		llicata	Akt phosphorylates serine at position 1416 in girdin, and phosphorylated girdin accumulates at the leading edge of migrating cells.	SIGNOR-252482	0.615
CDK2	protein	P24941	UNIPROT	RECQL4	protein	O94761	UNIPROT	up-regulates activity	phosphorylation	Ser251	EVSIRVGsPQPSSSG	9606	BTO:0002181								29229926	t		miannu	 During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs.	SIGNOR-277374	0.335
ADORA2B	protein	P29275	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257365	0.385
FYN	protein	P06241	UNIPROT	DCBLD2	protein	Q96PD2	UNIPROT	up-regulates activity	phosphorylation	Tyr732	CSSAQAQyDTPKAGK	-1									23770091	t	done	miannu	Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding.	SIGNOR-273947	0.357
NLGN4Y	protein	Q8NFZ3	UNIPROT	NRXN2	protein	Q9P2S2	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264153	0.2
PRKAA1	protein	Q13131	UNIPROT	BTRC	protein	Q9Y297	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser82	SLRQTYNsCARLCLN	9606	BTO:0002419								31406304	t		miannu	Glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1. 	SIGNOR-277475	0.2
CREB1	protein	P16220	UNIPROT	POMC	protein	P01189	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001073							11081181	t		lperfetto	Transcriptional activation of the proopiomelanocortin gene by cyclic AMP-responsive element binding protein|Further, expression of a dominant inhibitory mutant of CREB reduced cAMP stimulated transcription of the full length POMC promoter and the PTRE.	SIGNOR-268620	0.379
APH1A	protein	Q96BI3	UNIPROT	NCSTN	protein	Q92542	UNIPROT	up-regulates	binding			9606		BTO:0000142							12297508	t		gcesareni	By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.	SIGNOR-93259	0.967
JUN	protein	P05412	UNIPROT	SMAD3/JUN	complex	SIGNOR-C86	SIGNOR	form complex	binding			9606									9732876	t		gcesareni	These results show a ligand-dependent association of smad3 with c-jun	SIGNOR-59867	0.741
MAPK3	protein	P27361	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates	phosphorylation	Thr753	YACASPKtPIQAGGY	9606									16508002	t		gcesareni	Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity.	SIGNOR-144827	0.629
PSMD11	protein	O00231	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263351	0.899
GRK2	protein	P25098	UNIPROT	FPR1	protein	P21462	UNIPROT	down-regulates activity	phosphorylation	Ser332	TEDSTQTsDTATNST	-1									7836371	t		gcesareni	Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation.	SIGNOR-249680	0.2
ribosomal RNA	smallmolecule	CHEBI:18111	ChEBI	B-WICH complex	complex	SIGNOR-C447	SIGNOR	form complex	binding			9606									21559432	t		miannu	The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 	SIGNOR-269470	0.8
PYCARD	protein	Q9ULZ3	UNIPROT	NLRP1 inflammasome	complex	SIGNOR-C224	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256408	0.673
SEH1L	protein	Q96EE3	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262092	0.634
FGFR2	protein	P21802	UNIPROT	FGFR2	protein	P21802	UNIPROT	up-regulates activity	phosphorylation	Tyr769	TLTTNEEyLDLSQPL	9606	BTO:0000567								15629145	t		miannu	 Our data also show that tyrosine 769 is not involved in the regulation of the endocytic process of KGFR.Following ligand binding, KGFR is rapidly autophosphorylated on specific tyrosine residues	SIGNOR-276026	0.2
CSNK1A1	protein	P48729	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity	SIGNOR-183658	0.392
ITGB4	protein	P16144	UNIPROT	PMP22	protein	Q01453	UNIPROT	up-regulates activity	binding			10090									16436605	t	Regulation	miannu	PMP22 is in a complex with α6β4 integrin and laminin. PMP22 and β4 integrin are in a complex in a variety of cell types. The interaction with the integrins provides PMP22 with the ability to modulate the cell–ECM communications, as well as intracellular events. Signaling between the ECM and the intracellular compartment is essential for SC myelination, as well as cellular differentiation and motility, in general. The identification of PMP22 as a binding partner for an integrin signaling complex provides a major step toward understanding the role of this disease-linked molecule in the nervous system and in non-neural cell types.	SIGNOR-251896	0.382
PPM1D	protein	O15297	UNIPROT	MDM4	protein	O15151	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser403	DLAHSSEsQETISSM	9606									19808970	t		lperfetto	Here, we present evidence that Wip1 specifically dephosphorylates MdmX at Ser403 and indirectly suppresses phosphorylation of MdmX at Ser342 and Ser376.|Thus, Wip1 may need to be inhibited in the early stage of DNA damage response to facilitate rapid MdmX degradation.	SIGNOR-276951	0.444
4-aminopyridine	smallmolecule	CHEBI:34385	ChEBI	KCNJ13	protein	O60928	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9620703	t		miannu	Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations	SIGNOR-258924	0.8
FKBP5	protein	Q13451	UNIPROT	YY1	protein	P25490	UNIPROT	up-regulates activity				9606	BTO:0000848								34589486	f		miannu	FKBP51 Affects the Binding of YY1 Repressor to DR5 Gene. These results suggest that reduced YY1 DNA-binding activity in FKBP51-silenced cells corresponds to reduced YY1 acetylation.	SIGNOR-268792	0.2
KDM6A	protein	O15550	UNIPROT	HOXC11	protein	O43248	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24561908	t		miannu	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260026	0.308
SKP1	protein	P63208	UNIPROT	SCF-FBW7	complex	SIGNOR-C135	SIGNOR	form complex	binding			9606									15340381	t		gcesareni	The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions.	SIGNOR-243760	0.935
ATM	protein	Q13315	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	down-regulates	phosphorylation	Ser477	NSMNKLPsVSQLINP	9606									18769144	t		lperfetto	Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively	SIGNOR-180747	0.413
PSMB4	protein	P28070	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606									29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263355	0.885
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser167	GGRERLAsTNDKGSM	9606									11108261	t		lperfetto	Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt.	SIGNOR-244251	0.2
HMOX1	protein	P09601	UNIPROT	heme	smallmolecule	CHEBI:30413	ChEBI	down-regulates quantity	chemical modification			9606									16115609	t			The microsomal heme oxygenase system consists of heme oxygenase (HO) and NADPH-cytochrome P450 reductase, and plays a key role in the physiological catabolism of heme which yields biliverdin, carbon monoxide, and iron as the final products. Heme degradation proceeds essentially as a series of autocatalytic oxidation reactions involving heme bound to HO	SIGNOR-259333	0.8
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CDK1	protein	P06493	UNIPROT	down-regulates activity	chemical inhibition			-1									29901072	t		miannu	AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9.	SIGNOR-262218	0.8
PDK2	protein	Q15119	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates	phosphorylation	Ser300	SMSDPGVsYRTREEI	9606									17474719	t		gcesareni	Regulation of mammalian pdc activity is accomplished in large part by phosphorylation (resulting in inactivation) of the e1 component by a family of pyruvate dehydrogenase kinases (pdk 14 isozymes) and dephosphorylation (leading to activation) of phosphorylated e1 by a set of specific phosphatases (phosphopyruvate dehydrogenase phosphatase 12 isozymes) (1, 3-6). The subunit of the e1 component has three phosphorylation sites, named site 1 (ser-264), site 2 (ser-271), and site 3 (ser-203), and phosphorylation of any one of these three sites results in inactivation	SIGNOR-154640	0.667
ATP synthase	complex	SIGNOR-C264	SIGNOR	ATP	smallmolecule	CHEBI:15422	ChEBI	up-regulates quantity	chemical modification			9606									21874297	t		miannu	Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F(1), situated in the mitochondrial matrix, and F(o), located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. 	SIGNOR-261410	0.8
MC5R	protein	P33032	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257337	0.252
NFE2L2	protein	Q16236	UNIPROT	G6PD	protein	P11413	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22789539	f		miannu	We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). 	SIGNOR-267354	0.334
MC2R	protein	Q01718	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606									20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268694	0.496
CD40LG	protein	P29965	UNIPROT	PTPN7	protein	P35236	UNIPROT	down-regulates				9606	BTO:0000776								19047375	f		gcesareni	Coimmunoprecipitation and western blot analysis showed that heptp was phosphorylated in a pka-dependent manner, which inactivated heptp and allowed for increased free p38 mapk to be phosphorylated by the mapk cascade that was activated by cd40l	SIGNOR-182519	0.2
AURKB	protein	Q96GD4	UNIPROT	DSN1	protein	Q9H410	UNIPROT	down-regulates	phosphorylation	Ser100	RQSWRRAsMKETNRR	9606									20471944	t		lperfetto	To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant).	SIGNOR-165546	0.64
sunitinib	chemical	CHEBI:38940	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606									21993628	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-176748	0.8
UQCRH	protein	P07919	UNIPROT	Mitochondrial respiratory chain complex III	complex	SIGNOR-C279	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits	SIGNOR-262195	0.907
IL1RAPL2	protein	Q9NP60	UNIPROT	NCS1	protein	P62166	UNIPROT	up-regulates activity	binding			10116	BTO:0001009								12783849	t		miannu	IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.	SIGNOR-264476	0.327
FCRL3	protein	Q96P31	UNIPROT	PTPN11	protein	Q06124	UNIPROT	up-regulates activity	binding			-1									12051764	t		miannu	Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2.	SIGNOR-274014	0.392
CREBBP	protein	Q92793	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates	binding			9606			SIGNOR-C6						11062529	t		gcesareni	The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis.	SIGNOR-83843	0.675
CTCF	protein	P49711	UNIPROT	RARRES1	protein	P49788	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000356								22615834	f		miannu	 Epigenetic repression of RARRES1 is mediated by methylation of a proximal promoter and a loss of CTCF binding. knocking-down CTCF expression hampered RARRES1 expression, suggesting CTCF positively regulated RARRES1 transcription presumably by binding to unmethylated promoter poised at transcription-ready state. 	SIGNOR-253831	0.354
GAB1	protein	Q13480	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606									11043767	t		lperfetto	We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1.	SIGNOR-83343	0.428
POM121	protein	Q96HA1	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262071	0.465
C4B	protein	P0C0L5	UNIPROT	C3 convertase complex	complex	SIGNOR-C310	SIGNOR	form complex	binding			-1					cleavage:Arg756;Gly1446	KGQAGLQrALEILQE;TPLQLFEgRRNRRRR			17204478	t	complement C4b fragment:PRO_0000042703	lperfetto	 However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex	SIGNOR-263398	0.655
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	TTK	protein	P33981	UNIPROT	up-regulates				9606									19151762	f		lperfetto	Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68	SIGNOR-242619	0.7
MEN1	protein	O00255	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates	binding			9606									12874027	t		miannu	Menin interacts with fancd2 / loss of menin expression in mouse embryonic fibroblasts leads to increased sensitivity to dna damage. Furthermore, menin is localized to chromatin and nuclear matrix, and the association with nuclear matrix is enhanced by gamma-irradiation. Together, these results suggest that menin plays a critical role in repair of dna damage in concert with fancd2.	SIGNOR-103947	0.453
ROCK1	protein	Q13464	UNIPROT	ARHGAP24	protein	Q8N264	UNIPROT	up-regulates activity	phosphorylation	Thr577	SCRSSTTtCPEQDFF	9606	BTO:0000007								16862148	t		lperfetto	ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2).	SIGNOR-249301	0.444
CSNK2A1	protein	P68400	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	down-regulates	phosphorylation	Ser1479	HVYEKLSsIESDV	9606	BTO:0000938								15537897	t		gcesareni	Here we show that casein kinase ii (ck2) phosphorylates the serine residue (ser1480) within the c-terminal pdz ligand (iesdv) of the nr2b subunit of nmdar in vitro and in vivo. Phosphorylation of ser1480 disrupts the interaction of nr2b with the pdz domains of psd-95 and sap102 and decreases surface nr2b expression in neurons.	SIGNOR-130336	0.329
MRGPRX1	protein	Q96LB2	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257058	0.252
DLK1	protein	P80370	UNIPROT	SOX9	protein	P48436	UNIPROT	up-regulates	transcriptional regulation			9606									19254573	f		fspada	Pref-1 inhibits adipocyte differentiation through upregulating sox9 expression.	SIGNOR-209968	0.402
BACE2	protein	Q9Y5Z0	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Phe709	ENPTYKFfEQMQN	9606									10931940	t		lperfetto	BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating α- and β-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform.	SIGNOR-261779	0.561
PPP1CC	protein	P36873	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0002419								14633703	t			Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells	SIGNOR-248502	0.392
GRB7	protein	Q14451	UNIPROT	RND1	protein	Q92730	UNIPROT	up-regulates	binding			9606	BTO:0000150								10664463	t		gcesareni	We would like to propose that when cells are driven to divide by growth factor stimulation, grb7 relocalizes at the membrane, in the same subcellular compartment as rnd1, where they could interact in vivo.	SIGNOR-74914	0.612
PPP2CA	protein	P67775	UNIPROT	PP2Ca_R1A_Bd	complex	SIGNOR-C134	SIGNOR	form complex	binding			9606									23454242	t		gcesareni	[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity.	SIGNOR-243433	0.903
FGF12	protein	P61328	UNIPROT	SCN3A	protein	Q9NY46	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253444	0.237
PDPK1	protein	O15530	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Thr308	KDGATMKtFCGTPEY	9606									12808134	t		lperfetto	Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1).	SIGNOR-252611	0.736
PRKCA	protein	P17252	UNIPROT	SNAP25	protein	P60880	UNIPROT	unknown	phosphorylation	Thr138	GGFIRRVtNDARENE	9606									12459461	t		lperfetto	This study establishes that SNAP-25 is differentially phosphorylated by protein kinase C and protein kinase A in neuroendocrine PC12 cells. Using phosphopeptide mapping and site-directed mutagenesis we identified both Thr138 and Ser187 as the targets of SNAP-25 phosphorylation by protein kinase C	SIGNOR-249179	0.359
E2F1	protein	Q01094	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12110166	f		fspada	We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation	SIGNOR-90459	0.474
JAK2	protein	O60674	UNIPROT	ATOH1	protein	Q92858	UNIPROT	up-regulates quantity	phosphorylation	Tyr80	CTARAAQyLLHSPEL	9606	BTO:0004328								29168692	t		Gianni	We discovered tyrosine 78 of Atoh1 is phosphorylated by a Jak2-mediated pathway only in tumor-initiating cells and in human SHH-type medulloblastoma. Phosphorylation of tyrosine 78 stabilizes Atoh1, increases Atoh1’s transcriptional activity, and is independent of canonical Jak2 signaling.	SIGNOR-262201	0.346
CELF1	protein	Q92879	UNIPROT	EIF2S1	protein	P05198	UNIPROT	up-regulates activity	binding			10090		BTO:0000759							16931514	t		miannu	 These studies showed that both the increased levels of CUGBP1 and cdk4-mediated hyper-phosphorylation of CUGBP1 are involved in the age-associated induction of the CUGBP1-eIF2 complex. The CUGBP1-eIF2 complex is bound to C/EBPbeta mRNA in the liver of old animals, and this binding correlates with the increased amounts of liver-enriched activator protein and liver-enriched inhibitory protein.	SIGNOR-262736	0.253
PLK1	protein	P53350	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates	phosphorylation	Ser260	SLDSEDYsLSEEGQE	9606									19833129	t		gcesareni	Polo-like kinase-1 phosphorylates mdm2 at ser260 and stimulates mdm2-mediated p53 turnover.	SIGNOR-188471	0.478
GPR132	protein	Q9UNW8	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257444	0.376
UMPS	protein	P11172	UNIPROT	Pyrimidine_nucleotide_metabolic_process	phenotype	SIGNOR-PH85	SIGNOR	up-regulates													26059768	f		miannu	The bifunctional enzyme UMP synthase leads to the synthesis of uridine 5′-monophosphate (UMP). UMP could be considered one of the hub molecules in pyrimidine metabolism because it is the precursor of other pyrimidine nucleotides.	SIGNOR-253582	0.7
PRKCE	protein	Q02156	UNIPROT	ADAP1	protein	O75689	UNIPROT	unknown	phosphorylation	Thr276	GFRKRWFtMDDRRLM	-1									12893243	t		lperfetto	The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ | The phosphorylation site analysis was carried out twice after phosphorylation of centaurin-alpha1‚ with PKCalpha and once with PKC_. A similar pattern of phosphopeptides was obtained each time.	SIGNOR-249226	0.318
CSNK2A1	protein	P68400	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates	phosphorylation	Ser39	MKKIRLEsEEEGVPS	9606									15788687	t		lperfetto	Additionally, transfection of cdc2 with a mutation at ser(39) to ala, which is the ck2 phosphorylation site, partially inhibits cell cycle progression in g(1) to g(2) phase following 6-tg treatment.	SIGNOR-134846	0.361
EGR1	protein	P18146	UNIPROT	HSD11B2	protein	P80365	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15659537	f		miannu	 Overexpression of p50 inhibited HSD11B2 promoter activity and overexpression of Egr-1 inhibited transactivation of the HSD11B2 promoter by p65/p50. 	SIGNOR-253876	0.28
MAPK3	protein	P27361	UNIPROT	MKNK1	protein	Q9BUB5	UNIPROT	up-regulates	phosphorylation			9606									9155017	t		gcesareni	We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2.	SIGNOR-48352	0.556
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation	Ser259	SQRQRSTsTPNVHMV	9606	BTO:0000150;BTO:0001130								16854453	t		lperfetto	Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity.	SIGNOR-244337	0.2
motesanib	chemical	CHEBI:51098	ChEBI	RET	protein	P07949	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194572	0.8
INSR	protein	P06213	UNIPROT	PTPN1	protein	P18031	UNIPROT	up-regulates activity	phosphorylation	Tyr152	ISEDIKSyYTVRQLE	-1									11506178	t		lperfetto	Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B	SIGNOR-249368	0.778
INSR	protein	P06213	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates activity	phosphorylation	Tyr700	EGEEDTEyMTPSSRP	10090									11997497	t			Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation.	SIGNOR-251305	0.506
Av/b1 integrin	complex	SIGNOR-C175	SIGNOR	NANOG	protein	Q9H9S0	UNIPROT	up-regulates quantity by expression				10090									18757303	f		lperfetto	Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1.	SIGNOR-253276	0.328
LDHB	protein	P07195	UNIPROT	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	up-regulates				9606	BTO:0000164								34929314	f		lperfetto	LDHB is a glycolytic enzyme that catalyzes the conversion of lactic acid and NAD+ into pyruvate, NADH and H+. 	SIGNOR-267654	0.7
CDK1	protein	P06493	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	down-regulates activity	phosphorylation	Ser83	PRRSPRIsFFLEKEN	-1									23901111	t		miannu	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. 	SIGNOR-276118	0.699
MAP2K6	protein	P52564	UNIPROT	MAPK13	protein	O15264	UNIPROT	up-regulates	phosphorylation			9606									11242034	t		gcesareni	Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily.	SIGNOR-105698	0.645
KIF5B	protein	P33176	UNIPROT	SYBU	protein	Q9NX95	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								15459722	t		miannu	Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes.	SIGNOR-264811	0.578
SP3	protein	Q02447	UNIPROT	SCNN1A	protein	P37088	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004299								12684058	f	Regulation of expression	miannu	Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression.	SIGNOR-251951	0.2
CTDNEP1	protein	O95476	UNIPROT	BMPR1A	protein	P36894	UNIPROT	up-regulates	binding			9606									17141153	t		lperfetto	We show that dullard promotes the ubiquitin-mediated proteosomal degradation of bmp receptors (bmprs). Dullard preferentially complexes with the bmp type ii receptor (bmprii) and partially colocalizes with the caveolin-1-positive compartment, suggesting that dullard promotes bmpr degradation via the lipid raft-caveolar pathway	SIGNOR-150998	0.295
MYCBP2	protein	O75592	UNIPROT	RAN	protein	P62826	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			10090									26304119	t		Monia	MYCBP2 Is a Nuclear GEF for Ran in DRG Neurons—Next, we studied whether or not MYCBP2 modulates the interaction between Ran/RanGAP1. MYCBP2 contains an N-terminal RCC1-like domain (Fig. 8C) (13), and RCC1 is a known GEF for Ran, indicating a potential functional interaction between MYCBP2 and Ran.	SIGNOR-261204	0.3
(-)-anisomycin	chemical	CHEBI:338412	ChEBI	FOSB	protein	P53539	UNIPROT	up-regulates	chemical activation			9606									Other	t	CellSignaling	gcesareni		SIGNOR-189629	0.8
DAXX	protein	Q9UER7	UNIPROT	FAS	protein	P25445	UNIPROT	down-regulates	binding			9606									9215629	t		gcesareni	A c-terminal portion of daxx interacts with the fas death domain. The fas-binding domain of daxx is a dominant-negative inhibitor of both fas-induced apoptosis and jnk activation.	SIGNOR-49473	0.69
PDK2	protein	Q15119	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates	phosphorylation	Ser300	SMSDPGVsYRTREEI	-1									7782287	t		gcesareni	Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase.	SIGNOR-33141	0.667
HIF1A	protein	Q16665	UNIPROT	FAM162A	protein	Q96A26	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15082785	t		Giulio	In this work, we report the identification of an HIF-1 alpha-responsive proapoptotic molecule, HGTD-P. Its expression was directly regulated by HIF-1 alpha through a hypoxia-responsive element on the HGTD-P promoter region.	SIGNOR-260292	0.286
SNX9	protein	Q9Y5X1	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates				9606									11799118	f		gcesareni	We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor.The cdc42 target ack2 interacts with sorting nexin 9 (sh3px1) to regulate epidermal growth factor receptor degradation.	SIGNOR-114167	0.556
SMURF1	protein	Q9HCE7	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	ubiquitination			9606									22298955	t	Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes	gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps	SIGNOR-195660	0.695
copper(1+)	smallmolecule	CHEBI:49552	ChEBI	SOD1	protein	P00441	UNIPROT	up-regulates activity	chemical activation												1542024	t		lperfetto	Copper as a cofactor and regulator of copper,zinc superoxide dismutase	SIGNOR-272299	0.8
naltrexone	chemical	CHEBI:7465	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258767	0.8
MTOR	protein	P42345	UNIPROT	MKNK2	protein	Q9HBH9	UNIPROT	down-regulates activity	phosphorylation	Ser74	KRGRATDsFSGRFED	9606	BTO:0000007								32170339	t		miannu	MTOR phosphorylates MNK2a on Ser74. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G. 	SIGNOR-277516	0.278
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	BCL2L1	protein	Q07817	UNIPROT	down-regulates	phosphorylation	Ser62	PSWHLADsPAVNGAT	9606	BTO:0001130								12633850	t		lperfetto	We have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation in summary, our studies suggest that the phosphorylation of bcl-xl by stress response kinase signaling might oppose the anti-apoptotic function of bcl-xl	SIGNOR-99215	0.2
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Ile)	smallmolecule	CHEBI:29174	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269501	0.8
NOTCH1	protein	P46531	UNIPROT	TCF12	protein	Q99081	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22577461	f		miannu	E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r.	SIGNOR-197514	0.374
H2BC11	protein	P06899	UNIPROT	Nucleosome_H3.3 variant	complex	SIGNOR-C339	SIGNOR	form complex	binding			9606									15776021	t		miannu	Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes.	SIGNOR-263875	0.2
AURKB	protein	Q96GD4	UNIPROT	KIF2C	protein	Q99661	UNIPROT	down-regulates	phosphorylation	Ser111	KESLRSRsTRMSTVS	9606									17567953	t		lperfetto	Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres.	SIGNOR-155894	0.72
HMGB2	protein	P26583	UNIPROT	POU2F2	protein	P09086	UNIPROT	up-regulates activity	binding			10090									7720710	t	2	miannu	HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins	SIGNOR-240108	0.325
SCRIB	protein	Q14160	UNIPROT	Synaptic_vesicle_exocytosis	phenotype	SIGNOR-PH160	SIGNOR	up-regulates				9606	BTO:0000938								19458197	f		miannu	Our data supports a model by which scribble functions downstream of beta-catenin to cluster synaptic vesicles at developing synapses.	SIGNOR-265827	0.7
ZAP70	protein	P43403	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	phosphorylation	Tyr126	RDAMVRDyVRQTWKL	9606	BTO:0000661								7961936	t		lperfetto	We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. By comparative two-dimensional phosphopeptide mapping, we show that ZAP-70 isolated from Jurkat T cells also autophosphorylates at Tyr-292 and Tyr-126	SIGNOR-247044	0.2
BMPR1A	protein	P36894	UNIPROT	SOST	protein	Q9BQB4	UNIPROT	up-regulates				9606									19874086	f		gcesareni	These results demonstrate that bmpria in osteoblasts negatively regulates endogenous bone mass and wnt/beta-catenin signaling and that this regulation may be mediated by the activities of sost and dkk1.	SIGNOR-188958	0.337
GABRG2	protein	P18507	UNIPROT	GABA-A (a3-b1-g2) receptor	complex	SIGNOR-C332	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263758	0.62
MAP3K3	protein	Q99759	UNIPROT	MAP2K6	protein	P52564	UNIPROT	up-regulates				9606									10347227	f		gcesareni	However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2.	SIGNOR-68020	0.408
mTORC1	complex	SIGNOR-C3	SIGNOR	APOB	protein	P04114	UNIPROT	down-regulates quantity by repression	translation regulation			9606									23721961	f		miannu	Activation of mTORC1 also has dual effects on ApoB synthesis: it inhibits ApoB secretion by decreasing ApoB translation, but promotes ApoB secretion by inhibiting sortilin.	SIGNOR-252117	0.274
TUBGCP4	protein	Q9UGJ1	UNIPROT	g-TuRC complex	complex	SIGNOR-C282	SIGNOR	form complex	binding			-1									31862189	t		lperfetto	Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.”	SIGNOR-262328	0.813
F2R	protein	P25116	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257219	0.564
AMPK	complex	SIGNOR-C15	SIGNOR	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSSN	10116									11069105	t			AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells. AMPK-mediated PFK-2 activation is likely to be involved in the stimulation of heart glycolysis during ischaemia.	SIGNOR-260011	0.391
FN1	protein	P02751	UNIPROT	SDC4	protein	P31431	UNIPROT	up-regulates activity	binding			9606									23290138	t		apalma	Sdc4 is a high affinity receptor for fibronectin (FN) […] Therefore, we conclude that Sdc4 binds FN on activated satellite cells.	SIGNOR-255846	0.7
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser756	HSCLEQAs	9606									10195894	t			Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.	SIGNOR-251284	0.2
JARID2	protein	Q92833	UNIPROT	GATA4	protein	P43694	UNIPROT	down-regulates activity	binding			10116	BTO:0003324								15542826	t		miannu	JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4.	SIGNOR-224697	0.468
F2RL1	protein	P55085	UNIPROT	CORO1C	protein	Q9ULV4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254838	0.2
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser180	GSSASFIsDTFSPYT	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248684	0.613
FGF2	protein	P09038	UNIPROT	ENPP1	protein	P22413	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004473								19049325	f		miannu	FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2.	SIGNOR-252191	0.26
PPARG	protein	P37231	UNIPROT	ACADM	protein	P11310	UNIPROT	down-regulates activity	binding			9606	BTO:0001370								28974683	t		Federica	This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation	SIGNOR-261264	0.354
DLC1	protein	Q96QB1	UNIPROT	MYH9	protein	P35579	UNIPROT	down-regulates activity	binding			9606	BTO:0004006						phosphorylation:Ser1943	RKGAGDGsDEEVDGK	26977077	t		miannu	Our study has shown that Dlc1 interacts with non-muscle myosin heavy chain II-A (Myh9), plectin and spectrin proteins in different multiprotein complexes. Overexpression of Dlc1 led to increased phosphorylation of Myh9 protein and activation of Rac1 GTPase. Dlc1 interacts with phosphorylated Myh9 (Ser-1943). This association of Dlc1 with S1943 phosphorylated Myh9, suggests that Dlc1 may be involved in reduced Myh9 filament stability.	SIGNOR-269283	0.2
PIP5K1C	protein	O60331	UNIPROT	ADP(3-)	smallmolecule	CHEBI:456216	ChEBI	up-regulates quantity	chemical modification			9606									9367159	t		miannu	Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities	SIGNOR-277287	0.8
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	MEF2C	protein	Q06413	UNIPROT	down-regulates	binding			9606									21902831	t		lperfetto	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-216963	0.292
NDUFA5	protein	Q16718	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46].	SIGNOR-262156	0.821
9-cis-retinoic acid	chemical	CHEBI:50648	ChEBI	RXRG	protein	P48443	UNIPROT	up-regulates activity	chemical activation			9606									18321241	t		miannu	Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma).	SIGNOR-259239	0.8
GPR119	protein	Q8TDV5	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257415	0.252
3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide	chemical	CHEBI:92223	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-201695	0.8
PPP1CB	protein	P62140	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606									14633703	t			Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells	SIGNOR-252604	0.394
CHUK	protein	O15111	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	down-regulates activity	phosphorylation	Ser418	TTENRFHsLPFSLTK	9606	BTO:0000938								24614225	t		lperfetto	Thus, serine 418 is phosphorylated in vivo. Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204688	0.524
GPHN	protein	Q9NQX3	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606	BTO:0000938								25882190	f		miannu	Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses.	SIGNOR-264975	0.7
PTPN1	protein	P18031	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates	dephosphorylation	Tyr1234	RDMYDKEyYSVHNKT	9606									16537444	t		gcesareni	Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion.	SIGNOR-145141	0.621
MEF2C	protein	Q06413	UNIPROT	MYH2	protein	Q9UKX2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0001103							15728583	t		lperfetto	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238718	0.443
STK38	protein	Q15208	UNIPROT	STK38	protein	Q15208	UNIPROT	up-regulates	phosphorylation	Ser281	NRRQLAFsTVGTPDY	9606									12493777	t		lperfetto	We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo	SIGNOR-96679	0.2
MRGPRX2	protein	Q96LB1	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257059	0.2
PICK1	protein	Q9NRD5	UNIPROT	ASIC1	protein	P78348	UNIPROT	up-regulates activity	relocalization			10116	BTO:0000938								11802773	t		miannu	we found that the PDZ domain-containing protein PICK1 (protein interacting with C kinase) interacts specifically with the C-termini of BNC1 and ASIC. Our studies showing association of recombinant PICK1 with ASIC and BNC1, and the presence of both PICK1 and ASIC in the synaptosomal fraction	SIGNOR-223417	0.554
PTGIR	protein	P43119	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257078	0.409
TRPS1	protein	Q9UHF7	UNIPROT	GDF5	protein	P43026	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0005092								18363966	f	Regulation of expression	miannu	Treatment of cells with Gdf5 enhanced Trps1 protein levels and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner. Nuclear translocation of Trps1 was also induced by Gdf5. These effects were blocked by a dominant negative form of activin-linked kinase 6 (dn-Alk6) and by SB203580, an inhibitor of the p38 MAPK pathway. Conversely, Gdf5 expression was suppressed by the over-expression of Trps1.	SIGNOR-251866	0.311
APH1B	protein	Q8WW43	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates	binding			9606									12522139	t		gcesareni	Biochemical and genetic studies have recently identified nicastrin, aph-1, and pen-2 as essential cofactors that physically interact with ps1 and are necessary for the gamma-secretase activity.	SIGNOR-97107	0.907
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	LIPE	protein	Q05469	UNIPROT	up-regulates activity	phosphorylation	Ser951	GFHPRRSsQGATQMP										19018281	t		miannu	 Our results demonstrate that PKA activates human HSL against lipid substrates in vitro primarily through phosphorylation of Ser649 and Ser650. 	SIGNOR-276175	0.2
CDK1	protein	P06493	UNIPROT	NUMA1	protein	Q14980	UNIPROT	down-regulates	phosphorylation	Thr2055	MAFSILNtPKKLGNS	9606									23921553	t		llicata	Cdk1-mediated phosphorylation at t2055 negatively regulates numa cortical localization and that this phosphorylation is counteracted by ppp2ca phosphatase activity.	SIGNOR-194825	0.571
APC-c	complex	SIGNOR-C150	SIGNOR	KIF2C	protein	Q99661	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								25504441	t		miannu	Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. 	SIGNOR-276864	0.281
ruxolitinib	chemical	CHEBI:66919	ChEBI	JAK2	protein	O60674	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206670	0.8
UPF2	protein	Q9HAU5	UNIPROT	UPF1	protein	Q92900	UNIPROT	up-regulates activity	binding			-1									18066079	t		miannu	UPF2 and UPF3b increase UPF1 ATPase activity	SIGNOR-265246	0.979
GATOR2	complex	SIGNOR-C193	SIGNOR	GATOR1	complex	SIGNOR-C192	SIGNOR	down-regulates activity	binding			7227									23723238	t			Thus, GATOR2 is an inhibitor of an inhibitor (GATOR1) of the amino acid sensing branch of the TORC1 pathway	SIGNOR-253564	0.825
GOLGA2	protein	Q08379	UNIPROT	GORASP1	protein	Q9BQQ3	UNIPROT	up-regulates activity	binding			9606									23555793	t		miannu	The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane.	SIGNOR-261239	0.875
DUSP5	protein	Q16690	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	down-regulates	dephosphorylation			9606									10224087	t	inferred from 70% of family members	gcesareni	Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway	SIGNOR-269912	0.2
RIMS2	protein	Q9UQ26	UNIPROT	RAB3A	protein	P20336	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								31679900	t		miannu	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264377	0.758
CPSF complex	complex	SIGNOR-C53	SIGNOR	PAPOLA	protein	P51003	UNIPROT	up-regulates activity	relocalization			9606									14749727	t		lperfetto	Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna.	SIGNOR-268323	0.787
RPL13A	protein	P40429	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262485	0.83
TSHZ3	protein	Q63HK5	UNIPROT	CASP4	protein	P49662	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000938								19343227	t		miannu	Chromatin immunoprecipitation showed a direct interaction of FE65 and Teashirt3 with the promoter region of CASP4. The results were consistent with a model in which reduced expression of Teashirt3, mediated by genetic or other causes, increases caspase-4 expression, leading to progression of AD. 	SIGNOR-264815	0.274
ARHGEF2	protein	Q92974	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260529	0.799
SNRNP40	protein	Q96DI7	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270644	0.699
DNMT3B	protein	Q9UBC3	UNIPROT	HOXB13	protein	Q92826	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001033								22808286	f	 	miannu	 EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex.	SIGNOR-254145	0.259
MC3R	protein	P41968	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257026	0.252
RAC3	protein	P60763	UNIPROT	CIB1	protein	Q99828	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								11756406	t		Gianni	We here report that CIB, a protein that binds to the alpha(IIb)beta(3) fibrinogen receptor, interacts exclusively with activated (V12) Rac3 but not Rac1 or Rac2. Binding of V12Rac3 to CIB was mediated by the C-terminal end of Rac3 and by Rac3 membrane localization	SIGNOR-269060	0.354
EEF1A2	protein	Q05639	UNIPROT	Pro-tRNA(Pro)	smallmolecule	CHEBI:29154	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269534	0.8
PRKCZ	protein	Q05513	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser304	GAPPRRSsIRNAHSI	9606									12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89260	0.402
SPI1	protein	P17947	UNIPROT	TAL2	protein	Q16559	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24086757	f		irozzo	We show that Tal2 is a direct target gene of the myeloid transcription factor PU.1, which is a key transcription factor for osteoclast gene expression	SIGNOR-259086	0.2
NOTCH1	protein	P46531	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates	binding			9606	BTO:0000776								9528794	t		gcesareni	We provide evidence that notch and deltex may act on e47 by inhibiting signaling through ras because (i) full e47 activity was found to be dependent on ras and (ii) both notch and deltex inhibited gal4-jun, a hybrid transcription factor whose activity is dependent on signaling from ras to sapk/jnk.	SIGNOR-56150	0.438
IFNG	protein	P01579	UNIPROT	S100A10	protein	P60903	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567;BTO:0002923								12645529	f		miannu	The effect of interferon (IFN)-gamma on p11 expression was studied in two human epithelial cell lines (BEAS-2B and HeLa). Treatment with IFN-gamma resulted in increased steady-state levels of p11 mRNA and protein expression, with a time-dependent and dose-dependent effect. 	SIGNOR-255236	0.27
SRC	protein	P12931	UNIPROT	DDR2	protein	Q16832	UNIPROT	up-regulates	phosphorylation	Tyr741	NLYSGDYyRIQGRAV	9606									16186108	t		gcesareni	Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues.	SIGNOR-140767	0.388
MAPK3	protein	P27361	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser344	QDDDAPLsPMLYSSS	9606									19282669	t		lperfetto	Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway	SIGNOR-252962	0.583
ZNF503	protein	Q96F45	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity				10090									25538248	f		Monia	Zpo2-overexpressing cells demonstrated high levels of pFAK compared with the control (Fig. 6A). Additionally, Western blot analysis indicated that, in response to Zpo2 expression, both EpH4.9 and PyMT cells increase FAK activity, as demonstrated by higher levels of pFAK staining (Fig. 6B).	SIGNOR-261191	0.2
PAK5	protein	Q9P286	UNIPROT	GATA1	protein	P15976	UNIPROT	up-regulates activity	phosphorylation	Ser161	SSLPVPNsAYGGPDF	9606	BTO:0000150								25726523	t		lperfetto	GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. 	SIGNOR-275655	0.2
ELANE	protein	P08246	UNIPROT	F5	protein	P12259	UNIPROT	up-regulates activity	cleavage	Ile847	LQPDVTGiRLLSLGA	-1									9242537	t		lperfetto	Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex. 	SIGNOR-263637	0.373
EGFR	protein	P00533	UNIPROT	PCNA	protein	P12004	UNIPROT	up-regulates	phosphorylation	Tyr211	QLTFALRyLNFFTKA	9606	BTO:0000150								17115032	t		lperfetto	Here, we show that the chromatin-bound pcna protein is phosphorylated on tyr 211, which is required for maintaining its function on chromatin and is dependent on the tyrosine kinase activity of egf receptor (egfr) in the nucleus. Phosphorylation on tyr 211 by egfr stabilizes chromatin-bound pcna protein and associated functions.	SIGNOR-150852	0.346
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRID1	protein	Q9ULK0	UNIPROT	up-regulates activity	chemical activation			9606									27586965	t		miannu	Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors	SIGNOR-264468	0.8
PYY	protein	P10082	UNIPROT	NPY4R	protein	P50391	UNIPROT	up-regulates	binding			9606									7592911	t		gcesareni	Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid.	SIGNOR-29767	0.656
MIB1	protein	Q86YT6	UNIPROT	SMN1	protein	Q16637	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								23615451	t		miannu	In this study, we show that the E3 ubiquitin ligase, mind bomb 1 (Mib1), interacts with and ubiquitinates SMN and facilitates its degradation. Knocking down Mib1 levels increases SMN protein levels in cultured cells. 	SIGNOR-272664	0.328
RUNX1	protein	Q01196	UNIPROT	ITGA2B	protein	P08514	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17725493	f	 	miannu	 We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. 	SIGNOR-254193	0.472
PRKACA	protein	P17612	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								16199882	t		gcesareni	Although pka did not affect the formation of a complex between glycogen synthase kinase 3beta (gsk-3beta), beta-catenin, and axin, phosphorylation of beta-catenin by pka inhibited ubiquitination of beta-catenin in intact cells and in vitro.	SIGNOR-140902	0.459
MARK2	protein	Q7KZI7	UNIPROT	KIF13B	protein	Q9NQT8	UNIPROT	down-regulates activity	phosphorylation	Ser1410	SNKGRWEsQQDVSQT	9534	BTO:0000298								20194617	t		miannu	We report here the identification of GAKIN/KIF13B as a novel in vivo substrate for Par1b and present evidence that GAKIN/KIF13B plays a critical role in axon formation in neurons, which is negatively regulated by Par1b-mediated phosphorylation. Par1b phosphorylates GAKIN/KIF13B at both Ser1381 and Ser1410.	SIGNOR-262956	0.425
SMAD7	protein	O15105	UNIPROT	TAB3	protein	Q8N5C8	UNIPROT	up-regulates	binding			9606									17384642	t		gcesareni	The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling.	SIGNOR-153920	0.391
ROCK1	protein	Q13464	UNIPROT	ADD1	protein	P35611	UNIPROT	up-regulates	phosphorylation	Thr445	QKQQREKtRWLNSGR	9606		BTO:0000671							10209029	t		lperfetto	Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480	SIGNOR-66992	0.384
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11486031	f		gcesareni	Moreover, as determined by using coimmunoprecipitation assays, each maml protein was found to be capable of forming a multiprotein complex with the intracellular domain of each notch receptor (icn1 to -4) and csl in vivo	SIGNOR-254349	0.2
ACTL6B	protein	O94805	UNIPROT	Muscle cell-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C483	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex.	SIGNOR-270740	0.7
SH3GLB1	protein	Q9Y371	UNIPROT	Endocytosis	phenotype	SIGNOR-PH123	SIGNOR	up-regulates				9606									25517094	f		miannu	Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. 	SIGNOR-263886	0.7
PRKCA	protein	P17252	UNIPROT	HMGN1	protein	P05114	UNIPROT	down-regulates	phosphorylation	Ser25	KRRSARLsAKPPAKV	9606									10739259	t		lperfetto	Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.	SIGNOR-76286	0.311
prostaglandin H2(1-)	smallmolecule	CHEBI:57405	ChEBI	prostaglandin E2(1-)	smallmolecule	CHEBI:606564	ChEBI	up-regulates quantity	precursor of			-1									10922363	t		Luana	Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently.	SIGNOR-269765	0.8
TNFRSF6B	protein	O95407	UNIPROT	FASLG	protein	P48023	UNIPROT	down-regulates	binding			9606	BTO:0001271;BTO:0000661	BTO:0000763							10318773	t		amattioni	Tr6 specifically binds fas ligand. Tr6 may play a regulatory role for suppressing in fasl- mediated cell death.	SIGNOR-67434	0.671
SMARCD2	protein	Q92925	UNIPROT	Brain-specific SWI/SNF SMARCA2 variant	complex	SIGNOR-C485	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270745	0.771
ISYNA1	protein	Q9NPH2	UNIPROT	1D-myo-inositol 1-phosphate	smallmolecule	CHEBI:18297	ChEBI	up-regulates quantity	chemical modification			9606									15464731	t	 	lperfetto	Human myo-inositol 1-phosphate synthase (IP synthase; E.C. 5.5.1.4), encoded by ISYNA1, catalyzes the de novo synthesis of inositol 1-phosphate from glucose 6-phosphate.	SIGNOR-254131	0.8
POLR1B	protein	Q9H9Y6	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding												22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266154	0.866
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BS1	protein	P57053	UNIPROT	down-regulates activity	monoubiquitination	Lys35	RKRKRSRkESYSVYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271984	0.2
TAGAP	protein	Q8N103	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260523	0.424
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr522	SSPGSPGtPGSRSRT	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249322	0.754
AKT2	protein	P31751	UNIPROT	CYCS	protein	P99999	UNIPROT	down-regulates activity	phosphorylation	Tyr47	KTGQAPGySYTAANK	-1									32781572	t		miannu	Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.	SIGNOR-277236	0.298
CREBBP	protein	Q92793	UNIPROT	MYBL1	protein	P10243	UNIPROT	up-regulates activity	binding			9534									9210395	t	2	miannu	CBP co-operates functionally with A-Myb	SIGNOR-240984	0.492
GRK3	protein	P35626	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser373	SMGTLRTsISVERQI	9606	BTO:0000007								11517230	t		gcesareni	...expression of GRK4Ž drastically increased the basal level of32P incorporation into B2R.[€]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation.	SIGNOR-249658	0.2
GSK3B	protein	P49841	UNIPROT	JUNB	protein	P17275	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser251	QTVPEARsRDATPPV	9606	BTO:0000567								22710716	t		miannu	 Thus, JunB phosphorylation at S251 and T255 by GSK3β is primed by phosphorylation at S259 by a yet to-be-identified kinase.Phosphorylation at S251, T255 and S259 is required for JunB degradation. 	SIGNOR-276418	0.2
PPM1D	protein	O15297	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser395	SQESEDYsQPSTSSS	9606									17936559	t			Here we show that the wild-type p53-induced phosphatase 1 (Wip1), or PPM1D, downregulates p53 protein levels by stabilizing Mdm2 and facilitating its access to p53. Wip1 interacts with and dephosphorylates Mdm2 at serine 395, a site phosphorylated by the ATM kinase. 	SIGNOR-248324	0.669
CTNND2	protein	Q9UQB3	UNIPROT	CDH2	protein	P19022	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0001109								14610055	t		miannu	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 	SIGNOR-252131	0.476
IRX1	protein	P78414	UNIPROT	ERMAP	protein	Q96PL5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002392								20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed.	SIGNOR-261667	0.2
ZNRF3	protein	Q9ULT6	UNIPROT	FZD2	protein	Q14332	UNIPROT	down-regulates	relocalization			9606									23151663	t		gcesareni	Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6.	SIGNOR-199650	0.297
bisphenol F	chemical	CHEBI:34575	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			-1									31995776	t		miannu	This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . 	SIGNOR-268731	0.8
DGC	complex	SIGNOR-C217	SIGNOR	GABA-A (a2-b1-g2) receptor	complex	SIGNOR-C331	SIGNOR	up-regulates quantity	binding			9606	BTO:0000938;BTO:0002606								22626542	t		miannu	 In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses.	SIGNOR-265433	0.2
FBXL12	protein	Q9NXK8	UNIPROT	CAMK1	protein	Q14012	UNIPROT	down-regulates quantity	ubiquitination			10090	BTO:0002268								23707388	t		Monia	Here, we show that a ubiquitin E3 ligase component, F-box protein Fbxl12, mediates CaMKI degradation via a proteasome-directed pathway leading to disruption of cyclin D1/cdk4 complex. Endogenous Fbxl12 and CaMKI interacted as demonstrated after Fbxl12 immuno-precipitation followed by immunoblot analysis with CaMKI antibodies assembly and resultantG1 arrest in lung epithelia. Fbxl12 targets CaMKI for ubiquitination.	SIGNOR-261193	0.489
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	PPARG	protein	P37231	UNIPROT	up-regulates	binding			9606									18596912	t		lperfetto	The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform.	SIGNOR-244971	0.2
SMARCC2	protein	Q8TAQ2	UNIPROT	Brain-specific SWI/SNF SMARCA2 variant	complex	SIGNOR-C485	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270746	0.837
PPP1CA	protein	P62136	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0002419								14633703	t			Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells	SIGNOR-248559	0.436
TNF	protein	P01375	UNIPROT	TNFRSF1A	protein	P19438	UNIPROT	up-regulates activity	binding			9606									21133840	t		simone vumbaca	TNF alpha and IFN gamma exhibit a cross-talk at the level of TNFR1 to induce activation of macrophages	SIGNOR-256025	0.923
HCK	protein	P08631	UNIPROT	CSF3R	protein	Q99062	UNIPROT	up-regulates activity	phosphorylation	Tyr752	GTSDQVLyGQLLGSP	-1									9790917	t			Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling. the ability of Hck to phosphorylate the G-CSF-R in vitro, both Y728 and Y763 fit the Src consensus phosphorylation site	SIGNOR-251263	0.393
AMPK	complex	SIGNOR-C15	SIGNOR	TSC	complex	SIGNOR-C101	SIGNOR	up-regulates activity	phosphorylation			10090	BTO:0002572		SIGNOR-C15						16959574	t		lperfetto	GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation	SIGNOR-217749	0.463
PRKACA	protein	P17612	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates activity	phosphorylation	Thr130	GEKSRYEtSLNLTTK	9606	BTO:0000007								33110360	t		miannu	We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence.	SIGNOR-277536	0.2
PTPRF	protein	P10586	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606									15896785	t	10226025:Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473.	acerquone	Knock-down of lar by the l3 sirna probe markedly inhibited the insulin-stimulated increase in the phosphorylation of protein kinase b (pkb, also called akt) on serine 473 by >90%	SIGNOR-137246	0.349
RFC5	protein	P40937	UNIPROT	RF-C complex	complex	SIGNOR-C375	SIGNOR	form complex	binding												12930972	t		lperfetto	RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned 	SIGNOR-265509	0.758
CSNK1A1	protein	P48729	UNIPROT	YWHAQ	protein	P27348	UNIPROT	down-regulates activity	phosphorylation	Ser232	LTLWTSDsAGEECDA	-1									9360956	t		llicata	This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins. 	SIGNOR-250795	0.494
MMP24	protein	Q9Y5R2	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272368	0.7
AKT1	protein	P31749	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates	phosphorylation	Thr32	QSRPRSCtWPLPRPE	9606									16272144	t		lperfetto	Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression	SIGNOR-252486	0.755
PPARGC1A	protein	Q9UBK2	UNIPROT	SLC2A4	protein	P14672	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887;BTO:0001103							17609368	f		gcesareni	Pgc-1alpha protein is required for ampk action on glut4 gene expression and mitochondrial function.	SIGNOR-156769	0.613
IL17A	protein	Q16552	UNIPROT	KLF15	protein	Q9UIH9	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									23332504	f		fspada	Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic.	SIGNOR-192474	0.2
PDGFRA	protein	P16234	UNIPROT	PDGFRA	protein	P16234	UNIPROT	up-regulates activity	phosphorylation	Tyr1018	RLSADSGyIIPLPDI	9823	BTO:0004007								7535778	t		miannu	We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ.	SIGNOR-250250	0.2
PBX2	protein	P40425	UNIPROT	FGF8	protein	P55075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003560								10026229	t		miannu	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 	SIGNOR-265778	0.254
SMARCB1	protein	Q12824	UNIPROT	SMARCA2	protein	P51531	UNIPROT	up-regulates activity	binding			9606									10078207	t		miannu	The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.	SIGNOR-65181	0.921
MAPK1	protein	P28482	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser221	DHEKKAYsFCGTVEY	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-219308	0.748
glycogen	smallmolecule	CHEBI:28087	ChEBI	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	up-regulates quantity	precursor of			9606									3346228	t			Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267950	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates	phosphorylation	Thr178	NHNHRIRtNPAIVKT	9606		BTO:0000887;BTO:0001103							17609368	t		lperfetto	Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538.	SIGNOR-216651	0.483
SLK	protein	Q9H2G2	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates	phosphorylation			9606		BTO:0000671							16316999	t		gcesareni	Induction of apoptosis by the ste20-like kinase slk, a germinal center kinase that activates apoptosis signal-regulating kinase and p38	SIGNOR-142665	0.256
PRKCD	protein	Q05655	UNIPROT	KRT8	protein	P05787	UNIPROT	up-regulates	phosphorylation	Ser74	TVNQSLLsPLVLEVD	9606									15972820	t		Manara	The present study showed that shear stress, but not stretch, activates PKC delta and phosphorylates K8 Ser-73, which then mediates the disassembly/reorganization of keratin IF in AEC.	SIGNOR-260887	0.329
PEX6	protein	Q13608	UNIPROT	PEX5	protein	P50542	UNIPROT	up-regulates activity	binding			10029									16314507	t			Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. ​(Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner. 	SIGNOR-253619	0.588
PIK3R1	protein	P27986	UNIPROT	PIP3	smallmolecule	CHEBI:16618	ChEBI	up-regulates quantity				10116									21798082	f		lperfetto	Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2).	SIGNOR-175678	0.8
PPP1CA	protein	P62136	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	dephosphorylation	Ser217	YTRTGSEsPKVCSDQ	9606									17318175	t			The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 	SIGNOR-248553	0.338
CREB1	protein	P16220	UNIPROT	PK	proteinfamily	SIGNOR-PF80	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									16308421	f	inferred from family member	gcesareni	In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1	SIGNOR-270285	0.252
TET2	protein	Q6N021	UNIPROT	WT1	protein	P19544	UNIPROT	up-regulates activity	binding			9606	BTO:0000670;BTO:0000738								25601757	t		irozzo	 In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes.	SIGNOR-255703	0.461
CDC42	protein	P60953	UNIPROT	WAS	protein	P42768	UNIPROT	up-regulates activity	binding			9606	BTO:0000132								27871158	t		lperfetto	Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex	SIGNOR-261869	0.956
betamethasone	chemical	CHEBI:3077	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									17561562	t	dermatitis	gcesareni		SIGNOR-251686	0.8
PPM1A	protein	P35813	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	dephosphorylation			9606									16751101	t		lpetrilli	Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.	SIGNOR-146922	0.606
PAX3	protein	P23760	UNIPROT	MEOX1	protein	P50221	UNIPROT	up-regulates activity	binding			-1									11423130	t		miannu	We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family.	SIGNOR-222235	0.432
PRKCA	protein	P17252	UNIPROT	PA2G4	protein	Q9UQ80	UNIPROT	unknown	phosphorylation	Thr366	QSSASRKtQKKKKKK	9606	BTO:0004737								11325528	t		lperfetto	We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC.	SIGNOR-249092	0.441
INTS9	protein	Q9NV88	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261471	0.789
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	KCNK18	protein	Q7Z418	UNIPROT	down-regulates activity	phosphorylation	Ser252	QAMERSNsCPELVLG	-1									18397886	t		miannu	Phosphorylation of serine 264 in mouse TRESK was required for the binding of 14-3-3η. PKA was used to phosphorylate serine 264 in our further in vitro experiments.	SIGNOR-263154	0.2
TRAF2	protein	Q12933	UNIPROT	BIRC3	protein	Q13489	UNIPROT	up-regulates	binding			9606									18997792	t		gcesareni	A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution.	SIGNOR-182124	0.888
2'-deoxyadenosine	smallmolecule	CHEBI:17256	ChEBI	2'-deoxyadenosine 5'-monophosphate(2-)	smallmolecule	CHEBI:58245	ChEBI	up-regulates quantity	precursor of												20637175	t		lperfetto	Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis	SIGNOR-275811	0.8
NR3C1	protein	P04150	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates quantity	transcriptional regulation			10116									15793248	f			We show here that dexamethasone upregulates transcription and expression of the serum- and glucocorticoid-inducible kinase 1 (SGK1) in insulin-secreting cells, an effect reversed by mifepristone (RU486), an antagonist of the nuclear glucocorticoid receptor.	SIGNOR-255926	0.474
KRAS	protein	P01116	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	binding			9606									10882715	t		gcesareni	Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade.	SIGNOR-78911	0.841
TRIM37	protein	O94972	UNIPROT	TRIM37	protein	O94972	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0001538								14561866	t		miannu	In this paper, we present data showing that TRIM37, a member of the TRIM subfamily of RING finger proteins, is autoubiquitinated in a RING domain-dependent manner.  However, we feel tempted to speculate that the most likely mechanism, in which TRIM37-mediated ubiquitination could be involved, is proteasomal degradation of a target protein and, possibly, its own turnover.	SIGNOR-271503	0.2
PRKCB	protein	P05771	UNIPROT	EIF4E	protein	P06730	UNIPROT	up-regulates	phosphorylation	Ser209	DTATKSGsTTKNRFV	10090									8662663	t		lperfetto	Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins.[..] This suggests a two-step model for the phosphorylation (and activation) of eIF4E by growth factors and hormones: first, dissociation of eIF4E .	SIGNOR-248946	0.355
MAPK9	protein	P45984	UNIPROT	PIN1	protein	Q13526	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser115	SQFSDCSsAKARGDL	9606	BTO:0002932								34048060	t		miannu	Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation.	SIGNOR-277563	0.2
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGC4	protein	Q9Y5F7	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265693	0.2
PALB2	protein	Q86YC2	UNIPROT	BRCA2	protein	P51587	UNIPROT	up-regulates	binding			9606	BTO:0000150								16793542	t		miannu	Palb2 colocalizes with brca2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions.	SIGNOR-147217	0.94
olanzapine	chemical	CHEBI:7735	ChEBI	HTR1B	protein	P28222	UNIPROT	up-regulates activity	chemical activation			10116		BTO:0001311							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258507	0.8
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	VRK3	protein	Q8IV63	UNIPROT	up-regulates activity	phosphorylation	Ser108	RPPTPKSsPQKTRKS										27346674	t		lperfetto	Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding|Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation|	SIGNOR-275545	0.365
(2S)-2-[[2-(2,3-dihydro-1H-inden-5-yloxy)-9-[(4-phenylphenyl)methyl]-6-purinyl]amino]-3-phenyl-1-propanol	chemical	CHEBI:94469	ChEBI	ARFGAP1	protein	Q8N6T3	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								17460038	t			Through affinity chromatography and subsequent functional assays, we showed that QS11 binds and inhibits the GTPase activating protein of ADP-ribosylation factor 1 (ARFGAP1), suggesting that QS11 modulates Wnt/beta-catenin signaling through an effect on protein trafficking. Consistent with its function as an ARFGAP inhibitor, QS11 inhibits migration of ARFGAP overexpressing breast cancer cells	SIGNOR-261914	0.8
FBXL7	protein	Q9UJT9	UNIPROT	BIRC5	protein	O15392	UNIPROT	down-regulates quantity by destabilization	binding			10090	BTO:0002268								25778398	t		miannu	Fbxl7 targets survivin for polyubiquitylation and proteasomal degradation.these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. These results suggest that both Lys-90 and Lys-91 are critical for Fbxl7-mediated polyubiquitylation.	SIGNOR-272436	0.311
MYD88	protein	Q99836	UNIPROT	DHX9	protein	Q08211	UNIPROT	up-regulates activity	binding			9606	BTO:0002042								20696886	t		miannu	 We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing.	SIGNOR-260955	0.469
sabcomeline	chemical	CHEBI:134846	ChEBI	CHRM3	protein	P20309	UNIPROT	up-regulates activity	chemical activation			10116									9399977	t		miannu	 SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes	SIGNOR-258677	0.8
CSNK2A1	protein	P68400	UNIPROT	F5	protein	P12259	UNIPROT	down-regulates activity	phosphorylation	Ser692	IPDDDEDsYEIFEPP	-1									9525959	t		llicata	Factor Va, the essential cofactor for prothrombinase, is phosphorylated on the acidic COOH terminus of the heavy chain of the cofactor, at Ser692, by a platelet membrane-associated casein kinase II (CKII). | The phosphorylated cofactor has increased susceptibility to inactivation by activated protein C, since phosphorylated factor Va was found to be inactivated approximately 3-fold faster than its native counterpart. 	SIGNOR-250862	0.311
NF2	protein	P35240	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	up-regulates activity	binding			10090	BTO:0003324								27402866	t	Hippo pathway	Gianni	NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart.	SIGNOR-269948	0.422
adrenaline	smallmolecule	CHEBI:33568	ChEBI	ADRB3	protein	P13945	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)	SIGNOR-257877	0.8
PHLPP1	protein	O60346	UNIPROT	PRKCB	protein	P05771	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser661	QNEFAGFsYTNPEFV	9606									18162466	t			These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation.|n contrast, results from siRNA depletion and overexpression experiments indicate that the hydrophobic motif site (Ser660) is regulated by PHLPP isoforms, 	SIGNOR-248326	0.347
PLCB1	protein	Q9NQ66	UNIPROT	1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	up-regulates quantity	chemical modification			-1									23880553	t		miannu	Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate.	SIGNOR-256496	0.8
SRSF1	protein	Q07955	UNIPROT	Alternative_Splicing_Regulation	phenotype	SIGNOR-PH204	SIGNOR	up-regulates				9606									26273603	f		miannu	In particular, SRSF1 recognizes SREs in its own transcripts, leading to alternative splicing, with some transcript forms being degraded by nonsense-mediated mRNA decay (NMD).	SIGNOR-273861	0.7
MMP10	protein	P09238	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272355	0.7
VRK1	protein	Q99986	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Thr18	EPPLSQEtFSDLWKL	9606	BTO:0000567								10951572	t		gcesareni	Vrk1 phosphorylates murine p53 in threonine 18. This threonine is within the p53 hydrophobic loop (residues 13-23) required for the interaction of p53 with the cleft of its inhibitor mdm-2.	SIGNOR-81222	0.539
IDH	complex	SIGNOR-C396	SIGNOR	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	chemical modification			9606									28139779	t		miannu	Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP.	SIGNOR-266252	0.8
RPS6KA4	protein	O75676	UNIPROT	HMGN1	protein	P05114	UNIPROT	unknown	phosphorylation	Ser7	sSAEGAAK	10090	BTO:0000452								12773393	t		lperfetto	The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 and HMG-14 at Ser6 after stimulation of primary embryonic fibroblasts by TPA or anisomycin.	SIGNOR-249216	0.341
SH3RF1	protein	Q7Z6J0	UNIPROT	MAP3K12	protein	Q12852	UNIPROT	up-regulates	binding			9606	BTO:0000938								12514131	t		gcesareni	One explanation as provided by our model is that mlk3 and dlk interact indirectly via posh with mutual activation when both are wild-type the multidomain protein posh binds to the constitutively active form of rac1, which is known to regulate the activity of mlks, while jip1 binds to mlks and additional components of the jnk pathway and appears to be capable of activating mlks	SIGNOR-97060	0.384
GRM6	protein	O15303	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264354	0.7
SRC	protein	P12931	UNIPROT	MUC1	protein	P15941	UNIPROT	up-regulates	phosphorylation	Tyr1229	SSTDRSPyEKVSAGN	9606									11152665	t		lperfetto	The c-src tyrosine kinase regulates signaling of the human df3/muc1 carcinoma-associated antigen with gsk3 beta and betBeta-catenin c-src phosphorylates the muc1 cytoplasmic domain at a yekv motif c-src-mediated phosphorylation of muc1 increases binding of muc1 and betBeta-catenin	SIGNOR-85938	0.455
ADAM17	protein	P78536	UNIPROT	HBEGF	protein	Q99075	UNIPROT	up-regulates activity	cleavage			9606									26284334	t		miannu	ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF	SIGNOR-259844	0.575
SRC	protein	P12931	UNIPROT	CAV1	protein	Q03135	UNIPROT	down-regulates activity	phosphorylation	Tyr14	VDSEGHLyTVPIREQ	9606									12921535	t		lperfetto	Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn	SIGNOR-118007	0.756
INSR	protein	P06213	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr285	TEADGELyVFNTPSG	10090									10978177	t			HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin	SIGNOR-251311	0.492
BMP2	protein	P12643	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	up-regulates	binding			10090	BTO:0001957								11714695	t		lperfetto	For this, bmp-2 binds first to the high affinity receptor bri and then recruits brii into the signaling complex.	SIGNOR-237000	0.856
MYO3A	protein	Q8NEV4	UNIPROT	MYO3A	protein	Q8NEV4	UNIPROT	down-regulates activity	phosphorylation	Thr919	TRHARETtNMKTQTV	9534									24214986	t		Manara	We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919) | Thus, the phosphorylation sites in loop 2 (Thr-908 and Thr-919) are likely responsible for the down-regulation of MYO3A motor activity observed in our current and previous work	SIGNOR-260924	0.2
DNMT1	protein	P26358	UNIPROT	IL32	protein	P24001	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000018								20889550	f	 	lperfetto	A virus or dsRNA in human PBMCs from healthy volunteers. We demonstrate that the NF-κB and CREB pathways play key roles in the activation of IL-32 production in response to influenza virus infection in A549 human lung epithelial cells.|Overexpression assays combined with RNA interference show that DNA methyltransferases DNMT1 and DNMT3b are critical for IL32 promoter methylation and gene silencing before viral infection. 	SIGNOR-254126	0.349
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CEP76	protein	Q8TAP6	UNIPROT	down-regulates activity	phosphorylation	Ser83	VEQELPSsPKQPICF	9606	BTO:0000007								27065328	t		miannu	Cep76 is phosphorylated by cyclin A/CDK2 at a single site S83. These data suggest that the phosphomimetic mutant is functional and that phosphorylation at S83 is critical for Cep76 to suppress centriole amplification.	SIGNOR-262603	0.305
dexamethasone	chemical	CHEBI:41879	ChEBI	GLUL	protein	P15104	UNIPROT	up-regulates quantity by expression				10090									8099704	f		miannu	GS transcripts were measured by laser densitometry and normalized to actin, and GS specific activity was also determined. Following a single injection of dexamethasone (0.5 mg/kg), lung GS activity increased by 40% at 4 hours and by 75% at 8 hours. The dexamethasone-mediated increase in GS activity was associated with a marked increase in GS mRNA levels, which preceded the increase in enzyme activity by approximately 2 hours.	SIGNOR-267827	0.8
MARCHF9	protein	Q86YJ5	UNIPROT	SLAMF1	protein	Q13291	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001522								19457934	t		miannu	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. 	SIGNOR-271537	0.2
HIC1	protein	Q14526	UNIPROT	EFNA1	protein	P20827	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20154726	f	 	miannu	 we show that HIC1 is a direct transcriptional repressor of the gene encoding ephrin-A1, a cell surface ligand implicated in the pathogenesis of epithelial cancers. 	SIGNOR-254240	0.369
C8B	protein	P07358	UNIPROT	Membrane attack complex	complex	SIGNOR-C313	SIGNOR	form complex	binding			-1									30552328	t		lperfetto	The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer	SIGNOR-263444	0.575
GNAS	protein	P63092	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	binding			-1									11007482	t			Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src	SIGNOR-256527	0.49
TRAF6	protein	Q9Y4K3	UNIPROT	KLF4	protein	O43474	UNIPROT	up-regulates quantity by stabilization	ubiquitination	Lys32	SGPAGREkTLRQAGA	9606	BTO:0002181								31281496	t		miannu	We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization.	SIGNOR-277464	0.29
PRKCB	protein	P05771	UNIPROT	TRPV6	protein	Q9H1D0	UNIPROT	down-regulates activity	phosphorylation	Ser184	LARRASVsARATGTA	-1									19805577	t		miannu	 This regulation requires PKC(betaII) and defined phosphorylation sites within the ARD and the C-terminus. Both regulatory sites act synergistically to constitute a novel mechanism by which ATP stabilizes channel activity and acts as a metabolic switch for Ca(2+) influx. Decreases in ATP concentration or activation of PKC(betaII) disable regulation of the channels by ATP, rendering them more susceptible to inactivation and rundown and preventing Ca(2+) overload.	SIGNOR-276265	0.2
BTK	protein	Q06187	UNIPROT	GTF2I	protein	P78347	UNIPROT	up-regulates activity	phosphorylation	Tyr398	QSHVEDLyVEGLPEG	9534									11373296	t		lperfetto	These residues, tyr248, tyr357, and tyr462, were also found to be the major sites for btk-dependent phosphorylation of bap/tfii-i in vivo. Residues tyr357 and tyr462 are contained within the loop regions of adjacent helix-loop-helix-like repeats within bap/tfii-i. Mutation of either tyr248, tyr357, or tyr462 to phenylalanine reduced transcription from a c-fos promoter relative to wild-type bap/tfii-i in transfected cos-7 cells, consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation.	SIGNOR-108342	0.532
CCNC	protein	P24863	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	phosphorylation			9606									15546612	t	Leads to a following ubiquitination and degradation	gcesareni	Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.	SIGNOR-130592	0.458
COPS8	protein	Q99627	UNIPROT	COP9 signalosome variant 2	complex	SIGNOR-C487	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270763	0.919
PTPN22	protein	Q9Y2R2	UNIPROT	LCK	protein	P06239	UNIPROT	down-regulates activity	dephosphorylation	Tyr394	RLIEDNEyTAREGAK	9606									16461343	t			In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22.	SIGNOR-248836	0.741
GRK3	protein	P35626	UNIPROT	CCR5	protein	P51681	UNIPROT	down-regulates activity	phosphorylation	Ser337	EAPERASsVYTRSTG	9534	BTO:0000298								10085131	t			Serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. CCR5 phosphorylation and desensitization through a GRK-mediated mechanism	SIGNOR-251464	0.2
CSNK2A1	protein	P68400	UNIPROT	HSP90AB1	protein	P08238	UNIPROT	down-regulates	phosphorylation	Ser255	PKIEDVGsDEEDDSG	9606									18591256	t		gcesareni	Although the kinase responsible for hsp90? Phosphorylation in vivo is not known, it has been reported that ck2 can phosphorylate these sites in vitro (24). Thus, we prephosphorylated recombinant hsp90? With ck2 before addition to the reaction. Remarkably, hsp90? Phosphorylation greatly reduced its ability to inhibit apaf-1 oligomerization and caspase-9 recruitment (fig. 5b). These results indicate that the phosphorylation status of hsp90? Significantly impacts its ability to inhibit apoptosome formation.	SIGNOR-179264	0.339
CDK1	protein	P06493	UNIPROT	EIF4G2	protein	P78344	UNIPROT	up-regulates activity	phosphorylation	Thr508	AQPPRTQtPPLGQTP	9606	BTO:0000007								29530922	t		miannu	To test whether CDK1 phosphorylates T508, Flag-DAP5 was purified from dox-induced HEK293 cells and incubated with active recombinant JNK2 or CDK1 in the presence of ATP (Fig. 3G). DAP5(T508) was phosphorylated only upon incubation with CDK1 (Fig. 3G). 	SIGNOR-266387	0.346
KSR1	protein	Q8IVT5	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								29433126	t		miannu	 In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. 	SIGNOR-273880	0.638
PRKCA	protein	P17252	UNIPROT	APLP2	protein	Q06481	UNIPROT	unknown	phosphorylation	Thr723	LRKRQYGtISHGIVE	-1									9109675	t		lperfetto	We report here that a cytoplasmic domain peptide from APLP1 is phosphorylated in vitro by protein kinase C and that a cytoplasmic domain peptide from APLP2 is phosphorylated in vitro by protein kinase C and cdc2 kinase.	SIGNOR-248970	0.346
ABL1	protein	P00519	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates activity	phosphorylation	Tyr231	NANGEAVyCKFHYKT	9606									12777400	t		Manara	These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386	SIGNOR-260769	0.412
coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	acetyl-CoA(4-)	smallmolecule	CHEBI:57288	ChEBI	up-regulates quantity	precursor of												10843999	t		lperfetto	The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP.	SIGNOR-271825	0.8
PRKCA	protein	P17252	UNIPROT	PPP1R14A	protein	Q96A00	UNIPROT	up-regulates activity	phosphorylation	Thr38	QKRHARVtVKYDRRE	9606									32471307	t		lperfetto	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.	SIGNOR-249259	0.503
GABA-A (a4-b2-d) receptor	complex	SIGNOR-C326	SIGNOR	CRHR2	protein	Q13324	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268593	0.2
PRKCD	protein	Q05655	UNIPROT	PA2G4	protein	Q9UQ80	UNIPROT	up-regulates	phosphorylation	Ser360	ELKALLQsSASRKTQ	9606	BTO:0000938								21145366	t		gcesareni	Trk receptor activation by both ngf and bdnf induced phosphorylation of ebp1 at the s360 upon the activation of protein kinase c (pkc ) and triggered dissociation of p48 from retinoblastoma (rb	SIGNOR-170348	0.488
MAPK1	protein	P28482	UNIPROT	RPS3	protein	P23396	UNIPROT	unknown	phosphorylation	Thr42	SGVEVRVtPTRTEII	9606									15950189	t		llicata	Erk phosphorylates threonine 42 residue of ribosomal protein s3.	SIGNOR-136075	0.2
PRKCG	protein	P05129	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Ser840	VRSAFTTsTVVRMHV	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249282	0.425
CIITA	protein	P33076	UNIPROT	HLA-E	protein	P13747	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								11137213	f	 	 	HLA-E is inducible by CIITA through the SXY regulatory module. HLA-F is inducible by NF-kappaB through the kappaB1 site of enhancer A, is responsive to IFN-gamma through the ISRE, and is inducible by CIITA	SIGNOR-254019	0.475
959122-11-3	chemical	CID:24768261	PUBCHEM	DGAT1	protein	O75907	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205695	0.8
lapatinib	chemical	CHEBI:49603	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001949								21443688	t		Luana	YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ.	SIGNOR-257901	0.8
anthra[1,9-cd]pyrazol-6(2H)-one	chemical	CHEBI:90695	ChEBI	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	down-regulates	chemical inhibition			9606									11717429	t	inferred from 70% of family members	gcesareni	We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). To determine whether jnk activity is required for stress-induced translocation of bax to the mitochondria, we examined the effect of sp600125, a jnk inhibitor.	SIGNOR-269885	0.8
HSPA9	protein	P38646	UNIPROT	iron-sulfur cluster	smallmolecule	CHEBI:30408	ChEBI	up-regulates activity	relocalization												27714045	t		lperfetto	Cluster transfer from ISCU to recipient apoproteins is assisted by a dedicated chaperone/cochaperone (HSPA9/HSC20) system that facilitates cluster release from the primary scaffold ISCU and transfer to recipient apoproteins or to intermediate carriers	SIGNOR-262131	0.8
FGF13	protein	Q92913	UNIPROT	SCN10A	protein	Q9Y5Y9	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253439	0.2
DRD5	protein	P21918	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256771	0.459
MKX	protein	Q8IYA7	UNIPROT	SCX	protein	Q7RTU7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001592							33115953	t		miannu	MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2). 	SIGNOR-267213	0.427
RUNX1	protein	Q01196	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	down-regulates activity	binding			9606									22021368	t		apalma	We found that AML1 inhibits NF-κB signaling through interaction with IκB kinase complex in the cytoplasm. Remarkably, AML1 mutants found in myeloid tumors lack the ability to inhibit NF-κB signaling, and human cases with AML1-related leukemia exhibits distinctly activated NF-κB signaling	SIGNOR-255690	0.2
UNC5A	protein	Q6ZN44	UNIPROT	DCC	protein	P43146	UNIPROT	down-regulates activity	binding			9606		BTO:0001484							25881791	t		miannu	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268164	0.648
PARP1	protein	P09874	UNIPROT	CHD2	protein	O14647	UNIPROT	up-regulates quantity	binding			9606									26895424	t		miannu	Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage.	SIGNOR-264526	0.2
DEPDC5	protein	O75140	UNIPROT	GATOR1	complex	SIGNOR-C192	SIGNOR	form complex	binding			9606									23723238	t		miannu	Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5	SIGNOR-255280	0.949
TNFSF11	protein	O14788	UNIPROT	TNFRSF11A	protein	Q9Y6Q6	UNIPROT	up-regulates activity	binding			9606									12897775	t		miannu	RANKL, a member of the tumour necrosis factor superfamily, is most abundantly expressed as a cell-surface protein by bone-marrow stromal cells. It interacts with its receptor RANK (which is encoded by Tnfrsf11a) on macrophages and mature osteoclasts.	SIGNOR-253042	0.892
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	RPS6	protein	P62753	UNIPROT	up-regulates	phosphorylation	Ser240	RLSSLRAsTSKSESS	9606									21233202	t		lperfetto	In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity	SIGNOR-252765	0.2
CKM complex	complex	SIGNOR-C406	SIGNOR	CCNH	protein	P51946	UNIPROT	down-regulates activity	phosphorylation	Ser5	sSQKRHWT	9606									10993082	t		gcesareni	Here we show that cdk8/cyclin c can regulate transcription by targeting the cdk7/cyclin h subunits of the general transcription initiation factor iih (tfiih). cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity. In addition, mimicking cdk8 phosphorylation of cyclin h in vivo has a dominant-negative effect on cell growth.	SIGNOR-273139	0.447
LPCAT4	protein	Q643R3	UNIPROT	1-O-acyl-sn-glycero-3-phosphocholine	chemical	CHEBI:58168	ChEBI	down-regulates quantity	chemical modification			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272772	0.8
SNAIL/RELA/PARP1	complex	SIGNOR-C198	SIGNOR	FN1	protein	P02751	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000452;BTO:0002625								22223884	f		alessandro	Taken together, our results indicate that Snail1, p65NF-κB and PARP1 interact to activate the expression of fibronectin and other ECM genes involved in cell movement. This mechanism is functional not only in epithelial cells undergoing EMT but also in fibroblasts.	SIGNOR-254529	0.421
superoxide	smallmolecule	CHEBI:18421	ChEBI	ROS	stimulus	SIGNOR-ST2	SIGNOR	up-regulates				9606									35681445	f		lperfetto	The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment.	SIGNOR-272277	0.7
CPT1A	protein	P50416	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	chemical modification			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267132	0.8
AKT3	protein	Q9Y243	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates	phosphorylation	Ser364	FGQRDRSsSAPNVHI	9606									10869359	t		gcesareni	We show that phosphorylation of b-raf by akt occurs at multiple residues within its aminoterminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity.	SIGNOR-78693	0.294
NCOA1	protein	Q15788	UNIPROT	APOA5	protein	Q6Q788	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f		miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-255064	0.381
AKT1	protein	P31749	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	down-regulates activity	phosphorylation	Ser19	KMAVESPsDSAENGQ	9606	BTO:0000815								33574926	t		miannu	Akt interacts with and phosphorylates RSK2 at S19. 	SIGNOR-277548	0.268
zotepine	chemical	CHEBI:32316	ChEBI	HTR2A	protein	P28223	UNIPROT	down-regulates activity	chemical inhibition			10090	BTO:0000331								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258552	0.8
IKBKG	protein	Q9Y6K9	UNIPROT	BCL10	protein	O95999	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0000007								14695475	t		Barakat	Here we show that Bcl10 targets NEMO for lysine-63-linked ubiquitination. Notably, a mutant form of NEMO that cannot be ubiquitinated inhibited Bcl10-induced NF-κB activation.	SIGNOR-274149	0.82
MVD	protein	P53602	UNIPROT	NRAS	protein	P01111	UNIPROT	up-regulates quantity by stabilization				9534									12646231	f		miannu	An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B)	SIGNOR-265889	0.2
TGFB1	protein	P01137	UNIPROT	SLC5A5	protein	Q92911	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									14623893	f		miannu	The sodium/iodide symporter mediates the active transport of iodide in thyroid follicular cells. A number of agents regulate NIS expression; among these, TGF-β is a potent inhibitor of both iodide uptake and NIS gene expression	SIGNOR-259912	0.2
Guanfacine	chemical	CHEBI:5558	ChEBI	ADRA2B	protein	P18089	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258920	0.8
CDK5	protein	Q00535	UNIPROT	DNM1	protein	Q05193	UNIPROT	up-regulates activity	phosphorylation	Ser774	SVPAGRRsPTSSPTP	-1									12855954	t		llicata	Here, we show that cyclin-dependent kinase 5 (Cdk5) phosphorylates dynamin I on Ser 774 and Ser 778 in vitro, which are identical to its endogenous phosphorylation sites in vivo. Cdk5 antagonists and expression of dominant-negative Cdk5 block phosphorylation of dynamin I, but not of amphiphysin or AP180, in nerve terminals and inhibit SVE. 	SIGNOR-250661	0.531
AR	protein	P10275	UNIPROT	KLK3	protein	P07288	UNIPROT	up-regulates quantity by expression	transcriptional regulation												20069563	t	 	 	TH1 also associates with AR at the active androgen-responsive prostate-specific antigen (PSA) promoter in the nucleus of LNCaP cells. Decrease of endogenous AR protein by TH1 interferes with androgen-induced luciferase reporter expression and reduces endogenous PSA expression.	SIGNOR-253657	0.816
FGFR1	protein	P11362	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates	phosphorylation	Tyr249	APGPQDIyDVPPVRG	9606									12601080	t		lperfetto	Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas.	SIGNOR-98492	0.259
TBX22	protein	Q9Y458	UNIPROT	MSX2	protein	P35548	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9031	BTO:0005956								20033915	t		miannu	 the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22. 	SIGNOR-265567	0.314
TSHR	protein	P16473	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606		BTO:0001379							32698392	t		scontino	Activation of TSHR and the linked signaling cascades through binding of circulating TSH plays a pivotal role in controlling thyrocyte growth and in regulating thyroid hormone production/secretion. This is executed through switching on different subtypes of G proteins and signaling pathways. Among them, the Gαs- and Gαq-induced cascades are of the greatest importance, as they have been tightly linked to specific intracellular signal transductions downstream of TSHR in response to stimulations	SIGNOR-267138	0.546
PAK1	protein	Q13153	UNIPROT	ARAF	protein	P10398	UNIPROT	up-regulates	phosphorylation	Ser299	KNLGYRDsGYYWEVP	9606	BTO:0000848								15710605	t		lperfetto	Phosphorylation of endogenous a-raf, b-raf and raf-1 on the homologous pak phosphorylation sites (serine 299, serine 445, or serine 338 respectively)we found that the phosphorylation of a-raf on serine 299 was also stimulated by egf, although the duration of phosphorylation on this site was much shorter than for raf-1. Thus, by analogy with raf-1, phosphorylation of this site may play an important role in the a-raf activation mechanism.	SIGNOR-236342	0.27
histidine	smallmolecule	CHEBI:27570	ChEBI	His-tRNA(His)	smallmolecule	CHEBI:29155	ChEBI	up-regulates quantity	precursor of			9606									10430027	t		miannu	Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 	SIGNOR-270492	0.8
OXTR	protein	P30559	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									30739093	t		miannu	OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq).	SIGNOR-270330	0.429
1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	PRKCZ	protein	Q05513	UNIPROT	up-regulates activity	binding			9606									14967450	t	PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine.	lperfetto	The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified.	SIGNOR-242599	0.8
PTPN1	protein	P18031	UNIPROT	LAT	protein	O43561	UNIPROT	down-regulates	dephosphorylation			9606									12857726	t		gcesareni	Our results demonstrate that ptp1b plays an important role in the integrin-mediated dephosphorylation of lat in human platelets and is involved in the control of irreversible aggregation upon fcgammariia stimulation.	SIGNOR-103599	0.481
NUCKS1	protein	Q9H1E3	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									26323318	f		miannu	 From these results, we can conclude that NUCKS1 plays a role in HR DNA repair, as does its paralog RAD51AP1. we have tested and uncovered a role for NUCKS1 in HR and in maintaining DNA replication integrity and genome stability. 	SIGNOR-261960	0.7
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser177	ASSGSSAsFISDTFS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248514	0.386
PRKACA	protein	P17612	UNIPROT	APC	protein	P25054	UNIPROT	down-regulates activity	phosphorylation	Ser2054	MPKKKKPsRLKGDNE	9606									11050185	t		miannu	Changing a serine residue (Ser(2054)) to aspartic acid mutated the potential protein kinase A site adjacent to NLS2(APC), resulting in both inhibition of the NLS2(APC)-mediated nuclear import of a chimeric beta-galactosidase fusion protein and a reduction of full-length APC nuclear localization.	SIGNOR-250335	0.311
bethanechol	chemical	CHEBI:3084	ChEBI	CHRM3	protein	P20309	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258623	0.8
PPP5C	protein	P53041	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates activity	dephosphorylation	Ser211	PGKETNEsPWRSDLL	9606	BTO:0000093								19586900	t			Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.|Inhibition of GR phosphorylation at Ser-211 is associated with decreased nuclear retention of GR and decreased gene transcription.	SIGNOR-248538	0.521
PRKG1	protein	Q13976	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Thr143	RCFTRKYtLPPGVDP	9606									19593530	t	11383510: to test the hypothesis that cGK could inhibit platelet aggregation by phosphorylating Hsp27 and interfering with the MAPKAP kinase phosphorylation of Hsp27, the known MAPKAP kinase 2-phosphorylation sites (Ser15, Ser78, and Ser82) as well as Thr143 were replaced by negatively charged amino acids, which are considered to mimic phosphate groups, and tested in actin polymerization experiments. Mimicry at the MAPKAP kinase 2 phosphorylation sites led to mutants with a stimulating effect on actin polymerization	lperfetto	Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization	SIGNOR-186792	0.278
AKT2	protein	P31751	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606									19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites.	SIGNOR-236675	0.742
MRPS34	protein	P82930	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261443	0.651
PRKACA	protein	P17612	UNIPROT	ABCA1	protein	O95477	UNIPROT	up-regulates activity	phosphorylation	Ser1042	GGMQRKLsVALAFVG	10090	BTO:0000801								12196520	t		miannu	Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins.	SIGNOR-250326	0.485
EPX	protein	P11678	UNIPROT	RNASE3	protein	P12724	UNIPROT	up-regulates activity	post translational modification			9606	BTO:0000399								18694936	t		miannu	Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.	SIGNOR-261705	0.493
PRKCH	protein	P24723	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates activity	phosphorylation	Ser710	GEKSFRRsVVGTPAY										12058027	t		lperfetto	Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.	SIGNOR-275957	0.2
CSNK2A1	protein	P68400	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates	phosphorylation	Ser282	EGRGEVGsAGDMRAA	9606	BTO:0000150;BTO:0000567								20043841	t		lperfetto	Additionally protein kinase ck2 was identified as a kinase that phosphorylated eralpha at s282 and s559 s282 and s559 represent the second and third sites of er_ regulation by ck2. Remarkably, mutation of s282 or s559 to alanine resulted in near opposite functional effects on er_ as compared to mutation of s167 to alanine. Er_ ligand independent transcriptional activity was markedly enhanced upon mutation of s282 and s559 to alanine	SIGNOR-162653	0.248
CDK1	protein	P06493	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Thr373	VNVIPPHtPVRTVMN	9606									1756735	t		lperfetto	The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2.	SIGNOR-21564	0.675
PPP2CA	protein	P67775	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates activity	dephosphorylation	Thr32	QSRPRSCtWPLQRPE	9606									20110348	t		gcesareni	Pp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a.	SIGNOR-163688	0.411
MAPK14	protein	Q16539	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates activity	phosphorylation	Thr293	QSAQSLAtPVVSVAT	9606									9858528	t	The effect has been demonstrated using Q06413-3	lperfetto	Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain	SIGNOR-62792	0.683
CHEVI complex	complex	SIGNOR-C269	SIGNOR	Platelet_aggregation	phenotype	SIGNOR-PH81	SIGNOR	up-regulates				9606									27319744	f		lperfetto	VPS33B association with VIPAS39, α-tubulin, and SEC22B was identified by co-immunoprecipitation, mass spectra, and immunoblotting in human embryonic kidney 293T (HEK293T) cells. Also, pull-down experiments revealed that VIPAS39 bound to intact VPS33B; in contrast, α-tubulin and SEC22B separately interacted with the sec1-like domains of VPS33B. Vps33b deficiency in megakaryocytes disturbs the redistribution of Vipas39 and Sec22b to proplatelets, and interrupted the co-localization of Sec22b with Vwf-positive vesicles	SIGNOR-261833	0.7
zotepine	chemical	CHEBI:32316	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258553	0.8
PRKCB	protein	P05771	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser170	SFKLSGFsFKKNKKE	-1									8422248	t		lperfetto	These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III.	SIGNOR-248929	0.663
iodide	smallmolecule	CHEBI:16382	ChEBI	3,5-diiodo-L-tyrosine	smallmolecule	CHEBI:15768	ChEBI	up-regulates quantity	precursor of			9606									23349248	t		miannu	After transport through the apical membrane, I‚àí is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO).	SIGNOR-259913	0.8
DUSP2	protein	Q05923	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606									8626452	t		fstefani	Pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively.	SIGNOR-40915	0.735
MAPK1	protein	P28482	UNIPROT	ERF	protein	P50548	UNIPROT	down-regulates	phosphorylation	Thr526	GEAGGPLtPRRVSSD	9606									7588608	t		lperfetto	Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf	SIGNOR-29505	0.578
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	MCM10	protein	Q7L590	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								22570418	t		miannu	By screening the known DDB1 interacting proteins, we discovered that VprBP is the substrate recognition subunit that targets Mcm10 for degradation. Hence, these results establish that Cul4-DDB1-VprBP ubiquitin ligase mediates the stress-induced proteolysis of replication factor, Mcm10.	SIGNOR-272045	0.392
ZBTB20	protein	Q9HC78	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								23776228	t		miannu	ChIP and next generation high-throughput DNA sequencing assay showed that ZBTB20 specifically bound to IκBα gene promoter (+1 to +60 region) after TLR activation. ZBTB20 could inhibit IκBα gene transcription, govern IκBα protein expression, and then promote NF-κB activation. Therefore, transcriptional repressor ZBTB20 is needed to promote full activation of TLR signaling and TLR-triggered innate immune response by selectively suppressing the suppressor IκBα gene transcription.	SIGNOR-266868	0.261
CDK5	protein	Q00535	UNIPROT	ERBB3	protein	P21860	UNIPROT	up-regulates activity	phosphorylation	Thr873	LLYSEAKtPIKWMAL	10116	BTO:0004102								12824184	t		llicata	We demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. 	SIGNOR-250664	0.346
WNT11	protein	O96014	UNIPROT	FZD6	protein	O60353	UNIPROT	up-regulates activity	binding			9606	BTO:0000551;BTO:0000848								16273260	t		gcesareni	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-141431	0.66
ATP5MG	protein	O75964	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261408	0.2
1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-)	smallmolecule	CHEBI:60110	ChEBI	phosphatidylglycerol(1-)	smallmolecule	CHEBI:60523	ChEBI	up-regulates quantity	precursor of			10090									21641550	t		lperfetto	PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis.	SIGNOR-267027	0.8
ALG1	protein	Q9BT22	UNIPROT	alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol)	smallmolecule	CHEBI:133994	ChEBI	up-regulates quantity	chemical modification			9606									28575298	t		lperfetto	The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum.	SIGNOR-260418	0.8
CHEK2	protein	O96017	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates activity	phosphorylation	Ser216	SGLYRSPsMPENLNR	9606									12835754	t		lperfetto	Activated chk2 in turn phosphorylates cdc25c at serine-216 contributing to the g2/m checkpoints. Cds1 phosphorylates and inactivates cdc25 in vitro|CDC25C is phosphorylated on Ser 216 throughout interphase, but not in mitosis. This creates a binding site for 14‐3‐3 proteins | It has been suggested that 14‐3‐3 protein binding is responsible for retaining Cdc25C in the cytoplasm during interphase, thereby contributing to the prevention of premature initiation of mitotic events 	SIGNOR-102779	0.852
NFE2	protein	Q16621	UNIPROT	HBG1	protein	P69891	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000426								16287851	f	Regulation of expression	miannu	NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells.	SIGNOR-251841	0.508
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606	BTO:0000007								16403219	t		miannu	Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.	SIGNOR-259422	0.2
AURKB	protein	Q96GD4	UNIPROT	MAPRE3	protein	Q9UPY8	UNIPROT	up-regulates	phosphorylation	Ser176	MQTSGRLsNVAPPCI	9606									23712260	t		lperfetto	Phosphorylation of eb3 at s176 by aurora b ensures successful cytokinesis completion by promoting midbody mt stability and midbody stabilization.	SIGNOR-202130	0.485
CSNK2A2	protein	P19784	UNIPROT	SLC18A2	protein	Q05940	UNIPROT	unknown	phosphorylation	Ser511	PIGEDEEsESD	-1									9045708	t		llicata	Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. 	SIGNOR-251038	0.311
RUNX2	protein	Q13950	UNIPROT	VEGFC	protein	P49767	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001610								22641097	f		miannu	 Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells.	SIGNOR-255081	0.2
Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	OXTR	protein	P30559	UNIPROT	up-regulates	binding			9606									1313946	t		gcesareni	The oxytocin receptor, expressed in xenopus oocytes, specifically responds to oxytocin and induces an inward membrane current	SIGNOR-16758	0.2
ADORA2A	protein	P29274	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257413	0.252
IGF1R	protein	P08069	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates activity	phosphorylation	Tyr980	YASVNPEyFSAADVY	-1									7493944	t		lperfetto	The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.	SIGNOR-246256	0.2
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser171	PLCLSPAsSGSSASF	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248365	0.598
IL4R	protein	P24394	UNIPROT	IL2RG	protein	P31785	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0000801;BTO:0000876	BTO:0000887;BTO:0000763;BTO:0001260							12704343	t		milica	The type i il-4 receptors result from association of IL-4R With the common ? Chain (?c), which is also a component of the receptors for il-2, il-7, il-9, and il-15.	SIGNOR-100765	0.823
MAPK14	protein	Q16539	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates activity	phosphorylation	Ser90	GLFNELAsPFENEFK	9606	BTO:0000599								10085140	t		miannu	P38 directly phosphorylates ATF-2 at Thr-69, Thr-71, and Ser-90, resulting in stimulation of its trans-activating capacity.	SIGNOR-250090	0.786
PRKACA	protein	P17612	UNIPROT	PIM1	protein	P11309	UNIPROT	up-regulates activity	phosphorylation	Ser65	HSHSPRHsLRHSPGS	9606									30017192	t		miannu	In this study, we found that PKCα stabilized and activated PIM-1L by phosphorylation at Ser65. The PIM-1L phosphorylation suppressed sotrastaurin-induced apoptosis. These findings suggest that PKCα promotes cell survival and proliferation by upregulating PIM-1L in acute myeloid leukemia.	SIGNOR-256153	0.269
PLK3	protein	Q9H4B4	UNIPROT	CDC25C	protein	P30307	UNIPROT	unknown	phosphorylation	Ser216	SGLYRSPsMPENLNR	-1									10557092	t		lperfetto	The physical association and phosphorylation of Cdc25C protein phosphatase by Prk. | Further studies reveal that His6-Prk phosphorylates Cdc25C on serine216, a residue also phosphorylated by Chk1 and Chk2. Together, these observations strongly suggest that Prk's role in mitosis is at least partly mediated through direct regulation of Cdc25C.	SIGNOR-249030	0.721
NANOG	protein	Q9H9S0	UNIPROT	Pluripotency	phenotype	SIGNOR-PH43	SIGNOR	up-regulates				9606	BTO:0001086								16153702	f		flangone	Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes.	SIGNOR-242076	0.7
FGG	protein	P02679	UNIPROT	VWF	protein	P04275	UNIPROT	down-regulates activity	binding			9606									2243140	t	Regulation	miannu	Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a).	SIGNOR-251968	0.478
BLOC-1	complex	SIGNOR-C381	SIGNOR	Melanosome_assembly	phenotype	SIGNOR-PH180	SIGNOR	up-regulates				9606	BTO:0000847								22203680	f		lperfetto	Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes	SIGNOR-265939	0.7
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257966	0.8
PTPRF	protein	P10586	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	dephosphorylation			9606									12018405	t		lperfetto	Some 10 years ago, Hashimoto et al. (87) had shown that the LAR catalytic domain can dephosphorylate the EGFR receptor in vitro, and more recently, Kulas and colleagues (88) have demonstrated that the antisense mediated suppression of LAR can enhance the growth factor induced activation of EGFR in rat hepatoma cells.|These data indicate that LAR and RPTPsigma may have a significant role in GPCR induced EGFR signalling.Whereas in A431 cells LAR and RPTPsigma may act to suppress the EGFR in response to GPCR activation, it is possible that the converse may also be true in other cell types.	SIGNOR-277029	0.343
ARAP3	protein	Q8WWN8	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260457	0.5
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	IL16	protein	Q14005	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000782								14768064	t	inferred from 70% family members	lperfetto	The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 in antigen receptor-, sdf1alpha- and il-2-activated t cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response.	SIGNOR-270056	0.2
NUP98-HOXA9	fusion protein	SIGNOR-FP15	SIGNOR	HDAC1	protein	Q13547	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								28630438	t		miannu	NUP98-HOXA9 has an activator-repressor role in transcriptional regulation driven by p300 and HDAC1 interactions. The chromosomal translocation t(7;11)(p15, p15), encoding the fusion protein NUP98-HOXA9 (NHA9), is a rare poor risk cytogenetic event in AML associated with a particularly poor prognosis.In summary, NHA9 deregulates the expression of key leukemic genes, including MEIS1-HOXA9-PBX3 complex, through the enhancer binding and the direct interaction of the fusion protein with HDAC and p300 transcriptional regulators. 	SIGNOR-261498	0.2
RPL27A	protein	P46776	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262473	0.852
PLK1	protein	P53350	UNIPROT	BUB1B	protein	O60566	UNIPROT	up-regulates	phosphorylation	Ser676	LSPIIEDsREATHSS	9606									17785528	t		lperfetto	We identify s676 as a plk1-specific phosphorylation site on bubr1. These findings describe the first in vivo verified phosphorylation site for human bubr1, identify plk1 as the kinase responsible for causing the characteristic mitotic bubr1 upshift, and attribute a kt-specific function to the hyperphosphorylated form of bubr1 in the stabilization of kt-mt interactions.	SIGNOR-157646	0.834
GSK3B	protein	P49841	UNIPROT	PHLPP1	protein	O60346	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1359	VPRPHVQsVLLTPQD	9606	BTO:0002181								19797085	t		miannu	We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity. 	SIGNOR-276263	0.36
PPP1CA	protein	P62136	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates	dephosphorylation	Thr450	TAQMITItPPDQDDS	9606									20186153	t		gcesareni	Several stps have been reported to negatively regulate akt pathway. It has been shown that pp1 dephosphorylates akt and regulates cell survival.	SIGNOR-163961	0.436
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	SREBF2	protein	Q12772	UNIPROT	up-regulates	phosphorylation			9606									14988395	t	inferred from 70% family members	lperfetto	Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity.	SIGNOR-270012	0.2
IFNB1	protein	P01574	UNIPROT	TYK2	protein	P29597	UNIPROT	up-regulates				9606									10918594	f		gcesareni	Early events in type i ifn signaling are tyrosine phosphorylation of the type i ifn receptor subunits (ifnar1 and ifnar2), and the activation of the receptor-associated tyk-2 and jak-1 janus kinases.	SIGNOR-80103	0.535
NFIB	protein	O00712	UNIPROT	NEUROD4	protein	Q9HD90	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268898	0.2
CHEK2	protein	O96017	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser988	PPLFPIKsFVKTKCK	9606	BTO:0000150								14701743	t		gcesareni	In this study, we tested the hypothesis that the brca1-mediated regulation of recombination requires the chk2- and atm-dependent phosphorylation sites.	SIGNOR-120575	0.78
EIF2B5	protein	Q13144	UNIPROT	EIF2S3	protein	P41091	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269133	0.724
TNFRSF21	protein	O75509	UNIPROT	ROS	stimulus	SIGNOR-ST2	SIGNOR	down-regulates				9606									32454942	f		miannu	Further, data from our laboratories indicate that selective agonism of TNFR2 rescues neurons from oxidative stress-induced cell death [160] and excitotoxic cell death [161, 162]. Similarly, TNFR2 activation induces expression of antiapoptotic and detoxifying proteins and protects OPCs against oxidative stress.	SIGNOR-263831	0.7
MTA1	protein	Q13330	UNIPROT	CXCL1	protein	P09341	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000812								18719363	f		miannu	Screening for the expression of angiogenic cytokines expressed by ovarian cancer cells revealed MTA1-mediated upregulation of the oncogenic and angiogenic cytokine GRO (growth-regulated oncogene, CXCL1).	SIGNOR-254598	0.2
SRC	protein	P12931	UNIPROT	GRB10	protein	Q13322	UNIPROT	down-regulates	phosphorylation	Tyr67	NASLESLySACSMQS	9606									10871840	t		lperfetto	Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir.	SIGNOR-78706	0.459
AKAP11	protein	Q9UKA4	UNIPROT	PKA	proteinfamily	SIGNOR-PF17	SIGNOR	up-regulates quantity	binding			9606									21776420	t		miannu	We show that IQGAP2 is regulated by an interaction with the A-kinase anchoring protein AKAP220. Phosphorylation of IQGAP2 via AKAP220-anchored PKA leads to enhanced Rac binding. Since AKAPs function to direct PKA toward specific substrates, we proposed that the formation of an IQGAP2/AKAP220/PKA ternary complex sharpens the response to cAMP.	SIGNOR-273741	0.434
SHMT1	protein	P34896	UNIPROT	glycine	smallmolecule	CHEBI:15428	ChEBI	up-regulates quantity	chemical modification			9606									32439610	t		lperfetto	Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. 	SIGNOR-268223	0.8
PPP1R14A	protein	Q96A00	UNIPROT	PPP1CB	protein	P62140	UNIPROT	down-regulates activity	binding			-1									12144526	t		lperfetto	We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin	SIGNOR-265742	0.485
CDH11	protein	P55287	UNIPROT	α-Catenin	proteinfamily	SIGNOR-PF72	SIGNOR	up-regulates activity	binding			9606									10029089	t		miannu	Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin	SIGNOR-265825	0.498
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2J1	protein	Q9Y385	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271342	0.571
BIRC3	protein	Q13489	UNIPROT	RIPK3	protein	Q9Y572	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0000007								21931591	t		miannu	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.	SIGNOR-272714	0.633
HLX	protein	Q14774	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003980								20008130	t		Luana	In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.	SIGNOR-261622	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	DUSP6	protein	Q16828	UNIPROT	down-regulates	phosphorylation			9606									15632084	t	inferred from 70% family members	amattioni	Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3	SIGNOR-270205	0.2
GNB5	protein	O14775	UNIPROT	Adenylate_cyclase	proteinfamily	SIGNOR-PF92	SIGNOR	down-regulates activity	binding			9606	BTO:0004032								21303898	t		miannu	The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC	SIGNOR-267850	0.457
GRPR	protein	P30550	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257159	0.271
KIF5B	protein	P33176	UNIPROT	GABBR1	protein	Q9UBS5	UNIPROT	up-regulates activity	relocalization			10090									17532644	t		SARA	GABABR1 co-immunoprecipitated with Marlin-1 and kinesin-I, providing evidence for the existence of a complex between these proteins. Kinesin-I modulates GABAB receptor transport.	SIGNOR-260990	0.258
WNK3	protein	Q9BYP7	UNIPROT	SLC12A3	protein	P55017	UNIPROT	up-regulates activity	phosphorylation												21613606	t		lperfetto	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264624	0.468
Bombesin	smallmolecule	CHEBI:80229	ChEBI	GRPR	protein	P30550	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257509	0.8
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRIK2	protein	Q13002	UNIPROT	up-regulates activity	chemical activation			9606									27586965	t		miannu	Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors	SIGNOR-264471	0.8
1-acyl-sn-glycerol 3-phosphate(2-)	smallmolecule	CHEBI:57970	ChEBI	phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	up-regulates quantity	precursor of			9606									21173190	t		lperfetto	The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA). 	SIGNOR-267010	0.8
DUSP8	protein	Q13202	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	dephosphorylation			9606									23159405	t		gcesareni	M3/6 (dusp8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of jnk and, to a lesser extent, p38 mapk	SIGNOR-199695	0.574
dexamethasone	chemical	CHEBI:41879	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								8282004	t		miannu	The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4).	SIGNOR-258711	0.8
potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								11506885	f		miannu	Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height	SIGNOR-265590	0.7
CREBBP	protein	Q92793	UNIPROT	STAT2	protein	P52630	UNIPROT	up-regulates activity	acetylation	Lys390	QKTLTPEkGQSQGLI	9606	BTO:0000007								17923090	t		lperfetto	STAT2 is another important component of ISGF3 complex, and its acetylation was similar to IFNaR2 and IRF9 acetylation in many respects: CBP downregulation largely abolished STAT2 acetylation induction by IFNa (Figure 6A), and CBP was more potent than transferases tested in catalyzing STAT2 acetylation (Figure 6B). [...] Figure 6 (I) STAT2-K390R substitution has reduced activity in ISGF3 complex formation.	SIGNOR-217891	0.549
PPP2CA	protein	P67775	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates	dephosphorylation	Thr202	HDHTGFLtEYVATRW	9606							phosphorylation:Thr202	HDHTGFLtEYVATRW	16456541	t		gcesareni	B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk	SIGNOR-144322	0.632
RAB8A	protein	P61006	UNIPROT	Cilium_assembly	phenotype	SIGNOR-PH64	SIGNOR	up-regulates				9606									18694559	f		miannu	CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110	SIGNOR-252148	0.7
SNAI2	protein	O43623	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000356								21044962	f		miannu	 knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene.	SIGNOR-255176	0.472
NMDA	proteinfamily	SIGNOR-PF56	SIGNOR	CTTN	protein	Q14247	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000142								14684878	t		miannu	Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors.	SIGNOR-266598	0.2
ID3	protein	Q02535	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates activity	binding			10090	BTO:0004058			SIGNOR-C127					9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241134	0.546
DNAH10	protein	Q8IVF4	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0000667								31836722	f		miannu	 Epidermal expression of axonemal dynein heavy chain 10 (DNAH10) was increased 20-fold in samples having had regenerating dermis vs control. Our results associate DNAH10 expression with cell proliferation and inflammation as well as with the epidermal memory resulting from the previous regenerative signals of dermis.	SIGNOR-265550	0.7
KMT2D	protein	O14686	UNIPROT	HMT	complex	SIGNOR-C19	SIGNOR	form complex	binding			9606									17500065	t		lperfetto	The evolutionarily conserved hdpy-30, ash2l, rbbp5, and wdr5 likely constitute a subcomplex that is shared by all human set1-like hmt complexes.	SIGNOR-154763	0.829
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BC3	protein	P33778	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSIYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271983	0.2
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGA2	protein	Q9Y5H1	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265713	0.2
RET	protein	P07949	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates	phosphorylation	Tyr182	TDDEMTGyVATRWYR	9606									17126298	t		gcesareni	Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme.	SIGNOR-150879	0.338
SMAD1/5/8	proteinfamily	SIGNOR-PF35	SIGNOR	SMAD1/5/8/SMAD4	complex	SIGNOR-C215	SIGNOR	form complex	binding			9606									20957627	t		lperfetto	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.	SIGNOR-255838	0.67
Nucleosome_H2A.Z.2 variant	complex	SIGNOR-C323	SIGNOR	Transcritpional_activation	phenotype	SIGNOR-PH205	SIGNOR	down-regulates				9606									15623580	f		lperfetto	All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage.	SIGNOR-273456	0.7
EGFR	protein	P00533	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr5	yLDPNLNH	9606									20802513	t		llicata	In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.	SIGNOR-167650	0.581
Isoetharine	chemical	CHEBI:6005	ChEBI	DRD3	protein	P35462	UNIPROT	up-regulates activity	chemical activation			-1									7576010	t		miannu	The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1.	SIGNOR-258433	0.8
CDK1	protein	P06493	UNIPROT	TOB2	protein	Q14106	UNIPROT	up-regulates activity	phosphorylation	Ser254	PAPQSQLsPNAKEFV	-1									32404348	t	done	miannu	Taken together, these observations strongly support the notion that several different CDK-cyclin complexes are involved in the phosphorylation of Tob2 at S254.A more detailed regulatory context of Tob2 phosphorylation at S254 is provided by our findings from mass-spec and in vitro kinase analyses that suggest connections to PP2B and PP2C phosphatases and CDK-cyclin complexes, particularly CDK1, CDK2, and CDK4 (Table 1; Supplemental Table S2).One possibility is that the phosphorylation of S254 helps stabilize the interaction of Tob2 with the Ccr4–Not complex, which could contribute to Tob2's ability to recruit the entire Ccr4–Not complex and thus further enhances deadenylation. 	SIGNOR-273591	0.2
ASXL1	protein	Q8IXJ9	UNIPROT	HOXA9	protein	P31269	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22897849	f		miannu	 ASXL1 siRNA in human primary CD34+ cells form cord blood results in upregulation of HOXA5 and HOXA9 with ASXL1 knockdown (KD) as revealed by quantitative real-time PCR	SIGNOR-256127	0.446
PRLHR	protein	P49683	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256973	0.311
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	CEBPB	protein	P17676	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000801								19327116	t	inferred from 70% family members	gcesareni	Thr235 phosphorylation occurs in nuclei of differentiated macrophages, but not in monocytes.	SIGNOR-270045	0.2
AXL	protein	P30530	UNIPROT	YES1	protein	P07947	UNIPROT	up-regulates activity	phosphorylation	Tyr426	RLIEDNEyTARQGAK	9606	BTO:0001007								33941853	t		miannu	Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells.	SIGNOR-277555	0.2
PRKAA1	protein	Q13131	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser413	GLMQRSSsFPYTTKG	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-249677	0.509
RNF138	protein	Q8WVD3	UNIPROT	TCF7L2	protein	Q9NQB0	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								16714285	t		miannu	Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome. 	SIGNOR-271593	0.33
IC-87114	chemical	CHEBI:90686	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206193	0.8
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	JUN	protein	P05412	UNIPROT	up-regulates activity	binding			9606									9732876	t		lperfetto	Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos	SIGNOR-229545	0.702
TIMM9	protein	Q9Y5J7	UNIPROT	TIM22 complex	complex	SIGNOR-C424	SIGNOR	form complex	binding			9606	BTO:0000007								32901109	t		lperfetto	Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK).	SIGNOR-267702	0.568
SRGAP2	protein	O75044	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260517	0.587
DDHD1	protein	Q8NEL9	UNIPROT	long-chain fatty acid anion	smallmolecule	CHEBI:57560	ChEBI	up-regulates quantity	chemical modification			9606									22922100	t		miannu	Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 	SIGNOR-269653	0.8
CSF1R	protein	P07333	UNIPROT	CSF1R	protein	P07333	UNIPROT	up-regulates	phosphorylation	Tyr723	SSQGVDTyVEMRPVS	9606	BTO:0001271								15297464	t		lperfetto	Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins.	SIGNOR-127614	0.2
PRKCA	protein	P17252	UNIPROT	ADRA1B	protein	P35368	UNIPROT	down-regulates activity	phosphorylation	Ser406	RSQSRKDsLDDSGSC	9534	BTO:0000298								9353340	t		lperfetto	 Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. 	SIGNOR-248987	0.399
RYBP	protein	Q8N488	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates	binding			9606									8943360	t		gcesareni	We identified a novel protein, aap1 (abl-associated protein 1), that associates with these c-abl domains and fails to bind to the sh3 domain in the activated oncoprotein bcrabl. we conclude that aap1 inhibits c-abl tyrosine kinase activity	SIGNOR-45325	0.338
CTDSP1	protein	Q9GZU7	UNIPROT	TWIST1	protein	Q15672	UNIPROT	down-regulates activity	dephosphorylation	Ser68	GGGDEPGsPAQGKRG	9606	BTO:0000007								26975371	t		gcesareni	These results indicate that SCP1 is the phosphatase that counter-regulates the MAPK-mediated phosphorylation of S68-Twist1.	SIGNOR-245962	0.2
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGA8	protein	Q9Y5G5	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265702	0.2
gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	GABA-A (a4-b1-g2) receptor	complex	SIGNOR-C333	SIGNOR	up-regulates activity	chemical activation			9606									18790874	t	brain	lperfetto	Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS).	SIGNOR-263789	0.8
MYC	protein	P01106	UNIPROT	DNMT3A	protein	Q9Y6K1	UNIPROT	up-regulates activity	binding			9606									19786833	t		irozzo	Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. 	SIGNOR-255806	0.701
CDK2	protein	P24941	UNIPROT	CCP110	protein	O43303	UNIPROT	down-regulates activity	phosphorylation	Thr194	FPKTSSAtPQETLIS	-1									12361598	t		miannu	GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)	SIGNOR-265961	0.531
calcitriol	smallmolecule	CHEBI:17823	ChEBI	calcitetrol	smallmolecule	CHEBI:47799	ChEBI	up-regulates quantity	precursor of												30080183	t		lperfetto	Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH).	SIGNOR-270570	0.8
SOD1	protein	P00441	UNIPROT	ERN1	protein	O75460	UNIPROT	up-regulates activity	binding			10090	BTO:0004488								18519638	t	P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)		SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK	SIGNOR-262786	0.322
MAPK8	protein	P45983	UNIPROT	ITCH	protein	Q96J02	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0002417								15358865	t		gcesareni	Activation of the Jun amino-terminal kinase (JNK) mitogen-activated protein kinase cascade after T cell stimulation accelerated degradation of c-Jun and JunB through phosphorylation-dependent activation of the E3 ligase Itch.	SIGNOR-245315	0.644
AR	protein	P10275	UNIPROT	ARG1	protein	P05089	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001321								20711410	f		miannu	The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. 	SIGNOR-253738	0.2
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates	phosphorylation	Thr90	SPLLLTTtNSSEGLS	9606									11152499	t		tpavlidou	Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites.	SIGNOR-85789	0.2
WNT11	protein	O96014	UNIPROT	MUSK	protein	O15146	UNIPROT	up-regulates	binding			9606									23151663	t		gcesareni	Musk has an extracellular region with homology to the frizzled crd,binding of which by wnt11 stimulates a pcp-like pathway during neuromuscolar development. Here, we show that in vivo, wnt11r and wnt4a initiate musk translocation from muscle membranes to recycling endosomes we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase	SIGNOR-199641	0.47
ZAP70	protein	P43403	UNIPROT	DBNL	protein	Q9UJU6	UNIPROT	up-regulates	phosphorylation	Tyr334	QAEEEAVyEEPPEQE	9606	BTO:0000782								14557276	t		lperfetto	We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling. 	SIGNOR-118691	0.625
PRKCA	protein	P17252	UNIPROT	GRIA4	protein	P48058	UNIPROT	up-regulates	phosphorylation	Ser862	IRNKARLsITGSVGE	9606									12536214	t		gcesareni	Receptor internalization, altered;intracellular localization	SIGNOR-97554	0.551
Melanin-concentrating hormone	smallmolecule	CHEBI:80254	ChEBI	MCHR2	protein	Q969V1	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257541	0.8
Immune_response	phenotype	SIGNOR-PH17	SIGNOR	ARDS	phenotype	SIGNOR-PH128	SIGNOR	up-regulates				9606									32446778	f		miannu	The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm.	SIGNOR-261035	0.7
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ARRB2	protein	P32121	UNIPROT	up-regulates activity	phosphorylation	Ser14	TRVFKKSsPNCKLTV	10090	BTO:0002572								26324936	t	done	miannu	ERK1/2-dependent βarr2 phosphorylation on S14 and T276 induces CXCR4 intracellular sequestration.	SIGNOR-274018	0.2
PTPRF	protein	P10586	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606	BTO:0000938								27225731	f		miannu	LAR (for leukocyte common antigen-related) is a family of receptor protein tyrosine phosphatases (LAR-RPTPs) with three known members: LAR/PTPRF, PTPδ/PTPRD, and PTPσ/PTPRS. In mammals, LAR-RPTPs have been shown to regulate dendrite and excitatory synapse development and maintenance	SIGNOR-264090	0.7
PRKCA	protein	P17252	UNIPROT	HSPB8	protein	Q9UJY1	UNIPROT	up-regulates activity	phosphorylation	Thr63	LSSAWPGtLRSGMVP	9606		BTO:0000887							11342557	t		lperfetto	Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation	SIGNOR-107688	0.311
EP300	protein	Q09472	UNIPROT	SMAD2/STAT3/EP300	complex	SIGNOR-C203	SIGNOR	form complex	binding			9606									26194464	t		MARCO ROSINA	Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes.	SIGNOR-255025	0.674
LRP1B	protein	Q9NZR2	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0000038; BTO:0000675								28408316	f		irozzo	Forced expression of LRP1B in SW480 and SW620 cells inhibited the growth, migration and anchorage-independent growth of cancer cells.	SIGNOR-259091	0.7
VHL	protein	P40337	UNIPROT	HIF-1 complex	complex	SIGNOR-C418	SIGNOR	down-regulates	ubiquitination			9606									10944113	t		miannu	Here we show that the product of the von hippel-lindau (vhl) tumor suppressor gene mediated ubiquitylation and proteasomal degradation of hif-1 alpha under normoxic conditions via interaction with the core of the oxygen-dependent degradation domain of hif-1 alpha.	SIGNOR-80969	0.683
OPRM1	protein	P35372	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256990	0.624
PPM1B	protein	O75688	UNIPROT	CDK2	protein	P24941	UNIPROT	down-regulates activity	dephosphorylation			9606									20538721	t		miannu	CDK2 can be dephosphorylated and inactivated by protein phosphatase type 2C beta isoform long (PP2Cbetal), a unique phosphatase that was originally cloned from human liver.	SIGNOR-277153	0.369
MAPK11	protein	Q15759	UNIPROT	EWSR1	protein	Q01844	UNIPROT	unknown	phosphorylation	Thr79	QPPTGYTtPTAPQAY	9606									19076070	t		lperfetto	Here we report that ews and ews-fli1 become phosphorylated at thr79 . but the p38_/p38_ mapks were the major kinases phosphorylating ews-fli1. It will be important to investigate how the p38_/p38_-stimulated phosphorylation of ews-fusion proteins affects their ability to transactivate and their oncogenic potential.	SIGNOR-182774	0.2
CDK4	protein	P11802	UNIPROT	FOXM1	protein	Q08050	UNIPROT	up-regulates	phosphorylation	Thr620	SKSVLPRtPESWRLT	9606									22094256	t		lperfetto	We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627)	SIGNOR-177259	0.609
CDK9	protein	P50750	UNIPROT	XRN2	protein	Q9H0D6	UNIPROT	up-regulates activity	phosphorylation	Thr439	FTPSGILtPHALGSR	-1									26728557	t		miannu	Among the RNA processing factors phosphorylated by Cdk9 was the 5'-to-3' "torpedo" exoribonuclease Xrn2, required in transcription termination by Pol II, which we validated as a bona fide P-TEFb substrate in vivo and in vitro. Phosphorylation by Cdk9 or phosphomimetic substitution of its target residue, Thr439, enhanced enzymatic activity of Xrn2 on synthetic substrates in vitro. 	SIGNOR-277194	0.282
GIGYF2	protein	Q6Y7W6	UNIPROT	EIF4E2/GIGYF2 complex	complex	SIGNOR-C257	SIGNOR	form complex	binding			9606	BTO:0000568								22751931	t		SARA	A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|GIGYF2 interacts specifically with m4EHP. The stabilities of m4EHP and GIGYF2 proteins are coregulated.	SIGNOR-261009	0.713
MAPK9	protein	P45984	UNIPROT	SH3BP5	protein	O60239	UNIPROT	unknown	phosphorylation	Ser351	PGSLDLPsPVSLSEF	-1									15158451	t		miannu	 we have identified serine 321 as the major site of phosphorylation by both SAPK3 and JNK2. SAPK3 but not JNK2 also phosphorylates serine 391	SIGNOR-250142	0.377
PARP1	protein	P09874	UNIPROT	KDM5B	protein	Q9UGL1	UNIPROT	up-regulates activity	relocalization			9606									33859667	t		SaraGualdi	The mechanism of KDM5B recruitment is quite specific and requires the presence of nucleosomes containing histone variant MacroH2A1.1 and PARylation by PARP1.	SIGNOR-271574	0.363
CDK2	protein	P24941	UNIPROT	UHRF1	protein	Q96T88	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser675	KTKVEPYsLTAQQSS	-1									26727879	t		miannu	UHRF1 is phosphorylated by CDK2/cyclin A. In vitro kinase assay was performed with CDK2/cyclin A using recombinant wild-type UHRF1 or UHRF1-S674A mutant 	SIGNOR-277192	0.308
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGC3	protein	Q9UN70	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265674	0.2
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr70	RNSPVTKtPPRDLPT	9606									12747827	t		lperfetto	Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e.	SIGNOR-235964	0.753
ERBB2	protein	P04626	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606									8816440	t		gcesareni	Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3.	SIGNOR-147838	0.595
CBP/p300	complex	SIGNOR-C6	SIGNOR	THBD	protein	P07204	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15677570	f	 	miannu	We further show evidence suggesting that NF-κB inhibits TM expression indirectly by competition for the coactivator p300/CBP. 	SIGNOR-253908	0.2
NR1I3	protein	Q14994	UNIPROT	CYP2B6	protein	P20813	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18303024	f		miannu	 The CYP2B6 enzyme metabolizes commonly used therapeutics and also activates pro-drugs. The CAR directly binds to the distal enhancer element of the CYP2B6 promoter, which is essential in converging to its drug-sensing function onto promoter activity. However, this binding alone is not sufficient to activate the CYP2B6 promoter; the promoter requires EGR1 to enable CAR to activate the CYP2B6 promoter.	SIGNOR-253875	0.485
PRKAA2	protein	P54646	UNIPROT	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation	Ser638	FDFPKTPsSQNLLAL	9606			SIGNOR-C15						19584320	t		gcesareni	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-186641	0.483
GSK3B	protein	P49841	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates	phosphorylation	Ser137	PVSSPQSsPRLPRRP	9606									22778263	t		lperfetto	Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity.	SIGNOR-198142	0.276
AP1	complex	SIGNOR-C154	SIGNOR	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates activity				9606									21561061	f		Luana	AP-1 regulates transcription of many genes involved in viralpathogenesis, including pro-inflammatory and antiviral cytokineslike IL-6,33IL-8,34RANTES,35MCP-1,19interferons,9etc., thatare characteristic of an infection. SARS pathology is the result ofan exacerbated pro-inflammatory immune response by cytokinesin the lungs of patients and in infected animal models.	SIGNOR-260765	0.7
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGA1	protein	Q9Y5H4	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265686	0.2
LRRK2	protein	Q5S007	UNIPROT	CADPS2	protein	Q86UW7	UNIPROT	up-regulates quantity	transcriptional regulation			9606									28647363	f		gianni	This approach enabled us to disclose a differential effect of high levels of LRRK2 and aSyn on CADPS2 promoter activity. Specifically, CADPS2 transcriptional activity was enhanced by high cellular levels of LRRK2 and reduced by overexpression of aSyn. Consistently, CADPS2 mRNA levels were diminished in aSyn overexpressing cells.	SIGNOR-268928	0.297
GSK3A	protein	P49840	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser579	NVKSKIGsTENLKHQ	9606	BTO:0000938								9771888	t	The effect has been demonstrated using P10636-8	gcesareni	Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase.	SIGNOR-60651	0.44
TBK1	protein	Q9UHD2	UNIPROT	IRF5	protein	Q13568	UNIPROT	up-regulates	phosphorylation	Ser158	QRMLPSLsLTEDVKW	9606									22412986	t		lperfetto	Activation of interferon regulatory factor 5 by site specific phosphorylation. Although the gene induction by irf5 in the presence of tbk-1 was modest, phosphorylation by tbk-1 produced a significant shift in the mobility of irf5 in sds-page. For this reason we identified the residues that are phosphorylated on irf5 by tbk-1 with mass spectrometry. Ser-158 and ser-309 were found to be phosphorylated	SIGNOR-196528	0.558
MTHFD1	protein	P11586	UNIPROT	10-formyltetrahydrofolate(2-)	smallmolecule	CHEBI:57454	ChEBI	up-regulates quantity	chemical modification			-1									18767138	t		lperfetto	Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate	SIGNOR-268250	0.8
CSNK2A2	protein	P19784	UNIPROT	XRCC1	protein	P18887	UNIPROT	up-regulates activity	phosphorylation	Thr523	AGSTDENtDSEEHQE	9606	BTO:0000567								15367657	t		llicata	XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1.	SIGNOR-251052	0.473
ketanserin	chemical	CHEBI:6123	ChEBI	SLC18A2	protein	Q05940	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000318								8643547	t		miannu	Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2.	SIGNOR-258494	0.8
RNF5	protein	Q99942	UNIPROT	STING1	protein	Q86WV6	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys150	EISAVCEkGNFNVAH	9606	BTO:0000007								19285439	t		miannu	The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection.	SIGNOR-271484	0.2
POLD4	protein	Q9HCU8	UNIPROT	DNA polymerase delta 	complex	SIGNOR-C376	SIGNOR	form complex	binding			-1									12403614	t		lperfetto	Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme.	SIGNOR-265517	0.873
CAMK2A	protein	Q9UQM7	UNIPROT	ETS1	protein	P14921	UNIPROT	down-regulates	phosphorylation	Ser251	GKLGGQDsFESIESY	9606	BTO:0000782								12475968	t		lperfetto	Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition	SIGNOR-96330	0.313
UBE2J1	protein	Q9Y385	UNIPROT	DIO2	protein	Q92813	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys237	VCIVQRQkIAYLGGK	9606		BTO:0001379							29892818	t		scontino	ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244.	SIGNOR-267481	0.387
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	RARA	protein	P10276	UNIPROT	up-regulates activity	chemical activation			9606									17132853	t		miannu	The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 	SIGNOR-256194	0.8
PIAS1	protein	O75925	UNIPROT	DDX5	protein	P17844	UNIPROT	up-regulates	sumoylation	Lys53	WNLDELPkFEKNFYQ	9606									17369852	t		miannu	We demonstrate that the sumo e3 ligase pias1 interacts with p68 and enhances its sumo modification in vivo / sumo modification enhances p68 transcriptional repression activity and inhibits the ability of p68 to function as a coactivator of p53.	SIGNOR-153719	0.526
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation	Ser73	VGLLKLAsPELERLI	9606									9405416	t	Phosphorylation of c-Jun on Ser73 by JNK is sufficient to protect c-Jun from ubiquitination.	lperfetto	Phosphorylation by activated jnk protects c-jun from ubiquitination.	SIGNOR-53788	0.2
MYD88	protein	Q99836	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity	binding			10090	BTO:0003432								10217414	t		lperfetto	Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. Myd88 binds to both irak (il-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of irak with the receptor.	SIGNOR-67143	0.843
SRC	protein	P12931	UNIPROT	BCKDK	protein	O14874	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr246	RRLCEHKyGNAPRVR	9606	BTO:0001615								32238881	t		lperfetto	Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells. 	SIGNOR-275584	0.2
LATS2	protein	Q9NRM7	UNIPROT	MTF1	protein	Q14872	UNIPROT	down-regulates activity	phosphorylation	Ser152	EGCPRTYsTAGNLRT										35027733	t		lperfetto	The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1|the Hippo pathway kinase LATS phosphorylates and inhibits MTF1|LATS phosphorylates MTF1 at S152 and disrupts its association with the promoters of heavy metal response genes, resulting in the loss of heavy metal response gene expression	SIGNOR-275475	0.2
SP1	protein	P08047	UNIPROT	CRX	protein	O43186	UNIPROT	up-regulates activity	binding			9606									15781457	t		miannu	Zinc finger DNA-binding domains of both Sp1 and Sp3 interact with Crx. Sp4 and Sp1 produce much higher levels of transcriptional activation when co-transfected with Crx, they may additionally act by directly increasing the rate of transcriptional initiation by the general transcriptional apparatus through their activation domains.	SIGNOR-225336	0.328
PREX2	protein	Q70Z35	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260572	0.434
BTG2	protein	P78543	UNIPROT	KLK3	protein	P07288	UNIPROT	down-regulates quantity by repression	transcriptional regulation												21172304	f	 	 	Androgen-induced promoter activation and expression of prostate-specific antigen (PSA) are significantly attenuated by BTG2.	SIGNOR-253658	0.2
UBXN1	protein	Q04323	UNIPROT	NGLY1	protein	Q96IV0	UNIPROT	up-regulates activity	binding			9606									15362974	t		miannu	PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome.	SIGNOR-261060	0.465
HTR1D	protein	P28221	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257000	0.359
MAPK8	protein	P45983	UNIPROT	ITCH	protein	Q96J02	UNIPROT	up-regulates	phosphorylation			9606									16469705	t		gcesareni	Here we show that tnfalpha-mediated jnk activation accelerates turnover of the nf-kappab-induced antiapoptotic protein c-flip, an inhibitor of caspase-8. This is not due to direct c-flip phosphorylation but depends on jnk-mediated phosphorylation and activation of the e3 ubiquitin ligase itch, which specifically ubiquitinates c-flip and induces its proteasomal degradation.	SIGNOR-144456	0.644
CH5132799	chemical	CID:49784945	PUBCHEM	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190946	0.8
PLK1	protein	P53350	UNIPROT	CDC20	protein	Q12834	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser170	KTCRYIPsLPDRILD	-1									23643811	t		miannu	Plk1 directly bound to Cdc20 and phosphorylates it on serine-170 located in CRY-box. Whereas wild-type Cdc20 was degraded according to progress cell cycle beyond mitosis, the phosphorylation-defective mutant, which serine-170 was changed into alanine, was not destroyed in early G1 phase. 	SIGNOR-276493	0.976
NDUFB10	protein	O96000	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4	SIGNOR-262163	0.815
ABL1	protein	P00519	UNIPROT	SRCIN1	protein	Q9C0H9	UNIPROT	unknown	phosphorylation	Tyr396	LVKGEGLyADPYGLL	9606		BTO:0000142							23383002	t		llicata	Mapping of p140cap phosphorylation sites: the eplya and eglya motifs have a key role in tyrosine phosphorylation and csk binding, and are substrates of the abl kinase	SIGNOR-200858	0.2
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257936	0.8
EEF1A2	protein	Q05639	UNIPROT	Thr-tRNA(Thr)	smallmolecule	CHEBI:29163	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269536	0.8
LETM1	protein	O95202	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			10090									29123128	t		lperfetto	LETM1 is a mitochondrial inner membrane protein and several reports suggest that it mediates mitochondrial Ca2+ uptake and extrusion in a gradient-dependent manner	SIGNOR-262541	0.8
SYVN1	protein	Q86TM6	UNIPROT	SERPINI1	protein	Q99574	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								21507957	t		miannu	In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin.	SIGNOR-272757	0.2
SOD1	protein	P00441	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates activity	binding			9606		BTO:0001279							15233914	t	P00441:p.Gly94Ala (mutation disrupting interaction)		Familial amyotrophic lateral sclerosis (ALS)-linked mutations in the copper-zinc superoxide dismutase (SOD1) gene cause motor neuron death in about 3% of ALS cases. While the wild-type (wt) protein is anti-apoptotic, mutant SOD1 promotes apoptosis.|We now demonstrate that both wt and mutant SOD1 bind the anti-apoptotic protein Bcl-2, providing evidence of a direct link between SOD1 and an apoptotic pathway. This interaction is evident in vitro and in vivo in mouse and human spinal cord.|These findings provide new insights into the anti-apoptotic function of SOD1 and suggest that entrapment of Bcl-2 by large SOD1 aggregates may deplete motor neurons of this anti-apoptotic protein.	SIGNOR-262799	0.488
FOXO1	protein	Q12778	UNIPROT	IDH1	protein	O75874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25648147	t		miannu	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260090	0.261
MAST1	protein	Q9Y2H9	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates	phosphorylation			9606									15951562	t		gcesareni	Mast1 was found to associate to pten.	SIGNOR-138003	0.53
PSMA6	protein	P60900	UNIPROT	XBP1	protein	P17861	UNIPROT	down-regulates quantity by destabilization	binding			-1									19941857	t	1	miannu	We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination.	SIGNOR-239039	0.307
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-6-quinazolinyl]-2-propenamide	chemical	CHEBI:91467	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189942	0.8
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Thr130	PAQLLCStPNGLDRG	9606									10864927	t		lperfetto	Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b.	SIGNOR-216769	0.839
DTX1	protein	Q86Y01	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates activity	ubiquitination			7227									22162134	t		lperfetto	The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch	SIGNOR-254317	0.773
FBXW7	protein	Q969H0	UNIPROT	NFKB2	protein	Q00653	UNIPROT	down-regulates quantity by destabilization	binding			10090	BTO:0002572								22388891	t		miannu	Fbxw7α is a member of the F-box family of proteins, which function as the substrate-targeting subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Using differential purifications and mass spectrometry, we identified p100, an inhibitor of NF-κB signalling, as an interactor of Fbxw7α. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7α	SIGNOR-272907	0.404
FYN	protein	P06241	UNIPROT	CTLA4	protein	P16410	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr201	SPLTTGVyVKMPPTE	9606									9973379	t			CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.  Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4. 	SIGNOR-251161	0.762
SIRT1	protein	Q96EB6	UNIPROT	XPA	protein	P23025	UNIPROT	up-regulates activity	deacetylation	Lys67	ANVKAAPkIIDTGGG	9606	BTO:0002806								30327428	t		miannu	SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR	SIGNOR-262294	0.526
APC-c	complex	SIGNOR-C150	SIGNOR	CDR2	protein	Q01850	UNIPROT	down-regulates quantity by destabilization	ubiquitination												20383333	t		lperfetto	Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis.	SIGNOR-252024	0.2
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1784	TPTSPNYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273082	0.636
IKBKE	protein	Q14164	UNIPROT	TANK	protein	Q92844	UNIPROT	down-regulates activity	phosphorylation	Ser228	EEDTSFEsLSKFNVK	9534	BTO:0000298								10759890	t		miannu	IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex	SIGNOR-262718	0.734
PPM1F	protein	P49593	UNIPROT	CHEK1	protein	O14757	UNIPROT	down-regulates activity	dephosphorylation	Ser345	LVQGISFsQPTCPDH	9606									31944151	t		lperfetto	As a result, inactivation of Chk1 by POPX2 leads to impaired G1S checkpoint activation and cells are able to proceed from G1 to S phase despite DNA damage.|We also determined that POPX2 can dephosphorylate Chk1Ser317 and -Ser345 and is a potential regulator of Chk1 function in the cell.	SIGNOR-276988	0.2
GSK3A	protein	P49840	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	phosphorylation	Thr312	TMKTFCGtPEYLAPE	10090	BTO:0005655								23142783	t		gcesareni	GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function.	SIGNOR-252434	0.62
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates activity	phosphorylation	Ser710	GEKSFRRsVVGTPAY										12058027	t		lperfetto	Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.	SIGNOR-275951	0.2
MUTYH	protein	Q9UIF7	UNIPROT	CHEK1	protein	O14757	UNIPROT	up-regulates				9606									21615992	f		miannu	Hmyh is involved in the activation mechanism of chk1 upon dna damage, but not in stability or inactivation.	SIGNOR-173969	0.349
PTEN	protein	P60484	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	dephosphorylation	Tyr419	RLIEDNEyTARQGAK	9606									22482061	t		lperfetto	Antisense- or shRNA mediated downregulation of PTEN induced SRC Tyr416 phosphorylation, SRC activation, and ultimately elevated TZMB resistance, whereas induction of PTEN phosphatase activity directly dephosphorylated SRC Tyr416 residue and so abolished SRC activity .|These observations indicate that the loss of PTEN phosphatase activity induces SRC activation and so implicates SRC in shaping de novo TZMB resistance in PTEN deficient cells .	SIGNOR-277009	0.554
PPM1F	protein	P49593	UNIPROT	MAP3K7	protein	O43318	UNIPROT	down-regulates activity	dephosphorylation			9606									28906490	t		miannu	However, our current work shows that POPX2 can downregulate TAK1 and affect the anti-apoptotic activities of TAK1, implying that silencing POPX2 could facilitate TAK1 activation and will lead to increased cell survival.|We have also demonstrated that POPX2 can directly dephosphorylate TAK1 (XREF_FIG).	SIGNOR-277047	0.405
IL23R	protein	Q5VWK5	UNIPROT	TYK2	protein	P29597	UNIPROT	up-regulates	binding			9606	BTO:0000782								12023369	t		gcesareni	Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12.	SIGNOR-87841	0.566
PINK1	protein	Q9BXM7	UNIPROT	TUFM	protein	P49411	UNIPROT	down-regulates activity	phosphorylation	Ser219	ETPVIVGsALCALEG	9606	BTO:0000567								33113344	t		miannu	PINK1 interacts with the autophagy effector TUFm and phosphorylates TUFm at Ser222. These results indicated that p222-hTUFm sequestered more monomer Atg5 and reduced the conjugated Atg5-Atg12 complex to subdue mitophagy.	SIGNOR-266382	0.2
FYN	protein	P06241	UNIPROT	FYB1	protein	O15117	UNIPROT	up-regulates activity	phosphorylation	Tyr651	LDMGDEVyDDVDTSD	9606									10570256	t			 two tyrosines, Tyr595 and Tyr651, of FYB are major sites of phosphorylation by FYN-T and mediate binding to SLP-76 in Jurkat T cells. We further demonstrate that the loss of SLP-76 binding by mutation of these sites markedly reduced the ability of FYN-T-FYB-SLP-76 to up-regulate IL-2 transcription.	SIGNOR-251164	0.2
GSK3B	protein	P49841	UNIPROT	CABYR	protein	O75952	UNIPROT	unknown	phosphorylation	Thr151	PATPKTTtPPSSPPP	-1									15752768	t			GSK3β interacts with and phosphorylates CABYR in vitro. GSK3β interacts with and phosphorylates CABYR in vitro. the functional extent of the CABYR phosphorylation sites to participate in cellular processes through GSK3β remains to be investigated.	SIGNOR-251224	0.41
Scribble_complex_DLG4-LLGL2_variant	complex	SIGNOR-C505	SIGNOR	Cell_polarity	phenotype	SIGNOR-PH213	SIGNOR	up-regulates				9606									23397623	f		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270890	0.7
MAPK3	protein	P27361	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000763;BTO:0000149							10197981	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3.	SIGNOR-66781	0.608
FOXO3	protein	O43524	UNIPROT	FBXO32	protein	Q969P5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							21798082	f		lperfetto	Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome.	SIGNOR-235715	0.451
PRKCZ	protein	Q05513	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser328	QDAYRRNsVRFLQQR	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89272	0.402
CYCS	protein	P99999	UNIPROT	APAF1	protein	O14727	UNIPROT	up-regulates activity	binding			9606									15907471	t		lperfetto	Cytochrome c (Cyt c) is then released from the intermembrane space of the mitochondrion into the cytosol, where it binds to apoptotic protease-activating factor 1 (Apaf-1) in the presence of ATP/dATP to form the apoptosome.	SIGNOR-137295	0.786
CyclinD3/CDK6	complex	SIGNOR-C234	SIGNOR	PFKM	protein	P08237	UNIPROT	down-regulates activity	phosphorylation			-1									28607489	t		miannu	In vitro kinase reactions revealed that all three PFK1 isoforms (PFKP, PFKL, PFKM) and PKM2 were phosphorylated by cyclin D3-CDK6 (Extended Data Fig. 2a–d, Supplementary Table 4).	SIGNOR-276452	0.2
IL5	protein	P05113	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates				9606									21106848	f			It has been reported that IL-5 family members and selected chemotactic factors can activate the PI3K-Akt pathway in human blood eosinophils	SIGNOR-254351	0.406
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	IGFBP1	protein	P08833	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10358076	f		miannu	Reporter gene studies in hepg2 hepatoma cells show that fkhr stimulates insulin-like growth factor-binding protein-1 promoter activity through an irs	SIGNOR-252925	0.2
SUFU	protein	Q9UMX1	UNIPROT	GLIS3	protein	Q8NEA6	UNIPROT	down-regulates	binding			9606									21543335	t		fspada	These data indicate that the inhibition of glis3-mediated transactivation by sufu appears to rely on the interaction with glis3 through the ygh motif and is not related to an effect on the general transcriptional machinery	SIGNOR-173573	0.388
PPP6C	protein	O00743	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	up-regulates activity	dephosphorylation	Ser828	EHDSAEGsHTSGQSN	9606	BTO:0001109								28114302	t		miannu	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276517	0.335
IGF1R	protein	P08069	UNIPROT	FBN1	protein	P35555	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0000951								17200203	f	Indirect:regulation of expression	miannu	Decorin and IGF-I induce fibrillin-1 protein synthesis in normal rat kidney fibroblasts 	SIGNOR-251863	0.299
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	NOXA1	protein	Q86UR1	UNIPROT	down-regulates	phosphorylation			9606									20230789	t	inferred from 70% family members	lperfetto	Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity	SIGNOR-270203	0.2
PI3K	complex	SIGNOR-C156	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity				9606		BTO:0000150							19573809	f		lperfetto	However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth	SIGNOR-252704	0.785
TRIM28	protein	Q13263	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16107876	t	2	miannu	we present evidence that MDM2 interacts with the nuclear corepressor KAP1. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation.	SIGNOR-240405	0.581
Nucleosome_H2A.Z.1 variant	complex	SIGNOR-C322	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606									24311584	f		miannu	In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression.	SIGNOR-263713	0.7
STAT5A	protein	P42229	UNIPROT	PIM1	protein	P11309	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15498859	t		lperfetto	Pim-1 is know to be up regulated by signal transducer and activator of transcription 5 (stat5)	SIGNOR-249606	0.385
ITCH	protein	Q96J02	UNIPROT	H1-2	protein	P16403	UNIPROT	up-regulates activity	polyubiquitination	Lys46	PVSELITkAVAASKE	9606	BTO:0000815								30517763	t		miannu	ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. The results indicated that ITCH-mediated K46-Ubn is essential for the binding of histone H1.2 to chromatin.	SIGNOR-272926	0.2
Guanabenz	chemical	CHEBI:5553	ChEBI	ADRA2B	protein	P18089	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258910	0.8
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1899	SPTYSPTsPVYTPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269347	0.718
ATM	protein	Q13315	UNIPROT	NKX3-1	protein	Q99801	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr134	SRAAFSHtQVIELER	9606	BTO:0002181								23890999	t		miannu	ATM phosphorylates NKX3.1 on T166 and then T134, resulting in NKX3.1 ubiquitination and degradation resulting from an apparent regulatory interaction.	SIGNOR-276499	0.371
PAK1	protein	Q13153	UNIPROT	PXN	protein	P49023	UNIPROT	unknown	phosphorylation	Ser272	ELDELMAsLSDFKIQ	9606									16717130	t		llicata	We show that p21-activated kinase (pak)-induced phosphorylation of serine 273 in paxillin is a critical regulator of this turnover.	SIGNOR-146842	0.65
MAPK9	protein	P45984	UNIPROT	MAPK8IP1	protein	Q9UQF2	UNIPROT	up-regulates activity	phosphorylation	Thr103	LIDATGDtPGAEDDE	9606	BTO:0000298								12756254	t		lperfetto	Recruitment of jnk to jip1 and jnk-dependent jip1 phosphorylation regulates jnk module dynamics and activation it was observed that phosphorylation by jnk of jip1 on thr-103 and not other phosphorylated jip1 residues is necessary for the regulation of dlk association with jip1, dlk activation, and subsequent module activation.	SIGNOR-101201	0.765
TP53	protein	P04637	UNIPROT	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	down-regulates quantity by repression	transcriptional regulation			9606									27692180	t	inferred from family member	miannu	P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.	SIGNOR-270272	0.424
PK	proteinfamily	SIGNOR-PF80	SIGNOR	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation			-1									22306293	t			PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor	SIGNOR-268149	0.2
ARSA	protein	P15289	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates activity	acetylation			9606									237937	t	Regulation	miannu	ASA acetylates hemoglobin. Purified acetylated hemoglobin had a slightly increased oxygen affinity and decreased heme-heme interaction.	SIGNOR-251772	0.2
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	JUN	protein	P05412	UNIPROT	down-regulates activity				9606	BTO:0000801								10973958	f		lperfetto	NF-kB-, AP-1-, and Smad3-driven promoters all require p300/CREB-binding protein for their transactivation. Previous studies have suggested that NF-kB- and AP-1-driven promoters can be inhibited by competitive recruitment of coactivators such as p300/CPB to other unrelated promoters. We hypothesized that NF-kB and AP-1 compete with Smad3 for limiting quantities of p300. This hypothesis predicts that added p300 should alleviate TGF-b1/Smad3-mediated inhibition of inflammatory genes. Conversely, increasing doses of TGF-b1/Smad3 would compete away even overexpressed p300 from NF-kB/AP- 1-driven promoters.	SIGNOR-249557	0.702
dabrafenib	chemical	CHEBI:75045	ChEBI	LIMK1	protein	P53667	UNIPROT	down-regulates activity	chemical inhibition			-1									24720932	t		miannu	Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations	SIGNOR-259216	0.8
CRX	protein	O43186	UNIPROT	RHO	protein	P08100	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								15277472	f		miannu	 KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. 	SIGNOR-253820	0.485
ETV4	protein	P43268	UNIPROT	VIM	protein	P08670	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093;BTO:0000815								8895512	f	 	miannu	 Our results suggest that PEA3 specifically transactivates vimentin promoter through PEA3 site. Among members of the ETS transcription factor family only Erg showed ability to transactivate vimentin promoter besides PEA3.	SIGNOR-254070	0.2
BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	SMAD1	protein	Q15797	UNIPROT	up-regulates activity	phosphorylation	Ser463	SPHNPISsVS	9606		BTO:0000416							9136927	t		lperfetto	Here, we report that BMP receptors phosphorylate and activate Smad1 directly. Phosphorylation of Smad1 in vivo involves serines in the carboxy-terminal motif SSXS. These residues are phosphorylated directly by a BMP type I receptor in vitro	SIGNOR-217985	0.652
MEST	protein	Q5EB52	UNIPROT	LRP6	protein	O75581	UNIPROT	down-regulates activity				9606									21375506	f			Mest/Peg1 inhibited maturation of LRP6 by controlling the glycosylation of LRP6. Knockdown of Mest/Peg1, which might enhance Wnt signalling, blocked adipogenic differentiation of 3T3-L1 cells	SIGNOR-255826	0.2
PRKAA1	protein	Q13131	UNIPROT	INSIG1	protein	O15503	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr222	ITIAFLAtLITQFLV	9606	BTO:0000007								30733434	t		miannu	Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPKα1 subunit associates with Insig-1 in a dose-dependent manner.	SIGNOR-277430	0.259
CHUK	protein	O15111	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates activity	phosphorylation	Ser177	AKELDQGsLCTSFVG	-1									10022904	t		llicata	Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays.	SIGNOR-250771	0.653
SLC12A3	protein	P55017	UNIPROT	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	phosphorylation												21613606	t		lperfetto	Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12). 	SIGNOR-264633	0.8
PRKCZ	protein	Q05513	UNIPROT	ADD1	protein	P35611	UNIPROT	up-regulates	phosphorylation	Ser726	KKKFRTPsFLKKSKK	9606	BTO:0000938	BTO:0000671							9679146	t		gcesareni	These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc.	SIGNOR-59303	0.2
MYC	protein	P01106	UNIPROT	HECTD4	protein	Q9Y4D8	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001321								32814769	t		miannu	 We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. 	SIGNOR-267144	0.2
GSK3A	protein	P49840	UNIPROT	UNG	protein	P13051	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser64	EPGTPPSsPLSAEQL	9606	BTO:0000812								27875297	t		lperfetto	Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation 	SIGNOR-264886	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates	phosphorylation	Ser539	SLFNVSPsCSSFNSP	9606		BTO:0000887;BTO:0001103							17609368	t		lperfetto	Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538.	SIGNOR-216647	0.483
TSC22D3	protein	Q99576	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	relocalization			9606	BTO:0000738								20018851	t	inferred from 70% of family members		GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells.	SIGNOR-269854	0.409
NEDD4L	protein	Q96PU5	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	ubiquitination			9606									19917253	t		lperfetto	Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation	SIGNOR-232104	0.796
metformin	chemical	CHEBI:6801	ChEBI	PCK1	protein	P35558	UNIPROT	down-regulates quantity				9606									17909097	f		gcesareni	In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp.	SIGNOR-158062	0.8
BAMBI	protein	Q13145	UNIPROT	FZD5	protein	Q13467	UNIPROT	up-regulates	binding			9606		BTO:0000763							2662247	t		gcesareni	These data together suggest that bambi may form a ternary coreceptor complex with fzd5 and lrp6	SIGNOR-23040	0.577
IFNGR1	protein	P15260	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates	binding			9606									15864272	t		gcesareni	The only type ii ifn, ifn-, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2	SIGNOR-135955	0.703
MAPK3	protein	P27361	UNIPROT	KARS1	protein	Q15046	UNIPROT	up-regulates	phosphorylation	Ser207	PYEITLLsPCLHMLP	9606									19524539	t		gcesareni	Lysrs serves as a key signaling molecule in the immune response by regulating gene expression. Lysrs was phosphorylated on serine 207 in a mapk-dependent manner, released from the multisynthetase complex, and translocated into the nucleus.	SIGNOR-186125	0.2
ATM	protein	Q13315	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1457	SEKAVLTsQKSSEYP	9606	BTO:0000150								10550055	t		lperfetto	The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks	SIGNOR-72056	0.813
Tomivosertib	chemical	CID:118598754	PUBCHEM	MKNK2	protein	Q9HBH9	UNIPROT	down-regulates activity	chemical inhibition			9606									29526098	t		Simone Vumbaca	Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation.	SIGNOR-261117	0.8
N-acetyl-L-aspartate(2-)	smallmolecule	CHEBI:16953	ChEBI	acetic acid	smallmolecule	CHEBI:15366	ChEBI	up-regulates quantity	precursor of			9606									17194761	t		miannu	N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain.	SIGNOR-268085	0.8
GGCX	protein	P38435	UNIPROT	PROS1	protein	P07225	UNIPROT	up-regulates activity	carboxylation			9606									28125048	t		lperfetto	Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z	SIGNOR-265924	0.599
F2	protein	P00734	UNIPROT	F2R	protein	P25116	UNIPROT	up-regulates	binding			9606	BTO:0000150;BTO:0001130;BTO:0000848								23450633	t		gcesareni	Thrombin, actin through par1 promotes tumor cell proliferation, migration and contributes to the metastatic potenital of breast, prostate, gastrointestinal cancers and melanoma.	SIGNOR-199788	0.883
ATM	protein	Q13315	UNIPROT	SMC3	protein	Q9UQE7	UNIPROT	unknown	phosphorylation	Ser1083	ESERGSGsQSSVPSV	9606									18442975	t		llicata	Ser-1083 phosphorylation is ir-inducible, depends on atm and nijmegen breakage syndrome 1 (nbs1), and is required for intra-s phase checkpoint.	SIGNOR-178479	0.732
HDAC5	protein	Q9UQL6	UNIPROT	MEF2D	protein	Q14814	UNIPROT	down-regulates	binding			9606									11062529	t		gcesareni	The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis.	SIGNOR-84029	0.698
POLR2G	protein	P62487	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266165	0.868
PPM1L	protein	Q5SGD2	UNIPROT	CERT1	protein	Q9Y5P4	UNIPROT	up-regulates activity	dephosphorylation			9606									18165232	t		miannu	The expression of PP2Cepsilon also enhanced the association between CERT and VAPA.|These results suggest that CERT is a physiological substrate of PP2Cepsilon and that dephosphorylation of CERT by PP2Cepsilon may play an important role in the regulation of ceramide trafficking from the ER to the Golgi apparatus.	SIGNOR-277113	0.2
PPP1CA	protein	P62136	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	dephosphorylation	Ser77	YEPEGSAsPTPPYLK	9606									17318175	t			The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 	SIGNOR-248552	0.338
PLK1	protein	P53350	UNIPROT	TP73	protein	O15350	UNIPROT	down-regulates	phosphorylation	Thr27	SSLEPDStYFDLPQS	9606									18418051	t		llicata	P73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. tap73 is phosphorylated by this kinase on threonine-27 (thr-27) within the ta domain.	SIGNOR-178253	0.49
RHOA	protein	P61586	UNIPROT	PLD1	protein	Q13393	UNIPROT	up-regulates	binding			9606									11102529	t		gcesareni	Our results demonstrate that direct stimulation of pld1 in vivo by rhoa	SIGNOR-84953	0.685
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KA3	protein	P51812	UNIPROT	up-regulates	phosphorylation	Ser227	DHEKKAYsFCGTVEY	9606									10980595	t		lperfetto	We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway	SIGNOR-244692	0.2
AKAP12	protein	Q02952	UNIPROT	PKC	proteinfamily	SIGNOR-PF53	SIGNOR	up-regulates activity	relocalization												14657015	t		lperfetto	A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. 	SIGNOR-271838	0.471
DUSP6	protein	Q16828	UNIPROT	FOXO1	protein	Q12778	UNIPROT	up-regulates activity	dephosphorylation	Ser256	SPRRRAAsMDNNSKF	9606									22848439	t		lperfetto	It has been previously demonstrated that MKP-3 dephosphorylates FOXO1 on Ser256 and promotes nuclear translocation of FOXO1 , which subsequentially binds to the promoters of gluconeogenic genes and turns on the gluconeogenic program.|We also reported that MKP-3 can activate FOXO1 by at least dephosphorylating Ser 256, one of the Akt phosphorylation sites xref .	SIGNOR-276983	0.44
UBE2I	protein	P63279	UNIPROT	FOS	protein	P01100	UNIPROT	down-regulates activity	sumoylation	Lys265	SISSMELkTEPFDDF	9606				SIGNOR-C154					16055711	t		lperfetto	We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. 	SIGNOR-263013	0.373
ENO1	protein	P06733	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9534	BTO:0000318								2005901	t		Luana	This result suggests that MBP-1 in vivo acts as a sequence-specific repressor.	SIGNOR-261594	0.423
CSNK2A1	protein	P68400	UNIPROT	TOP2A	protein	P11388	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1365	TKTSPKLsNKELKPQ	9606	BTO:0003492								21254166	t		miannu	 This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361.	SIGNOR-276300	0.613
RUNX2	protein	Q13950	UNIPROT	CREBBP	protein	Q92793	UNIPROT	up-regulates	binding			9606									20551513	t		gcesareni	Mechanistic analysis revealed that the tak1-mkk3/6-p38 mapk axis phosphory-lated runx2, promoting its association with the coac-tivator creb-binding protein (cbp), which is re-quired to regulate osteoblast genetic programs.	SIGNOR-166170	0.416
LMX1A	protein	Q8TE12	UNIPROT	CUX2	protein	O14529	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									30770393	t		miannu	Lmx1a drives Cux2 expression in the cortical hem through activation of a conserved intronic enhancer. Lmx1a knockdown abolishes activation of the Cux2 enhancer in the cortical hem	SIGNOR-263961	0.289
WASL	protein	O00401	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								20498093	t		lperfetto	Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes.	SIGNOR-261003	0.781
Rigosertib sodium	chemical	CID:23696523	PUBCHEM	PLK1	protein	P53350	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-195028	0.8
SOCS1	protein	O15524	UNIPROT	IFNGR1	protein	P15260	UNIPROT	down-regulates	binding			9606									18708154	t		gcesareni	Suppressor of cytokine signaling (socs)-1, the key negative regulator of interferon (ifn)-gamma-dependent signaling, is induced in response to ifngamma. Socs-1 binds to and inhibits the ifngamma receptor-associated kinase janus-activated kinase (jak) 2 and inhibits its function in vitrothe binding of socs-1 to tyr441 also blocks the access of stat1 to tyr419 and that this effect may be the principal mechanism of inhibition of downstream signaling	SIGNOR-180140	0.661
DOK3	protein	Q7L591	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								32323266	t		scontino	An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.	SIGNOR-268448	0.571
CDKN1A	protein	P38936	UNIPROT	Cell_cycle_exit	phenotype	SIGNOR-PH41	SIGNOR	up-regulates				10090	BTO:0000222								9388774	f		gcesareni	The upregulation of the cyclin-dependent kinase inhibitor p21 and the dephosphorylation of retinoblastoma protein (pRb) appear to be critical regulatory events for the establishment ,,, the postmitotic ... states [in myoblasts differentiating into mature myotubes]	SIGNOR-241956	0.7
RNF111	protein	Q6ZNA4	UNIPROT	AP2M1	protein	Q96CW1	UNIPROT	up-regulates	ubiquitination			9606									20965945	t		gcesareni	Arkadia ubiquitylated the _?2 Subunit at lys130. In addition, arkadia interacted with the ap2 complex, and modified endocytosis of epidermal growth factor receptor (egfr) induced by egf. Arkadia thus appears to regulate egf signalling by modulating endocytosis of egfr through interaction with ap2 complex.	SIGNOR-168931	0.2
JAG1	protein	P78504	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	binding			7227									18660822	t	Binding Ca-dependent	lperfetto	We identify functional fragments of human notch-1 (n-1) and jagged-1 (j-1) which interact in a calcium-dependent manner.	SIGNOR-219253	0.626
SAGA complex	complex	SIGNOR-C465	SIGNOR	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	acetylation			9606									34811519	t		lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269627	0.2
SMO	protein	Q99835	UNIPROT	GNAI2	protein	P04899	UNIPROT	up-regulates activity	binding			9606									23074268	t		lperfetto	it was proposed that Smo might signal through activation of Gi proteins to reduce PKA activity.	SIGNOR-199162	0.403
PPP1CB	protein	P62140	UNIPROT	CASP2	protein	P42575	UNIPROT	up-regulates activity	dephosphorylation	Ser164	STDTVEHsLDNKDGP	-1									19531356	t		llicata	Nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2.	SIGNOR-248576	0.2
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	NFKB2	protein	Q00653	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0000567								14676825	t		lperfetto	Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase.	SIGNOR-217175	0.534
CAMK2G	protein	Q13555	UNIPROT	SPR	protein	P35270	UNIPROT	unknown	phosphorylation	Ser213	QQLARETsVDPDMRK										11825621	t		llicata	Phosphorylation sites of rat sepiapterin reductase (rSPR) by Ca2+/calmodulin-dependent protein kinase II were determined in the present study. Using specific monoclonal anti-phospho-Ser and -Thr antibodies, we found that only Ser residues of rSPR were phosphorylated. We constructed several point mutants of SPR by systematically replacing the three Ser residues by Ala ones. These mutants showed that all three Ser residues, i.e. S46, S196, and S214, of rSPR were phosphorylated. We also recognized that only Ser-213 of human SPR was phosphorylated. 	SIGNOR-250705	0.311
MDM2	protein	Q00987	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0001061								14761977	t		miannu	 MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit. The physical interaction between p21 and MDM2 was demonstrated both in vitro and in vivo with the binding region in amino acids 180-298 of the MDM2 protein.	SIGNOR-272954	0.664
MAP4K4	protein	O95819	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates	binding			9606									10807933	t		gcesareni	The existence of an at least trimolecular complex consisting of nik, tak1, and ikk2, although the precise sequence of activation as well as the possible location of the kinases within the signalosome remains to be elucidated.	SIGNOR-77404	0.563
MAPK9	protein	P45984	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates	phosphorylation	Ser62	LLPTPPLsPSRRSGL	9606									10551811	t		gcesareni	The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71.	SIGNOR-72104	0.368
CSNK2A1	protein	P68400	UNIPROT	EXOSC9	protein	Q06265	UNIPROT	up-regulates	phosphorylation	Ser392	QDAPIILsDSEEEEM	9606									19217413	t		lperfetto	Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay	SIGNOR-184031	0.2
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	IKBKB	protein	O14920	UNIPROT	down-regulates	cleavage	Asp242	VRQKSEVdIVVSEDL	9606									11741536	t		gcesareni	Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis.	SIGNOR-256441	0.373
COX5B	protein	P10606	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267749	0.787
DZIP3	protein	Q86Y13	UNIPROT	H2AC21	protein	Q8IUE6	UNIPROT	up-regulates activity	monoubiquitination	Lys119	IQAVLLPkKTESHKP	9606	BTO:0000007								18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271758	0.2
CSNK1A1L	protein	Q8N752	UNIPROT	GLI2	protein	P10070	UNIPROT	up-regulates	phosphorylation			9606									16481469	t		gcesareni	Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed	SIGNOR-144551	0.339
PIK3CA	protein	P42336	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	form complex	binding			9606									19805105	t		miannu	Phosphoinositol 3- kinase alpha (PI3Kα) is a heterodimeric enzyme formed by a catalytic subunit (p110α, encoded by PIK3CA) and one of several regulatory subunits (a major one being p85α, encoded by PI3KR1).	SIGNOR-255299	0.934
GNAO1	protein	P09471	UNIPROT	NDN	protein	Q99608	UNIPROT	up-regulates activity				9606	BTO:0002036								25012566	f		lperfetto	We subsequently analyzed whether Gαo modulates the cellular activities of Necdin. Notably, expression of Gαo significantly augmented Necdin-mediated cellular responses, such as proliferation and differentiation. Moreover, activation of type 1 cannabinoid receptor (CB1R), a Gi/oα-coupled receptor, augmented cell growth suppression, which was mediated by Gαo and Necdin in U87MG cells containing CB1R, Gαo, and Necdin as normal components.	SIGNOR-253388	0.241
SHH	protein	Q15465	UNIPROT	CP	protein	P00450	UNIPROT	down-regulates	binding			9606									17419683	t		gcesareni	Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms.	SIGNOR-154285	0.2
H4C1	protein	P62805	UNIPROT	Nucleosome_H3.1 variant	complex	SIGNOR-C324	SIGNOR	form complex	binding			-1									21812398	t		miannu	The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 	SIGNOR-263722	0.2
PTPRF	protein	P10586	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr999	YASSNPEyLSASDVF	9606									1303753	t		gcesareni	Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product.	SIGNOR-16247	0.563
ATM	protein	Q13315	UNIPROT	TDP1	protein	Q9NUW8	UNIPROT	up-regulates	phosphorylation	Ser81	PKRQKSGsQEDLGWC	9606									19851285	t		lperfetto	Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk)	SIGNOR-188772	0.56
phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	CDP-diacylglycerol(2-)	smallmolecule	CHEBI:58332	ChEBI	up-regulates quantity	precursor of			9606									25375833	t		lperfetto	CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA).	SIGNOR-267022	0.8
PLK1	protein	P53350	UNIPROT	TERF1	protein	P54274	UNIPROT	up-regulates	phosphorylation	Ser435	KKLKLISsDSED	9606									18625707	t		lperfetto	Plk1 phosphorylation of trf1 is essential for its binding to telomeres	SIGNOR-179461	0.382
superoxide	smallmolecule	CHEBI:18421	ChEBI	Oxidative_stress	phenotype	SIGNOR-PH215	SIGNOR	up-regulates				9606									29301787	f		lperfetto	Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD).	SIGNOR-272276	0.7
HDAC1	protein	Q13547	UNIPROT	BHC complex	complex	SIGNOR-C353	SIGNOR	form complex	binding			9606	BTO:0000567; BTO:0000007								15325272	t		miannu	BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells	SIGNOR-264500	0.716
CTDSPL	protein	O15194	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	dephosphorylation	Ser208	DAGSPNLsPNPMSPA	9606	BTO:0000007								17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248307	0.398
AMPK	complex	SIGNOR-C15	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser214	GGKERPGsKEEVDED	-1									21204788	t	done	miannu	AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 	SIGNOR-273926	0.258
LAMTOR3	protein	Q9UHA4	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates	binding			9606									15547943	t		gcesareni	We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations.	SIGNOR-130924	0.599
FGF13	protein	Q92913	UNIPROT	SCN1A	protein	P35498	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253419	0.282
6alpha-methylprednisolone	chemical	CHEBI:6888	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									9259419	t	rheumatoid arthritis	gcesareni		SIGNOR-251695	0.8
ARHGEF1	protein	Q92888	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606		BTO:0000887;BTO:0001260							10836144	t		gcesareni	Rhogefs catalyze the exchange of gdp for gtp and thereby activate rho.	SIGNOR-77914	0.825
ZDHHC2	protein	Q9UIJ5	UNIPROT	AKAP5	protein	P24588	UNIPROT	up-regulates activity	palmitoylation	Cys36	KEKASMLcFKRRKKA	10116	BTO:0004553								25589740	t			Here, we report that the recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms	SIGNOR-262295	0.338
PTK2	protein	Q05397	UNIPROT	RET	protein	P07949	UNIPROT	up-regulates	phosphorylation	Tyr905	DVYEEDSyVKRSQGR	9606									21454698	t		llicata	Focal adhesion kinase (fak) binds ret kinase via its ferm domain, priming a direct and reciprocal ret-fak transactivation mechanism. following gdnf stimulation, increased phosphorylation of fak at tyr-576/577 as well as phosphorylation of ret at tyr-905 was observed.	SIGNOR-173009	0.622
PRKACA	protein	P17612	UNIPROT	TRPM8	protein	Q7Z2W7	UNIPROT	up-regulates activity	phosphorylation	Ser9	SFRAARLsMRNRRND	9606	BTO:0000007								20110357	t	done	miannu	Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity.	SIGNOR-273792	0.2
RUVBL2	protein	Q9Y230	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270854	0.688
SMAD2/SMAD4	complex	SIGNOR-C8	SIGNOR	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	up-regulates				9606									30017632	f		miannu	Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes	SIGNOR-260440	0.7
CALM2	protein	P0DP24	UNIPROT	PPP3CB	protein	P16298	UNIPROT	up-regulates	binding			9606									11796223	t		miannu	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-266322	0.524
CDK1	protein	P06493	UNIPROT	KDM5B	protein	Q9UGL1	UNIPROT	down-regulates activity	phosphorylation	Ser1456	FKLERERsYELVRSA	9606	BTO:0000815								31776402	t		lperfetto	Phosphorylation of the histone demethylase KDM5B and regulation of the phenotype of triple negative breast cancer|Here, we demonstrate that KDM5B is phosphorylated at Ser1456 by the cyclin-dependent kinase 1 (CDK1). Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes.	SIGNOR-273435	0.261
AMPD1	protein	P23109	UNIPROT	ammonium	smallmolecule	CHEBI:28938	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0001103							1631143	t		miannu	AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells. 	SIGNOR-269775	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	NOX5	protein	Q96PH1	UNIPROT	up-regulates activity	phosphorylation	Ser521	WTNRLYEsFKASDPL	-1									21642394	t		miannu	In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475.	SIGNOR-276329	0.2
POU5F1	protein	Q01860	UNIPROT	NANOG	protein	Q9H9S0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001086								17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254939	0.761
APLNR	protein	P35414	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256960	0.255
PTEN	protein	P60484	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity				9606	BTO:0001271								20596030	f		lperfetto	Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfralpha was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib.	SIGNOR-252638	0.656
PRKACA	protein	P17612	UNIPROT	CACNA1D	protein	Q01668	UNIPROT	up-regulates activity	phosphorylation	Ser1773	AAHGKRPsIGNLEHV	-1									19074150	t		miannu	 We recently demonstrated that PKA activation led to increased alpha(1D) Ca(2+) channel activity in tsA201 cells by phosphorylation of the channel protein. Western blotting showed that the N terminus and C terminus were phosphorylated. Serines 1743 and 1816, two PKA consensus sites, were phosphorylated by PKA and identified by mass spectrometry.	SIGNOR-263109	0.374
PRKACA	protein	P17612	UNIPROT	AKAP12	protein	Q02952	UNIPROT	up-regulates activity	phosphorylation	Ser772	LVTPRKKsKSKLEEK	-1									14657015	t		lperfetto	Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin.	SIGNOR-271842	0.2
GADD45A	protein	P24522	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	binding			9606									20626350	t		gcesareni	Gadd45alfa appears to act as an endogenous inhibitor of the alternative p38alfa-activation pathway in t-cell, by binding to p38alfa and preventing tyr323 phosphorilation	SIGNOR-166584	0.474
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser106	PLNSVSPsPLMLLHP	9606									10428798	t		lperfetto	Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity.	SIGNOR-217288	0.43
CBX5	protein	P45973	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	binding			9606							methylation:Lys10	RTKQTARkSTGGKAP	19111658	t		miannu	 A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 	SIGNOR-264488	0.2
COPS6	protein	Q7L5N1	UNIPROT	COP9 signalosome variant 2	complex	SIGNOR-C487	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270767	0.924
BIRC3	protein	Q13489	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	ubiquitination	Lys377	NEPSLQSkLQDEANY	9606									18570872	t		amattioni	In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein.	SIGNOR-179104	0.737
SIK2	protein	Q9H0K1	UNIPROT	SIK2	protein	Q9H0K1	UNIPROT	up-regulates activity	phosphorylation	Ser343	RLKSHRSsFPVEQRL	-1									27478041	t		miannu	SIK2 S358 Autophosphorylation Is a Marker of SIK2 Activity	SIGNOR-277268	0.2
COL1A1	protein	P02452	UNIPROT	DDR1	protein	Q08345	UNIPROT	up-regulates activity	binding			9606	BTO:0001282								17318226	t		lperfetto	The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75. 	SIGNOR-272340	0.343
NUP205	protein	Q92621	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262083	0.673
NR2F2	protein	P24468	UNIPROT	NR2F1	protein	P10589	UNIPROT	up-regulates	binding			9606									10900149	t		gcesareni	Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site.	SIGNOR-79443	0.259
SMARCC2	protein	Q8TAQ2	UNIPROT	Neural progenitor-specific SWI/SNF	complex	SIGNOR-C477	SIGNOR	form complex	binding			9606									25195934	t		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270616	0.823
JAK1	protein	P23458	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	binding			9606									24710148	t		lperfetto	The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3).	SIGNOR-236369	0.793
SLC16A3	protein	O15427	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606									26384349	f		lperfetto	Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival.	SIGNOR-256581	0.7
CDK5	protein	Q00535	UNIPROT	DRD2	protein	P14416	UNIPROT	down-regulates activity	phosphorylation	Ser321	GLHSTPDsPAKPEKN	9606									24391960	t		miannu	These results indicate that Cdk5-mediated phosphorylation of S321 inhibits DRD2 function, providing a novel regulatory mechanism for dopamine signaling.	SIGNOR-259401	0.393
LEF1	protein	Q9UJU2	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19653274	f		gcesareni	Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation	SIGNOR-245351	0.621
SRF	protein	P11831	UNIPROT	ACTA2	protein	P62736	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887;BTO:0001260							15269336	f		gcesareni	The primary goal of the present study was to directly assess the role of the degeneracy of sm ?-Actin cargs in the regulation of smc-selective gene expression in vivo. in addition, our present studies address the possible role of this carg degeneracy, and the smc-selective srf coactivator myocardin, in regulating differential expression of carg-dependent smc genes and growth regulatory genes.	SIGNOR-126923	0.436
PLK1	protein	P53350	UNIPROT	BRCA2	protein	P51587	UNIPROT	down-regulates activity	phosphorylation	Ser205	LATPPTLsSTVLIVR	9606	BTO:0001938								12815053	t		lperfetto	M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1	SIGNOR-102490	0.556
ACSS1	protein	Q9NUB1	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	down-regulates quantity	chemical modification												10843999	t		lperfetto	The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP.	SIGNOR-271831	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Ser17	ARRSYVSsGEMMVGG	-1									7822264	t		llicata	On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II.	SIGNOR-250627	0.438
SGK1	protein	O00141	UNIPROT	SLC2A4	protein	P14672	UNIPROT	up-regulates activity	phosphorylation	Ser274	LERERPLsLLQLLGS	8355		BTO:0000887							17382906	t		lperfetto	We evaluated the putative role of sgk1 in the modulation of glut4. Coexpression of the kinase along with glut4 in xenopus oocytes stimulated glucose transport. The enhanced glut4 activity was paralleled by increased transporter abundance in the plasma membrane. Disruption of the sgk1 phosphorylation site on glut4 ((s274a)glut4) abrogated the stimulating effect of sgk1. In summary, sgk1 promotes glucose transporter membrane abundance via glut4 phosphorylation at ser274.	SIGNOR-236653	0.318
PRKAA1	protein	Q13131	UNIPROT	EEF2K	protein	O00418	UNIPROT	up-regulates	phosphorylation	Ser398	DSLPSSPsSATPHSQ	9606			SIGNOR-C15						22669845	t		gcesareni	In response to genotoxic stress, eef2k was activated by ampk (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eef2k phosphorylated eef2 and induced a temporary ribosomal slowdown at the stage of elongation	SIGNOR-197734	0.473
POLR1H	protein	Q9P1U0	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding												22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266156	0.2
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1647	SPSYSPTsPSYSPTS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248806	0.849
MECP2	protein	P51608	UNIPROT	ABCB1	protein	P08183	UNIPROT	down-regulates quantity by repression	transcriptional regulation												11865062	f	 	 	We have established that methyl-CpG binding protein 2 (MeCP2) is involved in methylation-dependent silencing of human MDR1 in cells that lack the known transcriptional repressors MBD2 and MBD3. In the repressed state the MDR1 promoter is methylated and assembled into chromatin enriched with MeCP2 and deacetylated histone. TSA induced significant acetylation of histones H3 and H4 but did not activate transcription. 5aC induced DNA demethylation, leading to the release of MeCP2, promoter acetylation, and partial relief of repression	SIGNOR-254033	0.2
CTNND1	protein	O60716	UNIPROT	VAV2	protein	P52735	UNIPROT	up-regulates	binding			9606									22946057	t		gcesareni	We demonstrate that p120-catenin participates in the stimulation of rac1 activity, binding directly to this protein. In addition we show that vav2 also binds to p120-catenin and is required for rac1 activation and for beta-catenin translocation to the nucleus.Vav2 And rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by ck1 and inhibited by tyrosine phosphorylation by src or fyn	SIGNOR-198941	0.595
SIRT1	protein	Q96EB6	UNIPROT	NCOR2	protein	Q9Y618	UNIPROT	up-regulates				9606									22395773	t		FFerrentino	In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription.	SIGNOR-253506	0.508
GATA1	protein	P15976	UNIPROT	HBG1	protein	P69891	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004911								20395365	f	Regulation	miannu	BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors.	SIGNOR-251806	0.385
AKT1	protein	P31749	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates	phosphorylation			9606									21620960	t		gcesareni	Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity.	SIGNOR-252515	0.755
ARPC3	protein	O15145	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	form complex	binding			9606									12479800	t			The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc	SIGNOR-251516	0.962
YY1	protein	P25490	UNIPROT	POSTN	protein	Q15063	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21839814	f		miannu	 In this study we demonstrate that the ability of the human POSTN promoter to drive transcription mostly depends on the activity of YingYang-1 (YY1) zinc finger transcription factor. YY1, whose regulatory role in biology includes, besides transcriptional control, also chromatin remodeling, DNA damage repair and tumorigenesis, acts as a strong negative modulator of the POSTN expression. 	SIGNOR-255621	0.2
GATA3	protein	P23771	UNIPROT	GATA3	protein	P23771	UNIPROT	up-regulates				9606									16386358	t			Experimental data indeed supports the existence of a positive circuit involvingGATA-3 that excludes IL-4 and STAT-6, specifically in mouse cells	SIGNOR-254300	0.2
BAZ2B	protein	Q9UIF8	UNIPROT	H3-5	protein	Q6NXT2	UNIPROT	down-regulates activity	binding			9606							acetylation:Lys15	ARKSTGGkAPRKQLA	31999386	t		miannu	The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation.	SIGNOR-266621	0.2
STK24	protein	Q9Y6E0	UNIPROT	STK38	protein	Q15208	UNIPROT	up-regulates	phosphorylation	Thr444	DWVFINYtYKRFEGL	9606	BTO:0000007								16314523	t		lperfetto	Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity.	SIGNOR-142467	0.39
HOOK3	protein	Q86VS8	UNIPROT	MARCO	protein	Q9UEW3	UNIPROT	down-regulates	binding			9606	BTO:0000801								17237231	t		miannu	We have identified a microtubule-binding protein, hook3, as a novel interacting partner of sr-a. / by transfecting small interfering rna targeting hook3, total and surface expression, receptor-mediated ligand uptake and protein stability of sr-a were significantly promoted, whereas the protein synthesis and maturation were not altered. We propose for the first time that hook3 may participate in the turnover of the endocytosed scavenger receptor	SIGNOR-152268	0.2
PRKCD	protein	Q05655	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser370	PAVPPRPsADLILNR	9606	BTO:0000130								12056906	t		esanto	Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?.	SIGNOR-89241	0.459
CDK1	protein	P06493	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Ser214	SRSGLYRsPSMPENL	9606			SIGNOR-C17						10864927	t		gcesareni	Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b.	SIGNOR-78420	0.853
TNFSF10	protein	P50591	UNIPROT	TNFRSF10A	protein	O00220	UNIPROT	up-regulates	binding			9606									14585074	t		amattioni	Trail interacts with tril-r1 and trail-r2 and activetes them	SIGNOR-101082	0.932
MAPK1	protein	P28482	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates activity	phosphorylation	Thr753	YACASPKtPIQAGGY	10116	BTO:0001009								16508002	t		lperfetto	Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity.	SIGNOR-236388	0.612
RNF167	protein	Q9H6Y7	UNIPROT	SLC22A18	protein	Q96BI1	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								16314844	t		miannu	 Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop.	SIGNOR-271551	0.541
apraclonidine	chemical	CHEBI:2788	ChEBI	ADRA2A	protein	P08913	UNIPROT	up-regulates activity	chemical activation			-1									8784451	t		miannu	 we describe full details of our studies with 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline (AGN 193080, 3), a potent, selective α2 adrenoceptor agonist that does not cross the blood−brain barrier.	SIGNOR-258497	0.8
AKT1	protein	P31749	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates	phosphorylation	Ser1177	TSRIRTQsFSLQERQ	9606									11729179	t		gcesareni	Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.	SIGNOR-112363	0.874
PRKD1	protein	Q15139	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser498	RPLSRTQsSPLPQSP	9606									22865920	t		lperfetto	When phosphorylated by camk/pkd, class iia hdacs bind 14-3-3 chaperone proteins, which facilitates their nuclear export, thereby relieving hdac-mediated transcriptional repression.	SIGNOR-198662	0.532
E2F1	protein	Q01094	UNIPROT	CCNE1	protein	P24864	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8649818	f		lperfetto	We have found that cell cycle regulation of cyclin E transcription is mediated by E2F binding sites present in the promoter. The activity of this promoter can be regulated negatively by pRB.	SIGNOR-245474	0.67
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	SLC2A3	protein	P11169	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27692180	t		miannu	HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 	SIGNOR-267451	0.367
BRD4	protein	O60885	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr58	KKFELLPtPPLSPSR	9606									32482868	t		lperfetto	We report that BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation, thereby regulating MYC target genes.	SIGNOR-262046	0.58
CDK1	protein	P06493	UNIPROT	MCL1	protein	Q07820	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr92	EVPDVTAtPARLLFF	9606			SIGNOR-C17						20526282	t		gcesareni	Mcl-1 is phosphorylated at two sites in mitosis, ser64 and thr92. Phosphorylation of thr92 by cyclin-dependent kinase 1 (cdk1)-cyclin b1 initiates degradation of mcl-1 in cells arrested in mitosis by microtubule poisons.	SIGNOR-165867	0.475
ARP2/3	complex	SIGNOR-C146	SIGNOR	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates				9606									12479800	f		lperfetto	The Arp2/3 complex concentrates at leading edges, where it catalyzes the growth of branched actin networks that are believed to provide the protrusive force for leading edge extension.	SIGNOR-251511	0.7
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	PCK1	protein	P35558	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22521266	t		gcesareni	Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase).	SIGNOR-252924	0.2
PPP2R5C	protein	Q13362	UNIPROT	PPP2CA	protein	P67775	UNIPROT	up-regulates activity	binding			9606									7592815	t			We have identified by two-hybrid interaction a new human gene family encoding PP2A B subunits. This family, denoted B56, contains three distinct genes, one of which is differentially spliced.	SIGNOR-268155	0.858
CORT	protein	O00230	UNIPROT	MRGPRX2	protein	Q96LB1	UNIPROT	up-regulates	binding			9606	BTO:0000938								16111673	t		gcesareni	The mrgx2 receptor has been shown to be activated by the peptides cortistatin and proadrenomedullin n-terminal peptides (pamp)	SIGNOR-139855	0.527
LPAR3	protein	Q9UBY5	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606									12531543	t		gcesareni	Lpa3couples to gq	SIGNOR-97400	0.46
afatinib	chemical	CHEBI:61390	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000551								22452896	t	Like lapatinib and neratinib, afatinib is a next generation tyrosine kinase inhibitor (TKI) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases.	gcesareni	Afatinib, an irreversible erbb-family blocker, has shown preclinical activity when tested in egfr mutant models with mutations that confer resistance to egfr tyrosine-kinase inhibitors.	SIGNOR-196760	0.8
MAPK3	protein	P27361	UNIPROT	APBB1	protein	O00213	UNIPROT	unknown	phosphorylation	Ser287	WEPPGRAsPSQGSSP	9606									14697653	t		lperfetto	Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved.	SIGNOR-120475	0.271
MAPK3	protein	P27361	UNIPROT	CASP8	protein	Q14790	UNIPROT	down-regulates	phosphorylation	Ser387	YLEMDLSsPQTRYIP	9606		BTO:0000149							24342355	t		lperfetto	We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity	SIGNOR-203480	0.706
NHS	protein	Q6T4R5	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	up-regulates activity	relocalization			9606									20332100	t		miannu	NHS knockdown also resulted in the mislocalization of the Arp2/3 complex and disruption of the actin cytoskeleton. in the absence of NHS, Arp2/3 localization and F-actin distribution are disrupted, suggesting that Arp2/3 actin-nucleation activity is mediated, in part, by NHS providing an additional functional link between NHS and actin. 	SIGNOR-253566	0.2
GSK3B	protein	P49841	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates activity	phosphorylation	Tyr216	RGEPNVSyICSRYYR	9606									20331603	t		lperfetto	Phosphorylation of the residue Tyrosine in 216 position results in the constitutive activity of GSK-3beta and believed to be important target for signal transduction.	SIGNOR-217865	0.2
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	estrone	smallmolecule	CHEBI:17263	ChEBI	up-regulates quantity	precursor of			-1									8994190	t		Luana	Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues. 	SIGNOR-269757	0.8
GSK3B	protein	P49841	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser37	YLDSGIHsGATTTAP	9606			SIGNOR-C110						11955436	t		gcesareni	Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC).	SIGNOR-116524	0.856
P-TEFb	complex	SIGNOR-C238	SIGNOR	MLLT1	protein	Q03111	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606	BTO:0000007								17135274	t		miannu	Phosphorylation of Af9 and Enl by P-TEFb promotes their proteolysis	SIGNOR-266799	0.708
AMPK	complex	SIGNOR-C15	SIGNOR	MTOR	protein	P42345	UNIPROT	up-regulates activity	phosphorylation	Ser1261	PMKKLHVsTINLQKA	10090	BTO:0002572								31186373	t		miannu	AMPK directly activates mTORC2 to promote cell survival during acute energetic stress. AMPK associates with and phosphorylates mTOR within mTORC2., these data indicate that AMPK phosphorylates mTOR on Ser1261 within mTORC2, an event that correlates with increased mTORC2 autophosphorylation and downstream signaling.	SIGNOR-262535	0.549
RalGAP1	complex	SIGNOR-C468	SIGNOR	RALA	protein	P11233	UNIPROT	down-regulates activity	guanine nucleotide exchange factor			10090	BTO:0000011								21148297	t		miannu	 Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. 	SIGNOR-269795	0.43
cisapride	chemical	CHEBI:3720	ChEBI	KCNH2	protein	Q12809	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9395068	t		miannu	A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG. cisapride displays specific, high affinity block of the human cardiac K+ channel HERG. It is likely that this interaction underlies the proarrhythmic effects of the drug observed under certain clinical settings.	SIGNOR-258672	0.8
YAP1	protein	P46937	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606									23075495	f		gcesareni	Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis.	SIGNOR-199214	0.7
PRPF4B	protein	Q13523	UNIPROT	KLF13	protein	Q9Y2Y9	UNIPROT	down-regulates	phosphorylation			9606									17513757	t		flangone	Using yeast two-hybrid screening of a human thymus cdna library, prp4, a serine/threonine protein kinase, was identified as a klf13-binding protein...coexpression of prp4 and klf13 increases nuclear localization of klf13 and ccl5 transcription.	SIGNOR-154951	0.348
SCHEMBL14517914	chemical	CID:10016910	PUBCHEM	CHEK1	protein	O14757	UNIPROT	down-regulates	chemical inhibition			9606									20068082	t		gcesareni	Xl844 (exelixis) a potent atp-competitive inhibitor of chk1 (ki, 2.2nm) and chk2 (ki, 0.07nm).	SIGNOR-163231	0.8
USF1	protein	P22415	UNIPROT	GCK	protein	P35557	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9677331	f		miannu	Cotransfection of an expression plasmid encoding USF1 into HepG2 hepatoma cells resulted in the activation of the glucokinase promoter, dependent on the integrity of the P2 element	SIGNOR-255597	0.294
VDAC1	protein	P21796	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates													10365962	f		lperfetto	Our results indicate that the Bcl-2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis.	SIGNOR-249615	0.7
PTPN2	protein	P17706	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606									10734133	t		flangone	Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1.	SIGNOR-75914	0.604
STOML2	protein	Q9UJZ1	UNIPROT	LCK	protein	P06239	UNIPROT	up-regulates activity	binding			9606									18641330	t		Giorgia	In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling.	SIGNOR-260376	0.2
INTS5	protein	Q6P9B9	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261465	0.901
PTGS1	protein	P23219	UNIPROT	prostaglandin G2(1-)	smallmolecule	CHEBI:82629	ChEBI	up-regulates quantity	chemical modification			-1									7592599	t		Luana	[14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2,	SIGNOR-269771	0.8
USP45	protein	Q70EL2	UNIPROT	ERCC4/ERCC1	complex	SIGNOR-C50	SIGNOR	up-regulates activity	deubiquitination			9606	BTO:0001938								25538220	t		miannu	USP45 associates with the ERCC1–XPF endonuclease. USP45 interacts specifically with ERCC1–XPF via its N-terminal 61 residues. USP45 deubiquitylates ERCC1. USP45 promotes survival of cells exposed to agents that induce DNA damage responses controlled by ERCC1–XPF endonuclease	SIGNOR-268504	0.541
ULK3	protein	Q6PHR2	UNIPROT	ULK3	protein	Q6PHR2	UNIPROT	up-regulates activity	phosphorylation	Ser300	KKDQEGDsAAALSLY	9606									20643644	t		Manara	We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. 	SIGNOR-260793	0.2
FGFR3	protein	P22607	UNIPROT	FGFR3	protein	P22607	UNIPROT	down-regulates activity	phosphorylation	Tyr770	LSAPFEQySPGGQDT	9606	BTO:0000007								11294897	t		lperfetto	Ligand stimulation leads to autophosphorylation of fgfr3these results suggest that y770 may negatively regulate the activation of pi 3-kinase by constitutively activated fgfr3	SIGNOR-106746	0.2
KDM5A	protein	P29375	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264301	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	CPS1	protein	P31327	UNIPROT	down-regulates quantity				9606									28538732	f		Luana	In KL cells, pharmacological activation of AMPK or expression of constitutively active AMPK reduced CPS1 mRNA and protein, and silencing AMPK increased CPS1 expression even in the presence of LKB1	SIGNOR-267920	0.275
LEF1	protein	Q9UJU2	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									17081971	f		amattioni	The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells.	SIGNOR-229764	0.7
DYDC1	protein	Q8WWB3	UNIPROT	SH3GL3	protein	Q99963	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								19545932	t		miannu	DYDC1 and SH3P13 interact in vitro and in vivo. We recently demonstrated that SH3P13, a BAR domain-containing protein, assists in regulatingclathrin-coated vesicle traffic that is crucial for acrosome biogenesis during spermatogenesis	SIGNOR-263882	0.314
RARG	protein	P13631	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates activity	binding			9606									15650024	t	inferred from family member	lperfetto	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs	SIGNOR-267804	0.393
MMP17	protein	Q9ULZ9	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272385	0.7
CEBPB	protein	P17676	UNIPROT	KLF5	protein	Q13887	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									16054042	f		fspada	Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter.	SIGNOR-210004	0.691
ULK1	protein	O75385	UNIPROT	ATG9A	protein	Q7Z3C6	UNIPROT	up-regulates activity	phosphorylation	Ser761	QSIPRSAsYPCAAPR	9606									25266655	t		miannu	Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK.	SIGNOR-266366	0.6
CASP6	protein	P55212	UNIPROT	Caspase 6 complex	complex	SIGNOR-C228	SIGNOR	form complex	binding								cleavage:Asp23	EENMTETdAFYKREM			21621544	t		lperfetto	It is generally recognized that effector caspases undergo proteolytic cleavage of the inactive zymogen at a specific aspartate residue, resulting in a large N-terminal p20 polypeptide chain and a small C-terminal p10 polypeptide chain, leading to a p202/p102 tetramer.	SIGNOR-256391	0.2
LCK	protein	P06239	UNIPROT	PRKCQ	protein	Q04759	UNIPROT	unknown	phosphorylation	Tyr90	SETTVELySLAERCR	9606									10652356	t		llicata	Tyrosine 90 (tyr-90) in the regulatory domain of pkctheta was identified as the major phosphorylation site by lck.	SIGNOR-74574	0.548
CAMKK1	protein	Q8N5S9	UNIPROT	CAMK4	protein	Q16566	UNIPROT	up-regulates	phosphorylation	Thr200	EHQVLMKtVCGTPGY	9606									15769749	t		gcesareni	Phosphorylation of ca(2+)/cam-bound camkiv on its activation loop threonine (residue thr(200) in human camkiv) by ca(2+)/calmodulin-dependent kinase kinase leads to increased camkiv kinase activity.	SIGNOR-134649	0.603
MAPK3	protein	P27361	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates	phosphorylation	Ser530	DGPPSPRsPVIGSEV	9606	BTO:0001271								15093545	t	The effect has been demonstrated using P29590-4	gcesareni	Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis.	SIGNOR-124317	0.345
ATM	protein	Q13315	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1330	QMRHQSEsQGVGLSD	9606	BTO:0000150								10550055	t		lperfetto	The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks	SIGNOR-72048	0.813
STAT3	protein	P40763	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0001103							18177723	f		andrea cerquone perpetuini	We identified cyclin D1 as a STAT3 target gene product downregulated in satellite cells from IL-6-deficient muscle in vitro and in vivo. 	SIGNOR-255411	0.78
MTNR1B	protein	P49286	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256986	0.252
UBE2I	protein	P63279	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	sumoylation	Lys159	APSSMMVkDEYVHDF	9606									12621041	t		gcesareni	The mh1 domain of smad4 was shown to associate physically with ubc9, the ubiquitin carrier protein (e2) conjugating enzyme in sumoylation. In cultured cells, smad4 is modified by sumo-1 at the endogenous level. The sumoylation sites were identified as two evolutionarily conserved lysine residues, lys-113 and lys-159, in the mh1 domain. We found that the mutations at lys-113 and lys-159 did not alter the ability of smad4 to form a complex with smad2 and fast on the mix.2 promoter. Importantly, sumo-1 overexpression enhanced tgf-beta-induced transcriptional responses. These findings identify sumoylation as a unique mechanism to modulate smad4-dependent cellular responses	SIGNOR-98997	0.609
MAPK3	protein	P27361	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									20068231	t		gcesareni	Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.	SIGNOR-163254	0.728
SH3GLB1	protein	Q9Y371	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates	binding			9606	BTO:0000567								16227588	t		gcesareni	Here, we provide evidence that bif-1 plays a regulatory role in apoptotic activation of not only bax but also bak and appears to be involved in suppression of tumorigenesis. while bif-1 did not directly interact with bak, it heterodimerized with bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the bax conformational change.	SIGNOR-141166	0.334
1038915-60-4	chemical	CID:24958200	PUBCHEM	PARP1	protein	P09874	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194399	0.8
SETD5	protein	Q9C0A6	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	methylation			-1									31515109	t		miannu	SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription.	SIGNOR-265350	0.2
MAPK3	protein	P27361	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates	phosphorylation	Thr693	RELVEPLtPSGEAPN	9606									1651322	t		lperfetto	It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation.	SIGNOR-20549	0.539
SRGAP3	protein	O43295	UNIPROT	RAC3	protein	P60763	UNIPROT	down-regulates				9606									12447388	f		miannu	Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo.	SIGNOR-95964	0.538
ATM	protein	Q13315	UNIPROT	FANCI	protein	Q9NVI1	UNIPROT	unknown	phosphorylation	Ser730	LDKSADFsQSTSIGI	9606	BTO:0000007								17412408	t			Three phosphorylation sites were detected in a human KIAA1794 protein: S730, T952, S1121, and two other sites in the mouse protein S555, T558. We renamed the KIAA1794 protein as FANCI, since, as shown below, the locus encoding this protein is mutated in an individual with Fanconi anemia complementation group I	SIGNOR-255590	0.542
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	HJURP	protein	Q8NCD3	UNIPROT	up-regulates activity	phosphorylation	Ser486	GLETRRLsLPSSKAK	-1									17256767	t		miannu	 These data define a new protein complex in mammalian cells where 14‐3‐3 associates with FAKTS through phosphorylated S479. Our research identifies a widely expressed eukaryotic protein FAKTS, as a new Akt/PKB substrate localized in the nucleus. Akt/PKB promotes FAKTS association with 14‐3‐3, placing FAKTS under the control of 14‐3‐3 proteins. FAKTS may play an important role in transmitting Akt/PKB‐mediated signals in the complex network of intracellular signal transduction. 	SIGNOR-262623	0.2
SB 203580	chemical	CHEBI:90705	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000567								15208625	t		gcesareni	Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme.	SIGNOR-126055	0.8
TBX21	protein	Q9UL17	UNIPROT	IFNG	protein	P01579	UNIPROT	up-regulates quantity by expression	transcriptional regulation												17541280	f			T-bet is crucially implicated in Th1 differentiation due to its strong promoting activity for IFN-gamma gene transcription	SIGNOR-254508	0.49
CLSPN	protein	Q9HAW4	UNIPROT	CHEK1	protein	O14757	UNIPROT	up-regulates	binding			9606									11090622	t		gcesareni	Binding of claspin to xchk1 is highly elevated in the presence of dna templates that trigger a checkpoint arrest of the cell cycle in xenopus egg extracts	SIGNOR-84474	0.786
AKT1	protein	P31749	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser167	GGRERLAsTNDKGSM	9606									11108261	t		lperfetto	Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt.	SIGNOR-84975	0.757
PLCG1	protein	P19174	UNIPROT	1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	up-regulates	chemical modification			9606									21918248	t		gcesareni	Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag.	SIGNOR-176606	0.8
CEBPA	protein	P49715	UNIPROT	Monocyte_differentiation 	phenotype	SIGNOR-PH101	SIGNOR	up-regulates activity				10090	BTO:0000725								19706798	f			Conditional cebpa deficiency in adult mice blocks the transition from common myeloid progenitors (CMP) to granulocyte monocyte progenitors (GMP) resulting in the accumulation of myeloid blasts	SIGNOR-259965	0.7
ABL1	protein	P00519	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates	phosphorylation	Tyr231	NANGEAVyCKFHYKT	9606									12950161	t		lperfetto	C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitro.catalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases	SIGNOR-86581	0.412
IKBKB	protein	O14920	UNIPROT	YWHAB	protein	P31946	UNIPROT	down-regulates	phosphorylation	Ser132	GDYFRYLsEVASGDN	9606									16024783	t		gcesareni	We provide a mechanism for these observations through the phosphorylation of 14-3-3beta by ikkbeta and pkcdelta on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm.	SIGNOR-138608	0.377
ZMIZ1	protein	Q9ULJ6	UNIPROT	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				10090	BTO:0001825								26522984	f		miannu	Our data suggest that Zmiz1 and Notch1 cooperatively recruit each other to chromatin through direct interaction via the TPR resulting in a slight increase in activating histone marks and decrease of repressive histone marks.	SIGNOR-263938	0.7
IC-87114	chemical	CHEBI:90686	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252662	0.8
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	NANOG	protein	Q9H9S0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002861								18682241	t		flangone	We also find that SMADs bind with the NANOG promoter and that SMAD2/3 activity enhances NANOG promoter activity.	SIGNOR-242052	0.433
EFNA1	protein	P20827	UNIPROT	EPHA8	protein	P29322	UNIPROT	up-regulates	binding			9606									17420126	t		gcesareni	Ephrins are cell-surface tethered guidance cues that bind to eph receptor tyrosine kinases in trans on opposing cells.	SIGNOR-154298	0.811
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates activity	ubiquitination			9534									11295495	t		lperfetto	The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk.	SIGNOR-235305	0.491
CHEK2	protein	O96017	UNIPROT	MDM4	protein	O15151	UNIPROT	down-regulates	phosphorylation	Ser342	SKLTHSLsTSDITAI	9606									16163388	t		lperfetto	Phosphorylation of s342 and s367 in vivo require the chk2 kinase. Chk2 also stimulates mdmx ubiquitination and degradation by mdm2	SIGNOR-140417	0.713
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates	dephosphorylation			9606									12840032	t	inferred from 70% of family members	lperfetto	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases	SIGNOR-269923	0.505
WEE1	protein	P30291	UNIPROT	CDK2	protein	P24941	UNIPROT	down-regulates	phosphorylation	Tyr15	EKIGEGTyGVVYKAR	9606	BTO:0000567								11029659	t		gcesareni	Identification and characterization of human wee1b, a new member of the wee1 family of cdk-inhibitory kinases.	SIGNOR-83139	0.651
EGFR	protein	P00533	UNIPROT	NCK1	protein	P16333	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								1333047	t			We show that epidermal growth factor or platelet-derived growth factor stimulation of intact human or murine cells leads to phosphorylation of Nck protein on tyrosine, serine, and threonine residues	SIGNOR-252089	0.592
ASXL1	protein	Q8IXJ9	UNIPROT	CDKN2A	protein	P42771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									29967380	t		miannu	Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in Asxl1G643fs/+ mice.	SIGNOR-260119	0.306
UBE2I	protein	P63279	UNIPROT	IRF7	protein	Q92985	UNIPROT	down-regulates activity	sumoylation	Lys452	EKSLVLVkLEPWLCR	9606	BTO:0002181								22951831	t		scontino	One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. We recently documented that LMP1 induces a third major protein modification by physically interacting with the SUMO-conjugating enzyme Ubc9 through CTAR3 and inducing the sumoylation of cellular proteins in latently infected cells. we identified that IRF7 is sumoylated at lysine 452. 	SIGNOR-266837	0.292
RET	protein	P07949	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates	phosphorylation	Thr180	RHTDDEMtGYVATRW	9606									8622669	t		gcesareni	Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme.	SIGNOR-40493	0.338
regorafenib	chemical	CHEBI:68647	ChEBI	ABCB1	protein	P08183	UNIPROT	down-regulates activity	chemical inhibition			9606									26254357	t		miannu	 It is suggested that in vitro, regorafenib is an inhibitor of ABCB1 and ABCG2, but not a substrate, and that its active metabolites, M2 (N-Oxide metabolite) and M5 (N-Oxide/N-desmethyl metabolite), are substrates of ABCB1 and ABCG2	SIGNOR-259182	0.8
TRAF6	protein	Q9Y4K3	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity	ubiquitination	Lys134	AEAWSPRkLPSSAST	9606	BTO:0000007								18347055	t			K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-_B	SIGNOR-262298	0.911
PTPRG	protein	P23470	UNIPROT	BLNK	protein	Q8WV28	UNIPROT	up-regulates activity	dephosphorylation	Tyr84	EHSDSEMyVMPAEEN	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254692	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	AMPH	protein	P49418	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000142							15262992	t	inferred from 70% family members	lperfetto	Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2.	SIGNOR-270197	0.2
RPS13	protein	P62277	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262439	0.889
SOCS1	protein	O15524	UNIPROT	JAK3	protein	P52333	UNIPROT	down-regulates activity	binding			9606									21508344	t		lperfetto	SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR).	SIGNOR-238642	0.697
ID3	protein	Q02535	UNIPROT	MYOD/E12E47	complex	SIGNOR-C127	SIGNOR	down-regulates activity	binding			10090	BTO:0004058								9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241158	0.496
STK10	protein	O94804	UNIPROT	MSN	protein	P26038	UNIPROT	up-regulates activity	phosphorylation	Thr558	LGRDKYKtLRQIRQG	9606									19255442	t		llicata	Evidence in jurkat cells that lok phosphorylates erm and that erm phosphorylation impedes migration.	SIGNOR-184433	0.394
NFE2L2	protein	Q16236	UNIPROT	TFB2M	protein	Q9H5Q4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15684387	f		lperfetto	Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC	SIGNOR-268998	0.253
SIRT5	protein	Q9NXA8	UNIPROT	CPS1	protein	P31327	UNIPROT	up-regulates activity	post translational modification			9606	BTO:0000567								24703693	t	deglutarylation	lperfetto	Glutarylation suppresses CPS1 activity, which is targeted by SIRT5 for removal|SIRT5 can catalyze the enzymatic removal of lysine glutarylation	SIGNOR-267643	0.523
MAPK11	protein	Q15759	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	unknown	phosphorylation	Ser863	LTQSAPAsPTNKGVH	9606				SIGNOR-C3					21757713	t		llicata	Arsenite treatment of cells activates p38_ and induces interaction between p38_ and raptor, a regulatory component of mtorc1, resulting in phosphorylation of raptor on ser(863) and ser(771). The phosphorylation of raptor on these sites enhances mtorc1 activity, and contributes largely to arsenite-induced mtorc1 activation.	SIGNOR-174874	0.361
DOK1	protein	Q99704	UNIPROT	ITGB3	protein	P05106	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257687	0.34
AKT1	protein	P31749	UNIPROT	PIKFYVE	protein	Q9Y2I7	UNIPROT	up-regulates	phosphorylation	Ser307	PARNRSAsITNLSLD	9606		BTO:0000887							15546921	t		gcesareni	Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme.	SIGNOR-252474	0.507
CLASP2	protein	O75122	UNIPROT	IQGAP1	protein	P46940	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								19638411	t		lperfetto	IQGAP1 is a novel CLASP2-interacting protein| nonphosphorylated CLASP2 on microtubules is allowed to associate with IQGAP1 for the coupling of microtubules to actin filaments at the front of migrating cells.	SIGNOR-264828	0.428
GARS1	protein	P41250	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									24898252	t		miannu	Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 	SIGNOR-270481	0.8
MAPK1	protein	P28482	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation	Ser540	KVMARSLsPPPELEE	10090	BTO:0000944								15851026	t		lperfetto	Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation.	SIGNOR-249454	0.668
PRKACA	protein	P17612	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates	phosphorylation			9606									10693759	t		gcesareni	In vertebrates,pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation	SIGNOR-75362	0.445
GOT2	protein	P00505	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	chemical modification			9606									31422819	t		miannu	This is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1).	SIGNOR-267518	0.8
PLK1	protein	P53350	UNIPROT	CCNB1	protein	P14635	UNIPROT	up-regulates activity	phosphorylation	Ser126	PILVDTAsPSPMETS	9606	BTO:0000567								11242082	t		lperfetto	Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation.	SIGNOR-105707	0.919
IKZF5	protein	Q9H5V7	UNIPROT	LNPEP	protein	Q9UIQ6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003420								15894523	f	 	miannu	Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. 	SIGNOR-255407	0.2
Orexin A	smallmolecule	CHEBI:80319	ChEBI	HCRTR1	protein	O43613	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257510	0.8
MAPK14	protein	Q16539	UNIPROT	HBP1	protein	O60381	UNIPROT	up-regulates	phosphorylation	Ser402	GFSKNCGsPGSSQLS	9606									14612426	t		lperfetto	A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression.	SIGNOR-119138	0.404
PPM1B	protein	O75688	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates	dephosphorylation	Ser181	DQGSLCTsFVGTLQY	9606									18930133	t		lperfetto	Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation	SIGNOR-181667	0.412
FUS	protein	P35637	UNIPROT	ATXN2	protein	Q99700	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			10090		BTO:0001279							28515487	f			This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease	SIGNOR-262809	0.468
DVL1	protein	O14640	UNIPROT	PLCB1	protein	Q9NQ66	UNIPROT	up-regulates activity				9606									19279717	t		areggio	Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin	SIGNOR-258978	0.278
MKRN1	protein	Q9UHC7	UNIPROT	TERT	protein	O14746	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002552								15805468	t		miannu	MKRN1 functions as an E3 ubiquitin-ligase for hTERT in vitro and in vivo. Furthermore, we have used the yeast two-hybrid method to identify a novel RING finger gene (MKRN1) encoding an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length. 	SIGNOR-271529	0.488
CTDSPL	protein	O15194	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	dephosphorylation	Ser187	NSHPFPHsPNSSYPN	9606	BTO:0000552								17085434	t			Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)	SIGNOR-248313	0.476
PPP1R3B	protein	Q86XI6	UNIPROT	GYS2	protein	P54840	UNIPROT	up-regulates	binding			9606		BTO:0000759							36551183	t		miannu	In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)	SIGNOR-271732	0.771
GRK3	protein	P35626	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser375	GTLRTSIsVERQIHK	9606	BTO:0000007								11517230	t			Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251462	0.2
MAPK1	protein	P28482	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser29	FDGSSCIsPTIVQQF	10090	BTO:0000944								15664191	t		lperfetto	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-249441	0.616
NR2E3	protein	Q9Y5X4	UNIPROT	NR1D1	protein	P20393	UNIPROT	up-regulates	binding			9606									15190009	t		gcesareni	All four proteins, nr2e3, nr1d1, nrl and crx, could be co-immunoprecipitated from the bovine retinal nuclear extract, suggesting their existence in a multi-protein transcriptional regulatory complex in vivo.	SIGNOR-125661	0.408
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	CDH1	protein	P12830	UNIPROT	down-regulates quantity by destabilization	ubiquitination										phosphorylation:Ser146	LLTFPNSsPGLRRQK	23972993	t	For phosphorylated residues see Figure 7	lperfetto	Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP	SIGNOR-274055	0.293
CCT129202	chemical	CID:16202152	PUBCHEM	AURKC	protein	Q9UQB9	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190883	0.8
MC1R	protein	Q01726	UNIPROT	Pigmentation	phenotype	SIGNOR-PH70	SIGNOR	up-regulates				9606									19656324	f		miannu	Alpha-melanocyte stimulating hormone (alpha-MSH) binds to melanocortin-1 receptor (MC1R) on melanocytes to stimulate pigmentation and modulate various cutaneous inflammatory responses. 	SIGNOR-252374	0.7
MAPK8	protein	P45983	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Thr278	SVSAATLtPSSQAVT	9606									19245816	t		gcesareni	In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed.	SIGNOR-184190	0.694
POLH	protein	Q9Y253	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									21242293	f		miannu	In this study we show that, in human cells, polη becomes phosphorylated by ATR at Ser601 after UV irradiation. Phosphorylation requires physical interaction of polη with Rad18 but is independent of PCNA monoubiquitination. We show that UV-induced phosphorylation of polη is required for normal survival and postreplication repair and is involved in checkpoint control.	SIGNOR-259061	0.7
OTUD7B	protein	Q6GQQ9	UNIPROT	RIPK1	protein	Q13546	UNIPROT	down-regulates activity	deubiquitination			9606	BTO:0000007								18178551	t		lperfetto	NF-kappaB Suppression by the Deubiquitinating Enzyme Cezanne|Our study provides several lines of evidence to suggest that Cezanne suppresses TNFR signaling to NF-κB by targeting RIP1 for deubiquitination.	SIGNOR-268411	0.519
AURKB	protein	Q96GD4	UNIPROT	ZWINT	protein	O95229	UNIPROT	up-regulates activity	phosphorylation	Thr251	TRPQEQStGDTMGRD	-1									21775627	t		lperfetto	Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores|During prometaphase, AurB phosphorylation of zwint-1 is required for recruitment of ZW10-, pT89 dynein-, and RZZ-dependent proteins to kinetochores. This is defective after AurB inhibition or after expression of the triple-A zwint-1 mutant. Triple-E mutant zwint-1 mimics phospho–zwint-1 in RZZ recruitment, even after AurB inhibition	SIGNOR-265010	0.637
AMPK	complex	SIGNOR-C15	SIGNOR	ACACA	protein	Q13085	UNIPROT	down-regulates activity	phosphorylation	Ser80	LHIRSSMsGLHLVKQ	9606									29899443	t			Human ACC1 is inactivated by phosphorylation at Ser80, Ser1201 and Ser1216 by AMP-activated protein kinase (AMPK) 	SIGNOR-267475	0.541
DNA polymerase alpha:primase complex	complex	SIGNOR-C262	SIGNOR	DNA_replication	phenotype	SIGNOR-PH53	SIGNOR	up-regulates													24043831	f		lperfetto	At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation 	SIGNOR-261344	0.7
CDK1	protein	P06493	UNIPROT	FOXK2	protein	Q01167	UNIPROT	up-regulates	phosphorylation	Ser373	SSRSAPAsPNHAGVL	9606									20810654	t		gcesareni	We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis.	SIGNOR-167822	0.38
PRKACA	protein	P17612	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates activity	phosphorylation	Ser51	LRPSTSRsLYASSPG	-1									2500966	t		miannu	Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure.	SIGNOR-250069	0.313
PTPRJ	protein	Q12913	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	9606									1715686	t		gcesareni	Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta.	SIGNOR-21295	0.309
IFNG	protein	P01579	UNIPROT	SLC11A1	protein	P49279	UNIPROT	up-regulates				9606	BTO:0000801								11909746	f			Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS)	SIGNOR-254038	0.356
FLI1	protein	Q01543	UNIPROT	MPL	protein	P40238	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002581								15466856	f	 	miannu	Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. 	SIGNOR-254163	0.248
SMO	protein	Q99835	UNIPROT	GPR161	protein	Q8N6U8	UNIPROT	down-regulates activity	relocalization			10090									23332756	f			Constitutive Gpr161 activity increases cAMP levels, which is reduced upon knockdown of Gαs, suggesting it to be a Gαs-coupled receptor.	SIGNOR-259937	0.324
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2E2	protein	Q96LR5	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271317	0.702
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	RPS3	protein	P23396	UNIPROT	up-regulates activity	phosphorylation	Thr70	GRRIRELtAVVQKRF	10116	BTO:0003060								20605787	t		miannu	Here, we show that human RPS3 is a physiological target of Akt kinase and a novel mediator of neuronal apoptosis. NGF stimulation resulted in phosphorylation of threonine 70 of RPS3 by Akt, and this phosphorylation was required for Akt binding to RPS3.our experiment demonstrated that Akt up-regulates the endonuclease activity of RPS3 via phosphorylation and led us to believe that Akt phosphorylation of RPS3 after DNA damage is an antiapoptotic signal or a molecular switch that extends the life of a cell after DNA damage.	SIGNOR-259816	0.2
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation	Tyr813	NSLFTPDyELLTEND	9606	BTO:0000007								15121872	t	16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition.	lperfetto	Tyrosine 813 is a site of jak2 autophosphorylation critical for activation of jak2 by sh2-b betawe show that phosphorylation of tyrosine 813 is required for the sh2 domain-containing adapter protein sh2-b beta to bind jak2 and to enhance the activity of jak2 and stat5b.	SIGNOR-235910	0.2
ALDOB	protein	P05062	UNIPROT	glycerone phosphate(2-)	smallmolecule	CHEBI:57642	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266484	0.8
NFKB1	protein	P19838	UNIPROT	CTCF	protein	P49711	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21912613	f	 	miannu	 In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription.	SIGNOR-254788	0.309
SRC	protein	P12931	UNIPROT	NELFCD	protein	Q8IXH7	UNIPROT	down-regulates activity	phosphorylation	Tyr14	GAIMDEDyYGSAAEW	9534									22238675	t		miannu	 Here we show that c-Src interacts with TH1 by GST-pull down assay, coimmunoprecipitation and confocal microscopy assay. The interaction leads to phosphorylation of TH1 at Tyr-6 in vivo and in vitro. Phosphorylation of TH1 decreases its association with A-Raf and PAK1.	SIGNOR-276402	0.344
PIKFYVE	protein	Q9Y2I7	UNIPROT	PAS complex	complex	SIGNOR-C190	SIGNOR	form complex	binding			9606	BTO:0000007								17556371	t		miannu	Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels.	SIGNOR-253529	0.932
UBE2I	protein	P63279	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates activity	sumoylation	Lys226	HPRLQALkEEPQTVP	9606				SIGNOR-C154					16055711	t		lperfetto	We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. 	SIGNOR-263002	0.43
LPCAT2	protein	Q7L5N7	UNIPROT	1-O-acyl-sn-glycero-3-phosphocholine	chemical	CHEBI:58168	ChEBI	down-regulates quantity	chemical modification			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272766	0.8
MAPK8	protein	P45983	UNIPROT	WDR62	protein	O43379	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr1053	PSSSLPQtPEQEKFL	9606	BTO:0000007								30566428	t		lperfetto	WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. |JNK1 can induce the phosphorylation of WDR62 T1053 	SIGNOR-271710	0.573
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	RANGAP1	protein	P46060	UNIPROT	up-regulates	phosphorylation	Ser442	STFLAFPsPEKLLRL	9606									15037602	t		lperfetto	Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain.	SIGNOR-216785	0.446
CALM3	protein	P0DP25	UNIPROT	GEM	protein	P55040	UNIPROT	up-regulates activity	binding			10116	BTO:0001009								14701738	t		miannu	Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells.	SIGNOR-266341	0.2
Kisspeptin-10	smallmolecule	CHEBI:80307	ChEBI	KISS1R	protein	Q969F8	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257527	0.8
LPAR2	protein	Q9HBW0	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257382	0.581
GNAS	protein	Q5JWF2	UNIPROT	Adenylate_cyclase	proteinfamily	SIGNOR-PF92	SIGNOR	up-regulates activity	binding			9606									12145344	t		lperfetto	HETEROTRIMERIC G PROTEINS are essential for cell signaling throughout the body. The stimulatory G protein, Gs, couples activation of a host of different transmembrane receptors to adenylyl cyclase stimulation, leading to intracellular generation of cAMP 	SIGNOR-268693	0.731
PAPOLA	protein	P51003	UNIPROT	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates quantity by stabilization	chemical modification			9606									19224921	t		lperfetto	Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner.	SIGNOR-268327	0.8
CREB1	protein	P16220	UNIPROT	CHGA	protein	P10645	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001007								12456801	t	 	 	Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation.	SIGNOR-254276	0.268
Av/b1 integrin	complex	SIGNOR-C175	SIGNOR	SOX2	protein	P48431	UNIPROT	up-regulates quantity by expression				10090									18757303	f		lperfetto	Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1.	SIGNOR-253273	0.319
CCL2	protein	P13500	UNIPROT	ARDS	phenotype	SIGNOR-PH128	SIGNOR	up-regulates				9606									32446778	f		miannu	Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection	SIGNOR-261032	0.7
HIF1A	protein	Q16665	UNIPROT	KDM5B	protein	Q9UGL1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271563	0.275
Y-27632	chemical	CHEBI:75393	ChEBI	ROCK2	protein	O75116	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207893	0.8
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDE1	protein	Q9NXR1	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr246	STGGTPLtPAARISA	9606	BTO:0000007								16682949	t	done	miannu	Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. 	SIGNOR-274086	0.525
GDNF	protein	P39905	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252184	0.431
CDK1	protein	P06493	UNIPROT	USP24	protein	Q9UPU5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2604	HLQQGSEsPMMIGEL	9606	BTO:0000018								27991932	t		lperfetto	 Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604.	SIGNOR-275603	0.2
MELK	protein	Q14680	UNIPROT	PDPK1	protein	O15530	UNIPROT	down-regulates activity	phosphorylation	Thr354	WENLHQQtPPKLTAY	9606	BTO:0000007								22544756	t		miannu	The results showed that MPK38 interacted with and inhibited PDK1 activity via Thr(354) phosphorylation. 	SIGNOR-276414	0.27
PRKCA	protein	P17252	UNIPROT	MGluR	proteinfamily	SIGNOR-PF55	SIGNOR	up-regulates activity	phosphorylation			-1									15894802	t	inferred from family member	lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-270278	0.569
MAP2K3	protein	P46734	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation	Tyr182	TDDEMTGyVATRWYR	9606									8622669	t		lperfetto	Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases.	SIGNOR-40353	0.715
UFL1	protein	O94874	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0000007								30886146	t		lperfetto	UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. UFL1 is recruited to double strand breaks by the MRE11/RAD50/NBS1 complex, and monoufmylates histone H4 following DNA damage.	SIGNOR-265073	0.2
CTDSP2	protein	O14595	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	dephosphorylation	Ser204	NHSMDAGsPNLSPNP	9606	BTO:0000007								17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248293	0.399
GNB/GNG	complex	SIGNOR-C202	SIGNOR	PLCB2	protein	Q00722	UNIPROT	up-regulates													23994464	t		apalma	However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits	SIGNOR-255015	0.528
UBE3A	protein	Q05086	UNIPROT	DLG4	protein	P78352	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								17121805	t		miannu	E6-induced degradation of DLG4 depends on E6AP in vivo.  Our findings as a whole indicate that E6AP is involved in E6-mediated ubiquitination and degradation of DLG4 both in vivo and in vitro.	SIGNOR-271397	0.357
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser175	SPASSGSsASFISDT	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248368	0.598
JAKMIP1	protein	Q96N16	UNIPROT	TUBB	protein	P07437	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000661								15277531	t		SARA	In Jamip1, the N-terminal region mediates the association with microtubules, when highly expressed, N-ter drastically affects the organization of microtubules that appear to be bundled, stabilized against the depolymerizing effect of nocodazole, and enriched in acetylated tubulin.	SIGNOR-260987	0.2
F9	protein	P00740	UNIPROT	Factor VIIIa-IXa	complex	SIGNOR-C320	SIGNOR	form complex	binding			10090		BTO:0000131							25769543	t		lperfetto	The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin.	SIGNOR-263552	0.758
Succinyl-CoA ATP variant	complex	SIGNOR-C398	SIGNOR	succinate(2-)	smallmolecule	CHEBI:30031	ChEBI	up-regulates quantity	chemical modification			9606									27487822	t		miannu	In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions.	SIGNOR-266269	0.8
CSNK2A1	protein	P68400	UNIPROT	SLC9A5	protein	Q14940	UNIPROT	down-regulates activity	phosphorylation	Ser709	SEEEEEEsDSSETEK	-1									21296876	t		miannu	CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis	SIGNOR-276252	0.2
MYCL	protein	P12524	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				10090		BTO:0000724							7882978	f		irozzo	These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation.	SIGNOR-259202	0.7
MAPK1	protein	P28482	UNIPROT	CIC	protein	Q96RK0	UNIPROT	down-regulates	phosphorylation	Ser1409	SAPEDPTsPKRKMRR	9606	BTO:0000848								21087211	t		gcesareni	Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3))[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3	SIGNOR-169875	0.381
JWOGUUIOCYMBPV-GMFLJSBRSA-N	chemical	CID:6918328	PUBCHEM	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257979	0.8
M1_polarization	phenotype	SIGNOR-PH54	SIGNOR	IFNG	protein	P01579	UNIPROT	up-regulates				9606	BTO:0000801								32454942	f		miannu	Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ	SIGNOR-263827	0.7
QRICH1	protein	Q2TAL8	UNIPROT	GARS1	protein	P41250	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269405	0.2
SKP2	protein	Q13309	UNIPROT	CYGB	protein	Q8WWM9	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								28948618	t		miannu	Skp2 induces ubiquitin-dependent degradation of Cygb. To this end, we performed an in vivo ubiquitination assay in HEK293T cells by transfecting relevant plasmids as indicated. The V5-Skp2DN was generated by deleting the N-terminal residues from 1 to 153 containing the F-box domain, which is involved in recruiting Skp2 to the SCF complex.	SIGNOR-272792	0.2
OSI-420	chemical	CID:18924996	PUBCHEM	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-195248	0.8
STUB1	protein	Q9UNE7	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	down-regulates quantity by destabilization	destabilization			9606	BTO:0002806								28813410	t		Barakat	Deletion of STUB1 resulted in a more profound increase in PD-L1 levels in CMTM6 deficient than in CMTM6 proficient cells, identifying STUB1 as an E3 ligase that causes destabilization of PD-L1 (Fig. 4f,g), either by direct modification of one of the lysines in the PD-L1 cytoplasmic domain or indirectly	SIGNOR-274979	0.2
PIP5K1C	protein	O60331	UNIPROT	1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-)	smallmolecule	CHEBI:58456	ChEBI	up-regulates quantity	chemical modification			9606									9367159	t		miannu	Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities	SIGNOR-277286	0.8
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Thr479	FSYSASGtA	9606	BTO:0000093								24670654	t		gcesareni	Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation	SIGNOR-252443	0.427
PRKACA	protein	P17612	UNIPROT	PLN	protein	P26678	UNIPROT	up-regulates activity	phosphorylation	Ser16	RSAIRRAsTIEMPQQ	10090									10988285	t		miannu	Phospholamban (PLB) can be phosphorylated at Ser(16) by cyclic AMP-dependent protein kinase. phosphorylation of Ser(16) is sufficient for mediating the maximal cardiac responses to beta-adrenergic stimulation.	SIGNOR-250030	0.468
JWOGUUIOCYMBPV-GMFLJSBRSA-N	chemical	CID:6918328	PUBCHEM	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257913	0.8
palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	precursor of			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267900	0.8
SSH2	protein	Q76I76	UNIPROT	CFL1	protein	P23528	UNIPROT	up-regulates activity	dephosphorylation	Ser3	sGVAVSDG	9606									14531860	t			Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH).	SIGNOR-248733	0.726
NHLRC1	protein	Q6VVB1	UNIPROT	AGL	protein	P35573	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9534	BTO:0000298								17908927	t		miannu	The E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL.	SIGNOR-271669	0.578
G6PC1	protein	P35575	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	down-regulates quantity	chemical modification			9606									12093795	t		miannu	Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis	SIGNOR-266582	0.8
CAMK2D	protein	Q13557	UNIPROT	TPD52	protein	P55327	UNIPROT	unknown	phosphorylation	Ser176	KNSPTFKsFEEKVEN	9606									20032513	t		gcesareni	Here we demonstrate, using site-specific mutations, that ca(2+)-sensitive phosphorylation at serine 136 modulates the accumulation of d52 at the plasma membrane within 2 min of cell stimulation	SIGNOR-162630	0.2
MPHOSPH10	protein	O00566	UNIPROT	IMP3	protein	Q9NV31	UNIPROT	up-regulates activity	binding			-1									28813493	t		miannu	Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA. 	SIGNOR-261173	0.875
AMFR	protein	Q9UKV5	UNIPROT	SERPINI1	protein	Q99574	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								21507957	t		miannu	In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin.	SIGNOR-272756	0.301
GTF2E2	protein	P29084	UNIPROT	TFIIE	complex	SIGNOR-C458	SIGNOR	form complex	binding			9606									31064989	t		lperfetto	The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur.	SIGNOR-269361	0.94
PRKCB	protein	P05771	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser25	QAFELILsPRSKESV	9606	BTO:0001271								7637391	t		gcesareni	Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation.	SIGNOR-30353	0.2
BAG6	protein	P46379	UNIPROT	PCK1	protein	P35558	UNIPROT	down-regulates quantity by destabilization	acetylation			9606	BTO:0000007								21726808	t		lperfetto	These results indicate that BAT3 and P300 can both exist in the PEPCK1 protein complex, suggesting the possibility that BAT3 could be an enhancer of PEPCK1 acetylation. | indicating a synergistic effect of BAT3 and P300 to promote PEPCK1 acetylation. 	SIGNOR-267598	0.347
ULK2	protein	Q8IYT8	UNIPROT	ATG13	protein	O75143	UNIPROT	up-regulates	phosphorylation			9606									19225151	t		gcesareni	Ulks directly phosphorylates atg13.	SIGNOR-184126	0.741
adenosine	smallmolecule	CHEBI:16335	ChEBI	ADORA3	protein	P0DMS8	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257449	0.8
MECP2	protein	P51608	UNIPROT	GAD1	protein	Q99259	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19029285	f		miannu	 induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. 	SIGNOR-254579	0.379
NMDA receptor_2D	complex	SIGNOR-C350	SIGNOR	CAMK2A	protein	Q9UQM7	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								11052931	t		miannu	The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD	SIGNOR-264217	0.566
ICAM1	protein	P05362	UNIPROT	Chemotaxis	phenotype	SIGNOR-PH93	SIGNOR	up-regulates				9606									23994464	f		apalma	Before leaving the vessel lumen, neutrophils crawl on the endothelium, primarily using cell surface Mac-1 integrins binding to endothelial ICAM-1. After finding the place for transmigration, neutrophils migrate to the interstitium through transcellular or paracellular routes and begin chemotaxing towards the site of infection/inflammation within the perivascular and interstitial space.	SIGNOR-255042	0.7
BECN1	protein	Q14457	UNIPROT	Vps34 Complex II	complex	SIGNOR-C241	SIGNOR	form complex	binding			-1									30397185	t		lperfetto	PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively.	SIGNOR-260319	0.903
MAP3K7	protein	O43318	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	phosphorylation	Ser192	HMTNNKGsAAWMAPE	9606									10702308	t		lperfetto	A mutant of TAK1 that lacks kinase activity is not phosphorylated either following IL-1 treatment or when coexpressed with TAB1, indicating that TAK1 phosphorylation is due to autophosphorylation. Furthermore, mutation to alanine of a conserved serine residue (Ser-192) in the activation loop between kinase domains VII and VIII abolishes both phosphorylation and activation of TAK1. These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser-192.	SIGNOR-235758	0.2
KLF2	protein	Q9Y5W3	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12426306	f		fspada	Constitutive overexpression of klf2 but not klf15 potently inhibits peroxisome proliferator-activated receptor-gamma (ppargamma) expression with no effect on the upstream regulators c/ebpbeta and c/ebpdelta.	SIGNOR-95519	0.43
GPR183	protein	P32249	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257110	0.252
INSR	protein	P06213	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr373	ASDTDSSyCIPTAGM	10090									10978177	t			HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin	SIGNOR-251312	0.492
PDPK1	protein	O15530	UNIPROT	PDPK1	protein	O15530	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser241	SKQARANsFVGTAQY	-1									12177059	t		miannu	PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated 	SIGNOR-250077	0.2
KPNA3	protein	O00505	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	relocalization			9606									20454918	t		gcesareni	Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7.	SIGNOR-254321	0.329
GRPR	protein	P30550	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256917	0.252
ATM	protein	Q13315	UNIPROT	MECOM	protein	Q03112	UNIPROT	up-regulates activity	phosphorylation	Ser1039	NSNHGSQsPRNVEER										29939287	t	phosphorylation site remapping based on Fig 1	lperfetto	To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif. 	SIGNOR-273434	0.2
F2	protein	P00734	UNIPROT	F8	protein	P00451	UNIPROT	up-regulates activity	cleavage	Arg759	KNNAIEPrSFSQNSR	-1									10350471	t		lperfetto	Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689.	SIGNOR-263641	0.746
(S)-selisistat	chemical	CHEBI:90371	ChEBI	SIRT1	protein	Q96EB6	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191511	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Ser266	QYLGSIAsPSVHPAT	9606	BTO:0002181								16046550	t	The effect has been demonstrated using Q01196-8	lperfetto	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-244707	0.2
PDGFRB	protein	P09619	UNIPROT	ABL2	protein	P42684	UNIPROT	up-regulates activity	phosphorylation	Tyr272	KCNKPTVyGVSPIHD	-1									34144039	t		miannu	 PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2.	SIGNOR-277305	0.308
EEF1A1P5	protein	Q5VTE0	UNIPROT	Thr-tRNA(Thr)	smallmolecule	CHEBI:29163	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269556	0.8
ABL1	protein	P00519	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates activity	phosphorylation	Tyr970	GEGYKKKyQQVDEEF	-1									19275932	t		miannu	C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis. 	SIGNOR-276143	0.507
P2RY2	protein	P41231	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257031	0.382
ERBB4	protein	Q15303	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	binding			9606									18793634	t		gcesareni	Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow.	SIGNOR-180895	0.589
CNBP	protein	P62633	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								23774591	t		Luana	These data verified that the binding of CNBP with c-myc promoter G-quadruplex can indeed down-regulate its associated gene expression for a certain period of time. This result with human CNBP is somehow consistent with previous reports that c-myc G-quadruplex serves as a silencer of c-myc transcription [7] and CNBP promotes the formation of c-myc G-quadruplex.	SIGNOR-261571	0.309
PRKACB	protein	P22694	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser311	SFRTPRDsKLEAPAE	9606									20151718	t		miannu	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation./Phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163780	0.276
NSD2	protein	O96028	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates	binding			9606	BTO:0001130								19481544	t		miannu	In this study, we discovered that nsd2 specifically interacts with the dna-binding domain of androgen receptor (ar) via its hmg domain, and the nuclear translocation of both nsd2 and ar is enhanced in the presence of ligand / the histone methyltransferase, nsd2, enhances androgen receptor-mediated transcription.	SIGNOR-186045	0.2
prostaglandin F2alpha	smallmolecule	CHEBI:15553	ChEBI	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606		BTO:0001103							20219869	f		apalma	Prostaglandins are able to affect muscle cell proliferation (142), differentiation (96) and fusion (141), and can also modulate muscle fiber growth and the synthesis and degradation of proteins in muscle	SIGNOR-255360	0.7
GSK3B	protein	P49841	UNIPROT	DNM1L	protein	O00429	UNIPROT	down-regulates activity	phosphorylation	Ser693	LVGQLYKsSLLDDLL	-1									23185298	t		miannu	After identifying Ser693 as a GSK3beta phosphorylation site, we also determined that K679 is crucial for GSK3beta-binding, which strongly suggests that Drp1 is a novel substrate for GSK3beta. Our results suggest that GSK3beta-mediated phosphorylation at Ser693 does cause a dramatic decrease of GTPase activity; in contrast, GSK3beta-mediated phosphorylation at Ser693 appears not to affect Drp1 inter-/intra-molecular interactions.	SIGNOR-276430	0.397
MECP2	protein	P51608	UNIPROT	BDNF	protein	P23560	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									18599437	f	 	 	MeCP2 is involved in gene silencing and known to affect the activity of brain-derived neurotrophic factor (BDNF)	SIGNOR-254023	0.486
PRKCA	protein	P17252	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser273	AGTRRREsLGKKAKR	-1									9677319	t		lperfetto	Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases.	SIGNOR-249004	0.292
GTF2F1	protein	P35269	UNIPROT	TFIIF	complex	SIGNOR-C394	SIGNOR	form complex	binding			-1									18218714	t		lperfetto	Human general transcription factor IIF (TFIIF), a component of the transcription pre-initiation complex (PIC) associated with RNA polymerase II (Pol II), was characterized by size-exclusion chromatography (SEC), electrospray ionization mass spectrometry (ESI-MS), and chemical cross-linking. Recombinant TFIIF, composed of an equimolar ratio of alpha and beta subunits, was bacterially expressed, purified to homogeneity, and found to have a transcription activity similar to a natural one in the human in vitro transcription system. 	SIGNOR-266194	0.962
BIRC3	protein	Q13489	UNIPROT	RIPK4	protein	P57078	UNIPROT	up-regulates activity	polyubiquitination		lys145	9606	BTO:0000007								21931591	t		miannu	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation.	SIGNOR-272709	0.362
MAPK3	protein	P27361	UNIPROT	CREM	protein	Q03060	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser277	ASPGSLHsPQQLAEE	10090	BTO:0001077								11466319	t		miannu	 The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway. 	SIGNOR-275978	0.419
GLI1	protein	P08151	UNIPROT	Cell_growth	phenotype	SIGNOR-PH33	SIGNOR	up-regulates				9606									3563490	f		gcesareni	The gli gene is a member of a select group of cellular genes that are genetically altered in primary human tumors.	SIGNOR-235196	0.7
PIM2	protein	Q9P1W9	UNIPROT	PK	proteinfamily	SIGNOR-PF80	SIGNOR	up-regulates quantity by stabilization	phosphorylation			9606									24142698	t	inferred from family member	Manara	Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels.	SIGNOR-270287	0.379
CDK14	protein	O94921	UNIPROT	TAGLN2	protein	P37802	UNIPROT	down-regulates activity	phosphorylation	Ser83	PVKKIQAsTMAFKQM										21577206	t		lperfetto	This newly identified oncogene–tumor suppressor cascade, where oncogenic PFTK1 inactivates a tumor suppressor gene TAGLN2 via phosphorylation|. Our data therefore underline much importance for S83 and S163 residues on TAGLN2 in its actin-binding capacity.	SIGNOR-265103	0.321
ZMIZ1	protein	Q9ULJ6	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	binding			10090	BTO:0001825								26522984	t		miannu	The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions	SIGNOR-263936	0.464
PRKDC	protein	P78527	UNIPROT	PRKAG1	protein	P54619	UNIPROT	up-regulates activity	phosphorylation	Thr284	LKCYLHEtLETIINR	-1									31983282	t		miannu	PRKDC interacted with the AMPK complex and phosphorylated its nucleotide-sensing γ1 subunit PRKAG1/AMPKγ1 at Ser192 and Thr284, both events being significantly reduced upon the activation of the AMPK complex. Alanine substitutions of PRKDC phosphorylation sites in PRKAG1 reduced AMPK complex activation without affecting its nucleotide sensing capacity. 	SIGNOR-277504	0.2
SIRT7	protein	Q9NRC8	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	deacetylation	Lys19	TGGKAPRkQLATKAA										22722849	t		lperfetto	SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. 	SIGNOR-275872	0.2
NMI	protein	Q13287	UNIPROT	SOX10	protein	P56693	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16214168	t		miannu	we identify an association of Sox10 with the N-myc interactor Nmi. Nmi modulated the transcriptional activity of Sox10 in reporter gene assays. Nmi effects varied between different Sox10 target gene promoters, indicating that Nmi function in vivo may be promoter-specific.	SIGNOR-225599	0.439
MAPK1	protein	P28482	UNIPROT	RXRA	protein	P19793	UNIPROT	down-regulates activity	phosphorylation	Thr82	HSMSVPTtPTLGFST	9606									17604322	t		lperfetto	In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 	SIGNOR-262958	0.513
SBF1	protein	O95248	UNIPROT	MTMR2	protein	Q13614	UNIPROT	up-regulates activity	binding			9534	BTO:0001538								12668758	t		miannu	We also demonstrate that MTMR2 interacts with MTMR5 via its coiled-coil domain and that mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization. 	SIGNOR-269803	0.62
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	BCL2	protein	P10415	UNIPROT	up-regulates activity	phosphorylation	Ser70	RDPVARTsPLQTPAA	-1									11323415	t		Luana	JNK1 directly phosphorylates Bcl2 at Ser70 in vitro and co-localizes with Bcl2 in mitochondrial membranes in vivo.	SIGNOR-261133	0.2
RPS6KA1	protein	Q15418	UNIPROT	NR4A3	protein	Q92570	UNIPROT	unknown	phosphorylation	Ser376	GRRGRLPsKPKSPLQ	9606	BTO:0000007								16223362	t		lperfetto	We have established that two related proteins, Nurr1 and Nor1, are also phosphorylated on the equivalent site by RSK in cells in response to mitogenic stimulation. | Similar to Nur77, when FLAG€“Nor1 was expressed in HEK-293 cells, its phosphorylation on Ser377 was stimulated by both PMA and EGF	SIGNOR-249297	0.319
SRC	protein	P12931	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates	phosphorylation	Tyr1165	RDIYETDyYRKGGKG	9606									8940173	t		lperfetto	Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor	SIGNOR-45126	0.564
PTGDR	protein	Q13258	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256898	0.252
WRC complex	complex	SIGNOR-C191	SIGNOR	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates				9606									20332100	f		miannu	The activated WAVE complex at the leading edge of lamellipodia promotes actin polymerization at the plasma membrane by activating the Arp2/3 complex. 	SIGNOR-253578	0.7
IKK-complex	complex	SIGNOR-C14	SIGNOR	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser36	RHDSGLDsMKDEEYE	9606	BTO:0000567								9346241	t		lperfetto	We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation	SIGNOR-209773	0.885
PRKCE	protein	Q02156	UNIPROT	GJA1	protein	P17302	UNIPROT	up-regulates	phosphorylation	Ser369	RPSSRASsRASSRPR	9606									16474210	t		lperfetto	We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity.	SIGNOR-144469	0.451
JAK2	protein	O60674	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1069	EDSFLQRySSDPTGA	9534									9363897	t			Tyrosine at residue 1,068 of the EGFR is proposed to be one of the principal phosphorylation sites and Grb2-binding sites stimulated by growth hormone via Jak2. Our results indicate that the role of EGFR in signalling by growth hormone is to be phosphorylated by Jak2, thereby providing docking sites for Grb2 and activating MAP kinases and gene expression, independently of the intrinsic tyrosine kinase activity of EGFR. 	SIGNOR-251347	0.599
LDHA	protein	P00338	UNIPROT	pyruvate	smallmolecule	CHEBI:15361	ChEBI	down-regulates quantity	chemical modification			9606									24929216	t			Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase.	SIGNOR-266918	0.8
GH1	protein	P01241	UNIPROT	GHR	protein	P10912	UNIPROT	up-regulates activity	binding			9606									7862673	t		miannu	Although growth hormone (GH) receptors (GHRs) in many species bind human (h) GH as well as their own GH, the hGHR only binds primate GH. 	SIGNOR-255451	0.854
CSNK1E	protein	P49674	UNIPROT	PER3	protein	P56645	UNIPROT	down-regulates activity	phosphorylation	Thr635	SQCGYSStIVHVPPP	9534	BTO:0000298								11865049	t		llicata	The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. 	SIGNOR-250820	0.734
EGFR	protein	P00533	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	binding			9606									11350724	t		lperfetto	Adaptors such as Shc, Grb2, Crk or the recently characterised Dok-R protein (Jones Dumont 1999) show a modular structure containing protein– protein interaction domains and putative phosphorylation sites and act as signalling platforms which extend the receptor’s repertoire of activated intracellular pathways.	SIGNOR-107712	0.911
GNE	protein	Q9Y223	UNIPROT	UDP-N-acetyl-alpha-D-glucosamine	smallmolecule	CHEBI:16264	ChEBI	down-regulates quantity	chemical modification												10745088	t		lperfetto	UDP-GlcNAc 2-epimerase is a bifunctional enzyme and catalyzes the first two steps of neuraminic acid synthesis in the cytosol, the conversion of UDP-N-acetylglucosamine to ManAc and the phosphorylation to ManAc-6-phosphate.	SIGNOR-266073	0.8
MAP2K4	protein	P45985	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates	phosphorylation	Tyr223	TSFMMTPyVVTRYYR	9606									15911620	t		lperfetto	Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19).	SIGNOR-137605	0.732
MAPK8	protein	P45983	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Thr450	TAQMITItPPDQDDS	10116	BTO:0003324								16306447	t		gcesareni	We report that JNKs are necessary for the reactivation of Akt after ischemic injury. We identified Thr450 of Akt as a residue that is phosphorylated by JNKs, and the phosphorylation status of Thr450 regulates reactivation of Akt after hypoxia, apparently by priming Akt for subsequent phosphorylation by 3-phosphoinositide-dependent protein kinase. 	SIGNOR-252426	0.438
HIPK2	protein	Q9H2X6	UNIPROT	HIPK2	protein	Q9H2X6	UNIPROT	up-regulates activity	phosphorylation	Ser882	IVIPDTPsPTVSVIT	9606	BTO:0002181								24145406	t		miannu	 Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site-specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation-acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo.	SIGNOR-276600	0.2
VHL	protein	P40337	UNIPROT	CARD9	protein	Q9H257	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								17936701	t			We found that pVHL associates with the NF-kappaB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2.	SIGNOR-266899	0.402
PPP2R5D	protein	Q14738	UNIPROT	PP2Ca_R1A_Bd	complex	SIGNOR-C134	SIGNOR	form complex	binding			9606									23454242	t		gcesareni	[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity.	SIGNOR-243439	0.851
FOXO1	protein	Q12778	UNIPROT	POMC	protein	P01189	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000614								28270795	f		miannu	 Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations. 	SIGNOR-263503	0.416
NANOG	protein	Q9H9S0	UNIPROT	Pluripotency	phenotype	SIGNOR-PH43	SIGNOR	up-regulates				9606	BTO:0001086								25126380	f		flangone	Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency. 	SIGNOR-242073	0.7
α-Catenin	proteinfamily	SIGNOR-PF72	SIGNOR	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000586								21598020	t		miannu	Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14	SIGNOR-265818	0.2
FGFR1	protein	P11362	UNIPROT	LDHA	protein	P00338	UNIPROT	up-regulates	phosphorylation	Tyr10	TLKDQLIyNLLKEEQ	9606									21969607	t		gcesareni	We found that the oncogenic receptor tyrosine kinase fgfr1 directly phosphorylates ldh-a. Phosphorylation at y10 and y83 enhances ldh-a activity by enhancing the formation of active, tetrameric ldh-a and the binding of ldh-a substrate nadh, respectively.	SIGNOR-176730	0.376
PRKCA	protein	P17252	UNIPROT	PTPN12	protein	Q05209	UNIPROT	down-regulates	phosphorylation	Ser39	FMRLRRLsTKYRTEK	9606									7520867	t		miannu	Ptp-pest is phosphorylated in vitro by both cyclic amp-dependent protein kinase (pka) and protein kinase c (pkc) at two major sites, which we have identified as ser39 and ser435 / phosphorylation of ser39 in vitro decreases the activity of ptp-pest by reducing its affinity for substrate.	SIGNOR-27300	0.327
NFIB	protein	O00712	UNIPROT	ROBO1	protein	Q9Y6N7	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268900	0.249
GSK3B	protein	P49841	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	phosphorylation	Ser493	CPPECPEsLHDLMCQ	9606	BTO:0002181								33388549	t		miannu	 Concurrently, ROCK1 was able to phosphorylate GSK-3β at Ser9, which phosphorylated Src at Ser51 and Ser492 residues, leading to Src inactivation 	SIGNOR-277544	0.392
bexarotene	chemical	CHEBI:50859	ChEBI	RXR	proteinfamily	SIGNOR-PF44	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0002058								17483357	t		miannu	Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification.	SIGNOR-259233	0.8
MC3R	protein	P41968	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257358	0.275
HNF1B	protein	P35680	UNIPROT	ALB	protein	P02768	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									1673926	f	Regulation	miannu	VHNF1 transactivated the albumin promoter in transfection experiments	SIGNOR-251930	0.297
NUP98-HOXA9	fusion protein	SIGNOR-FP15	SIGNOR	PECAM1	protein	P16284	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17442773	f		miannu	Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The platelet endothelial cell adhesion molecule PECAM1 is also downregulated by NUP98‐HOXA9.	SIGNOR-261500	0.2
IKZF4	protein	Q9H2S9	UNIPROT	LNPEP	protein	Q9UIQ6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003420								15894523	f	 	miannu	Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. 	SIGNOR-255406	0.2
MC4R	protein	P32245	UNIPROT	Food intake	phenotype	SIGNOR-PH152	SIGNOR	down-regulates				9606	BTO:0000614								33094623	f		miannu	Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. Adipose tissue derived hormone leptin induces negative energy balance by stimulating α-MSH and melanocortin-4 receptor (MC4R) (Friedman 1997, Kask et al. 1998). Increased melanocortin signaling in hypotalamus leads not only to decreased food intake but also increases sympathetic nervous system outflow to skeletal muscle, energy expenditure and physical activity	SIGNOR-263504	0.7
4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone	chemical	CHEBI:91395	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191409	0.8
carfilzomib	chemical	CHEBI:65347	ChEBI	PSMB10	protein	P40306	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000898								17591945	t		miannu	Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM.	SIGNOR-259308	0.8
MAPK1	protein	P28482	UNIPROT	IER3	protein	P46695	UNIPROT	up-regulates	phosphorylation	Thr18	MTILQAPtPAPSTIP	9606									12356731	t		lperfetto	Upon phosphorylation by erks, iex-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, iex-1 potentiates erk activation in response to various growth factors.	SIGNOR-93740	0.532
MAPK1	protein	P28482	UNIPROT	NUP50	protein	Q9UKX7	UNIPROT	down-regulates activity	phosphorylation	Ser221	KVAAETQsPSLFGST	9606									19767751	t		gcesareni	Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin.	SIGNOR-188139	0.2
C25H27N5O4S	chemical	CID:66577011	PUBCHEM	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189711	0.8
NRF1	protein	Q16656	UNIPROT	TFB2M	protein	Q9H5Q4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15684387	f		lperfetto	Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC	SIGNOR-268999	0.54
PRKCQ	protein	Q04759	UNIPROT	STK39	protein	Q9UEW8	UNIPROT	up-regulates activity	phosphorylation	Ser323	LCLQKDPsKRPTAAE	-1									14988727	t		miannu	Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta, but not by PKCalpha. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCtheta-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK. 	SIGNOR-276007	0.464
2-[2-Amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl]-5-[(4-bromobenzyl)oxy]phenol	smallmolecule	CID:135651766	PUBCHEM	GIPR	protein	P48546	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257498	0.8
ADORA1	protein	P30542	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256840	0.437
PRKAA1	protein	Q13131	UNIPROT	POU2F1	protein	P14859	UNIPROT	down-regulates	phosphorylation	Ser385	RRRKKRTsIETNIRV	9606									1684878	t		lperfetto	Mitosis-specific phosphorylation site in the homeodomain of oct-1 was phosphorylated in vitro by protein kinase a. Pka-mediated phosphorylation event was identified in the cns-specific pou domain protein brn-2/n-oct-3/pou3f2 (nieto et al. 2007). In this case, the modification, at a position homologous to oct1 s385, was found to alter binding specificity for complex dimeric sites.	SIGNOR-20971	0.2
IRAK3	protein	Q9Y616	UNIPROT	IRAK4	protein	Q9NWZ3	UNIPROT	down-regulates	binding			9606									25290089	t		flangone	Irak3 exerts negative regulatory effects through preventing (i) the dissociation of irak1 and irak4 from myd88 irak3 negatively regulates irak signalling through suppression of irak4 and irak1 activation	SIGNOR-205434	0.7
MECP2	protein	P51608	UNIPROT	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0004102								22262897	t	inferred from family member	Luana	Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A.	SIGNOR-270237	0.332
Guanfacine	chemical	CHEBI:5558	ChEBI	ADRA2C	protein	P18825	UNIPROT	up-regulates activity	chemical activation			9606									9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258918	0.8
FYN	protein	P06241	UNIPROT	CD79B	protein	P40259	UNIPROT	up-regulates activity	phosphorylation	Tyr207	DIDQTATyEDIVTLR	-1									9531288	t			CD79b cytoplasmic tail-containing GST fusion proteins were phosphorylated in vitro by baculovirus-produced Fyn, >80% of phosphorylation occurred on the N-terminal ITAM tyrosine. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). pY195 and pY206 in CD79b 	SIGNOR-251155	0.659
ATM	protein	Q13315	UNIPROT	TERF1	protein	P54274	UNIPROT	up-regulates activity	phosphorylation	Ser219	SKLLMIIsQKDTFHS	9606	BTO:0000567								11375976	t		lperfetto	Telomeric protein pin2/trf1 as an important atm target in response to double strand dna breaks. activated atm directly phosphorylated pin2/trf1 preferentially on the conserved ser(219)-gln site in vitro and in vivo.	SIGNOR-108419	0.59
YAP1	protein	P46937	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									23075495	f		gcesareni	Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis.	SIGNOR-199217	0.7
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2G1	protein	P62253	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271315	0.752
BTK	protein	Q06187	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates	phosphorylation	Tyr753	ERDINSLyDVSRMYV	9606									11606584	t		gcesareni	By measuring the ability of human plcgamma2 to restore calcium responses to the b-cell receptor stimulation or oxidative stress in a b-cell line (dt40) deficient in plcgamma2, we have demonstrated that two tyrosine residues, tyr(753) and tyr(759), were important for the plcgamma2 signaling function.Of the two kinases that previously have been proposed to phosphorylate plcgamma2, btk, and syk, purified btk had much greater ability to phosphorylate recombinant plcgamma2 in vitro, whereas syk efficiently phosphorylated adapter protein blnk.	SIGNOR-111069	0.77
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PHB2	protein	Q99623	UNIPROT	down-regulates	binding			10090									15173318	t		lperfetto	Akt binds prohibitin 2 and relieves its repression of myod and muscle differentiation	SIGNOR-234441	0.2
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1896	SPTSPTYsPTSPVYT	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273076	0.636
Benzofuro(3,2-d)pyrimidin-4(3H)-one, 8-chloro-2-((2S)-2-pyrrolidinyl)-	chemical	CID:135564632	PUBCHEM	CDC7	protein	O00311	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000179								22560567	t		Federica	In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413.	SIGNOR-261105	0.8
RNF7	protein	Q9UBF6	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates activity	ubiquitination			9606									23136067	t		miannu	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 	SIGNOR-271449	0.304
DISC1	protein	Q9NRI5	UNIPROT	PAFAH1B1	protein	P43034	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								17202468	t		miannu	Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3ε. 14-3-3ε is involved in the proper localization of NUDEL and LIS1 in axons. the association with NUDEL and LIS1 supports the notion that DISC1 contributes to the neuronal development and morphology 	SIGNOR-252163	0.49
RNF6	protein	Q9Y252	UNIPROT	LIMK1	protein	P53667	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								16204183	t		miannu	Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons. 	SIGNOR-271481	0.444
IKBKE	protein	Q14164	UNIPROT	TANK	protein	Q92844	UNIPROT	down-regulates activity	phosphorylation	Ser49	REQQEQLsLQQTIID	9534	BTO:0000298								10759890	t		miannu	IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex	SIGNOR-262722	0.734
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	leucine	smallmolecule	CHEBI:25017	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270413	0.8
MCM4	protein	P33991	UNIPROT	MCM	complex	SIGNOR-C268	SIGNOR	form complex	binding			9606									19946136	t			The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication.	SIGNOR-261674	0.765
TTN	protein	Q8WZ42	UNIPROT	OBSCN	protein	Q5VST9	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0003324								19840192	t		miannu	Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. 	SIGNOR-266728	0.596
S100A9	protein	P06702	UNIPROT	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	up-regulates quantity by stabilization	binding			9606	BTO:0000876								16690079	t		miannu	Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner	SIGNOR-261936	0.2
EGFR	protein	P00533	UNIPROT	RGS16	protein	O15492	UNIPROT	up-regulates	phosphorylation	Tyr177	RFLKSPAyRDLAAQA	9606									11602604	t		lperfetto	Rgs16 contains two conserved tyrosine residues in the rgs box, tyr(168) and tyr(177), which are predicted sites of phosphorylation. Rgs16 underwent phosphorylation in response to m2 muscarinic receptor or egfr stimulation in hek 293t or cos-7 cells, which required egfr kinase activity. Mutational analysis suggested that rgs16 was phosphorylated on both tyrosine residues (tyr(168) tyr(177)) after egf stimulation.Phosphorylated rgs16 demonstrated enhanced gtpase accelerating (gap) activity on galpha(i). Mutation of tyr(168) to phenylalanine resulted in a 30% diminution in rgs16 gap activity mutation of tyr(177) to phenylalanine had no effect on rgs16 gap activity but also abolished its regulation of g(i)-mediated signal transduction in these cells.	SIGNOR-111024	0.425
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	PDCD1	protein	Q15116	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys233	LDFQWREkTPEPPVP	9606	BTO:0000007								36104103	t		miannu	We identified FBW7 as a E3 ubiquitin ligase for PD-1 protein, in which FBW7 promotes the K48-linked polyubiquitination of PD-1 protein at Lys233 residue.	SIGNOR-277606	0.2
CREB1	protein	P16220	UNIPROT	PCSK1	protein	P29120	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8999965	f		miannu	 both CREB-1 and ATF-1 transactivate the human PC1 promoter in transient transfection experiments.	SIGNOR-253789	0.2
PRKACA	protein	P17612	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser531	GSRSRTPsLPTPPTR	-1									9614189	t		miannu	S214 can be rapidly and selectively phosphorylated in vitro by PKA, and this single site strongly affects tau's ability to bind and stabilize microtubules.	SIGNOR-250006	0.442
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2Q2	protein	Q8WVN8	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271329	0.49
Bafetinib	chemical	CID:24853523	PUBCHEM	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	down-regulates activity	chemical inhibition			9606									21154127	t		irozzo	Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase.	SIGNOR-255819	0.8
PDK2	protein	Q15119	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	phosphorylation	Ser232	NRYGMGTsVERAAAS	-1									11485553	t		lperfetto	Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.	SIGNOR-109559	0.667
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDUFV3	protein	P56181	UNIPROT	up-regulates activity	phosphorylation	Ser105	QPSSGREsPRH										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275601	0.2
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	DLGAP5	protein	Q15398	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								15145941	t		miannu	We show here that Fbx7, an F-box protein without WD repeats and leucine-rich repeats, is required for the proteasome-mediated proteolysis of the hepatoma up-regulated protein (HURP).Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module. Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance. In the SCFFbx7 complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner.	SIGNOR-271508	0.277
PRKDC	protein	P78527	UNIPROT	FH	protein	P07954	UNIPROT	up-regulates activity	phosphorylation	Thr236	IKIGRTHtQDAVPLT	-1									26237645	t		miannu	We show that exposure to ionizing radiation induces DNA-PK-dependent phosphorylation of nuclear fumarase at Thr 236, which leads to an interaction between fumarase and the histone variant H2A.Z at DNA double-strand break (DSB) regions. 	SIGNOR-266349	0.2
TAF10	protein	Q12962	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263926	0.893
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	DCX	protein	O43602	UNIPROT	unknown	phosphorylation	Ser28	SRMNGLPsPTHSAHC	-1									14741103	t		llicata	In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. These were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35 (Figure 3D). However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. | Therefore, S28 residue may be a substrate in vitro, but our best efforts failed to detect phosphorylation of S28 in vivo.	SIGNOR-250654	0.415
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser253	APRRRAVsMDNSNKY										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-252844	0.908
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1899	SPTYSPTsPVYTPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120144	0.316
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser400	AKTSTRSsAKTLKNR	9606	BTO:0000590								20679343	t		lperfetto	Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3?	SIGNOR-167290	0.729
MAPKAPK2	protein	P49137	UNIPROT	ARPC5	protein	O15511	UNIPROT	unknown	phosphorylation	Ser77	AVKDRAGsIVLKVLI	-1									12829704	t		miannu	MAPKAPK2 also phosphorylated p16-Arc in intact Arp2/3 complexes precipitated from neutrophil lysates. Mutation of serine-77 to alanine on the A isoform prevented phosphorylation by MAPKAPK2. 	SIGNOR-250144	0.358
PRKACA	protein	P17612	UNIPROT	HAND1	protein	O96004	UNIPROT	down-regulates activity	phosphorylation	Thr107	PKKERRRtESINSAF	10116	BTO:0001556								14636580	t		miannu	In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function.	SIGNOR-249991	0.299
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr70	RNSPVTKtPPRDLPT	9606	BTO:0000007		SIGNOR-C3						12747827	t		lperfetto	Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo.	SIGNOR-101127	0.924
PFAS	protein	O15067	UNIPROT	N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-)	smallmolecule	CHEBI:147286	ChEBI	down-regulates quantity	chemical modification			9606									33179964	t		miannu	The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure.	SIGNOR-267309	0.8
CSNK2A1	protein	P68400	UNIPROT	HSP90AB1	protein	P08238	UNIPROT	down-regulates	phosphorylation	Ser226	KEREKEIsDDEAEEE	9606									18591256	t		gcesareni	Although the kinase responsible for hsp90? Phosphorylation in vivo is not known, it has been reported that ck2 can phosphorylate these sites in vitro (24). Thus, we prephosphorylated recombinant hsp90? With ck2 before addition to the reaction. Remarkably, hsp90? Phosphorylation greatly reduced its ability to inhibit apaf-1 oligomerization and caspase-9 recruitment (fig. 5b). These results indicate that the phosphorylation status of hsp90? Significantly impacts its ability to inhibit apoptosome formation.	SIGNOR-179260	0.339
GH1	protein	P01241	UNIPROT	PRLR	protein	P16471	UNIPROT	up-regulates	binding			9606									7984244	t		gcesareni	Hprl does not bind to the hgh receptor, but hgh binds to both the hghr and hprlr, and mutagenesis studies have shown that the receptor-binding sites on hgh overlap.	SIGNOR-35575	0.766
MYOD1	protein	P15172	UNIPROT	FST	protein	P19883	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								15130492	f		lperfetto	MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA	SIGNOR-251727	0.398
PRKCD	protein	Q05655	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser46	AMDDLMLsPDDIEQW	9606									16377624	t		llicata	Here, we show that the pro-apoptotic kinase, protein kinase c delta (pkcdelta), is involved in phosphorylation of p53 on ser(46). pkcdelta potentiates p53-dependent apoptosis by ser(46) phosphorylation in response to genotoxic stress.	SIGNOR-143382	0.664
GSK3B	protein	P49841	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	up-regulates activity	phosphorylation	Thr53	PPGSLSStPLSTPCS	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159450	0.26
ARID1A	protein	O14497	UNIPROT	Brain-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C486	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270751	0.758
CDK4	protein	P11802	UNIPROT	MEF2A	protein	Q02078	UNIPROT	down-regulates	binding			9606			SIGNOR-C18						21902831	t		gcesareni	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-176515	0.288
MMP14	protein	P50281	UNIPROT	ADAM9	protein	Q13443	UNIPROT	down-regulates quantity by destabilization	cleavage			9606	BTO:0000007								22632802	t		Giulio	Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9|Western blotting using antibodies against ectodomain of ADAM9 detected a fragment (around 26 kDa) of ADAM9 in the conditioned culture medium from cells cotransfected with wild-type MT1-MMP, but not in that with catalytic activity-dead MT1-MMP (Figure 6A, top).	SIGNOR-260301	0.348
IL1B	protein	P01584	UNIPROT	IL1R2	protein	P27930	UNIPROT	down-regulates	binding			9606	BTO:0000876								8332913	t		gcesareni	Interleukin-1 (il-1) interacts with cells through two types of binding molecules, il-1 type i receptor (il-1r i) and il-1r ii. Il-1r ii inhibits il-1 activity by acting as a decoy target for il-1	SIGNOR-38302	0.874
NR0B1	protein	P51843	UNIPROT	NCOR2	protein	Q9Y618	UNIPROT	up-regulates activity	binding			9606	BTO:0002588								19237537	t		miannu	The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes.	SIGNOR-271785	0.402
CDK1	protein	P06493	UNIPROT	ERF	protein	P50548	UNIPROT	down-regulates	phosphorylation			9606			SIGNOR-C17						7588608	t		lperfetto	Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf	SIGNOR-29501	0.2
NLGN1	protein	Q8N2Q7	UNIPROT	NRXN3	protein	Q9Y4C0	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264164	0.823
PPARGC1A	protein	Q9UBK2	UNIPROT	IGF1	protein	P05019	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									23217713	t		miannu	PGC-1 alpha specifically induces IGF1 and represses myostatin, and expression of PGC-1a 4 in vitro and in vivo induces robust skeletal muscle hypertrophy	SIGNOR-256152	0.348
PRKCA	protein	P17252	UNIPROT	IQGAP1	protein	P46940	UNIPROT	up-regulates	phosphorylation	Ser1443	DKMKKSKsVKEDSNL	9606	BTO:0000150;BTO:0000938								15695813	t		gcesareni	Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth.	SIGNOR-133861	0.261
GABA-A (a3-b1-g2) receptor	complex	SIGNOR-C332	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000227							18790874	f	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263778	0.7
tyrosine	smallmolecule	CHEBI:18186	ChEBI	Tyr-tRNA(Tyr)	smallmolecule	CHEBI:29161	ChEBI	up-regulates quantity	precursor of			9606									16429158	t		miannu	YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr	SIGNOR-270524	0.8
SLBP	protein	Q14493	UNIPROT	H2BC13	protein	Q99880	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265389	0.2
LFNG	protein	Q8NES3	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606		BTO:0000975							12486116	t		gcesareni	We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1.	SIGNOR-96537	0.748
BIRC3	protein	Q13489	UNIPROT	BIRC3	protein	Q13489	UNIPROT	down-regulates activity	ubiquitination			9606	BTO:0000567								14960576	t		amattioni	Ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria.	SIGNOR-121880	0.2
PRKCQ	protein	Q04759	UNIPROT	FOSL1	protein	P15407	UNIPROT	up-regulates activity	phosphorylation	Thr217	LEPEALHtPTLMTTP	9606									27816489	t		Manara	PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors.	SIGNOR-260878	0.2
ITGB1BP1	protein	O14713	UNIPROT	ITGB1	protein	P05556	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257638	0.757
PRKACA	protein	P17612	UNIPROT	GJA5	protein	P36382	UNIPROT	up-regulates activity	phosphorylation	Ser120	RAKEVRGsGSYEYPV	9606	BTO:0003477								10728420	t		miannu	Gap junction channels formed of Cx40 are modulated by protein-kinase-A-mediated phosphorylation. Macroscopic conductance and permeability of Cx40 gap junctions is strongly increased by cAMP. two serine residues that can be phosphorylated by PKA, S120 and S345	SIGNOR-250357	0.311
LRIG1	protein	Q96JA1	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates	ubiquitination			9606									16123311	t		gcesareni	We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.	SIGNOR-139948	0.412
SOD2	protein	P04179	UNIPROT	hydrogen peroxide	smallmolecule	CHEBI:16240	ChEBI	up-regulates quantity	chemical modification			9606									29301787	t		lperfetto	Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD).	SIGNOR-272283	0.8
ATM	protein	Q13315	UNIPROT	AVEN	protein	Q9NQS1	UNIPROT	up-regulates activity	phosphorylation	Ser135	VNNESGEsQRGTDFS	-1									18571408	t		miannu	Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. We found that mutating S135 and S308 sites to Alanine largely dampened Aven’s phosphorylation by ATM (though some phosphorylation remained, due to either a contaminating kinase or an unidentified ATM phosphorylation site). 	SIGNOR-262636	0.392
MAPK1	protein	P28482	UNIPROT	SOS1	protein	Q07889	UNIPROT	down-regulates activity	phosphorylation	Ser1167	ESAPAESsPSKIMSK	9534	BTO:0004055								8816480	t		lperfetto	In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1	SIGNOR-235933	0.702
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation												21443865	t			The MAPT H1 haplotype and subhaplotypes may be associated with sporadic tauopathies including AD. And that, tau's phosphorylation is regulated by many protein kinases, including glycogen synthase kinase 3beta (GSK3B). 	SIGNOR-255486	0.729
PTEN	protein	P60484	UNIPROT	NDRG1	protein	Q92597	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11494141	f		miannu	Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 	SIGNOR-260054	0.404
AKT3	protein	Q9Y243	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606									19188143	t		gcesareni	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-183652	0.697
Amyloid_fibril_formation	phenotype	SIGNOR-PH59	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates				9606									15621017	f			It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK.	SIGNOR-255481	0.7
TLN1	protein	Q9Y490	UNIPROT	A3/b1 integrin	complex	SIGNOR-C161	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257610	0.641
ritanserin	chemical	CHEBI:64195	ChEBI	HTR2B	protein	P41595	UNIPROT	down-regulates activity	chemical inhibition			10036	BTO:0000452								9459568	t		miannu	The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-	SIGNOR-258691	0.8
AKT1	protein	P31749	UNIPROT	KDM5A	protein	P29375	UNIPROT	up-regulates activity	phosphorylation	Thr285	QMRQRKGtLSVNFVD	-1									27292631	t		miannu	We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment.	SIGNOR-274061	0.309
GZMB	protein	P10144	UNIPROT	IGF2R	protein	P11717	UNIPROT	up-regulates	binding			9606									11081635	t		gcesareni	The serine proteinase granzyme b is crucial for the rapid induction of target cell apoptosis by cytotoxic t cells. We now present evidence that this receptor is the cation-independent mannose 6-phosphate/insulin-like growth factor receptor (ci-mpr). Inhibition of the granzyme b ci-mpr interaction prevented granzyme b cell surface binding, uptake, and the induction of apoptosis.	SIGNOR-84314	0.417
INTS14	protein	Q96SY0	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261474	0.2
AKT1	protein	P31749	UNIPROT	PFKFB2	protein	O60825	UNIPROT	unknown	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606	BTO:0000567								12853467	t			14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling.	SIGNOR-252574	0.643
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Ser249	DTRQIQPsPPWSYDQ	9606	BTO:0002181								16046550	t	The effect has been demonstrated using Q01196-8	lperfetto	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-244703	0.2
MYC	protein	P01106	UNIPROT	BCR	protein	P11274	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000664;BTO:0004465								26179066	t		lperfetto	In the present study we demonstrate that MYC and its partner MAX bind to the BCR promoter, leading to up-regulation of BCR and BCR/ABL1 at both transcriptional and protein levels.|Here we describe a regulatory pathway modulating BCR and BCR/ABL1 expression, showing that the BCR promoter is under the transcriptional control of the MYC/MAX heterodimer.	SIGNOR-272144	0.371
EIF2B3	protein	Q9NR50	UNIPROT	Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269141	0.797
UBE3A	protein	Q05086	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys365	SLASQATkDGKKDKK	-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. 	SIGNOR-272745	0.476
CEBPA	protein	P49715	UNIPROT	Basophil_diff	phenotype	SIGNOR-PH116	SIGNOR	up-regulates activity				10090	BTO:0000725								23990620	f			Notably, enforced overexpression of C/EBP-α in BMCPs results in exclusive differentiation into basophils, whereas conditional deletion of C/EBP-α in these same cells promotes mast cell differentiation,1 suggesting that C/EBP-α is an essential “switch factor” for basophil lineage choice	SIGNOR-259968	0.7
ASXL1	protein	Q8IXJ9	UNIPROT	Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	up-regulates activity	binding			9606	BTO:0001271								22897849	t		irozzo	These data led us to hypothesize that ASXL1 interacts with the PRC2 complex; co-immunoprecipitation studies revealed that ASXL1 associates with members of the PRC2 complex including EZH2 and SUZ12 but not with the PRC1 repressive complex. Importantly, ASXL1 downregulation resulted in loss of EZH2 recruitment to the HOXA locus indicating a role of ASXL1 in recruiting the PRC2 complex to known leukemogenic loci.	SIGNOR-255923	0.544
tertatolol	chemical	CHEBI:135244	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029									9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258862	0.8
3-isobutyl-1-methyl-7H-xanthine	smallmolecule	CHEBI:34795	ChEBI	PDE1C	protein	Q14123	UNIPROT	down-regulates activity	chemical inhibition			9606									22014080	t			Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors.	SIGNOR-253017	0.8
Neurokinin A	smallmolecule	CHEBI:80311	ChEBI	TACR2	protein	P21452	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257587	0.8
NFYC	protein	Q13952	UNIPROT	SOX18	protein	P35713	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								18496767	f		miannu	 co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells	SIGNOR-254822	0.2
Unfolded_Proteins	stimulus	SIGNOR-ST22	SIGNOR	Protein_aggregates	phenotype	SIGNOR-PH142	SIGNOR	up-regulates													9502314	f		lperfetto	Inclusion body formation and other aggregates formed during protein folding have been assumed to arise from hydrophobic aggregation of the unfolded or denatured states	SIGNOR-262268	0.7
MAPK8IP1	protein	Q9UQF2	UNIPROT	MAPK9	protein	P45984	UNIPROT	down-regulates	binding			9606									10490659	t	JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660)	gcesareni	These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins.	SIGNOR-70854	0.765
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	SPTAN1	protein	Q13813	UNIPROT	down-regulates	cleavage			9606	BTO:0000150;BTO:0000567								9624143	t		amattioni	Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis.	SIGNOR-256450	0.661
BTRC	protein	Q9Y297	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates	binding			9606			SIGNOR-C5						15340381	t		gcesareni	Scfb-trcp continues to have a role in this phase, however, through its induced degradation of the cdk1 inhibitor, wee1.	SIGNOR-128439	0.403
AIP	protein	O00170	UNIPROT	GREB1	protein	Q4ZG55	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000093								21984905	f		miannu	We show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells. 	SIGNOR-253735	0.2
PLK1	protein	P53350	UNIPROT	KIZ	protein	Q2M2Z5	UNIPROT	up-regulates	phosphorylation	Thr379	WSTSSDLtISISEDD	9606									16980960	t		lperfetto	Here, we identify a novel centrosomal substrate of plk1, kizuna (kiz), depletion of which causes fragmentation and dissociation of the pericentriolar material from centrioles at prometaphase, resulting in multipolar spindles. Plk1 maintains the integrity of the spindle poles by phosphorylating kiz.	SIGNOR-149630	0.499
GRK2	protein	P25098	UNIPROT	FPR1	protein	P21462	UNIPROT	down-regulates activity	phosphorylation	Thr339	SDTATNStLPSAEVE	-1									7836371	t			Phosphorylation of the FPR carboxyl terminus by GRK2 is the result of a high affinity interaction and proceeds in a hierarchical manner. sequential mechanism of phosphorylation beginning with residues 328 and/or 329, followed by residues 331 and/or 332, and finally residues 334 through 339. Attenuation of receptor-mediated signal amplification in response to external stimuli, an essential step in the balance of cellular activation, may be mediated by receptor phosphorylation. 	SIGNOR-251452	0.2
QRICH1	protein	Q2TAL8	UNIPROT	VARS1	protein	P26640	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269408	0.2
ritonavir	chemical	CHEBI:45409	ChEBI	CYP2B6	protein	P20813	UNIPROT	up-regulates activity	chemical activation			9606									18285471	t		Luana	These results show that ritonavir induces human CYP2B6 activity. 	SIGNOR-257770	0.8
SRC	protein	P12931	UNIPROT	CAV2	protein	P51636	UNIPROT	down-regulates	phosphorylation	Tyr27	SHHSGLEyADPEKFA	9606									15504032	t		lperfetto	Here, we show that cav-2 is phosphorylated at both tyrosines 19 and 27. We reconstituted this phosphorylation event by recombinantly coexpressing c-src and cav-2.Further functional analysis revealed that tyrosine phosphorylation of cav-2 has no effect on its targeting to lipid rafts, but clearly disrupts the hetero-oligomerization of cav-2 with cav-1.	SIGNOR-129961	0.667
TNFRSF11A	protein	Q9Y6Q6	UNIPROT	Osteoclast_differentiation	phenotype	SIGNOR-PH76	SIGNOR	up-regulates				9606									17572386	f		miannu	Osteoclasts are fully differentiated, multi-nucleated cells originating from the hematopoietic monocyte-macrophage linage. RANKL, a member of the tumor necrosis factor (TNF) superfamily, and its receptor RANK are essential regulators of osteoclast maturation and activation	SIGNOR-253043	0.7
KCND3	protein	Q9UK17	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			10090									24762397	t		miannu	Kv4.3 belongs to voltage activated (Kv) K+ channel, mammalian Shal-related family. It is encoded by KCND3 gene and expressed in heart, brain and smooth muscle. Transient outward K+ current (I(to)) plays a crucial role in the early phase of cardiac action potential repolarization. Kv4.3 K(+) channel is an important component of I(to). The function and expression of Kv4.3 K(+) channel decrease in variety of heart diseases, especially in heart hypertrophy/heart failure.	SIGNOR-265657	0.8
retinol	smallmolecule	CHEBI:50211	ChEBI	retinal	smallmolecule	CHEBI:15035	ChEBI	up-regulates quantity	precursor of			9606									21621639	t		lperfetto	Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9	SIGNOR-265118	0.8
PDGFRB	protein	P09619	UNIPROT	NCK2	protein	O43639	UNIPROT	up-regulates	binding			9606									10026169	t		gcesareni	The sh2 domains of grb2, nck, and grb4 all precipitated activated pdgf receptor with similar efficiency.	SIGNOR-64740	0.598
MAPK1	protein	P28482	UNIPROT	PCBP2	protein	Q15366	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr213	SASFPHTtPSMCLNP	9606	BTO:0000664								17475908	t		miannu	We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 	SIGNOR-262913	0.324
NEK6	protein	Q9HC98	UNIPROT	BSG	protein	P35613	UNIPROT	down-regulates activity	phosphorylation	Ser368	GSAPLKSsGQHQNDK	9606									31016558	t	done	miannu	These results indicate that NEK6 directly interacts with CD147 and phosphorylates the protein at serine-252 in Huh-7 cells.	SIGNOR-273882	0.2
NFE2L2	protein	Q16236	UNIPROT	GSTA1	protein	P08263	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22459801	f		miannu	 Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed. 	SIGNOR-254644	0.35
AKT1	protein	P31749	UNIPROT	CLK2	protein	P49760	UNIPROT	up-regulates	phosphorylation	Ser34	HKRRRSRsWSSSSDR	9606	BTO:0000567								20682768	t		lperfetto	Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva	SIGNOR-167336	0.398
NMBR	protein	P28336	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates	binding			9606	BTO:0001130;BTO:0000551								11313903	t		gcesareni	These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways.	SIGNOR-107025	0.286
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	ERCC8	protein	Q13216	UNIPROT	up-regulates													24086043	f		lperfetto	TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2.	SIGNOR-275690	0.7
DAB2IP	protein	Q5VWQ8	UNIPROT	PIK3CA	protein	P42336	UNIPROT	down-regulates activity	binding			9606									27858941	t		miannu	DAB2IP inhibits the PI3K–AKT axis by directly interacting with both proteins, reducing phosphorylation and activation of AKT. The GAP activity of DAB2IP can further enforce inhibition of the PI3K–AKT axis by reducing Ras-dependent activation of PI3K p110α subunit.	SIGNOR-254750	0.2
PRKCA	protein	P17252	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser370	PAVPPRPsADLILNR	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89174	0.538
MBL2	protein	P11226	UNIPROT	MASP1	protein	P48740	UNIPROT	up-regulates activity	binding			9606	BTO:0000392								9087411	t		lperfetto	The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5). 	SIGNOR-263414	0.742
MINK1	protein	Q8N4C8	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	phosphorylation	Thr322	SNVNRNStIENTRRH	9606	BTO:0002181								21690388	t		miannu	Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation. 	SIGNOR-276336	0.2
RINT1	protein	Q6NUQ1	UNIPROT	NRZ complex	complex	SIGNOR-C358	SIGNOR	form complex	binding												25364732	t		lperfetto	NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay.	SIGNOR-265025	0.868
PARP1	protein	P09874	UNIPROT	SERPINF1	protein	P36955	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001949								18312852	f		miannu	 Upregulation of PEDF expression by PARP inhibition contributes to the decrease in hyperglycemia-induced apoptosis in HUVECs.	SIGNOR-254891	0.2
tibolone	chemical	CHEBI:32223	ChEBI	AR	protein	P10275	UNIPROT	up-regulates activity	chemical activation			9606									19464167	t		Luana	In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1).	SIGNOR-257823	0.8
CHEK1	protein	O14757	UNIPROT	FANCE	protein	Q9HB96	UNIPROT	up-regulates	phosphorylation	Ser374	LFLGRILsLTSSASR	9606									17296736	t		llicata	Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway.	SIGNOR-153023	0.705
GRM1	protein	Q13255	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening.	SIGNOR-264932	0.8
DZIP3	protein	Q86Y13	UNIPROT	H2AC1	protein	Q96QV6	UNIPROT	up-regulates activity	monoubiquitination	Lys119	IQAVLLPkKTESHHH	9606	BTO:0000007								18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271761	0.2
DDX20	protein	Q9UHI6	UNIPROT	SMN complex	complex	SIGNOR-C158	SIGNOR	form complex	binding												12065586	t		lperfetto	SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry.	SIGNOR-253117	0.853
AURKA	protein	O14965	UNIPROT	WWC1	protein	Q8IX03	UNIPROT	unknown	phosphorylation	Ser539	TSLSPRSsLSSPSPP	9606									21878642	t		llicata	We identified the highly conserved ser(539) as the primary phosphorylation site for aurora kinases.	SIGNOR-176359	0.253
BTG2	protein	P78543	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								22493435	f		miannu	BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2	SIGNOR-254648	0.2
RUNX1	protein	Q01196	UNIPROT	ANKRD26	protein	Q9UPS8	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000843								24430186	t		lperfetto	In healthy individual, RUNX1/FLI1 complex negatively regulates ANKRD26 gene expression in MKs.	SIGNOR-266069	0.2
TFEB	protein	P19484	UNIPROT	WDFY3	protein	Q8IZQ1	UNIPROT	up-regulates quantity by expression	transcriptional regulation												30145926	f		lperfetto	Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 	SIGNOR-276804	0.274
JAK2	protein	O60674	UNIPROT	STAT6	protein	P42226	UNIPROT	up-regulates activity	phosphorylation			9606									9852261	t		gcesareni	Stat6 activation is mediated through jak1 and jak2 tyrosine kinases.	SIGNOR-62585	0.658
HDAC1	protein	Q13547	UNIPROT	EGR1	protein	P18146	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21983014	f	 	 	In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression.	SIGNOR-254257	0.555
FOXO1	protein	Q12778	UNIPROT	SMURF1	protein	Q9HCE7	UNIPROT	up-regulates quantity	transcriptional regulation			10090	BTO:0001103								21798082	t			FoxO factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy F-box (MAFbx) and muscle ring finger 1 (MuRF1), leading to the ubiquitylation of myosin and other muscle proteins (see below), and their degradation via the proteasome	SIGNOR-256268	0.251
CDK1	protein	P06493	UNIPROT	EZH2	protein	Q15910	UNIPROT	down-regulates	phosphorylation	Thr487	APAEDVDtPPRKKKR	9606									21659531	t		lperfetto	Cdk1, which phosphorylates ezh2 at threonines 345 and 487.Phosphorylation of thr-345 and thr-487 promotes ezh2 ubiquitination and subsequent degradation by the proteasome	SIGNOR-174058	0.592
3-[(4-Bromophenyl)methyl]-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one	chemical	CID:10248127	PUBCHEM	ACHE	protein	P22303	UNIPROT	down-regulates activity	chemical inhibition			9606									17888667	t		Luana	AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE.	SIGNOR-257761	0.8
ITK	protein	Q08881	UNIPROT	CD28	protein	P10747	UNIPROT	up-regulates	phosphorylation	Tyr218	PPRDFAAyRS	9606	BTO:0000782;BTO:0001271								8992971	t		lperfetto	We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail	SIGNOR-45520	0.677
CAMTA1	protein	Q9Y6Y1	UNIPROT	NPPA	protein	P01160	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002004								21857646	t		Luana	CAMTA1 itself stimulates the expression of the anti-proliferative peptide NPPA.	SIGNOR-261570	0.442
JAK1	protein	P23458	UNIPROT	TYK2	protein	P29597	UNIPROT	up-regulates	phosphorylation	Tyr1054	AVPEGHEyYRVREDG	9606									8702790	t		llicata	These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055 and that this phosphorylation requires another kinase, most likely jak1.	SIGNOR-43080	0.505
Hexocyclium	chemical	CHEBI:5707	ChEBI	CHRM2	protein	P08172	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								2704370	t		miannu	In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 	SIGNOR-258389	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser626	SLECDMEsIIRSELM	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-249688	0.397
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	LIPE	protein	Q05469	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000944								11581251	t	inferred from 70% family members	lperfetto	Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL.	SIGNOR-270207	0.2
RECQL4	protein	O94761	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates activity				9606									27287744	f			RECQL4 is important for genome stability and DNA damage repair.	SIGNOR-258951	0.7
WNT3A	protein	P56704	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								21078818	t		gcesareni	Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have	SIGNOR-169660	0.783
PIK3CG	protein	P48736	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	phosphorylation	Ser70	LFGGFNSsDTVTSPQ	9606	BTO:0000007								27169346	t		miannu	PI3Kγ mediated phosphorylation of Src enhances Src activity protein kinase activity of PI3K phosphorylates serine residue 70 on Src to enhance its activity and induce EGFR transactivation following βAR stimulation. 	SIGNOR-277225	0.373
GBAF	complex	SIGNOR-C467	SIGNOR	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	up-regulates				9606									30397315	f		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269790	0.7
PTPN11	protein	Q06124	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			9606									11085989	t		miannu	 SHP-2 is thus a positive regulator of ERK by leptin receptors, and both the adaptor function and the phosphatase activity of SHP-2 are critical for this regulation. Based on these data, we conclude that tyrosinephosphorylation of SHP-2 is a mediator of ERK activation viaTyr-985. This is likely to occur via Grb-2 binding to SHP-2 atthe C terminus followed by activation of the Ras-Raf pathwayas suggested for other signaling systems (55, 56) and morerecently for the leptin receptor (33). 	SIGNOR-263498	0.725
CDK1	protein	P06493	UNIPROT	PTTG1	protein	O95997	UNIPROT	up-regulates	phosphorylation	Ser165	LFQLGPPsPVKMPSP	9606									10656688	t		llicata	Hpttg is phosphorylated by cdc2 at ser165 these results suggest that hpttg is induced by, and may have a role in, regulatory pathways involved in the control of cell proliferation.	SIGNOR-74619	0.617
PRKACA	protein	P17612	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates activity	phosphorylation	Ser429	PQRERKSsSSSEDRN	10116	BTO:0001009								11510412	t			The in vitro phosphorylation of a site unique to B-Raf (Ser429) has been proposed to be responsible for the negative regulation of the isoenzyme by Akt. Using phosphopetide mapping and site-directed mutagenesis we showed that Ser429 is phosphorylated upon cAMP elevation in PC12 cells and proposed that PKA is a major kinase phosphorylating the B-Raf-specific site in vivo	SIGNOR-259922	0.621
TBKBP1	protein	A7MCY6	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	up-regulates activity	relocalization			9606									31792381	t			TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation	SIGNOR-272469	0.623
MAPK3	protein	P27361	UNIPROT	PTTG1	protein	O95997	UNIPROT	up-regulates	phosphorylation	Ser165	LFQLGPPsPVKMPSP	9606									10906323	t		gcesareni	Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function.	SIGNOR-79519	0.309
FGFR4	protein	P22455	UNIPROT	FRS2	protein	Q8WU20	UNIPROT	up-regulates activity	phosphorylation			10116									9182757	t		lperfetto	In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.	SIGNOR-242661	0.673
FGF2	protein	P09038	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252279	0.7
STAT5A	protein	P42229	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									10072077	f			Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression	SIGNOR-254302	0.7
ZC3H12A	protein	Q5D1E8	UNIPROT	TAL1	protein	P17542	UNIPROT	up-regulates quantity	post transcriptional regulation			9606	BTO:0000007								30842549	t			Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA	SIGNOR-259944	0.2
LPAR	proteinfamily	SIGNOR-PF2	SIGNOR	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606									20331961	t	inferred from 70% family members	gcesareni	The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits)	SIGNOR-269966	0.2
MTMR1	protein	Q13613	UNIPROT	1-phosphatidyl-1D-myo-inositol 5-phosphate(3-)	smallmolecule	CHEBI:57795	ChEBI	up-regulates quantity	chemical modification			9606									18429927	t		miannu	PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 	SIGNOR-269805	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	MOS	protein	P00540	UNIPROT	down-regulates activity	phosphorylation	Ser73	LGAGGFGsVYKATYR	9606									8622681	t		Manara	The purified PKA catalytic subunit was able to phosphorylate recombinant p37v-mos in vitro, suggesting that the mechanism of in vivo inhibition of v-Mos kinase involves direct phosphorylation by PKA.	SIGNOR-260819	0.2
EXT1	protein	Q16394	UNIPROT	WNT8B	protein	Q93098	UNIPROT	up-regulates activity				9606									24860992	f		miannu	Decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern.	SIGNOR-264020	0.2
ERG	protein	P11308	UNIPROT	PIM	proteinfamily	SIGNOR-PF34	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002398								22140532	t		miannu	ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability.	SIGNOR-259408	0.2
Oxotremorine	chemical	CHEBI:7851	ChEBI	CHRM1	protein	P11229	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258651	0.8
SREBF2	protein	Q12772	UNIPROT	LDLR	protein	P01130	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21123766	t		miannu	 Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes.	SIGNOR-254453	0.765
VAV2	protein	P52735	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606									10618391	t		tpavlidou	Oligomerization of receptor protein tyrosine kinases such as the epidermal growth factor receptor (egfr) by their cognate ligands leads to activation of the receptor.We Demonstrate that vav-2 is phosphorylated on tyrosine residues in response to egf and associates with the egfr in vivo.	SIGNOR-73874	0.61
MKRN1	protein	Q9UHC7	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002552								19536131	t		miannu	Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. 	SIGNOR-271845	0.318
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation	Ser256	SPRRRAAsMDNNSKF	-1	BTO:0000318								10377430	t		lperfetto	Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus.	SIGNOR-252346	0.2
CRYAB	protein	P02511	UNIPROT	CRYGC	protein	P07315	UNIPROT	up-regulates activity	binding			-1									20621668	t		miannu	Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age.	SIGNOR-253622	0.547
MAPK1	protein	P28482	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates activity	phosphorylation	Tyr187	HTGFLTEyVATRWYR										1712480	t		lperfetto	Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.|	SIGNOR-249415	0.2
HIPK2	protein	Q9H2X6	UNIPROT	PDX1	protein	P52945	UNIPROT	unknown	phosphorylation	Ser268	LPPGLSAsPQPSSVA	10090	BTO:0000783;BTO:0002284								20637728	t			Our results suggest that HIPK2-mediated phosphorylation of PDX1 at Ser-269 might be a regulatory mechanism connecting signals generated by changes in extracellular glucose concentration to downstream effectors via changes in subnuclear localization of PDX1, thereby influencing islet cell differentiation and function	SIGNOR-255539	0.361
PTPN1	protein	P18031	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates	dephosphorylation			9606									9566916	t		gcesareni	These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo.	SIGNOR-56815	0.595
RET	protein	P07949	UNIPROT	RET	protein	P07949	UNIPROT	unknown	phosphorylation	Tyr1029	TPSDSLIyDDGLSEE	9534	BTO:0004055								8621380	t		lperfetto	Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map 	SIGNOR-248940	0.2
DERA	protein	Q9Y315	UNIPROT	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	chemical modification			9606									25229427	t		miannu	Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase.	SIGNOR-267098	0.8
MRPL11	protein	Q9Y3B7	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262382	0.749
FRG1	protein	Q14331	UNIPROT	KMT5B	protein	Q4FZB7	UNIPROT	down-regulates activity	binding			10090	BTO:0000165								23720823	t		miannu	Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. 	SIGNOR-266639	0.2
GCM2	protein	O75603	UNIPROT	PTH	protein	P01270	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004712								20558332	f	 	miannu	 We found that GCMB binds to the PTH gene 5'-promoter (-390/-383 bp) and positively regulates its transcription. 	SIGNOR-254200	0.419
sunitinib	chemical	CHEBI:38940	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258291	0.8
FGR	protein	P09769	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	down-regulates activity	phosphorylation	Tyr354	SSNQELIyEGRRLVL	9606	BTO:0002181								28618271	t		miannu	The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. 	SIGNOR-276725	0.2
GLI3	protein	P10071	UNIPROT	FGF8	protein	P55075	UNIPROT	down-regulates quantity	transcriptional regulation			10090									12435361	t		Gianni	Whereas Fgf8 expression was almost absent in Shh-/- mutants, it was up-regulated in Gli3-/-;Shh-/- double mutants, suggesting that SHH is not required for Fgf8 induction, and that GLI3 normally represses Fgf8 independently of SHH	SIGNOR-268949	0.458
P2RY11	protein	Q96G91	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257328	0.2
lurasidone	chemical	CHEBI:70735	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10030									20404009	t		Luana	In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype.	SIGNOR-257838	0.8
WNT9B	protein	O14905	UNIPROT	CHRNA1	protein	P02708	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000887							22309736	t		gcesareni	We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles.	SIGNOR-195978	0.2
IKBKB	protein	O14920	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation	Ser644	GLDFNFDsLISTQNV	9606	BTO:0000150								15084260	t		gcesareni	Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway	SIGNOR-124207	0.678
NFIB	protein	O00712	UNIPROT	NEUROD1	protein	Q13562	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268897	0.286
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser100	DEDSGKGsQPPSPPS	9606									20305697	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-164613	0.575
MST1	protein	P26927	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates activity	phosphorylation	Thr228	PQWNESFtFKLKPSD	9606	BTO:0002181								26414765	t		miannu	Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα. 	SIGNOR-277178	0.2
MMP15	protein	P51511	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272360	0.7
PRCC	protein	Q92733	UNIPROT	MAD2L2	protein	Q9UI95	UNIPROT	up-regulates	relocalization			9606									15218244	t		miannu	We found that the human papillary renal cell carcinoma-associated proteinprccinteracts with the cell cycle control proteinmad2b, and translocates this protein to the nucleus where it exerts its mitotic checkpoint function.	SIGNOR-126516	0.51
PSPH	protein	P78330	UNIPROT	L-serine	chemical	CHEBI:17115	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000142							12213811	t		lperfetto	Human phosphoserine phosphatase (HPSP) regulates the levels of glycine and d-serine, the putative co-agonists for the glycine site of the NMDA receptor in the brain. |Phosphoserine phosphatase (PSP)1 is an important enzyme in the phosphorylated pathway of serine biosynthesis, which contributes a major portion of the endogenous l-serine|he enzymatic reaction of PSP is Mg2+-dependent and results in the dephosphorylation of phospho-l-serine with the formation of a phosphoenzyme intermediate, which is subsequently autodephosphorylated. The resulting product, l-serine, is not only a precursor for the biosynthesis of glycine but also an uncompetitive inhibitor for the enzymatic reaction of PSP	SIGNOR-268571	0.8
MAPK8	protein	P45983	UNIPROT	EEF1A2	protein	Q05639	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser205	GDNMLEPsPNMPWFK	9606	BTO:0002181								23608534	t		miannu	Ribosome-associated JNK phosphorylates the eukaryotic translation elongation factor 1A isoform 2 (eEF1A2) on serines 205 and 358 to promote degradation of NSPs by the proteasome. 	SIGNOR-276491	0.383
ERBB2	protein	P04626	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606									8816440	t		gcesareni	Most breast, skin, lung, ovary, and gastrointestinal tract tumors express erbb-4, and heterodimerization of this receptor with erbb-2, may be involved in some cancer	SIGNOR-43844	0.508
PKN1	protein	Q16512	UNIPROT	MAP3K20	protein	Q9NYL2	UNIPROT	up-regulates	phosphorylation			9606									17251915	t		gcesareni	Phosphorylation of mltkalpha by pknalpha enhances its kinase activity	SIGNOR-152768	0.2
ERBB2	protein	P04626	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates	phosphorylation	Tyr1112	DPSPLQRySEDPTVP	9606		BTO:0000149							1706616	t		gcesareni	However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2.	SIGNOR-21211	0.2
NTS	protein	P30990	UNIPROT	NTSR2	protein	O95665	UNIPROT	down-regulates	binding			9606		BTO:0000975							9851594	t		gcesareni	Neurotensin binding to recombinant neurotensin nt2 receptor expressed in cho cells does not elicit a biological response as determined by second messenger measurements.	SIGNOR-62519	0.895
CRP	protein	P02741	UNIPROT	IL10	protein	P22301	UNIPROT	down-regulates quantity by repression	translation regulation			9606	BTO:0000801								16917108	f	Regulation	miannu	CRP significantly decreased IL-10 mRNA stability	SIGNOR-251824	0.481
AKT1	protein	P31749	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Ser246	LSRERVFsEDRARFY	-1									16549426	t		miannu	Autophosphorylation of Akt on Thr-72 and Ser-246 appeared to require prior phosphorylation of Akt on Thr-308 and Ser-473. Compared with wild-type Akt, Akt/T72A/S246A mutant exhibited markedly reduced basal Akt kinase activity and response to cellular stimulation by insulin-like growth factor-1, and also conferred less cellular resistance to doxorubicin-induced apoptosis.	SIGNOR-276055	0.2
CHRM1	protein	P11229	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257014	0.438
RPL3	protein	P39023	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262495	0.849
RPS6KA3	protein	P51812	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates activity	phosphorylation	Thr1109	DRKIIATtLSKLKLE	9606	BTO:0002181								23608533	t		miannu	We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding.	SIGNOR-276463	0.2
TACR2	protein	P21452	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256879	0.2
STK38	protein	Q15208	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates activity	phosphorylation	Ser127	PQHVRAHsSPASLQL	9606									25601544	t		Luana	We show that mammalian NDR1/2 kinases phosphorylate YAP1 on S127 and thereby negatively regulate YAP1 activity in tissue-cultured cells.	SIGNOR-259855	0.393
AURKB	protein	Q96GD4	UNIPROT	DES	protein	P17661	UNIPROT	down-regulates	phosphorylation	Thr17	RVSSYRRtFGGAPGF	-1									12686604	t		lperfetto	We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro.	SIGNOR-100115	0.526
ULK1	protein	O75385	UNIPROT	ULK1/Atg13/Fip200	complex	SIGNOR-C100	SIGNOR	form complex	binding			9606									23863160	t		lperfetto	In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation.	SIGNOR-209890	0.913
LRRK2	protein	Q5S007	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	phosphorylation	Thr595	NWRGMLKtSKAEELL	9606	BTO:0002181								23813973	t		miannu	LRRK2 G2019S directly bound to and phosphorylated Drp1 at Threonine595, whereas P110 treatment abolished this phosphorylation.Threonine595 phosphorylation of Drp1 by LRRK2 G2019S is required for Drp1-mediated mitochondrial fragmentation and excessive autophagy	SIGNOR-276495	0.586
IL15RA	protein	Q13261	UNIPROT	JAK3	protein	P52333	UNIPROT	up-regulates	phosphorylation			9606									30029643	t		areggio	Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated 	SIGNOR-256225	0.481
TLK2	protein	Q86UE8	UNIPROT	ASF1B	protein	Q9NVP2	UNIPROT	unknown	phosphorylation	Ser198	PGLLPENsMDCI	9606									20016786	t		Manara	We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 | hASF1b stability does not appear to depend on phosphorylation by TLKs, but recently it has been shown that hASF1b transcription is controlled by the cell-cycle regulated E2F transcription factors	SIGNOR-260788	0.72
MYT1L	protein	Q9UL68	UNIPROT	Demyelination	phenotype	SIGNOR-PH155	SIGNOR	down-regulates				9606									29397565	f		miannu	Myt1L (myelin transcription factor 1-like), mainly expressed in neurons, has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1L was expressed in oligodendrocyte lineage cells during myelination and remyelination. 	SIGNOR-266779	0.7
CSNK2A1	protein	P68400	UNIPROT	CFTR	protein	P13569	UNIPROT	down-regulates	phosphorylation	Thr1471	IAALKEEtEEEVQDT	9606									21930781	t		lperfetto	Cftr possesses two ck2 phosphorylation sites (s422 and t1471) the t1471 residue, previously described as a site for cftr phosphorylation by ck2 (25), seems to be critical for cftr turnover and processing.	SIGNOR-176627	0.281
GATA1	protein	P15976	UNIPROT	Erythrocyte_differentiation 	phenotype	SIGNOR-PH104	SIGNOR	up-regulates activity				10090	BTO:0004911								12032775	f			The zinc finger transcription factor GATA-1, a central mediator of erythroid gene expression, interacts with multiple proteins including FOG-1, EKLF, SP1, CBP/p300 and PU.1.	SIGNOR-259962	0.7
AHR	protein	P35869	UNIPROT	CYP1B1	protein	Q16678	UNIPROT	up-regulates quantity by expression	transcriptional regulation												17012224	t			The formation of the AHR/ARNT dimerization complex converts the AHR into a high affinity DNA-binding form that recognizes specific DNA recognition sites termed DREs. In this manner, the agonist activated AHR upregulates a battery of target genes, including those involved in the metabolism of chemical carcinogens, such as CYP1A1 and CYP1B1 . 	SIGNOR-253642	0.505
IKBKE	protein	Q14164	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	up-regulates activity	binding			9606									24622840	t		miannu	STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3. 	SIGNOR-260155	0.628
FUS	protein	P35637	UNIPROT	MPHOSPH9	protein	Q99550	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			10090		BTO:0001279							28515487	f			This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease	SIGNOR-262804	0.2
LATS2	protein	Q9NRM7	UNIPROT	PRPS1	protein	P60891	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser285	EDKMKHCsKIQVIDI	-1									34465890	t		miannu	 Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness.	SIGNOR-276504	0.2
TCF3	protein	P15923	UNIPROT	MYOD/E12E47	complex	SIGNOR-C127	SIGNOR	form complex	binding			10090		BTO:0001103							18094043	t		lperfetto	MyoD omodimers or heterodimers of MyoD plus E12 or E47 serve as transcription factor complexes that bind to CANNTG consensus sites in the promoter regions of genes, performing major functions in specification and differentiation of skeletl muscle precursor cells.	SIGNOR-241551	0.798
CFAP53	protein	Q96M91	UNIPROT	DNAH11	protein	Q96DT5	UNIPROT	up-regulates activity	binding			10090		BTO:0000379							33347437	t		miannu	CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B).	SIGNOR-265545	0.2
CCNF	protein	P41002	UNIPROT	CCP110	protein	O43303	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									20596027	t		miannu	Using a mode of substrate binding distinct from other F-box protein-substrate pairs, CP110 and Cyclin F physically associate on the centrioles during the G2 phase of the cell cycle, and CP110 is ubiquitylated by the SCF(Cyclin F) ubiquitin ligase complex, leading to its degradation. 	SIGNOR-266364	0.556
CDK5	protein	Q00535	UNIPROT	DNMT1	protein	P26358	UNIPROT	up-regulates	phosphorylation	Ser154	AKPEPSPsPRITRKS	9606									21565170	t		gcesareni	We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5	SIGNOR-173685	0.367
EPHB1	protein	P54762	UNIPROT	EPHB1	protein	P54762	UNIPROT	up-regulates activity	phosphorylation	Tyr594	GSPGMKIyIDPFTYE	10029	BTO:0000246								12223469	t			 Co-immunoprecipitation was used to confirm the interaction of Grb7 with the cytoplasmic domain of EphB1 as well as the full-length receptor in intact cells. This interaction is mediated by the SH2 domain of Grb7 and requires tyrosine autophosphorylation of EphB1. We also found that EphB1 could phosphorylate Grb7 and mutation of either Tyr-928 or Tyr-594 to Phe decreased this activity.	SIGNOR-251122	0.2
USP22	protein	Q9UPT9	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269578	0.65
CD3D	protein	P04234	UNIPROT	CD3	complex	SIGNOR-C432	SIGNOR	form complex	binding			9606									12507424	t		miannu	The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.	SIGNOR-255295	0.725
BNIP3	protein	Q12983	UNIPROT	RHEB	protein	Q15382	UNIPROT	down-regulates	binding			9606									17928295	t		gcesareni	Bnip3, a hypoxia-inducible bcl-2 homology 3 domain-containing protein, directly binds rheb and inhibits the mtor pathway. Bnip3 decreases rheb gtp levels in a manner depending on the binding to rheb.	SIGNOR-158274	0.742
TBX21	protein	Q9UL17	UNIPROT	IFNG	protein	P01579	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0003432								10761931	t		Luana	T-bet Transactivates the IFNγ Gene and Represses the IL-2 Gene in EL4 Cells	SIGNOR-266234	0.49
AGTR2	protein	P50052	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606	BTO:0001130;BTO:0000551								11313903	t		gcesareni	These neuropeptide gpcrs are coupled to the activation of phospholipase c, and therefore to calcium ele- vation and protein kinase c (pkc) activation, through g proteins of the alfaq family	SIGNOR-106995	0.487
RAD9A	protein	Q99638	UNIPROT	TOPBP1	protein	Q92547	UNIPROT	up-regulates	binding			9606									18594563	t		gcesareni	The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner	SIGNOR-179382	0.82
PRKAA1	protein	Q13131	UNIPROT	SYN1	protein	P17600	UNIPROT	down-regulates activity	phosphorylation	Ser9	NYLRRRLsDSNFMAN	9606									10880969	t		lperfetto	It has been reported that site 1 of syn i can be phosphorylated by pka. Pka-mediated synapsin i ser9 phosphorylation occurs in response to cgs 21680 treatment. Results show that the adenosine a2a receptor agonist, cgs 21680, increases neurotransmitter release, in particular, glutamate and noradrenaline and such response is mediated by protein kinase a activation, which in turn increased synapsin i phosphorylation	SIGNOR-78891	0.2
RPS6KA3	protein	P51812	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									14625384	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-119225	0.2
PPP6C	protein	O00743	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	up-regulates activity	dephosphorylation	Ser831	SAEGSHTsGQSNGRD	9606	BTO:0001109								28114302	t		miannu	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276513	0.335
PPP6C	protein	O00743	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	up-regulates activity	dephosphorylation	Thr830	DSAEGSHtSGQSNGR	9606	BTO:0001109								28114302	t		miannu	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276515	0.335
F2R	protein	P25116	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	down-regulates				9606	BTO:0000007								22972936	f		milica	Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase.	SIGNOR-192048	0.2
STK39	protein	Q9UEW8	UNIPROT	SLC12A2	protein	P55011	UNIPROT	up-regulates activity	phosphorylation												16990453	t		lperfetto	This phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1	SIGNOR-264642	0.621
FHIT	protein	P49789	UNIPROT	BIRC5	protein	O15392	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18077326	f		miannu	In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin.	SIGNOR-159870	0.273
PPP1R9B	protein	Q96SB3	UNIPROT	ARHGEF2	protein	Q92974	UNIPROT	up-regulates activity	binding			10090	BTO:0001976								15996550	t		miannu	The Rho Family GEF Lfc Interacts with Neurabin and Spinophilin. Neurabin and spinophilin are homologous protein phosphatase 1 and actin binding proteins that regulate dendritic spine function. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc	SIGNOR-269176	0.405
CSK	protein	P41240	UNIPROT	LCK	protein	P06239	UNIPROT	down-regulates	phosphorylation	Tyr505	FTATEGQyQPQP	9606	BTO:0000782								1639064	t		gcesareni	P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity.	SIGNOR-20371	0.518
GTF3A	protein	Q92664	UNIPROT	TFIIIB	complex	SIGNOR-C393	SIGNOR	up-regulates activity	relocalization			9606									8907699	t		lperfetto	One of the major functions of TFIIIA is to program the 5S RNA gene for transcription by binding directly to the ICR, which subsequently directs an ordered assembly of general factors to form a functional transcription complex.	SIGNOR-269309	0.523
FLT3	protein	P36888	UNIPROT	PTPRJ	protein	Q12913	UNIPROT	down-regulates activity				10090									22438257	f			Taken together, the described findings supported the notion that FLT3 ITD causes reduced DEP-1 activity compared with cells expressing WT FLT3 rather than alterations in mRNA or protein levels.	SIGNOR-261553	0.504
Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	HOXA9	protein	P31269	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20565746	f		irozzo	These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression.	SIGNOR-256126	0.349
metformin	chemical	CHEBI:6801	ChEBI	PRKAA2	protein	P54646	UNIPROT	up-regulates				9606									11602624	f		gcesareni	Here we report that metformin activates ampk in hepatocytes.	SIGNOR-111034	0.8
PPP1CC	protein	P36873	UNIPROT	CDK9	protein	P50750	UNIPROT	up-regulates	dephosphorylation	Thr186	NSQPNRYtNRVVTLW	9606									21533037	t		amattioni	Pp1 is an activator of cdk9. Pp1 dephosphorylates cdk9 thr186.	SIGNOR-173454	0.2
GSK3B	protein	P49841	UNIPROT	FOXP3	protein	Q9BZS1	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser274	TKASSVAsSDKGSCC	9606	BTO:0002181								27432879	t		miannu	Our previous study showed, by mass spectrometry analysis, that GSK-3β phosphorylates Foxp3 at Ser270 and Ser275	SIGNOR-277245	0.289
EIF4B	protein	P23588	UNIPROT	48S_initiation_complex	complex	SIGNOR-C454	SIGNOR	form complex	binding			9606									35489072	t		lperfetto	In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 	SIGNOR-269165	0.2
NR5A2	protein	O00482	UNIPROT	HSD3B2	protein	P26439	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001555								19022561	f		miannu	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 	SIGNOR-254873	0.372
CSNK2A1	protein	P68400	UNIPROT	EGR1	protein	P18146	UNIPROT	down-regulates activity	phosphorylation	Thr526	TNSFSAStGLSDMTA	10090	BTO:0000944								8662759	t		llicata	Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10.	SIGNOR-250858	0.477
SRC	protein	P12931	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates	phosphorylation	Tyr64	DTAGQEDyDRLRPLS	9606									14506284	t		gcesareni	Epidermal growth factor-dependent regulation of cdc42 is mediated by the src tyrosine kinaseegf signaling through src appears to have dual regulatory effects on cdc42: 1). it leads to the activation of cdc42 as mediated by the vav2 guanine nucleotide exchange factor, and 2). it results in the phosphorylation of cdc42, which stimulates the binding of rhogdi, perhaps to direct the movement of cdc42 to a specific cellular site to trigger a signaling response, because cdc42-rhogdi interactions are essential for cdc42-induced cellular transformation.	SIGNOR-118206	0.684
mTORC1	complex	SIGNOR-C3	SIGNOR	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Thr412	NQVFLGFtYVAPSVL	9606									17510057	t		lperfetto	Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size.	SIGNOR-217071	0.749
KAT6A	protein	Q92794	UNIPROT	KAT6A/PML	complex	SIGNOR-C55	SIGNOR	form complex	binding			9606	BTO:0001271								23431171	t		miannu	We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression	SIGNOR-201478	0.502
CALM2	protein	P0DP24	UNIPROT	KIF1A	protein	Q12756	UNIPROT	up-regulates activity	binding			10116	BTO:0003102								30021165	t		miannu	To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines	SIGNOR-266889	0.263
NR3C1	protein	P04150	UNIPROT	CEBPD	protein	P49716	UNIPROT	up-regulates quantity	transcriptional regulation			10090	BTO:0000011								1840554	t			The expression levels of both C/EBPB and C/EBPD are increased dramatically during the time of hormonal stimulation (see Fig. 8). Furthermore, the C/EBPB- and C/EBPD encoding genes are activated directly by adipogenic hormones 	SIGNOR-251648	0.321
NPY	protein	P01303	UNIPROT	NPY2R	protein	P49146	UNIPROT	up-regulates	binding			9606									9549761	t		gcesareni	Analogs of npy and pyy have been synthesized that contain a proline residue in position 34 of the molecule, i.e., [leu31, pro34]npy (fuhlendorff et al., 1990) or [pro34]pyy (grandt et al., 1994b), and are much more potent at y1 than y2receptors.	SIGNOR-56568	0.832
CDK1	protein	P06493	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	down-regulates activity	phosphorylation	Thr151	RSYSRLEtLGSASTS	-1									23901111	t		miannu	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. 	SIGNOR-276121	0.699
PRKCA	protein	P17252	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0000599								15730925	f		irozzo	PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC.	SIGNOR-256267	0.7
SOX2	protein	P48431	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19882665	f		miannu	We show that egfr-mediated signaling promotes sox2 expression, which in turn binds to the egfr promoter and directly upregulates egfr expression.	SIGNOR-189036	0.494
COPS5	protein	Q92905	UNIPROT	COP9 signalosome variant 2	complex	SIGNOR-C487	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270761	0.933
belinostat	chemical	CHEBI:61076	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257746	0.8
MARK1	protein	Q9P0L2	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser637	VDLSKVTsKCGSLGN	-1									10090741	t		miannu	We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. 	SIGNOR-250173	0.44
glycine	smallmolecule	CHEBI:15428	ChEBI	GlyR	proteinfamily	SIGNOR-PF62	SIGNOR	up-regulates activity	chemical activation			9606									18721822	t		miannu	The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. 	SIGNOR-264985	0.8
PHF12	protein	Q96QT6	UNIPROT	TLE4	protein	Q04727	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								11390640	t		miannu	We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE.	SIGNOR-266989	0.2
IRAK1	protein	P51617	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity	phosphorylation	Thr209	LCEISRGtHNFSEEL	9606	BTO:0000007								14625308	t		lperfetto	Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signalingthis identifies irak-1 as a novel type of adapter protein, which employs its own kinase activity to introduce negative charges adjacent to the protein interaction domain, which anchors irak-1 at the active receptor complex. Thus, irak-1 regulates its own availability as an adapter molecule by sequential autophosphorylation	SIGNOR-119212	0.2
ATP	smallmolecule	CHEBI:15422	ChEBI	AMPK	complex	SIGNOR-C15	SIGNOR	down-regulates	chemical inhibition			9606									21399626	t		lperfetto	Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive	SIGNOR-217481	0.8
PTPRG	protein	P23470	UNIPROT	PTK2	protein	Q05397	UNIPROT	down-regulates activity	dephosphorylation	Tyr577	YMEDSTYyKASKGKL	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254718	0.245
GSK3B	protein	P49841	UNIPROT	DROSHA	protein	Q9NRR4	UNIPROT	up-regulates activity	phosphorylation	Ser302	RDNRRSPsLERSYKK	-1									25699712	t		lperfetto	Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes. 	SIGNOR-264846	0.282
SLBP	protein	Q14493	UNIPROT	H2AC6	protein	Q93077	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265400	0.2
ICOS	protein	Q9Y6W8	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	binding			9606									18641334	t			ICOS ligation in concert with TCR stimulation results in strong PI3K activation in T lymphocytes. The ICOS cytoplasmic tail contains an YMFM motif that binds the p85alpha subunit of class IA PI3K, similar to the YMNM motif of CD28, suggesting a redundant function of the two receptors in PI3K signaling. 	SIGNOR-272539	0.478
trimethyl-[(5-methyl-2-furanyl)methyl]ammonium	chemical	CHEBI:94038	ChEBI	CHRM3	protein	P20309	UNIPROT	up-regulates activity	chemical activation			10029									9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258648	0.8
MAPK3	protein	P27361	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser73	VGLLKLAsPELERLI	9606									12169099	t		gcesareni	Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein.	SIGNOR-91383	0.774
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	phosphorylation	Tyr570	VRREVGDyGQLHETE	9606									21841788	t		lperfetto	The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570.	SIGNOR-176058	0.2
CDK1	protein	P06493	UNIPROT	NFAT5	protein	O94916	UNIPROT	up-regulates	phosphorylation	Thr135	TVQQHPStPKRHTVL	9606	BTO:0000007								21209322	t		lperfetto	High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. we performed in vitro kinase assays using the tonebp/orebp peptide containing t135 as substrate (figure 3b, right panel) and various recombinant kinases. The peptide is strongly phosphorylated by cdk5, less by cdk1.	SIGNOR-170882	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates activity	phosphorylation	Thr326	GCYSVPTtPEDFLSN										26375055	t		lperfetto	We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity	SIGNOR-276523	0.265
PLK1	protein	P53350	UNIPROT	BRCA2	protein	P51587	UNIPROT	unknown	phosphorylation	Thr203	SSLATPPtLSSTVLI	9606	BTO:0001938								12815053	t		lperfetto	Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation.	SIGNOR-249220	0.556
HSF4	protein	Q9ULV5	UNIPROT	DNASE2B	protein	Q8WZ79	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23507146	f	 	miannu	We found that HSF4 promoted the expression and DNase activity of DLAD by directly binding to the DLAD promoter. 	SIGNOR-254479	0.377
NRARP	protein	Q7Z6K4	UNIPROT	RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	down-regulates	binding			8355									11485984	t		lperfetto	Overexpression of nrarp in embryos blocks notch signaling and inhibits the activation of notch target genes by icd. We show that nrarp forms a ternary complex with the icd of xnotch1 and the csl protein xsu(h) and that in embryos nrarp promotes the loss of icd.	SIGNOR-219228	0.419
CSNK1A1	protein	P48729	UNIPROT	FADD	protein	Q13158	UNIPROT	down-regulates activity	phosphorylation	Ser194	QNRSGAMsPMSWNSD	9606									16061179	t		gcesareni	FADD is essential for death receptor (DR)-induced apoptosis.|Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities	SIGNOR-139307	0.338
CDK5	protein	Q00535	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates	phosphorylation	Ser137	PVSSPQSsPRLPRRP	9606									22778263	t		lperfetto	Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity.	SIGNOR-197945	0.2
SSTR1	protein	P30872	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256958	0.252
CSN1S1	protein	P47710	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	phosphorylation	Ser529	GLPNGLLsGDEDFSS	9606									21232017	t		gcesareni	Phosphorylation of serine 529 of p65 is mediated by casein kinase ii, but is prevented in nonstimulated cells by the interaction with ikba	SIGNOR-171222	0.2
ACVR2B	protein	Q13705	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	phosphorylation			10090									21966641	t		areggio	It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains	SIGNOR-254984	0.768
BKM120	chemical	CHEBI:71954	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190383	0.8
SLBP	protein	Q14493	UNIPROT	H2BW2	protein	P0C1H6	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265395	0.2
KDM6B	protein	O15054	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	demethylation	Lys28	LATKAARkSAPATGG	9606									24561908	t	This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions.	miannu	Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation.	SIGNOR-260018	0.2
COMT	protein	P21964	UNIPROT	3-methoxytyramine	smallmolecule	CHEBI:1582	ChEBI	up-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO.	SIGNOR-263998	0.8
silodosin	chemical	CHEBI:135929	ChEBI	ADRA1D	protein	P25100	UNIPROT	down-regulates activity	chemical inhibition			10029									7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258451	0.8
MRAP	protein	Q8TCY5	UNIPROT	MC5R	protein	P33032	UNIPROT	down-regulates activity	binding			10029	BTO:0000246								19329486	t		miannu	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252368	0.405
clozapine	chemical	CHEBI:3766	ChEBI	HTR2B	protein	P41595	UNIPROT	down-regulates activity	chemical inhibition			10036	BTO:0000452								9459568	t		miannu	The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-	SIGNOR-258681	0.8
STK11	protein	Q15831	UNIPROT	MARK4	protein	Q96L34	UNIPROT	up-regulates	phosphorylation	Thr214	TLGSKLDtFCGSPPY	9606									14976552	t		lperfetto	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122682	0.515
sphingosine 1-phosphate	smallmolecule	CHEBI:37550	ChEBI	S1PR4	protein	O95977	UNIPROT	up-regulates activity	chemical activation			9606									10753843	t			These results indicate that EDG-6 is a high affinity receptor for SPP, which couples to a G(i/o) protein, resulting in the activation of growth-related signaling pathways	SIGNOR-261143	0.8
prostaglandin F2alpha	smallmolecule	CHEBI:15553	ChEBI	Myoblast_fusion	phenotype	SIGNOR-PH98	SIGNOR	up-regulates				9606									20219869	f		apalma	Prostaglandins are able to affect muscle cell proliferation (142), differentiation (96) and fusion (141), and can also modulate muscle fiber growth and the synthesis and degradation of proteins in muscle	SIGNOR-256213	0.7
BAX	protein	Q07812	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									23567751	f		miannu	The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation.	SIGNOR-261494	0.7
CDK2	protein	P24941	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									15241418	t		lperfetto	We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity	SIGNOR-232134	0.733
RET	protein	P07949	UNIPROT	RET	protein	P07949	UNIPROT	up-regulates	phosphorylation	Tyr981	DNCSEEMyRLMLQCW	9606									14711813	t		lperfetto	Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesthe results suggest that phosphorylation of tyr981 is not obligatorily required for the catalytic activity but plays a supplementary role in initiating autophosphorylation of tyr905, which brings about the overall kinase activity.	SIGNOR-121169	0.2
ILK	protein	Q13418	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606									9736715	t		acerquone	Ilk can phosphorylate pkb-akt on serine-473, whereas kinase-deficient ilk severely inhibits endogenous phosphorylation of pkb-akt on serine-473, demonstrating that ilk is involved in agonist stimulated, pi(3)k-dependent, pkb-akt activation.	SIGNOR-252597	0.771
MAPK14	protein	Q16539	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity				9606									20626350	f		lperfetto	On the other hand, p38 alfa may negatively modulate akt activity, indipendently of pi3k by regulating the interaction between caveolin 1 and pp2a through a mechanism dependent on cell attachment.	SIGNOR-244461	0.63
ibuprofen	chemical	CHEBI:5855	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates activity	chemical inhibition			-1									22091869	t		Luana	 Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2. 	SIGNOR-258325	0.8
RFFL	protein	Q8WZ73	UNIPROT	RIPK1	protein	Q13546	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								18450452	t		miannu	We report that CARP-2, a RING domain-containing ubiquitin protein ligase (E3), is a negative regulator of TNF-induced NF-kappaB activation. By virtue of its phospholipid-binding FYVE domain, CARP-2 localized to endocytic vesicles, where it interacted with internalized TNF-receptor complex, resulting in RIP ubiquitination and degradation.	SIGNOR-271482	0.443
SPOP	protein	O43791	UNIPROT	MACROH2A1	protein	O75367	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								15897469	t		miannu	Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. BMI1 and MACROH2A1 interact with and are ubiquitinated by the CULLIN3 and SPOP ligase complex. 	SIGNOR-272657	0.2
DDR1	protein	Q08345	UNIPROT	PTPN11	protein	Q06124	UNIPROT	up-regulates activity	relocalization			9615	BTO:0000837								16611743	t		lperfetto	Overexpression of DDR1a/b increased the interaction of DDR1 with SHP-2 and up-regulated the tyrosine phosphatase activity of SHP-2.	SIGNOR-272403	0.381
F2R	protein	P25116	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257353	0.548
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr234	SFKKQEKtPKTPKGP	9606									12058066	t		lperfetto	Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association.	SIGNOR-216745	0.418
TSC2	protein	P49815	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	down-regulates				9606									12172553	f		gcesareni	Here, we show that tsc1-tsc2 inhibits the p70 ribosomal protein s6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4e binding protein 1 (4e-bp1, an inhibitor of translational initiation).	SIGNOR-91395	0.542
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser519	SGYSSPGsPGTPGSR	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-251588	0.695
BRAF	protein	P15056	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates activity	phosphorylation			10090									8131746	t		lperfetto	Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf.	SIGNOR-244827	0.779
SLBP	protein	Q14493	UNIPROT	H2AZ2	protein	Q71UI9	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265410	0.2
PPP2CA	protein	P67775	UNIPROT	STK3	protein	Q13188	UNIPROT	down-regulates	dephosphorylation	Thr180	DTMAKRNtVIGTPFW	9606									23431053	t		gcesareni	Rassf1a apparently protects mst1/2 against inactivation by pp2a, the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively.	SIGNOR-201266	0.683
MCHR1	protein	Q99705	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257302	0.509
LIF	protein	P15018	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates	binding			9606									9143707	t		gcesareni	Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors.Some Of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2	SIGNOR-48108	0.781
CSNK2A1	protein	P68400	UNIPROT	DDHD1	protein	Q8NEL9	UNIPROT	down-regulates activity	phosphorylation	Ser104	GSSLRYYsEGESGGG	-1									11328814	t		miannu	Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity	SIGNOR-262974	0.2
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270376	0.8
JAK1	protein	P23458	UNIPROT	IL2RB	protein	P14784	UNIPROT	up-regulates activity	phosphorylation	Tyr418	LSGEDDAyCTFPSRD	9534	BTO:0000298								8700888	t			In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc.	SIGNOR-251340	0.616
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BC11	protein	P06899	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSIYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271980	0.2
ACOT8	protein	O14734	UNIPROT	glutarate(2-)	smallmolecule	CHEBI:30921	ChEBI	up-regulates quantity	chemical modification												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271813	0.8
MAPK1	protein	P28482	UNIPROT	CAPN2	protein	P17655	UNIPROT	up-regulates	phosphorylation	Ser50	GTLFQDPsFPAIPSA	9606									14993287	t		lperfetto	Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo.	SIGNOR-123079	0.611
KDM5C	protein	P41229	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	demethylation			9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-265354	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	SLC2A4	protein	P14672	UNIPROT	up-regulates				9606									9415393	f	Translocation from intracellular compartment to cell surface in muscle and adipose tissue	gcesareni	Akt is not only capable of stimulating the translocation of glut4 to the cell surface. Endogenous akt is likely to play a significant physiological role in insulin-stimulated glucose uptake in insulin targets such as muscle and adipose tissue	SIGNOR-53968	0.2
WIPI1	protein	Q5MNZ9	UNIPROT	ATG16L1	protein	Q676U5	UNIPROT	up-regulates quantity	binding			9606	BTO:0001938								28561066	t		miannu	WIPI1 assists WIPI2 in recruiting ATG16L for LC3 lipidation. WIPI1-WIPI2 heterodimer may function more efficiently in ATG16L complex recruitment. 	SIGNOR-268477	0.595
MAP3K8	protein	P41279	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates	phosphorylation			9606									8131746	t		lperfetto	Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf	SIGNOR-244892	0.556
STOML2	protein	Q9UJZ1	UNIPROT	NDUFV1	protein	P49821	UNIPROT	up-regulates activity				9606	BTO:0000782								20359165	f		Giorgia	We found that SLP-2hi cells had significantly higher activities of NADH dehydrogenase and succinate dehydrogenase (P < 0.05), complexes I and II of the electron transport chain.	SIGNOR-260382	0.289
FGFR1	protein	P11362	UNIPROT	PDK1	protein	Q15118	UNIPROT	up-regulates	phosphorylation	Tyr136	AEDAKAIyDFTDTVI	9606									22195962	t		llicata	Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1	SIGNOR-191719	0.355
FYN	protein	P06241	UNIPROT	CD5	protein	P06127	UNIPROT	unknown	phosphorylation	Tyr487	DNSSDSDyDLHGAQR	-1									11298344	t			Tyrosine-mutated CD5 molecules have been used to show that residues Y429 and Y463 are targeted in vivo by protein tyrosine kinases following cell stimulation with anti-CD3 mAb or pervanadate. This is in agreement with data from direct in vitro kinase assays using purified recombinant Lck and Fyn protein tyrosine kinases.	SIGNOR-251152	0.505
Helicase	protein	P0DTD1-PRO_0000449630	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								32979938	t		miannu	We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F).	SIGNOR-262512	0.2
p38	proteinfamily	SIGNOR-PF16	SIGNOR	CDC25B	protein	P30305	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser103	ESSLSSEsSESSDAG	9606	BTO:0000567								21807946	t		miannu	 Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104).	SIGNOR-276349	0.2
HCK	protein	P08631	UNIPROT	ELMO1	protein	Q92556	UNIPROT	up-regulates	phosphorylation	Tyr720	IPKEPSNyDFVYDCN	9606									15952790	t		llicata	We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts.	SIGNOR-138158	0.59
PYGM	protein	P11217	UNIPROT	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	up-regulates quantity	chemical modification			9606									3346228	t		miannu	Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267390	0.8
S1PR3	protein	Q99500	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257062	0.47
H2AX	protein	P16104	UNIPROT	NBN	protein	O60934	UNIPROT	up-regulates	binding			9606									15635255	t		esanto	Nbs1 physically interacts with ?-H2ax to form nuclear foci at dna damage sites. The inhibition of this interaction by introduction of anti-?-H2ax antibody into cells abolishes nbs1 foci formation in response to dna damage.	SIGNOR-133020	0.2
ELL	protein	P55199	UNIPROT	ELL/ICE2	complex	SIGNOR-C49	SIGNOR	form complex	binding			9606	BTO:0001271								22195968	t		miannu	The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes.	SIGNOR-193461	0.63
FZD4	protein	Q9ULV1	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606									18077588	t		areggio	Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction.	SIGNOR-258964	0.635
AHCTF1	protein	Q8WYP5	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262086	0.515
AIMP1	protein	Q12904	UNIPROT	Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	form complex	binding			9606									32644155	t		miannu	In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes).	SIGNOR-270359	0.915
BMPR1B	protein	O00238	UNIPROT	STAMBP	protein	O95630	UNIPROT	up-regulates activity	phosphorylation	Ser243	SLKPGALsNSESIPT	9534	BTO:0000298								11483516	t		llicata	BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads.	SIGNOR-250597	0.294
DR1	protein	Q01658	UNIPROT	NC2 complex	complex	SIGNOR-C108	SIGNOR	form complex	binding			9606	BTO:0000567								18838386	t		miannu	NC2_ co-fractionated with NC2_ only in the low molecular weight complex (fractions 86–94) and an NC2_ antibody co-immunoprecipitated NC2_ (but not GCN5) in these fractions, which thus contain the classical NC2 complex	SIGNOR-226405	0.775
NODAL	protein	Q96S42	UNIPROT	ACVR1C	protein	Q8NER5	UNIPROT	up-regulates activity	binding			9606	BTO:0004094								15531507	t	Indirect_regulation of expression	miannu	Human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. activation of the Nodal-ALK7 signaling pathway leads to induction of apoptosis and inhibition of cell proliferation. 	SIGNOR-251936	0.621
GLI1	protein	P08151	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002572								16571352	f		lperfetto	Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1.	SIGNOR-209617	0.2
PAPOLA	protein	P51003	UNIPROT	mRNA_polyadenylation	phenotype	SIGNOR-PH200	SIGNOR	up-regulates				9606									19224921	f		lperfetto	Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner.	SIGNOR-268325	0.7
KRAS	protein	P01116	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates	phosphorylation	Ser67	RQLRKVRsVELDQLP	9606									12228228	t		gcesareni	Activation of ras may lead to two distinct ras-dependent pathways involving either a raf1/mek/mapk module or a mekk/sek/sapk module; jnk/sapk binds to the d domain near the nh2 terminus of mekk1 from approximately residues 6270 (9, 10). Pak1 can phosphorylate mekk1 on serine 67 within its jnk/sapk-binding d domain. Phosphorylation of mekk1 on serine 67 alters the state of the d domain, thereby decreasing its affinity for jnk/sapk. Under these conditions jnk/sapk is not recruited into the mekk1 signaling module.	SIGNOR-92793	0.374
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CTNNB1	protein	P35222	UNIPROT	up-regulates activity				9606									16293724	f		lperfetto	We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway.	SIGNOR-244225	0.2
RPL32	protein	P62910	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262468	0.824
Chaperone-mediated autophagy	phenotype	SIGNOR-PH118	SIGNOR	HK2	protein	P52789	UNIPROT	down-regulates quantity by destabilization				9606	BTO:0004424								26323688	t			Our proteome analysis revealed that HK2 is a CMA substrate and that its degradation by CMA is regulated by glucose availability.	SIGNOR-261247	0.7
CDK1	protein	P06493	UNIPROT	NPM1	protein	P06748	UNIPROT	unknown	phosphorylation	Ser70	EAMNYEGsPIKVTLA	9606									19933706	t		gcesareni	Simultaneous inactivation of two cdk phosphorylation sites at ser10 and ser70 (npm-aa) induced g(2)/m cell cycle arrest, phosphorylation of cdk1 at tyr15 (cdc2(tyr15)) and increased cytoplasmic accumulation of cdc25c.	SIGNOR-161801	0.534
TIM23 complex	complex	SIGNOR-C423	SIGNOR	Insertion into mitochondrial membrane	phenotype	SIGNOR-PH193	SIGNOR	up-regulates													32074073	f		lperfetto	Mitochondrial precursor proteins with amino-terminal presequences are imported via the presequence pathway, utilizing the TIM23 complex for inner membrane translocation. Initially, the precursors pass the outer membrane through the TOM complex and are handed over to the TIM23 complex where they are sorted into the inner membrane or translocated into the matrix.	SIGNOR-267709	0.7
clobetasol	chemical	CHEBI:205919	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates activity	chemical activation			9606									4594577	t		SimoneGraziosi	The clinical evaluation of a new topical corticosteroid, clobetasol propionate. An international controlled trial.	SIGNOR-269217	0.8
CAMK2G	protein	Q13555	UNIPROT	FLNA	protein	P21333	UNIPROT	unknown	phosphorylation	Ser2523	VTGPRLVsNHSLHET		BTO:0001141								11290523	t		llicata	Our TER experiments using a CaM peptide, which functions as a specific competitive inhibitor of nonmuscle filamin phosphorylation by CaM kinase II, strongly suggest that filamin phosphorylation is involved in endothelial cell barrier regulation, although the exact mechanism is not clear and consequent signaling events are not well understood. 	SIGNOR-250696	0.438
MAPK3	protein	P27361	UNIPROT	GTF2I	protein	P78347	UNIPROT	up-regulates	phosphorylation	Ser668	INTKALQsPKRPRSP	9606									10648599	t		lperfetto	Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation.	SIGNOR-74304	0.382
USP9X	protein	Q93008	UNIPROT	WT1	protein	P19544	UNIPROT	up-regulates quantity by stabilization	deubiquitination												32152317	t		lperfetto	Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. 	SIGNOR-275614	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	MASTL	protein	Q96GX5	UNIPROT	up-regulates activity	phosphorylation	Thr194	NMMDILTtPSMAKPR	8355									22354989	t		gcesareni	We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop	SIGNOR-243403	0.511
MAP3K8	protein	P41279	UNIPROT	MAP3K14	protein	Q99558	UNIPROT	up-regulates activity	phosphorylation	Thr559	TGDYIPGtETHMAPE	9606									9742107	t		lperfetto	In studies of NIK, we found that Thr-559 located within the activation loop of its kinase domain regulates NIK action. Alanine substitution of Thr-559 but not other serine or threonine residues within the activation loop abolishes its activity and its ability to phosphorylate and activate IKKalpha	SIGNOR-249387	0.539
COX7B	protein	P24311	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267745	0.653
CAMK2G	protein	Q13555	UNIPROT	SYN1	protein	P17600	UNIPROT	unknown	phosphorylation	Ser605	AGPTRQAsQAGPVPR										3118371	t		llicata	Sites 2 and 3 are serine residues phosphorylated by calcium/calmodulin-dependent protein kinase II.	SIGNOR-250708	0.458
QARS1	protein	P47897	UNIPROT	Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	form complex	binding			9606									32644155	t		miannu	In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes).	SIGNOR-270358	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	VASP	protein	P50552	UNIPROT	up-regulates activity	phosphorylation			9606									15066263	t		miannu	 Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts	SIGNOR-268286	0.2
AKT1	protein	P31749	UNIPROT	VCP	protein	P55072	UNIPROT	up-regulates	phosphorylation	Ser352	AATNRPNsIDPALRR	9606	BTO:0000150								16551632	t		llicata	Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I	SIGNOR-252491	0.523
CDKN1B	protein	P46527	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0002392								22343731	f		fcortellessa	 The results of the MTT assay and growth curves revealed that the cells transfected with pEGFP-p27kip1 had a significant growth inhibition when compared with cells transfected with pEGFP-NC (Fig. 5B and D). These data indicated that overexpression of p27kip1 could arrest cell-cycle progression and decrease proliferation of SGC-7901 cells.	SIGNOR-261687	0.7
Norbinaltorphimine	chemical	CHEBI:81529	ChEBI	OPRD1	protein	P41143	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258820	0.8
MAPK3	protein	P27361	UNIPROT	MKNK1	protein	Q9BUB5	UNIPROT	up-regulates	phosphorylation	Thr385	APEKGLPtPQVLQRN	9606	BTO:0000567								9155018	t		lperfetto	Mnk1 was phosphorylated and activated in vitro by erk1 and p38 map kinasespreliminary results showed that thr344 at least was one of the major sites phosphorylated by erk1	SIGNOR-48360	0.556
CAMK2B	protein	Q13554	UNIPROT	ETS1	protein	P14921	UNIPROT	down-regulates activity	phosphorylation	Ser257	DSFESIEsYDSCDRL		BTO:0003637								12475968	t		llicata	Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1 	SIGNOR-250685	0.313
PABIR1	protein	Q96E09	UNIPROT	PPP2R2A	protein	P63151	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								27588481	t		miannu	We demonstrate that the highly conserved protein in mammals, designated FAM122A, directly interacts with PP2A-Aα and B55α rather than B56α subunits, and inhibits the phosphatase activity of PP2A-Aα/B55α/Cα complex.	SIGNOR-266379	0.2
MAP3K7	protein	O43318	UNIPROT	NLK	protein	Q9UBE8	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000007								12482967	t		gcesareni	The tak1-nlk-mapk-related pathway antagonizes signalling between beta-catenin and transcription factor tcf.	SIGNOR-96425	0.635
RNF126	protein	Q9BV68	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								23026136	t		miannu	E3 ubiquitin ligase RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation.We showed that RNF126 interacts with p21 and RNF126 overexpression increased p21 protein ubiquitination in an E3 ligase activity-dependent manner.	SIGNOR-272033	0.336
USP7	protein	Q93009	UNIPROT	CHFR	protein	Q96EP1	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0000007								17442268	t		miannu	In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell.  USP7 mediates deubiquitination of Chfr.	SIGNOR-271462	0.443
IGF1R	protein	P08069	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates activity	phosphorylation	Tyr1346	SFDERQPyAHMNGGR	-1									8940173	t		miannu	The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.	SIGNOR-246260	0.2
TFE3	protein	P19532	UNIPROT	MCOLN1	protein	Q9GZU1	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276826	0.345
GRK2	protein	P25098	UNIPROT	ADRA2A	protein	P08913	UNIPROT	down-regulates activity	phosphorylation	Ser312	ALDLEESsSSDHAER	10029	BTO:0000246								7876239	t			The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization.	SIGNOR-251441	0.2
DDR1	protein	Q08345	UNIPROT	DDR1	protein	Q08345	UNIPROT	up-regulates activity	phosphorylation	Tyr513	LLLSNPAyRLLLATY	9606	BTO:0000007;BTO:0000356								9659899	t		llicata	The discoidin domain receptor tyrosine kinases are activated by collagen | Here, we present evidence that stimulating DDR1- and DDR2-expressing cells with various types of collagen induces receptor autophosphorylation.	SIGNOR-251086	0.2
CDC7	protein	O00311	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates	phosphorylation	Ser41	RTDALTSsPGRDLPP	9606									16899510	t		gcesareni	In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells.	SIGNOR-148717	0.961
NOTCH1	protein	P46531	UNIPROT	HOXA5	protein	P20719	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								16990763	f		gcesareni	Other than a role in t-cell development, the hox genes may be involved in alternative notchregulated processes in hematopoietic stem cells. Notch signaling is clearly important for self-renewal of hematopoietic progenitors (reviewed by radkte et al. 57). Interestingly, hoxa5, a9 and a10 were found to be part of the stem cell profile'	SIGNOR-149770	0.323
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	PROX1	protein	Q92786	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002181								36433955	t		miannu	Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation.	SIGNOR-277610	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	TRPC5	protein	Q9UL62	UNIPROT	down-regulates activity	phosphorylation	Ser796	GARAKSKsVSFNLGC	9606	BTO:0000007								21734191	t		miannu	We show that TRPC5 channels may become directly phosphorylated by PKA at serine residues 794 and 796, and that this phosphorylation abolishes the receptor-operated nonselective cation current mediated by TRPC5 channels in HEK-293 cells. 	SIGNOR-276339	0.2
TFDP1	protein	Q14186	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253859	0.564
estramustine	chemical	CHEBI:4868	ChEBI	MAP1A	protein	P78559	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001332								1647395	t		miannu	Estramustine is a novel anti-microtubule drug shown to bind MAP-1 and MAP-2 (microtubule-associated proteins) in vitro. In this paper we have shown that estramustine specifically binds MAP-1A in Du 145a cells, resulting in disruption of MAP-1A microtubules and inhibition of type IV collagenase secretion.	SIGNOR-259297	0.8
AKT2	protein	P31751	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	down-regulates	phosphorylation	Ser571	RMRSRSRsFSRHRSC	9606									17554339	t		miannu	Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1? At ser?570 Is required for akt to inhibit recruitment of pgc-1? To chromatin.	SIGNOR-155536	0.355
CYP11B2	protein	P19099	UNIPROT	11-deoxycorticosterone	smallmolecule	CHEBI:16973	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000048							33117906	t		lperfetto	The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone	SIGNOR-268681	0.8
MAPK3	protein	P27361	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates	phosphorylation	Thr235	SSSSPPGtPSPADAK	9606									19327116	t		gcesareni	Thr235 phosphorylation occurs in nuclei of differentiated macrophages, but not in monocytes.	SIGNOR-184917	0.654
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MAP2K1	protein	Q02750	UNIPROT	down-regulates activity	phosphorylation	Thr292	ETPPRPRtPGRPLSS	9534	BTO:0004055								14993270	t		lperfetto	We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling.	SIGNOR-244557	0.2
ANAPC7	protein	Q9UJX3	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	form complex	binding												16896351	t		lperfetto	The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex.	SIGNOR-252007	0.835
MARK1	protein	Q9P0L2	UNIPROT	MAP4	protein	P27816	UNIPROT	down-regulates activity	phosphorylation	Ser941	NVRSKVGsTENIKHQ	-1									8631898	t		miannu	Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 	SIGNOR-250171	0.449
4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide	chemical	CHEBI:91447	ChEBI	EPHB4	protein	P54760	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194916	0.8
PPP2CA	protein	P67775	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates	dephosphorylation	Thr450	TAQMITItPPDQDDS	9606									11839802	t		gcesareni	Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2a and dephosphorylation of akt and glycogen synthase kinase 3 beta	SIGNOR-252616	0.889
TRAF2	protein	Q12933	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates	binding			9606									10346818	t		amattioni	Oligomerization of the traf2 effector domain results in specific binding to mekk1, a protein kinase capable of jnk, p38, and ikk activation	SIGNOR-67552	0.705
MTOR	protein	P42345	UNIPROT	AKT1S1	protein	Q96B36	UNIPROT	down-regulates activity	phosphorylation	Ser183	PTQQYAKsLPVSVPV	9606	BTO:0000007		SIGNOR-C3	SIGNOR-C3					17517883	t		lperfetto	The proline-rich Akt substrate of 40 kilodaltons (PRAS40) was identified as a raptor-binding protein that is phosphorylated directly by mammalian target of rapamycin (mTOR) complex 1 (mTORC1) but not mTORC2 in vitro, predominantly at PRAS40 (Ser(183)).PRAS40 binding to raptor was also abolished by mutation of the major mTORC1 phosphorylation site, Ser(183), to Asp.	SIGNOR-154956	0.901
PTPN13	protein	Q12923	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates activity	dephosphorylation	Tyr226	KRNKPTVyGVSPNYD	9606									28924170	t		lperfetto	We also found that PTPN13 dephosphorylates and inhibits c-Abl.|While the above results indicated that calpain-2 could cleave PTPN13 and that PTPN13 could dephosphorylate c-Abl at tyrosine 245, they did not determine whether calpain-2-mediated cleavage of PTPN13 resulted in its inactivation and increased tyrosine phosphorylation of c-Abl at tyrosine 245.	SIGNOR-277012	0.399
LCK	protein	P06239	UNIPROT	CTLA4	protein	P16410	UNIPROT	unknown	phosphorylation	Tyr218	CEKQFQPyFIPIN	9606	BTO:0000007								9973379	t			Lck and Fyn, but not ZAP70, induce tyrosine phosphorylation of CTLA-4 in the cell line HEK293. Phosphorylation of CTLA-4 occurs on both Y201 and Y218.the role of Y218 in CTLA-4 biology is not known at the present	SIGNOR-251371	0.74
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2D2	protein	P62837	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271357	0.766
SUZ12/EZH2	complex	SIGNOR-C77	SIGNOR	YY1	protein	P25490	UNIPROT	up-regulates activity	binding			10090	BTO:0000165;BTO:0002314								20887952	t		lperfetto	TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter.	SIGNOR-235574	0.724
TSC2	protein	P49815	UNIPROT	TSC1	protein	Q92574	UNIPROT	up-regulates activity	binding			9606		BTO:0000142;BTO:0000671							10807585	t		lperfetto	Furthermore, tsc2 is directly phosphorylated by akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1.	SIGNOR-77400	0.933
EPAS1	protein	Q99814	UNIPROT	PTPRZ1	protein	P23471	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								15833863	f		miannu	A second hypoxia-responsive factor, HIF-2, can activate many of the same genes as HIF-1. Ten genes were preferentially activated by HIF-2alpha, including two (CACNA1A and PTPRZ1) implicated in neurologic diseases.	SIGNOR-264333	0.266
PTPN3	protein	P26045	UNIPROT	VCP	protein	P55072	UNIPROT	down-regulates activity	dephosphorylation	Tyr805	EDNDDDLyG	9606	BTO:0000007								10364224	t			Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs. 	SIGNOR-248461	0.491
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CALM2	protein	P0DP24	UNIPROT	up-regulates	chemical activation			10090									10448861	t		miannu	Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1.	SIGNOR-266318	0.8
AKT2	protein	P31751	UNIPROT	RALGAPA2	protein	Q2PPJ7	UNIPROT	down-regulates activity	phosphorylation	Ser486	SSWGRTYsFTSAMSR	10090				SIGNOR-C469					21148297	t		miannu	RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase. kt2 directly phosphorylated all three sites on RGC2 (Figure 5A).	SIGNOR-269797	0.43
LPAR2	protein	Q9HBW0	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates	binding			9606									15856019	t		gcesareni	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. Lpa2also can couple to the gi/o, g12/13, and gqfamilies.	SIGNOR-135840	0.61
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1693	SPTSPSYsPTSPSYS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248752	0.727
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDE1	protein	Q9NXR1	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr191	QKQEKPRtPMPSSVE	9606	BTO:0000007								16682949	t	done	miannu	Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. 	SIGNOR-274087	0.525
TFEB	protein	P19484	UNIPROT	BLOC1S3	protein	Q6QNY0	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4).	SIGNOR-276683	0.2
RELA	protein	Q04206	UNIPROT	NCOR2	protein	Q9Y618	UNIPROT	down-regulates activity	relocalization			10090									14982881	t			Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. This indicates that shuttling of p65 was necessary for Flt3-ITD-mediated SMRT nuclear export.	SIGNOR-261539	0.413
ATAD5	protein	Q96QE3	UNIPROT	BRD4	protein	O60885	UNIPROT	up-regulates	binding			9606	BTO:0000007								31875566	t		miannu	ATAD5 Interacts with BRD4 through a Conserved BET Protein-Binding Domain. BRD4-ATAD5 binds to acetyl-histones in nascent chromatin. BRD4 release from chromatin correlates with PCNA unloading. Disruption of the interaction between BRD4 and acetyl-histones or between BRD4 and ATAD5 reduces the PCNA amount on chromatin.	SIGNOR-266412	0.357
4'-epidoxorubicin	chemical	CHEBI:47898	ChEBI	TOP2A	protein	P11388	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002058								17639997	t		miannu	The combinatory use of low concentrations of SM with low-toxic topoisomerase II inhibitor epirubicin accelerated apoptotic cell death. 	SIGNOR-259282	0.8
E2F1	protein	Q01094	UNIPROT	RASGEF1B	protein	Q0VAM2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18396012	f		miannu	 We demonstrate that E2F1 induces ERK activation via a transcriptional mechanism and upregulates the expression of two guanine nucleotide exchange factors, RASGRP1 and RASGEF1B, which promote Ras activation. 	SIGNOR-253851	0.2
ARVCF	protein	O00192	UNIPROT	CDH3	protein	P22223	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0001109								14610055	t		miannu	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 	SIGNOR-252127	0.333
RPS6KA1	protein	Q15418	UNIPROT	EEF2K	protein	O00418	UNIPROT	down-regulates activity	phosphorylation	Ser366	SPQVRTLsGSRPPLL	9606	BTO:0000669								11500364	t		lperfetto	We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity	SIGNOR-109708	0.529
magnesium(2+)	chemical	CHEBI:18420	ChEBI	CIB2	protein	O75838	UNIPROT	up-regulates activity	chemical activation			9606									35408910	t		miannu	Calcium- and integrin-binding protein 2 (CIB2) is a small EF-hand protein capable of binding Mg2+ and Ca2+ ions.	SIGNOR-269666	0.8
LCK	protein	P06239	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates activity	phosphorylation	Tyr536	QKGQESEyGNITYPP	10090	BTO:0000782								8114715	t			Two sites (Y-536 and Y-564) which are directly phosphorylated by Lck in vitro are also phosphorylated in vivo in LSTRA cells. .	SIGNOR-251387	0.596
SIX4	protein	Q9UIU6	UNIPROT	UBA52	protein	P62987	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							9826681	f		gcesareni	We have demonstrated by studies of transgenic mice the importance of the mef3 motif present in the myogeninpromoter for its activation and have characterized the mef3 binding activity as consisting of two skeletal-muscle specific members of the six family, six1 and six4.	SIGNOR-62178	0.2
GNG12	protein	Q9UBI6	UNIPROT	AKT2	protein	P31751	UNIPROT	up-regulates	binding			9606	BTO:0000586								16293724	t		gcesareni	We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway.	SIGNOR-141792	0.386
TSC22D3	protein	Q99576	UNIPROT	NFKB2	protein	Q00653	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								11468175	t			GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits.	SIGNOR-253298	0.332
UNII-XH2662798I	chemical	CID:16156006	PUBCHEM	CDK1	protein	P06493	UNIPROT	down-regulates	chemical inhibition			9606									20068082	t		gcesareni	Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation, regulated by wee1- and myt1-mediated phosphorylation and cdc25c-mediated dephosphorylation. Cdc25a may also be involved in cdk1 dephosphorylation in the g2/m-phase checkpoint.	SIGNOR-163127	0.8
CD3E	protein	P07766	UNIPROT	CD3	complex	SIGNOR-C432	SIGNOR	form complex	binding			9606									12507424	t		miannu	The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.	SIGNOR-255294	0.8
TJP2	protein	Q9UDY2	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	binding			9606									23829894	t		milica	The Crumbs complex component AMOT co-localizes with MST1_ 2, LATS1_ 2 and YAP in a complex at the tight junction to control cell growth. Zona occludens-2 (ZO-2) in the tight junction, and a-catenin, b-catenin, or PTPN14 in the adherence junction, also bind to YAP_TAZ.	SIGNOR-230754	0.499
GSK3B	protein	P49841	UNIPROT	MNX1	protein	P50219	UNIPROT	down-regulates	phosphorylation	Ser77	ADRLRAEsPSPPRLL	9606									24425879	t		miannu	Here we show that gsk-3_ inactivates the proapoptotic activity of hlxb9 by phosphorylating hlxb9 at ser-78/ser-80 (phlxb9).	SIGNOR-203657	0.3
CDK5	protein	Q00535	UNIPROT	NDEL1	protein	Q9GZM8	UNIPROT	up-regulates activity	phosphorylation	Ser198	TRKSAPSsPTLDCEK	10090	BTO:0000142								12796778	t		llicata	Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function.	SIGNOR-250675	0.764
ATM	protein	Q13315	UNIPROT	TAOK1	protein	Q7L7X3	UNIPROT	up-regulates	phosphorylation			9606									17396146	t		gcesareni	The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells.	SIGNOR-154178	0.394
IRF5	protein	Q13568	UNIPROT	IL10	protein	P22301	UNIPROT	down-regulates	transcriptional regulation			9606	BTO:0000801								21240265	f			The role of IRF5 in inhibiting the transcription of the gene encoding IL-10 that we have identified here is important given its well- documented immunosuppressive activity.	SIGNOR-254514	0.436
ACVR1	protein	Q04771	UNIPROT	VPS39	protein	Q96JC1	UNIPROT	up-regulates activity	binding			9534									12941698	t		miannu	TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling.	SIGNOR-261376	0.2
BBC3	protein	Q9BXH1	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								15694340	t		lperfetto	Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.	SIGNOR-133808	0.649
SRC	protein	P12931	UNIPROT	ATG9A	protein	Q7Z3C6	UNIPROT	up-regulates activity	phosphorylation	Tyr8	MAQFDTEyQRLEASY	9606									27934868	t		miannu	 Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation. 	SIGNOR-266367	0.35
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1763	TPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273083	0.636
TBX5	protein	Q99593	UNIPROT	MTA2	protein	O94776	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20802524	f		miannu	TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. 	SIGNOR-255256	0.2
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DQB2	protein	P05538	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-253997	0.2
NOX5	protein	Q96PH1	UNIPROT	ROS	stimulus	SIGNOR-ST2	SIGNOR	up-regulates				9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264718	0.7
IRX1	protein	P78414	UNIPROT	FGF7	protein	P21781	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002392								20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 	SIGNOR-261654	0.2
GTF2F1	protein	P35269	UNIPROT	GTF2F1	protein	P35269	UNIPROT	down-regulates	phosphorylation	Thr389	RGNSRPGtPSAEGGS	9606									10428810	t		gcesareni	We show that tfiifalpha possesses a serine/threonine kinase activity, allowing an autophosphorylation of the two residues at position serine 385 and threonine 389. Mutation analysis strongly suggests that autophosphorylation of both sites regulates the transcription elongation process.	SIGNOR-69771	0.2
NLK	protein	Q9UBE8	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Ser128	QHVRAHSsPASLQLG	9606	BTO:0000007								27979971	t	done	miannu	Here, we report that osmotic stress stimulates transient YAP nuclear localization and increases YAP activity even when YAP Ser127 is phosphorylated. Osmotic stress acts via the NLK kinase to induce YAP Ser128 phosphorylation. Phosphorylation of YAP at Ser128 interferes with its ability to bind to 14-3-3, resulting in YAP nuclear accumulation and induction of downstream target gene expression. 	SIGNOR-273909	0.2
PRKACA	protein	P17612	UNIPROT	HTT	protein	P42858	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2548	TRFGRKLsIIRGIVE	-1									35908190	t		miannu	Moreover, phosphorylation of C-HEAT Ser2550 by cAMP-dependent protein kinase (PKA), the top hit in kinase activity screens, was found to hasten huntingtin degradation, such that levels of the catalytic subunit (PRKACA) were inversely related to huntingtin levels.	SIGNOR-277625	0.2
SLBP	protein	Q14493	UNIPROT	H2BC14	protein	Q99879	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265390	0.2
TFEB	protein	P19484	UNIPROT	NEU1	protein	Q99519	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19556463	f	Figure 1	lperfetto	Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 	SIGNOR-276544	0.2
CDK1	protein	P06493	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Ser214	SRSGLYRsPSMPENL	9606									10037602	t		gcesareni	Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity.	SIGNOR-64960	0.853
SB 203580	chemical	CHEBI:90705	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates	chemical inhibition			9606									10512765	t		gcesareni	Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme.	SIGNOR-71024	0.8
FLI1	protein	Q01543	UNIPROT	ERG	protein	P11308	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001106								21536859	f	 	miannu	 We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer.	SIGNOR-253921	0.317
RAE1	protein	P78406	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262095	0.569
AKT1	protein	P31749	UNIPROT	S1PR1	protein	P21453	UNIPROT	up-regulates activity	phosphorylation	Thr236	RTRSRRLtFRKNISK	9606									11583630	t		lperfetto	Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis	SIGNOR-252467	0.692
GSK3B	protein	P49841	UNIPROT	MITF	protein	O75030	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser419	S-->N	9606									25605940	t		miannu	We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here.	SIGNOR-276476	0.446
GRK2	protein	P25098	UNIPROT	SLC9A5	protein	Q14940	UNIPROT	down-regulates activity	phosphorylation	Ser711	EEEEESDsSETEKED										21296876	t		lperfetto	Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2.	SIGNOR-275501	0.2
TFEB	protein	P19484	UNIPROT	CTSA	protein	P10619	UNIPROT	up-regulates quantity by expression	transcriptional regulation												28552616	t		lperfetto	Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants	SIGNOR-276549	0.303
RNF146	protein	Q9NTX7	UNIPROT	AXIN2	protein	Q9Y2T1	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								21478859	t		lperfetto	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 	SIGNOR-263336	0.658
MTOR	protein	P42345	UNIPROT	ULK1	protein	O75385	UNIPROT	down-regulates activity	phosphorylation	Ser758	PVVFTVGsPPSGSTP	9606	BTO:0001938								21383122	t		lperfetto	When cells are replenished with rich medium, mtor is activated;it phosphorylates serine 638 and serine 758. The phosphorylation of ulk1 at serine 758 then leads to reassociation between ulk1 and ampk.	SIGNOR-172541	0.844
DRD3	protein	P35462	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257097	0.321
RBPJ	protein	Q06330	UNIPROT	HES1	protein	Q14469	UNIPROT	up-regulates quantity	transcriptional regulation			10090	BTO:0000165								10066785	t		gcesareni	ligand-induced Notch signaling up-regulated HES1 mRNA expression within 1h and subsequently reduced expression of MyoD mRNA	SIGNOR-243178	0.584
MAPK3	protein	P27361	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser363	TSRTPKDsPGIPPSA	9534	BTO:0001538								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-219337	0.705
TRIM33	protein	Q9UPN9	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	binding			9606	BTO:0000574;BTO:0002625;BTO:0000414								16751102	t		lperfetto	The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. Tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses.	SIGNOR-236064	0.623
LPAR3	protein	Q9UBY5	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates	binding			9606									22863277	t		gcesareni	Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2.	SIGNOR-198544	0.443
sphingosine 1-phosphate	smallmolecule	CHEBI:37550	ChEBI	LATS2	protein	Q9NRM7	UNIPROT	down-regulates				9606	BTO:0000007								22863277	f		milica	Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2.	SIGNOR-198553	0.8
PPARGC1A	protein	Q9UBK2	UNIPROT	ALDOB	protein	P05062	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f		miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-255055	0.247
PTPN2	protein	P17706	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates activity	dephosphorylation	Tyr1175	AQQDGKDyIVLPISE	9606									29955047	t		lperfetto	Collectively, our findings indicate that TC-PTP negatively regulates Flk-1 and JNK signaling via direct dephosphorylation of Flk-1 on its Y1173 residue, which contributes to increased epidermal apoptosis in response to UVB exposure.|TC-PTP dephosphorylates activated Flk-1 at Y1173 after UVB irradiation, which is followed by the suppression of JNK phosphorylation.|TC-PTP promotes UVB induced apoptosis in keratinocytes by dephosphorylating Flk-1 tyrosine residue 1173.	SIGNOR-276961	0.548
LCK	protein	P06239	UNIPROT	PECAM1	protein	P16284	UNIPROT	up-regulates activity	phosphorylation	Tyr713	KKDTETVySEVRKAV	9534									9624175	t		miannu	We demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances.	SIGNOR-262742	0.57
LSM5	protein	Q9Y4Y9	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270649	0.792
ELF4	protein	Q99607	UNIPROT	CXCL8	protein	P10145	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000130;BTO:0000782								14625302	f		miannu	Myeloid elf1-like factor is a potent activator of interleukin-8 expression in hematopoietic cells	SIGNOR-119204	0.243
3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid	chemical	CHEBI:91194	ChEBI	LPAR1	protein	Q92633	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193558	0.8
NRXN1	protein	Q9ULB1	UNIPROT	DAG1	protein	Q14118	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							22626542	t		miannu	 The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 	SIGNOR-265458	0.401
ABL1	protein	P00519	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates	phosphorylation	Tyr276	SDEDDEVyQVTVYQA	9606									21081495	t		lperfetto	Mdm2 has three known c-abl phosphorylation sites (tyr276, tyr394, and tyr405)these data show that c-abl is important for reducing mdm2 and mdmx protein levels after genotoxic stress and suggest another cellular mechanism for the stabilization and activation of p53.	SIGNOR-169699	0.705
DVL1	protein	O14640	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity	binding			9606									20837657	t		lperfetto	In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization.	SIGNOR-227914	0.701
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	down-regulates	phosphorylation	Thr806	NQMAKGTtEEMKYVL	9606									18680479	t		miannu	We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / t806d mps1 was significantly less active than t806a, demonstrating a potential negative correlation between phosphorylation and activity at this site.	SIGNOR-179908	0.2
RUNX3	protein	Q13761	UNIPROT	CFLAR	protein	O15519	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255087	0.2
CDK1	protein	P06493	UNIPROT	NDE1	protein	Q9NXR1	UNIPROT	up-regulates	phosphorylation			9606									16682949	t		gcesareni	We found that nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative cdc2 phosphorylation sites in nde1 and found that alteration of these sites diminishes phosphorylation by cdc2 in vitro and affects the stability of su48-nde1 interactions and the centrosomal localization of nde1.	SIGNOR-146734	0.64
ATF4	protein	P18848	UNIPROT	IARS1	protein	P41252	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269427	0.2
PTPN11	protein	Q06124	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity				9606									11085989	f		miannu	We show here that leptin can activate ERK signaling in thehypothalamus and that this stimulation is likely to occur viatwo pathways, both involving SHP-2.We have shown above that SHP-2 is a positive mediator of ERK activation by ObRb and that this requires both the phosphatase activity and tyrosine phosphorylation of SHP-2. Furthermore,Tyr-985 is required for maximal ERK phosphorylation. 	SIGNOR-263499	0.862
STK38L	protein	Q9Y2H1	UNIPROT	STK38L	protein	Q9Y2H1	UNIPROT	up-regulates	phosphorylation	Ser282	NRRQLAYsTVGTPDY	9606	BTO:0000007								16314523	t		lperfetto	Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity.	SIGNOR-142518	0.2
PPP6C	protein	O00743	UNIPROT	CGAS	protein	Q8N884	UNIPROT	down-regulates activity	dephosphorylation	Ser435	KHLDKFSsYHVKTAF	9606									32474700	t		lperfetto	In this study, we found that PPP6C suppressed phosphorylation of human cGAS (hcGAS) at S435 or mouse cGAS (mcGAS) at S420 in its substrate-binding pocket, thus preventing its binding to GTP and inhibiting the synthesis of cGAMP.|These data suggest that PPP6C inhibits cGAS activity.	SIGNOR-276990	0.2
PDGFRB	protein	P09619	UNIPROT	ABL2	protein	P42684	UNIPROT	up-regulates activity	phosphorylation	Tyr116	PNLFVALyDFVASGD	-1									34144039	t		miannu	 PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2.	SIGNOR-277304	0.308
nintedanib	chemical	CHEBI:85164	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190305	0.8
PPP1CA	protein	P62136	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates activity	dephosphorylation	Ser127	PQHVRAHsSPASLQL	9606									21909427	t		lperfetto	In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2.|PP1A dephosphorylates endogenous YAP2 at serine 127.	SIGNOR-276999	0.658
UBE2I	protein	P63279	UNIPROT	ZHX1	protein	Q9UKY1	UNIPROT	up-regulates quantity by stabilization	sumoylation	Lys159	TFDGSFVkEENAEQA	9606	BTO:0000007								23686912	t		miannu	Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. The sumoylation of zinc‐fingers and homeoboxes 1 (ZHX1) by ubc9 regulates its stability and transcriptional repression activity. However, in the current work, we demonstrated that ZHX1 was only SUMOylated by SUMO1. 	SIGNOR-263899	0.465
RNF135	protein	Q8IUD6	UNIPROT	DDX58	protein	O95786	UNIPROT	up-regulates activity	ubiquitination	Lys909	QTLYSKWkDFHFEKI	9606	BTO:0000007								19017631	t		miannu	Our data suggest that Riplet/RNF135 is a novel factor of the RIG-I pathway that is involved in the evoking of human innate immunity against RNA virus infection, and activates RIG-I through ubiquitination of its C-terminal region. 	SIGNOR-265569	0.756
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257984	0.8
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	MEF2A	protein	Q02078	UNIPROT	down-regulates	binding			9606									21902831	t		lperfetto	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-216960	0.271
HDAC2	protein	Q92769	UNIPROT	MECP2/SIN3A/HDAC complex	complex	SIGNOR-C360	SIGNOR	form complex	binding			9606	BTO:0000567								9620804	t		Luana	We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases.	SIGNOR-267736	0.71
EEF1B2	protein	P24534	UNIPROT	EEF1B complex	complex	SIGNOR-C460	SIGNOR	form complex	binding			9606									23699257	t		lperfetto	An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. The requirement for a guanine nucleotide exchange factor, the eEF1B complex, which in metazoans is composed of the subunits α, δ, and γ (also called eEF1B, eEF1D, and eEF1G, respectively)	SIGNOR-269390	0.821
WASHC5	protein	Q12768	UNIPROT	WASH complex	complex	SIGNOR-C258	SIGNOR	form complex	binding												23721880	t		lperfetto	The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53.	SIGNOR-261019	0.2
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates quantity by destabilization	cleavage	Phe708	YENPTYKfFEQMQN	-1									8943232	t		lperfetto	The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261776	0.502
idarubicin	chemical	CHEBI:42068	ChEBI	TOP2A	protein	P11388	UNIPROT	down-regulates activity	chemical inhibition			9606									20824055	t		miannu	Topoisomerase II (Top2) is a nuclear enzyme involved in several metabolic processes of DNA. Chemotherapy agents that poison Top2 are known to induce persistent protein-mediated DNA double strand breaks (DSB). In this report, by using knock down experiments, we demonstrated that Top2α was largely responsible for the induction of γH2AX and cytotoxicity by the Top2 poisons idarubicin and etoposide in normal human cells. 	SIGNOR-259327	0.8
GATA1	protein	P15976	UNIPROT	SPI1	protein	P17947	UNIPROT	down-regulates activity	binding			9606	BTO:0004826								10753833	t		irozzo	GATA-1 represses PU.1 activity.We have in this report found that the GATA-1 transcription factor is capable of functionally interfering with the PU.1 protein and have provided evidence that this interference is mediated through interaction between the PU.1 ETS domain and the GATA-1 C-finger region.	SIGNOR-256050	0.641
LPAR	proteinfamily	SIGNOR-PF2	SIGNOR	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-269963	0.2
GSK3B	protein	P49841	UNIPROT	ETS1	protein	P14921	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr265	YDSCDRLtQSWSSQS	9606	BTO:0000007								34023818	t		miannu	Here, we show that ETS1 forms a complex with glycogen synthase kinase-3β (GSK3β). Specifically, GSK3β-mediated phosphorylation of ETS1 at threonine 265 and serine 269 promoted protein stability, induced the transcriptional activation of matrix metalloproteinase (MMP)-9, and increased cell migration.	SIGNOR-277560	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	YAP1	protein	P46937	UNIPROT	down-regulates	phosphorylation	Ser127	PQHVRAHsSPASLQL	9606									12535517	t		gcesareni	One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73.	SIGNOR-97485	0.2
androst-5-ene-3beta,17beta-diol	smallmolecule	CHEBI:2710	ChEBI	testosterone	smallmolecule	CHEBI:17347	ChEBI	up-regulates quantity	precursor of			10116		BTO:0000534;BTO:0000056							1537836	t		lperfetto	We have recently characterized two types of rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) isoenzymes expressed in adrenals and gonads. | However, in the presence of NADH, type III isoenzyme, in common with the type I isoform, converts 5 alpha-androstane-3,17-dione (A-dione) and 5 alpha-dihydrotestosterone (DHT) to the corresponding 3 beta-hydroxysteroids.	SIGNOR-268640	0.8
CEBPA	protein	P49715	UNIPROT	CEBPA	protein	P49715	UNIPROT	up-regulates quantity	transcriptional regulation			9606	BTO:0001056								11283671	t		apalma	Here, we demonstrate that C/EBPα indeed activates its promoter in transient transfection assays in myeloid cells.	SIGNOR-255673	0.2
DUSP6	protein	Q16828	UNIPROT	MAPK7	protein	Q13164	UNIPROT	down-regulates activity	dephosphorylation			9606									18280112	t		lperfetto	However, whilst the interaction itself might be difficult to monitor, DUSP6 should still be able to promote the de-phosphorylation of ERK5 in cells if it is an ERK5 phosphatase.To test this HEK293 cells were transiently transfected with HA-ERK2 or HA-ERK5 together with EGFP-MEK1E (a constitutively active version of MEK1) or EGFP-MEK5D (a constitutively active version of MEK5).|Whilst one can envisage scenarios in which the interaction between DUSPs and their substrates might be transient, DUSP6 should still be able to promote the de-phosphorylation and inactivation of ERK5.	SIGNOR-277007	0.631
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser250	TGSPAELsPTTLSPV	9606									19115199	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-182992	0.739
FLI1	protein	Q01543	UNIPROT	KLF1	protein	Q13351	UNIPROT	down-regulates activity	binding			10090	BTO:0004475								12556498	t		irozzo	FLI-1 represses the transcriptional activity of EKLF.Our data indicate that the ETS domain of FLI-1 is absolutely required to inhibit EKLF activity. Since the FLI-1 ETS domain interacts with the DNA binding domain of EKLF, one possibility could be that FLI-1 inhibits the binding of EKLF to its DNA targets	SIGNOR-256044	0.378
5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin	chemical	CID:122187	PUBCHEM	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258865	0.8
VPS11	protein	Q9H270	UNIPROT	RDX	protein	P35241	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								21148287	t		Sara	Vps11 was found to interact with radixin. ERM proteins and the HOPS complex are required for the transition from early to late endosomes. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation. 	SIGNOR-261312	0.354
Factor FVIIa:TF	complex	SIGNOR-C319	SIGNOR	F9	protein	P00740	UNIPROT	up-regulates activity	binding			9606		BTO:0000131							32665005	t		lperfetto	During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury.	SIGNOR-263542	0.583
IRAK1	protein	P51617	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates activity	binding			9606									12242293	t		lperfetto	We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1	SIGNOR-92994	0.911
RPS6KA1	protein	Q15418	UNIPROT	EIF4B	protein	P23588	UNIPROT	up-regulates	phosphorylation	Ser422	RERSRTGsESSQTGT	9606									15071500	t		gcesareni	S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.	SIGNOR-123993	0.546
(R)-adrenaline	smallmolecule	CHEBI:28918	ChEBI	ADRA1B	protein	P35368	UNIPROT	up-regulates activity	chemical activation			10029									7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258443	0.8
POLR1C	protein	O15160	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding												22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266145	0.909
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000130								16778989	t	inferred from 70% family members	gcesareni	Inhibitors of the erk1/2 pathway abrogated gm-csf-induced phosphorylation of ser345, while p38 mapk inhibitor abrogated tnf-alpha-induced phosphorylation of ser345.These results show that the ala-mutated p47phox acts as a dominant-negative inhibitor of endogenous p47phox and clearly indicate that phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells.	SIGNOR-270091	0.2
EPHA3	protein	P29320	UNIPROT	EPHA3	protein	P29320	UNIPROT	up-regulates activity	phosphorylation	Tyr596	KLPGLRTyVDPHTYE	9606									11870224	t			Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3	SIGNOR-251115	0.2
SH3RF1	protein	Q7Z6J0	UNIPROT	MAPK8IP1	protein	Q9UQF2	UNIPROT	up-regulates	binding			9606									16571722	t		gcesareni	We find that posh and jips directly associate with one another to form a multiprotein complex, pjac (posh-jip apoptotic complex), that includes all of the known kinase components of the pathway. Our observations indicate that this complex is required for jnk activation and cell death in response to apoptotic stimuli.	SIGNOR-145393	0.288
ACSS1	protein	Q9NUB1	UNIPROT	acetyl-CoA(4-)	smallmolecule	CHEBI:57288	ChEBI	up-regulates quantity	chemical modification												10843999	t		lperfetto	The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP.	SIGNOR-271829	0.8
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3C15	protein	Q71DI3	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269635	0.2
SIRT1	protein	Q96EB6	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606									14976264	f		lperfetto	Sirt1 inhibited foxo3's ability to induce cell death.	SIGNOR-217884	0.7
MYC	protein	P01106	UNIPROT	TYMS	protein	P04818	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18677108	t		miannu	Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.	SIGNOR-267374	0.345
EGFR	protein	P00533	UNIPROT	CALM1	protein	P0DP23	UNIPROT	down-regulates	phosphorylation	Tyr100	FDKDGNGyISAAELR	9606									7925415	t		lperfetto	Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.	SIGNOR-34691	0.414
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ARFIP2	protein	P53365	UNIPROT	unknown	phosphorylation	Ser260	GTRGRLEsAQATFQA	9606	BTO:0000938								15809304	t		llicata	Akt phosphorylated arfaptin 2 at ser(260). we have also demonstrated that arfaptin 2 phosphorylation restores proteasome activity that is inhibited by the presence of polyq-huntingtin in cells.	SIGNOR-135105	0.2
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1675	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269343	0.718
DNMT3A	protein	Q9Y6K1	UNIPROT	FGF21	protein	Q9NSA1	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									29091029	f		Gianni	Unbiased gene profiling studies revealed Fgf21 as a key negatively regulated Dnmt3a target gene in adipocytes with concordant changes in DNA methylation at the Fgf21 promoter region.	SIGNOR-262200	0.2
MAPK8IP1	protein	Q9UQF2	UNIPROT	MAPK8	protein	P45983	UNIPROT	down-regulates	binding			9606									18486448	t		gcesareni	The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus	SIGNOR-178655	0.879
RORA	protein	P35398	UNIPROT	NPAS2	protein	Q99743	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								20817722	t		miannu	Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.	SIGNOR-267980	0.652
ELK1	protein	P19419	UNIPROT	Cell_growth	phenotype	SIGNOR-PH33	SIGNOR	up-regulates				9606									23426362	f		lperfetto	AR required ELK1 to up-regulate a major subset of its target genes that was strongly and primarily enriched for cell growth functions	SIGNOR-233471	0.7
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H4C1	protein	P62805	UNIPROT	down-regulates activity	acetylation	Lys17	GLGKGGAkRHRKVLR	9606									16227571	t		miannu	We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. 	SIGNOR-263944	0.2
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	Ile-tRNA(Ile)	smallmolecule	CHEBI:29160	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270422	0.8
CSNK2A2	protein	P19784	UNIPROT	PPP1R1B	protein	Q9UD71	UNIPROT	up-regulates activity	phosphorylation	Ser45	LFRLSEHsSPEEEAS	-1									2557337	t		llicata	Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase	SIGNOR-251019	0.383
APC-c	complex	SIGNOR-C150	SIGNOR	KIFC1	protein	Q9BW19	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1									24510915	t		miannu	Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A). 	SIGNOR-266109	0.26
Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	Respiratory electron transport chain	phenotype	SIGNOR-PH141	SIGNOR	up-regulates													30030361	f		lperfetto	The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA).	SIGNOR-262140	0.7
AGTR1	protein	P30556	UNIPROT	GNG12	protein	Q9UBI6	UNIPROT	up-regulates	binding			9606									21289285	t		gcesareni	These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction.	SIGNOR-171763	0.408
BCOR	protein	Q6W2J9	UNIPROT	HOXA7	protein	P31268	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									26847029	f		irozzo	Importantly, our results showed that BCOR is a repressor of HoxA cluster of genes (HoxA5, HoxA7 and HoxA9) in myeloid cells. Knock-down of HoxA5, HoxA7 and HoxA9 significantly decreased the clonogenic growth of Bcor mutant and wild type cells, demonstrating the Hox genes, as targets of BCOR, played an important role in mediating BCOR’s function in regulating myeloid cell proliferation.	SIGNOR-256013	0.2
CCKBR	protein	P32239	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256765	0.267
ERG	protein	P11308	UNIPROT	VWF	protein	P04275	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								9444957	f	 	miannu	Cotransfection of Ets-1 and Erg expression plasmids is sufficient to induce the -60/+19 vWF promoter activity in HeLa cells.	SIGNOR-253914	0.25
PTPN1	protein	P18031	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates	dephosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606									15821101	t		gcesareni	Mechanism of protein tyrosine phosphatase 1b-mediated inhibition of leptin signalling. Ptp1b plays a critical role in the down-regulation of activated-stat3 by dephosphorylating tyr705, that is the phosphorylation site of activation of stat3.	SIGNOR-135211	0.569
CDK7	protein	P50613	UNIPROT	ERCC3	protein	P19447	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser90	HIFLEAFsPVYKYAQ	9606	BTO:0000567								30762924	t		miannu	These results led us to propose a model that spironolactone may trigger the phosphorylation of XPB at Ser90 by CDK7, which promotes the recognition and polyubiquitination of XPB by SCFFBXL18 for proteasomal degradation.	SIGNOR-277433	0.891
HUWE1	protein	Q7Z6Z7	UNIPROT	MFN2	protein	O95140	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								30217973	t		lperfetto	AMBRA1 regulates mitophagy at two critical steps. Upon mitophagy stimulation, AMBRA1 mediates the HUWE1 E3 ubiquitin ligase translocation from cytosol to mitochondria (light blue). AMBRA1 acts as a cofactor for HUWE1 E3 ubiquitin ligase activity, favouring its binding to its substrate MFN2 (and maybe other OMM substrates) and targeting it to the proteasome	SIGNOR-272978	0.43
LAT	protein	O43561	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			9606	BTO:0000661								10811803	t			Our results showed that three distal tyrosines, Tyr(171), Tyr(191), and Tyr(226), are responsible for Grb2-binding;	SIGNOR-251521	0.797
AKAP12	protein	Q02952	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates activity	relocalization												14657015	t		lperfetto	A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. 	SIGNOR-271836	0.471
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT2B	protein	Q93097	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242701	0.295
FOXO3	protein	O43524	UNIPROT	FBXO32	protein	Q969P5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								15109499	f		miannu	Constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers	SIGNOR-252070	0.451
MDFI	protein	Q99750	UNIPROT	MYF5	protein	P13349	UNIPROT	down-regulates activity	binding			10090	BTO:0000944								8797820	t	2	miannu	We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals.	SIGNOR-240433	0.378
GSC	protein	P56915	UNIPROT	EPHA7	protein	Q15375	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000596								9417125	t		Luana	We demonstrate that Goosecoid can act as a repressor of its own promoter activity in transient co-transfection experiments in mouse P19 cells and in Xenopus embryos. Autorepression depends on the presence of the homeodomain and is mediated through the prd element more proximal to the transcriptional start site.	SIGNOR-261613	0.2
CTSG	protein	P08311	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates activity	cleavage	Phe55	PNDKYEPfWEDEEKN	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263563	0.577
INSR	protein	P06213	UNIPROT	CALM2	protein	P0DP24	UNIPROT	down-regulates	phosphorylation	Tyr100	FDKDGNGyISAAELR	9606									3415247	t		miannu	The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.	SIGNOR-266320	0.358
PRKCD	protein	Q05655	UNIPROT	YWHAZ	protein	P63104	UNIPROT	down-regulates activity	phosphorylation	Ser58	VVGARRSsWRVVSSI	9606									12861023	t		lperfetto	We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. | Experimentally, S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1.	SIGNOR-249222	0.456
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates quantity				9606									19879762	f		lperfetto	In the case of DNA-damage, phosphorylation of both p53 and Mdm2 by the checkpoint kinases ATM, ATR, Chk1 and Chk2 contributes to the dissociation of the Mdm2-p53 complex, leading to enhanced cellular p53 levels that primarily accumulate in the nucleus.	SIGNOR-209690	0.7
MC5R	protein	P33032	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256941	0.296
sphingosine 1-phosphate	smallmolecule	CHEBI:37550	ChEBI	S1PR3	protein	Q99500	UNIPROT	up-regulates	chemical activation			9606									16794003	t		gcesareni	The evidence suggests that s1p acting on s1p receptors coupled to gq	SIGNOR-147233	0.8
KDM6A	protein	O15550	UNIPROT	HOXA1	protein	P49639	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24561908	t		miannu	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260019	0.376
SRC	protein	P12931	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates	phosphorylation	Tyr95	KFPECGFyGMYDKIL	9606									17804414	t		llicata	Critical for the regulation of pkd1 activity in response to oxidative stress are src- and abl-mediated tyrosine phosphorylations that eventually lead to protein kinase cdelta (pkcdelta)-mediated activation of pkd1. our data suggest that pkd1 phosphorylation at tyr95 generates a binding motif for pkcdelta, and that oxidative stress-mediated pkcdelta/pkd interaction results in pkd1 activation loop phosphorylation and activation.	SIGNOR-157716	0.421
ATM	protein	Q13315	UNIPROT	XRCC6	protein	P12956	UNIPROT	up-regulates activity	phosphorylation	Ser27	QEENLEAsGDYKYSG	9606	BTO:0001546								26337656	t	done	miannu	 Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks.	SIGNOR-274020	0.703
CAPN2	protein	P17655	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	cleavage			9606	BTO:0000590								25969760	t		lperfetto	Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains	SIGNOR-251611	0.445
MRPS6	protein	P82932	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261440	0.693
SMAD4	protein	Q13485	UNIPROT	SMAD1/5/8/SMAD4	complex	SIGNOR-C215	SIGNOR	form complex	binding			9606									20957627	t		lperfetto	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.	SIGNOR-255832	0.2
SRC	protein	P12931	UNIPROT	MPZL1	protein	O95297	UNIPROT	up-regulates	phosphorylation	Tyr241	SHQGPVIyAQLDHSG	9606									11751924	t		lperfetto	Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr	SIGNOR-113406	0.481
CEBPA	protein	P49715	UNIPROT	GFI1	protein	Q99684	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20924107	f		irozzo	We show here that C/EBPα interacts with a functional C/EBP binding site in the Gfi-1 5'-flanking region and enhances the promoter activity of Gfi-1.	SIGNOR-256068	0.384
MAPK1	protein	P28482	UNIPROT	GRB10	protein	Q13322	UNIPROT	up-regulates	phosphorylation	Ser476	MNILGSQsPLHPSTL	9606									15952796	t		lperfetto	We show that grb10 is a direct substrate of the p42/44 mitogen-activated protein kinase (mapk)we identified ser(150), ser(418), and ser(476) of human grb10zeta as mapk-mediated in vitro phosphorylation sites. Replacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation. Taken together, our findings suggest that phosphorylation of the adaptor protein may provide a feedback inhibitory mechanism by which grb10 regulates insulin signaling.	SIGNOR-138167	0.381
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Thr573	AENGLLMtPCYTANF	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252743	0.754
NUP42	protein	O15504	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262097	0.2
SOCS3	protein	O14543	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates				9606	BTO:0000801								21628332	f		lperfetto	SOCS3 attenuates IL-6-induced STAT3 anti-inflammatory effects, as well as IL-4-induced insulin receptor substrate-2/PI3K-mediated gene expression.	SIGNOR-249567	0.699
FGFR4	protein	P22455	UNIPROT	FGFR4	protein	P22455	UNIPROT	up-regulates activity	phosphorylation	Tyr754	LLAVSEEyLDLRLTF	-1									8576110	t			Analysis of the major autophosphorylation site Y754F mutant of FGFR-4 showed that binding of p85 and its serine phosphorylation were independent of receptor autophosphorylation at this site.	SIGNOR-251140	0.2
CD2AP	protein	Q9Y5K6	UNIPROT	ACTB	protein	P60709	UNIPROT	up-regulates activity	binding			9606	BTO:0000007;BTO:0001938								29175910	t		lperfetto	One such regulator is the adaptor protein CD2AP, which delivers capping proteins to the barbed ends of polymerizing F-actin. Capping growing filaments can promote the formation of actin branches by increasing the G-actin pool available to form branches	SIGNOR-264770	0.2
CERS2	protein	Q96G23	UNIPROT	ceramide	smallmolecule	CHEBI:17761	ChEBI	up-regulates quantity	chemical modification			9606									26887952	t	done	miannu	 Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity. 	SIGNOR-273994	0.8
GRK2	protein	P25098	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser373	SMGTLRTsISVERQI	9606	BTO:0000007								11517230	t			Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251445	0.2
FBXO22	protein	Q8NEZ5	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000356								31138683	t		lperfetto	SCFFBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis|we discovered Skp1-Cullin 1-FBXO22-ROC1 (SCFFBXO22) as the most dominating HDM2 E3 ubiquitin ligase from human proteome. The results of protein decay rate analysis, ubiquitination, siRNA-mediated silencing, and coimmunoprecipitation experiments support a hypothesis that FBXO22 targets cellular HDM2 for ubiquitin-dependent degradation. 	SIGNOR-273440	0.2
NBAS	protein	A2RRP1	UNIPROT	NRZ complex	complex	SIGNOR-C358	SIGNOR	form complex	binding												25364732	t		lperfetto	NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay.	SIGNOR-265024	0.791
coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	up-regulates quantity	precursor of			9606									19286649	t		miannu	ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor.	SIGNOR-268083	0.8
ADRB2	protein	P07550	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606									14500986	t			We have found that signaling via the erythrocyte beta2-adrenergic receptor and heterotrimeric guanine nucleotide-binding protein (Galphas) regulated the entry of the human malaria parasite Plasmodium falciparum.	SIGNOR-256149	0.646
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	chemical	CHEBI:95082	ChEBI	BRD4	protein	O60885	UNIPROT	down-regulates activity	chemical inhibition			-1									24015967	t		Gianni	This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation	SIGNOR-262204	0.8
ATM	protein	Q13315	UNIPROT	CREB1	protein	P16220	UNIPROT	down-regulates	phosphorylation	Thr100	LKRLFSGtQISTIAE	9606									15073328	t		lperfetto	Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp)	SIGNOR-124051	0.538
RPS6KA5	protein	O75582	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr46	GGTLFSTtPGGTRII										12213813	t		lperfetto	In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E	SIGNOR-262992	0.658
CDC20	protein	Q12834	UNIPROT	CCNB1	protein	P14635	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000567								11285280	t		miannu	These results suggested that cyclin A is a target of the Cdc20-associated APC/C in human cells.	SIGNOR-272578	0.966
C5AR1	protein	P21730	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates													1847994	f		lperfetto	The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 	SIGNOR-263462	0.7
PTPN1	protein	P18031	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606									22124607	t		lperfetto	Moreover, we reported that TCPTP knockdown in PTP1B deficient MEFS further enhanced IR activation, consistent with the two PTPs acting in a coordinated manner to attenuate insulin signalling .|Therefore, the inhibition of PTPs such as PTP1B that attenuate IR activation and signalling might be particularly effective in alleviating insulin resistance.|The prototypic family member PTP1B (encoded by PTPN1) dephosphorylates the IR beta subunit Y1162 and Y1163 activation loop autophosphorylation site to attenuate insulin signalling in vivo .	SIGNOR-276947	0.778
HBB	protein	P68871	UNIPROT	CYP2E1	protein	P05181	UNIPROT	up-regulates activity				9606	BTO:0000575								19325051	f	Regulation	miannu	Hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes.	SIGNOR-251764	0.2
CLK1	protein	P49759	UNIPROT	RBM17	protein	Q96I25	UNIPROT	up-regulates activity	phosphorylation	Ser222	EEQDRPRsPTGPSNS	9534	BTO:0001538								23519612	t		miannu	 In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 	SIGNOR-262707	0.324
tyrphostin B42	chemical	CHEBI:131968	ChEBI	JAK2	protein	O60674	UNIPROT	down-regulates activity	chemical inhibition			9606									11368440	t		gcesareni	The Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel	SIGNOR-238542	0.8
FLT3	protein	P36888	UNIPROT	FLT3	protein	P36888	UNIPROT	up-regulates	phosphorylation	Tyr597	FYVDFREyEYDLKWE	9606	BTO:0001271								11971190	t		lperfetto	Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation	SIGNOR-117579	0.2
SMG1	protein	Q96Q15	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									15175154	t		gcesareni	Hsmg-1 is a stress-activated kinase that phosphorylates p53 and hupf1 in vitrothe observation that hsmg-1 exhibits p53 (ser-15) kinase activity in vitro suggested that this pikk might be involved in genotoxic stress-induced p53 phosphorylation and stabilization in intact cells.	SIGNOR-125135	0.423
RAB6A	protein	P20340	UNIPROT	Synaptic_vesicle_exocytosis	phenotype	SIGNOR-PH160	SIGNOR	up-regulates				9534									20360680	f		miannu	We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles.	SIGNOR-266880	0.7
C1RL	protein	Q9NZP8	UNIPROT	HP	protein	P00738	UNIPROT	up-regulates activity	cleavage	Arg161	NPANPVQrILGGHLD	9534	BTO:0001538								15385675	t		miannu	We demonstrate that coexpression of the proform of Hp (proHp) and C1r-LP in COS-1 cells effected cleavage of proHp in the endoplasmic reticulum. This cleavage depended on proteolytic activity of C1r-LP because mutation of the putative active-site Ser residue abolished the reaction. Furthermore, incubation of affinity-purified C1r-LP and proHp led to the cleavage of the latter protein. ProHp appeared to be cleaved at the expected site because substitution of Gly for Arg-161 blocked the reaction.	SIGNOR-256358	0.383
PRKCD	protein	Q05655	UNIPROT	PTPN7	protein	P35236	UNIPROT	up-regulates activity	phosphorylation	Ser246	QYQEERRsVKHILFS	-1									16479000	t		miannu	HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. 	SIGNOR-276048	0.2
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr115	QPQPDSVyLVPTPSK	10090									12972425	t		lperfetto	Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs	SIGNOR-246381	0.797
ILK	protein	Q13418	UNIPROT	PPP1R12A	protein	O14974	UNIPROT	down-regulates activity	phosphorylation	Thr500	RLAYVAPtIPRRLAS	-1									12030846	t		miannu	 MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition	SIGNOR-262884	0.566
CDK5	protein	Q00535	UNIPROT	PMAIP1	protein	Q13794	UNIPROT	down-regulates	phosphorylation	Ser13	ARKNAQPsPARAPAE	9606	BTO:0001271								21145489	t		llicata	We show that noxa is phosphorylated on a serine residue (s(13)) in the presence of glucose. Phosphorylation promotes its cytosolic sequestration and suppresses its apoptotic function. We identify cdk5 as the noxa kinase	SIGNOR-170357	0.365
F2RL1	protein	P55085	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256752	0.2
MAPK1	protein	P28482	UNIPROT	NCOA1	protein	Q15788	UNIPROT	up-regulates	phosphorylation	Ser1185	GTPPASTsPFSQLAA	9606									10660621	t		lperfetto	Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene.	SIGNOR-74872	0.371
DRD1	protein	P21728	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256939	0.557
ABL2	protein	P42684	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates activity	phosphorylation	Tyr231	NANGEAVyCKFHYKT	9606									12777400	t		Manara	These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386	SIGNOR-260771	0.345
PLCG2	protein	P16885	UNIPROT	1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate	smallmolecule	CHEBI:18348	ChEBI	down-regulates quantity	chemical modification			9606									23000145	t		scontino	Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).	SIGNOR-268452	0.8
DDX17	protein	Q92841	UNIPROT	Microprocessor complex	complex	SIGNOR-C356	SIGNOR	up-regulates activity	binding			9606									26045258	t		miannu	In addition, nuclear YAP has also been found to regulate miRNA processing. Nuclear YAP/TAZ bind and sequester DEAD box helicase 17 (DDX17) (also known as p72) to repress its association with Microprocessor, a complex that regulates miRNA processing (Figure 3B). 	SIGNOR-277660	0.571
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1944	GSTYSPTsPGYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269352	0.718
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CEP76	protein	Q8TAP6	UNIPROT	down-regulates activity	phosphorylation	Ser83	VEQELPSsPKQPICF	9606	BTO:0001938								27065328	t		miannu	Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification. we conclude that Cep76 inhibits centriole disengagement and consequently amplification by blocking Plk1 activation at the centrosome.	SIGNOR-262730	0.305
TEAD1	protein	P28347	UNIPROT	BMP4	protein	P12644	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23673366	f		gcesareni	Taz induces bmp4 transcription through the tead family of transcription factors, which mediate bmp4 promoter activation through binding to tead response element 1 (tre1).	SIGNOR-202049	0.261
GNA13	protein	Q14344	UNIPROT	ARHGEF1	protein	Q92888	UNIPROT	up-regulates	gtpase-activating protein			9606									9641915	t		gcesareni	The guanine nucleotide exchange factor (gef) for rho, p115 rhogef, has an amino-terminal region with similarity to rgs proteins. Recombinant p115 rhogef and a fusion protein containing the amino terminus of p115 had specific activity as gtpase activating proteins toward the alpha subunits of the g proteins g12 and g13, but not toward members of the gs, gi, or gq subfamilies of galpha proteins. This gef may act as an intermediary in the regulation of rho proteins by g13 and g12.	SIGNOR-58413	0.591
IKBKB	protein	O14920	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	up-regulates activity	phosphorylation	Ser441	GHSPLSLsAQSVMEE	9606									24614225	t		lperfetto	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204736	0.529
MAPK9	protein	P45984	UNIPROT	BCL2L11	protein	O43521	UNIPROT	up-regulates activity	phosphorylation	Ser59	GDSCPHGsPQGPLAP										12818176	t		miannu	JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity. 	SIGNOR-250134	0.622
HRAS	protein	P01112	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation	Ser63	KNSDLLTsPDVGLLK	10090	BTO:0000944								12169099	t		lperfetto	c-Jun was first shown to be phosphorylated in its transactivation domain (Ser-63 and Ser-73) by ERKs and p54-JNK. This is consistent with other studies which show that PD98059 inhibits up-regulation of c-Jun protein in Ras-transformed NIH-3T3 cells	SIGNOR-235522	0.516
DYRK1A	protein	Q13627	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates	phosphorylation	Ser285	NHTLAPAsPAPARPR	9606		BTO:0000142							15262992	t		lperfetto	Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd	SIGNOR-126851	0.405
SRC	protein	P12931	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	phosphorylation	Tyr350	EPPDHQYyNDFPGKE	9606									8939605	t		lperfetto	Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway.	SIGNOR-44870	0.651
MC4R	protein	P32245	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257182	0.252
SGK1	protein	O00141	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation	Thr24	LPRPRSCtWPLPRPE	10090									19965929	t			We demonstrate that SGK1 affects differentiation by direct phosphorylation of Foxo1, thereby changing its cellular localization from the nucleus to the cytosol. In addition we show that SGK1-/- cells are unable to relocalize Foxo1 to the cytosol in response to dexamethasone.	SIGNOR-255925	0.603
PAICS	protein	P22234	UNIPROT	SAICAR(4-)	smallmolecule	CHEBI:58443	ChEBI	up-regulates quantity	chemical modification			9606									33179964	t		miannu	The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS).	SIGNOR-267322	0.8
Raf265 derivative	chemical	CID:23654923	PUBCHEM	RAF1	protein	P04049	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206394	0.8
ATM	protein	Q13315	UNIPROT	KIFC1	protein	Q9BW19	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser26	RPLIKAPsQLPLSGS	9606	BTO:0000815								33397932	t		miannu	 ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro.	SIGNOR-277295	0.2
MET	protein	P08581	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr407	IIDEEDTyTMPSTRD	9606									16782899	t		llicata	Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain	SIGNOR-147187	0.475
SFRP1	protein	Q8N474	UNIPROT	WNT1	protein	P04628	UNIPROT	down-regulates	binding			9606	BTO:0000782								10347172	t		gcesareni	Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling.	SIGNOR-67806	0.776
RAB5A	protein	P20339	UNIPROT	PIK3R4	protein	Q99570	UNIPROT	up-regulates activity	binding			10090									27411398	t		lperfetto	Vps34 PI 3-kinase activity18 is stimulated by complex formation with the protein kinase Vps15|Rab5GTP binds Vps15, enhancing Vps34 activity	SIGNOR-260708	0.434
imatinib	chemical	CHEBI:45783	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258120	0.8
MMUT	protein	P22033	UNIPROT	succinyl-CoA(5-)	smallmolecule	CHEBI:57292	ChEBI	up-regulates quantity	chemical modification			9606									1978672	t		miannu	Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA). 	SIGNOR-269109	0.8
GTF2H1	protein	P32780	UNIPROT	E2F1	protein	Q01094	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser403	PEEFISLsPPHEALD	-1									10428966	t			TFIIH-mediated phosphorylation of E2F-1 plays a role in triggering E2F-1 degradation during S phase. E2F-1 activation domain interacts with a kinase activity which phosphorylates two sites, Ser403 and Thr433, within the activation domain. We demonstrate that TFIIH is responsible for the E2F-1 phosphorylation observed in cell extracts and that endogenous E2F-1 interacts in vivo with p62, a component of TFIIH, during S phase. 	SIGNOR-251259	0.445
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	PLEC	protein	Q15149	UNIPROT	down-regulates	phosphorylation	Thr4539	GGLIEPDtPGRVPLD	9606	BTO:0000567								19709076	t		lperfetto	Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane.	SIGNOR-216904	0.396
MAPK3	protein	P27361	UNIPROT	RCAN1	protein	P53805	UNIPROT	up-regulates activity	phosphorylation	Ser167	FLISPPAsPPVGWKQ	10090	BTO:0000165								12063245	t		lperfetto	Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. 	SIGNOR-249478	0.388
PPM1A	protein	P35813	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	dephosphorylation	Ser199	PRPEHTKsVYTRSVI	10116									18586681	t			Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop.	SIGNOR-248492	0.342
TLK1	protein	Q9UKI8	UNIPROT	MAPKAPK5	protein	Q8IW41	UNIPROT	up-regulates activity	phosphorylation	Ser160	NLLFKDNsLDAPVKL	9606	BTO:0000007								35064619	t		miannu	We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells.	SIGNOR-276745	0.2
Normorphine	chemical	CHEBI:7633	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258822	0.8
MAPK3	protein	P27361	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation	Ser9	SGRPRTTsFAESCKP	10090	BTO:0002572								28646232	t		Gianni	We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels	SIGNOR-262523	0.299
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	SNW1	protein	Q13573	UNIPROT	up-regulates	binding			9606									10713164	t		gcesareni	Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta.	SIGNOR-254337	0.2
BRCA1-BARD1 complex	complex	SIGNOR-C297	SIGNOR	H2AX	protein	P16104	UNIPROT	up-regulates activity	ubiquitination			-1									12485996	t		lperfetto	Strikingly, as well as H2AX, the nucleosome core histones H2A, H2B, H3 and H4 were all ubiquitylated efficiently by BRCA1/BARD1, while the linker histone H1 was not (Figure 3).| Generally, histone proteins are required for compaction of nuclear DNA into chromatin, and their modification is thought to loosen this compaction. Therefore, one might envisage that ubiquitylation of γH2AX by BRCA1/BARD1 at DNA breaks modulates local chromatin packaging to facilitate the action of DNA repair enzymes. 	SIGNOR-263235	0.2
CSNK1A1	protein	P48729	UNIPROT	LGALS3	protein	P17931	UNIPROT	unknown	phosphorylation	Ser12	FSLHDALsGSGNPNP	-1									8253806	t		llicata	L-29, a soluble lactose-binding lectin, is phosphorylated on serine 6 and serine 12 in vivo and by casein kinase I.	SIGNOR-250789	0.312
PRKACA	protein	P17612	UNIPROT	NOLC1	protein	Q14978	UNIPROT	up-regulates activity	phosphorylation	Ser623	KGEKRASsPFRRVRE	-1									12167624	t		miannu	PKA-dependent Nopp140 phosphorylation is important for its role in agp gene activation. both Ser627 and Ser628 are phosphorylated by PKA.	SIGNOR-250020	0.311
NEK9	protein	Q8TD19	UNIPROT	NEK6	protein	Q9HC98	UNIPROT	up-regulates activity	phosphorylation	Ser206	SETTAAHsLVGTPYY	9606	BTO:0000007								12840024	t		lperfetto	Nercc1/nek9 activates the nek6 and nek7 kinases. Nercc1 catalyzes the direct phosphorylation of prokaryotic recombinant nek6 at ser206 in vitro concomitant with 20-25-fold activation of nek6 activity.	SIGNOR-102996	0.675
RAD23B	protein	P54727	UNIPROT	ERCC1	protein	P07992	UNIPROT	up-regulates activity	binding												24086043	t		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275703	0.638
NKX2-5	protein	P52952	UNIPROT	GATA4	protein	P43694	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19479054	f	 	 	Using antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5.	SIGNOR-253654	0.844
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation	Ser119	EILSRRPsYRKILND	9606									9829964	t			The nuclear factor CREB stimulates the expression of cellular genes following its protein kinase A-mediated phosphorylation at Ser-133. Ser-133 phosphorylation, in turn, activates target gene expression by promoting recruitment of the co-activator CBP. |When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP.	SIGNOR-251474	0.2
SRC	protein	P12931	UNIPROT	PPP2CA	protein	P67775	UNIPROT	down-regulates	phosphorylation	Tyr307	VTRRTPDyFL	9606	BTO:0000938								23796501	t		llicata	We found that ?-Syn gene overexpression in sk-n-sh cells and primary neurons led to pp2a/c phosphorylation at y307, a known target of src kinase, and consequent phosphatase inhibition.	SIGNOR-202192	0.442
SOD3	protein	P08294	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	down-regulates quantity	chemical modification			9606									29301787	t		lperfetto	Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD).	SIGNOR-272271	0.8
CCKBR	protein	P32239	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257037	0.277
RPGRIP1L	protein	Q68CZ1	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates	demethylation			9606									20080798	t		lperfetto	Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation.	SIGNOR-217412	0.2
AURKB	protein	Q96GD4	UNIPROT	BIRC5	protein	O15392	UNIPROT	down-regulates	phosphorylation	Thr117	KNKIAKEtNNKKKEF	9606									17457057	t		lperfetto	Phosphorylation by aurora-b negatively regulates survivin function . hat survivin is phosphorylated at t117 during mitosis, and once phosphorylated, dephosphorylation is crucial for chromosome congression and progression into anaphaseduring mitosis	SIGNOR-154569	0.786
midostaurin	chemical	CHEBI:63452	ChEBI	FGR	protein	P09769	UNIPROT	down-regulates activity	chemical inhibition			-1									30069632	t		Gianni	Midostaurin (PKC412, Rydapt®) is an oral multiple tyrosine kinase inhibitor. Main targets are the kinase domain receptor, vascular endothelial-, platelet derived-, and fibroblast growth factor receptor, stem cell factor receptor c-KIT, as well as mutated and wild-type FLT3 kinase	SIGNOR-261976	0.8
MAPK3	protein	P27361	UNIPROT	HSPB8	protein	Q9UJY1	UNIPROT	up-regulates activity	phosphorylation	Ser27	PFRDSPLsSRLLDDG	9606		BTO:0000887							11342557	t		lperfetto	Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation	SIGNOR-107676	0.346
RUNX1	protein	Q01196	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									29958106	t		miannu	RUNX1 represses MYC expression through direct binding at three downstream enhancer elements	SIGNOR-260093	0.344
FLT3	protein	P36888	UNIPROT	FLT3	protein	P36888	UNIPROT	up-regulates	phosphorylation	Tyr589	TGSSDNEyFYVDFRE	9606	BTO:0001271								11971190	t		lperfetto	Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation	SIGNOR-117571	0.2
CSK	protein	P41240	UNIPROT	PTPRC	protein	P08575	UNIPROT	up-regulates	phosphorylation	Tyr1218	MVSTFEQyQFLYDVI	9606	BTO:0000782								7507203	t		llicata	Tyrosine phosphorylation of cd45 phosphotyrosine phosphatase by p50csk kinase creates a binding site for p56lck tyrosine kinase and activates the phosphatase.	SIGNOR-26785	0.482
TLK1	protein	Q9UKI8	UNIPROT	MAPKAPK5	protein	Q8IW41	UNIPROT	up-regulates activity	phosphorylation	Ser386	HENGAEDsNVALEKL	9606	BTO:0000007								35064619	t		miannu	We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells.	SIGNOR-276747	0.2
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr165	PSPATDLyQVPPGPG	10090									12972425	t		lperfetto	Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs	SIGNOR-246385	0.797
PTPN12	protein	Q05209	UNIPROT	ARHGDIA	protein	P52565	UNIPROT	up-regulates activity	dephosphorylation			9606									25666508	t		miannu	Integrin-bound PTP-PEST dephosphorylates RhoGDI1.|Translocation of Src phosphorylated RhoGDI1 to the cell 's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1 and Cdc42 in the cytoplasm.|Translocation of Src-phosphorylated RhoGDI1 to the cell's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin-bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1/Cdc42 in the cytoplasm.	SIGNOR-277175	0.2
ABL1	protein	P00519	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation	Tyr170	LHSEPPVyANLSNFN	-1									10637231	t			Active nuclear Abl efficiently phosphorylate c-Jun. After phosphorylation of c-Jun by Abl on Tyr170, both proteins interacted via the SH2 domain of Abl.	SIGNOR-251428	0.542
GLI2	protein	P10070	UNIPROT	Myelination	phenotype	SIGNOR-PH206	SIGNOR	up-regulates													NBK6142	f	Whilst shh signalling is required for ventral oligodendrogenesis in the entire central nervous system, Gli2 activity only regulates oligodendrocyte development in the ventral spinal cord. Gli3 plays a nonessential role in ventral oligodendrogenesis during normal development. 	SimoneGraziosi		SIGNOR-269215	0.7
LPCAT4	protein	Q643R3	UNIPROT	1,2-diacyl-sn-glycero-3-phosphocholine	chemical	CHEBI:57643	ChEBI	up-regulates quantity	chemical modification			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272770	0.8
PRKCA	protein	P17252	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser464	LLKHVTQsSRKLIRA	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-129260	0.392
5-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylidene]thiazolidine-2,4-dione	chemical	CHEBI:94690	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189912	0.8
LCK	protein	P06239	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates	phosphorylation	Tyr564	SKHKEDVyENLHTKN	9606	BTO:0000782								8114715	t		llicata	The two sites (y-536 and y-564) which are directly phosphorylated by lck in vitro are also phosphorylated in vivo in lstra cells. One of these sites (y-564) is phosphorylated in t cells in response to lck activation.	SIGNOR-36121	0.596
NFIA	protein	Q12857	UNIPROT	MYOG	protein	P15173	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									32991581	t	brain	lperfetto	NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,	SIGNOR-263983	0.2
LCK	protein	P06239	UNIPROT	CD33	protein	P20138	UNIPROT	up-regulates	phosphorylation	Tyr340	EMDEELHyASLNFHG	9606									10887109	t		lperfetto	Human cd33 has two tyrosine residues in its cytoplasmic domain (y340 and y358). When phosphorylated, these tyrosines could function as docking sites for the phosphatases, shp-1 and/or shp-2, enabling cd33 to function as an inhibitory receptor. Lck is effective at phosphorylating y340	SIGNOR-78960	0.275
RNMT	protein	O43148	UNIPROT	mRNA_capping	phenotype	SIGNOR-PH178	SIGNOR	up-regulates				9606	BTO:0000567								26942677	f		lperfetto	The creation of translation-competent mRNA is dependent on RNA polymerase II transcripts being modified by addition of the 7-methylguanosine (m7G) cap. The factors that mediate splicing, nuclear export, and translation initiation are recruited to the transcript via the cap. The cap structure is formed by several activities and completed by RNMT (RNA guanine-7 methyltransferase), which catalyzes N7 methylation of the cap guanosine. 	SIGNOR-265503	0.7
CSNK2A2	protein	P19784	UNIPROT	PPP1R1B	protein	Q9UD71	UNIPROT	up-regulates activity	phosphorylation	Ser102	NLNENQAsEEEDELG	-1									2557337	t		llicata	Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase	SIGNOR-251018	0.383
PRKACA	protein	P17612	UNIPROT	DNAJC5	protein	Q9H3Z4	UNIPROT	unknown	phosphorylation	Ser10	DQRQRSLsTSGESLY	9606	BTO:0000938								18951872	t		gcesareni	Csp is phosphorylated in vivo on a single residue, ser10, and this phosphorylation regulates its cellular functions,[...]PKA Phosphorylation of full-length csp protein stimulated 14-3-3 binding, and this was abolished in a ser10-ala mutant csp, confirming the binding site as phospho-ser10	SIGNOR-181788	0.33
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1665	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273066	0.636
8-OH-DPAT	chemical	CHEBI:73364	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258847	0.8
DSCAML1	protein	Q8TD84	UNIPROT	AQP9	protein	O43315	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								30745319	t		miannu	Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels.	SIGNOR-264280	0.2
MMP2	protein	P08253	UNIPROT	Laminin-5	complex	SIGNOR-C184	SIGNOR	up-regulates activity	cleavage												9211848	t		lperfetto	Induction of Cell Migration by Matrix Metalloprotease-2 Cleavage of Laminin-5|MMP2 cleaved the Ln-5 gamma2 subunit at residue 587, exposing a putative cryptic promigratory site on Ln-5 that triggers cell motility. This altered form of Ln-5 is found in tumors and in tissues undergoing remodeling, but not in quiescent tissues. Cleavage of Ln-5 by MMP2 and the resulting activation of the Ln-5 cryptic site may provide new targets for modulation of tumor cell invasion and tissue remodeling.	SIGNOR-253239	0.438
MAPK3	protein	P27361	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates	phosphorylation	Thr292	YTAMDVAtGQEVAIK	9606									14993270	t		gcesareni	Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation.	SIGNOR-123074	0.344
NCOR2	protein	Q9Y618	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22395773	t		FFerrentino	In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription.	SIGNOR-253508	0.735
PER1	protein	O15534	UNIPROT	BMAL1/NPAS2	complex	SIGNOR-C431	SIGNOR	down-regulates activity	binding			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop.	SIGNOR-267974	0.704
PPP2CA	protein	P67775	UNIPROT	STK4	protein	Q13043	UNIPROT	down-regulates	dephosphorylation	Thr183	DTMAKRNtVIGTPFW	9606									23431053	t		gcesareni	Rassf1a apparently protects mst1/2 against inactivation by pp2a , the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively.	SIGNOR-201270	0.376
PPP4C	protein	P60510	UNIPROT	ACACA	protein	Q13085	UNIPROT	up-regulates activity	dephosphorylation	Ser80	LHIRSSMsGLHLVKQ	9606	BTO:0000599								25050742	t			PP4 was also found to directly interact with pACC1‑Ser79 in human HepG2 cells. In conclusion, the present study showed that PP4 may be a novel regulator in hepatic lipogenesis through dephosphorylating ACC1 on serine 79, suggesting that PP4 may be a promising therapeutic target in lipid metabolism disorders.	SIGNOR-267724	0.243
CSNK2B	protein	P67870	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates activity	phosphorylation	Ser1112	VPIAVGEsDFENLNT	9606	BTO:0000938								19064667	t		lperfetto	 We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275752	0.2
pictrelisib	chemical	CHEBI:65326	ChEBI	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0000149							21876152	t		gcesareni	Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed	SIGNOR-176295	0.8
A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by expression				10090									18757303	f		lperfetto	Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1.	SIGNOR-253278	0.398
PLCD4	protein	Q9BRC7	UNIPROT	1D-myo-inositol 1,4,5-trisphosphate	smallmolecule	CHEBI:16595	ChEBI	up-regulates	chemical modification			9606									8395015	t		gcesareni	Hydrolysis of phosphatidylinositol 4,5-bisphosphate (pip2) by phosphatidylinositol-specific phospholipase c (pi-plc) generates two second messengers, inositol 1,4,5-trisphosphate and 1,2-diacylglycerol.	SIGNOR-39041	0.8
PRKCA	protein	P17252	UNIPROT	PLEK	protein	P08567	UNIPROT	up-regulates	phosphorylation	Ser113	GQKFARKsTRRSIRL	9606									7559487	t		miannu	Pleckstrin is a substrate for protein kinase c / a combination of phosphopeptide analysis and site-directed mutagenesis shows that three residues in the intervening sequence between the two pleckstrin ph domains become phosphorylated: ser113, thr114, and ser117. /these results suggest that the phosphorylation of at least two of the sites is required for maximal pleckstrin activity	SIGNOR-28880	0.284
CD3G	protein	P09693	UNIPROT	RPS6KA4	protein	O75676	UNIPROT	up-regulates				9606	BTO:0000782								17668895	f		gcesareni	Tcr stimulation also activates the mitogen- and stress-activated kinases (msk) downstream of erk1/2.	SIGNOR-157148	0.2
CCT128930	chemical	CID:17751819	PUBCHEM	AKT2	protein	P31751	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck;ATP-competitive inhibitor of Akt2	gcesareni		SIGNOR-190868	0.8
PRKAA2	protein	P54646	UNIPROT	PDHA1	protein	P08559	UNIPROT	up-regulates activity	phosphorylation	Ser314	IQEVRSKsDPIMLLK	-1									33022274	t		miannu	AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex	SIGNOR-276838	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ITGB3	protein	P05106	UNIPROT	down-regulates activity	phosphorylation	Thr779	LYKEATStFTNITYR	-1									10896934	t			Threonine phosphorylation of the beta 3 integrin cytoplasmic tail, at a site recognized by PDK1 and Akt/PKB in vitro, regulates Shc binding.|We recently observed that phosphorylation of a threonine (Thr-753), six amino acids proximal to tyrosine 759 in beta(3) of the platelet specific integrin alpha(IIb)beta(3), inhibits outside-in signaling through this receptor.| A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. 	SIGNOR-251479	0.2
FZD1	protein	Q9UP38	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates activity	binding			9606									23151663	t		areggio	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. 	SIGNOR-258952	0.665
CDK8	protein	P49336	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Thr119	AGTAGALtPQHVRAH	-1									29967145	t		miannu	CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro.	SIGNOR-277648	0.327
ATF4	protein	P18848	UNIPROT	DYRK3	protein	O43781	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000578								31066068	t		miannu	Interestingly, the promoter activity of Dyrk3 was negatively regulated by ATF4, indicating a double-negative feedback loop.	SIGNOR-275453	0.2
NMBR	protein	P28336	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257047	0.271
NR0B2	protein	Q15466	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	down-regulates quantity by repression	transcriptional regulation			9606									11368516	f	inferred from family member	gcesareni	Shp (short heterodimer partner) is an orphan nuclear receptor lacking a dna binding domain that interacts with nuclear receptors (nr) including thyroid receptor (tr), retinoic acid receptors (rar and rxr), and estrogen receptors alpha and beta (eralpha and erbeta). Shp acts as a negative regulator of these receptors by inhibiting dna binding and transcriptional activation.	SIGNOR-270298	0.378
PRKCA	protein	P17252	UNIPROT	GMFB	protein	P60983	UNIPROT	unknown	phosphorylation	Thr27	KFRFRKEtNNAAIIM	-1									9030586	t		lperfetto	Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively.	SIGNOR-248961	0.327
regorafenib	chemical	CHEBI:68647	ChEBI	RTKs	proteinfamily	SIGNOR-PF38	SIGNOR	down-regulates activity	chemical inhibition			9606									26254357	t		miannu	A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF	SIGNOR-259452	0.8
Unfolded_Proteins	stimulus	SIGNOR-ST22	SIGNOR	CREB3L2	protein	Q70SY1	UNIPROT	up-regulates				9606									17178827	f		miannu	Although bbf2h7 protein is not expressed under normal conditions, it is markedly induced at the translational level during er stress, suggesting that bbf2h7 might contribute to only the late phase of unfolded protein response signaling.	SIGNOR-151312	0.7
MAPK1	protein	P28482	UNIPROT	CEP55	protein	Q53EZ4	UNIPROT	down-regulates	phosphorylation	Ser425	NREKVAAsPKSPTAA	9606									16198290	t		lperfetto	Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis.	SIGNOR-140890	0.374
zotepine	chemical	CHEBI:32316	ChEBI	HTR1B	protein	P28222	UNIPROT	down-regulates activity	chemical inhibition			10116		BTO:0001311							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258554	0.8
RB1CC1	protein	Q8TDY2	UNIPROT	ULK1/Atg13/Fip200	complex	SIGNOR-C100	SIGNOR	form complex	binding			9606									23863160	t		lperfetto	In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation.	SIGNOR-209887	0.914
CDON/SPAG9	complex	SIGNOR-C21	SIGNOR	MAP3K5	protein	Q99683	UNIPROT	unknown	binding			10090	BTO:0000165;BTO:0000222;BTO:0002181								22337877	t		lperfetto	Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts	SIGNOR-235557	0.363
CACNA2D3	protein	Q8IZS8	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									27583705	t		miannu	Our findings showed that increased intracellular calcium (Ca2+ ) mediated by overexpression of CACNA2D3 induced mitochondrial-mediated apoptosis, upregulation of NLK (through the Wnt/Ca2+ pathway) and inhibition of the epithelial-to-mesenchymal transition. 	SIGNOR-266853	0.8
ARF6	protein	P62330	UNIPROT	Endocytosis	phenotype	SIGNOR-PH123	SIGNOR	up-regulates													14973189	f		lperfetto	ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface	SIGNOR-272154	0.7
ATP6V1H	protein	Q9UI12	UNIPROT	AP-2 complex	complex	SIGNOR-C245	SIGNOR	up-regulates activity	binding			10090	BTO:0004122								29782852	t		miannu	ATP6V1H interacts with TGF-β receptor I and AP-2 complex to regulate the proliferation and differentiation of BMSCs. Lack of ATP6V1H function decreases bone formation in vivo	SIGNOR-266887	0.228
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	TICRR	protein	Q7Z2Z1	UNIPROT	up-regulates activity	phosphorylation	Ser1001	DIGVVEEsPEKGDEI	-1									21646402	t		miannu	 We found that Treslin also associated with TopBP1 in a Cdk-regulated manner in human cells and that Treslin was phosphorylated within a conserved Cdk consensus target sequence (on S976 in X. laevis and S1000 in humans). Recombinant human Cdk2-cyclin E also phosphorylated this residue of Treslin in vitro very effectively.	SIGNOR-273600	0.34
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257983	0.8
CGRRF1	protein	Q99675	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002548								31801577	t		miannu	CGRRF1 ubiquitinates EGFR through K48-linked ubiquitination, which leads to proteasome degradation.	SIGNOR-272220	0.2
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CDK1	protein	P06493	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189981	0.8
ZFYVE26	protein	Q68DK2	UNIPROT	TTC19	protein	Q6DKK2	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								20208530	t		miannu	We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B. FYVE-CENT binds directly to TTC19 and KIF13A.	SIGNOR-265542	0.477
INSR	protein	P06213	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	phosphorylation	Tyr368	STKMHGDyTLTLRKG	9534	BTO:0000298								8385099	t			The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor.	SIGNOR-251320	0.656
ROCK1	protein	Q13464	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates	phosphorylation	Ser20	KRPQRATsNVFAMFD	9606		BTO:0000887;BTO:0001260							8702756	t		gcesareni	Rho-kinase phosphorylates the mlc of intact myosin and activates its mgatpase activity in a gtp_?Rho-dependent manner.	SIGNOR-43031	0.633
GSK3B	protein	P49841	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	phosphorylation	Thr254	RQVAIVFRtPPYADPS	10090	BTO:0000249								22761446	t			Redundant functions of GSK-3_ and GSK-3_ through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation	SIGNOR-255828	0.364
PPP1CC	protein	P36873	UNIPROT	EIF2S1	protein	P05198	UNIPROT	up-regulates activity	dephosphorylation			9606									27629041	t		miannu	Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival	SIGNOR-254119	0.422
MAPK1	protein	P28482	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser732	RRVRKLPsTTL	9534									9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-219320	0.748
(1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid	chemical	CHEBI:94640	ChEBI	MGluR	proteinfamily	SIGNOR-PF55	SIGNOR	up-regulates	chemical activation			9606									Other	t	Selleck|inferred from family member	gcesareni		SIGNOR-270281	0.8
PRKCB	protein	P05771	UNIPROT	TRPV6	protein	Q9H1D0	UNIPROT	down-regulates activity	phosphorylation	Thr728	MPSVSRStSRSSANW	-1									19805577	t		miannu	 This regulation requires PKC(betaII) and defined phosphorylation sites within the ARD and the C-terminus. Both regulatory sites act synergistically to constitute a novel mechanism by which ATP stabilizes channel activity and acts as a metabolic switch for Ca(2+) influx. Decreases in ATP concentration or activation of PKC(betaII) disable regulation of the channels by ATP, rendering them more susceptible to inactivation and rundown and preventing Ca(2+) overload.	SIGNOR-276266	0.2
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	TP53	protein	P04637	UNIPROT	unknown	phosphorylation	Ser392	FKTEGPDsD	-1									10884347	t		llicata	Our previous data has shown that cyclin A-cdk2 is the major enzyme responsible for modifying p53 at Ser315 in vivo after irradiation damage and in this report we dissect the mechanism of cyclinA-cdk2 binding to and phosphorylation of p53.	SIGNOR-250751	0.803
ARF3	protein	P61204	UNIPROT	Vesicle_transport	phenotype	SIGNOR-PH172	SIGNOR	up-regulates													14973189	f		lperfetto	ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface	SIGNOR-272150	0.7
MMP7	protein	P09237	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272397	0.7
GREB1	protein	Q4ZG55	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									30154312	f		miannu	GREB1 is an early estrogen-responsive gene, and its expression is correlated with estrogen levels in breast cancer patients. Additionally, GREB1 responds to androgen in prostate cancer cells, and can stimulate the proliferation of breast, ovarian, and prostate cancer cells.	SIGNOR-265886	0.7
PRKD1	protein	Q15139	UNIPROT	ARFIP1	protein	P53367	UNIPROT	up-regulates	phosphorylation	Ser132	LELVRKWsLNTYKCT	9606									23695357	t		lperfetto	We report that arfaptins contain an amphipathic helix (ah) preceding the bar domain, which is essential for their binding to phosphatidylinositol 4-phosphate (pi(4)p)-containing liposomes and the tgn of mammalian cells. The binding of arfaptin1, but not arfaptin2, to pi(4)p is regulated by protein kinase d (pkd) mediated phosphorylation at ser100 within the ah. We also found that only arfaptin1 is required for the pkd-dependent trafficking of chromogranin a by the regulated secretory pathway.	SIGNOR-202101	0.396
PAX7-FOXO1	fusion protein	SIGNOR-FP11	SIGNOR	MET	protein	P08581	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25211658	t		miannu	Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA.	SIGNOR-251566	0.2
PTPRD	protein	P23468	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606	BTO:0000007								19478061	t			Transfection of wild-type PTPRD resulted in the specific dephosphorylation of STAT3 at tyrosine 705, a residue that must be phosphorylated for STAT3 to be active	SIGNOR-248442	0.533
POLR2E	protein	P19388	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266138	0.885
motesanib	chemical	CHEBI:51098	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194566	0.8
CSNK2A2	protein	P19784	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr102	RAAMFPEtLDEGMQI	-1									12432063	t		miannu	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin. 	SIGNOR-275993	0.453
CDK2	protein	P24941	UNIPROT	CDK7	protein	P50613	UNIPROT	up-regulates	phosphorylation	Thr170	GSPNRAYtHQVVTRW	9606									11113184	t		amattioni	Threonine-170 of cdk7 is phosphorylated in vitro by cdk2. Full activation of cdk7 requires phorylation of a conserved threonine residue at position 170 in its own t loop.	SIGNOR-85013	0.551
sirolimus	chemical	CHEBI:9168	ChEBI	LILRB1	protein	Q8NHL6	UNIPROT	down-regulates quantity by repression				9606									18652845	f		miannu	Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells.	SIGNOR-255476	0.8
CHRM5	protein	P08912	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257009	0.2
CDK1	protein	P06493	UNIPROT	HMGA2	protein	P52926	UNIPROT	down-regulates	phosphorylation	Ser59	PKGSKNKsPSKAAQK	9606									10636877	t		lperfetto	Architecture of high mobility group protein i-c dna complex and its perturbation upon phosphorylation by cdc2 kinase. Phosphorylation by cdc2 reduces binding strength of the mammalian and insect hmgi proteins to dna. After phosphorylation of the protein at ser-43 and ser-58 by cdc2 kinase multiple contacts of dbds, especially with the bases, are impaired and the protein binds to dna in a different way, extending the contacts to the sugar-phosphate backbone.	SIGNOR-74098	0.382
ABL1	protein	P00519	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr290	RQSVLVPyEPPQVGT	9606									19783996	t		Manara	In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. 	SIGNOR-260933	0.524
sorafenib tosylate	chemical	CHEBI:50928	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates activity	chemical inhibition			-1									16757355	t		miannu	Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 	SIGNOR-259224	0.8
IL1A	protein	P01583	UNIPROT	IL1R1	protein	P14778	UNIPROT	up-regulates activity	binding			9606	BTO:0000876								7964161	t		lperfetto	Interleukin-1 receptor (il-1r) is a cytokine receptor which binds interleukin 1.	SIGNOR-35077	0.759
SPAG5	protein	Q96R06	UNIPROT	CENPF	protein	P49454	UNIPROT	up-regulates activity				9606	BTO:0000567								17664331	f		lperfetto	Furthermore, although both the core kinetochore protein Hec1 and the spindle checkpoint kinase Bub1 were unaffected (Fig. 3 C), the kinetochore resident motor protein CENP-E (Yen et al., 1992) and its interaction partner CENP-F (Chan et al., 1998) were delocalized from the kinetochore in the absence of astrin. These cells remained cyclin B1 positive (unpublished data), confirming that they were still in mitosis. These data suggest that the presence of astrin is required for the kinetochore recruitment or maintenance of CENP-E and CENP-F.	SIGNOR-252042	0.345
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	down-regulates				9606	BTO:0001412								8394219	f			We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death. 	SIGNOR-255723	0.7
MEN1	protein	O00255	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15640349	f		irozzo	Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions.	SIGNOR-255889	0.415
GSK3B	protein	P49841	UNIPROT	MACF1	protein	Q9UPN3	UNIPROT	down-regulates activity	phosphorylation	Ser7310	ADPKKSAsRPGSRAG	9606	BTO:0004905								21295697	t		lperfetto	We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules.	SIGNOR-264430	0.446
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	TP53	protein	P04637	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189999	0.8
PPP4C	protein	P60510	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	up-regulates activity	dephosphorylation	Ser1618	LTKAADIsLDNLVEG	-1									24703952	t		lperfetto	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Depletion of PP4C, or PP4R3beta, causes persistence of phospho-T1609 and phospho-S1618	SIGNOR-264451	0.365
PPP1CA	protein	P62136	UNIPROT	CAD	protein	P27708	UNIPROT	down-regulates activity	dephosphorylation	Ser1406	CSGAGGRrLSSFVTK	-1									4092695	t		lperfetto	Cyclic AMP-dependent protein kinase phosphorylates two serine residues on the protein termed sites 1 and 2| Site 1: Arg-Leu-Ser(P)-Ser-Phe-Val-Thr-Lys Site 2: Ile-His-Arg-Ala-Ser(P)-Asp-Pro-Gly-Leu-Pro-Ala-Glu-Glu-Pro-Lys | Both phosphorylation and activation can be reversed using purified preparations of the catalytic subunits of protein phosphatases 1- and -2A, and inactivation also correlates better with dephosphorylation of site 1 rather than site 2.	SIGNOR-263741	0.337
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1668	SPSYSPTsPSYSPTS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248772	0.441
PRKCA	protein	P17252	UNIPROT	PLCB1	protein	Q9NQ66	UNIPROT	unknown	phosphorylation	Ser887	HSQPAPGsVKAPAKT	10090	BTO:0005065								11278470	t		lperfetto	. Two-dimensional phosphopeptide mapping and site-directed mutagenesis demonstrated that PKC promoted phosphorylation of PLC beta1 at serine 887 in the nucleus of IGF-I-treated cells. Overexpression of either a PLC beta1 mutant in which the PKC phosphorylation site Ser(887) was replaced by alanine, or a dominant-negative PKC alpha, resulted in a sustained activation of nuclear PLC following IGF-I stimulation.	SIGNOR-249081	0.703
MAPK3	protein	P27361	UNIPROT	LIFR	protein	P42702	UNIPROT	down-regulates	phosphorylation	Ser1044	WNLVSPDsPRSIDSN	9606									7777512	t		gcesareni	Thus, our results identify the human lifr as a substrate for mapk and suggest a mechanism of heterologous receptor regulation of lifr signaling occurring at ser-1044.	SIGNOR-32757	0.304
SOX4	protein	Q06945	UNIPROT	DICER1	protein	Q9UPY3	UNIPROT	up-regulates quantity	transcriptional regulation			9606	BTO:0000848								22689055	t			.... showed that Sox4 positively regulates Dicer expression by binding to its promoter sequences and enhancing its activity. We found that knockdown of Dicer enhances the matrigel invasion of melanoma cells by at least twofold. In addition, we revealed that overexpression of exogenous Dicer reverts the enhanced melanoma cell invasion upon Sox4 knockdown	SIGNOR-258987	0.406
HMGA2	protein	P52926	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									25300915	f		miannu	This study unraveled a novel function ofhmga2in induction of apoptosis in human primary cell lines	SIGNOR-205465	0.7
dopamine	smallmolecule	CHEBI:18243	ChEBI	3,4-dihydroxyphenylacetaldehyde	smallmolecule	CHEBI:27978	ChEBI	up-regulates quantity	precursor of			9606									NBK536726	t	brain	lperfetto	Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO.	SIGNOR-264181	0.8
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CSNK1D	protein	P48730	UNIPROT	up-regulates	binding			9606									12000790	t		lperfetto	Complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45).	SIGNOR-227908	0.519
EPRS1	protein	P07814	UNIPROT	Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	form complex	binding			9606									32644155	t		miannu	In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes).	SIGNOR-270356	0.2
EED	protein	O75530	UNIPROT	Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	form complex	binding			9606									23110252	t		lperfetto	The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48).	SIGNOR-241897	0.9
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser276	PQRSRSPsPQPSSHV	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248521	0.386
RPS6KA4	protein	O75676	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser362	AAAHRKGsSSNEPSS	9606									22187936	t		gcesareni	Rsk1/2 stabilize c-fos and increases its activity.	SIGNOR-191678	0.401
YY1	protein	P25490	UNIPROT	FCER1A	protein	P12319	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000732								11971001	f	 	 	Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells	SIGNOR-254290	0.2
HSP90AA1	protein	P07900	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates activity	binding			9606									15861399	t		miannu	The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes.	SIGNOR-251536	0.754
MMP14	protein	P50281	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates				10090									28709001	f			MMP14 Promotes Adipogenesis Downstream of or in Parallel to TIMP3	SIGNOR-255909	0.7
DDIT3	protein	P35638	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates quantity	transcriptional regulation			10090									7588595	t			We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process.	SIGNOR-255913	0.533
SYK	protein	P43405	UNIPROT	BTK	protein	Q06187	UNIPROT	up-regulates activity	phosphorylation	Tyr551	RYVLDDEyTSSVGSK	9606									11226282	t		lperfetto	We have demonstrated that BLNK mediates Syk-dependent Btk activation. In a reconstitution cell system, coexpression of BLNK allows Syk to phosphorylate Btk on its tyrosine 551, leading to the enhancement of Btk activity.	SIGNOR-247586	0.571
TRAM-34	chemical	CHEBI:34990	ChEBI	KCNN4	protein	O15554	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-207426	0.8
ADRA1A	protein	P35348	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256812	0.295
LCK	protein	P06239	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	phosphorylation	Tyr492	ALGADDSyYTARSAG	9606	BTO:0000782								7642520	t		lperfetto	When expressed in COS cells, Y493F-mutated ZAP-70 demonstrated normal basal kinase activity, but, unlike wild type ZAP-70, could not be activated by tyrosine phosphorylation induced by incubation with pervanadate or by co-expression of constitutively activated Lck	SIGNOR-30429	0.601
LRRK2	protein	Q5S007	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000938								21658387	t		lperfetto	Lrrk2 directly phosphorylates akt1 as a possible physiological substrate. These data establish that lrrk2 can protect neurons from apoptotic insult through a survival pathway in which lrrk2 signals to activate akt. Lrrk2-mediated phosphorylation of akt1 (ser473)	SIGNOR-244410	0.387
MLL Fusion	fusion protein	SIGNOR-FP14	SIGNOR	AEP complex	complex	SIGNOR-C117	SIGNOR	up-regulates activity	binding			9606	BTO:0005261								19956800	t		miannu	Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription.	SIGNOR-260131	0.2
SRC	protein	P12931	UNIPROT	ARHGEF4	protein	Q9NR80	UNIPROT	up-regulates	phosphorylation	Tyr165	VGSEEDLyDDLHSSS	9606	BTO:0000017								18653540	t		llicata	This observation strongly argues for the positive role of tyr94 phosphorylation in egf-induced asef activation following the activation of rac1.	SIGNOR-179601	0.318
ABL1	protein	P00519	UNIPROT	EPHB2	protein	P29323	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000938								11494128	t		lperfetto	Two-hybrid screens identified regions of abl and arg that bind to the ephb2 and epha4 receptors, suggesting a novel signaling connection involving the two kinase families.The connection between EphB2 and Abl/Arg appears to be reciprocal. Activated EphB2 causes tyrosine phosphorylation of Abl and Arg, and vice versa. Interestingly, treatment of COS cells and B35 neuronal-like cells with ephrin-B1 to activate endogenous EphB2 decreased the kinase activity of endogenous Abl.	SIGNOR-109668	0.497
AKT2	protein	P31751	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr32	QSRPRSCtWPLQRPE										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249639	0.742
CSNK2A2	protein	P19784	UNIPROT	PTPN1	protein	P18031	UNIPROT	unknown	phosphorylation			-1									9600099	t		llicata	In this study, we demonstrate that HPTP1B are multiple phosphorylated on threonine and tyrosine as well as serine near its N-terminus by CKII and p60c-src in vitro.	SIGNOR-251028	0.347
FFAR1	protein	O14842	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257184	0.2
INTS4	protein	Q96HW7	UNIPROT	DYNC1H1	protein	Q14204	UNIPROT	up-regulates quantity				9606	BTO:0000567								23904267	f		Monia	We propose a model in which nuclear localized Integrator complex, including ASUN, mediates 3′-end processing of snRNA, which in turn is required for normal processing of mRNA encoding a key regulator(s) of cytoplasmic dynein localization. When Integrator activity is compromised (e.g., by knockdown of an essential subunit), production of critical transcript(s) during interphase is impaired, leading to reduction of perinuclear dynein at G2/M.	SIGNOR-261186	0.2
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	unknown	phosphorylation	Tyr1007	VLPQDKEyYKVKEPG	-1									9111318	t			Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity	SIGNOR-251358	0.2
PPP1CB	protein	P62140	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606									14633703	t			Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells	SIGNOR-248575	0.394
SMURF	proteinfamily	SIGNOR-PF29	SIGNOR	SMAD6	protein	O43541	UNIPROT	down-regulates activity	relocalization			9606									22298955	t		lperfetto	Smurf1, with its WW domain, specifically binds to the PY motif of Smad6 and transports Smad6 into the cytoplasm.	SIGNOR-253261	0.2
PTPN1	protein	P18031	UNIPROT	ROS1	protein	P08922	UNIPROT	down-regulates	dephosphorylation	Tyr2115	DIYKNDYyRKRGEGL	9606									17416557	t		gcesareni	In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products.	SIGNOR-154207	0.38
CDK11A	protein	Q9UQ88	UNIPROT	CDK11B	protein	P21127	UNIPROT	up-regulates	phosphorylation	Thr726	KHEYFREtPLPIDPS	9606									21078675	t		lperfetto	Overall, our data indicated that thr-370 is responsible for the autophosphorylation, dimerization, and kinase activity of cdk11(p58)	SIGNOR-169628	0.309
PHF2	protein	O75151	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606	BTO:0000007								21532585	t		miannu	PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark.	SIGNOR-264516	0.2
Obatoclax	chemical	CID:16681698	PUBCHEM	BCL2	protein	P10415	UNIPROT	down-regulates	chemical inhibition			9606									23336025	t		gcesareni	Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol.	SIGNOR-200478	0.8
COMMD5	protein	Q9GZQ3	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity				9606									30021164	f		miannu	 We found that RhoA activity is decreased following COMMD5 depletion, suggesting that COMMD5 regulates cytoskeleton organization through RhoA signaling.We found that RhoA activity is decreased following COMMD5 depletion, suggesting that COMMD5 regulates cytoskeleton organization through RhoA signaling. However, the dynamics of Rho GTPase activities are highly complex and tightly regulated in order to achieve their specific subcellular localization (Marjoram et al., 2014); thus, the mechanism by which COMMD5 directly or indirectly regulates the activity of RhoA needs to be investigated further.	SIGNOR-261690	0.2
sertindole	chemical	CHEBI:9122	ChEBI	HTR1F	protein	P30939	UNIPROT	down-regulates activity	chemical inhibition			9534	BTO:0000298								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258544	0.8
CyclinA2/CDK1	complex	SIGNOR-C420	SIGNOR	G2/M_transition	phenotype	SIGNOR-PH52	SIGNOR	up-regulates				9606									29870721	f		lperfetto	Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis. 	SIGNOR-267572	0.7
CYBB	protein	P04839	UNIPROT	ROS	stimulus	SIGNOR-ST2	SIGNOR	up-regulates				9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264716	0.7
HSP90AA1	protein	P07900	UNIPROT	NOD2	protein	Q9HC29	UNIPROT	up-regulates quantity by stabilization	binding			9606									23019338	t		miannu	Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation. 	SIGNOR-252414	0.355
idelalisib	chemical	CHEBI:82701	ChEBI	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190813	0.8
IKBKB	protein	O14920	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	up-regulates activity	phosphorylation	Ser422	RFHSLPFsLTKMPNT	9606	BTO:0000938								24614225	t		lperfetto	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204720	0.529
nitric oxide	smallmolecule	CHEBI:16480	ChEBI	Vascular_Permeability	phenotype	SIGNOR-PH140	SIGNOR	up-regulates				9606	BTO:0001176								24078390	f	VEGF pathway	Gianni	After a period of controversial reports, evidence based on eNOS knockout mice and on eNOS-depleted EC established that microvascular hyperpermeability in response to an inflammatory challenge is regulated mainly by endothelial cells through eNOS-derived NO	SIGNOR-261947	0.7
CEBPB	protein	P17676	UNIPROT	SREBF1	protein	P36956	UNIPROT	up-regulates quantity	transcriptional regulation			10090									22355693	t			These results show that GSK3β is involved in regulating phosphorylation and activation of C/EBPβ and that this transcription factor is required to transactivate srebf1a expression, leading to the early steps of adipogenesis	SIGNOR-251645	0.421
PRKACA	protein	P17612	UNIPROT	NDE1	protein	Q9NXR1	UNIPROT	up-regulates	phosphorylation	Thr131	LERAKRAtIMSLEDF	9606		BTO:0000142							21677187	t		lperfetto	Here, we demonstrate that disc1 and pde4 modulate nde1 phosphorylation by camp-dependent protein kinase a (pka) and identify a novel pka substrate site on nde1 at threonine-131 (t131).Since phosphorylated t131 is detectable at multiple subcellular locations (centrosome, nucleus, postsynaptic density, proximal axon), there is potential for disc1/pde4 to influence several important brain processes that critically depend on the nde1/ndel1/lis1 comple	SIGNOR-174410	0.373
ATM	protein	Q13315	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									17967874	t		lperfetto	In this study, we show that the increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15.	SIGNOR-158632	0.838
MAPK14	protein	Q16539	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Thr311	NSLALSLtADQMVSA	9606									12138194	t		gcesareni	P38 mitogen-activated protein kinase was involved in estrogen receptor activation by estrogens and mekk1. Here, we report estrogen receptor-dependent p38 activation by estrogens in endometrial adenocarcinoma cells and in vitro and in vivo phosphorylation of the estrogen receptor alpha mediated through p38. The phosphorylation site was identified as threonine-311 (thr(311)), located in helix 1 of the hormone-binding domain.	SIGNOR-90823	0.609
IFNG	protein	P01579	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates				9606		BTO:0001760							11009425	f		gcesareni	In contrast, in differentiated myotubes, tnf plus interferon-gamma (ifn-gamma) signaling was required for nf-kappab-dependent down-regulation of myod and dysfunction of skeletal myofibers.	SIGNOR-82467	0.295
PRKG1	protein	Q13976	UNIPROT	TRPC3	protein	Q13507-3	UNIPROT	down-regulates	phosphorylation	Thr11	SPSLRRMtVMREKGR	9606	BTO:0000007								16331690	t	The effect has been demonstrated using Q13507-3	llicata	The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263.	SIGNOR-142957	0.417
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257939	0.8
PTPRG	protein	P23470	UNIPROT	PTPRG	protein	P23470	UNIPROT	down-regulates activity	binding			9606									25624455	t		miannu	The main regulatory mechanism of RPTP activity consists of the reversible transition from a homodimeric inactive form to a monomeric active form. PTPRG is constitutively expressed on monocyte plasma membrane as a homodimer with the WD involved in catalytic domain blockade.	SIGNOR-254737	0.2
PRKACA	protein	P17612	UNIPROT	MCOLN1	protein	Q9GZU1	UNIPROT	down-regulates	phosphorylation	Ser559	KFRRGSGsACSLLCC	9606									17988215	t		llicata	The stimulatory effect of h89 on mcoln1 function was not observed when ser(557) and ser(559) were mutated to alanine residues, indicating that these two residues are essential for pka-mediated negative regulation of mcoln1.	SIGNOR-158950	0.2
PRKCA	protein	P17252	UNIPROT	MARCKS	protein	P29966	UNIPROT	down-regulates activity	phosphorylation	Ser163	KRFSFKKsFKLSGFS	-1									1560845	t		gcesareni	Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin	SIGNOR-249650	0.72
3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one	chemical	CHEBI:91346	ChEBI	AKT2	protein	P31751	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000782								25336630	t		miannu	 stimulations were performed in the presence or absence of Akt inhibitor VIII, which selectively inhibits Akt1/Akt2 activity. 	SIGNOR-262228	0.8
SRC	protein	P12931	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates	phosphorylation	Tyr284	KIFPYEEyASWKTEK	9606									19114990	t		gcesareni	Tbetarii can also be phosphorylated by src, a non-rtk, on y284, which can serve as a docking site for the recruitment of grb2 and shc, thereby bridging tbetarii to mapk activation.	SIGNOR-182963	0.286
F2R	protein	P25116	UNIPROT	SDC4	protein	P31431	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254852	0.2
Tifluadom	chemical	CHEBI:9591	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029									9262330	t		miannu	We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine.	SIGNOR-258665	0.8
CSNK2B	protein	P67870	UNIPROT	SEC63	protein	Q9UGP8	UNIPROT	up-regulates activity	phosphorylation	Ser574	EEVSDKGsDSEEEET	9606	BTO:0000599								23287549	t		lperfetto	Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62.	SIGNOR-265270	0.2
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252849	0.908
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	DNA_fragmentation	phenotype	SIGNOR-PH22	SIGNOR	up-regulates				9606									10200555	f		amattioni	Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation	SIGNOR-256478	0.7
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	NUP50	protein	Q9UKX7	UNIPROT	down-regulates	phosphorylation			9606									19767751	t	inferred from 70% family members	gcesareni	Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin.	SIGNOR-270041	0.2
MMP2	protein	P08253	UNIPROT	HAPLN1	protein	P10915	UNIPROT	down-regulates quantity by destabilization	cleavage	His31	LDHDRAIhIQAENGP	-1									7694569	t		miannu	Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.	SIGNOR-256327	0.345
SRC	protein	P12931	UNIPROT	DAB1	protein	O75553	UNIPROT	up-regulates activity	phosphorylation	Tyr185	KQCEQAVyQTILEED	10090	BTO:0000938								11279201	t		lperfetto	Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons.	SIGNOR-247072	0.43
FLT3	protein	P36888	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity				10090									18192505	f			Inhibition of FLT3/ITD leads to a small decrease in RAC1 activity	SIGNOR-261536	0.2
RABGGTA	protein	Q92696	UNIPROT	RAB3A	protein	P20336	UNIPROT	up-regulates activity	lipidation			9606	BTO:0000007								18532927	t		miannu	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional	SIGNOR-265574	0.552
MUSK	protein	O15146	UNIPROT	DOK7	protein	Q18PE1	UNIPROT	up-regulates activity	phosphorylation	Tyr395	CLPGTVEyQVPTSLR	10090	BTO:0000165								20603078	t		miannu	Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes. 	SIGNOR-273845 	0.746
NEK2	protein	P51955	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr143	AVSPGTLtPTGVVSG										35705994	t		lperfetto	NEK2 promotes the migration and proliferation of ESCC via stabilization of YAP1 by phosphorylation at Thr-143	SIGNOR-276586	0.2
FCN2	protein	Q15485	UNIPROT	MASP1	protein	P48740	UNIPROT	up-regulates activity	binding			9606	BTO:0000392								11907111	t		lperfetto	H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway|Proteolytic activation of complement components by H-ficolin-MASP. 	SIGNOR-263411	0.781
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	ANXA3	protein	P12429	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000608								26095609	f		miannu	ANXA3 Induces a Feed-Forward Loop that Is Mediated by the MKK4/JNK Signaling Cascade. To substantiate the importance of the JNK/AP-1 pathway in ANXA3-driven HCC, we performed rescue experiments using the JNK-specific inhibitor (JNKi) SP600125. JNKi suppressed the oncogenic properties conferred by ANXA3 overexpression, as evidenced by the diminished abilities of HCC cells to form colonies, migrate, invade, induce angiogenesis, form hepatospheres, and resist apoptosis and chemotherapy (Figures 6F–6J). Interestingly, treatment of parental HCC cells or HCC cells overexpressing ANXA3 with JNKi resulted in not only a reduction in JNK activity and modulation of downstream target genes (c-MYC and p21) but also a marked decrease in ANXA3 expression, suggesting that ANXA3 induces a feed-forward loop that is mediated by MKK4/JNK signaling (Figures 6K–6L).	SIGNOR-262216	0.2
TRADD	protein	Q15628	UNIPROT	TRAF5	protein	O00463	UNIPROT	up-regulates	binding			9606									19632174	t		gcesareni	Upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor-associated factor 2 ,traf2.	SIGNOR-187058	0.596
LEF1	protein	Q9UJU2	UNIPROT	OCA2	protein	Q04671	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22234890	f		miannu	 the SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species.In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression.	SIGNOR-254555	0.256
RPS2	protein	P15880	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262431	0.902
ODC1	protein	P11926	UNIPROT	spermine	smallmolecule	CHEBI:15746	ChEBI	up-regulates quantity	chemical modification			9606									14617280	t		miannu	Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC)	SIGNOR-256035	0.8
PPP2CA	protein	P67775	UNIPROT	PRKCB	protein	P05771-2	UNIPROT	down-regulates activity	dephosphorylation	Thr641	TRHPPVLtPPDQEVI	10116									8749392	t			 Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme. 	SIGNOR-248622	0.434
CTDSP1	protein	Q9GZU7	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation	Ser245	NQSMDTGsPAELSPT	9606	BTO:0000007								17035229	t			SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248795	0.493
CCR2	protein	P41597	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity	phosphorylation			10090									20219869	t		areggio	The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. 	SIGNOR-255117	0.337
RET	protein	P07949	UNIPROT	GFRA1	protein	P56159	UNIPROT	up-regulates	binding			9606									10829012	t		gcesareni	Gdnfr-alpha-ligand complex, together with the tyrosine kinase receptor (cret) forms a functional receptor that activates downstream signal transduction pathways	SIGNOR-77587	0.745
STK3	protein	Q13188	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	phosphorylation	Ser872	HQRCLAHsLVGTPNY	9606									21808241	t		gcesareni	Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2.	SIGNOR-175797	0.592
DBH	protein	P09172	UNIPROT	dopamine	smallmolecule	CHEBI:18243	ChEBI	down-regulates quantity	chemical modification			10090									7961964	t	brain	lperfetto	Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway.	SIGNOR-264005	0.8
RASA1	protein	P20936	UNIPROT	HRAS	protein	P01112	UNIPROT	down-regulates	binding			9606									9219684	t		gcesareni	The three-dimensional structure of the complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved at a resolution of 2.5 angstroms.	SIGNOR-49477	0.842
POFUT1	protein	Q9H488	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606									12909620	t	Fucosylation	gcesareni	Notch_ is modified in its epidermal growth factor-like domains by the addition of_ fucose_ to serine or threonine residues. O-fucosylation is mediated by protein o-fucosyltransferase 1 and down-regulation of this enzyme by rna interference or mutation of the ofut1 gene in drosophila or by mutation of the pofut1 gene in mouse prevents notch signaling.	SIGNOR-104627	0.736
STUB1	protein	Q9UNE7	UNIPROT	HIF1A	protein	Q16665	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								19940151	t		miannu	 the ubiquitin ligase activity of CHIP regulates HIF-1α degradation.	SIGNOR-271426	0.384
FURIN	protein	P09958	UNIPROT	VWF	protein	P04275	UNIPROT	up-regulates activity	cleavage				BTO:0001538								8218226	t		Giorgia	Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine	SIGNOR-260368	0.495
GSK3A	protein	P49840	UNIPROT	GSK3A	protein	P49840	UNIPROT	up-regulates	phosphorylation	Tyr279	RGEPNVSyICSRYYR	9606	BTO:0000527								18701488	t		gcesareni	Gsk3a is activated by phosphorylation at tyr-279.	SIGNOR-180035	0.2
CD3E	protein	P07766	UNIPROT	NCK1	protein	P16333	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000661								12110186	t			We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck. 	SIGNOR-259934	0.379
SPAG9	protein	O60271	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	binding			9606	BTO:0000222								17074887	t	Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP	lperfetto	Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants.	SIGNOR-149979	0.542
FGFR1	protein	P11362	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates	phosphorylation	Tyr128	SKAQQGLyQVPGPSP	9606									12601080	t		lperfetto	Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas.	SIGNOR-98488	0.259
ATP7B	protein	P35670	UNIPROT	copper(1+)	smallmolecule	CHEBI:49552	ChEBI	up-regulates quantity	relocalization												24706876	t		lperfetto	WD is caused by mutations in ATP7B, a transporter that loads Cu(I) onto newly synthesized cupro-enzymes in the trans-Golgi network (TGN) and exports excess copper out of cells by trafficking from the TGN to the plasma membrane.	SIGNOR-272297	0.8
FYN	protein	P06241	UNIPROT	FYB1	protein	O15117	UNIPROT	up-regulates activity	phosphorylation	Tyr595	IEDDQEVyDDVAEQD	9606									10570256	t			 two tyrosines, Tyr595 and Tyr651, of FYB are major sites of phosphorylation by FYN-T and mediate binding to SLP-76 in Jurkat T cells. We further demonstrate that the loss of SLP-76 binding by mutation of these sites markedly reduced the ability of FYN-T-FYB-SLP-76 to up-regulate IL-2 transcription.	SIGNOR-251163	0.2
FOXP1	protein	Q9H334	UNIPROT	SEMA5B	protein	Q9P283	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0001176								24023716	t		Gianni	FoxP1 stimulates angiogenesis by repressing the inhibitory guidance protein semaphorin 5B in endothelial cells.	SIGNOR-269050	0.337
PEBP1	protein	P30086	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	binding			9606									10490027	t		gcesareni	Suppression of raf-1 kinase activity and map kinase by rkip. Rkip binds to raf-1, mek and erk, but not to ras.	SIGNOR-70838	0.753
(R)-carnitine	smallmolecule	CHEBI:16347	ChEBI	O-palmitoyl-L-carnitine	smallmolecule	CHEBI:17490	ChEBI	up-regulates quantity	precursor of			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267117	0.8
Elongator complex	complex	SIGNOR-C466	SIGNOR	TUBA3C	protein	P0DPH7	UNIPROT	up-regulates activity	acetylation			9606	BTO:0000007								19185337	t		miannu	Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. α-Tubulin Acetylation Promotes Radial Migration and Branching of Cortical Projection Neurons	SIGNOR-269716	0.254
PPP1CA	protein	P62136	UNIPROT	IKZF1	protein	Q13422	UNIPROT	up-regulates	dephosphorylation			9606	BTO:0001271								21750978	t		miannu	Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway	SIGNOR-174859	0.282
TPH1	protein	P17752	UNIPROT	tryptophan	smallmolecule	CHEBI:27897	ChEBI	down-regulates quantity	chemical modification			9606									31024440	t	brain	lperfetto	In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)].	SIGNOR-264009	0.8
3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	THRB	protein	P10828	UNIPROT	up-regulates activity	binding			9606		BTO:0001073							29407449	t		scontino	T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb.	SIGNOR-267254	0.8
ROCK1	protein	Q13464	UNIPROT	MYL12A	protein	P19105	UNIPROT	up-regulates activity	phosphorylation	Ser19	KRPQRATsNVFAMFD	9606	BTO:0000567								12185584	t		miannu	Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies. we showed that the inhibition of Rho-kinase reduced diphosphorylated MRLC in the center of cells even in the presence of phosphatase inhibitor, suggesting that Rho-kinase directly diphosphorylates MRLC (red arrow in Figure 6). Taken together, we propose a model of diphosphorylation of MRLC through dual pathways of both the direct phosphorylation and the inhibition of myosin phosphatase by Rho-kinase (Figure 6).	SIGNOR-263073	0.555
MYC	protein	P01106	UNIPROT	SHMT2	protein	P34897	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003291								18628958	t		miannu	Myc regulates the de novo purine and pyrimidine synthetic genes in multiple biological systems. Intriguingly, MYC was found to directly activate the expression of SHMT1, and SHMT2, which are enzymes involved in single carbon metabolism and are essential for dNTP synthesis	SIGNOR-267380	0.296
ZFHX3	protein	Q15911	UNIPROT	AFP	protein	P02771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11314020	f	 	miannu	 We investigated AFP gene regulation in AFP-GC by an active transcription factor, HNF1 (hepatocyte nuclear factor 1) and a repressive transcription factor, ATBF1 (AT motif binding factor 1). CAT assays showed the direct inhibition of AFP gene expression by ATBF1.	SIGNOR-254436	0.428
SMARCD1	protein	Q96GM5	UNIPROT	Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270694	0.787
MAD2L1BP	protein	Q15013	UNIPROT	MCC	complex	SIGNOR-C382	SIGNOR	down-regulates quantity by destabilization	binding			9606	BTO:0000567								25092294	t		miannu	We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4). 	SIGNOR-265979	0.474
TRIM28	protein	Q13263	UNIPROT	FBP1	protein	P09467	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000594								28394358	t		lperfetto	In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28. 	SIGNOR-267591	0.314
PKN1	protein	Q16512	UNIPROT	PGM1	protein	P36871	UNIPROT	up-regulates	phosphorylation	Thr467	SANDKVYtVEKADNF	9606	BTO:0001271								15378030	t		llicata	Pak1-mediated phosphorylation of pgm selectively on threonine 466 significantly increased pgm enzymatic activity	SIGNOR-128722	0.2
FAU	protein	P62861	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262443	0.833
IKBKB	protein	O14920	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser32	LLDDRHDsGLDSMKD										11815618	t		lperfetto	Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. The phosphorylation of I_Balpha on Ser32 and Ser36 is initiated by an IkapapB kinase (IKK) complex that includes a catalytic heterodimer composed of I_B kinase 1 (IKK-1) and IkapapB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator.	SIGNOR-249365	0.92
APAF1	protein	O14727	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates	binding			9606									9390557	t		gcesareni	During apoptosis, apaf-1 binds to cytochrome c and in the presence of atp/datp forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 .in particular, caspase-9 is recruited and activated by apaf-1 .casp9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cycs and datp, an event that leads to casp9 activation.	SIGNOR-53579	0.953
GLI2	protein	P10070	UNIPROT	IFITM5	protein	A6NNB3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23530031	f	 	miannu	Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation.	SIGNOR-254217	0.2
DLX3	protein	O60479	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17060321	f		gcesareni	Here we show that bmp2 induces dlx3, a homeodomain protein that activates runx2 gene transcription. Small interfering rna knockdown studies in osteoblasts validate that dlx3 is a potent regulator of runx2.	SIGNOR-150177	0.408
ITGB1BP1	protein	O14713	UNIPROT	A4/b1 integrin	complex	SIGNOR-C162	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257642	0.757
SMARCC1	protein	Q92922	UNIPROT	SWI/SNF ACTL6A-ARID1A-SMARCA2 variant	complex	SIGNOR-C470	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269824	0.829
SLC16A4	protein	O15374	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606									26384349	f		lperfetto	Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival.	SIGNOR-256582	0.7
TICAM1	protein	Q8IUC6	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								14530355	t		lperfetto	Toll/il-1 receptor domain-containing adaptor inducing ifn-beta (trif) associates with tnf receptor-associated factor 6 and tank-binding kinase 1, and activates two distinct transcription factors, nf-kappa b and ifn-regulatory factor-3, in the toll-like receptor signaling	SIGNOR-118458	0.814
MAPK9	protein	P45984	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									7737130	t		gcesareni	Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro.	SIGNOR-32433	0.686
MAP3K5	protein	Q99683	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	phosphorylation	Thr261	LVDSIAKtRDAGCRP	9606									8974401	t		lperfetto	A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase)	SIGNOR-45373	0.616
INSR	protein	P06213	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	phosphorylation	Tyr1011	DVFPCSVyVPDEWEV	-1									3166375	t		lperfetto	This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972	SIGNOR-233564	0.2
GSK3B	protein	P49841	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity by destabilization	phosphorylation			7227									11955435	t		lperfetto	We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog.	SIGNOR-219231	0.517
SCRIB	protein	Q14160	UNIPROT	Scribble_complex_DLG1-LLGL1_variant	complex	SIGNOR-C511	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270912	0.541
FYN	protein	P06241	UNIPROT	CD79A	protein	P11912	UNIPROT	up-regulates activity	phosphorylation	Tyr199	NLDDCSMyEDISRGL	-1									9531288	t			Lyn and Fyn phosphorylated the CD79a cytoplasmic portion of the fusion proteins well, with >80% of phosphorylation occurring at Y182. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM).	SIGNOR-251153	0.578
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr585	PPGLEYCyNPSHNPE	10116									19224897	t		lperfetto	Autophosphorylation of Y653 is followed by the ordered autophosphorylation of several key tyrosine residues within binding sites for the SH2 or PTB domains of signaling proteins that bind to and are phosphorylated by activated FGFR1. This second-stage autophosphorylation occurs on Y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of Y463 in the juxtamembrane region, Y766 in the C-terminal tail, and Y585 in the kinase insert region	SIGNOR-235682	0.2
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates	phosphorylation	Ser677	QMQPDTTsVVKDSQV	9606									19120698	t		llicata	Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity	SIGNOR-183022	0.2
TNF	protein	P01375	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates activity				10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253489	0.261
MAP1LC3A	protein	Q9H492	UNIPROT	Autophagosome_formation	phenotype	SIGNOR-PH36	SIGNOR	up-regulates				9606		BTO:0001623							20921139	f		lperfetto	We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation	SIGNOR-219406	0.7
LEO1	protein	Q8WVC0	UNIPROT	PAF1C	complex	SIGNOR-C471	SIGNOR	form complex	binding			9606	BTO:0000567								20178742	t		miannu	Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A). 	SIGNOR-269832	0.937
EDNRA	protein	P25101	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257378	0.523
PRKACA	protein	P17612	UNIPROT	PTPN11	protein	Q06124	UNIPROT	down-regulates activity	phosphorylation	Thr73	YGGEKFAtLAELVQY	9606	BTO:0002181								25802336	t		miannu	 We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity. 	SIGNOR-276891	0.427
PRKDC	protein	P78527	UNIPROT	RPA2	protein	P15927	UNIPROT	down-regulates activity	phosphorylation	Ser11	SGFESYGsSSYGGAG	-1									9295339	t		lperfetto	We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13	SIGNOR-248980	0.598
STAT3	protein	P40763	UNIPROT	Epithelial-mesenchymal_transition	phenotype	SIGNOR-PH45	SIGNOR	up-regulates				9606		BTO:0000452							26738736	f		miannu	Collectively, the activation of IL-6/STAT3 pathway contributed to the PSCs-induced EMT i	SIGNOR-277690	0.7
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CDK2	protein	P24941	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189984	0.8
NUMA1	protein	Q14980	UNIPROT	TUBG1	protein	P23258	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-117203	0.604
SNAI1	protein	O95863	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15311212	f		miannu	 known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT.	SIGNOR-255156	0.75
cyproterone acetate	chemical	CHEBI:50743	ChEBI	AR	protein	P10275	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191235	0.8
MEIS2	protein	O14770	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								21746878	t		miannu	We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.	SIGNOR-267242	0.2
MRPL18	protein	Q9H0U6	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262376	0.626
UBE2E3	protein	Q969T4	UNIPROT	NFKBIA	protein	P25963	UNIPROT	up-regulates quantity by stabilization	sumoylation	Lys21	EGPRDGLkKERLLDD	9606	BTO:0000007;BTO:0000567								10582246	t		lperfetto	In the presence of an E1 SUMO-1-activating enzyme, Ubch9 conjugated SUMO-1 to IkappaBalpha primarily on K21, which is also utilized for ubiquitin modification. Thus, SUMO-1-modified IkappaBalpha cannot be ubiquitinated and is resistant to proteasome-mediated degradation. 	SIGNOR-270545	0.353
PRKCA	protein	P17252	UNIPROT	RHO	protein	P08100	UNIPROT	unknown	phosphorylation	Ser343	TVSKTETsQVAPA	-1									9099669	t		lperfetto	Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343.	SIGNOR-248968	0.451
CDK1	protein	P06493	UNIPROT	NUSAP1	protein	Q9BXS6	UNIPROT	down-regulates	phosphorylation	Thr300	HKRSLTKtPARKSAH	9606									22101338	t		llicata	We report here that cdk1 phosphorylates nusap at threonine 300 and 338 in early mitosis. Phosphorylation of nusap inhibits its microtubule-binding activity in vitro and in vivo.	SIGNOR-177545	0.442
ID1	protein	P41134	UNIPROT	MYOD/HEB	complex	SIGNOR-C128	SIGNOR	down-regulates activity	binding			10090	BTO:0004058								9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241110	0.546
GRK2	protein	P25098	UNIPROT	SLC9A5	protein	Q14940	UNIPROT	down-regulates activity	phosphorylation	Thr714	EESDSSEtEKEDDEG										21296876	t		lperfetto	Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2.	SIGNOR-275502	0.2
ZNF804A	protein	Q7Z570	UNIPROT	INHBE	protein	P58166	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								23434502	t		miannu	ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 	SIGNOR-269462	0.2
PTPRF	protein	P10586	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606									10734133	t		gcesareni	Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product.	SIGNOR-76009	0.563
ADA	protein	P00813	UNIPROT	inosine	smallmolecule	CHEBI:17596	ChEBI	up-regulates quantity	chemical modification			-1									15926889	t		Luana	Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates	SIGNOR-269737	0.8
CYP11B2	protein	P19099	UNIPROT	aldosterone	smallmolecule	CHEBI:27584	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000048							33117906	t		lperfetto	The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone	SIGNOR-268685	0.8
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser315	DFRSRTNsNASTVSG	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252850	0.908
CREB1	protein	P16220	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000157								15955695	f		miannu	 In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro.	SIGNOR-253797	0.301
SYCP3	protein	Q8IZU3	UNIPROT	Synaptonemal_complex	complex	SIGNOR-C351	SIGNOR	form complex	binding			9606									22394509	t		miannu	The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region.	SIGNOR-264200	0.624
BMP7	protein	P18075	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates	transcriptional regulation			9606									18719589	f	Induction of mitochondrial biogenesis	fspada	Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16; ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways	SIGNOR-210056	0.294
MECP2	protein	P51608	UNIPROT	IGFBP3	protein	P17936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		BTO:0000142							17278996	f		miannu	 We found that MeCP2 directly regulates expression of insulin-like growth factor binding protein 3 (IGFBP3) gene in human and mouse brains. IGFBP3 overexpression was observed in the brains of mecp2-null mice and human RTT patients using real-time quantitative polymerase chain reaction and Western blot analyses. 	SIGNOR-254580	0.254
MAPK8	protein	P45983	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates activity	phosphorylation	Ser389	LSPIAPRsPAKLSFQ	9606	BTO:0000567								8846788	t		lperfetto	We find that the JNKs are the predominant Elk-1 activation domain kinases in extracts of UV-irradiated cells and that immunopurified JNK1/2 phosphorylate Elk-1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity.	SIGNOR-236455	0.494
AURKA	protein	O14965	UNIPROT	RASSF1	protein	Q9NS23	UNIPROT	down-regulates	phosphorylation	Thr206	GTSVRRRtSFYLPKD	9606									17563743	t		llicata	AuroraT-a appears to phosphorylate rassf1a at threonine202 and/or serine203 that reside within the known microtubule-binding domain of rassf1a. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of rassf1a, disrupt rassf1a interactions with microtubules and abolish its ability to induce m-phase cell cycle arrest.	SIGNOR-155819	0.46
CAMK2A	protein	Q9UQM7	UNIPROT	GFPT1	protein	Q06210	UNIPROT	up-regulates	phosphorylation	Ser261	CNLSRVDsTTCLFPV	9606									17941647	t		gcesareni	Amp-activated protein kinase and calcium/calmodulin-dependent kinase ii were identified to phosphorylate specifically ser243 in vitro. Phosphorylation by these two kinases results in an increase of enzymatic activity by 1.4-fold. These findings suggest for the first time that hgfat1 may be regulated by kinases other than pka.	SIGNOR-158486	0.2
HRH2	protein	P25021	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257317	0.252
MAPK1	protein	P28482	UNIPROT	APBB1	protein	O00213	UNIPROT	unknown	phosphorylation	Ser347	TFPAQSLsPEPLPQE	9606									14697653	t		lperfetto	Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved.	SIGNOR-120459	0.262
DRD1	protein	P21728	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257335	0.477
SRC	protein	P12931	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates activity	phosphorylation	Tyr463	NDTGSRYyKEIPLSE	9606									12637538	t		lperfetto	Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation.	SIGNOR-247324	0.421
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT3A	protein	P56704	UNIPROT	down-regulates activity				9606	BTO:0000815								21113658	f		lperfetto	In this context, SOSTDC1 leads to decreased cellular proliferation and inhibition of Wnt3a- and BMP-7-induced signaling	SIGNOR-242714	0.302
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr192	AGMGHDIyQVPPSMD	10090									12972425	t		lperfetto	Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs	SIGNOR-246393	0.797
MAPK1	protein	P28482	UNIPROT	BCL3	protein	P20749	UNIPROT	up-regulates activity	phosphorylation	Ser122	CPMEHPLsADIAMAT	-1									28689659	t		miannu	Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA. 	SIGNOR-277360	0.487
PLK1	protein	P53350	UNIPROT	RAD21	protein	O60216	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser175	REIMREGsAFEDDDM	9606	BTO:0000567								15737063	t		lperfetto	We suspected that the observed enhancement of Scc1's cleavability in the presence of Plk1 might be due to phosphorylation at two sites that are directly adjacent to the cleavage sites, Ser175 and Ser454, which we had found to be phosphorylated in mitosis in vivo (Table 1). We therefore mutated these two residues to alanine, thereby creating mutant Scc1-S175A/S454A (see Figure 1C), and tested the cleavability of this mutant in the absence or presence of Plk1 in vitro. |Scc1 phosphorylation is dispensable for cohesin dissociation from chromosomes in early mitosis but enhances the cleavability of Scc1 by separase. 	SIGNOR-275535	0.727
DAB2IP	protein	Q5VWQ8	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	binding			9606									27858941	t		miannu	DAB2IP inhibits the PI3K–AKT axis by directly interacting with both proteins, reducing phosphorylation and activation of AKT. The GAP activity of DAB2IP can further enforce inhibition of the PI3K–AKT axis by reducing Ras-dependent activation of PI3K p110α subunit.	SIGNOR-254751	0.512
POU2F1	protein	P14859	UNIPROT	HOXD11	protein	P31277	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25301728	f		miannu	Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11	SIGNOR-205564	0.265
GNAI1	protein	P63096	UNIPROT	HCK	protein	P08631	UNIPROT	up-regulates activity	binding			-1									11007482	t			Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases.	SIGNOR-256528	0.33
TEAD1	protein	P28347	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									21211055	f		gcesareni	Tead1 can regulate transcription of the foxo3a gene through the binding to the m-cat element, demonstrated with independent chip-pcr analysis, emsa and luciferase reporter system assay. The over-expression and inhibition analysis suggest that foxo3a was positively regulated by tead1.	SIGNOR-253003	0.31
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KA5	protein	O75582	UNIPROT	up-regulates	phosphorylation	Ser360	TEMDPTYsPAALPQS	9606									18267068	t		lperfetto	Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth.	SIGNOR-249572	0.2
1-(1-naphthalenyl)piperazine	chemical	CHEBI:108599	ChEBI	HTR2B	protein	P41595	UNIPROT	down-regulates activity	chemical inhibition			10036	BTO:0000452								9459568	t		miannu	The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-	SIGNOR-258683	0.8
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	MDM2	protein	Q00987	UNIPROT	up-regulates	phosphorylation	Ser166	SSRRRAIsETEENSD	9606	BTO:0000785								18467333	t		gcesareni	Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt.	SIGNOR-259433	0.2
BTG2	protein	P78543	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	up-regulates activity	binding			9606	BTO:0000093								22493435	t		miannu	BTG2 stimulation of antioxidant gene expression is also NFE2L2-dependent. We further demonstrate that BTG2 is a binding partner for NFE2L2 and increases its transcriptional activity.	SIGNOR-254647	0.2
belinostat	chemical	CHEBI:61076	ChEBI	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257960	0.8
FUS	protein	P35637	UNIPROT	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	down-regulates quantity by repression	post transcriptional regulation			10090		BTO:0001279							28515487	f	inferred from family member		This conclusion is also supported by the analysis of alternative splicing events inhFUS+/+;Smn+/‚àímice. As shown in Fig.6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected inhFUS+/+mice, is not further modified by SMN decrease	SIGNOR-270231	0.287
SB 203580	chemical	CHEBI:90705	ChEBI	MAPK11	protein	Q15759	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000222								15208625	t		fstefani	Pharmacological blockade of p38?/? Kinases by sb203580 inhibits the myogenic program3_5 by repressing the transcription of early (myogenin;myog) and late (muscle-creatine kinase;ckm) muscle genes in myoblasts induced to differentiate	SIGNOR-126052	0.8
N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide	chemical	CHEBI:91371	ChEBI	CDK9	protein	P50750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206139	0.8
STK11	protein	Q15831	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	up-regulates activity	phosphorylation	Ser669	EDDVLSSsSCGSNSD	9606	BTO:0002181								34216621	t		miannu	 Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction. 	SIGNOR-277321	0.591
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr36	LPPGDYStTPGGTLF	9606			SIGNOR-C3						17510057	t		lperfetto	In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size.	SIGNOR-154810	0.924
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32195003	f			Notch signaling is initiated by the interaction of Notch ligands and receptors on adjacent cells, which further triggers two proteolytic cleavage events. The first cleavage releases a functional extracellular domain (NECD); the second cleavage, mediated by γ-secretase, releases the intracellular domain (NICD) into the cytoplasm. The NICD then translocates to the nucleus, binds to the transcription factor CBF/Su (H)/LAG-2 (CSL), and recruits Mastermind-like protein 1 and p300/CBP to induce transcription of Notch target genes, including Hes1, p21, Akt, cyclin D1, and mTOR	SIGNOR-261534	0.2
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	Muscle_atrophy	phenotype	SIGNOR-PH40	SIGNOR	up-regulates				10090									25787076	f		miannu	The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice	SIGNOR-256475	0.7
Oxotremorine	chemical	CHEBI:7851	ChEBI	CHRM2	protein	P08172	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258653	0.8
PTPN1	protein	P18031	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates	dephosphorylation	Tyr1007	VLPQDKEyYKVKEPG	9606									15821101	t		gcesareni	Ptp1b has been shown to regulate the activation of cytokine receptors through the dephosphorylation of specific members of the jak family, namely jak2 and tyk2	SIGNOR-134955	0.79
CDK2	protein	P24941	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Ser276	VHPATPIsPGRASGM	9606									16046550	t	The effect has been demonstrated using Q01196-8	gcesareni	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-138936	0.2
FLT4	protein	P35916	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates activity	phosphorylation	Tyr1363	TFFTDNSy	9606	BTO:0000394								12881528	t		lperfetto	Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail.	SIGNOR-104092	0.2
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT5B	protein	Q9H1J7	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242727	0.281
NELFCD	protein	Q8IXH7	UNIPROT	NELF	complex	SIGNOR-C521	SIGNOR	form complex	binding			9606									18628398	t		miannu	The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. 	SIGNOR-271399	0.855
PLK1	protein	P53350	UNIPROT	ZMYM2	protein	Q9UBW7	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser309	DSLSPVAsLPKQIFQ										25855382	t		lperfetto	PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant	SIGNOR-275560	0.386
FOXO1	protein	Q12778	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				10090									12530968	f			Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice.	SIGNOR-254973	0.7
SMAD3	protein	P84022	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates activity	binding			9606									9843571	t		gcesareni	TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus.	SIGNOR-235168	0.698
TGFBR2	protein	P37173	UNIPROT	VPS39	protein	Q96JC1	UNIPROT	up-regulates activity	binding			9534									12941698	t		miannu	TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling.	SIGNOR-261374	0.331
ACHE	protein	P22303	UNIPROT	acetylcholine	smallmolecule	CHEBI:15355	ChEBI	down-regulates quantity	chemical modification												15841900	t			Acetylcholinesterase (AChE) is one of the most crucial enzymes for nerve response and function. AChE catalyzes the hydrolysis of acylcholine esters with a relative specificity for acetylcholine.|The intracellular effects of acetylcholine are mediated by the activation of nicotinic and muscarinic acetylcholine receptors (AChRs). AChE terminates transmission of neuronal impulses by rapid hydrolysis of acetylcholine.	SIGNOR-253983	0.8
CKM complex	complex	SIGNOR-C406	SIGNOR	SMAD3	protein	P84022	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr179	PQSNIPEtPPPGYLS	9606									19914161	t		lpetrilli	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-273142	0.421
TFPI	protein	P10646	UNIPROT	VLDLR	protein	P98155	UNIPROT	up-regulates	binding			9606									11278667	t		gcesareni	Binding studies revealed that full-length tfpi, but not the truncated tfpi molecule, is recognized by the very low density lipoprotein receptor (vldl receptor) indicating that this receptor is a novel high affinity endothelial cell receptor for tfpi	SIGNOR-106353	0.26
LRIG1	protein	Q96JA1	UNIPROT	ERBB4	protein	Q15303	UNIPROT	down-regulates				9606									23723069	f		miannu	Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases, including erbb and met receptors, and promotes receptor degradation.	SIGNOR-202146	0.591
GNAO1	protein	P09471	UNIPROT	TAOK2	protein	Q9UL54	UNIPROT	up-regulates				9606	BTO:0000007								12665513	f		lperfetto	These results suggest that go alpha q205l activates p38 through taos and mek3/6.	SIGNOR-235542	0.2
GGCX	protein	P38435	UNIPROT	Reduced Vitamin K	smallmolecule	CHEBI:8784	ChEBI	down-regulates quantity	chemical modification			9606									31226734	t		lperfetto	GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form.	SIGNOR-265908	0.8
PPM1D	protein	O15297	UNIPROT	KDM1A	protein	O60341	UNIPROT	down-regulates activity	dephosphorylation	Ser137	LSEDEYYsEEERNAK	9606	BTO:0002181								25999347	t		miannu	We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites.	SIGNOR-276905	0.478
CDK14	protein	O94921	UNIPROT	TAGLN2	protein	P37802	UNIPROT	down-regulates activity	phosphorylation	Ser163	KENPRNFsDNQLQEG										21577206	t		lperfetto	This newly identified oncogene–tumor suppressor cascade, where oncogenic PFTK1 inactivates a tumor suppressor gene TAGLN2 via phosphorylation|. Our data therefore underline much importance for S83 and S163 residues on TAGLN2 in its actin-binding capacity.	SIGNOR-265105	0.321
PPP2CA	protein	P67775	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation	Thr185	HDHTGFLtEYVATRW	9606							phosphorylation:Thr185	HDHTGFLtEYVATRW	16456541	t		gcesareni	B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk	SIGNOR-143052	0.604
CDH13	protein	P55290	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265853	0.514
PPM1B	protein	O75688	UNIPROT	PAX2	protein	Q02962	UNIPROT	down-regulates activity	dephosphorylation			9606		BTO:0000007							25631048	t			PPM1B can dephosphorylate the Pax2 activation domain and displace the adaptor protein PTIP, thus inhibiting H3K4 methylation and gene activation	SIGNOR-251712	0.2
LTA	protein	P01374	UNIPROT	LTBR	protein	P36941	UNIPROT	up-regulates	binding			9606									7995952	t		gcesareni	These experiments point toward the lt-alpha 1/beta 2 complex as the predominant membrane form of lt on the lymphocyte surface, and this complex is the primary ligand for the lt-beta receptor.	SIGNOR-35708	0.839
RIPK1	protein	Q13546	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	phosphorylation	Ser166	LASFKMWsKLNNEEH	-1									18408713	t		miannu	These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1)	SIGNOR-276159	0.2
(R)-salbutamol	chemical	CHEBI:8746	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			10030									20590599	t		Luana	Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. 	SIGNOR-257865	0.8
EFNA5	protein	P52803	UNIPROT	EPHA3	protein	P29320	UNIPROT	up-regulates	binding			9606									9330863	t		gcesareni	Highly promiscuous for ephrin-a ligands it binds preferentially efna5 and became active.	SIGNOR-52470	0.942
FN1	protein	P02751	UNIPROT	A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	up-regulates activity	binding												15721307	t		lperfetto	Integrin alpha8beta1-fibronectin interactions promote cell survival via PI3 kinase pathway.	SIGNOR-253304	0.669
TNKS	protein	O95271	UNIPROT	CASC3	protein	O15234	UNIPROT	down-regulates quantity by destabilization	ADP-ribosylation			9606									21478859	t		lperfetto	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 	SIGNOR-263383	0.2
PTPN11	protein	Q06124	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates	dephosphorylation	Tyr1023	DLVDAEEyLVPQQGF	-1									32024694	t		lperfetto	...which in turn suggests the importance SHP2 dephosphorylation of pTyr992 in EGFR and pTyr1023 in HER2 to mediate signaling.|More specifically, we show that acidic residues N-terminal to the substrate pTyr in EGFR and HER2 mediate specific binding by the SHP2 active site, leading to blockade of RasGAP binding and optimal signaling by the two receptors.	SIGNOR-262957	0.832
MRPS18B	protein	Q9Y676	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261452	0.758
bexarotene	chemical	CHEBI:50859	ChEBI	RXRB	protein	P28702	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002058								17483357	t		miannu	Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification.	SIGNOR-259231	0.8
MMP14	protein	P50281	UNIPROT	FGA	protein	P02671	UNIPROT	down-regulates quantity by destabilization	cleavage	Leu433	REYHTEKlVTSKGDK	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain	SIGNOR-263620	0.2
NUP62	protein	P37198	UNIPROT	SASS6	protein	Q6UVJ0	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								24107630	t		Simone	Furthermore, we found interactions and co-localization with γ-tubulin and SAS-6. Our results also point to a potential role of Nup62 in targeting gamma-tubulin and SAS-6 to the centrioles.	SIGNOR-261256	0.2
EML4-ALK	fusion protein	SIGNOR-FP8	SIGNOR	KRAS	protein	P01116	UNIPROT	up-regulates				9606									19483050	f		lperfetto	A recurrent gene fusion between echinoderm microtubule-associated protein-like 4 (EML4;and, occasionally, of other fusion partners) and the anaplastic lymphoma kinase (ALK) geneoccurs in of NSCLCs , resulting in activation of a potent ALK fusion protein.ALK fusion protein is usually found in never-smoker subjects. Although relatively rare, therelative paucity of fusion proteins known to contribute to lung cancer pathogenesis makes this a finding of biological interest. Although present understanding of the ALK fusion protein is limited, it may play a role in activating RAS. Thus it is negatively associated with thepresence of KRAS or EGFR mutations, and may favour ADC histology and never-smokerstatus.	SIGNOR-253216	0.2
3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	up-regulates quantity	precursor of			9606									24786789	t		miannu	Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle.	SIGNOR-266508	0.8
FGFR2	protein	P21802	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates				10090	BTO:0000011								12270934	f		lperfetto	 Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors	SIGNOR-235337	0.307
CSNK1A1	protein	P48729	UNIPROT	NFATC3	protein	Q12968	UNIPROT	down-regulates activity	phosphorylation	Thr204	NEAAARFtLGSPLTS	9606									9630228	t		lperfetto	Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4.	SIGNOR-109768	0.571
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	HSD11B2	protein	P80365	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15659537	f		miannu	 Overexpression of p50 inhibited HSD11B2 promoter activity and overexpression of Egr-1 inhibited transactivation of the HSD11B2 promoter by p65/p50. 	SIGNOR-253877	0.2
MAPK14	protein	Q16539	UNIPROT	PAK6	protein	Q9NQU5	UNIPROT	up-regulates	phosphorylation	Ser165	MPWPEPQsPRVLPNG	9606									15550393	t		gcesareni	The activation of pak6 by both p38 map kinase and mkk6 suggests that pak6 plays a role in the cellular response to stress-related signals.	SIGNOR-130979	0.2
COL18A1	protein	P39060	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									21949456	t			Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium	SIGNOR-254679	0.7
monoisononyl phthalate	chemical	CHEBI:132593	ChEBI	NR1I2	protein	O75469	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 	SIGNOR-268779	0.8
5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-)	smallmolecule	CHEBI:58467	ChEBI	IMP	smallmolecule	CHEBI:17202	ChEBI	up-regulates quantity	precursor of			9606									33179964	t		miannu	The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP.	SIGNOR-267328	0.8
domperidone	chemical	CHEBI:31515	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258381	0.8
PAK1	protein	Q13153	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates	phosphorylation	Ser16	EKEAARRsRRIDRHL	9606		BTO:0000671							9166747	t		gcesareni	Phosphorylation of either ser(16) by pak1 or ser(27) by pkc decreased the affinity of galpha(z) for gbetagamma;phosphorylation of both residues by pkc caused no further effect. Pak1 thus regulates galpha(z) function by attenuating the inhibitory effects of both gaps and gbetagamma.	SIGNOR-48673	0.2
CALM2	protein	P0DP24	UNIPROT	GEM	protein	P55040	UNIPROT	up-regulates activity	binding			10116	BTO:0001009								14701738	t		miannu	Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells.	SIGNOR-266325	0.2
PDK3	protein	Q15120	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	phosphorylation	Ser293	TYRYHGHsMSDPGVS	-1									11486000	t		lperfetto	Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes.	SIGNOR-109647	0.866
creatine	smallmolecule	CHEBI:16919	ChEBI	CKM	protein	P06732	UNIPROT	up-regulates activity	chemical activation			9606									18502307	t		miannu	Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 	SIGNOR-265810	0.8
GPC6	protein	Q9Y625	UNIPROT	SHH	protein	Q15465	UNIPROT	up-regulates activity	binding			9606									31756413	t		miannu	Based on results from in vitro experiments, we had previously proposed that GPC6 stimulates Hh signaling by interacting with Hh and Patched1 (Ptc1), and facilitating/stabilizing their interaction. 	SIGNOR-264029	0.465
HCK	protein	P08631	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates activity	phosphorylation	Tyr759	LYDVSRMyVDPSEIN	-1									7682059	t		lperfetto	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249364	0.531
CHN1	protein	P15882	UNIPROT	CDK5R1	protein	Q15078	UNIPROT	up-regulates	binding			9606									15013773	t		miannu	_-chimaerin was identified to interact with the p35 activator of cdk5. The complex of _-chimaerin, cdk5 and p35 is enzymatically functional	SIGNOR-123439	0.343
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	RANBP3	protein	Q9H6Z4	UNIPROT	unknown	phosphorylation	Ser126	VKRERTSsLTQFPPS	9606									18280241	t		llicata	Rsk phosphorylates serine 58 of ranbp3 in vitro and in vivo	SIGNOR-252770	0.2
ARVCF	protein	O00192	UNIPROT	CDH5	protein	P33151	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0001109								14610055	t		miannu	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 	SIGNOR-252129	0.35
HIPK2	protein	Q9H2X6	UNIPROT	HMGA1	protein	P17096	UNIPROT	down-regulates	phosphorylation	Ser36	PRKQPPVsPGTALVG	9606									17960875	t		gcesareni	Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation.	SIGNOR-158616	0.508
PRKAA1	protein	Q13131	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	up-regulates activity	phosphorylation	Ser374	GDTLLGLsDSEVEEL	-1									31805502	t		miannu	MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected.	SIGNOR-277494	0.2
glutaryl-CoA(5-)	smallmolecule	CHEBI:57378	ChEBI	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	precursor of												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271816	0.8
EPAS1	protein	Q99814	UNIPROT	KDM5A	protein	P29375	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271580	0.269
INSR	protein	P06213	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	phosphorylation	Tyr427	ELFDDPSyVNVQNLD										11075717	t			Insulin predominantly phosphorylates the Shc Tyr-317 residue. Phosphorylated Shc binds to Grb2 which forms a complex with Sos guanine nucleotide exchange factor for p21ras. 	SIGNOR-251325	0.698
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BRAF	protein	P15056	UNIPROT	down-regulates	phosphorylation	Thr401	STTGLSAtPPASLPG	9606									21135229	t		lperfetto	We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities.	SIGNOR-170339	0.2
MFN1	protein	Q8IWA4	UNIPROT	Mitochondrial_fusion	phenotype	SIGNOR-PH218	SIGNOR	up-regulates				9606									25486875	f		lperfetto	OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria	SIGNOR-272984	0.7
CAMKK2	protein	Q96RR4	UNIPROT	CAMK4	protein	Q16566	UNIPROT	up-regulates activity	phosphorylation	Thr200	EHQVLMKtVCGTPGY										7615569	t		llicata	Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation.	SIGNOR-250718	0.603
MAPK1	protein	P28482	UNIPROT	DDHD1	protein	Q8NEL9	UNIPROT	unknown	phosphorylation	Ser727	TIPSPVTsPVLSRRH	-1									11328814	t		miannu	Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity	SIGNOR-262972	0.2
T_cell_activation	phenotype	SIGNOR-PH73	SIGNOR	IL17A	protein	Q16552	UNIPROT	up-regulates quantity				9606	BTO:0002417								32454942	f		miannu	 interferon gamma- (IFNγ-) and interleukin-17- (IL-17-) secreting CD4+ T cells are believed to be the pathogenic initiators of MS [22], and in MS patients, the increased production of either IFNγ or IL-17 is associated with pathology 	SIGNOR-263819	0.7
FASLG	protein	P48023	UNIPROT	FAS	protein	P25445	UNIPROT	up-regulates activity	binding			9606	BTO:0000007	BTO:0000671							9228058	t		lperfetto	The death-inducing receptor fas is activated when cross-linked by the type ii membrane protein faslg (fasl)	SIGNOR-49688	0.9
GMPS	protein	P49915	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	chemical modification			9606									6698284	t		miannu	The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2).	SIGNOR-267341	0.8
ATG14	protein	Q6ZNE5	UNIPROT	Vps34 Complex I	complex	SIGNOR-C242	SIGNOR	form complex	binding			-1									30397185	t		lperfetto	PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively.	SIGNOR-260318	0.908
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606									22021368	f		apalma	Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB.	SIGNOR-255693	0.7
ALPL	protein	P05186	UNIPROT	Bone_mineralization	phenotype	SIGNOR-PH69	SIGNOR	up-regulates				9606									19049325	f		miannu	PC-1 and Tnap work together to produce normally mineralized bone matrix through the generation and hydrolysis of pyrophosphate.	SIGNOR-252196	0.7
EEF1D	protein	P29692	UNIPROT	ITGA7	protein	Q13683	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000165								16129691	t		lperfetto	alpha7 Integrin Expression Is Negatively Regulated by deltaEF1 during Skeletal Myogenesis	SIGNOR-241773	0.2
STX11-VAMP8 SNARE complex	complex	SIGNOR-C273	SIGNOR	Membrane_fusion	phenotype	SIGNOR-PH122	SIGNOR	up-regulates				9606	BTO:0000782								22767500	f		lperfetto	Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. 	SIGNOR-261900	0.7
PDGFRA	protein	P16234	UNIPROT	CRK	protein	P46108	UNIPROT	up-regulates	binding			9606									10733900	t		amattioni	Crk could bind to both pdgf alpha- and beta-receptors in vivo.	SIGNOR-75881	0.63
NUP188	protein	Q5SRE5	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262084	0.602
PTPRG	protein	P23470	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	dephosphorylation	Tyr1069	EDSFLQRySSDPTGA	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254699	0.494
MAPK3	protein	P27361	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000567								19777442	t		gcesareni	Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells.	SIGNOR-188172	0.46
AP1	complex	SIGNOR-C154	SIGNOR	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates activity				9606									31340499	f		Luana	AP-1 Transcription Factors as Regulators of Immune Responses in Cancer	SIGNOR-260766	0.7
WARS1	protein	P23381	UNIPROT	alpha-aminoacyl-tRNA	smallmolecule	CHEBI:2651	ChEBI	up-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 	SIGNOR-270801	0.8
superoxide	smallmolecule	CHEBI:18421	ChEBI	SOD3	protein	P08294	UNIPROT	up-regulates activity	precursor of			9606									29301787	t		lperfetto	Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD).	SIGNOR-272274	0.8
JAK1	protein	P23458	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	phosphorylation	Tyr701	DGPKGTGyIKTELIS	9606	BTO:0000567								11823427	t		lperfetto	The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosine“SH2 domain interactions	SIGNOR-236373	0.783
LTB4R2	protein	Q9NPC1	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256674	0.252
PINK1	protein	Q9BXM7	UNIPROT	PRKN	protein	O60260	UNIPROT	up-regulates activity	phosphorylation	Ser65	NCDLDQQsIVHIVQR	9606	BTO:0000007								22724072	t			PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65	SIGNOR-270345	0.2
KAT6B	protein	Q8WYB5	UNIPROT	KAT6A/KAT6B	complex	SIGNOR-C54	SIGNOR	form complex	binding			9606									17694082	t		miannu	Like gcn5/pcaf and p300/cbp, moz and morf are transcriptional co-activators with intrinsic hat activity.	SIGNOR-157307	0.39
PYCARD	protein	Q9ULZ3	UNIPROT	Pyrin inflammasome	complex	SIGNOR-C226	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256414	0.705
3-[4-(3-chlorophenyl)piperazin-1-yl]-1,1-diphenylpropan-2-ol hydrochloride	chemical	CHEBI:64057	ChEBI	HTR1D	protein	P28221	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190774	0.8
EGLN1	protein	Q9GZT9	UNIPROT	HIF1A	protein	Q16665	UNIPROT	down-regulates quantity by destabilization	hydroxylation			9606	BTO:0000567								32755251	t		lperfetto	Hypoxia-inducible factor-1 (HIF-1) is a key regulator of erythropoiesis. In this article, we report 3 novel mutations, P378S, A385T, and G206C, on the EGLN1 gene encoding the negative HIF-1α regulator prolyl hydroxylase domain-2 (PHD2) in 3 patients with isolated erythrocytosis. These mutations impair PHD2 protein stability and partially reduce PHD2 activity, leading to increased HIF-1α protein levels in cultured cells.|Oxygen-dependent hydroxylation by the prolyl hydroxylase domain-2 (PHD2) protein marks HIF-1alpha for ubiquitination by the von Hippel Lindau (VHL) tumor suppressor protein, leading to proteasomal degradation	SIGNOR-261994	0.915
GNB1	protein	P62873	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606	BTO:0000938								16537363	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt	SIGNOR-252679	0.51
EGLN3	protein	Q9H6Z9	UNIPROT	PK	proteinfamily	SIGNOR-PF80	SIGNOR	up-regulates activity	hydroxylation			9606	BTO:0000567								21620138	t			Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells.	SIGNOR-268146	0.447
Scribble_complex_DLG3-LLGL1_variant	complex	SIGNOR-C507	SIGNOR	Cell_polarity	phenotype	SIGNOR-PH213	SIGNOR	up-regulates				9606									23397623	f		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270898	0.7
PLK1	protein	P53350	UNIPROT	BUB1B	protein	O60566	UNIPROT	up-regulates	phosphorylation	Thr680	IEDSREAtHSSGFSG	9606									23079597	t		lperfetto	Phosphorylation of kard by plk1 promotes direct interaction of bubr1 with the pp2a-b56_ phosphatase that counters excessive aurora b activity at kinetochores. We propose that plk1 and bubr1 cooperate to stabilize kinetochore-microtubule interactions. Phosphorylation of t680 by plk1 is essential for kard function	SIGNOR-199222	0.834
PLK1	protein	P53350	UNIPROT	FBXO5	protein	Q9UKT4	UNIPROT	down-regulates	phosphorylation			9606									15469984	t		gcesareni	Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering scfbetatrcp-dependent destruction of the apc inhibitor emi1.	SIGNOR-129813	0.774
trimetrexate	chemical	CHEBI:9737	ChEBI	DHFR	protein	P00374	UNIPROT	down-regulates activity	chemical inhibition			9606									7981057	t		miannu	We examined the cytotoxicity and biochemical effects of the lipophilic antifol trimetrexate (TMQ) in two human colon carcinoma cell lines, SNU-C4 and NCI-H630, with different inherent sensitivity to TMQ. Dihydrofolate reductase (DHFR) and thymidylate synthase were quantitatively and qualitatively similar in both lines. During drug exposure, DHFR catalytic activity was inhibited by > or = 85% in both cell lines	SIGNOR-258482	0.8
EREG	protein	O14944	UNIPROT	ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	up-regulates	binding			9606									16829981	t	inferred from 70% of family members	gcesareni	For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4.	SIGNOR-269873	0.891
MAVS	protein	Q7Z434	UNIPROT	STING1	protein	Q86WV6	UNIPROT	up-regulates activity	binding			9606									24622840	t		miannu	MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. 	SIGNOR-260152	0.2
KLF11	protein	O14901	UNIPROT	SIN3A	protein	Q96ST3	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								11438660	t		miannu	detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.	SIGNOR-222344	0.501
4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide	chemical	CHEBI:94504	ChEBI	HDAC8	protein	Q9BY41	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191436	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Thr359	DTEFTSRtPKDSPGI	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-250557	0.2
STK4	protein	Q13043	UNIPROT	LATS1	protein	O95835	UNIPROT	up-regulates	phosphorylation	Thr1079	EHAFYEFtFRRFFDD	9606									15688006	t		milica	We show that Mst2 and hWW45 interact with each other in human cells and that both Mst2 and Mst1 are able to phosphorylate Lats1 and Lats2, thereby stimulating Lats kinase activity.	SIGNOR-133555	0.607
EPM2A	protein	O95278	UNIPROT	GSK3B	protein	P49841	UNIPROT	unknown	dephosphorylation	Ser9	SGRPRTTsFAESCKP	10090									16959610	t			Epm2a-encoded laforin is a phosphatase for GSK-3beta and an important repressor in the Wnt signaling pathway| only GSK-3β phosphorylation on Ser9 was affected by overexpression of laforin|Although GSK-3β is inactivated by phosphorylation at the Ser9 position, it is unclear if the inactivated enzyme can be reactivated by dephosphorylation.	SIGNOR-248345	0.474
GTF3C1	protein	Q12789	UNIPROT	TFIIIC	complex	SIGNOR-C392	SIGNOR	form complex	binding			9606									29378333	t		lperfetto	Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains	SIGNOR-266188	0.877
TP53	protein	P04637	UNIPROT	PHB	protein	P35232	UNIPROT	up-regulates activity	binding												16918502	t		lperfetto	Our previous studies have shown that prohibitin physically interacts with the marked-box domain of E2F family members and represses their transcriptional activity; in contrast, prohibitin could bind to and enhance the transcriptional activity of p53.	SIGNOR-268978	0.455
CEP63	protein	Q96MT8	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								26297806	t		lperfetto	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.	SIGNOR-271725	0.382
SOD2	protein	P04179	UNIPROT	dioxygen	smallmolecule	CHEBI:15379	ChEBI	up-regulates quantity	chemical modification			9606									29301787	t		lperfetto	Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD).	SIGNOR-272282	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BCL2	protein	P10415	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr74	ARTSPLQtPAAPGAA	9606	BTO:0000567								10669763	t		lperfetto	The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro.	SIGNOR-244494	0.2
PTP4A3	protein	O75365	UNIPROT	KRT8	protein	P05787	UNIPROT	down-regulates activity	dephosphorylation	Ser432	SAYGGLTsPGLSYSL	9606	BTO:0000586								19115206	t			the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL-3-interacting protein. Indeed, treatment with the PRL-3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431	SIGNOR-248341	0.276
prostaglandin E2(1-)	smallmolecule	CHEBI:606564	ChEBI	PTGER1	protein	P34995	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257569	0.8
UHMK1	protein	Q8TAS1	UNIPROT	SF1	protein	Q15637	UNIPROT	up-regulates	phosphorylation	Ser82	NPEDRSPsPEPIYNS	9606									16420481	t	The effect has been demonstrated using Q15637-2	gcesareni	Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding.	SIGNOR-143841	0.417
HTR3D	protein	Q70Z44	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606		BTO:0000142							18761359	f		miannu	The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release. 	SIGNOR-264319	0.7
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	up-regulates quantity	precursor of			9606									8755651	t		scontino	Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5’-position) to yield T3	SIGNOR-268127	0.8
SLX4	protein	Q8IY92	UNIPROT	ERCC4/ERCC1	complex	SIGNOR-C50	SIGNOR	up-regulates	binding			9606									24726326	t		lperfetto	Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair.	SIGNOR-217652	0.813
SLIT2	protein	O94813	UNIPROT	GPC1	protein	P35052	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000142							10364234	t		gcesareni	Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis.	SIGNOR-68428	0.587
HOOK3	protein	Q86VS8	UNIPROT	MSR1	protein	P21757	UNIPROT	down-regulates	binding			9606	BTO:0000801								17237231	t		miannu	We have identified a microtubule-binding protein, hook3, as a novel interacting partner of sr-a. / by transfecting small interfering rna targeting hook3, total and surface expression, receptor-mediated ligand uptake and protein stability of sr-a were significantly promoted, whereas the protein synthesis and maturation were not altered. We propose for the first time that hook3 may participate in the turnover of the endocytosed scavenger receptor	SIGNOR-152314	0.338
GRB2	protein	P62993	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates	binding			9606									12766170	t	Grb2-associated binding (Gab) scaffolding/adapter proteins are a family of three members including mammalian Gab1, Gab2, and Gab3 that are highly conserved.	lperfetto	The gab1 docking protein forms a platform for the assembly of a multiprotein signaling complex downstream from receptor tyrosine kinases. In general, recruitment of gab1 occurs indirectly, via the adapter protein grb2	SIGNOR-235917	0.868
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	ETV6	protein	P41212	UNIPROT	down-regulates	phosphorylation			10090									15060146	t	inferred from 70% family members	miannu	Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation.	SIGNOR-270120	0.2
PRKCA	protein	P17252	UNIPROT	LRRK1	protein	Q38SD2	UNIPROT	up-regulates activity	phosphorylation	Thr1075	NQRNRCStFRVKRNQ	-1									36040231	t		miannu	PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain. 	SIGNOR-276865	0.2
TSC22D1	protein	Q15714	UNIPROT	NPPC	protein	P23582	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									9022669	t		Luana	TSC-22 significantly enhanced CNP promoter activity in GH3 cells.	SIGNOR-266226	0.26
PRKCD	protein	Q05655	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser359	EERQTQRsKPQPAVP	9606	BTO:0000130								12056906	t		esanto	Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?.	SIGNOR-89237	0.459
ASCL1	protein	P50553	UNIPROT	DKK1	protein	O94907	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000527								23707066	t		gcesareni	We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1.	SIGNOR-245885	0.312
SOS2	protein	Q07890	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									21779497	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.	SIGNOR-175262	0.781
GEMIN4	protein	P57678	UNIPROT	SMN complex	complex	SIGNOR-C158	SIGNOR	form complex	binding												12065586	t		lperfetto	SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry.	SIGNOR-253118	0.801
MAP3K2	protein	Q9Y2U5	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								11343802	t		lperfetto	Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation	SIGNOR-107695	0.594
FOXA2	protein	Q9Y261	UNIPROT	SLCO1B3	protein	Q9NPD5	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									14739090	f		lperfetto	The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma.	SIGNOR-268987	0.2
ELOVL4	protein	Q9GZR5	UNIPROT	palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	down-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267892	0.8
RAGAC	complex	SIGNOR-C113	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity	relocalization			9606									20381137	t		gcesareni	The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb	SIGNOR-228158	0.677
GSK3B	protein	P49841	UNIPROT	CAP1	protein	Q01518	UNIPROT	up-regulates activity	phosphorylation	Ser310	PKPQTSPsPKRATKK	9606		BTO:0000763							30123351	t		lperfetto	We found that GSK3 phosphorylates S307 and S309 by using inhibitors LiCl. Inhibition of GSK3beta can cause loss of cell polarity as well as accumulation of stress fibers. We propose that GSK3 regulates CAP1 through at least two mechanisms. First, GSK3 (and potentially other kinases) phosphorylate CAP1 at S309 and promote CAP1 localization to the cytosol. Second, phosphorylation at S309 affects protein-protein interactions with actin and cofilin. The loss of this phospho-regulation by GSK3 inhibition is expected to disrupt CAP1 function and actin dynamics.	SIGNOR-264823	0.256
NRF1	protein	Q16656	UNIPROT	SLC46A1	protein	Q96NT5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20724482	f		miannu	Overexpression of NRF-1 or a constitutively active NRF-1 VP-16 construct resulted in increased reporter activity and PCFT mRNA levels. These novel findings identify NRF-1 as a major inducible transcriptional regulator of PCFT gene expression.	SIGNOR-254884	0.344
VEGFB	protein	P49765	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252276	0.7
SDF2L1	protein	Q9HCN8	UNIPROT	LRP4	protein	O75096	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								24140340	t		llicata	Here, we show that the chaperon Mesdc2 binds to the intracellular form of Lrp4 and promotes its glycosylation and cell-surface expression. These results suggest that Mesdc2 plays an essential role in NMJ formation by promoting Lrp4 maturation.	SIGNOR-237942	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PRKD1	protein	Q15139	UNIPROT	up-regulates activity	phosphorylation	Ser742	GEKSFRRsVVGTPAY										18692497	t		lperfetto	The results presented in this study indicate that during mitosis, PKD3 and PKD are phosphorylated at Ser(731) and Ser(744) within their activation loop by a mechanism that requires protein kinase C. Mitosis-associated PKD3 Ser(731) and PKD Ser(744) phosphorylation is related to the catalytic activation of these kinases as evidenced by in vivo phosphorylation of histone deacetylase 5, a substrate of PKD and PKD3. 	SIGNOR-275925	0.2
WWTR1	protein	Q9GZV5	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates	binding			9606									21084559	t		gcesareni	Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal.	SIGNOR-169841	0.536
EEF1A1P5	protein	Q5VTE0	UNIPROT	His-tRNA(His)	smallmolecule	CHEBI:29155	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269551	0.8
CYP21A2	protein	P08686	UNIPROT	progesterone	smallmolecule	CHEBI:17026	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000048							25855791	t		lperfetto	Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively	SIGNOR-268646	0.8
PER2	protein	O15055	UNIPROT	POU2F1	protein	P14859	UNIPROT	down-regulates activity	binding			9606	BTO:0001939								23836662	t		miannu	 This PER2-OCT1 interaction effectively converted OCT1 sites, which normally activate expression, into repressor sites by recruitment of a polycomb repressor complex including EZH2 and SUZ12, as well as HDAC2. 	SIGNOR-254148	0.2
PRKAA1	protein	Q13131	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation			6239			SIGNOR-C15						17900900	t		lperfetto	The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt.	SIGNOR-219247	0.509
CDKN3	protein	Q16667	UNIPROT	CDK2	protein	P24941	UNIPROT	down-regulates activity	dephosphorylation	Thr160	GVPVRTYtHEVVTLW	9606									11463386	t			The CDK-interacting protein phosphatase KAP dephosphorylates phosphoThr-160 (pThr-160) of the CDK2 activation segment, the site of regulatory phosphorylation that is essential for kinase activity.	SIGNOR-248724	0.738
PRKCH	protein	P24723	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates activity	phosphorylation	Ser43	VETWQEGsLKASCLY	-1									15604283	t		miannu	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276014	0.2
PRKCB	protein	P05771	UNIPROT	HABP4	protein	Q5JVS0	UNIPROT	down-regulates activity	phosphorylation	Thr354	RKPANDItSQLEINF	9606	BTO:0004974								14699138	t		lperfetto	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249247	0.293
ZMYND8	protein	Q9ULU4	UNIPROT	ADORA1	protein	P30542	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								21620140	t		Luana	We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8. 	SIGNOR-266208	0.2
INO80E	protein	Q8NBZ0	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270845	0.636
PLK1	protein	P53350	UNIPROT	BUB1B	protein	O60566	UNIPROT	up-regulates	phosphorylation	Thr792	PRNSAELtVIKVSSQ	9606									17376779	t		gcesareni	Bubr1 was phosphorylated by plk1 in vitro at two plk1 consensus sites in the kinase domain of bubr1	SIGNOR-153867	0.834
Bafetinib	chemical	CID:24853523	PUBCHEM	LYN	protein	P07948	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190227	0.8
AKT3	protein	Q9Y243	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	phosphorylation	Ser615	SYKIRFNsISCSDPL	9606	BTO:0001853								24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251626	0.463
PRKCA	protein	P17252	UNIPROT	GRK2	protein	P25098	UNIPROT	up-regulates activity	phosphorylation	Ser29	ATPAARAsKKILLPE	9606	BTO:0000007								11042191	t		lperfetto	Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells. 	SIGNOR-249058	0.2
Dynorphin B	chemical	CHEBI:80347	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258798	0.8
PLK1	protein	P53350	UNIPROT	ESPL1	protein	Q14674	UNIPROT	down-regulates activity	phosphorylation	Ser1399	KVNFSDDsDLEDPVS	9606	BTO:0002181								17974570	t		miannu	Although mutation of serine 1126 and threonine 1346 to alanine had no effect (lanes 2 and 5), additional mutation of threonine 1363 and serine 1399 rendered separase almost completely resistant to phosphorylation (lane 3). Serine 1399 seems to be the one residue within this large separase fragment that is most efficiently phosphorylated by polo-like kinase, because a corresponding point mutation was sufficient to reduce the labeling by 80% compared with wild type (lane 6).	SIGNOR-276082	0.763
TCF4	protein	P15884	UNIPROT	SSTR2	protein	P30874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001976								10207097	t		Luana	Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain.	SIGNOR-261618	0.366
EEF1A2	protein	Q05639	UNIPROT	Asp-tRNA(Asp)	smallmolecule	CHEBI:29158	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269527	0.8
ACVR1B	protein	P36896	UNIPROT	HBA1	protein	P69905	UNIPROT	up-regulates quantity by stabilization				9606									2920215	f	Regulation	miannu	Activin, also named FSH-releasing protein, was previously shown to induce hemoglobin accumulation in K562 cells and potentiate the proliferation and differentiation of CFU-E in human bone marrow cultures.	SIGNOR-251769	0.2
ZFAT	protein	Q4KMQ4	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates quantity				10090									24663380	f		francesca	Ano6 deficiency significantly reduces ERK/AKT phosphorylation. In addition, Ano6-KD also affected levels of phosphorylated and total AKT levels.	SIGNOR-261215	0.2
SUN5	protein	Q8TC36	UNIPROT	LINC complex	complex	SIGNOR-C303	SIGNOR	form complex	binding												24481844	t		lperfetto	LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM.	SIGNOR-263289	0.33
lysophosphatidic acids	smallmolecule	CHEBI:32957	ChEBI	LPAR1	protein	Q92633	UNIPROT	up-regulates	chemical activation			9606									16014605	t		gcesareni	Lpa exerts its downstream signaling by binding to the lpa(1), lpa(2), and lpa(3) (formerly edg-2, -4, and -7) family of seven-transmembrane, segmented, heterotrimeric guanine nucleotide-binding protein (g protein)-coupled receptors.	SIGNOR-138582	0.8
MAPK14	protein	Q16539	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates activity	phosphorylation	Thr581	PDNQPLKtPCFTLHY	9606									15568999	t		lperfetto	Msk1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the erk1/2 (extracellular-signal-regulated kinase) and p38 mapk (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites	SIGNOR-131375	0.594
PLK1	protein	P53350	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates	phosphorylation	Thr206	MTSELEStSLGDSDE	9606									20823832	t		lperfetto	Dvl2 bound to and was phosphorylated at thr206 by a mitotic kinase, polo-like kinase 1 (plk1), and this phosphorylation was required for spindle orientation and stable microtubule (mt)-kt attachment	SIGNOR-167858	0.478
PDGFRB	protein	P09619	UNIPROT	ABL2	protein	P42684	UNIPROT	up-regulates activity	phosphorylation	Tyr161	QGWVPSNyITPVNSL	-1									34144039	t		miannu	 PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2.	SIGNOR-277306	0.308
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606	BTO:0000007								9373175	t		gcesareni	Evidence that the inhibition of glycogen synthase kinase-3_ by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9	SIGNOR-242578	0.2
RXR	proteinfamily	SIGNOR-PF44	SIGNOR	PPARG	protein	P37231	UNIPROT	up-regulates activity	binding			9606									11237216	t		miannu	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-259057	0.2
ROS	stimulus	SIGNOR-ST2	SIGNOR	MAP3K5	protein	Q99683	UNIPROT	up-regulates				9606									11266364	f		lperfetto	TNF- but not Fas-induced apoptosis requires ROS-dependent activation of ASK1_JNK/p38 pathways. Thus, ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosis.	SIGNOR-226609	0.7
perfluorooctanoic acid	chemical	CHEBI:35549	ChEBI	ESR2	protein	Q92731	UNIPROT	up-regulates activity	chemical activation			-1									23764977	t		miannu	Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. 	SIGNOR-268765	0.8
HRH4	protein	Q9H3N8	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256815	0.409
MRPL9	protein	Q9BYD2	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262343	0.733
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CDKN1A	protein	P38936	UNIPROT	down-regulates activity	binding			9606	BTO:0000222								16982699	t		lperfetto	More importantly, the consequences of phosphorylation of either Thr145 or Ser146 are distinct. When p21 is phosphorylated on Thr145, it localizes to the nucleus and results in the disruption of the association between proliferating cell nuclear antigen and p21. Furthermore, phosphorylation of Thr145 promotes stabilization of p21	SIGNOR-244187	0.2
SLC24A4	protein	Q8NFF2	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264402	0.8
ING2	protein	Q9H160	UNIPROT	MMP13	protein	P45452	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001913								19437536	f		miannu	 ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression.	SIGNOR-254491	0.395
tRNA(Thr)	smallmolecule	CHEBI:29180	ChEBI	Thr-tRNA(Thr)	smallmolecule	CHEBI:29163	ChEBI	up-regulates quantity	precursor of			9606									25824639	t		miannu	Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 	SIGNOR-270507	0.8
MBOAT7	protein	Q96N66	UNIPROT	2-acyl-sn-glycero-3-phospho-D-myo-inositol	smallmolecule	CHEBI:62746	ChEBI	down-regulates quantity	chemical modification			-1									18772128	t		miannu	The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils.	SIGNOR-267246	0.8
LRRFIP2	protein	Q9Y608	UNIPROT	DVL3	protein	Q92997	UNIPROT	up-regulates	binding			9606									15677333	t		gcesareni	In particular, a previously unrecognized activator, lrrfip2 (leucine-rich repeat in flightless interaction protein 2), was found that interacts with dvl to increase the cellular levels of _-catenin and activate _-catenin/lef/tcf-dependent transcriptional activity	SIGNOR-133429	0.395
PAK1	protein	Q13153	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation	Ser405	KTQTPPVsPAPQPTE	9606									21079800	t		gcesareni	Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis.	SIGNOR-169690	0.695
MAPK1	protein	P28482	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr74	ARTSPLQtPAAPGAA	9606	BTO:0000567								10669763	t		lperfetto	In endothelial cells, tumor necrosis factor alpha (tnf-alpha) induces dephosphorylation and subsequent ubiquitin-dependent degradation of the antiapoptotic protein bcl-2. Here, we investigate the role of different putative phosphorylation sites to facilitate bcl-2 degradation	SIGNOR-74927	0.532
AGRP	protein	O00253	UNIPROT	MC4R	protein	P32245	UNIPROT	down-regulates activity	binding			9606									10318826	t		miannu	AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor.	SIGNOR-252379	0.767
BRMS1	protein	Q9HCU9	UNIPROT	EP300	protein	Q09472	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								23269275	t		miannu	BRMS1 suppresses lung cancer metastases through an E3 ligase function on histone acetyltransferase p300. BRMS1 induces polyubiquitination of p300, resulting in its proteasome-mediated degradation.	SIGNOR-266408	0.37
MAPK1	protein	P28482	UNIPROT	TXNIP	protein	Q9H3M7	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr349	HRLESPTtPLLDDMD	9606	BTO:0000018								31320475	t		miannu	ERK-dependent Txnip ubiquitination and proteasome degradation depended upon phosphorylation of a PXTP motif threonine (Thr349) located within the C-terminal α-arrestin domain and proximal to a previously characterized E3 ubiquitin ligase-binding site. 	SIGNOR-277468	0.299
MAP2K3	protein	P46734	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000130;BTO:0000801;BTO:0000876								7535770	t		lperfetto	Recently, two map kinase kinases (mkk3 and mkk4) that activate p38 map kinase have been identified. the mechanism of p38 activation is mediated by dual phosphorylation on thr-180 and tyr-182.	SIGNOR-236103	0.715
4-[2-(2-chloro-4-fluoroanilino)-5-methyl-4-pyrimidinyl]-N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]-1H-pyrrole-2-carboxamide	chemical	CHEBI:95049	ChEBI	MAPK1	protein	P28482	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001271								31482470	t		miannu	 In the present study, we have shown that ERK2 inhibitor VX-11e demonstrates a potent synergy with voreloxin in leukemia cell lines and that this effect is associated with the inhibition of proliferation, cell cycle arrest and induction of apoptosis.	SIGNOR-262244	0.8
HTR2B	protein	P41595	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257228	0.409
PRKCI	protein	P41743	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606	BTO:0000527								21419810	t		lperfetto	In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer	SIGNOR-172886	0.324
SF3B3	protein	Q15393	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270665	0.803
terazosin	chemical	CHEBI:9445	ChEBI	ADRA1A	protein	P35348	UNIPROT	down-regulates activity	chemical inhibition			9606		BTO:0001260							9379432	t		miannu	Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication	SIGNOR-258671	0.8
GRB2	protein	P62993	UNIPROT	MAP4K1	protein	Q92918	UNIPROT	up-regulates	binding			9606	BTO:0000782								9891069	t		gcesareni	The first and second proline-rich motifs containing the grb2 n-sh3-binding consensus sequence (-p-x-x-p-x-r/k-) were implicated in the binding of hpk1 to grb2.	SIGNOR-63994	0.465
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RHOA	protein	P61586	UNIPROT	up-regulates activity	phosphorylation	Ser88	LMCFSIDsPDSLENI	9534	BTO:0000298								26816343	t		miannu	We have recently reported that Rac1 is phosphorylated on threonine 108 (108T) by extracellular signal-regulated kinases (ERK) in response to epidermal growth factor (EGF) stimulation. Here, we provide evidence that RhoA is phosphorylated by ERK on 88S and 100T in response to EGF stimulation.	SIGNOR-277202	0.2
INPPL1	protein	O15357	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates				9606	BTO:0000776								10942391	f		lperfetto	Taken together, the data presented here demonstrate that ship inhibits akt primarily through regulation of akt membrane localization.	SIGNOR-244406	0.635
CDKL5	protein	O76039	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates activity	phosphorylation	Ser293	PAPARPRsPSQTRKG	10090									23651931	t		gcesareni	This 120-kDa protein was identified as amphiphysin 1 (Amph1) by LC-MS/MS analysis, and the site of phosphorylation by CDKL5 was determined to be Ser-293.| The phosphorylation mimic mutants, Amph1(S293E) and Amph1(S293D), showed significantly reduced affinity for endophilin, a protein involved in synaptic vesicle endocytosis	SIGNOR-245881	0.369
MAML1	protein	Q92585	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	acetylation			9606									17300219	t		gcesareni	The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin.	SIGNOR-265362	0.2
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1675	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120012	0.781
SREBF1	protein	P36956	UNIPROT	PKM	protein	P14618	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16308421	t		gcesareni	Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk)	SIGNOR-142297	0.295
PRKACA	protein	P17612	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser63	AAEERRKsHEAEVLK	9606									8376365	t		gcesareni	Phosphorylation at either ser(16) or ser(63) strongly reduced or abolished the ability of stathmin to bind to and sequester soluble tubulin and its ability to act as a catastrophe factor by directly binding to the microtubules. The known in vivo phosphorylation sites of stathmin are ser-16 and ser-63 for cyclic amp-dependent protein kinase (pka).	SIGNOR-38322	0.313
clozapine	chemical	CHEBI:3766	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258369	0.8
CLCN4	protein	P51793	UNIPROT	chloride	smallmolecule	CHEBI:17996	ChEBI	down-regulates quantity	relocalization			9606									28972156	t		miannu	ClC-3 and ClC-4 are two closely related intracellular chloride/proton exchangers that co-exist in neurons, glia, muscle, heart, and epithelial cells. ClC-4 is an intracellular Cl-/H+ exchanger that is highly expressed in the brain and whose dysfunction has been linked to intellectual disability and epilepsy. ClC-4 is retained in the endoplasmic reticulum (ER) upon overexpression in HEK293T cells. 	SIGNOR-265421	0.8
RPS6KA3	protein	P51812	UNIPROT	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606									2846551	t		gcesareni	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-23753	0.2
ITSN1	protein	Q15811	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000567								30540523	t		lperfetto	 Significantly, here we identify the long isoform of ITSN-1, which has Cdc42 GEF activity| We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A).	SIGNOR-260612	0.842
MAPK1	protein	P28482	UNIPROT	CTNND1	protein	O60716	UNIPROT	down-regulates activity	phosphorylation	Thr906	SLDNNYStPNERGDH	9615	BTO:0000837								32010791	t		miannu	 Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation. 	SIGNOR-277505	0.273
KAT2B	protein	Q92831	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269612	0.2
SOX4	protein	Q06945	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606	BTO:0000038								17875931	t		irozzo	We have demonstrated that Sox17 and Sox4 can directly interact with β-catenin and TCF/LEF proteins.Sox4 enhances β-catenin/TCF activity and the proliferation of SW480 cells.In contrast, Sox4 may function to stabilize β-catenin protein.	SIGNOR-256138	0.576
CAMK2A	protein	Q9UQM7	UNIPROT	SYNGAP1	protein	Q96PV0	UNIPROT	up-regulates activity	phosphorylation	Thr1077	RGKSQQLtVSAAQKP	-1									15358237	t		miannu	Certain phosphopeptides were detected only in samples phosphorylated in vitro under conditions that favor CaMKII activity (Mg2+-ATP, Ca2+, calmodulin, and peptide inhibitors of PKA and PKC). In samples phosphorylated in vitro in the presence of Ca2+/calmodulin, we also detected the peptide (R)GKS*QQLT*VSAAQKPR with phosphorylated residues corresponding to S-1058 and T-1062 of synaptic ras GTPase activating protein (SynGAP).	SIGNOR-262691	0.439
Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	SIRT6	protein	Q8N6T7	UNIPROT	up-regulates				9606									25815987	t		miannu	Intriguingly, SIRT6 is chromatin bound, controls lipid metabolism, and is enzymatically activated by fatty acids	SIGNOR-268156	0.7
IKBKB	protein	O14920	UNIPROT	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22056382	f			Tnf-α enhanced the transcriptional activity of a classical Notch target gene via Ikk2 by inducing histone H3 phosphorylation	SIGNOR-253585	0.2
PRPF3	protein	O43395	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction.	SIGNOR-271967	0.766
EDNRB	protein	P24530	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257254	0.432
WARS1	protein	P23381	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 	SIGNOR-270513	0.8
DAPT	chemical	CHEBI:86193	ChEBI	PSEN1	protein	P49768	UNIPROT	down-regulates	chemical inhibition			9606									16569643	t		gcesareni	The catalytic aspartates are necessary for binding of the transition state analogue inhibitor, l-685,458, to ps1. It is possible that these catalytic aspartates also contribute to the direct interaction of ps with dapt.	SIGNOR-145385	0.8
CSNK2A1	protein	P68400	UNIPROT	G3BP1	protein	Q13283	UNIPROT	down-regulates activity	phosphorylation	Ser149	VTEPQEEsEEEVEEP	9606	BTO:0001938								27920254	t		miannu	We also show that casein kinase 2 phosphorylates G3BP1 at serine 149 in vitro and in cells. These data support a role for casein kinase 2 in regulation of protein synthesis by downregulating stress granule formation through G3BP1.CK2 regulates SG disassembly during stress recovery.G3BP1 is among the strongest SG nucleating proteins, and previous work indicated that G3BP1 phosphorylation at S149 restricts stress granule assembly by partly inhibiting G3BP1 oligomerization 	SIGNOR-260748	0.241
miR-495	mirna	URS000075C517_9606	RNAcentral	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									26055960	f		miannu	Our results suggest that activating mutation of FLT3 in AML can lead, through the induction of JUN, to an increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently may causes block of myeloid differentiation.	SIGNOR-255801	0.4
MT-CYB	protein	P00156	UNIPROT	Mitochondrial respiratory chain complex III	complex	SIGNOR-C279	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits	SIGNOR-262193	0.88
PTPRJ	protein	Q12913	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	dephosphorylation	Tyr868	GSVEMCRyDPLQDNT	9606									28912580	t		miannu	These results support PTPRJ preferentially dephosphorylating Y813 and Y868 in JAK2.|We revealed that PTPRJ negatively regulates leptin signaling by dephosphorylating specific tyrosine residues (Y813 and Y868) in JAK2, the simultaneous phosphorylation of which plays a pivotal role in JAK2 activation.	SIGNOR-277094	0.329
AURKB	protein	Q96GD4	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	phosphorylation	Ser29	ATKAARKsAPATGGV	9606									11856369	t	Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription.	gcesareni	Histone code pathway involving h3 s28 phosphorylation and k27 acetylation activates transcription and antagonizes polycomb silencingaurora-b phosphorylates histone h3 at serine28 with regard to the mitotic chromosome condensation	SIGNOR-114852	0.2
USP7	protein	Q93009	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	deubiquitination												24317448	t		lperfetto	BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP|hese data indicate that BCR-ABL phosphorylation of HAUSP modulates HAUSP’s deubiquitinase activity toward PTEN.	SIGNOR-276533	0.731
PPP4C	protein	P60510	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	up-regulates activity	dephosphorylation	Thr1609	LGPYEAVtPLTKAAD	-1									24703952	t		lperfetto	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Depletion of PP4C, or PP4R3beta, causes persistence of phospho-T1609 and phospho-S1618	SIGNOR-264450	0.365
MAP2K7	protein	O14733	UNIPROT	MAPK13	protein	O15264	UNIPROT	up-regulates activity	phosphorylation	Tyr182	ADAEMTGyVVTRWYR	9606	BTO:0000007								10066767	t	done	miannu	 p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.	SIGNOR-273953	0.412
PLK1	protein	P53350	UNIPROT	BORA	protein	Q6PGQ7	UNIPROT	down-regulates	phosphorylation	Thr501	QMDSGYNtQNCGSNI	9606									18378770	t		gcesareni	Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp).	SIGNOR-178154	0.78
Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	43S_pre_initiation_complex	complex	SIGNOR-C453	SIGNOR	form complex	binding			9606									35489072	t		lperfetto	In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 	SIGNOR-269159	0.2
PLK1	protein	P53350	UNIPROT	HSF1	protein	Q00613	UNIPROT	down-regulates	phosphorylation	Ser216	IPLMLNDsGSAHSMP	9606									18794143	t		lperfetto	Hsf1 was phosphorylated by plk1 at ser(216) of the dsgxxs motif during the timing of mitosis and a phospho-defective mutant form of hsf1 inhibited mitotic progression. Phosphorylated hsf1 during spindle pole localization underwent ubiquitin degradation through the scf(beta-trcp) pathway.	SIGNOR-180915	0.455
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1724	SPSYSPTsPSYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269365	0.718
PPARGC1A	protein	Q9UBK2	UNIPROT	GPX1	protein	P07203	UNIPROT	up-regulates				10090									18074631	f		lperfetto	In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat.	SIGNOR-253396	0.322
EGFR	protein	P00533	UNIPROT	RASA1	protein	P20936	UNIPROT	unknown	phosphorylation	Tyr460	TVDGKEIyNTIRRKT	9606									1850098	t		llicata	We conclude that tyr-460 is a site of gap tyrosine phosphorylation by the egf receptor in vitro and likely in vivo. Gap tyr-460 is located immediately c terminal to the second gap sh2 domain, suggesting that its phosphorylation might have a role in regulating protein-protein interactions.	SIGNOR-21875	0.64
SEC61G	protein	P60059	UNIPROT	SEC61 complex	complex	SIGNOR-C368	SIGNOR	form complex	binding			-1									33925740	t		lperfetto	The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER	SIGNOR-265278	0.888
EP300	protein	Q09472	UNIPROT	CBP/p300	complex	SIGNOR-C6	SIGNOR	form complex	binding			9606									11559745	t		lperfetto	P300/cbp proteins: hats for transcriptional bridges and scaffolds	SIGNOR-110562	0.524
PRKACA	protein	P17612	UNIPROT	CIITA	protein	P33076	UNIPROT	down-regulates activity	phosphorylation	Ser1050	AASLLRLsLYNNCIC	9606	BTO:0000984								11416140	t		lperfetto	Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylation phosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription.	SIGNOR-108569	0.313
PAK2	protein	Q13177	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates activity	phosphorylation	Ser19	PAPPVRMsSTIFSTG	-1									10075701	t		miannu	Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites	SIGNOR-250224	0.2
(4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester	chemical	CHEBI:103931	ChEBI	ADRA1B	protein	P35368	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258465	0.8
PPM1F	protein	P49593	UNIPROT	PAK	proteinfamily	SIGNOR-PF13	SIGNOR	down-regulates	dephosphorylation			9606	BTO:0000150;BTO:0000093								20016286	t	inferred from 70% of family members	gcesareni	Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity.	SIGNOR-269882	0.399
F2	protein	P00734	UNIPROT	Fibrinogen	complex	SIGNOR-C311	SIGNOR	up-regulates activity	cleavage			9606		BTO:0000131							29880919	t		lperfetto	Thrombin is a key enzyme in the pathway and cleaves fibrinogen to fibrin, which spontaneously forms the insoluble polymer that is the basis for the haemostatic plug.	SIGNOR-263525	0.848
MAOA	protein	P21397	UNIPROT	3,4-dihydroxyphenylacetaldehyde	smallmolecule	CHEBI:27978	ChEBI	up-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL).	SIGNOR-264003	0.8
BAK1	protein	Q16611	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	up-regulates	relocalization			9606									14585074	t	Translocation from Mitochondria to Cytosol	amattioni	Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi	SIGNOR-118905	0.502
RPS6KB1	protein	P23443	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	down-regulates	phosphorylation	Ser477	NSMNKLPsVSQLINP	9606									18769144	t		lperfetto	Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively	SIGNOR-180771	0.2
STAT5A	protein	P42229	UNIPROT	PIM	proteinfamily	SIGNOR-PF34	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004479								29507660	f		irozzo	FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. 	SIGNOR-255733	0.423
MAPK3	protein	P27361	UNIPROT	GRB10	protein	Q13322	UNIPROT	up-regulates	phosphorylation	Ser476	MNILGSQsPLHPSTL	9606									15952796	t		lperfetto	Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation	SIGNOR-138175	0.304
TFIID	complex	SIGNOR-C343	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	binding			9606									27096372	t		miannu	Our structures suggest that a primary function of TFIID during PIC assembly is the proper positioning of TBP on the upstream promoter, which ultimately determines the placement of Pol II relative to the TSS. The structures presented here offer a structural framework for understanding the complex mechanism underlying TFIID function, shedding new light into the overlapping roles of TFIID as both a coactivator and a general platform for PIC assembly in the coordination of transcription initiation.	SIGNOR-263934	0.524
PTPN11	protein	Q06124	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	dephosphorylation	Tyr419	RLIEDNEyTARQGAK	10090									18482983	t			we identify SHP-2 and PTP-PEST as negative regulators of c-Src kinase | Inactivation of catalytically active c-Src kinase by the phosphatases SHP-2 or PTP-PEST by dephosphorylation of the tyrosine residue Tyr-416 within the c-Src kinase domain prevents the phosphorylation of villin	SIGNOR-248670	0.639
VASP	protein	P50552	UNIPROT	ATIC	protein	P31939	UNIPROT	up-regulates activity	phosphorylation	Tyr104	RVVACNLyPFVKTVA	9606	BTO:0002181								18845790	t		miannu	ATIC and VASP phosphorylation is dependent on NPM-ALK kinase activity. 	SIGNOR-276172	0.35
SLC9A3	protein	P48764	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265602	0.8
452342-67-5	chemical	CID:10202642	PUBCHEM	TGFBR1	protein	P36897	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193018	0.8
BCL7B	protein	Q9BQE9	UNIPROT	Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	form complex	binding			10090	BTO:0001086								19279220	t		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270721	0.461
PTPN2	protein	P17706	UNIPROT	FKBP4	protein	Q02790	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000567								12552015	t		tpavlidou	We have documented that a cellular protein that binds the immunosuppressant drug fk506, termed the fk506-binding protein (fkbp52), interacts with the single-stranded d sequence within the aav inverted terminal repeats, inhibits viral second-strand dna synthesis, and consequently limits high-efficiency transgene expression. Deliberate overexpression of the murine wild-type (wt) tc-ptp gene, but not that of a cysteine-to-serine (c-s) mutant, caused tyrosine dephosphorylation of fkbp52, leading to efficient viral second-strand dna synthesis and resulting in a significant increase in aav-mediated transduction efficiency in hela cells in vitro.	SIGNOR-97794	0.408
ABL1	protein	P00519	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates	phosphorylation	Tyr1357	HPQAASIyQSSEMKG	9606									18765637	t		lperfetto	Tyrosine phosphorylation of the nuclear receptor coactivator aib1/src-3 is enhanced by abl kinase and is required for its activity in cancer cellstyrosine kinase directly phosphorylates aib1/src-3 at y1357 and modulates the association of aib1 with c-abl, eralpha, the transcriptional cofactor p300,	SIGNOR-180571	0.354
CDC27	protein	P30260	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	form complex	binding												16896351	t		lperfetto	The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex.	SIGNOR-252003	0.887
NFIL3	protein	Q16649	UNIPROT	SOSTDC1	protein	Q6X4U4	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000093								25338303	f		lperfetto	E4BP4 is a repressor of epigenetically regulated SOSTDC1 expression in breast cancer cells.	SIGNOR-242767	0.2
GP1BB	protein	P13224	UNIPROT	GPIb-IX-V complex	complex	SIGNOR-C270	SIGNOR	form complex	binding			9606	BTO:0000132								16293600	t		lperfetto	The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1.	SIGNOR-261850	0.642
CRP	protein	P02741	UNIPROT	GCH1	protein	P30793	UNIPROT	down-regulates activity				9606	BTO:0004602								17942113	f		miannu	The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH(4), were significantly inhibited by CRP. Importantly, GTPCH1 is known to be regulated by cAMP-mediated pathway. In the present study, CRP-mediated inhibition of GTPCH1 activity was reversed by pretreatment with cAMP analogues. 	SIGNOR-252215	0.282
CHRM2	protein	P08172	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates				9606	BTO:0000007								12665513	f		lperfetto	Here we show that m2 muscarinic receptors and go require taos and mek3/6 as the primary intermediates activating p38 mapk in 293 cells	SIGNOR-235536	0.332
CIITA	protein	P33076	UNIPROT	HLA-DOB	protein	P13765	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								11823510	f	 	 	Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA. 	SIGNOR-254015	0.317
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	COLEC11	protein	Q9BWP8	UNIPROT	up-regulates activity	binding			-1									20956340	t		lperfetto	We finally show that CL-11 binds to intact bacteria, fungi, and viruses and that CL-11 decreases influenza A virus infectivity and forms complexes with DNA|it is conceivable that CL-11 plays a role in activation of the complement system and in the defense against invading microorganisms.	SIGNOR-263408	0.7
(S,S)-asenapine	chemical	CHEBI:71257	ChEBI	HTR1E	protein	P28566	UNIPROT	up-regulates activity	chemical activation			9534									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258568	0.8
PTPRE	protein	P23469	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	10116	BTO:0000575								15738637	t			In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver.	SIGNOR-248445	0.289
oligopeptide	smallmolecule	CHEBI:25676	ChEBI	peptide antigen	smallmolecule	CHEBI:166824	ChEBI	up-regulates quantity	precursor of			9606									31810556	t		scontino	Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol.	SIGNOR-267863	0.8
CDK1	protein	P06493	UNIPROT	TOP2A	protein	P11388	UNIPROT	unknown	phosphorylation	Ser1354	DFVPSDAsPPKTKTS	9606	BTO:0000567								7635160	t		llicata	We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. we have also shown that phosphorylation of ser1353 and ser1360 yields different phosphopeptide maps depending upon whether one or both of these sites are phosphorylated.	SIGNOR-30248	0.54
RUNX2	protein	Q13950	UNIPROT	MMP2	protein	P08253	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001610								22641097	f		miannu	 Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells.	SIGNOR-255082	0.335
PPM1B	protein	O75688	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates	dephosphorylation	Ser177	AKELDQGsLCTSFVG	9606									18930133	t		lperfetto	Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation	SIGNOR-181663	0.412
IRS1	protein	P35568	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9606									20966354	t		lperfetto	Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin.	SIGNOR-252695	0.758
PTH1R	protein	Q03431	UNIPROT	DKK1	protein	O94907	UNIPROT	down-regulates quantity													28363951	f		lperfetto	Furthermore, PTH acts on osteocytes to suppress the expression of sclerostin, an inhibitor of canonical Wnt signaling (Li, et al. 2005; Semenov, et al. 2005)). PTH action on sclerostin is primarily through cAMP signaling (Keller and Kneissel 2005) and mediated by Myocyte enhancer factor-2 (MEF2) transcriptional regulators (Leupin, et al. 2007). Using the cAMP signaling pathway in osteoblasts, PTH also inhibits the expression of Dickkopf 1 (Dkk1) (Guo et al. 2010a), which is another Wnt pathway inhibitor 	SIGNOR-270553	0.317
HTR1A	protein	P08908	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257197	0.252
MDM2	protein	Q00987	UNIPROT	NUMB	protein	P49757	UNIPROT	down-regulates	ubiquitination			9606	BTO:0001938								12646252	t		gcesareni	These data strongly suggest thatmdm2functions as the ubiquitin ligase toward hnumb and that it induces its degradation in intact cells.	SIGNOR-99497	0.456
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGA5	protein	Q9Y5G8	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265695	0.2
REST	protein	Q13127	UNIPROT	PENK	protein	P01210	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21832040	f		miannu	 HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK).	SIGNOR-255074	0.2
MECP2	protein	P51608	UNIPROT	DNMT1	protein	P26358	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								12473678	t		Luana	Thus, these results indicate that MeCP2-interacting Dnmt1 has significant maintenance DNA methyltransferase activity and that MeCP2 does not vanish Dnmt1 enzymatic activity.	SIGNOR-264541	0.545
STK38	protein	Q15208	UNIPROT	PANX2	protein	Q96RD6	UNIPROT	up-regulates activity	phosphorylation	Ser514	KKHARHFsLDVHPYI	10090		BTO:0000142							22445341	t		miannu	We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. 	SIGNOR-263032	0.2
PRKD1	protein	Q15139	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates	phosphorylation			9606	BTO:0001130								15695390	t		gcesareni	Our study has identified e-cadherin as a novel substrate of pkd1, and phosphorylation of e-cadherin by pkd1 is associated with increased cellular aggregation and decreased cellular motility in prostate cancer.	SIGNOR-133856	0.463
MAPK12	protein	P53778	UNIPROT	JUNB	protein	P17275	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10330170	f		gcesareni	Moreover, in addition to jnk, erk5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements.	SIGNOR-67532	0.37
ROBO	proteinfamily	SIGNOR-PF14	SIGNOR	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									15916964	t		lperfetto	Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities	SIGNOR-137639	0.2
U0126	chemical	CHEBI:90693	ChEBI	MAP2K2	protein	P36507	UNIPROT	down-regulates	chemical inhibition			9606									11160424	t		gcesareni	The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. U0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2.	SIGNOR-104942	0.8
BBC3	protein	Q9BXH1	UNIPROT	BCL2L2	protein	Q92843	UNIPROT	down-regulates	binding			9606									15694340	t		gcesareni	Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.	SIGNOR-133814	0.568
PRKDC	protein	P78527	UNIPROT	TOP1	protein	P11387	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser10	GDHLHNDsQIEADFR	9606	BTO:0002201								28415827	t		miannu	Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. 	SIGNOR-277352	0.46
SERPINA1	protein	P01009	UNIPROT	F2	protein	P00734	UNIPROT	down-regulates activity	binding			9606		BTO:0000131							17635716	t		lperfetto	Alpha1PI, historically known as alpha1-antitrypsin, is a 51 kDa, 394 amino acid glycoprotein, synthesized in the liver, circulating at c. 1.3 mg mL-1 with a half-life of 4.5 days 	SIGNOR-263524	0.435
HBB	protein	P68871	UNIPROT	Hemoglobin	complex	SIGNOR-C209	SIGNOR	form complex	binding			9606									18179859	t		miannu	AHSP does not bind to β-hemoglobin (βHb) or the hemoglobin tetramer, instead, it specifically binds to free αHb, avoiding its precipitation and its pro-oxidant activity. In the presence of βHb, the αHb-AHSP complex is dismembered and βHb displaces AHSP to generate the quaternary structure of hemoglobin	SIGNOR-255275	0.698
AVPR1B	protein	P47901	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257264	0.409
DDX39B	protein	Q13838	UNIPROT	TREX complex	complex	SIGNOR-C444	SIGNOR	form complex	binding			9606									33191911	t		miannu	The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56.	SIGNOR-268512	0.903
SP1	protein	P08047	UNIPROT	CADM1	protein	Q9BY67	UNIPROT	up-regulates quantity by expression	transcriptional regulation												18794147	f		lperfetto	Treatment with mithramycin A, an inhibitor of Sp1 or Sp3 binding, resulted in reduction of Cadm1 gene expression, therefore suggesting a potential role of Sp1/Sp3 in Cadm1 regulation.	SIGNOR-268958	0.255
FUBP1	protein	Q96AE4	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30500954	f		irozzo	Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug.	SIGNOR-259132	0.2
TGFB1	protein	P01137	UNIPROT	ACTA2	protein	P62736	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000764								20846954	f	Regulation	miannu	We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes. 	SIGNOR-251923	0.431
PRKDC	protein	P78527	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates activity	phosphorylation	Ser2612	MFVETQAsQGTLQTR	9606	BTO:0000773								12186630	t		lperfetto	 We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function.	SIGNOR-249155	0.2
PRKAA1	protein	Q13131	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	form complex	binding			9606	BTO:0000443	BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000759							16054041	t		lperfetto	Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits.	SIGNOR-139158	0.822
JMJD6	protein	Q6NYC1	UNIPROT	MEPCE	protein	Q7L2J0	UNIPROT	down-regulates activity	cleavage	Arg171	HPAFKRRrRVNSDCD	10090	BTO:0002572								32048991	t		miannu	JMJD6 cleaves MePCE. we propose that JMJD6 is the cognate protease of MePCE and cleaves at the R171 site within MePCE. Experiments using purified JMJD6 showed that it could make a cut in an enzyme called MePCE, which belongs to the group of proteins that hold P-TEFb in its inactive form. The levels of activated Pol II were lower in cells without JMJD6 and higher in those without MePCE. Together, the results suggest that JMJD6 cuts MePCE to release P-TEFb, which then activates Pol II. 	SIGNOR-261037	0.272
SMAD3	protein	P84022	UNIPROT	SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	form complex	binding			9606									9843571	t		lperfetto	TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus.	SIGNOR-229557	0.698
SLC4A10	protein	Q6U841	UNIPROT	chloride	smallmolecule	CHEBI:17996	ChEBI	down-regulates quantity	relocalization			9606									23056253	t		miannu	The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pH(i)) and chloride concentration ([Cl(-)](i)) in neurons. 	SIGNOR-264686	0.8
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates	phosphorylation	Thr255	DLPDMKEtKYTVDKR	9606									11152499	t		tpavlidou	We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity.	SIGNOR-85773	0.2
ITSN1	protein	Q15811	UNIPROT	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	up-regulates quantity by stabilization	binding												24789820	t		lperfetto	Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth	SIGNOR-260714	0.562
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	RCAN1	protein	P53805	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000165								12063245	t	inferred from 70% family members	lperfetto	Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. 	SIGNOR-270026	0.2
GRM2	protein	Q14416	UNIPROT	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							20055706	t		miannu	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264079	0.341
PAX7-FOXO1	fusion protein	SIGNOR-FP11	SIGNOR	FGFR4	protein	P22455	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25211658	f		miannu	Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA.	SIGNOR-251565	0.2
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser221	PRTSPIMsPRTSLAE	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248518	0.386
phenytoin	chemical	CHEBI:8107	ChEBI	UGT1A1	protein	P22309	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								21030469	t		Luana	Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation.	SIGNOR-258160	0.8
TGFBR2	protein	P37173	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates activity	phosphorylation	Thr200	LPLLVQRtIARTIVL	452646									7774578	t		lperfetto	The tgf-beta type ii receptor (t beta r-ii) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, t beta r-i, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling.	SIGNOR-32744	0.709
GEMIN2	protein	O14893	UNIPROT	SMN complex	complex	SIGNOR-C158	SIGNOR	form complex	binding												12065586	t		lperfetto	SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry.	SIGNOR-253116	0.867
RUNX1	protein	Q01196	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30500954	f		irozzo	Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug.	SIGNOR-259133	0.341
MAPK10	protein	P53779	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser73	VGLLKLAsPELERLI	9606									20395206	t		gcesareni	With epidermal growth factor treatment, overexpression of erk8 in jb6 cl41 cells caused an increased phosphorylation of c-jun at ser(63) and ser(73), resulting in increased activator protein-1 transactivation.	SIGNOR-164804	0.883
CALM2	protein	P0DP24	UNIPROT	GEM	protein	P55040	UNIPROT	up-regulates activity	binding			10116	BTO:0001009								14701738	t		miannu	Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells.	SIGNOR-266326	0.2
NCOA2	protein	Q15596	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates	binding			9606									18584035	t		gcesareni	Collectively, our data provide the first evidence that erbeta-deficiency protects against diet-induced ir and glucose intolerance which involves an augmented ppargamma signaling in adipose tissue. Moreover, our data suggest that the coactivators src1 and tif2 are involved in this interaction.	SIGNOR-179175	0.759
AKT1	protein	P31749	UNIPROT	VCP	protein	P55072	UNIPROT	up-regulates	phosphorylation	Ser746	AMRFARRsVSDNDIR	9606	BTO:0000150								16551632	t		llicata	Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I	SIGNOR-252492	0.523
CDC20	protein	Q12834	UNIPROT	UBE2S	protein	Q16763	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								19822757	t		lperfetto	Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity	SIGNOR-265082	0.866
MAPK14	protein	Q16539	UNIPROT	KRT8	protein	P05787	UNIPROT	up-regulates	phosphorylation	Ser74	TVNQSLLsPLVLEVD	9606									11788583	t		lperfetto	Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif ((68)nqsllspl) and becomes phosphorylated in cultured cells and organs during mitosis, cell stress, and apoptosis. Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase.The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.	SIGNOR-114079	0.574
CSNK2A1	protein	P68400	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser257	QIRLRRDsKEANARR	-1									9677319	t		llicata	CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin.	SIGNOR-250945	0.317
EEF2K	protein	O00418	UNIPROT	EEF2K	protein	O00418	UNIPROT	down-regulates	phosphorylation	Ser445	SGDSGYPsEKRGELD	9606									22669845	t		gcesareni	The combination of eef2k autophosphorylation (targeting ser445) and a yet to be identified kinase (targeting ser441) would be needed to generate the eef2k phosphodegron specifically in response to dna damage.	SIGNOR-197725	0.2
FABP7	protein	O15540	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264461	0.7
FZD3	protein	Q9NPG1	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			9606									14977528	t		gcesareni	Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families.	SIGNOR-122892	0.246
HCK	protein	P08631	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	down-regulates activity	phosphorylation	Tyr394	LNTIGLIyEKISLPK	9606	BTO:0002181								28618271	t		miannu	The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. 	SIGNOR-276727	0.2
STK3	protein	Q13188	UNIPROT	MOB1B	protein	Q7L9L4	UNIPROT	up-regulates	phosphorylation	Thr35	LLKHAEAtLGSGNLR	9606									21808241	t	The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific.	gcesareni	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction.	SIGNOR-175817	0.809
STAT5A	protein	P42229	UNIPROT	PIM1	protein	P11309	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15498859	t			Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells.	SIGNOR-261517	0.385
TTL	protein	Q8NG68	UNIPROT	TUBA1C	protein	Q9BQE3	UNIPROT	down-regulates	tyrosination			9606									22020298	t		miannu	Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization	SIGNOR-176918	0.45
ZNRF3	protein	Q9ULT6	UNIPROT	FZD8	protein	Q9H461	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								22575959	t			Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.	SIGNOR-260111	0.52
SIRT1	protein	Q96EB6	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	binding			10090		BTO:0001103							24003218	t		lperfetto	SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3	SIGNOR-252996	0.909
TFIID	complex	SIGNOR-C343	SIGNOR	GTF2B	protein	Q00403	UNIPROT	up-regulates activity	relocalization			9606									8990153	t		lperfetto	Early in PIC assembly, TFIIA can associate with and stabilize the TFIID–DNA or the TFIIB–TFIID–DNA complexes, allowing them to ward off the deleterious effects of inhibitory negative cofactors and enhance the stimulatory effects of transcriptional activators	SIGNOR-269308	0.639
PSMD1	protein	Q99460	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263354	0.901
PRKG1	protein	Q13976	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates	phosphorylation	Thr159	DNKLRRYtTFSKRKT	10090									12809504	t		gcesareni	Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha. 	SIGNOR-188185	0.28
SRC	protein	P12931	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Tyr326	EVLEDNDyGRAVDWW	9534	BTO:0004055								11445557	t		lperfetto	Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity.	SIGNOR-246377	0.663
chlorpromazine	chemical	CHEBI:3647	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258370	0.8
Aflibercept	chemical	SID:134445687	ChEBI	PGF	protein	P49763	UNIPROT	down-regulates activity	chemical inhibition			9606									22813448	t		miannu	Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor. 	SIGNOR-259385	0.8
L-arginine	chemical	CHEBI:16467	ChEBI	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				9606	BTO:0000567								27126896	f		Luana	 Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation.	SIGNOR-268018	0.8
TRAF6	protein	Q9Y4K3	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity	ubiquitination	Lys180	SPAPSSTkPGPESSV	9606									18347055	t			K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-_B	SIGNOR-252252	0.911
PPP1CA	protein	P62136	UNIPROT	NEK2	protein	P51955	UNIPROT	down-regulates	dephosphorylation			9606									17283141	t		gcesareni	Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1	SIGNOR-152949	0.382
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9606	BTO:0000876	BTO:0001103							11602185	f		apalma	The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding.	SIGNOR-255579	0.7
PIK3C3	protein	Q8NEB9	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates				9606									10698680	f		acerquone	Pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1)	SIGNOR-252633	0.446
SMARCD1	protein	Q96GM5	UNIPROT	Muscle cell-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C483	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex.	SIGNOR-270734	0.788
SKIL	protein	P12757	UNIPROT	SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	down-regulates activity	binding			9606	BTO:0000848								12793438	t		lperfetto	The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway	SIGNOR-253303	0.835
192927-92-7	chemical	CID:11957576	PUBCHEM	HTR1D	protein	P28221	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193814	0.8
DYRK2	protein	Q92630	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser88	DSGFCLDsPGPLDSK	9606	BTO:0002181								34363019	t		miannu	Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. 	SIGNOR-276737	0.2
CXCL12	protein	P48061	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates				9606	BTO:0000093								15882617	f		lperfetto	Stromal fibroblast-derived SDF-1 enhances tumor growth both by stimulating angiogenesis through recruiting circulating EPCs into the tumor mass (endocrine effect) and by direct paracrine stimulation of tumor cells through CXCR4 expressed on carcinoma cells	SIGNOR-252267	0.7
MAPK11	protein	Q15759	UNIPROT	MAPK11	protein	Q15759	UNIPROT	down-regulates activity	phosphorylation	Ser261	HARTYIQsLPPMPQK	-1									26976637	t		miannu	P38β Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261	SIGNOR-277214	0.2
Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	Axonal_growth_cone_formation	phenotype	SIGNOR-PH199	SIGNOR	up-regulates				9606	BTO:0000938								21106647	f		miannu	Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. 	SIGNOR-268383	0.7
CRHR1	protein	P34998	UNIPROT	Beta-endorphin	protein	P01189-PRO_0000024975	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001073							23504413	f		lperfetto	CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981).	SIGNOR-268614	0.2
TRiC	complex	SIGNOR-C539	SIGNOR	MYC	protein	P01106	UNIPROT	up-regulates quantity by stabilization	binding			9606									36185250	t		miannu	Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC).	SIGNOR-272872	0.271
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	GAB2	protein	Q9UQC2	UNIPROT	up-regulates	phosphorylation			9606									15356145	t	inferred from 70% family members	lperfetto	Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623.	SIGNOR-270133	0.2
SF3B1	protein	O75533	UNIPROT	B-WICH complex	complex	SIGNOR-C447	SIGNOR	form complex	binding			9606									21559432	t		miannu	The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 	SIGNOR-268819	0.414
ATP6V1H	protein	Q9UI12	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates activity	binding			10090	BTO:0004122								29782852	t		miannu	ATP6V1H interacts with TGF-β receptor I and AP-2 complex to regulate the proliferation and differentiation of BMSCs.	SIGNOR-266886	0.2
MFGE8	protein	Q08431	UNIPROT	SOCS3	protein	O14543	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21901532	f		miannu	In an attempt to clarify the direct anti-inflammatory role of MFG-E8, we revealed a distinct signaling pathway where MFG-E8 activates suppressor of cytokine signaling (SOCS) 3 gene expression via STAT3 mediated pathway, which in turn served as a negative regulator for LPS induced TLR4 signaling by targeting NF-κB p65 component, thereby attenuating the down-stream signaling for TNF-α production	SIGNOR-260653	0.354
gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	GABA-A (a4-b3-d) receptor	complex	SIGNOR-C327	SIGNOR	up-regulates activity	chemical activation			9606									18790874	t	brain	lperfetto	Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS).	SIGNOR-263785	0.8
SLC6A8	protein	P48029	UNIPROT	creatine	smallmolecule	CHEBI:16919	ChEBI	up-regulates quantity	relocalization			9606									18652074	t		miannu	CRT is essential for normal brain function as mutations in the CRT gene (SLC6A8) result in X-linked mental retardation, associated with the almost complete lack of creatine in the brain, severe speech and language delay, epilepsy, and autistic behaviour.	SIGNOR-265782	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	phosphorylation	Ser1166	SDDFKRDsVSGGGPC	9606	BTO:0000007								24431445	t		miannu	Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines.	SIGNOR-276617	0.2
RXRA	protein	P19793	UNIPROT	PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	up-regulates activity	binding			10090									17613434	t		irozzo	RXR Binding Increases the DNA-Binding Affinity of PML/RARA. Here, we demonstrate that the presence of the RARA heterodimeric partner RXR in the PML/RARA complex is required for leukemogenesis in transgenic mice. RXR greatly facilitates the binding of PML/RARA to DNA, but titration of RXR by PML/RARA could also contribute to transformation.	SIGNOR-255804	0.2
PLK4	protein	O00444	UNIPROT	FBXW5	protein	Q969U6	UNIPROT	down-regulates activity	phosphorylation	Ser151	SQFNKDDsLLLASGV										21725316	t		lperfetto	The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6.	SIGNOR-275476	0.56
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	GRB2	protein	P62993	UNIPROT	unknown	phosphorylation	Tyr160	QVPQQPTyVQALFDF	9606	BTO:0000007								20554525	t		lperfetto	Our data show that BCR-ABL also phosphorylates Grb2 in Tyr160Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation.	SIGNOR-247146	0.2
USP8	protein	P40818	UNIPROT	BACE1	protein	P56817	UNIPROT	up-regulates quantity by stabilization	deubiquitination	Lys501	ADDISLLk	9606	BTO:0003704								27302062	t		irozzo	Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization.Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501. 	SIGNOR-259101	0.462
RIPK2	protein	O43353	UNIPROT	IRF5	protein	Q13568	UNIPROT	up-regulates	phosphorylation	Ser435	EMFSGELsWSADSIR	9606									22412986	t		lperfetto	Activation of interferon regulatory factor 5 by site specific phosphorylation. Phosphorylation of carboxyl serines 451 and 462 appear the primary trigger of irf5 function in nuclear accumulation, transcription, and apoptosis. Rip2 activation of the irf5 aspartic acid substitutions showed a similar positive effect of s451d and s462d function in this assay	SIGNOR-196520	0.31
CSNK2A1	protein	P68400	UNIPROT	SLC9A5	protein	Q14940	UNIPROT	down-regulates activity	phosphorylation	Ser702	AVILTVEsEEEEEES	-1									21296876	t		miannu	CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis	SIGNOR-276253	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	IL4	protein	P05112	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								15048722	f			We demonstrate that NF-kappa B binds to the IL-4 promoter in vivo upon T cell activation. Inhibition of NF-kappa B nuclear translocation in living cells blocked binding of NF-kappa B to the IL-4 promoter. The data provide first evidence that NF-kappa B is directly involved in IL-4 transcription	SIGNOR-254497	0.418
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	GRB2	protein	P62993	UNIPROT	down-regulates activity	phosphorylation	Tyr52	DGFIPKNyIEMKPHP	9606	BTO:0000007								20554525	t		lperfetto	More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway.	SIGNOR-246293	0.2
L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	up-regulates quantity	precursor of			9606									31422819	t		miannu	This is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1).	SIGNOR-267512	0.8
APH1B	protein	Q8WW43	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates	binding			9606		BTO:0000142							12297508	t		gcesareni	By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.	SIGNOR-93310	0.905
DYRK1B	protein	Q9Y463	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates	phosphorylation	Thr288	VDLACTPtDVRDVDI	10090	BTO:0000165;BTO:0000222	BTO:0000887;BTO:0001103							15546868	t		lperfetto	Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner	SIGNOR-235801	0.422
PLCG2	protein	P16885	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser146	GRKRRQTsMTDFYHS	9606									31575057	t		gcesareni	Phosphorylation at Ser-146 by PKCδ increases p21 stability	SIGNOR-262963	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SI	protein	P14410	UNIPROT	unknown	phosphorylation	Ser7	sGLEISLI	-1									8521865	t		miannu	This paper reports the phosphorylation of the intracellular N-terminal tail of sucrase-isomaltase by protein kinase A and shows that this phosphorylation is targeted to Ser6 within a sequence Arg/Lys/Lys-Phe-Ser, which is conserved in all sucrase-isomaltase sequences known so far. 	SIGNOR-263157	0.2
NDUFB5	protein	O43674	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4	SIGNOR-262168	0.822
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259004	0.348
CIITA	protein	P33076	UNIPROT	S100A4	protein	P26447	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17143014	f		miannu	 IFN-gamma represses S100A4 promoter activity through induction of the class II transactivator (CIITA).	SIGNOR-253776	0.33
ADD2	protein	P35612	UNIPROT	4.1 complex	complex	SIGNOR-C386	SIGNOR	form complex	binding			9606	BTO:0000424								33187473	t		lperfetto	The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]	SIGNOR-266039	0.377
AL/b2 integrin	complex	SIGNOR-C169	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257712	0.446
SFRP1	protein	Q8N474	UNIPROT	WNT4	protein	P56705	UNIPROT	down-regulates	binding			9606		BTO:0000671							11287180	t		gcesareni	Sfrp-1 binds wnt-4 with considerable avidity and inhibits the dna-binding activity of tcf, an effector of wnt signaling,	SIGNOR-106556	0.721
MAPK8	protein	P45983	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates	phosphorylation	Ser173	PCPQPLRsPSLDNPT	9606									19153595	t		lperfetto	In this study, we show that another kinase, c-jun-nh(2)-terminal kinase (jnk), phosphorylates irf3 on its n-terminal serine 173 residuejnk1 can synergize the action of irf3(5d), but not the s173a-irf3(5d) mutant	SIGNOR-183489	0.55
FBXW7	protein	Q969H0	UNIPROT	CCNE1	protein	P24864	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0002524								17298674	t		miannu	Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme	SIGNOR-271643	0.585
PIK3C3	protein	Q8NEB9	UNIPROT	1-phosphatidyl-1D-myo-inositol 3-phosphate	smallmolecule	CHEBI:17283	ChEBI	up-regulates	chemical modification			9606									8999962	t		gcesareni	Vps34p phosphorylates phosphatidylinositol (ptdins) at the 3?-Position of the inositol ring, but not ptdins.	SIGNOR-45606	0.8
RPS6KA1	protein	Q15418	UNIPROT	TSC	complex	SIGNOR-C101	SIGNOR	down-regulates activity	phosphorylation			9606	BTO:0000007								15342917	t		lperfetto	The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1	SIGNOR-217900	0.712
CDK5	protein	Q00535	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates	phosphorylation	Ser114	RKLQGRPsPGPPAPE	9606	BTO:0000938								20213743	t		llicata	Together, our data suggest that cdk5 can phosphorylate enos at the ser-113 site and down-regulate enos-derived no levels.	SIGNOR-164080	0.38
DLST	protein	P36957	UNIPROT	OGDC	complex	SIGNOR-C397	SIGNOR	form complex	binding			9606									15953811	t		miannu	The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH.	SIGNOR-266254	0.902
CTDSP2	protein	O14595	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation	Ser255	ELSPTTLsPVNHSLD	9606	BTO:0000007								17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248299	0.421
dothiepin	chemical	CHEBI:36798	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9537821	t		miannu	Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 	SIGNOR-258877	0.8
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1861	TPTSPKYsPTSPKYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273055	0.556
LPAR5	protein	Q9H1C0	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256718	0.39
MAP2K4	protein	P45985	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates	phosphorylation			9606									8974401	t	Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif.	gcesareni	A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subgroups of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subgroups of map kinases, respectively. here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1).	SIGNOR-45360	0.732
haloperidol	chemical	CHEBI:5613	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258372	0.8
CSNK1D	protein	P48730	UNIPROT	SMARCA4	protein	P51532	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser35	LGPSPGPsPGSAHSM	9606	BTO:0001225								30177679	t		miannu	 We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation. 	SIGNOR-277407	0.2
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606									22703233	f		lperfetto	Our results establish a novel biological role for TGFbeta signaling in controlling expression of genes characteristic for alternatively activated macrophages. We speculate that lack of TbetaRII signaling reduces the anti-inflammatory M2 phenotype of macrophages because of reduced expression of these products.	SIGNOR-249551	0.7
MIB1	protein	Q86YT6	UNIPROT	DLL1	protein	O00548	UNIPROT	up-regulates activity	ubiquitination			9606									16140393	t		lperfetto	Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity.	SIGNOR-209750	0.731
(6R)-5,10-methenyltetrahydrofolate	smallmolecule	CHEBI:57455	ChEBI	10-formyltetrahydrofolate(2-)	smallmolecule	CHEBI:57454	ChEBI	up-regulates quantity	precursor of			9606									18767138	t		lperfetto	Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate	SIGNOR-268247	0.8
8-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	chemical	CHEBI:91845	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258860	0.8
NR2F1	protein	P10589	UNIPROT	LHCGR	protein	P22888	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9534									10644740	t		Luana	Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription.	SIGNOR-266218	0.279
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606									15486195	t	inferred from 70% family members	lperfetto	In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel	SIGNOR-270152	0.2
AP1G1	protein	O43747	UNIPROT	AP-1 complex	complex	SIGNOR-C248	SIGNOR	form complex	binding			9606									21097499	t		lperfetto	Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)	SIGNOR-260687	0.815
PLK1	protein	P53350	UNIPROT	NINL	protein	Q9Y2I6	UNIPROT	down-regulates activity	phosphorylation	Thr161	SDEEAEStKEAQNEL	-1									12852856	t		lperfetto	Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction	SIGNOR-103364	0.688
SRMS	protein	Q9H3Y6	UNIPROT	FKBP5	protein	Q13451	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr54	PMIGDKVyVHYKGKL	9606	BTO:0000567								34077419	t		miannu	SRMS binds FKBP51 and phosphorylates tyrosine 54. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway.	SIGNOR-277564	0.27
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser130	SGEQAEGsPGGPGDS	9606									19364816	t		gcesareni	Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1.|Phosphopeptide analysis of in vitro ERK2-phosphorylated p21(Cip1) revealed two phosphorylation sites, Thr57 and Ser130. 	SIGNOR-244618	0.2
PTPN7	protein	P35236	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	binding			9606	BTO:0000776								19047375	t		gcesareni	Thus, beta(2)ar stimulation on a b cell phosphorylates and inactivates heptp in a gs/camp/pka-dependent manner to release bound p38 mapk, making more available for phosphorylation and subsequent ige regulation	SIGNOR-182525	0.584
CHEK2	protein	O96017	UNIPROT	AATF	protein	Q9NY61	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser143	SKKSRSHsAKTPGFS	9606	BTO:0001109								17157788	t		lperfetto	Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability.	SIGNOR-264416	0.365
ZNF804A	protein	Q7Z570	UNIPROT	MGAM	protein	O43451	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								23434502	t		miannu	ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 	SIGNOR-269466	0.2
GRIPAP1	protein	Q4V328	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates activity	binding			9606	BTO:0002181;BTO:0000142								17761173	t		Giorgia	To examine whether GRASP‐1 interacts with MEKK1 and JNK1 in neurons, co‐immunoprecipitation experiments were performed with detergent‐solubilized extracts from cultured cortical neurons. Both antiJNK1 and anti‐MEKK1 antibodies immunoprecipitated GRASP‐1 from neuronal lysates. These results suggest that GRASP‐1 interacts with MEKK1 and JNK1 in neurons. GRASP-1 potently activates JNK pathway signaling, with no effect on ERK signaling. Such JNK pathway activating activity requires binding of GRASP-1 to both JNK and the upstream JNK pathway activator MEKK-1. 	SIGNOR-260639	0.315
PRKACA	protein	P17612	UNIPROT	VASP	protein	P50552	UNIPROT	unknown	phosphorylation	Ser157	EHIERRVsNAGGPPA	9606									16197368	t		llicata	We show that, in human platelets, vasp is phosphorylated by pkc on ser157, but not ser239, in response to phorbol ester stimulation, in a manner blocked by the pkc inhibitor bim i (bisindolylmaleimide i).	SIGNOR-140841	0.487
SCN10A	protein	Q9Y5Y9	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606									27262167	t		miannu	Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential.	SIGNOR-253408	0.8
SETD1B	protein	Q9UPS6	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606									32546568	t		miannu	SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks.	SIGNOR-265578	0.2
BRSK1	protein	Q8TDC3	UNIPROT	CDC25B	protein	P30305	UNIPROT	down-regulates activity	phosphorylation	Ser375	ARVLRSKsLCHDEIE	9606	BTO:0000567								15150265	t		lperfetto	Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectively phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3	SIGNOR-107404	0.521
KIF4A	protein	O95239	UNIPROT	Spindle_assembly	phenotype	SIGNOR-PH60	SIGNOR	up-regulates				9606									15297875	f		miannu	 These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins	SIGNOR-265986	0.7
MAPK1	protein	P28482	UNIPROT	GRB10	protein	Q13322	UNIPROT	up-regulates	phosphorylation	Ser150	PELCGPGsPPVLTPG	9606									15952796	t		lperfetto	We show that grb10 is a direct substrate of the p42/44 mitogen-activated protein kinase (mapk)we identified ser(150), ser(418), and ser(476) of human grb10zeta as mapk-mediated in vitro phosphorylation sites. Replacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation. Taken together, our findings suggest that phosphorylation of the adaptor protein may provide a feedback inhibitory mechanism by which grb10 regulates insulin signaling.	SIGNOR-138163	0.381
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	arginine	smallmolecule	CHEBI:29016	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270365	0.8
VRK1	protein	Q99986	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	up-regulates	phosphorylation			9606									22621922	t		miannu	The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells./ Vrk1 knockdown resulted in the defective formation of 53bp1 foci in response to ir both in number and size	SIGNOR-197625	0.408
TAOK2	protein	Q9UL54	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates	phosphorylation			9606									23431053	t		gcesareni	In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2	SIGNOR-201330	0.283
FZR1	protein	Q9UM11	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	up-regulates activity	binding			9534	BTO:0004055								12023018	t		miannu	We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity.	SIGNOR-272611	0.845
MAPK14	protein	Q16539	UNIPROT	SLC9A1	protein	P19634	UNIPROT	up-regulates	phosphorylation	Ser726	IDPASPQsPESVDLV	9606									18701649	t		gcesareni	Such results suggest that during apoptosis, oxidative stress could activate p38 mapk, phosphorylating nhe1 at s726 and s729.	SIGNOR-180044	0.552
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation			9606									18394876	t		lperfetto	The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity	SIGNOR-252859	0.908
CSAG2	protein	Q9Y5P2	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	up-regulates activity	binding			9606									32761762	t		miannu	Here, we show that the previously undescribed CSAG2 protein is a direct activator of SIRT1.  Biochemical studies revealed that CSAG2 directly binds to and stimulates SIRT1 activity toward multiple substrates. Importantly, CSAG2 enhances SIRT1‐mediated deacetylation of p53, inhibits p53 transcriptional activity, and improves cell survival in response to genotoxic stress. 	SIGNOR-261670	0.2
HRAS	protein	P01112	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation	Ser73	VGLLKLAsPELERLI	10116	BTO:0000452								1749429	t		lperfetto	Expression of oncogenic ha-ras augments transactivation by c-jun and stimulates its phosphorylation. Here we describe the mapping of the ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-jun activity and for cooperation with ha-ras in ocogenic transformation.	SIGNOR-236686	0.516
GSK3B	protein	P49841	UNIPROT	CCND2	protein	P30279	UNIPROT	down-regulates	phosphorylation	Thr280	DELDQAStPTDVRDI	9606									17486076	t		lperfetto	Glycogen synthase kinase-3beta and p38 phosphorylate cyclin d2 on thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells	SIGNOR-154668	0.435
DHX30	protein	Q7L2E3	UNIPROT	FASTKD2	protein	Q9NYY8	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									25683715	f		miannu	DHX30 siRNA treatment resulted in an increase of FASTKD2 levels, and FASTKD5 was increased in cells treated with siRNA for GRSF1.	SIGNOR-261225	0.393
captopril	chemical	CHEBI:3380	ChEBI	ACE	protein	P12821	UNIPROT	down-regulates activity	chemical inhibition			-1									9187274	t		miannu	We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range.	SIGNOR-258612	0.8
GLI2	protein	P10070	UNIPROT	Cell_migration	phenotype	SIGNOR-PH38	SIGNOR	up-regulates													33125874	f		SimoneGraziosi	Inhibition of Gli1 with simultaneous increase in Gli2 promotes migration of vNSC-derived cells to demyelinated lesions	SIGNOR-269223	0.7
MAPK14	protein	Q16539	UNIPROT	BAZ1B	protein	Q9UIG0	UNIPROT	up-regulates	phosphorylation	Ser158	KSDGACDsPSSDKEN	9606									19776015	t		gcesareni	Moreover, this region (wac domain) was also phosphorylated by recombinant proteins of p38_? And jnk2_? But not by akt1	SIGNOR-188160	0.2
MC4R	protein	P32245	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256797	0.501
DAGLA	protein	Q9Y4D2	UNIPROT	1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	down-regulates quantity	chemical modification			9606									26787883	t		miannu	Diacylglycerol lipases (DAGLα and DAGLβ) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol.	SIGNOR-264262	0.8
MAPKAPK2	protein	P49137	UNIPROT	ZFP36L1	protein	Q07352	UNIPROT	down-regulates	phosphorylation	Ser203	PRLQHSFsFAGFPSA	9606									18326031	t		lperfetto	Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation.	SIGNOR-161270	0.604
HOXC13	protein	P31276	UNIPROT	DSG4	protein	Q86SJ6	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000552								19683850	f	 	miannu	 we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle.	SIGNOR-254184	0.395
HACE1	protein	Q8IYU2	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								22036506	t			The CNF1 toxin of pathogenic Escherichia coli addresses Rac1 to ubiquitin-proteasome system (UPS). We report the essential role of the tumor suppressor HACE1, a HECT-domain containing E3 ubiquitin-ligase, in the targeting of Rac1 to UPS. HACE1 binds preferentially GTP-bound Rac1 and catalyzes its polyubiquitylation	SIGNOR-255538	0.374
ELP2	protein	Q6IA86	UNIPROT	Elongator complex	complex	SIGNOR-C466	SIGNOR	form complex	binding			9606									28601220	t		miannu	Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer.	SIGNOR-269709	0.774
Phenelzine	chemical	CHEBI:8060	ChEBI	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9537821	t		miannu	At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. 	SIGNOR-258743	0.8
EGFR	protein	P00533	UNIPROT	JAK1/STAT1/STAT3	complex	SIGNOR-C120	SIGNOR	up-regulates activity	phosphorylation			9606									15284024	t			Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min.	SIGNOR-252088	0.615
LPAR5	protein	Q9H1C0	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257113	0.2
CDK6	protein	Q00534	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Ser811	IYISPLKsPYKISEG	9606									15809340	t		gcesareni	Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively.	SIGNOR-135189	0.761
ENO2	protein	P09104	UNIPROT	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	up-regulates quantity	chemical modification			9606									29767008	t		miannu	Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits.	SIGNOR-266525	0.8
PRKD3	protein	O94806	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	up-regulates activity	phosphorylation	Ser155	FPLRKTVsEPNLKLR										18692497	t	Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7	lperfetto	Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].	SIGNOR-275932	0.2
ATF6	protein	P18850	UNIPROT	ATF6	protein	P18850	UNIPROT	up-regulates activity	binding			-1									12805554	t		miannu	E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins	SIGNOR-224202	0.2
LATS1	protein	O95835	UNIPROT	CDC26	protein	Q8NHZ8	UNIPROT	up-regulates activity	phosphorylation	Thr7	tRLELKLD										25723520	t		lperfetto	LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C|Here, we demonstrate that LATS1 phosphorylates the Thr7 (T7) residue of the APC/C component CDC26 directly	SIGNOR-275472	0.479
CSNK1G1	protein	Q9HCP0	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation	Ser322	PRTSSNAsTISGRLS	-1									11980723	t		llicata	Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR	SIGNOR-250822	0.471
ABL1	protein	P00519	UNIPROT	PSMA7	protein	O14818	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr106	EDPVTVEyITRYIAS	9606									25620702	t		Manara	PSMA7 degradation is suppressed by c-Abl-mediated tyrosine phosphorylation at Y106	SIGNOR-260937	0.406
SIRT1	protein	Q96EB6	UNIPROT	ACAN	protein	P16112	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21337390	f		miannu	 The inhibition of SIRT1 by siRNA induced OA-like gene expression changes, namely the significant down-regulation of aggrecan and up-regulation of COL10A1 and ADAMTS-5.	SIGNOR-255142	0.322
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGA7	protein	Q9Y5G6	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265687	0.2
quizartinib	chemical	CHEBI:90217	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258270	0.8
KIF1B	protein	O60333	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272519	0.7
CDK2	protein	P24941	UNIPROT	GATA3	protein	P23771	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr156	HLFTFPPtPPKDVSP	9606	BTO:0000567								24820417	t		miannu	Phosphorylation of GATA3 Thr-156 was detected in mouse thymocytes, and cyclin-dependent kinase 2 (CDK2) was identified as a respondent for phosphorylation at Thr-156. 	SIGNOR-276634	0.369
SP3	protein	Q02447	UNIPROT	HGF	protein	P14210	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									9223667	t		lperfetto	Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region.	SIGNOR-251741	0.2
linifanib	chemical	CHEBI:91435	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193663	0.8
SLC1A2	protein	P43004	UNIPROT	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	up-regulates quantity	relocalization			9606									26687113	t		miannu	After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5).	SIGNOR-264803	0.8
NFIB	protein	O00712	UNIPROT	EZH2	protein	Q15910	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24553933	f		miannu	Nfibbinds to the ezh2 promoter and overexpression ofnfibrepresses ezh2 transcription.	SIGNOR-204643	0.384
CDT1	protein	Q9H211	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								14672932	t			Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1.	SIGNOR-261681	0.806
R547	chemical	CID:6918852	PUBCHEM	CDK1	protein	P06493	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259792	0.8
MC2R	protein	Q01718	UNIPROT	cortisol	smallmolecule	CHEBI:17650	ChEBI	up-regulates quantity				9606		BTO:0000047							20371771	f		lperfetto	Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP). 	SIGNOR-268621	0.8
hesperadin	chemical	CHEBI:70726	ChEBI	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193128	0.8
ACTB	protein	P60709	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269293	0.486
CSNK2A1	protein	P68400	UNIPROT	TWIST1	protein	Q15672	UNIPROT	up-regulates	phosphorylation	Ser20	ADDSLSNsEEEPDRQ	9606									21559372	t		llicata	Further investigation revealed that il-6 stabilizes twist in scchn cell lines through casein kinase 2 (ck2) phosphorylation of twist residues s18 and s20, and that this phosphorylation inhibits degradation of twist.	SIGNOR-173672	0.2
M1_polarization	phenotype	SIGNOR-PH54	SIGNOR	TNF	protein	P01375	UNIPROT	up-regulates				9606	BTO:0000801								32454942	f		miannu	Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ	SIGNOR-263826	0.7
PLK1	protein	P53350	UNIPROT	WDCP	protein	Q9H6R7	UNIPROT	up-regulates activity	phosphorylation	Ser695	SHSPGAVsSLKVFTG	9606	BTO:0000007								30297404	t		miannu	PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11. we performed in vitro kinase assays followed by mass spectrometry and found that two sites (S686 and S695) in this cluster were phosphorylated. Thus, all of these results are in agreement that this cluster is phosphorylated by PLK1.	SIGNOR-273731	0.2
histamine	smallmolecule	CHEBI:18295	ChEBI	HRH3	protein	Q9Y5N1	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257514	0.8
PPP2CA	protein	P67775	UNIPROT	MAP3K3	protein	Q99759	UNIPROT	down-regulates	dephosphorylation	Ser520	RLQTICMsGTGMRSV	9606									20448038	t		lperfetto	Overexpression of pp2a catalytic subunit (pp2ac) beta-isoform results in dephosphorylation of mekk3 at thr-516 and ser-520 and termination of mekk3-mediated nf-kappab activation.	SIGNOR-165229	0.379
beta-alanine	smallmolecule	CHEBI:16958	ChEBI	GlyR	proteinfamily	SIGNOR-PF62	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000007								9009272	t	inferred from family member	miannu	For each mutant GlyR we examined the agonist efficacies of taurine and beta-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where beta-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human alpha-1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and beta-alanine act as full agonists of huma nalpha-1 GlyRs when expressed in this system.	SIGNOR-267795	0.8
DUSP9	protein	Q99956	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates	binding			9606									21908610	t		gcesareni	Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein.	SIGNOR-176589	0.691
EIF2AK2	protein	P19525	UNIPROT	AIM2 inflammasome	complex	SIGNOR-C222	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								22801494	t		miannu	Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. 	SIGNOR-263120	0.319
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	RB1	protein	P06400	UNIPROT	down-regulates activity	phosphorylation	Ser608	TAADMYLsPVRSPKK		BTO:0001968								10207050	t		llicata	In the present assay, ΔP3,4HA repressed E2F-mediated transcription similarly to wild-type pRB, suggesting that phosphorylation at other sites on ΔP3,4HA can disrupt its interaction with E2F and that these two sites are not sufficient to regulate E2F binding on DNA. This result is consistent with another report which showed that mutation of the human sites 8 and 9 (human Ser608 and Ser612) repressed E2F-mediated transcription to the same level as wild-type pRB (2). | Surprisingly, no one CDK site regulated the interaction of pRB with E2F when E2F was bound to DNA. Instead, disruption of transcriptional repression resulted from accumulation of phosphate groups on the RB molecule.	SIGNOR-250747	0.74
SLIT2	protein	O94813	UNIPROT	ROBO	proteinfamily	SIGNOR-PF14	SIGNOR	up-regulates	binding			-1									16226035	t		miannu	Here we describe and compare two human robo3 isoforms, robo3a and robo3b, which differ by the insertion of 26 amino acids at the n-terminus, and these forms appear to be evolutionary conserved. We investigated the bioactivity of these isoforms and show that they have different binding properties to slit.	SIGNOR-268377	0.938
HMGCS2	protein	P54868	UNIPROT	(3S)-3-hydroxy-3-methylglutaryl-CoA(5-)	smallmolecule	CHEBI:43074	ChEBI	up-regulates quantity	chemical modification												29597274	t		lperfetto	Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis	SIGNOR-267660	0.8
MYC	protein	P01106	UNIPROT	CCNE1	protein	P24864	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9188852	f		gcesareni	Our results suggest that this activation may involve at least two myc-dependent steps: the induction of cyclin e gene transcription followed by accumulation of cyclin e mrna in a protein synthesis-independent manner and the p27(kip1) association with cyce/cdk2 complexes containing newly synthesised cyce.	SIGNOR-49130	0.619
CDC25C	protein	P30307	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates activity	dephosphorylation	Thr14	IEKIGEGtYGVVYKG	9606									17634129	t		lperfetto	The activity of Cdc2 is regulated by the phosphatase Cdc25C. Dephosphorylation of Cdc2 at threonine 14 and tyrosine 15 by Cdc25C results in activation of Cdc2 and initiation of an autoactivation loop between Cdc25C and Cdc2 that efficiently drives cells into mitosis.|Cdc2 is activated by Cdc25C that removes phosphate groups from tyrosine 15 and threonine 14 .|Dephosphorylation of Cdc2 at threonine 14 and tyrosine 15 by Cdc25C results in activation of Cdc2 and initiation of an autoactivation loop between Cdc25C and Cdc2 that efficiently drives cells into mitosis.	SIGNOR-276945	0.853
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	RARA	protein	P10276	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								19058965	t		Luana	Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes. 	SIGNOR-258138	0.8
TNF	protein	P01375	UNIPROT	CTSK	protein	P43235	UNIPROT	up-regulates quantity by expression	transcriptional regulation												11920402	f		lperfetto	This is supported by our finding that inflammatory cytokines such as IL-1b and TNFa increase the expres- sion of cathepsin K mRNA 􏰌6–8-fold and increase the secretion of the mature enzyme.	SIGNOR-253317	0.367
2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-pyrazolyl]-3-azetidinyl]acetonitrile	chemical	CHEBI:95341	ChEBI	JAK2	protein	O60674	UNIPROT	down-regulates activity	chemical inhibition			9606									20363976	t		Luana	INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM).	SIGNOR-257832	0.8
NUP107	protein	P57740	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262090	0.817
CDK1	protein	P06493	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Thr739	SEGSGTAtPSALITT	9606		BTO:0000887;BTO:0001260	SIGNOR-C17						20150555	t		gcesareni	Moreover, we showed that sp1 is a novel mitotic substrate of cdk1/cyclin b1 and is phosphorylated by it at thr 739 before the onset of mitosis.	SIGNOR-163738	0.476
SLC5A5	protein	Q92911	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			10116									28192058	t		scontino	Active iodide (I-) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+/I- symporter (NIS). In the thyroid, NIS-mediated I- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis. 	SIGNOR-266961	0.8
BMP7	protein	P18075	UNIPROT	ACTR2	protein	P61160	UNIPROT	up-regulates	binding			9606									16446785	t		acerquone	The two ligands induce the formation of two ligand-receptor complexes, cbmp7 (blue) and ctgf-b (red), that share the type i receptor alk2	SIGNOR-144144	0.294
ELANE	protein	P08246	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Val53	SHVTGKGvTVETVFS	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263590	0.404
E2F1	protein	Q01094	UNIPROT	MCPH1	protein	Q8NEM0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22136275	f		miannu	 Overexpression of E2F1 led to the upregulation of MCPH1 transcription, and knocking down the endogenous E2F1 resulted in the inhibition of the MCPH1 promoter activity. 	SIGNOR-253848	0.353
ATP6AP1	protein	Q15904	UNIPROT	RAB7A	protein	P51149	UNIPROT	up-regulates activity	binding												22467241	t		lperfetto	We found that Ac45 colocalized with Rab7 in resorbing osteoclasts cultured on bone slices (Fig. 6A). In addition, a co-immunoprecipitation assay revealed that Ac45 directly interacted with Rab7| Therefore, Ac45’s role in extracellular acidification, lysosomal trafficking, and cathepsin K exocytosis may be through the Rab7 pathway.	SIGNOR-261484	0.294
ARID1B	protein	Q8NFD5	UNIPROT	BAF250b E3 ligase	complex	SIGNOR-C522	SIGNOR	form complex	binding			9606	BTO:0000567								20086098	t		miannu	In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro	SIGNOR-271437	0.342
USP7	protein	Q93009	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	deubiquitination			9606									16082221	t		gcesareni	Hausp counteracts the destabilizing effect of mdm2 by direct deubiquitination of p53.	SIGNOR-139456	0.732
ATP5ME	protein	P56385	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261407	0.2
SIRT2	protein	Q8IXJ6	UNIPROT	KAT2B	protein	Q92831	UNIPROT	down-regulates	binding			9606		BTO:0000887;BTO:0001103							12887892	t		gcesareni	Sir2 forms a complex with the acetyltransferase pcaf and myod and, when overexpressed, retards muscle differentiation.	SIGNOR-104248	0.547
AXIN1	protein	O15169	UNIPROT	CSNK1D	protein	P48730	UNIPROT	up-regulates	binding			9606			SIGNOR-C110						12000790	t		gcesareni	Complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45).	SIGNOR-87401	0.537
MAPK1	protein	P28482	UNIPROT	MBP	protein	P02686	UNIPROT	down-regulates	phosphorylation	Thr232	KNIVTPRtPPPSQGK	9606									1939237	t		lperfetto	Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence.	SIGNOR-22420	0.57
BCL3	protein	P20749	UNIPROT	NFKB2	protein	Q00653	UNIPROT	up-regulates				9606									16713561	f		gcesareni	The cyclin d1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of bcl-3-associated nf-kappab p50 and p52	SIGNOR-146771	0.554
FYN	protein	P06241	UNIPROT	AGAP2	protein	Q99490	UNIPROT	up-regulates	phosphorylation	Tyr1130	QGRTALFyARQAGSQ	9606									16841086	t		llicata	We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival.	SIGNOR-147936	0.444
RARA	protein	P10276	UNIPROT	NR4A1	protein	P22736	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									10772826	f		lperfetto	Retinoic acid and its receptors repress the expression and transactivation functions of nur77	SIGNOR-76980	0.296
CDK2	protein	P24941	UNIPROT	PGR	protein	P06401	UNIPROT	unknown	phosphorylation	Thr430	PPLPPRAtPSRPGEA	9606									11110801	t		llicata	In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676).	SIGNOR-85000	0.453
VAMP8	protein	Q9BV40	UNIPROT	STX11-VAMP8 SNARE complex	complex	SIGNOR-C273	SIGNOR	form complex	binding			9606	BTO:0000132								22767500	t		lperfetto	Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. 	SIGNOR-261896	0.568
PTPRJ	protein	Q12913	UNIPROT	RET	protein	P07949	UNIPROT	down-regulates activity	dephosphorylation	Tyr1062	TWIENKLyGMSDPNW	9606									16778204	t			The receptor-type protein tyrosine phosphatase J antagonizes the biochemical and biological effects of RET-derived oncoproteins.|PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels	SIGNOR-248700	0.281
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser108	DKYGQNEsFARIQVR	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276220	0.389
quetiapine	chemical	CHEBI:8707	ChEBI	HTR1E	protein	P28566	UNIPROT	up-regulates activity	chemical activation			9534									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258531	0.8
HES1	protein	Q14469	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates activity				9606	BTO:0001938								24300895	t			Altering the expression of HES1 did not obviously affect GR abundance (Figure 3A). However, genome-wide microarrays revealed that overexpression of HES1 resulted in inhibition of GR-mediated changes in the glucocorticoid regulated transcriptome, as compared to non-overexpressing controls	SIGNOR-253064	0.2
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	Av/b5 integrin	complex	SIGNOR-C178	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259006	0.357
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CC2D1A	protein	Q6P1N0	UNIPROT	up-regulates activity	phosphorylation	Ser208	PASTPTYsPAPTQPA										20171170	t	nucleus	lperfetto	We identified the Ser208 residue of Aki1 as a cyclin B1–Cdk1 phosphorylation site. Furthermore, cyclin B1–Cdk1 inhibitor treatment was shown to attenuate the level of Aki1 in complex with Scc1, suggesting that Aki1 phosphorylation by cyclin B1–Cdk1 contributes to Aki1–Scc1 complex formation. 	SIGNOR-268296	0.2
RNF4	protein	P78317	UNIPROT	PML	protein	P29590	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								23530056	t		miannu	Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4.	SIGNOR-272884	0.501
N'-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine	chemical	CHEBI:91340	ChEBI	CHUK	protein	O15111	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258085	0.8
PDK4	protein	Q16654	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	phosphorylation	Ser293	TYRYHGHsMSDPGVS	-1									11485553	t		lperfetto	Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.	SIGNOR-109617	0.674
CSNK1A1	protein	P48729	UNIPROT	NFATC3	protein	Q12968	UNIPROT	down-regulates activity	phosphorylation	Ser211	TLGSPLTsPGGSPGG	9606	BTO:0001131								9630228	t		lperfetto	Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4.	SIGNOR-109763	0.571
MAPK1	protein	P28482	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Ser447	GSPRTPVsPVKFSPG	9606	BTO:0000150								19085255	t		gcesareni	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase.	SIGNOR-182808	0.578
SLC27A3	protein	Q5K4L6	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264464	0.7
Linsitinib	chemical	CID:11640390	PUBCHEM	IGF1R	protein	P08069	UNIPROT	down-regulates activity	chemical inhibition			10090									24712877	t		lperfetto	Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β-cell functions, and β-cell proliferation in male mice	SIGNOR-262028	0.8
DIABLO	protein	Q9NR28	UNIPROT	XIAP	protein	P98170	UNIPROT	down-regulates	binding			9606									10929711	t		amattioni	Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity.	SIGNOR-171770	0.912
PRKCB	protein	P05771	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser299	KMAFRAKsKSCHDLS	-1									9677319	t		lperfetto	Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases.	SIGNOR-249009	0.308
sunitinib	chemical	CHEBI:38940	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258292	0.8
PTPRB	protein	P23467	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates activity	dephosphorylation	Tyr81	WEVGSITyDTLSAQA	9606									32653904	t		miannu	VE-PTP interacts with eNOS and dephosphorylates Tyr81	SIGNOR-277521	0.271
CAMK2D	protein	Q13557	UNIPROT	CAMK2D	protein	Q13557	UNIPROT	up-regulates	phosphorylation			9606									19725819	t		areggio	Upon binding of the Ca2+/calmodulin complex to the binding domain of CaMKII, it is activated via autophosphorylation, then remaining active independent of of Ca2+ levels.	SIGNOR-255954	0.2
PDGFRB	protein	P09619	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates activity	phosphorylation	Tyr775	SSNYMAPyDNYVPSA	-1									8940081	t		miannu	The SH2 domain of Grb7 can directly bind to the autophosphorylated PDGF beta-receptor in vitro. Grb7 association to the PDGF beta-receptor was dramatically reduced by replacement of tyrosine residues 716 or 775 with phenylalanine residues. 	SIGNOR-250259	0.2
LRRK2	protein	Q5S007	UNIPROT	LRRK2	protein	Q5S007	UNIPROT	up-regulates	phosphorylation	Thr2031	CCRMGIKtSEGTPGF	9606	BTO:0000938								20595391	t		lperfetto	Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2.	SIGNOR-166470	0.2
SKI	protein	P12755	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	binding			9606	BTO:0000848								12793438	t		lperfetto	The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway	SIGNOR-236155	0.73
ACTA2	protein	P62736	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									11988769	f		miannu	It has subsequently been shown that most myofibroblasts express α-SM actin (the actin isoform typically found in vascular SM cells)13,14 and that the expression of α-SM actin and collagen type I in these cells is coordinately regulated by transforming growth factor β1 (TGF-β1)15. All these observations indicate that the myofibroblast has a role in the synthesis of ECM and in force generation, which results in ECM reorganization and wound contraction	SIGNOR-277682	0.7
NFYA	protein	P23511	UNIPROT	GFI1B	protein	Q5VTD9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19965638	f	 	miannu	HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. 	SIGNOR-254434	0.2
GART	protein	P22102	UNIPROT	(6S)-5,6,7,8-tetrahydrofolate(2-)	smallmolecule	CHEBI:57453	ChEBI	up-regulates quantity	chemical modification			9606									11381136	t		miannu	The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR.	SIGNOR-267304	0.8
E2F1	protein	Q01094	UNIPROT	G1/S_transition	phenotype	SIGNOR-PH50	SIGNOR	up-regulates				9606									21524151	f		lperfetto	In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F	SIGNOR-245477	0.7
PDPK1	protein	O15530	UNIPROT	PAK1	protein	Q13153	UNIPROT	up-regulates activity	phosphorylation	Thr423	PEQSKRStMVGTPYW	9534	BTO:0000298								10995762	t		miannu	P21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). We identify threonine 423, a conserved threonine in the activation loop of kinase subdomain VIII, as the PDK1 phosphorylation site on PAK1.	SIGNOR-250267	0.364
MAPK11	protein	Q15759	UNIPROT	PIAS2	protein	O75928	UNIPROT	up-regulates activity	phosphorylation	Ser116	VTPHSPSsPVGSVLL	9606	BTO:0000007								16713578	t		miannu	The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles	SIGNOR-262947	0.267
NTS	protein	P30990	UNIPROT	NTSR1	protein	P30989	UNIPROT	up-regulates	binding			9606		BTO:0000975							1331689	t		gcesareni	The rat neurotensin receptor cdna sequence was transfected in chinese hamster ovary cells and cellular clones which stably express the corresponding protein were isolated and characterized. The scatchard analysis of the specific binding of [3h]neurotensin indicated a kd value of 0.45 +/- 0.08 nm and a bmax value of 3.27 +/- 0.29 pmol/mg of protein. ...Neurotensin Stimulated the phosphoinositides hydrolysis	SIGNOR-17369	0.928
MAPK8IP3	protein	Q9UPT6	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates	binding			9606									15767678	t		gcesareni	The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.	SIGNOR-134558	0.715
SOD1	protein	P00441	UNIPROT	dioxygen	smallmolecule	CHEBI:15379	ChEBI	up-regulates quantity	chemical modification			9606									29301787	t		lperfetto	Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD).	SIGNOR-272286	0.8
NFATC3	protein	Q12968	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001260								17079331	t		lperfetto	The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.	SIGNOR-251732	0.288
CDK2	protein	P24941	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									15241418	t		gcesareni	We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function	SIGNOR-126732	0.733
PRKCA	protein	P17252	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser159	KKKKKRFsFKKSFKL	-1									8422248	t		lperfetto	These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III.	SIGNOR-248925	0.72
streptozocin	chemical	CHEBI:9288	ChEBI	SLC2A2	protein	P11168	UNIPROT	down-regulates quantity	chemical inhibition			10090									9421374	t		miannu	In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLD-STZ-treated C57BL/6 male mice, whereas mRNA expression of beta-actin, glucokinase, and proinsulin remained unaffected. GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against beta-cells.	SIGNOR-259314	0.8
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1654	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120184	0.321
COLGALT2	protein	Q8IYK4	UNIPROT	COL3A1	protein	P02461	UNIPROT	up-regulates activity	glycosylation			-1									19075007	t			Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261158	0.378
HMOX1	protein	P09601	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26722274	f		irozzo	The results of the present study indicated that knockdown of HMOX-1 significantly enhanced doxorubicin-induced apoptosis and downregulated the expression of Bcl-2 and Bcl-xL in breast cancer cells.	SIGNOR-256304	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	MAPK8IP3	protein	Q9UPT6	UNIPROT	up-regulates	phosphorylation			9606									15767678	t	inferred from 70% family members	gcesareni	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-269984	0.2
NPAS2	protein	Q99743	UNIPROT	BMAL1/NPAS2	complex	SIGNOR-C431	SIGNOR	form complex	binding			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements.	SIGNOR-267966	0.518
AP3M1	protein	Q9Y2T2	UNIPROT	AP-3 complex	complex	SIGNOR-C247	SIGNOR	form complex	binding			9606									21097499	t		lperfetto	Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)	SIGNOR-260682	0.87
SMAD5	protein	Q99717	UNIPROT	HAND1	protein	O96004	UNIPROT	up-regulates quantity	transcriptional regulation			10090									22219353	t		Gianni	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268941	0.2
FOXA1	protein	P55317	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19127412	f		miannu	Foxa1 overexpression decreased the expression of bcl2, while foxa1 depletion increased the expression of bcl2	SIGNOR-161448	0.2
Terfenadine	chemical	CHEBI:9453	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									19660947	t		Luana	 hERG activity was initially determined in a high throughput patch clamp screening assay (Ionworks)5 while a human H1 binding assay was used to determine H1 binding affinity.6 Selected results were confirmed in vitro using an IonWorks Quattro patch clamp assay and in vivo in the guinea pig.7, 8 Histamine H1activity was confirmed in vivo in the guinea pig.7	SIGNOR-257825	0.8
tipifarnib	chemical	CHEBI:141969	ChEBI	FNTA	protein	P49354	UNIPROT	down-regulates activity	chemical inhibition			9606									11196150	t		lperfetto	In vitro, using isolated human farnesyl protein transferase, R115777 competitively inhibited the farnesylation of lamin B and K-RasB peptide substrates, with IC50s of 0.86 nM and 7.9 nM, respectively. In a panel of 53 human tumor cell lines tested for growth inhibition, approximately 75% were found to be sensitive to R115777.	SIGNOR-262033	0.8
MAPK14	protein	Q16539	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606									18691976	t		gcesareni	Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle.	SIGNOR-179912	0.606
POLR2F	protein	P61218	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding												22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266148	0.897
GSK3B	protein	P49841	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	down-regulates activity	phosphorylation	Thr2074	VTPSPPGtVLTSALS	9606	BTO:0000007								12794074	t		lperfetto	We show that gsk-3beta directly binds at c-terminal of the notch2 ankyrin repeats and phosphorylates thr-2068 and/or ser-2070, thr-2074, and thr-2093.	SIGNOR-101574	0.495
PEX1	protein	O43933	UNIPROT	Protein_localization_to_peroxisome	phenotype	SIGNOR-PH86	SIGNOR	up-regulates				9606									26476099	f			The Pex1 and Pex6 proteins are members of the AAA family of ATPases and are involved in peroxisome biogenesis.	SIGNOR-253616	0.7
ATF4	protein	P18848	UNIPROT	WARS2	protein	Q9UGM6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269430	0.249
CAD	protein	P27708	UNIPROT	N-carbamoyl-L-aspartate(2-)	smallmolecule	CHEBI:32814	ChEBI	up-regulates quantity	chemical modification			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-267425	0.8
PPM1A	protein	P35813	UNIPROT	CDK9	protein	P50750	UNIPROT	down-regulates activity	dephosphorylation	Thr186	NSQPNRYtNRVVTLW	9606									18829461	t		gcesareni	Taken together, our data indicate that PPM1A and to some extent PPM1B are important negative regulators of P-TEFb function	SIGNOR-248490	0.508
RASGEF1B	protein	Q0VAM2	UNIPROT	NRAS	protein	P01111	UNIPROT	up-regulates	binding			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-161481	0.303
MAP2K6	protein	P52564	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates activity				9606									10480932	t		Luana	P38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta.	SIGNOR-260720	0.733
MAPK13	protein	O15264	UNIPROT	RCSD1	protein	Q6JBY9	UNIPROT	down-regulates activity	phosphorylation	Ser68	GQNGEEKsPPNASHP	-1									15850461	t		miannu	CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263084	0.431
PSME2	protein	Q9UL46	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	up-regulates activity	binding												35932807	t		lperfetto	While PA28alpha beta is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28gamma is well-known to not only promote peptidase activity but also proteolytic activity of proteasome. 	SIGNOR-275868	0.614
sapitinib	chemical	CHEBI:132986	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190152	0.8
DUSP3	protein	P51452	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates activity	dephosphorylation	Tyr877	LDIDETEyHADGGKV	9606	BTO:0002552								21262974	t			Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. | We found that VHR decreased ErbB2 phosphorylation in vitro and in a cellular context, and the dephosphorylation of ErbB2 was more evident at Tyr-877 and Tyr-1221 than those at Tyr-1139 and Tyr-1248 (supplemental Fig. S1). Our data indicated that VHR was a cellular PTP against EGFR and ErbB2. 	SIGNOR-248533	0.271
IL1R1	protein	P14778	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000801								9625767	t		lperfetto	Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab	SIGNOR-249514	0.286
AKT2	protein	P31751	UNIPROT	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr235	QARKRKRtSIENRVR	9606	BTO:0004180								23041284	t		flangone	Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.	SIGNOR-242097	0.258
L-asparagine zwitterion	smallmolecule	CHEBI:58048	ChEBI	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	up-regulates quantity	precursor of			9606									24657844	t		miannu	Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia.	SIGNOR-267536	0.8
PLK1	protein	P53350	UNIPROT	MAD2L1BP	protein	Q15013	UNIPROT	down-regulates activity	phosphorylation	Ser102	KHFYRKPsPQAEEML	9606	BTO:0000567								31118282	t		miannu	 Purified Plk1 bound to p31comet and phosphorylated it, resulting in the suppression of its activity (with TRIP13) to disassemble checkpoint complexes. We conclude that Plk1 phosphorylates p31 on S102 and on five additional sites. The phosphorylation of the additional sites was possibly not detectable in HeLa cell extracts due to the opposing action of protein phosphatases.	SIGNOR-265970	0.384
PRKD3	protein	O94806	UNIPROT	SSH1	protein	Q8WYL5	UNIPROT	down-regulates activity	phosphorylation	Ser978	SPLKRSHsLAKLGSL										21832093	t		lperfetto	Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase	SIGNOR-275938	0.29
CSNK2A2	protein	P19784	UNIPROT	HDAC2	protein	Q92769	UNIPROT	up-regulates activity	phosphorylation	Ser424	CDEEFSDsEDEGEGG	9606	BTO:0000567								12082111	t		llicata	HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2.	SIGNOR-251003	0.398
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	LEF1	protein	Q9UJU2	UNIPROT	up-regulates	transcriptional regulation			9606									10890911	f		lperfetto	Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity	SIGNOR-217169	0.604
FOXO3	protein	O43524	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity	transcriptional regulation			10090	BTO:0002314								24749067	f		gcesareni	We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration.	SIGNOR-244076	0.384
SLBP	protein	Q14493	UNIPROT	H2AX	protein	P16104	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265405	0.2
PAK1	protein	Q13153	UNIPROT	ILK	protein	Q13418	UNIPROT	up-regulates	phosphorylation	Ser246	CPRLRIFsHPNVLPV	9606									17420447	t		lperfetto	We found that pak1 phosphorylates ilk at threonine-173 and serine-246 in vitro and in vivo. together, these results suggest that ilk is a pak1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin.	SIGNOR-154303	0.421
CTTN	protein	Q14247	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	up-regulates activity	binding			9606									11231575	t			Cortactin binds directly to the Arp2/3 complex and activates it to promote nucleation of actin filaments.	SIGNOR-251519	0.632
GRK6	protein	P43250	UNIPROT	LTB4R	protein	Q15722	UNIPROT	down-regulates activity	phosphorylation	Thr308	VAKLLEGtGSEASST	9534	BTO:0000298								12077128	t			Thr(308) is a major residue involved in GRK6-mediated desensitization of BLT1 signaling.	SIGNOR-251213	0.487
HOPX	protein	Q9BPY8	UNIPROT	LORICRIN	protein	P23490	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000667								21256618	f		miannu	 In the present study, we performed transcriptional profiling of cultured primary human keratinocytes and noted a robust induction of HOP upon calcium-induced cell differentiation. Overexpression of HOP using a lentiviral vector up-regulated FLG and LOR expression during keratinocyte differentiation. 	SIGNOR-254464	0.2
TRIM27	protein	P14373	UNIPROT	MAPK13	protein	O15264	UNIPROT	up-regulates				9606									12807881	f		miannu	We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38.	SIGNOR-102028	0.2
AURKA	protein	O14965	UNIPROT	CDC25B	protein	P30305	UNIPROT	up-regulates	phosphorylation	Ser353	VQNKRRRsVTPPEEQ	9606									16082213	t		lperfetto	We show that bypass of the g2/m checkpoint by the chk1 kinase inhibitor ucn-01 results in the activation of aurora-a and phosphorylation of cdc25b on s353	SIGNOR-139396	0.711
EGR1	protein	P18146	UNIPROT	SOD1	protein	P00441	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9867871	f	 	miannu	 The human copper-zinc superoxide dismutase gene (SOD1) proximal promoter is regulated by Sp1, Egr-1, and WT1 via non-canonical binding sites. Egr-1 and two splicing variants of the Egr-related protein WT1 were able to transactivate the SOD1 promoter in co-transfection experiments.	SIGNOR-253897	0.296
BIRC3	protein	Q13489	UNIPROT	RIPK4	protein	P57078	UNIPROT	up-regulates activity	polyubiquitination		lys51	9606	BTO:0000007								21931591	t		miannu	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation.	SIGNOR-272707	0.362
PRKACA	protein	P17612	UNIPROT	CCND1	protein	P24385	UNIPROT	unknown	phosphorylation	Ser90	NYLDRFLsLEPVKKS	-1									8058338	t		miannu	PKA phosphorylates three distinct serine residues in cyclin D1 at positions 90, 197 and 234.	SIGNOR-250347	0.338
ADL-5859	chemical	CID:46931003	PUBCHEM	OPRD1	protein	P41143	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-189278	0.8
MRTFA	protein	Q969V6	UNIPROT	KLF4	protein	O43474	UNIPROT	down-regulates				9606									21673106	f	miR-143 and miR-145 target KLF4	gcesareni	This result suggests that mrtf-a, but not myocd, is essential for bmp4-dependent induction ofmir-143/145gene transcription. Of the mirnas identified to target klf4, only mir-143 and mir-145 were induced at least 1.5-fold by both bmp4 and tgf- , suggesting that they may be critical for bmp4- and tgf- -mediated reduction of klf4.	SIGNOR-174261	0.2
oxaprozin	chemical	CHEBI:7822	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000132;BTO:0003652								9650852	t		miannu	We used human platelets cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 for measuring cyclooxygenase selectivity. The presence of the enzymes was confirmed by immunoblotting and immunoprecipitation analysis, and by the reverse transcriptase-polymerase chain reaction. Mean IC50 values (microM) for human platelet cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 and cyclooxygenase-1/-2 IC50 ratio of various NSAIDs were as follows: aspirin, 3.2, 26, 0.12; diclofenac, 0.037, 0.00097, 38; etodolac, 122, 0.68, 179; ibuprofen, 3.0, 3.5, 0.86; indomethacin, 0.013, 0.044, 0.30; loxoprofen (active metabolite), 0.38, 0.12, 3.2; NS-398, 12, 0.0095, 1263; oxaprozin, 2.2, 36, 0.061; zaltoprofen, 1.3, 0.34, 3.8; respectively.	SIGNOR-258930	0.8
TRIM11	protein	Q96F44	UNIPROT	PHOX2B	protein	Q99453	UNIPROT	down-regulates	ubiquitination			9606									22307522	t		miannu	The e3 ubiquitin ligasetrim11mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expandedphox2b.	SIGNOR-195878	0.499
FGF4	protein	P08620	UNIPROT	FGFR4	protein	P22455	UNIPROT	up-regulates	binding			9606									1385111	t		gcesareni	Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides.	SIGNOR-18567	0.659
RPL5	protein	P46777	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262457	0.889
PRKCA	protein	P17252	UNIPROT	KRT18	protein	P05783	UNIPROT	unknown	phosphorylation	Ser53	ISVSRSTsFRGGMGS	-1									7523419	t		lperfetto	Ser-52 in K18 is not glycosylated and matches consensus sequences for phosphorylation by CAM kinase, S6 kinase and protein kinase C, and all these kinases can phosphorylate K18 in vitro predominantly at that site.	SIGNOR-248894	0.311
HRH2	protein	P25021	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257250	0.252
BMP7	protein	P18075	UNIPROT	DLK1	protein	P80370	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20584981	f		fspada	Bmp7 could directly suppress pref-1 expression, thereby allowing the initiation of the adipogenic program.	SIGNOR-166426	0.295
NOG	protein	Q13253	UNIPROT	BMP2	protein	P12643	UNIPROT	down-regulates	binding			9606									12700180	t		lperfetto	Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides	SIGNOR-100657	0.804
MAPK9	protein	P45984	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Ser315	ITATSPAsMVGGKPG	9606									9335553	t		gcesareni	These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling.	SIGNOR-52696	0.698
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SMAD2	protein	Q15796	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000763;BTO:0000149							10197981	t		lperfetto	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3	SIGNOR-244576	0.2
TEK	protein	Q02763	UNIPROT	MYH1	protein	P12882	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000222								26042050	f		lperfetto	the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein.	SIGNOR-241541	0.2
SKA2	protein	Q8WVK7	UNIPROT	SKA complex	complex	SIGNOR-C364	SIGNOR	form complex	binding			-1									22483620	t		lperfetto	We show that the structure of the Ska core complex is a W-shaped dimer of coiled coils, formed by intertwined interactions between Ska1, Ska2, and Ska3. 	SIGNOR-265195	0.899
Cytoplasmic_Dynein	proteinfamily	SIGNOR-PF67	SIGNOR	Organelle_transport	phenotype	SIGNOR-PH159	SIGNOR	up-regulates													16440056	f		lperfetto	The most abundant cytoplasmic dynein complex, cytoplasmic dynein 1, is involved in functions as diverse as spindle-pole organization and nuclear migration during mitosis, the positioning and functioning of the endoplasmic reticulum, the Golgi apparatus, and the nucleus, and also the minus-end-directed transport of vesicles, including endosomes and lysosomes, along microtubules and retrograde axonal transport in neurons.	SIGNOR-265058	0.7
CEBPA	protein	P49715	UNIPROT	SOX4	protein	Q06945	UNIPROT	down-regulates	transcriptional regulation			9606									24183681	t		apalma	In summary, our data demonstrate that C/EBPα negatively regulates Sox4 transcription via direct DNA-binding.	SIGNOR-255675	0.392
MAPK3	protein	P27361	UNIPROT	KRT8	protein	P05787	UNIPROT	unknown	phosphorylation	Ser432	SAYGGLTsPGLSYSL	9606									22344252	t		llicata	Our data suggested a close relationship between k8(s431) phosphorylation and keratin reorganization in epithelial tumor cells.	SIGNOR-196141	0.429
2-Amino-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-7-(naphthalen-1-YL)-5-oxo-4H-chromene-3-carbonitrile	chemical	CID:25223366	PUBCHEM	SLC1A3	protein	P43003	UNIPROT	down-regulates activity	chemical inhibition			9606									19161278	t		Federica	The most potent analogue in the series, 1o, displayed high nanomolar inhibitory activity (IC50) 0.66μM) at EAAT1, with more than 400-foldselectivity compared to EAAT2 and EAAT3.	SIGNOR-261108	0.8
AR	protein	P10275	UNIPROT	BTG2	protein	P78543	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001321								16281084	f	 	 	 After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes.	SIGNOR-253674	0.385
PRKAR2B	protein	P31323	UNIPROT	PRKAR2B	protein	P31323	UNIPROT	up-regulates activity	phosphorylation	Ser114	NRFTRRAsVCAEAYN	10090									15822905	t		miannu	Ser114 (the autophosphorylation site) of human RII beta. Point mutation of the autophosphorylation site or in the nuclear location signal causes protein kinase A RII beta regulatory subunit to lose its ability to revert transformed fibroblasts.	SIGNOR-250076	0.2
RAB6C	protein	Q9H0N0	UNIPROT	VPS13B	protein	Q7Z7G8	UNIPROT	up-regulates activity	binding			10116	BTO:0003102								25492866	t		miannu	Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization. COH1 Interacts with All Three Mammalian RAB6 Homologues	SIGNOR-266871	0.2
GABRB1	protein	P18505	UNIPROT	GABA-A (a5-b1-g2) receptor	complex	SIGNOR-C335	SIGNOR	form complex	binding			9606									18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263766	0.627
STAT3	protein	P40763	UNIPROT	IL1RN	protein	P18510	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000130;BTO:0000876								20032313	f	 	miannu	The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. our findings uncover a novel mechanism whereby IL-10-activated STAT3 modulates IL-1ra transcription in LPS-treated phagocytes by making IL-1ra promoter accessible to readily available nuclear NF-kappaB.	SIGNOR-254795	0.485
STAT6	protein	P42226	UNIPROT	KLF4	protein	O43474	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22378047	t		lperfetto	STAT6 coordinates and synergizes with both PPAR? and KrŸppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function.	SIGNOR-249568	0.353
CDK1	protein	P06493	UNIPROT	ECT2	protein	Q9H8V3	UNIPROT	up-regulates	phosphorylation	Thr846	RAFSFSKtPKRALRR	9606			SIGNOR-C17						16247472	t		lperfetto	Thr-814 to ala greatly diminished the ability of p34cdk1/cyclin b to phosphorylate recombinant ect2-c protein (figure 1b, left panel). These data suggest that thr-814 is a major cdk1 phosphorylation site in ect2-c in vitrothe sequence thr-pro-lys-arg (tpkr) starting at amino acid 814we found that the t814a mutation slightly reduces the exchange activity of ect2 on rac1	SIGNOR-141179	0.594
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser256	SPRRRAAsMDNNSKF	-1	BTO:0000318								10377430	t		lperfetto	Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export.	SIGNOR-252856	0.908
PRKCA	protein	P17252	UNIPROT	PPP1R16B	protein	Q96T49	UNIPROT	down-regulates activity	phosphorylation	Ser331	SQLRHKSsLSRRTSS	-1									27939168	t	done	miannu	PKCα phosphorylated the full length recombinant TIMAP in in vitro kinase assay and Ser331 of TIMAP was shown to be phosphorylated by PKC. Phosphorylation of TIMAP upon PKC activation in endothelial cells results in enrichment of TIMAP in the membrane, but no such change can be observed in PKC depleted cells. Phosphorylation state of TIMAP, through affecting PP1 activity, has a remarkable effect on endothelial barrier function. 	SIGNOR-273802	0.2
SRP72	protein	O76094	UNIPROT	SRP68	protein	Q9UHB9	UNIPROT	up-regulates activity	binding			-1									30649417	t		miannu	Taken together our data show that binding of the SRP68/72 heterodimer follows an ultrasensitive response dependent on the SRP72 C-terminus. Although the large solenoids of SRP68/72 have not been structurally characterized due to intrinsic flexibility, they serve as important contact sites in ribosome interaction.	SIGNOR-261164	0.989
SCRIB	protein	Q14160	UNIPROT	Scribble_complex_DLG3-LLGL1_variant	complex	SIGNOR-C507	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270896	0.531
CBLL1	protein	Q75N03	UNIPROT	ANXA2	protein	P07355	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								31952268	t		miannu	By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. 	SIGNOR-271473	0.2
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	AP-1/clathrin vescicle	complex	SIGNOR-C251	SIGNOR	up-regulates				9606									25720354	f		scontino	APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. 	SIGNOR-267855	0.7
GRIA1	protein	P42261	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial.	SIGNOR-264947	0.8
TLRs	proteinfamily	SIGNOR-PF20	SIGNOR	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates				9606									20404851	f		lperfetto	The negative regulation of TLR-induced responses is important for sup- pressing inflammation and deleterious immune responses.	SIGNOR-216304	0.7
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Ser626	SLECDMEsIIRSELM	9606	BTO:0000007								17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-252884	0.398
heparan sulfate octasaccharide	smallmolecule	CHEBI:142519	ChEBI	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									27241222	f		miannu	Many observations in animal models deficient for HSPGs and recent observations of human genetic mutations for biosynthesis of HSPGs have identified the importance of HSPGs for normal embryonic development and ECM organization.	SIGNOR-264017	0.7
MARK4	protein	Q96L34	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser396	DDKKAKTsTRSSAKT	-1									21204788	t	done	miannu	AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 	SIGNOR-273935	0.429
PRKACA	protein	P17612	UNIPROT	HSF1	protein	Q00613	UNIPROT	up-regulates	phosphorylation	Ser320	ASPGRPSsVDTLLSP	9606									21085490	t		lperfetto	Protein kinase a binds and activates heat shock factor 1hsf1 binds avidly to the catalytic subunit of pka, (pkac_) and becomes phosphorylated on a novel serine phosphorylation site within its central regulatory domain (serine 320 or s320), both in vitro and in vivo. Intracellular pkac_ levels and phosphorylation of hsf1 at s320 were both required for hsf1 to be localized to the nucleus, bind to response elements in the promoter of an hsf1 target gene	SIGNOR-169853	0.32
SMAD7	protein	O15105	UNIPROT	SMURF2	protein	Q9HAU4	UNIPROT	up-regulates activity	relocalization			9606									19352540	t		lperfetto	Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway.	SIGNOR-168450	0.865
PCDH10	protein	Q9P2E7	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-269034	0.2
CDK1	protein	P06493	UNIPROT	LMNA	protein	P02545	UNIPROT	up-regulates	phosphorylation	Ser392	ERLRLSPsPTSQRSR	9606									18815303	t		gcesareni	Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm	SIGNOR-181318	0.553
PRLHR	protein	P49683	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257280	0.266
PTPN2	protein	P17706	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates				9606									12612081	f		acerquone	We found that insulin-induced ir tyrosine phosphorylation and pkb/akt sig- naling were enhanced in tcptp- cells and suppressed upon tcptp reconstitution, providing persuasive evidence that tcptp can regulate ir activation and signaling.	SIGNOR-98811	0.364
VRK2	protein	Q86Y07	UNIPROT	DTNBP1	protein	Q96EV8	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser299	RAKPPSSsSTCTDSA	-1									30062698	t		miannu	 We show that VRK2 phosphorylates Ser 297 and Ser 299 of dysbindin using in vitro kinase assay. In addition, we found that VRK2-mediated phosphorylation of dysbindin enhanced ubiquitination of dysbindin and consequently resulted in the decrease in its protein stability through western blotting. 	SIGNOR-277404	0.2
AKT2	protein	P31751	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000586			SIGNOR-C110					16293724	t		lperfetto	We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt by free G protein betagamma subunits and the direct association of the G protein alphas subunit with the regulator of G protein signaling (RGS) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway.	SIGNOR-235718	0.606
CSNK2A1	protein	P68400	UNIPROT	MDC1	protein	Q14676	UNIPROT	up-regulates	phosphorylation	Ser299	SQPPGEDsDTDVDDD	9606									18678890	t		gcesareni	The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites.	SIGNOR-179875	0.353
CAV3	protein	P56539	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255997	0.496
FLT3	protein	P36888	UNIPROT	PTPN6	protein	P29350	UNIPROT	down-regulates quantity	transcriptional regulation			9606	BTO:0004760								15574429	f			Furthermore, a small but reproducible growth/survival advantage was observed in both TF-1 and TF-1/ITD cells when SHP-1 expression was knocked down by RNAi. Taken together, these data provide the first evidence that suppression of SHP-1 by FLT3/ITD signaling may be another mechanism contributing to the transformation by FLT3/ITD mutations	SIGNOR-259950	0.374
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2G1	protein	P62253	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271349	0.701
AURKA	protein	O14965	UNIPROT	AURKAIP1	protein	Q9NWT8	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser70	MLVPRKMsVSPLESW	9606	BTO:0000567								17957726	t		miannu	AIP is phosphorylated on Serine 70 by Aurora‐A but not Aurora‐B and expression of phosphorylation mimic mutant of AIP results in prolonged protein stability compared to unphosphorylatable mutant. Phosphorylation of AIP Prolongs its Protein Stability	SIGNOR-262648	0.669
AKT2	protein	P31751	UNIPROT	TSC	complex	SIGNOR-C101	SIGNOR	down-regulates activity	phosphorylation			10090	BTO:0000011								19593385	t		lperfetto	In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis	SIGNOR-235852	0.666
leucine	smallmolecule	CHEBI:25017	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264748	0.7
RPS6KA1	protein	Q15418	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser287	SMSSCGSsGYFSSSP	9606									22017877	t		lperfetto	We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1	SIGNOR-176887	0.507
TFAP2C	protein	Q92754	UNIPROT	Pluripotency	phenotype	SIGNOR-PH43	SIGNOR	up-regulates													31583686	f		SimoneGraziosi	SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation. 	SIGNOR-269262	0.7
COLGALT1	protein	Q8NBJ5	UNIPROT	COL3A1	protein	P02461	UNIPROT	up-regulates activity	glycosylation			-1									19075007	t			Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261154	0.378
BTC	protein	P35070	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606	BTO:0000150								9528863	t		gcesareni	Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4.	SIGNOR-56365	0.737
MT-ND2	protein	P03891	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 	SIGNOR-262144	0.772
NFKBIA	protein	P25963	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates activity	binding			9606				SIGNOR-C13					1340770	t		lperfetto	Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b	SIGNOR-17688	0.727
AURKA	protein	O14965	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser315	LPNNTSSsPQPKKKP	9606									24173284	t		lperfetto	The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A	SIGNOR-120836	0.771
OGA	protein	O60502	UNIPROT	PFKL	protein	P17858	UNIPROT	up-regulates activity	deglycosylation	Ser529	CVIPATIsNNVPGTD	9606									26399441	t		lperfetto	Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 	SIGNOR-267608	0.2
LRRK2	protein	Q5S007	UNIPROT	ARHGEF7	protein	Q14155	UNIPROT	up-regulates	phosphorylation	Thr127	KVLSSLVtLNKVTAD	9606									21048939	t		gcesareni	Arhgef7 is interacting with lrrk2 in vitro and in vivo. Lrrk2 phosphorylates arhgef7 in vitro.Two Threonine residues, t107 and t143, within the arhgef7 n-terminus were identified with high confidence	SIGNOR-169221	0.468
ADSS1	protein	Q8N142	UNIPROT	Nucleotide_synthesis	phenotype	SIGNOR-PH179	SIGNOR	up-regulates				9606									10496970	f		miannu	Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP.	SIGNOR-267835	0.7
CSNK2A1	protein	P68400	UNIPROT	AQP4	protein	P55087	UNIPROT	down-regulates activity	phosphorylation	Ser316	EKKGKDQsGEVLSSV	9615	BTO:0000837								11742978	t		llicata	We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4-Cter proteins in which only one out of the three C-terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. 	SIGNOR-250828	0.426
FLCN	protein	Q8NFG4	UNIPROT	RRAGC	protein	Q9HB90	UNIPROT	up-regulates activity	gtpase-activating protein			9606	BTO:0000007								24095279	t			The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur	SIGNOR-256503	0.687
NEDD4L	protein	Q96PU5	UNIPROT	SCN5A	protein	Q14524	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000938								23778145	t		miannu	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 	SIGNOR-253456	0.476
TLR4	protein	O00206	UNIPROT	TLR4	protein	O00206	UNIPROT	up-regulates activity	binding			10090									22664090	t		gcesareni	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-252066	0.2
RAB4A	protein	P20338	UNIPROT	RUFY1	protein	Q96T51	UNIPROT	up-regulates activity	binding			9606									20534812	t		Giulio	Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.|We also found that enlargement of early endosomes mediated by RUFY1 requires its interaction with Rab4	SIGNOR-261280	0.667
CHRM5	protein	P08912	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257217	0.428
MAPK8	protein	P45983	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000782;BTO:0001271								18174237	t		gcesareni	Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome.	SIGNOR-160326	0.751
PRKCA	protein	P17252	UNIPROT	UNC5A	protein	Q6ZN44	UNIPROT	down-regulates quantity	phosphorylation	Ser532	EPSPDSWsLRLKKQS	10116	BTO:0003036								16554470	t		miannu	We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. 	SIGNOR-268179	0.2
CSNK2A2	protein	P19784	UNIPROT	UBE2R2	protein	Q712K3	UNIPROT	up-regulates activity	phosphorylation	Ser233	DCYDDDDsGNEES	9606									12037680	t		llicata	UBC3B is specifically phosphorylated by CK2 in vitro and in vivo. We mapped by deletions and site directed mutagenesis the phosphorylation site to a serine residue within the C-terminal domain in position 233 of UBC3B and in the corresponding serine residue of UBC3. | Following CK2-dependent phosphorylation both UBC3B and UBC3 bind to the F-box protein beta-TrCP, the substrate recognition subunit of an SCF (Skp1, Cul1, F-box) ubiquitin ligase. Furthermore, we observed that co-transfection of CK2alpha' together with UBC3B, but not with UBC3DeltaC, enhances the degradation of beta-catenin. 	SIGNOR-251047	0.461
NR0B2	protein	Q15466	UNIPROT	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									17909097	f	inferred from family member	gcesareni	As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells	SIGNOR-270256	0.2
RPS4Y2	protein	Q8TD47	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262448	0.2
HNF4A	protein	P41235	UNIPROT	PCK1	protein	P35558	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16308421	f		gcesareni	Pgc1alfa is thought to mediate transcription downstream of the nuclear receptor hepatocyte nuclear factor 4alfa (hnf4alfa) and the transcription factor foxo1 in the promoters of key gluconeogenic enzymes, including glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxylase (pepck)	SIGNOR-142204	0.357
GLI3	protein	P10071	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0002572								16571352	f		lperfetto	The basal expression of Gli1, Ptc1, and Hip1 was positively associated with the loss of Gli3 alleles.These findings implicate Gli3 as a repressor of Hh target gene expression.	SIGNOR-209638	0.437
IGF1R	protein	P08069	UNIPROT	PIK3C2A	protein	O00443	UNIPROT	up-regulates	phosphorylation			9606									7692086	t		gcesareni	Analysis of the ability of the full-length igfr and its mutant receptors described above to associate with phosphatidylinositol 3 kinase indicated that the association required ptk activity and tyrosine [?] Phosphorylation of the receptors and correlated well with their transforming activities	SIGNOR-32076	0.278
MTNR1B	protein	P49286	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256707	0.448
NFE2L3	protein	Q9Y4A8	UNIPROT	NQO1	protein	P15559	UNIPROT	down-regulates quantity by repression	transcriptional regulation												15385560	t		lperfetto	Deletion mutation analysis revealed that Nrf3 repression of NQO1 gene expression required heterodimerization and DNA binding domains but not transcriptional activation domain of Nrf3.	SIGNOR-268976	0.346
BRMS1	protein	Q9HCU9	UNIPROT	KDM1A	protein	O60341	UNIPROT	up-regulates activity	binding			9606	BTO:0000093								30416854	t		miannu	Our results have showed that BRMS1 together with LSD1 are required for inhibition of breast cancer cell migration and invasion. Collectively, these findings demonstrate that BRMS1 executes transcriptional suppression of breast cancer metastasis by associating with the LSD1 and thus can be targeted for breast cancer therapy.	SIGNOR-266409	0.26
EGFR	protein	P00533	UNIPROT	STAT5B	protein	P51692	UNIPROT	up-regulates	phosphorylation	Tyr740	AVCPQAHyNMYPQNP	9606									11751923	t		llicata	Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor.	SIGNOR-113397	0.827
ATM	protein	Q13315	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates	phosphorylation	Ser1404	EEIKSQNsQESTADE	9606									12086603	t		lperfetto	These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint	SIGNOR-90113	0.782
CCR3	protein	P51677	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates				9606									11591790	f			We and others have recently found that eotaxin activates extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein (MAP) kinases in eosinophils, and that these kinases are indispensable for eosinophil chemotaxis and degranulation	SIGNOR-254357	0.301
lapatinib	chemical	CHEBI:49603	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150								17892419	t		gcesareni	Recently, lapatinib, a small molecule dual inhibitor of both her2 and egf receptors, has been developed to expand the options for treating her-positive breast cancer.	SIGNOR-157867	0.8
TARDBP	protein	Q13148	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			9606	BTO:0004170								PMC7642658	t		lperfetto	Importantly, we found that TDP-43 protein could interact with GSK3β mRNA and regulate the level of GSK3β protein translation. Taken together, our findings suggest that TDP-43 may activate the Wnt/β-catenin pathway by targeting the inhibition of GSK3β protein translation|TDP-43 activates Wnt/β-catenin pathway probably by inhibiting the GSK3β protein translation. A. Interaction between TDP-43 protein and GSK3β mRNA was analyzed using RIP assay.	SIGNOR-262113	0.27
ITK	protein	Q08881	UNIPROT	CD28	protein	P10747	UNIPROT	up-regulates	phosphorylation	Tyr191	SRLLHSDyMNMTPRR	9606									22936936	t		lperfetto	We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor	SIGNOR-198747	0.677
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	TWIST1	protein	Q15672	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								21502402	t	inferred from 70% family members	llicata	Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro	SIGNOR-270122	0.2
DHX9	protein	Q08211	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								30137501	t		miannu	A DNA-sensing-independent Role of a Nuclear RNA Helicase, DHX9, in Stimulation of NF-κB-mediated Innate Immunity Against DNA Virus Infection. Taken together, our results show a critical role of nuclear DHX9 (as a transcription coactivator) in the stimulation of NF-κB-mediated innate immunity against DNA virus infection, independently of DHX9's DNA-sensing function. DHX9 interacts with NF-κB p65 and RNAPII in the nucleus during DNA virus infection	SIGNOR-260947	0.44
C3	protein	P01024	UNIPROT	C3AR1	protein	Q16581	UNIPROT	up-regulates activity	binding			9606					cleavage:Arg671;Arg748	QPAARRRrSVQLTEK;ASHLGLArSNLDEDI			8765043	t	complement C3a fragment: PRO_0000005910	lperfetto	A cDNA clone encoding the human C3a anaphylatoxin receptor (C3aR) was isolated from a pcDNAI/Amp expression library prepared from U-937 cells|The cDNA clone contained an insert of 4.3 kbp and was able to confer to transfected human HEK-293 cells the capacity to bind specifically iodinated human C3a. 	SIGNOR-263451	0.723
MTMR4	protein	Q9NYA4	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	dephosphorylation			9606									20061380	t		gcesareni	Here we demonstrate that myotubularin-related protein 4	SIGNOR-163034	0.495
7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one	chemical	CID:56593482	PUBCHEM	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			9606									22025698	t		Luana	Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. 	SIGNOR-258321	0.8
RPS6KB1	protein	P23443	UNIPROT	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606		BTO:0000562							9211863	t		gcesareni	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-49371	0.249
IRAK3	protein	Q9Y616	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	down-regulates activity				10090	BTO:0000801								12150927	f			IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection.	SIGNOR-259288	0.7
MTSS1	protein	O43312	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates	binding			9606		BTO:0001253							15545630	t		gcesareni	Mim is a shh-responsive gene that can potentiate gli transcriptional activity.MIM Appears to regulate target gene expression through its association with the gli complex	SIGNOR-130542	0.525
LSM7	protein	Q9UK45	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270647	0.796
MAPK11	protein	Q15759	UNIPROT	TCF3	protein	P15923	UNIPROT	up-regulates	phosphorylation	Ser139	LNSPGPLsPSGMKGT	9606		BTO:0000887							15719023	t	p38 MAPK in particular phosphorylates Ser140 of E47. Its been observed that phosphorylation of E47 improves its ability to form heterodimers with Myod transcription factor	gcesareni	Here we show that p38 mapk, whose activity is essential for myogenesis, regulates myod/e47 heterodimerization. Phosphorylation of e47 at ser140 by p38 induces myod/e47 association and activation of muscle-specific transcription, while the nonphosphorylatable e47 mutant ser140ala fails to heterodimerize with myod and displays impaired myogenic potentia	SIGNOR-134190	0.411
MRPS24	protein	Q96EL2	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261436	0.645
ATR	protein	Q13535	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates activity	phosphorylation	Ser1143	PMGSSHAsQVCSETP	9606	BTO:0002181								11114888	t		llicata	Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication.	SIGNOR-250581	0.792
CDK1	protein	P06493	UNIPROT	STIP1	protein	P31948	UNIPROT	down-regulates activity	phosphorylation	Ser189	LLGVDLGsMDEEEEI	10090	BTO:0000944								14754904	t		miannu	Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions.	SIGNOR-262729	0.267
DOK1	protein	Q99704	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257671	0.32
IRAK1	protein	P51617	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Thr86	YTLSRAQtVVVEYTH	9606									12496252	t		lperfetto	In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation	SIGNOR-96759	0.758
ADAM17	protein	P78536	UNIPROT	EREG	protein	O14944	UNIPROT	up-regulates activity	cleavage			9606									26284334	t		miannu	ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF	SIGNOR-259843	0.548
RPS6KA3	protein	P51812	UNIPROT	CASP8	protein	Q14790	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr263	SIRDRNGtHLDAGAL										21183680	t		lperfetto	The ribosomal S6 kinase 2 (RSK2) is a member of the p90 ribosomal S6 kinase (p90RSK) family of proteins and plays a critical role in proliferation, cell cycle, and cell transformation. Here, we report that RSK2 phosphorylates caspase-8, and Thr-263 was identified as a novel caspase-8 phosphorylation site. In addition, we showed that EGF induces caspase-8 ubiquitination and degradation through the proteasome pathway, and phosphorylation of Thr-263 is associated with caspase-8 stability.	SIGNOR-272997	0.378
SL-327	chemical	CHEBI:92211	ChEBI	MAP2K2	protein	P36507	UNIPROT	down-regulates	chemical inhibition			9606									11160424	t		gcesareni	The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity	SIGNOR-104930	0.8
IL1RAPL1	protein	Q9NZN1	UNIPROT	NCS1	protein	P62166	UNIPROT	up-regulates activity	binding			10116	BTO:0001009								12783849	t		miannu	IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.	SIGNOR-263962	0.615
MAPK3	protein	P27361	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser380	HQLFRGFsFVATGLM	9534									9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-219341	0.705
MAPK3	protein	P27361	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser389	LSPIAPRsPAKLSFQ	9606									7889942	t		gcesareni	Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-34661	0.582
PRKD1	protein	Q15139	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates activity	phosphorylation	Ser11	SFLVRKPsDPNRKPN	9606									20940406	t		lperfetto	Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding. Pkd1 regulates the expression of e-cadherin at the promoter level through direct phosphorylation of the transcriptional repressor snai1. Pkd1-mediated phosphorylation of snai1 occurs in the nucleus and generates a nuclear, inactive dna/snai1 complex that shows decreased interaction with its co-repressor ajuba.	SIGNOR-168537	0.479
AURKA	protein	O14965	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser94	SLLSRSSsGYFSFDT	9606	BTO:0002181								23912711	t		miannu	 We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL. 	SIGNOR-276248	0.384
IMPDH1	protein	P20839	UNIPROT	5'-xanthylic acid	smallmolecule	CHEBI:15652	ChEBI	up-regulates quantity	chemical modification			9606									19480389	t		miannu	IMPDH controls the gateway to guanine nucleotides, making it an “enzyme of consequence” for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS).	SIGNOR-267332	0.8
SOCS3	protein	O14543	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	binding			9606									24600449	t		miannu	The ability of SOCS3 to simultaneously bind to JAK and to the cytokine receptor explains the specificity of the suppression. SOCS3 binds JAK and gp130 receptor simultaneously, using two opposing surfaces: while the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by the gp130 receptor, a subdomain in the SH2 domain of SOCS3 is also required for inhibition of JAK, binding in a phospho-independent manner to a non-canonical surface of JAK2 (58, 59). The KIR of SOCS3 occludes the substrate-binding groove on JAK2.	SIGNOR-255329	0.789
SLC12A2	protein	P55011	UNIPROT	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	phosphorylation												21613606	t		lperfetto	Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12). 	SIGNOR-264634	0.8
IFNAR	complex	SIGNOR-C243	SIGNOR	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9606									21631354	t		miannu	These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity	SIGNOR-260436	0.2
TINF2	protein	Q9BSI4	UNIPROT	Shelterin complex	complex	SIGNOR-C306	SIGNOR	form complex	binding			9606	BTO:0000567								15383534	t		lperfetto	Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins.	SIGNOR-263320	0.883
MMP10	protein	P09238	UNIPROT	HAPLN1	protein	P10915	UNIPROT	down-regulates quantity by destabilization	cleavage	Leu40	QAENGPHlLVEAEQA	-1									7694569	t		miannu	Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.	SIGNOR-256332	0.329
ATR	protein	Q13535	UNIPROT	USP28	protein	Q96RU2	UNIPROT	up-regulates activity	phosphorylation	Ser714	ESSTNSSsQDYSTSQ										31938050	t		lperfetto	Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity.|Representative immunoblots of n = 3. C Immunoblotting of total and phosphorylated USP28 at serine 67 and 714 in A431 cells exposed to indicated concentrations of CPPD for 6 h.	SIGNOR-275851	0.2
TYSND1	protein	Q2T9J0	UNIPROT	TYSND1	protein	Q2T9J0	UNIPROT	down-regulates activity	cleavage			9606	BTO:0000567								22002062	t		miannu	Self-cleavage of Tysnd1 in the active oligomer most likely inactivates its protease activity. Subsequently, the cleaved products are degraded by PsLon and removed from the Tysnd1 oligomer. 	SIGNOR-261053	0.2
ACTL6A	protein	O96019	UNIPROT	GBAF	complex	SIGNOR-C467	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269789	0.593
SEMA3A	protein	Q14563	UNIPROT	NRP1	protein	O14786	UNIPROT	up-regulates activity	binding			9606									25335892	t		miannu	Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction.	SIGNOR-261815	0.911
FYN	protein	P06241	UNIPROT	CNN1	protein	P51911	UNIPROT	down-regulates activity	phosphorylation	Tyr182	SQQGMTAyGTRRHLY	9534									15206927	t			We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin	SIGNOR-251157	0.338
RPL22	protein	P35268	UNIPROT	RPL22L1	protein	Q6P5R6	UNIPROT	down-regulates				9606									23990801	f		miannu	We find that rpl22 directly represses expression of rpl22l1 mrna by binding to an internal hairpin structure.	SIGNOR-202600	0.386
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser268	VALPPGAsPQRSRSP	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248374	0.598
MAPK14	protein	Q16539	UNIPROT	RPS6KA4	protein	O75676	UNIPROT	up-regulates	phosphorylation	Ser347	PVYSPPGsPPPGDPR	9606	BTO:0000567								10806207	t		llicata	Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity.	SIGNOR-77212	0.586
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2L5	protein	A0A1B0GUS4	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271331	0.2
PRKCD	protein	Q05655	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Ser323	MVGGKPGsFRVRASS	9606	BTO:0000222	BTO:0000887;BTO:0001103							16611834	t		gcesareni	Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of ser-318 in irs1 by a janus kinase 2, irs2, and pkc-dependent pathway. we observed that insulin stimulates phosphorylation of ser(318) in irs-1, which is mediated, at least partially, by pkc-zeta.	SIGNOR-146105	0.632
PTK2	protein	Q05397	UNIPROT	ACTN4	protein	O43707	UNIPROT	down-regulates	phosphorylation	Tyr31	GGGSMGDyMAQEDDW	9606									23454549	t		lperfetto	Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin	SIGNOR-192195	0.54
EP300	protein	Q09472	UNIPROT	SMAD7	protein	O15105	UNIPROT	up-regulates	acetylation	Lys70	GKAVRGAkGHHHPHP	9606									15831498	t		gcesareni	Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300	SIGNOR-135473	0.476
ARNT	protein	P27540	UNIPROT	CYP1B1	protein	Q16678	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001033								16115918	f		miannu	Expressions of CYP1B1 mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1.	SIGNOR-253740	0.411
STK11	protein	Q15831	UNIPROT	CPS1	protein	P31327	UNIPROT	down-regulates quantity	transcriptional regulation			9606	BTO:0002553								28538732	f		Luana	LKB1 negatively regulates CPS1 transcription	SIGNOR-267919	0.301
RBM8A	protein	Q9Y5S9	UNIPROT	Exon junction complex	complex	SIGNOR-C369	SIGNOR	form complex	binding			-1									16923391	t		miannu	 The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. 	SIGNOR-265242	0.915
LPAR2	protein	Q9HBW0	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257324	0.252
MYT1	protein	Q01538	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0005949								30312684	t		miannu	Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression. Examination of the gene expression changes in cells expressing Myt1 or Myt1l suggests that both repress expression of the YAP1 transcriptional coactivator, which functions primarily in the Hippo signaling pathway. Expression of YAP1 and its target genes is reduced in Myt-expressing cells, and there is an inverse correlation between YAP1 and MYT1/MYT1L expression in human brain cancer datasets. Together, our data suggest that Myt1 and Myt1l directly repress expression of YAP1, a protein which promotes proliferation and GBM growth.	SIGNOR-266777	0.2
FYN	protein	P06241	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	up-regulates	phosphorylation	Tyr529	TITKTVEyLHAQGVV	9606									18156174	t		llicata	Epidermal growth factor stimulates rsk2 activation through activation of the mek/erk pathway and src-dependent tyrosine phosphorylation of rsk2 at tyr-529. By mass spectroscopy-based studies, we identified src tyrosine kinase family members src and fyn as upstream kinases of rsk2 tyr-529.	SIGNOR-160048	0.332
C5AR2	protein	Q9P296	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates													1847994	f		lperfetto	The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 	SIGNOR-263461	0.7
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2L6	protein	O14933	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271319	0.633
XBP1	protein	P17861-2	UNIPROT	Chaperone-mediated protein folding	phenotype	SIGNOR-PH120	SIGNOR	up-regulates				9606									15598891	f		miannu	ATF6 and XBP1 are transcription factors activated specifically in response to endoplasmic reticulum (ER) stress. Three cis-acting elements capable of binding to ATF6, XBP1 or both have been identified to date, namely ER stress-response element (ERSE), unfolded protein response element (UPRE) and ERSE-II. ERSE controls the expression of ER-localized molecular chaperones such as BiP that can refold unfolded proteins in the ER; transcription from ERSE is fully activated by ATF6 even in the absence of XBP1. In contrast, transcription from UPRE depends solely on XBP1 and it has been suggested that UPRE may control the expression of components of the ER-associated degradation system that can degrade unfolded proteins in the ER. 	SIGNOR-260185	0.7
PPP2R5C	protein	Q13362	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates	binding			9606									16456541	t	inferred from 70% of family members	gcesareni	B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk	SIGNOR-269922	0.498
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1738	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120208	0.321
Pyridostigmine	chemical	CHEBI:8665	ChEBI	ACHE	protein	P22303	UNIPROT	down-regulates activity	chemical inhibition			-1									20627738	t		Luana	The compounds 3-[(dimethylamino)carboxyl]oxy]-N,N,N-trimethylammonium methyl sulfate, better known as neostigmine methyl sulfate (3),1 and 3-[(dimethylcarbamoyl)oxy]-1-methylpyridinium bromide, pyridostigmine bromide (4)2 (Figure 1) are well known peripheral cholinesterase inhibitors 	SIGNOR-257879	0.8
PDK1	protein	Q15118	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	phosphorylation	Ser300	SMSDPGVsYRTREEI	-1									11485553	t		lperfetto	Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.	SIGNOR-109555	0.785
NR2F2	protein	P24468	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates	binding			9606									9826778	t		gcesareni	The orphan nuclear receptor, coup-tf ii, inactivates myogenesis by post-transcriptional regulation of myod function: coup-tf ii directly interacts with p300 and myod.	SIGNOR-62248	0.391
CSNK1A1	protein	P48729	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation	Thr1493	NPPPSPAtERSHYTM	9606									16341017	t		lperfetto	We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.Site ii, like site i, was phosphorylated, as detected by means of a phospho-specific antibody (ab1493, for phosphorylated t1493 in lrp6)	SIGNOR-143034	0.534
PRKG1	protein	Q13976	UNIPROT	TRPC3	protein	Q13507	UNIPROT	down-regulates	phosphorylation			9606									16331690	t	The effect has been demonstrated using Q13507-3	llicata	The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263.	SIGNOR-142964	0.417
SEC23B	protein	Q15437	UNIPROT	UBA52	protein	P62987	UNIPROT	unknown	binding												30605680	t		lperfetto	We validate the genotype-specific differential SEC23B–UBA52 (ribosomal protein RPL40) interaction.	SIGNOR-265305	0.2
PRKD1	protein	Q15139	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates	phosphorylation	Ser358	WPLSRTRsEPLPPSA	9606	BTO:0000782								15623513	t		lperfetto	Protein kinase d1 (pkd1) was activated after tcr engagement, interacted with hdac7, and phosphorylated three serines (ser155, ser318, and ser448) at its n terminus, leading to its export from the nucleus.	SIGNOR-132898	0.492
SNW1	protein	Q13573	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	binding			-1									10713164	t		llicata	SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.	SIGNOR-237617	0.584
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	RAD9A	protein	Q99638	UNIPROT	unknown	phosphorylation	Ser328	VLPSISLsPGPQPPK	9606									23028682	t		lperfetto	The forced activation of cyclin a-cdk2 in these cells by the overexpression of cyclin a,triggered rad9 phosphorylation at serine 328 and thereby promoted the interaction of rad9 with bcl-xl and the subsequent initiation of the apoptotic program.	SIGNOR-217268	0.411
MRPS9	protein	P82933	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261438	0.769
CSNK2A1	protein	P68400	UNIPROT	DEK	protein	P35659	UNIPROT	up-regulates	phosphorylation	Ser32	MPGPREEsEEEEDED	9606									15199154	t		amattioni	Dek is phosphorylated by the protein kinase ck2 in vitro and in vivo on ser32	SIGNOR-125912	0.356
KDM4C	protein	Q9H3R0	UNIPROT	Histone H2A	proteinfamily	SIGNOR-PF70	SIGNOR	down-regulates activity	demethylation			9606									29207681	t		miannu	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation	SIGNOR-265315	0.2
DARS1	protein	P14868	UNIPROT	Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	form complex	binding			9606									32644155	t		miannu	In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes).	SIGNOR-270362	0.2
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	SF3B1	protein	O75533	UNIPROT	up-regulates	phosphorylation	Thr244	GRAKGSEtPGATPGS	9606									12105215	t		lperfetto	To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313	SIGNOR-216686	0.354
MAPK14	protein	Q16539	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser389	LSPIAPRsPAKLSFQ	9606									9130707	t		gcesareni	We demonstrate here that elk-1 is barely activated by a third subclass of map kinases (p38), most likely because the critical residues ser383 and ser389 are poorly phosphorylated by p38 map kinase.	SIGNOR-47634	0.505
LSM6	protein	P62312	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270634	0.795
CIT	protein	O14578	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates activity	phosphorylation	Ser20	KRPQRATsNVFAMFD	-1									21457715	t		Giulio	Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation.	SIGNOR-260305	0.542
PTPN12	protein	Q05209	UNIPROT	GIT2	protein	Q14161	UNIPROT	down-regulates	dephosphorylation	Tyr286	EELAMDVyDEVDRRE	9606									16317044	t		fspada	Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest.	SIGNOR-142711	0.352
CDK4	protein	P11802	UNIPROT	SMAD3	protein	P84022	UNIPROT	unknown	phosphorylation	Ser204	NHSMDAGsPNLSPNP	-1									15241418	t		llicata	Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo.	SIGNOR-250766	0.748
ATG16L1	protein	Q676U5	UNIPROT	CLTCL1	protein	P53675	UNIPROT	up-regulates	binding			9606									20639872	t		gcesareni	Clathrin heavy-chain interacts with atg16l1, and is involved in the formation of atg16l1-positive early autophagosome precursors	SIGNOR-166705	0.31
SMAD6	protein	O43541	UNIPROT	SMAD1/4	complex	SIGNOR-C85	SIGNOR	down-regulates	binding			9606									12857866	t		lperfetto	Smad6 also inhibits bmp signaling by forming a complex with smad1 and by interfering with complex formation between smad1 and smad4	SIGNOR-217706	0.558
PTPA	protein	Q15257	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606									21159657	t		gcesareni	Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473)	SIGNOR-170699	0.2
risperidone	chemical	CHEBI:8871	ChEBI	HTR1B	protein	P28222	UNIPROT	down-regulates activity	chemical inhibition			10116		BTO:0001311							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258526	0.8
COLGALT2	protein	Q8IYK4	UNIPROT	COL1A1	protein	P02452	UNIPROT	up-regulates activity	glycosylation			-1									19075007	t			Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261156	0.417
RXRA	protein	P19793	UNIPROT	PPARA	protein	Q07869	UNIPROT	up-regulates	binding			9606									11237216	t		gcesareni	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-105345	0.578
ATG13	protein	O75143	UNIPROT	ULK1/Atg13/Fip200	complex	SIGNOR-C100	SIGNOR	form complex	binding			9606									23863160	t		lperfetto	In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation.	SIGNOR-209884	0.916
TACR3	protein	P29371	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257333	0.41
PRKCB	protein	P05771	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser379	DLILNRCsESTKRKL	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89213	0.549
PRKCA	protein	P17252	UNIPROT	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Thr475	TPLSSSNtIRRPRNY	-1									1322130	t		lperfetto	The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. | Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme. 	SIGNOR-248844	0.448
NPFF	protein	O15130	UNIPROT	NPFFR2	protein	Q9Y5X5	UNIPROT	up-regulates	binding			9606									11024015	t		gcesareni	Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems	SIGNOR-82961	0.764
FGF1	protein	P05230	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	binding			9606									11030354	t		lperfetto	Crystal structure of a ternary fgf-fgfr-heparin complex reveals a dual role for heparin in fgfr binding and dimerization.	SIGNOR-83143	0.912
KRAS	protein	P01116	UNIPROT	RASSF1	protein	Q9NS23	UNIPROT	up-regulates activity	binding			9606									22195963	t		lperfetto	Mutant K-Ras promotes MST2 activation in two ways (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex (Matallanas et al., 2008) and by forming an activating (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex K-Ras-RASSF1A€“MST2 complex, as reported here	SIGNOR-249585	0.638
FZR1	protein	Q9UM11	UNIPROT	DNM1L	protein	O00429	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000567								21325626	t		Barakat	Here we demonstrate that changes in mitochondrial dynamics as cells exit mitosis are driven in part through ubiquitylation of Drp1 catalyzed by the APC/Ccdh1 (anaphase-promoting complex/cyclosome and its coactivator (Cdh1) E3 ubiquiting ligase complex	SIGNOR-274127	0.356
P4HB	protein	P07237	UNIPROT	Collagen	proteinfamily	SIGNOR-PF103	SIGNOR	up-regulates quantity by stabilization	binding			9606									9545296	t		miannu	We also show that PDI associates independently with the C-propeptide of monomeric procollagen chains prior to trimer formation, indicating a role for this protein in coordinating the assembly of heterotrimeric molecules. This demonstrates that PDI has multiple functions in the folding of the same protein, that is, as a catalyst for disulfide bond formation, as a subunit of P4-H during proline hydroxylation, and independently as a molecular chaperone during chain assembly.	SIGNOR-269731	0.2
ATR	protein	Q13535	UNIPROT	CCAR2	protein	Q8N163	UNIPROT	up-regulates activity	phosphorylation	Thr454	AAEAAPPtQEAQGET	9606									22735644	t		lperfetto	 Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death. 	SIGNOR-267662	0.414
GAD2	protein	Q05329	UNIPROT	gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	up-regulates quantity	chemical modification			9606									32041144	t		miannu	Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce γ-aminobutyric acid (GABA), which exhibits several well-known physiological functions.	SIGNOR-267555	0.8
GSK3B	protein	P49841	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Thr366	ASSSTSVtPDVSDNE	9606									16107342	t		lperfetto	Gsk3beta Phosphorylates pten at thr-366 in intact cells phosphorylation of pten at thr-366 reduces the activity of pten in cells	SIGNOR-236641	0.435
FIZ1	protein	Q96SL8	UNIPROT	CRX	protein	O43186	UNIPROT	down-regulates activity	binding			9913									12566383	t		miannu	Interaction of Fiz1 and NRL-leucine zipper was validated by GST pulldown assays and co-immunoprecipitation from bovine retinal nuclear extracts. Fiz1 suppressed NRL- but not CRX-mediated transactivation of rhodopsin promoter activity in transiently transfected CV1 cells.	SIGNOR-223799	0.469
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	WWC1	protein	Q8IX03	UNIPROT	unknown	phosphorylation			9606		BTO:0000149							24269383	t	inferred from 70% family members	llicata	We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro.	SIGNOR-270208	0.2
CDC42	protein	P60953	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity				9606									21902831	f		lperfetto	Precisely how this complex results in p38 activation is not known, but complex recruitment of the gtpase cdc42 is required for p38 phosphorylation.	SIGNOR-176501	0.586
NMUR1	protein	Q9HB89	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256751	0.47
TPSAB1	protein	Q15661	UNIPROT	F2RL1	protein	P55085	UNIPROT	up-regulates activity	binding			10116									21999702	t		lperfetto	Mast cells contribute to tissue repair in fibrous tissues by stimulating proliferation of fibroblasts through the release of tryptase which activates protease-activated receptor-2 (PAR-2).|Taken together, our data show that tryptase can stimulate myoblast proliferation and this effect is part of a signaling cascade dependent on PAR-2 activation and on the downstream activation of COX-2.	SIGNOR-251744	0.254
ATF4	protein	P18848	UNIPROT	CARS1	protein	P49589	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269416	0.2
SEMA3A	protein	Q14563	UNIPROT	PLXNA1	protein	Q9UIW2	UNIPROT	up-regulates activity	binding			9606	BTO:0001176;BTO:0002036								25335892	t		miannu	We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin. 	SIGNOR-261813	0.763
SHPK	protein	Q9UHJ6	UNIPROT	sedoheptulose	smallmolecule	CHEBI:16802	ChEBI	down-regulates quantity	chemical modification			9606									22682222	t		miannu	The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose	SIGNOR-267083	0.8
PRKD1	protein	Q15139	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates	phosphorylation	Ser486	RPLSRAQsSPAAPAS	9606									18509061	t		gcesareni	We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf.	SIGNOR-178713	0.492
PTPN11	protein	Q06124	UNIPROT	CDC73	protein	Q6P1J9	UNIPROT	up-regulates activity	dephosphorylation			9606									21726809	t		miannu	We found in this work that SHP2 dephosphorylates parafibromin and Cdc73, a component of the nuclear RNA polymerase II associated factor (PAF) complex, which can function as a tumor suppressor or oncoprotein in a context dependent manner.	SIGNOR-277036	0.508
belinostat	chemical	CHEBI:61076	ChEBI	HDAC4	protein	P56524	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257957	0.8
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	KIF4A	protein	O95239	UNIPROT	up-regulates activity	phosphorylation	Thr1161	FFNPVCAtPNSKILK	-1									29771379	t		miannu	Kif4A T1161 was phosphorylated by Cdk1/Cyclin B1 in vitro. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization. 	SIGNOR-265995	0.463
ITGB1	protein	P05556	UNIPROT	A10/b1 integrin	complex	SIGNOR-C167	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253186	0.678
F2RL3	protein	Q96RI0	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			9606									22318735	t		gcesareni	Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13)	SIGNOR-196015	0.382
POU2F1	protein	P14859	UNIPROT	IL4	protein	P05112	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000782								11781715	f			Here we show that NFAT proteins are unable to bind to a combined octamer/NFAT site unless the octamer proteins are competed away	SIGNOR-254505	0.2
SRC	protein	P12931	UNIPROT	CEACAM1	protein	P13688	UNIPROT	up-regulates activity	phosphorylation	Tyr520	LTATEIIySEVKKQ	9606	BTO:0000007								9867848	t		lperfetto	Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515	SIGNOR-246475	0.436
MAPK3	protein	P27361	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates	phosphorylation			9606									21757713	t		lperfetto	The phosphorylation of Raptor on these sites enhances mTORC1 activity, and contributes largely to arsenite-induced mTORC1 activation.	SIGNOR-217544	0.393
SOX17	protein	Q9H6I2	UNIPROT	GLI2	protein	P10070	UNIPROT	up-regulates				10090									33083751	f		SimoneGraziosi	Sox17 ablation lowered endogenous Gli2 and Olig2+ cells	SIGNOR-269218	0.302
CDK8	protein	P49336	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									19914161	t		lpetrilli	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161557	0.547
IL1A	protein	P01583	UNIPROT	IL1R1	protein	P14778	UNIPROT	up-regulates activity	binding			9606	BTO:0001573								9565970	t		lperfetto	Il-1ri is responsible for il-1 signaling	SIGNOR-56718	0.759
4-[2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]aniline	chemical	CHEBI:92250	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258852	0.8
bosutinib	chemical	CHEBI:39112	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258088	0.8
NANOG	protein	Q9H9S0	UNIPROT	LAMB1	protein	P07942	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086;BTO:0005511								15983365	f		miannu	 Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 	SIGNOR-254628	0.269
MAPK3	protein	P27361	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates activity	phosphorylation	Ser8	MESEMLQsPLLGLGE	9606	BTO:0000007			SIGNOR-C3					21071439	t		lperfetto	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-169530	0.482
HES1	protein	Q14469	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000165	BTO:0000887							10066785	f		lperfetto	Notch signaling up-regulated hes1 mrna expression within 1 h and subsequently reduced expression of myod mrna.	SIGNOR-235596	0.299
Phagocytosis	phenotype	SIGNOR-PH97	SIGNOR	TNF	protein	P01375	UNIPROT	down-regulates quantity					BTO:0000801								22933625	f		apalma	Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype	SIGNOR-255446	0.7
PRKCB	protein	P05771	UNIPROT	DAB2	protein	P98082	UNIPROT	unknown	phosphorylation	Ser24	QAAPKAPsKKEKKKG	9534	BTO:0004055								10542228	t		lperfetto	We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function.	SIGNOR-249026	0.301
DGC	complex	SIGNOR-C217	SIGNOR	GABA-A	proteinfamily	SIGNOR-PF61	SIGNOR	up-regulates quantity	binding			9606	BTO:0000938;BTO:0002606								22626543	t		miannu	 In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses.	SIGNOR-265442	0.2
DDB2	protein	Q92466	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates	binding			9606	BTO:0000567								9418871	t		miannu	We show that ddb, a putative dna repair protein, associates with the activation domain of e2f1 / expression of ddb specifically stimulated e2f1-activated transcription	SIGNOR-54102	0.375
NF2	protein	P35240	UNIPROT	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	up-regulates activity	binding			9606									33058421	t		miannu	The Hippo pathway tumor suppressor Merlin/NF2 is known to be regulated by phosphorylation. Here, the E3 ubiquitin ligase NEDD4L is shown to promote Hippo pathway activation via ubiquitination of Merlin.	SIGNOR-263663	0.761
NANOG	protein	Q9H9S0	UNIPROT	CDX2	protein	Q99626	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086;BTO:0005511								15983365	f		miannu	 Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 	SIGNOR-254622	0.34
HTR7	protein	P34969	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257430	0.252
SAAL1	protein	Q96ER3	UNIPROT	CDK6	protein	Q00534	UNIPROT	up-regulates quantity by expression	post transcriptional regulation			9606									30513680	f		Giorgia	This study was performed to elucidate the molecular function of the synoviocyte proliferation-associated in collagen-induced arthritis (CIA) 1/serum amyloid A-like 1 (SPACIA1/SAAL1) in mice CIA, an animal model of rheumatoid arthritis (RA), and human RA-synovial fibroblasts (RASFs). Expression levels of cdk6, but not cdk4, which are D-type cyclin partners, were downregulated by SPACIA1/SAAL1 siRNA at the post-transcriptional level. The CDK6, expression of which is up-regulated by the SPACIA1/SAAL1 expression, might be a critical factor in the exacerbation of CIA.	SIGNOR-260386	0.2
CDK4	protein	P11802	UNIPROT	RBL1	protein	P28749	UNIPROT	up-regulates activity	phosphorylation	Ser964	MMDAPPLsPFPHIKQ	9606									12006580	t		llicata	Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression. 	SIGNOR-250764	0.8
STAT1	protein	P42224	UNIPROT	STAT1/STAT3	complex	SIGNOR-C118	SIGNOR	form complex	binding			10090	BTO:0000667								15284024	t		lperfetto	Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min.	SIGNOR-235661	0.596
RUNX2	protein	Q13950	UNIPROT	SP7	protein	Q8TDD2	UNIPROT	up-regulates	transcriptional regulation			10090									16574347	f		Giulio Giuliani	Osx promoter activity was up-regulated by 2 fold after Runx2 over-expression in ATDC5 cells. Osx Is Phosphorylated by p38 at Ser-73 and Ser-77	SIGNOR-255410	0.526
GDF11	protein	O95390	UNIPROT	ACVR2B	protein	Q13705	UNIPROT	up-regulates	binding			9606		BTO:0000671							16845371	t		acerquone	The identity of the receptors that mediate gdf11 signalling during embryogenesis remains unclear. gdf11 could only bind directly to acvr2b but not to any type i receptor	SIGNOR-147940	0.646
PRKACA	protein	P17612	UNIPROT	NOLC1	protein	Q14978	UNIPROT	up-regulates activity	phosphorylation	Ser622	KKGEKRAsSPFRRVR	-1									12167624	t		miannu	PKA-dependent Nopp140 phosphorylation is important for its role in agp gene activation. both Ser627 and Ser628 are phosphorylated by PKA.	SIGNOR-250019	0.311
SIRT3	protein	Q9NTG7	UNIPROT	SOD2	protein	P04179	UNIPROT	up-regulates activity	deacetylation												34929314	t		lperfetto	SOD2 is the key substrate of SIRT3 in mitochondria. The combination of SIRT3 and SOD2 leads to the deacetylation and activation of SOD2	SIGNOR-267646	0.642
CDK1	protein	P06493	UNIPROT	ECT2	protein	Q9H8V3	UNIPROT	up-regulates	phosphorylation	Thr444	TKSSKSStPVPSKQS	9606									16247472	t		lperfetto	Here we show that two mitotic kinases, cdk1 and polo-like kinase 1 (plk1), phosphorylate ect2 in vitro.Moreover, ect2 t412a, but not phosphomimic t412d, displayed a diminished accumulation of gtp-bound rhoa compared with wt ect2, suggesting that phosphorylation of thr-412 is critical for the catalytic activity of ect2.	SIGNOR-141175	0.594
ABCG1	protein	P45844	UNIPROT	HDL_assembly	phenotype	SIGNOR-PH61	SIGNOR	up-regulates				9606									16054053	f		miannu	ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. cholesterol efflux to HDL specifically requires ABCG1, whereas efflux to apoA1 requires ABCA1. These studies identify Abcg1 as a key gene involved in both cholesterol efflux to HDL and in tissue lipid homeostasis.	SIGNOR-252111	0.7
TAL1	protein	P17542	UNIPROT	Erythrocyte_differentiation 	phenotype	SIGNOR-PH104	SIGNOR	up-regulates activity				10090	BTO:0004911								23319051	f			Analysis of SclΔ40/Δ40 embryonic stem (ES) cells revealed impaired erythroid differentiation, which was accompanied by a failure to upregulate Scl when erythropoiesis was initiated. 	SIGNOR-259971	0.7
PTPN6	protein	P29350	UNIPROT	NFAT5	protein	O94916	UNIPROT	down-regulates activity	dephosphorylation	Tyr143	PKRHTVLyISPPPED	9606	BTO:0000007								20351292	t			We confirmed that SHP-1 is inhibitory by overexpressing it, which reduces TonEBP/OREBP transcriptional activity at 500 mosmol/kg. SHP-1 dephosphorylates TonEBP/OREBP at a known regulatory site, Y143, both in vivo and in vitro. It inhibits TonEBP/OREBP by both reducing TonEBP/OREBP nuclear localization, which is Y143 dependent, and by lowering high NaCl-induced TonEBP/OREBP transactivating activity	SIGNOR-248467	0.349
EAPP	protein	Q56P03	UNIPROT	MAOB	protein	P27338	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20980443	f		miannu	 we identified two novel transcriptional repressors of MAO B, E2F-associated phosphoprotein (EAPP) and R1 (RAM2/CDCA7L/JPO2), that down-regulate MAO B via MAO B core promoter, which contains Sp1 sites.	SIGNOR-253867	0.2
CDC14A	protein	Q9UNH5	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates	dephosphorylation	Thr698	KSIQATLtPSAMKSS	9606									20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis.	SIGNOR-164416	0.627
ACAN	protein	P16112	UNIPROT	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	up-regulates activity	binding			9606	BTO:0003858								16051604	t		lperfetto	Cartilage Oligomeric Matrix Protein/Thrombospondin 5 Supports Chondrocyte Attachment through Interaction with Integrins|We show that COMP/TSP5 can support chondrocyte attachment and that the RGD sequence in COMP/TSP5 and the integrin receptors alpha5beta1 and alphaVbeta3 on the chondrocytes are involved in mediating this attachment. The interactions of COMP/TSP5 with the integrins are dependent on COMP/TSP5 conformation.	SIGNOR-266988	0.326
CSNK2A1	protein	P68400	UNIPROT	CBX1	protein	P83916	UNIPROT	down-regulates	phosphorylation	Thr51	GFSDEDNtWEPEENL	9606									19657222	t		lperfetto	Two recent papers suggest that hp1 recruitment to damage sites, rather than its rapid mobilization, is the predominant behaviour exhibited by this protein. Our findings reconcile recent findings in a new model, wherein rapid hp1beta mobilization from dsbs is mediated by its phosphorylation on thr51 by ck2	SIGNOR-187450	0.308
TAB1	protein	Q15750	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	binding			9606									11847341	t		lperfetto	Here, we report an unexpected activation mechanism for p38alpha MAPK that does not involve the prototypic kinase cascade. Rather it depends on interaction of p38alpha with TAB1 [transforming growth factor-beta-activated protein kinase 1 (TAK1)-binding protein 1] leading to autophosphorylation and activation of p38alpha.	SIGNOR-114843	0.817
GRIK1	protein	P39086	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264342	0.7
CDK5RAP2	protein	Q96SN8	UNIPROT	WDR62	protein	O43379	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								26297806	t		lperfetto	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.	SIGNOR-271723	0.563
CDK5	protein	Q00535	UNIPROT	PIK3C3	protein	Q8NEB9	UNIPROT	down-regulates activity	phosphorylation	Thr668	ENLDLKLtPYKVLAT	9606	BTO:0000007								20513426	t		miannu	Phosphorylation of Vps34 on Thr159 inhibits its interaction with Beclin 1. two additional amino acids in Vps34, Thr159 and Thr668, were found to be phosphorylated only after co-transfection with Cdk5/p25 	SIGNOR-259811	0.365
FOXL2	protein	P58012	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606		BTO:0000975							16153597	f		miannu	We observed that foxl2 induces apoptosis in the ovarian cells unveiling a novel function of foxl2	SIGNOR-140391	0.7
ethanol	chemical	CHEBI:16236	ChEBI	GlyR	proteinfamily	SIGNOR-PF62	SIGNOR	up-regulates activity	chemical activation			8355	BTO:0000964								8700149	t	inferred from family member	miannu	Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations.	SIGNOR-270260	0.8
Membrane attack complex	complex	SIGNOR-C313	SIGNOR	Membrane_disruption	phenotype	SIGNOR-PH151	SIGNOR	up-regulates				-1									30552328	f		lperfetto	CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers	SIGNOR-263456	0.7
NUP98-HOXA9	fusion protein	SIGNOR-FP15	SIGNOR	CEBPA	protein	P49715	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17442773	f		miannu	Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The transcription factor CCAAT enhancer binding protein‐α (C/EBPα), a tumor suppressor gene and a crucial regulator of granulopoiesis through inhibition of c‐JUN, was downmodulated by NUP98‐HOXA9 	SIGNOR-261501	0.2
pregnenolone	smallmolecule	CHEBI:16581	ChEBI	17alpha-hydroxypregnenolone	smallmolecule	CHEBI:28750	ChEBI	up-regulates quantity	precursor of			9606		BTO:0001363;BTO:0000048;BTO:0000050							17192295	t		lperfetto	THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones.	SIGNOR-268648	0.8
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation			10029									17510057	t		lperfetto	In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size.	SIGNOR-235748	0.753
SF3B5	protein	Q9BWJ5	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270673	0.76
CDC25A	protein	P30304	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	dephosphorylation			9606									7744247	t		gcesareni	Cdc25a can act on substrates other than cdks, since it dephosphorylates the homeodomain transcription factor cut and interacts with and dephosphorylates the proto-oncogene raf-1, resulting in a significant decrease in raf-1 kinase activity	SIGNOR-32548	0.403
PRKDC	protein	P78527	UNIPROT	RPA2	protein	P15927	UNIPROT	down-regulates activity	phosphorylation	Ser12	GFESYGSsSYGGAGG	-1									9295339	t		lperfetto	We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13	SIGNOR-248981	0.598
NFIB	protein	O00712	UNIPROT	SLIT1	protein	O75093	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268899	0.252
NPC	complex	SIGNOR-C263	SIGNOR	mRNA-nucleus_export	phenotype	SIGNOR-PH127	SIGNOR	up-regulates				9606									28831067	f		lperfetto	The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export.	SIGNOR-263295	0.7
MAPK3	protein	P27361	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser106	PLNSVSPsPLMLLHP	9606									18372406	t		gcesareni	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity	SIGNOR-178145	0.692
EVI5	protein	O60447	UNIPROT	PLK1	protein	P53350	UNIPROT	down-regulates				9606									16439210	f		gcesareni	Evi5 antagonizes scf(betatrcp)-dependent emi1 ubiquitination and destruction by binding to a site adjacent to emi1's dsgxxs degron and blocking both degron phosphorylation by polo-like kinases and subsequent betatrcp binding.	SIGNOR-143683	0.603
SRC	protein	P12931	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates	phosphorylation	Tyr564	SKHKEDVyENLHTKN	9606									14699166	t		llicata	Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells.	SIGNOR-120492	0.543
CDK11B	protein	P21127	UNIPROT	EIF3F	protein	O00303	UNIPROT	up-regulates activity	phosphorylation	Ser46	PAAAPASsSDPAAAA										19245811	t		lperfetto	EIF3f is phosphorylated by CDK11p46 at Ser46 during apoptosis.|Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis. 	SIGNOR-273133	0.531
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR7	protein	P34969	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264289	0.8
EIF2AK4	protein	Q9P2K8	UNIPROT	EIF2S1	protein	P05198	UNIPROT	down-regulates activity	phosphorylation	Ser52	MILLSELsRRRIRSI	9606									32513922	t		gcesareni	Translation initiation factor 2α [eukaryotic translation initiation factor 2α (eIF2α)] kinase phosphorylates serine51 (Ser51) of eIF2α and downregulates cellular protein synthesis.	SIGNOR-246157	0.912
XPA	protein	P23025	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates activity				9606									30327428	f			A coordinated repair process mediated by the xeroderma pigmentosum complementation group proteins (XPs), which include XPA through XPG. XPA is indispensable in this pathway and has reported functions in DNA damage verification, stabilization of repair intermediates and positioning of NER factors	SIGNOR-258984	0.7
MAPK1	protein	P28482	UNIPROT	KRT8	protein	P05787	UNIPROT	unknown	phosphorylation	Ser432	SAYGGLTsPGLSYSL										16554440	t		lperfetto	Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002).	SIGNOR-249411	0.389
ZM447439	chemical	CHEBI:91376	ChEBI	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207923	0.8
PRKCD	protein	Q05655	UNIPROT	FLI1	protein	Q01543	UNIPROT	down-regulates	phosphorylation	Thr312	TNGEFKMtDPDEVAR	9606									24058639	t		miannu	After tgf-_ stimulation, fli1 phosphorylation by protein kinase c-_ induces disassembly of this transcription repressor complex and the acetylation of fli1 by pcaf, leading to the loss of fli1 dna binding. / phosphorylation of fli1 at threonine 312 decreases its interactions with p300 and hdac1	SIGNOR-202693	0.353
PLK1	protein	P53350	UNIPROT	BIRC5	protein	O15392	UNIPROT	up-regulates	phosphorylation	Ser20	FLKDHRIsTFKNWPF	9606									21148584	t		lperfetto	Thus, we conclude that plk1-mediated phosphorylation of sur at ser20 is critical for accurate chromosome segregation|SUR (survivin)	SIGNOR-170460	0.566
MAPK1	protein	P28482	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Thr359	DTEFTSRtPKDSPGI	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-219324	0.748
pirenzepine	chemical	CHEBI:8247	ChEBI	CHRM2	protein	P08172	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								2704370	t		miannu	In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 	SIGNOR-258396	0.8
EMSY	protein	Q7Z589	UNIPROT	BRCA2	protein	P51587	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								14651845	t		miannu	The EMSY protein interacts precisely with a highly conserved transactivating region at the N terminus of the breast cancer protein BRCA2, and has endogenous transcriptional repressor activity when recruited to a high basal promoter. We have suggested that the independent activation domain of BRCA2 within exon 3 might have some role in transcription (Milner et al., 1997). The identification of the repressor protein EMSY, which binds and silences this domain, is consistent with such a function. 	SIGNOR-263915	0.2
PRTN3	protein	P24158	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Thr74	SVLTGKLtTVFLPIV	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263596	0.381
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1696	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120016	0.781
FN1	protein	P02751	UNIPROT	FN1/SDC4	complex	SIGNOR-C210	SIGNOR	form complex	binding												23290138	t		apalma	We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells	SIGNOR-255285	0.7
AUTS2	protein	Q8WXX7	UNIPROT	DOCK1	protein	Q14185	UNIPROT	up-regulates activity	binding			10090	BTO:0001909								25533347	t		miannu	Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development.  AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells.	SIGNOR-266820	0.2
BLOC-1	complex	SIGNOR-C381	SIGNOR	Platelet_dense_granule_formation	phenotype	SIGNOR-PH181	SIGNOR	up-regulates				9606	BTO:0000132								12019270	f		lperfetto	BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton.	SIGNOR-265940	0.7
Set1-Ash2 HMT complex	complex	SIGNOR-C352	SIGNOR	MLL/SET subcomplex	complex	SIGNOR-C87	SIGNOR	form complex	binding			9606									24680668	t		miannu	Dimethylation of h3k4 requires a sub-complexincluding wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation.	SIGNOR-204744	0.835
Factor FVIIa:TF	complex	SIGNOR-C319	SIGNOR	F8	protein	P00451	UNIPROT	down-regulates activity	cleavage	Arg759	KNNAIEPrSFSQNSR	-1									10350471	t		lperfetto	N-Terminal sequencing along with time courses of proteolysis indicated that VIIa-TF/PL cleaved factor VIII first at R740, followed by concomitant cleavage at R336 and R372. |hus, heavy chain cleavage of factor VIII by VIIa-TF/PL produces an inactive factor VIII cofactor no longer capable of activation by thrombin.	SIGNOR-263644	0.468
SPC25	protein	Q9HBM1	UNIPROT	Ndc80 complex	complex	SIGNOR-C361	SIGNOR	form complex	binding												27881301	t		lperfetto	Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits	SIGNOR-265186	0.973
RPL28	protein	P46779	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262472	0.818
PRKD2	protein	Q9BZL6	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	up-regulates activity	phosphorylation	Ser498	RPLSRTQsSPLPQSP										18692497	t		lperfetto	Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].	SIGNOR-275929	0.299
CBLB	protein	Q13191	UNIPROT	FLT3	protein	P36888	UNIPROT	down-regulates activity	ubiquitination			10090	BTO:0001516								19276253	t		miannu	Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo.	SIGNOR-260106	0.331
phenytoin	chemical	CHEBI:8107	ChEBI	SCN2A	protein	Q99250	UNIPROT	down-regulates activity	chemical inhibition			10116									1658608	t		miannu	This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. 	SIGNOR-258352	0.8
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270399	0.8
erlotinib hydrochloride	chemical	CHEBI:53509	ChEBI	JAK2	protein	O60674	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001271								17178722	t	JAK2(V617F), a mutant of tyrosine kinase JAK2. Erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor.	gcesareni	This study shows that the anti-cancer drug erlotinib (tarceva) is a potent inhibitor of jak2(v617f) activity	SIGNOR-151274	0.8
TBXA2R	protein	P21731	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257139	0.554
AKT1	protein	P31749	UNIPROT	EZH2	protein	Q15910	UNIPROT	down-regulates activity	phosphorylation	Ser21	CWRKRVKsEYMRLRQ	9606									16224021	t		lperfetto	Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3	SIGNOR-141043	0.614
MAP3K14	protein	Q99558	UNIPROT	CHUK	protein	O15111	UNIPROT	up-regulates activity	phosphorylation	Ser176	AKDVDQGsLCTSFVG	9606				SIGNOR-C14					9520446	t		lperfetto	Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176. Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa.	SIGNOR-55942	0.684
KDM6A	protein	O15550	UNIPROT	HOXC13	protein	P31276	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24561908	t		miannu	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260027	0.27
CAPN1	protein	P07384	UNIPROT	CDK5R1	protein	Q15078	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000590								25969760	t		lperfetto	Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain	SIGNOR-251583	0.552
STAT6	protein	P42226	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20508200	f		lperfetto	Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation.	SIGNOR-249538	0.259
MAP2K7	protein	O14733	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates	phosphorylation	Tyr185	TNFMMTPyVVTRYYR	9606									11062067	t		lperfetto	In the present study, we found that mkk7 phosphorylates sapk2a/p38 exclusively at tyr-182, albeit at a low rate. Therefore one possibility is that the interaction of mkk7 and/or sapk1/jnk with another cellular protein alters the conformation of one of these enzymes in such a way as to facilitate phosphorylation of tyr-185 by mkk7 in vivo.	SIGNOR-83748	0.622
NFE2L2	protein	Q16236	UNIPROT	TBXAS1	protein	P24557	UNIPROT	up-regulates quantity by expression	transcriptional regulation												14565864	f		lperfetto	Ecotopic expression of NF-E2 related factors showed that Nrf2, but not Nrf1, Nrf3, or Bach1, activated TXAS promoter in a dose-dependent manner.	SIGNOR-268993	0.248
masitinib	chemical	CHEBI:63450	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258244	0.8
MAPK14	protein	Q16539	UNIPROT	NFATC1	protein	O95644	UNIPROT	down-regulates	phosphorylation	Ser172	YRDPSCLsPASSLSS	9606									10652349	t	Translocation from Nucleus to Cytoplasm	esanto	We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats.	SIGNOR-74560	0.606
MAPK8	protein	P45983	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation			9606									9724739	t		amattioni	Activated jnk phosphorylates p53	SIGNOR-59812	0.79
GNAI3	protein	P08754	UNIPROT	ADCY1	protein	Q08828	UNIPROT	down-regulates	binding			9606									8327893	t		gcesareni	Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required	SIGNOR-38032	0.578
HTR3A	protein	P46098	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606		BTO:0000142							18761359	f		miannu	The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release. 	SIGNOR-264316	0.7
CDC14A	protein	Q9UNH5	UNIPROT	SIRT2	protein	Q8IXJ6	UNIPROT	unknown	dephosphorylation	Ser368	PNPSTSAsPKKSPPP	9606									17488717	t			Here, we demonstrate that SIRT2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1, and dephosphorylated by the phosphatases CDC14A and CDC14B. Overexpression of SIRT2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation|Additionally, we found that SIRT2, like other Cdk1 targets, can be dephosphorylated by the phosphatases CDC14A and CDC14B. In contrast to a published report (8), we did not observe any degradation of SIRT2 by the 26 S proteasome in response to CDC14B overexpression|However, we cannot exclude the possibility that phosphorylation of serine 368 might affect the activity of SIRT2 on other unidentified acetylated substrates. 	SIGNOR-248834	0.433
PTGER4	protein	P35408	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256903	0.252
Unfolded_Proteins	stimulus	SIGNOR-ST22	SIGNOR	ERN1	protein	O75460	UNIPROT	up-regulates				9606									31226023	f		miannu	Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain	SIGNOR-260175	0.7
DOK1	protein	Q99704	UNIPROT	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257674	0.32
SP1	protein	P08047	UNIPROT	CBS	protein	P35520	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12427542	f	 	miannu	We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter. 	SIGNOR-254812	0.2
ATG4B	protein	Q9Y4P1	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	down-regulates activity				9606	BTO:0000586								29165041	f		lperfetto	 In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells.| In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity.	SIGNOR-275837	0.2
PPP2CA	protein	P67775	UNIPROT	PP2CA_R1A_R2A 	complex	SIGNOR-C132	SIGNOR	form complex	binding			9606									23454242	t		gcesareni	[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity.	SIGNOR-243424	0.933
PRKG2	protein	Q13237	UNIPROT	HCN2	protein	Q9UL51	UNIPROT	down-regulates activity	phosphorylation	Ser668	DRIGKKNsILLHKVQ	10090	BTO:0000142								21347269	t		miannu	Here, we show for the first time that in the HCN2 channel cGMP can also exert an inhibitory effect on gating via cGMP-dependent protein kinase II (cGKII)-mediated phosphorylation.We identify the proximal C-terminus of HCN2 as binding region of cGKII and show that cGKII phosphorylates HCN2 at a specific serine residue (S641) in the C-terminal end of the CNBD. The cGKII shifts the voltage-dependence of HCN2 activation to 2-5 mV more negative voltages and, hence, counteracts the stimulatory effect of cGMP on gating. 	SIGNOR-263185	0.2
CSNK2A1	protein	P68400	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	down-regulates activity	phosphorylation	Thr884	SKTSSSDtLSEEKNS	9606	BTO:0000567								31167143	t		miannu	Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations. 	SIGNOR-276732	0.2
CAMK4	protein	Q16566	UNIPROT	HDAC4	protein	P56524	UNIPROT	down-regulates activity	phosphorylation	Ser632	RPLSRAQsSPASATF										11470791	t		llicata	CaMKIV phosphorylates HDAC4 in vitro and promotes its nuclear-cytoplasmic shuttling in vivo. | Thus, CaMKIV can phosphorylate HDAC4 at Ser-467 and/or Ser-632 in vitro. | Collectively, our results suggest that CaMKIV reverses the transcriptional repression activity of HDAC4 by stimulating the mobilization of HDAC4 out of the nucleus.	SIGNOR-250712	0.603
REST	protein	Q13127	UNIPROT	CARTPT	protein	Q16568	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								18485095	f		miannu	 When expression of NRSF was down-regulated in HeLa cells using a RNA interfering technique, the transcriptional activity of the CART promoter or a NRSE reporter was significantly increased. Taken together, our data suggested that CART gene expression in neuroendocrine cells is strictly controlled by NRSF, via a mechanism dependent upon the CART NRSE.	SIGNOR-255073	0.2
GLUL	protein	P15104	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	down-regulates quantity	chemical modification			9606									30158707	t		miannu	Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction.	SIGNOR-267824	0.8
PRKAA1	protein	Q13131	UNIPROT	POU2F1	protein	P14859	UNIPROT	down-regulates	phosphorylation	Ser385	RRRKKRTsIETNIRV	9606									9368058	t		lperfetto	Mitosis-specific phosphorylation site in the homeodomain of oct-1 was phosphorylated in vitro by protein kinase a. Pka-mediated phosphorylation event was identified in the cns-specific pou domain protein brn-2/n-oct-3/pou3f2 (nieto et al. 2007). In this case, the modification, at a position homologous to oct1 s385, was found to alter binding specificity for complex dimeric sites.	SIGNOR-53254	0.2
IRF1	protein	P10914	UNIPROT	SOCS1	protein	O15524	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19482358	f		miannu	Socs1 expression is induced in the human keratinocytes HaCaT cell line through sequential activation of STAT1 and IRF-1	SIGNOR-226481	0.39
BRCA2	protein	P51587	UNIPROT	POLH	protein	Q9Y253	UNIPROT	up-regulates	binding			9606									24485656	t		miannu	Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates	SIGNOR-204538	0.533
TFAP2A	protein	P05549	UNIPROT	CRABP2	protein	P29373	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002828								17187826	f	 	miannu	 Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. 	SIGNOR-255400	0.351
EPAS1	protein	Q99814	UNIPROT	KDM2B	protein	Q8NHM5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271582	0.2
AARS1	protein	P49588	UNIPROT	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									32314272	t		miannu	Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N).	SIGNOR-270449	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PDE4D	protein	Q08499	UNIPROT	down-regulates	phosphorylation			9606									10828059	t	The effect has been demonstrated using Q08499-2	gcesareni	These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro.	SIGNOR-270174	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	RARA	protein	P10276	UNIPROT	down-regulates	phosphorylation	Ser96	FVCQDKSsGYHYGVS	9606	BTO:0000551								16417524	t		miannu	We report that akt, which is constitutively activated in nsclc cells, phosphorylates raralpha and inhibits its transactivation. / mutation of ser96 to alanine abrogated the suppressive effect of akt.	SIGNOR-143721	0.2
LCK	protein	P06239	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	binding			9606							phosphorylation:Tyr319	TSVYESPySDPEELK	8798643	t		lperfetto	Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation	SIGNOR-43659	0.601
PTPN12	protein	Q05209	UNIPROT	PTK2	protein	Q05397	UNIPROT	down-regulates activity	dephosphorylation	Tyr397	SVSETDDyAEIIDEE	10090	BTO:0000944								19595712	t			We demonstrate here that activated Ras induces tyrosine dephosphorylation and inhibition of FAK mediated by the Ras downstream Fgd1-Cdc42-PAK1-MEK-ERK signaling cascade.| PIN1 binding and prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397. Inhibition of FAK mediated by this signal relay promotes Ras-induced cell migration, invasion, and metastasis. 	SIGNOR-248661	0.554
EVX1	protein	P49640	UNIPROT	GSC	protein	P56915	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086								22178155	f	 	miannu	 We found that EVX1 repressed GSC expression and promoted formation of posterior streak-like progeny in response to BMP4, and conversely that GSC repressed EVX1 expression and was required for development of anterior streak-like progeny in response to activin. 	SIGNOR-254139	0.256
GTF2H2	protein	Q13888	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates activity	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606									10949034	t		Manara	TFIIH Phosphorylates Human Estrogen Receptor α at Serine 118 | We report here that Cdk7 overexpression stimulates transcription activation by ERα by stimulating phosphorylation of S118 in a ligand-dependent manner. 	SIGNOR-260817	0.26
BAX	protein	Q07812	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity	binding												8358790	t		lperfetto	Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered. 	SIGNOR-249612	0.619
SMCR8	protein	Q8TEV9	UNIPROT	ULK1	protein	O75385	UNIPROT	down-regulates quantity	transcriptional regulation			9606	BTO:0000007								28195531	t			While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. The latter phenotype involved association of SMCR8 with the ULK1 gene locus.	SIGNOR-252030	0.406
UQCRC2	protein	P22695	UNIPROT	Mitochondrial respiratory chain complex III	complex	SIGNOR-C279	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits	SIGNOR-262191	0.897
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GRK1	protein	Q15835	UNIPROT	down-regulates activity	phosphorylation	Ser21	AFIAARGsFDGSSSQ	-1									15946941	t	done	miannu	PKA Phosphorylates GRK1 on Ser21. Phosphorylation by PKA inhibits GRK1 activity.	SIGNOR-274079	0.2
CNOT1	protein	A5YKK6	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	form complex	binding			9606									19558367	t		lperfetto	In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules.	SIGNOR-268300	0.891
CREBBP	protein	Q92793	UNIPROT	DDX21	protein	Q9NR30	UNIPROT	down-regulates activity	acetylation	Lys600	HFKQSAEkLIEEKGA										28790157	t		lperfetto	Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21.	SIGNOR-275906	0.247
lapatinib	chemical	CHEBI:49603	ChEBI	CSK	protein	P41240	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001949								21443688	t		Luana	YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ.	SIGNOR-257900	0.8
RPS6KA3	protein	P51812	UNIPROT	NFATC4	protein	Q14934	UNIPROT	up-regulates	phosphorylation	Ser289	PALSRRGsLGEEGSE	10090									17213202	t		lperfetto	The results indicated that rsk2 phosphorylated two additional sites at ser289 (peptide 2) and ser344 (peptide 3)rsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo.	SIGNOR-234473	0.395
PPM1D	protein	O15297	UNIPROT	ATM	protein	Q13315	UNIPROT	down-regulates	dephosphorylation			9606									19360021	t		gcesareni	The negative regulator wip1 plays an important role in inhibiting atm, resulting in a pulse of atm activity.	SIGNOR-185135	0.504
MAPK1	protein	P28482	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation	Ser418	TEERLPSsPVYEDAA	9606	BTO:0000938								21079800	t		gcesareni	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-169678	0.481
GFI1	protein	Q99684	UNIPROT	SPI1	protein	P17947	UNIPROT	down-regulates activity	binding			10090	BTO:0000725								17197705	t		miannu	Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line.	SIGNOR-256043	0.613
MAP3K7	protein	O43318	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates activity				9606									9480845	f		lperfetto	Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene...[]...These Results suggest that tak1 induces nf-kappa b activation through a novel nik-independent signaling pathway	SIGNOR-55710	0.64
LEF1	protein	Q9UJU2	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19653274	f		irozzo	Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation	SIGNOR-256281	0.585
PTEN	protein	P60484	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates activity	dephosphorylation	Ser83	QQQQQETsPRQQQQQ	9606									24480624	f		miannu	Furthermore, PTEN depletion increased AR protein instability, and this effect was further enhanced by p300 silencing in LAPC4 cells .|Our data demonstrate that loss of PTEN increases AR phosphorylation at Ser81 and that Ser81 phosphorylation acts as a molecular beacon that is required for the binding of p300, a key event that subsequently leads to AR acetylation, inhibition of AR ubiquitination and AR stabilization (XREF_FIG).	SIGNOR-277077	0.599
SETD1A	protein	O15047	UNIPROT	Set1-Ash2 HMT complex	complex	SIGNOR-C352	SIGNOR	form complex	binding			9606	BTO:0000567								12670868	t		miannu	Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles.	SIGNOR-264478	0.896
PLK4	protein	O00444	UNIPROT	TUBGCP6	protein	Q96RT7	UNIPROT	up-regulates activity	phosphorylation	Ser1168	HGHVSDAsISLGESV	-1									22302995	t		miannu	Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication.	SIGNOR-262903	0.691
FKBP5	protein	Q13451	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				10090	BTO:0000142								30685540	f		Luana	Loss of FKBP5 Affects Neuron Synaptic Plasticity | In this study, a reduction in LTP in Fkbp5 knockout (KO) mice was observed when compared to WT mice, which correlated with changes to the glutamatergic and GABAergic signaling pathways. 	SIGNOR-265798	0.7
SRP54	protein	P61011	UNIPROT	U2AF1/U2AF2	complex	SIGNOR-C78	SIGNOR	up-regulates activity	binding			-1									8816452	t		Monia	We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65).	SIGNOR-261162	0.343
vinorelbine L-tartrate	chemical	CHEBI:32296	ChEBI	TUBB	protein	P07437	UNIPROT	down-regulates activity	chemical inhibition			9606									7740336	t		miannu	Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) and paclitaxel (Taxol; Bristol-Myers Oncology, Princeton, NJ) as single-agent therapy exhibit good activity in breast and lung cancers. Because these agents bind to distinct sites on tubulin and affect microtubules in opposite ways, a pilot study was conducted of the combination of vinorelbine and paclitaxel in patients with metastatic breast cancer or lung cancer who were refractory to first-line chemotherapy. 	SIGNOR-259348	0.8
PLK4	protein	O00444	UNIPROT	TUBGCP6	protein	Q96RT7	UNIPROT	up-regulates activity	phosphorylation	Ser1087	HGHVSNAsISLGESV	-1									22302995	t		miannu	Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication.	SIGNOR-262901	0.691
C9orf72	protein	Q96LT7	UNIPROT	ULK1/Atg13/Fip200	complex	SIGNOR-C100	SIGNOR	up-regulates activity	binding			9606									27334615	t		lperfetto	C9orf72 interacts with the ULK1 initiation complex|C9orf72 regulates translocation of the ULK1 complex to the phagophore via Rab1a	SIGNOR-261281	0.429
MRPL42	protein	Q9Y6G3	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262354	0.681
SPRY2	protein	O43597	UNIPROT	CBLB	protein	Q13191	UNIPROT	down-regulates	binding			9606									11053437	t		gcesareni	One function of hspry2 in signaling processes downstream of rtks may be to modulate c-cbl physiological function such as that seen with receptor-mediated endocytosis.	SIGNOR-83507	0.498
EP300	protein	Q09472	UNIPROT	TBXAS1	protein	P24557	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000018								14565864	f	 	miannu	 We also showed that forced expression of p300 upregulated TXAS gene in a dose-dependent manner. Mutation of NF-E2 site, but not TATA or initiator site, abolished the p300-mediated activation of TXAS gene.	SIGNOR-253906	0.2
CENPC	protein	Q03188	UNIPROT	CENP-A nucleosome	complex	SIGNOR-C321	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								20566683	t		miannu	CENP-C is required for centromere assembly. CENP-C and CENP-N bind to different sites on the same CENP-A nucleosomes. CENP-C, like CENP-N, interacts directly and specifically with CENP-A nucleosomes.	SIGNOR-263706	0.723
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate	smallmolecule	CHEBI:18348	ChEBI	1D-myo-inositol 1,4,5-trisphosphate	smallmolecule	CHEBI:16595	ChEBI	up-regulates quantity	precursor of			9606									23000145	t		scontino	Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).	SIGNOR-268450	0.8
MRGPRX1	protein	Q96LB2	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257259	0.2
CDK2	protein	P24941	UNIPROT	MYBL2	protein	P10244	UNIPROT	unknown	phosphorylation	Thr440	LDSCNSLtPKSTPVK		BTO:0000007								10095772	t		llicata	In summary, our work has identified several phosphorylation sites for cyclin A/Cdk2 in B-Myb and shown that mutation of at least one of these sites has a strong effect on the inducibility of the B-Myb transactivation potential by cyclin A/Cdk2.	SIGNOR-250738	0.711
PIM1	protein	P11309	UNIPROT	RPS19	protein	P39019	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000007								16266891	t		gcesareni	The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay.	SIGNOR-141411	0.45
CDK4	protein	P11802	UNIPROT	RBL1	protein	P28749	UNIPROT	up-regulates activity	phosphorylation	Thr369	KRSFAPStPLTGRRY	9606	BTO:0001938								12006580	t		llicata	Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression. 	SIGNOR-250765	0.8
WNK4	protein	Q96J92	UNIPROT	WNK4	protein	Q96J92	UNIPROT	down-regulates activity	phosphorylation	Ser335	KRASFAKsVIGTPEF	-1									25542968	t		miannu	 Elimination of the catalytic activity (D321A or D321K-K186D) or the autophosphorylation site (S335A) in mutant WNK4-L322F abrogated the positive effect on NCC. 	SIGNOR-276871	0.2
P2RY14	protein	Q15391	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256723	0.376
STK24	protein	Q9Y6E0	UNIPROT	RAB8A	protein	P61006	UNIPROT	up-regulates activity	phosphorylation	Thr72	AGQERFRtITTAYYR	-1									32227113	t		lperfetto	In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease	SIGNOR-260265	0.279
TP53	protein	P04637	UNIPROT	PERP	protein	Q96FX8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10733530	f		gcesareni	Perp induction is linked to p53-dependent apoptosis, including in response to e2f-1-driven hyperproliferation. Furthermore, analysis of the perp promoter suggests that perp is directly activated by p53.	SIGNOR-75877	0.626
MAPK7	protein	Q13164	UNIPROT	MAP2K5	protein	Q13163	UNIPROT	up-regulates	phosphorylation	Ser129	VNTRAGPsQHSSPAV	9606		BTO:0000671							12628002	t		lperfetto	Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)	SIGNOR-99127	0.69
PTPN2	protein	P17706	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates				9606									12612081	f		acerquone	We found that insulin-induced ir tyrosine phosphorylation and pkb/akt sig- naling were enhanced in tcptp- cells and suppressed upon tcptp reconstitution, providing persuasive evidence that tcptp can regulate ir activation and signaling.	SIGNOR-252640	0.364
CSNK2A1	protein	P68400	UNIPROT	GTF2A1	protein	P52655	UNIPROT	up-regulates activity	phosphorylation	Ser321	LNSEDDVsDEEGQEL	-1									11278496	t		llicata	We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function.	SIGNOR-250877	0.388
SET	protein	Q01105	UNIPROT	NME1	protein	P15531	UNIPROT	down-regulates	binding			9606									12628186	t		miannu	Tumor suppressor nm23-h1 is a granzyme a-activated dnase during ctl-mediated apoptosis, and the nucleosome assembly protein set is its inhibitor. / nm23-h1 binds to set and is released from inhibition by gzma cleavage of set.	SIGNOR-99205	0.717
CDK2	protein	P24941	UNIPROT	CDC6	protein	Q99741	UNIPROT	up-regulates	phosphorylation	Ser106	DNQLTIKsPSKRELA	9606			SIGNOR-C83						10339564	t		lperfetto	Based on these results, we propose that phosphorylation of hscdc6 by cdks regulates dna replication of at least two steps: first, by promoting initiation of dna replication and, second, through nuclear exclusion preventing dna rereplication. hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)	SIGNOR-67540	0.94
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	HJURP	protein	Q8NCD3	UNIPROT	up-regulates activity	binding			-1									17256767	t		miannu	 These data define a new protein complex in mammalian cells where 14‐3‐3 associates with FAKTS through phosphorylated S479. Our research identifies a widely expressed eukaryotic protein FAKTS, as a new Akt/PKB substrate localized in the nucleus. Akt/PKB promotes FAKTS association with 14‐3‐3, placing FAKTS under the control of 14‐3‐3 proteins. FAKTS may play an important role in transmitting Akt/PKB‐mediated signals in the complex network of intracellular signal transduction. 	SIGNOR-262624	0.2
ponatinib	chemical	CHEBI:78543	ChEBI	FGFR1	protein	P11362	UNIPROT	down-regulates activity	chemical inhibition			9606									23468082	t		miannu	Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. 	SIGNOR-259277	0.8
2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	chemical	CHEBI:93768	ChEBI	IGF1R	protein	P08069	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258116	0.8
CTDSPL2	protein	Q05D32	UNIPROT	HBG2	protein	P69892	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000664								20932329	f	Indirect:regulation of transcription	miannu	CTD small phosphatase like 2 (CTDSPL2) can increase ε- and γ-globin gene expression in K562 cells and CD34+ cells derived from umbilical cord blood.	SIGNOR-251777	0.2
USH1C	protein	Q9Y6N9	UNIPROT	TIP-LINK complex	complex	SIGNOR-C291	SIGNOR	form complex	binding			10090		BTO:0000630							23217710	t		lperfetto	The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction.	SIGNOR-262576	0.71
FYN	protein	P06241	UNIPROT	CNN1	protein	P51911	UNIPROT	down-regulates activity	phosphorylation	Tyr261	SQRGMTVyGLPRQVY	9534	BTO:0000298								15206927	t			We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin	SIGNOR-251158	0.338
TWIST1	protein	Q15672	UNIPROT	SRPX	protein	P78539	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255534	0.2
KIF5C	protein	O60282	UNIPROT	TRAK2	protein	O60296	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								24161670	t		miannu	Trafficking kinesin proteins (TRAKs) are kinesin adaptors. They bind the cargo binding domain of kinesin-1 motor proteins forming a link between the motor and their cargoes. This supports the idea that the KIF5A–TRAK2 interaction is multivalent and could act to ensure stable motor-cargo interaction during intracellular trafficking; dimerization of both motor and adaptor molecules further enhances this stability (Fig. 6). A similar multivalent profile was found for the TRAK2 binding site within the kinesin-1 isoform, KIF5C. 	SIGNOR-264064	0.566
SMAD1	protein	Q15797	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	phosphorylation			9606			SIGNOR-C85						20957627	t		lperfetto	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common(co-Smad; Smad4 in mammals) and shuttle into the nucleus.	SIGNOR-168734	0.655
SHMT2	protein	P34897	UNIPROT	glycine	smallmolecule	CHEBI:15428	ChEBI	up-regulates quantity	chemical modification			9606									32439610	t		lperfetto	Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. 	SIGNOR-268224	0.8
APOE	protein	P02649	UNIPROT	SORL1	protein	Q92673	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001260							11557679	t		gcesareni	Lr11 binds the apolipoprotein e (apoe)-rich lipoproteins, beta-very low density lipoproteins (vldls), with a high affinity similar to that of other members, such as the ldlr and vldl receptor.Incubation For 48 hours with beta-vldl of lr11-overexpressing cells, but not of control cells, promotes the appearance of numerous intracellular lipid droplets.	SIGNOR-110555	0.619
MARCHF5	protein	Q9NX47	UNIPROT	MFN1	protein	Q8IWA4	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								20103533	t		lperfetto	MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion.|Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate.	SIGNOR-272981	0.2
MARCHF5	protein	Q9NX47	UNIPROT	FIS1	protein	Q9Y3D6	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								16874301	t		miannu	MITOL associates with and ubiquitinates mitochondrial fission protein hFis1. (A) Ubiquitination of hFis1 by MITOL. Thus, MITOL may control the protein expression level of hFis1 through the ubiquitin–proteasome pathway.	SIGNOR-271896	0.2
CDC25C	protein	P30307	UNIPROT	CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	up-regulates activity	dephosphorylation	Thr14	IEKIGEGtYGVVYKG	9606	BTO:0001938								10913154	t		lperfetto	Cyclin B-Cdc2 complexes are maintained in an inactive state until the end of G2 by phosphorylation of the Thr14/Tyr15 residues. Around the time of nuclear translocation of the complex, these residues are dephosphorylated, resulting in the formation of an active cyclin B-Cdc2 complex (2). As mentioned, this dephosphorylation occurs by a Cdc25 protein phosphatase. Three Cdc25 family members have been identified to date, A, B and C, the last one being the active one at the onset of mitosis. The activity of Cdc25C itself can be enhanced through phosphorylation by cyclin B-Cdc2 (9, 10). Therefore, activation of cyclin B-Cdc2 has been proposed to result in an autocatalytic feedback loop to ensure rapid activation of these complexes at the G2/M transition	SIGNOR-251509	0.839
CAMK2A	protein	Q9UQM7	UNIPROT	DAGLA	protein	Q9Y4D2	UNIPROT	down-regulates activity	phosphorylation	Ser782	APLATMEsLSDTESL										23502535	t		lperfetto	Activated CaMKII interacted with the C-terminal domain of DGLalpha, phosphorylated two serine residues and inhibited DGLalpha activity. |CaMKIIalpha phosphorylates DGLalpha at Ser808 and Ser782	SIGNOR-275539	0.2
RAI1	protein	Q7Z5J4	UNIPROT	CRY1	protein	Q16526	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000614							22578325	f		miannu	Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. 	SIGNOR-266842	0.35
PRKAR1B	protein	P31321	UNIPROT	PRKACB	protein	P22694	UNIPROT	down-regulates activity	binding			9606									26687711	t			Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 	SIGNOR-258756	0.876
ATM	protein	Q13315	UNIPROT	MDM4	protein	O15151	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser367	PDCRRTIsAPVVRPK	9606									16943424	t		lperfetto	Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm.	SIGNOR-149296	0.725
JAG1	protein	P78504	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	up-regulates	binding			9606									10958687	t	Binding Calcium-dependent.	gcesareni	Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch.	SIGNOR-81364	0.623
PTPN2	protein	P17706	UNIPROT	STAT6	protein	P42226	UNIPROT	down-regulates activity	dephosphorylation			9606									17210636	t		gcesareni	These results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors	SIGNOR-235192	0.666
ACTL6A	protein	O96019	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269295	0.638
GTF2I	protein	P78347	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates quantity by expression	transcriptional regulation												16611241	f		lperfetto	For example, TFII-I binds to the Inr element of the T cell receptor Vbeta gene and activates its transcription in reporter gene assays (Cheriyath et al. 1998). TFII-I also activates transcription of c-fos and Goosecoid through binding to the serum response element and the distal element, respectively (Grueneberg et al. 1997; Ku et al. 2005).	SIGNOR-268535	0.328
BAG1	protein	Q99933	UNIPROT	PPP1R15A	protein	O75807	UNIPROT	down-regulates activity				9606	BTO:0000038								12724406	t		lperfetto	Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions.|BAG-1 negatively modulates GADD34-bound PP1 activity, and the expression of BAG-1 isoforms can also mask GADD34-mediated inhibition of colony formation and suppression of transcription. Our findings suggest that BAG-1 may function to suppress the GADD34-mediated cellular stress response and support a role for BAG-1 in the survival of cells undergoing stress.	SIGNOR-254117	0.456
4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide	chemical	CHEBI:91447	ChEBI	SRC	protein	P12931	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194925	0.8
HRH1	protein	P35367	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256921	0.2
ESRRA	protein	P11474	UNIPROT	RNF208	protein	Q9H0X6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								31862882	t		Gianni	Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner	SIGNOR-269052	0.2
ADCYAP1	protein	P18509	UNIPROT	ADCYAP1R1	protein	P41586	UNIPROT	up-regulates	binding			9606									8703026	t		gcesareni	Type i pacap receptors bind pacap-27 and -38. the potencies of the two forms of pacap are similar for adenylate cyclase stimulation, whereas pacap-38 is more potent than pacap-27 in phospholipase c activation.	SIGNOR-43225	0.873
MAPK3	protein	P27361	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates	phosphorylation	Ser780	DSLDSRLsPPAGLFT	9606		BTO:0000975							10194762	t		gcesareni	Serine 780 is the only substrate in full-length stat5a for active erk	SIGNOR-66247	0.694
GRK2	protein	P25098	UNIPROT	RPLP2	protein	P05387	UNIPROT	up-regulates	phosphorylation	Ser102	KDEKKEEsEESDDDM	9606									12379128	t		gcesareni	The phosphorylation sites in grk2-phosphorylated p2 are identified (s102 and s105) and are identical to the sites known to regulate p2 activity.	SIGNOR-94254	0.2
sitagliptin	chemical	CHEBI:40237	ChEBI	DPP4	protein	P27487	UNIPROT	down-regulates activity	chemical inhibition			9606									20927248	t		Luana	Sitagliptin is a competitive, reversible, fast and tight binding DPP-IV inhibitor	SIGNOR-257883	0.8
MAPK1	protein	P28482	UNIPROT	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation	Ser154	SSVSSSPsPPFGHSA	9606									12050114	t		gcesareni	Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation.	SIGNOR-88720	0.361
SCN9A	protein	Q15858	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606									27262167	t		miannu	Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential.	SIGNOR-253403	0.8
MRPS22	protein	P82650	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261434	0.722
MAP2K7	protein	O14733	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates activity	phosphorylation	Thr221	AGTSFMMtPYVVTRY	-1									10715136	t			Activation of JNK3 alpha 1 requires both MKK4 and MKK7. both MKK4 and MKK7 were required for bisphosphorylation and maximal enzyme activity. a processive mechanism for JNK3R1 activation that requires phosphorylation of Thr 221 by MKK7 prior to phosphorylation of Tyr 223 by MKK4	SIGNOR-251422	0.564
LPAR3	protein	Q9UBY5	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257141	0.252
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MTOR	protein	P42345	UNIPROT	up-regulates				9606		BTO:0000887;BTO:0001103							12782654	f		lperfetto	It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor.	SIGNOR-244314	0.2
D-threo-isocitrate(3-)	smallmolecule	CHEBI:15562	ChEBI	IDH2	protein	P48735	UNIPROT	up-regulates activity	chemical activation			9606									32943735	t			Wild-type IDH1 and IDH2 catalyze the reaction by converting isocitrate and NADP+ into α-KG and CO2 with the concomitant generation of NADPH in the cytosol and mitochondrial matrix	SIGNOR-267370	0.8
PRKCA	protein	P17252	UNIPROT	HMGN2	protein	P05204	UNIPROT	down-regulates	phosphorylation	Ser29	QRRSARLsAKPAPPK	9606									10739259	t		lperfetto	Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.	SIGNOR-76324	0.293
SRC	protein	P12931	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation			9606							phosphorylation:Tyr397	SVSETDDyAEIIDEE	17828307	t		gcesareni	Fak y397 phosphorylation promotes src sh2 domain binding to fak, presumably leading to conformational src activation with a fak-src complex.	SIGNOR-157767	0.633
WWTR1	protein	Q9GZV5	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									23075495	f		gcesareni	Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis.	SIGNOR-199211	0.7
FHL2	protein	Q14192	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates	binding			9606		BTO:0001129							10654935	t		gcesareni	Fhl2 contains a strong, autonomous transactivation function and binds specifically to the ar in vitro and in vivo.	SIGNOR-74703	0.538
ABL2	protein	P42684	UNIPROT	LGALS3	protein	P17931	UNIPROT	up-regulates	phosphorylation	Tyr79	GAPAPGVyPGPPSGP	9606									20150913	t		llicata	The sh (src homology)3 domains of c-abl/arg bind to a p(80)gppsgp motif of gal3, and tyr79 and tyr118 are the major tyrosine phosphorylation sites. A consequence of this interaction and phosphorylation is the significant impairment of chaperone-mediated autophagy of gal3.	SIGNOR-163747	0.2
(2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol	chemical	CHEBI:94562	ChEBI	FGFR1	protein	P11362	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258090	0.8
mTORC1	complex	SIGNOR-C3	SIGNOR	ULK1	protein	O75385	UNIPROT	down-regulates	phosphorylation			9606									19690328	t		lperfetto	The complementary inhibitory mechanism in which mtorc1 phosphorylates the autophagy regulatory complex containing unc-51-like kinase 1 (ulk1), the mammalian atg13 protein, and focal adhesion kinase interacting protein of 200 kd (fip200) has also been elucidated.	SIGNOR-217133	0.624
pimozide	chemical	CHEBI:8212	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258718	0.8
NSL1	protein	Q96IY1	UNIPROT	MIS12 complex	complex	SIGNOR-C362	SIGNOR	form complex	binding			-1									27881301	t		lperfetto	 Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits 	SIGNOR-265191	0.91
COPS2	protein	P61201	UNIPROT	COP9 signalosome variant 2	complex	SIGNOR-C487	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270766	0.921
TP73	protein	O15350	UNIPROT	PMAIP1	protein	Q13794	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17700533	f		miannu	Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. 	SIGNOR-255469	0.327
SOX9	protein	P48436	UNIPROT	DCC	protein	P43146	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003858								19745029	f		miannu	 Promoter analysis and transfection studies showed that the up-regulation of DCC in OA chondrocytes may be mediated by the transcription factors Sox9 and AP-2. 	SIGNOR-255188	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CHEK1	protein	O14757	UNIPROT	down-regulates	phosphorylation	Ser280	AKRPRVTsGGVSESP	9606									15107605	t		lperfetto	The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1.	SIGNOR-244206	0.2
NARS2	protein	Q96I59	UNIPROT	asparagine	smallmolecule	CHEBI:22653	ChEBI	down-regulates quantity	chemical modification			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270462	0.8
LPCAT2	protein	Q7L5N7	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	chemical modification			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272765	0.8
CLTA	protein	P09496	UNIPROT	AP-3/clathrin vescicle	complex	SIGNOR-C250	SIGNOR	form complex	binding			9606									23103167	t		lperfetto	Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors	SIGNOR-260672	0.755
MAPK14	protein	Q16539	UNIPROT	STAT4	protein	Q14765	UNIPROT	up-regulates	phosphorylation	Ser721	PSDLLPMsPSVYAVL	9606									17502367	t		gcesareni	All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).	SIGNOR-154787	0.581
NRZ complex	complex	SIGNOR-C358	SIGNOR	Vesicle_transport	phenotype	SIGNOR-PH172	SIGNOR	up-regulates													25364732	f		lperfetto	NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay.	SIGNOR-265026	0.7
CENPE	protein	Q02224	UNIPROT	Spindle_assembly	phenotype	SIGNOR-PH60	SIGNOR	up-regulates													20383333	f		lperfetto	Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology	SIGNOR-252013	0.7
BMP7	protein	P18075	UNIPROT	ACVR2B	protein	Q13705	UNIPROT	up-regulates	binding			9606									9748228	t		acerquone	We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes.	SIGNOR-60240	0.561
WDR62	protein	O43379	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	relocalization			10090									30566428	t		lperfetto	In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis	SIGNOR-271715	0.2
RNF111	protein	Q6ZNA4	UNIPROT	SKIL	protein	P12757	UNIPROT	down-regulates	ubiquitination			9606									17591695	t		gcesareni	Arkadia interacts with snon and induces its ubiquitination irrespective of tgf-beta/activin signaling, but snon is efficiently degraded only when it forms a complex with both arkadia and phosphorylated smad2 or smad3	SIGNOR-156430	0.713
KAT2B	protein	Q92831	UNIPROT	H3-4	protein	Q16695	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269621	0.2
CDK1	protein	P06493	UNIPROT	OSBP2	protein	Q969R2	UNIPROT	up-regulates activity	phosphorylation												30925160	t		lperfetto	CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.	SIGNOR-264878	0.2
PPP2CA	protein	P67775	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates	dephosphorylation	Ser24	APIRRRSsNYRAYAT	9606		BTO:0000887							15769444	t		lperfetto	The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2.	SIGNOR-134601	0.387
RPS6KA3	protein	P51812	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation	Ser119	EILSRRPsYRKILND	9606									8688081	t		lperfetto	MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression	SIGNOR-248951	0.716
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	CDKN1B	protein	P46527	UNIPROT	down-regulates activity	phosphorylation	Thr198	PGLRRRQt	9606									18593906	t		gcesareni	We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro.|Pim kinases promote cell cycle progression and tumorigenesis by down-regulating p27(Kip1) expression at both transcriptional and posttranslational levels.	SIGNOR-259425	0.2
beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	glycerone phosphate(2-)	smallmolecule	CHEBI:57642	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-268077	0.8
PLK1	protein	P53350	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates	phosphorylation	Ser53	GHSTGEDsAFQEPDS	9606	BTO:0000567								15070733	t		gcesareni	Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp.	SIGNOR-123832	0.626
HOXD12	protein	P35452	UNIPROT	MAFK	protein	O60675	UNIPROT	down-regulates activity	binding			-1									11036080	t		miannu	Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.	SIGNOR-221929	0.384
CDH2	protein	P19022	UNIPROT	CDON	protein	Q4KMG0	UNIPROT	up-regulates	binding			9606				SIGNOR-C21					20160094	t		gcesareni	We report here that n-cadherin ligation activates p38alpha/beta in myoblasts in a cdo-, bnip-2-, and jlp-dependent manner	SIGNOR-163844	0.633
PRKD1	protein	Q15139	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser275	DNVRYGIsNIDTTIE										34010649	t		lperfetto	The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-275948	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	KLC1	protein	Q07866	UNIPROT	down-regulates	phosphorylation			9606									21385839	t	inferred from 70% family members	gcesareni	Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro.	SIGNOR-270072	0.2
ADORA2A	protein	P29274	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256766	0.304
H4C1	protein	P62805	UNIPROT	Nucleosome_H3.3 variant	complex	SIGNOR-C339	SIGNOR	form complex	binding			9606									15776021	t		miannu	Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes.	SIGNOR-263877	0.2
TNF	protein	P01375	UNIPROT	COMT	protein	P21964	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0000099								19291302	f	Regulation of expression	miannu	COMT gene expression is downregulated by TNFα in primary rat astrocytes at both protein and mRNA levels.	SIGNOR-251963	0.295
CSNK1A1	protein	P48729	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	down-regulates activity	phosphorylation	Ser831	SAEGSHTsGQSNGRD	9606	BTO:0001109								28114302	t		miannu	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276508	0.378
SLC24A4	protein	Q8NFF2	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	down-regulates quantity	relocalization			9606									30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264392	0.8
FOXO1	protein	Q12778	UNIPROT	TRIM63	protein	Q969Q1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									18612045	f		lperfetto	Transcriptional reporter assays performed in both HepG2 and C2C12 cells demonstrate that the MuRF1 promoter is highly responsive to dexamethasone-activated glucocorticoid receptor (GR) and FoxO1 individually, while co-overexpression of GR and FoxO1 leads to a dramatic synergistic increase in reporter activity	SIGNOR-235367	0.416
lenalidomide	chemical	CHEBI:63791	ChEBI	CRBN	protein	Q96SW2	UNIPROT	down-regulates activity	chemical inhibition			9606									22552008	t		miannu	 Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.	SIGNOR-259284	0.8
PTPN1	protein	P18031	UNIPROT	PTPN1	protein	P18031	UNIPROT	down-regulates activity	dephosphorylation	Tyr66	LHQEDNDyINASLIK	-1									11506178	t			Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions.	SIGNOR-248423	0.2
SGK1	protein	O00141	UNIPROT	MAP3K3	protein	Q99759	UNIPROT	down-regulates activity	phosphorylation	Ser166	EPRSRHLsVSSQNPG	9534	BTO:0001538								12392720	t		miannu	It was shown that the recombinant MEKK3 protein and fluorescein-labeled MEKK3 peptides (FITC-(159)epRsRhlSVi(168) and FITC-(330)dpRgRlpSAd(339)) are phosphorylated by SGK1 in vitro. It was also observed that the intrinsic kinase activity of MEKK3 on Ser(189) of MKK3 (equivalent to Ser(207) of MKK6) decreased along with phosphorylation of Ser(166) and Ser(337) in MEKK3 in vitro and in vivo. Therefore, it is suggested that SGK1 inhibits MEKK3-MKK3/6 signal transduction by phosphorylation of MEKK3.	SIGNOR-250004	0.2
DDB1	protein	Q16531	UNIPROT	DCX DET1-COP1	complex	SIGNOR-C24	SIGNOR	form complex	binding			9606									17452440	t		lperfetto	Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes	SIGNOR-154505	0.892
RSPO3	protein	Q9BXY4	UNIPROT	SDC4	protein	P31431	UNIPROT	up-regulates	binding			9606									21397842	t		gcesareni	Here, we show that rspo3 binds syndecan 4 (sdc4) and that together they activate wnt/pcp signaling.	SIGNOR-172756	0.435
PPP2CA	protein	P67775	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates	dephosphorylation	Ser23	PAPIRRRsSNYRAYA	9606		BTO:0000887							15769444	t		lperfetto	The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2.	SIGNOR-134597	0.387
AURKB	protein	Q96GD4	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	phosphorylation	Ser269	GNLLGRNsFEVRVCA	9606									20959462	t		llicata	Importantly, the aurora b-mediated phosphorylation on ser(269) or thr(284) significantly compromises p53 transcriptional activity.	SIGNOR-168745	0.708
HSPB1	protein	P04792	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	down-regulates				9606									12855565	f		gcesareni	These data demonstrate that hsp27 inhibits the release of smac	SIGNOR-103539	0.335
AKT1	protein	P31749	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity				9606		BTO:0001103							15829723	t		apalma	GSK-3beta activity can be inhibited by Akt phosphorylation (12), which may provide a mechanism for Akt to promote muscle growth through inhibition of the negative regulator GSK-3beta.	SIGNOR-255109	0.783
PTPN11	protein	Q06124	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	dephosphorylation	Tyr771	ADIESSNyMAPYDNY	-1									7545675	t			Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides	SIGNOR-248669	0.739
GHSR	protein	Q92847	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256925	0.27
IL22RA2	protein	Q969J5	UNIPROT	IL22	protein	Q9GZX6	UNIPROT	up-regulates	binding			9606									11390453	t		gcesareni	Il-22 mediates inflammation and binds class ii cytokine receptor heterodimers il-22 ra1/crf2-4.	SIGNOR-86113	0.737
KU-60019	chemical	CID:15953870	PUBCHEM	ATM	protein	Q13315	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193597	0.8
MMP2	protein	P08253	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates	cleavage			9606									10652271	t		gcesareni	We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-beta (tgf-beta), which constitutes a novel mechanism of tgf-beta activation	SIGNOR-74384	0.572
CDK1	protein	P06493	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Thr444	RFIGSPRtPVSPVKF	9606		BTO:0000887;BTO:0001103							11705993	t		gcesareni	Interestingly, phosphorylation at several ser/thr residues within the c-terminal autoinhibitory tail appears to either activate or inhibit s6k1, depending on the cell cycle phase. phosphorylation of those residues (featured by the thr-421/ser-424 site) during mitosis pursued by cdk1 inactivates s6k1 we then assessed the phosphorylation status of the mitosis-specific inhibitory residue of s6k1, thr-421/ser-424, which is targeted by mitotic cdk1.	SIGNOR-111507	0.392
CSNK2B	protein	P67870	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Ser330	SFRVRASsDGEGTMS	-1									8349691	t		llicata	These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1.	SIGNOR-251073	0.324
GNB3	protein	P16520	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									14668344	t		gcesareni	Expression of the g__ sequestrant, _-transducin, inhibits both ras activation and membrane translocation of _-arrestin1, suggesting that g__ dimers from g_i2 and g_q activate different effectors to coordinately regulate the pi 3-kinase/akt pathway. , these data indicate that _-thrombin stimulates rapid pi 3-kinase activity and akt phosphorylation by the g__ dimers released from a ptx-sensitive g protein.	SIGNOR-252680	0.375
TFEB	protein	P19484	UNIPROT	CTSF	protein	Q9UBX1	UNIPROT	up-regulates quantity by expression	transcriptional regulation												30145926	f		lperfetto	Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 	SIGNOR-276805	0.374
MAP2K6	protein	P52564	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation	Thr180	RHTDDEMtGYVATRW	9534									8622669	t		lperfetto	These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase	SIGNOR-40423	0.733
PTEN	protein	P60484	UNIPROT	ABTB1	protein	Q969K4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11494141	f		miannu	Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 	SIGNOR-260050	0.365
PLK1	protein	P53350	UNIPROT	RACGAP1	protein	Q9H0H5	UNIPROT	up-regulates	phosphorylation	Thr260	QPWNSDStLNSRQLE	9606									19468302	t		llicata	Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex.	SIGNOR-185758	0.658
TP53	protein	P04637	UNIPROT	LRBA	protein	P50851	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15064745	f		miannu	 We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA.	SIGNOR-253847	0.278
IKK-complex	complex	SIGNOR-C14	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser644	GLDFNFDsLISTQNV	9606									19188143	t		lperfetto	Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway	SIGNOR-209769	0.534
ARHGEF7	protein	Q14155	UNIPROT	LRRK2	protein	Q5S007	UNIPROT	up-regulates	binding			9606									21048939	t		gcesareni	Arhgef7 is interacting with lrrk2 in vitro and in vivo. Gtpase activity of full-length lrrk2 increases in the presence of recombinant arhgef7. Arhgef7 might act as a guanine nucleotide exchange factor for lrrk2	SIGNOR-169217	0.468
CAMK2A	protein	Q9UQM7	UNIPROT	OPRM1	protein	P35372	UNIPROT	down-regulates	phosphorylation	Ser270	SVRMLSGsKEKDRNL	9606		BTO:0000671							10908300	t		gcesareni	The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization.	SIGNOR-79682	0.2
EZH2	protein	Q15910	UNIPROT	HOXB13	protein	Q92826	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001033								22808286	f	 	miannu	 EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex.	SIGNOR-254144	0.416
LPCAT4	protein	Q643R3	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	chemical modification			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272771	0.8
MBL2	protein	P11226	UNIPROT	MASP2	protein	O00187	UNIPROT	up-regulates activity	binding			9606									9087411	t		lperfetto	The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5). 	SIGNOR-263415	0.73
SMAD7	protein	O15105	UNIPROT	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	down-regulates				9606									30017632	f		miannu	Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. 	SIGNOR-260433	0.7
VHL	protein	P40337	UNIPROT	CDKN1C	protein	P49918	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000037								15824735	f		miannu	 three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL. 	SIGNOR-255601	0.2
3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione	chemical	CHEBI:91368	ChEBI	PRKACB	protein	P22694	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258211	0.8
ANXA1	protein	P04083	UNIPROT	FPR2	protein	P25090	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								15187149	t			We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2.	SIGNOR-259437	0.63
RING1	protein	Q06587	UNIPROT	Histone H2A	proteinfamily	SIGNOR-PF70	SIGNOR	down-regulates activity	ubiquitination			10090	BTO:0002572								16359901	t		miannu	Polycomb group (PcG) proteins exist in at least two biochemically distinct protein complexes, the EED-EZH2 complex and the PRC1 complex, that respectively possess H3-K27 methyltransferase and H2A-K119 ubiquitin E3 ligase activities. How the enzymatic activities are regulated and what their role is in Hox gene silencing are not clear. Here, we demonstrate that Bmi-1 and Ring1A, two components of the PRC1 complex, play important roles in H2A ubiquitylation and Hox gene silencing. We show that both proteins positively regulate H2A ubiquitylation. 	SIGNOR-271417	0.2
SH2B1	protein	Q9NRF2	UNIPROT	CD79B	protein	P40259	UNIPROT	down-regulates activity	dephosphorylation			9606	BTO:0000776			SIGNOR-C433; SIGNOR-C434; SIGNOR-C435; SIGNOR-C436					32323266	t		scontino	SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK.	SIGNOR-268458	0.2
N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide	chemical	CHEBI:91336	ChEBI	AURKC	protein	Q9UQB9	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207672	0.8
HIC1	protein	Q14526	UNIPROT	VEGFA	protein	P15692	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000815								24067369	f	 	miannu	 HIC1 suppressing the VEGF and c-Myc promoter activity and the colony formation of MDA-MB 231 cells were STAT3-dependent.	SIGNOR-254247	0.2
GTF2A2	protein	P52657	UNIPROT	TBP	protein	P20226	UNIPROT	up-regulates activity	binding			-1									8626665	t		lperfetto	The general transcription factor IIA (TFIIA) binds to the TATA binding protein (TBP) and mediates transcriptional activation by distinct classes of activators. |Our results show that different activators utilize the general factor TFIIA in unique ways and that TFIIA contributes transcription activation functions in addition to the facilitation of TBP-DNA binding.	SIGNOR-262591	0.897
β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35.	SIGNOR-266466	0.8
PRKCD	protein	Q05655	UNIPROT	GNAZ	protein	P19086	UNIPROT	unknown	phosphorylation	Ser27	DRHLRSEsQRQRREI	9606									8429024	t		lperfetto	Gz alpha variants containing selected substitutions of alanine for serine residues were expressed in human kidney 293 cells, and the ability of each to be phosphorylated in response to phorbol 12-myristate 13-acetate was examined. A focus was placed on Ser25 and Ser27, the 2 serine residues within a sequence of Gz alpha used to obtain a phosphorylation-sensitive antibody. The results demonstrate that Ser27 is the primary site of phosphorylation. Conversion of Ser27 to an alanine resulted in a 65% decrease in incorporation of [32P] phosphate; conversion of Ser25 had no effect.	SIGNOR-248932	0.509
CD40LG	protein	P29965	UNIPROT	IGSF6	protein	O95976	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									9809579	f		miannu	CD40L activation of dendritic cells down-regulates DORA, a novel member of the immunoglobulin superfamily	SIGNOR-261727	0.332
SRC	protein	P12931	UNIPROT	MYLK	protein	Q15746	UNIPROT	up-regulates	phosphorylation	Tyr464	QEGSIEVyEDAGSHY	9606									12408982	t		gcesareni	Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity.	SIGNOR-95238	0.427
PTPN7	protein	P35236	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Tyr187	HTGFLTEyVATRWYR	9606									10702794	t			HePTP efficiently dephosphorylated active ERK2 on the tyrosine residue in the activation loop in vitro. Together, these data identify ERK2 as a specific and direct target of HePTP and are consistent with a model in which HePTP negatively regulates ERK2 activity as part of a feedback mechanism	SIGNOR-248484	0.805
CHEK1	protein	O14757	UNIPROT	CLSPN	protein	Q9HAW4	UNIPROT	up-regulates	phosphorylation	Thr916	DELLDLCtGKFTSQA	9606									16963448	t		gcesareni	We found that thr-916 on claspin is phosphorylated by chk1, suggesting that chk1 regulates claspin during checkpoint response.	SIGNOR-149411	0.786
IL12A	protein	P29459	UNIPROT	IFNG	protein	P01579	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10653850	f		miannu	IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12	SIGNOR-260861	0.374
NKX2-5	protein	P52952	UNIPROT	TBX5	protein	Q99593	UNIPROT	up-regulates quantity by expression	transcriptional regulation												15095414	f	 	 	Mutation at the potential TBE-B and -C sites, and at the GC box and NKX2.5 sites significantly decreased luciferase activity, suggesting that the GC box and the potential TBE-B, -C, and NKX2.5 sites are functionally important for the activation of the promoter function.	SIGNOR-253650	0.795
GSK3B	protein	P49841	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates activity	phosphorylation	Ser847	SEAASLSsLNSSESD	-1									10671552	t			Phosphorylation of the E-cadherin Cytoplasmic Domain by CKII and GSK-3β Increases the Binding to β-catenin. pre-phosphorylation by CKII at Ser-855 and/or Ser-853 of E-cadherin is required before GSK-3β can phosphorylate at Ser-849.	SIGNOR-251225	0.575
Met-tRNA(Met)	chemical	CHEBI:16635	ChEBI	Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	form complex	binding			9606									32955564	t		lperfetto	In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3.	SIGNOR-269117	0.8
BIRC5	protein	O15392	UNIPROT	CPC	complex	SIGNOR-C554	SIGNOR	form complex	binding			9606									23175282	t		miannu	It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A).	SIGNOR-275424	0.793
PLD1	protein	Q13393	UNIPROT	phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	up-regulates	chemical modification			9606									9873061	t		gcesareni	The primary known function of phospholipase d (pld) is to generate phosphatidic acid (pa) via the hydrolysis of phosphatidylcholine. . phospholipase d (pld) hydrolyzes phospholipids to generate phosphatidic acid (pa).	SIGNOR-62882	0.8
STXBP4	protein	Q6ZWJ1	UNIPROT	STX4	protein	Q12846	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								15753124	t		miannu	Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.Thus, our data demonstrate that insulin-stimulated Akt2-dependent phosphorylation of Synip on serine residue 99 results in reduced binding interactions between Synip and Syntaxin4.	SIGNOR-262634	0.793
PHLPP2	protein	Q6ZVD8	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	down-regulates activity	dephosphorylation	Ser472	RPHFPQFsYSASGRE	9606									17386267	t		gcesareni	Knockdown studies reveal that PHLPP1 specifically modulates the phosphorylation of HDM2 and GSK-3alpha through Akt2, whereas PHLPP2 specifically modulates the phosphorylation of p27 through Akt3	SIGNOR-237439	0.671
CDK2	protein	P24941	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates activity	phosphorylation	Thr405	VGGSGIGtPPSVLKR		BTO:0000007								10593981	t		llicata	Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. 	SIGNOR-250737	0.711
INSR	protein	P06213	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr659	VADERVDyVVVDQQK	10090	BTO:0000944								10978177	t			HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin	SIGNOR-251317	0.492
CCNO	protein	P22674	UNIPROT	CDK13	protein	Q14004	UNIPROT	up-regulates activity	binding												37197505	t		lperfetto	Cyclin O promotes lung cancer progression and cetuximab resistance via cell cycle regulation and CDK13 interaction|CCNO promoted tumor cell proliferation and survival in vivo via CDK13|	SIGNOR-275618	0.274
acetylcholine	smallmolecule	CHEBI:15355	ChEBI	CHRM3	protein	P20309	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257470	0.8
WNT6	protein	Q9Y6F9	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates				9606		BTO:0000887;BTO:0001103							22944199	f		gcesareni	In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm.	SIGNOR-198916	0.33
AURKB	protein	Q96GD4	UNIPROT	RACGAP1	protein	Q9H0H5	UNIPROT	up-regulates activity	phosphorylation	Ser185	KKREKRRsTSRQFVD	9606	BTO:0000567								14744859	t		llicata	It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1	SIGNOR-250587	0.772
PRKCB	protein	P05771	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	unknown	phosphorylation	Ser473	PPSGTKKsKRGRGRP	9606									12529391	t		llicata	Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm.	SIGNOR-97283	0.2
ELOVL7	protein	A1L3X0	UNIPROT	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267895	0.8
azelastine	chemical	CHEBI:2950	ChEBI	HRH3	protein	Q9Y5N1	UNIPROT	down-regulates activity	chemical inhibition			10030	BTO:0000246								21381763	t		Luana	Azelastine was used as a standard, with affinities (pKi) for H1 and H3 8.9 and 6.8, respectively. 	SIGNOR-257895	0.8
CDK6	protein	Q00534	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Thr187	NAGSVEQtPKKPGLR	9606	BTO:0000776;BTO:0000785								16160006	t		gcesareni	Phosphorylation on thr-187, by cdk2 leads to protein ubiquitination and proteasomal degradationp27(kip1) was phosphorylated by v-cyclin-cdk6 predominantly on ser10, which enhances its cytoplasmic localization. Interestingly, upon reactivation of kshv lytic cycle, v-cyclin-cdk6 phosphorylated p27(kip1) on thr187, which resulted in down-regulation of p27(kip1) protein levels.	SIGNOR-140405	0.85
COL15A1	protein	P39059	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									21949456	t			Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium	SIGNOR-254678	0.7
CSNK2A1	protein	P68400	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates activity	phosphorylation	Ser85	GSEGDSEsGEEEELG	-1									2046671	t		llicata	Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Mutation of serine 85 alone had a smaller but significant effect on phosphorylation that may be due to alteration in the protein kinase recognition site.	SIGNOR-250957	0.532
PRKCA	protein	P17252	UNIPROT	GRIA2	protein	P42262	UNIPROT	unknown	phosphorylation	Ser880	YNVYGIEsVKI	9606	BTO:0000007								10501226	t		lperfetto	Here, we show that the C terminus of GluR2 of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor is phosphorylated by protein kinase C and that serine-880 is the major phosphorylation site. This phosphorylation also occurs in human embryonic kidney (HEK) cells by addition of 12-O-tetradecanoylphorbol 13-acetate.	SIGNOR-249022	0.698
STK11	protein	Q15831	UNIPROT	STK11	protein	Q15831	UNIPROT	down-regulates activity	phosphorylation	Thr189	LLLTTGGtLKISDLG	9606		BTO:0000781							11430832	t		lperfetto	These data suggest that the phosphorylation of thr-189 negatively regulates lkb1 activity.	SIGNOR-109028	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	SKI	protein	P12755	UNIPROT	down-regulates	phosphorylation	Thr458	QPRKRKLtVDTPGAP	9606									19875456	t		llicata	The phosphorylation of ski at threonine 458 is induced by akt pathway activators including insulin, insulin-like growth factor-1, and hepatocyte growth factor. The phosphorylation of ski causes its destabilization and reduces ski-mediated inhibition of expression of another negative regulator of tgf-beta, smad7	SIGNOR-188969	0.2
AKT1	protein	P31749	UNIPROT	GATA1	protein	P15976	UNIPROT	up-regulates	phosphorylation	Ser310	QTRNRKAsGKGKKKR	9606									16107690	t		llicata	We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter.	SIGNOR-139782	0.529
Stress_granules	phenotype	SIGNOR-PH124	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606									27920254	f		miannu	Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis.	SIGNOR-260865	0.7
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2G2	protein	P60604	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271344	0.655
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1864	SPKYSPTsPKYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120220	0.321
FLI1	protein	Q01543	UNIPROT	GP6	protein	Q9HCN6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001549								12359731	f	 	miannu	 Deletion analyses and site-directed mutagenesis identified Sp1(227), GATA(177), and Ets(48) sites as essential for GPVI expression. We show that transcription factors GATA-1, Fli-1, and Sp1 can bind to and activate this promoter.	SIGNOR-254157	0.2
AURKB	protein	Q96GD4	UNIPROT	WWC1	protein	Q8IX03	UNIPROT	unknown	phosphorylation	Ser539	TSLSPRSsLSSPSPP	9606									21878642	t		llicata	We identified the highly conserved ser(539) as the primary phosphorylation site for aurora kinases.	SIGNOR-176363	0.253
FGF17	protein	O60258	UNIPROT	FGFR2	protein	P21802	UNIPROT	up-regulates	binding			9606									8663044	t		tpavlidou	Fgfs bind and activate high-affinity receptor tyrosine kinases. The cloning of fgf receptors (fgfrs) has identified four distinct genes	SIGNOR-42365	0.687
PAK6	protein	Q9NQU5	UNIPROT	PACSIN1	protein	Q9BY11	UNIPROT	up-regulates activity	phosphorylation	Ser346	SQAGDRGsVSSYDRG	-1									22371566	t		miannu	We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. 	SIGNOR-263021	0.2
LMO3	protein	Q8TAP4	UNIPROT	ASCL1	protein	P50553	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21573214	f		miannu	Overexpression of both LMO3 and HEN2 induced expression of Mash1, suggesting that they might function as a transcriptional activator for Mash1.	SIGNOR-254825	0.369
FOXO1	protein	Q12778	UNIPROT	BCL2L11	protein	O43521	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12913110	f		lperfetto	FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons.	SIGNOR-209654	0.556
POLR3C	protein	Q9BUI4	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266131	0.878
MCL1	protein	Q07820	UNIPROT	BAK1	protein	Q16611	UNIPROT	down-regulates	binding			9606									17289999	t		gcesareni	Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax	SIGNOR-149774	0.608
EEF1A2	protein	Q05639	UNIPROT	Gln-tRNA(Gln)	smallmolecule	CHEBI:29166	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269530	0.8
MAP3K3	protein	Q99759	UNIPROT	RCAN1	protein	P53805	UNIPROT	up-regulates	phosphorylation	Ser167	FLISPPAsPPVGWKQ	9606	BTO:0000782								12809556	t		gcesareni	Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation	SIGNOR-102294	0.46
etorphine	chemical	CHEBI:4912	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258803	0.8
SRC_kinase_family	proteinfamily	SIGNOR-PF32	SIGNOR	KCND3	protein	Q9UK17	UNIPROT	up-regulates activity	phosphorylation	Tyr108	GKLHYPRyECISAYD										22198508	t		lperfetto	Our results demonstrate that human atrial I(to) and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue|We found that human atrial I(to) was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2.	SIGNOR-275566	0.2
NANOG	protein	Q9H9S0	UNIPROT	NANOG	protein	Q9H9S0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16840789	t		Luana	We conclude that the Nanog enhancer activity is regulated by both Sall4 and Nanog. 	SIGNOR-266080	0.2
YY1	protein	P25490	UNIPROT	HSPA5	protein	P11021	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15899857	f		miannu	 YY1, a constitutively expressed multifunctional transcription factor, activates the Grp78 promoter only under ER stress conditions.	SIGNOR-255620	0.309
LPAR4	protein	Q99677	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256785	0.357
lysophosphatidic acids	smallmolecule	CHEBI:32957	ChEBI	LPAR3	protein	Q9UBY5	UNIPROT	up-regulates	chemical activation			9606									16014605	t		gcesareni	Lpa exerts its downstream signaling by binding to the lpa(1), lpa(2), and lpa(3) (formerly edg-2, -4, and -7) family of seven-transmembrane, segmented, heterotrimeric guanine nucleotide-binding protein (g protein)-coupled receptors.	SIGNOR-138585	0.8
ANK1	protein	P16157	UNIPROT	ATP2A1	protein	O14983	UNIPROT	down-regulates activity	binding			9986									28487373	t		lperfetto	We recently reported that small ankyrin 1 (sAnk1) interacts with the sarco(endo)plasmic reticulum Ca2+-ATPase in skeletal muscle (SERCA1) to inhibit its activity.	SIGNOR-265927	0.298
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606	BTO:0000938								9346240	t		lperfetto	Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins	SIGNOR-244148	0.2
AATF	protein	Q9NY61	UNIPROT	KLK3	protein	P07288	UNIPROT	up-regulates quantity by expression	transcriptional regulation												23146908	t	 	 	Chromatin immunoprecipitation in combination with siRNA-mediated knockdown revealed that recruitment of AATF and ZIPK to the PSA enhancer was dependent on AR, whereas recruitment of TSG101 was dependent on AATF.	SIGNOR-253669	0.2
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser733	TVREQDQsFTALDWS	9606			SIGNOR-C14	SIGNOR-C14					10195894	t		lperfetto	Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response	SIGNOR-66344	0.2
GART	protein	P22102	UNIPROT	10-formyltetrahydrofolate(2-)	smallmolecule	CHEBI:57454	ChEBI	down-regulates quantity	chemical modification			9606									11381136	t		miannu	The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR.	SIGNOR-267303	0.8
HIF1A	protein	Q16665	UNIPROT	KDM6B	protein	O15054	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271571	0.27
DVL1	protein	O14640	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	binding			9606									19365405	t		gcesareni	B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1.	SIGNOR-185274	0.565
GNAI1	protein	P63096	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	binding			-1									11007482	t			Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src	SIGNOR-256526	0.463
F10	protein	P00742	UNIPROT	Factor Va-Xa	complex	SIGNOR-C318	SIGNOR	form complex	binding			-1									2026608	t		lperfetto	The binding of factor Xa to factor Va in the presence of Ca2+ ions and phospholipid is fundamental for the activation of prothrombin to thrombin. |Regardless of which protein was labeled, a factor Xa-Va complex (s20,w = 9.8) was formed. The interaction is specific and reversible. I	SIGNOR-263557	0.765
MAPK14	protein	Q16539	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates activity	phosphorylation	Thr293	QSAQSLAtPVVSVAT	9606									9069290	t	The effect has been demonstrated using Q06413-3	lperfetto	We found that in monocytic cells, lps increases the transactivation activity of mef2c through p38-catalysed phosphorylation.	SIGNOR-47136	0.683
MAPK10	protein	P53779	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates	phosphorylation	Ser168	SEMKYLGsPITTVPK	9606									20220133	t		gcesareni	Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset.	SIGNOR-164085	0.247
PDPK2P	protein	Q6A1A2	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation			9606									15505410	t		gcesareni	Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (pdk) 1 and pdk2.	SIGNOR-252628	0.2
CYP26A1	protein	O43174	UNIPROT	all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	down-regulates activity	chemical inhibition			9606									9716180	t		Gianni	The RA-induced CYP26 was shown to be highly specific for the hydroxylation of all-trans-RA and did not recognize the 13-cis and 9-cis isomers. This substrate specificity is promising for finding retinoids that are not recognized by this enzyme and, therefore, could be more effective in growth inhibition of susceptible cancer cells.	SIGNOR-266425	0.8
MMP7	protein	P09237	UNIPROT	DCN	protein	P07585	UNIPROT	down-regulates quantity by destabilization	cleavage	Glu30	GLFDFMLeDEASGIG	-1									9148753	t		miannu	Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.	SIGNOR-256351	0.593
GRK2	protein	P25098	UNIPROT	FPR1	protein	P21462	UNIPROT	down-regulates activity	phosphorylation	Thr336	TQTSDTAtNSTLPSA	-1									7836371	t		gcesareni	Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation.	SIGNOR-249686	0.2
PTEN	protein	P60484	UNIPROT	PIK3CB	protein	P42338	UNIPROT	down-regulates activity				9606									18794881	f		lperfetto	The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)).	SIGNOR-236663	0.671
TP53	protein	P04637	UNIPROT	CCNG1	protein	P51959	UNIPROT	up-regulates quantity by expression	transcriptional regulation												7957050	t		lperfetto	Using a DNA binding assay, a specific p53 binding site was identified upstream from the cyclin G gene, which functioned as a p53-dependent cis-acting element in a transient transfection assay.	SIGNOR-268960	0.782
PDPK1	protein	O15530	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	up-regulates activity	phosphorylation	Thr388	NQAFLGFtYVAPSVL	-1									11733037	t		miannu	 Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities.	SIGNOR-250272	0.595
SCNN1B	protein	P51168	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606									26772908	t		miannu	The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity.	SIGNOR-269276	0.8
P2RY10	protein	O00398	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257005	0.2
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	HR	protein	O43593	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273463	0.8
ETV6	protein	P41212	UNIPROT	HBA1	protein	P69905	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15958056	f	Regulation of expression	miannu	Upon erythropoietin exposure, overexpressed TEL stimulated hemoglobin synthesis 	SIGNOR-251794	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation	Ser73	VGLLKLAsPELERLI	9606									17158707	t		lperfetto	The JNK-mediated phosphorylation of both Ser63 and Ser73 within the transactivation domain of c-Jun (Table _(Table1)1) potentiates its transcriptional activity	SIGNOR-36466	0.2
PRTN3	protein	P24158	UNIPROT	Pr3-ANCA	complex	SIGNOR-C475	SIGNOR	up-regulates activity	binding			9606		BTO:0000133							15972951	t		lperfetto	ANCAs comprise a group of autoantibodies directed against proteins contained in the lysosomal compartments of neutrophils and monocytes. The primary target antigens have been identified as proteinase 3 (Pr3), a 29-kd neutral serine proteinase, and myeloperoxidase (MPO), a 140-kd protein involved in the generation of reactive oxygen species.2 To date, detection of ANCAs has proven to be a helpful diagnostic tool and many clinical studies have confirmed that Pr3-ANCA and MPO-ANCA are highly specific for Wegener's granulomatosis and microscopic polyangiitis, respectively	SIGNOR-270581	0.2
NOTCH4	protein	Q99466	UNIPROT	HEY2	protein	Q9UBP5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12548545	f		gcesareni	Herp1 appears to be important particularly in the development of vascular tissue, and herp1might be regulated by vascular-specific isoforms of ligands and receptors such as dll4 and notch4	SIGNOR-97630	0.601
SF3B1	protein	O75533	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606	BTO:0000664;BTO:0000565								25428262	f		irozzo	Taken together, these data show that SF3B1 knockdown results in inhibition of cell growth, induction of cell cycle arrest and impairment of erythroid differentiation in myeloid cell lines.[…]SF3B1 knockdown compared with the scramble control, suggesting that normal SF3B1 function is required for erythroid differentiation.	SIGNOR-256004	0.7
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT11	protein	O96014	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242721	0.28
RBBP4	protein	Q09028	UNIPROT	MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263837	0.813
LCK	protein	P06239	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000782								17998336	t	inferred from 70% of family members	gcesareni	The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1.	SIGNOR-269899	0.2
CDK1	protein	P06493	UNIPROT	ORC1	protein	Q13415	UNIPROT	up-regulates	phosphorylation	Thr375	AQNEATStPHRIRRK	9606									11931757	t		lperfetto	Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.	SIGNOR-116329	0.621
MAP4K1	protein	Q92918	UNIPROT	MAP4K1	protein	Q92918	UNIPROT	up-regulates	phosphorylation	Thr165	ISAQIGAtLARRLSF	9606	BTO:0000782								15743830	t		gcesareni	Activation of hematopoietic progenitor kinase 1 involves relocation, autophosphorylation, and transphosphorylation by protein kinase d1.	SIGNOR-134490	0.2
Melanotan II	chemical	CID:92432	PUBCHEM	MC3R	protein	P41968	UNIPROT	up-regulates activity	binding					BTO:0000614							17702843	t		lperfetto	Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases.	SIGNOR-253065	0.8
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGB6	protein	Q9Y5F9	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265706	0.2
pipamperone	chemical	CHEBI:78549	ChEBI	HTR2A	protein	P28223	UNIPROT	down-regulates activity	chemical inhibition			10090	BTO:0000331								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258572	0.8
HSD3B2	protein	P26439	UNIPROT	progesterone	smallmolecule	CHEBI:17026	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000048							2243100	t		lperfetto	Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens.	SIGNOR-268634	0.8
PTPN6	protein	P29350	UNIPROT	CSF2RB	protein	P32927	UNIPROT	down-regulates	dephosphorylation	Tyr628	PPPGSLEyLCLPAGG	9606									11812650	t		gcesareni	However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2.	SIGNOR-114597	0.5
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr235	QARKRKRtSIENRVR	9606	BTO:0004180								23041284	t		flangone	Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.	SIGNOR-242092	0.2
F2R	protein	P25116	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257011	0.399
RPS6KA3	protein	P51812	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	phosphorylation			9606									10464286	t		gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-265347	0.2
MAPK12	protein	P53778	UNIPROT	RCSD1	protein	Q6JBY9	UNIPROT	down-regulates activity	phosphorylation	Ser108	LPGASPKsPGLKAMV	-1									15850461	t		miannu	Peptide T2 was sequenced and shown to comprise residues 79–112 of CapZIP, phosphorylated at Ser-108 (Figure 2B). The identity of peptide T1 is unknown. These experiments established that the SAPK3/p38γ substrate was CapZIP. Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown). An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263083	0.519
APOBEC3H	protein	Q6NTF7	UNIPROT	Clearance_of_foreign intracellular_DNA	phenotype	SIGNOR-PH132	SIGNOR	up-regulates				9606									29367246	f		lperfetto	The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24).	SIGNOR-261330	0.7
MAPKAPK2	protein	P49137	UNIPROT	ZFP36	protein	P26651	UNIPROT	down-regulates activity	phosphorylation	Ser184	HPPVLRQsISFSGLP	-1									14688255	t		miannu	We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated.	SIGNOR-250153	0.687
STAT3	protein	P40763	UNIPROT	SOCS3	protein	O14543	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12565872	t			We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells	SIGNOR-253583	0.699
LYN	protein	P07948	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Tyr88	KGSLPEFyYRPPRPP	9606									21423214	t		gcesareni	We previously reported that y88 phosphorylation of p27(kip1) by oncogenic tyrosine kinases impairs p27(kip1)-mediated cdk inhibition, and initiates its ubiquitin-dependent proteasomal degradation.	SIGNOR-172904	0.533
SLC44A2	protein	Q8IWA5	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates				9606									12761501	f		Giorgia	Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways	SIGNOR-260390	0.2
DYRK1A	protein	Q13627	UNIPROT	DNM1	protein	Q05193	UNIPROT	down-regulates	phosphorylation	Ser857	ASPSRPEsPRPPFDL	9606		BTO:0000142							15287745	t		lperfetto	Mnb/dyrk1a was shown to phosphorylate dynamin 1 and alter its interactions with several sh3 domain-containing endocytic accessory proteins.Phosphorylation At s795 and s857 was confirmed in full-length dynamin 1, and s857 was subsequently determined to be the major mnb/dyrk1a phosphorylation site in vitro. Phosphorylation at s857 was demonstrated to be the basis for altering the binding of dynamin 1 to amphiphysin 1 and grb 2 by site-directed mutants mimicking phosphorylation.	SIGNOR-127444	0.426
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SCRIB	protein	Q14160	UNIPROT	unknown	phosphorylation	Ser853	LPLLPPEsPGPLRQR	9606	BTO:0000007								20622900	t		miannu	HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further.	SIGNOR-263065	0.2
CTBP1	protein	Q13363	UNIPROT	CLDN7	protein	O95471	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001570								19277896	t	 	lperfetto	ChIP assays revealed that SNAI1P is recruited on the CLDN7 gene promoter along with the co-repressor CtBP1 and the effector HDAC1.	SIGNOR-254105	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation			9606		BTO:0000763;BTO:0000149							10197981	t	inferred from 70% family members	gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-270065	0.2
CAMK1	protein	Q14012	UNIPROT	PPME1	protein	Q9Y570	UNIPROT	up-regulates activity	phosphorylation	Ser15	MHLGRLPsRPPLPGS	9606	BTO:0002181								24841198	t		miannu	When the CaMKI activity is elevated, it phosphorylates PME-1 at Ser15.	SIGNOR-276636	0.404
SLBP	protein	Q14493	UNIPROT	Histone H2B	proteinfamily	SIGNOR-PF68	SIGNOR	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265375	0.2
MAPK3	protein	P27361	UNIPROT	CIC	protein	Q96RK0	UNIPROT	down-regulates	phosphorylation	Ser1409	SAPEDPTsPKRKMRR	9606	BTO:0000848								21087211	t		gcesareni	Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3	SIGNOR-169879	0.383
GSK3B	protein	P49841	UNIPROT	ATXN3	protein	P54252	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser256	LRRAIQLsMQGSSRN	9606	BTO:0000007								17434145	t		lperfetto	Phosphorylation of ataxin-3 by glycogen synthase kinase 3beta at serine 256 regulates the aggregation of ataxin-3|	SIGNOR-264821	0.478
CAMKK2	protein	Q96RR4	UNIPROT	PRKAA2	protein	P54646	UNIPROT	up-regulates	phosphorylation	Thr172	SDGEFLRtSCGSPNY	9606	BTO:0000567			SIGNOR-C15					19958286	t		gcesareni	These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo.	SIGNOR-161929	0.606
MAPK10	protein	P53779	UNIPROT	ATN1	protein	P54259	UNIPROT	down-regulates activity	phosphorylation	Ser739	EEYETPEsPVPPARS	9606		BTO:0000142							12812981	t		lperfetto	Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment,	SIGNOR-102394	0.2
p38	proteinfamily	SIGNOR-PF16	SIGNOR	TP53BP1	protein	Q12888	UNIPROT	down-regulates activity	phosphorylation	Thr1609	LGPYEAVtPLTKAAD	-1									24703952	t		lperfetto	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK 	SIGNOR-264445	0.2
CyclinD3/CDK6	complex	SIGNOR-C234	SIGNOR	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser88	DSGFCLDsPGPLDSK	9606	BTO:0000017								28192398	t		miannu	We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation. 	SIGNOR-277341	0.615
ABL1	protein	P00519	UNIPROT	PDP1	protein	Q9P0J1	UNIPROT	down-regulates activity	phosphorylation	Tyr94	SILKANEySFKVPEF	10090	BTO:0000944								24962578	t		miannu	Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients. 	SIGNOR-276641	0.271
CHUK	protein	O15111	UNIPROT	BCL3	protein	P20749	UNIPROT	up-regulates activity	phosphorylation	Ser122	CPMEHPLsADIAMAT	-1									28689659	t		miannu	Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA. 	SIGNOR-277362	0.439
furtrethonium	chemical	CHEBI:134764	ChEBI	CHRM1	protein	P11229	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258645	0.8
SMAD7	protein	O15105	UNIPROT	SMURF1	protein	Q9HCE7	UNIPROT	up-regulates activity	binding			9534	BTO:0000298								11278251	t		miannu	Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7. 	SIGNOR-272942	0.877
GSK3B	protein	P49841	UNIPROT	MAFB	protein	Q9Y5Q3	UNIPROT	up-regulates	phosphorylation			9606									18042454	t		miannu	We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.	SIGNOR-159473	0.2
GHSR	protein	Q92847	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257255	0.252
COL6A2	protein	P12110	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									21949456	t			Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present.	SIGNOR-254674	0.7
EEF1A1	protein	P68104	UNIPROT	Gly-tRNA(Gly)	smallmolecule	CHEBI:29156	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269521	0.8
AFF2	protein	P51816	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	up-regulates activity	binding			9606									17135274	t		miannu	Here, we provide the first evidence for a direct role of AF4 in the regulation of transcriptional elongation by RNA polymerase II (Pol II). We demonstrate that mouse Af4 functions as a positive regulator of Pol II transcription elongation factor b (P-TEFb) kinase and, in complex with MLL fusion partners Af9, Enl and Af10, as a mediator of histone H3-K79 methylation by recruiting Dot1 to elongating Pol II. These pathways are interconnected and tightly regulated by the P-TEFb-dependent phosphorylation of Af4, Af9 and Enl which controls their transactivation activity and/or protein stability. 	SIGNOR-266797	0.2
A11/b1 integrin	complex	SIGNOR-C168	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257710	0.553
BDKRB2	protein	P30411	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257399	0.2
FPR1	protein	P21462	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256682	0.409
HTR2A	protein	P28223	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256742	0.355
CSNK2A1	protein	P68400	UNIPROT	AQP4	protein	P55087	UNIPROT	down-regulates activity	phosphorylation	Ser285	MEVEDNRsQVETDDL	9615	BTO:0000837								11742978	t		llicata	We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4-Cter proteins in which only one out of the three C-terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. 	SIGNOR-250827	0.426
ixabepilone	chemical	CHEBI:63605	ChEBI	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	down-regulates activity	chemical inhibition			9606									18945860	t		miannu	Ixabepilone, the first drug in a new class of microtubule-stabilizing agents called epothilones, offers a new treatment option for patients with metastatic or locally advanced breast cancer who are refractory to standard chemotherapy.	SIGNOR-259450	0.8
BIRC2	protein	Q13490	UNIPROT	TRAF2	protein	Q12933	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									20651737	t		lperfetto	Engagement of cd40 with its ligand cd40l results in the recruitment of the TRAF3/TRAF2/cIAP Complex to the receptor. At the receptor, traf3 undergoes ciap-dependent k48-linked polyubiquitylation (ub) that targets it for proteasomal degradation. In the absence of traf3, nik protein levels accumulate as it can no longer be recruited to the TRAF2/cIAP Complex.	SIGNOR-167057	0.868
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	up-regulates quantity	transcriptional regulation			9606	BTO:0000889								17785433	t			Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration	SIGNOR-267494	0.363
MMP13	protein	P45452	UNIPROT	FGG	protein	P02679	UNIPROT	down-regulates quantity by destabilization	cleavage	Tyr27	LSSTCVAyVATRDNC	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain 	SIGNOR-263614	0.2
AURKB	protein	Q96GD4	UNIPROT	INCENP	protein	Q9NQS7	UNIPROT	up-regulates	phosphorylation	Ser894	RYHKRTSsAVWNSPP	9606									12925766	t		gcesareni	Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites.	SIGNOR-118015	0.973
DAPK3	protein	O43293	UNIPROT	DAPK3	protein	O43293	UNIPROT	up-regulates	phosphorylation	Thr306	TTRLKEYtIKSHSSL	9606									15611134	t		lperfetto	Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311	SIGNOR-132475	0.2
IRF8	protein	Q02556	UNIPROT	NCF2	protein	P19878	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001412								11483597	f		miannu	we found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP.	SIGNOR-222789	0.298
GYPB	protein	P06028	UNIPROT	Ankyrin complex	complex	SIGNOR-C383	SIGNOR	form complex	binding			9606	BTO:0000424								22465511	t		lperfetto	The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) 	SIGNOR-266021	0.374
TKT	protein	P29401	UNIPROT	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	chemical modification			9606									24929114	t		miannu	Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates.	SIGNOR-267088	0.8
IRS2	protein	Q9Y4H2	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates activity	binding			9606									22810696	t		lperfetto	These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients.	SIGNOR-251492	0.672
FRK	protein	P42685	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr444	QQNRFPDyLEAIPGT	9606	BTO:0002035								35723276	t		miannu	Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP. 	SIGNOR-275457	0.278
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1717	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120020	0.781
BIRC2	protein	Q13490	UNIPROT	UBE2J1	protein	Q9Y385	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								28321712	t		miannu	We also found that ubiquitin-ligase (E3), c-IAP1 preferentially interacts with phosphorylated Ube2j1. Moreover, we noticed that phosphorylated Ube2j1 is rapidly degraded by the proteasome during ER stress cell recovery. Taken together, these data suggest that Ube2j1 and its phosphorylation is important for transient ER stress cell recovery and the phosphorylated Ube2j1 is degraded by the proteasome.	SIGNOR-263092	0.377
CDK1	protein	P06493	UNIPROT	HMGA1	protein	P17096	UNIPROT	down-regulates	phosphorylation	Thr78	KTRKTTTtPGRKPRG	9606									1939057	t		lperfetto	Phosphorylation of the dna-binding domain of nonhistone high-mobility group i protein by cdc2 kinase: reduction of binding affinity	SIGNOR-22338	0.392
PDGFRB	protein	P09619	UNIPROT	RASA1	protein	P20936	UNIPROT	up-regulates	binding			9606									11896619	t		miannu	The gtpase activating protein (gap) of ras binds only to beta-receptors / we have previously shown that the binding site for gtpase activating protein of ras (rasgap) in the pdgf beta-receptor, tyr771, is phosphorylated to a much lower extent in the heterodimeric configuration of pdgf alpha- and beta-receptors, compared to the pdgf beta-receptor homodimer. / the decreased recruitment of the rasgap to the receptor leads to prolonged activation of the ras/map kinase pathway	SIGNOR-115843	0.561
P2RY6	protein	Q15077	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257189	0.2
HNF1B	protein	P35680	UNIPROT	AKR1C4	protein	P17516	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003846								2044952	f	2	miannu	Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene.HNF-1_ binds to the target element in the rat DBP gene in the liver, while vHNF-1 recognizes a target element in extrahepatic tissues. The ability of vHNF-1-A to activate the rat DBP gene is much higher than that of vHNF-1-C.	SIGNOR-239960	0.2
MAPK14	protein	Q16539	UNIPROT	DDIT3	protein	P35638	UNIPROT	up-regulates activity	phosphorylation	Ser79	EVTSTSQsPHSPDSS	9606									8650547	t		lperfetto	...undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, chop is phosphorylated on these residues by p38 mitogen-activated protein kinase (map kinase). phosphorylation of chop on these residues enhanced its ability to function as a transcriptional activator.	SIGNOR-42200	0.593
CDK1	protein	P06493	UNIPROT	INCENP	protein	Q9NQS7	UNIPROT	up-regulates	phosphorylation	Thr412	DTEIANStPNPKPAA	9606									16378098	t		gcesareni	Here, we report that cdk1 phosphorylates thr 59 and thr 388 on inner centromere protein (incenp), which regulates the localization and kinase activity of aurora-b from prophase to metaphase. The replacement of endogenous incenp with t388a resulted in the delay of progression from metaphase to anaphase.	SIGNOR-143387	0.75
PRKG1	protein	Q13976	UNIPROT	TRPC7	protein	Q9HCX4	UNIPROT	up-regulates activity	phosphorylation	Thr15	KNMQRRHtTLREKGR	9534	BTO:0000298								21402151	t		miannu	In vitro and in vivo kinase assays have revealed that cGK-Iα phosphorylates mouse TRPC7 but not mouse TRPC3. Site-directed mutagenesis analysis revealed that TRPC7 was phosphorylated by cGK-Iα at threonine 15. Phosphorylation of TRPC7 significantly suppressed carbachol-induced calcium influx and CREB phosphorylation. These data indicate that cGK-Iα interacts with and phosphorylates TRPC7, contributing to the quick and accurate regulation of calcium influx and CREB phosphorylation.	SIGNOR-263184	0.2
Angiotensin-1	protein	P01019-PRO_0000032457	UNIPROT	ACE2	protein	Q9BYF1	UNIPROT	up-regulates activity	binding			9606									32201502	t		miannu	 At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function.	SIGNOR-260226	0.2
FANCF	protein	Q9NPI8	UNIPROT	Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	form complex	binding			9606	BTO:0000567								17396147	t		lperfetto	This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo 	SIGNOR-263242	0.906
RAB6B	protein	Q9NRW1	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				10116									25492866	f		miannu	Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons	SIGNOR-266874	0.7
ARID5B	protein	Q14865	UNIPROT	PHF2	protein	O75151	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								21532585	t		miannu	 We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity.	SIGNOR-264515	0.543
TBX22	protein	Q9Y458	UNIPROT	DLX5	protein	P56178	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9031	BTO:0005956								20033915	t		miannu	 the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22. 	SIGNOR-265566	0.313
SMAD3	protein	P84022	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11689553	t		lperfetto	Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter.	SIGNOR-251494	0.673
CPT1B	protein	Q92523	UNIPROT	palmitoyl-CoA(4-)	smallmolecule	CHEBI:57379	ChEBI	down-regulates quantity	chemical modification			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267127	0.8
FES	protein	P07332	UNIPROT	PECAM1	protein	P16284	UNIPROT	up-regulates activity	phosphorylation	Tyr690	PLNSDVQyTEVQVSS	9606	BTO:0000007								12972546	t		miannu	PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1.	SIGNOR-262867	0.28
CDC14A	protein	Q9UNH5	UNIPROT	SPAG5	protein	Q96R06	UNIPROT	down-regulates activity	dephosphorylation			9606									27325694	t		miannu	We also demonstrate that Cdc14A dephosphorylates Astrin, and therefore the overexpression of Cdc14A sequesters Astrin in the centrosome and results in aberrant chromosome alignment.	SIGNOR-277066	0.2
Diprenorphine	chemical	CHEBI:4650	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258790	0.8
LRRK2	protein	Q5S007	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0000938								24916379	t		lperfetto	Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling	SIGNOR-205115	0.387
MAPK1	protein	P28482	UNIPROT	RUNX1	protein	Q01196	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser266	QYLGSIAsPSVHPAT	9606	BTO:0002181								16046550	t		miannu	We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 	SIGNOR-268219	0.2
SLC2A1	protein	P11166	UNIPROT	glucose	chemical	CHEBI:17234	ChEBI	up-regulates quantity	relocalization			9606									23506862	t		miannu	GLUT1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells.	SIGNOR-267460	0.8
SMURF	proteinfamily	SIGNOR-PF29	SIGNOR	SMAD7	protein	O15105	UNIPROT	down-regulates activity	ubiquitination			9606									12519765	t		lperfetto	Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ubiquitin ligase, interacts with inhibitory Smad7 and induces translocation of Smad7 to the cytoplasm	SIGNOR-253260	0.2
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	PAX7	protein	P23759	UNIPROT	up-regulates quantity by expression				9606		BTO:0001103;BTO:0002314							22493066	f		gcesareni	We provide evidence that notch and deltex may act on e47 by inhibiting signaling through ras because (i) full e47 activity was found to be dependent on ras and (ii) both notch and deltex inhibited gal4-jun, a hybrid transcription factor whose activity is dependent on signaling from ras to sapk/jnk.	SIGNOR-254343	0.2
NEDD4L	protein	Q96PU5	UNIPROT	SCN10A	protein	Q9Y5Y9	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000938								23778145	t		miannu	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 	SIGNOR-253463	0.326
BAIAP2	protein	Q9UQB8	UNIPROT	WASF2	protein	Q9Y6W5	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								11130076	t		miannu	 Here we demonstrate that IRSp53, a substrate for insulin receptor with unknown function, is the 'missing link' between Rac and WAVE. Activated Rac binds to the amino terminus of IRSp53, and carboxy-terminal Src-homology-3 domain of IRSp53 binds to WAVE to form a trimolecular complex. From studies of ectopic expression, we found that IRSp53 is essential for Rac to induce membrane ruffling, probably because it recruits WAVE, which stimulates actin polymerization mediated by the Arp2/3 complex.	SIGNOR-265556	0.794
FOXO6	protein	A8MYZ6	UNIPROT	IDH1	protein	O75874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25648147	t		miannu	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260103	0.2
FLT1	protein	P17948	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	phosphorylation	Tyr320	RKDTKEIyTHFTCAT	-1									33139573	t		miannu	RTKs directly phosphorylate Gαi on Y154, 155, and Y320.	SIGNOR-277231	0.26
RALGDS	protein	Q12967	UNIPROT	RIN1	protein	Q13671	UNIPROT	up-regulates activity	binding			9606									10545207	t		miannu	Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors.	SIGNOR-220923	0.511
RASGEF1B	protein	Q0VAM2	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates	binding			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183835	0.301
SLC24A3	protein	Q9HC58	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264401	0.8
BTK	protein	Q06187	UNIPROT	BMX	protein	P51813	UNIPROT	up-regulates	phosphorylation	Tyr224	DSNSKKIyGSQPNFN	9606									12573241	t		lperfetto	Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. For bmx, we obtained two phosphorylated sites, y215 and y223 (fig. 6c). The bmx-y215 is a conserved tyrosine, which is homologous to btk-y223 and itk-y180	SIGNOR-98032	0.34
SRC	protein	P12931	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates	phosphorylation	Tyr247	VKGKSDPyHATSGAL	9606									16916748	t		lperfetto	The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites.	SIGNOR-148913	0.608
FOXO1	protein	Q12778	UNIPROT	IDH1	protein	O75874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25648147	t		miannu	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260101	0.261
NPFFR1	protein	Q9GZQ6	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256987	0.252
PRKACA	protein	P17612	UNIPROT	CACNA1C	protein	Q13936	UNIPROT	up-regulates activity	phosphorylation	Ser1897	LLRKANPsRCHSRES	10090									28119464	t			These findings reveal an essential role for _1C phosphorylation at Ser1928 in stimulating CaV1.2 channel activity and vasoconstriction by AKAP-targeted PKA upon exposure to increased glucose and in diabetes	SIGNOR-251709	0.479
EZH2	protein	Q15910	UNIPROT	SSTR1	protein	P30872	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004094								22144423	f	 	miannu	 For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci.	SIGNOR-254143	0.2
WWC1	protein	Q8IX03	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	up-regulates activity				9606	BTO:0000007								20159598	f	Hippo pathway	Gianni	These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis.	SIGNOR-269951	0.455
MAP2K6	protein	P52564	UNIPROT	MAPK12	protein	P53778	UNIPROT	up-regulates	phosphorylation	Thr183	RQADSEMtGYVVTRW	9606									19230643	t		gcesareni	Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily . the p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms . p38mapks are activated by dual phosphorylation on a t-x-y motif in the activation loop through the action of map kinase kinases	SIGNOR-184134	0.644
Riluzole	chemical	CHEBI:8863	ChEBI	UGT1A1	protein	P22309	UNIPROT	down-regulates activity	chemical inhibition			9606									21030469	t		Luana	Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation.	SIGNOR-258053	0.8
ME1	protein	P48163	UNIPROT	NADPH(4-)	smallmolecule	CHEBI:57783	ChEBI	up-regulates quantity	chemical modification			9606									24769394	t		miannu	The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle	SIGNOR-267055	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PDE4D	protein	Q08499	UNIPROT	up-regulates activity	phosphorylation	Ser125	CRAMDRTsYAVETGH	9534									12023945	t		miannu	Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5.	SIGNOR-273939	0.2
(S)-(-)-sulpiride	chemical	CHEBI:64119	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029									8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258734	0.8
linifanib	chemical	CHEBI:91435	ChEBI	CSF1R	protein	P07333	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258241	0.8
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1644	SPTSPSYsPTSPSYS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248781	0.441
BRIP1	protein	Q9BX63	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates activity	binding			9606	BTO:0000093;BTO:0003323								11301010	t		irozzo	BRCA1 interacts in vivo with a novel protein, BACH1, a member of the DEAH helicase family. BACH1 binds directly to the BRCT repeats of BRCA1. Moreover, BACH1 likely contributes to the DNA repair function of BRCA1 [].	SIGNOR-259185	0.787
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	EZR	protein	P15311	UNIPROT	up-regulates	phosphorylation	Thr567	QGRDKYKtLRQIRQG	9606									15531580	t		lperfetto	Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression	SIGNOR-244263	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	FGFR1	protein	P11362	UNIPROT	down-regulates	phosphorylation			9606									23405013	t	inferred from 70% family members	lperfetto	Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling	SIGNOR-270013	0.2
FGF13	protein	Q92913	UNIPROT	SCN11A	protein	Q9UI33	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253435	0.2
DUSP3	protein	P51452	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Tyr187	HTGFLTEyVATRWYR	9534	BTO:0004055								10224087	t			Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2	SIGNOR-248536	0.658
PLK3	protein	Q9H4B4	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9606									18650425	t		gcesareni	Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun.	SIGNOR-179551	0.379
MAGED1	protein	Q9Y5V3	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates				9606	BTO:0000222	BTO:0000887							20646279	f		gcesareni	These data demonstrate for the first time that maged1 is an important factor required for proper skeletal myoblast differentiation and muscle healing.	SIGNOR-166896	0.7
vasopressin	smallmolecule	CHEBI:9937	ChEBI	AVPR1A	protein	P37288	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257461	0.8
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									23431053	t		lperfetto	Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ	SIGNOR-230750	0.419
PDPK1	protein	O15530	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Thr308	KDGATMKtFCGTPEY	9606		BTO:0000142							10226025	t		acerquone	Protein kinase b (pkb) is activated by phosphorylation of thr308 and of ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (pdk1) but the identity of the kinase that phosphorylates ser473 (provisionally termed pdk2) is unknown.	SIGNOR-67363	0.736
CSNK2A2	protein	P19784	UNIPROT	GTF2A1L	protein	Q9UNN4	UNIPROT	up-regulates activity	phosphorylation	Ser357	DGSGDTSsNEEIGST	-1									12107178	t		llicata	ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.	SIGNOR-250992	0.424
EIF1AY	protein	O14602	UNIPROT	Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	up-regulates activity	relocalization			9606									12514125	t		lperfetto	Translation initiation factor 1A (eIF1A) is predicted to bind in the decoding site of the 40S ribosome and has been implicated in recruitment of the eIF2-GTP-Met-tRNA i Met ternary complex (TC) and ribosomal scanning. 	SIGNOR-269148	0.2
STK4	protein	Q13043	UNIPROT	MOB1A	protein	Q9H8S9	UNIPROT	up-regulates	phosphorylation	Thr35	LLKHAEAtLGSGNLR	9606									23431053	t		milica	Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity	SIGNOR-201310	0.896
ILK	protein	Q13418	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA	-1									11313365	t		miannu	ILK Phosphorylates PKB/Akt on Serine 473 To become fully activated, PKB/Akt requires phosphorylation at two sites, threonine 308 and serine 473, in a phosphatidylinositol (PI) 3-kinase-dependent manner.	SIGNOR-252596	0.771
PRKCA	protein	P17252	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	phosphorylation	Ser259	FPLRKTAsEPNLKVR	10116	BTO:0002320								15367659	t		lperfetto	We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. | Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E	SIGNOR-249268	0.2
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1654	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120004	0.781
PAK2	protein	Q13177	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates	phosphorylation			9606									16837009	t		gcesareni	A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinasesa key step in the activation process is the phosphorylation of the activation loop of one pak kinase domain by another, but little is known about the underlying recognition events that make this phosphorylation specific.	SIGNOR-147874	0.2
CBP/p300	complex	SIGNOR-C6	SIGNOR	SMAD3	protein	P84022	UNIPROT	up-regulates activity	acetylation			9606									9865691	t		lperfetto	The closely related CBP and p300 proteins are also important coactivators for Smad activity. CBP and p300 act as coactivators of several transcription factors by bringing the sequence-specific activators within proximity of the general transcription machinery and by modifying the chromatin structure through histone acetylation.In response to TGF-b, Smad3 associates with CBP/p300 and TGF-b-induced C-terminal phosphorylation of Smad3 promotes this association. This association with CBP/p300 is likely to be essential for transcriptional activity of Smad3.	SIGNOR-227553	0.682
PIM1	protein	P11309	UNIPROT	MARK3	protein	P27448	UNIPROT	down-regulates	phosphorylation	Ser96	KTQLNPTsLQKLFRE	9606									15319445	t		gcesareni	Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1.	SIGNOR-128260	0.427
SIAH1	protein	Q8IUQ4	UNIPROT	SNCAIP	protein	Q9Y6H5	UNIPROT	down-regulates	ubiquitination			9606									16174773	t		lperfetto	Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system	SIGNOR-140612	0.662
CDKN2C	protein	P42773	UNIPROT	CDK6	protein	Q00534	UNIPROT	down-regulates	binding			9606									8891723	t		miannu	The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb.	SIGNOR-44601	0.875
AKT1	protein	P31749	UNIPROT	MAPKAP1	protein	Q9BPZ7	UNIPROT	up-regulates activity	phosphorylation	Thr86	GIRRRSNtAQRLERL	10090	BTO:0002572								26235620	t		miannu	Akt phosphorylates SIN1 at T86, enhancing mTORC2 kinase activity, which leads to phosphorylation of Akt S473 by mTORC2, thereby catalyzing full activation of Akt.	SIGNOR-276932	0.691
APC-c	complex	SIGNOR-C150	SIGNOR	IRS2	protein	Q9Y4H2	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								32554797	t		miannu	We conducted an unbiased proteomic screen to uncover novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that controls the abundance of key cell cycle regulators. We found that IRS2 levels are regulated by APC/C activity and that IRS2 is a direct APC/C target in G1 Consistent with the APC/C's role in degrading cell cycle regulators. Consistent with this observation, we found that APC/C inhibition decreased the polyubiquitylation of HA-tagged IRS2 in HeLa cells treated with MG132 (Fig. 2G).	SIGNOR-272196	0.2
HIF1A	protein	Q16665	UNIPROT	KDM4C	protein	Q9H3R0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271570	0.2
CDC25A	protein	P30304	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates activity	dephosphorylation	Tyr15	EKIGEGTyGVVYKAR	9606									10454565	t			The phosphatase activity of Cdc25A is necessary for Cdk2 activation, most likely due to dephosphorylation on Tyr-15 and Thr-14 of Cdk2.	SIGNOR-248482	0.824
F2RL1	protein	P55085	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257144	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SOS1	protein	Q07889	UNIPROT	down-regulates activity	phosphorylation			9606		BTO:0000763;BTO:0000149							20724475	t		lperfetto	ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. 	SIGNOR-244591	0.2
PRKCZ	protein	Q05513	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser249	ARTFSRMsLLHKHQE	9606	BTO:0001939								30804505	t		miannu	APKC kinases phosphorylate S249 of SNAI1, which leads to protein degradation.	SIGNOR-277437	0.2
CASP8	protein	Q14790	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates activity	cleavage	Asp333	DTVAENDdGGFSEEW	-1									10069390	t		lperfetto	Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.	SIGNOR-261754	0.376
CCAN complex	complex	SIGNOR-C365	SIGNOR	Spindle_assembly	phenotype	SIGNOR-PH60	SIGNOR	up-regulates				9606									18007590	f		lperfetto	Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis.	SIGNOR-265214	0.7
PTPRB	protein	P23467	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									10734133	t		gcesareni	Identification of tyrosine phosphatases that dephosphorylate the insulin receptor.	SIGNOR-75997	0.349
PRKACA	protein	P17612	UNIPROT	GJA5	protein	P36382	UNIPROT	up-regulates activity	phosphorylation	Ser345	HSDKRRLsKASSKAR	9606	BTO:0003477								10728420	t		miannu	Gap junction channels formed of Cx40 are modulated by protein-kinase-A-mediated phosphorylation. Macroscopic conductance and permeability of Cx40 gap junctions is strongly increased by cAMP. two serine residues that can be phosphorylated by PKA, S120 and S345	SIGNOR-249982	0.311
EXOSC5	protein	Q9NQT4	UNIPROT	Exosome_Complex	complex	SIGNOR-C255	SIGNOR	form complex	binding			-1									24189234	t		miannu	The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 	SIGNOR-261385	0.925
ATG7	protein	O95352	UNIPROT	MAP1LC3A	protein	Q9H492	UNIPROT	up-regulates	binding			9606									22170151	t		gcesareni	Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe	SIGNOR-195236	0.867
DAB2IP	protein	Q5VWQ8	UNIPROT	PROX1	protein	Q92786	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									27476001	f		miannu	DAB2IP regulates EMT and metastasis of prostate cancer through targeting PROX1 transcription and destabilizing HIF1α protein. In this study, based on different PCa cell lines and knockout mice, we showed that PROX1 could be suppressed by DAB2IP, a novel member of the Ras GTPase-activating protein family and a critical player in control of epithelial-mesenchymal transition (EMT) and PCa metastasis. 	SIGNOR-254764	0.2
MTHFR	protein	P42898	UNIPROT	(6R)-5,10-methylenetetrahydrofolate(2-)	smallmolecule	CHEBI:15636	ChEBI	down-regulates quantity	chemical modification			9606									10720211	t		lperfetto	Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine.	SIGNOR-268228	0.8
PPP5C	protein	P53041	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	dephosphorylation	Ser338	RPRGQRDsSYYWEIE	-1									16892053	t			Protein phosphatase 5 (PP5) was identified as an inactivator that associates with Raf-1 on growth factor stimulation and selectively dephosphorylates an essential activating site, Ser 338. The PP5-mediated dephosphorylation of Ser 338 inhibited Raf-1 activity and downstream signalling to MEK	SIGNOR-248537	0.438
AKT1	protein	P31749	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser328	QDAYRRNsVRFLQQR	9606	BTO:0000130								10559253	t		esanto	Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis.	SIGNOR-252587	0.577
PRKAA1	protein	Q13131	UNIPROT	CRTC1	protein	Q6UUV9	UNIPROT	down-regulates	phosphorylation			9606			SIGNOR-C15						21331044	t		gcesareni	Here we show that both ampk and calcineurin modulate longevity exclusively through post-translational modification of crtc-1, the sole c. elegans crtc. We demonstrate that crtc-1 is a direct ampk target.	SIGNOR-172136	0.289
ATM	protein	Q13315	UNIPROT	WRN	protein	Q14191	UNIPROT	unknown	phosphorylation	Ser1292	MTIGMHLsQAVKAGC	-1									10608806	t		llicata	We determined a general phosphorylation consensus sequence for ATM and identified putative in vitro targets by using glutathione S-transferase peptides as substrates. Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself.	SIGNOR-250578	0.821
PELI1	protein	Q96FA3	UNIPROT	BIRC3	protein	Q13489	UNIPROT	up-regulates quantity by stabilization	ubiquitination			9606	BTO:0002552								27248820	t		miannu	Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity.	SIGNOR-259395	0.467
NLRP1	protein	Q9C000	UNIPROT	NLRP1 inflammasome	complex	SIGNOR-C224	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256407	0.631
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	GRB2	protein	P62993	UNIPROT	down-regulates activity	phosphorylation	Tyr209	TGMFPRNyVTPVNRN	9606	BTO:0000007								20554525	t		lperfetto	More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway.	SIGNOR-246281	0.2
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	small nuclear RNA	smallmolecule	CHEBI:74035	ChEBI	up-regulates quantity	chemical modification												27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-266144	0.8
GDNF	protein	P39905	UNIPROT	NRN1	protein	Q9NPD7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252183	0.263
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1913	SPKYSPTsPTYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120240	0.321
CoREST-HDAC complex	complex	SIGNOR-C105	SIGNOR	SCN3A	protein	Q9NY46	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								16140033	f		lperfetto	This suggests that the HDACs in the LSD1 complex are likely to function upstream of CoREST/LSD1, generating a hypoacetylated histone substrate, which can then be better recognized by CoREST/LSD1. Further supporting this model, we found that inhibition of HDAC activity by TSA resulted in derepression of two LSD1 target genes, the human neuronal-specific sodium channel (SCN) genes, SCNA2 and SCNA3 (Figure 1H).	SIGNOR-268542	0.252
FOXO3	protein	O43524	UNIPROT	DIO2	protein	Q92813	UNIPROT	up-regulates quantity by expression	transcriptional regulation												20978344	f			Forkhead box O3 (FoxO3) was identified as a key molecule inducing D2 expression and thereby increasing intracellular T3 production. Accordingly, FoxO3-depleted primary myoblasts also had a differentiation deficit that could be rescued by high levels of T3.	SIGNOR-256204	0.35
PPP2CB	protein	P62714	UNIPROT	PRKCD	protein	Q05655	UNIPROT	down-regulates activity	dephosphorylation	Ser645	LNEKARLsYSDKNLI	10090	BTO:0000944								11959144	t			PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex	SIGNOR-248595	0.304
GABA-A (a4-b2-d) receptor	complex	SIGNOR-C326	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000227							18790874	f	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263774	0.7
JAK2	protein	O60674	UNIPROT	EPOR	protein	P19235	UNIPROT	up-regulates activity	phosphorylation	Tyr504	AEPLPPSyVACS										12441334	t			JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2	SIGNOR-251355	0.806
CDK5R1	protein	Q15078	UNIPROT	CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	form complex	binding			9606									11331872	t		lperfetto	Induced p35 forms a complex with Cdk5 and activates its kinase activity	SIGNOR-250682	0.942
AXL	protein	P30530	UNIPROT	AXL	protein	P30530	UNIPROT	up-regulates activity	phosphorylation	Tyr779	ADCLDGLyALMSRCW	-1									9178760	t		llicata	Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins	SIGNOR-250591	0.2
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2S	protein	Q16763	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271309	0.763
CAMK2A	protein	Q9UQM7	UNIPROT	CREB1	protein	P16220	UNIPROT	down-regulates	phosphorylation	Ser142	RKILNDLsSDAPGVP	9606	BTO:0000938								11970864	t		gcesareni	Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer.	SIGNOR-117344	0.576
AR	protein	P10275	UNIPROT	ARG2	protein	P78540	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20711410	f	 	 	 The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. This observation was correlated in vivo in patients by immunohistochemistry.	SIGNOR-253671	0.266
SHANK3	protein	Q9BYB0	UNIPROT	GRIA2	protein	P42262	UNIPROT	up-regulates quantity	binding			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264602	0.2
MST1R	protein	Q04912	UNIPROT	ABL1	protein	P00519	UNIPROT	up-regulates activity	phosphorylation												35569509	t		lperfetto	This suggests that by interacting with Sdc4, either directly or indirectly, RON is activated via transphosphorylation when clustered, engages the ABL1 SH2 domain, and activates ABL1 by phosphorylation.	SIGNOR-272999	0.276
ARPC5	protein	O15511	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	form complex	binding			9606									12479800	t			The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc	SIGNOR-251518	0.959
DHCR24	protein	Q15392	UNIPROT	DHCR7	protein	Q9UBM7	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								25637936	t		miannu	DHCR7 coimmunoprecipitates DHCR24. Overexpression of functional DHCR24 increases DHCR7 activity. Because knockdown of DHCR24 has no effect on DHCR7 mRNA (Fig. 3A), this implies that this phenomenon is occurring posttranscriptionally. Thus, the interaction between the two terminal steps of cholesterol synthesis appears to have functional consequences.	SIGNOR-267249	0.64
TBXA2R	protein	P21731	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256744	0.252
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser262	TFRPRSSsNASSVST	9606									16272144	t		lperfetto	Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression	SIGNOR-252854	0.908
RET	protein	P07949	UNIPROT	RET	protein	P07949	UNIPROT	up-regulates	phosphorylation	Tyr806	PLLLIVEyAKYGSLR	9606									14711813	t		llicata	Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. these facts suggest that tyr806 and tyr809, located in this unique position, play a novel supplemental role for the activation loop upon phosphorylation.	SIGNOR-121153	0.2
PAK2	protein	Q13177	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates activity	phosphorylation	Ser197	TKSIYTRsVIDPVPA	-1									10075701	t		miannu	Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites	SIGNOR-250226	0.2
L-cysteine zwitterion	smallmolecule	CHEBI:35235	ChEBI	pyruvate	smallmolecule	CHEBI:15361	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000671;BTO:0000759;BTO:0002688							19961860	t		lperfetto	 the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production.	SIGNOR-275815	0.8
SRP54	protein	P61011	UNIPROT	SRSF2	protein	Q01130	UNIPROT	up-regulates activity	binding			-1									8816452	t		Monia	We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65).	SIGNOR-261160	0.349
PRC1	protein	O43663	UNIPROT	CENPE	protein	Q02224	UNIPROT	up-regulates activity	binding			9606									15297875	t		miannu	These data indicate that PRC1 binds to KIF4, MKLP1 and CENP-E during late mitosis; however, it apparently does not interact simultaneously with more than one of these motor proteins.	SIGNOR-265990	0.601
BMI1	protein	P35226	UNIPROT	Polycomb repressive complex 1	complex	SIGNOR-C408	SIGNOR	form complex	binding			9606									31608994	t		miannu	PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b	SIGNOR-266812	0.787
PAK	proteinfamily	SIGNOR-PF13	SIGNOR	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000567								16129686	t		lperfetto	Inhibition of pak kinase activity dramatically decreased phosphorylation of mek1 at ser(298) in response to either pdgf or egf.	SIGNOR-244920	0.564
MCRS1	protein	Q96EZ8	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270844	0.504
SRC	protein	P12931	UNIPROT	TERT	protein	O14746	UNIPROT	down-regulates	phosphorylation	Tyr707	QDPPPELyFVKVDVT	9606									12808100	t		lperfetto	Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via src kinase family-dependent phosphorylation of tyrosine 707	SIGNOR-102097	0.428
ABL1	protein	P00519	UNIPROT	PSTPIP1	protein	O43586	UNIPROT	unknown	phosphorylation	Tyr345	PERNEGVyTAIAVQE	10090	BTO:0004055								11163214	t		gcesareni	These data suggest that Tyr-344 is a major c-Abl phosphorylation site, or that phosphorylation of Tyr-344 is required for subsequent phosphorylation at other tyrosine residues.	SIGNOR-246219	0.616
MAPK8	protein	P45983	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606									11896587	t		llicata	These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells.	SIGNOR-115831	0.79
AKT2	protein	P31751	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates activity	phosphorylation	Ser167	GGRERLAsTNDKGSM	9534	BTO:0001538								11139588	t			AKT activate ERalpha in the absence of estrogen. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT.	SIGNOR-251490	0.524
EIF2B1	protein	Q14232	UNIPROT	Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269139	0.758
WDR59	protein	Q6PJI9	UNIPROT	GATOR2	complex	SIGNOR-C193	SIGNOR	form complex	binding			9606									23723239	t		miannu	Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5	SIGNOR-255303	0.828
UBE3A	protein	Q05086	UNIPROT	PSMB1	protein	P20618	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								28559284	t		lperfetto	Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits.	SIGNOR-265131	0.363
SMAD6	protein	O43541	UNIPROT	BMPR1A	protein	P36894	UNIPROT	down-regulates				10090	BTO:0000165								10564272	f		gcesareni	We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2	SIGNOR-236861	0.727
CSNK2A1	protein	P68400	UNIPROT	SLC18A2	protein	Q05940	UNIPROT	unknown	phosphorylation	Ser513	GEDEESEsD	-1									9045708	t		llicata	Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. 	SIGNOR-250952	0.351
PHLPP2	protein	Q6ZVD8	UNIPROT	AKT2	protein	P31751	UNIPROT	down-regulates activity	dephosphorylation	Ser474	RTHFPQFsYSASIRE	9606	BTO:0001544								19261608	t			The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.	SIGNOR-248729	0.588
SMARCE1	protein	Q969G3	UNIPROT	Brain-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C486	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270752	0.791
CARD11	protein	Q9BXL7	UNIPROT	CBM	complex	SIGNOR-C555	SIGNOR	form complex	binding			9606									15122200	t		miannu	CARMA1, the adaptor protein BCL-10 (B-cell lymphoma 10) and the caspase-like protein MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) form a signalling complex that has a key role in antigen-receptor-mediated activation of the nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK) pathways.	SIGNOR-276296	0.82
PRTN3	protein	P24158	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Thr57	GKGVTVEtVFSVDEF	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263595	0.381
CASP3	protein	P42574	UNIPROT	Muscle_atrophy	phenotype	SIGNOR-PH40	SIGNOR	up-regulates				10090									25787076	f		miannu	The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice	SIGNOR-255336	0.7
NBN	protein	O60934	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates	binding			9606									18854157	t		gcesareni	Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm	SIGNOR-181631	0.852
CDK8	protein	P49336	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	phosphorylation			9606									15546612	t		gcesareni	Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.	SIGNOR-130640	0.534
CITED2	protein	Q99967	UNIPROT	MMP13	protein	P45452	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003859								12960175	f		miannu	 CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway.	SIGNOR-253777	0.378
IL1R1	protein	P14778	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates activity				9606									9625767	f		lperfetto	Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab)	SIGNOR-249512	0.507
CSNK2A1	protein	P68400	UNIPROT	DDIT3	protein	P35638	UNIPROT	down-regulates activity	phosphorylation	Ser14	PFSFGTLsSWELEAW	9606	BTO:0000567								12876286	t		llicata	CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites 	SIGNOR-250850	0.35
DLGAP2	protein	Q9P1A6	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								9115257	t		miannu	SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.	SIGNOR-264210	0.692
PTPRJ	protein	Q12913	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	dephosphorylation	Tyr530	FTSTEPQyQPGENL	10116									15735685	t			The rat tyrosine phosphatase eta increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue	SIGNOR-248705	0.622
GGCX	protein	P38435	UNIPROT	F10	protein	P00742	UNIPROT	up-regulates activity	carboxylation	Glu59	HLERECMeETCSYEE	-1									9538022	t		lperfetto	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263668	0.598
TRIM27	protein	P14373	UNIPROT	STK38L	protein	Q9Y2H1	UNIPROT	up-regulates activity	ubiquitination	Lys73	RRSQHARkETEFLRL	10090									35670107	t	K6 corresponds to the 6th Lysine, which is in position 73 in the full length sequence	lperfetto	TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of the serine/threonine kinase 38-like (STK38L) kinase. In turn, STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination of ULK1	SIGNOR-270346	0.2
H1-2	protein	P16403	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	down-regulates activity	binding			9606	BTO:0001938								22249259	t	done	miannu	Similarly, DNA-PK-mediated phosphorylation of H1.2 at T146 enhances p53 transcriptional activity by impeding H1.2 binding to p53 and thereby attenuating its suppressive effects on p53 transactivation. 	SIGNOR-273833	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation			9606									21620960	t		gcesareni	Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity.	SIGNOR-252824	0.908
AKT1	protein	P31749	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606	BTO:0000938								9346240	t		lperfetto	Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins	SIGNOR-52859	0.816
FGF2	protein	P09038	UNIPROT	FGFR2	protein	P21802	UNIPROT	up-regulates	binding			10116		BTO:0001130							7687739	t		lperfetto	The FGF-R2(IIIb) isoform displays high affinity for stromal cell-derived FGF-7, whereas the FGF-R2(IIIc) isoform does not recognize FGF-7 but has high affinity for the FGF-2 member of the FGF ligand family	SIGNOR-236033	0.894
melatonin	smallmolecule	CHEBI:16796	ChEBI	MTNR1B	protein	P49286	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257546	0.8
PRKACA	protein	P17612	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation	Ser8	MPLNRTLsMSSLPGL	-1									6263629	t			A reinvestigation of the phosphorylation of Rabbit Skeletal-muscle glycogen synthase by cyclic AMP dependent Protein Kinase: identification of the third site of phosphorylation at Serine-7	SIGNOR-253008	0.489
PRKCA	protein	P17252	UNIPROT	GMFB	protein	P60983	UNIPROT	unknown	phosphorylation	Ser72	QPRFIVYsYKYQHDD	-1									9030586	t		lperfetto	Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively.	SIGNOR-248959	0.327
Thrombin	smallmolecule	CHEBI:9574	ChEBI	F2RL2	protein	O00254	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257486	0.8
ABL1	protein	P00519	UNIPROT	MTOR	protein	P42345	UNIPROT	down-regulates	phosphorylation			9606									10753870	t		gcesareni	Abl binds directly to raft1 and phosphorylates raft1 in vitro and in vivo. c-abl inhibits autophosphorylation of raft1 and raft1-mediated phosphorylation p70(s6k).	SIGNOR-76562	0.465
ABL1	protein	P00519	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity	phosphorylation	Tyr78	SSISTPHyEDIPFTR	10090									25368164	t			We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ.	SIGNOR-255912	0.347
alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	UDP-alpha-D-glucose(2-)	chemical	CHEBI:58885	ChEBI	up-regulates quantity	precursor of			9606									8631325	t		miannu	UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi.	SIGNOR-267924	0.8
ACP1	protein	P24666	UNIPROT	EPHA2	protein	P29317	UNIPROT	down-regulates activity	dephosphorylation	Tyr575	RQSPEDVyFSKSEQL	-1									21538645	t		gcesareni	The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates	SIGNOR-246031	0.646
MAPK10	protein	P53779	UNIPROT	HNRNPK	protein	P61978	UNIPROT	up-regulates activity	phosphorylation	Ser216	ILDLISEsPIKGRAQ	9606									11259409	t		miannu	JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein.	SIGNOR-250081	0.345
TTK	protein	P33981	UNIPROT	CDCA8	protein	Q53HL2	UNIPROT	up-regulates	phosphorylation			9606									18243099	t		amattioni	Direct phosphorylation of the aurora b regulator borealin by mps1 enhances aurora b activity and is essential for chromosome alignment	SIGNOR-160604	0.472
PAK2	protein	Q13177	UNIPROT	CASP7	protein	P55210	UNIPROT	down-regulates	phosphorylation	Ser239	WRSPGRGsWFVQALC	9606	BTO:0000150								21555521	t		gcesareni	Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis.	SIGNOR-173655	0.357
PRKDC	protein	P78527	UNIPROT	XRCC6	protein	P12956	UNIPROT	up-regulates activity	phosphorylation	Ser33	ASGDYKYsGRDSLIF	9606	BTO:0001546								26337656	t	done	miannu	 Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks.	SIGNOR-274023	0.939
MAML2	protein	Q8IZL2	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12370315	f		gcesareni	We recently cloned a mammalian homologue of the mastermind gene of drosophila melanogaster, maml1 (mastermind-like-1 molecule) and determined that it functions as a transcriptional coactivator for notch receptors.	SIGNOR-94065	0.832
PRKACA	protein	P17612	UNIPROT	PTPN11	protein	Q06124	UNIPROT	down-regulates activity	phosphorylation	Ser189	GGGERFDsLTDLVEH	9606	BTO:0002181								25802336	t		miannu	 We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity. 	SIGNOR-276892	0.427
3-isobutyl-1-methylxanthine	chemical	CHEBI:48518	ChEBI	CEBPB	protein	P17676	UNIPROT	up-regulates				9606									11279134	f		fspada	The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin	SIGNOR-106481	0.8
CDKN1B	protein	P46527	UNIPROT	Cell_cycle_progress 	phenotype	SIGNOR-PH42	SIGNOR	down-regulates				9606									8033212	f		gcesareni	p27Kip1, a cyclin-dependent kinase inhibitor implicated in G1 phase arrest by TGF beta and cell-cell contact. p27Kip1 associates with cyclin E-Cdk2 complexes in vivo and in vitro, prevents their activation, and inhibits previously activated complexes, and p27Kip1 overexpression obstructs cell entry into S phase.	SIGNOR-241967	0.7
KIF13A	protein	Q9H1H9	UNIPROT	ZFYVE26	protein	Q68DK2	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								20208530	t		miannu	We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B.	SIGNOR-265539	0.427
PGK2	protein	P07205	UNIPROT	3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa.	SIGNOR-266506	0.8
SSH1	protein	Q8WYL5	UNIPROT	CFL1	protein	P23528	UNIPROT	up-regulates activity	dephosphorylation	Ser3	sGVAVSDG	9606									14531860	t			Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH).	SIGNOR-248762	0.778
SRC	protein	P12931	UNIPROT	GRB2	protein	P62993	UNIPROT	unknown	phosphorylation	Tyr160	QVPQQPTyVQALFDF	9606	BTO:0000007								20554525	t		lperfetto	In our work we show that, in contrast to BCR-ABL and prolactin, NPM-ALK phosphorylates Grb2 mainly in Tyr160)Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation.	SIGNOR-247138	0.626
CALM1	protein	P0DP23	UNIPROT	Calcineurin	complex	SIGNOR-C155	SIGNOR	up-regulates	binding			9606									11796223	t		gcesareni	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-252337	0.571
IRX1	protein	P78414	UNIPROT	KDR	protein	P35968	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002392								20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed.	SIGNOR-261664	0.2
PPP2CA	protein	P67775	UNIPROT	DCK	protein	P27707	UNIPROT	down-regulates activity	dephosphorylation	Ser74	EFEELTMsQKNGGNV										24462681	t		lperfetto	Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation	SIGNOR-275803	0.2
MICU1	protein	Q9BPX6	UNIPROT	MCU_MICUB_variant	complex	SIGNOR-C499	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270859	0.679
GTF2IRD1	protein	Q9UHL9	UNIPROT	GTF2I	protein	P78347	UNIPROT	down-regulates				9534	BTO:0004055								11438732	f		lperfetto	Here we describe a repressor (MusTRD1/BEN) that appears to specifically regulate the nucleocytoplasmic shuttling of TFII-I. Nuclear exclusion of TFII-I results in a repression of its target reporter gene, and such repression can be alleviated when MusTRD1/BEN is retained in the cytoplasm through targeted mutation.	SIGNOR-268534	0.426
FGF14	protein	Q92915	UNIPROT	SCN11A	protein	Q9UI33	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253437	0.261
APC-c	complex	SIGNOR-C150	SIGNOR	CCNF	protein	P41002	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									27653696	t		miannu	We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1. 	SIGNOR-266362	0.436
sirolimus	chemical	CHEBI:9168	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									18636076	t		gcesareni	Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kda fk506- and rapamycin-binding protein (fkbp12, or fkbp) and the fkbp-rapamycin binding (frb) domain of the mammalian target of rapamycin (mtor) kinase. autophagy is negatively regulated by the mammalian target of rapamycin (mtor) and can be induced in all mammalian cell types by the mtor inhibitor rapamycin.	SIGNOR-179483	0.8
CSNK2A3	protein	Q8NEV1	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates activity	phosphorylation	Ser1124	LNTEEFSsESDMEES	9606	BTO:0000938								19064667	t		lperfetto	 We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275755	0.2
CDC7	protein	O00311	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates	phosphorylation	Ser27	GNDPLTSsPGRSSRR	9606									16446360	t		gcesareni	In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells.	SIGNOR-143992	0.961
SUZ12	protein	Q15022	UNIPROT	Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	form complex	binding			9606									23110252	t		lperfetto	The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48).	SIGNOR-241900	0.924
UBR5	protein	O95071	UNIPROT	PCK1	protein	P35558	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								21726808	t		lperfetto	Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase |UBR5 ubiquitinates the acetylated PEPCK1	SIGNOR-267600	0.313
ATM	protein	Q13315	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser46	AMDDLMLsPDDIEQW	9606									11875057	t		gcesareni	In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization.	SIGNOR-115344	0.838
CSNK2A1	protein	P68400	UNIPROT	TCF7L2	protein	Q9NQB0	UNIPROT	up-regulates activity	phosphorylation	Ser58	ESETNQNsSSDSEAE	-1									11711551	t		llicata	We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. 	SIGNOR-250962	0.365
maraviroc	chemical	CHEBI:63608	ChEBI	CCL5	protein	P13501	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194127	0.8
CDK8	protein	P49336	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									19914168	t		lpetrilli	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161646	0.547
MCTS1	protein	Q9ULC4	UNIPROT	DENR	protein	O43583	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								17878526	t		miannu	The MCT-1 protein modifies mRNA translational profiles through its interaction with DENR/DRP, a protein containing an SUI1 domain involved in recognition of the translation initiation codon. 	SIGNOR-269674	0.77
TBP	protein	P20226	UNIPROT	TFIIIB	complex	SIGNOR-C393	SIGNOR	form complex	binding												29378333	t		lperfetto	Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1).	SIGNOR-266192	0.828
MAP3K7	protein	O43318	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization				9606	BTO:0000567								9480845	f		lperfetto	Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene.	SIGNOR-55716	0.658
FYN	protein	P06241	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates activity	phosphorylation	Tyr753	ERDINSLyDVSRMYV	-1									7682059	t		lperfetto	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249339	0.556
GABA-A	proteinfamily	SIGNOR-PF61	SIGNOR	CRHR2	protein	Q13324	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268599	0.2
PTK2	protein	Q05397	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr576	RYMEDSTyYKASKGK	9606									7529876	t		llicata	We found that maximal kinase activity of fak immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of fak by src (or other src family kinases) is an important step in the formation of an active signaling complex.	SIGNOR-27875	0.2
COL4A5	protein	P29400	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									12778132	t			Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6)	SIGNOR-254669	0.7
MAPK3	protein	P27361	UNIPROT	PCYT1A	protein	P49585	UNIPROT	down-regulates	phosphorylation	Ser315	GRMLQAIsPKQSPSS	9606		BTO:0000763							15788406	t		gcesareni	Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis.	SIGNOR-134841	0.439
PTPN13	protein	Q12923	UNIPROT	PDCD10	protein	Q9BUL8	UNIPROT	down-regulates activity	dephosphorylation			9606									17657516	t			In addition, our yeast two-hybrid analysis revealed that CCM3 also binds to the 270-kDa nonreceptor protein tyrosine phos- phatase FAP-1 in a region predicted to contain the C- terminal phosphatase domain [23]. We have shown that this catalytic domain is capable to dephosphorylate CCM3. By dephosphorylation, FAP-1 might therefore negatively reg- ulate CCM3 activity and downstream signaling.	SIGNOR-248714	0.586
GGCX	protein	P38435	UNIPROT	F2	protein	P00734	UNIPROT	up-regulates activity	carboxylation	Glu50	RANTFLEeVRKGNLE	-1									10556651	t		lperfetto	We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 	SIGNOR-263676	0.655
ATF4	protein	P18848	UNIPROT	HSPA5	protein	P11021	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16205636	f		miannu	Suppression of ATF4 expression by small interfering RNA (siRNA) partially inhibited the celecoxib-dependent upregulation of GRP78. 	SIGNOR-253749	0.655
WNT5A	protein	P41221	UNIPROT	ROR1	protein	Q01973	UNIPROT	up-regulates	binding			9606	BTO:0001546								26690702	t		gcesareni	Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis.	SIGNOR-173331	0.737
MAPK6	protein	Q16659	UNIPROT	KALRN	protein	O60229	UNIPROT	up-regulates activity	phosphorylation			-1									22508986	t		miannu	The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements.	SIGNOR-263094	0.38
PVR	protein	P15151	UNIPROT	CD226	protein	Q15762	UNIPROT	up-regulates activity	binding			9606	BTO:0000914								30591568	t		lperfetto	We focused on receptor-ligand interactions between CAFs and NK cell and found that cell-surface poliovirus receptor (PVR/CD155), a ligand of activating NK receptor DNAM-1, was downregulated in the CAFs compared with NEFs. |Poliovirus receptor (PVR/CD155) is a ligand of the paired NK receptors, DNAM-1 (activating) and TIGIT (inhibiting). NK cells can kill cancer cells expressing PVR via the DNAM-1-mediated activating signaling (11,12). 	SIGNOR-261424	0.814
NLGN3	protein	Q9NZ94	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								18923512	t	brain	lperfetto	Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.	SIGNOR-264189	0.746
BMP1	protein	P13497	UNIPROT	COL1A1	protein	P02452	UNIPROT	up-regulates activity	cleavage			9534	BTO:0000298								11283002	t		miannu	BMP-1myc Expressed in COS-7 Cells Exhibits Procollagen C-proteinase Activity. Bone morphogenetic protein (BMP)-1, which belongs to the tolloid subgroup of astacin-like zinc metalloproteinases, cleaves the C-propeptides of procollagen at the physiologic site and is, therefore, a procollagen C-proteinase (PCP). Cleavage occurs between a specific alanine or glycine residue (depending on the procollagen chain) and an invariant aspartic acid residue in each of the three chains of procollagen.	SIGNOR-256342	0.668
lysine	smallmolecule	CHEBI:25094	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264755	0.7
trandolapril	chemical	CHEBI:9649	ChEBI	ACE	protein	P12821	UNIPROT	down-regulates activity	chemical inhibition			10116									7527095	t		miannu	The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. 	SIGNOR-258427	0.8
FOS	protein	P01100	UNIPROT	AP1	complex	SIGNOR-C154	SIGNOR	form complex	binding			9606									25875593	t		irozzo	C-Fos dimerizes with c-Jun to form the transcription activator protein-1 (AP-1) which binds to the specific recognition site.	SIGNOR-256368	0.951
GABA-A (a4-b3-d) receptor	complex	SIGNOR-C327	SIGNOR	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	relocalization			9606									18790874	t	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263809	0.8
TCF12	protein	Q99081	UNIPROT	NOTCH3	protein	Q9UM47	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								22577461	f		miannu	Hebalt positively regulates t-cell genes, such as pt_ and notch3	SIGNOR-197517	0.26
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257987	0.8
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT7B	protein	P56706	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242733	0.295
POLR2F	protein	P61218	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266170	0.873
PRKACA	protein	P17612	UNIPROT	PLIN1	protein	O60240	UNIPROT	down-regulates activity	phosphorylation	Ser277	QAVSRRRsEVRVPWL	10090									11751901	t		miannu	PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.‚  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276)	SIGNOR-250029	0.482
BUB1	protein	O43683	UNIPROT	MAD2L1	protein	Q13257	UNIPROT	up-regulates activity	relocalization												11402067	t		lperfetto	Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity	SIGNOR-252018	0.958
SMURF	proteinfamily	SIGNOR-PF29	SIGNOR	SMAD4	protein	Q13485	UNIPROT	down-regulates activity	ubiquitination			9606	BTO:0002181								15817471	t	In the presence of smad6 or smad7 acting as adaptors	lperfetto	Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes.	SIGNOR-253259	0.2
MMP28	protein	Q9H239	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272395	0.7
CIITA	protein	P33076	UNIPROT	HLA-DQB1	protein	P01920	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								11332992	f	 	 	The class II transactivator (CIITA) regulates expression of the classical and non-classical MHC class II genes, HLA-DR, -DP, -DQ and -DM,	SIGNOR-254017	0.496
ROR2	protein	Q01974	UNIPROT	ROR2	protein	Q01974	UNIPROT	up-regulates	binding			9606									23151663	t		gcesareni	Wnt5a induces homodimerization and activation of ror2 receptor tyrosine kinase	SIGNOR-199588	0.2
CSNK2A1	protein	P68400	UNIPROT	NPHP1	protein	O15259	UNIPROT	up-regulates	phosphorylation	Ser121	PTEEEEEsESEDSED	9606									16308564	t		lperfetto	Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting.	SIGNOR-142343	0.2
somatostatin	smallmolecule	CHEBI:64628	ChEBI	SSTR4	protein	P31391	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257584	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	JUND	protein	P17535	UNIPROT	up-regulates	phosphorylation			9606									22327296	t	inferred from 70% family members	gcesareni	Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase.	SIGNOR-270183	0.2
SAV1	protein	Q9H4B6	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates	binding			9606									21084559	t	Sav1 interacts with Mst1/2 through the SARAH domains present in both Sav1 and Mst1/2.	gcesareni	Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst.	SIGNOR-169832	0.882
SNTG2	protein	Q9NY99	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255995	0.522
CDK5	protein	Q00535	UNIPROT	EPRS1	protein	P07814	UNIPROT	down-regulates	phosphorylation	Ser886	LSQSSDSsPTRNSEP	9606									19647514	t		lperfetto	Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation	SIGNOR-187383	0.2
MAP2K7	protein	O14733	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates activity	phosphorylation	Thr183	ACTNFMMtPYVVTRY	-1									11062067	t			MKK7 phosphorylates SAPK2a p38 exclusively at Tyr-182. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7.	SIGNOR-251417	0.622
NUP58	protein	Q9BVL2	UNIPROT	 p62_complex	complex	SIGNOR-C259	SIGNOR	form complex	binding			10116	BTO:0000154								2050741	t		Simone	Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function.	SIGNOR-261260	0.2
ZAP70	protein	P43403	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates	phosphorylation	Tyr426	NEEWYVSyITRPEAE	9606	BTO:0000782								8702662	t		lperfetto	A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function	SIGNOR-42976	0.798
TARDBP	protein	Q13148	UNIPROT	HNRNPA1	protein	P09651	UNIPROT	up-regulates	post transcriptional regulation			9606	BTO:0000567								29562314	t	in ALS TDP-43 induces alternative splicing of HNTNPA1 which increases its pathogenic aggregation.		TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis	SIGNOR-262824	0.414
KRAS	protein	P01116	UNIPROT	BRAF	protein	P15056	UNIPROT	up-regulates activity	binding			9606									21779497	t		miannu	The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.	SIGNOR-156906	0.872
WDR45	protein	Q9Y484	UNIPROT	ATG2B	protein	Q96BY7	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								28561066	t		miannu	WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation. 	SIGNOR-268484	0.668
TP53BP1	protein	Q12888	UNIPROT	RIF1	protein	Q5UIP0	UNIPROT	up-regulates activity	binding			10090									23333305	t		miannu	RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination.	SIGNOR-259058	0.672
ABL2	protein	P42684	UNIPROT	SIVA1	protein	O15304	UNIPROT	up-regulates	phosphorylation	Tyr34	RGVCAERySQEVFEK	9606									11278261	t		llicata	Our results also demonstrate that mutation of the siva-1 tyr48 site abrogates the apoptotic function of siva-1 and that apoptosis induced by siva-1 is dependent on expression of kinase-active arg.	SIGNOR-104992	0.34
AARS1	protein	P49588	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									32314272	t		miannu	Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N).	SIGNOR-270450	0.8
SP1	protein	P08047	UNIPROT	SLC19A1	protein	P41440	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								15652157	f	 	 	Collectively, these results identify transcriptionally important regions in the hRFC-C minimal promoter that include a GC-box and CCAAT-box, and suggest that cooperative interactions between Sp1 and C/EBP beta are essential for hRFC-C transactivation.	SIGNOR-254064	0.2
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	IL7R	protein	P16871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								22577461	f		lperfetto	Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells	SIGNOR-254345	0.2
MAPK1	protein	P28482	UNIPROT	PAX5	protein	Q02548	UNIPROT	down-regulates activity	phosphorylation	Ser189; Ser283	SGILGITsPSADTNK;DMKANLAsPTPADIG	9606	BTO:0003079								22593617	t		Gianni	In this study, we demonstrated that PAX5 was phosphorylated by ERK1/2 in vitro and in vivo at serines 189 and 283. This phosphorylation attenuated the transcriptional repression of BLIMP1 by PAX5.	SIGNOR-269087	0.358
PTGS2	protein	P35354	UNIPROT	prostaglandin H2(1-)	smallmolecule	CHEBI:57405	ChEBI	up-regulates quantity	chemical modification			-1									7592599	t		Luana	[14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2,	SIGNOR-269776	0.8
IL17A	protein	Q16552	UNIPROT	KRT17	protein	Q04695	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000667								21796151	f		miannu	 IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms.	SIGNOR-255232	0.35
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	CASP3	protein	P42574	UNIPROT	down-regulates activity				9606	BTO:0002882								11684015	f		lperfetto	BCR/ABL Tyrosine Kinase Enhances Expression of RAD51 by Stimulation of STAT5-Mediated Transactivation and Inhibition of Caspase-3-Dependent Degradation|	SIGNOR-271704	0.2
MAPK1	protein	P28482	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser642	NACTLTTsPRLPVF	10090	BTO:0000944								15664191	t		lperfetto	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-249444	0.616
DGC	complex	SIGNOR-C217	SIGNOR	NRXN1	protein	P58400	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							11470830	t		miannu	In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan.	SIGNOR-265447	0.351
SRC	protein	P12931	UNIPROT	FCRL3	protein	Q96P31	UNIPROT	up-regulates activity	phosphorylation	Tyr722	EEDDEENyENVPRVL	-1									12051764	t		miannu	Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2.	SIGNOR-274009	0.2
RAB3A	protein	P20336	UNIPROT	Dense-core_vesicle_exocytosis	phenotype	SIGNOR-PH184	SIGNOR	up-regulates				9606									31679900	f		miannu	Here, we identify the SEC4 ortholog RAB3 and its neuronal effector, RIM1, as essential molecules for neuropeptide and neurotrophin release from dense-core vesicles (DCVs) in mammalian neurons. 	SIGNOR-264375	0.7
CSNK2A1	protein	P68400	UNIPROT	MDC1	protein	Q14676	UNIPROT	up-regulates	phosphorylation	Ser376	LQESQAGsDTDVEEG	9606									18678890	t		gcesareni	The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites.	SIGNOR-179879	0.353
PPP2R5C	protein	Q13362	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates	dephosphorylation	Ser41	SLSESEEsQDSSDSI	9606									20730097	t		lperfetto	We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf2	SIGNOR-167568	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	AR	protein	P10275	UNIPROT	down-regulates activity	phosphorylation	Ser792	CVRMRHLsQEFGWLQ	9534	BTO:0001538								11404460	t		lperfetto	Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790	SIGNOR-244136	0.2
6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide	chemical	CHEBI:92401	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258006	0.8
MAOA	protein	P21397	UNIPROT	(R)-adrenaline	smallmolecule	CHEBI:28918	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000142							20493079	t		Luana	The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied.	SIGNOR-269744	0.8
CDK1	protein	P06493	UNIPROT	SREBF1	protein	P36956	UNIPROT	up-regulates	phosphorylation	Ser439	AGSPFQSsPLSLGSR	9606			SIGNOR-C17						16880739	t		llicata	Cdk1/cyclin b-mediated phosphorylation stabilizes srebp1 during mitosis.	SIGNOR-148354	0.292
PYCARD	protein	Q9ULZ3	UNIPROT	NLRP3 inflammasome	complex	SIGNOR-C225	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256411	0.816
COX4I1	protein	P13073	UNIPROT	Oxidative_phosphorylation	phenotype	SIGNOR-PH78	SIGNOR	up-regulates				10090									23021218	f		lperfetto	PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). 	SIGNOR-253101	0.7
MAPK9	protein	P45984	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Tyr632	GRKGSGDyMPMSPKS	9606									14579029	t		gcesareni	Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632	SIGNOR-118877	0.698
AURKB	protein	Q96GD4	UNIPROT	NDC80	protein	O14777	UNIPROT	down-regulates	phosphorylation	Ser15	SGGAGRLsMQELRSQ	9606									20471944	t		lperfetto	To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant).	SIGNOR-165554	0.842
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Leu649	NKGAIIGlMVGGVVI	-1									10605825	t		lperfetto	In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D.	SIGNOR-261783	0.502
DSCAM	protein	O60469	UNIPROT	SH2D2A	protein	Q9NP31	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								30745319	t		miannu	Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels.	SIGNOR-264279	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	HNRNPK	protein	P61978	UNIPROT	up-regulates	phosphorylation	Ser216	ILDLISEsPIKGRAQ	9606									11259409	t		lperfetto	Using modified jnk and its atp analogue enables the detection of novel jnk substrates. Among substrates identified using this approach is heterogeneous nuclear ribonucleoprotein k, which is involved in transcription and post-transcriptional mrna metabolism. The newly identified substrate can be phosphorylated by jnk on amino acids 216 and 353, which contribute to heterogeneous nuclear ribonucleoprotein k mediated transcriptional activities.	SIGNOR-105758	0.2
PI3K	complex	SIGNOR-C156	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0000876	BTO:0001103							19436055	f		apalma	Low pM concentrations of GM-CSF mediate βc Ser585 phosphorylation, leading to 14-3-3 binding, PI-3 kinase activation, and hemopoietic cell survival, whereas at concentrations of 10 pM or more, GM-CSF mediates βc Tyr577 phosphorylation, Shc recruitment, and PI-3 kinase activation, thereby promoting both survival and proliferation.	SIGNOR-255577	0.7
PPP1CB	protein	P62140	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	dephosphorylation	Ser469	AHEENPEsILDEHVQ	9606									17318175	t			The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 	SIGNOR-248570	0.2
6-(3,4-Dimethoxyphenyl)-3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole	chemical	CID:661498	PUBCHEM	DCTPP1	protein	Q9H773	UNIPROT	down-regulates activity	chemical inhibition			9606									28145708	t		Federica	Here we report on thediscovery of a series of 3,6-disubstituted triazolothiadiazolesas potent dCTPase inhibitors. 	SIGNOR-261113	0.8
OPHN1	protein	O60890	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	gtpase-activating protein			9606	BTO:0000938								12932438	t		miannu	OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro	SIGNOR-268397	0.62
CSNK1A1	protein	P48729	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser265	PRSSSNAsSVSTRLS	9606	BTO:0001109								28945225	t		miannu	Here we report that CK1α similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268. 	SIGNOR-277325	0.2
EFNA3	protein	P52797	UNIPROT	EPHA8	protein	P29322	UNIPROT	up-regulates	binding			9606									9330863	t		tpavlidou	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52387	0.741
ZNF774	protein	Q6NX45	UNIPROT	MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	up-regulates activity	binding			9606	BTO:0000578								31659254	t		miannu	Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription. 	SIGNOR-265559	0.25
ITK	protein	Q08881	UNIPROT	CD28	protein	P10747	UNIPROT	up-regulates	phosphorylation	Tyr191	SRLLHSDyMNMTPRR	9606	BTO:0000782;BTO:0001271								8992971	t		lperfetto	We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor	SIGNOR-45512	0.677
ACTR3	protein	P61158	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	form complex	binding			9606									12479800	t			The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc	SIGNOR-251513	0.916
DLL1	protein	O00548	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	binding												23729744	t		apalma	The NECD undergoes O-linked glycosylation during Notch synthesis and secretion, which is crucial for proper folding of the Notch receptor and the interaction with its ligand DSL (Delta, Serrate, Lag-2)(Rana and Haltiwanger, 2011). The Notch receptor on the signal-receiving cell binds directly to ligands located on the apposing signal-sending cell	SIGNOR-255369	0.625
IFNB1	protein	P01574	UNIPROT	IFNAR	complex	SIGNOR-C243	SIGNOR	up-regulates activity	binding			9606									11278538	t		miannu	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-260335	0.762
CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	STAR	protein	P49675	UNIPROT	up-regulates quantity by expression	transcriptional regulation			93934	BTO:0000475								17431006	t	 	lperfetto	One such gene was identified, encoding steroidogenic acute regulatory protein (StAR), which showed 24-h changes in expression in the F1 follicle coinciding with those of Per2. Evidence that StAR gene expression is clock driven was obtained by showing that its 5' flanking region contains E-box enhancers that bind to CLOCK/BMAL1 heterodimers to activate gene transcription	SIGNOR-253700	0.29
IRF2BPL	protein	Q9H1B7	UNIPROT	PENK	protein	P01210	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000938								17627301	t		miannu	EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.	SIGNOR-267155	0.313
TNF	protein	P01375	UNIPROT	SCNN1A	protein	P37088	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0005760								16877633	f	Regulation of expression	miannu	 TNF, a proinflammatory cytokine present in several lung pathologies, decreases the expression and activity of the epithelial Na(+) channel (ENaC) by approximately 70% in alveolar epithelial cells.	SIGNOR-251954	0.311
CID 122201421	chemical	CID:122201421	PUBCHEM	BRD4	protein	O60885	UNIPROT	down-regulates activity	chemical inhibition			9606									26035625	t		Monia	Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4; These data confirmed that BRD4 is removed from the cell nuclei in a time dependent manner due to the presence of MZ1	SIGNOR-261097	0.8
CHMP3	protein	Q9Y3E7	UNIPROT	Viral_budding	phenotype	SIGNOR-PH125	SIGNOR	up-regulates				-1									30989108	f		miannu	ESCRT-III has been proposed to assemble inside the membrane neck formed at a late stage of a budding vesicle or an enveloped virus. The membrane neck needs to be constricted to proceed to membrane fission, thereby splitting the vesicle or virus from the cellular membrane. CHMP2A and CHMP3 are engaged late in ESCRT-III assembly, recruit VPS4 (31, 42), and block Snf7 (CHMP4) polymerization	SIGNOR-260845	0.7
IFNGR1	protein	P15260	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates	binding			9606									17063185	t		flangone	Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively	SIGNOR-150197	0.703
MAPK3	protein	P27361	UNIPROT	CCDC6	protein	Q16204	UNIPROT	up-regulates activity	phosphorylation	Ser244	QPVSAPPsPRDISME	9606	BTO:0000007								14712216	t		miannu	We have characterized the H4(D10S170) gene product, showing that it is a ubiquitously expressed 55 KDa nuclear and cytosolic protein that is phosphorylated following serum stimulation. This phosphorylation was found to depend on mitogen-activated protein kinase (MAPK) Erk1/2 activity and to be associated to the relocation of H4(D10S170) from the nucleus to the cytosol. S244 is the major target residue of ERK1	SIGNOR-276003	0.374
USP5	protein	P45974	UNIPROT	FOXM1	protein	Q08050	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0002181								26912724	t		miannu	 Wnt signaling activation inhibits FoxM1 phosphorylation by GSK3-Axin complex and leads to interaction between FoxM1 and deubiquitinating enzyme USP5, thereby deubiquitination and stabilization of FoxM1.	SIGNOR-277210	0.358
PPP2R1A	protein	P30153	UNIPROT	PP2Ca_R1A_Bd	complex	SIGNOR-C134	SIGNOR	form complex	binding			9606									23454242	t		gcesareni	[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity.	SIGNOR-243436	0.906
arachidonic acid	smallmolecule	CHEBI:15843	ChEBI	PTGS2	protein	P35354	UNIPROT	up-regulates				9606									15878913	f		miannu	 AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription.	SIGNOR-255394	0.8
CD70	protein	P32970	UNIPROT	CD27	protein	P26842	UNIPROT	up-regulates	binding			9606		BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000672							8120384	t		gcesareni	The molecule defining the cd70 ag is identical to the recently defined ligand for cd27. Bioassays demonstrated that the cd70 cdna clone expressed in african green monkey kidney cells would induce the proliferation of pha-costimulated t cells. Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner.	SIGNOR-36357	0.765
CCNA2	protein	P20248	UNIPROT	CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	form complex	binding			9606									19056339	t		lperfetto	We therefore compared human cyclin a1- and cyclin a2-containing cdk complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate prb and p53. Differences in biochemical activity were observed in cdk2 but not cdk1 when complexed with cyclin a1 versus cyclin a2. Further, cdk1/cyclin a1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates prb and p53 than cdk2/cyclin a2.	SIGNOR-182566	0.976
STK11	protein	Q15831	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	up-regulates activity	phosphorylation	Thr183	SDGEFLRtSCGSPNY	-1									16054095	t		lperfetto	The AMP-activated protein kinase (AMPK) is a critical regulator of energy balance at both the cellular and whole-body levels. Two upstream kinases have been reported to activate AMPK in cell-free assays, i.e., the tumor suppressor LKB1 and calmodulin-dependent protein kinase kinase.	SIGNOR-139297	0.581
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CDK2	protein	P24941	UNIPROT	up-regulates	phosphorylation	Thr39	LKKIRLDtETEGVPS	9606									18354084	t		lperfetto	Akt phosphorylates cdk2 at threonine 39 residue both in vitro and in vivo. Although cdk2 threonine 39 phosphorylation mediated by akt enhances cyclin-a binding, it is dispensable for its basal binding and the kinase activity.	SIGNOR-244176	0.2
TGFB3	protein	P10600	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates	binding			9606									11157754	t		miannu	T?RII Is known to bind the isoforms tgf??1 And tgf??3. Binding of these ligands causes recruitment of the type i receptor (t?RI) into a signalling receptor complex followed by activation of t?RI Through transphosphorylation	SIGNOR-104798	0.861
sphingosine 1-phosphate(1-)	smallmolecule	CHEBI:60119	ChEBI	S1PR3	protein	Q99500	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257579	0.8
SHC1	protein	P29353	UNIPROT	SOS1	protein	Q07889	UNIPROT	up-regulates	binding			10090	BTO:0005065								17673906	t		lperfetto	TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases.	SIGNOR-236363	0.762
BMPR1A	protein	P36894	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity				10090									8533096	f		ggiuliani	We also examined whether TAK1 was activated by bone morphogenetic protein (BMP). BMP-4 also stimulated TAK1 activity in a time- and dose-dependent manner	SIGNOR-255815	0.386
CSNK1E	protein	P49674	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	down-regulates	phosphorylation			9606									15747065	t		gcesareni	Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex.CK1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays.	SIGNOR-134497	0.271
AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	Platelet_Adhesion 	phenotype	SIGNOR-PH137	SIGNOR	up-regulates				9606	BTO:0000132								25297919	f		lperfetto	VWF binding to GPIb-IX-V induces platelet activation, converting the major integrin αIIbβ3 from a low affinity to a high affinity receptor capable of engaging the C4 domain of VWF. This last step is essential for stable adhesion 	SIGNOR-261867	0.7
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	LIFR	protein	P42702	UNIPROT	down-regulates	phosphorylation			9606									7777512	t	inferred from 70% family members	gcesareni	Thus, our results identify the human lifr as a substrate for mapk and suggest a mechanism of heterologous receptor regulation of lifr signaling occurring at ser-1044.	SIGNOR-270001	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation	Ser540	KVMARSLsPPPELEE	10090	BTO:0000944								15851026	t		lperfetto	Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation.	SIGNOR-249455	0.2
CD28	protein	P10747	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			9606									24098653	t		fspada	Binding of the py site in cd28 (py-m-n-m) by pi3k and grb2 through their sh2 domains is a key step that triggers the cd28 signal transduction for t cell activation and differentiation	SIGNOR-202706	0.691
FOXO3	protein	O43524	UNIPROT	RBL2	protein	Q08999	UNIPROT	up-regulates quantity	transcriptional regulation			9606	BTO:0000944								11884591	t		gcesareni	Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression.	SIGNOR-238606	0.296
WWP1	protein	Q9H0M0	UNIPROT	SMAD7	protein	O15105	UNIPROT	up-regulates	binding			9606									15221015	t		gcesareni	Wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor.	SIGNOR-126128	0.72
G3BP1	protein	Q13283	UNIPROT	DDX58	protein	O95786	UNIPROT	up-regulates quantity				9606									31827077	f		miannu	We further identified that G3BP1 is able to interact with RIG-I and boost its expression. RIG-I expression could be stabilized by G3BP1 via antagonizing RNF125-mediated RIG-I degradation. Secondly, we demonstrated that G3BP1 potentiates the self-association and auto-ubiquitination of RNF125. Hence, it is more likely that G3BP1 first promotes RNF125 degradation by enhancing self-association and auto-ubiquitination of RNF125, and then RIG-I degradation mediated by RNF125 is alleviated	SIGNOR-261319	0.346
ABL1	protein	P00519	UNIPROT	PLCG1	protein	P19174	UNIPROT	down-regulates activity	phosphorylation	Tyr1003	KGKKFLQyNRLQLSR	9606	BTO:0002181								12652307	t		miannu	C-Abl induces Tyr phosphorylation of PLC-γ1 in vivo. These findings demonstrate that c-Abl phosphorylates PLC-γ1 in vivo predominantly at Tyr 771 and Tyr 1003.c-Abl phosphorylation of PLC-γ1 causes downregulation of PLC activity.	SIGNOR-276002	0.571
NAE1	protein	Q13564	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000938								25568892	f		lperfetto	Overexpression of AppBp1 in primary neurons induces apoptosis through the neddylation pathway	SIGNOR-251579	0.7
MAPK1	protein	P28482	UNIPROT	LIFR	protein	P42702	UNIPROT	down-regulates	phosphorylation	Ser1044	WNLVSPDsPRSIDSN	9606									7777512	t		gcesareni	Indeed, phosphorylation of the cytoplasmic domain of the low-affinity lif receptor alpha-subunit (lifr) in mono q-fractionated, lif-stimulated 3t3-l1 extracts occurred only in those fractions containing activated mapk;ser-1044 served as the major phosphorylation site in the human lifr for mapk both in agonist-stimulated 3t3-l1 lysates and by recombinant extracellular signal-regulated kinase 2 in vitro	SIGNOR-32753	0.377
Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates activity	ubiquitination			9606									17396147	t		lperfetto	Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo 	SIGNOR-263249	0.763
NEFH	protein	P12036	UNIPROT	Neurofilament L/H	complex	SIGNOR-C208	SIGNOR	form complex	binding			9606	BTO:0000938								19468066	t		miannu	Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H	SIGNOR-255273	0.446
CCL4	protein	P13236	UNIPROT	CCR5	protein	P51681	UNIPROT	up-regulates activity	binding			10090									20219869	t		areggio	The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. 	SIGNOR-255116	0.857
RNF168	protein	Q8IYW5	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									31225475	f		miannu	L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.	SIGNOR-266789	0.7
C3AR1	protein	Q16581	UNIPROT	Chemotaxis	phenotype	SIGNOR-PH93	SIGNOR	up-regulates				9606									9108406	f		lperfetto	We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro.	SIGNOR-263471	0.7
SNRPD2	protein	P62316	UNIPROT	U1 snRNP complex	complex	SIGNOR-C480	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270685	0.933
KRT1	protein	P04264	UNIPROT	MPO	protein	P05164	UNIPROT	up-regulates quantity	binding			9606									17591979	t	Regulation of binding	miannu	CK1 and CK9 specifically bind MPO. MPO is internalized by endothelial cells through a direct interaction with the endothelial surface protein CK1	SIGNOR-251886	0.249
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	VIM	protein	P08670	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser39	TTSTRTYsLGSALRP	9606									20856200	t		llicata	The binding of akt (tail region) to vim (head region) results in vim ser39 phosphorylation enhancing the ability of vim to induce motility and invasion while protecting vim from caspase-induced proteolysis.	SIGNOR-167971	0.2
PRKAA1	protein	Q13131	UNIPROT	FOXO4	protein	P98177	UNIPROT	up-regulates	phosphorylation			9606			SIGNOR-C15						17900900	t		gcesareni	The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation	SIGNOR-157947	0.354
PRRX1	protein	P54821	UNIPROT	MAFG	protein	O15525	UNIPROT	down-regulates activity	binding			-1									11036080	t		miannu	Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.	SIGNOR-221961	0.344
PROC	protein	P04070	UNIPROT	F5	protein	P12259	UNIPROT	down-regulates activity	cleavage	Arg707	ESTVMATrKMHDRLE	-1									7989361	t		lperfetto	The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. 	SIGNOR-263630	0.583
ATM	protein	Q13315	UNIPROT	ITCH	protein	Q96J02	UNIPROT	up-regulates activity	phosphorylation	Ser162	TCSENGVsLCLPRLE	9606									23435430	t		miannu	Here we uncover ATM as a novel positive modulator of ITCH E3-ubiquitin ligase activity. A single residue on ITCH protein, S161, which is part of an ATM SQ consensus motif, is required for ATM-dependent activation of ITCH.	SIGNOR-276488	0.267
AKAP8L	protein	Q9ULX6	UNIPROT	mRNA-nucleus_export	phenotype	SIGNOR-PH127	SIGNOR	up-regulates				9606									11402034	f		miannu	These results support the proposal that both RHA and HAP95 facilitated the nuclear export of unspliced, CTE-containing mRNA in human cells. we have extended this earlier study by mapping the functional domains of HAP95 and providing strong evidence for a direct role of HAP95 in RHA-mediated nuclear export of CTE-containing mRNA.	SIGNOR-260953	0.7
CALM2	protein	P0DP24	UNIPROT	PPP3CC	protein	P48454	UNIPROT	up-regulates	binding			9606									11796223	t		miannu	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-266324	0.535
3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol	chemical	CHEBI:94691	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207251	0.8
SLBP	protein	Q14493	UNIPROT	H2BC3	protein	P33778	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265385	0.2
EGFR	protein	P00533	UNIPROT	SCAMP1	protein	O15126	UNIPROT	up-regulates activity	phosphorylation	Tyr37	VPPGLDEyNPFSDSR	-1									9658162	t		miannu	In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation	SIGNOR-262857	0.341
RAD21L Cohesin complex	complex	SIGNOR-C355	SIGNOR	Meiotic_recombination	phenotype	SIGNOR-PH162	SIGNOR	up-regulates				10090		BTO:0000534							21242291	f		miannu	RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21.	SIGNOR-264539	0.7
NFATC2	protein	Q13469	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001260								17079331	t		lperfetto	The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.	SIGNOR-251731	0.411
AKT1	protein	P31749	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	unknown	phosphorylation			9606									12588998	t		gcesareni	Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro	SIGNOR-265320	0.2
PRKCA	protein	P17252	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Ser146	RPSQRHGsKYLATAS	-1									2413024	t		lperfetto	MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 	SIGNOR-248870	0.503
CB-5083	chemical	CID:73051434	PUBCHEM	VCP	protein	P55072	UNIPROT	down-regulates activity	chemical inhibition			-1									26565666	t		miannu	Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-5083.	SIGNOR-260189	0.8
MET	protein	P08581	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr285	TEADGELyVFNTPSG	9606	BTO:0000018								10734310	t		miannu	Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF.	SIGNOR-250552	0.661
PABPC4	protein	Q13310	UNIPROT	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates quantity by stabilization	binding			9606									25480299	t		lperfetto	As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length.	SIGNOR-268319	0.8
TEK	protein	Q02763	UNIPROT	TEK	protein	Q02763	UNIPROT	up-regulates activity	phosphorylation	Tyr1102	MLEERKTyVNTTLYE	10090	BTO:0000944								12082108	t		lperfetto	Recently, insights into Tie2 activation were provided by a solution of the Tie2 crystal structure (12). This structural analysis revealed several novel features, including two potential autoinhibitory mechanismsIn the unphosphorylated state, the hydroxyl groups of two important tyrosine residues, Tyr1101 and Tyr1112 (murine residue numbers), are hydrogen-bonded to surrounding residues, which may stabilize the C tail in this inhibitory conformationDeletion of the Tie2 C Tail Enhances Autophosphorylation and Kinase Activity in VitroDeletion of the C tail dramatically enhanced Tie2 autophosphorylation, despite the removal of Tyr1112, which was previously shown to be an important autophosphorylation site	SIGNOR-246657	0.2
SP1	protein	P08047	UNIPROT	PCYT1A	protein	P49585	UNIPROT	up-regulates quantity by expression	transcriptional regulation			7227	BTO:0001677								10744779	t		Luana	Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter	SIGNOR-266231	0.2
TAL1	protein	P17542	UNIPROT	FUBP1	protein	Q96AE4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30653565	t		irozzo	TAL1 directly activates the FUBP1 promoter, leading to increased FUBP1 expression during erythroid differentiation.	SIGNOR-259131	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	CAD	protein	P27708	UNIPROT	up-regulates	phosphorylation			9606									15890648	t	inferred from 70% family members	lperfetto	Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol	SIGNOR-269998	0.2
ODAD4	protein	Q96NG3	UNIPROT	Cilium_movement	phenotype	SIGNOR-PH171	SIGNOR	up-regulates				10090									27486780	f		miannu	Our results in mice suggest that TTC25 plays an essential role in the correct function of motile cilia at the ventral node and is therefore important for the development of left-right body asymmetry.	SIGNOR-265548	0.7
Elongator complex	complex	SIGNOR-C466	SIGNOR	TUBA3D	protein	P0DPH8	UNIPROT	up-regulates activity	acetylation			9606	BTO:0000007								19185337	t		miannu	Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. α-Tubulin Acetylation Promotes Radial Migration and Branching of Cortical Projection Neurons	SIGNOR-269715	0.254
BRCA1-A complex	complex	SIGNOR-C296	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	down-regulates													25400280	f		lperfetto	 Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks.	SIGNOR-263226	0.7
acetylcholine	smallmolecule	CHEBI:15355	ChEBI	CHRM2	protein	P08172	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257469	0.8
ELANE	protein	P08246	UNIPROT	F5	protein	P12259	UNIPROT	down-regulates activity	cleavage	Thr1795	SRSSWRLtSSEMKKS	-1									9242537	t		lperfetto	Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity.	SIGNOR-263634	0.373
DLX5	protein	P56178	UNIPROT	MSX2	protein	P35548	UNIPROT	down-regulates activity	binding			10090	BTO:0000947								9111364	t	2	miannu	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240925	0.553
DOCK6	protein	Q96HP0	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor												23462102	t		lperfetto	Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton. 	SIGNOR-275670	0.507
FLT3	protein	P36888	UNIPROT	SOCS2	protein	O14508	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									12468433	f			We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling	SIGNOR-261545	0.439
estramustine	chemical	CHEBI:4868	ChEBI	ESR2	protein	Q92731	UNIPROT	up-regulates activity	chemical activation			9606									14755680	t		miannu	A variety of new estrogenic/anti‐estrogenic/selective estrogen receptor modulator (SERM)‐like compounds, including 2‐methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies. 	SIGNOR-259299	0.8
SRC	protein	P12931	UNIPROT	CTNND1	protein	O60716	UNIPROT	up-regulates activity	phosphorylation	Tyr302	DYGMMSDyGTARRTG	-1									11382764	t		lperfetto	Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302	SIGNOR-246504	0.92
SRD5A1	protein	P18405	UNIPROT	17beta-hydroxy-5alpha-androstan-3-one	smallmolecule	CHEBI:16330	ChEBI	up-regulates quantity	chemical modification			9606									15861399	t		miannu	Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. 	SIGNOR-251534	0.8
PRKCH	protein	P24723	UNIPROT	ANXA1	protein	P04083	UNIPROT	up-regulates	phosphorylation	Ser27	EYVQTVKsSKGGPGS	9606									24103589	t		lperfetto	The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization.	SIGNOR-202792	0.2
GSK3B	protein	P49841	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser114	EEDHVDLsLSCTLVP	9606	BTO:0000093								17283049	t		lperfetto	Glycogen synthase kinase 3beta phosphorylates p21waf1/cip1 for proteasomal degradation after uv irradiationhere, we show that ser-114 phosphorylation of p21 protein by glycogen synthase kinase 3beta (gsk-3beta) is required for its degradation in response to uv irradiation	SIGNOR-152941	0.411
MT-ND1	protein	P03886	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46].	SIGNOR-262143	0.805
regorafenib	chemical	CHEBI:68647	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			9606									24756792	t		miannu	In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically.	SIGNOR-259214	0.8
PLK1	protein	P53350	UNIPROT	CLSPN	protein	Q9HAW4	UNIPROT	down-regulates	phosphorylation	Ser30	EADSPSDsGQGSYET	9606									16885021	t		gcesareni	We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase	SIGNOR-148442	0.765
Quadazocine	chemical	CID:115077	PUBCHEM	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258420	0.8
MAPK8	protein	P45983	UNIPROT	CTBP1	protein	Q13363	UNIPROT	down-regulates	phosphorylation	Ser422	AHPPHAPsPGQTVKP	9606	BTO:0000551								16984892	t		lperfetto	In this study, we found that c-jun nh2-terminal kinase 1 activation triggered ctbp phosphorylation on ser-422 and subsequent degradation,	SIGNOR-149721	0.367
PRKCD	protein	Q05655	UNIPROT	G6PD	protein	P11413	UNIPROT	up-regulates	phosphorylation	Thr236	NIACVILtFKEPFGT	9606		BTO:0001260							20649491	t		lperfetto	A pkc activator, significantly increased g6pd phosphorylation and activity, whereas single (s210a, t266a) and double (s210a/t266a) mutations at sites flanking the g6pd active site significantly inhibited phosphorylation, shifted the isoelectric point, and reduced enzyme activity.	SIGNOR-167053	0.2
CEBPB	protein	P17676	UNIPROT	GDF15	protein	Q99988	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								24086573	t	 	 	Promoter analysis and chromatin immunoprecipitation analysis revealed that CEBPB could contribute to K7174-mediated transcriptional activation of GDF15.	SIGNOR-254050	0.279
SHC1	protein	P29353	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			9606	BTO:0000776								10207047	t		lperfetto	The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation.	SIGNOR-235881	0.965
estramustine	chemical	CHEBI:4868	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			9606									14755680	t		miannu	A variety of new estrogenic/anti‐estrogenic/selective estrogen receptor modulator (SERM)‐like compounds, including 2‐methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies. 	SIGNOR-259296	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity	phosphorylation			10090	BTO:0002572								28646232	t		Gianni	We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels	SIGNOR-262519	0.358
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	KAT2A	protein	Q92830	UNIPROT	up-regulates activity	phosphorylation	Ser372	EEIYGANsPIWESGF										24870244	t		lperfetto	Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT)	SIGNOR-275496	0.402
CHEK1	protein	O14757	UNIPROT	TLK2	protein	Q86UE8	UNIPROT	down-regulates activity	phosphorylation	Ser750	PHIRKSVsTSSPAGA	-1									12955071	t		miannu	Chk1 phosphorylates GST-fusion fragments of TLK1 in vitro.When Chk1 protein was depleted in cells transfected with pSuper-Chk1, TLK activity was not suppressed after short aphidicolin treatment of S-phase cells (Figure 8a, b).	SIGNOR-262740	0.273
glutaryl-CoA(5-)	smallmolecule	CHEBI:57378	ChEBI	glutarate(2-)	smallmolecule	CHEBI:30921	ChEBI	up-regulates quantity	precursor of												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271811	0.8
SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	up-regulates				9606									33941852	f			Multi-subunit ATPase-dependent chromatin remodelling complexes SWI/SNF (switch/sucrose non-fermentable) are fundamental epigenetic regulators of gene transcription. 	SIGNOR-268623	0.7
TAF9	protein	Q16594	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263920	0.603
ARVCF	protein	O00192	UNIPROT	ERBIN	protein	Q96RT1	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								11821434	t		miannu	We characterized the interactions between the Erbin PDZ domain and both ARVCF and δ-catenin in vitro and in vivo. endogenous δ-catenin and Erbin co-localized in and co-immunoprecipitated from neurons. These results suggest that δ-catenin and ARVCF may function to mediate the association of Erbin with the junctional cadherin-catenin complex.	SIGNOR-252119	0.2
LPAR5	protein	Q9H1C0	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256861	0.394
XRCC3	protein	O43542	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates quantity by stabilization	binding			9606									23438602	t		miannu	XRCC3 activation is essential for the recruitment of RAD51 to the sites of DNA lesions. It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation. 	SIGNOR-262667	0.737
KNG1	protein	P01042	UNIPROT	BDKRB2	protein	P30411	UNIPROT	up-regulates activity	binding			9606					cleavage:Arg381;Arg389	GMISLMKrPPGFSPF;PPGFSPFrSSRIGEI			28966616	t		lperfetto	BK binds receptor B2 (B2R) and triggers inflammation, edema, and symptoms of anaphylaxis.	SIGNOR-263554	0.852
MAP3K7	protein	O43318	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	phosphorylation	Ser192	HMTNNKGsAAWMAPE	-1									20538596	t		lperfetto	Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation.	SIGNOR-232153	0.2
KLF9	protein	Q13886	UNIPROT	SIN3A	protein	Q96ST3	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								11438660	t		miannu	detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.	SIGNOR-222434	0.456
CCND1	protein	P24385	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	down-regulates				9606		BTO:0001103							20219869	f		apalma	Importantly, NF-kB can promote the expression and stability of cyclin D1 in muscle (4, 35, 39, 132), leading to increased cell proliferation and inhibition of differentiation. 	SIGNOR-255351	0.7
FAM83G	protein	A6ND36	UNIPROT	CSNK1A1L	protein	Q8N752	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								29789297	t		miannu	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273753	0.344
MEPCE	protein	Q7L2J0	UNIPROT	P-TEFb	complex	SIGNOR-C238	SIGNOR	down-regulates activity	binding			10090	BTO:0002572								32048991	t		miannu	JMJD6 cleaves MePCE. we propose that JMJD6 is the cognate protease of MePCE and cleaves at the R171 site within MePCE. Experiments using purified JMJD6 showed that it could make a cut in an enzyme called MePCE, which belongs to the group of proteins that hold P-TEFb in its inactive form. The levels of activated Pol II were lower in cells without JMJD6 and higher in those without MePCE. Together, the results suggest that JMJD6 cuts MePCE to release P-TEFb, which then activates Pol II. 	SIGNOR-261038	0.565
STK39	protein	Q9UEW8	UNIPROT	CFTR	protein	P13569	UNIPROT	down-regulates activity	phosphorylation			10090		BTO:0000988							21317537	t		lperfetto	WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression,	SIGNOR-264643	0.353
BLOC1S6	protein	Q9UL45	UNIPROT	BLOC-1	complex	SIGNOR-C381	SIGNOR	form complex	binding			9606	BTO:0002946								22203680	t		lperfetto	We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter.	SIGNOR-265931	0.725
vorinostat	chemical	CHEBI:45716	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257950	0.8
IKBKB	protein	O14920	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	form complex	binding			9606									20300203	t		gcesareni	The kinase(s) responsible for the phosphorylation of the ikb inhibitors remained elusive for many years, until the biochemical purification of a cytoplasmic high-molecular weight complex migrating around 700900 kda and containing two related catalytic subunits, ikkalfa and ikkbeta.	SIGNOR-164509	0.808
MYC	protein	P01106	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000785								20551174	f		lperfetto	In tissue culture, ectopic expression of Myc suppresses the cell cycle arrest that occurs in response to several anti-mitogenic signals such as transforming growth factor β (TGFβ), since Myc represses expression of the cyclin-dependent kinase inhibitors (CKIs) p15ink4b, p21cip1, and p57kip2 via interaction with Miz1	SIGNOR-267574	0.772
PIM1	protein	P11309	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates activity	phosphorylation	Thr198	PGLRRRQt	9606									18593906	t		gcesareni	We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro.|Pim kinases promote cell cycle progression and tumorigenesis by down-regulating p27(Kip1) expression at both transcriptional and posttranslational levels.	SIGNOR-179300	0.39
EP300	protein	Q09472	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates	binding			9606			SIGNOR-C6						22298955	t		gcesareni	Ski and snon also prevent smads from binding to the transcriptional coactivator p300/cbp	SIGNOR-195582	0.414
PKN1	protein	Q16512	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser256	SPRRRAAsMDNNSKF	9606	BTO:0000150								12560069	t		lperfetto	Furthermore, estrogen induced phosphorylation and perinuclear localization of the cell survival forkhead transcription factor fkhr in the cytoplasm in a pak1-dependent manner. In addition, pak1 directly interacted with fkhr and phosphorylated it. The noticed phosphorylation-dependent exclusion of fkhr from the nucleus impaired the ability of fkhr to activate its target fas ligand promoter containing the fkhr binding motif (fre) in cells treated with estrogen or expressing catalytically active pak1.	SIGNOR-252968	0.2
2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol	chemical	CHEBI:93773	ChEBI	RAF1	protein	P04049	UNIPROT	down-regulates	chemical inhibition			9606									12970777	t		gcesareni	The raf inhibitor l-779,450. This raf inhibitor was less effective on b-raf- or mek1-responsive cells, demonstrating the specificity of this drug.	SIGNOR-100358	0.8
SPRY1	protein	O43609	UNIPROT	SOS1	protein	Q07889	UNIPROT	down-regulates	binding			9606									11585837	t		gcesareni	Taken together, these results establish mammalian sprouty proteins as important negative regulators of growth factor signaling and suggest that sprouty proteins act downstream of the grb2.Sos Complex to selectively uncouple growth factor signals from ras activation and the map kinase pathway.	SIGNOR-110948	0.395
GPR55	protein	Q9Y2T6	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256670	0.2
HDAC3	protein	O15379	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000150								25726523	t		lperfetto	GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. 	SIGNOR-275662	0.26
MAPK1	protein	P28482	UNIPROT	TSC1	protein	Q92574	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000150;BTO:0001573								17671177	t		gcesareni	Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin.	SIGNOR-157162	0.469
CIB1	protein	Q99828	UNIPROT	AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	down-regulates activity	binding			9606	BTO:0000132								16418530	t		lperfetto	In response to agonist stimulation, the alphaIIbbeta3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. This process contributes to both normal hemostasis and thrombosis. Activation of alphaIIbbeta3 is believed to occur in part via engagement of the beta3 cytoplasmic tail with talin; however, the role of the alphaIIb tail and its potential binding partners in regulating alphaIIbbeta3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the alphaIIb tail, is an endogenous inhibitor of alphaIIbbeta3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced alphaIIbbeta3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to alphaIIbbeta3, thus providing a model for tightly controlled regulation of alphaIIbbeta3 activation.	SIGNOR-253357	0.416
STK39	protein	Q9UEW8	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates	binding			9606		BTO:0000142							10980603	t		gcesareni	Spak, a ste20/sps1-related kinase that activates the p38 pathway. p38, one of the three major mapks, can be coimmunoprecipitated with spak and with nkcc1 in an activity-dependent manner. The amount of p38 coimmunoprecipitated with the kinase and the cotransporter significantly decreases upon cellular stress,	SIGNOR-81541	0.368
HIC1	protein	Q14526	UNIPROT	VLDLR	protein	P98155	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001938;BTO:0000815								24076391	f	 	miannu	The Reelin receptors ApoER2 and VLDLR are direct target genes of HIC1. ectopic expression of HIC1 in U2OS and MDA-MB-231 cell lines decreases expression of the ApoER2 and VLDLR genes, encoding two canonical tyrosine kinase receptors for Reelin. 	SIGNOR-254244	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	TSC1	protein	Q92574	UNIPROT	down-regulates	phosphorylation	Thr417	SLPQATVtPPRKEER	9606	BTO:0000680;BTO:0001573;BTO:0001286								14551205	t		lperfetto	Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex	SIGNOR-216953	0.426
RAD51AP1	protein	Q96B01	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates activity	binding			9606									17996711	t		miannu	Homologous recombination (HR) repairs chromosome damage and is indispensable for tumor suppression in humans. RAD51 mediates the DNA strand-pairing step in HR. RAD51 associated protein 1 (RAD51AP1) is a RAD51-interacting protein whose function has remained elusive. Biochemical and cytological results show that RAD51AP1 functions at a step subsequent to the assembly of the RAD51-ssDNA nucleoprotein filament. Purified RAD51AP1 binds both dsDNA and a D loop structure and, only when able to interact with RAD51, greatly stimulates the RAD51-mediated D loop reaction.	SIGNOR-261962	0.762
PPP3CC	protein	P48454	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	dephosphorylation	Ser637	VPVARKLsAREQRDC	9606									18838687	t			When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.	SIGNOR-248506	0.265
quinpirole	chemical	CHEBI:75401	ChEBI	DRD3	protein	P35462	UNIPROT	up-regulates activity	chemical activation			-1									7576010	t		miannu	 D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole.	SIGNOR-258440	0.8
PRKCD	protein	Q05655	UNIPROT	CREBBP	protein	Q92793	UNIPROT	unknown	phosphorylation	Ser437	CLPLKNAsDKRNQQT										11463380	t		lperfetto	This study demonstrates that transcriptional control of mitogen-responsive genes by AP-1 and Pit-1 response elements involves direct phosphorylation of CBP and that growth factor€“dependent phosphorylation of CBP within the GF box is indispensable for signaling via these sites. 	SIGNOR-249104	0.374
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	PPARGC1A	protein	Q9UBK2	UNIPROT	down-regulates				9606									16308421	f		gcesareni	Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner.	SIGNOR-252915	0.2
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser104	GKGSQPPsPPSPAPS	9606									20305697	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-164617	0.575
SERPING1	protein	P05155	UNIPROT	F12	protein	P00748	UNIPROT	down-regulates activity	binding			9606		BTO:0000131							26707513	t		lperfetto	C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1). 	SIGNOR-263517	0.631
MAP3K8	protein	P41279	UNIPROT	MAP2K2	protein	P36507	UNIPROT	up-regulates	phosphorylation	Ser226	LIDSMANsFVGTRSY	9606	BTO:0000007								15466476	t		lperfetto	Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases.	SIGNOR-129698	0.415
CSNK1G2	protein	P78368	UNIPROT	CERT1	protein	Q9Y5P4	UNIPROT	down-regulates	phosphorylation	Ser132	SSLRRHGsMVSLVSG	9606	BTO:0000567	BTO:0000975							19005213	t		lperfetto	These results indicate that ckigamma2 hyperphosphorylates the serine-repeat motif of cert, thereby inactivating cert and down-regulating the synthesis of sphingomyelin.	SIGNOR-182160	0.2
EPHB1	protein	P54762	UNIPROT	CASKIN1	protein	Q8WXD9	UNIPROT	up-regulates activity	phosphorylation	Tyr336	TGNDRVGyFPSSLGE	9534									23181695	t		miannu	EphB1 phosphorylates Caskin1 on tyrosine 296 and 336. Tyrosine phosphorylated Caskin1 then likely promotes reorganization of the actin cytoskeleton leading to spine formation. 	SIGNOR-262861	0.287
ITCH	protein	Q96J02	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates	ubiquitination			9606	BTO:0001573								17115028	t		gcesareni	The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation. we demonstrate that the hedgehog transcription factor gli1 is targeted by numb for itch-dependent ubiquitination, which suppresses hedgehog signals, thus arresting growth and promoting cell differentiation	SIGNOR-150847	0.559
TGFBR2	protein	P37173	UNIPROT	PARD6A	protein	Q9NPB6	UNIPROT	up-regulates	phosphorylation	Ser345	RGDGSGFsL	9606	BTO:0004183								15761148	t		lperfetto	We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. [...] These data suggest that T_RII phosphorylates Par6 at its penultimate residue, Ser345.	SIGNOR-227484	0.443
RBBP8	protein	Q99708	UNIPROT	BRCC ubiquitin ligase complex	complex	SIGNOR-C295	SIGNOR	up-regulates activity	relocalization												24832651	t		lperfetto	DNA damage activates ATM and CHK2 kinases, which mediate phosphorylation of CtIP and BRCA1. Phosphorylated CtIP associates with BRCA1 and with the MRN complex leading to the recruitment of the BRCC complex at the site of DNA damage where HR is initiated.	SIGNOR-263202	0.593
SREBF1	protein	P36956	UNIPROT	MTTP	protein	P55157	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11111091	f		miannu	SREBP1 increased the expression of MTP and increased the assembly and secretion of VLDL containing apo B100. 	SIGNOR-252113	0.425
SYBU	protein	Q9NX95	UNIPROT	STX1A	protein	Q16623	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								15459722	t		miannu	Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes.	SIGNOR-264812	0.433
CLTC	protein	Q00610	UNIPROT	AP-1/clathrin vescicle	complex	SIGNOR-C251	SIGNOR	form complex	binding			9606									23103167	t		lperfetto	Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors	SIGNOR-260676	0.735
STK11	protein	Q15831	UNIPROT	NUAK2	protein	Q9H093	UNIPROT	up-regulates	phosphorylation	Thr208	HQGKFLQtFCGSPLY	9606									14976552	t		llicata	A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold.	SIGNOR-122717	0.277
TESK1	protein	Q15569	UNIPROT	TESK1	protein	Q15569	UNIPROT	up-regulates activity	phosphorylation	Ser220	EPLAVVGsPYWMAPE	9606	BTO:0000567								10207045	t		lperfetto	Site-directed mutagenesis analyses revealed that Ser-215 within the activation loop of the kinase domain is the site of serine autophosphorylation of TESK1. Replacement of Ser-215 by alanine almost completely abolished serine autophosphorylation and histone H3 kinase activities.	SIGNOR-246667	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Thr179	SSPDKRLtLSQIYEW	9606	BTO:0000007								17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-252885	0.398
CSNK2A1	protein	P68400	UNIPROT	SPIB	protein	Q01892	UNIPROT	down-regulates	phosphorylation	Ser144	DSPALEVsDSESDEA	9606									10618498	t		lperfetto	Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability	SIGNOR-73883	0.44
GPC4	protein	O75487	UNIPROT	WNT5A	protein	P41221	UNIPROT	up-regulates	binding			9606									22302992	t		gcesareni	Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways	SIGNOR-195752	0.381
PPP2CA	protein	P67775	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	up-regulates activity	dephosphorylation	Ser486	RPLSRAQsSPAAPAS	9606									18339811	t			Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. 	SIGNOR-248649	0.322
5-phospho-α-D-ribose 1-diphosphate	smallmolecule	CHEBI:58017	ChEBI	orotidine 5'-phosphate(3-)	smallmolecule	CHEBI:57538	ChEBI	up-regulates quantity	precursor of			9606									2912371	t		miannu	Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase).	SIGNOR-267435	0.8
PRKCD	protein	Q05655	UNIPROT	CYTH1	protein	Q15438	UNIPROT	unknown	phosphorylation	Thr395	RKKKVSStKRH	9606	BTO:0001948								11438522	t		lperfetto	We show here that a serine/threonine motif within the short polybasic stretch of cytohesin-1 is phosphorylated by purified protein kinase C delta in vitro. Furthermore, the respective residues are also found to be phosphorylated after phorbol ester stimulation in vivo. Biochemical and functional analyses show that phosphorylated cytohesin-1 is able to tightly associate with the actin cytoskeleton, and we further demonstrate that phosphorylation of the protein is required for maximal leukocyte function antigen-1-mediated adhesion of Jurkat cells to intercellular adhesion molecule 1. 	SIGNOR-249099	0.328
COPS5	protein	Q92905	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0000007								27866850	t		Barakat	The results suggested that TNF-α upregulates expression of CSN5, which interacts and deubiquitinates PD-L1 for protein stabilization.	SIGNOR-274977	0.2
OPTN	protein	Q96CV9	UNIPROT	Cell_growth	phenotype	SIGNOR-PH33	SIGNOR	up-regulates				10090	BTO:0005118								22194658	f	same result in PC12 cell 	miannu	SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA.	SIGNOR-259877	0.7
TBL1Y	protein	Q9BQ87	UNIPROT	CTBP1	protein	Q13363	UNIPROT	down-regulates quantity by destabilization	binding			9606									18374649	t		Luana	TBL1 interacts in vivo with CtBP and promote its proteasomal degradation	SIGNOR-260902	0.2
PTPN1	protein	P18031	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates	dephosphorylation			9606									15632081	t		gcesareni	Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs	SIGNOR-132959	0.733
SERPINA5	protein	P05154	UNIPROT	FN1	protein	P02751	UNIPROT	down-regulates activity	binding			9606	BTO:0000594								24388360	t		miannu	SERPINA5 inhibits HCC cell migration by directly interacting with fibronectin. SERPINA5 disrupts the fibronectin–integrin β1 signaling pathway.	SIGNOR-265881	0.319
BTK	protein	Q06187	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates activity	phosphorylation	Tyr753	ERDINSLyDVSRMYV	9606	BTO:0000776								11507089	t		lperfetto	These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2.	SIGNOR-109754	0.77
IDH2	protein	P48735	UNIPROT	D-threo-isocitrate(3-)	smallmolecule	CHEBI:15562	ChEBI	down-regulates quantity				9606									26178471	t		lperfetto	Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG)	SIGNOR-253136	0.8
CCNK	protein	O75909	UNIPROT	CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	form complex	binding			9606									22012619	t		miannu	We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells	SIGNOR-176786	0.914
TICAM2	protein	Q86XR7	UNIPROT	TICAM1	protein	Q8IUC6	UNIPROT	up-regulates activity	binding			9606	BTO:0000801								14519765	t		lperfetto	Tram binds trif directly and recruits it to tlr4	SIGNOR-118367	0.568
LTB	protein	Q06643	UNIPROT	LTBR	protein	P36941	UNIPROT	up-regulates activity	binding			9606	BTO:0000782	BTO:0000975							7995952	t		lperfetto	These experiments point toward the lt-alpha 1/beta 2 complex as the predominant membrane form of lt on the lymphocyte surface, and this complex is the primary ligand for the lt-beta receptor.	SIGNOR-35759	0.837
EGFR	protein	P00533	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr307	MRHVSISyDIPPTPG	-1									10734310	t		lperfetto	Gab1 is also phosphorylated in response to epidermal growth factor (egf) but is unable to induce tubule formation. nine tyrosines are phosphorylated by both receptors. Three of them (y307, y373, y407) bind phospholipase c-gamma (plc-gamma).	SIGNOR-233233	0.751
TAF1A	protein	Q15573	UNIPROT	SL1 complex	complex	SIGNOR-C464	SIGNOR	form complex	binding			9606									30693017	t		lperfetto	SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation.	SIGNOR-269566	0.818
PTK2B	protein	Q14289	UNIPROT	ASAP1	protein	Q9ULH1	UNIPROT	down-regulates activity	phosphorylation	Tyr767	RDKQRLSyGAFTNQI	9606	BTO:0000007								12771146	t		miannu	The tyrosine kinase Pyk2 regulates Arf1 activity by phosphorylation and inhibition of the Arf-GTPase-activating protein ASAP1. Pyk2 directly phosphorylates ASAP1 on tyrosine residues in vitro and increases ASAP1 tyrosine phosphorylation when co-expressed in HEK293T cells.Phosphorylation of tyrosine 308 and 782 affects the phosphoinositide binding profile of ASAP1, and fluorimetric Arf-GTPase assays with purified proteins revealed an inhibition of ASAP1 GTPase-activating protein activity by Pyk2-mediated tyrosine phosphorylation.	SIGNOR-263187	0.469
PPM1D	protein	O15297	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates	dephosphorylation	Ser395	SQESEDYsQPSTSSS	9606									17936559	t		gcesareni	Wip1 interacts with and dephosphorylates mdm2 at serine 395, a site phosphorylated by the atm kinase. Dephosphorylated mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation.	SIGNOR-158328	0.669
EDNRB	protein	P24530	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257166	0.412
PRKAB2	protein	O43741	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	form complex	binding			9606									16054041	t		gcesareni	Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits.	SIGNOR-139167	0.854
NFATC3	protein	Q12968	UNIPROT	GPC6	protein	Q9Y625	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								21871017	t		miannu	 NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype.	SIGNOR-264024	0.2
NANOG	protein	Q9H9S0	UNIPROT	GATA2	protein	P23769	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086;BTO:0005511								15983365	f		miannu	 Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 	SIGNOR-254625	0.358
MRPS31	protein	Q92665	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261445	0.695
MAGEA3	protein	P43357	UNIPROT	TRIM28	protein	Q13263	UNIPROT	up-regulates activity	binding			9606	BTO:0000594								28394358	t		lperfetto	In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28. 	SIGNOR-267592	0.446
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PDE4D	protein	Q08499	UNIPROT	down-regulates	phosphorylation			9606									10828059	t	The effect has been demonstrated using Q08499-2	gcesareni	These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro.	SIGNOR-270069	0.2
ARRB1	protein	P49407	UNIPROT	SLC9A5	protein	Q14940	UNIPROT	down-regulates activity	relocalization												21296876	t		lperfetto	Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs)	SIGNOR-275505	0.41
MAPK14	protein	Q16539	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates activity	phosphorylation	Ser505	SPVAGVHsPMASSGN	9606	BTO:0000093								15383283	t		miannu	P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators.	SIGNOR-250103	0.505
H3-3A	protein	P84243	UNIPROT	Nucleosome_H3.3 variant	complex	SIGNOR-C339	SIGNOR	form complex	binding			9606									15776021	t		miannu	Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes.	SIGNOR-263876	0.2
CLK1	protein	P49759	UNIPROT	RBM17	protein	Q96I25	UNIPROT	up-regulates activity	phosphorylation	Ser291	EKDASKKsDSNPLTE	9534									23519612	t		miannu	 In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 	SIGNOR-262710	0.324
DYRK1B	protein	Q9Y463	UNIPROT	DYRK1B	protein	Q9Y463	UNIPROT	up-regulates	phosphorylation	Tyr271	CQLGQRIyQYIQSRF	9606									10910078	t		lperfetto	Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site	SIGNOR-79806	0.2
PPP3CB	protein	P16298	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	dephosphorylation	Ser637	VPVARKLsAREQRDC	9606									18838687	t			When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.	SIGNOR-248361	0.281
CSNK2A2	protein	P19784	UNIPROT	NOL3	protein	O60936	UNIPROT	up-regulates activity	phosphorylation	Thr149	SEAVQSGtPEEPEPE	9606									12191471	t		miannu	Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm.	SIGNOR-262836	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates	phosphorylation			9606									18722121	t		lperfetto	Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity	SIGNOR-252794	0.474
MAP3K11	protein	Q16584	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates	phosphorylation	Thr261	LVDSIAKtRDAGCRP	9606									10727406	t		gcesareni	These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo.	SIGNOR-75836	0.608
IKBKB	protein	O14920	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	down-regulates activity	phosphorylation	Ser68	LRDAIRQsNQILRER	9606			SIGNOR-C14	SIGNOR-C14					17977820	t		lperfetto	In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I	SIGNOR-158659	0.962
GSK3B	protein	P49841	UNIPROT	GLI2	protein	P10070	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser863	DPISTDAsRRSSEAS	9606	BTO:0000007								16611981	t		lperfetto	The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3.	SIGNOR-249590	0.544
NKX3-1	protein	Q99801	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity				9606									16697957	t		miannu	NKX3.1 negatively regulates AKT activity in an AR-dependent manner	SIGNOR-251552	0.503
SRF	protein	P11831	UNIPROT	NKX3-1/SRF	complex	SIGNOR-C25	SIGNOR	form complex	binding			9606		BTO:0000887;BTO:0001260							10993896	t		lperfetto	A novel complex element containing a juxtaposed nkx-binding site (nke) and an srf-binding element (sre) in the proximal promoter region was found to be necessary for the nkx3-1/srf coactivation of smga transcription.	SIGNOR-82090	0.405
PRKCA	protein	P17252	UNIPROT	IL2RA	protein	P01589	UNIPROT	unknown	phosphorylation	Ser268	WQRRQRKsRRTI	9606	BTO:0000782								2303462	t		lperfetto	The interleukin-2 (il-2) receptor, the leukocyte-specific membrane glycoprotein, t200, and the class i major histocompatibility antigens (hla) have been identified as substrates for protein kinase c from these studies, it was concluded that ser-247 is the major site of phosphorylation in the il-2 receptor and that thr-250 is a minor site.	SIGNOR-22984	0.267
9-HODE	chemical	CHEBI:72651	ChEBI	GPR132	protein	Q9UNW8	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257501	0.8
CSNK2A2	protein	P19784	UNIPROT	HDAC1	protein	Q13547	UNIPROT	up-regulates activity	phosphorylation	Ser421	IACEEEFsDSEEEGE	9606	BTO:0000661								11602581	t		llicata	Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1.	SIGNOR-250999	0.407
SMAD7	protein	O15105	UNIPROT	SMURF1	protein	Q9HCE7	UNIPROT	up-regulates activity	relocalization			9606									19352540	t		lperfetto	Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway.	SIGNOR-185131	0.877
MAPK14	protein	Q16539	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates activity	phosphorylation	Ser360	TEMDPTYsPAALPQS	9606									15568999	t		lperfetto	Msk1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the erk1/2 (extracellular-signal-regulated kinase) and p38 mapk (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites	SIGNOR-130736	0.594
FYN	protein	P06241	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Tyr18	MEDHAGTyGLGDRKD	9606									14999081	t		lperfetto	In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn.	SIGNOR-123099	0.552
AMPK	complex	SIGNOR-C15	SIGNOR	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation	Ser638	FDFPKTPsSQNLLAL	9606									21205641	t		lperfetto	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-216461	0.469
PRKCA	protein	P17252	UNIPROT	CREBBP	protein	Q92793	UNIPROT	down-regulates	phosphorylation			9606									20577053	t		gcesareni	The action of metformin was shown to be mediated through activation of apkc?/?, Which phosphorylates cbp at ser436, and disrupts the transcriptionally active creb-cbp-crtc2 complex,	SIGNOR-166368	0.264
SRC	protein	P12931	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr861	PIGNQHIyQPVGKPD	9606									15735019	t		miannu	Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates	SIGNOR-150492	0.633
ING1	protein	Q9UK53	UNIPROT	CASP3	protein	P42574	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001938								15662138	f		miannu	Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. 	SIGNOR-254489	0.261
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	NLRP3	protein	Q96P20	UNIPROT	down-regulates activity	phosphorylation	Ser295	HKIVRKPsRILFLMD	-1									27548431	t		miannu	PKA directly phosphorylated the cytoplasmic receptor NLRP3 and attenuated its ATPase function. We found that Ser295 in human NLRP3 was critical for rapid inhibition and PKA phosphorylation.	SIGNOR-277274	0.2
GALR1	protein	P47211	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256830	0.427
CCKAR	protein	P32238	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257148	0.254
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	MGluR	proteinfamily	SIGNOR-PF55	SIGNOR	up-regulates activity	chemical activation			9606									25042998	t		miannu	Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate	SIGNOR-264688	0.8
HECTD3	protein	Q5T447	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates activity	polyubiquitination			9606	BTO:0004461								28716524	t		miannu	HECTD3 binds and ubiquitinates caspase-9.HECTD3 inhibits caspase-9 oligomerization and association with Apaf-1. HECTD3 suppressing caspase-9 activation is dependent on T157 phosphorylation by ERK.	SIGNOR-272329	0.2
MAP3K7	protein	O43318	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates activity	phosphorylation	Ser181	DQGSLCTsFVGTLQY	9606				SIGNOR-C14					11460167	t		lperfetto	Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta.	SIGNOR-109494	0.744
SRC	protein	P12931	UNIPROT	SRCIN1	protein	Q9C0H9	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								8647432	t		miannu	Phosphorylation of multiple tyrosine-containing motifs found on Sin correlated with c-Crk and cellular phosphoprotein binding to Sin as well as increased c-Src activity. These data suggest that (1) SH2 and SH3 ligand sites on Sin cooperatively activate the signaling potential of c-Src, (2) Sin acts as both an activator and a substrate for c-Src, and (3) phosphorylated Sin may serve as a signaling effector molecule for Src by binding to multiple cellular proteins.	SIGNOR-263196	0.51
PTGER2	protein	P43116	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates				9606	BTO:0000586								17251915	f		gcesareni	Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa).	SIGNOR-152805	0.3
MYCL	protein	P12524	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0002891								27546534	f		irozzo	Our findings demonstrate that stable expression of the L-MYC gene in NSC008 cells promotes their survival and proliferation while preserving their migration and differentiation properties in vitro and in vivo.	SIGNOR-259109	0.7
UBE2I	protein	P63279	UNIPROT	PLAG1	protein	Q6DJT9	UNIPROT	down-regulates	sumoylation	Lys244	NQELLKVkTEPVDFL	9606									15208321	t		miannu	Sumoylation decreases the transcriptional activity of plag1 / plag1 is sumoylated at 2 specific lysine residues (lys-244 and lys-263)	SIGNOR-126044	0.281
PTPRG	protein	P23470	UNIPROT	PTK2	protein	Q05397	UNIPROT	down-regulates activity	dephosphorylation	Tyr861	PIGNQHIyQPVGKPD	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254720	0.245
PI4KA	protein	P42356	UNIPROT	ADP(3-)	smallmolecule	CHEBI:456216	ChEBI	up-regulates quantity	chemical modification			9606									10101268	t		miannu	The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 	SIGNOR-269104	0.8
APOBEC3G	protein	Q9HC16	UNIPROT	Clearance_of_foreign intracellular_DNA	phenotype	SIGNOR-PH132	SIGNOR	up-regulates				9606									29367246	f		lperfetto	The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24).	SIGNOR-261329	0.7
5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide	chemical	CID:73755145	PUBCHEM	FLT1	protein	P17948	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259807	0.8
CENP-A nucleosome	complex	SIGNOR-C321	SIGNOR	Centromere_assembly	phenotype	SIGNOR-PH154	SIGNOR	up-regulates				9606	BTO:0000567								20566683	f		miannu	Centromeres contain specialized nucleosomes in which histone H3 is replaced by the histone variant centromere protein A (CENP-A). CENP-A nucleosomes are thought to act as an epigenetic mark that specifies centromere identity.	SIGNOR-263704	0.7
FMR1	protein	Q06787	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates quantity	post transcriptional regulation			10090		BTO:0000142							32118033	t		lperfetto	These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.	SIGNOR-262108	0.487
SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	NANOG	protein	Q9H9S0	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269237	0.764
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606									23552696	t		lperfetto	Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1	SIGNOR-245428	0.2
TSPAN7	protein	P41732	UNIPROT	DRD2	protein	P14416	UNIPROT	down-regulates quantity	binding			9606	BTO:0000007								28223337	t		miannu	 Tetraspanin-7 (TSPAN7) is expressed to variable degrees in different tissues, with the highest level in the brain, and multiple mutations in TSPAN7 have been implicated in intellectual disability. Our results showed that TSPAN7 was associated with DRD2 and reduced its surface expression by enhancing DRD2 internalization.Finally, TSPAN7 negatively affects DRD2-mediated signaling.	SIGNOR-265557	0.254
SMG1	protein	Q96Q15	UNIPROT	UPF1	protein	Q92900	UNIPROT	up-regulates	phosphorylation	Ser1089	GLSQPELsQDSYLGD	9606									23356578	t		lperfetto	Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively	SIGNOR-200785	0.971
MTOR	protein	P42345	UNIPROT	MAF1	protein	Q9H063	UNIPROT	down-regulates	phosphorylation	Ser68	PPQTSGLsPSRLSKS	9606									20233713	t		gcesareni	The identification of maf1 as an mtor-regulated phosphoprotein implicates mtor in the broader regulatory mechanisms governing pol iii activity in cancer cells.	SIGNOR-164348	0.7
1-phosphatidyl-1D-myo-inositol 4-phosphate(3-)	smallmolecule	CHEBI:58178	ChEBI	1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-)	smallmolecule	CHEBI:58456	ChEBI	up-regulates quantity	precursor of			9606									9367159	t		miannu	Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities	SIGNOR-277288	0.8
ERMP1	protein	Q7Z2K6	UNIPROT	UPR	phenotype	SIGNOR-PH131	SIGNOR	up-regulates activity				9606	BTO:0000093								27566589	f			Furthermore, we show that this protein is an important player in the UPR and defense against oxidative stress. ERMP1 expression is strongly affected by reticular stress induced by thapsigargin and other oxidative stresses. ERMP1 silencing during reticular stress impairs the activation of PERK, a key sensor of the UPR activation.	SIGNOR-261295	0.7
BAK1	protein	Q16611	UNIPROT	AIFM1	protein	O95831	UNIPROT	up-regulates	relocalization			9606									23003569	t		gcesareni	First, bax/bak-mediated momp leads to the release of a significant part of the cyt c, smac/diablo and htra2/omi proteins. in a third step, cyt c, smac/diablo and htra2/omi, which were released into the cytosol, trigger caspase activation. This is necessary to alter the physical association of aif and endog with the im to enable their relocation to the cytosol.	SIGNOR-192092	0.303
ABL1	protein	P00519	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr149	SVTAPSPyAQPSSTF	9606									19783996	t		Manara	In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. 	SIGNOR-260934	0.524
NME1	protein	P15531	UNIPROT	SMO	protein	Q99835	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001567								17671192	f		miannu	To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 	SIGNOR-255168	0.2
GUCY1B2	protein	O75343	UNIPROT	GUCY1A2-B2	complex	SIGNOR-C137	SIGNOR	form complex	binding			9606									10977868	t		gcesareni	This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity	SIGNOR-243974	0.2
FZR1	protein	Q9UM11	UNIPROT	AURKA	protein	O14965	UNIPROT	down-regulates quantity by destabilization	binding			9534	BTO:0004055								12023018	t		miannu	We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity.	SIGNOR-272610	0.542
CSNK2A1	protein	P68400	UNIPROT	HMGA1	protein	P17096	UNIPROT	unknown	phosphorylation	Ser102	EEGISQEsSEEEQ	-1									2806554	t		llicata	Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells.	SIGNOR-250892	0.335
PRKCZ	protein	Q05513	UNIPROT	HABP4	protein	Q5JVS0	UNIPROT	down-regulates activity	phosphorylation	Thr354	RKPANDItSQLEINF	9606	BTO:0004974								14699138	t		lperfetto	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249251	0.295
GABARAP	protein	O95166	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity	binding			9606									11146101	t		lperfetto	N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions	SIGNOR-219391	0.335
TP53	protein	P04637	UNIPROT	FGF2	protein	P09038	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									10029407	f		miannu	 p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1.	SIGNOR-255431	0.453
AMHR2	protein	Q16671	UNIPROT	ACVR1	protein	Q04771	UNIPROT	up-regulates	binding			9606									14746809	t		gcesareni	See table2	SIGNOR-121593	0.533
PRKCB	protein	P05771	UNIPROT	SLC6A9	protein	P48067-2	UNIPROT	down-regulates activity	phosphorylation	Thr590	PALLEHRtGRYAPTI	9823									21864610	t		miannu	We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 	SIGNOR-262927	0.2
BMI1	protein	P35226	UNIPROT	NDN	protein	Q99608	UNIPROT	down-regulates				9606	BTO:0000007								24392140	f		lperfetto	In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, whereas Bmi1 counteracts necdin-mediated repression of E2F1-dependent Cdk1 promoter activity.	SIGNOR-253386	0.255
DAPK3	protein	O43293	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates	phosphorylation	Thr19	KKRPQRAtSNVFAMF	9606									19851336	t		lperfetto	More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.	SIGNOR-188793	0.501
Amyloid_fibril_formation	phenotype	SIGNOR-PH59	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates													26721223	f			Excessive accumulation of Aβ protein in the AD brain may lead to a decrease in the levels of phosphatidylinositol-3 kinase (PI3K) and the serine/threonine protein kinase B (Akt) activity. 	SIGNOR-255493	0.7
SSU72	protein	Q9NP77	UNIPROT	STAG2	protein	Q8N3U4	UNIPROT	up-regulates activity	dephosphorylation	Ser1224	PASIMDEsVLGVSMF										20818333	t		lperfetto	Additional experiments revealed that Ssu72 directly interacts with Rad21 and SA2 in vitro and in vivo, and associates with sister chromatids in human cells. Interestingly, depletion or mutational inactivation of Ssu72 phosphatase activity caused the premature resolution of sister chromatid arm cohesion, whereas the overexpression of Ssu72 yielded high resistance to this resolution.|anti‐phospho SA2 serine 1224	SIGNOR-275531	0.302
CAMK2D	protein	Q13557	UNIPROT	SCN5A	protein	Q14524	UNIPROT	down-regulates	phosphorylation	Thr594	LHGKKNStVDCNGVV	9606									22514276	t		miannu	A stable interaction between ?(C)-camkii and the intracellular loop between domains 1 and 2 of na(v)1.5 was observed. This region was also phosphorylated by ?(C)-camkii, specifically at the ser-516 and thr-594 sites.Wild-type (wt) and phosphomutant hna(v)1.5 were co-expressed with gfp-?(C)-camkii in hek293 cells, and i(na) was recorded. As observed in myocytes, camkii shifted wt i(na) availability to a more negative membrane potential and enhanced accumulation of i(na) into an intermediate inactivated state, but these effects were abolished by mutating either of these sites to non-phosphorylatable ala residues.	SIGNOR-197067	0.48
CDK1	protein	P06493	UNIPROT	NDUFA12	protein	Q9UI09	UNIPROT	up-regulates activity	phosphorylation	Thr120	HKFNVTGtPEQYVPY										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275588	0.2
TRAF2	protein	Q12933	UNIPROT	TRAF1	protein	Q13077	UNIPROT	up-regulates	binding			9606									8069916	t		amattioni	Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2.	SIGNOR-35881	0.618
GGCX	protein	P38435	UNIPROT	F10	protein	P00742	UNIPROT	up-regulates activity	carboxylation	Glu79	EDSDKTNeFWNKYKD	-1									9538022	t		lperfetto	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263674	0.598
PPP2CA	protein	P67775	UNIPROT	RB1	protein	P06400	UNIPROT	up-regulates	dephosphorylation			9606									10702384	t		gcesareni	This dephosphorylation returns prb to its active, growth suppressive state.	SIGNOR-75398	0.483
IL22	protein	Q9GZX6	UNIPROT	IL22RA1	protein	Q8N6P7	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0000876								12941475	t		fspada	In addition, il-22 mediates inflammation and binds class ii cytokine receptor heterodimers il-22 ra1/crf2-4.	SIGNOR-86340	0.89
IRF9	protein	Q00978	UNIPROT	IFNAR2	protein	P48551	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								17923090	t		lperfetto	By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2.	SIGNOR-217779	0.717
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000007								15342917	t		lperfetto	The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1	SIGNOR-252796	0.474
NR1I2	protein	O75469	UNIPROT	UGT1A1	protein	P22309	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18172616	f	 	miannu	 This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities.	SIGNOR-254440	0.469
LYN	protein	P07948	UNIPROT	IRF5	protein	Q13568	UNIPROT	down-regulates activity	phosphorylation	Tyr335	QLQGQDLyAIRLCQC	9606	BTO:0002181								27521268	t		miannu	Lyn Kinase Suppresses the Transcriptional Activity of IRF5. Here, we found that Lyn physically interacted with IRF5 to inhibit ubiquitination and phosphorylation of IRF5 in the TLR-MyD88 pathway, thereby suppressing the transcriptional activity of IRF5 in a manner independent of Lyn's kinase activity.	SIGNOR-277248	0.335
RPS6KA1	protein	Q15418	UNIPROT	CDC25B	protein	P30305	UNIPROT	up-regulates	phosphorylation	Thr355	NKRRRSVtPPEEQQE	9606									23708659	t		lperfetto	Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.	SIGNOR-202125	0.256
HIC1	protein	Q14526	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates activity	transcriptional regulation			9606	BTO:0000815								24067369	f	 	miannu	 HIC1 suppressing the VEGF and c-Myc promoter activity and the colony formation of MDA-MB 231 cells were STAT3-dependent.	SIGNOR-254245	0.33
KDR	protein	P35968	UNIPROT	KDR	protein	P35968	UNIPROT	up-regulates	phosphorylation	Tyr1214	VCDPKFHyDNTAGIS	9606	BTO:0000801;BTO:0000876								17658244	t		gcesareni	Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability.	SIGNOR-157093	0.2
TRIM27	protein	P14373	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates				9606		BTO:0000671							12807881	f		miannu	Rfp expression in hek 293 cells activated jnk1	SIGNOR-102034	0.26
CBFbeta-MYH11	fusion protein	SIGNOR-FP3	SIGNOR	RUNX1	protein	Q01196	UNIPROT	down-regulates activity	binding			9606									29958106	t		miannu	The genes encoding CBFβ and RUNX1 are frequent targets of mutations in hematologic malignancies. The chromosome inversion inv(16)(p13;q22), found in 8% of acute myeloid leukemia (AML) cases, fuses the CBFB and MYH11 genes to produce the leukemic oncoprotein CBFβ-SMMHC. This fusion protein has higher affinity and altered stoichiometry for RUNX1 relative to the native CBFβ (Cao et al., 1997; Lukasik et al., 2002). During development, CBFβ-SMMHC expression blocks definitive hematopoiesis and embryos die at mid-gestation (Castilla et al., 1996), a similar phenotype to that of Runx1- and Cbfb-knock out embryos (Wang et al., 1996a; Wang et al., 1996b), indicating that CBFβ-SMMHC has a dominant negative effect on RUNX function. 	SIGNOR-255743	0.2
FADS6	protein	Q8N9I5	UNIPROT	long-chain fatty acyl-CoA(4-)	smallmolecule	CHEBI:83139	ChEBI	down-regulates quantity	chemical modification			9606									15189125	t		miannu	Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity.	SIGNOR-267910	0.8
F2RL3	protein	Q96RI0	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates	binding			9606									17158345	t		gcesareni	Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13)	SIGNOR-151162	0.357
KDM3A	protein	Q9Y4C1	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									16603237	t		miannu	Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. 	SIGNOR-276845	0.2
SUMO1	protein	P63165	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates	sumoylation	Lys490	QCPRKVIkMESEEGK	9534									9756909	t		lperfetto	We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation.	SIGNOR-261787	0.771
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1871	SPKYSPTsPKYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269368	0.718
PPP2CB	protein	P62714	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	dephosphorylation	Ser57	KKDRFYRsILPGDKT	10116									18586681	t			Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation.	SIGNOR-248598	0.2
PLK1	protein	P53350	UNIPROT	CENPQ	protein	Q7L2Z9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr135	PKKMEDLtNVSSLLN	9606	BTO:0000567								25670858	t		lperfetto	Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 	SIGNOR-265234	0.57
LCK	protein	P06239	UNIPROT	CD28	protein	P10747	UNIPROT	up-regulates	phosphorylation	Tyr191	SRLLHSDyMNMTPRR	9606									22936936	t		lperfetto	We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor	SIGNOR-198755	0.745
CSNK1A1	protein	P48729	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates activity	phosphorylation	Ser77	YEPEGSAsPTPPYLK	-1									17318175	t		lperfetto	Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling.	SIGNOR-249191	0.776
IL1B	protein	P01584	UNIPROT	DIO	proteinfamily	SIGNOR-PF83	SIGNOR	down-regulates quantity by repression	transcriptional regulation			10116									9397972	f	inferred from family member	scontino	From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells grown in TSH-containing medium. These include TNF-a, IL-lb and INF-g but not TGF-b.	SIGNOR-267812	0.2
PRKCZ	protein	Q05513	UNIPROT	ATP1A1	protein	P05023	UNIPROT	up-regulates activity	phosphorylation	Ser16	KYEPAAVsEQGDKKG	9606	BTO:0000018								12671055	t		miannu	Na,K-ATPase alpha(1) subunit was phosphorylated by PKC in hypoxia-treated AEC. In AEC treated with a PKC-zeta antagonist peptide or with the Na,K-ATPase alpha(1) subunit lacking the PKC phosphorylation site (Ser-18), hypoxia failed to decrease Na,K-ATPase abundance and function.	SIGNOR-263181	0.2
budesonide	chemical	CHEBI:3207	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									9753485	t	Crohn's Disease	gcesareni		SIGNOR-251690	0.8
AT9283	chemical	CID:11696609	PUBCHEM	JAK3	protein	P52333	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190020	0.8
CDK2	protein	P24941	UNIPROT	MCM4	protein	P33991	UNIPROT	down-regulates activity	phosphorylation	Thr19	GSRRGRAtPAQTPRS	9606	BTO:0000567								12714602	t		lperfetto	We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex.	SIGNOR-100893	0.758
PTPN6	protein	P29350	UNIPROT	SOCS1	protein	O15524	UNIPROT	up-regulates	binding			9606									14551136	t		gcesareni	All together, our results indicate that shp-1 inhibits prlr and epor signaling by recruitment and targeting of socs-1 to jak2, highlighting a new mechanism of shp-1 regulation of cytokine-receptor signaling.	SIGNOR-118572	0.332
H2AX	protein	P16104	UNIPROT	MDC1	protein	Q14676	UNIPROT	up-regulates	binding			9606									16377563	t		fstefani	Here, we demonstrate that mammalian mdc1/nfbd1 directly binds to phospho-h2ax (gammah2ax) by specifically interacting with the phosphoepitope at the gammah2ax carboxyl terminus.	SIGNOR-143377	0.2
HOXA10	protein	P31260	UNIPROT	MYLK	protein	Q15746	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002196								15886193	t		Luana	Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively	SIGNOR-261643	0.2
CDK20	protein	Q8IZL9	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates	phosphorylation	Thr160	GVPVRTYtHEVVTLW	9606									14597612	t		gcesareni	P42 is essential for the phosphorylation of thr-160 and activation of cdk2.	SIGNOR-118986	0.394
PRKACA	protein	P17612	UNIPROT	PPP1R8	protein	Q12972	UNIPROT	down-regulates activity	phosphorylation	Ser199	PKRKRKNsRVTFSED	-1									9407077	t		miannu	NIPP-1 is the RNA-binding subunit of a major species of protein phosphatase-1 in the nucleus. The purified recombinant protein was a potent (Ki = 9.9 +/- 0.3 pM) and specific inhibitor of protein phosphatase-1 and was stoichiometrically phosphorylated by protein kinases A and CK2. At physiological ionic strength, phosphorylation by these protein kinases drastically decreased the inhibitory potency of free NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A	SIGNOR-250033	0.496
GSK3B	protein	P49841	UNIPROT	UNG	protein	P13051	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser64	EPGTPPSsPLSAEQL	9606	BTO:0000812								27875297	t		lperfetto	Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation 	SIGNOR-264884	0.2
MDM2	protein	Q00987	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									22337874	t		lperfetto	The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2.	SIGNOR-196116	0.968
UBQLN2	protein	Q9UHD9	UNIPROT	HNRNPA3	protein	P51991	UNIPROT	up-regulates quantity by stabilization	binding												25616961	t		lperfetto	We screened a yeast two-hybrid library using the central domain of ubiquilin-2 hoping to identify proteins whose binding is affected by the UBQLN2 mutations.||Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein 	SIGNOR-262272	0.459
PRKCA	protein	P17252	UNIPROT	CD5	protein	P06127	UNIPROT	unknown	phosphorylation	Thr436	FHRNHTAtVRSHAEN	9606	BTO:0000661								11123317	t		lperfetto	Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. 	SIGNOR-249071	0.345
PPP1CA	protein	P62136	UNIPROT	BRCA1	protein	P38398	UNIPROT	down-regulates activity	dephosphorylation	Ser1423	AVLEQHGsQPSNSYP	9606	BTO:0000007								17603999	t			Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524.	SIGNOR-248561	0.384
MARK1	protein	Q9P0L2	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser641	KVTSKCGsLGNIHHK	9606									21215781	t	The effect has been demonstrated using P10636-8	lperfetto	Mark and pka phosphorylate several sites within the repeats (notably the kxgs motifs including ser262, ser324, and ser356, plus ser320)tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process	SIGNOR-171054	0.44
ATM	protein	Q13315	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1524	LQNRNYPsQEELIKV	9606	BTO:0000150								10550055	t		lperfetto	The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm	SIGNOR-72068	0.813
YAP1	protein	P46937	UNIPROT	TP73	protein	O15350	UNIPROT	up-regulates	binding			9606									21808241	t	The WW domain of YAP binds to PPXY-containing p73 family members.	gcesareni	Yap also interacts with p73, a p53 family pro-apoptotic transcription factor, to induce expression of genes such as bax, puma and pml.	SIGNOR-175934	0.704
PCK1	protein	P35558	UNIPROT	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	down-regulates quantity	chemical modification			9606									30193097	t		miannu	 PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP). 	SIGNOR-266588	0.8
1-phospho-alpha-D-glucuronic acid	smallmolecule	CHEBI:681	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			-1									7576010	t		miannu	The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1.Similarly, the affinities of D3 receptors for quinpirole and dopamine were much higher than the affinities of D:! receptors for the agonists in the presence of Gpp(NH)p and NaCl when [1251]-NCQ-298 was used to label receptors; however, when Gpp(NH)p and NaCl were not present, and when [12sI]-7-OH-PIPAT was used, receptors bound quinpirole and dopamine with nearly equal affinities (Table 1). 	SIGNOR-258435	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	SYNGAP1	protein	Q96PV0	UNIPROT	up-regulates activity	phosphorylation	Ser1073	PPLQRGKsQQLTVSA	-1									14970204	t		miannu	Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. The Major Phosphorylation Sites, Serines 764/765, 1058, and 1123, All Contribute to Regulation of GAP Activity of synGAP by CaMKII	SIGNOR-262687	0.439
EIF4E	protein	P06730	UNIPROT	eIF4F_complex	complex	SIGNOR-C44	SIGNOR	form complex	binding			9606									11408474	t		miannu	Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f.	SIGNOR-108515	0.84
EIF1	protein	P41567	UNIPROT	43S_pre_initiation_complex	complex	SIGNOR-C453	SIGNOR	form complex	binding			9606									35489072	t		lperfetto	In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 	SIGNOR-269161	0.778
CKM complex	complex	SIGNOR-C406	SIGNOR	H3-4	protein	Q16695	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR										18418385	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	lperfetto	However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo.	SIGNOR-273174	0.2
SRC	protein	P12931	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	unknown	phosphorylation	Tyr45	GLEPVGHyEEVELTE	9606									16640565	t		llicata	Src kinase phosphorylates s6k in the n-terminus. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vitro. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vivo.	SIGNOR-146292	0.347
AHR	protein	P35869	UNIPROT	AHR-ARNT	complex	SIGNOR-C125	SIGNOR	form complex	binding			-1									9020169	t	2	miannu	SIM1 and SIM2, and the mammalian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins are members of the basic-helix-loop-helix·PAS family of transcription factors. In the yeast two-hybrid system, we demonstrate strong constitutive interaction of ARNT with SIM1 and SIM2 and fully ligand-dependent interaction of ARNT with AHR. SIM1 inhibits binding of the AHR·ARNT dimer to the xenobiotic response element in vitro Introduction of SIM1 into hepatoma cells inhibits transcriptional transactivation by the endogenous AHR·ARNT dimer.	SIGNOR-240817	0.744
RAI1	protein	Q7Z5J4	UNIPROT	PER2	protein	O15055	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									22578325	f		miannu	Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. 	SIGNOR-266840	0.314
GRK5	protein	P34947	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation			9606									2787365	t		gcesareni	 we found that g protein-coupled receptor kinases 5 and 6 (grk5/6), traditionally known to phosphorylate and desensitize 7tm g protein-coupled receptors, directly phosphorylate the pppsp motifs on single transmembrane lrp6 and regulate wnt/lrp6 signaling	SIGNOR-23330	0.529
MRGPRD	protein	Q8TDS7	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	down-regulates				10090	BTO:0000801								30918468	f		Luana	Our data suggested that both Ang-(1-7) and alamandine, through their respective receptors Mas and MrgD, promote an anti-inflammatory reprogramming of M(LPS+IFN-γ)/M1 macrophages under inflammatory circumstances and potentiate the reprogramming induced by IL-4.	SIGNOR-262310	0.7
PXN	protein	P49023	UNIPROT	IPP complex	complex	SIGNOR-C380	SIGNOR	up-regulates activity	relocalization												16493410	t		lperfetto	Integrin-linked kinase (ILK), and isoforms of particularly interesting Cys-His-rich protein (PINCH) and parvin form the IPP complex (Fig. 2) in the cytoplasm, and this complex is recruited to focal adhesions through interactions with other factors, such as paxillin.	SIGNOR-265767	0.577
PPM1F	protein	P49593	UNIPROT	CAMK2A	protein	Q9UQM7	UNIPROT	down-regulates	dephosphorylation	Thr286	SCMHRQEtVDCLKKF	9606	BTO:0000938								15140879	t		gcesareni	Ppm1f specifically dephosphorylates the phospho-thr-286 in autophosphorylated camkii substrate and thus deactivates the camkii in vitro.	SIGNOR-124309	0.337
SYN3	protein	O14994	UNIPROT	Synaptic_vesicle_exocytosis	phenotype	SIGNOR-PH160	SIGNOR	down-regulates				9606	BTO:0000938								33809712	f		miannu	Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet.	SIGNOR-264107	0.7
ETS1	protein	P14921	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates quantity	transcriptional regulation			9606									1722028	t			Furthermore, the possible involvement of an Ets protein in the control of c-fos has interesting implications for proto-oncogene cooperation in cellular growth control.	SIGNOR-256495	0.707
CEBPA	protein	P49715	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates				10090									17139329	f		fferrentino	C/EBPα induces many adipocyte genes directly, and in vivo studies indicate an important role for this factor in the development of adipose tissue.	SIGNOR-132946	0.7
PRKCA	protein	P17252	UNIPROT	NOX5	protein	Q96PH1	UNIPROT	up-regulates	phosphorylation	Thr540	KRLSRSVtMRKSQRS	9606									24505490	t		llicata	A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498.	SIGNOR-204554	0.2
IGF1R	protein	P08069	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates activity	phosphorylation	Tyr1161	FGMTRDIyETDYYRK	9606									7493944	t		lperfetto	Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor.	SIGNOR-26582	0.2
AIMP1	protein	Q12904	UNIPROT	SMURF2	protein	Q9HAU4	UNIPROT	up-regulates	binding			9606									18448069	t		lpetrilli	Here, we report that aimp1 negatively regulates tgf-? Signaling via stabilization of smurf2.	SIGNOR-178498	0.399
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257906	0.8
afatinib	chemical	CHEBI:61390	ChEBI	ERBB4	protein	Q15303	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002058								24643470	t		miannu	This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. 	SIGNOR-259295	0.8
MED23	protein	Q9ULK4	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266665	0.728
PPM1F	protein	P49593	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates	dephosphorylation			9606									20016286	t		gcesareni	Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity.	SIGNOR-162146	0.399
FOXO3	protein	O43524	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000222								18854138	f		gcesareni	Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts.	SIGNOR-181618	0.397
PTPN22	protein	Q9Y2R2	UNIPROT	CBL	protein	P22681	UNIPROT	down-regulates	dephosphorylation	Ser798	SDISNASsSFGWLSL	9606	BTO:0000782								10068674	t		amattioni	The tyrosine phosphatase lyp1 was found to be constitutively associated with the proto-oncogene c-cbl in thymocytes and t cells. Overexpression of lyp1 reduces cbl tyrosine phosphorylation. It is known that cbl is heavily tyrosine phosphorylated after tcr stimulation and can associate with the syk and zap tyrosine kinases, negatively regulating their activities. Tyrosine phosphatases keep cbl in a basally dephosphorylated state.	SIGNOR-65405	0.395
topotecan	chemical	CHEBI:63632	ChEBI	TOP1	protein	P11387	UNIPROT	down-regulates activity	chemical inhibition			9606									11166732	t		miannu	Topotecan is a topoisomerase I inhibitor which is currently evaluated as an adjuvant agent for malignant glioma.	SIGNOR-259317	0.8
PPP1CA	protein	P62136	UNIPROT	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	down-regulates activity	dephosphorylation			9606									14751588	t		miannu	Dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein, 32 kDa (DARPP-32) is a key element of dopamine/D1/DARPP-32/protein phosphatase-1 (PP-1) signaling cascades of mammalian brain. Phosphorylation of AMPA receptors due to DARPP-32/PP1 signaling cascade increases AMPA channel activity and currents	SIGNOR-265060	0.504
retinol	smallmolecule	CHEBI:50211	ChEBI	retinal	smallmolecule	CHEBI:15035	ChEBI	up-regulates quantity	precursor of			9606									21621639	t		lperfetto	Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9	SIGNOR-265112	0.8
CSNK1G1	protein	Q9HCP0	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser322	PRTSSNAsTISGRLS	-1									11980723	t		llicata	Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR	SIGNOR-252901	0.471
PLK1	protein	P53350	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser24	GYLRKPKsMHKRFFV	9606									15849359	t		lperfetto	Phosphorylation of ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by mouse pelle-like kinase/interleukin-1 receptor-associated kinase| irs-1 mutants s24d or s24e (mimicking phosphorylation at ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of irs-1 and impaired ability of irs-1 to bind and activate pi-3 kinase in response to insulin.	SIGNOR-135688	0.271
CDK2	protein	P24941	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates	phosphorylation	Ser123	EEGFGSSsPVKSPAA	9606									16085715	t		gcesareni	Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp. During the s and g2 phases, s123 (wee1) is phosphorylated by a cdk (possibly cdk2).	SIGNOR-139469	0.651
ILK	protein	Q13418	UNIPROT	CFL1	protein	P23528	UNIPROT	down-regulates	phosphorylation	Ser3	sGVAVSDG	9606									18252715	t		gcesareni	Actin (de)polymerization is regulated by cofilin, the ser(3) phosphorylation (ps(3)cofilin) of which inhibits its actin-severing activity. To determine how ilk regulates ps(3)cofilin, we examined the effects of ilk on ps(3)cofilin using normal rie1 cells.	SIGNOR-160756	0.357
DYRK1A	protein	Q13627	UNIPROT	DNM1	protein	Q05193	UNIPROT	down-regulates	phosphorylation	Ser795	VPPARPGsRGPAPGP	9606		BTO:0000142							15287745	t		lperfetto	Mnb/dyrk1a was shown to phosphorylate dynamin 1 and alter its interactions with several sh3 domain-containing endocytic accessory proteins.Phosphorylation At s795 and s857 was confirmed in full-length dynamin 1, and s857 was subsequently determined to be the major mnb/dyrk1a phosphorylation site in vitro. Phosphorylation at s857 was demonstrated to be the basis for altering the binding of dynamin 1 to amphiphysin 1 and grb 2 by site-directed mutants mimicking phosphorylation.	SIGNOR-127440	0.426
SMOC1	protein	Q9H4F8	UNIPROT	BGLAP	protein	P02818	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20359165	f		lperfetto	The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells	SIGNOR-260400	0.2
HIF1A	protein	Q16665	UNIPROT	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	up-regulates				9606	BTO:0001336								28623342	f			Our results demonstrate that SF(synovial fibroblasts) are highly dependent on glycolytic metabolism and that HIF-1α plays a regulatory role in glycolysis even under aerobic conditions.	SIGNOR-259380	0.7
3-isobutyl-1-methyl-7H-xanthine	smallmolecule	CHEBI:34795	ChEBI	CEBPB	protein	P17676	UNIPROT	up-regulates				9606									8754811	f		fspada	The differentiation of 3t3 preadipocytes into adipocytes is accompanied by a transient induction of c/ebpbeta and c/ebpdelta expression in response to treatment of the cells with methylisobutylxanthine (mix) and dexamethasone (dex), respectively	SIGNOR-210068	0.8
CDK2	protein	P24941	UNIPROT	CDKN2D	protein	P55273	UNIPROT	up-regulates	phosphorylation	Ser76	VQDTSGTsPVHDAAR	9606									22558186	t		lperfetto	Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively. Nuclear translocation of p19ink4d induced by dna damage was shown to be dependent on serine 76 phosphorylation.	SIGNOR-197270	0.529
ERCC8	protein	Q13216	UNIPROT	ERCC6	protein	Q03468	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								16751180	t		miannu	 We have previously shown that CSA is a subunit of an E3 ubiquitin ligase complex. Here we demonstrate that CSB is a substrate of this ligase: Following UV irradiation, CSB is degraded at a late stage of the repair process in a proteasome- and CSA-dependent manner.	SIGNOR-271406	0.601
FUBP1	protein	Q96AE4	UNIPROT	CCND2	protein	P30279	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19637194	f		irozzo	A positive cell cycle regulator that we found down-regulated in Hep3B cells upon FBP1 inactivation was cyclin D2. In addition, Cyclin D2 mRNA levels were diminished in the FBP1 knockdown cells, whereas the amount of Cyclin D1 mRNA remained unaffected. Numerous studies have classified D-type cyclins as cell cycle–promoting oncoproteins important for cellular transformation, and our results suggest that cyclin D2 is a candidate FBP1-regulated oncoprotein in HCC.	SIGNOR-259124	0.2
TFEB	protein	P19484	UNIPROT	NAGLU	protein	P54802	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19556463	f	Figure 1	lperfetto	Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 	SIGNOR-276543	0.33
AGK	protein	Q53H12	UNIPROT	TIM22 complex	complex	SIGNOR-C424	SIGNOR	form complex	binding			9606	BTO:0000007								32901109	t		lperfetto	Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK).	SIGNOR-267708	0.361
MTOR	protein	P42345	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates activity	phosphorylation	Ser855	QRVLDTSsLTQSAPA	9606	BTO:0000007								19864431	t		lperfetto	Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855))	SIGNOR-174882	0.989
CACNA1D	protein	Q01668	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									28642685	t		miannu	Rab interacting molecules (RIMs) are multi-domain proteins that positively regulate the number of Ca2+ channels at the presynaptic active zone (AZ). Several molecular mechanisms have been demonstrated for RIM-binding to components of the presynaptic Ca2+ channel complex, the key signaling element at the AZ. Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α–subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). 	SIGNOR-264359	0.8
CDC25A	protein	P30304	UNIPROT	CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	up-regulates activity	dephosphorylation			9606	BTO:0000007								23429262	t		lperfetto	We show that the miRNA-induced silencing of CDC25A increases the tyrosine phosphorylation status of CDK4/6 cyclin-dependent kinases which, in turn, abolishes CDK4/6 capacity to associate with D-type cyclins. This prevents CDK4/6 kinases’ activation, impairs downstream events such as cyclin E stimulation and sequesters cells in early G1.	SIGNOR-245456	0.638
ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	2'-3'-cGAMP(2-)	smallmolecule	CHEBI:143093	ChEBI	up-regulates quantity	precursor of												23258413	t		lperfetto	Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family.	SIGNOR-276594	0.8
PRKCE	protein	Q02156	UNIPROT	ALDH2	protein	P05091	UNIPROT	up-regulates activity	phosphorylation	Thr429	MQILKFKtIEEVVGR	-1									28056995	t		lperfetto	 Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (epsilonPKC). |e identified S279 as a critical εPKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by εPKC likely also protects the enzyme against reactive aldehydes. 	SIGNOR-271866	0.286
Autophagy	phenotype	SIGNOR-PH31	SIGNOR	Protein_aggregates	phenotype	SIGNOR-PH142	SIGNOR	up-regulates													32218723	f		lperfetto	In many neurodegenerative conditions protein aggregation may occurs without specific GOF mutations in genes encoding aggregate-prone proteins. In these conditions protein aggregation is associated to the decline of cellular degradative functions, specifically of the autophagy-lysosomal pathway (ALP) (Figure 1).	SIGNOR-262269	0.7
CSNK1E	protein	P49674	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates activity	phosphorylation	Ser64	LQTDGNRsSHSRLGR	9606	BTO:0000567								11583622	t		llicata	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250805	0.35
SOST	protein	Q9BQB4	UNIPROT	WNT3A	protein	P56704	UNIPROT	down-regulates				9606									22298955	f	Interacts with LRP4 (via the extracellular domain);the interaction facilitates the Wnt signaling. Interacts with LRP5 (via the first two YWTD-EGF repeat domains);the interaction inhibits Wnt-mediated signaling.	gcesareni	It has been shown that both sclerostin and dkk1 act physiologically as downstream mole-cules of bmp signaling to inhibit canonical wnt sig-naling and therefore negatively regulate bone mass	SIGNOR-195684	0.568
SIRT1	protein	Q96EB6	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	deacetylation			9606									15126506	t		gcesareni	Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes.	SIGNOR-252993	0.909
TLRs	proteinfamily	SIGNOR-PF20	SIGNOR	Interferon_Production	phenotype	SIGNOR-PH16	SIGNOR	up-regulates				9606									20404851	f		lperfetto	TLR signaling pathways can be largely classified as either MyD88-dependent pathways, which drive the induction of inflammatory cytokines, or TRIF-dependent pathways, which are responsible for the induction of type I interferon as well as inflammatory cytokines3.	SIGNOR-216310	0.7
PRKCE	protein	Q02156	UNIPROT	ADAP1	protein	O75689	UNIPROT	unknown	phosphorylation	Ser87	AARARFEsKVPSFYY										12893243	t		lperfetto	The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ | The phosphorylation site analysis was carried out twice after phosphorylation of centaurin-alpha1‚ with PKCalpha and once with PKC_. A similar pattern of phosphopeptides was obtained each time.	SIGNOR-249224	0.318
HIF1A	protein	Q16665	UNIPROT	KDM2A	protein	Q9Y2K7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271566	0.2
Naphtho[1,2-d]thiazol-2-amine	chemical	CID:94880	PUBCHEM	KCNN1	protein	Q92952	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								18955585	t		Luana	Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. 	SIGNOR-258026	0.8
CRYBB2	protein	P43320	UNIPROT	CRYBB1	protein	P53674	UNIPROT	up-regulates activity	binding			9606									16319073	t		miannu	At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency.	SIGNOR-252153	0.2
DYRK1A	protein	Q13627	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates	phosphorylation	Ser272	EEPSPLPsPTASPNH	9606		BTO:0000142							15262992	t		lperfetto	Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd	SIGNOR-126843	0.405
HTR6	protein	P50406	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256801	0.479
R547	chemical	CID:6918852	PUBCHEM	CDK4	protein	P11802	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258274	0.8
DNMT1	protein	P26358	UNIPROT	BAG3	protein	O95817	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001109								18413740	f	 	lperfetto	In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+)	SIGNOR-254110	0.2
F2	protein	P00734	UNIPROT	LRP1	protein	Q07954	UNIPROT	up-regulates	binding			9606									8626456	t		gcesareni	In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp	SIGNOR-41090	0.287
ATIC	protein	P31939	UNIPROT	10-formyltetrahydrofolate(2-)	smallmolecule	CHEBI:57454	ChEBI	down-regulates quantity	chemical modification			9606									33179964	t		miannu	The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP.	SIGNOR-267325	0.8
TRIM25	protein	Q14258	UNIPROT	DDX58	protein	O95786	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0000007								17392790	t	lys63	miannu	The carboxy-terminal SPRY domain of TRIM25 interacts with the N-terminal CARDs of RIG-I; this interaction effectively delivers the Lys 63-linked ubiquitin moiety to the N-terminal CARDs of RIG-I, resulting in a marked increase in RIG-I downstream signalling activity.  Thus, we demonstrate that TRIM25 E3 ubiquitin ligase induces the Lys 63-linked ubiquitination of RIG-I, which is crucial for the cytosolic RIG-I signalling pathway to elicit host antiviral innate immunity.	SIGNOR-271645	0.796
MECP2	protein	P51608	UNIPROT	RELN	protein	P78509	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19029285	f		miannu	 induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. 	SIGNOR-254578	0.389
NOXO1	protein	Q8NFA2	UNIPROT	NOXA1	protein	Q86UR1	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000007								20943948	t		lperfetto	Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation	SIGNOR-264709	0.77
STAT3	protein	P40763	UNIPROT	RORC	protein	P51449	UNIPROT	up-regulates				9606									18454151	f			The inflammatory cytokines IL-6, IL-21 and IL-23 share signaling pathways by activating both STAT1 and STAT3, while IL-1beta is thought to activate the kinases IRAK1 and IRAK2 through recruitment of the adaptor MyD88. Thus, STAT3 is likely to be a common denominator in the induction of RORgammaT and IL-17 expression	SIGNOR-254303	0.626
PRKACA	protein	P17612	UNIPROT	ADD2	protein	P35612	UNIPROT	down-regulates activity	phosphorylation	Ser726	KKKEKVEs	-1									8810272	t		miannu	Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of - and -adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin. 	SIGNOR-250333	0.286
STC2/HMOX1	complex	SIGNOR-C244	SIGNOR	heme	smallmolecule	CHEBI:30413	ChEBI	down-regulates quantity by destabilization													22503972	t		lperfetto	Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme.	SIGNOR-260405	0.8
CHMP5	protein	Q9NZZ3	UNIPROT	ESCRT-III	complex	SIGNOR-C379	SIGNOR	form complex	binding			-1									26775243	t		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission.	SIGNOR-265527	0.705
UCHL5	protein	Q9Y5K5	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	deubiquitination			9606									16027725	t		lperfetto	Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases	SIGNOR-217610	0.386
SREBF2	protein	Q12772	UNIPROT	PCSK9	protein	Q8NBP7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21123766	t		miannu	 Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes.	SIGNOR-254459	0.48
PTPN2	protein	P17706	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates activity	dephosphorylation	Tyr1214	VCDPKFHyDNTAGIS	9606	BTO:0000007								18840653	t			We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well. 	SIGNOR-248401	0.548
OPHN1	protein	O60890	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	gtpase-activating protein			9606	BTO:0000938								12932438	t		miannu	OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro	SIGNOR-268399	0.573
JAK1	protein	P23458	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0002882								9305869	t			Janus kinase-dependent activation of insulin receptor substrate 1	SIGNOR-251343	0.697
PRKCZ	protein	Q05513	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser370	PAVPPRPsADLILNR	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89284	0.402
PIM3	protein	Q86V86	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606	BTO:0000007								16403219	t		lperfetto	All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death.	SIGNOR-249605	0.353
ACVR1	protein	Q04771	UNIPROT	SMAD5	protein	Q99717	UNIPROT	up-regulates				10090	BTO:0000165								10564272	f		gcesareni	We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2	SIGNOR-236848	0.749
BAK1	protein	Q16611	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									23567751	f		miannu	The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation.	SIGNOR-261493	0.7
NDN	protein	Q99608	UNIPROT	BMI1	protein	P35226	UNIPROT	down-regulates				9606	BTO:0000007								24392140	f		lperfetto	In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity,	SIGNOR-253384	0.255
PEX12	protein	O00623	UNIPROT	PEX5	protein	P50542	UNIPROT	up-regulates activity	ubiquitination			-1									19687296	t		miannu	Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. 	SIGNOR-253020	0.675
PKN1	protein	Q16512	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser163	KRFSFKKsFKLSGFS	9534	BTO:0000298								8557118	t		lperfetto	PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163.	SIGNOR-248938	0.372
RAN	protein	P62826	UNIPROT	XPO1	protein	O14980	UNIPROT	up-regulates activity	binding												31075303	t	Ran ID inferred from sequence: KRHLTGEFEKKYVATLGVEV	lperfetto	The nuclear export by CRM1 requires an interaction with the small GTPase Ras-related nuclear antigen (Ran), which cycles between GTP- and GDP-bound states. The binding of Ran GTP to CRM1 in the nucleus increases the affinity of CRM1 for cargo proteins 	SIGNOR-275848	0.926
GSK3B	protein	P49841	UNIPROT	NIFK	protein	Q9BYG3	UNIPROT	up-regulates activity	phosphorylation	Thr234	TVDSQGPtPVCTPTF	-1									16244663	t		miannu	The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1.	SIGNOR-262698	0.2
MAPK1	protein	P28482	UNIPROT	APBB1	protein	O00213	UNIPROT	unknown	phosphorylation	Thr709	PKRLGAHtP	9606									14697653	t		lperfetto	Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved.	SIGNOR-120463	0.262
EP300	protein	Q09472	UNIPROT	CPT1B	protein	Q92523	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534	BTO:0001538								15199055	f	 	 	Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle.	SIGNOR-254260	0.2
SRC	protein	P12931	UNIPROT	CTNND1	protein	O60716	UNIPROT	up-regulates activity	phosphorylation	Tyr291	DDQRSMGyDDLDYGM	-1									11382764	t		lperfetto	Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302	SIGNOR-246496	0.92
GGCX	protein	P38435	UNIPROT	F10	protein	P00742	UNIPROT	up-regulates activity	carboxylation			9606									31226734	t		lperfetto	Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.	SIGNOR-265921	0.598
NFIB	protein	O00712	UNIPROT	EPHA8	protein	P29322	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268903	0.2
TP53	protein	P04637	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									7834749	t	Nuclear p53	amattioni	Bax is a p53 primary-response gene, presumably involved in a p53-regulated pathway for induction of apoptosis	SIGNOR-33922	0.743
GPRIN1	protein	Q7Z2K8	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				10116									22956546	f		Luana	 GAP-43 and G protein regulated inducer of neurite outgrowth 1 (Gprin1) in differentiating cells.	SIGNOR-265799	0.7
MAPK1	protein	P28482	UNIPROT	MBP	protein	P02686	UNIPROT	down-regulates	phosphorylation	Thr232	KNIVTPRtPPPSQGK	9606		BTO:0000142							16401070	t		lperfetto	Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence.	SIGNOR-143477	0.57
Isradipine	chemical	CHEBI:6073	ChEBI	CACNA1C	protein	Q13936	UNIPROT	down-regulates activity	chemical inhibition			9606									10072735	t		miannu	The protein expression as measured by3H-(+)-PN 200-110-binding (Bmax) and Western Blot analysis withcalsequestrin as reference was similar in left ventricular failing and non-failing myocardium. However, both werereduced in atrial compared to ventricular tissue in failing and non-failing hearts. The KDremained unchanged.	SIGNOR-259076	0.8
RBBP7	protein	Q16576	UNIPROT	HNuRF	complex	SIGNOR-C448	SIGNOR	form complex	binding			9606	BTO:0000007								14609955	t		miannu	 hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays.	SIGNOR-268815	0.558
ADP	chemical	CHEBI:16761	ChEBI	AMPK	complex	SIGNOR-C15	SIGNOR	up-regulates	chemical activation			9606									21399626	t		lperfetto	Amp binding to the gamma-regulatory domain promotes phosphorylation by the upstream kinase, protects the enzyme against dephosphorylation, as well as causing allosteric activation.Adp also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive.	SIGNOR-217475	0.8
1-phosphatidyl-1D-myo-inositol 5-phosphate(3-)	smallmolecule	CHEBI:57795	ChEBI	1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-)	smallmolecule	CHEBI:58456	ChEBI	up-regulates quantity	precursor of			9606									9367159	t		Gianni	The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities'. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K	SIGNOR-268865	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PTPN7	protein	P35236	UNIPROT	up-regulates activity	phosphorylation			-1									16226275	t	inferred from 70% family members	lperfetto	First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|	SIGNOR-270202	0.2
CSNK2A1	protein	P68400	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates	phosphorylation	Ser13	ESFTMASsPAQRRRG	9606									16446360	t		gcesareni	In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2	SIGNOR-144004	0.262
MAPK1	protein	P28482	UNIPROT	CSNK2A1	protein	P68400	UNIPROT	up-regulates	phosphorylation	Ser362	ISSVPTPsPLGPLAG	9606	BTO:0000527								19941816	t		lperfetto	Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity	SIGNOR-161851	0.376
MYC	protein	P01106	UNIPROT	IMPDH1	protein	P20839	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003291								18628958	t		miannu	Here, we report that the majority of genes in human purine and pyrimidine biosynthesis pathway were induced and directly bound by c-Myc in the P493-6 human Burkitt's lymphoma model cell line. The mRNA levels of IMPDH1 and IMPDH2, the rate-limiting enzyme in purine de novo synthesis, increased with MYC induction both in vitro and in vivo.	SIGNOR-267378	0.245
EGR1	protein	P18146	UNIPROT	PCSK2	protein	P16519	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9359835	f	 	miannu	 we show that the transcription factor EGR-1 interacts with two distinct elements within the proximal human PC2 promoter region. Transfection experiments also demonstrate that EGR-1 is able to enhance PC2 promoter activity.	SIGNOR-253896	0.2
CDK2	protein	P24941	UNIPROT	SKP2	protein	Q13309	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser64	SNLGHPEsPPRKRLK										18239684	t		lperfetto	The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1).	SIGNOR-249173	0.792
SP1	protein	P08047	UNIPROT	SLC2A1	protein	P11166	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									9148896	f		lperfetto	These data suggest a regulatory model in which MyoD activation during myogenesis causes the down-regulation of Sp1, which contributes to the repression of GLUT1 gene transcription and, therefore, leads to the reduction in GLUT1 expression and glucose transport.	SIGNOR-241485	0.367
CD38	protein	P28907	UNIPROT	NAD(+)	smallmolecule	CHEBI:15846	ChEBI	down-regulates quantity	chemical modification			9606									18626062	t		miannu	The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR.	SIGNOR-264246	0.8
PTEN	protein	P60484	UNIPROT	RAB7A	protein	P51149	UNIPROT	up-regulates activity	dephosphorylation	Tyr183	QETEVELyNEFPEPI	-1									26869029	t		lperfetto	PTEN dephosphorylates Rab7 on two conserved residues S72 and Y183, which are necessary for GDP dissociation inhibitor (GDI)-dependent recruitment of Rab7 on to late endosomes and subsequent maturation.	SIGNOR-276959	0.383
MTOR	protein	P42345	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Thr390	DSKFTRQtPVDSPDD	9606									11914378	t			Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain,[…] Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings.	SIGNOR-255839	0.96
SIK2	protein	Q9H0K1	UNIPROT	MLXIPL	protein	Q9NP71	UNIPROT	down-regulates				10090									24841198	f		lperfetto	Moreover, SIK2 was shown to down-regulate the carbohydrate-responsive element-binding protein (ChREBP)-mediated lipogenesis in hepatocytes through the inhibitory phosphorylation of p300/Ser89 and to prevent steatosis in mice	SIGNOR-265746	0.33
PTPN1	protein	P18031	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	10090	BTO:0000944								11579209	t		lperfetto	Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor.	SIGNOR-235495	0.778
ID3	protein	Q02535	UNIPROT	TCF12	protein	Q99081	UNIPROT	down-regulates activity	binding			10090	BTO:0004058			SIGNOR-C128					9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241152	0.479
Naphtho[1,2-d]thiazol-2-amine	chemical	CID:94880	PUBCHEM	KCNN3	protein	Q9UGI6	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								18955585	t		Luana	Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. 	SIGNOR-258024	0.8
RAI1	protein	Q7Z5J4	UNIPROT	CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000614							22578325	f		miannu	Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. 	SIGNOR-266844	0.39
mTORC2	complex	SIGNOR-C2	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation			9606									21157483	t		lperfetto	Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism	SIGNOR-251982	0.634
HMGA1	protein	P17096	UNIPROT	POU3F1	protein	Q03052	UNIPROT	up-regulates activity	binding			9606	BTO:0002127								7791781	t	2	miannu	Direct contacts were identified between the POU domain of Tst-1/Oct-6 and a short stretch of 10 amino acids in the central portion of HMG-I/Y. In the presence of HMG-I/Y, Tst-1/Oct-6 exhibited an increased affinity for this AT-rich element.	SIGNOR-240155	0.311
THEM4	protein	Q5T1C6	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates	binding			9606									11598301	t		lperfetto	Here, we describe a protein partner for pkbalpha termed ctmp, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of pkbalpha at the plasma membrane. Binding of ctmp reduces the activity of pkbalpha by inhibiting phosphorylation on serine 473 and threonine 308.	SIGNOR-244455	0.687
LAMP2	protein	P13473	UNIPROT	Chaperone-mediated autophagy	phenotype	SIGNOR-PH118	SIGNOR	up-regulates activity				10029	BTO:0000977								8662539	f			Here, the lysosomal membrane glycoprotein LGP96 was identified as a receptor for the selective import and degradation of proteins within lysosomes. Specific substrates of this proteolytic pathway bound to the cytosolic tail of a 96-kilodalton lysosomal membrane protein in two different binding assays.	SIGNOR-259990	0.7
PXN	protein	P49023	UNIPROT	ILK	protein	Q13418	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001260							11304546	t		gcesareni	Co-immunoprecipitation from fibroblasts confirmed that the association between paxillin and ilk occurs in vivo in both adherent cells and cells in suspension. [__] thus, paxillin binding is necessary for efficient focal adhesion targeting of ilk and may therefore impact the role of ilk in integrin-mediated signal transduction events.	SIGNOR-106824	0.792
FYN	protein	P06241	UNIPROT	PTPRT	protein	O14522	UNIPROT	down-regulates activity	phosphorylation	Tyr915	Y-->K										19816407	t		lperfetto	Synapse formation by PTPRT was inhibited by phosphorylation of tyrosine 912 within the membrane-proximal catalytic domain of PTPRT by Fyn. This tyrosine phosphorylation reduced phosphatase activity of PTPRT	SIGNOR-275543	0.425
ABL1	protein	P00519	UNIPROT	PLSCR1	protein	O15162	UNIPROT	unknown	phosphorylation	Tyr69	PVPNQPVyNQPVYNQ	9606									11390389	t		lperfetto	C-abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. Phosphorylation was abolished by mutation of tyr residues tyr(69)/tyr(74) within the tandem repeat sequence (68)vynqpvynqp(77) of plscr1	SIGNOR-86013	0.393
glycine	smallmolecule	CHEBI:15428	ChEBI	GLRB	protein	P48167	UNIPROT	up-regulates activity	chemical activation			9606		BTO:0001175;BTO:0001279;BTO:0000146							18721822	t		miannu	The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. 	SIGNOR-264983	0.8
TBCK	protein	Q8TEA7	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									23977024	f		miannu	Depletion of TBCK significantly inhibits cell proliferation, reduces cell size, and disrupts the organization of actin, but not microtubule.	SIGNOR-266700	0.7
MAPK3	protein	P27361	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates activity	relocalization			9606									18596912	t		lperfetto	The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform	SIGNOR-179407	0.409
EEF1A1	protein	P68104	UNIPROT	Pro-tRNA(Pro)	smallmolecule	CHEBI:29154	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269514	0.8
LATS2	protein	Q9NRM7	UNIPROT	CDC26	protein	Q8NHZ8	UNIPROT	up-regulates activity	phosphorylation	Thr7	tRLELKLD										25723520	t		lperfetto	LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C	SIGNOR-275474	0.473
AURKA	protein	O14965	UNIPROT	FAF1	protein	Q9UNN5	UNIPROT	down-regulates activity	phosphorylation	Ser289	ITDVHMVsDSDGDDF	9606									18790738	t		llicata	This study reports that aurora-a (aur-a) phosphorylates fas-associated factor-1 (faf1) at ser-289 and ser-29 our findings support the negative feedback regulation of aur-a via phosphorylation of the death-promoting protein, faf1	SIGNOR-180887	0.2
RDH5	protein	Q92781	UNIPROT	retinol	smallmolecule	CHEBI:50211	ChEBI	down-regulates quantity	chemical modification			9606									21621639	t		lperfetto	Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS10	SIGNOR-265113	0.8
TBL1XR1	protein	Q9BZK7	UNIPROT	BCL3	protein	P20749	UNIPROT	down-regulates	ubiquitination			9606									20547759	t		miannu	We also defined the e3 ligase tblr1 as a protein involved in bcl-3 degradation	SIGNOR-166111	0.411
SRC	protein	P12931	UNIPROT	VAMP7	protein	P51809	UNIPROT	up-regulates activity	phosphorylation	Tyr45	SENNKLTySHGNYLF	9534	BTO:0000298								23471971	t	done	miannu	We found that TI-VAMP is phosphorylated in vitro by c-Src kinase on tyrosine 45 of the Longin domain.Mimicking tyrosine 45 phosphorylation activates both t-SNARE binding and exocytosis of TI-VAMP.	SIGNOR-273819	0.291
STK4	protein	Q13043	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates activity	phosphorylation	Thr187	KRNTVIGtPFWMAPE	9534	BTO:0004055								12223493	t		lperfetto	Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationWe define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity.	SIGNOR-247581	0.2
ROBO	proteinfamily	SIGNOR-PF14	SIGNOR	CDC25B	protein	P30305	UNIPROT	down-regulates	phosphorylation	Ser375	ARVLRSKsLCHDEIE	9606	BTO:0000567;BTO:0000938	BTO:0000142							15150265	t		lperfetto	P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteinsphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3	SIGNOR-124847	0.2
CALU	protein	O43852	UNIPROT	GGCX	protein	P38435	UNIPROT	down-regulates activity	binding			10116		BTO:0000759							15075329	t		lperfetto	Results are presented that demonstrate that the endoplasmic reticulum chaperone protein calumenin is associated with gamma-carboxylase and inhibits its activity.	SIGNOR-265910	0.412
PRKCQ	protein	Q04759	UNIPROT	STK39	protein	Q9UEW8	UNIPROT	up-regulates activity	phosphorylation	Ser309	MMKKYGKsFRKLLSL	-1									14988727	t		miannu	Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta, but not by PKCalpha. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCtheta-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK. 	SIGNOR-276006	0.464
NGFR	protein	P08138	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates				9606									14699954	f		amattioni	Jnk3 is expressed exclusively in the nervous system and recent evidence indicates that this jnk isoform may be required for p75ntr-mediated cell death	SIGNOR-120561	0.426
Wnt	proteinfamily	SIGNOR-PF40	SIGNOR	LRP5	protein	O75197	UNIPROT	up-regulates	binding			9606									15578921	t	inferred from 70% family members	gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-269961	0.2
BRCC3	protein	P46736	UNIPROT	H2AC11	protein	P0C0S8	UNIPROT	down-regulates	deubiquitination			9606									20656690	t		gcesareni	Brcc36 regulates the abundance of lys(63)-linked ubiquitin chains at chromatin and that one of its substrates is diubiquitinated histone h2a	SIGNOR-167142	0.2
CSNK2A2	protein	P19784	UNIPROT	CAV1	protein	Q03135	UNIPROT	unknown	phosphorylation	Ser88	FDGIWKAsFTTFTVT	-1									8058322	t		llicata	Here, we have identified this serine kinase activity as a casein kinase II-like enzyme, since the phosphorylation of caveolin-rich membrane domains is stimulated and inhibited by known effectors of casein kinase II (poly-L-lysine, endogenous polyamines, and a casein kinase II inhibitor peptide), but is unaffected by modulators of other known kinases. In support of these observations, caveolin contains a consensus sequence for casein kinase II phosphorylation in its cytoplasmic N-terminal domain (Ser-88)	SIGNOR-250981	0.362
FOS	protein	P01100	UNIPROT	HSD3B2	protein	P26439	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19022561	t		miannu	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 	SIGNOR-254877	0.2
STAT3	protein	P40763	UNIPROT	IL10	protein	P22301	UNIPROT	up-regulates	transcriptional regulation			9606									22378047	f			IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype	SIGNOR-254515	0.783
HRH4	protein	Q9H3N8	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256672	0.494
5-phospho-beta-D-ribosylaminium(1-)	smallmolecule	CHEBI:58681	ChEBI	N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-)	smallmolecule	CHEBI:143788	ChEBI	up-regulates quantity	precursor of			9606									34283828	t		miannu	In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR).	SIGNOR-267296	0.8
TLK1	protein	Q9UKI8	UNIPROT	RAD9A	protein	Q99638	UNIPROT	unknown	phosphorylation	Ser328	VLPSISLsPGPQPPK	9606									24376897	t	The effect has been demonstrated using Q9UKI8-2	llicata	Here we show that rad9 is phosphorylated in a tlk-dependent manner in vitro and in vivo, and that t355 within the c-terminal tail is the primary targeted residue.	SIGNOR-203499	0.462
Naphtho[1,2-d]thiazol-2-amine	chemical	CID:94880	PUBCHEM	KCNN4	protein	O15554	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								18955585	t		Luana	Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. 	SIGNOR-258025	0.8
17beta-hydroxy-5alpha-androstan-3-one	smallmolecule	CHEBI:16330	ChEBI	COMT	protein	P21964	UNIPROT	up-regulates				9606									17612537	f	Regulation of expression	miannu	Catechol O-methyltransferase expression in granulosa cells was up-regulated by insulin, DHT, and ATRA. 	SIGNOR-251962	0.8
RNF146	protein	Q9NTX7	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									21478859	t		lperfetto	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 	SIGNOR-263335	0.633
CDK1	protein	P06493	UNIPROT	USP16	protein	Q9Y5T5	UNIPROT	up-regulates	phosphorylation	Ser552	DLEVLTSsPTRNLNG	9606									24013421	t		llicata	Here, we report that cyclin-dependent kinase 1 (cdk1) phosphorylates the histone h2a deubiquitinase ubp-m at serine 552 (s552p), and, importantly, this phosphorylation is required for cell cycle progression.	SIGNOR-202678	0.467
MAPK1	protein	P28482	UNIPROT	STMN3	protein	Q9NZ72	UNIPROT	unknown	phosphorylation	Ser68	PSDLSPEsPMLSSPP	-1									22577147	t		lperfetto	Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta	SIGNOR-264895	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser106	PLNSVSPsPLMLLHP	9606	BTO:0000567								17615152	t		lperfetto	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity	SIGNOR-244651	0.2
TRIM63	protein	Q969Q1	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys74	DTGRILSkLHTVQPK	-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). 	SIGNOR-272738	0.413
SOX9	protein	P48436	UNIPROT	MITF	protein	O75030	UNIPROT	up-regulates activity	binding			10090									20530484	t		miannu	BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles.	SIGNOR-255183	0.393
ADCY1	protein	Q08828	UNIPROT	PRKACA	protein	P17612	UNIPROT	up-regulates activity				9606									27065076	f		Gianni	Adenylate cyclases (AC) produce cAMP from adenosin-tri-phosphate (ATP). High levels of cytosolic cAMP lead to activation of protein kinase A (PKA)	SIGNOR-262528	0.492
PTGS2	protein	P35354	UNIPROT	IL4	protein	P05112	UNIPROT	up-regulates				9606									22225874	t		FFerrentino	Cox2 Is a Direct Srf Target Gene and Controls Il4 Expression	SIGNOR-255967	0.458
ARTN	protein	Q5T4W7	UNIPROT	GFRA3	protein	O60609	UNIPROT	up-regulates	binding			9606	BTO:0000938								9883723	t		gcesareni	Here, we report the identification of artemin, a novel member of the gdnf family, and demonstrate that it is the ligand for the former orphan receptor gfralpha3-ret. Artemin can also activate the gfralpha1-ret complex.	SIGNOR-63009	0.753
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser321	SKPSGNDsCELRNLK	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276212	0.389
BRAF	protein	P15056	UNIPROT	SLC5A5	protein	Q92911	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19861538	t		miannu	The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression.	SIGNOR-251989	0.2
MAP2K4	protein	P45985	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation	Thr180	RHTDDEMtGYVATRW	9606									7535770	t		lperfetto	Recently, two MAP kinase kinases (MKK3 and MKK4) that activate p38 MAP kinase have been identified. The mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182	SIGNOR-27973	0.574
FBXO22	protein	Q8NEZ5	UNIPROT	BACH1	protein	O14867	UNIPROT	down-regulates quantity	ubiquitination			9606									31257023	t			Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22.	SIGNOR-259331	0.285
CTSH	protein	P09668	UNIPROT	BGLAP	protein	P02818	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly58	RYLYQWLgAPVPYPD	-1									9076588	t		miannu	This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 	SIGNOR-256324	0.286
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MAP3K8	protein	P41279	UNIPROT	up-regulates activity	phosphorylation	Ser400	EDQPRCQsLDSALLE	9606	BTO:0000007								12138205	t			Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator.	SIGNOR-251480	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SOS1	protein	Q07889	UNIPROT	down-regulates activity	phosphorylation	Ser1167	ESAPAESsPSKIMSK	9534	BTO:0004055								8816480	t		lperfetto	In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1	SIGNOR-244584	0.2
GRK1	protein	Q15835	UNIPROT	GRK1	protein	Q15835	UNIPROT	down-regulates activity	phosphorylation	Ser21	AFIAARGsFDGSSSQ	-1									1527025	t			The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase.	SIGNOR-251186	0.2
NUDT21	protein	O43809	UNIPROT	CFI complex	complex	SIGNOR-C388	SIGNOR	form complex	binding			9606									8626397	t		lperfetto	We report here the purification of CF Im from HeLa cell nuclear extracts. Three polypeptides of 68, 59, and 25 kDa copurified with CF Im activity.	SIGNOR-266122	0.947
PPM1A	protein	P35813	UNIPROT	RELA	protein	Q04206	UNIPROT	down-regulates activity	dephosphorylation	Ser276	SMQLRRPsDRELSEP	9606									23812431	t		lperfetto	23 Here we show that PPM1A directly dephosphorylated RelA at S536 and S276, with resultant inhibition of NF-kappaB transactivation and decreased expression of target genes, notably including MCP-1 and CCL2.|Taken together, these data suggest that dephosphorylation of S276 by PPM1A may contribute to inhibit RelA transcriptional activity, but the majority of PPM1A activity to inhibit RelA transcription relies on dephos phorylation of S536 of RelA.|We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited Nuclear factor-\u03baB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1/chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis.	SIGNOR-276963	0.361
CSNK2A2	protein	P19784	UNIPROT	EIF2B5	protein	Q13144	UNIPROT	up-regulates activity	phosphorylation	Ser718	KEAEEESsEDD	9606									11500362	t		llicata	Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro. 	SIGNOR-250990	0.377
MPHOSPH10	protein	O00566	UNIPROT	IMP4	protein	Q96G21	UNIPROT	up-regulates activity	binding			-1									28813493	t		miannu	Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA. 	SIGNOR-261174	0.808
pindolol	chemical	CHEBI:8214	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9550290	t		miannu	Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists.	SIGNOR-258884	0.8
CSNK1D	protein	P48730	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates	phosphorylation	Ser262	DSEDYSLsEEGQELS	9606									12167711	t		gcesareni	Hypophosphorylation of mdm2 augments p53 stability.	SIGNOR-91199	0.351
PTPRG	protein	P23470	UNIPROT	PDGFRA	protein	P16234	UNIPROT	up-regulates activity	dephosphorylation	Tyr754	ERKEVSKySDIQRSL	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254714	0.251
USF1	protein	P22415	UNIPROT	JMJD1C	protein	Q15652	UNIPROT	up-regulates activity	binding			9606		BTO:0000759							32034158	t		miannu	We show that, by direct interaction with USF-1, JMJD1C is recruited to lipogenic promoters. We also show that JMJD1C is phosphorylated at T505 by mammalian target of rapamyci (mTOR) to be recruited to lipogenic genes in response to insulin/feeding. 	SIGNOR-265167	0.2
SOX2	protein	P48431	UNIPROT	Pluripotency	phenotype	SIGNOR-PH43	SIGNOR	up-regulates				9606	BTO:0001086								16153702	f		flangone	Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes.	SIGNOR-242064	0.7
KAT8	protein	Q9H7Z6	UNIPROT	MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	form complex	binding			9606		BTO:0000567							16227571	t		miannu	We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. 	SIGNOR-263943	0.803
PPARGC1A	protein	Q9UBK2	UNIPROT	MSTN	protein	O14793	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									23217713	t		miannu	PGC-1 alpha specifically induces IGF1 and represses myostatin, and expression of PGC-1a 4 in vitro and in vivo induces robust skeletal muscle hypertrophy	SIGNOR-256151	0.37
CAMK2B	protein	Q13554	UNIPROT	ETS1	protein	P14921	UNIPROT	down-regulates activity	phosphorylation	Ser251	GKLGGQDsFESIESY		BTO:0003637								12475968	t		llicata	Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1 	SIGNOR-250684	0.313
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	LCK	protein	P06239	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000567								8618896	t	inferred from 70% family members	lperfetto	Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation.	SIGNOR-270074	0.2
NR5A2	protein	O00482	UNIPROT	CYP11B1	protein	P15538	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002588								11564608	f		miannu	 The ability of LRH-1 to enhance transcription of the gene encoding human 11 beta- hydroxylase (hCYP11B1) was then examined using the H295R adrenal cell line. LRH-1 co-transfection with hCYP11B1 luciferase promoter constructs caused a 25-fold induction of luciferase activity. Furthermore, co-transfection of a hCYP11B1 reporter construct containing a mutation in the SF-1 binding cis-element abolished the stimulatory effect of both SF-1 and LRH-1. Electrophoretic mobility shift assay (EMSA) demonstrated that LRH-1 could bind to the SF-1 response element. Taken together, our data suggested that LRH-1 is expressed in the adrenal, and can substitute for SF-1 to enhance transcription of genes encoding certain of the steroid-metabolizing enzymes. 	SIGNOR-254880	0.35
PRKCG	protein	P05129	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser558	VPTYESAsIRRFQEG	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-129324	0.326
HTR1A	protein	P08908	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256972	0.434
CSNK2B	protein	P67870	UNIPROT	IKZF1	protein	Q13422	UNIPROT	down-regulates	phosphorylation	Ser295	LSDTPYDsSASYEKE	9606									21750978	t		miannu	We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo	SIGNOR-174848	0.2
FGR	protein	P09769	UNIPROT	ACO2	protein	Q99798	UNIPROT	unknown	phosphorylation	Tyr544	FDPGQDTyQHPPKDS	-1									17997986	t		miannu	Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations.	SIGNOR-262869	0.2
MDFI	protein	Q99750	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates activity	binding			10090	BTO:0000944								8797820	t	2	miannu	We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals.	SIGNOR-240436	0.512
FEV	protein	Q99581	UNIPROT	ICAM1	protein	P05362	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12761502	f		miannu	Fev acts as a transcriptional repressor through its dna-binding ets domain and alanine-rich domain. / we show here that fev dramatically represses both basal and ectopically ets-activated transcription driven by the icam-1 promoter, and that the effect is dose dependent.	SIGNOR-101246	0.2
MAPK1	protein	P28482	UNIPROT	THRB	protein	P10828	UNIPROT	down-regulates activity	phosphorylation	Ser142	IQKNLHPsYSCKYEG	9606									12809513	t		llicata	We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay.	SIGNOR-102216	0.39
PDPK1	protein	O15530	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	up-regulates	phosphorylation	Ser227	DHEKKAYsFCGTVEY	9606									10480933	t		gcesareni	We characterize two monoclonal antibodies raised against phosphorylated forms of the n- and c-terminal domain of rsk2 (p-s227 and p-t577, respectively). Using these two antibodies, we show that stress signals, such as uv light, induce phosphorylation and activation of the three rsks.	SIGNOR-70612	0.639
NCOA1	protein	Q15788	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	binding			9606									9427757	t		miannu	Steroid receptor co-activator (src1) is one of a number of transcriptional co-activators that are capable of potentiating the activity of nuclear receptors including the oestrogen receptor (er).	SIGNOR-54442	0.839
HNRNPA1	protein	P09651	UNIPROT	TRA2B	protein	P62995	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									31311954	t		lperfetto	HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells.	SIGNOR-262288	0.683
TIMELESS	protein	Q9UNS1	UNIPROT	CRY1	protein	Q16526	UNIPROT	up-regulates activity	binding			9534									23418588	t		miannu	We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization. 	SIGNOR-268053	0.696
HK2	protein	P52789	UNIPROT	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor.	SIGNOR-266456	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates quantity by expression				9606									15044535	f		gcesareni	These results indicate that nf-kb actions occur upstream of p53 to regulate both p53 levels and activity.	SIGNOR-123602	0.501
AKT2	protein	P31751	UNIPROT	STK4	protein	Q13043	UNIPROT	down-regulates	phosphorylation	Thr387	TMKRRDEtMQPAKPS	9606									23431053	t		gcesareni	Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt.	SIGNOR-201125	0.265
PLK1	protein	P53350	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser53	GHSTGEDsAFQEPDS	9606	BTO:0000567								16085715	t		miannu	 In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms.  S123 phosphorylation creates a PBD-binding motif and accelerates S53 phosphorylation by Plk1.	SIGNOR-276040	0.626
PCSK2	protein	P16519	UNIPROT	Neurophysin 1	protein	P01178-PRO_0000020496	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0001073								11690596	t		miannu	Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension.	SIGNOR-270337	0.2
EIF3_complex	complex	SIGNOR-C401	SIGNOR	EIF4G3	protein	O43432	UNIPROT	up-regulates activity	stabilization			9606									17581632	t		lperfetto	EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 	SIGNOR-269157	0.395
HOXB8	protein	P17481	UNIPROT	ACTA2	protein	P62736	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0002196								15886193	t		Luana	Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively	SIGNOR-261641	0.2
CDK1	protein	P06493	UNIPROT	CHEK1	protein	O14757	UNIPROT	up-regulates	phosphorylation	Ser286	TSGGVSEsPSGFSKH	9606									21765472	t		lperfetto	Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency	SIGNOR-175071	0.419
GATA1	protein	P15976	UNIPROT	GATA2	protein	P23769	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12432220	f		irozzo	Closer examination revealed a cross-regulatory mechanism by which GATA-1 can control the expression of GATA-2 and vice versa, possibly via essential GATA binding sites in their cis-acting elements.In this model, GATA-2 activates GATA-1 gene expression, while GATA-1 represses GATA-2 gene expression. 	SIGNOR-256058	0.419
PRKCD	protein	Q05655	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates	phosphorylation			9606									17183360	t		gcesareni	By contrast, after uv stimulation, rela directly induces the expression of pkcdelta, which in turn activates jnk.	SIGNOR-151428	0.483
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	CHKB	protein	Q9Y259	UNIPROT	up-regulates activity	phosphorylation	Ser40	PKRRRASsLSRDAER										27149373	t		lperfetto	Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. 	SIGNOR-275631	0.2
COLEC11	protein	Q9BWP8	UNIPROT	MASP1	protein	P48740	UNIPROT	up-regulates activity	binding			-1									20956340	t		lperfetto	On the basis of the significant concentration of CL-11 in circulation and CL-11's interaction with various microorganisms and MASP-1 and/or MASP-3, it is conceivable that CL-11 plays a role in activation of the complement system and in the defense against invading microorganisms.	SIGNOR-263409	0.607
Inflammation	phenotype	SIGNOR-PH12	SIGNOR	IL4	protein	P05112	UNIPROT	up-regulates				9606	BTO:0000399								11290754	f		apalma	Our findings indicate that chemokines acting via CCR3-initiated signaling pathways can very rapidly mobilize preformed stores of IL-4 from within human eosinophils. The means of extracellular release was by noncytotoxic, vesicular transport	SIGNOR-255494	0.7
N-[4-[2-ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridinyl]benzamide	chemical	CHEBI:91360	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates activity	chemical inhibition			-1									16162000	t		miannu	A novel structural class of 4-phenyl-5-pyridyl-1,3-thiazoles was optimized as inhibitors of p38 MAP kinase and the proinflammatory cytokine TNF-α. it only significantly inhibited p38α (IC50 = 7.1 nM) and p38β (IC50 = 200 nM) in a concentration-dependent manner and was approximately 28 times more selective for p38α over p38β. 	SIGNOR-262223	0.8
PLG	protein	P00747	UNIPROT	F2R	protein	P25116	UNIPROT	up-regulates activity	cleavage	Arg41	TNATLDPrSFLLRNP	-1									10978167	t		lperfetto	Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site.	SIGNOR-263571	0.62
CCDC6-RET	fusion protein	SIGNOR-FP9	SIGNOR	SHC1	protein	P29353	UNIPROT	up-regulates activity	binding			9606									16946010	t		miannu	RET/PTC is tumorigenic in thyroid follicular cells; it transforms thyroid cells in culture and gives rise to thyroid carcinomas in transgenic mice. effects of RET/PTC activation require signaling along the MAPK pathway and, more specifically, the presence of the functional BRAF kinase. all breakpoints in the RET gene occur within intron 11, leaving intact the TK domain of the receptor and enabling the RET/PTC oncoprotein to bind SHC via Y1062 and activate the RAS-RAF-MAPK cascade	SIGNOR-251986	0.2
IKBKE	protein	Q14164	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Ser398	VDLHISNsHPLSLTS	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178375	0.732
PPP2R2A	protein	P63151	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	binding			10090	BTO:0000944								18042541	t		gcesareni	Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural |Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells.subunit (A), catalytic subunit (C), and a variable regulatory subunit (B).	SIGNOR-243526	0.474
SAICAR(4-)	smallmolecule	CHEBI:58443	ChEBI	5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-)	smallmolecule	CHEBI:58475	ChEBI	up-regulates quantity	precursor of			9606									22812634	t		miannu	ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case	SIGNOR-266609	0.8
axitinib	chemical	CHEBI:66910	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258075	0.8
THBS1	protein	P07996	UNIPROT	NGF	protein	P01138	UNIPROT	up-regulates	binding			9606									10708953	t		lpetrilli	We have identified a mechanism for the activation of latent tgf-beta that involves binding of the secreted and extracellular matrix protein, thrombospondin-1 (tsp-1), to the latent precursor.	SIGNOR-75624	0.282
CXCL1	protein	P09341	UNIPROT	PRKACA	protein	P17612	UNIPROT	down-regulates	binding			9606									17251915	t		gcesareni	As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp.	SIGNOR-152594	0.2
CDK4	protein	P11802	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Ser249	AVIPINGsPRTPRRG	9606									15809340	t		gcesareni	Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively.	SIGNOR-135181	0.927
FHIT	protein	P49789	UNIPROT	AXIN2	protein	Q9Y2T1	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18077326	f		miannu	In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin.	SIGNOR-159867	0.275
MYC	protein	P01106	UNIPROT	HNRNPA2B1	protein	P22626	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20010808	t			We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2,	SIGNOR-268691	0.365
SMURF2	protein	Q9HAU4	UNIPROT	TGFBR2	protein	P37173	UNIPROT	down-regulates activity	ubiquitination			9606									22298955	t		lperfetto	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-195681	0.577
RAC2	protein	P15153	UNIPROT	PAK1	protein	Q13153	UNIPROT	up-regulates	binding			9606									9705280	t		gcesareni	This report shows that rac1 binds to and stimulates the kinase activity of pak1 approximately 2- and 4-5-fold, respectively, better than rac2.	SIGNOR-59546	0.773
PTK2	protein	Q05397	UNIPROT	ACTN1	protein	P12814	UNIPROT	down-regulates	phosphorylation	Tyr12	DSQQTNDyMQPEEDW	9606									23454549	t		lperfetto	Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin .	SIGNOR-192126	0.555
LCK	protein	P06239	UNIPROT	CHN2	protein	P52757	UNIPROT	down-regulates activity	phosphorylation	Tyr153	KMTTNPIyEHIGYAT	9606	BTO:0000661								19201754	t		miannu	We now demonstrate Lck-dependent phosphorylation of beta2-chimaerin in response to TCR triggering. We identify Tyr-153 as the Lck-dependent phosphorylation residue and show that its phosphorylation negatively regulates membrane stabilization of beta2-chimaerin, decreasing its GAP activity to Rac. 	SIGNOR-276240	0.2
CSNK2A1	protein	P68400	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates activity	phosphorylation	Ser79	AGALYSGsEGDSESG	-1									2046671	t		llicata	Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated. 	SIGNOR-250956	0.532
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DRB5	protein	Q30154	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-254003	0.288
IRAK1	protein	P51617	UNIPROT	GLIPR2	protein	Q9H4G4	UNIPROT	up-regulates activity	phosphorylation	Ser58	ILKHSPEsSRGQCGE	9606	BTO:0001370								25544559	t		miannu	We found that TIRAP-MyD88 dependent kinase IRAK1 phosphorylated GAPR-1 at Serine 58 site. The phosphorylation of GAPR-1 promoted its interaction with TRAM-TRIF dependent inhibitor TMED7, and impaired TMED7-mediated disruption of the TRAM-TRIF complex to trigger IFN-β and the IL10 secretion.	SIGNOR-262887	0.332
PAK3	protein	O75914	UNIPROT	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation	Ser744	GLKVGVSsRINEWLT	9606		BTO:0000887;BTO:0001260							20858431	t		gcesareni	We investigated the effects of phosphorylation by p(21)-activated kinase 3 (pak) and calmodulin on the 22 kda c-terminal fragment of caldesmon (cad22). We substituted the major pak sites, ser-672 and ser-702, with either alanine or aspartic acid to mimic nonphosphorylated and constitutively phosphorylated states of caldesmon, respectively. Phosphorylation at these sites weakened ca(2+)-calmodulin binding further and reduced the inhibitory activity of cad22 in the absence of ca(2+)-calmodulin.	SIGNOR-167980	0.2
MAPK1	protein	P28482	UNIPROT	CEP55	protein	Q53EZ4	UNIPROT	down-regulates	phosphorylation	Ser428	KVAASPKsPTAALNE	9606									16198290	t		lperfetto	Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis.	SIGNOR-140894	0.374
ORC5	protein	O43913	UNIPROT	ORC	complex	SIGNOR-C419	SIGNOR	form complex	binding			9606									32808929	t		lperfetto	The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA	SIGNOR-267563	0.964
PPM1D	protein	O15297	UNIPROT	BAX	protein	Q07812	UNIPROT	down-regulates activity	dephosphorylation			9606									23907458	t		lperfetto	34 In this study, a novel function of Wip1 was identified, that is, its ability to dephosphorylate directly and thus inactivate apoptotic BAX protein in response to gamma irradiation.|To ascertain whether Wip1 dephosphorylates BAX, recombinant Wip1 was incubated with previously reported BAX-derived phosphopeptides containing Ser87, Ser163, Thr167, and Ser184 in an in vitro phosphatase assay. xref , xref Peptides containing phospho-Thr180 from p38 MAPK and phospho-Thr31 from UNG2 were used as a positive and negative control, respectively.  xref  As shown in xref , purified Wip1 did not dephosphorylate the four BAX-derived phosphopeptides.	SIGNOR-276993	0.2
PTPRF	protein	P10586	UNIPROT	BCAR1	protein	P56945	UNIPROT	down-regulates quantity by destabilization	dephosphorylation			9606									10320483	t		lperfetto	LAR specifically dephosphorylates and destabilizes p130Cas and may play a role in regulating cell adhesion-mediated cell survival.|Transmembrane tyrosine phosphatase LAR induces apoptosis by dephosphorylating and destabilizing p130Cas.	SIGNOR-276998	0.344
Inner_mitochondrial_membrane	complex	SIGNOR-C411	SIGNOR	Mitochondrial_biogenesis	phenotype	SIGNOR-PH32	SIGNOR	up-regulates													25627476	f		lperfetto	Mitochondrial phospholipids are important components of this system. Phospholipids make up the characteristic outer and inner membranes that give mitochondria their shape. 	SIGNOR-267005	0.7
ARNTL	protein	O00327	UNIPROT	PER2	protein	O15055	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f			Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253629	0.736
STK11	protein	Q15831	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	up-regulates activity	phosphorylation	Ser732	EAINEAIsVKQEVTD	9606	BTO:0002181								34216621	t		miannu	 Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction. 	SIGNOR-277323	0.591
NFASC	protein	O94856	UNIPROT	ANK1	protein	P16157	UNIPROT	up-regulates quantity	relocalization			10116		BTO:0000227							7961622	t		miannu	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266718	0.671
RPS6KA1	protein	Q15418	UNIPROT	RPS6	protein	P62753	UNIPROT	up-regulates	phosphorylation	Ser240	RLSSLRAsTSKSESS	9606									21233202	t		lperfetto	In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity	SIGNOR-171243	0.608
DLG4	protein	P78352	UNIPROT	DLGAP1	protein	O14490	UNIPROT	up-regulates activity	relocalization			9606									18923512	t	brain	lperfetto	Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). 	SIGNOR-264196	0.93
MAPK14	protein	Q16539	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser33	LPENNVLsPLPSQAM	9606	BTO:0000093								11258706	t		lperfetto	P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.	SIGNOR-105741	0.765
SYN2	protein	Q92777	UNIPROT	Synaptic_vesicle_exocytosis	phenotype	SIGNOR-PH160	SIGNOR	down-regulates				9606	BTO:0000938								33809712	f		miannu	Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet.	SIGNOR-264106	0.7
trimethyl-[(5-methyl-2-furanyl)methyl]ammonium	chemical	CHEBI:94038	ChEBI	CHRM4	protein	P08173	UNIPROT	up-regulates activity	chemical activation			10029									9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258646	0.8
CDK5	protein	Q00535	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606	BTO:0000938								17591690	t		gcesareni	Here, we demonstrate for the first time that cdk5 interacts with p53 and increases its stability through posttranslational regulation, leading to accumulation of p53, particularly in the nucleus. We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 in vitro,	SIGNOR-156418	0.722
USO1	protein	O60763	UNIPROT	GOLGB1	protein	Q14789	UNIPROT	up-regulates activity	binding			9606									23555793	t		miannu	The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane.	SIGNOR-261237	0.834
CHKB	protein	Q9Y259	UNIPROT	O-phosphonatoethanaminium(1-)	smallmolecule	CHEBI:58190	ChEBI	up-regulates quantity	chemical modification												29928787	t		lperfetto	In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells.	SIGNOR-275639	0.8
GABA-A (a6-b1-g2) receptor	complex	SIGNOR-C334	SIGNOR	CRHR2	protein	Q13324	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268596	0.2
PTPRG	protein	P23470	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates activity	dephosphorylation	Tyr694	LAKAVDGyVKPQIKQ	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254730	0.268
FYN	protein	P06241	UNIPROT	SLAMF1	protein	Q13291	UNIPROT	up-regulates activity	phosphorylation	Tyr307	QDPCTTIyVAATEPV	9534	BTO:0000298								11806999	t			All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327. 	SIGNOR-251182	0.647
PRKCI	protein	P41743	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606	BTO:0000527								21419810	t		lperfetto	In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer	SIGNOR-172890	0.324
GFs	stimulus	SIGNOR-ST12	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates				9606									23863153	f		lperfetto	Growth factors and nutrients regulate the mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] by different mechanisms. The players that link growth factors and mTORC1 activation have been known for several years and mouse models have validated its relevance for human physiology and disease.	SIGNOR-219382	0.7
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	CIC	protein	Q96RK0	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000848								21087211	t	inferred from 70% family members	gcesareni	Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3	SIGNOR-270090	0.2
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257971	0.8
SMARCD2	protein	Q92925	UNIPROT	SWI/SNF ACTL6A-ARID1A-SMARCA2 variant	complex	SIGNOR-C470	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269821	0.753
CNR2	protein	P34972	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256700	0.444
SIRT1	protein	Q96EB6	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates quantity by destabilization	deacetylation			10090		BTO:0001103							24003218	t		lperfetto	SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3	SIGNOR-217975	0.804
ARVCF	protein	O00192	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0001109								14610055	t		miannu	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 	SIGNOR-252133	0.432
N-[4-[(4-Ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[(E)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)ethenyl]-4-methylbenzamide	chemical	CID:53302361	PUBCHEM	BRAF	protein	P15056	UNIPROT	down-regulates activity	chemical inhibition			-1									32069833	t		lperfetto	HG6-64-1 is a specific BRAF inhibitor	SIGNOR-261986	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	RAC1	protein	P63000	UNIPROT	down-regulates activity	phosphorylation	Ser71	YDRLRPLsYPQTDVF	9606	BTO:0003476								10617634	t		gcesareni	The results suggest that Akt kinase of the phosphoinositide 3-kinase signal transduction pathway phosphorylates serine 71 of Rac1 as one of its authentic substrates and modulates the Rac1 signal transduction pathway through phosphorylation.	SIGNOR-248036	0.2
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2T	protein	Q9NPD8	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271350	0.472
HDLBP	protein	Q00341	UNIPROT	CTCF	protein	P49711	UNIPROT	up-regulates activity	binding			9606	BTO:0000599								24725430	t		miannu	Vigilin interacts with CCCTC-binding factor (CTCF) and is involved in CTCF-dependent regulation of the imprinted genes Igf2 and H19. vigilin is present at several known CTCF target sites, such as the promoter regions of c-myc and BRCA1, the locus control region of β-globin, and several regions within the Igf2/H19 locus. These results reveal the functional relevance of vigilin and CTCF, and show that the CTCF-vigilin complex contributes to regulation of Igf2/H19.	SIGNOR-266693	0.495
GSK3B	protein	P49841	UNIPROT	GLI2	protein	P10070	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser832	GISPYFSsRRSSEAS	9606	BTO:0000007								16611981	t		lperfetto	The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3.	SIGNOR-249589	0.544
SMARCA5	protein	O60264	UNIPROT	WICH	complex	SIGNOR-C449	SIGNOR	form complex	binding			9606									16603771	t		miannu	We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling.	SIGNOR-268827	0.923
Enolase	proteinfamily	SIGNOR-PF74	SIGNOR	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9534	BTO:0000318								2005901	t	inferred from family member	Luana	This result suggests that MBP-1 in vivo acts as a sequence-specific repressor.	SIGNOR-270308	0.2
ATM	protein	Q13315	UNIPROT	DCK	protein	P27707	UNIPROT	up-regulates activity	phosphorylation	Ser74	EFEELTMsQKNGGNV										27879648	t		lperfetto	Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in order to activate the cell cycle G2/M checkpoint. 	SIGNOR-275798	0.411
DDX46	protein	Q7L014	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270669	0.559
CSNK2A1	protein	P68400	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates activity	phosphorylation	Ser853	SSLNSSEsDKDQDYD	10090									10671552	t		llicata	Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | Under these conditions, phosphorylation of the E-cadherin double mutant S853A/S855A was reduced by 25% as compared with wt E-cadherin. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion.	SIGNOR-250841	0.41
PMP22	protein	Q01453	UNIPROT	ITGA6	protein	P23229	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21518455	f	Regulation	miannu	Peripheral myelin protein-22 (PMP22) modulates alpha 6 integrin expression in the human endometrium. Overexpression of PMP22 was sufficient to increase α6 integrin surface expression with a concominant increase in binding to the extracellular matrix laminin, while a reduction in PMP22 suppressed α6 integrin surface expression.	SIGNOR-251897	0.357
ARHGEF17	protein	Q96PE2	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260542	0.53
MELK	protein	Q14680	UNIPROT	MELK	protein	Q14680	UNIPROT	up-regulates	phosphorylation	Thr494	TGTDKLMtGVISPER	9606									16216881	t		lperfetto	We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase.	SIGNOR-141030	0.2
DYRK4	protein	Q9NR20	UNIPROT	DYRK4	protein	Q9NR20	UNIPROT	up-regulates activity	phosphorylation	Tyr264	SSCYEHQkVYTYIQS	9606									21127067	t		Manara	Autophosphorylation of DYRK4 in the Activation Loop Is Required for Kinase Activity	SIGNOR-260827	0.2
PLK1	protein	P53350	UNIPROT	TNKS	protein	O95271	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr1128	VEEEMQStIREHRDG	9606	BTO:0000567								21818122	t		miannu	Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends. 	SIGNOR-276244	0.439
GSK3B	protein	P49841	UNIPROT	BICD1	protein	Q96G01	UNIPROT	up-regulates activity	phosphorylation	Thr597	KEPSPTKtPTISPVI	9606	BTO:0000567								17139249	t		miannu	Therefore, at least Ser585 and Thr597 in BICD1 are important phosphorylation sites for BICD1 to exert its functions, and GSK-3β-dependent phosphorylation is required for the interaction of BICD1 with dynein.	SIGNOR-262744	0.336
YAP1	protein	P46937	UNIPROT	RRM2	protein	P31350	UNIPROT	up-regulates quantity by expression	transcriptional regulation					BTO:0001939							30224758	f		lperfetto	 By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 	SIGNOR-276569	0.2
BMP2	protein	P12643	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates				9606									12589053	f		fspada	Specific inhibitors for p38 kinase inhibited bmp2-induced adipocytic differentiation and transcriptional activation of ppargamma, whereas overexpression of smad6 had no effect on transcriptional activity of ppargamma.	SIGNOR-98369	0.401
Elongator complex	complex	SIGNOR-C466	SIGNOR	RAB3IL1	protein	Q8TBN0	UNIPROT	up-regulates activity	binding			-1									15780940	t		miannu	Our results raise the possibility that regulation of polarized exocytosis is an evolutionarily conserved function of the entire Elongator complex and that FD results from a dysregulation of neuronal exocytosis. Our results raise the possibility that regulation of polarized exocytosis is an evolutionarily conserved function of the entire Elongator complex and that FD results from a dysregulation of neuronal exocytosis. We show that elp1Δ suppression of sec2ts is not a result of reduced transcriptional elongation and that Elp1p physically associates with Sec2p. The Sec2p interaction domain of Elp1p is necessary for both Elp1p function and for the polarized localization of Sec2p. Mutations in human Elp1p (IKAP) are a known cause of familial dysautonomia (FD). 	SIGNOR-269714	0.276
MAPK3	protein	P27361	UNIPROT	MBP	protein	P02686	UNIPROT	down-regulates	phosphorylation	Thr232	KNIVTPRtPPPSQGK	9606		BTO:0000142							16401070	t		lperfetto	Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence.	SIGNOR-143481	0.516
NMDA receptor_2D	complex	SIGNOR-C350	SIGNOR	CTTN	protein	Q14247	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000142								14684878	t		miannu	Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors.	SIGNOR-266602	0.292
miR-495	mirna	URS000075C517_9606	RNAcentral	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				10090									26344767	t		Luana	To further determine whether MeCP2 regulates the expression of miR-199a, we also re-expressed MeCP2 in MeCP2-KO neurons. As expected, this restored the level of mature-miR-199a expression to that in WT neurons	SIGNOR-264545	0.4
ETV2	protein	O00321	UNIPROT	SPI1	protein	P17947	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									24583263	f		irozzo	We also identify Spi1 as a common downstream target gene of Etv2 and Gata2. We provide evidence that Etv2 and Gata2 bind to the Spi1 promoter in vitro and in vivo. Etv2 and Gata2 synergistically transactivate Spi1 gene expression.	SIGNOR-256006	0.262
AKT2	protein	P31751	UNIPROT	HTRA2	protein	O43464	UNIPROT	down-regulates	phosphorylation	Ser212	RVRVRLLsGDTYEAV	9606									17311912	t		lperfetto	Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212	SIGNOR-153327	0.2
BMPR1A	protein	P36894	UNIPROT	SMAD1/4	complex	SIGNOR-C85	SIGNOR	up-regulates activity				10090									19620713	f		ggiuliani	The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17).	SIGNOR-255787	0.702
MAP3K3	protein	Q99759	UNIPROT	MAP2K3	protein	P46734	UNIPROT	up-regulates activity	phosphorylation	Ser218	ISGYLVDsVAKTMDA	9606	BTO:0000298								9162092	t		lperfetto	These data indicate that mkk3 is preferentially activated by mekk3, whereas mkk4 is activated both by mekk2 and mekk3.	SIGNOR-48625	0.538
RET	protein	P07949	UNIPROT	FRS2	protein	Q8WU20	UNIPROT	up-regulates	binding			9606									11360177	t		gcesareni	Tyrosine 1062 in ret provides a site for the interaction of multiple signaling molecules and that the balance of shc and snt/frs2 binding may affect the nature of the intracellular signaling for cell proliferation, differentiation and survival induced by activated ret	SIGNOR-108244	0.664
Interferon-type-I	proteinfamily	SIGNOR-PF50	SIGNOR	NUP98	protein	P52948	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16036565	f		miannu	Nup98/Nup96 (41) and Rae1 (17)are up regulated by interferons, which revert the mRNAexport block induced by VSV M protein	SIGNOR-260870	0.2
PRKG1	protein	Q13976	UNIPROT	TRPC6	protein	Q9Y210	UNIPROT	down-regulates activity	phosphorylation	Thr70	RLAHRRQtVLREKGR	-1									19961855	t		miannu	PKG phosphorylated TRPC6, and both T70 and S322 were targeted. Both sites were functionally relevant, as 8Br-cGMP strongly suppressed current in wild-type TRPC6 channels, but not in those with phospho-silencing mutations (T70A, S322A or S322Q). 	SIGNOR-276272	0.473
CCKBR	protein	P32239	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256908	0.268
GFs	stimulus	SIGNOR-ST12	SIGNOR	AKT2	protein	P31751	UNIPROT	up-regulates activity				9606									23300340	f		lperfetto	Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation	SIGNOR-245405	0.7
MAPK12	protein	P53778	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr522	SSPGSPGtPGSRSRT	-1									9199504	t		miannu	Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective.	SIGNOR-250087	0.504
PRKCA	protein	P17252	UNIPROT	GRM1	protein	Q13255	UNIPROT	down-regulates activity	phosphorylation	Thr695	GSKKKICtRKPRFMS	9606									10823959	t		lperfetto	Furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr(695) selectively disrupts mGluR1alpha-G(q/11) interaction without affecting signaling through G(s).	SIGNOR-249043	0.393
CSNK2A1	protein	P68400	UNIPROT	SSRP1	protein	Q08945	UNIPROT	down-regulates activity	phosphorylation	Ser657	KSSSRQLsESFKSKE	9606	BTO:0000007								15659405	t		llicata	CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity.	SIGNOR-250960	0.689
GRK3	protein	P35626	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser366	EPIQMENsMGTLRTS	9606	BTO:0000007								11517230	t			Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251460	0.2
CDC23	protein	Q9UJX2	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	form complex	binding												16896351	t		lperfetto	The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex.	SIGNOR-252008	0.913
CREB1	protein	P16220	UNIPROT	PK	proteinfamily	SIGNOR-PF80	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									16308421	f		gcesareni	In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1	SIGNOR-268144	0.252
YBX1	protein	P67809	UNIPROT	CXCR4	protein	P61073	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17072343	f		miannu	 YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. 	SIGNOR-255611	0.272
CDK2	protein	P24941	UNIPROT	CHEK1	protein	O14757	UNIPROT	up-regulates	phosphorylation	Ser286	TSGGVSEsPSGFSKH	9606									21765472	t		lperfetto	Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency	SIGNOR-175079	0.535
ITCH	protein	Q96J02	UNIPROT	JUNB	protein	P17275	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			10090	BTO:0001045								11828324	t		miannu	Itch promotes Ub conjugation to JunB Molecularly, Itch associated with and induced ubiquitination of JunB, a transcription factor that is involved in TH2 differentiation. However, in Itch−/− T cells under the same conditions, degradation of JunB was markedly delayed. 	SIGNOR-272619	0.417
PDE1C	protein	Q14123	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	down-regulates quantity	chemical modification			9606									22014080	t			PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values	SIGNOR-253399	0.8
PARVA	protein	Q9NVD7	UNIPROT	IPP complex	complex	SIGNOR-C380	SIGNOR	form complex	binding												16493410	t		lperfetto	Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton.	SIGNOR-265761	0.729
ATR	protein	Q13535	UNIPROT	MCC	protein	P23508	UNIPROT	up-regulates activity	phosphorylation	Ser120	LRSELSQsQHEVNED	9606	BTO:0001109								21779472	t		miannu	MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. 	SIGNOR-273515	0.2
PRKCD	protein	Q05655	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser275	LSAFRRTsLAGGGRR	9606		BTO:0000562							17075052	t		gcesareni	The triple aspartic acid mutation shows greater distance between the two thick myosin filaments (affects the steric arrangement of the filament distances) in heart tissue. Mutation is cardioprotective during stress (ischemia-reprofusion injury) against apoptosis similar to isoproterenol treatment.	SIGNOR-150347	0.2
L-arginine	chemical	CHEBI:16467	ChEBI	NOS2	protein	P35228	UNIPROT	up-regulates					BTO:0000801	BTO:0001103							25386178	f		apalma	In mammalian cells, arginine can be catabolized by four classes of enzymes (Figure ​(Figure1):1): NOS, arginase, arginine decarboxylase (ADC), and arginine:glycine amidinotransferase (AGAT)	SIGNOR-255554	0.8
CDC14A	protein	Q9UNH5	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates	dephosphorylation	Ser705	TPSAMKSsPQIPHQT	9606									20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis.	SIGNOR-164412	0.627
PRKAG3	protein	Q9UGI9	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	form complex	binding			9606									16054041	t		gcesareni	Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits.	SIGNOR-139179	0.708
dabrafenib	chemical	CHEBI:75045	ChEBI	SIK1	protein	P57059	UNIPROT	down-regulates activity	chemical inhibition			-1									24720932	t		miannu	Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations	SIGNOR-259219	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser221	DHEKKAYsFCGTVEY	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-250553	0.2
Netrin	proteinfamily	SIGNOR-PF97	SIGNOR	NEO1	protein	Q92859	UNIPROT	up-regulates activity	binding			9606		BTO:0001484							21558366	t		miannu	In mammals, three secreted netrins, netrin 1, 3 and 4, and two membrane-tethered glycophosphatidylinositol (GPI)-linked (see Glossary, Box 1) netrins, netrin G1 and G2, have been identified. In mammals, receptors for the secreted netrins include deleted in colorectal cancer (DCC), the DCC paralogue neogenin, the UNC-5 homologues UNC5A-D, and Down syndrome cell adhesion molecule (DSCAM).	SIGNOR-268172	0.2
PCSK5	protein	Q92824	UNIPROT	OXT	protein	P01178	UNIPROT	down-regulates quantity	cleavage			9606	BTO:0001073								11690596	t		miannu	Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension.	SIGNOR-270327	0.251
ATG16L1	protein	Q676U5	UNIPROT	ATG12/5/16L1	complex	SIGNOR-C109	SIGNOR	form complex	binding			9606		BTO:0000007							18321988	t		lperfetto	Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex).	SIGNOR-226696	0.882
RET/PTC2	protein	Q15300	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606									12637586	t		Manara	In addition, RET/PTC-mediated cellular transformation and proliferation of transformed cells require tyrosine 705 phosphorylation of STAT3 in NIH3T3 cells. We conclude that STAT3 activation by the RET/PTC tyrosine kinase is one of the critical signaling pathways for the regulation of specific genes, such as cyclin D1, vascular endothelial growth factor, and intercellular adhesion molecule 1, and for cellular transformation.	SIGNOR-260917	0.2
CTDP1	protein	Q9Y5B0	UNIPROT	MASTL	protein	Q96GX5	UNIPROT	down-regulates activity	dephosphorylation	Ser453	NFELVDSsPCKKIIQ	9606									26653855	t		lperfetto	Taken together, these data suggest that Fcp1 bound and dephosphorylated Gwl at S90 and S453, and possibly at other Cdk1 dependent sites, during mitosis exit and that Fcp1 catalyzed dephosphorylation lowered Gwl activity towards Ensa and ARPP19, allowing PP2A-B55 to autoactivate.|Together, these data indicate that Fcp1 dependent dephosphorylation greatly reduces S67-Ensa kinase activity of Gwl and that, downstream inactivation of Cdk1, Fcp1 deficit substantially blunts inactivation of Gwl.	SIGNOR-276971	0.446
MAPK1	protein	P28482	UNIPROT	SOS1	protein	Q07889	UNIPROT	down-regulates activity	phosphorylation	Ser1178	IMSKHLDsPPAIPPR	9534	BTO:0004055								8816480	t		lperfetto	In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1	SIGNOR-235925	0.702
CARD8	protein	Q9Y2G2	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	binding			9606									16678772	t		amattioni	Tucan is a recently identified card-containing protein that can complex with caspase-9 and prevent cytochrome c-induced caspase activation.	SIGNOR-146663	0.436
KDM6A	protein	O15550	UNIPROT	ERG	protein	P11308	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									29736013	t		miannu	Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase	SIGNOR-260033	0.2
DLG4	protein	P78352	UNIPROT	GRIN2A	protein	Q12879	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000007								9278515	t	brain	lperfetto	The PDZ domains of PSD-95 and related proteins interact with the COOH-terminal sequences of K+channels and NMDA2 receptors (3). By these interactions, PSD-95 may mediate the clustering of K+ channels and NMDA receptors at synapses.	SIGNOR-264194	0.804
CAV1	protein	Q03135	UNIPROT	SLC1A2	protein	P43004	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								26690923	t		miannu	EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. 	SIGNOR-264809	0.251
TP53	protein	P04637	UNIPROT	SLC2A4	protein	P14672	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									27692180	t		miannu	P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.	SIGNOR-267465	0.343
ID2	protein	Q02363	UNIPROT	MYOD/HEB	complex	SIGNOR-C128	SIGNOR	down-regulates activity	binding			10090	BTO:0004058								9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241143	0.562
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Ala657	MVGGVVIaTVIVITL	-1									10605825	t		lperfetto	In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D.	SIGNOR-261738	0.502
ECM	stimulus	SIGNOR-ST20	SIGNOR	AE/b7 integrin	complex	SIGNOR-C186	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259040	0.7
beta-alanine	smallmolecule	CHEBI:16958	ChEBI	GlyR	proteinfamily	SIGNOR-PF62	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000007								9009272	t	inferred from family member	miannu	For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system.	SIGNOR-270261	0.8
AURKA	protein	O14965	UNIPROT	LDHB	protein	P07195	UNIPROT	up-regulates activity	phosphorylation	Ser162	PKHRVIGsGCNLDSA	9606	BTO:0000567								31804482	t		miannu	Aurora-A-mediated phosphorylation of LDHB serine 162 significantly increases its activity in reducing pyruvate to lactate, which efficiently promotes NAD+ regeneration, glycolytic flux, lactate production and bio-synthesis with glycolytic intermediates. 	SIGNOR-277493	0.2
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser326	PPKMWKTsPDPSPVS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248523	0.386
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	FOS	protein	P01100	UNIPROT	up-regulates	phosphorylation			9606									7816602	t	inferred from 70% family members	lperfetto	Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions.	SIGNOR-270105	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	INSIG2	protein	Q9Y5U4	UNIPROT	down-regulates activity				10090		BTO:0000759							21723501	f			MTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2.	SIGNOR-256212	0.2
CDK2	protein	P24941	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	down-regulates	phosphorylation	Ser477	NSMNKLPsVSQLINP	9606									18769144	t		lperfetto	Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively	SIGNOR-180759	0.249
ADSS1	protein	Q8N142	UNIPROT	N(6)-(1,2-dicarboxylatoethyl)-AMP(4-)	smallmolecule	CHEBI:57567	ChEBI	up-regulates quantity	chemical modification			9606									10496970	t		miannu	Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 	SIGNOR-267348	0.8
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	GK	protein	P32189	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18805788	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription foxo1 localizes to the nucleus, where it represses hnf-4-dependent activity of the gk promoter as a corepressor.	SIGNOR-252919	0.2
ROCK1	protein	Q13464	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Thr7	tSAARRSY	-1									12686604	t		lperfetto	We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro.	SIGNOR-100192	0.316
olanzapine	chemical	CHEBI:7735	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10116		BTO:0000601							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258509	0.8
SIRT1	protein	Q96EB6	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	deacetylation			9606									22223095	t		gcesareni	The acetylation marks on notch1-icd are removed by the deacetylase sirt1, suggesting that both deacetylation of notch1-icd and of histones inhibit notch signaling.	SIGNOR-195333	0.436
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PAPOLA	protein	P51003	UNIPROT	up-regulates activity	phosphorylation	Ser558	GSSQGRNsPAPAVTA	10090	BTO:0000964								34048556	t		lperfetto	Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity.	SIGNOR-268343	0.2
ADK	protein	P55263	UNIPROT	ATP	smallmolecule	CHEBI:15422	ChEBI	down-regulates quantity	chemical modification			9606									33961946	t		miannu	Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5′-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S).	SIGNOR-267839	0.8
MAPK1	protein	P28482	UNIPROT	TP53BP2	protein	Q13625	UNIPROT	up-regulates activity	phosphorylation	Ser827	NSDMPAPsPGLDYEP	-1									24312625	t		lperfetto	Hence ASPP2 can be phosphorylated at serine 827 by MAPK1 in vitro.|Phosphorylation of ASPP2 by MAPK is required for RAS-induced increased binding to p53 and increased transactivation of pro-apoptotic genes.	SIGNOR-264414	0.267
PRKACA	protein	P17612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606									10230394	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.	SIGNOR-67387	0.521
AURKB	protein	Q96GD4	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Ser38	LGPGTRLsLARMPPP	-1									12686604	t		lperfetto	We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro.	SIGNOR-100169	0.449
PRKACA	protein	P17612	UNIPROT	CTNND1	protein	O60716	UNIPROT	down-regulates	phosphorylation	Ser879	LIDRNQKsDKKPDRE	9606		BTO:0000763							22798526	t		lperfetto	We showed that pkc_ phosphorylation of p120 at serine (s)879 in response to thrombin or lipopolysaccharide challenge reduced p120 binding affinity for ve-cadherin and mediated aj disassembly secondary to ve-cadherin internalization	SIGNOR-198288	0.2
TGFBR2	protein	P37173	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606	BTO:0001660								9435577	t		lperfetto	These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells.	SIGNOR-252732	0.42
CBP/p300	complex	SIGNOR-C6	SIGNOR	SMAD1	protein	Q15797	UNIPROT	up-regulates	binding			9606									12419246	t		lperfetto	Thus, Ski/SnoN represses TGFβ signaling by multiple mechanisms. In addition to recruitment of a transcriptional repressor complex and dissociation of the transcriptional coactivator p300/CBP from the Smads	SIGNOR-217217	0.406
ROCK1	protein	Q13464	UNIPROT	Membrane_blebbing	phenotype	SIGNOR-PH24	SIGNOR	up-regulates				9606									11283607	f	Cleaved by CASP3	amattioni	Activation of rock i by caspase-3 seems to be responsible for bleb formation in apoptotic cells.	SIGNOR-106549	0.7
MAP3K14	protein	Q99558	UNIPROT	MAP3K14	protein	Q99558	UNIPROT	up-regulates activity	phosphorylation			9606									20651737	t		lperfetto	As nik levels increase, nik presumably becomes activated by autophosphorylation (p).	SIGNOR-167063	0.2
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr585	PPGLEYCyNPSHNPE	10116	BTO:0002809;BTO:0001009								8622701	t		lperfetto	In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1	SIGNOR-236187	0.2
tRNA(Tyr)	smallmolecule	CHEBI:29182	ChEBI	Tyr-tRNA(Tyr)	smallmolecule	CHEBI:29161	ChEBI	up-regulates quantity	precursor of			9606									16429158	t		miannu	YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr	SIGNOR-270523	0.8
SMO	protein	Q99835	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates	binding			9606									16885213	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-148493	0.403
GAB1	protein	Q13480	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									11043767	t		lperfetto	We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1.	SIGNOR-252676	0.491
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	RXRB	protein	P28702	UNIPROT	up-regulates activity	chemical activation			9606									17132853	t		miannu	The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 	SIGNOR-256191	0.8
PRKCA	protein	P17252	UNIPROT	PDE3A	protein	Q14432	UNIPROT	up-regulates	phosphorylation	Ser312	SKSHRRTsLPCIPRE	9606									19261611	t		gcesareni	Phosphorylation and activation of pde3a required the activation of pkc	SIGNOR-184448	0.2
NUDT3	protein	O95989	UNIPROT	AKT2	protein	P31751	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271								10983986	t		miannu	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-81759	0.2
NFKB1	protein	P19838	UNIPROT	IEX-1L	protein	O75353	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9703517	f		gcesareni	Transcription factors of the nuclear factor-kappab/rel (nf-kappab) family may be important in cell survival by regulating unidentified, anti-apoptotic genes. One such gene that protects cells from apoptosis induced by fas or tumor necrosis factor type alpha (tnf), iex-1l, is described here. Its transcription induced by tnf was decreased in cells with defective nf-kappab activation, rendering them sensitive to tnf-induced apoptosis, which was abolished by transfection with iex-1l.	SIGNOR-59539	0.2
STAT3	protein	P40763	UNIPROT	GAP43	protein	P17677	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0000099								26865625	t		miannu	 In this study, we demonstrated for the first time that growth-associated protein 43 (GAP43), a well known growth cone protein that promotes axonal regeneration, can be induced in rat brain astrocytes by the proinflammatory endotoxin lipopolysaccharide via both nuclear factor-κB and signal transducer and activator of transcription 3-mediated transcriptional activation.	SIGNOR-266772	0.306
PPM1D	protein	O15297	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates activity	dephosphorylation			9606									11101524	t		lperfetto	Wip1 selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue	SIGNOR-84793	0.456
PPP2CA	protein	P67775	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606									20626350	t		gcesareni	In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a . p38 mapks activity stimulates the physical association between pp2a and erk complex, leading to mkk1/2 dephosphorylation by pp2a.	SIGNOR-166655	0.604
CYSLTR2	protein	Q9NS75	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256746	0.2
PRKACA	protein	P17612	UNIPROT	SYN2	protein	Q92777	UNIPROT	down-regulates activity	phosphorylation	Ser10	NFLRRRLsDSSFIAN	-1									10571231	t		miannu	Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I 	SIGNOR-250059	0.331
IRF1	protein	P10914	UNIPROT	IRF8	protein	Q02556	UNIPROT	up-regulates activity	binding			9606									11483597	t		miannu	We found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP.	SIGNOR-222841	0.404
CDH1	protein	P12830	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									20940130	t		gcesareni	P12Beta-catenin_ also associates to the_ wnt_ co-receptor lrp5/6, an interaction mediated by e-cadherin.	SIGNOR-168464	0.372
PDX1	protein	P52945	UNIPROT	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000627								8866550	f	inferred from family member	miannu	 The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription.	SIGNOR-270264	0.59
CDK1	protein	P06493	UNIPROT	SGO1	protein	Q5FBB7	UNIPROT	up-regulates activity	phosphorylation	Thr346	LEEGVHLtPFRQKVS	9606									24055156	t		lperfetto	The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl.	SIGNOR-265263	0.2
CAMK1G	protein	Q96NX5	UNIPROT	EIF4G3	protein	O43432	UNIPROT	up-regulates	phosphorylation	Ser1156	NTFMRGGsSKDLLDN	9606									22514323	t		lperfetto	Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by camki-mediated phosphorylation of ser1156 in eukaryotic initiation factor eif4gii (4gii).	SIGNOR-197149	0.2
ITGAM	protein	P11215	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606									12393465	f		apalma	CD11b, another marker for differentiation, was also less expressed in patients with t(8;21) in comparison to patients without t(8;21)	SIGNOR-255662	0.7
GAST	protein	P01350	UNIPROT	CCKBR	protein	P32239	UNIPROT	up-regulates	binding			9606		BTO:0000142							10368033	t		gcesareni	A segment of five amino acids in the second extracellular loop of the cck-b receptor was shown to be essential for the high affinity of the natural peptide agonits, gastrin,	SIGNOR-66987	0.776
PRKDC	protein	P78527	UNIPROT	RPA2	protein	P15927	UNIPROT	unknown	phosphorylation	Thr21	YGGAGGYtQSPGGFG	9606									14872059	t		llicata	We show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro.	SIGNOR-121873	0.598
PTPN3	protein	P26045	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates activity	dephosphorylation	Tyr534	NFLMDNAyFCEADAK	10029									12907755	t			PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 	SIGNOR-248459	0.441
CDK2	protein	P24941	UNIPROT	LIG3	protein	P49916	UNIPROT	down-regulates	phosphorylation	Ser210	TTTGQVTsPVKGASF	9606									17040896	t		llicata	Dna ligase iii_ is specifically phosphorylated in replicating cells by the cell cycle kinase cdk2. However, in response to oxidative dna damage, dna ligase iii_ is dephosphorylated in a pathway that is dependent upon the dna damage-activated, phosphatidylinositol 3-phosphate (pi3)1-related kinase atm.	SIGNOR-150121	0.429
TRAF2	protein	Q12933	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	ubiquitination	Lys377	NEPSLQSkLQDEANY	9606	BTO:0000007								8702708	t		lperfetto	Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2.	SIGNOR-42984	0.891
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	AMPH	protein	P49418	UNIPROT	unknown	phosphorylation	Ser276	PLPSPTAsPNHTLAP	-1									11113134	t		llicata	Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. 	SIGNOR-250645	0.361
RET	protein	P07949	UNIPROT	GRB10	protein	Q13322	UNIPROT	up-regulates	binding			9606									8631863	t		gcesareni	Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell	SIGNOR-41699	0.522
PDGFRB	protein	P09619	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates activity	phosphorylation	Tyr716	RPPSAELySNALPVG	-1									8940081	t		miannu	The SH2 domain of Grb7 can directly bind to the autophosphorylated PDGF beta-receptor in vitro. Grb7 association to the PDGF beta-receptor was dramatically reduced by replacement of tyrosine residues 716 or 775 with phenylalanine residues. 	SIGNOR-250256	0.2
PI4K2B	protein	Q8TCG2	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									10101268	t		miannu	The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 	SIGNOR-269100	0.8
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	RB1	protein	P06400	UNIPROT	down-regulates activity	phosphorylation	Thr5	tPRKTAAT	-1									9139732	t		llicata	In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB.	SIGNOR-250762	0.858
PRKCA	protein	P17252	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser315	AHSIHQRsRKRLSQD	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89158	0.538
NRP1	protein	O14786	UNIPROT	PHACTR1	protein	Q9C0D0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21939755	f		miannu	Recently, we identified a new Vascular Endothelial Growth Factor (VEGF)-A(165)-induced gene Phactr-1, (Phosphatase Actin Regulator-1). We found that neuropilin-1 (NRP-1) and VEGF-R1 depletion inhibited Phactr-1 mRNA expression while NRP-2 and VEGF-R2 depletion had no effect.	SIGNOR-260061	0.2
TAOK2	protein	Q9UL54	UNIPROT	MAP2K3	protein	P46734	UNIPROT	up-regulates activity	phosphorylation	Ser218	ISGYLVDsVAKTMDA	9606	BTO:0000007								11279118	t		lperfetto	Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells	SIGNOR-106462	0.654
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1889	SPTTPKYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273078	0.636
CSNK2A1	protein	P68400	UNIPROT	CDC34	protein	P49427	UNIPROT	down-regulates activity	phosphorylation	Ser203	APAPDEGsDLFYDDY	9606	BTO:0000567								11546811	t		lperfetto	The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm.	SIGNOR-110383	0.403
PRKD1	protein	Q15139	UNIPROT	PTRH2	protein	Q9Y3E5	UNIPROT	up-regulates	phosphorylation	Ser5	sLVMEYLA	9606									18703509	t		lperfetto	Overexpression of constitutively active pkd or pkd activation by treatment with phorbol 12-myristate 13-acetate results in phosphorylation of two serine residues (ser5 and ser87) in a form of bit1 that is confined to the cytoplasm and concomitantly increases the apoptotic activity of cytoplasmic bit1	SIGNOR-180085	0.305
MAPK3	protein	P27361	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Thr739	SEGSGTAtPSALITT	9606	BTO:0000552								14744793	t		gcesareni	We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription.	SIGNOR-248070	0.638
TNFRSF17	protein	Q02223	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates				9606									10903733	f	inferred from 70% of family members	miannu	Overexpression of bcma activates the p38 mapk	SIGNOR-269917	0.268
HOXD11	protein	P31277	UNIPROT	MEIS1	protein	O00470	UNIPROT	up-regulates activity	binding			-1									9343407	t	2	miannu	We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets.	SIGNOR-241229	0.416
BLK	protein	P51451	UNIPROT	BCR-Dl	complex	SIGNOR-C436	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000776								32323266	t		scontino	The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases.	SIGNOR-268217	0.633
SLC36A1	protein	Q7Z2H8	UNIPROT	alanine	smallmolecule	CHEBI:16449	ChEBI	up-regulates quantity	relocalization			9606									12748860	t		lperfetto	Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut.	SIGNOR-264739	0.8
Alkannin	chemical	CHEBI:2578	ChEBI	PK	proteinfamily	SIGNOR-PF80	SIGNOR	down-regulates activity	chemical inhibition			9606	BTO:0000093;BTO:0000018								21516121	t	inferred from family member	lperfetto	Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2.	SIGNOR-270284	0.8
SRC	protein	P12931	UNIPROT	CTTN	protein	Q14247	UNIPROT	down-regulates activity	phosphorylation	Tyr421	RLPSSPVyEDAASFK	-1									15169891	t		lperfetto	Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP.	SIGNOR-246513	0.795
WNT5A	protein	P41221	UNIPROT	FZD2	protein	Q14332	UNIPROT	down-regulates	binding			9606									19910923	t		gcesareni	Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway.Wnt5a Internalized fz2 probably with ror1 or ror2 through the clathrin-mediated route, whereas wnt5a competed with wnt3a for binding to fz2 to inhibit the beta-catenin pathway.	SIGNOR-189120	0.757
CALM3	protein	P0DP25	UNIPROT	CAMKK1	protein	Q8N5S9	UNIPROT	up-regulates	binding			9606									10770941	t		miannu	The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases	SIGNOR-266344	0.626
aclidinium	chemical	CHEBI:65346	ChEBI	CHRM1	protein	P11229	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000131								19653626	t		Luana	This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects.	SIGNOR-258152	0.8
AREL1	protein	O15033	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002552								23479728	t		lperfetto	Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists|	SIGNOR-267668	0.386
CHUK	protein	O15111	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	up-regulates activity	phosphorylation	Ser441	GHSPLSLsAQSVMEE	9606	BTO:0000938								24614225	t		lperfetto	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204708	0.524
haloperidol	chemical	CHEBI:5613	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258373	0.8
HDAC2	protein	Q92769	UNIPROT	YY1	protein	P25490	UNIPROT	down-regulates activity	deacetylation			-1									11486036	t		miannu	Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs.	SIGNOR-268836	0.76
MAPK11	protein	Q15759	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	unknown	phosphorylation			9606									21757713	t		lperfetto	Arsenite treatment of cells activates p38_ and induces interaction between p38_ and raptor, a regulatory component of mtorc1, resulting in phosphorylation of raptor on ser(863) and ser(771). The phosphorylation of raptor on these sites enhances mtorc1 activity, and contributes largely to arsenite-induced mtorc1 activation.	SIGNOR-217580	0.336
CIITA	protein	P33076	UNIPROT	HLA-DPB1	protein	P04440	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								11889043	f	 	 	Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment.	SIGNOR-254006	0.489
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation			9606									21620960	t		gcesareni	Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity.	SIGNOR-252847	0.908
RRAGD	protein	Q9NQL2	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates	binding			9606									20006481	t		lperfetto	Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor	SIGNOR-217550	0.636
MAPK8	protein	P45983	UNIPROT	FOXO4	protein	P98177	UNIPROT	up-regulates	phosphorylation	Thr455	ALGTPVLtPPTEAAS	9606									15538382	t		lperfetto	Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment.	SIGNOR-130385	0.597
DLK1	protein	P80370	UNIPROT	FN1	protein	P02751	UNIPROT	up-regulates	binding			9606									20457810	t		fspada	We show a direct interaction of pref-1 and fibronectin via the pref-1 juxtamembrane domain and fibronectin c-terminal domain	SIGNOR-165347	0.379
ARID2	protein	Q68CP9	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	form complex	binding			9606									15627498	t		lperfetto	We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers.	SIGNOR-241756	0.72
DUSP2	protein	Q05923	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates activity	dephosphorylation			9606									28252035	t		miannu	DUSP2 can dephosphorylate both ERK3 and ERK4 when expressed in mammalian cells.|Finally, we demonstrate that DUSP2 inhibits ERK3 and ERK4 mediated activation of MK5.	SIGNOR-277069	0.384
SLBP	protein	Q14493	UNIPROT	H2AC7	protein	P20671	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265399	0.2
NME1	protein	P15531	UNIPROT	NETO2	protein	Q8NC67	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17671192	f		miannu	To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 	SIGNOR-255166	0.26
KLK3	protein	P07288	UNIPROT	PTHLH	protein	P12272	UNIPROT	up-regulates activity	binding			-1									8683730	t		lperfetto	 Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner.|The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production.	SIGNOR-270548	0.432
GNAS	protein	P63092	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606		BTO:0000887;BTO:0001103;BTO:0001760							22179044	t		gcesareni	Notably, the fzd7 receptor complex was associated with g_?(s) and pi(3)k and these components were required for wnt7a to activate the akt/mtor growth pathway in myotubes. These data led us to hypothesize that g_?s Mediates the activation of pi3kinase following wnt7a binding to fzd7.	SIGNOR-252678	0.365
Complement C1 complex	complex	SIGNOR-C309	SIGNOR	C2	protein	P06681	UNIPROT	up-regulates activity	cleavage	Ser20	LYPGLADsAPSCPQN										31331124	t		lperfetto	C1s subsequently activate serum proteins C4 and C2. C4 is cleaved to fragment C4a, which is an anaphylatoxin, and to fragment C4b, which is deposited on the adjacent surfaces. C2 is cleaved to a fragment C2b, and larger fragment C2a, which binds noncovalently to C4b on the target cell membrane. This forms the C4b2a complex	SIGNOR-263421	0.477
CSNK1D	protein	P48730	UNIPROT	PRH1	protein	P02810	UNIPROT	up-regulates	phosphorylation	Ser24	QDLDEDVsQEDVPLV	9606	BTO:0000007	BTO:0000671							10684652	t		lperfetto	Ser22 may be phosphorylated by a g-ck that recognizes an atypical substrate sequence or by a novel kinase. While prp1 secreted from salivary glands is fully phosphorylated at ser8 and 22	SIGNOR-75272	0.2
GARS1	protein	P41250	UNIPROT	Gly-tRNA(Gly)	smallmolecule	CHEBI:29156	ChEBI	up-regulates quantity	chemical modification			9606									24898252	t		miannu	Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 	SIGNOR-270482	0.8
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	CEBPA	protein	P49715	UNIPROT	down-regulates activity	binding			9606									12524424	t		lperfetto	C/EBPbeta and C/EBPdelta were found to physically interact with Smad3 and Smad4, and Smad3 cooperated with Smad4 and TGF-beta signaling to repress the transcriptional activity of C/EBPs.	SIGNOR-250571	0.375
MAPK9	protein	P45984	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606									11896587	t		llicata	These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells.	SIGNOR-115835	0.738
CD79A	protein	P11912	UNIPROT	BCR-Dk	complex	SIGNOR-C435	SIGNOR	form complex	binding			9606	BTO:0000776								32323266	t		scontino	BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition.	SIGNOR-268196	0.641
PLEKHG1	protein	Q9ULL1	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260563	0.329
ITCH	protein	Q96J02	UNIPROT	TNIP2	protein	Q8NFZ5	UNIPROT	down-regulates	ubiquitination			9606									16469705	t		gcesareni	Here we show that tnfa-mediated jnk activation accelerates turnover of the NF-kappaBinduced antiapoptotic protein c-flip, an inhibitor of caspase-8. This is not due to direct c-flip phosphorylation but depends on jnk-mediated phosphorylation and activationof the e3ubiquitin ligaseitch, which speci?cally Ubiquitinates c-flip and induces its proteasomal degradation.	SIGNOR-144453	0.272
SHH	protein	Q15465	UNIPROT	CP	protein	P00450	UNIPROT	down-regulates	binding			9606									15618519	t		gcesareni	Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms.	SIGNOR-132672	0.2
KDM6A	protein	O15550	UNIPROT	ETV6	protein	P41212	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									29736013	t		miannu	Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase	SIGNOR-260032	0.306
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	G6PC1	protein	P35575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22521266	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-252920	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	USP24	protein	Q9UPU5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2604	HLQQGSEsPMMIGEL	9606	BTO:0000018								27991932	t		lperfetto	 Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604.	SIGNOR-275609	0.26
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Thr8	MSSILPFtPPVVKRL	9606		BTO:0000763;BTO:0000149							10197981	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-66775	0.739
CDK2	protein	P24941	UNIPROT	RNF4	protein	P78317	UNIPROT	up-regulates activity	phosphorylation	Thr112	DVYVTTHtPRNARDE	9606	BTO:0002181								25948581	t		miannu	Here we reported that CDK2 could phosphorylate RNF4 on T26 and T112 and enhance RNF4 E3 ligase activity, which is important for MDC1 degradation and proper HR repair during S phase. 	SIGNOR-276901	0.2
MAPK3	protein	P27361	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates activity	phosphorylation	Ser863	LTQSAPAsPTNKGVH	9606				SIGNOR-C3					21071439	t		lperfetto	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-169534	0.482
PRKACA	protein	P17612	UNIPROT	GLI2	protein	P10070	UNIPROT	down-regulates	phosphorylation			9606									17419683	t		gcesareni	In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation	SIGNOR-154273	0.445
MAFA	protein	Q8NHW3	UNIPROT	PC	protein	P11498	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17149590	f		miannu	 the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA.	SIGNOR-254561	0.253
RCHY1	protein	Q96PM5	UNIPROT	POLH	protein	Q9Y253	UNIPROT	down-regulates activity	monoubiquitination	Lys686	HQGKRNPkSPLACTN	9606									21791603	t		miannu	Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709).	SIGNOR-272731	0.563
MAPK9	protein	P45984	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates activity	phosphorylation	Ser389	LSPIAPRsPAKLSFQ	9606	BTO:0000567								8846788	t		lperfetto	However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity.	SIGNOR-247062	0.471
CDK1	protein	P06493	UNIPROT	MAPK6	protein	Q16659	UNIPROT	up-regulates	phosphorylation	Thr698	KSIQATLtPSAMKSS	9606			SIGNOR-C17						20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.	SIGNOR-164499	0.461
MAPK1	protein	P28482	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	phosphorylation	Thr277	GSRTAPYtPNLPHHQ	9606									12801888	t		lpetrilli	Phosphorylation of thr276 is shown to be important for tgf-?-Induced nuclear accumulation and, as a consequence, transcriptional activity of smad4. these results suggest that smad4 can be phosphorylated by erk2 at thr276.	SIGNOR-101660	0.526
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1721	SPTSPSYsPTSPSYS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248754	0.727
MAPK9	protein	P45984	UNIPROT	NFATC2	protein	Q13469	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000782								14517246	t		gcesareni	Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin	SIGNOR-118223	0.557
CSNK2A1	protein	P68400	UNIPROT	WAS	protein	P42768	UNIPROT	up-regulates	phosphorylation	Ser484	RSRAIHSsDEGEDQA	9606									12769847	t		gcesareni	Here we identify two phosphorylation sites in the vca domain of wasp at serines 483 and 484. S483 and s484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the vca domain for the arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length wasp molecule.	SIGNOR-101268	0.361
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH12	protein	P55289	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265830	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ARHGAP22	protein	Q7Z5H3	UNIPROT	up-regulates activity	phosphorylation	Ser16	ARRARSKsLVMGEQS	9606	BTO:0000007								21969604	t		miannu	Akt phosphorylates RhoGAP22 at the 14-3-3 binding site and is required for insulin-stimulated 14-3-3 binding. we have demonstrated that Akt is the kinase responsible for phosphorylation of Ser16 in order to mediate 14-3-3 binding to RhoGAP22.	SIGNOR-262613	0.2
UV stress	stimulus	SIGNOR-ST7	SIGNOR	RRM2B	protein	Q7LG56	UNIPROT	up-regulates				9606	BTO:0001061								14583450	f		miannu	Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3.	SIGNOR-259362	0.7
PRPS2	protein	P11908	UNIPROT	5-phospho-α-D-ribose 1-diphosphate	smallmolecule	CHEBI:58017	ChEBI	up-regulates quantity	chemical modification			9606									16939420	t		miannu	PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP.	SIGNOR-267082	0.8
SH3BP4	protein	Q9P0V3	UNIPROT	TFRC	protein	P02786	UNIPROT	down-regulates	binding			9606									16325581	t		miannu	Here, we report that ttp (sh3bp4), a sh3-containing protein, specifically regulates the internalization of the transferrin receptor (tfr). / overexpression of ttp specifically inhibits tfr internalization	SIGNOR-142840	0.36
ITGA8	protein	P53708	UNIPROT	A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253181	0.812
3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	PRKAR1A	protein	P10644	UNIPROT	down-regulates activity	chemical inhibition			9606									26687711	t			Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 	SIGNOR-258759	0.8
PRKCZ	protein	Q05513	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser315	AHSIHQRsRKRLSQD	9606									12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89264	0.402
MAPK9	protein	P45984	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	phosphorylation	Ser605	LFVQLLYsPIENIQR	9606									18423204	t		amattioni	Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt.	SIGNOR-178262	0.657
S1PR1	protein	P21453	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates				9606									9488656	f		gcesareni	Edg-1 is known to activate the mitogen-activated protein (map) kinase known as extracellular signal-regulated kinase 2 (erk-2) through pertussis toxin (ptx)sensitive giprotein	SIGNOR-54770	0.482
hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	GABA-A (a5-b1-g2) receptor	complex	SIGNOR-C335	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000938								26136660	t		miannu	The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 	SIGNOR-264926	0.8
NCKAP1	protein	Q9Y2A7	UNIPROT	NHS	protein	Q6T4R5	UNIPROT	up-regulates activity	binding			9606									20332100	t		miannu	We show that the WHD of NHS interacts with the Abi family of proteins, HSPC300, Nap1 and Sra1, and is important for the localization of NHS to the leading edge.	SIGNOR-253576	0.2
SMURF1	protein	Q9HCE7	UNIPROT	BMPR2	protein	Q13873	UNIPROT	down-regulates	ubiquitination			9606									17317136	t		gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-153402	0.542
NEK11	protein	Q8NG66	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser82	GSSESTDsGFCLDSP	9606									19734889	t		lperfetto	Nek11 regulates cdc25a degradation and the ir-induced g2/m checkpointincubation of wild-type cdc25a with nek11 led to a marked increase in phosphorylation of ser 82 and 88 as detected with the phosphospecific antibody recognizing these sites	SIGNOR-187867	0.43
CDK1	protein	P06493	UNIPROT	PAPOLA	protein	P51003	UNIPROT	up-regulates activity	phosphorylation	Ser558	GSSQGRNsPAPAVTA	10090	BTO:0000964								34048556	t		lperfetto	Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity.	SIGNOR-268340	0.261
PTPN1	protein	P18031	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates activity	dephosphorylation	Tyr446	GTEPEPVySMEAADY	9534	BTO:0004055								18387954	t			Here, we have identified cortactin, a central regulator of actin cytoskeletal dynamics, as a substrate of PTP1B. A trapping mutant of PTP1B binds cortactin at the phosphorylation site Tyr446, |Cortactin exerts its effects on the actin cytoskeleton by interacting directly with the Arp2/3 complex , F-actin |Src phosphorylates murine cortactin predominantly at three key sites in vitro, Tyr421, Tyr466, and Tyr482 (corresponding to Tyr421, Tyr470, and Try486 in human cortactin), resulting in decreased actin cross-linking activity	SIGNOR-248432	0.532
UBE2D3	protein	P61077	UNIPROT	MPG	protein	P29372	UNIPROT	up-regulates activity	binding			-1									25207814	t		miannu	Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E)	SIGNOR-271928	0.2
cyclosporin A	chemical	CHEBI:4031	ChEBI	PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	down-regulates	chemical inhibition			9606									15276472	t	inferred from 70% of family members	gcesareni	Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins.	SIGNOR-269889	0.8
CSNK2A1	protein	P68400	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Thr811	ADDSSSStSSDSLGG	-1									8349691	t		llicata	These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1.	SIGNOR-250910	0.345
IRAK1	protein	P51617	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity	phosphorylation	Thr66	CERSGQRtASVLWPW	9534	BTO:0001538								12138165	t			T66E mutations interfered with the ability of IRAK to autophosphorylate. Thr-66 mutations abolished the capacity of IRAK to dimerize. 	SIGNOR-251327	0.2
DMPK	protein	Q09013	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates	phosphorylation	Thr159	DNKLRRYtTFSKRKT	10090									12809504	t		llicata	Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha. 	SIGNOR-236982	0.293
RAPH1	protein	Q70E73	UNIPROT	VASP	protein	P50552	UNIPROT	up-regulates activity	binding			9606									20417104	t		miannu	 Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins.	SIGNOR-268426	0.597
PTGER3	protein	P43115	UNIPROT	GNG12	protein	Q9UBI6	UNIPROT	up-regulates	binding			9606	BTO:0000938								12038972	t		gcesareni	Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i)	SIGNOR-88195	0.426
Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	Pluripotency	phenotype	SIGNOR-PH43	SIGNOR	up-regulates				10090	BTO:0001086								19279220	f		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270728	0.7
FGF11	protein	Q92914	UNIPROT	SCN2A	protein	Q99250	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253430	0.255
RPL26	protein	P61254	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262497	0.857
3-(dibutylamino)-1-[1,3-dichloro-6-(trifluoromethyl)-9-phenanthrenyl]-1-propanol	chemical	CHEBI:94392	ChEBI	KCNH2	protein	Q12809	UNIPROT	down-regulates activity	chemical inhibition			-1									19222165	t		Luana	4 inhibited cloned hERG potassium ion channel repolarization with an IC50 comparable to other antimalarial agents in this class (Table 6).	SIGNOR-257816	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CAD	protein	P27708	UNIPROT	up-regulates activity	phosphorylation	Thr456	KVYFLPItPHYVTQV	-1									17485345	t		miannu	The multifunctional protein CAD initiates de novo pyrimidine biosynthesis in mammalian cells. CAD is activated by MAP kinase (Erk1/2) just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. MAP kinase phosphorylates Thr456, while PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation. 	SIGNOR-267441	0.2
CEP250	protein	Q9BV73	UNIPROT	Centrosome_separation	phenotype	SIGNOR-PH177	SIGNOR	down-regulates				9606	BTO:0000567								24035387	t		miannu	C-Nap1 and rootletin have been previously reported to be the important centrosome linker components involved in centrosome cohesion.	SIGNOR-273705	0.7
NANOGP8	protein	Q6NSW7	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10900	BTO:0000667								23839044	f		Luana	Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun.	SIGNOR-266091	0.2
PRKACA	protein	P17612	UNIPROT	SUFU	protein	Q9UMX1	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser346	RAPSRKDsLESDSST	9606									21317289	t		gcesareni	We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation	SIGNOR-172003	0.443
PRKAA1	protein	Q13131	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates	phosphorylation	Ser155	FPLRKTVsEPNLKLR	9606			SIGNOR-C15						21892142	t		gcesareni	Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs).	SIGNOR-176487	0.276
selumetinib	chemical	CHEBI:90227	ChEBI	MAP2K1	protein	Q02750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190191	0.8
PDPK1	protein	O15530	UNIPROT	PDPK1	protein	O15530	UNIPROT	unknown	phosphorylation	Ser396	SSSSSSHsLSASDTG	9606									10455013	t		lperfetto	3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity	SIGNOR-236764	0.2
ROCK1	protein	Q13464	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates activity	phosphorylation	Ser72	SSAVRLRsSVPGVRL	9534	BTO:0000298								9565595	t		lperfetto	We found that vimentin, the most widely expressed intermediate filament protein, served as an excellent substrate for Rho-associated kinase (Rho-kinase) and that vimentin phosphorylated by Rho-kinase lost its ability to form filaments in vitro. Two amino-terminal sites on vimentin, Ser38 and Ser71, were identified as the major phosphorylation sites for Rho-kinase, and Ser71 was the most favored and unique phosphorylation site for Rho-kinase in vitro. 	SIGNOR-248998	0.374
alvocidib	chemical	CHEBI:47344	ChEBI	CDK7	protein	P50613	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192446	0.8
PTPRF	protein	P10586	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr999	YASSNPEyLSASDVF	9606									10734133	t		lperfetto	Many cellular receptors signal via tyrosine phosphorylation. The tyrosine kinases required for this activity are often recruited upon ligand bindingAlternatively, receptors themselves have kinase activity, like insulin receptors. In either case, the receptors are returned to their original state through the activity of protein-tyrosine phosphatases (PTPs)The major candidate PTPs previously implicated in IRK dephosphorylation are PTP-1b and LAR.	SIGNOR-76017	0.563
NME1	protein	P15531	UNIPROT	KSR1	protein	Q8IVT5	UNIPROT	unknown	phosphorylation	Ser406	TRLRRTEsVPSDINN	-1									12105213	t		miannu	Mutation of Ser392 to alanine consistently reduced Nm23-H1 phosphorylation, confirming it as a site of Nm23-H1 kinase activity The unique phosphorylation pattern of KSR by Nm23-H1 will be the subject of further investigation to determine its effects on KSR protein binding, subcellular localization, response to various signals, etc.	SIGNOR-250299	0.56
ACTN1	protein	P12814	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				9606									17243894	f		miannu	On most principal neurons in the mammalian brain (e.g., pyramidal neurons of cortex and hippocampus, Purkinje cells of cerebellum, medium spiny neurons of striatum), the postsynaptic specialization is housed on tiny actin rich protrusions called dendritic spines The size, shape, motility, and stability of dendritic spines depend largely on actin, the primary cytoskeleton within spines.	SIGNOR-264618	0.7
STUB1	protein	Q9UNE7	UNIPROT	SMAD5	protein	Q99717	UNIPROT	down-regulates	ubiquitination			9606									21454478	t		gcesareni	In addition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r/co-smad complex and further promoting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner	SIGNOR-172996	0.349
SOD1	protein	P00441	UNIPROT	S100A4	protein	P26447	UNIPROT	up-regulates quantity				10116	BTO:0000452;BTO:0000099	BTO:0001279							31623154	f	P00441:p.Gly94Ala (mutation increasing interaction)		We found that S100A4 was significantly up-regulated in astrocytes and microglia in the spinal cord of a transgenic rat SOD1-G93A model of amyotrophic lateral sclerosis	SIGNOR-262783	0.2
PRKG2	protein	Q13237	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates activity	phosphorylation	Ser557	AKASRTSsKHKEDVY	9606	BTO:0002181								21177494	t		miannu	 PKGII directly phosphorylated and stimulated SHP-1 activity	SIGNOR-276287	0.2
GGCX	protein	P38435	UNIPROT	F2	protein	P00734	UNIPROT	up-regulates activity	carboxylation	Glu59	RKGNLEReCVEETCS	-1									10556651	t		lperfetto	We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 	SIGNOR-263678	0.655
GTF2H2C	protein	Q6P1K8	UNIPROT	TFIIH	complex	SIGNOR-C457	SIGNOR	form complex	binding			9606									30860024	t		lperfetto	Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 	SIGNOR-269317	0.711
MEF2D	protein	Q14814	UNIPROT	MYH10	protein	P35580	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0001103							15728583	t		lperfetto	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238766	0.328
SEC61A2	protein	Q9H9S3	UNIPROT	SEC61 complex	complex	SIGNOR-C368	SIGNOR	form complex	binding			-1									33925740	t		lperfetto	The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER	SIGNOR-267728	0.641
RB1	protein	P06400	UNIPROT	ITGA10	protein	O75578	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									24287699	f		lperfetto	Integrin α10 expression is pRb-dependent in mouse osteoblasts|pRb-activated expression of integrin α10 mRNA is effectively translated into higher levels of integrin α10 protein as visualized by immunofluorescence	SIGNOR-253348	0.2
PCM1	protein	Q15154	UNIPROT	NIN	protein	Q8N4C6	UNIPROT	up-regulates	relocalization			9606									12403812	t		miannu	Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome	SIGNOR-95077	0.417
MAP3K1	protein	Q13233	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								12049732	t		miannu	ERK1/2 MAP kinases are important regulators in cellular signaling, whose activity is normally reversibly regulated by threonine-tyrosine phosphorylation. In contrast, we have found that stress-induced ERK1/2 activity is downregulated by ubiquitin/proteasome-mediated degradation of ERK1/2. The PHD domain of MEKK1, a RING finger-like structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro and in vivo. Therefore, MEKK1 functions not only as an upstream activator of the ERK and JNK through its kinase domain, but also as an E3 ligase through its PHD domain, providing a negative regulatory mechanism for decreasing ERK1/2 activity.	SIGNOR-272609	0.524
FOXO1	protein	Q12778	UNIPROT	G6PC1	protein	P35575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20577053	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-166349	0.2
TRIM25	protein	Q14258	UNIPROT	ZFHX3	protein	Q15911	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002999								22452784	t		miannu	In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels.	SIGNOR-272048	0.463
PRKCA	protein	P17252	UNIPROT	GABRR1	protein	P24046	UNIPROT	unknown	phosphorylation	Ser447	SQRSSYVsMRIDTHA	-1									12175859	t		miannu	Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation	SIGNOR-262754	0.341
PEA15	protein	Q15121	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates				9606									11702783	f		gcesareni	Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase.	SIGNOR-111502	0.758
LRP2	protein	P98164	UNIPROT	PTCH1	protein	Q13635	UNIPROT	up-regulates quantity	binding			9606		BTO:0000142							26872844	t		miannu	LRP2 Promotes SHH Activity in Neurogenic Niches of the Developing and Adult Brain. In the RDVM, LRP2 forms a co-receptor complex with PTCH1 facilitating SHH binding and internalization of SHH/PTCH1 complexes, a prerequisite for pathway activation (Fig. 3B).	SIGNOR-265257	0.475
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation			9606									17900900	t		lperfetto	The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation	SIGNOR-252886	0.398
STK11	protein	Q15831	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Thr382	DHYRYSDtTDSDPEN	9606									21779440	t		gcesareni	The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity	SIGNOR-161122	0.624
YAP1	protein	P46937	UNIPROT	TUBB	protein	P07437	UNIPROT	up-regulates quantity by expression	transcriptional regulation					BTO:0001939							30224758	f		lperfetto	 By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 	SIGNOR-276571	0.2
IFNG	protein	P01579	UNIPROT	DIO1	protein	P49895	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									9397972	f		scontino	From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y.	SIGNOR-267487	0.2
MITF	protein	O75030	UNIPROT	TYR	protein	P14679	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000847								10080955	f		miannu	 Microphthalmia transcription factor MITF, a melanocyte-specific basic helix-loop-helix protein, has been shown to transactivate tyrosinase and TRP-1 genes in vitro by binding to a shared regulatory sequence known as M box. both activation of positive factors such as MITF and inactivation of negative regulatory factors may be required for TRP-1 gene expression during melanocytic differentiation.	SIGNOR-254593	0.596
F2R	protein	P25116	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257127	0.424
PRKACA	protein	P17612	UNIPROT	LATS1	protein	O95835	UNIPROT	up-regulates	phosphorylation			10090									23644383	t		milica	Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381.	SIGNOR-236991	0.2
AKT1	protein	P31749	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates	phosphorylation	Ser134	ANLNRSTsVPENPKS	9606	BTO:0000731								24291004	t		lperfetto	Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus	SIGNOR-252543	0.499
SIRT1	protein	Q96EB6	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates activity	deacetylation			9606									14976264	t		lperfetto	Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress	SIGNOR-122405	0.909
PRKACA	protein	P17612	UNIPROT	GP1BB	protein	P13224	UNIPROT	down-regulates activity	phosphorylation	Ser191	ARAAARLsLTDPLVA	-1									2504723	t		miannu	Platelet glycoprotein Ib beta is phosphorylated on serine 166 by cyclic AMP-dependent protein kinase. phosphorylation of this residue may contribute to the inhibitory actions of cyclic AMP by inhibiting collagen-induced polymerization of actin.	SIGNOR-249986	0.316
MASP2	protein	O00187	UNIPROT	C4A	protein	P0C0L4	UNIPROT	up-regulates activity	cleavage	Arg756	KGQAGLQrALEILQE	-1									17204478	t		lperfetto	MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a).	SIGNOR-263434	0.793
PRKCB	protein	P05771	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates	phosphorylation	Ser42	AKKKSKIsASRKLQL	9606									15769444	t		lperfetto	Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.	SIGNOR-134624	0.2
IL10	protein	P22301	UNIPROT	SCN1A	protein	P35498	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									23357618	f		miannu	Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α.	SIGNOR-253497	0.2
PRKACA	protein	P17612	UNIPROT	LASP1	protein	Q14847	UNIPROT	down-regulates activity	phosphorylation	Ser146	MEPERRDsQDGSSYR	9606									22665060	t		llicata	Phosphorylation of lasp-1 by pka at serine 146 induces translocation of the lasp-1/zo-2 complex from the cytoplasm to the nucleus. Interaction occurs within the carboxyterminal proline-rich motif of zo-2 and the sh3 domain in lasp-1.	SIGNOR-197720	0.311
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	MYH3	protein	P11055	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136647	0.462
ILF3	protein	Q12906	UNIPROT	NF90-NF45	complex	SIGNOR-C443	SIGNOR	form complex	binding			-1									18458058	t		miannu	Nuclear factor 90 (NF90) and its C-terminally extended isoform, NF110, have been isolated as DNA- and RNA-binding proteins together with the less-studied protein NF45. These complexes have been implicated in gene regulation, but little is known about their cellular roles and whether they are redundant or functionally distinct. We show that heterodimeric core complexes, NF90-NF45 and NF110-NF45, exist within larger complexes that are more labile and contain multiple NF90/110 isoforms and additional proteins. This study identified NF45 as an unstable regulatory subunit of NF90-NF45 complexes and uncovered their critical role in normal cell division. Furthermore, the study revealed that NF90 is functionally distinct from NF110 and is more important for cell growth.	SIGNOR-268488	0.591
MECP2	protein	P51608	UNIPROT	DEAF1	protein	O75398	UNIPROT	up-regulates activity	binding			10090	BTO:0000142								29636529	t		Gianni	We show that MeCP2 enhances Deaf1 binding to its HTR1A site and co-immunoprecipitates with Deaf1 in cells and brain tissue.To address the role of MeCP2 in HTR1A regulation in vivo, mice with conditional knockout of MeCP2 in adult 5-HT neurons (MeCP2 cKO) were generated. These mice exhibited increased 5-HT1A autoreceptor levels and function, consistent with MeCP2 enhancement of Deaf1 repression in 5-HT neurons.	SIGNOR-269063	0.2
CDK1	protein	P06493	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1497	EPGVERSsPSKCPSL	9606	BTO:0000551								19683496	t		gcesareni	However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci.	SIGNOR-187603	0.511
ZEB1	protein	P37275	UNIPROT	GRHL2	protein	Q6ISB3	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000150								23814079	f		miannu	 we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc finger enhancer-binding protein 1 (ZEB1), which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells. 	SIGNOR-255623	0.444
PKI-587	chemical	CID:44516953	PUBCHEM	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252650	0.8
CSNK1E	protein	P49674	UNIPROT	CSNK1E	protein	P49674	UNIPROT	down-regulates activity	phosphorylation	Thr334	ALPPGPPtGATANRL	9606	BTO:0000007								10542239	t		llicata	Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T	SIGNOR-250812	0.2
PALB2	protein	Q86YC2	UNIPROT	POLH	protein	Q9Y253	UNIPROT	up-regulates	binding			9606									24485656	t		miannu	Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates	SIGNOR-204541	0.517
CARM1	protein	Q86X55	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	down-regulates				9606	BTO:0000725								24332853	f		miannu	PRMT4 blocks myeloid differentiation of human hematopoietic stem/progenitor cells While PRMT4 promotes differentiation in several biological systems including T cell, adipocyte and muscle development, it blocks differentiation in the hematopoietic system, allowing HSPCs to maintain stemness. 	SIGNOR-261968	0.7
YWHAQ	protein	P27348	UNIPROT	GEM	protein	P55040	UNIPROT	up-regulates quantity by stabilization	binding			9534									14701738	t		miannu	In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase	SIGNOR-261724	0.269
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	tRNA(Arg)	smallmolecule	CHEBI:29171	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270363	0.8
MAPK3	protein	P27361	UNIPROT	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation	Ser154	SSVSSSPsPPFGHSA	9606	BTO:0000782								12151396	t		gcesareni	Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk	SIGNOR-91059	0.36
TRIM13	protein	O60858	UNIPROT	CD3D	protein	P04234	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								17314412	t		miannu	RFP2, a gene frequently lost in various malignancies, encodes a protein with RING finger, B-box, and coiled-coil domains that belongs to the RBCC/TRIM family of proteins.Rfp2 Regulates the Stability of the ERAD Substrate CD3-δ. In summary, these experiments demonstrate that Rfp2 functions as a RING-dependent ERAD E3 ubiquitin ligase and regulates the degradation of the ER substrate, CD3-δ.	SIGNOR-271644	0.2
Neuregulin	proteinfamily	SIGNOR-PF37	SIGNOR	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606									14967450	t	Does not bind to the ERBB1, ERBB2 and ERBB3 receptors	gcesareni	The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4.	SIGNOR-269970	0.2
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1668	SPSYSPTsPSYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269364	0.718
SRC	protein	P12931	UNIPROT	ITGB3	protein	P05106	UNIPROT	down-regulates activity	phosphorylation	Tyr773	DTANNPLyKEATSTF	9606	BTO:0003904								11723131	t		lperfetto	The phosphorylation level of beta(3) integrin was modulated using a temperature-sensitive v-Src kinase. Increased beta(3) phosphorylation abolished alpha(v)beta(3)- but not alpha(5)beta(1)-mediated adhesion to fibronectin. Thus, phosphorylation of the cytoplasmic domain of beta(3) is a negative regulator of alpha(v)beta(3)-fibronectin binding strength.	SIGNOR-247202	0.647
PTPN1	protein	P18031	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	dephosphorylation	Tyr1016	DVVDADEyLIPQQGF	-1									8621392	t			We have shown previously that amino acid residues flanking the phosphotyrosine are important for efficient PTP1 catalysis (Table 1 and Refs. 9, 10, and 17). For example, the kcat/Km value for the undecapeptide, EGFR988-989 (epidermal growth factor autophosphorylation site Tyr992, residues 988-998) (Asp-Ala-Asp-Glu-pTyr-Leu-Ile-Pro-Gln-Gln-Gly) is 3220-fold higher than that of phosphotyrosine (Table 1). We further demonstrated that a minimum of six amino acid residues are required for the most efficient PTP1 binding and catalysis.	SIGNOR-248407	0.751
Tandospirone citrate	chemical	CHEBI:32182	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258861	0.8
WT1	protein	P19544	UNIPROT	SLC29A4	protein	Q7RTT9	UNIPROT	up-regulates quantity by expression	transcriptional regulation												18523561	t		lperfetto	ENT4 is transcriptionally activated by both isoforms of EWS/WT1 as evidenced by promoter-reporter and chromatin immunoprecipitation (ChIP) analyses.	SIGNOR-268985	0.278
AKT1	protein	P31749	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606	BTO:0000938								9346240	t		lperfetto	Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins	SIGNOR-52863	0.816
MTHFD1	protein	P11586	UNIPROT	formate	smallmolecule	CHEBI:15740	ChEBI	up-regulates quantity	chemical modification			-1									18767138	t		lperfetto	Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate	SIGNOR-268251	0.8
DRD5	protein	P21918	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257244	0.364
MAPK1	protein	P28482	UNIPROT	METTL3	protein	Q86U44	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser525	YGMIERLsPGTRKIE	9606	BTO:0000007								33217317	t		miannu	 Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.	SIGNOR-265948	0.276
RCAN1	protein	P53805	UNIPROT	PPP3CA	protein	Q08209	UNIPROT	down-regulates activity	binding			9606									12554096	t			MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure	SIGNOR-252025	0.652
MAPK11	protein	Q15759	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation			9606									17254968	t		gcesareni	We show that prak activates p53 by direct phosphorylation.	SIGNOR-152843	0.594
PRKACA	protein	P17612	UNIPROT	GLI2	protein	P10070	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606									19056373	t		gcesareni	These results indicate that phosphorylation of Gli2 by PKA induces Gli2 processing and destabilization 	SIGNOR-182573	0.445
MAPK14	protein	Q16539	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity				9606									12181443	f		lperfetto	We show [] that the kinase activity and s473 phosphorylation of akt induced by lpa and s1p requires both mitogen-activated protein (map) kinase kinase (mek) and p38 map kinase. [] among different stimuli tested, platelet-derived growth factor stimulates s473 phosphorylation of akt in a mek- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1?stimulated Akt s473 phosphorylation require p38 but not mek.	SIGNOR-244465	0.63
IQSEC2	protein	Q5JU85	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	relocalization			10090		BTO:0000142							18164504	t		miannu	Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6.	SIGNOR-264907	0.486
SREBF1	protein	P36956	UNIPROT	Lipogenesis	phenotype	SIGNOR-PH30	SIGNOR	up-regulates				10090									15589694	f		lperfetto	In vivo studies using transgenic and knockout mice suggest that SREBP-1c is involved in FA synthesis and insulin induced glucose metabolism (particularly in lipogenesis),	SIGNOR-228614	0.7
PPM1A	protein	P35813	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	down-regulates activity	dephosphorylation	Ser172	EDDEQFVsLYGTEEY	9606									27419230	t		lperfetto	Furthermore, PPM1A, but not PPM1B, serves as an efficient phosphatase to dephosphorylate Ser 172 residue of both TBK1 and IKKepsilon kinases, which is critical for their kinase activities.|In a similar in vitro phosphatase assay, incubation of PPM1A also eliminated TBK1 and IKKepsilon phosphorylation at Ser 172 residue, evidenced by phospho-S172 immunoblotting (XREF_FIG, F and G).|These observations suggest that PPM1A may block kinase activities of TBK1 and IKKepsilon.	SIGNOR-276966	0.421
terbutaline	chemical	CHEBI:9449	ChEBI	ADRB3	protein	P13945	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)	SIGNOR-257871	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser289	RSHSESAsPSALSSS	10090									15664191	t		lperfetto	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-244677	0.2
MYO10	protein	Q9HD67	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				9606									27580874	f		miannu	Myosin X is required for filopodia formation and extension. myosin X functions as an antiparallel dimer in cells with a unique geometry optimized for movement on actin bundles. Myosin X facilitates initiation and elongation of filopodia, which implies favouring formation of parallel bundled F-actin filaments.	SIGNOR-268283	0.7
KIF18B	protein	Q86Y91	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272525	0.7
DAPK3	protein	O43293	UNIPROT	MYL12B	protein	O14950	UNIPROT	up-regulates	phosphorylation	Thr19	KKRPQRAtSNVFAMF	9606									1178183	t		gcesareni	Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge.	SIGNOR-16047	0.526
PTPRJ	protein	Q12913	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Tyr187	HTGFLTEyVATRWYR	-1									19494114	t		llicata	Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases.|Pulldown and in vitro dephosphorylation assays confirmed our prediction and demonstrated an overall specificity of DEP-1 in targeting the phosphorylated tyrosine 204 of ERK1/2.	SIGNOR-248708	0.415
PTPRA	protein	P18433	UNIPROT	KCNB1	protein	Q14721	UNIPROT	down-regulates	dephosphorylation			9606									16870705	t		gcesareni	Ptpalpha inhibits kv channels more strongly than ptpepsilon;this correlates with constitutive association of ptpalpha with kv2.1, driven by membranal localization of ptpalpha.	SIGNOR-148301	0.2
PDK1	protein	Q15118	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	phosphorylation	Ser293	TYRYHGHsMSDPGVS	-1									11485553	t		lperfetto	Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.	SIGNOR-109551	0.785
PTK6	protein	Q13882	UNIPROT	EPS8	protein	Q12929	UNIPROT	up-regulates activity	phosphorylation	Tyr498	YAFSSNIyTRGSHLD	9606	BTO:0000007								27738316	t		miannu	Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis. 	SIGNOR-263189	0.366
RFX4	protein	Q33E94	UNIPROT	IFT172	protein	Q9UG01	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19887680	f		miannu	We find that Ift172, which encodes an intraflagellar transport protein necessary for ciliogenesis, is a direct transcriptional target of Rfx4	SIGNOR-223319	0.354
PINK1	protein	Q9BXM7	UNIPROT	CYCS	protein	P99999	UNIPROT	down-regulates quantity				9606	BTO:0000938								20012177	t		lperfetto	There is a strong cyto-protective role of PINK1 in maintaining mitochondrial homeostasis via different mechanisms. Overexpression of wild-type PINK1 in SH-SY5Y neuroblastoma cells stabilizes respiring mitochondrial networks through various mechanisms that include maintaining mitochondrial membrane potential, reducing basal and neurotoxin-induced ROS, suppression of cytochrome c release, reversal of toxin-induced fission, and suppression of autophagy	SIGNOR-249704	0.393
MACROH2A1	protein	O75367	UNIPROT	rRNA_transcription	phenotype	SIGNOR-PH145	SIGNOR	down-regulates													16428466	f		miannu	These data unambiguously identify mH2A as a strong transcriptional repressor and show that the repressive effect of mH2A is realized on at least two different transcription activation chromatin-dependent pathways: histone acetylation and nucleosome remodeling.	SIGNOR-272930	0.7
BBIP1	protein	A8MTZ0	UNIPROT	BBsome complex	complex	SIGNOR-C288	SIGNOR	form complex	binding			9606	BTO:0004910								19081074	t		lperfetto	We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 	SIGNOR-262561	0.654
SMURF1	protein	Q9HCE7	UNIPROT	HOMER2	protein	Q9NSB8	UNIPROT	unknown	ubiquitination			-1									20804422	t		miannu	Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay.	SIGNOR-272699	0.2
CSNK2A1	protein	P68400	UNIPROT	KIF1C	protein	O43896	UNIPROT	unknown	phosphorylation	Ser1092	PRMRRQRsAPDLKES	-1									10559254	t		llicata	Serine 1092 was a substrate for the protein kinase casein kinase II in vitro, and inhibition of casein kinase II in cells diminished the association of KIF1C with 14-3-3gamma. Our data thus suggest that KIF1C can form dimers and is associated with proteins of the 14-3-3 family.	SIGNOR-250912	0.314
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2D3	protein	P61077	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271314	0.833
PPP2CB	protein	P62714	UNIPROT	PRKCD	protein	Q05655	UNIPROT	down-regulates activity	dephosphorylation	Thr507	FGESRAStFCGTPDY	10090	BTO:0000944								11959144	t			PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex	SIGNOR-248594	0.304
CERS4	protein	Q9HA82	UNIPROT	ceramide	smallmolecule	CHEBI:17761	ChEBI	up-regulates quantity	chemical modification			9606									26887952	t	done	miannu	 Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity. 	SIGNOR-273998	0.8
AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	FGG	protein	P02679	UNIPROT	up-regulates activity	binding			9606	BTO:0000132								16418530	t		lperfetto	In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation.	SIGNOR-253360	0.546
AVPR1B	protein	P47901	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257063	0.27
CSNK1E	protein	P49674	UNIPROT	PER3	protein	P56645	UNIPROT	down-regulates activity	phosphorylation	Ser634	ISQCGYSsTIVHVPP	9534	BTO:0000298								11865049	t		llicata	The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. 	SIGNOR-250819	0.734
C5 convertase complex	complex	SIGNOR-C312	SIGNOR	C5	protein	P01031	UNIPROT	up-regulates activity	cleavage	Arg677	KEILRPRrTLQKKIE										31331124	t		lperfetto	 Association of C3b with C3 convertases (C3bBb or C4b2a) results in formation of C5 convertases, C3bBbC3b and C4b2aC3b, which initiate the lytic pathway by cleavage of C5 to C5a and C5b	SIGNOR-263452	0.538
6-[2-tert-butyl-5-(6-methyl-2-pyridinyl)-1H-imidazol-4-yl]quinoxaline	chemical	CHEBI:91391	ChEBI	TGFBR1	protein	P36897	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206715	0.8
MAPK1	protein	P28482	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Thr179	PQSNIPEtPPPGYLS	9606									10197981	t		llicata	Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain.	SIGNOR-66746	0.736
romidepsin	chemical	CHEBI:61080	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257993	0.8
NFIX	protein	Q14938	UNIPROT	ANOS1	protein	P23352	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268884	0.2
MAPK3	protein	P27361	UNIPROT	RRN3	protein	Q9NYV6	UNIPROT	up-regulates	phosphorylation	Ser649	PVLYMQPsPL	9606									12620228	t		llicata	Erk-dependent phosphorylation of the transcription initiation factor tif-ia is required for rna polymerase i transcription and cell growth. phosphopeptide mapping and mutational analysis reveals two serine residues (s633 and s649) that are phosphorylated by erk and rsk kinases. Replacement of s649 by alanine inactivates tif-ia, inhibits pre-rrna synthesis, and retards cell growth.	SIGNOR-98984	0.2
STK11	protein	Q15831	UNIPROT	PRKAA2	protein	P54646	UNIPROT	up-regulates	phosphorylation	Thr172	SDGEFLRtSCGSPNY	9606				SIGNOR-C15					14976552	t		gcesareni	We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli	SIGNOR-122725	0.61
CDC25A	protein	P30304	UNIPROT	PKM	protein	P14618	UNIPROT	up-regulates activity	dephosphorylation	Ser37	MCRLDIDsPPITARN	9606									27485204	t		lperfetto	Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2 dependent beta-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.|Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2-dependent \u03b2-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.	SIGNOR-276967	0.5
FLT3	protein	P36888	UNIPROT	CEBPB	protein	P17676	UNIPROT	down-regulates quantity by repression	transcriptional regulation												16146838	f		lperfetto	Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1.	SIGNOR-250563	0.301
E2F1	protein	Q01094	UNIPROT	DLK1	protein	P80370	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19874716	t		lperfetto	Using luciferase reporter assay, ChIP assay and EMSA, we found that the -211/-194 region of the pref-1 promoter is essential for the binding of E2F1 as well as E2F1-dependent transcriptional activation.	SIGNOR-271684	0.2
KIT	protein	P10721	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity				9534	BTO:0001538								7509796	t			Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells	SIGNOR-255949	0.709
MAPK3	protein	P27361	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Thr325	TELEPLCtPVVTCTP								phosphorylation:Ser374;Ser362	PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS	16055710	t		lperfetto	Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos	SIGNOR-263012	0.707
HTR1D	protein	P28221	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256721	0.409
FES	protein	P07332	UNIPROT	PECAM1	protein	P16284	UNIPROT	up-regulates activity	phosphorylation	Tyr713	KKDTETVySEVRKAV	9606	BTO:0000007								12972546	t		miannu	PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1.	SIGNOR-262868	0.28
ERG	protein	P11308	UNIPROT	WNT3A	protein	P56704	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001321								23913826	t		Luana	Interestingly, our data showed that ERG drastically induced Wnt ligand gene expression.	SIGNOR-261598	0.2
ITCH	protein	Q96J02	UNIPROT	MAVS	protein	Q7Z434	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys371	PTSMVLTkVSASTVP	9606	BTO:0002181								19881509	t		Giorgia	These data collectively indicate that AIP4 is the E3 ligase for MAVS.|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation	SIGNOR-260362	0.631
porfimer	chemical	CHEBI:60652	ChEBI	LDLR	protein	P01130	UNIPROT	up-regulates activity	chemical activation			9606									1450993	t		miannu	Porphyrins are transported in blood mainly by lipoproteins, and the low density lipoprotein (LDL) receptor-mediated pathway is probably one of the important factors involved in the selective accumulation of porphyrins by tumor tissues, as cancer cells generally express much more LDL receptors than normal cells. 	SIGNOR-259302	0.8
DAPK1	protein	P53355	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates	phosphorylation	Thr119	LSRRLKVtGDLFDIM	9606	BTO:0000007								19180116	t		gcesareni	The activated form of DAPK triggers autophagy in a beclin-1-dependent manner. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy.	SIGNOR-183548	0.72
NOC3L	protein	Q8WTT2	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates				10090	BTO:0000011								15564382	f			Fad24, a mammalian homolog of Noc3p, is a positive regulator in adipocyte differentiation	SIGNOR-253060	0.7
PTPN1	protein	P18031	UNIPROT	TRPV6	protein	Q9H1D0	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000007								17197020	t		gcesareni	We conclude that phosphorylation/dephosphorylation of tyrosines in position 161 and 162 is essential for regulation of ca2+ influx through trpv6 ca2+ channels in hek293 cells. Co-transfection with src led to tyrosine phosphorylation of trpv6 which could be dephosphorylated by ptp1b. y161/162 are essential for tyrosine phosphorylation-dependent modulation of trpv6-mediated ca2+ entry.	SIGNOR-151711	0.615
AKT1	protein	P31749	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates activity	phosphorylation	Ser186	RQRKRHKsDSISLSF	9606									11504915	t		lperfetto	Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186.	SIGNOR-116274	0.804
ITGB2	protein	P05107	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257711	0.552
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1763	TPTSPSYsPTSPSYS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248756	0.727
lapatinib	chemical	CHEBI:49603	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258131	0.8
TBK1	protein	Q9UHD2	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	phosphorylation	Ser536	SGDEDFSsIADMDFS	9606									15489227	t		lperfetto	Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.	SIGNOR-129951	0.602
Non-structural protein 10	protein	P0C6X7-PRO_0000037317	UNIPROT	IFTAP	protein	Q86VG3	UNIPROT	unknown	binding			4932									18433331	t		lperfetto	In our previous work, we isolated a gene from a cDNA library of human embryo lung tissue, which en- coded a novel protein that specifically interacted with nsp-10 of SARS-CoV in a yeast trap experiment.|Since nsp- 10 of SARS-CoV is involved in viral genomic replica- tion and was observed to interact with ATF5, the cellular initiation factor of the RNA pol II complex (13), we in- ferred that HEPIS may also be involved in cellular gene transcription. Therefore, the significance of HEPIS ex- pression in cells needed to be further investigated. The work we describe here suggests that HEPIS represses cel- lular transcription initiation through interaction with a component of the RNA pol II complex	SIGNOR-260251	0.2
JAK2	protein	O60674	UNIPROT	IFNGR2	protein	P38484	UNIPROT	up-regulates activity	binding			9606	BTO:0000801								23898330	t		lperfetto	In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation	SIGNOR-249489	0.688
HCK	protein	P08631	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates activity	phosphorylation	Tyr753	ERDINSLyDVSRMYV	-1									7682059	t		lperfetto	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249363	0.531
MECP2	protein	P51608	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000093								15870696	f		miannu	 Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters	SIGNOR-254573	0.4
MAPK1	protein	P28482	UNIPROT	DUSP1	protein	P28562	UNIPROT	down-regulates	phosphorylation	Ser323	HCSAEAGsPAMAVLD	9606									16286470	t		lperfetto	The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain	SIGNOR-141601	0.799
CDC25B	protein	P30305	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates activity	dephosphorylation	Tyr15	EKIGEGTyGVVYKGR	9606									25384584	t		lperfetto	CDC25B facilitates dephosphorylation of the key cell cycle regulator CDC2 (also called CDK1) at Tyr15 or Thr14, thereby initiating the G 2 /M transition ( xref ).|CDC25B facilitates dephosphorylation of the key cell cycle regulator CDC2 (also called CDK1) at Tyr15 or Thr14, thereby initiating the G2/M transition ( ).	SIGNOR-276970	0.823
RPS6KA5	protein	O75582	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									10464286	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-70440	0.2
N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide	chemical	CHEBI:94525	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257973	0.8
PRKCA	protein	P17252	UNIPROT	SHOC2	protein	Q9UQ13	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser297	GLRYNRLsAIPRSLA										29383184	t		lperfetto	PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8.	SIGNOR-275567	0.2
CHEK2	protein	O96017	UNIPROT	RB1	protein	P06400	UNIPROT	up-regulates activity	phosphorylation	Ser612	MYLSPVRsPKKKGST	9606	BTO:0000093								17380128	t		lperfetto	Phosphorylation of prb at ser612 by chk1/2 leads to a complex between prb and e2f-1 after dna damageprb inhibits cell cycle progression through interactions with the e2f family of transcription factors. Here, we report that dna damage induced not only the dephosphorylation of prb at cdk phosphorylation sites and the binding of prb to e2f-1, but also the phosphorylation of prb at ser612. Phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1	SIGNOR-153908	0.433
MAPK1	protein	P28482	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser250	TGSPAELsPTTLSPV	9606		BTO:0000763							12193595	t		miannu	Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction.	SIGNOR-91718	0.711
ZNF384	protein	Q8TF68	UNIPROT	MMP1	protein	P03956	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000944								10669742	t		Luana	Luciferase activity driven by the MMP-1 promoter also increased by 2.5- to 3-fold. In contrast, CIZ had no effect on the luciferase activity from the MMP-1 promoter that was mutated at the CIZ binding consensus sequence. These results show that the CIZ transactivates the MMP-1 promoter through this sequence.	SIGNOR-266229	0.313
PRKCA	protein	P17252	UNIPROT	SRF	protein	P11831	UNIPROT	down-regulates	phosphorylation	Ser162	LRRYTTFsKRKTGIM	10090									16537394	t		lperfetto	Mimicking phosphorylation of serine-162, a target of protein kinase c-alpha, with an aspartic acid substitution (srf-s162d) completely inhibited srf-dna binding and blocked alpha-actin gene transcription pkc? Highly phosphorylated serine-162.	SIGNOR-234461	0.248
NTHL1	protein	P78549	UNIPROT	Base-excision_repair	phenotype	SIGNOR-PH222	SIGNOR	up-regulates													23545420	f		lperfetto	The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1).	SIGNOR-275717	0.7
CSNK1D	protein	P48730	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser721	PVVSGDTsPRHLSNV	9606	BTO:0000007								14761950	t	The effect has been demonstrated using P10636-8	lperfetto	Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells.	SIGNOR-121713	0.381
ZAP70	protein	P43403	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates	phosphorylation	Tyr145	PVEDDADyEPPPSND	9606	BTO:0000782								8702662	t		lperfetto	A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function	SIGNOR-42968	0.798
phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	pyruvate	smallmolecule	CHEBI:15361	ChEBI	up-regulates quantity	precursor of			9606									15996096	t		miannu	Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A).	SIGNOR-266533	0.8
MYO5A	protein	Q9Y4I1	UNIPROT	VAMP2	protein	P63027	UNIPROT	up-regulates activity	binding			9606									21077886	t		miannu	Another potential role of myosin Va in LDCV exocytosis lies in facilitating the formation of the SNARE complex, which is needed for fusion of the vesicle with the plasma membrane. Notably, myosin Va binds to at least two SNARE proteins in a Ca2+-dependent manner: at micromolar Ca2+-levels, it binds to VAMP2 located in the membrane of the cargo vesicle via its globular tail domain	SIGNOR-269281	0.462
VAV1	protein	P15498	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	binding			9606	BTO:0000725								9151714	t		Barakat	In summary, we demonstrate here that Y315 in ZAP-70 is required to interact with the Vav SH2 domain, and is critical for ZAP-70–mediated gene activation.	SIGNOR-274150	0.833
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1651	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273090	0.745
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	MAML2	protein	Q8IZL2	UNIPROT	up-regulates	binding			9606									12386158	t		gcesareni	Other than a role in t-cell development, the hox genes may be involved in alternative notchregulated processes in hematopoietic stem cells. Notch signaling is clearly important for self-renewal of hematopoietic progenitors (reviewed by radkte et al. 57). Interestingly, hoxa5, a9 and a10 were found to be part of the stem cell profile'	SIGNOR-254347	0.2
PRKAA2	protein	P54646	UNIPROT	DUSP1	protein	P28562	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser334	AVLDRGTsTTTVFNF	9606	BTO:0000007								25799226	t		miannu	Taken together, these results imply that nicotine acts via AMPKα2 to phosphorylate MKP1 at Ser334, instigating MKP1 ubiquitination and proteasome-mediated degradation.	SIGNOR-276890	0.276
ALDOC	protein	P09972	UNIPROT	glycerone phosphate(2-)	smallmolecule	CHEBI:57642	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266485	0.8
FLT3	protein	P36888	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity				9606									16266983	f		gcesareni	We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway.	SIGNOR-252626	0.443
N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-(2,6-dimethoxyphenoxy)ethanamine	chemical	CHEBI:64098	ChEBI	ADRA1B	protein	P35368	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258466	0.8
PIM2	protein	Q9P1W9	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									10837473	t		gcesareni	Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax	SIGNOR-78015	0.4
dabrafenib	chemical	CHEBI:75045	ChEBI	CDK16	protein	Q00536	UNIPROT	down-regulates activity	chemical inhibition			9606									29112787	t		Monia	We have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations. We confirmed NEK9 to be a potent target of dabrafenib by in vitro kinase assays, with inhibition of NEK9 observed in the single-digit nanomolar range.	SIGNOR-261073	0.8
PPP1R3A	protein	Q16821	UNIPROT	GYS1	protein	P13807	UNIPROT	up-regulates	dephosphorylation			9606		BTO:0000887;BTO:0001103							8250835	t		gcesareni	In skeletal muscle, the activation of glycogen synthase by insulin involves the dephosphorylation of serine residues that are phosphorylated by gsk3 and dephosphorylated by the glycogen-associated form of protein phosphatase-l (pp1g).	SIGNOR-37301	0.493
F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	Axonal_growth_cone_formation	phenotype	SIGNOR-PH199	SIGNOR	up-regulates				9606	BTO:0000938								21106647	f		miannu	Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. 	SIGNOR-268387	0.7
CSNK1E	protein	P49674	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	phosphorylation	Ser45	GATTTAPsLSGKGNP	9606									12000790	t		gcesareni	However, ck1epsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the beta-catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated ck1epsilon as a candidate s45-kinase in several assays, both in vitro and in vivo.	SIGNOR-87448	0.643
HTR4	protein	Q13639	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257367	0.252
AKT1	protein	P31749	UNIPROT	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr235	QARKRKRtSIENRVR	9606	BTO:0004180								23041284	t		flangone	Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.	SIGNOR-252545	0.471
HBA1	protein	P69905	UNIPROT	CYP2E1	protein	P05181	UNIPROT	up-regulates activity				9606	BTO:0000575								19325051	f	Regulation	miannu	Hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes.	SIGNOR-251765	0.2
MAPK1	protein	P28482	UNIPROT	MYB	protein	P10242	UNIPROT	unknown	phosphorylation	Ser532	KIKQEVEsPTDKSGN	-1									8960373	t		lperfetto	Functional analysis of phosphorylation at serine 532 of human c-Myb by MAP kinase| Expression of a constitutively active form of Ras together with c-Myb in transient transfection experiments had no effect on the transcriptional activity of c-Myb, while expression of a polypeptide containing the c-Myb C-terminal domain stimulated c-Myb activity. This effect is reduced upon MAPK-dependent phosphorylation of serine 532. 	SIGNOR-249420	0.492
BECN1	protein	Q14457	UNIPROT	USP13	protein	Q92995	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0003704								21962518	t		Giulio	We found that endogenous Beclin1 can interact with USP13 and the interaction was reduced in the presence of spautin-1 (Figure 5C). Interestingly, the DUB activities were significantly increased when USP13 and USP10 coincubated together or with Beclin1 or all 3 proteins together, suggesting the DUB activity can be significantly enhanced when USP13 interacts with its substrate Beclin1 or USP10.	SIGNOR-260296	0.511
STOML2	protein	Q9UJZ1	UNIPROT	SDHD	protein	O14521	UNIPROT	up-regulates activity				9606									20359165	f		Giorgia	We found that SLP-2hi cells had significantly higher activities of NADH dehydrogenase and succinate dehydrogenase (P < 0.05), complexes I and II of the electron transport chain.	SIGNOR-260383	0.21
HTR4	protein	Q13639	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257041	0.252
EPHA2	protein	P29317	UNIPROT	EPHA2	protein	P29317	UNIPROT	up-regulates	phosphorylation	Tyr588	QLKPLKTyVDPHTYE	9606									18387945	t		lperfetto	The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells.	SIGNOR-178169	0.2
PRKACB	protein	P22694	UNIPROT	PHKA2	protein	P46019	UNIPROT	down-regulates activity	phosphorylation			9606									10487978	t			Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.	SIGNOR-267412	0.307
anthra[1,9-cd]pyrazol-6(2H)-one	chemical	CHEBI:90695	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates	chemical inhibition			9606									21159646	t		gcesareni	In comparison, in the same assay conditions, the previously reported mps1 inhibitor sp600125 (13) was 10-fold less potent than nms-p715 on mps1 and, in addition, it was highly unspecific, being more active on at least 12 kinases including mitotic kinases with ic50 values well below 1 ?mol/l	SIGNOR-170614	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation	Ser556	GLGCRLHsAPNLSDL	9606									21205641	t		lperfetto	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-216457	0.469
AGTR1	protein	P30556	UNIPROT	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	up-regulates				9606									32201502	f		MIANNU	Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis.	SIGNOR-260234	0.7
TCL1A	protein	P56279	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	up-regulates	binding			9606									10983986	t		miannu	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-81434	0.485
PPP5C	protein	P53041	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates activity	dephosphorylation	Thr842	CTETFTGtLQYMAPE	10090									11689443	t		llicata	After exposure of cells to H2O2, ASK1 is transiently activated by autophosphorylation at Thr845. The protein then associates with PP5 (protein serine/threonine phosphatase 5), which inactivates ASK1 by dephosphorylation of Thr845.	SIGNOR-248540	0.584
USP5	protein	P45974	UNIPROT	UBC	protein	P0CG48	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270822	0.84
ADAM17	protein	P78536	UNIPROT	MUC1	protein	P15941	UNIPROT	down-regulates	cleavage			9606									12441351	t		gcesareni	These characteristics along with studies conducted with cell lines genetically deficient in various adams (for a disintegrin and metalloprotease) identified tumor necrosis factor-alpha converting enzyme (tace)/adam 17 as a muc1 sheddase.	SIGNOR-95630	0.314
PRKAA1	protein	Q13131	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr198	PGLRRRQt	10090									30033086	t		Luana	P27Kip1-Mediated Cell Survival Is Dependent on AMPK-Specific Thr198 Phosphorylation|AMPK-dependent phosphorylation of p27Kip1 on Thr198 promotes p27Kip1 protein stability, resulting in more autophagy and less apoptosis.	SIGNOR-259859	0.27
PRKAA2	protein	P54646	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	form complex	binding			9606									16054041	t		gcesareni	Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits.	SIGNOR-139161	0.823
prostaglandin F2alpha(1-)	smallmolecule	CHEBI:57404	ChEBI	PTGFR	protein	P43088	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257573	0.8
EPO	protein	P01588	UNIPROT	EPOR	protein	P19235	UNIPROT	up-regulates	binding			-1									9774108	t		gcesareni	Human erythropoietin is a haematopoietic cytokine required for the differentiation and proliferation of precursor cells into red blood cells. It activates cells by binding and orientating two cell-surface erythropoietin receptors (EPORs) which trigger an intracellular phosphorylation cascade.	SIGNOR-60663	0.873
indometacin	chemical	CHEBI:49662	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates activity	chemical inhibition			10116		BTO:0000135							15770365	t		Simone Vumbaca	Indomethacin, a nonselective cyclooxygenase inhibitor, may prevent AAA formation by inhibiting cyclooxygenase-2 (COX-2) activity.	SIGNOR-261089	0.8
ARF6	protein	P62330	UNIPROT	Vesicle_transport	phenotype	SIGNOR-PH172	SIGNOR	up-regulates													14973189	f		lperfetto	ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface	SIGNOR-272153	0.7
POLR3A	protein	O14802	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266133	0.863
TLRs	proteinfamily	SIGNOR-PF20	SIGNOR	TICAM1	protein	Q8IUC6	UNIPROT	up-regulates activity	binding			10090									22664090	t		gcesareni	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-252095	0.2
ANAPC5	protein	Q9UJX4	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	form complex	binding												16896351	t		lperfetto	The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex.	SIGNOR-252005	0.92
SEPTIN4	protein	O43236	UNIPROT	XIAP	protein	P98170	UNIPROT	down-regulates quantity	binding			9534	BTO:0004055								15029247	t		lperfetto	The mitochondrial ARTS protein promotes apoptosis through targeting XIAP.|Binding of ARTS to XIAP is direct, as recombinant ARTS and XIAP proteins can bind to each other in vitro. ARTS binding to XIAP is specific and related to its pro-apoptotic function, as mutant forms of ARTS (or related septins) that fail to bind XIAP failed to induce apoptosis. ARTS leads to decreased XIAP protein levels and caspase activation. Our data suggest that ARTS induces apoptosis by antagonizing IAPs.	SIGNOR-267671	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	HNF4A	protein	P41235	UNIPROT	down-regulates activity	phosphorylation	Ser303	DPDAKGLsDPGKIKR	-1									12740371	t		miannu	Here we demonstrate that AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. 	SIGNOR-263106	0.312
pralatrexate	chemical	CHEBI:71223	ChEBI	DHFR	protein	P00374	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002207								19221750	t		Luana	This study reports a head-to-head comparison of in vitro and in vivo activities of three antifolates: pralatrexate, methotrexate, and pemetrexed. A clear difference was demonstrated among the antifolates in regulation of enzymatic activity. Pralatrexate demonstrated a unique activity profile relative to methotrexate and pemetrexed	SIGNOR-257815	0.8
vincaleukoblastine sulfate	chemical	CHEBI:9984	ChEBI	TUBE1	protein	Q9UJT0	UNIPROT	down-regulates activity	chemical inhibition			9606									15579115	t		miannu	Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. 	SIGNOR-259258	0.8
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser172	LCLSPASsGSSASFI	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248680	0.613
PGM2	protein	Q96G03	UNIPROT	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	up-regulates quantity	chemical modification			9606									32898648	t		miannu	Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P).	SIGNOR-267933	0.8
CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	PER3	protein	P56645	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f		lperfetto	Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253683	0.587
MEF2D	protein	Q14814	UNIPROT	Myog/SWI/SNF complex	complex	SIGNOR-C94	SIGNOR	form complex	binding			9606		BTO:0001103							17194702	t		miannu	Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle	SIGNOR-151679	0.633
PYG	proteinfamily	SIGNOR-PF96	SIGNOR	glycogen	smallmolecule	CHEBI:28087	ChEBI	down-regulates quantity	chemical modification			9606									3346228	t			Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267953	0.8
CPT1C	protein	Q8TCG5	UNIPROT	O-palmitoyl-L-carnitine	smallmolecule	CHEBI:17490	ChEBI	up-regulates quantity	chemical modification			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267131	0.8
CSNK2A1	protein	P68400	UNIPROT	CFTR	protein	P13569	UNIPROT	down-regulates	phosphorylation	Ser511	ENIIFGVsYDEYRYR	9606									21930781	t		lperfetto	Serine 511 has been previously implicated in the regulation of cftr by ck2, as the mutant s511d was found to be insensitive to tbb in xenopus oocytes but to have no major impact on the single-channel behavior of cftr	SIGNOR-176623	0.281
DUOX1	protein	Q9NRD9	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	up-regulates quantity	chemical modification			9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264726	0.8
(-)-anisomycin	chemical	CHEBI:338412	ChEBI	MAPK11	protein	Q15759	UNIPROT	up-regulates	chemical activation			9606									Other	t	CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb	gcesareni		SIGNOR-189675	0.8
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	ATP2A1	protein	O14983	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136300	0.317
CDC25A	protein	P30304	UNIPROT	CCNA2	protein	P20248	UNIPROT	up-regulates activity	dephosphorylation			9606									16682204	t		miannu	Cdc25A dephosphorylates and activates CyclinE\u2013Cdk2, CyclinA\u2013Cdk2 and CyclinB\u2013Cdk1, whereas Cdc25B and Cdc25C primarily target CyclinB\u2013Cdk1  [4,5] .	SIGNOR-277136	0.679
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Ser1068	HKNETMLsPREKIFY	9606									11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130.	SIGNOR-104667	0.843
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DRB1	protein	P01911	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	t	 		The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-253977	0.288
GART	protein	P22102	UNIPROT	N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-)	smallmolecule	CHEBI:143788	ChEBI	up-regulates quantity	chemical modification			9606									34283828	t		miannu	In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR).	SIGNOR-267300	0.8
MAPK8	protein	P45983	UNIPROT	PPM1J	protein	Q5JR12	UNIPROT	down-regulates	phosphorylation	Ser93	HAGRAVQsPPDTGRR	9606									18553930	t		gcesareni	Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells.	SIGNOR-178930	0.352
RB1	protein	P06400	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates	binding			9606									21902831	t		gcesareni	Cycline/cdk2 blocks myod-induced gene expression through the phosphorylation of rb, preventing rb from binding and transactivating myod, and triggering s phase entry instead of differentiation.	SIGNOR-176563	0.403
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	AKT1	protein	P31749	UNIPROT	down-regulates activity	cleavage			-1									10579725	t		lperfetto	P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro	SIGNOR-256447	0.622
6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)-3-pyridinecarboxamide	chemical	CHEBI:94489	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207681	0.8
PRKACA	protein	P17612	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	phosphorylation	Ser17	DASQRRRsLEPAENV	9606									11804588	t		gcesareni	PKA activated Src both in vitro and in vivo by phosphorylating Src on serine 17 within its amino terminus	SIGNOR-247988	0.367
PRKD3	protein	O94806	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	up-regulates activity	phosphorylation	Ser259	FPLRKTAsEPNLKVR										18692497	t		lperfetto	Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].	SIGNOR-275926	0.268
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	EVL	protein	Q9UI08	UNIPROT	up-regulates activity	phosphorylation			9606									15066263	t		miannu	 Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts	SIGNOR-268287	0.2
MAPK1	protein	P28482	UNIPROT	GAB2	protein	Q9UQC2	UNIPROT	up-regulates	phosphorylation	Ser623	ALDFQPSsPSPHRKP	9606									15356145	t		lperfetto	Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623.	SIGNOR-128727	0.667
MTOR	protein	P42345	UNIPROT	TFEB	protein	P19484	UNIPROT	down-regulates activity	phosphorylation	Ser211	LVGVTSSsCPADLTQ	9606	BTO:0000567		SIGNOR-C3						22692423	t		gcesareni	Our data points to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. [...]Our study has revealed a specific role for phosphorylation of TFEB S211 in the negative regulation of the nuclear abundance of TFEB. This occurs through the promotion of 14-3-3 binding and the masking of the nearby NLS on TFEB.	SIGNOR-248270	0.492
BTRC	protein	Q9Y297	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys773	RRNPAGTkWMEHVKL	9606	BTO:0000938								17283082	t		lperfetto	Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage.	SIGNOR-145116	0.657
TNF	protein	P01375	UNIPROT	LPL	protein	P06858	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									3063839	f	Regulation of expression	miannu	 Cytokines, notably TNF and IL-1, suppress synthesis of lipoprotein lipase which decreases the rate of TGFA clearance.	SIGNOR-251853	0.401
CSNK1G2	protein	P78368	UNIPROT	PER1	protein	O15534	UNIPROT	down-regulates	phosphorylation			9606									15917222	t		miannu	Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1.	SIGNOR-137751	0.402
GSK3B	protein	P49841	UNIPROT	EIF2B5	protein	Q13144	UNIPROT	down-regulates activity	phosphorylation	Ser540	MDSEEPDsRGGSPQM	9606	BTO:0000007								11500362	t			We identify multiple phosphorylation sites in the largest, catalytic, subunit (epsilon) of mammalian eIF2B. Glycogen synthase kinase 3 (GSK3) is responsible for phosphorylating Ser535. This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo. eIF2Bϵ from mammals or insects is a substrate for glycogen synthase kinase 3 (GSK3), and this inhibits the activity of eIF2B 	SIGNOR-251237	0.561
PRKCA	protein	P17252	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser26	GTASRPSsSRSYVTT	-1									2500966	t		lperfetto	We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65.	SIGNOR-248882	0.289
DUSP6	protein	Q16828	UNIPROT	FOXO1	protein	Q12778	UNIPROT	up-regulates	dephosphorylation			9606									22521266	t		gcesareni	Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase).	SIGNOR-197194	0.44
MTOR	protein	P42345	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Ser394	TRQTPVDsPDDSTLS	9823		BTO:0004712							23486913	t		lperfetto	Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway	SIGNOR-201530	0.96
PRKACA	protein	P17612	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Ser141	MASQKRPsQRHGSKY	-1									2413024	t		miannu	Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161	SIGNOR-250010	0.352
PRKCA	protein	P17252	UNIPROT	GABRR1	protein	P24046	UNIPROT	unknown	phosphorylation	Ser440	RSSPQRKsQRSSYVS	-1									12175859	t		miannu	Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation	SIGNOR-262753	0.341
PTMS	protein	P20962	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								16150697	t		miannu	Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner. Immunoprecipitation analysis showed that in the presence of glucocorticoid hormone, p300 and CREB-binding protein are coprecipitated with MTI-II. Furthermore, the knockdown of endogenous MTI-II by RNAi reduces the transcriptional activity of GR in cells.	SIGNOR-268461	0.327
PRKAR2A	protein	P13861	UNIPROT	PRKACA	protein	P17612	UNIPROT	down-regulates activity	binding			9606									26687711	t			Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 	SIGNOR-258752	0.871
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser217	AHYSPRTsPIMSPRT	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248372	0.598
progesterone	smallmolecule	CHEBI:17026	ChEBI	CACNA2D3	protein	Q8IZS8	UNIPROT	up-regulates quantity				9606									31746409	f		miannu	In vivo and in vitro, the addition of P4 upregulated the expression of CACNA2D3 and silencing of CACNA2D3 impaired the function of P4 on cell apoptosis and proliferation.	SIGNOR-266856	0.8
PRKCA	protein	P17252	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	phosphorylation	Ser139	EEWTRHGsFVNKPTR	10090	BTO:0000944								12052829	t		lperfetto	Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms.	SIGNOR-263047	0.41
KPNA2	protein	P52292	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	relocalization			9606									32979938	t		miannu	The results from Figure 1C suggest that ORF6 inhibits IFN-β production through IRF3 or a component downstream of IRF3. Thus, we examined the effect of ORF6 on IRF3 nuclear translocation. Upon poly(I:C) treatment, IRF3 translocated to the cell nucleus in the absence of ORF6, whereas the expression of ORF6 blocked its nuclear translocation (Figure 2D). Karyopherin α 1–6 (KPNA1–6) are importing factors for nuclear translocation of cargos, including IRF3, IRF7, and STAT1 (Chook and Blobel, 2001). Co-immunoprecipitation showed that ORF6 selectively interacted with KPNA2, but not the other KPNAs (Figure 2E), suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Figure 2F).	SIGNOR-262514	0.2
1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone	chemical	CHEBI:93753	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192604	0.8
SLC9A8	protein	Q9Y2E8	UNIPROT	hydron	chemical	CHEBI:15378	ChEBI	down-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265598	0.8
lysophosphatidic acids	smallmolecule	CHEBI:32957	ChEBI	LPAR1	protein	Q92633	UNIPROT	up-regulates	chemical activation			10116	BTO:0003293								8276865	t		milica	LPA activates its own G protein-coupled receptor(s) leading to stimulation of phospholipase C and inhibition of adenylate cyclase.	SIGNOR-37365	0.8
CEBPD	protein	P49716	UNIPROT	SOD1	protein	P00441	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000792								20385105	f		miannu	 Expression of CEBPD reduced cisplatin-induced reactive oxygen species (ROS) and apoptosis in NTUB1 cells by inducing the expression of Cu/Zn-superoxide dismutase (SOD1) via direct promoter transactivation. 	SIGNOR-253774	0.2
SEC23IP	protein	Q9Y6Y8	UNIPROT	SEC23A	protein	Q15436	UNIPROT	up-regulates activity	binding			10090	BTO:0000142								10400679	t		lperfetto	The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway.	SIGNOR-265307	0.554
MAPK1	protein	P28482	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates activity	phosphorylation	Thr125	PEVLRPEtPRPVDIG	10090	BTO:0000782								16888006	t		lperfetto	ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition	SIGNOR-148616	0.55
DKK1	protein	O94907	UNIPROT	LRP6	protein	O75581	UNIPROT	down-regulates	binding			9606									11448771	t		gcesareni	We report that dkk-1 is a high-affinity ligand for lrp6 and inhibits wnt signaling by preventing fz-lrp6 complex formation induced by wnt. Dkk1 has been shown to inhibit wnt by binding to and antagonizing lrp5/6.	SIGNOR-109247	0.901
ITGB4	protein	P16144	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									9428518	t		gcesareni	Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation.	SIGNOR-252697	0.4
WSB1	protein	Q9Y6I7	UNIPROT	HIPK2	protein	Q9H2X6	UNIPROT	down-regulates	ubiquitination			9606									18093972	t		lperfetto	Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by wd40 repeat/socs box protein wsb-1	SIGNOR-160032	0.586
sirolimus	chemical	CHEBI:9168	ChEBI	CD40	protein	P25942	UNIPROT	down-regulates quantity by repression				9606									18652845	f		miannu	Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells.	SIGNOR-255474	0.8
FN1/SDC4	complex	SIGNOR-C210	SIGNOR	WNT7A	protein	O00755	UNIPROT	up-regulates													23290138	t		apalma	We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells	SIGNOR-255287	0.318
SGK1	protein	O00141	UNIPROT	NDRG2	protein	Q9UN36	UNIPROT	up-regulates	phosphorylation	Thr330	TRLSRSRtASLTSAA	9606	BTO:0000567	BTO:0000887;BTO:0001103;BTO:0000763							15461589	t		llicata	Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344	SIGNOR-129676	0.405
TCF4	protein	P15884	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18852287	t			Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription.	SIGNOR-253324	0.38
MAPK1	protein	P28482	UNIPROT	AHNAK	protein	Q09666	UNIPROT	unknown	phosphorylation	Ser5099	DVEFDIKsPKFKAEA	10090	BTO:0000944								22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262763	0.259
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	FCN2	protein	Q15485	UNIPROT	up-regulates activity	binding			-1									11907111	t		lperfetto	H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates.	SIGNOR-263407	0.7
TNKS1BP1	protein	Q9C0C2	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	form complex	binding			9606									19558367	t		lperfetto	In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules.	SIGNOR-268304	0.626
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Pyl)	smallmolecule	CHEBI:15185	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269494	0.8
hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	GABA-A (a4-b2-d) receptor	complex	SIGNOR-C326	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000938								26136660	t		miannu	The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 	SIGNOR-264924	0.8
(2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol	chemical	CHEBI:94562	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258091	0.8
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270372	0.8
NCKAP1	protein	Q9Y2A7	UNIPROT	WRC complex	complex	SIGNOR-C191	SIGNOR	form complex	binding			9606									21107423	t		miannu	WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems	SIGNOR-253569	0.911
GFPT1	protein	Q06210	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	chemical modification			9606									21310273	t		miannu	GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans	SIGNOR-267818	0.8
ESR1	protein	P03372	UNIPROT	SNAI2	protein	O43623	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18588516	f	 	miannu	The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor).	SIGNOR-254230	0.433
FBXW7	protein	Q969H0	UNIPROT	GATA2	protein	P23769	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Thr176	HLFGFPPtPPKEVSP	9606	BTO:0000007								25670854	t		irozzo	Here, we demonstrate that F-box/WD repeat-containing protein 7 (Fbw7/Fbxw7), a component of Skp1, Cullin 1, F-box-containing complex (SCF)-type E3 ligase, is an E3 ligase for GATA2. GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation.	SIGNOR-256005	0.397
MECP2	protein	P51608	UNIPROT	MGMT	protein	P16455	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								15657354	f	 	 	Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT.	SIGNOR-254035	0.312
POLE3	protein	Q9NRF9	UNIPROT	DNA polymerase epsilon	complex	SIGNOR-C377	SIGNOR	form complex	binding			9606	BTO:0000567								10801849	t		lperfetto	Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon.	SIGNOR-265522	0.902
CNOT11	protein	Q9UKZ1	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	form complex	binding			9606									19558367	t		lperfetto	In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules.	SIGNOR-268308	0.816
PDPK1	protein	O15530	UNIPROT	PKN1	protein	Q16512	UNIPROT	up-regulates	phosphorylation	Thr774	GYGDRTStFCGTPEF	9606									10753910	t		miannu	It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively)	SIGNOR-76640	0.547
KRAS	protein	P01116	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606									21779497	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner.	SIGNOR-175213	0.768
CDK1	protein	P06493	UNIPROT	SUN1	protein	O94901	UNIPROT	down-regulates activity	phosphorylation	Ser334	FLLLAGLsLRGQGNF	9606									25482198	t		miannu	Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions. 	SIGNOR-263100	0.366
SYK	protein	P43405	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates activity	phosphorylation	Tyr771	IGTAEPDyGALYEGR	9606	BTO:0000776								8657103	t		lperfetto	Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771.	SIGNOR-246572	0.764
FNIP1	protein	Q8TF40	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								27353360	t		miannu	FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle. 	SIGNOR-261413	0.565
CSNK1D	protein	P48730	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates	binding			9606				SIGNOR-C110					12000790	t		gcesareni	We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms.	SIGNOR-87433	0.537
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser552	VVRTPPKsPSSAKSR	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-251590	0.695
FIG4	protein	Q92562	UNIPROT	MCOLN1	protein	Q9GZU1	UNIPROT	up-regulates activity				9606									23165282	f		miannu	PI(3,5)P2 begins to be synthesized on endosomal membranes and is additionally required for the activation of lysosomal TRPML1/MCOLN1 channels. Thus, a deficiency of FIG4/PI(3,5)P2 would impair TRPML1/MCOLN1 channel function, leading to the accumulation of calcium in the lysosomes.	SIGNOR-253536	0.363
TWIST2	protein	Q8WVJ9	UNIPROT	ERBB3	protein	P21860	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255501	0.2
panobinostat	chemical	CHEBI:85990	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257749	0.8
FANCD2	protein	Q9BXW9	UNIPROT	BRCA2	protein	P51587	UNIPROT	up-regulates activity	relocalization			9606									15199141	t		lperfetto	FANCD2-Ub then promotes BRCA2 loading into a chromatin complex.	SIGNOR-263253	0.806
PRIM2	protein	P49643	UNIPROT	DNA primase complex	complex	SIGNOR-C261	SIGNOR	form complex	binding			-1									24043831	t		lperfetto	Here, we describe the crystal structure of human primase in heterodimeric form consisting of full-length catalytic subunit and a C-terminally truncated large subunit.	SIGNOR-261340	0.99
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	OTX2	protein	P32243	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269248	0.44
Sound_vibration	stimulus	SIGNOR-ST27	SIGNOR	TIP-LINK complex	complex	SIGNOR-C291	SIGNOR	up-regulates				10090		BTO:0000630							23217710	f		lperfetto	Sound induced vibrations or motion lead to deflection of the stereociliary bundles, which directly control the activity of the mechanotransduction channels in stereocilia. It is thought that tip links, fine extracellular filaments that connect the tips of neighboring stereocilia, transmit tension force onto the transduction channels	SIGNOR-262581	0.7
GATA2	protein	P23769	UNIPROT	CYBB	protein	P04839	UNIPROT	down-regulates quantity	transcriptional regulation			9606									10734088	t			These results suggest that GATA-1 is an activator and that GATA-2 is a relative competitive inhibitor of GATA-1 in the expression of the gp91(phox) gene in human eosinophils.	SIGNOR-259948	0.253
SMURF1	protein	Q9HCE7	UNIPROT	TRIB2	protein	Q92519	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002181								24089522	t		miannu	 In this study, we found that TRIB2 was up-regulated and exhibited high stability in liver cancer cells compared with other cells. We performed a structure-function analysis of TRIB2 and identified a domain (amino acids 1-5) at the N terminus that interacted with the E3 ubiquitin ligase Smurf1 and was critical for protein stability. Deletion of this domain extended TRIB2 half-life time accompanied with a more significant malignant property compared with wild type TRIB2.	SIGNOR-275432	0.42
THRA	protein	P10827	UNIPROT	GATA2	protein	P23769	UNIPROT	down-regulates activity	binding			9606		BTO:0001073							29407449	t		scontino	We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2.	SIGNOR-267257	0.2
EFNA1	protein	P20827	UNIPROT	EPHA1	protein	P21709	UNIPROT	up-regulates	binding			9606									9576626	t		tpavlidou	Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity	SIGNOR-56898	0.825
PRKDC	protein	P78527	UNIPROT	HNRNPU	protein	Q00839	UNIPROT	up-regulates	phosphorylation	Ser59	AMEPGNGsLDLGGDS	9606									19351595	t		lperfetto	We identify heterogeneous nuclear ribonucleoprotein u (hnrnp-u), also termed scaffold attachment factor a (saf-a), as a specific substrate for dna-pk. We show that hnrnp-u is phosphorylated at ser59 by dna-pk in vitro and in cells in response to dna double-strand breaks	SIGNOR-185058	0.385
SMARCC1	protein	Q92922	UNIPROT	Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270696	0.825
TSC22D3	protein	Q99576	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000011								12671681	f			In this study, we showed that GILZ, which is transcriptionally induced by GCs, inhibits the transcription of the PPAR-γ2 gene and blocks adipocyte differentiation	SIGNOR-253296	0.272
PRDM16	protein	Q9HAZ2	UNIPROT	SKI	protein	P12755	UNIPROT	up-regulates	binding			9606									19049980	t		miannu	Biochemical analysis demonstrated that mel1 interacts with ski and inhibits tgf-_ signaling by stabilizing the inactive smad3-ski complex on the promoter of tgf-_ target genes.	SIGNOR-182529	0.331
BLK	protein	P51451	UNIPROT	BCR-Ml	complex	SIGNOR-C434	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000776								32323266	t		scontino	The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases.	SIGNOR-268211	0.633
IPO5	protein	O00410	UNIPROT	DSCAML1	protein	Q8TD84	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								30745319	t		miannu	DSCAM and DSCAML1 specifically interacted with the importin beta IPO5, whereas deletion of the identified NLSs abolished this specific interaction and suppressed nuclear translocation of the DSCAM/L1 ICDs in cell lines and cultured neurons. This suggests a direct role of IPO5 in the nuclear import of the DSCAM/L1 ICDs.	SIGNOR-264274	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	MTOR	protein	P42345	UNIPROT	down-regulates activity	phosphorylation	Thr2446	NKRSRTRtDSYSAGQ	9606									15905173	t		lperfetto	Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain	SIGNOR-137255	0.2
RPS15A	protein	P62244	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262436	0.848
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	SLC11A1	protein	P49279	UNIPROT	up-regulates				9606	BTO:0000801								11909746	f			Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS)	SIGNOR-254039	0.7
BMPR1A	protein	P36894	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates activity	phosphorylation			9606									19620713	t		lperfetto	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-255263	0.721
(~{s})-(4-Fluoranyl-2-Propyl-Phenyl)-(1~{h}-Imidazol-2-Yl)methanol	chemical	CID:126961334	PUBCHEM	F2RL1	protein	P55085	UNIPROT	down-regulates activity	chemical inhibition			-1									28445455	t		Simone Vumbaca	The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. | Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling.	SIGNOR-261118	0.8
RPS6KA3	protein	P51812	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									10464286	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-70432	0.2
RNF8	protein	O76064	UNIPROT	ACD	protein	Q96AP0	UNIPROT	up-regulates quantity by stabilization	polyubiquitination	Lys147	QDLDVQKkLYDCLEE	9606									22101936	t		miannu	The Rnf8 RING-finger domain is essential for Tpp1 stability and retention at telomeres. Rnf8 physically interacts with Tpp1 to generate Ubc13-dependent Lys63 polyubiquitin chains that stabilize Tpp1 at telomeres. The conserved Tpp1 residue Lys233 is important for Rnf8-mediated Tpp1 ubiquitylation and localization to telomeres.	SIGNOR-272722	0.2
Elongator complex	complex	SIGNOR-C466	SIGNOR	TUBA3E	protein	Q6PEY2	UNIPROT	up-regulates activity	acetylation			9606	BTO:0000007								19185337	t		miannu	Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. 	SIGNOR-269718	0.254
MMP26	protein	Q9NRE1	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272393	0.7
MMP27	protein	Q9H306	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272394	0.7
sulpiride	chemical	CHEBI:32168	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			-1									7576010	t		miannu	The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. When receptors were labeled with [lzs1]-NCQ-298, D2 and D3 receptors displayed similar potencies for sulpiride, a D2 receptor antagonist (Figure 3A, Table I). 	SIGNOR-258431	0.8
PRKCA	protein	P17252	UNIPROT	NRGN	protein	Q92686	UNIPROT	up-regulates activity	phosphorylation	Ser36	AAAKIQAsFRGHMAR	-1									8080473	t		lperfetto	Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM.	SIGNOR-248913	0.402
ARID5B	protein	Q14865	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									29326336	f		miannu	ARID5B transcriptionally activates the oncogene MYC in T-ALL cells	SIGNOR-256156	0.278
SEM1	protein	P60896	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263343	0.2
AKT1	protein	P31749	UNIPROT	BLVRA	protein	P53004	UNIPROT	up-regulates activity	phosphorylation	Ser230	LKRNRYLsFHFKSGS										15870194	t		lperfetto	Site-directed mutagenesis, mass spectrometry, and kinetic analyses identified S(230) in hBVR (225)RNRYLSF sequence as the Akt1 target.	SIGNOR-275517	0.302
BAZ1B	protein	Q9UIG0	UNIPROT	WICH	complex	SIGNOR-C449	SIGNOR	form complex	binding			9606									16603771	t		miannu	We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling.	SIGNOR-268828	0.923
FOXO1	protein	Q12778	UNIPROT	IGFBP1	protein	P08833	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10358076	f		miannu	Reporter gene studies in hepg2 hepatoma cells show that fkhr stimulates insulin-like growth factor-binding protein-1 promoter activity through an irs	SIGNOR-68152	0.387
EPAS1	protein	Q99814	UNIPROT	KDM5C	protein	P41229	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271579	0.282
C5	protein	P01031	UNIPROT	C5AR2	protein	Q9P296	UNIPROT	up-regulates	binding			9606					cleavage:Arg751;Arg677	HKDMQLGrLHMKTLL;KEILRPRrTLQKKIE			11773063	t	complement C5a (anaphylatoxin) fragment: PRO_0000005988	gcesareni	Here we report that the orphan receptor c5l2/gpr77, which shares 35% amino acid identity with cd88, binds c5a with high affinity.	SIGNOR-113558	0.649
WNT11	protein	O96014	UNIPROT	FZD7	protein	O75084	UNIPROT	up-regulates activity	binding			7227									10862746	t		gcesareni	Consistent with this, xfz7 biochemically and functionally interacts with xwnt11	SIGNOR-78406	0.701
CAMK2G	protein	Q13555	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity	phosphorylation	Ser561	PFLSRHNsKSSIFSF	9606	BTO:0000938								32611770	t		lperfetto	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275793	0.274
TYMS	protein	P04818	UNIPROT	dUMP(2-)	smallmolecule	CHEBI:246422	ChEBI	down-regulates quantity	chemical modification			9606									21876188	t		lperfetto	In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR.	SIGNOR-268234	0.8
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1623	SPTSPSYsPTSPSYS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248780	0.441
EIF2B4	protein	Q9UI10	UNIPROT	Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269142	0.765
BCL2	protein	P10415	UNIPROT	CYCS	protein	P99999	UNIPROT	down-regulates activity				9606	BTO:0000567								12624108	f		lperfetto	Bcl-2 blocked the release of mitochondrial cytochrome c	SIGNOR-99063	0.63
AKT1	protein	P31749	UNIPROT	RARA	protein	P10276	UNIPROT	down-regulates	phosphorylation	Ser96	FVCQDKSsGYHYGVS	9606	BTO:0000551								16417524	t		miannu	We report that akt, which is constitutively activated in nsclc cells, phosphorylates raralpha and inhibits its transactivation. / mutation of ser96 to alanine abrogated the suppressive effect of akt.	SIGNOR-252489	0.584
ABL1	protein	P00519	UNIPROT	WASF3	protein	Q9UPY6	UNIPROT	up-regulates activity	phosphorylation	Tyr486	SRRIAVEySDSDDDS	9606									17623672	t			WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3.	SIGNOR-259077	0.565
PTH1R	protein	Q03431	UNIPROT	CYP27B1	protein	O15528	UNIPROT	up-regulates quantity													28363951	f		lperfetto	These PTH actions are mainly mediated by Gsalpha signaling, which induces the expression of the gene encoding 25-hydroxyvitamin D 1alpha-hydroxylase (Cyp27b1) and destabilizes the transcript encoding vitamin D 24-hydroxylase (Cyp24a1) 	SIGNOR-270554	0.307
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser515	SGDRSGYsSPGSPGT	9606	BTO:0000590								9832145	t		lperfetto	Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. 	SIGNOR-249354	0.729
CD40	protein	P25942	UNIPROT	BIK	protein	Q13323	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								12324477	f		gcesareni	Bik expression was weakly but significantly down-regulated by cd27 but up-regulated by cd40.	SIGNOR-93390	0.2
EED	protein	O75530	UNIPROT	SUZ12/EED	complex	SIGNOR-C76	SIGNOR	form complex	binding			9606									16712789	t		miannu	Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2.	SIGNOR-146755	0.942
NFATC1	protein	O95644	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001260								17079331	t		lperfetto	The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.	SIGNOR-251730	0.427
STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	MOB1A	protein	Q9H8S9	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000007								18362890	t	inferred from 70% family members	gcesareni	These findings indicate that the phosphorylation of mob1 at thr74 by mst2 is essential to make a complex of mob1, mst2 and ndr1, and to fully activate ndr1	SIGNOR-270220	0.2
KLF2	protein	Q9Y5W3	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates	transcriptional regulation			9606									12426306	f		fspada	Constitutive overexpression of klf2 but not klf15 potently inhibits peroxisome proliferator-activated receptor-gamma (ppargamma) expression with no effect on the upstream regulators c/ebpbeta and c/ebpdelta.	SIGNOR-210019	0.43
MAPK1	protein	P28482	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates activity	phosphorylation	Ser226	IDENCLLsPLAGEDD	-1									9199329	t		lperfetto	Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.	SIGNOR-249428	0.607
MAPK8	protein	P45983	UNIPROT	YWHAB	protein	P31946	UNIPROT	down-regulates	phosphorylation	Ser186	FYYEILNsPEKACSL	9606									15696159	t		llicata	The c-jun n-terminal kinase (jnk) protein is activated in the cellular response to dna damage and phosphorylates 14-3-3 on ser 184 these results support a role for 14-3-3 proteins in inhibiting c-abl-mediated apoptosis by sequestering c-abl into the cytoplasm. these findings support a model in which jnk phosphorylation of 14-3-3 proteins induces dissociation of the c-abl_14-3-3 complex and thereby targeting of c-abl to the nucleus.	SIGNOR-133875	0.2
ID1	protein	P41134	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates activity	binding			10090	BTO:0000222								8380166	t	2	miannu	Id1 and Id2 interacted strongly with MyoD and Myf-5.Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-240265	0.491
PHF12	protein	Q96QT6	UNIPROT	TLE1	protein	Q04724	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								11390640	t		miannu	We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE.	SIGNOR-266994	0.2
PRKCD	protein	Q05655	UNIPROT	LIMK2	protein	P53671	UNIPROT	down-regulates	phosphorylation	Ser283	EGTLRRRsLRRSNSI	9606									16820362	t	Translocation from Cytosol to Nucleus	gcesareni	Recently we have shown that limk2 shuttles between cytoplasm and nucleus in endothelial cells and that nuclear import is inhibited by protein kinase c-mediated phosphorylation of ser-283.	SIGNOR-147716	0.258
AKT1	protein	P31749	UNIPROT	CARD11	protein	Q9BXL7	UNIPROT	up-regulates activity	phosphorylation	Ser558	MQPPRSRsSIMSITA	-1									24548923	t		miannu	Here we show that Akt-mediated NF-κB activation is mediated at least in part through direct phosphorylation of the adaptor protein Carma1, which we previously demonstrated could interact with Akt in a TCR ligation-dependent manner. The putative Akt phosphorylation sites in Carma1 are distinct from known PKC consensus sites. Mutation of S551, S637 and S645 in Carma1 to non-phosphorylatable residues decreased phosphorylation of GST-Carma1-linker construct by Akt in vitro. 	SIGNOR-276254	0.538
sertindole	chemical	CHEBI:9122	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258542	0.8
NOS3	protein	P29474	UNIPROT	nitric oxide	smallmolecule	CHEBI:16480	ChEBI	up-regulates quantity	chemical modification			9606									24379783	t		lperfetto	Nitric oxide (NO) is a major mediator of endothelial function and is synthesized in endothelial cells by endothelial nitric oxide synthase (eNOS).	SIGNOR-251629	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	CTBP1	protein	Q13363	UNIPROT	down-regulates	phosphorylation	Ser158	REGTRVQsVEQIREV	9606									23291169	t		lperfetto	We found that an activated amp-activated protein kinase (ampk) phosphorylates ctbp1 on ser-158 upon metabolic stresses. Moreover, ampk-mediated phosphorylation of ctbp1 (s158) attenuates the repressive function of ctbp1	SIGNOR-216604	0.2
PPP2CB	protein	P62714	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Thr55	DDIEQWFtEDPGPDE	9606									17245430	t			A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55| In this study, we reported that the specific B regulatory subunits of PP2A B56gamma1 and B56gamma3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis	SIGNOR-248583	0.412
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1892	TPKYSPTsPTYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269346	0.718
MGluR	proteinfamily	SIGNOR-PF55	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening.	SIGNOR-264930	0.8
STK39	protein	Q9UEW8	UNIPROT	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation	Ser91	ASFHAYDsHTNTYYL	9606	BTO:0000007								21321328	t		miannu	We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity.	SIGNOR-263130	0.596
CASP9	protein	P55211	UNIPROT	CASP3	protein	P42574	UNIPROT	up-regulates activity	cleavage			9606									15657060	t		lperfetto	Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3.	SIGNOR-133267	0.622
CDK1	protein	P06493	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	phosphorylation	Thr125	PEVLRPEtPRPVDIG	9606			SIGNOR-C17						16287866	t		gcesareni	Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle.	SIGNOR-141621	0.441
SLBP	protein	Q14493	UNIPROT	H2BU1	protein	Q8N257	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265388	0.2
CDC42	protein	P60953	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates	binding			9606									14657655	t		gcesareni	Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent.	SIGNOR-119885	0.386
HAP1	protein	P54257	UNIPROT	NEUROD1	protein	Q13562	UNIPROT	up-regulates activity	binding			-1									12881483	t		lperfetto	We identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2). Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2	SIGNOR-234602	0.333
NFE2L2	protein	Q16236	UNIPROT	SOD2	protein	P04179	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22493435	t		miannu	BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2	SIGNOR-254652	0.464
SNAP23	protein	O00161	UNIPROT	STX11-SNAP23 SNARE complex	complex	SIGNOR-C272	SIGNOR	form complex	binding			9606	BTO:0000132								22767500	t		lperfetto	Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. 	SIGNOR-261895	0.735
PDPK1	protein	O15530	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Thr252	HDGTVTHtFCGTIEY	-1									9445476	t		gcesareni	The results presented here are consistent with PDK1 as the in vivo kinase responsible for mediating Thr252 phosphorylation in the catalytic domain of p70s6k.	SIGNOR-243338	0.714
CDK2	protein	P24941	UNIPROT	MAP3K11	protein	Q16584	UNIPROT	up-regulates activity	phosphorylation	Ser770	LISRPRPsPLRSRID	-1									35843311	t		miannu	Using in vitro kinase assays and phosphomutants, we determined that CDK1 phosphorylates MLK3 on Ser548 and decreases MLK3 activity during mitosis, whereas CDK2 phosphorylates MLK3 on Ser770 and increases MLK3 activity during G1/S and G2 phases.	SIGNOR-277604	0.2
PLK1	protein	P53350	UNIPROT	ATXN10	protein	Q9UBB4	UNIPROT	down-regulates	phosphorylation	Thr82	ASSLQLItECFRCLR	9606									21857149	t		lperfetto	Phosphorylation of ataxin-10 by polo-like kinase 1 is required for cytokinesis. Plk1 phosphorylates ataxin-10 at s77 and t82 in vitro. we found that ataxin-10 is ubiquitinated, and is subject to proteasome-dependent degradation, which is delayed in the 2a mutant. We propose a model in which plk1 phosphorylation of ataxin-10 influences its degradation and cytokinesis	SIGNOR-176126	0.361
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	BRAF	protein	P15056	UNIPROT	down-regulates	phosphorylation	Ser364	FGQRDRSsSAPNVHI	9606									10869359	t		lperfetto	We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf	SIGNOR-244152	0.2
CDK8	protein	P49336	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser214	PTSSDPGsPFQMPAD	9606									19914168	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161634	0.392
Noncanonical PRC1	complex	SIGNOR-C151	SIGNOR	CDK1	protein	P06493	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000011								25533466	f		miannu	We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis.	SIGNOR-252249	0.526
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGB5	protein	Q9Y5G0	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265714	0.2
CHKB	protein	Q9Y259	UNIPROT	choline	smallmolecule	CHEBI:15354	ChEBI	down-regulates quantity	chemical modification												27149373	t		lperfetto	Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes	SIGNOR-275635	0.8
P2RY4	protein	P51582	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256727	0.357
NRBF2	protein	Q96F24	UNIPROT	Vps34 Complex I	complex	SIGNOR-C242	SIGNOR	down-regulates activity	binding			9606	BTO:0001938				phosphorylation:Ser113;Ser120	AEDAEGQsPLSQKYS;SPLSQKYsPSTEKCL			24785657	t		miannu	We have now identified NRBF2 (nuclear receptor-binding factor 2) as a new member of Vps34 Complex I. NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L, but not the Vps34 Complex II component UVRAG (UV radiation resistance-associated gene). NRBF2 directly interacts with Vps15 via the Vps15 WD40 domain as well as other regions of Vps15. Thus NRBF2 plays a critical role in the induction of starvation-induced autophagy as a specific member of Vps34 Complex I.	SIGNOR-265880	0.708
WNT3A	protein	P56704	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606	BTO:0000568								16890161	t		gcesareni	Here, we present evidence that lrp6 is internalized with caveolin and that the components of this endocytic pathway are required not only for wnt-3a-induced internalization of lrp6 but also for accumulation of beta-catenin.	SIGNOR-148671	0.783
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CALM1	protein	P0DP23	UNIPROT	up-regulates	chemical activation			10090									10448861	t		lperfetto	Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1.	SIGNOR-235590	0.8
OFD1	protein	O75665	UNIPROT	ULK1/Atg13/Fip200	complex	SIGNOR-C100	SIGNOR	down-regulates quantity by destabilization	binding			9606									34027042	t		miannu	We showed for the first time that the centrosomal protein OFD1, which is mutated in Oral-Facial-Digital type I syndrome, inhibits early phases of the LC3-mediated autop hagic cascade by acting as a receptor for unc-51-like kinase (ULK1) complex turnover. we demon strated that OFD1 is a novel autophagy receptor which selectively promotes the autophagic degradation of ATG13 via direct interaction with the C3/GABARAP family of proteins (Figure 1). 	SIGNOR-269106	0.2
IMPDH2	protein	P12268	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30518405	f		miannu	We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. 	SIGNOR-260959	0.2
CDK9	protein	P50750	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser195	PNSSYPNsPGSSSST	9606									19914168	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161658	0.325
GRK6	protein	P43250	UNIPROT	GRK6	protein	P43250	UNIPROT	unknown	phosphorylation	Thr485	LDIEQFStVKGVELE	9534	BTO:0000298								10334944	t			GRK6 Is Autophosphorylated in COS-7 Cells. GRK6, like GRK5, is autophosphorylated on Ser484 and Thr485. Whether the autophosphorylation of GRK6 modulates its activity remains however to be established.	SIGNOR-251212	0.2
MAPK1	protein	P28482	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	phosphorylation	Ser206	SSSTYPHsPTSSDPG	9606									9335504	t		llicata	In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1	SIGNOR-52687	0.59
IGF1R	protein	P08069	UNIPROT	IRS4	protein	O14654	UNIPROT	up-regulates	phosphorylation			9606									9553137	t		gcesareni	Insulin-like growth factor i acting through its receptor was as effective as insulin in eliciting tyrosine phosphorylation of irs-4.	SIGNOR-56604	0.643
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1951	SPGYSPTsPTYSLTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269372	0.718
Oxotremorine	chemical	CHEBI:7851	ChEBI	CHRM4	protein	P08173	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258650	0.8
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1717	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269357	0.718
CSNK1D	protein	P48730	UNIPROT	KIR3DL1	protein	P43629	UNIPROT	up-regulates	phosphorylation	Ser385	AGNRTANsEDSDEQD	9606									17911614	t		gcesareni	In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.	SIGNOR-158121	0.2
MYOD1	protein	P15172	UNIPROT	MYH7	protein	P12883	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								17111365	f	Regulation	miannu	Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner. 	SIGNOR-251958	0.397
sorafenib tosylate	chemical	CHEBI:50928	ChEBI	BRAF	protein	P15056	UNIPROT	down-regulates activity	chemical inhibition			-1									16757355	t		miannu	This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant). 	SIGNOR-259220	0.8
CDK1	protein	P06493	UNIPROT	EEF2K	protein	O00418	UNIPROT	down-regulates	phosphorylation	Ser359	GTEEKCGsPQVRTLS	9606									18337751	t		gcesareni	Phosphorylation at ser359 inhibits eef2k activity even at high calcium concentrations. we demonstrate that cdc2 contributes to controlling eef2 phosphorylation in cells. inactivation of eef2k by cdc2 may serve to keep eef2 active during mitosis	SIGNOR-177982	0.375
ECM	stimulus	SIGNOR-ST20	SIGNOR	Av/b5 integrin	complex	SIGNOR-C178	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259038	0.7
mTORC1	complex	SIGNOR-C3	SIGNOR	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates				10090									19593385	f		lperfetto	Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master transcriptional regulator of adipocyte differentiation.	SIGNOR-235349	0.7
TSH	complex	SIGNOR-C412	SIGNOR	TSHR	protein	P16473	UNIPROT	up-regulates activity	binding			9606		BTO:0001379							25905363	t		scontino	The thyroid-stimulating hormone (TSH) receptor (TSHR) is a member of the glycoprotein hormone receptors (GPHRs), a sub-group of class A G protein-coupled receptors (GPCRs). TSHR and its ligand thyrotropin are of essential importance for growth and function of the thyroid gland.	SIGNOR-267048	0.56
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr267	SQYGQEVyDTPPMAV	10090									12972425	t		lperfetto	Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs	SIGNOR-246401	0.797
NEUROG3	protein	Q9Y4Z2	UNIPROT	NEUROG1	protein	Q92886	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19028584	f		miannu	Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated.	SIGNOR-254632	0.252
PIN1	protein	Q13526	UNIPROT	IRF3	protein	Q14653	UNIPROT	down-regulates quantity by destabilization	binding			9606									16699525	t		lperfetto	Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339–Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication.	SIGNOR-252256	0.627
FOXJ1	protein	Q92949	UNIPROT	DNAI1	protein	Q9UI46	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000939								23822649	t		miannu	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266932	0.377
CNR1	protein	P21554	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257003	0.444
STK11	protein	Q15831	UNIPROT	MARK1	protein	Q9P0L2	UNIPROT	up-regulates	phosphorylation	Thr215	TVGNKLDtFCGSPPY	9606									14976552	t		lperfetto	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122545	0.42
NR3C1	protein	P04150	UNIPROT	NCOA1	protein	Q15788	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9590696	t		gcesareni	Transactivation of these templates depends on the association of the GR with co-activators such as SRC-1/NcoA1, GRIP-1/TIF-2/NcoA2 and p300/CBP.	SIGNOR-251682	0.76
DUSP9	protein	Q99956	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	binding			9606									21908610	t		gcesareni	Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein.	SIGNOR-176583	0.686
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates	phosphorylation	Thr232	GGLPEVAtPESEEAF	9606									7816602	t		lperfetto	Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions.	SIGNOR-252359	0.784
SNRPD3	protein	P62318	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270637	0.82
IRAK4	protein	Q9NWZ3	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser288	QKSGQDVsQAQRQIK	9606	BTO:0000130								17217339	t		lperfetto	Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation.	SIGNOR-152011	0.39
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	GORASP1	protein	Q9BQQ3	UNIPROT	down-regulates activity	phosphorylation	Ser373	FEVSFLDsPGAQAQA	10116									15678101	t		Giulio	The pS376 antibody gave the strongest staining when Golgi apparatus fragmentation is initiated during prophase and in metaphase when it has become converted into a haze of small vesicles and some larger tubulovesicular remnants (Figure 4A). Therefore, GRASP65, like GM130, is phosphorylated in mitotic entry on Cdk1–cyclin B sites during the period when the Golgi apparatus is fragmented.	SIGNOR-260606	0.558
MAPK1	protein	P28482	UNIPROT	PLA2G4A	protein	P47712	UNIPROT	unknown	phosphorylation	Ser505	LNTSYPLsPLSDFAT	9606	BTO:0000567								9468497	t		llicata	The inhibitor of the 38-kda stress-activated protein kinase (p38(mapk)), sb 203580, reduced phosphorylation of both ser-505 and ser-727 by 50 and 60%, respectively, in thrombin-stimulated platelets.	SIGNOR-55706	0.642
PRKCA	protein	P17252	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser10	TRSVSSSsYRRMFGG	-1									2500966	t		lperfetto	We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65.	SIGNOR-248877	0.289
TWIST2	protein	Q8WVJ9	UNIPROT	AKR1C2	protein	P52895	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255498	0.2
CRK	protein	P46108	UNIPROT	MAP4K1	protein	Q92918	UNIPROT	up-regulates	binding			9606	BTO:0000782								9891069	t	HPK1 phosphorylated Crk mainly on threonine and weakly on serine	gcesareni	We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk.	SIGNOR-63988	0.674
CEBPB	protein	P17676	UNIPROT	HSD11B1	protein	P28845	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19088256	t		lperfetto	In conclusion, C/EBPalpha and C/EBPbeta control basal transcription, and TNF-alpha upregulates 11beta-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPbeta to the human HSD11B1 promoter.	SIGNOR-268972	0.289
cabozantinib	chemical	CHEBI:72317	ChEBI	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207845	0.8
SMC3	protein	Q9UQE7	UNIPROT	MXI1	protein	P50539	UNIPROT	down-regulates activity	binding			9534	BTO:0000318								9528857	t	2	miannu	We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions.	SIGNOR-241223	0.413
PRKCD	protein	Q05655	UNIPROT	KCNE3	protein	Q9Y6H6	UNIPROT	up-regulates activity	phosphorylation	Ser82	LILGYTRsRKVDKRS										21911611	t		lperfetto	Currents mediated by the complex formed by KCNQ1 and the mutant KCNE3-S82A β-subunit (mutation of the site for PKCdelta-promoted phosphorylation and modulation of the activity of KCNE3) showed rapid run-down and insensitivity to E2. 	SIGNOR-275964	0.2
B2M	protein	P61769	UNIPROT	Class I MHC	complex	SIGNOR-C425	SIGNOR	form complex	binding			-1									28367149	t		scontino	One Ig domain is present in each chain of MHC class II, while the second Ig-type domain of MHC class I is provided by non-covalent association of the invariant light chain beta-2 microglobulin (beta2m) with the HC.|The MHC class I HC folds and assembles with beta2m in the lumen of the endoplasmic reticulum (ER)	SIGNOR-267777	0.2
5-phospho-α-D-ribose 1-diphosphate	smallmolecule	CHEBI:58017	ChEBI	5-phospho-beta-D-ribosylaminium(1-)	smallmolecule	CHEBI:58681	ChEBI	up-regulates quantity	precursor of			9606									9914248	t		miannu	Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. 	SIGNOR-267292	0.8
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)-4-pyrimidinyl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	chemical	CHEBI:91348	ChEBI	SYK	protein	P43405	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258295	0.8
Telatinib	chemical	CID:9808844	PUBCHEM	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207227	0.8
HIP1	protein	O00291	UNIPROT	REST	protein	Q13127	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21832040	f		miannu	 HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK).	SIGNOR-255076	0.2
ACOT4	protein	Q8N9L9	UNIPROT	glutarate(2-)	smallmolecule	CHEBI:30921	ChEBI	up-regulates quantity	chemical modification												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271817	0.8
NR5A1	protein	Q13285	UNIPROT	HSD3B2	protein	P26439	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001555								19022561	f	 	miannu	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 	SIGNOR-254868	0.421
GNA12	protein	Q03113	UNIPROT	ARHGEF12	protein	Q9NZN5	UNIPROT	up-regulates activity	binding			10090									12024019	t			P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation.	SIGNOR-256522	0.757
RPL18	protein	Q07020	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262481	0.846
GDNF	protein	P39905	UNIPROT	NCAM1	protein	P13591	UNIPROT	up-regulates activity	binding			10116	BTO:0002881								15212950	t		miannu	Recently, NCAM was identified as an alternative receptor for GDNF. These new results may explain the findings that, in several regions, the GDNF receptor (GFRa1) is highly expressed, while RET is undetectable.	SIGNOR-252189	0.688
precursor messenger RNA	smallmolecule	CHEBI:139356	ChEBI	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates quantity	precursor of			9606									19224921	t		lperfetto	Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation. 	SIGNOR-268314	0.8
EREG	protein	O14944	UNIPROT	ERBB3	protein	P21860	UNIPROT	up-regulates	binding			9606									16829981	t		gcesareni	For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4	SIGNOR-147856	0.576
MAPT	protein	P10636	UNIPROT	Neurofibrillary tangle formation	phenotype	SIGNOR-PH58	SIGNOR	up-regulates				9606									11578751	f		lperfetto	Tau is a multifunctional microtubule-associated protein that plays major roles in the assembly of microtubules, the stabilization of microtubules against dynamic instability, and in bridging these polymers with other cytoskeletal filaments 43, 44, 45, 46 and 47. In normal brain, the equilibrium between phosphorylations and dephosphorylations of tau modulates the stability of the cytoskeleton and consequently axonal morphology. The earliest modification found in Alzheimer brains consists of hyperphosphorylations on tau by the action of different protein kinase and phosphatase systems that appear to lead to structural and conformational changes in this protein, thus affecting its binding with tubulin and the capacity to promote microtubule assembly	SIGNOR-251642	0.7
PAICS	protein	P22234	UNIPROT	5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-)	smallmolecule	CHEBI:77657	ChEBI	down-regulates quantity	chemical modification			9606									33179964	t		miannu	The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS).	SIGNOR-268110	0.8
G6PC2	protein	Q9NQR9	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	down-regulates quantity	chemical modification			9606									12093795	t		miannu	Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis	SIGNOR-266583	0.8
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1766	SPSYSPTsPSYSPTS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248745	0.727
CDK1	protein	P06493	UNIPROT	NDUFV1	protein	P49821	UNIPROT	up-regulates activity	phosphorylation	Thr383	HESCGQCtPCREGVD										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275594	0.2
PIAS3	protein	Q9Y6X2	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	binding			9606									9388184	t		lperfetto	PIAS3 blocked the DNA- binding activity of Stat3 and inhibited Stat3-mediated gene activation. Although Stat1 is also phosphorylated in response to IL-6, PIAS3 did not interact with Stat1 or affect its DNA-binding or transcriptional activity. The results indicate that PIAS3 is a specific inhibitor of Stat3.	SIGNOR-238648	0.72
NEFL	protein	P07196	UNIPROT	Neurofilament L/M	complex	SIGNOR-C207	SIGNOR	form complex	binding			9606									19468066	t		miannu	Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H	SIGNOR-255270	0.533
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CCT2	protein	P78371	UNIPROT	unknown	phosphorylation	Ser260	GSRVRVDsTAKVAEI	9606									19332537	t		lperfetto	Furthermore, ha-tagged akt can phosphorylate gst-cct_ protein in vitro	SIGNOR-244172	0.2
STOML2	protein	Q9UJZ1	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	binding			9606									18641330	t		Giorgia	In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling.	SIGNOR-260377	0.2
SGK1	protein	O00141	UNIPROT	MKNK1	protein	Q9BUB5	UNIPROT	down-regulates activity	phosphorylation	Ser352	SEAKDLIsKLLVRDA	-1									28545025	t		miannu	We show that SGK1 phosphorylates MNK1 at a conserved site, which represses its activity. 	SIGNOR-277357 	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PTPRR	protein	Q15256	UNIPROT	up-regulates activity	phosphorylation												11493009	t	inferred from 70% family members	lperfetto	Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL.	SIGNOR-270021	0.2
MAPK1	protein	P28482	UNIPROT	XPO5	protein	Q9HAV4	UNIPROT	down-regulates activity	phosphorylation	Ser497	GSLCSVFsPSFVQWE	9606	BTO:0000007								27846390	t		lperfetto	Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. 	SIGNOR-262981	0.306
HIF1A	protein	Q16665	UNIPROT	NT5E	protein	P21589	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000414								12370277	f	 	miannu	Examination of the CD73 gene promoter identified at least one binding site for hypoxia-inducible factor-1 (HIF-1) and inhibition of HIF-1alpha expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible CD73 expression	SIGNOR-254423	0.296
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1861	TPTSPKYsPTSPKYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273105	0.745
carbachol	chemical	CHEBI:3385	ChEBI	CHRM4	protein	P08173	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258621	0.8
diarsenic trioxide	chemical	CHEBI:30621	ChEBI	PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	down-regulates quantity by destabilization	chemical inhibition			9606									24344243	t			ATO was shown to degrade PML-RARa via its PML moiety further reinforcing the idea that APL is addicted to the PML-RARa oncoprotein	SIGNOR-259924	0.8
STAT1	protein	P42224	UNIPROT	SOCS1	protein	O15524	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19482358	f		miannu	Socs1 expression is induced in the human keratinocytes HaCaT cell line through sequential activation of STAT1 and IRF-1	SIGNOR-226484	0.623
CAMK2G	protein	Q13555	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Ser1070	DSFLQRYsSDPTGAL		BTO:0000017								1309762	t		llicata	The mechanism of desensitization of kinase activity can be accounted for, in part, by the EGF-stimulated phosphorylation of the receptor at Ser1046/7, a substrate for the multifunctional calmodulin-dependent protein kinase II in vitro. Mutation of Ser1046/7 by replacement with Ala residues blocks desensitization of the EGF receptor protein-tyrosine kinase activity. 	SIGNOR-250694	0.369
CDK1	protein	P06493	UNIPROT	NUP98	protein	P52948	UNIPROT	down-regulates activity	phosphorylation	Ser623	RDSENLAsPSEYPEN	9606									21335236	t		gcesareni	We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks.	SIGNOR-172221	0.408
SRC	protein	P12931	UNIPROT	GRIN2A	protein	Q12879	UNIPROT	up-regulates	phosphorylation	Tyr1325	RLLEGNFyGSLFSVP	9606									19834457	t		lperfetto	The nr2a subunit of the nmda receptor is tyrosine-phosphorylated, with tyr 1325 as its one of the major phosphorylation sitewe also show that the tyr 1325 phosphorylation site is required for src-induced potentiation of the nmda receptor channel in the striatum.	SIGNOR-188531	0.586
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH13	protein	P55290	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265831	0.8
CSNK2A1	protein	P68400	UNIPROT	LIG1	protein	P18858	UNIPROT	up-regulates activity	phosphorylation	Ser66	KAARVLGsEGEEEDE	9606	BTO:0000567								12851383	t		lperfetto	Moreover, these data confirmed the occurrence of Ser66 phosphorylation, which was previously studied with a specific monoclonal antibody (23).	SIGNOR-103258	0.346
CAMK2A	protein	Q9UQM7	UNIPROT	GLO1	protein	Q04760	UNIPROT	up-regulates activity	phosphorylation	Thr107	ELTHNWGtEDDETQS	-1									32966793	t		miannu	This study is able to show that a phosphorylation of threonine-107 (T107) in the (rate-limiting) Glyoxalase 1 (Glo1) protein, mediated by Ca2+/calmodulin-dependent kinase II delta (CamKIIδ), is associated with elevated catalytic efficiency of Glo1 (lower KM; higher Vmax).	SIGNOR-273553	0.2
PRKACA	protein	P17612	UNIPROT	FXYD1	protein	O00168	UNIPROT	unknown	phosphorylation	Ser88	RSSIRRLsTRRR	9606									21220422	t		llicata	We conclude that phosphorylation of plm increases its oligomerization into tetramers, decreases its binding to nka, and alters the structures of both the tetramer and nka regulatory complex.	SIGNOR-171188	0.429
CAK complex	complex	SIGNOR-C456	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser371	AHSSHLKsKKGQSTS	9606									9315650	t		llicata	The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase.	SIGNOR-269327	0.446
HAX1	protein	O00165	UNIPROT	ATP2A2	protein	P16615	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								18971376	t		lperfetto	The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival.|Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels.	SIGNOR-262052	0.38
DLX5	protein	P56178	UNIPROT	SPP1	protein	P10451	UNIPROT	up-regulates quantity	transcriptional regulation			9031									17335796	t		gcesareni	Dlx5 initiates a complete osteogenic differentiation in these early primary cells, by triggering Runx2, osteopontin, alkaline phosphatase, and other gene expression according to the sequential temporal sequence observed during skull osteogenesis €œin vivo€.	SIGNOR-245340	0.382
BAF250b E3 ligase	complex	SIGNOR-C522	SIGNOR	Histone H2B	proteinfamily	SIGNOR-PF68	SIGNOR	down-regulates activity	ubiquitination			9606	BTO:0000567								20086098	t		miannu	In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro	SIGNOR-271441	0.2
PCDHA2	protein	Q9Y5H9	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-265661	0.2
PDP2	protein	Q9P2J9	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	dephosphorylation			9606									16510868	t		lpetrilli	We show that the mammalian pdps are important in dephosphorylation of bmp-activated smad1 but not tgf-beta-activated smad2 or smad3. Thus, pdps specifically inactivate smads in the bmp/dpp pathway. [...] These observations suggest that pdp1 and pdp2 are important for dephosphorylation of smad1.	SIGNOR-144909	0.245
gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	GABA-A (a6-b1-g2) receptor	complex	SIGNOR-C334	SIGNOR	up-regulates activity	chemical activation			9606									18790874	t	brain	lperfetto	Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS).	SIGNOR-263790	0.8
PROX1	protein	Q92786	UNIPROT	RORC	protein	P51449	UNIPROT	down-regulates													23723244	f		azuccotti	In this study, we identify Prospero-related homeobox 1 (Prox1) as a novel co-repressor of the retinoic acid-related orphan receptors, RORgamma and RORalpha. Prox1 interacts directly with RORgamma and RORalpha and negatively regulates their transcriptional activity.	SIGNOR-254507	0.274
F2RL3	protein	Q96RI0	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257419	0.404
ASXL1	protein	Q8IXJ9	UNIPROT	RARA	protein	P10276	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								16606617	t		irozzo	Therefore, ASXL1, a vertebrate PcG/TrxG protein, may mediate RA-regulated cell growth by modulating RAR activity.Finally, the ASXL1-induced accumulation of acetylated H3 may enhance the RAR-mediated transcriptional activity. In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells.	SIGNOR-255910	0.456
conivaptan	chemical	CHEBI:681850	ChEBI	AVPR2	protein	P30518	UNIPROT	down-regulates activity	chemical inhibition			-1									20471258	t		Luana	One of the targets, 13d, demonstrated improved V2-receptor binding and was further profiled for comparison with conivaptan, the program’s mixed V1a/V2 standard (Table 4). Compound 13d displayed similar V1a-receptor affinity, albeit with a 30-fold weaker V2-receptor affinity when compared to conivaptan.	SIGNOR-257844	0.8
NFRKB	protein	Q6P4R8	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270856	0.61
STK3	protein	Q13188	UNIPROT	MOB1A	protein	Q9H8S9	UNIPROT	up-regulates	phosphorylation	Thr35	LLKHAEAtLGSGNLR	9606									21808241	t	The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific.	gcesareni	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction.	SIGNOR-175809	0.844
CHL1	protein	O00533	UNIPROT	ANK1	protein	P16157	UNIPROT	up-regulates quantity	relocalization			10116		BTO:0000227							7961622	t		miannu	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266724	0.511
TRAPPC9	protein	Q96Q05	UNIPROT	MAP3K14	protein	Q99558	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								15951441	t		miannu	We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates. 	SIGNOR-269672	0.493
STAT5A	protein	P42229	UNIPROT	SLCO1B3	protein	Q9NPD5	UNIPROT	up-regulates quantity by expression	transcriptional regulation												15840840	t		lperfetto	PRL enhanced the binding of Stat5a to the OATP1B3 promoter and DNA-protein binding was inhibited in competition assays by excess OATP1B3 and Stat5 consensus oligomers but not by mutant Stat5 oligomers.|PRL and GH induction of Oatp1b2 and OATP1B3 promoter activity required cotransfection of Stat5a and PRLRL or GHR.	SIGNOR-268990	0.2
PEX2	protein	P28328	UNIPROT	PEX5	protein	P50542	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1									19687296	t		miannu	Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. 	SIGNOR-253021	0.599
CDC14B	protein	O60729	UNIPROT	KMT5A	protein	Q9NQR1	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser100	SKIYSYMsPNKCSGM	9606									20966048	t			The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis.	SIGNOR-248339	0.2
PTPN5	protein	P54829	UNIPROT	GRIN2A	protein	Q12879	UNIPROT	down-regulates activity	dephosphorylation			9606									27857196	t		miannu	STEP inhibition by TC-2153 enhanced Tyr phosphorylation of GluN2A (XREF_FIG, 1 EGTA+TC-2153, n = 5, P < 0.05 compared with 1mM EGTA) without altering phosphorylation of Src (XREF_FIG, 1 EGTA+TC-2153, n = 5, P> 0.05 compared with 1 EGTA).|These findings confirm that not only GluN2B and Fyn but also GluN2A are substrates of STEP.	SIGNOR-277089	0.443
PRKCD	protein	Q05655	UNIPROT	ITGB2	protein	P05107	UNIPROT	unknown	phosphorylation	Ser745	FEKEKLKsQWNNDNP	9606	BTO:0000751								11700305	t		lperfetto	Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |	SIGNOR-249120	0.334
NCOA2	protein	Q15596	UNIPROT	NR3C1	protein	P04150	UNIPROT	up-regulates activity	binding			10090	BTO:0000801								29170386	t			Here we report that GRIP1 loss in macrophages attenuates glucocorticoid induction of several anti-inflammatory targets, and that GC treatment of quiescent macrophages globally directs GRIP1 toward GR binding sites dominated by palindromic GC response elements (GRE), suggesting a non-redundant GRIP1 function as a GR coactivator.	SIGNOR-256095	0.832
PTPN22	protein	Q9Y2R2	UNIPROT	ZAP70	protein	P43403	UNIPROT	down-regulates	dephosphorylation	Tyr493	LGADDSYyTARSAGK	9606	BTO:0000007								16461343	t		miannu	Native ptpn22 dephosphorylated lck and zap70 at their activating tyrosine residues tyr-394 and tyr-493, respectively, but not at the regulatory tyrosines tyr-505 (lck) or tyr-319 (zap70).	SIGNOR-144345	0.693
NMDA	proteinfamily	SIGNOR-PF56	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264691	0.7
MAPK8	protein	P45983	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				9606									19279717	f		areggio	To date it is not clear whether any genes are transcribed downstream of these two GTPases for non-canonical signaling. The prevailing dogma remains that their primary roles are indeed solely for cytoskeletal modulation	SIGNOR-258976	0.7
ATM	protein	Q13315	UNIPROT	UFL1	protein	O94874	UNIPROT	up-regulates activity	phosphorylation	Ser462	DDDSDDEsQSSHTGK	9606	BTO:0001938								30886146	t		lperfetto	Furthermore, ATM phosphorylates UFL1 at serine 462, enhancing UFL1 E3 ligase activity and promoting ATM activation in a positive feedback loop. 	SIGNOR-265075	0.2
PRKCA	protein	P17252	UNIPROT	SNAP23	protein	O00161	UNIPROT	unknown	phosphorylation	Ser161	ENLTQVGsILGNLKD	9606									12930825	t		lperfetto	Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion.	SIGNOR-249227	0.334
REN	protein	P00797	UNIPROT	AGT	protein	P01019	UNIPROT	up-regulates activity	cleavage			9606									16816138	t			Angiotensinogen, an _-glycoprotein, is released from the liver (152, 250, 444) and is cleaved in the circulation by the enzyme renin that is secreted from the juxtaglomerular apparatus of the kidney (245, 250, 540, 631) to form the decapeptide angiotensin (ANG) I	SIGNOR-252297	0.927
HRAS	protein	P01112	UNIPROT	ARAF	protein	P10398	UNIPROT	up-regulates	binding			9606									21779497	t		lperfetto	The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.	SIGNOR-175183	0.831
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CLK2	protein	P49760	UNIPROT	up-regulates	phosphorylation	Ser34	HKRRRSRsWSSSSDR	9606	BTO:0000567								20682768	t		lperfetto	Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva	SIGNOR-244214	0.2
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR1E	protein	P28566	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264288	0.8
pyridoxal 5'-phosphate(2-)	smallmolecule	CHEBI:597326	ChEBI	PSAT1	protein	Q9Y617	UNIPROT	up-regulates activity	chemical activation			3702									30034403	t		lperfetto	Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction.	SIGNOR-268561	0.8
SRC	protein	P12931	UNIPROT	BAIAP2L1	protein	Q9UHR4	UNIPROT	up-regulates activity	phosphorylation	Tyr293	PAPSGRAyTSPLIDM	-1									21840312	t		miannu	Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility.	SIGNOR-263040	0.399
CDK2	protein	P24941	UNIPROT	LIG1	protein	P18858	UNIPROT	up-regulates activity	phosphorylation	Ser91	ALDCSQVsPPRPATS	9606	BTO:0000567								12851383	t		lperfetto	We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner.	SIGNOR-103254	0.468
TAB2	protein	Q9NYJ8	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	binding			9606									8638164	t		lperfetto	The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. . These results define tab2 as an adaptor linking tak1 and traf6 and as a mediator of tak1 activation in the il-1 signaling pathway . taken together, these results indicate that polyubiquitination of rip1 mediates the independent recruitment of tab2 and nemo, which in turn recruits tak1 and ikk, respectively, to tnf-r1.	SIGNOR-105860	0.934
OTUD7A	protein	Q8TE49	UNIPROT	RIPK1	protein	Q13546	UNIPROT	down-regulates activity	deubiquitination			9606	BTO:0000007								18178551	t		lperfetto	NF-kappaB Suppression by the Deubiquitinating Enzyme Cezanne|Our study provides several lines of evidence to suggest that Cezanne suppresses TNFR signaling to NF-κB by targeting RIP1 for deubiquitination.	SIGNOR-268410	0.2
PPP2CA	protein	P67775	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	dephosphorylation			9606									19951945	t		gcesareni	Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a.	SIGNOR-161919	0.2
MAPK9	protein	P45984	UNIPROT	NFATC3	protein	Q12968	UNIPROT	down-regulates	phosphorylation	Ser163	SYRESSLsPSPASSI	9606	BTO:0000782								9374467	t		lperfetto	Ser163 and ser165 represent the major sites of in vitro phosphorylation of nfat4 by jnk. / the negative regulation of nfat4 nuclear accumulation caused by jnk provides a mechanism for cell type?specific Responses to extracellular stimulation	SIGNOR-53364	0.698
MAPKAPK5	protein	Q8IW41	UNIPROT	KALRN	protein	O60229	UNIPROT	up-regulates activity	phosphorylation	Ser487	DVLQRPLsPGNSESL	-1									22508986	t		miannu	The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements. The fragment SR3-6, but not the mutated fragment SR3-6-S487A, is phosphorylated by MK5. 	SIGNOR-263093	0.357
PRKCG	protein	P05129	UNIPROT	OCLN	protein	Q16625	UNIPROT	up-regulates activity	phosphorylation	Ser340	DKRFYPEsSYKSTPV	9615									11502742	t		lperfetto	Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X. 	SIGNOR-249107	0.311
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Asp)	smallmolecule	CHEBI:29186	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269483	0.8
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1735	SPTSPSYsPTSPSYS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248788	0.441
crizotinib	chemical	CHEBI:64310	ChEBI	MET	protein	P08581	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258102	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation			9606									19282669	t	inferred from 70% family members	lperfetto	Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway	SIGNOR-270146	0.711
FRAT1	protein	Q92837	UNIPROT	EIF2B5	protein	Q13144	UNIPROT	up-regulates activity	binding												10481074	t		lperfetto	In contrast to the GS‐1 peptide, glycogen synthase and the eIF2B peptide, the GSK3‐catalysed phosphorylation of Tau was completely inhibited by FRATtide|This prevents GSK3 from phosphorylating and inhibiting glycogen synthase [2, 3] and protein synthesis initiation factor eIF2B	SIGNOR-262835	0.292
SNAI1	protein	O95863	UNIPROT	CLDN7	protein	O95471	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001570								19277896	f	 	lperfetto	We propose that CtBP1 is recruited by SNAI1P at the CLDN7 gene promoter indirectly through another yet to be identified protein. Based on our observations, we propose a model for SNAI1P-mediated down regulation of human CLDN7 gene expression by chromatin remodeling	SIGNOR-254104	0.417
FOXP3	protein	Q9BZS1	UNIPROT	IL10	protein	P22301	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								24315995	f		alessandro	FoxP3, a lineage-specification factor, executes its multiple activities mostly through transcriptional regulation of target genes. We identified an interleukin-10 (IL-10)-producing FoxP3(+) T regulatory cell population that contributes to IL-10-dependent type 2 cytokine bias in breast-cancer patients. Although genetic ablation of FOXP3 inhibited IL10 transcription, genome-wide analysis ruled out its role as a transcription factor for IL10	SIGNOR-254525	0.508
NCOA1	protein	Q15788	UNIPROT	ALDOB	protein	P05062	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f		miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-255061	0.2
MAPK11	protein	Q15759	UNIPROT	MAPK11	protein	Q15759	UNIPROT	up-regulates activity	phosphorylation	Thr180	RQADEEMtGYVATRW	-1									26976637	t		miannu	P38β Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261	SIGNOR-277216	0.2
ELANE	protein	P08246	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Val58	KGVTVETvFSVDEFS	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263591	0.404
U0126	chemical	CHEBI:90693	ChEBI	MAPK7	protein	Q13164	UNIPROT	down-regulates				9606									11782488	f		gcesareni	Bmk1activation by h2o2 was inhibited by both pd98059 and u0126, which were reported to inhibit mek5 as well as mek1/2.	SIGNOR-113782	0.8
PTH	protein	P01270	UNIPROT	MMP13	protein	P45452	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17656568	f		miannu	Parathyroid hormone (PTH) functions as an essential regulator of calcium homeostasis and as a mediator of bone remodeling. We have already shown that PTH stimulates the expression of matrix metalloproteinase-13 (MMP-13), which is responsible for degrading components of extracellular matrix. 	SIGNOR-254234	0.46
TLX1	protein	P31314	UNIPROT	ETS1	protein	P14921	UNIPROT	down-regulates activity	binding			9606	BTO:0002504								22516263	t		irozzo	We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement. 	SIGNOR-259097	0.48
ARID1B	protein	Q8NFD5	UNIPROT	Muscle cell-specific SWI/SNF ARID1B variant	complex	SIGNOR-C482	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270702	0.799
3-isobutyl-1-methyl-7H-xanthine	smallmolecule	CHEBI:34795	ChEBI	PPARG	protein	P37231	UNIPROT	up-regulates				9606									11279134	f		fspada	The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin	SIGNOR-209998	0.8
GSK3A	protein	P49840	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	phosphorylation			9606									19214430	t		gcesareni	Taken together, our results indicate that gsk-3alfa is a negative regulator of notch1/nicd.	SIGNOR-183969	0.325
CUDC-907	chemical	CID:54575456	PUBCHEM	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191212	0.8
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Ser1080	IFYYFSNsPSKRLRE	9606									11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130.	SIGNOR-104671	0.843
MCHR2	protein	Q969V1	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257268	0.57
PRKAA1	protein	Q13131	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation												22848740	t			When AMPK is stimulated, pre-existing FOXO3 becomes reverted toward an active form.	SIGNOR-255755	0.509
ULK1	protein	O75385	UNIPROT	ATG9A	protein	Q7Z3C6	UNIPROT	up-regulates activity	phosphorylation	Ser14	EYQRLEAsYSDSPPG	9606									27934868	t		miannu	 Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation. 	SIGNOR-266369	0.6
PYHIN1	protein	Q6K0P9	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0001570								16479015	t		miannu	Here, we show that IFIXalpha1 downregulates HDM2, a principal negative regulator of p53, at the posttranslational level. IFIXalpha1 destabilizes HDM2 protein and promotes its ubiquitination. The E3 ligase activity of HDM2 appears to be required for this IFIXalpha1 effect. Importantly, HDM2 downregulation is required for the IFIXalpha1-mediated increase of p53 protein levels, transcriptional activity, and nuclear localization, suggesting that IFIXalpha1 positively regulates p53 by acting as a negative regulator of HDM2. 	SIGNOR-268493	0.424
NMDA receptor_2B	complex	SIGNOR-C348	SIGNOR	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								11052931	t		miannu	Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor	SIGNOR-264223	0.801
SGK1	protein	O00141	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606									11154281	t		lperfetto	Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 	SIGNOR-249134	0.787
CSNK2A1	protein	P68400	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Ser129	SGSPSDNsGAEEMEV	9606	BTO:0000007								21735093	t		gcesareni	CK2 hyperactivates AKT by phosphorylation at Ser129	SIGNOR-252595	0.379
TESK2	protein	Q96S53	UNIPROT	DSTN	protein	P60981	UNIPROT	down-regulates activity	phosphorylation	Ser3	sGVQVADE	9606	BTO:0001363								11418599	t		lperfetto	The present study provides evidence that TESK2 can phosphorylate cofilin and ADF specifically at Ser-3. Since actin-depolymerizing and -severing activities of cofilin/ADF are abrogated by phosphorylation at Ser-3, TESK2 seems to play an important role in actin filament dynamics by inhibiting cofilin/ADF activity.	SIGNOR-246707	0.432
GLUL	protein	P15104	UNIPROT	ammonium	smallmolecule	CHEBI:28938	ChEBI	down-regulates quantity	chemical modification			9606									30158707	t		miannu	Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction.	SIGNOR-267825	0.8
PRKAA2	protein	P54646	UNIPROT	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation	Ser556	GLGCRLHsAPNLSDL	9606			SIGNOR-C15						21205641	t		gcesareni	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-170863	0.483
NET1	protein	Q7Z628	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260561	0.825
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	BCL2L11	protein	O43521	UNIPROT	down-regulates activity	phosphorylation	Ser87	FIFMRRSsLLSRSSS	9606									16282323	t		lperfetto	Recombinant Akt could directly phosphorylate a GST-Bim(EL) fusion protein and identified the Akt phosphorylation site in the Bim(EL) domain as Ser(87). Further, we demonstrated that cytokine stimulation promotes Bim(EL) binding to 14-3-3 proteins. Finally, we show that mutation of Ser(87) dramatically increases the apoptotic potency of Bim(EL).	SIGNOR-141581	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation			9606									16407412	t	inferred from 70% family members	gcesareni	Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a.	SIGNOR-270010	0.2
AURKB	protein	Q96GD4	UNIPROT	DIAPH2	protein	O60879	UNIPROT	up-regulates	phosphorylation	Ser196	SLTSNPVsWVNNFGH	9606									21397845	t		lperfetto	The microtubule binding fh2 domain of mdia3 is phosphorylated by aurora b kinase in vitro, and cells expressing the nonphosphorylatable mdia3 mutant cannot position chromosomes at the metaphase plate	SIGNOR-172803	0.293
Sin3B_complex	complex	SIGNOR-C409	SIGNOR	H3Y2	protein	P0DPK5	UNIPROT	down-regulates activity	binding			9606									21041488	t		miannu	We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin.	SIGNOR-266976	0.2
ITGAL	protein	P20701	UNIPROT	ICAM1	protein	P05362	UNIPROT	up-regulates	binding			9606	BTO:0000130								23994464	t		apalma	This leads to further neutrophil-endothelial cell interactions through the binding of LFA-1 to its endothelial counterreceptor ICAM-1 during the slow rolling phase	SIGNOR-255040	0.92
afatinib	chemical	CHEBI:61390	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258169	0.8
CSNK2A1	protein	P68400	UNIPROT	XRCC1	protein	P18887	UNIPROT	up-regulates	phosphorylation	Thr523	AGSTDENtDSEEHQE	9606									20471329	t		lperfetto	Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523	SIGNOR-165435	0.404
UBE2I	protein	P63279	UNIPROT	ZHX1	protein	Q9UKY1	UNIPROT	up-regulates quantity by stabilization	sumoylation	Lys454	VPTSQSVkHETALVN	9606	BTO:0000007								23686912	t		miannu	Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. The sumoylation of zinc‐fingers and homeoboxes 1 (ZHX1) by ubc9 regulates its stability and transcriptional repression activity. However, in the current work, we demonstrated that ZHX1 was only SUMOylated by SUMO1. 	SIGNOR-263900	0.465
citrate(3-)	smallmolecule	CHEBI:16947	ChEBI	ACACA	protein	Q13085	UNIPROT	up-regulates activity	binding			9606									6138356	t		miannu	Citrate, an allosteric activator of acetyl-CoA carboxylase, induces polymerization of an inactive protomeric form of the enzyme into an active filamentous form composed of 10-20 protomers. 	SIGNOR-267104	0.8
PAK	proteinfamily	SIGNOR-PF13	SIGNOR	NF2	protein	P35240	UNIPROT	down-regulates	phosphorylation			9606									18071304	t	inferred from 70% family members	lperfetto	Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth,	SIGNOR-269976	0.2
Enolase	proteinfamily	SIGNOR-PF74	SIGNOR	2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	down-regulates quantity	chemical modification			9606									29767008	t		miannu	Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits.	SIGNOR-266531	0.8
VPS11	protein	Q9H270	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								21148287	t		Sara	The interaction between the full-length Vps11 and ezrin was confirmed by immunoprecipitation and GST-pull down. ERM proteins and the HOPS complex are required for the transition from early to late endosomes	SIGNOR-261311	0.356
USP13	protein	Q92995	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0002181			SIGNOR-C242					21962518	t		Giulio	Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E)	SIGNOR-260295	0.511
PSMD14	protein	O00487	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263346	0.894
TBK1	protein	Q9UHD2	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000782								14679297	t		lperfetto	We show that purified recombinant ikk-epsilon and tbk1 directly phosphorylate the critical serine residues in irf3 allowing its translocation into the nucleus and production of interferon type i.	SIGNOR-120355	0.817
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates	phosphorylation	Ser37	YLDSGIHsGATTTAP	9606									19667122	t		lperfetto	Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta.	SIGNOR-187578	0.2
SIRT3	protein	Q9NTG7	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	deacetylation	Lys321	SDPIMLLkDRMVNSN	9606	BTO:0000007								25152236	t		lperfetto	SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells|SIRT3 deacetylates PDHA1 lysine 321 (K321)	SIGNOR-267636	0.493
PLG	protein	P00747	UNIPROT	APOH	protein	P02749	UNIPROT	down-regulates activity	cleavage	Lys336	HSSLAFWKTDASDVK	9606		BTO:0000131							9596664	t		lperfetto	Plasmin can reduce the function of human beta2 glycoprotein I by cleaving domain V into a nicked form| The cleavage site of r-Domain V and beta2GPI by plasmin was proved to be Lys 317-Thr 318 by amino acid sequence analysis of the digest and of the C-terminal peptide isolated by high-performance liquid chromatography. The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI. 	SIGNOR-266996	0.47
FGFR1	protein	P11362	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates	phosphorylation	Tyr410	GVVDSGVyAVPPPAE	9606									12601080	t		lperfetto	Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas.	SIGNOR-98569	0.259
EGFR	protein	P00533	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates activity				10090	BTO:0000667								15284024	f	JAK activation occurs upon ligand-mediated receptor multimerization because two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs.	lperfetto	Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion	SIGNOR-235655	0.615
BACE1	protein	P56817	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage												28923680	t			Beta-secretase 1 (BACE1) cleaves the type-I transmembrane protein APP to form the N-terminus of Aβ.	SIGNOR-255480	0.787
IDH3B	protein	O43837	UNIPROT	IDH	complex	SIGNOR-C396	SIGNOR	form complex	binding			9606									28139779	t		miannu	Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. 	SIGNOR-266249	0.682
P2RY12	protein	Q9H244	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256712	0.377
EGFR	protein	P00533	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates	phosphorylation			9606									22693070	t		lperfetto	The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation	SIGNOR-235689	0.728
GTF2A2	protein	P52657	UNIPROT	TFIIA	complex	SIGNOR-C395	SIGNOR	form complex	binding			9606	BTO:0000567								7724559	t		lperfetto	TFIIA purified from HeLa extracts consists of 35-, 19-, and 12-kDa subunits. Here we describe the isolation of a cDNA clone (hTFIIA gamma) encoding the 12-kDa subunit. 	SIGNOR-266196	0.938
FLT3	protein	P36888	UNIPROT	FLT3	protein	P36888	UNIPROT	unknown	phosphorylation	Tyr969	VSECPHTyQNRRPFS	10090	BTO:0001516								16627759	t		lperfetto	In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated.	SIGNOR-271920	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	HDAC6	protein	Q9UBN7	UNIPROT	up-regulates	phosphorylation	Ser1035	DHQTPPTsPVQGTTP	9606									24089523	t		lperfetto	Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1	SIGNOR-244545	0.2
CTDSP1	protein	Q9GZU7	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation	Ser255	ELSPTTLsPVNHSLD	9606	BTO:0000007								17035229	t			SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248797	0.493
GABRA3	protein	P34903	UNIPROT	GABA-A (a3-b1-g2) receptor	complex	SIGNOR-C332	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263756	0.586
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGA11	protein	Q9Y5H2	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265690	0.2
MAPK1	protein	P28482	UNIPROT	LIN28A	protein	Q9H9Z2	UNIPROT	down-regulates activity	phosphorylation	Ser200	EEEEEIHsPTLLPEA	9606	BTO:0000567								28179426	t		miannu	Here we show that Lin28a is directly phosphorylated by ERK1/2 kinases at Ser-200. 	SIGNOR-277338	0.266
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate	smallmolecule	CHEBI:18348	ChEBI	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	form complex	binding			9606									24789820	t		lperfetto	AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly. 	SIGNOR-260664	0.8
PPP1CC	protein	P36873	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	dephosphorylation	Ser77	YEPEGSAsPTPPYLK	9606									17318175	t			The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 	SIGNOR-248495	0.272
CAMK2B	protein	Q13554	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	up-regulates activity	phosphorylation	Ser418	TTENRFHsLPFSLTK	9606									24614225	t		lperfetto	Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity.	SIGNOR-25329	0.2
SMAD3	protein	P84022	UNIPROT	FOXP3	protein	Q9BZS1	UNIPROT	up-regulates				9606									15367216	t			The TCR, IL-2R, and TbetaR must all be stimulated to induce Foxp3 + Tregs. Failure to engage any one of these receptors prevents the generation of Foxp3 + Tregs	SIGNOR-254363	0.54
MRAP2	protein	Q96G30	UNIPROT	MC4R	protein	P32245	UNIPROT	down-regulates activity	binding			10029	BTO:0000246								19329486	t		miannu	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252363	0.519
NFIB	protein	O00712	UNIPROT	RBFOX3	protein	A6NFN3	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268912	0.2
QRICH1	protein	Q2TAL8	UNIPROT	VARS2	protein	Q5ST30	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269409	0.2
TRIM21	protein	P19474	UNIPROT	FASN	protein	P49327	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								27758890	t			FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels.	SIGNOR-267368	0.2
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGA10	protein	Q9Y5H3	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265704	0.2
CIITA	protein	P33076	UNIPROT	IL4	protein	P05112	UNIPROT	down-regulates	transcriptional regulation			9606	BTO:0000782								10946277	f			We identified two domains of CIITA that interact with two distinct domains of CBP/p300 that are also recognized by NF-AT. CIITA mutants that retain the ability to interact with CBP/p300 are sufficient to inhibit NF-AT-mediated IL-4 gene expression	SIGNOR-254499	0.417
NSD3	protein	Q9BZ95	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0002181								28205554	t		irozzo	Indeed, dose-dependent TR-FRET and affinity pull-down assay confirmed the interaction of NSD3-s with MYC. Supporting functional significance of the interaction, co-expression of NSD3-s, but not the MYC-binding defective fragment of NSD3-s (1–347), stabilized MYC protein and increased MYC transcriptional activity as revealed by a MYC-driven reporter assay.	SIGNOR-259199	0.2
MERTK	protein	Q12866	UNIPROT	MERTK	protein	Q12866	UNIPROT	up-regulates	phosphorylation	Tyr749	FGLSKKIySGDYYRQ	9606									8702477	t		gcesareni	By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain.	SIGNOR-42914	0.2
AURKB	protein	Q96GD4	UNIPROT	CHMP4C	protein	Q96CF2	UNIPROT	up-regulates	phosphorylation	Ser210	MSSTARRsRAASSQR	9606									22724069	t		lperfetto	Moreover, we find that the cpc's catalytic subunit, aurora b kinase, phosphorylates one of the three human snf7 paralogues-chmp4c-in its c-terminal tail, a region known to regulate its ability to form polymers and associate with membranes. Phosphorylation at these sites appears essential for chmp4c function because their mutation leads to cytokinesis defects. The introduction of the s214a and s215a mutations together with s210a almost completely abolished aurora b phosphorylation	SIGNOR-197967	0.483
MYC	protein	P01106	UNIPROT	ENO1	protein	P06733	UNIPROT	up-regulates quantity	transcriptional regulation			10116									10823814	t			C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.	SIGNOR-259989	0.423
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	TRIM71	protein	Q2Q1W2	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269247	0.289
MAPK1	protein	P28482	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Thr573	AENGLLMtPCYTANF	9534									9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252752	0.751
CYP17A1	protein	P05093	UNIPROT	17alpha-hydroxypregnenolone	smallmolecule	CHEBI:28750	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0001363;BTO:0000050;BTO:0000056							17192295	t		lperfetto	THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones.	SIGNOR-268655	0.8
SIRT1	protein	Q96EB6	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	deacetylation			10090									24003218	t		lperfetto	SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3	SIGNOR-217972	0.909
AMPK	complex	SIGNOR-C15	SIGNOR	TET2	protein	Q6N021	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0001412								31900833	t		miannu	Inactivation of AMPK suppressed the expression of ten-eleven translocation methylcytosine dioxygenase 2 (TET2) in tumor cells. Compound C-induced AMPK suppression causes downregulation TET2 and FOXP3 expression, leading to death of parental and HQ-selected U937 cells. These results confirm the connection of AMPK with the TET2–FOXP3 axis in modulating the survival of AML cells and suggest that suppression of the AMPK–TET2–FOXP3 axis suppresses the progression of AML and HQ-induced malignant transformation of AML cells. 	SIGNOR-260097	0.2
CDK3	protein	Q00526	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser73	VGLLKLAsPELERLI	9606									19118012	t		gcesareni	Egf-induced cdk3 activation caused c-jun phosphorylation at ser63 and ser73, resulting in increased ap-1 transactivation.	SIGNOR-183013	0.455
SNAP25	protein	P60880	UNIPROT	SNARE_complex 	complex	SIGNOR-C346	SIGNOR	form complex	binding			9606	BTO:0000938								30267828	t		miannu	The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells.	SIGNOR-263967	0.957
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Thr663	IATVIVItLVMLKKK	-1									10605825	t		lperfetto	In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D.	SIGNOR-261793	0.502
ATM	protein	Q13315	UNIPROT	ABL1	protein	P00519	UNIPROT	up-regulates	binding			9606									9168117	t		acerquone	Our results demonstrate that the sh3 domain of c-abl interacts with a dpapnpphfp motif (residues 1,373-1,382) of atm.These findings indicate that atm is involved in the activation of c-abl by dna damag	SIGNOR-48822	0.734
TJP2	protein	Q9UDY2	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates	binding			9606									21808241	t		milica	In addition, yap and taz interact with another tight junction protein zo-2, which was reported to increase nuclear localization of yap and tight-junction localization of taz.	SIGNOR-175931	0.485
PTPN6	protein	P29350	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	dephosphorylation			9534									8943354	t			Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1	SIGNOR-248466	0.719
SMAD4	protein	Q13485	UNIPROT	SMAD8/SMAD4	complex	SIGNOR-C206	SIGNOR	form complex	binding			9606									20957627	t		lperfetto	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.	SIGNOR-255269	0.67
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDUFS2	protein	O75306	UNIPROT	up-regulates activity	phosphorylation	Ser364	KVDDAKVsPPKRAEM										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275600	0.2
PTK2	protein	Q05397	UNIPROT	PXN	protein	P49023	UNIPROT	up-regulates activity	phosphorylation	Tyr31	FLSEETPySYPTGNH	9606									15688067	t		miannu	Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites.	SIGNOR-28247	0.912
N-acetylserotonin	smallmolecule	CHEBI:17697	ChEBI	ASMT	protein	P46597	UNIPROT	up-regulates activity	chemical activation			-1									22775292	t		miannu	Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS.	SIGNOR-265476	0.8
PTPRB	protein	P23467	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates	dephosphorylation			9606									12840032	t	inferred from 70% of family members	gcesareni	When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well	SIGNOR-269931	0.443
PCSK7	protein	Q16549	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000130								19544470	t		gcesareni	Addition of active p38a induced phosphorylation of wild-type c/ebp_? (c/ebp_?WT) on serine 21	SIGNOR-186202	0.2
CHEK1	protein	O14757	UNIPROT	RB1	protein	P06400	UNIPROT	up-regulates activity	phosphorylation	Ser612	MYLSPVRsPKKKGST	9606									17380128	t		llicata	These results suggest that ser612 is phosphorylated by chk1/2 after dna damage, leading to the formation of prb-e2f-1. phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1	SIGNOR-153904	0.432
AMBRA1	protein	Q9C0C7	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates activity	binding			9606									17589504	t		lperfetto	Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy	SIGNOR-156409	0.779
CSNK2A1	protein	P68400	UNIPROT	EGR1	protein	P18146	UNIPROT	down-regulates activity	phosphorylation	Thr391	TTHIRTHtGEKPFAC	10090	BTO:0000944								8662759	t		llicata	Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10.	SIGNOR-250857	0.477
SRC	protein	P12931	UNIPROT	HSP90AB1	protein	P08238	UNIPROT	up-regulates	phosphorylation	Tyr301	DDITQEEyGEFYKSL	9606									17855507	t		lperfetto	C-src directly phosphorylates hsp90 on tyrosine 300 residue and that this event is essential for vegf-stimulated enos association to hsp90 and thus no release from endothelial cells.	SIGNOR-157781	0.57
MMUT	protein	P22033	UNIPROT	(S)-methylmalonyl-CoA(5-)	smallmolecule	CHEBI:57327	ChEBI	down-regulates quantity	chemical modification			9606									1978672	t		miannu	Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA). 	SIGNOR-269108	0.8
TRAF3	protein	Q13114	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	up-regulates activity	binding			9606									24622840	t		miannu	MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. 	SIGNOR-260156	0.9
ULK1	protein	O75385	UNIPROT	FBP1	protein	P09467	UNIPROT	down-regulates activity	phosphorylation	Ser63	HLYGIAGsTNVTGDQ	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274032	0.2
MIB1	protein	Q86YT6	UNIPROT	DLL4	protein	Q9NR61	UNIPROT	up-regulates activity	ubiquitination			9606									16140393	t		lperfetto	Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity.	SIGNOR-209626	0.533
USP24	protein	Q9UPU5	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0000018								27991932	t		lperfetto	In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. |Knockdown of USP24 decreases Bax and p300 levels	SIGNOR-275607	0.275
MAPK3	protein	P27361	UNIPROT	HDAC6	protein	Q9UBN7	UNIPROT	up-regulates	phosphorylation	Thr1031	ASSTDHQtPPTSPVQ	9606									24089523	t		lperfetto	Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1	SIGNOR-202702	0.437
DHCR7	protein	Q9UBM7	UNIPROT	cholesterol	smallmolecule	CHEBI:16113	ChEBI	up-regulates quantity	chemical modification			9606									9634533	t		miannu	In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol D7 -reductase. This NADPH-dependent enzyme catalyzes the reduction of the D7 -diene bond in 7-DHC, to form cholesterol.	SIGNOR-267252	0.8
NCAPD3	protein	P42695	UNIPROT	Condensin II	complex	SIGNOR-C342	SIGNOR	form complex	binding			9606									32445620	t		miannu	The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction.	SIGNOR-263912	0.882
PHLPP1	protein	O60346	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	dephosphorylation			9606	BTO:0001544								19261608	t			The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.	SIGNOR-248331	0.752
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1644	SPTSPSYsPTSPSYS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248817	0.849
F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	down-regulates				9606									23450633	f	inferred from 70% of family members	gcesareni	Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism.	SIGNOR-269861	0.7
AKT1	protein	P31749	UNIPROT	STK3	protein	Q13188	UNIPROT	down-regulates	phosphorylation	Thr117	IIRLRNKtLIEDEIA	9606									20086174	t		llicata	We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2.	SIGNOR-163533	0.363
GNAO1	protein	P09471	UNIPROT	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	up-regulates activity	binding			-1									10224115	t			G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics.	SIGNOR-256540	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	HTRA2	protein	O43464	UNIPROT	down-regulates	phosphorylation	Ser212	RVRVRLLsGDTYEAV	9606									17311912	t		lperfetto	Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212	SIGNOR-153323	0.2
MAPK3	protein	P27361	UNIPROT	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation	Ser759	KTPDGNKsPAPKPSD	9606		BTO:0000887;BTO:0001260							11983427	t		amattioni	The actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759. This phosphorylation leads to markedly diminished actin affinity.	SIGNOR-86741	0.46
RPS6KA3	protein	P51812	UNIPROT	ATF4	protein	P18848	UNIPROT	up-regulates	phosphorylation	Ser245	TRGSPNRsLPSPGVL	9606									15109498	t		lperfetto	Here, we show that rsk2 is required for osteoblast differentiation and function. We identify the transcription factor atf4 as a critical substrate of rsk2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoblast-specific gene expression	SIGNOR-124436	0.623
GRB2	protein	P62993	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	relocalization			9606									11823423	t	GRB2 is an adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.	gcesareni	The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization.	SIGNOR-114704	0.901
MAPK14	protein	Q16539	UNIPROT	PXN	protein	P49023	UNIPROT	unknown	phosphorylation	Ser85	HQQPQSSsPVYGSSA	9606									14970194	t		llicata	Here, we show that paxillin is phosphorylated by p38mapk in vitro and in nerve growth factor (ngf)-induced pc-12 cells. Ser 85 (ser 83 for endogenous paxillin) is identified as one of major phosphorylation sites by phosphopeptide mapping and mass spectrometry.	SIGNOR-122108	0.336
SAICAR(4-)	smallmolecule	CHEBI:58443	ChEBI	fumarate(2-)	smallmolecule	CHEBI:29806	ChEBI	up-regulates quantity	precursor of			9606									22812634	t		miannu	ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case	SIGNOR-268068	0.8
REN	protein	P00797	UNIPROT	Angiotensin-1	protein	P01019-PRO_0000032457	UNIPROT	up-regulates quantity	cleavage			9606									32201502	t		miannu	 Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10).	SIGNOR-260225	0.2
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	MYOD1	protein	P15172	UNIPROT	down-regulates activity	transcriptional regulation			9606									12244043	f		areggio	Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes	SIGNOR-254987	0.625
MACC1	protein	Q6ZN28	UNIPROT	MET	protein	P08581	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000038								19098908	t		Luana	Human colon carcinoma SW480 cells express virtually no MACC1. MACC1 cDNA transfection led not only to strong increases in MACC1 mRNA expression (Fig. 3a), but also to a 40-fold upregulation of the HGF receptor MET mRNA expression (Fig. 3b). This was confirmed on the protein level	SIGNOR-266058	0.405
PRKAA1	protein	Q13131	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser498	RPLSRTQsSPLPQSP	9606			SIGNOR-C15						21892142	t		gcesareni	Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)	SIGNOR-176483	0.347
CDH5	protein	P33151	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265867	0.751
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC4	protein	P56524	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257941	0.8
LEPR	protein	P48357	UNIPROT	POMC	protein	P01189	UNIPROT	up-regulates quantity													27154742	f		lperfetto	Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production	SIGNOR-253074	0.479
MAP3K5	protein	Q99683	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								17110930	t		Barakat	Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK	SIGNOR-274148	0.576
CENPL	protein	Q8N0S6	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265199	0.653
PRDM1	protein	O75626	UNIPROT	CIITA	protein	P33076	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000776								12626569	f		miannu	The positive regulatory domain i binding factor 1 (prdi-bf1 or blimp-1) protein represses the transcription of specific target genes, including c-myc, the mhc class ii trans-activator, pax-5, and cd23b	SIGNOR-99116	0.433
MAPK8	protein	P45983	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates	phosphorylation	Thr69	SRDPVARtSPLQTPA	9606									18570871	t		gcesareni	Together, our findings demonstrate that jnk1-mediated multisite phosphorylation of bcl-2 stimulates starvation-induced autophagy by disrupting the bcl-2/beclin 1 complex.	SIGNOR-179096	0.564
GALR2	protein	O43603	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257136	0.316
HMOX1	protein	P09601	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26722274	f		irozzo	The results of the present study indicated that knockdown of HMOX-1 significantly enhanced doxorubicin-induced apoptosis and downregulated the expression of Bcl-2 and Bcl-xL in breast cancer cells.	SIGNOR-256303	0.252
CDK5	protein	Q00535	UNIPROT	ADD1	protein	P35611	UNIPROT	up-regulates activity	phosphorylation	Thr724	KKKKKFRtPSFLKKS	9606	BTO:0000815								31548578	t		miannu	We found that Cdk5 directly phosphorylated the actin-binding protein adducin-1 (ADD1) at T724 in vitro and in intact cells.	SIGNOR-277487	0.258
SRC	protein	P12931	UNIPROT	HNRNPK	protein	P61978	UNIPROT	down-regulates	phosphorylation	Tyr380	YAGGRGSyGDLGGPI	9606									12052863	t		lperfetto	We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown).	SIGNOR-88915	0.609
CSNK2A1	protein	P68400	UNIPROT	DDX58	protein	O95786	UNIPROT	down-regulates	phosphorylation	Thr770	DSILRLQtWDEAVFR	9606									21068236	t		lperfetto	Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of rig-i are phosphorylated by casein kinase ii (ck2) in the resting state of the cell and dephosphorylated when cells are infected by rna virus. Mutation at aa position 770 or 854 to 855 of rig-i renders it constitutively active	SIGNOR-169408	0.2
Aldolase	proteinfamily	SIGNOR-PF75	SIGNOR	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266490	0.8
GSK3A	protein	P49840	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates	phosphorylation	Ser129	ICPSLPYsPVSSPQS	9606									22778263	t		lperfetto	Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity.	SIGNOR-198122	0.272
RASGEF1A	protein	Q8N9B8	UNIPROT	NRAS	protein	P01111	UNIPROT	up-regulates	binding			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183829	0.357
INTS6	protein	Q9UL03	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261463	0.842
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	SP3	protein	Q02447	UNIPROT	down-regulates activity	dephosphorylation			9606									12684058	t		lperfetto	Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression.	SIGNOR-264652	0.2
KIF14	protein	Q15058	UNIPROT	Cilium_assembly	phenotype	SIGNOR-PH64	SIGNOR	up-regulates				9606									32348467	f		miannu	 We show that RNAi depletion of KIF14 specifically leads to defects in ciliogenesis and basal body (BB) biogenesis, as its absence hampers the efficiency of primary cilium formation and the dynamics of primary cilium elongation, and disrupts the localization of the distal appendage proteins SCLT1 and FBF1 and components of the IFT-B complex. 	SIGNOR-266421	0.7
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	DHPS	protein	P49366	UNIPROT	up-regulates activity	phosphorylation	Ser233	KNHIPVFsPALTDGS	9606	BTO:0000007								32989218	t		miannu	 The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. 	SIGNOR-266376	0.2
PDPK1	protein	O15530	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000007								15175348	t		lperfetto	In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation	SIGNOR-244934	0.275
amitriptyline	chemical	CHEBI:2666	ChEBI	CHRM4	protein	P08173	UNIPROT	down-regulates activity	chemical inhibition			10029									8100134	t		miannu	Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 	SIGNOR-258704	0.8
GAST	protein	P01350	UNIPROT	EGR1	protein	P18146	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000269							22228178	f	 	 	Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation.	SIGNOR-254252	0.351
ROCK1	protein	Q13464	UNIPROT	LIMK2	protein	P53671	UNIPROT	up-regulates activity	phosphorylation	Thr526	NGKSYDEtVDIFSFG	9534	BTO:0000298								11018042	t		lperfetto	Specific Activation of LIM kinase 2 via Phosphorylation of Threonine 505 by ROCK, a Rho-dependent Protein Kinase	SIGNOR-249053	0.616
RAB22A	protein	Q9UL26	UNIPROT	BLOC-2	complex	SIGNOR-C252	SIGNOR	up-regulates activity	relocalization			9606									30404817	t		lperfetto	Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis.	SIGNOR-260696	0.2
TNF	protein	P01375	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates				9606									11287630	f		lperfetto	Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase	SIGNOR-106593	0.496
KDR	protein	P35968	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	relocalization			9825	BTO:0004007				phosphorylation:Tyr1175	AQQDGKDyIVLPISE			9405464	t	VEGF pathway	Gianni	In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function.	SIGNOR-261949	0.7
ITGB5	protein	P18084	UNIPROT	Av/b5 integrin	complex	SIGNOR-C178	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253208	0.763
PRKCA	protein	P17252	UNIPROT	ARHGDIB	protein	P52566	UNIPROT	down-regulates	phosphorylation	Ser31	YKPPPQKsLKELQEM	9606									22469974	t		llicata	These results reveal a mechanism of downregulation of rhogdi2 activity through pkc-mediated phosphorylation of ser31.	SIGNOR-196765	0.2
OTX1	protein	P32242	UNIPROT	BEST1	protein	O76090	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									18849347	f		miannu	Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity.	SIGNOR-254887	0.313
NF1	protein	P21359	UNIPROT	ADCY2	protein	Q08462	UNIPROT	up-regulates				9606									24431436	f		miannu	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-203983	0.291
GGCX	protein	P38435	UNIPROT	F10	protein	P00742	UNIPROT	up-regulates activity	carboxylation	Glu72	EEAREVFeDSDKTNE	-1									9538022	t		lperfetto	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263673	0.598
PLK1	protein	P53350	UNIPROT	RIOK2	protein	Q9BVS4	UNIPROT	up-regulates activity	phosphorylation	Ser548	KSSLEAAsFWGE	-1									21880710	t		miannu	 Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. 	SIGNOR-262939	0.441
SMURF2	protein	Q9HAU4	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates activity	ubiquitination			9606									11163210	t		lperfetto	Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.	SIGNOR-104999	0.698
TP53	protein	P04637	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14522900	f		miannu	 In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction	SIGNOR-254484	0.873
CH5132799	chemical	CID:49784945	PUBCHEM	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190937	0.8
NUP58	protein	Q9BVL2	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262077	0.2
GABA-B receptor	complex	SIGNOR-C336	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000227							9872316	f	brain	lperfetto	GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals.	SIGNOR-263794	0.7
NR3C1	protein	P04150	UNIPROT	CAV1	protein	Q03135	UNIPROT	up-regulates	binding			9606									23339905	t		gcesareni	He mGR appears to reside in caveolae and its association with caveolin-1 (Cav-1) was clearly detected in two of the four cell lines investigated using double recognition proximity ligation assay.	SIGNOR-251683	0.388
F2RL2	protein	O00254	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256904	0.2
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC1	protein	O95644	UNIPROT	up-regulates	dephosphorylation			9606	BTO:0000782								14722106	t		gcesareni	Once activated, calcineurin directly dephosphorylates NFAT proteins that are present in a hyperphosphorylated latent form in the cytoplasm and induces their rapid translocation into the nucleus, where in concert with nuclear partner proteins such as the AP-1 transcription factor complex, they are able to bind cooperatively to their target promoter elements and activate the transcription of specific NFAT target genes	SIGNOR-252313	0.821
PRPS2	protein	P11908	UNIPROT	D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	down-regulates quantity	chemical modification			9606									16939420	t		miannu	PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP.	SIGNOR-267081	0.8
PTPRG	protein	P23470	UNIPROT	PXN	protein	P49023	UNIPROT	up-regulates activity	dephosphorylation	Tyr118	VGEEEHVySFPNKQK	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254721	0.262
VPS4A	protein	Q9UN37	UNIPROT	CHMP2A	protein	O43633	UNIPROT	up-regulates activity	cleavage			-1									30989108	t		Giorgia	Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission.	SIGNOR-260846	0.909
CREB1	protein	P16220	UNIPROT	PAX3	protein	P23760	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001103							21902831	f		gcesareni	Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes.	SIGNOR-176539	0.32
TNKS2	protein	Q9H2K2	UNIPROT	PSMF1	protein	Q92530	UNIPROT	down-regulates quantity by destabilization	ADP-ribosylation			9606	BTO:0000007								23622245	t		lperfetto	We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31.	SIGNOR-263386	0.474
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates	dephosphorylation			9606									18676376	t		lperfetto	Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes.	SIGNOR-233435	0.613
PTBP2	protein	Q9UKA9	UNIPROT	KHSRP	protein	Q92945	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								11003644	t		lperfetto	Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA.	SIGNOR-261268	0.476
EEF1A1P5	protein	Q5VTE0	UNIPROT	Lys-tRNA(Lys)	smallmolecule	CHEBI:16047	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269542	0.8
Dinaciclib	chemical	CID:46926350	PUBCHEM	CDK5	protein	Q00535	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191328	0.8
CTDNEP1	protein	O95476	UNIPROT	LPIN1	protein	Q14693	UNIPROT	up-regulates activity	dephosphorylation	Ser106	IPMHLATsPILSEGA	9606	BTO:0001131								17420445	t			Dullard significantly dephosphorylates mouse lipin 1b only in BHK cells (Fig. 5A). This is most clearly seen by using the antibody prepared against the phosphorylation site Ser-106.|Dephosphorylation of lipin results in its translocation to the nuclear envelope and endoplasmic reticulum membranes from the cytosol and generation of diacylglycerol	SIGNOR-248346	0.771
ACSS3	protein	Q9H6R3	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	down-regulates quantity	chemical modification												10843999	t		lperfetto	The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP.	SIGNOR-271834	0.8
PRKCB	protein	P05771	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser465	LKHVTQSsRKLIRAD	9606									15381704	t	The effect has been demonstrated using P28329-3	gcesareni	Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity.	SIGNOR-129284	0.289
HSD3B1	protein	P14060	UNIPROT	17alpha-hydroxyprogesterone	smallmolecule	CHEBI:17252	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000050							2139411	t		lperfetto	The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione.	SIGNOR-268636	0.8
MAPK9	protein	P45984	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									20068231	t		gcesareni	Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.	SIGNOR-163266	0.686
PPARG	protein	P37231	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity				9606									23128507	t	PAX8-PPARγ fusion protein	miannu	The PAX8-PPARγ rearrangement leads to strong induction of the PPARγ protein and the consequent abrogation of the normal PPARγ function. PPARγ overexpression abolishes the PTEN-inhibitory effect on immunoactive AKT, which in turn induces the PI3K signaling pathway.	SIGNOR-251997	0.47
FYN	protein	P06241	UNIPROT	LAT	protein	O43561	UNIPROT	up-regulates	phosphorylation	Tyr200	SMESIDDyVNVPESG	9606	BTO:0000782								16938345	t		gcesareni	Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk.	SIGNOR-149174	0.739
RPS6KA4	protein	O75676	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	phosphorylation	Ser276	SMQLRRPsDRELSEP	9606				SIGNOR-C13					17183360	t		gcesareni	Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) msk 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf-kb isoform p65 and stat 1 and 3.	SIGNOR-151436	0.275
FYN	protein	P06241	UNIPROT	CAV1	protein	Q03135	UNIPROT	down-regulates activity	phosphorylation	Tyr14	VDSEGHLyTVPIREQ	9606									12921535	t		lperfetto	Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn.Therefore,	SIGNOR-118003	0.71
8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione	chemical	CHEBI:92539	ChEBI	ADRA1A	protein	P35348	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190604	0.8
GSK3B	protein	P49841	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates	phosphorylation	Ser231	LSTSSSSsPPGTPSP	9606					phosphorylation:Thr235	IFGATDYtSSIDVWS			17601773	t		fspada	Mass spectrometric analysis revealed that cdk2/cyclinA phosphorylates C/EBPbeta on Thr(188) and is required for phosphorylation (on Ser(184) or Thr(179)) of C/EBPbeta by GSK3beta and maintenance of DNA binding activity. However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs.	SIGNOR-156514	0.469
NEFM	protein	P07197	UNIPROT	Neurofilament L/M	complex	SIGNOR-C207	SIGNOR	form complex	binding			9606									19468066	t		miannu	Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H	SIGNOR-255271	0.533
NDUFV1	protein	P49821	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24].	SIGNOR-262183	0.857
PI3K	complex	SIGNOR-C156	SIGNOR	PIP3	smallmolecule	CHEBI:16618	ChEBI	up-regulates quantity	chemical modification			9606									24647478	t		lperfetto	Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478	SIGNOR-252712	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	PRKAA1	protein	Q13131	UNIPROT	down-regulates activity	phosphorylation	Ser486	DDEITEAKsGTATPQRS	-1									17023420	t			We show that AMPK α-Ser485/491 can be a site for autophosphorylation, which may play a role in limiting AMPK activation in response to energy depletion or other regulators	SIGNOR-256113	0.822
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser171	PLCLSPAsSGSSASF	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252318	0.635
EIF4B	protein	P23588	UNIPROT	EIF4A1	protein	P60842	UNIPROT	up-regulates activity	binding			-1									11418588	t			Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability	SIGNOR-261293	0.862
CSKMT	protein	A8MUP2	UNIPROT	CS	protein	O75390	UNIPROT	down-regulates activity	methylation	Lys395	LLEQGKAkNPWPNVD										34929314	t		lperfetto	A mitochondrial matrix-located methyltransferase, methyltransferase-like protein 12 (METTL12), has been reported to methylate CS on the lysine 368 (K368) [15] and K395 residues [16] which are near the active site of CS. The methylation on K395 inhibits CS activity, which can be antagonized by its substrate oxaloacetate.	SIGNOR-267638	0.2
KDR	protein	P35968	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	relocalization			9825	BTO:0004007				phosphorylation:Tyr1175	AQQDGKDyIVLPISE			9405464	t	VEGF pathway	Gianni	In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function.	SIGNOR-261948	0.673
CDK7	protein	P50613	UNIPROT	CDK12	protein	Q9NYV4	UNIPROT	up-regulates activity	phosphorylation	Thr893	SEESRPYtNKVITLW										24662513	t		lperfetto	Although Cdk12/CycK kinase complex lacking T-loop phosphorylation showed some basal activity towards a CTD substrate prephosphorylated at position Ser7, its activity was significantly increased upon coexpression with the CAK from S. cerevisiae (Supplementary Fig. 9a). Mutation of T893 to E to mimic phosphorylation showed no effect on basal kinase activity. Quantitative phosphorylation of a single residue occurred upon coexpression with Cak1, as determined by ESI mass spectrometry (Supplementary Fig. 9b). 	SIGNOR-275509	0.488
acyl-CoA	smallmolecule	CHEBI:17984	ChEBI	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	precursor of			-1									18772128	t		miannu	The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils.	SIGNOR-268106	0.8
COL4A6	protein	Q14031	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates activity	binding												35267698	t		lperfetto	Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23].	SIGNOR-272352	0.396
MTA1	protein	Q13330	UNIPROT	SNAI2	protein	O43623	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000812								18719363	f		miannu	 MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG.	SIGNOR-254597	0.436
LIMS1	protein	P48059	UNIPROT	IPP complex	complex	SIGNOR-C380	SIGNOR	form complex	binding												16493410	t		lperfetto	Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton.	SIGNOR-265763	0.739
TTL	protein	Q8NG68	UNIPROT	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	down-regulates	tyrosination			9606									22020298	t		miannu	Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization	SIGNOR-266826	0.2
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr46	GGTLFSTtPGGTRII	9606									12747827	t		lperfetto	Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e.	SIGNOR-236698	0.753
SNRPD2	protein	P62316	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270661	0.763
NFATC2	protein	Q13469	UNIPROT	MYOF	protein	Q9NZM1	UNIPROT	up-regulates	transcriptional regulation			9606									23612709	f			Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin 	SIGNOR-255461	0.2
FOXO6	protein	A8MYZ6	UNIPROT	TRIM63	protein	Q969Q1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							21798082	f		lperfetto	Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome.	SIGNOR-236567	0.276
dobutamine	chemical	CHEBI:4670	ChEBI	YAP1	protein	P46937	UNIPROT	down-regulates				9606									23431053	f	These results suggest that the activity of YAP/TAZ can be either up-regulated or down-regulated by GPCR signaling,depending on which Galfa protein is activated	gcesareni	Dobutamine is an agonist for the beta1 adrenergic receptor, which likely inhibits yap by activating gaalfas.	SIGNOR-201259	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PTPN11	protein	Q06124	UNIPROT	down-regulates activity	phosphorylation	Ser189	GGGERFDsLTDLVEH	9606	BTO:0002181								25802336	t		miannu	 We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity. 	SIGNOR-276894	0.2
CLK4	protein	Q9HAZ1	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates	phosphorylation	Thr735	DTEWRSVtLPRDLQS	9606									18794806	t		lperfetto	Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3	SIGNOR-181052	0.276
CAD	protein	P27708	UNIPROT	CAD	protein	P27708	UNIPROT	up-regulates activity	phosphorylation	Thr1037	QQCRVLGtSPEAIDS	-1									11986331	t		llicata	Autophosphorylation resulted in a 2-fold increase in CPSase activity, an increased sensitivity to the feedback inhibitor UTP, and decreased allosteric activation by 5-phosphoribosyl-1-pyrophosphate	SIGNOR-250610	0.2
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606	BTO:0000567								10673501	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-75009	0.784
GNB/GNG	complex	SIGNOR-C202	SIGNOR	PLCB3	protein	Q01970	UNIPROT	up-regulates													23994464	t		apalma	However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits	SIGNOR-255016	0.367
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000938								20444238	t	inferred from 70% family members	gcesareni	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-270051	0.2
RAB38	protein	P57729	UNIPROT	AP-1 complex	complex	SIGNOR-C248	SIGNOR	up-regulates activity	relocalization			9606									23247405	t		lperfetto	Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes.	SIGNOR-260701	0.2
DDB1	protein	Q16531	UNIPROT	Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	form complex	binding			9606									22649780	t		gcesareni	The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors	SIGNOR-234802	0.917
FFAR4	protein	Q5NUL3	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257158	0.252
MMP9	protein	P14780	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272399	0.7
KLKB1	protein	P03952	UNIPROT	HGF	protein	P14210	UNIPROT	up-regulates activity	cleavage	Arg494	CAKTKQLrVVNGIPT	-1									12372819	t		miannu	 the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. 	SIGNOR-256512	0.328
IKBKB	protein	O14920	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates	phosphorylation			9606									10469655	t		lperfetto	Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway.	SIGNOR-217400	0.865
flumazenil	chemical	CHEBI:5103	ChEBI	GABA-A (a6-b1-g2) receptor	complex	SIGNOR-C334	SIGNOR	up-regulates activity	chemical activation			9606		BTO:0000227							18790874	t	brain	lperfetto	Receptors containing the alpha4 or alpha6 subunits, together with beta and gamma2, do not bind the traditional BZ agonists, including zolpidem, but demonstrate high affinity for some ligands, notably the imidazobenzodiazepines such as flumazenil and Ro15-4513, or bretazenil	SIGNOR-263806	0.8
GHSR	protein	Q92847	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256782	0.287
MTOR	protein	P42345	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser639	YMPMSPKsVSAPQQI	10116	BTO:0000452								11287630	t		lperfetto	Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten	SIGNOR-106590	0.758
BRD2	protein	P25440	UNIPROT	ZMYND8	protein	Q9ULU4	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000007								29018219	t		lperfetto	ZMYND8 and BRD2 therefore work together to protect H4Ac domains from HDAC activity.|Further, when BRD2 was depleted, ZMYND8 accumulation was lost (Fig. 2e), indicating that either BRD2, or the underlying H4Ac, is required for ZMYND8 loading. 	SIGNOR-262036	0.292
CDK8	protein	P49336	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser214	PTSSDPGsPFQMPAD	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-189141	0.392
RNF8	protein	O76064	UNIPROT	Histone H2A	proteinfamily	SIGNOR-PF70	SIGNOR	up-regulates	ubiquitination			9606									20551964	t		gcesareni	Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist.	SIGNOR-265313	0.2
SIRT1	protein	Q96EB6	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21633182	t		miannu	 Interestingly, SIRT1 suppresses PPARγ but activates PGC-1α , and thus affects the clock network through multiple mechanisms.	SIGNOR-268032	0.688
BMPR1B	protein	O00238	UNIPROT	SMAD9	protein	O15198	UNIPROT	up-regulates activity	phosphorylation			9606									19620713	t		lperfetto	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-255264	0.697
GDNF	protein	P39905	UNIPROT	RHOQ	protein	P17081	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252185	0.2
SNARE_complex 	complex	SIGNOR-C346	SIGNOR	Membrane_fusion	phenotype	SIGNOR-PH122	SIGNOR	up-regulates				9606	BTO:0000938								30267828	f		miannu	The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. The event directly leading to membrane fusion is theassembly of the C-terminal end of the SNARE-complex,and the linker domains, which couples the releasedenergy directly to the fusion of the membranes	SIGNOR-263973	0.7
SEC61 complex	complex	SIGNOR-C368	SIGNOR	SEC63	protein	Q9UGP8	UNIPROT	up-regulates activity	binding												33925740	t		lperfetto	This is where allosteric effectors of the Sec61 complex (BiP together with Sec62/Sec63 complex or TRAP complex) (Figure 2 and Figure 5) and auxiliary membrane protein insertases (EMC and TMCO1 complex) join the game	SIGNOR-265274	0.887
WDR83	protein	Q9BRX9	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates	binding			9606									15118098	t		gcesareni	Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex.	SIGNOR-124470	0.504
NGFR	protein	P08138	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									14699954	f		amattioni	Neurotrophin binding to p75ntrhas also been shown to induce apoptosis	SIGNOR-120558	0.7
STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	ABL1	protein	P00519	UNIPROT	down-regulates	phosphorylation			9606									18794806	t	inferred from 70% family members	lperfetto	Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3	SIGNOR-270219	0.2
PRKCD	protein	Q05655	UNIPROT	CXCR4	protein	P61073	UNIPROT	down-regulates activity	phosphorylation	Ser325	LTSVSRGsSLKILSK	9606									10521508	t		Manara	Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization.	SIGNOR-260899	0.2
BMS-754807	chemical	CHEBI:88339	ChEBI	INSR	protein	P06213	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001802								19996272	t		lperfetto	BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR 	SIGNOR-262026	0.8
CAMK2D	protein	Q13557	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser516	LSLTRGLsRTSMKPR	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275776	0.48
POLR2E	protein	P19388	UNIPROT	PAQosome co-chaperone complex	complex	SIGNOR-C516	SIGNOR	form complex	binding			9606									30484152	t		miannu	The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92. 	SIGNOR-270923	0.2
IDH	complex	SIGNOR-C396	SIGNOR	D-threo-isocitrate(3-)	smallmolecule	CHEBI:15562	ChEBI	down-regulates quantity	chemical modification			9606									28139779	t		miannu	Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP.	SIGNOR-266251	0.8
oxotremorine M	chemical	CHEBI:38322	ChEBI	CHRM1	protein	P11229	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258656	0.8
ODC1	protein	P11926	UNIPROT	L-ornithine	smallmolecule	CHEBI:15729	ChEBI	down-regulates quantity	chemical modification			9606									14617280	t		miannu	Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC)	SIGNOR-256037	0.8
FOXA2	protein	Q9Y261	UNIPROT	AHSG	protein	P02765	UNIPROT	up-regulates quantity by expression	transcriptional regulation												16595698	f		lperfetto	CCAAT enhancer binding protein beta and hepatocyte nuclear factor 3beta are necessary and sufficient to mediate dexamethasone-induced up-regulation of alpha2HS-glycoprotein/fetuin-A gene expression.	SIGNOR-271676	0.236
LAMTOR3	protein	Q9UHA4	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates	binding			9606									15547943	t		lperfetto	We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations.	SIGNOR-244874	0.6
RELA	protein	Q04206	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000801								27337441	t		lperfetto	Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation	SIGNOR-251737	0.681
TNFRSF1A	protein	P19438	UNIPROT	TRADD	protein	Q15628	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								7758105	t		lperfetto	We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed.	SIGNOR-32739	0.799
MCU_MICUB_variant	complex	SIGNOR-C499	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270864	0.8
RIPK3	protein	Q9Y572	UNIPROT	OGDC	complex	SIGNOR-C397	SIGNOR	up-regulates activity	phosphorylation			-1									29358703	t		miannu	Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135.	SIGNOR-268066	0.2
TACR3	protein	P29371	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256794	0.2
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	SNAI2	protein	O43623	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser54	ILSSGAYsPITVWTT	9606									24662826	t		miannu	At G1/S transition, cyclin E-cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation.	SIGNOR-276628	0.292
RORA	protein	P35398	UNIPROT	ARNTL	protein	O00327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24737872	t		miannu	 As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression.	SIGNOR-268002	0.677
Adenylate_cyclase	proteinfamily	SIGNOR-PF92	SIGNOR	ATP	smallmolecule	CHEBI:15422	ChEBI	down-regulates quantity	chemical modification			9606									11376933	t		miannu	To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis.	SIGNOR-267843	0.8
DLX2	protein	Q07687	UNIPROT	ARX	protein	Q96QS3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18923043	f	Regulation	miannu	Dlx overexpression induces ectopic expression of endogenous Arx and its isolated enhancer, whereas loss of Dlx expression results in reduced Arx expression	SIGNOR-251972	0.278
CRK	protein	P46108	UNIPROT	MAP4K5	protein	Q9Y4K4	UNIPROT	up-regulates activity	binding			-1									9788432	t		lperfetto	Two novel candidates for signalling partners of Crk family adapter proteins, the hematopoietic progenitor kinase 1 (HPK1) and the kinase homologous to SPS1/STE20 (KHS), were found to bind with great selectivity to the first SH3 domains of c-Crk and CRKL.|These results make it likely that HPK1 and KHS participate in the signal transduction of Crk family adapter proteins in certain cell types.	SIGNOR-262830	0.371
CAK complex	complex	SIGNOR-C456	SIGNOR	CDK12	protein	Q9NYV4	UNIPROT	up-regulates activity	phosphorylation	Thr893	SEESRPYtNKVITLW										24662513	t		lperfetto	Although Cdk12/CycK kinase complex lacking T-loop phosphorylation showed some basal activity towards a CTD substrate prephosphorylated at position Ser7, its activity was significantly increased upon coexpression with the CAK from S. cerevisiae (Supplementary Fig. 9a). Mutation of T893 to E to mimic phosphorylation showed no effect on basal kinase activity. Quantitative phosphorylation of a single residue occurred upon coexpression with Cak1, as determined by ESI mass spectrometry (Supplementary Fig. 9b). 	SIGNOR-275510	0.519
PIAS4	protein	Q8N2W9	UNIPROT	SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	down-regulates activity	binding			9606									12904571	t		lperfetto	Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity.	SIGNOR-217731	0.586
procaterol	chemical	CHEBI:135209	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. 	SIGNOR-257863	0.8
PTH1R	protein	Q03431	UNIPROT	SOST	protein	Q9BQB4	UNIPROT	down-regulates quantity													28363951	f		lperfetto	Furthermore, PTH acts on osteocytes to suppress the expression of sclerostin, an inhibitor of canonical Wnt signaling (Li, et al. 2005; Semenov, et al. 2005)). PTH action on sclerostin is primarily through cAMP signaling (Keller and Kneissel 2005) and mediated by Myocyte enhancer factor-2 (MEF2) transcriptional regulators (Leupin, et al. 2007). Using the cAMP signaling pathway in osteoblasts, PTH also inhibits the expression of Dickkopf 1 (Dkk1) (Guo et al. 2010a), which is another Wnt pathway inhibitor 	SIGNOR-270552	0.392
ILK	protein	Q13418	UNIPROT	NACA	protein	E9PAV3	UNIPROT	up-regulates	phosphorylation	Ser1906	PELEEQDsTQATTQQ	9606									15299025	t		lperfetto	The inactivation of gsk3? In response to adhesion and ilk activation (6) would then result in a thr-159-hypophosphorylated ?-Nac that would become unavailable for proteasome degradation but would become a substrate for the ilk kinase activity on residue ser-43. The ser-43-phosphorylated ?-Nac would preferentially interact with c-jun (30), translocate to the nucleus, and potentiate transcription	SIGNOR-127631	0.401
CTNNB1	protein	P35222	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16510874	f		gcesareni	Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro.Chromatin Immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp.	SIGNOR-19153	0.737
CSNK2A1	protein	P68400	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	phosphorylation	Ser529	GLPNGLLsGDEDFSS	9606									10938077	t		gcesareni	Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II.|Furthermore, our results indicate that the association between IkappaBalpha and p65 inhibits p65 phosphorylation by CKII and that degradation of IkappaBalpha allows CKII to phosphorylate p65 to increase NF-kappaB transactivation potential.	SIGNOR-149635	0.455
SIRT2	protein	Q8IXJ6	UNIPROT	AFP	protein	P02771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								14522900	f		miannu	 In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity.	SIGNOR-254487	0.26
CAMK2A	protein	Q9UQM7	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Thr594	LHGKKNStVDCNGVV	9606									33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275772	0.383
[4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone	chemical	CHEBI:91441	ChEBI	AURKA	protein	O14965	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258232	0.8
N-formyl-L-methionyl-L-leucyl-L-phenylalanine	smallmolecule	CHEBI:53490	ChEBI	FPR1	protein	P21462	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257492	0.8
LYN	protein	P07948	UNIPROT	PPP1R15A	protein	O75807	UNIPROT	up-regulates	phosphorylation			9606									11517336	t		gcesareni	Gadd34 was tyrosine-phosphorylated in vivo in a lyn-dependent manner.	SIGNOR-109934	0.34
EGR3	protein	Q06889	UNIPROT	NAB2	protein	Q15742	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000848								20506119	f		miannu	In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2.	SIGNOR-253882	0.501
HOXC13	protein	P31276	UNIPROT	LAMB2	protein	P55268	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534	BTO:0000298								10835276	t		Luana	The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells.	SIGNOR-261644	0.2
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates activity	phosphorylation	Tyr101	EGLSMGNyIGLINRI	9606	BTO:0001282								16373505	t			PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation. 	SIGNOR-251112	0.2
Tuberoinfundibular peptide of 39 residues	smallmolecule	CHEBI:80275	ChEBI	PTH2R	protein	P49190	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257576	0.8
EYA1	protein	Q99502	UNIPROT	H2AX	protein	P16104	UNIPROT	down-regulates	dephosphorylation	Tyr143	ATQASQEy	9606									20965415	t		gcesareni	Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3.	SIGNOR-168879	0.2
RHOA	protein	P61586	UNIPROT	PKN1	protein	Q16512	UNIPROT	up-regulates activity	binding			10090	BTO:0004732								27270401	t	no	miannu	PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. 	SIGNOR-275465	0.847
IGF1R	protein	P08069	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates				9606									15829723	f		apalma	Mechanical loading increases IGF-I release, and IGF-I can stimulate Ca2+ influx and thereby activate calcineurin	SIGNOR-255100	0.8
GSK3B	protein	P49841	UNIPROT	MACF1	protein	Q9UPN3	UNIPROT	down-regulates activity	phosphorylation	Ser7318	RPGSRAGsRAGSRAS	9606	BTO:0004905								21295697	t		lperfetto	We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules.	SIGNOR-264432	0.446
EZH2	protein	Q15910	UNIPROT	SNAI2	protein	O43623	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									23836662	f	 	miannu	 We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes.	SIGNOR-254146	0.51
TBK1	protein	Q9UHD2	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Ser385	MARVGGAsSLENTVD	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178391	0.817
SAV1	protein	Q9H4B6	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								19212654	t		miannu	The human WW45 protein enhances MST1-mediated apoptosis in vivo In this model, hWW45 binds both MST1 and LATS through its coiled-coil domains and WW domains, respectively, and facilitates the phosphorylation of LATS by MST1. This model could explain the enhanced apoptotic efficacy of MST1 with the over-expression of hWW45 and the attenuated MST1-induced apoptosis with the down-regulation of endogenous hWW45. 	SIGNOR-263661	0.891
GNB5	protein	O14775	UNIPROT	ADCY1	protein	Q08828	UNIPROT	down-regulates activity	binding			9606	BTO:0004032								21303898	t		miannu	The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC	SIGNOR-264996	0.432
SRC	protein	P12931	UNIPROT	WNK4	protein	Q96J92	UNIPROT	down-regulates activity	phosphorylation	Tyr1113	PSPVWMNySYSSLCL	9606	BTO:0002181								25805816	t		miannu	Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4. 	SIGNOR-276897	0.2
SMURF	proteinfamily	SIGNOR-PF29	SIGNOR	BMPR2	protein	Q13873	UNIPROT	down-regulates	ubiquitination			9606									22298955	t	inferred from 70% family members	gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps.	SIGNOR-270215	0.2
PIK3IP1	protein	Q96FE7	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates activity	binding			9606									24316979	t		miannu	We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition.	SIGNOR-260073	0.282
MARCHF9	protein	Q86YJ5	UNIPROT	PTPRA	protein	P18433	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001522								19457934	t		miannu	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. 	SIGNOR-271540	0.2
RAF1	protein	P04049	UNIPROT	EEF1A2	protein	Q05639	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser21	GHVDSGKsTTTGHLI	-1									22378069	t		miannu	Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf. 	SIGNOR-276407	0.2
MYC	protein	P01106	UNIPROT	CLK3	protein	P49761	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002932								32453420	t	done	miannu	C-Myc enhances transcriptional activation of CLK3 promoter in CCA cells. 	SIGNOR-274123	0.2
CNOT4	protein	O95628	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	form complex	binding			9606									19558367	t		lperfetto	In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules.	SIGNOR-268302	0.77
PRKACA	protein	P17612	UNIPROT	MAP2	protein	P11137	UNIPROT	down-regulates activity	phosphorylation	Ser1742	KAQAKVGsLDNAHHV	9606	BTO:0000567								11029056	t		miannu	CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA	SIGNOR-250003	0.366
RORC	protein	P51449	UNIPROT	IL17A	protein	Q16552	UNIPROT	up-regulates	transcriptional regulation			9606									16990136	t		mrosina	We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells	SIGNOR-255029	0.558
PRKCI	protein	P41743	UNIPROT	ECT2	protein	Q9H8V3	UNIPROT	up-regulates	phosphorylation	Thr359	YLYEKANtPELKKSV	9606	BTO:0000551								21189248	t		gcesareni	Our data support a model in which pkc?-Mediated phosphorylation regulates ect2 binding to the oncogenic pkc?-Par6 complex thereby activating rac1 activity and driving transformed growth and invasion.	SIGNOR-170790	0.488
LPAR5	protein	Q9H1C0	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257205	0.339
PRKCD	protein	Q05655	UNIPROT	PRKCD	protein	Q05655	UNIPROT	up-regulates	phosphorylation	Ser645	LNEKARLsYSDKNLI	9606									9305920	t		gcesareni	Taken together, our results demonstrate that serine 643 of pkc-delta is a major autophosphorylation site, and phosphorylation of this site plays an important role in controlling its enzymatic activity and biological function. The enzymatic activity of pkc-deltas643a mutant as measured by phosphorylating the pkc-delta pseudosubstrate region-derived substrate was also reduced more than 70% in comparison to that of pkc-deltawt.	SIGNOR-51000	0.2
UCHL1	protein	P09936	UNIPROT	UBC	protein	P0CG48	UNIPROT	up-regulates quantity	cleavage			9606									9521656	t		lperfetto	These data suggest that the physiological role of UCH is to hydrolyze small adducts of ubiquitin and to generate free monomeric ubiquitin from ubiquitin proproteins, but not to deubiquitinate ubiquitin-protein conjugates or disassemble polyubiquitin chains	SIGNOR-249693	0.858
Cap-binding complex	complex	SIGNOR-C440	SIGNOR	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates	relocalization			9606									32873578	t		lperfetto	The largely nuclear cap-binding complex (CBC) binds to the 5′ caps of RNA polymerase II (RNAPII)-synthesized transcripts and serves as a dynamic interaction platform for a myriad of RNA processing factors that regulate gene expression. 	SIGNOR-268360	0.8
RAB32	protein	Q13637	UNIPROT	BLOC-2	complex	SIGNOR-C252	SIGNOR	up-regulates activity	relocalization			9606									23247405	t		lperfetto	Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes.	SIGNOR-260695	0.307
GUCY1A1	protein	Q02108	UNIPROT	GUCY1A3-B2	complex	SIGNOR-C139	SIGNOR	form complex	binding			9606									10977868	t		gcesareni	This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity	SIGNOR-244116	0.2
MAPK14	protein	Q16539	UNIPROT	MKNK1	protein	Q9BUB5	UNIPROT	up-regulates	phosphorylation	Thr255	ITTPELTtPCGSAEY	9606									9155017	t		gcesareni	Mnk1, but not mnk2, also binds strongly to the stress-activated kinase, p38.	SIGNOR-48346	0.656
NUMA1	protein	Q14980	UNIPROT	TUBB4B	protein	P68371	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-117078	0.378
MAPK1	protein	P28482	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Thr573	AENGLLMtPCYTANF	9606									9687510	t		lperfetto	Thus, MAPK1/ERK1 and MAPK2/ERK2 activate three closely related protein kinases known as MAPK_activated protein kinases_1a, _1b and _1c (MAPKAP_K1a/b/c; also known as RSK1/2/3)	SIGNOR-252753	0.751
CDK5RAP2	protein	Q96SN8	UNIPROT	CEP152	protein	O94986	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								26297806	t		lperfetto	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.	SIGNOR-271721	0.747
N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	chemical	CHEBI:91418	ChEBI	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001271								21697284	t		gcesareni	Cocrystallization of the met kinase domain in complex with nvp-bvu972 revealed a key role for y1230 in binding of nvp-bvu972, as previously reported for multiple other selective met inhibitors.	SIGNOR-174555	0.8
HIC1	protein	Q14526	UNIPROT	LRP8	protein	Q14114	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001938;BTO:0000815								24076391	f	 	miannu	The Reelin receptors ApoER2 and VLDLR are direct target genes of HIC1. ectopic expression of HIC1 in U2OS and MDA-MB-231 cell lines decreases expression of the ApoER2 and VLDLR genes, encoding two canonical tyrosine kinase receptors for Reelin. 	SIGNOR-254243	0.2
AURKB	protein	Q96GD4	UNIPROT	DES	protein	P17661	UNIPROT	down-regulates	phosphorylation	Ser12	YSSSQRVsSYRRTFG	-1									12686604	t		lperfetto	We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro.	SIGNOR-100107	0.526
ZAP70	protein	P43403	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates	phosphorylation	Tyr128	DGEDDGDyESPNEEE	9606	BTO:0000782								9047237	t		lperfetto	Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient.	SIGNOR-46859	0.798
CDC14A	protein	Q9UNH5	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates	dephosphorylation	Ser684	IGIPQFHsPVGSPLK	9606									20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis.	SIGNOR-164404	0.627
tolbutamide	chemical	CHEBI:27999	ChEBI	CFTR	protein	P13569	UNIPROT	down-regulates activity	chemical inhibition			10090									1281220	t		miannu	The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 microM, respectively.	SIGNOR-258345	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	TRPC5	protein	Q9UL62	UNIPROT	down-regulates activity	phosphorylation	Ser794	SGGARAKsKSVSFNL	9606	BTO:0000007								21734191	t	done	miannu	Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A).	SIGNOR-273790	0.2
PRKCA	protein	P17252	UNIPROT	LMNA	protein	P02545	UNIPROT	unknown	phosphorylation	Ser525	NTWGCGNsLRTALIN	-1									8477740	t		lperfetto	An interphase-specific phosphorylation at Ser525 matching the PKC consensus sequence and of peptides phosphorylated by unknown kinases was determined.	SIGNOR-248935	0.369
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser250	TGSPAELsPTTLSPV	9606		BTO:0000763;BTO:0000149							10197981	t		lperfetto	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-244723	0.2
MTOR	protein	P42345	UNIPROT	MAF1	protein	Q9H063	UNIPROT	down-regulates	phosphorylation	Ser60	PHVLEALsPPQTSGL	9606			SIGNOR-C3						20516213	t		fstefani	The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly.	SIGNOR-165791	0.7
ABL1	protein	P00519	UNIPROT	STK3	protein	Q13188	UNIPROT	up-regulates	phosphorylation	Tyr81	MQQCDSPyVVKYYGS	9606	BTO:0000938								22590567	t		llicata	We demonstrate that c-abl kinase phosphorylates mst2 at an evolutionarily conserved site, y81, within the kinase domain. We further show that the phosphorylation of mst2 by c-abl leads to the disruption of the interaction with raf-1 proteins and the enhancement of homodimerization of mst2 proteins. It thereby enhances the mst2 activation and induces neuronal cell death.	SIGNOR-197538	0.2
MAPK3	protein	P27361	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation			9606									20974802	t		gcesareni	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6.	SIGNOR-169004	0.32
SOCS1	protein	O15524	UNIPROT	IRAK1	protein	P51617	UNIPROT	down-regulates	binding			9606									12433373	t		flangone	Coimmunoprecipitation analyses demonstrated association of socs-1 with irak...This Finding suggests that socs-1 might suppress myd88-dependent signal pathways at least by binding to irak	SIGNOR-95528	0.411
WT1	protein	P19544	UNIPROT	NPHS1	protein	O60500	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15504938	t			The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner	SIGNOR-252299	0.503
AR	protein	P10275	UNIPROT	NKX3-1	protein	Q99801	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16697957	t		miannu	Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events.	SIGNOR-251546	0.518
GSK3B	protein	P49841	UNIPROT	PTTG1	protein	O95997	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser183	SNLLQSPsSILSTLD	9606	BTO:0000567								21757741	t		miannu	Here, we demonstrate that glycogen synthase kinase-3β (GSK3β) phosphorylates securin to promote its proteolysis via SCF(βTrCP) E3 ubiquitin ligase.	SIGNOR-276345	0.2
ATF4	protein	P18848	UNIPROT	LARS1	protein	Q9P2J5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269420	0.2
LRP6	protein	O75581	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates activity													15229249	f			We speculate that DKK1 produced by βAP-treated neurons suppresses the canonical Wnt signaling pathway by interacting with LRP5/6 and therefore facilitates GSK3β activation. 	SIGNOR-255484	0.787
GDP	smallmolecule	CHEBI:17552	ChEBI	GNAI1	protein	P63096	UNIPROT	down-regulates	chemical inhibition			9606									12040175	t		gcesareni	Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis.	SIGNOR-88226	0.8
SMURF1	protein	Q9HCE7	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0000298								11278251	t		miannu	Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7. 	SIGNOR-272943	0.681
Goserelin	chemical	CHEBI:5523	ChEBI	LHCGR	protein	P22888	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0001033								11900209	t		miannu	LHRH analogues, such as goserelin, reduce circulating concentrations of oestrogen in premenopausal women via an inhibitory effect on the hypothalamic–pituitary–ovarian axis. At the cellular level, LHRH analogues bind to LHRH receptors on pituitary gland cells, an action which causes an initial surge in the secretion of luteinizing hormone (LH). Once bound to ligand, these LHRH receptors form clusters, which are then sequestered within the cell, thereby reducing the number of unoccupied LHRH receptors.	SIGNOR-259162	0.8
IFNAR	complex	SIGNOR-C243	SIGNOR	CCL7	protein	P80098	UNIPROT	up-regulates quantity by expression				10090									32283152	f		miannu	The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages.	SIGNOR-260852	0.279
RBBP5	protein	Q15291	UNIPROT	MLL/SET subcomplex	complex	SIGNOR-C87	SIGNOR	form complex	binding			9606									24680668	t		miannu	Dimethylation of h3k4 requires a sub-complexincluding wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation.	SIGNOR-204825	0.902
CREBBP	protein	Q92793	UNIPROT	IRF9	protein	Q00978	UNIPROT	up-regulates activity	acetylation	Lys81	TGGPAVWkTRLRCAL	9606	BTO:0000007								17923090	t		lperfetto	CBP was also the most effective one among the acetyltransferases tested for catalyzing IRF9 acetylation in 293T cells. [²] Figure 5 (F) K81 acetylation is required for IRF9 dimerization between the N-terminal 1-118 and the C-terminal 340-393 regions. In the left panel, Myc-DBD (1- 118) of IRF9 was cotransfected with 118-393, 118-339, or 1-393 (FL) of IRF9 in 293T cells. Anti-IRF9 (C-terminal region) precipitates were analyzed with anti-Myc or anti-IRF9. Anti-IRF9 precipitates, prepared from 293T cells cotransfected with the C-terminal fragment 118-393 of IRF9 and Myctagged DBD of different forms, were analyzed with anti-Myc or anti-IRF9 (right panel).	SIGNOR-217787	0.368
CTH	protein	P32929	UNIPROT	L-selenocystathionine zwitterion	smallmolecule	CHEBI:62226	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000671;BTO:0000759;BTO:0002688							19961860	t		lperfetto	 the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production.	SIGNOR-275823	0.8
PRKCB	protein	P05771	UNIPROT	SLC6A9	protein	P48067-2	UNIPROT	down-regulates activity	phosphorylation	Thr276	DGIMYYLtPQWDKIL	9823									21864610	t		miannu	We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 	SIGNOR-262926	0.2
RARA	protein	P10276	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11788593	f		gcesareni	We show that retinoic acid receptor (rar)-selective ligands reduce egfr level and the magnitude and duration of egfr activation in egf-stimulated cells	SIGNOR-114087	0.405
F2RL2	protein	O00254	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256761	0.2
LAT	protein	O43561	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates activity	binding			9606					phosphorylation:Tyr161;Tyr200	DDYHNPGyLVVLPDS;SMESIDDyVNVPESG			11368773	t		lperfetto	By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.	SIGNOR-246065	0.388
BCL2	protein	P10415	UNIPROT	BECN1	protein	Q14457	UNIPROT	down-regulates	binding			9606									18570871	t		gcesareni	In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function.	SIGNOR-179084	0.731
RPS6KA2	protein	Q15349	UNIPROT	L1CAM	protein	P32004	UNIPROT	up-regulates activity	phosphorylation	Ser1152	RSKGGKYsVKDKEDT	10116	BTO:0001009								8663493	t		lperfetto	Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152.	SIGNOR-248949	0.493
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CEBPB	protein	P17676	UNIPROT	up-regulates activity	phosphorylation	Thr235	SSSSPPGtPSPADAK	9606	BTO:0000551								19723873	t		gcesareni	Phosphorylation of cebpb at thr(235) peaked at 16 hours in il-1beta-stimulated cells. The mek inhibitor u0126 inhibited this phosphorylation and reduced mmp-1 gene induction.	SIGNOR-238303	0.2
NME1	protein	P15531	UNIPROT	L1CAM	protein	P32004	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17671192	f		miannu	To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 	SIGNOR-255161	0.2
GSK3A	protein	P49840	UNIPROT	RICTOR	protein	Q6R327	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr1695	EAEAVLAtPPKQPIV	9606	BTO:0002181								25897075	t		miannu	We show that this process is dependent on glycogen synthase kinase 3 (GSK3): GSK3 was associated with rictor and directly phosphorylated the Thr-1695 site in a putative CDC4 phospho-degron motif of rictor; mutation of this site impaired the interaction between rictor and FBXW7, decreased rictor ubiquitination, and increased rictor stability. 	SIGNOR-276899	0.395
ZFPM1	protein	Q8IX07	UNIPROT	Erythrocyte_differentiation 	phenotype	SIGNOR-PH104	SIGNOR	up-regulates activity				10090	BTO:0000725								22068055	f			We here use conditional removal of the GATA-1 and FOG-1 transcription factors to identify FOG-1 as required for the formation of all committed Mk- and E-lineage progenitors, whereas GATA-1 was observed to be specifically required for E-lineage commitment.	SIGNOR-259964	0.7
CENPO	protein	Q9BU64	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265209	0.821
A4/b1 integrin	complex	SIGNOR-C162	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269011	0.7
C1QBP	protein	Q07021	UNIPROT	C1QB	protein	P02746	UNIPROT	down-regulates activity	binding							SIGNOR-C308					28018340	t		lperfetto	Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping.	SIGNOR-263403	0.346
BUB1	protein	O43683	UNIPROT	CDC20	protein	Q12834	UNIPROT	down-regulates activity	phosphorylation	Thr157	VLYSQKAtPGSSRKT	9606	BTO:0000567								15525512	t		llicata	Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. 	SIGNOR-250609	0.992
RAP1A	protein	P62834	UNIPROT	CAMK1	protein	Q14012	UNIPROT	up-regulates activity				9606									21791615	f		miannu	The present study indicates that Epac1 and Rap1 are involved in activation of CaMKI for Ser47 phosphorylation in GCM1. We found here that cAMP-dependent activation of Epac1 and Rap1 but not PKA is able to activate CaMKI to mediate Ser47 (S47) phosphorylation in GCM1. 	SIGNOR-262683	0.296
PRKACA	protein	P17612	UNIPROT	CLDN3	protein	O15551	UNIPROT	unknown	phosphorylation	Thr192	PPREKKYtATKVVYS	9606									15905176	t		llicata	Our results suggest that claudin-3 phosphorylation by pka, a kinase frequently activated in ovarian cancer, may provide a mechanism for the disruption of tjs in this cancer.	SIGNOR-137291	0.311
CSNK2A2	protein	P19784	UNIPROT	SAT1	protein	P21673	UNIPROT	unknown	phosphorylation	Ser146	FYKRRGAsDLSSEEG	-1									8954982	t		llicata	Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149.	SIGNOR-251034	0.329
MLL/SET subcomplex	complex	SIGNOR-C87	SIGNOR	MLL2 complex	complex	SIGNOR-C88	SIGNOR	form complex	binding			9606									24680668	t		miannu	The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation.	SIGNOR-204822	0.715
PRKACA	protein	P17612	UNIPROT	PRKAA2	protein	P54646	UNIPROT	down-regulates	phosphorylation	Ser173	DGEFLRTsCGSPNYA	9606									19942859	t		gcesareni	Pka associates with and phosphorylates ampk?1 At ser-173 to impede threonine thr-172 phosphorylation and thus activation of ampk1 by lkb1 in response to lipolytic signals	SIGNOR-161860	0.398
CDK2	protein	P24941	UNIPROT	RNF4	protein	P78317	UNIPROT	up-regulates activity	phosphorylation	Thr26	RTREATStPEISLEA	9606	BTO:0002181								25948581	t		miannu	Here we reported that CDK2 could phosphorylate RNF4 on T26 and T112 and enhance RNF4 E3 ligase activity, which is important for MDC1 degradation and proper HR repair during S phase. 	SIGNOR-276900	0.2
FGF2	protein	P09038	UNIPROT	HBA1	protein	P69905	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									8142649	f	Regulation	miannu	Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production.	SIGNOR-251796	0.2
PCDHA13	protein	Q9Y5I0	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-265672	0.2
MMP12	protein	P39900	UNIPROT	F12	protein	P00748	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly376	SMTRVVGgLVALRGA	-1									10930399	t		lperfetto	The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage.	SIGNOR-263611	0.335
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1675	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120100	0.316
ATM	protein	Q13315	UNIPROT	USP28	protein	Q96RU2	UNIPROT	down-regulates activity	phosphorylation	Ser495	STSTESSsQDVESTF										31938050	t		lperfetto	Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure ​Figure55D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites.|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization.	SIGNOR-275854	0.318
MLLT1	protein	Q03111	UNIPROT	AEP complex	complex	SIGNOR-C117	SIGNOR	form complex	binding			9606	BTO:0000664								20153263	t	1	miannu	These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells.	SIGNOR-239228	0.68
mTORC2	complex	SIGNOR-C2	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0000182;BTO:0000018								15718470	t		lperfetto	The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1	SIGNOR-252600	0.634
DCK	protein	P27707	UNIPROT	2'-deoxyguanosine 5'-monophosphate(2-)	smallmolecule	CHEBI:57673	ChEBI	up-regulates quantity	chemical modification												20637175	t		lperfetto	Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis	SIGNOR-275809	0.8
MAPK1	protein	P28482	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates activity	phosphorylation	Ser279	SSPTAPLsPMSPPGY	9606	BTO:0000567								9535909	t		lperfetto	These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.	SIGNOR-249402	0.595
cinolazepam	chemical	CHEBI:59514	ChEBI	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	up-regulates activity	chemical activation			9606		BTO:0000227							18790874	t	brain	lperfetto	The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005).	SIGNOR-263801	0.8
EID2	protein	Q8N6I1	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	binding			9606									14612439	t		gcesareni	In this study, we examined the effect of eid-2 on smad-mediated tgf- signaling. Here, we show that eid-2 inhibits tgf- /smad transcriptional responses. Eid-2 interacts constitutively with smad proteins, and most strongly with smad3.	SIGNOR-119171	0.406
KPNA4	protein	O00629	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	relocalization			9606									20454918	t		gcesareni	Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7.	SIGNOR-165314	0.291
PKN1	protein	Q16512	UNIPROT	ARHGEF2	protein	Q92974	UNIPROT	down-regulates	phosphorylation	Ser886	PVDPRRRsLPAGDAL	9606									14970201	t		lperfetto	Here we identify a region in the carboxyl terminus of gef-h1 that is important for suppression of its guanine nucleotide exchange activity by microtubules. This portion of the protein includes a coiled-coil motif, a proline-rich motif that may interact with src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. We show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules.	SIGNOR-122191	0.295
ALK	protein	Q9UM73	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	binding			9606	BTO:0000785								14968112	t		gcesareni	Npm-alk has been shown to activate signal transducer and activator of transcription (stat) 3, a transcriptional regulator of cyclin d3.Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1.	SIGNOR-122085	0.452
GRK2	protein	P25098	UNIPROT	SLC9A5	protein	Q14940	UNIPROT	down-regulates activity	phosphorylation	Ser712	EEEESDSsETEKEDD										21296876	t		lperfetto	Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2.	SIGNOR-275500	0.2
TBK1	protein	Q9UHD2	UNIPROT	TNIP1	protein	Q15025	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser122	KPPSSGTsSEFEVVT										36574265	t		lperfetto	TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1	SIGNOR-275733	0.383
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	RUNX3	protein	Q13761	UNIPROT	down-regulates	phosphorylation	Ser356	SSSGGDRsPTRMLAS	9606									19351720	t		lperfetto	Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation.	SIGNOR-216980	0.528
FERMT2	protein	Q96AC1	UNIPROT	FBLIM1	protein	Q8WUP2	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								26037143	t		miannu	Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. 	SIGNOR-266108	0.776
PRKCA	protein	P17252	UNIPROT	HAND1	protein	O96004	UNIPROT	unknown	phosphorylation	Ser109	KERRRTEsINSAFAE	9606									14636580	t		lperfetto	In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. 	SIGNOR-249242	0.292
PAK4	protein	O96013	UNIPROT	PXN	protein	P49023	UNIPROT	unknown	phosphorylation	Ser272	ELDELMAsLSDFKIQ	9606	BTO:0001130								20406887	t		llicata	We find that pak4 is localised at focal adhesions, is immunoprecipitated with paxillin and phosphorylates paxillin on serine 272.	SIGNOR-164889	0.522
N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-(2,6-dimethoxyphenoxy)ethanamine	chemical	CHEBI:64098	ChEBI	ADRA1A	protein	P35348	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258472	0.8
PTPN13	protein	Q12923	UNIPROT	PDCD10	protein	Q9BUL8	UNIPROT	down-regulates	dephosphorylation			9606									17657516	t		gcesareni	We also show that ccm3 directly binds to serine/threonine kinase 25 (stk25, ysk1, sok1) and the phosphatase domain of fas-associated phosphatase-1 (fap-1, ptpn13, ptp-bas, ptp-bl).	SIGNOR-157076	0.586
GOLGA3	protein	Q08378	UNIPROT	GOPC	protein	Q9HD26	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								15951434	t		miannu	Golgin-160 belongs to the golgin family of Golgi-localized proteins, which have been implicated in Golgi structure and function. PIST (also known as GOPC, CAL, and FIG) has been implicated in the trafficking of a subset of plasma membrane proteins, supporting a role of golgin-160 in vesicular trafficking. binding of golgin-160, TC10, and syntaxin-6 to PIST may coordinate membrane trafficking of some plasma membrane proteins in cell types where these proteins are expressed.	SIGNOR-261234	0.494
NEK3	protein	P51956	UNIPROT	NEK3	protein	P51956	UNIPROT	down-regulates activity	phosphorylation	Thr165	FACTYVGtPYYVPPE	-1									27489110	t		Manara	Autophosphorylation at Thr-165 is required for NEK3 kinase activity in vitro.	SIGNOR-260919	0.2
CSNK2A1	protein	P68400	UNIPROT	KDM1A	protein	O60341	UNIPROT	up-regulates activity	phosphorylation	Ser131	DESLANLsEDEYYSE	9606	BTO:0002181								25999347	t		miannu	We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites.	SIGNOR-276902	0.323
MAPK1	protein	P28482	UNIPROT	ABI1	protein	Q8IZP0	UNIPROT	up-regulates	phosphorylation	Ser183	PPTQKPPsPPMSGRG	9606									21419341	t		lperfetto	Our mass spectrometry also identified abi1 s183 and s225 on abi1 (numbering corresponds to abi1 isoform 1) as sites phosphorylated on endogenous protein and in the wildtype erk-dependent in vitro phosphorylated sample. these data indicate erk phosphorylation of abi1 is required for basal and egf-induced wrc interaction with the wrp2/3 complex.	SIGNOR-172869	0.421
RFC3	protein	P40938	UNIPROT	RF-C complex	complex	SIGNOR-C375	SIGNOR	form complex	binding												12930972	t		lperfetto	RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned 	SIGNOR-265507	0.822
LNX1	protein	Q8TBB1	UNIPROT	CLDN17	protein	P56750	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1									22889411	t		miannu	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272900	0.298
MASTL	protein	Q96GX5	UNIPROT	ENSA	protein	O43768	UNIPROT	up-regulates activity	phosphorylation	Ser67	KGQKYFDsGDYNMAK	-1									21164014	t		gcesareni	We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry.	SIGNOR-243690	0.723
PELP1	protein	Q8IZL8	UNIPROT	Rix1 complex	complex	SIGNOR-C373	SIGNOR	form complex	binding			9606	BTO:0000007								22190735	t		miannu	LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes.	SIGNOR-265469	0.792
AKT1	protein	P31749	UNIPROT	SLC2A4	protein	P14672	UNIPROT	up-regulates				9606									9415393	f	Translocation from intracellular compartment to cell surface in muscle and adipose tissue	gcesareni	Akt is not only capable of stimulating the translocation of glut4 to the cell surface. Endogenous akt is likely to play a significant physiological role in insulin-stimulated glucose uptake in insulin targets such as muscle and adipose tissue	SIGNOR-252580	0.566
ATM	protein	Q13315	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation			9606									12024016	t		gcesareni	Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner.	SIGNOR-87845	0.813
tandutinib	chemical	CHEBI:90237	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258298	0.8
MAPK1	protein	P28482	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser721	PVVSGDTsPRHLSNV	9606	BTO:0000590								10737616	t		lperfetto	Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease.	SIGNOR-249418	0.553
EGFR	protein	P00533	UNIPROT	CCDC50	protein	Q8IVM0	UNIPROT	down-regulates activity	phosphorylation	Tyr279	TDGEDADyTHFTNQQ	9606	BTO:0000567								19059208	t		miannu	We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling.	SIGNOR-262851	0.425
cabozantinib	chemical	CHEBI:72317	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207842	0.8
ATG9A	protein	Q7Z3C6	UNIPROT	YWHAE	protein	P62258	UNIPROT	up-regulates activity	binding			9606									25266655	t		miannu	Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK.	SIGNOR-266368	0.2
TWIST1	protein	Q15672	UNIPROT	CTPS1	protein	P17812	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255518	0.2
HOMER1	protein	Q86YM7	UNIPROT	SHANK1	protein	Q9Y566	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								17243894	t		miannu	It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD	SIGNOR-264243	0.735
Normorphine	chemical	CHEBI:7633	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258823	0.8
abarelix	chemical	CHEBI:337298	ChEBI	GNRHR	protein	P30968	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001033								22416801	t		miannu	 Two GnRH antagonists are currently available: abarelix and degarelix. 	SIGNOR-259159	0.8
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	BCL2	protein	P10415	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								16990763	f		gcesareni	Addition of jag-1 peptide induced ikkalpha mediated nf-kappab activation, as well as increased ppargamma expression.	SIGNOR-254344	0.2
UTS2R	protein	Q9UKP6	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257426	0.409
IL20	protein	Q9NYY1	UNIPROT	IL20RB	protein	Q6UXL0	UNIPROT	up-regulates	binding			9606									11163236	t		gcesareni	An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis.	SIGNOR-151874	0.759
RAD21	protein	O60216	UNIPROT	ERG	protein	P11308	UNIPROT	down-regulates activity	relocalization			9606	BTO:0001545								26607380	t		miannu	Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity.	SIGNOR-261515	0.2
SELPLG	protein	Q14242	UNIPROT	SELE	protein	P16581	UNIPROT	up-regulates	binding			9606	BTO:0000130								9024699	t		gcesareni	PSGL-1 was shown to mediate rolling of human neutrophils on p- and e-selectin in vitro.	SIGNOR-46330	0.763
(4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester	chemical	CHEBI:103931	ChEBI	ADRA1A	protein	P35348	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258463	0.8
GSK3B	protein	P49841	UNIPROT	CTPS1	protein	P17812	UNIPROT	down-regulates activity	phosphorylation	Ser571	RDTYSDRsGSSSPDS	9606	BTO:0000007								17681942	t		miannu	Mutation of Ser-571 demonstrated that Ser-571 was the major site phosphorylated by GSK3 in intact human embryonic kidney 293 cells by GSK3 in vitro. Furthermore, mutation of Ser-575 prevented the phosphorylation of Ser-571, suggesting that phosphorylation of Ser-575 was necessary for priming the GSK3 phosphorylation of Ser-571. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity. 	SIGNOR-276070	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation			10090	BTO:0000944								15851026	t	inferred from 70% family members	lperfetto	Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation.	SIGNOR-270108	0.2
POU5F1	protein	Q01860	UNIPROT	RARG	protein	P13631	UNIPROT	up-regulates quantity													27499297	f		SimoneGraziosi	OCT4 positively controls the level of RARgamma	SIGNOR-269222	0.307
BRAF	protein	P15056	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates quantity	relocalization			9606									19861538	f		miannu	The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression.	SIGNOR-251987	0.252
PF-03814735	chemical	CID:49830590	PUBCHEM	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205953	0.8
PTPRE	protein	P23469	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	dephosphorylation	Tyr530	FTSTEPQyQPGENL	9534									15522235	t		llicata	PTPepsilonM activated c-Src kinase probably by directly dephosphorylating phospho-Tyr527, a negative regulatory site of c-Src.	SIGNOR-238074	0.41
CAMK2A	protein	Q9UQM7	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates activity	phosphorylation	Thr160	NKLRRYTtFSKRKTG										10753652	t		llicata	Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. | Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. | The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors.	SIGNOR-250639	0.376
PML	protein	P29590	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	binding			9606									15356634	t		lperfetto	Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome.	SIGNOR-232090	0.527
PSMC2	protein	P35998	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263374	0.872
CDK1	protein	P06493	UNIPROT	TK1	protein	P04183	UNIPROT	down-regulates	phosphorylation	Ser13	LPTVLPGsPSKTRGQ	9606	BTO:0000567								12435275	t		gcesareni	Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase.	SIGNOR-95574	0.521
Endothelin-1	smallmolecule	CHEBI:80240	ChEBI	EDNRA	protein	P25101	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257482	0.8
SATB2	protein	Q9UPW6	UNIPROT	UPF3B	protein	Q9BZI7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								23925499	f		miannu	 chromatin immunoprecipitation demonstrates that SATB2 binds to the UPF3B promoter, and a luciferase reporter assay confirmed that SATB2 expression significantly activates gene transcription using the UPF3B promoter. 	SIGNOR-255137	0.341
PPP1R8	protein	Q12972	UNIPROT	PPP1CA	protein	P62136	UNIPROT	down-regulates activity	binding			-1									1322907	t			We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity.	SIGNOR-255657	0.64
CDK2	protein	P24941	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates activity	phosphorylation	Thr520	DNTPHTPtPFKNALE	9606									10593981	t		llicata	Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity.	SIGNOR-250741	0.711
pralatrexate	chemical	CHEBI:71223	ChEBI	DHFR	protein	P00374	UNIPROT	down-regulates activity	chemical inhibition			9606									23409799	t		miannu	Pralatrexate is a small molecule with a chemical formula C23H23N7O5 and a molecular weight of 477.48 g/mol (Box 1). It competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase.	SIGNOR-259353	0.8
MAP3K20	protein	Q9NYL2	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates activity	phosphorylation			9606									12220515	t		gcesareni	This result suggests that ZAK activates JNK/SAPK mediated by downstream target, MKK7	SIGNOR-243342	0.2
ERG	protein	P11308	UNIPROT	TDRD1	protein	Q9BXT4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001033								23555854	f	 	miannu	 we report that ERG and TDRD1 are co-expressed in human prostate cancers and we provide a mechanistic explanation for the observed co-expression. We demonstrate that ERG activates TDRD1 transcription by inducing loss of DNA methylation at the TDRD1 promoter-associated CpG island. 	SIGNOR-254068	0.2
CHRM5	protein	P08912	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257291	0.357
MAPK13	protein	O15264	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser25	QAFELILsPRSKESV	9606	BTO:0000782;BTO:0001271								8125092	t		gcesareni	Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase.	SIGNOR-36362	0.389
ANK2	protein	Q01484	UNIPROT	DMD	protein	P11532	UNIPROT	up-regulates quantity	relocalization			10090		BTO:0001103							19109891	t		miannu	We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4.	SIGNOR-266712	0.546
CSNK2A1	protein	P68400	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Thr382	DHYRYSDtTDSDPEN	9606									21779440	t		gcesareni	The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity	SIGNOR-89826	0.667
AKT2	protein	P31751	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates activity	binding			9606	BTO:0000222								16982699	t		gcesareni	Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.	SIGNOR-149705	0.669
AKT1	protein	P31749	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606									11108261	t		lperfetto	Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt.	SIGNOR-84971	0.757
FADS1	protein	O60427	UNIPROT	arachidonoyl-CoA	smallmolecule	CHEBI:15514	ChEBI	up-regulates quantity	chemical modification			9606									15189125	t		miannu	Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity.	SIGNOR-267911	0.8
Monobutylphthalate	chemical	CHEBI:88522	ChEBI	PPARA	protein	Q07869	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000816								16326050	t		miannu	Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast	SIGNOR-268750	0.8
MICU1	protein	Q9BPX6	UNIPROT	 MCU_MICU3_variant	complex	SIGNOR-C501	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270871	0.688
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1735	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273043	0.556
BTRC	protein	Q9Y297	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	ubiquitination			9606			SIGNOR-C5						23431053	t		gcesareni	This cascade of phosphorylation allows the binding of scfbetatrcp that promotes the ubiquitination and degradation of yap.	SIGNOR-201138	0.527
MAPK14	protein	Q16539	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									10085140	t		gcesareni	On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38.	SIGNOR-65597	0.786
CHRM1	protein	P11229	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256735	0.385
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ALYREF	protein	Q86V81	UNIPROT	up-regulates	phosphorylation	Thr219	GGGTRRGtRGGARGR	9606									18562279	t		llicata	Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export.	SIGNOR-179054	0.2
GDC-0879	chemical	CHEBI:83405	ChEBI	BRAF	protein	P15056	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192592	0.8
FUS	protein	P35637	UNIPROT	VPS16	protein	Q9H269	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			10090		BTO:0001279							28515487	f			This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease	SIGNOR-262808	0.2
PRKD2	protein	Q9BZL6	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	up-regulates activity	phosphorylation	Ser155	FPLRKTVsEPNLKLR										18692497	t	Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7	lperfetto	Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].	SIGNOR-275933	0.448
GMPS	protein	P49915	UNIPROT	guanosine 5'-monophosphate	smallmolecule	CHEBI:17345	ChEBI	up-regulates quantity	chemical modification			9606									6698284	t		miannu	The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2).	SIGNOR-267338	0.8
CADPS2	protein	Q86UW7	UNIPROT	VAMP2	protein	P63027	UNIPROT	up-regulates activity	binding			9606	BTO:0000938			SIGNOR-C346					24363652	t		miannu	 CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly.	SIGNOR-264341	0.257
MMP3	protein	P08254	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272396	0.7
CHRM5	protein	P08912	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257125	0.256
L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	precursor of			9606									31422819	t		miannu	This is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1).	SIGNOR-267516	0.8
STAT1	protein	P42224	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606									21433395	f		miannu	The signal transducer and activator of transcription (STAT) family of transcription factors transduce signals from a variety of extracellular stimuli, and are important mediators of inflammation, cell survival, differentiation, and proliferation. STATs are activated in response to growth factors, cytokines, and G-CSF binding to cell surface receptor tyrosine kinases. Although structurally similar, the seven STAT family members possess diverse biological roles. For example, STAT1 activation is pro-inflammatory and anti-proliferative, while STAT3 activation is anti-inflammatory and pro-apoptotic.	SIGNOR-263651	0.7
TP53RK	protein	Q96S44	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									17712528	t		gcesareni	The intrinsic transcriptional activity of p53 was up-regulated by a transient transfection of prpk to cos-7 cells. Prpk was shown to bind to p53 and to phosphorylate p53 at ser-15.	SIGNOR-157471	0.751
PRKN	protein	O60260	UNIPROT	SEPTIN5	protein	Q99719	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									14559152	t		miannu	SEPT5_v2 is highly homologous to another septin, SEPT5, which was recently identified as a target for parkin-mediated ubiquitination. SEPT5_v2 binds to parkin at the amino terminus and in the ring finger domains.Parkin ubiquitinates SEPT5_v2 in vitro, and both SEPT5_v1 and SEPT5_v2 accumulate in brains of patients with ARJP, suggesting that parkin is essential for the normal metabolism of these proteins. 	SIGNOR-272673	0.2
TLR9	protein	Q9NR96	UNIPROT	TICAM2	protein	Q86XR7	UNIPROT	up-regulates activity	binding			10090									22664090	t		scontino	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266750	0.412
L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	beta-alanine zwitterion	smallmolecule	CHEBI:57966	ChEBI	up-regulates quantity	precursor of			9606									22718265	t		miannu	Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate α-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of α-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce γ-aminobutyric acid (GABA), β-alanine and hypotaurine, respectively; these amine products play important role in living organisms.	SIGNOR-267547	0.8
MLXIPL	protein	Q9NP71	UNIPROT	ACACA	protein	Q13085	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000759							15496471	t		Luana	The present study provides evidence for a direct and dominant role of ChREBP in the glucose regulation of two key liver lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS)	SIGNOR-267946	0.448
MAPK1	protein	P28482	UNIPROT	MCL1	protein	Q07820	UNIPROT	up-regulates	phosphorylation	Thr163	TDGSLPStPPPAEEE	9606									12223490	t		gcesareni	We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage.	SIGNOR-92593	0.543
AKT2	protein	P31751	UNIPROT	KHSRP	protein	Q92945	UNIPROT	down-regulates	phosphorylation	Ser193	GLPERSVsLTGAPES	10116									17177604	t		lperfetto	AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRP’s ability to promote rapid mRNA decay.	SIGNOR-151220	0.351
KAT5	protein	Q92993	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	acetylation	Lys2029	NAVDDLGkSALHWAA	9606									17636029	t		gcesareni	This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60.	SIGNOR-156911	0.424
TSC1	protein	Q92574	UNIPROT	MTOR	protein	P42345	UNIPROT	down-regulates activity				9606	BTO:0000007;BTO:0001938								12271141	f		lperfetto	These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor. Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mtor)-mediated signaling to eukaryotic initiation factor 4e-binding protein 1 (4e-bp1) and ribosomal protein s6 kinase 1 (s6k1).	SIGNOR-93130	0.695
SHOX	protein	O15266	UNIPROT	NPPB	protein	P16860	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17881654	f		miannu	 The ability of SHOX to transactivate the NPPB endogenous promoter was demonstrated in luciferase reporter assays using serial deletions of the NPPB promotor region. Binding of SHOX to the NPPB promoter was also demonstrated in vivo by chromatin fixation and immunoprecipitation. We also demonstrate the lack of promoter activation in two SHOX mutants from patients with Leri-Weill syndrome. 	SIGNOR-255138	0.295
MAPK1	protein	P28482	UNIPROT	GTF2I	protein	P78347	UNIPROT	up-regulates	phosphorylation	Ser674	QSPKRPRsPGSNSKV	9606									10648599	t		lperfetto	Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation.	SIGNOR-74300	0.372
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Thr522	SSPGSPGtPGSRSRT	9606	BTO:0000590								12226093	t	The effect has been demonstrated using P10636-8	lperfetto	Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease.	SIGNOR-251600	0.695
DLG3	protein	Q92796	UNIPROT	NMDA receptor_2B	complex	SIGNOR-C348	SIGNOR	up-regulates activity	relocalization					BTO:0000227							32904533	t		lperfetto	DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses.	SIGNOR-266007	0.727
MAPK1	protein	P28482	UNIPROT	GORASP2	protein	Q9H8Y8	UNIPROT	unknown	phosphorylation	Thr225	QMAGTPItPLKDGFT	9606	BTO:0000567								11408587	t		lperfetto	Furthermore, ERK2 directly phosphorylated GRASP55 on the same residues that generated the MPM2 phospho-epitope.|The obvious next challenge is to demonstrate the precise role of these phosphorylation events.	SIGNOR-249404	0.639
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									16670091	f		lperfetto	 FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. 	SIGNOR-252910	0.2
FZD9	protein	O00144	UNIPROT	SPRY4	protein	Q9C004	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15705594	f		miannu	In NSCLC cells, Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not beta-catenin/T cell factor activity.	SIGNOR-253035	0.285
INS	protein	P01308	UNIPROT	SLC2A4	protein	P14672	UNIPROT	up-regulates activity				9606		BTO:0000887							9415393	f		lperfetto	Studies in adipose cells have demonstrated that insulin stimulates its receptor to phosphorylate tyrosine residues in irs-1, leading to activation of phosphatidylinositol 3-kinase, which plays a necessary role in mediating the translocation of the insulin-responsive glucose transporter glut4 to the cell surface.	SIGNOR-236781	0.512
CTNNBIP1	protein	Q9NSA3	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9606									10898789	t		gcesareni	We identify a novel beta-catenin-interacting protein, icat, that was found to inhibit the interaction of beta-catenin with tcf-4 and represses beta-catenin-tcf-4-mediated transactivation.	SIGNOR-79399	0.808
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	precursor of			9606									29084849	t		miannu	Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7.	SIGNOR-267530	0.8
MACF1	protein	Q9UPN3	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates quantity by destabilization				9606	BTO:0000938								16815997	f		lperfetto	In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes.	SIGNOR-227997	0.411
NR1D1	protein	P20393	UNIPROT	NR2E3	protein	Q9Y5X4	UNIPROT	up-regulates				9606									15190009	f		gcesareni	Our results show that nr1d1 (rev-erb?) Also functions as a transcriptional activator of rod genes in the presence of nr2e3	SIGNOR-125658	0.408
BMPR2	protein	Q13873	UNIPROT	BMPR1A	protein	P36894	UNIPROT	up-regulates activity	binding			10090									10712517	t		ggiuliani	Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known BMP type I receptors (BR-Ia and BR-Ib) and the BMP type II receptor (BR-II). Coimmunoprecipitation studies detected the formation of heteromeric and homomeric complexes among all the BMP receptor types even in the absence of ligand.	SIGNOR-255781	0.615
AL/b2 integrin	complex	SIGNOR-C169	SIGNOR	ICAM1	protein	P05362	UNIPROT	up-regulates activity	binding			10090	BTO:0003104								12808052	t		lperfetto	The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity.	SIGNOR-253364	0.829
CORT	protein	O00230	UNIPROT	GHSR	protein	Q92847	UNIPROT	up-regulates	binding			9606									12161511	t		gcesareni	In human tissues cst-14 as well as cst-17 but not ss-14 bind the gh secretagogue receptor (ghs-r).	SIGNOR-91134	0.484
ACSL5	protein	Q9ULC5	UNIPROT	long-chain fatty acid anion	smallmolecule	CHEBI:57560	ChEBI	down-regulates quantity	chemical modification			9606									24269233	t			ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity	SIGNOR-267713	0.8
HSP90AA1	protein	P07900	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates	binding			9606									9580552	t		miannu	The binding of hsp90 to enos enhances the activation of enos.	SIGNOR-57211	0.751
CACNA1A	protein	O00555	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606		BTO:0000227							30849329	f		miannu	Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]).	SIGNOR-264328	0.7
MECP2	protein	P51608	UNIPROT	PTPN1	protein	P18031	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000478								26214522	f		Luana	 We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models.	SIGNOR-264552	0.2
PBRM1	protein	Q86U86	UNIPROT	CRABP2	protein	P29373	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15601824	f		miannu	We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues.	SIGNOR-131552	0.432
PRKCG	protein	P05129	UNIPROT	HABP4	protein	Q5JVS0	UNIPROT	down-regulates activity	phosphorylation	Thr375	GRGARGGtRGGRGRI	9606	BTO:0004974								14699138	t		lperfetto	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249255	0.296
EGFR	protein	P00533	UNIPROT	CALM2	protein	P0DP24	UNIPROT	down-regulates	phosphorylation	Tyr100	FDKDGNGyISAAELR	9606									3415247	t		miannu	Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.	SIGNOR-266319	0.352
ULK2	protein	Q8IYT8	UNIPROT	DENND3	protein	A2RUS2	UNIPROT	up-regulates activity	phosphorylation	Ser490	ELAPRNSsLRLTDTA	9606									25925668	t		lperfetto	ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12.	SIGNOR-264733	0.2
MYC	protein	P01106	UNIPROT	PTBP1	protein	P26599	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20010808	t			We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2,	SIGNOR-268689	0.451
UBE2D1	protein	P51668	UNIPROT	TRIM2	protein	Q9C040	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								18687884	t		miannu	Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination. Together, our results indicate that TRIM2 is an ubiquitin ligase that binds to and ubiquitinates NF-L and that TRIM2 deficiency leads to neurodegeneration in mice likely by altering NF-L metabolism with consequent NF-L accumulation in axons and impairment of axonal transport.	SIGNOR-271775	0.281
LARP4B	protein	Q92615	UNIPROT	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	up-regulates				9606									20573744	f		miannu	Our data suggest LARP4B to act as a general stimulatory factor of translation, associated in poly(A)-mRNA-bound mRNP complexes. Under physiological conditions, LARP4B co-sedimented with polysomes in cellular extracts, suggesting a role in translation. In agreement with this notion, overexpression of LARP4B stimulated protein synthesis, whereas knockdown of the factor by RNA interference impaired translation of a large number of cellular mRNAs.	SIGNOR-260942	0.7
CSNK2A1	protein	P68400	UNIPROT	ATF1	protein	P18846	UNIPROT	down-regulates	phosphorylation	Ser41	SLSESEEsQDSSDSI	9606									20730097	t		lperfetto	Although the functional impact of ck-mediated atf1 phosphorylation is still unclear, we found that mutation of ser-36 and ser-41 increased cbp kix domain binding by up to four fold (fig. 2g). This result is consistent with the negative impact of ck-mediated phosphorylation on cbp binding affinity of creb that we previously reported	SIGNOR-167552	0.3
IL18	protein	Q14116	UNIPROT	IFNG	protein	P01579	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10653850	f		miannu	IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement.	SIGNOR-260860	0.48
MAPK8	protein	P45983	UNIPROT	RCSD1	protein	Q6JBY9	UNIPROT	down-regulates activity	phosphorylation	Ser83	PKFKVKSsPLIEKLQ	-1									15850461	t		miannu	CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263086	0.291
SRC	protein	P12931	UNIPROT	GIT1	protein	Q9Y2X7	UNIPROT	up-regulates activity	phosphorylation	Tyr284	EELAMDVyDEVDRRE	9534	BTO:0000298								24699139	t		miannu	Tyrosines 246 and 293 are required to hold GIT1 in a closed conformation.Hyperphosphorylation of GIT1-N by Src and pervanadate does not affect its binding in vitro to full length GIT1 proteins. Mutations Y246E and Y293E of GIT1 enhance binding to paxillin. 	SIGNOR-276627	0.559
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	PPARG	protein	P37231	UNIPROT	down-regulates activity				9606									17139329	f		fferrentino	Phosphorylation of receptor-regulated SMADs (for example, SMAD1 or SMAD3) stimulates dimer formation with SMAD4 and translocation to the nucleus, where the SMADs regulate the transcription of target gene SMAD3 binds to C/EBPs and inhibits their transcriptional activity, including their ability to transactivate the Pparg2 promoter	SIGNOR-253537	0.419
RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	HIF1A	protein	Q16665	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								19808903	t		lperfetto	We report a Notch signal-induced pathway that leads to transcriptional activation of HIF1-alpha gene.	SIGNOR-209720	0.454
AKT1	protein	P31749	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates activity	phosphorylation	Ser197	APRRRAAsMDSSSKL	10090	BTO:0004245								10217147	t			Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo.	SIGNOR-252568	0.755
GSK3B	protein	P49841	UNIPROT	GRB14	protein	Q14449	UNIPROT	down-regulates activity	phosphorylation	Ser362	QGRSGCSsQSISPMR	-1									28130417	t		lperfetto	Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3.	SIGNOR-264867	0.328
CREBBP	protein	Q92793	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates	acetylation			9606		BTO:0000887	SIGNOR-C6						10944526	t		gcesareni	Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.	SIGNOR-81050	0.599
CLK1	protein	P49759	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates	phosphorylation	Thr735	DTEWRSVtLPRDLQS	9606									18794806	t		lperfetto	Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3	SIGNOR-181031	0.261
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser525	TSMKPRSsRGSIFTF	-1									12242273	t		miannu	These results demonstrate that the effect of PKA stimulation to increase cardiac INa requires at least 2 processes: phosphorylation of consensus sites in the I-II interdomain linker, and one or more additional molecular events mediated by the kinase, that could include phosphorylation of other substrates/proteins.	SIGNOR-275991	0.2
UNII-XH2662798I	chemical	CID:16156006	PUBCHEM	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates				9606									20068082	f		gcesareni	Pf-00477736 also significantly enhances docetaxel efficacy in vitro and in vivo, in association with decreased cdc25c cytoplasmic phosphorylation (ser216) and histone h3 phosphorylation (ser10)(42).	SIGNOR-265352	0.8
5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide	chemical	CID:73755145	PUBCHEM	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258288	0.8
GSK3B	protein	P49841	UNIPROT	HSF1	protein	Q00613	UNIPROT	down-regulates	phosphorylation	Ser303	RVKEEPPsPPQSPRV	9606									8940068	t		gcesareni	Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1.	SIGNOR-44995	0.539
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser512	PPKSGDRsGYSSPGS	9606	BTO:0000590								9771888	t		lperfetto	Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. 	SIGNOR-249353	0.729
NOG	protein	Q13253	UNIPROT	BMP4	protein	P12644	UNIPROT	down-regulates	binding			9606									12700180	t		lperfetto	Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides	SIGNOR-100660	0.808
MAPKAPK2	protein	P49137	UNIPROT	RCSD1	protein	Q6JBY9	UNIPROT	down-regulates activity	phosphorylation	Ser244	PPLRRSPsRTEKQEE	-1									15850461	t		miannu	Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263080	0.491
KLF15	protein	Q9UIH9	UNIPROT	RBP3	protein	P10745	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								15277472	f		miannu	 KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. 	SIGNOR-253816	0.268
G6PC3	protein	Q9BUM1	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	down-regulates quantity	chemical modification			9606									12093795	t		miannu	Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis	SIGNOR-266570	0.8
CSNK2A1	protein	P68400	UNIPROT	CDC25B	protein	P30305	UNIPROT	up-regulates activity	phosphorylation	Ser186	EAGSGAAsSSGEDKE	-1									12527891	t		llicata	Mass spectrometry analysis demonstrates that at least two serine residues, Ser-186 and Ser-187, are phosphorylated in vivo. | Finally, we demonstrate that phosphorylation of CDC25B by protein kinase CK2 increases the catalytic activity of the phosphatase in vitro as well as in vivo. 	SIGNOR-250836	0.343
AEBP2	protein	Q6ZN18	UNIPROT	Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	form complex	binding			9606									23110252	t		lperfetto	The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48).	SIGNOR-241903	0.861
NFYC	protein	Q13952	UNIPROT	GCH1	protein	P30793	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15496512	f		miannu	Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter.	SIGNOR-252234	0.2
RORC	protein	P51449	UNIPROT	Th17	phenotype	SIGNOR-PH94	SIGNOR	up-regulates				9606									16990136	f		MARCO ROSINA	Our results demonstrate that RORgt is the transcription factor that directs the differentiation of inflammatory Th17 cells	SIGNOR-255028	0.7
Interferon-type-I	proteinfamily	SIGNOR-PF50	SIGNOR	MOV10	protein	Q9HCE1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32496609	f		miannu	Mov10 is a processing body (P-body) protein and an interferon-stimulated gene that can affect replication of retroviruses, hepatitis B virus, and hepatitis C virus (HCV).	SIGNOR-261137	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation	Ser73	VGLLKLAsPELERLI	9606	BTO:0000938								12040039	t		lperfetto	Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Thus, neuronal stress selectively activates JNK2/3 in the presence of mechanisms maintaining constitutive JNK1 activity, and this JNK2/3 activity selectively targets c-Jun, which is isolated from constitutive JNK1 activity.	SIGNOR-236149	0.2
MLL-AF4	fusion protein	SIGNOR-FP4	SIGNOR	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates				9606	BTO:0000725								21389315	f		irozzo	Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair.	SIGNOR-256650	0.7
TRAF6	protein	Q9Y4K3	UNIPROT	TICAM1	protein	Q8IUC6	UNIPROT	up-regulates	polyubiquitination			9606									20047764	t		miannu	Here, we show that the TRAF family proteins directly bind TICAM-1 and demonstrate that TRAF2 and TRAF6 bind different sites of the N-terminal TICAM-1 and accelerate its polyubiquitination. we speculate that polyubiquitination of TICAM-1 by TRAF2 and TRAF6 is required for TICAM-1 to induce IRF-3 and NF-κB activation. This is supported by the observation that polyubiquitination of TICAM-1 was required for TRAF3-binding to TICAM-1	SIGNOR-271428	0.823
PRKACA	protein	P17612	UNIPROT	SUFU	protein	Q9UMX1	UNIPROT	up-regulates	phosphorylation	Ser346	RAPSRKDsLESDSST	9606									21317289	t		gcesareni	We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation	SIGNOR-200496	0.443
PRKCD	protein	Q05655	UNIPROT	BLVRA	protein	P53004	UNIPROT	up-regulates activity	phosphorylation	Ser237	SFHFKSGsLENVPNV										22584576	t		lperfetto	LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation.	SIGNOR-275526	0.2
STAT1	protein	P42224	UNIPROT	TLR3	protein	O15455	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16628196	f		miannu	The activation of STAT1 by IFNs not only induces chemokine production, but also results in the expression of IRF-7 and TLR3, thus amplifying the dsRNA-provoked reaction in a positive-feedback manner during viral infection.	SIGNOR-255230	0.46
NLGN4Y	protein	Q8NFZ3	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								18923512	t	brain	lperfetto	Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.	SIGNOR-264190	0.2
POLR3E	protein	Q9NVU0	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266129	0.845
DUSP1	protein	P28562	UNIPROT	MAPK8	protein	P45983	UNIPROT	down-regulates	dephosphorylation			9606									9020184	t		gcesareni	Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2.	SIGNOR-46079	0.781
CSNK2A1	protein	P68400	UNIPROT	TELO2	protein	Q9Y4R8	UNIPROT	down-regulates	phosphorylation	Ser487	AQLAGSDsDLDSDDE	9606									20864032	t		lperfetto	Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. ere, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2)	SIGNOR-168036	0.2
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser235	SPQDSPPsKASPAQD	9606									21215781	t		lperfetto	Cdk5 regulates app (amyloid precursor protein) processing and tau hyperphosphorylationtau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules	SIGNOR-171018	0.754
LE-TGN SNARE	complex	SIGNOR-C157	SIGNOR	IGF2R	protein	P11717	UNIPROT	up-regulates activity	relocalization			9606									18195106	t		lperfetto	These findings place the retromer complex upstream of both STX10 function and the GCC185 tethering complex in MPR transport. Together, our data suggest that STX10, STX16, Vti1a, and VAMP3 are important for the trafficking of both CD- and CI-MPRs.|Thus, MPRs must pass through a compartment of pH ≤ 5.5 before returning to the Golgi to carry out their biological function.	SIGNOR-253083	0.465
UV stress	stimulus	SIGNOR-ST7	SIGNOR	CDKN2A	protein	P42771	UNIPROT	up-regulates				9606									11830546	f		miannu	The expression of the melanoma susceptibility gene product p16 is increased after UVR both in epidermally derived cell lines and in human skin. The increased expression of p16 after exposure to suberythemal doses of UVR is potentiated by α-MSH, a ligand for MC1R, and this effect is mimicked by cAMP, the intracellular mediator of α-MSH signaling via the MC1 receptor.	SIGNOR-252376	0.7
PIM1	protein	P11309	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									16403219	t		miannu	Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.	SIGNOR-250390	0.379
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser713	GAEIVYKsPVVSGDT	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-251591	0.695
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	MAPK6	protein	Q16659	UNIPROT	up-regulates	phosphorylation	Ser688	QFHSPVGsPLKSIQA	9606									20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.	SIGNOR-216801	0.373
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	NFKB1	protein	P19838	UNIPROT	up-regulates activity	ubiquitination			9534	BTO:0004055								11295495	t		lperfetto	The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk.	SIGNOR-217190	0.501
BCAR1	protein	P56945	UNIPROT	EGR1	protein	P18146	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								22431919	f		miannu	In MCF-7 cells, we identified a positive feedback loop where p130(Cas) positively regulates EGR1 and NAB2, which in turn induce p130(Cas) expression.	SIGNOR-253892	0.2
CASP9	protein	P55211	UNIPROT	Apoptosome	complex	SIGNOR-C230	SIGNOR	form complex	binding			-1									10206961	t		lperfetto	 APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9. 	SIGNOR-256429	0.915
CDK8	protein	P49336	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2516	FLTPSPEsPDQWSSS	-1									25344755	t		lperfetto	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273177	0.534
MKNK1	protein	Q9BUB5	UNIPROT	SPRY2	protein	O43597	UNIPROT	down-regulates	phosphorylation	Ser112	APLSRSIsTVSSGSR	9606									19864419	t		llicata	The spry2/nedd4 association involves the ww domains of nedd4 and requires phosphorylation of the mnk2 kinase sites, ser(112) and ser(121), on spry2. mnk2 silencing decreased spry2-nedd4 interactions and also augmented the ability of spry2 to inhibit fibroblast growth factor signaling. endogenous and overexpressed nedd4 polyubiquitinate spry2 via lys(48) on ubiquitin and decrease its stability.	SIGNOR-188889	0.509
SYMPK	protein	Q92797	UNIPROT	mRNA_polyadenylation	phenotype	SIGNOR-PH200	SIGNOR	up-regulates				9606									16230528	f		lperfetto	Reconstitution experiments reveal that symplekin, previously shown to be necessary for cytoplasmic poly(A) tail elongation and translational activation of mRNAs during Xenopus oocyte maturation, is the essential heat-labile component. 	SIGNOR-268368	0.7
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Thr1097	SMIRTGEtPTKKRGI	9606	BTO:0001938								11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130.	SIGNOR-104695	0.843
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	RAR	proteinfamily	SIGNOR-PF45	SIGNOR	up-regulates activity	chemical activation			9606									17132853	t		miannu	The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 	SIGNOR-256197	0.8
IL1B	protein	P01584	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity				9606	BTO:0002417								32454942	f		miannu	IL-1β, an inflammatory cytokine primarily expressed in activated macrophages, monocytes, and microglia, significantly contributes to MS development. IL-1β promotes differentiation of T cells into Th17 cells via the STAT3 pathway and thereby promotes and aggravates the inflammatory environment in the CNS	SIGNOR-263820	0.572
PTEN	protein	P60484	UNIPROT	EGR2	protein	P11161	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11494141	f		miannu	Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 	SIGNOR-260049	0.311
Cy3-bifunctional dye zwitterion	chemical	CHEBI:37990	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. 	SIGNOR-257858	0.8
AML1-ETO	fusion protein	SIGNOR-FP1	SIGNOR	PTGS2	protein	P35354	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004850								23645839	f		miannu	 AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells.	SIGNOR-255683	0.2
IMP	smallmolecule	CHEBI:17202	ChEBI	5'-xanthylic acid	smallmolecule	CHEBI:15652	ChEBI	up-regulates quantity	precursor of			9606									19480389	t		miannu	IMPDH controls the gateway to guanine nucleotides, making it an “enzyme of consequence” for virtually every organism. Humans and other mammals have two IMPDH genes, encoding hIMPDH1 and hIMPDH2. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS).	SIGNOR-267330	0.8
SSTR4	protein	P31391	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256823	0.425
AMPK	complex	SIGNOR-C15	SIGNOR	WDR45	protein	Q9Y484	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0001938								28561066	t		miannu	WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes.	SIGNOR-268480	0.318
HOXB8	protein	P17481	UNIPROT	MYLK	protein	Q15746	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0002196								15886193	t		Luana	Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively	SIGNOR-261640	0.2
MAPK8	protein	P45983	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Ser307	TRRSRTEsITATSPA	9606		BTO:0000887;BTO:0001103							14579029	t		gcesareni	Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1.	SIGNOR-118857	0.767
PPP3CA	protein	Q08209	UNIPROT	Calcineurin	complex	SIGNOR-C155	SIGNOR	form complex	binding			9606									14623295	t		miannu	Calcineurin is a heterodimer consisting of a catalytic subunit with a molecular mass of about 59 kDa (calcienurin A or CNA) and a regulatory subunit with a molecular mass of 19 kDa (calcineurin B or CNB). 	SIGNOR-255291	0.953
sunitinib	chemical	CHEBI:38940	ChEBI	CSF1R	protein	P07333	UNIPROT	down-regulates activity	chemical inhibition			9606									17367763	t		miannu	Sunitinib (SU-11248, Sutent) inhibits at least eight receptor protein-tyrosine kinases including vascular endothelial growth factor receptors 1-3 (VEGFR1-VEGFR3), platelet-derived growth factor receptors (PDGFRalpha and PDGFRbeta), stem cell factor receptor (Kit), Flt-3, and colony-stimulating factor-1 receptor (CSF-1R). 	SIGNOR-259319	0.8
CBX1	protein	P83916	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	binding			9606							methylation:Lys10	RTKQTARkSTGGKAP	19111658	t		miannu	 A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 	SIGNOR-264491	0.2
RACGAP1	protein	Q9H0H5	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260512	0.569
ORC2	protein	Q13416	UNIPROT	ORC	complex	SIGNOR-C419	SIGNOR	form complex	binding			9606									32808929	t		lperfetto	The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA	SIGNOR-267566	0.97
AURKA	protein	O14965	UNIPROT	DLGAP5	protein	Q15398	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser830	QEHARHIsFGGNLIT	9606	BTO:0000007								15987997	t		miannu	Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life.	SIGNOR-262652	0.741
AGTR1	protein	P30556	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257223	0.477
Cortistatin14	smallmolecule	CID:16133803	PUBCHEM	MRGPRX2	protein	Q96LB1	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257544	0.8
PPP2CB	protein	P62714	UNIPROT	KRT8	protein	P05787	UNIPROT	unknown	dephosphorylation	Ser432	SAYGGLTsPGLSYSL	9606	BTO:0000182								16554440	t			K8 Ser431-P is a physiologic substrate to PP2A during hyposmotic conditions and possibly other biologic contexts.	SIGNOR-248588	0.2
GATAD2B	protein	Q8WXI9	UNIPROT	MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263857	0.775
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	AX/b2 integrin	complex	SIGNOR-C171	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259026	0.413
ABL1	protein	P00519	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates quantity	phosphorylation	Tyr88	KGSLPEFyYRPPRPP	9606	BTO:0000007;BTO:0000567								17254966	t		gcesareni	A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL	SIGNOR-245293	0.578
ARID3A	protein	Q99856	UNIPROT	Immunoglobulin delta heavy chain	protein	P0DOX3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								16738337	t		lperfetto	In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels.| Figure ​3 shows that both anti-Bright and anti-TFII-I precipitated the bf150 Bright binding site from the B-cell line but not from a T-cell line that contains but does not express the V1 gene.	SIGNOR-268531	0.2
TOP2B	protein	Q02880	UNIPROT	PBX3	protein	P40426	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24463367	f		lperfetto	While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development	SIGNOR-242308	0.2
CASP6	protein	P55212	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates activity	cleavage	Asp345	EEWEAQRdSHLGPHR	-1									10069390	t		lperfetto	Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.	SIGNOR-261759	0.379
NR0B2	protein	Q15466	UNIPROT	ESR2	protein	Q92731	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									10648597	f		gcesareni	These novel insights provide a mechanistic explanation for the inhibitory role of shp in nuclear receptor signaling, and they may explain how shp functions as a negative coregulator or corepressor for ligand-activated receptors, a novel and unique function for an orphan nuclear receptor.	SIGNOR-74291	0.609
PLAAT3	protein	P53816	UNIPROT	PPP2CA	protein	P67775	UNIPROT	down-regulates				9606									17374643	f		miannu	The alpha-isoform of the regulatory subunit a of protein phosphatase 2a (pr65alpha) as a new interaction partner of hrsl3 / we demonstrate that hrsl3 binds to the endogenous pr65alpha, thereby partially sequestering the catalytic subunit pr36 from the pr65 protein complex, and inhibiting pp2a catalytic activity.	SIGNOR-153772	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	DAGLA	protein	Q9Y4D2	UNIPROT	down-regulates activity	phosphorylation	Ser808	RSIRGSPsLHAVLER										23502535	t		lperfetto	Activated CaMKII interacted with the C-terminal domain of DGLalpha, phosphorylated two serine residues and inhibited DGLalpha activity. |CaMKIIalpha phosphorylates DGLalpha at Ser808 and Ser782	SIGNOR-275540	0.2
RACK1	protein	P63244	UNIPROT	PPP2CA	protein	P67775	UNIPROT	up-regulates activity	binding			9606									24726876	t		miannu	RACK1 Mediates the Formation of the IRF3-RACK1-PP2A Complex and Promotes the Dephosphorylation of IRF3.Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection.	SIGNOR-260945	0.2
YARS1	protein	P54577	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									16429158	t		miannu	YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr	SIGNOR-270521	0.8
ITGB1	protein	P05556	UNIPROT	Av/b1 integrin	complex	SIGNOR-C175	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253202	0.829
PPP4C	protein	P60510	UNIPROT	BANF1	protein	O75531	UNIPROT	up-regulates	dephosphorylation	Ser4	sQKHRDFV	9606									24265311	t		lperfetto	Herein, we demonstrate we demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. We have identified the major phosphatase responsible for dephosphorylation of ser-4 to be protein phosphatase 4 catalytic subunit.	SIGNOR-203281	0.2
PTPN3	protein	P26045	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates activity	dephosphorylation	Tyr537	CKNVVPLyDLLLEML	9606									26079946	t		miannu	Our recent studies further demonstrated that PTPH1 dephosphorylates estrogen receptor at Y537, increases estrogen receptor stability and nuclear accumulation, and enhances breast cancer sensitivity to anti-estrogens [ ].	SIGNOR-277127	0.2
PAK1	protein	Q13153	UNIPROT	NLRP3	protein	Q96P20	UNIPROT	up-regulates activity	phosphorylation	Thr659	KIEINLStRMDHMVS	9606	BTO:0002181								33432150	t		miannu	Pak1 phosphorylates NLRP3 to promote inflammasome activation.	SIGNOR-277547	0.2
Ethylketocyclazocine	chemical	CHEBI:4901	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258799	0.8
YES1	protein	P07947	UNIPROT	SOCS1	protein	O15524	UNIPROT	down-regulates activity	phosphorylation	Tyr80	LLDACGFyWGPLSVH	-1									31101761	t		miannu	SOCS1 is phosphorylated on Y80 by SRC family kinase members SRC and YES1. 	SIGNOR-276858	0.2
AKT2	protein	P31751	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									10949026	t		gcesareni	Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155.	SIGNOR-81110	0.504
MAPK1	protein	P28482	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates				9606	BTO:0000801								11842088	f		gcesareni	In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation.	SIGNOR-114771	0.488
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ADAR	protein	P55265	UNIPROT	down-regulates activity	phosphorylation	Thr1033	RLGERLRtMSCSDKI	-1									31095429	t		miannu	AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively, and overexpression of the phosphomimic mutants ADAR1p110 (T738D) and ADAR2 (T553D) resulted in a 50-100% reduction in editase activity. 	SIGNOR-266357	0.2
IKK-complex	complex	SIGNOR-C14	SIGNOR	CYLD	protein	Q9NQC7	UNIPROT	down-regulates activity	phosphorylation	Ser418	TTENRFHsLPFSLTK	9606	BTO:0000661								15870263	t		gianni	In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits.	SIGNOR-266435	0.615
VARS1	protein	P26640	UNIPROT	tRNA(Val)	smallmolecule	CHEBI:29183	ChEBI	down-regulates quantity	chemical modification			9606									30755602	t		miannu	Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 	SIGNOR-270525	0.8
PPARG	protein	P37231	UNIPROT	ARNTL	protein	O00327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									19041764	t		miannu	 Rosiglitazone treatment induced aortic expression of Bmal1 mRNA, and ChIP and promoter assays revealed that Bmal1 is a direct PPARgamma target gene. These studies have uncovered a role for vascular PPARgamma as a peripheral factor participating in regulation of cardiovascular rhythms.	SIGNOR-268026	0.409
GNB5	protein	O14775	UNIPROT	ADCY5	protein	O95622	UNIPROT	down-regulates activity	binding			9606	BTO:0004032								21303898	t		miannu	The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC	SIGNOR-264998	0.432
MTOR	protein	P42345	UNIPROT	ELP1	protein	O95163	UNIPROT	up-regulates activity	phosphorylation	Ser1174	SETSSVVsGSEMSGK										29925953	t		lperfetto	Human ELP1 S1174 phosphorylation was triggered by insulin treatment, as shown by the specific phosphorylated (p)ELP1 (S1174) antibody, and addition of a phosphorylation-mutant variant of the ELP1 protein (ELP1(S1174A)) to ELP1-depleted BRAFV600E melanoma cells failed to rescue cell survival |In line with these findings, mTORC2 activity, but not mTORC1, was required for the insulin-induced phosphorylation of Elp1 S1174	SIGNOR-275541	0.2
KANSL1	protein	Q7Z3B3	UNIPROT	NSL histone acetyltransferase	complex	SIGNOR-C413	SIGNOR	form complex	binding			9606	BTO:0000007								20018852	t		miannu	Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex.	SIGNOR-267164	0.658
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	SLBP	protein	Q14493	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr62	RRPESFTtPEGPKPR	9606	BTO:0000567								18490441	t		lperfetto	Phosphorylation of threonine 61 by cyclin a/Cdk1 triggers degradation of stem-loop binding protein at the end of S phase	SIGNOR-265259	0.421
PI3K	complex	SIGNOR-C156	SIGNOR	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9534	BTO:0004055								14665640	f		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-252706	0.7
PTK6	protein	Q13882	UNIPROT	ARAP1	protein	Q96P48	UNIPROT	up-regulates activity	phosphorylation	Tyr231	PEFDDSDyDEVPEEG	9606	BTO:0000007								20554524	t		miannu	ARAP1 associated with PTK6 in an EGF/EGF receptor (EGFR)-dependent manner. In addition, the SH2 domain of PTK6, particularly the Arg(105) residue that contacts the phosphate group of the tyrosine residue, was essential for the association. Moreover, PTK6 phosphorylated residue Tyr(231) in the N-terminal domain of ARAP1. Expression of ARAP1, but not of the Y231F mutant, inhibited the down-regulation of EGFR in HEK293 cells expressing PTK6. These results demonstrate that PTK6 enhances EGFR signaling by inhibition of EGFR down-regulation through phosphorylation of ARAP1 in breast cancer cells.	SIGNOR-263188	0.463
ROBO	proteinfamily	SIGNOR-PF14	SIGNOR	CCND2	protein	P30279	UNIPROT	down-regulates	phosphorylation	Thr280	DELDQAStPTDVRDI	9606									17486076	t		lperfetto	These results indicate that cyclin d2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by thr280 phosphorylation by gsk3beta or p38	SIGNOR-154672	0.2
DNA-PK	complex	SIGNOR-C107	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									10854421	f		miannu	The DNA-dependent protein kinase (DNA-PK), consisting of Ku and the DNA-PK catalytic subunit (DNA-PKcs), and the DNA ligase IV-XRCC4 complex function together in the repair of DNA double-strand breaks by non-homologous end joining.	SIGNOR-264531	0.7
GRK1	protein	Q15835	UNIPROT	GRK1	protein	Q15835	UNIPROT	down-regulates activity	phosphorylation	Ser491	IQDVGAFsTVKGVAF	-1									1527025	t			The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase.	SIGNOR-251187	0.2
DCC	protein	P43146	UNIPROT	CACNA1C	protein	Q13936	UNIPROT	up-regulates activity				9606									12827203	t		miannu	DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER.	SIGNOR-268291	0.2
SLBP	protein	Q14493	UNIPROT	H2BC11	protein	P06899	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265381	0.2
CKM complex	complex	SIGNOR-C406	SIGNOR	E2F1	protein	Q01094	UNIPROT	down-regulates activity	phosphorylation	Ser375	PVDEDRLsPLVAADS	9606									22945643	t		lperfetto	Cdk8 regulates e2f1 transcriptional activity through s375 phosphorylation.	SIGNOR-273138	0.37
SALL4	protein	Q9UJQ4	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000356								23954296	f		miannu	 Our shRNA-mediated SALL4 knockdown system and SALL4 overexpression system revealed that SALL4 suppresses the expression of adhesion gene CDH1, and positively regulates the CDH1 suppressor ZEB1. 	SIGNOR-255124	0.31
DCC-2036	chemical	CHEBI:62166	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191313	0.8
CAD	protein	P27708	UNIPROT	L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	down-regulates quantity	chemical modification			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-267418	0.8
APOH	protein	P02749	UNIPROT	cardiolipin	smallmolecule	CHEBI:28494	ChEBI	down-regulates quantity by destabilization	binding			9606									9596664	t		lperfetto	The most relevant physiological role of beta2GPI is supposed to be the regulation of the function of anionic phospholipids like cardiolipin (CL). |Anticardiolipin antibodies or lupus anticoagulants are strongly associated with thrombosis. In these autoimmune diseases with anti-phospholipid antibody syndrome, beta2GPI is a cofactor in the recognition of the phospholipid antigen, CL, by anti-CL antibodies.	SIGNOR-266998	0.8
AKT1	protein	P31749	UNIPROT	ZYX	protein	Q15942	UNIPROT	down-regulates	phosphorylation	Ser142	PQPREKVsSIDLEID	9606									17572661	t		llicata	Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus zyxin is a substrate of caspases, but akt phosphorylation fails to protect its proteolytic degradation	SIGNOR-156122	0.427
DFFB	protein	O76075	UNIPROT	DNA_fragmentation	phenotype	SIGNOR-PH22	SIGNOR	up-regulates				9606	BTO:0000661								9422513	f	Cleavage of ICAD/DFF-45	amattioni	The specific cleavage of icad/dff-45 by caspase-3 relieves the inhibition and promotes the endonuclease activity of cad, resulting in apoptotic dna fragmentation	SIGNOR-54358	0.7
NGF	protein	P01138	UNIPROT	GCH1	protein	P30793	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0001676								16190874	f		miannu	We examined intracellular signals required for NGF-induced expression of the GCH gene in PC12D cells. The activity of GCH was increased up to 5-fold after the NGF treatment. The human GCH promoter activity was significantly enhanced by NGF treatment. 	SIGNOR-252228	0.252
MAPK8	protein	P45983	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates activity	phosphorylation	Ser71	SRRSGLCsPSYVAVT	9606	BTO:0000007;BTO:0000567								10551811	t		lperfetto	The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71.	SIGNOR-236384	0.574
TNFRSF21	protein	O75509	UNIPROT	ROS	stimulus	SIGNOR-ST2	SIGNOR	down-regulates				9606									32454942	f		miannu	Further, data from our laboratories indicate that selective agonism of TNFR2 rescues neurons from oxidative stress-induced cell death [160] and excitotoxic cell death [161, 162]. Similarly, TNFR2 activation induces expression of antiapoptotic and detoxifying proteins and protects OPCs against oxidative stress.	SIGNOR-263830	0.7
IRF2	protein	P14316	UNIPROT	CIITA	protein	P33076	UNIPROT	up-regulates quantity by expression	transcriptional regulation												11464288	t		lperfetto	In addition to IRF-1, IRF-2, another member of the IRF family, also activates the human CIITA type IV promoter, and IRF-2 cooperates with IRF-1 to activate the promoter in transient transfection assays.	SIGNOR-271681	0.506
ACAN	protein	P16112	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									10922468	t		lperfetto	Degradation of aggrecan, the major proteoglycan of the cartilage ECM responsible for the load-bearing and elastic properties of this tissue, is one of the earliest detectable events in arthritic cartilage degeneration. MMPs have been implicated in proteolysis and the subsequent loss of aggrecan from cartilage during arthritis	SIGNOR-266982	0.7
HERPUD1	protein	Q15011	UNIPROT	HSPA5	protein	P11021	UNIPROT	up-regulates quantity by stabilization	relocalization			9606									29295953	t		miannu	A key inhibitor of the turnover and Nt-arginylation of BiP was HERP (homocysteine-responsive ER protein), a 43-kDa ER membrane-integrated protein that is an essential component of ER-associated protein degradation. 	SIGNOR-261346	0.423
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									17339337	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability. We have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-153463	0.784
PRKACA	protein	P17612	UNIPROT	HRH1	protein	P35367	UNIPROT	down-regulates	phosphorylation	Ser398	WKRLRSHsRQYVSGL	9606									15328002	t		gcesareni	Two amino acid residues (ser396, ser398) on hr1 were determined to be pkc phosphorylation sites by in vitro phosphorylation studies.Site-directed mutagenesis studies suggests that the ser398 residue was primarily involved in pkc-mediated desensitization. Possibly, phosphorylation of the residues is required for receptor transport from endosomes to lysosomes.	SIGNOR-128415	0.2
IL12A	protein	P29459	UNIPROT	T_cell_activation	phenotype	SIGNOR-PH73	SIGNOR	up-regulates				9606									10653850	f		miannu	IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement.	SIGNOR-260966	0.7
PRKCA	protein	P17252	UNIPROT	SHOC2	protein	Q9UQ13	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr71	VAFSVDNtIKRPNPA										29383184	t		lperfetto	PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8.	SIGNOR-275568	0.2
HEY2	protein	Q9UBP5	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	binding			9606									16682003	t	The NotchIC-RBP-Jkappa complex activates target genes, such as those encoding the Hrt and Hes families. The interaction did not interfere with the formation or DNA-binding of the NotchIC-RBP-Jkappa complex, indicating direct inhibition by Hrt and Hes as co-repressors.	gcesareni	Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression.	SIGNOR-146690	0.759
CDK1	protein	P06493	UNIPROT	TPX2	protein	Q9ULW0	UNIPROT	down-regulates activity	phosphorylation	Thr72	NLQQAIVtPLKPVDN	-1									25688093	t		lperfetto	In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle	SIGNOR-265096	0.622
STAT6	protein	P42226	UNIPROT	MRC1	protein	P22897	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20508200	f		lperfetto	Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation.	SIGNOR-249535	0.406
TRAF2	protein	Q12933	UNIPROT	BIRC3	protein	Q13489	UNIPROT	up-regulates	binding			9606									18621737	t		gcesareni	A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution.	SIGNOR-179452	0.888
AURKA	protein	O14965	UNIPROT	FADD	protein	Q13158	UNIPROT	up-regulates	phosphorylation	Ser203	MSWNSDAsTSEAS	9606									21978935	t		lperfetto	Here, we report that aur-a phosphorylates s203 of the fas associated with death domain protein (fadd)phosphorylation of s203 by aur-a serves to prime fadd for plk1-mediated phosphorylation at s194	SIGNOR-176739	0.35
hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	GABA-A (a6-b1-g2) receptor	complex	SIGNOR-C334	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000938								26136660	t		miannu	The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 	SIGNOR-264927	0.8
U0126	chemical	CHEBI:90693	ChEBI	MAPK7	protein	Q13164	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000938	BTO:0000142							11160424	t		gcesareni	Pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity and neuronal survival. Interestingly, erk5 activation by egf in cos7 cells is also blocked by these inhibitors suggesting that the erk5 pathway may also regulate cellular processes credited previously to erk1/2.	SIGNOR-104945	0.8
NLGN4X	protein	Q8N0W4	UNIPROT	NRXN2	protein	P58401	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264160	0.76
PHF12	protein	Q96QT6	UNIPROT	SIN3A	protein	Q96ST3	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								11390640	t		miannu	Pf1 interacts with mSin3A in vivo. Gal4-Pf1 repressed activity of the reporter gene fivefold relative to Gal4 alone (Fig. ​(Fig.5A),5A), suggesting that DNA-bound Pf1 was capable of recruiting functional mSin3A complexes.	SIGNOR-266995	0.787
MAPK10	protein	P53779	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser38	SVPEFPLsPPKKKDL	9606									20630875	t		gcesareni	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress.	SIGNOR-166690	0.307
TSLP	protein	Q969D9	UNIPROT	CRLF2	protein	Q9HC73	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0000876								11418668	t		gcesareni	Human tslp is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human tslp receptor and the il-7r alpha-chain.	SIGNOR-108920	0.922
F2	protein	P00734	UNIPROT	F2R	protein	P25116	UNIPROT	up-regulates activity	cleavage	Arg41	TNATLDPrSFLLRNP	-1									10978167	t		lperfetto	Thrombin cleaved PAR1E at the Arg41-Ser42 activation site at concentrations known to induce cellular activation, supporting a native conformation of the recombinant polypeptide. 	SIGNOR-263569	0.883
BCHE	protein	P06276	UNIPROT	acetylcholine	smallmolecule	CHEBI:15355	ChEBI	down-regulates quantity	chemical modification												15841900	t			The other subgroup, butyrylcholinesterase (BuChE) (or acyl- choline acyl-hydrolase, EC 3.1.1.8) also known as plasma, serum, benzoyl, false, butyryl, nonspecific, or type II ChE. BuChE exists in plasma and has more than eleven isoenzy- me variants. BuChE is also present in liver, smooth muscle, intestines, pancreas, heart and white matter of brain |It hydrolyzes butyrylcholine 4 times more rapidly than acetylcholine. 	SIGNOR-253982	0.8
DYRK2	protein	Q92630	UNIPROT	CARHSP1	protein	Q9Y2V2	UNIPROT	unknown	phosphorylation	Ser32	RSRERSPsPLRGNVV	9606		BTO:0000671							15910284	t		lperfetto	Dyrk2 (dual-specificity tyrosine-phosphorylated and -regulated protein kinase 2) phosphorylated crhsp24 at ser30, ser32 and ser41 in vitro, and ser41 was identified as a site phosphorylated in cells.	SIGNOR-137478	0.263
NFE2	protein	Q16621	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000426								16287851	f	Regulation of expression	miannu	NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells.	SIGNOR-251839	0.493
MAPK1	protein	P28482	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates activity	phosphorylation	Thr125	PEVLRPEtPRPVDIG	9606									12792650	t		lperfetto	Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK	SIGNOR-101544	0.55
SLC9A2	protein	Q9UBY0	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265601	0.8
vincaleukoblastine sulfate	chemical	CHEBI:9984	ChEBI	TUBD1	protein	Q9UJT1	UNIPROT	down-regulates activity	chemical inhibition			9606									15579115	t		miannu	Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. 	SIGNOR-259257	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	CHKA	protein	P35790	UNIPROT	up-regulates activity	phosphorylation	Ser279	KKLHKLLsYNLPLEL	9606	BTO:0000527								34929314	t		lperfetto	Glucose deprivation induces the binding of choline kinase α2 (CHKα2) to lipid droplets, followed by a continuous PTMs to promote lipolysis of lipid droplets, which are in turn mediated by AMPK-dependent CHKα2 Serine 279 phosphorylation and KAT5-dependent CHKα2 Lysine 247 acetylation. 	SIGNOR-267647	0.2
RPS6KB1	protein	P23443	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser287	SMSSCGSsGYFSSSP	9606									22017876	t		llicata	Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation.	SIGNOR-176862	0.659
TAF4	protein	O00268	UNIPROT	ATF7	protein	P17544	UNIPROT	down-regulates activity	binding			9534	BTO:0004055								15735663	t		miannu	These results not only demonstrate an interaction between ATF7 and TAF4 but also indicate, as in the case of TAF12 (see Figure 3e), that no additional cellular component is required for this binding. They also suggest that TAF4 may interfere with the formation of ATF7–TAF12 subcomplexes, thereby inhibiting ATF7-induced transactivation.	SIGNOR-225300	0.406
PPP2CA	protein	P67775	UNIPROT	CILK1	protein	Q9UPZ9	UNIPROT	down-regulates	dephosphorylation	Thr157	IRSKPPYtDYVSTRW	9606	BTO:0002181								15988018	t		lperfetto	In addition, mass spectrometry showed that pp2a treatment completely abolished the dually phosphorylated form, leaving only the singly phosphorylated form (data not shown). We conclude that a portion of ick in unstimulated and asynchronized hek293t cells is dually phosphorylated on the tdy motif.	SIGNOR-138428	0.2
CAMK2D	protein	Q13557	UNIPROT	Myoblast_fusion	phenotype	SIGNOR-PH98	SIGNOR	up-regulates				9606									19725819	f		areggio	In the cytoplasm where the activated CaMKII localises it induces signalling pathways that are mainly involved in mitochondrial biogenesis and expression of contractile protein	SIGNOR-255955	0.7
CHIR-98014	chemical	CID:53396311	PUBCHEM	GSK3A	protein	P49840	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190985	0.8
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1763	TPTSPSYsPTSPSYS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248789	0.441
PFAS	protein	O15067	UNIPROT	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	up-regulates quantity	chemical modification			9606									33179964	t		miannu	The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure.	SIGNOR-267312	0.8
CDK1	protein	P06493	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Ser249	AVIPINGsPRTPRRG	9606									1756735	t		lperfetto	The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2.	SIGNOR-21548	0.675
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser250	TGSPAELsPTTLSPV	9606		BTO:0000763							12193595	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-91734	0.739
CNTF	protein	P26441	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates	binding			9606									9143707	t		gcesareni	Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2.	SIGNOR-47991	0.669
PRKACA	protein	P17612	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser275	LSAFRRTsLAGGGRR	9606		BTO:0000887							20151718	t		miannu	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163752	0.278
EGFR	protein	P00533	UNIPROT	PLD2	protein	O14939	UNIPROT	up-regulates activity	phosphorylation	Tyr179	RLLTMSFyRNYHAMT	9606									9837959	t		llicata	Using transiently transfected human embryonic kidney fibroblasts (HEK293), we demonstrate here that PLD1 activity, and to a lesser extent PLD2 activity, is stimulated in response to epidermal growth factor (EGF). PLD2, but not PLD1, associates with the EGF receptor in a ligand-independent manner and becomes tyrosine-phosphorylated upon EGF receptor activation. Tyrosine 11 (Tyr-11) of PLD2 was identified as the specific phosphorylation site. Mutation of this residue to phenylalanine enhanced basal activity almost 2-fold	SIGNOR-251095	0.532
MAPK1	protein	P28482	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates	phosphorylation	Ser38	EGRQPSPsPSPTERA	9606	BTO:0001271								15093545	t	The effect has been demonstrated using P29590-4	gcesareni	We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3).	SIGNOR-124244	0.366
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	DOCK6	protein	Q96HP0	UNIPROT	up-regulates activity	phosphorylation	Ser1194	GQRSRLAsMLDSDTE										23462102	t		lperfetto	Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching	SIGNOR-275667	0.2
QRICH1	protein	Q2TAL8	UNIPROT	IARS1	protein	P41252	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269406	0.2
AP-2 complex	complex	SIGNOR-C245	SIGNOR	AAK1	protein	Q2M2I8	UNIPROT	up-regulates activity	binding			10116	BTO:0000142								15496985	t		Giorgia	We therefore characterised protein ligands using liquid chromatography tandem mass spectrometry (LC‐MS/MS) and confirmed this using Western blotting to recognise both major and minor bands. Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs	SIGNOR-260393	0.64
ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	P2RY4	protein	P51582	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257564	0.8
PHLPP1	protein	O60346	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0000527								15808505	t		gcesareni	Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth.	SIGNOR-252601	0.752
PAK1	protein	Q13153	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Ser339	PRGQRDSsYYWEIEA	9606									18775988	t		gcesareni	P21-activated protein kinases (paks) are serine/threonine protein kinases that phosphorylate raf-1 at ser-338 and ser-339.	SIGNOR-180812	0.584
FYN	protein	P06241	UNIPROT	BCR-Mk	complex	SIGNOR-C433	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000776								32323266	t		scontino	The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases.	SIGNOR-268207	0.619
USP9X	protein	Q93008	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	deubiquitination	Lys519	DYPRQSIkETPCWIE	9606									19135894	t		gcesareni	Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4.	SIGNOR-183285	0.633
3,5-diiodo-L-tyrosine	smallmolecule	CHEBI:15768	ChEBI	L-alanine zwitterion	smallmolecule	CHEBI:57972	ChEBI	up-regulates quantity	precursor of			9606									28153798	t		scontino	The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines.	SIGNOR-268122	0.8
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1924	SPTSPKYsPTSPTYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203596	0.77
TLN1	protein	Q9Y490	UNIPROT	AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	up-regulates activity	binding			9606	BTO:0000132								16418530	t		lperfetto	In response to agonist stimulation, the alphaIIbbeta3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. This process contributes to both normal hemostasis and thrombosis. Activation of alphaIIbbeta3 is believed to occur in part via engagement of the beta3 cytoplasmic tail with talin; however, the role of the alphaIIb tail and its potential binding partners in regulating alphaIIbbeta3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the alphaIIb tail, is an endogenous inhibitor of alphaIIbbeta3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced alphaIIbbeta3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to alphaIIbbeta3, thus providing a model for tightly controlled regulation of alphaIIbbeta3 activation.	SIGNOR-253358	0.686
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates activity	phosphorylation	Tyr162	QLAAKLAyLQILSEE	9606	BTO:0001282								16373505	t			PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation. 	SIGNOR-251113	0.2
MAPKAPK3	protein	Q16644	UNIPROT	HSPB1	protein	P04792	UNIPROT	unknown	phosphorylation	Ser15	FSLLRGPsWDPFRDW	-1									8774846	t		miannu	MAPKAP kinase-3 and MAPKAP kinase-2 phosphorylated peptide substrates with similar kinetic constants and phosphorylated the same serine residues in HSP27 at the same relative rates.The three serine residues in HSP27 phosphorylated by MAPKAPK2 were also phosphorylated at the same relative rates by MAPKAP-K3 (Ser-82>>Ser-78 >Ser-15)	SIGNOR-250159	0.672
HTR1A	protein	P08908	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257088	0.305
mycophenolic acid	chemical	CHEBI:168396	ChEBI	IMPDH2	protein	P12268	UNIPROT	down-regulates activity	chemical inhibition			-1									10677226	t		Federica	Mycophenolic acid (MPA) is a species-specific inhibitor of IMPDH; mammalian IMPDHsare very sensitive to MPA	SIGNOR-261077	0.8
CSNK1A1	protein	P48729	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates activity	phosphorylation	Ser64	LQTDGNRsSHSRLGR	9606	BTO:0000567								11583622	t		llicata	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250785	0.289
MAPK1	protein	P28482	UNIPROT	MCRIP1	protein	C9JLW8	UNIPROT	down-regulates activity	phosphorylation	Ser21	KRTSSPRsPPSSSEI	9606									25728771	t		lperfetto	When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation	SIGNOR-264775	0.2
HIF1A	protein	Q16665	UNIPROT	TM9SF4	protein	Q92544	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001545								25961573	t		miannu	Here, we investigated the impact of hypoxia on TM9SF4 expression in leukemic cells and identified TM9SF4 as a direct target of HIF-1α, downregulated in these cells by hypoxia. Then, we found that the hypoxia-mediated downregulation of TM9SF4 expression is associated with a decrease of cell adhesion of leukemic cells to fibronectin, thus demonstrating that human TM9SF4 is a new molecule involved in leukemic cell adhesion.	SIGNOR-266705	0.2
MAPK8IP1	protein	Q9UQF2	UNIPROT	RBPJ	protein	Q06330	UNIPROT	down-regulates	binding			9606									20508646	t	Interferes with binding to Noth1-ICD.	gcesareni	Here, we show that jip1 suppresses notch1 activity. Jip1 was found to physically associate with either intracellular domain of notch1 or rbp-jk and interfere with the interaction between them.	SIGNOR-165713	0.2
phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	MTOR	protein	P42345	UNIPROT	up-regulates	chemical activation			9606									11729323	t		gcesareni	Pa directly interacted with the domain in mtor that is targeted by rapamycin, and this interaction was positively correlated with mtor's ability to activate downstream effectors.	SIGNOR-112379	0.8
CABIN1	protein	Q9Y6J0	UNIPROT	MEF2C	protein	Q06413	UNIPROT	down-regulates				9606									17172641	f		gcesareni	Thus, cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress mef2 transcriptional activity.	SIGNOR-151205	0.655
SRCAP	protein	Q6ZRS2	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates activity	binding			9606									20432434	t		miannu	The SNF2-related CBP activator protein (SRCAP) serves as a coactivator for several nuclear receptors including the androgen receptor (AR). SRCAP is an ATPase that is the core subunit of a large multiprotein complex and was shown to incorporate the histone variant H2A.Z into nucleosomes. In this report, we demonstrate that SRCAP is expressed in the epithelium of normal prostate and in prostate carcinoma cells, and is associated with AR in the nucleus	SIGNOR-255221	0.42
ETV3	protein	P41162	UNIPROT	DDX20	protein	Q9UHI6	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000944								22028472	t		miannu	ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation.	SIGNOR-262779	0.73
PRKD1	protein	Q15139	UNIPROT	SSH1	protein	Q8WYL5	UNIPROT	down-regulates	phosphorylation	Ser937	SNLTRSSsSDSIHSV	9606	BTO:0000150								19567672	t		llicata	Pkd-mediated phosphorylation of serines 937 and 978 regulates ssh1l subcellular localization by binding of 14-3-3 proteins 14-3-3 proteins associate with ssh1l when phosphorylated at serines 937 and 978, thereby sequestering ssh1l in the cytoplasm and preventing translocation of the phosphatase to f-actin_rich membrane protrusions	SIGNOR-186467	0.494
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257937	0.8
CLU	protein	P10909	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0001321								20068069	t		miannu	CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation.	SIGNOR-271433	0.2
MAPK6	protein	Q16659	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates	phosphorylation	Ser857	PPYNRAVsLDSPVSV	9606	BTO:0000551								22505454	t		gcesareni	Here, we report that erk3 interacted with and phosphorylated steroid receptor coactivator 3 (src-3), an oncogenic protein overexpressed in multiple human cancers at serine 857 (s857)	SIGNOR-196957	0.459
PLK1	protein	P53350	UNIPROT	TNKS	protein	O95271	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr930	LAHGADPtMKNQEGQ	9606	BTO:0000567								21818122	t		miannu	Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends. 	SIGNOR-276243	0.439
JAK1	protein	P23458	UNIPROT	IFNGR2	protein	P38484	UNIPROT	up-regulates activity	phosphorylation			9606									19041276	t		lperfetto	The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process.	SIGNOR-249491	0.647
F2RL1	protein	P55085	UNIPROT	FOSL1	protein	P15407	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254839	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	EWSR1	protein	Q01844	UNIPROT	unknown	phosphorylation			9606									19076070	t	inferred from 70% family members	lperfetto	Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2.	SIGNOR-270172	0.2
BBC3	protein	Q9BXH1	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates	binding			9606									1557433	t		gcesareni	The first Helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma	SIGNOR-20064	0.504
KAT5	protein	Q92993	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	acetylation	Lys2049	DAAVVLLkNGANKDM	9606									17636029	t		gcesareni	This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60.	SIGNOR-156915	0.424
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	ITGB5	protein	P18084	UNIPROT	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259005	0.2
MRPL53	protein	Q96EL3	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262345	0.647
PTH1R	protein	Q03431	UNIPROT	SLC34A1	protein	Q06495	UNIPROT	down-regulates quantity													28363951	f		lperfetto	PTH inhibits reabsorption of phosphate from the glomerular filtrate in RPT by decreasing the abundance of sodium-phosphate co-transporters NPT2a and NPT2c on the apical membrane, thus enhancing renal phosphate excretion	SIGNOR-270556	0.314
palmitoyl-CoA(4-)	smallmolecule	CHEBI:57379	ChEBI	O-palmitoyl-L-carnitine	smallmolecule	CHEBI:17490	ChEBI	up-regulates quantity	precursor of			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-268107	0.8
Cohesin complex	complex	SIGNOR-C304	SIGNOR	Chromosome_segregation	phenotype	SIGNOR-PH44	SIGNOR	up-regulates				9606									30544080	f		miannu	Cohesin, one of structural maintenance of chromosomes (SMC) complexes, forms a ring-shaped protein complex, and mediates sister chromatid cohesion for accurate chromosome segregation and precise genome inheritance.	SIGNOR-264523	0.7
ARHGEF7	protein	Q14155	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates				9606									17562871	f		gcesareni	We propose that the association of plcgamma1 with complexes containing git1 and beta-pix is essential for its role in integrin-mediated cell spreading and motility. As a component of this complex, plcgamma1 is also involved in the activation of cdc42 and rac1.	SIGNOR-155744	0.621
DNAJC3	protein	Q13217	UNIPROT	EIF2AK3	protein	Q9NZJ5	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								25329545	t		gcesareni	The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK	SIGNOR-246201	0.603
MAPK1	protein	P28482	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser301	SSSPNNLsPTGWSQP	10090	BTO:0000944								15664191	t		lperfetto	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-249443	0.616
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1868	SPTSPKYsPTSPKYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273062	0.636
RALGAPB	protein	Q86X10	UNIPROT	RalGAP1	complex	SIGNOR-C468	SIGNOR	form complex	binding			10090	BTO:0000011								21148297	t		miannu	 Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. 	SIGNOR-269792	0.422
CSNK2A1	protein	P68400	UNIPROT	ANP32B	protein	Q92688	UNIPROT	up-regulates	phosphorylation	Thr244	GEKRKREtDDEGEDD	9606									17178712	t		gcesareni	Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna	SIGNOR-151261	0.235
MIB1	protein	Q86YT6	UNIPROT	MIB1	protein	Q86YT6	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									12351649	t		miannu	The RING finger motifs of DIP-1 have E3 ligase activity that can auto-ubiquitinate DIP-1 in vitro. In vivo, DIP-1 is detected as a polyubiquitinated protein, suggesting that the intracellular levels of DIP-1 are regulated by the ubiquitin-proteasome system. 	SIGNOR-272603	0.2
CDK1	protein	P06493	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Ser122	DQHLMKCsPAQLLCS	9606			SIGNOR-C17						10864927	t		gcesareni	Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b.	SIGNOR-78416	0.853
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PHF2	protein	O75151	UNIPROT	up-regulates activity	phosphorylation	Ser954	QKSKKKKsAKRKLTP	9606	BTO:0000007								21532585	t		miannu	PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h).	SIGNOR-264512	0.2
DMXL2	protein	Q8TDJ6	UNIPROT	MADD	protein	Q8WXG6	UNIPROT	up-regulates quantity	binding			10116		BTO:0000142							11809763	t		miannu	We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles.	SIGNOR-265581	0.461
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser378	SKKGQSTsRHKKLMF	9606	BTO:0001321								15659650	t		lperfetto	The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage.	SIGNOR-74835	0.784
RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	precursor messenger RNA	smallmolecule	CHEBI:139356	ChEBI	up-regulates quantity	chemical modification			9606									22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs.	SIGNOR-266176	0.8
PPP2CA	protein	P67775	UNIPROT	PRKCB	protein	P05771	UNIPROT	down-regulates activity	dephosphorylation	Thr500	WDGVTTKtFCGTPDY	10116									8749392	t			 Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme. 	SIGNOR-248620	0.434
DGC	complex	SIGNOR-C217	SIGNOR	NRXN2	protein	Q9P2S2	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							11470830	t		miannu	In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan.	SIGNOR-265448	0.285
A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression				9606									24241034	f		lperfetto	Importantly, autocrine and paracrine interactions of α9β1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-α and IL-1β in synovial macrophages.	SIGNOR-253313	0.365
formestane	chemical	CHEBI:75172	ChEBI	CYP19A1	protein	P11511	UNIPROT	down-regulates activity	chemical inhibition			-1									7083195	t		miannu	Recently, it was discovered that 4-hydroxy-4-androstene-3,17-dione, 4-androstene-3,6,17-trione, and 1,4,6-androstatriene-3,17-dione, compounds previously reported to be competitive inhibitors of aromatase, cause a time-dependent loss of aromatase activity in human placental microsomes.	SIGNOR-258407	0.8
ACSS3	protein	Q9H6R3	UNIPROT	acetyl-CoA(4-)	smallmolecule	CHEBI:57288	ChEBI	up-regulates quantity	chemical modification												10843999	t		lperfetto	The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP.	SIGNOR-271832	0.8
TWIST1	protein	Q15672	UNIPROT	ICAM1	protein	P05362	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002590								17487558	f		miannu	 Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells	SIGNOR-255515	0.268
PRKAA1	protein	Q13131	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Thr179	SSPDKRLtLSQIYEW	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-238804	0.509
FOXO3	protein	O43524	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates quantity	transcriptional regulation			10090	BTO:0002314								24749067	f		gcesareni	We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration.	SIGNOR-254320	0.384
CAMK2B	protein	Q13554	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	phosphorylation	Ser552	QDTQRRTsMGGTQQQ	9606									24117889	t		lperfetto	Camkii represses transcriptionally active beta-catenin to mediate acute ethanol neurodegeneration and can phosphorylate beta-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human beta-catenin at t332, t472, and s552	SIGNOR-202825	0.294
TLR4	protein	O00206	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity	phosphorylation			9606									28137827	t		miannu	Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation.	SIGNOR-261930	0.44
clozapine	chemical	CHEBI:3766	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3).	SIGNOR-258835	0.8
ALK	protein	Q9UM73	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	binding			9606	BTO:0000785								16084951	t		gcesareni	Npm-alk has been shown to activate signal transducer and activator of transcription (stat) 3, a transcriptional regulator of cyclin d3.Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1.	SIGNOR-139460	0.452
MAPK1	protein	P28482	UNIPROT	BCL6	protein	P41182	UNIPROT	down-regulates	phosphorylation	Ser343	KSDCQPNsPTESCSS	9606	BTO:0000782;BTO:0000785								9649500	t		gcesareni	Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway.	SIGNOR-58485	0.503
APP	protein	P05067	UNIPROT	NAE1	protein	Q13564	UNIPROT	up-regulates activity	binding			9606	BTO:0000590								25568892	t		lperfetto	Alzheimer's disease (AD) is the gradual loss of the cognitive function due to neuronal death. Currently no therapy is available to slow down, reverse or prevent the disease. Here we analyze the existing data in literature and hypothesize that the physiological function of the Amyloid Precursor Protein (APP) is activating the AppBp1 pathway and this function is gradually lost during the progression of AD pathogenesis.	SIGNOR-251577	0.725
UBXN8	protein	O00124	UNIPROT	VCP	protein	P55072	UNIPROT	down-regulates quantity	relocalization			9606									21949850	t		SARA	The human protein named Rep8 or Ubxd6 as a new cofactor of p97. Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation.	SIGNOR-261002	0.535
PDYN	protein	P01213	UNIPROT	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258415	0.656
PRKCA	protein	P17252	UNIPROT	PRKG1	protein	Q13976	UNIPROT	up-regulates	phosphorylation	Thr59	THIGPRTtRAQGISA	9606									12609995	t		gcesareni	Antibodies generated against phosphorylated threonine 58 were used to demonstrate phosphorylation in response to pma treatment of the cells with kinetics similar to vasodilator-stimulated phosphoprotein phosphorylation. A phospho-mimetic mutation at this site (t58e) generated a partially activated pkg that was more sensitive to cgmp levels. A phospho- mutation (t58a) revealed that this residue is important but not sufficient for pkg activation by pkc.	SIGNOR-98803	0.35
CSNK1A1	protein	P48729	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser82	GSSESTDsGFCLDSP	9606									20348946	t		lperfetto	Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a	SIGNOR-164738	0.338
ELANE	protein	P08246	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Val76	LTGKLTTvFLPIVYT	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263592	0.404
BTRC	protein	Q9Y297	UNIPROT	PER1	protein	O15534	UNIPROT	down-regulates	ubiquitination			9606									15917223	t		miannu	We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1	SIGNOR-137755	0.551
PRKCA	protein	P17252	UNIPROT	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	unknown	phosphorylation			-1									10366608	t	inferred from 70% of family members	lperfetto	In addition, we identified threonine 830 as a potential PKC phosphorylation site.	SIGNOR-269853	0.704
RBCK1	protein	Q9BYM8	UNIPROT	BACH1	protein	O14867	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090									17682061	t		miannu	HOIL-1 bound Bach1 in vivo and thus stimulated its polyubiquitination in vitro. These results suggest that heme regulates the polyubiquitination of Bach1 and subsequent degradation and that HOIL-1 may function as an E3 ligase in this process.	SIGNOR-236971	0.351
MAPK14	protein	Q16539	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser46	AMDDLMLsPDDIEQW	9606	BTO:0000093								10581258	t		lperfetto	P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.	SIGNOR-72703	0.765
GABA-A (a5-b1-g2) receptor	complex	SIGNOR-C335	SIGNOR	CRHR2	protein	Q13324	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268595	0.2
PRKCA	protein	P17252	UNIPROT	ITGB4	protein	P16144	UNIPROT	down-regulates	phosphorylation	Ser1360	VLRSPSGsQRPSVSD	9606									15121854	t		lperfetto	Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures	SIGNOR-124494	0.51
Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257719	0.67
2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	up-regulates quantity	precursor of			9606									29767008	t		miannu	Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits.	SIGNOR-266521	0.8
EAF2	protein	Q96CJ1	UNIPROT	ELL	protein	P55199	UNIPROT	up-regulates	binding			9606									16006523	t		miannu	The eaf1-related eaf2 protein is also a positive regulator of ell elongation activity	SIGNOR-138540	0.736
FBXW11	protein	Q9UKB1	UNIPROT	BTRC	protein	Q9Y297	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0002419								31406304	t		miannu	Glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1. 	SIGNOR-277476	0.572
DUSP1	protein	P28562	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	down-regulates	dephosphorylation			9606									10617468	t	inferred from 70% of family members	gcesareni	The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1.	SIGNOR-269910	0.2
MET-enkephalin	smallmolecule	CHEBI:6618	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257551	0.8
PRKCA	protein	P17252	UNIPROT	HLA-A	protein	P04439	UNIPROT	unknown	phosphorylation	Ser359	SAQGSDVsLTACKV										2941417	t		lperfetto	As shown in Fig. 6A, the HLA heavy chain was phosphorylated by kinase C. | The major site of in vivo phosphorylation of the HLA-B7 heavy chain was localized to Ser-335 which is conserved in all specificitie	SIGNOR-248891	0.328
NFIA	protein	Q12857	UNIPROT	WNT5A	protein	P41221	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268877	0.2
NRP2	protein	O60462	UNIPROT	VEGFC	protein	P49767	UNIPROT	up-regulates	binding			9606	BTO:0000938								16816121	t		gcesareni	By in vitro binding studies we found that both vegf-c and vegf-d interact with np2, vegf-c in a heparin-independent and vegf-d in a heparin-dependent manner.	SIGNOR-147530	0.739
PCSK7	protein	Q16549	UNIPROT	KHSRP	protein	Q92945	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000222	BTO:0000887							16364914	t		gcesareni	Ksrp phosphorylated by p38 displays compromised binding to are-containing transcripts and fails to promote their rapid decay,although it retains the ability to interact with the mrna degradation machinery.	SIGNOR-143167	0.2
CIITA	protein	P33076	UNIPROT	HLA-DRA	protein	P01903	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002417								10886240	f	 	 	These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma.	SIGNOR-254008	0.603
CSNK2A1	protein	P68400	UNIPROT	CDC25B	protein	P30305	UNIPROT	up-regulates activity	phosphorylation	Ser187	AGSGAASsSGEDKEN	-1									12527891	t		llicata	Mass spectrometry analysis demonstrates that at least two serine residues, Ser-186 and Ser-187, are phosphorylated in vivo. | Finally, we demonstrate that phosphorylation of CDC25B by protein kinase CK2 increases the catalytic activity of the phosphatase in vitro as well as in vivo. 	SIGNOR-250837	0.343
ZFP36	protein	P26651	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates quantity by destabilization	post transcriptional regulation												25815583	t			The TTP binding site in the 3′ UTR of MyoD would permit TTP-mediated mRNA decay	SIGNOR-253597	0.297
CSNK2A1	protein	P68400	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	phosphorylation	Thr112	EGMQIPStQFDAAHP	9606	BTO:0000007								12432063	t		llicata	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin	SIGNOR-250848	0.54
GSK3B	protein	P49841	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation			9606									33081032	t		miannu	GSK3β regulates S6K1 activity positively through modulating phosphorylation of S6K1 at p.Ser371. 	SIGNOR-263513	0.366
NCOA2	protein	Q15596	UNIPROT	RXRA	protein	P19793	UNIPROT	up-regulates	binding			9606									11851396	t		gcesareni	Here, it is demonstrated that mutation of the h11 phenylalanine residues diminishes the ability of rxr to associate with the p160 coactivators tif2 and p/cip, but has little effect on ligand-dependent interactions of the receptor with the unrelated coactivator tif1.	SIGNOR-114847	0.788
MAPK3	protein	P27361	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser296	SPSALSSsPNNLSPT	10090									15664191	t		lperfetto	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-143692	0.622
SGK1	protein	O00141	UNIPROT	NDRG1	protein	Q92597	UNIPROT	down-regulates	phosphorylation	Ser330	LMRSRTAsGSSVTSL	9606									20416281	t		llicata	Ndrg1/cap43 is phosphorylated at serine/threonine sites in its c-terminal domain by serum- and glucocorticoid-regulated kinase 1 (sgk1). we further introduced mutations at the serine and threonine sites at 328 [t328a], 330 [s330a] and 346 [t346a], which are susceptible to phosphorylation by sgk1, and also constructed double mutants [t328a, s330a], [t328a, t346a] and [s330a, t346a]. Expression of all these mutants, with the exception of [s330a, t346a], suppressed the production of cxc chemokine to similar levels as their wild-type counterpart.	SIGNOR-164898	0.588
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Thr522	SSPGSPGtPGSRSRT	9606	BTO:0000590								12226093	t	The effect has been demonstrated using P10636-8	lperfetto	Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease.	SIGNOR-92607	0.754
AMPK	complex	SIGNOR-C15	SIGNOR	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	up-regulates	phosphorylation			9606									20647423	t		lperfetto	Ampk recruitment and h2b ser36 phosphorylation colocalized within genes activated by ampk-dependent pathways, both in promoters and in transcribed regions.	SIGNOR-216471	0.2
MAP3K4	protein	Q9Y6R4	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity				9606									21152872	f		lperfetto	We found that mekk1/mekk4 as opposed to ask1, are responsible for trail-induced c-jun nh2-terminal kinase (jnk) or p38 activation,	SIGNOR-170534	0.396
TRIM59	protein	Q8IWR1	UNIPROT	IRF3	protein	Q14653	UNIPROT	down-regulates activity				9606	BTO:0000567; BTO:0002181								22588174	f		Giorgia	TRIM59 also inhibited the phosphorylation of IRF3 and IRF7, which induces dimerization, suggesting that TRIM59 negatively regulates kinases for IRF3/7 (IKKe/TBK1) or their upstream signal	SIGNOR-260373	0.264
RPS6KB1	protein	P23443	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	down-regulates	phosphorylation	Ser560	LARLGCSsCLDYFTT	9606									18769144	t		lperfetto	Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively	SIGNOR-180775	0.2
PTPN13	protein	Q12923	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	9606									15611135	t		gcesareni	We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines.	SIGNOR-132551	0.263
MT-ND3	protein	P03897	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 	SIGNOR-262145	0.77
2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid	chemical	CID:135461425	PUBCHEM	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258188	0.8
MAPK14	protein	Q16539	UNIPROT	ELK3	protein	P41970	UNIPROT	up-regulates	phosphorylation	Ser357	IHFWSSLsPVAPLSP	9606									9130707	t		gcesareni	Tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387. Mutation of these sites to alanine severely reduces c-fos sre-dependent transcription mediated by sap-1a and p38 map kinase.	SIGNOR-47681	0.386
MSL2	protein	Q9HCI7	UNIPROT	H2BC21	protein	Q16778	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSIYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271976	0.2
CLTCL1	protein	P53675	UNIPROT	AP-3/clathrin vescicle	complex	SIGNOR-C250	SIGNOR	form complex	binding			9606									23103167	t		lperfetto	Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors	SIGNOR-260673	0.719
MRPL12	protein	P52815	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262381	0.641
FLT1	protein	P17948	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	binding			9606									9398617	t		gcesareni	We conclude that both flt-1 and kdr have the potential to signal through plc gamma via phosphotyrosine residues located in juxta-membrane and carboxyl tail regions	SIGNOR-53743	0.664
PRKCB	protein	P05771	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates activity	phosphorylation	Thr495	TGITRKKtFKEVANA	9606	BTO:0001853								24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251630	0.315
CDK12	protein	Q9NYV4	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1924	SPTSPKYsPTSPTYS	9606									22012619	t		miannu	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176829	0.775
TAL1	protein	P17542	UNIPROT	Megakaryocyte_differentiation 	phenotype	SIGNOR-PH103	SIGNOR	up-regulates activity				10090	BTO:0004911								29713515	f			The truncated form TAL1-s is required for erythroid progenitors differentiation, while the full-length protein TAL1-l is required for megakaryocytic differentiation of progenitor cells.	SIGNOR-259969	0.7
(S,S)-asenapine	chemical	CHEBI:71257	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029									9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258848	0.8
NUAK1	protein	O60285	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser392	FKTEGPDsD	9606									21317932	t		gcesareni	Here we showed that in the presence of wild-type lkb1, nuak1 directly interacts with and phosphorylates p53 in vitro and in vivo.	SIGNOR-172012	0.527
LIN28A	protein	Q9H9Z2	UNIPROT	IGF2	protein	P01344	UNIPROT	up-regulates quantity by expression	translation regulation			9606									17473174	t		miannu	Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency	SIGNOR-277339	0.408
MAPK1	protein	P28482	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Ser83	PTIPGVTsPSSDEPP	9606	BTO:0000007								11691836	t		lperfetto	The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding 	SIGNOR-249391	0.649
AKT1	protein	P31749	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates activity	phosphorylation	Ser792	CVRMRHLsQEFGWLQ	9534	BTO:0001538								11404460	t		lperfetto	Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790	SIGNOR-108508	0.605
NEDD9	protein	Q14511	UNIPROT	AURKA	protein	O14965	UNIPROT	up-regulates activity	binding			9606									16184168	t		miannu	HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins.	SIGNOR-262653	0.588
PRKG1	protein	Q13976	UNIPROT	SF1	protein	Q15637	UNIPROT	down-regulates activity	phosphorylation	Ser20	PSKKRKRsRWNQDTM	10116	BTO:0000947								10449420	t		lperfetto	 PKG phosphorylates SF1 at Ser20, which inhibits the SF1-U2AF65 interaction leading to a block of pre-spliceosome assembly. Mutation of Ser20 to Ala or Thr also inhibits the interaction with U2AF65, indicating that Ser20 is essential for binding.	SIGNOR-249018	0.449
PRKCA	protein	P17252	UNIPROT	SDC4	protein	P31431	UNIPROT	up-regulates activity	phosphorylation	Ser179	MKKKDEGsYDLGKKP	10116	BTO:0001176								11916978	t		lperfetto	The phosphorylation state of Ser(183) in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP(2)), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) alpha. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCalpha activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCalpha and -delta were able to specifically phosphorylate Ser(183) in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCdelta but not a DN PKCalpha mutant.	SIGNOR-249149	0.722
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO4	protein	P98177	UNIPROT	down-regulates activity	phosphorylation	Ser197	APRRRAAsMDSSSKL	10090	BTO:0004245								10217147	t			Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo.	SIGNOR-251477	0.2
PAK1	protein	Q13153	UNIPROT	PA2G4	protein	Q9UQ80	UNIPROT	up-regulates	phosphorylation	Thr261	QYGLKMKtSRAFFSE	9606	BTO:0000150								18283314	t		llicata	We found that pak1 phosphorylated ebp1 in vitro and mapped the phosphorylation site to threonine 261. these studies demonstrate for the first time that ebp1 is a substrate of pak1 and the importance of the pak1 phosphorylation site for the functional activity of ebp1 in breast cancer cells.	SIGNOR-160963	0.2
AR	protein	P10275	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9606									15861399	f		miannu	AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation	SIGNOR-251539	0.7
MAPK14	protein	Q16539	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									20068231	t		gcesareni	Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.	SIGNOR-163250	0.786
FGG	protein	P02679	UNIPROT	VTN	protein	P04004	UNIPROT	down-regulates activity	binding			9606									2243140	t	Regulation	miannu	Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a).	SIGNOR-251969	0.431
MRPL54	protein	Q6P161	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262336	0.644
MDC1	protein	Q14676	UNIPROT	NBN	protein	O60934	UNIPROT	up-regulates	binding			9606									19230643	t		gcesareni	Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1.	SIGNOR-184141	0.829
RXRB	protein	P28702	UNIPROT	PPARD	protein	Q03181	UNIPROT	up-regulates	binding			9606									11237216	t		gcesareni	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-105451	0.536
NR5A2	protein	O00482	UNIPROT	STAR	protein	P49675	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001555								19022561	f		miannu	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 	SIGNOR-254870	0.359
CDK1	protein	P06493	UNIPROT	KIF11	protein	P52732	UNIPROT	up-regulates activity	phosphorylation	Thr926	LDIPTGTtPQRKSYL	9606									19001501	t	done	miannu	Nek6 phosphorylated Eg5 at several sites in vitro and one of these sites, Ser1033, is phosphorylated in vivo during mitosis. Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles. 	SIGNOR-273887	0.658
BTAF1	protein	O14981	UNIPROT	TBP	protein	P20226	UNIPROT	up-regulates activity	binding			9986									15509807	t		miannu	We present evidence that the NC2alpha subunit interacts with BTAF1. Addition of NC2alpha or the NC2 complex can stimulate the ability of BTAF1 to interact with TBP.	SIGNOR-263919	0.731
GSK3B	protein	P49841	UNIPROT	BICD1	protein	Q96G01	UNIPROT	up-regulates activity	phosphorylation	Ser585	SEPVAKEsTEASKEP	9606	BTO:0000567								17139249	t		miannu	Therefore, at least Ser585 and Thr597 in BICD1 are important phosphorylation sites for BICD1 to exert its functions, and GSK-3β-dependent phosphorylation is required for the interaction of BICD1 with dynein.	SIGNOR-262743	0.336
CAMK2A	protein	Q9UQM7	UNIPROT	HRH1	protein	P35367	UNIPROT	down-regulates	phosphorylation	Thr140	LRYLKYRtKTRASAT	9606		BTO:0000975							15107581	t	Translocation from Endosome to Lysosome	gcesareni	As we have shown previously, human h1r can be phosphorylated in vitro by several kinases includingpka, pkc, pkg, and camk ii in summary, these data suggest that thr140, thr142, ser396, ser398, and thr478 can be phosphorylated by the kinases described above (table 2).	SIGNOR-124348	0.286
NCOR2	protein	Q9Y618	UNIPROT	PGR	protein	P06401	UNIPROT	down-regulates	acetylation			9606	BTO:0000150;BTO:0001130								12771131	t		gcesareni	In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases.	SIGNOR-101289	0.605
IRAK4	protein	Q9NWZ3	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser345	QARPGPQsPGSPLEE	9606	BTO:0000130								17217339	t		lperfetto	Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.These results strongly support the observation that irak-4 is a kinase for p47phox in vivo. We also detected the signature of phosphorylation at ser320 and ser345	SIGNOR-152019	0.39
NR3C1	protein	P04150	UNIPROT	TSC22D3	protein	Q99576	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001372								9430225	f			In thymocytes and peripheral T cells, GILZ gene expression is induced by DEX	SIGNOR-253295	0.425
ITCH	protein	Q96J02	UNIPROT	TRPC4	protein	Q9UBN4	UNIPROT	down-regulates activity	ubiquitination			9606	BTO:0000007								17110928	t		miannu	Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane.	SIGNOR-272624	0.356
MAPK14	protein	Q16539	UNIPROT	MAPKAPK2	protein	P49137	UNIPROT	up-regulates activity	phosphorylation	Thr206	PNAILKLtDFGFAKE	-1									7592979	t		miannu	In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction	SIGNOR-250101	0.758
TRIM25	protein	Q14258	UNIPROT	AMFR	protein	Q9UKV5	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								24810856	t		miannu	We further demonstrate that TRIM25 ubiquitylates gp78 and that overexpression of TRIM25 accelerates the degradation of gp78. Our data suggest that TRIM25 not only cooperates with gp78 in polyubiquitylation of AMF but also gauges the steady-state level of gp78. 	SIGNOR-272176	0.371
SRC	protein	P12931	UNIPROT	GSN	protein	P06396	UNIPROT	unknown	phosphorylation	Tyr603	LKTPSAAyLWVGTGA	-1									10210201	t		llicata	Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624.	SIGNOR-250782	0.576
PRKAA1	protein	Q13131	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates activity	phosphorylation	Ser408	GPLPRAPsISTVEPK	9606									26190112	t		Luana	AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency.	SIGNOR-259860	0.339
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	binding			9606		BTO:0000887;BTO:0001103							12058061	t		gcesareni	In the cytoplasm, 14-3-3 proteins bind the phosphorylated hdac5 and retain it in the cytosol.	SIGNOR-89444	0.2
SOSTDC1	protein	Q6X4U4	UNIPROT	BMP4	protein	P12644	UNIPROT	down-regulates activity				10090									18032587	f		lperfetto	SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7	SIGNOR-242749	0.684
CASP6	protein	P55212	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	cleavage	Asp329	EMEEDSYdSFGEPSY	-1									10069390	t		lperfetto	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261750	0.37
OSM	protein	P13725	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates	binding			9606	BTO:0001271								9143707	t		gcesareni	Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2.	SIGNOR-48114	0.741
all-cis-5,8,11,14,17-icosapentaenoic acid	smallmolecule	CHEBI:28364	ChEBI	FBN1	protein	P35555	UNIPROT	up-regulates quantity by expression				9606									16467281	f	Regulation of expression	miannu	It was found that EPA increased collagen and elastic fibers (tropoelastin and fibrillin-1) expression by increasing transformin growth factor-beta expression in aged human skin.	SIGNOR-251910	0.8
WNT5A	protein	P41221	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates activity				10090		BTO:0000887;BTO:0001103							9753670	f		gcesareni	Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm.	SIGNOR-60376	0.297
PRKCA	protein	P17252	UNIPROT	MYL9	protein	P24844	UNIPROT	down-regulates	phosphorylation	Thr10	SKRAKAKtTKKRPQR	9606									22136066	t		lperfetto	Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity	SIGNOR-191536	0.282
GSK3B	protein	P49841	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser33	QQQSYLDsGIHSGAT	9606	BTO:0000938	BTO:0000142	SIGNOR-C110						19303846	t		gcesareni	DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin.	SIGNOR-184781	0.856
PP2Ca_R1A_Bd	complex	SIGNOR-C134	SIGNOR	DCK	protein	P27707	UNIPROT	down-regulates activity	dephosphorylation	Ser74	EFEELTMsQKNGGNV										24462681	t		lperfetto	Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation	SIGNOR-275802	0.2
STK4	protein	Q13043	UNIPROT	H2BC3	protein	P33778	UNIPROT	unknown	phosphorylation	Ser15	APAPKKGsKKAITKA	9606									21212262	t		lperfetto	The mst1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, jnk/p38, histone h2b and foxo. Mst1 induces apoptosis by phosphorylating histone h2b on a relatively conserved site, ser-14 in mammalian cells	SIGNOR-171009	0.2
LPAR4	protein	Q99677	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256928	0.357
MCF2	protein	P10911	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260557	0.652
PTPN2	protein	P17706	UNIPROT	STAT1	protein	P42224	UNIPROT	down-regulates activity	dephosphorylation			9606									15780598	t		lperfetto	Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.	SIGNOR-133279	0.724
CDK1	protein	P06493	UNIPROT	RANGAP1	protein	P46060	UNIPROT	up-regulates	phosphorylation	Ser428	EPAPVLSsPPPADVS	9606			SIGNOR-C17						15037602	t		lperfetto	Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain.	SIGNOR-123516	0.472
PTEN	protein	P60484	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates				9606									17157787	f	PTEN is a suppressor of RAS-AKT function	gcesareni	Moreover, suppressors of ras akt function, such as the tumor-suppressor pten, and the attenuation of ras signaling involved in senescence, could be thus viewed as modulators of the gli code	SIGNOR-151134	0.362
EGLN3	protein	Q9H6Z9	UNIPROT	HIF1A	protein	Q16665	UNIPROT	down-regulates quantity by destabilization	hydroxylation			9606									24990963	t		lperfetto	There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization	SIGNOR-262000	0.79
EP300	protein	Q09472	UNIPROT	PCK1	protein	P35558	UNIPROT	down-regulates quantity by destabilization	acetylation	Lys70	EGILRRLkKYDNCWL	9606	BTO:0000007								21726808	t		lperfetto	Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 	SIGNOR-267597	0.526
LTB4R	protein	Q15722	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256970	0.268
PRKCA	protein	P17252	UNIPROT	SLC6A9	protein	P48067-2	UNIPROT	down-regulates activity	phosphorylation	Thr19	GAVPSEAtKRDQNLK	9823									21864610	t		miannu	We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 	SIGNOR-262919	0.337
E2F1	protein	Q01094	UNIPROT	RRM1	protein	P23921	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253852	0.304
PRKCD	protein	Q05655	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	unknown	phosphorylation	Ser473	PPSGTKKsKRGRGRP	9606									12529391	t		gcesareni	Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm.	SIGNOR-97287	0.262
testolactone	chemical	CHEBI:9460	ChEBI	CYP19A1	protein	P11511	UNIPROT	down-regulates activity	chemical inhibition			-1									7083195	t		miannu	Recently, it was discovered that 4-hydroxy-4-androstene-3,17-dione, 4-androstene-3,6,17-trione, and 1,4,6-androstatriene-3,17-dione, compounds previously reported to be competitive inhibitors of aromatase, cause a time-dependent loss of aromatase activity in human placental microsomes.We report here that 1,4-androstadiene 3,17-dione (Ki 0.32 microM; kinact 0.91 X 10(-3)/sec) and testolactone (Ki 35 microM; kinact 0.36 X 10(-3)/sec) also cause a similar loss of aromatase activity. 	SIGNOR-258406	0.8
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	down-regulates	phosphorylation	Ser1112	LLEDGSEsPAKRICP	9606									12006580	t		gcesareni	When expressed in u2os cells, the phosphorylation-deficient mutant p130(delta)(cdk4), in which the cdk4 specific sites were mutated to alanine residues, imposed a more sustained g1 arrest than a constitutively active prb(delta)(cdk), known to repress all cellular e2f activity	SIGNOR-87492	0.843
GPR35	protein	Q9HC97	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257204	0.2
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	CTNNB1	protein	P35222	UNIPROT	up-regulates	phosphorylation	Tyr654	RNEGVATyAAAVLFR	9606	BTO:0001271								17318191	t		lperfetto	Bcr-abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylationthe notion that y86 and y654 are located respectively within the n_ and c_terminal transcriptional domains of __catenin suggests that one or both residues might regulate the transactivating function of __catenin. In this regard, phosphorylation of y654 was reported to strengthen __catenin association with the basal transcription factor tata_binding protein (tbp)	SIGNOR-153431	0.2
CDK12	protein	Q9NYV4	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1889	SPTTPKYsPTSPTYS	9606									22012619	t		miannu	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176813	0.775
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	UBTF	protein	P17480	UNIPROT	up-regulates activity	phosphorylation	Ser484	ERGKLPEsPKRAEEI	10090	BTO:0000944								10202152	t		llicata	We have identified Ser484 as a direct target for cyclin-dependent kinase 4 (cdk4)-cyclin D1- and cdk2-cyclin E-directed phosphorylation. Mutation of Ser484 impairs rDNA transcription in vivo and in vitro. 	SIGNOR-250755	0.379
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXA2	protein	Q9Y261	UNIPROT	down-regulates activity	phosphorylation	Thr156	KTYRRSYtHAKPPYS	9606									14500912	t			Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression.	SIGNOR-254974	0.2
IRAK4	protein	Q9NWZ3	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								11960013	t		lperfetto	In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1.	SIGNOR-117315	0.672
MAPK12	protein	P53778	UNIPROT	SNTA1	protein	Q13424	UNIPROT	up-regulates	phosphorylation	Ser201	PLQRQPSsPGPTPRN	9606		BTO:0001103							10212242	t		lperfetto	Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates.	SIGNOR-67065	0.655
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CCL11	protein	P51671	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16604092	f		miannu	Rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling.	SIGNOR-254661	0.266
UBE2J1	protein	Q9Y385	UNIPROT	DIO	proteinfamily	SIGNOR-PF83	SIGNOR	down-regulates quantity by destabilization	ubiquitination			9606		BTO:0001379							29892818	t	inferred from family member	scontino	ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244.	SIGNOR-270242	0.387
ALDH1A1	protein	P00352	UNIPROT	all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	up-regulates quantity	chemical modification			9606									21621639	t		lperfetto	All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step.	SIGNOR-265123	0.8
CSNK2A2	protein	P19784	UNIPROT	WAS	protein	P42768	UNIPROT	up-regulates activity	phosphorylation	Ser483	KRSRAIHsSDEGEDQ	9606									12769847	t		llicata	We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule. 	SIGNOR-251048	0.354
DLL4	protein	Q9NR61	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								16140393	t		lperfetto	Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate.	SIGNOR-209735	0.628
SLC38A2	protein	Q96QD8	UNIPROT	L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	up-regulates quantity	relocalization			9606									26724577	t			Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine.	SIGNOR-266913	0.8
CRP	protein	P02741	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates quantity by destabilization													17942113	f		miannu	C-reactive protein (CRP), a cardiovascular risk marker, induces endothelial dysfunction. CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity in human aortic endothelial cells (HAECs). CRP treatment significantly decreased levels of BH4 thereby promoting eNOS uncoupling. we found that CRP decreased the eNOS dimer/monomer ratio further supporting eNOS uncoupling.	SIGNOR-252217	0.477
ACLY	protein	P53396	UNIPROT	acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	up-regulates quantity	chemical modification			9606									19286649	t		miannu	ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor.	SIGNOR-267103	0.8
ADA	protein	P00813	UNIPROT	ADORA1	protein	P30542	UNIPROT	up-regulates activity	binding			-1									18680557	t		miannu	The results show that human ADA, apart from reducing the adenosine concentration and thus preventing A(1)R desensitization, binds to A(1)R behaving as an allosteric effector that markedly enhances agonist affinity and increases receptor functionality. 	SIGNOR-269105	0.59
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser12	LASDFAFsPPPGGGG	-1									31306665	t		lperfetto	Recently, Liu et al. [3] identified CyclinE/CDK2 to be the kinase phosphorylating OCT4 on serine 12 (S12), serine 355 (S355) and threonine 322 (T322) by elegantly combining genetics and biochemistry. Knockout of all five G1 cyclins (D1, D2, D3, E1 and E2) in mESCs (coined Q-KO cells) and consequent inactivation of CDK2/4/ 6 leads to perturbation of the pluripotent state and to the adaption of the trophectoderm cell fate. This was attributed to reduced phosphorylation of OCT4 (as well as SOX2 and NANOG) leading to an increase of protein turnover [3].	SIGNOR-264437	0.325
CBL	protein	P22681	UNIPROT	LCK	protein	P06239	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								11904433	t		miannu	Coexpression in 293T cells demonstrated that Lck kinase activity and Cbl ubiquitin ligase activity were essential for Lck ubiquitination and negative regulation of Lck-dependent serum response element-luciferase reporter activity. The Lck SH3 domain was pivotal for Cbl-Lck association and Cbl-mediated Lck degradation, with a smaller role for interactions mediated by the Cbl tyrosine kinase-binding domain.	SIGNOR-272614	0.699
CSNK1E	protein	P49674	UNIPROT	CSNK1E	protein	P49674	UNIPROT	down-regulates activity	phosphorylation	Ser368	NTSPRAIsRVDRERK	9606	BTO:0000007								10542239	t		llicata	Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T	SIGNOR-250808	0.2
LIF	protein	P15018	UNIPROT	MYH7	protein	P12883	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									10212267	f	Regulation of expression	miannu	Increase of protein synthesis rate and β-MHC gene expression in cardiac myocytes by ET-1 and LIF.	SIGNOR-251959	0.2
RBSN	protein	Q9H1K0	UNIPROT	Early Endosome	complex	SIGNOR-C246	SIGNOR	form complex	binding			9606									19924646	t		lperfetto	Rabenosyn-5 is another FYVE-domain-containing Rab5 effector that localizes to EE 	SIGNOR-260624	0.2
CDK19	protein	Q9BWU1	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr2511	VPEHPFLtPSPESPD	-1									25344755	t		lperfetto	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273137	0.307
SMARCA4	protein	P51532	UNIPROT	SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270608	0.83
Papain-like proteinase	protein	P0C6X7-PRO_0000037311	UNIPROT	STING1	protein	Q86WV6	UNIPROT	down-regulates activity	binding			9606									22312431	t		miannu	Here we show that human coronavirus (HCoV) NL63 and severe acute respiratory syndrome (SARS) CoV papain-like proteases (PLP) antagonize innate immune signaling mediated by STING (stimulator of interferon genes, also known as MITA/ERIS/MYPS). STING resides in the endoplasmic reticulum and upon activation, forms dimers which assemble with MAVS, TBK-1 and IKKε, leading to IRF-3 activation and subsequent induction of interferon (IFN). We found that expression of the membrane anchored PLP domain from human HCoV-NL63 (PLP2-TM) or SARS-CoV (PLpro-TM) inhibits STING-mediated activation of IRF-3 nuclear translocation and induction of IRF-3 dependent promoters. Both catalytically active and inactive forms of CoV PLPs co-immunoprecipitated with STING	SIGNOR-260247	0.2
TANK	protein	Q92844	UNIPROT	TRAF2	protein	Q12933	UNIPROT	down-regulates activity	binding			9534	BTO:0000298								10759890	t		miannu	IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex	SIGNOR-262714	0.722
SIRT1	protein	Q96EB6	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	deacetylation			9606	BTO:0000007								14976264	t		lperfetto	Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress	SIGNOR-252994	0.909
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	binding			9606	BTO:0001130								1010227	t		gcesareni	Progressive increase in akt activation during prostate cancer progression led to increase phosphorylation of foxo3a and binding with 14-3-3, which potentially affected its transcriptional activity in age-specific manner.	SIGNOR-252819	0.702
Blood vessel damage	stimulus	SIGNOR-ST26	SIGNOR	F3	protein	P13726	UNIPROT	up-regulates				9606		BTO:0000131							32665005	f		lperfetto	During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury.	SIGNOR-263541	0.7
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	MAPK15	protein	Q8TD08	UNIPROT	up-regulates	chemical activation			9606	BTO:0000150								11043579	t		gcesareni	Estrogen rapidly activates the mitogen-activated protein kinases, erk-1 and erk-2, via an as yet unknown mechanism.	SIGNOR-83277	0.8
ACTL6B	protein	O94805	UNIPROT	Brain-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C486	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270758	0.672
CNOT10	protein	Q9H9A5	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	form complex	binding			9606									19558367	t		lperfetto	In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules.	SIGNOR-268305	0.736
TLN1	protein	Q9Y490	UNIPROT	A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257628	0.458
TLRs	proteinfamily	SIGNOR-PF20	SIGNOR	TIRAP	protein	P58753	UNIPROT	up-regulates activity	binding			9606									20404851	t		lperfetto	These differences are explained by the discovery of TIR domain’containing adaptor molecules, including MyD88, TIRAP (Mal), TRIF and TRAM, which are recruited by distinct TLRs and activate distinct signaling pathways	SIGNOR-216298	0.2
AURKB	protein	Q96GD4	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									12588998	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.	SIGNOR-98293	0.2
MAPK8	protein	P45983	UNIPROT	ITCH	protein	Q96J02	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000575								16469705	t		gcesareni	This is not due to direct c-FLIP phosphorylation but depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch,	SIGNOR-245310	0.644
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1693	SPTSPSYsPTSPSYS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248821	0.849
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	GRIP1	protein	Q9Y3R0	UNIPROT	up-regulates activity	phosphorylation	Ser734	SLKGKPLsEAIHLLQ	-1									11301320	t		miannu	 Here we show that epidermal growth factor regulates the activities of the p160 GRIP1 through the extracellular signal-regulated kinase (ERK) family of mitogen-activated protein kinases. ERKs phosphorylate GRIP1 at a specific site, Ser-736, the integrity of which is required for full growth factor induction of GRIP1 transcriptional activation and coactivator function. 	SIGNOR-263056	0.2
CDK1	protein	P06493	UNIPROT	NDUFV3	protein	P56181	UNIPROT	up-regulates activity	phosphorylation	Ser105	QPSSGREsPRH										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275593	0.2
OXSR1	protein	O95747	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	phosphorylation	Thr84	LPSDFEHtIHVGFDA	9606	BTO:0000567								14707132	t		miannu	OSR1 phosphorylated threonine 84 in the N-terminal regulatory domain of PAK1. phosphorylation of PAK1 by OSR1 desensitizes PAK1 to activation by small G proteins, providing a modulatory input to PAK1 activity. 	SIGNOR-250210	0.39
SRC	protein	P12931	UNIPROT	WASF1	protein	Q92558	UNIPROT	up-regulates	phosphorylation	Tyr125	PIPLQETyDVCEQPP	9606									16317717	t		lperfetto	The wave/scar proteins regulate actin polymerisation at the leading edge of motile cells via activation of the arp2/3 complex in response to extracellular cues.Src-dependent phosphorylation of scar1 promotes its association with the arp2/3 complex	SIGNOR-142724	0.418
CDKN1A	protein	P38936	UNIPROT	CDK2	protein	P24941	UNIPROT	down-regulates	binding			9606	BTO:0000222								16982699	t		gcesareni	Considering that akt1 phosphorylates p21, this dissociation likely results from phosphorylation of p21 and release of cdk2.	SIGNOR-149711	0.953
fexofenadine	chemical	CHEBI:5050	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002126								18446005	t		Luana	We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells	SIGNOR-257785	0.8
RBPJ	protein	Q06330	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates quantity by repression	transcriptional regulation												23729744	f		apalma	 In the absence of NICD, CSL forms complexes with a variety of co-repressors to suppress the transcription of Notch target genes	SIGNOR-255373	0.949
A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	SOX2	protein	P48431	UNIPROT	up-regulates quantity by expression				10090									18757303	f		lperfetto	Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1.	SIGNOR-253279	0.379
PRKCD	protein	Q05655	UNIPROT	NR2F6	protein	P10588	UNIPROT	down-regulates	phosphorylation	Ser83	CKSFFKRsIRRNLSY	9606	BTO:0000782								18701084	t		esanto	Ser-83 on recombinant nr2f6is a pkc substrate site;mutation of ser-83 (but not ser-89) to alanine strongly reduced pkc-mediated nr2f6 phosphorylation, confirming ser-83 as the major pkc phosphorylation site in nr2f6;the dna-binding capacity of nr2f6 is antagonized by a (p)ser-83 switch on nr2f6.	SIGNOR-180017	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	CRTC2	protein	Q53ET0	UNIPROT	down-regulates	phosphorylation	Ser170	PSALNRTsSDSALHT	9606									21892142	t		lperfetto	Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation	SIGNOR-216541	0.423
CSNK2A2	protein	P19784	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates activity	phosphorylation	Ser133	NAIRYIEsLQELLRE	-1									9461343	t		llicata	Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity. 	SIGNOR-251016	0.311
NMDA receptor_2C	complex	SIGNOR-C349	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264134	0.7
CDK1	protein	P06493	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates	phosphorylation	Ser168	SEMKYLGsPITTVPK	9606									10037602	t		gcesareni	Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity.	SIGNOR-64972	0.853
PRKCA	protein	P17252	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Thr841	RSAFTTStVVRMHVG	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249285	0.425
MAPK1	protein	P28482	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Ser551	ELQAPVRsPITRSFA	10029	BTO:0000246								15379552	t		lperfetto	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-249397	0.584
TP63	protein	Q9H3D4	UNIPROT	SYNE3	protein	Q6ZMZ3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0005098								28595999	t		lperfetto	Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets.	SIGNOR-263280	0.2
CIITA	protein	P33076	UNIPROT	HLA-DMB	protein	P28068	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								9300700	f	 	 	The class II transactivator (CIITA) is a highly specific transcription factor that activates only genes known to be involved in the class II MHC processing pathway, including class II MHC, invariant chain, and HLA-DMA/B genes.	SIGNOR-254014	0.36
(S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide	chemical	CID:6918848	PUBCHEM	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			9606									31908417	t		miannu	The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs.	SIGNOR-262251	0.8
PTPRH	protein	Q9HD43	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									10734133	t		gcesareni	These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase	SIGNOR-76080	0.273
MAP2K7	protein	O14733	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates activity	phosphorylation	Ser407	STEQTLAsDTDSSLD	-1									11062067	t			MKK7 also phosphorylates JNK2 alpha 2 at Thr-404 and Ser-407 in vitro. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7.	SIGNOR-251416	0.622
IKBKE	protein	Q14164	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser419	TPDDFLNsVDEMDTG	9606									28481329	t		miannu	Virus-activated kinase IKKɛ phosphorylated YAP at Ser403 and thereby triggered degradation of YAP in lysosomes and, consequently, relief of YAP-mediated inhibition of the cellular antiviral response. 	SIGNOR-277355	0.451
GABA-B receptor	complex	SIGNOR-C336	SIGNOR	GNB5	protein	O14775	UNIPROT	up-regulates activity	binding			9606									30541966	t		miannu	GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase.	SIGNOR-265064	0.458
NPFFR2	protein	Q9Y5X5	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256988	0.275
Factor FVIIa:TF	complex	SIGNOR-C319	SIGNOR	F5	protein	P12259	UNIPROT	down-regulates activity	cleavage	Arg737	LAAALGIrSFRNSSL	-1									10026263	t		lperfetto	Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 	SIGNOR-263646	0.496
gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	GABA-A (a4-b2-d) receptor	complex	SIGNOR-C326	SIGNOR	up-regulates activity	chemical activation			9606									18790874	t	brain	lperfetto	Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS).	SIGNOR-263784	0.8
MAPKAPK5	protein	Q8IW41	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser37	NVLSPLPsQAMDDLM	9606	BTO:0001286								17254968	t		llicata	Furthermore, we show that prak activates p53 by direct phosphorylation. prak phosphorylates p53 at ser37	SIGNOR-152847	0.752
RPE	protein	Q96AT9	UNIPROT	D-xylulose 5-phosphate(2-)	smallmolecule	CHEBI:57737	ChEBI	up-regulates quantity	chemical modification			9606									34775382	t		miannu	The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux.	SIGNOR-267068	0.8
STK11	protein	Q15831	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	up-regulates activity	phosphorylation			-1									14976552	t		lperfetto	We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP_activated protein kinase (AMPK).	SIGNOR-242602	0.595
FFAR1	protein	O14842	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257338	0.2
NR3C1	protein	P04150	UNIPROT	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity	transcriptional regulation			9600	BTO:0000567								26652733	t	inferred from family member		Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-270258	0.2
PLK1	protein	P53350	UNIPROT	CENPQ	protein	Q7L2Z9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr256	SQMKSMStFIEEAYK	9606	BTO:0000567								25670858	t		lperfetto	Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 	SIGNOR-265229	0.57
SMAD5	protein	Q99717	UNIPROT	SMAD5/SMAD4	complex	SIGNOR-C205	SIGNOR	form complex	binding			9606	 BTO:0000165;BTO:0002974; BTO:0002809								9442019	t		ggiuliani	These data suggest that activation of Smad5 and subsequent Smad5-DPC4 complex formation are key steps in the BMP signaling pathway, which mediates BMP-2-induced osteoblastic differentiation of the C2C12 mesenchymal cells.	SIGNOR-255775	0.659
MRPL10	protein	Q7Z7H8	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262383	0.647
UFD1	protein	Q92890	UNIPROT	CD4	protein	P01730	UNIPROT	down-regulates quantity by destabilization	binding			9606									20442859	t		miannu	These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L.	SIGNOR-252421	0.2
5-[6-[(4-methyl-1-piperazinyl)methyl]-1-benzimidazolyl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]-2-thiophenecarboxamide	chemical	CHEBI:91333	ChEBI	PLK1	protein	P53350	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258221	0.8
DLK1	protein	P80370	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates activity	binding			10090	BTO:0002572								21419176	t		gcesareni	Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts.	SIGNOR-172830	0.497
DCTN2	protein	Q13561	UNIPROT	Cytoplasmic_Dynein	proteinfamily	SIGNOR-PF67	SIGNOR	up-regulates activity	relocalization												25364732	t		lperfetto	ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores	SIGNOR-265018	0.2
GRB2	protein	P62993	UNIPROT	SOS1	protein	Q07889	UNIPROT	up-regulates activity	relocalization			9606	BTO:0001412								10570290	t	GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP	lperfetto	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.	SIGNOR-236792	0.91
RIPK1	protein	Q13546	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	phosphorylation	Ser15	NVIKMKSsDFLESAE	-1									18408713	t		miannu	These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1)	SIGNOR-276162	0.2
RNF34	protein	Q969K3	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	down-regulates quantity by destabilization	ubiquitination												26971449	t		lperfetto	We then examined the effect of necdin on ubiquitin-dependent degradation of PGC-1α using Rnf34, a PGC-1α E3 ubiquitin ligase22. Rnf34 reduced the PGC-1α level, and necdin completely inhibited the reduction (Fig. 4i). In addition, necdin strongly suppressed Rnf34-mediated ubiquitination of PGC-1α (Fig. 4j). Necdin also protected PGC-1α against ubiquitination mediated by Fbxw7, another PGC-1α E3 ubiquitin ligase23 (Fig. 4k). These data indicate that necdin stabilizes PGC-1α by inhibiting its degradation in the ubiquitin-proteasomal system.	SIGNOR-253393	0.324
CUDC-907	chemical	CID:54575456	PUBCHEM	HDAC3	protein	O15379	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191209	0.8
EIF2AK3	protein	Q9NZJ5	UNIPROT	EIF2S1	protein	P05198	UNIPROT	down-regulates	phosphorylation	Ser52	MILLSELsRRRIRSI	9606									17998206	t		lperfetto	The endoplasmic reticulum (er)-resident protein kinase perk attenuates protein synthesis in response to er stress through the phosphorylation of translation initiation factor eif2_ at serine 51 / a modification that blocks initiation	SIGNOR-159160	0.757
SMC3	protein	Q9UQE7	UNIPROT	Cohesin complex	complex	SIGNOR-C304	SIGNOR	form complex	binding												28430577	t		lperfetto	Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin	SIGNOR-263312	0.908
SELENOF	protein	O60613	UNIPROT	UGGT2	protein	Q9NYU1	UNIPROT	up-regulates activity	binding			9606									24415556	t		miannu	The enzymatic activity of UGGT2 is enhanced by complex formation with Sep15	SIGNOR-261373	0.2
KCNQ2	protein	O43526	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	up-regulates quantity	relocalization			9606									19298256	t		miannu	KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations.	SIGNOR-265982	0.8
profenamine	chemical	CHEBI:313639	ChEBI	MAPK10	protein	P53779	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0000142							19261605	t	Inhibitor of p38;ATP binding pocket	gcesareni	Indazole-based inhibitors exemplified by sr-3737 were potent inhibitors of both jnk3 (ic50 12 nm).	SIGNOR-184443	0.8
WWTR1	protein	Q9GZV5	UNIPROT	TEAD	proteinfamily	SIGNOR-PF22	SIGNOR	up-regulates activity	binding			9606									23431053	t		miannu	YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death	SIGNOR-230722	0.894
CTNNB1	protein	P35222	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates				9606	BTO:0000222								10937998	f		fspada	Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma).	SIGNOR-80592	0.555
MAPK3	protein	P27361	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Thr336	GGPGPERtPGSGSGS	9606									7889942	t		gcesareni	Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-34669	0.582
GRK2	protein	P25098	UNIPROT	IGF1R	protein	P08069	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1278	EPGFREVsFYYSEEN	-1									22509025	t		miannu	GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation	SIGNOR-276413	0.2
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	CDKN2B	protein	P42772	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11013220	f		irozzo	Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β.	SIGNOR-256286	0.588
SRC	protein	P12931	UNIPROT	STAP2	protein	Q9UGK3	UNIPROT	up-regulates activity	phosphorylation	Tyr322	GDGPAVDyENQDVAS	9606									12540842	t		lperfetto	To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src.	SIGNOR-247337	0.415
GABRG2	protein	P18507	UNIPROT	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263752	0.641
(5Z)-5-(quinoxalin-6-ylmethylidene)-1,3-thiazolidine-2,4-dione	chemical	CHEBI:45302	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates activity	chemical inhibition			10090	BTO:0000099								31195053	t		miannu	We identified the protective effect of the PI3Kγ inhibitor AS605240 against stroke-related injury in the mouse model of transient intraluminal middle cerebral artery occlusion (tMCAO). in this study, the effects of AS605240 on astrocytes were studied in cell cultures.	SIGNOR-262224	0.8
PRKCG	protein	P05129	UNIPROT	KIR3DL1	protein	P43629	UNIPROT	down-regulates	phosphorylation	Ser415	QRKITRPsQRPKTPP	9606									17911614	t		gcesareni	Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.	SIGNOR-158133	0.2
DYRK1A	protein	Q13627	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Thr529	TPGSRSRtPSLPTPP	9606									21215781	t	The effect has been demonstrated using P10636-8	lperfetto	Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna	SIGNOR-171038	0.44
CKM complex	complex	SIGNOR-C406	SIGNOR	SMAD1	protein	Q15797	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser206	SSSTYPHsPTSSDPG	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-273144	0.346
PRKCB	protein	P05771	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser594	HKAAVPAsEKLLLLK	9606									15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-129292	0.289
NRG2	protein	O14511	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606									14967450	t		gcesareni	The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4.	SIGNOR-122056	0.78
Phenelzine	chemical	CHEBI:8060	ChEBI	MAOA	protein	P21397	UNIPROT	down-regulates activity	chemical inhibition			-1									18426226	t		Luana	Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine.	SIGNOR-257777	0.8
GPR35	protein	Q9HC97	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256996	0.252
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9606	BTO:0000830								15526160	f		miannu	 c-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. 	SIGNOR-254952	0.7
UQCRB	protein	P14927	UNIPROT	Mitochondrial respiratory chain complex III	complex	SIGNOR-C279	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits	SIGNOR-262194	0.924
TRAF6	protein	Q9Y4K3	UNIPROT	MALT1	protein	Q9UDY8	UNIPROT	up-regulates	ubiquitination			9606	BTO:0000782								17948050	t		gcesareni	Traf6 associates with malt1 in response to t-cell activation and can function as an e3 ligase for malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of malt1. Multiple lysine residues in the c-terminus of malt1 serve as acceptor sites for the assembly of polyubiquitin chains. (articolo-abstract)	SIGNOR-158554	0.746
MAPK14	protein	Q16539	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20162623	f	Indirect:regulation	miannu	Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). 	SIGNOR-251837	0.2
ILF2	protein	Q12905	UNIPROT	NF90-NF45	complex	SIGNOR-C443	SIGNOR	form complex	binding			-1									18458058	t		miannu	Nuclear factor 90 (NF90) and its C-terminally extended isoform, NF110, have been isolated as DNA- and RNA-binding proteins together with the less-studied protein NF45. These complexes have been implicated in gene regulation, but little is known about their cellular roles and whether they are redundant or functionally distinct. We show that heterodimeric core complexes, NF90-NF45 and NF110-NF45, exist within larger complexes that are more labile and contain multiple NF90/110 isoforms and additional proteins. This study identified NF45 as an unstable regulatory subunit of NF90-NF45 complexes and uncovered their critical role in normal cell division. Furthermore, the study revealed that NF90 is functionally distinct from NF110 and is more important for cell growth.	SIGNOR-268487	0.591
MYO9A	protein	B2RTY4	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260508	0.546
PTK6	protein	Q13882	UNIPROT	EPS8	protein	Q12929	UNIPROT	up-regulates activity	phosphorylation	Tyr535	LKTQPKKyAKSKYDF	9606	BTO:0000007								28214294	t		miannu	Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis. 	SIGNOR-263191	0.366
CXCL8	protein	P10145	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252288	0.7
CUL3	protein	Q13618	UNIPROT	TNFAIP1	protein	Q13829	UNIPROT	up-regulates activity	binding			9606									19782033	t		miannu	 BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.	SIGNOR-264232	0.473
AKT2	protein	P31751	UNIPROT	PKP1	protein	Q13835	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser185	KTTQNRYsFYSTCSG	-1									23444369	t		miannu	Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry.	SIGNOR-273494	0.27
propionic acid	chemical	CHEBI:30768	ChEBI	FFAR2	protein	O15552	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257489	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TWIST1	protein	Q15672	UNIPROT	up-regulates	phosphorylation	Ser42	GGRKRRSsRRSAGGG	9606									20400976	t		lperfetto	Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis.	SIGNOR-244373	0.2
FYN	protein	P06241	UNIPROT	CD300LF	protein	Q8TDQ1	UNIPROT	up-regulates activity	phosphorylation	Tyr263	AEDQEPTyCNMGHLS										17202342	t		lperfetto	Y236 (YVTM) and Y263 (YCNM) fit with the consensus motif reported to bind the p85α regulatory subunit of PI3K (16). |The association between IREM-1 and p85α was only perceived in the presence of c-Fyn, suggesting that tyrosine phosphorylation of IREM-1 cytoplasmic tail of IREM-1 was required for the interaction.	SIGNOR-275620	0.351
IFNGR1	protein	P15260	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates	binding			9606									17063185	t		flangone	Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively	SIGNOR-150194	0.691
RAD50	protein	Q92878	UNIPROT	MRE11/RAD50/NBS1	complex	SIGNOR-C147	SIGNOR	form complex	binding												17713585	t		lperfetto	The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50.	SIGNOR-251506	0.911
CHEK2	protein	O96017	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity	phosphorylation	Ser124	PALKRSHsDSLDHDI	9606									12676583	t		Manara	Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A	SIGNOR-260835	0.837
KDM5C	protein	P41229	UNIPROT	SYN1	protein	P17600	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									31691806	f		miannu	The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice.	SIGNOR-264314	0.353
BACH2	protein	Q9BYV9	UNIPROT	XBP1	protein	P17861	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0005014								24821775	f		miannu	Expression and activity of the UPR downstream effector XBP1 is regulated positively by STAT5 and negatively by the B-cell-specific transcriptional repressors BACH2 and BCL6.	SIGNOR-253756	0.395
LCK	protein	P06239	UNIPROT	IL2RB	protein	P14784	UNIPROT	unknown	phosphorylation	Tyr418	LSGEDDAyCTFPSRD	-1									10214954	t			Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510.	SIGNOR-251378	0.629
TKT	protein	P29401	UNIPROT	sedoheptulose 7-phosphate	smallmolecule	CHEBI:15721	ChEBI	up-regulates quantity	chemical modification			9606									24929114	t		miannu	Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates.	SIGNOR-267087	0.8
CSNK2A1	protein	P68400	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates activity	phosphorylation	Ser129	NEAYEMPsEEGYQDY	9606									10617630	t		lperfetto	In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2.| together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of alpha-synuclein could affect its binding to membranes.	SIGNOR-73803	0.492
MAPK14	protein	Q16539	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									10085140	t		gcesareni	On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38.	SIGNOR-65601	0.786
ROCK1	protein	Q13464	UNIPROT	SOX9	protein	P48436	UNIPROT	up-regulates	phosphorylation	Ser181	YQPRRRKsVKNGQAE	9606									20039424	t		lperfetto	Rho kinase-dependent activation of sox9 in chondrocytes. In vitro, rock directly phosphorylated sox9 at ser(181), and the overexpression of rock or the activation of the rhoa pathway in sw1353 chondrosarcoma cells increased sox9(ser181) phosphorylation	SIGNOR-162643	0.31
SIK1	protein	P57059	UNIPROT	CRTC2	protein	Q53ET0	UNIPROT	down-regulates	phosphorylation	Ser171	SALNRTSsDSALHTS	9606									16817901	t		miannu	These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities.	SIGNOR-147707	0.63
NMBR	protein	P28336	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257373	0.448
3-isobutyl-1-methyl-7H-xanthine	smallmolecule	CHEBI:34795	ChEBI	PDE1B	protein	Q01064	UNIPROT	down-regulates activity	chemical inhibition			9606									22014080	t			Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors.	SIGNOR-253400	0.8
GABA-A (a6-b2-d) receptor	complex	SIGNOR-C328	SIGNOR	CRHR2	protein	Q13324	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268597	0.2
Activated PSC	phenotype	SIGNOR-PH224	SIGNOR	TGFB2	protein	P61812	UNIPROT	up-regulates quantity				9606		BTO:0000988							38540204	t		miannu	Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction	SIGNOR-277674	0.7
SLBP	protein	Q14493	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265373	0.2
MECP2	protein	P51608	UNIPROT	CRH	protein	P06850	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000142								17108082	t		Luana	Collectively, these results point to a specific association between WT MeCP2 and the methylated promoter region of Crh in vivo. In contrast, the MeCP2308 protein was not detected at the Crh promoter. | Thus, the results of seqChIP indicate that MeCP2 preferentially associates with a transcriptionally inactive, dimethyl-histone H3 Lys-9-rich form of the Crh promoter in mice.	SIGNOR-264548	0.481
LCK	protein	P06239	UNIPROT	SH2B3	protein	Q9UQQ2	UNIPROT	up-regulates	phosphorylation	Tyr273	LEMPDNLyTFVLKVK	9606									9169414	t		lperfetto	In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation.	SIGNOR-48850	0.587
NR3C1	protein	P04150	UNIPROT	NFIL3	protein	Q16649	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19805059	t		miannu	GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription	SIGNOR-268051	0.301
SIM2	protein	Q14190	UNIPROT	ARNT	protein	P27540	UNIPROT	up-regulates activity	binding			-1									9020169	t	2	miannu	We demonstrate that both SIM1 and SIM2 can heterodimerize via their helix-loop-helix·PAS regions with ARNT, but not with AHR, and that they do not form homodimers. Furthermore, SIM1 may have a dual role, both negatively affecting AHR·ARNT binding to the XRE and also acting in concert with ARNT as a novel DNA-binding heterodimer.	SIGNOR-240808	0.51
LEPR	protein	P48357	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								11018044	t		miannu	LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. 	SIGNOR-263495	0.751
JAK1	protein	P23458	UNIPROT	IL10RA	protein	Q13651	UNIPROT	up-regulates activity	phosphorylation	Tyr446	AAVAFQGyLRQTRCA										10433356	t			Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3). 	SIGNOR-251338	0.801
LPAR	proteinfamily	SIGNOR-PF2	SIGNOR	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-269969	0.2
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0000007								14976264	f		lperfetto	Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress	SIGNOR-252938	0.7
KDM5B	protein	Q9UGL1	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264303	0.2
NR1D2	protein	Q14995	UNIPROT	ARNTL	protein	O00327	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24577401	t		miannu	A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription.	SIGNOR-268006	0.482
APC-c	complex	SIGNOR-C150	SIGNOR	Mitotic_checkpoint	phenotype	SIGNOR-PH28	SIGNOR	up-regulates				9606									25092294	f		miannu	We then found that the joint action of TRIP13 and p31comet also promotes MCC disassembly, releases APC/C from checkpoint inhibition, and inactivates the mitotic checkpoint.	SIGNOR-265978	0.7
AURKB	protein	Q96GD4	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates	phosphorylation			9606									10464286	t		gcesareni	Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.	SIGNOR-265321	0.2
CCK	protein	P06307	UNIPROT	CCKBR	protein	P32239	UNIPROT	up-regulates	binding			9606									10368033	t		gcesareni	Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b	SIGNOR-66339	0.867
SETD2	protein	Q9BYW2	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	methylation	Lys525	QLNMLGEkLLGPNAS	9606	BTO:0000007								28753426	t		Gianni	SETD2 enhances antiviral immunity by directly methylating STAT1 on K525. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response.	SIGNOR-269091	0.269
PKN1	protein	Q16512	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser637	VDLSKVTsKCGSLGN	9606	BTO:0000938	BTO:0000975							11104762	t	The effect has been demonstrated using P10636-8	lperfetto	Phosphorylation of tau is regulated by pknthere is a pkn-specific phosphorylation site, ser-320, in mbdsthus pkn serves as a regulator of microtubules by specific phosphorylation of tau, which leads to disruption of tubulin assembly.	SIGNOR-84958	0.334
DUSP9	protein	Q99956	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	dephosphorylation			9606		BTO:0000887							11988087	t	This interaction is observed for Mus musculus Pyst3 gene, which encodes for DUSP9	gcesareni	These properties define the ability of this enzyme to dephosphorylate and inactivate erk1/2 and p38a, but not jnk (c-jun n-terminal kinase) in vivo.	SIGNOR-87150	0.687
MK-2206	chemical	CHEBI:67271	ChEBI	AKT3	protein	Q9Y243	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001286								21841310	t		gcesareni	Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation.	SIGNOR-176049	0.8
PRKCQ	protein	Q04759	UNIPROT	WIPF1	protein	O43516	UNIPROT	up-regulates activity	phosphorylation	Ser488	RNESRSGsNRRERGA	-1									12504004	t		lperfetto	TCR engagement also causes PKCtheta-dependent phosphorylation of WIP, causing the disengagement of WASP from the WIP-WASP complex, thereby releasing it from WIP inhibition. These results suggest that the ZAP-70-CrkL-WIP pathway and PKCtheta link TCR to WASP activation. | These results suggest that phosphorylation at S488 disrupts WIP binding to WASP.	SIGNOR-249181	0.328
KLF4	protein	O43474	UNIPROT	PBX1	protein	P40424	UNIPROT	up-regulates activity	binding			9606	BTO:0000093								21746878	t		miannu	We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.	SIGNOR-267237	0.457
KDM4C	protein	Q9H3R0	UNIPROT	H2AC4	protein	P04908	UNIPROT	down-regulates activity	demethylation	Lys 10	GRGKQGGkARAKAKT	9606									29207681	t		miannu	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 	SIGNOR-263863	0.2
L-tryptophan	smallmolecule	CHEBI:16828	ChEBI	5-hydroxy-L-tryptophan	smallmolecule	CHEBI:17780	ChEBI	up-regulates quantity	precursor of			9606									31024440	t	brain	lperfetto	In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)].	SIGNOR-264184	0.8
SLIT1	protein	O75093	UNIPROT	ROBO	proteinfamily	SIGNOR-PF14	SIGNOR	up-regulates	binding			9606									16226035	t		gcesareni	Here we describe and compare two human robo3 isoforms, robo3a and robo3b, which differ by the insertion of 26 amino acids at the n-terminus, and these forms appear to be evolutionary conserved. We investigated the bioactivity of these isoforms and show that they have different binding properties to slit.	SIGNOR-141111	0.893
TRIM63	protein	Q969Q1	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys365	SLASQATkDGKKDKK	-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). 	SIGNOR-272741	0.413
G6PC1	protein	P35575	UNIPROT	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	up-regulates quantity	chemical modification			9606									12093795	t		miannu	Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis	SIGNOR-266564	0.8
STK19	protein	P49842	UNIPROT	NRAS	protein	P01111	UNIPROT	up-regulates activity	phosphorylation	Ser89	FAINNSKsFADINLY	9606	BTO:0003476								30712867	t		lperfetto	STK19 Phosphorylates NRAS Protein at Serine 89|STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation.|	SIGNOR-264566	0.312
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1675	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120192	0.321
STK11	protein	Q15831	UNIPROT	SIK1	protein	P57059	UNIPROT	up-regulates activity	phosphorylation	Thr182	KSGEPLStWCGSPPY	9606									18946175	t		miannu	Salt inducible kinase (SIK) 1, a member of the AMP-activated kinase (AMPK) family, is activated by the AMPK-activator LKB1 which phosphorylates SIK1 at Thr182. 	SIGNOR-262844	0.566
ASXL1	protein	Q8IXJ9	UNIPROT	RARA	protein	P10276	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16606617	f		irozzo	We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR.	SIGNOR-255933	0.456
RPL39	protein	P62891	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262490	0.836
MAPK1	protein	P28482	UNIPROT	DYNC1I2	protein	Q13409	UNIPROT	unknown	phosphorylation	Ser87	YWVPPPMsPSSKSVS	10090									22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262772	0.2
SYNJ1	protein	O43426	UNIPROT	MYO1E	protein	Q12965	UNIPROT	up-regulates activity	binding			10116		BTO:0000142							17257598	t		miannu	We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. 	SIGNOR-265423	0.438
Caspase 8 complex	complex	SIGNOR-C231	SIGNOR	CYCS	protein	P99999	UNIPROT	up-regulates activity				9606	BTO:0000661								10364179	f	Translocation from Mitochondria to Cytosol	lperfetto	Caspase-8 triggered rapid cytochrome c release from mitochondria. The effect was indirect.	SIGNOR-256473	0.495
INSR	protein	P06213	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity	phosphorylation	Tyr576	RYMEDSTyYKASKGK	-1									9507031	t			P125(Fak) sequence comprising amino acids 568-582, which contains tyrosines 576 and 577 of the kinase domain regulatory loop, is phosphorylated by the insulin receptor. p125(Fak) phosphorylation by the receptor results in its activation.	SIGNOR-251323	0.36
NFE2L2	protein	Q16236	UNIPROT	HMOX1	protein	P09601	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24024136	t		irozzo	In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).	SIGNOR-256276	0.669
RBCK1	protein	Q9BYM8	UNIPROT	IRF3	protein	Q14653	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								18711448	t		miannu	Here we show that the E3 ubiquitin ligase RBCC protein interacting with PKC1 (RBCK1) catalyzes the ubiquitination and degradation of IRF3. We transfected 293 cells with expression plasmids for Flag-IRF3, HA-ubiquitin, and HA-RBCK1. Coimmunoprecipitation and western blot analysis indicated that RBCK1 significantly polyubiquitinated IRF3 (Figure 4D).	SIGNOR-271737	0.331
PPP2CA	protein	P67775	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates	dephosphorylation	Ser253	APRRRAVsMDNSNKY	9606									20110348	t		gcesareni	Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a.	SIGNOR-163680	0.411
L-serine	chemical	CHEBI:17115	ChEBI	glycine	smallmolecule	CHEBI:15428	ChEBI	up-regulates quantity	precursor of			9606									32439610	t		lperfetto	Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. 	SIGNOR-268222	0.8
IKBKE	protein	Q14164	UNIPROT	TANK	protein	Q92844	UNIPROT	down-regulates activity	phosphorylation	Ser178	TATETQCsVPIQCTD	9534	BTO:0000298								10759890	t		miannu	IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex	SIGNOR-262716	0.734
TAF7	protein	Q15545	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263928	0.896
midostaurin	chemical	CHEBI:63452	ChEBI	PRKCA	protein	P17252	UNIPROT	down-regulates activity	chemical inhibition												16969355	t		lperfetto	Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases	SIGNOR-261981	0.8
MAML1	protein	Q92585	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606									11390662	t		gcesareni	Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1.Maml1 functions as a transcriptional co-activator for notch signalling.	SIGNOR-86117	0.921
GEMIN6	protein	Q8WXD5	UNIPROT	SMN complex	complex	SIGNOR-C158	SIGNOR	form complex	binding												12065586	t		lperfetto	SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry.	SIGNOR-253120	0.827
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRIA2	protein	P42262	UNIPROT	up-regulates activity	chemical activation			9606									30825796	t		miannu	In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses	SIGNOR-264609	0.8
KCNQ5	protein	Q9NR82	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	up-regulates quantity	relocalization			9606									19298256	t		miannu	KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations.	SIGNOR-265983	0.8
CSNK2A1	protein	P68400	UNIPROT	PIN4	protein	Q9Y237	UNIPROT	down-regulates activity	phosphorylation	Ser19	AGKGGAAsGSDSADK	9606	BTO:0000567								12860119	t		lperfetto	As proved by MALDI-TOF mass spectrometry and MS/MS fragmentation, hPar14 is phosphorylated at Ser19 in vitro and in vivo. In human HeLa cells the protein is most likely modified by casein kinase 2 (CK2). |In contrast to wild-type hPar14, the in vitro DNA-binding affinity of the Glu19 mutant is strongly reduced, suggesting that only the dephosphorylated protein is the active DNA-binding form of hPar14 in the nucleus.	SIGNOR-265753	0.331
KLF2	protein	Q9Y5W3	UNIPROT	THBD	protein	P07204	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19661484	f		miannu	 Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4. 	SIGNOR-254543	0.442
FLT3	protein	P36888	UNIPROT	FLT3	protein	P36888	UNIPROT	up-regulates activity	phosphorylation	Tyr589	TGSSDNEyFYVDFRE	10090	BTO:0001516								16627759	t		lperfetto	In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated.|This finding suggests that the combination of tyrosine residues 589 and 591 is required for activation of STAT-5 signaling pathways.	SIGNOR-271926	0.2
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	SP1	protein	P08047	UNIPROT	up-regulates activity	binding			9606	BTO:0001412								18025157	t			We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein.	SIGNOR-255749	0.2
AURKA	protein	O14965	UNIPROT	TACC3	protein	Q9Y6A5	UNIPROT	up-regulates activity	phosphorylation	Ser558	ESALRKQsLYLKFDP	9606	BTO:0001109								17545617	t		miannu	 We show that this conserved serine on human TACC3 (Ser(558)) is also phosphorylated by Aurora A. Moreover, phosphorylation of TACC3 by Aurora A in human cells is essential for its proper localization to centrosomes and proximal mitotic spindles. Inhibition of Aurora A with the selective small molecule inhibitor MLN8054 in cultured human tumor cells resulted in mislocalization of TACC3 away from mitotic spindles in a concentration-dependent manner.	SIGNOR-262655	0.934
GPR119	protein	Q8TDV5	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257040	0.281
HSPA8	protein	P11142	UNIPROT	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	down-regulates quantity by destabilization	binding												24789820	t		lperfetto	Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane.	SIGNOR-260718	0.525
KIF13A	protein	Q9H1H9	UNIPROT	TTC19	protein	Q6DKK2	UNIPROT	up-regulates activity	binding			9606									20208530	t		miannu	We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B.	SIGNOR-265540	0.445
EEF1A1	protein	P68104	UNIPROT	Translational_elongation	phenotype	SIGNOR-PH210	SIGNOR	up-regulates				9606									23699257	f		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269393	0.7
BTK	protein	Q06187	UNIPROT	GTF2I	protein	P78347	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000776								9012831	t		gcesareni	We now describe a protein, bap-135, that is associated with btk in b cells and is a substrate for phosphorylation by btk.Taken together, these observations suggest that bap-135 may reside downstream of btk in a signaling pathway originating at the bcr.	SIGNOR-46060	0.532
GATA4	protein	P43694	UNIPROT	α-Catenin	proteinfamily	SIGNOR-PF72	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002320								21598020	t		miannu	GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter	SIGNOR-265815	0.253
NTRK2	protein	Q16620	UNIPROT	FRS3	protein	O43559	UNIPROT	up-regulates activity	phosphorylation	Tyr455	PARSSDSyAVIDLKK	9606									11432792	t		miannu	The tyrosine phosphoryla tion of FRS2/SNT2 was stimulated dependently on the TrkB activation. to explore the possibility that tyrosine residues 417 and 455 on FRS2/SNT2 function as the binding sites for Shp2, we coexpressed Y417F or Y455F phenylalanine mutants and the Y417/455F double phenylalanine mutant of Myc/Histagged FRS2/SNT2 with TrkB. The active TrkB induced somewhat reduced tyrosine phosphorylation of all of the phenylalanine mutants of FRS2/SNT2 in comparison with tyrosine phosphorylation of the wild type 	SIGNOR-250203	0.584
clozapine	chemical	CHEBI:3766	ChEBI	HTR1F	protein	P30939	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258518	0.8
MAPK3	protein	P27361	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates activity	phosphorylation	Ser282	TAPLSPMsPPGYKLV	9606	BTO:0000567								9535909	t		lperfetto	These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.	SIGNOR-249467	0.626
PPP1CB	protein	P62140	UNIPROT	AHCYL1	protein	O43865	UNIPROT	unknown	dephosphorylation	Ser68	RSLSRSIsQSSTDSY	10090									17635105	t			Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1.	SIGNOR-248571	0.2
NANOG	protein	Q9H9S0	UNIPROT	GATA4	protein	P43694	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003298								22795133	f		lperfetto	Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)	SIGNOR-253162	0.455
GAD2	protein	Q05329	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	down-regulates quantity	chemical modification			9606									32041144	t		miannu	Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce γ-aminobutyric acid (GABA), which exhibits several well-known physiological functions.	SIGNOR-267554	0.8
PPP3CC	protein	P48454	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates activity	dephosphorylation	Ser75	EIRSRHSsYPAGTED	9606	BTO:0000007								10195903	t			Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 	SIGNOR-248528	0.372
A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	JAG1	protein	P78504	UNIPROT	up-regulates quantity by expression				10090									25786978	f		lperfetto	First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs.	SIGNOR-253288	0.31
PIK3AP1	protein	Q6ZUJ8	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606	BTO:0000801								22187458	t		gcesareni	Bcap is constitutively phosphorylated and associated with the p85 subunit of pi3k in macrophages. Tlr signaling causes the phosphorylation of the small amount of bcap that is associated with membranes in the resting state or the translocation of phosphorylated bcap from the cytoplasm to the membrane. This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Bcap is an essential activator of the pi3k pathway downstream of tlr signaling	SIGNOR-252701	0.502
TBX2	protein	Q13207	UNIPROT	MYOG	protein	P15173	UNIPROT	down-regulates activity	binding			9606									24470334	t			We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity.	SIGNOR-251561	0.252
PPP2CB	protein	P62714	UNIPROT	TRAF2	protein	Q12933	UNIPROT	down-regulates activity	dephosphorylation	Thr117	DGCTWKGtLKEYESC	10090									17188031	t			We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity. 	SIGNOR-248597	0.2
FYN	protein	P06241	UNIPROT	CD300LF	protein	Q8TDQ1	UNIPROT	up-regulates activity	phosphorylation	Tyr236	VDQVEVEyVTMASLP										17202342	t		lperfetto	Y236 (YVTM) and Y263 (YCNM) fit with the consensus motif reported to bind the p85α regulatory subunit of PI3K (16). |The association between IREM-1 and p85α was only perceived in the presence of c-Fyn, suggesting that tyrosine phosphorylation of IREM-1 cytoplasmic tail of IREM-1 was required for the interaction.	SIGNOR-275619	0.351
LPAR1	protein	Q92633	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256975	0.409
EGR1	protein	P18146	UNIPROT	GDF15	protein	Q99988	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000018								17715378	f	 	 	Isochaihulactone treatment increased the luciferase activity of NAG-1 in A549 cells transfected with the NAG-1 promoter construct. This induction increased expression of NAG-1 that was p53-independent and Sp1-dependent. Our findings suggest that NAG-1 expression is up-regulated by isochaihulactone through an ERK-dependent pathway involving the activation of EGR-1.	SIGNOR-254266	0.39
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	ERCC6	protein	Q03468	UNIPROT	up-regulates													24086043	f		lperfetto	TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2.	SIGNOR-275691	0.7
CDK2	protein	P24941	UNIPROT	ARID4A	protein	P29374	UNIPROT	down-regulates	phosphorylation	Ser864	RKILGQSsPEKKIRI	9606									21148318	t		gcesareni	In the present study we identified rbp1 as a novel cdk substrate. Rbp1 is phosphorylated by cdk2 on serines 864 and 1007, which are n- and c-terminal to the lxcxe motif, respectively. Cdk2-mediated phosphorylation of rbp1 or prb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation	SIGNOR-170455	0.437
PPP2R5C	protein	Q13362	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates	dephosphorylation	Ser44	ESEESQDsSDSIGSS	9606									20730097	t		lperfetto	We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf4	SIGNOR-167572	0.2
SIRT1	protein	Q96EB6	UNIPROT	EP300	protein	Q09472	UNIPROT	down-regulates	deacetylation	Lys1020	EERSTELkTEIKEEE	9606	BTO:0000150								19047049	t		gcesareni	Sirt1 induces deacetylation and repression of p300 itself (81). Mutational analysis demonstrated that sirt1 repression of p300 involves both lysine 1020 and lysine 1024	SIGNOR-182507	0.829
PTPN1	protein	P18031	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates	dephosphorylation	Tyr1021	PNEGDNDyIIPLPDP	9606									18567737	t		gcesareni	Interestingly, resveratrol increased the activity of protein tyrosine phosphatase ptp1b, which dephosphorylates pdgf-stimulated phosphorylation at tyrosine-751 and tyrosine-716 on pdgfr with concomitant reduction in akt and erk1/2 kinase activity. these results for the first time provide evidence that the stilbene resveratrol targets ptp1b to inhibit pdgfr mitogenic signaling.	SIGNOR-179068	0.679
CRB3	protein	Q9BUF7	UNIPROT	AMOT/MPP5/INADL/LIN7C	complex	SIGNOR-C27	SIGNOR	up-regulates	binding			10090	BTO:0000150								21145499	t		milica	Interestingly, knockdown of crb3, which facilitates crumbs complex assembly and localization to the apical junctions disrupted taz/yap interaction with multiple components of the complex, whereas the other knockdowns only disrupted their respective interaction.	SIGNOR-170399	0.537
SRC	protein	P12931	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606	BTO:0000007								14551213	t		lperfetto	In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants.	SIGNOR-247341	0.782
STAG2	protein	Q8N3U4	UNIPROT	CD69	protein	Q07108	UNIPROT	up-regulates				9606									14660624	f		miannu	Stag2 is able to enhance the activity of the tumor necrosis factor alpha, the cd69, and the human immunodeficiency virus long terminal repeat promoters in a nf-kappab-dependent manner.	SIGNOR-119985	0.2
isoprenaline	chemical	CHEBI:64317	ChEBI	ADRB3	protein	P13945	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								8982677	t		miannu	K i values of the agonists for [~25I]iodocyanopindolol binding to the COS-7 cell membranes are shown in Table 1. In the membranes expressing one of the 13-adrenoceptor subtypes, both isoproterenol and T-0509 caused monophasic dis- placement of [~25I]iodocyanopindolol, suggesting a single binding site of the agonists.	SIGNOR-258577	0.8
DYRK1A	protein	Q13627	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser329	STISGRLsPIMTEQD	9606									11311120	t		lperfetto	The kinase dyrk1a phosphorylates the transcription factor fkhr at ser329 in vitro, a novel in vivo phosphorylation siteser(329) phosphorylation also decreases the ability of fkhr to stimulate gene transactivation and reduces the proportion of fkhr present in the nucleus	SIGNOR-252909	0.521
ID1	protein	P41134	UNIPROT	MYOD/E12E47	complex	SIGNOR-C127	SIGNOR	down-regulates activity	binding			10090									9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241128	0.572
VAV1	protein	P15498	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260581	0.755
PTEN	protein	P60484	UNIPROT	PTK2	protein	Q05397	UNIPROT	down-regulates activity	dephosphorylation	Tyr397	SVSETDDyAEIIDEE	9606	BTO:0000356								10400703	t			The tumor suppressor PTEN is a phosphatase with sequence homology to tensin. PTEN dephosphorylates phosphatidylinositol 3,4, 5-trisphosphate (PIP3) and focal adhesion kinase (FAK), and it can inhibit cell growth, invasion, migration, and focal adhesions. We investigated molecular interactions of PTEN and FAK in glioblastoma and breast cancer cells lacking PTEN. The PTEN trapping mutant D92A bound wild-type FAK, requiring FAK autophosphorylation site Tyr397	SIGNOR-248547	0.815
PRKCA	protein	P17252	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates	phosphorylation	Ser985	PHLDRLVsARSVSPT	9606									8294430	t		fstefani	These data show that phosphorylation of ser985 is a key mechanism for the negative regulation of hgf/sf receptor.	SIGNOR-37718	0.259
PRKCD	protein	Q05655	UNIPROT	DAB2	protein	P98082	UNIPROT	down-regulates	phosphorylation	Ser24	QAAPKAPsKKEKKKG	9606	BTO:0000782								15280374	t		gcesareni	Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2.	SIGNOR-127198	0.3
MECP2	protein	P51608	UNIPROT	YBX1	protein	P67809	UNIPROT	up-regulates activity	binding												16251272	t		lperfetto	In this study, we show that MeCP2 interacts with the RNA-binding protein Y box-binding protein 1 and regulates splicing of reporter minigenes. Importantly, we found aberrant alternative splicing patterns in a mouse model of RTT. Thus, we uncovered a previously uncharacterized function of MeCP2 that involves regulation of splicing, in addition to its role as a transcriptional repressor.	SIGNOR-277700	0.521
MECP2	protein	P51608	UNIPROT	TET1	protein	Q8NFU7	UNIPROT	up-regulates activity	binding												28594324	t		lperfetto	MeCP2 and its partners, splicing factor Y-box binding protein 1 (YB-1) and methylcytosine dioxygenase 1 (Tet1), bind to BDNF chromatin in naı ̈ve but dissociate during conditioning|Knockdown of MeCP2 shows it is instrumental for splicing and inhibits Tet1 and CTCF binding thereby negatively impacting DNA methylation and conditioning-dependent splicing regulation. Thus, mutations in MECP2 can have secondary effects on DNA methylation and alternative splicing.	SIGNOR-277701	0.44
Activated PSC	phenotype	SIGNOR-PH224	SIGNOR	ACTA2	protein	P62736	UNIPROT	up-regulates quantity				9606		BTO:0000988							28232471	t		miannu	Upon activa- tion, PSCs express the myofibroblast protein α-smooth mus- cle actin (αSMA, gene name Acta2) and secrete factors that stimulate tumor growth, cell survival, and metastasis. As a result of the selective high expression of αSMA, we refer to these periglandular FAP+ αSMAhigh fibroblasts as myofibroblastic CAFs (myCAFs).	SIGNOR-277677	0.7
TGFB1	protein	P01137	UNIPROT	COL1A1	protein	P02452	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000988							35816922	t		miannu	COL1A1 expression is regulated by upstream genes and the binding of regulatory elements at multiple binding sites upstream of its promoter. During cancer progression, CAFs reorganize and cross-link COL1A1, which accumulates and stiffens in the tumor stroma [12], [18]. This process may involve fibrogenic factors, especially transforming growth factor-beta (TGF-β1). Indeed, a TGF-β1 response sequence was identified 174 nucleotides upstream of the COL1A1 transcription start site, and was shown to up-regulate COL1A1 promoter activity	SIGNOR-277678	0.499
CDK1	protein	P06493	UNIPROT	MAP3K11	protein	Q16584	UNIPROT	down-regulates activity	phosphorylation	Ser548	GQAWGRQsPRRLEDS	-1									35843311	t		miannu	Using in vitro kinase assays and phosphomutants, we determined that CDK1 phosphorylates MLK3 on Ser548 and decreases MLK3 activity during mitosis, whereas CDK2 phosphorylates MLK3 on Ser770 and increases MLK3 activity during G1/S and G2 phases.	SIGNOR-277603	0.2
GNB2	protein	P62879	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates				9606									23074268	f		gcesareni	Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance.	SIGNOR-199132	0.2
RPS6KA3	protein	P51812	UNIPROT	H2BC3	protein	P33778	UNIPROT	unknown	phosphorylation	Ser33	DGKKRKRsRKESYSI	9606									21646345	t		lperfetto	Here, we studied the histone h2b core domain and found that phosphorylation of h2b serine 32 occurs in normal cycling and mitogen-stimulated cells. Notably, this phosphorylation is elevated in skin cancer cell lines and tissues compared with normal counterparts. We identified ribosomal s6 kinase 2 (rsk2) as the kinase responsible for h2bs32 phosphorylation.	SIGNOR-174026	0.2
7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-2-ol	chemical	CHEBI:111176	ChEBI	DRD3	protein	P35462	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258725	0.8
RASA1	protein	P20936	UNIPROT	HRAS	protein	P01112	UNIPROT	down-regulates	binding			9606									10394594	t		lperfetto	The Ras protein sits at the center of a many-tiered cascade of molecular interactions. Most of the proteins along this cascade are activated by phosphorylation, but Ras uses a bound guanine nucleotide to toggle between its “on” and “off” states. Ras hydrolyzes GTP to GDP fairly quickly, turning itself “off,” and a collection of GTPase-activating proteins (GAPs) speed up the processthe complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved.	SIGNOR-68990	0.842
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	KAR	proteinfamily	SIGNOR-PF57	SIGNOR	up-regulates activity	chemical activation			9606									15919192	t		miannu	Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1–4); five kainate receptor genes (GluR5–7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits.	SIGNOR-264694	0.8
SOX6	protein	P35712	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003298								26893351	f			We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST	SIGNOR-255822	0.288
CDK1	protein	P06493	UNIPROT	CDC25A	protein	P30304	UNIPROT	up-regulates	phosphorylation	Ser18	RRLLFACsPPPASQP	9606									12411508	t		lperfetto	Mitotic stabilization of cdc25a reflects its phosphorylation on ser17 and ser115 by cyclin b-cdk1, modifications required to uncouple cdc25a from its ubiquitin-proteasome-mediated turnover.	SIGNOR-95260	0.837
NDUFA13	protein	Q9P0J0	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added	SIGNOR-262153	0.784
STAT5A	protein	P42229	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates	transcriptional regulation			9606									12540601	f		fspada	We have shown that stat5a is associated with the glucocorticoid receptor during adipogenesis in a highly regulated manner.	SIGNOR-210146	0.7
RPA3	protein	P35244	UNIPROT	Nucleotide-excision_repair	phenotype	SIGNOR-PH209	SIGNOR	up-regulates													24086043	f		lperfetto	The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275707	0.7
AKT1	protein	P31749	UNIPROT	MXD1	protein	Q05195	UNIPROT	down-regulates	phosphorylation	Ser145	IERIRMDsIGSTVSS	9606									19526459	t		llicata	Here, we present evidence that akt inhibits mad1-mediated transcription repression by physical interaction with and phosphorylation of mad1.	SIGNOR-252525	0.369
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGA4	protein	Q9Y5G9	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265697	0.2
SPRY4	protein	Q9C004	UNIPROT	TESK1	protein	Q15569	UNIPROT	down-regulates activity	binding			9606									15584898	t		miannu	Spry4 negatively regulates the kinase activity of TESK1 by associating with it through the C-terminal cysteine-rich region of Spry4	SIGNOR-253032	0.583
PDE4DIP	protein	Q5VU43	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	binding			9606									21569246	t		miannu	This study ascribes a novel function to mmgl isoform 4: it meets all criteria for classification as an akap, and we show that is involved in the phosphorylation of cmybpc as well as ctni, hence mmgl is an important regulator of cardiac contractility.	SIGNOR-173766	0.315
MAPK12	protein	P53778	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr498	KTPPAPKtPPSSGEP	-1									9199504	t		miannu	Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective.	SIGNOR-250086	0.504
PRKACA	protein	P17612	UNIPROT	TFAM	protein	Q00059	UNIPROT	up-regulates	phosphorylation	Ser55	SCPKKPVsSYLRFSK	9606									23201127	t		llicata	Here, we demonstrate that tfam is phosphorylated within its hmg box 1 (hmg1) by camp-dependent protein kinase in mitochondria. Hmg1 phosphorylation impairs the ability of tfam to bind dna and to activate transcription.	SIGNOR-199934	0.2
CSNK2A1	protein	P68400	UNIPROT	TLE1	protein	Q04724	UNIPROT	up-regulates	phosphorylation	Ser253	DNLVVDVsNEDPSSP	9606									22354967	t		lperfetto	These results show that tle1 is necessary for the maintenance of neuronal survival. Experiments using pharmacological inhibitors as well as expression of point mutants indicate that phosphorylation of tle1 by casein kinase-2 (ck2) at ser-239 and ser-253 is necessary for its survival-promoting activity.	SIGNOR-196146	0.326
MK-2206	chemical	CHEBI:67271	ChEBI	AKT2	protein	P31751	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001286								21841310	t		gcesareni	Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation.	SIGNOR-176046	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation			9606									21460634	t		lperfetto	Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition.	SIGNOR-216464	0.469
MECP2	protein	P51608	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001570								23242655	f	 	 	Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells.	SIGNOR-254024	0.4
MAPK1	protein	P28482	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates	phosphorylation	Ser2315	RSPQPVPsPRPQSQP	9606									17623675	t		gcesareni	Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression.	SIGNOR-156891	0.478
CFLAR	protein	O15519	UNIPROT	CASP8	protein	Q14790	UNIPROT	down-regulates activity	binding			9606									9794838	t		amattioni	Flip can be incorporated into the disc complex and blocks processing and activation of pro-caspase8	SIGNOR-61122	0.76
NUP153	protein	P49790	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262069	0.731
SIAH1	protein	Q8IUQ4	UNIPROT	NUMB	protein	P49757	UNIPROT	down-regulates	ubiquitination			9606									11752454	t		gcesareni	We report that siah-1 interacts directly with and promotes the degradation of the cell fate regulator numb.	SIGNOR-113469	0.409
belinostat	chemical	CHEBI:61076	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257955	0.8
CSNK2A1	protein	P68400	UNIPROT	SLC18A2	protein	Q05940	UNIPROT	unknown	phosphorylation	Ser511	PIGEDEEsESD	-1									9045708	t		llicata	Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. 	SIGNOR-250953	0.351
CDK8	protein	P49336	UNIPROT	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15546612	f		gcesareni	Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells.	SIGNOR-130637	0.2
COX6C	protein	P09669	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267750	0.739
CDK1	protein	P06493	UNIPROT	EP300	protein	Q09472	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2039	GLGQVGIsPLKPGTV	9606	BTO:0000551								24530506	t		miannu	In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels. 	SIGNOR-276456	0.413
MAPK3	protein	P27361	UNIPROT	MCL1	protein	Q07820	UNIPROT	up-regulates	phosphorylation	Thr163	TDGSLPStPPPAEEE	9606	BTO:0000150								18676833	t		fstefani	We then showed that erk could phosphorylate mcl-1 at two consensus residues, thr 92 and 163, which is required for the association of mcl-1 and pin1, resulting in stabilization of mcl-1.	SIGNOR-179812	0.45
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1714	SPTSPSYsPTSPSYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203536	0.77
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	ARHGEF2	protein	Q92974	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000567								18211802	t	inferred from 70% family members	gcesareni	Activates rhoa and as a result regulates actin assembly.	SIGNOR-270007	0.2
NODAL	protein	Q96S42	UNIPROT	TDGF1	protein	P13385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003879								20383200	f	Regulation	miannu	Nodal induced LIF and Cripto-1 expressions through Smad2 signaling pathway.	SIGNOR-251942	0.648
CDKN2AIP	protein	Q9NXV6	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	binding			9606									16803988	t		miannu	In the nucleoplasm, carf interacts with p53 and enhances its function.	SIGNOR-147360	0.393
GSK3B	protein	P49841	UNIPROT	HNRNPD	protein	Q14103	UNIPROT	down-regulates activity	phosphorylation	Ser83	DEGHSNSsPRHSEAA	9606	BTO:0001271								11903055	t		lperfetto	In kinase assays pka phosphorylated ser-87 of hnrnp d, whereas glycogen synthase kinase-3 beta (gsk-3 beta) phosphorylated ser-83, but only if ser-87 had been pre-phosphorylated by pka. Phosphorylation of ser-87 enhanced, whereas phosphorylation of ser-83 repressed, transactivation.	SIGNOR-102582	0.352
HNF1A	protein	P20823	UNIPROT	SLC22A9	protein	Q8IVM8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								20829431	t		lperfetto	Luciferase reporter gene constructs containing the OAT5 (SLC22A10) and OAT7 (SLC22A9) promoter regions were transactivated by HNF-1 in HepG2 cells.	SIGNOR-268982	0.2
JAK2	protein	O60674	UNIPROT	STAT5B	protein	P51692	UNIPROT	up-regulates	phosphorylation			9606									9575217	t		gcesareni	Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein	SIGNOR-56894	0.861
SH3RF1	protein	Q7Z6J0	UNIPROT	MAP3K11	protein	Q16584	UNIPROT	up-regulates	binding			9606	BTO:0000938								12514131	t		gcesareni	Taken together, these findings support a model in which apoptotic stimuli or posh overexpression induce direct association between posh and inactive mlks.	SIGNOR-97006	0.517
PTEN	protein	P60484	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates activity	dephosphorylation	Thr382	DHYRYSDtTDSDPEN	9606									22413754	t		miannu	Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites	SIGNOR-248546	0.2
PTPN1	protein	P18031	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates activity	dephosphorylation	Tyr1234	RDMYDKEyYSVHNKT	9606									18819921	t			Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases.	SIGNOR-248411	0.621
SF3B1	protein	O75533	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									25428262	f		irozzo	We have shown that SF3B1 knockdown in four myeloid cell lines resulted in inhibition of cell growth and disruption of the cell cycle.Taken together, these data show that SF3B1 knockdown results in inhibition of cell growth, induction of cell cycle arrest and impairment of erythroid differentiation in myeloid cell lines.	SIGNOR-256003	0.7
SMO	protein	Q99835	UNIPROT	ARRB1	protein	P49407	UNIPROT	up-regulates	binding			9606									23074268	t	The binding occours if Smo is phosphorylated	gcesareni	Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2	SIGNOR-199150	0.62
CASP3	protein	P42574	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates	cleavage	Asp546	ALQTDIVdLQRSPMG	9606									11741536	t		gcesareni	Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis.	SIGNOR-112796	0.373
CIITA	protein	P33076	UNIPROT	HLA-C	protein	P10321	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002269								11053628	f		miannu	 Transfection of CIITA in JEG-3 cells also upregulated functional HLA-B and HLA-C expression. 	SIGNOR-253775	0.454
PDPK1	protein	O15530	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606		BTO:0000142							10226025	t		acerquone	We have partially purified a kinase from brain extract that phosphorylates Ser473 of PKBalpha in a PtdIns(3,4,5)P3-dependent manner and that is immunoprecipitated with PDK1 antibodies.	SIGNOR-67367	0.736
FER	protein	P16591	UNIPROT	PECAM1	protein	P16284	UNIPROT	up-regulates activity	phosphorylation	Tyr713	KKDTETVySEVRKAV	9606	BTO:0000007								12972546	t		miannu	PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1.	SIGNOR-262866	0.329
IRF4	protein	Q15306	UNIPROT	M1_polarization	phenotype	SIGNOR-PH54	SIGNOR	down-regulates				9606									22378047	f		lperfetto	IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization.	SIGNOR-249561	0.7
IL4	protein	P05112	UNIPROT	IL4R	protein	P24394	UNIPROT	up-regulates activity	binding			9606	BTO:0000801								18852293	t		lperfetto	IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor.	SIGNOR-249527	0.941
BDKRB2	protein	P30411	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257090	0.435
CAMK2A	protein	Q9UQM7	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser516	LSLTRGLsRTSMKPR	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275770	0.383
PCDHA11	protein	Q9Y5I1	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-265670	0.2
MAPK1	protein	P28482	UNIPROT	GIGYF2	protein	Q6Y7W6	UNIPROT	unknown	phosphorylation	Ser30	SITSPPLsPALPKYK	10090									22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262775	0.2
PRKACA	protein	P17612	UNIPROT	SOX9	protein	P48436	UNIPROT	up-regulates	phosphorylation	Ser64	EPDLKKEsEEDKFPV	9606									15889150	t		llicata	We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta.	SIGNOR-137089	0.445
CAMK2G	protein	Q13555	UNIPROT	ADCY3	protein	O60266	UNIPROT	down-regulates activity	phosphorylation	Ser1076	NVASRMEsTGVMGNI	9606	BTO:0000007								8798667	t		llicata	Phosphorylation and inhibition of type III adenylyl cyclase by calmodulin-dependent protein kinase II in vivo. | Site-directed mutagenesis of a CaM kinase II consensus site (Ser-1076 to Ala-1076) in III-AC greatly reduced Ca2+-stimulated phosphorylation and inhibition of III-AC in vivo.	SIGNOR-250691	0.36
PRKCG	protein	P05129	UNIPROT	PA2G4	protein	Q9UQ80	UNIPROT	unknown	phosphorylation	Thr366	QSSASRKtQKKKKKK	9606	BTO:0004737								11325528	t		lperfetto	We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC.	SIGNOR-249094	0.286
HIPK2	protein	Q9H2X6	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates	phosphorylation	Ser10	NVRVSNGsPSLERMD	9606									21715331	t		lperfetto	Homeodomain-interacting protein kinase-2 stabilizes p27(kip1) by its phosphorylation at serine 10 and contributes to cell motility	SIGNOR-174617	0.257
LRAT	protein	O95237	UNIPROT	all-trans-retinyl ester	smallmolecule	CHEBI:63410	ChEBI	up-regulates quantity	chemical modification			10090									18093970	t		lperfetto	We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis	SIGNOR-265111	0.8
CDK1	protein	P06493	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates	phosphorylation	Ser200	YSGDSDAsSPRSNCS	9606			SIGNOR-C17						14749395	t		lperfetto	Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21.	SIGNOR-121601	0.372
(R)-adrenaline	smallmolecule	CHEBI:28918	ChEBI	ADRA1D	protein	P25100	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258459	0.8
SRC	protein	P12931	UNIPROT	HLA-A	protein	P04439	UNIPROT	unknown	phosphorylation	Tyr344	SDRKGGSyTQAASSD	9606									6304688	t		lperfetto	Hla-a2 and hla-b7 antigens are phosphorylated in vitro by rous sarcoma virus kinase (pp60v-src) at a tyrosine residue encoded in a highly conserved exon of the intracellular domain.	SIGNOR-25566	0.368
FRS2	protein	Q8WU20	UNIPROT	GRAP	protein	Q13588	UNIPROT	up-regulates	binding			9606									11997436	t		gcesareni	Complex formation between grb2 and frs2_ is mediated by y196, y306, y349, and y392 of frs2_ (designated direct grb2-binding sites;ref. 1). In addition, frs2_ recruits grb2 indirectly by means of the protein tyrosine phosphatase shp2 by way of residues y436 and y471 (designated shp2-binding sites;ref. 2).	SIGNOR-87169	0.346
L3MBTL1	protein	Q9Y468	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	down-regulates activity	binding			9606									29018219	t		lperfetto	L3MBTL1, a tumor suppressor with high affinity for H4K20me2, can block 53BP1 binding at DSBs	SIGNOR-262059	0.415
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	BCL2L11	protein	O43521	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12913110	f		lperfetto	FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons.	SIGNOR-252914	0.2
serotonin(1+)	smallmolecule	CHEBI:350546	ChEBI	HTR4	protein	Q13639	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257524	0.8
PTPRB	protein	P23467	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates activity	dephosphorylation	Tyr1175	AQQDGKDyIVLPISE	9606									19136612	t			VE-PTP/VEGFR2 complex formation resumes with time, leading to dephosphorylation and deactivation of VEGFR2 (right). B) In VE-PTP-deficient cells, such as after siRNA treatment, VEGFR2 activation (middle) is exaggerated, leading to increased phosphorylation at the Y951 and Y1175 phosphorylation sites	SIGNOR-248441	0.467
4-hydroxy-17beta-estradiol	smallmolecule	CHEBI:62845	ChEBI	17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	up-regulates quantity	precursor of			9606	BTO:0000093								8790407	t		Luana	These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens.	SIGNOR-269755	0.8
CAMK2B	protein	Q13554	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser516	LSLTRGLsRTSMKPR	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275773	0.394
RNF168	protein	Q8IYW5	UNIPROT	H2AX	protein	P16104	UNIPROT	unknown	ubiquitination	Lys14	TGGKARAkAKSRSSR	9606									22980979	t		lperfetto	We find that K63 ubiquitin chains are conjugated to RNF168-dependent H2A/H2AX monoubiquitination at K13-15 and not on K118-119.	SIGNOR-262063	0.2
2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[8-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]octyl]acetamide	chemical	CID:121427831	PUBCHEM	BRD2	protein	P25440	UNIPROT	down-regulates quantity	chemical inhibition			9606									29764999	t		Monia	DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells	SIGNOR-261095	0.8
CREB1	protein	P16220	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9606									20660310	f		amattioni	beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state	SIGNOR-229777	0.7
ULK2	protein	Q8IYT8	UNIPROT	DENND3	protein	A2RUS2	UNIPROT	up-regulates activity	phosphorylation	Ser472	THRRMVVsMPNLQDI	9606									25925668	t		lperfetto	ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12.	SIGNOR-264732	0.2
TGM2	protein	P21980	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	unknown	phosphorylation			9606									16407273	t		gcesareni	Tg2 is able to phosphorylate purified histone proteins, and h3 and h1 in chromatin preparations, and it is associated with chromatin in breast cancer cells.	SIGNOR-265369	0.2
26S Proteasome	complex	SIGNOR-C307	SIGNOR	oligopeptide	smallmolecule	CHEBI:25676	ChEBI	up-regulates quantity	cleavage			9606									15571818	t		scontino	The proteasome system is the central proteolytic system of the eukaryotic cell [1] and plays an important role in the generation of MHC-class I peptides. The enzyme complex responsible for the selectivity of intracellular protein degradation is the 26S proteasome that degrades poly-ubiquitinated substrates.	SIGNOR-267768	0.8
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	PYG	proteinfamily	SIGNOR-PF96	SIGNOR	down-regulates activity	dephosphorylation			9606	BTO:0002049								22225877	t			GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation	SIGNOR-267961	0.397
RHEB	protein	Q15382	UNIPROT	FKBP8	protein	Q14318	UNIPROT	down-regulates	binding			9606									17991864	t		gcesareni	Rheb interacts directly with fkbp38 and prevents its association with mtor in a guanosine 5'-triphosphate (gtp)-dependent manner.	SIGNOR-159016	0.552
SLBP	protein	Q14493	UNIPROT	H3Y1	protein	P0DPK2	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265419	0.2
CSNK2A1	protein	P68400	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates	phosphorylation	Ser422	NNNNRKTsNGDDSLF	9606									21930781	t		lperfetto	Cftr possesses two ck2 phosphorylation sites (s422 and t1471)this is consistent with an important role for s422 phosphorylation in increasing cftr activity.	SIGNOR-176619	0.281
CAMK2D	protein	Q13557	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser1934	LFRQQAGsGLSEEDA										28882890	t	Phosphosite is derived from Figure 2	lperfetto	C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation| Of 19 native NaV1.5 phosphorylation sites identified, two C-terminal phosphoserines at positions 1938 and 1989 showed increased phosphorylation in the CaMKIIδc-Tg compared with the WT ventricles. 	SIGNOR-275782	0.48
KCTD13	protein	Q8WZ19	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates quantity	binding			9606									19782033	t		miannu	 BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.	SIGNOR-264236	0.386
TRIM71	protein	Q2Q1W2	UNIPROT	LIN28B	protein	Q6ZN17	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0001950								24602972	t		miannu	In cells, TRIM71 negatively regulates Lin28B protein stability by catalyzing polyubiquitination. 	SIGNOR-272054	0.543
1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone	chemical	CHEBI:93753	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192620	0.8
JAK2	protein	O60674	UNIPROT	CSF2RA/CSF2RB	complex	SIGNOR-C212	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000876	BTO:0001103							19436055	t		apalma	The GM-CSF receptor does not have intrinsic tyrosine kinase activity, but associates with the tyrosine kinase Jak2 that is required for βc transphosphorylation and the initiation of signaling and biological activity	SIGNOR-255584	0.568
ROCK1	protein	Q13464	UNIPROT	ARHGAP24	protein	Q8N264	UNIPROT	up-regulates activity	phosphorylation	Thr452	GLEKTQTtPNGSLQA	9606	BTO:0000007								16862148	t		lperfetto	ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2).	SIGNOR-249310	0.444
CAMK2A	protein	Q9UQM7	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity	phosphorylation	Ser561	PFLSRHNsKSSIFSF	9606	BTO:0000938								32611770	t		lperfetto	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275784	0.282
NR3C1	protein	P04150	UNIPROT	KLF9	protein	Q13886	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000746								27777311	t			We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα	SIGNOR-256119	0.327
COL1A2	protein	P08123	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									11007770	f		gcesareni	The present study was designed to further characterize tgfbeta up-regulation of col1a2 and more generally, to increase our understanding of the tgfbeta signaling pathway that controls ecm accumulation.	SIGNOR-82405	0.7
POU5F1	protein	Q01860	UNIPROT	GATA6	protein	Q92908	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22795133	f		lperfetto	Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)	SIGNOR-253159	0.493
EDN1	protein	P05305	UNIPROT	EDNRB	protein	P24530	UNIPROT	up-regulates	binding			9606									16597412	t		gcesareni	Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors.	SIGNOR-145762	0.946
cholesta-5,7-dien-3beta-ol	smallmolecule	CHEBI:17759	ChEBI	cholesterol	smallmolecule	CHEBI:16113	ChEBI	up-regulates quantity	precursor of			9606									9634533	t		miannu	In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol D7 -reductase. This NADPH-dependent enzyme catalyzes the reduction of the D7 -diene bond in 7-DHC, to form cholesterol.	SIGNOR-267250	0.8
metformin	chemical	CHEBI:6801	ChEBI	CRTC2	protein	Q53ET0	UNIPROT	down-regulates				9606									16308421	f		gcesareni	It has been proposed that metformin stimulates crtc2 phosphorylation in response to metabolic signals such as energy stress through the lkb1-ampk/sik1 pathways, which promotes binding to 14-3-3 proteins, thereby sequestering crtc2 from the nucleus to the cytoplasm	SIGNOR-142207	0.8
SIRT2	protein	Q8IXJ6	UNIPROT	NEDD4	protein	P46934	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									23175188	f		miannu	 SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16.	SIGNOR-255144	0.265
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser37	YLDSGIHsGATTTAP	9606	BTO:0000938	BTO:0000142							19303846	t		lperfetto	GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation	SIGNOR-227874	0.892
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	Interferon_Production	phenotype	SIGNOR-PH16	SIGNOR	up-regulates				10090	BTO:0002572								20610653	f		lperfetto	Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors.	SIGNOR-216322	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	METTL1	protein	Q9UBP6	UNIPROT	down-regulates	phosphorylation	Ser27	YYRQRAHsNPMADHT	9606									3627513	t		lperfetto	The trna methylase mettl1 is phosphorylated and inactivated by pkb and rsk in vitro and in cells	SIGNOR-244307	0.2
CDK9	protein	P50750	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser214	PTSSDPGsPFQMPAD	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161577	0.325
DIO	proteinfamily	SIGNOR-PF83	SIGNOR	L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	down-regulates quantity	chemical modification			9606									34674502	t		scontino	Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule. 	SIGNOR-267043	0.8
BRAP	protein	Q7Z569	UNIPROT	CDC14A	protein	Q9UNH5	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0000007								19152073	t	k63	miannu	Brap2 promotes Lys-63 linked ubiquitination of HsCdc14A. Collectively, these results support the idea that Brap2 facilitates Lys-63 linked ubiquitin modification of HsCdc14A, which may not be targeted for degradation, but mainly for protein–protein interactions or other regulatory functions.	SIGNOR-271777	0.343
ITGB4	protein	P16144	UNIPROT	A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253200	0.761
CARM1	protein	Q86X55	UNIPROT	MDH1	protein	P40925	UNIPROT	down-regulates activity	acetylation	Arg230	FVTTVQQrGAAVIKA	9606									27840030	t		lperfetto	Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer|Arginine methylation at R248 negatively regulates MDH1 activity|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization	SIGNOR-267639	0.363
PRKDC	protein	P78527	UNIPROT	GOLPH3	protein	Q9H4A6	UNIPROT	up-regulates activity	phosphorylation	Thr148	KETQPPEtVQNWIEL	-1	BTO:0000567								24485452	t			In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents	SIGNOR-253558	0.323
PML	protein	P29590	UNIPROT	KAT6A/PML	complex	SIGNOR-C55	SIGNOR	form complex	binding			9606	BTO:0001271								23431171	t		miannu	We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression	SIGNOR-201489	0.502
CP	protein	P00450	UNIPROT	SMO	protein	Q99835	UNIPROT	down-regulates	binding			9606									16885213	t		gcesareni	Genetic and biochemical studies imply that smo can adopt an active conformation but that it is normally repressed by patched (ptch), a 12-transmembrane protein considered the receptor for hh	SIGNOR-148451	0.2
RPS6KA4	protein	O75676	UNIPROT	H3-4	protein	Q16695	UNIPROT	unknown	phosphorylation	Ser11	TKQTARKsTGGKAPR	10090									12773393	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	lperfetto	The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28	SIGNOR-249211	0.2
GPR132	protein	Q9UNW8	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256802	0.2
MAPK3	protein	P27361	UNIPROT	BAZ1B	protein	Q9UIG0	UNIPROT	up-regulates	phosphorylation	Ser158	KSDGACDsPSSDKEN	9606									19776015	t		gcesareni	Wstf, a specific component of two chromatin remodeling complexes (swi/snf-type winac and iswi-type wich), was phosphorylated by the stimulation of mapk cascades in vitro and in vivo. Ser-158 residue in the wac (wstf/acf1/cbpq46) domain, located close to the n terminus of wstf, was identified as a major phosphorylation target	SIGNOR-188164	0.2
NOTCH1	protein	P46531	UNIPROT	ZMIZ1	protein	Q9ULJ6	UNIPROT	up-regulates activity	binding			10090	BTO:0001825								26522984	t		miannu	The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions	SIGNOR-263937	0.464
PRKACA	protein	P17612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606									10230394	t		gcesareni	Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A|Collectively, these results implicate PKA as the principal mitochondria-based S112 kinase.	SIGNOR-67383	0.521
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	SCN2A	protein	Q99250	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000938								32599005	t		lperfetto	For example, protein kinase A (PKA) and protein kinase C (PKC) have been shown to phosphorylate multiple serine residues on the interdomain I-II and III-IV linkers of Nav1.2, significantly reducing current and increasing firing thresholds 	SIGNOR-275750	0.2
CHUK	protein	O15111	UNIPROT	COPS5	protein	Q92905	UNIPROT	down-regulates activity	phosphorylation	Ser201	KPPDEGPsEYQTIPL	-1									31950832	t		lperfetto	Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. 	SIGNOR-275507	0.329
EIF2S3	protein	P41091	UNIPROT	Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	form complex	binding			9606									32955564	t		lperfetto	In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3.	SIGNOR-269116	0.938
pimozide	chemical	CHEBI:8212	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258379	0.8
NFKB1	protein	P19838	UNIPROT	BIRC2	protein	Q13490	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9733516	f		gcesareni	Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2	SIGNOR-59948	0.421
AMPK	complex	SIGNOR-C15	SIGNOR	CRTC2	protein	Q53ET0	UNIPROT	down-regulates	phosphorylation	Ser171	SALNRTSsDSALHTS	10090	BTO:0000575								20577053	t		lperfetto	Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2	SIGNOR-216576	0.423
methylnaltrexone	chemical	CHEBI:136007	ChEBI	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10030									19282177	t		Luana	A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 	SIGNOR-258148	0.8
NRL	protein	P54845	UNIPROT	RBP3	protein	P10745	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								15277472	f		miannu	 KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. 	SIGNOR-253818	0.383
CCND3	protein	P30281	UNIPROT	Cell_cycle_exit	phenotype	SIGNOR-PH41	SIGNOR	up-regulates				10090	BTO:0000165								21898542	f		gcesareni	Our findings suggest that cyclin D3 primes myoblasts for differentiation by enhancing muscle specific gene expression and cell cycle exit	SIGNOR-241960	0.7
CSNK1D	protein	P48730	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates	phosphorylation	Ser143	FHPNVSSsHENLEPE	9606									22609948	t		lperfetto	Ck1_/__dependent phosphorylation of dvl2 at s143 and t224and that this event is critical to interact with plk1 in early stages of the cell cycle	SIGNOR-197547	0.519
PTPRC	protein	P08575	UNIPROT	LCK	protein	P06239	UNIPROT	up-regulates activity	dephosphorylation	Tyr505	FTATEGQyQPQP	10090	BTO:0000782								17719247	t			CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56(lck) tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56(lck) pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity.	SIGNOR-259933	0.79
ELANE	protein	P08246	UNIPROT	F2R	protein	P25116	UNIPROT	up-regulates activity	cleavage	Ala36	PESKATNaTLDPRSF	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus	SIGNOR-263565	0.441
PRRX1	protein	P54821	UNIPROT	MAF	protein	O75444	UNIPROT	down-regulates activity	binding			-1									11036080	t		miannu	Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.	SIGNOR-221893	0.36
FOXL2	protein	P58012	UNIPROT	CCND2	protein	P30279	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21862621	f	 	miannu	We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation.	SIGNOR-254178	0.402
FOXO1	protein	Q12778	UNIPROT	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									16308421	f	inferred from family member	gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-270251	0.327
MAPK1	protein	P28482	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	up-regulates activity	phosphorylation	Ser65	PCSSVPSsPSFCAPS	9606	BTO:0000567								11416124	t		lperfetto	These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription.	SIGNOR-108564	0.34
PRKAA2	protein	P54646	UNIPROT	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation	Ser638	FDFPKTPsSQNLLAL	9606			SIGNOR-C15						21205641	t		gcesareni	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-170867	0.483
PAK2	protein	Q13177	UNIPROT	PRL	protein	P01236	UNIPROT	up-regulates	phosphorylation	Ser207	LHCLRRDsHKIDNYL	9606									19555049	t		gcesareni	Phosphorylated form of prolactin has a higher affinity for heparin.	SIGNOR-186211	0.345
CASP7	protein	P55210	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates activity	cleavage	Asp345	EEWEAQRdSHLGPHR	-1									10069390	t		lperfetto	Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.	SIGNOR-261757	0.349
PRKAB1	protein	Q9Y478	UNIPROT	STIM1	protein	Q13586	UNIPROT	down-regulates activity	phosphorylation	Ser257	GLHRAEQsLHDLQER	10090	BTO:0000452								31381180	t		miannu	STIM1 is a novel exercise‐regulated AMPK substrate. Phosphorylation of STIM1 by AMPK suppresses SOCE	SIGNOR-277298	0.2
ARX	protein	Q96QS3	UNIPROT	EBF3	protein	Q9H4W6	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19627984	f	Regulation of expression	miannu	Arx is sufficient to repress Ebf3 endogenous expression and that its silencing in Arx mutant tissues partially rescues tangential cell movement. 	SIGNOR-251971	0.309
E2F1	protein	Q01094	UNIPROT	MT1G	protein	P13640	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000394								15735762	f	 	lperfetto	The E2F transcription factors induce the expression of many genes in response to specific extracellular stimuli. Here, we show that human metallothionein 1G (hMT1G) promoter is upregulated by E2F1 upon VEGF stimulation of human aortic endothelial cells.	SIGNOR-254132	0.34
sorafenib tosylate	chemical	CHEBI:50928	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			-1									16757355	t		miannu	Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 	SIGNOR-259226	0.8
CSNK1A1	protein	P48729	UNIPROT	NFATC3	protein	Q12968	UNIPROT	down-regulates activity	phosphorylation	Ser207	AARFTLGsPLTSPGG	9606	BTO:0001131								9630228	t		lperfetto	Dominant-negative cki? Induces nuclear import of nf-at4these results demonstrated that the cki? Phosphorylation sites identified in vitro were also specifically phosphorylated by cki? In vivo, and that these residues were crucial for the masking of the nls of nf-at4.	SIGNOR-109800	0.571
2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide	chemical	CHEBI:91353	ChEBI	MAP2K1	protein	Q02750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191021	0.8
MAPK1	protein	P28482	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr37	PPGDYSTtPGGTLFS	9606	BTO:0000007								11691836	t		lperfetto	The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding 	SIGNOR-249392	0.649
FOXJ1	protein	Q92949	UNIPROT	DNAH11	protein	Q96DT5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000939								23822649	t		miannu	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266931	0.369
wortmannin	chemical	CHEBI:52289	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606	BTO:0001271								7503989	t		gcesareni	Wortmannin inhibited the activity of partially purified pi3-kinase from calf thymus, as well as the pi3-kinase activity in anti-pi3-kinase p85 immunoprecipitates from rbl-2h3 cells, at a concentration as low as 1.0 nm and with ic50 values of 3.0 nm.	SIGNOR-252663	0.8
CHD8	protein	Q9HCK8	UNIPROT	DCX	protein	O43602	UNIPROT	down-regulates quantity	transcriptional regulation			10090									32839322	t		Gianni	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268915	0.2
PDPK1	protein	O15530	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates	phosphorylation	Thr256	EHNSTTStFCGTPEY	9606	BTO:0000007								10191262	t		lperfetto	This is followed by the ptdins(3,4,5)p3-independent phosphorylation at thr256 that activates sgk, and is catalysed by pdk1	SIGNOR-236796	0.634
3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	DIO2	protein	Q92813	UNIPROT	up-regulates quantity by expression				9606									29892818	f		scontino	Dio2 is a cAMP responsive gene. Thus, any signaling pathway or molecule that increases cAMP concentration will stimulate D2 activity.	SIGNOR-267281	0.8
MAPK14	protein	Q16539	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates activity	phosphorylation	Ser387	LSLPSTQsLNIKSEP	9606									9858528	t	The effect has been demonstrated using Q06413-3	lperfetto	Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain	SIGNOR-62788	0.683
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser115	PAPSSFSsTSVSSLE	9606									20305697	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-164629	0.575
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC4	protein	P56524	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257986	0.8
FOXH1	protein	O75593	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	binding			9606	BTO:0001538								9858566	t		lperfetto	FAST-2 also interacts directly with Smad2, a cytoplasmic protein which is translocated to the nucleus in response to TGF-beta, and forms a multimeric complex with Smad2 and Smad4 on the activin response element, a high-affinity binding site for FAST-1.	SIGNOR-108333	0.77
GSK3B	protein	P49841	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	binding			9606									17726008	t		gcesareni	Here we show that similar to the interaction with traf4 and axin, the kinase domain of mekk4 interacts with the multifunctional serine/threonine kinase gsk3beta. Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways	SIGNOR-157544	0.294
SATB1	protein	Q01826	UNIPROT	TAF11	protein	Q15544	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17343824	f		miannu	We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 	SIGNOR-255130	0.2
CTH	protein	P32929	UNIPROT	L-homocysteine zwitterion	smallmolecule	CHEBI:58199	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000671;BTO:0000759;BTO:0002688							19961860	t		lperfetto	 the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production.	SIGNOR-275825	0.8
RNF7	protein	Q9UBF6	UNIPROT	HIF1A	protein	Q16665	UNIPROT	down-regulates activity	ubiquitination			9606									23136067	t		miannu	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 	SIGNOR-271450	0.2
PPP2CA	protein	P67775	UNIPROT	AKT2	protein	P31751	UNIPROT	down-regulates activity	dephosphorylation	Thr309	SDGATMKtFCGTPEY	10090	BTO:0000944								15367694	t			Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes	SIGNOR-248633	0.736
CDK4	protein	P11802	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Ser795	SPYKFPSsPLRIPGG	9606			SIGNOR-C18						23336272	t		gcesareni	Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression.	SIGNOR-200487	0.927
porfimer	chemical	CHEBI:60652	ChEBI	FCGR1A	protein	P12314	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000876								2544592	t		miannu	Inhibition of the high affinity Fc receptor (Fc gamma RI) on human monocytes by porphyrin photosensitization is highly specific and mediated by the generation of superoxide radicals.	SIGNOR-259303	0.8
CHD8	protein	Q9HCK8	UNIPROT	TYMS	protein	P04818	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								19255092	t		miannu	In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells, finding out that CHD8 controls the expression of cyclin E2 (CCNE2) and thymidylate synthetase (TYMS), two genes expressed in the G1/S transition of the cell cycle. CHD8 was also able to co-activate the CCNE2 promoter in transient transfection experiments. Chromatin immunoprecipitation experiments demonstrated that CHD8 binds directly to the 5' region of both CCNE2 and TYMS genes. 	SIGNOR-268805	0.288
GAS6	protein	Q14393	UNIPROT	TYRO3	protein	Q06418	UNIPROT	up-regulates	binding			9606									7867073	t		gcesareni	We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function.	SIGNOR-34414	0.589
prednisone	chemical	CHEBI:8382	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									8143061	t	asthma	gcesareni		SIGNOR-251706	0.8
degarelix	chemical	CHEBI:135961	ChEBI	GNRHR	protein	P30968	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001033								22416801	t		miannu	 Two GnRH antagonists are currently available: abarelix and degarelix. 	SIGNOR-259160	0.8
GART	protein	P22102	UNIPROT	glycine	smallmolecule	CHEBI:15428	ChEBI	down-regulates quantity	chemical modification			9606									34283828	t		miannu	In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR).	SIGNOR-267299	0.8
PRKCB	protein	P05771	UNIPROT	CYTH2	protein	Q99418	UNIPROT	down-regulates activity	phosphorylation	Ser392	AARKKRIsVKKKQEQ	9606	BTO:0000567								10531036	t		lperfetto	ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'.	SIGNOR-249024	0.311
MRPL49	protein	Q13405	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262347	0.686
MRPL15	protein	Q9P015	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262378	0.686
MAPK1	protein	P28482	UNIPROT	MAPKAPK5	protein	Q8IW41	UNIPROT	up-regulates	phosphorylation	Thr182	IDQGDLMtPQFTPYY	9606									21666810	t		fstefani	Like mk2, mk5 could be phosphorylated and activated by p38mapk and erk2 in vitro, but not by sapk?/Jnk3	SIGNOR-174076	0.492
ELP4	protein	Q96EB1	UNIPROT	Elongator complex	complex	SIGNOR-C466	SIGNOR	form complex	binding			9606									28601220	t		miannu	Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer.	SIGNOR-269711	0.864
UBQLN2	protein	Q9UHD9	UNIPROT	Unfolded_Proteins	stimulus	SIGNOR-ST22	SIGNOR	down-regulates				10090									27477512	f		lperfetto	UBQLN2 recognizes client-bound HSP70 and links it to the proteasome to allow for the degradation of aggregated and misfolded proteins. 	SIGNOR-262267	0.7
DZIP3	protein	Q86Y13	UNIPROT	H2AC4	protein	P04908	UNIPROT	up-regulates activity	monoubiquitination	Lys119	IQAVLLPkKTESHHK	9606	BTO:0000007								18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271747	0.2
FGFR2	protein	P21802	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17543283	f		lperfetto	Furthermore, in cultures receiving FGF-2 before adipogenic induction, mRNA expression of peroxisome proliferator-activated receptor gamma (PPARgamma), a key transcription factor in adipogenesis, was upregulated.	SIGNOR-236220	0.286
PPP2R2A	protein	P63151	UNIPROT	PP2CA_R1A_R2A 	complex	SIGNOR-C132	SIGNOR	form complex	binding			9606									23454242	t		gcesareni	[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity.	SIGNOR-243430	0.897
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									15916964	t		lperfetto	Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities	SIGNOR-137631	0.2
SNX9	protein	Q9Y5X1	UNIPROT	DNM2	protein	P50570	UNIPROT	up-regulates	binding			9606	BTO:0000567								15703209	t		miannu	Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes.	SIGNOR-133976	0.804
AMPK	complex	SIGNOR-C15	SIGNOR	CRY1	protein	Q16526	UNIPROT	down-regulates	phosphorylation	Ser71	ANLRKLNsRLFVIRG	9606							phosphorylation:Ser71	ANLRKLNsRLFVIRG 	21892142	t		lperfetto	Ampk was shown to regulate the stability of the core clock component cry1 though phosphorylation of cry1 ser71, which stimulates the direct binding of the fbox protein fbxl3 to cry1, targeting it for ubiquitin-mediated degradation	SIGNOR-216546	0.349
GNA13	protein	Q14344	UNIPROT	ARHGEF11	protein	O15085	UNIPROT	up-regulates activity	binding			9606									11799111	t			This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho	SIGNOR-256517	0.623
BAZ1B	protein	Q9UIG0	UNIPROT	H2AX	protein	P16104	UNIPROT	up-regulates	phosphorylation	Tyr143	ATQASQEy	9606									19092802	t		gcesareni	We show that wstf phosphorylates tyr 142 of h2a.x, and that wstf activity has an important role in regulating several events that are critical for the dna damage response	SIGNOR-182831	0.2
IL11	protein	P20809	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates activity	binding			9606									28232471	t		miannu	Because GP130 is known to interact with other ligand-receptor pairs, we measured the expression of additional GP130 signaling partners in both organoids and PSCs in trans-well cultures. Of the GP130 ligands found to be expressed in PSCs, Il6, Il11, and leukemia inhibitory factor (Lif) were the most highly up-regulated in trans-well cultures when compared with PSC monocultures (Fig. 3 C). Both IL-11 and LIF are reported to have roles in cancer progression	SIGNOR-277689	0.703
GUCY1A3-B3	complex	SIGNOR-C140	SIGNOR	3',5'-cyclic GMP	smallmolecule	CHEBI:16356	ChEBI	up-regulates quantity	chemical modification			9606									10977868	t		gcesareni	Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types	SIGNOR-244105	0.8
SREBF2	protein	Q12772	UNIPROT	IDH1	protein	O75874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12923220	t		lperfetto	IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells|evidence that IDH1 may regulate lipogenesis in hepatic cells	SIGNOR-253133	0.282
NAE	complex	SIGNOR-C131	SIGNOR	CUL9	protein	Q8IWT3	UNIPROT	up-regulates activity	neddylation			9606									25504797	t		lperfetto	The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates.	SIGNOR-243169	0.46
PRKCQ	protein	Q04759	UNIPROT	PTPN7	protein	P35236	UNIPROT	up-regulates activity	phosphorylation	Ser246	QYQEERRsVKHILFS	9606	BTO:0000782								16479000	t		miannu	PKC θ is required for HePTP translocation to the immune synapse. PKC θ phosphorylates HePTP at S225 in primary T cells.	SIGNOR-276045	0.2
sapitinib	chemical	CHEBI:132986	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									20145185	t	AZD8931 has a unique pharmacologic profile providing equipotent EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models.	gcesareni	In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation.	SIGNOR-163727	0.8
MAPK14	protein	Q16539	UNIPROT	TAB1	protein	Q15750	UNIPROT	down-regulates activity	phosphorylation	Thr431	ASTLDEAtPTLTNQS	9606									19393267	t		lperfetto	Egfr-mediated phosphorylation of tab1 was completely inhibited by a chemical inhibitor and sirna of p38alpha. The phosphorylation of tab1 was occurred at ser-423 and thr-431, the residues underlying the p38-mediated feedback inhibition of tak1.	SIGNOR-185584	0.817
IHH	protein	Q14623	UNIPROT	PTCH2	protein	Q9Y6C5	UNIPROT	down-regulates activity	binding			9606		BTO:0001253							9811851	t		lperfetto	Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH.	SIGNOR-61314	0.784
AHSA1	protein	O95433	UNIPROT	HSP90AB1	protein	P08238	UNIPROT	up-regulates activity	binding			9606									16696853	t		miannu	The N-terminal region of Aha1 interacts with the central domain of Hsp90 and stimulates Hsp90 ATPase activity	SIGNOR-252212	0.681
STK4	protein	Q13043	UNIPROT	TNNI3	protein	P19429	UNIPROT	unknown	phosphorylation	Thr31	SNYRAYAtEPHAKKK	9606		BTO:0000671							18986304	t		llicata	Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143).	SIGNOR-182057	0.2
SRC	protein	P12931	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	phosphorylation	Tyr66	DTAGQEDyDRLRPLS	9606	BTO:0000567								23027962	t		lperfetto	When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity	SIGNOR-271701	0.655
Non-erythrocytic spectrin	complex	SIGNOR-C385	SIGNOR	Membrane_disruption	phenotype	SIGNOR-PH151	SIGNOR	down-regulates				9606									24302288	f		lperfetto	Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell	SIGNOR-266029	0.7
GPI	protein	P06744	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P.	SIGNOR-266461	0.8
INSR	protein	P06213	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	phosphorylation	Tyr580	LRKTRDQyLMWLTQK	9534	BTO:0000298								8385099	t			The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor.	SIGNOR-251321	0.656
SRC	protein	P12931	UNIPROT	ITGB2	protein	P05107	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000876								25624455	t		miannu	PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.	SIGNOR-254740	0.438
GSK3B	protein	P49841	UNIPROT	MACF1	protein	Q9UPN3	UNIPROT	down-regulates activity	phosphorylation	Ser7322	RAGSRAGsRASSRRG	9606	BTO:0004905								21295697	t		lperfetto	We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules.	SIGNOR-264433	0.446
POU3F4	protein	P49335	UNIPROT	POU3F2	protein	P20265	UNIPROT	up-regulates activity	binding			-1									9105675	t		miannu	POU proteins (Brain-1, Brain-2, Brain-4 and SCIP) serve as transcriptional transactivators. if they were to form homomeric and heteromeric complexes with each other, depending on the particular combination, they might have different DNA-binding specificities and, thus, activate different genes.	SIGNOR-220080	0.316
MAPK3	protein	P27361	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser345	QARPGPQsPGSPLEE	9606	BTO:0000130								16778989	t		gcesareni	Inhibitors of the erk1/2 pathway abrogated gm-csf-induced phosphorylation of ser345, while p38 mapk inhibitor abrogated tnf-alpha-induced phosphorylation of ser345.These results show that the ala-mutated p47phox acts as a dominant-negative inhibitor of endogenous p47phox and clearly indicate that phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells.	SIGNOR-147174	0.432
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	YAP1	protein	P46937	UNIPROT	up-regulates activity	binding			9606									33358571	t		miannu	The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter 	SIGNOR-277684	0.574
TP53	protein	P04637	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates				9606									15073170	f		gcesareni	Rather, p53 expression stimulates the serine/threonine kinase ribosomal s6 kinase 1 (rsk1), which in turn phosphorylates the p65 subunit of nf-kb.	SIGNOR-124038	0.366
GLI3	protein	P10071	UNIPROT	PTCH1	protein	Q13635	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19860666	t		gcesareni	GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin	SIGNOR-188884	0.699
PLK4	protein	O00444	UNIPROT	CENPJ	protein	Q9HC77	UNIPROT	up-regulates	phosphorylation	Ser595	ISFSSNSsFVLKILE	9606									20531387	t		lperfetto	Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap	SIGNOR-166007	0.792
Galanin	smallmolecule	CHEBI:80161	ChEBI	GALR1	protein	P47211	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257494	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	DUSP1	protein	P28562	UNIPROT	down-regulates	phosphorylation			9606									16286470	t	inferred from 70% family members	lperfetto	The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain	SIGNOR-270093	0.2
KATNB1	protein	Q9BVA0	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	down-regulates				9606	BTO:0000567								10751153	f		miannu	Katanin, a heterodimeric microtubule-severing ATPase, is found localized at mitotic spindle poles. In this paper we demonstrate that human p60 katanin and the C-terminal domain of human p80 katanin both bind microtubules in vitro. Association of these two proteins results in an increased microtubule affinity and increased microtubule-severing activity in vitro. Association of these subunits in transfected HeLa cells increases microtubule disassembly activity and targeting to spindle poles. 	SIGNOR-267181	0.7
YAP1	protein	P46937	UNIPROT	TEAD4	protein	Q15561	UNIPROT	up-regulates activity	binding			9606									33358571	t		miannu	The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter 	SIGNOR-277685	0.925
CDK5	protein	Q00535	UNIPROT	PPP1R2	protein	P41236	UNIPROT	unknown	phosphorylation	Thr73	MKIDEPStPYHSMMG	-1									11320080	t		llicata	Neuronal Cdc2-like protein kinase (Cdk5/p25) is associated with protein phosphatase 1 and phosphorylates inhibitor-2. | NCLK Phosphorylates Thr72 of I-2	SIGNOR-250672	0.363
TEAD4	protein	Q15561	UNIPROT	CCN2	protein	P29279	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33358571	t		miannu	The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter 	SIGNOR-277686	0.2
PTPN12	protein	Q05209	UNIPROT	PTK2	protein	Q05397	UNIPROT	down-regulates	dephosphorylation			9606									11432829	t		gcesareni	This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway.	SIGNOR-109035	0.554
RAD21L1	protein	Q9H4I0	UNIPROT	RAD21L Cohesin complex	complex	SIGNOR-C355	SIGNOR	form complex	binding			10090		BTO:0000534							21242291	t		miannu	RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21.	SIGNOR-264535	0.781
FAS	protein	P25445	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								7538908	t		lperfetto	Fas associates with rip. Rip is a novel form of apoptosis-inducing protein	SIGNOR-235430	0.637
glucocorticoid	smallmolecule	CHEBI:24261	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates activity	binding			9606									18049904	t		miannu	Glucocorticoid action in cells is mediated by a specific receptor protein, the glucocorticoid receptor (GR). GR is a member of a superfamily of ligand-inducible transcription factors that control a variety of physiological functions; such as, metabolism, development, and reproduction.	SIGNOR-268048	0.8
PLK3	protein	Q9H4B4	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									21098032	t		gcesareni	Kinase activity of plk3 was significantly activated by hyperosmotic stimulation. Further downstream, active plk3 phosphorylated atf-2 at the thr-71 site in vivo and in vitro.	SIGNOR-170004	0.2
NGLY1	protein	Q96IV0	UNIPROT	RAD23B	protein	P54727	UNIPROT	up-regulates activity	binding			9606									16401726	t		miannu	The XPCB domain of Rad23 binds Png1, which in turn facilitates the substrate recognition of Rad23. Through interactions with Ub chains and the proteasome mediated by the UBA and UBL domains in Rad23, Rad23 facilitates substrate transfer to the proteasome. 	SIGNOR-261061	0.813
AZ 960	chemical	CID:25099184	PUBCHEM	JAK2	protein	O60674	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190128	0.8
RAB7A	protein	P51149	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	binding			10116									16040606	t		Sara	Rab7-Rac1 interaction may mediate late endosomal transport between microtubules and microfilaments	SIGNOR-261304	0.281
CDK1	protein	P06493	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	down-regulates	phosphorylation	Thr286	VEGDAAEtPPRPRTP	9606									8114697	t		gcesareni	P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well	SIGNOR-36112	0.473
bortezomib	chemical	CHEBI:52717	ChEBI	PSMB5	protein	P28074	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000567								19428245	t		Luana	MG-132, which was one of the first synthetic inhibitors, interacts reversibly with the N-terminal threonine residue of the β5 active site.	SIGNOR-257820	0.8
FAM20C	protein	Q8IXL6	UNIPROT	HRC	protein	P23327	UNIPROT	up-regulates activity	phosphorylation	Ser96	EKEDEDVsKEYGHLL	10116	BTO:0001879								28784772	t		miannu	Here, we demonstrate that family with sequence similarity 20C (Fam20C), a recently characterized protein kinase in the secretory pathway, phosphorylates HRC on Ser96. HRC Ser96 phosphorylation was confirmed in cells and human hearts.The pSer96-HRC binds tighter to triadin than S96A-HRC, which cannot be phosphorylated. Conversely, S96A-HRC or unphosphorylated Ser96-HRC binds tighter to SERCA2a. This suggests that Ser96-HRC phosphorylation (P) regulates HRC’s interactions with the major SR Ca-cycling proteins. 	SIGNOR-273639	0.378
RELA	protein	Q04206	UNIPROT	IL1B	protein	P01584	UNIPROT	down-regulates activity	transcriptional regulation			10090	BTO:0000801								23667107	t		lperfetto	Early Inhibition of IL-1 beta Expression by IFN-gamma Is Mediated by Impaired Binding of NF-kappa B to the IL-1 beta Promoter but Is Independent of Nitric Oxide|We report that IFN-γ suppressed bacterial RNA and LPS induced IL-1β transcription in primary murine macrophages	SIGNOR-251736	0.537
PRKAA2	protein	P54646	UNIPROT	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation	Ser556	GLGCRLHsAPNLSDL	9606			SIGNOR-C15						19584320	t		gcesareni	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-186637	0.483
DLGAP2	protein	Q9P1A6	UNIPROT	SHANK3	protein	Q9BYB0	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264591	0.2
FYN	protein	P06241	UNIPROT	LAT	protein	O43561	UNIPROT	up-regulates	phosphorylation	Tyr220	SLDGSREyVNVSQEL	9606									16938345	t		gcesareni	Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk.	SIGNOR-148931	0.739
BAG1	protein	Q99933	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates activity	binding			9606	BTO:0000661								7834747	t		lperfetto	Cloning and functional analysis of BAG-1: A novel Bcl-2-binding protein with anti-cell death activity|	SIGNOR-254118	0.424
(R)-adrenaline	smallmolecule	CHEBI:28918	ChEBI	LATS1	protein	O95835	UNIPROT	up-regulates				9606									23075495	f		gcesareni	On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz.	SIGNOR-199196	0.8
PRKAR2B	protein	P31323	UNIPROT	PRKACA	protein	P17612	UNIPROT	down-regulates activity	binding			9606									26687711	t			Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 	SIGNOR-258754	0.876
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	E2F5	protein	Q15329	UNIPROT	up-regulates activity	phosphorylation	Thr261	SQSLTPVtPQKSSMA	9606									10783242	t		miannu	Here we show that E2F-5 is phosphorylated by the cyclin E-Cdk2 complex, which functions in the late G1 phase, but not by the early-G1-phase-acting cyclin D-CDK complex. A phosphorylation site in the trans-activation domain of E2F-5 stimulates transcription and cell-cycle progression by the recruitment of the p300/CBP family of co-activators, whose binding to E2F-5 is stabilized upon phosphorylation by cyclin E-Cdk2. 	SIGNOR-262732	0.627
FANCE	protein	Q9HB96	UNIPROT	Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	form complex	binding			9606	BTO:0000567								17396147	t		lperfetto	This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo 	SIGNOR-263247	0.836
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TKT	protein	P29401	UNIPROT	up-regulates activity	phosphorylation	Thr382	GCATRNRtVPFCSTF	9606	BTO:0000567								24981175	t		lperfetto	Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis. 	SIGNOR-265102	0.2
GGCX	protein	P38435	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	carboxylation	Glu79	EEAREVFeNTERTTE	10090		BTO:0001103							11133752	t		lperfetto	The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.	SIGNOR-263685	0.67
PDZRN3	protein	Q9UPQ7	UNIPROT	MUSK	protein	O15146	UNIPROT	down-regulates quantity	ubiquitination			9534	BTO:0000298								17576800	t		miannu	We have identified a PDZ domain containing RING finger 3 (PDZRN3) as a synapse-associated E3 ubiquitin ligase and have demonstrated that it regulates the surface expression of muscle-specific receptor tyrosine kinase (MuSK), the key organizer of postsynaptic development at the mammalian neuromuscular junction. PDZRN3 binds to MuSK and promotes its ubiquitination. Together, these data demonstrate that PDZRN3 is a catalytically active RING-type E3 ubiquitin ligase	SIGNOR-271664	0.56
GABA-A (a4-b1-g2) receptor	complex	SIGNOR-C333	SIGNOR	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	relocalization			9606									18790874	t	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263813	0.8
PIP3	smallmolecule	CHEBI:16618	ChEBI	AKT1	protein	P31749	UNIPROT	up-regulates activity	relocalization			9606									23633519	t		lperfetto	Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring.	SIGNOR-252641	0.8
TRIM32	protein	Q13049	UNIPROT	DBNDD1	protein	Q9H9R9	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9534	BTO:0000298								19349376	t		miannu	TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation.	SIGNOR-271422	0.2
mTORC2	complex	SIGNOR-C2	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0000132								21592956	t		lperfetto	Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1.	SIGNOR-217012	0.634
IKK-complex	complex	SIGNOR-C14	SIGNOR	IKK-complex	complex	SIGNOR-C14	SIGNOR	down-regulates	phosphorylation			9606									10195894	t		lperfetto	Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response	SIGNOR-216373	0.837
HDAC5	protein	Q9UQL6	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates activity	deacetylation			9606	BTO:0000007								16613856	t		lperfetto	HDAC4 and HDAC5 deacetylate Runx2, allowing the protein to undergo Smurf-mediated degradation	SIGNOR-227550	0.47
SRC	protein	P12931	UNIPROT	JUP	protein	P14923	UNIPROT	up-regulates activity	phosphorylation	Tyr644	RNEGTATyAAAVLFR	9606									14517306	t		lperfetto	Tyrosine phosphorylation of plakoglobin causes contrary effects on its association with desmosomes and adherens junction components and modulates beta-catenin-mediated transcriptionFor instance, Src, which mainly phosphorylates Tyr86 in beta-catenin, modifies Tyr643 in plakoglobin, decreasing the interaction with E-cadherin and alpha-catenin and increasing the interaction with the alpha-catenin-equivalent protein in desmosomes, desmoplakin.	SIGNOR-247310	0.655
E2F4	protein	Q16254	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates	transcriptional regulation			9606									12110166	f	During terminal adipocyte differentiation	fspada	we show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation	SIGNOR-210050	0.474
CCNC	protein	P24863	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates	phosphorylation			9606									15546612	t	Leads to a following ubiquitination and degradation	gcesareni	Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.	SIGNOR-254309	0.458
SLC24A2	protein	Q9UI40	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			9606									30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264394	0.8
RET	protein	P07949	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	phosphorylation			9606									12242309	t		lperfetto	Overexpressed rai resulted in the potentiation of the ret-dependent activation of phosphatidylinositol 3-kinase (pi3k) and akt. The ret/ptc receptor tyrosine kinase that responds to glial cell-line-derived neurotrophic factor also phosphorylated akt tyrosine residue 315 promoting activation of akt	SIGNOR-244443	0.329
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser172	LCLSPASsGSSASFI	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248511	0.386
SMARCD1	protein	Q96GM5	UNIPROT	GBAF	complex	SIGNOR-C467	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269785	0.673
CDK2	protein	P24941	UNIPROT	NFYA	protein	P23511	UNIPROT	up-regulates activity	phosphorylation	Ser320	GEGGRFFsPKEKDSP										12857729	t		llicata	Cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y. Cyclin A-cdk2 appears to associate with NF-Y both in vitro and in vivo. Furthermore, YA protein is phosphorylated in parallel with a cell cycle-dependent activation of cdk2 kinase and cyclin A expression. YA phosphorylation is unnecessary for heterotrimer formation with the YB-YC dimer. However, NF-Y containing a phosphorylation-deficient mutant form of YA, YA-aa, has its DNA binding activity impaired. \ To examine whether cdk2 phosphorylates the two serine residues at positions 320 and 326 in YA, we replaced either or both with alanine by site-directed mutagenesis. In a kinase assay using purified GST fusion proteins in vitro, cdk2 phosphorylated the wild type and both of the single-mutant proteins (YA-as and -sa), but not the double-mutant protein (YA-aa)	SIGNOR-250742	0.45
ASH2L	protein	Q9UBL3	UNIPROT	HMT	complex	SIGNOR-C19	SIGNOR	form complex	binding			9606									17500065	t		lperfetto	The evolutionarily conserved hdpy-30, ash2l, rbbp5, and wdr5 likely constitute a subcomplex that is shared by all human set1-like hmt complexes.	SIGNOR-154760	0.869
DAB2IP	protein	Q5VWQ8	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates activity	binding			9606									27858941	t		miannu	DAB2IP acts as a scaffold protein for PP2A to suppress DHT-elicited S81 phosphorylation of the AR, preventing its nuclear translocation and binding to androgen response elements. In addition, DAB2IP can compete with the AR for binding to c-Src, thus blocking the non-genomic AR pathway	SIGNOR-254758	0.335
SOCS3	protein	O14543	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity				9606									24600449	f		miannu	A main role of SOCS3 results from its binding to both the JAK kinase and the cytokine receptor, which results in the inhibition of STAT3 activation.	SIGNOR-255330	0.699
PP121	chemical	CHEBI:50915	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206292	0.8
2-[[(1R)-1-[7-methyl-2-(4-morpholinyl)-4-oxo-9-pyrido[1,2-a]pyrimidinyl]ethyl]amino]benzoic acid	chemical	CHEBI:91359	ChEBI	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190200	0.8
RBBP4	protein	Q09028	UNIPROT	HNuRF	complex	SIGNOR-C448	SIGNOR	form complex	binding			9606	BTO:0000007								14609955	t		miannu	 hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays.	SIGNOR-268816	0.673
SPRY4	protein	Q9C004	UNIPROT	TIMP1	protein	P01033	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002058								20501643	f		miannu	When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. 	SIGNOR-253038	0.2
CYSLTR1	protein	Q9Y271	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256883	0.2
SLITRK5	protein	O94991	UNIPROT	SHH	protein	Q15465	UNIPROT	down-regulates activity	binding			10090	BTO:0001593								34326333	t		miannu	 SLITRK5 interacts with SHH and PTCH1. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation.	SIGNOR-268437	0.2
AKT2	protein	P31751	UNIPROT	STK3	protein	Q13188	UNIPROT	down-regulates	phosphorylation	Thr117	IIRLRNKtLIEDEIA	9606	BTO:0000150								20231902	t		gcesareni	Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation.	SIGNOR-164302	0.264
SRC	protein	P12931	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates	phosphorylation	Tyr216	KLDSGGFyITSRTQF	9606	BTO:0000150								12753909	t		lperfetto	This study establishes that her2/hrg signaling selectively upregulates tyr phosphorylation of c-src at tyr-215 located within the sh2 domain, increases c-src kinase activity	SIGNOR-236246	0.2
CDK1	protein	P06493	UNIPROT	TSC1	protein	Q92574	UNIPROT	unknown	phosphorylation	Ser584	ETSIFTPsPCKIPPP	9606									14551205	t		llicata	In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain.	SIGNOR-118588	0.503
GRK2	protein	P25098	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	phosphorylation	Thr123	IVKCQKLtDDHVQFL	9606	BTO:0000801								17055984	t		lperfetto	Phosphorylation of p38 by grk2 at the docking groove unveils a novel mechanism for inactivating p38mapk p38 associates with grk2 endogenously and is phosphorylated by grk2 at thr-123, a residue located at its docking groove. Mimicking phosphorylation at this site impairs the binding and activation of p38 by mkk6 and diminishes the capacity of p38 to bind and phosphorylate its substrates	SIGNOR-150152	0.2
DSCAM	protein	O60469	UNIPROT	Axonal_growth_cone_formation	phenotype	SIGNOR-PH199	SIGNOR	up-regulates				10116	BTO:0000938								18585357	f		miannu	DSCAM is required for commissural axon guidance in vivo. DSCAM promotes axonal growth but is dispensable for cell body migration and for axon turning toward a local source of netrin-1 in whole spinal cord turning assays. 	SIGNOR-268396	0.7
STAT6	protein	P42226	UNIPROT	HSD3B2	protein	P26439	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15632317	f		miannu	 IL-4 induces HSD3B1 gene expression, along with IL-13, through STAT 6 activation. 	SIGNOR-255249	0.2
GNAI3	protein	P08754	UNIPROT	ADCY1	protein	Q08828	UNIPROT	down-regulates activity	binding			9606									19703466	t			Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma)	SIGNOR-256500	0.578
SH3GL1	protein	Q99961	UNIPROT	Endocytosis	phenotype	SIGNOR-PH123	SIGNOR	up-regulates				9606									25517094	f		miannu	Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. 	SIGNOR-263885	0.7
GABRB1	protein	P18505	UNIPROT	GABA-A (a6-b1-g2) receptor	complex	SIGNOR-C334	SIGNOR	form complex	binding			9606									18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263763	0.599
GSK3A	protein	P49840	UNIPROT	SFPQ	protein	P23246	UNIPROT	down-regulates	phosphorylation			9606									20932480	t		miannu	Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687	SIGNOR-168385	0.2
AML1-ETO	fusion protein	SIGNOR-FP1	SIGNOR	CEBPA	protein	P49715	UNIPROT	down-regulates activity	binding			9606	BTO:0001412								11283671	t		irozzo	AML1–ETO inhibits CEBPA autoregulation in myeloid cells.[…]It was also demonstrated that AML1–ETO and C/EBPα physically interact in vivo.	SIGNOR-255700	0.2
lofexidine	chemical	CHEBI:51368	ChEBI	ADRA2B	protein	P18089	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000246								22341244	t		Luana	Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism. 	SIGNOR-258331	0.8
PPP2R5D	protein	Q14738	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16239230	t		gcesareni	... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259.	SIGNOR-243420	0.425
AXIN1	protein	O15169	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates				9606									16601693	f		gcesareni	Axin promotes smad3 phosphorylation;phosphorylated smad3 dissociates from the axin complex and then combines with smad4 to activate transcription in the nucleus.	SIGNOR-145848	0.652
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGA12	protein	O60330	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265698	0.2
AMER1	protein	Q5JTC6	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates activity	relocalization			9606				SIGNOR-C110					21304492	t		gcesareni	Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6.	SIGNOR-171886	0.78
KMT2E	protein	Q8IZD2	UNIPROT	RARA	protein	P10276	UNIPROT	up-regulates activity	binding			9606									21205756	t		miannu	MLL5 binds to retinoic acid receptor α (RARα) and induces transcriptional activation of RARα target genes by methylation of lysine residues of histone H3.	SIGNOR-260041	0.341
MAPK3	protein	P27361	UNIPROT	APBB1	protein	O00213	UNIPROT	unknown	phosphorylation	Ser347	TFPAQSLsPEPLPQE	9606									14697653	t		lperfetto	Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved.	SIGNOR-120479	0.271
XPOT	protein	O43592	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								9660920	t		miannu	Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus.	SIGNOR-261393	0.448
XIAP	protein	P98170	UNIPROT	CASP3	protein	P42574	UNIPROT	down-regulates activity	binding			9606									10548111	t		amattioni	The linker region located adjacent to the bir2 domain also participates in the binding of xiap to the effector caspases (-3 and -7).	SIGNOR-71954	0.938
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	GSN	protein	P06396	UNIPROT	down-regulates	cleavage			9606	BTO:0000130								9323209	t		amattioni	Caspase-3 mediates cleavage of gelsolin, generating a fragment that severs actin filaments in an unregulated fashion. The cleavage of gelsolin causes cells to round up, detach and undergo nuclear fragmentation.	SIGNOR-256461	0.624
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates activity	phosphorylation	Tyr162	QLAAKLAyLQILSEE	-1									16373505	t		Manara	PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR.	SIGNOR-260783	0.2
PTPN1	protein	P18031	UNIPROT	STAT5B	protein	P51692	UNIPROT	down-regulates activity	dephosphorylation	Tyr699	TAKAVDGyVKPQIKQ	9534	BTO:0004055								10993888	t			A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b	SIGNOR-248429	0.662
AKT1	protein	P31749	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser304	GAPPRRSsIRNAHSI	9606	BTO:0000130								10559253	t		esanto	Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis.	SIGNOR-252586	0.577
DNMT3A	protein	Q9Y6K1	UNIPROT	TIMP2	protein	P16035	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19786833	f		irozzo	Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. 	SIGNOR-255807	0.2
MCHR1	protein	Q99705	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257147	0.412
IL1R1	protein	P14778	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity				9606	BTO:0000007								14625308	f		lperfetto	Formation of the signaling il-1 receptor complex results in the activation and hyperphosphorylation of irak-1.	SIGNOR-119208	0.912
CD38	protein	P28907	UNIPROT	NADP(+)	smallmolecule	CHEBI:18009	ChEBI	down-regulates quantity	chemical modification			9606									18626062	t		miannu	The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR.	SIGNOR-264247	0.8
UNC13A	protein	Q9UPW8	UNIPROT	SNARE_complex 	complex	SIGNOR-C346	SIGNOR	up-regulates activity	transcriptional regulation			9606	BTO:0000938								30267828	t		miannu	 In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2.	SIGNOR-263971	0.468
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr534	SRTPSLPtPPTREPK	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249324	0.754
CACNA1A	protein	O00555	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									20655485	t		miannu	The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release.	SIGNOR-266708	0.8
TLK1	protein	Q9UKI8	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	phosphorylation			-1									11314006	t	The effect has been demonstrated using Q9UKI8-2	lperfetto	Purified tlk1b phosphorylated histone h3 at s(10) with high specificity both in a mix of core histones and in isolated chromatin, suggesting that histone h3 is a physiological substrate for tlk1b. Phosphorylation of H3 has been linked to the activation of the immediate-early genes upon mitogenic stimulation, and to chromatin condensation during mitotic/meiotic events.	SIGNOR-265370	0.2
CEBPD	protein	P49716	UNIPROT	KLF5	protein	Q13887	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									16054042	f		fspada	Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter.	SIGNOR-210007	0.504
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates quantity by destabilization	cleavage	Ala617	ISEVKMDaEFRHDSG	-1									8943232	t		lperfetto	FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261737	0.502
morphine	chemical	CHEBI:17303	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258932	0.8
AURKB	protein	Q96GD4	UNIPROT	RACGAP1	protein	Q9H0H5	UNIPROT	up-regulates activity	phosphorylation	Thr145	AGNKRLStIDESGSI	9606	BTO:0000567								14744859	t		llicata	It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1	SIGNOR-250589	0.772
WWP2	protein	O00308	UNIPROT	TP73	protein	O15350	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								25071155	t		miannu	WWP2 ubiquitinates p73 and controls its protein stability. In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73. 	SIGNOR-272233	0.287
STK4	protein	Q13043	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation	Ser212	SSAGWKNsIRHNLSL	9606	BTO:0000782	BTO:0001253							22898666	t		gcesareni	Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1.	SIGNOR-252998	0.673
PRKACA	protein	P17612	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates activity	phosphorylation	Ser66	GVYATRSsAVRLRSS	-1									2500966	t		miannu	Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure.	SIGNOR-250068	0.313
PRKACA	protein	P17612	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates activity	phosphorylation	Ser429	PQRERKSsSSSEDRN	-1									11510412	t		miannu	Direct phosphorylation of B-Raf by PKA exerts a negative effect on its kinase activity, essentially via phosphorylation of Ser429	SIGNOR-250339	0.621
hydrogen peroxide	smallmolecule	CHEBI:16240	ChEBI	TXN	protein	P10599	UNIPROT	up-regulates	chemical activation			9606									15556622	t		gcesareni	We show that 10 and 50 microm h2o2 and short-term exposure to shear stress significantly increased trx-1 mrna and protein levels in endothelial cells.	SIGNOR-131049	0.8
AKT1	protein	P31749	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606	BTO:0000007								9381178	t			Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival.	SIGNOR-252563	0.816
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ADRB2	protein	P07550	UNIPROT	down-regulates	phosphorylation	Ser346	LLCLRRSsLKAYGNG	9606									11809767	t		lperfetto	Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation.	SIGNOR-114470	0.2
ADRA2B	protein	P18089	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256993	0.316
RANBP2	protein	P49792	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262088	0.613
ATM	protein	Q13315	UNIPROT	AURKB	protein	Q96GD4	UNIPROT	down-regulates				9606									18250156	f		gcesareni	Furthermore, atm-mediated i-2 phosphorylation results in the inhibition of the aurora-b kinase, the down-regulation of histone h3 serine 10 phosphorylation, and the activation of the g2/m checkpoint.	SIGNOR-160644	0.444
SMO	protein	Q99835	UNIPROT	GNG12	protein	Q9UBI6	UNIPROT	up-regulates	binding			9606									17251915	t		gcesareni	As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp.	SIGNOR-152817	0.2
CDC7	protein	O00311	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates	phosphorylation	Ser27	GNDPLTSsPGRSSRR	9606	BTO:0000567								16899510	t		gcesareni	In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells.	SIGNOR-148713	0.961
RELA	protein	Q04206	UNIPROT	NPPB	protein	P16860	UNIPROT	unknown	transcriptional regulation												15837525	f	 	 	In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription.	SIGNOR-253651	0.2
ABL1	protein	P00519	UNIPROT	PLK1	protein	P53350	UNIPROT	up-regulates activity	phosphorylation	Tyr425	SDKYGLGyQLCDNSV	9606									27899378	t		Manara	C-ABL can directly phosphorylate PLK1 and activate PLK1. | The above results indicate that c-ABL–mediated PLK1 Y425 phosphorylation regulates PLK1 ubiquitination and stability.	SIGNOR-260935	0.295
GRIA1	protein	P42261	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				10090	BTO:0000938								15115814	f		lperfetto	The targeting and clustering of AMPA and NMDA receptors to synapses in the CNS is essential for efficient excitatory synaptic transmission	SIGNOR-261433	0.7
RIN1	protein	Q13671	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates	binding			9606									11784866	t		gcesareni	We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1.	SIGNOR-113967	0.621
ARPC4	protein	P59998	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	form complex	binding			9606									12479800	t			The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc	SIGNOR-251517	0.964
ODC1	protein	P11926	UNIPROT	putrescine	smallmolecule	CHEBI:17148	ChEBI	up-regulates quantity	chemical modification			9606									14617280	t		miannu	Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC)	SIGNOR-256034	0.8
beta-D-fructofuranose 2,6-bisphosphate	smallmolecule	CHEBI:28602	ChEBI	PFKL	protein	P17858	UNIPROT	up-regulates activity	binding			9606									19454274	t			The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux	SIGNOR-267266	0.8
PRKCE	protein	Q02156	UNIPROT	NLRP5	protein	P59047	UNIPROT	up-regulates activity	phosphorylation	Ser331	MQRKKESsVTEFISR	9606	BTO:0000007								19542546	t		miannu	MATER protein as substrate of PKCepsilon in human cumulus cells. we performed coimmunoprecipitation experiments using HEK293T cells expressing human MATER; a similar approach was then followed in human cumulus/follicular cells. In MATER(+)HEK293T cells, we observed that this protein acts as a phosphorylation substrate of PKCepsilon. Since PKCepsilon is known to collaborate with antiapoptotic signalling pathways, this suggests a novel mechanism for the function of MATER in follicular maturation.	SIGNOR-263175	0.2
VRK1	protein	Q99986	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser73	VGLLKLAsPELERLI	9606									15378002	t		flangone	Vrk1 phosphorylates c-jun in ser63 and ser73 in vitro...VRK1 Activates c-jun dependent transcription	SIGNOR-127073	0.528
CDK1	protein	P06493	UNIPROT	SAMHD1	protein	Q9Y3Z3	UNIPROT	down-regulates	phosphorylation	Thr592	DVIAPLItPQKKEWN	9606									23602554	t		llicata	Cyclin a2/cdk1 phosphorylates samhd1 at the threonine 592 residue both in vitro and in vivo. Phosphorylation of samhd1 thr592 correlates with loss of its ability to restrict hiv-1.	SIGNOR-201913	0.506
levomilnacipran	chemical	CHEBI:136040	ChEBI	SLC6A3	protein	Q01959	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								18468895	t		Luana	Studies on a series of milnacipran analogs containing a heteroaromatic group as potent norepinephrine and serotonin transporter inhibitors	SIGNOR-257944	0.8
H2AZ2	protein	Q71UI9	UNIPROT	Nucleosome_H2A.Z.2 variant	complex	SIGNOR-C323	SIGNOR	form complex	binding			-1									24311584	t		miannu	In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined.	SIGNOR-263709	0.2
TCF20	protein	Q9UGU0	UNIPROT	MMP3	protein	P08254	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									7760812	t		Luana	This result indicates that expression of SPBP is sufficient to transactivate a minimal promoter containing a single copy of the SPRE, as well as the full-length stromelysin promoter. 	SIGNOR-266223	0.427
SAR1A	protein	Q9NR31	UNIPROT	SEC23A	protein	Q15436	UNIPROT	up-regulates quantity	binding							SIGNOR-C370					30605680	t		lperfetto	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 	SIGNOR-265299	0.817
PIGBOS1	protein	A0A0B4J2F0	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0002181								31653868	f		miannu	Here, we characterize a microprotein called PIGBOS and reveal a role for a mitochondrial protein in UPR signaling. Together, these results showed that loss of PIGBOS increases cellular sensitivity to ER stress, which in turn increases apoptosis and links PIGBOS levels to the ability of cells to survive stress.	SIGNOR-261042	0.7
HMGN1	protein	P05114	UNIPROT	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	down-regulates				-1									12213813	f		lperfetto	In vitro, binding of HMGN1 proteins to the nucleosomes reduces chromatin compaction and promotes overall accessibility to the nucleosomes	SIGNOR-262989	0.7
AMBRA1	protein	Q9C0C7	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates activity	binding			9606	BTO:0000007				dephosphorylation:Ser52	KRVELPDsPRSTFLL			23524951	t		lperfetto	In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function.	SIGNOR-272963	0.575
PRKCD	protein	Q05655	UNIPROT	SHC1	protein	P29353	UNIPROT	unknown	phosphorylation	Ser28	LEEGASGsTPPEELP	9606									16963224	t		llicata	Activated pkc delta was able to phosphorylate shca at ser29, as determined by mass spectrometry.	SIGNOR-149402	0.549
STAT1	protein	P42224	UNIPROT	NOS2	protein	P35228	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19029990	t		lperfetto	STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others.	SIGNOR-249497	0.44
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1927	SPKYSPTsPTYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120248	0.321
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	glutamine	smallmolecule	CHEBI:28300	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270389	0.8
MTNR1A	protein	P48039	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256985	0.252
CXCL12	protein	P48061	UNIPROT	ACKR3	protein	P25106	UNIPROT	up-regulates	binding			9606	BTO:0000782								16107333	t		gcesareni	Here we show that cxcl12, the only known natural ligand for cxcr4, binds to and signals through rdc1.	SIGNOR-139709	0.71
HTR4	protein	Q13639	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257416	0.252
CLIP1	protein	P30622	UNIPROT	DCTN1	protein	Q14203	UNIPROT	up-regulates activity	binding			9606									15381688	t		miannu	MT-unbound CLIP-170 can adopt a folded conformation through an intramolecular interaction of its terminal domains. Binding to MTs correlates with the unfolding of CLIP-170, which allows the interaction of the COOH-terminal domain with its binding partners, such as dynactin, resulting in their recruitment to the MT tip. The NH2 terminus of p150Glued binds directly to the COOH terminus of CLIP-170 through its second metal-binding motif.	SIGNOR-252164	0.772
mTORC1	complex	SIGNOR-C3	SIGNOR	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Thr390	DSKFTRQtPVDSPDD	9606									11914378	t		azuccotti	Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain [..]. Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings.	SIGNOR-255842	0.477
OFD1	protein	O75665	UNIPROT	ATG13	protein	O75143	UNIPROT	down-regulates quantity by destabilization	binding			9606									34027042	t		miannu	The OFD1 protein inhibits autophagosome biogenesis by selective autophagy-mediated degradation of Autophagy Related 13 (ATG13), a component of the unc-51-like kinase (ULK1) autophagy initiation complex.	SIGNOR-269107	0.2
LCK	protein	P06239	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates activity	phosphorylation	Tyr315	RADNDKEyLVLTLTK	9606	BTO:0002035								11948419	t		miannu	MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e).	SIGNOR-275983	0.382
KAT5	protein	Q92993	UNIPROT	H4C1	protein	P62805	UNIPROT	down-regulates activity	acetylation	Lys21	GGAKRHRkVLRDNIQ	9606									12776177	t		lperfetto	Thus, the TIP60 HAT complex is recruited to MYC-target genes and, probably with other other HATs, contributes to histone acetylation in response to mitogenic signals.	SIGNOR-262061	0.2
AVPR2	protein	P30518	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256897	0.272
SLC24A3	protein	Q9HC58	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			9606									30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264396	0.8
MAP2K1	protein	Q02750	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates activity	phosphorylation	Thr125	PEVLRPEtPRPVDIG										12792650	t		lperfetto	Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2	SIGNOR-249385	0.451
CSNK2A1	protein	P68400	UNIPROT	CAV1	protein	Q03135	UNIPROT	unknown	phosphorylation	Ser88	FDGIWKAsFTTFTVT	-1									8058322	t		llicata	Here, we have identified this serine kinase activity as a casein kinase II-like enzyme, since the phosphorylation of caveolin-rich membrane domains is stimulated and inhibited by known effectors of casein kinase II (poly-L-lysine, endogenous polyamines, and a casein kinase II inhibitor peptide), but is unaffected by modulators of other known kinases. In support of these observations, caveolin contains a consensus sequence for casein kinase II phosphorylation in its cytoplasmic N-terminal domain (Ser-88)	SIGNOR-250835	0.36
TBK1	protein	Q9UHD2	UNIPROT	IRF5	protein	Q13568	UNIPROT	up-regulates	phosphorylation	Ser293	VELFGPIsLEQVRFP	9606									22412986	t		lperfetto	Activation of interferon regulatory factor 5 by site specific phosphorylation. Although the gene induction by irf5 in the presence of tbk-1 was modest, phosphorylation by tbk-1 produced a significant shift in the mobility of irf5 in sds-page. For this reason we identified the residues that are phosphorylated on irf5 by tbk-1 with mass spectrometry. Ser-158 and ser-309 were found to be phosphorylated	SIGNOR-196532	0.558
DDB1	protein	Q16531	UNIPROT	RAD23B	protein	P54727	UNIPROT	up-regulates													24086044	f		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein).	SIGNOR-275689	0.631
dexamethasone	chemical	CHEBI:41879	ChEBI	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression				10090									11279134	f		lperfetto	The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin	SIGNOR-235328	0.8
NANOG	protein	Q9H9S0	UNIPROT	SOX17	protein	Q9H6I2	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003298								22795133	f		lperfetto	Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)	SIGNOR-253168	0.486
GABARAP	protein	O95166	UNIPROT	GABA-A	proteinfamily	SIGNOR-PF61	SIGNOR	up-regulates activity	binding			9606	BTO:0000938								25882190	t		miannu	GABARAP was originally isolated as a binding partner of the GABAA receptor γ2-subunit in a yeast two-hybrid screen, and was suggested to have a role in the targeting and clustering of GABAA receptors.	SIGNOR-264972	0.2
RPS6KA3	protein	P51812	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates	phosphorylation	Thr451	KRTRSKGtLRYMSPE	9606	BTO:0001286								17404396	t		gcesareni	Our data indicated that phosphorylation of pkr at thr(451) is mediated through erk2 and rsk2, but not through p38 kinase.	SIGNOR-154183	0.2
MAPKAPK2	protein	P49137	UNIPROT	KRT20	protein	P35900	UNIPROT	up-regulates activity	phosphorylation	Ser13	RSFHRSLsSSLQAPV	-1									20724476	t		miannu	P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13.	SIGNOR-263072	0.2
Viral_dsRNA	stimulus	SIGNOR-ST21	SIGNOR	G3BP1	protein	Q13283	UNIPROT	up-regulates activity	binding												30804210	t		SARA	The RGG domain of G3BP1 could mediate the direct binding of HCV-dsRNA and poly(IC)	SIGNOR-260979	0.7
AURKB	protein	Q96GD4	UNIPROT	MYBBP1A	protein	Q9BQG0	UNIPROT	unknown	phosphorylation	Ser1303	ARKKARLsLVIRSPS	9606									20177074	t		lperfetto	We identified mybbp1a as a novel aurora b substrate and serine 1303 as the major phosphorylation site	SIGNOR-163903	0.399
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser88	DSGFCLDsPGPLDSK	9606	BTO:0000017								28192398	t		miannu	We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation. 	SIGNOR-277342	0.638
AP1	complex	SIGNOR-C154	SIGNOR	CCL2	protein	P13500	UNIPROT	up-regulates activity	transcriptional regulation			9606									21561061	t		Luana	3b Potentiates AP-1-Dependent MCP-1 Promoter Activity	SIGNOR-260764	0.601
CUDC-101	chemical	CID:24756910	PUBCHEM	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									20143778	t		miannu	By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively.	SIGNOR-262256	0.8
MAP3K10	protein	Q02779	UNIPROT	NEUROD1	protein	Q13562	UNIPROT	up-regulates activity	binding			-1									12881483	t		lperfetto	we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2). Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2	SIGNOR-234599	0.338
PRKD1	protein	Q15139	UNIPROT	RIN1	protein	Q13671	UNIPROT	down-regulates	phosphorylation	Ser351	RPLLRSMsAAFCSLL	9606									11784866	t		gcesareni	Rin1 also binds to 14-3-3 proteins through a sequence including serine 351. Mutation of this residue abolished the 14-3-3 binding capacity of rin1 and led to more efficient blockade of ras-mediated transformation. The mutant protein, rin1(s351a), showed a shift in localization to the plasma membrane. Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation.	SIGNOR-113960	0.413
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2C	protein	O00762	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271356	0.598
AP1	complex	SIGNOR-C154	SIGNOR	CD3	complex	SIGNOR-C432	SIGNOR	up-regulates activity	binding			9606									16473826	t		scontino	When T cells encounter antigens via the T cell antigen receptor (TCR), information about the quantity and quality of antigen engagement is relayed to the intracellular signal transduction machinery. The TCR itself lacks a significant intracellular domain. Instead, it is associated with CD3 molecules that contain intracellular signaling domains that couple the TCR/CD3 complex to the downstream signaling machinery.	SIGNOR-267994	0.327
HDAC1	protein	Q13547	UNIPROT	CLDN7	protein	O95471	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001570								19277896	t	 	lperfetto	ChIP assays revealed that SNAI1P is recruited on the CLDN7 gene promoter along with the co-repressor CtBP1 and the effector HDAC1.|These data further suggest that HDAC1 is involved in the SNAI1P-mediated repression of the human CLDN7 gene promoter. 	SIGNOR-254106	0.2
MAPK14	protein	Q16539	UNIPROT	EEA1	protein	Q15075	UNIPROT	up-regulates	phosphorylation			9606									16138080	t		gcesareni	We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes.	SIGNOR-140085	0.47
OXSR1	protein	O95747	UNIPROT	SLC12A2	protein	P55011	UNIPROT	up-regulates	phosphorylation	Thr207	YYDTHTNtYYLRTFG	9606									16669787	t		miannu	We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1	SIGNOR-146517	0.54
IFNAR	complex	SIGNOR-C243	SIGNOR	Macrophage_activation	phenotype	SIGNOR-PH126	SIGNOR	up-regulates				10090									32283152	f		miannu	The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. 	SIGNOR-260848	0.7
MAPK1	protein	P28482	UNIPROT	MAPKAPK2	protein	P49137	UNIPROT	up-regulates	phosphorylation	Ser272	SNHGLAIsPGMKTRI	9606									8846784	t		fstefani	Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk.	SIGNOR-44339	0.52
OGT	protein	O15294	UNIPROT	PFKL	protein	P17858	UNIPROT	down-regulates activity	glycosylation	Ser529	CVIPATIsNNVPGTD	9606	BTO:0000007								22923583	t		lperfetto	O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway| O-GlcNAc transferase (OGT) catalyzes the transfer of N-acetylglucosamine from uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) to serine or threonine residues	SIGNOR-267585	0.282
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	KDM2A	protein	Q9Y2K7	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273478	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000762								12509763	t		lperfetto	Substrates for ERK1/2 include nuclear proteins such as C-JUN, this leads to activation of the AP-1 transcription factor, which is made up of FOS-JUN heterodimers.	SIGNOR-253214	0.2
SALL4	protein	Q9UJQ4	UNIPROT	ABCG2	protein	Q9UNQ0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21526180	f		miannu	 we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples	SIGNOR-255122	0.268
MVD	protein	P53602	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates quantity by stabilization				9534									12646231	f		miannu	An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B)	SIGNOR-265887	0.2
TNFAIP3	protein	P21580	UNIPROT	RIPK1	protein	Q13546	UNIPROT	down-regulates quantity	ubiquitination			9606									15258597	t			A20The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation.	SIGNOR-259977	0.64
FAM83G	protein	A6ND36	UNIPROT	CSNK1A1	protein	P48729	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								29789297	t		miannu	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273745	0.381
YAP1	protein	P46937	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates	binding			9606									23431053	t	YAP can specifically recognize the phosphorylated SMAD linker sequence containing the PY motif, and its presence is required for efficient transcription of BMP target genes.	gcesareni	Yap binds to the phosphorylated smad1 to activate gene transcription.	SIGNOR-201462	0.56
SSH3	protein	Q8TE77	UNIPROT	CFL1	protein	P23528	UNIPROT	up-regulates activity	dephosphorylation	Ser3	sGVAVSDG	9606									14531860	t			Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH).	SIGNOR-248759	0.71
SMURF2	protein	Q9HAU4	UNIPROT	SKIL	protein	P12757	UNIPROT	down-regulates activity	ubiquitination			9606		BTO:0002181;BTO:0005493							11389444	t		lperfetto	Tgf-beta also induces the association of smurf2 with the transcriptional co-repressor snon and we show that smad2 can function to mediate this interaction. This allows smurf2 hect domain to target snon for ubiquitin-mediated degradation by the proteasome.	SIGNOR-236090	0.728
STAT4	protein	Q14765	UNIPROT	S100A4	protein	P26447	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								22740693	f		miannu	It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4.	SIGNOR-255246	0.311
CDC14A	protein	Q9UNH5	UNIPROT	KMT5A	protein	Q9NQR1	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser100	SKIYSYMsPNKCSGM	9606									20966048	t			The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis.	SIGNOR-248835	0.2
MAPK1	protein	P28482	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates activity	phosphorylation	Ser863	LTQSAPAsPTNKGVH	9606				SIGNOR-C3					21071439	t		lperfetto	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-188916	0.533
Nucleosome_H3.1t variant	complex	SIGNOR-C325	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606									20498094	f		miannu	A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. 	SIGNOR-263728	0.7
GPR183	protein	P32249	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257202	0.264
GFI1B	protein	Q5VTD9	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000661								21261500	f	 	miannu	Here, we analyzed the MEF2C 5'-region, thus identifying potential regulatory binding sites for GFI1B, basic helix-loop-helix proteins, STAT5, and HOXA9/HOXA10. Chromatin immunoprecipitation and overexpression analyses demonstrated direct activation by GFI1B and LYL1 and inhibition by STAT5. 	SIGNOR-254206	0.287
PRDM1	protein	O75626	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12032779	f		miannu	 Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. 	SIGNOR-253828	0.449
NLK	protein	Q9UBE8	UNIPROT	TCF7L2	protein	Q9NQB0	UNIPROT	down-regulates	phosphorylation	Thr212	TYSNEHFtPGNPPPH	9606									12556497	t		llicata	Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk.	SIGNOR-97873	0.763
FAM83H	protein	Q6ZRV2	UNIPROT	CSNK1A1	protein	P48729	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								29789297	t		miannu	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273747	0.395
DYRK1A	protein	Q13627	UNIPROT	RCAN1	protein	P53805	UNIPROT	up-regulates	phosphorylation	Ser167	FLISPPAsPPVGWKQ	9606									12809556	t		gcesareni	In the present study, dyrk1a is shown to directly interact with and phosphorylate rcan1 at ser112 and thr192 residues. Dyrk1a-mediated phosphorylation of rcan1 at ser112 primes the protein for the gsk3_-mediated phosphorylation of ser108.	SIGNOR-102290	0.581
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	E2 conjugating enzyme	proteinfamily	SIGNOR-PF105	SIGNOR	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-270840	0.2
FUS	protein	P35637	UNIPROT	GEMIN6	protein	Q8WXD5	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								23022481	t		lperfetto	Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells	SIGNOR-262106	0.2
ruxolitinib phosphate	chemical	CHEBI:66917	ChEBI	JAK2	protein	O60674	UNIPROT	down-regulates activity	chemical inhibition			9606									23061804	t		miannu	Ruxolitinib is a selective inhibitor of Janus kinases (JAK) 1 and 2, which are involved in the signalling pathway of various cytokines and growth factors essential to haematopoiesis. 	SIGNOR-259171	0.8
FGF2	protein	P09038	UNIPROT	FGFR3	protein	P22607	UNIPROT	up-regulates	binding			9606									22298955	t		gcesareni	Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts.	SIGNOR-195588	0.813
GSK3B	protein	P49841	UNIPROT	STAT2	protein	P52630	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser393	LTPEKGQsQGLIWDF	9606	BTO:0002181								31843895	t		miannu	GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation.	SIGNOR-276764	0.293
FOXO3	protein	O43524	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									14981546	f			Induction of Foxo3a phosphorylation by FLT3-ITD receptors in Ba/F3 cells correlates with the suppression of Foxo-target genes p27Kip1 and the proapoptotic Bcl-2 family member Bim	SIGNOR-261527	0.738
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	DCX	protein	O43602	UNIPROT	unknown	phosphorylation	Thr289	AGPKASPtPQKTSAK	9606									14741103	t		llicata	In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35.	SIGNOR-250656	0.415
ANXA1	protein	P04083	UNIPROT	IL1B	protein	P01584	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									27426034	f		miannu	Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups	SIGNOR-261940	0.386
DUSP9	protein	Q99956	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	down-regulates	binding			9606									21908610	t	inferred from 70% of family members	gcesareni	Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein.	SIGNOR-269902	0.2
doxepin	chemical	CHEBI:4710	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9537821	t		miannu	Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 	SIGNOR-258879	0.8
GSK3B	protein	P49841	UNIPROT	OSBP2	protein	Q969R2	UNIPROT	up-regulates activity	phosphorylation												30925160	t		lperfetto	CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.	SIGNOR-264874	0.2
VRK1	protein	Q99986	UNIPROT	BANF1	protein	O75531	UNIPROT	down-regulates	phosphorylation	Thr3	tSQKHRDF	9606									16495336	t		gcesareni	We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell	SIGNOR-144791	0.873
dabrafenib	chemical	CHEBI:75045	ChEBI	NEK9	protein	Q8TD19	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0005011								29112787	t		Monia	We have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations. We confirmed NEK9 to be a potent target of dabrafenib by in vitro kinase assays, with inhibition of NEK9 observed in the single-digit nanomolar range.	SIGNOR-261072	0.8
EEF1A1	protein	P68104	UNIPROT	Ala-tRNA(Ala)	smallmolecule	CHEBI:17732	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269503	0.8
SRC	protein	P12931	UNIPROT	DGKA	protein	P23743	UNIPROT	up-regulates	phosphorylation	Tyr335	ILPPSSIyPSVLASG	9606									17700527	t		llicata	Diacylglycerol kinase-alpha phosphorylation by src on y335 is required for activation, membrane recruitment and hgf-induced cell motility.	SIGNOR-157365	0.472
BNIP2	protein	Q12982	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	binding			9606	BTO:0000222								18678706	t		lperfetto	Cdo-bnip-2-cdc42 complex stimulates cdc42 activation which in turn promotes p38 alpha/beta activity and cell differentiation.	SIGNOR-179861	0.698
RALA	protein	P11233	UNIPROT	FOXO4	protein	P98177	UNIPROT	up-regulates activity	phosphorylation	Thr451	PIPKALGtPVLTPPT	10090									11689711	t		gcesareni	We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT.	SIGNOR-248003	0.2
G3BP1	protein	Q13283	UNIPROT	G3BP2	protein	Q9UN86	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								23279204	t		miannu	Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli.	SIGNOR-260862	0.469
MAPKAPK2	protein	P49137	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates	phosphorylation			9606									20626350	t		gcesareni	Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2	SIGNOR-166640	0.565
4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one	chemical	CHEBI:94732	ChEBI	MAPK8	protein	P45983	UNIPROT	down-regulates	chemical inhibition			9606									18922779	t	BI-78D3 is substrate competitive.	gcesareni	Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell.	SIGNOR-181647	0.8
CTDSPL	protein	O15194	UNIPROT	RB1	protein	P06400	UNIPROT	up-regulates activity	dephosphorylation	Ser811	IYISPLKsPYKISEG	9606									15051889	t			ppRB (RB phosphorylated at Ser-807/811|Possible Mechanisms of HYA22 Action in Tumorigenesis: Dephosphorylation of RB by Transient Expression of HYA22 Isoforms.	SIGNOR-248305	0.303
FFAR2	protein	O15552	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257276	0.378
CDK2	protein	P24941	UNIPROT	ATRIP	protein	Q8WXE1	UNIPROT	unknown	phosphorylation	Ser239	VIKPEACsPQFGKTS	9606									17638878	t		lperfetto	Two novel phosphorylation sites on atrip were identified, s224 and s239	SIGNOR-156932	0.563
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1717	SPSYSPTsPSYSPTS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248811	0.849
ZIC1	protein	Q15915	UNIPROT	GLI3	protein	P10071	UNIPROT	up-regulates	relocalization			9606									11238441	t		lperfetto	Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels	SIGNOR-105497	0.364
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	IRS1	protein	P35568	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606		BTO:0001103							21798082	t		lperfetto	Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization.	SIGNOR-252787	0.2
PTPN11	protein	Q06124	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	dephosphorylation	Tyr751	SKDESVDyVPMLDMK	-1									7545675	t			Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides	SIGNOR-248668	0.739
BCL2L1	protein	Q07817	UNIPROT	BAX	protein	Q07812	UNIPROT	down-regulates	binding			9606									9670005	t		amattioni	The presence of an anti-apoptotic molecule such as bcl-2 or bcl-xl can inhibit the activation of bax following a death signal.	SIGNOR-59141	0.732
Melanotan II	chemical	CID:92432	PUBCHEM	MC4R	protein	P32245	UNIPROT	up-regulates activity	binding					BTO:0000614							17702843	t		lperfetto	Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases.	SIGNOR-253066	0.8
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates	phosphorylation	Thr686	VKDSQVGtVNYMPPE	9606									19120698	t		llicata	Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity, autophosphorylation at the p+1 loop (t686) is associated with the active kinase.	SIGNOR-183030	0.2
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	RHOA	protein	P61586	UNIPROT	down-regulates activity	phosphorylation	Tyr34	KDQFPEVyVPTVFEN	9606	BTO:0000567								23027962	t		lperfetto	When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity	SIGNOR-271700	0.2
STAT3	protein	P40763	UNIPROT	SALL4	protein	Q9UJQ4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000815								19151334	f		miannu	 We further tested the functional relationship between STAT3 and SALL4 using MDA-MB-231, a breast cell line carrying constitutive SALL4 expression and STAT3 activity. Down-regulation of the STAT3 activity using a dominant-negative construct resulted in a significant decrease in the expression of SALL4. 	SIGNOR-255244	0.566
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CDKN1B	protein	P46527	UNIPROT	down-regulates activity	phosphorylation	Thr157	GIRKRPAtDDSSTQN	9606									18570873	t		lperfetto	Mtor may promote g1 progression in part through sgk1 activation and deregulate the cell cycle in cancers through both akt- and sgk-mediated p27 t157 phosphorylation and cytoplasmic p27 mislocalization.	SIGNOR-244202	0.2
DTNBP1	protein	Q96EV8	UNIPROT	BLOC-1	complex	SIGNOR-C381	SIGNOR	form complex	binding			9606									22203680	t		lperfetto	We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter.	SIGNOR-265933	0.801
PRKG1	protein	Q13976	UNIPROT	RGS2	protein	P41220	UNIPROT	up-regulates activity	phosphorylation	Ser64	KPKTGKKsKQQAFIK	-1									14608379	t		lperfetto	Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction. 	SIGNOR-249241	0.671
COP9 signalosome variant 2	complex	SIGNOR-C487	SIGNOR	26S Proteasome	complex	SIGNOR-C307	SIGNOR	up-regulates activity	binding			9606									26497135	t		miannu	The COP9 signalosome (CSN) and the proteasomal LID are conserved macromolecular complexes composed of at least eight subunits with molecular weights of approximately 350 kDa. CSN and LID are part of the ubiquitin–proteasome pathway and cleave isopeptide linkages of lysine side chains on target proteins. CSN cleaves the isopeptide bond of ubiquitin-like protein Nedd8 from cullins, whereas the LID cleaves ubiquitin from target proteins sentenced for degradation. The evolutionary conserved ubiquitin proteasome pathway (UPP) mediates degradation of intracellular proteins in all eukaryotes. This essential process requires three protein complexes: E3 ubiquitin ligases as e.g., cullin-RING ligases (CRLs), CSN and the 26S proteasome.	SIGNOR-270794	0.321
G6PD	protein	P11413	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	down-regulates quantity	chemical modification			9606									24769394	t		miannu	G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress	SIGNOR-267050	0.8
ABL1	protein	P00519	UNIPROT	WRN	protein	Q14191	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000567;BTO:0001271								12944467	t		gcesareni	We thus hypothesized that wrn may interact with the abl tyrosine kinase in the dna damage response. Here, we provide evidence for a functional and physical interaction between wrn and c-abl, including wrn relocalization in response to dna damage, suggesting that this protein-protein interaction participates in a shared pathway of genome surveillance.	SIGNOR-86497	0.422
RABEPK	protein	Q7Z6M1	UNIPROT	M6PR	protein	P20645	UNIPROT	up-regulates activity	relocalization												9230071	t		lperfetto	P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking.	SIGNOR-253091	0.357
TSHZ3	protein	Q63HK5	UNIPROT	HDAC1	protein	Q13547	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								19343227	t		miannu	We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex.Endogenous HDAC1 was co-immunoprecipitated with FE65 when both FE65 and Teashirt3 were co-transfected (lane 4), but not when Teashirt3 or FE65 was omitted (lane 5 and 6), confirming that the association of HDAC1 with FE65 is dependent on, and mediated, by Teashirt3.	SIGNOR-264814	0.2
STK3	protein	Q13188	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	phosphorylation	Thr622	KEGGVTFtWVEKDIS	-1									35722967	t		miannu	Hippo pathway component MST2 kinase phosphorylates STAT3 at T622, which is located in the SH2 domain of STAT3. This phosphorylation blocks the SH2 domain in one STAT3 molecule to bind with the phosphorylated Y705 site in another STAT3 molecule, which further counteracts IL6-induced STAT3 dimerization and activation.	SIGNOR-277599	0.2
AGRP	protein	O00253	UNIPROT	MC3R	protein	P41968	UNIPROT	down-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268704	0.612
MAPK1	protein	P28482	UNIPROT	LIMA1	protein	Q9UHB6	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser604	FQSTSVKsPKTVSPP	9606									23188829	t		miannu	Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover.	SIGNOR-263055	0.2
PIP3	smallmolecule	CHEBI:16618	ChEBI	mTORC2	complex	SIGNOR-C2	SIGNOR	up-regulates activity	chemical activation			9606									26293922	t		gcesareni	PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation	SIGNOR-252430	0.8
FOXP2	protein	O15409	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002881								21832174	t		Gianni	FOXP2 binds directly to the 5' regulatory region of MET, and overexpression of FOXP2 results in transcriptional repression of MET. The expression of MET in restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence for MET contributing to ASD risk.	SIGNOR-269054	0.428
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Thr67	LSILSGGtPKRCLDL	9606									10864927	t		lperfetto	Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b.	SIGNOR-216777	0.839
PTK6	protein	Q13882	UNIPROT	PTK6	protein	Q13882	UNIPROT	up-regulates activity	phosphorylation	Tyr447	RLSSFTSyENPT	9606									12121988	t		lperfetto	Mutation of a C-terminal tyrosine (Tyr-447) increases enzyme activity and SH2 domain accessibility, consistent with a role for this residue in autoinhibition. | These results suggest that the Y447F and W44A mutations disrupt the normal intramolecular regulation of Brk and increase the catalytic activity of Brk.	SIGNOR-249152	0.2
MTOR	protein	P42345	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000132		SIGNOR-C2						21592956	t		lperfetto	Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1.	SIGNOR-244417	0.928
GRK5	protein	P34947	UNIPROT	ADRB2	protein	P07550	UNIPROT	unknown	phosphorylation	Thr393	DFVGHQGtVPSDNID	-1									8662852	t			 we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). 	SIGNOR-251200	0.682
SYN1	protein	P17600	UNIPROT	ACTB	protein	P60709	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								15265865	t		miannu	Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. 	SIGNOR-269184	0.304
COL2A1	protein	P02458	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	up-regulates	binding			9606									7688313	t		gcesareni	Both a2b1- and a1b1- integrins are implicated in chondrocyte adhesion to native collagene i and ii	SIGNOR-31881	0.451
AKT3	protein	Q9Y243	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser253	APRRRAVsMDNSNKY										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-252874	0.697
ZNF318	protein	Q5VUA4	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates activity	binding			9606									16469430	t		Monia	Using different promoters and cells, we confirmed that AR-mediated transactivation was repressed by TZF in a dose-dependent manner (Fig. 1A and B). Endogenous ARmediated transactivation was also inhibited by expression of TZF; These results indicate that amino acid residues 512–663 are essential for the repressive effect of TZF on AR-mediated transactivation.	SIGNOR-261187	0.379
GABA-A (a4-b2-d) receptor	complex	SIGNOR-C326	SIGNOR	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	relocalization			9606									18790874	t	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263808	0.8
YBX1	protein	P67809	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10644769	f		miannu	 these results indicate a role for both NF-Y and Sp1 in the transcriptional activation of the MDR1 gene by genotoxic stress, and indicate that YB-1, if involved, is not sufficient to mediate this activation.	SIGNOR-253873	0.393
UBE3A	protein	Q05086	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys122	SPVEDNEkDLVKLAK	-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. 	SIGNOR-272743	0.476
STAT3	protein	P40763	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16510571	f		lperfetto	Mutagenesis of STAT3 binding sites within the cyclin D1 promoter and chromatin immunoprecipitation studies showed an association between STAT3 and the transcriptional regulation of the human cyclin D1 gene.	SIGNOR-253049	0.78
KPNB1	protein	Q14974	UNIPROT	ISGF3 complex	complex	SIGNOR-C124	SIGNOR	up-regulates activity	relocalization			9534									17596301	t		lperfetto	Although ORF6 causes a relocalization of KPNA2 from the cytosol to the ER/Golgi membrane, KPNA2 is not directly involved in the translocation of the STAT1:STAT2:IRF9 (ISGF3) complex into the nucleus; rather, KPNA1 interacts with KPNB1 to initiate ISGF3's nuclear localization. 	SIGNOR-260274	0.274
ACACB	protein	O00763	UNIPROT	acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	down-regulates quantity	chemical modification			9606									20952656	t		miannu	ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA	SIGNOR-267106	0.8
NCSTN	protein	Q92542	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates	binding			9606		BTO:0000975							14572442	t	Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation	gcesareni	Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2.	SIGNOR-118852	0.964
ETS1	protein	P14921	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									11175361	f		miannu	Ets1 and Ets2 seem to play opposing roles in apoptosis. While Ets1 seems to activate pro-apoptotic pathways, Ets2 seems to inhibit apoptosis	SIGNOR-259869	0.7
SHC1	protein	P29353	UNIPROT	INPP5D	protein	Q92835	UNIPROT	up-regulates	binding			9606	BTO:0000776								10207047	t		gcesareni	The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation.	SIGNOR-66949	0.683
WNT1	protein	P04628	UNIPROT	FZD6	protein	O60353	UNIPROT	up-regulates activity	binding			9606		BTO:0000887;BTO:0001103							22944199	t		gcesareni	Distinctly, wnt1 signals through fzd receptors 1 and 6 in the epaxial domain of the somite, to regulate myf5 expression via the canonical bcatenin pathway.	SIGNOR-198846	0.68
TAB2	protein	Q9NYJ8	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates	binding			9606									25290089	t		lperfetto	The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.	SIGNOR-205446	0.558
CS	protein	O75390	UNIPROT	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	down-regulates quantity	chemical modification			9606									3013232	t		miannu	Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond.	SIGNOR-266239	0.8
clofarabine	chemical	CHEBI:681569	ChEBI	RRM2	protein	P31350	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000664								1707752	t		miannu	Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate	SIGNOR-258356	0.8
STUB1	protein	Q9UNE7	UNIPROT	CFTR	protein	P13569	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								11146634	t		miannu	Here we show that CHIP functions with Hsc70 to sense the folded state of CFTR and targets aberrant forms for proteasomal degradation by promoting their ubiquitination. 	SIGNOR-272584	0.484
PLK1	protein	P53350	UNIPROT	RACGAP1	protein	Q9H0H5	UNIPROT	up-regulates	phosphorylation	Ser170	ESLDWDSsLVKTFKL	9606									19468302	t		llicata	Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex.	SIGNOR-185750	0.658
SREBF2	protein	Q12772	UNIPROT	HMGCR	protein	P04035	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000759							31848472	t		miannu	The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription	SIGNOR-265161	0.508
PK	proteinfamily	SIGNOR-PF80	SIGNOR	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	down-regulates quantity	chemical modification			9606									15996096	t		miannu	Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A).	SIGNOR-266539	0.8
COMT	protein	P21964	UNIPROT	dopamine	smallmolecule	CHEBI:18243	ChEBI	down-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO.	SIGNOR-263997	0.8
SMARCD2	protein	Q92925	UNIPROT	Muscle cell-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C483	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex.	SIGNOR-270733	0.74
LCK	protein	P06239	UNIPROT	LAT	protein	O43561	UNIPROT	up-regulates	phosphorylation	Tyr220	SLDGSREyVNVSQEL	9606	BTO:0000782								16938345	t		gcesareni	Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation.	SIGNOR-149186	0.749
SRPK1	protein	Q96SB4	UNIPROT	SRPK1	protein	Q96SB4	UNIPROT	up-regulates	phosphorylation	Ser309	RPNKQEEsESPVERP	9606									22727668	t		llicata	We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1	SIGNOR-197985	0.2
CSNK1A1L	protein	Q8N752	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation			9606									19293931	t		gcesareni	Ck1 also phosphorylates lrp6 at the second ser residue in the pppspxs motif ck1_ in the lrp5/e-cadherin/p120-catenin complex temporally coincides with p120-catenin phosphorylation in ser268. moreover, and considering the close similarity between the catalytic domains of ck1_ and ck1_, it is possible that ck1_ is indeed responsible for the phosphorylation at ser1420 and ser1430 in lrp5/6 that negatively affects wnt signaling by still not defined mechanisms	SIGNOR-184699	0.257
BIRC3	protein	Q13489	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	ubiquitination	Lys377	NEPSLQSkLQDEANY	9606									18621737	t		amattioni	In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein.	SIGNOR-179443	0.737
ARF5	protein	P84085	UNIPROT	Vesicle_transport	phenotype	SIGNOR-PH172	SIGNOR	up-regulates													14973189	f		lperfetto	ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface	SIGNOR-272152	0.7
YAP1	protein	P46937	UNIPROT	BMP4	protein	P12644	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000222;BTO:0002314	BTO:0000887;BTO:0001103							23038772	f		gcesareni	In our analysis bmp4 (bone morphogenetic protein 4) and fstl3 (follistatin-related protein 3) increased their expression in response to hyap1 s127a overexpression.	SIGNOR-199066	0.324
CDK1	protein	P06493	UNIPROT	PKN1	protein	Q16512	UNIPROT	up-regulates activity	phosphorylation	Ser537	GTFSPGAsPGSEART	9606	BTO:0000567								31981797	t		miannu	CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines.	SIGNOR-276833	0.411
acadesine	chemical	CHEBI:28498	ChEBI	PRKAG1	protein	P54619	UNIPROT	up-regulates	chemical activation			9606				SIGNOR-C15					16879084	t		gcesareni	The activation of the ampk pathway by exendin-4 was induced by aicar, which was inhibited by compound c.	SIGNOR-148337	0.8
MAPK14	protein	Q16539	UNIPROT	MEF2D	protein	Q14814	UNIPROT	up-regulates activity	phosphorylation			9606									21902831	t		lperfetto	Through phosphorylation of mef2d, p38 recruits an ash2l-containing complex to myogenic loci during differentiation, which results in the marking of these genes for expression.	SIGNOR-176554	0.595
NTF4	protein	P34130	UNIPROT	NTRK1	protein	P04629	UNIPROT	up-regulates	binding			9606									11114882	t		gcesareni	Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb.	SIGNOR-85117	0.693
DLX5	protein	P56178	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	up-regulates				-1									19195802	f		Luana	DLX5 and adjacent DLX6 are homeobox genes working in neurogenesis.	SIGNOR-265797	0.7
PLK1	protein	P53350	UNIPROT	CTNNB1	protein	P35222	UNIPROT	unknown	phosphorylation	Ser718	QDDPSYRsFHSGGYG	9606									19001871	t		lperfetto	Ser-718 of beta-catenin was directly phosphorylated by recombinant plk1thus it may be possible that function of the additional phosphorylation site(s) in cooperation with the ser-718 is required for the regulation of _-catenin at m phase	SIGNOR-182150	0.408
PPP5C	protein	P53041	UNIPROT	CDC37	protein	Q16543	UNIPROT	down-regulates activity	dephosphorylation	Ser13	VWDHIEVsDDEDETH	9606									18922470	t			Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13|PP5/Ppt1 regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37.	SIGNOR-248539	0.659
glycine	smallmolecule	CHEBI:15428	ChEBI	GLRA2	protein	P23416	UNIPROT	up-regulates activity	chemical activation			9606		BTO:0001175;BTO:0001279;BTO:0000146							18721822	t		miannu	The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. 	SIGNOR-264981	0.8
ZAP70	protein	P43403	UNIPROT	DUSP3	protein	P51452	UNIPROT	up-regulates	phosphorylation	Tyr138	SPTLVIAyLMMRQKM	9606									12447358	t		gcesareni	We report here that vhr, a vaccinia virus vh1-related dual-specific protein phosphatase that inactivates the mitogen-activated kinases erk2 and jnk, is phosphorylated at y138 by zap-70. Tyr138 phosphorylation was required for vhr to inhibit the erk2-elk-1 pathway	SIGNOR-95877	0.547
CSNK2A1	protein	P68400	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Ser370	TSVTPDVsDNEPDHY	9606									21779440	t		gcesareni	The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity	SIGNOR-89818	0.667
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TTC3	protein	P53804	UNIPROT	up-regulates	phosphorylation	Ser378	AYTPRSLsAPIFTTS	9606									20059950	t		llicata	Phosphorylation of ttc3 at ser378 is required for efficient biological function together, these observations support that ttc3 is a phosphorylation target of akt both in an in vitro and in a cellular context	SIGNOR-162984	0.2
UBQLN2	protein	Q9UHD9	UNIPROT	HNRNPU	protein	Q00839	UNIPROT	up-regulates quantity by stabilization	binding												25616961	t		lperfetto	Confirmation of binding of recombinant full-length hnRNPA1 and hnRNPU proteins with ubiquilin-2 by GST-pull-down assays|Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein 	SIGNOR-262271	0.339
AKT2	protein	P31751	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	phosphorylation	Ser196	KLRRRFSsLHFMVEV	9606									15004527	t		gcesareni	Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity	SIGNOR-123243	0.508
perfluorohexanesulfonic acid	chemical	CHEBI:132448	ChEBI	AR	protein	P10275	UNIPROT	down-regulates activity	chemical inhibition			-1									23764977	t		miannu	Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. 	SIGNOR-268766	0.8
RAB5A	protein	P20339	UNIPROT	COMMD5	protein	Q9GZQ3	UNIPROT	up-regulates activity	binding			9606									30021164	t		miannu	The N terminus of COMMD5 binds to the endosomal Rab5, and its C terminus, including the COMMD domain, binds to the cytoskeletal scaffolding.	SIGNOR-261691	0.2
JAK3	protein	P52333	UNIPROT	PLD2	protein	O14939	UNIPROT	up-regulates	phosphorylation	Tyr415	ALGINSGySKRALML	9606									20176813	t		miannu	We identified three kinases capable of phosphorylating pld2 in vitro-epidermal growth factor receptor (egfr), jak3, and src (with jak3 reported for the first time in this study)-that phosphorylate an inhibitory, an activator, and an ambivalent (one that can yield either effect) site, respectively. Mass spectrometry analyses indicated the target of each of these kinases as y(296) for egfr, y(415) for jak3, and y(511) for src.	SIGNOR-163858	0.418
AKT1	protein	P31749	UNIPROT	CDKN1C	protein	P49918	UNIPROT	down-regulates	phosphorylation	Thr310	GVGSVEQtPRKRLR	9606	BTO:0000150								23421998	t		lperfetto	Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination	SIGNOR-252536	0.459
ACE2	protein	Q9BYF1	UNIPROT	Angiotensin-1	protein	P01019-PRO_0000032457	UNIPROT	up-regulates activity	cleavage	His42	RVYIHPFhLVIHNES	-1									11815627	t		miannu	The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus.	SIGNOR-260221	0.2
RXRA	protein	P19793	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates	binding			9606									10976919	t	inferred from family member	gcesareni	Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr).	SIGNOR-270292	0.714
PRKCA	protein	P17252	UNIPROT	ACO1	protein	P21399	UNIPROT	down-regulates	phosphorylation	Ser711	REFNSYGsRRGNDAV	9606		BTO:0000671							15636585	t		gcesareni	Irp1 ser-711 is a phosphorylation site, critical for regulation of rna-binding and aconitase activities.	SIGNOR-133188	0.2
ATR	protein	Q13535	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates activity	phosphorylation	Ser1387	EDCSGLSsQSDILTT	9606	BTO:0000773								11278964	t		lperfetto	Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion.	SIGNOR-106432	0.792
TCF7L1	protein	Q9HCS4	UNIPROT	NANOG	protein	Q9H9S0	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0001581								16894029	t		Luana	These experiments showed that Tcf3 is associated with chromatin in the Nanog promoter regions and that the DNA-binding activity of Tcf3 was required for repression.	SIGNOR-266081	0.348
RAB1A	protein	P62820	UNIPROT	ULK1	protein	O75385	UNIPROT	up-regulates activity	relocalization			9606									27334615	t		Sara	C9orf72 acts as an effector of Rab1a that recruits active Rab1a to theULK1 complex to promote translocation of the ULK1 complex to thephagophore during autophagy initiation	SIGNOR-261299	0.548
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	HEYL	protein	Q9NQ87	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887;BTO:0001260							11044625	f		gcesareni	The intracellular part of the notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor rbp-j.	SIGNOR-254339	0.2
GUCY1A2	protein	P33402	UNIPROT	GUCY1A2-B2	complex	SIGNOR-C137	SIGNOR	form complex	binding			9606									10977868	t		gcesareni	This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity	SIGNOR-243971	0.2
SRC	protein	P12931	UNIPROT	PKP3	protein	Q9Y446	UNIPROT	up-regulates activity	phosphorylation	Tyr195	PGGLDDRySLVSEQL	9606	BTO:0000552								25501895	t	done	miannu	We have discovered that reactive oxygen species (ROS) trigger the c-Src kinase-mediated tyrosine (Tyr)-195 phosphorylation of PKP3. This modification is associated with a change in the subcellular distribution of the protein. Specifically, PKP3 bearing phospho-Tyr-195 is released from the desmosomes, suggesting that phospho-Tyr-195 is relevant for the control of desmosome disassembly and function, at least in cells exposed to ROS. 	SIGNOR-273807	0.311
BRAF	protein	P15056	UNIPROT	EEF1A2	protein	Q05639	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser21	GHVDSGKsTTTGHLI	-1									22378069	t		miannu	Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf. 	SIGNOR-276406	0.333
LPAR3	protein	Q9UBY5	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257357	0.478
CSNK2A1	protein	P68400	UNIPROT	HNRNPC	protein	P07910	UNIPROT	down-regulates activity	phosphorylation	Ser260	SEGGADDsAEEGDLL	9606									15687492	t		gcesareni	In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C.	SIGNOR-133540	0.364
APC-c	complex	SIGNOR-C150	SIGNOR	CDC6	protein	Q99741	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								10995389	t		miannu	Furthermore, APC, in association with CDH1, ubiquitinates CDC6 in vitro, and both APC and CDH1 are required and limiting for CDC6 proteolysis in vivo.	SIGNOR-271386	0.486
MECP2	protein	P51608	UNIPROT	GPRIN1	protein	Q7Z2K8	UNIPROT	up-regulates quantity by expression	post transcriptional regulation			10090									18511691	t		Luana	MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.	SIGNOR-264679	0.304
SMO	protein	Q99835	UNIPROT	KIF7	protein	Q2M1P5	UNIPROT	up-regulates activity	relocalization			10090									19666503	t		lperfetto	Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factorsIn response to activation of Smo Kif7 at the cilia tip may antagonize Sufu to promote activation of Gli proteins.	SIGNOR-209605	0.618
CSNK2A1	protein	P68400	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates activity	phosphorylation	Ser64	LQTDGNRsSHSRLGR	9606	BTO:0000567								11583622	t		llicata	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250830	0.289
KDM1A	protein	O60341	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606	BTO:0000567								15620353	t		miannu	 Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. 	SIGNOR-264507	0.2
CTNNB1	protein	P35222	UNIPROT	SCRIB	protein	Q14160	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								21255999	t		miannu	Cadherins mediate the localization of vesicles to presynaptic compartments through multiple mechanisms. Cadherin-bound β-catenin then recruits scribble (Scrib) which acts as a scaffold for the further recruitment of proteins that mediate the localization of SVs.	SIGNOR-265826	0.431
IKK-complex	complex	SIGNOR-C14	SIGNOR	IKBKG	protein	Q9Y6K9	UNIPROT	unknown	phosphorylation	Ser43	PAMLHLPsEQGAPET	9606				SIGNOR-C14					17977820	t		lperfetto	In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I	SIGNOR-216403	0.928
CHD8	protein	Q9HCK8	UNIPROT	SOX11	protein	P35716	UNIPROT	down-regulates quantity	transcriptional regulation			10090									32839322	t		Gianni	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268923	0.2
PRKACA	protein	P17612	UNIPROT	MAP2	protein	P11137	UNIPROT	down-regulates activity	phosphorylation	Ser1710	HVTSKCGsLKNIRHR	9606	BTO:0000567								11029056	t		miannu	CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA	SIGNOR-250002	0.366
PRKAA2	protein	P54646	UNIPROT	PAK2	protein	Q13177	UNIPROT	unknown	phosphorylation	Ser20	APPVRMSsTIFSTGG	9606			SIGNOR-C15						22137581	t		llicata	Together, these results indicate that ampk phosphorylates endogenous ppp1r12c at s452 and pak2 at s20 in human cells.	SIGNOR-195110	0.244
CHUK	protein	O15111	UNIPROT	COPS5	protein	Q92905	UNIPROT	down-regulates activity	phosphorylation	Thr205	EGPSEYQtIPLNKIE	-1									31950832	t		lperfetto	Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. 	SIGNOR-275508	0.329
UBR5	protein	O95071	UNIPROT	RNF168	protein	Q8IYW5	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0001938								22884692	t		miannu	Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1. 	SIGNOR-266782	0.454
LPAR2	protein	Q9HBW0	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257169	0.445
ATM	protein	Q13315	UNIPROT	RRM2B	protein	Q7LG56	UNIPROT	up-regulates	phosphorylation	Ser72	TAEEVDLsKDLPHWN	9606									19015526	t		lperfetto	Atm-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53r2 protein against mdm2 to dna damage	SIGNOR-182423	0.527
DDX3X	protein	O00571	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates activity	binding			9606									33627125	t		miannu	DDX3X enhances transcription by interacting with transcription factors to promote their binding to the promoter of the target gene. The best characterized mechanism is its cooperation with the transcription factor SP1. The downstream genes of DDX3X-SP1-mediated transactivation include P21, KRAS, and MDM2	SIGNOR-269202	0.36
PLK1	protein	P53350	UNIPROT	NUDC	protein	Q9Y266	UNIPROT	up-regulates activity	phosphorylation	Ser274	KKINPENsKLSDLDS	9606	BTO:0000567								12852857	t		lperfetto	Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites.	SIGNOR-103403	0.719
MID1IP1	protein	Q9NPA3	UNIPROT	ACACB	protein	O00763	UNIPROT	up-regulates activity	binding			10029									20952656	t		miannu	Recently, we reported the discovery that MIG12, a 183 amino acid protein, binds to ACC1 and ACC2, which induces polymerization and subsequently increases the enzymatic activity of the protein	SIGNOR-267112	0.283
NBEAL2	protein	Q6ZNJ1	UNIPROT	IQGAP1	protein	P46940	UNIPROT	down-regulates				10090	BTO:0000132								29187380	f		lperfetto	We found that the level of Iqgap1, a protein that stabilizes the active forms of Cdc42 and Rac1, was also significantly higher in Nbeal2−/− platelets	SIGNOR-261890	0.2
ARHGAP12	protein	Q8IWW6	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260469	0.526
GSK3B	protein	P49841	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr58	KKFELLPtPPLSPSR	10116									11018017	t			Phosphorylation of Thr 58, likely mediated by GSK-3 but dependent on the prior phosphorylation of Ser 62, is associated with degradation of Myc.	SIGNOR-252080	0.709
SMARCB1	protein	Q12824	UNIPROT	Muscle cell-specific SWI/SNF ARID1B variant	complex	SIGNOR-C482	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270710	0.849
F2	protein	P00734	UNIPROT	GPIb-IX-V complex	complex	SIGNOR-C270	SIGNOR	up-regulates activity	binding			9606	BTO:0000132								25297919	t		lperfetto	Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1.	SIGNOR-261859	0.561
GLI3	protein	P10071	UNIPROT	PTCH1	protein	Q13635	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17419683	f		lperfetto	Binding of n-shh to ptch1 inhibits repression of smo, leading to activationof some genes and de-repression of others through the effects of smo on the gli family of transcription factors.	SIGNOR-154240	0.699
erlotinib hydrochloride	chemical	CHEBI:53509	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191502	0.8
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	PAK2	protein	Q13177	UNIPROT	up-regulates activity	phosphorylation	Thr169	TEAPAVVtEEEDDDE	9606	BTO:0004828								32483448	t		lperfetto	Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway	SIGNOR-273112	0.2
bepotastine	chemical	CHEBI:71204	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002126								18446005	t		Luana	We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells	SIGNOR-257781	0.8
Ac-Asp-Glu(3-)	smallmolecule	CHEBI:76931	ChEBI	N-acetyl-L-aspartate(2-)	smallmolecule	CHEBI:16953	ChEBI	up-regulates quantity	precursor of			9606									10085079	t		miannu	The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated.	SIGNOR-268124	0.8
DRAM2	protein	Q6UX65	UNIPROT	RHOC	protein	P08134	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30755245	f		irozzo	Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors.	SIGNOR-259143	0.2
CYP19A1	protein	P11511	UNIPROT	17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	up-regulates quantity	chemical modification			9606									395188	t		lperfetto	Studies show that aromatization (a reaction sequence unique in steroid biosynthesis) of androgens to estrogens is not limited to the female reproductive organs but also occurs in extragonadal tissue. Aromatization involves the loss of the angular C-19 methyl group and cis elimination of the 1beta and 2beta hydrogens from the androgen precursors, androstenedione and testosterone, to yield estrone and estradiol, respectively. In men, the production of estrone is 18 ug/day and is mainly extraglandular. Aromatase activity has also been shown in a variety of tissues in mammalian and other species.	SIGNOR-251528	0.8
LRP6	protein	O75581	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	relocalization			9606									18632848	t		amattioni	The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism.	SIGNOR-179469	0.829
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates	phosphorylation	Tyr221	IRAKIQDyHILTRKR	9606	BTO:0000007								15143187	t		lperfetto	Autophosphorylation of jak2 on tyrosines 221 and 570 regulates its activity with phosphorylation of tyrosine 221 increasing kinase activity	SIGNOR-236506	0.2
PTPN21	protein	Q16825	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	dephosphorylation	Tyr530	FTSTEPQyQPGENL	9606									15143158	t			Dephosphorylation of Y527 was more pronounced in cells expressing PTPD1 at each time point tested. PTPD1C1108S drastically inhibited Y527 dephosphorylation|Activation of src requires dephosphorylation of src residue Y527. This promotes displacement of the SH2 domain from this residue and subsequent autophosphorylation of residue Y416 within the activation loop	SIGNOR-248725	0.628
PTPN12	protein	Q05209	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606									10734133	t		gcesareni	Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190.	SIGNOR-75898	0.384
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1717	SPSYSPTsPSYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269384	0.718
AP-1/clathrin vescicle	complex	SIGNOR-C251	SIGNOR	RABGEF1	protein	Q9UJ41	UNIPROT	up-regulates activity	relocalization			10090									27411398	t		lperfetto	AP-1/sigma1A-ArfGAP1-Rabex-5 complex formation leads to more endosomal Rabex-5 and enhanced, Rab5GTP-stimulated Vps34 PI3-kinase activity, which is essential for multivesicular body endosome formation.	SIGNOR-260706	0.329
Neuromedin B	smallmolecule	CHEBI:80139	ChEBI	NMBR	protein	P28336	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257547	0.8
IKK-complex	complex	SIGNOR-C14	SIGNOR	NFKBIA	protein	P25963	UNIPROT	down-regulates	phosphorylation			9606									21232017	t		lperfetto	Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation	SIGNOR-216396	0.885
SLC9A3	protein	P48764	UNIPROT	hydron	chemical	CHEBI:15378	ChEBI	down-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265593	0.8
PIK3C3	protein	Q8NEB9	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	relocalization			9606									10698680	t		lperfetto	One of the best characterized targets of pi3k lipid products is the protein kinase akt or protein kinase b (pkb). In quiescent cells, pkb resides in the cytosol in a low-activity conformation. Upon cellular stimulation, pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1).	SIGNOR-75370	0.446
PRKCA	protein	P17252	UNIPROT	GRIN2A	protein	Q12879	UNIPROT	unknown	phosphorylation	Ser1416	ASYCSRDsRGHNDVY	10116									11104776	t		lperfetto	PKC-dependent phosphorylation of NR2A(Ser(1416)) as a key mechanism in inhibiting alphaCaMKII-binding and promoting dissociation of alphaCaMKII.NR2A complex.	SIGNOR-249065	0.52
RPS6KA1	protein	Q15418	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates	phosphorylation	Ser721	TPRLRSVsSYGNIRA	9606				SIGNOR-C3					18722121	t		llicata	Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity	SIGNOR-180462	0.564
MTMR3	protein	Q13615	UNIPROT	MTOR	protein	P42345	UNIPROT	down-regulates activity				9606	BTO:0000007			SIGNOR-C3					26787466	t		lperfetto	The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity.	SIGNOR-245105	0.361
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2D1	protein	P51668	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271345	0.711
RELA	protein	Q04206	UNIPROT	REL/RELA	complex	SIGNOR-C68	SIGNOR	form complex	binding			9606		BTO:0000671							9056676	t		miannu	Tnf-alpha induces the formation of a specific kappab binding complex, mainly composed of nf-kappab subunits rela and c-rel.	SIGNOR-46948	0.66
FGF2	protein	P09038	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15780951	f		gcesareni	Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/ fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts	SIGNOR-134791	0.46
ARHGAP21	protein	Q5T5U3	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260475	0.612
CDK2	protein	P24941	UNIPROT	MCM3	protein	P25205	UNIPROT	up-regulates	phosphorylation	Thr722	EEMPQVHtPKTADSQ	9606			SIGNOR-C16						21965652	t		gcesareni	In this study, we demonstrate that mcm3 is a substrate of cyclin e/cdk2 and can be phosphorylated by cyclin e/cdk2 at thr-722.	SIGNOR-176656	0.787
EPHA4	protein	P54764	UNIPROT	EPHA4	protein	P54764	UNIPROT	up-regulates activity	phosphorylation	Tyr602	TYVDPFTyEDPNQAV	-1									8622893	t			Two dimensional phosphopeptide mapping and site-directed mutagenesis defined juxtamembrane residue Y602 as a major site of in vitro autophosphorylation in Sek, whilst Y596 was phosphorylated to a lower stoichiometry. Complimentary approaches of in vitro binding assays and BIAcore analysis revealed a high affinity association between the Y602 Sek autophosphorylation site and the cytoplasmic tyrosine kinase p59fyn, an interaction mediated through the SH2 domain of this intracellular signalling molecule. 	SIGNOR-251119	0.2
PRKCZ	protein	Q05513	UNIPROT	PARD3	protein	Q8TEW0	UNIPROT	up-regulates	phosphorylation	Ser827	REGFGRQsMSEKRTK	9606									12390250	t		gcesareni	These results imply that serine 827 in the apkc binding site of par-3 is a target of apkc and that the regulated interaction between a protein kinase, apkc, and its substrate, par-3, plays an essential role in the establishment of cell polarity	SIGNOR-94523	0.699
LMAN2	protein	Q12907	UNIPROT	SERPINA1	protein	P01009	UNIPROT	up-regulates quantity by stabilization	binding			9606									20477988	t		miannu	Identification of α1‐antitrypsin as interaction partner of VIP36. The complex formed by VIP36 and alpha1-AT in the Golgi recycled back to the ER. The combined data are most consistent with a function of VIP36 in post-ER quality control of alpha1-AT. We propose that VIP36 acts in post‐ER quality control in the Golgi by binding incompletely folded α1‐AT, which inadvertently escaped ER quality control, and by recycling it back to the ER for an additional round of quality control. 	SIGNOR-261356	0.409
CLK1	protein	P49759	UNIPROT	RBM17	protein	Q96I25	UNIPROT	up-regulates activity	phosphorylation	Ser48	KSQRTKQsTVLAPVI	9534	BTO:0001538								23519612	t		miannu	 In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 	SIGNOR-262711	0.324
MRPS35	protein	P82673	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261442	0.664
GNAI2	protein	P04899	UNIPROT	Adenylate_cyclase	proteinfamily	SIGNOR-PF92	SIGNOR	down-regulates	binding			9606									8327893	t		gcesareni	Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required	SIGNOR-267849	0.618
STK38	protein	Q15208	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates activity	phosphorylation	Ser109	KSHSRQAsTDAGTAG	9606									25601544	t		Luana	We performed mass spectrometry to determine additional sites on YAP1 targeted by NDR, identifying three additional serines, namely S61, S109, and S164, to also be phosphorylated by NDR in vitro 	SIGNOR-259856	0.393
EREG	protein	O14944	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606	BTO:0000150								22891299	t		gcesareni	For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4.	SIGNOR-191788	0.695
CEBPA	protein	P49715	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12032779	f		miannu	 Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. 	SIGNOR-253830	0.503
PAK4	protein	O96013	UNIPROT	RAN	protein	P62826	UNIPROT	unknown	phosphorylation	Ser135	DRKVKAKsIVFHRKK	9606									20805321	t		llicata	We show that ran is a substrate for p21-activated kinase 4 (pak4) and that its phosphorylation on serine-135 increases during mitosis. our study suggests that pak4-mediated phosphorylation of gdp- or gtp-bound ran regulates the assembly of ran-dependent complexes on the mitotic spindle	SIGNOR-167671	0.312
CSNK2A1	protein	P68400	UNIPROT	TFAP2A	protein	P05549	UNIPROT	up-regulates	phosphorylation	Ser429	TDNNAKSsDKEEKHR	9606									21777522	t		lperfetto	Ck2 phosphorylates ap-2_ and increases its transcriptional activity	SIGNOR-175130	0.311
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr287	RDPLLEVyDVPPSVE	10090									12972425	t		lperfetto	Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs	SIGNOR-246405	0.797
HAUS3	protein	Q68CZ6	UNIPROT	HAUS complex	complex	SIGNOR-C281	SIGNOR	form complex	binding			9606	BTO:0000567								19369198	t		lperfetto	Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)	SIGNOR-262322	0.661
PAX7	protein	P23759	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									29681515	f		apalma	Carm1 specifically methylates Pax7 at multiple arginine residues in the N terminus of Pax7, facilitating the recruitment of the ASH2L:MLL1/2:WDR5:RBBP5 histone H3 lysine 4 (H3K4) methyltransferase complex to the proximal promoter of Myf5 resulting in permissive H3K4 tri-methylation (H3K4me3) of the surrounding chromatin	SIGNOR-255899	0.508
ATM	protein	Q13315	UNIPROT	NKX3-1	protein	Q99801	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr166	KNLKLTEtQVKIWFQ	9606	BTO:0002181								23890999	t		miannu	ATM phosphorylates NKX3.1 on T166 and then T134, resulting in NKX3.1 ubiquitination and degradation resulting from an apparent regulatory interaction.	SIGNOR-276500	0.371
IHH	protein	Q14623	UNIPROT	BMP2	protein	P12643	UNIPROT	up-regulates				9606									14973297	f		gcesareni	Ihh is found to be required for bmp-induced os-teogenesis of a limb-bud cell line in culture. Ihh sig-naling is directly required for the osteoblast lineage in developing long bones. Ihh functions in conjunction with other factors such as bmps to induce osteoblast differentiation. In vivo, ihh acts on potential progeni-tor cells to promote osteoblast differentiation and prevent chondrocyte differentiation.	SIGNOR-122200	0.533
NAA35	protein	Q5VZE5	UNIPROT	NatC	complex	SIGNOR-C417	SIGNOR	form complex	binding			9606									19398576	t		miannu	 We here identify and characterize the human NatC (hNatC) complex, containing the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31. This complex associates with ribosomes, and hMak3 acetylates Met-Leu protein N termini in vitro, suggesting a model in which the human NatC complex functions in cotranslational N-terminal acetylation.	SIGNOR-267234	0.752
IKBKB	protein	O14920	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates activity	phosphorylation	Ser923	DELRDSDsVCDSGVE	9606	BTO:0000007			SIGNOR-C13					11158290	t		lperfetto	Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway.	SIGNOR-104803	0.848
ER stress	stimulus	SIGNOR-ST9	SIGNOR	QRICH1	protein	Q2TAL8	UNIPROT	up-regulates				9606									33384352	f		miannu	QRICH1 promotes cell death under ER stress	SIGNOR-269398	0.7
YWHAB	protein	P31946	UNIPROT	NEFL	protein	P07196	UNIPROT	down-regulates activity	binding			9606									23230147	t		miannu	These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments.	SIGNOR-252396	0.257
RABGGTB	protein	P53611	UNIPROT	RAB5A	protein	P20339	UNIPROT	up-regulates activity	lipidation			9606	BTO:0000007								18532927	t		miannu	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional	SIGNOR-265573	0.468
PTK6	protein	Q13882	UNIPROT	KHDRBS1	protein	Q07666	UNIPROT	unknown	phosphorylation	Tyr435	ARPVKGAyREHPYGR	9606									16179349	t		lperfetto	We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal.	SIGNOR-249293	0.738
NFYA	protein	P23511	UNIPROT	SOX18	protein	P35713	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								18496767	f		miannu	 co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells	SIGNOR-254818	0.2
RORB	protein	Q92753	UNIPROT	ARNTL	protein	O00327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24737872	t		miannu	 As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression.	SIGNOR-268003	0.492
PBK	protein	Q96KB5	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Ser380	EPDHYRYsDTTDSDP	9606	BTO:0000567								24012691	t		miannu	PTEN is phosphorylated by TOPK and is required for mitotic entry. In addition, reduced PTEN phosphorylation levels upon TOPK knockdown correlated with decreased Akt activation (Fig. 4e) suggesting that TOPK mediated phosphorylation may lead to PTEN inactivation. By using various PTEN mutants in a kinase assay we concluded that TOPK phosphorylates PTEN at S380 residue in vitro (Fig. 4c). 	SIGNOR-271472	0.519
ABL1	protein	P00519	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates activity	phosphorylation	Tyr433	KIPQDGDyEFLKSWT	10116									21715626	t		Manara	 In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1.	SIGNOR-260927	0.348
2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	up-regulates quantity	precursor of			9606									29767008	t		miannu	Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits.	SIGNOR-266520	0.8
HRH1	protein	P35367	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257376	0.403
AKT1	protein	P31749	UNIPROT	SLC2A1	protein	P11166	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8940145	f		gcesareni	The constitutively active akt also increased the synthesis of the ubiquitously expressed glucose transporter 1. The increased glucose influx in the 3t3-l1 adipocytes directed lipid but not glycogen synthesis	SIGNOR-252579	0.565
FUS	protein	P35637	UNIPROT	CSDE1	protein	O75534	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation			9606	BTO:0000551								32808651	t		lperfetto	These findings demonstrated that LINC00205 facilitates malignant phenotypes in LC by recruiting FUS to stabilize CSDE1, suggesting LINC00205 as a potential target for LC therapy.|Subsequent RIP assay con- firmed such prediction, as CSDE1 mRNA was evidently precipitated by anti-FUS (Figure 3A).	SIGNOR-262110	0.2
CDK2	protein	P24941	UNIPROT	CCP110	protein	O43303	UNIPROT	down-regulates activity	phosphorylation	Ser170	RDSEGFNsPKQCDSS	-1									12361598	t		miannu	GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)	SIGNOR-265958	0.531
PTPRO	protein	Q16827	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation	Ser727	NTIDLPMsPRTLDSL	9606									24708807	t		miannu	In addition, this group found that PTPRO dephosphorylated STAT3 at Y705 and S727 then attenuated STAT3 signalling.	SIGNOR-277061	0.385
PDGFRA	protein	P16234	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity	phosphorylation	Tyr194	ALEKKSNyEVLEKDV	9606	BTO:0000567								20802513	t		miannu	Focal adhesion kinase (FAK) has a crucial role in integration of signals from integrins and growth factor receptors. In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor Met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate FAK on Tyr194 in the FERM domain (band 4.1 and ezrin/radixin/moesin homology domain). Upon binding to Met or phosphoinositides, FAK may undergo conformational changes, which renders Tyr194 accessible for phosphorylation. Substitution of Tyr194 with Phe significantly suppresses the activation of FAK by Met. 	SIGNOR-259400	0.408
RPS6KA3	protein	P51812	UNIPROT	HMGN1	protein	P05114	UNIPROT	down-regulates activity	phosphorylation	Ser25	KRRSARLsAKPPAKV	9606									11438671	t		lperfetto	We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets.	SIGNOR-249101	0.371
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1766	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269350	0.718
PRKCZ	protein	Q05513	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	phosphorylation	Ser311	RTYETFKsIMKKSPF	9606				SIGNOR-C13					17183360	t		gcesareni	Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k)	SIGNOR-151432	0.536
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates				9606									12692549	f		lperfetto	The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response.	SIGNOR-216319	0.7
MYT1L	protein	Q9UL68	UNIPROT	SIN3B	protein	O75182	UNIPROT	up-regulates activity	binding			10090	BTO:0002572								28379941	t		miannu	We found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. 	SIGNOR-266774	0.462
AKT1	protein	P31749	UNIPROT	KDM5A	protein	P29375	UNIPROT	up-regulates activity	phosphorylation	Ser1255	CLTERAMsWQDRARQ	-1									27292631	t		miannu	We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment.	SIGNOR-274059	0.309
BCAR1	protein	P56945	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	binding			9606	BTO:0000182								27447856	t		lperfetto	One such SH2-domain containing protein is the p85 subunit of PI3K, as its docking with tyrosine-phosphorylated p130cas activates the p110alpha subunit| tyrosine-165 and tyrosine-128 on p130cas both are phosphorylated to a greater extent in parental versus paxillin Y88F mutan	SIGNOR-263980	0.543
FYN	protein	P06241	UNIPROT	MED28	protein	Q9H204	UNIPROT	up-regulates	phosphorylation	Tyr64	ASLVSQDyVNGTDQE	9606	BTO:0001271;BTO:0000661								16899217	t		fstefani	To unravel the cellular functions of magicin, we used a yeast two-hybrid system and identified fyn tyrosine kinase as a specific binding partner for magicin. Fyn phosphorylates magicin in vitro.	SIGNOR-148700	0.457
NGF	protein	P01138	UNIPROT	NTRK1	protein	P04629	UNIPROT	up-regulates	binding			9606									11114882	t		gcesareni	Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb.	SIGNOR-85114	0.955
ADAM17	protein	P78536	UNIPROT	TNF	protein	P01375	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0000782								9034190	t		lperfetto	We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. [...]This enzyme (called the tnf-alpha-converting enzyme, or tace) is a new member of the family of mammalian adamalysins (or adams), for which no physiological catalytic function has previously been identified.	SIGNOR-46754	0.693
CDK1	protein	P06493	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Ser266	QYLGSIAsPSVHPAT	9606									16046550	t	The effect has been demonstrated using Q01196-8.	gcesareni	Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction.	SIGNOR-138912	0.347
A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates													15721307	f		lperfetto	We previously showed that α8β1-mediated adhesion of cells to fibronectin resulted in phosphorylation of FAK | FAK can activate PI3 kinase, either directly or indirectly through Src kinase [23]. 	SIGNOR-253309	0.535
SRP19	protein	P09132	UNIPROT	SRP54	protein	P61011	UNIPROT	up-regulates activity	binding			-1									30649418	t		miannu	Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54. 	SIGNOR-261168	0.962
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PTTG1	protein	O95997	UNIPROT	up-regulates	phosphorylation			9606									10906323	t	inferred from 70% family members	gcesareni	Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function.	SIGNOR-270155	0.2
AGRN	protein	O00468	UNIPROT	LRP4	protein	O75096	UNIPROT	up-regulates activity	binding			9606		BTO:0000887							23458718	t		miannu	AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer. 	SIGNOR-273849	0.843
UVRAG	protein	Q9P2Y5	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates activity	binding			9606									21311563	t		lperfetto	Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP(3)R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes	SIGNOR-171902	0.857
HIF1AN	protein	Q9NWT6	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	hydroxylation	Asn1955	LEASADAnIQDNMGR	9606									18299578	t		gcesareni	We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation.	SIGNOR-161057	0.565
SREBF1	protein	P36956	UNIPROT	FASN	protein	P49327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20373869	t		lperfetto	Ultimately, both the AKT and MAPK transduction pathways regulate FASN expression through the modulation of expression of sterol regulatory element-binding protein (SREBP)-1c, which binds to regulatory elements in the FASN promoter. Proto-oncogene FBI-1 (Pokemon), a transcription factor of the bric--brac tramtrack broad complex/pox viruses and zinc fingers (BTB/POZ) domain family, interacts directly with SREBP-1c through its DNA-binding domain to synergistically activate the transcription of FASN	SIGNOR-242884	0.511
MAP2K7	protein	O14733	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates	phosphorylation	Thr183	AGTSFMMtPYVVTRY	9606									11062067	t		amattioni	Jnk full activation requires the phosphorylation of a threonine and a tyrosine residue in a thr-pro-tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (mkk)4 and mkk7. Mkk7 shows a striking preference for the threonine residue (thr-183).	SIGNOR-83736	0.686
CDK2	protein	P24941	UNIPROT	CCNE1	protein	P24864	UNIPROT	down-regulates	phosphorylation	Ser399	GLLTPPQsGKKQSSG	9606									14536078	t		amattioni	Phosphorylation-triggered ubiquitination has been proposed to be the major pathway regulating cyclin e protein abundance. Cdk2 activity is required for cyclin e turnover in vivo because it phosphorylates s384. Mutation of ser384 to alanine also rendered cyclin e resistant to degradation	SIGNOR-118555	0.954
PRKCA	protein	P17252	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	phosphorylation	Ser139	EEWTRHGsFVNKPTR	10090									12052829	t		lperfetto	Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms.	SIGNOR-249150	0.41
AKT1	protein	P31749	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	phosphorylation	Ser196	KLRRRFSsLHFMVEV	9606									15004527	t		gcesareni	Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity	SIGNOR-252472	0.768
MAPK1	protein	P28482	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser345	QARPGPQsPGSPLEE	9606	BTO:0000130								16778989	t		gcesareni	Erk1/2 are the kinases involved in p47phox_ phosphorylation on ser345 in gm-csfprimed human neutrophils._ Phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells	SIGNOR-147170	0.463
MAPK1	protein	P28482	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	unknown	phosphorylation	Ser863	LTQSAPAsPTNKGVH	9606				SIGNOR-C3					21071439	t		llicata	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-169522	0.533
LYN	protein	P07948	UNIPROT	BCR-Dl	complex	SIGNOR-C436	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000776								32323266	t		scontino	The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases.	SIGNOR-268215	0.697
MAPK1	protein	P28482	UNIPROT	PITPNM1	protein	O00562	UNIPROT	up-regulates	phosphorylation	Thr794	LEMLVPStPTSTSGA	9606									15125835	t		lperfetto	Both cdk1 and erk2 induced phosphorylation of the wild-type nir2. Substitution of t794 by alanine reduced the phosphorylation by erk2, whereas the double mutations t794/1223a completely abolished it. The requirement of multiple nir2 phosphorylation sites for plk1 binding may provide a mechanism that sets a threshold for the nir2-plk1 interaction during mitosis.	SIGNOR-124650	0.2
EGFR	protein	P00533	UNIPROT	CCDC50	protein	Q8IVM0	UNIPROT	down-regulates activity	phosphorylation	Tyr304	SSHKGFHyKH	9606	BTO:0000567								19059208	t		miannu	We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling.	SIGNOR-262852	0.425
Scribble_complex_DLG5-LLGL2_variant	complex	SIGNOR-C506	SIGNOR	Cell_polarity	phenotype	SIGNOR-PH213	SIGNOR	up-regulates				9606									23397623	f		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270894	0.7
BTK	protein	Q06187	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates activity	phosphorylation	Tyr1197	LESEEELySSCRQLR	9606	BTO:0000776								11507089	t		lperfetto	These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2.	SIGNOR-109746	0.77
RORA	protein	P35398	UNIPROT	NR1D1	protein	P20393	UNIPROT	down-regulates activity	binding			9606	BTO:0000599								20817722	t		miannu	Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.	SIGNOR-267979	0.438
PLK1	protein	P53350	UNIPROT	STAG2	protein	Q8N3U4	UNIPROT	down-regulates activity	dephosphorylation	Thr1109	MWLSREQtLHTPVMM	9606	BTO:0000567								15737063	t		lperfetto	Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase	SIGNOR-275533	0.727
PPP3CB	protein	P16298	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates activity	dephosphorylation	Ser75	EIRSRHSsYPAGTED	9606	BTO:0000007								10195903	t			Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 	SIGNOR-248383	0.34
succinyl-CoA(5-)	smallmolecule	CHEBI:57292	ChEBI	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	precursor of												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271805	0.8
PPP2R2A	protein	P63151	UNIPROT	WEE1	protein	P30291	UNIPROT	up-regulates quantity by stabilization	dephosphorylation			9606	BTO:0000018								33108758	t		miannu	Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression.	SIGNOR-266381	0.393
CDK2	protein	P24941	UNIPROT	USP37	protein	Q86T82	UNIPROT	up-regulates activity	phosphorylation	Ser628	MVNSCITsPSTPSKK	9606			SIGNOR-C83						21596315	t		lperfetto	There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity	SIGNOR-265045	0.459
SMURF2	protein	Q9HAU4	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001593	BTO:0000140							22298955	t		lperfetto	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-120647	0.713
EXOC4	protein	Q96A65	UNIPROT	Exocyst_EXOC6B variant	complex	SIGNOR-C491	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270779	0.923
PDK2	protein	Q15119	UNIPROT	PDHA2	protein	P29803	UNIPROT	down-regulates	phosphorylation	Ser291	TYRYHGHsMSDPGVS	9606									16436377	t		gcesareni	Kinetic and regulatory properties of recombinant human pdh2 and pdh1 were compared in this study. Site-specific phosphorylation/dephosphorylation of the three phosphorylation sites by four pdh kinases (pdk1-4) and two pdh phosphatases (pdp1-2) were investigated by substituting serines with alanine or glutamate in pdhs.	SIGNOR-143970	0.529
tibolone	chemical	CHEBI:32223	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			9606									19464167	t		Luana	In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1).	SIGNOR-257821	0.8
MAPK3	protein	P27361	UNIPROT	MRTFA	protein	Q969V6	UNIPROT	down-regulates	phosphorylation	Ser454	TGSTPPVsPTPSERS	9606	BTO:0000150;BTO:0000551								22139079	t	Translocation from Nuleus to Cytoplasm	gcesareni	Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization.	SIGNOR-195157	0.2
CAMK2B	protein	Q13554	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000567								15980064	t		lperfetto	These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo.	SIGNOR-217493	0.2
MELK	protein	Q14680	UNIPROT	MELK	protein	Q14680	UNIPROT	up-regulates	phosphorylation	Ser529	KGAKVFGsLERGLDK	9606									16216881	t		lperfetto	We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase.	SIGNOR-141018	0.2
ITGAV	protein	P06756	UNIPROT	Av/b1 integrin	complex	SIGNOR-C175	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253201	0.829
MYOG	protein	P15173	UNIPROT	MYOG	protein	P15173	UNIPROT	up-regulates	transcriptional regulation			9606				SIGNOR-C92					17194702	t		miannu	Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle	SIGNOR-151694	0.2
alvocidib hydrochloride	chemical	CHEBI:90998	ChEBI	CDK1	protein	P06493	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192458	0.8
GNA13	protein	Q14344	UNIPROT	ARHGEF1	protein	Q92888	UNIPROT	up-regulates	binding			9606									9641916	t		gcesareni	Galpha13 bound tightly top115 rhogefand stimulated its capacity to catalyze nucleotide exchange onrho.	SIGNOR-58417	0.591
PTPN9	protein	P43378	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606									22394684	t		lperfetto	Results are presented as mean \u00b1 SD from three independent experiments. (B) PTPMeg2 inhibits STAT3-mediated transcriptional activity in a dose dependent manner.|These results indicate that PTPMeg2 inhibits STAT3 activation with certain specificity.|In this study, we demonstrated that PTPMeg2 dephosphorylates STAT3 at the Tyr705 residue by a direct interaction.	SIGNOR-276976	0.445
MAPK1	protein	P28482	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Ser312	TESITATsPASMVGG	9606	BTO:0004980								17242212	t		gcesareni	Our data suggest that il-6 impairs the vasodilator effects of insulin that are mediated by the irs-1/pi3-kinase/akt/enos pathway through activation of jnk and erk1/2.	SIGNOR-152418	0.667
TUBA3E	protein	Q6PEY2	UNIPROT	Neuron_migration	phenotype	SIGNOR-PH67	SIGNOR	up-regulates				9606	BTO:0000007								19185337	f		miannu	We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching.	SIGNOR-269726	0.7
CALM3	protein	P0DP25	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	down-regulates activity	binding			9606									11807557	t		miannu	Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias.	SIGNOR-266346	0.46
N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide	chemical	CHEBI:94525	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257933	0.8
NLRX1	protein	Q86UT6	UNIPROT	MAVS	protein	Q7Z434	UNIPROT	down-regulates activity	binding			9606	BTO:0000567; BTO:0002181								18200010	t		Giorgia	Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Co-immunoprecipitation studies demonstrate that HA–NLRX1 interacts with MAVS but not with other known mitochondrial outer membrane proteins (BCL2 and BCL2L1), indicating specificity of the NLRX1–MAVS interaction. Finally, endogenous NLRX1 associates strongly with endogenous MAVS after immunoprecipitation with two different MAVS antibodies	SIGNOR-260357	0.745
WNT5A	protein	P41221	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates activity	binding			9606		BTO:0000393							21903638	t		gcesareni	It has been shown that wnt5a activates the calcium signaling pathway in the presence of receptor fz2, 3, 4, 6 and receptor fz 5.	SIGNOR-176579	0.697
PAK1	protein	Q13153	UNIPROT	NET1	protein	Q7Z628	UNIPROT	down-regulates activity	phosphorylation	Ser152	PTPAKRRsSALWSEM	-1									15684429	t		miannu	In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner. 	SIGNOR-263019	0.252
NTRK1	protein	P04629	UNIPROT	NTRK1	protein	P04629	UNIPROT	up-regulates	phosphorylation	Tyr676	FGMSRDIySTDYYRV	9606									9099755	t		gcesareni	In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785	SIGNOR-47171	0.2
CHEK1	protein	O14757	UNIPROT	FANCE	protein	Q9HB96	UNIPROT	up-regulates	phosphorylation	Thr346	LGLLRLCtWLLALSP	9606									17296736	t		llicata	Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway.	SIGNOR-153027	0.705
PRKCA	protein	P17252	UNIPROT	ADAP1	protein	O75689	UNIPROT	unknown	phosphorylation	Thr276	GFRKRWFtMDDRRLM	-1									12893243	t		lperfetto	The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).	SIGNOR-249225	0.322
Neural progenitor-specific SWI/SNF	complex	SIGNOR-C477	SIGNOR	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	up-regulates				9606									25195934	f		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270621	0.7
α-Catenin	proteinfamily	SIGNOR-PF72	SIGNOR	YAP1	protein	P46937	UNIPROT	down-regulates activity	binding			9606									23431053	t		miannu	The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation.	SIGNOR-265820	0.2
MAPK11	protein	Q15759	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	unknown	phosphorylation	Ser771	SASSTLGsPENEEHI	9606				SIGNOR-C3					21757713	t		llicata	Arsenite treatment of cells activates p38_ and induces interaction between p38_ and raptor, a regulatory component of mtorc1, resulting in phosphorylation of raptor on ser(863) and ser(771). The phosphorylation of raptor on these sites enhances mtorc1 activity, and contributes largely to arsenite-induced mtorc1 activation.	SIGNOR-174870	0.361
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser255	ELSPTTLsPVNHSLD	9606		BTO:0000763							12193595	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-91738	0.739
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	ERF	protein	P50548	UNIPROT	down-regulates	phosphorylation			9606									7588608	t		lperfetto	Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf	SIGNOR-216852	0.375
AIFM2	protein	Q9BRQ8	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0003000								12135761	f		miannu	The PRG3 gene is a potential p53 target gene in a p53‐dependent apoptosis pathway. These results clearly indicate that the ectopic expression of PRG3 induces apoptosis.	SIGNOR-261809	0.7
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Thr331	CTPVVTCtPSCTAYT								phosphorylation:Ser374;Ser362	PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS	16055710	t		lperfetto	Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos	SIGNOR-263009	0.2
CAMK1	protein	Q14012	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	phosphorylation	Ser637	VPVARKLsAREQRDC										31063459	t		lperfetto	For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission	SIGNOR-262552	0.34
TOR1A	protein	O14656	UNIPROT	SNAPIN	protein	O95295	UNIPROT	up-regulates activity	binding			9606	BTO:0000793								18167355	t		Monia	In the present study, we used yeast two-hybrid analysis to identify a new binding partner of torsinA, the SNARE-associated protein snapin. We have reported that snapin shows a robust interaction with wild type and mutant torsinA. we have demonstrated that this portion of torsinA and/or the adjacent linker region has the additional role of recruiting snapin. we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA.	SIGNOR-261170	0.434
AMPK	complex	SIGNOR-C15	SIGNOR	NR2C2	protein	P49116	UNIPROT	down-regulates	phosphorylation	Ser351	HVISRDQsTPIIEVE	9606									21478464	t		lperfetto	Tr4 transactivation is inhibited via phosphorylation bymetformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression	SIGNOR-216537	0.2
Prefoldin co-chaperone	complex	SIGNOR-C513	SIGNOR	Chaperone-mediated protein folding	phenotype	SIGNOR-PH120	SIGNOR	up-regulates				9606									32699605	t		miannu	The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6)	SIGNOR-270936	0.7
RAB6C	protein	Q9H0N0	UNIPROT	Synaptic_vesicle_exocytosis	phenotype	SIGNOR-PH160	SIGNOR	up-regulates				9534									20360680	f		miannu	We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles.	SIGNOR-266882	0.7
PPP1CA	protein	P62136	UNIPROT	PREX1	protein	Q8TCU6	UNIPROT	up-regulates activity	dephosphorylation	Ser834	LSLGPRLsLCEDSPM	9606									22242915	t		lperfetto	MS analysis of wild-type P-Rex1 and a PP1\u03b1-binding-deficient mutant revealed that endogenous PP1\u03b1 dephosphorylates P-Rex1 on at least three residues, Ser834, Ser1001 and Ser1165.|The phosphatase activity of PP1\u03b1 is required for P-Rex1 activation.	SIGNOR-277022	0.2
monobenzyl phthalate	chemical	CHEBI:132612	ChEBI	SLC5A5	protein	Q92911	UNIPROT	up-regulates quantity by expression				10116									16257484	f		miannu	DIDP, BBP and DOP stimulate NIS mRNA expression. Here, hNIS promoter construct (N3) was up-regulated 2.5-fold by DIDP, 2.6-fold by BBP and 2.4-fold by DOP in the presence of TSH. Likewise, these phthalates also enhanced rNIS endogenous mRNA expression, which increased ca. 2-fold after 48 h of treatment compared with the expression level generated by TSH only. At 72 h, mRNA content was unchanged.	SIGNOR-268743	0.8
PPM1A	protein	P35813	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	dephosphorylation	Ser177	AKELDQGsLCTSFVG	9606									18930133	t			PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation.	SIGNOR-248486	0.313
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	DLX5	protein	P56178	UNIPROT	up-regulates	phosphorylation			9606									21619873	t		gcesareni	Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5.	SIGNOR-173976	0.2
NEK7	protein	Q8TDX7	UNIPROT	KIF14	protein	Q15058	UNIPROT	up-regulates activity	phosphorylation	Ser607	NLIDLAGsERCSTAH	9606	BTO:0000565								28630147	t		miannu	Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). 	SIGNOR-266417	0.38
EIF2B3	protein	Q9NR50	UNIPROT	EIF2S1	protein	P05198	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269126	0.827
SMAD9	protein	O15198	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	phosphorylation			9606									20957627	t		gcesareni	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.	SIGNOR-168740	0.67
LEF1	protein	Q9UJU2	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9606									17081971	f		amattioni	The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells.	SIGNOR-229767	0.7
MAPK8	protein	P45983	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates	phosphorylation	Ser226	IDENCLLsPLAGEDD	9606									12351702	t		gcesareni	Taken together, these findings suggest that jnk-mediated phosphorylation of the gr-ser226 enhances gr nuclear export and may contribute to termination of gr-mediated transcription.	SIGNOR-93558	0.623
CSNK2A1	protein	P68400	UNIPROT	EEF1D	protein	P29692	UNIPROT	unknown	phosphorylation	Ser162	DDIDLFGsDNEEEDK	9606	BTO:0000567								21936567	t		lperfetto	Direct phosphorylation of eef1d by ck2 was shown by performing ck2 assays with eef1d -flag from hela cells. Dramatic increases in eef1d phosphorylation following _-phosphatase treatment and phospho- eef1d antibody recognizing eef1d ps162 indicated phosphorylation at the ck2 site in cells.	SIGNOR-176632	0.333
PTPRJ	protein	Q12913	UNIPROT	RET	protein	P07949	UNIPROT	down-regulates activity	dephosphorylation	Tyr905	DVYEEDSyVKRSQGR	9606									16778204	t			The receptor-type protein tyrosine phosphatase J antagonizes the biochemical and biological effects of RET-derived oncoproteins.|PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels	SIGNOR-248701	0.281
NFE2L3	protein	Q9Y4A8	UNIPROT	PLA2G7	protein	Q13093	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22247257	t		lperfetto	Moreover, we demonstrated that nuclear factor erythroid 2-related factor 3 (Nrf3) regulates Pla2g7 gene expression through direct binding to the promoter regions of Pla2g7 gene.	SIGNOR-268979	0.372
BMP1	protein	P13497	UNIPROT	COL7A1	protein	Q02388	UNIPROT	up-regulates quantity	cleavage	Ala2821	RPLPSYAaDTAGSQL	9606	BTO:0000667								11986329	t		miannu	 We show that bone morphogenetic protein-1 (BMP-1), which exhibits procollagen C-proteinase activity, cleaves the C-terminal propeptide from human procollagen VII. The cleavage occurs at the BMP-1 consensus cleavage site SYAA/DTAG within the NC-2 domain. Proteinases of the bone morphogenetic protein-1 family convert procollagen VII to mature anchoring fibril collagen.	SIGNOR-256338	0.587
MAP2K1	protein	Q02750	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates activity	phosphorylation			9606									12270934	t		lperfetto	Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis.	SIGNOR-235940	0.739
magnesium(2+)	chemical	CHEBI:18420	ChEBI	Exosome_Complex	complex	SIGNOR-C255	SIGNOR	form complex	binding			-1									24189234	t		miannu	The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 	SIGNOR-267755	0.8
BAG3	protein	O95817	UNIPROT	HSPA8	protein	P11142	UNIPROT	up-regulates activity	binding			-1									27474740	t		lperfetto	Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70.	SIGNOR-254116	0.78
PRKACA	protein	P17612	UNIPROT	SUFU	protein	Q9UMX1	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser342	LAHDRAPsRKDSLES	9606									21317289	t		gcesareni	We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation. 	SIGNOR-171999	0.443
MAP1LC3B	protein	Q9GZQ8	UNIPROT	ATG3	protein	Q9NT62	UNIPROT	up-regulates	binding			9606									22170151	t		gcesareni	Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe.	SIGNOR-191549	0.828
MAK	protein	P20794	UNIPROT	MAK	protein	P20794	UNIPROT	up-regulates activity	phosphorylation	Tyr159	SQPPYTDyVSTRWYR	9606									21986944	t		Manara	We conclude that dual phosphorylation on the TDY motif is crucial for MAK activity, and that the autokinase activity is required for this phosphorylation	SIGNOR-260780	0.2
NACC1	protein	Q96RE7	UNIPROT	ZBTB14	protein	O43829	UNIPROT	up-regulates activity	binding			-1									19121354	t		miannu	NAC1 potentiated ZF5 mediated repression in Gal4-DBD fusion transient assays. GST pulldown assays further confirmed protein–protein interactions between these proteins and NAC1.	SIGNOR-226443	0.292
ATM	protein	Q13315	UNIPROT	ZNF148	protein	Q9UQR1	UNIPROT	up-regulates	phosphorylation	Ser202	GEKPFQCsQCDMRFI	9606									17560543	t		lperfetto	Here we found that zbp-89 is phosphorylated by atm kinase in vitro and in vivo. Disruption of the atm phosphorylation motif (202)sq within the zinc finger domain of zbp-89 attenuated its ability to enhance p21(waf1) activation by butyrate. Moreover, disruption of the atm phosphorylation site abrogated the ability of zbp-89 to potentiate butyrate induction of endogenous p21(waf1) expression.	SIGNOR-155634	0.369
PRKCA	protein	P17252	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates activity	phosphorylation	Ser39	TTSTRTYsLGSALRP										2500966	t		lperfetto	We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65.	SIGNOR-248885	0.289
ZBED1	protein	O96006	UNIPROT	GATA4	protein	P43694	UNIPROT	down-regulates quantity by repression	transcriptional regulation			7227	BTO:0001138								22021382	f	1	miannu	XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression.	SIGNOR-239736	0.2
CHEK1	protein	O14757	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser37	NVLSPLPsQAMDDLM	9606	BTO:0001321								15659650	t		lperfetto	CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37	SIGNOR-217799	0.772
FHL5	protein	Q5TD97	UNIPROT	CREM	protein	Q03060	UNIPROT	up-regulates activity	binding			9606									10086359	t		miannu	ACT (for activator of CREM in testis), a LIM-only protein which specifically associates with CREM. ACT is expressed coordinately with CREM in a tissue- and developmentally regulated manner. It strongly stimulates CREM transcriptional activity in yeast and mammalian cells and contains an intrinsic activation function.	SIGNOR-222111	0.651
MAP2K5	protein	Q13163	UNIPROT	MAPK7	protein	Q13164	UNIPROT	up-regulates	phosphorylation			9606									11782488	t		gcesareni	Kato et al. reported that mek5 specifically activates bmk1 but not other mammalian map kinasesin vivo.	SIGNOR-113770	0.69
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	NOXO1	protein	Q8NFA2	UNIPROT	up-regulates activity	phosphorylation	Ser159	SRAAGRLsIHSLEAQ	9606									28336130	t		lperfetto	Importantly, the constitutive activity of NoxO1 can be modulated. NoxO1 phosphorylation by PKC at Ser154 doubles its binding ability to NoxA1, which in turn acts as a molecular switch, allowing optimal interaction of NoxO1 with p22phox	SIGNOR-264728	0.2
KNG1	protein	P01042	UNIPROT	GPIb-IX-V complex	complex	SIGNOR-C270	SIGNOR	up-regulates activity	binding			9606	BTO:0000132								25297919	t		lperfetto	Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1.	SIGNOR-261858	0.428
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1665	SPTSPSYsPTSPSYS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248750	0.727
APIP	protein	Q96GX9	UNIPROT	APAF1	protein	O14727	UNIPROT	down-regulates	binding			9606									15262985	t		acerquone	Taken together, these results suggest that apip functions to inhibit muscle ischemic damage by binding to apaf-1 in the apaf-1/caspase-9 apoptosis pathway.	SIGNOR-126797	0.542
WNT1	protein	P04628	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates activity				10090		BTO:0000887;BTO:0001103							22944199	f		gcesareni	In explant cultures of mouse paraxial mesoderm, Wnt1 induced expression of the MRF Myf5, whereas Wnt7a or Wnt6 preferentially activated the MRF MyoD	SIGNOR-198849	0.344
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Ser477	PQFSYSAsGTA	9606	BTO:0000093								24670654	t		gcesareni	Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation	SIGNOR-252440	0.427
α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	up-regulates				9606									23680095	t		miannu	Glycolysis is a cytoplasmic non-oxidative reaction for glucose degradation that is composed of 9 pro cesses. A non-specific HK enzyme by using ATP phosphorylates glucose following entrance to the cell and converts it to G6P.	SIGNOR-267959	0.7
GSK3B	protein	P49841	UNIPROT	FOXM1	protein	Q08050	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser474	S-->A	9606	BTO:0002181								26912724	t		miannu	GSK3 phosphorylates FoxM1 on serine 474 which induces FoxM1 ubiquitination mediated by FBXW7.	SIGNOR-277208	0.362
MAPK1	protein	P28482	UNIPROT	PARVA	protein	Q9NVD7	UNIPROT	up-regulates activity	phosphorylation	Ser4	sPQKSPSV	9606									22955285	t		lperfetto	Actopaxin (alpha-parvin) is a paxillin, integrin-linked kinase, and F-actin binding focal adhesion protein with several serine phosphorylation sites in the amino terminus that contribute to the regulation of cell spreading and migration.|Actopaxin phosphorylation of Ser4/8 enhances cell migration whereas a nonphosphorylatable (Quint) mutant suppresses migration in U2OS osteosarcoma cells (7).	SIGNOR-265760	0.262
ESR1	protein	P03372	UNIPROT	TFF1	protein	P04155	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000356								11517191	f	 	 	ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression	SIGNOR-253938	0.745
BRCA1	protein	P38398	UNIPROT	BRCA1-BARD1 complex	complex	SIGNOR-C297	SIGNOR	form complex	binding												25400280	t		lperfetto	 Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks.	SIGNOR-263224	0.785
F2RL1	protein	P55085	UNIPROT	KLF6	protein	Q99612	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254841	0.2
ZIC3	protein	O60481	UNIPROT	GLI3	protein	P10071	UNIPROT	up-regulates	binding			9606									17764085	t		lperfetto	Zic3 functions as a transcriptional coactivator of gli3 when it physically associates with gli3	SIGNOR-157637	0.382
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr234	SFKKQEKtPKTPKGP	9606									14670079	t		lperfetto	We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication.	SIGNOR-216690	0.415
ITGA5	protein	P08648	UNIPROT	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253177	0.913
PAK	proteinfamily	SIGNOR-PF13	SIGNOR	MAP2K1	protein	Q02750	UNIPROT	up-regulates	phosphorylation	Ser298	RTPGRPLsSYGMDSR	9606	BTO:0000567								16129686	t		gcesareni	Inhibition of pak kinase activity dramatically decreased phosphorylation of mek1 at ser(298) in response to either pdgf or egf.	SIGNOR-140039	0.2
SRC	protein	P12931	UNIPROT	GRIN2A	protein	Q12879	UNIPROT	up-regulates activity	phosphorylation	Tyr1387	GRCPSDPyKHSLPSQ	-1									10195142	t		lperfetto	To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain.	SIGNOR-247171	0.586
pregnenolone	smallmolecule	CHEBI:16581	ChEBI	progesterone	smallmolecule	CHEBI:17026	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000048							2243100	t		lperfetto	Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens.	SIGNOR-268630	0.8
2-cyclohexyl-6-methoxy-N-(1-propan-2-yl-4-piperidinyl)-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine	chemical	CHEBI:95074	ChEBI	EHMT1	protein	Q9H9B1	UNIPROT	down-regulates activity	chemical inhibition			-1									26320100	t		miannu	 Using a small-molecule screen, we found that UNC0638, a selective inhibitor of EHMT1 and EHMT2 histone methyltransferases, induces γ-globin expression. 	SIGNOR-262239	0.8
FLT3	protein	P36888	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	phosphorylation	Tyr350	EPPDHQYyNDFPGKE	9606									10482988	t		miannu	Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. 	SIGNOR-251147	0.434
selumetinib	chemical	CHEBI:90227	ChEBI	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates activity	chemical inhibition			9606	BTO:0001950								25487801	t		Luana	Inhibitors of MEK1/2 (trametinib) and/or ERK1/2 (selumetinib) had the strongest and most conserved inhibitory activities, suggesting that MEK1/2 and ERK1/2 may have unique capabilities as stand-alone or combinatorial therapies for MERS-CoV infections. 	SIGNOR-262313	0.8
CHEK1	protein	O14757	UNIPROT	BLM	protein	P54132	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr182	SHFVRVStAQKSKKG	9606	BTO:0002181								26028025	t		miannu	We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges. 	SIGNOR-276909	0.772
PDK2	protein	Q15119	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA										19951971	t		lperfetto	PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. The phosphorylation of AKT on Ser473 by PDK2 acts as a €œgain control€ for AKT and regulates its degree of activation. The sirolimus-insensitive mTORC2 complex exhibits PDK2 activity	SIGNOR-249630	0.74
NR5A2	protein	O00482	UNIPROT	CYP19A1	protein	P11511	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001555								19022561	f		miannu	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 	SIGNOR-254872	0.419
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser276	PQRSRSPsPQPSSHV	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248376	0.598
PTPRF	protein	P10586	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606									1303753	t		gcesareni	Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product.	SIGNOR-16239	0.563
CAMK2A	protein	Q9UQM7	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	phosphorylation	Ser1303	NKLRRQHsYDTFVDL		BTO:0003036								8940188	t		llicata	By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons.	SIGNOR-250630	0.687
FOXO3	protein	O43524	UNIPROT	BCL2L11	protein	O43521	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12913110	f		lperfetto	In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal.	SIGNOR-209657	0.763
AURKB	protein	Q96GD4	UNIPROT	HDAC4	protein	P56524	UNIPROT	down-regulates	phosphorylation	Ser265	QKVAERRsSPLLRRK	9606									22865920	t		lperfetto	We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions	SIGNOR-198646	0.268
INPPL1	protein	O15357	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates				9606	BTO:0000776								10942391	f		gcesareni	Taken together, the data presented here demonstrate that ship inhibits akt primarily through regulation of akt membrane localization.	SIGNOR-80706	0.635
ADAM10	protein	O14672	UNIPROT	EGF	protein	P01133	UNIPROT	up-regulates activity	cleavage			9606									26284334	t		miannu	Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin	SIGNOR-259840	0.549
BLOC1S5	protein	Q8TDH9	UNIPROT	BLOC-1	complex	SIGNOR-C381	SIGNOR	form complex	binding			9606									22203680	t		lperfetto	We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter.	SIGNOR-265938	0.68
ADCY5	protein	O95622	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates quantity	chemical modification			9606									15385642	t		miannu	Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions.	SIGNOR-264999	0.8
TFEB	protein	P19484	UNIPROT	GNS	protein	P15586	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19556463	f	Figure 1	lperfetto	Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 	SIGNOR-276540	0.318
PRKACA	protein	P17612	UNIPROT	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	up-regulates	phosphorylation			9606									12536214	t	inferred from family member	gcesareni	We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus.	SIGNOR-270232	0.487
nilotinib	chemical	CHEBI:52172	ChEBI	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	down-regulates activity	chemical inhibition			9606									19108785	t		irozzo	Nilotinib is an oral second-generation bcr-abl TKI indicated for the treatment of imatinib resistant or -intolerant Ph+ CML-CP and -AP in adults. Nilotinib binds to inactive configuration of the abl kinase, thus preventing the tyrosine phosphorylation of proteins involved in bcr-abl signal transduction. Nilotinib binds to the inactive (unphosphorylated) configuration of the abl TK, with the P-Ioop folding over, disrupting the ATP binding site and catalytic activity of the enzyme.	SIGNOR-255818	0.8
PLK1	protein	P53350	UNIPROT	SNCB	protein	Q16143	UNIPROT	down-regulates activity	phosphorylation	Ser118	LMEPEGEsYEDPPQE	9606									19889641	t		lperfetto	Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation.	SIGNOR-176079	0.323
PRKCE	protein	Q02156	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Ser840	VRSAFTTsTVVRMHV	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249281	0.405
PPP2CB	protein	P62714	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	up-regulates activity	dephosphorylation	Ser155	FPLRKTVsEPNLKLR	9606									18339811	t			Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.	SIGNOR-248603	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GRK7	protein	Q8WTQ7	UNIPROT	up-regulates activity	phosphorylation	Ser36	ELQRRRRsLALPGLQ	8355		BTO:0001175							18803695	t		miannu	 Recently, we have defined sites of phosphorylation by cAMP-dependent protein kinase (PKA) in the amino termini of both GRK1 and GRK7 in vitro. To determine the conditions under which GRK7 is phosphorylated in vivo, we have generated an antibody that recognizes GRK7 phosphorylated on Ser36, the PKA phosphorylation site. Using this phospho-specific antibody, we have shown that GRK7 is phosphorylated in vivo and is located in the cone inner and outer segments of mammalian, amphibian and fish retinas. The conservation of phosphorylation at Ser36 in GRK7 in these different species (which span a 400 million-year evolutionary period), and its light-dependent regulation, indicates that phosphorylation plays an important role in the function of GRK7	SIGNOR-263152	0.2
DNMT3B	protein	Q9UBC3	UNIPROT	BAG1	protein	Q99933	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001109								18413740	f	 	lperfetto	DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation 	SIGNOR-254109	0.332
PRKACA	protein	P17612	UNIPROT	KCNJ3	protein	P48549	UNIPROT	unknown	phosphorylation	Ser385	NSKERHNsVECLDGL	9606									19151997	t		llicata	Using this approach, we identified s385 as an in vitro phosphorylation site. Mutation of this residue to alanine resulted in a reduced sensitivity of kir3.1* currents to h89 and forskolin, confirming an in vivo role for this novel site of the kir3.1 channel subunit in its regulation by pka.	SIGNOR-183475	0.326
MAPK14	protein	Q16539	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser301	S-->T	-1									30301786	t		miannu	P38α phosphorylates and destabilizes p63.	SIGNOR-277414	0.313
TAB2	protein	Q9NYJ8	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	binding			9606									14633987	t		lperfetto	These results suggest that TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction.	SIGNOR-119370	0.934
SMURF	proteinfamily	SIGNOR-PF29	SIGNOR	SMAD1	protein	Q15797	UNIPROT	down-regulates	ubiquitination			9606									22298955	t	inferred from 70% family members	gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-270214	0.2
BFAR	protein	Q9NZS9	UNIPROT	CASP8	protein	Q14790	UNIPROT	down-regulates	binding			9606	BTO:0000093								11733517	t		gcesareni	We also demonstrate that the mitochondrial protein bar, which has been shown to simultaneously bind caspase-8 and bcl-2	SIGNOR-112585	0.378
ATG7	protein	O95352	UNIPROT	MAP1LC3C	protein	Q9BXW4	UNIPROT	up-regulates activity	binding			10090									22170151	t		lperfetto	Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe	SIGNOR-191540	0.781
CDC26	protein	Q8NHZ8	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	form complex	binding												16896351	t		lperfetto	The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex.	SIGNOR-252011	0.845
ATR	protein	Q13535	UNIPROT	CDS1	protein	Q92903	UNIPROT	up-regulates				9606									15530773	f		gcesareni	The pikk kinases serve as transducers of the damege signel, ultimately phosphorylating and activating the downstream effector kinases: checkpoint kinases 1 and 2.	SIGNOR-130187	0.356
ERBB2	protein	P04626	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	binding			9606									1676673	t		gcesareni	Activated egfr binds the sh2 domain of phospholipase c-gamma (plc-gamma), activating plc-gamma-mediated downstream signaling.	SIGNOR-20815	0.633
FAM83H	protein	Q6ZRV2	UNIPROT	CSNK1D	protein	P48730	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								29789297	t		miannu	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273768	0.332
MAPK7	protein	Q13164	UNIPROT	MAPK7	protein	Q13164	UNIPROT	up-regulates activity	phosphorylation	Thr733	LPPVFSGtPKGSGAG	9606	BTO:0000567								20667468	t		miannu	Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803.	SIGNOR-259822	0.2
SRC	protein	P12931	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Tyr340	RGQRDSSyYWEIEAS	9606									10998357	t		gcesareni	We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain.	SIGNOR-82150	0.588
PPM1A	protein	P35813	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	dephosphorylation	Ser608	ENTEDQYsLVEDDED	10090	BTO:0000944								15016818	t			Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2C_ dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity	SIGNOR-252724	0.329
WNT3A	protein	P56704	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates activity				9606									18772438	f		gcesareni	Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki.	SIGNOR-180803	0.677
ruxolitinib phosphate	chemical	CHEBI:66917	ChEBI	JAK1	protein	P23458	UNIPROT	down-regulates activity	chemical inhibition			9606									23061804	t		miannu	Ruxolitinib is a selective inhibitor of Janus kinases (JAK) 1 and 2, which are involved in the signalling pathway of various cytokines and growth factors essential to haematopoiesis. 	SIGNOR-259170	0.8
JAK1	protein	P23458	UNIPROT	STAT2	protein	P52630	UNIPROT	up-regulates activity	phosphorylation	Tyr690	NLQERRKyLKHRLIV										9020188	t			STAT2 plays a pivotal role in IFN-a signaling. It is recruited to the activated receptor first and, after phosphorylation by JAK kinases on tyrosine 690, provides a docking site for the SH2 domain of STAT1.	SIGNOR-251344	0.76
TGFBR1	protein	P36897	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates				9606									26194464	f		MARCO ROSINA	TbRI phosphorylates not only the C-termini of R-Smads but also activates various protein kinases including mitogen-activated protein kinases (MAPKs): extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK (p38), which then phosphorylate the variable linker regions of R-Smad	SIGNOR-255033	0.318
BUB1	protein	O43683	UNIPROT	BUB3	protein	O43684	UNIPROT	up-regulates activity	relocalization												11402067	t		lperfetto	Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity	SIGNOR-252019	0.942
CDK1	protein	P06493	UNIPROT	AMBRA1	protein	Q9C0C7	UNIPROT	up-regulates activity	phosphorylation	Ser1252	QPTLPSSsPVPIPVS	9606	BTO:0000567								37584777	t	phosphorylation site remapping based on mass spec table	lperfetto	CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects.	SIGNOR-272968	0.2
drospirenone	chemical	CHEBI:50838	ChEBI	NR3C2	protein	P08235	UNIPROT	down-regulates activity	chemical inhibition			10116	BTO:0000671								1493716	t		miannu	Dihydrospirorenone is a potent aldosterone antagonist 8 times as potent as spironolactone and antiandrogenic (0.3 times cyproterone acetate). The high binding affinity of dihydrospirorenone to the binding sites of the mineralocorticoid receptor of rat kidney with an RBA value of 230% compared to aldosterone is remarkable. This reflects the strong antimineralocorticoid activity of this compound which was evaluated in adrenalectomized rats.	SIGNOR-258349	0.8
INS	protein	P01308	UNIPROT	DUSP6	protein	Q16828	UNIPROT	down-regulates				9606									22521266	f		gcesareni	In conclusion,insulinlikely promotes mkp-3 protein degradation	SIGNOR-197203	0.392
CSNK2A1	protein	P68400	UNIPROT	MRE11	protein	P49959	UNIPROT	up-regulates activity	phosphorylation	Ser689	KGVDFESsEDDDDDP	-1									28436950	t		miannu	Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689.	SIGNOR-265895	0.2
MMP1	protein	P03956	UNIPROT	COL2A1	protein	P02458	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly774	RGDVGEKgPEGAPGK	-1									17318226	t		lperfetto	In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4. 	SIGNOR-272338	0.456
PLK1	protein	P53350	UNIPROT	PKMYT1	protein	Q99640	UNIPROT	unknown	phosphorylation	Ser426	CSLLLDSsLSSNWDD	9606	BTO:0000567								12738781	t		lperfetto	These results suggest that Ser-426 is a major phosphorylation site by Plk1, and Thr-495 is a second major site. 	SIGNOR-249207	0.707
SMURF1	protein	Q9HCE7	UNIPROT	RAD23A	protein	P54725	UNIPROT	unknown	ubiquitination			-1									20804422	t		miannu	Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay.	SIGNOR-272691	0.297
MAPK11	protein	Q15759	UNIPROT	KRT8	protein	P05787	UNIPROT	up-regulates	phosphorylation	Ser74	TVNQSLLsPLVLEVD	9606									11788583	t		lperfetto	Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.	SIGNOR-114063	0.402
CDK5	protein	Q00535	UNIPROT	TPX2	protein	Q9ULW0	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser486	LPITVPKsPAFALKN	9606		BTO:0003897							31272499	t		lperfetto	CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular tumorigenesis	SIGNOR-265100	0.277
PRKACA	protein	P17612	UNIPROT	KCNJ2	protein	P63252	UNIPROT	down-regulates activity	phosphorylation	Ser425	PRPLRREsEI	-1									19843922	t		miannu	PKA consensus site S425 required for PKA-mediated effects on Kir2.1 channels. PKA activation reduced outward IK1 for heteromeric Kir2.1 WT+V227F channels after 2 hours of PKA activation. 	SIGNOR-276267	0.2
wortmannin	chemical	CHEBI:52289	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									8162590	t		gcesareni	The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase.	SIGNOR-252666	0.8
RAP1GDS1	protein	P52306	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates	binding			9606									21242305	t		miannu	Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc	SIGNOR-171347	0.616
CREB1	protein	P16220	UNIPROT	NR4A3	protein	Q92570	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								17668895	f		gcesareni	Phosphorylation of creb by msk has been linked to the transcription of nur77, nor1 and c-fos downstream of mapk signalling in various cell types.	SIGNOR-157154	0.34
WNT5A	protein	P41221	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131838	0.697
PHKG1	protein	Q16816	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser554	RTPPKSPsSAKSRLQ	-1									8999860	t		miannu	Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules	SIGNOR-250283	0.318
OTULIN	protein	Q96BN8	UNIPROT	UBC	protein	P0CG48	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270820	0.704
TFAP2B	protein	Q92481	UNIPROT	PTGDS	protein	P41222	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002605								15743775	f		miannu	 Deletion and mutation of the AP-2 element at -98 in the L-PGDS gene promoter result in a drastic decrease in the reporter activity (Figs. 1 and 2). Results from the EMSA and ChIP assay demonstrated that AP-2β bound to the AP-2 element both in vitro and in TE671 cells	SIGNOR-255425	0.2
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	CCNA1	protein	P78396	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11090075	f			Overexpression of cyclin A1 observed in APL cells is caused by the expression of the aberrant fusion proteins, PML-RARα and PLZF-RARα. PML-RARα itself can lead to activation of the cyclin A1 promoter.Since both fusion proteins disrupt the normal RARα function, our results strongly suggested that the RARα pathway negatively regulates the expression of cyclin A1 and that this negative regulation is disrupted by the aberrant fusion proteins.	SIGNOR-255725	0.2
EEF1A1P5	protein	Q5VTE0	UNIPROT	Asn-tRNA(Asn)	smallmolecule	CHEBI:29265	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269546	0.8
AXIN2	protein	Q9Y2T1	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	up-regulates activity	binding			9606		BTO:0000142;BTO:0000671;BTO:0000763							10911903	t		lperfetto	It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains.	SIGNOR-228003	0.729
TCL1A	protein	P56279	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	binding			9606	BTO:0000782;BTO:0001271								10983986	t		lperfetto	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-244449	0.823
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	STK11	protein	Q15831	UNIPROT	down-regulates activity	phosphorylation	Ser428	SSKIRRLsACKQQ	9606									25846811	t		lperfetto	Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK.	SIGNOR-244595	0.2
FBLN5	protein	Q9UBX5	UNIPROT	ELN	protein	P15502	UNIPROT	up-regulates	binding			9606									19570982	t		miannu	Our data show that fibulin-5 can interact with tropoelastin or with fibrillin-1, implying a chaperone role for fibulin-5 in directing elastin onto microfibrils	SIGNOR-186603	0.753
SLIT2	protein	O94813	UNIPROT	ROBO4	protein	Q8WZ75	UNIPROT	up-regulates	binding			9606	BTO:0000938								12941633	t		gcesareni	We show that robo4 binds slit and inhibits cellular migration in a heterologous expression system, analogous to the role of known robo receptors in the nervous system.	SIGNOR-86380	0.655
PRKACB	protein	P22694	UNIPROT	PHKA1	protein	P46020	UNIPROT	down-regulates activity	phosphorylation			9606									10487978	t			Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.	SIGNOR-267413	0.307
CASP3	protein	P42574	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	cleavage	Asp329	EMEEDSYdSFGEPSY	-1									10069390	t		lperfetto	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261749	0.415
POU5F1	protein	Q01860	UNIPROT	TBXT	protein	O15178	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254929	0.2
DOCK6	protein	Q96HP0	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor												23462102	t		lperfetto	Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton. 	SIGNOR-275671	0.663
ZC3H12A	protein	Q5D1E8	UNIPROT	GATA2	protein	P23769	UNIPROT	up-regulates quantity	post transcriptional regulation			9606	BTO:0000007								30842549	t			Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA	SIGNOR-259943	0.2
PRL	protein	P01236	UNIPROT	LPL	protein	P06858	UNIPROT	down-regulates activity				9606									12679477	f	Regulation	miannu	 PRL inhibits lipoprotein lipase activity in human white adipose tissue	SIGNOR-251851	0.335
SLC2A1	protein	P11166	UNIPROT	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	up-regulates quantity	relocalization			9606									23506862	t		miannu	GLUT1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells.	SIGNOR-267458	0.8
SREBF2	protein	Q12772	UNIPROT	PON1	protein	P27169	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20728021	t		miannu	 we conclude that quercetin exhibits its antiatherogenic property by eliciting the translocation of the mature SREBP2 from endoplasmic reticulum to the nucleus, where it binds to SRE-like sequence in the PON1 promoter and up-regulates PON1 gene transcription and PON1 activity.	SIGNOR-255224	0.302
LRRC4	protein	Q9HBW1	UNIPROT	CDK4	protein	P11802	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		BTO:0000142							25526788	f		miannu	LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway.	SIGNOR-264059	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	FERMT2	protein	Q96AC1	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser186	YSSPGLYsKTMTPTY	9606	BTO:0000567								35469017	t		miannu	 CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry.	SIGNOR-276714	0.2
Polycomb repressive complex 1	complex	SIGNOR-C408	SIGNOR	Histone H2A	proteinfamily	SIGNOR-PF70	SIGNOR	down-regulates activity	ubiquitination			9606									25519132	t		miannu	Mechanism of transcriptional activation. PRC1 can monoubiquitinate H2AK119 through its RING1B component. 	SIGNOR-266815	0.2
PPARG	protein	P37231	UNIPROT	IL10	protein	P22301	UNIPROT	up-regulates quantity by expression	transcriptional regulation												20553736	f		lperfetto	Pigment epithelium-derived factor induces interleukin-10 expression in human macrophages by induction of PPAR gamma.	SIGNOR-271688	0.379
GSK3B	protein	P49841	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser33	QQQSYLDsGIHSGAT	9606			SIGNOR-C110						11955436	t		gcesareni	Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC).	SIGNOR-116520	0.856
BCL11A	protein	Q9H165	UNIPROT	HBG1	protein	P69891	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004911								20395365	f	Regulation	miannu	BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors.	SIGNOR-251802	0.46
SMAD7	protein	O15105	UNIPROT	TAB1	protein	Q15750	UNIPROT	down-regulates	binding			9606									11737269	t		lpetrilli	Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads.	SIGNOR-112645	0.561
MAPK3	protein	P27361	UNIPROT	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation	Ser154	SSVSSSPsPPFGHSA	9606									12050114	t		gcesareni	Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation.	SIGNOR-88732	0.36
ATR	protein	Q13535	UNIPROT	NBN	protein	O60934	UNIPROT	up-regulates	phosphorylation	Ser343	TTPGPSLsQGVSVDE	9606									17526493	t		gcesareni	We demonstrate that mrn and atr/atr-interacting protein (trip) interact with each other, and the forkhead-associated/breast cancer c-terminal domains (fha/brct) of nbs1 play a significant role in mediating this interaction. Mutations in the fha/brct domains do not prevent atr activation but specifically impair atr-mediated nbs1 phosphorylation at ser-343, which results in a defect in the s-phase checkpoint.	SIGNOR-155214	0.777
A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269009	0.7
PRKCG	protein	P05129	UNIPROT	MGluR	proteinfamily	SIGNOR-PF55	SIGNOR	up-regulates activity	phosphorylation			-1									15894802	t	inferred from family member	lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-270279	0.463
PIK3R3	protein	Q92569	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									9415396	t		gcesareni	The region between the src homology 2 (sh2) domains of p55pik bound to the nh2 terminus region of p110alpha	SIGNOR-252723	0.73
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CASP9	protein	P55211	UNIPROT	down-regulates	phosphorylation	Thr125	PEVLRPEtPRPVDIG	9606									16287866	t		lperfetto	Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle.	SIGNOR-216876	0.431
BRAF	protein	P15056	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser218	VSGQLIDsMANSFVG	10090	BTO:0000944								8131746	t		lperfetto	Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf.	SIGNOR-235475	0.779
CENPM	protein	Q9NSP4	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265211	0.69
L-tryptophan	smallmolecule	CHEBI:16828	ChEBI	5-hydroxy-L-tryptophan	smallmolecule	CHEBI:17780	ChEBI	up-regulates quantity	precursor of			9606									31024440	t	brain	lperfetto	In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)].	SIGNOR-264185	0.8
ACOX1	protein	Q15067	UNIPROT	TP73	protein	O15350	UNIPROT	down-regulates quantity by destabilization	binding			9606									31401980	t		miannu	Downregulation of ACOX1 increased p73, but not p53, expression. p73 expression was critical for apoptosis induction induced by ACOX1 downregulation. ACOX1 reduced p73 expression by destabilizing p73 protein. We also found that ACOX1 interacted with p73 protein	SIGNOR-261056	0.2
LEPR	protein	P48357	UNIPROT	PTPN11	protein	Q06124	UNIPROT	up-regulates activity	binding			9606									11085989	t		miannu	Because the long leptin receptor lacking tyrosine 985 exhibits a significantly reduced ability to activate ERK phosphorylation, this residue is at least in part mediating stimulation of the ERK pathway by ObRb. This residue binds SHP-2 and is required for tyrosine phosphorylation of SHP-2	SIGNOR-263506	0.483
PTPRC	protein	P08575	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	dephosphorylation	Tyr1008	LPQDKEYyKVKEPGE	10090									11201744	t			CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells 	SIGNOR-248349	0.484
PLK1	protein	P53350	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates activity	phosphorylation	Ser129	NEAYEMPsEEGYQDY	9606									19889641	t		lperfetto	Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation.	SIGNOR-189045	0.358
PHLPP2	protein	Q6ZVD8	UNIPROT	PRKCB	protein	P05771	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser661	QNEFAGFsYTNPEFV	9606									18162466	t			These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation.|n contrast, results from siRNA depletion and overexpression experiments indicate that the hydrophobic motif site (Ser660) is regulated by PHLPP isoforms, 	SIGNOR-248727	0.333
NFYA	protein	P23511	UNIPROT	NFY	complex	SIGNOR-C1	SIGNOR	form complex	binding			9606									9885213	t		lperfetto	Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding.	SIGNOR-63013	0.963
CHGA	protein	P10645	UNIPROT	Peptide_hormone_processing	phenotype	SIGNOR-PH88	SIGNOR	up-regulates				10090									12456801	f			CgA was initially identified as the major soluble matrix protein of secretory vesicles formed in neuroendocrine cells. Its functions include modulation of secretory granule stability, prohormone processing, and regulation of peptide sorting into secretory pathways	SIGNOR-254275	0.7
PRKCA	protein	P17252	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser257	QIRLRRDsKEANARR	-1	BTO:0002320								9677319	t		lperfetto	Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases.	SIGNOR-249002	0.292
GIGYF2	protein	Q6Y7W6	UNIPROT	GRB10	protein	Q13322	UNIPROT	up-regulates activity	binding			10090									20670374	t		miannu	We demonstrated that, in cultured cells and mammalian brains, GIGYF2 interacts and colocalises with Grb10, promoting ligand‐induced ubiquitination of IGF‐1R, and thereby regulates receptor degradation	SIGNOR-260057	0.616
EGR1	protein	P18146	UNIPROT	PITX1	protein	P78337	UNIPROT	up-regulates activity	binding			10090									19106114	t		miannu	GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. 	SIGNOR-254916	0.529
beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	glycerone phosphate(2-)	smallmolecule	CHEBI:57642	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-268075	0.8
DTNBP1	protein	Q96EV8	UNIPROT	ABI1	protein	Q8IZP0	UNIPROT	up-regulates activity	binding			10116		BTO:0000601							20531346	t		miannu	Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1. 	SIGNOR-265660	0.36
simvastatin	chemical	CHEBI:9150	ChEBI	HMGCR	protein	P04035	UNIPROT	down-regulates activity	chemical inhibition			-1									1433193	t		miannu	Substitution of hydroxy and hydroxyalkyl functionality at C-7 of the hexahydronaphthalene nucleus of simvastatin has provided novel analogs. The synthetic strategy employed epoxidation or Lewis acid-catalyzed aldol reaction of the 8-keto silyl enol ether as a key reactive intermediate. These analogs were evaluated as potential hypocholesterolemic agents via initial determination of their ability to inhibit HMG-CoA reductase in vitro. 	SIGNOR-258348	0.8
PROX1	protein	Q92786	UNIPROT	Epithelial-mesenchymal_transition	phenotype	SIGNOR-PH45	SIGNOR	up-regulates				9606	BTO:0001033								27476001	f		miannu	Our present study reveals that DAB2IP prevents EMT and metastasis of prostate cancer through targeting PROX1 gene transcription and destabilizing HIF1α protein, which provides a new insight into mechanism that DAB2IP regulates EMT and PCa metastasis. 	SIGNOR-254767	0.7
FCHO1	protein	O14526	UNIPROT	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	up-regulates quantity by stabilization	binding												24789820	t		lperfetto	Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth	SIGNOR-260715	0.502
F11	protein	P03951	UNIPROT	GPIb-IX-V complex	complex	SIGNOR-C270	SIGNOR	up-regulates activity	binding			9606	BTO:0000132								25297919	t		lperfetto	Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1.	SIGNOR-261857	0.471
SREBF2	protein	Q12772	UNIPROT	ABCG5	protein	Q9H222	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21123766	f		miannu	 these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α.	SIGNOR-254455	0.434
PRKAA2	protein	P54646	UNIPROT	PROX1	protein	Q92786	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser79	KLLKRANsYEDAMMP	9606	BTO:0002181								36433955	t		miannu	Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation.	SIGNOR-277608	0.2
WNT3A	protein	P56704	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates activity	binding			9606	BTO:0000222								10601008	t		gcesareni	Here we focus on the role of Wnts, their putative receptors Frizzled and the soluble antagonist Frzb1 in regulating mammalian myogenesis. Although it is becoming evident that the signaling downstream of Frizzled receptors is much more complex than anticipated, it is conceivable that it may lead to transcriptional activation of Myf5 and MyoD and to initiation of myogenesis.	SIGNOR-73039	0.626
STAT5A	protein	P42229	UNIPROT	SOCS3	protein	O14543	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									12468433	t			We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling	SIGNOR-261548	0.623
ULK1/Atg13/Fip200	complex	SIGNOR-C100	SIGNOR	AMBRA1	protein	Q9C0C7	UNIPROT	up-regulates activity	phosphorylation			10090									20921139	t		lperfetto	When autophagy is induced, ulk1 phosphorylates ambra1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Ambra1-dlc1 dissociates from the dynein complex upon ulk1-dependent ambra1 phosphorylation.	SIGNOR-219388	0.656
DYRK1A	protein	Q13627	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates	phosphorylation	Thr286	EEVDLACtPTDVRDV	9606									24119401	t		lperfetto	Dyrk1a controls the rate of cycd1 degradation by directly phosphorylating cycd1 at thr 286 and thereby regulates the fraction of cycling cells.	SIGNOR-202838	0.406
SUCLG2	protein	Q96I99	UNIPROT	Succinyl-CoA GTP variant	complex	SIGNOR-C399	SIGNOR	form complex	binding			9606									32627745	t		miannu	Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS). 	SIGNOR-266264	0.927
tRNA(Glu)	smallmolecule	CHEBI:29175	ChEBI	Glu-tRNA(Glu)	smallmolecule	CHEBI:29157	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270385	0.8
AKAP8L	protein	Q9ULX6	UNIPROT	mRNA-nucleus_export	phenotype	SIGNOR-PH127	SIGNOR	up-regulates				9606									11402034	f		miannu	These results support the proposal that both RHA and HAP95 facilitated the nuclear export of unspliced, CTE-containing mRNA in human cells. we have extended this earlier study by mapping the functional domains of HAP95 and providing strong evidence for a direct role of HAP95 in RHA-mediated nuclear export of CTE-containing mRNA.	SIGNOR-260949	0.7
FOXI1	protein	Q12951	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20972246	f	 	miannu	Results of transiently transfected vas deferens cells with either the -33G wild-type or the -33A variant CFTR directed luciferase reporter gene confirmed that the -33A variant, which alters the FOXI1 (Forkhead box I1) binding, significantly decreases the CFTR promoter activity.	SIGNOR-254176	0.256
POLR2H	protein	P52434	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266140	0.863
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	APBB1	protein	O00213	UNIPROT	unknown	phosphorylation			9606									14697653	t	inferred from 70% family members	lperfetto	Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved.	SIGNOR-270054	0.2
SAV1	protein	Q9H4B6	UNIPROT	STK3	protein	Q13188	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0005238								16930133	t	Hippo pathway	Gianni	Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation.	SIGNOR-261957	0.827
DUSP10	protein	Q9Y6W6	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	dephosphorylation			9606									10391943	t		gcesareni	Mkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk, but not mapk/erk. p38 is a preferred substrate	SIGNOR-68983	0.682
PAX8	protein	Q06710	UNIPROT	TG	protein	P01266	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11786384	t		miannu	The transcription factor Pax8 plays an important role in the expression of the differentiated phenotype of thyroid follicular cells. It has recently been shown that Pax8 is necessary for thyroglobulin (Tg) gene expression.	SIGNOR-251998	0.472
PRKG1	protein	Q13976	UNIPROT	SLC6A4	protein	P31645	UNIPROT	up-regulates	phosphorylation	Thr276	SIWKGVKtSGKVVWV	9606	BTO:0000567								17913921	t		gcesareni	These results are consistent with the hypothesis that pkg phosphorylates hsert at thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by tm5.	SIGNOR-158186	0.392
CDK1	protein	P06493	UNIPROT	UBA1	protein	P22314	UNIPROT	up-regulates	phosphorylation	Ser835	ELKATLPsPDKLPGF	9606	BTO:0000567								7724583	t		lperfetto	Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Thus, the serine at position 835 is a phosphorylation site. Taking these findings into consideration, we consider that cyclin b might be one of the substrates targeted by the specific ubiquitin conjugation pathway activated by the phosphorylation of e1 with cdc2 kinase.	SIGNOR-32225	0.414
SP1	protein	P08047	UNIPROT	UGT1A4	protein	P22310	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								19546240	f	 	miannu	 our data indicate that up-regulation of UGT1A4 expression by E(2) is mediated by both ER alpha and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy.	SIGNOR-254076	0.2
3,5-dichloro-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-2-hydroxy-6-methoxybenzamide	chemical	CHEBI:92070	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258856	0.8
PRKACA	protein	P17612	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation	Ser43	FGYQRRAsDDGKLTD	9606									11971957	t		gcesareni	Serine 43 phosphorylation decreased the binding to ras in serum-starved but not in mitogen-stimulated cells. However, the kinase activity of a rafs43a mutant was fully inhibited by pka.	SIGNOR-86145	0.481
CSNK2A1	protein	P68400	UNIPROT	MYB	protein	P10242	UNIPROT	down-regulates activity	phosphorylation	Ser11	RPRHSIYsSDEDDED	-1									7735324	t		llicata	For c-Myb mutational analysis of the CKII phosphorylation sites showed altered steady state DNA binding. Replacing Ser-11/12 by alanine residues resulted in increased DNA binding compared to wt c-Myb or Myb Asp-11/12 as demonstrated by up to 10-fold differences in the dissociation constants. 	SIGNOR-250918	0.346
GSK3B	protein	P49841	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation	Ser653	PSLSRHSsPHQSEDE										11427888	t			Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. 	SIGNOR-251241	0.673
JAK1	protein	P23458	UNIPROT	IL2RB	protein	P14784	UNIPROT	up-regulates activity	phosphorylation	Tyr536	LPLNTDAyLSLQELQ	9534	BTO:0000298								8700888	t			In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc.	SIGNOR-251341	0.616
SP3	protein	Q02447	UNIPROT	ITGA11	protein	Q9UKX5	UNIPROT	up-regulates quantity by expression				9606	BTO:0001282								16300938	t		lperfetto	We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors.	SIGNOR-253351	0.2
TET2	protein	Q6N021	UNIPROT	OGT	protein	O15294	UNIPROT	up-regulates	binding			9606									23353889	t		miannu	Tet2 and tet3 associate with the o_glcnac transferase ogt / tet2 and tet3 promote ogt_mediated glcnacylation	SIGNOR-200695	0.456
TGFBR2	protein	P37173	UNIPROT	TGFBR2	protein	P37173	UNIPROT	down-regulates activity	phosphorylation	Ser416	SVDDLANsGQVGTAR	9606	BTO:0000972				phosphorylation:Ser213	TRKLMEFsEHCAIIL			9155023	t		lperfetto	Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function.	SIGNOR-246737	0.2
USP8	protein	P40818	UNIPROT	STAM	protein	Q92783	UNIPROT	up-regulates quantity	binding			9606	BTO:0000567								16520378	t			Stability of the UBPY binding partner STAM is dramatically compromised in UBPY knockdown cells.	SIGNOR-266904	0.551
SMAD2	protein	Q15796	UNIPROT	SMAD2/SMURF2	complex	SIGNOR-C11	SIGNOR	form complex	binding			9606									11389444	t		gcesareni	We show that in the presence of tgf-beta, smad2 interacts through its proline-rich ppxy motif with the tryptophan-rich ww domains of smurf2, a recently identified e3 ubiquitin ligases.	SIGNOR-108487	0.77
ATM	protein	Q13315	UNIPROT	CCAR2	protein	Q8N163	UNIPROT	up-regulates activity	phosphorylation	Thr454	AAEAAPPtQEAQGET	9606									22735644	t		lperfetto	 Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death. 	SIGNOR-267661	0.571
COL21A1	protein	Q96P44	UNIPROT	DDR2	protein	Q16832	UNIPROT	up-regulates activity	binding			9606	BTO:0001282								17318226	t		lperfetto	The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75. 	SIGNOR-272343	0.2
RIMS1	protein	Q86UR5	UNIPROT	CACNA1D	protein	Q01668	UNIPROT	up-regulates activity	binding			9606	BTO:0005822								28642685	t		miannu	Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells.	SIGNOR-264358	0.374
AKT1	protein	P31749	UNIPROT	CDCA7	protein	Q9BWT1	UNIPROT	down-regulates	phosphorylation	Thr163	SRRPRRRtFPGVASR	9606									23166294	t		llicata	The prosurvival kinase akt phosphorylates cdca7 at threonine 163, promoting binding to 14-3-3, dissociation from myc, and sequestration to the cytoplasm. we have mapped the domains of interaction and have discovered that akt phosphorylates cdca7 near this contact region, leading to loss of its association with myc, binding to 14-3-3 proteins, and exclusion from the nucleus.	SIGNOR-252533	0.346
MERTK	protein	Q12866	UNIPROT	MLKL	protein	Q8NB16	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr376	DRVKSTAyLSPQELE	9606	BTO:0000007								31230815	t	done	miannu	TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6).	SIGNOR-274118	0.2
PPP2CA	protein	P67775	UNIPROT	PRKCD	protein	Q05655	UNIPROT	down-regulates activity	dephosphorylation	Ser645	LNEKARLsYSDKNLI	9606									11959144	t			PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex	SIGNOR-248638	0.385
N-(3-aminopropyl)-N-[(1R)-1-[7-chloro-4-oxo-3-(phenylmethyl)-2-quinazolinyl]-2-methylpropyl]-4-methylbenzamide	chemical	CHEBI:94692	ChEBI	KIF11	protein	P52732	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193483	0.8
PTPN11	protein	Q06124	UNIPROT	STAT1	protein	P42224	UNIPROT	down-regulates activity	dephosphorylation	Tyr701	DGPKGTGyIKTELIS	9606	BTO:0000007								12270932	t			SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei|In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) |Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity.	SIGNOR-248672	0.733
PRKCA	protein	P17252	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Ser285	VDAQGTLsKIFKLGG	-1									2413024	t		lperfetto	MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 	SIGNOR-248874	0.503
SMO	protein	Q99835	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates	phosphorylation			9606									18455992	t		gcesareni	Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion.	SIGNOR-178607	0.404
CDK1	protein	P06493	UNIPROT	REPS2	protein	Q8NFH8	UNIPROT	down-regulates activity	phosphorylation	Ser463	RPRSRSYsSTSIEEA	10029									10764745	t		miannu	Phosphorylation of POB1 and Epsin by p34cdc2 kinase. Their phosphorylation sites (Ser411 of POB1 and Ser357 of Epsin) were determined. Phosphorylated Epsin and EpsinS357D formed a complex with α-adaptin less efficiently than wild type Epsin. 	SIGNOR-262724	0.347
ORC	complex	SIGNOR-C419	SIGNOR	DNA_replication	phenotype	SIGNOR-PH53	SIGNOR	up-regulates				9606									32808929	f		lperfetto	The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA	SIGNOR-267561	0.7
SIRT7	protein	Q9NRC8	UNIPROT	H3C15	protein	Q71DI3	UNIPROT	up-regulates activity	deacetylation	Lys19	TGGKAPRkQLATKAA										22722849	t		lperfetto	SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. 	SIGNOR-275875	0.2
AKT2	protein	P31751	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates	phosphorylation	Ser939	SFRARSTsLNERPKS	9606									12150915	t		gcesareni	We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex.	SIGNOR-91041	0.719
DLG4	protein	P78352	UNIPROT	Postsynaptic density assembly	phenotype	SIGNOR-PH163	SIGNOR	up-regulates				9606									17243894	f		miannu	 PSD-95 (the best-studied scaffold protein of the PSD, which binds to NR2 subunits of NMDA receptors) was found to be highly abundant in the adult forebrain PSD	SIGNOR-264230	0.7
LTB4R	protein	Q15722	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256834	0.252
PRKACA	protein	P17612	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates	phosphorylation	Ser236	IDKNRRKsCQACRLR	9606									9891036	t		lperfetto	Phosphorylation of human estrogen receptor alpha by protein kinase a regulates dimerizationeralpha is phosphorylated by protein kinase a (pka) on serine-236 within the dna binding domain. Mutation of serine-236 to glutamic acid prevents dna binding by inhibiting dimerization by eralpha	SIGNOR-63984	0.466
KPNA2	protein	P52292	UNIPROT	RNMT	protein	O43148	UNIPROT	down-regulates activity	binding			9606									26942677	t		lperfetto	KPNA2 Inhibits RNMT Activity|We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor.	SIGNOR-265502	0.421
NFKB1	protein	P19838	UNIPROT	CD80	protein	P33681	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000776								12860928	f	 	 	Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. 	SIGNOR-253934	0.303
GTF2I	protein	P78347	UNIPROT	USF1	protein	P22415	UNIPROT	up-regulates activity	binding			9606									21282467	t		lperfetto	TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription	SIGNOR-268538	0.503
CCT137690	chemical	CID:25154041	PUBCHEM	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190895	0.8
Muscle cell-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C483	SIGNOR	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	up-regulates				9606									25195934	f		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270741	0.7
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation			9606									20974802	t		lperfetto	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6.	SIGNOR-244662	0.2
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGB2	protein	Q9Y5G2	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265688	0.2
WWP2	protein	O00308	UNIPROT	WWP1	protein	Q9H0M0	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								25071155	t		miannu	WWP1 in complex with WWP2 specifically regulates ΔNp73.  In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73. 	SIGNOR-272231	0.2
FBXO32	protein	Q969P5	UNIPROT	Muscle_atrophy	phenotype	SIGNOR-PH40	SIGNOR	up-regulates				10090		BTO:0001103							11717410	f			Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases	SIGNOR-255344	0.7
CSNK2A1	protein	P68400	UNIPROT	IKZF1	protein	Q13422	UNIPROT	down-regulates	phosphorylation	Ser63	NVKVETQsDEENGRA	9606	BTO:0001271								21750978	t		miannu	We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo	SIGNOR-174832	0.294
STK3	protein	Q13188	UNIPROT	MOB1A	protein	Q9H8S9	UNIPROT	up-regulates	phosphorylation	Thr12	FSSRSSKtFKPKKNI	9606									21808241	t	The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific.	gcesareni	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction.	SIGNOR-175805	0.844
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257909	0.8
adenosine	smallmolecule	CHEBI:16335	ChEBI	ADORA3	protein	P0DMS8	UNIPROT	up-regulates activity	binding			-1									14662005	t		Luana	Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3.	SIGNOR-268422	0.8
PRKACA	protein	P17612	UNIPROT	KCNH2	protein	Q12809	UNIPROT	up-regulates	phosphorylation	Ser890	RQRKRKLsFRRRTDK	9606									10488078	t		lperfetto	Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a)	SIGNOR-70726	0.311
PI3K	complex	SIGNOR-C156	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation			9606									15526160	t		miannu	C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo.	SIGNOR-254950	0.785
MFGE8	protein	Q08431	UNIPROT	GRK2	protein	P25098	UNIPROT	up-regulates quantity by expression				10090	BTO:0000763								22634615	f		Giorgia	Our findings showed MFG-E8–mediated upregulation of GRK2, which can be correlated with reduction of surface CXCR2. The MFG-E8 effect is mediated by αvβ3 integrin to upregulate GRK2 expression and results in downregulation of surface CXCR2 levels in neutrophils, leading to decrease of neutrophil migration	SIGNOR-260648	0.2
TWIST1	protein	Q15672	UNIPROT	MMP2	protein	P08253	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003879								20646316	f		miannu	Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1.	SIGNOR-255525	0.385
DMTF1	protein	Q9Y222	UNIPROT	AREG	protein	P15514	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004532								19816943	t		Luana	 Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. 	SIGNOR-261582	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KA5	protein	O75582	UNIPROT	up-regulates activity	phosphorylation	Ser376	EKLFQGYsFVAPSIL	9606									15568999	t		lperfetto	In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1	SIGNOR-249574	0.2
serotonin	smallmolecule	CHEBI:28790	ChEBI	3,4-dihydroxyphenylacetaldehyde	smallmolecule	CHEBI:27978	ChEBI	up-regulates quantity	precursor of			9606									31024440	t	brain	lperfetto	Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA).	SIGNOR-264187	0.8
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2G2	protein	P60604	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271310	0.71
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	EWSR1	protein	Q01844	UNIPROT	unknown	phosphorylation			9606									19076070	t	inferred from 70% family members	lperfetto	Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2.	SIGNOR-270062	0.2
GSK3B	protein	P49841	UNIPROT	GFI1	protein	Q99684	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser94	EDFWRPPsPSASPAS	9606	BTO:0000498								31289136	t		miannu	GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation.	SIGNOR-277466	0.2
ATG2B	protein	Q96BY7	UNIPROT	Autophagosome_formation	phenotype	SIGNOR-PH36	SIGNOR	up-regulates				9606	BTO:0001938								28561066	f		miannu	WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation. 	SIGNOR-268486	0.7
INS	protein	P01308	UNIPROT	LPL	protein	P06858	UNIPROT	up-regulates activity				9606									21966368	f	Regulation	miannu	Insulin has a major effect on LPL regulation in adipose tissue since in mature adipocytes insulin not only increases the level of LPL mRNA but also regulates LPL activity through both posttranscriptional and posttranslational mechanisms 	SIGNOR-251858	0.478
PPP3CC	protein	P48454	UNIPROT	KSR2	protein	Q6VAB6	UNIPROT	up-regulates activity	dephosphorylation	Thr290	NKLKPPGtPPPSSRK	10090									19560418	t			These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3	SIGNOR-248526	0.262
ZDHHC13	protein	Q8IUH4	UNIPROT	MC1R	protein	Q01726	UNIPROT	up-regulates activity	palmitoylation			10090	BTO:0000847								28869973	t		miannu	Collectively these results suggest that ZDHHC13 phosphorylation by ATR following UVB irradiation promotes its interaction with MC1R to stimulate MC1R palmitoylation.Activating MC1R palmitoylation rescues the defect of MC1R RHC variants	SIGNOR-273518	0.278
MAPK3	protein	P27361	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									12110590	t		gcesareni	Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway.	SIGNOR-90533	0.728
ANK2	protein	Q01484	UNIPROT	CACNA1B	protein	Q00975	UNIPROT	up-regulates quantity	binding			10090		BTO:0000142							24394417	t		miannu	Here, we demonstrate that ankyrin-B associates with Cav2.1 and Cav2.2 in cortex, cerebellum, and brain stem. Additionally, using in vitro and in vivo techniques, we demonstrate that ankyrin-B, via its membrane-binding domain, associates with a highly conserved motif in the DII/III loop domain of Cav2.1 and Cav2.2. Collectively, our findings identify an interaction between ankyrin-B and both Cav2.1 and Cav2.2 at the amino acid level that is necessary for proper Cav2.1 and Cav2.2 targeting in vivo.	SIGNOR-266707	0.266
EXT1/EXT2	complex	SIGNOR-C51	SIGNOR	heparan sulfate octasaccharide	smallmolecule	CHEBI:142519	ChEBI	up-regulates quantity	chemical modification			9606									20377530	t		miannu	HS (heparan sulfate) is synthesized by HS co-polymerases encoded by the EXT1 and EXT2 genes (exostosin 1 and 2), which are known as causative genes for hereditary multiple exostoses, a dominantly inherited genetic disorder characterized by multiple cartilaginous tumours. 	SIGNOR-264016	0.8
FAM83H	protein	Q6ZRV2	UNIPROT	CSNK1E	protein	P49674	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								29789297	t		miannu	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273764	0.337
NCAPH2	protein	Q6IBW4	UNIPROT	Condensin II	complex	SIGNOR-C342	SIGNOR	form complex	binding			9606									32445620	t		miannu	The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction.	SIGNOR-263910	0.9
AKT1	protein	P31749	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates	phosphorylation	Ser197	APRRRAAsMDSSSKL	9606									16272144	t		lperfetto	Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression	SIGNOR-252484	0.755
CDK5	protein	Q00535	UNIPROT	VRK3	protein	Q8IV63	UNIPROT	up-regulates activity	phosphorylation	Ser108	RPPTPKSsPQKTRKS										27346674	t		lperfetto	Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding|Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation|	SIGNOR-275544	0.365
CDK12	protein	Q9NYV4	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1882	SPTSPTYsPTTPKYS	9606									22012619	t		miannu	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176809	0.775
RORA	protein	P35398	UNIPROT	NLGN1	protein	Q8N2Q7	UNIPROT	up-regulates quantity by expression	transcriptional regulation												28608249	t		lperfetto	Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005).	SIGNOR-265136	0.2
ECM	stimulus	SIGNOR-ST20	SIGNOR	AM/b2 integrin	complex	SIGNOR-C170	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259052	0.7
POLR1D	protein	P0DPB5	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding												22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266158	0.89
JAK3	protein	P52333	UNIPROT	SIGLEC10	protein	Q96LC7	UNIPROT	unknown	phosphorylation	Tyr691	PKGTQADyAEVKFQ	9606									11733002	t		lperfetto	These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. however, it is not clear whether y691 is capable of binding sap or a similar protein. Future studies will attempt to elucidate the signaling activities associated with y691	SIGNOR-112487	0.2
PRKACA	protein	P17612	UNIPROT	NOLC1	protein	Q14978	UNIPROT	up-regulates	phosphorylation	Ser623	KGEKRASsPFRRVRE	9606									12167624	t		gcesareni	Here we demonstrate that protein kinase a (pka)-dependent phosphorylation of nopp140 at ser 627, together with c/ebpbeta, induces agp gene expression synergistically.	SIGNOR-91186	0.311
EIF3C	protein	Q99613	UNIPROT	EIF3_complex	complex	SIGNOR-C401	SIGNOR	form complex	binding			-1									16920360	t		miannu	Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 	SIGNOR-266398	0.93
ESRRA	protein	P11474	UNIPROT	NR2F6	protein	P10588	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000156								15955695	f		miannu	 In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro.	SIGNOR-253796	0.251
MTA1	protein	Q13330	UNIPROT	CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	up-regulates activity	binding			10090									24089055	t	 	lperfetto	Here we provide genetic and biochemical evidence that metastasis-associated protein 1 (MTA1), a widely upregulated gene product in human cancers, is an integral component of the circadian molecular machinery. | The CLOCK-BMAL1 heterodimer activates MTA1 transcription through a conserved E-box element at its promoter. MTA1, in turn, interacts with and recruits CLOCK-BMAL1 at its own and CRY1 promoters and promotes their transcription.	SIGNOR-253723	0.2
PRKG2	protein	Q13237	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser82	RALSRQLsSGVSEIR	9606									19593530	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	lperfetto	Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization	SIGNOR-186943	0.2
PRKAA1	protein	Q13131	UNIPROT	ULK1	protein	O75385	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007		SIGNOR-C15						21460634	t		lperfetto	Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition.	SIGNOR-173038	0.552
TP53	protein	P04637	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates activity	binding			9606									14963330	t		lperfetto	Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program	SIGNOR-178690	0.743
4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide	chemical	CHEBI:94128	ChEBI	BCL2	protein	P10415	UNIPROT	down-regulates	chemical inhibition			9606									23336025	t		gcesareni	Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol.	SIGNOR-200460	0.8
RNF41	protein	Q9H4P4	UNIPROT	USP8	protein	P40818	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002181								23750007	t		irozzo	RNF41 redistributes and ubiquitylates USP8, and reduces USP8 levels.	SIGNOR-259106	0.875
ZWINT	protein	O95229	UNIPROT	KNL1 complex	complex	SIGNOR-C363	SIGNOR	form complex	binding												27881301	t		lperfetto	KNL1C (known as Spc105 complex in S. cerevisiae) contains the KNL1 and ZWINT subunits.	SIGNOR-265194	0.2
KAT2B	protein	Q92831	UNIPROT	P300/PCAF	complex	SIGNOR-C7	SIGNOR	form complex	binding			9606									21131905	t		lperfetto	Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators.	SIGNOR-170276	0.769
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	SP1	protein	P08047	UNIPROT	up-regulates activity	phosphorylation	Ser59	GGQESQPsPLALLAA	10090	BTO:0000944								11598016	t		gcesareni	Mutation of Sp1 Ser59 abrogates the cyclin A€“CDK augmentation of Sp1-dependent transcriptional transactivation	SIGNOR-248240	0.423
MAPK3	protein	P27361	UNIPROT	NR3C2	protein	P08235	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser238	QGTPLTCsPNVENRG	9606	BTO:0005043								22798426	t		miannu	 Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276112	0.358
PRKCA	protein	P17252	UNIPROT	GJB1	protein	P08034	UNIPROT	up-regulates activity	phosphorylation	Ser233	NPPSRKGsGFGHRLS										8390988	t		lperfetto	Phosphorylation of connexin-32 by protein kinase C prevents its proteolysis by mu-calpain and m-calpain. |In agreement with other authors (see Saez et al., 1990b), we have found that phosphorylation of connexin-32 by protein kinase A and protein kinase C occurs in serine residues, although we have detected trace amounts of phosphothreonine in connexin-32 phosphorylated by protein kinase C (results not shown). Indeed, Se233 has been shown to be the major phosphorylation site catalyzed by protein kinase A. However, Ser233, Ser239, and perhaps other serines are phosphorylated by protein kinase C (Saez et al., 1990b).	SIGNOR-248920	0.368
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1948	SPTSPGYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273036	0.556
AKT1	protein	P31749	UNIPROT	CARHSP1	protein	Q9Y2V2	UNIPROT	unknown	phosphorylation	Ser52	TRRTRTFsATVRASQ	9606		BTO:0000671							15910284	t		lperfetto	These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf	SIGNOR-252478	0.352
phenformin	chemical	CHEBI:8064	ChEBI	KCNJ8	protein	Q15842	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000783	BTO:0001260							20188727	t		lperfetto	Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel |Phenformin but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1).	SIGNOR-262030	0.8
PPP3CA	protein	Q08209	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates	dephosphorylation			9606									21880741	t		gcesareni	Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.	SIGNOR-176370	0.817
CBLC	protein	Q9ULV8	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0001538								12226085	t		miannu	In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination. 	SIGNOR-272605	0.762
AURKB	protein	Q96GD4	UNIPROT	KIF4A	protein	O95239	UNIPROT	up-regulates activity	phosphorylation	Thr799	PPKLRRRtFSLTEVR	-1									28992084	t		miannu	Using in vitro kinase assays, we found that active AMPK and Aurora B phosphorylated KIF4A at Ser801 and Thr799 respectively in a time-dependent manner (Figure 5D). KIF4A is phosphoregulated by AMPK and Aurora B. Although AMPK phosphorylation increased the ATPase activity of KIF4A, Aurora B phosphorylation resulted in a stronger increase (Figure 5I), which might be consistent with the more powerful kinase function of Aurora B during mitosis.	SIGNOR-265992	0.533
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				9606	BTO:0000567								27126896	f		Luana	 Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation.	SIGNOR-268017	0.8
MYC	protein	P01106	UNIPROT	MYCT1	protein	Q8N699	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11909865	t		miannu	MT-MC1 is a widely expressed nuclear protein whose overexpression, unlike that of c-Myc targets reported previously, recapitulates multiple c-Myc phenotypes. These include promotion of apoptosis, alteration of morphology, enhancement of anchorage-independent growth, tumorigenic conversion, promotion of genomic instability, and inhibition of hematopoietic differentiation. The MT-MC1 promoter is a direct c-Myc target; it contains two consensus E-box elements, both of which bind c-Myc.	SIGNOR-261736	0.303
PRDM1	protein	O75626	UNIPROT	CCL2	protein	P13500	UNIPROT	down-regulates quantity by repression	transcriptional regulation												19915049	t		lperfetto	Blimp-1 binds to the proinflammatory cytokine/chemokine genes, Il-6 and Ccl2, and negatively regulates their expression.	SIGNOR-271679	0.2
TAOK1	protein	Q7L7X3	UNIPROT	MAP2K3	protein	P46734	UNIPROT	up-regulates activity	phosphorylation	Ser218	ISGYLVDsVAKTMDA	9606	BTO:0000007								9786855	t		lperfetto	The activation of and binding to MEK3 by TAO1 implicates TAO1 in the regulation of the p38-containing stress-responsive MAP kinase pathway	SIGNOR-60818	0.559
CKM	protein	P06732	UNIPROT	N-phosphocreatine	smallmolecule	CHEBI:17287	ChEBI	up-regulates quantity	chemical modification			9606									18502307	t		miannu	Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 	SIGNOR-265788	0.8
PRKCQ	protein	Q04759	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Thr841	RSAFTTStVVRMHVG	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249290	0.294
TRAF6	protein	Q9Y4K3	UNIPROT	TAB1	protein	Q15750	UNIPROT	up-regulates activity	binding			9606									25290089	t		lperfetto	The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.	SIGNOR-205455	0.86
ARID1B	protein	Q8NFD5	UNIPROT	Histone H2B	proteinfamily	SIGNOR-PF68	SIGNOR	down-regulates activity	ubiquitination			-1									20086098	t		miannu	The immunopurified BAF250b E3 ubiquitin ligase was found to target histone H2B at lysine 120 for monoubiquitination in vitro. 	SIGNOR-271442	0.2
CLASP2	protein	O75122	UNIPROT	CLIP2	protein	Q9UDT6	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								15631994	t		lperfetto	CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. 	SIGNOR-265093	0.608
FGF9	protein	P31371	UNIPROT	BMP2	protein	P12643	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15780951	f	FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1.	gcesareni	Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts.	SIGNOR-134794	0.384
CDK5	protein	Q00535	UNIPROT	LMTK2	protein	Q8IWU2	UNIPROT	down-regulates	phosphorylation			9606									12832520	t		gcesareni	Cprk displays catalytic activity in in vitro kinase assays and is itself phosphorylated by cdk5/p35. Cdk5/p35 inhibits cprk activity.	SIGNOR-102717	0.512
ABL1	protein	P00519	UNIPROT	ATR	protein	Q13535	UNIPROT	up-regulates	phosphorylation	Tyr310	FPFEAEAyRNIEPVY	9606									20798688	t		lperfetto	C-abl can phosphorylate atr on y291 and y310 and this phosphorylation appears to have a positive role in atr activation under genotoxic stress.	SIGNOR-167636	0.582
SDHC	protein	Q99643	UNIPROT	Mitochondrial respiratory chain complex II	complex	SIGNOR-C278	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites	SIGNOR-262186	0.953
RANBP3	protein	Q9H6Z4	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	relocalization			9606									19289081	t		lperfetto	RanBP3 directly recognizes dephosphorylated Smad2/3, which results from the activity of nuclear Smad phosphatases, and mediates nuclear export of Smad2/3 in a Ran-dependent manner.	SIGNOR-217634	0.447
PPP2R5C	protein	Q13362	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates	binding			9606									16456541	t		gcesareni	B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk	SIGNOR-144328	0.395
TNF	protein	P01375	UNIPROT	PIK3CD	protein	O00329	UNIPROT	up-regulates				9606									10485710	f		gcesareni	Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)	SIGNOR-70622	0.268
DAB2IP	protein	Q5VWQ8	UNIPROT	Cell_migration	phenotype	SIGNOR-PH38	SIGNOR	down-regulates				9606									27858941	f		miannu	DAB2IP inactivation promotes tumor growth and survival, development, and proliferation of CSC, and resistance to chemo- and radiotherapy. It induces EMT, increases cell migration and invasion, and counteracts pro-apoptotic signaling.	SIGNOR-254778	0.7
L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	N-acetyl-L-aspartate(2-)	smallmolecule	CHEBI:16953	ChEBI	up-regulates quantity	precursor of			9606									19524112	t		miannu	The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA.	SIGNOR-267519	0.8
NR4A3	protein	Q92570	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity	binding			9606									30455429	t		miannu	NR4A3 physically interacted with an anti-apoptotic Bcl-2 protein hence sequestering it from blunting apoptosis.	SIGNOR-259399	0.2
MYC	protein	P01106	UNIPROT	LDHA	protein	P00338	UNIPROT	up-regulates quantity	transcriptional regulation			10116									9192621	f			Our studies have linked c-Myc to the induction of LDH-A, whose expression increases lactate production and is necessary for c-Myc-mediated transformation	SIGNOR-259367	0.577
SMAD1/4	complex	SIGNOR-C85	SIGNOR	RUNX2	protein	Q13950	UNIPROT	up-regulates activity	binding			9606									15573378	t		ggiuliani	The Runx2 WT and deletion constructs (1 –495, 1–464, and 1–432) all physically interact with the BMP2 responsive Smad 1	SIGNOR-255782	0.567
SMARCE1	protein	Q969G3	UNIPROT	Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	form complex	binding			10090	BTO:0001086								19279220	t		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270720	0.741
Av/b8 integrin	complex	SIGNOR-C185	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269029	0.7
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGB4	protein	Q9UN71	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265679	0.2
STAT1/STAT3	complex	SIGNOR-C118	SIGNOR	JAK1/STAT1/STAT3	complex	SIGNOR-C120	SIGNOR	form complex	binding			10090									15284024	t		lperfetto	Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min.	SIGNOR-235658	0.741
NDN	protein	Q99608	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000671								24349431	t		lperfetto	Deletion mapping demonstrated that the C-terminus of cystin and both termini of necdin are required for their mutual interaction. Speculating that these two proteins may function to regulate gene expression, we developed a luciferase reporter assay and observed that necdin strongly activated the Myc P1 promoter, and cystin did so more modestly.	SIGNOR-253381	0.269
MAPK8	protein	P45983	UNIPROT	JUND	protein	P17535	UNIPROT	up-regulates	phosphorylation	Ser100	LGLLKLAsPELERLI	9606									22327296	t		gcesareni	Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase.	SIGNOR-196038	0.789
RPS6KA5	protein	O75582	UNIPROT	TH	protein	P07101	UNIPROT	up-regulates	phosphorylation	Ser40	GQGAPGPsLTGSPWP	9606									12421349	t	The effect has been demonstrated using P07101-3	gcesareni	Recombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax. studies on th from several species suggest that ser40 is the main site involved in direct activation of th	SIGNOR-95491	0.343
LRFN5	protein	Q96NI6	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606	BTO:0000938								27225731	f		miannu	These results suggest that postsynaptic SALM5 promotes synapse development by trans-synaptically interacting with presynaptic LAR-RPTPs and is important for the regulation of excitatory synaptic strength.	SIGNOR-264085	0.7
ENAH	protein	Q8N8S7	UNIPROT	Axonal_growth_cone_formation	phenotype	SIGNOR-PH199	SIGNOR	up-regulates				9606									18508258	f		miannu	Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance.	SIGNOR-268389	0.7
MAP1LC3C	protein	Q9BXW4	UNIPROT	Autophagosome_formation	phenotype	SIGNOR-PH36	SIGNOR	up-regulates				9606		BTO:0001623							20921139	f		lperfetto	We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation	SIGNOR-219399	0.7
NUP210	protein	Q8TEM1	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262072	0.585
AURKB	protein	Q96GD4	UNIPROT	CPC	complex	SIGNOR-C554	SIGNOR	form complex	binding			9606									23175282	t		miannu	It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A).	SIGNOR-275426	0.857
IKBKB	protein	O14920	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser644	GLDFNFDsLISTQNV	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway	SIGNOR-252947	0.678
SRC	protein	P12931	UNIPROT	EMD	protein	P50402	UNIPROT	down-regulates	phosphorylation	Tyr95	KGYNDDYyEESYFTT	9606	BTO:0000567	BTO:0000887							19789182	t		llicata	Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf	SIGNOR-188316	0.463
STAT5A	protein	P42229	UNIPROT	MEF2C	protein	Q06413	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21261500	f		miannu	STAT5 binds directly to the promoter region and potently mediates repression of MEF2C, probably via HDAC recruitment.	SIGNOR-254207	0.282
RBPJ	protein	Q06330	UNIPROT	RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	form complex	binding												12361602	t		apalma	Notch is cleaved and translocates to the nucleus, where it activates a family of transcription factors, exemplified by Suppressor of Hairless and CBF/RJBk	SIGNOR-255379	0.949
CDC20	protein	Q12834	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	up-regulates activity	binding												16896351	t		lperfetto	In addition to E2 enzymes, APC/C activity is also strictly dependent on one of several co-activator proteins that associate with APC/C during specific periods of the cell cycle. The best studied of these are Cdc20 and Cdh1	SIGNOR-252014	0.872
PTK6	protein	Q13882	UNIPROT	PTK6	protein	Q13882	UNIPROT	up-regulates	phosphorylation	Tyr342	RLIKEDVyLSHDHNI	9606	BTO:0000150								12121988	t		miannu	Autophosphorylation increases enzyme activity of wild-type brk but not of a y342a mutant form of brk.	SIGNOR-90604	0.2
CYP19A1	protein	P11511	UNIPROT	17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000975							27702664	t		lperfetto	The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively	SIGNOR-268669	0.8
KATNB1	protein	Q9BVA0	UNIPROT	KATNA1	protein	O75449	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000567								10751153	t		miannu	In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer 	SIGNOR-267173	0.779
MAP3K1	protein	Q13233	UNIPROT	CRTC1	protein	Q6UUV9	UNIPROT	up-regulates	phosphorylation			9606									18784253	t		miannu	We report on the activation oftorc1through mekk1-mediated phosphorylation.	SIGNOR-180816	0.326
MAP2K4	protein	P45985	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates	phosphorylation			9606									11062067	t	Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif.	gcesareni	A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1).	SIGNOR-83721	0.732
okadaic acid	chemical	CHEBI:44658	ChEBI	STK4	protein	Q13043	UNIPROT	up-regulates				9606									23493077	f		gcesareni	Okadaic acid has been frequently used to enhance the phosphorylation of mst1 and mst2 and to trigger the activation of the hippo pathway.	SIGNOR-201554	0.8
MAPK14	protein	Q16539	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates	phosphorylation	Ser389	ARIQAAAsTPTNATA	9606		BTO:0000142							18451303	t		gcesareni	Here, we show that p38 mitogen-activated protein kinase (mapk) also inactivates gsk3beta by direct phosphorylation at its c terminus, and this inactivation can lead to an accumulation of beta-catenin.	SIGNOR-178603	0.294
EGLN3	protein	Q9H6Z9	UNIPROT	PKM	protein	P14618	UNIPROT	up-regulates activity	hydroxylation	Pro408	LAPITSDpTEATAVG	9606	BTO:0000567								21620138	t			Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells.	SIGNOR-267477	0.447
CXCL1	protein	P09341	UNIPROT	GLI3	protein	P10071	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16885213	f		gcesareni	The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i).	SIGNOR-148460	0.2
DNAH17	protein	Q9UFH2	UNIPROT	Cilium_movement	phenotype	SIGNOR-PH171	SIGNOR	up-regulates				9606	BTO:0001277								31178125	f		miannu	Our study provides a comprehensive analysis of ODA heavy chain distribution in human spermatozoa and demonstrates the importance of DNAH17 (β-HC) in sperm flagellum structure and motility. We demonstrate that DNAH17 (β-HC) mutations are associated with a loss of ODAs and male infertility but not with PCD.	SIGNOR-265549	0.7
MAPK8	protein	P45983	UNIPROT	PKMYT1	protein	Q99640	UNIPROT	up-regulates	phosphorylation			9606	BTO:0001286								19204086	t	The results showed that residues 140 to 205 of JNK1 have the ability to interact with Myt1.	gcesareni	A kinase assay using gst-myt1 revealed that active jnk1 or jnk3, but not jnk2, phosphorylated myt1 in vitro.	SIGNOR-183899	0.342
EIF2AK2	protein	P19525	UNIPROT	NLRC4 inflammasome	complex	SIGNOR-C223	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								22801494	t		miannu	Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. 	SIGNOR-263121	0.314
Crenolanib	chemical	CID:10366136	PUBCHEM	PDGFRA	protein	P16234	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191121	0.8
STK16	protein	O75716	UNIPROT	STK16	protein	O75716	UNIPROT	unknown	phosphorylation	Thr185	EGSRQALtLQDWAAQ	-1									18184589	t		Manara	Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition.	SIGNOR-260803	0.2
TAC1	protein	P20366	UNIPROT	TACR2	protein	P21452	UNIPROT	up-regulates	binding			9606									8925404	t		gcesareni	The mammalian tachykinins include substance p, neurokinin a and neurokinin b, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated nk1, nk2 and nk3, respectively. The interaction of tachykinin with its receptor activates gq, which in turn activates phospholipase c to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (ip3) and diacylglycerol (dag).	SIGNOR-44773	0.871
FBXW7	protein	Q969H0	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity	ubiquitination			9606			SIGNOR-C135						20852628	t		gcesareni	We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it.	SIGNOR-243545	0.754
KDM5C	protein	P41229	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264306	0.2
tyrphostin B42	chemical	CHEBI:131968	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189386	0.8
baicalein	chemical	CHEBI:2979	ChEBI	CYP2C9	protein	P11712	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190236	0.8
1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone	chemical	CHEBI:93753	ChEBI	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192607	0.8
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	CAD	protein	P27708	UNIPROT	down-regulates activity	dephosphorylation	Ser1406	GAGGRRLsSFVTKGY	-1									4092695	t		lperfetto	Cyclic AMP-dependent protein kinase phosphorylates two serine residues on the protein termed sites 1 and 2| Site 1: Arg-Leu-Ser(P)-Ser-Phe-Val-Thr-Lys Site 2: Ile-His-Arg-Ala-Ser(P)-Asp-Pro-Gly-Leu-Pro-Ala-Glu-Glu-Pro-Lys | Both phosphorylation and activation can be reversed using purified preparations of the catalytic subunits of protein phosphatases 1- and -2A, and inactivation also correlates better with dephosphorylation of site 1 rather than site 2.	SIGNOR-264653	0.2
nociceptin	smallmolecule	CHEBI:80266	ChEBI	OPRL1	protein	P41146	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257553	0.8
barium(2+)	chemical	CHEBI:37136	ChEBI	KCNJ13	protein	O60928	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9620703	t		miannu	Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations	SIGNOR-258925	0.8
ATR	protein	Q13535	UNIPROT	XPA	protein	P23025	UNIPROT	up-regulates activity	phosphorylation	Ser196	RSLEVWGsQEALEEA	9606									30327428	t			ATR mediated phosphorylation of XPA on S196 enhances cAMP-mediated optimization of NER, and is promoted by SIRT1-mediated deacetylation of XPA on K63, K67 and K215.	SIGNOR-258985	0.505
INSR	protein	P06213	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr242	FFQQQMIyDSPPSRA	10090									10978177	t			HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin	SIGNOR-251310	0.492
SRC	protein	P12931	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr317	PPTPGNTyQIPRTFP	9606	BTO:0000007								19881549	t		lperfetto	Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis	SIGNOR-236306	0.693
PLK1	protein	P53350	UNIPROT	RAD21	protein	O60216	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser454	EPSRLQEsVMEASRT	9606	BTO:0000567								15737063	t		lperfetto	We suspected that the observed enhancement of Scc1's cleavability in the presence of Plk1 might be due to phosphorylation at two sites that are directly adjacent to the cleavage sites, Ser175 and Ser454, which we had found to be phosphorylated in mitosis in vivo (Table 1). We therefore mutated these two residues to alanine, thereby creating mutant Scc1-S175A/S454A (see Figure 1C), and tested the cleavability of this mutant in the absence or presence of Plk1 in vitro. |Scc1 phosphorylation is dispensable for cohesin dissociation from chromosomes in early mitosis but enhances the cleavability of Scc1 by separase. 	SIGNOR-275536	0.727
GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000227							18790874	f	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263776	0.7
GYPA	protein	P02724	UNIPROT	Ankyrin complex	complex	SIGNOR-C383	SIGNOR	form complex	binding			9606	BTO:0000424								22465511	t		lperfetto	The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) 	SIGNOR-266018	0.371
ISCU	protein	Q9H1K1	UNIPROT	Mitochondrial Fe-S Cluster Assembly Complex	complex	SIGNOR-C276	SIGNOR	form complex	binding			-1									27519411	t		lperfetto	As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry.	SIGNOR-262128	0.722
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CDK2	protein	P24941	UNIPROT	down-regulates activity	chemical inhibition			-1									29901072	t		miannu	AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9.	SIGNOR-262219	0.8
PRDM1	protein	O75626	UNIPROT	PAX5	protein	Q02548	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12052884	f		miannu	Blimp-1-dependent repression of pax-5 is required for differentiation of b cells to immunoglobulin m-secreting plasma cells	SIGNOR-89032	0.518
TBX2	protein	Q13207	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	down-regulates				9606									24470334	f			TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells	SIGNOR-251563	0.7
PRLHR	protein	P49683	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256837	0.281
beta-D-fructofuranose 2,6-bisphosphate	smallmolecule	CHEBI:28602	ChEBI	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	up-regulates quantity	precursor of			-1									30553771	t			PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species	SIGNOR-267274	0.8
ETS1	protein	P14921	UNIPROT	MMP9	protein	P14780	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22270366	f	 	miannu	 VEGF-induced MMP-9 and MMP-13 promoter activities were down-regulated in ETS-1 siRNA-transfected cells. it is hypothesized that the activation of PI3K/AKT and p38 MAPK by VEGF results in ETS-1 gene expression, which activates MMP-9 and MMP-13, leading to the invasion and scattering of SKOV-3 cells. 	SIGNOR-254083	0.387
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	SQSTM1	protein	Q13501	UNIPROT	up-regulates	phosphorylation	Thr269	GGKRSRLtPVSPESS	9606	BTO:0000551								20974803	t		lperfetto	Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis.	SIGNOR-216936	0.355
CREB5	protein	Q02930	UNIPROT	DGKG	protein	P49619	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21132541	f		miannu	 Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition),	SIGNOR-253804	0.2
RUNX2/EP300	complex	SIGNOR-C211	SIGNOR	BGLAP	protein	P02818	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002648								12697832	f		Giulio Giuliani	In agreement with our studies in ROS 17/2.8 cells, coexpression of p300 and Runx2/Cbfa1 resulted in marked enhancement of the OC promoter activity, further indicating that both factors cooperate to stimulate this promoter.	SIGNOR-255420	0.435
PAFAH1B1	protein	P43034	UNIPROT	NDEL1	protein	Q9GZM8	UNIPROT	up-regulates activity	binding			10090	BTO:0000938								11163259	t		miannu	We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 is required for the proper distribution of NUDEL and cellular components regulated by CDHC function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex	SIGNOR-252157	0.838
CAMK2G	protein	Q13555	UNIPROT	TH	protein	P07101	UNIPROT	up-regulates activity	phosphorylation	Ser19	KGFRRAVsELDAKQA										1680128	t		llicata	 In both isoforms, Ser-40 was found to be phosphorylated by PKA, and Ser-19 and Ser-40 were found to be phosphorylated by CaM-PK II. The putative phosphorylation site generated by alternative splicing (Ser-31) was phosphorylated specifically by CaM-PK II in TH-2 only. | Unlike TH-1, phosphorylation of TH-2 by CaM-PK II resulted in an increase of the Ki value for dopamine.	SIGNOR-250709	0.338
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1651	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273040	0.556
SETDB2	protein	Q96T68	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	methylation	Lys 10	RTKQTARkSTGGKAP	9606	BTO:0000007								20404330	t		miannu	 Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression.	SIGNOR-263896	0.2
SRC	protein	P12931	UNIPROT	ANXA1	protein	P04083	UNIPROT	unknown	phosphorylation	Thr216	AGERRKGtDVNVFNT	9606									24103589	t		lperfetto	Location of sites in human lipocortin i that are phosphorylated by protein tyrosine kinases and protein kinases a and cthe primary site of phosphorylation by protein kinase c was also near the amino terminus at ser-27. The major site of phosphorylation by adenosine cyclic 3',5'-phosphate dependent protein kinase was on the carboxy-terminal half of the molecule at thr-216	SIGNOR-202800	0.398
CDK1	protein	P06493	UNIPROT	NDUFB6	protein	O95139	UNIPROT	up-regulates activity	phosphorylation	Ser29	WLKDQELsPREPVLP										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275591	0.2
(2S)-3-(4-acetamidophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide	chemical	CHEBI:94760	ChEBI	AR	protein	P10275	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-189623	0.8
SRF	protein	P11831	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates				9606									22225874	t		FFerrentino	Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy.	SIGNOR-255966	0.286
MAPK3	protein	P27361	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates activity	phosphorylation	Thr125	PEVLRPEtPRPVDIG	9606									12792650	t		lperfetto	Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk	SIGNOR-101548	0.551
CDK1	protein	P06493	UNIPROT	TSC1	protein	Q92574	UNIPROT	down-regulates	phosphorylation	Thr417	SLPQATVtPPRKEER	9606	BTO:0000680;BTO:0001573;BTO:0001286		SIGNOR-C17						14551205	t		lperfetto	Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex	SIGNOR-118584	0.503
TAK-875	chemical	CID:24857286	PUBCHEM	FFAR1	protein	O14842	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-207182	0.8
CTH	protein	P32929	UNIPROT	L-cysteine zwitterion	smallmolecule	CHEBI:35235	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000671;BTO:0000759;BTO:0002688							19961860	t		lperfetto	 the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production.	SIGNOR-275818	0.8
CBP/p300	complex	SIGNOR-C6	SIGNOR	DDX5	protein	P17844	UNIPROT	up-regulates	binding			9606									12527917	t		miannu	Cbp/p300 interact with p68 rna helicase / the atpase activity of p68 is required for the specific transcriptional activation of cbp	SIGNOR-97274	0.469
DERA	protein	Q9Y315	UNIPROT	2-deoxy-D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:62877	ChEBI	down-regulates quantity	chemical modification			9606									25229427	t		miannu	Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase.	SIGNOR-267097	0.8
PP2CA_R1A_R2A 	complex	SIGNOR-C132	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	dephosphorylation			10090	BTO:0000944								18042541	t		gcesareni	Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B).	SIGNOR-243530	0.671
GSK3B	protein	P49841	UNIPROT	RCAN1	protein	P53805	UNIPROT	up-regulates activity	phosphorylation	Ser163	PDKQFLIsPPASPPV	10090	BTO:0000165								12063245	t		lperfetto	Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. 	SIGNOR-249359	0.497
LDHB	protein	P07195	UNIPROT	pyruvate	smallmolecule	CHEBI:15361	ChEBI	down-regulates quantity	chemical modification			9606									24929216	t		lperfetto	Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase.	SIGNOR-267656	0.8
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3-4	protein	Q16695	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269638	0.2
KLF1	protein	Q13351	UNIPROT	KLF8	protein	O95600	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000759							18687676	t		Luana	Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly. 	SIGNOR-266050	0.253
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDUFB6	protein	O95139	UNIPROT	up-regulates activity	phosphorylation	Ser29	WLKDQELsPREPVLP										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275599	0.251
DOK1	protein	Q99704	UNIPROT	A3/b1 integrin	complex	SIGNOR-C161	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257672	0.32
diazepam	chemical	CHEBI:49575	ChEBI	GABA-A (a2-b1-g2) receptor	complex	SIGNOR-C331	SIGNOR	up-regulates activity	chemical activation			9606		BTO:0000227							18790874	t	brain	lperfetto	The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5. 	SIGNOR-263797	0.8
CDK1	protein	P06493	UNIPROT	USP24	protein	Q9UPU5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1616	NSHSPAGsAAISQQD	9606	BTO:0000018								27991932	t		lperfetto	 Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604.	SIGNOR-275605	0.2
GRIPAP1	protein	Q4V328	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates activity	binding			9606	BTO:0002181								17761173	t		Giulio	We investigated signal transduction pathways that might lie downstream of GRASP-1 and found that GRASP-1 potently activates JNK pathway signaling, with no effect on ERK signaling. Such JNK pathway activating activity requires binding of GRASP-1 to both JNK and the upstream JNK pathway activator MEKK-1.	SIGNOR-260607	0.316
ANKRD11	protein	Q6UB99	UNIPROT	NTRK2	protein	Q16620	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000142							29274743	t		miannu	Ankrd11 knockdown decreases the levels of bdnf and Trkb mRNAs. Next, we examine whether ANKRD11 accesses the Trkb promoter in cortical neurons. We performed the chromatin immunoprecipitation assay (ChIP) using an ANKRD11 antibody followed by PCR to amplify the Trkb promoter region. We found that ANKRD11 binds to the Trkb promoter (Fig. 6E). As expected, the level of ANKRD11 binding was decreased in the Ankrd11 knockdown condition.	SIGNOR-266731	0.2
LCK	protein	P06239	UNIPROT	SIGLEC10	protein	Q96LC7	UNIPROT	unknown	phosphorylation	Tyr691	PKGTQADyAEVKFQ	9606									11733002	t		lperfetto	These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. however, it is not clear whether y691 is capable of binding sap or a similar protein. Future studies will attempt to elucidate the signaling activities associated with y691	SIGNOR-112499	0.263
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1623	SPTSPSYsPTSPSYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203512	0.77
acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	(3S)-3-hydroxy-3-methylglutaryl-CoA(5-)	smallmolecule	CHEBI:43074	ChEBI	up-regulates quantity	precursor of												29597274	t		lperfetto	Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis	SIGNOR-267651	0.8
USP24	protein	Q9UPU5	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0000018								27991932	t		lperfetto	In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. |Knockdown of USP24 decreases Bax and p300 levels	SIGNOR-275606	0.2
ATR	protein	Q13535	UNIPROT	MCC	protein	P23508	UNIPROT	up-regulates activity	phosphorylation	Ser118	SELRSELsQSQHEVN	9606	BTO:0001109								21779472	t		miannu	MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. 	SIGNOR-273514	0.2
WNT11	protein	O96014	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131637	0.567
JAK3	protein	P52333	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates	phosphorylation	Tyr694	LAKAVDGyVKPQIKQ	9606									18250158	t		gcesareni	For these assays, coexpression of wt jak3 with stat5a was found to result in tyrosine phosphorylation of stat5a (lane 2) mediated by jak3, since stat5a coexpressed with the kinase-inactive k855a mutant form of jak3 was not tyrosine phosphorylated.	SIGNOR-160672	0.85
MAPK1	protein	P28482	UNIPROT	PTPN7	protein	P35236	UNIPROT	up-regulates activity	phosphorylation	Ser93	ALQRQPPsPKQLEEE	-1									16226275	t		lperfetto	First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|	SIGNOR-249436	0.805
ZAP70	protein	P43403	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	phosphorylation	Tyr493	LGADDSYyTARSAGK	9606									16049944	t		lperfetto	Zap-70 is modified by auto-phosphorylation of various tyrosine residues and is activated by specific phosphorylation of the tyrosine residue y-493	SIGNOR-139098	0.2
CSNK2A2	protein	P19784	UNIPROT	MS4A1	protein	P11836	UNIPROT	unknown	phosphorylation	Ser289	PPQDQESsPIENDSS	9606	BTO:0000776								7678037	t		llicata	These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells.	SIGNOR-251012	0.311
mTORC1	complex	SIGNOR-C3	SIGNOR	ATP6V1A	protein	P38606	UNIPROT	up-regulates quantity by expression				10090									21804531	f		Giorgia	These data suggested that V-ATPase mRNA levels were upregulated by mTORC1 through a transcriptional mechanism. Tfeb is required for mTORC1-induced V-ATPase expression.	SIGNOR-260636	0.262
CRP	protein	P02741	UNIPROT	IL10	protein	P22301	UNIPROT	down-regulates quantity	post transcriptional regulation			9606									16917108	f	Regulation	miannu	CRP significantly decreased IL-10 mRNA stability	SIGNOR-251825	0.481
LTK	protein	P29376	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000938								9223670	t		gcesareni	Recently, we demonstrated that ltk utilizes shc and irs-1 as two major substrates and while both equally activate the ras pathway, only irs-1 suppresses apoptosis of hematopoietic cells.	SIGNOR-49531	0.32
cabazitaxel	chemical	CHEBI:63584	ChEBI	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	down-regulates activity	chemical inhibition			9606									21770474	t		miannu	Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization	SIGNOR-259445	0.8
CAV1	protein	Q03135	UNIPROT	HMGA1	protein	P17096	UNIPROT	up-regulates activity	relocalization			9606									22706202	t	 	miannu	CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization.	SIGNOR-254428	0.269
SGK1	protein	O00141	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Thr157	GIRKRPAtDDSSTQN	9606									18570873	t		gcesareni	Activated sgk1 and p27 phosphorylation at t157, and both were inhibited by short-term rapamycin treatment and by sgk1 shrna.	SIGNOR-179117	0.482
NCBP1	protein	Q09161	UNIPROT	IRF8	protein	Q02556	UNIPROT	up-regulates activity	binding			9606	BTO:0001413								11483597	t		miannu	we found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP.	SIGNOR-222939	0.2
NR3C1	protein	P04150	UNIPROT	NR3C2	protein	P08235	UNIPROT	up-regulates				9606									11154266	f		lperfetto	These results indicate that functional interactions between the glucocorticoid and mineralocorticoid receptors in activating specific gene transcription are probably more complex than has been previously appreciated.	SIGNOR-85987	0.522
ATM	protein	Q13315	UNIPROT	MDM4	protein	O15151	UNIPROT	down-regulates	phosphorylation			9606									16082221	t		gcesareni	Atm directly and indirectly induces mdm2 and mdmx phosphorylation, resulting in decreased activity and stability of these proteins. We recently provided a mechanism for the reduced stability of mdm2 and mdmx by showing that atm-dependent phosphorylation lowers their affinity for the deubiquitinating enzyme hausp.	SIGNOR-139403	0.725
MAPK3	protein	P27361	UNIPROT	SPHK1	protein	Q9NYA1	UNIPROT	up-regulates	phosphorylation	Ser225	VGSKTPAsPVVVQQG	9606									14532121	t		gcesareni	Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation.	SIGNOR-118550	0.59
TPO	protein	P07202	UNIPROT	3-iodo-L-tyrosine	smallmolecule	CHEBI:27847	ChEBI	up-regulates quantity	chemical modification			9606									16098474	t		scontino	TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. 	SIGNOR-266957	0.8
STK38	protein	Q15208	UNIPROT	RAB3IP	protein	Q96QF0	UNIPROT	up-regulates activity	phosphorylation	Ser288	KGHTRNKsTSSAMSG	10090		BTO:0000142							22445341	t		miannu	We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. 	SIGNOR-263036	0.375
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1714	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273069	0.636
TIMM9	protein	Q9Y5J7	UNIPROT	TIM22 complex	complex	SIGNOR-C424	SIGNOR	form complex	binding			9606	BTO:0000007								32901109	t		lperfetto	Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK).	SIGNOR-267704	0.568
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	AKT1S1	protein	Q96B36	UNIPROT	down-regulates	binding			9606				SIGNOR-C3					20006481	t		gcesareni	Akt can phosphorylate pras40, a raptor binding protein that also acts as an inhibitor of torc1. Akt-mediated phosphorylation of pras40 again promotes 14-3-3 binding, in this case leading to relief from pras40-mediated inhibition.	SIGNOR-162003	0.2
GATA1	protein	P15976	UNIPROT	HDAC3	protein	O15379	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000150								25726523	t		lperfetto	GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. 	SIGNOR-275664	0.53
GATA1	protein	P15976	UNIPROT	HDAC4	protein	P56524	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000150								25726523	t		lperfetto	GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. 	SIGNOR-275665	0.566
CCL2	protein	P13500	UNIPROT	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates				9606									32283152	f		miannu	High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity.	SIGNOR-261027	0.7
beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	up-regulates quantity	precursor of			9606									30616754	t		lperfetto	FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle	SIGNOR-267588	0.8
suprofen	chemical	CHEBI:9362	ChEBI	PTGS1	protein	P23219	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001061								18667313	t		Luana	Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2. 	SIGNOR-257809	0.8
ZNRF3	protein	Q9ULT6	UNIPROT	LRP6	protein	O75581	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								22575959	t			Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.	SIGNOR-260112	0.642
IKBKB	protein	O14920	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	unknown	phosphorylation	Ser43	PAMLHLPsEQGAPET	9606				SIGNOR-C14					12657630	t			IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376|Thus far, we have no compelling evidence that inducible phosphorylation of these IKKgamma domains is important for their assigned functions. 	SIGNOR-251287	0.962
YES1	protein	P07947	UNIPROT	YES1	protein	P07947	UNIPROT	up-regulates activity	phosphorylation	Tyr426	RLIEDNEyTARQGAK	9606									9794236	t		lperfetto	Autophosphorylation of Src and Yes blocks their inactivation by Csk phosphorylation	SIGNOR-247014	0.2
TTL	protein	Q8NG68	UNIPROT	TUBA1A	protein	Q71U36	UNIPROT	down-regulates	tyrosination			9606									22020298	t		miannu	Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization	SIGNOR-176912	0.513
SRGAP3	protein	O43295	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates				9606									12447388	f		miannu	Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo.	SIGNOR-95918	0.547
D-serine	smallmolecule	CHEBI:16523	ChEBI	NMDA receptor_2D	complex	SIGNOR-C350	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0002609								12393813	t		lperfetto	D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically 	SIGNOR-268280	0.8
(-)-anisomycin	chemical	CHEBI:338412	ChEBI	MAPK8	protein	P45983	UNIPROT	up-regulates	chemical activation			9606									Other	t	CellSignaling	gcesareni		SIGNOR-189702	0.8
SSH1	protein	Q8WYL5	UNIPROT	CORO1B	protein	Q9BR76	UNIPROT	up-regulates	dephosphorylation	Ser2	sFRKVVRQ	9606									17350576	t		gcesareni	Coronin 1b inhibits filament nucleation by arp2/3 complex and this inhibition is attenuated by phosphorylation of coronin 1b at serine 2, a site targeted by ssh1l.	SIGNOR-153604	0.458
MAP2K7	protein	O14733	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000007								9890973	t	Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif	gcesareni	Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)these results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway.	SIGNOR-63972	0.564
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser262	TFRPRSSsNASSVST	10090									10217147	t			Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo.	SIGNOR-252862	0.908
GRIA4	protein	P48058	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								30825796	f		miannu	In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses	SIGNOR-264614	0.7
GRIK4	protein	Q16099	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264345	0.7
BRCC3	protein	P46736	UNIPROT	Histone H2A	proteinfamily	SIGNOR-PF70	SIGNOR	down-regulates	deubiquitination			9606									20656690	t		gcesareni	Brcc36 regulates the abundance of lys(63)-linked ubiquitin chains at chromatin and that one of its substrates is diubiquitinated histone h2a	SIGNOR-265312	0.2
RNF146	protein	Q9NTX7	UNIPROT	AXIN2	protein	Q9Y2T1	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								21799911	t			By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins.	SIGNOR-259997	0.658
CSNK2B	protein	P67870	UNIPROT	HOXB6	protein	P17509	UNIPROT	unknown	phosphorylation	Ser214	LLSASQLsAEEEEEK	-1									10327653	t		llicata	Using two-dimensional tryptic phosphopeptide mapping and purified protein kinases, we demonstrate that Hoxb-6 is phosphorylated in vitro by casein kinase II and cAMP-dependent protein kinase. The casein kinase II phosphorylation site was mapped to serine-214. 	SIGNOR-251071	0.311
IL6ST	protein	P40189	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates				9606									16306329	f		mrosina	Upon formation of the IL-6/IL-6Ralpha/gp130 hexameric signaling complex, two distinct signaling pathways are activated: 1) Janus kinase (JAK)/signal transducers and activator of transcription (STAT) and 2) the Src homology 2-containing tyrosine phosphatase (SHP-2)/extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathways	SIGNOR-255022	0.282
EREG	protein	O14944	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606									16829981	t		gcesareni	For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4.	SIGNOR-147859	0.695
MAPK1	protein	P28482	UNIPROT	UBTF	protein	P17480	UNIPROT	down-regulates	phosphorylation	Thr201	DIPEKPKtPQQLWYT	9606									11741541	t		lperfetto	Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna	SIGNOR-112809	0.402
IL3	protein	P08700	UNIPROT	NFIL3	protein	Q16649	UNIPROT	up-regulates				10090									10082541	f		lperfetto	We previously reported that NFIL3 is an IL-3-responsive gene in Baf-3 cells	SIGNOR-242763	0.543
GNAL	protein	P38405	UNIPROT	Adenylate_cyclase	proteinfamily	SIGNOR-PF92	SIGNOR	up-regulates activity	binding			9606	BTO:0004032								21303898	t		miannu	D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum.	SIGNOR-267852	0.628
PLK1	protein	P53350	UNIPROT	CENPQ	protein	Q7L2Z9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser138	MEDLTNVsSLLNMER	9606									25670858	t		lperfetto	Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 	SIGNOR-265228	0.57
AKT1	protein	P31749	UNIPROT	ARFIP2	protein	P53365	UNIPROT	unknown	phosphorylation	Ser260	GTRGRLEsAQATFQA	9606	BTO:0000938								15809304	t		llicata	Akt phosphorylated arfaptin 2 at ser(260). we have also demonstrated that arfaptin 2 phosphorylation restores proteasome activity that is inhibited by the presence of polyq-huntingtin in cells.	SIGNOR-252476	0.472
ROCK1	protein	Q13464	UNIPROT	ARHGAP35	protein	Q9NRY4	UNIPROT	down-regulates	phosphorylation	Ser1150	LERGRKVsIVSKPVL	9606		BTO:0000887;BTO:0001260							19103606	t		gcesareni	Rho-kinase, an effector of rhoa, phosphorylated p190a rhogap at ser(1150) and attenuated p190a rhogap activity in cos7 cells.	SIGNOR-182849	0.425
GNAI1	protein	P63096	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								11099498	t			These findings indicate that both G alpha(i) and G beta gamma stimulate Rac and Cdc42 pathways with lysophosphatidic acid-induced cell spreading on fibronectin	SIGNOR-256530	0.447
KRT1	protein	P04264	UNIPROT	APC	protein	P25054	UNIPROT	up-regulates activity	phosphorylation			9606									18359618	t	Regulation of catabolism	miannu	Phosphorylation of this central repeat region of APC significantly enhances its affinity for β-catenin. When the repeats are phosphorylated by the cooperative action of CK1 and GSK3β, the binding interaction is significantly altered and enhanced.	SIGNOR-251879	0.2
BCL2	protein	P10415	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	down-regulates				9606									14585074	f		amattioni	Bcl- confers protection to apoptosis by interference with bax/bak-mediated release of the pro-apoptotic mitochodrial factors smac/diablo and htra2/omi	SIGNOR-88885	0.471
RPS6KB1	protein	P23443	UNIPROT	RPS6	protein	P62753	UNIPROT	up-regulates activity	phosphorylation	Ser235	IAKRRRLsSLRASTS	10090									15809305	t		lperfetto	A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size.	SIGNOR-135172	0.936
PPM1D	protein	O15297	UNIPROT	UNG	protein	P13051	UNIPROT	down-regulates activity	dephosphorylation			9606									15327777	t		miannu	PPM1D dephosphorylation of UNG2 is correlated with reduced UNG2 activity on uracil-containing templates.|This result suggests that PPM1D specifically inhibits UNG2 and not other uracil DNA glycosylases.	SIGNOR-277156	0.387
PPP1R15A	protein	O75807	UNIPROT	PPP1CC	protein	P36873	UNIPROT	up-regulates	relocalization			9606									14718519	t		lpetrilli	We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI.	SIGNOR-120734	0.686
LCK	protein	P06239	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	down-regulates activity	phosphorylation	Tyr394	LNTIGLIyEKISLPK	9606	BTO:0002181								28618271	t		miannu	The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. 	SIGNOR-276723	0.2
azelastine	chemical	CHEBI:2950	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			10030	BTO:0000246								21381763	t		Luana	Azelastine was used as a standard, with affinities (pKi) for H1 and H3 8.9 and 6.8, respectively. 	SIGNOR-257894	0.8
PLAG1	protein	Q6DJT9	UNIPROT	IGF2	protein	P01344	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14695992	f		miannu	Plag1 has been shown be a transcriptional activator of igf2	SIGNOR-120363	0.429
MAFA	protein	Q8NHW3	UNIPROT	SLC2A2	protein	P11168	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17149590	f		miannu	 the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA.	SIGNOR-254565	0.381
MAPK3	protein	P27361	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation			10090									8387505	t		lperfetto	The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases	SIGNOR-38999	0.705
PTPN11	protein	Q06124	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates	dephosphorylation	Tyr718	IPERDSRySQPLHEE	9606									19287004	t		lperfetto	Previously we have shown that tyrosine 718 of ask1 when phosphorylated is critical for socs1 binding and socs1-mediated degradation of ask1we identified jak2 and shp2 as a tyr-718-specific kinase and phosphatase, respectively.	SIGNOR-184604	0.374
ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	SHC3	protein	Q92529	UNIPROT	up-regulates	relocalization			9606									16729043	t	inferred from 70% family members	gcesareni	Like erbb1, erbb4 recruits grb2, shc and stat5.	SIGNOR-269962	0.2
RARA	protein	P10276	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates				9606									10607566	f		gcesareni	We shown that retinoic acid (ra) decreases the activity of the beta-catenin-lef/tcf signaling pathway	SIGNOR-73274	0.383
MAPK1	protein	P28482	UNIPROT	ABI1	protein	Q8IZP0	UNIPROT	up-regulates	phosphorylation	Ser222	TSPARLGsQHSPGRT	9606									21419341	t		lperfetto	Our mass spectrometry also identified abi1 s183 and s225 on abi1 (numbering corresponds to abi1 isoform 1) as sites phosphorylated on endogenous protein and in the wildtype erk-dependent in vitro phosphorylated sample. these data indicate erk phosphorylation of abi1 is required for basal and egf-induced wrc interaction with the wrp2/3 complex.	SIGNOR-172873	0.421
ATM	protein	Q13315	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity				9606		BTO:0000887							18534819	f		lperfetto	The decreased atm expression suggests that atm is involved in the development of insulin resistance through down-regulation of akt activity.	SIGNOR-244392	0.462
GSK3B	protein	P49841	UNIPROT	AHR	protein	P35869	UNIPROT	up-regulates activity	phosphorylation	Ser723	ELDYPMGsFEPSPYP	9606	BTO:0000567								34198826	t		miannu	A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR.	SIGNOR-276658	0.253
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	BACE1	protein	P56817	UNIPROT	up-regulates activity	phosphorylation	Thr252	YTGSLWYtPIRREWY	10116	BTO:0001009								26317805	t		miannu	First, we show that BACE1 is phosphorylated by the p25/Cdk5 complex at Thr252 and that this phosphorylation increases BACE1 activity. 	SIGNOR-276934	0.384
GSK3B	protein	P49841	UNIPROT	AHR	protein	P35869	UNIPROT	up-regulates activity	phosphorylation	Ser727	PMGSFEPsPYPTTSS	9606	BTO:0000567								34198826	t		miannu	A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR.	SIGNOR-276659	0.253
QRICH1	protein	Q2TAL8	UNIPROT	WARS2	protein	Q9UGM6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269411	0.2
9-cis-retinoic acid	chemical	CHEBI:50648	ChEBI	RXR	proteinfamily	SIGNOR-PF44	SIGNOR	up-regulates activity	chemical activation			9606									18321241	t		miannu	Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma).	SIGNOR-259240	0.8
TWIST1	protein	Q15672	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255520	0.2
ASH1L	protein	Q9NR48	UNIPROT	NRXN1	protein	Q9ULB1	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000942								27229316	t		Gianni	Our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning.	SIGNOR-269056	0.262
DTNA	protein	Q9Y4J8	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255989	0.456
PRKCA	protein	P17252	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser101	AAPEAGAsPVEKEAP	-1									8034575	t		lperfetto	Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites.	SIGNOR-248909	0.72
calciol	smallmolecule	CHEBI:28940	ChEBI	vitamin D	smallmolecule	CHEBI:27300	ChEBI	up-regulates quantity	precursor of			9606		BTO:0001253							30080183	t		lperfetto	Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin	SIGNOR-270564	0.8
DAB2IP	protein	Q5VWQ8	UNIPROT	KRAS	protein	P01116	UNIPROT	down-regulates activity	gtpase-activating protein			9606									27858941	t		miannu	The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP.	SIGNOR-254746	0.497
VRK1	protein	Q99986	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr73	ADQTPTPtRFLKNCE	9606									15105425	t		gcesareni	Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level.	SIGNOR-124334	0.379
RPS14	protein	P62263	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262438	0.911
RPL36AL	protein	Q969Q0	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262493	0.781
UCHL3	protein	P15374	UNIPROT	Ubiquitin	proteinfamily	SIGNOR-PF89	SIGNOR	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270832	0.866
mTORC2	complex	SIGNOR-C2	SIGNOR	FBXW8	protein	Q8N3Y1	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser85	DVASRSRsPLAREGA	10090	BTO:0002572								23142081	t		miannu	MTORC2 stabilizes Fbw8 by phosphorylation at Ser86	SIGNOR-271940	0.268
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	phosphorylation			9606									19115199	t		lperfetto	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-217613	0.739
IGF1R	protein	P08069	UNIPROT	PDPK1	protein	O15530	UNIPROT	up-regulates	phosphorylation	Tyr376	DEDCYGNyDNLLSQF	9606									20044479	t		lperfetto	We have described that upon ligand binding, igf-1r directly interacts with and phosphorylates pdk1 at tyr373/376	SIGNOR-236544	0.348
DZIP3	protein	Q86Y13	UNIPROT	H2AC7	protein	P20671	UNIPROT	up-regulates activity	monoubiquitination	Lys119	IQAVLLPkKTESHHK	9606	BTO:0000007								18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271753	0.2
SMARCC1	protein	Q92922	UNIPROT	Muscle cell-specific SWI/SNF ARID1B variant	complex	SIGNOR-C482	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270709	0.823
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	IL6	protein	P05231	UNIPROT	up-regulates	transcriptional regulation			9606	BTO:0000801								20086235	f			Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2)	SIGNOR-254511	0.622
CAMK2A	protein	Q9UQM7	UNIPROT	CAMK2A	protein	Q9UQM7	UNIPROT	down-regulates	phosphorylation	Ser314	MLATRNFsGGKSGGN	9606									1324926	t		lperfetto	After removal of ca2+/calmodulin, the autonomous kinase undergoes a burst of inhibitory autophosphorylation at sites distinct from the autonomy site. Ca(2+)-independent autophosphorylation occurs within the calmodulin binding domain at thr305, thr306, and ser314	SIGNOR-17308	0.2
DLGAP5	protein	Q15398	UNIPROT	SHANK2	protein	Q9UPX8	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264599	0.463
PRKG1	protein	Q13976	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates	phosphorylation	Ser813	DIYSRRLsQETGLEI	9606									1377674	t		lperfetto	Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function	SIGNOR-18253	0.521
MAP2K2	protein	P36507	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates	phosphorylation	Thr202	HDHTGFLtEYVATRW	9606		BTO:0000142							1411546	t		gcesareni	The primary structure of mek, a protein kinase that phosphorylates the erk gene product	SIGNOR-19240	0.73
TSPOAP1	protein	O95153	UNIPROT	RIMS2	protein	Q9UQ26	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264368	0.2
FUBP1	protein	Q96AE4	UNIPROT	PMAIP1	protein	Q13794	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19637194	f		irozzo	FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In particular, elevated expression of the Bcl-2 family members Bik and Noxa was detected. 	SIGNOR-259128	0.2
SLC24A5	protein	Q71RS6	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	down-regulates quantity	relocalization			9606									30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264393	0.8
PLK1	protein	P53350	UNIPROT	RIOK2	protein	Q9BVS4	UNIPROT	up-regulates activity	phosphorylation	Ser335	TKEGSEFsFSDGEVA	-1									21880710	t		miannu	 Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. F urthermore, time-lapse imaging data show that overexpression of Rio2 but not Rio2 S3A results in a slowed metaphase-anaphase transition. Collectively, these findings strongly indicate that the Plk1-mediated phosphorylation of Rio2 regulates metaphase-anaphase transition during mitotic progression.	SIGNOR-262937	0.441
CSNK2A2	protein	P19784	UNIPROT	CCAR2	protein	Q8N163	UNIPROT	up-regulates activity	phosphorylation	Thr454	AAEAAPPtQEAQGET	9606									24962073	t		lperfetto	CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. |In our results, CK2alpha affected the|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1	SIGNOR-267667	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RXRA	protein	P19793	UNIPROT	down-regulates activity	phosphorylation	Thr82	HSMSVPTtPTLGFST	9606									17604322	t		lperfetto	In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 	SIGNOR-262960	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606		BTO:0000562							11069105	t		lperfetto	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-216623	0.391
SUCLA2	protein	Q9P2R7	UNIPROT	Succinyl-CoA ATP variant	complex	SIGNOR-C398	SIGNOR	form complex	binding			9606									32627745	t		miannu	Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS). 	SIGNOR-266262	0.986
PTPN11	protein	Q06124	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	dephosphorylation	Tyr896	EPKSPGEyVNIEFGS	9606									10660596	t		gcesareni	The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling.	SIGNOR-74860	0.893
1-[4-Amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-2-fluoroethanone	chemical	CID:644243	PUBCHEM	RPS6KA2	protein	Q15349	UNIPROT	down-regulates activity	chemical inhibition			10116	BTO:0002135								31505737	t		miannu	Since p90RSK was activated in the diabetic hearts in mice, we investigated whether FMK (an inhibitor of p90RSK) could protect INS-1 cells (a pancreatic β-cell line) from HG-induced β-cell dysfunction and glucotoxicity. 	SIGNOR-262231	0.8
CSNK2A2	protein	P19784	UNIPROT	EIF2B5	protein	Q13144	UNIPROT	up-regulates activity	phosphorylation	Ser717	LKEAEEEsSEDD	9606									11500362	t		llicata	Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro. 	SIGNOR-250989	0.377
PZP	protein	P20742	UNIPROT	MMP2	protein	P08253	UNIPROT	down-regulates activity	binding			-1									9344465	t		lperfetto	Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261804	0.335
SUN1	protein	O94901	UNIPROT	NXF1	protein	Q9UBU9	UNIPROT	up-regulates activity	binding			9606	BTO:0000567		SIGNOR-C303						28831067	t		lperfetto	SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1.	SIGNOR-263296	0.363
IRAK1	protein	P51617	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Ser293	FNTLAFPsMKRKDVV	9606	BTO:0000007								12496252	t		lperfetto	In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation	SIGNOR-96735	0.758
CIB2	protein	O75838	UNIPROT	TMC2	protein	Q8TDI7	UNIPROT	up-regulates activity	binding			10090	BTO:0004744								28663585	t		miannu	 Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia.	SIGNOR-269665	0.36
WNT5A	protein	P41221	UNIPROT	ROR1	protein	Q01973	UNIPROT	up-regulates	binding			9606									23151663	t		gcesareni	Ror1 and ror2 bind wnt5a.	SIGNOR-199644	0.737
GARS1	protein	P41250	UNIPROT	glycine	smallmolecule	CHEBI:15428	ChEBI	down-regulates quantity	chemical modification			9606									24898252	t		miannu	Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 	SIGNOR-270478	0.8
ZNRF1	protein	Q8ND25	UNIPROT	CAV1	protein	Q03135	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys39	MADELSEkQVYDAHT	9606	BTO:0000007								28593998	t		miannu	The ubiquitin ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation. ZNRF1 mediates CAV1 polyubiquitination at lysine 39 and promote CAV1 degradation to modulate TLR4-mediated immune response. 	SIGNOR-272327	0.373
RXRG	protein	P48443	UNIPROT	MBP	protein	P02686	UNIPROT	up-regulates quantity	transcriptional regulation												31390799	f		SimoneGraziosi	RXRγ gene silencing reduces the ability of the drugs to promote MBP expression.	SIGNOR-269266	0.2
ponatinib	chemical	CHEBI:78543	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									23430109	t		lperfetto	AP24534 also inhibited SRC (IC50: 5.4 nM) and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases (Table 1 and Table S1)	SIGNOR-261984	0.8
MECP2/SIN3A/HDAC complex	complex	SIGNOR-C360	SIGNOR	BDNF	protein	P23560	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0004102								14593184	t		Luana	Moreover, increased Bdnf transcription involves dissociation of the MeCP2–histone deacetylase–mSin3A repression complex from its promoter.	SIGNOR-265071	0.38
MAPK9	protein	P45984	UNIPROT	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation	Ser152	PASSVSSsPSPPFGH	9606									12151396	t		gcesareni	Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro.	SIGNOR-91067	0.346
KEL	protein	P23276	UNIPROT	EDN3	protein	P14138	UNIPROT	up-regulates activity	cleavage	Trp117	YCHLDIIwINTPEQT	-1									10438732	t		miannu	These data demonstrate that the Kell blood group protein is a proteolytic enzyme that processes big ET-3, generating ET-3, a potent bioactive peptide with multiple biological roles.	SIGNOR-256354	0.663
asparagine	smallmolecule	CHEBI:22653	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264753	0.7
PRKCD	protein	Q05655	UNIPROT	ADD2	protein	P35612	UNIPROT	unknown	phosphorylation	Ser726	KKKEKVEs	-1									8810272	t		lperfetto	Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites for PKC.	SIGNOR-248953	0.288
STK39	protein	Q9UEW8	UNIPROT	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation	Ser91	ASFHAYDsHTNTYYL	9606	BTO:0000007								21321328	t		miannu	 We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A).	SIGNOR-276308	0.596
CSNK2A1	protein	P68400	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	phosphorylation	Ser327	DPEMEEDsYDSFGEP	-1									9558331	t		llicata	In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites.	SIGNOR-250933	0.311
2-cyclohexyl-6-methoxy-N-(1-propan-2-yl-4-piperidinyl)-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine	chemical	CHEBI:95074	ChEBI	EHMT2	protein	Q96KQ7	UNIPROT	down-regulates activity	chemical inhibition			-1									26320100	t		miannu	 Using a small-molecule screen, we found that UNC0638, a selective inhibitor of EHMT1 and EHMT2 histone methyltransferases, induces γ-globin expression. 	SIGNOR-262240	0.8
PDPK1	protein	O15530	UNIPROT	PRKCE	protein	Q02156	UNIPROT	up-regulates	phosphorylation	Thr566	LNGVTTTtFCGTPDY	9606									11964154	t		llicata	In the present study, we analysed the contribution of the phosphoinositide-dependent kinase 1 (pdk-1) and pkcepsilon kinase activity in controlling the phosphorylation of thr(566) and ser(729). pdk-1 phosphorylation of the activation loop triggers autophosphorylation of the hydrophobic motif	SIGNOR-117320	0.553
TRADD	protein	Q15628	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	binding			9606									8612133	t		lperfetto	We show that tradd interacts strongly with rip;rip is a serinethreonine kinase that is recruited by tradd to tnfr1 in a tnf-dependent process.	SIGNOR-40043	0.935
HMGB1	protein	P09429	UNIPROT	HOXD11	protein	P31277	UNIPROT	up-regulates activity	binding			-1									8890171	t	2	miannu	We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.	SIGNOR-240559	0.296
CCP110	protein	O43303	UNIPROT	Centrosome_separation	phenotype	SIGNOR-PH177	SIGNOR	down-regulates				9606									12361598	f		miannu	Reduction in CP110 Protein Levels or Loss of CP110 Phosphorylation Promotes Centrosome Separation.	SIGNOR-265964	0.7
Set1-Ash2 HMT complex	complex	SIGNOR-C352	SIGNOR	H3-4	protein	Q16695	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606									12670868	t		miannu	 The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. 	SIGNOR-264483	0.2
6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide	chemical	CHEBI:92401	ChEBI	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258001	0.8
PHF2	protein	O75151	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	demethylation			9606									21532585	t		miannu	PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark.	SIGNOR-265343	0.2
RPS6KB1	protein	P23443	UNIPROT	PDPK1	protein	O15530	UNIPROT	down-regulates activity	phosphorylation	Ser549	VWRQRYQsHPDAAVQ	9606									35318320	t		miannu	 Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT.	SIGNOR-273844	0.714
FOXO1	protein	Q12778	UNIPROT	G6PC1	protein	P35575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22521266	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-197197	0.2
FYN	protein	P06241	UNIPROT	KCND3	protein	Q9UK17	UNIPROT	up-regulates activity	phosphorylation	Tyr108	GKLHYPRyECISAYD	9606	BTO:0000007								22198508	t		miannu	 These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels.	SIGNOR-276396	0.2
PRKCA	protein	P17252	UNIPROT	CSPG4	protein	Q6UVK1	UNIPROT	up-regulates activity	phosphorylation	Thr2252	YLRKRNKtGKHDVQV	9606	BTO:0002035								15504744	t		miannu	Protein kinase C (PKC)-alpha phosphorylation of recombinant NG2 cytoplasmic domain and phorbol ester-induced PKC-dependent phosphorylation of full-length NG2 expressed in U251 cells are both blocked by mutation of Thr(2256), identifying this residue as a primary phosphorylation site. PKC-alpha-mediated NG2 phosphorylation at Thr(2256) is therefore a key step for initiating cell polarization and motility.	SIGNOR-263162	0.2
ATF4	protein	P18848	UNIPROT	ASNS	protein	P08243	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002182								18940792	f		miannu	C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene.	SIGNOR-253838	0.637
MTOR	protein	P42345	UNIPROT	MAF1	protein	Q9H063	UNIPROT	down-regulates	phosphorylation	Ser68	PPQTSGLsPSRLSKS	9606			SIGNOR-C3						20516213	t		fstefani	The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly.	SIGNOR-165795	0.7
SMAD6	protein	O43541	UNIPROT	TAB1	protein	Q15750	UNIPROT	down-regulates	binding			9606									11737269	t		lpetrilli	Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads.	SIGNOR-112642	0.549
FADS3	protein	Q9Y5Q0	UNIPROT	long-chain fatty acyl-CoA(4-)	smallmolecule	CHEBI:83139	ChEBI	down-regulates quantity	chemical modification			9606									15189125	t		miannu	Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity.	SIGNOR-267909	0.8
CBX3	protein	Q13185	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	binding			9606									19111658	t		miannu	A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing.	SIGNOR-265324	0.2
CLK2	protein	P49760	UNIPROT	PTPN1	protein	P18031	UNIPROT	up-regulates activity	phosphorylation	Ser50	RNRYRDVsPFDHSRI	9606									10480872	t		gcesareni	The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation.	SIGNOR-70603	0.327
NCSTN	protein	Q92542	UNIPROT	APH1A	protein	Q96BI3	UNIPROT	up-regulates	binding			9606		BTO:0000142							12297508	t		gcesareni	We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch).	SIGNOR-93313	0.967
PRKACB	protein	P22694	UNIPROT	NGFR	protein	P08138	UNIPROT	up-regulates	phosphorylation	Ser303	PEGEKLHsDSGISVD	9606	BTO:0000938								12682012	t		llicata	Pka phosphorylates the p75 receptor and regulates its localization to lipid rafts. activation of camp?PKA Is required for translocation of p75ntr to lipid rafts, and for biochemical and biological activities of p75ntr, such as inactivation of rho and the neurite outgrowth.	SIGNOR-99755	0.609
Silmitasertib	chemical	CID:24748573	PUBCHEM	CSNK2A2	protein	P19784	UNIPROT	down-regulates activity	chemical inhibition			9606									21159648	t		Federica	In this study, we describe CX-4945, a potent and selective orally bioavailable small molecule inhibitor of CK2.	SIGNOR-261130	0.8
NLK	protein	Q9UBE8	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	phosphorylation			9606									20118921	t		gcesareni	Nlk-phosphorylated notch1icd is impaired in its ability to form a transcriptionally_ active_ ternary_ complex.	SIGNOR-163697	0.391
TOMM70	protein	O94826	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	up-regulates activity	binding			9534									12526792	t		miannu	The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting.	SIGNOR-261379	0.2
UBE2L3	protein	P68036	UNIPROT	NEDD4	protein	P46934	UNIPROT	up-regulates activity	ubiquitination			-1									19240029	t		miannu	Only UbcH5 and Related Class I E2s Support Ubiquitination of S5a—UbcH5 belongs to the Class I family of E2s which contains a catalytic core (UBC domain) without a distinct Ub binding domain (38). To test whether other Class I E2s can also support ubiquitination of S5a, we assayed the ubiquitination of S5a with UbcH7 and the E3s, Nedd4, or Parkin. With either of these E3s, UbcH7 supported ubiquitination of S5a (Fig. 8, A and B). In addition, another Class I E2, Ubc4, a close homolog of UbcH5, supported ubiquitination of S5a by the APC, a multimeric Ring finger E3 responsible for cell cycle progression through mitosis (39) (Fig. 8C). Thus, multiple Class I E2s can support ubiquitination of S5a by various types of E3s (Table 1).	SIGNOR-272735	0.56
ROCK1	protein	Q13464	UNIPROT	ARHGAP24	protein	Q8N264	UNIPROT	up-regulates activity	phosphorylation	Ser391	RSSMNNGsPTALSGS	9606	BTO:0000007								16862148	t		lperfetto	ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2).	SIGNOR-249309	0.444
RPS6KA5	protein	O75582	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates activity	phosphorylation	Ser212	DETERAYsFCGTIEY	9606									15568999	t		lperfetto	Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro.	SIGNOR-131387	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252825	0.908
WNT1	protein	P04628	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131574	0.781
GSK3B	protein	P49841	UNIPROT	PIAS1	protein	O75925	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser13	ELKQMVMsLRVSELQ	10090	BTO:0002268								26157031	t		miannu	We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. We found that GSK3β phosphorylation of PIAS1 provided a phosphodegron for HECTD2 targeting. 	SIGNOR-276924	0.338
CHUK	protein	O15111	UNIPROT	BCL3	protein	P20749	UNIPROT	up-regulates activity	phosphorylation	Ser454	PSPAPGGs	-1									28689659	t		miannu	Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA. 	SIGNOR-277363	0.439
POLR2L	protein	P62875	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding			9606									22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266151	0.904
MAPK1	protein	P28482	UNIPROT	CDC42EP1	protein	Q00587	UNIPROT	unknown	phosphorylation	Ser113	SPAPPAIsPIIKNAI	10090	BTO:0000944								22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262765	0.2
MAPKAPK2	protein	P49137	UNIPROT	EEF2K	protein	O00418	UNIPROT	unknown	phosphorylation	Ser377	PPLLRPLsENSGDEN	-1									12171600	t		miannu	Identification of Ser-377 as the site on eEF2 kinase phosphorylated in vitro by MAPKAP-K2, MAPKAP-K3 and MAPKAP-K5. Maximal phosphorylation of eEF2 kinase by MAPKAP-K2 (Figure 5) or MAPKAP-K5 (results not shown) had no effect on its activity.	SIGNOR-249710	0.358
ASPM	protein	Q8IZT6	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates quantity by expression	transcriptional regulation												16123590	f	 	 	Here, we report that downregulation of endogenous ASPM by siRNA decreases protein levels of endogenous BRCA1. ASPM localizes to the centrosome in interphase and to the spindle poles from prophase through telophase. These findings indicate that ASPM may be involved in mitotic spindle function, possibly, through regulation of BRCA1.	SIGNOR-253936	0.276
MAP3K2	protein	Q9Y2U5	UNIPROT	MAP2K5	protein	Q13163	UNIPROT	up-regulates				9606	BTO:0000007;BTO:0000782								11073940	f		gcesareni	Mekk2 activated bmk1/erk5 to a greater extent, which might correlate with a higher affinity mekk2-mek5 interaction. A dominant negative form of mek5 blocked the activation of bmk1/erk5 by mekk2	SIGNOR-84184	0.751
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates	phosphorylation	Ser242	NQRKAKRsLAPRFDL	9606									11152499	t		tpavlidou	We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity.	SIGNOR-85765	0.2
PRKACA	protein	P17612	UNIPROT	RAP1B	protein	P61224	UNIPROT	up-regulates	phosphorylation	Ser179	PGKARKKsSCQLL	9606									19651783	t		llicata	These results provide a mechanistic explanation for the differential effects of rap1 phosphorylation by pka on effector protein interaction. camp is one among several pathways leading to rap1 activation	SIGNOR-187410	0.504
HSP90AA1	protein	P07900	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates	binding			9606									21511880	t		gcesareni	We report the crucial underlying role of the intranuclear heat shock protein 90 molecular chaperone complex in pulsatile GR regulation. Pharmacological interference of heat shock protein 90 (HSP90) with geldanamycin during the intranuclear chaperone cycle completely ablated GR's cyclical activity, cyclical cAMP response element-binding protein (CREB) binding protein (CBP)/p300 recruitment, and the associated cyclical acetylation at the promoter region.	SIGNOR-251667	0.724
folic acid	smallmolecule	CHEBI:27470	ChEBI	dihydrofolate(2-)	smallmolecule	CHEBI:57451	ChEBI	up-regulates quantity	precursor of			9606	BTO:0000575								19706381	t		lperfetto	However, since the synthesis of folic acid (FA, pteroylglutamic acid) as a provitamin in 1945, DHFR has taken on another role: reduction of FA to 7,8-DHF (Fig. 1)	SIGNOR-268263	0.8
RNF8	protein	O76064	UNIPROT	L3MBTL2	protein	Q969R5	UNIPROT	up-regulates activity	ubiquitination			9606									31225475	t		miannu	L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.	SIGNOR-266787	0.244
HIF1AN	protein	Q9NWT6	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	hydroxylation	Asn2022	INSHADVnAVDDLGK	9606									18299578	t		gcesareni	We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation.	SIGNOR-161061	0.565
PRKACA	protein	P17612	UNIPROT	PLIN1	protein	O60240	UNIPROT	down-regulates activity	phosphorylation	Ser81	EPVVRRLsTQFTAAN	10090	BTO:0000944								11751901	t		miannu	PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276)	SIGNOR-250492	0.482
PLK1	protein	P53350	UNIPROT	CCNB1	protein	P14635	UNIPROT	up-regulates activity	phosphorylation	Ser147	EDLCQAFsDVILAVN	9606	BTO:0000567								11242082	t		lperfetto	Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation.	SIGNOR-105719	0.919
FLT3	protein	P36888	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates activity				9606									28213513	f			Our finding that RUNX1 protein levels are dependent on FLT3-ITD signaling in AML cells and that, together, they synergize to generate AML. […]Our work demonstrated that Tyr phosphorylation within the ID region of RUNX1 is critical for its oncogenic potential,	SIGNOR-256307	0.37
purmorphamine	chemical	CHEBI:63053	ChEBI	SMO	protein	Q99835	UNIPROT	up-regulates	chemical activation			9606									17419683	t		gcesareni	The activity of smo toward gi was stimulated severalfold with the synthetic agonist purmorphamine and inhibited almost completely by cyclopamine and other antagonists of shh.	SIGNOR-154282	0.8
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser180	GSSASFIsDTFSPYT	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248515	0.386
TWIST2	protein	Q8WVJ9	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255499	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GLI1	protein	P08151	UNIPROT	down-regulates activity	phosphorylation	Thr374	PGCTKRYtDPSSLRK	9534	BTO:0000298								16293631	t		miannu	 Here, we report that activation of PKA retains Gli1 in the cytoplasm.Mutation analysis identifies Thr374 as a major PKA site determining Gli1 protein localization. 	SIGNOR-276044	0.2
CTNNB1	protein	P35222	UNIPROT	SOX2	protein	P48431	UNIPROT	up-regulates activity	binding			10090	BTO:0002572	BTO:0002181							24482235	t		flangone	The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes.	SIGNOR-242087	0.697
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	NOS2	protein	P35228	UNIPROT	up-regulates	transcriptional regulation					BTO:0001103							20219869	f			Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6.	SIGNOR-256250	0.447
PRKCZ	protein	Q05513	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser45	GATTTAPsLSGKGNP	9606	BTO:0002181								25660024	t		miannu	 Yap and β-catenin are direct substrates of PKCζ. Similar MS/MS analysis to map the sites phosphorylated in β-catenin by PKCζ identified S45 and several sites of low abundance that included S552 and S675 (Figure S3C). 	SIGNOR-276878	0.582
MTOR	protein	P42345	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	form complex	binding			9606									25628925	t		lperfetto	Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)	SIGNOR-205615	0.897
CDK2	protein	P24941	UNIPROT	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr234	SFKKQEKtPKTPKGP	9606			SIGNOR-C16						12058066	t		gcesareni	Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association.	SIGNOR-89609	0.578
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	EDC3	protein	Q96F86	UNIPROT	down-regulates activity	phosphorylation	Ser161	SFRRRHNsWSSSSRH	10029	BTO:0000246								20051463	t		miannu	Together these data show that recombinant EDC3 co-immunoprecipitates with endogenous 14-3-3 isoforms in response to insulin in vivo and is phosphorylated at the putative 14-3-3 binding and AKT phosphorylation site Ser-161. Collectively, these data suggest that Ser-161 in EDC3 is phosphorylated in response to insulin principally by AKT and that this subsequently triggers 14-3-3 binding. Constitutive 14-3-3 binding to EDC3 alters p-body morphology and function	SIGNOR-262631	0.2
CHCHD1	protein	Q96BP2	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261460	0.666
KDM4B	protein	O94953	UNIPROT	BBC3	protein	Q96PG8	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001109								28073943	f		miannu	 JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. 	SIGNOR-263733	0.2
ATM	protein	Q13315	UNIPROT	PEX5	protein	P50542	UNIPROT	up-regulates activity	phosphorylation	Ser141	DYNETDWsQEFISEV	9606	BTO:0000007								26344566	t			Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy. 	SIGNOR-262792	0.511
MRTFB	protein	Q9ULH7	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								14565952	t		llicata	MKL2 binds to and activates SRF similar to myocardin and MKL1.	SIGNOR-237671	0.2
RPS6KA1	protein	Q15418	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606		BTO:0001103							21798082	t		lperfetto	Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization.	SIGNOR-175687	0.367
MAPK1	protein	P28482	UNIPROT	GORASP1	protein	Q9BQQ3	UNIPROT	down-regulates activity	phosphorylation	Ser274	DPLPGPGsPSHSAPD	10116	BTO:0000951								15834132	t		miannu	Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events. 	SIGNOR-262841	0.273
CALM2	protein	P0DP24	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	up-regulates	binding			9606	BTO:0000782	BTO:0000142							9822657	t		miannu	The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk.	SIGNOR-266329	0.556
PRKACA	protein	P17612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606									10949026	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.	SIGNOR-81137	0.521
KRN-633	chemical	CID:9549295	PUBCHEM	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193588	0.8
HIC1	protein	Q14526	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates quantity by repression	binding			9606	BTO:0000815								24067369	t	 	miannu	 HIC1 interacts with the DNA binding domain of STAT3 and suppresses the binding of STAT3 to its target gene promoters. HIC1 C-terminal domain binds to STAT3. HIC1 mutant defective in STAT3 interaction reduced its repressive effect on STAT3 DNA binding activity, the reporter activity and gene expression of the VEGF and c-Myc genes, and cell growth in MDA-MB 231 cells. 	SIGNOR-254246	0.375
NTRK2	protein	Q16620	UNIPROT	NTRK2	protein	Q16620	UNIPROT	up-regulates activity	phosphorylation	Tyr817	LAKASPVyLDILG	10090	BTO:0000944								10533983	t		miannu	TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. the Y785F mutation abolish the BDNF-inducible tyrosine phosphorylation of PLCy, but receptors containing this mutation are also defective in the ability to induce the tyrosine phosphorylation of the c-cbl proto-oncogene product.	SIGNOR-250312	0.2
NMDA receptor_2B	complex	SIGNOR-C348	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264133	0.7
CSNK1E	protein	P49674	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser45	GATTTAPsLSGKGNP	9606	BTO:0000007								12176352	t		gcesareni	Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces Beta-catenin phosphorylation at a single site: serine 45 (S45).	SIGNOR-244102	0.643
CSRP3	protein	P50461	UNIPROT	MYOG	protein	P15173	UNIPROT	up-regulates activity	binding			10090	BTO:0004058								9234731	t	2	miannu	we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements.	SIGNOR-241113	0.535
2-(2-amino-3-methoxyphenyl)chromen-4-one	chemical	CHEBI:77954	ChEBI	MAP2K1	protein	Q02750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205743	0.8
MAPK12	protein	P53778	UNIPROT	MAPK12/CARM1	complex	SIGNOR-C218	SIGNOR	form complex	binding												29681515	t		apalma	Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated	SIGNOR-255981	0.346
CKM complex	complex	SIGNOR-C406	SIGNOR	SMAD1	protein	Q15797	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser195	PNSSYPNsPGSSSST	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-273140	0.346
Food intake	phenotype	SIGNOR-PH152	SIGNOR	vitamin D	smallmolecule	CHEBI:27300	ChEBI	up-regulates quantity				9606									30080183	f		lperfetto	Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin. Vitamin D can also be obtained from nutrition. 	SIGNOR-270565	0.7
ROCK1	protein	Q13464	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates activity	phosphorylation			9606									15068801	t		gcesareni	Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter.	SIGNOR-123717	0.301
IRF2	protein	P14316	UNIPROT	TAP1	protein	Q03518	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15778351	f		miannu	 We also show that this cytokine-dependent expression of TAP1 transcripts depends on STAT1 and IFN regulatory factor-2 (IRF-2), but not on IRF-1, and provide evidence that IRF-2 constitutively binds to the TAP1 gene promoter and enhances TAP1 promoter activity. 	SIGNOR-254530	0.2
CSNK2A1	protein	P68400	UNIPROT	PPP1R2	protein	P41236	UNIPROT	up-regulates	phosphorylation	Ser121	YRIQEQEsSGEEDSD	9606									9405437	t		gcesareni	Recombinant inh2 was phosphorylated by kinases in cytosols prepared from g1 and s phase cells. The amount of inh2 kinase attributed to casein kinase 2, based on inhibition by heparin, increased 2.6-fold from g1 to s phase	SIGNOR-53857	0.311
RUSC1	protein	Q9BVN2	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates	binding			9606									15024033	f		miannu	Overexpression studies in PC12 cells indicate that Nesca facilitates neurotrophin-dependent neurite outgrowth at nonsaturating doses of nerve growth factor (NGF).	SIGNOR-272776	0.7
TUT1	protein	Q9H6E5	UNIPROT	mRNA_polyadenylation	phenotype	SIGNOR-PH200	SIGNOR	up-regulates				9606									21102410	f		miannu	Star-PAP is a poly (A) polymerase (PAP) that is putatively required for 3'-end cleavage and polyadenylation of a select set of pre-messenger RNAs (mRNAs)	SIGNOR-272322	0.7
NAT8L	protein	Q8N9F0	UNIPROT	acetyl-CoA(4-)	smallmolecule	CHEBI:57288	ChEBI	down-regulates quantity	chemical modification			9606									19524112	t		miannu	The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA.	SIGNOR-267522	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FANCA	protein	O15360	UNIPROT	unknown	phosphorylation	Ser1149	CLRSRDPsLMVDFIL	-1									11855836	t			FANCA is phosphorylated at Ser1149 by Akt. The biological significance of FANCA phosphorylation and its regulation by Akt remains unclear at this time.	SIGNOR-251476	0.2
CAMK2D	protein	Q13557	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity	phosphorylation	Thr642	RSVKRNStVDCNGVV	9606	BTO:0000938								32611770	t		lperfetto	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275792	0.285
TBK1	protein	Q9UHD2	UNIPROT	DDAH2	protein	O95865	UNIPROT	down-regulates activity	phosphorylation	Thr211	DHPYASLtLPDDAAA										33850055	t		lperfetto	TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o	SIGNOR-275647	0.2
ID4	protein	P47928	UNIPROT	SOX2	protein	P48431	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21531766	f		miannu	We found that ID4 enhanced SOX2 protein expression by suppressing microRNA-9* (miR-9*), which can repress SOX2 by targeting its 3'-untranslated region. 	SIGNOR-255180	0.421
MAPK3	protein	P27361	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Ser441	SPRRFIGsPRTPVSP	10116									15774499	t		lperfetto	Thr 421/Ser 424 have been reported to be targeted by ERK1, 2 (39), JNK or p38 MAPKs (36). Interestingly, with a comparable kinetics, FSH represses ERK1, 2 constitutive phosphorylation in Sertoli cells isolated from 19-d-old rats	SIGNOR-111515	0.59
HES5	protein	Q5TA89	UNIPROT	ATOH1	protein	Q92858	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938								30030829	f		lperfetto	The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 	SIGNOR-265145	0.417
COLGALT1	protein	Q8NBJ5	UNIPROT	COL1A2	protein	P08123	UNIPROT	up-regulates activity	glycosylation			-1									19075007	t			Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261153	0.404
PRKCA	protein	P17252	UNIPROT	MEP1B	protein	Q16820	UNIPROT	down-regulates quantity	phosphorylation	Ser687	KKYRERMsSNRPNLT	9534	BTO:0001538								12941954	t		miannu	These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.	SIGNOR-263172	0.2
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation			10090	BTO:0002572								18423396	t		lperfetto	Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation.	SIGNOR-252851	0.908
PSMA2	protein	P25787	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263367	0.846
PPARG	protein	P37231	UNIPROT	NR1D1	protein	P20393	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000011								12821652	t		miannu	Mutations of the 5' or 3' half-sites of the response element totally abrogated PPARgamma binding and transcriptional activation, identifying this site as a novel type of functional PPARgamma response element. Finally, ectopic expression of Rev-Erbalpha in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARgamma ligand rosiglitazone. These results identify Rev-Erbalpha as a target gene of PPARgamma in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation.	SIGNOR-268022	0.281
DDX17	protein	Q92841	UNIPROT	RNA helicases DDX5/DDX17	complex	SIGNOR-C34	SIGNOR	form complex	binding			9606		BTO:0000887;BTO:0001103							17011493	t		lperfetto	We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod.	SIGNOR-149961	0.434
SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	PIM2	protein	Q9P1W9	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269241	0.27
UBE2I	protein	P63279	UNIPROT	ZHX1	protein	Q9UKY1	UNIPROT	up-regulates quantity by stabilization	sumoylation	Lys626	KKKSKALkEEKMEID	9606	BTO:0000007								23686912	t		miannu	Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. The sumoylation of zinc‐fingers and homeoboxes 1 (ZHX1) by ubc9 regulates its stability and transcriptional repression activity. However, in the current work, we demonstrated that ZHX1 was only SUMOylated by SUMO1. 	SIGNOR-263901	0.465
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PDE3B	protein	Q13370	UNIPROT	up-regulates activity	phosphorylation	Ser318	CKIFRRPsLPCISRE	10090	BTO:0000011								10454575	t		gcesareni	PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B.	SIGNOR-248027	0.2
RXRA	protein	P19793	UNIPROT	CPT1B	protein	Q92523	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15356291	f		miannu	 Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1beta promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1beta gene promoter by MEF2C and PPARalpha-RXRalpha, a precise arrangement of its binding sites was essential.	SIGNOR-254582	0.2
HDAC2	protein	Q92769	UNIPROT	ZNF318	protein	Q5VUA4	UNIPROT	up-regulates activity	binding			9606	BTO:0001321								16469430	t		Monia	A central domain of TZF is required for repression of AR-mediated transactivation. The results revealed that HDAC2 was coimmunoprecipitated with TZF (Fig. 6A), These results indicate that AR, TZF and HDAC2 form a ternary complex during the repression of AR-mediated transactivation.	SIGNOR-261188	0.335
LPAR3	protein	Q9UBY5	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256890	0.434
SOX9	protein	P48436	UNIPROT	PRAME	protein	P78395	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000849								19273910	f		miannu	 Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. 	SIGNOR-255191	0.323
AKT1	protein	P31749	UNIPROT	HTRA2	protein	O43464	UNIPROT	down-regulates	phosphorylation	Ser212	RVRVRLLsGDTYEAV	9606									17311912	t		lperfetto	Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212	SIGNOR-252500	0.329
CRBN	protein	Q96SW2	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								31591562	t		miannu	CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs.When thalidomide binds to CRBN, substrate specificity of CRL4CRBN is altered and CRBN neomorphically binds to ∆Np63, TAp63 and other neosubstrates and ubiquitinates them for proteasomal degradation.	SIGNOR-272214	0.2
serotonin(1+)	smallmolecule	CHEBI:350546	ChEBI	HTR1E	protein	P28566	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257519	0.8
MAPK1	protein	P28482	UNIPROT	TFCP2	protein	Q12800	UNIPROT	down-regulates	phosphorylation	Ser291	TYVNNSPsPGFNSSH	9606									19237534	t		lperfetto	We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309.	SIGNOR-184168	0.34
SMARCC1	protein	Q92922	UNIPROT	Muscle cell-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C483	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex.	SIGNOR-270736	0.814
CAMK2A	protein	Q9UQM7	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	up-regulates activity	phosphorylation	Ser362	FYTLNGSsVDSQPQS	9606	BTO:0004553								24614225	t		gianni	NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity.	SIGNOR-266442	0.311
TEX12	protein	Q9BXU0	UNIPROT	Synaptonemal_complex	complex	SIGNOR-C351	SIGNOR	form complex	binding			9606									22394509	t		miannu	The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region.	SIGNOR-264203	0.64
PCBP2	protein	Q15366	UNIPROT	ITCH	protein	Q96J02	UNIPROT	up-regulates activity	binding			9606	BTO:0002181								19881509	t		Giorgia	Only AIP4 associated with PCBP2 and caused MAVS degradation. The interaction between PCBP2 and AIP4 was abrogated when the linker region or WB2 of PCBP2 was deleted, which confirmed our previous data indicating that this region was critical for PCBP2-mediated degradation of MAVS	SIGNOR-260361	0.599
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser516	GDRSGYSsPGSPGTP	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249352	0.729
CEBPB	protein	P17676	UNIPROT	STAR	protein	P49675	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003697								18583320	t	 	 	Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells.	SIGNOR-254046	0.374
TRADD	protein	Q15628	UNIPROT	FADD	protein	Q13158	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								8565075	t		lperfetto	The strong interaction between tradd and fadd occurs via their death domains.	SIGNOR-39951	0.774
CAMK4	protein	Q16566	UNIPROT	PHB2	protein	Q99623	UNIPROT	down-regulates	phosphorylation	Ser91	RARPRKIsSPTGSKD	9606		BTO:0000887							21689744	t		lperfetto	Here we show that calcium/calmodulin-dependent kinase iv (camk iv) specifically binds to the c terminus of phb2 and phosphorylates phb2 at serine 91. Camk iv effectively decreased phb2-mediated repression of mef2 activity through phosphorylation	SIGNOR-174437	0.345
CSNK2A1	protein	P68400	UNIPROT	SEC63	protein	Q9UGP8	UNIPROT	up-regulates activity	phosphorylation	Ser748	DSEGFEDsFEEEEEE	9606	BTO:0000599								23287549	t		lperfetto	Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62.	SIGNOR-265271	0.295
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	proline	smallmolecule	CHEBI:26271	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270429	0.8
CSNK2B	protein	P67870	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Thr88	KHLVALYtRDEHFAI	-1									8349691	t		llicata	These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1.	SIGNOR-251076	0.324
NTRK3	protein	Q16288	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	binding			9606	BTO:0000938								10235685	t		gcesareni	Unglycosylated trka core protein is phosphorylated even in the absence of ligand stimulation and displays constitutive kinase activity as well as constitutive interaction with the signaling molecules shc and plc-gamma.	SIGNOR-67404	0.602
MDM2	protein	Q00987	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression				9606									18292944	f		amattioni	Overexpression of hdm2 resulted in a decrease in the level of p21waf1	SIGNOR-160977	0.664
Caspase 7 complex	complex	SIGNOR-C232	SIGNOR	PARP1	protein	P09874	UNIPROT	down-regulates	cleavage			9606									11058599	t		amattioni	Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis.	SIGNOR-256470	0.708
NFYC	protein	Q13952	UNIPROT	GFI1B	protein	Q5VTD9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19965638	f	 	miannu	HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. 	SIGNOR-254433	0.305
AIM2 inflammasome	complex	SIGNOR-C222	SIGNOR	Caspase 1 complex	complex	SIGNOR-C220	SIGNOR	up-regulates activity	cleavage												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256382	0.2
etoposide	chemical	CHEBI:4911	ChEBI	TOP2B	protein	Q02880	UNIPROT	down-regulates activity	chemical inhibition			9606									16101488	t		miannu	Etoposide is an important chemotherapeutic agent that is used to treat a wide spectrum of human cancers. It has been in clinical use for more than two decades and remains one of the most highly prescribed anticancer drugs in the world. The primary cytotoxic target for etoposide is topoisomerase II. 	SIGNOR-259326	0.8
belinostat	chemical	CHEBI:61076	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257959	0.8
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr463	MLAGVSEyELPEDPR	10116	BTO:0003293								19224897	t		lperfetto	This second-stage autophosphorylation occurs on Y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of Y463 in the juxtamembrane region, Y766 in the C-terminal tail, and Y585 in the kinase insert region	SIGNOR-235762	0.2
PPM1L	protein	Q5SGD2	UNIPROT	MAP3K7	protein	O43318	UNIPROT	down-regulates activity	dephosphorylation			-1									12556533	t		miannu	Co-immunoprecipitation experiments indicated that PP2Cepsilon associates stably with TAK1 and attenuates the binding of TAK1 to MKK4 or MKK6.|PP2Cepsilon dephosphorylated TAK1 in vitro.	SIGNOR-277114	0.604
STAT1	protein	P42224	UNIPROT	KRT17	protein	Q04695	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21796151	f		miannu	 IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms.	SIGNOR-255233	0.2
trametinib	chemical	CHEBI:75998	ChEBI	MAP2K1	protein	Q02750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192823	0.8
sildenafil	chemical	CHEBI:9139	ChEBI	PDE5A	protein	O76074	UNIPROT	down-regulates activity	chemical inhibition			-1									10385692	t		Luana	Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds.	SIGNOR-258343	0.8
BCL2	protein	P10415	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606									1286168	f		lperfetto	Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis	SIGNOR-249611	0.7
GRK1	protein	Q15835	UNIPROT	RHO	protein	P08100	UNIPROT	up-regulates activity	phosphorylation	Ser338	DEASATVsKTETSQV	-1									8617805	t			That light-dependent phosphorylation of Rho is mediated primarily by RK. Addition of an inhibitory antibody against rhodopsin kinase (RK) lowered phosphorylation at Ser334, Ser338, and Ser343, without changing the ratio between phosphorylation sites. upon illumination, Ser334c, Ser338, and Ser343 are phosphorylated.	SIGNOR-251190	0.922
MAP3K5	protein	Q99683	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates	phosphorylation	Ser98	GGRRPGTsPALLQGT	9606									17325029	t		lperfetto	P21cip1 is phosphorylated in vitro by both ask1 and jnk1 at s98. /phosphorylation of p21cip1 at s98, which in vivo appears to be regulated by ask1, may therefore mediate negative feedback in the ask1 signaling pathway.	SIGNOR-153440	0.575
CHUK	protein	O15111	UNIPROT	CREBBP	protein	Q92793	UNIPROT	up-regulates	binding			9606									12789342	t		gcesareni	Ikk-alpha interacts with creb-binding protein and in conjunction with rel a is recruited to nf-kappab-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone h3.	SIGNOR-101539	0.533
TYK2	protein	P29597	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation			9606									10542297	t		lperfetto	Stat3 activation requires kinase function of tyk2.	SIGNOR-71781	0.676
MAPK8	protein	P45983	UNIPROT	MFN2	protein	O95140	UNIPROT	down-regulates quantity	phosphorylation	Ser27	HMAEVNASPLKHFVT	9606	BTO:0001938								22748923	t		Barakat	We demonstrate that a critical component of the mitochondrial fusion apparatus, the mitofusin Mfn2, is a target for phosphorylation in response to a variety of cellular stresses. We provide direct evidence that JNK mediates this phosphorylation.	SIGNOR-274138	0.441
VRK1	protein	Q99986	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	unknown	phosphorylation			9606									17938195	t		gcesareni	We show that histone h3 is phosphorylated by vaccinia-related kinase 1 (vrk1). Direct phosphorylation of thr3 and ser10 in h3 by vrk1 both in vitro and in vivo was observed. Loss of vrk1 activity was associated with a marked decrease in h3 phosphorylation during mitosis.	SIGNOR-265371	0.2
PRKCB	protein	P05771	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser370	PAVPPRPsADLILNR	9606									12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89209	0.549
PPP3CC	protein	P48454	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									18177723	f		lperfetto	Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy 	SIGNOR-251735	0.2
ABL1	protein	P00519	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	phosphorylation	Tyr1197	STAENAEyLRVAPQS	9606									16943190	t		lperfetto	we show that activated Abl phosphorylates the EGFR primarily on tyrosine 1173Furthermore, we show that activated Abl allows the ligand-activated EGFR to escape Cbl-dependent down-regulation by inhibiting the accumulation of Cbl at the plasma membrane in response to epidermal growth factor stimulation and disrupting the formation of the EGFR.Cbl complex without affecting Cbl protein stability. These findings reveal a novel role for Abl in promoting increased cell-surface expression of the EGFR and suggest that Abl/EGFR signaling may cooperate in human	SIGNOR-149277	0.429
NuA4 complex	complex	SIGNOR-C459	SIGNOR	H4C1	protein	P62805	UNIPROT	down-regulates activity	acetylation			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269286	0.2
WNT9B	protein	O14905	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-132111	0.607
PPM1L	protein	Q5SGD2	UNIPROT	ERN1	protein	O75460	UNIPROT	up-regulates activity	dephosphorylation			9606									24327956	t		miannu	Overall, our study establishes that PP2Ce mediated IRE1 regulation in ER stress signaling is a potentially important molecular basis for its genetic contribution to metabolic syndrome.Lin et al. [36] have reported that different durations and composition of ER stress signaling pathways can dictate cell fate and the balance between survival and death.|Recombinant wildtype PP2Ce, but not a phosphatase-dead mutant (PP2Ce-D302A), effectively dephosphorylated the phosphor-Ser724 site of IRE1\u03b1 protein (p-IRE1\u03b1)  (A).	SIGNOR-277074	0.315
CHUK	protein	O15111	UNIPROT	MAP3K14	protein	Q99558	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr559	TGDYIPGtETHMAPE	9606	BTO:0000776								20501937	t		lperfetto	Upon activation by nik, ikkalfa phosphorylates nik, triggering its proteolysis.	SIGNOR-165622	0.684
TRIM27	protein	P14373	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates				9606		BTO:0000671							12807881	f	inferred from 70% of family members	miannu	We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38.	SIGNOR-269915	0.275
FYN	protein	P06241	UNIPROT	DCBLD2	protein	Q96PD2	UNIPROT	up-regulates activity	phosphorylation	Tyr677	LPITGPEyATPIIMD	-1									23770091	t	done	miannu	Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding.	SIGNOR-273943	0.357
BAP1	protein	Q92560	UNIPROT	CDKN2B	protein	P42772	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									26470845	t		lperfetto	Since we found that ASXL1 and BAP1 both are enriched at the INK4B locus, our results suggest that activation of the INK4B locus requires ASXL1/BAP1-mediated deubiquitinylation of H2AK119ub1.	SIGNOR-241656	0.2
PPP2CA	protein	P67775	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	down-regulates activity	dephosphorylation	Ser472	RPHFPQFsYSASGRE	9606									18160256	t			Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248653	0.725
RPS6KA1	protein	Q15418	UNIPROT	YBX1	protein	P67809	UNIPROT	up-regulates	phosphorylation	Ser102	NPRKYLRsVGDGETV	9606	BTO:0000150								19036157	t		lperfetto	We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue.	SIGNOR-182497	0.56
nintedanib	chemical	CHEBI:85164	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			-1									18559524	t		Luana	In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers.	SIGNOR-257799	0.8
HDAC4	protein	P56524	UNIPROT	MMP13	protein	P45452	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0005173								17656568	f	 	miannu	 We have hypothesized that histone deacetylases (HDACs) are involved with PTH-induced MMP-13 gene expression in the osteoblastic cell line, UMR 106-01. We have shown that PTH profoundly regulates HDAC4 in UMR 106-01 cells through a PKA-dependent pathway, leading to removal of HDAC4 from the MMP-13 promoter and its enhanced transcription. 	SIGNOR-254235	0.333
PDX1	protein	P52945	UNIPROT	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000627								8866550	f	inferred from family member	miannu	 The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription.	SIGNOR-267798	0.59
CTNNB1	protein	P35222	UNIPROT	TCF4	protein	P15884	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								11713476	t		amattioni	beta-catenin interacts with the TCF/Lef family transcription factors.	SIGNOR-178042	0.677
ERG	protein	P11308	UNIPROT	PIM1	protein	P11309	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22140532	f	 	miannu	 ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability.	SIGNOR-254065	0.2
CSNK2A1	protein	P68400	UNIPROT	TELO2	protein	Q9Y4R8	UNIPROT	down-regulates	phosphorylation	Ser491	GSDSDLDsDDEFVPY	9606									23263282	t		lperfetto	Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. Here, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2)	SIGNOR-200206	0.2
UGP2	protein	Q16851	UNIPROT	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	down-regulates quantity	chemical modification			9606									8631325	t		miannu	UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi.	SIGNOR-267926	0.8
RIPK2	protein	O43353	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	up-regulates activity				9606				SIGNOR-C14					16493424	f		miannu	In the case of NOD2, activation of RICK leads to K63 (Lys63)-linked polyubiquitylation of IKKgamma, the scaffold of the inhibitor of NF-kappaB (IkappaB)-kinase complex (the IKK complex), which also consists of IKKalpha and IKKbeta. This is followed by the phosphorylation of IKKbeta, as well as the phosphorylation of IkappaB and the release of nuclear factor-kappaB (NF-kappaB) for translocation to the nucleus. So, in activating the IKK complex, RICK either activates an E3 ubiquitin ligase that promotes K63-linked polyubiquitylation or inhibits an enzyme (such as cylindromatosis protein, CYLD) that de-ubiquitylates proteins that are modified with K63-linked polyubiquitin, so RICK does not require its own kinase activity for this function.	SIGNOR-252413	0.664
PPARA	protein	Q07869	UNIPROT	AQP3	protein	Q92482	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003204								17150915	f		miannu	 To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA.	SIGNOR-255045	0.302
IRX1	protein	P78414	UNIPROT	BPI	protein	P17213	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002392								20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 	SIGNOR-261652	0.2
ASPG	protein	Q86U10	UNIPROT	L-asparagine zwitterion	smallmolecule	CHEBI:58048	ChEBI	down-regulates quantity	chemical modification			9606									24657844	t		miannu	Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia.	SIGNOR-267537	0.8
FGG	protein	P02679	UNIPROT	Platelet_aggregation	phenotype	SIGNOR-PH81	SIGNOR	up-regulates													16418530	f		lperfetto	In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation.	SIGNOR-253373	0.7
APOBEC3A	protein	P31941	UNIPROT	Clearance_of_foreign intracellular_DNA	phenotype	SIGNOR-PH132	SIGNOR	up-regulates				9606									29367246	f		lperfetto	The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24).	SIGNOR-261332	0.7
SERPINA1	protein	P01009	UNIPROT	F12	protein	P00748	UNIPROT	down-regulates activity	binding			9606		BTO:0000131							26707513	t		lperfetto	C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1). 	SIGNOR-263515	0.337
MARS1	protein	P56192	UNIPROT	Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	form complex	binding			9606									32644155	t		miannu	In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes).	SIGNOR-270352	0.2
nintedanib	chemical	CHEBI:85164	ChEBI	FGFR4	protein	P22455	UNIPROT	down-regulates activity	chemical inhibition			-1									18559524	t		Luana	In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers.	SIGNOR-257803	0.8
JQ1	chemical	CHEBI:137113	ChEBI	BRD3	protein	Q15059	UNIPROT	down-regulates activity	chemical inhibition			-1									20871596	t		lperfetto	Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. 	SIGNOR-261988	0.8
SMAD6	protein	O43541	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates activity	binding			9606									22298955	t	Create a non-functional complex with smad4 and competes with R-smad.	lperfetto	On the other hand, Smad6 competes with R-Smad and forms a non-functional complex with Smad4, which will inhibit BMP signaling in bone formation. Smad6 is involved in a negative feedback loop regulating BMP signaling and is required to limit BMP signaling during endochondral bone formation.	SIGNOR-195648	0.556
COL4A3	protein	Q01955	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates activity	binding												35267698	t		lperfetto	Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23].	SIGNOR-272351	0.41
beta-D-fructofuranose 2,6-bisphosphate	smallmolecule	CHEBI:28602	ChEBI	PFKP	protein	Q01813	UNIPROT	up-regulates activity	binding			9606									19454274	t			The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux	SIGNOR-267268	0.8
DCC	protein	P43146	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	binding			9606									15494734	t		miannu	Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling.	SIGNOR-268372	0.516
FLT3	protein	P36888	UNIPROT	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	up-regulates activity				9606	BTO:0002144								28194038	f			Here, we report that FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity	SIGNOR-259982	0.7
MAPK3	protein	P27361	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates	phosphorylation	Ser21	PMSSHLQsPPHAPSS	9606	BTO:0000876								14701740	t		lperfetto	Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21.	SIGNOR-120570	0.38
LRFN5	protein	Q96NI6	UNIPROT	PTPRD	protein	P23468	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								27225731	t		miannu	SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1). 	SIGNOR-264086	0.281
PKN1	protein	Q16512	UNIPROT	PKN1	protein	Q16512	UNIPROT	up-regulates activity	phosphorylation	Ser374	GLYSRSGsLSGRSSL	-1									10467162	t		lperfetto	Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect.	SIGNOR-249021	0.2
NDUFA11	protein	Q86Y39	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)	SIGNOR-262142	0.8
MYD88	protein	Q99836	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates activity	binding			9606									28404732	t		miannu	In innate immunity, nearly all Toll-like receptors (TLRs), as well as the receptors of the interleukin 1 (IL-1) family of cytokines, initiate signaling by recruiting the adaptor protein MyD88. This is followed by the interaction of IL-1-receptor (IL-R)-associated kinase 4 (IRAK4) with MyD88 and then the interaction of other IRAK family members with IRAK4, to form an oligomeric complex, termed the Myddosome (8, 9). IRAK1 and IRAK2 can then interact with TRAF6 (10, 11) and induce TRAF6 dimerization (12), which triggers the activation of its E3 ligase activity	SIGNOR-260160	0.92
IL3	protein	P08700	UNIPROT	IL3RA	protein	P26951	UNIPROT	up-regulates	binding			9606									11700046	t		gcesareni	The results demonstrate that both the association and dissociation rates for the binding of il-3 to the il-3ralpha are altered by truncation and by amino acid substitution at individual sites. Intracellular signaling studies using k116w and e43n demonstrate that differences in the il-3alpha binding characteristics are reflected in magnitude and kinetics of stat5 phosphorylation.	SIGNOR-111404	0.884
NXPH1	protein	P58417	UNIPROT	NRXN1	protein	Q9ULB1	UNIPROT	up-regulates	binding			9606	BTO:0000938								9856994	t		gcesareni	Purification of neurexin ialpha revealed that it is tightly complexed to a secreted glycoprotein called neurexophilin 1	SIGNOR-62775	0.565
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	KAT5	protein	Q92993	UNIPROT	up-regulates activity	phosphorylation	Ser86	TKNGLPGsRPGSPER	9606	BTO:0000567								12468530	t		llicata	Baculovirus-based expression and purification of Tip60 combined with mass spectrometry allowed the identification of serines 86 and 90 as two major sites of phosphorylation in vivo. The phosphorylation of Tip60 was found to modulate its histone acetyltransferase activity. One of the identified phosphorylated serines, Ser-90, was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylatedin vitro by the cyclin B/Cdc2 complex.	SIGNOR-250641	0.428
CALM2	protein	P0DP24	UNIPROT	EEF2K	protein	O00418	UNIPROT	up-regulates	binding			9606									11015200	t		miannu	The calmodulin-binding region is located between amino acids 51 and 96	SIGNOR-266321	0.472
FRK	protein	P42685	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr407	SGLSMSSySVPRTPD	9606	BTO:0002035								35723276	t		miannu	Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP. 	SIGNOR-275456	0.278
F2RL1	protein	P55085	UNIPROT	CTSD	protein	P07339	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	 PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 	SIGNOR-254860	0.2
D-thyroxine	smallmolecule	CHEBI:30659	ChEBI	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0003736								6777394	t	inferred from 70% of family members	miannu	 The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response.	SIGNOR-269878	0.8
SIRT1	protein	Q96EB6	UNIPROT	NCOR1	protein	O75376	UNIPROT	up-regulates				9606									22395773	t		FFerrentino	In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription.	SIGNOR-253505	0.641
TARS1	protein	P26639	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									25824639	t		miannu	Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 	SIGNOR-270505	0.8
GSK3B	protein	P49841	UNIPROT	MYOCD	protein	Q8IZQ8	UNIPROT	down-regulates activity	phosphorylation	Ser638	PQCSPQHsPLGAVKS	9606	BTO:0000007								16141410	t			In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity	SIGNOR-251250	0.406
SRC	protein	P12931	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	phosphorylation	Tyr289	MELQTYRyHGHSMSD	9606	BTO:0000007								26848621	t		miannu	Src inactivated PDH through direct phosphorylation of tyrosine-289 of PDH E1α subunit (PDHA1). 	SIGNOR-277204	0.356
NFIX	protein	Q14938	UNIPROT	EPHA4	protein	P54764	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268908	0.2
PRKCA	protein	P17252	UNIPROT	CBL	protein	P22681	UNIPROT	down-regulates quantity	phosphorylation	Ser642	PRLGSTFsLDTSMSM	9606	BTO:0000782								11024037	t		lperfetto	However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway. 	SIGNOR-249057	0.327
HEY1	protein	Q9Y5J3	UNIPROT	MYOG	protein	P15173	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000165;BTO:0000222	BTO:0000887;BTO:0001103							19917614	f		lperfetto	Our results indicate instead that hey1 is recruited to the promoter regions of myogenin and mef2c, two genes whose induction is critical for myogenesis.	SIGNOR-235822	0.379
PIK3AP1	protein	Q6ZUJ8	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates	binding			9606	BTO:0000801								22187458	t		gcesareni	Bcap is constitutively phosphorylated and associated with the p85 subunit of pi3k in macrophages. Tlr signaling causes the phosphorylation of the small amount of bcap that is associated with membranes in the resting state or the translocation of phosphorylated bcap from the cytoplasm to the membrane. This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Bcap is an essential activator of the pi3k pathway downstream of tlr signaling	SIGNOR-191673	0.61
nintedanib	chemical	CHEBI:85164	ChEBI	FGFR1	protein	P11362	UNIPROT	down-regulates activity	chemical inhibition			-1									18559524	t		Luana	In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers.	SIGNOR-257804	0.8
AKT2	protein	P31751	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser315	DFRSRTNsNASTVSG										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-252864	0.757
MPO-ANCA	complex	SIGNOR-C474	SIGNOR	superoxide	smallmolecule	CHEBI:18421	ChEBI	up-regulates				10090		BTO:0000133							15972951	f		lperfetto	Anti-MPO IgG (250 μg/ml) induces significant superoxide anion production in TNF-α-primed peritoneal exudate cells from WT C57BL/6 mice (black bars) as compared to normal mouse IgG (250 μg/ml) or buffer alone.	SIGNOR-270589	0.8
BCL2L11	protein	O43521	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates activity	binding			9606									22492984	t		lperfetto	Bim, and puma bind with high affinity to all pro-survival proteins	SIGNOR-196935	0.825
CUDC-101	chemical	CID:24756910	PUBCHEM	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									20143778	t		miannu	By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively.	SIGNOR-262258	0.8
SSTR3	protein	P32745	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256677	0.561
ARRB2	protein	P32121	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000971								12488444	t		miannu	Our current results demonstrated that the binding of Mdm2 to beta-arrestin 2 was significantly enhanced by stimulation of GPCRs. Activation of GPCRs led to formation of a ternary complex of Mdm2, beta-arrestin 2, and GPCRs and thus recruited Mdm2 to GPCRs at plasma membrane. Moreover, the binding of beta-arrestin 2 to Mdm2 suppressed the self-ubiquitination of Mdm2 and consequently reduced the Mdm2-mediated p53 degradation and ubiquitination.	SIGNOR-272592	0.444
RPS6KA3	protein	P51812	UNIPROT	TH	protein	P07101	UNIPROT	up-regulates	phosphorylation	Ser71	RFIGRRQsLIEDARK	9606									7901013	t	The effect has been demonstrated using P07101-3	gcesareni	Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax	SIGNOR-34686	0.271
PRPF4	protein	O43172	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270622	0.698
(R)-adrenaline	smallmolecule	CHEBI:28918	ChEBI	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	up-regulates				9606									23075495	f	inferred from 70% of family members	gcesareni	On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz.	SIGNOR-269867	0.8
episterol ester	smallmolecule	CHEBI:52393	ChEBI	CNR1	protein	P21554	UNIPROT	up-regulates activity	chemical activation			9606		BTO:0000142							29751000	t		miannu	2-AG is an endocannabinoid that activates the cannabinoid CB1 receptor.	SIGNOR-264266	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	DUSP1	protein	P28562	UNIPROT	down-regulates	phosphorylation			9606									16286470	t	inferred from 70% family members	lperfetto	The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain	SIGNOR-270189	0.2
CAMK2G	protein	Q13555	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser498	RPLSRTQsSPLPQSP	9606		BTO:0000887							11114197	t		gcesareni	Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.	SIGNOR-85102	0.403
AKT1	protein	P31749	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									24743741	f			Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases.	SIGNOR-254372	0.7
CSNK2A1	protein	P68400	UNIPROT	SPTBN1	protein	Q01082	UNIPROT	down-regulates	phosphorylation	Ser2110	PEPSTKVsEEAESQQ	9606									17088250	t		miannu	We show here that the short c-terminal splice variant of betaii-spectrin (betaiisigma2) is a substrate for phosphorylation. In vitro, protein kinase ck2 phosphorylates ser-2110 and thr-2159 / phosphorylation of ?II?2 C-terminal fragment inhibits its interaction with ?II N-terminal fragment.	SIGNOR-150467	0.339
methiothepin	chemical	CHEBI:64203	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9550290	t		miannu	Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists.	SIGNOR-258892	0.8
Activated PSC	phenotype	SIGNOR-PH224	SIGNOR	TGFB1	protein	P01137	UNIPROT	up-regulates quantity				9606		BTO:0000988							38540204	t		miannu	Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction	SIGNOR-277673	0.7
FLT3	protein	P36888	UNIPROT	GRB10	protein	Q13322	UNIPROT	up-regulates activity	binding			10090	BTO:0001516								23246379	t			These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K–Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells.	SIGNOR-255947	0.371
pazopanib	chemical	CHEBI:71219	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258260	0.8
NSL histone acetyltransferase	complex	SIGNOR-C413	SIGNOR	H4C1	protein	P62805	UNIPROT	down-regulates activity	acetylation	Lys6	kGGKGLGK	9606									20018852	t		miannu	Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8.	SIGNOR-267167	0.2
BLVRA	protein	P53004	UNIPROT	PRKCB	protein	P05771	UNIPROT	up-regulates	phosphorylation	Thr500	WDGVTTKtFCGTPDY	9606									17227757	t		llicata	Human biliverdin reductase, a previously unknown activator of protein kinase c ?II the phosphorylation of thr500 was confirmed by immunoblotting of hbvr.pkc betaii immunocomplex.	SIGNOR-152181	0.311
EDN3	protein	P14138	UNIPROT	EDNRB	protein	P24530	UNIPROT	up-regulates	binding			9606		BTO:0000975							8086489	t		gcesareni	These results demonstrate that lys-161 of the receptor is important for high affinity binding with et-3 which, in part, confers the non-selective binding characteristics of the etb receptor for et isopeptides.	SIGNOR-36017	0.791
PKM	protein	P14618	UNIPROT	HIF-1 complex	complex	SIGNOR-C418	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								21620138	t			PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements,	SIGNOR-267473	0.399
TACR1	protein	P25103	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256919	0.2
SNAPIN	protein	O95295	UNIPROT	SNAP25	protein	P60880	UNIPROT	up-regulates activity	binding			9606	BTO:0000793								18167355	t		miannu	In the present study, we used yeast two-hybrid analysis to identify a new binding partner of torsinA, the SNARE-associated protein snapin. We have reported that snapin shows a robust interaction with wild type and mutant torsinA. we have demonstrated that this portion of torsinA and/or the adjacent linker region has the additional role of recruiting snapin. we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA.	SIGNOR-261171	0.601
MAPK14	protein	Q16539	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity	phosphorylation	Ser87	AAAGPALsPVPPVVH	9606									19336399	t		gcesareni	The protein's reduced antiapoptotic capacity was related to phosphorylation of its threonine 56 and serine 87 residues by virally activated p38mapk	SIGNOR-184936	0.339
LCK	protein	P06239	UNIPROT	EZR	protein	P15311	UNIPROT	unknown	phosphorylation	Tyr146	KEVHKSGyLSSERLI	-1									12560083	t			Lck phosphorylated ezrin in vitro, and the major phosphotyrosine was identified as Y145. Whether tyrosine phosphorylation of ezrin is an alternative mechanism to regulate dynamic changes of the actin cytoskeleton, as has been suggested in EGF-, PDGF- or HGF-treated epithelial cells, is still unclear. Alternatively, Lck-induced tyrosine phosphorylation of ezrin may be linked to its other functions, including participation in signaling pathways that control proliferation and apoptosis	SIGNOR-251374	0.52
UBE2E1	protein	P51965	UNIPROT	MPG	protein	P29372	UNIPROT	up-regulates activity	binding			-1									25207814	t		miannu	Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E)	SIGNOR-271929	0.2
mono(2-ethylhexyl) phthalate	chemical	CHEBI:17243	ChEBI	PPARA	protein	Q07869	UNIPROT	up-regulates activity	chemical activation			-1									16326050	t		miannu	Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast	SIGNOR-268749	0.8
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DOB	protein	P13765	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-254000	0.26
FZR1	protein	Q9UM11	UNIPROT	SKIL	protein	P12757	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								11741538	t		miannu	 We demonstrate that the anaphase-promoting complex (APC) is a ubiquitin ligase required for the destruction of SnoN and that the APC pathway is regulated by TGF-beta. The destruction box of SnoN is required for its degradation in response to TGF-beta signaling. Furthermore, the APC activator CDH1 and Smad3 synergistically regulate SnoN degradation. Under these circumstances, CDH1 forms a quaternary complex with SnoN, Smad3, and APC. 	SIGNOR-272621	0.393
APC-c	complex	SIGNOR-C150	SIGNOR	SKIL	protein	P12757	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								11741538	t		miannu	 We demonstrate that the anaphase-promoting complex (APC) is a ubiquitin ligase required for the destruction of SnoN and that the APC pathway is regulated by TGF-beta. The destruction box of SnoN is required for its degradation in response to TGF-beta signaling. Furthermore, the APC activator CDH1 and Smad3 synergistically regulate SnoN degradation. Under these circumstances, CDH1 forms a quaternary complex with SnoN, Smad3, and APC. 	SIGNOR-272622	0.33
YWHAE	protein	P62258	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	binding			9606									12042314	t		miannu	14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue.	SIGNOR-88297	0.519
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MAP3K5	protein	Q99683	UNIPROT	down-regulates activity	phosphorylation	Ser83	ATRGRGSsVGGGSRR	9606	BTO:0000007								11154276	t		lperfetto	Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1.	SIGNOR-104646	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	SH3RF1	protein	Q7Z6J0	UNIPROT	down-regulates	phosphorylation	Ser304	KNTKKRHsFTSLTMA	9606									17535800	t		miannu	We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac, as does phosphomimetic s304d and s304e mutation of posh.	SIGNOR-155229	0.2
1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester	chemical	CHEBI:92418	ChEBI	CHRM4	protein	P08173	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258634	0.8
CASP3	protein	P42574	UNIPROT	SPTAN1	protein	Q13813	UNIPROT	down-regulates	cleavage			9606	BTO:0000150;BTO:0000567								9624143	t		amattioni	Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis.	SIGNOR-57891	0.661
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1910	TPTSPKYsPTSPTYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203588	0.77
Ionizing radiation	stimulus	SIGNOR-ST16	SIGNOR	ELE1-RET	fusion protein	SIGNOR-FP10	SIGNOR	up-regulates				9606									23128507	f		miannu	In PTC, genomic rearrangements juxtapose the RET tyrosine kinase domain to unrelated genes, thereby creating dominantly transforming oncogenes, denominated RET/PTC. The RET/PTC rearrangements are the 2nd most common genetic alteration described in PTC and observed in ∼13–43% of cases, mostly in pediatric cancers or in individuals exposed to ionizing radiation from nuclear accidents	SIGNOR-251984	0.7
CSNK2A2	protein	P19784	UNIPROT	ARRB2	protein	P32121	UNIPROT	unknown	phosphorylation	Thr382	EFDTNYAtDDDIVFE	-1									11877451	t		llicata	We found that arrestin-3 is constitutively phosphorylated at Thr-382 and becomes dephosphorylated upon beta(2)-adrenergic receptor activation in COS-1 cells. Casein kinase II (CKII) appears to be the major kinase mediating arrestin-3 phosphorylation, since 1) Thr-382 is contained within a canonical consensus sequence for CKII phosphorylation and 2) wild type arrestin-3 but not a T382A mutant is phosphorylated by CKII in vitro. | However, additional analysis reveals that arrestin-3 phosphorylation may regulate formation of a large arrestin-3-containing protein complex. 	SIGNOR-250977	0.314
WNK1	protein	Q9H4A3	UNIPROT	OXSR1	protein	O95747	UNIPROT	up-regulates	phosphorylation	Thr185	TRNKVRKtFVGTPCW	9606									17190791	t		gcesareni	Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1)	SIGNOR-151663	0.496
PRKCA	protein	P17252	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates activity	phosphorylation	Ser959	DHSVRINsVGSTASS	9823	BTO:0004007								7539802	t		lperfetto	We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling.	SIGNOR-248900	0.51
CSNK2A1	protein	P68400	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Ser99	HFAIAADsEAEQDSW	-1									8349691	t		llicata	These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1.	SIGNOR-250909	0.345
RCOR1	protein	Q9UKL0	UNIPROT	KDM1A	protein	O60341	UNIPROT	up-regulates activity	binding			-1									16140033	t		miannu	CoREST protects LSD1 from proteasomal degradation and also plays an indispensable role in LSD1-mediated demethylation of nucleosomal substrates in vitro. in contrast to CoREST, which is a positive regulator of LSD1 activity, the in vitro evidence presented above suggests that BHC80 may function to inhibit LSD1 activity.	SIGNOR-264506	0.954
2-(2-amino-3-methoxyphenyl)chromen-4-one	chemical	CHEBI:77954	ChEBI	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates	chemical inhibition			9606	BTO:0000938	BTO:0000142							11160424	t		lperfetto	The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity.	SIGNOR-244930	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PAX5	protein	Q02548	UNIPROT	down-regulates activity	phosphorylation	Ser189; Ser283	SGILGITsPSADTNK;DMKANLAsPTPADIG	9606	BTO:0003079								22593617	t		Gianni	In this study, we demonstrated that PAX5 was phosphorylated by ERK1/2 in vitro and in vivo at serines 189 and 283. This phosphorylation attenuated the transcriptional repression of BLIMP1 by PAX5.	SIGNOR-269088	0.2
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606									10801407	t		gcesareni	The tumour suppressor protein p53 is stabilised and activated in response to ionising radiation. This is known to depend on the kinase atm;recent results suggest atm acts via the downstream kinase chk2/hcds1, which stabilises p53 at least in part by direct phosphorylation of residue serine 20	SIGNOR-77144	0.784
IL15RA	protein	Q13261	UNIPROT	TYK2	protein	P29597	UNIPROT	up-regulates				9606									30029643	t			Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated	SIGNOR-256253	0.247
ponatinib	chemical	CHEBI:78543	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									23430109	t		lperfetto	We assessed the in vitro activity of ponatinib against clinically relevant FLT3-ITD mutant isoforms that confer resistance to AC220 or sorafenib. Substitution of the FLT3 "gatekeeper" phenylalanine with leucine (F691L) conferred mild resistance to ponatinib, but substitutions at the FLT3 activation loop (AL) residue D835 conferred a high degree of resistance.	SIGNOR-261983	0.8
UBE3A	protein	Q05086	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	down-regulates activity	ubiquitination			9606	BTO:0000007								28559284	t			Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A	SIGNOR-270339	0.312
PTPN11	protein	Q06124	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation	Tyr705	DPGSAAPyLKTKFIC	9615	BTO:0000837								16611743	t		lperfetto	In addition, SHP-2 dephosphorylates tyrosine-phosphorylated Stat1/3/5A (Ohtani et al., 2000; Wu et al., 2002; Chen et al., 2003), and downregulates Stat3-mediated biological actions (Ohtani et al., 2000).|Inhibition of collagen-induced Stat3 tyrosine-705 (Stat3-p-Tyr)	SIGNOR-272404	0.761
SLC9A6	protein	Q92581	UNIPROT	hydron	chemical	CHEBI:15378	ChEBI	down-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265596	0.8
GSK3B	protein	P49841	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Thr41	GIHSGATtTAPSLSG	9606			SIGNOR-C110						23151663	t		gcesareni	Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells.	SIGNOR-199512	0.856
TACR1	protein	P25103	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257048	0.307
EFNA1	protein	P20827	UNIPROT	EPHA3	protein	P29320	UNIPROT	up-regulates	binding			9606									9576626	t		tpavlidou	Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity	SIGNOR-56904	0.811
ACD	protein	Q96AP0	UNIPROT	RPA2	protein	P15927	UNIPROT	down-regulates activity	binding						SIGNOR-C306						18680434	t		lperfetto	The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA	SIGNOR-263327	0.2
SMDT1	protein	Q9H4I9	UNIPROT	MCU_MICU2_variant	complex	SIGNOR-C502	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270875	0.619
BST1	protein	Q10588	UNIPROT	NADP(+)	smallmolecule	CHEBI:18009	ChEBI	down-regulates quantity	chemical modification			9606									18626062	t		miannu	The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR.	SIGNOR-264251	0.8
NLK	protein	Q9UBE8	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	down-regulates activity	phosphorylation	Ser863	LTQSAPAsPTNKGVH	9606	BTO:0000007								26588989	t	done	miannu	NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment. 	SIGNOR-273908	0.334
RITA1	protein	Q96K30	UNIPROT	RBPJ	protein	Q06330	UNIPROT	down-regulates	binding			9606									21102556	t		gcesareni	Thus, we propose that rita acts as a negative modulator of the notch signalling pathway, controlling the level of nuclear rbp-j/cbf-1, where its amounts are limiting.	SIGNOR-170089	0.428
PAX6	protein	P26367	UNIPROT	GCG	protein	P01275	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000120								12783165	f		miannu	In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3.	SIGNOR-254905	0.596
WNT5A	protein	P41221	UNIPROT	RYK	protein	P34925	UNIPROT	up-regulates	binding			9606									22773843	t		areggio	Purified human RYK binds to mouse Wnt1, 3a and 5a expressed in HEK293 cells. Separate experiments show that human RYK also immunopreciptitates human VANGL2 when the proteins are co-expressed in HEK293 cells.	SIGNOR-258970	0.776
MAPK3	protein	P27361	UNIPROT	APBB1	protein	O00213	UNIPROT	unknown	phosphorylation	Ser175	EEEEDLSsPPGLPEP	9606									14697653	t		lperfetto	Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved.	SIGNOR-120467	0.271
SPRED1	protein	Q7Z699	UNIPROT	NF1	protein	P21359	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								32697994	t		miannu	Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS.	SIGNOR-273660	0.623
WNT5A	protein	P41221	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates				9606									21078818	f		gcesareni	We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3)	SIGNOR-169669	0.406
β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35 Three different subunits have been identified in humans: PFK-M (muscle), PFK-L (liver), and PFK-P (platelet).The subunits are expressed in a tissue-specific manner and, in erythrocytes, 5 isoenzymes of varying subunit composition (M4, M3L1, M2L2, ML3, and L4) can be identified.	SIGNOR-266463	0.8
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser235	SPQDSPPsKASPAQD	9606									21215781	t		lperfetto	Cdk5 regulates app (amyloid precursor protein) processing and tau hyperphosphorylationtau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules	SIGNOR-251587	0.695
ARHGEF26	protein	Q96DR7	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260545	0.568
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	ABCB1	protein	P08183	UNIPROT	up-regulates activity	dephosphorylation	Ser661	SSNDSRSsLIRKRST	9606	BTO:0000007								24333728	t			Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp	SIGNOR-272512	0.2
PTPN11	protein	Q06124	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates activity	dephosphorylation	Tyr32	QNHFVDEyDPTIEDS	9606	BTO:0000007								26617336	t		irozzo	Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling.	SIGNOR-255982	0.647
practolol	chemical	CHEBI:258351	ChEBI	ADRB1	protein	P08588	UNIPROT	down-regulates activity	chemical inhibition			10030	BTO:0000246								10079020	t		Luana	In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue	SIGNOR-258336	0.8
ITCH	protein	Q96J02	UNIPROT	NFE2	protein	Q16621	UNIPROT	down-regulates activity	ubiquitination			9606	BTO:0000007								18718448	t		lperfetto	Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination| Interestingly, Itch suppressed the transactivation activity of p45/NF-E2 by adding a Lys63-linked polyubiquitin chain. Confocal microscopy revealed that ubiquitinated p45/NF-E2 became localized in the cytoplasm when Itch was over-expressed. Thus, Itch-mediated ubiquitination of p45/NF-E2 does not target the protein for proteasomal degradation, but instead retains p45/NF-E2 in the cytoplasm, where it cannot function as a transactivator.	SIGNOR-275553	0.423
PPP2CA	protein	P67775	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	dephosphorylation			9606									18160256	t			Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248655	0.889
HES5	protein	Q5TA89	UNIPROT	NEUROG1	protein	Q92886	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938								30030829	f		lperfetto	The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 	SIGNOR-265141	0.417
Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	Dendritic_spine_morphogenesis	phenotype	SIGNOR-PH183	SIGNOR	up-regulates				9606									14684878	f		miannu	Dendritic spines are small protrusions found on dendrites of principal neurons of mammalian brain. Serving as postsynaptic compartments for individual excitatory inputs, spines show rapid movements and shape changes that are influenced by synaptic activity. The structural modifications of spines are believed to represent morphological correlates of synaptic plasticity. The form and motility of spines are determined mainly by the actin cytoskeleton	SIGNOR-266596	0.7
FOXO1	protein	Q12778	UNIPROT	PCK1	protein	P35558	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22521266	t		gcesareni	Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase).	SIGNOR-197200	0.441
PPM1K	protein	Q8N3J5	UNIPROT	BCKDHA	protein	P12694	UNIPROT	up-regulates activity	dephosphorylation	Ser337	TYRIGHHsTSDDSSA	10090									19411760	t			BCKD is inhibited by phosphorylation of its E1alpha subunit at Ser293, which is catalyzed by BCKD kinase. During BCAA excess, phosphorylated Ser293 (pSer293) becomes dephosphorylated through the concerted inhibition of BCKD kinase and the activity of an unknown intramitochondrial phosphatase. Using unbiased, proteomic approaches, we have found that a mitochondrial-targeted phosphatase, PP2Cm, specifically binds the BCKD complex and induces dephosphorylation of Ser293 in the presence of BCKD substrates	SIGNOR-248758	0.773
PROC	protein	P04070	UNIPROT	F5	protein	P12259	UNIPROT	down-regulates activity	cleavage	Arg534	KSRSLDRrGIQRAAD	-1									7989361	t		lperfetto	The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. 	SIGNOR-263629	0.583
KNL1	protein	Q8NG31	UNIPROT	BUB1	protein	O43683	UNIPROT	up-regulates	binding			9606									17981135	t		gcesareni	Association of the amino and middle domain of blinkin with the tpr domains in the amino termini of bubr1 and bub1 is essential for bubr1 and bub1 to execute their distinct mitotic functions	SIGNOR-158378	0.2
Norbinaltorphimine	chemical	CHEBI:81529	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258819	0.8
ACTR5	protein	Q9H9F9	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270850	0.69
Neuregulin	proteinfamily	SIGNOR-PF37	SIGNOR	ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	up-regulates activity	binding			9606									18415007	t		miannu	The neuregulin family consists of four genes, NRG1-4 which can each encode products containing a domain related to the epidermal growth factor family of ligands. they may be released by regulated proteolysis to act as soluble proteins which can interact and activate members of the EGF receptor family of receptor tyrosine kinases	SIGNOR-256161	0.906
HIPK2	protein	Q9H2X6	UNIPROT	PAX6	protein	P26367	UNIPROT	up-regulates activity	phosphorylation	Thr304	QPIPQPTtPVSSFTS	9606	BTO:0001938								16407227	t			HIPK2 phosphorylates the activation domain of Pax6, which augments Pax6 transactivation by enhancing its interaction with p300. Mass spectrometric analysis identified three Pax6 phosphorylation sites as threonines 281, 304, and 373. 	SIGNOR-251270	0.476
STUB1	protein	Q9UNE7	UNIPROT	CBX4	protein	O00257	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys280	GMQAVKIkSGEVAEG	9606	BTO:0002181								32111827	t		miannu	The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα. 	SIGNOR-277514	0.2
BLK	protein	P51451	UNIPROT	BCR-Dk	complex	SIGNOR-C435	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000776								32323266	t		scontino	The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases.	SIGNOR-268214	0.633
RUNX3	protein	Q13761	UNIPROT	DNASE1	protein	P24855	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002384								17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255092	0.2
PRKACA	protein	P17612	UNIPROT	ADD2	protein	P35612	UNIPROT	down-regulates activity	phosphorylation	Ser713	KKKFRTPsFLKKSKK	-1									8810272	t		miannu	Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of - and -adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin. 	SIGNOR-250332	0.286
JAK2	protein	O60674	UNIPROT	ITGB2	protein	P05107	UNIPROT	up-regulates activity	phosphorylation			9606									25624455	t		miannu	PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.	SIGNOR-254738	0.268
GABARAP	protein	O95166	UNIPROT	TBC1D25	protein	Q3MII6	UNIPROT	up-regulates	binding			9606									21383079	t		gcesareni	In this study, we report evidence demonstrating that oatl1, a putative rab guanosine triphosphatase-activating protein (gap), is a novel binding partner of atg8 homologues in mammalian cells. Oatl1 is recruited to isolation membranes and autophagosomes through direct interaction with atg8 homologues and is involved in the fusion between autophagosomes and lysosomes through its gap activity.	SIGNOR-172536	0.587
TRIM63	protein	Q969Q1	UNIPROT	Muscle_atrophy	phenotype	SIGNOR-PH40	SIGNOR	up-regulates activity				10090									25549588	f		areggio	Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX), are markedly induced in almost all types of atrophy. 	SIGNOR-254993	0.7
PHF7	protein	Q9BWX1	UNIPROT	SMARCD3	protein	Q6STE5	UNIPROT	form complex	binding			9606									33941892	t		miannu	Mechanistically, PHF7 localizes to cardiac super enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, it increases chromatin accessibility and transcription factor binding at these sites. Furthermore, PHF7 recruits cardiac transcription factors to activate a positive transcriptional autoregulatory circuit in reprogramming. PHF7 interacts with SMARCD3 to promote reprogramming.	SIGNOR-269816	0.2
PDGFA	protein	P04085	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252286	0.7
GRK5	protein	P34947	UNIPROT	ADRB2	protein	P07550	UNIPROT	unknown	phosphorylation	Ser396	GHQGTVPsDNIDSQG	-1									8662852	t			 we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). 	SIGNOR-251195	0.682
CDK12	protein	Q9NYV4	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1910	TPTSPKYsPTSPTYS	9606									22012619	t		miannu	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176821	0.775
PRKCA	protein	P17252	UNIPROT	EGLN2	protein	Q96KS0	UNIPROT	down-regulates	phosphorylation	Ser132	GGDAPSPsKRPWARQ	9606									18710826	t		tpavlidou	Thus, recombinant phd1 was examined for in vitro phosphorylation using protein kinase a, protein kinase calpha, casein kinase i and ii and erk2. The protein was most strongly phosphorylated by protein kinase calpha, and the phosphorylation sites were found to be ser-132, ser-226 and ser-234.Mutation Of ser-132 or ser-234 to asp or glu diminished the enzymatic activity to 25-60%, while mutation of ser-226 scarcely influenced the activity.	SIGNOR-180199	0.34
RNF10	protein	Q8N5U6	UNIPROT	MEOX2	protein	P50222	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								16335786	t		miannu	RFN10 co-immunoprecipitates with MEOX2. RNF10 potentiates MEOX2 transcriptional activation	SIGNOR-236968	0.383
STK4	protein	Q13043	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates	phosphorylation	Thr735	DTEWRSVtLPRDLQS	9606									18794806	t		lperfetto	Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3	SIGNOR-181060	0.348
POLDIP3	protein	Q9BY77	UNIPROT	TREX complex	complex	SIGNOR-C444	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								22928037	t		miannu	 PDIP3 and ZC11A Function in mRNA Export. PDIP3 and ZC11A associate with UAP56 and the TREX complex in an ATP-dependent manner. 	SIGNOR-268515	0.602
AKT1	protein	P31749	UNIPROT	LONP1	protein	P36776	UNIPROT	up-regulates activity	phosphorylation	Ser173	VFLKRDDsNESDVVE	9606	BTO:0001061								31406245	t		lperfetto	In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity.	SIGNOR-265724	0.255
RIMBP3	protein	Q9UFD9	UNIPROT	RIMS2	protein	Q9UQ26	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264365	0.365
MAPK1	protein	P28482	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Thr232	GGLPEVAtPESEEAF	9606	BTO:0004971								7816602	t		lperfetto	Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions.	SIGNOR-235877	0.784
PLK1	protein	P53350	UNIPROT	KIF2C	protein	Q99661	UNIPROT	up-regulates activity	phosphorylation	Ser715	MQLEEQAsRQISSKK	9606	BTO:0002181								26206521	t		miannu	 Active PLK1, in turn, phosphorylates MCAK at Ser715 which promotes its microtubule depolymerase activity essential for faithful chromosome segregation.	SIGNOR-276931	0.804
POU5F1	protein	Q01860	UNIPROT	PAX6	protein	P26367	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003298								22795133	f		lperfetto	Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)	SIGNOR-253163	0.469
AP-1 complex	complex	SIGNOR-C248	SIGNOR	SORT1	protein	Q99523	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								31767632	t		miannu	The short intracellular domain of sortilin binds several cytoplasmic adaptor proteins (e.g., the AP-1 complex and GGA1 to -3), most of which target two well-defined motifs: a C-terminal acidic cluster dileucine motif and a YXXΦ motif in the proximal third of the domain. Both motifs contribute to endocytosis as well as Golgi-endosome trafficking of sortilin.	SIGNOR-273720	0.437
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	BIRC2	protein	Q13490	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9916987	f		gcesareni	The iaps have been shown to be induced by nf-kappab or v-rel in multiple cell lines and conversely, hiap1 and hiap2 have been shown to activate nf-kappab possibly forming a positive feed-back loop.	SIGNOR-64100	0.534
BRCC ubiquitin ligase complex	complex	SIGNOR-C295	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates													24832651	f		lperfetto	The exact function of the BRCC complex in HR is not entirely elucidated, but its E3 ligase activity may promote the mobilization and stabilization of the complex at broken chromatin sites were the complex can stabilize the formation of RAD51 filaments thus facilitating the repair process	SIGNOR-263204	0.7
UCK1	protein	Q9HA47	UNIPROT	cytidine 5'-monophosphate(2-)	smallmolecule	CHEBI:60377	ChEBI	up-regulates quantity	chemical modification												11306702	t		lperfetto	Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. 	SIGNOR-275859	0.8
PTPN6	protein	P29350	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Tyr86	VADIDGQyAMTRAQR	9606									20840866	t		lperfetto	In the present investigation, we demonstrate that SHP-1 dephosphorylates \u03b2-catenin on tyrosines 86 and 654 and promotes its proteasomal degradation.|SHP-1 inhibits \u03b2-catenin function by inducing its degradation and interfering with its association with TATA-binding protein.	SIGNOR-277013	0.539
KLK2	protein	P20151	UNIPROT	NCOA4	protein	Q13772	UNIPROT	up-regulates				9606	BTO:0001130								24122203	f		miannu	Klk2may cooperate with the ar coregulator, ara70, to enhance ar transactivation	SIGNOR-202885	0.312
SEMA3F	protein	Q13275	UNIPROT	NRP2	protein	O60462	UNIPROT	up-regulates	binding			9606									16816121	t		esanto	In the nervous system, neuropilins mediate axon retraction and guidance by binding class iii semaphorins. We found that sema3f could compete with metabolically labeled vegf-c for the binding to np1-ig and np2-ig fusion proteins.	SIGNOR-147608	0.633
MAP3K11	protein	Q16584	UNIPROT	MAP2K3	protein	P46734	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0001538								9003778	t		lperfetto	Immunoprecipitated mlk-3 catalyzed the phosphorylation of sek1 in vitro, and co-transfected mlk-3 induced phosphorylation of sek1 and mkk3 at sites required for activation, suggesting direct regulation of these protein kinases.	SIGNOR-45788	0.47
ABL1	protein	P00519	UNIPROT	DDX5	protein	P17844	UNIPROT	up-regulates	phosphorylation	Tyr593	NGMNQQAyAYPATAA	9606									17018282	t		llicata	These results suggested that p68 was phosphorylated by c-abl in ht-29 cells under stimulation of pdgf. we demonstrated that tyrosine phosphorylation of p68 at y593 mediated pdgf-stimulated epithelial-mesenchymal transition (emt). We showed that pdgf treatment led to phosphorylation of p68 at y593 in the cell nucleus. The y593-phosphorylated p68 (referred to as phosphor-p68) promotes beta-catenin nuclear translocation via a wnt-independent pathway.	SIGNOR-149988	0.366
DUSP19	protein	Q8WTR2	UNIPROT	MAPK8	protein	P45983	UNIPROT	down-regulates	dephosphorylation			9606									11959861	t		gcesareni	Skrp1 was highly specific for c-jun n-terminal kinase (jnk) in vitro and effectively suppressed the jnk activation in response to tumor necrosis factor alpha or thapsigargin skrp1 does not bind directly to its target jnk, but co-precipitation of skrp1 with the mapk kinase mkk7, a jnk activator, was found in vitro and in vivo.	SIGNOR-117260	0.432
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser174	LSPASSGsSASFISD	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248681	0.613
MARK1	protein	Q9P0L2	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser641	KVTSKCGsLGNIHHK	-1									10090741	t		miannu	We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. 	SIGNOR-250174	0.44
PRKCA	protein	P17252	UNIPROT	SNAP25	protein	P60880	UNIPROT	up-regulates	phosphorylation	Ser187	RIMEKADsNKTRIDE	9606	BTO:0000938								18171919	t		llicata	Phosphorylation of snap-25 at ser187 mediates enhancement of exocytosis by a phorbol ester in ins-1 cells.	SIGNOR-160313	0.359
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	ACTA1	protein	P68133	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136175	0.352
PRKD1	protein	Q15139	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates	phosphorylation	Ser910	KALGERVsIL	9606									19029298	t		llicata	We show that pkd1-ser916 autophosphorylation does not necessarily correlate with pkd1 activity. Rather, autophosphorylation at ser916 is required for subsequent autophosphorylation at ser748.	SIGNOR-182480	0.2
CAPRIN1	protein	Q14444	UNIPROT	G3BP1	protein	Q13283	UNIPROT	up-regulates activity	binding			9606									17210633	t		SARA	Caprin-1 and G3BP-1 were directly or indirectly associated in a stable complex. The Caprin-1/G3BP-1 complex occurs in cytoplasmic RNA granules	SIGNOR-260982	0.608
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	PYGL	protein	P06737	UNIPROT	down-regulates activity	dephosphorylation	Ser15	QEKRRQIsIRGIVGV	9606									22225877	t			GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation	SIGNOR-267403	0.2
MED22	protein	Q15528	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266661	0.737
RPS6KA1	protein	Q15418	UNIPROT	ETV1	protein	P50549	UNIPROT	up-regulates activity	phosphorylation	Ser216	PMYQRQMsEPNIPFP	9606									12213813	t		lperfetto	Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation.	SIGNOR-249163	0.356
CYFIP1	protein	Q7L576	UNIPROT	WRC complex	complex	SIGNOR-C191	SIGNOR	form complex	binding			9606									21107423	t		miannu	WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems	SIGNOR-253568	0.901
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	LIFR	protein	P42702	UNIPROT	down-regulates	phosphorylation			9606									7777512	t	inferred from 70% family members	gcesareni	Thus, our results identify the human lifr as a substrate for mapk and suggest a mechanism of heterologous receptor regulation of lifr signaling occurring at ser-1044.	SIGNOR-270134	0.2
NSMCE4A	protein	Q9NXX6	UNIPROT	SMC5/6 	complex	SIGNOR-C374	SIGNOR	form complex	binding			-1									27427983	t		miannu	The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks	SIGNOR-265486	0.826
P2RY4	protein	P51582	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257006	0.2
JMJD1C	protein	Q15652	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									32034158	t		miannu	We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state.	SIGNOR-265171	0.2
AHR	protein	P35869	UNIPROT	UGT1A1	protein	P22309	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18172616	f		miannu	Human UDP-glucuronosyltransferase (UGT)1A1 is a critical enzyme responsible for detoxification and metabolism of endogenous and exogenous lipophilic compounds, such as potentially neurotoxic bilirubin and the anticancer drug irinotecan SN-38, via conjugation with glucuronic acid. A 290-bp distal enhancer module, phenobarbital-responsive enhancer module of UGT1A1 (gtPBREM), fully accounts for constitutive androstane receptor (CAR)-, pregnane X receptor (PXR)-, glucocorticoid receptor (GR)-, and aryl hydrocarbon receptor (AhR)-mediated activation of the UGT1A1 gene.	SIGNOR-253734	0.416
NRG4	protein	Q8WWG1	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606									14967450	t	Does not bind to the ERBB1, ERBB2 and ERBB3 receptors	gcesareni	The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4.	SIGNOR-122062	0.684
NMI	protein	Q13287	UNIPROT	SOX10	protein	P56693	UNIPROT	down-regulates activity	binding			9606									16214168	t		miannu	We identify an association of Sox10 with the N-myc interactor Nmi. Nmi modulated the transcriptional activity of Sox10 in reporter gene assays. Nmi effects varied between different Sox10 target gene promoters, indicating that Nmi function in vivo may be promoter-specific.	SIGNOR-225602	0.439
MAPK1	protein	P28482	UNIPROT	PDE4D	protein	Q08499	UNIPROT	down-regulates	phosphorylation	Ser715	YQSTIPQsPSPAPDD	9606	BTO:0000007								10022832	t	The effect has been demonstrated using Q08499-2	gcesareni	These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro.	SIGNOR-64326	0.36
AKT3	protein	Q9Y243	UNIPROT	UPF1	protein	Q92900	UNIPROT	up-regulates activity	phosphorylation	Thr151	FCNGRGNtSGSHIVN	9606	BTO:0002181								35675814	t		miannu	AKT-Mediated UPF1 Phosphorylation at T151 Promotes UPF1 Helicase Activity	SIGNOR-277596	0.2
GSK3B	protein	P49841	UNIPROT	BORA	protein	Q6PGQ7	UNIPROT	up-regulates	phosphorylation	Ser278	PISSPTFsPIEFQIG	9606									23442801	t		lperfetto	It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation	SIGNOR-201519	0.261
WNT1	protein	P04628	UNIPROT	Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	up-regulates activity	binding			10090		BTO:0000887							16936075	t		lperfetto	Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6)	SIGNOR-253126	0.758
DAPK1	protein	P53355	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser39	GDRGRRKsRFALFKR	9606	BTO:0003575								33052227	t		miannu	DAPK1, which directly binds to and phosphorylates Pellino1 at Ser39, leading to Pellino1 poly-ubiquitination and turnover.	SIGNOR-277531	0.2
CSNK2A1	protein	P68400	UNIPROT	MYB	protein	P10242	UNIPROT	down-regulates activity	phosphorylation	Ser12	PRHSIYSsDEDDEDF	-1									7735324	t		llicata	For c-Myb mutational analysis of the CKII phosphorylation sites showed altered steady state DNA binding. Replacing Ser-11/12 by alanine residues resulted in increased DNA binding compared to wt c-Myb or Myb Asp-11/12 as demonstrated by up to 10-fold differences in the dissociation constants. 	SIGNOR-250919	0.346
TRADD	protein	Q15628	UNIPROT	TRAF2	protein	Q12933	UNIPROT	up-regulates activity	binding			10090	BTO:0000459								18621737	t		lperfetto	The high affinity of the tradd-traf2 interaction is required for efficient suppression of apoptosis upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor- associated factor 2 ,traf2 these results provide evidence that tradd can serve as an adaptor protein and recruit traf1, traf2, or both to tnfrsf1a. The demonstration that tradd interacts with traf2 and fadd, and can recruit both to tnfrsf1a, suggested that traf2 and fadd may be involved in tnfrsf1a tradd-mediated signaling. That these interactions define two distinct signaling pathways emanating from tradd (figure 9) is supported by the ability of traf2 and fadd to activate nf-kb and induce apoptosis, respectively.	SIGNOR-179446	0.865
CDK1	protein	P06493	UNIPROT	ECT2	protein	Q9H8V3	UNIPROT	down-regulates	phosphorylation	Thr373	VSMLSLNtPNSNRKR	9606			SIGNOR-C17						16170345	t		lperfetto	We show that phosphorylation of ect2 at threonine-341 (t341) affects the autoregulatory mechanism of ect2. In g2/m phase, ect2 was phosphorylated at t341 most likely by cyclin b/cyclin-dependent kinase 1 (cdk1) ect2 is biologically active even when it is not phosphorylated at t341	SIGNOR-140549	0.594
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser721	PVVSGDTsPRHLSNV	9606	BTO:0000590								20679343	t	The effect has been demonstrated using P10636-8	lperfetto	Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3?	SIGNOR-167294	0.729
SMARCC2	protein	Q8TAQ2	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	form complex	binding			9606									15627498	t		miannu	We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers.	SIGNOR-132936	0.865
4E2RCat	chemical	CID:2287236	PUBCHEM	EIF4G1	protein	Q04637	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000414								21507972	t		miannu	Characterization of 4E2RCat, an inhibitor of eIF4E-eIF4G interaction. Herein we describe a molecule from this screen that prevents the interaction between eIF4E (the cap-binding protein) and eIF4G (a large scaffolding protein), inhibiting cap-dependent translation. This inhibitor significantly decreased human coronavirus 229E (HCoV-229E) replication, reducing the percentage of infected cells and intra- and extracellular infectious virus titers. 	SIGNOR-260188	0.8
STK11	protein	Q15831	UNIPROT	STK11	protein	Q15831	UNIPROT	up-regulates activity	phosphorylation	Thr185	KPGNLLLtTGGTLKI	9606	BTO:0000007;BTO:0000567								12805220	t		lperfetto	It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity.	SIGNOR-101840	0.2
olaparib	chemical	CHEBI:83766	ChEBI	PARP1	protein	P09874	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-195016	0.8
CDK1	protein	P06493	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser315	LPNNTSSsPQPKKKP	9606			SIGNOR-C17						24173284	t		lperfetto	The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A	SIGNOR-167779	0.598
CASP3	protein	P42574	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	cleavage			-1									10579725	t		lperfetto	P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro	SIGNOR-252624	0.622
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1871	SPKYSPTsPKYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269337	0.718
COP1	protein	Q8NHY2	UNIPROT	ACACB	protein	O00763	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								16794074	t		miannu	TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).	SIGNOR-271599	0.2
CASP8	protein	Q14790	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates activity	cleavage	Asp60	GYDELQTdGNRSSHS	9606	BTO:0000093								9727492	t		amattioni	Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity	SIGNOR-59655	0.874
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser96	TSLSDEDsGKGSQPP	9606									20305697	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-164637	0.575
PRKACA	protein	P17612	UNIPROT	CACNA1S	protein	Q13698	UNIPROT	up-regulates activity	phosphorylation	Ser1575	PEICRTVsGDLAAEE	-1									20937870	t		miannu	 To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2. 	SIGNOR-263112	0.329
KAT2A	protein	Q92830	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269595	0.2
RAE1	protein	P78406	UNIPROT	mRNA-nucleus_export	phenotype	SIGNOR-PH127	SIGNOR	up-regulates				9606									20498086	f		miannu	The export of mRNAs is a multistep process, involving the packaging of mRNAs into messenger ribonucleoprotein particles (mRNPs), their transport through nuclear pore complexes, and mRNP remodeling events prior to translation. Ribonucleic acid export 1 (Rae1) and Nup98 are evolutionarily conserved mRNA export factors that are targeted by the vesicular stomatitis virus matrix protein to inhibit host cell nuclear export. these data suggest that the Rae1*Nup98 complex directly binds to the mRNP at several stages of the mRNA export pathway.	SIGNOR-260871	0.7
EGFR	protein	P00533	UNIPROT	PTPN1	protein	P18031	UNIPROT	up-regulates	phosphorylation	Tyr66	LHQEDNDyINASLIK	9606									9355745	t		llicata	After binding to egfr, ptp1b becomes tyrosine-phosphorylated at tyr-66 phosphorylation of ptp1b by egfr enhances its catalytic activity	SIGNOR-52950	0.751
PABPC3	protein	Q9H361	UNIPROT	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates quantity by stabilization	binding			9606									25480299	t		lperfetto	As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length.	SIGNOR-268321	0.8
CDK1	protein	P06493	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Thr67	LSILSGGtPKRCLDL	9606									10037602	t		gcesareni	Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity.	SIGNOR-64968	0.853
PDPK1	protein	O15530	UNIPROT	PLK1	protein	P53350	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007;BTO:0001914								23887393	t		gcesareni	Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency	SIGNOR-243519	0.2
CDKN1B	protein	P46527	UNIPROT	CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	down-regulates activity	binding			9606									17409098	t		lperfetto	P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e).	SIGNOR-217505	0.878
CAMK2A	protein	Q9UQM7	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation												15621017	t			Thus, the increased immunoreactivity of CaMKII-α of the remaining neurons may be the consequence of the altered calcium dynamics in neurons. There is evidence indicating that CaMKII might participate in tau phosphorylation in AD. 	SIGNOR-255490	0.578
GDNF	protein	P39905	UNIPROT	PAFAH1B1	protein	P43034	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization.	SIGNOR-252171	0.2
WNT5B	protein	Q9H1J7	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606	BTO:0000551;BTO:0000848								16273260	t		gcesareni	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-141440	0.622
ADAM10	protein	O14672	UNIPROT	BTC	protein	P35070	UNIPROT	up-regulates activity	cleavage			9606									26284334	t		miannu	Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin	SIGNOR-259839	0.382
PLK2	protein	Q9NYY3	UNIPROT	SNCB	protein	Q16143	UNIPROT	down-regulates activity	phosphorylation	Ser118	LMEPEGEsYEDPPQE	9606									19889641	t		lperfetto	Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation.	SIGNOR-189049	0.251
ITGB1BP1	protein	O14713	UNIPROT	A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257645	0.757
PRKAA1	protein	Q13131	UNIPROT	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	down-regulates quantity by repression	transcriptional regulation			9606									21892142	f	inferred from family member	gcesareni	Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation	SIGNOR-270257	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	XIAP	protein	P98170	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser87	VGRHRKVsPNCRFIN	9606		BTO:0001023							14645242	t		lperfetto	Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin.	SIGNOR-244377	0.2
MLF1	protein	P58340	UNIPROT	COPS3	protein	Q9UNS2	UNIPROT	up-regulates	binding			9606									15861129	t		miannu	As downstream elements of mlf1 leading to cell growth arrest due to p53 accumulation, we identified two factors, csn3, the third component of the cop9 signalosome (csn), and cop1, a recently characterized e3 ubiquitin ligase for p53	SIGNOR-135937	0.412
FYCO1	protein	Q9BQS8	UNIPROT	MAP1LC3B	protein	Q9GZQ8	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								26468287	t		Giulio	The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures.	SIGNOR-260597	0.532
RPL10	protein	P27635	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262501	0.77
EGR2	protein	P11161	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16054051	t		fspada	Ectopic expression of krox20 can transactivate the c/ebpbeta promoter and increase c/ebpbeta gene expression in 3t3-l1 preadipocytes	SIGNOR-139292	0.515
STXBP1	protein	P61764	UNIPROT	NRXN1	protein	Q9ULB1	UNIPROT	up-regulates activity	binding			9534									11036064	t		miannu	We propose that all these neurexin complexes can interact with Munc18. Both Mint1 and Mint2 could function as direct adaptors of Munc18 to neurexins, whereas Mint1 in addition could recruit Munc18 to CASK-neurexin (Fig. 5 B). 	SIGNOR-264040	0.507
3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide	chemical	CHEBI:131156	ChEBI	CHEK1	protein	O14757	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190203	0.8
TAC1	protein	P20366	UNIPROT	OXT	protein	P01178	UNIPROT	up-regulates quantity													35045339	f		lperfetto	Social touch-like tactile stimulation activates a tachykinin 1-oxytocin pathway to promote social interactions|Functionally, activation of PVH-projecting Tac1+ neurons increases firing of oxytocin neurons, promotes social interactions, and increases preference for the social touch context, whereas reducing activity of Tac1+ neurons abolishes ST-induced oxytocin neuronal firing.	SIGNOR-268576	0.576
SPAST	protein	Q9UBP0	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9534	BTO:0000298								15716377	f		Gianni	Using purified components, we also show that Spastin interacts directly with microtubules and is sufficient for severing. These studies suggest that defects in microtubule severing are a cause of axonal degeneration in human disease.	SIGNOR-269045	0.7
SLC6A4	protein	P31645	UNIPROT	serotonin	smallmolecule	CHEBI:28790	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000227								16789923	t		miannu	 The function of the serotonin transporter (SERT) is to take up and release serotonin (5-hydroxytyptamine (5-HT)) from cells and this function of SERT in the central nervous system (CNS) is well-documented; SERT is the target of selective serotonin reuptake inhibitors used in the treatment of CNS disorders, such as depression.	SIGNOR-263953	0.8
RAB32	protein	Q13637	UNIPROT	AP-1 complex	complex	SIGNOR-C248	SIGNOR	up-regulates activity	relocalization			9606									23247405	t		lperfetto	Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes.	SIGNOR-260700	0.2
DMTF1	protein	Q9Y222	UNIPROT	DSPP	protein	Q9NZW4	UNIPROT	up-regulates quantity by expression	transcriptional regulation												23349460	t		lperfetto	In addition, our in vitro analyses showed that DMP1 and its 57-kDa C-terminal fragment significantly up-regulated the Dspp promoter activities in a mesenchymal cell line.	SIGNOR-271685	0.2
TACR2	protein	P21452	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257015	0.439
IRF2BP2	protein	Q7Z5L9	UNIPROT	IRF2	protein	P14316	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								12799427	t		miannu	We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation.	SIGNOR-224073	0.652
LATS2	protein	Q9NRM7	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates	phosphorylation	Ser89	AQHVRSHsSPASLQL	9606									22658639	t	Together the YAP/TAZ-TEAD complex promotes proliferative and survival programs.	milica	In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus.	SIGNOR-197651	0.686
PRKCB	protein	P05771	UNIPROT	TP73	protein	O15350	UNIPROT	up-regulates activity	phosphorylation	Ser388	VPQPLVDsYRQQQQL	9606									19158275	t		miannu	Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388. 	SIGNOR-276234	0.2
MAPK1	protein	P28482	UNIPROT	NOXA1	protein	Q86UR1	UNIPROT	down-regulates	phosphorylation	Ser282	VGKQAPLsPGLPAMG	9606									20230789	t		lperfetto	Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity	SIGNOR-164227	0.331
CTDSP1	protein	Q9GZU7	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates activity	dephosphorylation			9606									32764831	t		miannu	CTDSP1 activates DNA-PKcs and enhances DNA-PKcs dependent topoI degradation in response to irinotecan .|Our novel finding indicates that CTDSP1 dephosphorylates DNA-PKcs, changes its kinase activity, and regulates irinotecan-induced topoI degradation.	SIGNOR-277101	0.2
CCR1	protein	P32246	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606									25230753	f			CCL3, an eosinophil precursor-produced chemokine that signals through CCR1, promotes terminal differentiation of CCR1-positive eosinophil precursors in the absence of IL-5, highlighting an autocrine loop capable of sustaining eosinophil differentiation	SIGNOR-254369	0.7
DUSP26	protein	Q9BV47	UNIPROT	FGFR1	protein	P11362	UNIPROT	down-regulates activity	dephosphorylation			9606									28701747	t		miannu	NEAP and DUSP26 dephosphorylated TrkA and FGFR1 directly.|We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells	SIGNOR-277104	0.2
POMT2	protein	Q9UKY4	UNIPROT	POMT 	complex	SIGNOR-C372	SIGNOR	form complex	binding			9606	BTO:0000007								16698797	t		miannu	 Here we have shown that POMT1 forms a complex with POMT2 and the complex possesses protein O-mannosyltransferase activity. Results indicate that POMT1 and POMT2 associate physically and functionally in vivo.  Mutations in the POMT1 and POMT2 genes are considered to be the cause of Walker-Warburg syndrome. Here, we have demonstrated that POMT1 and POMT2 form a functional complex in vivo using immunoprecipitating techniques. Furthermore, we showed that the mutations of POMT1 protein found in WWS patients do not prevent complex formation with POMT2 but they do abolish activity of the complex.	SIGNOR-265429	0.586
Caspase 8 complex	complex	SIGNOR-C231	SIGNOR	CASP9	protein	P55211	UNIPROT	up-regulates activity				-1									10988287	f		lperfetto	One indirect means through which caspase-8 might regulate caspase-9 activation is through a bcl-2-regulated pathway.	SIGNOR-256479	0.59
PSMB8	protein	P28062	UNIPROT	MCL1	protein	Q07820	UNIPROT	down-regulates quantity by destabilization				9606	BTO:0003445								19443843	t		Gianni	Surprisingly, siRNA knockdown of PSMB8 (LMP7), an ‘immunoproteasome’ component, reversed IFNγ-induced sensitivity to Fas ligation and prevented Fas/IFNγ-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-XL. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-XL levels after IFNγ treatment	SIGNOR-261974	0.2
CDK1	protein	P06493	UNIPROT	RPS3	protein	P23396	UNIPROT	up-regulates	phosphorylation	Thr221	KDEILPTtPISEQKG	9606									21871177	t		gcesareni	These results suggest that the phosphorylation of rps3 by cdk1 occurs at thr221 during g2/m phase and, moreover, that this event is important for nuclear accumulation of rps3.	SIGNOR-176131	0.371
PTK2	protein	Q05397	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr397	SVSETDDyAEIIDEE	9606									17828307	t		gcesareni	Fak y397 phosphorylation promotes src sh2 domain binding to fak, presumably leading to conformational src activation with a fak-src complex.	SIGNOR-157763	0.2
CDK1	protein	P06493	UNIPROT	MAPK6	protein	Q16659	UNIPROT	up-regulates	phosphorylation	Ser684	IGIPQFHsPVGSPLK	9606			SIGNOR-C17						20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.	SIGNOR-164487	0.461
OTULIN	protein	Q96BN8	UNIPROT	Ubiquitin	proteinfamily	SIGNOR-PF89	SIGNOR	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270829	0.704
RPS6KA3	protein	P51812	UNIPROT	KRT18	protein	P05783	UNIPROT	unknown	phosphorylation	Ser53	ISVSRSTsFRGGMGS	-1									7523419	t		lperfetto	Ser-52 in K18 is not glycosylated and matches consensus sequences for phosphorylation by CAM kinase, S6 kinase and protein kinase C, and all these kinases can phosphorylate K18 in vitro predominantly at that site.	SIGNOR-248895	0.304
α-Catenin	proteinfamily	SIGNOR-PF72	SIGNOR	YAP1	protein	P46937	UNIPROT	down-regulates activity	binding			9606									23431053	t		miannu	The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation.	SIGNOR-265823	0.2
TAX1BP1	protein	Q86VP1	UNIPROT	TRAF3	protein	Q13114	UNIPROT	down-regulates activity	binding												21885437	t		lperfetto	ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi. 	SIGNOR-275737	0.479
SMARCB1	protein	Q12824	UNIPROT	E2F1	protein	Q01094	UNIPROT	down-regulates				9606									12226744	f		miannu	We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6.	SIGNOR-92788	0.249
TLN1	protein	Q9Y490	UNIPROT	Av/b5 integrin	complex	SIGNOR-C178	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257630	0.572
CASP3	protein	P42574	UNIPROT	GORASP1	protein	Q9BQQ3	UNIPROT	up-regulates activity	cleavage	Asp390	LPQLTLPdSLTSAAS										17761173	t		lperfetto	In contrast, Caspase‐3 cleavage of GRASP‐1 releases the C‐terminal fragment, which in turn activates JNK signaling by serving as a scaffold protein 	SIGNOR-260613	0.405
PAK	proteinfamily	SIGNOR-PF13	SIGNOR	MYLK	protein	Q15746	UNIPROT	down-regulates activity	phosphorylation			-1									10748018	t	inferred from 70% family members	miannu	PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991.	SIGNOR-269973	0.2
PPP2CB	protein	P62714	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates activity	dephosphorylation	Ser129	NEAYEMPsEEGYQDY	9606									21562258	t			α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129	SIGNOR-248592	0.279
CSNK2A1	protein	P68400	UNIPROT	SNCA	protein	P37840	UNIPROT	up-regulates	phosphorylation	Ser87	KTVEGAGsIAAATGF	9606	BTO:0000938								10617630	t		lperfetto	In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes.	SIGNOR-73807	0.492
PAX1	protein	P15863	UNIPROT	MEOX1	protein	P50221	UNIPROT	up-regulates activity	binding			-1									11423130	t		miannu	We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family.	SIGNOR-222193	0.527
SOX4	protein	Q06945	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606	BTO:0003104								24970928	t		irozzo	The findings in this study raise the possibility that Sox4 may also antagonize Lef1 (Tcf1 is not expressed in pro-B lymphocytes) function by controlling the stability of β-catenin in pro-B lymphocytes. 	SIGNOR-256139	0.576
CDK1	protein	P06493	UNIPROT	PKN1	protein	Q16512	UNIPROT	up-regulates activity	phosphorylation	Ser916	TGEAPTLsPPRDARP	9606	BTO:0000567								31981797	t		miannu	CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines.	SIGNOR-276832	0.411
GRB2	protein	P62993	UNIPROT	SOS1	protein	Q07889	UNIPROT	up-regulates activity	relocalization			10090	BTO:0000669								23452850	t	GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP	lperfetto	Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate.	SIGNOR-235773	0.91
MARK2	protein	Q7KZI7	UNIPROT	PINK1	protein	Q9BXM7	UNIPROT	up-regulates activity	phosphorylation	Thr313	EGLGHGRtLFLVMKN	-1									22238344	t		miannu	 MARK2 phosphorylated and activated the cleaved form of PINK1 (ΔN-PINK1; amino acids 156-581). Thr-313 was the primary phosphorylation site, a residue mutated to a non-phosphorylatable form (T313M) in a frequent variant of PD. 	SIGNOR-276401	0.374
HNF4A	protein	P41235	UNIPROT	G6PC1	protein	P35575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18805788	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-181271	0.2
PRKCD	protein	Q05655	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates activity	phosphorylation	Thr909	PKSYLPQtVRQGGYM	-1									12361954	t		lperfetto	Finally, we identified Thr-890, a putative PKC phosphorylation site on gp130, to be critical for the effect of PKCdelta. Our data indicate that PKCdelta plays important regulatory roles in IL-6 signaling.	SIGNOR-249177	0.339
SATB2	protein	Q9UPW6	UNIPROT	IGHM	protein	P01871	UNIPROT	up-regulates quantity	transcriptional regulation			9606									14701874	t		gianni	The SATB2 protein was shown to bind MAR sequences flanking the enhancer of the endogenous immunoglobulin μ heavy chain (IgH) gene in vivo, and this binding was found to correlate with an increase in the expression of a transfected rearranged μ wild-type gene	SIGNOR-268933	0.2
IFNA1	protein	P01562	UNIPROT	IFNAR2	protein	P48551	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								11278538	t		lperfetto	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-219298	0.611
DGCR8	protein	Q8WYQ5	UNIPROT	Microprocessor complex	complex	SIGNOR-C356	SIGNOR	form complex	binding			9606	BTO:0000552								24581491	t		lperfetto	Microprocessor minimally comprises the ribonuclease DROSHA and its double-stranded RNA-binding partner DGCR8 (Denli et al., 2004; Gregory et al., 2004). Microprocessor recognizes pri-miRNA through the stem-loop (Zeng et al., 2005) and the stem-loop-ssRNA junction (Han et al., 2006), and cleaves both the 5′ and 3′ flanking segments to generate pre-miRNA.	SIGNOR-264849	0.922
D-serine	smallmolecule	CHEBI:16523	ChEBI	NMDA receptor_2C	complex	SIGNOR-C349	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0002609								12393813	t		lperfetto	D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically 	SIGNOR-268279	0.8
CSF1R	protein	P07333	UNIPROT	CSF1R	protein	P07333	UNIPROT	down-regulates	phosphorylation	Tyr969	PLLQPNNyQFC	9606	BTO:0001271								15297464	t		lperfetto	Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) following ligand binding, the csf-1r is rapidly internalized and degraded. This process begins with multiubiquitination of the csf-1r mediated by c-cbl (20), an e3-type ubiquitin ligase	SIGNOR-127626	0.2
IL10RA	protein	Q13651	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates activity	binding			9606	BTO:0000801;BTO:0000776								10347215	t		miannu	Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor alpha Chain) and tyk2 (associated with the il-10 receptor beta Chain) and induces the activation of stat1, stat3, and, in some cells, stat5.	SIGNOR-68010	0.801
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	RASSF1	protein	Q9NS23	UNIPROT	down-regulates	binding			9606									21776416	t		gcesareni	Basal inactivation of rassf1a is achieved by rassf1a self association and via 14-3-3 interactions (to isoforms s and e) at serine 175/178/179 of rassf1a.	SIGNOR-175121	0.2
CDK1	protein	P06493	UNIPROT	TOP2A	protein	P11388	UNIPROT	unknown	phosphorylation	Ser1361	SPPKTKTsPKLSNKE	9606	BTO:0000567								7635160	t		llicata	We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. we have also shown that phosphorylation of ser1353 and ser1360 yields different phosphopeptide maps depending upon whether one or both of these sites are phosphorylated.	SIGNOR-30252	0.54
TNFSF13B	protein	Q9Y275	UNIPROT	TNFRSF13C	protein	Q96RJ3	UNIPROT	up-regulates activity	binding			9606	BTO:0000782								15851487	t		lperfetto	Baff specifically binds baff receptor	SIGNOR-135713	0.778
SEC23B	protein	Q15437	UNIPROT	COPII vesicle	complex	SIGNOR-C370	SIGNOR	form complex	binding			9606	BTO:0000567								30605680	t		lperfetto	The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat	SIGNOR-265288	0.696
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	STK3	protein	Q13188	UNIPROT	down-regulates	phosphorylation	Thr117	IIRLRNKtLIEDEIA	9606									20086174	t		lperfetto	We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2.	SIGNOR-244345	0.2
arginine	smallmolecule	CHEBI:29016	ChEBI	Arg-tRNA(Arg)	smallmolecule	CHEBI:18366	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270370	0.8
KAT2B	protein	Q92831	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates	acetylation			9606		BTO:0000887							10944526	t		gcesareni	Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo	SIGNOR-81056	0.632
mTORC1	complex	SIGNOR-C3	SIGNOR	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates activity				10090	BTO:0002314								25047835	f			Knockdown (KD) of either mTORC or its subunit Raptor delayed SC activation without influencing the differentiation program.	SIGNOR-256273	0.7
CDK2	protein	P24941	UNIPROT	PELP1	protein	Q8IZL8	UNIPROT	up-regulates	phosphorylation	Ser991	PALPPPEsPPKVQPE	9606									20807815	t		llicata	We identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we conclude that pelp1 is a novel substrate of interphase cdks and that its phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function.	SIGNOR-167766	0.376
PD173955	chemical	CHEBI:49791	ChEBI	SRC	protein	P12931	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258264	0.8
CEBPA	protein	P49715	UNIPROT	HAMP	protein	P81172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001950								18671304	f		miannu	 HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter.	SIGNOR-253770	0.302
superoxide	smallmolecule	CHEBI:18421	ChEBI	SOD1	protein	P00441	UNIPROT	up-regulates activity	precursor of			9606									29301787	t		lperfetto	Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD).	SIGNOR-272288	0.8
SESN1	protein	Q9Y6P5	UNIPROT	GATOR2	complex	SIGNOR-C193	SIGNOR	down-regulates activity	binding			10090	BTO:0002572								25457612	t			We describe AMPK-independent mechanism of mTORC1 regulation by the Sestrins, in which the Sestrins inhibit mTORC1 localization to the lysosomes in a Rag-dependent manner through an interaction with GATOR2	SIGNOR-253559	0.439
PICK1	protein	Q9NRD5	UNIPROT	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	up-regulates activity	binding			9534	BTO:0000298								25784538	t	inferred from family member	miannu	RAB39B directs GluA2 trafficking in neurons. GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a–c). The existence of such complex is supported by our co-immunoprecipitation experiments shown above.	SIGNOR-270236	0.801
CDC25A	protein	P30304	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000093								15672448	t		gcesareni	We found that cdc25a physically interacted with and de-phosphorylated phospho-erk both in vitro and in cell culture.	SIGNOR-133392	0.405
SARS1	protein	P49591	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									24095058	t		miannu	As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis	SIGNOR-270495	0.8
CBX1	protein	P83916	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	binding			9606									19111658	t		miannu	A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing.	SIGNOR-265323	0.2
EGR1	protein	P18146	UNIPROT	HYAL1	protein	Q12794	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004796								18718911	f		miannu	In 253J-Lung and HT1376 bladder cancer cell lines, which show high HYAL-1 expression, transcription factors Egr-1, AP-2, and NFκB bind the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription.	SIGNOR-253878	0.2
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	NRAS	protein	P01111	UNIPROT	up-regulates activity				9534									8402896	f		miannu	BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation. 	SIGNOR-261506	0.2
PTPN1	protein	P18031	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	dephosphorylation	Tyr740	TGESDGGyMDMSKDE	-1									7545675	t			Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides	SIGNOR-248413	0.679
BMPR1B	protein	O00238	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates	phosphorylation			9606									19620713	t		gcesareni	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-187190	0.628
SRC	protein	P12931	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates activity	phosphorylation	Tyr1161	FGMTRDIyETDYYRK	-1									7493944	t		lperfetto	The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.	SIGNOR-246272	0.564
MAML1	protein	Q92585	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	binding			9606		BTO:0000887							18758483	t		gcesareni	Unexpectedly, however, emerging evidence implicate maml proteins as exciting key transcriptional co-activators in other signal transduction pathways including: muscle differentiation and myopathies (mef2c), tumor suppressor pathway (p53) and colon carcinoma survival (beta-catenin).	SIGNOR-180136	0.316
PRKCD	protein	Q05655	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser304	GAPPRRSsIRNAHSI	9606									12056906	t		esanto	Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?.	SIGNOR-89221	0.459
POLR1E	protein	Q9GZS1	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding												22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266153	0.788
FER	protein	P16591	UNIPROT	FER	protein	P16591	UNIPROT	up-regulates activity	phosphorylation	Tyr714	RQEDGGVySSSGLKQ	9534									10998246	t			P94fer undergoes autophosphorylation in-trans in vivo and that oligomerization mediates this process. the N-terminal sequences of the FER tyrosine kinases direct their different cellular autophosphorylation states, thereby dictating their different cellular functions.	SIGNOR-251133	0.2
PRKAA1	protein	Q13131	UNIPROT	FOXO1	protein	Q12778	UNIPROT	up-regulates	phosphorylation			9606			SIGNOR-C15						17900900	t		gcesareni	The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt.	SIGNOR-157941	0.434
MAPK14	protein	Q16539	UNIPROT	NFATC4	protein	Q14934	UNIPROT	down-regulates activity	phosphorylation	Ser168	QGGGAFFsPSPGSSS	10029	BTO:0001131								11997522	t		miannu	P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity.	SIGNOR-250107	0.411
HSD17B11	protein	Q8NBQ5	UNIPROT	androst-5-ene-3beta,17beta-diol	smallmolecule	CHEBI:2710	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0001363							30943210	t		lperfetto	Testicular 17betaHSD3 converts DHEA to androstenediol and androstenedione to testosterone	SIGNOR-268660	0.8
mifepristone	chemical	CHEBI:50692	ChEBI	NR1I2	protein	O75469	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000318								9727070	t		miannu	As shown in Fig. 4 A, hPXR was activated by the synthetic steroids dexamethasone, dexamethasone-t-butylacetate, PCN, RU486, spironolactone, and cyproterone-acetate. Dexamethasone-t-butylacetate and RU486 were the most efficacious activators of hPXR among the synthetic steroids tested. 	SIGNOR-258829	0.8
GTF2B	protein	Q00403	UNIPROT	FOXF2	protein	Q12947	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								9722567	t		miannu	The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB. FREAC-2 dependent activation of transcription by TFIIB.	SIGNOR-220317	0.505
PRKACA	protein	P17612	UNIPROT	PHOX2A	protein	O14813	UNIPROT	down-regulates	phosphorylation	Ser153	RKQERAAsAKGAAGA	9606									19564421	t		llicata	Phox2a becomes phosphorylated by protein kinase a (pka) on ser153, which prevents association of phox2a with dna and terminates p27(kip1) transcription.	SIGNOR-186462	0.311
EGFR	protein	P00533	UNIPROT	IKBKE	protein	Q14164	UNIPROT	up-regulates activity	phosphorylation	Tyr179	SVYGTEEyLHPDMYE	9606									27287717	t		miannu	EGFRL858R/T790M phosphorylates IKBKE at tyrosine residues. While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179. 	SIGNOR-277243	0.26
BCL7C	protein	Q8WUZ0	UNIPROT	GBAF	complex	SIGNOR-C467	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269780	0.518
ARHGEF4	protein	Q9NR80	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260532	0.729
HBA1	protein	P69905	UNIPROT	Hemoglobin	complex	SIGNOR-C209	SIGNOR	form complex	binding			9606									18179859	t		miannu	AHSP does not bind to β-hemoglobin (βHb) or the hemoglobin tetramer, instead, it specifically binds to free αHb, avoiding its precipitation and its pro-oxidant activity. In the presence of βHb, the αHb-AHSP complex is dismembered and βHb displaces AHSP to generate the quaternary structure of hemoglobin	SIGNOR-255274	0.698
EML4-ALK	fusion protein	SIGNOR-FP8	SIGNOR	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000944								21415216	t		irozzo	We also found that phosphorylation of both the mitogen-activated proteinkinase (MAPK) ERK and STAT3 was markedly increased inthe cells expressing either variant of EML4-ALK[.]. Oncogenic EML4-ALK tyrosine kinase activates ERKand STAT3 signaling pathways	SIGNOR-259203	0.2
RARA	protein	P10276	UNIPROT	SLCO1B3	protein	Q9NPD5	UNIPROT	up-regulates quantity by expression	transcriptional regulation												15322262	t		lperfetto	Taken together, these findings suggest that the LPS-induced down-regulation of Oatp4 is likely due to reduction in the binding of HNF1alpha, C/EBP, HNF3, and RXR:RAR to the Oatp4 promoter.	SIGNOR-268989	0.2
C5AR1	protein	P21730	UNIPROT	CR1	protein	P17927	UNIPROT	up-regulates quantity by expression													1847994	f		lperfetto	The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 	SIGNOR-263466	0.464
ABL1	protein	P00519	UNIPROT	PLCG1	protein	P19174	UNIPROT	down-regulates activity	phosphorylation	Tyr771	IGTAEPDyGALYEGR	9606	BTO:0002181								12652307	t		miannu	C-Abl induces Tyr phosphorylation of PLC-γ1 in vivo. These findings demonstrate that c-Abl phosphorylates PLC-γ1 in vivo predominantly at Tyr 771 and Tyr 1003.c-Abl phosphorylation of PLC-γ1 causes downregulation of PLC activity.	SIGNOR-276001	0.571
NOX3	protein	Q9HBY0	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	up-regulates quantity	chemical modification			9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264722	0.8
SRC	protein	P12931	UNIPROT	HDAC3	protein	O15379	UNIPROT	up-regulates activity	phosphorylation	Tyr331	PYSEYFEyFAPDFTL	-1									30317579	t		miannu	C-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form). 	SIGNOR-277486	0.394
NFX1	protein	Q12986	UNIPROT	TERT	protein	O14746	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17267499	t		miannu	NFX1-123 positively regulated hTERT expression, as its knockdown decreased hTERT mRNA levels and telomerase activity and its overexpression increased telomerase activity. NFX1-123 was found to interact with cytoplasmic poly(A) binding proteins (PABPCs), and together they synergistically augmented expression from the hTERT promoter when activated by HPV16 E6.	SIGNOR-261050	0.505
MAPK3	protein	P27361	UNIPROT	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation	Ser759	KTPDGNKsPAPKPSD	9606		BTO:0001260							10514499	t		lperfetto	Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin.	SIGNOR-71041	0.46
GSK3B	protein	P49841	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	phosphorylation			9606									12123574	t		gcesareni	Here, we observed that gsk3beta was able to bind and phosphorylate notch1ic in vitro, and attenuation of gsk3beta activity reduced phosphorylation of notchic in vivo.Functionally, ligand-activated signaling through the endogenous notch1 receptor was reduced in gsk3beta fibroblasts, implying a positive role for gsk3beta in mammalian notch signaling.	SIGNOR-90608	0.475
CSNK2B	protein	P67870	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates activity	phosphorylation	Ser64	LQTDGNRsSHSRLGR	9606	BTO:0000567								11583622	t		llicata	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-251053	0.289
PPP6C	protein	O00743	UNIPROT	MAP3K7	protein	O43318	UNIPROT	down-regulates activity	dephosphorylation	Thr187	CDIQTHMtNNKGSAA	9606									17079228	t			Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway|From proteomic analysis of TAK1-binding proteins, we identified protein phosphatase 6 (PP6), a type-2A phosphatase, and demonstrated that PP6 associated with and inactivated TAK1 by dephosphorylation of Thr-187.	SIGNOR-248292	0.379
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser274	ASPQRSRsPSPQPSS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248375	0.598
TBK1	protein	Q9UHD2	UNIPROT	REL/RELA	complex	SIGNOR-C68	SIGNOR	up-regulates	phosphorylation			9606									16888014	t		lperfetto	The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel.	SIGNOR-217667	0.584
HPS5	protein	Q9UPZ3	UNIPROT	BLOC-2	complex	SIGNOR-C252	SIGNOR	form complex	binding			9606									15030569	t		lperfetto	Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS7	SIGNOR-260689	0.702
lurasidone	chemical	CHEBI:70735	ChEBI	HTR7	protein	P34969	UNIPROT	down-regulates activity	chemical inhibition			10030	BTO:0000246								20404009	t		Luana	In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype. 	SIGNOR-257840	0.8
ACOT8	protein	O14734	UNIPROT	succinyl-CoA(5-)	smallmolecule	CHEBI:57292	ChEBI	down-regulates quantity	chemical modification												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271810	0.8
MPHOSPH10	protein	O00566	UNIPROT	UTP3	protein	Q9NQZ2	UNIPROT	up-regulates activity	binding			-1									28813493	t		miannu	 Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome.	SIGNOR-261176	0.931
CSNK1A1	protein	P48729	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity.	SIGNOR-183664	0.2
CHEK1	protein	O14757	UNIPROT	CHEK1	protein	O14757	UNIPROT	up-regulates activity	phosphorylation	Ser296	GFSKHIQsNLDFSPV	9606	BTO:0001938								23068608	t		lperfetto	TheSer296autophosphorylation ofCHK1is mainly regulated by an intramolecular mechanism in response to DNA damage.	SIGNOR-217904	0.2
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1917	SPTSPTYsPTSPKYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273050	0.556
ADAM17	protein	P78536	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates activity	cleavage			9606	BTO:0000567								10882063	t		gcesareni	... here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to tace (tnfalpha-converting enzyme), a member of the adam (a disintegrin and metalloprotease domain) family of metalloproteases.	SIGNOR-254334	0.729
SRPK2	protein	P78362	UNIPROT	ACIN1	protein	Q9UKV3	UNIPROT	up-regulates	phosphorylation	Ser1180	GPRSRSRsRDRRRKE	9606	BTO:0001271								18559500	t		lperfetto	Here, we show that srpk2 binds and phosphorylates acinus, an sr protein essential for rna splicing, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin a1 but not a2 up-regulation. Acinus s422d, an srpk2 phosphorylation mimetic, enhances cyclin a1 transcription, whereas acinus s422a, an unphosphorylatable mutant, blocks the stimulatory effect of srpk2	SIGNOR-179006	0.488
CDC25A	protein	P30304	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates activity	dephosphorylation	Thr14	VEKIGEGtYGVVYKA	9606									10454565	t			The phosphatase activity of Cdc25A is necessary for Cdk2 activation, most likely due to dephosphorylation on Tyr-15 and Thr-14 of Cdk2.	SIGNOR-248481	0.824
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	SOD2	protein	P04179	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21357467	f		gcesareni	The nfkb p65/p50 heterodimer increases sod2, and p50/p50 suppresses it nf-kb p65/p50 binds to the enhancer and is important for cytokine-induced sod2	SIGNOR-172392	0.494
PDGFRA	protein	P16234	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	phosphorylation			9606									7535778	t		miannu	Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production.	SIGNOR-28176	0.634
XL765	chemical	CHEBI:71958	ChEBI	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207878	0.8
zotepine	chemical	CHEBI:32316	ChEBI	ADRA2B	protein	P18089	UNIPROT	down-regulates activity	chemical inhibition			10116									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258559	0.8
CRYBB2	protein	P43320	UNIPROT	Maintenance_of_lens_transparency	phenotype	SIGNOR-PH65	SIGNOR	up-regulates				9606									16319073	f		miannu	At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency.	SIGNOR-252151	0.7
WWTR1	protein	Q9GZV5	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22470139	f		miannu	Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation.	SIGNOR-255607	0.536
FGF11	protein	Q92914	UNIPROT	SCN11A	protein	Q9UI33	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253438	0.2
CDK1	protein	P06493	UNIPROT	RAB5B	protein	P61020	UNIPROT	unknown	phosphorylation	Ser123	KELQRQAsPSIVIAL	9606									10403367	t		lperfetto	Cdc2 kinase preferentially phosphorylates ser-123 of rab5b. More work will be required to establish how phosphorylation of the three rab5 isoforms influences their function in the endocytic pathway	SIGNOR-69233	0.331
ESR1	protein	P03372	UNIPROT	NCOA2	protein	Q15596	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11477071	f		lperfetto	Er_ mutants unable to bind coactivators drastically decrease estradiol regulation of ap-1-mediated transcription and overexpression of the coactivator grip1	SIGNOR-109520	0.81
GUCY1A3-B2	complex	SIGNOR-C139	SIGNOR	3',5'-cyclic GMP	smallmolecule	CHEBI:16356	ChEBI	up-regulates quantity	chemical modification			9606									10977868	t		gcesareni	Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types	SIGNOR-244122	0.8
PDPK1	protein	O15530	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Thr308	KDGATMKtFCGTPEY										19951971	t		lperfetto	PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain.	SIGNOR-249629	0.736
WNT9A	protein	O14904	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-132073	0.645
GAPDH	protein	P04406	UNIPROT	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	down-regulates quantity	chemical modification			9606									11724794	t		miannu	GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion	SIGNOR-266495	0.8
KIF2C	protein	Q99661	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272529	0.7
PPP2CB	protein	P62714	UNIPROT	RALA	protein	P11233	UNIPROT	down-regulates	dephosphorylation	Ser194	NGKKKRKsLAKRIRE	9606									17540176	t		miannu	Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function	SIGNOR-155353	0.293
STK40	protein	Q8N2I9	UNIPROT	CEBPB	protein	P17676	UNIPROT	down-regulates quantity by destabilization	binding			10090	BTO:0000078								32795415	t		Gianni	The COP1-interacting protein STK40 (Durzynska et al., 2017), which was detected in c/EBPβ complexes from BMDMs (Figure 1B), also appeared to contribute to the suppression of c/EBPβ in microglia. Specifically, deletion of the STK40 pseudokinase increased the amount of c/EBPβ protein without increasing the amount of Cebpb mRNA	SIGNOR-261925	0.283
AURKB	protein	Q96GD4	UNIPROT	ZWINT	protein	O95229	UNIPROT	up-regulates activity	phosphorylation	Ser262	MGRDPGVsFKAVGLQ	-1									21775627	t		lperfetto	Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores|During prometaphase, AurB phosphorylation of zwint-1 is required for recruitment of ZW10-, pT89 dynein-, and RZZ-dependent proteins to kinetochores. This is defective after AurB inhibition or after expression of the triple-A zwint-1 mutant. Triple-E mutant zwint-1 mimics phospho–zwint-1 in RZZ recruitment, even after AurB inhibition	SIGNOR-265011	0.637
AUTS2	protein	Q8WXX7	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606									25533347	f		miannu	AUTS2 is involved in neurite outgrowth and branch formation in neurons.	SIGNOR-266818	0.7
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr529	TPGSRSRtPSLPTPP	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249323	0.754
PTPN1	protein	P18031	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	dephosphorylation	Tyr1021	PNEGDNDyIIPLPDP	-1									7545675	t			Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides	SIGNOR-248417	0.679
GSK3B	protein	P49841	UNIPROT	DROSHA	protein	Q9NRR4	UNIPROT	up-regulates activity	phosphorylation	Ser300	RHRDNRRsPSLERSY	-1									25699712	t		lperfetto	Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes. 	SIGNOR-264845	0.282
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3-2	protein	Q5TEC6	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269633	0.2
HARS1	protein	P12081	UNIPROT	His-tRNA(His)	smallmolecule	CHEBI:29155	ChEBI	up-regulates quantity	chemical modification			9606									10430027	t		miannu	Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 	SIGNOR-270490	0.8
LPAR4	protein	Q99677	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257383	0.357
MAPK1	protein	P28482	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates	phosphorylation	Ser40	RQPSPSPsPTERAPA	9606	BTO:0001271								15093545	t		llicata	We report here that as(2)o(3) treatment induces phosphorylation of the pml protein through a mitogen-activated protein (map) kinase pathway. Increased pml phosphorylation is associated with increased sumoylation of pml and increased pml-mediated apoptosis.	SIGNOR-124248	0.366
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2W	protein	Q96B02	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271374	0.502
CDK5	protein	Q00535	UNIPROT	AMPH	protein	P49418	UNIPROT	unknown	phosphorylation	Ser272	EEPSPLPsPTASPNH	-1									11113134	t		llicata	Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. 	SIGNOR-250648	0.537
COMMD5	protein	Q9GZQ3	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates quantity	relocalization			9606									30021164	f		miannu	Here, we demonstrate that COMMD5 is crucial for the stability of the cytoskeleton. Its silencing leads to a major re-organization of actin and microtubule networks. The N terminus of COMMD5 binds to the endosomal Rab5, and its C terminus, including the COMMD domain, binds to the cytoskeletal scaffolding. COMMD5 participates in long-range endosome transport, including epidermal growth factor receptor (EGFR) recycling, and provides the strength to deform and assist the scission of vesicles into sorting endosomes. This study establishes the molecular mechanism by which COMMD5 acts as an adaptor protein to coordinate endosomal trafficking and reveals its important role for EGFR transport and activity.	SIGNOR-261692	0.2
STK4	protein	Q13043	UNIPROT	FOXO1	protein	Q12778	UNIPROT	up-regulates	phosphorylation	Ser212	SSAGWKNsIRHNLSL	9606									18394876	t		gcesareni	Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1.	SIGNOR-178186	0.582
BLK	protein	P51451	UNIPROT	FCGR2A	protein	P12318	UNIPROT	up-regulates activity	phosphorylation	Tyr288	YETADGGyMTLNPRA	-1									8756631	t		lperfetto	To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.	SIGNOR-249311	0.448
AKT3	protein	Q9Y243	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Thr32	QSRPRSCtWPLQRPE										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-252876	0.697
D-thyroxine	smallmolecule	CHEBI:30659	ChEBI	THRA	protein	P10827	UNIPROT	up-regulates activity	chemical activation			9606									6777394	t		miannu	 The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response.	SIGNOR-258402	0.8
EGF	protein	P01133	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606									12648462	t		lperfetto	The mammalian ligands that bind the egf receptor (egfr [her1, erb-b1]) include egf, transforming growth factor- (tgf), heparin-binding egf-like growth factor (hb-egf), amphiregulin (ar), betacellulin (btc), epiregulin (epr), and epigen	SIGNOR-22716	0.948
TRIM59	protein	Q8IWR1	UNIPROT	IRF7	protein	Q92985	UNIPROT	down-regulates activity				9606	BTO:0000567; BTO:0002181								22588174	f		Giorgia	TRIM59 also inhibited the phosphorylation of IRF3 and IRF7, which induces dimerization, suggesting that TRIM59 negatively regulates kinases for IRF3/7 (IKKe/TBK1) or their upstream signal	SIGNOR-260374	0.261
AURKA	protein	O14965	UNIPROT	SGO1	protein	Q5FBB7	UNIPROT	up-regulates activity	phosphorylation			-1									16824953	t		lperfetto	Loss of INCENP/Aurora B in Mitosis Correlates with Delocalization of MEI-S332|MEI-S332 Is Phosphorylated by Aurora B In Vitro|Of these, MEI-S332S124,125,126A was a poor substrate for Aurora B kinase in vitro	SIGNOR-252046	0.2
ZBTB16	protein	Q05516	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				10090	BTO:0002882								9710637	f		fcortellessa	PLZF overexpression leads to apoptosis. 	SIGNOR-261686	0.7
LIG4	protein	P49917	UNIPROT	Lig4-Xrcc4 complex	complex	SIGNOR-C354	SIGNOR	form complex	binding			-1									19837014	t		miannu	The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals. 	SIGNOR-264533	0.95
FYN	protein	P06241	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									15537652	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Here we provide evidence that fyn kinase, a member of the src kinase family, is involved in the uvb-induced phosphorylation of histone h3 at serine 10	SIGNOR-130274	0.2
haloperidol	chemical	CHEBI:5613	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258523	0.8
CSNK1A1	protein	P48729	UNIPROT	HNRNPC	protein	P07910	UNIPROT	down-regulates activity	phosphorylation	Ser299	EGEDDRDsANGEDDS	9606									15687492	t		gcesareni	In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C.	SIGNOR-133536	0.361
DICER1/hAgo2/PRKRA	complex	SIGNOR-C41	SIGNOR	NcRNA_processing	phenotype	SIGNOR-PH95	SIGNOR	up-regulates				9606									23661684	f		lperfetto	To test small RNA processing by such PACT-containing complexes, we tested the substrates described above for cleavage rates (pre-let-7a, pre-miR-34c and dsRNA W1) and product length specificity (pre-miR-200a and pre-miR-34c). The results of these experiments showed that Dicer–Ago2–TRBP and Dicer–Ago2–PACT produce the same miRNA products from pre-miR-200a and pre-miR-34c substrates as observed for Dicer–TRBP and Dicer–PACT, respectively (Figure 3A).	SIGNOR-255322	0.7
ROS	stimulus	SIGNOR-ST2	SIGNOR	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates				10090									18074631	f		lperfetto	In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat.	SIGNOR-253397	0.7
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	MEF2D	protein	Q14814	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser110	GEDSLEQsPLLEDKY	10090	BTO:0000944								25733682	t		miannu	 MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding. 	SIGNOR-276888	0.268
SCARB1	protein	Q8WTV0	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	binding			10090									26059978	t		Giulio	Importantly, coimmunoprecipitation of SR-BI and Src demonstrated that the two proteins are directly associated in WT macrophages (Fig. 7B), suggesting that SR-BI plays a direct role in activation of Src in macrophages.	SIGNOR-260314	0.378
sunitinib	chemical	CHEBI:38940	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			9606									20570526	t		Luana	Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors],	SIGNOR-257850	0.8
PLK1	protein	P53350	UNIPROT	TRIOBP	protein	Q9H2D6	UNIPROT	up-regulates	phosphorylation	Thr447	ASSPSRAtRDNPTTS	9606									22820163	t		lperfetto	Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1	SIGNOR-198357	0.34
CHD8	protein	Q9HCK8	UNIPROT	SOX2	protein	P48431	UNIPROT	down-regulates quantity	transcriptional regulation			10090									32839322	t		Gianni	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268921	0.323
NLRP3 inflammasome	complex	SIGNOR-C225	SIGNOR	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606									32133002	f		miannu	Both the NLRP3 inflammasome activation and the subsequent inflammation play significant roles in defending against viral infections. However, aberrant NLRP3 inflammasome activation or chronic inflammation can also lead to severe pathological injury. Accordingly, activation of the NLRP3 inflammasome and its associated inflammation is a double-edged sword for host to defense viral infection. Modulating the NLRP3 inflammasome activity can prove to be a promising strategy for the intervention of viral diseases.	SIGNOR-260346	0.7
GSK3B	protein	P49841	UNIPROT	BORA	protein	Q6PGQ7	UNIPROT	up-regulates	phosphorylation	Ser274	TSPSPISsPTFSPIE	9606									23442801	t		lperfetto	It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation	SIGNOR-201515	0.261
FREM1	protein	Q5H8C1	UNIPROT	NPNT	protein	Q6UXI9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									22613833	t		lperfetto	The loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1-dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome.	SIGNOR-253308	0.375
solifenacin	chemical	CHEBI:135530	ChEBI	CHRM2	protein	P08172	UNIPROT	down-regulates activity	chemical inhibition			-1									21524581	t		Luana	The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference	SIGNOR-258311	0.8
RBM38	protein	Q9H0Z9	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation			9606									17050675	t		Luana	Here, we found that RNPC1, an RNA-binding protein and a target of the p53 family, is required for maintaining the stability of the basal and stress-induced p21 transcript. 	SIGNOR-275391	0.325
ATM	protein	Q13315	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	up-regulates	phosphorylation	Thr302	PEPEVLStQEDLFDQ	9606									22621922	t		gcesareni	Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm.	SIGNOR-197619	0.869
GSK3B	protein	P49841	UNIPROT	FBXO4	protein	Q9UKT5	UNIPROT	up-regulates	phosphorylation	Ser12	EPRSGTNsPPPPFSD	9606									21242966	t		lperfetto	Gsk3beta-mediated phosphorylation of fbx4 ser12 during the g1/s transition regulates fbx4 dimerization, which in turn governs fbx4-driven e3 ligase activity.	SIGNOR-171648	0.2
FGF13	protein	Q92913	UNIPROT	SCN4A	protein	P35499	UNIPROT	down-regulates activity	binding			9606		BTO:0001103							20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253431	0.255
KLF13	protein	Q9Y2Y9	UNIPROT	SIN3A	protein	Q96ST3	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								11438660	t		miannu	detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.	SIGNOR-222437	0.443
B4GALT1	protein	P15291	UNIPROT	D-glucopyranose	smallmolecule	CHEBI:4167	ChEBI	down-regulates quantity	chemical modification			9606									16157350	t		miannu	Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 	SIGNOR-268468	0.8
KDM2B	protein	Q8NHM5	UNIPROT	CDK1	protein	P06493	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000011								25533466	f		miannu	We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis.	SIGNOR-252244	0.283
USP14	protein	P54578	UNIPROT	CXCR4	protein	P61073	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0000007								26523394	t		lperfetto	The physical interaction of CXCR4 and USP14 is paralleled by USP14-catalyzed deubiquitination of the receptor|We also observed that ubiquitination of CXCR4 facilitated receptor degradation, whereas overexpression of USP14 or RNAi-induced knockdown of USP14 blocked CXCL12-mediated CXCR4 degradation	SIGNOR-265057	0.459
SMAD4	protein	Q13485	UNIPROT	SMAD5/SMAD4	complex	SIGNOR-C205	SIGNOR	form complex	binding			9606									20957627	t		lperfetto	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.	SIGNOR-255267	0.659
PAK1	protein	Q13153	UNIPROT	AURKA	protein	O14965	UNIPROT	up-regulates	phosphorylation	Thr288	APSSRRTtLCGTLDY	9606									24867643	t		lperfetto	The upstream pak1 kinase can phosphorylate aurora a at t288, autophosphorylation appears to be the essential mode of activation. Our experiments suggest that phosphorylation of t288 is important for regulation of the aurora2 kinase both for its activity and its stability	SIGNOR-205110	0.392
PPP3CA	protein	Q08209	UNIPROT	NFATC3	protein	Q12968	UNIPROT	up-regulates	dephosphorylation			9606									21880741	t		gcesareni	Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.	SIGNOR-176376	0.519
TMLHE	protein	Q9NVH6	UNIPROT	N(6),N(6),N(6)-trimethyl-L-lysine	smallmolecule	CHEBI:17311	ChEBI	down-regulates quantity	chemical modification			9606									11431483	t		miannu	Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. 	SIGNOR-269681	0.8
bisphenol A	chemical	CHEBI:33216	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			-1									31995776	t		miannu	This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . 	SIGNOR-268729	0.8
SOX9	protein	P48436	UNIPROT	CEBPD	protein	P49716	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19254573	t		fspada	Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation	SIGNOR-184283	0.275
neratinib	chemical	CHEBI:61397	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000551								17311002	t		gcesareni	However, the same cells were highly sensitive to the irreversible dual-specificity egfr/erbb2 kinase inhibitor hki-272, as were those overexpressing wild-type erbb2.	SIGNOR-153318	0.8
PRKCB	protein	P05771	UNIPROT	TFEB	protein	P19484	UNIPROT	up-regulates activity	phosphorylation	Ser466	SKASSRRsSFSMEEG	10090									23599343	t			This occurs following PKCβ phosphorylation of TFEB on three serine residues located in its last 15 amino acids. This post-translational modification stabilizes and increases the activity of this transcription factor.	SIGNOR-255315	0.337
NR2F1	protein	P10589	UNIPROT	RXRA	protein	P19793	UNIPROT	up-regulates	binding			9606									10900149	t		lperfetto	Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site	SIGNOR-79440	0.529
SMAD6	protein	O43541	UNIPROT	MAP3K7	protein	O43318	UNIPROT	down-regulates activity	binding			10116									11737269	t		lperfetto	Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads.	SIGNOR-235571	0.551
CTDSPL	protein	O15194	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation	Thr220	QSNYIPEtPPPGYIS	9606	BTO:0000007								17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248309	0.475
MAP4K1	protein	Q92918	UNIPROT	T_cell_activation	phenotype	SIGNOR-PH73	SIGNOR	down-regulates				9606	BTO:0000661								17353368	f	phosphorilation: Ser376	Barakat	Thus, our study reveals the mechanism of a novel negative feedback loop initiated from SLP-76 to modulate signal intensity during T cell activation.	SIGNOR-274563	0.7
RDX	protein	P35241	UNIPROT	Platelet_aggregation	phenotype	SIGNOR-PH81	SIGNOR	up-regulates				9606	BTO:0000132								35267019	f		miannu	Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. Taken together, these results suggest that Rev-erbα potentiates platelet activation via an OPHN-1-mediated RhoA/ERM signalling pathway.	SIGNOR-268433	0.7
SPI1	protein	P17947	UNIPROT	CD68	protein	P34810	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000801								12676954	f			However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element.	SIGNOR-254286	0.334
PRKD1	protein	Q15139	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									20179209	t		lperfetto	Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated	SIGNOR-163920	0.311
CSNK2A1	protein	P68400	UNIPROT	CARD9	protein	Q9H257	UNIPROT	down-regulates activity	phosphorylation	Thr531	NTTGSDNtDTEGS	9606	BTO:0000567								17936701	t			PVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2	SIGNOR-262290	0.352
POU3F2	protein	P20265	UNIPROT	GNRH1	protein	P01148	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11875100	f		miannu	 Functional studies demonstrated that Brn-2 increased promoter activity of the human and mouse GnRH genes.	SIGNOR-254928	0.284
RASGEF1C	protein	Q8N431	UNIPROT	NRAS	protein	P01111	UNIPROT	up-regulates	binding			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-161511	0.2
SELPLG	protein	Q14242	UNIPROT	SELP	protein	P16109	UNIPROT	up-regulates	binding			9606	BTO:0000130;BTO:0000150;BTO:0000551	BTO:0000975							9129046	t		gcesareni	The major ligand for p-selectin on leukocytes is p-selectin glycoprotein ligand-1 (PSGL-1)	SIGNOR-47625	0.925
MYLK	protein	Q15746	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates	phosphorylation	Thr19	KKRPQRAtSNVFAMF	9606									19851336	t		lperfetto	More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.	SIGNOR-188801	0.833
STXBP1	protein	P61764	UNIPROT	STX1A	protein	Q16623	UNIPROT	up-regulates activity	binding			10116									9395480	t		miannu	Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1.	SIGNOR-264042	0.919
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ALOX5	protein	P09917	UNIPROT	up-regulates activity	phosphorylation	Ser664	QLPYYYLsPDRIPNS	9606	BTO:0000567								12670876	t		lperfetto	Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells.	SIGNOR-264442	0.2
PRKCZ	protein	Q05513	UNIPROT	PRKCZ	protein	Q05513	UNIPROT	up-regulates	phosphorylation	Thr560	TSEPVQLtPDDEDAI	9606									11141077	t		gcesareni	Our findings suggest that insulin, via pip(3), provokes increases in pkc-zeta enzyme activity through (a) pdk-1-dependent t410 loop phosphorylation, (b) t560 autophosphorylation	SIGNOR-85505	0.2
SIRT1	protein	Q96EB6	UNIPROT	HYOU1	protein	Q9Y4L1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								22564731	f		miannu	Our results indicate a novel mechanism by which SIRT1 regulates ER stress by overexpression of ORP150, and suggest that SIRT1 ameliorates palmitate-induced insulin resistance in HepG2 cells via regulation of ER stress.	SIGNOR-255143	0.383
CDK1	protein	P06493	UNIPROT	RNMT	protein	O43148	UNIPROT	up-regulates activity	phosphorylation	Thr77	SSSCGKDtPSKKRKL	9606	BTO:0000007								26942677	t		lperfetto	We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor.	SIGNOR-265501	0.258
BTF3	protein	P20290	UNIPROT	HPSE2	protein	Q8WWQ2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17312387	f		miannu	 BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others.	SIGNOR-253765	0.2
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH16	protein	O75309	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265833	0.8
TEC	protein	P42680	UNIPROT	STAP1	protein	Q9ULZ2	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								10518561	t		miannu	 In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Efficient phosphorylation of BRDG1 by Tec required the PH and SH2 domains as well as the kinase domain of the latter. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 transcripts are abundant in the human B cell line Ramos, and the endogenous protein underwent tyrosine phosphorylation in response to BCR stimulation. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling.	SIGNOR-261817	0.4
PPM1B	protein	O75688	UNIPROT	DYRK1A	protein	Q13627	UNIPROT	down-regulates activity	dephosphorylation	Ser258	NTNFRGVsLNLTRKF	9606									33380426	t		miannu	In conclusion, our study demonstrates that DYRK1A autophosphorylates Ser258, the dephosphorylation target of PPM1B, and PPM1B negatively regulates DYRK1A activity.|We found that PPM1B dephosphorylates DYRK1A at Ser258, contributing to the inhibition of DYRK1A activity.	SIGNOR-277108	0.238
GLI1	protein	P08151	UNIPROT	HHIP	protein	Q96QV1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002572								16571352	f		lperfetto	Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1.	SIGNOR-209623	0.617
TGFB1	protein	P01137	UNIPROT	SKP2	protein	Q13309	UNIPROT	down-regulates				9606									21212736	f		gcesareni	Skp2, a f-box protein that determines the substrate specificity for scf ubiquitin ligase, has recently been demonstrated to be degraded by cdh1/apc in response to tgfbeta signaling.	SIGNOR-171013	0.261
GFI1	protein	Q99684	UNIPROT	ETS1	protein	P14921	UNIPROT	down-regulates activity	binding			9606	BTO:0002181								17213822	t	 	miannu	Co-immunoprecipitation analyses and glutathione-S-transferase pull-down assays revealed that ETS1 bound directly to GFI1 via its Ets domain, and GFI1 bound to ETS1 via its zinc-finger domain. Luciferase (Luc) assays using artificial reporters showed that GFI1 repressed ETS1-mediated transcriptional activation and ETS1 repressed GFI1-mediated transcriptional activation, in a dose-dependent manner. 	SIGNOR-254201	0.437
UBE2E1	protein	P51965	UNIPROT	ZSWIM2	protein	Q8NEG5	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16522193	t		miannu	MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin. 	SIGNOR-271555	0.344
PTPN11	protein	Q06124	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	dephosphorylation	Tyr209	TGMFPRNyVTPVNRN	9606									23420874	t		lperfetto	Using an in vitro experiment in which purified full-length wild-type Shp2 (WT Shp2) was incubated with phosphorylated C-SH3 domain of Grb2 we demonstrated that Shp2 can dephosphorylate Grb2 on residue Y209 (XREF_FIG).	SIGNOR-276995	0.725
NLK	protein	Q9UBE8	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606	BTO:0000150								17563747	t		gcesareni	Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna.	SIGNOR-155828	0.354
PTPN1	protein	P18031	UNIPROT	ACTN1	protein	P12814	UNIPROT	down-regulates activity	dephosphorylation	Tyr12	DSQQTNDyMQPEEDW	9534	BTO:0000298								16291744	t	down-regulates binding to src	lperfetto	Here we report that protein-tyrosine phosphatase 1B (PTP 1B) is an alpha-actinin phosphatase. PTP 1B-dependent dephosphorylation of alpha-actinin was seen in COS-7 cells|No dephosphorylation was observed in cells coexpressing the alpha-actinin phosphorylation mutant Y12F and PTP 1B. |A reversible interaction between alpha-actinin and Src enables the dephosphorylation of alpha-actinin by PTP 1B, releasing Src	SIGNOR-270539	0.34
RPS6KB1	protein	P23443	UNIPROT	TARBP2	protein	Q15633	UNIPROT	up-regulates activity	phosphorylation	Ser283	ILSLRSCsLGSLGAL	-1									27407113	t		miannu	We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. 	SIGNOR-274065	0.329
SB 203580	chemical	CHEBI:90705	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000567								11606413	t		gcesareni	Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme.	SIGNOR-111064	0.8
ETNK1	protein	Q9HBU6	UNIPROT	O-phosphonatoethanaminium(1-)	smallmolecule	CHEBI:58190	ChEBI	up-regulates quantity	chemical modification												36583229	t		lperfetto	ETNK1 encodes ethanolamine kinase 1, which is involved in the de novo biosynthesis of phosphatidylethanolamine and is responsible for the phosphorylation of ethanolamine to phosphoethanolamine	SIGNOR-275641	0.8
IYD	protein	Q6PHW0	UNIPROT	iodide	smallmolecule	CHEBI:16382	ChEBI	up-regulates quantity	chemical modification			9606									28153798	t		scontino	MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide.	SIGNOR-267034	0.8
MTOR	protein	P42345	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser312	TESITATsPASMVGG	10116	BTO:0000452								11287630	t		lperfetto	Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten	SIGNOR-106574	0.758
Exosome_Complex	complex	SIGNOR-C255	SIGNOR	XBP1	protein	P17861-2	UNIPROT	up-regulates quantity	relocalization			9606									30319453	t		miannu	When the ER stress-induced unfolded protein response (UPR) is activated, the X-box binding protein 1 (XBP1) mRNA is spliced by inositol-requiring enzyme-1α (IRE1α) to produce the spliced form of XBP1 (sXBP1). In the present study, we found that sXBP1 mRNA in the cell may be incorporated into the exosomes and was released extracellularly. Spliced form of XBP1 mRNA was incorporated into the exosomes of HEK293T cells, which overexpress IRE1α. We found that one of the ER stress signal-induced transcripts, sXBP1, was incorporated into the exosomes. Our results suggest that exosomes may play a vital role in the extracellular release of ER stress signals.	SIGNOR-260946	0.2
MAPKAPK2	protein	P49137	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser82	RALSRQLsSGVSEIR	9606									20626350	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	gcesareni	Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27.	SIGNOR-166637	0.803
BLOC-1	complex	SIGNOR-C381	SIGNOR	histamine	smallmolecule	CHEBI:18295	ChEBI	up-regulates quantity	relocalization			9606									23805129	t		lperfetto	The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules 	SIGNOR-265998	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ATXN1	protein	P54253	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser775	ATRKRRWsAPESRKL	9606	BTO:0000567								12757707	t			Interaction of Ataxin-1 and 14-3-3 Requires Akt Phosphorylation at S776. 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation.	SIGNOR-251468	0.2
TP53	protein	P04637	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0000452								7667317	f			P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts	SIGNOR-255669	0.7
Av/b1 integrin	complex	SIGNOR-C175	SIGNOR	UTF1	protein	Q5T230	UNIPROT	up-regulates quantity by expression				10090									18757303	f		lperfetto	Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1.	SIGNOR-253275	0.264
FZR1	protein	Q9UM11	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								23287467	t		miannu	 Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1.	SIGNOR-272897	0.845
GRB10	protein	Q13322	UNIPROT	IGF1R	protein	P08069	UNIPROT	down-regulates	binding			9606									21659604	t		gcesareni	Grb10 negatively regulates growth factor signaling. It binds the insulinand insulin-like growth factor 1 (igf-1) receptors, and mice without grb10 are larger and exhibit enhanced insulin sensitivity	SIGNOR-174062	0.728
SRC	protein	P12931	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates	phosphorylation	Tyr1333	ARGGQVFyNSEYGEL	9606									20431062	t		lperfetto	Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk.	SIGNOR-165039	0.491
TNFRSF13C	protein	Q96RJ3	UNIPROT	B_cell_maturation	phenotype	SIGNOR-PH15	SIGNOR	up-regulates				9606	BTO:0000776								24432023	f		lperfetto	Non-canonical nf-kb signaling initiated by baff influences b cell biology at multiple junctures.	SIGNOR-204361	0.7
MTHFD2L	protein	Q9H903	UNIPROT	10-formyltetrahydrofolate(2-)	smallmolecule	CHEBI:57454	ChEBI	up-regulates quantity	chemical modification			10116									21163947	t		lperfetto	Conversion of these 1-carbon units to formate requires several folate-interconverting enzymes in mitochondria. The enzyme(s) responsible for conversion of 5,10-methylene-tetrahydrofolate (CH(2)-THF) to 10-formyl-THF in adult mammalian mitochondria are currently unknown. A new mitochondrial CH(2)-THF dehydrogenase isozyme, encoded by the MTHFD2L gene, has now been identified. 	SIGNOR-268253	0.8
ZAP70	protein	P43403	UNIPROT	SH2B3	protein	Q9UQQ2	UNIPROT	up-regulates	phosphorylation	Tyr273	LEMPDNLyTFVLKVK	9606	BTO:0000782								9169414	t		lperfetto	In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation.	SIGNOR-48854	0.37
PLK4	protein	O00444	UNIPROT	TUBGCP6	protein	Q96RT7	UNIPROT	up-regulates activity	phosphorylation	Ser1114	HGHVSNAsIRVGENV	-1									22302995	t		miannu	Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication.	SIGNOR-262902	0.691
PTPRC	protein	P08575	UNIPROT	LCK	protein	P06239	UNIPROT	down-regulates activity	dephosphorylation	Tyr394	RLIEDNEyTAREGAK	9606									11259588	t			Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity	SIGNOR-248351	0.79
MAPK14	protein	Q16539	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000567								9687510	t		lperfetto	Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38,.	SIGNOR-59454	0.594
serotonin(1+)	smallmolecule	CHEBI:350546	ChEBI	HTR6	protein	P50406	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257525	0.8
ATR	protein	Q13535	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates	phosphorylation	Thr691	YGLEEYDtQDGIAIN	9606									16943440	t		lperfetto	In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents	SIGNOR-149309	0.66
CDK2	protein	P24941	UNIPROT	RPL12	protein	P30050	UNIPROT	unknown	phosphorylation	Ser38	KIGPLGLsPKKVGDD	9606									18847512	t		llicata	Finally, we selected one novel substrate, the ribosomal protein rl12, for further study: site-directed mutagenesis and phosphopeptide mapping confirmed that cdk2 phosphorylates rl12 in vitro and in vivo on the same site determined by our methods.	SIGNOR-181603	0.2
PTGER1	protein	P34995	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256954	0.252
IFNG	protein	P01579	UNIPROT	IFNGR2/INFGR1	complex	SIGNOR-C142	SIGNOR	up-regulates activity	binding			9606	BTO:0000801								23898330	t		lperfetto	In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation	SIGNOR-249487	0.758
CHEK1	protein	O14757	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates	phosphorylation	Thr309	LRKGRGEtRICKIYD	9606									15665856	t		gcesareni	We demonstrate that chk1 interacts with rad51, and that rad51 is phosphorylated on thr 309 in a chk1-dependent manner	SIGNOR-133375	0.837
KDM3B	protein	Q7LBC6	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9534									16603237	t		miannu	We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation.	SIGNOR-266634	0.2
ARHGAP22	protein	Q7Z5H3	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260477	0.509
MYLIP	protein	Q8WY64	UNIPROT	MYLIP	protein	Q8WY64	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0001976								14550572	t		miannu	MIR contains, beside the ERM domain, a RING zinc finger region.  The present study shows that the ubiquitin ligase activity of the RING can also be directed towards the protein itself indicating that the degradation of MIR can be regulated by autoubiquitination. 	SIGNOR-271480	0.2
RSPO2	protein	Q6UXX9	UNIPROT	LGR4	protein	Q9BXB1	UNIPROT	up-regulates	binding			9606									21693646	t		gcesareni	Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation.	SIGNOR-174486	0.758
SKIL	protein	P12757	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates activity	binding			9606									12793438	t		lperfetto	The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway	SIGNOR-236152	0.882
AKT2	protein	P31751	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates	phosphorylation	Thr1462	GLRPRGYtISDSAPS	9606									12150915	t		gcesareni	We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex.	SIGNOR-91045	0.719
PRKD2	protein	Q9BZL6	UNIPROT	SSH1	protein	Q8WYL5	UNIPROT	down-regulates	phosphorylation	Ser937	SNLTRSSsSDSIHSV	9606									21525957	t		gcesareni	Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1.	SIGNOR-173441	0.296
ULBP2	protein	Q9BZM5	UNIPROT	KLRK1	protein	P26718	UNIPROT	up-regulates	binding			9606	BTO:0000782								10894171	t		gcesareni	Here we describe a family of gpi-anchored cell surface proteins that function as ligands for the mouse activating nkg2d receptor. These molecules are encoded by the retinoic acid early inducible (rae-1) and h60 minor histocompatibility antigen genes on mouse chromosome 10 and show weak homology with mhc class i.	SIGNOR-79233	0.606
BI 2536	chemical	CID:11364421	PUBCHEM	PLK1	protein	P53350	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-259702	0.8
SP1	protein	P08047	UNIPROT	HYAL1	protein	Q12794	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004796								18718911	f		miannu	 in cells which do not express HYAL-1, we found SP1 binding to the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription.	SIGNOR-253879	0.2
CSNK2A1	protein	P68400	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	phosphorylation	Thr393	RNLSDAAtKQEGMEG	9534	BTO:0000298								12700239	t		llicata	The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability.	SIGNOR-250849	0.54
MAP2K6	protein	P52564	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates activity				9534									9430721	t		Luana	The p38 MAP kinase kinase MKK6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma MAP kinase isoforms	SIGNOR-260721	0.733
MRE11	protein	P49959	UNIPROT	PIH1D1	protein	Q9NWS0	UNIPROT	up-regulates activity	binding			9606					phosphorylation:Ser688;Ser689;Ser561;Ser558	SKGVDFEsSEDDDDD;KGVDFESsEDDDDDP;MANDSDDsISAATNK;AEQMANDsDDSISAA			28436950	t		miannu	Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689.	SIGNOR-265898	0.2
ADSS2	protein	P30520	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	down-regulates quantity	chemical modification			9606									10496970	t		miannu	Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 	SIGNOR-267345	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation	Ser643	CFTPKGSsLKIEERA	9606		BTO:0001260							2170388	t		gcesareni	Smooth muscle caldesmon was phosphorylated by smooth muscle calmodulin-dependent protein kinase. Ii	SIGNOR-22631	0.2
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1616	TPQSPSYsPTSPSYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii	SIGNOR-203508	0.77
ZNRF3	protein	Q9ULT6	UNIPROT	FZD5	protein	Q13467	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								22575959	t			Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.	SIGNOR-260118	0.495
NVP-AEW541	chemical	CID:11476171	PUBCHEM	IGF1R	protein	P08069	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194892	0.8
NCOA4	protein	Q13772	UNIPROT	KLK3	protein	P07288	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004191								18649734	f	 	 	The PSA promoter activity was detected by transient expression assay in the PC-J and LNCaP cells but not in androgen insensitive PC-3 cells. When the PC-J cells were cotransfected with androgen receptor, androgen receptor coactivators and PSA reporter vector cells, the reporter assays indicated that nuclear receptor coactivator 4 (NCOA4) but not androgen receptor activator 24 (ARA24) increased the sensitivity and maximum stimulation of dihydrotestosterone (DHT)-inducing PSA promoter activity.	SIGNOR-253659	0.334
FZD3	protein	Q9NPG1	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606									14977528	t		gcesareni	Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families.	SIGNOR-122895	0.394
AURKA	protein	O14965	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser308	KAEFCNKsKQPGLAR	9606									14990569	t		lperfetto	Previous studies have shown that the brca1 breast cancer tumor suppressor also localizes to the centrosome and that brca1 inactivation results in loss of the g(2)-m checkpoint. We demonstrate here that aurora-a physically binds to and phosphorylates brca1. We propose that brca1 phosphorylation by aurora-a plays a role in g(2) to m transition of cell cycle	SIGNOR-123065	0.663
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1626	SPSYSPTsPSYSPTS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248769	0.441
PPP2CB	protein	P62714	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	down-regulates activity	dephosphorylation	Thr305	TDAATMKtFCGTPEY	9606									18160256	t		llicata	Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248611	0.472
FGA	protein	P02671	UNIPROT	ITGAX	protein	P20702	UNIPROT	up-regulates	binding			9606									7679388	t		gcesareni	To map the binding sites for four distinct ligands for mac-l: ic3b, fibrinogen, icam-1. __the i domain on the ot chain of mac-1 is an important recognition site for all four ligands.	SIGNOR-31320	0.36
RFX5	protein	P48382	UNIPROT	HLA-DRA	protein	P01903	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000460								10586057	t		Luana	In this report, we correlate the loss of IFN-γ induction of MHC class II genes with the identification of a molecular defect in an essential regulator, namely RFX5. | We have further confirmed this finding by showing that new RFX5 leucine mutants created in vitro are incapable of transactivating a class II promoter, suggesting the identification of residues essential for RFX activity.	SIGNOR-266228	0.518
SMC4	protein	Q9NTJ3	UNIPROT	Condensin II	complex	SIGNOR-C342	SIGNOR	form complex	binding			9606									32445620	t		miannu	The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction.	SIGNOR-263909	0.81
lysophosphatidic acids	smallmolecule	CHEBI:32957	ChEBI	LPAR2	protein	Q9HBW0	UNIPROT	up-regulates	chemical activation			9606									8276865	t		gcesareni	Lpa activates its own g protein-coupled receptor(s) leading to stimulation of phospholipase c and inhibition of adenylate cyclase.	SIGNOR-37368	0.8
PRPS1	protein	P60891	UNIPROT	D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	down-regulates quantity	chemical modification			9606									16939420	t		miannu	PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP.	SIGNOR-267078	0.8
PRKACA	protein	P17612	UNIPROT	LRP1	protein	Q07954	UNIPROT	up-regulates activity	phosphorylation	Ser4520	GGHGSRHsLASTDEK	10029									11158305	t		miannu	LRP phosphorylation is mediated by PKA at residue serine 76 of its cytoplasmic tail and that this phosphorylation contributes to receptor-mediated endocytosis.	SIGNOR-250000	0.329
MAPK3	protein	P27361	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates	phosphorylation	Thr581	PDNQPLKtPCFTLHY	9606									15568999	t		gcesareni	In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758.	SIGNOR-131383	0.567
SRC	protein	P12931	UNIPROT	ITGB3	protein	P05106	UNIPROT	down-regulates activity	phosphorylation	Tyr785	STFTNITyRGT	9606									11723131	t		lperfetto	The phosphorylation level of beta(3) integrin was modulated using a temperature-sensitive v-Src kinase. Increased beta(3) phosphorylation abolished alpha(v)beta(3)- but not alpha(5)beta(1)-mediated adhesion to fibronectin. Thus, phosphorylation of the cytoplasmic domain of beta(3) is a negative regulator of alpha(v)beta(3)-fibronectin binding strength.	SIGNOR-247207	0.647
PIEZO2	protein	Q9H5I5	UNIPROT	Hair cells mechanotransduction channel	complex	SIGNOR-C290	SIGNOR	form complex	binding			10090		BTO:0000630							23217710	t		lperfetto	The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012).	SIGNOR-262572	0.407
MUL1	protein	Q969V5	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	sumoylation	Lys594	GNWRGMLKTSKAEEL	9606	BTO:0000007								19638400	t		Barakat	Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms.	SIGNOR-274128	0.55
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	MAPK3	protein	P27361	UNIPROT	up-regulates				9606	BTO:0000150								11043579	f		gcesareni	Estrogen rapidly activates the mitogen-activated protein kinases, erk-1 and erk-2, via an as yet unknown mechanism.	SIGNOR-83280	0.8
SOCS1	protein	O15524	UNIPROT	JAK1	protein	P23458	UNIPROT	down-regulates	binding			9606									11133764	t		gcesareni	Jab/socs1/ssi-1 is an il-2 induced inhibitor of il-2 signaling that functions by inhibiting jak kinase activity	SIGNOR-85352	0.721
GLI2	protein	P10070	UNIPROT	BMP2	protein	P12643	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16880529	f		gcesareni	The zinc finger transcription factor gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling	SIGNOR-148346	0.441
CSNK2A1	protein	P68400	UNIPROT	ATXN3	protein	P54252	UNIPROT	up-regulates activity	phosphorylation	Ser236	LQRALALsRQEIDME	9606	BTO:0000007								19542537	t		miannu	Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). The main phosphorylation of ATXN3 in vivo thus occurred at serine residues within the three conserved UIMs.	SIGNOR-276225	0.2
NFE2L2	protein	Q16236	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0000599								26194347	f		irozzo	Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes.	SIGNOR-256262	0.7
GSK3B	protein	P49841	UNIPROT	MCL1	protein	Q07820	UNIPROT	down-regulates	phosphorylation	Ser159	NNTSTDGsLPSTPPP	9606									16543145	t		gcesareni	We investigated the role of glycogen synthase kinase-3 (gsk-3), which is inactivated by akt, for its role in the regulation of apoptosis. Upon il-3 withdrawal, protein levels of mcl-1 decreased but were sustained by pharmacological gsk-3, which prevented cytochrome c release and apoptosis. Mcl-1 was phosphorylated by gsk-3 at a conserved gsk-3 phosphorylation site (s159). S159 phosphorylation of mcl-1 was induced by il-3 withdrawal or pi3k inhibition and prevented by akt or gsk-3, and it led to increased ubiquitinylation and degradation of mcl-1.	SIGNOR-145200	0.515
orantinib	chemical	CHEBI:91088	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207438	0.8
CADPS	protein	Q9ULU8	UNIPROT	STX1A	protein	Q16623	UNIPROT	up-regulates activity	binding			9606	BTO:0000938			SIGNOR-C346					24363652	t		miannu	 CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1	SIGNOR-264336	0.412
FOXP2	protein	O15409	UNIPROT	AUTS2	protein	Q8WXX7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000142							25232744	t		miannu	By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets.	SIGNOR-266832	0.332
CHUK	protein	O15111	UNIPROT	AMBRA1	protein	Q9C0C7	UNIPROT	up-regulates activity	phosphorylation	Ser1043	CRPEALNsGVEYYWD	9606	BTO:0000567								30217973	t		lperfetto	Furthermore, we show that mitophagy function of AMBRA1 is post-translationally controlled, upon HUWE1 activity, by a positive phosphorylation on its serine 1014. This modification is mediated by the IKKα kinase and induces structural changes in AMBRA1, thus promoting its interaction with LC3/GABARAP (mATG8) proteins and its mitophagic activity. 	SIGNOR-272974	0.2
MAPK1	protein	P28482	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser294	QLSKWPGsPTSRSSD	9606									18204439	t		lperfetto	Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation.	SIGNOR-252957	0.71
POU4F3	protein	Q15319	UNIPROT	LHX3	protein	Q9UBR4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000630							17331196	t		lperfetto	Using oligonucleotide microarrays to generate expression profiles of inner ears of Pou4f3(ddl/ddl) mutant and wild-type mice, we have identified and validated Lhx3, a LIM domain transcription factor, as an in vivo target gene regulated by Pou4f3. Lhx3 is a hair cell-specific gene expressed in all hair cells of the auditory and vestibular system as early as embryonic day 16. The level of Lhx3 mRNA is greatly reduced in the inner ears of embryonic Pou4f3 mutant mice. Our data also show that the expression of Lhx3 is regulated differently in auditory and vestibular hair cells.	SIGNOR-262586	0.409
MEF2A	protein	Q02078	UNIPROT	MYH2	protein	Q9UKX2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0001103							15728583	t		lperfetto	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238703	0.331
COPS8	protein	Q99627	UNIPROT	COP9 signalosome variant 1	complex	SIGNOR-C489	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270770	0.925
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide	chemical	CHEBI:125619	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258844	0.8
BIRC2	protein	Q13490	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0000459								18621737	t		amattioni	c-IAPs are ubiquitin ligases capable of promoting polymerization of non-degradative Lys-63-linked polyubiquitin chains on the critical adapter in the canonical NF-_B signaling pathway, RIP1. c-IAPs are E3 ligases and RIP1 ubiquitination is critical for propagation of TNF_-induced NF-_B activation	SIGNOR-179439	0.76
prostaglandin E2(1-)	smallmolecule	CHEBI:606564	ChEBI	PTGER2	protein	P43116	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257570	0.8
DUSP3	protein	P51452	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates activity	dephosphorylation			9534	BTO:0004055								10224087	t	inferred from 70% of family members		Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2	SIGNOR-269928	0.658
FYN	protein	P06241	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Tyr142	AVVNLINyQDDAELA	-1									12640114	t			Interaction of beta-catenin with alpha-catenin is regulated by the phosphorylation of beta-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn tyrosine kinases.  Transfection of these kinases to epithelial cells disrupted the association between both catenins.	SIGNOR-251162	0.845
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	NUP153	protein	P49790	UNIPROT	unknown	phosphorylation			9606									19767751	t	inferred from 70% family members	llicata	These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport.	SIGNOR-270044	0.2
MAPK3	protein	P27361	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Thr444	RFIGSPRtPVSPVKF	10116									15774499	t		lperfetto	Thr 421/Ser 424 have been reported to be targeted by ERK1, 2 (39), JNK or p38 MAPKs (36). Interestingly, with a comparable kinetics, FSH represses ERK1, 2 constitutive phosphorylation in Sertoli cells isolated from 19-d-old rats	SIGNOR-134662	0.59
SRC	protein	P12931	UNIPROT	GTF2I	protein	P78347	UNIPROT	up-regulates activity	phosphorylation	Tyr248	EESEDPDyYQYNIQA	9534	BTO:0004055								11934902	t		lperfetto	c-Src-dependent transcriptional activation of TFII-ITFII-I is a multifunctional transcription factor that is also involved in signal transduction. Here we show that TFII-I undergoes a c-Src-dependent tyrosine phosphorylation on tyrosine residues 248 and 611 and translocates to the nucleus in response to growth factor signaling	SIGNOR-247185	0.466
N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide	chemical	CHEBI:94525	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194551	0.8
ATF4	protein	P18848	UNIPROT	FGF19	protein	O95750	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000195								23205607	t	 	lperfetto	Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress	SIGNOR-253727	0.2
CREBBP	protein	Q92793	UNIPROT	CBP/p300	complex	SIGNOR-C6	SIGNOR	form complex	binding			9606									11559745	t		lperfetto	P300/cbp proteins: hats for transcriptional bridges and scaffolds	SIGNOR-110559	0.524
CDK1	protein	P06493	UNIPROT	DLG1	protein	Q12959	UNIPROT	unknown	phosphorylation	Ser158	FVSHSHIsPIKPTEA	9606									19066288	t		llicata	We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor.	SIGNOR-182753	0.403
HOXA7	protein	P31268	UNIPROT	IVL	protein	P07476	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000667								11435435	f		miannu	Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes. 	SIGNOR-254473	0.2
IKBKB	protein	O14920	UNIPROT	BCL3	protein	P20749	UNIPROT	up-regulates activity	phosphorylation	Ser122	CPMEHPLsADIAMAT	-1									28689659	t		miannu	Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA. 	SIGNOR-277364	0.374
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CLK2	protein	P49760	UNIPROT	up-regulates	phosphorylation	Thr127	RRRRRSRtFSRSSSQ	9606	BTO:0000567								20682768	t		lperfetto	Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva	SIGNOR-244218	0.2
TBK1	protein	Q9UHD2	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation			9606									24622840	t		miannu	STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3. 	SIGNOR-260154	0.817
GRIK5	protein	Q16478	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264346	0.7
IKBKB	protein	O14920	UNIPROT	BCL3	protein	P20749	UNIPROT	up-regulates activity	phosphorylation	Ser454	PSPAPGGs	-1									28689659	t		miannu	Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA. 	SIGNOR-277365	0.374
RPS6KA5	protein	O75582	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	phosphorylation	Ser29	ATKAARKsAPATGGV	9606									20129940	t		gcesareni	Upon activation of the erk and p38 mapk pathways, the msk1/2-mediated nucleosomal response, including h3 phosphorylation at serine 28 or 10, is coupled with the induction of immediate-early (ie) gene transcription.	SIGNOR-163712	0.2
PTPN11	protein	Q06124	UNIPROT	CSF2RB	protein	P32927	UNIPROT	up-regulates	dephosphorylation			9606							phosphorylation:Tyr628	PPPGSLEyLCLPAGG	9162089	t		gcesareni	Shp2 is thought to act as a positive mediator of growth factor signals.. Hp2 could act as an adaptor between the activated c and grb2, thus leading to activation of the ras/mitogen-activated protein kinase pathway, known to be activated by il-3	SIGNOR-48557	0.489
PTPN11	protein	Q06124	UNIPROT	GAB1	protein	Q13480	UNIPROT	down-regulates	dephosphorylation	Tyr627	KGDKQVEyLDLDLDS	9606									10068651	t		lperfetto	Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro.	SIGNOR-236262	0.952
SRC	protein	P12931	UNIPROT	CHKA	protein	P35790	UNIPROT	up-regulates activity	phosphorylation	Tyr333	LMLIDFEySSYNYRG	9606	BTO:0000093								21822308	t		miannu	We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333.	SIGNOR-266350	0.343
ZNF304	protein	Q9HCX3	UNIPROT	CDKN2B	protein	P42772	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000391								24623306	t		Luana	Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells.	SIGNOR-266099	0.284
TRAF6	protein	Q9Y4K3	UNIPROT	MAP3K8	protein	P41279	UNIPROT	up-regulates activity				9606	BTO:0000007								16371247	f			The activation of Cot-MKK1-ERK1/ERK2 signalling pathway by IL-1 is dependent on the activity of the transducer protein TRAF6.	SIGNOR-252254	0.428
LATS2	protein	Q9NRM7	UNIPROT	VEPH1	protein	Q14D04	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000938								22055343	f	In the neuronal differentiation	lperfetto	Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9	SIGNOR-177071	0.2
MAPK1	protein	P28482	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates	phosphorylation	Ser360	TEMDPTYsPAALPQS	9606		BTO:0000887							11940578	t		gcesareni	Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth.	SIGNOR-116485	0.6
NFATC2	protein	Q13469	UNIPROT	FST	protein	P19883	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15130492	t		lperfetto	MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA	SIGNOR-251729	0.2
LRRK2	protein	Q5S007	UNIPROT	MSN	protein	P26038	UNIPROT	up-regulates activity	phosphorylation	Thr558	LGRDKYKtLRQIRQG	9606									17447891	t		lperfetto	This led to the discovery that moesin, a protein which anchors the actin cytoskeleton to the plasma membrane, is efficiently phosphorylated by lrrk2, at thr558. Moesin phosphorylation could be essential to support the cytoskeletal changes accompanying this process.	SIGNOR-154498	0.569
ATR	protein	Q13535	UNIPROT	DBF4	protein	Q9UBU7	UNIPROT	down-regulates	phosphorylation	Ser539	GLITINSsQEHLTVQ	9606									22123827	t		lperfetto	Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication.	SIGNOR-177809	0.643
GABRB1	protein	P18505	UNIPROT	GABA-A (a4-b1-g2) receptor	complex	SIGNOR-C333	SIGNOR	form complex	binding			9606									18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263760	0.604
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH5	protein	P33151	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265845	0.8
DYNLL1	protein	P63167	UNIPROT	AMBRA1	protein	Q9C0C7	UNIPROT	down-regulates	binding			9606									20921139	t		gcesareni	The beclin 1vps34 complex is tethered to the cytoskeleton through an interaction between the beclin 1interacting protein ambra1 and dynein light chains 1/2.	SIGNOR-168255	0.53
IRF2BPL	protein	Q9H1B7	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000498								29374064	t		miannu	FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. 	SIGNOR-267153	0.2
ABL1	protein	P00519	UNIPROT	YTHDC1	protein	Q96MU7	UNIPROT	down-regulates	phosphorylation			9606									15175272	t		lperfetto	We show that yt521-b is tyrosine phosphorylated by c-abl in the nucleus.We propose that tyrosine phosphorylation causes sequestration of YT521-B in an insoluble nuclear form, which abolishes the ability of YT521-B to change alternative splice sites.	SIGNOR-125167	0.309
MAPK8	protein	P45983	UNIPROT	HNRNPK	protein	P61978	UNIPROT	up-regulates activity	phosphorylation	Ser353	DSAIDTWsPSEWQMA	9606									11259409	t		lperfetto	The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein.	SIGNOR-105251	0.381
PRKACG	protein	P22612	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser284	AGGGRRIsDSHEDTG	9606		BTO:0000887							20151718	t		miannu	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163788	0.278
MAPK10	protein	P53779	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000567								17686459	t		gcesareni	Here we demonstrate that jnk3 can phosphorylate smac. Phosphorylation of smac by jnk3 attenuates its interaction with xiap. These results suggest that jnk3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between smac and xiap.	SIGNOR-157280	0.349
IL1B	protein	P01584	UNIPROT	MC1R	protein	Q01726	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000847								9767234	f		miannu	MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression.	SIGNOR-252385	0.264
MAPK1	protein	P28482	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr56	FSSQPGHtPHPAASR	9606									10669763	t		lperfetto	Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo.	SIGNOR-74923	0.532
SIRT1	protein	Q96EB6	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	deacetylation			9606									25280219	t			SIRT1 overexpression was associated with down-modulation of p53 activity in FLT3-ITD AML CD34+ cells. SIRT1 can negatively regulate p53 by deacetylating several lysine sites	SIGNOR-261562	0.797
PSEN1	protein	P49768	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9606									2195779	t		gcesareni	Importantly, our data show that binding of ps1 to cadherin mediates the effects of ps1 on the phosphorylation, ubiquitination, and destabilization of beta-catenin. Thus, cadherins mediate both the association of ps1 and beta-catenin and the effects of ps1 on the cellular levels of beta-catenin	SIGNOR-22837	0.802
INSR	protein	P06213	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates activity	phosphorylation	Tyr774	SENEDDGyDVPKPPV	10090	BTO:0000944								11997497	t			Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation.	SIGNOR-251306	0.506
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CAPN1	protein	P07384	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000590								25969760	t		lperfetto	The data obtained from those studies suggest that the mechanisms leading to the formation of the hallmark lesions of AD might be linked. One of such mechanisms seems to be the dysregulation of calcium homeostasis that results in the abnormal activation of calpains. Calpains are a family of Ca2+-dependent cysteine proteases that play a key role in multiple cell functions including cell development, differentiation and proliferation, axonal guidance, growth cone motility, and cell death, among others. 	SIGNOR-251580	0.8
DZIP3	protein	Q86Y13	UNIPROT	H2AC11	protein	P0C0S8	UNIPROT	up-regulates activity	monoubiquitination	Lys119	IQAVLLPkKTESHHK	9606	BTO:0000007								18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271749	0.2
BUB1	protein	O43683	UNIPROT	CDC20	protein	Q12834	UNIPROT	down-regulates activity	phosphorylation	Ser41	EAAGPAPsPMRAANR	9606	BTO:0000567								15525512	t		llicata	Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. 	SIGNOR-250606	0.992
AURKB	protein	Q96GD4	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									14583461	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.	SIGNOR-118894	0.2
hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	GABA-A (a3-b1-g2) receptor	complex	SIGNOR-C332	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000938								26136660	t		miannu	The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 	SIGNOR-264922	0.8
SMARCA4	protein	P51532	UNIPROT	ZEB1	protein	P37275	UNIPROT	up-regulates	binding			9606									20418909	t		miannu	Zeb1 represses e-cadherin transcription / we reported that brg1 binds to the ntr of zeb1 acting as its co-repressor in the regulation of the e-cadherin promoter.	SIGNOR-165017	0.413
NR4A3	protein	Q92570	UNIPROT	BBC3	protein	Q9BXH1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30455429	t		miannu	Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax.	SIGNOR-259396	0.2
IFNG	protein	P01579	UNIPROT	LPL	protein	P06858	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0001030								10909770	f	Regulation of expression	miannu	The suppression of lipoprotein lipase expression in J774.2 macrophages by IFN-gamma and TNF-alpha is mediated at the transcriptional level.	SIGNOR-251854	0.364
NMS	protein	Q5H8A3	UNIPROT	NMUR1	protein	Q9HB89	UNIPROT	up-regulates	binding			9606		BTO:0000142							15635449	t		gcesareni	Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus.	SIGNOR-133074	0.719
DYRK2	protein	Q92630	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser185	SAPARMLsSNERDSS	9606	BTO:0002181								34363019	t		miannu	Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. 	SIGNOR-276739	0.2
perfluorooctane-1-sulfonic acid	chemical	CHEBI:39421	ChEBI	PPARD	protein	Q03181	UNIPROT	up-regulates activity	chemical activation			-1									31332417	t		miannu	In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group.	SIGNOR-268757	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates activity	phosphorylation	Thr178	NHNHRIRtNPAIVKT	9606									20640476	t		lperfetto	AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1	SIGNOR-209936	0.483
SMAD2	protein	Q15796	UNIPROT	MEF2A	protein	Q02078	UNIPROT	up-regulates	binding			10090	BTO:0000165	BTO:0001760	SIGNOR-C8						11160896	t		lperfetto	Our studies indicate that smad2 and 4 (smad2/4) complexes cooperate with mef2 regulatory proteins in a gal4-based one-hybrid reporter gene assay.	SIGNOR-235846	0.398
HRH2	protein	P25021	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257049	0.252
SKP2	protein	Q13309	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity	ubiquitination			9606			SIGNOR-C136						20852628	t		gcesareni	The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain	SIGNOR-243548	0.726
GNRHR	protein	P30968	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257331	0.454
CHD4	protein	Q14839	UNIPROT	CD79A	protein	P11912	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000776								23071088	f	 	lperfetto	However, NuRD complexes greatly reduce activation of the B cell-specific mb-1 (Cd79a) gene by the transcription factors EBF1 and Pax5|We conclude that repressive functions of MBD2-containing NuRD complexes are dependent on cooperative interactions between the major domains of CHD4 with histones and DNA and on binding of methylated DNA by MBD2.	SIGNOR-254090	0.251
TRIM58	protein	Q8NG06	UNIPROT	DYNC1I2	protein	Q13409	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									25241935	t		miannu	Trim58 ubiquitinates dynein and promotes its proteasomal degradation. Trim58 binds DIC directly, polyubiquitinates it in vitro, and induces proteasomal degradation of the dynein holocomplex in vivo. 	SIGNOR-272841	0.304
NEDD4L	protein	Q96PU5	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates	ubiquitination			9606									19917253	t		gcesareni	Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation	SIGNOR-161710	0.771
FASTKD2	protein	Q9NYY8	UNIPROT	Stress_granules	phenotype	SIGNOR-PH124	SIGNOR	up-regulates				9606									25683715	f		miannu	DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. 	SIGNOR-261227	0.7
SRC	protein	P12931	UNIPROT	HNRNPK	protein	P61978	UNIPROT	down-regulates	phosphorylation	Tyr234	PNFYDETyDYGGFTM	9606									12052863	t		lperfetto	We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown).	SIGNOR-88907	0.609
USP8	protein	P40818	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0000567								20736164	t		irozzo	USP8 is known to deubiquitinate EGFR in response to ligand stimulation. USP8 depletion accelerates receptor turnover, whereas loss of hepatocyte growth factor-regulated substrate (Hrs) rescues this phenotype, indicating that USP8 protects EGFR from degradation via an Hrs-dependent pathway. [..]As EGFR stabilization against lysosomal turnover requires deubiquitination by USP8.	SIGNOR-259102	0.7
GRM1	protein	Q13255	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264347	0.7
POLR2H	protein	P52434	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266172	0.819
PRKCB	protein	P05771	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser303	RGAPPRRsSIRNAHS	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89182	0.549
SLC2A2	protein	P11168	UNIPROT	glucose	chemical	CHEBI:17234	ChEBI	up-regulates quantity	relocalization			9606									25421524	t			The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion.	SIGNOR-267386	0.8
PIWIL1	protein	Q96J94	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	up-regulates	binding			9606	BTO:0003081								32203416	t		miannu	PIWIL1 leads to the constitutive activation of APC/C in PDAC cells. Here, we show that in the absence of piRNAs, human PIWIL1 in PDAC functions as an oncoprotein by activating the anaphase promoting complex/cyclosome (APC/C) E3 complex, which then targets a critical cell adhesion-related protein, Pinin, to enhance PDAC metastasis. Collectively, these results demonstrate that Pinin is an authentic substrate of APC/CPIWIL1 in PDAC cells.	SIGNOR-272202	0.2
6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide	chemical	CHEBI:92401	ChEBI	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258000	0.8
HOXA10	protein	P31260	UNIPROT	MEF2C	protein	Q06413	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000661								21261500	f	 	miannu	Overexpression of HOXA9 or HOXA10 in JURKAT cells by lentiviral transduction resulted in decreased expression of MEF2C, indicating repression by these homeodomain proteins. HOXA9/10 inhibits expression of MEF2C via NMYC	SIGNOR-254212	0.288
BTRC	protein	Q9Y297	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys784	HVKLERLkQVNGMFP	9606	BTO:0000938								17283082	t		lperfetto	Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage.	SIGNOR-249577	0.657
TOMM7	protein	Q9P0U1	UNIPROT	TOM40 complex	complex	SIGNOR-C421	SIGNOR	form complex	binding			9606	BTO:0000567								18331822	t		lperfetto	The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex.	SIGNOR-267680	0.762
bufexamac	chemical	CHEBI:31317	ChEBI	HDAC10	protein	Q969S8	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000664								21258344	t		Luana	 We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor.	SIGNOR-257891	0.8
levomethadone	chemical	CHEBI:136003	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258809	0.8
STK4	protein	Q13043	UNIPROT	PRDX1	protein	Q06830	UNIPROT	down-regulates activity	phosphorylation	Thr18	PAPNFKAtAVMPDGQ	-1									23386615	t		miannu	Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183.	SIGNOR-276486	0.2
denileukin diftitox	smallmolecule	SID:125240988	ChEBI	IL2RG	protein	P31785	UNIPROT	up-regulates activity	chemical activation			9606									15757436	t		miannu	Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells. 	SIGNOR-259394	0.8
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1787	SPNYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120216	0.321
Laminin-1	complex	SIGNOR-C183	SIGNOR	A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	up-regulates activity	binding												2351695	t		lperfetto	In combination, the anti-alpha 1- and anti-alpha 6-specific antibodies completely inhibited JAR cell attachment to LN and fragment E1. Thus, the alpha 1/beta 1 and alpha 6/beta 1 integrin heterodimers each function as LN receptors and act together to mediate the interactions of human JAR choriocarcinoma cells with LN.	SIGNOR-253256	0.537
AV412	chemical	CID:11700696	PUBCHEM	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190053	0.8
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	ECT2	protein	Q9H8V3	UNIPROT	up-regulates	phosphorylation	Thr846	RAFSFSKtPKRALRR	9606	BTO:0001938								16247472	t		lperfetto	Thr-814 to ala greatly diminished the ability of p34cdk1/cyclin b to phosphorylate recombinant ect2-c protein (figure 1b, left panel). These data suggest that thr-814 is a major cdk1 phosphorylation site in ect2-c in vitrothe sequence thr-pro-lys-arg (tpkr) starting at amino acid 814we found that the t814a mutation slightly reduces the exchange activity of ect2 on rac1	SIGNOR-216928	0.5
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Thr336	GGPGPERtPGSGSGS	9606									7889942	t		gcesareni	Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-252082	0.2
CIITA	protein	P33076	UNIPROT	HLA-DMB	protein	P28068	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								11889043	f	 	 	Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment.	SIGNOR-254010	0.36
PPM1D	protein	O15297	UNIPROT	MAPK12	protein	P53778	UNIPROT	down-regulates	dephosphorylation	Thr183	RQADSEMtGYVVTRW	9606									15870257	t		gcesareni	Ppm1d selectively inhibits p38 activation by dephosphorylating thr 180.	SIGNOR-135976	0.301
MAPK8	protein	P45983	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Ser315	ITATSPAsMVGGKPG	9606		BTO:0000887;BTO:0001103							14579029	t		gcesareni	Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1.	SIGNOR-118861	0.767
NEK2	protein	P51955	UNIPROT	NEK2	protein	P51955	UNIPROT	up-regulates	phosphorylation	Thr170	ARILNHDtSFAKTFV	9606									17197699	t		gcesareni	Thus, it appears that autophosphorylation of thr-170 and/or ser-171 in nek2 may fine-tune overall activity of nek2 in vivo. regardless, the importance of thr-175 suggested by its conservation in many other kinases is underlined by the t175a mutant that shows reduced kinase activity and a significant reduction in efficiency of cs.	SIGNOR-151759	0.2
bisindolylmaleimide i	chemical	CID:2396	PUBCHEM	PRKCA	protein	P17252	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	CellSignaling	gcesareni		SIGNOR-190344	0.8
CTBP1	protein	Q13363	UNIPROT	BRCA1	protein	P38398	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21681822	t		irozzo	Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells.	SIGNOR-259196	0.586
OXTR	protein	P30559	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257332	0.409
FGFR3	protein	P22607	UNIPROT	FGFR3	protein	P22607	UNIPROT	up-regulates activity	phosphorylation	Tyr648	DVHNLDYyKKTTNGR	9606	BTO:0000007								11294897	t		lperfetto	Ligand stimulation leads to autophosphorylation of fgfr3the two tyrosine residues in the YYKK Motif of the activation loop of fgfrs are required for kinase activity of fgfr1 and fgfr3.	SIGNOR-106734	0.2
MAPRE1	protein	Q15691	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates	binding												17889670	t		lperfetto	Microtubule plus end binding proteins (+TIPs) localize to the dynamic plus ends of microtubules, where they stimulate microtubule growth and recruit signaling molecules. Three main +TIP classes have been identified (XMAP215, EB1, and CLIP-170)	SIGNOR-264831	0.7
GSK3B	protein	P49841	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	up-regulates activity	phosphorylation	Ser61	PLSTPCSsVPSSPSF	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159446	0.26
CDK1	protein	P06493	UNIPROT	CGAS	protein	Q8N884	UNIPROT	down-regulates activity	phosphorylation	Ser305	MKRKRGGsPAVTLLI										32351706	t		lperfetto	The major mitotic kinase CDK1-cyclin B complex phosphorylates human cGAS at S305 or mouse cGAS at S291, which inhibits its ability to synthesize cGAMP upon mitotic entry. 	SIGNOR-276526	0.2
MLL1 complex	complex	SIGNOR-C89	SIGNOR	PAX7/MLL1 complex	complex	SIGNOR-C90	SIGNOR	form complex	binding			9606	BTO:0002314	BTO:0000887;BTO:0001103							22863532	t		miannu	Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5.	SIGNOR-198620	0.2
CHEK2	protein	O96017	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser364	PLLSRMGsLRAPVDE	9606									22558186	t		gcesareni	Among these effector proteins, chk1 phosphorylates tlk12 and rad51, while brca, pik3, pml and e2f1 are chk2 substrates.	SIGNOR-197278	0.5
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606									19282669	t	inferred from 70% family members	lperfetto	Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway	SIGNOR-270070	0.2
IRF3	protein	Q14653	UNIPROT	Interferon_Production	phenotype	SIGNOR-PH16	SIGNOR	up-regulates				10090	BTO:0002572								20610653	f		lperfetto	Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors.	SIGNOR-126962	0.7
HMGB1	protein	P09429	UNIPROT	IL2RA	protein	P01589	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000661								7862168	f	2	miannu	The interleukin 2 receptor alpha-chain (IL-2R alpha) gene is rapidly and potently induced in T cells in response to mitogenic stimuli. Previously, an inducible enhancer between nucleotides -299 and -228 that contains NF-kappa B and CArG motifs was identified. We now report the characterization of a second essential positive regulatory element located between nucleotides -137 and -64 that binds Elf-1 and HMG-I(Y). Transcription from the IL-2R alpha promoter was inhibited when either the Elf-1 or the HMG-I(Y) binding site was mutated. Coexpression of both proteins activated transcription of the -137 to -64 element in COS-7 cells.	SIGNOR-240113	0.2
ESR1	protein	P03372	UNIPROT	NR0B2	protein	Q15466	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									10648597	f		gcesareni	We demonstrate that shp variants, carrying either interaction-defective nr box mutations or a deletion of the repressor domain, have lost the capacity to inhibit agonist-dependent transcriptional estrogen receptor activation.	SIGNOR-74288	0.633
SOCS3	protein	O14543	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates				9606									16543409	f		lperfetto	Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFkappaB and the MAPKs JNK and p38, but the mechanism is unknown	SIGNOR-253052	0.4
PCNA	protein	P12004	UNIPROT	DNA polymerase delta 	complex	SIGNOR-C376	SIGNOR	up-regulates activity	binding			9534	BTO:0004055								12930972	t		lperfetto	Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA).	SIGNOR-265511	0.763
lapatinib	chemical	CHEBI:49603	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001949								21443688	t		Luana	YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ.	SIGNOR-257898	0.8
AP2M1	protein	Q96CW1	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates	relocalization			9606									19351721	t		gcesareni	The removal of the epidermal growth factor receptor (egfr) from the cell surface by endocytosis is triggered by receptor activation, but many facets of egfr trafficking remain unresolvedthe ap-2 complex is involved in the internalization of activated egfr.	SIGNOR-185124	0.504
IFNGR2	protein	P38484	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	binding			9606	BTO:0000801								23898330	t		lperfetto	In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation	SIGNOR-249504	0.688
PTPRT	protein	O14522	UNIPROT	PXN	protein	P49023	UNIPROT	down-regulates activity	dephosphorylation	Tyr88	PQSSSPVyGSSAKTS	9606	BTO:0000182								27447856	t	brain	lperfetto	To this end, using a phospho-proteomics approach, we identified and validated paxillin and STAT3 as the substrates of PTPRT [15, 16]|the PTPRT target site on paxillin is a previously uncharacterized tyrosine-88 residue (paxillin Y88)|In this study, we also show how pY88 paxillin transduces a signal to activate Akt	SIGNOR-263978	0.474
CAMK2A	protein	Q9UQM7	UNIPROT	CD44	protein	P16070	UNIPROT	up-regulates	phosphorylation	Ser706	LNGEASKsQEMVHLV	9606									9580567	t		gcesareni	We demonstrate here that cd44 is phosphorylated to high stoichiometry in resting cells and that ca(2+)/calmodulin-dependent protein kinase ii is a cd44 ser(325) kinase.	SIGNOR-57376	0.2
LRRK2	protein	Q5S007	UNIPROT	SH3GL1	protein	Q99961	UNIPROT	down-regulates	phosphorylation			9606									22998870	t		miannu	We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association.	SIGNOR-192068	0.479
CHEK2	protein	O96017	UNIPROT	AATF	protein	Q9NY61	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser510	KKVDRKAsKGRKLRF	9606	BTO:0001109								17157788	t		lperfetto	Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability.	SIGNOR-264418	0.365
PRKCD	protein	Q05655	UNIPROT	RPS3	protein	P23396	UNIPROT	up-regulates	phosphorylation	Ser6	sKKRKFVA	9606									19059439	t		llicata	Here we show that pkcdelta phosphorylates rps3 resulting in its mobilization in the nucleus to repair damaged dna. pkc? Kinase assay then indicated that at least two residues, serine 6 and threonine 221, are phosphorylated by pkc?	SIGNOR-182619	0.2
DYNLT1	protein	P63172	UNIPROT	ARHGEF2	protein	Q92974	UNIPROT	down-regulates activity	binding			9606	BTO:0002181								29089450	t		miannu	Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser151 This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules.	SIGNOR-277369	0.292
FYN	protein	P06241	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	phosphorylation	Tyr1474	GSSNGHVyEKLSSIE	-1									11483655	t		lperfetto	We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases	SIGNOR-247176	0.76
C5AR2	protein	Q9P296	UNIPROT	CR1	protein	P17927	UNIPROT	up-regulates quantity by expression													1847994	f		lperfetto	The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 	SIGNOR-263465	0.346
STAT3	protein	P40763	UNIPROT	T_cell_activation	phenotype	SIGNOR-PH73	SIGNOR	up-regulates				9606									32454942	f		miannu	IL-1β, an inflammatory cytokine primarily expressed in activated macrophages, monocytes, and microglia, significantly contributes to MS development. IL-1β promotes differentiation of T cells into Th17 cells via the STAT3 pathway and thereby promotes and aggravates the inflammatory environment in the CNS	SIGNOR-263821	0.7
STRA6	protein	Q9BX79	UNIPROT	retinol	smallmolecule	CHEBI:50211	ChEBI	up-regulates quantity	relocalization			9913									17255476	t		lperfetto	We identified in bovine retinal pigment epithelium cells STRA6, a multitransmembrane domain protein, as a specific membrane receptor for RBP. STRA6 binds to RBP with high affinity and has robust vitamin A uptake activity from the vitamin A-RBP complex	SIGNOR-265107	0.8
RPS6KB1	protein	P23443	UNIPROT	SREBF1	protein	P36956	UNIPROT	up-regulates				10090	BTO:0002572								20670887	f		lperfetto	We find that srebp1 and 2 promote proliferation downstream of mtorc1, and the activation of these transcription factors is mediated by s6k1.	SIGNOR-167190	0.437
CSNK2A1	protein	P68400	UNIPROT	HDAC2	protein	Q92769	UNIPROT	up-regulates	phosphorylation	Ser394	EDAVHEDsGDEDGED	9606									20388487	t		gcesareni	Protein kinase ck2-mediated phosphorylation of hdac2 regulates co-repressor formation, deacetylase activity and acetylation of hdac2 by cigarette smoke and aldehydesstudies using unfractionated cell extracts with ck2 inhibitors suggest that protein kinase ck2 is the major source of hdac2 kinase. Finally, and perhaps most interesting, hdac2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. Together, our data indicate that like many hdacs, hdac2 is regulated by post-translational modification, particularly phosphorylation.	SIGNOR-164795	0.608
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0000876	BTO:0001103							11602185	f		apalma	The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding.	SIGNOR-255580	0.7
romidepsin	chemical	CHEBI:61080	ChEBI	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257995	0.8
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser111	SPPSPAPsSFSSTSV	9606									15448698	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-129410	0.575
RAD51	protein	Q06609	UNIPROT	SYCP3	protein	Q8IZU3	UNIPROT	up-regulates activity	binding			10090				SIGNOR-C351					10525529	t		miannu	The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process.	SIGNOR-264205	0.371
NR1I2	protein	O75469	UNIPROT	CYP3A4	protein	P08684	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000003								18540626	f		miannu	 Among approximately 40 kinds of phytochemicals, tangeretin and ginkgolides A and B markedly induced the PXR-dependent transcriptional activity and also the activity of the human MDR1 promoter. The expression levels of MDR1 mRNA as well as of CYP3A4 mRNA, another gene regulated by PXR, were significantly increased by these phytochemicals.	SIGNOR-254835	0.537
GCG	protein	P01275	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates				9606									23075495	f		gcesareni	On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz.	SIGNOR-199205	0.2
Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	GABA-A (a4-b3-d) receptor	complex	SIGNOR-C327	SIGNOR	up-regulates				9606									33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors	SIGNOR-268584	0.2
MTA1	protein	Q13330	UNIPROT	MTA3	protein	Q9BTC8	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18719363	f		miannu	 MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG.	SIGNOR-254595	0.638
PRKD1	protein	Q15139	UNIPROT	DLC1	protein	Q96QB1	UNIPROT	down-regulates	phosphorylation	Ser1244	NTLKRENsSPRVMQR	9606									21087603	t		gcesareni	The tumor suppressor protein dlc1 is regulated by pkd-mediated gap domain phosphorylation.Our results thus show that pkd-mediated phosphorylation of dlc1 on serine 807 negatively regulates dlc1 cellular function.	SIGNOR-169994	0.381
FAM20C	protein	Q8IXL6	UNIPROT	ERO1A	protein	Q96HE7	UNIPROT	up-regulates activity	phosphorylation	Ser145	GAVDESLsEETQKAV	9606	BTO:0000567								29858230	t		miannu	We further show that ER oxidoreductin 1α (Ero1α), the pivotal sulfhydryl oxidase that catalyzes disulfide formation in the ER, is phosphorylated by Fam20C in the Golgi apparatus and retrograde-transported to the ER mediated by ERp44. The phosphorylation of Ser145 greatly enhances Ero1α oxidase activity and is critical for maintaining ER redox homeostasis and promoting oxidative protein folding.	SIGNOR-277395	0.2
CYLD	protein	Q9NQC7	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	down-regulates	deubiquitination			9606		BTO:0001253							12917689	t		lperfetto	The nf-kappab activation by cyld is mediated, at least in part, by the deubiquitination and inactivation of tnfr-associated factor 2 (traf2) and, to a lesser extent, traf6.	SIGNOR-117856	0.781
NOTCH1	protein	P46531	UNIPROT	NFKB2	protein	Q00653	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9528780	f		gcesareni	In transient-transfection assays we show that truncated notch-1 strongly induces nf-kappab2 promoter activity.	SIGNOR-56097	0.293
CAV1	protein	Q03135	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									16890161	t		gcesareni	Overall, our data suggest that wnt-3a triggers the interaction of lrp6 with caveolin and promotes recruitment of axin to lrp6 phosphorylated by glycogen synthase kinase-3beta and that caveolin thereby inhibits the binding of beta-catenin to axin.	SIGNOR-148665	0.663
DAB2IP	protein	Q5VWQ8	UNIPROT	GATA1	protein	P15976	UNIPROT	up-regulates activity	binding			9606									27858941	t		miannu	DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene	SIGNOR-254770	0.2
CSNK1A1	protein	P48729	UNIPROT	MDM4	protein	O15151	UNIPROT	up-regulates	phosphorylation	Ser289	DDLEDSKsLSDDTDV	9606									23028042	t		lperfetto	Previous studies showed that casein kinase 1? (ck1?) Stably associates with mdmx, stimulates mdmx-p53 binding, and cooperates with mdmx to inactivate p53ck1? Binding to the mdmx central domain and phosphorylation of s289 disrupts the intramolecular interaction, allowing the n terminus to bind p53 with increased affinity. After dna damage, the mdmx-ck1? Complex is disrupted by chk2-mediated phosphorylation of mdmx at s367, leading to reduced mdmx-p53 binding.	SIGNOR-199015	0.378
HNF1A	protein	P20823	UNIPROT	UGT1A8	protein	Q9HAW9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000195								15044625	t	 	 	Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.	SIGNOR-253972	0.285
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	IQGAP2	protein	Q13576	UNIPROT	up-regulates activity	phosphorylation	Thr716	EYMHRRQtFIDNTDS	9606									21776420	t		miannu	We show that IQGAP2 is regulated by an interaction with the A-kinase anchoring protein AKAP220. Phosphorylation of IQGAP2 via AKAP220-anchored PKA leads to enhanced Rac binding. Since AKAPs function to direct PKA toward specific substrates, we proposed that the formation of an IQGAP2/AKAP220/PKA ternary complex sharpens the response to cAMP.	SIGNOR-273742	0.2
PYGB	protein	P11216	UNIPROT	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	up-regulates quantity	chemical modification			9606									3346228	t		miannu	Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267396	0.8
HIF1AN	protein	Q9NWT6	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates	hydroxylation			9606									18299578	t		gcesareni	We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation.	SIGNOR-254324	0.565
TTI1	protein	O43156	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates quantity by stabilization	binding			9606	BTO:0000007								20427287	t		miannu	MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. 	SIGNOR-272002	0.603
PTTG1	protein	O95997	UNIPROT	LGALS1	protein	P09382	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002428								19351864	f		miannu	PTTG induced S100A4 and galectin-1 mRNA and protein expression as assessed by Western blot and reverse transcription-PCR. 	SIGNOR-255068	0.2
SUMO1	protein	P63165	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates activity	sumoylation	Lys490	QCPRKVIkMESEEGK	9534	BTO:0000298								9756909	t		lperfetto	We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins |We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites. The PML mutant with Lys to Arg substitutions in all three sites is expressed normally, but cannot be sentrinized|Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies.	SIGNOR-270541	0.771
PTPN6	protein	P29350	UNIPROT	PTK2B	protein	Q14289	UNIPROT	down-regulates	dephosphorylation	Tyr402	CSIESDIyAEIPDET	9606									10521452	t		gcesareni	Raftk binds constitutively to the protein tyrosine phosphatase shptp1.SHPTP1 Plays a negative role in pyk2/raftk signaling by dephosphorylating raftk on tyr-402, thereby inhibiting the interaction of the sh2 domain of c-src with raftk	SIGNOR-71414	0.365
Corticotropin	protein	P01189-PRO_0000024969	UNIPROT	HSD3B1	protein	P14060	UNIPROT	up-regulates quantity				9606									24631756	f		lperfetto	CTH signaling promotes the single steroidogenic rate limiting step, which is the conversion of cholesterol to pregnenolone by Cholesterol Side-Chain Cleavage Enzyme (P450scc), encoded in the CYP11A1 gene. This is conferred by a direct stimulating effect of ACTH on the promoter of CYP11A1 (Chung et al., 1997, Liu and Simpson, 1997, Hu et al., 2001). Further, it stimulates conversion of pregnenolone to 17-hydroxypregnenolone by upregulating the expression of 3β hydroxysteroid dehydrogenase enzyme (3β-HSD)	SIGNOR-268720	0.2
NFIB	protein	O00712	UNIPROT	NFIB	protein	O00712	UNIPROT	down-regulates activity	binding			9606									9099724	t	2	miannu	Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function.	SIGNOR-240883	0.2
PTPN12	protein	Q05209	UNIPROT	PSTPIP1	protein	O43586	UNIPROT	down-regulates activity	dephosphorylation	Tyr345	PERNEGVyTAIAVQE	10090									11711533	t			We also demonstrate that PTP-PEST dephosphorylates PSTPIP at tyrosine 344. Importantly, we identified tyrosine 344 as the main phosphorylation site of PSTPIP by performing tryptic phosphopeptide maps. |The biological functions of the complexes formed between PSTPIP and SH2 domain-containing tyrosine kinases may be to transmit the signals from activated EGF and PDGF receptor.|Furthermore, we show that PSTPIP is phosphorylated downstream of the activated PDGF and EGF receptors. This phosphorylation of PSTPIP is most likely mediated by c-Abl	SIGNOR-248656	0.631
WNT5A	protein	P41221	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity				9606									21078818	f		lperfetto	We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3)	SIGNOR-227961	0.435
creatine	smallmolecule	CHEBI:16919	ChEBI	CKMT1A	protein	P12532	UNIPROT	up-regulates activity	chemical activation			9606									18502307	t		miannu	Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 	SIGNOR-265786	0.8
RAR	proteinfamily	SIGNOR-PF45	SIGNOR	RXRA	protein	P19793	UNIPROT	up-regulates	binding			9606									1310351	t	inferred from 70% family members	gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-269954	0.2
AP-2 complex	complex	SIGNOR-C245	SIGNOR	ITSN1	protein	Q15811	UNIPROT	up-regulates activity	binding			10116	BTO:0000142								15496985	t		Giorgia	Intersectins 1 and 2, epsin2, NECAP and sorting nexin9 were identified as α‐appendage ligands in mass spectrometry of these samples	SIGNOR-260397	0.643
PLP1	protein	P60201	UNIPROT	Myelination	phenotype	SIGNOR-PH206	SIGNOR	up-regulates													26519753	f		SimoneGraziosi	Proteolipid protein (PLP) is a major component only in the CNS myelin of terrestrial species and is involved in compaction of the extracellular apposition.	SIGNOR-269265	0.7
AMPK	complex	SIGNOR-C15	SIGNOR	TSC1	protein	Q92574	UNIPROT	up-regulates	phosphorylation			9606									14651849	t		lperfetto	Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity.	SIGNOR-216441	0.41
PIM2	protein	Q9P1W9	UNIPROT	PK	proteinfamily	SIGNOR-PF80	SIGNOR	up-regulates quantity by stabilization	phosphorylation			9606									24142698	t		Manara	Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels.	SIGNOR-268151	0.379
NXPH1	protein	P58417	UNIPROT	NRXN3	protein	Q9Y4C0	UNIPROT	up-regulates	binding			9606	BTO:0000938								9856994	t		gcesareni	We show that neurexophilins 1 and 3 but not 4 (neurexophilin 2 is not expressed in rodents) bind to a single individual lns domain, the second overall lns domain in all three alpha-neurexins.	SIGNOR-60643	0.384
DYRK2	protein	Q92630	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser107	NPMRRIHsLPQKLLG	9606	BTO:0002181								34363019	t		miannu	Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. 	SIGNOR-276738	0.2
GSK3B	protein	P49841	UNIPROT	SNCAIP	protein	Q9Y6H5	UNIPROT	down-regulates	phosphorylation	Ser556	AQKSEGKsLPSSPSS	9606									16174773	t		lperfetto	Synphilin-1 s556a mutant, which is less phosphorylated by gsk3beta, formed more inclusion bodies than wild type synphilin-1. Mutation analysis showed that ser556 is a major gsk3beta phosphorylation site in synphilin-1	SIGNOR-140609	0.5
PRKCD	protein	Q05655	UNIPROT	EP300	protein	Q09472	UNIPROT	down-regulates	phosphorylation	Ser89	SELLRSGsSPNLNMG	9606									12379484	t		lperfetto	Inhibition of histone acetyltransferase function of p300 by pkcdeltawe found that pkcdelta but not classical pkc, specifically phosphorylates p300 at serine 89 in vitro and in vivo. This phosphorylation causes inhibition of p300 intrinsic hat activity.	SIGNOR-94263	0.374
lysophosphatidylinositol 22:6	smallmolecule	CHEBI:138556	ChEBI	GPR55	protein	Q9Y2T6	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257507	0.8
MTOR	protein	P42345	UNIPROT	GRB10	protein	Q13322	UNIPROT	up-regulates	phosphorylation			9606			SIGNOR-C3						21659604	t		gcesareni	The adaptor protein grb10 was identified as an mtorc1 substrate that mediates the phosphoinositide 3-kinase.	SIGNOR-174071	0.424
TACR2	protein	P21452	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256736	0.261
ADORA2A	protein	P29274	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257239	0.306
HDAC4	protein	P56524	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates activity	binding			9534									15537544	t		lperfetto	Here we report that HDAC4, which is expressed in prehypertrophic chondrocytes, regulates chondrocyte hypertrophy and endochondral bone formation by interacting with and inhibiting the activity of Runx2, a transcription factor necessary for chondrocyte hypertrophy.PDPK1	SIGNOR-226680	0.54
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1668	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120188	0.321
BMPR1B	protein	O00238	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates				10090									10564272	f		lperfetto	We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2	SIGNOR-235622	0.628
KLF4	protein	O43474	UNIPROT	MEIS2	protein	O14770	UNIPROT	up-regulates activity	binding			9606									21746878	t		miannu	We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.	SIGNOR-267238	0.272
KDM5B	protein	Q9UGL1	UNIPROT	PAX9	protein	P55771	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								12657635	t		miannu	Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression	SIGNOR-223875	0.497
DNM1L	protein	O00429	UNIPROT	Mitochondrial_fission	phenotype	SIGNOR-PH143	SIGNOR	up-regulates				9606	BTO:0000567								17301055	f		Barakat	Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission	SIGNOR-274132	0.7
SLC27A2	protein	O14975	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264462	0.7
CDK1	protein	P06493	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	down-regulates activity	phosphorylation	Ser1678	ITSEEERsPAKRGRK	-1									30685087	t		lperfetto	Nuclear import of 53BP1 is required for proper localization of 53BP1 and maintenance of genome integrity. 53BP1 has a classical bipartite nuclear localization signal (NLS) of sequence 1666-GKRKLITSEEERSPAKRGRKS-1686. Ser1678 within the 53BP1 NLS can be phosphorylated by CDK1/cyclin B, and a phosphomimetic substitution of Ser1678 with aspartate has been shown to negatively regulate nuclear import of 53BP1.	SIGNOR-264412	0.618
PPM1G	protein	O15355	UNIPROT	USP7	protein	Q93009	UNIPROT	down-regulates activity	dephosphorylation			9606									22361354	t		miannu	Here, we report that in response to DNA damage USP7 is downregulated by the ATM dependent protein phosphatase PPM1G, thus downregulating Mdm2 and activating the p53 response.|We have now shown that when DNA damage is detected, PPM1G is activated and dephosphorylates USP7 isoform protein that leads to its degradation and consequently to Mdm2 degradation and accumulation of p53 ( A).	SIGNOR-277159	0.525
SENP1	protein	Q9P0U3	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates quantity by destabilization	desumoylation	Lys276	NVVYRDLkLENLMLD	10090	BTO:0002572								23884910	t		gcesareni	Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity.	SIGNOR-252738	0.284
AP1	complex	SIGNOR-C154	SIGNOR	CXCL8	protein	P10145	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32446778	f		miannu	The up-regulation of the CXCL8 gene expression, could be due to a direct effect of the virus at the cellular level. Indeed, intestinal and lung cells lines infected by SARS-CoV, promptly increase their secretion of CXCL8 [88]. This observation would fit with the notion that the expression of CXCL8 is dependent on the tran-scription factor Activator protein 1 (AP-1), which was shown to bestrongly up-regulated by SARS-CoV	SIGNOR-261029	0.563
KHSRP	protein	Q92945	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by destabilization	post transcriptional regulation			10090	BTO:0000165								16364914	t		lperfetto	Importantly, KSRP knockdown in C2C12 GM cells (Figure 2D) stabilized endogenous my- ogenin and p21 transcripts (Figure 2E). Furthermore, stable knockdown of KSRP, using shRNA, induced the accumulation of p21 mRNA in C2C12 GM while it did not affect the expression of late myogenic markers (MHC and muscle-creatine kinase [MCK])	SIGNOR-235859	0.255
LAT	protein	O43561	UNIPROT	VAV1	protein	P15498	UNIPROT	up-regulates activity	binding			9606					phosphorylation:Tyr255;Tyr220	EEEGAPDyENLQELN;SLDGSREyVNVSQEL			11368773	t		lperfetto	By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.	SIGNOR-246045	0.742
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1717	SPSYSPTsPSYSPTS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248775	0.441
SRC	protein	P12931	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Tyr315	TFCGTPEyLAPEVLE	9534									11445557	t		lperfetto	Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity.	SIGNOR-252620	0.663
STK3	protein	Q13188	UNIPROT	LATS1	protein	O95835	UNIPROT	up-regulates	phosphorylation	Thr1079	EHAFYEFtFRRFFDD	9606	BTO:0000007								15688006	t	Two of these, S909 and T1079, were required for Lats1 activation.	milica	Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1.	SIGNOR-132927	0.603
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MYC	protein	P01106	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser62	LLPTPPLsPSRRSGL	10116	BTO:0004725								11018017	t			Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK.	SIGNOR-252079	0.2
Netrin	proteinfamily	SIGNOR-PF97	SIGNOR	UNC5	proteinfamily	SIGNOR-PF98	SIGNOR	up-regulates activity	binding			9606									25881791	t		miannu	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268174	0.849
EPS15	protein	P42566	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	binding			10029	BTO:0002988								15383614	t		gcesareni	We suggest that the ubiquitinated EGFR or another c-Cbl substrate that is ubiquitinated upon EGFR activation recruits Eps15 to the plasma membrane via its UIM. This event would facilitate EGFR internalization via a clathrin-dependent route in which Eps15 plays a role	SIGNOR-243278	0.746
SRC	protein	P12931	UNIPROT	LPIN1	protein	Q14693	UNIPROT	up-regulates activity	phosphorylation	Tyr413	DPEVAALyFPKNGDP	9606	BTO:0002181								33203880	t		miannu	Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride.	SIGNOR-277293	0.2
ATR	protein	Q13535	UNIPROT	KIFC1	protein	Q9BW19	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser26	RPLIKAPsQLPLSGS	9606	BTO:0000815								33397932	t		miannu	 ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro.	SIGNOR-277296	0.259
CDK1	protein	P06493	UNIPROT	RCC1	protein	P18754	UNIPROT	up-regulates activity	phosphorylation	Ser2	sPKRIAKR	-1									15014043	t		miannu	Human RCC1 is phosphorylated on Ser 2 and Ser 11 in mitosis by Cdc2 kinase. We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation.	SIGNOR-262701	0.518
PRKCG	protein	P05129	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	down-regulates	phosphorylation	Thr603	PCCIVTStYGWTANM	9606									24117238	t		lperfetto	Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_, and, more interestingly, this threonine residue set serves as a 'phosphorylation switch' for hsp90_ binding or release of pkc_. Moreover, phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity.	SIGNOR-202820	0.26
UVB radiation	stimulus	SIGNOR-ST17	SIGNOR	IL1A	protein	P01583	UNIPROT	up-regulates				9606									9767234	f		miannu	UVB can stimulate the synthesis of IL-1, TNF-a and ET-1, and other cytokines by keratinocytes.	SIGNOR-252384	0.7
CUX1	protein	P39880	UNIPROT	PIK3IP1	protein	Q96FE7	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24316979	t		miannu	We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition.	SIGNOR-260072	0.377
AKT1	protein	P31749	UNIPROT	MAP3K8	protein	P41279	UNIPROT	up-regulates activity	phosphorylation	Ser400	EDQPRCQsLDSALLE	9606	BTO:0000007								12138205	t			Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator.	SIGNOR-252571	0.538
ESRRA	protein	P11474	UNIPROT	SNAI2	protein	O43623	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15955695	f		miannu	 In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro.	SIGNOR-253790	0.255
RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	HEY1	protein	Q9Y5J3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								21193018	t		lperfetto	Activated NICD-RBP-Jk complex displaces co-repressors and recruits coactivator (co-A) mediating the transcription of target genes such as Hes-1 (hairy enhancer of split), cyclin D, Hey-1 (hairy/enhancer-of-split related with YRPW motif) and others [1213].	SIGNOR-170854	0.705
LYN	protein	P07948	UNIPROT	DAPP1	protein	Q9UN19	UNIPROT	up-regulates activity	phosphorylation	Tyr139	KVEEPSIyESVRVHT		BTO:0000776								10880360	t		lperfetto	Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins.	SIGNOR-249378	0.609
PLAUR	protein	Q03405	UNIPROT	ITGB3	protein	P05106	UNIPROT	up-regulates activity	binding			9606									27383564	t			Recent evidence suggests that the activation of b3 integrin in podocytes mediates uPAR-induced cellular events leading to proteinuria 	SIGNOR-253333	0.448
PRKCE	protein	Q02156	UNIPROT	OPRD1	protein	P41143	UNIPROT	unknown	phosphorylation	Ser344	CGRPDPSsFSRAREA	9606	BTO:0000007								11085981	t		lperfetto	In the current study, we identified a PKC-mediated phosphorylation site in the delta-opioid receptor (DOR) and demonstrated that activation of PKC by stimulation of other types of GPCR or increase in intracellular Ca2+concentration in HEK 293 cells induces heterologous phosphorylation of DOR. Our results further established that DOR phosphorylation at Ser-344 by PKC results in internalization of DOR in HEK 293 cells through a beta-arrestin- and clathrin-mediated mechanism.	SIGNOR-249064	0.372
MAPK14	protein	Q16539	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates activity				9606	BTO:0001255								12839928	f		miannu	Activation of p38 MAPK is required for arsenite-induced apoptosis and MEK1,2 dephosphorylation in human skin fibroblasts. Our data suggest the presence of a continuous negative feedback from p38α and p38β to MEK1,2 as simultaneous inhibition of p38α and p38β isoforms in normal quiescent cells resulted in accumulation of phosphorylated MEK1,2 (Fig. 2A) ⇓ . This negative regulation of MEK1,2 in normal cells could be considered a means to control MEK1,2-mediated proliferation and expression of transformation-related genes. 	SIGNOR-263511	0.659
Macrophage_activation	phenotype	SIGNOR-PH126	SIGNOR	ARDS	phenotype	SIGNOR-PH128	SIGNOR	up-regulates				9606									32446778	f		miannu	The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm.	SIGNOR-261021	0.7
3-phosphonato-D-glyceroyl phosphate(4-)	smallmolecule	CHEBI:57604	ChEBI	3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa.	SIGNOR-266501	0.8
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser213	QNIPAHYsPRTSPIM	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248371	0.598
lurasidone	chemical	CHEBI:70735	ChEBI	HTR2A	protein	P28223	UNIPROT	down-regulates activity	chemical inhibition			10030									20404009	t		Luana	Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 
2C receptors.	SIGNOR-257841	0.8
GFI1	protein	Q99684	UNIPROT	Granulocyte_differentiation	phenotype	SIGNOR-PH102	SIGNOR	up-regulates				9606									20861919	f		irozzo	In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation.	SIGNOR-256084	0.7
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser153	SWTRVFQsWWDRNLG	9606	BTO:0000007								10837486	t		lperfetto	We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites.	SIGNOR-252767	0.2
GNAI1	protein	P63096	UNIPROT	Adenylate_cyclase	proteinfamily	SIGNOR-PF92	SIGNOR	down-regulates activity	binding			9606									15922020	t		miannu	Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated.	SIGNOR-267853	0.618
PPP1CA	protein	P62136	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates activity	dephosphorylation	Thr125	PEVLRPEtPRPVDIG	9606									16888006	t			ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition. Until now, the phosphatase responsible for Thr(125) dephosphorylation has not been described. Here, we demonstrate that in IL-2-proliferating cells, phosphorylated serine/threonine phosphatase type 1alpha (PP1alpha) associates with phosphorylated caspase-9.	SIGNOR-248565	0.2
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	SLC25A12	protein	O75746	UNIPROT	up-regulates activity	chemical activation			9606									12084073	t		miannu	Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. 	SIGNOR-265152	0.8
NEDD4	protein	P46934	UNIPROT	SAG	protein	P10523	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								25216516	t		miannu	Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation. 	SIGNOR-272843	0.383
PRKAA2	protein	P54646	UNIPROT	CRTC2	protein	Q53ET0	UNIPROT	down-regulates	phosphorylation	Ser171	SALNRTSsDSALHTS	9606			SIGNOR-C15						16148943	t		gcesareni	Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2	SIGNOR-140238	0.471
SP1	protein	P08047	UNIPROT	DHCR24	protein	Q15392	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22431021	f		miannu	 activation of Sp1 by oxidative stress is involved in the promotion of expression of DHCR24 by HCV.	SIGNOR-255200	0.2
KDM4C	protein	Q9H3R0	UNIPROT	H3-4	protein	Q16695	UNIPROT	down-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									29207681	t		miannu	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 	SIGNOR-263867	0.2
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr653	RDIHHIDyYKKTTNG	10116	BTO:0002809;BTO:0001009								8622701	t		lperfetto	In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of fgfr1 and is therefore essential for fgfr1-mediated biological responses.	SIGNOR-236195	0.2
PLK3	protein	Q9H4B4	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Ser191	EDQAEEIsDELMEFS	9606									14968113	t		lperfetto	Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation	SIGNOR-122090	0.721
DOK1	protein	Q99704	UNIPROT	A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257676	0.32
CAPN1	protein	P07384	UNIPROT	GSK3A	protein	P49840	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000590								25969760	t		lperfetto	Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase	SIGNOR-251585	0.2
SRC	protein	P12931	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates	phosphorylation	Tyr419	RLIEDNEyTARQGAK	9606									7578094	t		lperfetto	These data are consistent with autophosphorylation on y-419 as predicted. Intermolecular autophosphorylation is consistent with the ability of srctk to dimerize, which is analogous to activation of receptor tyrosine kinases such as the egf receptor kinase in response to growth factors.	SIGNOR-29369	0.2
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Leu)	smallmolecule	CHEBI:29169	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269489	0.8
NEDD4L	protein	Q96PU5	UNIPROT	SCN2A	protein	Q99250	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000938								23778145	t		miannu	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 	SIGNOR-253459	0.323
TGFb	proteinfamily	SIGNOR-PF5	SIGNOR	TGFBR2	protein	P37173	UNIPROT	up-regulates activity	binding			9606	BTO:0000801								22703233	t		miannu	TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex.	SIGNOR-256179	0.2
AKT1	protein	P31749	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates	phosphorylation			9606		BTO:0001103							15829723	t		apalma	Once phosphorylated, Akt can act on a broad spectrum of substrates that can influence cell survival and proliferation and protein synthesis (65). Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K	SIGNOR-255844	0.72
PI3K	complex	SIGNOR-C156	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity				9606									12167717	f		lperfetto	PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473,	SIGNOR-252715	0.785
TGFBR2	protein	P37173	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates	binding			9606	BTO:0001660								9435577	t		lperfetto	These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells.	SIGNOR-227521	0.459
PKN3	protein	Q6P5Z2	UNIPROT	ARHGAP18	protein	Q8N392	UNIPROT	up-regulates activity	phosphorylation	Thr154	AVQKRVEtVSQTLRK	-1									33092266	t		lperfetto	We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA.|These results support our data from phosphoproteomic screen and suggest that ARHGAP18 can be phosphorylated by PKN3 on Thr154, Ser156 and Thr158.	SIGNOR-264570	0.2
CASP3	protein	P42574	UNIPROT	DFFA	protein	O00273	UNIPROT	up-regulates activity	cleavage			9606									9108473	t		lperfetto	DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3.	SIGNOR-47416	0.746
RNF146	protein	Q9NTX7	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates quantity	ubiquitination			9606									21799911	t			By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins.	SIGNOR-259996	0.633
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	Fatty_Acid_Biosynthesis	phenotype	SIGNOR-PH190	SIGNOR	up-regulates				9606		BTO:0000759							24692351	f		scontino	TH stimulates both lipolysis and lipogenesis, although the direct action is lipolysis with lipogenesis thought to be stimulated to restore fat stores. Fatty acids produced from TH-induced lipolysis are the substrate for the increase in thermogenesis.	SIGNOR-267489	0.7
SGCG	protein	Q13326	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255987	0.453
NLGN3	protein	Q9NZ94	UNIPROT	NRXN3	protein	Q9Y4C0	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264162	0.82
estrone	smallmolecule	CHEBI:17263	ChEBI	17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	up-regulates quantity	precursor of			-1									8099587	t		Luana	17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone. 	SIGNOR-269763	0.8
CDT1	protein	Q9H211	UNIPROT	MCM	complex	SIGNOR-C268	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								14672932	t			Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1.	SIGNOR-261679	0.782
EFNA4	protein	P52798	UNIPROT	EPHA5	protein	P54756	UNIPROT	up-regulates	binding			9606									9330863	t		tpavlidou	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52430	0.804
PPARGC1A	protein	Q9UBK2	UNIPROT	Mitochondrial_biogenesis	phenotype	SIGNOR-PH32	SIGNOR	up-regulates				9606									23277535	f		gcesareni	PGC1a is a positive regulator of mitochondrial biogenesis and respiration, adaptive thermogenesis, gluconeogenesis as well as many other metabolic proc	SIGNOR-228618	0.7
MAP3K7	protein	O43318	UNIPROT	NFKB1	protein	P19838	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								9480845	f		lperfetto	These results suggest that tak1 induces nf-kappa b activation through a novel nik-independent signaling pathway.	SIGNOR-55713	0.581
CDK19	protein	Q9BWU1	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2513	EHPFLTPsPESPDQW	-1									25344755	t		lperfetto	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273136	0.307
AUTS2	protein	Q8WXX7	UNIPROT	PREX1	protein	Q8TCU6	UNIPROT	up-regulates activity	binding			10090	BTO:0001909								25533347	t		miannu	Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development.  AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells.	SIGNOR-266817	0.255
SLC1A3	protein	P43003	UNIPROT	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	up-regulates quantity	relocalization			9606									26687113	t		miannu	After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). In glia or in neurons, EAATs mediate the re-uptake of synaptically released glutamate via the coupled co-transport of three Na+, one H+, and one glutamate, in counter-transport to one K+. 	SIGNOR-264802	0.8
LYN	protein	P07948	UNIPROT	ACLY	protein	P53396	UNIPROT	up-regulates activity	phosphorylation	Tyr252	EAYPEEAyIADLDAK	9606	BTO:0000007								32420483	t	done	miannu	 We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells.	SIGNOR-274105	0.2
KDR	protein	P35968	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity				10090									22264731	t	VEGF pathway	Gianni	Here we show that genetic or pharmacological FAK inhibition in ECs prevents VEGF-stimulated permeability downstream of VEGF receptor or Src tyrosine kinase activation in vivo. VEGF promotes tension-independent FAK activation	SIGNOR-261945	0.475
ZBTB14	protein	O43829	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									10080939	f		miannu	ZF5, which we have cloned as a transcriptional repressor on the mouse c-myc promoter	SIGNOR-220537	0.321
PRKDC	protein	P78527	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates activity	phosphorylation	Thr2647	QQHDFTLtQTADGRS	9606	BTO:0000773								12186630	t		lperfetto	 We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function.	SIGNOR-249160	0.2
TNK2	protein	Q07912	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Tyr176	EKATGRYyAMKILKK	10090									20333297	t		gcesareni	Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation.	SIGNOR-252446	0.437
SAV1	protein	Q9H4B6	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates quantity by stabilization	binding			9606									16930133	t	Hippo pathway	Gianni	Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation.	SIGNOR-261958	0.882
PDPK1	protein	O15530	UNIPROT	AKT2	protein	P31751	UNIPROT	up-regulates activity	phosphorylation	Thr309	SDGATMKtFCGTPEY	9606									15743829	t		lperfetto	Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. Pdk1 phosphorylates akt-2 at thr 309 in the catalytic domain, leading to enzymatic activation.	SIGNOR-134485	0.718
MYOG	protein	P15173	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates				9606		BTO:0001103							28163303	f		apalma	During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function	SIGNOR-255112	0.7
STK38	protein	Q15208	UNIPROT	XPO1	protein	O14980	UNIPROT	up-regulates activity	phosphorylation	Ser1055	EKHKRQMsVPGIFNP	9606	BTO:0000567								31544310	t		miannu	We further uncover that STK38 modulates XPO1 export activity by phosphorylating XPO1 on serine 1055, thus regulating its own nuclear exit. 	SIGNOR-277483	0.2
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	G1/S_transition	phenotype	SIGNOR-PH50	SIGNOR	up-regulates				9606									21524151	f		lperfetto	In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F	SIGNOR-245480	0.7
IFNAR	complex	SIGNOR-C243	SIGNOR	TYK2	protein	P29597	UNIPROT	up-regulates activity	binding			9606									15120645	t		miannu	Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48).	SIGNOR-260146	0.8
PIM1	protein	P11309	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation	Ser257	SWLGARSsRPASPCN	-1									31730483	t		miannu	Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 	SIGNOR-276767	0.629
MAPK3	protein	P27361	UNIPROT	SOX9	protein	P48436	UNIPROT	up-regulates	transcriptional regulation			9606									20457810	f		fspada	Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression.	SIGNOR-209965	0.391
CDK5	protein	Q00535	UNIPROT	PARP1	protein	P09874	UNIPROT	down-regulates activity	phosphorylation	Ser782	YSLLRGGsDDSSKDP	-1									21922195	t		miannu	These results would suggest that the phosphorylation of PARP-1 via Cdk5's kinase activity is necessary for its persistence at damage sites.Based on these results and the recruitment data, we hypothesize that the phosphorylation of the PARP-1 protein by Cdk5 on one or more of the serines 782, 785, and 786 results in an attenuation of its ribosylating activity facilitating its persistence at the sites of DNA damage.	SIGNOR-276357	0.261
SMARCA2	protein	P51531	UNIPROT	Neural progenitor-specific SWI/SNF	complex	SIGNOR-C477	SIGNOR	form complex	binding			9606									25195934	t		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270610	0.817
IGF1	protein	P05019	UNIPROT	MMP13	protein	P45452	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003858								12734180	f		miannu	In the present study we investigated the inhibitory effects of IGF-1 and OP-1 on MMP-13 expression in human chondrocytes. We found that the suppressive effect of IGF-1 and OP-1 on the MMP-13 promoter activity was dose-dependent at the transcriptional level with a corresponding decrease in the level of MMP-13 protein. 	SIGNOR-254802	0.364
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270420	0.8
KCNB1	protein	Q14721	UNIPROT	VAPB	protein	O95292	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000007								29941597	t		lperfetto	Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions.	SIGNOR-262121	0.2
KAT2A	protein	Q92830	UNIPROT	H3Y1	protein	P0DPK2	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkATAWQAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269597	0.2
CLP1	protein	Q92989	UNIPROT	CFII complex	complex	SIGNOR-C387	SIGNOR	form complex	binding			9606	BTO:0000567								30139799	t		lperfetto	Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1.	SIGNOR-266120	0.885
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser274	ASPQRSRsPSPQPSS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248689	0.613
MLL-AF9	fusion protein	SIGNOR-FP5	SIGNOR	RUNX1	protein	Q01196	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24449215	f		irozzo	However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins.	SIGNOR-255851	0.2
DACT2	protein	Q5SW24	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates	binding			9606									17197390	t		lpetrilli	Here, we provide evidence that unlike dpr1 that modulates wnt signaling, mdpr2 negatively regulates tgf-? Signaling and promotes tgf-? Receptor degradation in lysosomes. these results suggest that mdpr2 interferes with tgf-? By directly binding to and targeting the receptors for lysosomal inhibitor-sensitive degradation.	SIGNOR-151750	0.401
MLL-AF9	fusion protein	SIGNOR-FP5	SIGNOR	MECOM	protein	Q03112	UNIPROT	up-regulates quantity by expression	methylation			10090	BTO:0001271								22553314	t		irozzo	We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia.	SIGNOR-255858	0.2
SIRT1	protein	Q96EB6	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates				9606									14976264	f		lperfetto	Sirt1 inhibited foxo3's ability to induce cell death.	SIGNOR-256662	0.7
CSNK2A1	protein	P68400	UNIPROT	BMI1	protein	P35226	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser110	SADAANGsNEDRGEV	9606									28270146	t		miannu	Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. e-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function. 	SIGNOR-277345	0.272
IL20RA	protein	Q9UHF4	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates	binding			9606									15120645	t		gcesareni	Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain.	SIGNOR-124486	0.465
PIM1	protein	P11309	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation	Ser335	GDGVPVKsRKTTLEQ	-1									31730483	t		miannu	Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 	SIGNOR-276776	0.629
HTR7	protein	P34969	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257381	0.325
PRKAA1	protein	Q13131	UNIPROT	HDAC4	protein	P56524	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000938	BTO:0000887	SIGNOR-C15						21565617	t		gcesareni	We show here that in liver, class iia hdacs (hdac4, 5, and 7) are phosphorylated and excluded from the nucleus by ampk family kinases.	SIGNOR-173689	0.275
ASPA	protein	P45381	UNIPROT	N-acetyl-L-aspartate(2-)	smallmolecule	CHEBI:16953	ChEBI	down-regulates quantity	chemical modification			9606									17194761	t		miannu	N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain.	SIGNOR-267526	0.8
PLK1	protein	P53350	UNIPROT	PINX1	protein	Q96BK5	UNIPROT	down-regulates	phosphorylation	Thr141	DLSSRSKtDLDCIFG	9606									20573420	t		lperfetto	Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation.	SIGNOR-166329	0.37
NR3C1	protein	P04150	UNIPROT	UGT1A1	protein	P22309	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18172616	f	 	miannu	 This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities.	SIGNOR-254439	0.286
CHMP1B	protein	Q7LBR1	UNIPROT	ESCRT-III	complex	SIGNOR-C379	SIGNOR	form complex	binding			-1									26775243	t		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission.	SIGNOR-265524	0.705
Cell-Cell_contact	stimulus	SIGNOR-ST13	SIGNOR	STK3	protein	Q13188	UNIPROT	up-regulates				9606									22683405	f		milica	In response to growth inhibitory signal (e.g. cell–cell contact), MST1/2 in active form phosphorylates LATS1/2 that sequentially phosphorylates YAP at Ser-127.	SIGNOR-230696	0.7
PAICS	protein	P22234	UNIPROT	5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium	smallmolecule	CHEBI:137981	ChEBI	down-regulates quantity	chemical modification			9606									33179964	t		miannu	The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS).	SIGNOR-267317	0.8
EFNB3	protein	Q15768	UNIPROT	EPHB3	protein	P54753	UNIPROT	up-regulates	binding			9606									9330863	t		tpavlidou	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52624	0.815
SIRT2	protein	Q8IXJ6	UNIPROT	PGAM	proteinfamily	SIGNOR-PF78	SIGNOR	up-regulates activity	deacetylation			9606									24786789	t		miannu	 Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2.	SIGNOR-266519	0.284
PRKCG	protein	P05129	UNIPROT	CYTH2	protein	Q99418	UNIPROT	down-regulates activity	phosphorylation	Ser392	AARKKRIsVKKKQEQ	9606	BTO:0000567								10531036	t		lperfetto	ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'.	SIGNOR-249025	0.337
threonine	smallmolecule	CHEBI:26986	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264761	0.7
CPT1A	protein	P50416	UNIPROT	Fatty_acid_oxidation	phenotype	SIGNOR-PH129	SIGNOR	up-regulates activity				9606									31900483	f			As the key rate-limiting enzyme of FAO, carnitine palmitoyltransferase I (CPT1) regulates FAO and facilitates adaptation to the environment, both in health and in disease, including cancer. The CPT1 family of proteins contains 3 isoforms: CPT1A, CPT1B, and CPT1C. This review focuses on CPT1A, the liver isoform that catalyzes the rate-limiting step of converting acyl-coenzyme As into acyl-carnitines, which can then cross membranes to get into the mitochondria	SIGNOR-267757	0.7
NDUFS2	protein	O75306	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46].	SIGNOR-262176	0.861
retinal	smallmolecule	CHEBI:15035	ChEBI	all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	up-regulates quantity	precursor of			9606									21621639	t		lperfetto	All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step.	SIGNOR-265127	0.8
paclitaxel	chemical	CHEBI:45863	ChEBI	TUBB1	protein	Q9H4B7	UNIPROT	down-regulates activity	chemical inhibition			9606									28298489	t		miannu	Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap.	SIGNOR-259347	0.8
PRKAA2	protein	P54646	UNIPROT	HAS2	protein	Q92819	UNIPROT	down-regulates activity	phosphorylation	Thr110	LQSVKRLtYPGIKVV	9534	BTO:0000298								21228273	t		miannu	We found that AMPK phosphorylated Thr-110 of human HAS2, which inhibits its enzymatic activity.	SIGNOR-276299	0.2
PI3K	complex	SIGNOR-C156	SIGNOR	PIK3CG	protein	P48736	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								14665640	t		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-252721	0.585
IRX2	protein	Q9BZI1	UNIPROT	CCL5	protein	P13501	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003885								26560478	f		Luana	Our results imply that the IRX2 transcription factor might represent a novel metastasis associated protein that acts as a negative regulator of cellular motility and as a repressor of chemokine expression. 	SIGNOR-266043	0.2
PRTN3	protein	P24158	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Val76	LTGKLTTvFLPIVYT	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263601	0.381
CBY1	protein	Q9Y3M2	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9606									12712206	t		gcesareni	Here we report a conserved nuclear protein, named chibby, which was identified in a screen for proteins that directly interact with the c-terminal region of beta-catenin. In mammalian cultured cells we demonstrate that chibby inhibits beta-catenin-mediated transcriptional activation by competing with lef-1 to bind to beta-catenin.	SIGNOR-100835	0.68
PRKD1	protein	Q15139	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606									20179209	t		lperfetto	Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated	SIGNOR-163928	0.311
ethanol	chemical	CHEBI:16236	ChEBI	GLRA2	protein	P23416	UNIPROT	up-regulates activity	chemical activation			8355	BTO:0000964								8700149	t		miannu	Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations.	SIGNOR-258496	0.8
PTPN6	protein	P29350	UNIPROT	TYK2	protein	P29597	UNIPROT	down-regulates				9606	BTO:0000150;BTO:0001271;BTO:0000785;BTO:0000661;BTO:0003076								14624462	f		lperfetto	We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation	SIGNOR-119200	0.589
MAPK8	protein	P45983	UNIPROT	NFATC2	protein	Q13469	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000782								14517246	t		gcesareni	Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin jnk directly regulated nuclear factor of activated t-cell (nfat) activation in culture and in transgenic mice containing an nfat-dependent luciferase reporter.	SIGNOR-118217	0.742
perfluorohexanesulfonic acid	chemical	CHEBI:132448	ChEBI	PPARD	protein	Q03181	UNIPROT	up-regulates activity	chemical activation			-1									31332417	t		miannu	In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group.	SIGNOR-268755	0.8
HMGB1	protein	P09429	UNIPROT	HOXD10	protein	P28358	UNIPROT	up-regulates activity	binding			-1									8890171	t	2	miannu	We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.	SIGNOR-240556	0.296
axitinib	chemical	CHEBI:66910	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258076	0.8
SMARCD3	protein	Q6STE5	UNIPROT	Neural progenitor-specific SWI/SNF	complex	SIGNOR-C477	SIGNOR	form complex	binding			9606									25195934	t		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270613	0.764
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	XPO5	protein	Q9HAV4	UNIPROT	down-regulates activity	phosphorylation	Thr345	GADSDVEtPSNFGKY	9606	BTO:0000007								27846390	t		lperfetto	Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. 	SIGNOR-262986	0.2
CERS3	protein	Q8IU89	UNIPROT	ceramide	smallmolecule	CHEBI:17761	ChEBI	up-regulates quantity	chemical modification			9606									26887952	t	done	miannu	 Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity. 	SIGNOR-273995	0.8
tofacitinib	chemical	CHEBI:71200	ChEBI	JAK3	protein	P52333	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258302	0.8
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1917	SPTSPTYsPTSPKYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273100	0.745
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Met)	smallmolecule	CHEBI:29173	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269491	0.8
CSNK2A1	protein	P68400	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Ser380	EPDHYRYsDTTDSDP	9606									21779440	t		gcesareni	The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity	SIGNOR-152348	0.667
SEC61B	protein	P60468	UNIPROT	SEC61 complex	complex	SIGNOR-C368	SIGNOR	form complex	binding			-1									33925740	t		lperfetto	The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER	SIGNOR-265277	0.905
phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	PRKCZ	protein	Q05513	UNIPROT	up-regulates	chemical activation			9606									12401205	t		gcesareni	The pkc isoform pkc-zeta appear to be activated by direct interactions with pa	SIGNOR-94867	0.8
PRKDC	protein	P78527	UNIPROT	LIG4	protein	P49917	UNIPROT	down-regulates	phosphorylation	Ser668	DVEFCVMsGTDSQPK	9606									15194694	t		lperfetto	Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability.	SIGNOR-125869	0.801
POLR2J	protein	P52435	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266161	0.82
3-[[3-[(dimethylamino)methyl]anilino]-phenylmethylidene]-N,N-dimethyl-2-oxo-1H-indole-6-carboxamide	chemical	CHEBI:91423	ChEBI	MAP2K5	protein	Q13163	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190374	0.8
BBS2	protein	Q9BXC9	UNIPROT	BBsome complex	complex	SIGNOR-C288	SIGNOR	form complex	binding			9606	BTO:0004910								19081074	t		lperfetto	We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 	SIGNOR-262557	0.807
phosphatidylinositol bisphosphate	smallmolecule	CHEBI:37328	ChEBI	CADPS	protein	Q9ULU8	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								24363652	t		miannu	CAPS exhibits low affinity but functionally significant interactions with plasma membrane PIP2 via its central PH (pleckstrin homology) domain (82, 111). PIP2 enhanced CAPS stimulation of SNARE-dependent liposome fusion with wild-type but not with mutant PH domain CAPS proteins	SIGNOR-264334	0.8
NOTCH1	protein	P46531	UNIPROT	RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	form complex	binding			9606									7566092	t			Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter.	SIGNOR-254381	0.949
ID1	protein	P41134	UNIPROT	MYOD/E2-2	complex	SIGNOR-C129	SIGNOR	down-regulates activity	binding			10090	BTO:0004058								9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241125	0.57
MAPK3	protein	P27361	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation	Ser418	TEERLPSsPVYEDAA	9606	BTO:0000938								21079800	t		gcesareni	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-169686	0.433
AKT1	protein	P31749	UNIPROT	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Ser48	QLSLRTVsLGAGAKD	9606	BTO:0001345								25071014	t		miannu	We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53.	SIGNOR-276667	0.551
AKT3	protein	Q9Y243	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser315	DFRSRTNsNASTVSG										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249644	0.697
CFHR1	protein	Q03591	UNIPROT	C3	protein	P01024	UNIPROT	up-regulates activity	binding			-1							cleavage:Arg748	ASHLGLArSNLDEDI	27814381	t	complement C3b fragment: PRO_0000005911	lperfetto	 Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. |these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b	SIGNOR-263475	0.826
CDK2	protein	P24941	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates	phosphorylation			9606									19188143	t		gcesareni	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity	SIGNOR-183655	0.502
STK3	protein	Q13188	UNIPROT	NEK2	protein	P51955	UNIPROT	up-regulates	phosphorylation	Ser438	EKNYQLKsRQILGMR	9606									21076410	t		lperfetto	Our data suggest that mst2 phosphorylates nek2a thereby recruiting nek2a to centrosomes and promoting phosphorylation and displacement of centrosomal linker proteins	SIGNOR-169539	0.246
PRKCZ	protein	Q05513	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates activity	phosphorylation	Ser177	AKELDQGsLCTSFVG	9606									10022904	t		lperfetto	Activation of IkappaB kinase beta by protein kinase C isoforms. | Interestingly, recombinant active zetaPKC and alphaPKC are able to stimulate in vitro the activity of IKKbeta but not that of IKKalpha. In addition, evidence is presented here that recombinant zetaPKC directly phosphorylates IKKbeta in vitro, involving Ser177 and Ser181. Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-kappaB pathway at the level of IKKbeta activation and IkappaB degradation.	SIGNOR-249015	0.495
BBS7	protein	Q8IWZ6	UNIPROT	BBsome complex	complex	SIGNOR-C288	SIGNOR	form complex	binding			9606	BTO:0004910								19081074	t		lperfetto	We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 	SIGNOR-262556	0.844
POU5F1	protein	Q01860	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086								19968627	f	 	miannu	 p21 protein levels were repressed by Oct-4 and were induced by the down-regulation of Oct-4 in ZHBTc4 ES cells. 	SIGNOR-255043	0.413
XRCC4	protein	Q13426	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									10854421	f		miannu	The DNA-dependent protein kinase (DNA-PK), consisting of Ku and the DNA-PK catalytic subunit (DNA-PKcs), and the DNA ligase IV-XRCC4 complex function together in the repair of DNA double-strand breaks by non-homologous end joining.	SIGNOR-264530	0.7
CHRM4	protein	P08173	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256965	0.357
GHSR	protein	Q92847	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257429	0.409
PPP2CB	protein	P62714	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	up-regulates activity	dephosphorylation	Ser486	RPLSRAQsSPAAPAS	9606									18339811	t			Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.	SIGNOR-248606	0.2
EGFR	protein	P00533	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity				10090	BTO:0000667								15284024	f	JAK activation occurs upon ligand-mediated receptor multimerization because two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs.	lperfetto	Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion	SIGNOR-235870	0.599
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1763	TPTSPSYsPTSPSYS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248825	0.849
NDUFA12	protein	Q9UI09	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24].	SIGNOR-262152	0.823
PLK1	protein	P53350	UNIPROT	PIN1	protein	Q13526	UNIPROT	up-regulates	phosphorylation	Ser65	SHLLVKHsQSRRPSS	9606	BTO:0000567								16118204	t		llicata	Here we demonstrate that ser-65 in pin1 is the major site for plk1-specific phosphorylation, and the polo-box domain of plk1 is required for this phosphorylation. Interestingly, the phosphorylation of pin1 by plk1 does not affect its isomerase activity but rather is linked to its protein stability. pin1 is ubiquitinated in hela s3 cells, and substitution of glu for ser-65 reduces the ubiquitination of pin1.	SIGNOR-139919	0.435
LATS2	protein	Q9NRM7	UNIPROT	AMOT	protein	Q4VCS5	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser175	QGHVRSLsERLMQMS										24101513	t		lperfetto	Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130	SIGNOR-275846	0.532
MPHOSPH10	protein	O00566	UNIPROT	RPS5	protein	P46782	UNIPROT	up-regulates activity	binding			-1									28813493	t		miannu	 Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome.	SIGNOR-261175	0.607
HPS1	protein	Q92902	UNIPROT	BLOC-3	complex	SIGNOR-C253	SIGNOR	form complex	binding			9606									20048159	t		lperfetto	Two of these genes, HPS1 and HPS4, encode components of the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Herein we show that recombinant HPS1-HPS4 produced in insect cells can be efficiently isolated as a 1:1 heterodimer.	SIGNOR-260691	0.744
PRKCE	protein	Q02156	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates activity	phosphorylation	Ser43	VETWQEGsLKASCLY	-1									15604283	t		miannu	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276020	0.2
ENMD-2076	chemical	CID:16041424	PUBCHEM	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191466	0.8
F2RL2	protein	O00254	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257360	0.388
NAE	complex	SIGNOR-C131	SIGNOR	CUL4B	protein	Q13620	UNIPROT	up-regulates activity	neddylation			9606									25504797	t		lperfetto	The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates.	SIGNOR-243163	0.599
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1917	SPTSPTYsPTSPKYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii	SIGNOR-203592	0.77
ATM	protein	Q13315	UNIPROT	DGCR8	protein	Q8WYQ5	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser677	RVGKQLAsQKILQLL	9606	BTO:0002181								34188037	t		miannu	 Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs. 	SIGNOR-277307	0.274
PRKRA	protein	O75569	UNIPROT	DICER1/hAgo2/PRKRA	complex	SIGNOR-C41	SIGNOR	form complex	binding			9606									23661684	t		lperfetto	Immunoprecipitation and reconstitution experiments in various systems have shown that Dicer associates with proteins in the Argonaute (Ago) family of endonucleases and with specific double-stranded RNA-binding proteins (dsRBPs) (3–7). | In humans, these dsRBPs are protein activator of PKR (PACT) (5) and trans-activation response RNA-binding protein (TRBP) (3,4).	SIGNOR-255318	0.76
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr128	SKAQQGLyQVPGPSP	9606									22710723	t		lperfetto	Furthermore, we demonstrate that src phosphorylates p130cas y128. We engineered crc cells homozygous for a p130cas y128f knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation	SIGNOR-197927	0.797
PTEN	protein	P60484	UNIPROT	ABI1	protein	Q8IZP0	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Tyr213	PPTVPNDyMTSPARL	9606									32673396	t		lperfetto	After dephosphorylation by PTEN, Abi1 is degraded by calpains.|We demonstrate that PTEN dephosphorylation of Abi1 at Y213 and S216 results in Abi1 degradation through the calpain pathway.	SIGNOR-276948	0.243
[4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone	chemical	CHEBI:91441	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258127	0.8
MAP3K5	protein	Q99683	UNIPROT	ZNF622	protein	Q969S3	UNIPROT	up-regulates	phosphorylation	Thr318	KGKSFYStEAVQAHM	9606									21771788	t		gcesareni	Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis.	SIGNOR-175117	0.501
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SOX9	protein	P48436	UNIPROT	up-regulates	transcriptional regulation			9606									20457810	f		lperfetto	Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression.	SIGNOR-244750	0.2
PIM1	protein	P11309	UNIPROT	EPAS1	protein	Q99814	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser435	GKAILPPsQPWATEL	9606	BTO:0002181								34211090	t		miannu	PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Moreover, phosphorylation of the analogous site in HIF-2α (S435) stabilizes the protein through the same mechanism, indicating post-translational modification within the oxygen-dependent degradation domain as a mechanism of regulating the HIF-α subunits.	SIGNOR-277310	0.2
RPS6	protein	P62753	UNIPROT	Ribosome biogenesis	phenotype	SIGNOR-PH164	SIGNOR	up-regulates				-1									19812304	f		Luana	The stimulation of S6K1 activity by mTORC1 leads to increases in mRNA biogenesis, cap-dependent translation and elongation, and the translation of ribosomal proteins through regulation of the activity of many proteins, such as S6K1 aly/REF-like target (SKAR), programmed cell death 4 (PDCD4), eukaryotic elongation factor 2 kinase (eEF2K) and ribosomal protein S6 	SIGNOR-264617	0.7
CDK1	protein	P06493	UNIPROT	CSNK2A1	protein	P68400	UNIPROT	up-regulates	phosphorylation	Thr344	SSMPGGStPVSSANM	9606									7592773	t		lperfetto	Four residues within this domain, thr-344, thr-360, ser-362, and ser-370, conform to the minimal consensus sequence for p34cdc2 phosphorylationthe high stoichiometry of phosphorylation suggests that phosphorylation could regulate functional properties of ckii and that it could in some way participate in the burst of phosphorylation that accompanies the activation of p34graphic at the ggraphic-m transition	SIGNOR-29525	0.361
GDNF	protein	P39905	UNIPROT	LAMA3	protein	Q16787	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252175	0.2
HSPA1A	protein	P0DMV8	UNIPROT	FLCN	protein	Q8NFG4	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								27353360	t			These data suggest that inhibition of Hsp70 does not lead to an increase in misfolded FLCN but instead to its degradation.	SIGNOR-256506	0.2
PRKCA	protein	P17252	UNIPROT	SRC	protein	P12931	UNIPROT	unknown	phosphorylation	Ser12	KSKPKDAsQRRRSLE	-1									2996780	t		lperfetto	We propose that protein kinase C is responsible for this modification based on the following evidence. First, the tumor promoters, 12-O-tetradecanoylphorbol-13-acetate and teleocidin, and synthetic diacylglycerol, known activators of protein kinase C in vivo, cause nearly complete phosphorylation of pp60src at serine 12. Second, among five purified serine/threonine-specific protein kinases tested, only protein kinase C phosphorylates pp60c-src and pp60v-src in vitro at serine 12. Third, purified protein kinase C phosphorylates a synthetic peptide corresponding to the N-terminal 20 amino acids of pp60c-src at serine 12. The physiological significance of this novel phosphorylation is discussed.	SIGNOR-248893	0.582
TBX2	protein	Q13207	UNIPROT	CDKN2A	protein	Q8N726	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									25211658	t		lperfetto	TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS	SIGNOR-249594	0.502
ELOVL6	protein	Q9H5J4	UNIPROT	palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	down-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267887	0.8
N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-)	smallmolecule	CHEBI:147286	ChEBI	2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine	smallmolecule	CHEBI:147287	ChEBI	up-regulates quantity	precursor of			9606									33179964	t		miannu	The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure.	SIGNOR-267307	0.8
RAB5B	protein	P61020	UNIPROT	Early Endosome	complex	SIGNOR-C246	SIGNOR	form complex	binding			9606									19924646	t		lperfetto	The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22	SIGNOR-276874	0.46
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser256	SPRRRAAsMDNNSKF	-1	BTO:0000318								10377430	t		lperfetto	Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export.	SIGNOR-252831	0.908
PRKCA	protein	P17252	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Ser190	RGAPKRGsGKDSHHP	-1									2413024	t		lperfetto	MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 	SIGNOR-248871	0.503
Caspase-2 PIDDosome	complex	SIGNOR-C292	SIGNOR	BID	protein	P55957	UNIPROT	up-regulates activity	cleavage			9606									20158568	t		miannu	 Inactive caspase-2 monomers are recruited to the PIDDosome in response to certain cellular stresses. This results in dimerization and activation of caspase-2. Caspase-2 cleaves and activates Bid to induce MOMP eventually resulting in activation of executioner caspases by caspase-9-mediated cleavage.	SIGNOR-262644	0.553
1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone	chemical	CHEBI:93753	ChEBI	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192617	0.8
RET	protein	P07949	UNIPROT	DOK5	protein	Q9P104	UNIPROT	up-regulates	binding			9606									11470823	t		gcesareni	Dok-4 and dok-5 enhance c-ret-dependent activation of mitogen-activated protein kinase	SIGNOR-109516	0.607
MAPK3	protein	P27361	UNIPROT	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation	Ser789	QSVDKVTsPTKV	9606		BTO:0001260							10514499	t		lperfetto	Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin.	SIGNOR-71045	0.46
MAPK1	protein	P28482	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates activity	phosphorylation	Ser376	EKLFQGYsFVAPSIL										15568999	t		lperfetto	In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1	SIGNOR-249445	0.6
TRIM38	protein	O00635	UNIPROT	TRIM38	protein	O00635	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								21306652	t		miannu	Our study shows that, similar to other TRIM family members, TRIM38 is localized in the cytoplasm. TRIM38 increases ubiquitination of other cellular proteins and catalyzes self-ubiquitination. TRIM38 also promotes K63- and K48-linked ubiquitination of cellular proteins. An intact RING domain is important for the functions of TRIM38. In addition, enterovirus 71 infection induces TRIM38 degradation.	SIGNOR-271906	0.2
ATF4	protein	P18848	UNIPROT	NARS1	protein	O43776	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269422	0.2
DYRK2	protein	Q92630	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser321	QSLSLASsPKGTIEN	9606	BTO:0002181								34363019	t		miannu	Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. 	SIGNOR-276735	0.2
MED25	protein	Q71SY5	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266681	0.574
FERMT3	protein	Q86UX7	UNIPROT	ITGB3	protein	P05106	UNIPROT	up-regulates activity	binding			10090	BTO:0000132;BTO:0003292								18278053	t		lperfetto	 Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis|Kindlin-3 was also able to interact with the wild-type beta1 and beta3 integrin tails (Fig. 3c), in the presence and absence of Talin1 (Supplementary Fig. 3 online), and the F3 subdomain of Kindlin-3 was sufficient for this interaction and this interaction occurred in a direct manner	SIGNOR-266066	0.639
WT1	protein	P19544	UNIPROT	DNMT3A	protein	Q9Y6K1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23042785	t		irozzo	Here, we show that Wilms' tumour 1 (WT1), a developmental master regulator that can also act as a tumour suppressor or oncoprotein, transcriptionally regulates the de novo DNA methyltransferase 3A (DNMT3A) and that cellular WT1 levels can influence DNA methylation of gene promoters genome-wide. we demonstrate that depletion of WT1 by short-interfering RNAs leads to reduced DNMT3A in Wilms' tumour cells and human embryonal kidney-derived cell lines. Chromatin immunoprecipitation assays demonstrate WT1 recruitment to the DNMT3A promoter region and reporter assays confirm that WT1 directly transactivates DNMT3A expression.	SIGNOR-255904	0.389
UBE2I	protein	P63279	UNIPROT	FOXL2	protein	P58012	UNIPROT	up-regulates	sumoylation	Lys25	PETGRTVkEPEGPPP	9606									19744555	t		miannu	Foxl2 is sumoylated by ubc9, and this ubc9-mediated sumoylation is essential to the transcriptional activity of foxl2 on the star promoter. / the sumoylation site was identified at lysine 25 of foxl2	SIGNOR-187901	0.686
KAT2B	protein	Q92831	UNIPROT	H3-5	protein	Q6NXT2	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269625	0.2
PHKG1	protein	Q16816	UNIPROT	PHKG1	protein	Q16816	UNIPROT	unknown	phosphorylation	Ser31	EILGRGVsSVVRRCI	-1									7935360	t		miannu	Phosphopeptides correspond to sequences occurring in the gamma-subunit of phosphorylase kinase […] undergoes autophosphorylation. phosphorylation occurs primarily at Ser30 while in the latter an additional reaction takes place at Ser81.	SIGNOR-250388	0.2
WNT10B	protein	O00744	UNIPROT	FZD1	protein	Q9UP38	UNIPROT	up-regulates	binding			9606									12055200	t		fspada	Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 6	SIGNOR-89134	0.651
methoxamine	chemical	CHEBI:6839	ChEBI	ADRA1A	protein	P35348	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258455	0.8
SMO	protein	Q99835	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-199165	0.403
TCF3	protein	P15923	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000150								26212009	t		lperfetto	The p21-activated kinase 5 (PAK5) is overexpressed in advanced cancer and the transcription factor E47 is a direct repressor of E-cadherin and inducer of epithelial-mesenchymal transition (EMT). |In this study, we found that PAK5-mediated E47 phosphorylation promoted EMT in advanced colon cancer. PAK5 interacted with E47 and phosphorylated E47 on Ser39 under hepatocyte growth factor (HGF) stimulation	SIGNOR-275654	0.316
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	SLC2A1	protein	P11166	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8940145	f		gcesareni	The constitutively active akt also increased the synthesis of the ubiquitously expressed glucose transporter 1. The increased glucose influx in the 3t3-l1 adipocytes directed lipid but not glycogen synthesis	SIGNOR-45064	0.2
ELK4	protein	P28324	UNIPROT	INSIG2	protein	Q9Y5U4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								20145255	t		Luana	Under these conditions, a significant reduction in INSIG2 expression was only observed when SAP1a siRNA was used. These observations provide supporting evidence that SAP1a may be one of the transactivators of the human INSIG2 promoter.	SIGNOR-261592	0.2
FUS	protein	P35637	UNIPROT	HNRNPA2B1	protein	P22626	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			10090									28515487	f			This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease	SIGNOR-262802	0.491
PAK1	protein	Q13153	UNIPROT	MYLK	protein	Q15746	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000567								10092231	t		miannu	P21-activated kinase 1 (PAK1) phosphorylates MLCK, resulting in decreased MLCK activity. 	SIGNOR-250317	0.537
ATF6B	protein	Q99941	UNIPROT	HSPA5	protein	P11021	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								14973138	t		Luana	 Accordingly, N-terminal fragments of each ATF6 isoform (N-ATF6α and N-ATF6β) were overexpressed in HeLa cells and the effects on GRP78 induction were assessed. When expressed at similar levels, N-ATF6α conferred ∼200-fold greater GRP78 promoter activation than N-ATF6β. 	SIGNOR-261566	0.46
SRC	protein	P12931	UNIPROT	ITGAL	protein	P20701	UNIPROT	down-regulates activity	phosphorylation			9606									25624455	t		miannu	PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.	SIGNOR-254741	0.408
SMO	protein	Q99835	UNIPROT	MAG	protein	P20916	UNIPROT	up-regulates quantity	transcriptional regulation												27639396	f		SimoneGraziosi	We found that inactivation of Shh signaling caused a dose-dependent decrease in myelin basic protein (MBP) and myelin associated glycoprotein (MAG) in differentiating OLGs.	SIGNOR-269227	0.2
GSK3B	protein	P49841	UNIPROT	AHR	protein	P35869	UNIPROT	up-regulates activity	phosphorylation	Ser444	GKDSATTsTLSKDSL	9606	BTO:0000567								34198826	t		miannu	A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR.	SIGNOR-276664	0.253
RABGGTA	protein	Q92696	UNIPROT	RAB5A	protein	P20339	UNIPROT	up-regulates activity	lipidation			9606	BTO:0000007								18532927	t		miannu	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional	SIGNOR-265572	0.607
PPP1CA	protein	P62136	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation	Ser727	NTIDLPMsPRTLDSL	9606	BTO:0000599;BTO:0001594								19440292	t			Avicins dephosphorylate Stat3 in a variety of human tumor cell lines, leading to a decrease in the transcriptional activity of Stat3.| However, PD98059, an inhibitor of MEK1/2, had no significant effects on avicin-induced dephosphorylation of Stat3 (Ser 727) 	SIGNOR-248563	0.335
PRKCZ	protein	Q05513	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser379	DLILNRCsESTKRKL	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89288	0.402
neratinib	chemical	CHEBI:61397	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150								23632474	t	Neratinib (HKI-272) is a tyrosine kinase inhibitor, under investigation for the treatment breast cancer and other solid tumours.	gcesareni	Ineratinib is a potent irreversible pan-erbb tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (her)-2-positive breast cancer and other solid tumours.	SIGNOR-202015	0.8
NEK9	protein	Q8TD19	UNIPROT	MAP1LC3B	protein	Q9GZQ8	UNIPROT	down-regulates activity	phosphorylation	Thr50	QLPVLDKtKFLVPDH	-1									31857374	t	done	miannu	LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1).	SIGNOR-273904	0.2
PAFAH1B1	protein	P43034	UNIPROT	DYNC1H1	protein	Q14204	UNIPROT	up-regulates activity	binding			10090	BTO:0000938								11163259	t		miannu	We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex	SIGNOR-252158	0.883
succinate(2-)	smallmolecule	CHEBI:30031	ChEBI	fumarate(2-)	smallmolecule	CHEBI:29806	ChEBI	up-regulates quantity	precursor of			9606									16143825	t		miannu	Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions.	SIGNOR-266275	0.8
MYOD1	protein	P15172	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates	transcriptional regulation			9606									25211658	t			P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells	SIGNOR-251574	0.412
SRC	protein	P12931	UNIPROT	DDR2	protein	Q16832	UNIPROT	up-regulates	phosphorylation	Tyr736	FGMSRNLySGDYYRI	9606									16186108	t		gcesareni	Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues.	SIGNOR-140728	0.388
Avacopan	chemical	CID:49841217	PUBCHEM	C5AR2	protein	Q9P296	UNIPROT	down-regulates activity	binding			9606									31734405	t		lperfetto	CCX168 (avocapan), a C5aR antagonist, has proven its safety and efficiency in phase I and phase II trials conducted in AAV patients.	SIGNOR-263474	0.8
N(6),N(6),N(6)-trimethyl-L-lysine	smallmolecule	CHEBI:17311	ChEBI	3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine	smallmolecule	CHEBI:15786	ChEBI	up-regulates quantity	precursor of			9606									11431483	t		miannu	Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. 	SIGNOR-269685	0.8
MAPK1	protein	P28482	UNIPROT	MCRIP1	protein	C9JLW8	UNIPROT	down-regulates activity	phosphorylation	Thr30	PSSSEIFtPAHEENV	9606									25728771	t		lperfetto	When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation	SIGNOR-264774	0.2
DOK1	protein	Q99704	UNIPROT	Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257688	0.34
CDK16	protein	Q00536	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser10	NVRVSNGsPSLERMD	9606	BTO:0000567								25205104	t		lperfetto	In vitro kinase assays showed PCTAIRE1 phosphorylates p27 at Ser10. PCTAIRE1 silencing modulated Ser10 phosphorylation on p27 and led to its accumulation in cancer cells but not in nontransformed cells.|Together our findings reveal an unexpected role for PCTAIRE1 in regulating p27 stability, mitosis, and tumor growth, suggesting PCTAIRE1 as a candidate cancer therapeutic target.	SIGNOR-273016	0.338
EIF2AK2	protein	P19525	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser392	FKTEGPDsD	9606									10348343	t		gcesareni	The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro.	SIGNOR-68033	0.552
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	FBXO32	protein	Q969P5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								15109499	t			The activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression.	SIGNOR-252926	0.2
KU-55933	chemical	CID:5278396	PUBCHEM	ATM	protein	Q13315	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000793								28341201	t		miannu	KU-55933 blocked phosphorylation of ATM in H2O2 and Dox models of cell damage. the neuroprotective efficacy of KU-55933, a potent inhibitor of ATM, against cell damage evoked by oxidative stress (hydrogen peroxide, H2O2) has been studied in human neuroblastoma SH-SY5Y cells and compared with the efficacy of this agent in models of doxorubicin (Dox)- and staurosporine (St)-evoked cell death.	SIGNOR-262536	0.8
(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	ADRA2A	protein	P08913	UNIPROT	up-regulates activity	chemical activation			9606									9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258897	0.8
(6R)-5,10-methylenetetrahydrofolate(2-)	smallmolecule	CHEBI:15636	ChEBI	(6S)-5-methyltetrahydrofolate(2-)	smallmolecule	CHEBI:18608	ChEBI	up-regulates quantity	precursor of			9606									10720211	t		lperfetto	Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine.	SIGNOR-268230	0.8
MRAP2	protein	Q96G30	UNIPROT	MC2R	protein	Q01718	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								19329486	t		miannu	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor.	SIGNOR-252361	0.553
sunitinib	chemical	CHEBI:38940	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000776								20185585	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-163953	0.8
PRKCZ	protein	Q05513	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Ser641	GKVYGKTsHLRAHLR	9606									16943418	t		gcesareni	The hdac inhibitor tsa-induced cell-specific phosphatase release from the promoter, which serves as an 'on' mechanism for sp1 phosphorylation by phosphatidylinositol 3-kinase/protein kinase czeta (pi3k/pkczeta) at ser641, leading to p107 repressor derecruitment and lhr transcriptional activation.	SIGNOR-149287	0.498
RPS6KB1	protein	P23443	UNIPROT	SRPK2	protein	P78362	UNIPROT	up-regulates activity	phosphorylation	Ser494	HDRSRTVsASSTGDL	9606	BTO:0000007								29153836	t	no	miannu	 Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins.	SIGNOR-275459	0.364
ENO3	protein	P13929	UNIPROT	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	up-regulates quantity	chemical modification			9606									29767008	t		miannu	Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits.	SIGNOR-266526	0.8
Loratadine	chemical	CHEBI:6538	ChEBI	SLC6A15	protein	Q9H2J7	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								25318072	t		Simone Vumbaca	Loratadine, a clinically used histamine H1 receptor antagonist, was identified as a selective inhibitor of B0AT2. Our studies provide thefirst chemical tool for B0AT2.	SIGNOR-261092	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser324	RDLELPLsPSLLGGP	9606									7889942	t		gcesareni	Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-252085	0.2
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	L-asparagine zwitterion	smallmolecule	CHEBI:58048	ChEBI	up-regulates quantity	precursor of			9606									29084849	t		miannu	Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7.	SIGNOR-268071	0.8
SHANK2	protein	Q9UPX8	UNIPROT	ACTN1	protein	P12814	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264584	0.301
PTK6	protein	Q13882	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Tyr315	TFCGTPEyLAPEVLE	9606	BTO:0000150	BTO:0001129							20606012	t		gcesareni	Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6.	SIGNOR-252618	0.454
ATM	protein	Q13315	UNIPROT	RNF20	protein	Q5VTR2	UNIPROT	up-regulates	phosphorylation			9606									21763684	t		gcesareni	E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm.	SIGNOR-174949	0.537
IL10	protein	P22301	UNIPROT	SCN4A	protein	P35499	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									23357618	f		miannu	Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α.	SIGNOR-253500	0.2
TCF3	protein	P15923	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23684607	f	 	miannu	 The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins.	SIGNOR-255385	0.321
TLN1	protein	Q9Y490	UNIPROT	ITGB2	protein	P05107	UNIPROT	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257618	0.707
BTRC	protein	Q9Y297	UNIPROT	GLI2	protein	P10070	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0002572								16611981	t	The interaction between BTRC and Gli2 occur whne Gli2 is phosphorilated.	lperfetto	The phosphorylated gli2 protein interacts with beta-trcp, and is ubiquitinated and degraded by the proteasome	SIGNOR-146109	0.636
metformin	chemical	CHEBI:6801	ChEBI	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity by expression				9606									17909097	f	inferred from family member	gcesareni	In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp.	SIGNOR-267789	0.8
TFG	protein	Q92734	UNIPROT	SEC16A	protein	O15027	UNIPROT	up-regulates	binding			9606									21478858	t		miannu	We identify tfg-1, a new conserved regulator of protein secretion that interacts directly with sec-16 and controls the export of cargoes from the endoplasmic reticulum in caenorhabditis elegans. Hydrodynamic studies indicate that tfg-1 forms hexamers that facilitate the co-assembly of sec-16 with copii subunits.	SIGNOR-173242	0.629
CAMK2A	protein	Q9UQM7	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates	phosphorylation	Ser110	SFSEQTRsLDGRLQV	9606				SIGNOR-C8					11027280	t		gcesareni	Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgf-beta-dependent smad2-smad3 interactions.	SIGNOR-82966	0.528
PAN2-PAN3 deadenylation complex	complex	SIGNOR-C553	SIGNOR	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	down-regulates quantity by destabilization	chemical modification			9606									34280615	t		miannu	There are two major deadenylase complexes, Ccr4-Not and Pan2-Pan3, which shorten the 3′ poly(A) tail of mRNA and are conserved from yeast to human.The Ccr4-Not complex has two catalytic subunits including the Ccr4 (Carbon catabolite repressor 4) and Pop2 (PGK promoter directed overproduction). The Pan2-Pan3 complex comprises the catalytic subunit Pan2, a member of the RNase D family, and the regulatory subunit Pan3. Degradation of mRNA begins with either shortening of the poly(A) tail by deadenylases or removal of 5′ cap structure by the decapping enzyme Dcp1-Dcp2.	SIGNOR-273872	0.8
PRKCA	protein	P17252	UNIPROT	ADRA1B	protein	P35368	UNIPROT	down-regulates activity	phosphorylation	Ser396	RPWTRGGsLERSQSR	9534	BTO:0000298								9353340	t		lperfetto	 Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. 	SIGNOR-248985	0.399
PRKCE	protein	Q02156	UNIPROT	GAD1	protein	Q99259	UNIPROT	down-regulates activity	phosphorylation	Thr91	RDARFRRtETDFSNL	-1									15147202	t		lperfetto	We have identified one specific phosphorylation site, threonine 91 (T91), in hGAD67 that can be phosphorylated by PKA using MALDI-TOF. Site-directed mutation of T91 to alanine abolished PKA-mediated phosphorylation and inhibition of GAD activity.	SIGNOR-249264	0.326
LYN	protein	P07948	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates activity	phosphorylation	Tyr759	LYDVSRMyVDPSEIN	-1									7682059	t		lperfetto	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249384	0.603
ULK1	protein	O75385	UNIPROT	PFKM	protein	P08237	UNIPROT	down-regulates activity	phosphorylation	Ser74	EATWESVsMMLQLGG	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274035	0.2
PRKD1	protein	Q15139	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates	phosphorylation	Ser910	KALGERVsIL	9606	BTO:0000776								10473617	t		llicata	Activation of the serine kinase protein kinase d (pkd)/pkcmicro is controlled by the phosphorylation of two serine residues within its activation loop via a pkc-dependent signaling cascade. In this study we have identified the c-terminal serine 916 residue as an in vivo phosphorylation site within active pkd/pkcmu. moreover, using different mutants of pkd/pkcmu, we show that serine 916 is not trans-phosphorylated by an upstream kinase but is rather an autophosphorylation event that occurs following activation of pkd/pkcmu.	SIGNOR-70525	0.2
RAB6C	protein	Q9H0N0	UNIPROT	VPS13B	protein	Q7Z7G8	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								25492866	t		miannu	Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 Golgi Localization Is Mediated by Active RAB6 . COH1 Interacts with All Three Mammalian RAB6 Homologues	SIGNOR-269204	0.2
TBX5	protein	Q99593	UNIPROT	FGF10	protein	O15520	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18451335	f	 	miannu	 TBX5 is expressed, among others, in the embryonic heart and forelimbs.8 In the heart, it regulates transcription of downstream genes such as the atrial natriuretic factor (NPPA) and fibroblast growth factor 10 (FGF10) by the binding to T-box binding elements (TBEs),11 often in combination with the NKX2-5 transcription factor.	SIGNOR-255383	0.46
FGFR1	protein	P11362	UNIPROT	PDK1	protein	Q15118	UNIPROT	up-regulates	phosphorylation	Tyr243	ARRLCDLyYINSPEL	9606									22195962	t		llicata	Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1	SIGNOR-191723	0.355
HOXD12	protein	P35452	UNIPROT	MAFG	protein	O15525	UNIPROT	down-regulates activity	binding			-1									11036080	t		miannu	Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.	SIGNOR-221958	0.383
NR3C1	protein	P04150	UNIPROT	DUSP1	protein	P28562	UNIPROT	up-regulates quantity				10090	BTO:0000944								11742987	t		gcesareni	Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1|Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. In NIH-3T3 fibroblasts, although glucocorticoids up-regulate the MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity. 	SIGNOR-253546	0.563
CSNK1A1	protein	P48729	UNIPROT	PSEN2	protein	P49810	UNIPROT	unknown	phosphorylation	Ser9	LTFMASDsEEEVCDE	-1									8972483	t		llicata	In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. 	SIGNOR-250792	0.4
MASP1	protein	P48740	UNIPROT	C2	protein	P06681	UNIPROT	up-regulates activity	cleavage	Arg243	KTKESLGrKIQIQRS	9606	BTO:0000392								11907111	t		lperfetto	The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase	SIGNOR-263417	0.516
ADP	chemical	CHEBI:16761	ChEBI	PRKAG1	protein	P54619	UNIPROT	up-regulates	chemical activation			9606				SIGNOR-C15					21399626	t		gcesareni	Amp binding to the gamma-regulatory domain promotes phosphorylation by the upstream kinase, protects the enzyme against dephosphorylation, as well as causing allosteric activation.Adp also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive.	SIGNOR-172813	0.8
LPAR3	protein	Q9UBY5	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257406	0.411
WNK3	protein	Q9BYP7	UNIPROT	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation												21613606	t		lperfetto	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264626	0.514
NARS2	protein	Q96I59	UNIPROT	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270465	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser483	IRRPRNYsVGSRPLK	9606	BTO:0000567	BTO:0000562							12853467	t		lperfetto	These findings suggest that pkb-dependent binding of 14-3-3s to phospho-ser483 of cardiac pfk-2 mediates the stimulation of glycolysis by growth factor.	SIGNOR-103462	0.2
EXOSC7	protein	Q15024	UNIPROT	Exosome_Complex	complex	SIGNOR-C255	SIGNOR	form complex	binding			-1									24189234	t		miannu	The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 	SIGNOR-261386	0.918
SYK	protein	P43405	UNIPROT	SH3BP2	protein	P78314	UNIPROT	up-regulates activity	phosphorylation	Tyr448	GDDSDEDyEKVPLPN	9534	BTO:0004055								12709437	t		lperfetto	By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk.	SIGNOR-246596	0.569
ABL1	protein	P00519	UNIPROT	RAD9A	protein	Q99638	UNIPROT	up-regulates activity	phosphorylation	Tyr28	AVHSLSRiGDELYLE	9606									11971963	t		Manara	The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. | c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to Bcl-xL |these findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress.	SIGNOR-260843	0.491
PAK3	protein	O75914	UNIPROT	MYO6	protein	Q9UM54	UNIPROT	up-regulates activity	phosphorylation	Thr405	TAGGTKGtVIKVPLK	-1									11517222	t		miannu	P21-activated kinase 3 phosphorylated myosin VI, and the site was identified as Thr(406). The phosphorylation of myosin VI significantly facilitated the actin-translocating activity of myosin VI. 	SIGNOR-250244	0.341
ARHGAP9	protein	Q9BRR9	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260464	0.59
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser107	SQPPSPPsPAPSSFS	9606									15448698	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-129406	0.575
PLAUR	protein	Q03405	UNIPROT	KRT1	protein	P04264	UNIPROT	up-regulates activity	binding			9606									14691569	t	Regulation of binding	miannu	Cytokeratin 1 binds to both gC1qR and u-PAR. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored.	SIGNOR-251880	0.293
PRKAB1	protein	Q9Y478	UNIPROT	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation			9606			SIGNOR-C15						21460634	t		gcesareni	Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition	SIGNOR-173044	0.516
KAT6A	protein	Q92794	UNIPROT	KAT6A/KAT6B	complex	SIGNOR-C54	SIGNOR	form complex	binding			9606	BTO:0001271								17694082	t		miannu	Like gcn5/pcaf and p300/cbp, moz and morf are transcriptional co-activators with intrinsic hat activity.	SIGNOR-157304	0.39
CSNK2A1	protein	P68400	UNIPROT	MRE11	protein	P49959	UNIPROT	up-regulates activity	phosphorylation	Ser561	MANDSDDsISAATNK	-1									28436950	t		miannu	Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689.	SIGNOR-265894	0.2
STAT5A	protein	P42229	UNIPROT	IGF1	protein	P05019	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								10050749	t		lperfetto	Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α	SIGNOR-251743	0.446
FGFR4	protein	P22455	UNIPROT	FGFR4	protein	P22455	UNIPROT	up-regulates	phosphorylation	Tyr642	RGVHHIDyYKKTSNG	9606	BTO:0001130								18670643	t		lperfetto	Binding of fgf to fgf receptors leads to receptor dimerization and subsequent tyrosine autophosphorylation and phosphorylation of target substrates. Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanismthis antibody specifically recognizes tyr642/643 in fgfr-4.	SIGNOR-179776	0.2
UBE3A	protein	Q05086	UNIPROT	SOX9	protein	P48436	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								24155239	t		miannu	We show that E6-AP ubiquitinates SOX9 in vitro and in vivo and that SOX9 levels are enhanced after addition of the proteasome inhibitor bortezomib. Similar, siRNA knockdown of E6-AP and the E2 ligase Ubc9 increased cellular SOX9 amounts, supporting the notion that SOX9 may be ubiquitinated in hypertrophic chondrocytes by E6-AP and degraded by proteasomes.	SIGNOR-272134	0.264
PIK3CA	protein	P42336	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9534	BTO:0004055								14665640	f		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242649	0.7
RBPJ	protein	Q06330	UNIPROT	PAX7	protein	P23759	UNIPROT	up-regulates	binding			9606									22493066	t		gcesareni	Nicd regulates pax7 through interaction with rbp-j, which binds to two consensus sites upstream of the pax7 gene.	SIGNOR-196948	0.371
KRAS	protein	P01116	UNIPROT	PIK3CD	protein	O00329	UNIPROT	up-regulates	binding			9606									21779497	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k	SIGNOR-175210	0.62
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	LIPE	protein	Q05469	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000944								11581251	t	inferred from 70% family members	lperfetto	Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL.	SIGNOR-270119	0.2
DDC	protein	P20711	UNIPROT	tyramine	smallmolecule	CHEBI:15760	ChEBI	up-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain 	SIGNOR-263994	0.8
GABRB1	protein	P18505	UNIPROT	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263751	0.629
RNF8	protein	O76064	UNIPROT	XRN2	protein	Q9H0D6	UNIPROT	up-regulates activity	ubiquitination			9606									37697435	t		miannu	Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. 	SIGNOR-277195	0.2
RPL15	protein	P61313	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262483	0.867
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ARRB1	protein	P49407	UNIPROT	down-regulates	phosphorylation			9606									10347142	t	inferred from 70% family members	gcesareni	Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation	SIGNOR-270190	0.2
PHA-767491	chemical	CID:11715767	PUBCHEM	CDK9	protein	P50750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206115	0.8
RPS6KA5	protein	O75582	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									14625384	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-119233	0.2
TGFBR2	protein	P37173	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates activity	phosphorylation	Thr200	LPLLVQRtIARTIVL	-1									8576253	t		giulio giuliani	From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TβR-I in TGF-β signaling. Although it was reported that TGF-β-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TβR-II may phosphorylate these residues as minor phosphorylation site(s).	SIGNOR-255962	0.709
DUOX2	protein	Q9NRD8	UNIPROT	ROS	stimulus	SIGNOR-ST2	SIGNOR	up-regulates				9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264720	0.7
2'-deoxycytidine	smallmolecule	CHEBI:15698	ChEBI	2'-deoxycytosine 5'-monophosphate(2-)	smallmolecule	CHEBI:57566	ChEBI	up-regulates quantity	precursor of												20637175	t		lperfetto	Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis	SIGNOR-275810	0.8
SP1	protein	P08047	UNIPROT	TNC	protein	P24821	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000452								15001984	t		Luana	Sp1 and Ets1 are potent transactivators of the TN-C promoter.	SIGNOR-261600	0.2
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2E2	protein	Q96LR5	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271351	0.614
E2F1	protein	Q01094	UNIPROT	HIC1	protein	Q14526	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19491197	f		miannu	 expression of E2F1 in the p53(-/-) hepatocellular carcinoma cell line Hep3B led to an increase of endogenous HIC1 mRNA, although bisulfite genomic sequencing of the HIC1 promoter revealed that the region bearing the two E2F1 binding sites is hypermethylated. In addition, endogenous E2F1 induced by etoposide treatment bound to the HIC1 promoter. Moreover, inhibition of E2F1 strongly reduced the expression of etoposide-induced HIC1. 	SIGNOR-253844	0.293
PGM2	protein	Q96G03	UNIPROT	2-deoxy-alpha-D-ribose 1-phosphate	smallmolecule	CHEBI:11563	ChEBI	down-regulates quantity	chemical modification			9606									17804405	t		miannu	Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses.	SIGNOR-267094	0.8
PRKACA	protein	P17612	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity	phosphorylation	Ser1006	GHGVRRAsDPVRTGS	9606									10693759	t		lperfetto	Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3.	SIGNOR-75339	0.445
TBK1	protein	Q9UHD2	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	up-regulates	phosphorylation	Ser403	ESLSQMLsMGFSDEG	9606	BTO:0000801								22921120	t		llicata	Tbk-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on ser-403, a residue essential for its role in autophagic clearance.	SIGNOR-191944	0.702
TFEB	protein	P19484	UNIPROT	MAP1LC3B	protein	Q9GZQ8	UNIPROT	up-regulates quantity by expression	transcriptional regulation												28552616	t		lperfetto	As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes;	SIGNOR-276559	0.401
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser104	FPPLNSVsPSPLMLL	9606									11108261	t		lperfetto	Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt.	SIGNOR-244243	0.2
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	DEK	protein	P35659	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002181								21282377	t		miannu	 These data suggest that the E3 ligase SCFFbxw7-α degrades p-DEK in a GSK-3β–dependent manner.Therefore, the phosphorylation of DEK by GSK-3β is a crucial step to mediate Tpm RNA splicing.	SIGNOR-276304	0.293
TRIM27	protein	P14373	UNIPROT	ULK1	protein	O75385	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys569	DLHVVRPkLPKPPTD	10090									35670107	t		lperfetto	TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48-linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels	SIGNOR-272540	0.2
RIPK1	protein	Q13546	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	phosphorylation	Ser14	LNVIKMKsSDFLESA	-1									18408713	t		miannu	These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1)	SIGNOR-276161	0.2
FANCB	protein	Q8NB91	UNIPROT	Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	form complex	binding			9606	BTO:0000567								17396147	t		lperfetto	This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo 	SIGNOR-263241	0.839
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser525	TSMKPRSsRGSIFTF	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275766	0.2
DLGAP5	protein	Q15398	UNIPROT	SHANK3	protein	Q9BYB0	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264600	0.2
TIAM1	protein	Q13009	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260577	0.74
MAPK8	protein	P45983	UNIPROT	MAPK8IP1	protein	Q9UQF2	UNIPROT	unknown	phosphorylation	Thr205	PLKTGEQtPPHEHIC	9534	BTO:0000298								12756254	t		miannu	After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1.	SIGNOR-250127	0.879
DLD	protein	P09622	UNIPROT	Glycine cleavage system	complex	SIGNOR-C437	SIGNOR	form complex	binding			9606									16051266	t		lperfetto	The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide.	SIGNOR-268243	0.634
CASP8	protein	Q14790	UNIPROT	CASP7	protein	P55210	UNIPROT	up-regulates	cleavage			9606									9727491	t		gcesareni	Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them.	SIGNOR-58118	0.729
CSNK2A1	protein	P68400	UNIPROT	SAT1	protein	P21673	UNIPROT	unknown	phosphorylation	Ser149	RRGASDLsSEEGWRL	-1									8954982	t		llicata	Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149.	SIGNOR-250950	0.33
E2F1	protein	Q01094	UNIPROT	CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									8649818	f		lperfetto	We have found that cell cycle regulation of cyclin E transcription is mediated by E2F binding sites present in the promoter. The activity of this promoter can be regulated negatively by pRB.	SIGNOR-245471	0.569
PRKCD	protein	Q05655	UNIPROT	EIF2S1	protein	P05198	UNIPROT	unknown	phosphorylation	Ser52	MILLSELsRRRIRSI	-1									1677563	t		lperfetto	Of four other protein kinases tested only protein kinase C (PKC) phosphorylated P(45-56), with complete dependence on phosphatidylserine. Only the residue corresponding to serine-51 in eIF-2 alpha was phosphorylated by HCR, dsI or PKC.	SIGNOR-248853	0.315
PAK2	protein	Q13177	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates activity	phosphorylation	Ser26	GTASRPSsSRSYVTT	-1									11895474	t		miannu	In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK. 	SIGNOR-250237	0.311
UQCRFS1	protein	P47985	UNIPROT	Mitochondrial respiratory chain complex III	complex	SIGNOR-C279	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits	SIGNOR-262190	0.933
CTH	protein	P32929	UNIPROT	L-selenocysteine zwitterion	smallmolecule	CHEBI:57843	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000671;BTO:0000759;BTO:0002688							19961860	t		lperfetto	 the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production.	SIGNOR-275821	0.8
CSNK2A1	protein	P68400	UNIPROT	GAP43	protein	P17677	UNIPROT	unknown	phosphorylation	Ser203	PTETGESsQAEENIE	-1									1828073	t		llicata	Phosphorylation of neuromodulin (GAP-43) by casein kinase II. Identification of phosphorylation sites and regulation by calmodulin.|	SIGNOR-250867	0.311
LINC complex	complex	SIGNOR-C303	SIGNOR	NPC	complex	SIGNOR-C263	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								28831067	t		lperfetto	The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export.	SIGNOR-263292	0.2
CYC-116	chemical	CID:6420138	PUBCHEM	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191224	0.8
GEM	protein	P55040	UNIPROT	ROCK2	protein	O75116	UNIPROT	down-regulates activity	binding			9606									14701738	t		miannu	 Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively.	SIGNOR-261721	0.294
PRKCA	protein	P17252	UNIPROT	RPL10	protein	P27635	UNIPROT	unknown	phosphorylation	Ser168	GRQKIHIsKKWGFTK	-1									9016777	t		lperfetto	Moreover, QM is phosphorylated by PKC and the extent of phosphorylation by PKC is correlated with the extent of inhibition of binding of QM to c-Jun. 	SIGNOR-248958	0.311
CDC25C	protein	P30307	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates	dephosphorylation	Thr14	IEKIGEGtYGVVYKG	9606									19574738	t		gcesareni	Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation by cdc25c	SIGNOR-186617	0.853
PTPN1	protein	P18031	UNIPROT	PITX1	protein	P78337	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Tyr179	EDVYAAGySYNNWAA	9606									27752061	t		lperfetto	PTP1B dephosphorylates PITX-1 at Y160, 175 and Y179.|Through directly dephosphorylating PITX-1 at Y160, Y175 and Y179, PTP1B promoted proteasomal degradation of PITX-1, thus leaded in downregulating p120RasGAP and CRC cell survival.	SIGNOR-276973	0.362
MAPK14	protein	Q16539	UNIPROT	RPS6KA4	protein	O75676	UNIPROT	up-regulates	phosphorylation	Thr568	SPGVPMQtPCFTLQY	9606	BTO:0000567								10806207	t		llicata	Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity.	SIGNOR-77220	0.586
SRC	protein	P12931	UNIPROT	SH3PXD2A	protein	Q5TCZ1	UNIPROT	up-regulates activity	phosphorylation												20943948	t		lperfetto	 Recently, we have shown that tyrosine kinase c-Src substrate Tks4 and Tks5 proteins are novel members of the organizer superfamily	SIGNOR-264706	0.647
PIK3R4	protein	Q99570	UNIPROT	PIK3C3	protein	Q8NEB9	UNIPROT	up-regulates activity	binding			10090									27411398	t		lperfetto	Vps34 PI 3-kinase activity18 is stimulated by complex formation with the protein kinase Vps15|Rab5GTP binds Vps15, enhancing Vps34 activity	SIGNOR-260709	0.938
dehydroepiandrosterone	chemical	CHEBI:28689	ChEBI	androst-4-ene-3,17-dione	smallmolecule	CHEBI:16422	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000056							2139411	t		lperfetto	The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione.	SIGNOR-268641	0.8
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1696	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269342	0.718
ECM	stimulus	SIGNOR-ST20	SIGNOR	Av/b6 integrin	complex	SIGNOR-C179	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259039	0.7
SMAD7	protein	O15105	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates activity	binding			9606									9892110	t		lperfetto	SMAD7 functions as an antagonist to TGFB by binding to the TBRI and thus inhibiting activation of SMAD2 and SMAD3.	SIGNOR-64088	0.781
IRAK4	protein	Q9NWZ3	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Ser82	HSISYTLsRAQTVVV	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276132	0.643
CSNK1D	protein	P48730	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	phosphorylation	Thr1493	NPPPSPAtERSHYTM	9606									35487243	t		miannu	Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493	SIGNOR-275403	0.2
CALM1	protein	P0DP23	UNIPROT	GEM	protein	P55040	UNIPROT	up-regulates activity	binding			10116									14701738	t		miannu	Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells.	SIGNOR-261726	0.337
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser366	PGGSRAHsSHLKSKK	9606	BTO:0000567								10673501	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-75013	0.784
CTDSP1	protein	Q9GZU7	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	dephosphorylation	Ser195	PNSSYPNsPGSSSST	9606	BTO:0000552								17085434	t			Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)	SIGNOR-248799	0.476
INSR	protein	P06213	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	phosphorylation	Tyr632	GRKGSGDyMPMSPKS	10116									11416002	t		lperfetto	All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells	SIGNOR-236709	0.911
HTR2C	protein	P28335	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256734	0.298
RUVBL2	protein	Q9Y230	UNIPROT	R2SP co-chaperone	complex	SIGNOR-C517	SIGNOR	form complex	binding			9606									29844425	t		miannu	Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes.	SIGNOR-270940	0.51
PRIM1	protein	P49642	UNIPROT	DNA primase complex	complex	SIGNOR-C261	SIGNOR	form complex	binding			-1									24043831	t		lperfetto	Here, we describe the crystal structure of human primase in heterodimeric form consisting of full-length catalytic subunit and a C-terminally truncated large subunit.	SIGNOR-261339	0.99
Osmotic_stress	stimulus	SIGNOR-ST28	SIGNOR	TARDBP	protein	Q13148	UNIPROT	down-regulates activity	relocalization			9606	BTO:0000312								33172210	f			We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne	SIGNOR-262818	0.7
UPF1	protein	Q92900	UNIPROT	Upf-EJC	complex	SIGNOR-C367	SIGNOR	form complex	binding			9606	BTO:0000567								17803942	t		miannu	The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1	SIGNOR-265237	0.968
PD-153035 hydrochloride	chemical	CHEBI:91075	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205716	0.8
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	SLITRK1	protein	Q96PX8	UNIPROT	up-regulates activity	phosphorylation	Ser695	DCGSHSLsD	-1									19640509	t		miannu	In our studies, SICD was phosphorylated by PKA, PKC, and CK2, and association of SLITRK1 with 14-3-3 was regulated by phosphorylation at Ser695. Co-precipitation experiments demonstrated much greater recovery of 14-3-3 in SLITRK1 precipitates when wild-type or S695E was used, as compared with S695A, consistent with the results with purified peptides.	SIGNOR-273635	0.2
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	form complex	binding					BTO:0001103							12361602	t		apalma	Notch is cleaved and translocates to the nucleus, where it activates a family of transcription factors, exemplified by Suppressor of Hairless and CBF/RJBk	SIGNOR-255380	0.95
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT4	protein	P56705	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242707	0.283
GDNF	protein	P39905	UNIPROT	NRG1	protein	Q02297	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252182	0.373
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	KCNK9	protein	Q9NPC2	UNIPROT	down-regulates activity	phosphorylation	Thr341	IEEISPStLKNSLFP	9606	BTO:0004232								17374744	t		miannu	PKC acts directly on hTASK3 channels to phosphorylate an identified amino acid in the C terminus region (Thr341), thereby reducing channel current. 	SIGNOR-276059	0.2
MAPK3	protein	P27361	UNIPROT	UBTF	protein	P17480	UNIPROT	down-regulates	phosphorylation	Thr201	DIPEKPKtPQQLWYT	9606									11741541	t		lperfetto	Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna	SIGNOR-112817	0.56
MBD2	protein	Q9UBB5	UNIPROT	ALOX5	protein	P09917	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001412								19781662	f	 	 	Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene.	SIGNOR-254026	0.2
SIRT1	protein	Q96EB6	UNIPROT	CRTC1	protein	Q6UUV9	UNIPROT	up-regulates	deacetylation			9606	BTO:0000938	BTO:0000142							22179316	t		miannu	Sirt1 deacetylates and activates torc1	SIGNOR-191568	0.285
PRKCB	protein	P05771	UNIPROT	ANXA2	protein	P07355	UNIPROT	unknown	phosphorylation	Ser2	sTVHEILC	-1									8898866	t		lperfetto	A comparison of the phosphorylation patterns obtained identified Ser-II as the protein kinase C site responsible for regulating the annexin II-p11 interaction. Ser-II lies within the sequence mediating p11 binding, i.e. amino-acid residues 1 to 14 of annexin II, and phosphorylation at this site most likely leads to a direct spatial interference with p11 binding.	SIGNOR-248956	0.337
11-deoxycorticosterone	smallmolecule	CHEBI:16973	ChEBI	corticosterone	smallmolecule	CHEBI:16827	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000048							33117906	t		lperfetto	The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone	SIGNOR-268673	0.8
TRIM62	protein	Q9BVG3	UNIPROT	TRIM62	protein	Q9BVG3	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								23402750	t		miannu	A ubiquitination assay performed in HEK293T cells further confirmed the E3 ubiquitin ligase activity and self-ubiquitination activity of TRIM62 and the requirement of the RING finger domain. Importantly, the treatment of HEK293T cells with a proteasome inhibitor stabilized poly-ubiquitinated TRIM62, indicating that self-ubiquitination promoted the proteasomal degradation of TRIM62. 	SIGNOR-272102	0.2
MTOR	protein	P42345	UNIPROT	MTOR	protein	P42345	UNIPROT	up-regulates activity	phosphorylation	Ser2481	TVPESIHsFIGDGLV	10090	BTO:0000944		SIGNOR-C2	SIGNOR-C2					20022946	t		lperfetto	We have found that in HEK293 cells and 3T3-L1 adipocytes, insulin promotes both raptor- and rictor-associated mTOR Ser(P)-2481 in a wortmannin-sensitive manner. Thus, insulin signals via PI3K to promote both mTORC1- and mTORC2-associated mTOR Ser-2481 autophosphorylation.	SIGNOR-235427	0.2
TGFB1	protein	P01137	UNIPROT	MEF2D	protein	Q14814	UNIPROT	down-regulates				10090									14739161	f		lperfetto	Tgf-beta was shown to inhibit myogenin and mef2d expression and myotube formation in c2c12.	SIGNOR-235602	0.2
ZAP70	protein	P43403	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation	Tyr323	DEPVADPyDQSFESR	9606	BTO:0000782								15735648	t		lperfetto	Thus, phosphorylation of tyr323 dependent on the tyrosine kinase lck and mediated by zap70 serves as an important mechanism for tcr activation of p38 in t cells.	SIGNOR-134329	0.457
PPP1R15A	protein	O75807	UNIPROT	PPP1CC	protein	P36873	UNIPROT	up-regulates	binding			9606									14718519	t		gcesareni	We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate tbetari.	SIGNOR-120471	0.686
APC2	protein	O95996	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	up-regulates	binding			9606									9601641	t		lperfetto	Human axin (haxin) binds directly to beta-catenin, gsk3 beta, and apc in vitro, and the endogenous proteins are found in a complex in cells.	SIGNOR-227945	0.576
SMARCD1	protein	Q96GM5	UNIPROT	Neural progenitor-specific SWI/SNF	complex	SIGNOR-C477	SIGNOR	form complex	binding			9606									25195934	t		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270615	0.805
LFNG	protein	Q8NES3	UNIPROT	JAG1	protein	P78504	UNIPROT	down-regulates	binding			9606	BTO:0000007								15574878	t		gcesareni	Although jagged1-induced signaling was suppressed by lfng and mfng	SIGNOR-131560	0.501
IFNGR1	protein	P15260	UNIPROT	IFNGR2/INFGR1	complex	SIGNOR-C142	SIGNOR	form complex	binding			9606	BTO:0000801								19041276	t		lperfetto	The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process.	SIGNOR-249485	0.733
RPS6KB1	protein	P23443	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser639	YMPMSPKsVSAPQQI	10090	BTO:0002572								18498745	t		lperfetto	In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8	SIGNOR-236599	0.781
phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	pyruvate	smallmolecule	CHEBI:15361	ChEBI	up-regulates quantity	precursor of			9606									15996096	t		miannu	Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A).	SIGNOR-266538	0.8
TNFSF12	protein	O43508	UNIPROT	MYH3	protein	P11055	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			10090	BTO:0000165								17314137	t		miannu	TWEAK induces ubiquitination of MyHCf and expression of atrogin-1 and MuRF1 in myotubes. our data show that TWEAK rapidly increases the conjugation of ubiquitin to MyHCf (Fig. 3A) and ubiquitination preceded the degradation of MyHCf (Fig. 2C and Fig. 3A). 	SIGNOR-272628	0.2
ZNRF3	protein	Q9ULT6	UNIPROT	FZD6	protein	O60353	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								22575959	t			Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.	SIGNOR-260114	0.597
ANK2	protein	Q01484	UNIPROT	CACNA1A	protein	O00555	UNIPROT	up-regulates quantity	binding			10090									24394417	t		miannu	Here, we demonstrate that ankyrin-B associates with Cav2.1 and Cav2.2 in cortex, cerebellum, and brain stem. Additionally, using in vitro and in vivo techniques, we demonstrate that ankyrin-B, via its membrane-binding domain, associates with a highly conserved motif in the DII/III loop domain of Cav2.1 and Cav2.2. Collectively, our findings identify an interaction between ankyrin-B and both Cav2.1 and Cav2.2 at the amino acid level that is necessary for proper Cav2.1 and Cav2.2 targeting in vivo.	SIGNOR-266706	0.266
PIK3CD	protein	O00329	UNIPROT	PIK3CD	protein	O00329	UNIPROT	down-regulates	phosphorylation	Ser1039	NWLAHNVsKDNRQ	9606									10064595	t		gcesareni	Autophosphorylation of p110delta phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo in vitro autophosphorylation of p110delta completely down-regulates its lipid kinase activity.	SIGNOR-65186	0.2
Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	Neuron_migration	phenotype	SIGNOR-PH67	SIGNOR	up-regulates				9606									28347630	f		miannu	Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation	SIGNOR-266829	0.7
CSNK1A1	protein	P48729	UNIPROT	GLI2	protein	P10070	UNIPROT	down-regulates	phosphorylation			9606									17419683	t		gcesareni	In the absence of hedgehog signaling, gli1 is transcriptionally repressed, gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation, and gli3 is processed to a cleaved repressor.	SIGNOR-154222	0.549
FAF1	protein	Q9UNN5	UNIPROT	MAVS	protein	Q7Z434	UNIPROT	down-regulates activity	binding			9606	BTO:0002181								30472208	t		miannu	 We find that the scaffold protein FAF1 forms aggregates that negatively regulate MAVS.FAF1 antagonizes the poly-ubiquitination and aggregation of MAVS by competing with TRIM31 for MAVS association. 	SIGNOR-277619	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	KCNA5	protein	P22460	UNIPROT	down-regulates activity	phosphorylation	Ser592	KCNVKAKsNVDLRRS	9606	BTO:0000007								30279167	t		miannu	Thus, AMPK directly phosphorylates the α subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559. 	SIGNOR-273735	0.296
PRKCA	protein	P17252	UNIPROT	SLC6A9	protein	P48067-2	UNIPROT	down-regulates activity	phosphorylation	Ser625	PIVGSNGsSRLQDSR	9823									21864610	t		miannu	We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 	SIGNOR-262923	0.337
RAB1A	protein	P62820	UNIPROT	USO1	protein	O60763	UNIPROT	up-regulates activity	binding			-1									10903204	t		Giulio	Here, the tethering factor p115 was shown to be a Rab1 effector that binds directly to activated Rab1.	SIGNOR-261287	0.79
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	TRPC5	protein	Q9UL62	UNIPROT	down-regulates activity	phosphorylation	Ser796	GARAKSKsVSFNLGC	9606	BTO:0000007								21734191	t	done	miannu	Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A).	SIGNOR-273789	0.2
HIC1	protein	Q14526	UNIPROT	EPHA2	protein	P29317	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001211								22184117	f	 	miannu	 The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1). we observe that inactivation of endogenous HIC1 through RNA interference in normal breast epithelial cells results in the up-regulation of EphA2 and is correlated with increased cellular migration. chromatin immunoprecipitation (ChIP) and sequential ChIP experiments demonstrate that endogenous HIC1 proteins are bound, together with the MTA1 corepressor, to the EphA2 promoter in WI38 cells. 	SIGNOR-254241	0.319
ATM	protein	Q13315	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	down-regulates activity	phosphorylation	Ser85	ELLHFQAsQREEKEF	9606				SIGNOR-C14					16497931	t		lperfetto	Atm phosphorylates serine-85 of nemo to promote its ubiquitin-dependent nuclear export.	SIGNOR-144813	0.729
SETDB2	protein	Q96T68	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	methylation	Lys 10	RTKQTARkSTGGKAP	9606	BTO:0000007								20404330	t		miannu	 Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression.	SIGNOR-263895	0.2
PLAU	protein	P00749	UNIPROT	Epithelial-mesenchymal_transition	phenotype	SIGNOR-PH45	SIGNOR	up-regulates				9606									19055748	f		lperfetto	Our data show that functional blockade of SNAI1 (SNAI1-dominant negative (DN)) leads to a partial re-expression of E-cadherin, and induces differential expression of EMT-related genes. This is confirmed by RT-PCR of PA system genes, where PAI-1 and uPA are decreased.	SIGNOR-252264	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	HNRNPA1	protein	P09651	UNIPROT	down-regulates	phosphorylation	Ser199	SQRGRSGsGNFGGGR	9606									18562319	t		gcesareni	Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199.	SIGNOR-179059	0.2
NR3C1	protein	P04150	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates activity	binding			10116									9428795	t			We have shown that one of the functions of the GR to activate transcription of the AGP gene is to recruit C/EBPbeta and to maintain it bound at its target DNA sequences (SRU)	SIGNOR-251655	0.472
POMT 	complex	SIGNOR-C372	SIGNOR	DAG1	protein	Q14118	UNIPROT	up-regulates activity	glycosylation			9606	BTO:0000007								14699049	t		miannu	 we showed that coexpression of both POMT1 and POMT2 (another gene homologous to yeast protein O-mannosyltransferases) was necessary for the enzyme activity, but expression of either POMT1 or POMT2 alone was insufficient. The requirement of an active enzyme complex of POMT1 and POMT2 suggests that the regulation of protein O-mannosylation is complex. Further, protein O-mannosylation appears to be required for normal structure and function of α-dystroglycan in muscle and brain.	SIGNOR-265430	0.713
KITLG	protein	P21583	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates activity	binding			9606									17259966	t		miannu	The most relevant and still unique mast-cell growth factor is SCF, which is the ligand of KIT, a receptor with tyrosine-kinase activity that is expressed on the surface of all human and murine mast cells	SIGNOR-254946	0.933
KTN1	protein	Q86UP2	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30683916	f		miannu	Collectively, our findings revealed a novel mechanism wherein MALAT1 interacts with c-MYC to transactivate KTN1 for enhancing EGFR protein expression, which finally contributes to the development of cSCC.	SIGNOR-259906	0.2
PPP2CA	protein	P67775	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates	dephosphorylation			9606									20626350	t		lperfetto	In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a.	SIGNOR-244941	0.54
RET	protein	P07949	UNIPROT	RET	protein	P07949	UNIPROT	unknown	phosphorylation	Tyr826	SRKVGPGyLGSGGSR	9534	BTO:0004055								8621380	t		lperfetto	Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map 	SIGNOR-248942	0.2
EIF2AK2	protein	P19525	UNIPROT	CDK1	protein	P06493	UNIPROT	down-regulates	phosphorylation	Tyr4	yTKIEKIG	9606									20395957	t		lperfetto	Our findings demonstrate that (i) pkr, ser/thr kinase, phosphorylates its new substrate cdc2 at the tyr 4 residue, (ii) pkr-mediated tyr 4-phosphorylation facilitates cdc2 ubiquitination and proteosomal degradation	SIGNOR-164809	0.333
RPS6KA4	protein	O75676	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates	phosphorylation			9606									17183360	t		lperfetto	Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) msk 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf-kb isoform p65 and stat 1 and 3.	SIGNOR-217373	0.278
STIL	protein	Q15468	UNIPROT	PIN1	protein	Q13526	UNIPROT	up-regulates	binding			9606	BTO:0001271								16024801	t		miannu	Cell cycle-dependent phosphorylation of sil is required for its interaction with pin1, a regulator of mitosis. Point mutation of the seven (s/t)p sites between amino acids 567 and 760 reduces mitotic phosphorylation of sil, pin1 binding, and spindle checkpoint duration.	SIGNOR-138677	0.368
IKK-complex	complex	SIGNOR-C14	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser644	GLDFNFDsLISTQNV	9606	BTO:0000150								15084260	t		lperfetto	Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation.	SIGNOR-252950	0.536
TRAF2	protein	Q12933	UNIPROT	MAP4K2	protein	Q12851	UNIPROT	up-regulates	binding			9606									9712898	t		gcesareni	Both full-lenght gck and the gck-ctd can form complexes in vivo with traf2.	SIGNOR-59685	0.514
SB-202190	chemical	CHEBI:79090	ChEBI	PCSK7	protein	Q16549	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000876								9738669	t		gcesareni	Sb202190, a selective inhibitor of p38 mitogen activated protein kinase, is a powerful regulator of lps-induced mrnas in monocytes.	SIGNOR-60130	0.8
TBK1	protein	Q9UHD2	UNIPROT	STING1	protein	Q86WV6	UNIPROT	up-regulates activity	phosphorylation	Ser358	VPSTSTMsQEPELLI	9606	BTO:0000007								18818105	t		miannu	MITA was phosphorylated by TBK1, which is required for MITA-mediated activation of IRF3. Our results suggest that MITA is a critical mediator of virus-triggered IRF3 activation and IFN expression and further demonstrate the importance of certain mitochondrial proteins in innate antiviral immunity. Consistent with its inability to activate IRF-E, the mutation of S358 to alanine impaired the ability of MITA to interact with TBK1 and to enhance the interaction between TBK1 and IRF3	SIGNOR-263136	0.2
IRX5	protein	P78411	UNIPROT	KCND2	protein	Q9NZV8	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000387								16239150	t		Luana	Irx5 Directly Represses the Kcnd2 Promoter	SIGNOR-266045	0.503
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Thr154	VVSGPAAtPTAQHLR	9606	BTO:0001938								21364637	t		miannu	JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells	SIGNOR-277643	0.2
STAT1	protein	P42224	UNIPROT	IL12B	protein	P29460	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000801								19029990	f		lperfetto	STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others.	SIGNOR-249500	0.445
STAT5A	protein	P42229	UNIPROT	CISH	protein	Q9NSE2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15769897	t			The STAT5 target gene CIS, a member of the suppressor of cytokine signaling (SOCS) protein family, was highly induced by Flt3-ITD	SIGNOR-261544	0.657
PRKCA	protein	P17252	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser24	GYLRKPKsMHKRFFV	9606									16574739	t		flangone	We show that pkcalpha is likely to be directly involved in ser24 phosphorylation...These observations are entirely consistent with a recent independent study demonstrating that the IRS1-S24D mutant shows impaired insulin-stimulated IR-IRS-1 interactions, tyrosine phosphorylation of IRS-1, recruitment/activation of PI 3-Kinase, and insulin-stimulated Glut4 translocation	SIGNOR-145398	0.396
CERF	complex	SIGNOR-C340	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606		BTO:0000227							15640247	f		miannu	CERF is an ATP-dependent chromatin remodeler. CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. 	SIGNOR-263892	0.7
OTX2	protein	P32243	UNIPROT	RBP3	protein	P10745	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10354480	f		miannu	OTX2, as well as CRX, a homeodomain protein very similar to OTX2, activates the human IRBP promoter in co-transfection experiments.	SIGNOR-254889	0.311
Complement C1q	complex	SIGNOR-C308	SIGNOR	Complement C1 complex	complex	SIGNOR-C309	SIGNOR	form complex	binding			-1									29449492	t		lperfetto	The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases	SIGNOR-263396	0.616
LATS1	protein	O95835	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates	phosphorylation	Ser89	AQHVRSHsSPASLQL	9606									21808241	t	Together,the YAP/TAZ-TEAD complex promotes proliferative and survival programs.	gcesareni	Activated lats1/2 in turn phosphorylate and inhibit yap/taz transcription co-activators.	SIGNOR-175783	0.783
SRC	protein	P12931	UNIPROT	AFAP1	protein	Q8N556	UNIPROT	unknown	phosphorylation	Tyr453	PEALHYDyIDVEMSA	9534									9655255	t		lperfetto	In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110.	SIGNOR-246355	0.589
TWIST2	protein	Q8WVJ9	UNIPROT	ILK	protein	Q13418	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255504	0.2
RBPJ	protein	Q06330	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11432830	f		gcesareni	The rbp-jkappa protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated notch1 through rbp-jkappa-dependent transcription.	SIGNOR-109042	0.313
CDK1	protein	P06493	UNIPROT	NINL	protein	Q9Y2I6	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser589	NRHSPSWsPDGRRRQ	9606									20890132	t		miannu	 In this study, we show that Nlp can be phosphorylated by cell cycle protein kinase Cdc2/cyclin B1. The phosphorylation sites of Nlp are mapped at Ser185 and Ser589. the phosphorylation at the site Ser589 by Cdc2/cyclin B1 plays an important role in Nlp protein stability probably due to its effect on protein degradation. 	SIGNOR-259831	0.397
CALM1	protein	P0DP23	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	up-regulates	binding			9606									9822657	t		gcesareni	The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk.	SIGNOR-61922	0.827
CHMP2A	protein	O43633	UNIPROT	ESCRT-III	complex	SIGNOR-C379	SIGNOR	form complex	binding			-1									26775243	t		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission.	SIGNOR-265532	0.761
SEC61A1	protein	P61619	UNIPROT	SEC61 complex	complex	SIGNOR-C368	SIGNOR	form complex	binding			-1									33925740	t		lperfetto	The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER	SIGNOR-265279	0.757
PAX6	protein	P26367	UNIPROT	PAX6	protein	P26367	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001874								17251190	f	Regulation	miannu	Pax6-stimulated activity of the Pax6 promoter is repressed by TGFβ signalling. TGFβ receptor activation represses Pax6 promoter activity by releasing Pax6 from autoregulating its own promoter.	SIGNOR-251873	0.2
INSR	protein	P06213	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	phosphorylation	Tyr896	EPKSPGEyVNIEFGS	9606									12220227	t		lperfetto	Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions.	SIGNOR-236725	0.911
MASP2	protein	O00187	UNIPROT	C4B	protein	P0C0L5	UNIPROT	up-regulates activity	cleavage	Gly1446	TPLQLFEgRRNRRRR	-1									17204478	t		lperfetto	MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a).	SIGNOR-263428	0.793
RAC1	protein	P63000	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates	binding			9606									17251915	t		gcesareni	The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor.	SIGNOR-152808	0.645
DUSP16	protein	Q9BY84	UNIPROT	MAPK8IP1	protein	Q9UQF2	UNIPROT	up-regulates	binding			9606	BTO:0000938								12524447	t		gcesareni	Here we report that jip-1 also binds the dual-specificity phosphatases mkp7 and m3/6 via a region independent of its jnk binding domain. when mkp7 is bound to jip-1 it reduces jnk activation leading to reduced phosphorylation of the jnk target c-jun	SIGNOR-97173	0.451
2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid	chemical	CID:135461425	PUBCHEM	FGFR3	protein	P22607	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259705	0.8
PDGFRA	protein	P16234	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates				9606									24743741	f			To further investigate the signaling pathway through which PDGFRα promotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα	SIGNOR-254376	0.353
EGR1	protein	P18146	UNIPROT	NAB2	protein	Q15742	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000848								20506119	f		miannu	In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2.	SIGNOR-253881	0.612
TBCA	protein	O75347	UNIPROT	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	up-regulates quantity by stabilization	binding			9606									28158450	t		miannu	These intermediates interact with a series of five tubulin-specific chaperones (termed TBCA-E); these function together as a nanomachine that assembles the α/β tubulin heterodimer	SIGNOR-261169	0.2
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	NDEL1	protein	Q9GZM8	UNIPROT	up-regulates activity	phosphorylation	Thr219	ASLSLPAtPVGKGTE	10090	BTO:0000142								12796778	t		llicata	Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function.	SIGNOR-250678	0.623
BUB1	protein	O43683	UNIPROT	CDC20	protein	Q12834	UNIPROT	down-regulates activity	phosphorylation	Ser153	NRLKVLYsQKATPGS	9606	BTO:0000567								15525512	t		llicata	Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro. 	SIGNOR-250604	0.992
WNT1	protein	P04628	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								21078818	t		gcesareni	Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.	SIGNOR-169645	0.781
GGCX	protein	P38435	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	carboxylation	Glu67	LERECMEeKCSFEEA	10090		BTO:0001103							11133752	t		lperfetto	The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.	SIGNOR-263691	0.67
TRIB3	protein	Q96RU7	UNIPROT	COP1	protein	Q8NHY2	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16794074	t		miannu	TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).	SIGNOR-271603	0.2
PBK	protein	Q96KB5	UNIPROT	ULK1	protein	O75385	UNIPROT	down-regulates activity	phosphorylation	Ser533	AEMRGGRsPRPGSSA	9606	BTO:0002181								31378785	t		miannu	We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1. 	SIGNOR-277472	0.2
SPI1	protein	P17947	UNIPROT	GATA1	protein	P15976	UNIPROT	down-regulates activity	binding			10090									10364157	t		irozzo	We find that PU.1 interacts directly with GATA-1, a zinc finger transcription factor required for erythroid differentiation. Interaction between PU.1 and GATA-1 requires intact DNA-binding domains in both proteins. PU.1 represses GATA-1-mediated transcriptional activation.	SIGNOR-256049	0.641
CYP17A1	protein	P05093	UNIPROT	pregnenolone	smallmolecule	CHEBI:16581	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0001363;BTO:0000048;BTO:0000050							17192295	t		lperfetto	THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones.	SIGNOR-268656	0.8
MAPK1	protein	P28482	UNIPROT	MAPKAPK2	protein	P49137	UNIPROT	up-regulates	phosphorylation	Thr222	TSHNSLTtPCYTPYY	9606									8846784	t		fstefani	Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk.	SIGNOR-44343	0.52
TRAF3	protein	Q13114	UNIPROT	MAP3K14	protein	Q99558	UNIPROT	down-regulates quantity by destabilization	binding			10090									15084608	t		lperfetto	Traf3 is physically associated with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome.	SIGNOR-124236	0.654
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser40	ASAAGGLsPVTNLTV	9606	BTO:0000017								28192398	t		miannu	We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation. 	SIGNOR-277340	0.638
PTPRG	protein	P23470	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity	dephosphorylation	Tyr397	SVSETDDyAEIIDEE	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254717	0.245
NFATC1	protein	O95644	UNIPROT	Myotube_hypertrophy	phenotype	SIGNOR-PH20	SIGNOR	up-regulates	transcriptional regulation			9606		BTO:0001103							14729474	f		apalma	To summarize, these two studies have generated important insights into the control of skeletal muscle hypertrophy by the calcineurin/NFATc1 signaling pathway	SIGNOR-256215	0.7
CDK2	protein	P24941	UNIPROT	FZR1	protein	Q9UM11	UNIPROT	down-regulates activity	phosphorylation	Ser151	DVSPYSLsPVSNKSQ		BTO:0000007								12560341	t		llicata	 A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus. 	SIGNOR-250732	0.733
CTTN	protein	Q14247	UNIPROT	Dendritic_spine_morphogenesis	phenotype	SIGNOR-PH183	SIGNOR	up-regulates				9606									14684878	f		miannu	Cortactin is an F-actin binding protein and activator of the Arp2/3 actin nucleation machinery that also interacts with the postsynaptic density (PSD) protein Shank. Cortactin is concentrated in dendritic spines of cultured hippocampal neurons, and the N-terminal half of the protein containing the Arp2/3 and F-actin binding domains is necessary and sufficient for spine targeting. 	SIGNOR-266595	0.7
LTK	protein	P29376	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000938								9223670	t		gcesareni	Recently, we demonstrated that ltk utilizes shc and irs-1 as two major substrates and while both equally activate the ras pathway, only irs-1 suppresses apoptosis of hematopoietic cells.	SIGNOR-49625	0.434
PPP2CA	protein	P67775	UNIPROT	IRF3	protein	Q14653	UNIPROT	down-regulates activity	dephosphorylation			9606									24726876	t		miannu	RACK1 Negatively Regulates the Type I IFN pathway. Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. 	SIGNOR-260944	0.318
RXRA	protein	P19793	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9606									12771132	t		gcesareni	Rxr agonists still inactivated endogenous beta-catenin via rxr alpha.	SIGNOR-101293	0.429
PTK2	protein	Q05397	UNIPROT	CTNNB1	protein	P35222	UNIPROT	unknown	phosphorylation	Tyr142	AVVNLINyQDDAELA	10090									22264731	t	VEGF pathway	Gianni	VEGF promotes tension-independent FAK activation, rapid FAK localization to cell-cell junctions, binding of the FAK FERM domain to the vascular endothelial cadherin (VE-cadherin) cytoplasmic tail, and direct FAK phosphorylation of β-catenin at tyrosine-142 (Y142) facilitating VE-cadherin-β-catenin dissociation and EC junctional breakdown.	SIGNOR-261946	0.414
PRKCB	protein	P05771	UNIPROT	ILF3	protein	Q12906	UNIPROT	up-regulates activity	phosphorylation	Ser647	RGRGRGGsIRGRGRG	9606									20870937	t		llicata	Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our results support a model in which PMA stimulation activates PKCβI to phosphorylate NF90-Ser647, and this phosphorylation triggers NF90 relocation to the cytoplasm and stabilize IL-2 mRNA. 	SIGNOR-168173	0.2
IL17A	protein	Q16552	UNIPROT	KLF2	protein	Q9Y5W3	UNIPROT	up-regulates	transcriptional regulation			9606									23332504	f		fspada	Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic. 	SIGNOR-210111	0.288
AP3D1	protein	O14617	UNIPROT	Neuronal AP-3	complex	SIGNOR-C445	SIGNOR	form complex	binding			9606	BTO:0000938								19497727	t		miannu	Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) 	SIGNOR-268519	0.809
TTK	protein	P33981	UNIPROT	CDCA8	protein	Q53HL2	UNIPROT	up-regulates	phosphorylation	Thr230	DSKEIFLtVPVGGGE	9606									19530738	t		lperfetto	We found that substitutions at borealin t230, recently identified as an mps1 phosphorylation site, can modulate the dimerization state of borealin. Mutation of this single residue to alanine or valine impairs aurora b activity during mitosis and causes chromosome segregation defects	SIGNOR-186147	0.472
HSP90AB1	protein	P08238	UNIPROT	APAF1	protein	O14727	UNIPROT	down-regulates	binding			9606									10944114	t		gcesareni	The present studies demonstrate that heat shock protein 90 (hsp90) forms a cytosolic complex with apaf-1 and thereby inhibits the formation of the active complex.	SIGNOR-81043	0.398
HOXA10	protein	P31260	UNIPROT	PHGDH	protein	O43175	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19778996	f		miannu	 PHGDH is expressed in both endometrial epithelial and stromal cells. HOXA10 represses endometrial PHGDH expression.	SIGNOR-254468	0.304
CASP3	protein	P42574	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates activity	cleavage			9606									14585074	t		lperfetto	Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation	SIGNOR-90397	0.622
RFC2	protein	P35250	UNIPROT	RF-C complex	complex	SIGNOR-C375	SIGNOR	form complex	binding												12930972	t		lperfetto	RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned 	SIGNOR-265506	0.76
PTPN13	protein	Q12923	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606									15611135	t		gcesareni	We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines.	SIGNOR-132555	0.263
GNAQ	protein	P50148	UNIPROT	PLCB1	protein	Q9NQ66	UNIPROT	up-regulates	binding			9606									8245028	t		gcesareni	The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits.	SIGNOR-37149	0.76
SOX17	protein	Q9H6I2	UNIPROT	SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	form complex	binding												23474895	t		SimoneGraziosi	Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm|We show that Sox17 partners with Oct4 and binds to a unique ‘compressed' Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at ‘canonical' binding sites. 	SIGNOR-269220	0.628
BID	protein	P55957	UNIPROT	BAK1	protein	Q16611	UNIPROT	up-regulates	binding			9606									12242151	t		gcesareni	We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome c. these data support a two-class model for bh3 domains: bid-like domains that activate bax, bak and bad-like domains that sensitize by occupying the pocket of antiapoptotic members.	SIGNOR-92942	0.815
CSNK1D	protein	P48730	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates	phosphorylation	Ser246	DSVSDQFsVEFEVES	9606									20708156	t		gcesareni	Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination	SIGNOR-167509	0.351
CD247	protein	P20963	UNIPROT	CD3	complex	SIGNOR-C432	SIGNOR	form complex	binding			9606									12507424	t		miannu	The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.	SIGNOR-255290	0.694
nitric oxide	smallmolecule	CHEBI:16480	ChEBI	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates				9606		BTO:0001103							20219869	t		apalma	Similarly, exposure of cells to oxidative stress, in particular, nitric oxide (NO) or peroxynitrite (ONOO), can activate NF-kB and cause its translocation.	SIGNOR-255350	0.8
TLN1	protein	Q9Y490	UNIPROT	AE/b7 integrin	complex	SIGNOR-C186	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257634	0.578
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGA1	protein	Q9Y5H4	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265708	0.2
PTGER1	protein	P34995	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257083	0.425
MAPK1	protein	P28482	UNIPROT	SOS1	protein	Q07889	UNIPROT	down-regulates activity	phosphorylation	Ser1132	TLPHGPRsASVSSIS	9534									8816480	t		lperfetto	In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1	SIGNOR-235742	0.702
HOXB2	protein	P14652	UNIPROT	OTX2	protein	P32243	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000946								9556594	t		Luana	Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively	SIGNOR-261634	0.262
AMPD1	protein	P23109	UNIPROT	IMP	smallmolecule	CHEBI:17202	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0001103							1631143	t		miannu	AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells. 	SIGNOR-269773	0.8
ATF4	protein	P18848	UNIPROT	ASNS	protein	P08243	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11960987	f		miannu	 Transcription from the asparagine synthetase (A.S.) gene is increased in response to either amino acid (amino acid response) or glucose (endoplasmic reticulum stress response) deprivation. the results provide both in vitro and in vivo evidence for a role of ATF4 in the transcriptional activation of the A.S. gene in response to nutrient deprivation.	SIGNOR-253747	0.637
CDK5	protein	Q00535	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Ser811	IYISPLKsPYKISEG	9606									15741232	t		gcesareni	Phosphorylation was observed 6 hours after p25 induction and was abolished in the presence of a cdk5 inhibitor, roscovitine, which does not inhibit the usual rb cyclin-d kinases cdk4 and cdk6. Furthermore, analyses of levels and subcellular localization of cdk-related cyclins did not reveal any change following cdk5 activation, arguing for a direct effect of cdk5 activity on rb protein. Rb phosphorylation was visualized using phosphorylation-dependent antibodies (p-rbser795 and p-rbser807/811).	SIGNOR-134468	0.342
ITGB1BP1	protein	O14713	UNIPROT	ITGB8	protein	P26012	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257667	0.318
PIM2	protein	Q9P1W9	UNIPROT	PSMD2	protein	Q13200	UNIPROT	up-regulates activity	phosphorylation	Ser361	ENNRFGGsGSQVDSA	-1									31843888	t	done	miannu	Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B). 	SIGNOR-273896	0.2
ROCK2	protein	O75116	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates activity	phosphorylation	Ser20	KRPQRATsNVFAMFD	9606									8702756	t		miannu	 Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. 	SIGNOR-261719	0.633
HOXB6	protein	P17509	UNIPROT	HBG1	protein	P69891	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15269212	t		Luana	HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion.	SIGNOR-261638	0.2
AURKB	protein	Q96GD4	UNIPROT	RASSF1	protein	Q9NS23	UNIPROT	down-regulates	phosphorylation	Ser207	TSVRRRTsFYLPKDA	9606									19276349	t		llicata	Here, we show that aurora a and b associate with and phosphorylate rassf1a on serine 203 aurora a regulates prometaphase progression by inhibiting the ability of rassf1a to suppress apc-cdc20 activity.	SIGNOR-184561	0.45
NRXN2	protein	P58401	UNIPROT	DAG1	protein	Q14118	UNIPROT	up-regulates activity	binding			9606									22626542	t		miannu	 The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 	SIGNOR-265461	0.265
lurasidone	chemical	CHEBI:70735	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10030									20404009	t		Luana	In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype.	SIGNOR-259462	0.8
desloratadine	chemical	CHEBI:291342	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002126								18446005	t		Luana	We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells	SIGNOR-257784	0.8
GSK3B	protein	P49841	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser106	PLNSVSPsPLMLLHP	9606									16076840	t		gcesareni	The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex.	SIGNOR-139320	0.347
doramapimod	chemical	CHEBI:40953	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258208	0.8
DYRK1A	protein	Q13627	UNIPROT	RCAN1	protein	P53805	UNIPROT	up-regulates	phosphorylation	Ser167	FLISPPAsPPVGWKQ	9606	BTO:0000782								16126726	t		gcesareni	We show that rcan1 self-associates and forms multimers, and that this process is promoted by the dyrk1a-mediated phosphorylation of rcan1 at the thr(192) residue. these results suggest that the phosphorylation of rcan1 by dyrk1a stimulates the formation of insoluble aggregates upon aging.	SIGNOR-139958	0.581
GDF5	protein	P43026	UNIPROT	TRPS1	protein	Q9UHF7	UNIPROT	up-regulates activity	relocalization			10090	BTO:0005092								18363966	t	Regulation of localization	miannu	Treatment of cells with Gdf5 enhanced Trps1 protein levels and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner. Nuclear translocation of Trps1 was also induced by Gdf5. These effects were blocked by a dominant negative form of activin-linked kinase 6 (dn-Alk6) and by SB203580, an inhibitor of the p38 MAPK pathway. Conversely, Gdf5 expression was suppressed by the over-expression of Trps1.	SIGNOR-251867	0.311
oxotremorine M	chemical	CHEBI:38322	ChEBI	CHRM2	protein	P08172	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258654	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SLC4A4	protein	Q9Y6R1	UNIPROT	up-regulates activity	phosphorylation	Ser1026	KKKKKKGsLDSDNDD	10090									11744745	t		miannu	Ser(982) in the C-terminus of kNBC1 is a target for PKA phosphorylation. Phosphorylation of Ser(982) in the sodium bicarbonate cotransporter kNBC1 shifts the HCO(3)(-) : Na(+) stoichiometry from 3 : 1 to 2 : 1 in murine proximal tubule cells Replacing Ser(982) at the C-terminus consensus PKA phosphorylation site with alanine resulted in a failure of PKA to phosphorylate the transporter and induce a stoichiometry shift.	SIGNOR-263158	0.2
SELP	protein	P16109	UNIPROT	GPIb-IX-V complex	complex	SIGNOR-C270	SIGNOR	up-regulates activity	binding			9606	BTO:0000132								25297919	t		lperfetto	Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1.	SIGNOR-261860	0.419
TOP2B	protein	Q02880	UNIPROT	RELN	protein	P78509	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24463367	f		lperfetto	While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development	SIGNOR-242207	0.2
AURKB	protein	Q96GD4	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Thr7	tSAARRSY	-1									12686604	t		lperfetto	We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro.	SIGNOR-100173	0.449
GSK3A	protein	P49840	UNIPROT	MAFB	protein	Q9Y5Q3	UNIPROT	down-regulates	phosphorylation			9606									18042454	t		miannu	We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.	SIGNOR-159432	0.2
SREBF1	protein	P36956	UNIPROT	IDH1	protein	O75874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12923220	t		lperfetto	IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells|evidence that IDH1 may regulate lipogenesis in hepatic cells	SIGNOR-253132	0.286
F2RL2	protein	O00254	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257301	0.357
SMOC1	protein	Q9H4F8	UNIPROT	Angiotensin-2	protein	P01019-PRO_0000032458	UNIPROT	up-regulates quantity				10090									30127878	f		lperfetto	In conclusion, the results of the present study suggested that SMOC1 silencing suppressed the Ang II-induced myocardial fibrosis of mouse MFBs through affecting the BMP2/Smad signaling pathway.	SIGNOR-260403	0.2
SRPK1	protein	Q96SB4	UNIPROT	RBM8A	protein	Q9Y5S9	UNIPROT	down-regulates	phosphorylation	Ser168	GGRRRSRsPDRRRR	9606									16100109	t		gcesareni	We demonstrate that y14 is phosphorylated at its repeated arginine/serine (rs) dipeptides, likely by sr protein-specific kinases. Phosphorylation of y14 abolished its interaction with ejc components as well as factors that function downstream of the ejc.	SIGNOR-139555	0.264
torkinib	chemical	CHEBI:90679	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258268	0.8
SGI-1776	chemical	CID:24795070	PUBCHEM	PIM2	protein	Q9P1W9	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206862	0.8
N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide	chemical	CHEBI:94525	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257934	0.8
FLT1	protein	P17948	UNIPROT	FLT1	protein	P17948	UNIPROT	up-regulates	phosphorylation	Tyr1213	GSSDDVRyVNAFKFM	9606									9722576	t		tpavlidou	By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor.	SIGNOR-59750	0.2
IPA-3	chemical	CHEBI:101355	ChEBI	PKN1	protein	Q16512	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0003897								23894351	t		lperfetto	In the current study, an allosteric small molecule PAK1 inhibitor, IPA-3, was evaluated for the potential in suppressing hepatocarcinogenesis. Consistent with other reports, inhibition of PAK1 activity was observed in several human HCC cell lines treated with various dosages of IPA-3.	SIGNOR-262017	0.8
IL4R	protein	P24394	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000782;BTO:0000801;BTO:0000876	BTO:0000887;BTO:0000763;BTO:0001260							12704343	t		milica	Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2.	SIGNOR-100768	0.547
L-thyroxine(1-)	chemical	CHEBI:60302	ChEBI	UGT1A1	protein	P22309	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								21030469	t		Luana	Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation.	SIGNOR-258051	0.8
2-N,6-N-Bis(2,3-dihydroxy-N-benzoyl)-L-serine amide	chemical	CHEBI:1219	ChEBI	DRD3	protein	P35462	UNIPROT	up-regulates activity	chemical activation			-1									7576010	t		miannu	 D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole.	SIGNOR-258437	0.8
IMPDH2	protein	P12268	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30518405	f		miannu	We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. 	SIGNOR-260960	0.2
ROCK1	protein	Q13464	UNIPROT	ARHGAP24	protein	Q8N264	UNIPROT	up-regulates activity	phosphorylation	Ser413	SVHKLDVsRSPPLMV	9606	BTO:0000007								16862148	t		lperfetto	ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2).	SIGNOR-249306	0.444
NCK1	protein	P16333	UNIPROT	SOS1	protein	Q07889	UNIPROT	up-regulates	binding			10029	BTO:0000246								7862111	t		lperfetto	We also found that nck binds directly to the guanine nucleotide exchange factor sos. / by binding to sos, nckmay bring sos to cell membrane where the ras protein is located.	SIGNOR-236321	0.598
RIPK2	protein	O43353	UNIPROT	IRF5	protein	Q13568	UNIPROT	up-regulates	phosphorylation	Ser446	DSIRLQIsNPDLKDR	9606									22412986	t		lperfetto	Activation of interferon regulatory factor 5 by site specific phosphorylation. Phosphorylation of carboxyl serines 451 and 462 appear the primary trigger of irf5 function in nuclear accumulation, transcription, and apoptosis. Rip2 activation of the irf5 aspartic acid substitutions showed a similar positive effect of s451d and s462d function in this assay	SIGNOR-196524	0.31
COL4A5	protein	P29400	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates activity	binding												35267698	t		lperfetto	Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23].	SIGNOR-272349	0.425
CDKN1B	protein	P46527	UNIPROT	CDK2	protein	P24941	UNIPROT	down-regulates	binding			9606				SIGNOR-C16					17409098	t		gcesareni	P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e).	SIGNOR-154191	0.949
MTHFR	protein	P42898	UNIPROT	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606	BTO:0000567								24769206	f		miannu	MTHFR promotes heterochromatin maintenance at the centromeric region.	SIGNOR-263889	0.7
PRKCD	protein	Q05655	UNIPROT	BLVRA	protein	P53004	UNIPROT	up-regulates activity	phosphorylation	Ser21	VGVGRAGsVRMRDLR										22584576	t		lperfetto	LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation.	SIGNOR-275525	0.2
RUNX2	protein	Q13950	UNIPROT	VEGFA	protein	P15692	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001610								22641097	f		miannu	 Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells.	SIGNOR-255084	0.459
miR-142-3p	mirna	URS000075AE07_9606	RNAcentral	MLL-AF4	fusion protein	SIGNOR-FP4	SIGNOR	down-regulates quantity by repression	post transcriptional regulation			10090									23132946	f		irozzo	In human leukemic cells with MLL rearrangements (e.g., MONOMAC-6 and THP-1 cells), we found that ectopic expression of miR-495 could significantly inhibit cell growth/proliferation and increase apoptosis while decreasing cell viability.	SIGNOR-255883	0.4
FUS	protein	P35637	UNIPROT	DHX9	protein	Q08211	UNIPROT	down-regulates activity	relocalization			9606	BTO:0000793								27460707	t	P35637:p.Pro525Leu (mutation causing interaction)		We found that ALS mutants of FUS co-localized with Caprin-1, DDX3X, and DHX9 in cytoplasmic inclusions that could lead to the mis-regulation of their respective pathways, providing further clues to the mechanism of ALS pathogenesis.|FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. | We also demonstrated the co-localization of DHX9, DDX3X and Caprin-1 with cytoplasmic EGFP-P525L mutant FUS inclusions in primary cortical neurons	SIGNOR-262810	0.46
OPRM1	protein	P35372	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256711	0.585
CACNA1C	protein	Q13936	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									30849329	t		miannu	Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]).	SIGNOR-264325	0.8
PRKCA	protein	P17252	UNIPROT	DDX5	protein	P17844	UNIPROT	down-regulates activity	phosphorylation	Ser557	VSAGIQTsFRTGNPT	-1									7525583	t		lperfetto	We report that p68 is phosphorylated by protein kinase C in vitro and binds calmodulin in a Ca(2+)-dependent manner. Both phosphorylation and calmodulin binding inhibited p68 ATPase activity | In addition, a 20-amino acid peptide corresponding to residues 549-568 of p68 was phosphorylated in a Ca- and phospholipid-dependent manner hy PKC 	SIGNOR-248896	0.341
TERT	protein	O14746	UNIPROT	Immortality	phenotype	SIGNOR-PH47	SIGNOR	up-regulates													11327115	f		lperfetto	Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers	SIGNOR-252292	0.7
BAX	protein	Q07812	UNIPROT	HTRA2	protein	O43464	UNIPROT	up-regulates	relocalization			9606									14585074	t	Translocation from Mitochondria to Cytosol	amattioni	Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi	SIGNOR-88590	0.319
AKT1	protein	P31749	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation	Thr24	LPRPRSCtWPLPRPE	-1	BTO:0000318								10377430	t		lperfetto	Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export.	SIGNOR-236163	0.866
EEF1A2	protein	Q05639	UNIPROT	Translational_elongation	phenotype	SIGNOR-PH210	SIGNOR	up-regulates				9606									23699257	f		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269394	0.7
GSK3B	protein	P49841	UNIPROT	MYOCD	protein	Q8IZQ8	UNIPROT	down-regulates activity	phosphorylation	Ser634	TFLSPQCsPQHSPLG	9606	BTO:0000007								16141410	t			In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity	SIGNOR-251249	0.406
NDN	protein	Q99608	UNIPROT	EID1	protein	Q9Y6B2	UNIPROT	up-regulates activity	binding			10090	BTO:0000165								18557765	t		llicata	The Prader-Willi syndrome protein necdin interacts with the E1A-like inhibitor of differentiation EID-1 and promotes myoblast differentiation.	SIGNOR-237614	0.383
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	MASTL	protein	Q96GX5	UNIPROT	up-regulates activity	phosphorylation	Thr207	PRQDYSRtPGQVLSL	8355									22354989	t		gcesareni	We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop	SIGNOR-249652	0.511
WNT9A	protein	O14904	UNIPROT	MUSK	protein	O15146	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000887							22309736	t		gcesareni	 we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase	SIGNOR-195975	0.409
AT9283	chemical	CID:11696609	PUBCHEM	JAK2	protein	O60674	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190017	0.8
NTN3	protein	O00634	UNIPROT	UNC5	proteinfamily	SIGNOR-PF98	SIGNOR	up-regulates activity	binding			9606		BTO:0001484							25881791	t		miannu	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268185	0.479
CCKBR	protein	P32239	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257150	0.27
BTK	protein	Q06187	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates activity	phosphorylation	Tyr694	LAKAVDGyVKPQIKQ	-1									11413148	t		llicata	Ectopically expressed BTK kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo. BTK-mediated tyrosine phosphorylation of ectopically expressed wild type (but not Tyr(694) mutant) STAT5A enhanced its DNA binding activity.	SIGNOR-250603	0.479
EFNB3	protein	Q15768	UNIPROT	EPHB3	protein	P54753	UNIPROT	up-regulates	binding			9606									9484836	t		gcesareni	Ephrin-b3, a ligand for the receptor ephb3, expressed at the midline of the developing neural tube.	SIGNOR-54711	0.815
KAT2A	protein	Q92830	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	acetylation			9606			SIGNOR-C465						34811519	t		lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269593	0.2
GABA-A (a5-b1-g2) receptor	complex	SIGNOR-C335	SIGNOR	CRHR1	protein	P34998	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268606	0.25
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser255	ELSPTTLsPVNHSLD	9606		BTO:0000763;BTO:0000149							10197981	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-66767	0.739
6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide	chemical	CHEBI:92401	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257999	0.8
SCRIB	protein	Q14160	UNIPROT	Scribble_complex_DLG4-LLGL1_variant	complex	SIGNOR-C509	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270904	0.523
CSNK1E	protein	P49674	UNIPROT	TRAF3	protein	Q13114	UNIPROT	up-regulates activity	phosphorylation	Ser349	QNWEEADsMKSSVES	9606									26928339	t		miannu	 CK1ɛ interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3. 	SIGNOR-277212	0.311
GSK3B	protein	P49841	UNIPROT	GRB14	protein	Q14449	UNIPROT	down-regulates activity	phosphorylation	Ser366	GCSSQSIsPMRSISE	-1									28130417	t		lperfetto	Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3.	SIGNOR-264869	0.328
Noncanonical PRC1	complex	SIGNOR-C151	SIGNOR	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				10090	BTO:0000011								25533466	f		miannu	We show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. 	SIGNOR-252248	0.7
PLD2	protein	O14939	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates				9606									18423386	f		mrosina	Altogether, these data suggest that PLD acting upstream of the MAP kinases ERK1/2 may play a key role in the regulation of IL-2 production by stimulated Jurkat cells.	SIGNOR-254983	0.57
TXK	protein	P42681	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates	phosphorylation	Tyr145	PVEDDADyEPPPSND	9606	BTO:0000782								8892604	t		lperfetto	Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function	SIGNOR-44669	0.717
NEK2	protein	P51955	UNIPROT	CEP250	protein	Q9BV73	UNIPROT	down-regulates	phosphorylation	Ser2394	LHHSLSHsLLAVAQA	9606									24695856	t		lperfetto	C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro.	SIGNOR-204837	0.766
ITGB7	protein	P26010	UNIPROT	AE/b7 integrin	complex	SIGNOR-C186	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253292	0.676
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	BNIP3	protein	Q12983	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27692180	t		miannu	HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 	SIGNOR-267454	0.389
oxymetazoline	chemical	CHEBI:7862	ChEBI	ADRA2C	protein	P18825	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258915	0.8
PRKD1	protein	Q15139	UNIPROT	TLR5	protein	O60602	UNIPROT	up-regulates	phosphorylation	Ser805	YQLMKHQsIRGFVQK	9606	BTO:0002181								17442957	t		lperfetto	Pkd phosphorylated the tlr5-derived target peptide in vitro, and phosphorylation of the putative target serine 805 in hek 293t cell-derived tlr5 was identified by mass spectrometry. These results demonstrate that both pkd1 and pkd2 are required for inflammatory responses following tlr2, tlr4, or tlr5 activation, although pkd1 is more strongly involved	SIGNOR-154473	0.361
MAPK11	protein	Q15759	UNIPROT	HBP1	protein	O60381	UNIPROT	up-regulates	phosphorylation	Ser402	GFSKNCGsPGSSQLS	9606									14612426	t		lperfetto	A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression.	SIGNOR-119134	0.403
LPAR3	protein	Q9UBY5	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257025	0.437
PAX7	protein	P23759	UNIPROT	Quiescence	phenotype	SIGNOR-PH25	SIGNOR	up-regulates				9606									15843801	f		gcesareni	We have identified a new cell population that expresses the transcription factors pax3 and pax7 (paired box proteins 3 and 7) but no skeletal-muscle-specific markers.	SIGNOR-135626	0.7
IKK-complex	complex	SIGNOR-C14	SIGNOR	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates	phosphorylation			9606									15489227	t		lperfetto	Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.	SIGNOR-216341	0.812
CITED2	protein	Q99967	UNIPROT	MMP1	protein	P03956	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003859								12960175	f		miannu	 CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway.	SIGNOR-253778	0.365
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	IGF1	protein	P05019	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269258	0.341
PTPN6	protein	P29350	UNIPROT	LYN	protein	P07948	UNIPROT	down-regulates activity	dephosphorylation	Tyr397	RVIEDNEyTAREGAK	10116									15537644	t			SHP-1 efficiently inhibits Lyn autophosphorylation and suppresses FcϵRI stimulation|We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397	SIGNOR-248471	0.724
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. 	SIGNOR-272751	0.523
MAP4K5	protein	Q9Y4K4	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity	phosphorylation			9606									16914735	t		lperfetto	Gckr can phosphorylate an n-terminal recombinant fusion protein of gsk3beta and enhance the in vivo phosphorylation of gsk3beta on serine 9reduction of gckr expression inhibits wnt3a-induced phosphorylation of gsk3beta at serine 9 and decreases the accumulation of cytosolic _-catenin.	SIGNOR-228006	0.2
retinal	smallmolecule	CHEBI:15035	ChEBI	all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	up-regulates quantity	precursor of			9606									21621639	t		lperfetto	All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step.	SIGNOR-265121	0.8
Angiotensin-2	protein	P01019-PRO_0000032458	UNIPROT	AGTR1	protein	P30556	UNIPROT	up-regulates activity	binding			9606									32201502	t		MIANNU	Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways	SIGNOR-260238	0.2
SMURF1	protein	Q9HCE7	UNIPROT	ZFAND5	protein	O76080	UNIPROT	unknown	ubiquitination			-1									20804422	t		miannu	Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay.	SIGNOR-272676	0.2
COL4A1	protein	P02462	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									12778132	t			Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6)	SIGNOR-254665	0.7
TPX2	protein	Q9ULW0	UNIPROT	KIF11	protein	P52732	UNIPROT	down-regulates activity	binding												26018074	t		lperfetto	Dimeric, but not monomeric, Eg5 was differentially inhibited by full-length and truncated TPX2, demonstrating that dimerization or residues in the neck region are important for the interaction of TPX2 with Eg5. 	SIGNOR-265097	0.514
BAP1	protein	Q92560	UNIPROT	ASXL3	protein	Q9C0F0	UNIPROT	up-regulates activity	binding			9606	BTO:0000189								32669118	t		miannu	We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers. 	SIGNOR-266761	0.546
ICE1	protein	Q9Y2F5	UNIPROT	ELL/ICE1	complex	SIGNOR-C48	SIGNOR	form complex	binding			9606	BTO:0001271								22195968	t		miannu	The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes.	SIGNOR-193486	0.554
ACTL6A	protein	O96019	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270847	0.576
RAB23	protein	Q9ULC3	UNIPROT	GLIS2	protein	Q9BZE0	UNIPROT	down-regulates				9606									16364285	f		gcesareni	Based on su(fu) function, we predict that rab23 can interact with all gli1 molecules including gli1, gli2 and gli3, and inhibit their transcriptional activities and nuclear localization.	SIGNOR-143163	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	CDC25B	protein	P30305	UNIPROT	up-regulates	phosphorylation	Ser353	VQNKRRRsVTPPEEQ	9606									23708659	t		lperfetto	Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.	SIGNOR-252781	0.2
CDK1	protein	P06493	UNIPROT	STIP1	protein	P31948	UNIPROT	down-regulates activity	phosphorylation	Thr198	DEEEEIAtPPPPPPP	10090	BTO:0000944								14754904	t		miannu	Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions. A lower level of phosphorylation was observed for the double mutant, suggesting that T332 might also be phosphorylated by cdc2 kinase.	SIGNOR-262727	0.267
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR5A	protein	P47898	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264298	0.8
SKIL	protein	P12757	UNIPROT	SMAD1/4	complex	SIGNOR-C85	SIGNOR	down-regulates	binding			9606									12419246	t		lperfetto	Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7	SIGNOR-217703	0.688
CDK1	protein	P06493	UNIPROT	DLG1	protein	Q12959	UNIPROT	unknown	phosphorylation	Ser443	FLGQTPAsPARYSPV	9606									19066288	t		llicata	We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor.	SIGNOR-182757	0.403
MRGPRX2	protein	Q96LB1	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257260	0.2
STK3	protein	Q13188	UNIPROT	Mob1	proteinfamily	SIGNOR-PF42	SIGNOR	up-regulates	phosphorylation			9606									21808241	t	The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific.	gcesareni	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction.	SIGNOR-269855	0.854
NR3C1	protein	P04150	UNIPROT	PCK1	protein	P35558	UNIPROT	up-regulates quantity	transcriptional regulation			9606									26652733	f			These results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK.	SIGNOR-256107	0.369
CDK2	protein	P24941	UNIPROT	TK1	protein	P04183	UNIPROT	down-regulates	phosphorylation	Ser13	LPTVLPGsPSKTRGQ	9606									12435275	t		gcesareni	Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase.	SIGNOR-95578	0.301
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1619	SPSYSPTsPSYSPTS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248804	0.849
PRKCA	protein	P17252	UNIPROT	SLC6A9	protein	P48067-2	UNIPROT	down-regulates activity	phosphorylation	Thr276	DGIMYYLtPQWDKIL	9823									21864610	t		miannu	We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 	SIGNOR-262920	0.337
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257940	0.8
JUN	protein	P05412	UNIPROT	SMAD4/JUN	complex	SIGNOR-C10	SIGNOR	form complex	binding			9606									9312063	t		gcesareni	Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter.	SIGNOR-51110	0.663
SPI1	protein	P17947	UNIPROT	FCRL6	protein	Q6DN72	UNIPROT	up-regulates quantity by expression	transcriptional regulation												12695521	f		lperfetto	Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression.	SIGNOR-268966	0.208
INO80D	protein	Q53TQ3	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270843	0.515
NEUROG3	protein	Q9Y4Z2	UNIPROT	NHLH1	protein	Q02575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19028584	f		miannu	Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. Ngn3 overexpression increased the NSCL1-expressing domain corresponding to young ganglion cells	SIGNOR-254634	0.266
L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	precursor of			9606									26003525	t		miannu	Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and α-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer.	SIGNOR-267508	0.8
RPS6KA3	protein	P51812	UNIPROT	NFATC4	protein	Q14934	UNIPROT	up-regulates	phosphorylation	Ser281	SGTPSSAsPALSRRG	10090									17213202	t		lperfetto	Serines 281 and 285 of the nfat3 protein might be target amino acids of rsk2 phosphorylationrsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo.	SIGNOR-234465	0.395
AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				-1									32527803	f	inferred from family member	Luana	AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by naïve ones.	SIGNOR-267783	0.7
SMURF1	protein	Q9HCE7	UNIPROT	ANXA6	protein	P08133	UNIPROT	unknown	ubiquitination			-1									20804422	t		miannu	Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay.	SIGNOR-272681	0.2
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	FLNA	protein	P21333	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000132								27871158	t		lperfetto	Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers. The actin cross-linking complex, GP1b/IX-filamin, translocates from the plasma membrane to the cytoskeleton during this step.	SIGNOR-261845	0.8
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	MBD4	protein	O95243	UNIPROT	up-regulates activity	phosphorylation	Ser165	CSMAALTsHLQNQSN										23195996	t		lperfetto	 Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12]	SIGNOR-275675	0.2
JAK2	protein	O60674	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates	phosphorylation	Tyr694	LAKAVDGyVKPQIKQ	4932									9575217	t		gcesareni	Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation	SIGNOR-56827	0.862
ACVR1	protein	Q04771	UNIPROT	SMAD5	protein	Q99717	UNIPROT	up-regulates	phosphorylation			9606									9748228	t		fspada	Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2	SIGNOR-60171	0.749
TBK1	protein	Q9UHD2	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Ser398	VDLHISNsHPLSLTS	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178403	0.817
PREX1	protein	Q8TCU6	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260569	0.708
MAF1	protein	Q9H063	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	down-regulates activity	binding												29378333	t		lperfetto	The synthesis of transfer RNA (tRNA) is directed by RNA polymerase III (Pol III) specialized in high-level transcription of short DNA templates. Pol III recruitment to tRNA genes is controlled by two general initiation factors, TFIIIB and TFIIIC. |Under stress conditions, tRNA synthesis is negatively regulated by the MAF1 protein, which interacts directly with Pol III. 	SIGNOR-266198	0.396
SOD1	protein	P00441	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates				10090	BTO:0004488								18519638	f	P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)		To investigate the role of ASK1 in the motor neurotoxicity by SOD1mut, we examined whether SOD1mut activates ASK1 as assessed by in vitro kinase assay. Expression of SOD1mut, but not SOD1wt, activated endogenous ASK1 (Fig. 4A, top panel). We next examined whether SOD1mut-induced ASK1 activation is mediated by ER stress.	SIGNOR-262789	0.377
NAB2	protein	Q15742	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								22431919	f		miannu	 Overexpression or short interfering RNA (siRNA)-mediated down-regulation of EGR1 or NAB2, and chromatin immunoprecipitations indicated that EGR1 and NAB2 act in concert to positively regulate p130(Cas)/BCAR1 expression in breast cancer cells.	SIGNOR-253889	0.2
CDK2	protein	P24941	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser106	PLNSVSPsPLMLLHP	9606			SIGNOR-C83						10428798	t		gcesareni	Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity.	SIGNOR-69714	0.491
FOXJ1	protein	Q92949	UNIPROT	DNALI1	protein	O14645	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23822649	t		miannu	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266933	0.404
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	AIM2	protein	O14862	UNIPROT	up-regulates activity													16037825	f		lperfetto	Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage	SIGNOR-256423	0.7
FBLN5	protein	Q9UBX5	UNIPROT	ELN	protein	P15502	UNIPROT	up-regulates activity	binding			9606									18267938	t		miannu	The binding of tropoelastin fragments to fibulin-5 was directly proportional to their propensity to coacervate. Furthermore, the addition of fibulin-5 to tropoelastin facilitated coacervation. Taken together, the present study shows that fibulin-5 enhances elastic fiber formation in part by improving the self-association properties of tropoelastin.	SIGNOR-252137	0.753
TPX2	protein	Q9ULW0	UNIPROT	CLASP1	protein	Q7Z460	UNIPROT	up-regulates activity	binding			9606	BTO:0000567				phosphorylation:Ser121;Ser125	PAQPQRRsLRLSAQK;QRRSLRLsAQKDLEQ			26240182	t		lperfetto	Phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells	SIGNOR-265090	0.477
3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one	chemical	CHEBI:91346	ChEBI	AKT3	protein	Q9Y243	UNIPROT	down-regulates activity	chemical inhibition												25309440	t		lperfetto	Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway.	SIGNOR-262012	0.8
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	RARB	protein	P10826	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								19058965	t		Luana	Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes. 	SIGNOR-258137	0.8
MAML1	protein	Q92585	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606									11101851	t		gcesareni	Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1.	SIGNOR-84827	0.921
D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	up-regulates quantity	precursor of			9606									19401148	t		miannu	Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 	SIGNOR-268134	0.8
IKBKG	protein	Q9Y6K9	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	phosphorylation	Ser536	SGDEDFSsIADMDFS	9606			SIGNOR-C14	SIGNOR-C13					15489227	t		lperfetto	Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.	SIGNOR-129947	0.857
MTOR	protein	P42345	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Thr412	NQVFLGFtYVAPSVL	9606	BTO:0000007		SIGNOR-C3						10579915	t		lperfetto	S6 kinases are under the control of the PI3K relative, mammalian Target Of Rapamycin (mTOR), which may serve an additional function as a checkpoint for amino acid availability.	SIGNOR-72682	0.96
DUSP6	protein	Q16828	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	down-regulates	dephosphorylation			9606									12840032	t	inferred from 70% of family members	gcesareni	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).	SIGNOR-269905	0.2
SGK1	protein	O00141	UNIPROT	WNK4	protein	Q96J92	UNIPROT	up-regulates activity	phosphorylation	Ser1201	FPTSRRNsLQRSEPP	-1									23054253	t		miannu	In addition, we identified a novel SGK1 phosphorylation site (S1201) in WNK4, and phosphorylation at this site is reduced by Ca(2+)/CaM.	SIGNOR-276421	0.425
PTPN5	protein	P54829	UNIPROT	BAK1	protein	Q16611	UNIPROT	up-regulates activity	dephosphorylation	Tyr108	QPTAENAyEYFTKIA	9606									20959805	t			In this study, we report that on apoptotic stimulation Bak undergoes dephosphorylation at tyrosine residue 108 (Y108), a critical event that is necessary but not sufficient for Bak activation, but is required both for early exposure of the occluded N-terminal domain and multimerisation.	SIGNOR-248542	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	GPHN	protein	Q9NQX3	UNIPROT	down-regulates	phosphorylation	Ser268	ASLSTTPsESPRAQA	9606		BTO:0000142							23408424	t		miannu	Erk phosphorylates gephyrin at ser-268 to regulate size of gephyrin postsynaptic scaffold and strength of gabaergic transmission./ Ser-268 phosphorylation restricts gephyrin cluster size via calpain 1 proteolysis	SIGNOR-200953	0.2
sufentanil	chemical	CHEBI:9316	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10030									21215785	t		Luana	Experiments were conducted to obtain K(i)'s for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR. The K(i) values obtained ranged from 0.1380 nM (sufentanil) to 12.486 μM (tramadol). 	SIGNOR-257890	0.8
NR0B2	protein	Q15466	UNIPROT	ESRRG	protein	P62508	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11705994	f		gcesareni	The current study also demonstrates that shp inhibits err_ transactivation.	SIGNOR-111620	0.477
SRC	protein	P12931	UNIPROT	RGS16	protein	O15492	UNIPROT	up-regulates	phosphorylation	Tyr168	TLMEKDSyPRFLKSP	9606									12588871	t		miannu	Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. / this result suggests src phosphorylates native rgs16 at residue tyr177 in vitro.	SIGNOR-98271	0.352
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates	binding			9606	BTO:0001130								1010227	t		gcesareni	Progressive increase in akt activation during prostate cancer progression led to increase phosphorylation of foxo3a and binding with 14-3-3, which potentially affected its transcriptional activity in age-specific manner.	SIGNOR-15849	0.2
EGR2	protein	P11161	UNIPROT	NAB2	protein	Q15742	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000782								20506119	f		miannu	 In T lymphocytes EGR2 and EGR3 have been shown to inhibit NAB2 expression.	SIGNOR-253885	0.594
PRKDC	protein	P78527	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates activity	phosphorylation	Ser435	LTVLNAFsQAPSTMQ	-1									8407951	t		lperfetto	 The carboxyl-terminal transcription activation domain was mapped within a 71-amino acid region that contains both DNA-PK phosphorylation sites. Amino acid substitutions that interfered with phosphorylation by DNA-PK at Ser-435/446 in GAL4-SRF fusion proteins were reduced in transactivation potency. From these data we suggest that DNA-PK phosphorylation may modulate SRF activity in vivo.	SIGNOR-248921	0.415
AKT2	protein	P31751	UNIPROT	STXBP4	protein	Q6ZWJ1	UNIPROT	down-regulates activity	phosphorylation	Ser99	GAKLRLEsAWEIAFI	10029	BTO:0000246								15753124	t		miannu	Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.Thus, our data demonstrate that insulin-stimulated Akt2-dependent phosphorylation of Synip on serine residue 99 results in reduced binding interactions between Synip and Syntaxin4.	SIGNOR-262635	0.433
tandutinib	chemical	CHEBI:90237	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207209	0.8
NR3C1	protein	P04150	UNIPROT	LCK	protein	P06239	UNIPROT	up-regulates	binding			9606									16888650	t		gcesareni	The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation.	SIGNOR-251685	0.362
MECP2	protein	P51608	UNIPROT	PTPN1	protein	P18031	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000452								26214522	t		Luana	In this study, we have demonstrated that the PTPN1 gene, which encodes PTP1B, was a direct target of MECP2 and that PTP1B protein levels were dramatically increased in Mecp2-mutant mice and in fibroblasts derived from patients with RTT.	SIGNOR-264546	0.2
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259000	0.441
NANOG	protein	Q9H9S0	UNIPROT	GATA6	protein	Q92908	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086;BTO:0005511								15983365	f		miannu	 Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 	SIGNOR-254627	0.473
TALDO1	protein	P37837	UNIPROT	D-erythrose 4-phosphate(2-)	smallmolecule	CHEBI:16897	ChEBI	up-regulates quantity	chemical modification			9606									19401148	t		miannu	Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 	SIGNOR-267092	0.8
GSK3B	protein	P49841	UNIPROT	CEBPA	protein	P49715	UNIPROT	up-regulates activity	phosphorylation	Thr226	HLQPGHPtPPPTPVP	10090	BTO:0000944								10567568	t			Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes.	SIGNOR-251231	0.387
PTPRG	protein	P23470	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	dephosphorylation	Tyr1008	LPQDKEYyKVKEPGE	9606	BTO:0000876								25624455	t		miannu	Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG.	SIGNOR-254690	0.291
1-(6,8-difluoro-2-methyl-4-quinolinyl)-3-[4-(dimethylamino)phenyl]urea	chemical	CHEBI:92941	ChEBI	HCRTR1	protein	O43613	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206733	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CEBPA	protein	P49715	UNIPROT	up-regulates	transcriptional regulation			10090	BTO:0000011								12270934	f		lperfetto	We demonstrate that exposure of post-confluent 3T3-L1 preadipocytes to insulin, isobutylmethylxanthine (MIX), dexamethasone (DEX), and fetal bovine serum induces a rapid but transient activation of MEK1 as indicated by extensive phosphorylation of ERK1 and ERK2 during the initial 2 h of adipogenesis. We further show that activation of MEK1 significantly enhances the transactivation of the C/EBPalpha minimal promoter during the early phase of the differentiation process.	SIGNOR-235322	0.2
resiquimod	chemical	CHEBI:36706	ChEBI	TLR7	protein	Q9NYK1	UNIPROT	up-regulates activity	chemical activation			9606									15661881	t		miannu	Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively.	SIGNOR-259246	0.8
IL15RA	protein	Q13261	UNIPROT	TIMP3	protein	P35625	UNIPROT	up-regulates				9606									30029643	f		areggio	Since recent study demonstrated desert Hedgehog (DHH) signaling can repressed FAP-derived adipocyte differentiation through Timp3 [30], we tested the mRNA expression of DHH and Timp3 in injured muscle with injection of IL-15. As expected, mRNA levels of DHH and Timp3 were both upregulated (Fig. 2f).	SIGNOR-256232	0.2
SCRIB	protein	Q14160	UNIPROT	Scribble_complex_DLG3-LLGL2_variant	complex	SIGNOR-C504	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270884	0.536
Condensin I	complex	SIGNOR-C341	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606									32445620	f		miannu	Human Condensin I and II Drive Extensive ATP-Dependent Compaction of Nucleosome-Bound DNA. the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction.	SIGNOR-263907	0.7
vorinostat	chemical	CHEBI:45716	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257948	0.8
PTCH1	protein	Q13635	UNIPROT	SMO	protein	Q99835	UNIPROT	down-regulates activity	binding			9606		BTO:0001757;BTO:0001298							12192414	t		lperfetto	We show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity.	SIGNOR-91709	0.779
HIRA complex 1	complex	SIGNOR-C461	SIGNOR	H3-3A	protein	P84243	UNIPROT	up-regulates quantity by stabilization	binding			9606									30285846	t		miannu	H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex.	SIGNOR-269439	0.2
SLBP	protein	Q14493	UNIPROT	H2BC17	protein	P23527	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265379	0.2
PTPRC	protein	P08575	UNIPROT	TYK2	protein	P29597	UNIPROT	down-regulates activity	dephosphorylation	Tyr1054	AVPEGHEyYRVREDG	10090									11201744	t			CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells 	SIGNOR-248357	0.416
GDF5	protein	P43026	UNIPROT	Ossification	phenotype	SIGNOR-PH74	SIGNOR	up-regulates				9606									21976273	f		miannu	Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. 	SIGNOR-252419	0.7
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CDH1	protein	P12830	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser36	HPGFDAEsYTFTVPR										23972993	t	For phosphorylated residues see Figure 7	lperfetto	Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP	SIGNOR-274051	0.419
MAPK1	protein	P28482	UNIPROT	SP3	protein	Q02447	UNIPROT	up-regulates	phosphorylation	Ser73	CSKIGPPsPGDDEEE	9606									17685427	t		llicata	Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73. in the inducible cell lines, expression of wild-type form of sp3 increases vegf production whereas the s73a form has a reduced potential reflecting its lower transcriptional activity.	SIGNOR-157272	0.31
CSNK2A1	protein	P68400	UNIPROT	ATF4	protein	P18848	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser215	IKEEDTPsDNDSGIC	9606	BTO:0000567								23123191	t		miannu	By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form. 	SIGNOR-276425	0.2
NRTN	protein	Q99748	UNIPROT	GFRA1	protein	P56159	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000142							9182803	t		gcesareni	A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling	SIGNOR-49119	0.728
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser328	QDAYRRNsVRFLQQR	9606	BTO:0000130								10559253	t		esanto	Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis.	SIGNOR-72137	0.2
DRD3	protein	P35462	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256981	0.453
HTR6	protein	P50406	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256944	0.359
naproxen	chemical	CHEBI:7476	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates activity	chemical inhibition			-1									9057869	t		miannu	Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). 	SIGNOR-258602	0.8
EGFR	protein	P00533	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000150								22693070	t		lperfetto	The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation.	SIGNOR-235692	0.876
CCP110	protein	O43303	UNIPROT	CALM2	protein	P0DP24	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16760425	t		miannu	We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis.	SIGNOR-266332	0.2
PRKACA	protein	P17612	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser63	AAEERRKsHEAEVLK	9606									8125092	t		gcesareni	Phosphorylation of either serine 16 or 63 is sufficient to inhibit stathmin in vitro. Phosphorylation at ser-63 reduces tubulin binding 10-fold and suppresses the mt polymerization inhibition activity.	SIGNOR-36374	0.313
PLK1	protein	P53350	UNIPROT	BORA	protein	Q6PGQ7	UNIPROT	down-regulates	phosphorylation	Ser497	SSNIQMDsGYNTQNC	9606									18521620	t		gcesareni	Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp).	SIGNOR-178803	0.78
MYOD1	protein	P15172	UNIPROT	MYOG	protein	P15173	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18676376	f		gcesareni	€ provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis.	SIGNOR-235009	0.436
LLGL1	protein	Q15334	UNIPROT	Scribble_complex_DLG4-LLGL1_variant	complex	SIGNOR-C509	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270903	0.526
HSPA1B	protein	P0DMV9	UNIPROT	ENPP1	protein	P22413	UNIPROT	up-regulates quantity	post transcriptional regulation			9606									19083193	t		miannu	We demonstrated the binding of heat shock protein 70 (HSP70) to ENPP1-3'UTR. Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation. 	SIGNOR-252198	0.2
JUN	protein	P05412	UNIPROT	AP1	complex	SIGNOR-C154	SIGNOR	form complex	binding			-1									3142692	t		irozzo	The c-Jun and c-fos proto-oncogenes encode proteins that form a complex which regulates transcription from promoters containing AP-1 activation elements. c-Jun has specific DNA binding activity, while c-Fos has homology to the putative DNA binding domain of c-Jun.	SIGNOR-256365	0.951
MAPK14	protein	Q16539	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	unknown	phosphorylation			9606									10806218	t		gcesareni	More importantly, incubation of active erk2 or p38 kinase with h3 protein resulted in phosphorylation of h3 at serine 10 in vitro. These results suggest that erk and p38 kinase are at least two important mediators of phosphorylation of h3 at serine 10.	SIGNOR-265338	0.2
MAP3K11	protein	Q16584	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates	phosphorylation	Ser257	ISGQLVDsIAKTRDA	9606									15328343	t		gcesareni	These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo.	SIGNOR-128420	0.608
SCN11A	protein	Q9UI33	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606									27262167	t		miannu	Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential.	SIGNOR-253407	0.8
CEBPB	protein	P17676	UNIPROT	GOT1	protein	P17174	UNIPROT	up-regulates quantity by expression	transcriptional regulation												8454627	t	 	 	In cotransfection experiments, the C/EBP beta protein trans-activated 10-15-fold the cAspAT gene promoter in HepG2 cells. Deletion studies revealed that regions P2 and P4 are critical for promoter activity. In gel retardation experiments, the P4 region bound different C/EBP-related proteins in different tissues	SIGNOR-254051	0.2
ANO6	protein	Q4KMQ2	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				10090									24663380	f		miannu	Using a shRNA KD approach, we show that Ano6-KD C2C12 myoblasts exhibit reduced proliferation capacity. Our data demonstrate that Ano6 is required to maintain the proliferative status of myoblasts.	SIGNOR-261213	0.7
U50488	chemical	CHEBI:73358	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029									9262330	t		miannu	We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine.	SIGNOR-258666	0.8
ELAVL3	protein	Q14576	UNIPROT	ADAM10	protein	O14672	UNIPROT	up-regulates quantity	post transcriptional regulation			9606									19221430	t		miannu	Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure	SIGNOR-266864	0.2
ACP1	protein	P24666	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	dephosphorylation			10090									17353188	t			Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3	SIGNOR-248458	0.328
WAVE complex	complex	SIGNOR-C271	SIGNOR	ARP2/3	complex	SIGNOR-C146	SIGNOR	up-regulates activity	binding			9606	BTO:0000132								27871158	t		lperfetto	Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex	SIGNOR-261876	0.528
STAT3	protein	P40763	UNIPROT	SOCS3	protein	O14543	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11159537	f		miannu	STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma.	SIGNOR-253050	0.699
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Thr220	QSNYIPEtPPPGYIS	9606		BTO:0000763;BTO:0000149							10197981	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-66771	0.739
PPP2CA	protein	P67775	UNIPROT	PPP1R1A	protein	Q13522	UNIPROT	unknown	dephosphorylation	Ser67	LKSTLAMsPRQRKKM	10116									11278334	t			In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation.	SIGNOR-248645	0.429
IRAK4	protein	Q9NWZ3	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Ser293	FNTLAFPsMKRKDVV	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276130	0.643
KDR	protein	P35968	UNIPROT	KDR	protein	P35968	UNIPROT	up-regulates	phosphorylation	Tyr1175	AQQDGKDyIVLPISE	9606	BTO:0000801;BTO:0000876								17658244	t		gcesareni	Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability.	SIGNOR-157089	0.2
PIK3CA	protein	P42336	UNIPROT	AKT2	protein	P31751	UNIPROT	up-regulates				9606	BTO:0000586								16293724	f		gcesareni	We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin.	SIGNOR-141814	0.658
CTTN	protein	Q14247	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				10116									23015759	f		miannu	Through alternative splicing, a single CTTNBP2 gene encodes three different transcripts, namely short (S), long (L), and intron forms. The interaction with cortactin is required for the function of CTTNBP2-S in dendritic spine formation because the CTTNBP2-S mutant, which no longer interacts with cortactin, is unable to rescue the spine defects resulting from CTTNBP2 knockdown. Thus CTTNBP2-S may control cortactin–F-actin cytoskeletons and regulate the formation and maintenance of dendritic spines in neurons.	SIGNOR-261696	0.7
CSNK2A1	protein	P68400	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	down-regulates activity	phosphorylation	Ser886	TSSSDTLsEEKNSEC	9606	BTO:0000567								31167143	t		miannu	Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations. 	SIGNOR-276731	0.2
RPS6KB1	protein	P23443	UNIPROT	RICTOR	protein	Q6R327	UNIPROT	down-regulates	phosphorylation	Thr1135	NRRIRTLtEPSVDFN	9606									19995915	t		gcesareni	Phosphorylation of rictor on thr1135 did not affect mtorc2 assembly, kinase activity, or cellular localization. However, cells expressing a rictor t1135a mutant were found to have increased mtorc2-dependent phosphorylation of akt	SIGNOR-161995	0.739
PAX7-FOXO1	fusion protein	SIGNOR-FP11	SIGNOR	SUV39H1	protein	O43463	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23435416	f		lperfetto	In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation. Although not shown directly, the authors speculated that KMT1A levels may be regulated by PAX3-FOXO1, as KMT1A expression was only increased on induction of differentiation in PAX3-FOXO1 positive cell lines	SIGNOR-249598	0.2
HMOX1	protein	P09601	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0000356								26722274	f		irozzo	Heme oxygenase-1 (HO-1) protects endothelial cells (EC) from undergoing apoptosis. These results indicated that HMOX-1 may be involved in conferring the chemoresistance of breast cancer cells, by preventing apoptosis and autophagy.	SIGNOR-256559	0.7
MAPK3	protein	P27361	UNIPROT	MYB	protein	P10242	UNIPROT	down-regulates	phosphorylation	Ser532	KIKQEVEsPTDKSGN	9606									8798443	t		llicata	Here we describe that human c-myb can be phosphorylated by mitogen-activated protein kinases (mapk's) at serine 532 of the carboxy (c-) terminal regulatory domain in vitro. expression of a constitutively active form of ras together with c-myb in transient transfection experiments had no effect on the transcriptional activity of c-myb, while expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532.	SIGNOR-43558	0.306
CDX2	protein	Q99626	UNIPROT	MEP1A	protein	Q16819	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22326557	t	 	 	TNF-α-induced down-regulation of CDX2 suppresses MEP1A expression in colitis|	SIGNOR-253965	0.484
PDPK1	protein	O15530	UNIPROT	PRKCQ	protein	Q04759	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000782								15802604	t		gcesareni	We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts.	SIGNOR-134869	0.552
PTPRF	protein	P10586	UNIPROT	FYN	protein	P06241	UNIPROT	down-regulates	dephosphorylation	Tyr420	RLIEDNEyTARQGAK	9606									12496362	t		lperfetto	Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule.	SIGNOR-96768	0.405
SRC	protein	P12931	UNIPROT	INPPL1	protein	O15357	UNIPROT	up-regulates	phosphorylation	Tyr986	NSFNNPAyYVLEGVP	9606									12235291	t		lperfetto	Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo.	SIGNOR-92931	0.551
YES1	protein	P07947	UNIPROT	YY1	protein	P25490	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0002181								26198631	t		miannu	YY1 phosphorylation is mediated by Src family kinases.	SIGNOR-276941	0.2
OGG1	protein	O15527	UNIPROT	Base-excision_repair	phenotype	SIGNOR-PH222	SIGNOR	up-regulates													23545420	f		lperfetto	The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1).	SIGNOR-275715	0.7
6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide	chemical	CHEBI:92401	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258002	0.8
JAK2	protein	O60674	UNIPROT	EPOR	protein	P19235	UNIPROT	up-regulates activity	phosphorylation	Tyr468	DSGISTDySSGDSQG										12441334	t			JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2	SIGNOR-251352	0.806
GSK3B	protein	P49841	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates	binding			9606			SIGNOR-C110	SIGNOR-C110					9734785	t		lperfetto	Interaction with beta-catenin and GSK-3beta was required for the Axin-mediated beta-catenin reduction.	SIGNOR-60046	0.917
CDK2	protein	P24941	UNIPROT	CDX2	protein	Q99626	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser291	PVSSLQAsVPGSVPG	9606									16027724	t		llicata	Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. 	SIGNOR-250729	0.489
SYK	protein	P43405	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates	phosphorylation	Tyr133	EMPSEEGyQDYEPEA	9606		BTO:0000975;BTO:0000142							11744621	t		llicata	Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers.	SIGNOR-113065	0.511
ZDHHC2	protein	Q9UIJ5	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	palmitoylation	Cys3	cLCIVTTK	9606									23836932	t			Plasma membrane targeting of DHHC2 palmitoyltransferase rapidly recruited PSD-95 to the plasma membrane and proved essential for postsynaptic nanodomain formation.	SIGNOR-262296	0.389
PRKACA	protein	P17612	UNIPROT	CAD	protein	P27708	UNIPROT	unknown	phosphorylation	Ser1859	PPRIHRAsDPGLPAE										11986331	t		miannu	CAD is down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation.	SIGNOR-250343	0.311
ZFP36	protein	P26651	UNIPROT	EIF4E2/GIGYF2 complex	complex	SIGNOR-C257	SIGNOR	up-regulates activity	relocalization			9606									30917308	t		lperfetto	A key factor in this regulation is tristetraprolin (TTP), an RNA-binding protein (RBP) that recruits RNA-destabilizing factors and the translation inhibitory complex 4EHP-GIGYF1/2 to AU-rich element (ARE)-containing mRNAs	SIGNOR-261015	0.2
MYCT1	protein	Q8N699	UNIPROT	CCNE1	protein	P24864	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30283340	f		miannu	MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. 	SIGNOR-261732	0.2
F2	protein	P00734	UNIPROT	F7	protein	P08709	UNIPROT	up-regulates activity				9606		BTO:0000131							29880919	t		lperfetto	Thrombin also activates the cofactors FVIII (to FVIIIa) and FV (to FVa) and activates platelets such that they provide a procoagulant membrane surface to which these proteins then bind	SIGNOR-263529	0.306
FAM13B	protein	Q9NYF5	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260503	0.409
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PCYT1A	protein	P49585	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000763							15788406	t	inferred from 70% family members	gcesareni	Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis.	SIGNOR-270151	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	up-regulates	phosphorylation			9606									12536214	t	inferred from family member	gcesareni	Receptor internalization, altered;intracellular localization	SIGNOR-270230	0.643
STAT3	protein	P40763	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									25194572	f		miannu	Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. IL-6 stimulation promoted an increase in the mRNA levels of both Stat3 and Myod1. Stat3 mediated this effect, as IL-6–dependent Myod1 upregulation was impaired after infection with the shStat3 lentivirus.	SIGNOR-255416	0.536
SRC	protein	P12931	UNIPROT	CEACAM1	protein	P13688	UNIPROT	up-regulates activity	phosphorylation	Tyr493	NKMNEVTySTLNFEA	9606	BTO:0000007								9867848	t		lperfetto	Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515	SIGNOR-246471	0.436
IL4R	protein	P24394	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates activity				10090									23582327	f			Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes	SIGNOR-256482	0.7
E2F1	protein	Q01094	UNIPROT	TYMS	protein	P04818	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253863	0.509
OPRL1	protein	P41146	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257117	0.254
PLK1	protein	P53350	UNIPROT	NEDD1	protein	Q8NHV4	UNIPROT	up-regulates activity	phosphorylation	Ser426	VNKGSDEsIGKGDGF	9606	BTO:0000567								19509060	t		lperfetto	Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation.	SIGNOR-272992	0.604
PRKACA	protein	P17612	UNIPROT	AKAP12	protein	Q02952	UNIPROT	up-regulates activity	phosphorylation	Ser698	RARRGSSsDEEGGPK	-1									14657015	t		lperfetto	Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin.	SIGNOR-271844	0.2
PLK1	protein	P53350	UNIPROT	NINL	protein	Q9Y2I6	UNIPROT	down-regulates activity	phosphorylation	Ser87	VRPSDEDsSSLESAA	-1									12852856	t		lperfetto	Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction	SIGNOR-103352	0.688
HBEGF	protein	Q99075	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606									14967450	t	Heparin-binding EGF-like growth factor??is synthesized as a membrane-anchored mitogenic and chemotactic glycoprotein.	gcesareni	Ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4	SIGNOR-121977	0.76
leucine	smallmolecule	CHEBI:25017	ChEBI	SESN2	protein	P58004	UNIPROT	down-regulates activity	chemical inhibition			9606									26449471	t			We find that leucine, but not arginine, disrupts the Sestrin2- GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20micromolar, which is the leucine concentration that half-maximally activates mTORC1	SIGNOR-254897	0.8
LRRK2	protein	Q5S007	UNIPROT	NSF	protein	P46459	UNIPROT	up-regulates activity	phosphorylation	Thr645	RKLLIIGtTSRKDVL	9606	BTO:0002181								26758690	t		miannu	LRRK2 phosphorylates full-length NSF at threonine 645 in the ATP binding pocket of D2 domain. Functionally, NSF phosphorylated by LRRK2 displays enhanced ATPase activity and increased rate of SNARE complex disassembling.	SIGNOR-277196	0.375
PRKACA	protein	P17612	UNIPROT	KDELR1	protein	P24390	UNIPROT	up-regulates	phosphorylation	Ser209	VLKGKKLsLPA	9606									14517323	t		llicata	We conclude that pka phosphorylation of serine 209 is required for the retrograde transport of the kdel receptor from the golgi complex to the er from which the retrieval of proteins bearing the kdel signal depends.	SIGNOR-118257	0.313
FUS	protein	P35637	UNIPROT	PA2G4	protein	Q9UQ80	UNIPROT	up-regulates activity	sumoylation	Lys93	VCHFSPLkSDQDYIL	9606	BTO:0000007								19946338	t		gcesareni	Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity €.. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity.	SIGNOR-236904	0.342
PTPN11	protein	Q06124	UNIPROT	GAB1	protein	Q13480	UNIPROT	down-regulates activity	dephosphorylation	Tyr589	SHDSEENyVPMNPNL	9606									10068651	t		lperfetto	Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro.	SIGNOR-236258	0.952
PCDHAC2	protein	Q9Y5I4	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-269038	0.2
acetylcholine	smallmolecule	CHEBI:15355	ChEBI	CHRM4	protein	P08173	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257471	0.8
PDPK1	protein	O15530	UNIPROT	SGK3	protein	Q96BR1	UNIPROT	up-regulates	phosphorylation			9606									15209375	t		gcesareni	One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.	SIGNOR-126236	0.472
PRKDC	protein	P78527	UNIPROT	XRCC4	protein	Q13426	UNIPROT	up-regulates activity	phosphorylation	Ser327	SLETLRNsSPEDLFD	9606	BTO:0002137								26774286	t		miannu	In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair. 	SIGNOR-277198	0.905
NPEPPS	protein	P55786	UNIPROT	peptide antigen	smallmolecule	CHEBI:166824	ChEBI	up-regulates quantity	chemical modification			9606									11062501	t			The proteasome generates exact major histocompatibility complex (MHC) class I ligands as well as NH2-terminal-extended precursor peptides| We performed in vitro peptide digests using recombinant PSA | PSA behaved exclusively as an aminopeptidase |BH and PSA act as complementary and redundant systems responsible for the final trimming of the correct NH2 terminus. 	SIGNOR-272468	0.8
SB 505124	chemical	CHEBI:100922	ChEBI	ACVR1C	protein	Q8NER5	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206739	0.8
CREBBP	protein	Q92793	UNIPROT	MYB	protein	P10242	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								8654374	t	2	miannu	the nuclear co-activator CREB binding protein (CBP). This protein interacts directly with both c-Myb and v-Myb and potentiates Myb-specific transcription	SIGNOR-240994	0.798
PRKD1	protein	Q15139	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606									20179209	t		lperfetto	Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated	SIGNOR-163924	0.311
PRKACA	protein	P17612	UNIPROT	ATP2B1	protein	P20020	UNIPROT	up-regulates activity	phosphorylation	Ser1178	APTKRNSsPPPSPNK	-1									2548572	t		miannu	The ATPase is phosphorylated only at this site by the cAMP-dependent protein kinase, and the phosphorylation is inhibited by calmodulin. The effect of the phosphorylation is to decrease the Km for Ca2+ of the purified ATPase from about 10 microM to about 1.4 microM and to increase the Vmax of ATP hydrolysis about 2-fold.	SIGNOR-262694	0.438
ADCY4	protein	Q8NFM4	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates quantity	chemical modification			9606									15385642	t		miannu	Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions.	SIGNOR-265006	0.8
Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	GABA-A (a5-b1-g2) receptor	complex	SIGNOR-C335	SIGNOR	up-regulates				9606									33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors	SIGNOR-268585	0.2
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	ATM	protein	Q13315	UNIPROT	up-regulates				9606									21034966	f		lperfetto	the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively.	SIGNOR-242612	0.7
CACNA1D	protein	Q01668	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606		BTO:0000227							30849329	f		miannu	Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]).	SIGNOR-264331	0.7
MAPK1	protein	P28482	UNIPROT	KDM4B	protein	O94953	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr305	IDYGKVAtQCTCRKD	9606	BTO:0001109								28945223	t		miannu	In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation. 	SIGNOR-276741	0.2
TLK1	protein	Q9UKI8	UNIPROT	MAPKAPK5	protein	Q8IW41	UNIPROT	up-regulates activity	phosphorylation	Ser354	VSLKPLHsVNNPILR	9606	BTO:0000007								35064619	t		miannu	We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells.	SIGNOR-276746	0.2
CLASP2	protein	O75122	UNIPROT	MAPRE1	protein	Q15691	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								19638411	t		lperfetto	GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells	SIGNOR-264829	0.617
SP1	protein	P08047	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10644769	f		miannu	 these results indicate a role for both NF-Y and Sp1 in the transcriptional activation of the MDR1 gene by genotoxic stress, and indicate that YB-1, if involved, is not sufficient to mediate this activation.	SIGNOR-253872	0.269
AURKA	protein	O14965	UNIPROT	ALDH1A1	protein	P00352	UNIPROT	up-regulates activity	phosphorylation	Thr442	KDIDKAItISSALQA	-1									28193222	t		miannu	AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species. 	SIGNOR-276748	0.381
FZD7	protein	O75084	UNIPROT	FZD7/SDC4	complex	SIGNOR-C216	SIGNOR	form complex	binding			9606	BTO:0002314	BTO:0001103							23290138	t		apalma	We next examined whether endogenous Fzd7 and Sdc4 form a receptor complex in satellite cells […] Therefore, we conclude that Fzd7 and Sdc4 form a co-receptor complex in activated satellite cells.	SIGNOR-255848	0.54
MAPK7	protein	Q13164	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates	phosphorylation	Ser78	ANPSPPPsPSQQINL	9606									11254654	t		lperfetto	Bmk1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinasebmk1 activates sgk by phosphorylation at serine 78.	SIGNOR-105728	0.396
MAPK14	protein	Q16539	UNIPROT	FOXC1	protein	Q12948	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser241	PSPPQPLsPAAALGS										31650548	t		lperfetto	P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation.	SIGNOR-275913	0.2
IRF3	protein	Q14653	UNIPROT	Interferon-type-I	proteinfamily	SIGNOR-PF50	SIGNOR	up-regulates quantity by expression	transcriptional regulation			10090									20610653	f		miannu	Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors.	SIGNOR-260330	0.2
SIRT1	protein	Q96EB6	UNIPROT	FOXO4	protein	P98177	UNIPROT	up-regulates	deacetylation			9606									15126506	t		gcesareni	Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes.	SIGNOR-124714	0.735
RPS6KB1	protein	P23443	UNIPROT	PDCD4	protein	Q53EL6	UNIPROT	down-regulates	phosphorylation	Ser67	KRRLRKNsSRDSGRG	9606									17053147	t		gcesareni	Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.	SIGNOR-150144	0.599
IRAK1	protein	P51617	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Thr288	QCPVGFNtLAFPSMK	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276136	0.758
RASSF1	protein	Q9NS23	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			9606	BTO:0002552								12024041	f		Luana	RASSF1A expression dramatically inhibits native cyclin D1 accumulation | Regulation of cyclin D1 accumulation by RASSF1A is independent of the cyclin D1 promoter and likely occurs through inhibition of mRNA translation.	SIGNOR-259455	0.56
(R)-carnitine	smallmolecule	CHEBI:16347	ChEBI	O-palmitoyl-L-carnitine	smallmolecule	CHEBI:17490	ChEBI	up-regulates quantity	precursor of			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267119	0.8
CUL3	protein	Q13618	UNIPROT	KCTD13	protein	Q8WZ19	UNIPROT	up-regulates activity	binding			9606									19782033	t		miannu	 BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.	SIGNOR-264233	0.552
ATR	protein	Q13535	UNIPROT	CHEK1	protein	O14757	UNIPROT	up-regulates	phosphorylation	Ser345	LVQGISFsQPTCPDH	9606									15775976	t		gcesareni	Atr activation typically leads to chk1 phosphorylation and activation. In response to genotoxic stress, chk1 is phosphorylated on serines 317 (s317) and 345 (s345) by the ataxia-telangiectasia-related (atr) protein kinase.	SIGNOR-134716	0.923
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate	smallmolecule	CHEBI:18348	ChEBI	AP-3/clathrin vescicle	complex	SIGNOR-C250	SIGNOR	form complex	binding			9606									23103167	t		lperfetto	Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors	SIGNOR-260669	0.8
CTNNB1	protein	P35222	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12589056	f		gcesareni	The resulting accumulation of beta-catenin leads to its nuclear translocation and binding to tcf/lef transcription factors to induce target genes including cyclin d1.	SIGNOR-98379	0.794
CDK8	protein	P49336	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Ser367	GTQNPVSsPGMSQEL	-1									29967145	t		miannu	CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro.	SIGNOR-277651	0.327
CSNK2A2	protein	P19784	UNIPROT	SET	protein	Q01105-2	UNIPROT	down-regulates	phosphorylation	Ser9	SAPAAKVsKKELNSN	9606									23374587	t	The effect has been demonstrated using Q01105-2	miannu	Ckii-mediated phosphorylation at ser9 hinders nuclear import of set	SIGNOR-200802	0.262
ERBB2	protein	P04626	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates	phosphorylation	Tyr1222	PAFDNLYyWDQDPPE	9606									15156151	t		gcesareni	Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227	SIGNOR-124860	0.2
AR	protein	P10275	UNIPROT	TMPRSS2	protein	O15393	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21761340	t	 	lperfetto	The prostate-specific TMPRSS2 gene, while upregulated by AR activity in luminal cells, is also transcribed in basal populations, confirming that AR acts as an expression modulator. 	SIGNOR-253687	0.595
GRIN1	protein	Q05586	UNIPROT	NMDA receptor_2A	complex	SIGNOR-C347	SIGNOR	form complex	binding			9606	BTO:0000938								12871085	t		miannu	The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits	SIGNOR-264120	0.714
PPARG	protein	P37231	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates				9606	BTO:0000801								17681149	f		lperfetto	Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways	SIGNOR-249556	0.386
EDNRA	protein	P25101	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257320	0.252
MAP3K7	protein	O43318	UNIPROT	MAP2K3	protein	P46734	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000222								21902831	t		lperfetto	TAK1 can phosphorylate and activate MAP kinase kinase 3/6 (MKK3/6), and numerous studies have demonstrated a requirement for MKK3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner.	SIGNOR-236093	0.483
WNT16	protein	Q9UBV4	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131674	0.602
VWF	protein	P04275	UNIPROT	GPIb-IX-V complex	complex	SIGNOR-C270	SIGNOR	up-regulates activity	binding			9606	BTO:0000132								25297919	t		lperfetto	Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and αIIbβ3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury	SIGNOR-261853	0.676
SFPQ	protein	P23246	UNIPROT	NONO/SFPQ	complex	SIGNOR-C62	SIGNOR	form complex	binding			9606									9756848	t		miannu	We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i	SIGNOR-60560	0.695
RUNX1	protein	Q01196	UNIPROT	 Core Binding Factor complex	complex	SIGNOR-C214	SIGNOR	form complex	binding			9606									12495904	t		irozzo	The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFβ, is essential for normal hematopoiesis	SIGNOR-255710	0.841
CSNK2A1	protein	P68400	UNIPROT	FAF1	protein	Q9UNN5	UNIPROT	down-regulates activity	phosphorylation	Ser289	ITDVHMVsDSDGDDF	9534									12832043	t		llicata	We previously identified the Fas-associated factor FAF1 as an in vitro substrate of protein kinase CK2 and determined Ser289 and Ser291 as phosphorylation sites.|Therefore we assume that CK2‐mediated FAF1 phosphorylation influences the nuclear localization of FAF1 | it implies that the major function of FAF1 might not be in the cytoplasm as an interacting partner of Fas.	SIGNOR-250863	0.331
pyruvate	smallmolecule	CHEBI:15361	ChEBI	(S)-lactate	smallmolecule	CHEBI:16651	ChEBI	up-regulates quantity	precursor of			9606									24929216	t			Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase.	SIGNOR-266920	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PRKACA	protein	P17612	UNIPROT	up-regulates				9606	BTO:0000938								16537363	f		gcesareni	Indicating that akt positively regulates shh signaling by controlling pka-mediated gli inactivation.	SIGNOR-145113	0.2
CSNK2A2	protein	P19784	UNIPROT	PPP1R2	protein	P41236	UNIPROT	up-regulates activity	phosphorylation	Ser121	YRIQEQEsSGEEDSD	-1									8288648	t		llicata	Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action.	SIGNOR-251020	0.311
KAT6A	protein	Q92794	UNIPROT	CCL3	protein	P10147	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000661								12771199	t		lperfetto	We further demonstrate that the histone acetyltransferase, MOZ, can activate the MIP-1a promoter in T-cells and that this activation is largely dependent upon the proximal RUNX site. Moreover, we show that co-expression of MOZ and RUNX1 can activate the MIP-1a promoter.	SIGNOR-251726	0.2
EEF1A2	protein	Q05639	UNIPROT	Met-tRNA(Met)	chemical	CHEBI:16635	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269524	0.8
INSR	protein	P06213	UNIPROT	FABP4	protein	P15090	UNIPROT	unknown	phosphorylation	Tyr20	SSENFDDyMKEVGVG	-1									1648089	t			Adipocyte lipid-binding protein is phosphorylated on tyrosine 19 in an insulin-stimulated fashion by the insulin receptor	SIGNOR-251309	0.398
BMX	protein	P51813	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates quantity	phosphorylation	Tyr12	NVLAKALyDNVAESP	10090	BTO:0002572								21937722	t		miannu	Recombinant Bmx kinase was found to effectively phosphorylate the wt CAS SH3 domain on Tyr-12 (Figure 2B). A novel phosphorylation site on CAS, Tyr-12 (Y12) within the ligand-binding hydrophobic pocket of the CAS SH3 domain, was identified and found to be enriched in Src-transformed cells and invasive human carcinoma cells. 	SIGNOR-276384	0.52
aripiprazole	chemical	CHEBI:31236	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002181								22025698	t		Luana	Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. 	SIGNOR-258319	0.8
alvocidib hydrochloride	chemical	CHEBI:90998	ChEBI	CDK4	protein	P11802	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192464	0.8
PRKCA	protein	P17252	UNIPROT	SDC2	protein	P34741	UNIPROT	unknown	phosphorylation	Ser188	LGERKPSsAAYQKAP	-1									9244383	t		lperfetto	We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198.	SIGNOR-248976	0.378
MAPK1	protein	P28482	UNIPROT	CIITA	protein	P33076	UNIPROT	up-regulates	phosphorylation	Ser280	TVHGLPTsPDRPGST	9606									18245089	t		gcesareni	We show in this study that the nuclear localized form of ciita is a predominantly phosphorylated form of the protein, whereas cytoplasmic ciita is predominantly unphosphorylated. Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. Double mutations of these residues increased nuclear ciita, indicating that these sites are not required for nuclear import. Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.	SIGNOR-160609	0.443
TGFB3	protein	P10600	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252284	0.7
NR5A1	protein	Q13285	UNIPROT	CYP19A1	protein	P11511	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19237537	t		miannu	The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes.	SIGNOR-271787	0.494
MAPK3	protein	P27361	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Thr187	NAGSVEQtPKKPGLR	9606	BTO:0000150								10931950	t		gcesareni	These data suggest that increased signaling by erbb receptors up-regulates mapk activity, which, in turn, phosphorylates and destabilizes p27, thus contributing to dysregulated cell cycle progression.	SIGNOR-80234	0.386
PFN1	protein	P07737	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				9606									18667433	f		areggio	 Additionally, the association of Ror2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration.	SIGNOR-258977	0.7
nitric oxide	smallmolecule	CHEBI:16480	ChEBI	GUCY1A2-B3	complex	SIGNOR-C138	SIGNOR	up-regulates activity	chemical activation			9606									15036565	t		gcesareni	One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP)	SIGNOR-243964	0.8
SIRT1	protein	Q96EB6	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates				10090		BTO:0001103							24003218	f		lperfetto	SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3	SIGNOR-252997	0.909
FYN	protein	P06241	UNIPROT	FCGR2A	protein	P12318	UNIPROT	up-regulates activity	phosphorylation	Tyr288	YETADGGyMTLNPRA	-1									8756631	t		lperfetto	To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.	SIGNOR-249336	0.513
BAIAP2	protein	Q9UQB8	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				10090	BTO:0001909								19171758	f		miannu	Ectopic expression of IRSp53 in mouse neuroblastoma N1E115 cells induces neurite outgrowth . Kank inhibits IRSp53-mediated neurite outgrowth in N1E115 cells	SIGNOR-265555	0.7
BRCA1	protein	P38398	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								16331276	f		miannu	We identified a foxa1 binding site within the brca1-responsive element of the p27(kip1) promoter and showed that foxa1 activated the promoter alone and in conjunction with brca1.	SIGNOR-142888	0.352
TGFB1	protein	P01137	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates				9606									18586026	f		gcesareni	These data show that tgf-beta-induced nf-kappab activation is through tak1/mek-mediated aktactivation, which is essential for tgf-beta to support of osteoclast survival	SIGNOR-179179	0.38
CSF2RA	protein	P15509	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates				9606									9028317	f		gcesareni	We show that the amount of jak2 physically associated with gm-csfr beta chain is increased after gm-csf stimulation and that gm-csf triggers both beta chain and jak2 tyrosine phosphorylation	SIGNOR-46334	0.513
ABL2	protein	P42684	UNIPROT	ABL2	protein	P42684	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr439	RLMTGDTyTAHAGAK	-1									15735735	t		miannu	The results show that Arg is stabilized in response to 0.1 mM H2O2 by autophosphorylation of Y-261, consistent with involvement of the Arg kinase function in regulating Arg levels. The results further demonstrate that c-Abl-mediated phosphorylation of Arg on Y-261 similarly confers Arg stabilization.. These findings indicate that abrogation of the Arg kinase function by the Y261F mutation is dependent on phosphorylation of the Y-439 site.). Our results thus indicate that phosphorylation of Arg on Y-261 plays a dual role in retaining the Arg kinase function and preventing Arg degradation by blocking ubiquitination (Figure 6).	SIGNOR-276032	0.2
retinal	smallmolecule	CHEBI:15035	ChEBI	all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	up-regulates quantity	precursor of			9606									21621639	t		lperfetto	All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step.	SIGNOR-265124	0.8
p38	proteinfamily	SIGNOR-PF16	SIGNOR	KRT20	protein	P35900	UNIPROT	up-regulates activity	phosphorylation	Ser13	RSFHRSLsSSLQAPV	-1									20724476	t		miannu	P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13.	SIGNOR-263070	0.2
EGFR	protein	P00533	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates	binding			9606	BTO:0000017								10358079	t		gcesareni	We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5.Egf stimulation and subsequent phosphorylation of egfr at tyrosine y978, y998 and y869 would then subsequently lead to recruitment and activation of stat5.	SIGNOR-68159	0.818
BBsome complex	complex	SIGNOR-C288	SIGNOR	RAB8A	protein	P61006	UNIPROT	up-regulates activity	binding			9606									17574030	t		lperfetto	Interestingly, the BBSome is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome.	SIGNOR-262562	0.456
PTPN11	protein	Q06124	UNIPROT	GAB1	protein	Q13480	UNIPROT	down-regulates activity	dephosphorylation	Tyr627	KGDKQVEyLDLDLDS	9606									11323411	t			These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro.	SIGNOR-248674	0.952
MAPK1	protein	P28482	UNIPROT	PDE4B	protein	Q07343	UNIPROT	up-regulates activity	phosphorylation	Ser659	YQSMIPQsPSPPLDE	-1									11030732	t		miannu	The short-form PDE4B2 isoenzyme was activated by Erk2 phosphorylation. These functional changes in PDE activity were mimicked by mutation of the target serine for Erk2 phosphorylation to the negatively charged amino acid, aspartic acid.	SIGNOR-275970	0.272
PRKCD	protein	Q05655	UNIPROT	HABP4	protein	Q5JVS0	UNIPROT	down-regulates activity	phosphorylation	Thr354	RKPANDItSQLEINF	9606	BTO:0004974								14699138	t		lperfetto	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249248	0.293
CDX2	protein	Q99626	UNIPROT	CDX2/PAX6/P300	complex	SIGNOR-C33	SIGNOR	form complex	binding			9606									10506141	t		lperfetto	In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300.	SIGNOR-70954	0.373
panobinostat	chemical	CHEBI:85990	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257754	0.8
ESRRA	protein	P11474	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000159								15955695	f		miannu	 In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro.	SIGNOR-253799	0.2
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	PRKCZ	protein	Q05513	UNIPROT	up-regulates	chemical activation			9606									10777564	t		gcesareni	Wnt ligands working through frizzled receptors have a differential ability to stimulate release of intracellular calcium (ca(2+)) and activation of protein kinase c (pkc).	SIGNOR-76991	0.8
WNK3	protein	Q9BYP7	UNIPROT	SLC12A5	protein	Q9H2X9	UNIPROT	down-regulates activity	phosphorylation												21613606	t		lperfetto	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264628	0.474
LYST	protein	Q99698	UNIPROT	RAB5B	protein	P61020	UNIPROT	down-regulates activity	binding			7227									33725482	t		lperfetto	Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment	SIGNOR-266002	0.2
PRKCA	protein	P17252	UNIPROT	CBL	protein	P22681	UNIPROT	down-regulates quantity	phosphorylation	Ser639	PDVPRLGsTFSLDTS	9606	BTO:0000782								11024037	t		lperfetto	However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway. 	SIGNOR-249056	0.327
SEPTIN6	protein	Q14141	UNIPROT	SEPT6/SEPT7	complex	SIGNOR-C72	SIGNOR	form complex	binding			9606									16914550	t		miannu	We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains.	SIGNOR-148895	0.2
ROS	stimulus	SIGNOR-ST2	SIGNOR	ARNT	protein	P27540	UNIPROT	up-regulates quantity by expression													22387692	f	 	lperfetto	Although the regulation mechanism of the ARNT expression is largely unknown, earlier studies reported that the human ARNT protein level was decreased by hydrogen peroxide or reactive oxygen species.	SIGNOR-253689	0.7
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257988	0.8
CDK2	protein	P24941	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates	phosphorylation	Thr494	TPLHRDKtPLHQKHA	9606			SIGNOR-C83						9840932	t		lperfetto	The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk4	SIGNOR-62365	0.711
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257910	0.8
TNFSF14	protein	O43557	UNIPROT	TNFRSF14	protein	Q92956	UNIPROT	up-regulates	binding			9606		BTO:0000763							10894944	t		gcesareni	A member of the tumor necrosis factor (tnf) superfamily, human tnfsf14 (htnfsf14)/hvem-l (herpes virus entry mediator ligand) was isolated as a cellular ligand for hvem/tr2 and human lymphotoxin beta receptor (ltbetar). Tnfsf14 induces apoptosis and suppresses tumor formation	SIGNOR-79328	0.855
HNF4G	protein	Q14541	UNIPROT	AKR1C4	protein	P17516	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003846								2044952	f	2	miannu	Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-4_ is a necessary factor for the activation of the human DD4 gene. is much higher than that of vHNF-1-C.	SIGNOR-240013	0.2
RPS6KA4	protein	O75676	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates	phosphorylation			9606									11909979	t		gcesareni	Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1.	SIGNOR-116252	0.599
MET	protein	P08581	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr576	RYMEDSTyYKASKGK	9606									16782899	t		llicata	Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain	SIGNOR-147191	0.475
BMP7	protein	P18075	UNIPROT	PRDM16	protein	Q9HAZ2	UNIPROT	up-regulates	transcriptional regulation			9606									18719589	f		fspada	Bmp7 activates a full program of€š brown€š adipogenesis€š including induction of early regulators of€š brown€š fat fate prdm16 (pr-domain-containing 16; ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha; ref. 5), increased expression of the€š brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways	SIGNOR-210053	0.414
PTPN1	protein	P18031	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates	dephosphorylation			9606									15632081	t		gcesareni	Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs	SIGNOR-252639	0.733
FLT3	protein	P36888	UNIPROT	HK2	protein	P52789	UNIPROT	up-regulates activity				9606	BTO:0002144								28194038	f			FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity	SIGNOR-261322	0.262
EIF3H	protein	O15372	UNIPROT	EIF3_complex	complex	SIGNOR-C401	SIGNOR	form complex	binding			-1									16920360	t		miannu	Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 	SIGNOR-266393	0.915
CYLD	protein	Q9NQC7	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates				9606	BTO:0001286								16713561	f		gcesareni	Cyld was also recently shown to deubiquitylate the p50 and p52 co-activator bcl-3, leading to both cyclin d1 expression and proliferation in keratinocytes	SIGNOR-146777	0.401
MAPK1	protein	P28482	UNIPROT	PITPNM1	protein	O00562	UNIPROT	up-regulates	phosphorylation	Thr1223	AEREGPGtPPTTLAR	9606									15125835	t		lperfetto	Both cdk1 and erk2 induced phosphorylation of the wild-type nir2. Substitution of t794 by alanine reduced the phosphorylation by erk2, whereas the double mutations t794/1223a completely abolished it. The requirement of multiple nir2 phosphorylation sites for plk1 binding may provide a mechanism that sets a threshold for the nir2-plk1 interaction during mitosis.	SIGNOR-124646	0.2
FGFR3	protein	P22607	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606	BTO:0000007								10918587	t			Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. 	SIGNOR-251139	0.615
MAPK1	protein	P28482	UNIPROT	NR3C2	protein	P08235	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser361	TLRDVVPsPDTQEKG	9606	BTO:0005043								22798426	t		miannu	 Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276109	0.291
AURKB	protein	Q96GD4	UNIPROT	DES	protein	P17661	UNIPROT	down-regulates	phosphorylation	Ser60	VYQVSRTsGGAGGLG	-1									12686604	t		lperfetto	We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro.	SIGNOR-100111	0.526
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BC20P	protein	Q6DN03	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSIYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271988	0.2
IL6	protein	P05231	UNIPROT	IL6R	protein	P08887	UNIPROT	up-regulates activity	binding			9606									18923185	t		miannu	IL-6 and IL-11 are the only members of the family that signal via the induction of a gp130 homodimer after binding their specific -receptors, IL-6R and IL-11R. When IL-6 binds to the homodimerized IL-6Rα/gp130Rβ, it results in a signaling cascade that is initiated by the autophoshorylation and activation of JAK.	SIGNOR-255324	0.916
G6PC1	protein	P35575	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	down-regulates quantity	chemical modification			9606									12093795	t		miannu	Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis	SIGNOR-266568	0.8
FGF12	protein	P61328	UNIPROT	SCN4A	protein	P35499	UNIPROT	down-regulates activity	binding			9606									20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253432	0.258
SLC24A1	protein	O60721	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			9606									30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264395	0.8
FGR	protein	P09769	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	down-regulates activity	phosphorylation	Tyr394	LNTIGLIyEKISLPK	9606	BTO:0002181								28618271	t		miannu	The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. 	SIGNOR-276722	0.2
ARID1A	protein	O14497	UNIPROT	SWI/SNF ACTL6A-ARID1A-SMARCA2 variant	complex	SIGNOR-C470	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269818	0.801
WARS1	protein	P23381	UNIPROT	tryptophan	smallmolecule	CHEBI:27897	ChEBI	down-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 	SIGNOR-270510	0.8
GATA1	protein	P15976	UNIPROT	HOXA10	protein	P31260	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17688409	f		miannu	Transcription factors GATA-1 and Fli-1 regulate human HOXA10 expression in megakaryocytic cells. Mutation of the GATA-1 and the Ets-1 motifs amplified the expression of HOXA10 in HEL and K562 cells, confirming the importance of these cis-acting elements in regulating HOXA10 expression in megakaryocytic cells. Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression. 	SIGNOR-254470	0.312
IKK-complex	complex	SIGNOR-C14	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation			9606									23332762	t		lperfetto	Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation.	SIGNOR-216399	0.266
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1882	SPTSPTYsPTTPKYS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120136	0.316
MNAT1	protein	P51948	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates activity	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606									10949034	t		Manara	Human Estrogen Receptor α Is Phosphorylated at Serine 118 In Vivo by Cdk7	SIGNOR-260837	0.406
O-phosphonato-L-serine(2-)	smallmolecule	CHEBI:57524	ChEBI	L-serine	chemical	CHEBI:17115	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000142							12213811	t		lperfetto	Human phosphoserine phosphatase (HPSP) regulates the levels of glycine and d-serine, the putative co-agonists for the glycine site of the NMDA receptor in the brain. |Phosphoserine phosphatase (PSP)1 is an important enzyme in the phosphorylated pathway of serine biosynthesis, which contributes a major portion of the endogenous l-serine|he enzymatic reaction of PSP is Mg2+-dependent and results in the dephosphorylation of phospho-l-serine with the formation of a phosphoenzyme intermediate, which is subsequently autodephosphorylated. The resulting product, l-serine, is not only a precursor for the biosynthesis of glycine but also an uncompetitive inhibitor for the enzymatic reaction of PSP	SIGNOR-268569	0.8
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)-4-pyrimidinyl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	chemical	CHEBI:91348	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258294	0.8
TRIM26	protein	Q12899	UNIPROT	IRF3	protein	Q14653	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								25763818	t		miannu	TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus. 	SIGNOR-272440	0.659
ZMYND8	protein	Q9ULU4	UNIPROT	MMP1	protein	P03956	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001033								27477906	t		lperfetto	Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported	SIGNOR-262042	0.2
CASK	protein	O14936	UNIPROT	TBR1	protein	Q16650	UNIPROT	up-regulates	binding			9534	BTO:0000298								10749215	t		miannu	Here we report that, through its guanylate kinase domain, CASK interacts with Tbr-1, a T-box transcription factor that is involved in forebrain development. CASK enters the nucleus and binds to a specific DNA sequence (the T-element) in a complex with Tbr-1. CASK acts as a coactivator of Tbr-1 to induce transcription of T-element containing genes, including reelin, a gene that is essential for cerebrocortical development. 	SIGNOR-266835	0.471
ADORA2B	protein	P29275	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257307	0.252
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3-2	protein	Q5TEC6	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269641	0.2
ITGB1BP1	protein	O14713	UNIPROT	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257643	0.757
RAF1	protein	P04049	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	down-regulates	binding			9606									15618521	t	inferred from 70% of family members	gcesareni	Raf-1 prevents dimerization and phosphorylation of the activation loop of mst2 independently of its protein kinase activity.Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (mst2)	SIGNOR-269942	0.366
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	TNNC2	protein	P02585	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136755	0.349
SIAH1	protein	Q8IUQ4	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	relocalization			9606									20940030	t		gcesareni	The overexpression of siah1 causes the re-localization of notch from the cell surface to the cytoplasm and to the nucleus, which is indicative of notch activation	SIGNOR-168460	0.264
ESR2	protein	Q92731	UNIPROT	SCN10A	protein	Q9Y5Y9	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938	BTO:0001264							22169964	f		miannu	17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice	SIGNOR-253474	0.2
PRKCD	protein	Q05655	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser320	QRSRKRLsQDAYRRN	9606	BTO:0000130								12056906	t		esanto	Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?.	SIGNOR-89229	0.459
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	dephosphorylation			9606									14633703	t		lperfetto	Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells	SIGNOR-264659	0.452
PIK3CA	protein	P42336	UNIPROT	PIP3	smallmolecule	CHEBI:16618	ChEBI	up-regulates quantity	chemical modification			9606									24367090	t	AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring	miannu	Insulin activation of phosphoinositide 3-kinase (pi3k) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (pip3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (pten) blocks pi3k signaling by dephosphorylating pip3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 2	SIGNOR-147948	0.8
STAT3	protein	P40763	UNIPROT	POMC	protein	P01189	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								19049975	t		miannu	We show that phospho-STAT3 activates POMC promoter in response to leptin signaling through a mechanism that requires an SP1-binding site in the POMC promoter. 	SIGNOR-263497	0.625
SP1	protein	P08047	UNIPROT	ITGA11	protein	Q9UKX5	UNIPROT	up-regulates quantity by expression				9606	BTO:0001282								16300938	t		lperfetto	We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors.	SIGNOR-253350	0.2
DRD3	protein	P35462	UNIPROT	GNB5	protein	O14775	UNIPROT	up-regulates activity	binding			9606									21303898	t		miannu	The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC	SIGNOR-264994	0.427
Corticotropin	protein	P01189-PRO_0000024969	UNIPROT	CYP11A1	protein	P05108	UNIPROT	up-regulates quantity				9606									24631756	f		lperfetto	CTH signaling promotes the single steroidogenic rate limiting step, which is the conversion of cholesterol to pregnenolone by Cholesterol Side-Chain Cleavage Enzyme (P450scc), encoded in the CYP11A1 gene. This is conferred by a direct stimulating effect of ACTH on the promoter of CYP11A1 (Chung et al., 1997, Liu and Simpson, 1997, Hu et al., 2001). Further, it stimulates conversion of pregnenolone to 17-hydroxypregnenolone by upregulating the expression of 3β hydroxysteroid dehydrogenase enzyme (3β-HSD)	SIGNOR-268719	0.2
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	RB1	protein	P06400	UNIPROT	down-regulates activity	phosphorylation	Thr356	DSFETQRtPRKSNLD	-1									9139732	t		llicata	In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB.	SIGNOR-250760	0.858
EP400	protein	Q96L91	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269289	0.695
GSK3B	protein	P49841	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	phosphorylation	Ser44	GKSSVLEsLVGRDLL	9606	BTO:0000007								25192600	t		miannu	 We identified glycogen synthase kinase (GSK)3β-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation.	SIGNOR-276848	0.397
RAD21	protein	O60216	UNIPROT	RUNX1	protein	Q01196	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24321385	t		miannu	We observed that depletion of RAD21 (but not CTCF) enhanced RUNX1 transcription in human HL-60 myelocytic leukemia cells	SIGNOR-259973	0.288
2''-O-acetyl-ADP-D-ribose(2-)	smallmolecule	CHEBI:83767	ChEBI	ADP-D-ribose(2-)	smallmolecule	CHEBI:57967	ChEBI	up-regulates quantity	precursor of			9606									32257385	t		miannu	MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins	SIGNOR-269841	0.8
WNT3A	protein	P56704	UNIPROT	Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	up-regulates activity	binding			9606									21078818	t		gcesareni	Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt Beta-catenin signaling.	SIGNOR-253128	0.802
SMCR8	protein	Q8TEV9	UNIPROT	WIPI2	protein	Q9Y4P8	UNIPROT	up-regulates quantity	transcriptional regulation			9606	BTO:0000007								28169830	t			Global mRNA expression analysis revealed that SMCR8 regulates transcription of several other autophagy genes including WIPI2	SIGNOR-252028	0.275
SPI1	protein	P17947	UNIPROT	SPI1	protein	P17947	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15767686	f		irozzo	These data suggest that a potential positive autoregulatory loop mediated through an upstream regulatory element is essential for proper PU.1 gene expression.These data demonstrate that PU.1 protein is in a complex binding to a site within the kb −14 URE, suggesting that autoregulation through this region might be important for expression of PU.1.	SIGNOR-256070	0.2
GATOR1	complex	SIGNOR-C192	SIGNOR	RRAGB	protein	Q5VZM2	UNIPROT	down-regulates activity	gtpase-activating protein			-1									23723238	t			GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer.	SIGNOR-253563	0.732
CDK1	protein	P06493	UNIPROT	ANAPC1	protein	Q9H1A4	UNIPROT	up-regulates	phosphorylation	Ser355	AALSRAHsPALGVHS	9606									14657031	t		lperfetto	Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation	SIGNOR-119705	0.574
CHEK2	protein	O96017	UNIPROT	PML	protein	P29590	UNIPROT	unknown	phosphorylation	Ser117	ESLQRRLsVYRQIVD	9606									12402044	t		llicata	Hcds1/chk2 phosphorylates pml at ser 117 in vitro. hcds1/chk2 phosphorylates pml in vivo.	SIGNOR-94872	0.407
afatinib	chemical	CHEBI:61390	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150								22418700	t		gcesareni	Afatinib is an oral, erbb family blocker, which covalently binds and irreversibly blocks all kinase-competent erbb family members.	SIGNOR-196621	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CIC	protein	Q96RK0	UNIPROT	down-regulates	phosphorylation	Ser1409	SAPEDPTsPKRKMRR	9606	BTO:0000848								21087211	t		lperfetto	Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3	SIGNOR-244630	0.2
IGF1R	protein	P08069	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates activity	phosphorylation	Tyr1161	FGMTRDIyETDYYRK	-1									8940173	t		miannu	The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.	SIGNOR-246248	0.2
KRT14	protein	P02533	UNIPROT	TRADD	protein	Q15628	UNIPROT	down-regulates activity	binding			9606									11684708	t	Regulation of binding	miannu	 TRADD specifically bound K18 and K14, type I (acidic) keratins. it is possible that epidermal K14 may function as an inhibitor of TNF–TNFR1 signaling through an association with TRADD.	SIGNOR-251907	0.353
Laminin-1	complex	SIGNOR-C183	SIGNOR	A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	up-regulates activity	binding												12123670	t		lperfetto	We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1.	SIGNOR-253221	0.537
KCNMA1	protein	Q12791	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			9606	BTO:0000938								31152168	t		miannu	The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. 	SIGNOR-269191	0.8
CHRM2	protein	P08172	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256685	0.49
AKT1	protein	P31749	UNIPROT	TBC1D4	protein	O60343	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000887							12637568	t		gcesareni	Recently, we identified a 160-kda protein in adipocytes, designated as160, that is phosphorylated by the insulin-activated kinase akt	SIGNOR-252594	0.756
SMAD2	protein	Q15796	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates activity	binding			9606					phosphorylation:Ser465;Ser467	SPSVRCSsMS;SVRCSSMs			11274206	t		gcesareni	the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4	SIGNOR-235183	0.708
FGF2	protein	P09038	UNIPROT	FGFR3	protein	P22607	UNIPROT	up-regulates	binding			9606									15780951	t		gcesareni	Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts.	SIGNOR-134788	0.813
TFAP2A	protein	P05549	UNIPROT	ECM1	protein	Q16610	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17187826	f	 	miannu	 Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. 	SIGNOR-255401	0.2
MYC	protein	P01106	UNIPROT	HLA-G	protein	P17693	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000848								8206526	f		miannu	 In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene.	SIGNOR-254607	0.263
ATF4	protein	P18848	UNIPROT	CARS2	protein	Q9HA77	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269417	0.26
CDK3	protein	Q00526	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr2511	VPEHPFLtPSPESPD	-1									25344755	t		lperfetto	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273167	0.245
CASP4	protein	P49662	UNIPROT	GSDMD	protein	P57764	UNIPROT	up-regulates activity	cleavage	Asp275	CLHNFLTdGVPAEGA	9606	BTO:0000007								26375003	t		lperfetto	 Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence |	SIGNOR-256417	0.636
ABI1	protein	Q8IZP0	UNIPROT	ABL1	protein	P00519	UNIPROT	up-regulates	binding			9606									9010225	t		gcesareni	Our results are in agreement with previous report showing that abi-1, the putative mouse homologue of e3b1, is a abl binding protein	SIGNOR-45994	0.876
CSNK1E	protein	P49674	UNIPROT	CSNK1E	protein	P49674	UNIPROT	down-regulates activity	phosphorylation	Thr337	PGPPTGAtANRLRSA	9606	BTO:0000007								10542239	t		llicata	Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T	SIGNOR-250813	0.2
DTX1	protein	Q86Y01	UNIPROT	ASCL1	protein	P50553	UNIPROT	down-regulates	binding			9606									11564735	t		gcesareni	Through its binding to p300, dtx1 inhibited transcriptional activation by the neural-specific helix-loop-helix-type transcription factor mash1	SIGNOR-110626	0.265
PRKCE	protein	Q02156	UNIPROT	TRPV1	protein	Q8NER1	UNIPROT	up-regulates activity	phosphorylation	Thr705	WKLQRAItILDTEKS	9534	BTO:0000298								14523239	t		lperfetto	We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. 	SIGNOR-249235	0.2
CDK12	protein	Q9NYV4	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1931	SPTSPTYsPTSPKGS	9606									22012619	t		miannu	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176833	0.775
SGX-523	chemical	CHEBI:90624	ChEBI	MET	protein	P08581	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258282	0.8
CALM2	protein	P0DP24	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	binding			9606	BTO:0001853								24379783	t		miannu	Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer	SIGNOR-266323	0.518
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	Glu-tRNA(Glu)	smallmolecule	CHEBI:29157	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270386	0.8
GSK3B	protein	P49841	UNIPROT	EIF2B2	protein	P49770	UNIPROT	down-regulates	binding			9606									21798082	t		gcesareni	Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b).	SIGNOR-175475	0.2
CSNK2A2	protein	P19784	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Ser370	TSVTPDVsDNEPDHY	-1									12297295	t		llicata	We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366). 	SIGNOR-251025	0.693
PAK3	protein	O75914	UNIPROT	PAK3	protein	O75914	UNIPROT	up-regulates activity	phosphorylation	Ser154	VNNQKYMsFTSGDKS	-1									11278486	t		miannu	Both in vivo and in vitro analyses demonstrate that, although most phosphorylation events in the PAK N-terminal regulatory domain play no direct role in activation, a phosphorylation of alphaPAK serine 144 or betaPAK serine 139, which lie in the kinase inhibitory domain, significantly contribute to activation. 	SIGNOR-250245	0.2
SKIL	protein	P12757	UNIPROT	SMAD2/SMAD4	complex	SIGNOR-C8	SIGNOR	down-regulates activity	binding			9606	BTO:0000848								12793438	t		lperfetto	The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway	SIGNOR-253302	0.837
AKT1	protein	P31749	UNIPROT	STK3	protein	Q13188	UNIPROT	down-regulates	phosphorylation	Thr384	GTMKRNAtSPQVQRP	9606									20086174	t		llicata	We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2.	SIGNOR-163537	0.363
mTORC1	complex	SIGNOR-C3	SIGNOR	BTRC	protein	Q9Y297	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0002572								33861966	t		miannu	 mTORC1 regulates the stability of CREB2. Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). 	SIGNOR-267829	0.291
AGRP	protein	O00253	UNIPROT	MC4R	protein	P32245	UNIPROT	down-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268709	0.767
EFNA1	protein	P20827	UNIPROT	EPHA2	protein	P29317	UNIPROT	up-regulates	binding			9606									9330863	t		tpavlidou	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-51939	0.935
SLBP	protein	Q14493	UNIPROT	H2AB2	protein	P0C5Z0	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265407	0.2
DYRK1A	protein	Q13627	UNIPROT	DYRK1A	protein	Q13627	UNIPROT	up-regulates activity	phosphorylation	Tyr321	LGQRIYQyIQSRFYR	9606	BTO:0000298								11672423	t		lperfetto	Direct identification of phosphorylated residues by tandem ms confirmed that tyr-321, but not tyr-319, was phosphorylated. When expressed in cos-7 cells, dyrk1a was found to be fully phosphorylated on tyr-321. A catalytically inactive mutant of dyrk1a contained no detectable phosphotyrosine, indicating that tyr-321 is autophosphorylated by dyrk1a.	SIGNOR-111145	0.2
NBN	protein	O60934	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates	binding			9606									15758953	t		gcesareni	Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm	SIGNOR-134508	0.852
ALK	protein	Q9UM73	UNIPROT	ATIC	protein	P31939	UNIPROT	up-regulates activity	phosphorylation	Tyr104	RVVACNLyPFVKTVA	9606	BTO:0002181								18845790	t		miannu	ATIC and VASP phosphorylation is dependent on NPM-ALK kinase activity. ATIC activity is enhanced in the presence of NPM-ALK in vitro.The ATIC activity is enhanced by NPM-ALK in HEK-293T-Rex cells. 	SIGNOR-276171	0.387
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ELK1	protein	P19419	UNIPROT	up-regulates activity	phosphorylation			9606									23616010	t		lperfetto	Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1.	SIGNOR-233520	0.2
D-ribulose 5-phosphate	smallmolecule	CHEBI:17363	ChEBI	D-xylulose 5-phosphate(2-)	smallmolecule	CHEBI:57737	ChEBI	up-regulates quantity	precursor of			9606									34775382	t		miannu	The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux.	SIGNOR-267063	0.8
INSR	protein	P06213	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	phosphorylation	Tyr368	STKMHGDyTLTLRKG	9534									8385099	t			The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor.	SIGNOR-252692	0.601
MVD	protein	P53602	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	lipidation			10090									25378391	t		miannu	Akt modulated the pathway by phosphorylating mevalonate diphosphate decarboxylase (MDD) at Ser96. These data suggest that Akt regulates Rac1 activity by directly phosphorylating MDD at Ser96, which augments Rac1 geranylgeranylation. 	SIGNOR-265892	0.2
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Gln)	smallmolecule	CHEBI:29168	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269485	0.8
9,11-Methanoepoxy PGH2	chemical	CID:5311493	PUBCHEM	TBXA2R	protein	P21731	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257589	0.8
GSK3B	protein	P49841	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser211	SSVKLRGsSLFMDTE	-1									24817118	t		miannu	Serine 211 phosphorylation occurred under control conditions in the absence of CK1δ and in the presence of GSK3-β (Fig. 5, D and E). 	SIGNOR-276632	0.335
ABL1	protein	P00519	UNIPROT	PRKD1	protein	Q15139	UNIPROT	unknown	phosphorylation	Tyr432	KEGWMVHyTSKDTLR	9606	BTO:0000567								12637538	t		gcesareni	Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. [..] Mutation of the other two sites, Tyr432 and Tyr502, had no significant influence on PKD activity.	SIGNOR-246211	0.345
NEDD4L	protein	Q96PU5	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	ubiquitination			9606									19917253	t		lperfetto	Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation	SIGNOR-217622	0.771
PTPRA	protein	P18433	UNIPROT	PTPRA	protein	P18433	UNIPROT	down-regulates activity	dephosphorylation	Tyr798	YIDAFSDyANFK	9606									7518772	t			Transient overexpression of c-Src together with RPTP alpha in human embryonic kidney 293 cells increased phosphorylation of Tyr789, suggesting that c-Src may phosphorylate RPTP alpha in vivo. RPTP alpha had autodephosphorylation activity in vitro. When expressed in 293 cells the level of Tyr789 phosphorylation was higher in a non-functional mutant of RPTP alpha than in wild type RPTP alpha, indicating that RPTP alpha may have autodephosphorylation activity in vivo as well.|We show that RPTP alpha, but not a mutant of RPTP alpha with a Tyr-->Phe mutation at position 789, bound to GRB2 in vitro.	SIGNOR-248439	0.2
MAPK8	protein	P45983	UNIPROT	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates activity	phosphorylation	Ser73	VGLLKLAsPELERLI	9534	BTO:0000298								8137421	t		miannu	JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain.	SIGNOR-252355	0.811
ELANE	protein	P08246	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates activity	cleavage	Val72	GLTEYRLvSINKSSP	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263567	0.441
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1672	SPTSPSYsPTSPSYS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248751	0.727
ATM	protein	Q13315	UNIPROT	LARP7	protein	Q4G0J3	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr440	ANREECRtQEKVNAT										32726637	t		lperfetto	Altogether, the results suggest that ATM-mediated T440 phosphorylation enhances LARP7-BARD1 interaction and facilitates BRCA1/BARD1-mediated LARP7 ubiquitination and degradation.	SIGNOR-275580	0.2
PRSS2	protein	P07478	UNIPROT	F2RL1	protein	P55085	UNIPROT	up-regulates activity	cleavage	Arg36	TNRSSKGrSLIGKVD	-1									10978167	t		lperfetto	Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3. 	SIGNOR-263603	0.2
SRC	protein	P12931	UNIPROT	GIT1	protein	Q9Y2X7	UNIPROT	up-regulates activity	phosphorylation	Tyr246	PDHKNGHyIIPQMAD	9534	BTO:0000298								24699139	t		miannu	Tyrosines 246 and 293 are required to hold GIT1 in a closed conformation.Hyperphosphorylation of GIT1-N by Src and pervanadate does not affect its binding in vitro to full length GIT1 proteins. Mutations Y246E and Y293E of GIT1 enhance binding to paxillin. 	SIGNOR-276626	0.559
GNB1	protein	P62873	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates				9606									23074268	f		gcesareni	Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance.	SIGNOR-199129	0.382
STK16	protein	O75716	UNIPROT	STK16	protein	O75716	UNIPROT	unknown	phosphorylation	Ser197	AAQRCTIsYRAPELF	-1									18184589	t		Manara	Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition.	SIGNOR-260804	0.2
RAD50	protein	Q92878	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates	binding			9606									18854157	t		gcesareni	One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase.	SIGNOR-181634	0.806
EGFL7	protein	Q9UHF1	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	up-regulates				9606									20372059	f		miannu	EGFL7 drives the formation of neurons from neural stem cells. In the embryonic and adult brain this process is essential for neurogenesis and homeostasis of the nervous system. In this review, we discuss the implications of our findings for adult neurogenesis and illustrate the potential of EGFL7 to serve as an agent to increase neurogenesis and the self-renewal potential of the brain	SIGNOR-266859	0.7
PLK1	protein	P53350	UNIPROT	SUN1	protein	O94901	UNIPROT	down-regulates activity	phosphorylation	Ser138	RPPVLDEsWIREQTT	9606									25482198	t		miannu	Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions. 	SIGNOR-263098	0.466
EZH2	protein	Q15910	UNIPROT	Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	form complex	binding			9606									23110252	t		lperfetto	The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48).	SIGNOR-241894	0.911
MAPK8	protein	P45983	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	up-regulates	phosphorylation	Thr530	YLSELPPtPLHVSED	9606									20027304	t	This phosphorylation increased sirt1 nuclear localization	gcesareni	Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53.	SIGNOR-162322	0.621
CCL3	protein	P10147	UNIPROT	CCR5	protein	P51681	UNIPROT	up-regulates activity	binding			10090									15075201	t		lperfetto	The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days. 	SIGNOR-251724	0.739
MIF	protein	P14174	UNIPROT	CD74	protein	P04233	UNIPROT	up-regulates activity	binding			9606									12782713	t		gcesareni	MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal-regulated kinase-1/2 MAP kinase cascade, cell proliferation, and PGE2 production	SIGNOR-252060	0.725
CBFbeta-MYH11	fusion protein	SIGNOR-FP3	SIGNOR	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	down-regulates				9606									29958106	f		miannu	In adult hematopoiesis, allelic CBFβ-SMMHC expression alters hematopoietic stem cell (HSC) differentiation, with clonal expansion of the short-term HSCs and pre-leukemic myeloid progenitor cells 	SIGNOR-255736	0.7
TLN1	protein	Q9Y490	UNIPROT	Av/b8 integrin	complex	SIGNOR-C185	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257637	0.515
GRPR	protein	P30550	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257314	0.252
TNFRSF1B	protein	P20333	UNIPROT	TRAF2	protein	Q12933	UNIPROT	up-regulates activity	binding			9606									8069916	t		lperfetto	Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly.	SIGNOR-34645	0.697
SLBP	protein	Q14493	UNIPROT	H3C15	protein	Q71DI3	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265414	0.2
RBM10	protein	P98175	UNIPROT	CASP3	protein	P42574	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30403180	f		irozzo	In this study, we report that RBM10 acts as a tumor suppressor in osteosarcoma via the inhibition of cell growth, cell migration and invasion and the induction of cell apoptosis by inhibiting Bcl-2, activating caspase-3, and producing TNF-α. We also found that RBM10 overexpression significantly inhibited the expression of Bcl-2 and induced the expression of caspase-3 	SIGNOR-259152	0.2
sunitinib	chemical	CHEBI:38940	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			9606									20570526	t		Luana	Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors],	SIGNOR-257849	0.8
EXOC2	protein	Q96KP1	UNIPROT	Exocyst_EXOC6 variant	complex	SIGNOR-C492	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270785	0.96
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Ser639	DEICIAGsPLTPRRV	9606									11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130.	SIGNOR-104679	0.843
LATS2	protein	Q9NRM7	UNIPROT	PRPS2	protein	P11908	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr285	EDKMKHCtKIQVIDI	-1									34465890	t		miannu	 Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness.	SIGNOR-276507	0.2
TNF	protein	P01375	UNIPROT	SCN10A	protein	Q9Y5Y9	UNIPROT	up-regulates activity				10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253493	0.28
MRPL33	protein	O75394	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262364	0.683
CBFB	protein	Q13951	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates quantity by stabilization	binding			10090									11179217	t		irozzo	We observed previously that the RUNX proteins are susceptible to proteolytic degradation (Ogawa et al., 1993b). In this study, we show that the ubiquitin‚proteasome system is largely responsible for this degradation. We also show that when PEBP2Œ≤ dimerizes with RUNX it inhibits the ubiquitylation of RUNX, which is necessary for the protein to be targeted for proteolysis by the proteasome.	SIGNOR-255712	0.841
SGK1	protein	O00141	UNIPROT	NDRG2	protein	Q9UN36	UNIPROT	up-regulates	phosphorylation	Thr348	GNRSRSRtLSQSSES	9606	BTO:0000567	BTO:0000887;BTO:0001103;BTO:0000763							15461589	t		llicata	Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344	SIGNOR-129680	0.405
TP53	protein	P04637	UNIPROT	DRAM2	protein	Q6UX65	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30755245	f		irozzo	DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression.	SIGNOR-259148	0.312
creatine	smallmolecule	CHEBI:16919	ChEBI	CKMT2	protein	P17540	UNIPROT	up-regulates activity	chemical activation			9606									18502307	t		miannu	Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 	SIGNOR-265785	0.8
SNRPB	protein	P14678	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270628	0.771
ADORA2A	protein	P29274	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256909	0.321
4-trimethylammoniobutanal	smallmolecule	CHEBI:18020	ChEBI	4-(trimethylammonio)butanoate	smallmolecule	CHEBI:16244	ChEBI	up-regulates quantity	precursor of			9606									11802770	t		miannu	Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). 	SIGNOR-269696	0.8
P300/PCAF	complex	SIGNOR-C7	SIGNOR	SMAD3	protein	P84022	UNIPROT	up-regulates	binding			9606	BTO:0000150								15009097	t		lperfetto	Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo.	SIGNOR-217233	0.676
CDK2	protein	P24941	UNIPROT	CDKN2D	protein	P55273	UNIPROT	up-regulates	phosphorylation	Thr141	RRDARGLtPLELALQ	9606									22558186	t		lperfetto	Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively.we propose a sequential phosphorylation model for p19 in which modification at s76 would enable a second phosphorylation event at t141. The phosphorylation-induced structural changes could have functional implicancies for p19 in the dna damage response	SIGNOR-197274	0.529
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	XRCC4	protein	Q13426	UNIPROT	up-regulates activity	ubiquitination	Lys296	QENQLQEkENSRPDS	9606	BTO:0002137								26774286	t		miannu	In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair. 	SIGNOR-277200	0.307
SRC	protein	P12931	UNIPROT	DAB1	protein	O75553	UNIPROT	up-regulates activity	phosphorylation	Tyr220	PETEENIyQVPTSQK	10090									11279201	t		lperfetto	Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons.	SIGNOR-247080	0.43
NFKBIA	protein	P25963	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	binding			9606				SIGNOR-C13					1340770	t		lperfetto	Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b.	SIGNOR-17691	0.887
NCR2	protein	O95944	UNIPROT	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates				9606	BTO:0000914								22021614	f		miannu	NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown. Proliferating cell nuclear Ag (PCNA) is overexpressed in cancer cells. In this study, we show that the NKp44 receptor recognizes PCNA. Their interaction inhibits NK cell function through NKp44/ITIM. 	SIGNOR-260044	0.7
ADRA1D	protein	P25100	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256951	0.281
NDN	protein	Q99608	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates quantity by stabilization	binding			9606									26971449	t		lperfetto	Necdin binds and stabilizes PGC-1α|Necdin strongly stabilizes PGC-1α by inhibiting its ubiquitin-dependent degradation. Forced expression of necdin enhances mitochondrial function in primary cortical neurons and human SH-SY5Y neuroblastoma cells to prevent mitochondrial respiratory chain inhibitor-induced degeneration.	SIGNOR-253390	0.331
STRADA	protein	Q7RTN6	UNIPROT	STK11	protein	Q15831	UNIPROT	up-regulates activity	binding			9606									12805220	t		Gianni	Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419	SIGNOR-247560	0.938
APOA1	protein	P02647	UNIPROT	HDL_assembly	phenotype	SIGNOR-PH61	SIGNOR	up-regulates				9606									23077142	f		miannu	Cholesterol efflux is the first step in the formation of HDL, which is initiated through the action of ATP binding cassette transporter (ABC) A1 on apolipoprotein (apo) A-I that produces nascent HDL (nHDL).	SIGNOR-252110	0.7
HERC5	protein	Q9UII4	UNIPROT	NME2	protein	P22392	UNIPROT	up-regulates quantity by stabilization	ubiquitination			9606	BTO:0000007								18535780	t		miannu	HERC5 is required for ubiquitination of Nm23B. In summary, Nm23B ubiquitination is mediated by HERC5. Stable Nm23B protein in presence of HERC5 as well as proteasome-independent ubiquitination suggest that ubiquitination of Nm23B serves a different purpose than marking it for degradation.	SIGNOR-271778	0.311
PRKAA1	protein	Q13131	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation			6239			SIGNOR-C15						17900900	t		lperfetto	The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt.	SIGNOR-252983	0.509
XRCC4	protein	Q13426	UNIPROT	DNA-PK	complex	SIGNOR-C107	SIGNOR	up-regulates activity	binding			9606	BTO:0002137								26774286	t		miannu	In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair. 	SIGNOR-277201	0.816
MAP3K4	protein	Q9Y6R4	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								9841871	t		lperfetto	When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro.	SIGNOR-62369	0.549
MAPK3	protein	P27361	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates	phosphorylation			9606									19864431	t		lperfetto	Here we focus primarily although not exclusively on raptor Ser(863) phosphorylation. We report that insulin promotes mTORC1-associated phosphorylation of raptor Ser(863) via the canonical PI3K/TSC/Rheb pathway in a rapamycin-sensitive manner. mTORC1 activation by other stimuli (e.g. amino acids, epidermal growth factor/MAPK signaling, and cellular energy) also promote raptor Ser(863) phosphorylation.	SIGNOR-217559	0.393
CSNK1E	protein	P49674	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates	phosphorylation	Thr41	YSTTPGGtLFSTTPG	9606	BTO:0000150								24247720	t		lperfetto	Mechanistic investigations showed that ck1_ interacted with and phosphorylated 4e-bp1 at two novel sites t41 and t50, which were essential for 4e-bp1 inactivation along with increased mrna translation and cell proliferation.	SIGNOR-203240	0.2
CDC14B	protein	O60729	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates	dephosphorylation	Ser684	IGIPQFHsPVGSPLK	9606									20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis.	SIGNOR-164471	0.552
KDM2B	protein	Q8NHM5	UNIPROT	RNF2	protein	Q99496	UNIPROT	up-regulates activity	binding			9606									17296600	t		miannu	BcoR and Fbxl10/Jhdm1B are among the most abundant Ring1B/Rnf2 interactors identified with the highest confidence, and their association has been validated by coimmunoprecipitation studies; hence we call this the Fbxl10-BcoR complex. The assembly of Fbxl10-BcoR complex(es), the associations among its various subunits, and its functional significance remain to be characterized but are presently under investigation.	SIGNOR-252242	0.628
VTI1A	protein	Q96AJ9	UNIPROT	LE-TGN SNARE	complex	SIGNOR-C157	SIGNOR	form complex	binding			9606	BTO:0000567								18195106	t		lperfetto	We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport	SIGNOR-253081	0.804
EFNA5	protein	P52803	UNIPROT	EPHA5	protein	P54756	UNIPROT	up-regulates	binding			9606									9330863	t		tpavlidou	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52476	0.893
PRKACB	protein	P22694	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									10949026	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136.	SIGNOR-81141	0.403
ABL1	protein	P00519	UNIPROT	KAT5	protein	Q92993	UNIPROT	down-regulates activity	phosphorylation	Tyr294	HPPGNEIyRKGTISF	9606	BTO:0000007								24044023	t		miannu	We present evidence that Tip60 is modified on tyrosine 327 by Abl kinase. We show that this causes functional changes in HAT activity and the subcellular localization of TIP60, which forms a complex with Abl kinase. The Tip60 mutation Y327F abolished tyrosine phosphorylation, reduced the inhibition of Tip60 HAT activity, and caused G0-G1 arrest and association with FE65. 	SIGNOR-276598	0.633
AP2M1	protein	Q96CW1	UNIPROT	SLC24A2	protein	Q9UI40	UNIPROT	down-regulates quantity	binding			9606	BTO:0000938			SIGNOR-C245					23431067	t		miannu	 we report that the first tyrosine motif of NCKX2 interacts with AP2M1 and that the interaction is required for endocytosis of NCKX2 from the dendritic surface. Furthermore, we show that a Src family kinase (SFK) modulates the endocytosis of NCKX2 by tyrosine-phosphorylation of the AP-2 recognition motif in NCKX2.	SIGNOR-264388	0.2
AGPAT4	protein	Q9NRZ5	UNIPROT	phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	up-regulates	chemical modification			9606									21173190	t		lperfetto	The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA). 	SIGNOR-267014	0.8
docetaxel anhydrous	chemical	CHEBI:4672	ChEBI	TUBB1	protein	Q9H4B7	UNIPROT	down-regulates activity	chemical inhibition			9606									23337758	t		miannu	Tubulin exists in the cell as dimers of α and β subunits, which complexes with a variety of regulatory proteins. There is a dynamic equilibrium between free and polymerized tubulin causing a state called "dynamic instability," which is a target of anticancer drugs, which inhibit tubulin through polymerization (taxanes, epothilones) or depolymerization (vinca alkaloids). Docetaxel-based therapy was the first such treatment to demonstrate a survival benefit in men with castration-resistant prostate cancer. 	SIGNOR-259343	0.8
DNM1L	protein	O00429	UNIPROT	Mitochondrial_fission	phenotype	SIGNOR-PH143	SIGNOR	up-regulates				10090	BTO:0002295								31063459	f		lperfetto	Mitochondrial fission is governed primarily by the cytoplasmic dynamin-related protein 1 (Drp1). Drp1 is a conserved dynamin GTPase superfamily protein that is translocated from its cytoplasmic pool to the outer mitochondrial membrane, where Drp1 then assembles into constrictive ring-like multimeric structures, ultimately driving mitochondrial fragmentation through a GTP-dependent mechanism|We have also previously reported that ROCK1-mediated Drp1S600 phosphorylation resulted in enhanced mitochondrial fission in podocytes	SIGNOR-262553	0.7
5'-xanthylic acid	smallmolecule	CHEBI:15652	ChEBI	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	precursor of			9606									6698284	t		miannu	The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2).	SIGNOR-268095	0.8
OXSR1	protein	O95747	UNIPROT	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation	Ser130	GPKVNRPsLLEIHEQ	9606	BTO:0000007								21321328	t		miannu	 We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A).	SIGNOR-276309	0.517
AP-2 complex	complex	SIGNOR-C245	SIGNOR	Endocytosis	phenotype	SIGNOR-PH123	SIGNOR	up-regulates				10116	BTO:0000142								15496985	f		lperfetto	Intersectins 1 and 2, epsin2, NECAP and sorting nexin9 were identified as α‐appendage ligands in mass spectrometry of these samples	SIGNOR-260416	0.7
SOD2	protein	P04179	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	down-regulates quantity	chemical modification			9606									29301787	t		lperfetto	Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD).	SIGNOR-272281	0.8
ITGB7	protein	P26010	UNIPROT	A4/b7 integrin	complex	SIGNOR-C187	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253294	0.852
PTPRZ1	protein	P23471	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	dephosphorylation			9606									23100427	t		miannu	PTPRZ1 constitutively promotes the tyrosine dephosphorylation of \u03b2-catenin, and thus \u03b2-catenin participation in TCF-mediated transcription.	SIGNOR-277044	0.386
CSRP3	protein	P50461	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity	binding			10090	BTO:0004058								9234731	t	2	miannu	we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements.	SIGNOR-241116	0.48
SIK3	protein	Q9Y2K2	UNIPROT	CRTC2	protein	Q53ET0	UNIPROT	down-regulates activity	phosphorylation	Ser70	RSSHYGGsLPNVNQI	9606	BTO:0000567								16306228	t		lperfetto	We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression 	SIGNOR-249171	0.62
MAPK8	protein	P45983	UNIPROT	ATN1	protein	P54259	UNIPROT	down-regulates activity	phosphorylation	Ser739	EEYETPEsPVPPARS	9606		BTO:0000142							12812981	t		lperfetto	Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment,	SIGNOR-102398	0.386
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CCL2	protein	P13500	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001103							20219869	f		apalma	Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6.	SIGNOR-255356	0.567
MAP4K3	protein	Q8IVH8	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates	phosphorylation			9606									9820741	t		gcesareni	With regard to at least mekk1, serine/threonine kinases such as nik,glkand hpk1 appear also to be important for regulation	SIGNOR-61814	0.429
INSR	protein	P06213	UNIPROT	DOK1	protein	Q99704	UNIPROT	up-regulates activity	phosphorylation	Tyr398	ARVKEEGyELPYNPA	10029	BTO:0000246								11551902	t			Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398. p62(dok) is a direct substrate for the IR tyrosine kinase and that phosphorylation at Tyr(362) and Tyr(398) plays an essential role for p62(dok) to interact with its effectors and negatively regulate the insulin signaling pathway.	SIGNOR-251308	0.542
WT1	protein	P19544	UNIPROT	Urogenital_tract	phenotype	SIGNOR-PH71	SIGNOR	up-regulates activity				10090									10101119	f			The Wilms' Tumour gene WT1 has important functions during development. Knock-out mice were shown to have defects in the urogenital system and to die at embryonic day E13.5, probably due to heart failure.	SIGNOR-252302	0.7
MTOR	protein	P42345	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates	phosphorylation	Ser422	AEAFLGFsYAPPTDS	9606			SIGNOR-C3						18570873	t		llicata	Mtor phosphorylated sgk1, but not sgk1-s422a, in vitro. Sgk1 phosphorylated p27 in vitro. These data implicate sgk1 as an mtorc1 (mtor-raptor) substrate. mtor may promote g1 progression in part through sgk1 activation	SIGNOR-179113	0.844
TWIST1	protein	Q15672	UNIPROT	AKR1C2	protein	P52895	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255510	0.2
ITCH	protein	Q96J02	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	ubiquitination			9606		BTO:0001253							10940313	t		gcesareni	Itch binds to the n-terminal portion of the notch intracellular domain via its ww domains and promotes ubiquitination of notch through its hect ubiquitin ligase domain.	SIGNOR-80702	0.629
GFs	stimulus	SIGNOR-ST12	SIGNOR	RTKs	proteinfamily	SIGNOR-PF38	SIGNOR	up-regulates				9606									17306385	t		miannu	Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate.	SIGNOR-256169	0.7
NFATC4	protein	Q14934	UNIPROT	PTGS2	protein	P35354	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21871017	t		miannu	 NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration	SIGNOR-264027	0.286
NR3C1	protein	P04150	UNIPROT	TIMELESS	protein	Q9UNS1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19805059	t		miannu	GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription	SIGNOR-268052	0.255
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1910	TPTSPKYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273081	0.636
MYT1L	protein	Q9UL68	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0005949								30312684	t		miannu	Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression. Examination of the gene expression changes in cells expressing Myt1 or Myt1l suggests that both repress expression of the YAP1 transcriptional coactivator, which functions primarily in the Hippo signaling pathway. Expression of YAP1 and its target genes is reduced in Myt-expressing cells, and there is an inverse correlation between YAP1 and MYT1/MYT1L expression in human brain cancer datasets. Together, our data suggest that Myt1 and Myt1l directly repress expression of YAP1, a protein which promotes proliferation and GBM growth.	SIGNOR-266778	0.2
Cell_cycle_exit	phenotype	SIGNOR-PH41	SIGNOR	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates				10090									9388774	f		gcesareni	Myogenic precursor cells withdraw irreversibly from the cell cycle as they differentiate into mature myotubes. Cell cycle exit occurs early during the differentiation program and is required for normal expression of the contractile phenotype.	SIGNOR-243206	0.7
ammonium	smallmolecule	CHEBI:28938	ChEBI	L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	up-regulates quantity	precursor of			9606									30158707	t		miannu	Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction.	SIGNOR-267823	0.8
MS4A2	protein	Q01362	UNIPROT	FCER1	complex	SIGNOR-C200	SIGNOR	form complex	binding			9606	BTO:0000830								16470226	t		Alessandro Palma	FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling.	SIGNOR-254960	0.668
AMPK	complex	SIGNOR-C15	SIGNOR	ZNF692	protein	Q9BU19	UNIPROT	down-regulates	phosphorylation	Ser470	VAAHRSKsHPALLLA	9606									17097062	t		lperfetto	Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp.	SIGNOR-216519	0.2
PRKAA1	protein	Q13131	UNIPROT	MCU	protein	Q8NE86	UNIPROT	up-regulates activity	phosphorylation	Ser57	TVHQRIAsWQNLGAV	-1									30858581	t		lperfetto	Cellular ATP levels drop during early mitosis, and the mitochondrial Ca2+ transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). |In vitro kinase assays showed that AMPK immunoprecipitated from cells as well as recombinant AMPK phosphorylated MCU at Ser57	SIGNOR-275547	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									14625384	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-252806	0.2
PRKAA1	protein	Q13131	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Ser555	RALSNSVsNMGLSES	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-252977	0.509
MC1R	protein	Q01726	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256956	0.353
SRC	protein	P12931	UNIPROT	BTK	protein	Q06187	UNIPROT	up-regulates activity	phosphorylation	Tyr551	RYVLDDEyTSSVGSK	9606									8629002	t			This interaction of BTK with SRC kinases transphosphorylated BTK on tyrosine at residue 551, which led to BTK activation.	SIGNOR-251100	0.508
MAG	protein	P20916	UNIPROT	Myelination	phenotype	SIGNOR-PH206	SIGNOR	up-regulates													17241126	f		SimoneGraziosi	The myelin-associated glycoprotein (MAG) is a type I transmembrane glycoprotein localized in periaxonal Schwann cell and oligodendroglial membranes of myelin sheaths where it functions in glia-axon interactions.	SIGNOR-269231	0.7
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2B	protein	P63146	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271368	0.651
GALR3	protein	O60755	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257114	0.252
HES1	protein	Q14469	UNIPROT	RBPJ	protein	Q06330	UNIPROT	down-regulates	binding			9606									16682003	t		gcesareni	Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression.	SIGNOR-146684	0.584
CSNK2A1	protein	P68400	UNIPROT	DAXX	protein	Q9UER7	UNIPROT	up-regulates	phosphorylation	Ser737	PEEIIVLsDSD	9606									21474068	t		lperfetto	Daxx-sim is phosphorylated by ck2 kinase at residues s737 and s739. Phosphorylation promotes daxx-sim binding affinity toward sumo-1 over sumo-2/3, causing daxx preference for sumo-1 conjugation and interaction with sumo-1-modified factors.	SIGNOR-173105	0.332
CRX	protein	O43186	UNIPROT	RBP3	protein	P10745	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10354480	f		miannu	OTX2, as well as CRX, a homeodomain protein very similar to OTX2, activates the human IRBP promoter in co-transfection experiments.	SIGNOR-254890	0.39
CDK1	protein	P06493	UNIPROT	KAT5	protein	Q92993	UNIPROT	up-regulates	phosphorylation	Ser90	LPGSRPGsPEREVPA	9606									16103124	t		lperfetto	Moreover, app stabilized tip60 through cdk-dependent phosphorylation	SIGNOR-139653	0.491
GATA3	protein	P23771	UNIPROT	TBX21	protein	Q9UL17	UNIPROT	down-regulates				9606									16386358	f			Conversely, T-bet is capable of inhibiting GATA-3 (Szabo et al., 2000). The mutual inhibition between GATA-3 and T-bet ensures that Th1 and Th2 cells express one or the other molecule (T-bet in Th1, and GATA-3 in Th2), but not both	SIGNOR-254296	0.753
SPEN	protein	Q96T58	UNIPROT	RBPJ	protein	Q06330	UNIPROT	down-regulates	binding			9606									12374742	t		gcesareni	We identified sharp as an rbp-jkappa/cbf-1-interacting corepressor in a yeast two-hybrid screen.	SIGNOR-94201	0.691
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	HEY1	protein	Q9Y5J3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165;BTO:0001593								15207708	f		gcesareni	Deltex, meltrin beta, ifi-202, and ifi-204 were also upregulated by notchic in the 2b4.11 t cell hybridoma, whereas ifi-d3 was expressed constitutively at relatively high levels and slightly upregulated by notchic, and pre-talfa was not expressed. Deltex, meltrin beta, pre-talfa, ifi-202, and ifi-204 were upregulated by notchic expression in the akr1 dp thymoma cell line, whereas ifi-d3 was not expressed	SIGNOR-254341	0.2
FGF2	protein	P09038	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates				9606									20974802	f		gcesareni	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription	SIGNOR-168998	0.388
CDCA5	protein	Q96FF9	UNIPROT	WAPL	protein	Q7Z5K2	UNIPROT	down-regulates activity	binding			7227									21111234	t		lperfetto	We show that DNA replication and cohesin acetylation promote binding of Sororin to cohesin, and that Sororin displaces Wapl from its binding partner Pds5. 	SIGNOR-265266	0.2
PTCRA	protein	Q6ISU1	UNIPROT	LCK	protein	P06239	UNIPROT	up-regulates activity	binding			9606									20626350	t		lperfetto	However, non-canonical mechanisms of p38alfa activation have been also described. One is apparently specific to antigen receptor stimulated t-lymphocytes. This involves phosphorylation of p38alfa on tyr323 by the tcr-proximal tyrosine kinase zap70 and p56lck.	SIGNOR-166658	0.341
MAPK8	protein	P45983	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000007								20974802	t		gcesareni	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription.	SIGNOR-169007	0.392
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates activity	phosphorylation	Ser511	RREERSLsAPGNLLT	9534	BTO:0000298								32913128	t		miannu	 Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues. 	SIGNOR-277240	0.2
HRK	protein	O00198	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates	binding			9606									9130713	t		gcesareni	Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1.	SIGNOR-47794	0.484
MAOA	protein	P21397	UNIPROT	serotonin	smallmolecule	CHEBI:28790	ChEBI	down-regulates quantity	chemical modification			9606									31024440	t	brain	lperfetto	Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA).	SIGNOR-264014	0.8
LETM1	protein	O95202	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	up-regulates				9606	BTO:0000567								18628306	f		lperfetto	LETM1 knockdown obviously reduced the formation of the supercomplexes (Fig. 5C, arrowhead). Complexes I and IV failed to form, and the assembly of complex III was significantly decreased. By contrast, the assembly of complex II (succinate dehydrogenase) and complex V (ATP synthase) – which are not proton pumps – was unaffected.	SIGNOR-262548	0.294
N-[3-[[5-bromo-4-[2-(1H-imidazol-5-yl)ethylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide	chemical	CHEBI:91357	ChEBI	PDPK1	protein	O15530	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190804	0.8
SNRPF	protein	P62306	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270658	0.697
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	CDKN2B	protein	P42772	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17873901	f		gcesareni	Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity	SIGNOR-252917	0.2
MMP17	protein	Q9ULZ9	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272362	0.7
TNKS	protein	O95271	UNIPROT	AXIN2	protein	Q9Y2T1	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									19759537	t		lperfetto	Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway.	SIGNOR-187975	0.765
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	RB1	protein	P06400	UNIPROT	down-regulates activity	phosphorylation	Ser795	SPYKFPSsPLRIPGG	9606	BTO:0000150								23336272	t		lperfetto	Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression.	SIGNOR-216992	0.858
CCL3	protein	P10147	UNIPROT	CCR5	protein	P51681	UNIPROT	up-regulates activity	binding			10090									20219869	t		areggio	The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. 	SIGNOR-255115	0.739
P2RY1	protein	P47900	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257185	0.2
CSNK1A1	protein	P48729	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates activity	phosphorylation	Thr59	EGYDELQtDGNRSSH	9606	BTO:0000567								11583622	t		llicata	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250786	0.289
MAPK1	protein	P28482	UNIPROT	TNKS1BP1	protein	Q9C0C2	UNIPROT	unknown	phosphorylation	Thr1032	GGLFSPStAHVPDGA	10090	BTO:0000944								22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262781	0.2
WDR62	protein	O43379	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates activity	relocalization			10090									30566428	t		lperfetto	In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis	SIGNOR-271716	0.3
PRKACA	protein	P17612	UNIPROT	RGS14	protein	O43566	UNIPROT	up-regulates activity	phosphorylation	Thr495	SATGKRQtCDIEGLV	-1									12534294	t		miannu	RGS14 is phosphorylated in vitro at Ser258 and Thr494 by PKA. cAMP-induced phosphorylation as an important modulator of RGS14 function since phosphorylation could enhance RGS14 binding to Galpha(i)-GDP	SIGNOR-250046	0.343
mTORC2	complex	SIGNOR-C2	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Ser477	PQFSYSAsGTA	9606	BTO:0000093								24670654	t		gcesareni	Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation	SIGNOR-252441	0.634
GSK3B	protein	P49841	UNIPROT	GATA6	protein	Q92908	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser37	REPSTPPsPISSSSS	9606	BTO:0000182								27273097	t		miannu	We identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin. 	SIGNOR-277241	0.314
CSNK2A1	protein	P68400	UNIPROT	XRCC1	protein	P18887	UNIPROT	up-regulates	phosphorylation	Thr488	GAEDSGDtEDELRRV	9606									20471329	t		lperfetto	Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair	SIGNOR-165427	0.404
IFNG	protein	P01579	UNIPROT	IFNGR1	protein	P15260	UNIPROT	up-regulates	binding			9606									10986460	t		fspada	Molecular interactions among cytokines and cytokine receptors form the basis of many cell-signaling pathways relevant to immune function. Interferon-g (ifng) signals through a multimeric receptor complex consistingof two different but structurally related transmembrane chains: the high-affinityreceptor-binding subunit (ifn-gra) and a species-specific accessory factor (af-1 or ifn-grb).	SIGNOR-81804	0.882
ADNP	protein	Q9H2P0	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									24365867	f		miannu	Here, we show for the first time that hippocampal ADNP deficiency paralleled reduced beclin1 expression which, in turn, parallels increased tauopathy and cell death. We now show that ADNP directly interacts with LC3B, implicating the requirement of a healthy ADNP system for the apoptotic/autophagy processes.	SIGNOR-266760	0.252
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC4	protein	Q14934	UNIPROT	up-regulates	dephosphorylation			9606									21880741	t		gcesareni	Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.	SIGNOR-252322	0.552
TPO	protein	P07202	UNIPROT	L-tyrosine zwitterion	smallmolecule	CHEBI:58315	ChEBI	down-regulates quantity	chemical modification			9606									16098474	t		scontino	TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. 	SIGNOR-266956	0.8
8-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	chemical	CHEBI:91845	ChEBI	HTR2B	protein	P41595	UNIPROT	down-regulates activity	chemical inhibition			10036	BTO:0000452								9459568	t		miannu	The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-	SIGNOR-258693	0.8
PTEN	protein	P60484	UNIPROT	PPM1A	protein	P35813	UNIPROT	up-regulates	binding			9606									18482992	t		lpetrilli	Upon complex formation with pten, ppm1a is protected from degradation induced by the tgf-? Signaling. this study establishes a novel role for nuclear pten in the stabilization of ppm1a.	SIGNOR-178643	0.313
NLK	protein	Q9UBE8	UNIPROT	TCF7L2	protein	Q9NQB0	UNIPROT	down-regulates	phosphorylation	Thr201	PHHVHPLtPLITYSN	9606									12556497	t		llicata	Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk.	SIGNOR-97819	0.763
CRHR1	protein	P34998	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding												22869609	t		lperfetto	Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3	SIGNOR-268617	0.471
PRKCG	protein	P05129	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates activity	phosphorylation	Ser346	EWEAQRDsHLGPHRS	9606	BTO:0000007								14576165	t		lperfetto	A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis.	SIGNOR-249238	0.2
EIF2AK2	protein	P19525	UNIPROT	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates				9606									27712625	f		miannu	The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum.	SIGNOR-260159	0.7
C9orf72	protein	Q96LT7	UNIPROT	RAB1A	protein	P62820	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								27334615	t		miannu	C9orf72 acts as an effector of Rab1a that recruits active Rab1a to theULK1 complex to promote translocation of the ULK1 complex to thephagophore during autophagy initiation	SIGNOR-261297	0.488
MEN1	protein	O00255	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				10090									16415155	f		irozzo	We also found that menin is important for the proliferation of MLL oncoprotein-transformed myeloid cells, pointing to a paradoxically oncogenic role for the tumor suppressor menin in proliferation of transformed myeloid cells.	SIGNOR-255895	0.7
MPP5	protein	Q8N3R9	UNIPROT	AMOT/MPP5/INADL/LIN7C	complex	SIGNOR-C27	SIGNOR	form complex	binding			9606									24366813	t		lperfetto	To gain a more detailed view on the organization of this cell polarity network linked to yap1 we included several proteins of the cell junction complex (amot, mpp5, lin7a),	SIGNOR-203494	0.67
PPP2CA	protein	P67775	UNIPROT	CARD11	protein	Q9BXL7	UNIPROT	down-regulates activity	dephosphorylation	Ser644	NLMFRKFsLERPFRP	9606									21157432	t			NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation.	SIGNOR-248650	0.314
CREB5	protein	Q02930	UNIPROT	CFB	protein	P00751	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		 BTO:0002809							21132541	f		miannu	 Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition),	SIGNOR-253802	0.2
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	ESR2	protein	Q92731	UNIPROT	up-regulates activity	chemical activation			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258592	0.8
FANCG	protein	O15287	UNIPROT	Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	form complex	binding			9606	BTO:0000567								17396147	t		lperfetto	This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo 	SIGNOR-263243	0.922
SMURF2	protein	Q9HAU4	UNIPROT	BMPR1A	protein	P36894	UNIPROT	down-regulates	ubiquitination			9606									22298955	t		gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-192898	0.533
NTRK1	protein	P04629	UNIPROT	ARHGAP32	protein	A7KAX9	UNIPROT	up-regulates	relocalization			9606									12446789	t		gcesareni	Grit translocation was regulated by receptor stimulation	SIGNOR-95809	0.585
FGFR3	protein	P22607	UNIPROT	GLO1	protein	Q04760	UNIPROT	up-regulates activity	phosphorylation	Tyr136	GIAVPDVySACKRFE	-1									34838714	t		miannu	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276181	0.2
MAPK14	protein	Q16539	UNIPROT	MEF2A	protein	Q02078	UNIPROT	up-regulates activity	phosphorylation	Thr312	QATQPLAtPVVSVTT	9606									9858528	t		lperfetto	We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a	SIGNOR-62780	0.646
PRKACA	protein	P17612	UNIPROT	STK38	protein	Q15208	UNIPROT	down-regulates activity	phosphorylation	Ser10	MTGSTPCsSMSNHTK	-1									22142472	t		miannu	GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively.  Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress.	SIGNOR-276391	0.299
risperidone	chemical	CHEBI:8871	ChEBI	HTR1F	protein	P30939	UNIPROT	down-regulates activity	chemical inhibition			9534									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258524	0.8
HOXA9	protein	P31269	UNIPROT	MEF2C	protein	Q06413	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000661								21261500	f	 	miannu	Overexpression of HOXA9 or HOXA10 in JURKAT cells by lentiviral transduction resulted in decreased expression of MEF2C, indicating repression by these homeodomain proteins. HOXA9/10 inhibits expression of MEF2C via NMYC	SIGNOR-254211	0.339
ATM	protein	Q13315	UNIPROT	NFAT5	protein	O94916	UNIPROT	up-regulates	phosphorylation	Ser1247	AMQSNSPsQEQQQQQ	9606									15173573	t		lperfetto	Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp	SIGNOR-125077	0.275
NRF1	protein	Q16656	UNIPROT	ENOX1	protein	Q8TC92	UNIPROT	up-regulates				9606	BTO:0000934								23939472	f		lperfetto	We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. 	SIGNOR-261488	0.268
ITGB1BP1	protein	O14713	UNIPROT	AM/b2 integrin	complex	SIGNOR-C170	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257651	0.318
BMPR1A	protein	P36894	UNIPROT	SMAD1/5/8	proteinfamily	SIGNOR-PF35	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000165;BTO:0002974; BTO:0002809								9442019	t		ggiuliani	In this study, we isolated human Smad5 and found that Smad5 was involved in BMP-2 signaling cascades, which mediate the bone-inducing effects of BMP-2. Smad5 was directly serine-phosphorylated by BMPIR through a physical interaction. The activated Smad5 subsequently formed a complex with DPC4, and this complex was then translocated to the nucleus.	SIGNOR-255830	0.773
KDM1A	protein	O60341	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	demethylation			9606	BTO:0000567								15620353	t		miannu	Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription.	SIGNOR-265332	0.2
CPT1A	protein	P50416	UNIPROT	palmitoyl-CoA(4-)	smallmolecule	CHEBI:57379	ChEBI	down-regulates quantity	chemical modification			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267126	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19763573	f		miannu	 PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-kappaB.	SIGNOR-254654	0.265
PRKACA	protein	P17612	UNIPROT	KCNK9	protein	Q9NPC2	UNIPROT	up-regulates	phosphorylation	Ser373	RLMKRRKsV	9606	BTO:0000007								21357689	t		llicata	Patch clamp analysis, flow cytometry, and immunocytochemistry studies of hek293 transfected with wt hk2p3.1 and cultured in the presence of pka activators or inhibitors all confirm that activation of pka resulted in an increase in hk2p3.1 current expression (figs. 4_4?6) and demonstrate the dynamic regulatory effect of pka activity on k2p3.1 channel expression.	SIGNOR-172466	0.2
CID 132010322	chemical	CID:132010322	PUBCHEM	BRD3	protein	Q15059	UNIPROT	down-regulates activity	chemical inhibition			9606									31969702	t		Luana	ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4 	SIGNOR-261104	0.8
U2AF1	protein	Q01081	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									31144421	f		miannu	 Our results further showed that knockdown of U2AF1 significantly Western blot analysis revealed an increase in the protein levels of downstream targets of p53 following U2AF1 knockdown. The data further showed that depletion of U2AF1 altered alternatively spliced apoptosis-associated gene transcripts in CFU-E cells. Our findings elucidate the role of U2AF1 in human erythropoiesis and reveal the underlying mechanisms.	SIGNOR-261512	0.2
IL23A	protein	Q9NPF7	UNIPROT	IL12RB1	protein	P42701	UNIPROT	up-regulates	binding			9606									12671732	t		gcesareni	Based on these analyses, we propose an integrated model of il-12rbeta1 structure and function. This significantly enhances our molecular understanding of the human il-12 and il-23 systems.	SIGNOR-99716	0.631
IDH3A	protein	P50213	UNIPROT	IDH	complex	SIGNOR-C396	SIGNOR	form complex	binding			9606									28139779	t		miannu	Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. 	SIGNOR-266248	0.714
TFEB	protein	P19484	UNIPROT	ANKFY1	protein	Q9P2R3	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2)	SIGNOR-276782	0.2
CTF1	protein	Q16619	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates	binding			9606									9030543	t		gcesareni	In the cos-7 cell line demonstrate that gp130-gp190 heterocomplex formation is essential for ct-1 signaling	SIGNOR-46509	0.611
GSK3B	protein	P49841	UNIPROT	CDX2	protein	Q99626	UNIPROT	unknown	phosphorylation	Ser287	EPLSPVSsLQASVPG	-1									16027724	t			GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines)	SIGNOR-251228	0.389
TJP2	protein	Q9UDY2	UNIPROT	ARVCF	protein	O00192	UNIPROT	down-regulates activity	relocalization			9615									15456900	t	Regulation of binding	miannu	We identified ARVCF as a binding partner of ZO-1 and ZO-2 and characterized the role of PDZ-domain proteins in plasma membrane and nuclear localization of ARVCF. ZO-2, in contrast, relocated to the nucleus with ARVCF, and, given the interaction between the ZO-2 PDZ domains and ARVCF, raised the possibility that ZO-2 may play a role in nuclear localization of ARVCF. Such a role for ZO-2 is indeed supported by the ability of the ZO-2 PDZ domain to efficiently relocate ARVCF from the plasma membrane to the nucleus in a process that required the ability of the two proteins to interact and the presence of a functional NLS in the ZO-2 PDZ domains. Thus, ZO-2 could be involved in nuclear translocation and/or retention of ARVCF and play a role in regulating postulated functions of ARVCF in gene expression	SIGNOR-252122	0.378
TFEB	protein	P19484	UNIPROT	APOA4	protein	P06727	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2)	SIGNOR-276783	0.2
kaempferol	chemical	CHEBI:28499	ChEBI	AHR-ARNT	complex	SIGNOR-C125	SIGNOR	down-regulates activity	chemical inhibition												17012224	t			However, kaempferol inhibited the ability of BNF to induce formation of the AHR/ARNT DNA-binding complex at all concentrations tested 	SIGNOR-253641	0.8
TFEB	protein	P19484	UNIPROT	CALCOCO1	protein	Q9P1Z2	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2)	SIGNOR-276784	0.2
LYN	protein	P07948	UNIPROT	DOK3	protein	Q7L591	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000776								32323266	t		scontino	An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.	SIGNOR-268447	0.418
ABL1	protein	P00519	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates	phosphorylation	Tyr970	GEGYKKKyQQVDEEF	9606	BTO:0000150;BTO:0000527								19275932	t		gcesareni	These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis.	SIGNOR-184556	0.507
CSNK2A1	protein	P68400	UNIPROT	CERS6	protein	Q6ZMG9	UNIPROT	up-regulates activity	phosphorylation	Ser347	RSDIESSsDEEDSEP	9606	BTO:0000007								26887952	t		miannu	Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue. 	SIGNOR-273989	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606									19282669	t	inferred from 70% family members	lperfetto	Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway	SIGNOR-270175	0.2
NELF	complex	SIGNOR-C521	SIGNOR	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	down-regulates activity	binding			9606									18628398	t		miannu	The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. 	SIGNOR-271403	0.384
MAP2K3	protein	P46734	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation			9534									7839144	t		lperfetto	Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase.	SIGNOR-232156	0.715
DHODH	protein	Q02127	UNIPROT	ubiquinol	smallmolecule	CHEBI:17976	ChEBI	up-regulates quantity	chemical modification			9606									30449682	t		miannu	OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway	SIGNOR-267432	0.8
POLR2A	protein	P24928	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	up-regulates activity	relocalization			-1									20457598	t		lperfetto	The pol II CTD specifically mediates recruitment of Integrator to the promoter of snRNA genes to activate transcription and direct 3' end processing of the transcripts.	SIGNOR-261476	0.65
PLEKHG6	protein	Q3KR16	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260567	0.566
RSPO1	protein	Q2MKA7	UNIPROT	ZNRF3	protein	Q9ULT6	UNIPROT	down-regulates quantity	relocalization			9606	BTO:0000007								22575959	t			Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3.	SIGNOR-260113	0.796
PRKACA	protein	P17612	UNIPROT	PPP1R9B	protein	Q96SB3	UNIPROT	down-regulates activity	phosphorylation	Ser94	SERGVRLsLPRASSL	9606	BTO:0000007								12417592	t		miannu	Spinophilin is phosphorylated in vitro by protein kinase A (PKA). two major sites of phosphorylation, Ser-94 and Ser-177, that are located within the actin-binding domain of spinophilin. Phosphorylation of spinophilin by PKA modulated the association between spinophilin and the actin cytoskeleton. phosphorylation of spinophilin reduced the stoichiometry of the spinophilin-actin interaction. In contrast, the ability of spinophilin to bind to PP1 remained unchanged. 	SIGNOR-250035	0.314
MAP3K1	protein	Q13233	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606									17563747	t		lperfetto	Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna.	SIGNOR-236346	0.296
L-homocysteine zwitterion	smallmolecule	CHEBI:58199	ChEBI	hydrosulfide	smallmolecule	CHEBI:29919	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000671;BTO:0000759;BTO:0002688							19961860	t		lperfetto	 the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production.	SIGNOR-275816	0.8
BRAP	protein	Q7Z569	UNIPROT	KSR1	protein	Q8IVT5	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								23105109	t		miannu	Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. 	SIGNOR-272028	0.646
UBASH3B	protein	Q8TF42	UNIPROT	CBL	protein	P22681	UNIPROT	down-regulates	binding			9606									15159412	t		gcesareni	Sts-1 and sts-2 contain sh3 domains that interacted with cbl, ub-associated domains, which bound directly to mono-ub or to the egfr/ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of sts-1/2. Ligand-induced recruitment of sts-1/sts-2 into activated egfr complexes led to inhibition of receptor internalization, reduction in the number of egfr-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways.	SIGNOR-124897	0.454
EDNRB	protein	P24530	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256781	0.296
UCHL3	protein	P15374	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates activity	deubiquitination	Lys58	AVAYAPKkELINIKG										27941124	t		lperfetto	Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. | UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2.|Our results suggested that three lysine sites (56, 57, and 63) on RAD51 that are close to E59 are deubiquitinated by UCHL3. 	SIGNOR-275908	0.33
NEK7	protein	Q8TDX7	UNIPROT	TERF1	protein	P54274	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser114	AIIHGLSsLTACQLR	9606	BTO:0000567								28216227	t	done	miannu	Mechanistically, Nek7 interacts with and phosphorylates TRF1 on Ser114, which prevents TRF1 from binding to Fbx4, an Skp1-Cul1-F box E3 ligase subunit, thereby alleviating proteasomal degradation of TRF1, leading to a stable association of TRF1 with Tin2 to form a shelterin complex.	SIGNOR-273903	0.348
MRPL45	protein	Q9BRJ2	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262351	0.706
DYRK1A	protein	Q13627	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation	Ser641	YRYPRPAsVPPSPSL	9534	BTO:0000298								14593110	t		miannu	DYRK Family Protein Kinases Phosphorylate and Inactivate Glycogen Synthase. both protein kinases phosphorylate site 3a but no other sites that affect glycogen synthase activity.	SIGNOR-260632	0.27
CSNK2A1	protein	P68400	UNIPROT	GTF2A1	protein	P52655	UNIPROT	up-regulates activity	phosphorylation	Ser280	VDGTGDTsSEEDEDE	-1									11278496	t		llicata	We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function.	SIGNOR-250874	0.388
MAPK14	protein	Q16539	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser383	IHFWSTLsPIAPRSP	9606									9130707	t		gcesareni	We demonstrate here that elk-1 is barely activated by a third subclass of map kinases (p38), most likely because the critical residues ser383 and ser389 are poorly phosphorylated by p38 map kinase.	SIGNOR-47630	0.505
GGCX	protein	P38435	UNIPROT	F2	protein	P00734	UNIPROT	up-regulates activity	carboxylation			9606									31226734	t		lperfetto	Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.	SIGNOR-265918	0.655
CARM1	protein	Q86X55	UNIPROT	SMARCC1	protein	Q92922	UNIPROT	up-regulates activity	methylation	Arg1064	PGNILGPrVPLTAPN	9606	BTO:0000007;BTO:0000356								24434208	t			CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation.	SIGNOR-251708	0.554
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RAMAC	protein	Q9BTL3	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser36	YLKRPPEsPPIVEEW	9606									27452456	t		miannu	During differentiation, ERK1/2 phosphorylates RAM serine-36, targeting it for ubiquitination and proteasomal degradation, ultimately resulting in changes in gene expression associated with loss of pluripotency.	SIGNOR-277267	0.2
PRKCZ	protein	Q05513	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	up-regulates activity	phosphorylation	Ser472	RPHFPQFsYSASGRE	9534	BTO:0001538								12162751	t		lperfetto	Full activation of the PKB enzyme requires phosphorylation of a threonine in the activation	SIGNOR-249153	0.529
SRC	protein	P12931	UNIPROT	VIL1	protein	P09327	UNIPROT	up-regulates activity	phosphorylation	Tyr60	KTASSLSyDIHYWIG	9606	BTO:0000567								15342783	t		lperfetto	These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton	SIGNOR-247437	0.37
MMP16	protein	P51512	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272361	0.7
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1763	TPTSPSYsPTSPSYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203552	0.77
ESR1	protein	P03372	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates quantity by expression	transcriptional regulation												14764652	f		lperfetto	Estrogen-induced transcriptional activities of both ERalpha and ERbeta and mRNA expression of estrogen-responsive genes, including pS2, c-myc, and cyclin D1, were suppressed by PP5 but enhanced by PP5 antisense oligonucleotide.	SIGNOR-271691	0.284
AKT2	protein	P31751	UNIPROT	PCBP1	protein	Q15365	UNIPROT	down-regulates activity	phosphorylation	Ser43	VKRIREEsGARINIS	10090	BTO:0004183								20154680	t		miannu	 We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation.TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs.	SIGNOR-262625	0.442
SRC	protein	P12931	UNIPROT	NECTIN2	protein	Q92692	UNIPROT	unknown	phosphorylation	Tyr505	EGEEEEEyLDKINPI	-1									10962558	t		miannu	An inhibitor specific for Src family kinase or expression of Csk reduced tyrosine phosphorylation of nectin-2delta. In addition, Src kinase tyrosine phosphorylates the recombinant cytoplasmic region of nectin-2delta in vitro. The major tyrosine phosphorylation site of nectin-2delta was Tyr505 in the cytoplasmic region	SIGNOR-263200	0.2
bromocriptine	chemical	CHEBI:3181	ChEBI	DRD3	protein	P35462	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258367	0.8
propan-2-ol	smallmolecule	CHEBI:17824	ChEBI	TLCD3B	protein	Q71RH2	UNIPROT	up-regulates activity	binding			9606		BTO:0000140							30010626	t		lperfetto	Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2	SIGNOR-270575	0.8
AKT1	protein	P31749	UNIPROT	PARK7	protein	Q99497	UNIPROT	up-regulates activity	phosphorylation	Thr125	GFGSKVTtHPLAKDK										32858971	t		lperfetto	Using a proteomic approach, we identified on DJ-1 a novel threonine phosphorylation (T125) that was found, by the in-silico tool scansite 4, as part of a putative Akt consensus. |Deglycase activity of DJ-1 on histones proteins, investigated by coupling 2D tau gel with LC-MS/MS and 2D-TAU (Triton-Acid-Urea)-Western blot, was found correlated with its phosphorylation status that, in turn, depends from Akt activation. 	SIGNOR-275582	0.479
ULK1	protein	O75385	UNIPROT	PFKM	protein	P08237	UNIPROT	down-regulates activity	phosphorylation	Ser762	YEIDLDTsDHAHLEH	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274036	0.2
RNA helicases DDX5/DDX17	complex	SIGNOR-C34	SIGNOR	NFAT5	protein	O94916	UNIPROT	up-regulates activity	binding			9606	BTO:0000815								22266867	t	done	miannu	In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. 	SIGNOR-274113	0.36
MAPK14	protein	Q16539	UNIPROT	PIP4K2B	protein	P78356	UNIPROT	down-regulates	phosphorylation	Ser326	SYGTPPDsPGNLLSF	9606									16949365	t		gcesareni	Inhibition of pip4kbeta activity occurs through the direct phosphorylation of pip4kbeta at ser326 by the p38 stress-activated protein kinase.	SIGNOR-149359	0.2
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates quantity	transcriptional regulation			10090									24749067	f		gcesareni	We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration.	SIGNOR-254306	0.2
bisindolylmaleimide i	chemical	CID:2396	PUBCHEM	PRKCG	protein	P05129	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	CellSignaling	gcesareni		SIGNOR-190356	0.8
MAPK8	protein	P45983	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9534	BTO:0004055								8137421	t		lperfetto	The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity.	SIGNOR-235766	0.905
adenosine	smallmolecule	CHEBI:16335	ChEBI	PI4K2B	protein	Q8TCG2	UNIPROT	down-regulates activity	chemical inhibition			-1									21704602	t		Luana	Both PI4K2A and PI4K2B were inhibited by adenosine at concentrations that do not significantly inhibit PI4KA and PI4KB actitvity	SIGNOR-258316	0.8
UCHL3	protein	P15374	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates activity	deubiquitination	Lys64	KKELINIkGISEAKA										27941124	t		lperfetto	Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. | UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2.|Our results suggested that three lysine sites (56, 57, and 63) on RAD51 that are close to E59 are deubiquitinated by UCHL3. 	SIGNOR-275909	0.33
PRKACA	protein	P17612	UNIPROT	UBE3A	protein	Q05086	UNIPROT	down-regulates activity	phosphorylation	Thr508	MYSERRItVLYSLVQ	10090		BTO:0000142							26255772	t		gcesareni	These data suggest that PKA phosphorylation at T485 inhibits UBE3A ubiquitin ligase activity in cells.	SIGNOR-236899	0.333
STK24	protein	Q9Y6E0	UNIPROT	STK24	protein	Q9Y6E0	UNIPROT	up-regulates	phosphorylation	Thr190	DTQIKRNtFVGTPFW	9606		BTO:0000671							17046825	t		gcesareni	Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (mst3) involves paxillin and protein-tyrosine phosphatase-pest.	SIGNOR-150131	0.2
DIO	proteinfamily	SIGNOR-PF83	SIGNOR	iodide	smallmolecule	CHEBI:16382	ChEBI	up-regulates quantity	chemical modification			9606									34674502	t		scontino	Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule. 	SIGNOR-267045	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser555	RALSNSVsNMGLSES	-1									17711846	t	done	miannu	Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626).	SIGNOR-274093	0.397
JARID2	protein	Q92833	UNIPROT	NKX2-5	protein	P52952	UNIPROT	down-regulates activity	binding			10116	BTO:0003324								15542826	t		miannu	JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4.	SIGNOR-224787	0.467
PIK3C2A	protein	O00443	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates				9606									9430633	f		gcesareni	Activation of pi 3-kinase causes plc gamma ph domain-mediated membrane targeting and plc gamma activation.	SIGNOR-54707	0.382
PTPN12	protein	Q05209	UNIPROT	SHC1	protein	P29353	UNIPROT	down-regulates	dephosphorylation	Tyr350	EPPDHQYyNDFPGKE	9606									8939605	t		gcesareni	The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions.	SIGNOR-44862	0.661
KCNE3	protein	Q9Y6H6	UNIPROT	KCNQ1	protein	P51787	UNIPROT	up-regulates activity	binding												21911611	t		lperfetto	Sexual dimorphism and oestrogen regulation of KCNE3 expression modulates the functional properties of KCNQ1 K⁺ channels|The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation	SIGNOR-275923	0.648
PKN1	protein	Q16512	UNIPROT	MARCKS	protein	P29966	UNIPROT	down-regulates activity	phosphorylation	Ser163	KRFSFKKsFKLSGFS	-1									8557118	t		gcesareni	PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163.	SIGNOR-249651	0.372
CDC25C	protein	P30307	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates activity	dephosphorylation			9606									32518522	t		miannu	At the interval CDC25C inhibits ASK1, dephosphorylating pThr838 in its activation loop.|CDC25C dephosphorylates ASK1 to inhibit its activity during the interphase.	SIGNOR-277100	0.293
S1PR2	protein	O95136	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256728	0.451
PDK1	protein	Q15118	UNIPROT	PDH	complex	SIGNOR-C402	SIGNOR	down-regulates activity	phosphorylation			9606	BTO:0003291								16517405	t		miannu	PDK1 is a direct HIF-1 target gene. We found that the gene encoding pyruvate dehydrogenase kinase 1 (PDK1) is a direct target of HIF-1. PDK1 phosphorylates the pyruvate dehydrogenase (PDH) E1α subunit and inactivates the PDH enzyme complex that converts pyruvate to acetyl-coenzyme A, thereby inhibiting pyruvate metabolism via the tricarboxylic acid (TCA) cycle	SIGNOR-267445	0.629
5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol	chemical	CID:104895	PUBCHEM	CNR1	protein	P21554	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257473	0.8
PIM1	protein	P11309	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0001321								34697370	t		miannu	PIM1 phosphorylates the AR and 14-3-3 ζ and coordinates their interaction. PIM1 phosphorylation of the AR and 14-3-3 ζ enhances their interaction and shifts their occupancy on chromatin, resulting in 14-3-3 ζ co-regulation of AR, likely by recruiting other AR co-regulators such as hnRNPK and TRIM28. 	SIGNOR-277575	0.391
Daunorubicin hydrochloride	chemical	CHEBI:31456	ChEBI	TOP2A	protein	P11388	UNIPROT	down-regulates activity	chemical inhibition			9606									1963303	t		miannu	DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives. 	SIGNOR-259322	0.8
FBXO32	protein	Q969P5	UNIPROT	Muscle_atrophy	phenotype	SIGNOR-PH40	SIGNOR	up-regulates				10090		BTO:0001103							20871233	f			Atrogin-1, but not MuRF-1, was induced at both the gene and protein level as ApcMin/+ mice aged from 3 to 6 months of age, going from a pre-cachectic to a cachectic state. Atrogin-1 mRNA and protein levels were also elevated in ApcMin/+ mice when we over-expressed IL-6 in the circulation. 	SIGNOR-255343	0.7
ABL1	protein	P00519	UNIPROT	RAPH1	protein	Q70E73	UNIPROT	up-regulates activity	phosphorylation	Tyr1226	GGSHISGyATLRRGP	-1									20417104	t		miannu	Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C).	SIGNOR-262605	0.289
MAPK1	protein	P28482	UNIPROT	NOXA1	protein	Q86UR1	UNIPROT	down-regulates	phosphorylation	Ser282	VGKQAPLsPGLPAMG	9606	BTO:0000007								20110267	t		llicata	These results demonstrated a critical role of noxa1 phosphorylation on ser-282 and ser-172 in preventing nox1 hyperactivation through the decrease of noxa1 interaction to nox1 and rac1.	SIGNOR-163659	0.331
ZC3H11A	protein	O75152	UNIPROT	TREX complex	complex	SIGNOR-C444	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								22928037	t		miannu	 PDIP3 and ZC11A Function in mRNA Export. PDIP3 and ZC11A associate with UAP56 and the TREX complex in an ATP-dependent manner. 	SIGNOR-268516	0.462
MTOR	protein	P42345	UNIPROT	Myotube_hypertrophy	phenotype	SIGNOR-PH20	SIGNOR	up-regulates				9606		BTO:0000887;BTO:0001103;BTO:0001760							22179044	f		gcesareni	In differentiated myofibres, we observed that wnt7a binding to fzd7 directly activates the akt/mtor growth pathway, thereby inducing myofibre hypertrophy.	SIGNOR-191564	0.7
PREX2	protein	Q70Z35	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260571	0.592
SLBP	protein	Q14493	UNIPROT	H2BC15	protein	Q99877	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265392	0.2
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	KDM2B	protein	Q8NHM5	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273472	0.8
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	LDHA	protein	P00338	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27692180	t		miannu	HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 	SIGNOR-267456	0.644
TGFB1	protein	P01137	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates quantity by expression				9606									17283133	f		gcesareni	In normal primary endometrial epithelial cells (eecs), tgfbeta directly induced a dose-dependent increase in p27 protein levels and its nuclear localization	SIGNOR-152945	0.294
cortisone	chemical	CHEBI:16962	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									14817168	t	allergy	gcesareni		SIGNOR-251691	0.8
3-N-Me-Phe-morphiceptin	chemical	CID:115335	PUBCHEM	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258417	0.8
CTCF	protein	P49711	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11706010	f		miannu	 Depleting HeLa cell nuclear extract of endogenous CTCF specifically reduced transcriptional activity from the APP promoter. CTCF activates transcription from the APP promoter and that the activation domain is located on the N-terminal side of the zinc finger domain.	SIGNOR-253823	0.268
IGF1R	protein	P08069	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates	binding			9606									18595745	t		gcesareni	Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively)	SIGNOR-179386	0.706
PRKD2	protein	Q9BZL6	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	up-regulates activity	phosphorylation	Ser259	FPLRKTAsEPNLKVR										18692497	t		lperfetto	Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].	SIGNOR-275927	0.299
5-chloro-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	chemical	CHEBI:91338	ChEBI	ALK	protein	Q9UM73	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207132	0.8
FOXC1	protein	Q12948	UNIPROT	RBPJ	protein	Q06330	UNIPROT	up-regulates	binding			9606									21871448	t		gcesareni	We demonstrate that physical interactions occur between wt1, foxc1/2 and rbpj, suggestive of the formation of multimeric transcriptional complexes.	SIGNOR-176183	0.28
BUB1B	protein	O60566	UNIPROT	Mitotic_checkpoint	phenotype	SIGNOR-PH28	SIGNOR	up-regulates				9606									20888775	f		gcesareni	The multidomain protein kinases bub1 and bubr1 (mad3 in yeast, worms and plants) are central components of the mitotic checkpoint for spindle assembly (sac)	SIGNOR-168195	0.7
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH7	protein	Q9ULB5	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265847	0.8
CDK9	protein	P50750	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser315	LPNNTSSsPQPKKKP	9606									24173284	t		lperfetto	The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A	SIGNOR-145311	0.551
PRKCH	protein	P24723	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606									19836308	t		lperfetto	Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).	SIGNOR-188585	0.2
TGFB1	protein	P01137	UNIPROT	MYOCD	protein	Q8IZQ8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887;BTO:0001260							21673106	f		gcesareni	These results indicate that (i) tgf- and klf4 regulate myocd transcription positively and negatively, respectively. When __90% of smad4 was down-regulated myocd mrna induction by tgf- was abolished, suggesting that smad4 plays a critical role in transcriptional activation of the myocd gene	SIGNOR-174396	0.271
POMC	protein	P01189	UNIPROT	MC1R	protein	Q01726	UNIPROT	up-regulates activity	binding			9606	BTO:0000847								19656324	t		miannu	Alpha-melanocyte stimulating hormone (alpha-MSH) binds to melanocortin-1 receptor (MC1R) on melanocytes to stimulate pigmentation and modulate various cutaneous inflammatory responses. 	SIGNOR-252370	0.758
SNAI1	protein	O95863	UNIPROT	CTBP1	protein	Q13363	UNIPROT	up-regulates activity				9606	BTO:0001570								19277896	f	 	lperfetto	We propose that CtBP1 is recruited by SNAI1P at the CLDN7 gene promoter indirectly through another yet to be identified protein. Based on our observations, we propose a model for SNAI1P-mediated down regulation of human CLDN7 gene expression by chromatin remodeling	SIGNOR-254103	0.482
FYN	protein	P06241	UNIPROT	CHN2	protein	P52757	UNIPROT	down-regulates	phosphorylation	Tyr21	VSSDAEEyQPPIWKS	9606									17560670	t		llicata	Ere we report that beta2-chimaerin is tyrosine-phosphorylated by src-family kinases (sfks) upon cell stimulation with epidermal growth factor (egf). these results suggest tyr-21 phosphorylation as a novel, sfk-dependent mechanism that negatively regulates beta2-chimaerin rac-gap activity.	SIGNOR-155709	0.2
olaparib	chemical	CHEBI:83766	ChEBI	PARP3	protein	Q9Y6F1	UNIPROT	down-regulates activity	chemical inhibition			9606									25981132	t		miannu	The PARP inhibitor olaparib is currently tested in clinical phase 1 trials to define safe dose levels in combination with RT. 	SIGNOR-259320	0.8
NDUFA3	protein	O95167	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added	SIGNOR-262155	0.785
STUB1	protein	Q9UNE7	UNIPROT	CBX4	protein	O00257	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys178	LQYQGGHkEAPSPTC	9606	BTO:0002181								32111827	t		miannu	The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα. 	SIGNOR-277513	0.2
HRC	protein	P23327	UNIPROT	ATP2A2	protein	P16615	UNIPROT	down-regulates activity	binding			10116	BTO:0001879								28784772	t		miannu	Furthermore, a Ser96Asp HRC variant, which mimics constitutive phosphorylation of Ser96, diminished delayed aftercontractions in HRC null cardiac myocytes. This HRC phosphomimetic variant was also able to rescue the aftercontractions elicited by the Ser96Ala variant, demonstrating that phosphorylation of Ser96 is critical for the cardioprotective function of HRC. Phosphorylation of HRC on Ser96 regulated the interactions of HRC with both triadin and SERCA2a, suggesting a unique mechanism for regulation of SR Ca homeostasis. 	SIGNOR-273662	0.384
PTPN11	protein	Q06124	UNIPROT	NTRK2	protein	Q16620	UNIPROT	down-regulates activity	dephosphorylation			9606									28947394	t		miannu	Conversely, PTPN11 knockdown lead to increased Y 515 phosphorylation of TrkB compared to the scramble control in the neuronal cells.|This study established that TrkB activation as demonstrated by receptor phosphorylation at Tyr 515 in the SH-SY5Y cells is negatively regulated by PTPN11 actions.	SIGNOR-277123	0.695
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser713	GAEIVYKsPVVSGDT	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249345	0.729
CREBBP	protein	Q92793	UNIPROT	POU1F1	protein	P28069	UNIPROT	up-regulates activity	binding			9606		BTO:0001379							10931853	t		scontino	 We and others have recently shown that CBP can constitutively bind to Pit-1 and synergistically activate transcription of promoters containing Pit-1 DNA-binding sites.	SIGNOR-267204	0.388
GGCX	protein	P38435	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	carboxylation	Glu73	EEKCSFEeAREVFEN	10090		BTO:0001103							11133752	t		lperfetto	The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.	SIGNOR-263693	0.67
ARHGAP1	protein	Q07960	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260458	0.859
EPHA2	protein	P29317	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	binding			9606									12400011	t		gcesareni	We also show that the interaction of epha2 with grb2 is indirect and mediated by shc and that this complex is necessary for epha2-mediated activation of erk kinases.	SIGNOR-94804	0.599
IKBKB	protein	O14920	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation	Ser644	GLDFNFDsLISTQNV	9606									19188143	t		gcesareni	Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway	SIGNOR-183684	0.678
PPP2R2A	protein	P63151	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16239230	t		gcesareni	... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259.	SIGNOR-243417	0.44
MAPK1	protein	P28482	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Ser434	SFEPKIRsPRRFIGS	9606									14967450	t		gcesareni	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-121984	0.578
JAK2	protein	O60674	UNIPROT	IFNGR2/INFGR1	complex	SIGNOR-C142	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000801								23898330	t		lperfetto	In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation	SIGNOR-249493	0.695
CRHR1	protein	P34998	UNIPROT	POMC	protein	P01189	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001073							23504413	f		lperfetto	CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981).	SIGNOR-268612	0.641
BCL11A	protein	Q9H165	UNIPROT	HBG1	protein	P69891	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20712774	f	Regulation	miannu	BCL11A maintains silencing of gamma-globin expression in adult erythroid cells and functions as a direct transcriptional regulator of the fetal to adult hemoglobin switch in humans. we found that BCL11A plays a central role in the evolutionarily divergent globin gene switches of mammals. As a factor critical for gamma-globin gene silencing, BCL11A should be considered as a therapeutic target to increase HbF in a directed manner in beta-thalassemia patients.	SIGNOR-251774	0.46
BUB1	protein	O43683	UNIPROT	PLK1	protein	P53350	UNIPROT	up-regulates	binding			9606	BTO:0000567				phosphorylation:Thr609	SAAQLAStPFHKLPV 			16760428	t		gcesareni	The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609	SIGNOR-147061	0.859
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	IKBKB	protein	O14920	UNIPROT	down-regulates	cleavage	Asp546	ALQTDIVdLQRSPMG	9606									11741536	t		gcesareni	Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis.	SIGNOR-256435	0.373
FER	protein	P16591	UNIPROT	PECAM1	protein	P16284	UNIPROT	up-regulates activity	phosphorylation	Tyr690	PLNSDVQyTEVQVSS	9606	BTO:0000007								12972546	t		miannu	PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1.	SIGNOR-262865	0.329
Glycine cleavage system	complex	SIGNOR-C437	SIGNOR	glycine	smallmolecule	CHEBI:15428	ChEBI	down-regulates quantity	chemical modification			9606									16051266	t		lperfetto	The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide.	SIGNOR-268238	0.8
APH1A	protein	Q96BI3	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates	binding			9606		BTO:0000142							12297508	t		gcesareni	Gamma secretase subunit. Leads to ps1/ps2 eterodimer complex stabilisation. By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.	SIGNOR-93265	0.921
3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	Gluconeogenesis	phenotype	SIGNOR-PH35	SIGNOR	up-regulates				9606		BTO:0000759							24692351	f		scontino	It has been previously established that T3 stimulates gluconeogenesis, especially in the hyperthyroid state, and that hypothyroidism is associated with reduced gluconeogenesis.	SIGNOR-267490	0.7
SNX6	protein	Q9UNH7	UNIPROT	IGF2R	protein	P11717	UNIPROT	down-regulates quantity	binding			9606	BTO:0000567								32150533	t		miannu	 Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.	SIGNOR-269443	0.373
PSMB2	protein	P49721	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263358	0.886
phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	RAC1	protein	P63000	UNIPROT	up-regulates	chemical activation			9606									18480413	t		gcesareni	The c-terminal polybasic motif of rac1 is responsible for direct interaction with pa,	SIGNOR-178632	0.8
PSAT1	protein	Q9Y617	UNIPROT	3-phosphonatooxypyruvate(3-)	smallmolecule	CHEBI:18110	ChEBI	up-regulates activity	chemical modification			3702									30034403	t		lperfetto	Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction.	SIGNOR-268562	0.8
Isoetharine	chemical	CHEBI:6005	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			-1									7576010	t		miannu	The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1.	SIGNOR-258432	0.8
TWIST1	protein	Q15672	UNIPROT	NF1	protein	P21359	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255530	0.281
MAPK1	protein	P28482	UNIPROT	ERF	protein	P50548	UNIPROT	up-regulates	phosphorylation	Ser161	SPTEDPRsPPACSSS	9606									10330152	t		lperfetto	The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a).	SIGNOR-67520	0.578
LCK	protein	P06239	UNIPROT	LCP2	protein	Q13094	UNIPROT	unknown	phosphorylation	Tyr426	NEEWYVSyITRPEAE	-1									8702662	t			Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro	SIGNOR-251382	0.744
PTPRE	protein	P23469	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr999	YASSNPEyLSASDVF	10116									15738637	t			In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver.	SIGNOR-248443	0.289
PIP5K1C	protein	O60331	UNIPROT	1-phosphatidyl-1D-myo-inositol 4-phosphate(3-)	smallmolecule	CHEBI:58178	ChEBI	down-regulates activity	chemical modification			9606									9367159	t		miannu	Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities	SIGNOR-277284	0.8
HMGB1	protein	P09429	UNIPROT	HOXC6	protein	P09630	UNIPROT	up-regulates activity	binding			-1									8890171	t		miannu	We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.	SIGNOR-219937	0.301
PRKDC	protein	P78527	UNIPROT	H2AX	protein	P16104	UNIPROT	up-regulates	phosphorylation			9606									23620287	t		gcesareni	Dna-dependentprotein_ kinase_ (dna-pk) that phosphorylate h2ax at dsbs	SIGNOR-192443	0.2
CREB1	protein	P16220	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001103							21902831	f		gcesareni	Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes.	SIGNOR-176536	0.473
GSK3A	protein	P49840	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr57	LSSTPLStPCSSVPS	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159398	0.2
GSK3B	protein	P49841	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates activity	phosphorylation	Ser249	LSPIDMEsQERIKAE	-1									1846781	t		lperfetto	Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity.	SIGNOR-18684	0.7
CHRM5	protein	P08912	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256873	0.2
LRRK2	protein	Q5S007	UNIPROT	PRDX3	protein	P30048	UNIPROT	down-regulates activity	phosphorylation	Thr146	SHLAWINtPRKNGGL	9606	BTO:0000793								21850687	t		miannu	Here, we show that LRRK2 interacts with human peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin (Trx) peroxidases. Importantly, mutations in the LRRK2 kinase domain significantly increased phosphorylation of PRDX3 compared to wild-type. The increase in PRDX3 phosphorylation was associated with decreased peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells. 	SIGNOR-262891	0.423
PIP5K1C	protein	O60331	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates activity	chemical modification			9606									9367159	t		miannu	Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities	SIGNOR-277285	0.8
PTPN1	protein	P18031	UNIPROT	PRKCD	protein	Q05655	UNIPROT	down-regulates	dephosphorylation			9606									11350745	t		gcesareni	Dephosphorylation of tyrosine residues by ptp1b, a protein tyrosine phosphatase, reduced the enhanced pkcdelta activity.	SIGNOR-107754	0.2
AML1-ETO	fusion protein	SIGNOR-FP1	SIGNOR	CEBPA	protein	P49715	UNIPROT	down-regulates activity	binding			9606	BTO:0001271								11283671	t		apalma	Here we show that AML1–ETO blocks C/EBPα –dependent activation of its own promoter and thereby inhibits autoregulation.	SIGNOR-255672	0.2
HCK	protein	P08631	UNIPROT	ELMO1	protein	Q92556	UNIPROT	up-regulates	phosphorylation	Tyr216	VLNSHDLyQKVAQEI	9606									15952790	t		llicata	We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts.	SIGNOR-138146	0.59
FYN	protein	P06241	UNIPROT	DCC	protein	P43146	UNIPROT	up-regulates activity	phosphorylation	Tyr1261	PTLESAQyPGILPSP	10090	BTO:0001909								15557120	t		miannu	Fyn tyrosine kinase, but not Src, regulates the phosphorylation of DCC in N1E-115 neuroblastoma cells.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1. these results show that DCC is phosphorylated by Fyn, but not Src, in N1E-115 cells, and that tyrosines 1261 and 1418 are the major phosphorylation sites of Fyn in vivo.	SIGNOR-268175	0.554
MAPK8	protein	P45983	UNIPROT	STAT6	protein	P42226	UNIPROT	down-regulates	phosphorylation	Ser707	IPPYQGLsPEESVNV	9606									21123173	t		llicata	Deactivation of stat6 through serine 707 phosphorylation by jnk.	SIGNOR-170153	0.362
RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	ribosomal RNA	smallmolecule	CHEBI:18111	ChEBI	up-regulates quantity	chemical modification			9606									22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266159	0.8
PRKD1	protein	Q15139	UNIPROT	SSH1	protein	Q8WYL5	UNIPROT	up-regulates activity	phosphorylation	Ser99	KLAVRLEsAWADRVR										23841590	t		lperfetto	Protein kinase D-mediated phosphorylation at Ser99 regulates localization of p21-activated kinase n the present study, we add another level of complexity to PAK4 regulation by showing that phosphorylation at Ser99 is required for its targeting to the leading edge. This phosphorylation is mediated by PKD1 (protein kinase D1). Phosphorylation of PAK4 at Ser99 also mediates binding to 14-3-3 protein, and is required for the formation of a PAK4-LIMK-PKD1 complex that regulates cofilin activity and directed cell migration|	SIGNOR-275939	0.494
PRKD3	protein	O94806	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser172	GQLVRNDsLWHRSDS										34010649	t		lperfetto	The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-275940	0.2
P-TEFb	complex	SIGNOR-C238	SIGNOR	AFF2	protein	P51816	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606	BTO:0000007								17135274	t		miannu	P-TEFb phosphorylates Af4 and down-regulates its transactivation activity. P-TEFb also phosphorylates AF4 which down-regulates its transactivation activity, providing a negative feedback mechanism for the control of P-TEFb elongation activity	SIGNOR-266798	0.398
valproic acid	chemical	CHEBI:39867	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								11742974	t		Federica	Here we show that VPA inhibits corepressor-associated HDACs at therapeutically employed concentrations and acts as a potent inducer of differentiation in several types of transformed cells.	SIGNOR-261078	0.8
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	STAT5A	protein	P42229	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0002882								8642285	t		irozzo	Phosphorylation of STAT1 and STAT5 was directly due to the tyrosine kinase activity of Bcr/Abl since it could be activated or deactivated by temperature shifting of cells expressing the Bcr/Abl ts mutant.These data suggest that STATs can be activated directly by Bcr/Abl, possibly bypassing JAK family kinase activation.	SIGNOR-255813	0.2
KIF5A	protein	Q12840	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272523	0.7
canertinib	chemical	CHEBI:61399	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000017;BTO:0000195								10753475	t	Canertinib is an irreversible tyrosine-kinase inhibitor with activity against EGFR (IC50 0.8 nM), HER-2 (IC50 19 nM) and ErbB-4 (IC50 7 nM).	gcesareni	Quinazoline analogues with 7-alkoxyamine solubilizing s were potent irreversible inhibitors of the isolated egfr enzyme, with ic(50[app]) values from 2 to 4 nm, and potently inhibited both egfr and erbb2 autophosphorylation in cells.	SIGNOR-76554	0.8
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2U	protein	Q5VVX9	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271371	0.584
TNF	protein	P01375	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606									10485710	t		gcesareni	Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)	SIGNOR-70625	0.301
PPP1CB	protein	P62140	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser370	KKTIVNDsRESCVEE	9606									23277204	t			Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity.	SIGNOR-248577	0.2
NR0B2	protein	Q15466	UNIPROT	NR5A2	protein	O00482	UNIPROT	down-regulates	binding			9606									15723037	t		gcesareni	Modulation of human nuclear receptor lrh-1 activity by phospholipids and shpthe human nuclear receptor liver receptor homolog 1 (hlrh-1) plays an important role in the development of breast carcinomas. This orphan receptor is efficiently downregulated by the unusual co-repressor shp	SIGNOR-134202	0.579
SIRT3	protein	Q9NTG7	UNIPROT	IDH2	protein	P48735	UNIPROT	up-regulates	deacetylation	Lys413	VESGAMTkDLAGCIH	9606									22416140	t		miannu	Site-specific, genetic incorporation of n(_)-acetyllysine into position 413 of idh2 revealed that acetylated idh2 displays a dramatic 44-fold loss in activity. Deacetylation by sirt3 fully restored maximum idh2 activity.	SIGNOR-196617	0.644
ATM	protein	Q13315	UNIPROT	RNF40	protein	O75150	UNIPROT	up-regulates activity	phosphorylation	Ser114	ALLRCHEsQGELSSA	9606	BTO:0000007								21362549	t		miannu	ATM-Mediated Phosphorylation of RNF20 and RNF40 in Response to DNA Damage and Its Requirement for Damage-Induced H2B Monoubiquitylation 	SIGNOR-276315	0.455
AKT1	protein	P31749	UNIPROT	MEF2D	protein	Q14814	UNIPROT	up-regulates				9606	BTO:0000222	BTO:0000887;BTO:0001103							10896679	f		lperfetto	Two candidates that may function as mediators of pi3-k in the phosphorylation of mef2 proteins are pkb and big map kinase 1.	SIGNOR-79338	0.585
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1931	SPTSPTYsPTSPKGS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273074	0.636
PRKCD	protein	Q05655	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates activity	phosphorylation	Ser348	PGPQSPGsPLEEERQ	-1									24632950	t		miannu	Of note, PKCδ, when it was activated by PDPK1, directly bound to the SH3-N domain of p47(phox) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47(phox) C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation.PKCδ phosphorylates p47phox for K-Ras-induced ROS generation. PKCδ binds to the SH3-N domain and phosphorylates Ser348 and Ser379 residues in p47phox for K-RasV12-induced ROS generation and consequent malignant transformation.	SIGNOR-276623	0.459
FKBP1A	protein	P62942	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates activity	binding			9606	BTO:0005493								8756725	t		lperfetto	Blocking fkbp12/type i receptor interaction with fk506 nonfunctional derivatives enhances the ligand activity, indicating that fkbp12 binding is inhibitory to the signaling pathways of the tgf beta family ligands	SIGNOR-236142	0.847
MAPK9	protein	P45984	UNIPROT	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation	Ser154	SSVSSSPsPPFGHSA	9606									12050114	t		gcesareni	Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro.	SIGNOR-88744	0.346
CHD2	protein	O14647	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates quantity	relocalization			9606									26895424	t		miannu	Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage.	SIGNOR-264527	0.2
CBLB	protein	Q13191	UNIPROT	NCK1	protein	P16333	UNIPROT	up-regulates activity	binding			9606	BTO:0000782								16503409	t		lperfetto	Activated Cbl and Cbl-b interacted with Crk-L, Zap-70, Nck, PLC-gamma	SIGNOR-236054	0.504
PRKCD	protein	Q05655	UNIPROT	ITGB2	protein	P05107	UNIPROT	up-regulates	phosphorylation	Thr758	NPLFKSAtTTVMNPK	9606	BTO:0000782								18550856	t		gcesareni	In this study, we present evidence that pkc isoforms are the major protein kinases that phosphorylate the c terminus of the integrin cd18 chain in leukocytes. Ser-745 is identified as a novel phosphorylation site in the integrin cytoplasmic domain. Additionally, we show that a thr-758-phosphorylated integrin peptide can interact with 14-3-3 proteins in leukocyte lysates	SIGNOR-178897	0.334
USP7	protein	Q93009	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates	deubiquitination			9606									16082221	t		gcesareni	Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins.	SIGNOR-139450	0.762
FGF12	protein	P61328	UNIPROT	SCN11A	protein	Q9UI33	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253436	0.268
TLN1	protein	Q9Y490	UNIPROT	ITGB8	protein	P26012	UNIPROT	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257636	0.457
SOS1	protein	Q07889	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									25624485	t	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.	gcesareni	Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts 	SIGNOR-175256	0.821
PRKACA	protein	P17612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser99	PFRGRSRsAPPNLWA	-1									10949026	t		gcesareni	Survival factors, acting through kinases such as Akt and PKA, induce endogenous BAD phosphorylation at two evolutionarily conserved sites, Ser-112 and Ser-136, which leads to the translocation of BAD from the mitochondria to the cytoplasm and the inhibition of BAD-dependent death 	SIGNOR-180780	0.521
PRKD3	protein	O94806	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser275	DNVRYGIsNIDTTIE										34010649	t		lperfetto	The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-275946	0.2
GSK3B	protein	P49841	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates activity	phosphorylation	Tyr216	RGEPNVSyICSRYYR	9606	BTO:0000007								14570592	t		lperfetto	However, in the present study, we clearly demonstrate that GSK3_ is capable of catalysing the autophosphorylation of Tyr216 in vitro.	SIGNOR-236564	0.2
HLF	protein	Q16534	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates				9606									23415677	f		miannu	Ectopic hlf expression inhibits apoptosis in murine and human cells, suggesting that hlf is regulating a conserved transcriptional program that inhibits cell death.	SIGNOR-256647	0.7
ADORA2A	protein	P29274	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257306	0.252
MAPK8	protein	P45983	UNIPROT	EIF4ENIF1	protein	Q9NRA8	UNIPROT	up-regulates	phosphorylation	Ser513	NLESHLMsPAEIPGQ	9606									22966201	t		llicata	Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress.	SIGNOR-198992	0.329
carbamazepine	chemical	CHEBI:3387	ChEBI	SCN2A	protein	Q99250	UNIPROT	down-regulates activity	chemical inhibition			10116									1658608	t		miannu	This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. 	SIGNOR-258353	0.8
OPTN	protein	Q96CV9	UNIPROT	BDNF	protein	P23560	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									22194658	f	same result in PC12 cell 	miannu	SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA.	SIGNOR-259878	0.284
PRKCA	protein	P17252	UNIPROT	PTPN12	protein	Q05209	UNIPROT	down-regulates	phosphorylation	Ser435	KKLERNLsFEIKKVP	9606									7520867	t		llicata	Ptp-pest is phosphorylated in vitro by both cyclic amp-dependent protein kinase (pka) and protein kinase c (pkc) at two major sites, which we have identified as ser39 and ser435. our results suggest that both pkc and pka are capable of phosphorylating, and therefore inhibiting, ptp-pest in vivo	SIGNOR-27304	0.327
ADRA1A	protein	P35348	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257279	0.608
KDM4B	protein	O94953	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	demethylation			9606									30759871	t		miannu	The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. The majority of studies regarding its function describe it as an activator that removes repressive H3K9me3 and H3K9me2 at or near regulated promoters in order to facilitate expression of the indicated pathways.	SIGNOR-265359	0.2
ABL1	protein	P00519	UNIPROT	TOP1	protein	P11387	UNIPROT	up-regulates activity	phosphorylation	Tyr268	AKMLDHEyTTKEIFR	9606									15448168	t		Manara	This study demonstrates that ABL1-dependent phosphorylation up-regulates topo I activity. The ABL1 SH3 domain bound directly to the N-terminal region of topo I. The results demonstrate that ABL1 phosphorylated topo I at Tyr268 in core subdomain II.	SIGNOR-260775	0.408
PAK2	protein	Q13177	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates activity	phosphorylation	Ser39	TTSTRTYsLGSALRP	-1									11895474	t		miannu	In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK. 	SIGNOR-250239	0.311
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Thr594	RLYDYEItDQYIYMV	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276221	0.389
Factor FVIIa:TF	complex	SIGNOR-C319	SIGNOR	F8	protein	P00451	UNIPROT	down-regulates activity	cleavage	Arg391	SPSFIQIrSVAKKHP	-1									10350471	t		lperfetto	N-Terminal sequencing along with time courses of proteolysis indicated that VIIa-TF/PL cleaved factor VIII first at R740, followed by concomitant cleavage at R336 and R372. |hus, heavy chain cleavage of factor VIII by VIIa-TF/PL produces an inactive factor VIII cofactor no longer capable of activation by thrombin.	SIGNOR-263642	0.468
MMP1	protein	P03956	UNIPROT	COL2A1	protein	P02458	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly906	EGPPGPQgLAGQRGI	9606									8609233	t		miannu	MMP-1 cleaves type II collagen at the peptide bond Gly906-Leu907 Proteolysis of triple-helical collagen is an important step in the progression toward irreversible tissue damage in osteoarthritis. Earlier work on the expression of enzymes in cartilage suggested that collagenase-1 (MMP-1) contributes to the process. 	SIGNOR-256341	0.456
ITGB1	protein	P05556	UNIPROT	A3/b1 integrin	complex	SIGNOR-C161	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253174	0.797
STK11	protein	Q15831	UNIPROT	BRSK2	protein	Q8IWQ3	UNIPROT	up-regulates	phosphorylation	Thr174	VGDSLLEtSCGSPHY	9606									14976552	t		lperfetto	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122485	0.481
PYCARD	protein	Q9ULZ3	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates	relocalization			9606									16964285	t		gcesareni	Asc directly induces bax-mediated apoptosis. Asc induces the translocation of bax to the mitochondria, bax-dependent cycs release from the mitochondria and casp9 activation.	SIGNOR-149522	0.36
CDK2	protein	P24941	UNIPROT	CCP110	protein	O43303	UNIPROT	down-regulates activity	phosphorylation	Thr566	NTRQQMDtPMVSCGN	-1									12361598	t		miannu	GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)	SIGNOR-265959	0.531
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	aspartic acid	smallmolecule	CHEBI:22660	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270373	0.8
MAPK3	protein	P27361	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9606									12169099	t		gcesareni	Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein.	SIGNOR-91379	0.774
FLT3	protein	P36888	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									14981546	f			FLT3-ITD signaling contributes to transcriptional inhibition of p27Kip1 and Bim gene expression	SIGNOR-261525	0.329
CSNK2A1	protein	P68400	UNIPROT	MME	protein	P08473	UNIPROT	down-regulates	phosphorylation	Ser6	sQMDITDI	9606									20957047	t		lperfetto	The cytoplasmic n-terminal domain of nep interacts with the phosphatase and tensin homologue deleted on chromosome 10 (pten) thereby regulating intracellular signaling via akt. Ser 6 is efficiently phosphorylated by protein kinase ck2. The phosphorylation of the cytoplasmic domain of nep inhibits its interaction with pten.	SIGNOR-168673	0.328
F2	protein	P00734	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates activity	cleavage	Phe43	ATLDPRSfLLRNPND	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263570	0.883
MRPL58	protein	Q14197	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262344	0.2
PDGFRB	protein	P09619	UNIPROT	ABL2	protein	P42684	UNIPROT	up-regulates activity	phosphorylation	Tyr299	HKLGGGQyGEVYVGV	-1									34144039	t		miannu	 PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2.	SIGNOR-277301	0.308
MAPK8	protein	P45983	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Ser315	ITATSPAsMVGGKPG	9606									12510059	t		gcesareni	Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1.	SIGNOR-96940	0.767
ZNF76	protein	P36508	UNIPROT	TBP	protein	P20226	UNIPROT	down-regulates activity	binding			9606									15280358	t		miannu	We identified ZNF76 as a novel transcriptional repressor that targets TBP. ZNF76 interacts with TBP through both its N and C termini. ZNF76 targets TBP for transcriptional repression.	SIGNOR-224650	0.408
AKT1	protein	P31749	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	down-regulates activity	phosphorylation			-1									16340011	t		gcesareni	It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase.	SIGNOR-252739	0.297
HTR2C	protein	P28335	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257355	0.481
SPOP	protein	O43791	UNIPROT	BRMS1	protein	Q9HCU9	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								22085717	t		Gianni	Intriguingly, BRMS1 turns out to be a potent substrate that is ubiquitinated by the Cul3-SPOP complex. Knockdown of SPOP increases the level of BRMS1 protein and represses the expression of BRMS1 repressive target genes such as OPN and uPA in breast cancer cells.	SIGNOR-268857	0.411
TWIST2	protein	Q8WVJ9	UNIPROT	PFDN4	protein	Q9NQP4	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255507	0.2
RNF5	protein	Q99942	UNIPROT	SLC26A4	protein	O43511	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								22750442	t		miannu	E3 ubiquitin ligase Rma1 is involved in Pendrin degradation	SIGNOR-271497	0.2
MDM2	protein	Q00987	UNIPROT	HIF1A	protein	Q16665	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001109								10640274	t		miannu	We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation.	SIGNOR-271385	0.628
PDGFRB	protein	P09619	UNIPROT	ABL2	protein	P42684	UNIPROT	up-regulates activity	phosphorylation	Tyr139	EKLRVLGyNQNGEWS	-1									34144039	t		miannu	 PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2.	SIGNOR-277302	0.308
CDK1	protein	P06493	UNIPROT	CKAP2	protein	Q8WWK9	UNIPROT	up-regulates	phosphorylation	Thr623	FKELKFLtPVRRSRR	9606			SIGNOR-C17						19369249	t		llicata	Among these, thr-622 was specifically phosphorylated by cdk1-cyclin b1 both in vitro and in vivo. these findings suggest that cdk1-cyclin b1-mediated phosphorylation of tmap is important for and contributes to proper regulation of microtubule dynamics and establishment of functional bipolar spindles during mitosis.	SIGNOR-185317	0.291
PDGFRB	protein	P09619	UNIPROT	ABL2	protein	P42684	UNIPROT	up-regulates activity	phosphorylation	Tyr303	GGQYGEVyVGVWKKY	-1									34144039	t		miannu	 PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2.	SIGNOR-277303	0.308
MAPK8	protein	P45983	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates	phosphorylation			9606									17525747	t		gcesareni	Our studies revealed a novel mechanism in which phosphorylation of jnk2 is mediated by jnk1 before phosphorylation of p53, and then p53 is directly phosphorylated by jnk2 at ser6.	SIGNOR-155205	0.574
MYC	protein	P01106	UNIPROT	CDC25A	protein	P30304	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11154267	t		lperfetto	Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen	SIGNOR-245465	0.613
WNT7B	protein	P56706	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates				9606		BTO:0000887;BTO:0001103							22944199	f		gcesareni	In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod.	SIGNOR-198925	0.3
UBE3A	protein	Q05086	UNIPROT	ALDH1A2	protein	O94788	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								29076503	t		lperfetto	Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner. 	SIGNOR-265135	0.2
SP1	protein	P08047	UNIPROT	IFITM5	protein	A6NNB3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23530031	f	 	miannu	Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation.	SIGNOR-254218	0.2
MAPK3	protein	P27361	UNIPROT	STMN2	protein	Q93045	UNIPROT	down-regulates activity	phosphorylation	Ser73	EAPRTLAsPKKKDLS	10116	BTO:0000142								9525956	t		lperfetto	SCG10, a growth cone-enriched MT-destabilizing protein, has been recently characterized as an in vitro substrate for various serine/threonine kinases including PKA, MAP kinase, and CDK (19). We have found that SCG10 is phosphorylated in vivo in developing rat brain.| The sites for MAP kinase phosphorylation were identified as Ser-62 and Ser-73 of SCG10|By expressing a series of phosphorylation site mutants, we showed that the MT-destabilizing effect of SCG10 could be modulated. While the nonphosphorylatable mutant showed higher activity than the wild-type protein, the activity of the mutant in which phosphorylation on all four sites was mimicked by an aspartate residue was greatly reduced. These data suggest that the nonphosphorylated state of SCG10 represents the most active form of the protein.	SIGNOR-249116	0.359
DYRK1B	protein	Q9Y463	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	phosphorylation	Ser279	KVAERRSsPLLRRKD	10090									15546868	t		lperfetto	Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent mannermirk phosphorylates hdac5 at ser-279	SIGNOR-235809	0.38
CDC42BPA	protein	Q5VT25	UNIPROT	CDC42BPA	protein	Q5VT25	UNIPROT	up-regulates activity	phosphorylation	Thr403	HLPFVGFtYTSSCVL	9534	BTO:0000298								11283256	t		miannu	N terminus-mediated dimerization and transautophosphorylation are essential for MRCKα catalytic activity. Three mutations, S234A, T240A, and T403A, strongly affected the in vitro autophosphorylation activity of FLAG-MRCKα-CAT1–473 (Fig. ​(Fig.5D).5D).	SIGNOR-275973	0.2
NFE2L2	protein	Q16236	UNIPROT	TBXAS1	protein	P24557	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14565864	t	 	miannu	Ecotopic expression of NF-E2 related factors showed that Nrf2, but not Nrf1, Nrf3, or Bach1, activated TXAS promoter in a dose-dependent manner. 	SIGNOR-253907	0.248
CSNK1A1	protein	P48729	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser318	SRTNSNAsTVSGRLS	9606									20110348	t		lperfetto	Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export	SIGNOR-252899	0.392
bisphenol A	chemical	CHEBI:33216	ChEBI	ESR2	protein	Q92731	UNIPROT	up-regulates activity	chemical activation			-1									9751507	t		miannu	Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings. 	SIGNOR-268739	0.8
PTPN6	protein	P29350	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	dephosphorylation	Tyr530	FTSTEPQyQPGENL	9606									17974954	t			Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B	SIGNOR-248472	0.543
DPM3	protein	Q9P2X0	UNIPROT	DPM complex	complex	SIGNOR-C289	SIGNOR	form complex	binding			9606									10835346	t		lperfetto	Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3.	SIGNOR-262565	0.779
CSNK2A2	protein	P19784	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr112	EGMQIPStQFDAAHP	-1									12432063	t		miannu	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin. 	SIGNOR-275994	0.453
PDPK1	protein	O15530	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Thr412	NQVFLGFtYVAPSVL	9606									9445476	t		gcesareni	A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.	SIGNOR-55310	0.714
5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol	chemical	CID:104895	PUBCHEM	CNR2	protein	P34972	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257474	0.8
GNAQ	protein	P50148	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates	binding			9606									17606614	t		gcesareni	Recently, the dbl-family guanine nucleotide exchange factor (gef) p63rhogef/geft has been described as a novel mediator of galpha(q/11) signaling to rhoa based on its ability to synergize with galpha(q/11) resulting in enhanced rhoa signaling in cells.	SIGNOR-156534	0.593
CREB5	protein	Q02930	UNIPROT	TNFRSF11B	protein	O00300	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21132541	f		miannu	 Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition),	SIGNOR-253812	0.2
CAMKK1	protein	Q8N5S9	UNIPROT	CAMK4	protein	Q16566	UNIPROT	up-regulates	phosphorylation	Thr200	EHQVLMKtVCGTPGY	9606									15143065	t		lperfetto	In response to an increase in intracellular Ca2+, CaMKIV binds Ca2+/CaM and becomes phosphorylated on T200 by CaMKK.	SIGNOR-124732	0.603
SYN2	protein	Q92777	UNIPROT	ACTB	protein	P60709	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								15265865	t		miannu	Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. 	SIGNOR-269182	0.2
CLK1	protein	P49759	UNIPROT	SRSF1	protein	Q07955	UNIPROT	up-regulates activity	phosphorylation			-1									8617202	t		miannu	 In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors.	SIGNOR-273857	0.695
TP53INP1	protein	Q96A56	UNIPROT	MAP1LC3C	protein	Q9BXW4	UNIPROT	up-regulates	binding			9606									22421968	t		gcesareni	These data indicate that cell death observed after tp53inp1-lc3 interaction depends on both autophagy and caspase activity. We conclude that tp53inp1 could act as a tumor suppressor by inducing cell death by caspase-dependent autophagy.	SIGNOR-196676	0.283
p38	proteinfamily	SIGNOR-PF16	SIGNOR	FH	protein	P07954	UNIPROT	up-regulates activity	phosphorylation	Thr90	GVTERMPtPVIKAFG	9606	BTO:0002058								30683654	t		miannu	In this study, we found that TGFβ induces FH Thr 90 phosphorylation by p38. Upon Notch activation, nuclear NICD promotes the interaction between CSL and p38-phosphorylated FH and thus FH/CSL/p53/Smad complex formation; this facilitates FH recruitment to p53-targed p21 promoter, where FH inhibits KDM2A-mediated demethylation of H3K36me2 through local production of fumarate	SIGNOR-266316	0.2
ropinirole	chemical	CHEBI:8888	ChEBI	DRD3	protein	P35462	UNIPROT	up-regulates activity	chemical activation			-1									9057850	t		miannu	Compound (R)-6, the most active compound, showed dopaminergic D2 activity and also had affinity for the 5HT1A serotonin receptor subtype. Its dopaminergic activity was more selective for the D2 receptor subtype (259-fold D2/D3 selectivity) than propylamine analogue (R)-2 (14-fold selectivity) or other dopaminergic standards (e.g., pergolide, lisuride, bromocriptine, and ropinirole, 1.0-, 3.4-, 8.7-, and 2.6-fold selectivities, respectively)	SIGNOR-258601	0.8
SRP54	protein	P61011	UNIPROT	SRSF1	protein	Q07955	UNIPROT	up-regulates activity	binding			-1									8816452	t		Monia	We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65).	SIGNOR-261161	0.304
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MITF	protein	O75030	UNIPROT	down-regulates	phosphorylation	Ser180	PGSSAPNsPMAMLTL	9606									10673502	t	The effect has been demonstrated using O75030-9	gcesareni	The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation.	SIGNOR-249575	0.2
CFAP53	protein	Q96M91	UNIPROT	DNAH5	protein	Q8TE73	UNIPROT	up-regulates activity	binding			10090		BTO:0000379							33347437	t		miannu	CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B).	SIGNOR-265544	0.2
MAP2K1	protein	Q02750	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates activity	phosphorylation	Tyr216	RGEPNVSyICSRYYR	9606		BTO:0001253							15020233	t		lperfetto	In vitro kinase assay was carried out using a recombinant human active mek1 and we found that gsk-3beta was phosphorylated on tyr(216) by this kinase in a dose- and time-dependent manner. Further, the pretreatment of fibroblasts with u0126 inhibited serum-induced nuclear translocation of gsk-3beta. These results suggested that mek1/2 induces tyrosine phosphorylation of gsk-3beta and this cellular event might induce nuclear translocation of gsk-3beta.	SIGNOR-236622	0.35
PRKAA1	protein	Q13131	UNIPROT	LIPE	protein	Q05469	UNIPROT	down-regulates	phosphorylation	Ser855	EPMRRSVsEAALAQP	9606			SIGNOR-C15						9636039	t		gcesareni	Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase.	SIGNOR-58255	0.388
JAK3	protein	P52333	UNIPROT	JAK3	protein	P52333	UNIPROT	up-regulates	phosphorylation	Tyr980	LLPLDKDyYVVREPG	9606									9391116	t		gcesareni	We found that jak3 is autophosphorylated on multiple sites including y980 and y981. Compared with the activity of wild-type (wt) jak3, mutant y980f demonstrated markedly decreased kinase activity, and optimal phosphorylation of jak3 on other sites was dependent on y980 phosphorylation. The mutant y980f also exhibited reduced phosphorylation of its substrates, gammac and stat5a. In contrast, mutant y981f had greatly increased kinase activity, whereas the double mutant, yy980/981ff, had intermediate activity.	SIGNOR-53590	0.2
GGCX	protein	P38435	UNIPROT	F10	protein	P00742	UNIPROT	up-regulates activity	carboxylation	Glu66	EETCSYEeAREVFED	-1									9538022	t		lperfetto	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263671	0.598
PRKDC	protein	P78527	UNIPROT	POU2F1	protein	P14859	UNIPROT	down-regulates	phosphorylation	Thr226	LQAQNLLtQLPQQSQ	9606									9368058	t		lperfetto	Through a similar strategy, t226 and s232 were characterized as the dna-pk phosphorylation sites	SIGNOR-53262	0.335
PRKACA	protein	P17612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									10230394	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.	SIGNOR-67379	0.521
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	Cadherins	proteinfamily	SIGNOR-PF71	SIGNOR	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 	SIGNOR-265811	0.8
PTPRC	protein	P08575	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	dephosphorylation	Tyr1007	VLPQDKEyYKVKEPG	10090									11201744	t			CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells 	SIGNOR-248348	0.484
ATP5PF	protein	P18859	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261398	0.2
MTOR	protein	P42345	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates	phosphorylation	Ser422	AEAFLGFsYAPPTDS	9606			SIGNOR-C2						18925875	t		gcesareni	Mtorc2 immunoprecipitated from wild-type, but not from mlst8- or rictor-knockout cells, phosphorylated sgk1 at ser(422)	SIGNOR-181531	0.844
PRKACA	protein	P17612	UNIPROT	PLCG1	protein	P19174	UNIPROT	down-regulates	phosphorylation	Ser1248	HGRAREGsFESRYQQ	9606	BTO:0000782;BTO:0000661								1370476	t		llicata	The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl.	SIGNOR-17901	0.2
PRRX1	protein	P54821	UNIPROT	MAFB	protein	Q9Y5Q3	UNIPROT	down-regulates activity	binding			-1									11036080	t		miannu	Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.	SIGNOR-221899	0.31
CEBPD	protein	P49716	UNIPROT	CXCL1	protein	P09341	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000801								23028973	f	 	 	CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions.	SIGNOR-254060	0.276
CDK1	protein	P06493	UNIPROT	TK1	protein	P04183	UNIPROT	down-regulates	phosphorylation	Ser13	LPTVLPGsPSKTRGQ	9606									14697231	t		gcesareni	Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase.	SIGNOR-120368	0.521
Complement C1 complex	complex	SIGNOR-C309	SIGNOR	C4A	protein	P0C0L4	UNIPROT	up-regulates activity	cleavage	Gly1446	TPLQLFEgRRNRRRR	-1									9087411	t		lperfetto	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263439	0.63
TLN1	protein	Q9Y490	UNIPROT	Av/b6 integrin	complex	SIGNOR-C179	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257632	0.572
PRKAA2	protein	P54646	UNIPROT	EEF2K	protein	O00418	UNIPROT	down-regulates activity	phosphorylation	Ser366	SPQVRTLsGSRPPLL	-1									14709557	t		miannu	AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase	SIGNOR-250319	0.48
PRKG1	protein	Q13976	UNIPROT	PLCB3	protein	Q01970	UNIPROT	down-regulates activity	phosphorylation	Ser26	VETLRRGsKFIKWDE	10116	BTO:0004576								11278298	t		lperfetto	PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG.	SIGNOR-249079	0.522
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH3	protein	P22223	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265843	0.8
P2RY1	protein	P47900	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257273	0.2
PRL	protein	P01236	UNIPROT	KRT19	protein	P08727	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000667								20103718	f	Regulation	miannu	PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes.	SIGNOR-251905	0.264
PRKDC	protein	P78527	UNIPROT	NHEJ1	protein	Q9H9Q4	UNIPROT	unknown	phosphorylation	Ser245	PHTSNSAsLQGIDSQ	9606									18644470	t		lperfetto	Here, we have identified two major in vitro dna-pk phosphorylation sites in the c-terminal region of xlf, serines 245 and 251. We show that these represent the major phosphorylation sites in xlf in vivo and that serine 245 is phosphorylated in vivo by dna-pk, while serine 251 is phosphorylated by ataxia-telangiectasia mutated (atm).	SIGNOR-179532	0.654
CRYBB2	protein	P43320	UNIPROT	CRYBB3	protein	P26998	UNIPROT	up-regulates activity	binding			9606									16319073	t		miannu	At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency.	SIGNOR-252152	0.463
TAX1BP1	protein	Q86VP1	UNIPROT	TNFAIP3	protein	P21580	UNIPROT	up-regulates activity	binding			9606	BTO:0000782;BTO:0001271								10435631	t		lperfetto	Tx1bp1 appears to be a novel a20-binding protein which mediate the anti-apoptotic activity of a20; tax1bp1 phosphorylation was pivotal for cytokine-dependent interactions among tax1bp1, a20, itch and rnf11 and downregulation of signaling by the transcription factor nf-Kb.	SIGNOR-69921	0.67
RNF4	protein	P78317	UNIPROT	NFYB	protein	P25208	UNIPROT	up-regulates activity	binding			9606									15496512	t		miannu	Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter.	SIGNOR-252230	0.2
GPR17	protein	Q13304	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257087	0.357
ADRA1A	protein	P35348	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257195	0.409
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates activity	phosphorylation	Thr446	LKNDGKRtRSKGTLR	4932									11337501	t			Trans-autophosphorylation of Thr-446 and Thr-451 by the two kinase moieties in a PKR dimer. autophosphorylation in the activation loop would promote proper alignment of key catalytic residues, or the correct orientation of the two lobes of the PKR kinase domain, required for substrate binding or phosphoryl transfer	SIGNOR-251110	0.2
okadaic acid	chemical	CHEBI:44658	ChEBI	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	up-regulates				9606									23493077	f	inferred from 70% of family members	gcesareni	Okadaic acid has been frequently used to enhance the phosphorylation of mst1 and mst2 and to trigger the activation of the hippo pathway.	SIGNOR-269947	0.8
CAMK2G	protein	Q13555	UNIPROT	PEA15	protein	Q15121	UNIPROT	unknown	phosphorylation	Ser116	KDIIRQPsEEEIIKL		BTO:0000099								9721757	t		llicata	Partly purified PEA-15 was a substrate in vitro for CaMKII, but not for casein kinase II. Two-dimensional phosphopeptide mapping demonstrated that the site phosphorylated in vitro by CaMKII was also phosphorylated in intact astrocytes in response to endothelin. CaMKII phosphorylated selectively Ser116 and had no effect on Ser104, but in vitro phosphorylation by CaMKII appeared to facilitate further phosphorylation by protein kinase C. 	SIGNOR-250701	0.351
PHC2	protein	Q8IXK0	UNIPROT	Polycomb repressive complex 1	complex	SIGNOR-C408	SIGNOR	form complex	binding			9606									31608994	t		miannu	PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b	SIGNOR-266810	0.78
MCM5	protein	P33992	UNIPROT	MCM	complex	SIGNOR-C268	SIGNOR	form complex	binding			9606									19946136	t			The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication.	SIGNOR-261675	0.763
EGR1	protein	P18146	UNIPROT	SF1	protein	Q15637	UNIPROT	up-regulates activity	binding			10090									19106114	t		miannu	GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. 	SIGNOR-254914	0.298
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	ITLN1	protein	Q8WWA0	UNIPROT	up-regulates activity	binding												26148048	t			Human intelectin-1 (hIntL-1) does not bind known human glycan epitopes but does interact with multiple glycan epitopes found exclusively on microbes: β-linked D-galactofuranose (β-Galf), D-phosphoglycerol-modified glycans, heptoses, D-glycero-D-talo-oct-2-ulosonic acid (KO) and 3-deoxy-D-manno-oct-2-ulosonic acid (KDO). | This ligand selectivity suggests that hIntL-1 functions in microbial surveillance.	SIGNOR-272498	0.7
ERRFI1	protein	Q9UJM3	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates quantity by destabilization	binding			10090	BTO:0001867								20421427	t			We report here an additional mechanism of EGFR suppression mediated by RALT, demonstrating that RALT-bound EGF receptors undergo endocytosis and eventual degradation into lysosomes	SIGNOR-252073	0.66
SOD1	protein	P00441	UNIPROT	Protein_aggregates	phenotype	SIGNOR-PH142	SIGNOR	up-regulates quantity				9606	BTO:0000312								22051914	f		lperfetto	SOD1 inclusions are found in motor neurons of patients with FALS, 	SIGNOR-262279	0.7
HNF1A	protein	P20823	UNIPROT	CDH17	protein	Q12864	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972;BTO:0004168								20568120	t	 	 	The present study aims to identify the transcription factors which interact and regulate CDH17 promoter activity that might contribute to the up-regulation of CDH17 gene in human HCC|we identified hepatic nuclear factor 1α (HNF1α) and caudal-related homeobox 2 (CDX2) binding sites at the proximal promoter region which modulate the CDH17 promoter activities in two HCC cell lines (Hep3B and MHCC97L)	SIGNOR-253970	0.319
MAPK9	protein	P45984	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser6	sDPSVEPP	9606									17525747	t		gcesareni	Our studies revealed a novel mechanism in which phosphorylation of jnk2 is mediated by jnk1 before phosphorylation of p53, and then p53 is directly phosphorylated by jnk2 at ser6. |Role of map kinases in uvb-induced phosphorylation of p53 at serine 20.	SIGNOR-155209	0.738
MMP3	protein	P08254	UNIPROT	HBEGF	protein	Q99075	UNIPROT	up-regulates	cleavage			9606	BTO:0000150								11043579	t		gcesareni	It was concluded that mmp-3 cleaves hb-egf at a specific site in the jm domain and that this enzyme might regulate the conversion of hb-egf from being a juxtacrine to a paracrine/autocrine growth factor.	SIGNOR-83339	0.497
ABL1	protein	P00519	UNIPROT	RIN1	protein	Q13671	UNIPROT	up-regulates	phosphorylation			9606									9144171	t		gcesareni	We also report that the amino-terminal domain of rin1 contains sequences that can mediate interactions with the abl tyrosine kinase and that rin1 is itself tyrosine phosphorylated by c-abl.	SIGNOR-48142	0.746
RBX1	protein	P62877	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000093								20130088	t		miannu	I3C-dependent activation of the aryl hydrocarbon receptor (AhR) initiates Rbx-1 E3 ligase-mediated ubiquitination and proteasomal degradation of ERalpha protein.	SIGNOR-271434	0.35
PRKAA1	protein	Q13131	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates activity	phosphorylation	Thr178	NHNHRIRtNPAIVKT	9606		BTO:0000887;BTO:0001103	SIGNOR-C15						17609368	t		lperfetto	Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538.	SIGNOR-156780	0.561
SHANK1	protein	Q9Y566	UNIPROT	Postsynaptic density assembly	phenotype	SIGNOR-PH163	SIGNOR	up-regulates				9606	BTO:0000938								28179641	f		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. 	SIGNOR-264605	0.7
UBE2L3	protein	P68036	UNIPROT	RNF19B	protein	Q6ZMZ0	UNIPROT	up-regulates activity	binding			9606	BTO:0000914								16709802	t		miannu	We demonstrated that both UbcH7 and UbcH8 bind to full-length NKLAM.  We demonstrated decreased protein expression and enhanced ubiquitination of URKL-1 in the presence of NKLAM. These data indicate that NKLAM is a RING finger protein that binds Ubcs and 	SIGNOR-271591	0.494
APBA3	protein	O96018	UNIPROT	STXBP1	protein	P61764	UNIPROT	up-regulates activity	binding			10116									9395480	t		miannu	Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1.	SIGNOR-264036	0.48
HMGA2	protein	P52926	UNIPROT	CCNA2	protein	P20248	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14645522	f		miannu	Transcriptional activation of the cyclin a gene by the architectural transcription factor hmga2	SIGNOR-119496	0.318
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	CDC7	protein	O00311	UNIPROT	up-regulates activity	phosphorylation	Thr376	QVAPRAGtPGFRAPE										10846177	t		llicata	Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks.	SIGNOR-250726	0.585
JAK1	protein	P23458	UNIPROT	IFNGR2/INFGR1	complex	SIGNOR-C142	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000801								19041276	t		lperfetto	The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process.	SIGNOR-249492	0.669
SYCE1	protein	Q8N0S2	UNIPROT	Synaptonemal_complex	complex	SIGNOR-C351	SIGNOR	form complex	binding			9606									22394509	t		miannu	The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region.	SIGNOR-264201	0.656
lofexidine	chemical	CHEBI:51368	ChEBI	ADRA2C	protein	P18825	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000246								22341244	t		Luana	Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism. 	SIGNOR-258330	0.8
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	SMARCA4	protein	P51532	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0001225								30177679	t		miannu	 We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation. 	SIGNOR-277409	0.284
DGC	complex	SIGNOR-C217	SIGNOR	GABA-A (a5-b1-g2) receptor	complex	SIGNOR-C335	SIGNOR	up-regulates quantity	binding			9606	BTO:0000938;BTO:0002606								22626542	t		miannu	 In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses.	SIGNOR-265438	0.2
TESK1	protein	Q15569	UNIPROT	CFL1	protein	P23528	UNIPROT	down-regulates activity	phosphorylation	Ser3	sGVAVSDG	9606	BTO:0000567								11294912	t		lperfetto	These results suggest that TESK1 functions downstream of integrins and plays a key role in integrin-mediated actin reorganization, presumably through phosphorylating and inactivating cofilin. We propose that tesk1 and lim-kinases commonly phosphorylate cofilin but are regulated in different ways and play distinct roles in actin reorganization in living cells.	SIGNOR-106777	0.545
RAB39B	protein	Q96DA2	UNIPROT	PICK1	protein	Q9NRD5	UNIPROT	up-regulates activity	binding			9534	BTO:0000298								25784538	t		miannu	GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a–c). The existence of such complex is supported by our co-immunoprecipitation experiments shown above.	SIGNOR-264045	0.384
PRKG2	protein	Q13237	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	phosphorylation	Ser254	WTYPRKEsGRLVEPV	9606	BTO:0001007								35066967	t		miannu	Secretory PKG II inhibited PDGF‐BB ‐induced PDGFRβ activation via phosphorylating its Ser254. 	SIGNOR-277577	0.276
(S,S)-asenapine	chemical	CHEBI:71257	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			10116									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258569	0.8
PPP1CC	protein	P36873	UNIPROT	DDX58	protein	O95786	UNIPROT	up-regulates activity	dephosphorylation	Ser8	MTTEQRRsLQAFQDY	9606	BTO:0000007								23499489	t		lperfetto	We identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.|endogenous RIG-I and MDA5 that interacted with PP1 exhibited markedly decreased phosphorylation levels at S8 and S88, respectively 	SIGNOR-264580	0.2
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr70	RNSPVTKtPPRDLPT	9823	BTO:0001840		SIGNOR-C3						23486913	t		lperfetto	These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation	SIGNOR-219273	0.924
STX11-VAMP8 SNARE complex	complex	SIGNOR-C273	SIGNOR	Platelet_degranulation	phenotype	SIGNOR-PH138	SIGNOR	up-regulates				9606	BTO:0000782								22767500	f		lperfetto	Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. 	SIGNOR-261902	0.7
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257938	0.8
INS	protein	P01308	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	binding			10029									16956584	t		lperfetto	Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface.	SIGNOR-236748	0.932
JWOGUUIOCYMBPV-GMFLJSBRSA-N	chemical	CID:6918328	PUBCHEM	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257976	0.8
UDP-N-acetyl-alpha-D-glucosamine	smallmolecule	CHEBI:16264	ChEBI	N-acyl-D-mannosamine 6-phosphate(2-)	smallmolecule	CHEBI:57666	ChEBI	up-regulates quantity	precursor of												10745088	t		lperfetto	UDP-GlcNAc 2-epimerase is a bifunctional enzyme and catalyzes the first two steps of neuraminic acid synthesis in the cytosol, the conversion of UDP-N-acetylglucosamine to ManAc and the phosphorylation to ManAc-6-phosphate.	SIGNOR-266075	0.8
RSPO3	protein	Q9BXY4	UNIPROT	LGR5	protein	O75473	UNIPROT	up-regulates	binding			9606									21693646	t		gcesareni	Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation	SIGNOR-174535	0.643
CCAN complex	complex	SIGNOR-C365	SIGNOR	Chromosome_segregation	phenotype	SIGNOR-PH44	SIGNOR	up-regulates				9606	BTO:0000567								18007590	f		lperfetto	Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis.	SIGNOR-265219	0.7
HSPA1A	protein	P0DMV8	UNIPROT	APAF1	protein	O14727	UNIPROT	down-regulates	binding			9606									10934467	t		gcesareni	Here we show that the documented anti-apoptotic effect of the principal heat-shock protein, hsp70, is mediated through its direct association with the caspase-recruitment domain (card) of apaf-1 and through apoptosome formation	SIGNOR-80451	0.443
FOXF2	protein	Q12947	UNIPROT	IRF2BPL	protein	Q9H1B7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000498								29374064	t		miannu	FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. 	SIGNOR-267152	0.256
MAPK1	protein	P28482	UNIPROT	MAPKAPK2	protein	P49137	UNIPROT	up-regulates	phosphorylation	Thr334	QSTKVPQtPLHTSRV	9606									8846784	t		fstefani	Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk.	SIGNOR-44347	0.52
FRS2	protein	Q8WU20	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			10116	BTO:0002809								9182757	t		fspada	In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.	SIGNOR-236953	0.795
RHOA	protein	P61586	UNIPROT	DIAPH1	protein	O60610	UNIPROT	up-regulates activity				9606	BTO:0000815								22820501	t		lperfetto	We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells. 	SIGNOR-253108	0.777
PLG	protein	P00747	UNIPROT	F2R	protein	P25116	UNIPROT	up-regulates activity	cleavage	Lys32	RARRPESkATNATLD	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus	SIGNOR-263573	0.62
STARD8	protein	Q92502	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260520	0.49
N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide	chemical	CHEBI:91408	ChEBI	JAK2	protein	O60674	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258301	0.8
TLRs	proteinfamily	SIGNOR-PF20	SIGNOR	NLRP3	protein	Q96P20	UNIPROT	up-regulates quantity by expression													28531279	f		lperfetto	The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3	SIGNOR-256428	0.2
MYC	protein	P01106	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				10090		BTO:0000724							7882978	f		irozzo	These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation.	SIGNOR-259110	0.7
PTPN12	protein	Q05209	UNIPROT	WAS	protein	P42768	UNIPROT	down-regulates activity	dephosphorylation	Tyr291	AETSKLIyDFIEDQG	10090									14707117	t			Mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities|WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST	SIGNOR-248660	0.456
MLL-ENL	fusion protein	SIGNOR-FP7	SIGNOR	MEIS1	protein	O00470	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14701735	f		irozzo	Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function.	SIGNOR-255862	0.2
NLRX1	protein	Q86UT6	UNIPROT	PCBP2	protein	Q15366	UNIPROT	up-regulates activity	binding			9606									28956771	t		Giorgia	Moreover, poly(rC) binding protein 2 (PCBP2) interacts with NLRX1 to participate in the NLRX1-induced degradation of MAVS and the inhibition of antiviral responses during HCV infection.	SIGNOR-260359	0.411
SUFU	protein	Q9UMX1	UNIPROT	GLI3	protein	P10071	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								20463034	t		Gianni	We show that loss of suppressor of fused (Sufu; an inhibitory effector for Gli proteins) results in destabilization of Gli2 and Gli3 full-length activators but not of their C-terminally processed repressors, whereas overexpression of Sufu stabilizes them.	SIGNOR-268868	0.885
DAPK3	protein	O43293	UNIPROT	DAPK3	protein	O43293	UNIPROT	up-regulates	phosphorylation	Thr299	PERRRLKtTRLKEYT	9606									15611134	t		lperfetto	Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311.Abrogation of phosphorylation of thr299, thr306, and ser311 had little effect on enzyme activity, but mutation of thr299 and thr300 to alanine resulted in redistribution of zipk from the cytosol to the nucleus	SIGNOR-132471	0.2
BRCA1	protein	P38398	UNIPROT	ERCC6	protein	Q03468	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								21756275	t		miannu	BRCA1 polyubiquitinates CSB and this polyubiquitination and subsequent degradation of CSB occur following UV irradiation, even in the absence of Cockayne syndrome A (CSA) protein. 	SIGNOR-272754	0.452
SLC16A2	protein	P36021	UNIPROT	3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	down-regulates quantity	relocalization			9606									28153798	t		scontino	T4 and T3 are released from the thyroid cell through transporters present at the basolateral plasma membrane of thyrocytes (Fig. 1). The most important transporter known to be responsible for thyroid hormone transport is the SLC16A2 monocarboxylate transporter 8 (MCT8), which can promote both uptake and efflux of TH and is involved in the release of TH from the thyroid gland.	SIGNOR-267139	0.8
IRAK1	protein	P51617	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Ser82	HSISYTLsRAQTVVV	9606	BTO:0000007								12496252	t		lperfetto	In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation	SIGNOR-96747	0.758
CCNC	protein	P24863	UNIPROT	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15546612	f		gcesareni	Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells.	SIGNOR-130589	0.2
TGFB1	protein	P01137	UNIPROT	CCNA2	protein	P20248	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									7592630	f		gcesareni	Expression of one of these components, cyclin a, is inhibited by tgf-beta treatment. We have identified a 760-base pair fragment of the human cyclin a gene promoter that is sufficient to confer tgf-beta responsiveness.	SIGNOR-29516	0.289
POLR1D	protein	P0DPB6	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606									12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266137	0.858
MRPL39	protein	Q9NYK5	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262358	0.648
CSNK2A1	protein	P68400	UNIPROT	EIF2S2	protein	P20042	UNIPROT	up-regulates	phosphorylation	Ser67	DTRKKDAsDDLDDLN	9606	BTO:0000567								16225457	t		lperfetto	The n-terminal domain of the human eif2beta subunit and the ck2 phosphorylation sites are required for its function. These results suggest that ser2 and ser67 contribute to the important role of the n-terminal region of eif2beta for its function in mammals.	SIGNOR-141051	0.355
LRRK2	protein	Q5S007	UNIPROT	LRRK2	protein	Q5S007	UNIPROT	up-regulates	phosphorylation	Thr1967	QQDKASLtRTLQHRI	9606	BTO:0000938								19824698	t		lperfetto	We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. substitution of thr1969 located in close proximity to thr1967 had little effect on its kinase activity	SIGNOR-188417	0.2
ZBTB16	protein	Q05516	UNIPROT	ZBTB16/ZBTB32	complex	SIGNOR-C80	SIGNOR	form complex	binding			9606									10572087	t		miannu	We show that fazf is a transcriptional repressor and it readily forms heterodimers with plzf.	SIGNOR-72377	0.368
IL2	protein	P60568	UNIPROT	TNFSF10	protein	P50591	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000782								22128144	f	 	miannu	We observe that the CD8(+) T-cell autocrine growth factor IL-2 coordinately increases Nab2 expression and decreases TRAIL expression. 	SIGNOR-253895	0.366
TNF	protein	P01375	UNIPROT	TNFRSF21	protein	O75509	UNIPROT	up-regulates	binding			9606		BTO:0000142							9714541	t		gcesareni	We report the identification and initial characterization of dr6, a new member of the tnf receptor family possessing a cytoplasmic death domain.	SIGNOR-59745	0.344
AT-406	chemical	CID:25022340	PUBCHEM	BIRC2	protein	Q13490	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189954	0.8
PRKCE	protein	Q02156	UNIPROT	ALDH2	protein	P05091	UNIPROT	up-regulates activity	phosphorylation	Ser296	KSPNIIMsDADMDWA	-1									28056995	t		lperfetto	 Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (epsilonPKC). |e identified S279 as a critical εPKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by εPKC likely also protects the enzyme against reactive aldehydes. 	SIGNOR-271864	0.286
SGCB	protein	Q16585	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255986	0.494
PTPRB	protein	P23467	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates activity	dephosphorylation	Tyr1356	YVHVNATyVNVKCVA	9606									21454675	t			Receptor-type protein tyrosine phosphatase beta (RPTP-beta) directly dephosphorylates and regulates hepatocyte growth factor receptor (HGFR/Met) function.|Expression of RPTP-β in primary human keratinocytes reduces both basal and HGF-induced Met phosphorylation at tyrosine 1356 and inhibits downstream MEK1/2 and Erk activation	SIGNOR-248440	0.371
CNTNAP1	protein	P78357	UNIPROT	CNTN1	protein	Q12860	UNIPROT	up-regulates activity	relocalization			10090	BTO:0001221								11069942	t		Gianni	These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr.	SIGNOR-269073	0.61
SRC	protein	P12931	UNIPROT	TNK2	protein	Q07912	UNIPROT	up-regulates activity	phosphorylation	Tyr859	KKVSSTHyYLLPERP	-1									36178070	t		miannu	We identified two Src phosphorylation sites within the MHR (Y859, Y860). Addition of Src-phosphorylated MHR to the Ack1 KD enhanced enzymatic activity. 	SIGNOR-276342	0.393
LCK	protein	P06239	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates activity	phosphorylation	Tyr240	RREDKFMyFEFPQPL	9606	BTO:0002035								11948419	t		miannu	MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e).	SIGNOR-275984	0.382
TRIP13	protein	Q15645	UNIPROT	MCC	complex	SIGNOR-C382	SIGNOR	down-regulates quantity by destabilization	binding			9606	BTO:0000567								25092294	t		miannu	We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4). 	SIGNOR-265972	0.531
tetrabenazine	chemical	CHEBI:9467	ChEBI	SLC18A2	protein	Q05940	UNIPROT	down-regulates activity	chemical inhibition			9606									8643547	t		miannu	Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2.	SIGNOR-258491	0.8
PRKACA	protein	P17612	UNIPROT	TRPM8	protein	Q7Z2W7	UNIPROT	up-regulates activity	phosphorylation	Thr17	MRNRRNDtLDSTRTL	9606	BTO:0000007								20110357	t	done	miannu	Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity.	SIGNOR-273791	0.2
PAK5	protein	Q9P286	UNIPROT	DDX5	protein	P17844	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr69	HPDLARRtAQEVETY	9606	BTO:0000150								34936874	t		lperfetto	PAK5 promotes RNA helicase DDX5 sumoylation and miRNA-10b processing in a kinase-dependent manner in breast cancer|The increased expression levels of PAK5 and phospho-DDX5 threonine 69 are associated with metastasis and poor clinical outcomes of patients. PAK5 facilitates the phosphorylation-dependent sumoylation of DDX5 to stabilize DDX5. Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing.	SIGNOR-275658	0.2
TNF	protein	P01375	UNIPROT	MC1R	protein	Q01726	UNIPROT	down-regulates activity	transcriptional regulation			9606	BTO:0000847								9767234	f		miannu	MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression.	SIGNOR-252381	0.294
CAPRIN2	protein	Q6IMN6	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									19619488	t		gcesareni	A cytoplasmic protein in vertebrates, referred to as caprin-2, binds to lrp6 and facilitates lrp6 phosphorylation by gsk3	SIGNOR-187177	0.365
PPP2CA	protein	P67775	UNIPROT	RELA	protein	Q04206	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000848			SIGNOR-C13					11591705	t		gcesareni	Rela was dephosphorylated by a purified pp2a core enzyme, a heterodimer formed by the catalytic subunit of pp2a (pp2ac) and pr65, in a concentration-dependent manner.These data suggest that the constitutive activation of rela in melanoma cells could be due, at least in part, to the deficiency of pp2a, which exhibits decreased dephosphorylation of nf-kappa b/rela.	SIGNOR-110959	0.471
ACAN	protein	P16112	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									16051604	t		lperfetto	Cartilage oligomeric matrix protein/thrombospondin 5 (COMP/TSP5) is a major component of the extracellular matrix of the musculoskeletal system. 	SIGNOR-266983	0.7
PRKDC	protein	P78527	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates activity	phosphorylation	Thr2620	QGTLQTRtQEGSLSA	-1									12186630	t		lperfetto	 We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function.	SIGNOR-249158	0.2
CDK6	protein	Q00534	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Thr401	SKALRIStPLTGVRY	9606	BTO:0001938								11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus)	SIGNOR-104719	0.667
FAM107A	protein	O95990	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271								10983986	t		miannu	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-81800	0.2
AREG	protein	P15514	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	binding			9606									10209155	t	Amphiregulin is an autocrine growth factor	lperfetto	ErbB ligands include: EGF, transforming growth factor (TGF)_, and amphiregulin which only bind ErbB1	SIGNOR-67000	0.764
MAPK1	protein	P28482	UNIPROT	NR3C2	protein	P08235	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser263	NVGSPLSsPLSSMKS	9606	BTO:0005043								22798426	t		miannu	 Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276105	0.291
PBRM1	protein	Q86U86	UNIPROT	RARB	protein	P10826	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15601824	f		miannu	We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues.	SIGNOR-132378	0.43
MAPKAPK2	protein	P49137	UNIPROT	LSP1	protein	P33241	UNIPROT	unknown	phosphorylation	Ser252	PKLARQAsIELPSMA	-1									8995217	t		miannu	LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils. . Inspection of the human LSP1 protein sequence (22) identifies two serine residues at positions 204 and 252 as potential phosphorylation sites. The results show that LSP1 is a substrate for MAPKAP kinase 2 in vitro and that the phosphorylation site(s) are located in the C-terminal 152 amino acid residues, as predicted from the sequence.	SIGNOR-250148	0.622
PTPN11	protein	Q06124	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	dephosphorylation	Tyr1179	GLENGLNyIDLDLVK	9606									7515062	t		gcesareni	The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling.	SIGNOR-27024	0.893
SKA3	protein	Q8IX90	UNIPROT	SKA complex	complex	SIGNOR-C364	SIGNOR	form complex	binding			-1									22483620	t		lperfetto	We show that the structure of the Ska core complex is a W-shaped dimer of coiled coils, formed by intertwined interactions between Ska1, Ska2, and Ska3. 	SIGNOR-265196	0.916
TNFRSF21	protein	O75509	UNIPROT	TRADD	protein	Q15628	UNIPROT	up-regulates	binding			9606									14585074	t		amattioni	Dr6 interacts with tradd	SIGNOR-100184	0.6
FGF2	protein	P09038	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates				9606									20974802	f		gcesareni	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription.	SIGNOR-168992	0.402
AKT2	protein	P31751	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser256	SPRRRAAsMDNNSKF	9606									10377430	t		lperfetto	Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus.	SIGNOR-252871	0.757
MAPK1	protein	P28482	UNIPROT	CASP8	protein	Q14790	UNIPROT	down-regulates	phosphorylation	Ser387	YLEMDLSsPQTRYIP	9606		BTO:0000149							24342355	t		lperfetto	We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity	SIGNOR-203473	0.749
CAMK2G	protein	Q13555	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	phosphorylation	Ser727	TDNLLPMsPEEFDEV		BTO:0000944								11972023	t		llicata	For maximal gene activation, S727 in the transcription activation domain of Stat1 also is inducibly phosphorylated by IFN-gamma. We previously purified a group of nuclear proteins that interact specifically with the Stat1 transcription activation domain. In this report, we identified one of them as the multifunctional Ca(2+)/calmodulin-dependent kinase (CaMK) II. We demonstrate that IFN-gamma mobilizes a Ca(2+) flux in cells and activates CaMKII. CaMKII can interact directly with Stat1 and phosphorylate Stat1 on S727 in vitro. Inhibition of Ca(2+) flux or CaMKII results in a lack of S727 phosphorylation and Stat1-dependent gene activation, suggesting in vivo phosphorylation of Stat1 S727 by CaMKII. 	SIGNOR-250706	0.485
COPS3	protein	Q9UNS2	UNIPROT	COP9 signalosome variant 1	complex	SIGNOR-C489	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270769	0.915
lanreotide	chemical	CHEBI:135901	ChEBI	SSTR2	protein	P30874	UNIPROT	up-regulates activity	chemical activation			9606									25060168	t		miannu	Octreotide long-acting release (LAR) and lanreotide Autogel (ATG) are the two somatostatin analogs currently approved for treatment of acromegaly and neuroendocrine tumors (NETs). The strength of these drugs has been their specificity for somatostatin receptor subtype 2. 	SIGNOR-259242	0.8
Elongator complex	complex	SIGNOR-C466	SIGNOR	TUBA4A	protein	P68366	UNIPROT	up-regulates activity	acetylation			9606	BTO:0000007								19185337	t		miannu	Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. 	SIGNOR-269722	0.254
PPP2CA	protein	P67775	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	dephosphorylation			9606		BTO:0000671							16239230	t		miannu	Both pp2a holoenzymes were found to associate with raf1 and catalyze dephosphorylation of inhibitory phospho-ser-259. Together these findings indicate that pp2a abalphac and abdeltac holoenzymes function as positive regulators of raf1-mek1/2-erk1/2 signaling by targeting raf1.	SIGNOR-141170	0.573
TRADD	protein	Q15628	UNIPROT	CASP8	protein	Q14790	UNIPROT	up-regulates activity	binding			9606									14585074	t		amattioni	Tradd recruits caspase-8	SIGNOR-118591	0.906
AKT1	protein	P31749	UNIPROT	CHUK	protein	O15111	UNIPROT	up-regulates	phosphorylation	Thr23	EMRERLGtGGFGNVC	9606				SIGNOR-C14					19609947	t		gcesareni	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-187006	0.653
MARCHF5	protein	Q9NX47	UNIPROT	DNM1L	protein	O00429	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								16874301	t		miannu	We found that MITOL associated with and ubiquitinated mitochondrial fission protein hFis1 and Drp1.Pulse–chase experiment also indicated that MITOL overexpression promoted Drp1 turnover.	SIGNOR-271894	0.2
OXTR	protein	P30559	UNIPROT	DRD2	protein	P14416	UNIPROT	up-regulates activity	binding			10116									27425032	t		miannu	Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling.	SIGNOR-270333	0.383
KLF4	protein	O43474	UNIPROT	MYOCD	protein	Q8IZQ8	UNIPROT	down-regulates				9606		BTO:0000887;BTO:0001260							21673106	f		gcesareni	Finally, we demonstrate that the basal expression of both myocd and mrtf-a is negatively regulated by klf4. . The mechanism of inhibition of myocd or mrtf-a by klf4 is currently unclear and warrants future study.	SIGNOR-174255	0.479
YAP1	protein	P46937	UNIPROT	TEAD3	protein	Q99594	UNIPROT	up-regulates	binding			9606									23431053	t	Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4	gcesareni	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.	SIGNOR-201471	0.844
PPP1CA	protein	P62136	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates	dephosphorylation			9606									12840032	t		fstefani	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases	SIGNOR-103155	0.455
PRKD1	protein	Q15139	UNIPROT	CTTN	protein	Q14247	UNIPROT	down-regulates	phosphorylation	Ser348	EAVTSKTsNIRANFE	9606	BTO:0000150								19038333	t		lperfetto	Here we have investigated the possible role of pkd as a cortactin kinase. Using a mass spectrometric approach, we found that pkd phosphorylates cortactin on ser 298 examination of cortactin phosphorylation kinetics revealed that ser 298 serves as a priming site for subsequent phosphorylation of ser 348	SIGNOR-182502	0.433
RIPK3	protein	Q9Y572	UNIPROT	MLKL	protein	Q8NB16	UNIPROT	up-regulates activity	phosphorylation	Ser358	ELRKTQTsMSLGTTR	10090									24012422	t		gianni	MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays	SIGNOR-266427	0.742
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	MAP3K5	protein	Q99683	UNIPROT	down-regulates	binding			9606	BTO:0000567								10411906	t	Ser-967 is a critical component of the 14-3-3 interaction site of ASK1 and suggest that phosphorylation of this residue may be the major mode of regulation of 14-3-3 binding to ASK1	gcesareni	14-3-3 may suppress ask1-induced cell death by directly inhibiting the catalytic activity of ask1.	SIGNOR-69408	0.2
ATM	protein	Q13315	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1497	EPGVERSsPSKCPSL	9606	BTO:0000150								10550055	t		gcesareni	However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci.	SIGNOR-72064	0.813
BECN1	protein	Q14457	UNIPROT	USP10	protein	Q14694	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0003704								21962518	t		lperfetto	Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. 	SIGNOR-260298	0.488
CD3	complex	SIGNOR-C432	SIGNOR	TCR	complex	SIGNOR-C153	SIGNOR	form complex	binding			9606									12507424	t		miannu	The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ	SIGNOR-269472	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser293	GSTKRRKsMSGASPK	9606									23708659	t		lperfetto	Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.	SIGNOR-252793	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	KLK3	protein	P07288	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001321								11909978	t	 	 	NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer.	SIGNOR-253667	0.267
MAP2K1	protein	Q02750	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Ser307	TRRSRTEsITATSPA	9606		BTO:0000887							11160134	t		lperfetto	Thus, at least three kinases mediate phosphorylation of ser307, including jnk, serine kinases in the pi 3-kinase cascade that are activated byinsulinor igf-1, and mek1-sensitive kinase cascades during tnf-alfa stimulation.	SIGNOR-236611	0.36
a7/b1 integrin	complex	SIGNOR-C126	SIGNOR	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	down-regulates activity													9925758	f		lperfetto	These data indicate that alpha7 expression leads to the functional down regulation of alpha5beta1 integrin by decreasing ligand binding affinity and surface expression. In conclusion, the data reported establish the existence of a negative cooperativity between alpha7 and alpha5 integrins that may be important in determining functional regulation of integrins during myogenic differentiation.	SIGNOR-253251	0.747
ERBB2	protein	P04626	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates	phosphorylation	Tyr1196	GAVENPEyLTPQGGA	9606	BTO:0000150								15156151	t		gcesareni	Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227	SIGNOR-124856	0.2
MAPK1	protein	P28482	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Ser59	GGQESQPsPLALLAA	9606	BTO:0000452								19318349	t		gcesareni	PKCalpha, which was activated in senescent cells by ROS strongly activated Erk1/2, and the SA-pErk1/2 in turn phosphorylated Sp1 on Ser(59). Sp1-enhanced transcription of p21(Sdi1) resulted in regulation of cellular senescence in primary human diploid fibroblast cells.	SIGNOR-248075	0.629
5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide	chemical	CID:73755145	PUBCHEM	FLT1	protein	P17948	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258287	0.8
LCK	protein	P06239	UNIPROT	CD3E	protein	P07766	UNIPROT	up-regulates activity	phosphorylation	Tyr199	RKGQRDLySGLNQRR	9534									11855827	t			Tyrosine Phosphorylation of CD8- Chimeras by Lck and ZAP-70 in COS Cells. both Y170F and Y181F chimeric proteins could be efficiently phosphorylated by Lck in vivo. phosphorylation of Y170 and Y181 within CD3- –ITAM provides to CD3- the potential to interact with multiple downstream effectors and signaling pathways.	SIGNOR-251369	0.679
AURKB	protein	Q96GD4	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	phosphorylation	Ser29	ATKAARKsAPATGGV	9606									21282660	t	Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription.	gcesareni	Histone code pathway involving h3 s28 phosphorylation and k27 acetylation activates transcription and antagonizes polycomb silencingaurora-b phosphorylates histone h3 at serine28 with regard to the mitotic chromosome condensation	SIGNOR-171717	0.2
HCRTR2	protein	O43614	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257290	0.409
CD79A	protein	P11912	UNIPROT	BCR-Dl	complex	SIGNOR-C436	SIGNOR	form complex	binding			9606	BTO:0000776								32323266	t		scontino	BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition.	SIGNOR-268200	0.641
CSNK2A1	protein	P68400	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr112	EGMQIPStQFDAAHP	-1									12432063	t		miannu	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin. 	SIGNOR-275997	0.54
FGFR1	protein	P11362	UNIPROT	PDP1	protein	Q9P0J1	UNIPROT	down-regulates activity	phosphorylation	Tyr94	SILKANEySFKVPEF	10090	BTO:0000944								24962578	t		miannu	Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients. 	SIGNOR-276640	0.296
CSNK2A1	protein	P68400	UNIPROT	TERF1	protein	P54274	UNIPROT	up-regulates	phosphorylation	Thr122	LTACQLRtIYICQFL	9606									18347021	t		lperfetto	Regulation of telomeric repeat binding factor 1 binding to telomeres by casein kinase 2-mediated phosphorylation. Mapping of the ck2 target site identified threonine 122 as a substrate in trf1. A threonine to alanine change at this position led to a diminished dna binding due to reduced dimerization of trf1.	SIGNOR-178034	0.2
CSNK2A1	protein	P68400	UNIPROT	XRCC1	protein	P18887	UNIPROT	up-regulates	phosphorylation	Thr519	EDPYAGStDENTDSE	9606									20471329	t		lperfetto	Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523	SIGNOR-165431	0.404
PBX4	protein	Q9BYU1	UNIPROT	FGF8	protein	P55075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003560								10026229	t		miannu	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 	SIGNOR-265780	0.2
CSNK2A1	protein	P68400	UNIPROT	TSPY1	protein	Q01534	UNIPROT	up-regulates activity	phosphorylation	Thr300	PPEEGTEtSGDSQLL	-1									16426576	t		llicata	CK2-dependent C-terminal phosphorylation at T300 directs the nuclear transport of TSPY protein	SIGNOR-250969	0.2
CSNK2B	protein	P67870	UNIPROT	OCLN	protein	Q16625	UNIPROT	unknown	phosphorylation	Ser408	DYTTGGEsCDELEED	9606	BTO:0002043								12804768	t		llicata	Mutagenesis of serine 407 to alanine resulted in reduced ability of the kinase to phosphorylate occludin. The threonine 403 to alanine mutant had a smaller effect but the double mutant (T403/S407A) was even less phosphorylated than either of the single mutants. These data are consistent with the claim that CK2 is the kinase in brain extracts responsible for phosphorylation of occludin.	SIGNOR-251079	0.426
GSK3B	protein	P49841	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates	phosphorylation	Ser163	GGWDGLLsYFGTPTW	9606	BTO:0000938								15525785	t		lperfetto	Glycogen synthase kinase-3beta phosphorylates bax and promotes its mitochondrial localization during neuronal apoptosis. Gsk-3beta directly phosphorylated bax(alpha) on ser163	SIGNOR-130141	0.383
ACTB	protein	P60709	UNIPROT	Brain-specific SWI/SNF SMARCA2 variant	complex	SIGNOR-C485	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270748	0.484
EGFR	protein	P00533	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr102	YDLKLQEyQSAIKVE	9606									26718225	t		miannu	 Here, we found that nuclear EGFR induced phosphorylation of PPARγ at Tyr-74 leading to PPARγ ubiquitination and degradation by mouse double minute 2 (MDM2) ubiquitin ligase. 	SIGNOR-277190	0.529
DVL2	protein	O14641	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	up-regulates	binding			9606									17529994	t		lperfetto	Dishevelled (dvl) transduces the wnt signal by interacting with the cytoplasmic axin complex.	SIGNOR-227920	0.638
SRC	protein	P12931	UNIPROT	BDKRB2	protein	P30411	UNIPROT	up-regulates	phosphorylation	Tyr347	RKKSWEVyQGVCQKG	9606									16226010	t		lperfetto	Here we demonstrate that egf is capable of inducing src-mediated phosphorylation of the tyrosine residues 177 and 347 of bkr. Their replacement by phenylalanine led to bkr mutants which are unable to activate the camp pathway.	SIGNOR-141107	0.265
PRKACA	protein	P17612	UNIPROT	DUOX1	protein	Q9NRD9	UNIPROT	up-regulates	phosphorylation	Ser955	KDLCRRAsYISQDMI	9606									19144650	t		llicata	We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade	SIGNOR-183449	0.2
ARHGAP11A	protein	Q6P4F7	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260466	0.529
CAMK2A	protein	Q9UQM7	UNIPROT	HRH1	protein	P35367	UNIPROT	down-regulates	phosphorylation	Ser398	WKRLRSHsRQYVSGL	9606		BTO:0000975							15107581	t	Translocation from Endosome to Lysosome	gcesareni	As we have shown previously, human h1r can be phosphorylated in vitro by several kinases includingpka, pkc, pkg, and camk ii in summary, these data suggest that thr140, thr142, ser396, ser398, and thr478 can be phosphorylated by the kinases described above (table 2).	SIGNOR-124344	0.286
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	tRNA(Glu)	smallmolecule	CHEBI:29175	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270379	0.8
BTRC	protein	Q9Y297	UNIPROT	EZH2	protein	Q15910	UNIPROT	down-regulates	ubiquitination			9606	BTO:0000785								24469040	t		lperfetto	_-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs _-trcp-mediated ezh2 degradation.	SIGNOR-204481	0.383
KIF18A	protein	Q8NI77	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272526	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ADARB1	protein	P78563	UNIPROT	down-regulates activity	phosphorylation	Thr553	LQGERLLtMSCSDKI	-1									31095429	t		miannu	AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively, and overexpression of the phosphomimic mutants ADAR1p110 (T738D) and ADAR2 (T553D) resulted in a 50-100% reduction in editase activity. 	SIGNOR-266358	0.2
PRKACA	protein	P17612	UNIPROT	NF2	protein	P35240	UNIPROT	down-regulates	phosphorylation	Ser518	DTDMKRLsMEIEKEK	9606									18071304	t		lperfetto	Merlin localizes to the cell membrane where it links the actin cytoskeleton to membrane proteins.we identify a novel pka phosphorylation site, serine 10, in the n terminus of merlin. s10a reduces the amount of cellular f-actin and merlin s10d stabilizes f-actin filaments.	SIGNOR-159844	0.379
RXRA	protein	P19793	UNIPROT	RARA	protein	P10276	UNIPROT	up-regulates	binding			9606									1310351	t		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16665	0.711
CAPN3	protein	P20807	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates activity	cleavage			9606									25969760	t		lperfetto	Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase	SIGNOR-251607	0.275
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	OPTN	protein	Q96CV9	UNIPROT	up-regulates activity	polyubiquitination	Lys501	LQLAVLLkENDAFED	9606	BTO:0000567								32014991	t		miannu	DCAF4-mediated ubiquitination of OPTN facilitates the degradation of DBR-exposed SOD1. OPTN is involved in degradation of DBR-exposed SOD1. These data demonstrate that DCAF4-including CRL4 complex mediates OPTN ubiquitination at lysine 501, and this ubiquitination is absent in the ALS-related OPTNmut.	SIGNOR-272209	0.2
VRK1	protein	Q99986	UNIPROT	H3C1	protein	P68431	UNIPROT	unknown	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									17938195	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	We show that histone h3 is phosphorylated by vaccinia-related kinase 1 (vrk1). Direct phosphorylation of thr3 and ser10 in h3 by vrk1 both in vitro and in vivo was observed. Loss of vrk1 activity was associated with a marked decrease in h3 phosphorylation during mitosis.	SIGNOR-158436	0.2
FLI1	protein	Q01543	UNIPROT	IL10	protein	P22301	UNIPROT	up-regulates	transcriptional regulation			9606	BTO:0000801								20879862	f			In terms of cytokine expression, increased FLI-1 levels specifically enhanced IL-10 expression	SIGNOR-254516	0.2
COL4A4	protein	P53420	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	up-regulates activity	binding			9606	BTO:0000664								12123670	t		lperfetto	We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1.	SIGNOR-253245	0.432
PRKACA	protein	P17612	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates	phosphorylation	Ser1177	TSRIRTQsFSLQERQ	9606									11729179	t		gcesareni	Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase aon serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.	SIGNOR-112371	0.373
MAPK1	protein	P28482	UNIPROT	RPS3	protein	P23396	UNIPROT	up-regulates	phosphorylation	Thr42	SGVEVRVtPTRTEII	9606									15950189	t		lperfetto	Erk phosphorylates threonine 42 residue of ribosomal protein s3.	SIGNOR-137955	0.2
FAS	protein	P25445	UNIPROT	FAS	protein	P25445	UNIPROT	up-regulates activity	binding			9606									14585074	t		lperfetto	The fas receptor, upon binding to the fasl, trimerizes	SIGNOR-85991	0.2
SMO	protein	Q99835	UNIPROT	TIAM1	protein	Q13009	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000142							20654717	t		gcesareni	This latter work suggested that inactive smo prevents rac1 activation by interacting with the rac guanine nucleotide exchange factor (gef) t-lymphoma invasion and metastasis 1 (tiam1). This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1	SIGNOR-167070	0.271
EIF3B	protein	P55884	UNIPROT	EIF3_complex	complex	SIGNOR-C401	SIGNOR	form complex	binding			-1									16920360	t		miannu	Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 	SIGNOR-266399	0.949
USP8	protein	P40818	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates quantity	destabilization			9606	BTO:0000567								16520378	t			Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation.	SIGNOR-266903	0.432
3-isobutyl-1-methylxanthine	chemical	CHEBI:48518	ChEBI	PPARG	protein	P37231	UNIPROT	up-regulates				9606									11279134	f		fspada	The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin	SIGNOR-106484	0.8
PPP2CB	protein	P62714	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	dephosphorylation	Ser177	AKELDQGsLCTSFVG	9606	BTO:0000176								19607706	t			Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha|Chronic Ser 177/181 phosphorylation of IKKβ was due to UVB-induced inhibition of the catalytic subunit of the Ser-Thr phosphatase PP2A (PP2Ac)	SIGNOR-248581	0.262
ELF3	protein	P78545	UNIPROT	SPRR1B	protein	P22528	UNIPROT	up-regulates quantity by expression	transcriptional regulation												12682075	f	 	 	Consistent with this, overexpression of EBS-binding proteins ESE-1 and ESE-3 significantly stimulated SPRR1B promoter activity. Furthermore, preceding SPRR1B transcription, PMA up-regulated mRNA expression of ETS family members such as ESE-1 and ESE-3	SIGNOR-254281	0.2
MAPK1	protein	P28482	UNIPROT	PDE4D	protein	Q08499	UNIPROT	up-regulates	phosphorylation			9606									10828059	t	The effect has been demonstrated using Q08499-4	llicata	The short pde4d1 isoenzyme is activated by erk2 phosphorylation this signifies that erk2 phosphorylated pde4d1 at a single site, ser491, that is cognate to the single erk2 phosphorylation site (ser579) found in pde4d3.	SIGNOR-77559	0.36
FYN	protein	P06241	UNIPROT	TXK	protein	P42681	UNIPROT	up-regulates activity	phosphorylation	Tyr420	RYVLDDEyVSSFGAK										11353545	t		lperfetto	We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association.	SIGNOR-249341	0.354
MIF	protein	P14174	UNIPROT	CD74	protein	P04233	UNIPROT	up-regulates	binding			9606									12782713	t		miannu	Mif binds to the extracellular domain of cd74, and cd74 is required for mif-induced activation of the extracellular signal-regulated kinase-1/2 map kinase cascade, cell proliferation, and pge2 production.	SIGNOR-101526	0.725
CHUK	protein	O15111	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	phosphorylation	Ser536	SGDEDFSsIADMDFS	9606	BTO:0000007;BTO:0000567		SIGNOR-C14	SIGNOR-C13					15489227	t		lperfetto	Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.	SIGNOR-129931	0.841
S1PR1	protein	P21453	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256992	0.357
KRAS	protein	P01116	UNIPROT	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	up-regulates				9606	BTO:0000797								27340238	f			These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein.	SIGNOR-259372	0.7
CSNK2A2	protein	P19784	UNIPROT	XRCC1	protein	P18887	UNIPROT	up-regulates activity	phosphorylation	Ser518	GEDPYAGsTDENTDS	9606	BTO:0000567								15367657	t		llicata	XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1.	SIGNOR-251050	0.473
MAPK8	protein	P45983	UNIPROT	ELK3	protein	P41970	UNIPROT	down-regulates activity	phosphorylation												11042694	t		miannu	JNK binds to the J box in the middle of the protein, and binding is required for phosphorylation of the adjacent EXport motif. Both the binding and phosphorylation sites (the JEX element) are important for Net export.	SIGNOR-250139	0.328
IL15RA	protein	Q13261	UNIPROT	IL2RB	protein	P14784	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001103							17709786	t		milica	The il-15 receptor comprises a heterotrimeric complex consisting of the common ?cytokine Receptor (?c), the il-2 ? Receptor subunit (il-2r?), And an il-15-specific ? Receptor (il-15r?)	SIGNOR-157418	0.791
MYOD/E12E47	complex	SIGNOR-C127	SIGNOR	VEGFA	protein	P15692	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0001103							18094043	t		lperfetto	we further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter.	SIGNOR-241545	0.339
RPS6KB1	protein	P23443	UNIPROT	TRIB2	protein	Q92519	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser83	FRAVHLHsGEELVCK	9606	BTO:0002181								24089522	t		miannu	Furthermore, Smurf1-mediated ubiquitination required phosphorylation of TRIB2 by p70 S6 kinase (p70S6K) via another domain (amino acids 69-85) that is also essential for correct TRIB2 subcellular localization. Mutation of Ser-83 diminished p70S6K-induced phosphorylation of TRIB2.	SIGNOR-275433	0.362
MC4R	protein	P32245	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257392	0.252
ZAP70	protein	P43403	UNIPROT	DUSP3	protein	P51452	UNIPROT	up-regulates activity	phosphorylation	Tyr138	SPTLVIAyLMMRQKM	9534	BTO:0001538								12447358	t		miannu	ZAP-70 and Syk also tyrosine-phosphorylated VHR in COS-1 cells (Fig. 2d), whereas other kinases (Csk, Lck, Fyn, Jak2, Bcr-Abl and Itk) had little effect. Finally, recombinant ZAP-70 readily phosphorylated VHR in vitro (Fig. 2f). 	SIGNOR-276000	0.547
GSK3B	protein	P49841	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser102	GGFPPLNsVSPSPLM	9606									16076840	t		gcesareni	The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex.	SIGNOR-139312	0.347
FADS2	protein	O95864	UNIPROT	long-chain fatty acyl-CoA(4-)	smallmolecule	CHEBI:83139	ChEBI	down-regulates quantity	chemical modification			9606									15189125	t		miannu	Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity.	SIGNOR-267908	0.8
POLR3H	protein	Q9Y535	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266126	0.86
FN1	protein	P02751	UNIPROT	A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								7559467	t		lperfetto	The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin.	SIGNOR-253305	0.669
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Arg)	smallmolecule	CHEBI:29171	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269481	0.8
CCT239065	chemical	CID:44131523	PUBCHEM	LCK	protein	P06239	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190910	0.8
CSNK2B	protein	P67870	UNIPROT	CDC34	protein	P49427	UNIPROT	unknown	phosphorylation	Thr233	DDEDDSGtEES	9606	BTO:0000567								11546811	t		llicata	CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm. 	SIGNOR-251061	0.357
PPP2CA	protein	P67775	UNIPROT	AKT2	protein	P31751	UNIPROT	down-regulates activity	dephosphorylation	Thr309	SDGATMKtFCGTPEY	9606									18160256	t			Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248630	0.736
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Ser477	PQFSYSAsGTA	9606	BTO:0000093								24670654	t		gcesareni	Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation	SIGNOR-252450	0.427
CDK7	protein	P50613	UNIPROT	E2F1	protein	Q01094	UNIPROT	down-regulates	phosphorylation	Thr433	DCDFGDLtPLDF	9606									10428966	t		lperfetto	These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase. here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain.	SIGNOR-69780	0.506
JAK2	protein	O60674	UNIPROT	PDP1	protein	Q9P0J1	UNIPROT	down-regulates activity	phosphorylation	Tyr94	SILKANEySFKVPEF	10090	BTO:0000944								24962578	t		miannu	Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients. 	SIGNOR-276642	0.267
3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	PRKAR1B	protein	P31321	UNIPROT	down-regulates activity	chemical inhibition			9606									26687711	t			Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 	SIGNOR-258760	0.8
SHH	protein	Q15465	UNIPROT	PTCH1	protein	Q13635	UNIPROT	down-regulates activity	binding			9606									15618519	t		lperfetto	Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. .Ptch Exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms.	SIGNOR-132675	0.941
IKBKB	protein	O14920	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser527	RFRKRTHsAGTSPTI	-1									12351658	t			IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.	SIGNOR-251296	0.644
KMT2D	protein	O14686	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	binding			9606									16603732	t		miannu	A novel estrogen receptor (er)alpha coactivator complex, the mll2 complex, which consists of mll2, ash2, rbq3, and wdr5, was identified / disrupting the interaction between eralpha and the mll2 complex with small interfering rnas specific against mll2 or an mll2 fragment representing the interacting region with eralpha significantly inhibited the eralpha transcription activity.	SIGNOR-145865	0.466
CDK16	protein	Q00536	UNIPROT	PRC1	protein	O43663	UNIPROT	up-regulates activity	phosphorylation	Thr481	RRGLAPNtPGKARKL	9606	BTO:0000815								35449080	t		lperfetto	Mechanistically, CDK16 exerts its function by phosphorylating protein regulator of cytokinesis 1 (PRC1) to regulate spindle formation during mitosis.|Indeed, immunoblot analysis showed that PRC1 phosphorylation at the T481 site (CDK-dependent major phosphorylation site) fluctuated with the abundance of CDK16 protein in the cell cycle process 	SIGNOR-273017	0.35
ACTR2	protein	P61160	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	form complex	binding			9606									12479800	t			The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc	SIGNOR-251512	0.926
DRD4	protein	P21917	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256982	0.449
SREBF1	protein	P36956	UNIPROT	SND1	protein	Q7KZF4	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									29296233	t		irozzo	These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression.	SIGNOR-259137	0.2
GSK3B	protein	P49841	UNIPROT	ERG	protein	P11308	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr180	KDDFQRLtPSYNADI	9606	BTO:0001033								32871104	t		miannu	Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3β and WEE1, respectively.	SIGNOR-277528	0.2
WNT7A	protein	O00755	UNIPROT	FZD7	protein	O75084	UNIPROT	up-regulates activity	binding												23290138	t		Simone Vumbaca	Wnt7a-Fzd7 signaling stimulates symmetric stem cell divisions	SIGNOR-255646	0.665
CSNK2A1	protein	P68400	UNIPROT	DDX58	protein	O95786	UNIPROT	down-regulates	phosphorylation	Ser854	HPKPKQFsSFEKRAK	9606									21068236	t		lperfetto	Phosphorylation of rig-i by casein kinase ii inhibits its antiviral response. Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of rig-i are phosphorylated by casein kinase ii (ck2)	SIGNOR-169400	0.2
PRKCA	protein	P17252	UNIPROT	TRPC3	protein	Q13507	UNIPROT	down-regulates	phosphorylation	Ser703	SLVPSPKsFVYFIMR	9606		BTO:0000671							15533987	t		gcesareni	There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712.	SIGNOR-130269	0.354
SPI1	protein	P17947	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									17041602	f		miannu	Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets. 	SIGNOR-256065	0.572
MAPK9	protein	P45984	UNIPROT	MAPK8IP3	protein	Q9UPT6	UNIPROT	up-regulates	phosphorylation	Thr265	GQSSAAAtPSTTGTK	9606									15767678	t		gcesareni	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134568	0.652
SRC	protein	P12931	UNIPROT	STAP2	protein	Q9UGK3	UNIPROT	up-regulates activity	phosphorylation	Tyr22	GVLPSHYyESFLEKK	9606									12540842	t		lperfetto	To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src.	SIGNOR-247333	0.415
CDC42BPA	protein	Q5VT25	UNIPROT	CDC42BPA	protein	Q5VT25	UNIPROT	up-regulates activity	phosphorylation	Thr240	QSSVAVGtPDYISPE	9534	BTO:0000298								11283256	t		miannu	N terminus-mediated dimerization and transautophosphorylation are essential for MRCKα catalytic activity. Three mutations, S234A, T240A, and T403A, strongly affected the in vitro autophosphorylation activity of FLAG-MRCKα-CAT1–473 (Fig. ​(Fig.5D).5D).	SIGNOR-275975	0.2
LTB4R	protein	Q15722	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257196	0.252
EP300	protein	Q09472	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	acetylation			9606			SIGNOR-C6						21131905	t		fspada	These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription.	SIGNOR-265328	0.2
LCK	protein	P06239	UNIPROT	CD3D	protein	P04234	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000782								2470098	t			Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex.	SIGNOR-259929	0.552
ABL1	protein	P00519	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates activity	phosphorylation	Tyr386	YRARVANyQRDGPMC	9606	BTO:0000093								12777400	t		lperfetto	C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases	SIGNOR-101302	0.412
BRCA1	protein	P38398	UNIPROT	TOP1	protein	P11387	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002201								28415827	t		miannu	Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. Taken together, we conclude that BRCA1 is the E3 ligase for topoI, and the rate of topoI proteasomal degradation determines CPT response.	SIGNOR-277353	0.476
CALM3	protein	P0DP25	UNIPROT	PPP3CC	protein	P48454	UNIPROT	up-regulates	binding			9606									11796223	t		miannu	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-266340	0.54
PRKACA	protein	P17612	UNIPROT	KCNK3	protein	O14649	UNIPROT	up-regulates activity	phosphorylation	Ser393	GLMKRRSsV	9606									21357689	t		lperfetto	Mutation of the ser393 to alanine, which can neither be phosphorylated nor mimic a phosphorylated residue, resulted in the channel failing to pass current all of our findings support the conclusion that camp-dependent protein kinase is responsible for the phosphorylation of the terminal serine in both k2p3.1 and k2p9.1.	SIGNOR-172430	0.2
GATA3	protein	P23771	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				10090									11021798	f		fspada	Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage.	SIGNOR-78830	0.7
PRKCA	protein	P17252	UNIPROT	SNAP25	protein	P60880	UNIPROT	unknown	phosphorylation	Ser187	RIMEKADsNKTRIDE	9606									12459461	t		lperfetto	This study establishes that SNAP-25 is differentially phosphorylated by protein kinase C and protein kinase A in neuroendocrine PC12 cells. Using phosphopeptide mapping and site-directed mutagenesis we identified both Thr138 and Ser187 as the targets of SNAP-25 phosphorylation by protein kinase C	SIGNOR-249178	0.359
CSNK2A1	protein	P68400	UNIPROT	ABCC1	protein	P33527	UNIPROT	up-regulates	phosphorylation	Thr249	WSLNKEDtSEQVVPV	9606									22695718	t		lperfetto	Casein kinase 2_ regulates multidrug resistance-associated protein 1 function via phosphorylation of thr249. This study supports a model in which ck2_ potentiates mrp1 function via direct phosphorylation of thr249.	SIGNOR-197844	0.381
CDK5	protein	Q00535	UNIPROT	LMTK2	protein	Q8IWU2	UNIPROT	up-regulates	phosphorylation	Ser1450	LQTSKYFsPPPPARS	9606	BTO:0000938	BTO:0000142							22220831	t		gcesareni	Here, we demonstrate that lmtk2 is phosphorylated on serine-1418 (lmtk2ser ) by cdk5/p35 and present evidence that this regulates its ability to phosphorylate pp1cthr __	SIGNOR-195329	0.512
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates activity	phosphorylation	Ser706	ARIIGEKsFRRSVVG										12058027	t		lperfetto	Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.	SIGNOR-275952	0.2
RSPO2	protein	Q6UXX9	UNIPROT	FZD4	protein	Q9ULV1	UNIPROT	down-regulates quantity	ubiquitination			9606									22575959	t		miannu	Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.	SIGNOR-260117	0.32
PRKCA	protein	P17252	UNIPROT	CBL	protein	P22681	UNIPROT	down-regulates quantity	phosphorylation	Ser619	RELTNRHsLPFSLPS	9606	BTO:0000782								11024037	t		lperfetto	However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway. 	SIGNOR-249054	0.327
HOXA10	protein	P31260	UNIPROT	MYCN	protein	P04198	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000661								21261500	f	 	miannu	 HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. 	SIGNOR-254215	0.2
AKT1	protein	P31749	UNIPROT	CYCS	protein	P99999	UNIPROT	down-regulates activity	phosphorylation	Tyr47	KTGQAPGySYTAANK	-1									32781572	t		miannu	Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.	SIGNOR-277237	0.48
STRN	protein	O43815	UNIPROT	PPP2CA	protein	P67775	UNIPROT	up-regulates activity	binding			10090	BTO:0000938								29802198	t		miannu	The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms	SIGNOR-261698	0.658
EIF2AK2	protein	P19525	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser32	LLDDRHDsGLDSMKD										10723127	t		lperfetto	As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation.	SIGNOR-249335	0.515
SMC1A	protein	Q14683	UNIPROT	RAD21L Cohesin complex	complex	SIGNOR-C355	SIGNOR	form complex	binding			10090		BTO:0000534							21242291	t		miannu	RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21.	SIGNOR-264538	0.776
PFKM	protein	P08237	UNIPROT	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35.	SIGNOR-266471	0.8
SRC	protein	P12931	UNIPROT	FCRL3	protein	Q96P31	UNIPROT	up-regulates activity	phosphorylation	Tyr662	PGDSNPIySQIWSIQ	-1									12051764	t		miannu	Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2.	SIGNOR-274010	0.2
PRKCA	protein	P17252	UNIPROT	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation	Ser677	AIVSKIDsRLEQYTS	9606		BTO:0000887;BTO:0001260							8182108	t		gcesareni	Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase.	SIGNOR-36796	0.365
NDN	protein	Q99608	UNIPROT	E2F1	protein	Q01094	UNIPROT	down-regulates activity	binding			10090	BTO:0000920								24392139	t		lperfetto	Necdin interacts with E2F transcription factors and suppresses E2F1-dependent transcriptional activation of the cyclin-dependent kinase Cdk1 gene. Here we show that necdin serves as a suppressor of NPC proliferation in the embryonic neocortex.	SIGNOR-253382	0.583
AKT1	protein	P31749	UNIPROT	HK2	protein	P52789	UNIPROT	up-regulates activity	phosphorylation	Thr473	QHRARQKtLEHLQLS	9606	BTO:0000192								31435020	t			K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization	SIGNOR-259984	0.458
GRIA4	protein	P48058	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial.	SIGNOR-264950	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression				9606		BTO:0001103							20219869	t		apalma	Importantly, NF-kB can promote the expression and stability of cyclin D1 in muscle (4, 35, 39, 132), leading to increased cell proliferation and inhibition of differentiation. 	SIGNOR-255358	0.483
PRKCA	protein	P17252	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser290	GRIVARNsRKMAFRA	-1									9677319	t		lperfetto	Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases.	SIGNOR-249006	0.292
HIP1	protein	O00291	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001130								16027218	f		miannu	Hip1 as a transcriptional regulator of the ar / silencing hip1 expression reduces the transcriptional activity and protein levels of the ar	SIGNOR-138820	0.2
SMAD3	protein	P84022	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	up-regulates activity				9606	BTO:0000599								10890911	f		lperfetto	Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity	SIGNOR-229308	0.53
Sin3B_complex	complex	SIGNOR-C409	SIGNOR	H3-4	protein	Q16695	UNIPROT	down-regulates activity	binding			9606									21041483	t		miannu	We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin.	SIGNOR-266971	0.2
HIPK2	protein	Q9H2X6	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000452								19820693	f		Luana	We show that MeCP2 cooperates with HIPK2 in induction of apoptosis and that Ser 80 phosphorylation is required together with the DNA binding of MeCP2. | We found increased cell death in each of the tested cell lines not only, as expected, when HIPK2 was overexpressed but also with MeCP2 alone. When both proteins were expressed together, the number of dead cells increased in an additive manner. 	SIGNOR-264551	0.7
PTPRH	protein	Q9HD43	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates activity	dephosphorylation			10029	BTO:0000246								12907755	t			Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR	SIGNOR-248802	0.298
CDK8	protein	P49336	UNIPROT	H3-4	protein	Q16695	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR										18418385	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	lperfetto	However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo.	SIGNOR-273175	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	GSK3B	protein	P49841	UNIPROT	down-regulates	phosphorylation												28712664	t			AKT phosphorylates and inhibits GSK3 in addition to many other substrates including TSC2, FOXO proteins, TBC1D4.	SIGNOR-255488	0.2
SNX6	protein	Q9UNH7	UNIPROT	IGF1R	protein	P08069	UNIPROT	down-regulates quantity	binding			9606	BTO:0000567								32150533	t		miannu	 Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.	SIGNOR-269445	0.2
TGFB1	protein	P01137	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates activity				9606									19114990	f		lperfetto	First, TGF-beta can rapidly activate PI3K, as indicated by the phosphorylation of its downstream effector Akt	SIGNOR-217812	0.278
PRKCB	protein	P05771	UNIPROT	STXBP1	protein	P61764	UNIPROT	down-regulates activity	phosphorylation	Ser313	SLKDFSSsKRMNTGE	9913	BTO:0000259								12519779	t		lperfetto	Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation.	SIGNOR-249186	0.406
ITGB6	protein	P18564	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257724	0.471
MAPK1	protein	P28482	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Ser447	GSPRTPVsPVKFSPG	9606									14967450	t		gcesareni	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-121988	0.578
IKBKG	protein	Q9Y6K9	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates activity	binding			9606			SIGNOR-C14	SIGNOR-C14					12192055	t		lperfetto	The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation	SIGNOR-91705	0.962
CLOCK	protein	O15516	UNIPROT	DPYD	protein	Q12882	UNIPROT	up-regulates quantity by expression	transcriptional regulation												17699798	f			Regulation of Genes of the Circadian Clock in Human Colon Cancer: Reduced Period-1 and Dihydropyrimidine Dehydrogenase Transcription Correlates in High-Grade Tumors| The highly significant correlation of DPD mRNA with Per1 mRNA expression suggests control of DPD transcription by the endogenous cellular clock, which is more pronounced in women.	SIGNOR-253986	0.265
IFNG	protein	P01579	UNIPROT	HLA-B	protein	P01889	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									2507660	f	Regulation	miannu	HLA-B (class I) and C13 gene expression was transcriptionally activated by IFN-gamma and IFN-alpha 2	SIGNOR-251926	0.338
SRSF2	protein	Q01130	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27524244	t		miannu	Using MDM2 P1 and P2 promoter-reporter systems, we screened clones regulating MDM2 transcriptions in a p53-independent manner by overexpression. Nine clones from the screening library showed enhanced MDM2 promoter activity and MDM2 expression in p53-deficient HCT116 cells. Among them, six clones, including NTRK2, GNA15, SFRS2, EIF5A, ELAVL1, and YWHAB mediated MAPK signaling for expressing MDM2.	SIGNOR-260076	0.283
MMP12	protein	P39900	UNIPROT	FGA	protein	P02671	UNIPROT	down-regulates quantity by destabilization	cleavage	Phe540	FSPMLGEfVSETESR	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain	SIGNOR-263623	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GAD1	protein	Q99259	UNIPROT	down-regulates activity	phosphorylation	Thr91	RDARFRRtETDFSNL	9606	BTO:0000142								15147202	t		miannu	Here, we report the effect of phosphorylation on the two well-defined GAD isoforms, namely, GAD65 and GAD67, using highly purified preparations of recombinant human brain GAD65 and GAD67. GAD65 was activated by phosphorylation, while GAD67 was inhibited by phosphorylation.We further demonstrate that protein kinase A (PKA) and protein kinase C isoform epsilon are the protein kinases responsible for phosphorylation and regulation of GAD67 and GAD65, respectively. We have identified one specific phosphorylation site, threonine 91 (T91), in hGAD67 that can be phosphorylated by PKA using MALDI-TOF. 	SIGNOR-276009	0.2
PPP1R14B	protein	Q96C90	UNIPROT	PPP1CB	protein	P62140	UNIPROT	down-regulates activity	binding			-1									12144526	t		lperfetto	We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin	SIGNOR-265743	0.291
GRIA2	protein	P42262	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								30825796	f		miannu	In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses	SIGNOR-264612	0.7
FZD2	protein	Q14332	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606									18077588	t		areggio	Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction.	SIGNOR-258965	0.654
CSNK1A1	protein	P48729	UNIPROT	CBX4	protein	O00257	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr437	ARSISTPtCLGGSPA	9606	BTO:0002181								32111827	t		miannu	The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα. 	SIGNOR-277512	0.2
RNF11	protein	Q9Y3C5	UNIPROT	STAMBP	protein	O95630	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								14755250	t		miannu	RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome.	SIGNOR-272953	0.548
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	GAD2	protein	Q05329	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000142								15147202	t		miannu	Here, we report the effect of phosphorylation on the two well-defined GAD isoforms, namely, GAD65 and GAD67, using highly purified preparations of recombinant human brain GAD65 and GAD67. GAD65 was activated by phosphorylation, while GAD67 was inhibited by phosphorylation.We further demonstrate that protein kinase A (PKA) and protein kinase C isoform epsilon are the protein kinases responsible for phosphorylation and regulation of GAD67 and GAD65, respectively.	SIGNOR-276010	0.2
PRKACA	protein	P17612	UNIPROT	PARP1	protein	P09874	UNIPROT	up-regulates activity	phosphorylation	Ser785	LRGGSDDsSKDPIDV	9606	BTO:0001412								25069723	t		miannu	 In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain). 	SIGNOR-276653	0.2
PRKACA	protein	P17612	UNIPROT	SUFU	protein	Q9UMX1	UNIPROT	up-regulates	phosphorylation	Ser342	LAHDRAPsRKDSLES	9606									23337587	t		gcesareni	Interestingly, sufu stability is regulated via dual phosphorylation at ser342/ser346 by pka and gsk3, and blocking sufu phosphorylation either by mutating ser346 to ala or by treating cultured cells with pka inhibitors attenuates sufu ciliary accumulation, whereas phospho-mimetic forms of sufu exhibits increased ciliary localization	SIGNOR-200492	0.443
PRKACA	protein	P17612	UNIPROT	ETV1	protein	P50549	UNIPROT	up-regulates activity	phosphorylation	Ser191	HRFRRQLsEPCNSFP	9606									12213813	t		lperfetto	The camp-dependent protein kinase a (pka) phosphorylates er81 on ser(191)/ser(216)ser(191) and ser(216), were identified, whose mutation to alanine reduces er81 activity upon erk-mapk stimulation.	SIGNOR-92447	0.296
MUL1	protein	Q969V5	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys284	LENLMLDkDGHIKIT	9606	BTO:0000007								22410793	t		gcesareni	The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability.	SIGNOR-252437	0.488
Nucleosome_H3.3 variant	complex	SIGNOR-C339	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606									15776021	f		miannu	Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states.	SIGNOR-263878	0.7
ACE2	protein	Q9BYF1	UNIPROT	Membrane_fusion	phenotype	SIGNOR-PH122	SIGNOR	up-regulates				9606									32231345	f	doi.org/10.1101/2020.03.09.983247	miannu	Unlike SARS-CoV, live SARS-CoV-2-infected cells were found to form typical syncytium, suggesting that SARS-CoV-2 may mainly utilize the plasma membrane fusion pathway to enter and replicate inside host cells. Consistently, in the cell–cell fusion system, SARS-CoV-2 S protein could effectively mediate the formation of syncytium between the effector cell and the target cell in the absence of an exogenous proteolytic enzyme, e.g., trypsin, while SARS-CoV S protein could not. Actually, the plasma membrane fusion pathway is more efficient than the endosomal membrane fusion pathway for most viruses because the latter is more prone to activating the host cell antiviral immunity.	SIGNOR-260286	0.7
PRKACA	protein	P17612	UNIPROT	STMN2	protein	Q93045	UNIPROT	down-regulates activity	phosphorylation	Ser50	KQINKRAsGQAFELI	9534	BTO:0000298								9525956	t		miannu	Using in vitro phosphorylated recombinant protein, four phosphorylation sites were identified in the SCG10 sequence. Ser-50 and Ser-97 were the target sites for protein kinase A. phosphorylation negatively regulates the microtubule-depolymerizing activity of SCG10 and that all four sites participate in this regulation	SIGNOR-250056	0.313
PRKCB	protein	P05771	UNIPROT	RAB11A	protein	P62491	UNIPROT	unknown	phosphorylation	Ser177	TEIYRIVsQKQMSDR	-1									22188018	t		miannu	 This report shows for the first time that Rab11 is differentially phosphorylated by distinct PKC isoenzymes and that this post-translational modification might be a regulatory mechanism of intracellular trafficking.Our results demonstrate that classical PKC (PKCα and PKCβII but not PKCβI) directly phosphorylate Rab11 in vitro. In addition, novel PKCε and PKCη but not PKCδ isoenzymes also phosphorylate Rab11. Mass spectrometry analysis revealed that Ser 177 is the Rab11 residue to be phosphorylated in vitro by either PKCβII or PKCε. 	SIGNOR-263169	0.2
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1616	TPQSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273079	0.636
PIM1	protein	P11309	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr455	LAMSPLPtAETPKPL	9606	BTO:0002181								34211090	t		miannu	PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes.	SIGNOR-277311	0.2
RPS6KB1	protein	P23443	UNIPROT	URI1	protein	O94763	UNIPROT	down-regulates activity	phosphorylation	Ser372	AKRKRKNsTGSGHSA	9606	BTO:0000567								17936702	t		miannu	Here we report that the prefoldin chaperone URI represents a mitochondrial substrate of S6K1. In growth factor-deprived or rapamycin-treated cells, URI forms stable complexes with protein phosphatase (PP)1gamma at mitochondria, thereby inhibiting the activity of the bound enzyme. Growth factor stimulation induces disassembly of URI/PP1gamma complexes through S6K1-mediated phosphorylation of URI at serine 371. 	SIGNOR-262943	0.35
BMP7	protein	P18075	UNIPROT	DLK1	protein	P80370	UNIPROT	down-regulates	transcriptional regulation			9606									20584981	f		fspada	Bmp7 could directly suppress pref-1 expression, thereby allowing the initiation of the adipogenic program. 	SIGNOR-210074	0.295
GSK3B	protein	P49841	UNIPROT	ROR2	protein	Q01974	UNIPROT	down-regulates activity	phosphorylation	Ser864	PKPSSHHsGSGSTST	9606			SIGNOR-C110						21078818	t		gcesareni	We identify ror2 ser 864 as a critical residue phosphorylated by gsk3 and required for noncanonical receptor activation by wnt5a, analogous to the priming phosphorylation of low-density receptor-related protein 6 (lrp6) in response to wnt3a.	SIGNOR-169642	0.317
PRKACA	protein	P17612	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation	Ser698	PEWPRRAsCTSSTSG	-1									196939	t			The results presented in this paper show that the phosphorylation of glycogen synthetase a by cyclic AMP-dependent protein kinase results in the phosphorylation of two distinct serines termed site-l and site-2, which account for 90% of the total phosphorylation	SIGNOR-253009	0.489
ROS	stimulus	SIGNOR-ST2	SIGNOR	PAX2	protein	Q02962	UNIPROT	up-regulates quantity by expression				10090									16985513	f			High glucose-induced Pax-2 gene expression is mediated, at least in part, via ROS generation and activation of the nuclear factor kappa B signaling pathway, but not via protein kinase C, p38 mitogen-activated protein kinase (MAPK), and p44/42 MAPK signaling.	SIGNOR-252295	0.7
PTPRO	protein	Q16827	UNIPROT	LYN	protein	P07948	UNIPROT	down-regulates activity	dephosphorylation			9606									20564182	t		miannu	Both Lyn and ZAP70 were dephosphorylated by wild-type PTPROt, but not by its catalytic site mutant.|Lyn kinase and ZAP70 are substrates of PTPROt in B-cells: Lyn inactivation by PTPROt sensitizes leukemia cells to VEGF-R inhibitor pazopanib.	SIGNOR-277144	0.331
PCM1	protein	Q15154	UNIPROT	CEP250	protein	Q9BV73	UNIPROT	up-regulates	relocalization			9606									15659651	t		miannu	Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1	SIGNOR-133334	0.532
GRB2	protein	P62993	UNIPROT	SOS1	protein	Q07889	UNIPROT	up-regulates activity	relocalization			9606									8479541	t	GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP	lperfetto	Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.	SIGNOR-39163	0.91
GGCX	protein	P38435	UNIPROT	F10	protein	P00742	UNIPROT	up-regulates activity	carboxylation	Glu46	TRANSFLeEMKKGHL	-1									9538022	t		lperfetto	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263664	0.598
BIRC2	protein	Q13490	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	ubiquitination			9606									16603398	t		amattioni	In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein.	SIGNOR-145036	0.76
PRKCA	protein	P17252	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates activity	phosphorylation	Ser710	GEKSFRRsVVGTPAY										12058027	t		lperfetto	Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.	SIGNOR-275954	0.371
GALR2	protein	O43603	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257356	0.252
PRKCH	protein	P24723	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates	phosphorylation	Ser710	GEKSFRRsVVGTPAY	9606									12058027	t		gcesareni	Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs.	SIGNOR-89427	0.2
MASP1	protein	P48740	UNIPROT	C4B	protein	P0C0L5	UNIPROT	up-regulates activity	cleavage	Gly1446	TPLQLFEgRRNRRRR	-1									9087411	t		lperfetto	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263429	0.663
ABL1	protein	P00519	UNIPROT	WASF3	protein	Q9UPY6	UNIPROT	up-regulates activity	phosphorylation	Tyr337	LPAQIIEyYNPSGPP	9606	BTO:0000815								17623672	t			WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3.	SIGNOR-262301	0.565
UHMK1	protein	Q8TAS1	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser38	SVPEFPLsPPKKKDL	9606									19033656	t		gcesareni	This promigratory phenotype resulted from increased stathmin protein levels, caused by a lack of kis-mediated stathmin phosphorylation at serine 38 and diminished stathmin protein degradation.	SIGNOR-182489	0.525
BRAF	protein	P15056	UNIPROT	MAP2K2	protein	P36507	UNIPROT	up-regulates	phosphorylation	Ser226	LIDSMANsFVGTRSY	9606		BTO:0000142							8668348	t		gcesareni	We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l.	SIGNOR-42668	0.739
mTORC2	complex	SIGNOR-C2	SIGNOR	RRM1	protein	P23921	UNIPROT	up-regulates activity	phosphorylation	Ser631	IYTRRVLsGEFQIVN	9606	BTO:0002552								34126361	t		miannu	Mechanistically, mTORC2 directly interacted and phosphorylated RNR large subunit RRM1 at Ser 631. Ser631 phosphorylation of RRM1 enhanced its interaction with small subunit RRM2 to maintain sufficient RNR enzymatic activity for efficient DNA replication.	SIGNOR-277566	0.308
CEBPD	protein	P49716	UNIPROT	MSTN	protein	O14793	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									24011072	f		miannu	To identify whether p-Stat3 acts through C/EBPδ to stimulate myostatin, we knocked down C/EBPδ using siRNA. In this case, the IL-6-induced increase in myostatin expression was blocked when C/EBPδwas suppressed even though p-Stat3 was increased	SIGNOR-255332	0.291
FYN	protein	P06241	UNIPROT	PTPRJ	protein	Q12913	UNIPROT	up-regulates activity	phosphorylation	Tyr1320	NTTAMTIyENLAPVT	9606	BTO:0000007								22898603	t		miannu	 We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin.	SIGNOR-276374	0.374
MAPK3	protein	P27361	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation	Ser418	TEERLPSsPVYEDAA	9606									20444238	t		gcesareni	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-165212	0.433
ODC1	protein	P11926	UNIPROT	spermine	smallmolecule	CHEBI:15746	ChEBI	up-regulates quantity	chemical modification			9606									14617280	t		miannu	Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC)	SIGNOR-256036	0.8
FGA	protein	P02671	UNIPROT	Fibrinogen	complex	SIGNOR-C311	SIGNOR	form complex	binding			-1									25427968	t		lperfetto	Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively).	SIGNOR-263392	0.759
AKT1	protein	P31749	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr32	QSRPRSCtWPLQRPE										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249625	0.908
PRKCD	protein	Q05655	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser315	AHSIHQRsRKRLSQD	9606	BTO:0000130								12056906	t		esanto	Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?.	SIGNOR-89225	0.459
fluticasone	chemical	CHEBI:5134	ChEBI	SMO	protein	Q99835	UNIPROT	up-regulates activity	chemical activation			10090									20439738	t		gcesareni	We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling.	SIGNOR-248206	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	M1_polarization	phenotype	SIGNOR-PH54	SIGNOR	up-regulates				9606									30060484	f		miannu	The bacterial endotoxin LPS is a known agonist of TLR2 that activates the expression of proinflammatory cytokines and the phosphorylation of MAPKs and NFκB [49]. In addition, the activation of the MAPK and NFκB signaling cascades drive inflammation and macrophage polarization. 	SIGNOR-249519	0.7
nefazodone	chemical	CHEBI:7494	ChEBI	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			-1									9871604	t		miannu	Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. Nefazodone has similar affinities at hSERT, hNET, and hDAT, but has low potency	SIGNOR-259069	0.8
RET	protein	P07949	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates	phosphorylation	Tyr187	HTGFLTEyVATRWYR	9606									16153436	t		gcesareni	We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).	SIGNOR-140294	0.433
KAT8	protein	Q9H7Z6	UNIPROT	FASN	protein	P49327	UNIPROT	down-regulates quantity by destabilization	acetylation			9606	BTO:0000007								27758890	t			Overexpression of Myc-KAT8 increased the acetylation level of endogenous FASN by 2.2-fold (Fig. 3C). In contrast, knockdown of KAT8 decreased endogenous FASN acetylation by as much as 55%	SIGNOR-267366	0.2
CDH23	protein	Q9H251	UNIPROT	TIP-LINK complex	complex	SIGNOR-C291	SIGNOR	form complex	binding			10090		BTO:0000630							23217710	t		lperfetto	The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction.	SIGNOR-262579	0.633
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1871	SPKYSPTsPKYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120044	0.781
AP-2 complex	complex	SIGNOR-C245	SIGNOR	EPN1	protein	Q9Y6I3	UNIPROT	up-regulates activity	binding			10116	BTO:0000142								15496985	t		Giorgia	Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs	SIGNOR-260395	0.549
Jervine	chemical	CHEBI:6088	ChEBI	SMO	protein	Q99835	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000527								21679342	t		gcesareni	Cyclopamine (c27h41no2) and jervine (c27h39no3) were discovered and in particular, a series of studies with the hh pathway inhibitor, cyclopamine, has brought about this expectation. cyclopamine suppresses the hh signaling pathway through direct interaction with smo.	SIGNOR-174420	0.8
MET	protein	P08581	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			9606									22128289	t		irozzo	For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS. 	SIGNOR-256261	0.682
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	HK1	protein	P19367	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27692180	t		miannu	HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 	SIGNOR-267452	0.359
MAPK9	protein	P45984	UNIPROT	SFN	protein	P31947	UNIPROT	down-regulates	phosphorylation	Ser186	FHYEIANsPEEAISL	9606									15071501	t	JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8	gcesareni	Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-189	SIGNOR-124027	0.2
APOB	protein	P04114	UNIPROT	LDLR	protein	P01130	UNIPROT	up-regulates	binding			9606									11986215	t		gcesareni	In the case of ldl, binding of apolipoprotein b (apob) to the ldl-r18-20 and proteoglycans17 21 initiates plasma clearance and lipoprotein degradation	SIGNOR-87035	0.798
EIF5B	protein	O60841	UNIPROT	Met-tRNA(Met)	chemical	CHEBI:16635	ChEBI	up-regulates activity	relocalization			9606									30551605	t		lperfetto	EIF5B was also shown to deliver Met-tRNAi into the P-site of the ribosome in an eIF2-independent translation initiation mechanism utilized by the CSFV and HCV IRESs 	SIGNOR-269119	0.8
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser174	LSPASSGsSASFISD	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252326	0.635
ITGA1	protein	P56199	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253169	0.748
IGF1R	protein	P08069	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity				10090									11715022	f		lperfetto	We show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy.	SIGNOR-235373	0.398
GOLGA7	protein	Q7Z5G4	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates activity	palmitoylation			9606	BTO:0000007								16000296	t		miannu	Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein.	SIGNOR-261351	0.357
FGF11	protein	Q92914	UNIPROT	SCN1A	protein	P35498	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253422	0.263
NFATC2	protein	Q13469	UNIPROT	MYOG	protein	P15173	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18676376	f		gcesareni	€ provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis.	SIGNOR-235006	0.288
LYN	protein	P07948	UNIPROT	PTGS2	protein	P35354	UNIPROT	up-regulates activity	phosphorylation	Tyr120	PPTYNADyGYKSWEA	-1									24970799	t		miannu	We report that FYN phosphorylates human COX2 on Tyr 446, and while corresponding phospho-mimetic COX2 mutation promotes COX2 activity, the phosphorylation blocking mutation prevents FYN-mediated increase in COX2 activity. FYN and LYN kinases phosphorylate COX2 on two distinct residues in vitro. 	SIGNOR-276643	0.395
EP300	protein	Q09472	UNIPROT	MEF2A	protein	Q02078	UNIPROT	up-regulates	binding			9606									11796223	t		lperfetto	Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription.	SIGNOR-232165	0.855
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	NFATC1	protein	O95644	UNIPROT	up-regulates	relocalization			9606		BTO:0001103							11062529	t	inferred from 70% family members	gcesareni	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-269989	0.2
PRKCH	protein	P24723	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates activity	phosphorylation	Ser185	SAYVGRLsARPKLKA	-1									15604283	t		miannu	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276015	0.2
PPP2CB	protein	P62714	UNIPROT	ATM	protein	Q13315	UNIPROT	down-regulates activity	dephosphorylation	Ser1981	SLAFEEGsQSTTISS	9606									15510216	t			Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro. 	SIGNOR-248601	0.272
F7	protein	P08709	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	binding			9606		BTO:0000131	SIGNOR-C319						29880919	t		lperfetto	TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively.	SIGNOR-263544	0.529
CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	PUM2	protein	Q8TB72	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			9606									31320642	t		lperfetto	In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins	SIGNOR-268347	0.375
EIF3G	protein	O75821	UNIPROT	EIF3_complex	complex	SIGNOR-C401	SIGNOR	form complex	binding			-1									16920360	t		miannu	Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 	SIGNOR-266394	0.934
DMTF1	protein	Q9Y222	UNIPROT	GAS1	protein	P54826	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0004532								19816943	f		Luana	 Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. 	SIGNOR-261588	0.2
MAPK8	protein	P45983	UNIPROT	MCL1	protein	Q07820	UNIPROT	up-regulates	phosphorylation	Thr163	TDGSLPStPPPAEEE	9606									12223490	t		gcesareni	We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage.	SIGNOR-92597	0.543
Set1-Ash2 HMT complex	complex	SIGNOR-C352	SIGNOR	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	methylation			9606									12670868	t		miannu	The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated.	SIGNOR-265349	0.2
flutamide	chemical	CHEBI:5132	ChEBI	AR	protein	P10275	UNIPROT	down-regulates activity	chemical inhibition			9606									18571420	t		Luana	Among the compounds obtained, N-[4-[(benzyl)(4-nitrophenyl)amino]-1-methylpyrrole-2-carbonyl]pyrrolidine (22) is as potent an AR antagonist as the typical anilide-type AR antagonists hydroxyflutamide and bicalutamide. 	SIGNOR-257807	0.8
AKT1	protein	P31749	UNIPROT	AGAP2	protein	Q99490	UNIPROT	up-regulates	phosphorylation	Ser985	THLSRVRsLDLDDWP	9606	BTO:0001130								19176382	t		llicata	In addition, we have found that activated akt can bind and phosphorylate ggap2 at serine 629, which enhances gtp binding by ggap2.	SIGNOR-183543	0.511
MASP2	protein	O00187	UNIPROT	C4B	protein	P0C0L5	UNIPROT	up-regulates activity	cleavage	Arg679	EKTTRKKrNVNFQKA	-1									17204478	t		lperfetto	MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a).	SIGNOR-263422	0.793
MAPK3	protein	P27361	UNIPROT	SHOC2	protein	Q9UQ13	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr507	GLGENLLtHLPEEIG	9606	BTO:0000007								30865892	t		miannu	Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation.	SIGNOR-277443	0.342
ASXL3	protein	Q9C0F0	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	down-regulates activity	binding			9606	BTO:0000972								25450400	t	inferred from family member	miannu	We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRα and TRβ, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXRα and TRβ were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXRα target genes through its recruitment to the LXR-response elements. 	SIGNOR-270302	0.2
MAPK14	protein	Q16539	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser46	AMDDLMLsPDDIEQW	9606	BTO:0000567								15642743	t		lperfetto	Recombinant p38 phosphorylated recombinant p53 on serine 46 in vitro. Inhibition of p38 MAPK by pharmacological inhibitors, dominant-negative p38, or small interfering RNA, suppressed p53S46P	SIGNOR-226620	0.765
PTPN2	protein	P17706	UNIPROT	JAK1	protein	P23458	UNIPROT	down-regulates activity	dephosphorylation	Tyr1034	AIETDKEyYTVKDDR	10090									11909529	t			The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3|We have identified JAK1 and JAK3 as physiological substrates of TCPTP.| Using a site-specific antibody directed against the activation loop phosphotyrosines in JAK1 (pY1022/pY1023), we found that these sites were in fact dephosphorylated by TCPTP	SIGNOR-248395	0.758
MAPKAP1	protein	Q9BPZ7	UNIPROT	PRKCE	protein	Q02156	UNIPROT	up-regulates activity	binding			9606									21806543	t		miannu	In the present study, we have identified the mTORC2 subunit Sin1 as a direct binding partner of the PKC (protein kinase C) ε kinase domain and map the interaction to the central highly conserved region of Sin1. Exploiting the conformational dependence for PKC phosphorylation, we demonstrate that mTORC2 is essential for acute priming of PKC. 	SIGNOR-276348	0.266
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	DLX5	protein	P56178	UNIPROT	up-regulates	phosphorylation			9606									22298955	t		lperfetto	Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5.	SIGNOR-244228	0.2
RPS6KA3	protein	P51812	UNIPROT	NFATC4	protein	Q14934	UNIPROT	up-regulates	phosphorylation	Ser344	QAVALPRsEEPASCN	10090	BTO:0000165;BTO:0000222	BTO:0000887;BTO:0001103;BTO:0001760							17213202	t		lperfetto	The results indicated that rsk2 phosphorylated two additional sites at ser289 (peptide 2) and ser344 (peptide 3)rsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo.	SIGNOR-235652	0.395
PDPK1	protein	O15530	UNIPROT	PRKCG	protein	P05129	UNIPROT	up-regulates	phosphorylation			9606									15209375	t		gcesareni	One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.	SIGNOR-126072	0.2
PI3K	complex	SIGNOR-C156	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity				9606		BTO:0000150							19573809	f		lperfetto	However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth	SIGNOR-252703	0.785
RPS6KA1	protein	Q15418	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates	phosphorylation	Ser722	PRLRSVSsYGNIRAV	9606				SIGNOR-C3					18722121	t		llicata	Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity	SIGNOR-180466	0.564
PRKCZ	protein	Q05513	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates activity	phosphorylation	Ser185	SAYVGRLsARPKLKA	-1									15604283	t		miannu	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276017	0.2
PCDH15	protein	Q96QU1	UNIPROT	TMC2	protein	Q8TDI7	UNIPROT	up-regulates activity	binding			9606	BTO:0000007	BTO:0000630							25114259	t		lperfetto	Although several studies show that the tip links, composed of PCDH15 and CDH23, are required for normal mechanotransduction, it is unclear how they are coupled to the transduction machinery. Likewise, it has been demonstrated that the transmembrane channel-like proteins TMC1 and TMC2 are required for mechanosensitive responses in hair cells, but how they interact with other components of the mechanotransduction complex is not known. Here, we show that TMC1 and TMC2 can interact with PCDH15, thereby establishing a critical connection between the tip link and these putative components of the mechanotransduction channel in hair cells.	SIGNOR-262583	0.449
MYO1E	protein	Q12965	UNIPROT	Receptor_mediated_ endocytosis	phenotype	SIGNOR-PH121	SIGNOR	up-regulates				10116		BTO:0000142							17257598	f		miannu	We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. 	SIGNOR-265425	0.7
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser64	EPGTPPSsPLSAEQL	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276094	0.275
COMMD5	protein	Q9GZQ3	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				9606									30021164	f		miannu	In this study, we identified a specific and crucial role for COMMD5 in the endocytic trafficking machinery, and especially we determined COMMD5 as an actin- and tubulin-binding protein. Our results provide further insight into the essential role of COMMD5 on every aspect of cellular processes, from membrane receptor trafficking to cytoskeleton organization, cell migration, and junctions. Here, we demonstrate that COMMD5 is crucial for the stability of the cytoskeleton. Its silencing leads to a major re-organization of actin and microtubule networks.	SIGNOR-261693	0.7
imatinib	chemical	CHEBI:45783	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258225	0.8
KAT2B	protein	Q92831	UNIPROT	H3-2	protein	Q5TEC6	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269616	0.2
MAPK3	protein	P27361	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates activity	phosphorylation	Ser25	QAFELILsPRSKESV	9606									9731215	t		lperfetto	Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. 	SIGNOR-249482	0.563
INSR	protein	P06213	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	phosphorylation	Tyr607	NENTEDQySLVEDDE	9534	BTO:0000298								8385099	t			The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor.	SIGNOR-252693	0.601
SDC4	protein	P31431	UNIPROT	FZD7/SDC4	complex	SIGNOR-C216	SIGNOR	form complex	binding			9606	BTO:0002314	BTO:0001103							23290138	t		apalma	We next examined whether endogenous Fzd7 and Sdc4 form a receptor complex in satellite cells […] Therefore, we conclude that Fzd7 and Sdc4 form a co-receptor complex in activated satellite cells.	SIGNOR-255847	0.54
palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	precursor of			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267879	0.8
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Ser400	SRDESTDsGLSMSSY	9606									21364637	t		miannu	JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells	SIGNOR-277645	0.2
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									14585074	f		amattioni	Caspase-3 is responsible for apoptosis execution	SIGNOR-256548	0.7
CSNK2B	protein	P67870	UNIPROT	SEC63	protein	Q9UGP8	UNIPROT	up-regulates activity	phosphorylation	Ser576	VSDKGSDsEEEETNR	9606	BTO:0000599								23287549	t		lperfetto	Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62.	SIGNOR-265268	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	KCNJ4	protein	P48050	UNIPROT	up-regulates activity	phosphorylation	Ser443	NISYRREsAI	9606	BTO:0000007								19635485	t		miannu	Kir2.3 can be phosphorylated by PKAin vitro. We further show that the phosphorylation/dephosphorylation of Ser443 within the C-terminal Kir2.3 PDZ-binding motif RRESAI dynamically regulates the Kir2.3/TIP-1 association in heterologous HEK293T cells. These data suggest that TIP-1 may act as an important regulator for the endocytic pathway of Kir2.3.	SIGNOR-263153	0.2
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1763	TPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273058	0.556
RMDN3	protein	Q96TC7	UNIPROT	VAPB-PTPIP51 complex	complex	SIGNOR-C275	SIGNOR	form complex	binding			10116		BTO:0000142							30841933	t		lperfetto	Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction.	SIGNOR-262119	0.626
GSK3B	protein	P49841	UNIPROT	SREBF1	protein	P36956	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser430	DTLTPPPsDAGSPFQ	9606	BTO:0000007								19126544	t		lperfetto	Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1.	SIGNOR-236030	0.499
PRKCB	protein	P05771	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates activity	phosphorylation	Ser43	VETWQEGsLKASCLY	-1									15604283	t		miannu	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276022	0.2
ARHGEF7	protein	Q14155	UNIPROT	CBLC	protein	Q9ULV8	UNIPROT	down-regulates	binding			9606									14505571	t		gcesareni	Here, we show that activation of cdc42 protects the egf receptor from the negative regulatory activity of the c-cbl ubiquitin ligase. Activated cdc42 binds to p85cool-1 (for cloned-out-of-library)/beta-pix (for pak-interactive exchange factor), a protein that directly associates with c-cbl. This inhibits the binding of cbl by the egf receptor and thus prevents cbl from catalyzing receptor ubiquitination	SIGNOR-118135	0.2
CLK2	protein	P49760	UNIPROT	SRSF1	protein	Q07955	UNIPROT	up-regulates activity	phosphorylation			-1									8617202	t		miannu	 In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors.	SIGNOR-273858	0.302
PTGER3	protein	P43115	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates	binding			9606									12038972	t		gcesareni	Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i)	SIGNOR-88143	0.427
ATF4	protein	P18848	UNIPROT	TARS2	protein	Q9BW92	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269428	0.2
PDGFRB	protein	P09619	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates activity	phosphorylation	Tyr579	VSSDGHEyIYVDPMQ	9606	BTO:0000599								9642269	t		miannu	We used two platelet-derived growth factor beta-receptor (beta-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the beta-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain-containing proteins.	SIGNOR-250254	0.2
JAK1	protein	P23458	UNIPROT	STAT6	protein	P42226	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000801								23124025	t		lperfetto	IL-4-stimulated Stat6 activation is mediated by Jak1 whereas Tyk2 is required for Stat6 activation in IL-13-treated monocytes	SIGNOR-249531	0.757
VTN	protein	P04004	UNIPROT	A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								7559467	t		lperfetto	The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin.	SIGNOR-253307	0.56
CNOT2	protein	Q9NZN8	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	form complex	binding			9606									19558367	t		lperfetto	In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules.	SIGNOR-268306	0.823
COL12A1	protein	Q99715	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									21949456	t			Types XII and XIV collagen are fibril-associated collagens with interrupted triple helices (FACITs) localized primarily to perimysium.23 While they appear to link fibrillar collagen to other ECM components, their precise function is not known	SIGNOR-254671	0.7
RIPK1	protein	Q13546	UNIPROT	TNFRSF10A	protein	O00220	UNIPROT	up-regulates				9606									18545270	f		gcesareni	The death domain of the rip1 kinase binds to death receptors such as tumor necrosis factor-related apoptosis-inducing ligand receptor 1,trailr1.	SIGNOR-177952	0.614
PRKCE	protein	Q02156	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser464	LLKHVTQsSRKLIRA	9606									15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation	SIGNOR-129300	0.316
NODAL	protein	Q96S42	UNIPROT	LIF	protein	P15018	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003879								20383200	f	Regulation	miannu	Nodal induced LIF and Cripto-1 expressions through Smad2 signaling pathway.	SIGNOR-251941	0.27
HNF1A	protein	P20823	UNIPROT	UGT1A10	protein	Q9HAW8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000195								15044625	t	 	 	Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.	SIGNOR-253971	0.253
MAP2K6	protein	P52564	UNIPROT	MAP2K6	protein	P52564	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								10347227	t		lperfetto	However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2.	SIGNOR-236122	0.2
2-(6,7-dimethoxy-4-quinazolinyl)-5-(2-pyridinyl)-1,2,4-triazol-3-amine	chemical	CHEBI:91330	ChEBI	ATM	protein	Q13315	UNIPROT	down-regulates activity	chemical inhibition			-1									18794134	t		Gianni	A targeted compound library was screened for potential inhibitors of the ATM kinase, and CP466722 was identified.	SIGNOR-261975	0.8
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser177	ASSGSSAsFISDTFS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252325	0.635
DYRK1B	protein	Q9Y463	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates				10090	BTO:0000165;BTO:0000222	BTO:0000887;BTO:0001103							15546868	f		lperfetto	Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner	SIGNOR-235816	0.287
rRNA_transcription	phenotype	SIGNOR-PH145	SIGNOR	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	up-regulates													25838379	f		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by means of single-particle electron cryogenic microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three ribosomal RNA molecules.	SIGNOR-262599	0.7
CHMP1A	protein	Q9HD42	UNIPROT	ESCRT-III	complex	SIGNOR-C379	SIGNOR	form complex	binding			-1									26775243	t		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission.	SIGNOR-265531	0.641
FYN	protein	P06241	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	unknown	phosphorylation	Tyr1070	ISTHTVTyGNIEGNA	-1									11024032	t			Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro.	SIGNOR-251170	0.76
RXRA	protein	P19793	UNIPROT	THRA	protein	P10827	UNIPROT	up-regulates	binding			9606									10976919	t		gcesareni	Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr).	SIGNOR-81446	0.651
prazosin	chemical	CHEBI:8364	ChEBI	ADRA1B	protein	P35368	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258469	0.8
3C-like proteinase	protein	P0C6X7-PRO_0000037312	UNIPROT	ATP6V1G1	protein	O75348	UNIPROT	down-regulates activity	cleavage			-1									16226257	t		lperfetto	Cleavage of the V-ATPase G1 fusion protein by SARS-CoV 3CLpro was found in this study (Fig. 3), implying that 3CLpro potentially cleaves the cellular V-ATPase G1, and affects the function of vacuolar H(+)-ATPase. Meanwhile, a significant intracellular acidification has been demonstrated in the 3CLpro-expressing cells (Fig. 4D). The result correlated well with previous reports in that V-ATPase-specific inhibitors cause acidic pHi [28], [29], and influences cell apoptosis	SIGNOR-260264	0.2
BDKRB1	protein	P46663	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257362	0.409
ketotifen	chemical	CHEBI:92511	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002126								18446005	t		Luana	We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells	SIGNOR-257789	0.8
PRKAA1	protein	Q13131	UNIPROT	CCNY	protein	Q8ND76	UNIPROT	up-regulates activity	phosphorylation	Ser326	SARKRSAsADNLTLP										32723157	t		lperfetto	Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. |Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16	SIGNOR-273011	0.2
Carebastine	chemical	CID:65820	PUBCHEM	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002126								18446005	t		Luana	We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells	SIGNOR-257783	0.8
ropinirole	chemical	CHEBI:8888	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			-1									9057850	t		miannu	Compound (R)-6, the most active compound, showed dopaminergic D2 activity and also had affinity for the 5HT1A serotonin receptor subtype. Its dopaminergic activity was more selective for the D2 receptor subtype (259-fold D2/D3 selectivity) than propylamine analogue (R)-2 (14-fold selectivity) or other dopaminergic standards (e.g., pergolide, lisuride, bromocriptine, and ropinirole, 1.0-, 3.4-, 8.7-, and 2.6-fold selectivities, respectively)	SIGNOR-258600	0.8
KAT2B	protein	Q92831	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates	binding			9606		BTO:0000887							10944526	t		gcesareni	Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo	SIGNOR-81059	0.632
TBK1	protein	Q9UHD2	UNIPROT	STAT6	protein	P42226	UNIPROT	up-regulates	phosphorylation	Tyr641	MGKDGRGyVPATIKM	9606									22000020	t		gcesareni	We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing.	SIGNOR-176775	0.661
LCK	protein	P06239	UNIPROT	CD3E	protein	P07766	UNIPROT	up-regulates activity	phosphorylation	Tyr188	PPVPNPDyEPIRKGQ	9534	BTO:0004055								11855827	t			Tyrosine Phosphorylation of CD8- Chimeras by Lck and ZAP-70 in COS Cells. both Y170F and Y181F chimeric proteins could be efficiently phosphorylated by Lck in vivo. phosphorylation of Y170 and Y181 within CD3- –ITAM provides to CD3- the potential to interact with multiple downstream effectors and signaling pathways.	SIGNOR-251368	0.679
CDK1	protein	P06493	UNIPROT	NINL	protein	Q9Y2I6	UNIPROT	up-regulates activity	phosphorylation	Ser185	NRHSPSWsPDGRRRQ	9606									20890132	t		miannu	 In this study, we show that Nlp can be phosphorylated by cell cycle protein kinase Cdc2/cyclin B1. The phosphorylation sites of Nlp are mapped at Ser185 and Ser589. Interestingly, the Cdc2/cyclin B1 phosphorylation site Ser185 of Nlp is required for its recognition by PLK1, which enable Nlp depart from centrosomes to allow the establishment of a mitotic scaffold at the onset of mitosis .	SIGNOR-259830	0.397
PRKCZ	protein	Q05513	UNIPROT	STK11	protein	Q15831	UNIPROT	up-regulates activity	phosphorylation	Ser428	SSKIRRLsACKQQ	9606									18250273	t		llicata	We conclude that pkc-zeta phosphorylates lkb1 at ser428, resulting in lkb1 nuclear export and hence ampk activation.	SIGNOR-160681	0.326
MAPK3	protein	P27361	UNIPROT	LIN28A	protein	Q9H9Z2	UNIPROT	down-regulates activity	phosphorylation	Ser200	EEEEEIHsPTLLPEA	9606	BTO:0000567								28179426	t		miannu	Here we show that Lin28a is directly phosphorylated by ERK1/2 kinases at Ser-200. 	SIGNOR-277337	0.281
PTPRG	protein	P23470	UNIPROT	DOK2	protein	O60496	UNIPROT	up-regulates activity	dephosphorylation	Tyr139	CMEENELySSAVTVG	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254698	0.2
MRPL40	protein	Q9NQ50	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262356	0.713
GSK3B	protein	P49841	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation	Ser645	RPASVPPsPSLSRHS	-1									6772446	t			Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-.	SIGNOR-253006	0.673
RPS6KA3	protein	P51812	UNIPROT	TINF2	protein	Q9BSI4	UNIPROT	unknown	phosphorylation	Ser330	ASTGKSKsPCQTLGG	9606									23977114	t		lperfetto	Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase rsk2. The consequence of tin2 phosphorylation during mitosis remains to be determined	SIGNOR-202536	0.351
STAT5A	protein	P42229	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15003515	f			Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site. 	SIGNOR-261518	0.33
APEX1	protein	P27695	UNIPROT	SLC5A5	protein	Q92911	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								14630715	t		Luana	These data demonstrate a role for APE/Ref-1 protein in the transcriptional regulation of NIS gene expression by itself and in cooperation with PAX8. 	SIGNOR-261564	0.2
HACD1	protein	B0YJ81	UNIPROT	FASN	protein	P49327	UNIPROT	up-regulates activity	chemical activation			9606									18554506	t			Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases,	SIGNOR-267760	0.2
DPYSL2	protein	Q16555	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates				9606	BTO:0000938								25040932	f		lperfetto	In the non-phosphorylated state, CRMP2 binding to tubulin induces the promotion of tubulin polymerisation leading to dendrite outgrowth while	SIGNOR-264841	0.7
N-[(2S)-1-[[(2S)-1-[[3-[4-(Aminomethyl)piperidine-1-carbonyl]phenyl]methylamino]-3-methyl-1-oxopentan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]-1,2-oxazole-5-carboxamide	chemical	CID:49843508	PUBCHEM	F2RL1	protein	P55085	UNIPROT	down-regulates activity	chemical inhibition			9606									20873792	t		Simone Vumbaca	Agonist GB110 (19, EC50 0.28 μM) selectively induced PAR2-, but not PAR1-, mediated intracellular Ca2+ release in HT29 human colorectal carcinoma cells.	SIGNOR-261125	0.8
VAV1	protein	P15498	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates				9606									9013873	f		lperfetto	Vav may link gp130 activation to downstream mapk activation in hematopoietic cells.	SIGNOR-244640	0.524
PPP1R8	protein	Q12972	UNIPROT	PP1	proteinfamily	SIGNOR-PF54	SIGNOR	down-regulates activity	binding			-1									1322907	t		lperfetto	We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity.	SIGNOR-264673	0.667
HTR1F	protein	P30939	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256816	0.425
CAMK2A	protein	Q9UQM7	UNIPROT	PDC	protein	P20941	UNIPROT	unknown	phosphorylation	Ser54	KEILRQMsSPQSRNG										11331285	t		llicata	In this study, we report that Pd was rapidly phosphorylated by Ca(2+)/calmodulin-dependent kinase II, resulting in 100-fold greater inhibition of Gbetagamma binding than cAMP-dependent protein kinase phosphorylation. Furthermore, Pd phosphorylation by Ca(2+)/calmodulin-dependent kinase II at Ser-54 and Ser-73 led to binding of the phosphoserine-binding protein 14-3-3.	SIGNOR-250636	0.311
EEF1A1	protein	P68104	UNIPROT	Tyr-tRNA(Tyr)	smallmolecule	CHEBI:29161	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269518	0.8
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	G0/G1_transition	phenotype	SIGNOR-PH219	SIGNOR	up-regulates													12640120	f		lperfetto	Transition through this point requires cdk6/4-cyclin D, since inhibition with TAT-p16INK4A during the first 3 to 5 h prevents cell cycle entry and maintains both naive and memory T cells in G0.	SIGNOR-273193	0.7
KDM6B	protein	O15054	UNIPROT	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606									22378047	f		lperfetto	IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization.	SIGNOR-249564	0.7
PRKAA1	protein	Q13131	UNIPROT	ZNF692	protein	Q9BU19	UNIPROT	down-regulates	phosphorylation	Ser470	VAAHRSKsHPALLLA	9606			SIGNOR-C15						17097062	t		gcesareni	Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp.	SIGNOR-150590	0.2
LPAR1	protein	Q92633	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256839	0.494
PRKCB	protein	P05771	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates activity	phosphorylation	Ser185	SAYVGRLsARPKLKA	-1									15604283	t		miannu	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276023	0.2
ING1	protein	Q9UK53	UNIPROT	AFP	protein	P02771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								14522900	f	 	miannu	 In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity.	SIGNOR-254480	0.2
ROCK1	protein	Q13464	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				9606									19279717	f		areggio	To date it is not clear whether any genes are transcribed downstream of these two GTPases for non-canonical signaling. The prevailing dogma remains that their primary roles are indeed solely for cytoskeletal modulation	SIGNOR-258975	0.7
RASSF1	protein	Q9NS23	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates	binding			9606									22683405	t	Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage	gcesareni	Rassf1a and mst1 co-exist as a complex localizing at microtubules throughout the cell cycle, of which the rassf1a mst1 interaction is stimulatory to the mst1 kinase activity.	SIGNOR-197744	0.801
PSME3	protein	P61289	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	up-regulates activity	binding												35932807	t		lperfetto	While PA28alpha beta is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28gamma is well-known to not only promote peptidase activity but also proteolytic activity of proteasome. 	SIGNOR-275869	0.628
PTEN	protein	P60484	UNIPROT	PIP3	smallmolecule	CHEBI:16618	ChEBI	down-regulates quantity	chemical modification			9606									11875759	t		lperfetto	PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT.	SIGNOR-228145	0.8
SNRPG	protein	P62308	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270659	0.72
PTPN11	protein	Q06124	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	dephosphorylation	Tyr570	VRREVGDyGQLHETE	9606									30108215	t		miannu	Consistently, JAK2/STAT3 signaling was enhanced by overexpression of SHP2   with decreased levels of pJAK2   and increased levels of pJAK2   and pSTAT3  , while it was found suppressed by overexpression of SHP2   (Fig.\u00a06b).|We demonstrate that SHP2 can dephosphorylate JAK2 at Y570 to promote TGF\u03b2-dependent activation of JAK2 and its downstream mediator STAT3 (Supplementary Fig.\u00a04a).	SIGNOR-277037	0.786
PPP2R5B	protein	Q15173	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates	dephosphorylation	Thr308	KDGATMKtFCGTPEY	9606									16495456	t		gcesareni	Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt.	SIGNOR-144808	0.647
SYK	protein	P43405	UNIPROT	HCLS1	protein	P14317	UNIPROT	up-regulates	phosphorylation	Tyr378	EPEPENDyEDVEEMD	9606									9104825	t		llicata	Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis.	SIGNOR-47338	0.652
CAK complex	complex	SIGNOR-C456	SIGNOR	CDK2	protein	P24941	UNIPROT	up-regulates activity	phosphorylation	Thr160	GVPVRTYtHEVVTLW	-1									10085115	t		llicata	Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP.	SIGNOR-269330	0.611
SMURF1	protein	Q9HCE7	UNIPROT	CALCOCO1	protein	Q9P1Z2	UNIPROT	unknown	ubiquitination			-1									20804422	t		miannu	Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay.	SIGNOR-272688	0.2
BMP7	protein	P18075	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									18719589	f		lperfetto	Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways	SIGNOR-180311	0.328
2',2'-difluoro-2'-deoxyuridine	chemical	CHEBI:83486	ChEBI	TYMS	protein	P04818	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0003207								25562513	t		miannu	2',2'-Difluoro-2'-deoxycytidine (dFdC, gemcitabine) is a cytidine analogue active against several solid tumor types, such as ovarian, pancreatic and non-small cell lung cancer. The compound has a complex mechanism of action. Because of the structural similarity of one metabolite of dFdC, dFdUMP, with the natural substrate for thymidylate synthase (TS) dUMP, we investigated whether dFdC and its deamination product 2',2'-difluoro-2'-deoxyuridine (dFdU) would inhibit TS. This study was performed using two solid tumor cell lines: the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000. The specific TS inhibitor Raltitrexed (RTX) was included as a positive control. Using the in situ TS activity assay measuring the intracellular conversion of [5-(3)H]-2'-deoxyuridine or [5-(3)H]-2'-deoxycytidine to dTMP and tritiated water, it was observed that dFdC and dFdU inhibited TS. 	SIGNOR-259351	0.8
pazopanib	chemical	CHEBI:71219	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001949								18620382	t		Luana	Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively.	SIGNOR-257739	0.8
BMP4	protein	P12644	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	up-regulates activity	binding			9606									8006002	t		fspada	BMP-4 bound to ALK-3 and ALK-6 efficiently	SIGNOR-236932	0.847
Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding			9606		BTO:0000887;BTO:0001103							22944199	t		gcesareni	Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism.	SIGNOR-253125	0.2
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates activity	phosphorylation	Ser189	DEEFREPsTGKTCLP	-1									19661060	t		miannu	Activation of the TRPV4 ion channel is enhanced by phosphorylation. TRPV4 is phosphorylated in response to activation of PKC. We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.	SIGNOR-276230	0.2
BMP2	protein	P12643	UNIPROT	BMPR2	protein	Q13873	UNIPROT	up-regulates	binding			9606				SIGNOR-C29					7791754	t		fspada	Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.	SIGNOR-33425	0.793
CDC34	protein	P49427	UNIPROT	SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	up-regulates activity	binding			9606									25425648	t		miannu	The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association.Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases. 	SIGNOR-277331	0.766
CAK complex	complex	SIGNOR-C456	SIGNOR	TP53	protein	P04637	UNIPROT	unknown	phosphorylation	Ser33	LPENNVLsPLPSQAM	9606									9372954	t		llicata	We have mapped a major site of phosphorylation by cak to ser-33 of p53 and have demonstrated as well that p53 is phosphorylated at this site in vivo.	SIGNOR-269326	0.446
TLR8	protein	Q9NR97	UNIPROT	TNF	protein	P01375	UNIPROT	up-regulates quantity				9606	BTO:0004721;BTO:0002900								15661881	f		miannu	TLR8 functions in monocytes and myeloid DC and is involved in the production of proinflammatory cytokines such as TNF-α. 	SIGNOR-259249	0.461
PRKCA	protein	P17252	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates activity	phosphorylation	Ser43	VETWQEGsLKASCLY	-1									15604283	t		miannu	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276024	0.2
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH2	protein	P19022	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265842	0.8
AKT2	protein	P31751	UNIPROT	PKP1	protein	Q13835	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr180	GSKGQKTtQNRYSFY	-1									23444369	t		miannu	Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry.	SIGNOR-273485	0.27
FYN	protein	P06241	UNIPROT	FCGR2C	protein	P31995	UNIPROT	up-regulates activity	phosphorylation	Tyr294	YETADGGyMTLNPRA	-1									8756631	t		miannu	Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation	SIGNOR-262677	0.2
RPS6KA5	protein	O75582	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Ser65	FLMECRNsPVTKTPP										12213813	t		lperfetto	In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E	SIGNOR-262993	0.658
AKT1	protein	P31749	UNIPROT	METTL1	protein	Q9UBP6	UNIPROT	down-regulates	phosphorylation	Ser27	YYRQRAHsNPMADHT	9606									3627513	t		lperfetto	The trna methylase mettl1 is phosphorylated and inactivated by pkb and rsk in vitro and in cells	SIGNOR-24994	0.341
STK38L	protein	Q9Y2H1	UNIPROT	ULK1	protein	O75385	UNIPROT	down-regulates quantity	phosphorylation	Ser495	GVLARKMsLGGGRPY	10090									35670107	t			STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination	SIGNOR-270348	0.2
SLC1A1	protein	P43005	UNIPROT	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	up-regulates quantity	relocalization			9606									26687113	t		miannu	After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5).	SIGNOR-264804	0.8
GFs	stimulus	SIGNOR-ST12	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity				9606									23300340	f		lperfetto	Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation	SIGNOR-245411	0.7
GSK3B	protein	P49841	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr58	KKFELLPtPPLSPSR	9606									16023596	t		gcesareni	Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.	SIGNOR-138603	0.709
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PML	protein	P29590	UNIPROT	up-regulates	phosphorylation			9606	BTO:0001271								15093545	t	The effect has been demonstrated using P29590-4	gcesareni	Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis.	SIGNOR-270153	0.2
CDK2	protein	P24941	UNIPROT	CCP110	protein	O43303	UNIPROT	down-regulates activity	phosphorylation	Ser516	ASSQCIAsPNFGTVS	-1									12361598	t		miannu	GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)	SIGNOR-265963	0.531
FANCL	protein	Q9NW38	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0000567		SIGNOR-C300						17396147	t		lperfetto	Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo 	SIGNOR-263250	0.897
BORA	protein	Q6PGQ7	UNIPROT	AURKA	protein	O14965	UNIPROT	up-regulates	binding			9606									16890155	t		gcesareni	Both drosophila and human bora can bind to aurora-a and activate the kinase in vitro.	SIGNOR-148661	0.717
YAP1	protein	P46937	UNIPROT	TEAD2	protein	Q15562	UNIPROT	up-regulates	binding			9606									23431053	t	Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4.	gcesareni	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.	SIGNOR-201468	0.879
AMER1	protein	Q5JTC6	UNIPROT	WT1	protein	P19544	UNIPROT	up-regulates	binding			9606									19416806	t		miannu	Wtx binds wt1, a zinc-finger transcription factor that is inactivated in wilms tumor. / the ability of wtx to enhance wt1-mediated transactivation suggests a physiologically significant interaction between these 2 tumor suppressors.	SIGNOR-185644	0.45
PAK3	protein	O75914	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates	phosphorylation	Ser150	TLRRVRIsADAMMQA	9606		BTO:0000887							15769444	t		lperfetto	In vitro addition of pak3 to skinned rat cardiac fibres increased myofilament ca2+ sensitivity with no change in maximal ca2+-activated force [67]. These effects were associated with pak3-induced phosphorylation of myofilament proteins, including ctni which was phosphorylated at a novel site, ser149, located in the region forming a ca2+-sensitive interaction with the n-terminal regulatory domain of tnc.	SIGNOR-134593	0.2
GPR34	protein	Q9UPC5	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256831	0.2
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates	phosphorylation			9606									11971971	t		lperfetto	Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.	SIGNOR-244776	0.747
TGFBR1	protein	P36897	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	phosphorylation	Ser465	SPSVRCSsMS	9534	BTO:0001538								9346908	t		lperfetto	Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-_ (TGF-_) type I receptor, T_RI. Phosphorylation sites on smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. In this report, we show that T_RI specifically phosphorylates Smad2 on serines 465 and 467.These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals.	SIGNOR-236107	0.819
SNIP1	protein	Q8TAD8	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates	binding			9606				SIGNOR-C6					10887155	t		gcesareni	In this study, we characterize a novel nuclear protein, termed snip1 its principal mechanism of action appears to be through transcription by binding to cbp/p300 and interfering with the ability of these coactivators to interact with smad4	SIGNOR-78984	0.573
CRYAA	protein	P02489	UNIPROT	Maintenance_of_lens_transparency	phenotype	SIGNOR-PH65	SIGNOR	up-regulates				9606									22982024	f		miannu	Aberrant protein interactions can lead to aggregation and insolubilization, such as occurs during cataract formation. Deamidation, a prevalent age-related modification in the lens of the eye, decreases stability of the major lens proteins, crystallins. Deamidation did not disrupt specific αA/βB2 interactions but favored aggregation before complex formation with αA. We conclude that deamidation contributes to cataract formation through destabilization of crystallins before they can be rescued by α-crystallin.	SIGNOR-252156	0.7
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1651	SPTSPSYsPTSPSYS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248782	0.441
NME2	protein	P22392	UNIPROT	NME2	protein	P22392	UNIPROT	up-regulates activity	phosphorylation	Ser44	AMKFLRAsEEHLKQH	9606	BTO:0000093								8245015	t		miannu	An acid-stable (nonhistidine) phosphorylation was identified on autophosphorylated purified recombinant Nm23 proteins and [32P]orthophosphate-labeled human breast carcinoma and murine melanoma Nm23. Phosphoamino acid analysis identified serine as the acid-stable phosphorylation and serine 44 as the major site of phosphorylation. The biological relevance of the novel phosphorylation identified herein is suggested by the direct correlation of in vivo Nm23 acid-stable phosphorylation levels, but not Nm23 NDPK activity, with suppression of tumor metastatic potential among control and nm23-1 transfected murine melanoma cells.	SIGNOR-250201	0.2
STAT5A	protein	P42229	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000574								9168989	f	Regulation	miannu	We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin.	SIGNOR-251784	0.246
CASP3	protein	P42574	UNIPROT	GSN	protein	P06396	UNIPROT	down-regulates activity	cleavage	Asp403	WRDPDQTdGLGLSYL	9606									9671712	t		miannu	We showed that human gelsolin was cleaved during Fas-mediated apoptosis in vivo and that the caspase-3 cleavage site of human gelsolin was at D352 of DQTD352G. gelsolin seems to have dual functions, i.e., it both prevents and, once cleaved, induces cell death.	SIGNOR-256357	0.624
SYK	protein	P43405	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates activity	phosphorylation	Tyr658	SDFEGFSyVNPQFVH	9606	BTO:0000830								12881490	t		lperfetto	We present evidence that Tyr-662 and Tyr-658 of PKCbetaI and PKCalpha, respectively, are phosphorylated by Syk in the membrane compartment of FcepsilonRI-stimulated mast cells. These phosphorylations require prior PKC autophosphorylation of the adjacent serine residues (Ser-661 and Ser-657, respectively) and generate a binding site for the SH2 domain of the adaptor protein Grb-2.	SIGNOR-246581	0.4
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates				9606									22021368	f		apalma	Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB.	SIGNOR-256654	0.7
NEK7	protein	Q8TDX7	UNIPROT	KIF14	protein	Q15058	UNIPROT	up-regulates activity	phosphorylation	Ser1220	NLHSSHSsGLMDKSS	9606	BTO:0000565								28630147	t		miannu	Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). 	SIGNOR-266418	0.38
SUN1	protein	O94901	UNIPROT	SPDYA	protein	Q5MJ70	UNIPROT	up-regulates activity	binding			9606	BTO:0000007		SIGNOR-C305						33015044	t		lperfetto	In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | Taken together, we speculate that speedy A is likely capable of interacting with both telomeres and the LINC complex and thus might function as the missing linkage between telomeres and the LINC complex during prophase I, stabilizing the telomere–NE connection	SIGNOR-263301	0.25
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	NR3C1	protein	P04150	UNIPROT	down-regulates	phosphorylation	Ser226	IDENCLLsPLAGEDD	-1									9199329	t		lperfetto	Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.	SIGNOR-93554	0.2
HOXD12	protein	P35452	UNIPROT	MAFF	protein	Q9ULX9	UNIPROT	down-regulates activity	binding			-1									11036080	t		miannu	Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.	SIGNOR-221884	0.388
CDX2	protein	Q99626	UNIPROT	UGT1A8	protein	Q9HAW9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000195								15044625	t	 	 	Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.	SIGNOR-253969	0.263
BCL2	protein	P10415	UNIPROT	HTRA2	protein	O43464	UNIPROT	down-regulates				9606									14585074	f		amattioni	Bcl- confers protection to apoptosis by interference with bax/bak-mediated release of the pro-apoptotic mitochodrial factors smac/diablo and htra2/omi	SIGNOR-89189	0.254
ADAM17	protein	P78536	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates				9606									20626350	f		gcesareni	Such phosphorylation is required for tace mediated ectodomain shedding of tgfalfa family ligands, which results in the activation of egfr and cell proliferation.	SIGNOR-166568	0.473
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	ATR	protein	Q13535	UNIPROT	up-regulates				9606									21034966	f		lperfetto	the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively.	SIGNOR-242609	0.7
RYK	protein	P34925	UNIPROT	FZD8	protein	Q9H461	UNIPROT	up-regulates	binding			9606									17035295	t		gcesareni	Interaction between ryk and fz has been reported, suggesting that the two proteins may form a multi-receptor complex signalling through the canonical pathway	SIGNOR-150010	0.699
NTNG1	protein	Q9Y2I2	UNIPROT	LRRC4C	protein	Q9HCJ2	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								19467332	t		miannu	The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively.	SIGNOR-264047	0.768
sorafenib	chemical	CHEBI:50924	ChEBI	BRAF	protein	P15056	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000848								21654832	t		gcesareni	Inhibition of map kinases mek, jnk, p38, and multikinases (braf, craf, vegfp by sorafenib) in wm-115 and m14 human melanoma cell lines led to either significant reduction or complete inhibition of the plk-1 protein expression.	SIGNOR-174036	0.8
PTPRK	protein	Q15262	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606									25612622	t		miannu	In this study, we investigated whether receptor-type tyrosine protein phosphatase kappa (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3 specifying motif, negatively regulates STAT3 activation in NKTCL.|Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705).	SIGNOR-277060	0.383
GGCX	protein	P38435	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									31539109	f		miannu	GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05).	SIGNOR-261232	0.2
1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	PRKCA	protein	P17252	UNIPROT	up-regulates	binding			9606									23630338	t	PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine.	gcesareni	C1a domain is critical for the dag-induced activation of pkcalfa.Furthermore, calcium and diacylglycerol activate protein kinase c, resulting in the phosphorylation of a large variety of substrates.	SIGNOR-202007	0.8
CEBPG	protein	P53567	UNIPROT	SFTPD	protein	P35247	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11912209	t	 	 	Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.	SIGNOR-254058	0.2
RTKs	proteinfamily	SIGNOR-PF38	SIGNOR	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			9606									17306385	t		miannu	The adaptor protein Grb2 can bind with activated RTKs through an SH2 domain-phosphotyrosine interaction, while through the SH3 domain (a binding domain specific to proline-rich sequences) Grb2 interacts with the guanine nucleotide exchange factor, Sos.	SIGNOR-256167	0.2
SNCAIP	protein	Q9Y6H5	UNIPROT	Lewy_body_formation	phenotype	SIGNOR-PH56	SIGNOR	up-regulates				9606									19224863	f		miannu	Synphilin-1 interacts in vivo with α-synuclein, and their coexpression promotes the formation of Lewy body-like inclusions	SIGNOR-272596	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	unknown	phosphorylation			9606									12588998	t		lperfetto	Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro	SIGNOR-265319	0.2
ATP1A3	protein	P13637	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	down-regulates quantity	relocalization			9606	BTO:0000938								22797008	t		miannu	The sodium/potassium transporting ATPase subunit alpha-3 (AT1A3; syn.: sodium pump subunit alpha-3; E.C. 3.6.3.9; UniProtKB ID: Q6PIC6) belongs to the cation transport ATPase (P-type) 3.A.3 family catalyzing hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action generates the electrochemical gradient of sodium and potassium ions thus providing energy for active transport of various nutrients. Three sodium/potassium transporting ATPase isoforms are expressed in the brain but AT1A3 is detectable in neurons exclusively.	SIGNOR-265792	0.8
CARS1	protein	P49589	UNIPROT	tRNA(Cys)	smallmolecule	CHEBI:29167	ChEBI	down-regulates quantity	chemical modification			9606									11347887	t		miannu	Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine.	SIGNOR-270469	0.8
DLGAP3	protein	O95886	UNIPROT	SHANK2	protein	Q9UPX8	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264593	0.779
PRKCA	protein	P17252	UNIPROT	THOC5	protein	Q13769	UNIPROT	up-regulates	phosphorylation	Ser6	sKKRKPKV	9606	BTO:0000801;BTO:0000876								15221008	t		llicata	We conclude m-csf-mediated activation of pkcalpha can potentiate fmip action to initiate survival/differentiation signaling.	SIGNOR-126572	0.332
indometacin	chemical	CHEBI:49662	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates activity	chemical inhibition			-1									9057869	t		miannu	Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). 	SIGNOR-258606	0.8
CSNK1A1	protein	P48729	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser267	PPTTSSDsEEEQEDE	9606	BTO:0000007								22025562	t		miannu	 Together, our findings provide evidence for CK1α-mediated destruction of c-Myc and identify c-Myc S252 as a crucial CK1α phosphorylation site for c-Myc degradation.	SIGNOR-276387	0.286
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation	Tyr972	EYLGTKRyIHRDLAT	9606	BTO:0000007								20304997	t		lperfetto	Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity	SIGNOR-236294	0.2
AURKB	protein	Q96GD4	UNIPROT	H1-4	protein	P10412	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser27	VKKKARKsAGAAKRK	9606	BTO:0000093								21511733	t		miannu	 we showed previously that phosphorylation of S27 in human histone H1.4 (H1.4S27-P), prevents binding of heterochromatin protein 1 (HP1) family members (officially known as chromobox protein homologs) to the neighboring dimethylated K26. Here, we present the first functional characterization of H1.4S27-P in vivo and in vitro. We show that H1.4S27 phosphorylation is cell-cycle-regulated and its levels peak on metaphase chromosomes. We identify further Aurora B as the kinase phosphorylating H1.4S27.	SIGNOR-262658	0.2
MIPOL1	protein	Q8TD10	UNIPROT	RELA	protein	Q04206	UNIPROT	down-regulates activity				9606									31609475	f		miannu	In our results, we also showed that re-expression of MIPOL1 is associated with suppression phosphorylation of AKT and p65, a subunit of NF-ҡB. This suggests that MIPOL1 may inhibit invasion by suppression of phosphorylation of AKT and p65 to further inhibit the expression of MMP-9	SIGNOR-261136	0.2
CTNND1	protein	O60716	UNIPROT	CDH3	protein	P22223	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0003564								14610055	t		miannu	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 	SIGNOR-252124	0.742
GRIK1	protein	P39086	UNIPROT	D-serine	smallmolecule	CHEBI:16523	ChEBI	up-regulates quantity	relocalization			9606	BTO:0002609								12393813	t		lperfetto	Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine	SIGNOR-268272	0.8
EXT1	protein	Q16394	UNIPROT	EXT1/EXT2	complex	SIGNOR-C51	SIGNOR	form complex	binding			9606									11518722	t		miannu	Biochemical analysis shows that ext1 and ext2 are type ii transmembrane glycoproteins and form a golgi-localized hetero-oligomeric complex that catalyzes the polymerization of hs	SIGNOR-109938	0.563
PTPN7	protein	P35236	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000007								10415025	t		fstefani	Lc-ptp dephosphorylated erk2 in vitro. the complex formation of lc-ptp with erk is the essential mechanism for the suppression. Taken collectively, these results indicate that lc-ptp suppresses mitogen-activated protein kinase directly in vivo.	SIGNOR-69448	0.805
ENDOG	protein	Q14249	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates				9606									21210296	f		gcesareni	Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore.	SIGNOR-170972	0.358
HK2	protein	P52789	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor.	SIGNOR-266446	0.8
ABL1	protein	P00519	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	phosphorylation	Tyr449	IIQHCSNySTQELLR	9606	BTO:0000793								29022905	t		miannu	In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation.	SIGNOR-277327	0.263
PRKD1	protein	Q15139	UNIPROT	KIDINS220	protein	Q9ULH0	UNIPROT	unknown	phosphorylation	Ser918	RTITRQMsFDLTKLL	10116									10998417	t		lperfetto	Our results provide the first physiological substrate for PKD and indicate that Kidins220 is phosphorylated by PKD at serine 919 in vivo.	SIGNOR-249052	0.534
APAF1	protein	O14727	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								9390557	t		lperfetto	Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation.	SIGNOR-53576	0.953
APH1A	protein	Q96BI3	UNIPROT	gamma-secretase	complex	SIGNOR-C98	SIGNOR	form complex	binding			9606									25610395	t		lperfetto	-Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2)	SIGNOR-209714	0.958
CSNK1D	protein	P48730	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates	phosphorylation	Ser253	SVEFEVEsLDSEDYS	9606									20708156	t		gcesareni	Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination	SIGNOR-167513	0.351
ATR	protein	Q13535	UNIPROT	PI4K2A	protein	Q9BTU6	UNIPROT	down-regulates				9606									18082599	f		gcesareni	Plk1 itself is negatively regulated by the ddr in an atm/atr-dependent manner.	SIGNOR-159933	0.282
TOB1	protein	P50616	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	down-regulates activity	binding			9606	BTO:0000567								18377426	t		miannu	We found that Tob associates with the CCR4-NOT complex. The carboxyl-terminal half of Tob interacted with Cnot1, a core protein of the CCR4-NOT complex. We further showed that the deadenylase activity associated with the complex was suppressed in vitro by Tob. 	SIGNOR-273616	0.651
neostigmine	chemical	CHEBI:7514	ChEBI	ACHE	protein	P22303	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001239								17888667	t		Luana	AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE.	SIGNOR-257758	0.8
PPP2CA	protein	P67775	UNIPROT	PRKCD	protein	Q05655	UNIPROT	down-regulates activity	dephosphorylation	Thr507	FGESRAStFCGTPDY	9606									11959144	t			PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex	SIGNOR-248637	0.385
FOXO4	protein	P98177	UNIPROT	FBXO32	protein	Q969P5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							21798082	f		lperfetto	Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome.	SIGNOR-236554	0.383
ketoprofen	chemical	CHEBI:6128	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001061								18667313	t		Luana	Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2. 	SIGNOR-257811	0.8
HSD17B2	protein	P37059	UNIPROT	17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	up-regulates quantity	chemical modification			-1									8099587	t		Luana	17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone. 	SIGNOR-269764	0.8
MAP2K1	protein	Q02750	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	up-regulates	phosphorylation			9606									12270934	t	inferred from 70% of family members	lbriganti	Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis.	SIGNOR-269909	0.2
KDM5C	protein	P41229	UNIPROT	BDNF	protein	P23560	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									31691806	f		miannu	The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice.	SIGNOR-264315	0.278
HDAC1	protein	Q13547	UNIPROT	GAD1	protein	Q99259	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19029285	f		miannu	 induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. 	SIGNOR-254576	0.287
FST	protein	P19883	UNIPROT	INHBA	protein	P08476	UNIPROT	down-regulates activity	binding			9606									22037168	t		gcesareni	Blocking activin action by pre-treatment with its binding protein, follistatin, modifies the inflammatory cytokine cascade, and reduces the severity of the subsequent inflammatory response and mortality	SIGNOR-235134	0.84
FYN	protein	P06241	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation	Tyr323	DEPVADPyDQSFESR	10090	BTO:0000782								15735648	t		miannu	Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323.	SIGNOR-276031	0.466
NOD2	protein	Q9HC29	UNIPROT	Autophagy	phenotype	SIGNOR-PH31	SIGNOR	up-regulates				9606	BTO:0000567								19898471	f		miannu	Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria.	SIGNOR-252403	0.7
PCNA	protein	P12004	UNIPROT	NCR2	protein	O95944	UNIPROT	down-regulates activity	binding			9606									22021614	t		miannu	NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown. 	SIGNOR-260043	0.311
MAPK1	protein	P28482	UNIPROT	SREBF2	protein	Q12772	UNIPROT	up-regulates	phosphorylation	Ser432	NQNVLLMsPPASDSG	9606									14988395	t		lperfetto	Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity.	SIGNOR-123041	0.365
GSK3B	protein	P49841	UNIPROT	AHR	protein	P35869	UNIPROT	up-regulates activity	phosphorylation	Ser436	LRTKNGTsGKDSATT	9606	BTO:0000567								34198826	t		miannu	A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR.	SIGNOR-276666	0.253
PRKCA	protein	P17252	UNIPROT	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation	Ser643	CFTPKGSsLKIEERA	9606		BTO:0000887;BTO:0001260							8182108	t		gcesareni	Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase.	SIGNOR-36788	0.365
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	IRS1	protein	P35568	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser312	TESITATsPASMVGG	10116	BTO:0004428								12510059	t		lperfetto	Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylationOne of the specific Ser phosphorylation sites in IRS-1 that has been proposed to negatively modulate the insulin signal is Ser312 (numbered according to the human sequence). Prior studies have demonstrated that IRS-1 associates with and is phosphorylated by JNK in vitro on Ser312	SIGNOR-235777	0.2
CCT137690	chemical	CID:25154041	PUBCHEM	AURKC	protein	Q9UQB9	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190898	0.8
SMAD3	protein	P84022	UNIPROT	SMAD3/PIAS3	complex	SIGNOR-C204	SIGNOR	form complex	binding			9606									26194464	t		mrosina	In summary, the TGF-b/IL-6/TCR-pERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation	SIGNOR-255034	0.58
MAPK3	protein	P27361	UNIPROT	IRX2	protein	Q9BZI1	UNIPROT	up-regulates activity	phosphorylation	Ser325	PGAPPPAsKPKLWSL	-1									15133517	t		miannu	To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target.	SIGNOR-263061	0.2
PRKAA1	protein	Q13131	UNIPROT	SLC2A4	protein	P14672	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17609368	f		gcesareni	Several in vivo studies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochrome c, uncoupling protein 3 (ucp-3)] and proteins involved in glucose uptake (glut4)are increased at the transcriptional level in skeletal muscle.	SIGNOR-156786	0.307
ATF2	protein	P15336	UNIPROT	YTHDC2	protein	Q9H6S0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001911								24269672	t		lperfetto	Collectively, these data show that YTHDC2 plays an important role in tumor cells growth and activation/recruitment of c-Jun and ATF-2 to the YTHDC2 promoter is necessary for the transcription of YTHDC2, and that HDAC activity is required for the efficient expression of YTHDC2 in both of hepatocyte and HCC cells.	SIGNOR-269001	0.278
IKK-complex	complex	SIGNOR-C14	SIGNOR	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000007								19609947	t		lperfetto	Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta.	SIGNOR-216365	0.812
IKBKE	protein	Q14164	UNIPROT	IRF7	protein	Q92985	UNIPROT	up-regulates	phosphorylation	Ser471	GTQREGVsSLDSSSL	9606									10893229	t		gcesareni	In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3.	SIGNOR-79139	0.675
ginkgolide B	chemical	CHEBI:5356	ChEBI	PTAFR	protein	P25105	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192684	0.8
PTK2	protein	Q05397	UNIPROT	NANOG	protein	Q9H9S0	UNIPROT	up-regulates activity	phosphorylation	Tyr35	ICGPEENyPSLQMSS	9606	BTO:0000007								22493428	t		miannu	 In addition, FAK directly phosphorylates Nanog in a dose-dependent manner by in vitro kinase assay and in cancer cells in vivo. The site-directed mutagenesis of Nanog tyrosines, Y35F and Y174F, blocked phosphorylation and binding by FAK.	SIGNOR-276409	0.278
MMP27	protein	Q9H306	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272371	0.7
SMARCE1	protein	Q969G3	UNIPROT	Muscle cell-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C483	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex.	SIGNOR-270731	0.812
IFNG	protein	P01579	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates activity				10090									23667107	f			Early inhibition of IL-1β expression by IFN-γ is mediated by impaired binding of NF-κB to the IL-1β promoter but is independent of nitric oxide.	SIGNOR-255937	0.442
PLK1	protein	P53350	UNIPROT	CEP192	protein	Q8TEP8	UNIPROT	up-regulates activity	phosphorylation	Thr44	GLPVAVStLARDRSS	9606	BTO:0000007								26012549	t		miannu	In the presence of AurA binding, Plk1 preferentially phosphorylates and interacts with the T44 motif of Cep192 through the “self-priming and binding” mechanism	SIGNOR-266405	0.593
SNTB1	protein	Q13884	UNIPROT	MAPK12	protein	P53778	UNIPROT	down-regulates	binding			10090	BTO:0002314	BTO:0001103							29681515	t		apalma	Basal localization of the p38g/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through b1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38g/b1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation	SIGNOR-255901	0.376
AKT1	protein	P31749	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									12588998	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro	SIGNOR-98285	0.2
DEPTOR	protein	Q8TB45	UNIPROT	mTORC2	complex	SIGNOR-C2	SIGNOR	down-regulates activity	binding			9606	BTO:0000007								19446321	t			DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival	SIGNOR-251659	0.715
MRGPRX1	protein	Q96LB2	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256786	0.2
EPB42	protein	P16452	UNIPROT	Ankyrin complex	complex	SIGNOR-C383	SIGNOR	form complex	binding			9606	BTO:0000424								22465511	t		lperfetto	The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) 	SIGNOR-266014	0.405
LRFN5	protein	Q96NI6	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606	BTO:0000938								21736948	f		miannu	The SALM (synaptic adhesion-like molecule) family of adhesion molecules, also known as Lrfn, belongs to the superfamily of leucine-rich repeat (LRR)-containing adhesion molecules. Proteins of the SALM family, which includes five known members (SALMs 1-5), have been implicated in the regulation of neurite outgrowth and branching, and synapse formation and maturation.SALM3 and SALM5, but not other SALMs, possess synaptogenic activity, inducing presynaptic differentiation in contacting axons.	SIGNOR-264093	0.7
ZDHHC5	protein	Q9C0B5	UNIPROT	EZH2	protein	Q15910	UNIPROT	down-regulates activity	palmitoylation			9606	BTO:0000526								28775165	t			Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the tumor suppressor EZH2.	SIGNOR-261144	0.2
DAMPS	stimulus	SIGNOR-ST18	SIGNOR	AP-3/clathrin vescicle	complex	SIGNOR-C250	SIGNOR	up-regulates				9606									25720354	f		scontino	APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. 	SIGNOR-267858	0.7
YARS1	protein	P54577	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									16429158	t		miannu	YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr	SIGNOR-270519	0.8
AKT2	protein	P31751	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Thr157	GIRKRPAtDDSSTQN	9606	BTO:0000150								12244303	t		gcesareni	Akt-induced t157 phosphorylation causes retention of p27(kip1) in the cytoplasm, precluding p27(kip1)-induced g1 arrest.[__]Thus, cytoplasmic relocalization of p27(kip1), secondary to akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27(kip1) are functionally inactivated and the proliferation of breast cancer cells is sustained.	SIGNOR-93122	0.511
TULP3	protein	O75386	UNIPROT	GPR161	protein	Q8N6U8	UNIPROT	up-regulates activity	relocalization			10090									23332756	t			Upon knockdown of Tulp3 using siRNA in IMCD3 cells, ciliary localization of Gpr161 was severely reduced	SIGNOR-259938	0.593
CLOCK	protein	O15516	UNIPROT	PER3	protein	P56645	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f			Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253635	0.586
ER stress	stimulus	SIGNOR-ST9	SIGNOR	BBC3	protein	Q9BXH1	UNIPROT	up-regulates				9606									22492984	f		miannu	Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins	SIGNOR-196938	0.7
RARA	protein	P10276	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates activity	binding			9606									15650024	t	inferred from family member	gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-267801	0.516
MCHR2	protein	Q969V1	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257067	0.409
ACACA	protein	Q13085	UNIPROT	malonyl-CoA	smallmolecule	CHEBI:15531	ChEBI	up-regulates quantity	chemical modification			9606									20952656	t		miannu	ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA	SIGNOR-267109	0.8
PHLPP2	protein	Q6ZVD8	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	down-regulates activity	dephosphorylation	Thr390	DSKFTRQtPVDSPDD	9606	BTO:0000182								21986499	t		gcesareni	We show that PHLPP preferentially dephosphorylates the hydrophobic motif T389 site in S6K1 in vitro	SIGNOR-248247	0.504
MC4R	protein	P32245	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257440	0.252
CHL1	protein	O00533	UNIPROT	ANK2	protein	Q01484	UNIPROT	up-regulates quantity	relocalization			10116		BTO:0000227							7961622	t		miannu	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266722	0.418
PRKAA2	protein	P54646	UNIPROT	ACACB	protein	O00763	UNIPROT	down-regulates activity	phosphorylation	Ser222	PTMRPSMsGLHLVKR	9606									14613924	t		miannu	ACCβ(Ser221) is a known target for AMPK in human skeletal muscle	SIGNOR-250316	0.638
DDIT3	protein	P35638	UNIPROT	ASNS	protein	P08243	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002181								18940792	f		miannu	C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene.	SIGNOR-253837	0.382
SMARCA2	protein	P51531	UNIPROT	CERF	complex	SIGNOR-C340	SIGNOR	form complex	binding			9606		BTO:0000227							15640247	t		miannu	Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation.	SIGNOR-263890	0.395
LPCAT4	protein	Q643R3	UNIPROT	acyl-CoA(4-)	chemical	CHEBI:58342	ChEBI	down-regulates quantity	chemical modification			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272773	0.8
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGC5	protein	Q9Y5F6	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265683	0.2
MED14	protein	O60244	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266676	0.832
BTF3	protein	P20290	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17312387	f	 	 	In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis.	SIGNOR-253950	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	IRX2	protein	Q9BZI1	UNIPROT	up-regulates activity	phosphorylation			-1									15133517	t	inferred from 70% family members	miannu	To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target.	SIGNOR-270097	0.2
oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	precursor of			9606									31422819	t		miannu	This is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1).	SIGNOR-267511	0.8
LONP1	protein	P36776	UNIPROT	STAR	protein	P49675	UNIPROT	down-regulates quantity by destabilization	cleavage			10116	BTO:0000542								17579211	t		lperfetto	Turnover of mitochondrial steroidogenic acute regulatory (StAR) protein by Lon protease: the unexpected effect of proteasome inhibitors	SIGNOR-265726	0.272
SMURF	proteinfamily	SIGNOR-PF29	SIGNOR	SKIL	protein	P12757	UNIPROT	down-regulates activity	ubiquitination			9606		BTO:0002181;BTO:0005493							11389444	t		lperfetto	Tgf-beta also induces the association of smurf2 with the transcriptional co-repressor snon and we show that smad2 can function to mediate this interaction. This allows smurf2 hect domain to target snon for ubiquitin-mediated degradation by the proteasome.	SIGNOR-253262	0.2
CDON	protein	Q4KMG0	UNIPROT	SPAG9	protein	O60271	UNIPROT	up-regulates activity	binding			9606	BTO:0000222								18678706	t	p38 together with Bnip-2 and CDC42 to activate p38alfa/beta activity	lperfetto	During myoblast differentiation, the promyogenic cell surface receptor cdo binds to the p38alpha/beta pathway scaffold protein jlp and, via jlp, p38alpha/beta itself.	SIGNOR-179870	0.477
1,1-dioxo-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3-one	chemical	CHEBI:93578	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258851	0.8
RELA	protein	Q04206	UNIPROT	COMT	protein	P21964	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000100								19291302	f	Regulation of expression	miannu	TNFα-dependent COMT downregulation was indeed mediated by the NF-κB pathway. Transient expression of p65, the essential component of NF-κB complexes, or IKKβ, the major positive regulator of NF-κB activition, significantly decreased P2-COMT reporter expression.	SIGNOR-251964	0.2
EPM2A	protein	O95278	UNIPROT	NHLRC1	protein	Q6VVB1	UNIPROT	up-regulates activity	binding			10116	BTO:0003234								18029386	t		miannu	Here, we provide evidence indicating that the formation of the laforin–malin complex is positively regulated by AMPK. We show that laforin, but not malin, can interact physically with the catalytic subunit of AMPK and that purified AMPK phosphorylates GST::laforin in vitro. 	SIGNOR-271729	0.78
ADP	chemical	CHEBI:16761	ChEBI	P2RY12	protein	Q9H244	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257560	0.8
EEF1A1	protein	P68104	UNIPROT	Trp-tRNA(Trp)	smallmolecule	CHEBI:29159	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269517	0.8
D1-D2-G-X3 complex	complex	SIGNOR-C301	SIGNOR	CHEK2	protein	O96017	UNIPROT	up-regulates activity				9606	BTO:0000567								23438602	f		lperfetto	Interestingly, as with ATM (40, 41), XRCC3-deficient cells exhibited RDS and impaired CHK2 activation|Notably, early activation of CHK2 in S/G2 phase was downstream of XRCC3 recruitment as well as its phosphorylation at the sites of DSBs. NBS1 also has been shown to be involved in the early activation of CHK2 in response to IR (42). It is likely that NBS1-dependent CHK2 phosphorylation is mediated through XRCC3 activation.	SIGNOR-263262	0.489
ITGB8	protein	P26012	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates				9606		BTO:0000142							11970960	f		lperfetto	Integrin _v_8-mediated tgf_ activation is also required to regulate neurovascular homeostasis in the adult brain	SIGNOR-117386	0.54
CHRM4	protein	P08173	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256829	0.376
BDKRB2	protein	P30411	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256838	0.375
PPM1D	protein	O15297	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	dephosphorylation	Ser15	PSVEPPLsQETFSDL	9606									15870257	t			PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair.	SIGNOR-248319	0.576
SARS1	protein	P49591	UNIPROT	alpha-aminoacyl-tRNA	smallmolecule	CHEBI:2651	ChEBI	up-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 	SIGNOR-270802	0.8
nepicastat	chemical	CHEBI:139334	ChEBI	DBH	protein	P09172	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194625	0.8
NR3C1	protein	P04150	UNIPROT	PCK1	protein	P35558	UNIPROT	up-regulates quantity	transcriptional regulation			10116									11069927	f			In the liver, glucocorticoids induce a 10-15-fold increase in the rate of transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene, which encodes a key gluconeogenic enzyme	SIGNOR-253056	0.369
Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	GABA-A (a6-b2-d) receptor	complex	SIGNOR-C328	SIGNOR	up-regulates				9606									33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors	SIGNOR-268587	0.2
CRLS1	protein	Q9UJA2	UNIPROT	cardiolipin	smallmolecule	CHEBI:28494	ChEBI	up-regulates	chemical modification			10090									16678169	t		lperfetto	The mitochondrial phospholipid cardiolipin is synthesized from cytidinediphosphate-diacylglycerol and phosphatidylglycerol, a process catalyzed by the enzyme cardiolipin synthase.	SIGNOR-267028	0.8
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1693	SPTSPSYsPTSPSYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii	SIGNOR-203532	0.77
IL10	protein	P22301	UNIPROT	SCN11A	protein	Q9UI33	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									23357618	f		miannu	Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α.	SIGNOR-253502	0.2
MAPK1	protein	P28482	UNIPROT	PRDX6	protein	P30041	UNIPROT	up-regulates	phosphorylation	Thr177	TAEKRVAtPVDWKDG	9606		BTO:0000763							19140803	t		miannu	These results show that the mapks can mediate phosphorylation of prdx6 at thr-177 with a consequent marked increase in its aipla(2) activity.	SIGNOR-183379	0.68
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GRK7	protein	Q8WTQ7	UNIPROT	down-regulates activity	phosphorylation	Ser23	YLQARKPsDCDSKEL	-1									15946941	t		miannu	 We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA.Phosphorylation of GRK1 and GRK7 by PKA reduces the ability of GRK1 and GRK7 to phosphorylate rhodopsin in vitro. 	SIGNOR-276036	0.2
MYOG	protein	P15173	UNIPROT	PAX7	protein	P23759	UNIPROT	down-regulates quantity by destabilization				10090	BTO:0004058								17548510	f		Simone Vumbaca	Indeed, we observed a reduction in Pax7 protein levels upon ectopic myogenin expression in MM14 myoblasts, even under proliferation conditions	SIGNOR-255638	0.506
p38	proteinfamily	SIGNOR-PF16	SIGNOR	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				9606									11591790	f			The p21 G protein Rho and its targets, Rho-associated coiled-coil forming protein kinases (p160ROCK/ROCK I/ROKβ and Rho kinase/ROCK II/ROKα), play a crucial role in actin cytoskeleton reorganization	SIGNOR-254360	0.7
ITGB1BP1	protein	O14713	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257639	0.757
pictrelisib	chemical	CHEBI:65326	ChEBI	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0000149							21876152	t		gcesareni	Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed	SIGNOR-176298	0.8
OPTN	protein	Q96CV9	UNIPROT	SNAP25	protein	P60880	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									22194658	f	same result in PC12 cell 	miannu	SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA.	SIGNOR-259880	0.2
PPARGC1A	protein	Q9UBK2	UNIPROT	NRF1	protein	Q16656	UNIPROT	up-regulates activity				9606									26971449	f		lperfetto	PGC-1 family transcriptional coactivators enhance the activities of the nuclear respiratory factors NRF1 and NRF2, which induce transactivation of many genes encoding mitochondria-specific proteins involved in respiratory chain, mitochondrial DNA transcription/replication and protein import/assembly	SIGNOR-253391	0.698
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	phosphorylation			9606									17643117	t		gcesareni	Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation.	SIGNOR-265365	0.2
SP1	protein	P08047	UNIPROT	TBXA2R	protein	P21731	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000565								19747485	f			Collectively, data establish that regulated WT1 followed by sequential Egr1 and Sp1 binding to elements within Prm1 mediate repression and subsequent induction of TPα during differentiation into the megakaryocytic phenotype, shedding significant insights into factors regulating TPα expression therein.	SIGNOR-254254	0.2
DLG3	protein	Q92796	UNIPROT	NMDA receptor_2D	complex	SIGNOR-C350	SIGNOR	up-regulates activity	relocalization					BTO:0000227							32904533	t		lperfetto	DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses.	SIGNOR-266009	0.633
NADP(3-)	smallmolecule	CHEBI:58349	ChEBI	NADPH(4-)	smallmolecule	CHEBI:57783	ChEBI	up-regulates quantity	precursor of			9606									33064660	t		miannu	Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP.	SIGNOR-268078	0.8
Norzotepine	chemical	CID:10041551	PUBCHEM	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								20223878	t		Luana	These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity.	SIGNOR-257831	0.8
PKN1	protein	Q16512	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates	phosphorylation	Ser256	SPRRRAAsMDNNSKF	9606	BTO:0000150								12560069	t		lperfetto	Furthermore, estrogen induced phosphorylation and perinuclear localization of the cell survival forkhead transcription factor fkhr in the cytoplasm in a pak1-dependent manner. In addition, pak1 directly interacted with fkhr and phosphorylated it. The noticed phosphorylation-dependent exclusion of fkhr from the nucleus impaired the ability of fkhr to activate its target fas ligand promoter containing the fkhr binding motif (fre) in cells treated with estrogen or expressing catalytically active pak1.	SIGNOR-97882	0.2
denopamine	chemical	CHEBI:135359	ChEBI	ADRB1	protein	P08588	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. 	SIGNOR-257860	0.8
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1665	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273091	0.745
NRL	protein	P54845	UNIPROT	RHO	protein	P08100	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								15277472	f		miannu	 KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. 	SIGNOR-253819	0.456
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation			9606		BTO:0000176							14967450	t	inferred from 70% family members	lperfetto	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-270103	0.2
SIRT1	protein	Q96EB6	UNIPROT	NHLH2	protein	Q02577	UNIPROT	up-regulates activity	deacetylation	Lys49	EEAEGDGkGGSRAAL	10090		BTO:0000142							22169038	t		miannu	SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter	SIGNOR-254830	0.39
OGA	protein	O60502	UNIPROT	PFKP	protein	Q01813	UNIPROT	up-regulates activity	deglycosylation	Ser540	VMVPATVsNNVPGSD	9606									26399441	t		lperfetto	Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 	SIGNOR-267606	0.2
AURKB	protein	Q96GD4	UNIPROT	RACGAP1	protein	Q9H0H5	UNIPROT	up-regulates activity	phosphorylation	Ser187	REKRRSTsRQFVDGP	9606	BTO:0000567								14744859	t		llicata	It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1	SIGNOR-250588	0.772
TFAP4	protein	Q01664	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001109								19505873	f		miannu	AP-4 Mediates E-box-dependent Complex Formation for Transcriptional Repression of HDM2	SIGNOR-226596	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	FOXO4	protein	P98177	UNIPROT	up-regulates	phosphorylation	Thr227	PAPPEGAtPTSPVGH	9606	BTO:0000848	BTO:0001253							20959475	t		lperfetto	Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451).	SIGNOR-168758	0.2
MMP14	protein	P50281	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272359	0.7
IL22	protein	Q9GZX6	UNIPROT	IL22RA2	protein	Q969J5	UNIPROT	down-regulates	binding			9606		BTO:0000763;BTO:0000149							11390453	t		gcesareni	We identified a gene encoding a protein of 231 aa, showing 33 and 34% amino acid identity with the extracellular domains of the il-22 receptor and of the il-20r/cytokine receptor family 2-8,the recombinant protein was found to bind il-10-related t cell-derived inducible factor/il-22, and to inhibit the activity of this cytokine on hepatocytes and intestinal epithelial cells. We propose to name this natural cytokine antagonist il-22bp for il-22 binding protein. respectively, but lacking the transmembrane and cytoplasmic domains	SIGNOR-86110	0.737
SGI-1776	chemical	CID:24795070	PUBCHEM	PIM1	protein	P11309	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206859	0.8
STUB1	protein	Q9UNE7	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	ubiquitination			9606									21454478	t		gcesareni	In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner	SIGNOR-172993	0.334
LRFN5	protein	Q96NI6	UNIPROT	PTPRF	protein	P10586	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								27225731	t		miannu	SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1). 	SIGNOR-264087	0.359
ANKS1B	protein	Q7Z6G8	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								26356309	t		miannu	The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95.	SIGNOR-264228	0.463
CSNK2A1	protein	P68400	UNIPROT	CAST	protein	P20810	UNIPROT	up-regulates activity	phosphorylation	Ser655	QDPIDALsGDLDSCP	9606	BTO:0002036								29581866	t		miannu	 We also showed that casein kinase 2, a pro-survival kinase overexpressed in many cancer types, phosphorylated calpastatin at Ser-633. Our results indicate that calpastatin phosphorylation promotes radiation resistance in GBM cells by increasing the activity of calpain proteases, which are known to promote survival and invasion in cancer.	SIGNOR-277388	0.2
HUNK	protein	P57058	UNIPROT	ITM2A	protein	O43736	UNIPROT	up-regulates activity	phosphorylation	Thr35	TVRTQILtGKELRVA	9606	BTO:0000007								31438969	t		miannu	ITM2A is phosphorylated at T35 and the phosphorylation status of ITM2A contributes to breast cancer proliferation. Moreover, we found that ITM2A was phosphorylated at T35 by HUNK, a serine/threonine kinase significantly correlated with human breast cancer overall survival and HER2-induced mammary tumorigenesis.	SIGNOR-273640	0.2
DLGAP1	protein	O14490	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								9115257	t		miannu	SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.	SIGNOR-264209	0.93
RBBP8	protein	Q99708	UNIPROT	BRCA1-C complex	complex	SIGNOR-C299	SIGNOR	form complex	binding								phosphorylation:Ser327	ELPTRVSsPVFGATS			25400280	t		lperfetto	The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2|The interaction between BRCA1 and CtIP within this complex is mediated by CDK‐dependent phosphorylation of CtIP‐S327	SIGNOR-263220	0.2
MYOD1	protein	P15172	UNIPROT	DES	protein	P17661	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000222								25653159	t		lperfetto	MyoD and HDAC2 repress myogenic late genes at early times of differentiation.A time course of Ckm, Des and Acta1 gene expression demonstrated that these genes were prematurely expressed when differentiation was driven by myogenin and Mef2D1b (Figure _(Figure6A).6A). Since MyoD is not expressed under these conditions, it cannot bind to these genes; ChIP assays demonstrated that HDAC2 also was not present on the Ckm, Des and Acta1 regulatory sequences under these conditions (Figure _(Figure6B).6B). Therefore the presence of MyoD and HDAC2 prior to gene expression functions to repress late gene expression at early times of differentiation.	SIGNOR-241762	0.243
MAP2K6	protein	P52564	UNIPROT	MAPK13	protein	O15264	UNIPROT	up-regulates activity	phosphorylation	Thr180	RHADAEMtGYVVTRW	9606	BTO:0000007								10066767	t	done	miannu	 p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.	SIGNOR-273952	0.645
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser378	SKKGQSTsRHKKLMF	9606	BTO:0000776								17339337	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-153479	0.784
RPS6KA5	protein	O75582	UNIPROT	PLA2G4A	protein	P47712	UNIPROT	up-regulates activity	phosphorylation	Ser727	RQNPSRCsVSLSNVE	9606	BTO:0000007								10978317	t		lperfetto	Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases.	SIGNOR-249051	0.359
SPX	protein	Q9BT56	UNIPROT	GALR2	protein	O43603	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								24517231	t		lperfetto	Coevolution of the spexin/galanin/kisspeptin family: Spexin activates galanin receptor type II and III.	SIGNOR-268574	0.347
paliperidone	chemical	CHEBI:82978	ChEBI	HTR1D	protein	P28221	UNIPROT	down-regulates activity	chemical inhibition			10116	BTO:0000529								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258562	0.8
IL6	protein	P05231	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates activity	binding			9606	BTO:0001271								15895091	t		miannu	A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (il-6) and its a-receptor (il-6ralpha) revealed a hexameric architecture in which the gp130 membrane-distal regions were approximately 100 a apart, in contrast to the close apposition seen between short cytokine receptor complexes.	SIGNOR-48041	0.864
PRKACA	protein	P17612	UNIPROT	GRK2	protein	P25098	UNIPROT	up-regulates activity	phosphorylation	Ser685	VPLVQRGsANGL	-1									11278469	t		miannu	PKA directly phosphorylates GRK2 on serine 685. This modification increases G subunit binding to GRK2 and thus enhances the ability of the kinase to translocate to the membrane and phosphorylate the receptor.	SIGNOR-250334	0.2
CDK5	protein	Q00535	UNIPROT	BAG3	protein	O95817	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser291	STPLHSPsPIRVHTV	9606	BTO:0002181								31955914	t		miannu	CDK5-mediated phosphorylation on S297 promotes BAG3 degradation.	SIGNOR-277502	0.2
CSNK2A1	protein	P68400	UNIPROT	HMGA1	protein	P17096	UNIPROT	unknown	phosphorylation	Ser99	KEEEEGIsQESSEEE	-1									2806554	t		llicata	Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. | After an 80 min incubation with CK-II, both serines were fully phosphorylated to 1 mol/mol and serine-99 to 0.3 mol/mol.	SIGNOR-250894	0.335
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PFKFB2	protein	O60825	UNIPROT	unknown	phosphorylation	Ser483	IRRPRNYsVGSRPLK	9606	BTO:0000567								12853467	t			14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling.	SIGNOR-251485	0.2
NF2	protein	P35240	UNIPROT	STK3	protein	Q13188	UNIPROT	up-regulates activity	binding			10090	BTO:0003324								27402866	t	Hippo pathway	Gianni	NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart.	SIGNOR-261955	0.333
NKX3-1	protein	Q99801	UNIPROT	ACTG2	protein	P63267	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19797053	f		miannu	 These results demonstrate the ability of MYOCD to discriminate among several juxtaposed CArG elements, presumably through its novel partnership with NKX3.1, to optimally transactivate the human ACTG2 promoter.	SIGNOR-254619	0.291
PAK1	protein	Q13153	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser16	KELEKRAsGQAFELI	9606									14645234	t		gcesareni	Pak1 phosphorylates op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays. Furthermore, phosphorylation of either serine 16 or 63 is sufficient to inhibit op18/stathmin in vitro.	SIGNOR-119483	0.384
MAVS	protein	Q7Z434	UNIPROT	CASP8	protein	Q14790	UNIPROT	up-regulates	relocalization			9606									16406812	t		gcesareni	Another protein suggested to play a role in caspase-8 translocation to mitochondria is the mitochondrial membrane protein cardif	SIGNOR-143572	0.57
NEK2	protein	P51955	UNIPROT	NEK2	protein	P51955	UNIPROT	up-regulates	phosphorylation	Thr175	HDTSFAKtFVGTPYY	9606									17197699	t		gcesareni	Enzymatic activity, induced;	SIGNOR-151763	0.2
JDP2	protein	Q8WYK2	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates activity	binding			9606									18671972	t		miannu	JDP2 dimerizes with other AP-1 proteins such as activating transcription factor-2 (ATF2) and Jun to repress transcription from promoters that contain a cyclic AMP-responsive element (CRE).	SIGNOR-226398	0.627
MAPK14	protein	Q16539	UNIPROT	SMARCD3	protein	Q6STE5	UNIPROT	up-regulates activity	phosphorylation			9606									21902831	t		lperfetto	P38 phosphorylates the baf60 subunit of the swi-snf chromatin remodelling complex, and p38 recruits this complex to differentiation-specific loci.	SIGNOR-176557	0.375
AKT1	protein	P31749	UNIPROT	NIBAN1	protein	Q9BZQ8	UNIPROT	unknown	phosphorylation	Ser602	ASPARRAsAILPGVL	9606									22510990	t		llicata	We demonstrate here that ultraviolet irradiation induces phosphorylation of niban at s602 by akt, which increases the association of niban with nucleophosmin and disassociation of nucleophosmin from the mdm2 complex.	SIGNOR-252530	0.2
AKT1	protein	P31749	UNIPROT	TSC	complex	SIGNOR-C101	SIGNOR	down-regulates activity	phosphorylation			10090	BTO:0000944								12150915	t		lperfetto	We have shown thataktregulates the tsc1-tsc2 complex by directly phosphorylating tsc2. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1akt has been shown to directly phosphorylate two sites on tsc2 (s939 and t1462 on the full-length human protein), which are conserved and phosphorylated in drosophila tsc2, and is likely to phosphorylate two or three additional sites (s981 and s1130/s1132).	SIGNOR-235628	0.778
CRKL	protein	P46109	UNIPROT	PIK3CB	protein	P42338	UNIPROT	up-regulates activity	binding			9606	BTO:0005029								28723560	t		irozzo	 Here, we identify CRKL as a member of the class of PI3Kβ-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110β-dependent PI3K signaling and cell proliferation.In conclusion, our study identified CRKL as an important regulator of PI3K activity in PTEN-deficient tumor cells through its association with p110β/p85.	SIGNOR-255821	0.451
ACSL5	protein	Q9ULC5	UNIPROT	long-chain fatty acyl-CoA(4-)	smallmolecule	CHEBI:83139	ChEBI	up-regulates quantity	chemical modification			9606									24269233	t			ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity	SIGNOR-267712	0.8
AP1M1	protein	Q9BXS5	UNIPROT	AP-1 complex	complex	SIGNOR-C248	SIGNOR	form complex	binding			9606									21097499	t		lperfetto	Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)	SIGNOR-260686	0.888
olanzapine	chemical	CHEBI:7735	ChEBI	HTR1E	protein	P28566	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258508	0.8
MAPK1	protein	P28482	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates	phosphorylation	Thr43	KVTTVVAtPGQGPDR	9606	BTO:0000150;BTO:0000680								16039586	t		lperfetto	Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin.	SIGNOR-138894	0.39
SMAD3	protein	P84022	UNIPROT	NKX2-1	protein	P43699	UNIPROT	down-regulates activity	binding			9606	BTO:0004299								18003659	t		miannu	TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function. 	SIGNOR-254169	0.295
NLGN2	protein	Q8NFZ4	UNIPROT	NRXN2	protein	P58401	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264161	0.824
FOXO1	protein	Q12778	UNIPROT	AGRP	protein	O00253	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									28270795	f		miannu	 Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations. 	SIGNOR-263501	0.452
EGFL7	protein	Q9UHF1	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates activity	binding			10090	BTO:0002881								19503073	t		miannu	Here we have identified transmembrane receptors of the Notch family as EGFL7-binding molecules. Secreted EGFL7 binds to a region in Notch involved in ligand-mediated receptor activation, thus acting as an antagonist of Notch signalling. Expression of EGFL7 in neural stem cells (NSCs) in vitro decreased Notch-specific signalling and consequently, reduced proliferation and self-renewal of NSCs. 	SIGNOR-266860	0.488
ATM	protein	Q13315	UNIPROT	RBBP8	protein	Q99708	UNIPROT	down-regulates	phosphorylation	Ser664	IDPGADLsQYKMDVT	9606	BTO:0000150								10910365	t		llicata	Atm phosphorylates ctip at serine residues 664 and 745 our study suggests another dna damage-response pathway in which the signal is transmitted through phosphorylation of ctip by atm, leading to dissociation of the ctip_ctbp repressor complex from brca1, which in turn, activate transcription of gadd45	SIGNOR-79872	0.823
17beta-estradiol 3-sulfate(1-)	smallmolecule	CHEBI:136582	ChEBI	17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	up-regulates quantity	precursor of			-1									7779757	t		Luana	HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM.	SIGNOR-269748	0.8
MAP2K4	protein	P45985	UNIPROT	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	up-regulates activity	phosphorylation			9606									11062067	t		lperfetto	Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1).	SIGNOR-83729	0.74
CBFbeta-MYH11	fusion protein	SIGNOR-FP3	SIGNOR	TP53	protein	P04637	UNIPROT	down-regulates activity	binding			10090	BTO:0002882								26387755	t			Here, we show that p53 activity is inhibited in inv(16)+ AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8).Altogether, these results indicate that CM fusion protein binds to p53 and impairs acetylation and activation of p53.	SIGNOR-255737	0.2
CDC7	protein	O00311	UNIPROT	PSIP1	protein	O75475	UNIPROT	up-regulates	phosphorylation	Ser206	MVKQPCPsESDIITE	9606	BTO:0001271;BTO:0000785								7231784	t		llicata	We now report identification of the cdc7-activator of s-phase kinase (ask) heterodimer as a novel interactor of ledgf. the kinase phosphorylated ledgf in vitro, with ser-206 being the major target, and ledgf phosphorylated at this residue could be detected during s phase of the cell cycle. Ledgf potently stimulated the enzymatic activity of cdc7-ask, increasing phosphorylation of mcm2 in vitro by more than 10-fold.	SIGNOR-25763	0.341
PRKN	protein	O60260	UNIPROT	SNCAIP	protein	Q9Y6H5	UNIPROT	up-regulates quantity by stabilization	ubiquitination			9606	BTO:0000007								11590439	t		miannu	Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1. Co-expression of alpha-synuclein, synphilin-1 and parkin result in the formation of Lewy-body-like ubiquitin-positive cytosolic inclusions. 	SIGNOR-272595	0.2
TTK	protein	P33981	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Thr18	EPPLSQEtFSDLWKL	9606									19332559	t		llicata	Ttk/hmps1 mediates the p53-dependent postmitotic checkpoint by phosphorylating p53 at thr18. phosphorylation at thr18 enhances p53-dependent activation of not only p21 but also lats2, two mediators of the postmitotic checkpoint.	SIGNOR-184931	0.514
GSK3B	protein	P49841	UNIPROT	SPI1	protein	P17947	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser140	EEEGERQsPPLEVSD	9606	BTO:0002181								33188146	t		miannu	We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7.	SIGNOR-277542	0.2
RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	PAX7	protein	P23759	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001103;BTO:0002314							22493066	t		lperfetto	Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells NICD regulates Pax7 through interaction with RBP-J_, which binds to two consensus sites upstream of the Pax7 gene.	SIGNOR-219365	0.386
MAP2K6	protein	P52564	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation			9606									20551513	t		ggiuliani	Expression of a constitutively active mutant of MKK6 (MKK6-glu) (39), but not a kinase-inactive mutant of MKK6 (MKK6-K82A) (39), strongly promoted human MSC differentiation to osteoblasts as shown by increased ALP activity and extracellular matrix mineralization (Figure 4E). Furthermore, MKK6-glu–expressing osteoblasts were treated with inhibitors of p38, JNK, and MEK (Figure 4F). Only treatment with the p38 inhibitor SB203580 blocked the effects of MKK6-glu.	SIGNOR-255780	0.733
AKT3	protein	Q9Y243	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser82	RALSRQLsSGVSEIR	9606									19593530	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	lperfetto	First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.	SIGNOR-186780	0.29
SKI	protein	P12755	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates activity	binding			9606	BTO:0000848								12793438	t		lperfetto	The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway	SIGNOR-236074	0.813
GGCX	protein	P38435	UNIPROT	F7	protein	P08709	UNIPROT	up-regulates activity	carboxylation			9606									31226734	t		lperfetto	Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.	SIGNOR-265919	0.675
GALNT8	protein	Q9NY28	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	glycosylation			9606									35220009	t		miannu	Interestingly, the O-GalNAcylation of EGFR, which is the key factor related to the metastasis cascade, was impacted by GALNT8. Furthermore, our results suggested that the GALNT8-mediated O-GalNAcylation led to the suppression of the EGFR signaling pathway and metastatic potential in breast cancer cells. 	SIGNOR-269679	0.2
CBL	protein	P22681	UNIPROT	SYK	protein	P43405	UNIPROT	down-regulates activity	ubiquitination			9606	BTO:0000007								11742985	t		miannu	Intact tyrosine kinase-binding and RING finger domains of Cbl were found to be essential for Syk ubiquitylation in 293T cells and for in vitro Syk ubiquitylation. Altogether, our results support an essential role for Cbl ubiquitin ligase activity in the negative regulation of Syk, and establish that ubiquitylation provides a mechanism of Cbl-mediated negative regulation of cytoplasmic targets.	SIGNOR-272620	0.808
SF3B6	protein	Q9Y3B4	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270675	0.595
4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide	chemical	CHEBI:94128	ChEBI	BCL2	protein	P10415	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189150	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	GORASP1	protein	Q9BQQ3	UNIPROT	down-regulates activity	phosphorylation	Ser274	DPLPGPGsPSHSAPD	10116									18762583	t		Giulio	Supporting the conclusion that phosphorylation of GRASP65 at Ser277 by ERK is critical for Golgi polarization. We have demonstrated a closely integrated mechanism in which Golgi remodeling by phosphorylation of GRASP65 acts as a negative regulator of Golgi and, surprisingly, centrosome orientation. Our data indicate that ERK phosphorylates GRASP65 in interphase cells, resulting in the loss of GRASP65 oligomerization and causing subsequent Golgi cisternal unstacking.	SIGNOR-260605	0.2
DAB2IP	protein	Q5VWQ8	UNIPROT	ZEB1	protein	P37275	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									27858941	f		miannu	Through inhibition of PI3K–AKT signaling, DAB2IP also represses ZEB1, another CSC determinant.	SIGNOR-254772	0.271
PYGB	protein	P11216	UNIPROT	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	up-regulates quantity	chemical modification			9606									3346228	t			Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267952	0.8
AURKB	protein	Q96GD4	UNIPROT	AURKB	protein	Q96GD4	UNIPROT	up-regulates	phosphorylation	Thr232	APSLRRKtMCGTLDY	9606									14722118	t		lperfetto	We report here that human aurora-b is phosphorylated at thr-232 through interaction with the inner centromere protein (incenp) in vivo. The phosphorylation of thr-232 occurs by means of an autophosphorylation mechanism, which is indispensable for the aurora-b kinase activity.	SIGNOR-121340	0.2
GNAI3	protein	P08754	UNIPROT	Adenylate_cyclase	proteinfamily	SIGNOR-PF92	SIGNOR	down-regulates activity	binding			9606									19703466	t		miannu	Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma)	SIGNOR-267851	0.578
ZFYVE9	protein	O95405	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	relocalization			9606									20515759	t		lperfetto	Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor.	SIGNOR-59145	0.855
NFATC1	protein	O95644	UNIPROT	GPC6	protein	Q9Y625	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								21871017	t		miannu	 NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype.	SIGNOR-264022	0.254
MEF2A	protein	Q02078	UNIPROT	MYF6	protein	P23409	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									7739551	t		lperfetto	Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis.	SIGNOR-238709	0.573
enalapril	chemical	CHEBI:4784	ChEBI	ACE	protein	P12821	UNIPROT	down-regulates activity	chemical inhibition			10116									7527095	t		miannu	The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. However, comparison of ACE inhibitory activities of the diacid forms of trandolapril and enalapril, i.e., trandolaprilat and enalaprilat, measured in vitro on various tissues, showed that trandolaprilat was only three- to fivefold more active than enalaprilat.	SIGNOR-258428	0.8
TNFRSF1A	protein	P19438	UNIPROT	TRADD	protein	Q15628	UNIPROT	up-regulates activity	binding			10090	BTO:0002572;BTO:0000801								21232017	t		miannu	TRADD and RIP1 contain a C‐terminal death domain which mediates binding to the death domain of TNFR1. Upon association with ligated TNFR1, TRADD further recruits the adapter protein TRAF2 via its N‐terminal TRAF‐binding domain	SIGNOR-245029	0.799
TTC5	protein	Q8N0Z6	UNIPROT	JMY	protein	Q8N9B5	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								15448695	t		miannu	DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY	SIGNOR-262647	0.512
MYO9B	protein	Q13459	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260509	0.764
RELA	protein	Q04206	UNIPROT	TRAF2	protein	Q12933	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9733516	f		lperfetto	Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2	SIGNOR-59960	0.516
MAP3K7	protein	O43318	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates activity	phosphorylation	Ser177	AKELDQGsLCTSFVG	9606				SIGNOR-C14					11460167	t		lperfetto	Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta.	SIGNOR-109490	0.744
PTK6	protein	Q13882	UNIPROT	KHDRBS1	protein	Q07666	UNIPROT	unknown	phosphorylation	Tyr440	GAYREHPyGRY	9606	BTO:0000567								16179349	t		lperfetto	We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal. |Tyrosine 440 was identified as a principal modulator of Sam68 localization and this site was phosphorylated in response to EGF treatment in human breast tumor cell lines.	SIGNOR-249294	0.738
Immunoglobulin delta heavy chain	protein	P0DOX3	UNIPROT	BCR-Dl	complex	SIGNOR-C436	SIGNOR	form complex	binding			9606	BTO:0000776								20176268	t		scontino	Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes.	SIGNOR-268199	0.2
Nalmefene	chemical	CHEBI:7457	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258811	0.8
WICH	complex	SIGNOR-C449	SIGNOR	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	up-regulates activity	binding			9606									16603771	t		miannu	We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling.	SIGNOR-268829	0.395
Caspase 8 complex	complex	SIGNOR-C231	SIGNOR	CASP7	protein	P55210	UNIPROT	up-regulates	cleavage			9606									9727491	t		gcesareni	Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them.	SIGNOR-256459	0.729
Angiotensin 1-7	protein	P01019-PRO_0000420660	UNIPROT	Alamandine	chemical	CID:44192273	PUBCHEM	up-regulates activity	catalytic activity			-1									24389733	t		Luana	Newly discovered peptide, alamandine, have been identified. Alamandine is generated by catalysis of Ang A via ACE2 or directly from Ang-(1–7).	SIGNOR-262307	0.8
LATS2	protein	Q9NRM7	UNIPROT	SNAI1	protein	O95863	UNIPROT	up-regulates	phosphorylation	Thr203	QGHVRTHtGEKPFSC	9606									21952048	t		lperfetto	Lats2 kinase potentiates snail1 activity by promoting nuclear retention upon phosphorylation. during tgf_-induced emt lats2 is activated and snail1 phosphorylated at t203.	SIGNOR-176647	0.543
PRKCZ	protein	Q05513	UNIPROT	PTPN7	protein	P35236	UNIPROT	up-regulates activity	phosphorylation	Ser246	QYQEERRsVKHILFS	-1									16479000	t		miannu	HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. 	SIGNOR-276047	0.263
HDAC5	protein	Q9UQL6	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates	deacetylation			9606									16613856	t		gcesareni	Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation	SIGNOR-145983	0.47
TRIP11	protein	Q15643	UNIPROT	THRA	protein	P10827	UNIPROT	up-regulates	binding			9606									9256431	t		miannu	Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity.	SIGNOR-50348	0.395
Compound A [PMID:15866883]	chemical	CID:51529932	PUBCHEM	LTB4R2	protein	Q9NPC1	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257535	0.8
BAD	protein	Q92934	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	down-regulates activity	binding												7834748	t		lperfetto	Bad binds more strongly to Bcl-x, than Bcl-2 in mammalian cells, and it reversed the death repressor activity of Bcl-x,, but not that of Bcl-2. When Bad dimerized with Bcl-x,, Bax was displaced and apoptosis was restored.	SIGNOR-249617	0.841
HIF1A	protein	Q16665	UNIPROT	ALAS2	protein	P22557	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000664								21207956	f	 	miannu	Hypoxia-induced expression of erythroid-specific ALAS2 is mediated by HIF1 in erythroid cells.	SIGNOR-254421	0.2
ESR1	protein	P03372	UNIPROT	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates activity	binding			9606									18247370	t		miannu	The primary conclusion of the results reported here is that ERα and c‐jun, c‐fos and ATF‐2, but not Fra‐2 AP‐1 factors interact “in vivo” with specific estrogen‐responsive regulatory sequences and AP‐1 cis‐elements within the F promoter of the human ERα gene in osteoblast‐like SaOS‐2 cells. 	SIGNOR-263656	0.71
MTA3	protein	Q9BTC8	UNIPROT	MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263852	0.775
HCK	protein	P08631	UNIPROT	ELMO1	protein	Q92556	UNIPROT	up-regulates	phosphorylation	Tyr395	AKHHQDAyIRIVLEN	9606									15952790	t		llicata	We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts.	SIGNOR-138150	0.59
ITK	protein	Q08881	UNIPROT	BMX	protein	P51813	UNIPROT	up-regulates activity	phosphorylation	Tyr224	DSNSKKIyGSQPNFN	-1									12573241	t			Itk phosphorylated Bmx-SH3 to a low extent. pY positions correspond to the residues Y215 and Y223 in Bmx. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.	SIGNOR-251332	0.339
TLN1	protein	Q9Y490	UNIPROT	A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257614	0.618
BDNF	protein	P23560	UNIPROT	NTRK2	protein	Q16620	UNIPROT	up-regulates	binding			9606									7679912	t		gcesareni	Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb	SIGNOR-31597	0.811
SRC	protein	P12931	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr220	RHSVVVPyEPPEVGS	9606	BTO:0002181								25071020	t		miannu	We recently found that ISGylation of the p53 tumor suppressor is an important novel mechanism to control its stability. Here we identified that Isg15-dependent regulation of p53 can be enhanced by different oncogenes. We further show that the Src-mediated phosphorylation of p53 on Tyr126 and Tyr220 has a positive effect on p53 ISGylation by enhancing Herc5 binding.	SIGNOR-276669	0.54
EIF5A	protein	P63241	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534									15371445	t		miannu	 eIF5A regulated p53 protein expression. Further analysis by reverse transcription PCR showed eIF5A-activated p53 transcription. The effect of eIF5A on p53 transcriptional activity was further demonstrated by the increasing expressions of p21 and Bax, well known target genes of p53. 	SIGNOR-266375	0.373
UBE2N	protein	P61088	UNIPROT	H2AX	protein	P16104	UNIPROT	up-regulates	ubiquitination			9606									18077395	t		gcesareni	In an h2ax- and mdc1-dependent manner , rnf8/ubc13 complexes go to sites of dna damage through their fha domain and initiate the synthesis of k63 polyubiquitin chains on chromatin that recruit the brca1 a complex through the uim domains of rap80.	SIGNOR-159880	0.2
JAK1	protein	P23458	UNIPROT	STAT6	protein	P42226	UNIPROT	up-regulates activity	phosphorylation			9606									9852261	t		gcesareni	Stat6 activation is mediated through jak1 and jak2 tyrosine kinases	SIGNOR-62582	0.757
GSK3B	protein	P49841	UNIPROT	APC	protein	P25054	UNIPROT	up-regulates	phosphorylation			9606			SIGNOR-C110	SIGNOR-C110					10698523	t		lperfetto	Gsk-3beta-dependent phosphorylation of apc.	SIGNOR-75366	0.748
PFKFB4	protein	Q16877	UNIPROT	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	up-regulates quantity	chemical modification			-1									30553771	t		miannu	PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species	SIGNOR-268118	0.8
MAPK1	protein	P28482	UNIPROT	EWSR1	protein	Q01844	UNIPROT	unknown	phosphorylation	Thr79	QPPTGYTtPTAPQAY	9606									19076070	t		lperfetto	Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2.	SIGNOR-182770	0.251
CCP110	protein	O43303	UNIPROT	CETN2	protein	P41208	UNIPROT	up-regulates activity	binding			9606									16760425	t		miannu	We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis.	SIGNOR-265967	0.687
SMAD2/SMAD4	complex	SIGNOR-C8	SIGNOR	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates activity	binding			9606									22926518	t		miannu	The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors.	SIGNOR-256180	0.526
GOPC	protein	Q9HD26	UNIPROT	CFTR	protein	P13569	UNIPROT	down-regulates	binding			9606									11707463	t		miannu	Cal binds to cftr / cal affects insertion of cftr to the plasma membrane as well as its half-life in the plasma membrane.	SIGNOR-111671	0.711
NANOGP8	protein	Q6NSW7	UNIPROT	FGFR2	protein	P21802	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10900	BTO:0000667								23839044	f		Luana	Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun.	SIGNOR-266090	0.2
LIMK1	protein	P53667	UNIPROT	CFL2	protein	Q9Y281	UNIPROT	down-regulates activity	phosphorylation	Ser3	sGVTVNDE	9606									9655398	t		lperfetto	Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3;. Here we show that lim-kinase 1 (limk-1), a serine/threonine kinase containing lim and pdz domains, phosphorylates cofilin at ser 3, both in vitro and in vivo	SIGNOR-58596	0.691
ATR	protein	Q13535	UNIPROT	RAD17	protein	O75943	UNIPROT	up-regulates activity	phosphorylation	Ser646	ETWSLPLsQNSASEL	9606	BTO:0000567								11687627	t		lperfetto	Here we demonstrate that atr but not atm phosphorylates the human rad17 (hrad17) checkpoint protein on ser(635) and ser(645) in vitro.The rfc-related checkpoint protein rad17, a phosphorylation substrate of atr, is critical for atr-mediated checkpoint signaling and cell survival.	SIGNOR-111248	0.853
DLD	protein	P09622	UNIPROT	OGDC	complex	SIGNOR-C397	SIGNOR	form complex	binding			9606									15953811	t		miannu	The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH.	SIGNOR-266256	0.849
ANG	protein	P03950	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252280	0.7
OTX2	protein	P32243	UNIPROT	BEST1	protein	O76090	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									18849347	f		miannu	Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity.	SIGNOR-254888	0.359
PRKCE	protein	Q02156	UNIPROT	PTPN7	protein	P35236	UNIPROT	up-regulates activity	phosphorylation	Ser246	QYQEERRsVKHILFS	-1									16479000	t		miannu	HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. 	SIGNOR-276050	0.2
MAPK1	protein	P28482	UNIPROT	PPP2R5C	protein	Q13362	UNIPROT	down-regulates	phosphorylation	Ser337	QLAKCVSsPHFQVAE	9606									16456541	t		gcesareni	Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit.	SIGNOR-144313	0.491
DLG3	protein	Q92796	UNIPROT	NMDA receptor_2A	complex	SIGNOR-C347	SIGNOR	up-regulates activity	relocalization					BTO:0000227							32904533	t		lperfetto	DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses.	SIGNOR-266006	0.709
ATM	protein	Q13315	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Thr68	SSLETVStQELYSIP	9606	BTO:0000007								10973490	t		gcesareni	Here we show that in vitro, atm phosphorylates the ser-gln/thr-gln (sq/tq) cluster domain (scd) on chk2, which contains seven sq/tq motifs, and thr68 is the major in vitro phosphorylation site by atm. Atm predominantly phosphorylates chk2 at thr68, promoting homodimerization and activation via intramolecular trans-autophosphorylation at thr383/387.	SIGNOR-81438	0.83
KLF3	protein	P57682	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18391014	f		fspada	We find that c/ebpalpha is derepressed in klf3 and ctbp knockout fibroblasts and adipocytes from klf3 knockout mice.	SIGNOR-161370	0.305
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1913	SPKYSPTsPTYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120060	0.781
PRKACA	protein	P17612	UNIPROT	KCNN2	protein	Q9H2S1	UNIPROT	down-regulates	phosphorylation	Ser568	SSRRRRSsSTAPPTS	9606									16513649	t		llicata	Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization	SIGNOR-145040	0.2
ING1	protein	Q9UK53	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								14522900	f		miannu	 In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity.	SIGNOR-254483	0.313
NKD1	protein	Q969G9	UNIPROT	DVL3	protein	Q92997	UNIPROT	down-regulates	binding			9606		BTO:0000671							15064403	t		gcesareni	Naked (nkd)1 and nkd2 are mammalian homologs of drosophila naked cuticle, which negatively regulates canonical wnt signaling by binding dishevelled. various reports using cell culture assays indicate that nkd-mediated wnt antagonism involves dvl degradation	SIGNOR-123695	0.696
PRKAA1	protein	Q13131	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	down-regulates activity	phosphorylation	Ser486	DDEITEAKsGTATPQRS	-1									17023420	t			We show that AMPK α-Ser485/491 can be a site for autophosphorylation, which may play a role in limiting AMPK activation in response to energy depletion or other regulators	SIGNOR-256114	0.2
GTF2A1	protein	P52655	UNIPROT	TFIIA	complex	SIGNOR-C395	SIGNOR	form complex	binding			9606	BTO:0000567								7724559	t		lperfetto	TFIIA purified from HeLa extracts consists of 35-, 19-, and 12-kDa subunits. Here we describe the isolation of a cDNA clone (hTFIIA gamma) encoding the 12-kDa subunit. 	SIGNOR-266197	0.938
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	MYOG	protein	P15173	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001103							17194702	f		miannu	Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes	SIGNOR-151688	0.366
GAB2	protein	Q9UQC2	UNIPROT	ARHGAP32	protein	A7KAX9	UNIPROT	up-regulates	relocalization			9606									12819203	t		gcesareni	Gc-gap, a rho family gtpase-activating protein that interacts with signaling adapters gab1 and gab2we propose that gab1 and gab2 in cooperation with other adapter molecules might regulate the cellular localization of gc-gap under specific stimuli.	SIGNOR-102628	0.382
RPS9	protein	P46781	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262415	0.873
RRAGD	protein	Q9NQL2	UNIPROT	RAGBD	complex	SIGNOR-C116	SIGNOR	form complex	binding			9606									20381137	t		gcesareni	Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant	SIGNOR-228182	0.77
PPP1CA	protein	P62136	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates activity	dephosphorylation	Ser259	SQRQRSTsTPNVHMV	9606									16630891	t			We have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site of Raf proteins	SIGNOR-251649	0.274
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	SNAI2	protein	O43623	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser104	KDHSGSEsPISDEEE	9606									24662826	t		miannu	At G1/S transition, cyclin E-cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation.	SIGNOR-276629	0.292
TP53	protein	P04637	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									24212651	f		miannu	P53 is a nuclear transcription factor with a pro-apoptotic function	SIGNOR-256664	0.7
DUSP4	protein	Q13115	UNIPROT	MAPK9	protein	P45984	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000782								8626452	t		fstefani	We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. . Mkp-2 had detectable activity against jnk2, although full inactivation of jnk2 was not observed even at the higher phosphatase concentration.	SIGNOR-40929	0.601
MAPK1	protein	P28482	UNIPROT	PLCB1	protein	Q9NQ66	UNIPROT	up-regulates activity	phosphorylation	Ser982	KKKSEPSsPDHGSST	-1									11287604	t		lperfetto	coimmunoprecipitation detected a specific association between the activated erk and plc beta1 within the nucleus. In vitro studies revealed that recombinant plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 this result suggests that erk-evoked phosphorylation of plc beta1 at serine 982 plays a critical role in the activation of the nuclear pi cycle and is also crucial to the mitogenic action of igf-i.	SIGNOR-106561	0.406
MAPK14	protein	Q16539	UNIPROT	DUSP1	protein	P28562	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								11062068	t		gcesareni	Here we have shown that mkp-1 associates directly with p38 map kinase both in vivo and in vitro, and that this interaction enhances the catalytic activity of mkp-1. The point mutation asp-316-->asn in the c-terminus of p38, analogous to the erk2 (extracellular-signal-regulated kinase 2) sevenmaker mutation, dramatically decreases its binding to mkp-1 and substantially compromises its stimulatory effect on the catalytic activity of this phosphatase.	SIGNOR-83752	0.798
EGFR	protein	P00533	UNIPROT	STAT5B	protein	P51692	UNIPROT	up-regulates	phosphorylation	Tyr743	PQAHYNMyPQNPDSV	9606	BTO:0000007;BTO:0000150								11751923	t		llicata	Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor.	SIGNOR-113401	0.827
SGK1	protein	O00141	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser315	DFRSRTNsNASTVSG	9606	BTO:0000007								11154281	t		lperfetto	We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. However, sgk and akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on fkhrl1. While both kinases can phosphorylate thr-32, sgk displays a marked preference for ser-315 whereas akt favors ser-253.	SIGNOR-252989	0.787
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser217	AHYSPRTsPIMSPRT	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248517	0.386
KDM6A	protein	O15550	UNIPROT	ZBTB16	protein	Q05516	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									29736013	t		miannu	UTX catalytic activity has been reported to upregulate expression of the master transcription factor PLZF and to modulate superenhancer accessibility in invariant natural killer T cells.	SIGNOR-260038	0.316
MECP2	protein	P51608	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000093								15870696	f		miannu	 Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters	SIGNOR-254571	0.276
RLIM	protein	Q9NVW2	UNIPROT	LDB1	protein	Q86U70	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			10029	BTO:0000246								11882901	t		miannu	Here we identify RLIM as a ubiquitin protein ligase that is able to target CLIM cofactors for degradation through the 26S proteasome pathway. 	SIGNOR-272617	0.585
AURKA	protein	O14965	UNIPROT	MAPRE3	protein	Q9UPY8	UNIPROT	up-regulates	phosphorylation	Ser176	MQTSGRLsNVAPPCI	9606									19696028	t		llicata	Aurora-a and aurora-b phosphorylate eb3 at ser-176 in a spatial and cell cycle-specific manner, respectively during mitosis two kinases, aurora-a and aurora-b, phosphorylate eb3 at ser-176, and the resulting phosphorylation disrupts the eb3-siah-1 complex. Indeed, eb3 is stabilized during mitosis and facilitates cell cycle progression.	SIGNOR-187657	0.453
BTRC	protein	Q9Y297	UNIPROT	RAP1GAP	protein	P47736	UNIPROT	down-regulates	ubiquitination			9606									25329897	t		lperfetto	Here, we demonstrated that rap1gap is ubiquitinated and degraded through proteasome pathway in mitosis. Proteolysis of rap1gap requires the plk1 kinase and _-trcp ubiquitin ligase complex.	SIGNOR-203548	0.348
PLK1	protein	P53350	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1791	REPLGEDsVGLKPLK	9606	BTO:0000552								31597699	t		miannu	As shown in Fig. S4D, the C-terminal NOTCH1 fragment was readily phosphorylated by PLK1. Additionally, when the two putative phosphorylation sites, Ser-1791 and Ser-2349, were replaced by Ala, WT NOTCH1-IC but not the mutant was efficiently phosphorylated (Fig. S4E). We found that mutation of Ser-1791/2349 promotes NOTCH1-IC stabilization (Fig. S4F).	SIGNOR-277491	0.411
CCN2	protein	P29279	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									18528331	t		gcesareni	Igfbp-4 physically interacted with a wnt receptor, frizzled 8 (frz8), and a wnt co-receptor, low-density lipoprotein receptor-related protein 6 (lrp6), and inhibited the binding of wnt3a to frz8 and lrp6.	SIGNOR-178875	0.2
BCL6	protein	P41182	UNIPROT	SUMO1	protein	P63165	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000182								22723377	f	 	 	QPCR analysis of the resulting gene expression levels identified three genes that were affected in opposite sense by the downregulation of either BCL-6 or STAT5, namely cyclin D2 (CCND2), cyclin-dependent kinase inhibitor p15INK4B (CDKN2B), and SUMO1	SIGNOR-253929	0.31
H4C1	protein	P62805	UNIPROT	CENP-A nucleosome	complex	SIGNOR-C321	SIGNOR	form complex	binding			-1									23324462	t		miannu	 In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro.	SIGNOR-263701	0.2
CSNK2A1	protein	P68400	UNIPROT	FAF1	protein	Q9UNN5	UNIPROT	down-regulates activity	phosphorylation	Ser291	DVHMVSDsDGDDFED	9534									12832043	t		llicata	We previously identified the Fas-associated factor FAF1 as an in vitro substrate of protein kinase CK2 and determined Ser289 and Ser291 as phosphorylation sites.|Therefore we assume that CK2‐mediated FAF1 phosphorylation influences the nuclear localization of FAF1 | it implies that the major function of FAF1 might not be in the cytoplasm as an interacting partner of Fas.	SIGNOR-250864	0.331
INSR	protein	P06213	UNIPROT	ADRB2	protein	P07550	UNIPROT	down-regulates activity	phosphorylation	Tyr132	CVIAVDRyFAITSPF	10029	BTO:0000246								8557631	t			Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors. 	SIGNOR-251299	0.385
MYCN	protein	P04198	UNIPROT	ABCC1	protein	P33527	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									7923112	f		miannu	 Decreased expression of the N-myc oncogene in neuroblastoma cell lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, was paralleled by down-regulation of MRP gene expression, contrasting with increased expression of the MDR1 gene. 	SIGNOR-254617	0.278
PRKCD	protein	Q05655	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates	phosphorylation	Ser616	PIPIMPAsPQKGHAV	9606									17301055	t		gcesareni	Drp1 was specifically phosphorylated in mitosis by cdk1/cyclin b on ser-585. Exogenous expression of unphosphorylated mutant drp1s585a led to reduced mitotic mitochondrial fragmentation.	SIGNOR-153148	0.2
HCK	protein	P08631	UNIPROT	WAS	protein	P42768	UNIPROT	up-regulates activity	phosphorylation	Tyr291	AETSKLIyDFIEDQG	9534	BTO:0000298								12235133	t	done	miannu	Hck induces tyrosine phosphorylation of WASp. Here we show that the Src family kinase Hck induces phosphorylation of WASp-Tyr(291) independently of Cdc42 and that this causes a shift in the mobility of WASp upon SDS-PAGE. A phospho-mimicking mutant, WASp-Y291E, exhibited an enhanced ability to stimulate actin polymerization in a cell-free system and when microinjected into primary macrophages induced extensive filopodium formation with greater efficiency than wild-type WASp or a Y291F mutant. We propose that phosphorylation of Tyr(291) directly regulates WASp function.	SIGNOR-273957	0.572
bufexamac	chemical	CHEBI:31317	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000664								21258344	t		Luana	 We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor.	SIGNOR-257892	0.8
CSNK1A1	protein	P48729	UNIPROT	SLC18A2	protein	Q05940	UNIPROT	unknown	phosphorylation	Ser513	GEDEESEsD	-1									9045708	t		llicata	Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. 	SIGNOR-250793	0.327
NOX4	protein	Q9NPH5	UNIPROT	ROS	stimulus	SIGNOR-ST2	SIGNOR	up-regulates				9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264717	0.7
MAP1LC3B	protein	Q9GZQ8	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	up-regulates	binding			9606									19250911	t		gcesareni	Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation.	SIGNOR-184255	0.832
PLK3	protein	Q9H4B4	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Ser62	SSSGTLSsLETVSTQ	-1									16481012	t		miannu	Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity. 	SIGNOR-276052	0.644
GSK3B	protein	P49841	UNIPROT	FRAT1	protein	Q92837	UNIPROT	down-regulates activity	phosphorylation	Ser188	RLQQRRGsQPETRTG	9606	BTO:0002181								16982607	t		miannu	Protein kinase A (PKA) was found to phosphorylate Ser188 in vitro as well as in intact cells. Importantly, activation of endogenous cAMP-coupled beta-adrenergic receptors with norepinephrine stimulated the phosphorylation of FRAT1 at Ser188. GSK-3 was also able to phosphorylate FRAT1 at Ser188 and other residues in vitro or when overexpressed in intact cells.  Phosphorylation of Ser188 by PKA inhibited the ability of FRAT1 to activate beta-catenin-dependent transcription.	SIGNOR-276057	0.765
HIF1A	protein	Q16665	UNIPROT	EPO	protein	P01588	UNIPROT	up-regulates quantity	transcriptional regulation			9606									8756616	t			We demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells	SIGNOR-256593	0.63
BMP2	protein	P12643	UNIPROT	ALPL	protein	P05186	UNIPROT	up-regulates				9606									22298955	f		gcesareni	FGF-2 null mice have impaired nuclear accumulation of Runx2 and hindered BMP-2 induced bone formation and ALP activity	SIGNOR-114589	0.449
PSMC1	protein	P62191	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263373	0.866
SP3	protein	Q02447	UNIPROT	CYP27A1	protein	Q02318	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11867220	f		miannu	 Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells.	SIGNOR-255197	0.2
MAPK8	protein	P45983	UNIPROT	MAPK8IP3	protein	Q9UPT6	UNIPROT	up-regulates	phosphorylation	Thr286	SVPSAAVtPLNESLQ	9606									15767678	t		gcesareni	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134549	0.715
PPP2CA	protein	P67775	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	down-regulates	dephosphorylation			9606									23431053	t	inferred from 70% of family members	gcesareni	Rassf1a apparently protects mst1/2 against inactivation by pp2a, the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively.	SIGNOR-269940	0.734
NR3C1	protein	P04150	UNIPROT	TRIM63	protein	Q969Q1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									18612045	f		areggio	Consistent with these findings, DEX-induced upregulation of MuRF1 is significantly attenuated in mice expressing a homodimerization-deficient GR despite no effect on the degree of muscle loss in these mice vs. their wild-type counterparts. Finally, chromatin immunoprecipitation analysis reveals that both GR and FOXO1 bind to the endogenous MuRF1 promoter in C(2)C(12) myotubes, and IGF-I inhibition of DEX-induced MuRF1 expression correlates with the loss of FOXO1 binding.	SIGNOR-254992	0.336
CDK1	protein	P06493	UNIPROT	RAB11FIP3	protein	O75154	UNIPROT	up-regulates quantity	phosphorylation	Ser102	GPRGQLAsPDAPGPG	9606	BTO:0000567								22401586	t	done	miannu	FIP3 is phosphorylated on S102 in a cell cycle-dependent manner. We identify four sites of phosphorylation of FIP3 in vivo, S-102, S-280, S-347 and S-450 and identify S-102 as a target for Cdk1-cyclin B in vitro. Of these, we show that S-102 is phosphorylated in metaphase and is dephosphorylated as cells enter telophase. 	SIGNOR-273588	0.2
PLX-4720	chemical	CHEBI:90295	ChEBI	BRAF	protein	P15056	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258267	0.8
CLK1	protein	P49759	UNIPROT	PTPN1	protein	P18031	UNIPROT	up-regulates activity	phosphorylation	Ser242	MDKRKDPsSVDIKKV	-1									10480872	t		llicata	The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. 	SIGNOR-250773	0.353
NDUFV3	protein	P56181	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24].	SIGNOR-262185	0.774
OTULIN	protein	Q96BN8	UNIPROT	UBB	protein	P0CG47	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270819	0.656
VWF	protein	P04275	UNIPROT	AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	up-regulates activity	binding			9606	BTO:0000132								25297919	t		lperfetto	Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and αIIbβ3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury	SIGNOR-261854	0.671
CSF2	protein	P04141	UNIPROT	CSF2RA/CSF2RB	complex	SIGNOR-C212	SIGNOR	up-regulates	binding			9606	BTO:0000876	BTO:0001103							9680354	t		apalma	GM-CSF elicits these diverse responses through the GM-CSF receptor (GMR).	SIGNOR-255581	0.856
CRBN	protein	Q96SW2	UNIPROT	SALL4	protein	Q9UJQ4	UNIPROT	down-regulates quantity by destabilization	binding			9606									32071327	t		miannu	Thalidomide-induced teratogenicity is dependent on its binding to cereblon (CRBN), the substrate receptor of the Cul4A-DDB1-CRBN-RBX1 E3 ubiquitin ligase complex. Thalidomide binding to CRBN elicits subsequent ubiquitination and proteasomal degradation of CRBN neosubstrates including SALL4, a transcription factor of which polymorphisms phenocopy thalidomide-induced limb defects in humans. 	SIGNOR-272208	0.2
MAPK1	protein	P28482	UNIPROT	XPO5	protein	Q9HAV4	UNIPROT	down-regulates activity	phosphorylation	Ser416	GFPSKTDsPSCEYSR	9606	BTO:0000007								27846390	t		lperfetto	Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. 	SIGNOR-262978	0.306
SIRT7	protein	Q9NRC8	UNIPROT	H3-2	protein	Q5TEC6	UNIPROT	up-regulates activity	deacetylation	Lys38	PATGGVKkPHRYRPG										30653310	t		lperfetto	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 	SIGNOR-275883	0.2
FOXO3	protein	O43524	UNIPROT	CITED2	protein	Q99967	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								18158893	f		gcesareni	Foxo3a induces expression of cited2	SIGNOR-160127	0.454
PTAFR	protein	P25105	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256789	0.2
BHLHE40	protein	O14503	UNIPROT	PER2	protein	O15055	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000944								14672706	f	 	lperfetto	Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression	SIGNOR-253717	0.486
LCK	protein	P06239	UNIPROT	SIGLEC10	protein	Q96LC7	UNIPROT	up-regulates	phosphorylation	Tyr597	RHSTILDyINVVPTA	9606									11733002	t		lperfetto	These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling	SIGNOR-112491	0.263
CDK2	protein	P24941	UNIPROT	SF3B1	protein	O75533	UNIPROT	unknown	phosphorylation	Thr313	HGSGWAEtPRTDRGG	9606			SIGNOR-C16						12105215	t		llicata	We indeed found that sap155-(223_322) and sap155-(1_491) are excellent substrates for in vitrophosphorylation by cyclin e-cdk2 as well as cyclin b-cdk1	SIGNOR-90442	0.354
DGC	complex	SIGNOR-C217	SIGNOR	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	up-regulates quantity	binding			9606	BTO:0000938;BTO:0002606								22626542	t		miannu	 In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses.	SIGNOR-265432	0.2
RANGAP1	protein	P46060	UNIPROT	MYCBP2	protein	O75592	UNIPROT	down-regulates quantity by destabilization	relocalization			10090									26304119	t		Monia	SUMOylated RanGAP1 Inhibits MYCBP2 Activity and Mediates Its Transport to the Nucleus. Surprisingly, we did not find MYCBP2-dependent ubiquitylation of SUMOylated RanGAP1 but instead a strong inhibition of the ubiquitin ligase activity of MYCBP2 in the presence of SUMOylated RanGAP1, as determined by the presence of ubiquitylated proteins. this effect was specific for SUMOylated RanGAP1, because the unmodified form of RanGAP1 did not affect MYCBP2-dependent protein ubiquitylation. , SUMOylated RanGAP1 inhibited the ubiquitin ligase activity of MYCBP2, and it is tempting to speculate that SUMOylated RanGAP1 inhibits the ubiquitin ligase activity of MYCBP2 to ensure MYCBP2 silencing during its transport to the nucleus	SIGNOR-261203	0.319
PTGFR	protein	P43088	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256810	0.357
IRF8	protein	Q02556	UNIPROT	CYBB	protein	P04839	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001412								11483597	f		miannu	we found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP.	SIGNOR-222710	0.357
NBEAL2	protein	Q6ZNJ1	UNIPROT	DOCK7	protein	Q96N67	UNIPROT	up-regulates activity	binding			10090	BTO:0000132								29187380	t		lperfetto	In summary, from 129 binding partners of Nbeal2 identified by mass spectrometry, we have confirmed the interaction of 3, Dock7, Sec16a, and Vac14, by different biochemical and cellular approaches|Given the significant reduction of Dock7 levels and its altered localization in Nbeal2−/− platelets, we postulated that this canonical signaling pathway may be disrupted and set out to test this using control and Nbeal2−/− platelets.	SIGNOR-261891	0.39
WNT6	protein	Q9Y6F9	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates				9606		BTO:0000887;BTO:0001103							9753670	f		gcesareni	In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm.	SIGNOR-60418	0.33
JAK1	protein	P23458	UNIPROT	TYK2	protein	P29597	UNIPROT	up-regulates	phosphorylation	Tyr1055	VPEGHEYyRVREDGD	9606									8702790	t		llicata	These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055 and that this phosphorylation requires another kinase, most likely jak1.	SIGNOR-43084	0.505
SNRPD3	protein	P62318	UNIPROT	U1 snRNP complex	complex	SIGNOR-C480	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270686	0.924
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	KLC1	protein	Q07866	UNIPROT	down-regulates	phosphorylation			9606									21385839	t	inferred from 70% family members	gcesareni	Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro.	SIGNOR-270176	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	FOS	protein	P01100	UNIPROT	up-regulates	phosphorylation	Thr232	GGLPEVAtPESEEAF	9606									7816602	t		lperfetto	Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions.	SIGNOR-251525	0.2
DVL1	protein	O14640	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	binding			9534				SIGNOR-C110					10196136	t		lperfetto	We have recently found that Dvl-1 directly binds to Axin and that the binding of Dvl-1 to Axin does not affect the interaction of GSK-3beta with Axin. It is possible that the binding of Dvl to Axin induces the structural change of the Axin complex; therefore GSK-3beta does not effectively phosphorylate Axin. This is the first demostration showing that Dvl inhibits the function of GSK-3beta directly.	SIGNOR-219356	0.813
FLT3	protein	P36888	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									14981546	f			FLT3-ITD signaling contributes to transcriptional inhibition of p27Kip1 and Bim gene expression	SIGNOR-261524	0.295
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	RRM1	protein	P23921	UNIPROT	up-regulates activity	phosphorylation	Ser559	PYETYEGsPVSKGIL	9606									32712628	t		miannu	Here, we report that RRM1 is phosphorylated at Ser 559 by CDK2/cyclin A during S/G2 phase. And this S559 phosphorylation of RRM1enhances RNR enzymatic activity and is required for maintaining sufficient dNTPs during normal DNA replication.	SIGNOR-277522	0.327
ARRB2	protein	P32121	UNIPROT	KIF3A	protein	Q9Y496	UNIPROT	up-regulates	binding			9606									16908539	t		gcesareni	We demonstrate that _-arrestins mediate the activity-dependent interaction of smo and the kinesin motor protein kif3a.	SIGNOR-148773	0.623
PDHA1	protein	P08559	UNIPROT	PDH	complex	SIGNOR-C402	SIGNOR	form complex	binding			9606									20160912	t		miannu	The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently.	SIGNOR-266544	0.801
EPHA4	protein	P54764	UNIPROT	EPHA4	protein	P54764	UNIPROT	up-regulates activity	phosphorylation	Tyr596	LNQGVRTyVDPFTYE	-1									8622893	t			Two dimensional phosphopeptide mapping and site-directed mutagenesis defined juxtamembrane residue Y602 as a major site of in vitro autophosphorylation in Sek, whilst Y596 was phosphorylated to a lower stoichiometry.	SIGNOR-251118	0.2
SMARCB1	protein	Q12824	UNIPROT	CCNA2	protein	P20248	UNIPROT	down-regulates				9606									12226744	f		miannu	We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6.	SIGNOR-92782	0.351
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates activity	phosphorylation	Ser495	KTMIRKRsFGNPFEG	9534	BTO:0000298								32913128	t		miannu	 Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues. 	SIGNOR-277238	0.2
JAK1	protein	P23458	UNIPROT	PTPN11	protein	Q06124	UNIPROT	up-regulates activity	phosphorylation	Tyr327	NSKPKKSyIATQGCL	9534									8995399	t		lperfetto	Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2	SIGNOR-236274	0.759
CDC34	protein	P49427	UNIPROT	SCF-FBW7	complex	SIGNOR-C135	SIGNOR	up-regulates activity	binding			9606									25425648	t		miannu	The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association.Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases. 	SIGNOR-277333	0.796
LPCAT1	protein	Q8NF37	UNIPROT	1-O-acyl-sn-glycero-3-phosphocholine	chemical	CHEBI:58168	ChEBI	down-regulates quantity	chemical modification			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272762	0.8
TRIO	protein	O75962	UNIPROT	DCC	protein	P43146	UNIPROT	up-regulates quantity	binding			10116	BTO:0004102								23230270	t		miannu	TrioY2622 is required for both netrin-1-induced activation of Rac1 and enhanced association with DCC. Phosphorylation of Trio at Tyr2622 participates in maintaining the level of surface DCC at the growth cone plasma membrane leading to axon outgrowth. Therefore, we propose that TrioY2622 is essential for the proper assembly and stability of the DCC/Trio signaling complex at the cell surface of growth cones in order to mediate netrin-1-induced cortical axon outgrowth.	SIGNOR-273856	0.587
EGR1	protein	P18146	UNIPROT	CHGA	protein	P10645	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001007								12456801	t	 	 	Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation.	SIGNOR-254265	0.2
PKN1	protein	Q16512	UNIPROT	SNAI1	protein	O95863	UNIPROT	up-regulates	phosphorylation	Ser246	QACARTFsRMSLLHK	9606	BTO:0000150								15833848	t		lperfetto	Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functionswe found for the first time that pak1 promotes transcription repression activity of snail from e-cadherin, occludin, and aromatase promoters. Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions.	SIGNOR-135609	0.2
PAK1	protein	Q13153	UNIPROT	LIMK1	protein	P53667	UNIPROT	up-regulates activity	phosphorylation	Thr508	PDRKKRYtVVGNPYW	9606									10559936	t		lperfetto	Activation of lim-kinase by pak1 couplesp21-activated kinase (pak1) phosphorylates lim-kinase at threonine residue 508 within lim-kinase's activation loop	SIGNOR-72142	0.597
DLGAP4	protein	Q9Y2H0	UNIPROT	SHANK2	protein	Q9UPX8	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264596	0.732
GSK3B	protein	P49841	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	up-regulates activity	phosphorylation	Ser49	CHRLPPGsLSSTPLS	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159442	0.26
CDK6	protein	Q00534	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Ser397	SMVGGERsPPRILPP	9606	BTO:0000007								21059642	t	The effect has been demonstrated using Q01196-8	gcesareni	Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20).	SIGNOR-169330	0.598
APH1A	protein	Q96BI3	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates	binding			9606									12522139	t		gcesareni	Biochemical and genetic studies have recently identified nicastrin, aph-1, and pen-2 as essential cofactors that physically interact with ps1 and are necessary for the gamma-secretase activity.	SIGNOR-97068	0.946
INSR	protein	P06213	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	phosphorylation	Tyr999	YASSNPEyLSASDVF	-1									3166375	t		lperfetto	This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972	SIGNOR-106526	0.2
CDC34	protein	P49427	UNIPROT	SCF-SKP2	complex	SIGNOR-C136	SIGNOR	up-regulates activity	binding			9606									25425648	t		miannu	The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association.Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases. 	SIGNOR-277334	0.76
MAPK1	protein	P28482	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Ser434	SFEPKIRsPRRFIGS	9606	BTO:0000150								19085255	t		gcesareni	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase.	SIGNOR-182804	0.578
IKK-complex	complex	SIGNOR-C14	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser25	AERGLGPsPAGDGPS	10090	BTO:0002572								23332762	t		lperfetto	Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation.	SIGNOR-209776	0.266
DVL1	protein	O14640	UNIPROT	APC	protein	P25054	UNIPROT	down-regulates activity	binding			9606									10330181	t		amattioni	Dvl-1 inhibits Axin-promoted GSK-3_-dependent phosphorylation of _-catenin and APC, leading to beta-catenin stabilization.	SIGNOR-167951	0.684
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	BMP7	protein	P18075	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269260	0.318
EPAS1	protein	Q99814	UNIPROT	AP1	complex	SIGNOR-C154	SIGNOR	down-regulates activity	binding			9606	BTO:0000093								24383088	t		miannu	 Co-transfection experiments revealed that HIF-2α had greater potency on the GLIS1 promoter activation than HIF-1α. Subsequent studies using wild-type and mutant HIF-2α demonstrated that DNA binding activity was not necessary but TADs were critical for GLIS1 induction. Finally, co-transfection experiments indicated that HIF-2α cooperated with AP-1 family members in upregulating GLIS1 transcription. These results suggest that the hypoxic signaling pathway may play a pivotal role in regulating the reprogramming factor GLIS1, via non-canonical mechanisms involving partner transcription factor rather than by direct HIF transactivation.	SIGNOR-269042	0.351
EGF	protein	P01133	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates	binding			9606									11279155	t		tpavlidou	To better understand the role of the egfr tyrosine kinase, we analyzed signaling by a kinase-inactive egfr (k721m) in erbb-devoid 32d cells. K721m alone exhibited no detectable signaling capacity, whereas coexpression of k721m with erbb2, but not erbb3 or erbb4, resulted in egf-dependent mitogen-activated protein kinase (mapk) activation. The kinase activity, but not tyrosine phosphorylation, of erbb2 was required for egf-induced mapk activation.	SIGNOR-106497	0.784
ATM	protein	Q13315	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Ser35	SQGSSSQsQGISSSS	9606	BTO:0000007								10973490	t		lperfetto	Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir	SIGNOR-81403	0.83
TLN1	protein	Q9Y490	UNIPROT	A11/b1 integrin	complex	SIGNOR-C168	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257617	0.574
HIP1	protein	O00291	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									11007801	f		miannu	Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain.	SIGNOR-82463	0.7
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2E3	protein	Q969T4	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271330	0.708
MTOR	protein	P42345	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606									18691976	t		gcesareni	Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle.	SIGNOR-161439	0.738
SHH	protein	Q15465	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates				9606	BTO:0000222;BTO:0002314	BTO:0000887							17688959	f		gcesareni	Most importantly, we report that shh induces mapk/erk and phosphoinositide 3-kinase (pi3k)-dependent akt phosphorylation and that activation of both signaling pathways is essential for shh's signaling in muscle cells. However, the effect of shh on akt phosphorylation is more robust than that on mapk/erk, and data suggest that shh influences these pathways in a manner similar to igf-i.	SIGNOR-157291	0.484
MAP1LC3C	protein	Q9BXW4	UNIPROT	WDFY3	protein	Q8IZQ1	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								24668264	t		miannu	 Here, we show that ALFY binds selectively to LC3C and the GABARAPs through a LIR in its WD40 domain. Binding of ALFY to GABARAP is indispensable for its recruitment to LC3B-positive structures and, thus, for the clearance of certain p62 structures by autophagy.	SIGNOR-266795	0.612
NR3C1	protein	P04150	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates activity				9606									25910399	f			Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases [.. }The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged.	SIGNOR-266901	0.7
SKP1	protein	P63208	UNIPROT	CUL1	protein	Q13616	UNIPROT	up-regulates	binding			9606									10023660	t		gcesareni	The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin.	SIGNOR-64511	0.958
CPT1C	protein	Q8TCG5	UNIPROT	(R)-carnitine	smallmolecule	CHEBI:16347	ChEBI	down-regulates quantity	chemical modification			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267122	0.8
SMAD7	protein	O15105	UNIPROT	SMURF2	protein	Q9HAU4	UNIPROT	up-regulates activity	relocalization			9606									11163210	t		lperfetto	Smurf2 is nuclear, but binding to smad7 induces export and recruitment to the activated tgf beta receptor, where it causes degradation of receptors and smad7 via proteasomal and lysosomal pathways.	SIGNOR-104996	0.865
venetoclax	chemical	CHEBI:133021	ChEBI	BCL2	protein	P10415	UNIPROT	down-regulates activity	chemical inhibition			9606									23291630	t		miannu	Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.	SIGNOR-261938	0.8
MRPL1	protein	Q9BYD6	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262384	0.655
TUBB	protein	P07437	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	binding			9606									17429065	t		lpetrilli	Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin.	SIGNOR-154319	0.2
PRKCA	protein	P17252	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser163	KRFSFKKsFKLSGFS	9606									16116087	t		llicata	The present experiments demonstrate that ptn stimulates phosphorylation of serines 713 and 726 in the marcks domain of _-adducin (and serine 724 in _-adducin) and serines 152 and 156 in the marcks protein itself through the activation of either pkc _ or _ and perhaps other pkc(s) isoforms.	SIGNOR-139910	0.72
GUCY1B2	protein	O75343	UNIPROT	GUCY1A3-B2	complex	SIGNOR-C139	SIGNOR	form complex	binding			9606									10977868	t		gcesareni	This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity	SIGNOR-244119	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TBC1D7	protein	Q9P0N9	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser124	GKLPRSPsFPLEPDD	9606	BTO:0000007								30143532	t		miannu	 Sequence analysis identified a putative site for both Akt-mediated phosphorylation and 14-3-3 binding at Ser-124, and we found that Akt phosphorylates TBC1D7 at Ser-124. However, this phosphorylation had no effect on the binding of TBC1D7 to TSC1, but stabilized TBC1D7.	SIGNOR-273541	0.2
Nalorphine	chemical	CHEBI:7458	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258815	0.8
PPM1D	protein	O15297	UNIPROT	ATM	protein	Q13315	UNIPROT	down-regulates activity	dephosphorylation	Ser1981	SLAFEEGsQSTTISS	9606									16949371	t			Here, we report that deficiency of Wip1 resulted in activation of the ataxia-telangiectasia mutated (ATM) kinase. In turn, overexpression of Wip1 was sufficient to reduce activation of the ATM-dependent signaling cascade after DNA damage. Wip1 dephosphorylated ATM Ser1981, a site critical for ATM monomerization and activation	SIGNOR-248325	0.504
PRKCA	protein	P17252	UNIPROT	PIP5K1B	protein	O14986	UNIPROT	down-regulates	phosphorylation	Ser413	PSKKRCNsIAALKAT	9606									23909401	t		lperfetto	Collaboration of ampk and pkc to induce phosphorylation of ser413 on pip5k1b resulting in decreased kinase activity and reduced ptdins(4,5)p2 synthesis in response to oxidative stress and energy restriction. we demonstrate that pkc can directly phosphorylate ser413 in vitro	SIGNOR-194820	0.2
CREB1	protein	P16220	UNIPROT	G6PC1	protein	P35575	UNIPROT	up-regulates quantity	transcriptional regulation			9606									26652733	t			Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-256105	0.2
TIMM44	protein	O43615	UNIPROT	TIM23 complex	complex	SIGNOR-C423	SIGNOR	form complex	binding												32074073	t		lperfetto	The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE.	SIGNOR-267689	0.718
CDK1	protein	P06493	UNIPROT	AMBRA1	protein	Q9C0C7	UNIPROT	up-regulates activity	phosphorylation	Thr1238	ASWDQPGtPGREPTQ	9606	BTO:0000567								37584777	t	phosphorylation site remapping based on mass spec table	lperfetto	CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects.	SIGNOR-272966	0.2
CHEK2	protein	O96017	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser178	LFTQRQNsAPARMLS	9606									14559997	t	Phosphorylation is the signal for ubiquitination	gcesareni	The order and fidelity of cell cycle events in mammals is intimately linked to the integrity of the Chk1 kinase-Cdc25A phosphatase pathway. Chk1 phosphorylation targets Cdc25A for destruction and, as shown here, inhibits interactions between Cdc25A and its mitotic substrate cyclin B1-Cdk1. Phosphorylation of Cdc25A on serine 178 and threonine 507 facilitates 14-3-3 binding, and Chk1 phosphorylates both residues in vitro.	SIGNOR-118759	0.837
MYCN	protein	P04198	UNIPROT	CTSD	protein	P07339	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18566016	f		miannu	 In primary neuroblastomas, high CTSD messenger RNA (mRNA) levels were associated with amplified MYCN, a strong predictive marker of adverse outcome. Chromatin immunoprecipitation and luciferase promoter assays revealed that MYCN protein binds to the CTSD promoter and activates its transcription, suggesting a direct link between deregulated MYCN and CTSD mRNA expression. 	SIGNOR-254618	0.2
MYC	protein	P01106	UNIPROT	IMPDH2	protein	P12268	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003291								18628958	t		miannu	Here, we report that the majority of genes in human purine and pyrimidine biosynthesis pathway were induced and directly bound by c-Myc in the P493-6 human Burkitt's lymphoma model cell line. The mRNA levels of IMPDH1 and IMPDH2, the rate-limiting enzyme in purine de novo synthesis, increased with MYC induction both in vitro and in vivo.	SIGNOR-267377	0.299
NTN4	protein	Q9HB63	UNIPROT	UNC5A	protein	Q6ZN44	UNIPROT	up-regulates	binding			9606									12598531	t		gcesareni	The unc5hs are axon guidance receptors that mediate netrin-1-dependent chemorepulsion, and dependence receptors that mediate netrin-1-independent apoptosis.	SIGNOR-98483	0.595
DYRK2	protein	Q92630	UNIPROT	SIAH2	protein	O43255	UNIPROT	up-regulates	phosphorylation	Ser68	GGGAGPVsPQHHELT	9606									22878263	t		llicata	In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis.	SIGNOR-198729	0.42
PRKCA	protein	P17252	UNIPROT	ARHGEF1	protein	Q92888	UNIPROT	up-regulates activity	phosphorylation	Ser240	TKSGDKKsGRNFFRK	9606									32881857	t		miannu	We showed that the first and second phase of RhoA activity are dependent on p63 and Ca2+/PKC, respectively, and further identified phosphorylation of serine 240 on p115 RhoGEF by PKC to be the mechanistic link between PKC and RhoA.	SIGNOR-277530	0.451
GGCX	protein	P38435	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									31539109	f		miannu	GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05).	SIGNOR-261231	0.2
PRKCB	protein	P05771	UNIPROT	VTN	protein	P04004	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser381	RNRKGYRsQRGHSRG	-1									9030777	t		lperfetto	Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin.	SIGNOR-248963	0.307
MSN	protein	P26038	UNIPROT	Platelet_aggregation	phenotype	SIGNOR-PH81	SIGNOR	up-regulates				9606	BTO:0000132								35267019	f		miannu	Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. Taken together, these results suggest that Rev-erbα potentiates platelet activation via an OPHN-1-mediated RhoA/ERM signalling pathway.	SIGNOR-268434	0.7
MAPK14	protein	Q16539	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates activity	phosphorylation	Ser543	SLLSTLSsPGPKLDN	9606	BTO:0000093								15383283	t		miannu	P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators.	SIGNOR-250104	0.505
EGFR	protein	P00533	UNIPROT	KCND3	protein	Q9UK17	UNIPROT	up-regulates activity	phosphorylation	Tyr136	GDCCYEEyKDRKREN	9606	BTO:0000007								22198508	t		miannu	 These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels.	SIGNOR-276397	0.2
BMPR1A	protein	P36894	UNIPROT	SMAD5	protein	Q99717	UNIPROT	up-regulates				10090	BTO:0000165								10564272	f		lperfetto	We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2	SIGNOR-235361	0.676
ADORA2B	protein	P29275	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257414	0.278
2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid	chemical	CID:135461425	PUBCHEM	PDGFRA	protein	P16234	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258082	0.8
GPR84	protein	Q9NQS5	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256704	0.288
SP2	protein	Q02086	UNIPROT	PCYT1A	protein	P49585	UNIPROT	down-regulates quantity by repression	transcriptional regulation			7227	BTO:0001677								10744779	t		Luana	Sp3 is an activator, and Sp2 a repressor, of the Ctpct promoter in SL2 cells. 	SIGNOR-266230	0.2
BIRC5	protein	O15392	UNIPROT	CASP3	protein	P42574	UNIPROT	down-regulates	binding			9606									9850056	t		amattioni	Survivin binds specifically to caspase-3. Survivin protected from apoptosis induced by overexpression of procaspase-3 and inhibited the processing of these zymogens into active caspases. Survivin, which is commonly expressed in human tumor cell lines, can bind the effector cell death proteases caspase-3 in vitro and inhibits caspase activity	SIGNOR-62484	0.502
UTS2R	protein	Q9UKP6	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257319	0.252
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser262	TFRPRSSsNASSVST	9606									16272144	t		lperfetto	Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression	SIGNOR-252829	0.908
DOT1L	protein	Q8TEK3	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27856324	f		irozzo	Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4.	SIGNOR-255880	0.2
perfluorooctane-1-sulfonic acid	chemical	CHEBI:39421	ChEBI	AR	protein	P10275	UNIPROT	down-regulates activity	chemical inhibition			-1									23764977	t		miannu	Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. 	SIGNOR-268767	0.8
STX11	protein	O75558	UNIPROT	Platelet_degranulation	phenotype	SIGNOR-PH138	SIGNOR	up-regulates				9606									22767500	f		lperfetto	In contrast to previous studies,13,15,16,19 the results of the present study show that syntaxin-2 and syntaxin-4 are not required for release, but that syntaxin-11 is critical for platelet exocytosis.	SIGNOR-261893	0.7
FMR1	protein	Q06787	UNIPROT	SHANK1	protein	Q9Y566	UNIPROT	up-regulates quantity	post transcriptional regulation			10090									32118033	t		lperfetto	These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.	SIGNOR-262109	0.41
FHOD1	protein	Q9Y613	UNIPROT	ACTB	protein	P60709	UNIPROT	up-regulates quantity by stabilization	binding			9606									14576350	t		miannu	Fhos, a mammalian formin, directly binds to F-actin via a region N-terminal to the FH1 domain and forms a homotypic complex via the FH2 domain to promote actin fiber formation	SIGNOR-276613	0.35
ABL1	protein	P00519	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	phosphorylation	Tyr368	CGGARICyIFHETFG	9606	BTO:0000793								29022905	t		miannu	In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation.	SIGNOR-277329	0.263
GSK3B	protein	P49841	UNIPROT	KLF5	protein	Q13887	UNIPROT	down-regulates	phosphorylation	Ser303	QATYFPPsPPSSEPG	9606									24398687	t		lperfetto	Stability of the klf5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3_ (gsk3_) and recognition by f-box and wd repeat domain-containing 7 (fbw7) of a phosphodegron sequence surrounding serine 303 in klf5	SIGNOR-203627	0.375
3,5-diiodo-L-tyrosine	smallmolecule	CHEBI:15768	ChEBI	3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	up-regulates quantity	precursor of			9606									28153798	t		scontino	The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines.	SIGNOR-268121	0.8
FBXO6	protein	Q9NRD1	UNIPROT	ERO1A	protein	Q96HE7	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								27855403	t		miannu	Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex	SIGNOR-272326	0.2
DYRK1A	protein	Q13627	UNIPROT	CCNL2	protein	Q96S94	UNIPROT	unknown	phosphorylation	Ser338	PAPKLVEsPKEGKGS	9534	BTO:0000298								14623875	t		llicata	DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase. 	SIGNOR-251088	0.591
PPM1A	protein	P35813	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates activity	dephosphorylation			9606									9707433	t		lperfetto	Moreover, when expressed in mammalian cells, pp2ca inhibited the activation of the p38 and jnk cascades induced by environmental stresses. Both in vivo and in vitro observations indicated that pp2ca dephosphorylated and inactivated mapkks (mkk6 and sek1) and a mapk (p38) in the stress-responsive mapk cascades. Furthermore, a direct interaction of pp2ca and p38 was demonstrated by a co-immunoprecipitation assay	SIGNOR-59618	0.417
RNF128	protein	Q8TEB7	UNIPROT	ARHGDIB	protein	P52566	UNIPROT	up-regulates quantity by stabilization	polyubiquitination			9606	BTO:0000661								17114425	t		miannu	We found that RhoGDIα and RhoGDIβ are ubiquitin E3 substrates of GRAIL. GRAIL uses nonlysine 48-ubiquitin linkage in polyubiquitinating RhoGDI. GRAIL was subsequently demonstrated to bind and ubiquitinate RhoGDI, although GRAIL-mediated ubiquitination of RhoGDI did not result in proteosomal degradation. Our data suggest that ubiquitination of RhoGDI by GRAIL does not result in proteolytic degradation. In fact, GRAIL activity appeared to increase RhoGDI stability.	SIGNOR-271621	0.2
tRNA(Met)	smallmolecule	CHEBI:29173	ChEBI	Met-tRNA(Met)	chemical	CHEBI:16635	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270401	0.8
NPRL2	protein	Q8WTW4	UNIPROT	GATOR1	complex	SIGNOR-C192	SIGNOR	form complex	binding			9606									23723238	t		miannu	Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5	SIGNOR-255281	0.955
GSK3B	protein	P49841	UNIPROT	CTPS1	protein	P17812	UNIPROT	down-regulates activity	phosphorylation	Ser574	YSDRSGSsSPDSEIT	9606	BTO:0000007								17681942	t		miannu	We found that low serum conditions increased phosphorylation of endogenous CTPS1 and this phosphorylation was inhibited by the glycogen synthase kinase 3 (GSK3) inhibitor indirubin-3'-monoxime and GSK3beta short interfering RNAs, demonstrating the involvement of GSK3 in phosphorylation of endogenous human CTPS1. Separating tryptic peptides from [(32)P]orthophosphate-labeled cells and analyzing the phosphopeptides by mass spectrometry identified Ser-574 and Ser-575 as phosphorylated residues. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity. 	SIGNOR-276068	0.2
FZD3	protein	Q9NPG1	UNIPROT	GNB3	protein	P16520	UNIPROT	up-regulates	binding			9606									17251915	t		gcesareni	In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor.	SIGNOR-152603	0.357
YY1	protein	P25490	UNIPROT	SUZ12/EZH2/YY1	complex	SIGNOR-C102	SIGNOR	form complex	binding			10090									20887952	t		lperfetto	TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter.	SIGNOR-235580	0.2
CDH20	protein	Q9HBT6	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265859	0.302
malonyl-CoA	smallmolecule	CHEBI:15531	ChEBI	CPT1B	protein	Q92523	UNIPROT	down-regulates activity	binding			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267115	0.8
SIRT7	protein	Q9NRC8	UNIPROT	FBL	protein	P22087	UNIPROT	up-regulates activity	deacetylation	Lys206	DLINLAKkRTNIIPV										30540930	t		lperfetto	Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206)	SIGNOR-275893	0.274
PRKCH	protein	P24723	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates	phosphorylation	Ser738	ARIIGEKsFRRSVVG	9606									10197446	t		llicata	These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748.	SIGNOR-66730	0.362
ROCK1	protein	Q13464	UNIPROT	MYL12B	protein	O14950	UNIPROT	up-regulates	phosphorylation	Thr19	KKRPQRAtSNVFAMF	9606									12185584	t		gcesareni	Here we found that rho-kinase has an activity for mrlc diphosphorylation at both threonine 18 and serine 19 in nonmuscle cells using sequential column chromatographies.	SIGNOR-91546	0.609
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CLIP1	protein	P30622	UNIPROT	up-regulates activity	phosphorylation	Thr287	KIGFPSTtPAKAKAN										19687009	t		lperfetto	Cdc2 phosphorylates T287|CLIP-170, the founding member of microtubule “plus ends tracking” proteins, is involved in many critical microtubule-related functions, including recruitment of dynactin to the microtubule plus ends and formation of kinetochore-microtubule attachments during metaphase. |These results demonstrate that Cdc2-mediated phosphorylation of CLIP-170 is essential for the normal function of this protein during cell cycle progression.	SIGNOR-275471	0.464
afatinib	chemical	CHEBI:61390	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189359	0.8
SRC	protein	P12931	UNIPROT	GRIN2A	protein	Q12879	UNIPROT	up-regulates activity	phosphorylation	Tyr1105	CSEVERTyLKTKSSS	-1									10195142	t		lperfetto	To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain.	SIGNOR-247163	0.586
EFNA3	protein	P52797	UNIPROT	EPHA5	protein	P54756	UNIPROT	up-regulates	binding			9606									9330863	t		tpavlidou	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52381	0.811
CDON/SPAG9	complex	SIGNOR-C21	SIGNOR	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	binding			9606	BTO:0000222								17074887	t	p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors.	gcesareni	One way this occurs is via the interaction of JLP with the Cdo cytoplasmic tail. JLP is, in turn, bound to p38α/β. This interaction facilitates p38 activation during differentiation and is important for Cdo's effects in myogenesis.	SIGNOR-272542	0.492
PTGS2	protein	P35354	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606	BTO:0000007								32995789	f		miannu	Given our finding that COX-2 signaling does not regulate viral entry or replication, the role of COX-2 induction upon SARS-CoV-2 infection remains an area for future investigation. Rather than directly affecting viral entry or replication, COX-2 induction may regulate the severe lung inflammation and injury seen in COVID-19 patients (35, 36), though it is unclear whether COX-2 would be beneficial, neutral, or detrimental to disease. COX-2 could enhance lung injury in COVID-19, as PGE2 has been reported to induce IL-1β and exacerbate lung injury in bone marrow transplant mice	SIGNOR-262509	0.7
PPP2CA	protein	P67775	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	dephosphorylation	Ser253	APRRRAVsMDNSNKY	9606									18593906	t		gcesareni	Pp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a.	SIGNOR-252971	0.411
Membrane attack complex	complex	SIGNOR-C313	SIGNOR	Cell_killing	phenotype	SIGNOR-PH149	SIGNOR	up-regulates				-1									30552328	f		lperfetto	Our work provides a structural basis for understanding how β-pore forming proteins breach the membrane and reveals a mechanism for how MAC kills pathogens and regulates cell functions.	SIGNOR-263454	0.7
SRC	protein	P12931	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr576	RYMEDSTyYKASKGK	9606									15735019	t		miannu	Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates	SIGNOR-150484	0.633
SIK1	protein	P57059	UNIPROT	CRTC3	protein	Q6UUV7	UNIPROT	down-regulates	phosphorylation	Ser162	SALNRTNsDSALHTS	9606	BTO:0000007;BTO:0000567								16817901	t		miannu	These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities.	SIGNOR-147703	0.429
ATF6	protein	P18850	UNIPROT	HSPA5	protein	P11021	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								14973138	t		Luana	 Accordingly, N-terminal fragments of each ATF6 isoform (N-ATF6α and N-ATF6β) were overexpressed in HeLa cells and the effects on GRP78 induction were assessed. When expressed at similar levels, N-ATF6α conferred ∼200-fold greater GRP78 promoter activation than N-ATF6β. 	SIGNOR-261565	0.816
S1PR2	protein	O95136	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257123	0.357
MAPK1	protein	P28482	UNIPROT	RCAN1	protein	P53805	UNIPROT	up-regulates activity	phosphorylation	Ser167	FLISPPAsPPVGWKQ	10090	BTO:0000165								12063245	t		lperfetto	Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. 	SIGNOR-249198	0.274
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	A11/b1 integrin	complex	SIGNOR-C168	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259022	0.457
EGR3	protein	Q06889	UNIPROT	NAB2	protein	Q15742	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000782								20506119	f		miannu	 In T lymphocytes EGR2 and EGR3 have been shown to inhibit NAB2 expression.	SIGNOR-253884	0.501
CDK2	protein	P24941	UNIPROT	PGR	protein	P06401	UNIPROT	unknown	phosphorylation	Ser20	HVAGGPPsPEVGSPL	9606									11110801	t		llicata	In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676).	SIGNOR-84980	0.453
INSR	protein	P06213	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity	phosphorylation	Tyr577	YMEDSTYyKASKGKL	-1									9507031	t			P125(Fak) sequence comprising amino acids 568-582, which contains tyrosines 576 and 577 of the kinase domain regulatory loop, is phosphorylated by the insulin receptor. p125(Fak) phosphorylation by the receptor results in its activation.	SIGNOR-251324	0.36
TRBC1	protein	P01850	UNIPROT	TCR	complex	SIGNOR-C153	SIGNOR	form complex	binding			9606									12507424	t		miannu	The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ	SIGNOR-255298	0.2
MYO1E	protein	Q12965	UNIPROT	Endocytosis	phenotype	SIGNOR-PH123	SIGNOR	up-regulates				10116		BTO:0000142							17257598	f		miannu	We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. 	SIGNOR-265426	0.7
TUBGCP5	protein	Q96RT8	UNIPROT	g-TuRC complex	complex	SIGNOR-C282	SIGNOR	form complex	binding			-1									31862189	t		lperfetto	Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.”	SIGNOR-262329	0.815
ITGB1BP1	protein	O14713	UNIPROT	A11/b1 integrin	complex	SIGNOR-C168	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257648	0.757
PRKCA	protein	P17252	UNIPROT	HRH1	protein	P35367	UNIPROT	down-regulates	phosphorylation	Ser398	WKRLRSHsRQYVSGL	9606		BTO:0000975							15107581	t	Translocation from Endosome to Lysosome	fspada	The peptide p9-s396a/s398a (both ser396 and ser398 to alanines) was phosphorylated only slightly or not phosphorylated by these kinases. Thus both ser396 and ser398 can be phosphorylated by camk ii and pkc	SIGNOR-124352	0.2
FGFR1	protein	P11362	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates				9606									12270934	f		lperfetto	Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors	SIGNOR-244865	0.315
domperidone	chemical	CHEBI:31515	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258721	0.8
2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide	chemical	CHEBI:91353	ChEBI	MAP2K1	protein	Q02750	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258203	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	MAPKAPK2	protein	P49137	UNIPROT	up-regulates	phosphorylation			9606									14967450	t	inferred from 70% family members	gcesareni	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-270117	0.2
PDGFRB	protein	P09619	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates	phosphorylation	Tyr1021	PNEGDNDyIIPLPDP	9606									1396585	t		llicata	These data show that tyrosine phosphorylation of plc-gamma is dependent on autophosphorylation of the pdgf beta-receptor at tyr1009 and tyr1021.	SIGNOR-18579	0.2
GATA3	protein	P23771	UNIPROT	IL4	protein	P05112	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								12876556	f			Initiation of transcription of the gene encoding IL-4 in naive T(H) cells is regulated by the T(H) 2-specific transcription factor GATA3	SIGNOR-254500	0.503
PTK2	protein	Q05397	UNIPROT	PXN	protein	P49023	UNIPROT	up-regulates activity	phosphorylation	Tyr118	VGEEEHVySFPNKQK	9606									15688067	t		miannu	Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites.	SIGNOR-28243	0.912
NCOA2	protein	Q15596	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates activity	binding			9606									24239470	t		miannu	The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis	SIGNOR-251530	0.898
ATR	protein	Q13535	UNIPROT	MCM6	protein	Q14566	UNIPROT	up-regulates	phosphorylation			9606									21070963	t		gcesareni	Together these data strongly support the conclusion that mec1 directly targets the s/tq sites in mcm4 and mcm6, although it is formally possible that mec1 and mrc1 activate a different s/tq-directed kinase to target mcm4 and mcm6.	SIGNOR-169450	0.544
GSK3B	protein	P49841	UNIPROT	RXRA	protein	P19793	UNIPROT	up-regulates activity	phosphorylation	Ser66	NGMGPPFsVISSPMG	9606	BTO:0000007								29137318	t		miannu	GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis. 	SIGNOR-277370	0.279
PTPRF	protein	P10586	UNIPROT	DAPK1	protein	P53355	UNIPROT	up-regulates activity	dephosphorylation	Tyr491	CAAWHGYySVAKALC	9606	BTO:0002181								17803936	t		miannu	 Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation. 	SIGNOR-276075	0.2
F5	protein	P12259	UNIPROT	Factor Va-Xa	complex	SIGNOR-C318	SIGNOR	form complex	binding			-1									2026608	t		lperfetto	The binding of factor Xa to factor Va in the presence of Ca2+ ions and phospholipid is fundamental for the activation of prothrombin to thrombin. |Regardless of which protein was labeled, a factor Xa-Va complex (s20,w = 9.8) was formed. The interaction is specific and reversible. I	SIGNOR-263558	0.765
PTPRF	protein	P10586	UNIPROT	DAPK1	protein	P53355	UNIPROT	up-regulates activity	dephosphorylation	Tyr490	HCAAWHGyYSVAKAL	9606	BTO:0002181								17803936	t		miannu	 Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation. 	SIGNOR-276076	0.2
Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	FANCI	protein	Q9NVI1	UNIPROT	up-regulates activity	ubiquitination												18985065	t		lperfetto	Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding	SIGNOR-263267	0.69
GSK3A	protein	P49840	UNIPROT	TSC2	protein	P49815	UNIPROT	up-regulates	phosphorylation			9606							phosphorylation:Ser1387	QPLSKSSsSPELQTL 	16959574	t		gcesareni	Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation.	SIGNOR-149377	0.37
CHUK	protein	O15111	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr931	VCDSGVEtSFRKLSF	9606	BTO:0000567			SIGNOR-C13					10469655	t		lperfetto	All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391).	SIGNOR-70461	0.737
CDK4	protein	P11802	UNIPROT	MEF2C	protein	Q06413	UNIPROT	down-regulates				9606									21902831	t		gcesareni	Not much is known about how this occurs, but inhibition of mef2c by cdk4 prevents the association of mef2 with its transcriptional coactivator, glucocorticoid receptor-interacting protein 1 (grip1).	SIGNOR-176521	0.287
FZD7	protein	O75084	UNIPROT	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding			9606									22944199	t		gcesareni	Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism.	SIGNOR-198831	0.2
PTPRB	protein	P23467	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	9606									10734133	t		gcesareni	Identification of tyrosine phosphatases that dephosphorylate the insulin receptor.	SIGNOR-75989	0.349
TSC22D3	protein	Q99576	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates activity	relocalization			9606	BTO:0000738								20018851	t			GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells.	SIGNOR-256148	0.255
MAPK1	protein	P28482	UNIPROT	JUND	protein	P17535	UNIPROT	up-regulates	phosphorylation	Ser100	LGLLKLAsPELERLI	9606									22327296	t		gcesareni	Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase.	SIGNOR-196030	0.545
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGA8	protein	Q9Y5G5	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265680	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	ARRB1	protein	P49407	UNIPROT	down-regulates	phosphorylation			9606									10347142	t	inferred from 70% family members	gcesareni	Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation	SIGNOR-270094	0.2
LAMTOR3	protein	Q9UHA4	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates	binding			9606									9733512	t		gcesareni	A protein called mp1 (mek partner 1) was identified that bound specifically to mek1 and erk1 and facilitated their activation. When overexpressed in cultured cells, mp1 enhanced activation of erk1 and activation of a reporter driven by the transcription factor elk-1.	SIGNOR-59877	0.589
CCT3	protein	P49368	UNIPROT	TRiC	complex	SIGNOR-C539	SIGNOR	form complex	binding			9606									36185250	t		miannu	Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC).	SIGNOR-272864	0.74
GOT2	protein	P00505	UNIPROT	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	down-regulates quantity	chemical modification			9606									31422819	t			Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate.	SIGNOR-266923	0.8
STK11	protein	Q15831	UNIPROT	STRADA	protein	Q7RTN6	UNIPROT	up-regulates activity	phosphorylation	Thr329	GLSDSLTtSTPRPSN	9606	BTO:0000007								12805220	t		lperfetto	Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419	SIGNOR-261950	0.938
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	GRB10	protein	Q13322	UNIPROT	up-regulates	phosphorylation			9606									15952796	t	inferred from 70% family members	lperfetto	Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation	SIGNOR-270077	0.2
CSNK2A1	protein	P68400	UNIPROT	KIR3DL1	protein	P43629	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser385	AGNRTANsEDSDEQD	-1									17911614	t		miannu	Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. It seems that phosphorylation of 3DL1 by CK does not significantly affect receptor inhibitory function or turnover, at least in the assays that we have used so far.	SIGNOR-276077	0.2
GSK3B	protein	P49841	UNIPROT	CCND3	protein	P30281	UNIPROT	down-regulates	phosphorylation	Thr283	QGPSQTStPTDVTAI	9606									16331257	t		lperfetto	We have previously shown that both basal and camp-induced degradation of cyclin d3 in reh cells is dependent on thr-283 phosphorylation by glycogen synthase kinase-3beta (gsk-3beta).	SIGNOR-142880	0.415
DYRK3	protein	O43781	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	down-regulates activity	phosphorylation	Ser1330	PAFGRVSsPPNAMMS	9606	BTO:0000578								31066068	t		miannu	Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity.	SIGNOR-275451	0.2
ZEB2	protein	O60315	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15311212	f		miannu	 known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT.	SIGNOR-255159	0.503
RXRB	protein	P28702	UNIPROT	NRIP1	protein	P48552	UNIPROT	up-regulates	binding			9606									12403842	t		gcesareni	Receptor interacting protein 140 (rip140) is a coregulator for a large number of transcription factors. Rip140 interacts with retinoic acid receptor (rar) and retinoid x receptor (rxr) with or without ligands	SIGNOR-95160	0.585
MAPK1	protein	P28482	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates	phosphorylation	Ser10	NVRVSNGsPSLERMD	9606									10831586	t		gcesareni	Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.	SIGNOR-77651	0.354
MC4R	protein	P32245	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257069	0.252
CDK7	protein	P50613	UNIPROT	RARG	protein	P13631	UNIPROT	up-regulates activity	phosphorylation	Ser79	EMVPSSPsPPPPPRV	9534									10748061	t		Luana	RARg Is Phosphorylated by cdk7 in Its B and F Regions | Mutation into alanine of Ser-77 and Ser-79 located in the A/B region reduced the transcriptional activity of hRARg1 (Fig. 9A), confirming that these phosphorylation sites are required for optimal transcription.	SIGNOR-259852	0.393
GLI2	protein	P10070	UNIPROT	HHIP	protein	Q96QV1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002572								16571352	f		lperfetto	Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1.	SIGNOR-209635	0.57
RACK1	protein	P63244	UNIPROT	TRPM6	protein	Q9BX84	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								18258429	t		Manara	We identified RACK1 as the first TRPM6-associated protein and demonstrated that RACK1 inhibits TRPM6 channel activity depending on the phosphorylation state T1851 in the α-kinase domain.	SIGNOR-260921	0.2
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1668	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269333	0.718
RPL26L1	protein	Q9UNX3	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262496	0.757
UBTF	protein	P17480	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				10090	BTO:0002882								15169904	f		miannu	Pescadillo (PES1) and the upstream binding factor (UBF1) play a role in ribosome biogenesis, which regulates cell size, an important component of cell proliferation. We have investigated the effects of PES1 and UBF1 on the growth and differentiation of cell lines derived from 32D cells, an interleukin-3 (IL-3)-dependent murine myeloid cell line. Parental 32D cells and 32D IGF-IR cells (expressing increased levels of the type 1 insulin-like growth factor I [IGF-I] receptor [IGF-IR]) do not express insulin receptor substrate 1 (IRS-1) or IRS-2. 32D IGF-IR cells differentiate when the cells are shifted from IL-3 to IGF-I. Ectopic expression of IRS-1 inhibits differentiation and transforms 32D IGF-IR cells into a tumor-forming cell line. We found that PES1 and UBF1 increased cell size and/or altered the cell cycle distribution of 32D-derived cells but failed to make them IL-3 independent. PES1 and UBF1 also failed to inhibit the differentiation program initiated by the activation of the IGF-IR, which is blocked by IRS-1. 32D IGF-IR cells expressing PES1 or UBF1 differentiate into granulocytes like their parental cells. In contrast, PES1 and UBF1 can transform mouse embryo fibroblasts that have high levels of endogenous IRS-1 and are not prone to differentiation. Our results provide a model for one of the theories of myeloid leukemia, in which both a stimulus of proliferation and a block of differentiation are required for leukemia development.	SIGNOR-260077	0.7
ITGB1BP1	protein	O14713	UNIPROT	ITGB7	protein	P26010	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257664	0.29
LCK	protein	P06239	UNIPROT	CD5	protein	P06127	UNIPROT	up-regulates activity	phosphorylation	Tyr453	ASHVDNEySQPPRNS	9606	BTO:0000782								11298344	t		lperfetto	Tyrosine phosphorylation of cd5 requires lck activity. We propose that t cell activation mediates cd5 tyrosine phosphorylation at residues y429 and y463 mainly through the activation of lck	SIGNOR-106799	0.558
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2J1	protein	Q9Y385	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271308	0.582
GATA3	protein	P23771	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates	binding			9606									17139329	t		fferrentino	Whereas others, such as GATA2/3 and SMAD3, physically interact with C/EBPα to inhibit its transcriptional activity on the Pparg2 promoter.	SIGNOR-250569	0.37
FUS	protein	P35637	UNIPROT	GEMIN4	protein	P57678	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								23022481	t		lperfetto	Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells	SIGNOR-262105	0.2
FOXO3	protein	O43524	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates quantity	transcriptional regulation			10090	BTO:0004245								10783894	t		gcesareni	AFX transcriptionally activates p27kip1, resulting in increased protein levels.	SIGNOR-238610	0.738
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-258999	0.2
POLD1	protein	P28340	UNIPROT	DNA polymerase delta 	complex	SIGNOR-C376	SIGNOR	form complex	binding			-1									12403614	t		lperfetto	Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme.	SIGNOR-265518	0.922
FLT3	protein	P36888	UNIPROT	FLT3	protein	P36888	UNIPROT	up-regulates activity	phosphorylation	Tyr969	VSECPHTyQNRRPFS	9606									31395582	t		lperfetto	A mutation at tyrosine 969, which inhibits activation of downstream signaling by FLT3-ITD.	SIGNOR-271919	0.2
GRIA3	protein	P42263	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial.	SIGNOR-264949	0.8
ADCY8	protein	P40145	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates quantity	chemical modification			9606									15385642	t		miannu	Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions.	SIGNOR-265002	0.8
CALM1	protein	P0DP23	UNIPROT	PPP3CC	protein	P48454	UNIPROT	up-regulates	binding			9606									11796223	t		gcesareni	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-114104	0.657
lovastatin	chemical	CHEBI:40303	ChEBI	HMGCR	protein	P04035	UNIPROT	down-regulates activity	chemical inhibition			-1									6933445	t		miannu	Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.	SIGNOR-258403	0.8
Exon junction complex	complex	SIGNOR-C369	SIGNOR	mRNA-nucleus_export	phenotype	SIGNOR-PH127	SIGNOR	up-regulates				9606									11532962	f		lperfetto	The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay	SIGNOR-268313	0.7
CEBPA	protein	P49715	UNIPROT	SPI1	protein	P17947	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									17671233	f		irozzo	C/EBPα binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment.Transcriptional induction of PU.1 by C/EBPα may play a role in myeloid lineage specification.	SIGNOR-256055	0.544
GXYLT1	protein	Q4G148	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	up-regulates	binding			9606									22117070	t		gcesareni	We have previously identified two human genes, gxylt1 and gxylt2, encoding glucoside xylosyltransferases responsible for the transfer of xylose to o-linked glucose. The identity of the enzyme further elongating the glycan to generate the final trisaccharide xylose-xylose-glucose, however, remained unknown. Here, we describe that the human gene c3orf21 encodes a udp-xylose:alfa-xyloside alfa1,3-xylosyltransferase, acting on xylose-alfa1,3-glucosebeta1-containing acceptor structures. We have, therefore, renamed it xxylt1 (xyloside xylosyltransferase 1). Xxylt1 cannot act on a synthetic acceptor containing an alfa-linked xylose alone, but requires the presence of the underlying glucose. Activity on notch egf repeats was proven by in vitro xylosylation of a mouse notch1 fragment recombinantly produced in sf9 insect cells, a bacterially expressed egf repeat from mouse notch2 modified in vitro by rumi and gxylt2 and in vivo by co-expression of the enzyme with the notch1 fragment. The enzyme was shown to be a typical type ii membrane-bound glycosyltransferase localized in the endoplasmic reticulum.	SIGNOR-177694	0.343
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BANP	protein	Q8N9N5	UNIPROT	down-regulates activity	phosphorylation	Thr337	VKSFSRRtPNSSSYC	9606	BTO:0000567								26080397	t		miannu	ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68. 	SIGNOR-266377	0.2
CDK2	protein	P24941	UNIPROT	CCP110	protein	O43303	UNIPROT	down-regulates activity	phosphorylation	Ser366	GSYAKLPsPEPSMSP	-1									12361598	t		miannu	GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)	SIGNOR-265960	0.531
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Thr157	GIRKRPAtDDSSTQN	9606									18593906	t		gcesareni	We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro.	SIGNOR-259426	0.2
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	CASP2	protein	P42575	UNIPROT	up-regulates activity	dephosphorylation	Ser164	STDTVEHsLDNKDGP	-1									19531356	t		lperfetto	Nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2.	SIGNOR-264661	0.2
ribavirin	chemical	CHEBI:63580	ChEBI	IMPDH2	protein	P12268	UNIPROT	down-regulates activity	chemical inhibition			9606									22555152	t		Federica	Ribavirin, a well-known IMPDH inhibitor, was included as a reference drug. As expected, this compound markedly inhibited IMPDH activity in a dose-dependent manner in bothtumour cell lines	SIGNOR-261079	0.8
PTPN6	protein	P29350	UNIPROT	KDR	protein	P35968	UNIPROT	unknown	dephosphorylation	Tyr996	EEAPEDLyKDFLTLE	9606	BTO:0000007								18840653	t			Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175	SIGNOR-248476	0.654
EEF1A1P5	protein	Q5VTE0	UNIPROT	Asp-tRNA(Asp)	smallmolecule	CHEBI:29158	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269547	0.8
BMPR2	protein	Q13873	UNIPROT	BMPR1B	protein	O00238	UNIPROT	up-regulates	phosphorylation			9606			SIGNOR-C29	SIGNOR-C29					18756288	t		gcesareni	Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1.	SIGNOR-180548	0.608
CDON	protein	Q4KMG0	UNIPROT	BNIP2	protein	Q12982	UNIPROT	up-regulates activity	binding			9606									18678706	t		lperfetto	Bnip-2 and jlp are brought together through mutual interaction with cdo. the cdo-bnip-2 interaction stimulates cdc42 activity, which in turn promotes p38alpha/beta activity and cell differentiation.	SIGNOR-179864	0.485
ERBB4	protein	Q15303	UNIPROT	SHC3	protein	Q92529	UNIPROT	up-regulates	relocalization			9606									16729043	t		gcesareni	Like erbb1, erbb4 recruits grb2, shc and stat5.	SIGNOR-146891	0.479
A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257702	0.586
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	RAPGEF2	protein	Q9Y4G8	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002181								24290981	t		miannu	Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase.	SIGNOR-276606	0.2
USF1	protein	P22415	UNIPROT	CEBPA	protein	P49715	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									7862113	f		irozzo	 Our studies show that the human C/EBPa protein stimulates USF to bind to a USF consensus element within C/EBPa promoter and activates it by two- to threefold.The mechanism by which C/EBPa enhances USF binding and transactivation is currently under study.	SIGNOR-255702	0.323
CDC25A	protein	P30304	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates	dephosphorylation	Thr14	VEKIGEGtYGVVYKA	9606									12411508	t		gcesareni	Cell division cycle 25 a (cdc25a), a dual-specificity protein phosphatase, is one of the most crucial cell cycle regulators, which removes the inhibitory phosphorylation in cyclin-dependent kinases (cdks), such as cdk2, cdk4, and cdk6, and positively regulates the activities of cdks that lead to cell cycle progression.	SIGNOR-95252	0.824
RPS6KA5	protein	O75582	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									18508628	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	In addition to ser10, msk was also found to phosphorylate a second site on h3, ser28 (75). It should be noted that while both ser10 and ser28 in h3 are extensively phosphorylated during mitosis, this is independent of msks and is catalysed by aurora kinases. In contrast, msks only phosphorylate a small proportion of the total cellular histone h3 in response to mitogens or stress. The spatial distribution of ser10 and ser28 phosphorylation is very tightly regulated in cells. In vitro, msk1 will phosphorylate one histone h3 molecule on both ser10 and ser28. Surprisingly it has been shown that in cells msk phosphorylates either ser10 or ser28 but not both on individual nucleosomes.	SIGNOR-178704	0.2
MAPK1	protein	P28482	UNIPROT	NR4A1	protein	P22736	UNIPROT	up-regulates activity	phosphorylation	Thr143	CSAPSPStPSFQPPQ	10116	BTO:0001009								11883936	t		lperfetto	NGFI-B is an inducible orphan nuclear receptor that initiates apoptosis. Growth factors such as EGF activate the MAP kinase ERK, whose activity may determine if a cell survives or undergoes apoptosis. EGF stimulation of cells leads to phosphorylation of threonine in NGFI-B. Thr-142 of NGFI-B is comprised in a consensus MAP kinase site and was identified as a preferred substrate for ERK2 (but not ERK1) in vitro.	SIGNOR-249430	0.66
NTRK1	protein	P04629	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	binding			9606	BTO:0000938								10708759	t		esanto	Autophosphorylated trka binds directly to plc?, Abl, and shc.	SIGNOR-75408	0.837
Nucleosome_H3.1 variant	complex	SIGNOR-C324	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606									21812398	f		miannu	The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 	SIGNOR-263723	0.7
A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257707	0.535
EPGN	protein	Q6UW88	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606									16829981	t		gcesareni	Areg (amphiregulin), btc (beta-cellulin), egf, epgn (epigen), ereg (epiregulin), hbegf, nrg1, nrg2, nrg3, nrg4 and tgfa (tgfalpha) constitute egf family ligands for erbb family receptors.	SIGNOR-147835	0.404
SNCA	protein	P37840	UNIPROT	CADPS2	protein	Q86UW7	UNIPROT	down-regulates quantity	transcriptional regulation			9606									28647363	f		gianni	This approach enabled us to disclose a differential effect of high levels of LRRK2 and aSyn on CADPS2 promoter activity. Specifically, CADPS2 transcriptional activity was enhanced by high cellular levels of LRRK2 and reduced by overexpression of aSyn. Consistently, CADPS2 mRNA levels were diminished in aSyn overexpressing cells.	SIGNOR-268929	0.279
DNMT3A	protein	Q9Y6K1	UNIPROT	MEIS1	protein	O00470	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									28288143	f		miannu	Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations.Under these circumstances, those AML patients carrying the alteration in the DNA methyltransferase would undergo a hypomethylation event at the MEIS1 promoter that would lead to the overexpression of this key oncogene in leukemia.	SIGNOR-256125	0.335
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	PIN1	protein	Q13526	UNIPROT	down-regulates activity	chemical inhibition			9606									30093655	t			ATRA inhibits leukemia, breast, and liver cancer by targeting isomerase Pin1, a master regulator of oncogenic signaling networks.	SIGNOR-259925	0.8
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	FLNA	protein	P21333	UNIPROT	down-regulates quantity by destabilization	dephosphorylation			9606									16442073	t	inferred from 70% family members		Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation.	SIGNOR-269986	0.2
ponatinib	chemical	CHEBI:78543	ChEBI	FGFR1	protein	P11362	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002058								23563700	t		miannu	Ponatinib was able to significantly inhibit the growth of primary lung cancer cultures in vitro. Our data indicate that pharmacological inhibition of FGFR1 kinase activity with ponatinib may be effective for the treatment of lung cancer patients whose tumors overexpress FGFR1.	SIGNOR-259276	0.8
CSNK1A1	protein	P48729	UNIPROT	SLC18A2	protein	Q05940	UNIPROT	unknown	phosphorylation	Ser511	PIGEDEEsESD	-1									9045708	t		llicata	Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells. 	SIGNOR-250794	0.327
ibuprofen	chemical	CHEBI:5855	ChEBI	PTGS1	protein	P23219	UNIPROT	down-regulates activity	chemical inhibition			-1									9057869	t		miannu	Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). 	SIGNOR-258605	0.8
CSNK1D	protein	P48730	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates	phosphorylation	Ser46	PASYSFCsGKGVGIK	9606				SIGNOR-C110					12000790	t		gcesareni	We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45 . This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/mscomplex of axin and casein kinase i (cki) induces betBeta-catenin phosphorylation at a single site: serine 45 (s45)	SIGNOR-87437	0.537
TWIST1	protein	Q15672	UNIPROT	CD44	protein	P16070	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002590								17487558	f		miannu	 Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells	SIGNOR-255512	0.53
SRC	protein	P12931	UNIPROT	SH3GL1	protein	Q99961	UNIPROT	down-regulates	phosphorylation	Tyr315	QPSCKALyDFEPEND	9606									16054026	t		lperfetto	Further, we identified an interaction between fak's second pro-rich motif and endophilin a2's sh3 domain. This interaction served as an autophosphorylation-dependent scaffold to allow src phosphorylation of endophilin a2 at tyr315. Tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. Together, these results suggest a regulatory mechanism of cell invasion whereby fak promotes cell-surface presentation of mt1-mmp by inhibiting endophilin a2-dependent endocytosis.	SIGNOR-139150	0.625
CSNK2A1	protein	P68400	UNIPROT	KIR3DL1	protein	P43629	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser388	RTANSEDsDEQDPEE	-1									17911614	t		miannu	Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. It seems that phosphorylation of 3DL1 by CK does not significantly affect receptor inhibitory function or turnover, at least in the assays that we have used so far.	SIGNOR-276078	0.2
TBP	protein	P20226	UNIPROT	SL1 complex	complex	SIGNOR-C464	SIGNOR	form complex	binding			9606									30693017	t		lperfetto	SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation.	SIGNOR-269562	0.738
nintedanib	chemical	CHEBI:85164	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates activity	chemical inhibition			-1									18559524	t		Luana	In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers.	SIGNOR-257801	0.8
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates	binding			9606									21084559	t		gcesareni	Phosphorylation of yap ser127 and of the corresponding sites in yki and taz generates a protein-binding motif for the 14-3-3 family proteins, which, upon binding by a 14-3-3 protein, leads to their cytoplasmic retention.	SIGNOR-169716	0.2
KLKB1	protein	P03952	UNIPROT	KNG1	protein	P01042	UNIPROT	up-regulates activity	cleavage	Arg381	GMISLMKrPPGFSPF	9606		BTO:0000131			cleavage:Arg390	CTTKTSTrIVGGTNS			28966616	t		lperfetto	Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1).	SIGNOR-263547	0.772
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CASP9	protein	P55211	UNIPROT	down-regulates activity	phosphorylation			9606									12792650	t	inferred from 70% family members	lperfetto	Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk	SIGNOR-270184	0.2
SMAD6	protein	O43541	UNIPROT	HOXC8	protein	P31273	UNIPROT	up-regulates activity	binding			9606									10722652	t		gcesareni	Smad6 interacts with hox transcription factors as part of the negative feedback circuit in the bmp signaling pathway	SIGNOR-75823	0.545
CBL	protein	P22681	UNIPROT	PIK3R2	protein	O00459	UNIPROT	down-regulates	ubiquitination			9606									11526404	t		lperfetto	Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner.	SIGNOR-110063	0.588
IGF1	protein	P05019	UNIPROT	PPP3CC	protein	P48454	UNIPROT	up-regulates				10090	BTO:0000165;BTO:0002314	BTO:0000887;BTO:0001103;BTO:0001760							10448861	f		lperfetto	Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1.	SIGNOR-235828	0.2
WWP1	protein	Q9H0M0	UNIPROT	SMAD7	protein	O15105	UNIPROT	up-regulates activity	ubiquitination			9606									15221015	t		lperfetto	Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor.	SIGNOR-227466	0.72
DAPK1	protein	P53355	UNIPROT	TPM1	protein	P09493	UNIPROT	up-regulates activity	phosphorylation	Ser283	HALNDMTsI	9606	BTO:0000007								17895359	t		miannu	 We identified, for the first time, death-associated protein kinase 1 (DAP kinase 1) as the kinase that phosphorylates tropomyosin-1 in response to ERK activation by hydrogen peroxide (H(2)O(2)). We also report that the phosphorylation of tropomyosin-1 mediated by DAP kinase occurs on Ser283. Our finding that tropomyosin-1 is phosphorylated downstream of ERK and DAP kinase and that it helps regulate the formation of stress fibers will aid understanding the role of this protein in regulating the endothelial functions associated with cytoskeletal remodeling.	SIGNOR-262845	0.28
PRKACG	protein	P22612	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser275	LSAFRRTsLAGGGRR	9606		BTO:0000887							20151718	t		miannu	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163784	0.278
PRKAA1	protein	Q13131	UNIPROT	GBF1	protein	Q92538	UNIPROT	down-regulates	phosphorylation	Thr1337	GKIHRSAtDADVVNS	9606			SIGNOR-C15						18063581	t		lperfetto	These results indicate that gbf1 is a novel ampk substrate and that the ampk-mediated phosphorylation of gbf1 at thr(1337) has a critical role, presumably by attenuating the function of gbf1, in the disassembly of the golgi apparatus induced under stress conditions that lower the intracellular atp concentration.	SIGNOR-159639	0.2
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGA11	protein	Q9Y5H2	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265712	0.2
WNT5A	protein	P41221	UNIPROT	FZD2	protein	Q14332	UNIPROT	down-regulates	binding			9606									2808370	t		gcesareni	Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway.	SIGNOR-23441	0.757
STAT1	protein	P42224	UNIPROT	MUC4	protein	Q99102	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001861								19757157	t	 	lperfetto	Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level.	SIGNOR-254099	0.402
PLK1	protein	P53350	UNIPROT	CENPQ	protein	Q7L2Z9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser253	HNSSQMKsMSTFIEE	9606	BTO:0000567								25670858	t		lperfetto	Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 	SIGNOR-265232	0.57
WIPF1	protein	O43516	UNIPROT	Early Endosome	complex	SIGNOR-C246	SIGNOR	up-regulates				9606									19121306	f		lperfetto	However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin.	SIGNOR-260611	0.2
PPARGC1A	protein	Q9UBK2	UNIPROT	CPT1B	protein	Q92523	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534	BTO:0001538								15199055	f	 	 	Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle.	SIGNOR-254262	0.415
ELANE	protein	P08246	UNIPROT	F5	protein	P12259	UNIPROT	up-regulates activity	cleavage	Ile1512	KEFNPLViVGLSKDG	-1									9242537	t		lperfetto	Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex. 	SIGNOR-263633	0.373
PRKCE	protein	Q02156	UNIPROT	OCLN	protein	Q16625	UNIPROT	up-regulates	phosphorylation	Thr424	IREYPPItSDQQRQL	9606									21545357	t		lperfetto	Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions.	SIGNOR-173639	0.2
STK39	protein	Q9UEW8	UNIPROT	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation	Ser130	GPKVNRPsLLEIHEQ	9606	BTO:0000007								21321328	t		miannu	 We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A).	SIGNOR-276305	0.596
MAP2K4	protein	P45985	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	phosphorylation	Ser257	ISGQLVDsIAKTRDA	-1									9162092	t			Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4.	SIGNOR-251420	0.2
SRC	protein	P12931	UNIPROT	PDPK1	protein	O15530	UNIPROT	up-regulates	phosphorylation	Tyr373	SEDDEDCyGNYDNLL	9606									20643654	t		miannu	Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376	SIGNOR-166718	0.566
DLG4	protein	P78352	UNIPROT	TANC1	protein	Q9C0D5	UNIPROT	up-regulates activity	binding			10116		BTO:0000142							21068316	t		miannu	 In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses.	SIGNOR-266894	0.616
2-(4-morpholinyl)-6-(1-thianthrenyl)-4-pyranone	chemical	CHEBI:91372	ChEBI	ATM	protein	Q13315	UNIPROT	down-regulates	chemical inhibition			9606									15604286	t		gcesareni	Through screening a small molecule compound library developed for the phosphatidylinositol 3'-kinase-like kinase family, we identified an atp-competitive inhibitor, 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (ku-55933), that inhibits atm with an ic(50) of 13 nmol/l and a ki of 2.2 nmol/l	SIGNOR-132441	0.8
GRIN1	protein	Q05586	UNIPROT	NMDA receptor_2D	complex	SIGNOR-C350	SIGNOR	form complex	binding			9606	BTO:0000938								12871085	t		miannu	The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits	SIGNOR-264126	0.649
LRFN4	protein	Q6PJG9	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606	BTO:0000938								21736948	f		miannu	This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments.	SIGNOR-264097	0.7
MSX1	protein	P28360	UNIPROT	DLX2	protein	Q07687	UNIPROT	down-regulates activity	binding			10090	BTO:0000944								9111364	t	2	miannu	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240929	0.408
FGF12	protein	P61328	UNIPROT	SCN2A	protein	Q99250	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253428	0.315
PRKCB	protein	P05771	UNIPROT	ITGB7	protein	P26010	UNIPROT	unknown	phosphorylation	Thr783	PLYKSAItTTINPRF	10090	BTO:0001825								12682249	t		lperfetto	Beta7 subunit is phosphorylated even in unstimulated TK-1 cells. Activation of TK-1 cells with anti-CD3 (Fig. 5_A) and PDBu (Fig. 5_B) increased the phosphorylation 15€“20%. | The result shows that the fourth amino acid of the tryptic peptide was phosphorylated. This phosphorylated threonine residue is most likely the first threonine (Thr782) of threonine triplet (Thr782€“784). 	SIGNOR-249200	0.421
mTORC1	complex	SIGNOR-C3	SIGNOR	ISCU	protein	Q9H1K1	UNIPROT	up-regulates	phosphorylation	Ser14	FRLRRAAsALLLRSP	9606									23508953	t		lperfetto	Here, we demonstrate that mtorc1 associates with iscu and phosphorylates iscu at serine 14. This phosphorylation stabilized iscu protein.	SIGNOR-217082	0.2
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Thr642	CIAGSPLtPRRVTEV	9606	BTO:0001938								11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130.	SIGNOR-104703	0.843
CAMK2G	protein	Q13555	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates	phosphorylation			9606									12482967	t		gcesareni	Camkii interacts with and phosphorylates tak1.	SIGNOR-96422	0.2
CDK5	protein	Q00535	UNIPROT	DLC1	protein	Q96QB1	UNIPROT	up-regulates activity	phosphorylation	Ser946	SVSPCPSsPKQIHLD	9606	BTO:0002181								25452387	t		miannu	The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. 	SIGNOR-276446	0.2
WNT10A	protein	Q9GZT5	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates				9606									21872687	f		fspada	We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b	SIGNOR-176187	0.479
SLBP	protein	Q14493	UNIPROT	H2AC4	protein	P04908	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265397	0.2
DUSP4	protein	Q13115	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Thr185	HDHTGFLtEYVATRW	10116									7535768	t			Dephosphorylation and Inactivation of ERKs|A single protein kinase, MEK, activates ERK2 by phosphorylating threonine 183 and tyrosine 185	SIGNOR-248717	0.752
KCNJ8	protein	Q15842	UNIPROT	KATP channel	complex	SIGNOR-C274	SIGNOR	form complex	binding			9606									28842488	t		lperfetto	ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits.	SIGNOR-262054	0.644
KDM6A	protein	O15550	UNIPROT	HOXA5	protein	P20719	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24561908	t		miannu	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260023	0.274
PLK1	protein	P53350	UNIPROT	ESPL1	protein	Q14674	UNIPROT	down-regulates activity	phosphorylation	Thr1363	AGPHVPFtVFEEVCP	9606	BTO:0002181								17974570	t		miannu	Although mutation of serine 1126 and threonine 1346 to alanine had no effect (lanes 2 and 5), additional mutation of threonine 1363 and serine 1399 rendered separase almost completely resistant to phosphorylation (lane 3). Serine 1399 seems to be the one residue within this large separase fragment that is most efficiently phosphorylated by polo-like kinase, because a corresponding point mutation was sufficient to reduce the labeling by 80% compared with wild type (lane 6).	SIGNOR-276083	0.763
PRKCB	protein	P05771	UNIPROT	EEF1A2	protein	Q05639	UNIPROT	up-regulates activity	phosphorylation	Ser53	AAEMGKGsFKYAWVL	10090									20923971	t		miannu	PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein.	SIGNOR-263166	0.2
SAGA complex	complex	SIGNOR-C465	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	down-regulates				9606									15970593	f		lperfetto	Transcription initiation is a major regulatory step in eukaryotic gene expression. Co-activators establish transcriptionally competent promoter architectures and chromatin signatures to allow the formation of the pre-initiation complex (PIC), comprising RNA polymerase II (Pol II) and general transcription factors (GTFs).|this observation appears remarkably prevalent for chromatin-modifying and remodeling complexes. Here, we use the modular organization of the evolutionary conserved Spt-Ada-Gcn5 acetyltransferase (SAGA) complex as a paradigm to illustrate how co-activators share and combine a relatively limited set of functional tools.	SIGNOR-269569	0.7
RXRA	protein	P19793	UNIPROT	THRB	protein	P10828	UNIPROT	up-regulates	binding			9606									10976919	t		gcesareni	Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr	SIGNOR-81449	0.712
DZIP3	protein	Q86Y13	UNIPROT	H2AC6	protein	Q93077	UNIPROT	up-regulates activity	monoubiquitination	Lys119	IQAVLLPkKTESHHK	9606	BTO:0000007								18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271759	0.2
ATXN7L3	protein	Q14CW9	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269579	0.76
DUSP22	protein	Q9NRW4	UNIPROT	LCK	protein	P06239	UNIPROT	down-regulates activity	dephosphorylation			9606									27557500	t		miannu	Because JKAP dephosphorylates and inactivates Lck in T cells [ xref ], we studied whether JKAP downregulation results in Lck activation in SLE T cells.	SIGNOR-277148	0.277
DUSP26	protein	Q9BV47	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	dephosphorylation	Ser20	PLSQETFsDLWKLLP	9606									20562916	t			Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma|Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis	SIGNOR-248765	0.373
AMPK	complex	SIGNOR-C15	SIGNOR	ALDH2	protein	P05091	UNIPROT	up-regulates activity	phosphorylation	Thr356	GNPFDSKtEQGPQVD	10090	BTO:0000801								30375985	t		lperfetto	Further studies demonstrate that in the absence of LDLR, AMPK phosphorylates ALDH2 at threonine 356 and enables its nuclear translocation. Nuclear ALDH2 interacts with HDAC3 and represses transcription of a lysosomal proton pump protein ATP6V0E2, critical for maintaining lysosomal function, autophagy, and degradation of oxidized low-density lipid protein. 	SIGNOR-271862	0.255
EIF2AK1	protein	Q9BQI3	UNIPROT	HBB	protein	P68871	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19946423	f	Regulation of expression	miannu	Translation of α- and β-globin is tightly controlled by eIF2 and downregulated by HRI.	SIGNOR-251780	0.2
quizartinib	chemical	CHEBI:90217	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206331	0.8
CDK5	protein	Q00535	UNIPROT	KIF13B	protein	Q9NQT8	UNIPROT	down-regulates activity	phosphorylation	Thr506	SEGQVMLtPQKNTRT	10029	BTO:0000246								27512725	t		miannu	Overexpression of Cdk5 or its activator p35 promoted and inhibition of Cdk5 activity prevented the KIF13B-TRPV1 association, indicating that Cdk5 promotes TRPV1 anterograde transport by mediating the motor-cargo association. Cdk5 phosphorylates KIF13B at Thr-506, a residue located in the FHA domain. T506A mutation reduced the motor-cargo interaction and the cell-permeable TAT-T506 peptide, targeting to the Thr-506, decreased TRPV1 surface localization, demonstrating the essential role of Thr-506 phosphorylation in TRPV1 transport. 	SIGNOR-262737	0.374
CHUK	protein	O15111	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates	phosphorylation			9606									10469655	t		lperfetto	All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391).	SIGNOR-217397	0.789
MARCHF8	protein	Q5T0T0	UNIPROT	HLA-DRB3	protein	P79483	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys254	FIYFRNQkGHSGLQP	9606									19117940	t		miannu	Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination.	SIGNOR-271408	0.2
SARS1	protein	P49591	UNIPROT	serine	smallmolecule	CHEBI:17822	ChEBI	down-regulates quantity	chemical modification			9606									24095058	t		miannu	As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis	SIGNOR-270494	0.8
AURKA	protein	O14965	UNIPROT	INCENP	protein	Q9NQS7	UNIPROT	up-regulates activity	phosphorylation			7227									16824953	t		lperfetto	INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop	SIGNOR-252047	0.714
AURKB	protein	Q96GD4	UNIPROT	HASPIN	protein	Q8TF76	UNIPROT	up-regulates activity	phosphorylation	Ser93	RVPKDRPsLTVTPKR	9606	BTO:0000567								21658950	t		miannu	Phosphorylation by Aurora B is required for full Haspin activity toward H3T3 in mitosis	SIGNOR-262657	0.2
TANC2	protein	Q9HCD6	UNIPROT	KIF1A	protein	Q12756	UNIPROT	up-regulates activity	binding			10116	BTO:0003102								30021165	t		miannu	Kinesin-3 Family Member KIF1A Interacts with Liprin-α and TANC2. TANC2 and Liprin-α Recruit KIF1A-Driven DCVs in Dendritic Spines. Upon Ca2+/CaM binding, KIF1A is activated, allowing for DCV loading and motility. KIF1A-driven DCVs are recruited in dendritic spines by liprin-α and TANC2, which ensure a precise mechanism of synaptic tagging for the vesicles.	SIGNOR-266891	0.25
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Thr60	AGQEEPGtPPSSPLS	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276086	0.283
BMP2	protein	P12643	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates				9606									21793042	f		gcesareni	Upon bmp binding to the bmpr-ii, bmpr-i is recruited to form an activated quaternary complex, which then phosphorylates and activates intracellular smad proteins. Receptor smads bind to a co-smad and translocate to the nucleus to serve as transcription factors.	SIGNOR-175273	0.488
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									10656682	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-74823	0.784
APC-c	complex	SIGNOR-C150	SIGNOR	FBXW5	protein	Q969U6	UNIPROT	down-regulates quantity by destabilization	ubiquitination												21725316	t		lperfetto	We show that FBXW5 levels are controlled by the anaphase-promoting (APC/C) complex, which targets FBXW5 for degradation during mitosis and G1, thereby helping to reset the centrosome duplication machinery.	SIGNOR-275477	0.373
ANK3	protein	Q12955	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								17620337	t		miannu	Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. Ankyrin-G also recruits beta-2-spectrin to E-cadherin-beta-catenin complexes, thus providing a direct connection between E-cadherin and the spectrin/actin skeleton. 	SIGNOR-266710	0.33
MAP3K14	protein	Q99558	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates				9606									9020361	f		amattioni	Nik stimulates nf-kappab activity	SIGNOR-46212	0.36
SRC	protein	P12931	UNIPROT	ARHGDIA	protein	P52565	UNIPROT	down-regulates	phosphorylation	Tyr156	YGPRAEEyEFLTPVE	9606									16943322	t		llicata	We show here that src kinase binds and phosphorylates rhogdi both in vitro and in vivo at tyr156. analysis of rho gtpase-rhogdi complexes using in vitro assays of complexation and in vivo by coimmunoprecipitation analysis indicates that src-mediated phosphorylation of tyr156 causes a dramatic decrease in the ability of rhogdi to form a complex with rhoa, rac1, or cdc42.	SIGNOR-149282	0.41
RPL12	protein	P30050	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262487	0.869
S100A9	protein	P06702	UNIPROT	Macrophage_differentiation	phenotype	SIGNOR-PH99	SIGNOR	down-regulates				10090									18809714	f		miannu	We report here that up-regulation of S100A9 in myeloid precursors in cancer inhibits DC and macrophage differentiation and induces accumulation of MDSCs. This may represent a universal molecular mechanism of tumor-induced abnormalities in myeloid cells in cancer, directly linking inflammation and immune suppression.	SIGNOR-261933	0.7
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									18177723	f	inferred from 70% family members	lperfetto	Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy 	SIGNOR-269987	0.2
STK4	protein	Q13043	UNIPROT	PRDX1	protein	Q06830	UNIPROT	down-regulates activity	phosphorylation	Thr183	GWKPGSDtIKPDVQK	-1									23386615	t		miannu	Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183.	SIGNOR-276485	0.2
PTPRG	protein	P23470	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254705	0.373
PTPN1	protein	P18031	UNIPROT	PITX1	protein	P78337	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Tyr160	LDLCKGGyVPQFSGL	9606									27752061	t		lperfetto	PTP1B dephosphorylates PITX-1 at Y160, 175 and Y179.|Through directly dephosphorylating PITX-1 at Y160, Y175 and Y179, PTP1B promoted proteasomal degradation of PITX-1, thus leaded in downregulating p120RasGAP and CRC cell survival.	SIGNOR-276974	0.362
FBXW11	protein	Q9UKB1	UNIPROT	SKP1	protein	P63208	UNIPROT	up-regulates	binding			9606									10023660	t		gcesareni	The scf is composed of skp1, cdc53/cul1, and a specificity-conferring f-box protein. F-box proteins contain two domains, an f-box motif that binds skp1 and allows assembly into skp1/cdc53 complexes, and a second proteinprotein interaction domain that interacts specifically with one or more target proteins. Cdc53/cul1, in turn, interacts with both the e2 and the skp1/f-box protein complex.	SIGNOR-64505	0.793
ACTN1	protein	P12814	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates quantity by stabilization	binding			9606									27871158	t		lperfetto	Actin exists in polymer where filamin and α-actinin act as cross-linkers with approximately 1:10 ratios 	SIGNOR-261852	0.7
UBE3A	protein	Q05086	UNIPROT	NELFCD	protein	Q8IXH7	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								17131388	t		miannu	In this paper, we identify here trihydrophobin 1 (TH1), an integral subunit of the human negative transcription elongation factor (NELF) complex, as a novel E6-AP interaction protein and a target of E6-AP-mediated degradation. Overexpression of E6-AP results in degradation of TH1 in a dose-dependent manner, whereas knock-down of endogenous E6-AP elevates the TH1 protein level. 	SIGNOR-271404	0.331
P2RY13	protein	Q9BPV8	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257143	0.2
JUN	protein	P05412	UNIPROT	TCF4	protein	P15884	UNIPROT	up-regulates	binding			9606									16007074	t		gcesareni	Phosphorylation-dependent interaction between c-jun and tcf4;c-jun and tcf4 cooperatively activated the c-jun promoter in reporter assays	SIGNOR-138544	0.4
MTOR	protein	P42345	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Thr412	NQVFLGFtYVAPSVL	10090	BTO:0002572								12782654	t		lperfetto	S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation.	SIGNOR-101336	0.96
DYRK1B	protein	Q9Y463	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates activity	phosphorylation	Ser153	SMTDFYHsKRRLIFS	10090									15851482	t		lperfetto	Mirk exerts its anti-apoptotic effects during muscle differentiation at least in part through effects on the cell cycle inhibitor and pro-survival molecule p21cip1. Overexpression and rna interference experiments demonstrated that mirk phosphorylates p21 within its nuclear localization domain at ser-153 causing a portion of the typically nuclear p21 to localize in the cytoplasm.Translocation to the cytoplasm enables p21 to block apoptosis through inhibitory interaction with pro-apoptotic molecules.	SIGNOR-235635	0.261
RPS6KA2	protein	Q15349	UNIPROT	NR4A1	protein	P22736	UNIPROT	down-regulates activity	phosphorylation	Ser351	GRRGRLPsKPKQPPD	10116									11883936	t	From PMID 9395454: We have shown that the in vitro phosphorylation of Ser350 located within the "A-box," a motif necessary for DNA binding by NGFI-B, results in a decrease in the binding of NGFI-B to its response element	lperfetto	Phosphorylation of a residue in the DNA-binding region (Ser-350 of NGFI-B and 354 of Nur77) has been described in detail to have effect on the transcriptional function of the protein [11, 24]. Growth-related kinase pp90rsk, but not ERK1 (pp44mapk), was shown to phosphorylate recombinant Nur77 in vitro in the DNA binding domain, but not the amino-terminus, using an immune complex kinase as- say [11].	SIGNOR-249429	0.376
GARS1	protein	P41250	UNIPROT	tRNA(Gly)	smallmolecule	CHEBI:29176	ChEBI	down-regulates quantity	chemical modification			9606									24898252	t		miannu	Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 	SIGNOR-270477	0.8
FBXO22	protein	Q8NEZ5	UNIPROT	BAG3	protein	O95817	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0002181								34215846	t		miannu	We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCFFBXO22. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377.	SIGNOR-277319	0.2
ROCK1	protein	Q13464	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates activity	phosphorylation	Thr19	KKRPQRAtSNVFAMF	-1									21457715	t		Giulio	Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation.	SIGNOR-260308	0.633
MYLIP	protein	Q8WY64	UNIPROT	VLDLR	protein	P98155	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								20427281	t		miannu	Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation.	SIGNOR-271487	0.686
MAPK1	protein	P28482	UNIPROT	KCND2	protein	Q9NZV8	UNIPROT	up-regulates activity	phosphorylation	Thr602	TAIISIPtPPVTTPE	10116	BTO:0000601								11080179	t		miannu	We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP.	SIGNOR-262935	0.376
ITGB1BP1	protein	O14713	UNIPROT	A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257644	0.757
COLGALT2	protein	Q8IYK4	UNIPROT	COL1A2	protein	P08123	UNIPROT	up-regulates activity	glycosylation			-1									19075007	t			Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261157	0.374
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DQA2	protein	P01906	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-253996	0.274
GATA1	protein	P15976	UNIPROT	RUNX1T1	protein	Q06455	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002731								20487545	f	Regulation	miannu	GATA-1 transcription factor binds and transactivates the ETO proximal promoter in an erythroid/megakaryocytic-specific manner. Thus, trans-acting factors that are essential in erythroid/megakaryocytic differentiation govern ETO expression.	SIGNOR-251929	0.305
Exon junction complex	complex	SIGNOR-C369	SIGNOR	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates activity	relocalization			9606									11532962	t		lperfetto	The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay	SIGNOR-268315	0.8
sodium(1+)	chemical	CHEBI:29101	ChEBI	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								29863287	f		miannu	Axonal excitability is an important determinant for the accuracy, direction, and velocity of neuronal signaling. The mechanisms underlying spike generation in the axonal initial segment and transmitter release from presynaptic terminals have been intensely studied and revealed a role for several specific ionic conductances, including the persistent sodium current (INaP ).	SIGNOR-265182	0.7
VPS39	protein	Q96JC1	UNIPROT	SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	down-regulates quantity	binding			9534									12941698	t		miannu	Overexpression of TLP blocks TGF-β-induced formation of Smad3/4 complexes while it does not alter Smad2/4 complex levels. 	SIGNOR-261378	0.321
SRC	protein	P12931	UNIPROT	HDAC3	protein	O15379	UNIPROT	up-regulates activity	phosphorylation	Tyr328	EELPYSEyFEYFAPD	-1									30317579	t		miannu	C-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form). 	SIGNOR-277485	0.394
NRXN2	protein	Q9P2S2	UNIPROT	NLGN2	protein	Q8NFZ4	UNIPROT	up-regulates activity	binding			9606									22626544	t		miannu	 The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites	SIGNOR-265454	0.824
NRAS	protein	P01111	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates activity	binding			9606									21779497	t		lperfetto	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k	SIGNOR-175222	0.837
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Thr534	SRTPSLPtPPTREPK	9606									17078951	t	The effect has been demonstrated using P10636-8	lperfetto	Here, we found that prephosphorylation by pka promotes gsk-3beta-catalyzed tau phosphorylation at thr181, ser199, ser202, thr205, thr217, thr231, ser396 and ser422	SIGNOR-150364	0.729
EGR2	protein	P11161	UNIPROT	Monocyte_differentiation 	phenotype	SIGNOR-PH101	SIGNOR	up-regulates				9606	BTO:0001412								1864967	f		irozzo	Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression. Taken together, the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes.	SIGNOR-256089	0.7
TFEB	protein	P19484	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	up-regulates quantity by expression	transcriptional regulation												30145926	f		lperfetto	Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 	SIGNOR-276802	0.293
HAUS4	protein	Q9H6D7	UNIPROT	HAUS complex	complex	SIGNOR-C281	SIGNOR	form complex	binding			9606	BTO:0000567								19369198	t		lperfetto	Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)	SIGNOR-262324	0.815
prostaglandin F2alpha	smallmolecule	CHEBI:15553	ChEBI	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606		BTO:0001103							3308494	f		apalma	The results suggest a role for prostanoids in the regulation of both human myoblast proliferation and differentiation	SIGNOR-255362	0.7
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	HDAC4	protein	P56524	UNIPROT	up-regulates activity	phosphorylation	Ser584	EPGQRQPsEQELLFR	-1									30661366	t		miannu	 In vitro kinase assays have established that Ser584 and Ser265/266 are phosphorylated by protein kinase A (PKA). Overexpression of site-specific HDAC4 mutants (S584A, S265/266A) in HEK 293T cells, followed by HDAC activity assays, revealed the mutants to be less active than the wild-type protein. 	SIGNOR-277423	0.2
DISP1	protein	Q96F81	UNIPROT	SHH	protein	Q15465	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								22902404	t		lperfetto	We show that the vertebrate homologue, dispatched-a (dispa) interacts with human sonic hedgehog (hshh) via its cholesterol anchor, and that this interaction is necessary for hshh secretion. binding to dispa is necessary but not sufficient for hshh secretion	SIGNOR-191888	0.718
FBXW11	protein	Q9UKB1	UNIPROT	SUFU	protein	Q9UMX1	UNIPROT	up-regulates	binding			9606	BTO:0001130;BTO:0000848;BTO:0000527								10564661	t		tpavlidou	We found that in vitro-translated 35s- labeled slimb indeed specifically bound to su(fu) in the gst pull-down assay. In our functional gli reporter assay, slimb alone did not alter gli-induced reporter expression;however, when cotransfected with hsu(fu), slimb significantly potentiated the inhibitory effect of su(fu) on gli activity.	SIGNOR-72240	0.297
NTRK2	protein	Q16620	UNIPROT	NTRK2	protein	Q16620	UNIPROT	unknown	phosphorylation	Tyr707	DVYSTDYyRVGGHTM	10090	BTO:0000944								10533983	t		miannu	TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785.	SIGNOR-250207	0.2
RAPGEF6	protein	Q8TEU7	UNIPROT	NRAS	protein	P01111	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183799	0.336
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1654	SPSYSPTsPSYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269369	0.718
CDC25A	protein	P30304	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates activity	dephosphorylation	Tyr15	EKIGEGTyGVVYKGR	9606									10454565	t			Phosphatase activity of Cdc25A is critical for its activating capacity (data not shown). In this context, it should also be mentioned that Cdc25A is able to activate cyclin B-Cdk1 in vitro	SIGNOR-248480	0.837
MTOR	protein	P42345	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Ser394	TRQTPVDsPDDSTLS	10090	BTO:0002572								12782654	t		lperfetto	S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation.	SIGNOR-101328	0.96
warfarin	chemical	CHEBI:10033	ChEBI	VKORC1	protein	Q9BQB6	UNIPROT	down-regulates activity	chemical inhibition			9606									27941861	t		lperfetto	Warfarin and vitamin K compete for binding to Phe55 in human VKOR|Our results challenge the prevailing concept of noncompetitive warfarin inhibition because K vitamers and warfarin share binding sites on VKOR that include Phe55, a key residue binding either the substrate or inhibitor.	SIGNOR-265911	0.8
PTPRG	protein	P23470	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates activity	dephosphorylation	Tyr703	DHAEAALyKNLLHSK	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254709	0.2
HNuRF	complex	SIGNOR-C448	SIGNOR	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606		BTO:0000142							14609955	f		miannu	Human NURF (hNURF) is enriched in brain, and we demonstrate that it regulates human Engrailed, a homeodomain protein that regulates neuronal development in the mid-hindbrain. Furthermore, we show that hNURF potentiates neurite outgrowth in cell culture. Taken together, our data suggess a role for an ISWI complex in neuronal growth.	SIGNOR-268838	0.7
CDK1	protein	P06493	UNIPROT	ESCO1	protein	Q5FWF5	UNIPROT	down-regulates	phosphorylation			9606									23314252	t		gcesareni	We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases , cdc7-dbf4 and the gsk-3 homolog mck1.	SIGNOR-200400	0.487
CTNND1	protein	O60716	UNIPROT	ZBTB33	protein	Q86T24	UNIPROT	down-regulates				9606									23481205	f		gcesareni	Nuclear signaling is affected by the interaction ofp120with kaiso, a transcription factor regulatingwnt-responsive genes. in addition, p120 cytoplasmic localization results in sequestration of kaiso in the cytoplasm and its inactivation	SIGNOR-192369	0.818
PAK1	protein	Q13153	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation	Ser418	TEERLPSsPVYEDAA	9606									20444238	t		gcesareni	Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis.	SIGNOR-165220	0.695
TRIM32	protein	Q13049	UNIPROT	DTNBP1	protein	Q96EV8	UNIPROT	down-regulates quantity	ubiquitination			9534	BTO:0000298								19349376	t		miannu	TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation.	SIGNOR-265658	0.554
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2K	protein	P61086	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271333	0.839
TBK1	protein	Q9UHD2	UNIPROT	IKBKE	protein	Q14164	UNIPROT	up-regulates activity	binding			9606									18353649	t		lperfetto	Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction	SIGNOR-178053	0.628
SMO	protein	Q99835	UNIPROT	GNB1	protein	P62873	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-199174	0.357
PPP5C	protein	P53041	UNIPROT	CILK1	protein	Q9UPZ9	UNIPROT	down-regulates activity	dephosphorylation	Thr157	IRSKPPYtDYVSTRW	9606									16954377	t		llicata	MAK and MRK require dual phosphorylation in a TDY motif catalyzed by an unidentified human threonine kinase and tyrosine autophosphorylation.| Protein phosphatase 5 (PP5) interacts with MRK in a complex and dephosphorylates MRK at T157 in vitro and in situ. 	SIGNOR-248541	0.2
EEF1A1P5	protein	Q5VTE0	UNIPROT	Cys-tRNA(Cys)	smallmolecule	CHEBI:29152	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269548	0.8
CREM	protein	Q03060	UNIPROT	IL2	protein	P60568	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000782								12626549	t		Luana	In this study we show that CREM is transcriptionally induced in T cells following stimulation through CD3 and CD28, binds to the IL-2 promoter in vivo, and suppresses IL-2 production.	SIGNOR-261576	0.495
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	CDC25B	protein	P30305	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								21807946	t		miannu	 Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104).	SIGNOR-276353	0.386
ABL1	protein	P00519	UNIPROT	LGALS3	protein	P17931	UNIPROT	unknown	phosphorylation	Tyr107	AYPATGPyGAPAGPL	9606									20600357	t		llicata	In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility.	SIGNOR-166493	0.364
KNSTRN	protein	Q9Y448	UNIPROT	KIF2B	protein	Q8N4N8	UNIPROT	down-regulates activity	relocalization			9606	BTO:0001938								22535524	t		lperfetto	The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation.	SIGNOR-252053	0.418
PIM2	protein	Q9P1W9	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation			-1									31730483	t		miannu	In addition to PIM1, also PIM2 and PIM3 were able to phosphorylate WT, but not MM NFATC1 in vitro (Fig. ​(Fig.22c).	SIGNOR-276772	0.265
LYN	protein	P07948	UNIPROT	FCGR2B	protein	P31994	UNIPROT	up-regulates activity	phosphorylation	Tyr292	GAENTITySLLMHPD	-1									8756631	t		lperfetto	Therefore, we conclude that FcgammaRIIb1 phosphorylation upon BCR-FcgammaR coligation is most likely due to BCR-associated Lyn	SIGNOR-249380	0.44
GF	proteinfamily	SIGNOR-PF39	SIGNOR	RTKs	proteinfamily	SIGNOR-PF38	SIGNOR	up-regulates activity	binding			9606									17306385	t		miannu	Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate.	SIGNOR-256163	0.2
PRKDC	protein	P78527	UNIPROT	DNA-PK	complex	SIGNOR-C107	SIGNOR	form complex	binding			9606									17308091	t		miannu	Complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established	SIGNOR-226026	0.933
JAK2	protein	O60674	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates activity	phosphorylation	Tyr340	RGQRDSSyYWEIEAS	10090	BTO:0001482								8876196	t			 JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process.	SIGNOR-251361	0.6
TIMM50	protein	Q3ZCQ8	UNIPROT	TIM23 complex	complex	SIGNOR-C423	SIGNOR	form complex	binding												32074073	t		lperfetto	The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE.	SIGNOR-267696	0.641
CDK5	protein	Q00535	UNIPROT	ERBB3	protein	P21860	UNIPROT	up-regulates activity	phosphorylation	Ser1123	RSRSRSRsPRPRGDS	10116	BTO:0004102								12824184	t		llicata	We demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. 	SIGNOR-250663	0.346
MRGPRX2	protein	Q96LB1	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257327	0.2
SNARE_complex 	complex	SIGNOR-C346	SIGNOR	Synaptic_vesicle_exocytosis	phenotype	SIGNOR-PH160	SIGNOR	up-regulates				9606	BTO:0000938								30267828	f		miannu	The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells.	SIGNOR-265065	0.7
MAPK3	protein	P27361	UNIPROT	BRD4	protein	O60885	UNIPROT	down-regulates activity				9606									32482868	t		lperfetto	The MYC stabilizing kinase, ERK1, regulates MYC levels directly and indirectly by inhibiting BRD4 kinase activity.	SIGNOR-262048	0.317
PPP3CA	protein	Q08209	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									18177723	f		lperfetto	Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy 	SIGNOR-251733	0.253
CCKAR	protein	P32238	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257410	0.462
PAK2	protein	Q13177	UNIPROT	CASP7	protein	P55210	UNIPROT	down-regulates	phosphorylation	Ser30	DAKPDRSsFVPSLFS	9606	BTO:0000150								21555521	t		gcesareni	Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis.	SIGNOR-173659	0.357
PAK5	protein	Q9P286	UNIPROT	PAK5	protein	Q9P286	UNIPROT	up-regulates activity	phosphorylation	His19	SGPSNFEhRVHTGFD	-1									12860998	t		miannu	Active form of Cdc42, but not Rac1 and Rho, protein was able to activate the purified GST-Pak5 autophosphorylation and kinase activity. Mutations of Pak5, which disrupted the interaction of Cdc42 and Pak5, also abolished the induction of autophosphorylation.  The H19L/H22L mutant of Pak5 was insensitive to the Cdc42-induced autophosphorylation. 	SIGNOR-250248	0.2
SHC1	protein	P29353	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			10090	BTO:0005065								17673906	t		lperfetto	TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases.	SIGNOR-236366	0.965
MIB1	protein	Q86YT6	UNIPROT	RYK	protein	P34925	UNIPROT	down-regulates	ubiquitination			9606									21875946	t		gcesareni	We discovered that ryk both physically and functionally interacts with the e3 ubiquitin ligase mind bomb 1 (mib1).We Found that overexpressed ryk and mib1 colocalized and that the overexpression of mib1 leads to the loss of surface ryk expression. In addition, biochemical studies revealed that mib1 promotes the ubiquitination and degradation of ryk. Endogenous ryk and mib1 were required for the wnt-dependent activation of wnt/ctnnb1 signaling	SIGNOR-176282	0.333
LPAR	proteinfamily	SIGNOR-PF2	SIGNOR	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-269967	0.2
PTK2	protein	Q05397	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr576	RYMEDSTyYKASKGK	9606		BTO:0000671							15694384	t		llicata	Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925.	SIGNOR-133841	0.2
GSK3B	protein	P49841	UNIPROT	DPYSL2	protein	Q16555	UNIPROT	down-regulates activity	phosphorylation	Thr509	PVCEVSVtPKTVTPA	9606							phosphorylation:Ser522	PASSAKTsPAKQQAP	25040932	t		lperfetto	Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition	SIGNOR-264839	0.713
RUNX2	protein	Q13950	UNIPROT	SNAI2	protein	O43623	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22641097	f		miannu	 Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells.	SIGNOR-255080	0.406
SL1 complex	complex	SIGNOR-C464	SIGNOR	UBTF	protein	P17480	UNIPROT	up-regulates activity	binding			9606									15970593	t		lperfetto	Therefore, we propose that SL1 directs PIC formation, functioning in core promoter binding, RNA polymerase I recruitment, and UBF stabilization and that SL1-promoter complex formation is a necessary prerequisite to the assembly of functional and stable PICs that include the UBF activator in mammalian cells. 	SIGNOR-269567	0.652
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation			9606									21798082	t		lperfetto	Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b).	SIGNOR-252820	0.908
LSM-1231	chemical	CHEBI:91471	ChEBI	NTRK2	protein	Q16620	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259759	0.8
SPTB	protein	P11277	UNIPROT	Erythrocytic spectrin	complex	SIGNOR-C384	SIGNOR	form complex	binding			9606	BTO:0000424								24302288	t		lperfetto	Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell	SIGNOR-266024	0.729
NEDD1	protein	Q8NHV4	UNIPROT	g-TuRC complex	complex	SIGNOR-C282	SIGNOR	up-regulates activity	binding			9606									19029337	t		miannu	It has been reported that NEDD1 directly interacts with and recruits the gamma-tubulin ring complex to centrosomes and to spindle MTs to promote MT nucleation and spindle assembly	SIGNOR-261422	0.757
ARNT	protein	P27540	UNIPROT	CA9	protein	Q16790	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22387692	f	 	lperfetto	The miR-24-dependent down-regulation of ARNT decreased the expression of its downstream genes such as CYP1A1 and carbonic anhydrase IX. 	SIGNOR-253706	0.504
EIF2AK1	protein	Q9BQI3	UNIPROT	EIF2S1	protein	P05198	UNIPROT	up-regulates	phosphorylation	Ser49	IEGMILLsELSRRRI	9606									3352609	t		lperfetto	The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases present in the reticulocyte lysate. These findings support the hypothesis that the serine 48 residue is required for high-affinity interaction between eif2 alpha(p) and eif2b.	SIGNOR-24539	0.886
SLIT2	protein	O94813	UNIPROT	ROBO3	protein	Q96MS0	UNIPROT	up-regulates activity	binding			-1									16226035	t		miannu	This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation.	SIGNOR-268381	0.646
PRKCA	protein	P17252	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates activity	phosphorylation	Thr115	ADRRKAAtMRERRRL	9534									1335366	t		lperfetto	FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains.	SIGNOR-248845	0.37
NOTCH1	protein	P46531	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								16990763	f		lperfetto	Other notch target genes identi?ed In the thymoma cell line were dtx1 (gene for deltex1), i?-202, i?-204, i?-D3, adam19 (meltrinb).24 a number of other genes have been reported as being notch targets, including notch1 itself,28 nrarp in xenopus embryos,29 bcl2 in thymoma cells,30 ccnd1 (gene for cyclin d1) in a kidney cell line,31 dkn1a (gene for cyclindependent kinase inhibitor 1a (p21, cip1)) in keratinocytes32 and tcf3 (gene for e2a).	SIGNOR-149777	0.2
MRPL19	protein	P49406	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262375	0.707
CDK2	protein	P24941	UNIPROT	NPAT	protein	Q14207	UNIPROT	up-regulates	phosphorylation	Thr1270	SDLPVPRtPGSGAGE	9606									10995387	t		llicata	Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter.	SIGNOR-82137	0.458
NUMA1	protein	Q14980	UNIPROT	TUBA4A	protein	P68366	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116788	0.494
SMAD2	protein	Q15796	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	binding			9606									9670020	t		lperfetto	Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGF-beta type I receptor, and this oligomerization does not require Smad4	SIGNOR-232149	0.2
VAPB-PTPIP51 complex	complex	SIGNOR-C275	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				10116		BTO:0000142							30841933	f		lperfetto	Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction.	SIGNOR-262120	0.7
FADD	protein	Q13158	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	binding			9606									22890322	t		lperfetto	Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8	SIGNOR-191781	0.784
EDNRA	protein	P25101	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257253	0.275
D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	sedoheptulose 7-phosphate	smallmolecule	CHEBI:15721	ChEBI	up-regulates quantity	precursor of			9606									24929114	t		miannu	Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates.	SIGNOR-268140	0.8
SP1	protein	P08047	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000944								23936544	t		lperfetto	 MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-β mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-β production	SIGNOR-251740	0.301
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257929	0.8
MAP2K7	protein	O14733	UNIPROT	MAPK13	protein	O15264	UNIPROT	up-regulates activity	phosphorylation	Thr180	RHADAEMtGYVVTRW	9606	BTO:0000007								10066767	t	done	miannu	 p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.	SIGNOR-273954	0.412
ZBTB16	protein	Q05516	UNIPROT	RSAD2	protein	Q8WXG1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003846								19523849	t		lperfetto	Promoter regions from the PLZF-regulated transcripts Rsad2 and Ifit2 were fused to luciferase and activity was measured after IFN treatment. Overexpression of PLZF in RCC1 or ACHN cells produced a dose-dependent induction of the reporter promoters. 	SIGNOR-261023	0.2
GMIP	protein	Q9P107	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260506	0.42
PPP1CA	protein	P62136	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	binding			9606									14592972	t		gcesareni	Pp1 recognizes cdc25 directly by interacting with a pp1-binding motif in the cdc25 n-terminus.	SIGNOR-118917	0.483
UNC80	protein	Q8N2C7	UNIPROT	NALCN	protein	Q8IZF0	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								19535918	t		miannu	UNC80 is a protein that is associated with the NALCN Na(+) leak cation channel, and is required for the activation of this channel by the neuropeptide substance P through GPCRs in a G-protein-independent fashion. Here, we show that UNC80 binds Src kinases and recruits Src into the channel complex. 	SIGNOR-265180	0.803
NEK9	protein	Q8TD19	UNIPROT	NEDD1	protein	Q8NHV4	UNIPROT	up-regulates activity	phosphorylation	Ser377	EKAGLPRsINTDTLS	-1									22818914	t		miannu	Nek9 phosphorylates NEDD1 on Ser377 driving its recruitment and thereby that of γ-tubulin to the centrosome in mitotic cells. 	SIGNOR-263016	0.439
CDK1	protein	P06493	UNIPROT	RPA2	protein	P15927	UNIPROT	up-regulates activity	phosphorylation	Ser23	GAGGYTQsPGGFGSP	9606									1318195	t		llicata	Cdc2 family kinases phosphorylate a human cell dna replication factor, rpa, and activate dna replication. therefore, the serines on rpa p34 that were necessary for phosphorylation by cdc2 kinase were also necessary for phosphorylation in the cell	SIGNOR-16971	0.52
DPF2	protein	Q92785	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								20460684	t		miannu	REQ is required for the oncogenic activity induced by RelB/p52. . Through in vitro binding experiments, REQ was found to bind to several SWI/SNF complex subunits and also to the p52 NF-κB subunit through its nuclear localization signal containing the N-terminal region. In this study, we present evidence that REQ is a specific adaptor protein that links RelB/p52 with Brm-type SWI/SNF complexes and thereby plays pivotal roles at the most downstream stages of the noncanonical NF-κB pathway. We further show that REQ is required for oncogenesis in several human tumor cell lines in which the noncanonical NF-κB pathway is aberrantly regulated.REQ and Brm specifically promote RelB/p52-dependent transcriptional activity.	SIGNOR-261964	0.307
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser23	ARKRHAPsPEPAVQG	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276088	0.292
PTPN11	protein	Q06124	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Tyr1007	VLPQDKEyYKVKEPG	9606									14522994	t			We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association	SIGNOR-248665	0.786
BDKRB1	protein	P46663	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257411	0.424
PRTN3	protein	P24158	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates activity	cleavage	Ala92	PAFISEDaSGYLTSS	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263576	0.43
ATM	protein	Q13315	UNIPROT	AVEN	protein	Q9NQS1	UNIPROT	up-regulates activity	phosphorylation	Ser308	NILPDQTsQDLKSKE	-1									18571408	t		miannu	Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. We found that mutating S135 and S308 sites to Alanine largely dampened Aven’s phosphorylation by ATM (though some phosphorylation remained, due to either a contaminating kinase or an unidentified ATM phosphorylation site). 	SIGNOR-262637	0.392
PPP3CB	protein	P16298	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									18177723	f		lperfetto	Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy 	SIGNOR-251734	0.2
CHEK1	protein	O14757	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser124	PALKRSHsDSLDHDI	9606									20068082	t		gcesareni	The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216).	SIGNOR-163134	0.852
HHAT	protein	Q5VTY9	UNIPROT	SHH	protein	Q15465	UNIPROT	up-regulates	palmitoylation			9606									15075292	t		gcesareni	Our molecular analysis of knockout mice deficient in skn, the murine homolog of the drosophila ski gene, which catalyzes hh palmitoylation, and gene-targeted mice producting a non palmitoylated form of shh indicates that hh palmitoylation is essential for its activity as well as the generation of a protein gradient in the developing embryos	SIGNOR-124118	0.67
ATM	protein	Q13315	UNIPROT	AATF	protein	Q9NY61	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser189	EGDDAEDsQGESEED	9606	BTO:0001109								17157788	t		lperfetto	The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. |DNA damage stabilizes Che-1 protein|In addition, substitution of Che-1 Ser187 with an alanine (Che-1S187A) prevented Che-1 phosphorylation by ATM (Figure 2F), supporting this residue as an ATM-target site.	SIGNOR-264415	0.362
PRKACA	protein	P17612	UNIPROT	TAL1	protein	P17542	UNIPROT	down-regulates	phosphorylation	Ser122	DGRMVQLsPPALAAP	9606									22310283	t		gcesareni	Thus, our data revealed a novel interplay between pka phosphorylation and tal1-mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis.	SIGNOR-195987	0.2
SPOP	protein	O43791	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								25278611	t		miannu	Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. 	SIGNOR-272827	0.493
PATJ	protein	Q8NI35	UNIPROT	AMOT/MPP5/INADL/LIN7C	complex	SIGNOR-C27	SIGNOR	form complex	binding			9606									24366813	t		lperfetto	To gain a more detailed view on the organization of this cell polarity network linked to yap1 we included several proteins of the cell junction complex (amot, mpp5, lin7a),	SIGNOR-203488	0.2
PAF1C	complex	SIGNOR-C471	SIGNOR	TCEA1	protein	P23193	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								20178742	t		miannu	HPAF1C Independently and Cooperatively (with SII) Stimulates Transcription Elongation. Direct Interactions of hPAF1C with Pol II and SII Are Required for Its Intrinsic and Synergistic Effects on Chromatin Transcription.	SIGNOR-269838	0.619
HDLBP	protein	Q00341	UNIPROT	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606									33941620	f		miannu	Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer.	SIGNOR-266694	0.7
bafilomycin A1	chemical	CHEBI:22689	ChEBI	ATP6V1A	protein	P38606	UNIPROT	down-regulates activity	chemical inhibition			9606									9572882	t		Simone Vumbaca	The macrolide antibiotic bafilomycin A1 is a very potent and specific inhibitor of V-ATPases.	SIGNOR-261084	0.8
PRKACA	protein	P17612	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	phosphorylation	Ser675	QDYKKRLsVELTSSL	9606	BTO:0000007								16476742	t		lperfetto	In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin	SIGNOR-144482	0.459
GLI1	protein	P08151	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23074268	f		gcesareni	Canonical hh signaling plays an essential role in cell proliferation throught introduction of the genes encoding cyclin d1 and n-myc	SIGNOR-199126	0.563
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser555	RALSNSVsNMGLSES	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-249682	0.397
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	ITGB6	protein	P18564	UNIPROT	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259007	0.2
FLT3	protein	P36888	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression				9606									25280219	f			MYC expression was relatively higher (P <0Æ1) in theFLT3/ITD-positive AML samples compared to non-mutant FLT3 AML.	SIGNOR-261556	0.372
ERBB2	protein	P04626	UNIPROT	DOCK7	protein	Q96N67	UNIPROT	up-regulates	phosphorylation	Tyr1257	METVPQLyDFTETHN	9606									18426980	t		llicata	We show that the nrg1 receptor erbb2 directly binds and activates dock7 by phosphorylating tyr-1118. thus, dock7 functions as an intracellular substrate for erbb2 to promote schwann cell migration. This provides an unanticipated mechanism through which ligand-dependent tyrosine phosphorylation can trigger the activation of rho gtpase-gefs of the dock180 family.	SIGNOR-178348	0.511
HSD17B1	protein	P14061	UNIPROT	17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	up-regulates quantity	chemical modification			-1									8994190	t		Luana	Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues. 	SIGNOR-269760	0.8
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	GSN	protein	P06396	UNIPROT	down-regulates activity	cleavage	Asp403	WRDPDQTdGLGLSYL	9606									9671712	t		miannu	We showed that human gelsolin was cleaved during Fas-mediated apoptosis in vivo and that the caspase-3 cleavage site of human gelsolin was at D352 of DQTD352G. gelsolin seems to have dual functions, i.e., it both prevents and, once cleaved, induces cell death.	SIGNOR-256433	0.624
DDC	protein	P20711	UNIPROT	5-hydroxy-L-tryptophan	smallmolecule	CHEBI:17780	ChEBI	down-regulates quantity	chemical modification			9606									31024440	t	brain	lperfetto	In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT	SIGNOR-264013	0.8
SP1	protein	P08047	UNIPROT	HGF	protein	P14210	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									9223667	t		lperfetto	Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region.	SIGNOR-251739	0.2
CDK1	protein	P06493	UNIPROT	HASPIN	protein	Q8TF76	UNIPROT	up-regulates activity	phosphorylation	Thr128	RPPQKCStPCGPLRL	9606	BTO:0000567								24413556	t		miannu	Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis.	SIGNOR-275419	0.2
CEBPD	protein	P49716	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000011								10649448	f		gcesareni	We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPdelta; C/EBPdelta then binds to PPARgamma2 promoter and transactivates PPARgamma2 gene expression. 	SIGNOR-253062	0.579
F2RL1	protein	P55085	UNIPROT	SERPINB2	protein	P05120	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	 PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 	SIGNOR-254856	0.2
3-iodo-L-tyrosine	smallmolecule	CHEBI:27847	ChEBI	iodide	smallmolecule	CHEBI:16382	ChEBI	up-regulates quantity	precursor of			9606									28153798	t		scontino	MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide.	SIGNOR-268094	0.8
ARHGAP28	protein	Q9P2N2	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260483	0.482
MAML1	protein	Q92585	UNIPROT	CDK8	protein	P49336	UNIPROT	up-regulates	binding			9606									15546612	t		gcesareni	Mastermind recruits cycc:cdk8 to phosphorylate the notch icd and coordinate activation with turnover	SIGNOR-130715	0.58
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1626	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-119996	0.781
CSNK2A1	protein	P68400	UNIPROT	ATF1	protein	P18846	UNIPROT	down-regulates	phosphorylation	Ser36	AQQVSSLsESEESQD	9606									20730097	t		lperfetto	Although the functional impact of ck-mediated atf1 phosphorylation is still unclear, we found that mutation of ser-36 and ser-41 increased cbp kix domain binding by up to four fold (fig. 2g). This result is consistent with the negative impact of ck-mediated phosphorylation on cbp binding affinity of creb that we previously reported	SIGNOR-167544	0.3
PPP3CA	protein	Q08209	UNIPROT	FLNA	protein	P21333	UNIPROT	down-regulates	dephosphorylation	Ser2152	TRRRRAPsVANVGSH	9606									16442073	t		gcesareni	We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells	SIGNOR-143979	0.262
MYC	protein	P01106	UNIPROT	SURF1	protein	Q15526	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10858544	f		miannu	 We show that although the Surf-1/Surf-2 promoter does not contain Myc binding sites (E-boxes), Myc over-expression, or the activation of a Myc-oestrogen receptor fusion protein, activates transcription in the Surf-1 direction and that this response to Myc requires a functional YY1 binding site. Our data suggest that the MAP kinase cascade is required for the stimulation of Surf-1 promoter activity and that the Myc-YY1 interaction mediates this response.	SIGNOR-254615	0.2
Caspase 6 complex	complex	SIGNOR-C228	SIGNOR	LMNA	protein	P02545	UNIPROT	down-regulates	cleavage			9606									11058599	t		amattioni	Lamin a breakdown is largely mediated by caspase-6 during the execution phase of apoptosis.	SIGNOR-256457	0.648
BAZ1B	protein	Q9UIG0	UNIPROT	B-WICH complex	complex	SIGNOR-C447	SIGNOR	form complex	binding			9606									21559432	t		miannu	The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 	SIGNOR-268826	0.553
SOD1	protein	P00441	UNIPROT	hydrogen peroxide	smallmolecule	CHEBI:16240	ChEBI	up-regulates quantity	chemical modification			9606									29301787	t		lperfetto	Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD).	SIGNOR-272287	0.8
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates	phosphorylation	Ser582	LNKLQQHsDKIIRLY	9606									18680479	t		miannu	We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / autophosphorylation outside the activation segment was also important for activity in vitro, since s582a/s582d and y811f mutants exhibited decreased activity	SIGNOR-179896	0.2
SMAD7	protein	O15105	UNIPROT	SMURF1	protein	Q9HCE7	UNIPROT	up-regulates activity	relocalization			9606									21791611	t		lperfetto	One of the major mechanisms underlying the inhibitory effect of Smad7 on TGF-_ signaling operates through accelerating T_RI turnover by recruiting ubiquitin E3 ligases such as Smurf1 and Smurf2	SIGNOR-175269	0.877
PRKD1	protein	Q15139	UNIPROT	FAM83G	protein	A6ND36	UNIPROT	up-regulates activity	phosphorylation	Ser356	YALVKAKsVDEIAKI	10029									32570757	t		lperfetto	Taken together, these data demonstrate that FAM83G S356 phosphorylation modulates HSP27 phosphorylation and apoptosis regulation and that HSP27 is a counterpart of FAM83G.|an active form of PKD1/PKCm could phosphorylate the FAM83G peptide, including the S356 portion.|We also demonstrated that the phosphorylation of the FAM83G S356 residue was required for the reduction of the live cell number, as the CHO cells were unaffected upon the overexpression of a FAM83G S356A mutant resistant to S356 phosphorylation. 	SIGNOR-264764	0.2
AURKB	protein	Q96GD4	UNIPROT	NSUN2	protein	Q08J23	UNIPROT	down-regulates	phosphorylation	Ser139	SRKILRKsPHLEKFH	9606									17215513	t		lperfetto	Aurora-b phosphorylated nsun2 at ser139. Aurora-b-phosphorylation and the phosphorylation-mimic mutation (s139e) suppressed methyltransferase activities of nsun2.	SIGNOR-152001	0.709
HNF1A	protein	P20823	UNIPROT	AFP	protein	P02771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								7549116	f		miannu	 HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter in the HepG2 cells. 	SIGNOR-254637	0.336
EGR1	protein	P18146	UNIPROT	HPSE	protein	Q9Y251	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001671;BTO:0001345								16007175	t	 	 	Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer.	SIGNOR-254267	0.379
GNA11	protein	P29992	UNIPROT	PLCB1	protein	Q9NQ66	UNIPROT	up-regulates activity	binding			9606									27515033	t		scontino	TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C.	SIGNOR-267203	0.607
GATA3	protein	P23771	UNIPROT	FOXC2	protein	Q99958	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22120723	f	 	miannu	 We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner.	SIGNOR-254089	0.337
EEF1B complex	complex	SIGNOR-C460	SIGNOR	EEF1A1P5	protein	Q5VTE0	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. 	SIGNOR-269389	0.2
5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide	chemical	CID:73755145	PUBCHEM	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258289	0.8
IL4R	protein	P24394	UNIPROT	IL2RG	protein	P31785	UNIPROT	up-regulates	binding			9606									8266078	t		gcesareni	Il-2r gamma was demonstrated to be a component of the il-4 receptor on the basis of chemical cross-linking data, the ability of il-2r gamma to augment il-4 binding affinity, and the requirement for il-2r gamma in il-4-mediated phosphorylation of insulin receptor substrate-1.	SIGNOR-37362	0.823
MAP3K2	protein	Q9Y2U5	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates	phosphorylation			9606									11343802	t		lperfetto	Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation	SIGNOR-244888	0.424
GSK1059615	chemical	CHEBI:71955	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192771	0.8
ATP	smallmolecule	CHEBI:15422	ChEBI	PRKAG1	protein	P54619	UNIPROT	down-regulates	chemical inhibition			9606			SIGNOR-C15						21680840	t		gcesareni	AMPK is an ___ heterotrimer activated by decreasing concentrations of adenosine triphosphate (ATP) and increasing AMP concentrations.	SIGNOR-228607	0.8
(-)-selegiline	chemical	CHEBI:9086	ChEBI	MAOB	protein	P27338	UNIPROT	down-regulates activity	chemical inhibition			-1									21377879	t		Luana	All the compounds were found as extremely potent and selective towards MAO-B, (Table 2) with at least 100 times more potent than the positive control selegiline. 	SIGNOR-258136	0.8
TRAF6	protein	Q9Y4K3	UNIPROT	TAB2	protein	Q9NYJ8	UNIPROT	up-regulates activity	binding			9606									25290089	t		lperfetto	The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.	SIGNOR-205458	0.931
CDH1	protein	P12830	UNIPROT	AE/b7 integrin	complex	SIGNOR-C186	SIGNOR	up-regulates	binding			9606	BTO:0000782								7969453	t		gcesareni	Here we show that heterotypic adhesive interactions between epithelial cells and intraepithelial lymphocytes in vitro are mediated by e-cadherin and the alpha e beta 7 integrin.	SIGNOR-35210	0.638
PRKD1	protein	Q15139	UNIPROT	SSH1	protein	Q8WYL5	UNIPROT	down-regulates activity	phosphorylation	Ser978	SPLKRSHsLAKLGSL										21832093	t		lperfetto	Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase	SIGNOR-275936	0.494
PPM1B	protein	O75688	UNIPROT	MPRIP	protein	Q6WCQ1	UNIPROT	down-regulates activity	dephosphorylation			9606									25751141	t		lperfetto	Ppm1b prevents Rip3 auto-activation in resting cells.|Together, these data demonstrate that Ppm1b dephosphorylates Rip3 and thus negatively regulates TNF induced necroptosis in L929 cells.	SIGNOR-277019	0.2
CSNK1E	protein	P49674	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates activity	phosphorylation	Ser844	GSGSEAAsLSSLNSS										17353278	t		lperfetto	Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846	SIGNOR-274047	0.262
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	TFCP2	protein	Q12800	UNIPROT	down-regulates	phosphorylation			9606									19237534	t	inferred from 70% family members	lperfetto	We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309.	SIGNOR-270201	0.2
BDKRB1	protein	P46663	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257149	0.409
LEPR	protein	P48357	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	binding			9606	BTO:0001282								18718905	t		miannu	 Janus kinase 2 (JAK2) is associated with LEPRb and autophosphorylates in response to leptin. JAK2 also phosphorylates LEPRb, STAT3, and multiple other downstream molecules. 	SIGNOR-263491	0.766
TEAD1	protein	P28347	UNIPROT	FOXM1	protein	Q08050	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22286761	f		gcesareni	Yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor.	SIGNOR-194371	0.276
CAMKK1	protein	Q8N5S9	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Thr308	KDGATMKtFCGTPEY										10833263	t		llicata	Protein kinase B (PKB) was recently reported to be activated on the phosphorylation of Thr(308) by Ca(2+)/calmodulin-dependent protein kinase kinase alpha (CaM-kinase kinase alpha), suggesting that PKB was regulated through not only the phosphoinositide 3-kinase pathway but also the Ca(2+)/calmodulin protein kinase pathway.	SIGNOR-250714	0.388
AMPK	complex	SIGNOR-C15	SIGNOR	GLI1	protein	P08151	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr1074	QRGSSGHtPPPSGPP										26190112	t			Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency.	SIGNOR-253543	0.3
GNB1	protein	P62873	UNIPROT	PLCB1	protein	Q9NQ66	UNIPROT	down-regulates	binding			9606									8870665	t		gcesareni	These results indicate that g-protein beta gamma subunits constitute a mechanism by which g-protein mediate a rapid and transient plc- beta 1.	SIGNOR-44369	0.461
L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	up-regulates quantity	precursor of			9606									31422819	t		miannu	Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate.	SIGNOR-266921	0.8
SRC	protein	P12931	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Tyr326	EVLEDNDyGRAVDWW	9534	BTO:0004055								11445557	t		lperfetto	Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity.	SIGNOR-252623	0.663
NTRK2	protein	Q16620	UNIPROT	KCNA3	protein	P22001	UNIPROT	down-regulates	phosphorylation	Tyr163	FDAILYYyQSGGRIR	9606	BTO:0000938	BTO:0000671							19166614	t		gcesareni	Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein.	SIGNOR-183523	0.387
ANKRD11	protein	Q6UB99	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	binding			9606	BTO:0000093								18840648	t		miannu	Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53.	SIGNOR-266734	0.314
PMCH	protein	P20382	UNIPROT	MCHR2	protein	Q969V1	UNIPROT	up-regulates	binding			9606		BTO:0000142							10471841	t		gcesareni	Upon several purification steps, followed by mass spectrometric analysis and peptide sequencing, the ligand was identified as melanin concentrating hormone (mch), revealing that the orphan slc-1 is the mch receptor.	SIGNOR-70520	0.596
PTPRJ	protein	Q12913	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates activity	dephosphorylation	Tyr204	HTGFLTEyVATRWYR	-1									19494114	t			Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases|Pulldown and in vitro dephosphorylation assays confirmed our prediction and demonstrated an overall specificity of DEP-1 in targeting the phosphorylated tyrosine 204 of ERK1/2.	SIGNOR-248707	0.47
CSAD	protein	Q9Y600	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	down-regulates quantity	chemical modification			9606									22718265	t		miannu	Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate α-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of α-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce γ-aminobutyric acid (GABA), β-alanine and hypotaurine, respectively; these amine products play important role in living organisms.	SIGNOR-267548	0.8
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	CITED2	protein	Q99967	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								18158893	f		gcesareni	Foxo3a induces expression of cited2	SIGNOR-252933	0.2
CSF1R	protein	P07333	UNIPROT	SOCS1	protein	O15524	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24890514	f		miannu	CSF-1R also induces the expression/activation of several other regulators of multipotent progenitor proliferation/differentiation (Fig. 4A). These include […] the adaptor proteins suppressor of cytokine signaling 1 (Socs1)	SIGNOR-255574	0.503
SREBF1	protein	P36956	UNIPROT	LRP1	protein	Q07954	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20980003	f		miannu	 In the present study we report that specific silencing of either SREBP-1 or SREBP-2 enhanced LRP1 whereas overexpression of the active SREBP isoforms decreased LRP1 expression.	SIGNOR-254462	0.281
MAPK3	protein	P27361	UNIPROT	PLCB1	protein	Q9NQ66	UNIPROT	up-regulates activity	phosphorylation	Ser982	KKKSEPSsPDHGSST	-1									11287604	t		lperfetto	Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982	SIGNOR-106565	0.422
silodosin	chemical	CHEBI:135929	ChEBI	ADRA1B	protein	P35368	UNIPROT	down-regulates activity	chemical inhibition			10029									7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258449	0.8
PPP3CB	protein	P16298	UNIPROT	TFEB	protein	P19484	UNIPROT	up-regulates activity	dephosphorylation	Ser142	AGNSAPNsPMAMLHI	9606	BTO:0000007								26000950	t			Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation.	SIGNOR-255307	0.384
BBOX1	protein	O75936	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	down-regulates quantity	chemical modification			9606									11802770	t		miannu	In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine.	SIGNOR-269698	0.8
GCK	protein	P35557	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor.	SIGNOR-266448	0.8
CDK1	protein	P06493	UNIPROT	RRM2	protein	P31350	UNIPROT	down-regulates	phosphorylation	Thr33	SLVDKENtPPALSGT	9606									22632967	t		gcesareni	We found that, during g2, following cdk-mediated phosphorylation of thr33, rrm2 is degraded via scf(cyclin f) to maintain balanced dntp pools and genome stability.	SIGNOR-197630	0.518
CDK2	protein	P24941	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1497	EPGVERSsPSKCPSL	9606	BTO:0000551								19683496	t		gcesareni	However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci.	SIGNOR-187607	0.664
RAB1A	protein	P62820	UNIPROT	C9orf72	protein	Q96LT7	UNIPROT	up-regulates activity	binding			9606									27334615	t		lperfetto	Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology.	SIGNOR-261282	0.488
EGR1	protein	P18146	UNIPROT	COL4A2	protein	P08572	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21931594	f	Regulation	miannu	Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1)	SIGNOR-251918	0.2
GSK3B	protein	P49841	UNIPROT	MACF1	protein	Q9UPN3	UNIPROT	down-regulates activity	phosphorylation	Ser7330	RASSRRGsDASDFDL	9606	BTO:0004905								21295697	t		lperfetto	We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules.	SIGNOR-264435	0.446
TFIIH	complex	SIGNOR-C457	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606									10949034	t		lperfetto	Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7.	SIGNOR-269356	0.306
HNF4A	protein	P41235	UNIPROT	NPC1L1	protein	Q9UHC9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21123766	f		miannu	Our results showed a positive correlation between changes in NPC1L1 and changes in both SREBP-2 and HNF-4α mRNA expression, a finding that supports the notion that these transcription factors stimulate intestinal NPC1L1 expression. 	SIGNOR-254460	0.263
OSU-03012	chemical	CHEBI:131196	ChEBI	PDPK1	protein	O15530	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-197715	0.8
GRPR	protein	P30550	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257046	0.271
ESR2	protein	Q92731	UNIPROT	CRH	protein	P06850	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000614							8408641	t		lperfetto	Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.|Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro. 	SIGNOR-268722	0.396
TRIM27	protein	P14373	UNIPROT	WASHC1	protein	A8K0Z3	UNIPROT	up-regulates activity	ubiquitination	Lys220	DAPLSISkREQLEQQ	9606									23452853	t		miannu	Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport.	SIGNOR-253514	0.2
CDC14B	protein	O60729	UNIPROT	CDCA3	protein	Q99618	UNIPROT	up-regulates	dephosphorylation			9606									18662541	t		gcesareni	The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1	SIGNOR-179664	0.286
DLGAP1	protein	O14490	UNIPROT	SHANK3	protein	Q9BYB0	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264588	0.2
VAV1	protein	P15498	UNIPROT	SYK	protein	P43405	UNIPROT	up-regulates	binding			9606									11331248	t		lperfetto	Vav interacts with the tyrosine kinase syk	SIGNOR-107049	0.918
MAPK3	protein	P27361	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Thr453	SGPIIIRtPTVGPNG	9606	BTO:0000552								14744793	t		gcesareni	We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription.	SIGNOR-248062	0.638
TFEB	protein	P19484	UNIPROT	TPP1	protein	O14773	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19556463	f	Figure 1	lperfetto	Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 	SIGNOR-276548	0.293
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	DNM1L	protein	O00429	UNIPROT	up-regulates activity	phosphorylation	Ser616	PIPIMPAsPQKGHAV	9606	BTO:0000007								25658205	t		Barakat	Here, we show that expression of oncogenic Ras or direct activation of the MAPK pathway leads to increased mitochondrial fragmentation and that blocking this phenotype, through knockdown of the mitochondrial fission-mediating GTPase Drp1, inhibits tumor growth. This fission is driven by Erk2-mediated phosphorylation of Drp1 on Serine 616, and both this phosphorylation and mitochondrial fragmentation are increased in human pancreatic cancer.	SIGNOR-275407	0.2
MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	NOTCH2	protein	Q04721	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000578								31659254	t		miannu	Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription. 	SIGNOR-265560	0.275
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	DIAPH1	protein	O60610	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr768	PVLPFGLtPKKLYKP	9606	BTO:0002588								23325789	t		miannu	 DIAPH1 is phosphorylated in response to dibutyryl cAMP (Bt2cAMP) at Thr-759 via a pathway that requires extracellular signal-related kinase (ERK).We also show that Bt2cAMP promotes the PKA- and ERK-dependent phosphorylation of DIAPH1 at T759 and that mutation of this site alters the stability of the protein and the rate of cAMP-stimulated mitochondrial movement.	SIGNOR-276483	0.2
TFEB	protein	P19484	UNIPROT	IL6R	protein	P08887	UNIPROT	up-regulates quantity by expression	transcriptional regulation												30145926	f		lperfetto	Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 	SIGNOR-276798	0.2
MC3R	protein	P41968	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257142	0.252
ROBO	proteinfamily	SIGNOR-PF14	SIGNOR	CDC25C	protein	P30307	UNIPROT	down-regulates	phosphorylation	Ser216	SGLYRSPsMPENLNR	9606	BTO:0000567;BTO:0000938	BTO:0000142							15150265	t		lperfetto	P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteinsphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3	SIGNOR-124851	0.2
PRKACA	protein	P17612	UNIPROT	ITPR1	protein	Q14643	UNIPROT	down-regulates activity	phosphorylation	Ser1764	RPSGRREsLTSFGNG	-1									12529267	t		miannu	IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site. 	SIGNOR-249997	0.537
DUSP26	protein	Q9BV47	UNIPROT	NTRK1	protein	P04629	UNIPROT	down-regulates activity	dephosphorylation			9606									28701747	t		miannu	NEAP and DUSP26 dephosphorylated TrkA and FGFR1 directly.|We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells	SIGNOR-277105	0.379
biphenyl-4,4'-diol	chemical	CHEBI:34367	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			-1									9751507	t		miannu	Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings. 	SIGNOR-268740	0.8
EGFR	protein	P00533	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1016	DVVDADEyLIPQQGF	9606	BTO:0000567								10653583	t	Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer	lperfetto	After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine.	SIGNOR-236475	0.2
MAP3K11	protein	Q16584	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates				9606									9003778	f		gcesareni	The kinase-inactive mlk-3 failed to activate sapk, demonstraiting that mlk-3 catalytic activity is necessary for the induction of the sapk pathway.	SIGNOR-45791	0.61
CTBP1	protein	Q13363	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21681822	t		irozzo	Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells.	SIGNOR-259197	0.585
PRKCQ	protein	Q04759	UNIPROT	FOSL1	protein	P15407	UNIPROT	up-regulates activity	phosphorylation	Thr227	LEPEALHtPTLMTTP	9606									27816489	t		Manara	PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors.	SIGNOR-260879	0.2
PTGS2	protein	P35354	UNIPROT	prostaglandin F2alpha	smallmolecule	CHEBI:15553	ChEBI	up-regulates	chemical modification			9606									20219869	t		apalma	NSAIDs are strong inhibitors of cycloxygenases (COX), and thereby impair the metabolism of arachidonic acid that is necessary for the synthesis of prostaglandins	SIGNOR-255359	0.8
TGIF1	protein	Q15583	UNIPROT	WWP1	protein	Q9H0M0	UNIPROT	up-regulates	binding			9606									15359284	t		gcesareni	We demonstrate that tiul1 degrades not only the activated type i receptor in association with smad7 but also smad2 in association with tgif.the steady-state levels of tgif are not affected by tiul1, but the interaction of tiul1 with tgif allows this ubiquitin ligase to target smad2 for degradation.	SIGNOR-128854	0.336
FOXA2	protein	Q9Y261	UNIPROT	OTX2	protein	P32243	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								10623575	t		miannu	Here we show that OTX2 directly associates with LIM1 and HNF-3beta. The luciferase assay with the P3C sequence, a specific DNA binding sequence for paired-class homeobox genes, has demonstrated that LIM1 enhances, but HNF-3beta represses, OTX2-directed gene expression.	SIGNOR-221164	0.565
MAPK1	protein	P28482	UNIPROT	GABRR1	protein	P24046	UNIPROT	unknown	phosphorylation	Thr394	SGLPPPRtAMLDGNY	-1									12175859	t		miannu	Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation	SIGNOR-262749	0.289
N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	chemical	CHEBI:91418	ChEBI	AXL	protein	P30530	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258109	0.8
MDM2	protein	Q00987	UNIPROT	MDM4	protein	O15151	UNIPROT	down-regulates	ubiquitination			9606									16511560	t		lperfetto	The mdm2 homolog mdmx is an important regulator of p53 during mouse embryonic development. Dna damage promotes mdmx phosphorylation, nuclear translocation, and degradation by mdm2.	SIGNOR-144970	0.72
MAPK8	protein	P45983	UNIPROT	NLRP3	protein	Q96P20	UNIPROT	up-regulates activity	phosphorylation	Ser198	GKTKTCEsPVSPIKM	-1									28943315	t		miannu	JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly.	SIGNOR-277324	0.378
WFS1	protein	O76024	UNIPROT	ATP1B1	protein	P05026	UNIPROT	up-regulates quantity	binding			9534	BTO:0000298								17947299	t		SARA	Sodium-potassium ATPase 1 Subunit Is a Molecular Partner of Wolframin, an Endoplasmic Reticulum Protein Involved in ER Stress|We conclude that the interaction may be important for Na+/K+ ATPase beta1 subunit maturation	SIGNOR-260999	0.408
AKT1	protein	P31749	UNIPROT	PEA15	protein	Q15121	UNIPROT	up-regulates activity	phosphorylation	Ser116	KDIIRQPsEEEIIKL	9606	BTO:0000007								12808093	t		lperfetto	Protein kinase b/akt binds and phosphorylates ped/pea-15, stabilizing its antiapoptotic action.	SIGNOR-102092	0.533
CRY2	protein	Q49AN0	UNIPROT	CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	down-regulates activity	binding			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop.	SIGNOR-267976	0.927
SMO	protein	Q99835	UNIPROT	STK36	protein	Q9NRP7	UNIPROT	up-regulates	binding			9606									17089004	t		gcesareni	Smo then activates stk36 serine/threonine kinase to stabilize gli family members and to phosphorylate sufu for nuclear accumulation of gli.| sufu binds to the kinesin cos2 to transduce the hh signal downstream of smo	SIGNOR-150540	0.495
DAB2IP	protein	Q5VWQ8	UNIPROT	14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	down-regulates activity	binding			9606									27858941	t		miannu	DAB2IP then displaces the inhibitory binding between ASK1 and 14-3-3 protein, favoring ASK1 activation	SIGNOR-254773	0.302
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	G6PC1	protein	P35575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20577053	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-252923	0.2
CSK	protein	P41240	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606									22479394	t	Leads to Furin-cleavage activity	gcesareni	We found that the notch-1-furin interaction is regulated by the non-receptor tyrosine kinase, c-src. c-src and notch-1 are physically associated, and this association is responsible for notch-1 processing and activation	SIGNOR-196824	0.285
3-phosphonatooxypyruvate(3-)	smallmolecule	CHEBI:18110	ChEBI	O-phosphonato-L-serine(2-)	smallmolecule	CHEBI:57524	ChEBI	up-regulates quantity	precursor of			3702									30034403	t		lperfetto	Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction.	SIGNOR-268563	0.8
pirenzepine	chemical	CHEBI:8247	ChEBI	CHRM3	protein	P20309	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								2704370	t		miannu	In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 	SIGNOR-258395	0.8
AR	protein	P10275	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates activity	binding			9606									15861399	t		miannu	The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes.	SIGNOR-251537	0.2
WNT5A	protein	P41221	UNIPROT	ROR2	protein	Q01974	UNIPROT	up-regulates	binding			9606	BTO:0001546								26690702	t		gcesareni	Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis.	SIGNOR-199647	0.767
ANXA3	protein	P12429	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity				9606	BTO:0000018								27995049	f		miannu	We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells. 	SIGNOR-262211	0.281
MAPK10	protein	P53779	UNIPROT	KIF5C	protein	O60282	UNIPROT	down-regulates activity	phosphorylation	Ser176	CTERFVSsPEEVMDV	-1									19525941	t		miannu	Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. JNK3 phosphorylates kinesin-1 at Ser176	SIGNOR-262950	0.326
PARK7	protein	Q99497	UNIPROT	MTA1/DJ1 complex 	complex	SIGNOR-C123	SIGNOR	form complex	binding			9606	BTO:0000567								21368136	t	1	miannu	we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3.	SIGNOR-239448	0.333
PLK1	protein	P53350	UNIPROT	SUZ12	protein	Q15022	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser546	SMSEFLEsEDGEVEQ										25855382	t		lperfetto	PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|In SUZ12, residues 539, 541 and 546 phosphorylated by Plk1 in vitro	SIGNOR-275556	0.371
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser12	KTLYSFFsPSPARKR	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276091	0.292
CSNK2A2	protein	P19784	UNIPROT	STX1A	protein	Q16623	UNIPROT	unknown	phosphorylation	Ser14	ELRTAKDsDDDDDVA	10116	BTO:0000142								10844023	t		llicata	We generated an antibody that specifically recognizes a casein kinase II-mediated phosphorylation on serine-14 of syntaxin 1. In this report we show that this phosphorylation occurs in vivo and is developmentally regulated in the rat brain | Phosphorylated syntaxin is preferentially associated with SNAP-25 and localizes to discrete domains of the axonal plasma membrane that do not colocalize with pools of synaptic vesicles.	SIGNOR-251043	0.372
PRKCG	protein	P05129	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	unknown	phosphorylation	Ser473	PPSGTKKsKRGRGRP	9606									12529391	t		llicata	Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm.	SIGNOR-97295	0.2
NDUFAB1	protein	O14561	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1	SIGNOR-262161	0.815
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	TRIM63	protein	Q969Q1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							21798082	f		lperfetto	Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome.	SIGNOR-252946	0.2
CDH22	protein	Q9UJ99	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265860	0.339
USH1G	protein	Q495M9	UNIPROT	TIP-LINK complex	complex	SIGNOR-C291	SIGNOR	form complex	binding			10090		BTO:0000630							23217710	t		lperfetto	The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction.	SIGNOR-262578	0.59
PTEN	protein	P60484	UNIPROT	NCL	protein	P19338	UNIPROT	up-regulates activity	dephosphorylation	Thr84	PAKKAAVtPGKKAAA	9606									28332494	t		miannu	The fact that PTEN\u03b2 interacts with nucleolin and dephosphorylates nucleolin at Thr84 raised a question as to whether nucleolin mediates PTEN\u03b2 regulation of rDNA transcription, and thus represents a direct mechanism by which PTEN\u03b2 controls ribosomal biogenesis.	SIGNOR-277166	0.273
STK4	protein	Q13043	UNIPROT	MOB1A	protein	Q9H8S9	UNIPROT	up-regulates	phosphorylation	Thr35	LLKHAEAtLGSGNLR	9606									21808241	t	MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors.	gcesareni	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction.	SIGNOR-175833	0.896
LIFR	protein	P42702	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates	binding			9606									24710148	t		milica	The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3).	SIGNOR-204850	0.587
GRK2	protein	P25098	UNIPROT	SLC9A5	protein	Q14940	UNIPROT	down-regulates activity	phosphorylation	Ser709	SEEEEEEsDSSETEK										21296876	t		lperfetto	Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2.	SIGNOR-275504	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	up-regulates activity	phosphorylation	Ser772	LFKKIFPsLELNITD	9606	BTO:0004553								24614225	t		gianni	NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity.	SIGNOR-266441	0.311
CDK1	protein	P06493	UNIPROT	KIF22	protein	Q14807	UNIPROT	up-regulates activity	phosphorylation	Thr463	QGAPLLStPKRERMV	9606			SIGNOR-C17						12727876	t		lperfetto	Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes	SIGNOR-100964	0.35
Brivanib alaninate	chemical	CID:11154925	PUBCHEM	FLT4	protein	P35916	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190729	0.8
CHEK2	protein	O96017	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser124	PALKRSHsDSLDHDI	9606									11298456	t		Manara	We conclude that Chk2-dependent phosphorylation of Cdc25A on Ser 123 represents a critical step in promoting its rapid destruction in response to IR-induced DNA damage.	SIGNOR-260778	0.837
1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane	chemical	CHEBI:125354	ChEBI	CXCR4	protein	P61073	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206268	0.8
IFNLR1	protein	Q8IU57	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates	binding			9606									15120645	t		gcesareni	Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain.	SIGNOR-124480	0.77
OSM	protein	P13725	UNIPROT	OSMR	protein	Q99650	UNIPROT	up-regulates	binding			9606									16286453	t		gcesareni	The oncostatin m receptor (osmr) is part of receptor complexes for oncostatin m and interleukin-31.	SIGNOR-141588	0.786
BLOC-3	complex	SIGNOR-C253	SIGNOR	RAB38	protein	P57729	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									23174301	t		lperfetto	HPS1/HPS4 was active exclusively for RAB32 and RAB38. Moreover, when overexpressed with HPS1 in HeLa cells, a mitochondrially restricted form of HPS4 preferentially recruited GFP-tagged RAB32 or RAB38 – but not the related RAB7 or RAB9 – to mitochondria. Activity in both assays required both HPS1 and HPS4. Finally, depletion of HPS1 or HPS4 by siRNA in a pigmented human melanoma cell line, MNT-1, resulted in the mislocalization of RAB32. These data provide strong evidence that BLOC-3 is a selective GEF for RAB32 and RAB38 	SIGNOR-260694	0.551
TLE2	protein	Q04725	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	down-regulates	binding			9606									19460168	t		gcesareni	Mapping studies reveal that groucho/tle binds two regions in lef-1.	SIGNOR-185736	0.621
SIRT1	protein	Q96EB6	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates activity				10090	BTO:0000165								12887892	t		gcesareni	Sir2 forms a complex with the acetyltransferase PCAF and MyoD and, when overexpressed, retards muscle differentiation	SIGNOR-241963	0.605
FGF2	protein	P09038	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates				9606									15765505	f		gcesareni	Runx2 is an important mediator of the expression of bmp-2 in response to fgf stimulation in cranial bone development.	SIGNOR-134512	0.453
SLBP	protein	Q14493	UNIPROT	H2AB1	protein	P0C5Y9	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265411	0.2
CDK2	protein	P24941	UNIPROT	CDC6	protein	Q99741	UNIPROT	down-regulates activity	phosphorylation	Ser74	TPHLPPCsPPKQGKK	9606			SIGNOR-C83						10339564	t		lperfetto	Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction.	SIGNOR-67548	0.94
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC4	protein	P56524	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257930	0.8
MKX	protein	Q8IYA7	UNIPROT	SOX5	protein	P35711	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001592							33115953	t		miannu	MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2). 	SIGNOR-267214	0.3
HSD3B1	protein	P14060	UNIPROT	testosterone	smallmolecule	CHEBI:17347	ChEBI	up-regulates quantity	chemical modification			10116		BTO:0000534;BTO:0000056							1537836	t		lperfetto	We have recently characterized two types of rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) isoenzymes expressed in adrenals and gonads. | However, in the presence of NADH, type III isoenzyme, in common with the type I isoform, converts 5 alpha-androstane-3,17-dione (A-dione) and 5 alpha-dihydrotestosterone (DHT) to the corresponding 3 beta-hydroxysteroids.	SIGNOR-268637	0.8
LYN	protein	P07948	UNIPROT	BCR-Mk	complex	SIGNOR-C433	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000776								32323266	t		scontino	The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases.	SIGNOR-268206	0.697
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Ser)	smallmolecule	CHEBI:29179	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269496	0.8
PRKN	protein	O60260	UNIPROT	GPR37	protein	O15354	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									12666095	t		lperfetto	Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R).	SIGNOR-249706	0.2
DAXX	protein	Q9UER7	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates	binding			9606	BTO:0000776;BTO:0000785								11483955	t		gcesareni	Tgf-beta-induced apoptosis is mediated by the adapter protein daxx that facilitates jnk activation	SIGNOR-109542	0.508
MECOM	protein	Q03112	UNIPROT	TEK	protein	Q02763	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000669								15889140	t		Luana	We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2 	SIGNOR-266063	0.2
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr46	GGTLFSTtPGGTRII	9606	BTO:0000007		SIGNOR-C3						12747827	t		lperfetto	Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo.	SIGNOR-101123	0.924
TWIST1	protein	Q15672	UNIPROT	RBL2	protein	Q08999	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255535	0.2
XIAP	protein	P98170	UNIPROT	CASP7	protein	P55210	UNIPROT	down-regulates quantity by destabilization	binding			-1									11257231	t		lperfetto	Our crystal structure of the complex between xiap (linker-bir2) and caspase-7 surprisingly revealed that the linker is the major determinant of binding and inhibition for the caspase.	SIGNOR-105732	0.854
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	up-regulates				9606									30017632	f		miannu	Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes	SIGNOR-260441	0.7
PRKCD	protein	Q05655	UNIPROT	PRKCD	protein	Q05655	UNIPROT	unknown	phosphorylation	Ser304	RASRRSDsASSEPVG	9606									19366211	t		llicata	This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop.	SIGNOR-185295	0.2
RET	protein	P07949	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates	phosphorylation	Tyr182	TDDEMTGyVATRWYR	9606									17548358	t		gcesareni	Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme.	SIGNOR-155381	0.338
LSM-20934	chemical	CHEBI:109533	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258850	0.8
PTPRJ	protein	Q12913	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates activity	dephosphorylation	Tyr1349	STFIGEHyVHVNATY	9606	BTO:0000007								12475979	t			When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric receptor colony stimulating factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365)),	SIGNOR-248702	0.591
EPAS1	protein	Q99814	UNIPROT	KDM2A	protein	Q9Y2K7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271581	0.2
CALM1	protein	P0DP23	UNIPROT	EEF2K	protein	O00418	UNIPROT	up-regulates	binding			9606									11015200	t		gcesareni	The calmodulin-binding region is located between amino acids 51 and 96	SIGNOR-82505	0.477
PLK1	protein	P53350	UNIPROT	CCNT1	protein	O60563	UNIPROT	down-regulates activity	phosphorylation	Ser564	KTYSLSSsFSSSSST	9606	BTO:0002181								23977272	t		miannu	 Further analysis indicated that Plk1 could phosphorylate cyclin T1 at Ser564 and inhibit the kinase activity of cyclin T1/Cdk9 complex on phosphorylation of the C-terminal domain (CTD) of RNA polymerase II. 	SIGNOR-276501	0.389
PTPRC	protein	P08575	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates	dephosphorylation			9606	BTO:0000776;BTO:0003076								11994288	t		gcesareni	These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3,	SIGNOR-87154	0.466
BCR-Mk	complex	SIGNOR-C433	SIGNOR	SYK	protein	P43405	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								32323266	t		scontino	The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK).	SIGNOR-268439	0.703
DCTPP1	protein	Q9H773	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003878								27612427	f		Monia	DCTPP1 attenuates the sensitivity of human gastric cancer cells to 5-fluorouracil by up-regulating MDR1 expression epigenetically; Moreover, low expression of DCTPP1 led to the increase in intracellular 5-methyl-dCTP, which was strongly associated with the promoter hyper-methylation, leading to the subsequent low-expression of MDR1 and the increased intracellular accumulation of 5-FU in DCTPP1-knockdown BGC-823 cells. These results provide new insights into the roles of DCTPP1 as a chemosensitizer in clinical application.	SIGNOR-261178	0.335
AVPR1A	protein	P37288	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256805	0.435
ZW10	protein	O43264	UNIPROT	DCTN2	protein	Q13561	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567		SIGNOR-C357						20462495	t		lperfetto	ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores	SIGNOR-265016	0.708
ASIP	protein	P42127	UNIPROT	MC2R	protein	Q01718	UNIPROT	down-regulates activity	binding			9606									20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and α, β, and γ melanocyte–stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268695	0.513
PREX2	protein	Q70Z35	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	catalytic activity			9606	BTO:0000007								25829446	t		irozzo	Here, we used cell biology, biochemistry, and genetic approaches to show that PTEN suppresses cell movement by blocking PREX2 GEF–catalyzed activation of the GTPase RAC1. PTEN binds PREX2 and directly inhibits GEF activity.	SIGNOR-259191	0.592
GADD45GIP1	protein	Q8TAE8	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262385	0.623
FGFR4	protein	P22455	UNIPROT	GLO1	protein	Q04760	UNIPROT	up-regulates activity	phosphorylation	Tyr136	GIAVPDVySACKRFE	-1									34838714	t		miannu	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276182	0.2
5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole	chemical	CHEBI:92005	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258857	0.8
captopril	chemical	CHEBI:3380	ChEBI	ACE2	protein	Q9BYF1	UNIPROT	down-regulates activity	chemical inhibition			-1									9187274	t		Monia	The interaction of captopril at one active site of wild-type ACE impeding substrate interaction with the other active site.	SIGNOR-261069	0.8
IKBKG	protein	Q9Y6K9	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates	phosphorylation			9606			SIGNOR-C14						15489227	t		lperfetto	Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.	SIGNOR-217382	0.783
ARHGEF15	protein	O94989	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260540	0.553
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	GJA1	protein	P17302	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000567								9535909	t	inferred from 70% family members	lperfetto	These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.	SIGNOR-270148	0.2
PPP3CC	protein	P48454	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates	relocalization			9606	BTO:0000222	BTO:0000887;BTO:0001103							18676376	t		gcesareni	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-179796	0.69
FERMT3	protein	Q86UX7	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			10090	BTO:0000132;BTO:0003292								18278053	t		lperfetto	 Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis|Kindlin-3 was also able to interact with the wild-type beta1 and beta3 integrin tails (Fig. 3c), in the presence and absence of Talin1 (Supplementary Fig. 3 online), and the F3 subdomain of Kindlin-3 was sufficient for this interaction and this interaction occurred in a direct manner	SIGNOR-266065	0.396
ID1	protein	P41134	UNIPROT	TCF12	protein	Q99081	UNIPROT	down-regulates activity	binding			10090	BTO:0004058			SIGNOR-C128					9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241104	0.601
PDK4	protein	Q16654	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	phosphorylation	Ser232	NRYGMGTsVERAAAS	-1									11485553	t		lperfetto	Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.	SIGNOR-109621	0.674
TNF	protein	P01375	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates activity				10090									10485710	f		lperfetto	Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k).	SIGNOR-70616	0.277
FOXF1	protein	Q12946	UNIPROT	GH2	protein	P01242	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16772323	f	 	miannu	Overexpression of FOXF1 in BeWo and HepG2 cells induced the GHV promoter, whereas overexpression of FOXF2 was without effect. These studies indicate that FOXF1 induces GHV expression by interaction with a FOXF1/FOXF2 cis-element in the proximal promoter.	SIGNOR-254175	0.2
pictrelisib	chemical	CHEBI:65326	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0000149							21876152	t		gcesareni	Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed	SIGNOR-176292	0.8
CHEK2	protein	O96017	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser293	GSTKRRKsMSGASPK	9606									12676583	t	Phosphorylation is the signal for ubiquitination	gcesareni	We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases.	SIGNOR-99733	0.837
SIRT5	protein	Q9NXA8	UNIPROT	HMGCS2	protein	P54868	UNIPROT	up-regulates activity	post translational modification	Lys83	YNNVEAGkYTVGLGQ	9606	BTO:0000007								24315375	t	desuccinylation	lperfetto	We demonstrate that SIRT5 regu-lates succinylation of the rate-limiting ketogenicenzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2) both in vivo and in vitro.|Succinylation of Lysine Residues within the SubstrateBinding Pocket Inhibits HMGCS2 Activity|Here, we use a label-freequantitative proteomic approach to characterizethe lysine succinylome in liver mitochondria and itsregulation by the desuccinylase SIRT5	SIGNOR-267641	0.351
AKT1	protein	P31749	UNIPROT	RNF11	protein	Q9Y3C5	UNIPROT	down-regulates quantity	phosphorylation	Thr135	DWLMRSFtCPSCMEP	9606	BTO:0003474								16123141	t		gcesareni	Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity	SIGNOR-252558	0.469
iodide	smallmolecule	CHEBI:16382	ChEBI	TPO	protein	P07202	UNIPROT	up-regulates activity	chemical activation			9606		BTO:0004708							23349248	t		miannu	After transport through the apical membrane, Iodide is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO).	SIGNOR-268139	0.8
GABA-A (a6-b3-d) receptor	complex	SIGNOR-C329	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000227							18790874	f	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263783	0.7
GADL1	protein	Q6ZQY3	UNIPROT	beta-alanine zwitterion	smallmolecule	CHEBI:57966	ChEBI	up-regulates quantity	chemical modification			9606									22718265	t		miannu	Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate α-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of α-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce γ-aminobutyric acid (GABA), β-alanine and hypotaurine, respectively; these amine products play important role in living organisms.	SIGNOR-267546	0.8
GPR35	protein	Q9HC97	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256717	0.2
FBXO31	protein	Q5XUX0	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0002181								29343641	t		miannu	FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2.	SIGNOR-277380	0.328
CSNK2A1	protein	P68400	UNIPROT	C1R	protein	P00736	UNIPROT	down-regulates activity	phosphorylation	Ser206	TEASGYIsSLEYPRS	-1									8635594	t		llicata	We provide evidence that this kinase phosphorylates Clr at the level of Ser189. | Accessibility of Ser189 was low in intact C1r, due in part to the presence of one of the oligosaccharides borne by the alpha region, further reduced in the presence of calcium, and abolished when C1r was incorporated into the C1s-C1r-C1r-C1s tetramer or the C1 complex.	SIGNOR-250833	0.311
DVL1P1	protein	P54792	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates	binding			9606									23151663	t		gcesareni	Our findings suggest a molecular interaction between pka, hdpr1, and dvl and a possible contribution of this interaction to tumorigenesis.	SIGNOR-199454	0.2
TNF	protein	P01375	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606									18231581	f		lperfetto	Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS	SIGNOR-260258	0.7
SRC_kinase_family	proteinfamily	SIGNOR-PF32	SIGNOR	Degranulation	phenotype	SIGNOR-PH92	SIGNOR	up-regulates				9606									16470226	f		Alessandro Palma	So, the association of aggregated FcεRI with the preferentially activated LYN in lipid rafts might be sufficient to shift the equilibrium of FcεRI from a nonphosphorylated state to a phosphorylated state, thereby initiating FcεRI-mediated degranulation	SIGNOR-254956	0.7
CECR2	protein	Q9BXF3	UNIPROT	CERF	complex	SIGNOR-C340	SIGNOR	form complex	binding			9606		BTO:0000227							15640247	t		miannu	Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation.	SIGNOR-263891	0.395
EGR1	protein	P18146	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003336								29212876	t		miannu	Previous studies have reported that the PPARγ proximal promoter contains an overlapping binding site for Egr-1, which is involved in the down-regulation of PPARγ. In the present study, we have provided direct evidence that leptin causes PPARγ reduction in primary cultured PASMC; this effect is coupled to leptin-induced ERK1/2 activation and subsequent induction of Egr-1, which further down-regulates PPARγ expression and results in PASMC proliferation. The present study confirmed that ERK1/2 signaling cascade mediated leptin-induced PPARγ reduction by up-regulation of Egr-1 in PASMC.	SIGNOR-263508	0.606
SYVN1	protein	Q86TM6	UNIPROT	GPR37	protein	O15354	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									18241051	t		miannu	We demonstrated that endogenous HRD1 interacts with Pael-R, and that HRD1 promotes the degradation of Pael-R and protects cell death caused by the accumulation of Pael-R.	SIGNOR-272631	0.409
ANAPC11	protein	Q9NYG5	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	form complex	binding												16896351	t		lperfetto	The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex.	SIGNOR-252010	0.86
TEC	protein	P42680	UNIPROT	TEC	protein	P42680	UNIPROT	up-regulates	phosphorylation	Tyr206	RLERGQEyLILEKND	9606									12573241	t		lperfetto	Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated	SIGNOR-98098	0.2
CSNK2A1	protein	P68400	UNIPROT	UBE2R2	protein	Q712K3	UNIPROT	up-regulates activity	phosphorylation	Ser233	DCYDDDDsGNEES	9606									12037680	t		lperfetto	Ck2-dependent phosphorylation of the e2 ubiquitin conjugating enzyme ubc3b induces its interaction with beta-trcp and enhances beta-catenin degradation	SIGNOR-88050	0.344
DVL2	protein	O14641	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606	BTO:0000331								10196136	t		amattioni	Dvl is required for lrp6 phosphorylation, which is essential for subsequent steps of signal transduction.	SIGNOR-66362	0.678
NMDA receptor_2A	complex	SIGNOR-C347	SIGNOR	CAMK2A	protein	Q9UQM7	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								11052931	t		miannu	The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD	SIGNOR-264214	0.649
CENPW	protein	Q5EE01	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265202	0.622
CENPU	protein	Q71F23	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265203	0.807
PPP2R2B	protein	Q00005	UNIPROT	PP2Ca_R1A_Bd 	complex	SIGNOR-C133	SIGNOR	form complex	binding			9606									23454242	t		gcesareni	[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity.	SIGNOR-243507	0.752
RPIA	protein	P49247	UNIPROT	D-ribulose 5-phosphate	smallmolecule	CHEBI:17363	ChEBI	down-regulates quantity	chemical modification			9606									34775382	t		miannu	The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux.	SIGNOR-267067	0.8
DMPK	protein	Q09013	UNIPROT	PLN	protein	P26678	UNIPROT	up-regulates	phosphorylation			9606		BTO:0000887							15598648	t		gcesareni	Coimmunoprecipitation studies showed that dmpk and pln can physically associate. Furthermore, purified wild-type dmpk, but not a kinase-deficient mutant (k110a dmpk), phosphorylates pln in vitro	SIGNOR-131371	0.519
E2F1	protein	Q01094	UNIPROT	LRBA	protein	P50851	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15064745	f		miannu	 We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA.	SIGNOR-253846	0.2
leuprolide acetate	chemical	CHEBI:63597	ChEBI	GNRHR	protein	P30968	UNIPROT	up-regulates activity	chemical activation			9606									22416801	t		miannu	Clinical data have shown that the GnRH antagonist, degarelix, is associated with more rapid PSA suppression and improved PSA PFS compared with the GnRH agonist, leuprolide.	SIGNOR-259163	0.8
tolcapone	chemical	CHEBI:63630	ChEBI	COMT	protein	P21964	UNIPROT	down-regulates activity	chemical inhibition			10090									26919286	t		miannu	The present work illustrates the potential therapeutic efficacy of COMT inhibition in alleviating cognitive impairment. A brain-penetrant COMT inhibitor, tolcapone, was tested in normal and phencyclidine-treated rats and COMT-Val transgenic mice.	SIGNOR-258475	0.8
DIO2	protein	Q92813	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20978344	f		miannu	The active thyroid hormone 3,5,3' triiodothyronine (T3) is a major regulator of skeletal muscle function. The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4). Here we show that type 2 deiodinase (D2) is essential for normal mouse myogenesis and muscle regeneration. Indeed, D2-mediated increases in T3 were essential for the enhanced transcription of myogenic differentiation 1 (MyoD) and for execution of the myogenic program. 	SIGNOR-256203	0.268
ARF1	protein	P84077	UNIPROT	Vesicle_transport	phenotype	SIGNOR-PH172	SIGNOR	up-regulates													14973189	f		lperfetto	ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface	SIGNOR-272149	0.7
mTORC2	complex	SIGNOR-C2	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Thr450	TAQMITItPPDQDDS	10090	BTO:0002572								18566586	t		gcesareni	MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt	SIGNOR-252438	0.634
DIO3	protein	P55073	UNIPROT	iodide	smallmolecule	CHEBI:16382	ChEBI	up-regulates quantity	chemical modification			9606									34674502	t		scontino	Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3.	SIGNOR-266952	0.8
Hypoxia	stimulus	SIGNOR-ST25	SIGNOR	HIF-1 complex	complex	SIGNOR-C418	SIGNOR	up-regulates				9606									27692180	f		miannu	Hypoxia-Inducible Factor-1 (HIF-1) is a key transcription factor that regulates gene expression under hypoxic conditions (Semenza, 2012, 2010a). HIF-1 consists of two subunits, HIF-1α and HIF-1β. While HIF-1β protein is constitutively expressed and present in excess, HIF-1α protein has a short half-life	SIGNOR-267449	0.7
PLK1	protein	P53350	UNIPROT	FADD	protein	Q13158	UNIPROT	down-regulates activity	phosphorylation	Ser194	QNRSGAMsPMSWNSD	9606									20890306	t		gcesareni	Fas-associated death domain-containing protein (FADD) was first identified as an adapter molecule involved in formation of a death-inducing signaling complex upon Fas stimulation| Plk1 phosphorylates fadd at ser-194 in response to treatment with taxol Phosphorylation by polo-like kinase 1 induces the tumor-suppressing activity of FADD	SIGNOR-168204	0.471
PRKCB	protein	P05771	UNIPROT	SDC2	protein	P34741	UNIPROT	unknown	phosphorylation	Ser188	LGERKPSsAAYQKAP	-1									9244383	t		lperfetto	We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198.	SIGNOR-248977	0.333
SIK2	protein	Q9H0K1	UNIPROT	CEP250	protein	Q9BV73	UNIPROT	down-regulates	phosphorylation	Ser2392	AGLHHSLsHSLLAVA	9606									20708153	t		lperfetto	Here, we show that the salt inducible kinase 2 (sik2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, c-nap1, through s2392 phosphorylation	SIGNOR-167488	0.326
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PHF2	protein	O75151	UNIPROT	up-regulates activity	phosphorylation	Ser757	NARVKKEsGSSAAGI	9606	BTO:0000007								21532585	t		miannu	PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h).	SIGNOR-264510	0.2
GLA	protein	P06280	UNIPROT	1,3-dichloro-7-hydroxy-9,9-dimethyl-9H-acridin-2-one	smallmolecule	CHEBI:52012	ChEBI	up-regulates quantity by expression	chemical modification			-1									31996391	t		lperfetto	DDAOG is cleaved by -galactosidase ( Lindvall et al., 2009 ) in the Trpv1 cells to produce 7-hydroxy-9H(I,3-dichloro-9,9-dimethylacridin-2-one (DDAO).	SIGNOR-261334	0.8
TFAP4	protein	Q01664	UNIPROT	SALL2	protein	Q9Y467	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000452								21228219	f		miannu	 The transcription factor AP4 increases along with SALL2 in quiescent cells and positively regulates SALL2 expression.	SIGNOR-255426	0.2
BACH1	protein	O14867	UNIPROT	HK2	protein	P52789	UNIPROT	up-regulates quantity	transcriptional regulation			9606									31257027	t			BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells.	SIGNOR-259338	0.2
PRKCB	protein	P05771	UNIPROT	PTPN11	protein	Q06124	UNIPROT	unknown	phosphorylation	Ser576	CAEMREDsARVYENV	9606									11781100	t		lperfetto	 In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta.	SIGNOR-249136	0.336
CLTCL1	protein	P53675	UNIPROT	AP-1/clathrin vescicle	complex	SIGNOR-C251	SIGNOR	form complex	binding			9606									23103167	t		lperfetto	Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors	SIGNOR-260679	0.719
GTF3A	protein	Q92664	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	up-regulates activity	binding												9308965	t		lperfetto	At present, it is known that transcription factors TFIIIB, TFIIIC2, TFIIIC1, and TFIIIA (5S gene only) are involved in transcription of tRNA, VA RNA, and 5S RNA genes by human RNA Pol III.	SIGNOR-266180	0.446
CAMK1	protein	Q14012	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser498	RPLSRTQsSPLPQSP	9606		BTO:0000887							11114197	t		gcesareni	Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.	SIGNOR-85022	0.43
midostaurin	chemical	CHEBI:63452	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258247	0.8
AKT2	protein	P31751	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation	Ser256	SPRRRAAsMDNNSKF	9606									10377430	t		lperfetto	Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus.	SIGNOR-68652	0.645
ELK3	protein	P41970	UNIPROT	MYH6	protein	P13533	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								12933792	f	 	miannu	From HeLa cells an Ets family of protein, Ets-related protein (ERP), binds to double-stranded PNR element. The ERP.PNR complex inhibited the activity of the basal transcription complex from homologous as well as heterologous promoters in a PNR position-independent manner, suggesting that ERP acts as a silencer of alpha-MHC gene expression in non-muscle cells.	SIGNOR-253900	0.2
PRKCA	protein	P17252	UNIPROT	LRP1	protein	Q07954	UNIPROT	up-regulates	phosphorylation	Ser4517	LYMGGHGsRHSLAST	9606									15272003	t		lperfetto	Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc.	SIGNOR-126958	0.2
ACE2	protein	Q9BYF1	UNIPROT	Angiotensin-1	protein	P01019-PRO_0000032457	UNIPROT	up-regulates activity	cleavage	Pro40	GDRVYIHpFHLVIHN	-1									11815627	t		miannu	The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus.	SIGNOR-260222	0.2
PTPRJ	protein	Q12913	UNIPROT	PLCG1	protein	P19174	UNIPROT	unknown	dephosphorylation			9606									11259588	t			Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation	SIGNOR-248706	0.376
CDK4	protein	P11802	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Ser811	IYISPLKsPYKISEG	9606									15809340	t		gcesareni	Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively.	SIGNOR-135185	0.927
INS	protein	P01308	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates				10090									12530968	f		lperfetto	The forkhead transcription factor foxo1 is regulated by insulin via akt-dependent phosphorylation and nuclear exclusion.	SIGNOR-252627	0.745
SPOP	protein	O43791	UNIPROT	GLI2	protein	P10070	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								20463034	t		Gianni	RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins	SIGNOR-268860	0.698
GW 791343 HYDROCHLORIDE	chemical	CID:9848159	PUBCHEM	P2RX7	protein	Q99572	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193116	0.8
ILK	protein	Q13418	UNIPROT	PPP1R14B	protein	Q96C90	UNIPROT	up-regulates activity	phosphorylation	Thr57	VRRQGKVtVKYDRKE	-1									12144526	t		lperfetto	We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin	SIGNOR-265741	0.371
NUTF2	protein	P61970	UNIPROT	NUP62	protein	P37198	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								7744965	t		Simone	Our data suggest that NTF2 interacts directly with NPC protein 1362 and exerts its effect at a relatively late step in the nuclear protein import pathway. We obtained a cDNA encoding NTF2 and showed that the recombinant protein restores transport activity to p62-pretreated cytosol.	SIGNOR-261255	0.84
ATXN7	protein	O15265	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269576	0.663
DDC	protein	P20711	UNIPROT	serotonin	smallmolecule	CHEBI:28790	ChEBI	up-regulates quantity	chemical modification			7955									23940784	t	brain	lperfetto	AADC is responsible for the decarboxylation step in the catecholamine and dopamine biosynthesis. Dopamine and serotonin can be synthesized by AADC from L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively [7]. A deficiency in AADC will lead to reduced biogenic monoamines, including dopamine, norepinephrine, epinephrine, and serotonin	SIGNOR-263987	0.8
INPP5D	protein	Q92835	UNIPROT	phosphatidylinositol bisphosphate	smallmolecule	CHEBI:37328	ChEBI	up-regulates quantity	chemical modification			9606									23650141	t		gcesareni	PtdIns(3,4)P2 is commonly reported as a product of the SH2 domain-containing inositol 5-phosphatases 1/2 (SHIP1 and SHIP2) that dephosphorylate PtdIns(3,4,5)P3 at the 5-position	SIGNOR-252427	0.8
VRK2	protein	Q86Y07	UNIPROT	DCX DET1-COP1	complex	SIGNOR-C24	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								24298020	t		miannu	Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not.The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.COP1 functions as an E3 ligase by forming a supercomplex that also includes heterodimeric substrate receptor DET1, adaptor DDB1, scaffold Cul4A, and RBX1 to recruit the E2 enzyme	SIGNOR-272874	0.331
GNG2	protein	P59768	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606	BTO:0000938								16537363	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt.	SIGNOR-252683	0.426
KANSL1	protein	Q7Z3B3	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates				9606	BTO:0000567								26243146	f		miannu	Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. 	SIGNOR-267170	0.7
HIPK2	protein	Q9H2X6	UNIPROT	PAX6	protein	P26367	UNIPROT	up-regulates activity	phosphorylation	Thr373	GRSYDTYtPPHMQTH	9606	BTO:0001938								16407227	t			HIPK2 phosphorylates the activation domain of Pax6, which augments Pax6 transactivation by enhancing its interaction with p300. Mass spectrometric analysis identified three Pax6 phosphorylation sites as threonines 281, 304, and 373. 	SIGNOR-251271	0.476
CAMK2A	protein	Q9UQM7	UNIPROT	ETS2	protein	P15036	UNIPROT	down-regulates	phosphorylation	Ser310	LDVQRVPsFESFEDD	9606									19182667	t		lperfetto	Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters	SIGNOR-183600	0.2
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC4	protein	P56524	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257911	0.8
GPR119	protein	Q8TDV5	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257308	0.252
PLK1	protein	P53350	UNIPROT	BRCA2	protein	P51587	UNIPROT	down-regulates activity	phosphorylation	Ser206	ATPPTLSsTVLIVRN	9606									12815053	t		lperfetto	M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1	SIGNOR-102494	0.556
LCK	protein	P06239	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates	phosphorylation	Tyr315	RADNDKEyLVLTLTK	9606									11948419	t		gcesareni	Thus, y240a and y315a are involved in the ability of mmac/pten to dephosphorylate ptdins and regulate tumor cell growth in vitro and in vivo.	SIGNOR-116499	0.382
GFPT1	protein	Q06210	UNIPROT	L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	down-regulates quantity	chemical modification			9606									21310273	t		miannu	GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans	SIGNOR-267816	0.8
MAPK8	protein	P45983	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Thr739	SEGSGTAtPSALITT	9606									19245816	t		gcesareni	In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed.	SIGNOR-184194	0.694
ARHGEF6	protein	Q15052	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				9606	BTO:0000599								23776207	f		lperfetto	Activation of ARF6 promotes cortical actin assembly (9) and plasma membrane remodeling 	SIGNOR-272236	0.7
MAOB	protein	P27338	UNIPROT	3,4-dihydroxyphenylacetaldehyde	smallmolecule	CHEBI:27978	ChEBI	up-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO.	SIGNOR-264004	0.8
CDK2	protein	P24941	UNIPROT	NPM1	protein	P06748	UNIPROT	unknown	phosphorylation	Ser70	EAMNYEGsPIKVTLA	9606	BTO:0001271								19933706	t		gcesareni	Simultaneous inactivation of two cdk phosphorylation sites at ser10 and ser70 (npm-aa) induced g(2)/m cell cycle arrest, phosphorylation of cdk1 at tyr15 (cdc2(tyr15)) and increased cytoplasmic accumulation of cdc25c.	SIGNOR-161805	0.578
TFEC	protein	O14948	UNIPROT	MYH9	protein	P35579	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								11467950	f		miannu	we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies.	SIGNOR-222551	0.2
NFATC2	protein	Q13469	UNIPROT	IL4	protein	P05112	UNIPROT	up-regulates	transcriptional regulation			9606									23612709	f			Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin 	SIGNOR-255460	0.525
RBPJ	protein	Q06330	UNIPROT	NFKB2	protein	Q00653	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									9528780	f		gcesareni	Rbp-jkappa is a strong transcriptional repressor of nf-kappab2. Moreover, this repression can be overcome by activated notch-1.	SIGNOR-56100	0.27
KIT	protein	P10721	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates	phosphorylation	Tyr936	SESTNHIySNLANCS	9606									10377264	t		miannu	Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr	SIGNOR-68647	0.2
SKP2	protein	Q13309	UNIPROT	CDT1	protein	Q9H211	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								10790373	t		miannu	 Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3. 	SIGNOR-272565	0.68
A4/b7 integrin	complex	SIGNOR-C187	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257728	0.546
PRKCB	protein	P05771	UNIPROT	TRPV1	protein	Q8NER1	UNIPROT	up-regulates activity	phosphorylation	Thr705	WKLQRAItILDTEKS	9606	BTO:0000007								24920628	t		miannu	PKCβII causes the downregulation of TRPV1 by phosphorylating the channel. The increased threonine phosphorylation was substantially reduced by mutating Thr705, showing that Thr705 is indeed a major PKCβII phosphorylation site.	SIGNOR-276638	0.2
KEAP1	protein	Q14145	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	down-regulates quantity	ubiquitination			9606									31257023	t			Keap1 is a substrate receptor of a Cul3-RING ubiquitin ligase (CRL3) that, in physiological conditions, constitutively binds and targets Nrf2 for degradation	SIGNOR-259335	0.808
SIRT1	protein	Q96EB6	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	deacetylation	Lys14	VKEGWLHkRGEYIKT	10090		BTO:0000562							21775285	t		gcesareni	We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation.	SIGNOR-252445	0.62
CDK1	protein	P06493	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr70	RNSPVTKtPPRDLPT	9606									11553333	t		lperfetto	Phosphorylation of 4e-bp1 is critical in causing its dissociation from eif-4e, leaving 4e available to form translationally active eif-4f complexes, switching on mrna translation. We show that the cyclin-dependent kinase, cdc2, phosphorylates 4e-bp1 at thr-70 and that phosphorylation of this site is permissive for ser-65 phosphorylation. Crucially, the increased phosphorylation of 4e-bp1 during mitosis results in its complete dissociation from eif-4e.	SIGNOR-110416	0.407
CIITA	protein	P33076	UNIPROT	HLA-G	protein	P17693	UNIPROT	unknown	transcriptional regulation			9606	BTO:0000776								11137218	f	 	 	 The X1 box is the binding site for the ubiquitous RFX complex consisting of three subunits; the X2 box is bound by the X2BP/ATF/CREB family factors. The basic S-X-Y regulatory module interacts with CIITA, which is expressed constitutively in APCs, but may be inducible in others cell types by IFN-gamma|We propose that the X region in the HLA-G gene promoter might participate to the combination of factors which play a role in HLA-G gene activation	SIGNOR-254021	0.459
MAPK1	protein	P28482	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates	phosphorylation	Ser523	GVSDVPTsPTLQRPT	9534	BTO:0004055								16705159	t	16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling.	lperfetto	We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner	SIGNOR-236331	0.492
CACNA1G	protein	O43497	UNIPROT	Action_potential 	phenotype	SIGNOR-PH82	SIGNOR	up-regulates				10090									33393208	t		miannu	Adult hippocampal neurogenesis plays an important role in neuronal plasticity and maintenance in mammals. Low-threshold voltage-gated T-type calcium channels produce calcium spikes that increase fast action potentials in newborn cells in the hippocampal dentate gyrus (DG)	SIGNOR-264033	0.7
TGFBR2	protein	P37173	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates	phosphorylation			9606									26194464	t		MARCO ROSINA	TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI).	SIGNOR-255032	0.709
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation			9606									14662762	t	inferred from 70% family members	lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-270156	0.2
TWIST2	protein	Q8WVJ9	UNIPROT	SRPX	protein	P78539	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255497	0.208
CHIR 99021	chemical	CHEBI:91091	ChEBI	GSK3B	protein	P49841	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191000	0.8
PTPN18	protein	Q99952	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Tyr1248	PTAENPEyLGLDVPV	9606	BTO:0000007								25081058	t		lperfetto	PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop.	SIGNOR-262597	0.658
ZNF224	protein	Q9NZL3	UNIPROT	Aldolase	proteinfamily	SIGNOR-PF75	SIGNOR	down-regulates quantity by repression	transcriptional regulation			9606									17900823	f	inferred from family member	miannu	 We previously reported that ZNF224, a novel Krüppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. 	SIGNOR-270227	0.505
N-hydroxy-1-[(4-methoxyphenyl)methyl]-6-indolecarboxamide	chemical	CHEBI:94192	ChEBI	HDAC8	protein	Q9BY41	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189684	0.8
Ac-Asp-Glu(3-)	smallmolecule	CHEBI:76931	ChEBI	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	precursor of			9606									10085079	t		miannu	The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated.	SIGNOR-267540	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser82	RALSRQLsSGVSEIR	9606									19593530	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	lperfetto	First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.	SIGNOR-186772	0.2
2-(4-morpholinyl)-6-(1-thianthrenyl)-4-pyranone	chemical	CHEBI:91372	ChEBI	ATM	protein	Q13315	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193600	0.8
RPS6KA1	protein	Q15418	UNIPROT	CDC25B	protein	P30305	UNIPROT	up-regulates	phosphorylation	Ser353	VQNKRRRsVTPPEEQ	9606									23708659	t		lperfetto	Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.	SIGNOR-202121	0.256
MTCP1	protein	P56278	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	binding			9606	BTO:0000782;BTO:0001271								10983986	t		lperfetto	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-244413	0.458
PGD	protein	P52209	UNIPROT	NADPH(4-)	smallmolecule	CHEBI:57783	ChEBI	up-regulates quantity	chemical modification			9606									24769394	t		miannu	The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle	SIGNOR-267053	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	LIPE	protein	Q05469	UNIPROT	down-regulates	phosphorylation	Ser855	EPMRRSVsEAALAQP	9606									9636039	t		lperfetto	Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase.	SIGNOR-216507	0.377
INSR	protein	P06213	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	phosphorylation	Tyr607	NENTEDQySLVEDDE	9534									8385099	t			The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor.	SIGNOR-251322	0.656
TFEB	protein	P19484	UNIPROT	BLOC1S2	protein	Q6QNY1	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4).	SIGNOR-276682	0.2
mTORC1	complex	SIGNOR-C3	SIGNOR	MAF1	protein	Q9H063	UNIPROT	down-regulates	phosphorylation	Ser60	PHVLEALsPPQTSGL	9606									20516213	t		lperfetto	The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly.	SIGNOR-217149	0.467
CYP1B1	protein	Q16678	UNIPROT	17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	up-regulates quantity	chemical modification			9606	BTO:0000093								8790407	t		Luana	These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens.	SIGNOR-269756	0.8
BIRC5	protein	O15392	UNIPROT	XIAP	protein	P98170	UNIPROT	up-regulates	binding			9606									15218035	t		gcesareni	Formation of a survivin-xiap complex promotes increased xiap stability against ubiquitination/proteasomal destruction and synergistic apoptosis	SIGNOR-126367	0.509
PRKACA	protein	P17612	UNIPROT	RARA	protein	P10276	UNIPROT	down-regulates activity	phosphorylation	Ser219	NSSEQRVsLDIDLWD	9606									20215566	t		miannu	 Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity. 	SIGNOR-276281	0.378
CDK5	protein	Q00535	UNIPROT	SYN1	protein	P17600	UNIPROT	up-regulates	phosphorylation	Ser551	PAARPPAsPSPQRQA	9606									10880969	t		lperfetto	Synapsin i (syni), a major sv phosphoprotein involved in the regulation of sv trafficking and neurotransmitter release, is one of the presynaptic substrates of cdk5, which phosphorylates it in its c-terminal region at ser(549) (site 6) and ser(551) (site 7). Phosphorylation of syni by cdk5 is physiologically regulated and enhances its binding to f-actin.	SIGNOR-78883	0.581
dothiepin	chemical	CHEBI:36798	ChEBI	CHRM5	protein	P08912	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8100134	t		miannu	Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 	SIGNOR-258695	0.8
CSNK2A2	protein	P19784	UNIPROT	WAS	protein	P42768	UNIPROT	up-regulates activity	phosphorylation	Ser484	RSRAIHSsDEGEDQA	9606	BTO:0001412								12769847	t		llicata	We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule. 	SIGNOR-251049	0.354
ETS2	protein	P15036	UNIPROT	BGLAP	protein	P02818	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11175361	t		miannu	Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin	SIGNOR-259875	0.2
enzalutamide	chemical	CHEBI:68534	ChEBI	AR	protein	P10275	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194325	0.8
paclitaxel	chemical	CHEBI:45863	ChEBI	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	down-regulates activity	chemical inhibition			9606									28298489	t		miannu	Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap.	SIGNOR-259449	0.8
RAF1	protein	P04049	UNIPROT	STK3	protein	Q13188	UNIPROT	down-regulates	binding			9606									15618521	t		gcesareni	Raf-1 prevents dimerization and phosphorylation of the activation loop of mst2 independently of its protein kinase activity.Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (mst2)	SIGNOR-132824	0.366
IKBKB	protein	O14920	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser307	TRRSRTEsITATSPA	-1									12351658	t			IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.	SIGNOR-251292	0.644
SEMA3A	protein	Q14563	UNIPROT	PLXNA4	protein	Q9HCM2	UNIPROT	up-regulates activity	binding			9606	BTO:0001176;BTO:0002036								25335892	t		miannu	We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin. 	SIGNOR-261811	0.755
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	E2 conjugating enzyme	proteinfamily	SIGNOR-PF105	SIGNOR	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-270841	0.2
FUBP1	protein	Q96AE4	UNIPROT	CDKN2B	protein	P42772	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19637194	f		irozzo	The cell cycle inhibitor p15 was also up-regulated upon FBP1 knockdown. Our analysis of HCC cells after FBP1 knockdown suggests that p15 mRNA levels may also (directly or indirectly) depend on FBP1 activity.	SIGNOR-259126	0.26
ZAP70	protein	P43403	UNIPROT	LAT	protein	O43561	UNIPROT	up-regulates activity	phosphorylation	Tyr200	SMESIDDyVNVPESG	9606									11368773	t		lperfetto	In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127.	SIGNOR-247026	0.762
UBQLN2	protein	Q9UHD9	UNIPROT	Stress_granules	phenotype	SIGNOR-PH124	SIGNOR	up-regulates				10090	BTO:0001976								26521126	f		lperfetto	We report that UBQLN2 up-regulation cause a cellular stress which leads to MAPK activation. Interestingly, kinases have been recently shown to have a critical role in TDP-43 accumulation in stress granules following a chronic stress	SIGNOR-262266	0.7
TGFB1	protein	P01137	UNIPROT	PPP2R2A	protein	P63151	UNIPROT	up-regulates activity	binding			9606									19114990	t		lperfetto	The Balpha subunit interacts directly with activated T_RI. The Balpha interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity	SIGNOR-217894	0.357
CDK1	protein	P06493	UNIPROT	MDM4	protein	O15151	UNIPROT	down-regulates	phosphorylation	Ser96	SFSVKDPsPLYDMLR	9606									15735705	t		lperfetto	Cdc2p34 phosphorylates mdmx on ser 96 in vitro. Mutation within this site (mdmx(s96a)) impairs, whereas phosphomimic substitution (mdmx(s96d)) increases the cytoplasmic localization of mdmx, suggesting that cdk2/cdc2p34 phosphorylation is required for export of mdmx from the nucleus	SIGNOR-134388	0.416
MARK1	protein	Q9P0L2	UNIPROT	MAP2	protein	P11137	UNIPROT	down-regulates activity	phosphorylation	Ser1540	KSPEKRSsLPRPSSI	-1									8631898	t		miannu	Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 	SIGNOR-250163	0.428
PPP2CB	protein	P62714	UNIPROT	RALA	protein	P11233	UNIPROT	down-regulates	dephosphorylation	Ser183	RARKMEDsKEKNGKK	9606									17540176	t		miannu	Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function	SIGNOR-155349	0.293
Angiotensin 1-7	protein	P01019-PRO_0000420660	UNIPROT	MAS1	protein	P04201	UNIPROT	up-regulates activity	binding			9606									23488800	t		miannu	Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7). 	SIGNOR-260229	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MKNK1	protein	Q9BUB5	UNIPROT	up-regulates activity	phosphorylation			-1									9155018	t			These results indicate that MNK1 is a novel class of protein kinase that is activated through both the ERK and p38 MAP kinase signaling pathways	SIGNOR-253013	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	MYOD1	protein	P15172	UNIPROT	down-regulates	phosphorylation	Ser5	sPPLRDVD	9606	BTO:0000222								14749395	t		lperfetto	Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21.	SIGNOR-216924	0.325
MED26	protein	O95402	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266664	0.656
PPBP	protein	P02775	UNIPROT	OPRD1	protein	P41143	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258412	0.357
Food intake	phenotype	SIGNOR-PH152	SIGNOR	folic acid	smallmolecule	CHEBI:27470	ChEBI	up-regulates				9606									19706381	f		lperfetto	The U.S. Reference Daily Intake (Daily Value) for FA is 0.4 mg for adults to aid in the prevention of birth defects and anemia, or double this amount for pregnant or lactating women.	SIGNOR-268262	0.7
ROS	stimulus	SIGNOR-ST2	SIGNOR	Demyelination	phenotype	SIGNOR-PH155	SIGNOR	up-regulates				9606									32454942	f		miannu	Next to their interaction with adaptive immune cells, activated microglia can secrete cytotoxic cytokines and oxidative products, such as ROS and NO radicals in MS lesions thereby promoting oxidative stress and contributing to myelin destruction	SIGNOR-263828	0.7
MAP2K3	protein	P46734	UNIPROT	MAPK13	protein	O15264	UNIPROT	up-regulates activity	phosphorylation	Thr180	RHADAEMtGYVVTRW	9606	BTO:0000007								10066767	t	done	miannu	 p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.	SIGNOR-273950	0.59
KAT2A	protein	Q92830	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269594	0.2
RPS6KA5	protein	O75582	UNIPROT	Histone H2A	proteinfamily	SIGNOR-PF70	SIGNOR	down-regulates	phosphorylation			9606									15010469	t		gcesareni	We found that msk1 phosphorylated histone h2a on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by msk1.	SIGNOR-265314	0.2
MAX	protein	P61244	UNIPROT	MNT	protein	Q99583	UNIPROT	up-regulates activity	binding			9606									7954804	t	2	miannu	the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences.	SIGNOR-240354	0.359
FLT4	protein	P35916	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates activity	phosphorylation	Tyr1337	QVFYNSEyGELSEPS	9606	BTO:0000394								12881528	t		lperfetto	Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail.	SIGNOR-104088	0.2
APC-c	complex	SIGNOR-C150	SIGNOR	ANLN	protein	Q9NQW6	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								16040610	t		miannu	 Ubiquitination of anillin required a destruction-box and was mediated by Cdh1, an activator of APC/C. Overexpression of Cdh1 reduced the levels of anillin, whereas inactivation of APC/C(Cdh1) increased the half-life of anillin.	SIGNOR-272655	0.266
MAPK1	protein	P28482	UNIPROT	TAGLN2	protein	P37802	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser145	ARDDGLFsGDPNWFP	9606	BTO:0003491								30041673	t		lperfetto	ERK2 interacted with 29-31 amino acids of transgelin-2 and subsequently phosphorylated the S145 residue of transgelin-2. S145 phosphorylation of transgelin-2 played important roles in cell proliferation and tumorigenesis of PDAC.| We found that the protein stability of transgelin-2 was regulated by KRAS. ERK-mediated phosphorylation resulted in accumulation of transgelin-2 protein.	SIGNOR-265221	0.272
PRKACA	protein	P17612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									18794113	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.	SIGNOR-180902	0.521
IL15RA	protein	Q13261	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates					BTO:0000782								30029643	t		areggio	Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated 	SIGNOR-256227	0.439
Hypoxia	stimulus	SIGNOR-ST25	SIGNOR	EGLN1	protein	Q9GZT9	UNIPROT	down-regulates				9606									32755251	f		lperfetto	Under hypoxic conditions, PHD2 activity is limited, and therefore HIF-1α protein is stabilized, leading to an increase in the transcription of erythropoietin as well as hundreds of target genes that coordinate diverse processes	SIGNOR-261995	0.7
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2R2	protein	Q712K3	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271358	0.776
AURKA	protein	O14965	UNIPROT	MBD3	protein	O95983	UNIPROT	up-regulates	phosphorylation	Ser24	REEVPRRsGLSAGHR	9606	BTO:0000567								12354758	t		llicata	These results suggest that the biochemical changes of mbd3 may be intimately related to the targeting of mbd3 to centrosomes. aurora-a phosphorylates mbd3	SIGNOR-93693	0.289
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates quantity by destabilization	cleavage	Met666	VIVITLVmLKKKQYT	-1									8943232	t		lperfetto	FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261789	0.502
ADSL	protein	P30566	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									22812634	t		miannu	ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case	SIGNOR-266607	0.8
PDGFRB	protein	P09619	UNIPROT	TNK2	protein	Q07912	UNIPROT	up-regulates activity	phosphorylation	Tyr635	PLPPPPAyDDVAQDE	9606	BTO:0002036								25257795	t		miannu	 Mutational analysis suggested that Y635 of ACK1 is a PDGFR-β phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT. 	SIGNOR-276854	0.365
SCF-SKP2	complex	SIGNOR-C136	SIGNOR	CCNE1	protein	P24864	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1							phosphorylation:Ser399;Thr395	GLLTPPQsGKKQSSG;PLPSGLLtPPQSGKK	11533444	t		lperfetto	The amount of cyclin E protein present in the cell is tightly controlled by ubiquitin-mediated proteolysis. Here we identify the ubiquitin ligase responsible for cyclin E ubiquitination as SCFFbw7 and demonstrate that it is functionally conserved in yeast, flies, and mammals. Fbw7 associates specifically with phosphorylated cyclin E, and SCFFbw7 catalyzes cyclin E ubiquitination in vitro	SIGNOR-267558	0.632
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BC15	protein	Q99877	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSVYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271993	0.2
TBXA2R	protein	P21731	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257023	0.447
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	up-regulates quantity	precursor of			9606									33179964	t		miannu	The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure.	SIGNOR-267308	0.8
PRKCD	protein	Q05655	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates	phosphorylation	Ser727	TDNLLPMsPEEFDEV	9606									17502367	t		gcesareni	All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).	SIGNOR-154791	0.571
PPP2CA	protein	P67775	UNIPROT	MAP3K3	protein	Q99759	UNIPROT	down-regulates	dephosphorylation	Ser526	MSGTGMRsVTGTPYW	9606									20448038	t		lperfetto	Pp2ac binds to the phosphorylated mekk3 and subsequently dephosphorylate mekk3 at thr-516, ser-520, and ser-526 residues to terminate mekk3-mediated ikkbeta/Nf-kappaB Activation	SIGNOR-165233	0.379
EEF1A1	protein	P68104	UNIPROT	Glu-tRNA(Glu)	smallmolecule	CHEBI:29157	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269509	0.8
DIO1	protein	P49895	UNIPROT	3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	up-regulates quantity	chemical modification			9606									1400883	t		scontino	The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production.	SIGNOR-266945	0.8
TOP2A	protein	P11388	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	down-regulates				9606									15942022	f		lperfetto	Down-regulation of DNA topoisomerase IIalpha leads to prolonged cell cycle transit in G2 and early M phases and increased survival to microtubule-interacting agents	SIGNOR-242537	0.7
LYN	protein	P07948	UNIPROT	CD19	protein	P15391	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000776								25673924	t		lperfetto	CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades.	SIGNOR-242891	0.765
NRXN3	protein	Q9Y4C0	UNIPROT	DAG1	protein	Q14118	UNIPROT	up-regulates activity	binding			9606									22626542	t		miannu	 The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 	SIGNOR-265463	0.2
AMT	protein	P48728	UNIPROT	Glycine cleavage system	complex	SIGNOR-C437	SIGNOR	form complex	binding			9606									16051266	t		lperfetto	The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide.	SIGNOR-268242	0.727
SGK1	protein	O00141	UNIPROT	SLC1A3	protein	P43003	UNIPROT	up-regulates activity	phosphorylation	Thr482	LDRLRTTtNVLGDSL	-1									12911626	t		miannu	 Site‐directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4‐2 protein (S382A,S468ANedd4‐2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Introduction of a negative charge at the SGK phosphorylation site in the EAAT1 protein leads to a strong stimulation of the carrier, whereas replacement with alanine markedly decreases the EAAT1‐mediated current. These observations suggest that SGK1 exerts its effect not only by phosphorylation of Nedd4‐2 but also by phosphorylation of EAAT1.	SIGNOR-263075	0.425
MAPK8	protein	P45983	UNIPROT	EEF1A2	protein	Q05639	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser358	GQISAGYsPVIDCHT	9606	BTO:0002181								23608534	t		miannu	Ribosome-associated JNK phosphorylates the eukaryotic translation elongation factor 1A isoform 2 (eEF1A2) on serines 205 and 358 to promote degradation of NSPs by the proteasome. 	SIGNOR-276492	0.383
MYLIP	protein	Q8WY64	UNIPROT	LRP8	protein	Q14114	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								20427281	t		miannu	Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation.	SIGNOR-271486	0.456
SIRT2	protein	Q8IXJ6	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by stabilization				9606									23175188	f		miannu	Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation.	SIGNOR-255148	0.478
PK	proteinfamily	SIGNOR-PF80	SIGNOR	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation			-1									22306293	t	inferred from family member		PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor	SIGNOR-270312	0.2
MST1	protein	P26927	UNIPROT	H2BC3	protein	P33778	UNIPROT	unknown	phosphorylation	Ser15	APAPKKGsKKAITKA	9606									21212262	t		lperfetto	The mst1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, jnk/p38, histone h2b and foxo. Mst1 induces apoptosis by phosphorylating histone h2b on a relatively conserved site, ser-14 in mammalian cells	SIGNOR-171005	0.2
LPAR6	protein	P43657	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257212	0.396
RB1	protein	P06400	UNIPROT	UBTF	protein	P17480	UNIPROT	down-regulates activity	binding			-1									7877691	t		lperfetto	Activity of RNA polymerase I transcription factor UBF blocked by Rb gene product	SIGNOR-262589	0.383
SUN2	protein	Q9UH99	UNIPROT	RAB5A	protein	P20339	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								10818110	t		Sara	Rab5ip represents a novel rab5 interacting protein that may function on endocytic vesicles as a receptor for rab5-GDP and participate in the activation of rab5	SIGNOR-261309	0.429
CSNK1E	protein	P49674	UNIPROT	DVL3	protein	Q92997	UNIPROT	down-regulates activity	phosphorylation	Ser280	DGGIYIGsIMKGGAV	-1									24993822	t		miannu	Co-expression of CK1ϵ with FLAG-Dvl3 retards electrophoretic migration and induces phosphorylation-dependent shift of Dvl (PS-Dvl3). mutations of Ser-280 and Ser-311 prevent efficient activation of Wnt/β-catenin by Dvl3.	SIGNOR-276645	0.653
NARS2	protein	Q96I59	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270466	0.8
PTPRG	protein	P23470	UNIPROT	CDK2	protein	P24941	UNIPROT	down-regulates activity	dephosphorylation	Tyr15	EKIGEGTyGVVYKAR	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254695	0.302
TAK-901	chemical	CID:16124208	PUBCHEM	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207191	0.8
ACTL6A	protein	O96019	UNIPROT	SWI/SNF ACTL6A-ARID1A-SMARCA2 variant	complex	SIGNOR-C470	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269827	0.829
NVP-ADW742	chemical	CID:9825149	PUBCHEM	IGF1R	protein	P08069	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194883	0.8
MAPK1	protein	P28482	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606									12466266	t		gcesareni	Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity;ser118 is phosphorylated by mitogen-activated protein kinase (mapk) in vitro and in cells treated with epidermal growth factor (egf) and insulin-like growth factor (igf) in vivo.	SIGNOR-96072	0.657
RBPJ	protein	Q06330	UNIPROT	RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	form complex	binding												23729744	t		apalma	The released NICD translocates directly to the nucleus, where it forms a transcriptional complex with the DNA-binding protein CSL (CBF1, Suppressor of Hairless, Lag1), Mastermind (Mam) and transcriptional co-activators to drive the expression of Notch target genes	SIGNOR-255378	0.949
AKT3	protein	Q9Y243	UNIPROT	CHUK	protein	O15111	UNIPROT	up-regulates	phosphorylation	Thr23	EMRERLGtGGFGNVC	9606				SIGNOR-C14					19609947	t		gcesareni	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-187062	0.389
BAG5	protein	Q9UL15	UNIPROT	HSPA1B	protein	P0DMV9	UNIPROT	down-regulates activity	binding			9606	BTO:0000142								15603737	t		Monia	Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction.	SIGNOR-261197	0.668
BMPR2	protein	Q13873	UNIPROT	ACVR1/BMPR2	complex	SIGNOR-C30	SIGNOR	form complex	binding			9606									7791754	t		lperfetto	Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.	SIGNOR-33437	0.701
NAE	complex	SIGNOR-C131	SIGNOR	CUL2	protein	Q13617	UNIPROT	up-regulates activity	neddylation			9606									25504797	t		lperfetto	The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates.	SIGNOR-243154	0.532
CDK2	protein	P24941	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates activity	phosphorylation	Ser393	RGELIPIsPSTEVGG		BTO:0000007								10593981	t		llicata	Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. 	SIGNOR-250734	0.711
CYP17A1	protein	P05093	UNIPROT	17alpha-hydroxyprogesterone	smallmolecule	CHEBI:17252	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0001363;BTO:0000050;BTO:0000056							17192295	t		lperfetto	THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones.	SIGNOR-268658	0.8
MAPK8	protein	P45983	UNIPROT	ITCH	protein	Q96J02	UNIPROT	up-regulates activity	phosphorylation	Ser240	RRVSGNNsPSLSNGG	9606	BTO:0000007								16446428	t		gcesareni	Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222	SIGNOR-245323	0.644
CTSH	protein	P09668	UNIPROT	BGLAP	protein	P02818	UNIPROT	down-regulates quantity by destabilization	cleavage	Arg94	IGFQEAYrRFYGPV	-1									9076588	t		miannu	This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 	SIGNOR-256325	0.286
HOXD12	protein	P35452	UNIPROT	MEIS1	protein	O00470	UNIPROT	up-regulates activity	binding			-1									9343407	t	2	miannu	We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets.	SIGNOR-241232	0.432
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	ORC2	protein	Q13416	UNIPROT	up-regulates	phosphorylation	Thr116	LASELAKtPQKSVSF	9606									11931757	t		lperfetto	We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.	SIGNOR-217296	0.699
STK4	protein	Q13043	UNIPROT	PRDX1	protein	Q06830	UNIPROT	down-regulates activity	phosphorylation	Thr90	CHLAWVNtPKKQGGL	-1									23386615	t		miannu	Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183.	SIGNOR-276487	0.2
D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	precursor of			9606									24929114	t		miannu	Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates.	SIGNOR-268142	0.8
AR	protein	P10275	UNIPROT	NR5A1	protein	Q13285	UNIPROT	up-regulates	binding			9606									11518799	t		gcesareni	Ar suppresses transcription of the lhbeta subunit by interacting with steroidogenic factor-1.	SIGNOR-109996	0.418
AP1	complex	SIGNOR-C154	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									9878062	f		lperfetto	AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation.	SIGNOR-252356	0.7
RFC4	protein	P35249	UNIPROT	RF-C complex	complex	SIGNOR-C375	SIGNOR	form complex	binding												12930972	t		lperfetto	RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned 	SIGNOR-265508	0.799
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	YAP1	protein	P46937	UNIPROT	down-regulates	binding			9606									21084559	t		gcesareni	Phosphorylation of yap ser127 and of the corresponding sites in yki and taz generates a protein-binding motif for the 14-3-3 family proteins, which, upon binding by a 14-3-3 protein, leads to their cytoplasmic retention. One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73.	SIGNOR-169719	0.2
NARS1	protein	O43776	UNIPROT	tRNA(Asn)	smallmolecule	CHEBI:29172	ChEBI	down-regulates quantity	chemical modification			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270453	0.8
dexamethasone	chemical	CHEBI:41879	ChEBI	CEBPA	protein	P49715	UNIPROT	up-regulates				9606									11279134	f		fspada	The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin	SIGNOR-250568	0.8
KDM3B	protein	Q7LBC6	UNIPROT	PPARA	protein	Q07869	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0005964								19194461	t		miannu	 We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. 	SIGNOR-266637	0.2
OXGR1	protein	Q96P68	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257310	0.2
NALCN	protein	Q8IZF0	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								32698188	t		miannu	Persistently depolarizing sodium (Na+) leak currents enhance electrical excitability. The ion channel responsible for the major background Na+ conductance in neurons is the Na+ leak channel, non-selective (NALCN)	SIGNOR-265181	0.8
ASAP2	protein	O43150	UNIPROT	ARF6	protein	P62330	UNIPROT	up-regulates activity	gtpase-activating protein			-1									10022920	t		miannu	Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain.  In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6.  Pap protein exhibits Arf GAP activity in vitro. 	SIGNOR-269706	0.654
Sin3B_complex	complex	SIGNOR-C409	SIGNOR	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	binding			9606	BTO:0000007								21041486	t	inferred from 70% of family members	miannu	We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin.	SIGNOR-269844	0.2
KPNA3	protein	O00505	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	relocalization			9606									20454918	t		gcesareni	Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7.	SIGNOR-165280	0.329
CHEK1	protein	O14757	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	phosphorylation			9606									18243098	t		gcesareni	We identify chk1 as the kinase responsible for h3-t11 phosphorylation. H3-t11 phosphorylation occurs throughout the cell cycle and is chk1 dependent in vivo.Phosphorylation at thr-12 (h3t11ph) by pkn1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of lys-10 (h3k9me) by kdm4c/jmjd2c.	SIGNOR-265326	0.2
CSNK2A1	protein	P68400	UNIPROT	PSMA3	protein	P25788	UNIPROT	unknown	phosphorylation	Ser250	SLKEEDEsDDDNM	-1									8619999	t		llicata	Several C8 protein constructs allow the location of the CKII phosphorylation sites to be the COOH terminal portion of the protein, and direct mutational analyses show that Ser-243 and Ser-250 are the residues of the C8 subunit phosphorylated by CKII. The in vitro phosphorylation of the proteasome by CKII does not affect its proteolytic activity (on proteins or fluorogenic synthetic peptides), therefore suggesting its involvement in the interaction of the proteasome with other cellular proteins, i.e. in the formation of the 26S complex and/or in the interaction with the nuclear translocation machinery.	SIGNOR-250939	0.389
EP300	protein	Q09472	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates quantity by stabilization	acetylation	Lys378	TIRMSFVkGWGAEYR	9606									16862174	t		miannu	Smad proteins are crucial for the intracellular signaling of transforming growth factor-beta (TGF-beta). Upon their receptor-induced activation, Smad proteins are phosphorylated and translocated to the nucleus to activate the transcription of a select set of target genes. Here, we show that the co-activator p300/CBP bound and acetylated Smad3 as well as Smad2 in vivo, and that the acetylation was stimulated by TGF-beta.A major acetylation site of Smad3 by p300/CBP is Lys-378 in the MH2 domain (Smad3C) known to be critical for the regulation of transcriptional activity.	SIGNOR-260431	0.726
PLK1	protein	P53350	UNIPROT	VIM	protein	P08670	UNIPROT	up-regulates	phosphorylation	Ser83	GVRLLQDsVDFSLAD	9606	BTO:0000150								18056432	t		gcesareni	We observed that plk1 phosphorylates vimentin on ser82, which in turn regulates cell surface levels of 1 integrin.	SIGNOR-159386	0.2
MMP10	protein	P09238	UNIPROT	HAPLN1	protein	P10915	UNIPROT	down-regulates quantity by destabilization	cleavage	His31	LDHDRAIhIQAENGP	-1									7694569	t		miannu	Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.	SIGNOR-256331	0.329
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PHKA1	protein	P46020	UNIPROT	down-regulates activity	phosphorylation			9606									10487978	t			Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.	SIGNOR-267409	0.2
PTK2B	protein	Q14289	UNIPROT	STAP1	protein	Q9ULZ2	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								10518561	t		miannu	 In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling.	SIGNOR-261818	0.358
GPR119	protein	Q8TDV5	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256768	0.392
PRKACA	protein	P17612	UNIPROT	AKAP12	protein	Q02952	UNIPROT	up-regulates activity	phosphorylation	Ser696	KKRARRGsSSDEEGG	-1									14657015	t		lperfetto	Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin.	SIGNOR-271843	0.2
gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	up-regulates activity	chemical activation			9606									18790874	t	brain	lperfetto	Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS).	SIGNOR-263786	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606	BTO:0000938	BTO:0004249							23125836	f		miannu	PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex	SIGNOR-264961	0.7
C2	protein	P06681	UNIPROT	C3 convertase complex	complex	SIGNOR-C310	SIGNOR	form complex	binding			-1					cleavage:Arg243	KTKESLGrKIQIQRS			17204478	t	complement C2a fragment: PRO_0000027612	lperfetto	 However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex	SIGNOR-263399	0.627
LYN	protein	P07948	UNIPROT	SLC4A1	protein	P02730	UNIPROT	unknown	phosphorylation	Tyr904	EEEGRDEyDEVAMPV	-1									10942405	t			Lyn phosphorylates Y904 and Y359 of band 3. The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton movements, and anion transport.	SIGNOR-251414	0.343
A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	TERT	protein	O14746	UNIPROT	up-regulates quantity by expression				10090									18757303	f		lperfetto	Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1.	SIGNOR-253280	0.312
PRKCZ	protein	Q05513	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser303	RGAPPRRsSIRNAHS	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89252	0.402
HDAC7	protein	Q8WUI4	UNIPROT	PLAGL2	protein	Q9UPG8	UNIPROT	down-regulates	deacetylation			9606									16207715	t		miannu	Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.	SIGNOR-140953	0.26
SMURF1	protein	Q9HCE7	UNIPROT	SMAD5	protein	Q99717	UNIPROT	down-regulates	ubiquitination			9606									22298955	t	Ubiquitin-mediated proteolysis.	gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-195663	0.76
PF-03814735	chemical	CID:49830590	PUBCHEM	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205956	0.8
RNF144B	protein	Q7Z419	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001109								12853982	t		miannu	P53RFP, a p53-inducible RING-finger protein, regulates the stability of p21WAF1. Here we report the isolation of a novel transcriptional target of p53, designated p53RFP (p53-inducible RING-finger protein), whose product has E3 ubiquitin ligase activity. Its expression was negatively correlated to that of p21(WAF1) protein; p53RFP is likely to play a role in the regulation of this protein, probably through interaction with, and ubiquitination of, p21(WAF1). 	SIGNOR-271478	0.366
PRTN3	protein	P24158	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Val55	VTGKGVTvETVFSVD	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263599	0.381
TTL	protein	Q8NG68	UNIPROT	TUBA3E	protein	Q6PEY2	UNIPROT	down-regulates	tyrosination			9606									22020298	t		miannu	Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization	SIGNOR-176924	0.435
RAB9A	protein	P51151	UNIPROT	GCC2	protein	Q8IWJ2	UNIPROT	up-regulates activity													18195106	t		lperfetto	Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector	SIGNOR-253087	0.521
LAMA4	protein	Q16363	UNIPROT	Laminin-8	complex	SIGNOR-C181	SIGNOR	form complex	binding												10809728	t		lperfetto	Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. 	SIGNOR-253226	0.504
LGALS3	protein	P17931	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates quantity by stabilization				9606	BTO:0000664								21821001	f		miannu	Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells.	SIGNOR-261907	0.2
LRP6	protein	O75581	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity	binding			9606									19107203	t	PPPSPxS motif in LRP6/5 must be phosphorylated.	lperfetto	These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin.These Observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence.	SIGNOR-227942	0.723
PTK2	protein	Q05397	UNIPROT	TLN1	protein	Q9Y490	UNIPROT	up-regulates activity	binding			9606									15688067	t		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257731	0.676
PDX1	protein	P52945	UNIPROT	GCK	protein	P35557	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8866550	f		miannu	 The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription.	SIGNOR-254911	0.59
CAMK1	protein	Q14012	UNIPROT	GCM1	protein	Q9NP62	UNIPROT	up-regulates activity	phosphorylation	Ser47	YAKHIYSsEDKNAQR	9606	BTO:0000007								21791615	t		miannu	We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation.	SIGNOR-262680	0.396
DOK7	protein	Q18PE1	UNIPROT	MUSK	protein	O15146	UNIPROT	up-regulates	binding			9606									23467009	t		gcesareni	In addition, dok7, a cytoplasmic adaptor protein, is also required for musk activation in vivo. This review focuses on the physical interplay between these proteins and musk for activation and downstream signaling, which culminates in nmj formation.	SIGNOR-192264	0.746
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser14	LYSFFSPsPARKRHA	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276100	0.267
MAPK14	protein	Q16539	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates activity	phosphorylation	Ser867	SPVSVGSsPPVKNIS	9606	BTO:0000093								15383283	t		miannu	P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators.	SIGNOR-250106	0.505
MLL-AF4	fusion protein	SIGNOR-FP4	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									21389315	f		irozzo	Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair. 	SIGNOR-255872	0.7
PRKCA	protein	P17252	UNIPROT	F3	protein	P13726	UNIPROT	up-regulates	phosphorylation	Ser285	RKAGVGQsWKENSPL	9606									23195225	t		lperfetto	We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. The phosphorylation of ser253 is known to be mediated by protein kinase c_	SIGNOR-199872	0.2
PKG	proteinfamily	SIGNOR-PF77	SIGNOR	3-phosphonato-D-glyceroyl phosphate(4-)	smallmolecule	CHEBI:57604	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa.	SIGNOR-266504	0.8
DAPK3	protein	O43293	UNIPROT	DAPK3	protein	O43293	UNIPROT	up-regulates	phosphorylation	Ser311	EYTIKSHsSLPPNNS	9606									15611134	t		lperfetto	Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311.	SIGNOR-132455	0.2
NLGN4X	protein	Q8N0W4	UNIPROT	NRXN1	protein	Q9ULB1	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264145	0.763
PIN1	protein	Q13526	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606									19151708	t		gcesareni	Prolyl-isomerase pin1 interacts with notch1 and affects notch1 activation. Pin1 potentiates notch1 cleavage by gamma-secretase, leading to an increased release of the active intracellular domain and ultimately enhancing notch1. pin1 potentiates notch1 cleavage by gamma-secretase	SIGNOR-183461	0.393
FGF14	protein	Q92915	UNIPROT	SCN9A	protein	Q15858	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253425	0.2
DUSP3	protein	P51452	UNIPROT	NPM1	protein	P06748	UNIPROT	down-regulates activity	dephosphorylation			9606									33777934	t		lperfetto	In the absence of DUSP3, these three residues remain phosphorylated and favor the dissociation equilibrium of NPM homo-oligomerization and/or its association with ARF, therefore promoting an early nuc|Therefore, here we focused on the molecular mechanisms used by DUSP3-NPM interaction to affect the abovementioned cellular responses and found out that DUSP3 dephosphorylates three tyrosine residues (Y29, Y67, and Y271) of NPM.	SIGNOR-277005	0.2
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1787	SPNYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269336	0.718
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				-1									14663477	f		Luana	Multiple studies supporting the role of Akt in apoptosis suppression have connected Akt to cell death regulation either by demonstrating its downregulation following pro-apoptotic insults, or by using gene-transfer experiments that transduce both activated, anti-apoptotic and inactive, pro-apoptotic mutants of Akt.	SIGNOR-260215	0.7
MAP3K7	protein	O43318	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	phosphorylation	Thr184	GTACDIQtHMTNNKG	-1									20538596	t		lperfetto	Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation.	SIGNOR-227544	0.2
GATA1	protein	P15976	UNIPROT	GATA2	protein	P23769	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21853041	t		miannu	GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1.	SIGNOR-256060	0.419
SAR1A	protein	Q9NR31	UNIPROT	SEC24C	protein	P53992	UNIPROT	up-regulates quantity	binding							SIGNOR-C370					30605680	t		lperfetto	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 	SIGNOR-265302	0.698
SOS2	protein	Q07890	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									21779497	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.	SIGNOR-175265	0.704
NAA15	protein	Q9BXJ9	UNIPROT	NatA	complex	SIGNOR-C415	SIGNOR	form complex	binding			9606	BTO:0000007								15496142	t		miannu	Protein acetyltransferases and deacetylases have been implicated in oncogenesis, apoptosis and cell cycle regulation. Most of the protein acetyltransferases described acetylate epsilon-amino groups of lysine residues within proteins. We now describe the human homologue of Nat1p, NATH (NAT human), as the partner of the hARD1 (human ARD1) protein. Included in the characterization of the NATH and hARD1 proteins is the following: (i) endogenous NATH and hARD1 proteins are expressed in human epithelial, glioma and promyelocytic cell lines; (ii) NATH and hARD1 form a stable complex, as investigated by reciprocal immunoprecipitations followed by MS analysis; (iii) NATH-hARD1 complex expresses N-terminal acetylation activity; (iv) NATH and hARD1 interact with ribosomal subunits, indicating a co-translational acetyltransferase function	SIGNOR-267225	0.95
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606									16403219	t		lperfetto	All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death.	SIGNOR-259421	0.2
CDK8	protein	P49336	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR										18418385	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	lperfetto	However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo.	SIGNOR-273173	0.2
INO80 complex	complex	SIGNOR-C498	SIGNOR	DNA_replication	phenotype	SIGNOR-PH53	SIGNOR	up-regulates				9606									25016522	f		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 	SIGNOR-270858	0.7
ATM	protein	Q13315	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	up-regulates	phosphorylation	Ser1219	DDTESLHsQGEEEFD	9606									22621922	t		gcesareni	Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm.	SIGNOR-197611	0.869
CEBPB	protein	P17676	UNIPROT	CREB1	protein	P16220-1	UNIPROT	up-regulates activity	binding			9534	BTO:0000298								12773552	t		miannu	We conclude that C/EBP-β can directly bind to the N-terminal Q1 domain of CREB in addition to binding to the leucine zipper domain. The transactivation potential of full-length CREB fused to the DNA-binding domain of Gal4 was increased synergistically by calcium and cGMP, and overexpression of C/EBP-β enhanced the effect, while a dominant negative C/EBP inhibited it	SIGNOR-263654	0.578
EFR3A	protein	Q14156	UNIPROT	PI4KA	protein	P42356	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								34504076	t		miannu	PI4KA is recruited to plasma membrane by the adapter protein EFR3, which has two isoforms, EFR3A and EFR3B	SIGNOR-269092	0.483
PABPN1	protein	Q86U42	UNIPROT	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates quantity by stabilization	binding			9606									25480299	t		lperfetto	As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length.	SIGNOR-268320	0.8
L-ornithine	smallmolecule	CHEBI:15729	ChEBI	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates activity													24669294	f		apalma	While investigating the factors that regulate macrophage arginine metabolism, Mills and colleagues found that macrophages activated in mouse strains with Th1 and Th2 backgrounds differed qualitatively in their ability to respond to the classic stimuli IFN-γ or lipopolysaccharide (LPS) or both and defined an important metabolic difference in the pathway: M1 macrophages made the toxic nitric oxide (NO), whereas M2 macrophages made the trophic polyamines	SIGNOR-256076	0.7
MAPKAPK2	protein	P49137	UNIPROT	ETV1	protein	P50549	UNIPROT	up-regulates	phosphorylation			9606									20626350	t		gcesareni	Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2	SIGNOR-166625	0.595
COL1A1	protein	P02452	UNIPROT	DDR2	protein	Q16832	UNIPROT	up-regulates activity	binding			9606	BTO:0001282								17318226	t		lperfetto	The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75. 	SIGNOR-272342	0.434
RUNX2	protein	Q13950	UNIPROT	Osteoblast_differentiation	phenotype	SIGNOR-PH9	SIGNOR	up-regulates				10090									9182762	f		gcesareni	Osf2/cbfa1 as an osteoblast-specific transcription factor and as a regulator of osteoblast differentiation	SIGNOR-48940	0.7
CEBPB	protein	P17676	UNIPROT	SLC5A8	protein	Q8N695	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20082847	t	 	 	Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription.	SIGNOR-254054	0.2
CDK4	protein	P11802	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Thr826	LPTPTKMtPRSRILV	9606			SIGNOR-C18						9139732	t		miannu	We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein.	SIGNOR-47899	0.927
CACNA1E	protein	Q15878	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									30849329	t		miannu	CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. 	SIGNOR-264322	0.8
PTK2	protein	Q05397	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr577	YMEDSTYyKASKGKL	9606									7529876	t		llicata	We found that maximal kinase activity of fak immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of fak by src (or other src family kinases) is an important step in the formation of an active signaling complex.	SIGNOR-27879	0.2
PAK5	protein	Q9P286	UNIPROT	SYNJ1	protein	O43426	UNIPROT	up-regulates activity	phosphorylation			-1									22371566	t		miannu	We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. 	SIGNOR-263026	0.2
TBK1	protein	Q9UHD2	UNIPROT	STX17	protein	P56962	UNIPROT	up-regulates activity	phosphorylation	Ser202	SQQEKIDsIADHVNS	9606	BTO:0000007								30827897	t	done	miannu	Stx17 is phosphorylated by TBK1 whereby phospho-Stx17 controls the formation of the ATG13+FIP200+ mammalian pre-autophagosomal structure (mPAS) in response to induction of autophagy. TBK1 phosphorylates Stx17 at S202.	SIGNOR-273812	0.296
pipamperone	chemical	CHEBI:78549	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258571	0.8
PPP2CA	protein	P67775	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	dephosphorylation			9606									20704570	t		gcesareni	Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a.	SIGNOR-167480	0.2
VHL	protein	P40337	UNIPROT	KLF10	protein	Q13118	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003781								18359287	f		lperfetto	In this study, we show that both TGFBI and KLF10 are down-regulated by VHL in 786-0 cells, and that KLF10 may serve as a transactivator of the TGFBI promoter.	SIGNOR-253213	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	TSC	complex	SIGNOR-C101	SIGNOR	down-regulates activity	phosphorylation			9606	BTO:0000007								15342917	t		lperfetto	The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1	SIGNOR-256311	0.714
ECM	stimulus	SIGNOR-ST20	SIGNOR	A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259037	0.7
APOE	protein	P02649	UNIPROT	VLDLR	protein	P98155	UNIPROT	up-regulates	binding			9606									11278667	t		gcesareni	Several ligands for the vldl receptor have been identified in addition to tfpi. These include apolipoprotein e (apoe)	SIGNOR-106221	0.635
PKP2	protein	Q99959	UNIPROT	DSP	protein	P15924	UNIPROT	up-regulates quantity by stabilization	binding			10090	BTO:0003264								22781308	t		Simone	In contrast to the proper membrane localization of PKP2 and DSP after cotransfection of both WT proteins, mutant PKP2 C796R protein was not able to interact with FLAG-DSP to enable assembly at the junctional plaque, indicating the requirement of functional PKP2 for DSP integration into the desmosome.	SIGNOR-261254	0.779
MAPK9	protein	P45984	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	phosphorylation	Ser191	SRHAIMRsPQMVSAI	9606									18423204	t		amattioni	Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt.	SIGNOR-178258	0.657
PTGS2	protein	P35354	UNIPROT	Prostacycline	smallmolecule	CID:159	PUBCHEM	up-regulates	chemical modification			9606									11751058	t		gcesareni	Cox catalyzes two enzymatic activities;namely, the conversion of aa to the hydroperoxy endoperoxide pgg2, followed by its subsequent reduction to the labile product pgh2. Pgh2_ is the common substrate for a number of different cell-specific synthases, which convert pgh2_ to the individual pgs or tx, including pge2, pgi2_ (prostacyclin), pgd2, pgf2alfa, and txa2	SIGNOR-113300	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation			9606									21440011	t		lperfetto	Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs	SIGNOR-252833	0.908
NEDD4L	protein	Q96PU5	UNIPROT	SCN11A	protein	Q9UI33	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000938								23778145	t		miannu	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 	SIGNOR-253462	0.293
GLUL	protein	P15104	UNIPROT	L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	up-regulates quantity	chemical modification			9606									30158707	t		miannu	Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction.	SIGNOR-267826	0.8
CDKL5	protein	O76039	UNIPROT	LRRC4C	protein	Q9HCJ2	UNIPROT	unknown	phosphorylation	Ser631	PLLIRMNsKDNVQET	9606									22922712	t		llicata	Cdkl5 binds and phosphorylates the cell adhesion molecule ngl-1. This phosphorylation event ensures a stable association between ngl-1 and psd95.	SIGNOR-192035	0.44
CDK5	protein	Q00535	UNIPROT	HTR1A	protein	P08908	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr314	LPSEAGPtPCAPASF	9534	BTO:0004055								30712943	t		lperfetto	Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT 1A receptor via phosphorylation|5-HT1AR was phosphorylated by the Cdk5-p35 complex at Thr314 in the third cytoplasmic loop.	SIGNOR-264406	0.274
KSR1	protein	Q8IVT5	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Thr269	NVHMVSTtLPVDSRM	9606									11134016	t		lperfetto	Here we show that phosphorylation of c-raf-1 on thr(269) by ksr is necessary for optimal activation in response to egf stimulation.	SIGNOR-85386	0.638
pralidoxime	chemical	CHEBI:8354	ChEBI	ACHE	protein	P22303	UNIPROT	up-regulates activity	chemical activation			-1									21215642	t		Luana	These compounds were synthesized, evaluated in vitro on human AChE (hAChE) inhibited by tabun, paraoxon, methylparaoxon and DFP and then compared to commercial hAChE reactivators (pralidoxime, HI-6, trimedoxime, obidoxime, methoxime) or previously prepared compounds (K027, K203). Three of these novel compounds showed a promising ability to reactivate hAChE comparable or better than the used standards. 	SIGNOR-257889	0.8
MAP3K7	protein	O43318	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates activity	phosphorylation			9606				SIGNOR-C14					19632174	t		lperfetto	Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta.	SIGNOR-187242	0.744
Brain-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C486	SIGNOR	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	up-regulates				9606		BTO:0000143							25195934	f		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270759	0.7
bexarotene	chemical	CHEBI:50859	ChEBI	RXRG	protein	P48443	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002058								17483357	t		miannu	Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification.	SIGNOR-259232	0.8
ARHGAP31	protein	Q2M1Z3	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260489	0.546
TFEB	protein	P19484	UNIPROT	PPM1D	protein	O15297	UNIPROT	up-regulates quantity by expression	transcriptional regulation												28552616	t		lperfetto	As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes;	SIGNOR-276557	0.2
APC-c	complex	SIGNOR-C150	SIGNOR	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. 	SIGNOR-272750	0.42
PKM	protein	P14618	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606									22306293	t		llicata	Pkm2 activates transcription of mek5 by phosphorylating stat3 at y705. pkm2 regulates mek5 transcription via activation of stat3	SIGNOR-195766	0.457
TFEB	protein	P19484	UNIPROT	NDUFAF2	protein	Q8N183	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4).	SIGNOR-276703	0.2
NBEAL2	protein	Q6ZNJ1	UNIPROT	SELP	protein	P16109	UNIPROT	up-regulates				9606	BTO:0000132								28082341	f		lperfetto	Recent in vitro megakaryopoiesis studies using HSCs from GPS patients with NBEAL2 mutations showed normal MK differentiation with defective proplatelet formation and reduced α-granule proteins such as von Willebrand factor (VWF), thrombospondin and P-selectin.	SIGNOR-261885	0.302
NF1	protein	P21359	UNIPROT	ADCY4	protein	Q8NFM4	UNIPROT	up-regulates				9606									24431436	f		miannu	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-204091	0.291
TLR4	protein	O00206	UNIPROT	TICAM1	protein	Q8IUC6	UNIPROT	up-regulates activity	binding			10090									22664090	t		gcesareni	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-252067	0.844
HMGB1	protein	P09429	UNIPROT	HOXD3	protein	P31249	UNIPROT	up-regulates activity	binding			-1									8890171	t		miannu	We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.	SIGNOR-219980	0.301
FGR	protein	P09769	UNIPROT	SRC	protein	P12931	UNIPROT	unknown	phosphorylation	Tyr530	FTSTEPQyQPGENL	-1									9208935	t			An eicosapeptide encompassing the C-terminal tail of c-Src (Tyr527) which is conserved in most Src-related protein kinases, is phosphorylated by C-terminal Src kinase (CSK) and by the two Src-related protein kinases c-Fgr and Lyn, with similar kinetic constants. 	SIGNOR-251145	0.63
3-(4-{[5-Fluoro-2-(4-methylphenyl)phenyl]methoxy}phenyl)propanoic acid	chemical	CID:57522038	PUBCHEM	FFAR4	protein	Q5NUL3	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257491	0.8
SGK1	protein	O00141	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates activity	phosphorylation	Thr198	PGLRRRQt	9606									18570873	t		gcesareni	Activated sgk1 and p27 phosphorylation at t157, and both were inhibited by short-term rapamycin treatment and by sgk1 shrna.|Akt acts downstream of PI3K to phosphorylate p27 at T157 and T198, leading to impaired nuclear p27 import, p27 accumulation in the cytoplasm, and loss of cyclin E-Cdk2 inhibition	SIGNOR-179121	0.482
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	HIF1A	protein	Q16665	UNIPROT	up-regulates activity	chemical activation												20383689	t		lperfetto	HIF prolyl hydroxylase-3 mediates alpha-ketoglutarate-induced apoptosis and tumor suppression|The hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) are enzymes that are functionally inactivated in hypoxia, as they use both oxygen and alpha-ketoglutarate as substrates to hydroxylate target prolyl residues.	SIGNOR-253138	0.8
PTPRG	protein	P23470	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates activity	dephosphorylation	Tyr413	TAPESLAyNKFSIKS	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254691	0.347
CSNK1A1	protein	P48729	UNIPROT	HNRNPC	protein	P07910	UNIPROT	down-regulates activity	phosphorylation	Ser260	SEGGADDsAEEGDLL	9606									15687492	t		gcesareni	In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C.	SIGNOR-133532	0.361
COL4A4	protein	P53420	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates activity	binding												35267698	t		lperfetto	Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23].	SIGNOR-272350	0.435
IGF1	protein	P05019	UNIPROT	Calcineurin	complex	SIGNOR-C155	SIGNOR	up-regulates				10090									10448861	f		lperfetto	Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1.	SIGNOR-252306	0.269
CCNO	protein	P22674	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates activity	binding												37197505	t		lperfetto	CDK2 is the predominant activating complex form of CCNO, but CCNO can bind to CDK1 to form an activating complex in the absence of CDK2. 	SIGNOR-275617	0.341
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation	Ser119	EILSRRPsYRKILND	9606	BTO:0000938								10558990	t		lperfetto	The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival.	SIGNOR-252782	0.2
PPP2CA	protein	P67775	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	down-regulates	dephosphorylation			9606									20626350	t		gcesareni	In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a.	SIGNOR-166649	0.54
MAPK1	protein	P28482	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606									17615152	t		gcesareni	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.	SIGNOR-156856	0.657
SLC24A1	protein	O60721	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	down-regulates quantity	relocalization			9606									30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264390	0.8
ATM	protein	Q13315	UNIPROT	RAD9A	protein	Q99638	UNIPROT	up-regulates activity	phosphorylation	Ser272	LSDTDSHsQDLGSPE	9606		BTO:0000763							11278446	t		lperfetto	Hyperphosphorylation of hrad9 induced by ir is dependent on atm. Ser(272) of hrad9 is phosphorylated directly by atm in vitro. / our results suggest that the atm-mediated phosphorylation of hrad9 is required for ir-induced checkpoint activation.	SIGNOR-105243	0.759
PAK1	protein	Q13153	UNIPROT	HACE1	protein	Q8IYU2	UNIPROT	down-regulates activity	phosphorylation	Ser385	LMKNKRDsTEITSIL	9606	BTO:0004980								29362425	t			Using a proteomic approach, we identified serine 385 as a target of group-I PAK kinases […] We have established in vitro that HACE1 is a direct target of PAK1 kinase activity.	SIGNOR-255537	0.2
MTOR	protein	P42345	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser307	TRRSRTEsITATSPA	10116	BTO:0000452								11287630	t		lperfetto	Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten	SIGNOR-106570	0.758
MEF2C	protein	Q06413	UNIPROT	MYF6	protein	P23409	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165;BTO:0000222								7739551	t		lperfetto	Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis.	SIGNOR-238652	0.548
PRKN	protein	O60260	UNIPROT	MFN2	protein	O95140	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000793								20871098	t		miannu	Parkin and PINK1 are required for ubiquitination of MFN-1 and MFN-2.  Decreases in MFN-1 and MFN-2 protein levels seen at later timepoints are difficult to interpret as it is unclear whether this is due to degradation by the proteasome and/or loss of whole mitochondria by mitophagy.	SIGNOR-272780	0.2
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1889	SPTTPKYsPTSPTYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii	SIGNOR-203580	0.77
ITGB1	protein	P05556	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253170	0.748
MAPK3	protein	P27361	UNIPROT	ARHGAP26	protein	Q9UNA1	UNIPROT	unknown	phosphorylation	Ser685	PMFSAPSsPMPTSST	-1									9525907	t		miannu	In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling.	SIGNOR-262945	0.2
CUL2	protein	Q13617	UNIPROT	BAF250b E3 ligase	complex	SIGNOR-C522	SIGNOR	form complex	binding			9606	BTO:0000567								20086098	t		miannu	In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro	SIGNOR-271440	0.61
PRKCA	protein	P17252	UNIPROT	RHO	protein	P08100	UNIPROT	unknown	phosphorylation	Ser334	PLGDDEAsATVSKTE	-1									9099669	t		lperfetto	Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343.	SIGNOR-248966	0.451
TARDBP	protein	Q13148	UNIPROT	DICER1	protein	Q9UPY3	UNIPROT	up-regulates quantity	post transcriptional regulation			7227									32620127	t		lperfetto	Molecularly, we observed that TBPH regulates the expression levels of Dicer-2 by direct protein-mRNA interactions in vivo.|In agreement with this idea, we found that the suppression of TDP-43 induces the downregulation of Dicer in human neuroblastoma cell lines signifying that the TDP-43 function is required to prevent defects in Dicer protein expression or stability	SIGNOR-262114	0.383
FNTA	protein	P49354	UNIPROT	MRAS	protein	O14807	UNIPROT	up-regulates activity				9606									24294527	t		lperfetto	Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials.	SIGNOR-242553	0.2
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Thr32	QSRPRSCtWPLQRPE										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-252846	0.908
CACNA1G	protein	O43497	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									30849329	t		miannu	Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]).	SIGNOR-264324	0.8
regorafenib	chemical	CHEBI:68647	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates activity	chemical inhibition			9606									24756792	t		miannu	In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically.	SIGNOR-259206	0.8
MAPK1	protein	P28482	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser195	PNSSYPNsPGSSSST	9606									19914168	t		lpetrilli	Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3	SIGNOR-161686	0.59
EGFR	protein	P00533	UNIPROT	VAV2	protein	P52735	UNIPROT	up-regulates	phosphorylation	Tyr142	TENDDDVyRSLEELA	9606									12454019	t		miannu	To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor.	SIGNOR-95972	0.61
Oxotremorine	chemical	CHEBI:7851	ChEBI	CHRM3	protein	P20309	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258652	0.8
GRPEL1	protein	Q9HAV7	UNIPROT	HSPA8	protein	P11142	UNIPROT	down-regulates activity	binding			9606	BTO:0000793								11311562	t		miannu	As we had observed earlier,HMGE bound avidly to DnaK (Fig. 5A). In addition, bothMt-Hsp70 and Hsc70 bound to GST-HMGE, but Hsc70 appeared to bind with lower affinity. HMGE inhibitedthe co-chaperone enhancement of Hsc70 ATPase activity byapproximately 50% (Table 1). 	SIGNOR-261241	0.638
PHF20	protein	Q9BVI0	UNIPROT	NSL histone acetyltransferase	complex	SIGNOR-C413	SIGNOR	form complex	binding			9606	BTO:0000007								20018852	t		miannu	Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex.	SIGNOR-267159	0.67
CSNK2A2	protein	P19784	UNIPROT	NKX3-1	protein	Q99801	UNIPROT	up-regulates	phosphorylation	Thr93	EAETLAEtEPERHLG	9606	BTO:0001130								16581776	t		llicata	In vitro kinase assays followed by mass spectrometric analyses demonstrated that ck2 phosphorylated recombinant nkx3.1 on thr89 and thr93. We have also determined that nkx3.1 is degraded primarily through a proteasomal pathway, suggesting that phosphorylation by ck2 protects nkx3.1 from degradation.	SIGNOR-145505	0.321
CoREST-HDAC complex	complex	SIGNOR-C105	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606									32101746	f		miannu	 The CoREST complex is one of seven families of class I histone deacetylase complexes that have specialized physiological functions but are all thought to act as repressors of gene expression. CoREST is unique within these complexes in that it removes both acetyl and methyl modifications through the activity of its demethylase (LSD1) and deacetylase (HDAC1) enzymes.	SIGNOR-263861	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TBC1D4	protein	O60343	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000887							12637568	t		gcesareni	Recently, we identified a 160-kda protein in adipocytes, designated as160, that is phosphorylated by the insulin-activated kinase akt	SIGNOR-99300	0.2
MAPK1	protein	P28482	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation			9606									9922370	t		gcesareni	Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity	SIGNOR-64169	0.616
prednisolone	chemical	CHEBI:8378	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									11777359	t	rheumatoid arthritis	gcesareni		SIGNOR-251699	0.8
PAX2	protein	Q02962	UNIPROT	PAX2/TLE4	complex	SIGNOR-C152	SIGNOR	form complex	binding			9606									16631587	t		miannu	Several Pax proteins are able to interact with groucho (TLE) family members. Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1.	SIGNOR-256359	0.469
MCU_MICU2_variant	complex	SIGNOR-C502	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270878	0.8
MAPK3	protein	P27361	UNIPROT	NR3C2	protein	P08235	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser263	NVGSPLSsPLSSMKS	9606	BTO:0005043								22798426	t		miannu	 Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276108	0.358
FYN	protein	P06241	UNIPROT	WAS	protein	P42768	UNIPROT	up-regulates activity	phosphorylation	Tyr291	AETSKLIyDFIEDQG	10090	BTO:0000775								14707117	t	done	miannu	TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation. 	SIGNOR-273960	0.579
APBA1	protein	Q02410	UNIPROT	NRXN1	protein	Q9ULB1	UNIPROT	up-regulates activity	binding			9534	BTO:0000298								11036064	t		miannu	Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa. 	SIGNOR-264038	0.653
RHOQ	protein	P17081	UNIPROT	SLC2A4	protein	P14672	UNIPROT	up-regulates				9606									12242347	f		gcesareni	Tc10 is activated afte rinsulin stimulation, and its activation is required for insulin-stimulated glucose uptake and glut4 translocation	SIGNOR-93117	0.445
SYN2	protein	Q92777	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates activity	binding			9606	BTO:0000938								15265865	t		miannu	Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. 	SIGNOR-269185	0.7
CALM1	protein	P0DP23	UNIPROT	KIF1A	protein	Q12756	UNIPROT	up-regulates activity	binding			10116	BTO:0003102								30021165	t		miannu	To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. We show that Ca2+/CaM-dependent modulation on KIF1A allows for binding to vesicular cargo. Our results indicate that at low calcium concentrations, the tail domain of KIF1A does not bind to vesicular cargo, whereas at high calcium concentrations, CaM binds KIF1A, allowing for subsequent DCV motility. 	SIGNOR-266888	0.278
hydroxyurea	chemical	CHEBI:44423	ChEBI	RRM2	protein	P31350	UNIPROT	down-regulates activity	chemical inhibition			9606									14583450	t		miannu	 In PC3 cells, hydroxyurea inhibited hRRM2 and resulted in increased sensitivity to UV irradiation.	SIGNOR-259355	0.8
PPP1CA	protein	P62136	UNIPROT	BRCA1	protein	P38398	UNIPROT	down-regulates activity	dephosphorylation	Ser988	PPLFPIKsFVKTKCK	9606	BTO:0000007								17603999	t			Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524.	SIGNOR-248560	0.384
HDAC3	protein	O15379	UNIPROT	YY1	protein	P25490	UNIPROT	down-regulates activity	deacetylation			-1									11486036	t		miannu	Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs.	SIGNOR-268837	0.582
GSK3B	protein	P49841	UNIPROT	AHR	protein	P35869	UNIPROT	up-regulates activity	phosphorylation	Thr697	EMDSMPYtQNFISCN	9606	BTO:0000567								34198826	t		miannu	A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR.	SIGNOR-276661	0.253
FBXW11	protein	Q9UKB1	UNIPROT	ZNF281	protein	Q9Y2X9	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001615						phosphorylation:Ser638	PRVDLHTsGEHSELV	29179460	t		lperfetto	E3 ligase the beta-transducin repeat-containing protein 2 (beta-TrCP2) governs the ubiquitination and degradation of ZNF281. In human CRC specimens, endogenous beta-TrCP2 were inversely correlated with ZNF281.	SIGNOR-264897	0.2
SMAD4	protein	Q13485	UNIPROT	SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	form complex	binding			9606									9843571	t		lperfetto	TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus.	SIGNOR-229560	0.698
CDK5	protein	Q00535	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser38	SVPEFPLsPPKKKDL	9606									20630875	t		gcesareni	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. The kinases involved in phosphorylating stmn ser-16 and ser-63 include camp-dependent protein kinase (pka) and pak1, whereas stmn ser-25 and ser-38 have been shown to be targets for proline-directed serine/threonine kinases such as cyclin-dependent kinases, erk1/2, and members of the p38 mapk subfamily.	SIGNOR-166682	0.386
PKI-587	chemical	CID:44516953	PUBCHEM	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205986	0.8
PDIA6	protein	Q15084	UNIPROT	Metastasis	phenotype	SIGNOR-PH107	SIGNOR	up-regulates activity				10090	BTO:0004086								17420453	f			Overexpression of ERp5 promotes both in vitro migration and invasion and in vivo metastasis of breast cancer cells.	SIGNOR-256533	0.7
DOT1L	protein	Q8TEK3	UNIPROT	H3-3A	protein	P84243	UNIPROT	unknown	methylation	Lys80	REIAQDFkTDLRFQS	9606									12123582	t		miannu	HDOT1L Is a Nucleosomal H3-K79-Specific HMTase. We identified a human DOT1-like (DOT1L) protein and demonstrated that this protein possesses intrinsic H3-K79-specific histone methyltransferase (HMTase) activity in vitro and in vivo. Furthermore, we found that K79 methylation level is regulated throughout the cell cycle. By using two different methods, we demonstrate that the K79 methylation level decreases during S phase, reaches its lowest level in G2, increases during M phase, and maintains at a high level during G1 phase.	SIGNOR-267143	0.2
CEP350	protein	Q5VT06	UNIPROT	FGFR1OP/CEP350	complex	SIGNOR-C52	SIGNOR	form complex	binding			9606									16314388	t		miannu	Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring.	SIGNOR-142355	0.2
MAP3K10	protein	Q02779	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates	phosphorylation	Ser341	KALASIYsPDHSSNN	9606									19801649	t		llicata	Mlk2 inhibits e47 transactivation activity on the trkb promote	SIGNOR-161523	0.2
PRKCG	protein	P05129	UNIPROT	GRIA4	protein	P48058	UNIPROT	up-regulates	phosphorylation	Ser862	IRNKARLsITGSVGE	9606									12536214	t		gcesareni	We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus.	SIGNOR-97558	0.691
MYC	protein	P01106	UNIPROT	MYCBP2	protein	O75592	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001321								32814769	t		miannu	 We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. 	SIGNOR-267145	0.425
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CDKN1B	protein	P46527	UNIPROT	up-regulates	phosphorylation	Ser178	EENVSDGsPNAGSVE	9606									10831586	t		lperfetto	Indeed, p27kip1 was phosphorylated by p42 mapk (erk2) in vitrothese results suggest that ser(10) is the major site of phosphorylation of p27(kip1) and that phosphorylation at this site, like that at thr(187), contributes to regulation of p27(kip1) stability.	SIGNOR-244517	0.2
EFNA2	protein	O43921	UNIPROT	EPHA2	protein	P29317	UNIPROT	up-regulates	binding			9606									10072375	t		tpavlidou	Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8)	SIGNOR-65413	0.81
RAB33B	protein	Q9H082	UNIPROT	ATG16L1	protein	Q676U5	UNIPROT	up-regulates	binding			9606									18448665	t		gcesareni	Olgi-resident small gtpase rab33b interacts with atg16l and modulates autophagosome formation.	SIGNOR-178542	0.745
MAPK3	protein	P27361	UNIPROT	NR3C2	protein	P08235	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser287	SVKSPVSsPNNVTLR	9606	BTO:0005043								22798426	t		miannu	 Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276110	0.358
MAPK3	protein	P27361	UNIPROT	NR3C2	protein	P08235	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser227	FGSFPVHsPITQGTP	9606	BTO:0005043								22798426	t		miannu	 Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276111	0.358
CAK complex	complex	SIGNOR-C456	SIGNOR	CDK4	protein	P11802	UNIPROT	up-regulates	phosphorylation	Thr172	YSYQMALtPVVVTLW	9606									8139570	t		lperfetto	Phosphorylation of cdk4 on threonine 172 by a cdk-activating kinase (cak).  therefore, formation of the cyclin d-cdk4 complex and phosphorylation of the bound catalytic subunit are independently regulated, and in addition to the requirement for cak activity, serum stimulation is required to promote assembly of the complexes in mammalian cells.	SIGNOR-269329	0.56
CHEK2	protein	O96017	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates	phosphorylation			9606									22558186	t		gcesareni	In this report, we characterize the binding of sh2(chk) to specific phosphotyrosine sites on the c-kit protein sequence. the sh2(chk) binding to the two sites is direct and not through phosphorylated intermediates such as fyn or shc. this indicates that chk binds to the same site on c-kit to which fyn binds, possibly bringing the two into proximity on associated c-kit subunits and leading to the down-regulation of fyn by chk.	SIGNOR-197281	0.291
BMP15	protein	O95972	UNIPROT	BMPR2	protein	Q13873	UNIPROT	up-regulates	binding			9606		BTO:0000975		SIGNOR-C29					16446785	t		gcesareni	Here we have performed a detailed in situ hybridization analysis of the spatial and temporal expression patterns of the bmp ligands (bmp-2, -3, -3b, -4, -6, -7, -15), receptors (bmpr-ia, -ib, -ii), and bmp antagonist, follistatin, in rat ovaries over the normal estrous cycle.	SIGNOR-144098	0.553
EFNB3	protein	Q15768	UNIPROT	EPHA4	protein	P54764	UNIPROT	up-regulates	binding			9606									9330863	t		tpavlidou	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52621	0.832
TYK2	protein	P29597	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	phosphorylation	Tyr701	DGPKGTGyIKTELIS	-1									7657660	t		lperfetto	Co-expression of Stat1 with Tyk2, Jak1, or Jak2 resulted in the specific tyrosine phosphorylation of Stat1 at Tyr701Phosphorylation of purified Stat1 was necessary and sufficient for the acquisition of DNA binding activity.	SIGNOR-246943	0.767
CSNK2A1	protein	P68400	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser267	PPTTSSDsEEEQEDE	9606	BTO:0000007								22025562	t		miannu	 Together, our findings provide evidence for CK1α-mediated destruction of c-Myc and identify c-Myc S252 as a crucial CK1α phosphorylation site for c-Myc degradation.	SIGNOR-276388	0.519
IL10	protein	P22301	UNIPROT	SCN10A	protein	Q9Y5Y9	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0000938	BTO:0001264							23357618	f		miannu	Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α.	SIGNOR-253503	0.267
C1QBP	protein	Q07021	UNIPROT	C1QC	protein	P02747	UNIPROT	down-regulates activity	binding							SIGNOR-C308					28018340	t		lperfetto	Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping.	SIGNOR-263404	0.408
ZMYND8	protein	Q9ULU4	UNIPROT	VEGFA	protein	P15692	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001033								27477906	t		lperfetto	Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported	SIGNOR-262041	0.2
AKT1	protein	P31749	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606	BTO:0000007								9381178	t			Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival.	SIGNOR-252562	0.816
SHANK3	protein	Q9BYB0	UNIPROT	Postsynaptic density assembly	phenotype	SIGNOR-PH163	SIGNOR	up-regulates				9606	BTO:0000938								28179641	f		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. 	SIGNOR-264607	0.7
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr653	QDSPDGQyENSEGGW	10090									12972425	t		lperfetto	Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs	SIGNOR-246417	0.797
ZNF692	protein	Q9BU19	UNIPROT	PCK1	protein	P35558	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17097062	f		gcesareni	In this study, we demonstrate that a newly identified transcription factor, arebp, is a novel target of ampk. Arebps function is to repress transcription of the pepck gene upon phosphorylation by ampk.	SIGNOR-150556	0.2
GABRA2	protein	P47869	UNIPROT	GABA-A (a2-b1-g2) receptor	complex	SIGNOR-C331	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263753	0.594
neuropeptide FF receptor agonist	smallmolecule	CHEBI:141000	ChEBI	NPFFR2	protein	Q9Y5X5	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257550	0.8
FLNA	protein	P21333	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates activity	binding			9606									20156194	t		miannu	We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself	SIGNOR-260628	0.262
CDK12	protein	Q9NYV4	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1896	SPTSPTYsPTSPVYT	9606									22012619	t		miannu	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176817	0.775
RAB3GAP1	protein	Q15042	UNIPROT	RAB3A	protein	P20336	UNIPROT	down-regulates activity	gtpase-activating protein			10116		BTO:0000142							11809763	t		miannu	Rab3A, a member of the Rab3 small G protein family, regulates Ca(2+)-dependent exocytosis of neurotransmitter. The cyclical activation and inactivation of Rab3A are essential for the Rab3A action in exocytosis. GDP-Rab3A is activated to GTP-Rab3A by Rab3 GDP/GTP exchange protein (Rab3 GEP), and GTP-Rab3A is inactivated to GDP-Rab3A by Rab3 GTPase-activating protein (Rab3 GAP). 	SIGNOR-265580	0.453
HECTD1	protein	Q9ULT8	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								22431752	t		Monia	We demonstrate that Hectd1 is a functional ubiquitin ligase and that one of its substrates is Hsp90, a chaperone protein with both intra- and extracellular clients. Identification of Hsp90 in both proteomic screens suggested that members of the Hsp90 superfamily may be substrates of Hectd1. Myc-Hectd1ANK and HA-Hsp90bd (the fragment identified in the yeast two-hybrid screen) bind in an in vitro binding assay (Fig. 3 D) and when coexpressed in HEK293T cells. Hectd1 is required for K63-linked Ubn of Hsp90. Together, these results demonstrate that Hectd1-dependent Ubn of Hsp90 targets it away from the membrane and the secretory pathway.	SIGNOR-261199	0.2
ADRA1B	protein	P35368	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256950	0.281
MAPK3	protein	P27361	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates activity	phosphorylation	Tyr204	HTGFLTEyVATRWYR										1712480	t		lperfetto	Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.|	SIGNOR-249472	0.2
CLOCK	protein	O15516	UNIPROT	CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	form complex	binding			-1									22653727	t	 	lperfetto	Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex|The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock.	SIGNOR-253709	0.769
CSF1R	protein	P07333	UNIPROT	CSF1R	protein	P07333	UNIPROT	up-regulates	phosphorylation	Tyr708	NIHLEKKyVRRDSGF	9606	BTO:0001271								15297464	t		lperfetto	Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins.	SIGNOR-127540	0.2
GATA2	protein	P23769	UNIPROT	TRH	protein	P20396	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534									33201916	t		scontino	The rat prepro-TRH gene is activated by GATA2.	SIGNOR-267258	0.267
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1766	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120212	0.321
PAK2	protein	Q13177	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates activity	phosphorylation	Ser20	APPVRMSsTIFSTGG	-1									10075701	t		miannu	Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197. 	SIGNOR-250227	0.2
CAMK2D	protein	Q13557	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity	phosphorylation	Ser561	PFLSRHNsKSSIFSF	9606	BTO:0000938								32611770	t		lperfetto	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275790	0.285
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1941	SPKGSTYsPTSPGYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273034	0.556
Nutlin-3	smallmolecule	CID:216345	PUBCHEM	TP73	protein	O15350	UNIPROT	up-regulates				9606									17700533	t		miannu	These results provide the first evidence that Nutlin-3 disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73 and thus, provides a rationale for the use of Nutlin-3 in the large number of human tumors in which p53 is inactivated.	SIGNOR-255472	0.8
A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	DLL1	protein	O00548	UNIPROT	up-regulates quantity by expression				10090									25786978	f		lperfetto	First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs.	SIGNOR-253286	0.27
CAMK2D	protein	Q13557	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity	phosphorylation	Ser641	RRSVKRNsTVDCNGV	9606	BTO:0000938								32611770	t		lperfetto	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275791	0.285
CDK2	protein	P24941	UNIPROT	MCM4	protein	P33991	UNIPROT	down-regulates activity	phosphorylation	Ser54	ELQPMPTsPGVDLQS	9606			SIGNOR-C83						12714602	t		lperfetto	We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a.	SIGNOR-100885	0.758
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	KCNJ1	protein	P48048	UNIPROT	up-regulates activity	phosphorylation	Ser201	FSKNAVIsKRGGKLC	-1									12221079	t		miannu	We conclude that ROMK1 is a substrate of PKC and that serine residues 4 and 201 are the two main PKC phosphorylation sites that are essential for the expression of ROMK1 in the cell surface.	SIGNOR-275990	0.2
PRKAA2	protein	P54646	UNIPROT	PPP1R12C	protein	Q9BZL4	UNIPROT	down-regulates	phosphorylation	Ser452	AGLQRSAsSSWLEGT	9606			SIGNOR-C15						22137581	t		lperfetto	Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo.	SIGNOR-195148	0.262
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	GRB2	protein	P62993	UNIPROT	down-regulates activity	phosphorylation	Tyr7	yDFKATAD	9606	BTO:0000007								20554525	t		lperfetto	More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway.	SIGNOR-246285	0.2
ATRX	protein	P46100	UNIPROT	GATA4	protein	P43694	UNIPROT	down-regulates quantity by repression	transcriptional regulation			7227	BTO:0001138								22021382	f	1	miannu	XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression.	SIGNOR-239733	0.415
Integrator complex	complex	SIGNOR-C265	SIGNOR	FOSL1	protein	P15407	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									25675981	f		lperfetto	The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes.	SIGNOR-261477	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	VASP	protein	P50552	UNIPROT	down-regulates	phosphorylation	Thr278	LARRRKAtQVGEKTP	9606									17082196	t		lperfetto	Pharmacological ampk inhibitors and activators and ampk mutants revealed that the kinase specifically targets residue thr-278 but not ser-157 or ser-239. Quantitative fluorescence-activated cell sorter analysis and serum response factor transcriptional reporter assays, which quantify the cellular f-/g-actin equilibrium, indicated that ampk-mediated vasp phosphorylation impaired actin stress fiber formation and altered cell morphology.	SIGNOR-216515	0.2
WNT3A	protein	P56704	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins are a large family of secreted glycoproteins. Wnt proteins bind to the Frizzled receptors and LRP5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131829	0.783
FBXW5	protein	Q969U6	UNIPROT	SASS6	protein	Q6UVJ0	UNIPROT	down-regulates quantity by destabilization	ubiquitination												21725316	t		lperfetto	We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. |expression of the wild-type form of FBXW5 accelerated the degradation of HsSAS-6 to a half-life of less than two hours	SIGNOR-275478	0.553
RHOA	protein	P61586	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates activity	binding			9606									8824197	t		areggio	We found that in the human kidney epithelial cell line, 293T, Cdc42 and all Rho proteins, RhoA, RhoB, and RhoC, but not Rac or Ras can induce activation of JNK.	SIGNOR-258974	0.821
BMS-599626	chemical	CID:10437018	PUBCHEM	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									17062696	t	AC480 significantly enhanced the radiosensitivity of HN-5 cells, expressing both EGFR and Her2.	gcesareni	The studies described here are intended to characterize the ability of bms-599626, a small-molecule inhibitor of the human epidermal growth factor receptor (her) kinase family, to modulate signaling and growth of tumor cells that depend on her1 and/or her2.	SIGNOR-150190	0.8
PRKCB	protein	P05771	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser320	QRSRKRLsQDAYRRN	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89197	0.549
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	PFKFB3	protein	Q16875	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11744734	t			PFKFB3, is highly induced by hypoxia and the hypoxia mimics cobalt and desferrioxamine. This induction could be replicated by the use of an inhibitor of the prolyl hydroxylase enzymes responsible for the von Hippel Lindau (VHL)-dependent destabilization and tagging of HIF-1α. The absolute dependence of the PFKFB3 gene on HIF-1 was confirmed by its overexpression in VHL-deficient cells and by the lack of hypoxic induction in mouse embryonic fibroblasts conditionally nullizygous for HIF-1α	SIGNOR-267388	0.354
NEK7	protein	Q8TDX7	UNIPROT	KIF11	protein	P52732	UNIPROT	up-regulates activity	phosphorylation	Ser1033	GINTLERsKVEETTE	10090	BTO:0000938								29899413	t	done	miannu	NEK7 regulates these processes in part through phosphorylation of the kinesin Eg5/KIF11, promoting its accumulation on microtubules in distal dendrites. 	SIGNOR-273890	0.418
MAPK8	protein	P45983	UNIPROT	RCSD1	protein	Q6JBY9	UNIPROT	down-regulates activity	phosphorylation	Ser216	SKSKAPGsPLSSEGA	-1									15850461	t		miannu	CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263087	0.291
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270391	0.8
PRKD1	protein	Q15139	UNIPROT	PLCG1	protein	P19174	UNIPROT	down-regulates activity	phosphorylation	Ser1248	HGRAREGsFESRYQQ	9606	BTO:0000661								1370476	t		lperfetto	Thus, phosphorylation of PLC-gamma 1 by PKC or PKA at serine 1248 may modulate the interaction of PLC-gamma 1 with the protein tyrosine kinase or the protein tyrosine phosphatase; this altered interaction may, at least in part, be responsible for the decreased tyrosine phosphorylation of PLC-gamma 1 seen in PMA- and forskolin-treated Jurkat cells.	SIGNOR-248846	0.413
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	CAD	protein	P27708	UNIPROT	up-regulates activity	phosphorylation	Ser1859	PPRIHRAsDPGLPAE	9606	BTO:0000007								23429703	t			Activation of mTORC1 led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis.	SIGNOR-267197	0.2
TRIM27	protein	P14373	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606		BTO:0000671							12807881	f		miannu	Here we show that ectopic expression of rfp in human embryonic kidney 293 cells causes extensive apoptosis, as assessed by multiple criteria.	SIGNOR-102019	0.7
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BC17	protein	P23527	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSIYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271982	0.2
AKT2	protein	P31751	UNIPROT	PTPN1	protein	P18031	UNIPROT	down-regulates activity	phosphorylation	Ser50	RNRYRDVsPFDHSRI	10090									11579209	t		lperfetto	We conclude that ptp1b is a novel substrate for akt and that phosphorylation of ptp1b by akt at ser(50) may negatively modulate its phosphatase activity creating a positive feedback mechanism forinsulin signaling	SIGNOR-235491	0.381
MAD2L2	protein	Q9UI95	UNIPROT	CDC20	protein	Q12834	UNIPROT	down-regulates activity	binding			-1									11459826	t		miannu	 The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20. We show here that a MAD2 homolog MAD2B also inhibits APC. MAD2B directly inhibits activation of APC by CDC20 and CDH1	SIGNOR-264903	0.471
CASP3	protein	P42574	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									14585074	f		amattioni	Caspase-3 is responsible for apoptosis execution	SIGNOR-256638	0.7
GSK3B	protein	P49841	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	phosphorylation	Ser468	AVFTDLAsVDNSEFQ	9606				SIGNOR-C13					17183360	t		gcesareni	Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) .	SIGNOR-151422	0.364
AMFR	protein	Q9UKV5	UNIPROT	CD3D	protein	P04234	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								11724934	t		miannu	Gp78 specifically recruits MmUBC7, a ubiquitin-conjugating enzyme (E2) implicated in ER-associated degradation (ERAD), through a region distinct from the RING finger. gp78 can target itself for proteasomal degradation in a RING finger- and MmUBC7-dependent manner. Importantly, gp78 can also mediate degradation of CD3-delta, a well-characterized ERAD substrate. 	SIGNOR-272670	0.486
CAMK2B	protein	Q13554	UNIPROT	ETS1	protein	P14921	UNIPROT	down-regulates activity	phosphorylation	Ser285	QRVPSYDsFDSEDYP		BTO:0003637								12475968	t		llicata	Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1 	SIGNOR-250687	0.313
AMPK	complex	SIGNOR-C15	SIGNOR	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates activity	phosphorylation	Ser539	SLFNVSPsCSSFNSP	9606									20640476	t		lperfetto	AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1	SIGNOR-209940	0.483
CDK1	protein	P06493	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates	phosphorylation	Ser337	IVSPPPSsPPSSLTT	9606									8087847	t		lperfetto	Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro.	SIGNOR-36026	0.687
QYDAFJUKVGVEKO-PKOVDKIBSA-N	smallmolecule	CID:16132339	PUBCHEM	MRGPRX1	protein	Q96LB2	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257543	0.8
BGJ-398	chemical	CHEBI:63451	ChEBI	FGFR4	protein	P22455	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190272	0.8
PRKCD	protein	Q05655	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Thr678	RHIVRKRtLRRLLQE	10090									1860884	t		lperfetto	These data indicate that activation of protein kinase C and subsequent phosphorylation of the EGF receptor at T654 lead to rapid physiological attenuation of EGF receptor signaling.	SIGNOR-248858	0.375
IL9	protein	P15248	UNIPROT	IL2RG	protein	P31785	UNIPROT	up-regulates	binding			9606									11418623	t		gcesareni	The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex	SIGNOR-108867	0.564
CDX1	protein	P47902	UNIPROT	VIL1	protein	P09327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19371634	f		miannu	We concluded that cdx2 regulates intestinal villin expression through recruiting brm-type swi/snf complex to the villin promoter.	SIGNOR-185483	0.301
SLC1A6	protein	P48664	UNIPROT	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	up-regulates quantity	relocalization			9606									26687113	t		miannu	After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5).	SIGNOR-264805	0.8
TLR4	protein	O00206	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity				9606	BTO:0000801								19592489	f		lperfetto	The transcription factor AP-1 consists of a variety of dimers composed of members of the Jun, Fos, and ATF families of proteins. The Jun proteins can both homo- and heterodimerize with Fos members to form transcriptionally active complexes. The stimulation of macrophage TLR4 receptor rapidly activates not only the NF-kappaB pathway but also MAPK pathways, including JNK, ERK, and p38. Many of the downstream targets of MAPK pathways are transcription factors that include c-Jun.	SIGNOR-249518	0.456
FASN	protein	P49327	UNIPROT	NADPH(4-)	smallmolecule	CHEBI:57783	ChEBI	down-regulates quantity	chemical modification			9606									15507492	t			Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the de novo biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH. 	SIGNOR-267759	0.8
ATRX	protein	P46100	UNIPROT	Immortality	phenotype	SIGNOR-PH47	SIGNOR	down-regulates				9606	BTO:0000584								26428317	f			Telomere length must be maintained for the immortalization of malignant cells […] alternative lengthening of telomeres status was perfectly correlated with the loss of expression of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein in pancreatic neuroendocrine tumors	SIGNOR-256595	0.7
TIMM10	protein	P62072	UNIPROT	TIM22 complex	complex	SIGNOR-C424	SIGNOR	form complex	binding			9606	BTO:0000007								32901109	t		lperfetto	Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK).	SIGNOR-267703	0.709
PIMREG	protein	Q9BSJ6	UNIPROT	PICALM	protein	Q13492	UNIPROT	down-regulates	relocalization			9606									16491119	t		miannu	The cats interaction domain of calm was mapped to aa 221-335 of calm. This domain is contained in the calm/af10 fusion protein. Cats localizes to the nucleus and shows a preference for nucleoli. Expression of cats was able to markedly increase the nuclear localization of calm and of the leukemogenic fusion protein calm/af10.	SIGNOR-144680	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	NOS3	protein	P29474	UNIPROT	up-regulates	phosphorylation	Ser1177	TSRIRTQsFSLQERQ	9606	BTO:0000567								18303014	t		lperfetto	The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner	SIGNOR-216627	0.266
MAPK14	protein	Q16539	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser33	LPENNVLsPLPSQAM	9606	BTO:0000093								22975381	t		lperfetto	P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.	SIGNOR-192057	0.765
NPTX1	protein	Q15818	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates activity	relocalization			10090	BTO:0000938								23069675	t		lperfetto	Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential	SIGNOR-261483	0.2
SYK	protein	P43405	UNIPROT	FCGR2C	protein	P31995	UNIPROT	up-regulates activity	phosphorylation	Tyr287	PEETNNDyETADGGY	-1									8756631	t		miannu	Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation	SIGNOR-262674	0.2
FBXO38	protein	Q6PIJ6	UNIPROT	KLF7	protein	O75840	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								14729953	t		miannu	Interaction between MoKA and KLF7 was confirmed by the in vitro glutathione S-transferase pull-down assay and by coimmunoprecipitation of the proteins overexpressed in mammalian cells. Functional assays documented that MoKA is a KLF7 coactivator	SIGNOR-224621	0.595
UDP(3-)	smallmolecule	CHEBI:58223	ChEBI	P2RY6	protein	Q15077	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257565	0.8
HRAS	protein	P01112	UNIPROT	PIK3CB	protein	P42338	UNIPROT	up-regulates activity	binding			9606									21779497	t		lperfetto	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner.	SIGNOR-175189	0.748
MAPK1	protein	P28482	UNIPROT	SOS1	protein	Q07889	UNIPROT	down-regulates activity	phosphorylation			9606									10197981	t		lperfetto	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3	SIGNOR-236242	0.702
PCBP2	protein	Q15366	UNIPROT	MAVS	protein	Q7Z434	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0002181								19881509	t		Giorgia	PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4.	SIGNOR-260360	0.631
FYN	protein	P06241	UNIPROT	DCBLD2	protein	Q96PD2	UNIPROT	up-regulates activity	phosphorylation	Tyr750	PAPDELVyQVPQSTQ	-1									23770091	t	done	miannu	Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding.	SIGNOR-273944	0.357
PRKAA1	protein	Q13131	UNIPROT	NR0B2	protein	Q15466	UNIPROT	up-regulates				9606									17909097	f		gcesareni	We have concluded that metformin inhibits hepatic gluconeogenesis through ampk-dependent regulation of shp	SIGNOR-158071	0.2
isoleucine	smallmolecule	CHEBI:24898	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264749	0.7
KIF14	protein	Q15058	UNIPROT	CIT	protein	O14578	UNIPROT	up-regulates activity	binding			9606									16431929	t		miannu	We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase. 	SIGNOR-266422	0.713
PLK1	protein	P53350	UNIPROT	BRCA2	protein	P51587	UNIPROT	unknown	phosphorylation	Ser206	ATPPTLSsTVLIVRN	9606	BTO:0001938								12815053	t		lperfetto	Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation.	SIGNOR-249219	0.556
PTPN1	protein	P18031	UNIPROT	PTPN1	protein	P18031	UNIPROT	down-regulates activity	dephosphorylation	Tyr153	SEDIKSYyTVRQLEL	-1									11506178	t			Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions.	SIGNOR-248425	0.2
CHFR	protein	Q96EP1	UNIPROT	SMARCA4	protein	P51532	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0000298								22285184	t		miannu	Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination.	SIGNOR-271457	0.338
SRC	protein	P12931	UNIPROT	ABL1	protein	P00519	UNIPROT	up-regulates activity	phosphorylation	Tyr393	RLMTGDTyTAHAGAK	9606									11847100	t		lperfetto	c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function.	SIGNOR-246311	0.517
ZSTK-474	chemical	CHEBI:90545	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207935	0.8
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BW1	protein	Q7Z2G1	UNIPROT	down-regulates activity	monoubiquitination			9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271989	0.2
PHKA1	protein	P46020	UNIPROT	PHKA1	protein	P46020	UNIPROT	up-regulates activity	phosphorylation	Ser972	KEFGVERsVRPTDSN	-1									10487978	t		miannu	Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation)	SIGNOR-250281	0.2
U69593	chemical	CHEBI:73357	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029									9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258827	0.8
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates quantity by destabilization	cleavage	Glu618	SEVKMDAeFRHDSGY	-1									8943232	t		lperfetto	The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261767	0.502
TXK	protein	P42681	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates activity	phosphorylation	Tyr128	DGEDDGDyESPNEEE	9606									10660534	t		lperfetto	Rlk phosphorylated the N-terminal region of SLP-76, a region that has been previously shown to serve as a target for ZAP-70. Loss of N-terminal YESP/YEPP sites of SLP-76 or the Rlk kinase activity attenuated cooperativity between Rlk and SLP-76	SIGNOR-246929	0.717
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	KCNMA1	protein	Q12791	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								31152168	t		miannu	The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. The BK channel can be allosterically activated by both changes in the membrane voltage (voltage-dependent activation pathway) and intracellular [Ca2+] concentration (calcium-dependent activation pathway)	SIGNOR-269192	0.8
HSPA1A	protein	P0DMV8	UNIPROT	ENPP1	protein	P22413	UNIPROT	up-regulates quantity	post transcriptional regulation			9606									19083193	t		miannu	We demonstrated the binding of heat shock protein 70 (HSP70) to ENPP1-3'UTR. Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation. 	SIGNOR-252197	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	ETS2	protein	P15036	UNIPROT	down-regulates	phosphorylation	Ser313	QRVPSFEsFEDDCSQ	9606									19182667	t		lperfetto	Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters	SIGNOR-183604	0.2
IKBKB	protein	O14920	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	phosphorylation	Ser536	SGDEDFSsIADMDFS	9606	BTO:0000007			SIGNOR-C13					15489227	t		lperfetto	Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.	SIGNOR-129935	0.882
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0000574								16146838	f		miannu	The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells.	SIGNOR-255732	0.7
C5AR1	protein	P21730	UNIPROT	SELL	protein	P14151	UNIPROT	down-regulates quantity by repression													1847994	f		lperfetto	The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 	SIGNOR-263468	0.332
INSR	protein	P06213	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates	phosphorylation	Tyr536	QKGQESEyGNITYPP	9606									7512963	t		llicata	Insulin stimulates the phosphorylation of tyr538 and the catalytic activity of ptp1c, a protein tyrosine phosphatase with src homology-2 domains. these results suggest that ptp1c is a target protein for the insulin receptor tyrosine kinase	SIGNOR-26870	0.365
CD79B	protein	P40259	UNIPROT	BCR-Dl	complex	SIGNOR-C436	SIGNOR	form complex	binding			9606	BTO:0000776								32323266	t		scontino	BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition.	SIGNOR-268201	0.641
EIF2S2	protein	P20042	UNIPROT	EGLN1	protein	Q9GZT9	UNIPROT	up-regulates quantity	translation regulation			9606	BTO:0000007								29530922	t		miannu	DAP5 is involved in PHD2 translation. Distinct responses to DAP5 depletion (under hypoxia) of primary MEFs versus malignant glioma cells suggest that DAP5-mediated control of PHD2 may have special significance in cancer. Neoplastic cells may exploit DAP5 for managing chronic oxygen deprivation, possibly contributing to their adaptation to growth/proliferation under hypoxia.	SIGNOR-266386	0.2
PTPN6	protein	P29350	UNIPROT	CSF2RB	protein	P32927	UNIPROT	down-regulates	dephosphorylation	Tyr628	PPPGSLEyLCLPAGG	9606									9162089	t		gcesareni	However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2.	SIGNOR-48561	0.5
Crenolanib	chemical	CID:10366136	PUBCHEM	PDGFRB	protein	P09619	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191124	0.8
HDAC4	protein	P56524	UNIPROT	MEF2C	protein	Q06413	UNIPROT	down-regulates	binding			9606		BTO:0000887							10737771	t		gcesareni	We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2.	SIGNOR-76234	0.701
PTPN6	protein	P29350	UNIPROT	KCNH2	protein	Q12809	UNIPROT	down-regulates	dephosphorylation			9606									12361947	t		gcesareni	Our results show that erg-1 is a shp-1 substrate constituting the first report that an ion current is regulated by shp-1.	SIGNOR-94007	0.2
ATM	protein	Q13315	UNIPROT	XPA	protein	P23025	UNIPROT	unknown	phosphorylation	Ser196	RSLEVWGsQEALEEA	-1									16540648	t		llicata	Kinase phosphorylation assays were done with synthesized short peptides (20-mer) with the sequences at Ser173 and Ser196 of XPA, respectively. Both peptides seemed to be good substrates for DNA-PK, ATR ( Fig. 2D), and ATM (data not shown).	SIGNOR-250580	0.61
SMN1	protein	Q16637	UNIPROT	SMN complex	complex	SIGNOR-C158	SIGNOR	form complex	binding												12065586	t		lperfetto	SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry.	SIGNOR-253115	0.726
NMDA receptor_2A	complex	SIGNOR-C347	SIGNOR	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								11052931	t		miannu	Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor	SIGNOR-264222	0.794
ATF4	protein	P18848	UNIPROT	PPP1R15A	protein	O75807	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									31226023	t		miannu	ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress.	SIGNOR-260172	0.648
PTPN12	protein	Q05209	UNIPROT	SHC1	protein	P29353	UNIPROT	down-regulates	dephosphorylation	Tyr349	EEPPDHQyYNDFPGK	9606									8939605	t		gcesareni	The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions.	SIGNOR-44361	0.661
PI-103	chemical	CHEBI:90524	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206172	0.8
WWTR1	protein	Q9GZV5	UNIPROT	PAX8	protein	Q06710	UNIPROT	up-regulates	binding			9606		BTO:0000763							19010321	t		miannu	Taz is a coactivator for pax8 and ttf-1, two transcription factors involved in thyroid differentiation. / we show that this interaction leads to a significant enhancement of the transcriptional activity of pax8 and ttf-1 on the thyroglobulin promoter thus suggesting a role of taz in the control of genes involved in thyroid development and differentiation.	SIGNOR-182253	0.308
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1896	SPTSPTYsPTSPVYT	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273051	0.556
PPP2CA	protein	P67775	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	dephosphorylation	Thr308	KDGATMKtFCGTPEY	10090	BTO:0000944								15367694	t			Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes	SIGNOR-248629	0.889
buspirone	chemical	CHEBI:3223	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9550290	t		miannu	Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists.	SIGNOR-258885	0.8
CSNK2A1	protein	P68400	UNIPROT	TLE1	protein	Q04724	UNIPROT	up-regulates	phosphorylation	Ser239	KDSSHYDsDGDKSDD	9606									15367661	t		lperfetto	These results suggest that ck2 phosphorylation of serine 239 of gro/tle1 is important for its function during neuronal differentiation.	SIGNOR-129026	0.326
PRKCZ	protein	Q05513	UNIPROT	ADARB1	protein	P78563	UNIPROT	up-regulates activity	phosphorylation	Ser216	SASPVPAsLAQPPLP	9606	BTO:0001615								29694894	t		miannu	 Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing. 	SIGNOR-277391	0.2
MAPK8	protein	P45983	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	up-regulates	phosphorylation	Ser27	ADREAASsPAGEPLR	9606									20027304	t	This phosphorylation increased sirt1 nuclear localization	gcesareni	Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53.	SIGNOR-162314	0.621
EPAS1	protein	Q99814	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20534544	f	Regulation	miannu	We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2alpha, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. 	SIGNOR-251791	0.289
PPP1CA	protein	P62136	UNIPROT	TRIM28	protein	Q13263	UNIPROT	up-regulates activity	dephosphorylation	Ser824	LPGAGLSsQELSGGP	9606									20424263	t		miannu	PP1\u03b1 dephosphorylates KAP1 at Ser 824 .	SIGNOR-277075	0.327
BICRA	protein	Q9NZM4	UNIPROT	GBAF	complex	SIGNOR-C467	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269781	0.2
ERCC3	protein	P19447	UNIPROT	TFIIH	complex	SIGNOR-C457	SIGNOR	form complex	binding			9606									30860024	t		lperfetto	Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 	SIGNOR-269313	0.887
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	HNRNPK	protein	P61978	UNIPROT	up-regulates	phosphorylation	Ser353	DSAIDTWsPSEWQMA	9606									11259409	t		lperfetto	When subjected to phosphorylation by erk, the most efficient decrease in erk phosphorylation was observed with the s353a mutantamong the mechanisms underlying k protein ability to confer increased transcriptional output are interconversion of duplex and single-stranded dna (59) and association with the c/ebp_ (60), each of which could be better affected by the phosphorylated form of the k protein, which may increase affinity to associated proteins or dna.	SIGNOR-105754	0.2
PRKCA	protein	P17252	UNIPROT	GJB1	protein	P08034	UNIPROT	up-regulates activity	phosphorylation	Ser229	QRRSNPPsRKGSGFG	-1									8390988	t		lperfetto	Phosphorylation of connexin-32 by protein kinase C prevents its proteolysis by mu-calpain and m-calpain. |In agreement with other authors (see Saez et al., 1990b), we have found that phosphorylation of connexin-32 by protein kinase A and protein kinase C occurs in serine residues, although we have detected trace amounts of phosphothreonine in connexin-32 phosphorylated by protein kinase C (results not shown). Indeed, Se233 has been shown to be the major phosphorylation site catalyzed by protein kinase A. However, Ser233, Ser239, and perhaps other serines are phosphorylated by protein kinase C (Saez et al., 1990b).	SIGNOR-248919	0.368
risperidone	chemical	CHEBI:8871	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258530	0.8
FBXO31	protein	Q5XUX0	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0002181								29343641	t		miannu	FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2.	SIGNOR-277379	0.423
SYK	protein	P43405	UNIPROT	SYK	protein	P43405	UNIPROT	up-regulates activity	phosphorylation	Tyr348	LPMDTEVyESPYADP	9606	BTO:0000776								9820500	t		lperfetto	These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520	SIGNOR-246609	0.2
ABL2	protein	P42684	UNIPROT	PSMA7	protein	O14818	UNIPROT	down-regulates	phosphorylation	Tyr153	QTDPSGTyHAWKANA	9606									16678104	t		lperfetto	Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised	SIGNOR-146589	0.591
PRLHR	protein	P49683	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257198	0.252
GRB2	protein	P62993	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates				9606	BTO:0001271								17904548	f		miannu	Grb2 mediates c-kit degradation through recruitment of cbl to c-kit, leading to ubiquitination of c-kit followed by internalization and degradation	SIGNOR-157956	0.635
MAPK14	protein	Q16539	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									12110590	t		gcesareni	Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway.	SIGNOR-90525	0.786
PBX2	protein	P40425	UNIPROT	FGF8	protein	P55075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003560								10026229	t		miannu	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 	SIGNOR-265804	0.254
PIH1D1	protein	Q9NWS0	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates quantity by stabilization	binding			9606	BTO:0000093								24036451	t		miannu	PIH1D1 interacts with mTOR complex 1 and enhances ribosome RNA transcription.PIH1D1 is important for mTORC1 assembly	SIGNOR-265897	0.344
PDPK1	protein	O15530	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Thr308	KDGATMKtFCGTPEY	10090									12808134	t		lperfetto	Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1).	SIGNOR-134477	0.736
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	AURKA	protein	O14965	UNIPROT	down-regulates	dephosphorylation			9606									11551964	t		lperfetto	Pp1 is shown to dephosphorylate active stk15 and abolish its activity in vitro.	SIGNOR-264651	0.2
PPP1CA	protein	P62136	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	up-regulates activity	dephosphorylation	Ser89	AQHVRSHsSPASLQL	9606									21189257	t		miannu	PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase.	SIGNOR-277116	0.526
MAP3K8	protein	P41279	UNIPROT	PLK1	protein	P53350	UNIPROT	up-regulates	phosphorylation	Thr210	YDGERKKtLCGTPNY	9606	BTO:0000567								12207013	t		miannu	Xplkk1 phosphorylates and activates mammalian plk / xplkk1 phosphorylates thr-210	SIGNOR-92274	0.2
LRFN1	protein	Q9P244	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606	BTO:0000938								21736948	f		miannu	This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments.	SIGNOR-264100	0.7
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1787	SPNYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120036	0.781
MAPK3	protein	P27361	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Thr476	EANYVPMtPGTFDFS	10029	BTO:0000246								15379552	t		lperfetto	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-249464	0.618
TFIIIB	complex	SIGNOR-C393	SIGNOR	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	up-regulates activity	binding			9606									9308965	t		lperfetto	Transcription by RNA polymerase III (Pol III) requires multiple general initiation factors that, in isolated form, assemble onto the promoter in an ordered fashion. Here, it is shown that all components required for transcription of the VA1 and tRNA genes, including TFIIIB, TFIIIC, and RNA Pol III, can be coimmunopurified from a HeLa cell line that constantly expresses a FLAG epitope-tagged subunit of human RNA Pol III.	SIGNOR-266181	0.644
YAP1	protein	P46937	UNIPROT	DVL1	protein	O14640	UNIPROT	down-regulates	binding			9606									23178811	t		gcesareni	Yap restricts elevated wnt independently of the axinapcgsk-3beta complex partly by limiting the activity of dishevelled (dvl).	SIGNOR-199806	0.34
SMARCA4	protein	P51532	UNIPROT	SMARCC2	protein	Q8TAQ2	UNIPROT	up-regulates	binding			9606									10078207	t		miannu	The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.	SIGNOR-65444	0.938
XRCC6	protein	P12956	UNIPROT	UBE2S	protein	Q16763	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000007								27593939	t		lperfetto	As shown in Figure 4, we found that Ku70 (Figure 4b) and Ku80 (Figure 4c) co-immunoprecipitated with UBE2S.>Taken together, these results demonstrate that ETO enhances the UBE2S–Ku70 interaction, and UBE2S can be recruited to the same sites of DSBs with Ku70 upon ETO treatment.	SIGNOR-265079	0.353
CLOCK	protein	O15516	UNIPROT	NR0B2	protein	Q15466	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									20674862	t	 	lperfetto	CLOCK knockdown activated MTP promoter and reduced small heterodimer partner (SHP, NROB2). CLOCK upregulated SHP by binding to its E box.	SIGNOR-253698	0.397
CAMK2G	protein	Q13555	UNIPROT	GRIA4	protein	P48058	UNIPROT	unknown	phosphorylation	Ser862	IRNKARLsITGSVGE										10366608	t		llicata	We found that GluR4 is phosphorylated on serine 842 within the C-terminal domain in vitro and in vivo. Serine 842 is phosphorylated by PKA, PKC, and CaMKII in vitro and is phosphorylated in transfected cells by PKA.	SIGNOR-250699	0.507
TOP2B	protein	Q02880	UNIPROT	EPHA7	protein	Q15375	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24463367	f		lperfetto	While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development	SIGNOR-242311	0.2
3,5-diiodo-L-tyrosine	smallmolecule	CHEBI:15768	ChEBI	iodide	smallmolecule	CHEBI:16382	ChEBI	up-regulates quantity	precursor of			9606									28153798	t		scontino	MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide.	SIGNOR-268093	0.8
HDAC1	protein	Q13547	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates	binding			9606									17183360	t		lperfetto	Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1.	SIGNOR-217409	0.557
INSR	protein	P06213	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	phosphorylation	Tyr612	TLHTDDGyMPMSPGV	10029	BTO:0000246								7651388	t		lperfetto	Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir).	SIGNOR-236756	0.911
MTOR	protein	P42345	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates activity	phosphorylation	Ser859	DTSSLTQsAPASPTN	9606	BTO:0000007								19346248	t		lperfetto	The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo.	SIGNOR-184959	0.989
AURKB	protein	Q96GD4	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	down-regulates activity	phosphorylation	Ser164	TSTPGRRsCFGFEGL	-1									23901111	t		miannu	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. 	SIGNOR-276113	0.614
CUL3	protein	Q13618	UNIPROT	LZTR1	protein	Q8N653	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								31337872	t		Gianni	Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a member of the BTB-Kelch superfamily, which interacts with the Cullin3 (CUL3)-based E3 ubiquitin ligase complex.	SIGNOR-269070	0.277
STK11	protein	Q15831	UNIPROT	MELK	protein	Q14680	UNIPROT	up-regulates	phosphorylation	Thr167	NKDYHLQtCCGSLAY	9606									16216881	t		fstefani	Site-directed mutagenesis indicated that thr167 and ser171, located between the dfg and ape motifs in the activation loop or t-loop, need to be autophosphorylated for melk to be active as a protein kinase (fig. 5). These sites are conserved in all other ampk-related protein kinases (fig. 4a), and the site corresponding to thr167 has been shown to be phosphorylated by protein kinase lkb1 (5).	SIGNOR-141038	0.2
MFGE8	protein	Q08431	UNIPROT	TNF	protein	P01375	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									22114683	f		Giorgia	Our study demonstrated the direct anti-inflammatory role of MFG-E8 in terms of attenuating TNF-α production in mouse peritoneal macrophages and RAW264.7 cells treated with LPS	SIGNOR-260650	0.317
MAP3K4	protein	Q9Y6R4	UNIPROT	MAP3K4	protein	Q9Y6R4	UNIPROT	up-regulates activity	phosphorylation	Thr1494	KLKNNAQtMPGEVNS	9606									17242196	t		lperfetto	Gadd45 binding also induced mtk1 dimerization via a dimerization domain containing a coiled-coil motif, which is essential for the trans autophosphorylation of mtk1 at thr-1493 in the kinase activation loop.	SIGNOR-152408	0.2
USF1	protein	P22415	UNIPROT	FMR1	protein	Q06787	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001363; BTO:0000142							11058604	f		miannu	 We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs.	SIGNOR-254882	0.32
ERCC1	protein	P07992	UNIPROT	ERCC4/ERCC1	complex	SIGNOR-C50	SIGNOR	form complex	binding			9606									16338413	t		miannu	Human ercc1/xpf interaction domains reveals a complementary role for the two proteins in nucleotide excision repair.	SIGNOR-142989	0.952
AKT2	protein	P31751	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates	phosphorylation	Thr1462	GLRPRGYtISDSAPS	9606									12172553	t		gcesareni	We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex.	SIGNOR-91392	0.719
FYN	protein	P06241	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	unknown	phosphorylation	Tyr1474	GSSNGHVyEKLSSIE	9606	BTO:0000007								11024032	t			Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed.	SIGNOR-251175	0.76
gamma-secretase	complex	SIGNOR-C98	SIGNOR	DSCAM	protein	O60469	UNIPROT	down-regulates quantity	cleavage			9606	BTO:0000938								30745319	t		miannu	γ‐secretase‐mediated intra‐membrane cleavage of DSCAM receptors results in the release of the DSCAM ICD, which is likely proceeded by shedding of the DSCAM ectodomain. Interaction of IPO5 with the NLS of DSCAM then leads to importin‐mediated nuclear import of the DSCAM ICD. In the nucleus, the DSCAM ICD may regulate the transcription of genes involved in neuronal development and function, thereby regulating processes such as neurite outgrowth, branching, and repulsion, as well as synapse formation, axon guidance, and neuronal cell death and survival.	SIGNOR-264271	0.2
SMO	protein	Q99835	UNIPROT	TIMP3	protein	P35625	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									28709001	f			We identified that ciliary Hh signaling in FAPs regulates expression of Timp3. Future experiments will determine whether Timp3 is a direct or indirect target of Hh signaling.	SIGNOR-255907	0.2
CCND1	protein	P24385	UNIPROT	HDAC3	protein	O15379	UNIPROT	up-regulates	binding			9606									15713663	t		gcesareni	Collectively, these studies suggest an important role of cyclin d1 in regulation of ppargamma-mediated adipocyte differentiation through recruitment of hdacs to regulate ppar response element local chromatin structure and ppargamma function.	SIGNOR-134056	0.421
FAM83H	protein	Q6ZRV2	UNIPROT	CSNK1A1L	protein	Q8N752	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								29789297	t		miannu	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273755	0.2
DYRK1A	protein	Q13627	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates	phosphorylation	Ser295	PARPRSPsQTRKGPP	9606		BTO:0000142							16733250	t		lperfetto	Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins.	SIGNOR-146906	0.405
EGFR	protein	P00533	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr589	SHDSEENyVPMNPNL	9606	BTO:0000527;BTO:0000017								9890893	t		lperfetto	Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689).	SIGNOR-236416	0.751
GSK2126458	chemical	CID:25167777	PUBCHEM	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192904	0.8
GP5	protein	P40197	UNIPROT	GPIb-IX-V complex	complex	SIGNOR-C270	SIGNOR	form complex	binding			9606	BTO:0000132								16293600	t		lperfetto	The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1.	SIGNOR-261849	0.647
SIRT1	protein	Q96EB6	UNIPROT	EP300	protein	Q09472	UNIPROT	down-regulates	deacetylation	Lys1024	TELKTEIkEEEDQPS	9606	BTO:0000150								19047049	t		gcesareni	Sirt1 induces deacetylation and repression of p300 itself (81). Mutational analysis demonstrated that sirt1 repression of p300 involves both lysine 1020 and lysine 1024	SIGNOR-182511	0.829
HCRTR1	protein	O43613	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257012	0.252
RAI1	protein	Q7Z5J4	UNIPROT	ARNTL	protein	O00327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									22578325	f		miannu	Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. 	SIGNOR-266843	0.323
SMARCAD1	protein	Q9H4L7	UNIPROT	TRIM28	protein	Q13263	UNIPROT	up-regulates activity	binding			9606									21549307	t	1	miannu	SMARCAD1 interacts with HDAC1 and KAP1 and is required for their binding to heterochromatin	SIGNOR-239838	0.519
LIMK1	protein	P53667	UNIPROT	AURKA	protein	O14965	UNIPROT	up-regulates activity	phosphorylation			-1									22214762	t		miannu	Here, we report a novel functional cooperativity between Aur-A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology. 	SIGNOR-276400	0.265
CSNK2A1	protein	P68400	UNIPROT	ATF1	protein	P18846	UNIPROT	down-regulates	phosphorylation	Ser44	ESEESQDsSDSIGSS	9606									20730097	t		lperfetto	These data suggested that atf1 is always hyperphosphorylated on the ck sites in vivo. Also, the antibody reactivity suggested that in addition to ser-36 and ser-41, ser-38 and ser-44 were phosphorylated in vivo. To accommodate these findings, we propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression.	SIGNOR-167556	0.3
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation			9606									9922370	t		lperfetto	Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity	SIGNOR-244688	0.2
PPP1CA	protein	P62136	UNIPROT	BRCA1	protein	P38398	UNIPROT	down-regulates activity	dephosphorylation	Ser1524	LQNRNYPsQEELIKV	9606	BTO:0000007								17603999	t			Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524.	SIGNOR-248562	0.384
CDK5	protein	Q00535	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates	phosphorylation	Thr354	HLGPHRStPESRAAV	9606									12056836	t		lperfetto	Cyclin-dependent kinase-5/p35 phosphorylates presenilin 1 to regulate carboxy-terminal fragment stabilityhere we demonstrate that cyclin dependent kinase-5/p35 (cdk5/p35) phosphorylates ps1 on threonine(354) within c-ps1 both in vitro and in vivo. Threonine(354) phosphorylation functions to selectively stabilize c-ps1.	SIGNOR-89145	0.526
CDK1	protein	P06493	UNIPROT	EZH2	protein	Q15910	UNIPROT	down-regulates	phosphorylation	Thr345	LTAERIKtPPKRPGG	9606									21659531	t		lperfetto	Cdk1, which phosphorylates ezh2 at threonines 345 and 487.Phosphorylation of thr-345 and thr-487 promotes ezh2 ubiquitination and subsequent degradation by the proteasome	SIGNOR-174054	0.592
DNM1L	protein	O00429	UNIPROT	Mitochondrial_fission	phenotype	SIGNOR-PH143	SIGNOR	up-regulates				9606									25486875	f		lperfetto	During fission, DRP1 is recruited from the cytosol to the outer mitochondrial membrane, where it assembles with FIS1 to constrict the mitochondrial tubule (2)	SIGNOR-272975	0.7
ZMYND11	protein	Q15326	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	binding												24675531	t		miannu	We found that full-length BS69 specifically interacted with H3K36me3 in native nucleosome co-immunoprecipitation (co-IP) experiments. We propose that BS69 specifically associates with H3K36me3-enriched chromatin through the PWWP domain, which facilitates the recruitment of MYND-bound transcription and chromatin remodeling factors including EZH2, HDAC1, Brg1 and E2F6 to target gene loci, thereby repressing target gene transcription.	SIGNOR-265353	0.2
SLC2A1	protein	P11166	UNIPROT	4.1 complex	complex	SIGNOR-C386	SIGNOR	form complex	binding			9606	BTO:0000424								33187473	t		lperfetto	The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]	SIGNOR-266038	0.37
CDK1	protein	P06493	UNIPROT	TP73	protein	O15350	UNIPROT	down-regulates activity	phosphorylation	Thr86	AASASPYtPEHAASV	9606			SIGNOR-C17						12676926	t		gcesareni	Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86.	SIGNOR-99742	0.536
ATG16L1	protein	Q676U5	UNIPROT	CLTC	protein	Q00610	UNIPROT	up-regulates	binding			9606									20639872	t		gcesareni	Clathrin heavy-chain interacts with atg16l1, and is involved in the formation of atg16l1-positive early autophagosome precursors.	SIGNOR-166702	0.473
Class II MHC:Antigen	complex	SIGNOR-C429	SIGNOR	T_cell_activation	phenotype	SIGNOR-PH73	SIGNOR	up-regulates				9606									31810556	f		scontino	Once they are formed, peptide/MHC class II molecules complexes are very stable and allow for sustained antigen presentation increasing the chances to encounter the matching CD4+ T lymphocytes. Once CD4+ T cells have become acti- vated, they in turn trigger macrophages to eliminate pathogens that have been previously internalized, and B lymphocytes to produce pathogen- specific antibodies.	SIGNOR-267873	0.7
SSTR1	protein	P30872	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256822	0.452
PCDH19	protein	Q8TAB3	UNIPROT	GABRA4	protein	P48169	UNIPROT	up-regulates quantity by stabilization	binding			10116	BTO:0003102			SIGNOR-C327,SIGNOR-C326,SIGNOR-C333					29360992	t		miannu	Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons. 	SIGNOR-267220	0.2
HIF1A	protein	Q16665	UNIPROT	IL1B	protein	P01584	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000801								24352507	t		lperfetto	We finally confirmed that in the absence of HIF-1α there was a significant reduction at the protein level in pro-caspase-1, activated caspase-1, pro-IL-1β, and ultimately active IL-1β (Fig. 4g and h). These data show that adenosine induced up-regulation of IL-1β is dependent on a CREB/HIF-1α pathway which is distinct from the NF-kB pathway used for initial production of IL-1β in response to LPS.	SIGNOR-251718	0.344
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRM1	protein	Q13255	UNIPROT	up-regulates activity	chemical activation			9606									25042998	t		miannu	Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate	SIGNOR-264069	0.8
CDK2	protein	P24941	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates activity	phosphorylation	Ser59	GGQESQPsPLALLAA	10090	BTO:0000944								11598016	t		gcesareni	Mutation of Sp1 Ser59 abrogates the cyclin A€“CDK augmentation of Sp1-dependent transcriptional transactivation	SIGNOR-248232	0.434
FUBP1	protein	Q96AE4	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26490982	f		irozzo	The human far upstream element (FUSE) binding protein 1 (FUBP1) belongs to an ancient family which is required for proper regulation of the c-Myc proto-oncogene. Our results indicated that FUBP1 may potentially stimulate c-Myc expression in ESCC and its expression may promote ESCC progression.	SIGNOR-259123	0.424
IL18	protein	Q14116	UNIPROT	T_cell_activation	phenotype	SIGNOR-PH73	SIGNOR	up-regulates				9606									10653850	f		miannu	IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement.	SIGNOR-260965	0.7
PRKACA	protein	P17612	UNIPROT	SLC2A2	protein	P11168	UNIPROT	down-regulates activity	phosphorylation	Ser491	VPETKGKsFEEIAAE	9534									8626492	t		miannu	GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity.	SIGNOR-250049	0.313
PREX2	protein	Q70Z35	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260570	0.416
Temsirolimus	chemical	CHEBI:79699	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									21081844	t		gcesareni	Temsirolimus, an inhibitor of mammalian target of rapamycin (mtor) complex 1, is approved for the treatment of metastatic renal cell carcinoma (rcc).	SIGNOR-169712	0.8
SMURF1	protein	Q9HCE7	UNIPROT	PARD6/SMURF1	complex	SIGNOR-C112	SIGNOR	form complex	binding			9606	BTO:0004183								15761148	t		lperfetto	The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT.	SIGNOR-227562	0.623
CLK2	protein	P49760	UNIPROT	CLK2	protein	P49760	UNIPROT	up-regulates	phosphorylation	Ser142	HSSRRAKsVEDDAEG	9606	BTO:0000567								20682768	t		lperfetto	Clk2 was reported to regulate its nuclear localization by autophosphorylating serine 141	SIGNOR-167344	0.2
2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid	chemical	CID:135461425	PUBCHEM	FGFR2	protein	P21802	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259704	0.8
AKT1	protein	P31749	UNIPROT	BAX	protein	Q07812	UNIPROT	down-regulates activity	phosphorylation	Ser184	VAGVLTAsLTIWKKM	9606	BTO:0003473								14766748	t		lperfetto	Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophilsWe suggest that Bax is regulated by phosphorylation of Ser(184) in an Akt-dependent manner and that phosphorylation inhibits Bax effects on the mitochondria by maintaining the protein in the cytoplasm, heterodimerized with antiapoptotic Bcl-2 family members	SIGNOR-252538	0.5
ACACA	protein	Q13085	UNIPROT	acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	down-regulates quantity	chemical modification			9606									20952656	t		miannu	ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA	SIGNOR-267105	0.8
ABL1	protein	P00519	UNIPROT	HIPK2	protein	Q9H2X6	UNIPROT	up-regulates activity	phosphorylation	Tyr367	TYLQSRYyRAPEIIL	9606									25944899	t		Manara	The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage	SIGNOR-260936	0.412
MAPK14	protein	Q16539	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates	phosphorylation			9606									20626350	t		gcesareni	A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins	SIGNOR-166594	0.439
IL31	protein	Q6EBC2	UNIPROT	OSMR	protein	Q99650	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0000876	BTO:0001253							15184896	t		gcesareni	Here we identify a four-helix bundle cytokine we have called interleukin 31 (il-31), which is preferentially produced by t helper type 2 cells. Il-31 signals through a receptor composed of il-31 receptor a and oncostatin m receptor.	SIGNOR-125347	0.6
JAK2	protein	O60674	UNIPROT	BRD4	protein	O60885	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr98	KLNLPDYyKIIKTPM	9606	BTO:0002181								34290255	t		miannu	JAK2 induces tyrosine phosphorylation of BRD4 at Y97/Y98, resulting in BRD4 stabilization. 	SIGNOR-277312	0.331
(S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide	chemical	CID:6918848	PUBCHEM	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002428								31908417	t		miannu	The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs.	SIGNOR-262253	0.8
RARA	protein	P10276	UNIPROT	RXRG	protein	P48443	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									1310351	f		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16469	0.653
ATM	protein	Q13315	UNIPROT	STK11	protein	Q15831	UNIPROT	up-regulates	phosphorylation	Thr367	IIYTQDFtVPGQVPE	9606	BTO:0000848								12234250	t		gcesareni	We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo.	SIGNOR-92873	0.59
Dihydromorphine	chemical	CHEBI:4575	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258788	0.8
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606									10428798	t		lperfetto	Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity.	SIGNOR-217292	0.43
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	YWHAZ	protein	P63104	UNIPROT	unknown	phosphorylation	Ser58	VVGARRSsWRVVSSI	9606	BTO:0000007								11956222	t		lperfetto	Ese data indicate that pkb/akt phosphorylates ser-58 on 14-3-3zeta both in vitro and in intact cells. The functional relevance of this phosphorylation remains to be determined.	SIGNOR-244381	0.2
ADNP	protein	Q9H2P0	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	up-regulates quantity	binding			9606	BTO:0000007								17878164	t		miannu	ADNP Co-precipitates with the SWI/SNF Complex through ADNP C-terminal Interaction. Down-regulation of ADNP by shRNA resulted in morphological changes that are in line with the fact that ADNP contains a homeodomain profile (2) and with the SWI/SNF complex function that is associated with cellular differentiation. Our results suggest that ADNP functionality plays a role in these changes.	SIGNOR-266757	0.362
NFIX	protein	Q14938	UNIPROT	ETV5	protein	P41161	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268886	0.2
MMP7	protein	P09237	UNIPROT	DCN	protein	P07585	UNIPROT	down-regulates quantity by destabilization	cleavage	Glu273	ANTPHLReLHLDNNK	-1									9148753	t		miannu	Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.	SIGNOR-256352	0.593
NFYC	protein	Q13952	UNIPROT	PHGDH	protein	O43175	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18378410	f		miannu	Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y.	SIGNOR-255211	0.2
CLTCL1	protein	P53675	UNIPROT	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	form complex	binding			9606									24789820	t		lperfetto	AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly. 	SIGNOR-260662	0.719
GRK5	protein	P34947	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser366	EPIQMENsMGTLRTS	9606	BTO:0000007								11517230	t			Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251210	0.466
SRC	protein	P12931	UNIPROT	TIAM1	protein	Q13009	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								12810717	t		gcesareni	Tiam1 cooperated with src to induce activation of rac1 in vivo and the formation of membrane ruffles.	SIGNOR-102354	0.643
SRC	protein	P12931	UNIPROT	PDCD6IP	protein	Q8WUM4	UNIPROT	down-regulates activity	phosphorylation	Tyr319	KKDNDFIyHDRVPDL	9606									15557335	t		miannu	Src phosphorylation of Alix/AIP1 modulates its interaction with binding partners and antagonizes its activities. Phosphorylation of Alix by Src caused it to translocate from the membrane and cytoskeleton to the cytoplasm and reduced its interaction with binding partners SETA/CIN85, epidermal growth factor receptor, and Pyk2. 	SIGNOR-263201	0.401
zotepine	chemical	CHEBI:32316	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606									20223878	t		Luana	These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity.	SIGNOR-257829	0.8
2-(4-(4,4-Bis(4-fluorophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxylic acid methyl ester	chemical	CID:127728	PUBCHEM	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3).	SIGNOR-258949	0.8
MAPK3	protein	P27361	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606	BTO:0000007								14551213	t		lperfetto	The hematopoietic-specific Galpha16 protein has recently been shown to mediate receptor-induced activation of the signal transducer and activator of transcription 3 (STAT3). In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727. Galpha16QL-induced STAT3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (ERK1),	SIGNOR-249450	0.709
SRC	protein	P12931	UNIPROT	PRKCI	protein	P41743	UNIPROT	up-regulates	phosphorylation	Tyr280	LKKTDRIyAMKVVKK	9606									11713277	t		llicata	Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain.	SIGNOR-111924	0.512
PTPN18	protein	Q99952	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates quantity by destabilization	dephosphorylation			9606									25081058	t		miannu	In the present study, we demonstrated that PTPN18 specifically dephosphorylates HER2 pY 1112, pY 1196 and pY 1248 sites among ten HER2 and EGFR C-terminal tyrosine phosphorylation sites (XREF_FIG).|Taken together, these data suggest that PTPN18 promotes the proteasome dependent degradation of HER2 through K48 linked polyubiquitination.	SIGNOR-277031	0.658
Ionizing radiation	stimulus	SIGNOR-ST16	SIGNOR	CCDC6-RET	fusion protein	SIGNOR-FP9	SIGNOR	up-regulates				9606									23128507	f		miannu	In PTC, genomic rearrangements juxtapose the RET tyrosine kinase domain to unrelated genes, thereby creating dominantly transforming oncogenes, denominated RET/PTC. The RET/PTC rearrangements are the 2nd most common genetic alteration described in PTC and observed in ∼13–43% of cases, mostly in pediatric cancers or in individuals exposed to ionizing radiation from nuclear accidents	SIGNOR-251999	0.7
N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine	chemical	CHEBI:92386	ChEBI	ADRA2C	protein	P18825	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258923	0.8
PRKACA	protein	P17612	UNIPROT	GRIK2	protein	Q13002	UNIPROT	up-regulates activity	phosphorylation	Ser715	FMSSRRQsVLVKSNE	9606	BTO:0000007								8094892	t		miannu	GluR6 glutamate receptor, transiently expressed in mammalian cells, is directly phosphorylated by PKA, and that intracellularly applied PKA increases the amplitude of the glutamate response. Site-specific mutagenesis of the serine residue (Ser 684) representing a PKA consensus site completely eliminates PKA-mediated phosphorylation of this site as well as the potentiation of the glutamate response. 	SIGNOR-250315	0.2
AKT1	protein	P31749	UNIPROT	ADAR	protein	P55265	UNIPROT	down-regulates activity	phosphorylation	Thr1033	RLGERLRtMSCSDKI	-1									31095429	t		miannu	AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively	SIGNOR-276193	0.286
CTNNA3	protein	Q9UI47	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000586								21598020	t		miannu	Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14	SIGNOR-265492	0.552
6-propyl-2-thiouracil	smallmolecule	CHEBI:8502	ChEBI	DIO	proteinfamily	SIGNOR-PF83	SIGNOR	down-regulates activity	chemical inhibition			9606		BTO:0001379							27347897	t	inferred from family member	scontino	The activity of D1 but not D2 or D3 is inhibited by 6n-propylthiouracil (PTU).	SIGNOR-270240	0.8
DAXX	protein	Q9UER7	UNIPROT	Immortality	phenotype	SIGNOR-PH47	SIGNOR	down-regulates				9606	BTO:0000584								26428317	f			Telomere length must be maintained for the immortalization of malignant cells […] alternative lengthening of telomeres status was perfectly correlated with the loss of expression of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein in pancreatic neuroendocrine tumors	SIGNOR-256596	0.7
POFUT1	protein	Q9H488	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	binding			9606									12909620	t	Fucosylation	gcesareni	Notch_ is modified in its epidermal growth factor-like domains by the addition of_ fucose_ to serine or threonine residues. O-fucosylation is mediated by protein o-fucosyltransferase 1 and down-regulation of this enzyme by rna interference or mutation of the ofut1 gene in drosophila or by mutation of the pofut1 gene in mouse prevents notch signaling.	SIGNOR-254326	0.736
gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	GABA-A (a6-b2-d) receptor	complex	SIGNOR-C328	SIGNOR	up-regulates activity	chemical activation			9606									18790874	t	brain	lperfetto	Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS).	SIGNOR-263792	0.8
RPS6KA3	protein	P51812	UNIPROT	HMGN1	protein	P05114	UNIPROT	down-regulates activity	phosphorylation	Ser21	KEEPKRRsARLSAKP	9606	BTO:0000567								11438671	t		lperfetto	We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets.	SIGNOR-249100	0.371
FYCO1	protein	Q9BQS8	UNIPROT	MAP1LC3A	protein	Q9H492	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								26468287	t		Giulio	The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures.	SIGNOR-260598	0.576
CSNK1A1	protein	P48729	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates activity	binding			9606				SIGNOR-C110					22083140	t		gcesareni	In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)]	SIGNOR-177233	0.562
MC3R	protein	P41968	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257230	0.252
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	ETV1	protein	P50549	UNIPROT	up-regulates activity	phosphorylation	Ser216	PMYQRQMsEPNIPFP	9606									12213813	t		lperfetto	Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation.	SIGNOR-252769	0.2
MMP14	protein	P50281	UNIPROT	F12	protein	P00748	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly376	SMTRVVGgLVALRGA	-1									10930399	t		lperfetto	The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage.	SIGNOR-263610	0.336
MID1	protein	O15344	UNIPROT	PPP2CA	protein	P67775	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0004725								11685209	t		miannu	MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation	SIGNOR-271467	0.465
FBP1	protein	P09467	UNIPROT	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	down-regulates quantity	chemical modification			9606									30616754	t		lperfetto	FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle	SIGNOR-267610	0.8
dopamine	smallmolecule	CHEBI:18243	ChEBI	3,4-dihydroxyphenylacetaldehyde	smallmolecule	CHEBI:27978	ChEBI	up-regulates quantity	precursor of			9606									NBK536726	t	brain	lperfetto	Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL).	SIGNOR-264180	0.8
GRM2	protein	Q14416	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening.	SIGNOR-264933	0.8
MAGI2	protein	Q86UL8	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	up-regulates activity	binding			9606		BTO:0000142							22626542	t		miannu	 S-SCAM is a member of the membrane-associated guanylate kinase (MAGUK) family of PDZ-domain-containing proteins that include the synaptic organising molecule PSD-95. The PDZ domain of S-SCAM binds to the C-terminal tail of NL2, forming a ternary complex at the cell membrane (Figure 2b). The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 	SIGNOR-265445	0.259
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	GSK3B	protein	P49841	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000150;BTO:0000680								16039586	t	inferred from 70% family members	lperfetto	Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin.	SIGNOR-270059	0.2
MYC	protein	P01106	UNIPROT	CDK4	protein	P11802	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12835716	t		gcesareni	C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation	SIGNOR-102734	0.587
LYN	protein	P07948	UNIPROT	CD19	protein	P15391	UNIPROT	up-regulates activity	phosphorylation	Tyr500	TSLGSQSyEDMRGIL	10090	BTO:0000776								10933394	t		lperfetto	Experiments with purified proteins demonstrated that CD19-Y513 was Lyn's initial phosphorylation and binding site. This led to processive phosphorylation of CD19-Y482, which recruited a second Lyn molecule, allowing for transphosphorylation and amplification of Lyn activation|Tyrosine phosphorylation of CD19 following BCR and/or CD19 ligation provides Src homology 2 (SH2) recognition motifs that recruit regulatory molecules to the cell surface. CD19 dually phosphorylated at CD19€“Y482 and CD19€“Y513 binds the tandem SH2 domains of phosphatidylinositol 3-kinase (PI 3-kinase) p85 subuni	SIGNOR-249376	0.765
MLL-AF4	fusion protein	SIGNOR-FP4	SIGNOR	DOT1L	protein	Q8TEK3	UNIPROT	up-regulates activity	binding			9606	BTO:0001133								18977325	t		irozzo	Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed.	SIGNOR-255871	0.2
MAPK14	protein	Q16539	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser392	FKTEGPDsD										10747897	t		miannu	We demonstrate that anisomycin- and tumor necrosis factor--induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase	SIGNOR-250114	0.765
REEP5	protein	Q00765	UNIPROT	CXCR1	protein	P25024	UNIPROT	up-regulates activity	binding			9606									27966653	t		miannu	 In this study, we found that CXCR1 interacted with REEP5 and REEP6, but CXCR2 did not. Overexpression of REEP5 and REEP6 enhanced IL-8-stimulated cellular responses through CXCR1, whereas depletion of the proteins led to the downregulation of the responses. 	SIGNOR-261366	0.331
PRKCZ	protein	Q05513	UNIPROT	PPP1R14A	protein	Q96A00	UNIPROT	up-regulates activity	phosphorylation	Thr38	QKRHARVtVKYDRRE	9606									32471307	t		lperfetto	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.	SIGNOR-249261	0.28
ADORA2B	protein	P29275	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257152	0.283
SAM complex	complex	SIGNOR-C422	SIGNOR	TOM40 complex	complex	SIGNOR-C421	SIGNOR	up-regulates activity	binding												18423394	t		lperfetto	Homology searches led to the identification of human Sam50 that is required for the biogenesis of human Tom40 [69]. A similar involvement was reported for metaxin 1 and metaxin 2 [70], which are homologs of Sam37 and Sam35, respectively	SIGNOR-267686	0.468
PRKACA	protein	P17612	UNIPROT	WT1	protein	P19544	UNIPROT	down-regulates	phosphorylation	Ser393	KTCQRKFsRSDHLKT	9606									9366517	t		llicata	Pka phosphorylated wt1 at ser-365 and ser-393 in vitro, as well as at additional sites, and this phosphorylation abolished the dna-binding activity of wt1 in vitro. Using wt1 mutants in which ser-365 and ser-393 were mutated to ala individually and in combination, we showed that phosphorylation of these sites was critical for inhibition of dna binding in vivo.	SIGNOR-53176	0.346
terbutaline	chemical	CHEBI:9449	ChEBI	ADRB1	protein	P08588	UNIPROT	up-regulates activity	chemical activation			10030									20590599	t		Luana	Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)	SIGNOR-257870	0.8
KIF5B	protein	P33176	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272520	0.7
PSPC1	protein	Q8WXF1	UNIPROT	LMX1B/SFPQ/PSPC1 complex	complex	SIGNOR-C106	SIGNOR	form complex	binding			10090	BTO:0000669								23308148	t		miannu	LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo.	SIGNOR-223973	0.414
MAPK8	protein	P45983	UNIPROT	PKM	protein	P14618	UNIPROT	up-regulates activity	phosphorylation	Thr365	CIMLSGEtAKGDYPL	9606	BTO:0002181								26258887	t		miannu	Active JNK1 specifically activates PKM2 but not PKM1. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365.	SIGNOR-276933	0.38
PHLPP1	protein	O60346	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	down-regulates activity	dephosphorylation	Thr390	DSKFTRQtPVDSPDD	9606									21986499	t		gcesareni	Here we report the identification of ribosomal protein S6 kinase 1 (S6K1) as a novel substrate of PHLPP.	SIGNOR-237454	0.59
BCR	protein	P11274	UNIPROT	YWHAQ	protein	P27348	UNIPROT	unknown	phosphorylation	Ser232	LTLWTSDsAGEECDA	-1									16045749	t		llicata	We show here that BCR interacts with at least five isoforms of 14-3-3 in vivo and phosphorylates 14-3-3tau on Ser233 and to a lesser extent 14-3-3zeta on Thr233	SIGNOR-250594	0.31
ARNTL	protein	O00327	UNIPROT	PER1	protein	O15534	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f			Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253628	0.722
EGFR	protein	P00533	UNIPROT	PKIA	protein	P61925	UNIPROT	up-regulates	phosphorylation	Tyr8	MTDVETTyADFIASG	9606									1956339	t		lperfetto	The difference in inhibitory potency between pki_ and pki_ has been attributed to the absence of a tyrosine residue (tyr7) in pki_ that is present in the nh2-terminal region of pki_. This suggests that the absence of a single amino acid residue can result in variations in how the catalytic subunit of camp-dependent protein kinase interacts with pki which ultimately can result in alterations in pki inhibitory potency.	SIGNOR-22455	0.311
PRKCE	protein	Q02156	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606									20179209	t		lperfetto	Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated	SIGNOR-163912	0.346
DAAM1	protein	Q9Y4D1	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	binding			9606									19365405	t		gcesareni	B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1.	SIGNOR-185268	0.816
CDON	protein	Q4KMG0	UNIPROT	ABL1	protein	P00519	UNIPROT	up-regulates activity	binding			9606	BTO:0000222								19470755	t		lperfetto	Abl binds a proline-rich motif in cdo via its sh3 domain, and these regions of abl and cdo are required for their promyogenic effects. Cdo is important for full abl kinase activity	SIGNOR-185762	0.495
PRKCE	protein	Q02156	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser465	LKHVTQSsRKLIRAD	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation	SIGNOR-129304	0.316
FBXW7	protein	Q969H0	UNIPROT	SCF-FBW7	complex	SIGNOR-C135	SIGNOR	form complex	binding			9606									15340381	t		gcesareni	The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions.	SIGNOR-243766	0.902
Caspase 6 complex	complex	SIGNOR-C228	SIGNOR	CASP8	protein	Q14790	UNIPROT	up-regulates	cleavage			9606									11455969	t		gcesareni	This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8.	SIGNOR-256468	0.722
GYPC	protein	P04921	UNIPROT	4.1 complex	complex	SIGNOR-C386	SIGNOR	form complex	binding			9606	BTO:0000424								33187473	t		lperfetto	The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]	SIGNOR-266034	0.371
MSX2	protein	P35548	UNIPROT	DLX2	protein	Q07687	UNIPROT	down-regulates activity	binding			10090	BTO:0000945								9111364	t	2	miannu	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240932	0.4
AP-2 complex	complex	SIGNOR-C245	SIGNOR	HIP1	protein	O00291	UNIPROT	up-regulates activity	binding			10116									11517213	t		Giorgia	HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2.|Here we demonstrate that HIP1 colocalizes with markers of clathrin-mediated endocytosis in neuronal cells and is highly enriched on clathrin-coated vesicles (CCVs) purified from brain homogenates. HIP1 binds to the clathrin adaptor protein 2 (AP2) and the terminal domain of the clathrin heavy chain, predominantly through a small fragment encompassing amino acids 276–335	SIGNOR-260392	0.43
Av/b6 integrin	complex	SIGNOR-C179	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257725	0.579
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	WNK1	protein	Q9H4A3	UNIPROT	up-regulates	phosphorylation	Thr60	EYRRRRHtMDKDSRG	9606									16081417	t		llicata	Phosphorylation of wnk1 on thr-58 contributes to sgk1 activation. these data suggest that activation of sgk1 by wnk1 requires the catalytic activity of akt.	SIGNOR-139391	0.2
NCAPH	protein	Q15003	UNIPROT	Condensin I	complex	SIGNOR-C341	SIGNOR	form complex	binding			9606									32445620	t		miannu	The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction.	SIGNOR-263906	0.968
MAPK1	protein	P28482	UNIPROT	CDC42EP1	protein	Q00587	UNIPROT	unknown	phosphorylation	Ser195	RRSDSLLsFRLDLDL	10090									22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262766	0.2
belinostat	chemical	CHEBI:61076	ChEBI	HDAC4	protein	P56524	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257743	0.8
PDPK1	protein	O15530	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Thr252	HDGTVTHtFCGTIEY	9606									19864428	t		gcesareni	A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. Phosphorylation and activation of p70s6k by pdk1.	SIGNOR-188907	0.714
CREB5	protein	Q02930	UNIPROT	RDX	protein	P35241	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		 BTO:0002816							21132541	f		miannu	 Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition),	SIGNOR-253809	0.2
MAPK3	protein	P27361	UNIPROT	JUND	protein	P17535	UNIPROT	up-regulates	phosphorylation	Ser100	LGLLKLAsPELERLI	9606									22327296	t		gcesareni	Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase.	SIGNOR-196034	0.471
CFLAR	protein	O15519	UNIPROT	CASP8	protein	Q14790	UNIPROT	down-regulates activity	binding			9606									14585074	t		amattioni	Flip can be incorporated into the disc complex and blocks processing and activation of pro-caspase8	SIGNOR-96402	0.76
IQSEC2	protein	Q5JU85	UNIPROT	ARF6	protein	P62330	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			10090		BTO:0000142							18164504	t		miannu	Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6.	SIGNOR-264906	0.471
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	BCR	protein	P11274	UNIPROT	down-regulates activity	phosphorylation	Tyr360	VSPSPTTyRMFRDKS	9534									8622703	t		Manara	These results indicate that tyrosine phosphorylation of Bcr by Bcr-Abl inhibits Bcr’s serine/threonine kinase activity.	SIGNOR-262530	0.2
Linsitinib	chemical	CID:11640390	PUBCHEM	INSR	protein	P06213	UNIPROT	down-regulates activity	chemical inhibition			10090									24712877	t		lperfetto	Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β-cell functions, and β-cell proliferation in male mice	SIGNOR-262029	0.8
SMARCA4	protein	P51532	UNIPROT	SMARCC1	protein	Q92922	UNIPROT	up-regulates	binding			9606									10078207	t		miannu	The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.	SIGNOR-65441	0.949
CDC7	protein	O00311	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates	phosphorylation	Ser108	DVEELTAsQREAAER	9606									19647517	t		lperfetto	Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry	SIGNOR-187388	0.961
PPM1A	protein	P35813	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates	dephosphorylation			9606									10644691	t		lperfetto	Pp2c utilizes axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that pp2c is a positive regulator of wnt signal transduction and mediates its effects through the dephosphorylation of axin.	SIGNOR-227955	0.369
PPP4R3A	protein	Q6IN85	UNIPROT	PPP4C	protein	P60510	UNIPROT	up-regulates	binding			9606									18715871	t		gcesareni	Our data demonstrate that pp4r4 forms a novel cytosolic complex with pp4c, independent from the complexes containing pp4r1, pp4r2.PP4R3, and alpha4, and that the regulatory subunits of pp4c have evolved different modes of interaction with the catalytic subunit.	SIGNOR-180244	0.2
SP1	protein	P08047	UNIPROT	THBD	protein	P07204	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22406829	f		miannu	 In carcinomas the expression of thrombomodulin (TM) is inversely correlated with tumour progression and metastasis. The expression of TM is negatively regulated by NF-?B- and GSK3-?-dependent signalling pathways and positively regulated by retinoic acid and transcription factor Sp1 in PrEC, LNCaP and PC-3 cells, but not in DU-145 cells. 	SIGNOR-255216	0.2
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1896	SPTSPTYsPTSPVYT	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273101	0.745
DGC	complex	SIGNOR-C217	SIGNOR	NRXN3	protein	Q9HDB5	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							11470830	t		miannu	In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan.	SIGNOR-265450	0.306
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Ser413	GLMQRSSsFPYTTKG	9606	BTO:0000007								17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-252881	0.398
CYP21A2	protein	P08686	UNIPROT	11-deoxycortisol	smallmolecule	CHEBI:28324	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000050							25855791	t		lperfetto	Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively	SIGNOR-268644	0.8
CBX2	protein	Q14781	UNIPROT	Polycomb repressive complex 1	complex	SIGNOR-C408	SIGNOR	form complex	binding			9606									31608994	t		miannu	PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b	SIGNOR-266808	0.763
SIRT1	protein	Q96EB6	UNIPROT	Cell_cycle_progress 	phenotype	SIGNOR-PH42	SIGNOR	down-regulates				9606	BTO:0000007								14976264	f		lperfetto	Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress	SIGNOR-267285	0.7
IL21R	protein	Q9HBE5	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates	binding			9606	BTO:0000776								12093291	t		gcesareni	Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5	SIGNOR-90266	0.612
N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide	chemical	CHEBI:91393	ChEBI	TEK	protein	Q02763	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194349	0.8
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2I	protein	P63279	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271312	0.547
mTORC1	complex	SIGNOR-C3	SIGNOR	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Thr412	NQVFLGFtYVAPSVL	9606									10567431	t		lperfetto	Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size.	SIGNOR-217056	0.749
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser171	PLCLSPAsSGSSASF	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248679	0.613
KAT5	protein	Q92993	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	acetylation	Lys2078	EGSYETAkVLLDHFA	9606									17636029	t		gcesareni	This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60.	SIGNOR-156923	0.424
PHLPP1	protein	O60346	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	down-regulates activity	dephosphorylation	Ser472	RPHFPQFsYSASGRE	9606	BTO:0001544								19261608	t			The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.	SIGNOR-248330	0.635
C3 convertase complex	complex	SIGNOR-C310	SIGNOR	C5 convertase complex	complex	SIGNOR-C312	SIGNOR	form complex	binding												31331124	t		lperfetto	C3b associates with C3 convertase to form C5 convertase and cleaves C5.	SIGNOR-263447	0.525
VIP	protein	P01282	UNIPROT	VIPR1	protein	P32241	UNIPROT	up-regulates	binding			9606									11897681	t		gcesareni	Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip).	SIGNOR-116122	0.859
SMARCA1	protein	P28370	UNIPROT	HNuRF	complex	SIGNOR-C448	SIGNOR	form complex	binding			9606	BTO:0000007								14609955	t		miannu	 hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays.	SIGNOR-268818	0.694
GLUD2	protein	P49448	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	chemical modification			9913									11254391	t		miannu	Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate.	SIGNOR-268557	0.8
CDK7	protein	P50613	UNIPROT	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser12	LASDFAFsPPPGGGG	9606	BTO:0001086								31306665	t		lperfetto	Here, we combined molecular and cellular biology with CRISPR/Cas9-mediated genome engineering to pinpoint the function of serine 12 of OCT4 in ESCs. Using chemical inhibitors and an antibody specific to OCT4 phosphorylated on S12, we identified cyclin-dependent kinase (CDK) 7 as upstream kinase. |Phosphorylation of OCT4 on S12 has been previously implicated to stabilize OCT4 by binding to PIN1, thereby preventing ubiquitinylation by WWP2.	SIGNOR-264404	0.2
ABT-737	chemical	CID:11228183	PUBCHEM	BCL2L2	protein	Q92843	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189174	0.8
MTOR	protein	P42345	UNIPROT	EIF4EBP2	protein	Q13542	UNIPROT	down-regulates	phosphorylation			9606									14967450	t		gcesareni	Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2).	SIGNOR-122014	0.651
CTDSPL	protein	O15194	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation	Ser245	NQSMDTGsPAELSPT	9606	BTO:0000007								17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248310	0.475
NRG3	protein	P56975	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606									14967450	t		gcesareni	The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4.	SIGNOR-122059	0.738
MAPK1	protein	P28482	UNIPROT	SMAD3	protein	P84022	UNIPROT	unknown	phosphorylation	Ser208	DAGSPNLsPNPMSPA	9606				SIGNOR-C9					15241418	t		llicata	We found that ser 203 and ser 207 were phosphorylated by map kinase and that thr 178 was phosphorylated mostly by cdk and to a lesser extent by map kinase	SIGNOR-126748	0.736
JUN	protein	P05412	UNIPROT	HSD3B2	protein	P26439	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001555								19022561	f		miannu	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 	SIGNOR-254874	0.274
GNAQ	protein	P50148	UNIPROT	ARHGEF12	protein	Q9NZN5	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								12024019	t			Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA.	SIGNOR-256520	0.431
CTSS	protein	P25774	UNIPROT	BGLAP	protein	P02818	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly58	RYLYQWLgAPVPYPD	-1									9076588	t		miannu	This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 	SIGNOR-256323	0.314
FGFR4	protein	P22455	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606									10918587	t			Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. 	SIGNOR-251142	0.411
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Ser21	TPPSTALsPGKMSEA	9606	BTO:0000007								21059642	t	The effect has been demonstrated using Q01196-8	lperfetto	Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20).	SIGNOR-216916	0.347
D-106669	chemical	CID:16048654	PUBCHEM	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252649	0.8
ABL1	protein	P00519	UNIPROT	PSTPIP1	protein	O43586	UNIPROT	up-regulates activity	phosphorylation	Tyr345	PERNEGVyTAIAVQE	9534	BTO:0004055								11163214	t			PSTPIP1 was phosphorylated by c-Abl. Tyr-344 is a major c-Abl phosphorylation site.PSTPIP1 was able to bridge c-Abl to the PEST-type PTPs.	SIGNOR-251431	0.616
SYK	protein	P43405	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates activity	phosphorylation	Tyr289	SSCGSSGyFSSSPTL	9606	BTO:0002181								34634301	t		miannu	We found that tyrosine (Tyr) 289 phosphorylation of DEPTOR impairs its interaction with mTOR, leading to increased mTOR activation. Using proximity biotinylation assays, we identified SYK (spleen tyrosine kinase) as a kinase involved in DEPTOR Tyr 289 phosphorylation in an ephrin (erythropoietin-producing hepatocellular carcinoma) receptor-dependent manner.	SIGNOR-277572	0.2
UMPS	protein	P11172	UNIPROT	orotic acid	smallmolecule	CHEBI:16742	ChEBI	down-regulates quantity	chemical modification			9606									18020427	t		miannu	Orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) catalyzes the Mg2+-dependent condensation of orotic acid (OA) with PRPP (5-alpha-d-phosphorylribose 1-diphosphate) to yield diphosphate (PPi) and the nucleotide OMP (orotidine 5'-monophosphate).	SIGNOR-253580	0.8
CHD4	protein	Q14839	UNIPROT	MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263856	0.828
KAT2B	protein	Q92831	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates	binding			9606									11058129	t		gcesareni	P/caf was found to interact directly with smad3 in vitro. Moreover, smad2 and smad3 interacted with p/caf upon tgf-beta type i receptor activation in cultured mammalian cells. these results demonstrate the co-activator function of p/caf for smad2 and smad3.	SIGNOR-83607	0.663
SAE1/SAE2 complex	complex	SIGNOR-C294	SIGNOR	JUN	protein	P05412	UNIPROT	down-regulates activity	sumoylation	Lys226	HPRLQALkEEPQTVP	9606	BTO:0000567			SIGNOR-C154					16055711	t		lperfetto	We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. 	SIGNOR-263006	0.257
AFF4	protein	Q9UHB7	UNIPROT	AEP complex	complex	SIGNOR-C117	SIGNOR	form complex	binding			9606	BTO:0000664								20153263	t	1	miannu	These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells.	SIGNOR-239224	0.547
KPNA4	protein	O00629	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	relocalization			9606									20454918	t		gcesareni	Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7.	SIGNOR-254322	0.291
DLL4	protein	Q9NR61	UNIPROT	PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	up-regulates activity	binding			9606	BTO:0000776								16140393	t		lperfetto	Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate.	SIGNOR-209744	0.2
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1941	SPKGSTYsPTSPGYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203604	0.77
CDK2	protein	P24941	UNIPROT	TP73	protein	O15350	UNIPROT	down-regulates activity	phosphorylation	Thr86	AASASPYtPEHAASV	9606			SIGNOR-C16						12676926	t		gcesareni	Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86.	SIGNOR-99746	0.556
FGB	protein	P02675	UNIPROT	Fibrinogen	complex	SIGNOR-C311	SIGNOR	form complex	binding			-1									25427968	t		lperfetto	Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively).	SIGNOR-263391	0.753
WDFY3	protein	Q8IZQ1	UNIPROT	Autophagy	phenotype	SIGNOR-PH31	SIGNOR	up-regulates				9606									22653340	f		miannu	ALFY is a large, scaffolding, multidomain protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy. 	SIGNOR-266794	0.7
PRKCA	protein	P17252	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	down-regulates activity	phosphorylation	Ser496	ATPQRSGsVSNYRSC	-1									27784766	t		miannu	Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle.	SIGNOR-276459	0.2
PAXIP1	protein	Q6ZW49	UNIPROT	PAX2	protein	Q02962	UNIPROT	up-regulates activity	binding			9606		BTO:0000007							17925232	t			PTIP promotes assembly of the ALR complex and H3K4 methylation at a PAX2-binding DNA element. Without PTIP, Pax2 binds to this element but does not assemble the ALR complex	SIGNOR-251711	0.589
ORC3	protein	Q9UBD5	UNIPROT	ORC	complex	SIGNOR-C419	SIGNOR	form complex	binding			9606									32808929	t		lperfetto	The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA	SIGNOR-267565	0.953
TWIST2	protein	Q8WVJ9	UNIPROT	GDF15	protein	Q99988	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255496	0.2
CHD8	protein	Q9HCK8	UNIPROT	NEFM	protein	P07197	UNIPROT	down-regulates quantity	transcriptional regulation			10090									32839322	t		Gianni	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268917	0.2
DUSP2	protein	Q05923	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000782								8626452	t		gcesareni	We show that the in vivo substrate specificities of individual phosphatases are unique. Pac1, mkp-2, and mkp-1 recognize erk and p38, erk and jnk, and erk, p38, and jnk, respectively	SIGNOR-40918	0.606
PDX1	protein	P52945	UNIPROT	INS	protein	P01308	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11309388	t			In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1.	SIGNOR-255541	0.63
CYLD	protein	Q9NQC7	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	deubiquitination			10090									29291351	t		gianni	Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades.	SIGNOR-266437	0.62
MBD1	protein	Q9UIS9	UNIPROT	ALOX5	protein	P09917	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001412								19781662	f	 	 	Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene.	SIGNOR-254030	0.2
PTEN	protein	P60484	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates activity	dephosphorylation	Ser380	EPDHYRYsDTTDSDP	9606									22413754	t		miannu	Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites	SIGNOR-248544	0.2
PRKACA	protein	P17612	UNIPROT	ARPP21	protein	Q9UBL0	UNIPROT	up-regulates activity	phosphorylation	Ser58	QERRKSKsGAGKGKL	-1									10854908	t		miannu	The specificity of antibody G534 was examined using recombinant full-length rat ARPP-21 phosphorylated by PKA. Radiolabeled ARPP-21 from a reaction containing [γ32P]ATP correlated with the detection of phospho-Ser55-ARPP-21 by immunoblotting (Fig. 1A, left and middle panels). 	SIGNOR-263107	0.2
PLK1	protein	P53350	UNIPROT	PINX1	protein	Q96BK5	UNIPROT	down-regulates	phosphorylation	Ser117	SFSLEEKsKISKNRV	9606									20573420	t		lperfetto	Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation.	SIGNOR-166321	0.37
NFKBIA	protein	P25963	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates activity	binding			9606									1340770	t		lperfetto	Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b	SIGNOR-217394	0.807
HIF1A	protein	Q16665	UNIPROT	IL1B	protein	P01584	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									17548584	t		svumbaca	The loss of macrophage expression of HIF-1 led to significant decreases in the production of TNF-a, IL-1a, IL-1b, and IL-12	SIGNOR-256235	0.344
IL1A	protein	P01583	UNIPROT	TNF	protein	P01375	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000667								19005488	f		miannu	UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. UVB and IL-1alpha treatment synergistically enhanced TNF-alpha secretion and mRNA levels in human keratinocytes, similar to the findings reported previously in human fibroblasts.	SIGNOR-252209	0.507
HDAC1	protein	Q13547	UNIPROT	HES1	protein	Q14469	UNIPROT	down-regulates quantity	transcriptional regulation			10090									18762022	f			These data suggest that the GR recruits cellular HDAC activities to the Hes1 promoter, thereby conferring transcriptional repression in response to GC signaling.	SIGNOR-253054	0.377
TYK2	protein	P29597	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation			9606									30029643	t			Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated	SIGNOR-256255	0.676
IKBKB	protein	O14920	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser644	GLDFNFDsLISTQNV	9606	BTO:0000150								15084260	t		gcesareni	Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway	SIGNOR-252948	0.678
CRYBB2	protein	P43320	UNIPROT	CRYBB2	protein	P43320	UNIPROT	up-regulates activity	binding			9606									16319073	t		miannu	βB2-crystallin is the major component of β-crystallin and is a dimer at low concentrations. At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency.	SIGNOR-252154	0.2
GSK3B	protein	P49841	UNIPROT	MAP3K11	protein	Q16584	UNIPROT	up-regulates activity	phosphorylation	Ser789	VSAGPRPsPLPSPQP	9606	BTO:0000007								17711861	t		miannu	 The activation of MLK3 by GSK-3beta occurred via phosphorylation of MLK3 on two amino acid residues, Ser(789) and Ser(793), that are located within the C-terminal regulatory domain of MLK3. 	SIGNOR-276071	0.341
DNA polymerase epsilon	complex	SIGNOR-C377	SIGNOR	DNA_replication	phenotype	SIGNOR-PH53	SIGNOR	up-regulates				9534	BTO:0004055								12930972	f		lperfetto	Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA).	SIGNOR-265514	0.7
SGO1	protein	Q5FBB7	UNIPROT	Cohesin complex	complex	SIGNOR-C304	SIGNOR	up-regulates quantity by stabilization	binding			9606	BTO:0000567								24055156	t		lperfetto	The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl.	SIGNOR-265264	0.2
SMURF1	protein	Q9HCE7	UNIPROT	FAF2	protein	Q96CS3	UNIPROT	unknown	ubiquitination			-1									20804422	t		miannu	Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay.	SIGNOR-272698	0.284
CSNK1G2	protein	P78368	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Ser418	LTQMGSPsIRCSSVS	9606									18794808	t		lpetrilli	Cki?2 Directly phosphorylates smad3 at ser418, leading to the increased ubiquitination and proteasomal degradation of activated smad3 following tgf-? Treatment.	SIGNOR-181069	0.342
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Thr119	AGTAGALtPQHVRAH	9606	BTO:0001938								21364637	t		miannu	JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells	SIGNOR-277641	0.2
MAPK14	protein	Q16539	UNIPROT	MAPKAPK3	protein	Q16644	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000944								11157753	t		lperfetto	These results, taken together, suggest the importance of the docking interaction in the efficient phosphorylation and activation of 3pk by p38.	SIGNOR-235451	0.7
ARHGAP5	protein	Q13017	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260461	0.821
HNF1B	protein	P35680	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								9671480	t	2	miannu	The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays.	SIGNOR-241323	0.38
RPS6KB1	protein	P23443	UNIPROT	EEF2K	protein	O00418	UNIPROT	down-regulates activity	phosphorylation	Ser366	SPQVRTLsGSRPPLL	9606									11500364	t		lperfetto	We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity	SIGNOR-109712	0.726
MAPK8	protein	P45983	UNIPROT	EIF4ENIF1	protein	Q9NRA8	UNIPROT	up-regulates	phosphorylation	Ser374	GLEQAILsPGQNSGN	9606									22966201	t		llicata	Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress.	SIGNOR-198988	0.329
PRKAR1A	protein	P10644	UNIPROT	PRKACA	protein	P17612	UNIPROT	down-regulates activity	binding			9606									26687711	t			Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 	SIGNOR-258751	0.881
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270407	0.8
CBP/p300	complex	SIGNOR-C6	SIGNOR	YY1	protein	P25490	UNIPROT	up-regulates activity	acetylation			-1									11486036	t		miannu	Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs.	SIGNOR-268834	0.638
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257967	0.8
CREBBP	protein	Q92793	UNIPROT	CSK	protein	P41240	UNIPROT	up-regulates	binding			9606									10801129	t		gcesareni	Here we present cbp--a transmembrane phosphoprotein that is ubiquitously expressed and binds specifically to the sh2 domain of csk. Cbp is involved in the membrane localization of csk and in the csk-mediated inhibition of c-src.	SIGNOR-77139	0.513
SOCS1	protein	O15524	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									14522994	t		lperfetto	Shp-2 regulates socs-1-mediated janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor	SIGNOR-118407	0.787
malonyl-CoA	smallmolecule	CHEBI:15531	ChEBI	long-chain fatty acid anion	smallmolecule	CHEBI:57560	ChEBI	up-regulates quantity	precursor of			9606									15507492	t			Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the de novo biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH. 	SIGNOR-267210	0.8
NUP160	protein	Q12769	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262094	0.699
GSK3A	protein	P49840	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr58	KKFELLPtPPLSPSR	9606									16023596	t		gcesareni	Similar to c-myc, similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.	SIGNOR-138596	0.415
SRC	protein	P12931	UNIPROT	CNKSR1	protein	Q969H4	UNIPROT	up-regulates activity	phosphorylation	Tyr26	LDDSLQDyPFEDWQL										26319181	t		lperfetto	We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. 	SIGNOR-275919	0.485
ETS2	protein	P15036	UNIPROT	Macrophage_differentiation	phenotype	SIGNOR-PH99	SIGNOR	up-regulates				9606									11175361	f		miannu	 the constitutive expression of ets2 in myeloblast leukemic cells induces their differentiation to macrophages 	SIGNOR-259871	0.7
PHGDH	protein	O43175	UNIPROT	3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	up-regulates activity	chemical modification			9606									25406093	t		lperfetto	PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG.	SIGNOR-268567	0.8
MELK	protein	Q14680	UNIPROT	MELK	protein	Q14680	UNIPROT	up-regulates	phosphorylation	Ser391	GAATPRTsQFTKYWT	9606									16216881	t		lperfetto	We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase.	SIGNOR-141002	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation	Ser259	SQRQRSTsTPNVHMV	9606									11971957	t		lperfetto	Mutation of serine 259 increased the basal raf-1 activity and rendered it largely resistant to inhibition by pka.	SIGNOR-216523	0.302
STAT6	protein	P42226	UNIPROT	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606									22025054	f		lperfetto	IL-4R signals through a JAKSTAT6 pathway, and many of the genes associated with mouse M2 macrophages are regulated by STAT6, including arginase 1 (Arg1), macrophage mannose receptor 1 (Mrc1; also known as Cd206), resistin-like-? (Retnla; also known as Fizz1) and chitinase 3-like 3 (Chi3l3; also known as Ym1).	SIGNOR-249541	0.7
L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	precursor of			9606									29084849	t		miannu	Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7.	SIGNOR-268070	0.8
SYN3	protein	O14994	UNIPROT	ACTB	protein	P60709	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								15265865	t		miannu	Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. 	SIGNOR-269183	0.2
PRKCG	protein	P05129	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates activity	phosphorylation	Ser185	SAYVGRLsARPKLKA	-1									15604283	t		miannu	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276019	0.2
DUSP7	protein	Q16829	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates	dephosphorylation			9606									12907755	t		gcesareni	Identification of protein tyrosine phosphatases with specificity for the ligand-activated growth hormone receptor.	SIGNOR-104545	0.318
Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates activity				10090	BTO:0000452								16892090	f	inferred from family member		HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host	SIGNOR-270309	0.7
BMPR1A	protein	P36894	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	form complex	binding			9606									7791754	t		lperfetto	Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii).	SIGNOR-255257	0.544
HSPA5	protein	P11021	UNIPROT	ERN1	protein	O75460	UNIPROT	down-regulates activity	binding			9606									31226023	t		miannu	Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain	SIGNOR-260176	0.815
F2RL3	protein	Q96RI0	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256772	0.305
ERO1B	protein	Q86YB8	UNIPROT	ERP44	protein	Q9BS26	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000567								11847130	t		Simone	Here, we report the functional characterization of a novel UPR-induced ER resident protein (ERp44) that forms mixed disulfides with both hEROs, as well as with partially unfolded Ig subunits.	SIGNOR-261048	0.2
MYLK2	protein	Q9H1R3	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates activity	phosphorylation	Thr80	NEPHESRtNSDIVET	9606	BTO:0000007								21556048	t		llicata	Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis.	SIGNOR-238118	0.411
SRR	protein	Q9GZT4	UNIPROT	D-serine	smallmolecule	CHEBI:16523	ChEBI	up-regulates quantity	chemical modification			10090		BTO:0000142							12393813	t		lperfetto	High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media.	SIGNOR-268270	0.8
PLK1	protein	P53350	UNIPROT	CASP8	protein	Q14790	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser305	IYQLMDHsNMDCFIC								phosphorylation:Ser387	YLEMDLSsPQTRYIP	24484936	t		lperfetto	By phosphorylating S387 in procaspase-8 Cdk1/cyclin B1 generates a phospho-epitope for the binding of the PBD of Plk1. Subsequently, S305 in procaspase-8 is phosphorylated by Plk1 during mitosis. Using an RNAi-based strategy we could demonstrate that the extrinsic cell death is increased upon Fas-stimulation when endogenous caspase-8 is replaced by a mutant (S305A) mimicking the non-phosphorylated form. Together, our data show that sequential phosphorylation by Cdk1/cyclin B1 and Plk1 decreases the sensitivity of cells toward stimuli of the extrinsic pathway during mitosis.	SIGNOR-272989	0.38
LYN	protein	P07948	UNIPROT	MAP4K1	protein	Q92918	UNIPROT	up-regulates activity	phosphorylation	Tyr381	SESSDDDyDDVDIPT	9534									11514608	t			BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. Tyr-379 within HPK1 is essential for binding to BASH and thus strongly suggest that the DDDYDDV sequence containing the phosphorylated Tyr-379 is the binding site for the BASH SH2 domain.	SIGNOR-251403	0.389
CHEK1	protein	O14757	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser279	VLKRPERsQEESPPG	9606									20068082	t		gcesareni	The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts);	SIGNOR-163142	0.852
Complement C1 complex	complex	SIGNOR-C309	SIGNOR	C4A	protein	P0C0L4	UNIPROT	up-regulates activity	cleavage	Arg679	EKTTRKKrNVNFQKA	-1									9087411	t		lperfetto	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263433	0.63
GABA-A (a6-b2-d) receptor	complex	SIGNOR-C328	SIGNOR	CRHR1	protein	P34998	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268608	0.27
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser274	ASPQRSRsPSPQPSS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252328	0.635
FANCL	protein	Q9NW38	UNIPROT	Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	form complex	binding			9606	BTO:0000567								17396147	t		lperfetto	This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo 	SIGNOR-263245	0.906
SLC46A1	protein	Q96NT5	UNIPROT	heme	smallmolecule	CHEBI:30413	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000575								32621820	t		lperfetto	SLC46A1 contributes to hepatic iron metabolism by importing heme in hepatocytes.	SIGNOR-268265	0.8
PI3K	complex	SIGNOR-C156	SIGNOR	PIK3CD	protein	O00329	UNIPROT	up-regulates activity	binding			9534									14665640	t		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-252720	0.607
ARVCF	protein	O00192	UNIPROT	CDH2	protein	P19022	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0001109								14610055	t		miannu	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 	SIGNOR-252128	0.478
IFNG	protein	P01579	UNIPROT	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates				9606									32283152	f		miannu	High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity.	SIGNOR-261024	0.7
RPL35	protein	P42766	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262466	0.856
GSK3B	protein	P49841	UNIPROT	DPYSL2	protein	Q16555	UNIPROT	down-regulates activity	phosphorylation	Thr514	SVTPKTVtPASSAKT	10116	BTO:0000938								15652488	t		lperfetto	Here, we showed that glycogen synthase kinase-3beta (gsk-3beta) phosphorylated crmp-2 at thr-514 and inactivated it	SIGNOR-133255	0.713
sphingosine 1-phosphate(1-)	smallmolecule	CHEBI:60119	ChEBI	S1PR2	protein	O95136	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257578	0.8
MAPK11	protein	Q15759	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates	phosphorylation			9606									16932740	t		gcesareni	P38 map kinase mediates stress-induced internalization of egfrthe underlying mechanism entails phosphorylation of egfr at a short segment (amino acids 1002-1022) containing multiple serines and threonines, as well as phosphorylation of two rab5 effectors, eea1 and gdi.	SIGNOR-149086	0.341
EDNRA	protein	P25101	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257427	0.447
PHLPP1	protein	O60346	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates activity	dephosphorylation	Thr387	TMKRRDEtMQPAKPS	9606									20513427	t			PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis.	SIGNOR-248329	0.3
LAT	protein	O43561	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates activity	binding			9606					phosphorylation:Tyr161;Tyr200	DDYHNPGyLVVLPDS;SMESIDDyVNVPESG			11368773	t		lperfetto	By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.	SIGNOR-246060	0.801
POLR2E	protein	P19388	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding												22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266147	0.918
HAUS complex	complex	SIGNOR-C281	SIGNOR	NEDD1	protein	Q8NHV4	UNIPROT	up-regulates activity	relocalization			9606									19427217	t		lperfetto	Under NuMA and HAUS6 codepletion conditions, NEDD1 levels on spindle microtubules remained low, suggesting that the suppression observed is not caused by more efficient localization of NEDD1 to spindle microtubules (Figure S9D). Taken together, our results suggest that HAUS and NuMA exert opposing activities necessary for robust bipolar spindle formation.	SIGNOR-262331	0.526
4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide	chemical	CHEBI:94128	ChEBI	BCL2L2	protein	Q92843	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189156	0.8
IKZF3	protein	Q9UKT9	UNIPROT	LNPEP	protein	Q9UIQ6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003420								15894523	f	 	miannu	Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. 	SIGNOR-255405	0.2
perifosine	chemical	CHEBI:67272	ChEBI	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates	chemical inhibition			9606	BTO:0001130								14617782	t	Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation	gcesareni	Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation.| Our results demonstrate that Akt is an important cellular target of perifosine action. In addition, these studies show that the membrane translocation of certain PH domain-containing molecules can be greatly perturbed by the alkylphospholipid class of drugs and imply further that the PI3K/Akt pathway contributes to regulation of p21(WAF1/CIP1) expression.	SIGNOR-119189	0.8
RPS6KA3	protein	P51812	UNIPROT	TINF2	protein	Q9BSI4	UNIPROT	unknown	phosphorylation	Ser295	FPFRNLGsPTQVISK	9606									23977114	t		lperfetto	Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase rsk2. The consequence of tin2 phosphorylation during mitosis remains to be determined	SIGNOR-202532	0.351
tazarotene	chemical	CHEBI:32184	ChEBI	RARB	protein	P10826	UNIPROT	up-regulates activity	chemical activation			9534									19058965	t		Luana	Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes. 	SIGNOR-258028	0.8
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	CEBPB	protein	P17676	UNIPROT	down-regulates activity	binding			9606									12524424	t		lperfetto	C/EBPbeta and C/EBPdelta were found to physically interact with Smad3 and Smad4, and Smad3 cooperated with Smad4 and TGF-beta signaling to repress the transcriptional activity of C/EBPs.	SIGNOR-97117	0.561
RXRB	protein	P28702	UNIPROT	THRA	protein	P10827	UNIPROT	up-regulates	binding			9606									10976919	t		gcesareni	Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr	SIGNOR-81452	0.636
IRAK1	protein	P51617	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity	phosphorylation	Thr387	RTQTVRGtLAYLPEE	9606									14625308	t		lperfetto	Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signalingthis identifies irak-1 as a novel type of adapter protein, which employs its own kinase activity to introduce negative charges adjacent to the protein interaction domain, which anchors irak-1 at the active receptor complex. Thus, irak-1 regulates its own availability as an adapter molecule by sequential autophosphorylation.	SIGNOR-119216	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO4	protein	P98177	UNIPROT	down-regulates activity	phosphorylation	Ser262	TFRPRSSsNASSVST	10090									10217147	t			Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo.	SIGNOR-251478	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9606	BTO:0000830								15526160	f			Numerous studies have implicated the critical importance of the Ras/Erk pathway in cell division and survival	SIGNOR-254948	0.7
CSNK2A1	protein	P68400	UNIPROT	ACE	protein	P12821	UNIPROT	up-regulates activity	phosphorylation	Ser1299	SHGPQFGsEVELRHS	9823	BTO:0001176								12386153	t		lperfetto	CK2 coprecipitated with ACE from endothelial cells, and CK2 phosphorylated both ACE and a peptide corresponding to the cytoplasmic tail. Mutation of serine(1270) within the CK2 consensus sequence almost abolished ACE phosphorylation.|These results indicate that the CK2-mediated phosphorylation of ACE regulates its retention in the plasma membrane and may determine plasma ACE levels.	SIGNOR-264425	0.307
MAP3K5	protein	Q99683	UNIPROT	MAP2K6	protein	P52564	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000298								8974401	t		lperfetto	A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively.	SIGNOR-45353	0.596
F2	protein	P00734	UNIPROT	F2R	protein	P25116	UNIPROT	up-regulates activity	cleavage	Arg25	PLLSARTrARRPESK	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus	SIGNOR-263568	0.883
ROR2	protein	Q01974	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates	binding			9606									18667433	t		gcesareni	Wnt5a stimulation induces activation of the c-jun n-terminal kinase jnk at the wound edge in a ror2-dependent manner, and inhibiting jnk activity abrogates wnt5a-induced lamellipodia formation and mtoc reorientation	SIGNOR-179671	0.437
PPP2R2C	protein	Q9Y2T4	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	binding			9606	BTO:0001938								18069897	t		gcesareni	We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC	SIGNOR-247966	0.2
WDR83	protein	Q9BRX9	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	binding			9606									15118098	t		gcesareni	Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex.	SIGNOR-124476	0.504
NKX2-5	protein	P52952	UNIPROT	MYL2	protein	P10916	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0003265								9043061	f	 	 	The mammalian homolog of the Drosophila tinman homeobox gene, Nkx2-5, is specifi- cally required for ventricular chamber-specific myosin light chain-2 (MLC-2v) expression and looping morphogenesis during mammalian heart development.	SIGNOR-253645	0.606
ETNK1	protein	Q9HBU6	UNIPROT	ethanolaminium(1+)	smallmolecule	CHEBI:57603	ChEBI	down-regulates quantity	chemical modification												36583229	t		lperfetto	ETNK1 encodes ethanolamine kinase 1, which is involved in the de novo biosynthesis of phosphatidylethanolamine and is responsible for the phosphorylation of ethanolamine to phosphoethanolamine	SIGNOR-275642	0.8
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	DCX	protein	O43602	UNIPROT	unknown	phosphorylation	Ser339	SPISTPTsPGSLRKH	9606									14741103	t		llicata	In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35.	SIGNOR-250673	0.415
NME2	protein	P22392	UNIPROT	NME2	protein	P22392	UNIPROT	up-regulates activity	phosphorylation	His118	QVGRNIIhGSDSVKS	-1									8132589	t		miannu	Using site-directed mutagenesis of the cDNA encoding NM23-H2, we have created a mutant substituting for the amino acid histidine 118, the presumed site of phosphorylation in the formation of the phosphoenzyme intermediate, the nonphosphorylatable amino acid phenylalanine. The H118F mutant protein is shown to be catalytically inactive	SIGNOR-250304	0.2
MAPK1	protein	P28482	UNIPROT	CDC42EP2	protein	O14613	UNIPROT	unknown	phosphorylation	Ser101	RELPDGPsPLLKNAI	10090									22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262770	0.251
PHLPP2	protein	Q6ZVD8	UNIPROT	PRKCB	protein	P05771	UNIPROT	down-regulates quantity	dephosphorylation	Ser661	QNEFAGFsYTNPEFV	9606	BTO:0000067								18162466	t		gcesareni	Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle	SIGNOR-237039	0.333
CSNK2A1	protein	P68400	UNIPROT	GTF2A1	protein	P52655	UNIPROT	up-regulates activity	phosphorylation	Ser281	DGTGDTSsEEDEDEE	-1									11278496	t		llicata	We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function.	SIGNOR-250875	0.388
SRC	protein	P12931	UNIPROT	GAK	protein	O14976	UNIPROT	up-regulates activity	phosphorylation	Tyr1149	CTQPRPNyASNFSVI	-1									28135906	t		miannu	GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. Cyclin G-associated kinase (GAK) harbors a consensus phosphorylation motif (Y412) for c-Src; however, its physiological significance remains elusive. Here, we show that GAK is phosphorylated by c-Src not only at Y412 but also at Y1149.	SIGNOR-263198	0.278
MAPK14	protein	Q16539	UNIPROT	CDKN1C	protein	P49918	UNIPROT	up-regulates	phosphorylation			9606									22820251	t		gcesareni	G1-s control by p38/hog1 sapks upon osmostress. Upon osmostress, activated p38 and hog1 sapks phosphorylate the s/cdk inhibitor p57 or sic1 respectively at one single residue. In mammalian cells (left panel), p57 phosphorylation on thr143 leads to an increase of the affinity of p57 towards the cyclin a/cdk2 complex leading to a g1 arrest.	SIGNOR-198390	0.265
TRIM27	protein	P14373	UNIPROT	ULK1	protein	O75385	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys572	VVRPKLPkPPTDPLG	10090									35670107	t		lperfetto	TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48-linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels	SIGNOR-272541	0.2
CAPN3	protein	P20807	UNIPROT	CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	up-regulates activity	cleavage			9606									25969760	t		lperfetto	Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain	SIGNOR-251602	0.33
TTC3	protein	P53804	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000944								20059950	t		gcesareni	TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus	SIGNOR-252436	0.404
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	SP1	protein	P08047	UNIPROT	up-regulates	binding			9606									10671503	t		lperfetto	Rela (p65) nf-kappab subunit interacts with the zinc finger dna-binding domain of sp1.	SIGNOR-216334	0.557
MAPK1	protein	P28482	UNIPROT	CIITA	protein	P33076	UNIPROT	up-regulates	phosphorylation	Ser280	TVHGLPTsPDRPGST	9606									15210796	t		gcesareni	We show in this study that the nuclear localized form of ciita is a predominantly phosphorylated form of the protein, whereas cytoplasmic ciita is predominantly unphosphorylated. Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. Double mutations of these residues increased nuclear ciita, indicating that these sites are not required for nuclear import. Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.	SIGNOR-126250	0.443
BCOR	protein	Q6W2J9	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	down-regulates				10090	BTO:0004850								26847029	f		irozzo	Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes.	SIGNOR-256010	0.7
Degranulation	phenotype	SIGNOR-PH92	SIGNOR	TPSAB1	protein	Q15661	UNIPROT	up-regulates quantity by expression				9606									24232182	f		apalma	Particularly, damage-activated mast cells almost instantly begin to secrete TNFa, histamine and tryptase and then initiate the de novo synthesis of other cytokines, such as interleukin (IL)6	SIGNOR-255348	0.7
TLR4	protein	O00206	UNIPROT	TICAM2	protein	Q86XR7	UNIPROT	up-regulates	binding			9606									18221795	t		fstefani	Mappit analysis of early toll-like receptor signalling events.	SIGNOR-160424	0.723
MAPK3	protein	P27361	UNIPROT	ARRB1	protein	P49407	UNIPROT	down-regulates	phosphorylation	Ser412	EEEDGTGsPQLNNR	9606									10347142	t		gcesareni	Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation	SIGNOR-67634	0.705
MET	protein	P08581	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr659	VADERVDyVVVDQQK	9606	BTO:0000018								10734310	t		miannu	Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF.	SIGNOR-250290	0.661
CDK1	protein	P06493	UNIPROT	KRT18	protein	P05783	UNIPROT	up-regulates	phosphorylation	Ser34	RPVSSAAsVYAGAGG	9606									9524113	t		lperfetto	We identified k18 ser33 as an interphase phosphorylation site, which increases its phosphorylation during mitosis in cultured cells and regenerating liver, and as an in vitro cdc2 kinase phosphorylation site. K18 ser33 phosphorylation dictates binding to 14_3_3 proteins	SIGNOR-55994	0.344
PRKCB	protein	P05771	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates activity	phosphorylation	Ser582	LWHFRYEsLKHPKAY	9606	BTO:0000007								23824069	t		miannu	 Remarkably we find that PKCβ phosphorylates Ser582 in the helical domain of the PI3Kγ catalytic subunit p110γ in response to clustering of the high-affinity IgE receptor (FcεRI) and/or store-operated Ca²⁺- influx in mast cells. Phosphorylation of p110γ correlates with the release of the p84 PI3Kγ adapter subunit from the p84-p110γ complex.As functional p84-p110γ is key to GPCR-mediated p110γ signaling, this suggests that PKCβ-mediated p110γ phosphorylation disconnects PI3Kγ from its canonical inputs from trimeric G proteins, and enables p110γ to operate downstream of Ca²⁺ and PKCβ.	SIGNOR-276496	0.516
PRKCA	protein	P17252	UNIPROT	CBL	protein	P22681	UNIPROT	down-regulates quantity	phosphorylation	Ser623	NRHSLPFsLPSQMEP	9606	BTO:0000782								11024037	t		lperfetto	However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway. 	SIGNOR-249055	0.327
NKX2-3	protein	Q8TAU0	UNIPROT	MADCAM1	protein	Q13477	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									10790368	t		Luana	We provide evidence that NKX2.3 can activate MAdCAM-1 transcription directly	SIGNOR-266219	0.441
CASP3	protein	P42574	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates activity	cleavage	Asp349	RVASTMTdGANTMIE	9534	BTO:0004055								11517310	t		lperfetto	In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus.	SIGNOR-109878	0.6
ERG	protein	P11308	UNIPROT	SPP1	protein	P10451	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21669963	f	 	miannu	 Using in vitro and in vivo molecular assays, we showed that ERG increases OPN expression and binds to an EBS (nt -115 to -118) in the OPN promoter.	SIGNOR-254066	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CD86	protein	P42081	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19164127	f	 	miannu	 We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. 	SIGNOR-254782	0.296
RPS6KB1	protein	P23443	UNIPROT	RPS6	protein	P62753	UNIPROT	up-regulates activity	phosphorylation	Ser236	AKRRRLSsLRASTSK	10090									15809305	t		lperfetto	A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size.	SIGNOR-135176	0.936
9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone	chemical	CID:71748056	PUBCHEM	BMX	protein	P51813	UNIPROT	down-regulates activity	chemical inhibition			-1									24556163	t		miannu	This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine 	SIGNOR-262232	0.8
ZNF292	protein	O60281	UNIPROT	GH1	protein	P01241	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									10687855	t		lperfetto	Rat Zn-15 is a transcription factor activating GH gene expression by synergistic interactions with Pit-1, named for 15 DNA-binding zinc fingers, including fingers IX, X, and XI that are responsible for GH promoter binding.	SIGNOR-268969	0.2
SMO	protein	Q99835	UNIPROT	GNB2	protein	P62879	UNIPROT	up-regulates	binding			9606									16885213	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-148589	0.2
PPP2CB	protein	P62714	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	down-regulates activity	dephosphorylation	Ser472	RPHFPQFsYSASGRE	9606									18160256	t			Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248610	0.472
SLC16A4	protein	O15374	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9606									26384349	f		lperfetto	Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival.	SIGNOR-242519	0.7
WNT5A	protein	P41221	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity				9606		BTO:0000887;BTO:0001103							9753670	f		gcesareni	Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm.	SIGNOR-60379	0.327
RASGRF2	protein	O14827	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260573	0.534
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	RHOA	protein	P61586	UNIPROT	down-regulates activity	phosphorylation	Tyr66	DTAGQEDyDRLRPLS	9606	BTO:0000567								23027962	t		lperfetto	When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity	SIGNOR-271699	0.2
HDAC1	protein	Q13547	UNIPROT	SNAI2	protein	O43623	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18588516	f	 	miannu	The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor).	SIGNOR-254228	0.596
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Thr24	LPRPRSCtWPLPRPE	-1	BTO:0000318								10377430	t		lperfetto	Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export.	SIGNOR-252857	0.908
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr362	SPPAEDVyDVPPPAP	10090									12972425	t		lperfetto	Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs	SIGNOR-246409	0.797
D-threo-isocitrate(3-)	smallmolecule	CHEBI:15562	ChEBI	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	precursor of			9606									28139779	t		miannu	Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP.	SIGNOR-266250	0.8
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	HIRA	protein	P54198	UNIPROT	up-regulates	phosphorylation	Thr555	LSPSVLTtPSKIEPM	9606									11238922	t		lperfetto	Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle.	SIGNOR-216670	0.331
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr234	SFKKQEKtPKTPKGP	9606									12058066	t		lperfetto	Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association.	SIGNOR-216662	0.415
PRKD1	protein	Q15139	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser275	DNVRYGIsNIDTTIE	9606	BTO:0002181								34010649	t		miannu	PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-277557	0.2
AP-2 complex	complex	SIGNOR-C245	SIGNOR	GABA-A	proteinfamily	SIGNOR-PF61	SIGNOR	down-regulates quantity	relocalization			9606	BTO:0000938								25600368	t		miannu	The endocytosis of GABAARs is regulated by the interaction of the AP2 complex with β and γ2 subunits. Phosphorylation of β3 (S408/S409) and γ2 (Y365/Y367) by PKA/PKC and Src/Fyn, respectively, prevents binding to AP2 and thus stabilizes these receptors at the cell surface.	SIGNOR-264990	0.2
TBK1	protein	Q9UHD2	UNIPROT	DDAH2	protein	O95865	UNIPROT	down-regulates activity	phosphorylation	Ser245	GGGDLPNsQEALQKL										33850055	t		lperfetto	TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o	SIGNOR-275648	0.2
TFEB	protein	P19484	UNIPROT	GBA	protein	P04062	UNIPROT	up-regulates quantity by expression	transcriptional regulation												28552616	t		lperfetto	Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants	SIGNOR-276551	0.332
KLK3	protein	P07288	UNIPROT	PTHLH	protein	P12272	UNIPROT	down-regulates activity	cleavage	Ser22	LLSYAVPsCGRSVEG	-1									8753751	t		lperfetto	Our study demonstrates that PTHrP is a substrate for PSA. The cleavage of the amino-terminal portion of PTHrP completely disrupts its ability to interact with the PTH/PTHrP receptor and thus inhibits its PTH-like activity. | Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments.	SIGNOR-270547	0.432
homocysteine	smallmolecule	CHEBI:17230	ChEBI	methionine	smallmolecule	CHEBI:16811	ChEBI	up-regulates quantity	precursor of			9606									10520212	t		lperfetto	Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels.	SIGNOR-253140	0.8
MAPK14	protein	Q16539	UNIPROT	MAPKAPK2	protein	P49137	UNIPROT	up-regulates activity	phosphorylation	Thr25	APPPQPPtPALPHPP	9606									8846784	t		lperfetto	Here we show that in vitro rk phosphorylates human gst-mapkap kinase-2 at thr25 in the proline-rich n-terminal region thr222 and ser272 in the catalytic domain and thr334 in the c-terminal domain. Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation	SIGNOR-44351	0.758
CPSF6	protein	Q16630	UNIPROT	CFI complex	complex	SIGNOR-C388	SIGNOR	form complex	binding			9606	BTO:0000567								8626397	t		lperfetto	We report here the purification of CF Im from HeLa cell nuclear extracts. Three polypeptides of 68, 59, and 25 kDa copurified with CF Im activity.	SIGNOR-266123	0.811
RPGRIP1L	protein	Q68CZ1	UNIPROT	RELA	protein	Q04206	UNIPROT	down-regulates	demethylation	Lys221	LLCDKVQkEDIEVYF	9606				SIGNOR-C13					20080798	t		miannu	Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation.	SIGNOR-163320	0.2
CNOT4	protein	O95628	UNIPROT	KDM5C	protein	P41229	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									19346402	t		miannu	 In our study, we show that the protein level of the yeast histone H3 Lys 4 (H3 K4) demethylase Jhd2/Kdm5 is modulated through polyubiquitination by the E3 ubiquitin ligase Not4 and turnover by the proteasome.  Finally, we show that human NOT4 can polyubiquitinate human JARID1C/SMCX, a homolog of Jhd2, suggesting that this is likely a conserved mechanism. We propose that Not4 is an E3 ubiquitin ligase that monitors and controls a precise amount of Jhd2 protein so that the proper balance between histone demethylase and histone methyltransferase activities occur in the cell, ensuring appropriate levels of H3 K4 trimethylation and gene expression.	SIGNOR-271468	0.561
LTBP2	protein	Q14767	UNIPROT	FBN1	protein	P35555	UNIPROT	up-regulates activity	binding			9606	BTO:0000452								19681046	t	Regulation	miannu	LTBP-2 interacts with fibrillin-1. The association of LTBP-2 with the ECM always coincided with that of fibrillin-1, and in fibroblast cultures the appearance of fibrillar fibrillin-1 structures preceded the assembly of LTBP-2 network. 	SIGNOR-251891	0.306
CREBBP	protein	Q92793	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates	binding			9606									9829964	t		gcesareni	When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp.	SIGNOR-62260	0.94
YWHAH	protein	Q04917	UNIPROT	KCNK18	protein	Q7Z418	UNIPROT	down-regulates activity	binding			-1									18397886	t		miannu	Phosphorylation of serine 264 in mouse TRESK was required for the binding of 14-3-3η. In the present study, we report that 14-3-3 proteins directly bind to the intracellular loop of TRESK and control the kinetics of the calcium-dependent regulation of the channel. Coexpression of 14-3-3η with TRESK blocked, whereas the coexpression of a dominant negative form of 14-3-3η accelerated the return of the K+ current to the resting state after the activation mediated by calcineurin in Xenopus oocytes. 	SIGNOR-263155	0.314
RNF8	protein	O76064	UNIPROT	H2AX	protein	P16104	UNIPROT	up-regulates	ubiquitination			9606									18001824	t		gcesareni	Rnf8 can ubiquitylate histone h2a and h2ax,	SIGNOR-159309	0.2
CD40LG	protein	P29965	UNIPROT	CD40	protein	P25942	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								12324477	t		lperfetto	Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated T cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner. cd40 binds its ligand cd40l.	SIGNOR-93432	0.927
SIK2	protein	Q9H0K1	UNIPROT	CRTC2	protein	Q53ET0	UNIPROT	down-regulates	phosphorylation	Ser171	SALNRTSsDSALHTS	9606									20577053	t		gcesareni	Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2	SIGNOR-166372	0.734
HSP90AA1	protein	P07900	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates	binding			9606									18591668	t		lpetrilli	The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs.	SIGNOR-179268	0.424
RPS6KA4	protein	O75676	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser362	AAAHRKGsSSNEPSS	9606									8248197	t		gcesareni	Rsk1/2 phosphorylates the transcription factor c-fos on s362 and increases its activity.	SIGNOR-37216	0.401
DTX1	protein	Q86Y01	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates	binding			9606									11564735	t		gcesareni	We found that a significant fraction of dtx1 proteins were localized in the nucleus and physically interacted with the transcriptional coactivator p300.	SIGNOR-110629	0.389
GABA-A (a6-b3-d) receptor	complex	SIGNOR-C329	SIGNOR	CRHR2	protein	Q13324	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268598	0.2
ALDH9A1	protein	P49189	UNIPROT	4-trimethylammoniobutanal	smallmolecule	CHEBI:18020	ChEBI	down-regulates quantity	chemical modification			9606									11802770	t		miannu	Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). 	SIGNOR-269692	0.8
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates	dephosphorylation			9606									18676376	t		lperfetto	Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes.	SIGNOR-233438	0.598
UBE2I	protein	P63279	UNIPROT	SOX6	protein	P35712	UNIPROT	down-regulates activity	sumoylation	Lys417	TSPVTQkVkDEAAAQP	9606									16442531	t			We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity.	SIGNOR-256130	0.374
Factor FVIIa:TF	complex	SIGNOR-C319	SIGNOR	F5	protein	P12259	UNIPROT	down-regulates activity	cleavage	Arg707	ESTVMATrKMHDRLE	-1									10026263	t		lperfetto	Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 	SIGNOR-263647	0.496
INPP4B	protein	O15327	UNIPROT	phosphatidylinositol bisphosphate	smallmolecule	CHEBI:37328	ChEBI	down-regulates quantity	chemical modification			9606									21127264	t		gcesareni	Collectively this data indicates INPP4B is the only PtdIns(3,4)P2 4-phosphatase expressed in breast cancer cells and suggests a correlation between INPP4B and hormone receptor status in human breast cancer	SIGNOR-252433	0.8
PGS1	protein	Q32NB8	UNIPROT	1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-)	smallmolecule	CHEBI:60110	ChEBI	up-regulates	chemical modification			9606									29034233	t		lperfetto	After activation of PA by the CDP-DAG synthase TAMM41 (Kutik et al., 2008), the phosphatidylglycerol phosphate synthase (PGS1) catalyzes the committed step by converting CDP-DAG to phosphatidylglycerol phosphate (PGP)	SIGNOR-267023	0.8
MAPK1	protein	P28482	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates activity	phosphorylation	Ser130	HLSIGTMsPSLGFPA	-1									35831023	t		miannu	We conclude that multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk.	SIGNOR-277600	0.329
PLK1	protein	P53350	UNIPROT	CCNB1	protein	P14635	UNIPROT	up-regulates activity	phosphorylation	Ser133	SPSPMETsGCAPAEE	9606	BTO:0000567								11242082	t		lperfetto	Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation.	SIGNOR-105715	0.919
GSK3B	protein	P49841	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser62	EPDSGSHsRQSSTDS	9606	BTO:0002181								22692215	t		miannu	GSK3 destabilizes TAZ. TAZS58A/S62A but not the TAZ S66A mutant diminished phos- phorylation by GSK3 
, suggesting that Ser-58 and Ser-62 are important for GSK3 
 phosphorylation, whereas the Ser-66 is not (Fig. 4D).	SIGNOR-277647	0.2
HLA1	proteinfamily	SIGNOR-PF87	SIGNOR	Class I MHC	complex	SIGNOR-C425	SIGNOR	form complex	binding			-1									28367149	t		scontino	One Ig domain is present in each chain of MHC class II, while the second Ig-type domain of MHC class I is provided by non-covalent association of the invariant light chain beta-2 microglobulin (beta2m) with the HC.|The MHC class I HC folds and assembles with beta2m in the lumen of the endoplasmic reticulum (ER)	SIGNOR-267776	0.965
TRMT10B	protein	Q6PF06	UNIPROT	TIM22 complex	complex	SIGNOR-C424	SIGNOR	form complex	binding			9606	BTO:0000007								32901109	t		lperfetto	Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK).	SIGNOR-267705	0.205
TP53	protein	P04637	UNIPROT	FNTB	protein	P49356	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26469958	f		lperfetto	In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3'-hydroxy-3'-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs.	SIGNOR-242353	0.2
PRKAB1	protein	Q9Y478	UNIPROT	PROX1	protein	Q92786	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser79	KLLKRANsYEDAMMP	9606	BTO:0002181								36433955	t		miannu	Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation.	SIGNOR-277609	0.2
PRKCA	protein	P17252	UNIPROT	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates activity	phosphorylation	Ser189	DEEFREPsTGKTCLP	9606									19661060	t		Manara	We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.	SIGNOR-260884	0.357
PRKACA	protein	P17612	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	phosphorylation	Ser1166	SDDFKRDsVSGGGPC	9606	BTO:0000007								24431445	t		miannu	Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines.	SIGNOR-276616	0.391
PDZD11	protein	Q5EBL8	UNIPROT	TSPAN33	protein	Q86UF1	UNIPROT	up-regulates activity	binding			10116	BTO:0003618								30463011	t		Simone	Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. The PLEKHA7-PDZD11 Complex Clusters ADAM10 at Junctions through Tspan33	SIGNOR-261252	0.333
PER2	protein	O15055	UNIPROT	CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	down-regulates activity	binding			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop.	SIGNOR-267977	0.752
PIN4	protein	Q9Y237	UNIPROT	Ribosome biogenesis	phenotype	SIGNOR-PH164	SIGNOR	up-regulates				9606	BTO:0000567								12860119	f		lperfetto	Par14 is a pre-rRNA processing factor involved in mammalian ribosome biogenesis, Par14 deficiency slowed cell growth (Fig. 3A) and reduced the production of 18 and 28 S rRNAs 	SIGNOR-265754	0.7
GNG2	protein	P59768	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance.	SIGNOR-199138	0.2
afatinib	chemical	CHEBI:61390	ChEBI	ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259441	0.8
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	L1CAM	protein	P32004	UNIPROT	up-regulates activity	phosphorylation	Ser1152	RSKGGKYsVKDKEDT	10116	BTO:0001009								8663493	t		lperfetto	Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152.	SIGNOR-252766	0.2
AURKA	protein	O14965	UNIPROT	DLGAP5	protein	Q15398	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser757	EGMELNSsITSQDVL	9606	BTO:0000007								15987997	t		miannu	Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life.	SIGNOR-262651	0.741
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	BCL2L11	protein	O43521	UNIPROT	up-regulates	phosphorylation	Thr116	SCDKSTQtPSPPCQA	9606									12591950	t		lperfetto	Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58)	SIGNOR-98392	0.2
NOX3	protein	Q9HBY0	UNIPROT	ROS	stimulus	SIGNOR-ST2	SIGNOR	up-regulates				9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264715	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MAPK14	protein	Q16539	UNIPROT	down-regulates activity				9606	BTO:0000150								12697749	f		lperfetto	Our data indicate that akt2 inhibits cisplatin-induced jnk/p38 and bax activation through phosphorylation of ask1	SIGNOR-244288	0.2
PRKDC	protein	P78527	UNIPROT	YBX1	protein	P67809	UNIPROT	up-regulates activity	phosphorylation	Thr89	EDVFVHQtAIKKNNP	9606	BTO:0000007								36475703	t		miannu	The DNA-PK subunits and YB-1 phosphorylated at T89 were found colocalized suggesting their in vivo interaction.DNA-PK directly phosphorylates YB-1 and, this way, modulates YB-1 function. Point mutation of YB-1 at this residue abrogated the translocation of YB-1 into the nucleus.	SIGNOR-277611	0.343
NFATC1	protein	O95644	UNIPROT	IL2	protein	P60568	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10022916	t		Barakat	Together, our results demonstrate that dnNFAT inhibits the production of IL-2. Thus, the NFAT transcription factor contributes to the regulation of IL-2 gene expression and therefore plays a critical role in the initiation of immune responses.	SIGNOR-275405	0.583
PLK2	protein	Q9NYY3	UNIPROT	CENPJ	protein	Q9HC77	UNIPROT	up-regulates	phosphorylation	Ser595	ISFSSNSsFVLKILE	9606									20531387	t		lperfetto	Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap	SIGNOR-166003	0.561
ZSWIM2	protein	Q8NEG5	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000007								16522193	f		miannu	MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin. 	SIGNOR-271556	0.7
PDPK1	protein	O15530	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Thr308	KDGATMKtFCGTPEY	9606									21798082	t		gcesareni	Pip3 acts in turn as a docking site for two kinases, phosphoinositidedependent kinase 1 (pdk1) and akt, and the subsequent phosphorylation of akt at serine 308 by pdk1, leading to akt activation.	SIGNOR-175675	0.736
PRKCD	protein	Q05655	UNIPROT	CDK5	protein	Q00535	UNIPROT	down-regulates activity	phosphorylation	Thr77	LHSDKKLtLVFEFCD	9606	BTO:0001332								29511352	t		miannu	This generates a binding site for the C2 domain of PKCδ, which in turn phosphorylates CDK5 on T77. The resulting dissociation of the CDK5R1/CDK5 complex abolishes the activity of CDK5. 	SIGNOR-277386	0.2
CDK9	protein	P50750	UNIPROT	P-TEFb	complex	SIGNOR-C238	SIGNOR	form complex	binding			-1									34955012	t		lperfetto	Cyclin-dependent-kinases (CDKs) are members of the serine/threonine kinase family and are highly regulated by cyclins, a family of regulatory subunits that bind to CDKs. CDK9 represents one of the most studied examples of these transcriptional CDKs. CDK9 forms a heterodimeric complex with its regulatory subunit cyclins T1, T2 and K to form the positive transcription elongation factor b (P-TEFb). 	SIGNOR-267740	0.964
TNF	protein	P01375	UNIPROT	SCN4A	protein	P35499	UNIPROT	up-regulates activity				10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253490	0.26
DOT1L	protein	Q8TEK3	UNIPROT	HECTD4	protein	Q9Y4D8	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001321								32814769	t		miannu	Overexpression of DOT1L decreased the expression of HECTD4 and MYCBP2 in LNCaP, C42B, and 22rv1 cells (Supplementary Fig. 5c), suggesting that DOT1L plays a role in repressing these targets either directly or indirectly.	SIGNOR-267150	0.2
Ubiquitin	proteinfamily	SIGNOR-PF89	SIGNOR	Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	form complex	binding			9606									24816100	t		miannu	The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin.	SIGNOR-270834	0.756
CDKN2A	protein	P42771	UNIPROT	CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	down-regulates activity	binding			9606									11154267	t		lperfetto	Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity	SIGNOR-245459	0.822
MAOA	protein	P21397	UNIPROT	dopamine	smallmolecule	CHEBI:18243	ChEBI	down-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL).	SIGNOR-264001	0.8
PRKCB	protein	P05771	UNIPROT	C5AR1	protein	P21730	UNIPROT	down-regulates	phosphorylation	Ser334	SVVRESKsFTRSTVD	9606									17145764	t		lperfetto	Dynamics of protein kinase c-mediated phosphorylation of the complement c5a receptor on serine 334. Analysis of c5ar ser/ala mutants that possess a single intact serine residue either at position 334 or at neighboring positions 327, 332, or 338 revealed functional redundancy of c-terminal phosphorylation sites since all 4 serine residues could individually support c5ar internalization and desensitization	SIGNOR-151011	0.2
MDM4	protein	O15151	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by stabilization	binding			9606									10218570	t		miannu	MDM2 has been shown to be degraded by the ubiquitin-proteasome pathway, while MDMX was a stable protein. Interaction of MDMX with MDM2 through the C-terminal RING finger domains resulted in inhibiting degradation of MDM2. These data indicate that MDMX functions as a regulator of MDM2.	SIGNOR-272932	0.72
MAPK1	protein	P28482	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Thr693	RELVEPLtPSGEAPN	-1									1651322	t		lperfetto	A growth factor-stimulated protein kinase activity that phosphorylates the epidermal growth factor (EGF) receptor at Thr669 has been described Anion-exchange chromatography demonstrated that this protein kinase activity was accounted for by two enzymes. The first peak of activity eluted from the column corresponded to the microtubule-associated protein 2 (MAP2) kinase	SIGNOR-20545	0.623
MDM2	protein	Q00987	UNIPROT	PER2	protein	O15055	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									30425162	t		miannu	We identified PER2 as a previously uncharacterized substrate for the ubiquitin ligase mouse double minute 2 homolog (MDM2) and found that MDM2 targeted PER2 for degradation in a manner independent of PER2 phosphorylation. 	SIGNOR-277421	0.363
peptide	smallmolecule	CHEBI:16670	ChEBI	Translation release factor ERF1-ERF3	complex	SIGNOR-C494	SIGNOR	up-regulates activity	binding			9606									29735640	t		miannu	Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3–guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide. 	SIGNOR-270815	0.8
ATP2A2	protein	P16615	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									16402920	t		lperfetto	In the present study, we have analysed the expression and functional characteristics of SERCA2c relative to SERCA2a and SERCA2b isoforms upon their stable heterologous expression in HEK-293 cells (human embryonic kidney 293 cells). All SERCA2 proteins induced an increased Ca2+ content in the ER of intact transfected cells.	SIGNOR-262050	0.8
FOXC1	protein	Q12948	UNIPROT	MMP10	protein	P09238	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31650548	t		lperfetto	Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX13|MMP10 was demonstrated as the direct target and mediator of FOXC1.	SIGNOR-275915	0.2
MAPK1	protein	P28482	UNIPROT	GRB10	protein	Q13322	UNIPROT	unknown	phosphorylation	Ser418	QQRKALLsPFSTPVR	-1									15952796	t		lperfetto	We identified Ser150, Ser418, and Ser476 of human Grb10 as MAPK-mediated in vitro phosphorylation sites.	SIGNOR-249405	0.381
TWIST2	protein	Q8WVJ9	UNIPROT	NR2F1	protein	P10589	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255506	0.2
ECM	stimulus	SIGNOR-ST20	SIGNOR	A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259048	0.7
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1738	SPSYSPTsPSYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269371	0.718
CDK1	protein	P06493	UNIPROT	KIF20B	protein	Q96Q89	UNIPROT	up-regulates activity	phosphorylation	Thr1644	VKHPGCTtPVTVKIP	9606									11470801	t		miannu	Here we report the identification of a novel KRP, termed KRMP1, which undergoes in vivo phosphorylation. The carboxyl-terminal globular tail domain is strongly phosphorylated by mitotic kinase activities almost attributed to cdc2 kinase, which is responsible for phosphorylation on residue Thr-1604 of KRMP1.	SIGNOR-262695	0.418
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	form complex	binding					BTO:0001103							22045613	t		svumbaca	NICD is translocated to the nucleus where it binds recombining binding protein-Jj (RBP-Jj) 	SIGNOR-255364	0.95
STAT3	protein	P40763	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates	transcriptional regulation			9606	BTO:0000801								22378047	f			IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype	SIGNOR-254517	0.612
ORC1	protein	Q13415	UNIPROT	ORC	complex	SIGNOR-C419	SIGNOR	form complex	binding			9606									32808929	t		lperfetto	The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA	SIGNOR-267567	0.944
HECTD4	protein	Q9Y4D8	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001321								32814769	t		miannu	 We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. 	SIGNOR-267146	0.2
GRK2	protein	P25098	UNIPROT	MC4R	protein	P32245	UNIPROT	down-regulates activity	phosphorylation	Thr312	RSQELRKtFKEIICC	9606									12639913	t		gcesareni	Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor.	SIGNOR-247770	0.2
BANP	protein	Q8N9N5	UNIPROT	KHDRBS1	protein	Q07666	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								26080397	t		miannu	SMAR1 Interacts with Sam68 in a Signal-Dependent Manner. HDAC6 in complex with SMAR1 deacetylates Sam68. Here, we document that SMAR1, in cooperation with histone deacetylase 6 (HDAC6), interacts with Sam68 and maintains it in a deacetylated state, concomitantly inhibiting the inclusion of CD44 alternate exons. 	SIGNOR-266201	0.313
SMAD2	protein	Q15796	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	up-regulates activity				9606	BTO:0000599								10890911	f		lperfetto	Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity	SIGNOR-78988	0.463
sirolimus	chemical	CHEBI:9168	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									21757781	t		gcesareni	Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kda fk506- and rapamycin-binding protein (fkbp12, or fkbp) and the fkbp-rapamycin binding (frb) domain of the mammalian ta rget of rapamycin (mtor) kinase. autophagy is negatively regulated by the mammalian target of rapamycin (mtor) and can be induced in all mammalian cell types by the mtor inhibitor rapamycin.	SIGNOR-174886	0.8
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257964	0.8
SMO	protein	Q99835	UNIPROT	GNB3	protein	P16520	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp	SIGNOR-199180	0.2
NR3C1	protein	P04150	UNIPROT	RXRA	protein	P19793	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12573484	f		gcesareni	Physiological concentrations of glucocorticoids increase cellular cyp2c9 (and cyp3a5) but also car, rxr and pxr levels via a gr-mediated mechanism	SIGNOR-98102	0.441
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser291	CDVKTDDsVVPCFMK	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276199	0.389
CDC20	protein	Q12834	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								23287467	t		miannu	 Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1.	SIGNOR-272896	0.872
PKNOX1	protein	P55347	UNIPROT	HOXB1	protein	P14653	UNIPROT	up-regulates activity	binding			-1									9482740	t	2	miannu	we observe the formation of a ternary Prep1-Pbx1-HOXB1 complex on a HOXB1-responsive target in vitro. Interaction with Prep1 enhances the ability of the HOXB1-Pbx1 complex to activate transcription in a cooperative fashion from the same target.	SIGNOR-241215	0.598
MAP2K1	protein	Q02750	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates	phosphorylation	Tyr204	HTGFLTEyVATRWYR	9606									9677429	t	MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade.	gcesareni	The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells.	SIGNOR-59157	0.741
PTH1R	protein	Q03431	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding												28363951	t		lperfetto	This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11.	SIGNOR-270551	0.485
PRKACA	protein	P17612	UNIPROT	CACNB2	protein	Q08289	UNIPROT	up-regulates activity	phosphorylation	Ser533	KKSQHRSsSSAPHHN										10441130	t		miannu	Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation	SIGNOR-250340	0.416
PPARGC1A	protein	Q9UBK2	UNIPROT	APOC3	protein	P02656	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f		miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-255059	0.28
ESR1	protein	P03372	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									16169518	t		gcesareni	Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k.	SIGNOR-252675	0.648
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606									27418133	f			The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines	SIGNOR-253587	0.7
CEBPD	protein	P49716	UNIPROT	IL23A	protein	Q9NPF7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000801								23028973	f	 	 	CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions.	SIGNOR-254061	0.2
ATM	protein	Q13315	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	unknown	phosphorylation	Ser29	IEDSQPEsQVLEDDS	9606									12697768	t		llicata	To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1	SIGNOR-100645	0.869
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	AL/b2 integrin	complex	SIGNOR-C169	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259024	0.446
POU5F1	protein	Q01860	UNIPROT	Pluripotency	phenotype	SIGNOR-PH43	SIGNOR	up-regulates				9606	BTO:0001086								16153702	f		flangone	Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes.	SIGNOR-242070	0.7
APOBEC3D	protein	Q96AK3	UNIPROT	Clearance_of_foreign intracellular_DNA	phenotype	SIGNOR-PH132	SIGNOR	up-regulates				9606									29367246	f		lperfetto	The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24).	SIGNOR-261328	0.7
PRKACA	protein	P17612	UNIPROT	HNRNPD	protein	Q14103	UNIPROT	up-regulates	phosphorylation	Ser87	SNSSPRHsEAATAQR	9606									11903055	t		gcesareni	Protein kinase a enhances, whereas glycogen synthase kinase-3 beta inhibits, the activity of the exon 2-encoded transactivator domain of heterogeneous nuclear ribonucleoprotein d in a hierarchical fashion.	SIGNOR-116144	0.355
KREMEN1	protein	Q96MU8	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates				9606									12050670	f		gcesareni	Dkk1 has been shown to inhibit wnt signalling by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to block wnt/beta-catenin signalling.	SIGNOR-88891	0.627
CCP110	protein	O43303	UNIPROT	CALM1	protein	P0DP23	UNIPROT	up-regulates activity	binding			9606									16760425	t		miannu	We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis.	SIGNOR-265965	0.325
FYN	protein	P06241	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation	Tyr349	EEPPDHQyYNDFPGK	9606	BTO:0000782								9710204	t		lperfetto	Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2.	SIGNOR-59623	0.721
PEX14	protein	O75381	UNIPROT	PEX13	protein	Q92968	UNIPROT	up-regulates activity	binding			-1									15798189	t		miannu	Pex14 interacts via its proline-rich motif with the SH3 domain of Pex13. We conclude that the association of Pex13 with Pex14 is an essential step in peroxisomal protein import 	SIGNOR-253029	0.918
mTORC2	complex	SIGNOR-C2	SIGNOR	SGK1	protein	O00141	UNIPROT	up-regulates	phosphorylation	Ser422	AEAFLGFsYAPPTDS	9606									18925875	t		lperfetto	Mtorc2 immunoprecipitated from wild-type, but not from mlst8- or rictor-knockout cells, phosphorylated sgk1 at ser(422)	SIGNOR-217016	0.654
DKK1	protein	O94907	UNIPROT	WNT3A	protein	P56704	UNIPROT	down-regulates				9606									22298955	f	Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6.	gcesareni	It has been shown that both sclerostin and dkk1 act physiologically as downstream molecules of bmp signaling to inhibit canonical wnt signaling and therefore negatively regulate bone mass.	SIGNOR-195573	0.725
RAC1	protein	P63000	UNIPROT	USP6	protein	P35125	UNIPROT	up-regulates	relocalization			9606									12612085	t		miannu	In quiescent cells, tre17 is localized to intracellular filamentous and punctate structures in the cytoplasm, folded in an inactive conformation. Upon growth factor addition, cdc42 and rac1 become activated and recruit tre17 to the plasma membrane. Stable membrane localization of tre17 also requires polymerized actin. This recruitment process leads to a conformational change in tre17, such that the n-terminal portion of the molecule further stimulates the accumulation of cortical actin.	SIGNOR-98938	0.344
dacomitinib	chemical	CHEBI:132268	ChEBI	ERBB4	protein	Q15303	UNIPROT	down-regulates	chemical inhibition			9606									23405260	t		gcesareni	The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor.	SIGNOR-200908	0.8
YY1	protein	P25490	UNIPROT	HOXB13	protein	Q92826	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001130								19013255	f	 	miannu	 Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers.	SIGNOR-254233	0.277
WNT3A	protein	P56704	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131826	0.689
CSNK2A2	protein	P19784	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates activity	phosphorylation	Ser1124	LNTEEFSsESDMEES	9606	BTO:0000938								19064667	t		lperfetto	 We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275758	0.2
IKBKB	protein	O14920	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	down-regulates activity	phosphorylation	Ser444	PLSLSAQsVMEELNT	9606	BTO:0000938								24614225	t		lperfetto	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204740	0.529
CDK1	protein	P06493	UNIPROT	CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	form complex	binding			9606									25603287	t		lperfetto	The central mitotic kinase, cyclin-dependent kinase-1 (human cdk1 is present through all stages of the cell cycle, but its activity is cell-cycle regulated by phosphorylation/dephosphorylation and cyclin binding.Cdk1-cyclin b phosphorylates ser/thr residues directly preceding pro; thus, it is classified as a proline-directed kinase.	SIGNOR-205593	1
LRRK2	protein	Q5S007	UNIPROT	DVL3	protein	Q92997	UNIPROT	up-regulates	binding			9606									23754980	t		gcesareni	Subsequent assays confirmed a direct interaction between the lrrk2 roccor domain and all three human dvl proteins, these data are consistent with a role for lrrk2 in the activation of canonical wnt signaling bringing dvl proteins to cellular membranes.	SIGNOR-202187	0.493
CSNK2A2	protein	P19784	UNIPROT	SPIB	protein	Q01892	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser144	DSPALEVsDSESDEA	9606	BTO:0000567								10618498	t		llicata	Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo	SIGNOR-251040	0.311
succinyl-CoA(5-)	smallmolecule	CHEBI:57292	ChEBI	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	precursor of												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271808	0.8
USP9X	protein	Q93008	UNIPROT	Ubiquitin	proteinfamily	SIGNOR-PF89	SIGNOR	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270831	0.632
YES1	protein	P07947	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Tyr407	SGLSMSSySVPRTPD	9606	BTO:0000578								35041461	t		miannu	Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C). 	SIGNOR-277653	0.71
YES1	protein	P07947	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	up-regulates activity	phosphorylation	Tyr305	PFLNGGPyHSREQST	9606	BTO:0000578								35041461	t		miannu	Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C). 	SIGNOR-277654	0.323
CDK2	protein	P24941	UNIPROT	RAD54L	protein	Q92698	UNIPROT	down-regulates activity	phosphorylation	Ser49	QIQECFLsPFRKPLS	-1									29295984	t		miannu	Effect of CDK2 phosphorylation on the RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM.	SIGNOR-273599	0.354
TPO	protein	P07202	UNIPROT	3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	up-regulates quantity	chemical modification			9606									28153798	t		scontino	The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines.	SIGNOR-267039	0.8
PGLS	protein	O95336	UNIPROT	6-phospho-D-gluconate	smallmolecule	CHEBI:16863	ChEBI	up-regulates quantity	chemical modification			9606									31586547	t		miannu	The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG).	SIGNOR-267058	0.8
GATA3	protein	P23771	UNIPROT	ERG	protein	P11308	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21536859	f	 	miannu	 We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer.	SIGNOR-253920	0.2
3-[[6-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]phenol	chemical	CHEBI:91384	ChEBI	GSK3B	protein	P49841	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207474	0.8
NLRP1 inflammasome	complex	SIGNOR-C224	SIGNOR	Caspase 1 complex	complex	SIGNOR-C220	SIGNOR	up-regulates activity	cleavage												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256380	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	STAT5A	protein	P42229	UNIPROT	up-regulates	phosphorylation			9606		BTO:0000975							10194762	t	inferred from 70% family members	gcesareni	Serine 780 is the only substrate in full-length stat5a for active erk	SIGNOR-270136	0.2
ABL1	protein	P00519	UNIPROT	PRKD1	protein	Q15139	UNIPROT	unknown	phosphorylation	Tyr502	TTANVVYyVGENVVN	9606	BTO:0000567								12637538	t		gcesareni	Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. [..] Mutation of the other two sites, Tyr432 and Tyr502, had no significant influence on PKD activity.	SIGNOR-246215	0.345
TBX2	protein	Q13207	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002267								25211658	t		lperfetto	TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS	SIGNOR-249593	0.353
SRC	protein	P12931	UNIPROT	RGS16	protein	O15492	UNIPROT	up-regulates	phosphorylation	Tyr177	RFLKSPAyRDLAAQA	9606									12588871	t		lperfetto	Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. hosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr).	SIGNOR-98275	0.352
HTR2B	protein	P41595	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257138	0.533
YAP1	protein	P46937	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates quantity by expression	transcriptional regulation												35216681	f		lperfetto	Importantly, YAP-dependent regulation of serum- and glucocorticoid-regulated kinase 1 (SGK1) is required to activate mTORC1/SREBP and stimulate de novo lipogenesis. 	SIGNOR-276585	0.285
STAP1	protein	Q9ULZ2	UNIPROT	TEC	protein	P42680	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								10518561	t		miannu	 In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling. BRDG1 may activate Tec by disrupting an intramolecular interaction.	SIGNOR-261819	0.4
PRKCA	protein	P17252	UNIPROT	ADRA1B	protein	P35368	UNIPROT	down-regulates activity	phosphorylation	Ser412	DSLDDSGsCLSGSQR	9534	BTO:0000298								9353340	t		lperfetto	 Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. 	SIGNOR-248989	0.399
PPAT	protein	Q06203	UNIPROT	L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	down-regulates quantity	chemical modification			9606									8106516	t			Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed”	SIGNOR-267187	0.8
PGM2	protein	Q96G03	UNIPROT	2-deoxy-D-ribose 5-phosphate	smallmolecule	CHEBI:16132	ChEBI	up-regulates quantity	chemical modification			9606									17804405	t		miannu	Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses.	SIGNOR-267095	0.8
TESK1	protein	Q15569	UNIPROT	CFL2	protein	Q9Y281	UNIPROT	down-regulates activity	phosphorylation	Ser3	sGVTVNDE	9606	BTO:0001363								11418599	t		lperfetto	Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin	SIGNOR-246719	0.327
PTMS	protein	P20962	UNIPROT	NCOA1	protein	Q15788	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								16150697	t		miannu	Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner. Immunoprecipitation analysis showed that in the presence of glucocorticoid hormone, p300 and CREB-binding protein are coprecipitated with MTI-II. Furthermore, the knockdown of endogenous MTI-II by RNAi reduces the transcriptional activity of GR in cells.	SIGNOR-268462	0.2
NOTCH1	protein	P46531	UNIPROT	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19165418	f		lperfetto	Several lines of evidence have suggested that these genes are indeed direct notch target genes: a) the promoters of hes1, hes5 and hes7 as well as hey1, hey2 and heyl subfamily of hes, related with yrpw motif) can be activated by a constitutive active form of notch1.	SIGNOR-183507	0.764
MAPK1	protein	P28482	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates activity	phosphorylation			9606	BTO:0000007								10567369	t		lperfetto	An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2	SIGNOR-244912	0.743
ALK	protein	Q9UM73	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	binding			9606	BTO:0000785								14968112	t		gcesareni	Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1.	SIGNOR-122082	0.53
p38	proteinfamily	SIGNOR-PF16	SIGNOR	FOXC1	protein	Q12948	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser241	PSPPQPLsPAAALGS										31650548	t		lperfetto	P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation.	SIGNOR-275914	0.2
ETS1	protein	P14921	UNIPROT	CD8A	protein	P01732	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8413295	f	 	miannu	Taken together, these results suggest that the human CD8 alpha gene is regulated by the interaction of multiple T-cell nuclear proteins with a transcriptional enhancer located in the last intron of the gene. Site-directed mutation of the Ets-1 and GATA-3 sites dramatically reduced enhancer activity. 	SIGNOR-254078	0.259
PRKACA	protein	P17612	UNIPROT	CAD	protein	P27708	UNIPROT	down-regulates activity	phosphorylation	Ser1406	GAGGRRLsSFVTKGY										11986331	t		miannu	CAD is down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation.	SIGNOR-250344	0.311
MASP1	protein	P48740	UNIPROT	C4A	protein	P0C0L4	UNIPROT	up-regulates activity	cleavage	Arg679	EKTTRKKrNVNFQKA	-1									9087411	t		lperfetto	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263432	0.59
LCK	protein	P06239	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606	BTO:0000782								14583609	t		gcesareni	Endogenous notch-1 associates with p56(lck) and pi3k. p56(lck) is required for the notch-1-mediated activation of akt/pkb function	SIGNOR-118902	0.469
CCT5	protein	P48643	UNIPROT	TRiC	complex	SIGNOR-C539	SIGNOR	form complex	binding			9606									36185250	t		miannu	Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC).	SIGNOR-272861	0.742
LDB1	protein	Q86U70	UNIPROT	LHX2	protein	P50458	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								17005264	t		miannu	Cofactor CLIM2 promotes the repressive action of LIM homeodomain transcription factor Lhx2 in the expression of porcine pituitary glycoprotein hormone alpha subunit gene.	SIGNOR-223962	0.555
USP1	protein	O94782	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	down-regulates activity	deubiquitination			9606	BTO:0000567			SIGNOR-C302					18082604	t		lperfetto	The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2|The level of monoubiquitinated FANCD2 protein increases in response to various types of DNA damage in mammalian cells	SIGNOR-263273	0.753
Ub:RBR_E3	complex	SIGNOR-C520	SIGNOR	Protein_ubiquitination	phenotype	SIGNOR-PH214	SIGNOR	up-regulates				9606									34199813	f		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. 	SIGNOR-271384	0.7
MARCHF9	protein	Q86YJ5	UNIPROT	PTPRJ	protein	Q12913	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001522								19457934	t		miannu	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. 	SIGNOR-271535	0.2
CSNK2A1	protein	P68400	UNIPROT	PTPRC	protein	P08575	UNIPROT	up-regulates	phosphorylation	Ser1009	DESSDDDsDSEEPSK	9606									10066810	t		gcesareni	Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein,	SIGNOR-65277	0.453
ACTB	protein	P60709	UNIPROT	Muscle cell-specific SWI/SNF ARID1B variant	complex	SIGNOR-C482	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270711	0.48
F2	protein	P00734	UNIPROT	F2RL1	protein	P55085	UNIPROT	up-regulates	binding			9606		BTO:0001253							11356985	t		gcesareni	Other major aspects of par-2 are highlighted, in particular the ability of several serine protease enzymes, in addition to trypsin, to function as activators of par-2.	SIGNOR-108183	0.594
fenoterol	chemical	CHEBI:149226	ChEBI	ADRB3	protein	P13945	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1). 	SIGNOR-257868	0.8
nafamostat	chemical	CHEBI:135466	ChEBI	TMPRSS2	protein	O15393	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002750								27550352	t		Monia	Nafamostat also blocked MERS-CoV infection in vitro. This inhibition was most likely a result of inhibition of TMPRSS2 on the plasma membrane. Because MERS-CoV may infect cells via a TMPRSS2-independent endocytotic pathway, we evaluated the effects of nafamostat on MERS-CoV infection using an in vitro virus infection assay	SIGNOR-261065	0.8
FYN	protein	P06241	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation	Tyr350	EPPDHQYyNDFPGKE	9606	BTO:0000782								9710204	t		lperfetto	Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2.	SIGNOR-59627	0.721
GNAQ	protein	P50148	UNIPROT	ARHGEF25	protein	Q86VW2	UNIPROT	up-regulates activity	binding			-1									17606614	t			P63RhoGEF is autoinhibited by the Dbl homology (DH)-associated pleckstrin homology (PH) domain; activated Galpha(q) relieves this autoinhibition by interacting with a highly conserved C-terminal extension of the PH domain	SIGNOR-256493	0.571
SYK	protein	P43405	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates	phosphorylation	Tyr136	SEEGYQDyEPEA	9606		BTO:0000975;BTO:0000142							11744621	t		llicata	Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers.	SIGNOR-113069	0.511
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates	binding			9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	In this study, we demonstrate that akt also regulates the activity of fkhrl1, a member of the forkhead family of transcription factors. In the presence of survival factors, akt phosphorylates fkhrl1, leading to fkhrl1's association with 14-3-3 proteins and fkhrl1's retention in the cytoplasm. Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-183608	0.2
YBX1	protein	P67809	UNIPROT	MMP13	protein	P45452	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17822788	f		miannu	 YB-1 binds to the MMP-13 promoter sequence and represses MMP-13 transactivation via the AP-1 site.	SIGNOR-255615	0.2
USP45	protein	Q70EL2	UNIPROT	SPDL1	protein	Q96EA4	UNIPROT	up-regulates activity	deubiquitination			9606	BTO:0001938								30258100	t		miannu	Spindly is mono-ubiquitylated and this ubiquitin can be removed by active USP45. K48 ubiquitylated complex that interacts with Spindly is also de-ubiquitylated by USP45. In the absence of USP45 catalytic activity, interaction is abolished and cell migration is affected similarly to the phenotype described for lack of Spindly.	SIGNOR-268505	0.2
MCRS1	protein	Q96EZ8	UNIPROT	NSL histone acetyltransferase	complex	SIGNOR-C413	SIGNOR	form complex	binding			9606	BTO:0000007								20018852	t		miannu	Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex.	SIGNOR-267161	0.633
CSNK2A1	protein	P68400	UNIPROT	SEPTIN2	protein	Q15019	UNIPROT	down-regulates	phosphorylation	Ser218	YHLPDAEsDEDEDFK	9606									16857012	t		lperfetto	Here we show that human septin 2 is phosphorylated in vivo at ser218 by casein kinase ii. Septin 2 binds and hydrolyses gtp. The purified protein has the capacity to polymerize into long filaments when loaded with gtp or gdp. Moreover, we show that the endogenous protein in hela cells, like that produced in insect cells, is phosphorylated by casein kinase ii and that this phosphorylation alters nucleotide binding.	SIGNOR-148010	0.2
PRKACA	protein	P17612	UNIPROT	ITPKB	protein	P27987	UNIPROT	down-regulates activity	phosphorylation			-1									9374536	t		miannu	Two isoforms of the inositol 1,4,5-trisphosphate 3-kinase have been identified, the A form and the B form. phosphorylation of isoform A by the cyclic AMP-dependent protein kinase increased activity 1.5-fold, whereas phosphorylation of isoform B decreased activity by 45%. major phosphorylation sites in the protein are Ser119 for PKA. Ser119 in the A isoform is conserved in the B isoform as Ser328	SIGNOR-249995	0.357
NLGN2	protein	Q8NFZ4	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606	BTO:0000938								25882190	f		miannu	Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses.	SIGNOR-264977	0.7
NRF1	protein	Q16656	UNIPROT	ENOX1	protein	Q8TC92	UNIPROT	up-regulates				9606	BTO:0000934								23939472	f		lperfetto	We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. 	SIGNOR-261451	0.268
PRKCA	protein	P17252	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates	phosphorylation	Ser738	ARIIGEKsFRRSVVG	9606									10197446	t		llicata	These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748.	SIGNOR-66666	0.421
ABL1	protein	P00519	UNIPROT	CRKL	protein	P46109	UNIPROT	down-regulates				9606									21779437	f		lperfetto	Negative regulation of crk by abl is essential for the antitumorigenic effects of ephrinb2,similar pathways may operate for crkl	SIGNOR-175138	0.705
CSNK2A1	protein	P68400	UNIPROT	WAS	protein	P42768	UNIPROT	up-regulates	phosphorylation	Ser483	KRSRAIHsSDEGEDQ	9606									12769847	t		gcesareni	Here we identify two phosphorylation sites in the vca domain of wasp at serines 483 and 484. S483 and s484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the vca domain for the arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length wasp molecule.	SIGNOR-101264	0.361
CDK12	protein	Q9NYV4	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates activity	phosphorylation	Thr134	LKFYDSNtVKQKYLS	9606	BTO:0004828								32483448	t		lperfetto	Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway	SIGNOR-273109	0.2
CYP17A1	protein	P05093	UNIPROT	progesterone	smallmolecule	CHEBI:17026	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0001363;BTO:0000048;BTO:0000050							17192295	t		lperfetto	THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones.	SIGNOR-268657	0.8
CDK5RAP2	protein	Q96SN8	UNIPROT	CEP63	protein	Q96MT8	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								26297806	t		lperfetto	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.	SIGNOR-271722	0.68
ATM	protein	Q13315	UNIPROT	USP10	protein	Q14694	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser337	ASGTLPVsQPKSWAS	9606	BTO:0001109								20096447	t		miannu	The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337. 	SIGNOR-276276	0.254
SLC12A1	protein	Q13621	UNIPROT	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	phosphorylation												21613606	t		lperfetto	Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12). 	SIGNOR-264635	0.8
MAPK3	protein	P27361	UNIPROT	SPIB	protein	Q01892	UNIPROT	unknown	phosphorylation	Thr56	VAPPVPAtPYEAFDP	9606	BTO:0000776								8632909	t		lperfetto	The threonine 56 was defined as the erk1 phosphorylation site by using phosphoamino-acid analyses and a spi-b mutant version	SIGNOR-41800	0.316
PRKCE	protein	Q02156	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									20179209	t		lperfetto	Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated	SIGNOR-163908	0.346
CDKN1A	protein	P38936	UNIPROT	Cell_cycle_progress 	phenotype	SIGNOR-PH42	SIGNOR	down-regulates				9606									24470334	f			The cell cycle regulator p21 is induced early in myoblast differentiation and functions to block cell cycle progression	SIGNOR-251564	0.7
YY1	protein	P25490	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270849	0.535
APOBEC3B	protein	Q9UH17	UNIPROT	Clearance_of_foreign intracellular_DNA	phenotype	SIGNOR-PH132	SIGNOR	up-regulates				9606									29367246	f		lperfetto	The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24).	SIGNOR-261331	0.7
MAPK1	protein	P28482	UNIPROT	SORBS3	protein	O60504	UNIPROT	unknown	phosphorylation	Ser530	DGPQLPTsPRLTAAA	9606									15184391	t	The effect has been demonstrated using O60504-2	llicata	Vinexin was directly phosphorylated by erk2 upon stimulation with egf at the serine 189 of vinexin _.	SIGNOR-125221	0.396
OPHN1	protein	O60890	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	gtpase-activating protein			9606	BTO:0000938								12932438	t		miannu	OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro	SIGNOR-268398	0.622
BMI1	protein	P35226	UNIPROT	CDKN2A	protein	Q8N726	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20551323	f		gcesareni	One important pathway in which bmi-1 acts to promote the overall growth of mice and cellular proliferation includes cdkn2a;bmi-1 represses the expression of cdkn2a, which encodes two cyclin-dependent kinase inhibitors, p16ink4a (p16) and p19arf	SIGNOR-259359	0.47
CSNK1D	protein	P48730	UNIPROT	PER2	protein	O15055	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606									11165242	t		miannu	Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2). 	SIGNOR-268000	0.864
TNKS2	protein	Q9H2K2	UNIPROT	BLZF1	protein	Q9H2G9	UNIPROT	down-regulates quantity by destabilization	ADP-ribosylation			9606	BTO:0000007								21478859	t		lperfetto	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 	SIGNOR-263384	0.2
STK4	protein	Q13043	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates	phosphorylation	Ser209	SSAGWKNsIRHNLSL	9606									22898666	t		gcesareni	Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity.	SIGNOR-191851	0.673
Axonemal_Dynein	proteinfamily	SIGNOR-PF66	SIGNOR	Microtubule-based_movement	phenotype	SIGNOR-PH170	SIGNOR	up-regulates													16440056	f		lperfetto	Dyneins are large multi-subunit protein complexes that undertake a wide range of roles within the cell. They are adenosine triphosphate (ATP)–driven, microtubule minus-end-directed molecular motors that can be divided, based on function, into two classes: axonemal and cytoplasmic dyneins	SIGNOR-265020	0.7
LCK	protein	P06239	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	phosphorylation	Tyr319	TSVYESPySDPEELK	-1									10202147	t	done	miannu	 In this report, we identify Tyr319 as a functionally important phosphorylation site in the ZAP-70 interdomain B region. Phosphorylation of Tyr319 promoted the association of ZAP-70 with the SH2 domains of two key signaling molecules, Lck and PLC-gamma1. These studies suggest that Tyr319 phosphorylation is required for the assembly of a ZAP-70-containing signaling complex that leads to the activation of the PLC-gamma1- and Ras-dependent signaling cascades in antigen-stimulated T cells. 	SIGNOR-273948	0.601
PRKACA	protein	P17612	UNIPROT	ETV1	protein	P50549	UNIPROT	up-regulates	phosphorylation	Ser334	PTYQRRGsLQLWQFL	9606									12213813	t		lperfetto	Pka targets er81 on ser(334) in vivo. Surprisingly, phosphorylation of ser(334) severely reduces the dna-binding ability of er81 but also enhances the transactivation potential of er81. These counteractive effects of pka phosphorylation on er81-dependent transcription may cause the selective up-regulation of promoters with high but not low affinity for er81.	SIGNOR-92455	0.296
AMPK	complex	SIGNOR-C15	SIGNOR	SREBF1	protein	P36956	UNIPROT	down-regulates	phosphorylation			9606									21892142	t		lperfetto	Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation	SIGNOR-216564	0.324
CHFR	protein	Q96EP1	UNIPROT	KIF22	protein	Q14807	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								19321445	t		miannu	Chfr ubiquitinates Kif22 and promotes its degradation.	SIGNOR-271469	0.408
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CCL20	protein	P78556	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22319003	t		lperfetto	Combined stimulation with IL-6, sIL-6R, and IL-17 increased the recruitment of phosphorylated NF-B to the CCL20 promoter, increased binding of coactivators such as p300 and CBP, and enhanced H3 and H4 histone acetylation, consistent with a transcriptionally active gene.	SIGNOR-271680	0.308
β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	beta-D-fructofuranose 2,6-bisphosphate	smallmolecule	CHEBI:28602	ChEBI	up-regulates quantity	precursor of			9606									9404080	t			A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively.	SIGNOR-267261	0.8
ECM	stimulus	SIGNOR-ST20	SIGNOR	Av/b8 integrin	complex	SIGNOR-C185	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259042	0.7
AVP	protein	P01185	UNIPROT	AVPR2	protein	P30518	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0000671;BTO:0001260							1560825	t		gcesareni	We report here the cloning of a complementary dna encoding the hepatic v1a arginine vasopressin receptor. The liver cdna encodes a protein with seven putative transmembrane domains, which binds arginine vasopressin.	SIGNOR-20185	0.728
CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	CRY1	protein	Q16526	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f		lperfetto	Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253679	0.937
IMPDH2	protein	P12268	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30518405	f		miannu	We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. 	SIGNOR-260957	0.2
FGF1	protein	P05230	UNIPROT	FGFR3	protein	P22607	UNIPROT	up-regulates	binding			9606									22298955	t		gcesareni	Reports also show that fgf/fgfr3 signals mediate some of the effects of tgf-beta on embryonic bone formation	SIGNOR-195585	0.793
RXRG	protein	P48443	UNIPROT	GLI2	protein	P10070	UNIPROT	up-regulates quantity	transcriptional regulation												31390799	f		SimoneGraziosi	Despite RXRγ being heavily down-regulated upon silencing (average silencing was about 80%), the reduction in Gli2 expression levels was statistically significant only for Clobetasol-treated but not for Gefitinib-treated cells.	SIGNOR-269267	0.262
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation	Ser319	TFRPRTSsNASTISG	9606									11237865	t		lperfetto	The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus	SIGNOR-252349	0.2
COX6A1	protein	P12074	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267747	0.723
AUTS2	protein	Q8WXX7	UNIPROT	Neuron_migration	phenotype	SIGNOR-PH67	SIGNOR	up-regulates				9606									28505103	f		miannu	Cytoplasmic AUTS2 regulates actin cytoskeleton to control neuronal migration and neurite extension, while nuclear AUTS2 controls transcription of various genes as a component of the polycomb complex 1 (PRC1).	SIGNOR-266816	0.7
ING1	protein	Q9UK53	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001938								15662138	f		miannu	Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. 	SIGNOR-254488	0.2
ATM	protein	Q13315	UNIPROT	ABL1	protein	P00519	UNIPROT	up-regulates	phosphorylation	Ser446	PYPGIDLsQVYELLE	9606	BTO:0000938								9168116	t		lperfetto	Ataxia telangiectasia mutant protein activates c-abl tyrosine kinase in response to ionizing radiation. Atm kinase domain corrects this defect, as it phosphorylates the c-abl tyrosine kinase in vitro at ser 465, leading to the activation of c-abl.	SIGNOR-48818	0.734
RBL2	protein	Q08999	UNIPROT	Cell_cycle_block	phenotype	SIGNOR-PH10	SIGNOR	up-regulates				10090	BTO:0000165								10801445	f		gcesareni	Although forced expression of either p130 or pRb in mouse C2 myoblasts efficiently blocked cell cycle progression, only p130 inhibited the differentiation program.	SIGNOR-267287	0.7
MDGA2	protein	Q7Z553	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26206665	f		miannu	Enhanced protein expression of p53 and p21 by MDGA2 was confirmed in MDGA2 overexpressed cells and xenograft tumours.	SIGNOR-264241	0.2
F10	protein	P00742	UNIPROT	APOH	protein	P02749	UNIPROT	down-regulates activity	cleavage	Lys336	HSSLAFWKTDASDVK	-1									9596664	t		lperfetto	In the previous study, we found that factor Xa can produce the nicked form by cleaving Lys 317-Thr 318, using recombinant human domain V (r-Domain V). |The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI. 	SIGNOR-266997	0.394
5-{3-[4-(2,3-Dichlorophenyl)piperidin-1-yl]propoxy}-1,3-benzothiazole	chemical	CID:56599142	PUBCHEM	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002181								22025698	t		Luana	Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. 	SIGNOR-258322	0.8
PHLPP1	protein	O60346	UNIPROT	PRKCB	protein	P05771	UNIPROT	down-regulates quantity	dephosphorylation	Ser661	QNEFAGFsYTNPEFV	9606	BTO:0000067								18162466	t		gcesareni	Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle	SIGNOR-237047	0.347
NBEAL2	protein	Q6ZNJ1	UNIPROT	VAC14	protein	Q08AM6	UNIPROT	unknown	binding			10090	BTO:0000132								29187380	t		lperfetto	In summary, from 129 binding partners of Nbeal2 identified by mass spectrometry, we have confirmed the interaction of 3, Dock7, Sec16a, and Vac14, by different biochemical and cellular approaches|Given the significant reduction of Dock7 levels and its altered localization in Nbeal2−/− platelets, we postulated that this canonical signaling pathway may be disrupted and set out to test this using control and Nbeal2−/− platelets.	SIGNOR-261892	0.304
FBXW11	protein	Q9UKB1	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates	ubiquitination	Lys22	GPRDGLKkERLLDDR	9606									9990853	t		gcesareni	We report here the identification of an ikappab-ubiquitin (ub) ligase complex containing the f-box/wd40-repeat protein, beta-trcp, a vertebrate homolog of drosophila slimb. beta-trcp binds to ikappabalpha only when the latter is specifically phosphorylated by an ikappab kinase complex. here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha.	SIGNOR-64321	0.521
WWP2	protein	O00308	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0001938								31048545	t		lperfetto	WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks|In response to DSBs, WWP2 targets the RNAPII subunit RPB1 for K48-linked ubiquitylation, thereby driving DNA-PK- and proteasome-dependent eviction of RNAPII.	SIGNOR-268851	0.396
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	Protein_degradation	phenotype	SIGNOR-PH96	SIGNOR	up-regulates				10090									25787076	f		miannu	The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice.	SIGNOR-256476	0.7
HNF4A	protein	P41235	UNIPROT	PCK1	protein	P35558	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20577053	f		gcesareni	Pgc1alfa is thought to mediate transcription downstream of the nuclear receptor hepatocyte nuclear factor 4alfa (hnf4alfa) and the transcription factor foxo1 in the promoters of key gluconeogenic enzymes, including glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxylase (pepck)	SIGNOR-166358	0.357
PIK3CG	protein	P48736	UNIPROT	PDPK1	protein	O15530	UNIPROT	up-regulates	binding			9606									9768361	t		gcesareni	Recent reports have also shown that the phosphoinositide-dependent protein kinase-1 (pdk-1), which binds with high affinity to the pi 3-kinase lipid product phosphatidylinositol-3,4,5-trisphosphate (ptdins-3,4,5-p), phosphorylates and potently activates two other pi 3-kinase targets, the protein kinases akt/pkb and p70s6k.	SIGNOR-60567	0.618
CPT1C	protein	Q8TCG5	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	chemical modification			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267134	0.8
BID	protein	P55957	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates	binding			9606									12242151	t		gcesareni	We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma	SIGNOR-92945	0.818
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Ser315	DFRSRTNsNASTVSG	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-183616	0.2
BTK	protein	Q06187	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates activity	phosphorylation	Tyr759	LYDVSRMyVDPSEIN	9606	BTO:0000776								11507089	t		lperfetto	These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2.	SIGNOR-109758	0.77
anthra[1,9-cd]pyrazol-6(2H)-one	chemical	CHEBI:90695	ChEBI	MAPK9	protein	P45984	UNIPROT	down-regulates	chemical inhibition			9606									11717429	t		gcesareni	We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm).	SIGNOR-111986	0.8
SND1	protein	Q7KZF4	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									30365124	f		irozzo	SND1 upregulation is a common phenomenon in different human malignant tissues. We found that SND1 overexpression significantly promoted cell proliferation and tumor growth in vitro and in vivo.	SIGNOR-259135	0.7
AXL	protein	P30530	UNIPROT	AXL	protein	P30530	UNIPROT	up-regulates activity	phosphorylation	Tyr866	EVHPAGRyVLCPSTT	-1									9178760	t		llicata	Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins	SIGNOR-250593	0.2
MAPK10	protein	P53779	UNIPROT	HNRNPK	protein	P61978	UNIPROT	down-regulates activity	phosphorylation	Ser284	RRDYDDMsPRRGPPP										11231586	t		miannu	Mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) efficiently phosphorylates hnRNP-K both in vitro and in vivo at serines 284 and 353. Our results establish the role of MAPK/ERK in phosphorylation-dependent cellular localization of hnRNP-K, which is required for its ability to silence mRNA translation.	SIGNOR-250082	0.345
RYK	protein	P34925	UNIPROT	DVL3	protein	Q92997	UNIPROT	up-regulates	binding			9606									15454084	t		gcesareni	Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled	SIGNOR-129574	0.413
GSK3B	protein	P49841	UNIPROT	PTTG1	protein	O95997	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser184	NLLQSPSsILSTLDV	9606	BTO:0000567								21757741	t		miannu	Here, we demonstrate that glycogen synthase kinase-3β (GSK3β) phosphorylates securin to promote its proteolysis via SCF(βTrCP) E3 ubiquitin ligase.	SIGNOR-276344	0.2
PRKCE	protein	Q02156	UNIPROT	MGluR	proteinfamily	SIGNOR-PF55	SIGNOR	up-regulates activity	phosphorylation			-1									15894802	t	inferred from family member	lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-270280	0.405
N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide	chemical	CHEBI:91399	ChEBI	CDK9	protein	P50750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207090	0.8
NFX1	protein	Q12986	UNIPROT	PABPC1	protein	P11940	UNIPROT	up-regulates activity	binding			9606	BTO:0004117								17267499	t		miannu	NFX1-123 augments the activation of hTERT expression through interactions with PABPCs	SIGNOR-226011	0.35
TFEB	protein	P19484	UNIPROT	PPARA	protein	Q07869	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Notably, TFEB regulates genes involved in several steps of lipid catabolism, which occur in different cellular compartments, such as the transport of fatty acid chains across the plasma membrane (for example, Cd36 and Fabps), and the β-oxidation of FFA in mitochondria (for example, Cpt1, Crat, Acadl, Acads and Hdad) and in peroxisomes (Cyp4a genes). 	SIGNOR-276706	0.281
MED29	protein	Q9NX70	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266658	0.76
perifosine	chemical	CHEBI:67272	ChEBI	AKT1	protein	P31749	UNIPROT	down-regulates	chemical inhibition			9606									22090271	t	Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation	gcesareni	Perifosine is an alkylphospholipid that targets the pleckstrin homology domain of akt and blocks its membrane translocation, hence preventing akt phosphorylation and activation	SIGNOR-252630	0.8
AAK1	protein	Q2M2I8	UNIPROT	NUMB	protein	P49757	UNIPROT	unknown	phosphorylation	Thr102	LRVVDEKtKDLIVDQ	9606									18657069	t		llicata	Numb is phosphorylated by aak1, while little aak1-dependent phosphorylation is observed in t102a numb immunoprecipitants	SIGNOR-179610	0.472
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates	dephosphorylation			9606									18676376	t		lperfetto	Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes.	SIGNOR-233441	0.386
PCDHA12	protein	Q9UN75	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-265673	0.2
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1763	TPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273108	0.745
CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	RC3H1	protein	Q5TC82	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			9606									31320642	t		lperfetto	In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins	SIGNOR-268348	0.336
ADCY3	protein	O60266	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates quantity	chemical modification			9606									15385642	t		miannu	Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions.	SIGNOR-265000	0.8
Vincristine sulfate	chemical	CHEBI:79401	ChEBI	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	down-regulates activity	chemical inhibition			9606		BTO:0000142							30599272	t		miannu	Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. 	SIGNOR-259254	0.8
PRKAA1	protein	Q13131	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates	phosphorylation	Ser358	WPLSRTRsEPLPPSA	9606			SIGNOR-C15						21892142	t		gcesareni	Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs).	SIGNOR-176491	0.276
TPH1	protein	P17752	UNIPROT	5-hydroxy-L-tryptophan	smallmolecule	CHEBI:17780	ChEBI	up-regulates quantity	chemical modification			9606									31024440	t	brain	lperfetto	In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)].	SIGNOR-264010	0.8
trametinib	chemical	CHEBI:75998	ChEBI	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates activity	chemical inhibition			9606									26347206	t		miannu	Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation. 	SIGNOR-259446	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	GLI1	protein	P08151	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser408	GPLPRAPsISTVEPK										26190112	t			Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency.	SIGNOR-253541	0.3
CAMK2G	protein	Q13555	UNIPROT	SYN1	protein	P17600	UNIPROT	unknown	phosphorylation	Ser568	PQATRQTsVSGPAPP										3118371	t		llicata	Sites 2 and 3 are serine residues phosphorylated by calcium/calmodulin-dependent protein kinase II.	SIGNOR-250707	0.458
AKT1	protein	P31749	UNIPROT	SOX2	protein	P48431	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr116	KYRPRRKtKTLMKKD	9606	BTO:0002428								30894683	t		miannu	Phosphorylation of SOX2 at threonine 116 by AKT inhibits the interaction of UBR5 with SOX2 and thus stabilizes SOX2. 	SIGNOR-277445	0.549
NLGN4Y	protein	Q8NFZ3	UNIPROT	NRXN1	protein	Q9ULB1	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264143	0.2
MAPK1	protein	P28482	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Thr331	CTPVVTCtPSCTAYT								phosphorylation:Ser374;Ser362	PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS	16055710	t		lperfetto	Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos	SIGNOR-263007	0.784
GRK2	protein	P25098	UNIPROT	OPRM1	protein	P35372	UNIPROT	down-regulates activity	phosphorylation	Thr356	FREFCIPtSSNIEQQ	9606	BTO:0000007								12123746	t		gcesareni	These results suggest that two C-terminal amino acids, Ser(355) and Thr(357), are required for short-term homologous desensitization and agonist-induced phosphorylation of mu-opioid receptors expressed in HEK 293 cells	SIGNOR-247782	0.2
FLT3	protein	P36888	UNIPROT	IDH1	protein	O75874	UNIPROT	up-regulates activity	phosphorylation	Tyr42	VELDLHSyDLGIENR	-1									34289383	t		lperfetto	Moreover, in an in vitro kinase assay, purified recombinant FLT3 (rFLT3) phosphorylated recombinant IDH2 R140Q mutant but did not alter its catalytic activity (Figure 1C), whereas rFLT3 phosphorylated mIDH1 protein and enhanced its catalytic activity	SIGNOR-267629	0.437
BCL2L11	protein	O43521	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000972								17960585	f		miannu	Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells.	SIGNOR-260426	0.7
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	phosphorylation	Ser523	GVSDVPTsPTLQRPT	9606									21841788	t		lperfetto	The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570.	SIGNOR-176054	0.2
PRKG1	protein	Q13976	UNIPROT	GABRR1	protein	P24046	UNIPROT	unknown	phosphorylation	Ser443	PQRKSQRsSYVSMRI	-1									12175859	t		miannu	Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The 1 IC-loop does not have consensus sequences for PKG, but we found that this enzyme phosphorylated the same sites as PKA: S422, S423 (Fig. 5A).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation	SIGNOR-262756	0.322
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser304	GAPPRRSsIRNAHSI	9606	BTO:0000130								10559253	t		esanto	Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis.	SIGNOR-72133	0.2
AMOT	protein	Q4VCS5	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	relocalization			9606	BTO:0000567								21205866	t		gcesareni	Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition.	SIGNOR-201135	0.728
NF90-NF45	complex	SIGNOR-C443	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									21969602	f		miannu	The NF90/NF45 complex participates in DNA break repair via nonhomologous end joining	SIGNOR-268490	0.7
YBX1	protein	P67809	UNIPROT	NDRG1	protein	Q92597	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17072343	f		miannu	 YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. 	SIGNOR-255612	0.25
SMURF1	protein	Q9HCE7	UNIPROT	UVRAG	protein	Q9P2Y5	UNIPROT	down-regulates activity	ubiquitination	Lys517	ENERLQYkTPPPSYN	9606	BTO:0000007								30686098	t		miannu	Here we report that UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. However, the deubiquitinase ZRANB1 specifically cleaves SMURF1-induced K29 and K33-linked polyubiquitin chains from UVRAG, thereby increasing the binding of UVRAG to RUBCN and inhibiting autophagy flux. 	SIGNOR-273652	0.2
GATA6	protein	Q92908	UNIPROT	PLXNA2	protein	O75051	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19666519	f		lperfetto	Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes.	SIGNOR-253149	0.248
KLF1	protein	Q13351	UNIPROT	FLI1	protein	Q01543	UNIPROT	down-regulates activity	binding			10090	BTO:0004475								12556498	t		irozzo	The present study also shows that EKLF itself inhibits FLI-1 activity. As suggested above for the inhibition of EKLF activity, the inhibition of FLI-1 activity most probably involves the indirect recruitment of EKLF to FLI-1 target promoters by protein-protein interaction.	SIGNOR-256046	0.378
MAPK14	protein	Q16539	UNIPROT	PLA2G4A	protein	P47712	UNIPROT	up-regulates activity	phosphorylation	Ser505	LNTSYPLsPLSDFAT	9606	BTO:0000132								8910365	t		lperfetto	These results provide the first direct evidence that p38 kinase is responsible for cpla2 phosphorylation in sfllrn-stimulated platelets and is involved in the early phosphorylation of cpla2 in thrombin-stimulated platelets	SIGNOR-44673	0.655
PDGFRB	protein	P09619	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	phosphorylation			9606									7535778	t		miannu	Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production.	SIGNOR-28179	0.853
MAPK3	protein	P27361	UNIPROT	RPS6KA2	protein	Q15349	UNIPROT	up-regulates	phosphorylation			9606									8939914	t		gcesareni	Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms	SIGNOR-44949	0.705
STK11	protein	Q15831	UNIPROT	MARK2	protein	Q7KZI7	UNIPROT	up-regulates	phosphorylation			9606									17573348	t		gcesareni	Here we show in vitro that lkb1 phosphorylates and activates mark2	SIGNOR-156126	0.569
NR1I3	protein	Q14994	UNIPROT	RXRA	protein	P19793	UNIPROT	up-regulates	binding			9606									12896978	t		gcesareni	Therefore, both car-rxr heterodimers and car monomers can contribute to the gene activating function of pbrems in car target genes.	SIGNOR-104441	0.479
glycine	smallmolecule	CHEBI:15428	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264745	0.7
cyclosporin A	chemical	CHEBI:4031	ChEBI	TTN	protein	Q8WZ42	UNIPROT	up-regulates				9606									17636278	f	Regulation of transcription		Cyclosporine A induces titin expression via MAPK/ERK signalling and improves proliferative and invasive potential of human trophoblast cells.	SIGNOR-251975	0.8
PCDHA1	protein	Q9Y5I3	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-265663	0.2
POLG	protein	P54098	UNIPROT	DNA polymerase gamma	complex	SIGNOR-C378	SIGNOR	form complex	binding			-1									19837034	t		lperfetto	Here, we report a crystal structure of human DNA Pol gamma holoenzyme. The holoenzyme is a heterotrimer containing one Pol gammaA subunit and a dimeric Pol gammaB subunit.	SIGNOR-265719	0.739
PTPN1	protein	P18031	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606	BTO:0000007								16582879	t			Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR	SIGNOR-248409	0.778
RNMT	protein	O43148	UNIPROT	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates quantity	chemical modification			9606									27422871	t		lperfetto	Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM. 	SIGNOR-268316	0.8
CSNK2B	protein	P67870	UNIPROT	RNF7	protein	Q9UBF6	UNIPROT	up-regulates activity	phosphorylation	Thr10	DVEDGEEtCALASHS	9606	BTO:0000567								12748192	t		llicata	In the present study, we show the evidence that CKBBP1 is phosphorylated on threonine residue at position 10 by CKII in vitro and in vivo. Most importantly, disruption of this phosphorylation in CKBBP1 results in accumulation of IκBα and p27Kip1 in HeLa cells and inhibits cell proliferation that appears to be linked to defects in G1/S transition.	SIGNOR-251081	0.334
NRG4	protein	Q8WWG1	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606		BTO:0000887							7477375	t	Does not bind to the ERBB1, ERBB2 and ERBB3 receptors	gcesareni	The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4.	SIGNOR-26280	0.684
1D-myo-inositol 1,4,5-trisphosphate	smallmolecule	CHEBI:16595	ChEBI	CAPZA1	protein	P52907	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000132								12788695	t		lperfetto	We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations.	SIGNOR-261842	0.8
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3C1	protein	P68431	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269636	0.2
SGK1	protein	O00141	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation	Ser1132	RDRVRSMsGGHGLRV	-1									27451907	t		miannu	SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2. 	SIGNOR-277265	0.597
CBS	protein	P35520	UNIPROT	L-serine zwitterion	smallmolecule	CHEBI:33384	ChEBI	down-regulates quantity	chemical modification			9606									23981774	t		lperfetto	Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. 	SIGNOR-275829	0.8
PTPN11	protein	Q06124	UNIPROT	ITK	protein	Q08881	UNIPROT	down-regulates activity	dephosphorylation			9606									33624224	t		miannu	Using genetic and pharmacological approaches, we discovered that SHP2 dephosphorylates ITK specifically downstream of PD-1 and that this event was associated with PD-1 inhibitory cellular functions.	SIGNOR-277174	0.33
NUMB	protein	P49757	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	binding			9606	BTO:0000150								18492217	t		gcesareni	Numb can actually interact in vivo with endogenous mdm2 and p53, resulting in a trimeric complex between the three proteins [10]. This interaction appears to regulate the stability of p53, as reduction of numb levels by rna interference (rnai) causes a decrease in the half-life of p53 and consequently a reduction in steady-state levels of the protein. Consistent with this observation, overexpression of numb increases the level of p53 in both unstressed and stressed cells.	SIGNOR-178668	0.531
GSK3B	protein	P49841	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	phosphorylation	Ser40	TQSSGKSsVLESLVG	9606	BTO:0000007								25192600	t		miannu	 We identified glycogen synthase kinase (GSK)3β-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation.	SIGNOR-276849	0.397
JQ1	chemical	CHEBI:137113	ChEBI	BRDT	protein	Q58F21	UNIPROT	down-regulates activity	chemical inhibition			-1									20871596	t		lperfetto	Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. 	SIGNOR-261990	0.8
HOXB8	protein	P17481	UNIPROT	TAGLN	protein	Q01995	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0002196								15886193	t		Luana	Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively	SIGNOR-261642	0.2
PRPF6	protein	O94906	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270625	0.761
PRKCQ	protein	Q04759	UNIPROT	ICAM3	protein	P32942	UNIPROT	up-regulates activity	phosphorylation	Ser518	REHQRSGsYHVREES	9606	BTO:0000661								9268366	t		lperfetto	Ser489 was a phosphorylation site in vitro for recombinant protein kinase Ctheta. Finally, treatment of Jurkat cells with chelerythrine chloride, a protein kinase C inhibitor, prevented ICAM-3-triggered spreading. 	SIGNOR-248979	0.339
CRP	protein	P02741	UNIPROT	CCL2	protein	P13500	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004910								26961257	f		miannu	In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained.	SIGNOR-252144	0.454
CREBBP	protein	Q92793	UNIPROT	INSM1	protein	Q01101	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000944								17300785	f		miannu	 The ngn3/E47 heterodimer selectively binds and activates the E-box3 of the INSM1 promoter. The endogenous ngn3 and CREB-binding protein (CBP) co-activator occupy the INSM1 promoter, resulting in hyper-acetylation of histone H3/H4 chromatin in a human neuroblastoma cell line, IMR-32.	SIGNOR-253813	0.2
YBX1	protein	P67809	UNIPROT	TYMS	protein	P04818	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001023								17072343	f		miannu	 YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. 	SIGNOR-255613	0.25
CHRNB3	protein	Q05901	UNIPROT	APC	protein	P25054	UNIPROT	up-regulates activity	binding			9606	BTO:0002916								14502292	t		miannu	Treatment of muscle cells with neural agrin causes tyrosine phosphorylation of the AChR β subunit and induces AChR clustering by promoting anchoring of the receptor protein to postsynaptic cytoskeleton. Regulation of acetylcholine receptor clustering by the tumor suppressor APC. By showing a direct requirement for APC in AChR clustering, our present study suggests that the Wnt/β-catenin pathway may crosstalk with the agrin signaling cascade during the formation of mammalian neuromuscular junction.	SIGNOR-264261	0.2
ADRA1A	protein	P35348	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257084	0.568
MYOF	protein	Q9NZM1	UNIPROT	Myoblast_fusion	phenotype	SIGNOR-PH98	SIGNOR	up-regulates				9606									23612709	f			Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin 	SIGNOR-255466	0.7
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	Gln-tRNA(Gln)	smallmolecule	CHEBI:29166	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270390	0.8
TNFAIP3	protein	P21580	UNIPROT	RIPK1	protein	Q13546	UNIPROT	down-regulates quantity	ubiquitination			9606									15258597	t			The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family, removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex. The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation.	SIGNOR-259978	0.64
BCL2	protein	P10415	UNIPROT	BAK1	protein	Q16611	UNIPROT	down-regulates	binding			9606									17289999	t		gcesareni	Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax bax/bak are kept in check by the pro-survival bcl-2 family members and also proposes that for apoptotic death to occur, all pro-survival bcl-2-like proteins present within a given cell need to be neutralised by bh3-only proteins, thereby derepressing bax/bak	SIGNOR-152980	0.662
MAPK14	protein	Q16539	UNIPROT	CDX2	protein	Q99626	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser287	EPLSPVSsLQASVPG	9606									16027724	t		miannu	ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation	SIGNOR-250093	0.425
CTNNB1	protein	P35222	UNIPROT	Metastasis	phenotype	SIGNOR-PH107	SIGNOR	up-regulates activity				10090	BTO:0004086								17420453	f			Overexpression of ERp5 promotes both in vitro migration and invasion and in vivo metastasis of breast cancer cells.	SIGNOR-256534	0.7
ROCK1	protein	Q13464	UNIPROT	FHOD1	protein	Q9Y613	UNIPROT	up-regulates	phosphorylation	Ser1131	AARERKRsRGNRKSL	9606									18239683	t		lperfetto	Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres.	SIGNOR-160544	0.315
REST	protein	Q13127	UNIPROT	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	down-regulates				9606									17453016	f			NRSF represses neuronal differentiation by binding to conserved NRS elements (NRSEs) in gene promoters in non-neuronal cells, where it associates with one of several large repressor complexes, including the transcriptional co-repressor mSIN3a/b, nuclear receptor co-repressor 1 (N-CoR1), and coREST/histone deacetylase 2 (HDAC2). In this way, NRSF keeps neural-specific genes turned off in non-neuronal cells. 	SIGNOR-268622	0.7
PRKCB	protein	P05771	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser257	QIRLRRDsKEANARR	-1									9677319	t		lperfetto	Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases.	SIGNOR-249003	0.308
PAK4	protein	O96013	UNIPROT	PACSIN1	protein	Q9BY11	UNIPROT	up-regulates activity	phosphorylation	Ser346	SQAGDRGsVSSYDRG	-1									22371566	t		miannu	We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. 	SIGNOR-263023	0.301
MAPK3	protein	P27361	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Ser454	YVPMNPNsPPRQHSS	10029	BTO:0000246								15379552	t		lperfetto	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-249460	0.618
MPO	protein	P05164	UNIPROT	MPO-ANCA	complex	SIGNOR-C474	SIGNOR	up-regulates activity	binding			9606		BTO:0000133							15972951	t		lperfetto	Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis are associated with myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (ANCAs).	SIGNOR-270585	0.2
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1675	SPSYSPTsPSYSPTS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248809	0.849
CDK1	protein	P06493	UNIPROT	KAT7	protein	O95251	UNIPROT	up-regulates	phosphorylation	Thr85	TRSQQQPtPVTPKKY	9606									18250300	t		lperfetto	Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate.	SIGNOR-160743	0.363
ATR	protein	Q13535	UNIPROT	ATRIP	protein	Q8WXE1	UNIPROT	up-regulates	phosphorylation	Ser68	EELDTLAsQALSQCP	9606									15451423	t		lperfetto	When dna is damaged, the atr-atrip complex is recruited to chromatin and is activated to transduce the checkpoint signal, but the precise kinase activation mechanism remains unknown. Here, we show that atrip is phosphorylated in an atr-dependent manner after genotoxic stimuli. The serine 68 and 72 residues are important for the phosphorylation in vivo and are required exclusively for direct modification by atr in vitro.	SIGNOR-129469	0.873
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CIB2	protein	O75838	UNIPROT	up-regulates activity	chemical activation			9606									35408910	t		miannu	Calcium- and integrin-binding protein 2 (CIB2) is a small EF-hand protein capable of binding Mg2+ and Ca2+ ions.	SIGNOR-269667	0.8
SPRY4	protein	Q9C004	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002058								20501643	f		miannu	When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. 	SIGNOR-253041	0.254
JNJ-28312141 free base	chemical	CID:11676971	PUBCHEM	CSF1R	protein	P07333	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259748	0.8
CSNK2A1	protein	P68400	UNIPROT	SLC9A5	protein	Q14940	UNIPROT	down-regulates activity	phosphorylation	Ser711	EEEEESDsSETEKED	-1									21296876	t		miannu	CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis	SIGNOR-276251	0.2
DLL3	protein	Q9NYJ7	UNIPROT	PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	up-regulates activity	binding			9606	BTO:0000776								16140393	t		lperfetto	Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate.	SIGNOR-209747	0.2
TAF1	protein	P21675	UNIPROT	GTF2A1	protein	P52655	UNIPROT	up-regulates	phosphorylation	Ser321	LNSEDDVsDEEGQEL	9606									11278496	t		llicata	Taf(ii) 250 phosphorylates human transcription factor iia on serine residues important for tbp binding and transcription activity.	SIGNOR-105745	0.662
GRM4	protein	Q14833	UNIPROT	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							20055706	t		miannu	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264082	0.327
POT1	protein	Q9NUX5	UNIPROT	RPA1	protein	P27694	UNIPROT	down-regulates activity	binding						SIGNOR-C306						18680434	t		lperfetto	The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA	SIGNOR-263325	0.299
lisinopril	chemical	CHEBI:43755	ChEBI	ACE	protein	P12821	UNIPROT	down-regulates activity	chemical inhibition			-1									12540854	t		Monia	The structure of tACE bound to the potent inhibitor lisinopril shows that the inhibitor binds in a highly ordered (overall B-factor of 15.26 A˚ 2)	SIGNOR-261070	0.8
PRKCE	protein	Q02156	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Thr841	RSAFTTStVVRMHVG	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249288	0.405
MMP19	protein	Q99542	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272363	0.7
MAPK1	protein	P28482	UNIPROT	PTPN7	protein	P35236	UNIPROT	up-regulates activity	phosphorylation	Thr66	EPICSVNtPREVTLH	-1									16226275	t		lperfetto	First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|	SIGNOR-249437	0.805
PB28 dihydrochloride	chemical	CID:46861545	PUBCHEM	TMEM97	protein	Q5BJF2	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000093								16891467	t		Federica	Cyclohexylpiperazine derivative PB28, a σ2 agonist and σ1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer	SIGNOR-261110	0.8
AKT1	protein	P31749	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates	phosphorylation			9606									21798082	t		gcesareni	Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b).	SIGNOR-175291	0.755
ETV2	protein	O00321	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				10090	BTO:0001086								24583263	f		irozzo	Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation.	SIGNOR-256009	0.7
AX/b2 integrin	complex	SIGNOR-C171	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269020	0.7
SRC	protein	P12931	UNIPROT	BDKRB2	protein	P30411	UNIPROT	up-regulates	phosphorylation	Tyr177	GVRWAKLySLVIWGC	9606									16226010	t		lperfetto	Here we demonstrate that egf is capable of inducing src-mediated phosphorylation of the tyrosine residues 177 and 347 of bkr. Their replacement by phenylalanine led to bkr mutants which are unable to activate the camp pathway.	SIGNOR-141103	0.265
BRAF	protein	P15056	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser252	DIWSMGLsLVEMAVG	-1									8413257	t		lperfetto	Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1.	SIGNOR-39062	0.779
TNFRSF10A	protein	O00220	UNIPROT	FADD	protein	Q13158	UNIPROT	up-regulates	binding			9606									14585074	t		amattioni	Fadd binds to ligated trailr1 or trail-r2	SIGNOR-97869	0.825
DLGAP4	protein	Q9Y2H0	UNIPROT	SHANK3	protein	Q9BYB0	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264597	0.2
NEDD4	protein	P46934	UNIPROT	KCNH2	protein	Q12809	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002181								26363003	t		SARA	We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels.	SIGNOR-260998	0.271
IRX1	protein	P78414	UNIPROT	H2BC21	protein	Q16778	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 	SIGNOR-261660	0.2
RNF4	protein	P78317	UNIPROT	SP1	protein	P08047	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								21983342	t		miannu	Here, we identified RNF4 as the ubiquitin E3 ligase of Sp1. From in vitro and in vivo experiments, we found that sumoylated Sp1 can recruit RNF4 as a ubiquitin E3 ligase that subjects sumoylated Sp1 to proteasomal degradation. 	SIGNOR-272720	0.398
PRKACA	protein	P17612	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Ser13	ITSAARRsYVSSGEM	-1									2155236	t		miannu	GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments.	SIGNOR-249711	0.286
PER1	protein	O15534	UNIPROT	SLC5A1	protein	P13866	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000195								22526585	f		miannu	 Our findings suggest that PER1 exerts an indirect suppressive effect on SGLT1, possibly acting via other clock-controlled genes binding to non-E-box sites on the SGLT1 promoter. 	SIGNOR-254912	0.344
CSNK2A1	protein	P68400	UNIPROT	GYS1	protein	P13807	UNIPROT	unknown	phosphorylation	Ser698	PEWPRRAsCTSSTSG	-1									2117608	t		llicata	With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action.	SIGNOR-250883	0.334
IGF1R	protein	P08069	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates	phosphorylation			9606		BTO:0001103							15829723	t		apalma	IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt.	SIGNOR-255104	0.864
PER2	protein	O15055	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									22260161	f		apalma	We have previously shown that PER2 is a downstream CCAAT-enhancer-binding protein (C/EBP)-target gene, and its disruption might be involved in the initiation and progression of acute myelogenous leukemia (AML)	SIGNOR-256370	0.7
WNT1	protein	P04628	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates activity				10090		BTO:0000887;BTO:0001103							9753670	f		gcesareni	Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5	SIGNOR-60285	0.344
PPP1CA	protein	P62136	UNIPROT	IFIH1	protein	Q9BYX4	UNIPROT	up-regulates activity	dephosphorylation	Ser88	EALRRTGsPLAARYM	9606	BTO:0000007								23499489	t		lperfetto	Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.	SIGNOR-264577	0.2
STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	SAV1	protein	Q9H4B6	UNIPROT	up-regulates activity	phosphorylation			9606									21084559	t		miannu	 Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst.	SIGNOR-256184	0.2
OGT	protein	O15294	UNIPROT	PFK	proteinfamily	SIGNOR-PF79	SIGNOR	down-regulates activity	glycosylation			9606	BTO:0000007								22923583	t		lperfetto	O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway| O-GlcNAc transferase (OGT) catalyzes the transfer of N-acetylglucosamine from uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) to serine or threonine residues	SIGNOR-267586	0.354
DOK1	protein	Q99704	UNIPROT	AL/b2 integrin	complex	SIGNOR-C169	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257681	0.301
CHN1	protein	P15882	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606									32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260499	0.651
FOXO1	protein	Q12778	UNIPROT	G6PC1	protein	P35575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16308421	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-142147	0.2
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	RBBP8	protein	Q99708	UNIPROT	up-regulates activity	phosphorylation	Ser327	ELPTRVSsPVFGATS	9606	BTO:0000567								15485915	t		lperfetto	 Ser327 site is a Ser-Pro site, a preferred phosphorylation site by cyclin-dependent kinases|Unlike wild-type CtIP, the S327A mutant did not bind to BRCA1 BRCT domains in vitro (Fig. ​(Fig.1C)1C) and failed to associate with BRCA1 in vivo (Fig. ​(Fig.1D),1D), suggesting that residue Ser327 of CtIP is critical for the CtIP-BRCA1 interaction.	SIGNOR-263227	0.548
FPR1	protein	P21462	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256961	0.252
AURKA	protein	O14965	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser93	SSLLSRSsSGYFSFD	9606	BTO:0002181								23912711	t		miannu	 We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL. 	SIGNOR-276247	0.384
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	AXIN1	protein	O15169	UNIPROT	down-regulates activity	dephosphorylation	Ser217	YTRTGSEsPKVCSDQ	9606									17318175	t		lperfetto	The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated	SIGNOR-264660	0.2
UBE3A	protein	Q05086	UNIPROT	PSMC2	protein	P35998	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								28559284	t		lperfetto	Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits.	SIGNOR-265132	0.395
EGFR	protein	P00533	UNIPROT	STAT5B	protein	P51692	UNIPROT	up-regulates	phosphorylation	Tyr725	AGGGSATyMDQAPSP	9606									11751923	t		llicata	Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor.	SIGNOR-113393	0.827
MC4R	protein	P32245	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256940	0.273
MAPK1	protein	P28482	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates	phosphorylation	Thr28	PTMPPPEtPSEGRQP	9606	BTO:0001271								15093545	t	The effect has been demonstrated using P29590-4	gcesareni	We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3).	SIGNOR-124313	0.366
GSK3A	protein	P49840	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	up-regulates activity	phosphorylation	Ser61	PLSTPCSsVPSSPSF	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159369	0.2
MEN1	protein	O00255	UNIPROT	MLL Fusion	fusion protein	SIGNOR-FP14	SIGNOR	up-regulates activity	binding			10090	BTO:0004730								16239140	t		miannu	We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity.	SIGNOR-260130	0.2
eletriptan	chemical	CHEBI:50922	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000567								10193663	t		Luana	This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues 	SIGNOR-258339	0.8
sapropterin	smallmolecule	CHEBI:59560	ChEBI	GCHFR	protein	P30047	UNIPROT	up-regulates activity	chemical activation			9606									11361142	t		miannu	The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine	SIGNOR-252204	0.8
PPP2CB	protein	P62714	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	up-regulates activity	dephosphorylation	Ser358	WPLSRTRsEPLPPSA	9606									18339811	t			Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.	SIGNOR-248605	0.2
FES	protein	P07332	UNIPROT	BCR	protein	P11274	UNIPROT	down-regulates	phosphorylation	Tyr246	SCGVDGDyEDAELNP	9606	BTO:0000007								8955135	t		lperfetto	In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1.	SIGNOR-45330	0.375
GDNF	protein	P39905	UNIPROT	GFRA2	protein	O00451	UNIPROT	up-regulates	binding			9606									9192898	t		gcesareni	Gdnf mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (gpi)-linked protein (designated gdnfr-alpha).	SIGNOR-49184	0.661
PDPK1	protein	O15530	UNIPROT	PDPK1	protein	O15530	UNIPROT	unknown	phosphorylation	Ser410	GLPQRSGsNIEQYIH	9606									10455013	t		lperfetto	3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity	SIGNOR-236772	0.2
CYP11B1	protein	P15538	UNIPROT	11-deoxycortisol	smallmolecule	CHEBI:28324	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000050							9814482	t		lperfetto	Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol.	SIGNOR-268679	0.8
PRKCB	protein	P05771	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser464	LLKHVTQsSRKLIRA	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity.	SIGNOR-129280	0.289
MAPK1	protein	P28482	UNIPROT	NR4A2	protein	P43354	UNIPROT	up-regulates	phosphorylation	Thr132	SSPPTPTtPGFQVQH	9606	BTO:0000938	BTO:0000142							17681692	t		llicata	We have shown that erk2 is a kinase to phosphorylate nurr1 on multiple sites. S126 and t132, which are located near af1 core of nurr1, are dominant sites phosphorylated by erk2. reporter gene assays show that nurr1delta124-133/t185a, an erk2 phospho-site mutant form, could not further increase its transcriptional activity on th promoter, suggesting that nurr1 phosphorylation by erk2 may regulate its transcriptional activity on th promoter.	SIGNOR-157171	0.405
VAMP2	protein	P63027	UNIPROT	Synaptic_vesicle_exocytosis	phenotype	SIGNOR-PH160	SIGNOR	up-regulates				9606	BTO:0000938								17331077	f		miannu	Synaptobrevin 2/VAMP2 (vesicle-associated membrane protein 2), a critical component of the synaptic vesicle-fusion machinery. On the SV membrane, VAMP2 is engaged in a complex with synaptophysin I, which is mutually exclusive with the formation of fusogenic SNARE complexes. 	SIGNOR-264103	0.7
ATIC	protein	P31939	UNIPROT	5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-)	smallmolecule	CHEBI:58467	ChEBI	up-regulates quantity	chemical modification			9606									33179964	t		miannu	The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP.	SIGNOR-267327	0.8
DYRK1A	protein	Q13627	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606	BTO:0000938								20696760	t		gcesareni	Dyrk1a phosphorylates p53 and inhibits proliferation of embryonic neuronal cells. we found that dyrk1a phosphorylates p53 at ser-15 in vitro and in immortalized rat embryonic hippocampal progenitor h19-7 cells. In addition, dyrk1a-induced p53 phosphorylation at ser-15 led to a robust induction of p53 target genes	SIGNOR-167407	0.429
EZH2	protein	Q15910	UNIPROT	DACT3	protein	Q96B18	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004094								22144423	f	 	miannu	 For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci.	SIGNOR-254142	0.254
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PDE4B	protein	Q07343	UNIPROT	up-regulates activity	phosphorylation	Ser133	GHSQRREsFLYRSDS	9534	BTO:0001538								12023945	t		miannu	Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms.	SIGNOR-275986	0.2
FLT1	protein	P17948	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	phosphorylation	Tyr155	LNDSAAYyLNDLDRI	-1									33139573	t		miannu	RTKs directly phosphorylate Gαi on Y154, 155, and Y320.	SIGNOR-277229	0.26
RUNX3	protein	Q13761	UNIPROT	PEA15	protein	Q15121	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002384								17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255097	0.2
CTCF	protein	P49711	UNIPROT	MGAT5B	protein	Q3V5L5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001976								21771782	f		miannu	 By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression.	SIGNOR-253826	0.2
ZFP36	protein	P26651	UNIPROT	EIF4E2/GIGYF1 complex	complex	SIGNOR-C256	SIGNOR	up-regulates activity	relocalization			9606									30917308	t		lperfetto	A key factor in this regulation is tristetraprolin (TTP), an RNA-binding protein (RBP) that recruits RNA-destabilizing factors and the translation inhibitory complex 4EHP-GIGYF1/2 to AU-rich element (ARE)-containing mRNAs	SIGNOR-261014	0.2
GABRA5	protein	P31644	UNIPROT	GABA-A (a5-b1-g2) receptor	complex	SIGNOR-C335	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263765	0.631
JUN	protein	P05412	UNIPROT	MTHFR	protein	P42898	UNIPROT	up-regulates				9606									18065414	f		lperfetto	The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression	SIGNOR-253147	0.276
PDGFRA	protein	P16234	UNIPROT	CRK	protein	P46108	UNIPROT	up-regulates	binding			9606									19426560	t		amattioni	Crk can interact directly with tyrosine kinase receptors (for example pdgfr?) And can transmit signals downstream	SIGNOR-185664	0.63
RNF7	protein	Q9UBF6	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates activity	ubiquitination			9606									23136067	t		miannu	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 	SIGNOR-271451	0.2
DYRK1B	protein	Q9Y463	UNIPROT	DYRK1B	protein	Q9Y463	UNIPROT	up-regulates	phosphorylation	Tyr273	LGQRIYQyIQSRFYR	9606									10910078	t		lperfetto	Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site	SIGNOR-79810	0.2
TP53INP1	protein	Q96A56	UNIPROT	GABARAP	protein	O95166	UNIPROT	up-regulates	binding			9606									22421968	t		gcesareni	Tp53inp1 is also able to interact with atg8-family proteins	SIGNOR-196664	0.351
MRPS28	protein	Q9Y2Q9	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-267732	0.621
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	PRKCA	protein	P17252	UNIPROT	up-regulates	chemical activation			9606		BTO:0000887;BTO:0001103							22944199	t		gcesareni	The wnt/ca2+ signaling pathway is defined by the activation of plc (phospholipase c) through wnt/fzd resulting in an increase in intracellular ca2+ levels, which activate pkcs (protein kinase c) and camkii (calcium-calmodulin-dependent kinase ii) or cn (calcineurin), a phosphatase that activates the transcription factor nfat (nuclear factor of activated t cell).	SIGNOR-198822	0.8
PRKCG	protein	P05129	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates activity	phosphorylation	Ser43	VETWQEGsLKASCLY	-1									15604283	t		miannu	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276018	0.2
3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione	chemical	CHEBI:91368	ChEBI	PRKCB	protein	P05771	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191493	0.8
MAPK3	protein	P27361	UNIPROT	LIPE	protein	Q05469	UNIPROT	up-regulates activity	phosphorylation	Thr891	NSETSSDtPEMSLSA	10090	BTO:0000944								11581251	t		lperfetto	Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL.	SIGNOR-249470	0.425
SCF-SKP2	complex	SIGNOR-C136	SIGNOR	MYC	protein	P01106	UNIPROT	down-regulates quantity	ubiquitination			9606									20852628	t		gcesareni	The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain	SIGNOR-243551	0.574
Neuronal AP-3	complex	SIGNOR-C445	SIGNOR	Melanosome_assembly	phenotype	SIGNOR-PH180	SIGNOR	up-regulates				9606									22203680	f		miannu	Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes	SIGNOR-268522	0.7
CSNK2A1	protein	P68400	UNIPROT	CALM1	protein	P0DP23	UNIPROT	down-regulates activity	phosphorylation	Thr80	MARKMKDtDSEEEIR	-1									26675311	t		miannu	Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. 	SIGNOR-266356	0.432
SMO	protein	Q99835	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-199159	0.496
CDC25A	protein	P30304	UNIPROT	CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	up-regulates activity	dephosphorylation			9606	BTO:0000093								11154267	t		lperfetto	Cyclin E-Cdk2 complexes from p16INK4a-expressing MCF-7 cells are activated in vitro and in vivo by Cdc25A	SIGNOR-245452	0.737
MAPK8IP2	protein	Q13387	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates	binding			9606									10490659	t	These data demonstrated that JIP2 increases JNK activation by the MLK signaling pathway	gcesareni	These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins.	SIGNOR-70866	0.556
SMURF	proteinfamily	SIGNOR-PF29	SIGNOR	BMPR1A	protein	P36894	UNIPROT	down-regulates	ubiquitination			9606									22298955	t	inferred from 70% family members	gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-270212	0.2
EGFR	protein	P00533	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates	binding			9606									14967450	t		lperfetto	The egf-r coimmunoprecipitated with p85 alpha	SIGNOR-121959	0.802
GRIP1	protein	Q9Y3R0	UNIPROT	KIF5C	protein	O60282	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							31757889	t		miannu	 HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C in vitro 	SIGNOR-264061	0.33
EIF2B4	protein	Q9UI10	UNIPROT	EIF2S2	protein	P20042	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269132	0.744
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	MAP3K8	protein	P41279	UNIPROT	down-regulates	binding			9606									22435554	t		lperfetto	Tpl-2 is stoichiometrically complexed with the nf-kb inhibitory protein, nf-kb1 p105, and the ubiquitin-binding protein abin-2, both of which are required to maintain tpl-2 protein stability. Binding to p105 also prevents tpl-2 from phosphorylating mek	SIGNOR-216289	0.553
CTDSPL	protein	O15194	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	dephosphorylation	Ser214	PTSSDPGsPFQMPAD	9606	BTO:0000552								17085434	t			Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)	SIGNOR-248316	0.476
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	MED1	protein	Q15648	UNIPROT	up-regulates	phosphorylation			9606									12356758	t	inferred from 70% family members	lperfetto	Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase	SIGNOR-270106	0.2
PBX1	protein	P40424	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity	binding			9606		BTO:0000887;BTO:0001103							15149596	t	Pbx is constitutively bound close to the Myogenin promoter and can recruit MyoD	lperfetto	These domains are necessary for the stable binding of myod to the myogenin promoter through an interaction with an adjacent protein complex containing the homeodomain protein pbx, which appears to be constitutively bound at this site	SIGNOR-124834	0.419
ATM	protein	Q13315	UNIPROT	FANCA	protein	O15360	UNIPROT	up-regulates	phosphorylation	Ser1449	AAPDADLsQEPHLF	9606									19109555	t		lperfetto	The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site	SIGNOR-182949	0.418
CAMK2A	protein	Q9UQM7	UNIPROT	ID1	protein	P41134	UNIPROT	up-regulates activity	phosphorylation	Ser36	GEVVRCLsEQSVAIS	9606	BTO:0001620								29079782	t		miannu	Here we show that CaMKII can directly phosphorylate Beclin 1 at Ser90 to promote K63-linked ubiquitination of Beclin 1 and activation of autophagy.	SIGNOR-277367	0.2
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1647	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120000	0.781
CSNK2A1	protein	P68400	UNIPROT	EIF5	protein	P55010	UNIPROT	up-regulates activity	phosphorylation	Ser174	DKENGSVsSSETPPP	9606									11861906	t		llicata	Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis.	SIGNOR-250861	0.402
DOK1	protein	Q99704	UNIPROT	A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257690	0.2
KIF1C	protein	O43896	UNIPROT	RAB6C	protein	Q9H0N0	UNIPROT	up-regulates quantity	relocalization			-1									20360680	t		miannu	Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation.	SIGNOR-266879	0.248
AURKA	protein	O14965	UNIPROT	PLK1	protein	P53350	UNIPROT	up-regulates	phosphorylation	Thr210	YDGERKKtLCGTPNY	9606									18615013	t		gcesareni	We find that aurora a (aurka) can directly phosphorylate plk1 on thr 210;activation of plk1 requires phosphorylation of a conserved threonine residue (thr 210).	SIGNOR-179422	0.649
EIF4A3	protein	P38919	UNIPROT	Exon junction complex	complex	SIGNOR-C369	SIGNOR	form complex	binding			-1									16923391	t		miannu	 The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. 	SIGNOR-265240	0.946
ATP5PO	protein	P48047	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261403	0.2
CBS	protein	P35520	UNIPROT	L-homocysteine zwitterion	smallmolecule	CHEBI:58199	ChEBI	down-regulates quantity	chemical modification			9606									23981774	t		lperfetto	Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. 	SIGNOR-275828	0.8
CDK1	protein	P06493	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Thr444	RFIGSPRtPVSPVKF	9606									15774499	t		gcesareni	The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain.	SIGNOR-134654	0.392
AKT2	protein	P31751	UNIPROT	ADARB1	protein	P78563	UNIPROT	down-regulates activity	phosphorylation	Thr553	LQGERLLtMSCSDKI	-1									31095429	t		miannu	AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively	SIGNOR-276196	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GRK7	protein	Q8WTQ7	UNIPROT	down-regulates activity	phosphorylation	Ser36	ELQRRRRsLALPGLQ	-1									15946941	t	done	miannu	PKA Phosphorylates GRK7 on Ser23 and Ser36. Phosphorylation by PKA inhibits GRK7 activity	SIGNOR-274080	0.2
nintedanib	chemical	CHEBI:85164	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates activity	chemical inhibition			-1									18559524	t		Luana	In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers.	SIGNOR-257800	0.8
AP-3 complex	complex	SIGNOR-C247	SIGNOR	Melanosome_assembly	phenotype	SIGNOR-PH180	SIGNOR	up-regulates				9606									22203680	f		lperfetto	Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes	SIGNOR-265941	0.7
CSNK1D	protein	P48730	UNIPROT	GJA1	protein	P17302	UNIPROT	up-regulates activity	phosphorylation	Ser330	AGSTISNsHAQPFDF	10116	BTO:0000067								12270943	t		lperfetto	We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation).	SIGNOR-249331	0.587
PRTN3	protein	P24158	UNIPROT	F2R	protein	P25116	UNIPROT	up-regulates activity	cleavage	Ala36	PESKATNaTLDPRSF	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus	SIGNOR-263575	0.43
NEUROG1	protein	Q92886	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	up-regulates				10090	BTO:0000938	BTO:0000142							18400164	f		lperfetto	While the mechanisms by which Ngn2 promotes neurogenesis have been characterized, little is known about how Ngn2 confers neuronal cell-type identity during spinal cord development. Ngn1 and Ngn2, two mammalian orthologs of the Drosophila proneural bHLH gene atonal, are expressed in overlapping patterns throughout the developing nervous system and act as important regulators of developmental neurogenesis	SIGNOR-265172	0.7
IFNG	protein	P01579	UNIPROT	GCH1	protein	P30793	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000142							20525234	f		miannu	Pro-inflammatory cytokines like interferon-γ (IFN-γ) induce expression of GTP-cyclohydrolase I in various brain cells. 	SIGNOR-252223	0.254
PIK3CB	protein	P42338	UNIPROT	PIP3	smallmolecule	CHEBI:16618	ChEBI	up-regulates quantity	chemical modification			9606									21779497	t		lperfetto	The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2)	SIGNOR-175241	0.8
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	RBL2	protein	Q08999	UNIPROT	up-regulates quantity	transcriptional regulation			9606	BTO:0000944								11884591	t		gcesareni	Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression.	SIGNOR-252934	0.2
PRKCB	protein	P05771	UNIPROT	LASP1	protein	Q14847	UNIPROT	down-regulates activity	phosphorylation	Ser146	MEPERRDsQDGSSYR	9606									12571245	t		lperfetto	Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration	SIGNOR-97942	0.2
GRM2	protein	Q14416	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264349	0.7
TWIST2	protein	Q8WVJ9	UNIPROT	RAP1A	protein	P62834	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255508	0.2
PRKG2	protein	Q13237	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser78	PAYSRALsRQLSSGV	9606									19593530	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	lperfetto	Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization	SIGNOR-186796	0.2
C3 convertase complex	complex	SIGNOR-C310	SIGNOR	C3	protein	P01024	UNIPROT	up-regulates activity	cleavage	Arg671	QPAARRRrSVQLTEK										31331124	t		lperfetto	This forms the C4b2a complex, which is a classical pathway C3 convertase. C4b2a cleaves C3, which is the central component of the complement cascade, to C3a, and anaphylatoxin, and C3b results in the activation of the lytic pathway	SIGNOR-263449	0.54
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	LTC4S	protein	Q16873	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001433								12574384	f	 	miannu	 activation of NF-kappaB and p50/p65 overexpression down-regulated the LTC(4) synthase gene. LPS down-regulates cysteinyl LT release and LTC(4) synthase gene expression in mononuclear phagocytes by an NF-kappaB-mediated mechanism.	SIGNOR-254799	0.26
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257926	0.8
OGDC	complex	SIGNOR-C397	SIGNOR	succinyl-CoA(5-)	smallmolecule	CHEBI:57292	ChEBI	up-regulates quantity	chemical modification			9606									15953811	t		miannu	The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH.	SIGNOR-266258	0.8
ATF4	protein	P18848	UNIPROT	YARS2	protein	Q9Y2Z4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269432	0.2
FBXW11	protein	Q9UKB1	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates	ubiquitination	Lys22	GPRDGLKkERLLDDR	9606									7479976	t		gcesareni	Here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha.	SIGNOR-26577	0.521
RPS6KB1	protein	P23443	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates	phosphorylation	Ser84	LTKKRALsISPLSDA	9606									22439934	t		gcesareni	In this study, we found that an activated mtor/s6k1 pathway promotes gli1 transcriptional activity and oncogenic function through s6k1-mediated gli1 phosphorylation at ser84, which releases gli1 from its endogenous inhibitor, sufu.	SIGNOR-196756	0.539
NFY	complex	SIGNOR-C1	SIGNOR	ID1	protein	P41134	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18025157	f			We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein.	SIGNOR-255746	0.272
PRKCB	protein	P05771	UNIPROT	MFN1	protein	Q8IWA4	UNIPROT	down-regulates activity	phosphorylation	Ser86	AFFGRTSsGKSSVIN	-1									30659190	t	done	miannu	Here we report that βIIPKC accumulates on the mitochondrial outer membrane and phosphorylates mitofusin 1 (Mfn1) at serine 86. Mfn1 phosphorylation results in partial loss of its GTPase activity and in a buildup of fragmented and dysfunctional mitochondria in heart failure.	SIGNOR-273826	0.2
CSNK1A1	protein	P48729	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates activity	phosphorylation	Ser844	GSGSEAAsLSSLNSS										17353278	t		lperfetto	Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846	SIGNOR-274045	0.317
HDAC3	protein	O15379	UNIPROT	SMAD7/HDAC1/E2F-1	complex	SIGNOR-C12	SIGNOR	up-regulates	binding			9606									23213415	t		lperfetto	Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes.	SIGNOR-217358	0.445
RAD23B	protein	P54727	UNIPROT	XPA	protein	P23025	UNIPROT	up-regulates activity	binding												24086043	t		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275697	0.761
TTBK2	protein	Q6IQ55	UNIPROT	KIF2A	protein	O00139	UNIPROT	down-regulates activity	phosphorylation	Ser135	SSAQQNGsVSDISPV	9534									26323690	t		Manara	TTBK2 phosphorylates KIF2A primarily at growing MT ends and counteracts the depolymerization activity of KIF2A	SIGNOR-260926	0.417
PRKCD	protein	Q05655	UNIPROT	RPS3	protein	P23396	UNIPROT	up-regulates activity	phosphorylation	Thr221	KDEILPTtPISEQKG	9606									19059439	t		Manara	Here we show that PKCδ phosphorylates rpS3 resulting in its mobilization in the nucleus to repair damaged DNA	SIGNOR-260895	0.2
PRKCZ	protein	Q05513	UNIPROT	PARD6A	protein	Q9NPB6	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser345	RGDGSGFsL	9606	BTO:0002181								23249950	t		miannu	APKC associates and phosphorylates Par6 on S345. aPKC expression stabilizes Par6 protein levels. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation. 	SIGNOR-276433	0.835
ERBB4	protein	Q15303	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates	binding			9606									16729043	t		gcesareni	We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5.	SIGNOR-146894	0.804
Immunoglobulin kappa light chain	protein	P0DOX7	UNIPROT	BCR-Dk	complex	SIGNOR-C435	SIGNOR	form complex	binding			9606	BTO:0000776								20176268	t		scontino	Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes.	SIGNOR-268194	0.2
TP53	protein	P04637	UNIPROT	AFP	protein	P02771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									14522900	f		miannu	 In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction	SIGNOR-254482	0.45
SF3A2	protein	Q15428	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270667	0.811
CSNK2A1	protein	P68400	UNIPROT	DNMT3A	protein	Q9Y6K1	UNIPROT	down-regulates activity	phosphorylation	Ser393	VCHDSDEsDTAKAVE	-1									25066127	t		miannu	This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin.	SIGNOR-276649	0.2
KLKB1	protein	P03952	UNIPROT	MST1	protein	P26927	UNIPROT	up-regulates activity	cleavage	Arg483	DQRRSKLrVVGGHPG	-1									10068459	t		miannu	Proteolytic cleavage of pro-MSP at a single site yields active MSP, a disulfide-linked alphabeta-chain heterodimer. human kallikrein cleaved only at Arg483–Val484, the cleavage site for formation of a- and b-chains.	SIGNOR-256511	0.329
COPS3	protein	Q9UNS2	UNIPROT	COP9 signalosome variant 2	complex	SIGNOR-C487	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270764	0.914
diazepam	chemical	CHEBI:49575	ChEBI	GABA-A (a3-b1-g2) receptor	complex	SIGNOR-C332	SIGNOR	up-regulates activity	chemical activation			9606		BTO:0000227							18790874	t	brain	lperfetto	The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5. 	SIGNOR-263798	0.8
PRKACG	protein	P22612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606									10949026	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.	SIGNOR-81157	0.409
palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	precursor of			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267880	0.8
MAPK3	protein	P27361	UNIPROT	MBP	protein	P02686	UNIPROT	down-regulates	phosphorylation	Thr232	KNIVTPRtPPPSQGK	9606									1939237	t		lperfetto	Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence.	SIGNOR-22424	0.516
SCF-SKP2	complex	SIGNOR-C136	SIGNOR	CDKN1B	protein	P46527	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1							phosphorylation:Thr187	NAGSVEQtPKKPGLR	10375532	t		miannu	Isolated SCF(Skp2) contained an E3 ubiquitin ligase activity towards p27. Our data thus suggest that SCF(Skp2) specifically targets p27 for degradation during cell-cycle progression.Immunodepletion of components of the complex - Cul-1, Skp1, or Skp2 - from the extract abolished p27 degradation, while addition of purified SCF(Skp2) to Skp2- depleted extract restored the capacity to degrade p27. 	SIGNOR-272933	0.683
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CDC6	protein	Q99741	UNIPROT	up-regulates	phosphorylation	Ser106	DNQLTIKsPSKRELA	9606									10339564	t		lperfetto	Based on these results, we propose that phosphorylation of hscdc6 by cdks regulates dna replication of at least two steps: first, by promoting initiation of dna replication and, second, through nuclear exclusion preventing dna rereplication. hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)	SIGNOR-217272	0.94
TOLLIP	protein	Q9H0E2	UNIPROT	IRAK1	protein	P51617	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								10854325	t		lperfetto	Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) 	SIGNOR-251980	0.792
MMP13	protein	P45452	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272358	0.7
BMI1	protein	P35226	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000785								19884659	f		gcesareni	Chromatin immunoprecipitation assays revealed the bmi-1 transcriptionally downregulated expression of the tumor suppressor pten in tumor cells through direct association with the pten locus.	SIGNOR-189040	0.567
MEF2C	protein	Q06413	UNIPROT	CDKL5	protein	O76039	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20513142	f	 	 	Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression|In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5.	SIGNOR-254031	0.358
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	AD/b2 integrin	complex	SIGNOR-C172	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259028	0.412
WASH complex	complex	SIGNOR-C258	SIGNOR	ARP2/3	complex	SIGNOR-C146	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								20498093	t		lperfetto	Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes.	SIGNOR-261006	0.2
PCDH19	protein	Q8TAB3	UNIPROT	GABRA5	protein	P31644	UNIPROT	up-regulates quantity by stabilization	binding			10116	BTO:0003102			SIGNOR-C335					29360992	t		miannu	Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons. 	SIGNOR-267219	0.261
SEMA3A	protein	Q14563	UNIPROT	PLXNA2	protein	O75051	UNIPROT	up-regulates	binding			9606									10679438	t		gcesareni	Plexins form stable complexes with neuropilin-1 or -2.	SIGNOR-75168	0.853
CSNK1A1	protein	P48729	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	down-regulates activity	phosphorylation	Thr830	DSAEGSHtSGQSNGR	9606	BTO:0001109								28114302	t		miannu	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276510	0.378
ANXA1	protein	P04083	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0004136								17464329	f		miannu	We next focused on the pro-apoptotic function of ANXA1 in AML1-ETO-expressing AML cells. In this regard, FK228 was found to increase the protein levels of both the full-length and 33 kDa N-terminal cleavage products of ANXA1, which led to the localization of ANXA1 on the plasma membrane. Conversely, the inhibition of ANXA1 function (by ANXA1 neutralizing antibody, which blocked ANXA1 localization on the plasma membrane) or expression (by siRNA) significantly reduced FK228-induced apoptosis, indicating that ANXA1 is involved in apoptosis induction in response to FK228. 	SIGNOR-261689	0.7
DNMT1	protein	P26358	UNIPROT	RELN	protein	P78509	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19029285	f		miannu	 induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. 	SIGNOR-254575	0.445
SNX5	protein	Q9Y5X3	UNIPROT	IGF1R	protein	P08069	UNIPROT	down-regulates quantity	binding			9606	BTO:0000567								32150533	t		miannu	 Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.	SIGNOR-269444	0.273
LRP5	protein	O75197	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates quantity	relocalization			10090									11336703	t		amattioni	Axin is a protein that interacts with the intracellular domain of LRP-5. LRP-5 active form bind Axin and induce LEF-1 activation by destabilizing Axin and stabilizing beta-catenin.	SIGNOR-236997	0.825
JQ1	chemical	CHEBI:137113	ChEBI	BRD2	protein	P25440	UNIPROT	down-regulates activity	chemical inhibition			-1									20871596	t		lperfetto	Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. 	SIGNOR-261987	0.8
RELB	protein	Q01201	UNIPROT	B_cell_maturation	phenotype	SIGNOR-PH15	SIGNOR	up-regulates				9606									26385063	f		miannu	We have shown here for the first time the role of RelB on lymphocyte development in humans. In the absence of RelB, B cells development is arrested, resulting in poor production of immunoglobulins and specific antibodies.	SIGNOR-263655	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PDCD4	protein	Q53EL6	UNIPROT	down-regulates	phosphorylation	Ser67	KRRLRKNsSRDSGRG	9606									17053147	t		gcesareni	Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.	SIGNOR-150140	0.2
CDK1	protein	P06493	UNIPROT	UBA1	protein	P22314	UNIPROT	up-regulates	phosphorylation	Ser4	sPLSKKRR	9606	BTO:0000150								7673335	t		lperfetto	Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Each serine residue was independently mutated to an alanine and analyzed by two-dimensional electrophoresis;only serine 4 was phosphorylated. Disruption of the basic amino acids within the nls resulted in loss of exclusive nuclear localization and a 90-95% decrease in the phosphorylation of ha1-e1	SIGNOR-31157	0.414
GSK3B	protein	P49841	UNIPROT	MAP3K11	protein	Q16584	UNIPROT	up-regulates activity	phosphorylation	Ser793	PRPSPLPsPQPAPRR	9606	BTO:0000007								17711861	t		miannu	 The activation of MLK3 by GSK-3beta occurred via phosphorylation of MLK3 on two amino acid residues, Ser(789) and Ser(793), that are located within the C-terminal regulatory domain of MLK3. 	SIGNOR-276072	0.341
ANXA1	protein	P04083	UNIPROT	TNF	protein	P01375	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									27426034	f		miannu	Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups	SIGNOR-261941	0.34
INSR	protein	P06213	UNIPROT	BLVRA	protein	P53004	UNIPROT	up-regulates activity	phosphorylation	Tyr198	EERKEDQyMKMTVCL										15870194	t		lperfetto	Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK 	SIGNOR-275514	0.494
OXSR1	protein	O95747	UNIPROT	SLC12A2	protein	P55011	UNIPROT	up-regulates	phosphorylation	Thr212	TNTYYLRtFGHNTMD	9606									16669787	t		miannu	We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1	SIGNOR-146521	0.54
LRRK2	protein	Q5S007	UNIPROT	LRRK2	protein	Q5S007	UNIPROT	up-regulates	phosphorylation	Ser2032	CRMGIKTsEGTPGFR	9606	BTO:0000938								20595391	t		lperfetto	Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2.	SIGNOR-166466	0.2
RPS6KA4	protein	O75676	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates activity	phosphorylation	Ser63	GILARRPsYRKILKD	10090	BTO:0000452								11909979	t		lperfetto	Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts 	SIGNOR-249145	0.599
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270388	0.8
GGCX	protein	P38435	UNIPROT	F2	protein	P00734	UNIPROT	up-regulates activity	carboxylation	Glu68	VEETCSYeEAFEALE	-1									10556651	t		lperfetto	We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 	SIGNOR-263681	0.655
GSK3B	protein	P49841	UNIPROT	SPAG5	protein	Q96R06	UNIPROT	up-regulates	phosphorylation	Thr937	ADEEPEStPVPLLGS	9606									18055457	t		lperfetto	Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta	SIGNOR-159582	0.274
CDK8	protein	P49336	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	phosphorylation	Ser727	TDNLLPMsPEEFDEV										29239838	t		lperfetto	We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation. 	SIGNOR-273179	0.402
MITF	protein	O75030	UNIPROT	BEST1	protein	O76090	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									20530484	f		miannu	 BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. 	SIGNOR-255185	0.386
CHFR	protein	Q96EP1	UNIPROT	SMARCB1	protein	Q12824	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0000298								22285184	t		miannu	Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination.	SIGNOR-271458	0.321
HP	protein	P00738	UNIPROT	HBA1	protein	P69905	UNIPROT	down-regulates quantity	binding			9606									9315856	t	Regulation of binding	miannu	Haptoglobin forms a complex of extremely high affinity with Hb via a well-characterized globin site. Our results show that upon Hb-haptoglobin binding, the globin radical, loses its ability to be terminated by forming globin dimers.	SIGNOR-251816	0.734
TFEB	protein	P19484	UNIPROT	CD36	protein	P16671	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2)	SIGNOR-276785	0.2
TJP1	protein	Q07157	UNIPROT	ARVCF	protein	O00192	UNIPROT	up-regulates activity	binding			9615	BTO:0000837								15456900	t	Regulation of binding	miannu	We identified ARVCF as a binding partner of ZO-1 and ZO-2 and characterized the role of PDZ-domain proteins in plasma membrane and nuclear localization of ARVCF. E-cadherin, ZO-1, and ARVCF are recruited to sites of initial cell-cell contact. Binding of the ZO-1 PDZ domains per se does not facilitate membrane recruitment of ARVCF, indicating a requirement for the intact ZO-1 and possibly its association with membrane proteins and/or the cytoskeleton for this process.	SIGNOR-252121	0.466
NPBWR1	protein	P48145	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256675	0.409
PRKCA	protein	P17252	UNIPROT	PPP1R14A	protein	Q96A00	UNIPROT	up-regulates activity	phosphorylation	Thr38	QKRHARVtVKYDRRE	9606									32471307	t		lperfetto	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225].	SIGNOR-96692	0.503
MAPK1	protein	P28482	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	down-regulates activity	phosphorylation			9606									12809513	t	inferred from family member	llicata	We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay.	SIGNOR-270303	0.424
HNF4A	protein	P41235	UNIPROT	C1QTNF5	protein	Q9BXJ0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000224								20621834	f		miannu	 Here we demonstrate the mechanism by which the CTRP5 gene is transcriptionally activated in the liver. CTRP5 is activated by HNF4alpha via the region -206/-167 of the human CTRP5 promoter.	SIGNOR-254448	0.2
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser519	SGYSSPGsPGTPGSR	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249317	0.754
GSK3A	protein	P49840	UNIPROT	MAF	protein	O75444	UNIPROT	down-regulates	phosphorylation			9606									18042454	t		miannu	We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.	SIGNOR-159361	0.2
MAPK3	protein	P27361	UNIPROT	HNRNPK	protein	P61978	UNIPROT	down-regulates activity	phosphorylation	Ser284	RRDYDDMsPRRGPPP	9606									11231586	t		lperfetto	Erk phosphorylation drives cytoplasmic accumulation of hnrnp-k and inhibition of mrna translation mitogen-activated protein kinase/extracellular-signal-regulated kinase (mapk/erk) efficiently phosphorylates hnrnp-k both in vitro and in vivo at serines 284 and 353.	SIGNOR-105238	0.351
TFEB	protein	P19484	UNIPROT	GNS	protein	P15586	UNIPROT	up-regulates quantity by expression	transcriptional regulation												32978159	f		lperfetto	Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14)	SIGNOR-276792	0.318
PTPN2	protein	P17706	UNIPROT	GJA1	protein	P17302	UNIPROT	up-regulates	dephosphorylation	Tyr247	VKGKSDPyHATSGAL	9606		BTO:0000671							24849651	t		lperfetto	Tc-ptp dephosphorylates cx43 residues y247 and y265, dephosphorylation maintained cx43 gap junctions at the plaque and partially reversed the channel closure caused by v-src-mediated phosphorylation of cx43.	SIGNOR-205097	0.331
RUNX1	protein	Q01196	UNIPROT	CDKN2A	protein	Q8N726	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12091906	f		irozzo	AML1 binds to a six base pair DNA sequence (TGT/cGGT) that is present in many hematopoietic-specific genes.The p53 promoter does not contain any perfect AML1 DNA-binding sites (TGT/cGGT), but the human p14ARF promoter contains eight such sites (Fig. 1a), as well as multiple sites that match the broader consensus sequence (PyGPy/AGGT) or that have a single change from the consensus site.AML1 regulates the p14ARF promoter through an AML1 consensus DNA-binding site.	SIGNOR-255713	0.268
RB1	protein	P06400	UNIPROT	G1/S_transition	phenotype	SIGNOR-PH50	SIGNOR	down-regulates				9606									21524151	f		lperfetto	In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F	SIGNOR-245483	0.7
nitric oxide	smallmolecule	CHEBI:16480	ChEBI	Demyelination	phenotype	SIGNOR-PH155	SIGNOR	up-regulates				9606									32454942	f		miannu	Next to their interaction with adaptive immune cells, activated microglia can secrete cytotoxic cytokines and oxidative products, such as ROS and NO radicals in MS lesions thereby promoting oxidative stress and contributing to myelin destruction	SIGNOR-263829	0.7
NTRK1	protein	P04629	UNIPROT	NTRK1	protein	P04629	UNIPROT	up-regulates	phosphorylation	Tyr791	LAQAPPVyLDVLG	9606									9099755	t		gcesareni	In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785	SIGNOR-47183	0.2
MAPK1	protein	P28482	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates activity	phosphorylation			9534	BTO:0004055								14993270	t		lperfetto	We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling.	SIGNOR-244916	0.743
PTBP2	protein	Q9UKA9	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			9606	BTO:0000567								11003644	t		lperfetto	Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA.	SIGNOR-261267	0.289
MAPK14	protein	Q16539	UNIPROT	NR3C1	protein	P04150	UNIPROT	up-regulates	phosphorylation	Ser211	PGKETNEsPWRSDLL	10090									20660302	t			We demonstrate here that AMPK differentially modulates glucocorticoid action by phosphorylating the human GR at serine 211 indirectly through the activation of p38 MAPK	SIGNOR-255952	0.49
MAPK3	protein	P27361	UNIPROT	NOS2	protein	P35228	UNIPROT	up-regulates	phosphorylation	Ser745	KSRQNLQsPTSSRAT	9606	BTO:0000007								17804409	t		esanto	Erk phosphorylated inos on ser745. Mutation of ser745 to ala did not affect basal inos activity but eliminated inos phosphorylation and activation in response to b1r agonist.	SIGNOR-157711	0.363
ATP5MC1	protein	P05496	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261399	0.2
KCNS1	protein	Q96KK3	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			10029	BTO:0000246								10484328	t		miannu	We describe the cloning and characterization of the first human members, hKv9.1 and hKv9.3, of the electrically silent delayed-rectifying-like K+ channel subfamily.	SIGNOR-269449	0.8
POGLUT1	protein	Q8NBL1	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	glycosylation			9606									22872643	t	O-glycosilation	gcesareni	O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus.	SIGNOR-198713	0.591
MTA3	protein	Q9BTC8	UNIPROT	MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263840	0.763
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	MAPK3	protein	P27361	UNIPROT	up-regulates	phosphorylation	Thr202	HDHTGFLtEYVATRW	9606									9677429	t	MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade.	lperfetto	The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells.	SIGNOR-244802	0.2
BLOC-3	complex	SIGNOR-C253	SIGNOR	RAB32	protein	Q13637	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									23174301	t		lperfetto	HPS1/HPS4 was active exclusively for RAB32 and RAB38. Moreover, when overexpressed with HPS1 in HeLa cells, a mitochondrially restricted form of HPS4 preferentially recruited GFP-tagged RAB32 or RAB38 – but not the related RAB7 or RAB9 – to mitochondria. Activity in both assays required both HPS1 and HPS4. Finally, depletion of HPS1 or HPS4 by siRNA in a pigmented human melanoma cell line, MNT-1, resulted in the mislocalization of RAB32. These data provide strong evidence that BLOC-3 is a selective GEF for RAB32 and RAB38 	SIGNOR-260693	0.546
PRKCH	protein	P24723	UNIPROT	ITGB2	protein	P05107	UNIPROT	unknown	phosphorylation	Ser745	FEKEKLKsQWNNDNP	9606	BTO:0000751								11700305	t		lperfetto	Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |	SIGNOR-249118	0.35
noradrenaline	smallmolecule	CHEBI:33569	ChEBI	adrenaline	smallmolecule	CHEBI:33568	ChEBI	up-regulates quantity	precursor of			9606									7961964	t	brain	lperfetto	In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline).	SIGNOR-264183	0.8
CAPRIN2	protein	Q6IMN6	UNIPROT	OXT	protein	P01178	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation			9606	BTO:0000007								35051932	t		lperfetto	Transcriptional and post-transcriptional regulation of oxytocin and vasopressin gene expression by CREB3L1 and CAPRIN2|Altogether, the data indicate that CAPRIN2 binds Oxt mRNA |Therefore, we propose that CAPRIN2 facilitates post-transcriptional modifications that increase Oxt transcript stability. 	SIGNOR-268556	0.2
Fanconi anemia ID complex	complex	SIGNOR-C302	SIGNOR	BRCA2	protein	P51587	UNIPROT	up-regulates													18985065	f		lperfetto	Once monoubiquitinated, the ID complex becomes associated with chromatin and is redistributed to DNA-damage sites, forming foci that are visible by immunofluorescence and colocalizing with other DNA-repair molecules, notably BRCA1, BRCA2 and γH2AX.	SIGNOR-263270	0.784
SMAD6	protein	O43541	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates	binding			9606									19352540	t		gcesareni	Mad6-pellino-1 interaction abrogated signaling mediated by a complex of irak1.	SIGNOR-185128	0.338
FLT4	protein	P35916	UNIPROT	SHC1	protein	P29353	UNIPROT	unknown	phosphorylation	Tyr427	ELFDDPSyVNVQNLD	9606									9927207	t		llicata	We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites.	SIGNOR-64190	0.574
IKBKB	protein	O14920	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	down-regulates activity	phosphorylation	Ser85	ELLHFQAsQREEKEF	9606			SIGNOR-C14	SIGNOR-C14					17977820	t		lperfetto	In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I	SIGNOR-158663	0.962
PTPN6	protein	P29350	UNIPROT	TRPV1	protein	Q8NER1	UNIPROT	down-regulates activity	dephosphorylation			10116									25790452	t		miannu	Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.|These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia.	SIGNOR-277129	0.2
cetirizine	chemical	CHEBI:3561	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7925364	t		miannu	The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum.	SIGNOR-258868	0.8
PTPN9	protein	P43378	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	dephosphorylation			9606									20335174	t		miannu	Conversely, increasing expression of PTPN9 wild type (WT) inhibits tyrosyl phosphorylation of ErbB2 and EGFR.|Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells.	SIGNOR-277130	0.315
PTPRB	protein	P23467	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	dephosphorylation			9606									27314562	t		miannu	Collectively, these results suggest that PTPRB inhibits Src activation and down -- regulation of PTPRB activates Src signalling pathway required for cell invasion in A549 cells.|Knockdown of PTPRB increased Src phosphorylation and cell invasion, which was reversed by Src inhibitor PP2.	SIGNOR-277132	0.458
methiothepin	chemical	CHEBI:64203	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258853	0.8
CNOT9	protein	Q92600	UNIPROT	GIGYF1	protein	O75420	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								20878056	t		miannu	Through interaction analysis of RQCD1 with full-length or partial proteins of GIGYF1 and GIGYF2, segments corresponding to 620-665th and 667-712th amino acids were identified as potential interacting regions on GIGYF1 and GIGYF2, respectively, with RQCD1. we found that RQCD1 was required for enhancement of the interaction of Grb10 with GIGYF1 and GIGYF2	SIGNOR-260059	0.2
CTCF	protein	P49711	UNIPROT	BCL6	protein	P41182	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001690								20733034	f		miannu	 Inhibition of DNA methyltransferases decreased BCL6 mRNA abundance, suggesting a role for these methylated CpGs in positively regulating BCL6 transcription. The enhancer-blocking transcription factor CTCF bound to this intronic region in a methylation-sensitive manner. Depletion of CTCF by short hairpin RNA in neoplastic plasma cells that do not express BCL6 resulted in up-regulation of BCL6 transcription. 	SIGNOR-253824	0.282
IL10	protein	P22301	UNIPROT	IL10RA	protein	Q13651	UNIPROT	up-regulates activity	binding			9606	BTO:0000801								26260587	t		lperfetto	IL10 is a classic anti-inflammatory cytokine and its molecular signalling pathway has been well characterized in macrophages and T lymphocytes. Secreted IL10 cytokine binds to the IL10 receptor 1 (IL10R1) on membrane surfaces, and IL10R1 dimerizes with IL10R2 to exert its downstream effects.	SIGNOR-249544	0.911
spermine	smallmolecule	CHEBI:15746	ChEBI	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									14617280	f		apalma	Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism	SIGNOR-255552	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	NUAK1	protein	O60285	UNIPROT	up-regulates	phosphorylation	Ser600	PARQRIRsCVSAENF	9606									12409306	t		esanto	Ser(600) in ark5 was found to be phosphorylated by active akt resulting in the activation of kinase activity.	SIGNOR-95247	0.2
PPM1G	protein	O15355	UNIPROT	SNRPN	protein	P63162	UNIPROT	up-regulates quantity by stabilization	dephosphorylation			9606									17984321	t		lperfetto	Dephosphorylation of survival motor neurons (SMN) by PPM1G and PP2Cgamma governs Cajal body localization and stability of the SMN complex.|This indicates that the catalytic activity of PPM1G promotes accumulation of the SMN complex in CBs and suggests that PPM1G is a major determinant of the SMN-complex localization in the nucleus.	SIGNOR-277021	0.2
CUDC-101	chemical	CID:24756910	PUBCHEM	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									20143778	t		miannu	By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively.	SIGNOR-262259	0.8
MAPK1	protein	P28482	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser104	FPPLNSVsPSPLMLL	9606	BTO:0000567								17615152	t		gcesareni	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity	SIGNOR-156848	0.657
RPS6KA1	protein	Q15418	UNIPROT	RANBP3	protein	Q9H6Z4	UNIPROT	up-regulates quantity	phosphorylation	Ser57	HGTGHPEsAGEHALE	9606	BTO:0000007								18280241	t		miannu	RSK phosphorylates RanBP3 at Serine 58 residue in vitro and in vivo.RanBP3 phosphorylation increases its affinity towards Ran	SIGNOR-276149	0.326
lovastatin	chemical	CHEBI:40303	ChEBI	NR1I2	protein	O75469	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000318								9727070	t		miannu	 The antihypercholesterolemic drug lovastatin also activated hPXR as did phenobarbital and the organochlorine pesticide transnonachlor (Fig. 4 A). Thus, hPXR is activated by a remarkably diverse group of synthetic compounds that are known to induce CYP3A4 gene expression (Fig. 4 C).	SIGNOR-258828	0.8
ROCK1	protein	Q13464	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates	phosphorylation	Thr567	QGRDKYKtLRQIRQG	9606									19386264	t		lperfetto	Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. We performed an in vitro kinase assay with 80 selected kinases on an ezrin peptide containing the t567 phosphorylation site (figure 3a). In this screen, we identified the mst and rock kinases as the most potent kinases for the ezrin peptide	SIGNOR-185567	0.722
MAP1LC3C	protein	Q9BXW4	UNIPROT	ATG3	protein	Q9NT62	UNIPROT	up-regulates activity	binding			10090	BTO:0002572								22170151	t		lperfetto	Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe	SIGNOR-191552	0.773
PFK	proteinfamily	SIGNOR-PF79	SIGNOR	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35.	SIGNOR-266470	0.8
ZWILCH	protein	Q9H900	UNIPROT	RZZ complex	complex	SIGNOR-C357	SIGNOR	form complex	binding			9606	BTO:0000567								20462495	t		lperfetto	The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico.	SIGNOR-265014	0.74
PAK1	protein	Q13153	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation	Ser405	KTQTPPVsPAPQPTE	9606									20444238	t		gcesareni	Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis.	SIGNOR-165216	0.695
DZIP3	protein	Q86Y13	UNIPROT	ATXN1	protein	P54253	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								24326307	t		miannu	HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation.	SIGNOR-272078	0.496
SHANK3	protein	Q9BYB0	UNIPROT	GRIA3	protein	P42263	UNIPROT	up-regulates quantity	binding			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264603	0.2
NCBP3	protein	Q53F19	UNIPROT	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates activity	relocalization			9606									26382858	t		lperfetto	The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. 	SIGNOR-268364	0.8
MAPK1	protein	P28482	UNIPROT	GTF2I	protein	P78347	UNIPROT	up-regulates	phosphorylation	Ser668	INTKALQsPKRPRSP	9606									10648599	t		lperfetto	Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation.	SIGNOR-74296	0.372
JAG1	protein	P78504	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	up-regulates	binding			9606									18660822	t	Binding Calcium-dependent.	gcesareni	Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch.	SIGNOR-179622	0.623
MAPK1	protein	P28482	UNIPROT	RUNX1	protein	Q01196	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr273	SPSVHPAtPISPGRA	9606	BTO:0002181								16046550	t		miannu	We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 	SIGNOR-268220	0.2
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser280	RSPSPQPsSHVAPQD	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252336	0.635
PPP2CA	protein	P67775	UNIPROT	RBL1	protein	P28749	UNIPROT	up-regulates	dephosphorylation			9606									15467457	t		miannu	Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation.	SIGNOR-129749	0.606
FYN	protein	P06241	UNIPROT	NMT1	protein	P30419	UNIPROT	unknown	phosphorylation	Tyr180	YTLLNENyVEDDDNM	-1									11594778	t			Human NMT was found to be phosphorylated by non-receptor tyrosine kinase family members of Lyn, Fyn and Lck. Tyr100 is the principle phosphorylation site on hNMT for Lyn and Fyn. The significance of a phosphorylation-dependent interaction between NMT and a tyrosine kinase is not known at present.	SIGNOR-251179	0.39
DNMT1	protein	P26358	UNIPROT	BAG4	protein	O95429	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001109								18413740	f	 	lperfetto	In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+)	SIGNOR-254112	0.2
GPR17	protein	Q13304	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256835	0.359
LYN	protein	P07948	UNIPROT	GLO1	protein	Q04760	UNIPROT	up-regulates activity	phosphorylation	Tyr136	GIAVPDVySACKRFE	-1									34838714	t		miannu	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276186	0.2
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	PDK1	protein	Q15118	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16517405	t		miannu	Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. 	SIGNOR-267446	0.42
RUNX2	protein	Q13950	UNIPROT	BGLAP	protein	P02818	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004958; BTO:0002648								9182762	f		Giulio Giuliani	Indeed, we identified Osf2/Cbfa1 binding sites in the promoter of four genes expressed only (the Osteocalcin genes) or highly (α1(I) collagen, Bsp, and Osteopontin) in osteoblasts. Each of these elements was able to bind Osf2/Cbfa1.	SIGNOR-255408	0.596
KCNC3	protein	Q14003	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			9606									11506885	t		miannu	Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height	SIGNOR-265587	0.8
FYN	protein	P06241	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	unknown	phosphorylation	Tyr1039	HSQLSDLyGKFSFKS	-1									11024032	t			Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro.	SIGNOR-251169	0.76
(6R)-5,10-methylenetetrahydrofolate(2-)	smallmolecule	CHEBI:15636	ChEBI	dihydrofolate(2-)	smallmolecule	CHEBI:57451	ChEBI	up-regulates quantity	precursor of			9606									21876188	t		lperfetto	In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR.	SIGNOR-268233	0.8
CAK complex	complex	SIGNOR-C456	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser376	LKSKKGQsTSRHKKL	9606									9315650	t		llicata	The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase.	SIGNOR-269328	0.446
SLITRK1	protein	Q96PX8	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606									19640509	f		miannu	Phosphorylation of SLITRK1 on the CK2 phosphorylation site modulated SLITRK1-enhanced neurite outgrowth.	SIGNOR-273658	0.7
MTR	protein	Q99707	UNIPROT	homocysteine	smallmolecule	CHEBI:17230	ChEBI	down-regulates quantity	chemical modification			9606									10520212	t		lperfetto	Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels.	SIGNOR-253142	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation			9606		BTO:0000887							20151718	t	inferred from 70% family members	miannu	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-270128	0.2
HARS1	protein	P12081	UNIPROT	histidine	smallmolecule	CHEBI:27570	ChEBI	down-regulates quantity	chemical modification			9606									10430027	t		miannu	Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 	SIGNOR-270486	0.8
N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonyl-1-piperazinyl)-1-piperidinyl]anilino]-4-pyrimidinyl]-2-imidazo[1,2-a]pyridinyl]-2-methoxybenzamide	chemical	CHEBI:91401	ChEBI	INSR	protein	P06213	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192883	0.8
CSNK2A1	protein	P68400	UNIPROT	GBF1	protein	Q92538	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser292	VVSPSTDsGLEFSSQ	9606	BTO:0002181								29898406	t		miannu	We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation.	SIGNOR-277397	0.2
CSNK2A1	protein	P68400	UNIPROT	PDCL	protein	Q13371	UNIPROT	unknown	phosphorylation	Ser25	SSSEDEDsDHEDKDR	9606									16717095	t		lperfetto	Together, these data make a strong case for ck2 phosphorylation events within the serines 18-20 and 25 sites in vivo. hey also show that phosphorylation of ser-25 and ser-296 plays no additional role in g__ expression.	SIGNOR-146837	0.36
Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	Respiratory electron transport chain	phenotype	SIGNOR-PH141	SIGNOR	up-regulates													30030361	f		lperfetto	The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA).	SIGNOR-262141	0.7
PRKCB	protein	P05771	UNIPROT	IBTK	protein	Q9P2D0	UNIPROT	down-regulates	phosphorylation	Ser1203	LHSVSSKsFRDFLLE	9606	BTO:0000776								21482705	t		llicata	We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane.	SIGNOR-173387	0.334
G3BP1	protein	Q13283	UNIPROT	DDX58	protein	O95786	UNIPROT	down-regulates activity	binding			9606	BTO:0002181								30804210	t		SARA	G3BP1 binds RIG-I and that this interaction involves the C-terminal RGG domain of G3BP1, G3BP1 significantly enhances RIG-I-induced ifn-b mRNA synthesis.	SIGNOR-260980	0.346
GSK3B	protein	P49841	UNIPROT	DPYSL3	protein	Q14195	UNIPROT	up-regulates activity	phosphorylation	Thr514	TTTPKGGtPAGSARG	10116									16611631	t		lperfetto	Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-146015	0.452
PRR5	protein	P85299	UNIPROT	mTORC2	complex	SIGNOR-C2	SIGNOR	form complex	binding			9606									25628925	t		lperfetto	Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)	SIGNOR-205621	0.666
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	up-regulates quantity	precursor of			9606									31422819	t		miannu	This is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1).	SIGNOR-267515	0.8
2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid	chemical	CID:135461425	PUBCHEM	FGFR1	protein	P11362	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259703	0.8
TNRC6B	protein	Q9UPQ9	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	up-regulates activity	binding			-1									17891150	t		miannu	The assay showed that full-length TNRC6B binds full-length human AGO2. We have identified and molecularly dissected important sequence and structure features in the conserved Ago hooks of S. pombe Tas3 and human TNRC6B. The effect of Ago hook peptides from the shuttling P-body component TNRC6B in our miRNA-mediated translational repression assay (Fig. 5b), in particular, hints at a novel regulatory role of Ago hooks in miRNA-mediated gene repression mechanisms.	SIGNOR-269680	0.787
MAPK3	protein	P27361	UNIPROT	NUP153	protein	P49790	UNIPROT	unknown	phosphorylation	Ser529	SPMFKFSsPIVKSTE	9606									19767751	t		llicata	These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport.	SIGNOR-188143	0.4
CDC14A	protein	Q9UNH5	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser688	QFHSPVGsPLKSIQA	9606									20236090	t			Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3.	SIGNOR-248831	0.627
SCH 23390	chemical	CHEBI:73297	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029									8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258732	0.8
TNIP1	protein	Q15025	UNIPROT	TAX1BP1	protein	Q86VP1	UNIPROT	up-regulates activity	relocalization												21885437	t		lperfetto	ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi. 	SIGNOR-275735	0.463
PRTN3	protein	P24158	UNIPROT	AGT	protein	P01019	UNIPROT	up-regulates activity	cleavage	Phe41	DRVYIHPfHLVIHNE	-1									11747312	t		miannu	Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.	SIGNOR-256314	0.261
CDK1	protein	P06493	UNIPROT	SUN1	protein	O94901	UNIPROT	down-regulates activity	phosphorylation	Ser48	KLDPVFDsPRMSRRS	9606	BTO:0000567								25482198	t		miannu	Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions. 	SIGNOR-263099	0.366
CRYAB	protein	P02511	UNIPROT	CRYGS	protein	P22914	UNIPROT	up-regulates activity	binding			-1									20621668	t		miannu	Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age.	SIGNOR-253623	0.555
NUP98	protein	P52948	UNIPROT	mRNA-nucleus_export	phenotype	SIGNOR-PH127	SIGNOR	up-regulates				9606									20498086	f		miannu	The export of mRNAs is a multistep process, involving the packaging of mRNAs into messenger ribonucleoprotein particles (mRNPs), their transport through nuclear pore complexes, and mRNP remodeling events prior to translation. Ribonucleic acid export 1 (Rae1) and Nup98 are evolutionarily conserved mRNA export factors that are targeted by the vesicular stomatitis virus matrix protein to inhibit host cell nuclear export. these data suggest that the Rae1*Nup98 complex directly binds to the mRNP at several stages of the mRNA export pathway.	SIGNOR-260872	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ZNF322	protein	Q6U7Q0	UNIPROT	up-regulates activity	phosphorylation	Thr262	IVHQRVHtGEKPYKC	9606	BTO:0002552								31399647	t		miannu	We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A.	SIGNOR-276753	0.2
2-hydroxyglutarate	smallmolecule	CHEBI:132941	ChEBI	FOXP3	protein	Q9BZS1	UNIPROT	down-regulates activity	chemical inhibition			9606									33114536	f		Luana	Moreover, glutamate oxaloacetate transaminase 1 (GOT1), an enzyme involved in glutamine metabolism, exerts pro-inflammatory effects by producing 2-hydroxyglutarate, which hinders the expression of FOXP3 and thus blocks the formation of Tregs. 	SIGNOR-268042	0.8
MAP1LC3A	protein	Q9H492	UNIPROT	O-phosphoethanolamine	smallmolecule	CHEBI:17553	ChEBI	up-regulates	binding			9606									22170151	t		gcesareni	Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe	SIGNOR-191546	0.8
MAPK7	protein	Q13164	UNIPROT	MEF2D	protein	Q14814	UNIPROT	up-regulates	phosphorylation	Ser180	LTDPRLLsPQQPALQ	9606	BTO:0000567								10849446	t		lperfetto	Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b. the sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo.	SIGNOR-236041	0.693
KATNAL2	protein	Q8IYT4	UNIPROT	KATNB1	protein	Q9BVA0	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								10751153	t		miannu	Katanin, a heterodimeric microtubule-severing ATPase, is found localized at mitotic spindle poles. In this paper we demonstrate that human p60 katanin and the C-terminal domain of human p80 katanin both bind microtubules in vitro. Association of these two proteins results in an increased microtubule affinity and increased microtubule-severing activity in vitro. Association of these subunits in transfected HeLa cells increases microtubule disassembly activity and targeting to spindle poles. 	SIGNOR-267180	0.603
CAMK2D	protein	Q13557	UNIPROT	ITPR2	protein	Q14571	UNIPROT	down-regulates activity	phosphorylation	Ser150	EKNAMRVsLDAAGNE	9534	BTO:0001538								23019322	t		miannu	Phopho-specific antibodies demonstrate that InsP(3)R2 Ser-150 is phosphorylated in vivo by CaMKIIδ. The results of this study show that serine 150 of the InsP(3)R2 is phosphorylated by CaMKII and results in a decrease in the channel open probability.	SIGNOR-262692	0.313
ROCK1	protein	Q13464	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	phosphorylation	Ser637	VPVARKLsAREQRDC	10090									31063459	t		lperfetto	We have also previously reported that ROCK1-mediated Drp1S600 phosphorylation resulted in enhanced mitochondrial fission in podocytes	SIGNOR-262549	0.32
NSMCE2	protein	Q96MF7	UNIPROT	SMC5/6 	complex	SIGNOR-C374	SIGNOR	form complex	binding			-1									27427983	t		miannu	The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks	SIGNOR-265484	0.879
IRAK1	protein	P51617	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Ser82	HSISYTLsRAQTVVV	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276139	0.758
TCF4	protein	P15884	UNIPROT	SOX9	protein	P48436	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15240568	f			The β-catenin–TCF4 complex activity is required for SOX9 expression.	SIGNOR-253323	0.402
CHEK2	protein	O96017	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser279	VLKRPERsQEESPPG	9606									12676583	t	Phosphorylation is the signal for ubiquitination	gcesareni	We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases.	SIGNOR-99729	0.837
PRKACA	protein	P17612	UNIPROT	SUFU	protein	Q9UMX1	UNIPROT	up-regulates	phosphorylation	Ser346	RAPSRKDsLESDSST	9606									23337587	t		gcesareni	Interestingly, sufu stability is regulated via dual phosphorylation at ser342/ser346 by pka and gsk3, and blocking sufu phosphorylation either by mutating ser346 to ala or by treating cultured cells with pka inhibitors attenuates sufu ciliary accumulation, whereas phospho-mimetic forms of sufu exhibits increased ciliary localization	SIGNOR-119099	0.443
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	NEFL	protein	P07196	UNIPROT	down-regulates activity	binding			9606									23230147	t	inferred from 70% family members	miannu	These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments.	SIGNOR-269953	0.2
dexamethasone	chemical	CHEBI:41879	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									20956975	t		fspada	Glucocorticoids, such as dexamethasone, have been used as in vitro inducers of adipogenesis. However, the roles of the glucocorticoid receptor (gr) in adipogenesis have not been well characterized yet. Here, we show that inhibition of gr activity using the gr antagonist ru486 prevents human mesenchymal stem cell and mouse embryonic fibroblast (mef) differentiation into adipocytes	SIGNOR-168562	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CSNK2A1	protein	P68400	UNIPROT	up-regulates	phosphorylation	Thr360	SGISSVPtPSPLGPL	9606	BTO:0000527								19941816	t		lperfetto	Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity	SIGNOR-244525	0.2
KHDRBS1	protein	Q07666	UNIPROT	NRXN1	protein	Q9ULB1	UNIPROT	up-regulates activity	post transcriptional regulation			10090	BTO:0000232								22196734	t		Gianni	Activity-dependent alternative splicing of Nrxn1 requires the KH-domain RNA binding protein SAM68 which associates with RNA response elements in the Nrxn1 pre-mRNA. Our findings uncover SAM68 as a key regulator of dynamic control of Nrxn1 molecular diversity and activity-dependent alternative splicing in the central nervous system.	SIGNOR-269057	0.339
RUNX2	protein	Q13950	UNIPROT	SPP1	protein	P10451	UNIPROT	up-regulates quantity	transcriptional regulation			10090	BTO:0001616								16670084	t		gcesareni	Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.	SIGNOR-245336	0.504
PHA-680632	chemical	CID:11249084	PUBCHEM	AURKC	protein	Q9UQB9	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206103	0.8
BMPR1A	protein	P36894	UNIPROT	SMAD8/SMAD4	complex	SIGNOR-C206	SIGNOR	up-regulates activity	phosphorylation			10090									19620713	t		ggiuliani	The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17).	SIGNOR-255786	0.689
ABL1	protein	P00519	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates activity	phosphorylation	Tyr934	AHASDEIyEIMQKCW	-1									19275932	t		miannu	C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis. 	SIGNOR-276141	0.507
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									27692180	t		miannu	HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 	SIGNOR-267500	0.363
Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	up-regulates				9606									18350175	f	inferred from family member	miannu	The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase.	SIGNOR-267782	0.7
MAPK1	protein	P28482	UNIPROT	PCBP2	protein	Q15366	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser173	MLETLSQsPPKGVTI	9606									17475908	t		miannu	We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 	SIGNOR-262910	0.324
MAPK8	protein	P45983	UNIPROT	EIF4ENIF1	protein	Q9NRA8	UNIPROT	up-regulates	phosphorylation	Ser587	YLRPRIPsPIGFTPG	9606									22966201	t		llicata	Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress.	SIGNOR-198996	0.329
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1944	GSTYSPTsPGYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120256	0.321
ACVR2B	protein	Q13705	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	phosphorylation			10090									21966641	t		areggio	It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains	SIGNOR-254985	0.677
EP300	protein	Q09472	UNIPROT	KRT16	protein	P08779	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12954631	f	 	miannu	 these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter.	SIGNOR-253904	0.2
APC	protein	P25054	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity	binding			9606									22083140	t		amattioni	Apc binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. APC cooperates with Axin to promote the phosphorylation of _-catenin by GSK3 [which requires priming phosphorylation by casein kinase 1, _-isoform (CK1_)].	SIGNOR-177230	0.918
PRKCG	protein	P05129	UNIPROT	EIF4E	protein	P06730	UNIPROT	unknown	phosphorylation	Ser209	DTATKSGsTTKNRFV	10090									8662663	t		lperfetto	Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins.	SIGNOR-248947	0.311
SMAD7	protein	O15105	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates quantity	transcriptional regulation			9606									30017632	t		miannu	The downstream molecules including mad2, smad3, smad4 and smad7 are involved in TGF-β1-induced EMT,while Smad7 blocks the smad3 expression	SIGNOR-260437	0.596
RUNX1	protein	Q01196	UNIPROT	BAALC	protein	Q8WXS3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22493267	f		miannu	 We show that BAALC overexpression occurs in the presence of the T allele of SNP rs62527607[GT], which creates a binding site for the activating RUNX1 transcription factor in the BAALC promoter region. The mechanism is demonstrated experimentally in vitro using luciferase reporter assays and electrophoretic mobility shift assay (EMSA) analysis. 	SIGNOR-255077	0.337
CTBP1	protein	Q13363	UNIPROT	BRCA1	protein	P38398	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									23303449	f		irozzo	Our findings suggest an important role of CtBP1 in the transcriptional control of p16INK4a and Brca1[.]. Breast Cancer Susceptibility Gene 1(Brca1), a core protein in DNA damage repair, was repressed by CtBP1 in melanoma cells.	SIGNOR-259194	0.586
DUSP1	protein	P28562	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates activity	dephosphorylation			9606									26734995	t		miannu	However, adenovirus mediated overexpression of MKP-1 only slightly decreased JNK and c-Jun phosphorylation compared with the severe inactivation of JNK activities induced by MKK7 knockdown.|The results suggested that HDACI-induced MKP-1 contributes to inactivation of JNK instead of ERK, consistent with the previous reports in other cell types	SIGNOR-277102	0.467
INSR	protein	P06213	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	phosphorylation	Tyr1190	DIYETDYyRKGGKGL	-1									2449432	t		lperfetto	We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151;	SIGNOR-106518	0.2
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	USP37	protein	Q86T82	UNIPROT	up-regulates activity	phosphorylation	Ser628	MVNSCITsPSTPSKK	9606	BTO:0000007;BTO:0000567								21596315	t		lperfetto	There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity	SIGNOR-265053	0.459
TWIST1	protein	Q15672	UNIPROT	SNAI2	protein	O43623	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20646316	f		miannu	Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1.	SIGNOR-255524	0.49
pazopanib hydrochloride	chemical	CHEBI:71217	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			-1									17620431	t		miannu	The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. 	SIGNOR-259167	0.8
DAP3	protein	P51398	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261459	0.75
MAPK11	protein	Q15759	UNIPROT	MAPK11	protein	Q15759	UNIPROT	down-regulates activity	phosphorylation	Ser243	MEVVGTPsPEVLAKI	-1									26976637	t		miannu	P38β Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261	SIGNOR-277215	0.2
PRKAA1	protein	Q13131	UNIPROT	SCD	protein	O00767	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21478464	f		miannu	Tr4 transactivation is inhibited via phosphorylation by metformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression.	SIGNOR-173161	0.279
N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine	chemical	CHEBI:92386	ChEBI	ADRA2A	protein	P08913	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258922	0.8
EFNA2	protein	O43921	UNIPROT	EPHA6	protein	Q9UF33	UNIPROT	up-regulates	binding			9606									10072375	t		tpavlidou	Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8)	SIGNOR-65419	0.741
CAMK2B	protein	Q13554	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity	phosphorylation	Thr642	RSVKRNStVDCNGVV	9606	BTO:0000938								32611770	t		lperfetto	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275789	0.275
CDK1	protein	P06493	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1189	QKGELSRsPSPFTHT	9606	BTO:0000150								10550055	t		gcesareni	However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci.	SIGNOR-72083	0.511
ASNS	protein	P08243	UNIPROT	L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	down-regulates quantity	chemical modification			9606									29084849	t		miannu	Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7.	SIGNOR-267532	0.8
JUN	protein	P05412	UNIPROT	AP1	complex	SIGNOR-C154	SIGNOR	form complex	binding			-1									2467839	t		irozzo	The protein products of the fos (Fos) and jun (Jun) proto-oncogenes have been shown to associate with a DNA element known as the transcription factor activator protein-1 (AP-1) binding site. Jun (previously known as the Fos-binding protein p39) and Fos form a protein complex in the nucleus. These data demonstrate a cooperative interaction between the protein products of two proto-oncogenes with a DNA element involved in transcriptional regulation.	SIGNOR-256361	0.951
AMBRA1	protein	Q9C0C7	UNIPROT	PPP2CB	protein	P62714	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								25438055	t	phosphorylation site remapping based on mass spec table	lperfetto	We found that AMBRA1 favours the interaction between c-Myc and its phosphatase PP2A and that, when mTOR is inhibited, it enhances PP2A activity on this specific target, thereby reducing the cell division rate. As expected, such a de-regulation of c-Myc correlates with increased tumorigenesis in AMBRA1-defective systems, thus supporting a role for AMBRA1 as a haploinsufficient tumour suppressor gene.	SIGNOR-272964	0.2
dexamethasone	chemical	CHEBI:41879	ChEBI	NR3C2	protein	P08235	UNIPROT	down-regulates activity	chemical inhibition			9534	BTO:0001538								8282004	t		miannu	The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4).	SIGNOR-258710	0.8
IKBKB	protein	O14920	UNIPROT	TSC1	protein	Q92574	UNIPROT	down-regulates	phosphorylation	Ser487	AAISRELsEITTAEA	9606	BTO:0000150								17693255	t		gcesareni	Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression.	SIGNOR-157296	0.627
PRKCA	protein	P17252	UNIPROT	AQP1	protein	P29972	UNIPROT	up-regulates	phosphorylation	Thr157	VLCVLATtDRRRRDL	9606		BTO:0000671							17522053	t		llicata	Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc).	SIGNOR-155102	0.2
PTPN1	protein	P18031	UNIPROT	PTK2	protein	Q05397	UNIPROT	down-regulates	dephosphorylation			9606									16291744	t		gcesareni	We show that coexpression of wild-type alpha-actinin and ptp 1b causes dephosphorylation at tyr-397 in fak.	SIGNOR-141637	0.354
PRKCA	protein	P17252	UNIPROT	EIF4E	protein	P06730	UNIPROT	up-regulates	phosphorylation	Ser209	DTATKSGsTTKNRFV	10090									8662663	t		lperfetto	Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins.[..] This suggests a two-step model for the phosphorylation (and activation) of eIF4E by growth factors and hormones: first, dissociation of eIF4E .	SIGNOR-248945	0.391
2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide	chemical	CHEBI:91353	ChEBI	MAP2K2	protein	P36507	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258204	0.8
SRC	protein	P12931	UNIPROT	GSN	protein	P06396	UNIPROT	unknown	phosphorylation	Tyr409	TDGLGLSyLSSHIAN	-1									10210201	t		llicata	Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624.	SIGNOR-250780	0.576
ER stress	stimulus	SIGNOR-ST9	SIGNOR	PRNP	protein	F7VJQ1	UNIPROT	up-regulates				9606	BTO:0000007								21478263	f			ER stress specifically increases the synthesis of AltPrP from PrP cDNA.	SIGNOR-253609	0.7
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1714	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273094	0.745
MAPK3	protein	P27361	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser425	TKGSGLGsPTSSFNS	9606									19282669	t		lperfetto	Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway	SIGNOR-184577	0.583
HSP90AA1	protein	P07900	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates	binding			9606									18591668	t		lpetrilli	The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs.	SIGNOR-179271	0.392
PPP2CA	protein	P67775	UNIPROT	PTTG1	protein	O95997	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser87	PLKQKQPsFSAKKMT	9606	BTO:0000567								24781523	t		miannu	CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase	SIGNOR-276378	0.301
MYC	protein	P01106	UNIPROT	CDKN2A	protein	P42771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12835716	t		gcesareni	C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a	SIGNOR-102743	0.758
(RS)-Ppcc	chemical	CID:16726095	PUBCHEM	SIGMAR1	protein	Q99720	UNIPROT	up-regulates activity	chemical activation			9606									17328523	t		Federica	We suggest that 4b may act as a ơ1/ơ2 agonist and that the ơ ligands may modulate TG-2 differently.	SIGNOR-261107	0.8
GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	CRHR2	protein	Q13324	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268589	0.253
PGK1	protein	P00558	UNIPROT	3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa.	SIGNOR-266505	0.8
CSNK2A1	protein	P68400	UNIPROT	ARRB2	protein	P32121	UNIPROT	unknown	phosphorylation	Thr382	EFDTNYAtDDDIVFE	-1									11877451	t		llicata	We found that arrestin-3 is constitutively phosphorylated at Thr-382 and becomes dephosphorylated upon beta(2)-adrenergic receptor activation in COS-1 cells. Casein kinase II (CKII) appears to be the major kinase mediating arrestin-3 phosphorylation, since 1) Thr-382 is contained within a canonical consensus sequence for CKII phosphorylation and 2) wild type arrestin-3 but not a T382A mutant is phosphorylated by CKII in vitro. | However, additional analysis reveals that arrestin-3 phosphorylation may regulate formation of a large arrestin-3-containing protein complex. 	SIGNOR-250829	0.324
CAD	protein	P27708	UNIPROT	hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	down-regulates quantity	chemical modification			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-267419	0.8
SIRT1	protein	Q96EB6	UNIPROT	XBP1	protein	P17861-2	UNIPROT	down-regulates activity	deacetylation			9606	BTO:0000007								20955178	t		miannu	P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR. 	SIGNOR-260430	0.389
CDK1	protein	P06493	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	down-regulates	phosphorylation	Thr292	ETPPRPRtPGRPLSS	9606									8114697	t		gcesareni	P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well	SIGNOR-36116	0.473
HOXD12	protein	P35452	UNIPROT	MAFB	protein	Q9Y5Q3	UNIPROT	down-regulates activity	binding			-1									11036080	t		miannu	Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.	SIGNOR-221896	0.385
CSNK1E	protein	P49674	UNIPROT	CSNK1E	protein	P49674	UNIPROT	down-regulates activity	phosphorylation	Ser408	RIPASQTsVPFDHLG	9606	BTO:0000007								10542239	t		llicata	Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T	SIGNOR-250810	0.2
GRK3	protein	P35626	UNIPROT	CCR5	protein	P51681	UNIPROT	down-regulates activity	phosphorylation	Ser349	STGEQEIsVGL	9534	BTO:0000298								10085131	t		gcesareni	Phosphoamino acid analysis revealed that RANTES-induced CCR5 phosphorylation selectively occurs on serine residues. Our findings with receptor mutants indicate that serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5.	SIGNOR-249679	0.2
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	ST7	protein	Q9NRC1	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0004297								30945288	t		miannu	We found that both CUL4A and CUL4B can form an E3 complex with DNA damage-binding protein 1 (DDB1) and DDB1-CUL4-associated factor 4 (DCAF4). In vitro and in vivo ubiquitination analyses indicate that CRL4DCAF4 E3 ligase specifically directs degradation of ST7 (suppression of tumorigenicity 7).	SIGNOR-272309	0.2
VAMP2	protein	P63027	UNIPROT	SNARE_complex 	complex	SIGNOR-C346	SIGNOR	form complex	binding			9606									30267828	t		miannu	The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells.	SIGNOR-263966	0.931
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	ATN1	protein	P54259	UNIPROT	down-regulates activity	phosphorylation			9606		BTO:0000142							12812981	t	inferred from 70% family members	lperfetto	Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment,	SIGNOR-269978	0.2
GSK3B	protein	P49841	UNIPROT	MITF	protein	O75030	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser405	QARAHGLsLIPSTGL	9606									25605940	t		miannu	We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here.	SIGNOR-276475	0.446
FYN	protein	P06241	UNIPROT	PTGS2	protein	P35354	UNIPROT	up-regulates activity	phosphorylation	Tyr446	DQSRQMKyQSFNEYR	-1									24970799	t		miannu	We report that FYN phosphorylates human COX2 on Tyr 446, and while corresponding phospho-mimetic COX2 mutation promotes COX2 activity, the phosphorylation blocking mutation prevents FYN-mediated increase in COX2 activity. FYN and LYN kinases phosphorylate COX2 on two distinct residues in vitro. 	SIGNOR-276644	0.399
LCK	protein	P06239	UNIPROT	IL2RB	protein	P14784	UNIPROT	unknown	phosphorylation	Tyr536	LPLNTDAyLSLQELQ	-1									10214954	t			Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510.	SIGNOR-251379	0.629
FLT3	protein	P36888	UNIPROT	FLT3	protein	P36888	UNIPROT	up-regulates	phosphorylation	Tyr599	VDFREYEyDLKWEFP	9606	BTO:0001271								11971190	t		lperfetto	Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation	SIGNOR-117583	0.2
(S)-adrenaline	smallmolecule	CHEBI:40751	ChEBI	ADRA1D	protein	P25100	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258452	0.8
DGC	complex	SIGNOR-C217	SIGNOR	GABA-A (a3-b1-g2) receptor	complex	SIGNOR-C332	SIGNOR	up-regulates quantity	binding			9606	BTO:0000938;BTO:0002606								22626542	t		miannu	 In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses.	SIGNOR-265434	0.2
PTPN2	protein	P17706	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates activity	dephosphorylation	Tyr1059	DIYKDPDyVRKGDAR	9606									29955047	t		lperfetto	Collectively, our findings indicate that TC-PTP negatively regulates Flk-1 and JNK signaling via direct dephosphorylation of Flk-1 on its Y1173 residue, which contributes to increased epidermal apoptosis in response to UVB exposure.|Use of a TC-PTP substrate trapping mutant for immunoprecipitation analysis showed that TC-PTP dephosphorylates four different tyrosine residues of Flk-1 -- Y1052, Y1057, Y1212, and Y994 -- in human umbilical vein endothelial cells; however, it did not dephosphorylate the Y1173 residue of Flk-1 38.	SIGNOR-276962	0.548
NFIB	protein	O00712	UNIPROT	NFIC	protein	P08651	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								9099724	t	2	miannu	Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function.	SIGNOR-240880	0.368
RALY	protein	Q9UKM9	UNIPROT	PRMT1	protein	Q99873	UNIPROT	up-regulates quantity	post transcriptional regulation			9606	BTO:0000567								30354839	t		lperfetto	RALY binds poly-U rich elements within several RNAs and regulates the expression as well as the stability of specific transcripts. Here we show that RALY binds PRMT1 mRNA and regulates its expression.|We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels	SIGNOR-262273	0.249
GRK6	protein	P43250	UNIPROT	MC1R	protein	Q01726	UNIPROT	down-regulates activity	phosphorylation			9606									15650023	t		miannu	Overexpression of GRK6 Inhibits Agonist-Induced cAMP Production in HBL Human Melanoma Cells, without Affecting MC1R Gene Expression	SIGNOR-252389	0.319
FCN3	protein	O75636	UNIPROT	MASP1	protein	P48740	UNIPROT	up-regulates activity	binding			9606	BTO:0000392								11907111	t		lperfetto	H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway|Proteolytic activation of complement components by H-ficolin-MASP. 	SIGNOR-263410	0.66
MAPK1	protein	P28482	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Thr336	GGPGPERtPGSGSGS	10090	BTO:0000944								7889942	t		lperfetto	We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-235467	0.544
NKX2-5	protein	P52952	UNIPROT	NPPB	protein	P16860	UNIPROT	unknown	transcriptional regulation												15837525	f	 	 	In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription.	SIGNOR-253649	0.334
GGCX	protein	P38435	UNIPROT	PROZ	protein	P22891	UNIPROT	up-regulates activity	carboxylation			9606									28125048	t		lperfetto	Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z	SIGNOR-265926	0.487
DAPK2	protein	Q9UIK4	UNIPROT	DAPK2	protein	Q9UIK4	UNIPROT	down-regulates activity	phosphorylation	Ser318	VRRRWKLsFSIVSLC	9606	BTO:0000007;BTO:0000356								11230133	t		llicata	Autophosphorylation restrains the apoptotic activity of DRP-1 kinase by controlling dimerization and calmodulin binding. | It comprises a single autophosphorylation event mapped to Ser308 within the CaM regulatory domain.	SIGNOR-251084	0.2
IFNL2	protein	Q8IZJ0	UNIPROT	IFNLR1	protein	Q8IU57	UNIPROT	up-regulates	binding			9606									12469119	t		gcesareni	Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.	SIGNOR-96206	0.7
TFEB	protein	P19484	UNIPROT	SGSH	protein	P51688	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19556463	f	Figure 1	lperfetto	Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 	SIGNOR-276546	0.32
EGR2	protein	P11161	UNIPROT	NAB2	protein	Q15742	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000848								20506119	f		miannu	In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2.	SIGNOR-253883	0.594
ITGB8	protein	P26012	UNIPROT	Av/b8 integrin	complex	SIGNOR-C185	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253290	0.828
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1626	SPSYSPTsPSYSPTS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248736	0.727
GPKOW	protein	Q92917	UNIPROT	DHX16	protein	O60231	UNIPROT	up-regulates quantity	binding												25296192	t		miannu	In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16. 	SIGNOR-266300	0.843
EGFR	protein	P00533	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1172	ISLDNPDyQQDFFPK	10090	BTO:0002882								16122376	t	Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer	lperfetto	EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work	SIGNOR-236531	0.2
hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000938								26136660	t		miannu	The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 	SIGNOR-264920	0.8
PRKD1	protein	Q15139	UNIPROT	SSH1	protein	Q8WYL5	UNIPROT	down-regulates	phosphorylation	Ser978	SPLKRSHsLAKLGSL	9606	BTO:0000150								19567672	t		llicata	Pkd-mediated phosphorylation of serines 937 and 978 regulates ssh1l subcellular localization by binding of 14-3-3 proteins 14-3-3 proteins associate with ssh1l when phosphorylated at serines 937 and 978, thereby sequestering ssh1l in the cytoplasm and preventing translocation of the phosphatase to f-actin_rich membrane protrusions	SIGNOR-186471	0.494
ITGB1BP1	protein	O14713	UNIPROT	Av/b2 integrin	complex	SIGNOR-C176	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257653	0.285
CAV1	protein	Q03135	UNIPROT	ANXA3	protein	P12429	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000608								26095609	f		miannu	 There has been no study regarding the route of entry of exogenous ANXA3 in any cell type thus far. We found exogenous ANXA3 to be internalized into HCC cells through caveolin-1-mediated, but not HSPG-mediated, endocytosis.	SIGNOR-262215	0.295
MAPK1	protein	P28482	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates	phosphorylation	Thr451	KRTRSKGtLRYMSPE	9606									9528799	t		gcesareni	Our results provide strong evidence that dsrna binding is required for dimerization of full-length pkr molecules in vivo, leading to autophosphorylation in the activation loop and stimulation of the eif2alpha kinase function of pkr.	SIGNOR-56337	0.2
PPP2CB	protein	P62714	UNIPROT	PRKCD	protein	Q05655	UNIPROT	down-regulates activity	dephosphorylation	Ser664	QSAFAGFsFVNPKFE	10090	BTO:0000944								11959144	t			PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex	SIGNOR-248596	0.304
ERAP1	protein	Q9NZ08	UNIPROT	oligopeptide	smallmolecule	CHEBI:25676	ChEBI	down-regulates quantity	chemical modification			9606									31810556	t		scontino	While peptides loaded onto MHC class I molecules are 8–11 amino acid residues long (a restriction based on the size and conformation of the peptide-binding groove of MHC class I molecules), peptides translocated by TAP can be significantly longer. These peptides will be trimmed to the correct length by ERAP-1.	SIGNOR-267771	0.8
PBX1	protein	P40424	UNIPROT	HOXB1	protein	P14653	UNIPROT	up-regulates activity	binding			-1									10052460	t	2	miannu	Pbx1 and exd act as cofactors that enhance the DNA binding specificity of Hox proteins. The structure of the HoxB1–Pbx1–DNA ternary complex shows that HoxB1 and Pbx1 bind to overlapping binding sites located on opposite faces of the DNA.	SIGNOR-241219	0.799
INSR	protein	P06213	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	phosphorylation	Tyr989	VPSSRGDyMTMQMSC	10116	BTO:0000443								7651388	t		lperfetto	All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10).	SIGNOR-235979	0.911
RNF216	protein	Q9NWF9	UNIPROT	TLR4	protein	O00206	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									15107846	t		miannu	Here we describe how a RING finger protein, Triad3A, acts as an E3 ubiquitin-protein ligase and enhances ubiquitination and proteolytic degradation of some TLRs. Triad3A overexpression promoted substantial degradation of TLR4 and TLR9 with a concomitant decrease in signaling, but did not affect TLR2 expression or signaling. 	SIGNOR-271504	0.397
GTP	smallmolecule	CHEBI:15996	ChEBI	Translation release factor ERF1-ERF3	complex	SIGNOR-C494	SIGNOR	form complex	binding			9606									29735640	t		miannu	Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex.	SIGNOR-275394	0.8
CTTNBP2	protein	Q8WZ74	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates activity	binding			10116	BTO:0000938								22262902	t		miannu	Fluorescence recovery after photobleaching further suggested that CTTNBP2 modulates the mobility of cortactin in neurons. CTTNBP2 may thus help to immobilize cortactin in dendritic spines and control the density of dendritic spines.	SIGNOR-269703	0.526
FADS6	protein	Q8N9I5	UNIPROT	arachidonoyl-CoA	smallmolecule	CHEBI:15514	ChEBI	up-regulates quantity	chemical modification			9606									15189125	t		miannu	Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity.	SIGNOR-267914	0.8
CDH8	protein	P55286	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates quantity	transcriptional regulation			9606	BTO:0000567								17938208	t		gianni	CHD8 binds to histone H3 di- and trimethylated on lysine 4. It resides on the human U6 promoter as well as the mRNA IRF3 promoter in vivo and contributes to efficient transcription from both these promoters	SIGNOR-266898	0.2
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	UBTF	protein	P17480	UNIPROT	up-regulates	phosphorylation	Ser389	INKKQATsPASKKPA	9606									11698641	t		lperfetto	Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity	SIGNOR-217304	0.37
MAPK1	protein	P28482	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Thr476	EANYVPMtPGTFDFS	10029	BTO:0000246								15379552	t		lperfetto	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-249400	0.584
SF3B5	protein	Q9BWJ5	UNIPROT	SF3b	complex	SIGNOR-C442	SIGNOR	form complex	binding			9606									32140746	t		lperfetto	Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a).	SIGNOR-268407	0.929
WIPI2	protein	Q9Y4P8	UNIPROT	ATG16L1	protein	Q676U5	UNIPROT	up-regulates quantity	binding			9606	BTO:0001938								28561066	t		miannu	WIPI1 assists WIPI2 in recruiting ATG16L for LC3 lipidation. WIPI1-WIPI2 heterodimer may function more efficiently in ATG16L complex recruitment. 	SIGNOR-268478	0.724
MKRN1	protein	Q9UHC7	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys292	EEENLRKkGEPHHEL	9606	BTO:0002552								19536131	t		miannu	Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. K291 and K292 of p53 are required for MKRN1-mediated degradation and ubiquitination of p53	SIGNOR-271847	0.443
ATIC	protein	P31939	UNIPROT	IMP	smallmolecule	CHEBI:17202	ChEBI	up-regulates quantity	chemical modification			9606									33179964	t		miannu	The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP.	SIGNOR-267329	0.8
WYE-687	chemical	CID:25229450	PUBCHEM	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck;ATP-competitive inhibitor mTOR	gcesareni		SIGNOR-207818	0.8
MDH1	protein	P40925	UNIPROT	NADH	smallmolecule	CHEBI:16908	ChEBI	up-regulates quantity	chemical modification			9606									24068518	t		miannu	Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle	SIGNOR-266287	0.8
RUNX2	protein	Q13950	UNIPROT	RUNX2/EP300	complex	SIGNOR-C211	SIGNOR	form complex	binding			10116	BTO:0002648								12697832	t		Giulio Giuliani	More interestingly, the bone-specific transcriptionfactor Runx2/Cbfa1 is present in the immunoprecipitated material, strongly indicating that in osteoblastic cells expressing OC, p300 and Runx2/Cbfa1 are components of the same nuclear protein complex.	SIGNOR-255419	0.464
GSK3B	protein	P49841	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation	Ser641	YRYPRPAsVPPSPSL	-1									6772446	t			Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-.	SIGNOR-253005	0.673
HTR1F	protein	P30939	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256673	0.425
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH22	protein	Q9UJ99	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265838	0.8
CASP8	protein	Q14790	UNIPROT	CASP3	protein	P42574	UNIPROT	up-regulates activity	cleavage			9606									21295084	t		amattioni	Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction.	SIGNOR-171767	0.713
CSNK2A1	protein	P68400	UNIPROT	CD5	protein	P06127	UNIPROT	up-regulates	phosphorylation	Ser485	QPDNSSDsDYDLHGA	9606									9834084	t		lperfetto	In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461)	SIGNOR-62311	0.348
ATM	protein	Q13315	UNIPROT	NFAT5	protein	O94916	UNIPROT	up-regulates	phosphorylation	Ser1197	HIQTPMLsQEQAQPP	9606									15173573	t		lperfetto	Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp	SIGNOR-125073	0.275
STAT3	protein	P40763	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27141364	t		irozzo	STAT3 and HIF-1α cooperatively enhance PD-L1 expression in EML4-ALK-translocated pADC cells under hypoxia.The protein-DNA binding assay revealed that pSTAT3 was bound to the PD-L1 promoter region in H23 cells transfected with EML4-ALK.	SIGNOR-259188	0.479
FADS3	protein	Q9Y5Q0	UNIPROT	arachidonoyl-CoA	smallmolecule	CHEBI:15514	ChEBI	up-regulates quantity	chemical modification			9606									15189125	t		miannu	Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity.	SIGNOR-267913	0.8
PLCG1	protein	P19174	UNIPROT	1D-myo-inositol 1,4,5-trisphosphate	smallmolecule	CHEBI:16595	ChEBI	up-regulates	chemical modification			9606									21918248	t		gcesareni	Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag.	SIGNOR-176609	0.8
TWIST1	protein	Q15672	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002590								17487558	f		miannu	 Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells	SIGNOR-255516	0.296
CFI complex	complex	SIGNOR-C388	SIGNOR	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates quantity	cleavage			9606									8626397	t		lperfetto	Purification and characterization of human cleavage factor Im involved in the 3' end processing of messenger RNA precursors|Gel retardation experiments confirmed the results obtained by UV cross-linking. In addition, we could show that CF Im stabilizes the binding of the cleavage and polyadenylation specificity factor (CPSF) to pre-mRNA and that CPSF and CF Im together form a slower migrating complex with pre-mRNA than the single protein factors. 	SIGNOR-266125	0.8
PTPN11	protein	Q06124	UNIPROT	SYK	protein	P43405	UNIPROT	down-regulates activity	dephosphorylation			9606									23182168	t		miannu	Another SHP isoform, SHP-2, has been linked to negative regulation of Syk.|Syk and LAT are differentially dephosphorylated by SHP-2 and SHP-1, respectively.	SIGNOR-277085	0.526
Caspase 8 complex	complex	SIGNOR-C231	SIGNOR	CASP7	protein	P55210	UNIPROT	up-regulates	cleavage			9606									18073771	t		amattioni	Active caspase-8 then proteolytically processes and activates caspase-7	SIGNOR-256454	0.729
PRKCA	protein	P17252	UNIPROT	CLIP1	protein	P30622	UNIPROT	down-regulates	phosphorylation	Ser312	ASLKRSPsASSLSSM	9606									20519438	t		lperfetto	Furthermore, by using phosphoproteomic analysis, we determined that s309 and s311 of clip-170 are phosphorylated in cells and mapped s311 as a protein kinase a (pka) phosphorylation site.phosphorylation of s311 may be critical for establishing the ?folded Back? Conformation of clip-170clip-170 open and folded back conformations represent active and inactive modes of the protein, respectively	SIGNOR-165857	0.2
caesium(1+)	chemical	CHEBI:49547	ChEBI	KCNJ13	protein	O60928	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9620703	t		miannu	Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations	SIGNOR-258926	0.8
SCAF11	protein	Q99590	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates activity	cleavage	Asp333	DTVAENDdGGFSEEW	-1									10069390	t		lperfetto	Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.	SIGNOR-261742	0.297
FBXW11	protein	Q9UKB1	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates	ubiquitination			9606									11359933	t		gcesareni	Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3.	SIGNOR-108240	0.264
AKT2	protein	P31751	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates				9606									17845852	f		gcesareni	Ras and akt signaling enhances the nuclear localization of gli1, counteracting its suppression by other modifiers that retain it in the cytoplasm, such as suppressor of fused (sufu).	SIGNOR-157770	0.279
9-cis-retinoic acid	chemical	CHEBI:50648	ChEBI	RARA	protein	P10276	UNIPROT	up-regulates activity	chemical activation			9606									18321241	t		miannu	Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma).	SIGNOR-259234	0.8
INSR	protein	P06213	UNIPROT	IRS2	protein	Q9Y4H2	UNIPROT	down-regulates activity	phosphorylation	Tyr628	PKVAYHPyPEDYGDI	-1									9195949	t			Tyr624 and Tyr628 are involved in the interaction between the IR and the KRLB domain of IRS-2, including tyrosine phosphorylation, and Tyr628 seems to be more important than Tyr624 in this process. the binding between the insulin receptor and the KRLB domain of IRS-2 results in tyrosine phosphorylation of the KRLB domain, and this leads to decreased binding of IRS-2 to the insulin receptor.	SIGNOR-251318	0.748
CHUK	protein	O15111	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser927	DSDSVCDsGVETSFR	9606	BTO:0000567			SIGNOR-C13					10469655	t		lperfetto	All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391).	SIGNOR-70453	0.737
MK-2461	chemical	CID:44137946	PUBCHEM	MERTK	protein	Q12866	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194381	0.8
BAD	protein	Q92934	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity	relocalization			9606	BTO:0000007								15694340	t		lperfetto	Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1.	SIGNOR-133756	0.792
NR3C1	protein	P04150	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									8639160	t		gcesareni	We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins	SIGNOR-251679	0.733
CEBPA	protein	P49715	UNIPROT	Granulocyte_differentiation	phenotype	SIGNOR-PH102	SIGNOR	up-regulates				9606									11283671	f		apalma	We previously reported that the transcription factor C/EBPα is sufficient to induce granulocytic differentiation in multipotential precursor cells, and that Cebpa -knockout mice have a selective block in granulocyte maturation	SIGNOR-255674	0.7
GSK3B	protein	P49841	UNIPROT	RBM38	protein	Q9H0Z9	UNIPROT	down-regulates	phosphorylation	Ser195	DQYPYAAsPATAASF	9606									24142875	t		lperfetto	Here, we showed that rnpc1 is phosphorylated at ser195 by glycogen synthase kinase 3 (gsk3). We also provided evidence that ser195 phosphorylation converts rnpc1 from a repressor to an activator of p53.	SIGNOR-203011	0.2
GSK3B	protein	P49841	UNIPROT	NFATC2	protein	Q13469	UNIPROT	down-regulates	phosphorylation			9606									15276472	t		lperfetto	Gsk3 was previously shown to directly phosphorylate the n-terminal regulatory domain of nfatc1, thus antagonizing the action of calcineurin and inhibiting nuclear shuttling of nfat.	SIGNOR-179784	0.543
HIF1A	protein	Q16665	UNIPROT	Metabolism	phenotype	SIGNOR-PH77	SIGNOR	up-regulates				9606									17415528	f			HIF-1 has been known as a major transcription factor for the induction of virtually all genes encoding glucose transporters and glycolytic enzymes, which allows hypoxic tumor cells to take up glucose more efficiently and metabolize pyruvate to lactate	SIGNOR-256591	0.7
PDPK1	protein	O15530	UNIPROT	AKT2	protein	P31751	UNIPROT	up-regulates activity	phosphorylation	Ser474	RTHFPQFsYSASIRE	9606									15743829	t		lperfetto	Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. Pdk1 phosphorylates akt-2 at thr 309 in the catalytic domain, leading to enzymatic activation.	SIGNOR-134481	0.718
FGF3	protein	P11487	UNIPROT	FGFR2	protein	P21802	UNIPROT	up-regulates	binding			9606									8663044	t		gcesareni	Using fgf 1 as an internal standard we have determined the relative activity of all the other members of the fgf family. These data should serve as a biochemical foundation for determining developmental, physiological, and pathophysiological processes that involve fgf signaling pathways	SIGNOR-42374	0.759
FGA	protein	P02671	UNIPROT	Platelet_aggregation	phenotype	SIGNOR-PH81	SIGNOR	up-regulates													16418530	f		lperfetto	In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation.	SIGNOR-253372	0.7
PRKCZ	protein	Q05513	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser359	EERQTQRsKPQPAVP	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89280	0.402
propranolol	chemical	CHEBI:8499	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9205951	t		miannu	The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively.	SIGNOR-258614	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000763;BTO:0000149							10197981	t	inferred from 70% family members	gcesareni	Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus	SIGNOR-270137	0.2
Elongator complex	complex	SIGNOR-C466	SIGNOR	TUBA1A	protein	Q71U36	UNIPROT	up-regulates activity	acetylation			9606	BTO:0000007								19185337	t		miannu	Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. 	SIGNOR-269717	0.339
EIF2AK2	protein	P19525	UNIPROT	KDM4C	protein	Q9H3R0	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser918	MFDDGSFsRDTFPED	9606	BTO:0003016								31888886	t		miannu	In the absence of Wnt3a, protein kinase R phosphorylated KDM4C at Ser918, inducing KDM4C ubiquitination and degradation.	SIGNOR-277497	0.2
TGFb	proteinfamily	SIGNOR-PF5	SIGNOR	SMAD3	protein	P84022	UNIPROT	up-regulates				9606				SIGNOR-C9					12524424	f		fspada	Because tgf-beta inhibits adipogenesis by signaling through smad3, we examined physical and functional interactions of smad3 and smad4 with c/ebpbeta, c/ebpdelta, and ppargamma2.	SIGNOR-97123	0.2
NCOR2	protein	Q9Y618	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates	acetylation			9606	BTO:0000150;BTO:0001130								12771131	t		gcesareni	In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases.	SIGNOR-101286	0.579
nafadotride	chemical	CHEBI:64191	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3).	SIGNOR-258854	0.8
C7	protein	P10643	UNIPROT	Membrane attack complex	complex	SIGNOR-C313	SIGNOR	form complex	binding			-1									30552328	t		lperfetto	The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer	SIGNOR-263443	0.447
YWHAZ	protein	P63104	UNIPROT	GEM	protein	P55040	UNIPROT	up-regulates quantity by stabilization	binding			9534	BTO:0000298								14701738	t		miannu	In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase	SIGNOR-261715	0.307
RAD23B	protein	P54727	UNIPROT	PAX3	protein	P23760	UNIPROT	down-regulates activity	binding			-1									17662948	t		llicata	Monoubiquitinated Pax3 was shuttled to the intrinsic proteasomal protein S5a by interacting specifically with the ubiquitin-binding protein Rad23B.	SIGNOR-237667	0.297
HECW2	protein	Q9P2P5	UNIPROT	TP73	protein	O15350	UNIPROT	up-regulates quantity by stabilization	ubiquitination			9534	BTO:0000298								12890487	t		miannu	P73 was efficiently ubiquitinated but stabilized in a NEDL2-dependent manner. Accordingly, p73 decayed at faster rates in the absence of NEDL2 than in its presence. Consistent with the NEDL2-mediated stabilization of p73, NEDL2 enhanced the p73-dependent transcriptional activation. Thus, our results suggest that NEDL2 activates the function of p73 by increasing its stability.	SIGNOR-269457	0.378
NMUR2	protein	Q9GZQ4	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257352	0.409
AV412	chemical	CID:11700696	PUBCHEM	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190050	0.8
CDK1	protein	P06493	UNIPROT	KIF2C	protein	Q99661	UNIPROT	down-regulates	phosphorylation	Thr537	LGQNKAHtPFRESKL	9606									20368358	t		llicata	We show here that cyclin-dependent kinase 1 (cdk1) phosphorylates t537 in the core domain of mcak and attenuates its microtubule-destabilizing activity in vitro and in vivo. Phosphorylation of mcak by cdk1 promotes the release of mcak from centrosomes and is required for proper spindle formation.	SIGNOR-164761	0.673
AKT2	protein	P31751	UNIPROT	PKP1	protein	Q13835	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser191	YSFYSTCsGQKAIKK	-1									23444369	t		miannu	Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry.	SIGNOR-273487	0.27
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	estrone	smallmolecule	CHEBI:17263	ChEBI	up-regulates quantity	precursor of			-1									8099587	t		Luana	17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone. 	SIGNOR-269761	0.8
EFR3A	protein	Q14156	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								34504076	t		miannu	 EFR3A directly binds to active KRAS through its C-terminus. EFR3A promotes the localization and nanoclustering of KRAS at the plasma membrane.	SIGNOR-269094	0.2
PTPN6	protein	P29350	UNIPROT	CASP8	protein	Q14790	UNIPROT	up-regulates activity	dephosphorylation	Tyr380	TDSEEQPyLEMDLSS	9606									18086677	t			Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis. 	SIGNOR-248477	0.361
SRC	protein	P12931	UNIPROT	BAIAP2L1	protein	Q9UHR4	UNIPROT	up-regulates activity	phosphorylation	Tyr37	LINLGKNyEKAVNAM	-1									21840312	t		miannu	Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility.	SIGNOR-263041	0.399
AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257717	0.552
PTPN11	protein	Q06124	UNIPROT	HOXA10	protein	P31260	UNIPROT	up-regulates	dephosphorylation			9606									19022774	t		fspada	We also identified hoxa10 as a substrate for shp2 in undifferentiated myeloid cells, an effect that diminished during myelopoiesis. However, a constitutively active form of shp2 dephosphorylated hoxa10 throughout ex vivo myelopoiesis and sustained repression of hoxa10 target genes involved in phagocyte effector functions.	SIGNOR-182475	0.38
POMT 	complex	SIGNOR-C372	SIGNOR	DGC	complex	SIGNOR-C217	SIGNOR	up-regulates activity	glycosylation			9606	BTO:0000007								14699049	t		miannu	 we showed that coexpression of both POMT1 and POMT2 (another gene homologous to yeast protein O-mannosyltransferases) was necessary for the enzyme activity, but expression of either POMT1 or POMT2 alone was insufficient. The requirement of an active enzyme complex of POMT1 and POMT2 suggests that the regulation of protein O-mannosylation is complex. Further, protein O-mannosylation appears to be required for normal structure and function of α-dystroglycan in muscle and brain.	SIGNOR-265431	0.413
FZD1	protein	Q9UP38	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates				9606	BTO:0000222								10937998	f		fspada	Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma)	SIGNOR-80598	0.281
IKBKB	protein	O14920	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser341	GTMSRPAsVDGSPVS	-1									12351658	t			IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.	SIGNOR-251294	0.644
GGCX	protein	P38435	UNIPROT	F2	protein	P00734	UNIPROT	up-regulates activity	carboxylation	Glu63	LERECVEeTCSYEEA	-1									10556651	t		lperfetto	We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 	SIGNOR-263680	0.655
SRC	protein	P12931	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Tyr341	GQRDSSYyWEIEASE	9606									12551923	t		gcesareni	We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain.	SIGNOR-97639	0.588
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates activity	binding			9606									22926518	t		miannu	The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors.	SIGNOR-256181	0.63
TNF	protein	P01375	UNIPROT	SCN11A	protein	Q9UI33	UNIPROT	up-regulates activity				10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253492	0.2
sertindole	chemical	CHEBI:9122	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10116									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258549	0.8
APC-c	complex	SIGNOR-C150	SIGNOR	KIF18A	protein	Q8NI77	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1									24510915	t		miannu	Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A). 	SIGNOR-266110	0.301
SRC	protein	P12931	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr577	YMEDSTYyKASKGKL	9606									15735019	t		miannu	Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates	SIGNOR-134212	0.633
CHEK1	protein	O14757	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606	BTO:0001321								15659650	t		lperfetto	CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37	SIGNOR-217795	0.772
HDAC8	protein	Q9BY41	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	deacetylation			10090	BTO:0002882								26387755	t			HDAC8 mediates CM-induced deacetylation of p53.Collectively, these results indicate that although binding to p53 and HDAC8 occurs through distinct regions of the CM protein, simultaneous interaction with HDAC8 and p53 is required for aberrant deacetylation and inactivation of p53.	SIGNOR-255738	0.468
JAK2	protein	O60674	UNIPROT	EPOR	protein	P19235	UNIPROT	up-regulates activity	phosphorylation	Tyr454	PTPPHLKyLYLVVSD										12441334	t			JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2	SIGNOR-251350	0.806
ZEB2	protein	O60315	UNIPROT	VDR	protein	P11473	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11432806	t		Luisa	ZEB, a Krüppel-type transcription factor known to repress the transcription of several genes, binds to two sites within the VDR promoter and activates the transcription of this receptor in a cell-specific manner. Transfection of ZEB into SW620 colon carcinoma cells results in an up-regulation of the expression of endogenous VDR, confirming the role of ZEB in the transcriptional activation of the VDR gene.	SIGNOR-268954	0.2
PRKCD	protein	Q05655	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates quantity	phosphorylation	Ser558	VPTYESAsIRRFQEG	9606	BTO:0000930								15381704	t		lperfetto	Finally, basal ChAT phosphorylation in neurons is mediated predominantly by PKC at Ser-476, with PKC activation increasing phosphorylation at Ser-440 and enhancing ChAT activity.	SIGNOR-249271	0.315
MARCHF9	protein	Q86YJ5	UNIPROT	FCGR2B	protein	P31994	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001522								19457934	t		miannu	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. 	SIGNOR-271541	0.2
NUMA1	protein	Q14980	UNIPROT	TUBA1B	protein	P68363	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116472	0.266
KIF5C	protein	O60282	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272518	0.7
RUNX1	protein	Q01196	UNIPROT	MECOM	protein	Q03112	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22689058	f		irozzo	Our results suggest that RUNX1 and EVI1 could be regulating each other. RUNX1 would activate EVI1 transcription, and when highly expressed, EVI1 could bind to RUNX1 at protein level, inhibiting its activity as a transcription factor, acting in a negative feedback.	SIGNOR-255715	0.509
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr498	KTPPAPKtPPSSGEP	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249326	0.754
JAK1	protein	P23458	UNIPROT	IL10RA	protein	Q13651	UNIPROT	up-regulates activity	phosphorylation	Tyr496	PPALAKGyLKQDPLE										10433356	t			Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3). 	SIGNOR-251339	0.801
PAK1	protein	Q13153	UNIPROT	NET1	protein	Q7Z628	UNIPROT	down-regulates activity	phosphorylation	Ser539	LTAQRRAsTVSSVTQ	-1									15684429	t		miannu	In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner. 	SIGNOR-263018	0.252
PRKCA	protein	P17252	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates activity	phosphorylation	Ser368	QRPSSRAsSRASSRP	10116									10871288	t		lperfetto	Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.	SIGNOR-249048	0.551
AKT1	protein	P31749	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser166	SSRRRAIsETEENSD	9606									15169778	t		gcesareni	Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation.	SIGNOR-124949	0.804
BCL2L1	protein	Q07817	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates activity	binding			9606									9539746	t		lperfetto	Bcl2l1 associates with casp9 and apaf-1 in mammalian cells.Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation	SIGNOR-56402	0.704
CDK9	protein	P50750	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser187	NSHPFPHsPNSSYPN	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161565	0.325
CREB5	protein	Q02930	UNIPROT	DGKG	protein	P49619	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		 BTO:0002810							21132541	f		miannu	 Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition),	SIGNOR-253803	0.2
PAK1	protein	Q13153	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606									10611223	t		lperfetto	Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau.	SIGNOR-73529	0.341
CABIN1	protein	Q9Y6J0	UNIPROT	HIRA complex 1	complex	SIGNOR-C461	SIGNOR	form complex	binding			9606									30285846	t		miannu	H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex.	SIGNOR-269435	0.685
PRKACA	protein	P17612	UNIPROT	PHKA1	protein	P46020	UNIPROT	up-regulates activity	phosphorylation			9606									10487978	t		miannu	Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.	SIGNOR-267411	0.418
CLOCK	protein	O15516	UNIPROT	PER1	protein	O15534	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f			Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253633	0.719
ANGPT1	protein	Q15389	UNIPROT	TIE1	protein	P35590	UNIPROT	up-regulates	binding			9606									11172728	t		gcesareni	We reasoned that there may be cooperative interactions among the angiopoietins (i.e., ligands for tie2) and tie1, the orphan receptor.	SIGNOR-105199	0.465
UXT	protein	Q9UBK9	UNIPROT	URI1 prefoldin co-chaperone	complex	SIGNOR-C514	SIGNOR	form complex	binding			9606									30484151	t		miannu	In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR93	SIGNOR-270916	0.627
AURKA	protein	O14965	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									12588998	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.	SIGNOR-98289	0.2
SHC1	protein	P29353	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates activity				10090	BTO:0000944								17673906	f		lperfetto	We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases.	SIGNOR-242625	0.614
CSNK2A1	protein	P68400	UNIPROT	GYS1	protein	P13807	UNIPROT	unknown	phosphorylation	Thr713	SKRNSVDtATSSSLS	-1									2117608	t		llicata	With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action.	SIGNOR-250884	0.334
CKM complex	complex	SIGNOR-C406	SIGNOR	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation			-1									25344755	t		lperfetto	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273160	0.379
CDON	protein	Q4KMG0	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	binding			9606	BTO:0000222								18678706	t		lperfetto	During myoblast differentiation, the promyogenic cell surface receptor cdo binds to the p38alpha/beta pathway scaffold protein jlp and, via jlp, p38alpha/beta itself	SIGNOR-179867	0.442
PTPN1	protein	P18031	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates activity	dephosphorylation	Tyr332	ILAIHDSyKPEFHSD	10029									12907755	t			PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 	SIGNOR-248418	0.478
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257980	0.8
(S)-adrenaline	smallmolecule	CHEBI:40751	ChEBI	ADRA1B	protein	P35368	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258453	0.8
SARS1	protein	P49591	UNIPROT	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									24095058	t		miannu	As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis	SIGNOR-270496	0.8
TSHB	protein	P01222	UNIPROT	SLC5A5	protein	Q92911	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14623893	t		miannu	I– uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane	SIGNOR-251995	0.39
HIPK1	protein	Q86Z02	UNIPROT	PAGE4	protein	O60829	UNIPROT	up-regulates activity	phosphorylation	Thr51	PGQEREGtPPIEERK	9606									24559171	t		Manara	Here, we have identified homeodomain-interacting protein kinase 1 (HIPK1), also a component of the stress-response pathway, as a kinase that phosphorylates PAGE4 at T51 | We show that phosphorylation of PAGE4 is critical for its transcriptional activity since mutating this T residue abolishes its ability to potentiate c-Jun transactivation. 	SIGNOR-260929	0.47
CDK1	protein	P06493	UNIPROT	PPP1CA	protein	P62136	UNIPROT	down-regulates activity	phosphorylation	Thr320	NPGGRPItPPRNSAK	9606									12202491	t		gcesareni	Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity.	SIGNOR-151799	0.556
PPP1CA	protein	P62136	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606									12840032	t		gcesareni	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)	SIGNOR-103152	0.457
RXRB	protein	P28702	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates	binding			9606									10882139	t		lperfetto	The nuclear receptor ppargamma/rxralpha heterodimer regulates glucose and lipid homeostasis	SIGNOR-78907	0.652
AE/b7 integrin	complex	SIGNOR-C186	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269030	0.7
PRKCZ	protein	Q05513	UNIPROT	ADD2	protein	P35612	UNIPROT	down-regulates	phosphorylation	Ser713	KKKFRTPsFLKKSKK	9606									16116087	t		gcesareni	We now demonstrate that ptn stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (pk) c substrate domain of beta-adducin through activation of either pkc alpha or beta.	SIGNOR-139914	0.279
VEZF1	protein	Q14119	UNIPROT	EDN1	protein	P05305	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004294								11504723	t		miannu	Vascular endothelial zinc finger 1 (Vezf1)/DB1 is a recently identified zinc finger-containing protein that is expressed specifically within endothelial cells during development. In this report, we demonstrate that Vezf1/DB1 is a nuclear localizing protein that potently and specifically activates transcription mediated by the human endothelin-1 promoter, in a Tax-independent manner, in transient transfection assays. Regulation of endothelin-1 promoter activity by Vezf1/DB1 provides a mechanism for endothelin-1 expression in the vascular endothelium during development and to maintain vascular tone	SIGNOR-266884	0.281
PPM1L	protein	Q5SGD2	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates	dephosphorylation	Thr838	GINPCTEtFTGTLQY	9606		BTO:0000142;BTO:0000671							17456047	t		gcesareni	Exogenous pp2cepsilon associated with exogenous ask1 in hek-293 cells under non-stressed conditions, inactivating ask1 by decreasing thr845 phosphorylation	SIGNOR-154554	0.324
IL6ST	protein	P40189	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates activity	phosphorylation	Ser659	WPNVPDPsKSHIAQW	-1									8511589	t		lperfetto	The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130.	SIGNOR-238621	0.2
selumetinib	chemical	CHEBI:90227	ChEBI	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	lperfetto		SIGNOR-244823	0.8
PF-04691502	chemical	CID:25033539	PUBCHEM	AKT1	protein	P31749	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck;inhibitor of phosphorylation of AktT308 and AktS473	gcesareni		SIGNOR-252631	0.8
PPP2CB	protein	P62714	UNIPROT	PPP1R1A	protein	Q13522	UNIPROT	unknown	dephosphorylation	Ser67	LKSTLAMsPRQRKKM	10116									11278334	t			In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation.	SIGNOR-248602	0.305
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	XBP1	protein	P17861	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser181	QQVQAQLsPLQNISP	9606	BTO:0001109								23277279	t		miannu	Phosphorylation of XBP-1u by ERK is critical for the increased interaction of XBP-1u and FoxO1.	SIGNOR-276439	0.2
BRK1	protein	Q8WUW1	UNIPROT	NHS	protein	Q6T4R5	UNIPROT	up-regulates activity	binding			9606									20332100	t		miannu	We show that the WHD of NHS interacts with the Abi family of proteins, HSPC300, Nap1 and Sra1, and is important for the localization of NHS to the leading edge.	SIGNOR-253574	0.2
GEM	protein	P55040	UNIPROT	CACNB2	protein	Q08289	UNIPROT	down-regulates activity	binding			9606									14701738	t		miannu	 Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively.	SIGNOR-261710	0.2
PGM2	protein	Q96G03	UNIPROT	D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	up-regulates quantity	chemical modification			9606									17804405	t		miannu	Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase.	SIGNOR-267076	0.8
CHD8	protein	Q9HCK8	UNIPROT	NEUROG1	protein	Q92886	UNIPROT	down-regulates quantity	transcriptional regulation			10090									32839322	t		Gianni	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268919	0.2
ATM	protein	Q13315	UNIPROT	RNF20	protein	Q5VTR2	UNIPROT	up-regulates activity	phosphorylation	Ser172	SSSEEMEsQLQERVE	9606	BTO:0000007								21362549	t		miannu	ATM-Mediated Phosphorylation of RNF20 and RNF40 in Response to DNA Damage and Its Requirement for Damage-Induced H2B Monoubiquitylation 	SIGNOR-276314	0.537
MYO5A	protein	Q9Y4I1	UNIPROT	ACTB	protein	P60709	UNIPROT	up-regulates activity	binding			9606									21077886	t		miannu	 Myosin Va regulates exocytosis of large dense-core vesicles (LDCVs). interestingly, inhibition of myosin Va potentiates LDCV exocytosis to the same extent as F-actin depolymerization does, suggesting that myosin Va cooperates with the actin cytoskeleton to impede or control LDCV exocytosis	SIGNOR-269280	0.419
(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one	chemical	CHEBI:125500	ChEBI	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029									9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258774	0.8
HDLBP	protein	Q00341	UNIPROT	CSF1R	protein	P07333	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000150								33941620	t		miannu	Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer.	SIGNOR-266696	0.35
PLK1	protein	P53350	UNIPROT	PLEKHG6	protein	Q3KR16	UNIPROT	up-regulates	phosphorylation	Thr574	HLVVTEDtDEDAPLV	9606	BTO:0000567								18694934	t		lperfetto	We reported previously that a guanine nucleotide exchange factor, myogef, localizes to the central spindle, activates rhoa, and is required for cytokinesis. In this study, we have found that plk1 (polo-like kinase 1) can phosphorylate myogef, thereby recruiting myogef to the central spindle as well as enhancing myogef activity toward rhoa. The in vitro kinase assay shows that plk1 can phosphorylate myogef on threonine 574.	SIGNOR-179954	0.427
SLBP	protein	Q14493	UNIPROT	H2BC4	protein	P62807	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265377	0.2
PRKCZ	protein	Q05513	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser594	HKAAVPAsEKLLLLK	9606									15381704	t	The effect has been demonstrated using P28329-3	gcesareni	Finally, basal chat phosphorylation in neurons is mediated predominantly by pkc at ser-476, with pkc activation increasing phosphorylation at ser-440 and enhancing chat activity.	SIGNOR-129340	0.291
CSNK1D	protein	P48730	UNIPROT	KIR3DL1	protein	P43629	UNIPROT	up-regulates	phosphorylation	Ser388	RTANSEDsDEQDPEE	9606									17911614	t		gcesareni	In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.	SIGNOR-158125	0.2
SP3	protein	Q02447	UNIPROT	LORICRIN	protein	P23490	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12200429	f		miannu	Loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins.	SIGNOR-254537	0.2
RPL3L	protein	Q92901	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262494	0.753
ARID5B	protein	Q14865	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									29326336	f		miannu	We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F).	SIGNOR-256159	0.2
CDK7	protein	P50613	UNIPROT	RARG	protein	P13631	UNIPROT	up-regulates activity	phosphorylation	Ser77	SEEMVPSsPSPPPPP	9534									10748061	t		Luana	RARg Is Phosphorylated by cdk7 in Its B and F Regions | Mutation into alanine of Ser-77 and Ser-79 located in the A/B region reduced the transcriptional activity of hRARg1 (Fig. 9A), confirming that these phosphorylation sites are required for optimal transcription.	SIGNOR-259853	0.393
MAP2K2	protein	P36507	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates	phosphorylation	Thr185	HDHTGFLtEYVATRW	9606									11971971	t		gcesareni	Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.	SIGNOR-86709	0.733
IL13	protein	P35225	UNIPROT	IL13RA1	protein	P78552	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0000801;BTO:0000876	BTO:0000887;BTO:0000763;BTO:0001260							12704343	t		milica	It is now known that this alternate receptor is a heterodimer, the type ii il-4 receptor or the il-13 receptor, which is comprised of IL-4R And IL-13R1.	SIGNOR-100750	0.847
INSR	protein	P06213	UNIPROT	CALM3	protein	P0DP25	UNIPROT	down-regulates	phosphorylation	Tyr100	FDKDGNGyISAAELR	9606									3415247	t		miannu	The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.	SIGNOR-266336	0.383
SRC	protein	P12931	UNIPROT	TNS3	protein	Q68CZ2	UNIPROT	up-regulates	phosphorylation	Tyr1206	SHSFRGAyGLAMKVA	9606	BTO:0000150;BTO:0000551;BTO:0000848								19732724	t		llicata	Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate	SIGNOR-187847	0.417
CBFA2T3	protein	O75081	UNIPROT	CBFA2T3/ZNF651	complex	SIGNOR-C197	SIGNOR	form complex	binding			9606	BTO:0000007								20116376	t			Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex.	SIGNOR-253956	0.467
MAPK1	protein	P28482	UNIPROT	MKNK2	protein	Q9HBH9	UNIPROT	up-regulates	phosphorylation			9606									9155017	t		gcesareni	We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity	SIGNOR-48338	0.582
CSNK2A1	protein	P68400	UNIPROT	MECOM	protein	Q03112	UNIPROT	up-regulates activity	phosphorylation	Ser726	PLKMEPQsPGEVKKL										23858473	t	phosphorylation site remapping based on Fig 5	lperfetto	We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. 	SIGNOR-273428	0.2
NLGN4X	protein	Q8N0W4	UNIPROT	NRXN3	protein	Q9Y4C0	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264165	0.76
STK11	protein	Q15831	UNIPROT	PRMT5	protein	O14744	UNIPROT	up-regulates activity	phosphorylation	Thr139	TNLARVLtNHIHTGH	-1									30289978	t		miannu	We found that PRMT5 is a bona fade substrate for LKB1. We identified T132, 139 and 144 residues, located in the TIM-Barrel domain of PRMT5, as target sites for LKB1 phosphorylation. The point mutation of PRMT5 T139/144 to A139/144 drastically decreased its methyltransferase activity, due probably to the loss of its interaction with regulatory proteins such as MEP50, pICln and RiOK1. 	SIGNOR-277411	0.2
MAPK3	protein	P27361	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser374	PSSDSLSsPTLLAL	9606									12972619	t		lperfetto	In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity.	SIGNOR-118023	0.707
PTGES3	protein	Q15185	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	up-regulates activity	binding			-1									9817749	t		lperfetto	The mutant Hsp90 proteins tested are defective in the binding and ATP hydrolysis-dependent cycling of the co-chaperone p23, which is thought to regulate the binding and release of substrate polypeptide from Hsp90. 	SIGNOR-262831	0.913
TGFBR2	protein	P37173	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates activity	phosphorylation	Thr176	PFISEGTtLKDLIYD	-1									8576253	t		giulio giuliani	From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TβR-I in TGF-β signaling. Although it was reported that TGF-β-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TβR-II may phosphorylate these residues as minor phosphorylation site(s).	SIGNOR-255961	0.709
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1616	TPQSPSYsPTSPSYS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248734	0.727
MELK	protein	Q14680	UNIPROT	MELK	protein	Q14680	UNIPROT	up-regulates	phosphorylation	Ser407	SNGVESKsLTPALCR	9606									16216881	t		lperfetto	We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase.	SIGNOR-141006	0.2
PLK1	protein	P53350	UNIPROT	RIOK2	protein	Q9BVS4	UNIPROT	up-regulates activity	phosphorylation	Ser380	PEQIKEDsLSEESAD	-1									21880710	t		miannu	 Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. 	SIGNOR-262938	0.441
IKBKE	protein	Q14164	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606	BTO:0000801								20717897	t		lperfetto	The activated ikk complex then phosphorylates ikbalfa (an inhibitor of nf-kb) thereby targeting it for ubiquitination and proteasomal degradation.	SIGNOR-167524	0.498
EML4-ALK	fusion protein	SIGNOR-FP8	SIGNOR	SMYD2	protein	Q9NRG4	UNIPROT	up-regulates activity	methylation			9606	BTO:0001911								28370702	t		irozzo	In the present study, we have shown that SMYD2‐mediated methylation of lysine 1610 on the EML4‐ALK fusion protein is likely to be critically important for autophosphorylation of some tyrosine residues and the oncogenic activity of the fused proteins.	SIGNOR-259175	0.2
AMP	smallmolecule	CHEBI:456215	ChEBI	MLXIPL	protein	Q9NP71	UNIPROT	down-regulates activity	chemical inhibition			10116									26984404	t			We discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3.	SIGNOR-255668	0.8
PAPOLB	protein	Q9NRJ5	UNIPROT	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates quantity by stabilization	chemical modification			9606									19224921	t		lperfetto	Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner.	SIGNOR-268328	0.8
SRT1720	chemical	CID:25232708	PUBCHEM	SIRT1	protein	Q96EB6	UNIPROT	up-regulates activity	chemical activation			9606									18046409	t	Selleck	gcesareni	Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol.	SIGNOR-207114	0.8
RPS6KA2	protein	Q15349	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606									19282669	t		gcesareni	The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival.	SIGNOR-184591	0.381
PRSS1	protein	P07477	UNIPROT	F2RL1	protein	P55085	UNIPROT	up-regulates activity	cleavage	Lys34	QGTNRSSkGRSLIGK	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263605	0.373
TBK1	protein	Q9UHD2	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates	binding			9606									14743216	t		fstefani	A physical and functional map of the human tnf-alpha/nf-kappa b signal transduction pathway.	SIGNOR-121576	0.412
GPR174	protein	Q9BXC1	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256900	0.2
PIP3	smallmolecule	CHEBI:16618	ChEBI	AKT2	protein	P31751	UNIPROT	up-regulates activity	chemical activation			9606									21779497	t		lperfetto	When active, pi3k converts phosphatidylinositol (4,5)-bisphosphate (pip2) into phosphatidylinositol (3,4,5)-trisphosphate (pip3). Pip3, in turn, binds the pleckstrin homology (ph) domain of akt/pkb, stimulating its kinase activity, resulting in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival.	SIGNOR-175247	0.8
tiotropium	chemical	CHEBI:90960	ChEBI	CHRM1	protein	P11229	UNIPROT	down-regulates activity	chemical inhibition			-1									8441333	t		miannu	A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors.	SIGNOR-258485	0.8
MAPK1	protein	P28482	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Thr359	DTEFTSRtPKDSPGI	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252751	0.751
PSEN1	protein	P49768	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	cleavage			9606				SIGNOR-C98					10593990	t	Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface.	gcesareni	Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains.	SIGNOR-72886	0.79
CREBRF	protein	Q8IUR6	UNIPROT	HERPUD1	protein	Q15011	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								16940180	t		Luana	Luman/CREB3 induces transcription of the endoplasmic reticulum (ER) stress response protein Herp through an ER stress response element.	SIGNOR-261575	0.2
Dynorphin A	smallmolecule	CHEBI:4727	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258794	0.8
PRKACA	protein	P17612	UNIPROT	NEDD4L	protein	Q96PU5	UNIPROT	down-regulates	phosphorylation	Ser448	IRRPRSLsSPTVTLS	9606									15328345	t		gcesareni	Nedd4-2 was a substrate for phosphorylation by pka in vitro and in cells;three nedd4-2 residues were phosphorylated by pka and were required for camp to inhibit nedd4-2 (relative functional importance ser-327 > ser-221 > thr-246).	SIGNOR-128429	0.2
SAE1/SAE2 complex	complex	SIGNOR-C294	SIGNOR	MBD4	protein	O95243	UNIPROT	up-regulates activity	sumoylation	Lys137	KNGETSLkPEDFDFT										31476572	t		lperfetto	MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro.	SIGNOR-275679	0.2
PTPRG	protein	P23470	UNIPROT	LIMK1	protein	P53667	UNIPROT	down-regulates activity	dephosphorylation	Tyr507	KPDRKKRyTVVGNPY	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254711	0.263
PIK3R4	protein	Q99570	UNIPROT	Vps34 Complex II	complex	SIGNOR-C241	SIGNOR	form complex	binding			-1									30397185	t		lperfetto	PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively.	SIGNOR-260321	0.881
RPS6KA1	protein	Q15418	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates	phosphorylation			9606									18722121	t		lperfetto	Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity	SIGNOR-217553	0.472
CKB	protein	P12277	UNIPROT	ACTB	protein	P60709	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000099								19333390	t		miannu	In summary, data presented here strongly suggest that locally generated ATP is an important regulator for actin-based cytoskeletal dynamics involved in cell extension and motility and that CK-B is a controlling enzyme in the compartmentalization of ATP availability. CK-B co-localizes with cortical actin and facilitates spreading of astrocytes	SIGNOR-265791	0.296
CSNK2A1	protein	P68400	UNIPROT	HMGN1	protein	P05114	UNIPROT	down-regulates	phosphorylation	Ser89	KTEESPAsDEAGEKE	9606									10739259	t		lperfetto	Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.	SIGNOR-76274	0.2
ACSS3	protein	Q9H6R3	UNIPROT	acetate	smallmolecule	CHEBI:30089	ChEBI	down-regulates quantity	chemical modification												10843999	t		lperfetto	The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP.	SIGNOR-271833	0.8
PHF1	protein	O43189	UNIPROT	HOXA9	protein	P31269	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20565746	t		miannu	These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression.	SIGNOR-260069	0.29
PRKAA1	protein	Q13131	UNIPROT	PDHA1	protein	P08559	UNIPROT	up-regulates activity	phosphorylation	Ser314	IQEVRSKsDPIMLLK	-1									33022274	t		miannu	AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex	SIGNOR-276839	0.2
DCC	protein	P43146	UNIPROT	CACNA1A	protein	O00555	UNIPROT	up-regulates activity				9606									12827203	t		miannu	DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER.	SIGNOR-268293	0.2
SMAD1/4	complex	SIGNOR-C85	SIGNOR	BMP4	protein	P12644	UNIPROT	up-regulates quantity by expression	transcriptional regulation			7227									19896409	f		lperfetto	BMPs first bind to and activate their transmembrane serine/threonine kinase receptors, which in turn phosphorylate the transcription factors Smad1/5/8 at its two C-terminal serines (SVS). Phosphorylated Smad1Cter binds to Smad4 (co-Smad) and translocates and accumulates in the nucleus, activating BMP-responsive genes (Fig. 2) [21] and [22], such as BMP4/7 and others.	SIGNOR-248842	0.584
SMURF1	protein	Q9HCE7	UNIPROT	RABEP2	protein	Q9H5N1	UNIPROT	unknown	ubiquitination			-1									20804422	t		miannu	Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay.	SIGNOR-272690	0.2
GNGT1	protein	P63211	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance.	SIGNOR-199144	0.383
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	NR4A3	protein	Q92570	UNIPROT	down-regulates activity	phosphorylation	Ser376	GRRGRLPsKPKSPLQ	9606	BTO:0000007								16223362	t		lperfetto	Phosphorylation of Nur77 on Ser354 has been suggested to reduce ability of Nur77 to bind DNA; however, the kinase responsible for this phosphorylation in cells has not been clearly established. In the present study, we show that Nur77 is phosphorylated on this site by RSK (ribosomal S6 kinase)	SIGNOR-252771	0.2
TLN1	protein	Q9Y490	UNIPROT	ITGB3	protein	P05106	UNIPROT	up-regulates activity	binding			10090									19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257625	0.784
CDH4	protein	P55283	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265866	0.506
Factor FVIIa:TF	complex	SIGNOR-C319	SIGNOR	F7	protein	P08709	UNIPROT	up-regulates activity	cleavage	Arg212	NASKPQGrIVGGKVC	9606		BTO:0000131							12524220	t		lperfetto	The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa.	SIGNOR-263521	0.932
MAS1	protein	P04201	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	down-regulates				9606									23488800	f		miannu	The discovery that Ang-(1-7) offsets the major biological effects of Ang II has contributed to the realization that the RAS is composed of two opposing axes. The first axis is constituted by the enzyme ACE, with Ang II as the end product, and the AT1 receptor as the main effector mediating the biological actions of Ang II. The second axis results from ACE2-mediated hydrolysis of Ang II, leading to production of Ang-(1-7), with Mas receptor as the main effector conveying the vasodilator, antiproliferative, anti-inflammatory and anti-fibrotic effects of Ang-(1-7). Activation of the ACE2/Ang-(1-7)/Mas axis decreases inflammatory cell function and fibrogenesis in diverse models of human diseases. 	SIGNOR-260228	0.7
COPS2	protein	P61201	UNIPROT	COP9 signalosome variant 1	complex	SIGNOR-C489	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270772	0.92
PRKDC	protein	P78527	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates activity	phosphorylation	Ser2624	QTRTQEGsLSARWPV	-1									12186630	t		lperfetto	 We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function.	SIGNOR-249156	0.2
CAMK2D	protein	Q13557	UNIPROT	KCNJ11	protein	Q14654	UNIPROT	down-regulates	phosphorylation	Thr224	MQVVRKTtSPEGEVV	9606									23223335	t		lperfetto	Results showed that activation of camkii triggered dynamin-dependent internalization of k(atp) channels. This process required phosphorylation of threonine at 180 and 224 and an intact (330)yskf(333) endocytosis motif of the k(atp) channel kir6.2 pore-forming subunit.	SIGNOR-200027	0.2
DRD5	protein	P21918	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257311	0.413
TP53	protein	P04637	UNIPROT	GMPS	protein	P49915	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599;BTO:0003477;BTO:0001670								27939741	t		miannu	Herein, we identified GMP synthetase (GMPS), a key enzyme of de novo purine biosynthesis, as an important p53 repression target using a large-scale proteomics approach. This p53-mediated repression of GMPS could be validated by immunoblotting in Sk-Hep1, HepG2, and HuH6 cells.	SIGNOR-267342	0.387
PIP4K2A	protein	P48426	UNIPROT	1-phosphatidyl-1D-myo-inositol 5-phosphate(3-)	smallmolecule	CHEBI:57795	ChEBI	down-regulates quantity	chemical modification			9606									9367159	t		Gianni	The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities'. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K	SIGNOR-268866	0.8
PTH1R	protein	Q03431	UNIPROT	SLC34A3	protein	Q8N130	UNIPROT	down-regulates quantity													28363951	f		lperfetto	PTH inhibits reabsorption of phosphate from the glomerular filtrate in RPT by decreasing the abundance of sodium-phosphate co-transporters NPT2a and NPT2c on the apical membrane, thus enhancing renal phosphate excretion	SIGNOR-270557	0.351
HAT1	protein	O14929	UNIPROT	H4C1	protein	P62805	UNIPROT	down-regulates activity	acetylation	Lys13	KGGKGLGkGGAKRHR	-1									28143904	t		lperfetto	Histone acetyltransferase 1 is the founding member of the histone acetyltransferase superfamily and catalyzes lysine acetylation of newly synthesized histone H4|Lys12 for direct attack of the acetyl group of the cofactor.| It is postulated that histone acetylation, through charge neutralization of the cationic histone tails, weakens nucleosomal electrostatic interactions with anionic DNA, thus destabilizing internucleosomal contacts and nucleosomal structure and facilitating access to the promoter region for RNA polymerase and transcription factors.	SIGNOR-264790	0.2
FANCA	protein	O15360	UNIPROT	Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	form complex	binding			9606	BTO:0000567								17396147	t		lperfetto	This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo 	SIGNOR-263240	0.95
COPS7A	protein	Q9UBW8	UNIPROT	COP9 signalosome variant 1	complex	SIGNOR-C489	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270771	0.914
CHRM5	protein	P08912	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257351	0.357
MAPK1	protein	P28482	UNIPROT	ETV3	protein	P41162	UNIPROT	down-regulates activity	phosphorylation	Ser139	SSGVVPQsAPPVPTA	10090									22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. Among the ERK2 substrates, we identified the E-twenty six (ETS) domain-containing protein ETV3. We determined that phosphorylation of this protein by ERK2 was functionally relevant, abrogating the DNA-binding activity of ETV3 at thousands of targets across the genome, thereby providing an additional mechanism for transcriptional regulation downstream of ERK2 activation.	SIGNOR-262758	0.414
NHLRC1	protein	Q6VVB1	UNIPROT	PPP1R3B	protein	Q86XI6	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								18029386	t		miannu	Here, we show that the laforin-malin complex downregulates PTG-induced glycogen synthesis in FTO2B hepatoma cells through a mechanism involving ubiquitination and degradation of PTG. We show here that laforin and malin play a crucial role in the regulation of glycogen biosynthesis in FTO2B hepatoma cells. In these cells, the laforin–malin complex counteracts the glycogenic effect of PTG because it promotes its ubiquitination and degradation. 	SIGNOR-271728	0.409
PRKCD	protein	Q05655	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates				9606		BTO:0000671							9335553	f		gcesareni	These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling.	SIGNOR-52707	0.632
PPME1	protein	Q9Y570	UNIPROT	PPP2CA	protein	P67775	UNIPROT	down-regulates activity	demethylation	Leu309	RRTPDYFl	-1									18394995	t		lperfetto	Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans.	SIGNOR-265748	0.902
FOXO3	protein	O43524	UNIPROT	Cell_cycle_progress 	phenotype	SIGNOR-PH42	SIGNOR	down-regulates				9606	BTO:0000007								14976264	f		lperfetto	Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress	SIGNOR-267283	0.7
SRC	protein	P12931	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Tyr340	RGQRDSSyYWEIEAS	9606									7692235	t		gcesareni	We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain.	SIGNOR-32081	0.588
ATM	protein	Q13315	UNIPROT	USP28	protein	Q96RU2	UNIPROT	down-regulates activity	phosphorylation	Ser67	DERVKEPsQDTVATE										31938050	t		lperfetto	Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure ​Figure55D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites.|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization.	SIGNOR-275852	0.318
FOXO3	protein	O43524	UNIPROT	Autophagy	phenotype	SIGNOR-PH31	SIGNOR	up-regulates activity				9606	BTO:0000007								22931788	f	AMPK signaling	Gianni	Forkhead box O (FOXO) transcriptional protein family members, including FOXO1 and FOXO3, are involved in the modulation of autophagy. However, whether there is redundancy between FOXO1 and FOXO3 in the ability to induce autophagy remains unclear. In this study, we showed that FOXO3 induced a transcription-dependent autophagy, and FOXO1 was required for this process.	SIGNOR-261952	0.7
LRRK2	protein	Q5S007	UNIPROT	ARFGAP1	protein	Q8N6T3	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000938	BTO:0000142							22363216	t		gcesareni	Arfgap1 is an lrrk2 kinase substrate whose gap activity is inhibited by lrrk2. The phosphorylation of arfgap1 by lrrk2 was subjected to mass spectrometry to determine the sites of phosphorylation. There was 95.3% coverage and serines(s155, s246, s284) and threonine (t189, t216, t292) are phosphorylated by lrrk2. Mutational analysis of these serine and threonine amino acids to alanine reveals that no single amino acid is the predominant phospho-amino acid.	SIGNOR-196267	0.598
ESR1	protein	P03372	UNIPROT	KDM4B	protein	O94953	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001248								20682797	f		miannu	Here, we show the histone demethylase JMJD2B is regulated by both ERalpha and HIF-1alpha, drives breast cancer cell proliferation in normoxia and hypoxia, and epigenetically regulates the expression of cell cycle genes such as CCND1, CCNA1, and WEE1. these data indicate that JMJD2B is a bona fide target of ERα and its expression in ER-positive breast cancer cells is mainly dependent on ERα.	SIGNOR-263737	0.589
USF1	protein	P22415	UNIPROT	CBS	protein	P35520	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12427542	f		miannu	We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter. 	SIGNOR-254814	0.2
FOXF2	protein	Q12947	UNIPROT	TBP	protein	P20226	UNIPROT	up-regulates activity	binding			-1									9722567	t		miannu	The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB.	SIGNOR-220373	0.417
IFNGR2	protein	P38484	UNIPROT	IFNGR2/INFGR1	complex	SIGNOR-C142	SIGNOR	form complex	binding			9606	BTO:0000801								19041276	t		lperfetto	The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process.	SIGNOR-249486	0.733
RUNX3	protein	Q13761	UNIPROT	CAPN10	protein	Q9HC96	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255091	0.2
RPS6KA1	protein	Q15418	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser293	GSTKRRKsMSGASPK	9606									23708659	t		lperfetto	Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.	SIGNOR-202113	0.375
bremazocine	chemical	CHEBI:3171	ChEBI	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258779	0.8
MAPK14	protein	Q16539	UNIPROT	MAPT	protein	P10636	UNIPROT	up-regulates	phosphorylation			9606									20626350	t		lperfetto	A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins.	SIGNOR-166611	0.322
ABL1	protein	P00519	UNIPROT	GLO1	protein	Q04760	UNIPROT	up-regulates activity	phosphorylation	Tyr136	GIAVPDVySACKRFE	-1									34838714	t		miannu	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276187	0.2
PIK3CD	protein	O00329	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9534	BTO:0004055								14665640	f		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242655	0.7
LCK	protein	P06239	UNIPROT	CD3G	protein	P09693	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000782								2470098	t			Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex.	SIGNOR-259931	0.541
LGALS3	protein	P17931	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0000664								21821001	f		miannu	The aim of this study was to investigate the role of inducible galectin-3 in leukemic cells escape of apoptotic stimuli. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. 	SIGNOR-261904	0.7
FAM20C	protein	Q8IXL6	UNIPROT	FGF23	protein	Q9GZV9	UNIPROT	down-regulates activity	phosphorylation	Ser180	IPRRHTRsAEDDSER	9606									24706917	t		Manara	Here we show that Fam20C directly phosphorylates FGF23 on Ser(180) | Our above results support, phosphorylation of FGF23 at Ser180 inhibits O-glycosylation and would therefore promote hormone proteolysis and thus inactivation. 	SIGNOR-260925	0.627
CRK	protein	P46108	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity	phosphorylation	Tyr397	SVSETDDyAEIIDEE	9606	BTO:0000007								11314030	t		llicata	Tyrosine phosphorylation FAK was strictly dependent upon c-Crk II expression | Crk-inducible FAK tyrosine phosphorylation was completely abrogated by co-expression with R38K Crk (lane 2), and decreased by co-expression with W170K Crk (lane 3), indicating that the SH2 domain of c-Crk is absolutely essential for this effect. In contrast, mutants in the C-terminus of Crk that include Y222F c-Crk, which abrogates the c-Abl phosphorylation site, and W276K Crk, which mutates the C-terminal SH3 domain, modestly increased FAK activation compared to wild-type c-Crk II.	SIGNOR-250777	0.722
MAPK3	protein	P27361	UNIPROT	KLC1	protein	Q07866	UNIPROT	down-regulates	phosphorylation	Ser460	YKACKVDsPTVTTTL	9606									21385839	t		gcesareni	Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro.	SIGNOR-172642	0.267
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GRK1	protein	Q15835	UNIPROT	down-regulates activity	phosphorylation	Ser21	AFIAARGsFDGSSSQ	9606									15946941	t		Luana	Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA. 	SIGNOR-260841	0.2
PTPRJ	protein	Q12913	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates	dephosphorylation	Tyr1059	DIYKDPDyVRKGDAR	9606									18936167	t		gcesareni	The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2.	SIGNOR-181676	0.687
TRIM25	protein	Q14258	UNIPROT	GPI	protein	P06744	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								24810856	t		miannu	Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF.	SIGNOR-272178	0.253
CARS1	protein	P49589	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									11347887	t		miannu	Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine.	SIGNOR-270471	0.8
Laminin-10	complex	SIGNOR-C182	SIGNOR	A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	up-regulates activity	binding												12123670	t		lperfetto	We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1.	SIGNOR-253222	0.55
testosterone	smallmolecule	CHEBI:17347	ChEBI	AR	protein	P10275	UNIPROT	up-regulates activity	chemical activation			9606									15861399	t		miannu	Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. 	SIGNOR-251553	0.8
CDC14B	protein	O60729	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates	dephosphorylation	Thr698	KSIQATLtPSAMKSS	9606									20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis.	SIGNOR-164483	0.552
PLK3	protein	Q9H4B4	UNIPROT	TOP2A	protein	P11388	UNIPROT	up-regulates	phosphorylation	Thr1343	FSDFDEKtDDEDFVP	9606									18062778	t		llicata	The direct phosphorylation of thr(1342) of topoisomerase iialpha by plk3 was demonstrated with an in vitro kinase assay, and overexpression of plk3 induced the phosphorylation of thr(1342) in cellular topoisomerase iialpha. it is possible that plk3 regulates the activity of topoisomerase iia by phosphorylation in a cell-cycle dependent manner. Another possibility is that plk3 regulates the activity of topoisomerase iia when the checkpoint is activated.	SIGNOR-159596	0.272
MAPK8IP1	protein	Q9UQF2	UNIPROT	MAPK8	protein	P45983	UNIPROT	down-regulates	binding			9606									9922370	t		gcesareni	The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus	SIGNOR-64175	0.879
RPS6KB1	protein	P23443	UNIPROT	MXD1	protein	Q05195	UNIPROT	down-regulates	phosphorylation	Ser145	IERIRMDsIGSTVSS	9606									18451027	t		llicata	Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway, which in turn promotes the transcriptional activity of myc.	SIGNOR-178590	0.309
PAFAH1B2	protein	P68402	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates				9606									23238734	f		miannu	We provide evidence that the loss of pafah1b2 potently reduces a_ by promoting the degradation of its immediate precursor, the _ctf.	SIGNOR-200188	0.2
STUB1	protein	Q9UNE7	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									12239347	t		miannu	We now show that the chaperone-binding ubiquitin ligase CHIP efficiently ubiquitinates and down-regulates ErbB2. CHIP expression shortens the half-life of both nascent and mature ErbB2 protein. In vitro ubiquitination assay shows that CHIP serves as a ubiquitin ligase for ErbB2, and both exogenously expressed and endogenous CHIP coprecipitate with the kinase. 	SIGNOR-272586	0.611
RAC1	protein	P63000	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates activity				9606									23151663	f		gcesareni	Planar cell polarity (pcp) signalling triggers activation of the small gtpases rhoa and rac1, which in turn activate rho kinase (rock) and jun-n-terminal kinase (jnk), respectively, leading to actin polymerization and microtubule stabilization.	SIGNOR-199539	0.645
GABA-A (a6-b1-g2) receptor	complex	SIGNOR-C334	SIGNOR	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	relocalization			9606									18790874	t	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263814	0.8
MYCT1	protein	Q8N699	UNIPROT	CASP3	protein	P42574	UNIPROT	up-regulates activity				9606									30283340	f		miannu	Herein, we observed that overexpression of MYCT1 induced apoptosis in HL-60 and KG-1a cells, and upregulated Bax, downregulated Bcl-2, and enhanced cleavage of caspase-3 and -9. Similar proapoptotic role of MYCT1 was also found in the AML cell xenografts. These results suggest that MYCT1 affects AML cell apoptosis by modulating the endogenous apoptotic pathways.	SIGNOR-261942	0.2
CSNK2A1	protein	P68400	UNIPROT	CEBPD	protein	P49716	UNIPROT	up-regulates activity	phosphorylation	Ser57	PAMYDDEsAIDFSAY	-1									25680545	t		miannu	Here, we have identified the CCAAT/enhancer binding protein δ (C/EBPδ) as a new substrate for CK2. Using point mutants of C/EBPδ the major phosphorylation site for CK2 was mapped to serine 57, which is located within the transactivation domain of C/EBPδ. For proper functioning as a transcription factor C/EBPδ has to be translocated into the nucleus where it forms heterodimers with other members of the C/EBP family of proteins and ATF4. Here, we found that CK2 phosphorylation does neither influence the subcellular localization of C/EBPδ nor its interaction with C/EBPβ, but rather does CK2 phosphorylation modulate the transcriptional activity of C/EBPδ. 	SIGNOR-276886	0.2
CSNK2A1	protein	P68400	UNIPROT	CERS6	protein	Q6ZMG9	UNIPROT	up-regulates activity	phosphorylation	Ser341	KVSKDDRsDIESSSD	9606	BTO:0000007								26887952	t		miannu	Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue. 	SIGNOR-273990	0.2
GSK3B	protein	P49841	UNIPROT	MACF1	protein	Q9UPN3	UNIPROT	down-regulates activity	phosphorylation	Ser7326	RAGSRASsRRGSDAS	9606	BTO:0004905								21295697	t		lperfetto	We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules.	SIGNOR-264434	0.446
ATM	protein	Q13315	UNIPROT	USP28	protein	Q96RU2	UNIPROT	down-regulates activity	phosphorylation	Ser714	ESSTNSSsQDYSTSQ										31938050	t		lperfetto	Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure ​Figure55D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites.|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization.	SIGNOR-275853	0.318
P300/PCAF	complex	SIGNOR-C7	SIGNOR	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	acetylation	Lys19	VKRLLGWkKSAGGSG	9606									17074756	t		lperfetto	Acetylation of the short isoform of Smad2 improves its DNA binding activity in vitro and enhances its association with target promoters in vivo, thereby augmenting its transcriptional activity. Smad2(FL) and Smad2(_E3) were also acetylated by P/CAF in vivo and the acetylation of both proteins was lost following mutation of Lys19 (Fig. 2D), suggesting that Lys19 in Smad2 is also targeted by P/CAF.	SIGNOR-217607	0.617
MERTK	protein	Q12866	UNIPROT	MERTK	protein	Q12866	UNIPROT	up-regulates	phosphorylation	Tyr753	KKIYSGDyYRQGRIA	9606									8702477	t		gcesareni	By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain.	SIGNOR-42918	0.2
CDC14B	protein	O60729	UNIPROT	APC	protein	P25054	UNIPROT	up-regulates	dephosphorylation			9606				SIGNOR-C110					18662541	t		gcesareni	The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1	SIGNOR-179636	0.2
NADP(3-)	smallmolecule	CHEBI:58349	ChEBI	NADPH(4-)	smallmolecule	CHEBI:57783	ChEBI	up-regulates quantity	precursor of			9606									34775382	t		miannu	6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule.	SIGNOR-268111	0.8
CSNK1A1L	protein	Q8N752	UNIPROT	GLIS2	protein	Q9BZE0	UNIPROT	up-regulates				9606									17289029	f		gcesareni	We decided to focus on the interaction between _-catenin and glis2. the critical role of the first zinc finger motif was confirmed by the observation that a point mutation in the first zinc finger motif, that destroys its tetrahedral configuration, abolished the interaction. _-catenin contains several functional domains, the amino terminus interacts with gsk3_ and casein kinase i_ (ck1) binding sites while its 12 armadillo repeats provides an interface for tcf/lefs, the co-activator cbp, and several other proteins	SIGNOR-152962	0.2
RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	rRNA_transcription	phenotype	SIGNOR-PH145	SIGNOR	up-regulates													22260999	f		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266177	0.7
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr666	GWMEDYDyVHLQGKE	9606									11604500	t		lperfetto	The loss of activity in the cas-f668/f670 mutant is consistent with the notion that src, once initially bound by its sh3 domain, phosphorylates the tyr668/670 site to further stabilize its interaction by sh2 binding.	SIGNOR-111060	0.797
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR2C	protein	P28335	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264283	0.8
EN2	protein	P19622	UNIPROT	FGF8	protein	P55075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003560								10026229	t		miannu	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression.	SIGNOR-265801	0.428
PIP3	smallmolecule	CHEBI:16618	ChEBI	PLEKHG1	protein	Q9ULL1	UNIPROT	up-regulates	chemical activation			9606									21041639	t		gcesareni	Phosphatidylinositol-3,4,5-trisphosphate (pip3), the product of pi3k activity and a key signaling molecule, acts by recruiting pleckstrin-homology (ph) domain-containing proteins to cell membranes	SIGNOR-169179	0.8
TGFB1	protein	P01137	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8142649	f	Regulation	miannu	Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production.	SIGNOR-251797	0.265
DOK1	protein	Q99704	UNIPROT	A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257675	0.32
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606		BTO:0000562							10521487	t		gcesareni	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-71419	0.2
RAI1	protein	Q7Z5J4	UNIPROT	CLOCK	protein	O15516	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									22578325	t		miannu	RAI1 Transcriptionally Activates CLOCK via an Intron 1 Enhancer Element. data suggest that RAI1 binds, directly or in a complex, to the first intron of CLOCK and enhances its transcriptional activity in vitro, supporting RAI1 as a positive regulator of CLOCK and an important part of the circadian loop of transcription. Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. 	SIGNOR-266839	0.457
MAPK14	protein	Q16539	UNIPROT	SLC9A1	protein	P19634	UNIPROT	up-regulates	phosphorylation	Thr718	KEDLPVItIDPASPQ	9606									11604491	t		llicata	Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728.	SIGNOR-111051	0.552
LCK	protein	P06239	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	binding			9606							phosphorylation:Tyr319	TSVYESPySDPEELK	10318843	t		lperfetto	Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation	SIGNOR-67443	0.601
MAPK3	protein	P27361	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates	phosphorylation	Thr753	YACASPKtPIQAGGY	9606									19933846	t		gcesareni	Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity.	SIGNOR-161819	0.629
GDNF	protein	P39905	UNIPROT	ALCAM	protein	Q13740	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252177	0.2
AP 23573	chemical	CHEBI:79700	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0000887							20554235	t		gcesareni	Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mtor inhibitors.	SIGNOR-166186	0.8
CSNK2B	protein	P67870	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates activity	phosphorylation	Thr59	EGYDELQtDGNRSSH	9606	BTO:0000567								11583622	t		llicata	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-251054	0.289
NLRP3 inflammasome	complex	SIGNOR-C225	SIGNOR	Pyroptosis	phenotype	SIGNOR-PH105	SIGNOR	up-regulates				9606									30166988	f		miannu	Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma.	SIGNOR-260356	0.7
CASP3	protein	P42574	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates	cleavage	Asp373	PATQCISdGKLNEGH	9606									11741536	t		gcesareni	Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis.	SIGNOR-112792	0.373
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	MITF	protein	O75030	UNIPROT	down-regulates	phosphorylation	Ser409	HGLSLIPsTGLCSPD	9606									10673502	t	The effect has been demonstrated using O75030-9	gcesareni	The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert.	SIGNOR-252791	0.2
CLK1	protein	P49759	UNIPROT	RBM17	protein	Q96I25	UNIPROT	up-regulates activity	phosphorylation	Ser202	EEDSRPRsQSSKAAI	9534	BTO:0001538								23519612	t		miannu	 In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. Clk1 promotes SPF45-induced exon 6 exclusion	SIGNOR-262705	0.324
BCL2	protein	P10415	UNIPROT	BAK1	protein	Q16611	UNIPROT	down-regulates	binding			9606									9463381	t		amattioni	Bcl-2 bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim)	SIGNOR-55546	0.662
SUMO1	protein	P63165	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates activity	sumoylation	Lys160	EAHQWFLkHEARPLA	9534	BTO:0000298								9756909	t		lperfetto	We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins |We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites. The PML mutant with Lys to Arg substitutions in all three sites is expressed normally, but cannot be sentrinized|Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies.	SIGNOR-270540	0.771
NF90-NF45	complex	SIGNOR-C443	SIGNOR	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression				10116									25566957	f		miannu	In the present study, we investigated the expression profiles of NF45 in the sciatic nerve of adult rats following crush injury.  in the TNF-α-induced Schwann cell proliferation assay, protein level of NF45 and cyclin E was elevated while expression of p21 was down-regulated. Further, when NF45 was knocked down, Schwann cell proliferation was interrupted and the expression of cyclin E was attenuated, while the expression of p21 was up-regulated. To repress the expression of p21 is one of the basic mechanisms for NF45-regulated cell proliferation.	SIGNOR-268491	0.25
PTPN6	protein	P29350	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									10734133	t		flangone	Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1.	SIGNOR-75934	0.365
TGFBR2	protein	P37173	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates activity	phosphorylation	Ser213	TRKLMEFsEHCAIIL	9606	BTO:0002181								9155023	t		lperfetto	Here we show that TbetaRII kinase is regulated intricately by autophosphorylation on at least three serine residues. Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition.	SIGNOR-236087	0.2
HES1	protein	Q14469	UNIPROT	ASCL1	protein	P50553	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938								30030829	f		lperfetto	The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 	SIGNOR-265146	0.453
canertinib	chemical	CHEBI:61399	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258196	0.8
ARAP2	protein	Q8WZ64	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606									32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260453	0.492
ATM	protein	Q13315	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Thr68	SSLETVStQELYSIP	-1									16481012	t		miannu	Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity. 	SIGNOR-276053	0.83
MLL-ENL	fusion protein	SIGNOR-FP7	SIGNOR	RUNX1	protein	Q01196	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24449215	f		miannu	However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions.	SIGNOR-260127	0.2
G3BP2	protein	Q9UN86	UNIPROT	Stress_granules	phenotype	SIGNOR-PH124	SIGNOR	up-regulates				9606	BTO:0000007								23279204	f		miannu	Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli.	SIGNOR-260864	0.7
MAPK1	protein	P28482	UNIPROT	RGS19	protein	P49795	UNIPROT	up-regulates	phosphorylation	Ser151	EDYVSILsPKEVSLD	9606									10993892	t		gcesareni	Phosphorylation of gaip by erk2 were abrogated when serine at position 151 in the rgs domain was substituted by an alanine residue using site-directed mutagenesis. Furthermore, the lysosomal-autophagic pathway was not stimulated in s151a-gaip mutant-expressing cells when compared with wild-type gaip-expressing cells. These results demonstrate that the gtpase-activating protein activity of gaip is stimulated by erk2 phosphorylation.	SIGNOR-82083	0.488
AMBRA1	protein	Q9C0C7	UNIPROT	HUWE1	protein	Q7Z6Z7	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567				phosphorylation:Ser1043	CRPEALNsGVEYYWD			30217973	t		lperfetto	AMBRA1 regulates mitophagy at two critical steps. Upon mitophagy stimulation, AMBRA1 mediates the HUWE1 E3 ubiquitin ligase translocation from cytosol to mitochondria (light blue). AMBRA1 acts as a cofactor for HUWE1 E3 ubiquitin ligase activity, favouring its binding to its substrate MFN2 (and maybe other OMM substrates) and targeting it to the proteasome	SIGNOR-272962	0.2
SHPRH	protein	Q149N8	UNIPROT	PCNA	protein	P12004	UNIPROT	up-regulates	ubiquitination			9606									19706603	t		gcesareni	We provide evidence that similar to rad5, shprh physically interacts with the human rad6rad18 and mms2ubc13 protein complexes, and importantly, we show that it exhibits an ubiquitin ligase activity and mediates mms2ubc13-dependent polyubiquitylation of pcna. Thus, shprh is a functional homolog of rad5.	SIGNOR-187757	0.532
HOMER	proteinfamily	SIGNOR-PF59	SIGNOR	SHANK1	protein	Q9Y566	UNIPROT	up-regulates activity	binding			9606									17243894	t		miannu	It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD	SIGNOR-264698	0.2
CDK4	protein	P11802	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates	binding			9606			SIGNOR-C18						21902831	t		gcesareni	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-176527	0.526
HRH2	protein	P25021	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256777	0.43
APLNR	protein	P35414	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256824	0.409
TEK	protein	Q02763	UNIPROT	TEK	protein	Q02763	UNIPROT	up-regulates activity	phosphorylation	Tyr1108	TYVNTTLyEKFTYAG	9606	BTO:0001176								20973951	t		miannu	This phosphorylation requires a kinase competent Tie2 as well as intact tyrosines 1100 and 1106 (Y1100 and Y1106) on the receptor. This suggests that Y1100 and Y1106 on Tie2 play a role in Grb14 mediated signal transduction downstream of this receptor.	SIGNOR-259833	0.2
SHC3	protein	Q92529	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	relocalization			9606									16829981	t		gcesareni	In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation.	SIGNOR-147865	0.811
PRKCD	protein	Q05655	UNIPROT	BAG3	protein	O95817	UNIPROT	up-regulates	phosphorylation	Ser187	SSSSSSAsLPSSGRS	9606									23108398	t		lperfetto	Pkc_-mediated phosphorylation of bag3 at ser187 site induces epithelial-mesenchymal transition and enhances invasiveness in thyroid cancer fro cells. we showed that bag3 was implicated in epithelial-mesenchymal transition (emt) procedure, and phosphorylation state at ser187 site had a critical role in emt regulation by bag3.	SIGNOR-199316	0.253
atropine	chemical	CHEBI:16684	ChEBI	CHRM4	protein	P08173	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								2704370	t		miannu	In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 	SIGNOR-258390	0.8
GSK3B	protein	P49841	UNIPROT	CLASP2	protein	O75122	UNIPROT	down-regulates activity	phosphorylation	Ser533	QGCSREAsRESSRDT	9534	BTO:0004055								19638411	t		lperfetto	GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells	SIGNOR-264825	0.529
HSP90AB1	protein	P08238	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates activity	binding			9606									15861399	t		miannu	The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes.	SIGNOR-251535	0.692
PTP4A2	protein	Q12974	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates	dephosphorylation			9606									14643450	t		amattioni	Cells overexpressing prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity	SIGNOR-119478	0.2
ADRB3	protein	P13945	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256896	0.435
INTS11	protein	Q5TA45	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261462	0.2
IL10RA	protein	Q13651	UNIPROT	Phagocytosis	phenotype	SIGNOR-PH97	SIGNOR	up-regulates													22933625	f		apalma	Recent findings have shown that IL-10 stimulation of macrophages isolated from skeletal muscles increases the phagocytic activity of macrophages	SIGNOR-255443	0.7
MAP4K1	protein	Q92918	UNIPROT	CARD11	protein	Q9BXL7	UNIPROT	up-regulates activity	phosphorylation	Ser559	QPPRSRSsIMSITAE	-1									19706536	t		miannu	HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro.	SIGNOR-276258	0.507
PRKCH	protein	P24723	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates	phosphorylation	Ser706	ARIIGEKsFRRSVVG	9606									12058027	t		gcesareni	Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs.	SIGNOR-89423	0.2
RNF216	protein	Q9NWF9	UNIPROT	TLR9	protein	Q9NR96	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									15107846	t		miannu	Here we describe how a RING finger protein, Triad3A, acts as an E3 ubiquitin-protein ligase and enhances ubiquitination and proteolytic degradation of some TLRs. Triad3A overexpression promoted substantial degradation of TLR4 and TLR9 with a concomitant decrease in signaling, but did not affect TLR2 expression or signaling. 	SIGNOR-271505	0.415
AMOT/MPP5/INADL/LIN7C	complex	SIGNOR-C27	SIGNOR	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates	binding			10090									21145499	t		milica	Because we found that multiple domains of taz/yap interacted with multiple components of the crumbs complex, which include pals1, lin7c, patj, and the crumbs regulator amot, we propose that this multifactoral interaction serves to ensure that assembly of the hippo pathway and efficient phosphorylation of taz/yap is coupled only by the assembly of the crumbs complex, rather than by any single component.	SIGNOR-170361	0.326
tacedinaline	chemical	CHEBI:90195	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258008	0.8
SYK	protein	P43405	UNIPROT	SYK	protein	P43405	UNIPROT	up-regulates activity	phosphorylation	Tyr526	LRADENYyKAQTHGK	9606	BTO:0000776								9820500	t		lperfetto	These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520	SIGNOR-246621	0.2
bis(2-ethylhexyl) phthalate	chemical	CHEBI:17747	ChEBI	NR1I2	protein	O75469	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). 	SIGNOR-268774	0.8
PDGFRB	protein	P09619	UNIPROT	CRK	protein	P46108	UNIPROT	up-regulates	binding			9606									19426560	t		amattioni	Crk can interact directly with tyrosine kinase receptors and can transmit signals downstream	SIGNOR-185667	0.591
CD36	protein	P16671	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	down-regulates													17326328	f		lperfetto	There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3	SIGNOR-252270	0.7
PPP2CA	protein	P67775	UNIPROT	CHEK1	protein	O14757	UNIPROT	down-regulates activity	dephosphorylation	Ser317	ENVKYSSsQPEPRTG	9606									17015476	t			Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo.	SIGNOR-248616	0.474
ACTL6B	protein	O94805	UNIPROT	SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270600	0.685
ITGB1	protein	P05556	UNIPROT	a7/b1 integrin	complex	SIGNOR-C126	SIGNOR	form complex	binding			9606	BTO:0000222;BTO:0002319								10199978	t		lperfetto	The alpha7beta1 integrin is a laminin receptor on the surface of skeletal myoblasts and myofibers. Alternative forms of both the alpha7 and beta1 chains are expressed in a developmentally regulated fashion during myogenesis. These different alpha7beta1 isoforms localize at specific sites on myofibers and appear to have distinct functions in skeletal muscle.	SIGNOR-241512	0.764
DOK1	protein	Q99704	UNIPROT	A4/b1 integrin	complex	SIGNOR-C162	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257673	0.32
RPS6KA3	protein	P51812	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606									19282669	t		lperfetto	The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival.	SIGNOR-184595	0.393
mono(2-ethylhexyl) phthalate	chemical	CHEBI:17243	ChEBI	PPARG	protein	P37231	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 	SIGNOR-268785	0.8
MAPK9	protein	P45984	UNIPROT	YWHAZ	protein	P63104	UNIPROT	down-regulates	phosphorylation	Ser184	FYYEILNsPEKACSL	9606									15071501	t		gcesareni	Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-188	SIGNOR-124031	0.2
LEPR	protein	P48357	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	down-regulates activity				9606	BTO:0003336								25343030	f		miannu	Leptin exerts an inhibitory effect on AMPK in the hypothalamus, thereby stimulating ACC and subsequently suppressing food intake.	SIGNOR-263510	0.383
PPM1A	protein	P35813	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates activity	dephosphorylation	Ser127	PQHVRAHsSPASLQL	9606									33630828	t		lperfetto	Although the authors show an in vitro kinase assay where PPM1A supposedly dephosphorylates YAP on Ser127, Fig. 4A lacks a positive control to ensure that PPM1A purified from cells is active.|The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration.	SIGNOR-276984	0.272
F2R	protein	P25116	UNIPROT	TNFRSF12A	protein	Q9NP84	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254846	0.2
ROCK1	protein	Q13464	UNIPROT	KCNK3	protein	O14649	UNIPROT	down-regulates	phosphorylation	Ser336	IPRDLSTsDTCVEQS	9606									21838752	t		lperfetto	Task1 channels contain two putative rho kinase phosphorylation sites, ser(336) and ser(393) . Mutation of ser(393) rendered task1 channels insensitive to et(a) - or et(b)-mediated current inhibition. In contrast, removal of ser(336) selectively attenuated et(a) -dependent task1 regulation without affecting the et(b) pathway.	SIGNOR-176025	0.2
PLEKHG5	protein	O94827	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260566	0.762
FNTA	protein	P49354	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates activity				9606									24294527	t		lperfetto	Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials.	SIGNOR-242559	0.39
CFAP53	protein	Q96M91	UNIPROT	Axonemal_Dynein	proteinfamily	SIGNOR-PF66	SIGNOR	up-regulates activity	binding			10090		BTO:0000379							33347437	t		miannu	CFAP53 associates with axonemal microtubules of tracheal cilia and interacts with dynein proteins and the docking complex (DC)	SIGNOR-265547	0.2
MRPL24	protein	Q96A35	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262369	0.708
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	CSF2RA/CSF2RB	complex	SIGNOR-C212	SIGNOR	up-regulates activity	phosphorylation			10090	BTO:0004052								14500898	t		irozzo	This up-regulation required BCR-ABL tyrosine kinase activity and led to IL-3Rbetac/beta chain tyrosine phosphorylation in the absence of detectable IL-3 production. These results suggested that cytokine-independent IL-3 receptor activation could be a dominant signaling component in BCR-ABL-induced leukemogenesis. However, the IL-3Rβc/β chain could act as a cofactor in BCR-ABL-induced leukemogenesis by activation of its many known oncogenic signaling pathways.	SIGNOR-256123	0.2
WT1	protein	P19544	UNIPROT	PODXL	protein	O00592	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11719225	t			Binding of WT1 to conserved elements within the Podocalyxin gene promoter results in potent transcriptional activation, and the specific expression pattern of Podocalyxin in the developing kidney mirrors that of WT1 itself.	SIGNOR-252300	0.421
NLGN4X	protein	Q8N0W4	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								18923512	t	brain	lperfetto	Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.	SIGNOR-264192	0.745
PRKAA1	protein	Q13131	UNIPROT	EP300	protein	Q09472	UNIPROT	down-regulates	phosphorylation	Ser89	SELLRSGsSPNLNMG	9606	BTO:0000801;BTO:0001271;BTO:0000876								21940946	t		gcesareni	The mechanism of ampk-mediated anti- inflammation involves the induction of p300 ser89 phosphor- ylation and subsequent inactivation of p300 hat activity.	SIGNOR-176637	0.384
TRIM25	protein	Q14258	UNIPROT	SFN	protein	P31947	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9534	BTO:0000298								12075357	t		miannu	Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest. 	SIGNOR-271548	0.59
JUND	protein	P17535	UNIPROT	FOSL1	protein	P15407	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									13679379	t		Luana	Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription. 	SIGNOR-261603	0.81
GRK5	protein	P34947	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates activity	phosphorylation	Ser129	NEAYEMPsEEGYQDY	9606									16957079	t		llicata	Grk5 phosphorylated ser-129 of alpha-synuclein at the plasma membrane and induced translocation of phosphorylated alpha-synuclein to the perikaryal area. Grk5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of alpha-synuclein.	SIGNOR-149372	0.621
MAPKAPK3	protein	Q16644	UNIPROT	HSPB1	protein	P04792	UNIPROT	unknown	phosphorylation	Ser78	PAYSRALsRQLSSGV	-1									8774846	t		miannu	MAPKAP kinase-3 and MAPKAP kinase-2 phosphorylated peptide substrates with similar kinetic constants and phosphorylated the same serine residues in HSP27 at the same relative rates.The three serine residues in HSP27 phosphorylated by MAPKAPK2 were also phosphorylated at the same relative rates by MAPKAP-K3 (Ser-82>>Ser-78 >Ser-15)	SIGNOR-250160	0.672
SKIL	protein	P12757	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	binding			9606									10531062	t		lperfetto	Thus, SnoN can interact with Smad4 and Smad2 and inhibit their abilities to activate transcription.	SIGNOR-227479	0.793
SUFU	protein	Q9UMX1	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates activity	relocalization			10090									10433919	t		lperfetto	Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling	SIGNOR-129068	0.885
ABL1	protein	P00519	UNIPROT	RAPH1	protein	Q70E73	UNIPROT	up-regulates activity	phosphorylation	Tyr426	LLRASGIyYVPKGKA	-1									20417104	t		miannu	Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C).	SIGNOR-262606	0.289
CSNK1A1	protein	P48729	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates activity	phosphorylation	Ser469	AHEENPEsILDEHVQ	-1									17318175	t		lperfetto	Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling.	SIGNOR-249192	0.776
HIF1A	protein	Q16665	UNIPROT	ALDOA	protein	P04075	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8955077	f	 	miannu	 we characterize hypoxia response elements in the promoters of the ALDA, ENO1, and Ldha genes. Our data establish that functional hypoxia-response elements consist of a pair of contiguous transcription factor binding sites at least one of which contains the core sequence 5'-RCGTG-3' and is recognized by HIF-1. These results provide further evidence that the coordinate transcriptional activation of genes encoding glycolytic enzymes which occurs in hypoxic cells is mediated by HIF-1.	SIGNOR-254422	0.344
PI3K	complex	SIGNOR-C156	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity				9606		BTO:0000586							16293724	f		lperfetto	We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein;G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt	SIGNOR-252711	0.785
YAP1	protein	P46937	UNIPROT	FSTL3	protein	O95633	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000222;BTO:0002314	BTO:0000887;BTO:0001103							23038772	f		gcesareni	In our analysis bmp4 (bone morphogenetic protein 4) and fstl3 (follistatin-related protein 3) increased their expression in response to hyap1 s127a overexpression.	SIGNOR-199072	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	ATP2A2	protein	P16615	UNIPROT	up-regulates activity	phosphorylation	Ser38	KLKERWGsNELPAEE	9606	BTO:0000007								7929371	t		llicata	SERCA2 and SERCA2 mutants S38A, S167A, and S531A were expressed in HEK-293 cells and tested for phosphorylation with CaM kinase. Mutant S38A was not phosphorylated, while mutants S167A and S531A were phosphorylated, suggesting that Ser38 is the site of CaM kinase phosphorylation in SERCA2. This conclusion was supported by the observation that phosphorylation of SERCA2 and mutants S167A and S531A by CaM kinase increased the Vmax for Ca2+ transport, while the Vmax for Ca2+ transport by mutant S38A was unaffected by exposure to a phosphorylation reaction mix.	SIGNOR-250616	0.406
chloride	smallmolecule	CHEBI:17996	ChEBI	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000227							18790874	f		miannu	GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-264989	0.7
MIB2	protein	Q96AX9	UNIPROT	JAG2	protein	Q9Y219	UNIPROT	up-regulates	ubiquitination			9606									15920166	t		gcesareni	Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2.	SIGNOR-137922	0.803
CCT2	protein	P78371	UNIPROT	TRiC	complex	SIGNOR-C539	SIGNOR	form complex	binding			9606									36185250	t		miannu	Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC).	SIGNOR-272860	0.746
SRC	protein	P12931	UNIPROT	UGT2B7	protein	P16662	UNIPROT	up-regulates	phosphorylation	Tyr438	RVINDPSyKENVMKL	9606									19289110	t		gcesareni	Overexpression of regular or active src, but not dominant-negative src, in 2b7-transfected cos-1 cells increased 2b7 activity and phospho-y438-2b7 by 50%	SIGNOR-184613	0.351
MAX	protein	P61244	UNIPROT	MAD1L1	protein	Q9Y6D9	UNIPROT	up-regulates activity	binding			9606									7954804	t	2	miannu	the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences.	SIGNOR-240357	0.305
CDH16	protein	O75309	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265855	0.373
DUSP3	protein	P51452	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	down-regulates activity	dephosphorylation			9534	BTO:0004055								10224087	t	inferred from 70% of family members		Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2	SIGNOR-269907	0.2
PPP2CA	protein	P67775	UNIPROT	MAPK15	protein	Q8TD08	UNIPROT	down-regulates	dephosphorylation	Thr175	GPEDQAVtEYVATRW	9606									16336213	t		lperfetto	Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20%	SIGNOR-142977	0.293
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr70	RNSPVTKtPPRDLPT	9606			SIGNOR-C3						10942774	t		lperfetto	Mammalian target of rapamycin-dependent phosphorylation of phas-i in four (s/t)p sites detected by phospho-specific antibodies.	SIGNOR-80797	0.924
thapsigargin	chemical	CHEBI:9516	ChEBI	ATP2A2	protein	P16615	UNIPROT	down-regulates activity	chemical inhibition			9534									30814986	t		lperfetto	Treatment of Vero cells with SERCA-specific inhibitor (Thapsigargin) at a concentration that is nontoxic to the cells significantly reduced Peste des petits ruminants virus (PPRV) and Newcastle disease virus (NDV) replication. |Thapsigargin inhibits NDV-induced SERCA2 expression in Vero cells	SIGNOR-262021	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	IL1B	protein	P01584	UNIPROT	up-regulates quantity	transcriptional regulation			9606	BTO:0001412								8021507	t			In these studies, we show that NF-kappa B induces transcription from the human pro-IL-1 beta (IL-1 beta) gene.	SIGNOR-255938	0.57
SH3RF1	protein	Q7Z6J0	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates	binding			9606									12514131	t		gcesareni	We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2.	SIGNOR-96955	0.337
IRF2	protein	P14316	UNIPROT	DST	protein	Q03001	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15560761	f		miannu	 Transient transfection studies with BPAG1 promoter-luciferase reporter gene plasmids and IRF1 and IRF2 expression plasmids revealed that IRF1 and IRF2 directly down-regulated BPAG1 gene transcription in cultured normal human epidermal keratinocytes.	SIGNOR-254493	0.2
PDPK1	protein	O15530	UNIPROT	CARD11	protein	Q9BXL7	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000782								15802604	t		gcesareni	We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts.	SIGNOR-134866	0.53
AMP	smallmolecule	CHEBI:456215	ChEBI	adenosine	smallmolecule	CHEBI:16335	ChEBI	up-regulates quantity	precursor of			-1									18940592	t		Luana	Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord.	SIGNOR-269738	0.8
IL15	protein	P40933	UNIPROT	IL2RG	protein	P31785	UNIPROT	up-regulates	binding			9606									11418623	t		gcesareni	The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex.	SIGNOR-108815	0.847
CDK1	protein	P06493	UNIPROT	FANCG	protein	O15287	UNIPROT	up-regulates	phosphorylation	Ser387	PRFSPPPsPPGPCMP	9606									15367677	t		gcesareni	S387a mutant abolished fancg fusion protein phosphorylation by cdc2.	SIGNOR-129061	0.361
KHDRBS1	protein	Q07666	UNIPROT	CREBBP	protein	Q92793	UNIPROT	down-regulates activity	binding			9606	BTO:0000093								12496368	t		miannu	These results suggest that Sam68 and CBP interact in vivo in a manner dependent on the FXE/DXXXL motif. Sam68 Represses CBP-dependent Transcriptional Activation	SIGNOR-266202	0.386
H2AC4	protein	P04908	UNIPROT	CENP-A nucleosome	complex	SIGNOR-C321	SIGNOR	form complex	binding			-1									23324462	t		miannu	 In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro.	SIGNOR-263700	0.2
PROS1	protein	P07225	UNIPROT	AXL	protein	P30530	UNIPROT	up-regulates	binding			9606									7867073	t		gcesareni	We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function.	SIGNOR-34483	0.479
quetiapine	chemical	CHEBI:8707	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258534	0.8
IL15	protein	P40933	UNIPROT	IL15RA	protein	Q13261	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001103							17709786	t			Interleukin-15 specificity and high affinity binding are conferred by the IL-5-specific but nonsignaling IL-15R alpha subunit, which is structurally similar (but not homologous) to the alpha receptor subunit of IL-2	SIGNOR-157415	0.863
BRCA1-BARD1 complex	complex	SIGNOR-C297	SIGNOR	H4C1	protein	P62805	UNIPROT	up-regulates activity	ubiquitination			-1									12485996	t		lperfetto	Strikingly, as well as H2AX, the nucleosome core histones H2A, H2B, H3 and H4 were all ubiquitylated efficiently by BRCA1/BARD1, while the linker histone H1 was not (Figure 3).| Generally, histone proteins are required for compaction of nuclear DNA into chromatin, and their modification is thought to loosen this compaction. Therefore, one might envisage that ubiquitylation of γH2AX by BRCA1/BARD1 at DNA breaks modulates local chromatin packaging to facilitate the action of DNA repair enzymes. 	SIGNOR-263234	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KA2	protein	Q15349	UNIPROT	up-regulates	phosphorylation			9606									8939914	t	inferred from 70% family members	gcesareni	Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms	SIGNOR-270144	0.2
SMAD1/5/8/SMAD4	complex	SIGNOR-C215	SIGNOR	RUNX2	protein	Q13950	UNIPROT	up-regulates	transcriptional regulation			10090	BTO:0000165								11073979	f		ggiuliani	As shown in Fig. 8A, overexpression of Smad5 by itself induced Runx2 expression even in the absence of BMP-2 (lane 5). Western blot analysis also confirmed the induced level of Runx2 protein in C2C12-Sm5 cells (Fig. 8B)	SIGNOR-255835	0.579
IKBKE	protein	Q14164	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Ser385	MARVGGAsSLENTVD	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikkepsilon And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178363	0.732
JUN	protein	P05412	UNIPROT	FOSL1	protein	P15407	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004603								13679379	t		Luana	Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription. 	SIGNOR-261604	0.82
KDM3B	protein	Q7LBC6	UNIPROT	H3-4	protein	Q16695	UNIPROT	down-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9534									16603237	t		miannu	We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation.	SIGNOR-266635	0.2
ARHGAP20	protein	Q9P2F6	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260473	0.412
PRKCE	protein	Q02156	UNIPROT	IQGAP1	protein	P46940	UNIPROT	up-regulates	phosphorylation	Ser1443	DKMKKSKsVKEDSNL	9606									21349850	t		gcesareni	Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth.	SIGNOR-172239	0.2
MAOA	protein	P21397	UNIPROT	3-methoxytyramine	smallmolecule	CHEBI:1582	ChEBI	down-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO.	SIGNOR-263999	0.8
MAPK14	protein	Q16539	UNIPROT	Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	up-regulates activity	phosphorylation			10029	BTO:0005787								20887952	t			The chromatin redistribution of PRC2 in differentiating SCs is regulated by the p38a kinase, which promotes the formation of a complex containing p38a, EZH2, and YY1, via direct phosphorylation of EZH2.	SIGNOR-253599	0.332
P2RY11	protein	Q96G91	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257060	0.2
IL1B	protein	P01584	UNIPROT	IL1RAP	protein	Q9NPH3	UNIPROT	up-regulates	binding			9606									9820540	t		gcesareni	The recently described il-1r accessory protein (il-1r acp) interacts with il-1beta and the il-1 type-ir (il-1ri).	SIGNOR-61744	0.862
GSK3B	protein	P49841	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates	phosphorylation	Ser231	LSTSSSSsPPGTPSP	9606							phosphorylation:Ser237	SSPPGTPsPADAKAP	22369944	t		fspada	However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs.	SIGNOR-196377	0.469
SMAD7	protein	O15105	UNIPROT	SMAD7/HDAC1/E2F-1	complex	SIGNOR-C12	SIGNOR	form complex	binding			9606									23213415	t		gcesareni	Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes	SIGNOR-199970	0.448
sumatriptan	chemical	CHEBI:10650	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000567								10193663	t		Luana	This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues 	SIGNOR-258340	0.8
CDK5	protein	Q00535	UNIPROT	NDEL1	protein	Q9GZM8	UNIPROT	up-regulates activity	phosphorylation	Ser231	GTENTFPsPKAIPNG	10090									12796778	t		llicata	Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function.	SIGNOR-250676	0.764
AMPK	complex	SIGNOR-C15	SIGNOR	CRTC1	protein	Q6UUV9	UNIPROT	down-regulates	phosphorylation			9606									21331044	t		lperfetto	Here we show that both ampk and calcineurin modulate longevity exclusively through post-translational modification of crtc-1, the sole c. elegans crtc. We demonstrate that crtc-1 is a direct ampk target.	SIGNOR-216529	0.289
PKN1	protein	Q16512	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Ser339	PRGQRDSsYYWEIEA	9606									15849194	t		llicata	P21-activated kinase 1 (pak1)-dependent phosphorylation of raf-1 regulates its mitochondrial localization, phosphorylation of bad, and bcl-2 association. moreover, the mitochondrial translocation of raf-1 and the interaction between raf-1 and bcl-2 are regulated by raf-1 phosphorylation at ser-338/ser-339.	SIGNOR-135679	0.2
fentanyl	chemical	CHEBI:119915	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258939	0.8
ALK	protein	Q9UM73	UNIPROT	GRB2	protein	P62993	UNIPROT	unknown	phosphorylation	Tyr160	QVPQQPTyVQALFDF	9606	BTO:0000007								20554525	t		lperfetto	Two phosphorylation sites on Grb2 have been identified thus far at position Tyr209 in BCR-ABL-expressing cells (16) and Tyr160 by pp60c-src (18)Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation.	SIGNOR-247142	0.479
CSF2	protein	P04141	UNIPROT	CSF2RA	protein	P15509	UNIPROT	up-regulates	binding			9606									9187659	t		gcesareni	We have determined the nmr structure of a ligand-binding domain of the granulocyte colony-stimulating factor (g-csf) receptor comparisons between the spectra of the 15n-labelled domain with and without g-csf indicate that the major ligand-recognition site is on the fg loop just upstream of the wsxws sequence.	SIGNOR-49126	0.851
TNFRSF14	protein	Q92956	UNIPROT	TRAF5	protein	O00463	UNIPROT	up-regulates activity	binding			9606									9153189	t		lperfetto	ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5|synergistic activation of NF-κB by ATAR and TRAF5 293 cells	SIGNOR-262592	0.613
UBE3A	protein	Q05086	UNIPROT	UBE3A	protein	Q05086	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001968								10864652	t		miannu	We show here that HPV16 E6 promotes the ubiquitination and degradation of E6AP itself. 	SIGNOR-271398	0.2
TIMP2	protein	P16035	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	down-regulates													17326328	f		lperfetto	There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3	SIGNOR-252273	0.7
ATOH7	protein	Q8N100	UNIPROT	POU4F2	protein	Q12837	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002181								11172005	t		Luana	Thus, these data suggest that the expression of Brn3b can be activated directly by Math5 and that it is also subject to positive feedback regulation by Brn3 proteins.	SIGNOR-261567	0.49
PTPRG	protein	P23470	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	dephosphorylation	Tyr319	TSVYESPySDPEELK	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254734	0.263
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606	BTO:0000007								9381178	t			Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival.	SIGNOR-251470	0.2
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Thr33	KFKNEDLtDELSLNK	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276204	0.389
PALB2	protein	Q86YC2	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								19369211	t		lperfetto	The BRCA1-PALB2 interaction is required for homologous recombination repair.Here, we report that PALB2, the partner and localizer of BRCA2, binds directly to BRCA1, and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex.	SIGNOR-244487	0.846
IRF4	protein	Q15306	UNIPROT	FCER2	protein	P06734	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								11342629	f	 	 	IFN-regulatory factor 4 (IRF-4) plays a critical role in mature B cell function. Using the transcriptional regulation of the human B cell activation marker CD23 as a model system, we have previously demonstrated that IRF-4 is induced in response to B cell-activating stimuli and that it acts as a transactivator of CD23 gene expression.	SIGNOR-253933	0.27
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser363	LKNKTESsLLAKLEE	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276209	0.2
MAPK14	protein	Q16539	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates activity	phosphorylation	Ser376	EKLFQGYsFVAPSIL										15568999	t		lperfetto	In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1	SIGNOR-249199	0.594
PRKCA	protein	P17252	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser594	HKAAVPAsEKLLLLK	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-129272	0.392
PKI-587	chemical	CID:44516953	PUBCHEM	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205989	0.8
SYK	protein	P43405	UNIPROT	MAP4K1	protein	Q92918	UNIPROT	up-regulates activity	phosphorylation	Tyr381	SESSDDDyDDVDIPT	9606									11514608	t		lperfetto	BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. BCR-mediated activation of HPK1 was impaired in Syk- or BASH-deficient B cells. The functional SH2 domain of BASH and Tyr-379 within HPK1 which we identified as a Syk-phosphorylation site were both necessary for interaction of both proteins and efficient HPK1 activation after BCR stimulation.	SIGNOR-246567	0.354
4-[6-[4-(1-piperazinyl)phenyl]-3-pyrazolo[1,5-a]pyrimidinyl]quinoline	chemical	CHEBI:91387	ChEBI	ACVR1	protein	Q04771	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193639	0.8
MAPK1	protein	P28482	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser425	TKGSGLGsPTSSFNS	9606									18204439	t		lperfetto	Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation.	SIGNOR-160415	0.71
BRCA1	protein	P38398	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0003323		SIGNOR-C297						12485996	t		lperfetto	The major genetic evidence supporting ubiquitin ligase function for BRCA1 in vivo comes from studies on the FANCD2 protein. Whereas in wild‐type cells the FANCD2 protein co‐localizes with BRCA1 in nuclear foci and becomes monoubiquitylated in response to DNA damage, HCC1937 cells, which encode a mutated form of BRCA1, are largely defective for both monoubiquitylation of FANCD2 and foci formation	SIGNOR-263236	0.839
9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone	chemical	CID:71748056	PUBCHEM	ITK	protein	Q08881	UNIPROT	down-regulates activity	chemical inhibition			-1									24556163	t		miannu	This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine 	SIGNOR-262236	0.8
PHF12	protein	Q96QT6	UNIPROT	Sin3B_complex	complex	SIGNOR-C409	SIGNOR	form complex	binding			9606	BTO:0000007								21041482	t		miannu	We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin.	SIGNOR-266969	0.791
PTPRJ	protein	Q12913	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	dephosphorylation	Tyr530	FTSTEPQyQPGENL	10116									26556953	t		lperfetto	Expression of Dep1 in transformed rat thyroid PCMPSV cells increased Src activity via Y527 dephosphorylation (corresponding to Y530 in human Src) without affecting the level of phosphorylated Y416 (Y419 in human Src).|Reciprocally, Dep1 can be phosphorylated by Src and Fyn on Y1311 and Y1320, leading to the dephosphorylation of Y530 Src by Dep1 .	SIGNOR-276977	0.622
HOXD9	protein	P28356	UNIPROT	MEIS1	protein	O00470	UNIPROT	up-regulates activity	binding			9606									10523646	t		miannu	We find that DNA binding by MEIS1A is absolutely required for the formation of a cooperative complex with HOXD9	SIGNOR-220721	0.522
HIPK2	protein	Q9H2X6	UNIPROT	HIPK2	protein	Q9H2X6	UNIPROT	up-regulates activity	phosphorylation	Thr880	QTIVIPDtPSPTVSV	9606	BTO:0002181								24145406	t		miannu	 Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site-specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation-acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo.	SIGNOR-276601	0.2
CDK12	protein	Q9NYV4	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1878	SPKYSPTsPTYSPTT	9606									22012619	t		miannu	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176805	0.775
MAPK1	protein	P28482	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates activity	phosphorylation	Ser282	TAPLSPMsPPGYKLV	9606	BTO:0000567								9535909	t		lperfetto	These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.	SIGNOR-249403	0.595
FFAR4	protein	Q5NUL3	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257420	0.435
RUNX2	protein	Q13950	UNIPROT	BGLAP	protein	P02818	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11331591	f		gcesareni	Tgf-beta inhibited the expression of the cbfa1 and osteocalcin genes, whose expression is controlled by cbfa1 in osteoblast-like cell lines. This inhibition was mediated by smad3, which interacts physically with cbfa1 and represses its transcriptional activity at the cbfa1-binding ose2 promoter sequence	SIGNOR-107160	0.596
DMAP1	protein	Q9NPF5	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269298	0.771
mTORC1	complex	SIGNOR-C3	SIGNOR	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Thr412	NQVFLGFtYVAPSVL	9606									10579915	t		lperfetto	Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response toinsulinand nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size.	SIGNOR-217060	0.749
CCNF	protein	P41002	UNIPROT	FZR1	protein	Q9UM11	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									27653696	t		miannu	We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1. 	SIGNOR-266363	0.517
MTNR1A	protein	P48039	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256849	0.475
Platelet_alpha_granule_formation	phenotype	SIGNOR-PH136	SIGNOR	VWF	protein	P04275	UNIPROT	up-regulates				9606									NBK559062	f		lperfetto	Exposed VWF bound to collagen from vascular injury and endothelial damage adheres to the GPIb receptor on platelets to initiate signaling pathways for platelet activation, the next step in primary hemostasis. VW|VWF released by Weibel-Palade bodies or alpha-granules can enter circulation or accumulate in the subendothelial matrix binding to collagen through its A3 domain. Once exposed under high shear stress conditions in the arterial circulation, VWF can bind to platelets via its A1 domain. 	SIGNOR-261863	0.7
GNRH1	protein	P01148	UNIPROT	EGR1	protein	P18146	UNIPROT	up-regulates activity	binding			10090									19106114	t		miannu	EGR1 bound to two binding sites on the LHB promoter and this binding was increased by GNRH1. Mutation of either site or knockdown of endogenous EGR1 decreased basal and/or GNRH1-regulated promoter activity. 	SIGNOR-254918	0.456
metaproterenol	chemical	CHEBI:6792	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline)	SIGNOR-257875	0.8
PPP2R1A	protein	P30153	UNIPROT	PPP2CB	protein	P62714	UNIPROT	up-regulates	binding			9606									16039140	t		miannu	Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme	SIGNOR-138886	0.886
HDAC2	protein	Q92769	UNIPROT	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	down-regulates				9606									28793257	f			Among histone-modifying enzymes, HDAC2 is a crit- ical negative regulator of structural and functional plasticity in the mammalian nervous system (Guan et al., 2009; Hanson et al., 2013). HDAC2 localizes to the promoters of numerous synap- tic-plasticity-associated genes, where it deacetylates histone substrates (Gra ̈ ff et al., 2012; Guan et al., 2009). Consistently, loss of HDAC2 or HDAC inhibitor treatments promotes synaptic gene expression, long-term synaptic plasticity, and memory pro- cesses, while HDAC2 overexpression has opposing effects 	SIGNOR-268624	0.7
GNAS	protein	P63092	UNIPROT	PLCB1	protein	Q9NQ66	UNIPROT	up-regulates activity	binding			9606									8245028	t		MIANNU	The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits.	SIGNOR-265066	0.33
PTPRG	protein	P23470	UNIPROT	STAT2	protein	P52630	UNIPROT	up-regulates activity	dephosphorylation	Tyr690	NLQERRKyLKHRLIV	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254728	0.2
PRDM16	protein	Q9HAZ2	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	down-regulates				9606	BTO:0000222	BTO:0000887;BTO:0001103							18719582	f		fspada	Loss of prdm16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of prdm16 in myoblasts induces their differentiation into brown fat cells.	SIGNOR-180301	0.7
ZNF202	protein	O95125	UNIPROT	POMGNT1	protein	Q8WZA1	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22419172	f		miannu	 Here, we describe the first dystroglycanopathy patient carrying an alteration in the promoter region of the POMGNT1 gene (protein O-mannose β-1,2-N-acetylglucosaminyltransferase 1), which involves a homozygous 9-bp duplication (-83_-75dup). Analysis of the downstream effects of this mutation revealed a decrease in the expression of POMGNT1 mRNA and protein because of negative regulation of the POMGNT1 promoter by the transcription factor ZNF202 (zinc-finger protein 202).	SIGNOR-255626	0.252
BMP2	protein	P12643	UNIPROT	BMPR2	protein	Q13873	UNIPROT	up-regulates activity	binding			9534				SIGNOR-C29					7791754	t		lperfetto	Under our assay conditions, bmp-2 binds better to bmpr-ii in combination with actr-i or bmpr-ib than in combination with bmpr-ia	SIGNOR-144101	0.793
PIAS3	protein	Q9Y6X2	UNIPROT	SMAD3/PIAS3	complex	SIGNOR-C204	SIGNOR	form complex	binding			9606									26194464	t		mrosina	In summary, the TGF-b/IL-6/TCR-ERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation	SIGNOR-255035	0.58
MASTL	protein	Q96GX5	UNIPROT	MASTL	protein	Q96GX5	UNIPROT	up-regulates activity	phosphorylation	Ser875	TAQHLTVsGFSL	8355					phosphorylation:Thr194;Thr207	NMMDILTtPSMAKPR;PRQDYSRtPGQVLSL			22354989	t		gcesareni	After this priming step, Gwl can intramolecularly phosphorylate its C-terminal tail at pS883; this site probably plays a role similar to that of the tail/Z motif of other AGC kinases.	SIGNOR-243409	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	SERPINA3	protein	P01011	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002600								11027208	f		miannu	We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. 	SIGNOR-254805	0.2
linifanib	chemical	CHEBI:91435	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258242	0.8
Lewy_body_formation	phenotype	SIGNOR-PH56	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000938								20479780	f		lperfetto	The genetic causes of PD seem to participate in con­ verging pathways to pathogenesis, but it is unclear whether all or only some of these pathways need to be activated for lewy body deposition and neuronal death to occur.	SIGNOR-249703	0.7
CSNK2A1	protein	P68400	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates activity	phosphorylation	Ser77	PTAGALYsGSEGDSE	-1									2046671	t		llicata	Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated. 	SIGNOR-250955	0.532
MAPK14	protein	Q16539	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Ser567	SLAWLSDsPLFDLIK	9606									20871633	t		llicata	P38 bypasses the cell cycle-associated hierarchical phosphorylation and directly phosphorylates rb on ser567, which is not phosphorylated during the normal cell cycle. Phosphorylation by p38, but not cdks, triggers an interaction between rb and the human homolog of murine double minute 2 (hdm2), leading to degradation of rb, release of e2f1 and cell death.	SIGNOR-168178	0.519
HCK	protein	P08631	UNIPROT	HCK	protein	P08631	UNIPROT	up-regulates activity	phosphorylation	Tyr51	ASPHCPVyVPDPTST	9606	BTO:0000007								10934191	t			Hck transiently expressed in human embryonic kidney 293T cells was found to be phosphorylated at Tyr-29 and Tyr-388, proving that Hck can also undergo autophosphorylation at both sites in vivo. autophosphorylation of Tyr-29 contributes significantly to the activation of Hck.	SIGNOR-251265	0.2
P2RY1	protein	P47900	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257072	0.2
NFYA	protein	P23511	UNIPROT	GCH1	protein	P30793	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15496512	f		miannu	Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter.	SIGNOR-252232	0.2
ROCK1	protein	Q13464	UNIPROT	ARHGAP24	protein	Q8N264	UNIPROT	up-regulates activity	phosphorylation	Ser402	LSGSKTNsPKNSVHK	9606	BTO:0000007								16862148	t		lperfetto	ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2).	SIGNOR-249304	0.444
TTK	protein	P33981	UNIPROT	CDCA8	protein	Q53HL2	UNIPROT	up-regulates	phosphorylation	Thr94	ATADLDItEINKLTA	9606									19530738	t		lperfetto	First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form.	SIGNOR-186155	0.472
POLR2K	protein	P53803	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266168	0.827
ILK	protein	Q13418	UNIPROT	ILK	protein	Q13418	UNIPROT	up-regulates activity	phosphorylation	Ser343	SMADVKFsFQCPGRM	9606									11313365	t		lperfetto	Although ilk has been shown to autophosphorylate serine 343 (s343) is in the hydrophobic motif fsf within the activation loop of the kinase domain and has previously been suggested to be the target of autophosphorylation (9). Mutation of serine 343 to alanine (s343a) resulted in the inability of ilk to stimulate phosphorylation of pkb/akt in cos cells (9).	SIGNOR-106838	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser552	VVRTPPKsPSSAKSR	9606	BTO:0000590								10090741	t		lperfetto	We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II.	SIGNOR-249316	0.578
IDH	complex	SIGNOR-C396	SIGNOR	NADH	smallmolecule	CHEBI:16908	ChEBI	up-regulates quantity	chemical modification			9606									28139779	t		miannu	Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP.	SIGNOR-266260	0.8
ID2	protein	Q02363	UNIPROT	MYOD/E2-2	complex	SIGNOR-C129	SIGNOR	down-regulates activity	binding			10090	BTO:0004058								9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241146	0.586
NMB	protein	P08949	UNIPROT	NMBR	protein	P28336	UNIPROT	up-regulates	binding			9606	BTO:0001130;BTO:0000551								11313903	t		gcesareni	These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins.	SIGNOR-107022	0.759
MTOR	protein	P42345	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser293	SSGYFSSsPTLSSSP	9606									22017875	t		llicata	Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome.	SIGNOR-176849	0.747
sertindole	chemical	CHEBI:9122	ChEBI	HTR1E	protein	P28566	UNIPROT	down-regulates activity	chemical inhibition			9534									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258543	0.8
F2R	protein	P25116	UNIPROT	THBS1	protein	P07996	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254850	0.308
MT-CO2	protein	P00403	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267748	0.758
NSD1	protein	Q96L73	UNIPROT	PRB4	protein	P10163	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003233								29156722	t		miannu	We here demonstrate that NSD1 could bind to the promoter regions of PRB4 and activate promoter activity by reducing the binding of H3K27me2 and increasing the binding of H3K36me2 on PRB4 promoter. 	SIGNOR-268459	0.35
PARL	protein	Q9H300	UNIPROT	PINK1	protein	Q9BXM7	UNIPROT	down-regulates quantity by destabilization	cleavage			9606	BTO:0000007								22354088	t		miannu	Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy.	SIGNOR-261364	0.634
beta-D-fructofuranose 2,6-bisphosphate	smallmolecule	CHEBI:28602	ChEBI	PFK	proteinfamily	SIGNOR-PF79	SIGNOR	up-regulates activity	binding			9606									19454274	t			The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux	SIGNOR-267262	0.8
TBK1	protein	Q9UHD2	UNIPROT	PRPS2	protein	P11908	UNIPROT	up-regulates activity	phosphorylation	Thr228	DMADTCGtICHAADK	-1									34343500	t		miannu	Here, we show that ionizing radiation results in TBK1-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2 at T228, thereby enhancing PRPS1/2 catalytic activity and promoting deoxyribonucleotide synthesis. 	SIGNOR-277317	0.2
PIK3AP1	protein	Q6ZUJ8	UNIPROT	PIK3CB	protein	P42338	UNIPROT	up-regulates	binding			9606	BTO:0000801								22187458	t		gcesareni	This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Therefore, bcap is an essential activator of the pi3k pathway downstream of tlr signaling, providing a brake to limit potentially pathogenic excessive tlr responses.	SIGNOR-191667	0.397
S1PR3	protein	Q99500	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257437	0.357
DYRK1A	protein	Q13627	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser330	RLSPIMAsTELDEVQ	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition.	SIGNOR-252907	0.521
MAP3K3	protein	Q99759	UNIPROT	MAP3K3	protein	Q99759	UNIPROT	up-regulates	phosphorylation	Ser526	MSGTGMRsVTGTPYW	9606	BTO:0000007								16407301	t		lperfetto	Phosphorylation of serine 526 is required for mekk3 activity, and association with 14-3-3 blocks dephosphorylationautophosphorylation of mekk3 at ser526	SIGNOR-143647	0.2
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	phosphorylation			9606		BTO:0000763;BTO:0000149							10197981	t		lperfetto	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-236067	0.739
DLG4	protein	P78352	UNIPROT	LRFN1	protein	Q9P244	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								21736948	t		miannu	 SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. Interactions between SALMs 1–3 and PSD-95 family proteinscould serve a number of functions. SALM1 and SALM2, which lack the ability to interact with a presynaptic ligand and thus cannot be directly targeted to sites of early synaptic adhesion, may require PSD-95 binding for their localization to early synapses.	SIGNOR-264095	0.767
SKP1	protein	P63208	UNIPROT	SCF-SKP2	complex	SIGNOR-C136	SIGNOR	form complex	binding			9606									15340381	t		gcesareni	The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions.	SIGNOR-243554	0.94
CDK5	protein	Q00535	UNIPROT	SYN1	protein	P17600	UNIPROT	up-regulates	phosphorylation	Ser553	ARPPASPsPQRQAGP	9606									10880969	t		lperfetto	Synapsin i (syni), a major sv phosphoprotein involved in the regulation of sv trafficking and neurotransmitter release, is one of the presynaptic substrates of cdk5, which phosphorylates it in its c-terminal region at ser(549) (site 6) and ser(551) (site 7). Phosphorylation of syni by cdk5 is physiologically regulated and enhances its binding to f-actin.	SIGNOR-78887	0.581
IKBKE	protein	Q14164	UNIPROT	TRAF3IP2	protein	O43734	UNIPROT	up-regulates activity	phosphorylation	Ser328	KVILNYPsPWDHEER	9606									21822257	t		miannu	 IKKi was required for IL-17-induced phosphorylation of Act1 on Ser311, adjacent to a putative TRAF-binding motif. Substitution of the serine at position 311 with alanine impaired the IL-17-mediated Act1-TRAF2-TRAF5 interaction and gene expression. Thus, IKKi is a kinase newly identified as modulating IL-17 signaling through its effect on Act1 phosphorylation and consequent function.	SIGNOR-262883	0.425
PPP2CB	protein	P62714	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	dephosphorylation	Thr423	PEQSKRStMVGTPYW	10116									18586681	t			Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation.	SIGNOR-248600	0.2
RPS6KB1	protein	P23443	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser286	SSMSSCGsSGYFSSS	9606									22017876	t		llicata	Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation.	SIGNOR-176858	0.659
BMP2	protein	P12643	UNIPROT	BMPR1A	protein	P36894	UNIPROT	up-regulates activity	binding			-1									18937504	t		ggiuliani	Here we report the high-resolution NMR structure of BMPR-IA ECD in solution, revealing that a large part of the ligand-binding epitope is unfolded and flexible before formation of the complex. The binding beta4beta5 loop of BMPR-IA passes through a structural rearrangement upon BMP-2 binding.	SIGNOR-255771	0.927
SH3GL2	protein	Q99962	UNIPROT	Endocytosis	phenotype	SIGNOR-PH123	SIGNOR	up-regulates				9606									25517094	f		miannu	Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. 	SIGNOR-263883	0.7
PEA15	protein	Q15121	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates				9606									11702783	f		gcesareni	Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase.	SIGNOR-111499	0.862
PPP2CA	protein	P67775	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	dephosphorylation	Thr423	PEQSKRStMVGTPYW	10116									18586681	t			Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation.	SIGNOR-248643	0.364
RING1	protein	Q06587	UNIPROT	FHL1	protein	Q13642	UNIPROT	up-regulates	binding			9606									14999091	t		gcesareni	The polycombprotein ring1 interacts with the lim domains of kyot2 in yeast and mammalian cells. The interaction between kyot2 and ring1 was detected both in vitro and in vivo	SIGNOR-123150	0.364
SHH	protein	Q15465	UNIPROT	CP	protein	P00450	UNIPROT	down-regulates	binding			9606									14556242	t		gcesareni	Two genes were newly identified to be shh responsive in neuroepithelial cell line mns-70: the metal-binding protein ceruloplasmin (cp) and the serine protease inhibitor inter-alpha-trypsine inhibitor heavy chain h3 (itih3). cp appeared to be regulated by gli-independent pathways.	SIGNOR-118612	0.2
DRD1	protein	P21728	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257269	0.272
AGT	protein	P01019	UNIPROT	AGTR2	protein	P50052	UNIPROT	up-regulates				9606	BTO:0001130								16597412	f		gcesareni	Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors.	SIGNOR-145680	0.819
BMP7	protein	P18075	UNIPROT	MMP13	protein	P45452	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003858								12734180	f		miannu	In the present study we investigated the inhibitory effects of IGF-1 and OP-1 on MMP-13 expression in human chondrocytes. We found that the suppressive effect of IGF-1 and OP-1 on the MMP-13 promoter activity was dose-dependent at the transcriptional level with a corresponding decrease in the level of MMP-13 protein. 	SIGNOR-254801	0.358
CCL21	protein	O00585	UNIPROT	ACKR4	protein	Q9NPB9	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								23341447	t		Luana	 In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines.	SIGNOR-268417	0.652
SALL4	protein	Q9UJQ4	UNIPROT	ZEB1	protein	P37275	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000356								23954296	f		miannu	 Our shRNA-mediated SALL4 knockdown system and SALL4 overexpression system revealed that SALL4 suppresses the expression of adhesion gene CDH1, and positively regulates the CDH1 suppressor ZEB1. 	SIGNOR-255123	0.255
POMC	protein	P01189	UNIPROT	MC2R	protein	Q01718	UNIPROT	up-regulates activity	binding			10029		BTO:0000047							20371771	t		lperfetto	Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP). 	SIGNOR-268615	0.776
INSR	protein	P06213	UNIPROT	DOK5	protein	Q9P104	UNIPROT	up-regulates				9606		BTO:0000887;BTO:0001103;BTO:0000671							12730241	f		lperfetto	Irs5/dok4 and irs6/dok5 represent two new signaling proteins with potential roles in insulin and igf-1 action	SIGNOR-101038	0.382
PCC	complex	SIGNOR-C414	SIGNOR	(S)-methylmalonyl-CoA(5-)	smallmolecule	CHEBI:57327	ChEBI	up-regulates quantity	chemical modification			9606									15890657	t		miannu	Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively.	SIGNOR-267186	0.8
PRKCA	protein	P17252	UNIPROT	PDE3A	protein	Q14432	UNIPROT	up-regulates	phosphorylation	Ser428	IPKRLRRsLPPGLLR	9606									19261611	t		llicata	Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding.	SIGNOR-184452	0.2
SLBP	protein	Q14493	UNIPROT	Histone H2A	proteinfamily	SIGNOR-PF70	SIGNOR	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265374	0.2
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGA7	protein	Q9Y5G6	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265709	0.2
BRAF	protein	P15056	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates activity	phosphorylation			-1									8413257	t		lperfetto	Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1.	SIGNOR-244831	0.779
RYK	protein	P34925	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates	binding			9606									15454084	t		gcesareni	Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled.	SIGNOR-129568	0.497
VWF	protein	P04275	UNIPROT	F8	protein	P00451	UNIPROT	up-regulates activity	binding			9606									23020315	t		miannu	Binding of FVIII to VWF is needed to maintain appropriate plasma levels, as FVIII plasma levels and half-life are remarkably reduced in the absence of VWF	SIGNOR-251967	0.782
ARAF	protein	P10398	UNIPROT	SLC9A3R2	protein	Q15599	UNIPROT	up-regulates activity	phosphorylation	Ser303	QESGLHLsPTAAEAK	9606	BTO:0002269								26310448	t		miannu	We also identify A-Raf as a kinase necessary for E3KARP phosphorylation at the G2/M stage of the cell cycle. Phosphorylation of Ser-303 regulates the localization, function, and dynamics of E3KARP	SIGNOR-273503	0.384
tamsulosin	chemical	CHEBI:9398	ChEBI	ADRA1A	protein	P35348	UNIPROT	down-regulates activity	chemical inhibition			10029									7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258474	0.8
GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	relocalization			9606									18790874	t	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263810	0.8
PRKCD	protein	Q05655	UNIPROT	CYTH1	protein	Q15438	UNIPROT	unknown	phosphorylation	Ser394	ARKKKVSsTKRH	9606	BTO:0001948								11438522	t		lperfetto	We show here that a serine/threonine motif within the short polybasic stretch of cytohesin-1 is phosphorylated by purified protein kinase C delta in vitro. Furthermore, the respective residues are also found to be phosphorylated after phorbol ester stimulation in vivo. Biochemical and functional analyses show that phosphorylated cytohesin-1 is able to tightly associate with the actin cytoskeleton, and we further demonstrate that phosphorylation of the protein is required for maximal leukocyte function antigen-1-mediated adhesion of Jurkat cells to intercellular adhesion molecule 1. 	SIGNOR-249098	0.328
PAX7	protein	P23759	UNIPROT	Quiescence	phenotype	SIGNOR-PH25	SIGNOR	up-regulates						BTO:0001103							15501225	f		svumbaca	Our work presented here provides a possible mechanism involving Pax-7 that allow satellite cells to exit the cell cycle, down-regulate MyoD, and prevent myogenin induction, phenotypes characteristic of the quiescent satellite cell.	SIGNOR-255366	0.7
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CDK1	protein	P06493	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258071	0.8
MAPK3	protein	P27361	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates activity	phosphorylation	Ser279	SSPTAPLsPMSPPGY	9606									9535909	t		lperfetto	These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.	SIGNOR-249466	0.626
GNAS	protein	P63092	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	up-regulates	binding			9606	BTO:0000586								16293724	t		lperfetto	We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin.	SIGNOR-227988	0.389
CDK1	protein	P06493	UNIPROT	UBE2A	protein	P49459	UNIPROT	up-regulates	phosphorylation	Ser120	LDEPNPNsPANSQAA	9606									11953320	t		llicata	Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity.	SIGNOR-116504	0.377
KNTC1	protein	P50748	UNIPROT	RZZ complex	complex	SIGNOR-C357	SIGNOR	form complex	binding			9606	BTO:0000567								20462495	t		lperfetto	The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico.	SIGNOR-265015	0.754
RANBP2	protein	P49792	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates quantity	relocalization			9606	BTO:0002932								28882106	t		irozzo	RanBP2 can increase the sumoylation of p27kip1. In our study, the target protein p27kip1 mainly acts as a tumor-suppressor gene in the nucleus, RanBP2 and SUMO1 act as oncogenes by promoting the nuclear-cytoplasmic translocation and debilitate the G1-arrest brought by p27kip1 accumulation in the nucleus.	SIGNOR-259115	0.2
SHC1	protein	P29353	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271;BTO:0000785								24737791	t		lperfetto	The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival	SIGNOR-236236	0.965
FAS	protein	P25445	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates	binding			9606									11495919	t		amattioni	Ask1 binds fas	SIGNOR-109676	0.68
LPAR4	protein	Q99677	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257258	0.2
MAPK14	protein	Q16539	UNIPROT	GATA2	protein	P23769	UNIPROT	up-regulates	phosphorylation			9606									25056917	t		miannu	P38_ increases gata_2 activity at endogenous target genes by inducing gata_2 multi_site phosphorylation.	SIGNOR-205242	0.273
KIT	protein	P10721	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	binding			9606									15526160	t		miannu	C-Kit stimulates rapid and transient tyrosine phosphorylation of JAK2. JAK2 was found to be constitutively associated with c-Kit, with increased association after ligand stimulation of c-Kit	SIGNOR-254954	0.597
progesterone	smallmolecule	CHEBI:17026	ChEBI	17alpha-hydroxyprogesterone	smallmolecule	CHEBI:17252	ChEBI	up-regulates quantity	precursor of			9606		BTO:0001363;BTO:0000048;BTO:0000050							17192295	t		lperfetto	THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones.	SIGNOR-268649	0.8
MT-ND6	protein	P03923	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 	SIGNOR-262149	0.757
SLBP	protein	Q14493	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265413	0.2
TFEB	protein	P19484	UNIPROT	ACACB	protein	O00763	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2)	SIGNOR-276780	0.2
HTR7	protein	P34969	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256783	0.5
CDK3	protein	Q00526	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2516	FLTPSPEsPDQWSSS	-1									25344755	t		lperfetto	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273168	0.245
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	SLX4	protein	Q8IY92	UNIPROT	up-regulates				-1									10542278	f		miannu	HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay.	SIGNOR-259063	0.7
LRP1B	protein	Q9NZR2	UNIPROT	DVL2	protein	O14641	UNIPROT	down-regulates activity	binding			9606									28408316	t		irozzo	In this study, we have shown that LRP1B inhibited the activity of beta-catenin/TCF signaling possibly by interacting with DVL2. The molecular mechanism study revealed that LRP1B interacted with DVL2, inhibited the interaction between DVL2 and Axin, and negatively regulated beta-catenin/TCF signaling.	SIGNOR-259090	0.394
IL6	protein	P05231	UNIPROT	IL6R	protein	P08887	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000142							8676083	t		fspada	We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of il-6 and soluble il-6r (sil-6r), a complex that is known to interact with and activate a signal transducing receptor component, gp130	SIGNOR-42866	0.916
SS18L1	protein	O75177	UNIPROT	CREBBP	protein	Q92793	UNIPROT	up-regulates	relocalization			9606	BTO:0000938								15488321	t		miannu	The calcium-responsive transactivator recruits creb binding protein to nuclear bodies.	SIGNOR-129926	0.406
PPM1A	protein	P35813	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates quantity by destabilization	dephosphorylation			9606									10644691	t			In addition, PP2C expression relieves Axin-mediated repression of LEF-1-dependent transcription. PP2C utilizes Axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that PP2C is a positive regulator of Wnt signal transduction and mediates its effects through the dephosphorylation of Axin.	SIGNOR-248488	0.446
GNG2	protein	P59768	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606	BTO:0000938								16537363	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt.	SIGNOR-145122	0.455
ATM	protein	Q13315	UNIPROT	UBQLN4	protein	Q9NRR5	UNIPROT	up-regulates activity	phosphorylation	Ser318	GNSDSSSsQPLRTEN	9606	BTO:0001938								30612738	t		lperfetto	These results suggest that UBQLN4 phosphorylation on S318 is functionally important for its role in the DSB response.>Particularly HRR is dependent on ATM activity (Dietlein et al., 2014). Here, we showed that UBQLN4 is an ATM substrate and that DSB sealing is markedly impaired in UBQLN4-depleted cells. HRR depends on a 5′-3′ DSB end resection, which is initiated by the MRE11 nuclease	SIGNOR-265076	0.2
CHGA	protein	P10645	UNIPROT	Secretory_granule_organization	phenotype	SIGNOR-PH87	SIGNOR	up-regulates				10090									12456801	f			CgA was initially identified as the major soluble matrix protein of secretory vesicles formed in neuroendocrine cells. Its functions include modulation of secretory granule stability, prohormone processing, and regulation of peptide sorting into secretory pathways	SIGNOR-254274	0.7
NCOR2	protein	Q9Y618	UNIPROT	BHLHE41	protein	Q9C0J9	UNIPROT	up-regulates	binding			9606									12897056	t		gcesareni	The spen protein, sharp (smrt/hdac1-associated repressor protein), was identified as a component of transcriptional repression complexes in both nuclear receptor and notch/rbp-jkappa signaling pathways.	SIGNOR-104489	0.2
PSMD8	protein	P48556	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263345	0.911
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser321	SKPSGNDsCELRNLK	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276213	0.2
TP73	protein	O15350	UNIPROT	BBC3	protein	Q96PG8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17700533	f	 	miannu	Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. 	SIGNOR-255467	0.451
vildagliptin	chemical	CHEBI:135285	ChEBI	DPP4	protein	P27487	UNIPROT	down-regulates activity	chemical inhibition			9606									19149538	t		Luana	Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched.	SIGNOR-257812	0.8
JAK1/STAT1/STAT3	complex	SIGNOR-C120	SIGNOR	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	up-regulates				9606									30029643	f		areggio	Taken together, our data show IL-15 can enhance the collagen deposition in vivo after muscle damage and this process can be prevented by blocking Jak-STAT pathway. 	SIGNOR-256231	0.7
NLGN2	protein	Q8NFZ4	UNIPROT	NRXN1	protein	Q9ULB1	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264146	0.819
GABPB2	protein	Q8TAK5	UNIPROT	HCFC1	protein	P51610	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								10675337	t		miannu	The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1–GABP interaction can inhibit GABP_dependent transcriptional activation	SIGNOR-221318	0.2
MAPK3	protein	P27361	UNIPROT	ETV6	protein	P41212	UNIPROT	down-regulates	phosphorylation	Ser257	ESHPKPSsPRQESTR	10090	BTO:0000944								15060146	t		miannu	Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation.	SIGNOR-260085	0.323
HES6	protein	Q96HZ4	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150;BTO:0000938								19891787	f		gcesareni	Expression of hes-6 resulted in induction of e2f-1, a crucial target gene for the transcriptional repressor hes-1	SIGNOR-189101	0.2
NODAL	protein	Q96S42	UNIPROT	ACVR1B	protein	P36896	UNIPROT	up-regulates activity	binding			9606									19874624	t	Regulation	miannu	Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors.	SIGNOR-251939	0.628
PRKACA	protein	P17612	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser673	RVQSKIGsLDNITHV	-1									12435421	t		miannu	Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly 	SIGNOR-250007	0.442
DRAP1	protein	Q14919	UNIPROT	BTAF1	protein	O14981	UNIPROT	up-regulates activity	binding			9986									15509807	t		miannu	We present evidence that the NC2alpha subunit interacts with BTAF1. Addition of NC2alpha or the NC2 complex can stimulate the ability of BTAF1 to interact with TBP.	SIGNOR-263918	0.52
CSNK1E	protein	P49674	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates	phosphorylation			9606				SIGNOR-C110					12000790	t		gcesareni	We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms.	SIGNOR-87444	0.737
CDK1	protein	P06493	UNIPROT	CENPA	protein	P49450	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser68	LIRKLPFsRLAREIC	9606	BTO:0000567								34758320	t		miannu	Here, we report that the phosphorylation of CENP-A Ser68 primes the ubiquitin-proteasome-mediated proteolysis of CENP-A during mitotic phase in human cultured cells.the mitotic CENP-A degradation specifically depends on Cdk1 activity. 	SIGNOR-277576	0.667
FGF14	protein	Q92915	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253413	0.564
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1920	SPTYSPTsPKYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269335	0.718
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	AMBRA1	protein	Q9C0C7	UNIPROT	up-regulates activity	phosphorylation	Ser1252	QPTLPSSsPVPIPVS	9606	BTO:0000567								37584777	t	phosphorylation site remapping based on mass spec table	lperfetto	CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects.	SIGNOR-272969	0.259
PIM2	protein	Q9P1W9	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr145	QGRKRRQtSMTDFYH	9606									20307683	t		lperfetto	Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellsere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo	SIGNOR-164646	0.413
MUSK	protein	O15146	UNIPROT	MUSK	protein	O15146	UNIPROT	up-regulates activity	phosphorylation			9606		BTO:0000887							23458718	t		miannu	AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer. 	SIGNOR-273851	0.2
GSK3A	protein	P49840	UNIPROT	GRB14	protein	Q14449	UNIPROT	down-regulates activity	phosphorylation	Ser362	QGRSGCSsQSISPMR	-1									28130417	t		lperfetto	Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3.	SIGNOR-264870	0.267
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NCOA3	protein	Q9Y6Q9	UNIPROT	down-regulates	phosphorylation	Ser728	VVKQEQLsPKKKENN	9606									22163316	t		lperfetto	We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase.	SIGNOR-216892	0.32
CSNK2A1	protein	P68400	UNIPROT	PDCL	protein	Q13371	UNIPROT	up-regulates	phosphorylation	Ser19	KLQYYYSsSEDEDSD	9606									16717095	t		lperfetto	Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2.	SIGNOR-146829	0.36
PRKAA1	protein	Q13131	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	down-regulates activity	phosphorylation	Ser792	DKMRRASsYSSLNSL	10090	BTO:0002572		SIGNOR-C15	SIGNOR-C3					18439900	t		lperfetto	The phosphorylation of raptor by ampk is required for the inhibition of mtorc1 and cell-cycle arrest induced by energy stress.	SIGNOR-161375	0.674
PARP1	protein	P09874	UNIPROT	POLA1	protein	P09884	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								9518481	t		Federica	We provide evidence that in proliferating cells: (i) PARP is physically associated with the catalytic subunit of the DNA polymerase α–primase tetramer, an association confirmed by confocal microscopy, demonstrating that both enzymes are co-localized at the nuclear periphery of HeLa cells.|(iii) PARP-deficient cells derived from PARP knock-out mice exhibited reduced DNA polymerase activity,	SIGNOR-261270	0.348
GSK3A	protein	P49840	UNIPROT	GRB14	protein	Q14449	UNIPROT	down-regulates activity	phosphorylation	Ser366	GCSSQSIsPMRSISE	-1									28130417	t		lperfetto	Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3.	SIGNOR-264872	0.267
GSK3A	protein	P49840	UNIPROT	NBR1	protein	Q14596	UNIPROT	down-regulates activity	phosphorylation	Thr586	HNTPVDVtPCMSPLP	-1									24879152	t		lperfetto	The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation|Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation. 	SIGNOR-261794	0.327
SNTA1	protein	Q13424	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255991	0.521
MK-2206	chemical	CHEBI:67271	ChEBI	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates	chemical inhibition			9606	BTO:0001286								21841310	t		gcesareni	Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation.	SIGNOR-176043	0.8
adenosine 5'-monophosphate	smallmolecule	CHEBI:16027	ChEBI	IMP	smallmolecule	CHEBI:17202	ChEBI	up-regulates quantity	precursor of			9606		BTO:0001103							1631143	t		miannu	AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells. 	SIGNOR-269774	0.8
quetiapine	chemical	CHEBI:8707	ChEBI	HTR1F	protein	P30939	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258536	0.8
EGR1	protein	P18146	UNIPROT	PDGFC	protein	Q9NRA1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0001685								15247255	f	 	 	The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad.|These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.|Egr-1 and Sp1 specifically bind the PDGF-C promoter	SIGNOR-254268	0.254
MMP2	protein	P08253	UNIPROT	DCN	protein	P07585	UNIPROT	down-regulates quantity by destabilization	cleavage	Glu30	GLFDFMLeDEASGIG	-1									9148753	t		miannu	Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.	SIGNOR-256349	0.682
Viral_dsRNA	stimulus	SIGNOR-ST21	SIGNOR	EIF2AK2	protein	P19525	UNIPROT	up-regulates				9606									31226023	f		miannu	PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses.	SIGNOR-260167	0.7
CAMK2A	protein	Q9UQM7	UNIPROT	ETS1	protein	P14921	UNIPROT	down-regulates	phosphorylation	Ser282	NSLQRVPsYDSFDSE	9606	BTO:0000782								12475968	t		lperfetto	Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition	SIGNOR-96338	0.313
quetiapine	chemical	CHEBI:8707	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10116									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258533	0.8
GABRA4	protein	P48169	UNIPROT	GABA-A (a4-b1-g2) receptor	complex	SIGNOR-C333	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263759	0.598
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3C15	protein	Q71DI3	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269643	0.2
AGTR2	protein	P50052	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	down-regulates													17326328	f		lperfetto	There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3	SIGNOR-252268	0.7
AATF	protein	Q9NY61	UNIPROT	BAX	protein	Q07812	UNIPROT	down-regulates quantity	transcriptional regulation			9606									22909821	t			We identify the transcriptional regulator apoptosis-antagonizing transcription factor (AATF)/Che-1 as a critical regulator of the cellular outcome of the p53 response. Upon genotoxic stress, AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation where AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes.	SIGNOR-259916	0.2
CSNK2A2	protein	P19784	UNIPROT	PTPRC	protein	P08575	UNIPROT	up-regulates activity	phosphorylation	Ser1005	EHDSDESsDDDSDSE	9606	BTO:0000661								10066810	t		llicata	Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment. 	SIGNOR-251030	0.445
CSNK2A1	protein	P68400	UNIPROT	ATXN3	protein	P54252	UNIPROT	up-regulates activity	phosphorylation	Ser335	SDLGDAMsEEDMLQA	9606	BTO:0000007								19542537	t		miannu	Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). The main phosphorylation of ATXN3 in vivo thus occurred at serine residues within the three conserved UIMs.	SIGNOR-276226	0.2
4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide	chemical	CHEBI:94506	ChEBI	CCNB1	protein	P14635	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193540	0.8
CSNK1A1	protein	P48729	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser287	SMSSCGSsGYFSSSP	9606									22017877	t		llicata	Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291.	SIGNOR-176875	0.2
PTPN12	protein	Q05209	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606	BTO:0000567	BTO:0000887;BTO:0001103							8454633	t		gcesareni	Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190.	SIGNOR-39151	0.384
IL10	protein	P22301	UNIPROT	IL10RB	protein	Q08334	UNIPROT	up-regulates	binding			9606	BTO:0000801;BTO:0000776								10347215	t		milica	Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling.	SIGNOR-68007	0.704
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	PTPN1	protein	P18031	UNIPROT	up-regulates activity	phosphorylation	Ser386	LRGAQAAsPAKGEPS	9606	BTO:0000567								23348582	t	phosphorylation site remapping based on mass spec table	lperfetto	Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B.|Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. 	SIGNOR-272971	0.517
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257931	0.8
IKBKB	protein	O14920	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	down-regulates activity	phosphorylation	Ser439	SIGHSPLsLSAQSVM	9606	BTO:0000938								24614225	t		lperfetto	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204732	0.529
BTRC	protein	Q9Y297	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates	ubiquitination			9606									14988407	t		gcesareni	Here we show that beta-trcp1, a f-box protein in the scf e3 ligase complex, interacts with smad4 and induces the degradation of smad4	SIGNOR-123057	0.396
GNB1	protein	P62873	UNIPROT	PLCB2	protein	Q00722	UNIPROT	up-regulates	binding			9606									1465133	t		gcesareni	Activation of plc-beta 2 by beta gamma subunits may be an important mechanism by which pertussis toxin-sensitive g proteins stimulate plc.	SIGNOR-19447	0.536
SMURF1	protein	Q9HCE7	UNIPROT	TBX6	protein	O95947	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								19561075	t		miannu	Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase.	SIGNOR-272784	0.26
MAPK1	protein	P28482	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates	phosphorylation	Thr45	PGGTLFStTPGGTRI	9606									11777913	t		gcesareni	Phosphorylation of 4e-bp1 is mediated by the p38/msk1 pathway in response to uvb irradiation. In the present study we demonstrated that uvb induced 4e-bp1 phosphorylation at multiple sites, thr-36, thr-45, ser-64, and thr-69, leading to dissociation of 4e-bp1 from eif-4e. Uvb-induced phosphorylation of 4e-bp1 was blocked by p38 kinase inhibitors, pd169316 and sb202190, and msk1 inhibitor, h89, but not by mitogen-activated protein kinase kinase inhibitors, pd98059 or u0126.	SIGNOR-113563	0.649
PRKCD	protein	Q05655	UNIPROT	EEF1A1	protein	P68104	UNIPROT	unknown	phosphorylation	Thr432	AVRDMRQtVAVGVIK										7890750	t		lperfetto	PKC delta phosphorylates eEF-1 alpha at Thr-431	SIGNOR-248902	0.34
EPX	protein	P11678	UNIPROT	RNASE2	protein	P10153	UNIPROT	up-regulates activity	post translational modification			9606	BTO:0000399								18694936	t		miannu	Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.	SIGNOR-261704	0.491
CYTH2	protein	Q99418	UNIPROT	ARF6	protein	P62330	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			10116	BTO:0003102								14565977	t		miannu	Effects of ARNO upon Axonogenesis Are Mediated by Downstream Activation of ARF6. ARNO/ARF6 signaling pathways that could modulate actin reorganization in the axonal growth cone. ARNO stimulates GTP exchange on ARF6, thereby increasing the amount of active ARF6.	SIGNOR-264910	0.883
ARHGAP31	protein	Q2M1Z3	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260490	0.66
DAB2IP	protein	Q5VWQ8	UNIPROT	HRAS	protein	P01112	UNIPROT	down-regulates activity	gtpase-activating protein			9606									27858941	t		miannu	The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP.	SIGNOR-254745	0.582
Immunoglobulin lambda-1 light chain	protein	P0DOX8	UNIPROT	BCR-Ml	complex	SIGNOR-C434	SIGNOR	form complex	binding			9606	BTO:0000776								32323265	t		scontino	An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs.	SIGNOR-268190	0.2
CHEK2	protein	O96017	UNIPROT	MDM4	protein	O15151	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser367	PDCRRTIsAPVVRPK	9606									18356162	t		lperfetto	The chk1 and chk2 kinases have also been shown to phosphorylate ser367, leading to 14-3-3 binding (34_36, 38, 44). In both cases, the outcome differed: in chk1-mediated phosphorylation, mdmx was translocated to the cytoplasm;in chk2-mediated phosphorylation, mdmx was degraded (34_36, 38, 44). It is possible that the damage response is mediated through additional phosphorylation sites other than ser367 and that, depending on the type of damage, certain sites will be modified, leading to different outcomes.	SIGNOR-178071	0.713
IDH1	protein	O75874	UNIPROT	D-threo-isocitrate(3-)	smallmolecule	CHEBI:15562	ChEBI	down-regulates quantity				9606									26178471	t		lperfetto	Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG)	SIGNOR-253137	0.8
IL17RC	protein	Q8NAC3	UNIPROT	IL17R complex	complex	SIGNOR-C260	SIGNOR	form complex	binding			9606	BTO:0001946								32024054	t		lperfetto	Importantly, IL-17 was involved in increased collagen production in cardiac fibroblasts in response to HG, with both subunits of the IL-17RA and IL-17RC heterodimer complex being important to mediating this response.	SIGNOR-261336	0.531
HNF4A	protein	P41235	UNIPROT	ABCG5	protein	Q9H222	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000398								21123766	f		miannu	 these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α.	SIGNOR-254457	0.284
MAPKAPK2	protein	P49137	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser78	PAYSRALsRQLSSGV	9606	BTO:0000938								12367505	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	gcesareni	Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27.	SIGNOR-94021	0.803
JAK2	protein	O60674	UNIPROT	PTPN11	protein	Q06124	UNIPROT	up-regulates activity	phosphorylation	Tyr327	NSKPKKSyIATQGCL	9534	BTO:0004055								8995399	t		lperfetto	Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2	SIGNOR-236270	0.786
MCRIP1	protein	C9JLW8	UNIPROT	CTBP1	protein	Q13363	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								25728771	t		lperfetto	CtBP is recruited to promoter elements of target genes by interacting with the DNA-binding transcriptional repressor ZEB1. We found that MCRIP1 binds to CtBP, thereby competitively inhibiting CtBP-ZEB1 interaction. When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.	SIGNOR-264776	0.2
CD55	protein	P08174	UNIPROT	ADGRE5	protein	P48960	UNIPROT	up-regulates	binding			9606		BTO:0000142							12417446	t		gcesareni	This interaction may facilitate cell activation and migration through the blood-brain barrier. In addition, cd97-cd55 interactions in the parenchyma of the brain may contribute to the inflammation.	SIGNOR-95458	0.2
DOK7	protein	Q18PE1	UNIPROT	CRK	protein	P46108	UNIPROT	up-regulates activity	binding			10090	BTO:0000165								20603078	t		miannu	Here, we identify two tyrosine residues in Dok-7 that are phosphorylated by Agrin stimulation, and show that two proteins, Crk and Crk-L, are recruited to these phosphorylation sites in Dok-7.	SIGNOR-273847	0.365
MAPK3	protein	P27361	UNIPROT	RXRA	protein	P19793	UNIPROT	down-regulates activity	phosphorylation	Ser260	NMGLNPSsPNDPVTN	9606									17604322	t		lperfetto	In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 	SIGNOR-88662	0.501
PDYN	protein	P01213	UNIPROT	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258416	0.657
VEPH1	protein	Q14D04	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000938								23989952	f	or inhibits the Hippo pathway to activate Yki	lperfetto	A double positive-feedback loop between melt and yki, wherein yki acti- vates melt expression, and melt promotes yki	SIGNOR-202540	0.2
CSNK2B	protein	P67870	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	phosphorylation	Thr102	RAAMFPEtLDEGMQI	9606	BTO:0000007								12432063	t		llicata	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin	SIGNOR-251066	0.587
CDK1	protein	P06493	UNIPROT	MASTL	protein	Q96GX5	UNIPROT	up-regulates activity	phosphorylation	Thr207	PRQDYSRtPGQVLSL	8355									22354989	t		gcesareni	We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop	SIGNOR-249653	0.492
SRC	protein	P12931	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	phosphorylation	Tyr34	KDQFPEVyVPTVFEN	9606	BTO:0000567								23027962	t		lperfetto	When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity	SIGNOR-271702	0.655
KATNAL2	protein	Q8IYT4	UNIPROT	Acrosome_assembly	phenotype	SIGNOR-PH156	SIGNOR	up-regulates				9606									28347630	f		miannu	The majority of elongated spermatids also displayed a detached acrosome (Fig 5B), indicating that KATNAL2, or KATNAL2-regulated structures, have a role in the deposition of ‘adhesive components’ into the acroplaxome. The acroplaxome is an electron dense structure that overlies the anterior pole of the sperm nucleus and is thought to play a pivotal role in acrosome formation and attachment. These data strongly suggest that KATNAL2 is required for multiple aspects of male haploid germ cell development, and depending on the cellular context, KATNAL2 may act in either a KATNB1-dependent (manchette function) and KATNB1-independent manner (acrosome and axoneme development).	SIGNOR-267179	0.7
AKT1	protein	P31749	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates	relocalization			10090	BTO:0002572								18423396	t		lperfetto	Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation.	SIGNOR-236209	0.866
NAE	complex	SIGNOR-C131	SIGNOR	ANAPC2	protein	Q9UJX6	UNIPROT	up-regulates activity	neddylation			9606									25504797	t		lperfetto	The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates.	SIGNOR-243175	0.379
PJA2	protein	O43164	UNIPROT	PRKAR2B	protein	P31323	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								21423175	t		miannu	Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits	SIGNOR-271858	0.2
SOAT1	protein	P35610	UNIPROT	cholesteryl ester	smallmolecule	CHEBI:17002	ChEBI	down-regulates quantity	chemical modification			9606									31848472	t		miannu	Excess cholesterol is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT; also known as SOAT) to cholesteryl esters	SIGNOR-265160	0.8
GPS1	protein	Q13098	UNIPROT	COP9 signalosome variant 1	complex	SIGNOR-C489	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270774	0.921
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	METTL3	protein	Q86U44	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser50	SPTFRSDsPVPTAPT	9606	BTO:0000007								33217317	t		miannu	 Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.	SIGNOR-265951	0.2
risperidone	chemical	CHEBI:8871	ChEBI	HTR2A	protein	P28223	UNIPROT	down-regulates activity	chemical inhibition			10090									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258529	0.8
MAP2	protein	P11137	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates quantity by stabilization	binding			9606	BTO:0000938								10704996	t		lperfetto	MAP2 interacts with MTs through its tubulin-binding domain which mainly associates with the acidic region of the C-terminal region of tubulin|no neurite growth is observed when MAP2 expression is suppressed in neuronal cell cultures after treatment with specific antisense oligonucleotides	SIGNOR-264837	0.7
IKBKB	protein	O14920	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser927	DSDSVCDsGVETSFR	9606	BTO:0000459			SIGNOR-C13					10469655	t		lperfetto	Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway.	SIGNOR-70469	0.848
MBD4	protein	O95243	UNIPROT	Base-excision_repair	phenotype	SIGNOR-PH222	SIGNOR	up-regulates													23545420	f		lperfetto	The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1).	SIGNOR-275714	0.7
GSK3B	protein	P49841	UNIPROT	NFKB1	protein	P19838	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser903	KTTSQAHsLPLSPAS	10090	BTO:0000452								12871932	t			GSK-3 beta forms an in vivo complex with and specifically phosphorylates NF-kappa B1/p105 at Ser-903 and Ser-907 in vitro. GSK-3 beta has a dual effect on p105: it stabilizes p105 under resting conditions and primes p105 for degradation upon tumor necrosis factor (TNF)-alpha treatment. Indeed, constitutive processing of p105 to p50 occurs at a higher rate in cells lacking GSK-3 beta with respect to wild-type cells and can be reduced upon reintroduction of GSK-3 beta by transfection. S903A and S907A point mutations impair p105 proteolysis in response to TNF-α.	SIGNOR-251251	0.396
CAK complex	complex	SIGNOR-C456	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser378	SKKGQSTsRHKKLMF	9606									9315650	t		llicata	The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase.	SIGNOR-269325	0.446
iloprost	chemical	CHEBI:63916	ChEBI	PTGIR	protein	P43119	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257574	0.8
DAPK1	protein	P53355	UNIPROT	DAPK1	protein	P53355	UNIPROT	down-regulates activity	phosphorylation	Ser308	ARKKWKQsVRLISLC	9606	BTO:0000007								11579085	t		lperfetto	The pro-apoptotic function of death-associated protein kinase is controlled by a unique inhibitory autophosphorylation-based mechanism.These results are consistent with a molecular model in which phosphorylation on ser(308) stabilizes a locked conformation of the cam-regulatory domain within the catalytic cleft and simultaneously also interferes with cam binding.	SIGNOR-110807	0.2
RNF111	protein	Q6ZNA4	UNIPROT	SKIL	protein	P12757	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								23530057	t		miannu	Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4.	SIGNOR-272885	0.713
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BC18	protein	Q5QNW6	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSVYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271987	0.2
SMARCB1	protein	Q12824	UNIPROT	Muscle cell-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C483	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex.	SIGNOR-270737	0.843
RFX3	protein	P48380	UNIPROT	Cilium_assembly	phenotype	SIGNOR-PH64	SIGNOR	up-regulates				10090									32725242	f		miannu	RFX2 and RFX3 are key regulators of ependymal cell ciliogenesis in vitro and in vivo. We show here that RFX2 and RFX3 have both redundant and specific functions in the biogenesis of motile cilia on mouse ependymal cells, whereas RFX1 does not seem to play a key regulatory role in this process.	SIGNOR-266927	0.7
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	MYBL2	protein	P10244	UNIPROT	up-regulates	phosphorylation	Ser577	RKPGLRRsPIKKVRK	9606									9840932	t		lperfetto	The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk5	SIGNOR-217252	0.708
FAS	protein	P25445	UNIPROT	FAS	protein	P25445	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								19305384	t		lperfetto	Fas/FasL, TRAIL/DR4, TRAIL/DR5 and TNF-alpha/TNFR1 are ligand/receptor pairs of the tumor necrosis factor/nerve growth factor family, which are able to induce apoptosis by trimerization of the receptor by its corresponding ligand.	SIGNOR-217809	0.2
R2SP co-chaperone	complex	SIGNOR-C517	SIGNOR	Chaperone-mediated protein folding	phenotype	SIGNOR-PH120	SIGNOR	up-regulates				9606									29844425	f		miannu	Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes.	SIGNOR-270941	0.7
PIK3R1	protein	P27986	UNIPROT	PIK3CB	protein	P42338	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								14665640	t		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242640	0.845
PRKDC	protein	P78527	UNIPROT	DCLRE1C	protein	Q96SD1	UNIPROT	up-regulates	phosphorylation	Ser645	NLSTNADsQSSSDFE	9606									16600297	t		lperfetto	Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin	SIGNOR-145841	0.687
SLC12A7	protein	Q9Y666	UNIPROT	chloride	smallmolecule	CHEBI:17996	ChEBI	down-regulates quantity	relocalization												21613606	t		lperfetto	Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12). 	SIGNOR-264639	0.8
TAB1	protein	Q15750	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	binding			9606									8638164	t		lperfetto	The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells.	SIGNOR-41941	0.927
MMP12	protein	P39900	UNIPROT	FGA	protein	P02671	UNIPROT	down-regulates quantity by destabilization	cleavage	Ala20	VVGTAWTaDSGEGDF	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain	SIGNOR-263622	0.2
ADCY1	protein	Q08828	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates	chemical modification			9606									17251915	t		gcesareni	Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases.	SIGNOR-152546	0.8
EIF3E	protein	P60228	UNIPROT	PLAU	protein	P00749	UNIPROT	up-regulates quantity	translation regulation			9606	BTO:0000815; BTO:0001938								20453879	f		irozzo	Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression.	SIGNOR-259155	0.2
SOX9	protein	P48436	UNIPROT	BEST1	protein	O76090	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									20530484	f		miannu	 BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. 	SIGNOR-255187	0.34
RFWD3	protein	Q6PCD5	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates activity	binding			9606	BTO:0002552								20173098	t		miannu	RFWD3 is a positive regulator of p53 abundance and regulates the G1 checkpoint in response to IR. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage. 	SIGNOR-271945	0.372
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine	chemical	CHEBI:91451	ChEBI	BRAF	protein	P15056	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258097	0.8
MYOD1	protein	P15172	UNIPROT	MYOD/E2-2	complex	SIGNOR-C129	SIGNOR	form complex	binding			9606									16847330	t	2	miannu	The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation.	SIGNOR-241100	0.689
F2	protein	P00734	UNIPROT	F2R	protein	P25116	UNIPROT	up-regulates	cleavage			9606									22972936	t	Thrombin acts on protease-activated receptors (PARs), a subfamily of G protein-coupled receptors (GPCR) that participate in a variety of biological process, including chemokine and cytokine release, tissue remodeling, inflammation, proliferation, and angiogenesis.	gcesareni	The par1 receptor subtype is activated when the n terminus is proteolytically cleaved by the serine protease thrombin, resulting in an irreversible activation of the receptor. Thrombin activates platelets by binding and cleaving protease-activated receptors 1 and 4 (par1 and par4).	SIGNOR-199007	0.883
GPR119	protein	Q8TDV5	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257241	0.252
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser672	VRGPVSGsPDSMNAS	9606	BTO:0000007								10195894	t			Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.	SIGNOR-251275	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	RPS6	protein	P62753	UNIPROT	up-regulates	phosphorylation	Ser236	AKRRRLSsLRASTSK	9606									17360704	t		gcesareni	We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism.	SIGNOR-252812	0.2
NCBP1	protein	Q09161	UNIPROT	Cap-binding complex	complex	SIGNOR-C440	SIGNOR	form complex	binding			9606									26382858	t		lperfetto	The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. 	SIGNOR-268359	0.969
LAMTOR5	protein	O43504	UNIPROT	LAMTOR	complex	SIGNOR-C26	SIGNOR	form complex	binding			9606									20381137	t		lperfetto	Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant	SIGNOR-164781	0.894
STAT3	protein	P40763	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0002314								18177723	f		miannu	Altogether, these data demonstrate that IL-6 loss results in deficient STAT3 signaling in activated satellite cells, leading to their reduced proliferation and myogenic progression, and highlight the major role played by the IL-6/STAT3 axis in controlling these processes during compensatory hypertrophy.	SIGNOR-255632	0.7
PRKAA1	protein	Q13131	UNIPROT	MLXIPL	protein	Q9NP71	UNIPROT	down-regulates	phosphorylation			9606			SIGNOR-C15						11724780	t		gcesareni	Ampk has also been suggested to phosphorylate the glucose-sensitive transcription factor chrebpthe dna binding activity, as assayed in a gel-shift assay of the truncated chrebp, was gradually inactivated with time by treatment with ampk	SIGNOR-112289	0.428
GFPT1	protein	Q06210	UNIPROT	D-fructofuranose 6-phosphate(2-)	smallmolecule	CHEBI:61527	ChEBI	down-regulates quantity	chemical modification			9606									21310273	t		miannu	GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans	SIGNOR-267815	0.8
KCNN4	protein	O15554	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			10116	BTO:0000078								25274816	t		miannu	KCa3.1 activation is expected to maintain a negative membrane potential, which will increase Ca2+ influx through nonvoltage gated Ca2+-release-activated Ca2+ (CRAC) channels that are prevalent in rat microglia	SIGNOR-276856	0.8
MLL2 complex	complex	SIGNOR-C88	SIGNOR	H3-4	protein	Q16695	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606									24680668	t		miannu	Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation.	SIGNOR-268800	0.2
TFEB	protein	P19484	UNIPROT	PPP1R15A	protein	O75807	UNIPROT	up-regulates quantity by expression	transcriptional regulation												32978159	t		lperfetto	We found that the main regulator of the starvation-induced transcriptional program, TFEB, counteracts protein synthesis inhibition by directly activating expression of GADD34, a component of the protein phosphatase 1 complex that dephosphorylates eIF2α.	SIGNOR-276789	0.2
CSNK1D	protein	P48730	UNIPROT	MTSS1	protein	O43312	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser322	SSVSSHDsGFISQDA	9606	BTO:0000567								24318128	t		miannu	Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation. 	SIGNOR-276611	0.333
CENPQ	protein	Q7L2Z9	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265207	0.779
LCK	protein	P06239	UNIPROT	SH2D2A	protein	Q9NP31	UNIPROT	up-regulates activity	phosphorylation	Tyr280	PKPSNPIyNEPDEPI	9606	BTO:0000782								18541536	t		miannu	 Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition.	SIGNOR-262888	0.597
PIP3	smallmolecule	CHEBI:16618	ChEBI	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	relocalization			9606									23119004	t		lperfetto	Binding of IGF to IGF-1R activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including AKT and PDK1.	SIGNOR-236509	0.8
MAPK9	protein	P45984	UNIPROT	NFATC3	protein	Q12968	UNIPROT	down-regulates	relocalization			9606									14517246	t		gcesareni	Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin.	SIGNOR-103360	0.698
SRC	protein	P12931	UNIPROT	CDH5	protein	P33151	UNIPROT	up-regulates	phosphorylation	Tyr685	LDARPSLyAQVQKPP	9606		BTO:0000975							16909109	t		llicata	In vitro src assay, the ve-cadherin cytoplasmic domain is directly phosphorylated by purified src as well as the tyrosine residue 685 (tyr)685-containing peptide finally, we found that in a vegf-induced wound-healing assay, cadherin adhesive activity was impaired by src kinase inhibitors.RPSLY(685)aqvq.	SIGNOR-148818	0.585
GOT1	protein	P17174	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	down-regulates quantity	chemical modification			9606									26003525	t		miannu	Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and α-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer.	SIGNOR-268064	0.8
PRKCA	protein	P17252	UNIPROT	RORA	protein	P35398	UNIPROT	unknown	phosphorylation	Ser35	ETPLNQEsARKSEPP	9606									20122401	t		llicata	Wnt5a/pkcalpha-dependent phosphorylation on serine residue 35 of roralpha is crucial to link roralpha to wnt/beta-catenin signaling, which exerts inhibitory function of the expression of wnt/beta-catenin target genes.	SIGNOR-163702	0.254
CSNK1E	protein	P49674	UNIPROT	TRAF3	protein	Q13114	UNIPROT	up-regulates activity	phosphorylation	Tyr116	EILALQIyCRNESRG	9606	BTO:0002181								32779804	t		miannu	We found that the interaction of CK1ε with TRAF3Y116F, TRAF3Y446F were markedly decreased compared with interactions with WT TRAF3 by Co‐IP (Figure 6C); as expected, TRAF3Y116F and TRAF3Y446F mutants exhibited reduced K63‐linked ubiquitination (Figure 6D). These data suggest that the phosphorylation of TRAF3 at Tyr 116 and Tyr 446 regulate CK1ε‐induced K63‐linked ubiquitination.	SIGNOR-277525	0.311
PAK2	protein	Q13177	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Thr89	QSSNGHItTTPTPTQ	9606	BTO:0000848								21177766	t		lperfetto	P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)	SIGNOR-170772	0.272
MAP3K4	protein	Q9Y6R4	UNIPROT	MAP2K3	protein	P46734	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000298								9305639	t		lperfetto	These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1.	SIGNOR-50891	0.627
sunitinib	chemical	CHEBI:38940	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									20185585	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-163947	0.8
MAPK3	protein	P27361	UNIPROT	MED1	protein	Q15648	UNIPROT	up-regulates	phosphorylation	Thr1032	SSSNRPFtPPTSTGG	9606									12356758	t		lperfetto	Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase	SIGNOR-93989	0.267
glycine	smallmolecule	CHEBI:15428	ChEBI	(6R)-5,10-methylenetetrahydrofolate(2-)	smallmolecule	CHEBI:15636	ChEBI	up-regulates quantity	precursor of			9606									16051266	t		lperfetto	The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide.	SIGNOR-268237	0.8
CSNK1D	protein	P48730	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	up-regulates	binding			9606									12000790	t		lperfetto	We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms.	SIGNOR-227973	0.519
MECOM	protein	Q03112	UNIPROT	RUNX1	protein	Q01196	UNIPROT	down-regulates activity	binding			10090									17575132	t		irozzo	The results that we present here support this model and show that EVI1 interacts with and inhibits RUNX1. As for GATA1, EVI1 seems to repress RUNX1 function by interacting specifically with its DNA-binding domain Runt, leading to destabilization and dissolution of the DNA-RUNX1 complex.	SIGNOR-255716	0.509
SCF-SKP2	complex	SIGNOR-C136	SIGNOR	CDK9	protein	P50750	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								11689688	t		miannu	Here we report that CDK9 is ubiquitinated and degraded by the proteasome whereas cyclin T1 is stable. SCF(SKP2) was recruited to CDK9/cyclin T1 via cyclin T1 in an interaction requiring its PEST domain. CDK9 ubiquitination was modulated by cyclin T1 and p45(SKP2). 	SIGNOR-272666	0.356
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CAMK2G	protein	Q13555	UNIPROT	up-regulates	chemical activation			9606									22944199	t		lperfetto	Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell).	SIGNOR-198816	0.8
RFXAP	protein	O00287	UNIPROT	RFX complex	complex	SIGNOR-C104	SIGNOR	form complex	binding			-1									10825209	t		miannu	RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes	SIGNOR-221568	0.813
CTNND2	protein	Q9UQB3	UNIPROT	CDH3	protein	P22223	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0001109								14610055	t		miannu	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 	SIGNOR-252130	0.298
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	UBTF	protein	P17480	UNIPROT	up-regulates	phosphorylation	Ser389	INKKQATsPASKKPA	9606									11698641	t		lperfetto	Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity	SIGNOR-216678	0.379
STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	MOB1B	protein	Q7L9L4	UNIPROT	up-regulates	phosphorylation			9606									21808241	t	The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific.	gcesareni	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction.	SIGNOR-270221	0.2
TLRs	proteinfamily	SIGNOR-PF20	SIGNOR	MYD88	protein	Q99836	UNIPROT	up-regulates activity	binding			10090									22664090	t		miannu	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-260151	0.2
MN1	protein	Q10571	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates activity	binding			-1									12569362	t		irozzo	Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300.	SIGNOR-256020	0.348
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Thr8	MSSILPFtPPVVKRL	9606		BTO:0000763							12193595	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-91746	0.739
MYC	protein	P01106	UNIPROT	CCNA2	protein	P20248	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001271								12835716	f		gcesareni	These results suggest that e2f1 and cyclin a2 may be induced by c-myc to mediate the onset of mammary cancer, whereas overexpression of cyclins d1 and e may occur later to facilitate tumor progression.	SIGNOR-102728	0.429
PCDHA5	protein	Q9Y5H7	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-265669	0.2
AGPAT4	protein	Q9NRZ5	UNIPROT	1-acyl-sn-glycerol 3-phosphate(2-)	smallmolecule	CHEBI:57970	ChEBI	down-regulates quantity	chemical modification			9606									21173190	t		lperfetto	The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA). 	SIGNOR-267015	0.8
AGTR1	protein	P30556	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256738	0.252
PRKG1	protein	Q13976	UNIPROT	CREB1	protein	P16220	UNIPROT	unknown	phosphorylation	Ser119	EILSRRPsYRKILND	-1									11175347	t		lperfetto	G-kinase phosphorylated GST-CREB, albeit less efficiently than A-kinase, but GST was not phosphorylated by either kinase (Figure 5a). GST-CREB purified from bacteria was similarly phosphorylated by G-kinase, whereas GST-CREB containing a serine 133 to alanine mutation was not (Figure 5b). These results demonstrate that G-kinase can directly phosphorylate CREB on serine 133.	SIGNOR-249076	0.642
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CDKN1B	protein	P46527	UNIPROT	down-regulates activity	phosphorylation	Thr198	PGLRRRQt	9606									12042314	t		lperfetto	Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation.	SIGNOR-244194	0.2
CSNK2A1	protein	P68400	UNIPROT	PIP4K2A	protein	P48426	UNIPROT	up-regulates	phosphorylation	Ser304	DGEEEGEsDGTHPVG	9606	BTO:0000567								10508590	t		lperfetto	Here, we demonstrate the partial purification of a protein kinase that phosphorylates the type iialpha pip kinase at a single site unique to that isoform - ser304. This kinase was identified as protein kinase ck2 (formerly casein kinase 2). Mutation of ser304 to aspartate to mimic its phosphorylation had no effect on pip kinase activity, but promoted both redistribution of the green fluorescent protein (gfp)-tagged enzyme in hela cells from the cytosol to the plasma membrane, and membrane ruffling.	SIGNOR-71014	0.429
CREB5	protein	Q02930	UNIPROT	LGALS3BP	protein	Q08380	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		 BTO:0002812							21132541	f		miannu	 Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition),	SIGNOR-253805	0.2
AKT1	protein	P31749	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates activity				9606	BTO:0000222	BTO:0000887;BTO:0001103							10896679	f		lperfetto	Two candidates that may function as mediators of pi3-k in the phosphorylation of mef2 proteins are pkb and big map kinase 1.	SIGNOR-79335	0.534
MMP9	protein	P14780	UNIPROT	A2M	protein	P01023	UNIPROT	down-regulates quantity by destabilization	cleavage	Arg719	VMGRGHArLVHVEEP	-1									9344465	t		lperfetto	The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261740	0.471
EFNB1	protein	P98172	UNIPROT	EPHB1	protein	P54762	UNIPROT	up-regulates	binding			9606									11713248	t		tpavlidou	We show here that despite its lack of kinase activity, ephb6 undergoes inducible tyrosine phosphorylation upon stimulation with the eph-b receptor subfamily ligand ephrin-b1. Overexpression of a catalytically active member of the eph-b subfamily, ephb1, resulted in increased ephb6 phosphorylation. Ephb1-induced ephb6 phosphorylation was ligand-dependent and required the functional catalytic activity of ephb1.	SIGNOR-111851	0.822
CASP3	protein	P42574	UNIPROT	NFKBIA	protein	P25963	UNIPROT	up-regulates quantity by stabilization	cleavage			-1									9367996	t		lperfetto	The cell-death protease cpp32 (caspase-3) in vitro specifically cleaved chicken and human ikappab-alpha at a conserved asp-ser sequence.Therefore, cleavage of I_B-_ by a CPP32-like protease could create what is sometimes called a super-repressor form of I_B-_ (20). That is, cleavage by CPP32 would block the ability of I_B-_ to undergo signal-induced degradation by removing the sites of signal-induced ubiquitination and by likely disrupting the ability of I_B-_ to become phosphorylated at critical Ser residues.	SIGNOR-51936	0.433
rizatriptan	chemical	CHEBI:48273	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			9606									10193663	t		Luana	This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues 	SIGNOR-258342	0.8
CDK1	protein	P06493	UNIPROT	PLK1	protein	P53350	UNIPROT	up-regulates activity	binding			9606									26259146	t		miannu	Moreover, CDK1 phosphorylates RSF1 at Ser1375, and this phosphorylation is necessary for PLK1 recruitment. Subsequently, PLK1 phosphorylates RSF1 at Ser1359, stabilizing PLK1 deposition.	SIGNOR-273589	0.593
EXT1	protein	Q16394	UNIPROT	WNT8A	protein	Q9H1J5	UNIPROT	up-regulates activity				9606									24860992	f		miannu	Decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern.	SIGNOR-264019	0.2
PRKACA	protein	P17612	UNIPROT	CSNK1A1L	protein	Q8N752	UNIPROT	up-regulates	phosphorylation			9606									16481469	t		lperfetto	Mutation of either the three pka sites or pka-primed cki sites prevents phosphorylation of ci by cki in vitro and blocks ci cleavage in embryos	SIGNOR-144557	0.375
CENPE	protein	Q02224	UNIPROT	BUB1B	protein	O60566	UNIPROT	up-regulates activity	binding			10090	BTO:0000452								12925705	t		lperfetto	Without CENP-E, diminished levels of BubR1 are recruited to kinetochores and BubR1 kinase activity remains at basal levels. CENP-E binds to and directly stimulates the kinase activity of purified BubR1 in vitro. Thus, CENP-E is required for enhancing recruitment of its binding partner BubR1 to each unattached kinetochore and for stimulating BubR1 kinase activity, implicating it as an essential amplifier of a basal mitotic checkpoint signal.	SIGNOR-252043	0.84
SMURF2	protein	Q9HAU4	UNIPROT	SMAD2/SMURF2	complex	SIGNOR-C11	SIGNOR	form complex	binding			9606									11389444	t		gcesareni	We show that in the presence of tgf-beta, smad2 interacts through its proline-rich ppxy motif with the tryptophan-rich ww domains of smurf2, a recently identified e3 ubiquitin ligases.	SIGNOR-108496	0.77
CALM1	protein	P0DP23	UNIPROT	PPP3CA	protein	Q08209	UNIPROT	up-regulates	binding			9606									11796223	t		gcesareni	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-114098	0.752
NOG	protein	Q13253	UNIPROT	BMPR2	protein	Q13873	UNIPROT	down-regulates activity	binding			9606	BTO:0001593	BTO:0000140		SIGNOR-C29					22298955	t	Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function	lperfetto	Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285)	SIGNOR-195612	0.572
STAT5A	protein	P42229	UNIPROT	PIM1	protein	P11309	UNIPROT	up-regulates quantity by expression	transcriptional regulation												16146838	t		lperfetto	The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells.	SIGNOR-249621	0.385
LYN	protein	P07948	UNIPROT	WAS	protein	P42768	UNIPROT	up-regulates activity	phosphorylation	Tyr291	AETSKLIyDFIEDQG	9606	BTO:0000801								17890224	t	done	miannu	We demonstrated that WASP is phosphorylated on tyrosine 291 in macrophages, and the WASP phosphorylation is important for the phagocytic cup formation. In addition, we showed that WASP and WASP-interacting protein (WIP) form a complex at the phagocytic cup and that the WASP.WIP complex plays a critical role in the phagocytic cup formation. 	SIGNOR-273959	0.387
YIF1B	protein	Q5BJH7	UNIPROT	HTR1A	protein	P08908	UNIPROT	up-regulates activity	relocalization			10116	BTO:0000938								18685031	t	nucleus	lperfetto	Together, our results provide strong evidence that Yif1B is a member of the ER/Golgi trafficking machinery, which plays a key role in specific targeting of 5-HT(1A)R to the neuronal dendrites. This finding opens up new pathways for the study of 5-HT(1A)R regulation by partner proteins and for the development of novel antidepressant drugs.|We confirmed 5-HT(1A)R-Yif1B interaction by glutathione S-transferase pull-down experiments using rat brain extracts and transfected cell lines. 	SIGNOR-268299	0.41
HOXA7	protein	P31268	UNIPROT	KRT10	protein	P13645	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11435435	f		miannu	Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes. 	SIGNOR-254472	0.2
TBP	protein	P20226	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263933	0.889
CCND1	protein	P24385	UNIPROT	CDK4	protein	P11802	UNIPROT	up-regulates	binding			9606									7736585	t		gcesareni	D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb,	SIGNOR-32295	0.964
PLK3	protein	Q9H4B4	UNIPROT	SNCB	protein	Q16143	UNIPROT	down-regulates activity	phosphorylation	Ser118	LMEPEGEsYEDPPQE	9606									19889641	t		lperfetto	Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation.	SIGNOR-189057	0.389
PRKCZ	protein	Q05513	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Ser670	CGKRFTRsDELQRHK	9606		BTO:0000887;BTO:0001260							18258854	t		llicata	Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter.	SIGNOR-160766	0.498
ASPG	protein	Q86U10	UNIPROT	ammonia	smallmolecule	CHEBI:16134	ChEBI	up-regulates quantity	chemical modification			9606									24657844	t		miannu	Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia.	SIGNOR-267539	0.8
ROCK1	protein	Q13464	UNIPROT	MAPK8IP3	protein	Q9UPT6	UNIPROT	up-regulates	phosphorylation	Ser365	RLDRTGSsPTQGIVN	9606									15767678	t		gcesareni	Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis.	SIGNOR-134588	0.339
MAPK1	protein	P28482	UNIPROT	SPHK1	protein	Q9NYA1	UNIPROT	up-regulates	phosphorylation	Ser225	VGSKTPAsPVVVQQG	9606									14532121	t		gcesareni	Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation.	SIGNOR-118546	0.547
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	MCM4	protein	P33991	UNIPROT	down-regulates	phosphorylation	Thr110	PRSGVRGtPVRQRPD	9606	BTO:0000567								12714602	t		lperfetto	We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a.	SIGNOR-217352	0.687
EIF3_complex	complex	SIGNOR-C401	SIGNOR	EIF4B	protein	P23588	UNIPROT	up-regulates activity	stabilization			9606									17581632	t		lperfetto	EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 	SIGNOR-269158	0.624
UBE3A	protein	Q05086	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys74	DTGRILSkLHTVQPK	-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. 	SIGNOR-272742	0.476
NLRX1	protein	Q86UT6	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	relocalization			9606	BTO:0002181								18219313	f		Giorgia	NLRX1 synergistically potentiated ROS production induced by tumour necrosis factor alpha, Shigella infection and double-stranded RNA, resulting in amplified NF-kappaB-dependent and JUN amino-terminal kinases-dependent signalling. We observed that NLRX1-positive cells showed increased p65 translocation as early as 15 min after infection, an effect that was maintained over time.	SIGNOR-260358	0.262
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	SP1	protein	P08047	UNIPROT	up-regulates activity	binding			-1									18025157	t			We show that PML-RARα physically interacts with Sp1 in the absence of DNA. In this report, we show that PML-RARα interacts with Sp1 and may interfere with the expression of genes that are not normally regulated by retinoic acid receptors.	SIGNOR-255729	0.2
DDX41	protein	Q9UJV9	UNIPROT	STING1	protein	Q86WV6	UNIPROT	up-regulates activity	binding			10090	BTO:0002572								25704810	t		miannu	The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site. 	SIGNOR-266403	0.2
pictrelisib	chemical	CHEBI:65326	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258113	0.8
mTORC1	complex	SIGNOR-C3	SIGNOR	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Thr390	DSKFTRQtPVDSPDD	9606									11914378	t			Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain,[…] Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings.	SIGNOR-255840	0.749
JAK1	protein	P23458	UNIPROT	IFNGR1	protein	P15260	UNIPROT	up-regulates	phosphorylation	Tyr457	KAPTSFGyDKPHVLV	9606									7615558	t		lperfetto	Interferon gamma activation of stat1alpha requires both jak1 and jak2 as well as tyrosine phosphorylation of the alpha chain of the ifngamma receptor.	SIGNOR-29866	0.691
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270424	0.8
belinostat	chemical	CHEBI:61076	ChEBI	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257952	0.8
EPGN	protein	Q6UW88	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606		BTO:0001253							20513444	t	EPGN may stimulate the phosphorylation of EGFR and mitogen-activated protein kinases	gcesareni	Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling.	SIGNOR-165779	0.638
BTK	protein	Q06187	UNIPROT	WAS	protein	P42768	UNIPROT	up-regulates activity	phosphorylation	Tyr291	AETSKLIyDFIEDQG	9606	BTO:0000007								10068673	t	done	miannu	These results demonstrate that WASP, under this experimental condition, can be tyrosine-phosphorylated by the kinase activity of Btk and that the direct interaction between WASP and the SH3 domain of Btk is required for this phosphorylation to occur.	SIGNOR-273958	0.732
MC4R	protein	P32245	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257336	0.252
MAPK1	protein	P28482	UNIPROT	BCL6	protein	P41182	UNIPROT	down-regulates	phosphorylation	Ser333	KGLVSPQsPQKSDCQ	9606	BTO:0000782;BTO:0000785								9649500	t		gcesareni	Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway.	SIGNOR-58481	0.503
PIAS3	protein	Q9Y6X2	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates	sumoylation			9606									15138572	t		gcesareni	Stat3 mediated signaling pathways can be inhibited by pias3 (protein inhibitor of activated stat3), which was recently found to regulate protein stability and function by its sumo (small-ubiquitin like modifiers) ligase activity in promoting sumoylation of important nuclear proteins.	SIGNOR-124723	0.72
FZD2	protein	Q14332	UNIPROT	SETDB1/NLK/CHD7	complex	SIGNOR-C189	SIGNOR	up-regulates activity													21952300	t		FFerrentino	The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43.	SIGNOR-253521	0.399
HK2	protein	P52789	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates activity				10090									16892090	f			HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host	SIGNOR-259979	0.7
NLGN1	protein	Q8N2Q7	UNIPROT	NRXN2	protein	P58401	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264159	0.824
FYN	protein	P06241	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	unknown	phosphorylation	Tyr1474	GSSNGHVyEKLSSIE										11483655	t		lperfetto	We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src and Fyn and compared this to phosphorylation by tyrosine kinases associated with the postsynaptic density (PSD)|Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases	SIGNOR-249338	0.76
PPP1CA	protein	P62136	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates	dephosphorylation	Thr125	PEVLRPEtPRPVDIG	9606									22311969	t		gcesareni	Pp1 dephosphorylated thr125 site of caspase-9 and activated caspase-9 to mediate il-2 deprivation-induced apoptosis.	SIGNOR-195992	0.2
PRKACA	protein	P17612	UNIPROT	PRKAR2B	protein	P31323	UNIPROT	up-regulates activity	phosphorylation	Ser114	NRFTRRAsVCAEAYN	9606									15187164	t		gcesareni	Serine 114 phosphorylation is required for both nuclear localization and down-regulation of il-2 production by riibeta.	SIGNOR-125545	0.876
CAD	protein	P27708	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	chemical modification			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-267421	0.8
NDUFS4	protein	O43181	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24].	SIGNOR-262178	0.84
PPP1R1B	protein	Q9UD71	UNIPROT	PPP1CB	protein	P62140	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								10604473	t		miannu	DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚ 	SIGNOR-264959	0.425
C5AR2	protein	Q9P296	UNIPROT	ITGAM	protein	P11215	UNIPROT	up-regulates quantity by expression													1847994	f		lperfetto	The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 	SIGNOR-263463	0.3
SH3KBP1	protein	Q96B97	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	binding			9606									24167568	t		gcesareni	The cin85 sh3 domains interact with c-cbl, an e3 ubiquitin ligase, via an unconventional pxxxpr ligand sequence, with the highest affinity displayed by the sh3-b domain. Interaction with cin85 recruits c-cbl to the amap1 complex where its ubiquitination activity is necessary for cancer cells to develop an invasive phenotype and to degrade the matrix.	SIGNOR-203139	0.737
TIRAP	protein	P58753	UNIPROT	MYD88	protein	Q99836	UNIPROT	up-regulates activity	binding			9606									25948473	t		lperfetto	Stimulation of Toll-like receptor (TLR) 4 leads to the activation of both MyD88-dependent and MyD88-independent pathways through the recruitment of adaptors TIRAP/MyD88 and TRIF/TRAM, respectively.	SIGNOR-110215	0.619
GPR132	protein	Q9UNW8	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257074	0.2
PLK3	protein	Q9H4B4	UNIPROT	HIF1A	protein	Q16665	UNIPROT	down-regulates	phosphorylation	Ser576	DDDFQLRsFDQLSPL	9606	BTO:0000567								18519666	t		lperfetto	Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditionsplk3 can potentially inhibit hif-1_ by physical interaction and direct phosphorylation	SIGNOR-178739	0.355
MAPK3	protein	P27361	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Thr359	DTEFTSRtPKDSPGI	9534	BTO:0001538								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252755	0.718
Shikonin	chemical	CHEBI:81068	ChEBI	PK	proteinfamily	SIGNOR-PF80	SIGNOR	down-regulates activity	chemical inhibition			9606	BTO:0000093;BTO:0000018								21516121	t	inferred from family member	lperfetto	Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2.	SIGNOR-270289	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity	phosphorylation			9606									16293724	t		lperfetto	We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt by free G protein betagamma subunits and the direct association of the G protein alphas subunit with the regulator of G protein signaling (RGS) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway.	SIGNOR-227952	0.545
CAMK2A	protein	Q9UQM7	UNIPROT	NOS1	protein	P29475	UNIPROT	down-regulates activity	phosphorylation	Ser852	SYKVRFNsVSSYSDS										10400690	t		llicata	It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation.	SIGNOR-250635	0.451
PMS1	protein	P54277	UNIPROT	MLH1/PMS1	complex	SIGNOR-C58	SIGNOR	form complex	binding			9606									10542278	t		miannu	We now show that hpms1 is expressed in human cells and that it interacts with hmlh1 with high affinity to form the heterodimer hmutl_.	SIGNOR-71774	0.694
CEP43	protein	O95684	UNIPROT	FGFR1OP/CEP350	complex	SIGNOR-C52	SIGNOR	form complex	binding			9606									16314388	t		miannu	Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring.	SIGNOR-142358	0.2
KDM5D	protein	Q9BY66	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264308	0.2
HOXB13	protein	Q92826	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001321								15604291	f	 	miannu	These results suggest that HOXB13 functions as an AR repressor to modulate the complex AR signaling and subsequent growth regulation of prostate cancer cells. 	SIGNOR-254475	0.509
MCHR2	protein	Q969V1	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257180	0.409
FGF2	protein	P09038	UNIPROT	ANKH	protein	Q9HCJ1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004473								19049325	f		miannu	FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2.	SIGNOR-252193	0.2
ITGAM	protein	P11215	UNIPROT	ICAM1	protein	P05362	UNIPROT	up-regulates	binding			9606									23994464	t		apalma	Before leaving the vessel lumen, neutrophils crawl on the endothelium, primarily using cell surface Mac-1 integrins binding to endothelial ICAM-1.	SIGNOR-255041	0.765
MAPK1	protein	P28482	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	unknown	phosphorylation	Ser8	MESEMLQsPLLGLGE	9606				SIGNOR-C3					21071439	t		llicata	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-169518	0.533
ROBO	proteinfamily	SIGNOR-PF14	SIGNOR	CCND3	protein	P30281	UNIPROT	down-regulates	phosphorylation	Thr283	QGPSQTStPTDVTAI	9606	BTO:0000782								15326477	t		lperfetto	P38sapk2 phosphorylates cyclin d3 at thr-283 and targets it for proteasomal degradation	SIGNOR-128402	0.2
ponatinib	chemical	CHEBI:78543	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001669								23539538	t		miannu	Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells	SIGNOR-259272	0.8
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1934	SPTYSPTsPKGSTYS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120160	0.316
P2RY1	protein	P47900	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257394	0.2
KAT6B	protein	Q8WYB5	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271;BTO:0000785		SIGNOR-C54						11965546	t		miannu	Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation.	SIGNOR-117335	0.41
BMPR1A	protein	P36894	UNIPROT	SMAD9	protein	O15198	UNIPROT	up-regulates activity	phosphorylation			9606									19620713	t		ggiuliani	To ascertain whether overexpression of BMPr1A can initiate adipocyte lineage commitment in the absence of its BMP ligand, constitutively active (CA)-BMPr1A and CA-BMPr1B were expressed in C3H10T1/2 stem cells using a mouse stem cell virus (MSCV) retroviral system. […]Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway.	SIGNOR-255772	0.696
CSNK2A1	protein	P68400	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser392	FKTEGPDsD	9606	BTO:0000568								10747897	t		llicata	Furthermore, we demonstrate that anisomycin- and tumor necrosis factor-alpha-induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase and CK2 activities.	SIGNOR-250967	0.654
MAPK1	protein	P28482	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	down-regulates activity	phosphorylation	Thr292	ETPPRPRtPGRPLSS	9534	BTO:0004055								14993270	t		lperfetto	We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling.	SIGNOR-236335	0.739
PRKCG	protein	P05129	UNIPROT	PEBP1	protein	P30086	UNIPROT	up-regulates activity	phosphorylation	Ser153	RGKFKVAsFRKKYEL	10116	BTO:0003036								12551925	t		lperfetto	Here we report that one mechanism involves dissociation of Raf kinase inhibitory protein (RKIP) from Raf-1. Classic and atypical but not novel PKC isoforms phosphorylate RKIP at serine 153 (Ser-153). RKIP Ser-153 phosphorylation by PKC either in vitro or in response to 12-O-tetradecanoylphorbol-13-acetate or epidermal growth factor causes release of RKIP from Raf-1, whereas mutant RKIP (S153V or S153E) remains bound. I	SIGNOR-249190	0.389
HCK	protein	P08631	UNIPROT	ELMO1	protein	Q92556	UNIPROT	up-regulates	phosphorylation	Tyr511	SKLQNLSyTEILKIR	9606									15952790	t		llicata	We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts.	SIGNOR-138154	0.59
LZTR1	protein	Q8N653	UNIPROT	KRAS	protein	P01116	UNIPROT	down-regulates activity	ubiquitination	Lys170	IRQYRLKkISKEEKT	9606	BTO:0000007								30442762	t		Gianni	By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane.	SIGNOR-269068	0.253
SEC13	protein	P55735	UNIPROT	GATOR2	complex	SIGNOR-C193	SIGNOR	form complex	binding			9606									23723239	t		miannu	Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5	SIGNOR-255305	0.857
PRKCA	protein	P17252	UNIPROT	ITGB2	protein	P05107	UNIPROT	unknown	phosphorylation	Thr758	NPLFKSAtTTVMNPK	9606	BTO:0000751								11700305	t		lperfetto	Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |	SIGNOR-249121	0.347
PTPN1	protein	P18031	UNIPROT	EPHA3	protein	P29320	UNIPROT	down-regulates activity	dephosphorylation	Tyr779	EDDPEAAyTTRGGKI	9606									21135139	t			Nevertheless, the finding that phosphorylation of the activation loop tyrosine (EphA3-Y779), a recently identified PTP1B substrate (Mertins et al., 2008), is essential for ligand-induced endocytosis (Janes et al., 2009)	SIGNOR-248426	0.428
HNF4A	protein	P41235	UNIPROT	AFP	protein	P02771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								9792724	f	 	miannu	 AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP.	SIGNOR-254446	0.415
CYP17A1	protein	P05093	UNIPROT	17alpha-hydroxyprogesterone	smallmolecule	CHEBI:17252	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0001363;BTO:0000048;BTO:0000050							17192295	t		lperfetto	THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones.	SIGNOR-268653	0.8
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	AP-3/clathrin vescicle	complex	SIGNOR-C250	SIGNOR	up-regulates				9606									25720354	f		scontino	APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. 	SIGNOR-267859	0.7
NRXN3	protein	Q9HDB5	UNIPROT	DAG1	protein	Q14118	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							22626542	t		miannu	 The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 	SIGNOR-265462	0.2
SMURF2	protein	Q9HAU4	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								11016919	t		miannu	The ability of Smurf2 to promote Smad2 destruction required the HECT catalytic activity of Smurf2 and depended on the proteasome-dependent pathway. Consistent with these results, Smurf2 potently reduced the transcriptional activity of Smad2. 	SIGNOR-272935	0.77
CASP3	protein	P42574	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates activity	cleavage	Asp330	LRTFDQLdAISSLPT	9606	BTO:0001412								15657060	t		lperfetto	In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits.	SIGNOR-133264	0.622
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	MEF2D	protein	Q14814	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser98	KGFNGCDsPEPDGED	10090	BTO:0000944								25733682	t		miannu	 MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding. 	SIGNOR-276887	0.268
MTOR	protein	P42345	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606		BTO:0001103							15829723	f		apalma	Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction	SIGNOR-255108	0.7
buprenorphine	chemical	CHEBI:3216	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9262330	t		miannu	We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine.	SIGNOR-258660	0.8
ARRB2	protein	P32121	UNIPROT	ADRB2	protein	P07550	UNIPROT	down-regulates activity	binding			-1									2163110	t			The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors	SIGNOR-256501	0.713
ECM	stimulus	SIGNOR-ST20	SIGNOR	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259043	0.7
RB1	protein	P06400	UNIPROT	TRIP11	protein	Q15643	UNIPROT	down-regulates	binding			9606									9256431	t		miannu	The wild-type rb is able to interact with the rb-binding domain of trip230 / rb represses trip230-mediated activation of tr-regulated transcription.	SIGNOR-50266	0.329
SMO	protein	Q99835	UNIPROT	GATA2	protein	P23769	UNIPROT	up-regulates activity				10090	BTO:0000011								16399502	f		fferrentino	In mammalian models [...] Hh signaling also inhibits mammalian adipogenesis. Hh signals elicit this function early in adipogenesis, upstream of PPARγ, potentially diverting preadipocytes as well as multipotent mesenchymal prescursors away from adipogenesis and toward osteogenesis. Hh may elicit these effects by inducing the expression of antiadipogenic transcription factors such as Gata2.	SIGNOR-251656	0.2
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser213	QNIPAHYsPRTSPIM	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248685	0.613
NPFF	protein	O15130	UNIPROT	NPFFR1	protein	Q9GZQ6	UNIPROT	up-regulates	binding			9606									11024015	t		gcesareni	Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems	SIGNOR-82916	0.738
SYP	protein	P08247	UNIPROT	VAMP2	protein	P63027	UNIPROT	up-regulates quantity	binding			9606									26903854	t		miannu	Recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. These cargoes are synaptophysin (for sybII) and SV2A (for synaptotagmin-1). SV2A Acts as an iTRAP to Direct Synaptotagmin-1 Retrieval to SVs.	SIGNOR-264117	0.619
GRK1	protein	Q15835	UNIPROT	RHO	protein	P08100	UNIPROT	up-regulates activity	phosphorylation	Ser334	PLGDDEAsATVSKTE	-1									8617805	t			That light-dependent phosphorylation of Rho is mediated primarily by RK. Addition of an inhibitory antibody against rhodopsin kinase (RK) lowered phosphorylation at Ser334, Ser338, and Ser343, without changing the ratio between phosphorylation sites. upon illumination, Ser334c, Ser338, and Ser343 are phosphorylated.	SIGNOR-251189	0.922
N-[5-[(2R)-2-methoxy-1-oxo-2-phenylethyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-1-piperazinyl)benzamide	chemical	CHEBI:94490	ChEBI	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191277	0.8
APOA1	protein	P02647	UNIPROT	APOE	protein	P02649	UNIPROT	up-regulates activity	relocalization			9606									20642861	t		miannu	ApoA-I stimulates apoE secretion in mature human adipocytes. The regulation of apoE secretion by apoA-I, is neither dependent upon an increase in gene transcription, nor upon increased release from the Golgi. It may therefore be assumed that, in macrophage models, apoE is stored mainly in the cytoplasm and/or on the cell surface, with apoA-I enabling secretion of this cytoplasmic pool	SIGNOR-252105	0.728
AMPK	complex	SIGNOR-C15	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser396	DDKKAKTsTRSSAKT	-1									21204788	t	done	miannu	AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 	SIGNOR-273930	0.258
EEF1A1P5	protein	Q5VTE0	UNIPROT	Glu-tRNA(Glu)	smallmolecule	CHEBI:29157	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269549	0.8
ELAVL4	protein	P26378	UNIPROT	ADAM10	protein	O14672	UNIPROT	up-regulates quantity	post transcriptional regulation			9606									19221430	t		miannu	Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure	SIGNOR-266865	0.2
oxymetazoline	chemical	CHEBI:7862	ChEBI	ADRA1B	protein	P35368	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258461	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TERT	protein	O14746	UNIPROT	up-regulates	phosphorylation	Ser227	GARRRGGsASRSLPL	9606									10224060	t		lperfetto	Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins.	SIGNOR-244361	0.2
ZIC1	protein	Q15915	UNIPROT	GLI3	protein	P10071	UNIPROT	up-regulates				9606	BTO:0002181								11238441	f		fspada	Moreover, gli proteins were translocated to cell nuclei by coexpressed zic proteins, and both proteins regulated each others transcriptional activity.In Nih3t3 and 293t cells, both gli1 and gli3 proteins were located predominantly in the cytoplasm (fig. 2, c, d, h, k, l, and p). Coexpression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels (fig. 2, e and m).	SIGNOR-105500	0.364
GLI3	protein	P10071	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150;BTO:0000551								19860666	f		gcesareni	Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin.	SIGNOR-188878	0.575
NSFL1C	protein	Q9UNZ2	UNIPROT	CTSL	protein	P07711	UNIPROT	down-regulates activity	binding			-1									15498563	t		lperfetto	The SEP domain of p47 acts as a reversible competitive inhibitor of cathepsin L.	SIGNOR-265043	0.2
pipamperone	chemical	CHEBI:78549	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10116		BTO:0000601							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258575	0.8
PTPN2	protein	P17706	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates activity	dephosphorylation	Tyr332	ILAIHDSyKPEFHSD	10029	BTO:0000246								12907755	t			PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 	SIGNOR-248391	0.298
NSD1	protein	Q96L73	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	methylation	Lys221	LLCDKVQkEDIEVYF	9606				SIGNOR-C13					20080798	t		miannu	Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation.	SIGNOR-163458	0.475
DUSP3	protein	P51452	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation			9606									32475380	t		miannu	DUSP3 interacted with the C-terminal domain of STAT3 and dephosphorylated p-Y705 of STAT3.|In summary, DUSP3 downregulated the transcriptional activity of STAT3 via dephosphorylation at Y705 and also suppressed the migratory activity of cancer cells.	SIGNOR-277070	0.2
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Thr564	LEEADNQtLDSYRNE	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276215	0.2
ERBB4	protein	Q15303	UNIPROT	SHC3	protein	Q92529	UNIPROT	up-regulates	relocalization			9606									16829981	t		gcesareni	Like erbb1, erbb4 recruits grb2, shc and stat5.	SIGNOR-147850	0.479
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	IKK-complex	complex	SIGNOR-C14	SIGNOR	up-regulates	phosphorylation			9606	BTO:0001454								19609947	t		lperfetto	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-244281	0.643
AR	protein	P10275	UNIPROT	BTG1	protein	P62324	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16281084	f	 	 	 After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes.	SIGNOR-253673	0.2
PPP1CC	protein	P36873	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser370	KKTIVNDsRESCVEE	9606	BTO:0001938								23277204	t			Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity.	SIGNOR-248504	0.2
PRKACA	protein	P17612	UNIPROT	WT1	protein	P19544	UNIPROT	down-regulates	phosphorylation	Ser365	KDCERRFsRSDQLKR	9606									9366517	t		llicata	Pka phosphorylated wt1 at ser-365 and ser-393 in vitro, as well as at additional sites, and this phosphorylation abolished the dna-binding activity of wt1 in vitro. Using wt1 mutants in which ser-365 and ser-393 were mutated to ala individually and in combination, we showed that phosphorylation of these sites was critical for inhibition of dna binding in vivo.	SIGNOR-53172	0.346
YES1	protein	P07947	UNIPROT	CDK4	protein	P11802	UNIPROT	down-regulates	phosphorylation	Tyr17	AEIGVGAyGTVYKAR	9606									18479465	t		lperfetto	We purified tyrosine 17 kinases from hela cells and found that the src family non-receptor tyrosine kinase c-yes contributes a large fraction of the tyrosine 17 kinase activity in hela lysatesthis site is equivalent to tyrosine 15 of cyclin dependent kinase 1, which undergoes inhibitory phosphorylation by wee1 and myt1	SIGNOR-178624	0.256
NPEPPS	protein	P55786	UNIPROT	oligopeptide	smallmolecule	CHEBI:25676	ChEBI	down-regulates quantity	chemical modification			9606									11062501	t			The proteasome generates exact major histocompatibility complex (MHC) class I ligands as well as NH2-terminal-extended precursor peptides| We performed in vitro peptide digests using recombinant PSA | PSA behaved exclusively as an aminopeptidase |BH and PSA act as complementary and redundant systems responsible for the final trimming of the correct NH2 terminus. 	SIGNOR-272467	0.8
MLL-ENL	fusion protein	SIGNOR-FP7	SIGNOR	HOXA9	protein	P31269	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14701735	f		irozzo	Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function.	SIGNOR-255863	0.2
GSK3B	protein	P49841	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation	Ser641	YRYPRPAsVPPSPSL										11427888	t			Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. 	SIGNOR-251239	0.673
NEO1	protein	Q92859	UNIPROT	Chemoattraction_of_axon	phenotype	SIGNOR-PH197	SIGNOR	up-regulates													17204444	f		miannu	Neogenin, a close relative of the axon guidance receptor Deleted in Colorectal Cancer (DCC), has been shown to be a receptor for members of the Netrin and Repulsive Guidance Molecule (RGM) families. While Netrin-1-Neogenin interactions result in a chemoattractive axon guidance response, the interaction between Neogenin and RGMa induces a chemorepulsive response. 	SIGNOR-268395	0.7
Wnt	proteinfamily	SIGNOR-PF40	SIGNOR	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606									15578921	t		Gianni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131577	0.2
CD300LB	protein	A8K4G0	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								20959446	t		lperfetto	The CD300b receptor is a non-classical activating receptor able to deliver signals by associating with the transmembrane adaptor protein DAP-12 and the intracellular mediator Grb-2.	SIGNOR-264833	0.477
MAPK1	protein	P28482	UNIPROT	RPS6KA2	protein	Q15349	UNIPROT	up-regulates	phosphorylation			9606									19282669	t		gcesareni	Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.	SIGNOR-161515	0.704
CDK1	protein	P06493	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates	phosphorylation	Ser332	TDSATIVsPPPSSPP	9606									8087847	t		lperfetto	Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro.	SIGNOR-36022	0.687
TFAP2C	protein	Q92754	UNIPROT	ECM1	protein	Q16610	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002828								17187826	f	 	miannu	 Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. 	SIGNOR-255396	0.291
CS	protein	O75390	UNIPROT	acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	down-regulates quantity	chemical modification			9606									3013232	t		miannu	Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond.	SIGNOR-266238	0.8
PRKG1	protein	Q13976	UNIPROT	GKAP1	protein	Q5VSY0	UNIPROT	unknown	phosphorylation	Ser106	SNPVQKDsREENWQE	9534									10671526	t		lperfetto	Although both cGK-Ialpha and -Ibeta, but not cAMP-dependent protein kinase, phosphorylated GKAP42 in vitro, GKAP42 was a good substrate only for cGK-Ialpha in intact cells, suggesting that the association with kinase protein is required for the phosphorylation in vivo.	SIGNOR-249037	0.645
KCNQ1	protein	P51787	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	up-regulates quantity	relocalization			9606									19298256	t		miannu	KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations.	SIGNOR-265981	0.8
ALK	protein	Q9UM73	UNIPROT	PIK3R3	protein	Q92569	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000762								27322022	t		lperfetto	Subsequent studies revealed that ALK promoted cell migration through the P3K-AKT pathway via the p55γ regulatory subunit of PI3K.	SIGNOR-253217	0.363
GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	CRHR1	protein	P34998	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268600	0.249
lofepramine	chemical	CHEBI:47782	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606									9537821	t		miannu	Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 	SIGNOR-258882	0.8
AKT1	protein	P31749	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser166	SSRRRAIsETEENSD	9606									11504915	t		lperfetto	Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186.	SIGNOR-116270	0.804
DAB2IP	protein	Q5VWQ8	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity	relocalization			10090									20080667	t		miannu	DAB2IP prevents β-catenin nuclear translocation.	SIGNOR-254755	0.304
IGF1	protein	P05019	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates activity	binding			9606									21798082	t		lperfetto	Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor.	SIGNOR-175662	0.955
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser96	TSLSDEDsGKGSQPP	9606									15448698	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-129422	0.575
PPP1CC	protein	P36873	UNIPROT	CDK9	protein	P50750	UNIPROT	up-regulates	dephosphorylation	Ser175	FGLARAFsLAKNSQP	9606									21533037	t		gcesareni	Protein phosphatase-1 activates cdk9 by dephosphorylating ser175	SIGNOR-173450	0.2
PRKDC	protein	P78527	UNIPROT	WRN	protein	Q14191	UNIPROT	up-regulates	phosphorylation	Ser467	DTSYVIEsDEDLEME	9606	BTO:0000007								24429382	t		llicata	Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair.	SIGNOR-203741	0.662
AKT1	protein	P31749	UNIPROT	GSK3A	protein	P49840	UNIPROT	down-regulates	phosphorylation	Ser21	SGRARTSsFAEPGGG	9606									11035810	t		gcesareni	In response to insulin, gsk3a inhibited by phosphorylation at ser-21 by pkb/akt1;phosphorylation at this site causes a conformational change, preventing access of substrates to the active site.	SIGNOR-252589	0.62
LRFN3	protein	Q9BTN0	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606	BTO:0000938								21736948	f		miannu	This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments.	SIGNOR-264101	0.7
axitinib	chemical	CHEBI:66910	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258074	0.8
SUV39H1	protein	O43463	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002267								23435416	f		lperfetto	The methyl marks H3K9me3 on the myoD promoter and H3K27me3 on the myogenin promoter have been shown to be under the control of the histone methyl transferase KMT1A and the HDM KDM4A, respectively, during normal myogenesis. In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation	SIGNOR-249600	0.525
TRAF6	protein	Q9Y4K3	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates activity	ubiquitination			9606									18758450	t		lperfetto	Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis.	SIGNOR-180562	0.2
PTPN11	protein	Q06124	UNIPROT	PTK2B	protein	Q14289	UNIPROT	down-regulates activity	dephosphorylation	Tyr906	CQLPPEGyVVVVKNV	9606									10880513	t		miannu	We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. |We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. Moreover, overexpression of dominant negative SHP2 blocked the protective effect of IL-6 against Dex-induced apoptosis. These findings demonstrate that SHP2 mediates the anti-apoptotic effect of IL-6 and suggest SHP2 as a novel therapeutic target in MM..... 1) RAFTK is a substrate of SHP2 in vitro and 2) dephosphorylation of RAFTK by SHP2 inhibits its kinase activity.	SIGNOR-277084	0.714
ERG	protein	P11308	UNIPROT	EZH2	protein	Q15910	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25277175	f		miannu	Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3.	SIGNOR-251555	0.351
PTPN12	protein	Q05209	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	dephosphorylation	Tyr530	FTSTEPQyQPGENL	9606									19350555	t		miannu	PTP-PEST increases dephosphorylation of Src at Y527 and activates it.|The data presented here supports our hypothesis that PTP-PEST activates Src via dephosphorylating it at Y527 (Tyr530 in human c-Src equivalent to Tyr527 in chicken Src).	SIGNOR-277086	0.545
AMPK	complex	SIGNOR-C15	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser420	KHPTPGSsDPLIQPS	-1									21204788	t		miannu	AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 	SIGNOR-273931	0.258
GRIN2B	protein	Q13224	UNIPROT	NMDA receptor_2B	complex	SIGNOR-C348	SIGNOR	form complex	binding			9606	BTO:0000938								12871085	t		miannu	The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits	SIGNOR-264123	0.716
NOG	protein	Q13253	UNIPROT	BMPR1A	protein	P36894	UNIPROT	down-regulates activity	binding			9031		BTO:0000140							12478285	t		lperfetto	Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors (PMID 22298955).Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors.	SIGNOR-219221	0.596
GATA2	protein	P23769	UNIPROT	KLF1	protein	Q13351	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									8195185	f		irozzo	Regulation of the Erythroid Kruppel-like Factor (EKLF) Gene Promoter by the Erythroid Transcription Factor GATA-l.Accordingly,we have also demonstrated that GATA-2, like GATA-1, is able to activate the EKLF promoter in NIH3T3.	SIGNOR-256052	0.442
PAK1	protein	Q13153	UNIPROT	NF2	protein	P35240	UNIPROT	down-regulates	phosphorylation	Ser518	DTDMKRLsMEIEKEK	9606									18071304	t		lperfetto	Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth,	SIGNOR-159764	0.63
PRKCG	protein	P05129	UNIPROT	GSK3A	protein	P49840	UNIPROT	down-regulates	phosphorylation	Ser21	SGRARTSsFAEPGGG	9606									11884598	t		gcesareni	Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway.	SIGNOR-115726	0.329
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	RPS6	protein	P62753	UNIPROT	up-regulates	phosphorylation	Ser244	LRASTSKsESSQK	9606									21233202	t		lperfetto	In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity	SIGNOR-252764	0.2
CARS1	protein	P49589	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									11347887	t		miannu	Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine.	SIGNOR-270473	0.8
bisphenol F	chemical	CHEBI:34575	ChEBI	AHR	protein	P35869	UNIPROT	up-regulates activity	chemical activation			-1									31995776	t		miannu	This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity.In our study, BPs showed AhR agonist activity only at the highest concentrations, and the mixture did not differ from the single BPs.	SIGNOR-268737	0.8
ITGAM	protein	P11215	UNIPROT	AM/b2 integrin	complex	SIGNOR-C170	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253191	0.744
BIRC2	protein	Q13490	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								12525502	t		miannu	 Here we show that cIAP1 and cIAP2 are E3 ubiquitin-protein isopeptide ligases (ubiquitin ligases) for Smac. cIAPs stimulate Smac ubiquitination both in vivo and in vitro, leading to Smac degradation. cIAP1 and cIAP2 associate with overlapping but distinct subsets of E2 (ubiquitin carrier protein) ubiquitin-conjugating enzymes. The substrate-dependent E3 activity of cIAPs is mediated by their RING domains and is dependent on the specific interactions between cIAPs and Smac.	SIGNOR-271392	0.891
PRKAA1	protein	Q13131	UNIPROT	HIPK2	protein	Q9H2X6	UNIPROT	up-regulates activity	phosphorylation	Ser121	LMRRSTVsLLDTYQK	-1									23871434	t		miannu	These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J).	SIGNOR-276467	0.2
GYS1	protein	P13807	UNIPROT	Glycogen_synthesis	phenotype	SIGNOR-PH39	SIGNOR	up-regulates				9534	BTO:0004055								14593110	f		lperfetto	Glycogen synthase, a key enzyme in the regulation of glycogen synthesis by insulin, is controlled by multisite phosphorylation.	SIGNOR-235751	0.7
leuprolide	chemical	CHEBI:6427	ChEBI	GNRHR	protein	P30968	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257499	0.8
STK38	protein	Q15208	UNIPROT	AAK1	protein	Q2M2I8	UNIPROT	up-regulates activity	phosphorylation	Ser637	AGHRRILsDVTHSAV	10090		BTO:0000142							22445341	t		miannu	We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. AAK1 phosphorylation regulates dendrite branching and length	SIGNOR-263034	0.274
GABARAPL2	protein	P60520	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								17580304	t		lperfetto	P62 binds both to lc3a and -b and the related gabarap family proteins/this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguisha	SIGNOR-156307	0.861
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation	Tyr221	IRAKIQDyHILTRKR	9606	BTO:0000007								15143187	t			JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity	SIGNOR-251356	0.2
PPP2CA	protein	P67775	UNIPROT	DDHD1	protein	Q8NEL9	UNIPROT	up-regulates activity	dephosphorylation	Ser711	NPAKEPTsVSENEGI	-1									11328814	t		miannu	Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity	SIGNOR-262975	0.2
IL22RA1	protein	Q8N6P7	UNIPROT	TYK2	protein	P29597	UNIPROT	up-regulates	binding			9606									12087100	t		gcesareni	Il-22 activates jak1 and tyk2	SIGNOR-90165	0.524
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	RPS3	protein	P23396	UNIPROT	unknown	phosphorylation			9606									15950189	t	inferred from 70% family members	llicata	Erk phosphorylates threonine 42 residue of ribosomal protein s3.	SIGNOR-270019	0.2
CDK1	protein	P06493	UNIPROT	BUB1B	protein	O60566	UNIPROT	up-regulates	phosphorylation	Thr620	RAARFVStPFHEIMS	9606									17785528	t		lperfetto	Here, we demonstrate that bubr1 is phosphorylated on the cdk1 site t620, which triggers the recruitment of plk1 and phosphorylation of bubr1 by plk1 both in vitro and in vivo. Phosphorylation does not appear to be required for spindle checkpoint function but instead is important for the stability of kinetochore-microtubule (kt-mt) interactions	SIGNOR-157642	0.768
PPM1A	protein	P35813	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	dephosphorylation	Ser608	ENTEDQYsLVEDDED	10090	BTO:0000944								15016818	t			Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2Cα dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity	SIGNOR-248489	0.329
LYRM4	protein	Q9HD34	UNIPROT	Mitochondrial Fe-S Cluster Assembly Complex	complex	SIGNOR-C276	SIGNOR	form complex	binding			-1									27519411	t		lperfetto	As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry.	SIGNOR-262126	0.7
CLOCK	protein	O15516	UNIPROT	MAGEL2	protein	Q9UJ55	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								22208286	t		miannu	Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization.	SIGNOR-253516	0.2
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	Pro-tRNA(Pro)	smallmolecule	CHEBI:29154	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270430	0.8
Factor FVIIa:TF	complex	SIGNOR-C319	SIGNOR	F5	protein	P12259	UNIPROT	down-regulates activity	cleavage	Arg1046	HHAPLSPrTFHPLRS	-1									10026263	t		lperfetto	Factor VIIa/tissue factor generates a form of factor V with unchanged specific activity, resistance to activation by thrombin, and increased sensitivity to activated protein C| In this study, we found that TF/VIIa was able to cleave multiple peptide bonds in the coagulation cofactor, factor V. SDS-PAGE analysis and sequencing indicated the factor V was cleaved at Arg679, Arg709, Arg1018, and Arg1192	SIGNOR-263645	0.496
WNT1	protein	P04628	UNIPROT	FZD1	protein	Q9UP38	UNIPROT	up-regulates activity	binding			10090		BTO:0000887							16936075	t		lperfetto	Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6)	SIGNOR-217827	0.69
AMPK	complex	SIGNOR-C15	SIGNOR	CRY1	protein	Q16526	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser71	ANLRKLNsRLFVIRG	9606									19833968	t		miannu	We demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Phosphorylation of S71 or S280 by AMPK destabilizes CRY1	SIGNOR-268046	0.349
PPM1G	protein	O15355	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates activity	dephosphorylation	Thr198	PGLRRRQt	9606									27822412	t		miannu	By using genomic phosphatase screening, we identified a PPM family phosphatase, PPM1G, which could reduce p27 phosphorylation at T198.|Functionally, ectopic expression of PPM1G enhanced p27 protein stability and delayed cell cycle progression from G1 to S phase.	SIGNOR-277112	0.2
PRKCE	protein	Q02156	UNIPROT	CTNND1	protein	O60716	UNIPROT	down-regulates	phosphorylation	Ser268	PQVRVGGsSVDLHRF	9606									21251911	t		lperfetto	We find that ctnnd1/p120ctn phosphorylation at serine 268 (p-s268) occurs in a strictly pkc_-dependent manner,serine/threonine phosphorylation of p120-ctn has been reported to affect the integrity of ajs [12], [24] and [25]. Xia et al. (2003) reported that several residues (ser122, ser252, ser268, ser288, thr310, ser312, ser873, and thr910) in p120ctn can be either phosphorylated or dephosphorylated upon pkc activation	SIGNOR-171712	0.2
EGFR	protein	P00533	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	binding			10090	BTO:0000944								7518560	t		lperfetto	Both competition experiments with synthetic phosphopeptides and dephosphorylation protection analysis demonstrated that y-1173 and y-992 are major and minor binding sites, respectively, for shc on the egfr.	SIGNOR-235481	0.911
alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	6-O-phosphono-D-glucono-1,5-lactone	smallmolecule	CHEBI:16938	ChEBI	up-regulates quantity	precursor of			9606									24769394	t		miannu	G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress	SIGNOR-267049	0.8
MAPK3	protein	P27361	UNIPROT	MITF	protein	O75030	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser180	PGSSAPNsPMAMLTL										10841026	t		lperfetto	More interestingly, ERK-dependent phosphorylation of MITF at Ser 73 is essential for MITF ubiquitinilation and degradation (87). Putting together all these findings, it can be proposed that MAPK activation inhibits melanogenesis due to an increased MITF degradation which is dependent on the MAPK-induced MITF phosphorylation and ubiquitinilation. In summary, although the phosphorylation of MITF at Ser73 increases its intrinsic transcriptional activity, this phosphorylation also targets MITF to the proteasome for its degradation. Consequently, the decrease in MITF levels leads to a down-regulation of melanogenic enzymes expression and to an inhibition of melanogenesis.	SIGNOR-249620	0.523
PRKACA	protein	P17612	UNIPROT	PTPN7	protein	P35236	UNIPROT	down-regulates	phosphorylation			9606									19047375	t		gcesareni	B2 adrenergic receptor stimulation induces the pka dependent phosphorylation of heptp and releases bound p38 mapk	SIGNOR-182522	0.367
PRKAG1	protein	P54619	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	form complex	binding			9606	BTO:0000443	BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000759							16054041	t		lperfetto	Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits.	SIGNOR-139170	0.755
FER	protein	P16591	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Tyr142	AVVNLINyQDDAELA	-1									12640114	t			Interaction of beta-catenin with alpha-catenin is regulated by the phosphorylation of beta-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn tyrosine kinases.  Transfection of these kinases to epithelial cells disrupted the association between both catenins.	SIGNOR-251131	0.706
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MFN1	protein	Q8IWA4	UNIPROT	up-regulates activity	phosphorylation	Thr562	LPRSLASTPTAPTTP	10090	BTO:0002572								25801171	t		Barakat	Finally, in Mfn1 -/- cells re-expressing the MFN1 T562A mutant, phosphorylation was undetectable even in the presence of EGF. Taken together, these data indicate that ERK phosphorylates MFN1 at T562.	SIGNOR-274134	0.2
JMY	protein	Q8N9B5	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								20498093	t		lperfetto	Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes.	SIGNOR-261005	0.315
TAB1	protein	Q15750	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	binding			10116	BTO:0003324								16407200	t		lperfetto	In contrast to MKK3-induced p38 kinase downstream effects, TAB-1-induced p38 kinase activation does not induce expression of pro-inflammatory genes, cardiac marker gene expression, or changes in cellular morphology. Rather, TAB-1 binds to p38 and prevents p38 nuclear localization.	SIGNOR-143576	0.817
PRKCD	protein	Q05655	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser159	KKKKKRFsFKKSFKL	-1									8422248	t		lperfetto	These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III.	SIGNOR-248924	0.469
CCKBR	protein	P32239	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257305	0.43
DUSP1	protein	P28562	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates	dephosphorylation			9606									10617468	t		gcesareni	The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1.	SIGNOR-73617	0.778
oxymetazoline	chemical	CHEBI:7862	ChEBI	ADRA2A	protein	P08913	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258917	0.8
CyclinD3/CDK6	complex	SIGNOR-C234	SIGNOR	PFKP	protein	Q01813	UNIPROT	down-regulates activity	phosphorylation	Ser679	MQQGGAPsPFDRNFG	9606	BTO:0000782								28607489	t		lperfetto	Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3–CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2.|Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity	SIGNOR-273033	0.2
RYK	protein	P34925	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates	binding			9606									15454084	t		gcesareni	Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled.	SIGNOR-129571	0.43
IFNLR1	protein	Q8IU57	UNIPROT	TYK2	protein	P29597	UNIPROT	up-regulates	binding			9606									15120645	t		gcesareni	Despite signaling through distinct receptor complexes, type i ifns and ifn-_s activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (fig. 6). In both cases, receptor engagement leads via the activation of the jak kinases jak1 and tyk2	SIGNOR-124483	0.542
PRKCB	protein	P05771	UNIPROT	OCLN	protein	Q16625	UNIPROT	up-regulates activity	phosphorylation	Ser340	DKRFYPEsSYKSTPV	9615	BTO:0000837								11502742	t		lperfetto	Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X. 	SIGNOR-249106	0.467
TEAD1	protein	P28347	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									20153295	f		lperfetto	We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor.	SIGNOR-235599	0.326
NAB2	protein	Q15742	UNIPROT	EGR2	protein	P11161	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000414								20506119	f		miannu	Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop. 	SIGNOR-253888	0.594
BTF3	protein	P20290	UNIPROT	MADCAM1	protein	Q13477	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000584								17312387	f	 	 	In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis.	SIGNOR-253945	0.2
FBXO5	protein	Q9UKT4	UNIPROT	ANAPC7	protein	Q9UJX3	UNIPROT	down-regulates	binding			9606									11751633	t		gcesareni	Emi1 can inhibit apc already activated by cdc20 or cdh1.	SIGNOR-113382	0.468
MAOB	protein	P27338	UNIPROT	(R)-adrenaline	smallmolecule	CHEBI:28918	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000142							20493079	t		Luana	The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied.	SIGNOR-269746	0.8
CBP/p300	complex	SIGNOR-C6	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	acetylation	Lys28	LATKAARkSAPSTGG	9606									21131905	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription.	SIGNOR-217214	0.2
GPR35	protein	Q9HC97	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256860	0.2
PRKCA	protein	P17252	UNIPROT	PLD2	protein	O14939	UNIPROT	up-regulates	phosphorylation	Ser243	RWLVVKDsFLLYMCL	9606									15979581	t		miannu	The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity	SIGNOR-138351	0.679
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGA3	protein	Q9Y5H0	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265677	0.2
GLI1/GLI2	complex	SIGNOR-C450	SIGNOR	BCL2	protein	P10415	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000304								32766732	t	GLI2 and GLI1 heterodimerize via the Zn-finger domain	SimoneGraziosi	GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. | RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells	SIGNOR-269211	0.381
EGF	protein	P01133	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									9168989	f	Regulation	miannu	We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin.	SIGNOR-251782	0.263
EEF2K	protein	O00418	UNIPROT	EEF2	protein	P13639	UNIPROT	down-regulates	phosphorylation	Thr57	RAGETRFtDTRKDEQ	9606									8386634	t		gcesareni	The eef-2 kinase could phosphorylate a synthetic peptide based on residues 49-60 of eef-2 (ragetrftdtrk), albeit only at a very low rate, and with a very high km, compared to eef-2 itself.	SIGNOR-38552	0.781
MRPL41	protein	Q8IXM3	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262355	0.697
GFs	stimulus	SIGNOR-ST12	SIGNOR	AKT3	protein	Q9Y243	UNIPROT	up-regulates activity				9606									23300340	f		lperfetto	Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation	SIGNOR-245408	0.7
GABA-A (a4-b1-g2) receptor	complex	SIGNOR-C333	SIGNOR	CRHR2	protein	Q13324	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268592	0.2
PRKCA	protein	P17252	UNIPROT	HSPB8	protein	Q9UJY1	UNIPROT	up-regulates	phosphorylation	Thr63	LSSAWPGtLRSGMVP	9606									22721717	t		lperfetto	Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation	SIGNOR-197949	0.311
NEK6	protein	Q9HC98	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606	BTO:0000007								20595392	t	done	miannu	Our data also show that NEK6 interacts with STAT3, an oncogenic transcription factor, and phosphorylates STAT3 on Ser(727), which is important for transcriptional activation. These results demonstrate that NEK6 interacts with and phosphorylates STAT3, an event that could play an important role in oncogenesis. For the maximal activation of STAT3 signaling, phosphorylation of both Tyr705 and Ser727 is required. Phosphorylation of Tyr705 induces dimerization, nuclear translocation, and DNA binding of the STAT3 protein, whereas phosphorylation of Ser727 is important for transcriptional activation.	SIGNOR-273901	0.34
MIF	protein	P14174	UNIPROT	HBA1	protein	P69905	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000664								16636133	f	Regulation of expression	miannu	MIF inhibits cytodifferentiation and hemoglobin synthesis of MEL cells. 	SIGNOR-251832	0.2
PHA-680632	chemical	CID:11249084	PUBCHEM	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206100	0.8
CDK2	protein	P24941	UNIPROT	FOXK2	protein	Q01167	UNIPROT	up-regulates	phosphorylation	Ser428	FAQSAPGsPLSSQPV	9606									20810654	t		gcesareni	We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis.	SIGNOR-167834	0.376
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	EGR1	protein	P18146	UNIPROT	up-regulates	binding			9606									10671503	t		lperfetto	The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo	SIGNOR-216328	0.407
INCENP	protein	Q9NQS7	UNIPROT	AURKA	protein	O14965	UNIPROT	up-regulates activity	binding			7227									16824953	t		lperfetto	INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop	SIGNOR-252048	0.714
ABL1	protein	P00519	UNIPROT	GRAP	protein	Q13588	UNIPROT	up-regulates	binding			9606	BTO:0001271								23399893	t		gcesareni	We show that the grb2-related adapter protein, gads, also associates with bcr-abl, specifically through y177 and demonstrate that bcr-abl-driven lymphoid disease requires gads	SIGNOR-200871	0.27
ADRA2A	protein	P08913	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256841	0.445
SKIL	protein	P12757	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	binding			9606				SIGNOR-C85					12419246	t		gcesareni	Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7	SIGNOR-195636	0.495
KDM1A	protein	O60341	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606	BTO:0000567								15620353	t		miannu	 Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. 	SIGNOR-264509	0.2
MAPK1	protein	P28482	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser221	DHEKKAYsFCGTVEY	9534									9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252750	0.751
PRKAA1	protein	Q13131	UNIPROT	KLC2	protein	Q9H0B6	UNIPROT	up-regulates	phosphorylation	Ser582	PRMKRASsLNFLNKS	9606			SIGNOR-C15						21725060	t		gcesareni	Consistent with phosphorylation of both ser545 and ser582 of klc2 contributing to its 14-3-3 binding, a ser545ala mutant of klc2 could be phosphorylated in vitro by ampk on ser582	SIGNOR-174681	0.2
ELOVL1	protein	Q9BW60	UNIPROT	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267896	0.8
UBE4B	protein	O95155	UNIPROT	FEZ1	protein	Q99689	UNIPROT	up-regulates activity	polyubiquitination			10116	BTO:0001009								15466860	t	K27	miannu	 E4B mediated the polyubiquitylation of FEZ1 but did not affect its intracellular stability, suggesting that such modification of FEZ1 is not a signal for its proteolysis. Polyubiquitylation of FEZ1 by E4B required Lys(27) of ubiquitin. Expression of a dominant-negative mutant of E4B in rat pheochromocytoma PC12 cells resulted in inhibition of neurite extension induced either by nerve growth factor or by coexpression of FEZ1 and constitutively active PKCzeta. These findings indicate that E4B serves as a ubiquitin ligase for FEZ1 and thereby regulates its function but not its degradation. The polyubiquitin chain attached by E4B to FEZ1 might therefore facilitate the interaction of FEZ1 with an unidentified target that functions in neuritogenesis.	SIGNOR-271510	0.4
SIAH2	protein	O43255	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates				9606									17003045	f		gcesareni	The ring finger ubiquitin ligase siah2 controls the stability of various substrates involved in stress and hypoxia responses, including the phd3, which controls the stability of hif-1alpha	SIGNOR-149893	0.37
PRKCG	protein	P05129	UNIPROT	GRK2	protein	P25098	UNIPROT	up-regulates	phosphorylation	Ser29	ATPAARAsKKILLPE	9606									11042191	t		acerquone	Phosphorylation of grk2 by protein kinase c abolishes its inhibition by calmodulinin vitro, grk2 was preferentially phosphorylated by pkc isoforms alpha, gamma, and delta	SIGNOR-83231	0.2
PRKAA1	protein	Q13131	UNIPROT	NRF1	protein	Q16656	UNIPROT	up-regulates				9606									15509864	f		gcesareni	In muscle, it causes increased dna binding by the transcription factors nrf1 (bergeron et al., 2001) and mef2 (zheng et al., 2001), which may be involved in regulation of mitochondrial genes and glut4, respectively.	SIGNOR-130076	0.2
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1619	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120084	0.316
TOMM40	protein	O96008	UNIPROT	TOM40 complex	complex	SIGNOR-C421	SIGNOR	form complex	binding			9606	BTO:0000567								18331822	t		lperfetto	The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex.	SIGNOR-267681	0.737
ITGB5	protein	P18084	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257722	0.58
CUL1	protein	Q13616	UNIPROT	ARIH1	protein	Q9Y4X5	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								24076655	t		miannu	Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin.	SIGNOR-268844	0.363
RPS6KA1	protein	Q15418	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser221	DHEKKAYsFCGTVEY	9606	BTO:0000007								20048145	t		lperfetto	Herein, we demonstrate that the n-terminal kinase domain (ntk) of rsk1 is necessary for interactions with pkarialpha. Substitution of the activation loop phosphorylation site (ser-221) in the ntk with the negatively charged asp residue abrogated the association between rsk1 and pkarialpha.	SIGNOR-162681	0.2
TAF3	protein	Q5VWG9	UNIPROT	TAF3/TRF3	complex	SIGNOR-C23	SIGNOR	form complex	binding			9606		BTO:0000887;BTO:0001103;BTO:0001760							18851836	t		lperfetto	We recently identified taf3 as a subunit specifically associated with trf3 to form a complex that is required for myogenic differentiation	SIGNOR-181611	0.686
RPS6KB1	protein	P23443	UNIPROT	CAD	protein	P27708	UNIPROT	up-regulates activity	phosphorylation	Ser1859	PPRIHRAsDPGLPAE	9606	BTO:0002181								23429703	t		miannu	CAD as a direct substrate of S6K1. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. The direct regulation of CAD by S6K1 serves as a mechanism to increase the pool of nucleotides available for the RNA and DNA synthesis that accompanies cell growth.	SIGNOR-267443	0.381
vitamin K epoxide	smallmolecule	CHEBI:28371	ChEBI	vitamin K	smallmolecule	CHEBI:28384	ChEBI	up-regulates quantity	precursor of			9606									31226734	t		lperfetto	This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR)	SIGNOR-265907	0.8
PFAS	protein	O15067	UNIPROT	L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	down-regulates quantity	chemical modification			9606									33179964	t		miannu	The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure.	SIGNOR-267310	0.8
PRKDC	protein	P78527	UNIPROT	CASP2	protein	P42575	UNIPROT	up-regulates	phosphorylation	Ser139	LSCDYDLsLPFPVCE	9606									19203584	t		lperfetto	Here we show that dna damage induced by gamma-radiation triggers the phosphorylation of nuclear caspase-2 at the s122 site within its prodomain, leading to its cleavage and activation. This phosphorylation is carried out by the nuclear serine/threonine protein kinase dna-pkcs	SIGNOR-183895	0.302
GABA-B receptor	complex	SIGNOR-C336	SIGNOR	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									30541966	t		miannu	GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase. 	SIGNOR-264965	0.406
GRK2	protein	P25098	UNIPROT	MC4R	protein	P32245	UNIPROT	down-regulates activity	phosphorylation	Ser330	GGLCDLSsRY	9606									12639913	t		gcesareni	Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor.	SIGNOR-249673	0.2
DOCK7	protein	Q96N67	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			10090	BTO:0000132								29187380	t		lperfetto	As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover.	SIGNOR-261886	0.728
PRKCZ	protein	Q05513	UNIPROT	NR1H4	protein	Q96RI1	UNIPROT	up-regulates	phosphorylation	Thr456	GRLTELRtFNHHHAE	9606	BTO:0000195								18668687	t	The effect has been demonstrated using Q96RI1-2	gcesareni	The effect of fic1 on fxr phosphorylation and nuclear localization and its effects on bsep promoter activity could be blocked with protein kinase c zeta (pkc zeta) inhibitors (pseudosubstrate or small interfering rna silencing). Recombinant pkc zeta directly phosphorylated immunoprecipitated fxr. The mutation of threonine 442 of fxr to alanine yielded a dominant negative protein,	SIGNOR-179771	0.39
FGFR3	protein	P22607	UNIPROT	FGFR3	protein	P22607	UNIPROT	up-regulates activity	phosphorylation	Tyr724	ANCTHDLyMIMRECW	9606	BTO:0000007								11294897	t		lperfetto	Ligand stimulation leads to autophosphorylation of fgfr3taken together, these results clearly implicate y724 in the activation of stat proteins by constitutively activated mutants of fgfr3 and suggest that both y724 and y760 are required for maximal stat activation.	SIGNOR-106738	0.2
TNK2	protein	Q07912	UNIPROT	SNX9	protein	Q9Y5X1	UNIPROT	up-regulates	phosphorylation			9606									16316319	t		gcesareni	We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor.	SIGNOR-142569	0.519
PRKCD	protein	Q05655	UNIPROT	BLVRA	protein	P53004	UNIPROT	up-regulates activity	phosphorylation	Ser33	DLRNPHPsSAFLNLI										22584576	t		lperfetto	LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation.	SIGNOR-275527	0.2
DVL1P1	protein	P54792	UNIPROT	CCDC88C	protein	Q9P219	UNIPROT	up-regulates	binding			9606									23151663	t		gcesareni	Daple binds to dvl and functions as a negative regulator of the wnt signalling pathway.	SIGNOR-199448	0.2
CSNK2A2	protein	P19784	UNIPROT	HMGA1	protein	P17096	UNIPROT	unknown	phosphorylation	Ser99	KEEEEGIsQESSEEE	-1									2806554	t		llicata	Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. | After an 80 min incubation with CK-II, both serines were fully phosphorylated to 1 mol/mol and serine-99 to 0.3 mol/mol.	SIGNOR-251006	0.333
MMP14	protein	P50281	UNIPROT	FGG	protein	P02679	UNIPROT	down-regulates quantity by destabilization	cleavage	Leu92	QLIKAIQlTYNPDES	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain	SIGNOR-263617	0.2
OXSR1	protein	O95747	UNIPROT	SLC12A3	protein	P55017	UNIPROT	up-regulates	phosphorylation	Thr60	MRTFGYNtIDVVPTY	9606	BTO:0000007	BTO:0000671							18270262	t		miannu	We demonstrate that the spak and osr1 kinases that are activated by wnk1 phosphorylate human ncc at three conserved residues (thr46, thr55 and thr60) / our results also indicate that phosphorylation of thr60 plays the most crucial role in triggering the activation of ncc in hek293 cells and its mutation also inhibits phosphorylation of the adjacent thr46 and thr55 sites.	SIGNOR-160833	0.398
HDAC2	protein	Q92769	UNIPROT	MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263850	0.788
CSNK2B	protein	P67870	UNIPROT	MME	protein	P08473	UNIPROT	unknown	phosphorylation	Ser6	sQMDITDI	9606	BTO:0003288								8943850	t		llicata	Taken together, these data indicate that CD10/NEP is itself phosphorylated by CKII and that CD10/NEP co-associates with additional tyrosine phosphoproteins including lyn.	SIGNOR-251078	0.383
MAPK1	protein	P28482	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser187	NSHPFPHsPNSSYPN	9606									9335504	t		llicata	In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1	SIGNOR-52674	0.59
PRKCD	protein	Q05655	UNIPROT	PRKCD	protein	Q05655	UNIPROT	up-regulates	phosphorylation	Ser299	NQVTQRAsRRSDSAS	9606									17603046	t		gcesareni	Here, we demonstrate that pkcdelta undergoes in vitro autophosphorylation at three sites within its v3 region (s299, s302, s304), each of which is unique to this pkc isoform and evolutionarily conserved	SIGNOR-156523	0.2
MAPK1	protein	P28482	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Thr273	SPSVHPAtPISPGRA	9606									16046550	t	The effect has been demonstrated using Q01196-8	miannu	We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 	SIGNOR-138981	0.2
FRK	protein	P42685	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr1552	HDLTETSyLPRQDLE	9606	BTO:0003323								29156836	t		miannu	Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552. Rak-mediated tyrosine phosphorylation of BRCA1 is essential for its stability and function 	SIGNOR-275454	0.2
FGF1	protein	P05230	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates activity	binding			9606		BTO:0001487							18940940	t		fspada	Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity.	SIGNOR-236936	0.912
CSNK1E	protein	P49674	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates	phosphorylation	Thr224	MSRFSSStEQSSASR	9606									22609948	t		lperfetto	We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle	SIGNOR-197555	0.68
NTRK2	protein	Q16620	UNIPROT	KCNA3	protein	P22001	UNIPROT	down-regulates	phosphorylation	Tyr162	SFDAILYyYQSGGRI	9606	BTO:0000938	BTO:0000671							19166614	t		gcesareni	Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein.	SIGNOR-183519	0.387
FGFR2	protein	P21802	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates				10090	BTO:0000011								12270934	f		lperfetto	Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors	SIGNOR-244868	0.307
N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide	chemical	CHEBI:91371	ChEBI	CDK1	protein	P06493	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206124	0.8
CDK5	protein	Q00535	UNIPROT	MAPK10	protein	P53779	UNIPROT	down-regulates activity	phosphorylation	Thr131	ISLLNVFtPQKTLEE	9606	BTO:0000007								11823425	t		llicata	Here, we show that cdk5 directly phosphorylates c-Jun N-terminal kinase 3 (JNK3) on Thr131 and inhibits its kinase activity, leading to reduced c-Jun phosphorylation.	SIGNOR-250668	0.351
AKT2	protein	P31751	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	phosphorylation	Ser196	KLRRRFSsLHFMVEV	9606									9812896	t		gcesareni	Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity	SIGNOR-61561	0.508
MAPK14	protein	Q16539	UNIPROT	KHSRP	protein	Q92945	UNIPROT	down-regulates activity	phosphorylation	Thr692	QAAYYGQtPGPGGPQ	10090	BTO:0000165								16364914	t		lperfetto	KSRP, an important factor for AU-rich element (ARE)-directed mRNA decay, undergoes p38-dependent phosphorylation during muscle differentiation. KSRP phosphorylated by p38 displays compromised binding to ARE-containing transcripts and fails to promote their rapid decay, although it retains the ability to interact with the mRNA degradation machinery	SIGNOR-235856	0.555
AMPK	complex	SIGNOR-C15	SIGNOR	PDHA1	protein	P08559	UNIPROT	up-regulates activity	phosphorylation	Ser295	RYHGHSMsDPGVSYR	-1									33022274	t		miannu	In vitro kinase assay revealed that PDHA could be readily phosphorylated by active AMPK complex in a dose-dependent manner (Figure 6C). 	SIGNOR-276835	0.257
HIF1A	protein	Q16665	UNIPROT	HIF-1 complex	complex	SIGNOR-C418	SIGNOR	form complex	binding			9606									27692180	t		miannu	HIF-1 consists of two subunits, HIF-1α and HIF-1β. While HIF-1β protein is constitutively expressed and present in excess, HIF-1α protein has a short half-life	SIGNOR-267447	0.777
TGFBI	protein	Q15582	UNIPROT	A3/b1 integrin	complex	SIGNOR-C161	SIGNOR	up-regulates activity	binding			10090	BTO:0001175								10906123	t		lperfetto	In addition, we demonstrated the functional receptor for betaig-h3 is alpha(3)beta(1) integrin. These results, therefore, establish the essential motifs within the 2nd and the 4th domains of betaig-h3, which interact with alpha(3)beta(1) integrin to mediate HCE cell adhesion to betaig-h3 and suggest that other proteins containing Asp-Ile in their fas-1 domains could possibly function as cell adhesion molecules.	SIGNOR-253211	0.43
arecoline	chemical	CHEBI:2814	ChEBI	CHRM2	protein	P08172	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258639	0.8
GSK3B	protein	P49841	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr57	LSSTPLStPCSSVPS	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159470	0.26
IGF1R	protein	P08069	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates activity	phosphorylation	Tyr1166	DIYETDYyRKGGKGL	9606									7493944	t		lperfetto	Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor.	SIGNOR-26590	0.2
KNL1	protein	Q8NG31	UNIPROT	BUB1B	protein	O60566	UNIPROT	up-regulates	binding			9606									17981135	t		gcesareni	Association of the amino and middle domain of blinkin with the tpr domains in the amino termini of bubr1 and bub1 is essential for bubr1 and bub1 to execute their distinct mitotic functions	SIGNOR-158894	0.2
CSNK2A1	protein	P68400	UNIPROT	PIAS1	protein	O75925	UNIPROT	up-regulates	phosphorylation	Ser468	DLTIDSSsDEEEEEP	9606									19217413	t		llicata	Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process.	SIGNOR-184047	0.337
AMPK	complex	SIGNOR-C15	SIGNOR	RB1	protein	P06400	UNIPROT	unknown	phosphorylation	Ser811	IYISPLKsPYKISEG	9606									19217427	t		lperfetto	Amp-activated protein kinase phosphorylates retinoblastoma protein. Rb phosphorylation sites, ser804 (ser811 in human), resembled the ampk consensus phosphorylation site.	SIGNOR-216635	0.2
RNF4	protein	P78317	UNIPROT	KDM5B	protein	Q9UGL1	UNIPROT	down-regulates quantity by destabilization	sumoylation			9606									33859667	t		SaraGualdi	Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015).	SIGNOR-271575	0.306
GRIN2A	protein	Q12879	UNIPROT	NMDA receptor_2A	complex	SIGNOR-C347	SIGNOR	form complex	binding			9606	BTO:0000938								12871085	t		miannu	The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits	SIGNOR-264121	0.714
XL-647	chemical	CID:10458325	PUBCHEM	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									22722787	t		gcesareni	Xl647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (egfr), vascular endothelial growth factor receptor 2, her2 and ephrin type-b receptor 4 (ephb4).	SIGNOR-197962	0.8
PRKCE	protein	Q02156	UNIPROT	ALDH2	protein	P05091	UNIPROT	up-regulates activity	phosphorylation	Thr202	KLGPALAtGNVVVMK	-1									28056995	t		lperfetto	 Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (epsilonPKC). |e identified S279 as a critical εPKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by εPKC likely also protects the enzyme against reactive aldehydes. 	SIGNOR-271865	0.286
BBS5	protein	Q8N3I7	UNIPROT	BBsome complex	complex	SIGNOR-C288	SIGNOR	form complex	binding			9606	BTO:0004910								19081074	t		lperfetto	We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 	SIGNOR-262559	0.877
PTPN11	protein	Q06124	UNIPROT	SLC25A4	protein	P12235	UNIPROT	down-regulates activity	dephosphorylation			9606									29255148	t		miannu	Specifically, SHP2-mediated dephosphorylation of ANT1 at Tyr 191 is essential for mitochondrial homeostasis and mitigation of NLRP3 inflammasome activation.|The interaction between SHP2 and ANT1 (Fig.\u00a0 xref ), and the opposite effects of SHP2 and ANT1 shRNAs in the activation of NLRP3 inflammasome (Figs.\u00a0 xref and xref ) raised the possibility that the SHP2 may inhibit ANT1 to suppress NLRP3 inflammasome activation.|To further determine which tyrosine phosphorylation site of ANT1 is dephosphorylated by SHP2, we created the dephosphorylated mutant of ANT1, in which tyrosine was replaced with phenylalanine (Y to F mutation).	SIGNOR-277124	0.275
NCAPD2	protein	Q15021	UNIPROT	Condensin I	complex	SIGNOR-C341	SIGNOR	form complex	binding			9606									32445620	t		miannu	The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction.	SIGNOR-263905	0.969
MED11	protein	Q9P086	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266670	0.779
CDKL5	protein	O76039	UNIPROT	MECP2	protein	P51608	UNIPROT	unknown	phosphorylation			-1									16935860	t		Luana	Phosphorylation assays performed with the wild-type protein confirm its capability to mediate the modification of MeCP2 in vitro, whereas Rett missense mutations within the conserved catalytic domain abrogate or significantly impair the enzymatic activity	SIGNOR-264702	0.621
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	Met-tRNA(Met)	chemical	CHEBI:16635	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270398	0.8
CR2	protein	P20023	UNIPROT	CD19	protein	P15391	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								31732528	t		scontino	Complement receptor type 2 (CR2)/CD21 plays a key role in the development of high-affinity Abs and long-lasting memory to foreign Ags. When CR2 is bound by its primary C3 activation fragment–derived ligand, designated C3d, it coassociates with CD19 on B cells to amplify BCR signaling. 	SIGNOR-266642	0.776
NUP54	protein	Q7Z3B4	UNIPROT	 p62_complex	complex	SIGNOR-C259	SIGNOR	form complex	binding			10116	BTO:0000154								2050741	t		Simone	Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function.	SIGNOR-261259	0.938
EXOC7	protein	Q9UPT5	UNIPROT	Exocyst_EXOC6 variant	complex	SIGNOR-C492	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270790	0.94
NCOA1	protein	Q15788	UNIPROT	Aldolase	proteinfamily	SIGNOR-PF75	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f	inferred from family member	miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-270223	0.2
RNF111	protein	Q6ZNA4	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	ubiquitination			10090	BTO:0000165;BTO:0000222								17341133	t		lperfetto	Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling.	SIGNOR-235394	0.672
RPA2	protein	P15927	UNIPROT	NBN	protein	O60934	UNIPROT	up-regulates	binding			9606									19586055	t		esanto	The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex. We observe a direct interaction between rpa with both nbs1 and mre11. By utilizing rpa bound to ssdna, we demonstrate that substituting rpa with phosphorylated rpa or a phosphomimetic weakens the interaction with the mrn complex.	SIGNOR-186651	0.53
STK11	protein	Q15831	UNIPROT	NUAK1	protein	O60285	UNIPROT	up-regulates	phosphorylation	Thr211	QKDKFLQtFCGSPLY	9606									14976552	t		llicata	A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold.	SIGNOR-122686	0.526
DUSP4	protein	Q13115	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates activity	dephosphorylation			10116									7535768	t	inferred from 70% of family members		Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK	SIGNOR-269933	0.752
ATR	protein	Q13535	UNIPROT	XPA	protein	P23025	UNIPROT	up-regulates	phosphorylation	Ser196	RSLEVWGsQEALEEA	9606									23178497	t		lperfetto	Atr phosphorylates xpa. at serine 196. Atr-mediated xpa phosphorylation enhances xpa stability by inhibiting herc2-mediated ubiquitination and subsequent degradation.	SIGNOR-199802	0.505
CTNNB1	protein	P35222	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			10090	BTO:0000165								19000719	t	Through Armadillo repeat domain	gcesareni	Beta-catenin can regulate the level and transcriptional activity of the notch1 and notch1 intracellular domain (nicd). The in vivo and in vitro results demonstrate that beta-catenin binds with notch1 and nicd, for which its armadillo repeat domain is essential.	SIGNOR-236858	0.766
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDE1	protein	Q9NXR1	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr215	ATGSVPStPIAHRGP	9606	BTO:0000007								16682949	t	done	miannu	Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. 	SIGNOR-274082	0.525
TIRAP	protein	P58753	UNIPROT	MYD88	protein	Q99836	UNIPROT	up-regulates activity	binding			9606									11544529	t		gcesareni	Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2.	SIGNOR-252063	0.619
CSNK2B	protein	P67870	UNIPROT	IKZF1	protein	Q13422	UNIPROT	down-regulates	phosphorylation	Thr23	ESPPVSDtPDEGDEP	9606	BTO:0001271								21750978	t		miannu	We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway	SIGNOR-174856	0.2
MLL2 complex	complex	SIGNOR-C88	SIGNOR	KDM6A	protein	O15550	UNIPROT	up-regulates quantity by stabilization	binding			9606									28669924	t		miannu	KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex. It acts as a scaffold protein within the complex and is responsible for maintaining the stability of UTX. UTX is the complex’s H3K27 demethylase. 	SIGNOR-268813	0.808
TGFBR1	protein	P36897	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	phosphorylation			9606									19701891	t		miannu	The binding of TGF‐β1 to its receptor complex activates the intracellular kinase domain of TGF‐βRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non‐Smad proteins (Smad‐independent pathway)	SIGNOR-254361	0.806
MAPK1	protein	P28482	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Ser434	SFEPKIRsPRRFIGS	9606									21035469	t		gcesareni	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-169150	0.578
PLN	protein	P26678	UNIPROT	ATP2A2	protein	P16615	UNIPROT	down-regulates activity	binding			10090									12838339	t			Heart failure can be traced, in part, to alterations in the activity of the sarcoplasmic reticulum Ca2+ pump that are induced by its interactions with phospholamban, a reversible inhibitor.	SIGNOR-252031	0.746
4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	chemical	CHEBI:49868	ChEBI	PLK1	protein	P53350	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258078	0.8
IGF1R	protein	P08069	UNIPROT	PDPK1	protein	O15530	UNIPROT	up-regulates	phosphorylation	Tyr373	SEDDEDCyGNYDNLL	9606									20643654	t		lperfetto	Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376 (11, 12, 14, 17), and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376	SIGNOR-166710	0.348
SOX9	protein	P48436	UNIPROT	CEBPB	protein	P17676	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19254573	f		fspada	Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation	SIGNOR-184280	0.332
TARS1	protein	P26639	UNIPROT	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									25824639	t		miannu	Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 	SIGNOR-270504	0.8
MK-2206	chemical	CHEBI:67271	ChEBI	AKT1	protein	P31749	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001286								21841310	t		gcesareni	Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation.	SIGNOR-252461	0.8
PDPK1	protein	O15530	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	up-regulates	phosphorylation	Thr228	HEGAVTHtFCGTIEY	9606									9445476	t		gcesareni	A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.	SIGNOR-55371	0.595
GSK3B	protein	P49841	UNIPROT	CRMP1	protein	Q14194	UNIPROT	up-regulates	phosphorylation	Thr509	PVYEVPAtPKYATPA	9606	BTO:0000938								16611631	t		lperfetto	In summary, phosphorylation of thr509 of human crmp1 appears to be regulated by two mechanisms; direct phosphorylation by cdk5, or by priming of ser522 by cdk5 followed by sequential phosphorylation of ser518, thr514, and thr509 by gsk3.	SIGNOR-145995	0.447
MAPK3	protein	P27361	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation	Ser405	KTQTPPVsPAPQPTE	9606	BTO:0000938								21079800	t		gcesareni	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-169682	0.433
GART	protein	P22102	UNIPROT	5-phospho-beta-D-ribosylaminium(1-)	smallmolecule	CHEBI:58681	ChEBI	down-regulates quantity	chemical modification			9606									34283828	t		miannu	In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR).	SIGNOR-267298	0.8
CHD8	protein	Q9HCK8	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9606									15367660	t		gcesareni	Duplin (axis duplication inhibitor) interacts with beta-catenin and prevents its binding to tcf, thereby inhibiting downstream wnt signaling	SIGNOR-128976	0.629
HNF4A	protein	P41235	UNIPROT	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									16308421	f	inferred from family member	gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-267790	0.26
PDPK1	protein	O15530	UNIPROT	SGK2	protein	Q9HBY8	UNIPROT	up-regulates activity	phosphorylation	Ser416	SSAFLGFsYAPEDDD										10548550	t		miannu	SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB.	SIGNOR-250376	0.581
MRPS11	protein	P82912	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261458	0.76
XBP1	protein	P17861	UNIPROT	NPPB	protein	P16860	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20170659	f		miannu	The promoter assay with overexpression of sXBP1 or norepinephrine showed that the proximal AP1/CRE-like element in the promoter region of BNP was critical for transcriptional regulation of BNP by sXBP1. 	SIGNOR-255609	0.2
CADM2	protein	Q8N3J6	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606	BTO:0000007								29506532	f		Gianni	The results indicated that CADM2 […} modulates EMT process and migration ability via focal adhesion kinase (FAK) /AKT signaling pathway in HCC.	SIGNOR-268855	0.2
ITGA6	protein	P23229	UNIPROT	PMP22	protein	Q01453	UNIPROT	up-regulates activity	binding			10090									16436605	t	Regulation	miannu	PMP22 is in a complex with α6β4 integrin and laminin. PMP22 and β4 integrin are in a complex in a variety of cell types. The interaction with the integrins provides PMP22 with the ability to modulate the cell–ECM communications, as well as intracellular events. Signaling between the ECM and the intracellular compartment is essential for SC myelination, as well as cellular differentiation and motility, in general. The identification of PMP22 as a binding partner for an integrin signaling complex provides a major step toward understanding the role of this disease-linked molecule in the nervous system and in non-neural cell types.	SIGNOR-251895	0.357
PRKAA2	protein	P54646	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	down-regulates	phosphorylation	Ser722	PRLRSVSsYGNIRAV	10090				SIGNOR-C3					18439900	t		lperfetto	These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK	SIGNOR-263045	0.681
IKBKB	protein	O14920	UNIPROT	BCL10	protein	O95999	UNIPROT	up-regulates activity	phosphorylation	Ser138	NNLSRSNsDESNFSE	9606	BTO:0000007								16818229	t		miannu	Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling.	SIGNOR-276292	0.765
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	NMDA receptor_2B	complex	SIGNOR-C348	SIGNOR	up-regulates activity	chemical activation			9606									12871085	t		miannu	The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate	SIGNOR-264129	0.8
SLC24A5	protein	Q71RS6	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			9606									30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264398	0.8
PDPK1	protein	O15530	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Thr412	NQVFLGFtYVAPSVL	9606									9445476	t		miannu	A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. 	SIGNOR-188911	0.714
ATE1	protein	O95260	UNIPROT	HSPA5	protein	P11021	UNIPROT	down-regulates quantity by destabilization	post transcriptional regulation			9606	BTO:0000567								29295953	t		miannu	 We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway.	SIGNOR-261345	0.3
AFDN	protein	P55196	UNIPROT	RIN1	protein	Q13671	UNIPROT	up-regulates activity	binding			9606									10545207	t		miannu	Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors.	SIGNOR-220926	0.2
IQSEC2	protein	Q5JU85	UNIPROT	GRIA2	protein	P42262	UNIPROT	up-regulates quantity	relocalization			9606		BTO:0000142							27009485	t		miannu	BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.	SIGNOR-264913	0.2
CREB3L1	protein	Q96BA8	UNIPROT	OXT	protein	P01178	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								35051932	f		lperfetto	Transcriptional and post-transcriptional regulation of oxytocin and vasopressin gene expression by CREB3L1 and CAPRIN2|By luciferase assays, we demonstrate that CREB3L1 may be a transcription factor regulating Oxt gene expression. By RNA immunoprecipitation assays and northern blot analysis of Oxt mRNA poly(A) tails, we have found that CAPRIN2 binds Oxt mRNA and regulates its poly(A) tail length.|To investigate transcriptional regulation of the OXT gene by CREB3L1, we performed luciferase assays using a proximal Oxt promoter region transfected in HEK293T cells. The expression of full-length CREB3L1 (CREB3L1FL) and a constitutively active CREB3L1 (CREB3L1CA) significantly increased luciferase activity by 5.4- and 3.2-fold, respectively, compared with controls	SIGNOR-268555	0.2
STK11	protein	Q15831	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Thr383	HYRYSDTtDSDPENE	9606									18321849	t		gcesareni	The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity	SIGNOR-161126	0.624
carfilzomib	chemical	CHEBI:65347	ChEBI	PSMB2	protein	P49721	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000898								17591945	t		miannu	Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM.	SIGNOR-259310	0.8
CSNK2A2	protein	P19784	UNIPROT	TCF7L2	protein	Q9NQB0	UNIPROT	up-regulates activity	phosphorylation	Ser60	ETNQNSSsDSEAERR	-1									11711551	t		llicata	We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. 	SIGNOR-251046	0.386
3,5-diiodo-L-tyrosine	smallmolecule	CHEBI:15768	ChEBI	L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	up-regulates quantity	precursor of			9606									28153798	t		scontino	The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines.	SIGNOR-267038	0.8
MAPK14	protein	Q16539	UNIPROT	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates													22933625	f		apalma	The IL-10-mediated shift in macrophage phenotype in injured muscle may be amplified by activation of mitogen-activated protein kinase (MAPK), especially p38 MAPK, through signaling that is antagonized by MAPK phosphatase-1 (MKP-1).	SIGNOR-255447	0.7
SHC1	protein	P29353	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			9823	BTO:0004007								10523831	t		lperfetto	Phosphorylation of the adapter protein shc by growth factor receptors provides association sites for grb2-sos, thereby activating the ras/map kinase pathway.	SIGNOR-235615	0.965
MTOR	protein	P42345	UNIPROT	NRBF2	protein	Q96F24	UNIPROT	up-regulates activity	phosphorylation	Ser120	SPLSQKYsPSTEKCL	9606	BTO:0001938								28059666	t		miannu	Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association.	SIGNOR-265875	0.2
PLK1	protein	P53350	UNIPROT	BRCA2	protein	P51587	UNIPROT	down-regulates activity	phosphorylation	Thr203	SSLATPPtLSSTVLI	9606									12815053	t		lperfetto	M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1	SIGNOR-102498	0.556
MLL-ENL	fusion protein	SIGNOR-FP7	SIGNOR	CBFB	protein	Q13951	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24449215	f		irozzo	However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins.	SIGNOR-255854	0.2
P-TEFb	complex	SIGNOR-C238	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation			9606									32048991	t		miannu	Phosphorylation of Pol II CTD by positive transcription elongation factor b (P-TEFb) is a necessary precursor event that enables productive transcription elongation. To perform this task, Pol II needs to be activated by a complex of proteins called P-TEFb; however, P-TEFb is usually found in an inactive form held by another group of proteins. Yet, it is unclear how P-TEFb is released and allowed to activate Pol II.	SIGNOR-261039	0.745
PDGFRA	protein	P16234	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates				9606									24743741	f			To further investigate the signaling pathway through which PDGFRαpromotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα. Thus, both PI3K-Akt and MEK2-MAPK pathways are necessary for PDGFRα-driven proliferation.	SIGNOR-254377	0.33
PRKCD	protein	Q05655	UNIPROT	TAGLN	protein	Q01995	UNIPROT	down-regulates activity	phosphorylation	Ser181	VIGLQMGsNRGASQA	-1									11053353	t		lperfetto	Of the three consensus protein kinase C or casein kinase II phosphorylation sites in SM22, only Ser-181 was readily phosphorylated by protein kinase C in vitro, and such phosphorylation greatly decreased actin binding.	SIGNOR-249061	0.332
PTPRG	protein	P23470	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates activity	dephosphorylation	Tyr1248	PTAENPEyLGLDVPV	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254701	0.293
CSNK2A1	protein	P68400	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates activity	phosphorylation	Thr59	EGYDELQtDGNRSSH	9606	BTO:0000567								11583622	t		llicata	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250831	0.289
PRKCD	protein	Q05655	UNIPROT	HABP4	protein	Q5JVS0	UNIPROT	down-regulates activity	phosphorylation	Thr375	GRGARGGtRGGRGRI	9606	BTO:0004974								14699138	t		lperfetto	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249254	0.293
E2F2	protein	Q14209	UNIPROT	CCNE1	protein	P24864	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8649818	f		gcesareni	We have found that cell cycle regulation of cyclin e transcription is mediated by e2f binding sites present in the promoter	SIGNOR-42020	0.592
CDK2	protein	P24941	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr40	DAESYTFtVPRRHLE										23972993	t	For phosphorylated residues see Figure 7	lperfetto	Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP	SIGNOR-274050	0.441
SRP19	protein	P09132	UNIPROT	SRP68	protein	Q9UHB9	UNIPROT	up-regulates activity	binding			-1									30649418	t		miannu	Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54. 	SIGNOR-261167	0.949
PRKCA	protein	P17252	UNIPROT	F11R	protein	Q9Y624	UNIPROT	unknown	phosphorylation	Thr92	DRVTFLPtGITFKSV	-1									7646439	t		lperfetto	Internal amino acid sequence analysis of the F11 antigen provided information concerning 68 amino acids and suggested two consensus phosphorylation sites for protein kinase C (PKC). The phosphorylation by PKC of the isolated F11 antigen was observed following stimulation by phorbol 12-myristate 13-acetate. 	SIGNOR-248901	0.327
NSD1	protein	Q96L73	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	methylation	Lys218	EIFLLCDkVQKEDIE	9606				SIGNOR-C13					20080798	t		miannu	Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation.	SIGNOR-163454	0.475
CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	SERPINE1	protein	P05121	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001615								22198637	t	 	lperfetto	Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1	SIGNOR-253712	0.506
AMPK	complex	SIGNOR-C15	SIGNOR	HIPK2	protein	Q9H2X6	UNIPROT	down-regulates activity	phosphorylation	Thr1116	AALGSTGtVAHLVAS										23871434	t	Phosphosite positions are derived from Figure S5	lperfetto	AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro	SIGNOR-275484	0.251
PRKACA	protein	P17612	UNIPROT	RGS13	protein	O14921	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr41	SFENLMAtKYGPVVY										20974683	t		miannu	Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation.we show that PKA activation also leads to increased steady-state RGS13 expression through RGS13 phosphorylation, which inhibits RGS13 protein degradation. RGS13 phosphorylation was diminished by mutation of an N-terminal Thr residue (T41) identified as a phosphorylation site by mass spectrometry. 	SIGNOR-259835	0.34
ABL1	protein	P00519	UNIPROT	CD19	protein	P15391	UNIPROT	up-regulates activity	phosphorylation	Tyr508	EDMRGILyAAPQLRS	10090									11120811	t		gcesareni	The results revealed that only tyrosine (Y)490 of CD19 was phosphorylated by c-Abl.	SIGNOR-245283	0.549
PLK1	protein	P53350	UNIPROT	SRI	protein	P30626	UNIPROT	unknown	phosphorylation	Thr155	YSTNGKItFDDYIAC	9606									24427308	t		lperfetto	Sorcin interacts physically with plk1, is phosphorylated by plk1 and induces plk1 autophosphorylation, thereby regulating kinase activity.	SIGNOR-203732	0.384
UBE2I	protein	P63279	UNIPROT	BHLHE40	protein	O14503	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								11278694	t		miannu	 Co-expression of STRA13 and UBC9 led to an increase of the pSTRA13 ubiquitination and subsequent degradation. These data established that UBC9/STRA13 association in cells is of physiological importance, presenting direct proof of UBC9 involvement in the ubiquitin-dependent degradation of pSTRA13. We also checked whether UBC9 is directly involved in pSTRA13 ubiquitination. Taken together, these results strongly suggest that pSTRA13 is targeted for proteolysis by the ubiquitin-dependent proteasome pathway through association with UBC9.	SIGNOR-272579	0.331
MAPK11	protein	Q15759	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates	phosphorylation	Ser360	TEMDPTYsPAALPQS	9606	BTO:0000567								9687510	t		gcesareni	Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha	SIGNOR-59443	0.597
ATM	protein	Q13315	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates	phosphorylation	Thr2609	LTPMFVEtQASQGTL	9606									17189255	t		gcesareni	Atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. In addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair.	SIGNOR-151441	0.689
RELA	protein	Q04206	UNIPROT	EGR1	protein	P18146	UNIPROT	up-regulates	binding			9606			SIGNOR-C13						10671503	t		gcesareni	The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo	SIGNOR-75001	0.444
ATM	protein	Q13315	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation			9606									17157788	t		miannu	Atm/atr are generally sensors of dna damage, but, together with the checkpoint kinases chk1 and chk2, they also function as response effectors by phosphorylation of key substrates, such as p53, brca1, and nbs1. In particular, p53 phosphorylation leads to protein accumulation and activation, which in turn promotes cell-cycle arrest or apoptosis.	SIGNOR-151138	0.838
phenylalanine	smallmolecule	CHEBI:28044	ChEBI	tyrosine	smallmolecule	CHEBI:18186	ChEBI	up-regulates quantity	precursor of			9606									NBK536726	t	brain	lperfetto	L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors	SIGNOR-264172	0.8
ASH1L	protein	Q9NR48	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	trimethylation	Lys37	APATGGVkKPHRYRP	-1									21239497	t		Gianni	We show that human ASH1L specifically methylates histone H3 Lys-36. Our data implicate that there may be a regulatory mechanism of ASH1L histone methyltransferases	SIGNOR-269055	0.2
MAPK14	protein	Q16539	UNIPROT	CDX2	protein	Q99626	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser295	LQASVPGsVPGVLGP	9606									16027724	t		miannu	ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation	SIGNOR-250095	0.425
PSAT1	protein	Q9Y617	UNIPROT	O-phosphonato-L-serine(2-)	smallmolecule	CHEBI:57524	ChEBI	up-regulates activity	chemical modification			3702									30034403	t		lperfetto	Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction.	SIGNOR-268560	0.8
PTPN6	protein	P29350	UNIPROT	MAP3K7	protein	O43318	UNIPROT	down-regulates activity	dephosphorylation			9606									31130074	t		miannu	Mechanistically, the association of EHEC Tir with SHP-1 facilitated the recruitment of SHP-1 to TAK1 and inhibited TAK1 phosphorylation, which then negatively regulated K63-linked polyubiquitination of TAK1 and downstream signal transduction.|SHP-1 inhibits TAK1 activity to down-regulate signal transduction and subsequent cytokine production.Innate immune responses are achieved by the activation of several pathogen-recognition receptors (PRPs), including TLRs, retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs).	SIGNOR-277128	0.3
hsa-mir-223	mirna	URS000037EC34_9606	RNAcentral	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606									24708856	t		miannu	We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2.	SIGNOR-255763	0.4
STAT5A	protein	P42229	UNIPROT	NR3C1/STAT5A	complex	SIGNOR-C84	SIGNOR	form complex	binding			9606									8878484	t		fspada	We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter.	SIGNOR-44379	0.546
RIPK3	protein	Q9Y572	UNIPROT	PDH	complex	SIGNOR-C402	SIGNOR	up-regulates activity	phosphorylation			-1									29358703	t		miannu	Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135.	SIGNOR-268065	0.2
MAPK8	protein	P45983	UNIPROT	NFATC3	protein	Q12968	UNIPROT	down-regulates	phosphorylation			9606									14517246	t		gcesareni	Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin	SIGNOR-118220	0.834
MOB1B	protein	Q7L9L4	UNIPROT	LATS1	protein	O95835	UNIPROT	up-regulates	binding			9606									21084559	t	Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases.	gcesareni	Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1.	SIGNOR-169795	0.918
Class II MHC:Antigen	complex	SIGNOR-C429	SIGNOR	Helper_T-lymphocyte_activation	phenotype	SIGNOR-PH196	SIGNOR	up-regulates				9606									31810556	f		scontino	Once they are formed, peptide/MHC class II molecules complexes are very stable and allow for sustained antigen presentation increasing the chances to encounter the matching CD4+ T lymphocytes. Once CD4+ T cells have become acti- vated, they in turn trigger macrophages to eliminate pathogens that have been previously internalized, and B lymphocytes to produce pathogen- specific antibodies.	SIGNOR-267874	0.7
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Ser688	RLFVENDsPSDGGTP	9606	BTO:0001938								11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130.	SIGNOR-104687	0.843
RXRA	protein	P19793	UNIPROT	PPARD	protein	Q03181	UNIPROT	up-regulates	binding			9606									11237216	t		lperfetto	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-105442	0.563
ROCK1	protein	Q13464	UNIPROT	MAPK8IP3	protein	Q9UPT6	UNIPROT	up-regulates	phosphorylation	Ser314	RAREKRDsRNMEVQV	9606									15767678	t		gcesareni	Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis.	SIGNOR-134580	0.339
MAPK1	protein	P28482	UNIPROT	IL16	protein	Q14005	UNIPROT	up-regulates	phosphorylation	Ser845	SIRQRISsFETFGSS	9606									14768064	t		lperfetto	The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 . the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response.	SIGNOR-121852	0.269
AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				-1									32527803	f	inferred from family member	Luana	AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by naïve ones.	SIGNOR-270304	0.7
TP53	protein	P04637	UNIPROT	THBS1	protein	P07996	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10029407	f		miannu	 p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1.	SIGNOR-255433	0.454
MAPK3	protein	P27361	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation	Ser405	KTQTPPVsPAPQPTE	9606									20444238	t		gcesareni	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-165208	0.433
PPARGC1A	protein	Q9UBK2	UNIPROT	CYP7A1	protein	P22680	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f		miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-255057	0.445
solifenacin	chemical	CHEBI:135530	ChEBI	CHRM1	protein	P11229	UNIPROT	down-regulates activity	chemical inhibition			-1									21524581	t		Luana	The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference	SIGNOR-258312	0.8
MAPK3	protein	P27361	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation			9606									10197981	t		gcesareni	Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus	SIGNOR-66755	0.508
MAPKAPK2	protein	P49137	UNIPROT	RTN4	protein	Q9NQC3	UNIPROT	unknown	phosphorylation	Ser107	VAPERQPsWDPSPVS	9606	BTO:0000567;BTO:0000801								16095439	t		llicata	Nogo-b is phosphorylated at ser107 in vitro by mapkap-k2	SIGNOR-139486	0.2
MAPK3	protein	P27361	UNIPROT	SPHK2	protein	Q9NRA0	UNIPROT	up-regulates	phosphorylation	Ser387	PATVEPAsPTPAHSL	9606	BTO:0000150								17311928	t		llicata	Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1	SIGNOR-153387	0.505
TFEB	protein	P19484	UNIPROT	GOLPH3L	protein	Q9H4A5	UNIPROT	up-regulates quantity by expression	transcriptional regulation												32978159	f		lperfetto	Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14)	SIGNOR-276793	0.2
RAG1	protein	P15918	UNIPROT	MTOR	protein	P42345	UNIPROT	up-regulates	relocalization			9606									22790199	t		gcesareni	Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated.	SIGNOR-198242	0.259
RPL11	protein	P62913	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262488	0.869
PPP1CC	protein	P36873	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	dephosphorylation	Ser217	YTRTGSEsPKVCSDQ	9606									17318175	t			The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 	SIGNOR-248496	0.272
PRKCA	protein	P17252	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates	phosphorylation	Thr567	QGRDKYKtLRQIRQG	9606	BTO:0000017								15647376	t		lperfetto	Phosphorylation of ezrin is required for both conformational activation and for signaling to downstream events. The activating c-terminal threonine phosphorylation on t567 was first described to be downstream of the rho pathway (matsui et al., 1998). Additional studies have implicated protein kinase c (pkc) 
 in the phosphorylation of ezrin t567.	SIGNOR-133223	0.531
SKIL	protein	P12757	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	binding			9606									12793438	t		lperfetto	The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway	SIGNOR-236099	0.793
RPS6KA3	protein	P51812	UNIPROT	MAD2L1	protein	Q13257	UNIPROT	up-regulates activity				9606	BTO:0000567								20383198	f		lperfetto	We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions.	SIGNOR-252039	0.2
ALDH1A3	protein	P47895	UNIPROT	retinal	smallmolecule	CHEBI:15035	ChEBI	down-regulates quantity	chemical modification			9606									21621639	t		lperfetto	All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step.	SIGNOR-265128	0.8
fenoterol	chemical	CHEBI:149226	ChEBI	ADRB1	protein	P08588	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1). 	SIGNOR-257867	0.8
EPAS1	protein	Q99814	UNIPROT	KDM6B	protein	O15054	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271586	0.2
PLK1	protein	P53350	UNIPROT	CENPU	protein	Q71F23	UNIPROT	down-regulates	phosphorylation	Thr78	FDPPLHStAIYADEE	9606									17081991	t		lperfetto	S77 and t78 of pbip1 are important for plk1-dependent pbip1 phosphorylation and degradation. Here, we demonstrate that a pbd-binding protein, pbip1, is crucial for recruiting plk1 to the interphase and mitotic kinetochores. Unprecedentedly, plk1 phosphorylated pbip1 at t78. Later in mitosis, plk1 also induced pbip1 degradation in a t78-dependent manner, thereby enabling itself to interact with other components critical for proper kinetochore functions	SIGNOR-150457	0.731
MSX1	protein	P28360	UNIPROT	LHX2	protein	P50458	UNIPROT	down-regulates activity	binding			-1									9697309	t	2	miannu	Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity	SIGNOR-241330	0.49
STAT6	protein	P42226	UNIPROT	GATA3	protein	P23771	UNIPROT	up-regulates				9606									12947222	t			GATA-3 plays a central role in regulating Th1 and Th2 cell differentiation. Upon interleukin (IL)-4 binding to its receptor, GATA-3 is induced through the action of Stat6	SIGNOR-254299	0.65
Histone H2B	proteinfamily	SIGNOR-PF68	SIGNOR	RNF168	protein	Q8IYW5	UNIPROT	up-regulates	binding			9606									19203578	t		gcesareni	Rnf168 is recruited to sites of dna damage by binding to ubiquitylated histone h2a.	SIGNOR-265372	0.2
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	NF2	protein	P35240	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								18332868	t		miannu	VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasome-mediated degradation.	SIGNOR-271674	0.333
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates quantity by destabilization	cleavage	Asp572	PWHSFGAdSVPANTE	-1									8943232	t		lperfetto	FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261761	0.502
GOT1	protein	P17174	UNIPROT	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	down-regulates quantity	chemical modification			9606									26003525	t		miannu	Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and α-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer.	SIGNOR-268061	0.8
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1668	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120008	0.781
RNF5	protein	Q99942	UNIPROT	CFTR	protein	P13569	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								21148293	t		miannu	JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation.	SIGNOR-271494	0.651
CDK7	protein	P50613	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates	phosphorylation	Thr161	GIPIRVYtHEVVTLW	9606									8344251	t		lperfetto	The mo15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (cdks) through phosphorylation of thr161 and its homologues	SIGNOR-38307	0.561
TBL1X	protein	O60907	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								20181957	t		miannu	TBL1 appears to serve two roles in regulating the activity of β-catenin. Besides the initially identified role of TBL1 in recruiting β-catenin to the SCF(TBL1) complex, it has also been shown to function as a transcriptional co-activator of β-catenin in recruiting it to the promoter site of Wnt target genes. Our results indicated that TBL1 can inhibit the polyubiquitination of β-catenin by Siah-1 in vitro (Fig. 3) and stabilize β-catenin in cells by protecting it from Siah-1-mediated ubiquitination and proteasomal degradation (Fig. 4).	SIGNOR-271954	0.643
PTEN	protein	P60484	UNIPROT	STAT5A	protein	P42229	UNIPROT	down-regulates	dephosphorylation			9606									20596030	t		miannu	The forced expression of pten in the eol-1r cells dephosphorylated akt, erk and stat5 /eol-1r cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (pten) gene. Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfr? Was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib.	SIGNOR-166481	0.451
GPC4	protein	O75487	UNIPROT	WNT3A	protein	P56704	UNIPROT	up-regulates	binding			9606									22302992	t		gcesareni	Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways	SIGNOR-195749	0.357
GBF1	protein	Q92538	UNIPROT	ARF1	protein	P84077	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9534	BTO:0000298								15616190	t		miannu	GBF1 Stimulates Production of Arf-GTP In Vivo	SIGNOR-277400	0.709
PRKG1	protein	Q13976	UNIPROT	TRPC3	protein	Q13507	UNIPROT	down-regulates	phosphorylation	Ser251	KNDYRKLsMQCKDFV	9606									16331690	t		gcesareni	There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712.	SIGNOR-142953	0.417
HBB	protein	P68871	UNIPROT	TNF	protein	P01375	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000876								11901318	f	Regulation of expression	miannu	Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes.	SIGNOR-251752	0.305
MSL1	protein	Q68DK7	UNIPROT	H2BC21	protein	Q16778	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSIYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271977	0.2
PRKCD	protein	Q05655	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates activity	phosphorylation	Ser418	KTQTPPVsPAPQPTE	10029									26490115	t		Manara	Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration. In addition, the MCP1-induced cortactin phosp	SIGNOR-260890	0.249
MEF2C	protein	Q06413	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9069290	f		gcesareni	One consequence of mef2c activation is increased c-jun gene transcription. Our results show that p38 may influence host defence and inflammation by maintaining the balance of c-jun protein consumed during infection	SIGNOR-47139	0.605
LPAR2	protein	Q9HBW0	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			9606									15856019	t		gcesareni	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13.	SIGNOR-135837	0.387
STK16	protein	O75716	UNIPROT	DRG1	protein	Q9Y295	UNIPROT	unknown	phosphorylation	Thr100	AYEFTTLtTVPGVIR	-1									18184589	t		Manara	It is therefore likely that MPSK1 regulates DRG1 function by either phosphorylation or through competition with other DRG1 binding partners.	SIGNOR-260806	0.401
TCL1A	protein	P56279	UNIPROT	AKT2	protein	P31751	UNIPROT	up-regulates	binding			9606									10983986	t		miannu	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-81683	0.531
CDK1	protein	P06493	UNIPROT	CUX1	protein	P39880	UNIPROT	down-regulates	phosphorylation	Ser1270	YQQKPYPsPKTIEDL	9606									11584018	t		lperfetto	Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter.	SIGNOR-110912	0.364
IFNG	protein	P01579	UNIPROT	NOD2	protein	Q9HC29	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003355								18647246	f		miannu	NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B.	SIGNOR-252408	0.397
PRKCD	protein	Q05655	UNIPROT	RPS3	protein	P23396	UNIPROT	up-regulates	phosphorylation	Thr221	KDEILPTtPISEQKG	9606									19059439	t		gcesareni	Here we show that pkcdelta phosphorylates rps3 resulting in its mobilization in the nucleus to repair damaged dna. Phosphorylated rps3 was only detected in non-ribosomal rps3 and the repair endonuclease activity of rps3 was increased by its phosphorylation.	SIGNOR-182623	0.2
MAPK8	protein	P45983	UNIPROT	CDT1	protein	Q9H211	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser391	LRSAAPSsPGSPRPA	9606	BTO:0000567								21930785	t		miannu	 We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2. 	SIGNOR-276361	0.378
(2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol	chemical	CHEBI:94562	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190708	0.8
CFH	protein	P08603	UNIPROT	C3	protein	P01024	UNIPROT	down-regulates activity	binding			9606									19050261	t		miannu	As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity)	SIGNOR-252141	0.916
AURKB	protein	Q96GD4	UNIPROT	NDC80	protein	O14777	UNIPROT	down-regulates	phosphorylation	Ser44	KPTFGKLsINKPTSE	9606									20471944	t		lperfetto	To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant).	SIGNOR-165558	0.842
ATF4	protein	P18848	UNIPROT	AARS1	protein	P49588	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269414	0.2
PRKCA	protein	P17252	UNIPROT	ARRB1	protein	P49407	UNIPROT	up-regulates activity	phosphorylation	Ser163	EKIHKRNsVRLVIRK	9606	BTO:0000661								24502978	t		miannu	 We demonstrate that β-arrestin-1 recruitment to the TCR, and bystander TCR and CXCR4 downregulation, are mechanistically mediated by the TCR-triggered PKC-mediated phosphorylation of β-arrestin-1 at Ser163. 	SIGNOR-276619	0.2
SIAH1	protein	Q8IUQ4	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	relocalization			9606									20940030	t		gcesareni	The overexpression of siah1 causes the re-localization of notch from the cell surface to the cytoplasm and to the nucleus, which is indicative of notch activation	SIGNOR-254330	0.264
maraviroc	chemical	CHEBI:63608	ChEBI	CCR5	protein	P51681	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194248	0.8
YAP1	protein	P46937	UNIPROT	GINS1	protein	Q14691	UNIPROT	up-regulates quantity by expression	transcriptional regulation					BTO:0001939							30224758	f		lperfetto	 By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 	SIGNOR-276566	0.2
KLF4	protein	O43474	UNIPROT	STAT6	protein	P42226	UNIPROT	up-regulates				9606	BTO:0000801								22378047	f		lperfetto	KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPAR?) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-kappaB activation.	SIGNOR-249569	0.353
WARS1	protein	P23381	UNIPROT	tRNA(Trp)	smallmolecule	CHEBI:29181	ChEBI	down-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 	SIGNOR-270509	0.8
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	Histone H2B	proteinfamily	SIGNOR-PF68	SIGNOR	down-regulates activity	monoubiquitination			9606	BTO:0000567								21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271978	0.2
FAS	protein	P25445	UNIPROT	FADD	protein	Q13158	UNIPROT	up-regulates activity	binding			9606									21959933	t		lperfetto	Aggregation-induced conformational changes in fas lead to the formation of the death-inducing signalling complex (disc) which involves recruitment of the adaptor protein fadd/mort1 through a homotypic interaction of death domains, present in both the intracellular region of fas and the c-terminus of fadd.	SIGNOR-176651	0.907
LTK	protein	P29376	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606	BTO:0000938								9223670	t		gcesareni	Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85	SIGNOR-49622	0.256
MAPK10	protein	P53779	UNIPROT	BCL2L11	protein	O43521	UNIPROT	up-regulates	phosphorylation	Thr116	SCDKSTQtPSPPCQA	9606									18498746	t		gcesareni	Jnk is the physiogically relevant uv-stimulated kinase that phosphorylates bimel on thr-112/jnk-induced bim apoptotic activity	SIGNOR-178683	0.677
PTPRS	protein	Q13332	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	dephosphorylation			9606									12018405	t		miannu	Similarly, Pestana et al. (89) have reported that overexpression of RPTPsigma in human A431 carcinoma cells partially inhibits EGFR activation, whereas antisense mediated suppression of RPTPsigma expression enhances EGFR activation, substrate phosphorylation, and signalling.|These data indicate that LAR and RPTPsigma may have a significant role in GPCR induced EGFR signalling.Whereas in A431 cells LAR and RPTPsigma may act to suppress the EGFR in response to GPCR activation, it is possible that the converse may also be true in other cell types.	SIGNOR-277145	0.44
GEM	protein	P55040	UNIPROT	ROCK2	protein	O75116	UNIPROT	down-regulates activity	binding			9534									16757346	t		miannu	We have found that Gem binds specifically to ROKβ in the coiled‐coil domain adjacent to the Rho binding site. The interaction between Gem and ROKβ leads to inhibition of MLC and MBS phosphorylation but not phosphorylation of LIMK, indicating that Gem exerts its effect by altering the substrate specificity of ROKβ	SIGNOR-261707	0.294
EEF1A1	protein	P68104	UNIPROT	Ile-tRNA(Ile)	smallmolecule	CHEBI:29160	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269512	0.8
LYN	protein	P07948	UNIPROT	ACLY	protein	P53396	UNIPROT	up-regulates activity	phosphorylation	Tyr227	KVDATADyICKVKWG	9606	BTO:0000007								32420483	t	done	miannu	 We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells.	SIGNOR-274104	0.2
CDK1	protein	P06493	UNIPROT	CDC16	protein	Q13042	UNIPROT	up-regulates	phosphorylation	Ser560	KTLKNIIsPPWDFRE	9606									14657031	t		lperfetto	Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation	SIGNOR-119762	0.623
HIPK2	protein	Q9H2X6	UNIPROT	ZBTB4	protein	Q9P1Z0	UNIPROT	down-regulates activity	phosphorylation	Thr795	AAERPGGtPTPVIAY	-1									19448668	t		miannu	The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4.	SIGNOR-262880	0.387
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	IRAK1	protein	P51617	UNIPROT	down-regulates activity	phosphorylation	Thr100	LRARDIItAWHPPAP	9606	BTO:0000007								11976320	t		gcesareni	CaMKKc and Akt overexpression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-kappaB activation.	SIGNOR-248008	0.2
CSNK2A1	protein	P68400	UNIPROT	SLBP	protein	Q14493	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr61	ERRPESFtTPEGPKP	9606							phosphorylation:Thr62	RRPESFTtPEGPKPR	18490441	t		lperfetto	Phosphorylation of Thr61 is necessary for subsequent phosphorylation of Thr60 by CK2 in vitro. Inhibitors of CK2 also prevent degradation of SLBP at the end of S phase. Thus, phosphorylation of Thr61 by cyclin A/Cdk1 primes phosphorylation of Thr60 by CK2 and is responsible for initiating SLBP degradation.	SIGNOR-265260	0.333
STK39	protein	Q9UEW8	UNIPROT	SLC12A6	protein	Q9UHW9	UNIPROT	down-regulates activity	phosphorylation	Ser96	IEDLSQNsITGEHSQ	-1									24043619	t		miannu	 We observed that in vitro activated STE20/SPS1-related proline/alanine-rich kinase (SPAK) complexed to its regulatory MO25 subunit phosphorylated KCC3 at Ser-96 and that in Xenopus laevis oocytes Ser-96 of human KCC3 is phosphorylated in isotonic conditions and becomes dephosphorylated during incubation in hypotonicity, leading to a dramatic increase in KCC3 function.	SIGNOR-276597	0.588
1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	PRKCQ	protein	Q04759	UNIPROT	up-regulates activity	binding			9606									14967450	t	PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine.	lperfetto	The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified.	SIGNOR-242596	0.8
BTG2	protein	P78543	UNIPROT	HOXB9	protein	P17482	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								10617598	t		miannu	The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation.	SIGNOR-220987	0.672
Difluprednate	chemical	CHEBI:31485	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates activity	chemical activation			-1									21182429	t		Luana	BMP had the highest K(i) value (8.4 × 10(-8) nmol/L), whereas DFB had the lowest (6.1 × 10(-11) nmol/L). The GCRBA of DFBA was intermediate to these 2 values (7.8 × 10(-10) nmol/L).	SIGNOR-257886	0.8
KDR	protein	P35968	UNIPROT	KDR	protein	P35968	UNIPROT	up-regulates	phosphorylation	Tyr1054	FGLARDIyKDPDYVR	9606	BTO:0000801;BTO:0000876								17658244	t		gcesareni	Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability.	SIGNOR-157081	0.2
CHD3	protein	Q12873	UNIPROT	MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263855	0.809
MMP25	protein	Q9NPA2	UNIPROT	MMP2	protein	P08253	UNIPROT	up-regulates activity	cleavage	Asn66	GCPKESCnLFVLKDT	-1									14583471	t		miannu	Direct activation of pro-matrix metalloproteinase-2 by leukolysin/membrane-type 6 matrix metalloproteinase/matrix metalloproteinase 25 at the asn(109)-Tyr bond. Leukolysin Cleaves ProMMP-2 at Asn66-Leu and Asn109-Tyr.	SIGNOR-256346	0.383
TDGF1	protein	P13385	UNIPROT	TGFB1	protein	P01137	UNIPROT	down-regulates activity	binding			9606									17030617	t		lperfetto	Ere, we provide evidence supporting a novel mechanism in which Cripto inhibits the tumor suppressor function of TGF-beta. Cripto bound TGF-beta and reduced the association of TGF-beta with its type I receptor, TbetaRI.	SIGNOR-150006	0.2
FYN	protein	P06241	UNIPROT	GRB10	protein	Q13322	UNIPROT	down-regulates	phosphorylation	Tyr67	NASLESLySACSMQS	9606									10871840	t		lperfetto	Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir.	SIGNOR-78702	0.388
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr654	DIHHIDYyKKTTNGR	10116	BTO:0002809;BTO:0001009								8622701	t		lperfetto	In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of fgfr1 and is therefore essential for fgfr1-mediated biological responses.	SIGNOR-236199	0.2
CDK1	protein	P06493	UNIPROT	HMGA2	protein	P52926	UNIPROT	down-regulates	phosphorylation	Ser44	QEPTGEPsPKRPRGR	9606									10636877	t		lperfetto	Architecture of high mobility group protein i-c dna complex and its perturbation upon phosphorylation by cdc2 kinase. Phosphorylation by cdc2 reduces binding strength of the mammalian and insect hmgi proteins to dna. After phosphorylation of the protein at ser-43 and ser-58 by cdc2 kinase multiple contacts of dbds, especially with the bases, are impaired and the protein binds to dna in a different way, extending the contacts to the sugar-phosphate backbone.	SIGNOR-74094	0.382
TNF	protein	P01375	UNIPROT	Demyelination	phenotype	SIGNOR-PH155	SIGNOR	up-regulates				9606									24507514	f		miannu	TNF-a is the most comprehensively studied cytokine in both EAE and MS. Most TNF-a overexpressing transgenic animals showed spontaneous pathology, characterized by progressive demyelination and macrophage infiltration	SIGNOR-263834	0.7
CYSLTR2	protein	Q9NS75	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256889	0.2
ATF1	protein	P18846	UNIPROT	PCSK1	protein	P29120	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8999965	f		miannu	 it was shown that both CREB-1 and ATF-1 transactivate the human PC1 promoter in transient transfection experiments.	SIGNOR-253742	0.2
MYCT1	protein	Q8N699	UNIPROT	CCND2	protein	P30279	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30283340	f		miannu	MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. 	SIGNOR-261731	0.2
MAPK11	protein	Q15759	UNIPROT	TWIST1	protein	Q15672	UNIPROT	up-regulates	phosphorylation	Ser68	GGGDEPGsPAQGKRG	9606	BTO:0000150								21502402	t		llicata	Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro	SIGNOR-173405	0.2
PTPN2	protein	P17706	UNIPROT	JAK3	protein	P52333	UNIPROT	down-regulates activity	dephosphorylation			9606									15780598	t		lperfetto	Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.	SIGNOR-133078	0.684
canertinib	chemical	CHEBI:61399	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258093	0.8
IL1B	protein	P01584	UNIPROT	GDF5	protein	P43026	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003742								19818765	f	Regulation	miannu	GDF-5 is suppressed by IL-1beta and enhances TGF-beta3-mediated chondrogenic differentiation in human rheumatoid fibroblast-like synoviocytes.	SIGNOR-251864	0.267
UHMK1	protein	Q8TAS1	UNIPROT	PAM	protein	P19021	UNIPROT	unknown	phosphorylation	Ser946	DRLSTEGsDQEKEDD	9606	BTO:0004055								10574929	t		lperfetto	Although P-CIP2 interacts with stathmin, it does not phosphorylate stathmin. Site-directed mutagenesis, phosphoamino acid analysis, and use of synthetic peptides demonstrate that PAM-Ser(949) is the major site phosphorylated by P-CIP2. B	SIGNOR-247009	0.456
N-tert-butyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-phenylpropanamide	chemical	CHEBI:104131	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9550290	t		miannu	Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists.	SIGNOR-258896	0.8
HCK	protein	P08631	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates activity	phosphorylation	Tyr771	IGTAEPDyGALYEGR	-1									7682059	t		lperfetto	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249361	0.666
PPP1CC	protein	P36873	UNIPROT	IFIH1	protein	Q9BYX4	UNIPROT	up-regulates activity	dephosphorylation	Ser88	EALRRTGsPLAARYM	9606									23499489	t		lperfetto	Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.	SIGNOR-264579	0.249
CSNK2A1	protein	P68400	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser36	RHDSGLDsMKDEEYE										10398585	t		lperfetto	Serine 32 and serine 36 of IkappaBalpha are directly phosphorylated by protein kinase CKII in vitro|Phosphorylation of IkappaBalpha at serine 32 (S32) and serine 36 (S36) is necessary for this stimuli-induced degradation	SIGNOR-249333	0.566
SIRT1	protein	Q96EB6	UNIPROT	RELA	protein	Q04206	UNIPROT	down-regulates activity	deacetylation	Lys310	KRTYETFkSIMKKSP	9606	BTO:0002207								15152190	t		gcesareni	SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310.	SIGNOR-238817	0.715
VHL	protein	P40337	UNIPROT	CARD9	protein	Q9H257	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								17936701	t			We found that pVHL associates with the NF-kappaB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2.	SIGNOR-257603	0.402
RET	protein	P07949	UNIPROT	RET	protein	P07949	UNIPROT	up-regulates	phosphorylation	Tyr809	LIVEYAKyGSLRGFL	9606									14711813	t		llicata	Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. these facts suggest that tyr806 and tyr809, located in this unique position, play a novel supplemental role for the activation loop upon phosphorylation.	SIGNOR-121157	0.2
RPS6KA3	protein	P51812	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									14625384	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-119229	0.2
FGF1	protein	P05230	UNIPROT	FGFR4	protein	P22455	UNIPROT	up-regulates	binding			9606									1385111	t		gcesareni	Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides.	SIGNOR-18454	0.821
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation			9606									17900900	t		lperfetto	The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt.	SIGNOR-252889	0.398
(R)-salbutamol	chemical	CHEBI:8746	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			9606									22182578	t		Luana	 Salbutamol is a well-known β2 adrenoceptor (β2AR) partial agonist. | In order to gain insight, we carried out binding and functional assays for BCSDs in HEK-293T cells transfected with the human β2AR (hβ2AR). The transfected hβ2AR showed similar affinity for BCSDs and salbutamol	SIGNOR-258326	0.8
pemetrexed	chemical	CHEBI:63616	ChEBI	DHFR	protein	P00374	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205819	0.8
ITGB4	protein	P16144	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606									9428518	t		gcesareni	Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation.	SIGNOR-54530	0.391
MAP3K9	protein	P80192	UNIPROT	MAP3K9	protein	P80192	UNIPROT	up-regulates activity	phosphorylation	Thr312	TKMSAAGtYAWMAPE	10029									15610029	t		lperfetto	We present here biochemical and biophysical evidence that MLK1 is activated by autophosphorylation in (or near) the activation loop. The activation loops of the MLK family are highly homologous, and so one might predict that the same residues would be key to their activation. Functional data presented here, however, demonstrate that the key residue for activation of MLK1, Thr312, differs from the key residue for activation of MLK3.	SIGNOR-249388	0.2
MC3R	protein	P41968	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257407	0.252
WARS1	protein	P23381	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 	SIGNOR-270511	0.8
PRKCA	protein	P17252	UNIPROT	HES1	protein	Q14469	UNIPROT	down-regulates activity	phosphorylation	Ser37	TASEHRKsSKPIMEK	-1									9389649	t		lperfetto	Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro.	SIGNOR-248992	0.335
RNF149	protein	Q8NC42	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0001109								22628551	t		miannu	We showed that RNF149 bound directly to the C-terminal kinase-containing domain of wild-type BRAF and induced ubiquitination, followed by proteasome-dependent degradation, of the latter protein. Functionally, RNF149 attenuated the increase in cell growth induced by wild-type BRAF. 	SIGNOR-272043	0.343
MAPK3	protein	P27361	UNIPROT	POU5F1	protein	Q01860	UNIPROT	down-regulates	phosphorylation	Ser111	ESNSDGAsPEPCTVT	9606									23024368	t		gcesareni	Phosphorylation of this site downregulates nanog, sox2, rex1 and upregulates bmp4, gata6, ddlx5.	SIGNOR-192101	0.351
ANK3	protein	Q12955	UNIPROT	DMD	protein	P11532	UNIPROT	up-regulates quantity	relocalization			10090		BTO:0001103							19109891	t		miannu	We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4.	SIGNOR-266715	0.375
CTSB	protein	P07858	UNIPROT	BGLAP	protein	P02818	UNIPROT	down-regulates quantity by destabilization	cleavage	Arg95	GFQEAYRrFYGPV	-1									9076588	t		miannu	This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 	SIGNOR-256320	0.335
RAPGEF4	protein	Q8WZA2	UNIPROT	RAP1B	protein	P61224	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9534	BTO:0000298								10777494	t		miannu	Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.	SIGNOR-263955	0.804
AKT1	protein	P31749	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	down-regulates	phosphorylation			9606									20086174	t	inferred from 70% of family members	llicata	We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2.	SIGNOR-269945	0.406
MARCHF1	protein	Q8TCQ1	UNIPROT	HLA-DRA	protein	P01903	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys244	FIIKGLRkSNAAERR	9606									19117940	t		miannu	Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination.	SIGNOR-271412	0.2
CEBPG	protein	P53567	UNIPROT	SLCO1B3	protein	Q9NPD5	UNIPROT	up-regulates quantity by expression	transcriptional regulation												15322262	t		lperfetto	Taken together, these findings suggest that the LPS-induced down-regulation of Oatp4 is likely due to reduction in the binding of HNF1alpha, C/EBP, HNF3, and RXR:RAR to the Oatp4 promoter.	SIGNOR-268986	0.2
AR	protein	P10275	UNIPROT	UCN	protein	P55089	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001509								23801677	t	 	lperfetto	When cells were treated with DHT alone, AR was upregulated and translocated into the nuclei, which might repress UCN1 expression via a potential androgen-responsive element found in human CRF family promoter|These data suggest that DHT differentially influences UCN1 levels under normal and inflammatory conditions in human umbilical vein endothelial cells, which involves AR-dependent and -independent mechanisms respectively. 	SIGNOR-253688	0.2
RPLP0	protein	P05388	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262451	0.819
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	CDC25C	protein	P30307	UNIPROT	down-regulates	phosphorylation			9606									20220133	t	inferred from 70% family members	gcesareni	Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset.	SIGNOR-269983	0.2
PHKG1	protein	Q16816	UNIPROT	PHKG1	protein	Q16816	UNIPROT	unknown	phosphorylation	Ser82	VDILRKVsGHPNIIQ	-1									7935360	t		miannu	Phosphopeptides correspond to sequences occurring in the gamma-subunit of phosphorylase kinase […] undergoes autophosphorylation. phosphorylation occurs primarily at Ser30 while in the latter an additional reaction takes place at Ser81.	SIGNOR-250389	0.2
ARHGAP10	protein	A1A4S6	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606									32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260465	0.655
PIN1	protein	Q13526	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates	binding			9606	BTO:0000150								23716601	t		esanto	Pin1 prolyl isomerase enhances recruitment of serine 62-phosphorylated myc and its coactivators to select promoters during gene activation.	SIGNOR-202134	0.554
KIF3B	protein	O15066	UNIPROT	Minus-end directed microtubule movement	phenotype	SIGNOR-PH217	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272537	0.7
DDB2	protein	Q92466	UNIPROT	DDB2/DDB1	complex	SIGNOR-C39	SIGNOR	form complex	binding			9606									9418871	t		miannu	Ddb was identified as a heterodimeric protein (48 and 127 kda) that binds to uv-damaged dna	SIGNOR-54099	0.936
ATM	protein	Q13315	UNIPROT	MDC1	protein	Q14676	UNIPROT	up-regulates	phosphorylation			9606									12607003	t		fstefani	We show that, in response to ionizing radiation, mdc1 is hyperphosphorylated in an atm-dependent manner, and rapidly relocalizes to nuclear foci that also contain the mre11 complex, phosphorylated histone h2ax and 53bp1.	SIGNOR-98798	0.842
SF3A1	protein	Q15459	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270668	0.719
SYT1	protein	P21579	UNIPROT	SNAP25	protein	P60880	UNIPROT	up-regulates activity	binding			9606	BTO:0000938			SIGNOR-C346					16679567	t		miannu	Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion	SIGNOR-263975	0.949
WDR5	protein	P61964	UNIPROT	Set1-Ash2 HMT complex	complex	SIGNOR-C352	SIGNOR	form complex	binding			9606	BTO:0000567								12670868	t		miannu	Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles.	SIGNOR-264480	0.916
PRKAA1	protein	Q13131	UNIPROT	PRPS2	protein	P11908	UNIPROT	down-regulates activity	phosphorylation	Ser180	GGAKRVTsIADRLNV	9606	BTO:0006038								29074724	t		lperfetto	We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production.	SIGNOR-265731	0.2
NLGN2	protein	Q8NFZ4	UNIPROT	NRXN1	protein	P58400	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264151	0.819
PHF2	protein	O75151	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									21532585	t		miannu	PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark.	SIGNOR-264517	0.2
POLR2J3	protein	Q9H1A7	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266173	0.691
TRAF6	protein	Q9Y4K3	UNIPROT	ECSIT	protein	Q9BQ95	UNIPROT	down-regulates activity	ubiquitination			10090									21525932	t		Giorgia	Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation	SIGNOR-260370	0.783
AKT1	protein	P31749	UNIPROT	BCL3	protein	P20749	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser41	KRPLRAPsPEPAAPR	-1									28689659	t		miannu	Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA. 	SIGNOR-277358	0.508
ITGB1	protein	P05556	UNIPROT	A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253182	0.812
CDKN2A	protein	Q8N726	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization				9606									12091906	f		apalma	P14/p19 ARF functions by antagonizing MDM2 and thereby stabilizing p53 (refs. 17,18). Thus, loss of p14/p19ARF impairs p53-mediated growth arrest and/or apoptosis in response to activated oncogenes	SIGNOR-255694	0.781
CDK5RAP2	protein	Q96SN8	UNIPROT	CDC20	protein	Q12834	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								19282672	t		Giulio	We show here that inhibition of CDK5RAP2 expression causes chromosome mis-segregation, fails to maintain the spindle checkpoint, and is associated with reduced expression of the spindle checkpoint proteins BUBR1 and MAD2 and an increase in chromatin-associated CDC20.|We found that the APC activator CDC20, but not others we exam-ined, was present in the CDK5RAP2 immunocomplex in HeLa cell extracts (Fig. 3A). CDK5RAP2 was detected in the CDC20 immunocomplex as well (Fig. 3B).	SIGNOR-260311	0.318
PP2CA_R1A_R2A 	complex	SIGNOR-C132	SIGNOR	RAF1	protein	P04049	UNIPROT	up-regulates activity	dephosphorylation	Ser259	SQRQRSTsTPNVHMV	9606	BTO:0000007								16239230	t		gcesareni	... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259.	SIGNOR-243534	0.501
ZAP70	protein	P43403	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates	phosphorylation	Tyr113	SSFEEDDyESPNDDQ	9606									9047237	t		lperfetto	Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient.	SIGNOR-46855	0.798
ARNT	protein	P27540	UNIPROT	AHR-ARNT	complex	SIGNOR-C125	SIGNOR	form complex	binding			-1									9020169	t	2	miannu	SIM1 and SIM2, and the mammalian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins are members of the basic-helix-loop-helix·PAS family of transcription factors. In the yeast two-hybrid system, we demonstrate strong constitutive interaction of ARNT with SIM1 and SIM2 and fully ligand-dependent interaction of ARNT with AHR. SIM1 inhibits binding of the AHR·ARNT dimer to the xenobiotic response element in vitro Introduction of SIM1 into hepatoma cells inhibits transcriptional transactivation by the endogenous AHR·ARNT dimer.	SIGNOR-240814	0.744
RPS6KA1	protein	Q15418	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606									11584304	t		lperfetto	S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity.	SIGNOR-110917	0.366
SIRT1	protein	Q96EB6	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates quantity	transcriptional regulation			9606									19553684	f		gcesareni	Collectively, these data indicate that SIRT1 controls PGC-1alpha gene expression in skeletal muscle and that MyoD is a key mediator of this action	SIGNOR-238790	0.792
PAK1	protein	Q13153	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								11804587	t		lperfetto	We show that pak1 forms homodimers in vivo and that its dimerization is regulated by the intracellular level of gtp-cdc42 or gtp-rac1. The dimerized pak1 adopts a trans-inhibited conformation.	SIGNOR-236338	0.2
sunitinib	chemical	CHEBI:38940	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0004479								20570526	t		Luana	Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors],	SIGNOR-257848	0.8
nicotine	smallmolecule	CHEBI:18723	ChEBI	CHRNB3	protein	Q05901	UNIPROT	up-regulates activity	chemical activation			9606		BTO:0000227							28901280	t		miannu	Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cysloop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes.	SIGNOR-264259	0.8
CSNK2A1	protein	P68400	UNIPROT	SHOX	protein	O15266	UNIPROT	up-regulates	phosphorylation	Ser106	EKREDVKsEDEDGQT	9606									16325853	t		lperfetto	We show also that casein kinase ii phosphorylates shox on serine 106 efficiently in vitro. S106a shox mutant, defective in phosphorylation, does not activate transcription and fails to induce cell-cycle arrest and apoptosis	SIGNOR-142875	0.343
TAOK2	protein	Q9UL54	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates activity	phosphorylation	Ser383	IHFWSTLsPIAPRSP	9606	BTO:0000007								12665513	t		lperfetto	Transfection studies demonstrated that TAO2 stimulates phosphorylation of the TCF Elk1 on the major activating site, Ser383, and that TAO2 stimulates transactivation of Elk1 and the related TCF, Sap1.	SIGNOR-246638	0.314
E2F1	protein	Q01094	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates activity	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253864	0.687
TWIST1	protein	Q15672	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15311212	f		miannu	 known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT.	SIGNOR-255157	0.498
ATR	protein	Q13535	UNIPROT	XRCC3	protein	O43542	UNIPROT	up-regulates activity	phosphorylation	Ser225	PFRCEFDsQASAPRA	9606									23438602	t		miannu	HXRCC3 S225 phosphorylation is mediated by ATR via an ATM-dependent signaling pathway. These data clearly indicate that ATR mediates the late activation of XRCC3 following DSB accumulation. 	SIGNOR-262666	0.478
[4,5,6,7-Tetrabromo-2-(Dimethylamino)-1h-Benzimidazol-1-Yl]acetic Acid	chemical	CID:46943415	PUBCHEM	CSNK2A2	protein	P19784	UNIPROT	down-regulates activity	chemical inhibition			-1									22115617	t		Federica	4,5,6,7-tetrabromo- and 4,5,6,7-tetraiodo-1H-benzimidazoles and their newly obtained N1- and 2-S-carboxyalkyl derivatives showed potent inhibitory activity against both these subunits. CK2α was up to 6 times more sensitive to the studied compounds than CK2α.	SIGNOR-261112	0.8
anthraflavic acid	chemical	CHEBI:34250	ChEBI	UGT1A1	protein	P22309	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								21030469	t		Luana	Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation.	SIGNOR-258156	0.8
PABPC1	protein	P11940	UNIPROT	NFX1	protein	Q12986	UNIPROT	up-regulates activity	binding			9606	BTO:0000009								17267499	t		Simone	We identifiednew protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) thatinteracted with NFX1-123 through its N-terminal PAM2 motif. Central to our findings were our observations that PABPCs copurify with NFX1-123, that a PAM2 motif is present in NFX1, and this motif and the PABPCs are important in the enhancement of hTERT activity by NFX1-123. 	SIGNOR-261052	0.35
CSNK1A1	protein	P48729	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser291	CGSSGYFsSSPTLSS	9606									22017877	t		llicata	Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291.	SIGNOR-176879	0.2
MECOM	protein	Q03112	UNIPROT	ANGPT2	protein	O15123	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15889140	t		Luana	We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2 	SIGNOR-266060	0.2
mono(2-ethylhexyl) phthalate	chemical	CHEBI:17243	ChEBI	PPARD	protein	Q03181	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 	SIGNOR-268784	0.8
PRKD2	protein	Q9BZL6	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates	phosphorylation	Ser876	QGLAERIsVL	9606									11062248	t		gcesareni	The addition of phorbol 12,13-dibutyrate in the presence of dioleoylphosphatidylserine stimulated the autophosphorylation of pkd2 in a synergistic fashion.In addition, we could identify the c-terminal ser(876) residue as an in vivo phosphorylation site within pkd2. Phosphorylation of ser(876) of pkd2 correlated with the activation status of the kinase.	SIGNOR-83834	0.2
SEH1L	protein	Q96EE3	UNIPROT	GATOR2	complex	SIGNOR-C193	SIGNOR	form complex	binding			9606									23723239	t		miannu	Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5	SIGNOR-255304	0.832
NLK	protein	Q9UBE8	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation	Ser329	STISGRLsPIMTEQD	9534	BTO:0001538								20061393	t	done	miannu	Here, we report that the transforming growth factor-beta-activated kinase (TAK1)-Nemo-like kinase (NLK) pathway negatively regulates FOXO1. We show that NLK binds and phosphorylates FOXO1 at Pro-directed Ser/Thr residues in the transactivation domain. The phosphorylation by TAK1-NLK pathway inhibits the transcriptional activity of FOXO1 and excludes FOXO1 from the nucleus, which is independent of phosphatidylinositol 3-kinase/Akt pathway. 	SIGNOR-273907	0.601
PTPN6	protein	P29350	UNIPROT	TRAF3	protein	Q13114	UNIPROT	down-regulates activity	dephosphorylation	Tyr116	EILALQIyCRNESRG	9606	BTO:0002181								32779804	t		miannu	We identified a direct interaction between SHP‐1 and TRAF3; the association between these two proteins resulted in diminished recruitment of CK1ε to TRAF3 and inhibited its K63‐linked ubiquitination; SHP‐1 inhibited K63‐linked ubiquitination of TRAF3 by promoting dephosphorylation at Tyr116 and Tyr446.	SIGNOR-277527	0.2
PRKAA1	protein	Q13131	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates	phosphorylation	Ser1177	TSRIRTQsFSLQERQ	9606	BTO:0000567		SIGNOR-C15						18303014	t		gcesareni	The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner	SIGNOR-160838	0.288
TFE3	protein	P19532	UNIPROT	CTSF	protein	Q9UBX1	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276817	0.2
ARNTL	protein	O00327	UNIPROT	CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	form complex	binding			-1									22653727	t	 	lperfetto	Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex|The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock.	SIGNOR-253708	0.769
ADRA2A	protein	P08913	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256698	0.535
MAP3K1	protein	Q13233	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser218	VSGQLIDsMANSFVG	10090	BTO:0000944								8131746	t		lperfetto	Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity.	SIGNOR-235587	0.645
ABL1	protein	P00519	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates activity	phosphorylation	Tyr153	LAYILSMePCGHCLI	9606									15657060	t		Manara	We show that ABL1 phosphorylates caspase-9 on Tyr-153 in vitro and in cells treated with DNA damaging agents. ! Moreover, inhibition of ABL1 with STI571 blocked DNA damage-induced autoprocessing of caspase-9 to the p35 subunit and activation of caspase-3.	SIGNOR-260792	0.528
MAPK8	protein	P45983	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates	phosphorylation			9606									10567572	t		amattioni	Jnk was capable of phosphorylating bcl-2. Phosphorylation of bcl-2 inactivates the molecule	SIGNOR-72364	0.564
prostaglandin E2(1-)	smallmolecule	CHEBI:606564	ChEBI	PTGER3	protein	P43115	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257571	0.8
GPER1	protein	Q99527	UNIPROT	GNG2	protein	P59768	UNIPROT	up-regulates activity	binding												10696571	t			GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; GNG2 stands for the subunit γ, which dissociates from the receptor after the binding of GTP on α-subunit.	SIGNOR-251104	0.357
ULK1/Atg13/Fip200	complex	SIGNOR-C100	SIGNOR	Autophagy	phenotype	SIGNOR-PH31	SIGNOR	up-regulates				9606									23863160	f		lperfetto	In mammals, two protein complexes, namely the ULK1/Atg13/FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin/Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation.	SIGNOR-209907	0.7
MYOD1	protein	P15172	UNIPROT	SP1	protein	P08047	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									9148896	t		lperfetto	These data suggest a regulatory model in which MyoD activation during myogenesis causes the down-regulation of Sp1, which contributes to the repression of GLUT1 gene transcription and, therefore, leads to the reduction in GLUT1 expression and glucose transport.	SIGNOR-241765	0.381
CDH11	protein	P55287	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265851	0.639
DAPK3	protein	O43293	UNIPROT	DAPK3	protein	O43293	UNIPROT	up-regulates	phosphorylation	Thr225	LGETKQEtLTNISAV	9606									15611134	t		gcesareni	Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates.	SIGNOR-132463	0.2
AKT1	protein	P31749	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr145	QGRKRRQtSMTDFYH	9606									16982699	t		gcesareni	Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.[...] We next investigated if phosphorylation of p21-t145 interfered with akt2 binding. As shown in fig. ?Fig.8e8e (right lane), phosphorylation of p21 on t145 effectively prevented akt2 interaction.	SIGNOR-149698	0.835
ALX4	protein	Q9H161	UNIPROT	NCAM1	protein	P13591	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003952								11696550	f		miannu	Alx4 Overexpression Represses Endogenous N-CAM Expression	SIGNOR-254548	0.2
LYN	protein	P07948	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	down-regulates activity	phosphorylation	Tyr374	PLPPAPAyLSSPLAL	9606	BTO:0000007								23131831	t		miannu	Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation. 	SIGNOR-276369	0.364
PRKN	protein	O60260	UNIPROT	RANBP2	protein	P49792	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								16332688	t		irozzo	Our findings suggested that the intracellular levels of RanBP2 and its functional activity may be modulated by Parkin-mediated ubiquitination and proteasomal pathways. Furthermore, Parkin controls the intracellular levels of sumoylated HDAC4, as a result of the ubiquitination and degradation of RanBP2.	SIGNOR-259116	0.2
GSK3B	protein	P49841	UNIPROT	HNRNPD	protein	Q14103	UNIPROT	down-regulates	phosphorylation	Ser83	DEGHSNSsPRHSEAA	9606									11903055	t		gcesareni	In kinase assays pka phosphorylated ser-87 of hnrnp d, whereas glycogen synthase kinase-3 beta (gsk-3 beta) phosphorylated ser-83, but only if ser-87 had been pre-phosphorylated by pka. Phosphorylation of ser-87 enhanced, whereas phosphorylation of ser-83 repressed, transactivation.	SIGNOR-116140	0.352
GATA2	protein	P23769	UNIPROT	Megakaryocyte_differentiation 	phenotype	SIGNOR-PH103	SIGNOR	up-regulates activity				10090									21605981	f			GATA1 and GATA2 are expressed principally in hematopoietic lineages, and have essential roles in the development of multiple hematopoietic cells, including erythrocytes and megakaryocytes.	SIGNOR-259960	0.7
pazopanib hydrochloride	chemical	CHEBI:71217	ChEBI	CSF1R	protein	P07333	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-199527	0.8
NLGN4X	protein	Q8N0W4	UNIPROT	NRXN1	protein	P58400	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264150	0.763
ARHGAP11B	protein	Q3KRB8	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260468	0.468
PRKCI	protein	P41743	UNIPROT	LLGL1	protein	Q15334	UNIPROT	up-regulates activity	phosphorylation	Ser659	RVKSLKKsLRQSFRR	9615									12725730	t		miannu	This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner.	SIGNOR-263179	0.651
YY1	protein	P25490	UNIPROT	HSD3B2	protein	P26439	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15291746	f		miannu	 These results designate YY1 as the factor responsible for the intron 1-mediated boost of the HSD3B2 gene basal promoter activity. 	SIGNOR-255619	0.2
STK3	protein	Q13188	UNIPROT	RCC1	protein	P18754	UNIPROT	up-regulates	phosphorylation	Ser11	KRIAKRRsPPADAIP	9606	BTO:0000007								19559616	t		miannu	MST2 Phosphorylates RCC1 In Vitro and In Vivo. Using an antibody generated against phospho-S2/11 in RCC1 [18], we found that these two residues were also efficiently phosphorylated by MST1 and MST2 (Figure 2D), further supporting that S2 and/or S11 are genuine MST2 phosphorylation targets.	SIGNOR-263145	0.2
PRKACA	protein	P17612	UNIPROT	TPPP	protein	O94811	UNIPROT	unknown	phosphorylation	Ser32	DRAAKRLsLESEGAG	-1									17693641	t		miannu	 Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. Thus our data suggest that ERK2 or Cdk5 can perturb the interaction of TPPP with tubulin, in contrast to PKA that is ineffective in this respect.	SIGNOR-262930	0.2
RORA	protein	P35398	UNIPROT	SHH	protein	Q15465	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001011								19381306	t		miannu	RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. 	SIGNOR-266846	0.254
CDK4	protein	P11802	UNIPROT	CELF1	protein	Q92879	UNIPROT	up-regulates activity	phosphorylation	Ser302	TSSGSSPsSSSSNSV	10090									16931514	t		miannu	 These studies showed that both the increased levels of CUGBP1 and cdk4-mediated hyper-phosphorylation of CUGBP1 are involved in the age-associated induction of the CUGBP1-eIF2 complex. The CUGBP1-eIF2 complex is bound to C/EBPbeta mRNA in the liver of old animals, and this binding correlates with the increased amounts of liver-enriched activator protein and liver-enriched inhibitory protein.	SIGNOR-262735	0.409
CEBPB	protein	P17676	UNIPROT	S100A9	protein	P06702	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001370								9706399	t	 	 	 Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells.	SIGNOR-254044	0.2
STAG1	protein	Q8WVM7	UNIPROT	Cohesin complex	complex	SIGNOR-C304	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-267729	0.913
RIPK1	protein	Q13546	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	up-regulates activity	binding			10090	BTO:0000452								10795740	t		gcesareni	We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation	SIGNOR-245026	0.662
UBE2D3	protein	P61077	UNIPROT	UBR5	protein	O95071	UNIPROT	up-regulates activity	ubiquitination			-1									11714696	t		miannu	Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with gamma-H2AX nuclear foci in DNA breaks.	SIGNOR-272669	0.475
NCSTN	protein	Q92542	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates	binding			9606									12471034	t	Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation	gcesareni	Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2.	SIGNOR-96253	0.964
PHF6	protein	Q8IWS0	UNIPROT	UBTF	protein	P17480	UNIPROT	down-regulates	binding			9606	BTO:0001271								23229552	t		miannu	We demonstrate that phf6 is a nucleolus, ribosomal rna promoter-associated protein. Phf6 directly interacts with upstream binding factor (ubf) through its phd1 domain and suppresses ribosomal rna (rrna) transcription by affecting the protein level of ubf	SIGNOR-200133	0.284
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	NOXA1	protein	Q86UR1	UNIPROT	down-regulates	phosphorylation			9606									20230789	t	inferred from 70% family members	lperfetto	Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity	SIGNOR-270114	0.2
PPP1CA	protein	P62136	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates	dephosphorylation			9606									12840032	t	inferred from 70% of family members	fstefani	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases	SIGNOR-269927	0.457
SYK	protein	P43405	UNIPROT	SLC4A1	protein	P02730	UNIPROT	up-regulates	phosphorylation	Tyr21	ENLEQEEyEDPDIPE	9606									10942405	t		llicata	Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites.	SIGNOR-80788	0.462
RAP1GDS1	protein	P52306	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates	binding			9606									21242305	t		miannu	Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob	SIGNOR-171415	0.426
GSK690693	chemical	CHEBI:90677	ChEBI	AKT1	protein	P31749	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258118	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser106	PLNSVSPsPLMLLHP	9606									11108261	t		lperfetto	Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt.	SIGNOR-244247	0.2
EFNA5	protein	P52803	UNIPROT	EPHA8	protein	P29322	UNIPROT	up-regulates	binding			9606									9330863	t		gcesareni	Efna5 are able to activate epha8	SIGNOR-52479	0.813
CAMK4	protein	Q16566	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser498	RPLSRTQsSPLPQSP	9606		BTO:0000887							11114197	t		gcesareni	Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs.	SIGNOR-85110	0.49
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	ABI1	protein	Q8IZP0	UNIPROT	down-regulates activity	phosphorylation	Ser216	VPNDYMTsPARLGSQ	9606	BTO:0000567								21900237	t		lperfetto	We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis.|Bcr-Abl-induced actin polymerization requires the Abi1 pathway, as the blockade of the signal transduction from Bcr-Abl to Abi1 abolishes the F-actin assembly|serine phosphorylation of Abi1 by CDK1/cyclin B serves as a cell cycle-dependent regulatory mechanism that inhibits actin assembly	SIGNOR-264452	0.43
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	tRNA(Leu)	smallmolecule	CHEBI:29169	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270411	0.8
CLCF1	protein	Q9UBD9	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates	binding			9606	BTO:0001271								9143707	t		gcesareni	Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-6	SIGNOR-47959	0.542
ITGB1BP1	protein	O14713	UNIPROT	ITGB6	protein	P18564	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257662	0.29
MAPK1	protein	P28482	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Thr220	QSNYIPEtPPPGYIS	9606		BTO:0000763							12193595	t		miannu	Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction.	SIGNOR-91726	0.711
WNT7B	protein	P56706	UNIPROT	FZD1	protein	Q9UP38	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0000763;BTO:0001260							15923619	t		gcesareni	Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling.	SIGNOR-137931	0.657
SSTR5	protein	P35346	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256833	0.425
SYCE3	protein	A1L190	UNIPROT	Synaptonemal_complex	complex	SIGNOR-C351	SIGNOR	form complex	binding			9606									22394509	t		miannu	The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region.	SIGNOR-264202	0.655
Phagocytosis	phenotype	SIGNOR-PH97	SIGNOR	IL1B	protein	P01584	UNIPROT	down-regulates quantity					BTO:0000801								22933625	f		apalma	Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype	SIGNOR-255445	0.7
PTHLH	protein	P12272	UNIPROT	PTH1R	protein	Q03431	UNIPROT	up-regulates activity	binding			-1									8683730	t		lperfetto	 Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner.|The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production.	SIGNOR-270549	0.753
MYO10	protein	Q9HD67	UNIPROT	DCC	protein	P43146	UNIPROT	up-regulates quantity	relocalization			10090	BTO:0000938								17237772	t		miannu	Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin.	SIGNOR-268282	0.672
STAP1	protein	Q9ULZ2	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								10679268	t		miannu	 STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells.	SIGNOR-261821	0.395
FYN	protein	P06241	UNIPROT	DCBLD2	protein	Q96PD2	UNIPROT	up-regulates activity	phosphorylation	Tyr655	GYADLDPyNSPGQEV	-1									23770091	t	done	miannu	Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding.	SIGNOR-273942	0.357
RPE	protein	Q96AT9	UNIPROT	D-ribulose 5-phosphate	smallmolecule	CHEBI:17363	ChEBI	down-regulates quantity	chemical modification			9606									34775382	t		miannu	The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux.	SIGNOR-267065	0.8
FBXW11	protein	Q9UKB1	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								10321728	t		miannu	We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo. 	SIGNOR-272544	0.418
paclitaxel	chemical	CHEBI:45863	ChEBI	TUBA4A	protein	P68366	UNIPROT	down-regulates activity	chemical inhibition			9606									28298489	t		miannu	Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap.	SIGNOR-259346	0.8
serotonin(1+)	smallmolecule	CHEBI:350546	ChEBI	HTR1F	protein	P30939	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257520	0.8
NOG	protein	Q13253	UNIPROT	GDF5	protein	P43026	UNIPROT	down-regulates activity	binding			9606									21976273	t		miannu	Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. Antagonists such as noggin counteract BMP signaling by covering the ligand's BMP type I (BMPRI) and type II (BMPRII, ActRII, ActRIIB) interaction sites. The mutation GDF5-S94N is located within the BMPRII interaction site, the so-called knuckle epitope, and was identified in patients suffering from multiple synostoses syndrome (SYNS).	SIGNOR-252420	0.688
CSNK1D	protein	P48730	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606									10606744	t		gcesareni	Protein kinase ck1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15.	SIGNOR-73266	0.559
histamine	smallmolecule	CHEBI:18295	ChEBI	HRH1	protein	P35367	UNIPROT	up-regulates activity	chemical activation			10029									7925364	t		miannu	The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum.	SIGNOR-258483	0.8
PDHX	protein	O00330	UNIPROT	PAX6	protein	P26367	UNIPROT	down-regulates activity	binding			9606	BTO:0000120								12783165	t		miannu	In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3.	SIGNOR-254903	0.2
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	COIL	protein	P38432	UNIPROT	up-regulates	phosphorylation	Ser184	NEEAKRKsPKKKEKC	9606	BTO:0000567;BTO:0000938								11102515	t		lperfetto	In particular, we have recently found that the cdk2/cyclin e complex can phosphorylate coilin in vitro . there is but a single consensus cdk2/cyclin e phosphorylation site in coilin, located at serine 184. when serine 184 was mutated to an alanine (s184a), mimicking a dephosphorylated state, a nucleolar mislocalization similar to that of gfp-coilin(1__†€ †_248) was observed	SIGNOR-216733	0.389
PRKCA	protein	P17252	UNIPROT	RALB	protein	P11234	UNIPROT	unknown	phosphorylation	Ser198	KSSKNKKsFKERCCL	9606									20940393	t		llicata	Here we test this hypothesis and show that ralb is phosphorylated at s198 by protein kinase c (pkc). this indicates phosphorylation of ralb is important for the development of lung metastasis in human bladder cancer cells.	SIGNOR-168532	0.295
TNF	protein	P01375	UNIPROT	TNFRSF1A	protein	P19438	UNIPROT	up-regulates activity	binding			9606									14732063	t		miannu	Tumour necrosis factor (TNF) exerts two main effects: a beneficial one as an anti-infection, anti-tumour cytokine, and a detrimental one in the systemic inflammatory response syndrome (SIRS). Two receptors (TNF-R) mediate these effects. two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b)	SIGNOR-253593	0.923
XL-647	chemical	CID:10458325	PUBCHEM	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207860	0.8
HAND2	protein	P61296	UNIPROT	HAND2	protein	P61296	UNIPROT	up-regulates activity	binding			-1									11812799	t		miannu	The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer	SIGNOR-223476	0.2
baicalein	chemical	CHEBI:2979	ChEBI	UGT1A1	protein	P22309	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								21030469	t		Luana	Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation.	SIGNOR-258158	0.8
ROS	stimulus	SIGNOR-ST2	SIGNOR	ATM	protein	Q13315	UNIPROT	up-regulates				9606	BTO:0000007								26344566	f			We report that the PEX5 peroxisome import receptor binds ataxia-telangiectasia mutated (ATM) and localizes this kinase to the peroxisome. In response to ROS, ATM signalling activates ULK1 and inhibits mTORC1 to induce autophagy.	SIGNOR-262791	0.7
NODAL	protein	Q96S42	UNIPROT	MMP2	protein	P08253	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003879								20383200	f	Regulation	miannu	Ectopic expression of Nodal or activation of Nodal signaling by addition of rNodal increased MMP-2 protein level and cell invasion. the expression level of Nodal correlates well with MMP-2 expression and cell invasion.	SIGNOR-251940	0.2
MAPK9	protein	P45984	UNIPROT	BAZ1B	protein	Q9UIG0	UNIPROT	up-regulates	phosphorylation	Ser158	KSDGACDsPSSDKEN	9606									19776015	t		gcesareni	Wstf, a specific component of two chromatin remodeling complexes (swi/snf-type winac and iswi-type wich), was phosphorylated by the stimulation of mapk cascades in vitro and in vivo. Ser-158 residue in the wac (wstf/acf1/cbpq46) domain, located close to the n terminus of wstf, was identified as a major phosphorylation target	SIGNOR-188168	0.2
SGK3	protein	Q96BR1	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606									11154281	t		lperfetto	Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 	SIGNOR-249135	0.447
dactolisib	chemical	CHEBI:71952	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000848								21803746	t	ATP-competitive inhibitor of PI3K and mTOR	gcesareni	The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific	SIGNOR-175706	0.8
ACTB	protein	P60709	UNIPROT	SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270599	0.486
RPS6KA5	protein	O75582	UNIPROT	HMGN1	protein	P05114	UNIPROT	down-regulates activity	phosphorylation	Ser7	sSAEGAAK										12213813	t		lperfetto	HMGN1 (formerly known as HMG-14) phosphorylation at Ser6 occurs concomitantly with IE gene expression. | MSK2 seems to be the most important kinase responsible for this modification |Accordingly, it was suggested that HMGN1 phosphorylation reduces binding of the protein to the nucleosomes	SIGNOR-262988	0.604
IL18	protein	Q14116	UNIPROT	IFNG	protein	P01579	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10653850	f		miannu	IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement.	SIGNOR-260858	0.48
ATM	protein	Q13315	UNIPROT	SMC1A	protein	Q14683	UNIPROT	up-regulates	phosphorylation	Ser966	GEDSVSGsQRISSIY	9606									11877377	t		lperfetto	Here we report that smc1 is a component of the dna damage response network that functions as an effector in the atm/nbs1-dependent s-phase checkpoint pathway. Smc1 associates with brca1 and is phosphorylated in response to ir in an atm- and nbs1-dependent manner. Using mass spectrometry, we established that atm phosphorylates s957 and s966 of smc1 in vivo.	SIGNOR-115496	0.693
SPRY2	protein	O43597	UNIPROT	CBLC	protein	Q9ULV8	UNIPROT	down-regulates				9606									12234920	f		gcesareni	Hspry2 prevents c-cbl-mediated ubiquitylation of egfrs. hspry2 interacts specifically with the c-cbl ring finger domain and displaces ubch7 from its binding site on the e3 ligase.	SIGNOR-92926	0.46
MTOR	protein	P42345	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Ser434	SFEPKIRsPRRFIGS	9823		BTO:0004712							23486913	t		lperfetto	Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway	SIGNOR-201534	0.96
TSC2	protein	P49815	UNIPROT	MTOR	protein	P42345	UNIPROT	down-regulates activity				9606	BTO:0000007;BTO:0001938								12271141	f		lperfetto	These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor	SIGNOR-93133	0.844
PRKAA1	protein	Q13131	UNIPROT	SNAI1	protein	O95863	UNIPROT	up-regulates	phosphorylation	Ser92	VAELTSLsDEDSGKG	9606									19923321	t		lperfetto	Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively.	SIGNOR-161783	0.2
IKBKG	protein	Q9Y6K9	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	form complex	binding			9606			SIGNOR-C14						12192055	t		lperfetto	The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation	SIGNOR-217436	0.928
NCOA1	protein	Q15788	UNIPROT	PGR	protein	P06401	UNIPROT	up-regulates				9606									10449719	f		miannu	Progesterone receptor (pr) functions as a transcription factor that modulates the transcription of target genes in response to progesterone and other signals. The transcriptional activity of pr requires the involvement of coactivators such as steroid receptor coactivator-1 (src-1).	SIGNOR-70149	0.674
PRKCG	protein	P05129	UNIPROT	PA2G4	protein	Q9UQ80	UNIPROT	unknown	phosphorylation	Ser363	ALLQSSAsRKTQKKK	9606									11325528	t		lperfetto	We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC.	SIGNOR-249091	0.286
NANOGP8	protein	Q6NSW7	UNIPROT	KDM3A	protein	Q9Y4C1	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10900	BTO:0000667								23918801	f		Luana	Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun.	SIGNOR-266092	0.2
CDK5	protein	Q00535	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser33	LPENNVLsPLPSQAM	9606									17591690	t		llicata	We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active	SIGNOR-156422	0.722
MTOR	protein	P42345	UNIPROT	mTORC2	complex	SIGNOR-C2	SIGNOR	form complex	binding			9606									25628925	t		lperfetto	Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)	SIGNOR-262534	0.727
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	IKBKB	protein	O14920	UNIPROT	down-regulates	cleavage	Asp373	PATQCISdGKLNEGH	9606									11741536	t		gcesareni	Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis.	SIGNOR-256436	0.373
TRIP11	protein	Q15643	UNIPROT	THRB	protein	P10828	UNIPROT	up-regulates	binding			9606									9256431	t		miannu	Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity.	SIGNOR-50421	0.321
VPS33B	protein	Q9H267	UNIPROT	CHEVI complex	complex	SIGNOR-C269	SIGNOR	form complex	binding			9606	BTO:0000007								29778605	t		lperfetto	It has been recently suggested that VPS33B and VIPAR comprise two subunits of a novel multi-subunit tethering complex (named "CHEVI")	SIGNOR-261830	0.782
arformoterol	chemical	CHEBI:408174	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			-1									20655218	t		Luana	Table 1. Human β2- and β1-adrenoceptor binding and calculated log D7.4 values for formoterol, indacaterol, salmeterol, S1319 and the representative library members 11–41	SIGNOR-257882	0.8
HIF1A	protein	Q16665	UNIPROT	IL1B	protein	P01584	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									25750431	t		svumbaca	The results of this study show that the absence of HIFs in MPs has no impact on the resolution of inflammation in two sterile models of skeletal muscle regeneration	SIGNOR-256236	0.344
CDK4	protein	P11802	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									19114991	t		lpetrilli	In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity	SIGNOR-182979	0.748
PPARG	protein	P37231	UNIPROT	CPT1B	protein	Q92523	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								15356291	f		miannu	 Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1beta promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1beta gene promoter by MEF2C and PPARalpha-RXRalpha, a precise arrangement of its binding sites was essential.	SIGNOR-254581	0.396
FGR	protein	P09769	UNIPROT	KCND3	protein	Q9UK17	UNIPROT	up-regulates activity	phosphorylation	Tyr108	GKLHYPRyECISAYD	9606	BTO:0000007								22198508	t		miannu	 These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels.	SIGNOR-276394	0.2
DLK1	protein	P80370	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				10090									8500166	f			This indicates that pref-1 functions as a negative regulator of adipocyte differentiation, possibly in a manner analogous to EGF-like proteins that govern cell fate decisions in invertebrates.	SIGNOR-254980	0.7
FLT3	protein	P36888	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15626738	f			FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells	SIGNOR-261550	0.254
XRCC3	protein	O43542	UNIPROT	D1-D2-G-X3 complex	complex	SIGNOR-C301	SIGNOR	form complex	binding			9606									18212739	t		lperfetto	These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). 	SIGNOR-263257	0.707
EMSY	protein	Q7Z589	UNIPROT	ZMYND11	protein	Q15326	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								14651845	t		miannu	The binding sites for HP1β and BS69 with EMSY abut each other, and are found directly adjacent to the ENT domain of EMSY. This demonstrates that EMSY has the capacity to contact directly at least two proteins which contain a Royal Family domain. Since this domain is found in proteins with a chromatin connection, we assume that EMSY functions, at least partly, in the regulation of chromatin.	SIGNOR-263916	0.2
USP37	protein	Q86T82	UNIPROT	FZR1	protein	Q9UM11	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								21596315	t		lperfetto	Here we show that USP37 binds the APC/C coactivator CDH1|Deubiquitinase USP37 is activated by CDK2 to antagonize APC(CDH1) and promote S phase entry	SIGNOR-265054	0.342
PHB	protein	P35232	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates quantity by repression	transcriptional regulation												16964284	f		lperfetto	We now present evidence that PHB, which has 54% homology at the protein level to the oestrogen receptor corepressor REA (repressor of oestrogen receptor activity), can repress androgen receptor (AR)-mediated transcription and androgen-dependent cell growth.	SIGNOR-268977	0.462
KX2-391	chemical	CID:23635314	PUBCHEM	SRC	protein	P12931	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193624	0.8
NARS2	protein	Q96I59	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270463	0.8
NDUFB6	protein	O95139	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4	SIGNOR-262169	0.821
FKBP8	protein	Q14318	UNIPROT	MTOR	protein	P42345	UNIPROT	down-regulates	binding			9606									17991864	t		gcesareni	Fkbp38 binds to mtor and inhibits its activity in a manner similar to that of the fkbp12-rapamycin complex.	SIGNOR-159013	0.582
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	TFAP2C	protein	Q92754	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269256	0.383
PLK3	protein	Q9H4B4	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									20068231	t		gcesareni	Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.	SIGNOR-163270	0.2
SMAD1/4	complex	SIGNOR-C85	SIGNOR	BMP7	protein	P18075	UNIPROT	up-regulates quantity by expression	transcriptional regulation			7227									19896409	f		lperfetto	BMPs first bind to and activate their transmembrane serine/threonine kinase receptors, which in turn phosphorylate the transcription factors Smad1/5/8 at its two C-terminal serines (SVS). Phosphorylated Smad1Cter binds to Smad4 (co-Smad) and translocates and accumulates in the nucleus, activating BMP-responsive genes (Fig. 2) [21] and [22], such as BMP4/7 and others.	SIGNOR-248843	0.562
KIF17	protein	Q9P2E2	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272530	0.7
EEF1A1P5	protein	Q5VTE0	UNIPROT	Ser-tRNA(Ser)	smallmolecule	CHEBI:29162	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269555	0.8
MAPK1	protein	P28482	UNIPROT	LIPE	protein	Q05469	UNIPROT	up-regulates activity	phosphorylation	Thr891	NSETSSDtPEMSLSA	10090	BTO:0000944								11581251	t		lperfetto	Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL.	SIGNOR-249413	0.375
HCRTR1	protein	O43613	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257294	0.409
DENND3	protein	A2RUS2	UNIPROT	RAB12	protein	Q6IQ22	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								25925668	t		lperfetto	ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12.|active Rab12 facilitates autophagosome trafficking, thus establishing a crucial role for the ULK/DENND3/Rab12 axis in starvation-induced autophagy.	SIGNOR-264734	0.609
CDH7	protein	Q9ULB5	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265869	0.548
AR	protein	P10275	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									15861399	f		miannu	AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation	SIGNOR-251540	0.7
ARHGEF10	protein	O15013	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260536	0.417
BID	protein	P55957	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates	binding			9606									17289999	t		gcesareni	We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma	SIGNOR-152929	0.818
KLF4	protein	O43474	UNIPROT	THBD	protein	P07204	UNIPROT	up-regulates activity	transcriptional regulation			9606									19661484	f		miannu	 Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4. 	SIGNOR-254546	0.307
EIF2B2	protein	P49770	UNIPROT	EIF2S3	protein	P41091	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269135	0.683
TNFSF11	protein	O14788	UNIPROT	TNFRSF11B	protein	O00300	UNIPROT	up-regulates	binding			9606									11733492	t		gcesareni	Receptor activator of nf-kappa b ligand (rankl, also known as odf and opgl), a member of the tumor necrosis factor (tnf) family, triggers osteoclastogenesis by forming a complex with its receptor, rank.	SIGNOR-112539	0.941
PBK	protein	Q96KB5	UNIPROT	H3C1	protein	P68431	UNIPROT	unknown	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									16982762	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Pbk/topk could phosphorylate histone h3 at ser10 in vitro and in vivo, and mediated its growth-promoting effect through histone h3 modification.	SIGNOR-149716	0.2
RALGAPB	protein	Q86X10	UNIPROT	RalGAP2	complex	SIGNOR-C469	SIGNOR	form complex	binding			10090	BTO:0000011								21148297	t		miannu	 Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. 	SIGNOR-269794	0.588
BRSK1	protein	Q8TDC3	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates	phosphorylation	Ser216	SGLYRSPsMPENLNR	9606									9543386	t		lperfetto	Overexpression of hssad1 resulted in an increased phosphorylation of cdc25c on ser-216 in vivo.Phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3	SIGNOR-56473	0.495
PTPN12	protein	Q05209	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates	dephosphorylation			9606									11731619	t		gcesareni	In intact hc11 cells, ptp-pest was constitutively associated with jak2, and in response to egf treatment there was an increased level of ptp-pest in jak2 complexes. An in vitro phosphatase assay, using prl-activated jak2 as the substrate and lysates from hc11 cells as the source of ptp-pest, revealed that jak2 could serve as a ptp-pest substrate.	SIGNOR-112383	0.384
8-OH-DPAT	chemical	CHEBI:73364	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029									9550290	t		miannu	Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists.	SIGNOR-258890	0.8
RAR	proteinfamily	SIGNOR-PF45	SIGNOR	RXR	proteinfamily	SIGNOR-PF44	SIGNOR	up-regulates activity	binding			9606									1310351	t		miannu	Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-256198	0.712
HES5	protein	Q5TA89	UNIPROT	ASCL1	protein	P50553	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938								30030829	f		lperfetto	The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 	SIGNOR-265147	0.544
JWOGUUIOCYMBPV-GMFLJSBRSA-N	chemical	CID:6918328	PUBCHEM	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257915	0.8
HACD	proteinfamily	SIGNOR-PF86	SIGNOR	FASN	protein	P49327	UNIPROT	up-regulates activity	chemical activation			9606									18554506	t			Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases,	SIGNOR-267764	0.2
CYBB	protein	P04839	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	up-regulates quantity	chemical modification			9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264723	0.8
PDP1	protein	Q9P0J1	UNIPROT	PDHA1	protein	P08559	UNIPROT	up-regulates activity	dephosphorylation	Ser300	SMSDPGVsYRTREEI	-1									7782287	t			Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism	SIGNOR-252056	0.722
BLK	protein	P51451	UNIPROT	FCGR2C	protein	P31995	UNIPROT	up-regulates activity	phosphorylation	Tyr310	TDDDKNIyLTLPPND	-1									8756631	t		miannu	Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation	SIGNOR-262673	0.2
MAPK10	protein	P53779	UNIPROT	MAPK8IP3	protein	Q9UPT6	UNIPROT	up-regulates	phosphorylation	Thr286	SVPSAAVtPLNESLQ	9606									15767678	t		gcesareni	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134537	0.738
BAG1	protein	Q99933	UNIPROT	HSPA8	protein	P11142	UNIPROT	down-regulates quantity by destabilization	binding			9534	BTO:0001538								11676916	t		miannu	BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association	SIGNOR-272589	0.891
SRC	protein	P12931	UNIPROT	ARHGEF2	protein	Q92974	UNIPROT	up-regulates activity	phosphorylation	Tyr198	IDEAEVIySELMSDF	9606	BTO:0002181								31420453	t		miannu	Src activates GEF-H1.	SIGNOR-277478	0.411
sirolimus	chemical	CHEBI:9168	ChEBI	IRS1	protein	P35568	UNIPROT	up-regulates				9606									16452206	f		gcesareni	The mtor inhibitory drug rapamycin up-regulates irs-1 protein levels and induces akt phosphorylation, protein kinase activity, and downstream signaling.	SIGNOR-144159	0.8
C3 convertase complex	complex	SIGNOR-C310	SIGNOR	C3	protein	P01024	UNIPROT	up-regulates activity	cleavage	Arg748	ASHLGLArSNLDEDI										31331124	t		lperfetto	This forms the C4b2a complex, which is a classical pathway C3 convertase. C4b2a cleaves C3, which is the central component of the complement cascade, to C3a, and anaphylatoxin, and C3b results in the activation of the lytic pathway	SIGNOR-263450	0.54
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PTPN7	protein	P35236	UNIPROT	up-regulates activity	phosphorylation			-1									16226275	t	inferred from 70% family members	lperfetto	First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|	SIGNOR-270111	0.2
TYRO3	protein	Q06418	UNIPROT	MLKL	protein	Q8NB16	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr376	DRVKSTAyLSPQELE	9606	BTO:0000007								31230815	t	done	miannu	TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6).	SIGNOR-274120	0.2
CHFR	protein	Q96EP1	UNIPROT	PARP1	protein	P09874	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0001109								23268447	t		miannu	 Here, we show that checkpoint with Forkhead-associated (FHA) and RING finger domain protein (CHFR), an E3 ubiquitin ligase, is recruited to DSBs by poly(ADP-ribose) (PAR). Moreover, CHFR ubiquitinates PAR polymerase 1 (PARP1) and regulates chromatin-associated PARP1 in vivo.  Moreover, the poly-ubiquitin chain on PARP1 could be recognized by both anti-K48 and K63-linked poly-ubiquitin chain antibodies, suggesting that CHFR mediates a mixed poly-ubiquitin chain linkage on PARP1. With MG132 treatment, ubiquitinated PARP1 was significantly accumulated (Figure 4D), suggesting that the ubiquitination of PARP1 is likely involved in protein degradation. Consistently, we found that following DNA damage, PARP1 quickly dissociated from the chromatin in the wild-type cells (Figure 4F). However, in the Chfr−/− cells, the dissociation of PARP1 from the chromatin was significantly delayed.	SIGNOR-271470	0.438
dimethyloxalylglycine	chemical	CHEBI:102218	ChEBI	EGLN3	protein	Q9H6Z9	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000018								28900510	t		lperfetto	We treated the A549 cells with the following EGLN/PHD inhibitors: dimethyloxalyglycine (DMOG), CoCl2, inhibitors of dioxygenases, and BAY 85-3494 (BAY), a specific inhibitor of EGLNs with highest potency against EGLN1.	SIGNOR-261993	0.8
SCRIB	protein	Q14160	UNIPROT	Scribble_complex_DLG5-LLGL1_variant	complex	SIGNOR-C508	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270900	0.445
CSNK2B	protein	P67870	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates activity	phosphorylation	Ser1126	TEEFSSEsDMEESKE	9606	BTO:0000938								19064667	t		lperfetto	 We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275760	0.2
MBD1	protein	Q9UIS9	UNIPROT	MGMT	protein	P16455	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								15657354	f	 	 	Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT.	SIGNOR-254036	0.254
JAK1/STAT1/STAT3	complex	SIGNOR-C120	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									30029643	f		areggio	In summary, our results indicate IL-15 can stimulate the proliferation of FAPs through Jak-STAT pathway. 	SIGNOR-256230	0.7
GRK2	protein	P25098	UNIPROT	FPR1	protein	P21462	UNIPROT	down-regulates activity	phosphorylation	Ser328	ERALTEDsTQTSDTA	-1									7836371	t		gcesareni	Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation.	SIGNOR-247763	0.2
P-TEFb	complex	SIGNOR-C238	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0001545								19516275	f		miannu	Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) inhibits the positive transcription elongation factor b (P-TEFb), which is a key RNA polymerase II (Pol II) transcriptional regulator. In transfected cells, mutated NPM1 associated with, and sequestered, HEXIM1 in cytoplasm, resulting in higher transcription of RNA pol II target genes, among which were some positive regulators of cell-cycle progression such as cyclin D1 and anti-apoptotic proteins such as Mcl-1	SIGNOR-260137	0.7
RNF41	protein	Q9H4P4	UNIPROT	PRKN	protein	O60260	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									18541373	t		miannu	Here we further demonstrated that overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner. More importantly, Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells, indicating Parkin is an Nrdp1 substrate.	SIGNOR-272639	0.2
PAK1	protein	Q13153	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	unknown	phosphorylation			9606									12151336	t		gcesareni	Histone h3 is a substrate of pak1 both in vitro and in vivo, and it specifically interacted with pak1 but not pak2 or pak3. Site-directed mutagenesis indicated that pak1 phosphorylates histone h3 on ser10.	SIGNOR-265363	0.2
DNM1L	protein	O00429	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	up-regulates activity	binding			10090	BTO:0002295								31063459	t		lperfetto	Importantly, we found that crosstalk between phosphorylated Drp1S600 (p-Drp1S600) and the actin-binding protein com- plex Arp2/3 is a required step in mitochondrial Drp1 recruitment and mitochondrial fission under HG conditions. 	SIGNOR-262550	0.287
CDK1	protein	P06493	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Ser276	VHPATPIsPGRASGM	9606									16046550	t	The effect has been demonstrated using Q01196-8.	gcesareni	Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction.	SIGNOR-138916	0.347
DAMPS	stimulus	SIGNOR-ST18	SIGNOR	NAIP	protein	Q13075	UNIPROT	up-regulates activity													16037825	f		lperfetto	Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage	SIGNOR-256420	0.7
RPS6KA1	protein	Q15418	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									10464286	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-70428	0.2
SRC	protein	P12931	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Tyr89	GSLPEFYyRPPRPPK	9606	BTO:0000150								17254967	t		lperfetto	Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27	SIGNOR-152839	0.511
MYOD1	protein	P15172	UNIPROT	MYOG	protein	P15173	UNIPROT	up-regulates quantity by expression	transcriptional regulation					BTO:0001103							12694204	t		Simone Vumbaca	We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation.	SIGNOR-255640	0.436
PRKCD	protein	Q05655	UNIPROT	GSK3A	protein	P49840	UNIPROT	down-regulates	phosphorylation	Ser21	SGRARTSsFAEPGGG	9606									11884598	t		gcesareni	Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway.	SIGNOR-115722	0.348
SPRY2	protein	O43597	UNIPROT	PTPN1	protein	P18031	UNIPROT	up-regulates				9606									12414790	f		gcesareni	Therefore, we conclude that an increase in soluble ptp1b activity contributes to the anti-migratory, but not anti-mitogenic, actions of hspry2.	SIGNOR-95313	0.426
PDPK1	protein	O15530	UNIPROT	PRKCB	protein	P05771	UNIPROT	up-regulates	phosphorylation			9606									15209375	t		gcesareni	One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.	SIGNOR-126069	0.5
ABL1	protein	P00519	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates activity	phosphorylation	Tyr463	NDTGSRYyKEIPLSE	9606									12637538	t		Manara	We show that Abl directly phosphorylates PKD at Tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of PKD	SIGNOR-260791	0.345
SRC	protein	P12931	UNIPROT	KCNJ1	protein	P48048	UNIPROT	down-regulates	phosphorylation	Tyr337	SKTKEGKyRVDFHNF	9606									12556363	t		flangone	Inhibition of c-src with herbimycin a significantly decreased the tyrosine phosphorylation level of romk1... tyrosine dephosphorylation enhances the exocytosis of romk1	SIGNOR-97803	0.318
PRKG1	protein	Q13976	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates	phosphorylation	Ser813	DIYSRRLsQETGLEI	9606									10581361	t		lperfetto	Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function	SIGNOR-72728	0.521
CDK9	protein	P50750	UNIPROT	RCHY1	protein	Q96PM5	UNIPROT	down-regulates	phosphorylation	Ser211	VAQTPMPsEYQNMTV	9606									23603988	t		lperfetto	We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr.	SIGNOR-201923	0.473
CDKN1A	protein	P38936	UNIPROT	PCNA	protein	P12004	UNIPROT	down-regulates	binding			9606									22911014	t		gcesareni	P21 exerts its effect on the cell cycle not only by inhibiting cyclin/cdk complexes, but also by inhibiting proliferating cell nuclear antigen (pcna)	SIGNOR-191939	0.754
6-O-phosphono-D-glucono-1,5-lactone	smallmolecule	CHEBI:16938	ChEBI	6-phospho-D-gluconate	smallmolecule	CHEBI:16863	ChEBI	up-regulates quantity	precursor of			9606									31586547	t		miannu	The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG).	SIGNOR-267056	0.8
UQCR11	protein	O14957	UNIPROT	Mitochondrial respiratory chain complex III	complex	SIGNOR-C279	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits	SIGNOR-262196	0.837
AML1-ETO	fusion protein	SIGNOR-FP1	SIGNOR	CDKN2A	protein	Q8N726	UNIPROT	down-regulates	transcriptional regulation			9606									12091906	t		apalma	We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO.	SIGNOR-255677	0.2
HMBOX1	protein	Q6NT76	UNIPROT	IFNG	protein	P01579	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002030								21839858	t		Luana	Additionally, by luciferase reporter assay, HMBOX1 displayed suppressive effect on the transcription activity of IFN-γ promoter. 	SIGNOR-261625	0.2
MAPK1	protein	P28482	UNIPROT	AHNAK	protein	Q09666	UNIPROT	unknown	phosphorylation	Thr5794	REFSGPStPTGTLEF	10090	BTO:0000944								22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262767	0.259
tacrolimus (anhydrous)	chemical	CHEBI:61049	ChEBI	Calcineurin	complex	SIGNOR-C155	SIGNOR	down-regulates	chemical inhibition			9606									15276472	t		gcesareni	Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins.	SIGNOR-252308	0.8
YWHAQ	protein	P27348	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	binding			9606									12042314	t		miannu	14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue.	SIGNOR-88300	0.503
IRX1	protein	P78414	UNIPROT	PTGER1	protein	P34995	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002392								20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 	SIGNOR-261656	0.2
YY1	protein	P25490	UNIPROT	ATP2C1	protein	P98194	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15955096	f		miannu	 when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter. 	SIGNOR-255193	0.2
CDK1	protein	P06493	UNIPROT	TOP2A	protein	P11388	UNIPROT	unknown	phosphorylation	Ser1247	KNENTEGsPQEDGVE	9606	BTO:0000567								7635160	t		llicata	We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. similarly, phosphopeptide 4 was absent from a mutant protein lacking ser1246	SIGNOR-30244	0.54
GPR37	protein	O15354	UNIPROT	ER stress	stimulus	SIGNOR-ST9	SIGNOR	up-regulates				9606									12666095	f		lperfetto	Parkin-associated endothelin receptor-like receptor (Pael-R). Overexpression of this protein causes it to become ubiquinated, insoluble, and unfolded, leading to endoplasmic reticulum stress and cell death. Furthermore, an insoluble form of Pael-R has been demonstrated to accumulate in the brains of patients with Parkin mutations, suggesting a possible toxic mechanism.	SIGNOR-249701	0.7
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270432	0.8
PRKACA	protein	P17612	UNIPROT	TPH2	protein	Q8IWU9	UNIPROT	up-regulates	phosphorylation	Ser19	YWARRGFsLDSAVPE	9606									18339632	t		llicata	We also demonstrate that phosphorylation of serine 19, a protein kinase a consensus site located in this n-terminal domain, results in increased tph2 stability and consequent increases in enzyme output in cell culture systems	SIGNOR-178018	0.256
KAT2B	protein	Q92831	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269592	0.662
GNRHR	protein	P30968	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256792	0.424
(S)-malate(2-)	smallmolecule	CHEBI:15589	ChEBI	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	up-regulates quantity	precursor of			9606									24068518	t		miannu	Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle	SIGNOR-266281	0.8
PER2	protein	O15055	UNIPROT	BMAL1/NPAS2	complex	SIGNOR-C431	SIGNOR	down-regulates activity	binding			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop.	SIGNOR-267973	0.739
(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	ADRA1A	protein	P35348	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257450	0.8
PRKACA	protein	P17612	UNIPROT	PDE10A	protein	Q9Y233	UNIPROT	unknown	phosphorylation	Thr15	SQHLTGLtDEKVKAY	9606	BTO:0000007								20610737	t		llicata	When coexpressed with the catalytic subunit of pka in transfected hek293 cells, wild-type (wt) pde10a2 (pde10a2wt) was phosphorylated at thr-16 these data confirm the previously reported findings that pka phosphorylation of pde10a2 on thr-16 results in a cytosolic localization	SIGNOR-166559	0.375
ERAP2	protein	Q6P179	UNIPROT	oligopeptide	smallmolecule	CHEBI:25676	ChEBI	down-regulates quantity	chemical modification			9606									15908954	t			The generation of many HLA class I peptides entails a final trimming step in the endoplasmic reticulum that, in humans, is accomplished by two 'candidate' aminopeptidases | We show here that one of these, ERAP1, was unable to remove several N-terminal amino acids that were trimmed efficiently by the second enzyme, ERAP2.	SIGNOR-272495	0.8
KLF15	protein	Q9UIH9	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000011								15664998	f		lperfetto	Moreover, KLF15 and C/EBPalpha acted synergistically to increase the activity of the PPARgamma2 gene promoter in 3T3-L1 adipocytes.	SIGNOR-235331	0.448
POLE4	protein	Q9NR33	UNIPROT	DNA polymerase epsilon	complex	SIGNOR-C377	SIGNOR	form complex	binding			9606	BTO:0000567								10801849	t		lperfetto	Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon.	SIGNOR-265521	0.913
WNT7A	protein	O00755	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131903	0.635
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	PPP1R1A	protein	Q13522	UNIPROT	unknown	dephosphorylation			10116									11278334	t	inferred from 70% family members		In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation.	SIGNOR-269991	0.2
CSF2RA/CSF2RB	complex	SIGNOR-C212	SIGNOR	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9606									19436055	t		miannu	As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of βc, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways	SIGNOR-255585	0.446
DSCAM	protein	O60469	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	down-regulates				9606	BTO:0000938								30745320	f		miannu	The DSCAM/L1 transcriptome data sets also contained a significant number of genes known to regulate synapse formation or function.Increased nuclear DSCAM levels inhibit synapse formation	SIGNOR-264321	0.7
PRKCD	protein	Q05655	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates activity	phosphorylation	Ser379	DLILNRCsESTKRKL	-1									24632950	t		miannu	Of note, PKCδ, when it was activated by PDPK1, directly bound to the SH3-N domain of p47(phox) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47(phox) C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation.PKCδ phosphorylates p47phox for K-Ras-induced ROS generation. PKCδ binds to the SH3-N domain and phosphorylates Ser348 and Ser379 residues in p47phox for K-RasV12-induced ROS generation and consequent malignant transformation.	SIGNOR-276622	0.459
MLST8	protein	Q9BVC4	UNIPROT	mTORC2	complex	SIGNOR-C2	SIGNOR	form complex	binding			9606									25628925	t		lperfetto	Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)	SIGNOR-205612	0.828
GRIP1	protein	Q9Y3R0	UNIPROT	GRIPAP1	protein	Q4V328	UNIPROT	up-regulates activity	binding			10116	BTO:0000142								10896157	t		Giorgia	We have identified several GRIP-associated proteins (GRASPs) that bind to distinct PDZ domains within GRIP. GRASP-1 is a neuronal rasGEF associated with GRIP and AMPA receptors in vivo. GRIP1 has seven PDZ domains, which mediate protein–protein interactions, allowing the recruitment of GRASP-1 to a large signal-transducing complex	SIGNOR-260638	0.524
PRKACA	protein	P17612	UNIPROT	PARP1	protein	P09874	UNIPROT	up-regulates activity	phosphorylation	Ser465	FLQDVSAsTKSLQEL	9606	BTO:0001412								25069723	t		miannu	 In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain). 	SIGNOR-276651	0.2
ABL1	protein	P00519	UNIPROT	SPTLC1	protein	O15269	UNIPROT	down-regulates	phosphorylation	Tyr164	KTEEAIIySYGFATI	9606									23629659	t		llicata	We demonstrated that the er-resident human protein serine palmitoyltransferase long chain-1 (sptlc1), which is the first enzyme of sphingolipid biosynthesis, is phosphorylated at tyr(164) by the tyrosine kinase abl. this occurred through the specific abl-mediated phosphorylation of sptlc1 on tyr164, leading to the attenuation of its activity.	SIGNOR-202003	0.2
LCK	protein	P06239	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	phosphorylation	Tyr427	ELFDDPSyVNVQNLD	9606	BTO:0000782								9710204	t			We show that during TCR signaling, the tyrosines Y239, Y240 and Y317 of Shc are the primary sites of tyrosine phosphorylation. CD4/Lck-dependent tyrosine phosphorylation on Shc was markedly diminished when Y317 was mutated, suggesting a preference of Lck for the Y317 site. tyrosine phosphorylation of Shc may play a key role in T lymphocyte proliferation via interaction of phosphorylated Shc with downstream molecules involved in activation of Ras and Myc proteins	SIGNOR-251388	0.734
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1668	SPSYSPTsPSYSPTS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248808	0.849
FUS	protein	P35637	UNIPROT	SMN1	protein	Q16637	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								23022481	t		lperfetto	Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells	SIGNOR-262107	0.38
PRKG1	protein	Q13976	UNIPROT	FHOD1	protein	Q9Y613	UNIPROT	up-regulates	phosphorylation	Ser1131	AARERKRsRGNRKSL	9606		BTO:0000887;BTO:0001260							15051728	t		lperfetto	Pkgi also directly phosphorylates fhod1, and studies with wild-type and mutant fhod1-derived peptides identify ser-1131 in the fhod1 c terminus as the unique pkgi phosphorylation site in fhod1. phosphorylation of three conserved residues within the dad domain activates fhod1 while binding to rac regulates fhod1 subcellular localization	SIGNOR-123646	0.361
PRKAA2	protein	P54646	UNIPROT	ACACA	protein	Q13085	UNIPROT	down-regulates	phosphorylation	Ser80	LHIRSSMsGLHLVKQ	9606		BTO:0000887;BTO:0001103	SIGNOR-C15						12015362	t		gcesareni	Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed.	SIGNOR-87583	0.685
PDH	complex	SIGNOR-C402	SIGNOR	acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	up-regulates quantity	chemical modification			9606									29059435	t		miannu	The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics.	SIGNOR-266541	0.8
FOXA2	protein	Q9Y261	UNIPROT	DLK1	protein	P80370	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									12865419	t			Taken together, these data suggest that Foxa-2 is a direct transcriptional activator of the Pref-1 gene.	SIGNOR-254971	0.339
MAPK14	protein	Q16539	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser383	IHFWSTLsPIAPRSP	9606	BTO:0000150								20727996	t		gcesareni	Elk-1 is a member of the e-twenty-six (ets) domain superfamily of transcription factors and has been traditionally associated with mitogen-induced immediate early gene transcription upon phosphorylation by mitogen activated protein kinases (erk/mapk).	SIGNOR-167539	0.505
MAPK7	protein	Q13164	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates	phosphorylation	Ser387	LSLPSTQsLNIKSEP	9606									9384584	t		lperfetto	Bmk1 dramatically enhances the transactivation activity of mef2c by phosphorylating a serine residue at amino acid position 387 in this transcription factor.	SIGNOR-53545	0.757
N-(cyanomethyl)-4-[2-[4-(4-morpholinyl)anilino]-4-pyrimidinyl]benzamide	chemical	CHEBI:91407	ChEBI	JAK1	protein	P23458	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191244	0.8
ROCK2	protein	O75116	UNIPROT	IRF4	protein	Q15306	UNIPROT	up-regulates	phosphorylation	Ser447	YHRSIRHsSIQE	9606	BTO:0000782								20697158	t		miannu	Carock2 phosphorylated irf4 at either of 2 distinct phosphorylation sites, s446 and s447 / rock2-mediated phosphorylation of irf4 regulated the synthesis of il-17 and il-21 and the differentiation of th17 cells.	SIGNOR-167467	0.428
LDHA	protein	P00338	UNIPROT	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	up-regulates				9606	BTO:0000164								9192621	f			The lactate dehydrogenase-A gene (LDH-A), whose product participates in normal anaerobic glycolysis and is frequently increased in human cancers, was identified as a c-Myc-responsive gene.	SIGNOR-259370	0.7
PTPRF	protein	P10586	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									1303753	t		gcesareni	Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product.	SIGNOR-16243	0.563
ATM	protein	Q13315	UNIPROT	L3MBTL2	protein	Q969R5	UNIPROT	up-regulates activity	phosphorylation			9606									31225475	t		miannu	L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.	SIGNOR-266785	0.2
CSNK2A2	protein	P19784	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Thr366	ASSSTSVtPDVSDNE	-1									12297295	t		llicata	We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366). 	SIGNOR-251026	0.693
E2F5	protein	Q15329	UNIPROT	CBP/p300	complex	SIGNOR-C6	SIGNOR	up-regulates activity	binding			9606	BTO:0001938								10783242	t		miannu	Here we show that E2F-5 is phosphorylated by the cyclin E-Cdk2 complex, which functions in the late G1 phase, but not by the early-G1-phase-acting cyclin D-CDK complex. A phosphorylation site in the trans-activation domain of E2F-5 stimulates transcription and cell-cycle progression by the recruitment of the p300/CBP family of co-activators, whose binding to E2F-5 is stabilized upon phosphorylation by cyclin E-Cdk2. These results indicate that phosphorylation of E2F-5 at the CDK site at position 251 by cyclin E–Cdk2 augments transcription by enhancing the interaction of E2F-5 with p300/CBP co-activator proteins.	SIGNOR-262733	0.557
CTSG	protein	P08311	UNIPROT	C3	protein	P01024	UNIPROT	up-regulates activity	cleavage	Leu751	LGLARSNlDEDIIAE	9606	BTO:0001412								1861080	t		miannu	Plasma membrane elastase and cathepsin G from U937 cells cleave C3 into C3a- and C3b-like fragments; further incubation leads to C3c- and C3dg-like fragments, as judged from SDS-PAGE analysis of the digests. Sequencing of the C3b-like fragment purified by reverse phase chromatography indicates that initial cleavage of C3 by purified cathepsin G occurs at two positions in the amino-terminal part of the alpha-chain, at a Arg-Ser bond located between residues 748 and 749 and at a Leu-Asp bond between residues 751 and 752.	SIGNOR-256348	0.582
ABL1	protein	P00519	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Tyr52	DSSKPAVyNYPEGAA	9606	BTO:0000150								20101225	t		gcesareni	Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes.	SIGNOR-163566	0.459
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser483	IRRPRNYsVGSRPLK	9606		BTO:0000562							23457334	t		lperfetto	Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (pfkfb2) isoenzyme by amino acids.	SIGNOR-192260	0.2
DNMT3A	protein	Q9Y6K1	UNIPROT	DNMT1/DNMT3A	complex	SIGNOR-C42	SIGNOR	form complex	binding			9606									12145218	t		miannu	We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation	SIGNOR-90842	0.775
ADORA2A	protein	P29274	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257151	0.266
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1864	SPKYSPTsPKYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120128	0.316
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser175	SPASSGSsASFISDT	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248682	0.613
HMGB1	protein	P09429	UNIPROT	AGER	protein	Q15109	UNIPROT	up-regulates activity	binding			10090									25014009	t		gcesareni	HMGB1 is known to influence cellular responses within the nervous system via two distinct receptor families; the Receptor for Advanced Glycation End-products (RAGE) and Toll-like receptors (TLRs)	SIGNOR-252059	0.797
AGPAT5	protein	Q9NUQ2	UNIPROT	1-acyl-sn-glycerol 3-phosphate(2-)	smallmolecule	CHEBI:57970	ChEBI	down-regulates quantity	chemical modification			9606									21173190	t		lperfetto	The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA). 	SIGNOR-267012	0.8
MAPKAPK5	protein	Q8IW41	UNIPROT	DNAJB1	protein	P25685	UNIPROT	up-regulates	phosphorylation	Ser171	VTHDLRVsLEEIYSG	9606									24309468	t		lperfetto	Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1.	SIGNOR-203464	0.44
CDK11A	protein	Q9UQ88	UNIPROT	SPDEF	protein	O95238	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser242	WTDSEVDsSCSGQPI	9606	BTO:0000007								26885618	t		lperfetto	In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|	SIGNOR-273021	0.364
DVL1	protein	O14640	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	binding			9606									27571105	t		areggio	Although there are other activators of PCP, Wnt5a can activate the PCP pathway by forming a complex with Fzd and Ror2 receptors, activating DVL, which in turn activates Rho-family small GTPases, including RhoA and Rac, and their downstream effectors, Rho-associated protein kinase (ROCK), the actin-binding protein, Filamin A and c-Jun N-terminal protein kinase (JNK)	SIGNOR-258971	0.609
PRKACA	protein	P17612	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation	Ser259	SQRQRSTsTPNVHMV	9606									11971957	t		gcesareni	Serines 43, 259, and 621 are phosphorylated by PKA in vitro and induced by cAMP in vivo.cAMP increased Raf-1 serine 259 phosphorylation in a PKA-dependent manner with kinetics that correlated with ERK deactivation.	SIGNOR-86141	0.481
KATNA1	protein	O75449	UNIPROT	KATNB1	protein	Q9BVA0	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								10751153	t		miannu	In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer 	SIGNOR-267174	0.779
PTPN1	protein	P18031	UNIPROT	TRPV6	protein	Q9H1D0	UNIPROT	down-regulates activity	dephosphorylation			9606	BTO:0000007								17197020	t		llicata	In HEK293 cells, transfected with the Ca2+ channel protein TRPV6, Ca2+ influx is increased and TRPV6 is tyrosine phosphorylated following addition of the tyrosine phosphatase inhibitor|PTP1B interacts with the N-terminal domain of TRPV6 within a region of amino acids 1-191 as shown by co-immunoprecipitation, bimolecular fluorescence complementation and the yeast 2-hybrid system. Point mutation of both tyrosines 161 and 162 in the TRPV6 protein abolishes the DMHV-effect on Ca2+ influx and tyrosine phosphorylation by Src. Single mutations of Y161 or Y162 shows that each of both tyrosines alone is sufficient for the DMHV-effect. We conclude that phosphorylation/dephosphorylation of tyrosines in position 161 and 162 is essential for regulation of Ca2+ influx through TRPV6 Ca2+ channels in HEK293 cells.	SIGNOR-248433	0.615
SH2B2	protein	O14492	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	binding			10029	BTO:0000977								10854852	t		lperfetto	APS-mediated recruitment of c-Cbl to the insulin receptor led to rapid ubiquitination of the insulin receptor beta-subunit in CHO. T-APS but not in parental CHO.T cells. These results suggest that the function of APS is to facilitate coupling of the insulin receptor to c-Cbl in order to catalyse the ubiquitination of the receptor and initiation of internalisation or degradation.	SIGNOR-78337	0.631
EGFR	protein	P00533	UNIPROT	GRB2	protein	P62993	UNIPROT	unknown	phosphorylation	Tyr209	TGMFPRNyVTPVNRN	9606	BTO:0000017								11726515	t		lperfetto	Phosphorylation of grb2 by bcr/abl or egf receptor reduced its sh3-dependent binding to sos in vivo, but not its sh2-dependent binding to bcr/abl. Tyr209 within the c-terminal sh3 domain of grb2 was identified as one of the tyrosine phosphorylation sites	SIGNOR-235738	0.921
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Ser399	DNITLPPsQPSPTGG	9606	BTO:0000007								17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-252880	0.398
D-glucitol	smallmolecule	CHEBI:17924	ChEBI	TARDBP	protein	Q13148	UNIPROT	down-regulates activity	relocalization			9606	BTO:0000312								33172210	f			We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne	SIGNOR-262817	0.8
ASXL3	protein	Q9C0F0	UNIPROT	KDM1A	protein	O60341	UNIPROT	down-regulates activity	binding			9606									25450400	t		miannu	Here, we showed that ASXL3 interacts with HP1α and LSD1, leading to transcriptional repression. 	SIGNOR-266764	0.27
ANK1	protein	P16157	UNIPROT	Ankyrin complex	complex	SIGNOR-C383	SIGNOR	form complex	binding			9606	BTO:0000424								22465511	t		lperfetto	The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) 	SIGNOR-266013	0.373
PRKACA	protein	P17612	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity	phosphorylation	Ser877	CFSSRRSsEASQAEG	9606									10693759	t		lperfetto	Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3.	SIGNOR-75351	0.445
STT3A	protein	P46977	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	up-regulates quantity by stabilization	glycosylation			9606	BTO:0001939								29765039	t		Barakat	Together, these results support a notion that the two STT3 isoforms regulate EMT-mediated PD-L1 induction through PD-L1 protein N-glycosylation and stabilization.	SIGNOR-274975	0.2
GPR174	protein	Q9BXC1	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256757	0.2
CDK7	protein	P50613	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser376	LKSKKGQsTSRHKKL	9606									9315650	t		llicata	The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase.	SIGNOR-51284	0.47
KDM5A	protein	P29375	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264299	0.2
ZNRF3	protein	Q9ULT6	UNIPROT	LRP6	protein	O75581	UNIPROT	down-regulates	ubiquitination			9606									22575959	t		gcesareni	Znrf3 is associated with the wnt receptor complex, and inhibits wnt by promoting the turnover of frizzled and lrp6. Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation, and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane.	SIGNOR-197420	0.642
STK4	protein	Q13043	UNIPROT	MOB1B	protein	Q7L9L4	UNIPROT	up-regulates	phosphorylation	Thr35	LLKHAEAtLGSGNLR	9606									21808241	t	MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors.	gcesareni	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction.	SIGNOR-175841	0.846
LRRK2	protein	Q5S007	UNIPROT	RAB10	protein	P61026	UNIPROT	down-regulates activity	phosphorylation	Thr73	AGQERFHtITTSYYR	9606	BTO:0000007								26824392	t		Giulio	To investigate whether the phosphorylation of Rab10 by LRRK2 is direct, we performed an in vitro kinase assay using recombinant components. Notably, we found that both wt and LRRK2-G2019S, but neither kinase inactive D1994A mutant nor small molecule-inhibited LRRK2, efficiently phosphorylated Rab10, proving a direct kinase-substrate relationship (Figure 2C). Furthermore, incubation of Rab10 with LRRK2 followed by tryptic digestion and MS analysis unambiguously identified T73 as the major phosphorylation site (Figure 2—figure supplement 1B)|In pathogenic conditions, in which LRRK2 is hyperactive, RabGTPases have strongly diminished affinities for GDIs.	SIGNOR-261277	0.337
RPS6KA1	protein	Q15418	UNIPROT	METTL1	protein	Q9UBP6	UNIPROT	down-regulates	phosphorylation	Ser27	YYRQRAHsNPMADHT	9606	BTO:0000007;BTO:0000567								15861136	t		gcesareni	Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro.	SIGNOR-135948	0.329
STUB1	protein	Q9UNE7	UNIPROT	SMAD5	protein	Q99717	UNIPROT	down-regulates	ubiquitination			9606									22298955	t		gcesareni	In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activi-ties of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manne	SIGNOR-195690	0.349
IKK-complex	complex	SIGNOR-C14	SIGNOR	NFKBIA	protein	P25963	UNIPROT	down-regulates	phosphorylation	Ser32	LLDDRHDsGLDSMKD	9606									9346241	t		lperfetto	We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation	SIGNOR-216385	0.885
UVRAG	protein	Q9P2Y5	UNIPROT	RINT1	protein	Q6NUQ1	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								24056303	t		lperfetto	We further show that UVRAG interacts with RINT-1, and acts as an integral component of the RINT-1-containing ER tethering complex, which couples phosphoinositide metabolism to COPI-vesicle tethering. Displacement or knockdown of UVRAG profoundly disrupted COPI cargo transfer to the ER and Golgi integrity	SIGNOR-265028	0.512
long-chain fatty acyl-CoA(4-)	smallmolecule	CHEBI:83139	ChEBI	arachidonoyl-CoA	smallmolecule	CHEBI:15514	ChEBI	up-regulates quantity	precursor of			9606									15189125	t		miannu	Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity.	SIGNOR-267905	0.8
E2F1	protein	Q01094	UNIPROT	BBC3	protein	Q96PG8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003476								17263886	f		miannu	 Up-regulation of the PUMA gene and protein by E2F-1 overexpression was detected by real-time PCR and Western blot analysis in the SK-MEL-2 melanoma cell line	SIGNOR-253843	0.408
BCL3	protein	P20749	UNIPROT	HDAC3	protein	O15379	UNIPROT	up-regulates	binding			9606									15469820	t		gcesareni	We show that bcl-3 is a substrate for the protein kinase gsk3 and that gsk3-mediated bcl-3 phosphorylation, which is inhibited by akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with hdac1, 3 and 6.	SIGNOR-129804	0.354
OXTR	protein	P30559	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257178	0.427
GRK2	protein	P25098	UNIPROT	ADRA2A	protein	P08913	UNIPROT	down-regulates activity	phosphorylation	Ser314	DLEESSSsDHAERPP	10029	BTO:0000246								7876239	t			The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization.	SIGNOR-251443	0.2
MAPK1	protein	P28482	UNIPROT	SLC2A4	protein	P14672	UNIPROT	up-regulates				9606									20231899	f		gcesareni	An erk pharmacological inhibitor, pd98059, and the pld inhibitor, 1-btoh, both attenuate (14)c-glucose uptake in muscle cells. Finally, the extracellular stresses caused by glucose deprivation or aminoimidazole carboxamide ribonucleotide (aicar;ampk activator) regulate (14)c-glucose uptake and cell surface glucose transport (glut) 4 through erk stimulation by ampk-mediated pld1 activation.	SIGNOR-164286	0.341
PRKCD	protein	Q05655	UNIPROT	ENOX2	protein	Q16206	UNIPROT	up-regulates	phosphorylation	Ser504	ENLKEKEsCASRLCA	9606									22659163	t		lperfetto	Tnox is phosphorylated by protein kinase c_ (pkc_) both in vitro and in vivo. Replacement of serine-504 with alanine significantly reduces phosphorylation by pkc_. C. overexpression of the s504a tnox mutant leads to diminished cell proliferation and migration, reflecting reduced stability of the unphosphorylatable tnox mutant protein.	SIGNOR-197706	0.2
AKT1	protein	P31749	UNIPROT	FBXW7	protein	Q969H0	UNIPROT	up-regulates activity	phosphorylation	Ser227	QQRRRITsVQPPTGL	9606	BTO:0000567								21620836	t		miannu	A reciprocal immunoprecipiation with anti-phospho-Akt substrate antibody followed by immunoblotting with anti-FLAG antibodies confirmed these findings (Fig. 1C). We concluded that Fbw7 is phosphorylated at S227 in vivo. Phosphorylation of Fbw7 is required for its biological activity. 	SIGNOR-276328	0.421
PPP4C	protein	P60510	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	dephosphorylation	Thr435	PTQAGEGtLSEALLQ	9606									15073167	t			Suppression of MEK/ERK signaling pathway enhances cisplatin-induced NF-kappaB activation by protein phosphatase 4-mediated NF-kappaB p65 Thr dephosphorylation	SIGNOR-248549	0.368
EGFR	protein	P00533	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								11887937	t		gcesareni	Activation of estrogen receptor-alpha (eralpha) by growth factors in the absence of estrogen is a well-documented phenomenon.Egfr tyrosine kinase in vitro stimulated the phosphorylation of recombinant er	SIGNOR-115734	0.61
TRAF2	protein	Q12933	UNIPROT	BIRC3	protein	Q13489	UNIPROT	up-regulates	binding			9606									8548810	t		amattioni	The c-iaps associate with traf1 and traf2	SIGNOR-39596	0.888
pazopanib hydrochloride	chemical	CHEBI:71217	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-200030	0.8
LNPEP	protein	Q9UIQ6	UNIPROT	Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	down-regulates quantity by destabilization	cleavage			9606									25767437	t		miannu	It has been shown that the steady state of the mature OT form can be controlled by an oxytocinase (P-LAP) that is produced in periphery and centrally by the OT-magnocellular neurons. Noticeably, P-LAP is also expressed in parvocellular OT neurons and in other brain structures| The OT intermediate forms are produced from E16.5 (see above) but the mature amidated OT form is detected only from birth. The released mature form is then degraded by an oxytocinase (PLAP)	SIGNOR-268552	0.2
MAPK3	protein	P27361	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation			10090									8387505	t		lperfetto	The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases	SIGNOR-252762	0.718
N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide	chemical	CHEBI:91336	ChEBI	AURKA	protein	O14965	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258303	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates activity	phosphorylation	Ser189	DEEFREPsTGKTCLP	9606									19661060	t		Manara	We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.	SIGNOR-260883	0.2
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	TOP2B	protein	Q02880	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								32015321	t		miannu	Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation.ATM binds with and phosphorylates TOP2β at Ser1134 to promote its degradation by VM-26. 	SIGNOR-277511	0.2
EP300	protein	Q09472	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	acetylation			9606									25545885	t		miannu	C-terminal acetylation of p53 by p300/CBP and PCAF promotes an open conformation of p53 by preventing the occlusion of the DNA binding domain by the C-terminal tail. This enhances p53 transcriptional activity, leading to growth arrest and/or apoptosis	SIGNOR-261496	0.909
FNTB	protein	P49356	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates activity				9606									24294527	t		lperfetto	Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials.	SIGNOR-242565	0.472
palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	precursor of			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267885	0.8
HIPK2	protein	Q9H2X6	UNIPROT	HDAC3	protein	O15379	UNIPROT	down-regulates activity	phosphorylation	Ser374	KMLNHAPsVQIHDVP	10090	BTO:0002572								34244427	t		miannu	Mechanistically, HIPK2 bound and phosphorylated histone deacetylase 3 (HDAC3) at serine 374 to inhibit its enzymatic activity, thus reducing the deacetylation of p65 at lysine 218 to suppress NF-κB activation.	SIGNOR-277568	0.2
PROC	protein	P04070	UNIPROT	F7	protein	P08709	UNIPROT	down-regulates activity	cleavage			9606		BTO:0000131							29880919	t		lperfetto	Activated protein C (APC), which cleaves and inactivates both FVIIIa and FVa, thereby shutting down both the tenase and prothrombinase complexes	SIGNOR-263527	0.238
Neutrophil_activation	phenotype	SIGNOR-PH211	SIGNOR	Neutrophil_degranulation	phenotype	SIGNOR-PH212	SIGNOR	up-regulates				9606		BTO:0000133							2161532	f		lperfetto	ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation. 	SIGNOR-270582	0.7
MAPK1	protein	P28482	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates activity	phosphorylation	Ser102	LQTVIRTsPSSLVAF	-1									35831023	t		miannu	We conclude that multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk.	SIGNOR-277601	0.329
MAPK1	protein	P28482	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates activity	phosphorylation	Ser116	FINSRCTsPGGSYGH	-1									35831023	t		miannu	We conclude that multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk.	SIGNOR-277602	0.329
RELN	protein	P78509	UNIPROT	VLDLR	protein	P98155	UNIPROT	up-regulates	binding			9606									11278667	t		gcesareni	The hypothesis that the vldl receptor signals in response to reelin binding was recently supported by studies (37) showing direct binding of reelin to the vldl receptor and changes in tyrosine phosphorylation in response to reelin-vldl receptor association.	SIGNOR-106295	0.784
APC2	protein	O95996	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity by destabilization	relocalization			9606	BTO:0000038								10980707	t		lperfetto	The tumour-suppressing activity of apc largely involves facilitating the proteasome-mediated degradation of b-cateninit is possible that once exported from the nucleus, apc directs b-catenin along the cytoskeletal network to sites of degradation.	SIGNOR-81545	0.785
SOCS3	protein	O14543	UNIPROT	JAK1	protein	P23458	UNIPROT	down-regulates activity	binding			9606									23454976	t		miannu	SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition	SIGNOR-253051	0.722
(-)-anisomycin	chemical	CHEBI:338412	ChEBI	PCSK7	protein	Q16549	UNIPROT	up-regulates	chemical activation			9606		BTO:0000142							16581040	t		gcesareni	These results indicate that activation of p38 mapk by anisomycin induces ltd and subsequently occludes electrically induced ltd	SIGNOR-145496	0.8
MAML1	protein	Q92585	UNIPROT	NOTCH4	protein	Q99466	UNIPROT	up-regulates	binding			9606									11101851	t		gcesareni	Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes4	SIGNOR-84916	0.698
GRPR	protein	P30550	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257421	0.409
FGF12	protein	P61328	UNIPROT	SCN1A	protein	P35498	UNIPROT	down-regulates activity	binding			9606									20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253420	0.394
SRC	protein	P12931	UNIPROT	RACK1	protein	P63244	UNIPROT	up-regulates	phosphorylation	Tyr228	LNEGKHLyTLDGGDI	9606									12400005	t		gcesareni	We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246	SIGNOR-94796	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	MEF2C	protein	Q06413	UNIPROT	down-regulates activity	phosphorylation	Ser396	NIKSEPVsPPRDRTT		BTO:0003166								16478538	t		llicata	Phosphorylation-facilitated sumoylation of MEF2C negatively regulates its transcriptional activity. | Intriguingly, we show that phosphorylation of S396 in MEF2C, a residue in close proximity to the major sumoylation site (K391) and known to be phosphorylated in vivo, enhances sumoylation of delta- N2-MEF2C in vitro. The S396A mutation reduces sumoylation of MEF2C in vivo and enhances the transcription activity of MEF2C in reporter assays. | CDK1/Cyclin B1 phosphorylated GST-MEF2C-ΔN2-WT to a greater extent than the MEF2C-ΔN2-S396A mutant, suggesting that Cdk1/Cyclin B1 can phosphorylate MEF2C at S396.	SIGNOR-250719	0.369
FGF5	protein	P12034	UNIPROT	FGFR2	protein	P21802	UNIPROT	up-regulates	binding			9606									8386828	t		gcesareni	Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2	SIGNOR-38995	0.701
codeine	chemical	CHEBI:16714	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258933	0.8
GSK3A	protein	P49840	UNIPROT	MITF	protein	O75030	UNIPROT	up-regulates	phosphorylation	Ser405	QARAHGLsLIPSTGL	9606									10587587	t	The effect has been demonstrated using O75030-9	gcesareni	Glycogen synthase kinase 3 (gsk3) was found to phosphorylate ser298 in vitro, thereby enhancing the binding of mitf to the tyrosinase promoter	SIGNOR-72878	0.299
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BC5	protein	P58876	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSVYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271985	0.2
MAPKAPK2	protein	P49137	UNIPROT	ZFP36L1	protein	Q07352	UNIPROT	down-regulates	phosphorylation	Ser54	GGFPRRHsVTLPSSK	9606									18326031	t		lperfetto	Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation.	SIGNOR-161274	0.604
APBA2	protein	Q99767	UNIPROT	NRXN1	protein	Q9ULB1	UNIPROT	up-regulates activity	binding			9534	BTO:0000298								11036064	t		miannu	Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa. 	SIGNOR-264039	0.62
TP53	protein	P04637	UNIPROT	MMP2	protein	P08253	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10029407	f		miannu	 p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1.	SIGNOR-255432	0.458
PRKCZ	protein	Q05513	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser675	QDYKKRLsVELTSSL	9606	BTO:0002181								25660024	t		miannu	 Yap and β-catenin are direct substrates of PKCζ. Similar MS/MS analysis to map the sites phosphorylated in β-catenin by PKCζ identified S45 and several sites of low abundance that included S552 and S675 (Figure S3C). 	SIGNOR-276880	0.582
CNTF	protein	P26441	UNIPROT	CRLF1	protein	O75462	UNIPROT	up-regulates	binding			9606									11294841	t		lperfetto	We recently demonstrated that cardiotrophin-like cytokine (clc) associates with the soluble orphan receptor cytokine-like factor-1 (clf) to form a heterodimeric cytokine that displayed activities only on cells expressing the tripartite cntf receptor on their surface	SIGNOR-106635	0.401
PRKACA	protein	P17612	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	up-regulates activity	phosphorylation	Ser279	KVAERRSsPLLRRKD	9606									22865920	t		lperfetto	PKA/Cdk5-mediated phosphorylation of HDAC5 at Ser279 within the NLS promotes nuclear localization of HDAC5 and interaction with the nuclear corepressor complex	SIGNOR-198658	0.2
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1724	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120204	0.321
PTPN1	protein	P18031	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates	dephosphorylation			9606									15821101	t		gcesareni	Ptp1b has been shown to regulate the activation of cytokine receptors through the dephosphorylation of specific members of the jak family, namely jak2 and tyk2	SIGNOR-135207	0.79
PRKDC	protein	P78527	UNIPROT	XRCC6	protein	P12956	UNIPROT	up-regulates activity	phosphorylation	Ser27	QEENLEAsGDYKYSG	9606	BTO:0001546								26337656	t	done	miannu	 Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks.	SIGNOR-274022	0.939
PHKG1	protein	Q16816	UNIPROT	PYGM	protein	P11217	UNIPROT	up-regulates activity	phosphorylation	Ser15	QEKRKQIsVRGLAGV	9606	BTO:0002049								22225877	t			It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15	SIGNOR-267398	0.671
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRID2	protein	O43424	UNIPROT	up-regulates activity	chemical activation			9606									27586965	t		miannu	Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors	SIGNOR-264469	0.8
PRKCD	protein	Q05655	UNIPROT	CHN2	protein	P52757	UNIPROT	down-regulates	phosphorylation	Ser171	EKVSRRLsRSKNEPR	9606									20335173	t		lperfetto	A novel cross-talk in diacylglycerol signaling: the rac-gap beta2-chimaerin is negatively regulated by protein kinase cdelta-mediated phosphorylation. phosphorylation of beta2-chimaerin on ser(169) located in the sh2-c1 domain linker region via protein kinase cdelta, which retained beta2-chimaerin in the cytosol and prevented its c1 domain-mediated translocation to membranes	SIGNOR-164687	0.272
CSNK2A1	protein	P68400	UNIPROT	HDAC3	protein	O15379	UNIPROT	up-regulates activity	phosphorylation	Ser424	DHDNDKEsDVEI	9606									15805470	t		llicata	A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.	SIGNOR-250889	0.517
DLGAP4	protein	Q9Y2H0	UNIPROT	SHANK1	protein	Q9Y566	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264595	0.682
CDK1	protein	P06493	UNIPROT	CLIP1	protein	P30622	UNIPROT	up-regulates activity	phosphorylation	Thr287	KIGFPSTtPAKAKAN										19687009	t		lperfetto	Cdc2 phosphorylates T287|CLIP-170, the founding member of microtubule “plus ends tracking” proteins, is involved in many critical microtubule-related functions, including recruitment of dynactin to the microtubule plus ends and formation of kinetochore-microtubule attachments during metaphase. |These results demonstrate that Cdc2-mediated phosphorylation of CLIP-170 is essential for the normal function of this protein during cell cycle progression.	SIGNOR-275470	0.468
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	AM/b2 integrin	complex	SIGNOR-C170	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259025	0.416
RPS6KA3	protein	P51812	UNIPROT	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606		BTO:0000562							9211863	t		gcesareni	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-49367	0.2
PLRG1	protein	O43660	UNIPROT	HNRNPM	protein	P52272	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								20467437	t	1	miannu	hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay.	SIGNOR-239444	0.735
DYRK1A	protein	Q13627	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates	phosphorylation	Ser276	PLPSPTAsPNHTLAP	9606		BTO:0000142							15262992	t		lperfetto	Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd	SIGNOR-126847	0.405
lipopolysaccharide	smallmolecule	CHEBI:16412	ChEBI	TLR4	protein	O00206	UNIPROT	up-regulates activity	chemical activation			10090									9851930	t			The mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane.	SIGNOR-252075	0.8
CSNK2A1	protein	P68400	UNIPROT	TWIST1	protein	Q15672	UNIPROT	up-regulates	phosphorylation	Ser18	SPADDSLsNSEEEPD	9606									21559372	t		llicata	Further investigation revealed that il-6 stabilizes twist in scchn cell lines through casein kinase 2 (ck2) phosphorylation of twist residues s18 and s20, and that this phosphorylation inhibits degradation of twist.	SIGNOR-173668	0.2
JAK2	protein	O60674	UNIPROT	EPOR	protein	P19235	UNIPROT	up-regulates activity	phosphorylation	Tyr485	GGLSDGPySNPYENS										12441334	t			JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2	SIGNOR-251353	0.806
ULK1	protein	O75385	UNIPROT	HK1	protein	P19367	UNIPROT	up-regulates activity	phosphorylation	Ser364	TRLGVEPsDDDCVSV	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274033	0.26
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	TIAM1	protein	Q13009	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002181								25124033	t		miannu	Phosphorylation of Ser329, Ser334, and Thr340 in Tiam1 is required for its interaction with βTrCP1. The proteolysis of Tiam1 is prevented by βTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site.	SIGNOR-276675	0.345
BHLHE41	protein	Q9C0J9	UNIPROT	BHLHE40	protein	O14503	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									14672706	f	 	lperfetto	We show here an autofeedback loop of Dec1 encoding a basic helix–loop–helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression.	SIGNOR-253714	0.516
WNT1	protein	P04628	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates				10116									11149923	f		gcesareni	Wnt-1 signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced by chemotherapeutic drugs, including both vincristine and vinblastine. Furthermore, we found that wnt-1-mediated cell survival was dependent on the activation of beta-catenin/t cell factor (tcf) transcription	SIGNOR-85760	0.735
CHUK	protein	O15111	UNIPROT	CREBBP	protein	Q92793	UNIPROT	up-regulates	phosphorylation	Ser1386	FVDSGEMsESFPYRT	9606	BTO:0000551								17434128	t		lperfetto	Phosphorylation of cbp by ikkalpha promotes cell growth by switching the binding preference of cbp from p53 to nf-kappabhere, we show that ikkalpha phosphorylates cbp at serine 1382 and serine 1386 and consequently increases cbp's hat and transcriptional activities	SIGNOR-154333	0.533
P2RY14	protein	Q15391	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257118	0.2
CGA	protein	P01215	UNIPROT	TSHR	protein	P16473	UNIPROT	up-regulates	binding			9606									12045258	t		miannu	Human thyrotropin (tsh), follitropin (fsh), lutropin (lh), and chorionic gonadotropin (cg) are members of the glycoprotein hormone family derived from heterodimerization of a common ? Subunit with hormone-specific ? Subunits. These hormones were originally purified from the anterior pituitary (tsh, lh, and fsh) and placenta (human cg) and shown to activate specific g protein_coupled receptors in the thyroid (tsh receptor) and gonads (lh and fsh receptors), respectively	SIGNOR-88519	0.409
PTCH1	protein	Q13635	UNIPROT	CDON/BOC/PTCH1	complex	SIGNOR-C95	SIGNOR	form complex	binding			10090									21664576	t		lperfetto	Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands.	SIGNOR-209602	0.569
SMAD1/4	complex	SIGNOR-C85	SIGNOR	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004058								12589053	f		lperfetto	Overexpression of Smad6, a natural antagonist for Smad1, blocked PPARgamma expression and adipocytic differentiation induced by BMP2	SIGNOR-236233	0.29
F2	protein	P00734	UNIPROT	Thrombin-Thrombomodulin	complex	SIGNOR-C316	SIGNOR	form complex	binding			9606		BTO:0000131							29880919	t		lperfetto	Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC).	SIGNOR-263549	0.903
IKK-complex	complex	SIGNOR-C14	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser644	GLDFNFDsLISTQNV	9606									19188143	t		lperfetto	Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway	SIGNOR-252951	0.536
CXCL8	protein	P10145	UNIPROT	CXCR1	protein	P25024	UNIPROT	up-regulates	binding			9606									11350788	t		gcesareni	Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades.	SIGNOR-107920	0.773
HTR1E	protein	P28566	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256848	0.423
CAMK2A	protein	Q9UQM7	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates	phosphorylation	Ser260	TLSPVNHsLDLQPVT	9606				SIGNOR-C8					11027280	t		gcesareni	Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgfbeta-dependent smad2-smad3 interactions.	SIGNOR-82974	0.528
PLK3	protein	Q9H4B4	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser73	VGLLKLAsPELERLI	9606									18650425	t		gcesareni	Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun.	SIGNOR-179555	0.379
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	EP300	protein	Q09472	UNIPROT	up-regulates	phosphorylation			9606				SIGNOR-C7					17964260	t		lperfetto	Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300.	SIGNOR-244239	0.2
RAP1GDS1	protein	P52306	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates	binding			9606									21242305	t		miannu	Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob	SIGNOR-171412	0.292
DHX9	protein	Q08211	UNIPROT	mRNA-nucleus_export	phenotype	SIGNOR-PH127	SIGNOR	up-regulates				9606									11402034	f		miannu	These results support the proposal that both RHA and HAP95 facilitated the nuclear export of unspliced, CTE-containing mRNA in human cells. we have extended this earlier study by mapping the functional domains of HAP95 and providing strong evidence for a direct role of HAP95 in RHA-mediated nuclear export of CTE-containing mRNA.	SIGNOR-260948	0.7
SRC	protein	P12931	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Tyr88	KGSLPEFyYRPPRPP	9606	BTO:0000150								17254967	t		lperfetto	Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27	SIGNOR-152835	0.511
LCK	protein	P06239	UNIPROT	TCR	complex	SIGNOR-C153	SIGNOR	up-regulates activity	phosphorylation			10090									2470098	t			Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex.	SIGNOR-259932	0.2
APBB1	protein	O00213	UNIPROT	TSHZ3	protein	Q63HK5	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								19343227	t		miannu	We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex.	SIGNOR-264813	0.374
PRKCD	protein	Q05655	UNIPROT	C5AR1	protein	P21730	UNIPROT	down-regulates	phosphorylation	Ser334	SVVRESKsFTRSTVD	9606									17145764	t		gcesareni	Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation.	SIGNOR-151015	0.2
MYOD1	protein	P15172	UNIPROT	MYOD/HEB	complex	SIGNOR-C128	SIGNOR	form complex	binding			9606									16847330	t	2	miannu	The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation.	SIGNOR-241122	0.66
CTNNB1	protein	P35222	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates				9606	BTO:0000222								10937998	f		fspada	Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma).	SIGNOR-80589	0.406
WWTR1	protein	Q9GZV5	UNIPROT	TEAD3	protein	Q99594	UNIPROT	up-regulates	binding			9606									23431053	t	YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death.	gcesareni	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.	SIGNOR-201415	0.686
CSNK1D	protein	P48730	UNIPROT	HIF1A	protein	Q16665	UNIPROT	down-regulates	phosphorylation	Ser247	KTFLSRHsLDMKFSY	9606									20699359	t		lperfetto	In this work, we investigate the phosphorylation of the n-terminal heterodimerization (pas) domain of hif-1alpha and identify ser247 as a major site of in vitro modification by casein kinase 1delta (ck1delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of hif-1alpha	SIGNOR-167476	0.329
SPI1	protein	P17947	UNIPROT	ACP5	protein	P13686	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11481336	f		miannu	The combination of MITF and PU.1 synergistically activated the TRAP promoter in transient assays.	SIGNOR-254585	0.354
SMC4	protein	Q9NTJ3	UNIPROT	Condensin I	complex	SIGNOR-C341	SIGNOR	form complex	binding			9606									32445620	t		miannu	The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction.	SIGNOR-263904	0.934
LINC complex	complex	SIGNOR-C303	SIGNOR	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates													24481844	f		lperfetto	The extensive covalent and non-covalent attachments as well as the binding avidity between three KASH domains with three SUN domains are thought to enable the LINC complex to transmit force between the cytoskeleton and the nucleoskeleton	SIGNOR-263293	0.7
XAV939	chemical	CHEBI:62878	ChEBI	TNKS	protein	O95271	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207830	0.8
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	BCL2L11	protein	O43521	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17960585	f		miannu	Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells.	SIGNOR-260425	0.478
TFDP1	protein	Q14186	UNIPROT	DHFR	protein	P00374	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253860	0.415
FNIP2	protein	Q9P278	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								27353360	t		miannu	FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle. 	SIGNOR-261414	0.422
PRKD3	protein	O94806	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser155	GRLKRERsMSENAVR										34010649	t		lperfetto	The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-275945	0.2
KLKB1	protein	P03952	UNIPROT	HGF	protein	P14210	UNIPROT	up-regulates activity	cleavage	Arg424	KNMEDLHrHIFWEPD	-1									12372819	t		miannu	 the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. 	SIGNOR-256513	0.328
MAPK1	protein	P28482	UNIPROT	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation	Ser789	QSVDKVTsPTKV	9606		BTO:0001260							10514499	t		lperfetto	Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin.	SIGNOR-71037	0.524
MC5R	protein	P33032	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257441	0.252
POLR1F	protein	Q3B726	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding												22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266157	0.2
USP9X	protein	Q93008	UNIPROT	RPS27A	protein	P62979	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270826	0.482
Ethylketocyclazocine	chemical	CHEBI:4901	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9262330	t		miannu	We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine.	SIGNOR-258663	0.8
COL4A6	protein	Q14031	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	up-regulates activity	binding			9606	BTO:0000664								12123670	t		lperfetto	We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1.	SIGNOR-253246	0.422
MAPK1	protein	P28482	UNIPROT	NEFH	protein	P12036	UNIPROT	up-regulates activity	phosphorylation	Ser526	PVKEEAKsPAEAKSP	10116	BTO:0000938								9592082	t		lperfetto	The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation. 	SIGNOR-249424	0.375
SEMA3C	protein	Q99985	UNIPROT	NRP2	protein	O60462	UNIPROT	up-regulates	binding			9606	BTO:0000938								16816121	t		gcesareni	Our experiments establish that small peptides containing the consensus decd sequence of sperm fertilinbeta bind specifically to an alpha6beta1 integrin receptor on the egg membrane. We conclude that fertilinbeta binds directly to the alpha6beta1 integrin on the egg surface and this partnership mediates sperm-egg fusion.	SIGNOR-147564	0.604
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	SLC2A1	protein	P11166	UNIPROT	up-regulates quantity	transcriptional regulation			10116									11120745	t			Collectively these results indicate that H-Ras up-regulates the glut1 promoter, at least in part, by increasing HIF-1alpha protein levels leading to transactivation of promoter through the HIF-1 binding site.	SIGNOR-267478	0.422
AP3B2	protein	Q13367	UNIPROT	Neuronal AP-3	complex	SIGNOR-C445	SIGNOR	form complex	binding			9606	BTO:0000938								19497727	t		miannu	Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) 	SIGNOR-268521	0.648
NHS	protein	Q6T4R5	UNIPROT	WRC complex	complex	SIGNOR-C191	SIGNOR	up-regulates activity	relocalization			9606									20332100	t		miannu	Excessive cell spreading and lamellipod extension as a result of NHS knockdown is likely to be a result of loss of WAVE complex regulation, leading to overactive WAVE activity or a dysregulation of nascent focal adhesions in lamellipodia.WAVE and NHS protein partners Abi1 and HSPC300, and the p34 subunit of the Arp2/3 complex, consistently localized at the edges of cells treated with NHS siRNA, independent of EGF stimulation and WAVE complex activation. These data show that localization of Abi1 and HSPC300 was altered in the absence of NHS.	SIGNOR-253577	0.2
PPM1A	protein	P35813	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates	dephosphorylation	Ser181	DQGSLCTsFVGTLQY	9606									18930133	t		lperfetto	Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation	SIGNOR-181659	0.313
FOXC1	protein	Q12948	UNIPROT	SOX4	protein	Q06945	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31650548	f		lperfetto	Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX15	SIGNOR-275917	0.326
TP53	protein	P04637	UNIPROT	CCNG1	protein	P51959	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									9688532	t		lperfetto	Individual promoter and intron p53-binding motifs from the rat Cyclin G1 promoter region support transcriptional activation by p53 but do not show co-operative activation.	SIGNOR-268961	0.782
MEF2A	protein	Q02078	UNIPROT	MYH1	protein	P12882	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15728583	t		lperfetto	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238748	0.362
MAPK1	protein	P28482	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser69	GPLAPPAsPGPFATR	9606									15486195	t		lperfetto	In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel	SIGNOR-129874	0.705
PRKCA	protein	P17252	UNIPROT	VTN	protein	P04004	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser381	RNRKGYRsQRGHSRG	-1									9030777	t		lperfetto	Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin.	SIGNOR-248962	0.323
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3C1	protein	P68431	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269628	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9606	BTO:0000938								12040039	t		lperfetto	Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Jnk2/3 activity selectively targets c-jun.	SIGNOR-236130	0.2
OGDH	protein	Q02218	UNIPROT	OGDC	complex	SIGNOR-C397	SIGNOR	form complex	binding			9606									15953811	t		miannu	The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH.	SIGNOR-266255	0.732
RHOXF1	protein	Q8NHV9	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by expression	transcriptional regulation												23317270	f		lperfetto	ShRNA knock down of RHOXF1 resulted in significantly decreased BCL2 expression in both cell lines but no change in CASP8 expression.	SIGNOR-268957	0.2
RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000785								16847353	t		lperfetto	C-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma	SIGNOR-209593	0.613
STK4	protein	Q13043	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates	phosphorylation	Ser209	SSAGWKNsIRHNLSL	9606									18394876	t		gcesareni	Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity.	SIGNOR-178190	0.673
PTK6	protein	Q13882	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates	phosphorylation	Tyr664	EGGWMEDyDYVHLQG	9606	BTO:0001130								22084245	t		lperfetto	Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 crk-associated substrate. Tyrosine residues 165 and 664 of p130cas were both phosphorylated by ptk6 in vitro	SIGNOR-177242	0.584
AP1B1	protein	Q10567	UNIPROT	AP-1 complex	complex	SIGNOR-C248	SIGNOR	form complex	binding			9606									21097499	t		lperfetto	Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)	SIGNOR-260685	0.813
MYOCD	protein	Q8IZQ8	UNIPROT	KLF4	protein	O43474	UNIPROT	down-regulates				9606									21673106	f	miR-143 and miR-145 target KLF4	gcesareni	These results further confirm that bmp4 requires mrtf-a, whereas tgf-_ requires myocd for the induction of pri-mir-143/145 and down-regulation of klf4.	SIGNOR-174319	0.479
ACP1	protein	P24666	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	dephosphorylation	Ser473	RPHFPQFsYSASGTA	10090									17353188	t			Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3	SIGNOR-248455	0.328
ATR	protein	Q13535	UNIPROT	XPA	protein	P23025	UNIPROT	up-regulates	phosphorylation	Ser196	RSLEVWGsQEALEEA	9606									16540648	t		miannu	Atr was the major kinase responsible for the cellular phosphorylation of xpa following uv irradiation / we propose that the phosphorylation of xpa by atr checkpoint may positively regulate ner activity and thus may facilitate the cells to recover from ner-related dna damages.	SIGNOR-145190	0.505
EIF2S1	protein	P05198	UNIPROT	Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	form complex	binding			9606									32955564	t		lperfetto	In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3.	SIGNOR-269114	0.944
PRKACA	protein	P17612	UNIPROT	KCNQ5	protein	Q9NR82	UNIPROT	up-regulates activity	phosphorylation	Ser88	GKQGARMsLLGKPLS	9606	BTO:0001660								30061510	t		miannu	We conclude that phosphorylation of S53 on the amino terminus of Kv7.5 is essential for PKA-dependent enhancement of channel activity in response to βAR activation in vascular and airway smooth muscle cells.	SIGNOR-265980	0.2
ERG	protein	P11308	UNIPROT	CDH5	protein	P33151	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18195090	t		Luana	Erg overexpression resulted in an approximate 1.8-fold transactivation of VE-cadherin promoter activity. Thus, our data indicate that Erg drives constitutive VE-cadherin expression in human ECs 	SIGNOR-261595	0.281
ADRM1	protein	Q16186	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263342	0.823
CCT7	protein	Q99832	UNIPROT	TRiC	complex	SIGNOR-C539	SIGNOR	form complex	binding			9606									36185250	t		miannu	Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC).	SIGNOR-272867	0.741
ACVR1	protein	Q04771	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates	phosphorylation			9606									9748228	t		fspada	Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2	SIGNOR-60174	0.69
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	FBXO32	protein	Q969P5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							21798082	f		lperfetto	Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome.	SIGNOR-252945	0.2
BRCA1-B complex	complex	SIGNOR-C298	SIGNOR	ATR	protein	Q13535	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								16530042	t		lperfetto	These results establish that TopBP1 can activate both Xenopus and human ATR. Furthermore, these experiments provide conclusive evidence that the kinase activity that is induced by TopBP1 is intrinsic to the ATR protein itself and is not due to a kinase that associates with ATR.	SIGNOR-263231	0.64
MAP3K5	protein	Q99683	UNIPROT	MAP3K6	protein	O95382	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								17210579	t		Manara	C-terminal region of ASK1 binds to ASK2 and inhibits the degradation of ASK2	SIGNOR-260831	0.53
PRKAA1	protein	Q13131	UNIPROT	TET2	protein	Q6N021	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser99	GGIKRTVsEPSLSGLL	9606	BTO:0001025								30022161	t			We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo	SIGNOR-256134	0.2
MAPK14	protein	Q16539	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates activity	phosphorylation	Thr300	TPVVSVAtPTLPGQG	9606									9858528	t	The effect has been demonstrated using Q06413-3	lperfetto	Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain	SIGNOR-62796	0.683
SOCS3	protein	O14543	UNIPROT	IL6ST	protein	P40189	UNIPROT	down-regulates activity	binding			9606									23454976	t		miannu	SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. The inhibitory protein SOCS3 plays a key part in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus kinases (JAKs) that initiate signaling within the cell. 	SIGNOR-255328	0.637
TYSND1	protein	Q2T9J0	UNIPROT	ACOX1	protein	Q15067	UNIPROT	up-regulates activity	cleavage			-1									17255948	t		miannu	 Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1.	SIGNOR-261057	0.682
GDNF	protein	P39905	UNIPROT	ID2	protein	Q02363	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252180	0.249
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2L3	protein	P68036	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271326	0.584
ATP5PD	protein	O75947	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261404	0.2
PRKD1	protein	Q15139	UNIPROT	CERT1	protein	Q9Y5P4	UNIPROT	down-regulates	phosphorylation	Ser132	SSLRRHGsMVSLVSG	9606									17591919	t		lperfetto	In this study, we identify cert as a novel in vivo pkd substrate. Phosphorylation on serine 132 by pkd decreases the affinity of cert toward its lipid target phosphatidylinositol 4-phosphate at golgi membranes and reduces ceramide transfer activity	SIGNOR-156500	0.2
MTOR	protein	P42345	UNIPROT	NRBF2	protein	Q96F24	UNIPROT	up-regulates activity	phosphorylation	Ser113	AEDAEGQsPLSQKYS	9606	BTO:0001938								28059666	t		miannu	Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association. 	SIGNOR-265874	0.2
CTDNEP1	protein	O95476	UNIPROT	BMPR2	protein	Q13873	UNIPROT	down-regulates	binding			9606									17141153	t		gcesareni	We show that dullard promotes the ubiquitin-mediated proteosomal degradation of bmp receptors	SIGNOR-151001	0.438
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser588	QTLSDSLsGSSLYST	-1									17711846	t	done	miannu	Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626).	SIGNOR-274096	0.397
MAPK3	protein	P27361	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser344	QDDDAPLsPMLYSSS	9606									19282669	t		lperfetto	Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway	SIGNOR-184573	0.583
MAPK1	protein	P28482	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation			9606									12832467	t		lperfetto	Efficient rsk activation by erk requires its interaction through a docking site located near the c terminus of rsk	SIGNOR-102645	0.748
regorafenib	chemical	CHEBI:68647	ChEBI	BRAF	protein	P15056	UNIPROT	down-regulates activity	chemical inhibition			9606									26254357	t		miannu	A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF	SIGNOR-259176	0.8
GRIN2C	protein	Q14957	UNIPROT	NMDA receptor_2C	complex	SIGNOR-C349	SIGNOR	form complex	binding			9606	BTO:0000938								12871085	t		miannu	The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits	SIGNOR-264125	0.594
Laminin-1	complex	SIGNOR-C183	SIGNOR	A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	up-regulates activity	binding			9606	BTO:0000414								24184828	t		miannu	Integrin α6β4 is a laminin receptor that is mainly expressed in the basal layer of epithelial tissues. The β4-integrin is unique because of its long cytoplasmic tail, which interacts with the intermediate filament network rather than actin. This interaction contributes to the ability of α6β4 to maintain the integrity of tissues normally exposed to shear stress. α6β4 integrin assembles its own signalling platform. 	SIGNOR-258998	0.505
CDK1	protein	P06493	UNIPROT	WAC	protein	Q9BTA9	UNIPROT	up-regulates activity	phosphorylation	Thr482	SSQPKVStPVVKQGP	9606	BTO:0000567								30021153	t		lperfetto	Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. 	SIGNOR-265033	0.2
ENO2	protein	P09104	UNIPROT	2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	down-regulates quantity	chemical modification			9606									29767008	t		miannu	Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits.	SIGNOR-266529	0.8
RPS6KB1	protein	P23443	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser639	YMPMSPKsVSAPQQI	10090									15306821	t		lperfetto	Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin.	SIGNOR-127203	0.781
TNF	protein	P01375	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity				10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253486	0.2
AKT1	protein	P31749	UNIPROT	HMOX1	protein	P09601	UNIPROT	unknown	phosphorylation	Ser188	LYRSRMNsLEMTPAV	9606	BTO:0000007								15581622	t		llicata	We have identified a putative consensus sequence for phosphorylation by akt/pkb of ho-1 at ser188. although the changes in activity are small, this study provides the first evidence for a role of the survival kinase akt in the regulation of ho-1.	SIGNOR-252506	0.577
ARNT	protein	P27540	UNIPROT	CCNE1	protein	P24864	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								21544813	f	 	lperfetto	Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC	SIGNOR-253692	0.285
AKT2	protein	P31751	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser315	DFRSRTNsNASTVSG	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites.	SIGNOR-252868	0.757
FANCG	protein	O15287	UNIPROT	SPTAN1	protein	Q13813	UNIPROT	up-regulates quantity by stabilization				9606	BTO:0000773								19102630	t		lperfetto	In FA cells, deficiencies in FA proteins lead to decreased stability of alphaRIISp |These results demonstrate that one of the FA proteins, FANCG, contains a motif that interacts directly with the SH3 domain of alphaIISp. We propose that this binding of FANCG to alphaIISp may be important for the stability of alphaIISp in cells and the role alphaIISp plays in the DNA repair process.|	SIGNOR-263275	0.374
SPP1	protein	P10451	UNIPROT	A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	up-regulates activity	binding			9606									24241034	t		lperfetto	Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed α9β1 integrins, a common receptor for osteopontin and tenascin-C.	SIGNOR-253311	0.607
ZMIZ1	protein	Q9ULJ6	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates activity	binding			9606	BTO:0001321								14609956	t		miannu	Our results demonstrate that hZimp10 is a novel AR interacting protein that augments AR-mediated transcription. Moreover, hZimp10 co-localized with AR and SUMO-1 at replication foci throughout S phase, and it was capable of enhancing sumoylation of AR in vivo.	SIGNOR-263935	0.698
ATM	protein	Q13315	UNIPROT	TTC5	protein	Q8N0Z6	UNIPROT	up-regulates activity	phosphorylation	Ser203	TGQNPKIsQQALSAY	9606									15448695	t		miannu	Here we report a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap. ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex.	SIGNOR-262645	0.519
CHN2	protein	P52757	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260500	0.624
TIMM21	protein	Q9BVV7	UNIPROT	TIM23 complex	complex	SIGNOR-C423	SIGNOR	form complex	binding												32074073	t		lperfetto	The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE.	SIGNOR-267698	0.613
CHRM5	protein	P08912	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256730	0.2
MTOR	protein	P42345	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Thr412	NQVFLGFtYVAPSVL	-1			SIGNOR-C3						10567431	t		lperfetto	We report here that a mammalian recombinant p70alpha polypeptide, extracted in an inactive form from rapamycin-treated cells, can be directly phosphorylated by the mTOR kinase in vitro predominantly at the rapamycin-sensitive site Thr-412. mTOR-catalyzed p70alpha phosphorylation in vitro is accompanied by a substantial restoration in p70alpha kinase activity toward its physiologic substrate	SIGNOR-72357	0.96
PCDH11X	protein	Q9BZA7	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	down-regulates				9606		BTO:0000227							25687328	f		miannu	Our previous research found that protocadherin 11 X-linked protein (Pcdh11x) is predominantly expressed in neurons and has an influence on dendritic branching. In this study, gain-of-function and loss-of-function experiments revealed that Pcdh11x acts as a negative regulator of dendritic branching in cultured cortical neurons derived from embryonic day 16 mice. Overexpression of wild-type Pcdh11x (Pcdh11x-GFP) reduced dendritic complexity, whereas knockdown of Pcdh11x increased dendritic branching.	SIGNOR-265163	0.7
afatinib	chemical	CHEBI:61390	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258066	0.8
ZAP70	protein	P43403	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	phosphorylation	Tyr319	TSVYESPySDPEELK	9606	BTO:0000661								10037717	t		lperfetto	We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function.	SIGNOR-247053	0.2
1-phosphatidyl-1D-myo-inositol 3-phosphate	smallmolecule	CHEBI:17283	ChEBI	Early Endosome	complex	SIGNOR-C246	SIGNOR	form complex	binding			9606									19924646	t		lperfetto	PtdIns(3)P-kinase/hVPS34/p150 (VPS34) is thought to be one of the first Rab5 effector proteins to be recruited to the EE . As suggested by its name, its primary role is to generate PtdIns(3)P, which is the most abundant phosphoinositide in the EE membrane. 	SIGNOR-260622	0.8
AKT1	protein	P31749	UNIPROT	PLN	protein	P26678	UNIPROT	down-regulates activity	phosphorylation	Thr17	SAIRRAStIEMPQQA	10090	BTO:0003265								19696029	t			Akt interacts with and phosphorylates PLN at Thr(17), the Ca(2+)-calmodulin-dependent kinase IIdelta site, whereas silencing Akt signaling, through the knock-out of phosphatidylinositol-dependent kinase-1, resulted in reduced phosphorylation of PLN at Thr(17).	SIGNOR-252578	0.293
ITK	protein	Q08881	UNIPROT	CD28	protein	P10747	UNIPROT	up-regulates	phosphorylation	Tyr209	TRKHYQPyAPPRDFA	9606	BTO:0000661								22936936	t		lperfetto	We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tailother studies demonstrated that tyr191 within the p190yap motif is one of two major phosphorylation sites in cd28-stimulated jurkat t cells, and the only tyrosine residue within the cd28 cytoplasmic tail that is essential for delivery of costimulatory signals	SIGNOR-198751	0.677
PRKCD	protein	Q05655	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates quantity	phosphorylation	Ser594	HKAAVPAsEKLLLLK	9606	BTO:0000930								15381704	t		lperfetto	Finally, basal ChAT phosphorylation in neurons is mediated predominantly by PKC at Ser-476, with PKC activation increasing phosphorylation at Ser-440 and enhancing ChAT activity.	SIGNOR-249272	0.315
NRG2	protein	O14511	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606		BTO:0000887							7477375	t		gcesareni	The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4.	SIGNOR-26211	0.78
PTPRB	protein	P23467	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	up-regulates	dephosphorylation			9606									12840032	t	inferred from 70% of family members	gcesareni	When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well	SIGNOR-269911	0.2
bradykinin	smallmolecule	CHEBI:3165	ChEBI	BDKRB1	protein	P46663	UNIPROT	up-regulates	chemical activation			9606	BTO:0001130;BTO:0000189								17251915	t		gcesareni	Neuropeptides such as grp, endothelin, bradykinin, neuromedin b (nmb), cholecystokinin (cck) and angiotensin ii activate their cognate gpcrs to stimulate cell proliferation in various cell types, and have a crucial role in many aggressive human cancers, including small-cell lung cancer (sclc), pancreatic cancer, hnscc and prostate cancer.	SIGNOR-152588	0.8
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	BAX	protein	Q07812	UNIPROT	up-regulates				9606									15071501	f	inferred from 70% family members	gcesareni	Demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria; these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins.	SIGNOR-269977	0.2
triptorelin	chemical	CHEBI:63633	ChEBI	GNRH1	protein	P01148	UNIPROT	up-regulates activity	chemical activation			9606									22416801	t		miannu	The comparative effects of degarelix and GnRH agonists were assessed in two studies in a rat model of prostate cancer.14 In a 2‐month study, rats receiving the GnRH agonist, triptorelin (0.5 mg/kg daily), experienced an initial testosterone surge, followed by suppression to castration levels by day 28, which was maintained for the remainder of the study.	SIGNOR-259158	0.8
Doxorubicin hydrochloride	chemical	CHEBI:31522	ChEBI	TOP2A	protein	P11388	UNIPROT	down-regulates activity	chemical inhibition			9606									1963303	t		miannu	DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives. 	SIGNOR-259324	0.8
SNX9	protein	Q9Y5X1	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates				9606									16316319	f		gcesareni	We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor.The cdc42 target ack2 interacts with sorting nexin 9 (sh3px1) to regulate epidermal growth factor receptor degradation.	SIGNOR-142566	0.556
NAT8L	protein	Q8N9F0	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	down-regulates quantity	chemical modification			9606									19524112	t		miannu	The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA.	SIGNOR-267521	0.8
NDUFB7	protein	P17568	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1	SIGNOR-262170	0.814
GABARAPL1	protein	Q9H0R8	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								17580304	t		lperfetto	P62 binds both to lc3a and -b and the related gabarap family proteins/this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguisha	SIGNOR-156304	0.787
NEK6	protein	Q9HC98	UNIPROT	EML4	protein	Q9HC35	UNIPROT	up-regulates activity	phosphorylation	Ser144	QSPQIRAsPSPQPSS	-1									31409757	t	done	miannu	The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules. Together, these data support a model in which NEK6- and NEK7-dependent phosphorylation promotes the dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression.	SIGNOR-273883	0.255
TP53	protein	P04637	UNIPROT	G6PD	protein	P11413	UNIPROT	down-regulates activity	binding			9606	BTO:0001938;BTO:0001109								21336310	t		miannu	The p53 protein binds to glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, and prevents the formation of the active dimer. 	SIGNOR-267468	0.571
PRKAA1	protein	Q13131	UNIPROT	ACACA	protein	Q13085	UNIPROT	down-regulates activity	phosphorylation	Ser1201	IPTLNRMsFSSNLNH	10116									7907095	t		miannu	We have isolated and purified from rat livers a novel kinase that phosphorylates and inactivates the carboxylase Ser1200 isphosphorylated by both CAMP-dependent protein kinase and AMP-activated protein kinase	SIGNOR-250400	0.688
Caspase 8 complex	complex	SIGNOR-C231	SIGNOR	BID	protein	P55957	UNIPROT	up-regulates activity	cleavage	Asp60	GYDELQTdGNRSSHS	9606	BTO:0000093								9727492	t		amattioni	Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity	SIGNOR-256443	0.874
MYO1E	protein	Q12965	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity	binding			9606	BTO:0000848								28348210	t		miannu	Myosin-1E (MYO1E), an actin-dependent molecular motor protein, directly interacts with FAK to induce Y397 autophosphorylation, which, in turn, causes changes in gene expression commonly observed in aggressive cancer.	SIGNOR-265427	0.2
FABP6	protein	P51161	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264460	0.7
BBS1	protein	Q8NFJ9	UNIPROT	BBsome complex	complex	SIGNOR-C288	SIGNOR	form complex	binding			9606	BTO:0004910								19081074	t		lperfetto	We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 	SIGNOR-262558	0.865
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates				9606									24692351	f		scontino	Skeletal muscle has been recognized as a key TH target for contractile function, regeneration, and transport as well as for metabolism and glucose disposal (237, 238). TH stimulation favors transition to fast-twitch fibers and transition to a faster myosin heavy chain (MHC) form.	SIGNOR-267620	0.7
PRKCA	protein	P17252	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser299	KMAFRAKsKSCHDLS	-1									9677319	t		lperfetto	Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases.	SIGNOR-249008	0.292
MTNR1A	protein	P48039	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257101	0.252
ARHGAP39	protein	Q9C0H5	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260495	0.559
ESR1	protein	P03372	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11000528	f		gcesareni	Inhibition of ar-induced transactivation that was er cdna dose-responsive and estradiol dependent	SIGNOR-82158	0.425
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRM7	protein	Q14831	UNIPROT	up-regulates activity	chemical activation			9606									25042998	t		miannu	Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate	SIGNOR-264072	0.8
MFN2	protein	O95140	UNIPROT	Mitochondrial_fusion	phenotype	SIGNOR-PH218	SIGNOR	up-regulates				9606									25486875	f		lperfetto	OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria	SIGNOR-272985	0.7
NR1D1	protein	P20393	UNIPROT	OPHN1	protein	O60890	UNIPROT	up-regulates activity	binding			9606	BTO:0000132								35267019	t		miannu	Rev-erbα regulates OPHN-1-mediated RhoA/ERM signalling in platelets., The results of the co-immunoprecipitation revealed that Rev-erbα coimmunoprecipitated with OPHN-1 in both mouse and human platelets and this interaction significantly increased upon stimulation with agonist U46619.	SIGNOR-268428	0.2
HNF1A	protein	P20823	UNIPROT	UGT1A9	protein	O60656	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000195								15044625	t	 	 	Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.	SIGNOR-253973	0.27
PTPRG	protein	P23470	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	dephosphorylation	Tyr701	DGPKGTGyIKTELIS	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254727	0.2
GPR132	protein	Q9UNW8	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257396	0.381
STX11-SNAP23 SNARE complex	complex	SIGNOR-C272	SIGNOR	Platelet_degranulation	phenotype	SIGNOR-PH138	SIGNOR	up-regulates				9606	BTO:0000782								22767500	f		lperfetto	Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. 	SIGNOR-261901	0.7
PRKACB	protein	P22694	UNIPROT	GPKOW	protein	Q92917	UNIPROT	up-regulates activity	phosphorylation	Thr316	GTASSRKtLWNQELY	-1									21880142	t		miannu	Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2.PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites.	SIGNOR-266310	0.311
MDM2	protein	Q00987	UNIPROT	CDKN2AIP	protein	Q9NXV6	UNIPROT	down-regulates	ubiquitination			9606									18292944	t		amattioni	Carf interacts with hdm2 and is ubiquitinated and negatively regulated by hdm2 by proteasome-dependent degradation.	SIGNOR-160974	0.378
minoxidil	chemical	CHEBI:6942	ChEBI	PLOD1	protein	Q02809	UNIPROT	down-regulates quantity by repression	chemical inhibition			10090		BTO:0000763							30481795	t		Monia	 treatment with minoxidil repressed the expression of the PLOD1, PLOD2, and PLOD3 genes and their encoded LH proteins, it exerted the most profound effects on PLOD1/LH1,	SIGNOR-261071	0.8
6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide	chemical	CHEBI:92401	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258003	0.8
PLK1	protein	P53350	UNIPROT	G6PD	protein	P11413	UNIPROT	up-regulates activity	phosphorylation	Thr466	REAWRIFtPLLHQIE	9606	BTO:0000007								29138396	t		lperfetto	We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules.|the kinase domain of Plk1 phosphorylates T406, T466 of G6PD	SIGNOR-267581	0.354
GSK3B	protein	P49841	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity by destabilization	phosphorylation			10090									16885213	t		lperfetto	Gli2 and Gli3 (in vertebrates) are phosphorylated by protein kinase A and glycogen synthase kinase-3_ and are proteolytically processed	SIGNOR-148475	0.517
Dihydromorphine	chemical	CHEBI:4575	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258787	0.8
ULK3	protein	Q6PHR2	UNIPROT	ULK3	protein	Q6PHR2	UNIPROT	up-regulates activity	phosphorylation	Ser350	ELKAIVSsSNQALLR	9606									20643644	t		Manara	We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. 	SIGNOR-260794	0.2
ARAF	protein	P10398	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates	phosphorylation			9606									21779497	t		lperfetto	Active raf phosphorylates mek.	SIGNOR-244809	0.742
BCL2	protein	P10415	UNIPROT	BECN1	protein	Q14457	UNIPROT	down-regulates	binding			9606									17446862	t		gcesareni	In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function.	SIGNOR-154477	0.731
SETDB2	protein	Q96T68	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	methylation			9606									20404330	t		miannu	Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression.	SIGNOR-265351	0.2
CEBPB	protein	P17676	UNIPROT	Neurodegeneration	phenotype	SIGNOR-PH139	SIGNOR	up-regulates activity				10090	BTO:0000078								32795415	f		Gianni	In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures.	SIGNOR-261926	0.7
SETD5	protein	Q9C0A6	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	methylation	Lys37	APATGGVkKPHRYRP	-1									31515109	t		miannu	SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription. 	SIGNOR-264621	0.2
MRGPRX1	protein	Q96LB2	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257171	0.2
ZNF148	protein	Q9UQR1	UNIPROT	SOX18	protein	P35713	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								18496767	f		miannu	 co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells	SIGNOR-254821	0.26
TLR4	protein	O00206	UNIPROT	TIRAP	protein	P58753	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								11544529	t		gcesareni	Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2.	SIGNOR-252064	0.772
YY1	protein	P25490	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000944								8266081	t		miannu	Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1.	SIGNOR-268794	0.562
MPG	protein	P29372	UNIPROT	STK36	protein	Q9NRP7	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									25278022	t		miannu	 Here, we show that MID1 catalyzes the ubiquitination and proteasomal cleavage of the GLI3 regulator Fu.	SIGNOR-272466	0.2
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser276	PQRSRSPsPQPSSHV	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252333	0.635
CSNK1D	protein	P48730	UNIPROT	PER1	protein	O15534	UNIPROT	down-regulates quantity by destabilization	phosphorylation			10090									11865049	t		miannu	We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. 	SIGNOR-267999	0.799
THOC5	protein	Q13769	UNIPROT	TREX complex	complex	SIGNOR-C444	SIGNOR	form complex	binding			9606									33191911	t		miannu	The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56.	SIGNOR-268506	0.927
AKT1	protein	P31749	UNIPROT	CABLES1	protein	Q8TDN4	UNIPROT	down-regulates activity	phosphorylation	Thr309	APLRRCRtLSGSPRP	-1									25361894	t		miannu	Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex.Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis.	SIGNOR-276756	0.347
ERBB2	protein	P04626	UNIPROT	BBC3	protein	Q9BXH1	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr172	PSPWRVLyNLIMGLL	9606	BTO:0000093								24236056	t		miannu	HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. 	SIGNOR-276474	0.286
LETM1	protein	O95202	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	up-regulates				9606	BTO:0000567								18628306	f		lperfetto	LETM1 knockdown obviously reduced the formation of the supercomplexes (Fig. 5C, arrowhead). Complexes I and IV failed to form, and the assembly of complex III was significantly decreased. By contrast, the assembly of complex II (succinate dehydrogenase) and complex V (ATP synthase) – which are not proton pumps – was unaffected.	SIGNOR-262547	0.256
PFKFB3	protein	Q16875	UNIPROT	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	down-regulates quantity	chemical modification			-1									9404080	t			A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively.	SIGNOR-267271	0.8
CHKA	protein	P35790	UNIPROT	PLIN3	protein	O60664	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr251	ERLRQHAyEHSLGKL	9606	BTO:0000527								34929314	t		lperfetto	In addition, as a protein kinase, CHKα2 phosphorylates PLIN2 at Tyrosine 232 and PLIN3 at Tyrosine 251. Phosphorylated PLIN2 and PLIN3 are separated from lipid droplets and degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation and glioblastoma growth 	SIGNOR-267650	0.2
MEF2D	protein	Q14814	UNIPROT	MYH2	protein	Q9UKX2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0001103							15728583	t		lperfetto	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238712	0.333
SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	SALL4	protein	Q9UJQ4	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269252	0.734
PRKCB	protein	P05771	UNIPROT	STXBP1	protein	P61764	UNIPROT	unknown	phosphorylation	Ser306	VSQEVTRsLKDFSSS	-1									12519779	t		lperfetto	Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation.	SIGNOR-249183	0.406
ABL1	protein	P00519	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	phosphorylation	Tyr81	WEVGSITyDTLSAQA	9606									32653904	t		miannu	Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS.	SIGNOR-277519	0.2
LDHA	protein	P00338	UNIPROT	(S)-lactate	smallmolecule	CHEBI:16651	ChEBI	up-regulates quantity	chemical modification			9606									24929216	t			Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase.	SIGNOR-266919	0.8
PAX5	protein	Q02548	UNIPROT	TLE4	protein	Q04727	UNIPROT	down-regulates activity	binding			9606	BTO:0002291								10811620	t		Gianni	Grg4 efficiently represses the transcriptional activity of Pax5 in an octapeptide-dependent manner. Similar protein interactions resulting in transcriptional repression were also observed between distantly related members of both the Pax2/5/8 and Groucho protein families	SIGNOR-269083	0.581
buprenorphine	chemical	CHEBI:3216	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258940	0.8
PDYN	protein	P01213	UNIPROT	OPRK1	protein	P41145	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								9262330	t		miannu	We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine.	SIGNOR-258411	0.657
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	MED13	protein	Q9UHV7	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007			SIGNOR-C406					23322298	t		miannu	The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association.	SIGNOR-266691	0.299
MKRN1	protein	Q9UHC7	UNIPROT	PABPC1	protein	P11940	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0000007								31640799	t		miannu	We show that MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) and associates with polysomes. MKRN1 is positioned upstream of poly(A) tails in mRNAs in a PABPC1-dependent manner. Ubiquitin remnant profiling and in vitro ubiquitylation assays uncover PABPC1 and ribosomal protein RPS10 as direct ubiquitylation substrates of MKRN1.Our data show that MKRN1 associates with polysomes and ubiquitylates RPS10, indicating a role in translational control. We hypothesize that ribosomes encountering the MKRN1-PABPC1 complex are stalled, possibly via ubiquitylation of RPS10 on K107 and other MKRN1 substrates.	SIGNOR-272215	0.357
TFEB	protein	P19484	UNIPROT	ACOT2	protein	P49753	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2)	SIGNOR-276781	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates	phosphorylation	Ser240	SDQQLNQsMDTGSPA	9606				SIGNOR-C8					11027280	t		gcesareni	Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgfbeta-dependent smad2-smad3 interactions.	SIGNOR-82970	0.528
CREB5	protein	Q02930	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates activity	binding			9534	BTO:0000318								8378084	t		miannu	CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription	SIGNOR-219655	0.617
CHMP3	protein	Q9Y3E7	UNIPROT	ESCRT-III	complex	SIGNOR-C379	SIGNOR	form complex	binding			-1									26775243	t		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission.	SIGNOR-265523	0.739
DOT1L	protein	Q8TEK3	UNIPROT	HOXA9	protein	P31269	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20854876	f		irozzo	Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented.	SIGNOR-256141	0.461
MTOR	protein	P42345	UNIPROT	MAF1	protein	Q9H063	UNIPROT	down-regulates	phosphorylation	Ser75	SPSRLSKsQGGEEEG	9606									20233713	t		flangone	Employing an mtor active-site inhibitor wye-125132 (wye-132), we have performed quantitative phospho-proteomics and identified a ser-75-containing phosphopeptide from maf1, a known repressor of rna polymerase iii (pol iii) transcriptionmaf1 mutant proteins carrying s75a alone or with s60a, t64a, and s68a (maf1-s75a, maf1-4a) progressively enhanced basal repression of trna in actively proliferating cells and attenuated amino acid-induced trna transcription	SIGNOR-164352	0.7
PRKACA	protein	P17612	UNIPROT	DUOX1	protein	Q9NRD9	UNIPROT	up-regulates	phosphorylation	Ser1217	SHHFRRRsFRGFWLT	9606									19144650	t		llicata	We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade	SIGNOR-183445	0.2
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BC9	protein	Q93079	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSVYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271991	0.2
NEK6	protein	Q9HC98	UNIPROT	HSPA1A	protein	P0DMV8	UNIPROT	up-regulates activity	phosphorylation	Thr66	VALNPQNtVFDAKRL	-1									30108182	t	done	miannu	Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr66 located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation. 	SIGNOR-273885	0.436
NEK6	protein	Q9HC98	UNIPROT	KIF11	protein	P52732	UNIPROT	up-regulates activity	phosphorylation	Ser1033	GINTLERsKVEETTE	9606	BTO:0001938								19001501	t	done	miannu	Nek6 phosphorylated Eg5 at several sites in vitro and one of these sites, Ser1033, is phosphorylated in vivo during mitosis. Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles. 	SIGNOR-273886	0.458
RPS6KB1	protein	P23443	UNIPROT	TARBP2	protein	Q15633	UNIPROT	up-regulates activity	phosphorylation	Ser286	LRSCSLGsLGALGPA	-1									27407113	t		miannu	We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. 	SIGNOR-274068	0.329
WNK3	protein	Q9BYP7	UNIPROT	SLC12A6	protein	Q9UHW9	UNIPROT	down-regulates activity	phosphorylation												21613606	t		lperfetto	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264629	0.457
PTPRJ	protein	Q12913	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606									1715686	t		gcesareni	Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta.	SIGNOR-21299	0.309
CSNK1E	protein	P49674	UNIPROT	PER3	protein	P56645	UNIPROT	down-regulates activity	phosphorylation	Ser628	LSLGSGIsQCGYSST	9534	BTO:0000298								11865049	t		llicata	The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. 	SIGNOR-250817	0.734
LYN	protein	P07948	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates activity	phosphorylation	Tyr771	IGTAEPDyGALYEGR	-1									7682059	t		lperfetto	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249381	0.642
anthra[1,9-cd]pyrazol-6(2H)-one	chemical	CHEBI:90695	ChEBI	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									21159646	t		gcesareni	In comparison, in the same assay conditions, the previously reported mps1 inhibitor sp600125 (13) was 10-fold less potent than nms-p715 on mps1 and, in addition, it was highly unspecific, being more active on at least 12 kinases including mitotic kinases.	SIGNOR-170611	0.8
PAK1	protein	Q13153	UNIPROT	NET1	protein	Q7Z628	UNIPROT	down-regulates activity	phosphorylation	Ser152	PTPAKRRsSALWSEM	-1									15684429	t		miannu	In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner. 	SIGNOR-263017	0.252
MAPK14	protein	Q16539	UNIPROT	EWSR1	protein	Q01844	UNIPROT	unknown	phosphorylation	Thr79	QPPTGYTtPTAPQAY	9606									19076070	t		lperfetto	Here we report that ews and ews-fli1 become phosphorylated at thr79 . but the p38_/p38_ mapks were the major kinases phosphorylating ews-fli1. It will be important to investigate how the p38_/p38_-stimulated phosphorylation of ews-fusion proteins affects their ability to transactivate and their oncogenic potential.	SIGNOR-182778	0.2
AKT2	protein	P31751	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates	phosphorylation			9606		BTO:0000887		SIGNOR-C7					17964260	t		gcesareni	Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300.	SIGNOR-158627	0.333
NHLRC1	protein	Q6VVB1	UNIPROT	EPM2A	protein	O95278	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								15930137	t		miannu	Here, we demonstrate that malin is a single subunit E3 ubiquitin (Ub) ligase and that its RING domain is necessary and sufficient to mediate ubiquitination. Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation. 	SIGNOR-271547	0.78
AMPK	complex	SIGNOR-C15	SIGNOR	AMPK	complex	SIGNOR-C15	SIGNOR	unknown	phosphorylation			9606	BTO:0000007								11171104	t		lperfetto	In contrast, the phosphorylation site mutations, ss24, 25aa and s182a, while having no effects on enzyme activity, are associated with nuclear redistribution of the subunit.	SIGNOR-216415	0.795
CDK6	protein	Q00534	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Thr273	SPSVHPAtPISPGRA	9606	BTO:0002181								16046550	t	The effect has been demonstrated using Q01196-8.	gcesareni	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-138965	0.598
L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	precursor of			9606									11863375	t		miannu	Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2	SIGNOR-266924	0.8
Avacopan	chemical	CID:49841217	PUBCHEM	C5AR1	protein	P21730	UNIPROT	down-regulates activity	binding			9606									31734405	t		lperfetto	CCX168 (avocapan), a C5aR antagonist, has proven its safety and efficiency in phase I and phase II trials conducted in AAV patients.	SIGNOR-263473	0.8
BCL10	protein	O95999	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	up-regulates	binding			9606				SIGNOR-C14					18287044	t		gcesareni	Here, we show that bcl10 undergoes k63-linked polyubiquitination in response to t cell activation and subsequently binds nemo, the regulatory subunit of ikk.	SIGNOR-160967	0.82
N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]-2-pyridinyl]methanesulfonamide	chemical	CHEBI:91370	ChEBI	PTK2	protein	Q05397	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206067	0.8
FOXO1	protein	Q12778	UNIPROT	Metabolism	phenotype	SIGNOR-PH77	SIGNOR	up-regulates													18391974	f			Forkhead proteins, and FoxO1 in particular, play a significant role in regulating whole body energy metabolism.	SIGNOR-253010	0.7
TFEB	protein	P19484	UNIPROT	IL1B	protein	P01584	UNIPROT	up-regulates quantity by expression	transcriptional regulation												32978159	f		lperfetto	Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14)	SIGNOR-276796	0.2
GRIK2	protein	Q13002	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264343	0.7
PIM1	protein	P11309	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation	Ser256	ESWLGARsSRPASPC	9606	BTO:0001061								31730483	t		miannu	Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 	SIGNOR-276768	0.629
ROCK1	protein	Q13464	UNIPROT	MYL12A	protein	P19105	UNIPROT	up-regulates activity	phosphorylation	Thr18	KKRPQRAtSNVFAMF	9606									12185584	t		miannu	Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies. 	SIGNOR-263074	0.555
sabcomeline	chemical	CHEBI:134846	ChEBI	CHRM2	protein	P08172	UNIPROT	up-regulates activity	chemical activation			10116									9399977	t		miannu	 SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes	SIGNOR-258674	0.8
POU4F1	protein	Q01851	UNIPROT	SCN9A	protein	Q15858	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000931								24493753	f		miannu	In neuroblastoma ND7 cells, a nuclear interaction between the developmentally regulated transcription factor Brn-3a and AR resulted in a complex which bound to multiple elements within the promoter region of SCN9A (Nav1.7) and upregulated channel expression.	SIGNOR-253465	0.303
CSNK2A2	protein	P19784	UNIPROT	SPIB	protein	Q01892	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser146	PALEVSDsESDEALV	9606	BTO:0000567								10618498	t		llicata	Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo	SIGNOR-251041	0.311
CSF1R	protein	P07333	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates				9606									24890514	t		apalma	Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-γ2 pathway	SIGNOR-255570	0.376
ESR1	protein	P03372	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000150;BTO:0000093;BTO:0000567								16144913	t		lperfetto	Our data show for the first time that eralpha binds to ppar response element and represses its transactivation	SIGNOR-140233	0.285
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PDE4B	protein	Q07343	UNIPROT	up-regulates activity	phosphorylation	Ser133	GHSQRREsFLYRSDS	9534	BTO:0001538								12023945	t	done	miannu	Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5.	SIGNOR-273940	0.2
GSK3B	protein	P49841	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation	Ser649	VPPSPSLsRHSSPHQ	-1									6772446	t			Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-.	SIGNOR-253007	0.673
SRC	protein	P12931	UNIPROT	BAIAP2L1	protein	Q9UHR4	UNIPROT	up-regulates activity	phosphorylation	Tyr156	GSRNALKyEHKEIEY	-1									21840312	t		miannu	Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility.	SIGNOR-263037	0.399
gamma-secretase	complex	SIGNOR-C98	SIGNOR	NOTCH3	protein	Q9UM47	UNIPROT	up-regulates activity	cleavage			9606									25610395	t		lperfetto	The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins.	SIGNOR-209726	0.558
belinostat	chemical	CHEBI:61076	ChEBI	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257958	0.8
PTPRJ	protein	Q12913	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr999	YASSNPEyLSASDVF	9606									1715686	t		gcesareni	Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta.	SIGNOR-21307	0.309
PTGER3	protein	P43115	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256716	0.427
POGZ	protein	Q7Z3K3	UNIPROT	AURKB	protein	Q96GD4	UNIPROT	up-regulates activity	binding			9606	BTO:0000932								20562864	t		miannu	 POGZ is required for the correct activation and dissociation of Aurora B kinase from chromosome arms during M phase. These results reveal POGZ as an essential protein that links HP1alpha dissociation with Aurora B kinase activation during mitosis.	SIGNOR-264497	0.329
CIB2	protein	O75838	UNIPROT	TMC1	protein	Q8TDI8	UNIPROT	up-regulates activity	binding			10090	BTO:0004744								28663585	t		miannu	 Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia.	SIGNOR-269664	0.341
MAT2B	protein	Q9NZL9	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0001938								30942439	f		miannu	MAT2B Promotes Proliferation and Inhibits Apoptosis in Osteosarcoma by Targeting Epidermal Growth Factor Receptor and Proliferating Cell Nuclear Antigen	SIGNOR-261243	0.7
CAMK2D	protein	Q13557	UNIPROT	VIM	protein	P08670	UNIPROT	unknown	phosphorylation	Ser83	GVRLLQDsVDFSLAD		BTO:0001444								16140754	t		llicata	Interestingly, viral DNA replication also resulted in the activation of calcium calmodulin-dependent protein kinase II (CaM kinase II) and phosphorylation of the N-terminal domain of vimentin on serine 82. Immunostaining showed that vimentin within the cage was phosphorylated on serine 82.	SIGNOR-250690	0.333
AURKA	protein	O14965	UNIPROT	TPX2	protein	Q9ULW0	UNIPROT	up-regulates activity	phosphorylation	Ser121	PAQPQRRsLRLSAQK	9606	BTO:0000567								26240182	t		lperfetto	Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells	SIGNOR-265089	0.963
regorafenib	chemical	CHEBI:68647	ChEBI	EPHA2	protein	P29317	UNIPROT	down-regulates activity	chemical inhibition			9606									24756792	t		miannu	In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically.	SIGNOR-259210	0.8
KPNA1	protein	P52294	UNIPROT	KPNB1	protein	Q14974	UNIPROT	up-regulates activity	binding			9534									17596301	t		lperfetto	Although ORF6 causes a relocalization of KPNA2 from the cytosol to the ER/Golgi membrane, KPNA2 is not directly involved in the translocation of the STAT1:STAT2:IRF9 (ISGF3) complex into the nucleus; rather, KPNA1 interacts with KPNB1 to initiate ISGF3's nuclear localization. 	SIGNOR-260273	0.855
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PGR	protein	P06401	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000150								10655479	t	inferred from 70% family members	gcesareni	Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation.	SIGNOR-270157	0.2
CDK5	protein	Q00535	UNIPROT	DLC1	protein	Q96QB1	UNIPROT	up-regulates activity	phosphorylation	Ser557	LEEFDVFsPKQDLVP	9606	BTO:0002181								25452387	t		miannu	The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. 	SIGNOR-276443	0.2
TLE1	protein	Q04724	UNIPROT	SIX3	protein	O95343	UNIPROT	up-regulates activity	binding			-1									12441302	t		lperfetto	Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. TLE1 over-expression induces an enlargement of the eye field and reinforcesSIX3/SIX6 capability of initiating retina formation	SIGNOR-234595	0.409
ZM 336372	chemical	CID:5730	PUBCHEM	RAF1	protein	P04049	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207911	0.8
MAP2K4	protein	P45985	UNIPROT	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0001950								21561061	t		Luana	Activation of JNK pathway components in 3b-expressing cells was assessed by analyzing levels of active phosphorylated formsof JNK and its upstream kinase MEK4. An enhanced phosphor-ylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP	SIGNOR-260759	0.74
HTR2A	protein	P28223	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257021	0.318
prazosin	chemical	CHEBI:8364	ChEBI	ADRA1D	protein	P25100	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258468	0.8
MAPK1	protein	P28482	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates	phosphorylation	Ser178	EENVSDGsPNAGSVE	9606									10831586	t		lperfetto	Indeed, p27kip1 was phosphorylated by p42 mapk (erk2) in vitrothese results suggest that ser(10) is the major site of phosphorylation of p27(kip1) and that phosphorylation at this site, like that at thr(187), contributes to regulation of p27(kip1) stability.	SIGNOR-77655	0.354
ECM	stimulus	SIGNOR-ST20	SIGNOR	A4/b1 integrin	complex	SIGNOR-C162	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259045	0.7
COX8A	protein	P10176	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267753	0.508
PI4K2B	protein	Q8TCG2	UNIPROT	1-phosphatidyl-1D-myo-inositol(1-)	smallmolecule	CHEBI:57880	ChEBI	down-regulates quantity	chemical modification			9606									10101268	t		miannu	The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 	SIGNOR-269099	0.8
CTNNBIP1	protein	Q9NSA3	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	binding			-1									12408824	t		llicata	The crystal structure of the beta-catenin/ICAT complex reveals the inhibitory mechanism of ICAT.	SIGNOR-238012	0.808
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	NMDA receptor_2D	complex	SIGNOR-C350	SIGNOR	up-regulates activity	chemical activation			9606									12871085	t		miannu	The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate	SIGNOR-264131	0.8
RXRB	protein	P28702	UNIPROT	PPARA	protein	Q07869	UNIPROT	up-regulates	binding			9606									11237216	t		gcesareni	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-105448	0.545
MYC	protein	P01106	UNIPROT	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	up-regulates quantity	transcriptional regulation			9606									17785433	t	inferred from family member		Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration.	SIGNOR-270270	0.465
5-[1-(2-hydroxyethyl)-3-pyridin-4-yl-4-pyrazolyl]-2,3-dihydroinden-1-one oxime	chemical	CHEBI:91434	ChEBI	BRAF	protein	P15056	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258112	0.8
PTK2	protein	Q05397	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates	binding			9606									9416004	t		gcesareni	Pi3-kinase has also been shown to bind fak in a cell cell adhesion-dipendent manner at the major autophosphorylation site y397. This association could live to activation of pi3-kinase and its downstream effectors.	SIGNOR-53979	0.535
MAPK3	protein	P27361	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Thr573	AENGLLMtPCYTANF	9534	BTO:0001538								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-219353	0.705
Phenelzine	chemical	CHEBI:8060	ChEBI	MAOB	protein	P27338	UNIPROT	down-regulates activity	chemical inhibition			-1									18426226	t		Luana	Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine.	SIGNOR-257778	0.8
PI3K	complex	SIGNOR-C156	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity				9606	BTO:0000938								9346240	f		lperfetto	Growth factors can promote cell survival by activating the phosphatidylinositide-3'-OH kinase and its downstream target, the serine-threonine kinase Akt	SIGNOR-252708	0.785
WNT11	protein	O96014	UNIPROT	MUSK	protein	O15146	UNIPROT	up-regulates	binding			9606									22309736	t		gcesareni	We provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase	SIGNOR-195966	0.47
POT1	protein	Q9NUX5	UNIPROT	RPA2	protein	P15927	UNIPROT	down-regulates activity	binding						SIGNOR-C306						18680434	t		lperfetto	The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA	SIGNOR-263324	0.416
A3/b1 integrin	complex	SIGNOR-C161	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257703	0.602
PRKCA	protein	P17252	UNIPROT	CYBA	protein	P13498	UNIPROT	up-regulates	phosphorylation	Thr147	ERPQIGGtIKQPPSN	-1									19948736	t		Manara	Phosphorylation of p22phox on threonine 147 enhances NADPH oxidase activity by promoting p47phox binding. | Threonine 147 of p22phox Is Phosphorylated by PKC-α and PKC-δ in Vitro	SIGNOR-260891	0.2
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1766	SPSYSPTsPSYSPTS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248778	0.441
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Thr564	LEEADNQtLDSYRNE	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276214	0.389
NFIX	protein	Q14938	UNIPROT	PKCtheta/Nfix	complex	SIGNOR-C121	SIGNOR	form complex	binding			10090	BTO:0000165								20178747	t		llicata	In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A.	SIGNOR-238016	0.2
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	GPER1	protein	Q99527	UNIPROT	up-regulates	chemical activation			9606									18262661	t		gcesareni	Recent studies have revealed the contribution of a novel estrogen receptor gpr30, which belongs to the family of seven-transmembrane g-protein-coupled receptors, to many of the rapid biological responses to estrogen.	SIGNOR-160778	0.8
OPTN	protein	Q96CV9	UNIPROT	NTF3	protein	P20783	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									22194658	f	same result in PC12 cell 	miannu	SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA.	SIGNOR-259879	0.251
CDK2	protein	P24941	UNIPROT	CDX2	protein	Q99626	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser283	RSVPEPLsPVSSLQA	9606									16027724	t		llicata	Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. 	SIGNOR-138825	0.489
HOXB3	protein	P14651	UNIPROT	OTX2	protein	P32243	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000946								9556594	t		Luana	Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively	SIGNOR-261635	0.2
APBA2	protein	Q99767	UNIPROT	STXBP1	protein	P61764	UNIPROT	up-regulates activity	binding			10116		BTO:0000142							9395480	t		miannu	Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1.	SIGNOR-264037	0.689
PAK2	protein	Q13177	UNIPROT	RPS6	protein	P62753	UNIPROT	unknown	phosphorylation	Ser236	AKRRRLSsLRASTSK	-1									1985906	t		miannu	The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide.	SIGNOR-250232	0.313
OSM	protein	P13725	UNIPROT	LIFR	protein	P42702	UNIPROT	up-regulates	binding			9606	BTO:0000801;BTO:0001271								1536831	t		gcesareni	Oncostatin m binds the high-affinity leukemia inhibitory factor receptor	SIGNOR-19873	0.715
MACF1	protein	Q9UPN3	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates quantity by destabilization				9606									16815997	f		gcesareni	In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes.	SIGNOR-147448	0.414
GATA1	protein	P15976	UNIPROT	AGGF1	protein	Q8N302	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19556247	f	 	miannu	 Overexpression of GATA1 increased expression of AGGF1. Knockdown of GATA1 expression by siRNA reduced expression of AGGF1, and resulted in endothelial cell apoptosis and inhibition of endothelial capillary vessel formation and cell migration, which was rescued by purified recombinant human AGGF1 protein.	SIGNOR-254188	0.382
RORA	protein	P35398	UNIPROT	PCP2	protein	Q8IVA1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001011								19381306	t		miannu	RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. 	SIGNOR-266849	0.2
LPAR6	protein	P43657	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256725	0.2
PPM1D	protein	O15297	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	down-regulates activity	dephosphorylation	Ser386	HQLFRGFsFVAITSD	10090									15206906	t			RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity	SIGNOR-248322	0.369
Ibutamoren	chemical	CID:178024	PUBCHEM	GHSR	protein	Q92847	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257497	0.8
GSC	protein	P56915	UNIPROT	EVX1	protein	P49640	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086								22178155	f	 	miannu	 We found that EVX1 repressed GSC expression and promoted formation of posterior streak-like progeny in response to BMP4, and conversely that GSC repressed EVX1 expression and was required for development of anterior streak-like progeny in response to activin. 	SIGNOR-254140	0.256
PCK2	protein	Q16822	UNIPROT	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	up-regulates quantity	chemical modification			9606									24632615	t		miannu	Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine.	SIGNOR-266557	0.8
DAB2IP	protein	Q5VWQ8	UNIPROT	PP2Ca_R1A_Bd 	complex	SIGNOR-C133	SIGNOR	up-regulates activity	binding			9606									20080667	t		miannu	DAB2IP interacts via its C2 domain with GSK3β, recruiting phosphatase PP2A for S9 de-phosphorylation and leading to GSK3β activation	SIGNOR-254753	0.2
DNA primase complex	complex	SIGNOR-C261	SIGNOR	DNA polymerase alpha:primase complex	complex	SIGNOR-C262	SIGNOR	form complex	binding			-1									24043831	t		lperfetto	At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation 	SIGNOR-261341	0.986
ITCH	protein	Q96J02	UNIPROT	SPART	protein	Q8N0X7	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								20719964	t		Sara	SPG20 Protein Spartin Is Recruited to Midbodies by ESCRT-III Protein Ist1 and Participates in Cytokinesis. Spartin colocalizes with Ist1 at the midbody, and depletion of Ist1 in cells significantly decreases the number of cells where spartin is present at midbodies. 	SIGNOR-261308	0.2
sorafenib	chemical	CHEBI:50924	ChEBI	BRAF	protein	P15056	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258283	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	EP300	protein	Q09472	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2039	GLGQVGIsPLKPGTV	9606	BTO:0000551								24530506	t		miannu	In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels. 	SIGNOR-276458	0.2
8-Hydroxy-7-(6-sulfo-naphthalen-2-ylazo)-quinoline-5-sulfonic acid	chemical	CID:92577	PUBCHEM	PTPN6	protein	P29350	UNIPROT	down-regulates activity	chemical inhibition			-1									19233143	t		lperfetto	In this study, we screened protein tyrosine phosphatases (PTPs) by in vitro phosphatase assays to identify PTPs that are inhibited by 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877), a potent inhibitor of SHP-1 and SHP-2 PTPs.	SIGNOR-261978	0.8
IFNA2	protein	P01563	UNIPROT	ISGF3 complex	complex	SIGNOR-C124	SIGNOR	up-regulates quantity by stabilization				9606									22171011	t	2	miannu	IFN-I (IFN-_ and IFN-_) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9.	SIGNOR-240684	0.47
CSNK2A1	protein	P68400	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Ser385	RYSDTTDsDPENEPF	9606									21779440	t		gcesareni	The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity	SIGNOR-89822	0.667
PRKACA	protein	P17612	UNIPROT	GABRR1	protein	P24046	UNIPROT	unknown	phosphorylation	Ser444	QRKSQRSsYVSMRID	-1									12175859	t		miannu	Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). These data, indicate that S422 and/or S423 are the major sites of PKA-mediated phosphorylation of the 1 GABA receptor.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation	SIGNOR-262750	0.289
DUOX2	protein	Q9NRD8	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	up-regulates quantity	chemical modification			9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264727	0.8
ERBB4	protein	Q15303	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			9606									16829981	t		gcesareni	Egfr and erbb4 had several docking sites for grb2, while erbb3 was characterized by six binding sites for pi3k. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength.	SIGNOR-147847	0.823
PLK3	protein	Q9H4B4	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Thr80	RMGSSEStDSGFCLD	9606									18167338	t		lperfetto	Here, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cdc25a to promote its proteolysis in early cell-cycle phases. Phosphorylation by gsk-3beta requires priming of cdc25a, and this can be catalyzed by polo-like kinase 3 (plk-3)	SIGNOR-160228	0.393
PRKACA	protein	P17612	UNIPROT	CACNG2	protein	Q9Y698	UNIPROT	down-regulates activity	phosphorylation	Thr321	NTANRRTtPV	9534									11805122	t		miannu	 phosphorylation of stargazin at T321 by PKA inhibits its interaction with PSD-95.	SIGNOR-250342	0.418
SLA	protein	Q13239	UNIPROT	EPHA2	protein	P29317	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000661						phosphorylation:Tyr594	TYVDPHTyEDPNQAV	24457997	t		lperfetto	These data are consistent with a model where SLAP induces Ephrin-independent EPHA2 degradation. | This activity is independent from CBL but requires SLAP SH3 interaction with the ubiquitination factor UBE4A and SLAP SH2 interaction with pTyr594-EPHA2.	SIGNOR-262964	0.424
ATM	protein	Q13315	UNIPROT	NOP53	protein	Q9NZM5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr289	PATEQAAtQESTFQE	9606	BTO:0000007								27829214	t		miannu	PICT-1 S233 and T289 were identified as the key phosphorylation sites in this pathway, as mutating both to alanine abolished UVB-induced increase of PICT-1 phosporylation. Inhibition of PIKKs or ATM (with wortmannin and KU55933, respectively) prevented the agglomeration and degradation of PICT-1, suggesting that ATM is a key regulator of PICT-1. 	SIGNOR-273507	0.2
GLUD2	protein	P49448	UNIPROT	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	down-regulates quantity	chemical modification			9913									11254391	t		miannu	Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate.	SIGNOR-268558	0.8
NHLH2	protein	Q02577	UNIPROT	HES1	protein	Q14469	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21573214	f		miannu	 Luciferase reporter assay demonstrated that the co-expression of LMO3 and HEN2 attenuates HES1 (a negative regulator for Mash1)-dependent reduction of luciferase activity driven by the Mash1 promoter. 	SIGNOR-254828	0.356
eplerenone	chemical	CHEBI:31547	ChEBI	NR3C2	protein	P08235	UNIPROT	down-regulates activity	chemical inhibition			-1									18038968	t		Luana	Indeed, eplerenone, 1, also acts as a mineralocorticoid receptor antagonist and is used to treat numerous patients for hypertension and congestive heart failure.	SIGNOR-257763	0.8
NCF1	protein	P14598	UNIPROT	NOX3	protein	Q9HBY0	UNIPROT	up-regulates activity	binding			9606									12672956	t		miannu	Stimulus-induced phosphorylation of p47phox causes a conformational change, by which both PX and SH3 domains become accessible to their membranous targets, phosphoinositides and p22phox, respectively. Cooperation of these two interactions, each being indispensable, enables p47phox to form a stable complex with cytochrome b558 (composed of the two subunit gp91phox and p22phox), leading to activation of the phagocyte NADPH oxidase.	SIGNOR-276624	0.612
SETD5	protein	Q9C0A6	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	methylation	Lys37	APATGGVkKPHRYRP	-1									31515109	t		miannu	SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription. 	SIGNOR-264620	0.2
TGFBR2	protein	P37173	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates activity	phosphorylation	Thr176	PFISEGTtLKDLIYD	9606									8576253	t		lperfetto	Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta	SIGNOR-246732	0.709
LBX1	protein	P52954	UNIPROT	ZEB1	protein	P37275	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002181								19651985	t		Luana	Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively 	SIGNOR-266054	0.333
MRPL30	protein	Q8TCC3	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262365	0.659
RPAP3	protein	Q9H6T3	UNIPROT	R2TP core co-chaperone	complex	SIGNOR-C515	SIGNOR	form complex	binding			9606									29662061	t		miannu	 Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90. 	SIGNOR-270927	0.89
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS3	protein	P23396	UNIPROT	unknown	phosphorylation			9606									15950189	t	inferred from 70% family members	llicata	Erk phosphorylates threonine 42 residue of ribosomal protein s3.	SIGNOR-270145	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	BRAF	protein	P15056	UNIPROT	down-regulates	phosphorylation	Thr440	EDRNRMKtLGRRDSS	9606									10869359	t		lperfetto	We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf	SIGNOR-244156	0.2
EGFR	protein	P00533	UNIPROT	KRT14	protein	P02533	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11875647	f	Regulation of expression	miannu	UVB increases keratin 5 and keratin 14 expression through direct activation of the EGF receptor in SVHK.	SIGNOR-251901	0.471
MFGE8	protein	Q08431	UNIPROT	IL1B	protein	P01584	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									23454767	f		Giorgia	We show that MFGE8 is an endogenous inhibitor of inflammasome-induced IL-1β production. MFGE8 inhibited necrotic cell–induced and ATP-dependent IL-1β production by macrophages through mediation of integrin β3 and P2X7 receptor interactions in primed cells. In conclusion, we demonstrated that MFGE8 regulates innate immunity through inhibition of inflammasome-induced IL-1β production.	SIGNOR-260649	0.268
vorinostat	chemical	CHEBI:45716	ChEBI	HDAC4	protein	P56524	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257922	0.8
CSNK2A1	protein	P68400	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates	phosphorylation	Ser249	LSPIDMEsQERIKAE	9606									1516134	t		lperfetto	Casein kinase ii is a negative regulator of c-jun dna binding and ap-1 activitywe show that two of these sites, thr-231 and ser-249, are phosphorylated by casein kinase ii (ckii).	SIGNOR-19603	0.574
ACSS2	protein	Q9NR19	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	down-regulates quantity	chemical modification												10843999	t		lperfetto	The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP.	SIGNOR-271828	0.8
MAP4K1	protein	Q92918	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates	phosphorylation			9606									8824585	t		gcesareni	Hpk1 binds and phosphorylates mekk1 directly,	SIGNOR-43996	0.431
PHF10	protein	Q8WUB8	UNIPROT	Neural progenitor-specific SWI/SNF	complex	SIGNOR-C477	SIGNOR	form complex	binding			9606									25195934	t		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270614	0.714
GSK3B	protein	P49841	UNIPROT	MYOCD	protein	Q8IZQ8	UNIPROT	down-regulates activity	phosphorylation	Ser451	NGFYHFGsTSSSPPI	9606	BTO:0000007								16141410	t			In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity	SIGNOR-251245	0.406
PARD6A	protein	Q9NPB6	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								22544755	t		lperfetto	The Par complex member Par-6, previously thought to inhibit aPKC, is a potent activator of aPKC in our assays. Par-6 and aPKC interact via PB1 domain heterodimerization, and this interaction activates aPKC by displacing the pseudosubstrate, although full activity requires the Par-6 CRIB-PDZ domains.	SIGNOR-227489	0.2
PTPN13	protein	Q12923	UNIPROT	STK25	protein	O00506	UNIPROT	down-regulates activity	dephosphorylation			9606									17657516	t			To investigate dephosphorylation of CCM3 by FAP-1, phosphorylated GST-CCM3 was incubated with cdFAP-1, and reactions were analyzed by autoradiography. Again, GST-STK25 phosphorylated GST-CCM3 and possessed autophosphorylation activity. cdFAP-1 of 0.005 U were sufficient to dephosphorylate GST-CCM3 as well as the kinase GST-STK25.|More recently, the Golgi matrix protein GM130 was shown to function as a scaffold protein for STK25 and to activate STK25 through stimulation of autophosphorylation.	SIGNOR-248711	0.431
NEK7	protein	Q8TDX7	UNIPROT	KIF14	protein	Q15058	UNIPROT	up-regulates activity	phosphorylation	Ser1219	KNLHSSHsSGLMDKS	9606	BTO:0000565								28630147	t		miannu	Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). 	SIGNOR-266419	0.38
perfluorooctane-1-sulfonic acid	chemical	CHEBI:39421	ChEBI	PPARG	protein	P37231	UNIPROT	up-regulates activity	chemical activation			10090	BTO:0000011								16731579	t		miannu	Taken together, these data show that of the NRs studied, PPARα is the most likely target of PFOA and PFOS, although PPARγ is also activated to some extent.	SIGNOR-268787	0.8
SMURF1	protein	Q9HCE7	UNIPROT	SMAD7	protein	O15105	UNIPROT	down-regulates activity	ubiquitination			9606									12519765	t		lperfetto	Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ubiquitin ligase, interacts with inhibitory Smad7 and induces translocation of Smad7 to the cytoplasm	SIGNOR-97064	0.877
FFAR3	protein	O14843	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256678	0.2
PRKACA	protein	P17612	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates activity	phosphorylation	Ser235	TTQLRLLsEDTDSQR	9606	BTO:0000007								33110360	t		miannu	We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence.	SIGNOR-277538	0.2
43S_pre_initiation_complex	complex	SIGNOR-C453	SIGNOR	48S_initiation_complex	complex	SIGNOR-C454	SIGNOR	form complex	binding			9606									35489072	t		lperfetto	In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 	SIGNOR-269167	0.2
PDPK2P	protein	Q6A1A2	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates	phosphorylation	Thr256	EHNSTTStFCGTPEY	9606									10191262	t		gcesareni	Our results are consistent with a model in which activation of sgk by igf-1 or hydrogen peroxide is initiated by a ptdins(3,4, 5)p3-dependent activation of pdk2, which phosphorylates ser422.	SIGNOR-66234	0.2
CSNK2A1	protein	P68400	UNIPROT	HMOX2	protein	P30519	UNIPROT	up-regulates activity	phosphorylation	Ser79	TALYFTYsALEEEME	10116	BTO:0003036								14527438	t		llicata	Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2. | CK2 activation is abolished by the S79A mutation but preserved in S179A and T248A mutations, indicating that S79 is the target of CK2-dependent activation of HO2	SIGNOR-250895	0.34
PRKAA1	protein	Q13131	UNIPROT	DDIT3	protein	P35638	UNIPROT	down-regulates activity	phosphorylation	Ser30	EDLQEVLsSDENGGT	10090									27650555	t		Luana	Here, we report that phosphorylation of CHOP at Ser30 by AMPKα1 triggers CHOP degradation resulting in reduced macrophage apoptosis and subsequent ameliorated plaque vulnerability in vivo.	SIGNOR-259864	0.268
SNRPB2	protein	P08579	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270654	0.692
CTDSP1	protein	Q9GZU7	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	dephosphorylation	Ser208	DAGSPNLsPNPMSPA	9606									17035229	t			SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248792	0.408
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation			-1									8929531	t		lperfetto	The rapid phosphorylation of bad following il-3 connects a proximal survival signal with the bcl-2 family, modulating this checkpoint for apoptosis.phosphorylatedBAD is bound to 14-3-3 within the cytosol, while only nonphosphorylated BAD is heterodimerized with membrane-bound BCL-XL.	SIGNOR-244497	0.2
MAPK1	protein	P28482	UNIPROT	KHDRBS1	protein	Q07666	UNIPROT	up-regulates	phosphorylation	Ser58	SRGGARAsPATQPPP	9606									12478298	t		lperfetto	In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites	SIGNOR-96410	0.652
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	GOLGB1	protein	Q14789	UNIPROT	down-regulates activity	cleavage	Asp1881	LSQISTKdGELKMLQ	9606									14970262	t		miannu	Giantin and syntaxin 5 are cleaved by caspase-3. Given that both giantin and syntaxin 5 are cleaved at an early stage during apoptosis, we anticipated that, at the very least, the delivery of ER-derived transport intermediates to the Golgi would be impaired in apoptotic cells.	SIGNOR-261235	0.256
CFL2	protein	Q9Y281	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	down-regulates quantity	binding			9606	BTO:0000132								27871158	t		lperfetto	Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers.	SIGNOR-261837	0.7
BRCA2	protein	P51587	UNIPROT	BRCC ubiquitin ligase complex	complex	SIGNOR-C295	SIGNOR	form complex	binding			9606	BTO:0000007								14636569	t		lperfetto	These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer	SIGNOR-263207	0.762
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser422	LSTPVVLsPGPQKP	9606									7889942	t		gcesareni	Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-252084	0.2
7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one	chemical	CID:56597938	PUBCHEM	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002181								22025698	t		Luana	Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. 	SIGNOR-258320	0.8
CASP6	protein	P55212	UNIPROT	LMNA	protein	P02545	UNIPROT	down-regulates	cleavage			9606									11058599	t		amattioni	Lamin a breakdown is largely mediated by caspase-6 during the execution phase of apoptosis.	SIGNOR-83611	0.648
CDC14B	protein	O60729	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser688	QFHSPVGsPLKSIQA	9606									20236090	t			Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3.	SIGNOR-248335	0.552
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	Glu-tRNA(Glu)	smallmolecule	CHEBI:29157	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270382	0.8
SIK2	protein	Q9H0K1	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Ser794	QHLRLSTsSGRLLYA	9606									12624099	t		gcesareni	These results suggest that highly expressed sik2 in insulin-stimulated adipocytes phosphorylates ser794_ of irs-1 and, as a result, might modulate the efficiency ofinsulinsignal transduction	SIGNOR-99055	0.586
CyclinD3/CDK6	complex	SIGNOR-C234	SIGNOR	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Ser276	VHPATPIsPGRASGM	9606									21059642	t	The effect has been demonstrated using Q01196-8	gcesareni	Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20).	SIGNOR-273029	0.562
CACNA1D	protein	Q01668	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									30849329	t		miannu	Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]).	SIGNOR-264326	0.8
PRKCE	protein	Q02156	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606									20179209	t		lperfetto	Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated	SIGNOR-163916	0.346
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	DUSP6	protein	Q16828	UNIPROT	down-regulates	phosphorylation			9606									15632084	t	inferred from 70% family members	amattioni	Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3	SIGNOR-270116	0.2
MYLK	protein	Q15746	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates	phosphorylation	Ser20	KRPQRATsNVFAMFD	9606									19851336	t		lperfetto	More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.	SIGNOR-188797	0.833
RUNX3	protein	Q13761	UNIPROT	FADD	protein	Q13158	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002384								17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255095	0.2
trimipramine	chemical	CHEBI:9738	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606									9537821	t		miannu	Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 	SIGNOR-258741	0.8
AKT1	protein	P31749	UNIPROT	ADRB2	protein	P07550	UNIPROT	down-regulates	phosphorylation	Ser345	ELLCLRRsSLKAYGN	9606									11809767	t		lperfetto	Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation.	SIGNOR-252469	0.362
PAK1	protein	Q13153	UNIPROT	ATG5	protein	Q9H1Y0	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr101	SALPWNItVHFKSFP										36528756	t		lperfetto	Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. |As PAK1-mediated phosphorylation at residue T101 protects ATG5 from ubiquitination-dependent degradation	SIGNOR-275835	0.2
CPSF3	protein	Q9UKF6	UNIPROT	mRNA_polyadenylation	phenotype	SIGNOR-PH200	SIGNOR	up-regulates				9606									30507380	f		lperfetto	Replication-dependent (RD) core histone mRNA produced during S-phase is the only known metazoan protein-coding mRNA presenting a 3' stem-loop instead of the otherwise universal polyA tail. A metallo β-lactamase (MBL) fold enzyme, cleavage and polyadenylation specificity factor 73 (CPSF73), is proposed to be the sole endonuclease responsible for 3' end processing of both mRNA classes.	SIGNOR-268337	0.7
PRKG1	protein	Q13976	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser78	PAYSRALsRQLSSGV	9606									19593530	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	lperfetto	Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization	SIGNOR-186784	0.278
PRKAA1	protein	Q13131	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser588	QTLSDSLsGSSLYST	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-249684	0.509
PDYN	protein	P01213	UNIPROT	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258414	0.663
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	BRCA1	protein	P38398	UNIPROT	down-regulates	phosphorylation	Ser632	LVVSRNLsPPNCTEL	9606	BTO:0000150								17334399	t		lperfetto	In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo.	SIGNOR-216984	0.579
MAP3K7	protein	O43318	UNIPROT	MAP3K4	protein	Q9Y6R4	UNIPROT	up-regulates activity				9606									9890973	f		lperfetto	These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway.	SIGNOR-63979	0.299
IFNA10	protein	P01566	UNIPROT	LPL	protein	P06858	UNIPROT	down-regulates activity				10090	BTO:0000944								1632769	f	Regulation	miannu	 Interleukin-1 and interferon-alpha and gamma induce lipolysis and decrease LPL activity but do not stimulate much PG production. These results demonstrate that cytokines enhance lipolysis and decrease LPL activity in 3T3 adipocytes by a PG independent mechanism.	SIGNOR-251859	0.2
PTK2	protein	Q05397	UNIPROT	ACTN1	protein	P12814	UNIPROT	down-regulates activity	phosphorylation	Tyr12	DSQQTNDyMQPEEDW	9534	BTO:0004055								11369769	t		lperfetto	The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase tyrosine 12 is the site of phosphorylation. The wild type recombinant protein was not phosphorylated in cells lacking the focal adhesion kinase (fak).Tyrosine phosphorylation reduced the amount of alpha-actinin that cosedimented with actin filaments.	SIGNOR-108329	0.555
PRKACA	protein	P17612	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									10464286	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation.	SIGNOR-70424	0.2
MAJIN	protein	Q3KP22	UNIPROT	TTM complex	complex	SIGNOR-C305	SIGNOR	form complex	binding			9606	BTO:0000007								30718482	t		lperfetto	Meiotic specific proteins TERB1, TERB2, and MAJIN form a stable complex that plays a critical role in regulating the recruitment of telomeres to the NE	SIGNOR-263303	0.2
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1882	SPTSPTYsPTTPKYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273102	0.745
EZH2	protein	Q15910	UNIPROT	SUZ12/EZH2	complex	SIGNOR-C77	SIGNOR	form complex	binding			9606									16712789	t		miannu	Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2.	SIGNOR-146758	0.96
ATF1	protein	P18846	UNIPROT	FTH1	protein	P02794	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17565989	f		miannu	Here we found that ATF1 (activating transcription factor 1) is a transcriptional repressor of the ferritin H ARE. 	SIGNOR-253741	0.2
FZD3	protein	Q9NPG1	UNIPROT	CXCL1	protein	P09341	UNIPROT	up-regulates	binding			9606									14977528	t		gcesareni	In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families.	SIGNOR-122886	0.2
MEN1	protein	O00255	UNIPROT	MLL-AF9	fusion protein	SIGNOR-FP5	SIGNOR	up-regulates activity	binding			10090	BTO:0004730								16239140	t		irozzo	We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...].	SIGNOR-255867	0.2
BHLHE40	protein	O14503	UNIPROT	BHLHE41	protein	Q9C0J9	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000944								14672706	f	 	lperfetto	Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression	SIGNOR-253716	0.516
MELK	protein	Q14680	UNIPROT	MELK	protein	Q14680	UNIPROT	up-regulates	phosphorylation	Ser431	ENVYTPKsAVKNEEY	9606									16216881	t		lperfetto	We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase.	SIGNOR-141010	0.2
SNRPD1	protein	P62314	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270660	0.734
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Thr417	KENSPCVtPVSTATH	9606	BTO:0001938								11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130.	SIGNOR-104699	0.843
ATM	protein	Q13315	UNIPROT	KHDC3L	protein	Q587J8	UNIPROT	up-regulates activity	phosphorylation	Thr156	VEVREAGtQRSVEVQ	9606	BTO:0001086								31609975	t		miannu	Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions. 	SIGNOR-273504	0.2
B4GALT1	protein	P15291	UNIPROT	lactose	smallmolecule	CHEBI:17716	ChEBI	up-regulates quantity	chemical modification			9606									16157350	t		miannu	Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 	SIGNOR-268469	0.8
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	MAPT	protein	P10636	UNIPROT	up-regulates	dephosphorylation	Thr529	TPGSRSRtPSLPTPP	9606		BTO:0000142							20308788	t	The effect has been demonstrated using P10636-8	lperfetto	Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro.	SIGNOR-164675	0.2
PLK1	protein	P53350	UNIPROT	KIF2B	protein	Q8N4N8	UNIPROT	up-regulates activity	phosphorylation	Ser204	HLDSSKIsVLEPPQE	9606									22535524	t		lperfetto	We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors.	SIGNOR-252050	0.647
NFE2L2	protein	Q16236	UNIPROT	PPAT	protein	Q06203	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22789539	f		miannu	We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). 	SIGNOR-267358	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	AQP5	protein	P55064	UNIPROT	up-regulates activity	phosphorylation	Ser156	STDSRRTsPVGSPAL	9606	BTO:0000007								26569106	t		lperfetto	 AQP5 can be directly phosphorylated by PKA at Ser 156 |Our data hint at a mechanism whereby phosphorylation of Ser 156 in AQP5 increases its membrane localization, thereby enhancing cancer cell proliferation.	SIGNOR-272087	0.2
NR1D1	protein	P20393	UNIPROT	NPAS2	protein	Q99743	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								20817722	t		miannu	In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.	SIGNOR-267981	0.617
IL4	protein	P05112	UNIPROT	Myoblast_fusion	phenotype	SIGNOR-PH98	SIGNOR	up-regulates				10090									12757709	f		miannu	These data demonstrate that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4, leading to muscle growth	SIGNOR-255896	0.7
FES	protein	P07332	UNIPROT	BCR	protein	P11274	UNIPROT	down-regulates activity	phosphorylation	Tyr246	SCGVDGDyEDAELNP	9606	BTO:0000007								8955135	t			In the present study, we demonstrate that BCR Tyr-246 and at least one of the closely spaced tyrosine residues, Tyr-279, Tyr-283, and Tyr-289 (3Y cluster), are phosphorylated by FES both in vitro and in 32Pi-labeled cells. Co-expression of BCR and FES in human 293T cells stimulated the tyrosine autophosphorylation of FES. By contrast, tyrosine phosphorylation of BCR by FES suppressed BCR serine/threonine kinase activity toward the 14-3-3 protein and BCR substrate, BAP-1. 	SIGNOR-251137	0.375
DDX21	protein	Q9NR30	UNIPROT	TICAM1	protein	Q8IUC6	UNIPROT	up-regulates activity	binding			10090									21703541	t		miannu	We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA.	SIGNOR-260192	0.27
GSK3B	protein	P49841	UNIPROT	FOXP3	protein	Q9BZS1	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser270	KMALTKAsSVASSDK	9606	BTO:0002181								27432879	t		miannu	Our previous study showed, by mass spectrometry analysis, that GSK-3β phosphorylates Foxp3 at Ser270 and Ser274	SIGNOR-277244	0.289
C5AR1	protein	P21730	UNIPROT	ITGAM	protein	P11215	UNIPROT	up-regulates quantity by expression													1847994	f		lperfetto	The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 	SIGNOR-263464	0.38
Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	methylation			9606									24987060	t		miannu	The presence of trimethylation of H3K27 (H3K27me3) at promoter regions is associated with gene repression. This modification is generated by the Polycomb repressive complex 2 (PRC2), composed of the SET domain-containing histone methyltransferase (HMT) EZH2 (enhancer of zeste homolog 2) or its functional homologue EZH1, and core accessory proteins (EED, SUZ12, and RbAp48) (Fig. 1A).	SIGNOR-265367	0.2
WRN	protein	Q14191	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates activity				9606									19652551	f			Our work provides the first demonstration of the major importance of WRN in repair of a specific class of DSB in human cells.	SIGNOR-258983	0.7
PTPN1	protein	P18031	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates	dephosphorylation	Tyr716	RPPSAELySNALPVG	9606									18567737	t		gcesareni	Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr.	SIGNOR-179072	0.679
RPS6KA3	protein	P51812	UNIPROT	YBX1	protein	P67809	UNIPROT	up-regulates	phosphorylation	Ser102	NPRKYLRsVGDGETV	9606	BTO:0000150								19036157	t		lperfetto	We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue.	SIGNOR-182165	0.555
CSNK2A1	protein	P68400	UNIPROT	SERINC3	protein	Q13530	UNIPROT	up-regulates activity	phosphorylation	Ser383	DTTTSGAsDEEDGQP	-1									30135209	t		miannu	The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro.	SIGNOR-273632	0.2
ADRA2B	protein	P18089	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257201	0.357
USP8	protein	P40818	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates quantity	destabilization			9606	BTO:0000567								16520378	t			Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation.	SIGNOR-266902	0.7
MAPK8	protein	P45983	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates	phosphorylation	Ser70	RDPVARTsPLQTPAA	9606									10567572	t		gcesareni	G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2..	SIGNOR-72125	0.564
NR3C1	protein	P04150	UNIPROT	G6PC1	protein	P35575	UNIPROT	up-regulates quantity	transcriptional regulation			9606									26652733	t			Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-256104	0.2
AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	LAMTOR	complex	SIGNOR-C26	SIGNOR	up-regulates				9606	BTO:0000007			SIGNOR-C3					20381137	f		lperfetto	The trimeric Ragulator complex, which comprises the p18, p14, and MP1 proteins, anchors the Rag GTPases to the lysosome, and, like the Rags, is necessary for mTORC1 activation by amino acids	SIGNOR-228152	0.7
PPP3CC	protein	P48454	UNIPROT	DNM2	protein	P50570	UNIPROT	unknown	dephosphorylation	Ser764	LQSASSHsPTPQRRP	10116									20496096	t			CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII).	SIGNOR-248508	0.253
DBP	protein	Q10586	UNIPROT	Aldolase	proteinfamily	SIGNOR-PF75	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								8383844	f	inferred from family member	miannu	 Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators	SIGNOR-270225	0.2
EEF1A1	protein	P68104	UNIPROT	Phe-tRNA(Phe)	smallmolecule	CHEBI:29153	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269520	0.8
TFE3	protein	P19532	UNIPROT	FLCN	protein	Q8NFG4	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	We found a TFE3-dependent increase in the amount of FLCN in ARPE-19 cells starved of nutrients for 24 hours (Fig. 3E). Accordingly, we found that overexpression of TFE3 in ARPE-19 cells resulted in an increase in FLCN protein abundance (Fig. 3F), as well as the mRNA abundance of FLCN and two FLCN-interacting proteins, FNIP1 and FNIP2 (Fig. 3G) (32).	SIGNOR-276819	0.458
FGFR3	protein	P22607	UNIPROT	CILK1	protein	Q9UPZ9	UNIPROT	down-regulates activity	phosphorylation	Tyr15	RQLGDGTyGSVLLGR	-1									30782830	t		miannu	FGF signaling partially abolished ICK's kinase activity, through FGFR-mediated ICK phosphorylation at conserved residue Tyr15, which interfered with optimal ATP binding.	SIGNOR-277436	0.2
SMO	protein	Q99835	UNIPROT	GATA3	protein	P23771	UNIPROT	up-regulates activity													17139329	t		fferrentino	That GATA is a downstream effector of the hedgehog pathway.	SIGNOR-253527	0.2
CDK5	protein	Q00535	UNIPROT	CRMP1	protein	Q14194	UNIPROT	up-regulates	phosphorylation	Thr509	PVYEVPAtPKYATPA	9606	BTO:0000938								18003833	t		lperfetto	These findings suggest that sema3a-induced spine development is regulated by phosphorylation of crmp1 by cdk5. Introduction of crmp1-wt, but not crmp1-t509a/s522a, a crmp1 mutant that cannot be phosphorylated by cdk5, rescued the defect in sema3a responsiveness.	SIGNOR-159318	0.608
WWP1	protein	Q9H0M0	UNIPROT	SMAD7	protein	O15105	UNIPROT	up-regulates activity	relocalization			9606									15221015	t		lperfetto	We found that WWP1 inhibited transcriptional activities induced by TGF-beta. Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor.	SIGNOR-126578	0.72
SH2B3	protein	Q9UQQ2	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22101255	f		miannu	Our results indicated that lnk/sh2b3 constrains expression of bcl-xl and participates in the regulation of hsc homeostasis by maintaining proper responses against various proapoptotic stimuli.	SIGNOR-177485	0.2
ASXL3	protein	Q9C0F0	UNIPROT	BRD4	protein	O60885	UNIPROT	up-regulates activity	binding			9606	BTO:0000189								32669118	t		miannu	We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers. 	SIGNOR-266762	0.2
GSK3A	protein	P49840	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	up-regulates activity	phosphorylation	Thr53	PPGSLSStPLSTPCS	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159373	0.2
SRC	protein	P12931	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Tyr74	HKPLEGKyEWQEVEK	9606									17254967	t		lperfetto	Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27	SIGNOR-152831	0.511
MASP1	protein	P48740	UNIPROT	C4A	protein	P0C0L4	UNIPROT	up-regulates activity	cleavage	Gly1446	TPLQLFEgRRNRRRR	-1									9087411	t		lperfetto	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263438	0.59
PRKCA	protein	P17252	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser303	RGAPPRRsSIRNAHS	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89150	0.538
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	ORC2	protein	Q13416	UNIPROT	up-regulates	phosphorylation	Thr226	SAPVGKEtPSKRMKR	9606									11931757	t		lperfetto	We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.	SIGNOR-217308	0.699
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2NL	protein	Q5JXB2	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271336	0.2
GSK3B	protein	P49841	UNIPROT	CIITA	protein	P33076	UNIPROT	up-regulates	phosphorylation	Ser373	VQARLERsSSKSLER	9606									17991736	t		gcesareni	Here we report that CIITA represses collagen transcription through a phosphorylation-dependent interaction between its proline/serine/threonine domain and co-repressor molecules such as histone deacetylase (HDAC2) and Sin3B. Mutation of a serine (S373A) in CIITA, within a glycogen synthase kinase 3 (GSK3) consensus site, decreases repression of collagen transcription by blocking interaction with Sin3B	SIGNOR-158959	0.352
LCK	protein	P06239	UNIPROT	VAV1	protein	P15498	UNIPROT	unknown	phosphorylation	Tyr160	VEEDEDLyDCVENEE	-1									10669745	t			Lck recognizes preferentially the tyrosine residue of Vav located at position 174 and, with significantly less affinity, those present at positions 142 and 160. It is now clear that this posttranslational modification will be involved in the activation of Vav, in the regulation of the strength of the signals emanating from this molecule, and also in the negative regulation of its function.	SIGNOR-251390	0.776
DOK1	protein	Q99704	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257670	0.32
STK39	protein	Q9UEW8	UNIPROT	CFTR	protein	P13569	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000007								21317537	t		miannu	SPAK phosphorylates the transporters to reduce their surface expression and thus their activity and consequently inhibits ductal secretion to stabilize the resting state. PP1 reverses the effect of SPAK. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression.	SIGNOR-263134	0.353
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1721	SPTSPSYsPTSPSYS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248787	0.441
YY1	protein	P25490	UNIPROT	ATP6V1A	protein	P38606	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									28592880	t		Giorgia	We investigated the relationship between transcription factor YY1 and ATP6V1A, and found that mRNA expression of YY1 had significant correlation with that of ATP6V1A. To validate that YY1 transcriptionally regulates ATP6V1A, we discovered that the ATP6V1A core promoter region contains three YY1 binding sites. Moreover, RNAi-mediated knockdown of YY1 in GC cells significantly decreased ATP6V1A mRNA and protein expression, while YY1 overexpression increased ATP6V1A expression level.	SIGNOR-260635	0.332
CAMK2G	protein	Q13555	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates activity	phosphorylation	Thr574	VDNIRSAtPEALAFV		BTO:0000932								12486117	t		llicata	Using mass spectrometry, we identified threonine 456 as a new phosphorylation site in choline acetyltransferase from A beta-(1-42)-treated cells and in purified recombinant ChAT phosphorylated in vitro by calcium/calmodulin-dependent protein kinase II (CaM kinase II). | This phosphorylation combination was observed in choline acetyltransferase from A beta-(1-42)-treated cells. Treatment of cells with A beta-(1-42) resulted in two phases of activation of choline acetyltransferase, the first within 30 min and associated with phosphorylation by protein kinase C and the second by 10 h and associated with phosphorylation by both CaM kinase II and protein kinase C.	SIGNOR-250693	0.311
MAPK10	protein	P53779	UNIPROT	BCL2L11	protein	O43521	UNIPROT	up-regulates activity	phosphorylation	Ser77	PGPFATRsPLFIFMR	10090									12818176	t		miannu	JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity. 	SIGNOR-250131	0.677
(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	ADRA2B	protein	P18089	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258898	0.8
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Thr548	KKVAVVRtPPKSPSS	9606									21215781	t	The effect has been demonstrated using P10636-8	lperfetto	However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules	SIGNOR-171022	0.754
MAP2K7	protein	O14733	UNIPROT	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	up-regulates activity	phosphorylation			9606									11062067	t		lperfetto	Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1).	SIGNOR-83725	0.686
SMARCB1	protein	Q12824	UNIPROT	Brain-specific SWI/SNF SMARCA2 variant	complex	SIGNOR-C485	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270747	0.83
bisindolylmaleimide i	chemical	CID:2396	PUBCHEM	PRKCD	protein	Q05655	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	CellSignaling	gcesareni		SIGNOR-190350	0.8
RPS6KB1	protein	P23443	UNIPROT	POLDIP3	protein	Q9BY77	UNIPROT	unknown	phosphorylation	Ser385	PRRVNSAsSSNPPAE	9606									15341740	t		llicata	Here we identify skar as a novel and specific binding partner and substrate of s6k1 but not s6k2. We find that serines 383 and 385 of human skar are insulin-stimulated and rapamycin-sensitive s6k1 phosphorylation sites.	SIGNOR-128499	0.758
MTHFD2L	protein	Q9H903	UNIPROT	(6R)-5,10-methenyltetrahydrofolate	smallmolecule	CHEBI:57455	ChEBI	up-regulates quantity	chemical modification			10116									21163947	t		lperfetto	Conversion of these 1-carbon units to formate requires several folate-interconverting enzymes in mitochondria. The enzyme(s) responsible for conversion of 5,10-methylene-tetrahydrofolate (CH(2)-THF) to 10-formyl-THF in adult mammalian mitochondria are currently unknown. A new mitochondrial CH(2)-THF dehydrogenase isozyme, encoded by the MTHFD2L gene, has now been identified. 	SIGNOR-268252	0.8
PRKAA1	protein	Q13131	UNIPROT	HNF4A	protein	P41235	UNIPROT	down-regulates activity	phosphorylation	Ser303	DPDAKGLsDPGKIKR	9606			SIGNOR-C15						12740371	t		lperfetto	Here we demonstrate that ampk directly phosphorylates hnf4 and represses its transcriptional activity. Ampk-mediated phosphorylation of hnf4 on serine 304 had a 2-fold effect	SIGNOR-101101	0.29
TNK2	protein	Q07912	UNIPROT	TNK2	protein	Q07912	UNIPROT	up-regulates activity	phosphorylation	Tyr284	LPQNDDHyVMQEHRK	-1									16472662	t			Purified ACK1 undergoes autophosphorylation at Tyr284, and autophosphorylation increases kinase activity	SIGNOR-251184	0.2
DCX DET1-COP1	complex	SIGNOR-C24	SIGNOR	CRTC2	protein	Q53ET0	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys629	DSSPGFSkEIAAALA	9606	BTO:0000007								17805301	t		miannu	 In the presence of relevant cofactors (DDB1, DET1), COP1 promoted the ubiquitination of wild-type but not COP1-interaction defective VP/AA TORC2 (Fig. 3e). COP1 also stimulated the ubiquitination of TORC2(K213R) but had no effect on TORC2(K628R), suggesting an important role for Lys 628 in this regard (Fig. 3e). We performed mass spectrometry studies to characterize residues in TORC2 that undergo COP1-mediated ubiquitination. This analysis revealed one major (Lys 628) and one minor (Lys 213) site on TORC2	SIGNOR-271665	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	MCRIP1	protein	C9JLW8	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000007								25728771	t	inferred from 70% family members	lperfetto	When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation	SIGNOR-270092	0.2
CSNK1A1	protein	P48729	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	up-regulates activity	phosphorylation	Ser349	SSKEVDPsTGELQSL	10090									37723657	t		miannu	Mechanistically, CSNK1A1 interacted with STING1 upon the CGAS-STING1 pathway activation and promoted STING1 autophagic degradation by enhancing the phosphorylation of SQSTM1/p62 at serine 351 (serine 349 in human), which was critical for SQSTM1-mediated STING1 autophagic degradation.	SIGNOR-273769	0.4
ACE2	protein	Q9BYF1	UNIPROT	AGT	protein	P01019	UNIPROT	up-regulates activity	cleavage	His42	RVYIHPFhLVIHNES	-1									11815627	t		miannu	The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus. 	SIGNOR-256317	0.75
PK	proteinfamily	SIGNOR-PF80	SIGNOR	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606									22306293	t		llicata	Pkm2 activates transcription of mek5 by phosphorylating stat3 at y705. pkm2 regulates mek5 transcription via activation of stat3	SIGNOR-268152	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation			9606									7889942	t	inferred from 70% family members	gcesareni	Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-270075	0.2
KATNAL2	protein	Q8IYT4	UNIPROT	TUBD1	protein	Q9UJT1	UNIPROT	down-regulates quantity by destabilization	binding			10090	BTO:0001363								29136647	t		miannu	Here we show that KATNAL2 is critical for numerous aspects of this developmental process, including the initiation of the axoneme from the basal body, suppression of the spermatid centriole duplication cycle, sperm nuclear sculpting via the manchette, the attachment of the acrosome to the nucleus and the tethering of elongated spermatids to Sertoli cells via the tubulobulbar complex and ultimately sperm release via spermiation. KATNAL2 does not sever microtubules composed of α- and β-tubulin but does interact with δ- and ε-tubulin	SIGNOR-267175	0.26
PPP1CA	protein	P62136	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	dephosphorylation	Thr495	TGITRKKtFKEVANA	9606	BTO:0001176								19036824	t			The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation	SIGNOR-248558	0.2
PRKACA	protein	P17612	UNIPROT	FXYD1	protein	O00168	UNIPROT	unknown	phosphorylation	Ser83	EEGTFRSsIRRLSTR	9606									21220422	t		llicata	We conclude that phosphorylation of plm increases its oligomerization into tetramers, decreases its binding to nka, and alters the structures of both the tetramer and nka regulatory complex.	SIGNOR-171184	0.429
YEATS4	protein	O95619	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269302	0.761
RALGAPA1	protein	Q6GYQ0	UNIPROT	RalGAP1	complex	SIGNOR-C468	SIGNOR	form complex	binding			10090	BTO:0000011								21148297	t		miannu	 Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. 	SIGNOR-269791	0.422
AURKB	protein	Q96GD4	UNIPROT	ZWINT	protein	O95229	UNIPROT	up-regulates activity	phosphorylation	Ser250	PTRPQEQsTGDTMGR	-1									21775627	t		lperfetto	Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores|During prometaphase, AurB phosphorylation of zwint-1 is required for recruitment of ZW10-, pT89 dynein-, and RZZ-dependent proteins to kinetochores. This is defective after AurB inhibition or after expression of the triple-A zwint-1 mutant. Triple-E mutant zwint-1 mimics phospho–zwint-1 in RZZ recruitment, even after AurB inhibition	SIGNOR-265009	0.637
EIF2B5	protein	Q13144	UNIPROT	EIF2S2	protein	P20042	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269128	0.873
valine	smallmolecule	CHEBI:27266	ChEBI	Val-tRNA(Val)	smallmolecule	CHEBI:29164	ChEBI	up-regulates quantity	precursor of			9606									30755602	t		miannu	Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 	SIGNOR-270532	0.8
SH3GLB2	protein	Q9NR46	UNIPROT	Endocytosis	phenotype	SIGNOR-PH123	SIGNOR	up-regulates				9606									25517094	f		miannu	Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. 	SIGNOR-263887	0.7
NF1	protein	P21359	UNIPROT	ADCY10	protein	Q96PN6	UNIPROT	up-regulates				9606									24431436	f		miannu	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-203921	0.276
CSNK2A1	protein	P68400	UNIPROT	CASQ2	protein	O14958	UNIPROT	unknown	phosphorylation	Ser385	DDDDDDNsDEEDNDD	-1									1985907	t		llicata	Both cardiac and skeletal muscle calsequestrins were phosphorylated by casein kinase II, but cardiac calsequestrin was phosphorylated to a higher stoichiometry and at least 50 times more rapidly. The site of rapid phosphorylation of cardiac calsequestrin was localized to the distinct COOH terminus, where a cluster of three closely spaced serine residues are found (S378DEESN-DDSDDDDE-COOH).	SIGNOR-250834	0.342
CXCL8	protein	P10145	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606									18231581	f		lperfetto	Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS	SIGNOR-260257	0.7
PRKACA	protein	P17612	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	phosphorylation	Ser615	SYKIRFNsISCSDPL	9606	BTO:0001853								24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251617	0.373
GSK3B	protein	P49841	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation	Ser645	RPASVPPsPSLSRHS										11427888	t			Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. 	SIGNOR-251238	0.673
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	BCL2	protein	P10415	UNIPROT	up-regulates	phosphorylation			9606									10669763	t	inferred from 70% family members	gcesareni	Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association.	SIGNOR-270064	0.2
PRKCD	protein	Q05655	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Ser323	MVGGKPGsFRVRASS	9606		BTO:0000671							15069075	t		gcesareni	Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of ser-318 in irs1 by a janus kinase 2, irs2, and pkc-dependent pathway. we observed that insulin stimulates phosphorylation of ser(318) in irs-1, which is mediated, at least partially, by pkc-zeta.	SIGNOR-123734	0.632
COLGALT1	protein	Q8NBJ5	UNIPROT	COL1A1	protein	P02452	UNIPROT	up-regulates activity	glycosylation			-1									19075007	t			Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261152	0.384
PAK4	protein	O96013	UNIPROT	ITGB5	protein	P18084	UNIPROT	up-regulates	phosphorylation	Ser762	AKFQSERsRARYEMA	9606									20507994	t		llicata	Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration.	SIGNOR-165706	0.463
NANOG	protein	Q9H9S0	UNIPROT	CGA	protein	P01215	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086;BTO:0005511								15983365	f		miannu	 Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 	SIGNOR-254623	0.2
MAPK14	protein	Q16539	UNIPROT	SLC9A1	protein	P19634	UNIPROT	up-regulates	phosphorylation	Ser729	ASPQSPEsVDLVNEE	9606									18701649	t		gcesareni	Such results suggest that during apoptosis, oxidative stress could activate p38 mapk, phosphorylating nhe1 at s726 and s729.	SIGNOR-180048	0.552
LATS1	protein	O95835	UNIPROT	PRPS2	protein	P11908	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr285	EDKMKHCtKIQVIDI	-1									34465890	t		miannu	 Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness.	SIGNOR-276506	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation			9606		BTO:0000176							14967450	t	inferred from 70% family members	lperfetto	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-270198	0.2
SCN8A	protein	Q9UQD0	UNIPROT	Action_potential 	phenotype	SIGNOR-PH82	SIGNOR	up-regulates				9606									26043074	f		miannu	The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons.	SIGNOR-253452	0.7
EIF2B1	protein	Q14232	UNIPROT	EIF2S1	protein	P05198	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269124	0.823
paliperidone	chemical	CHEBI:82978	ChEBI	HTR1B	protein	P28222	UNIPROT	down-regulates activity	chemical inhibition			10116		BTO:0001311							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258560	0.8
brimonidine	chemical	CHEBI:3175	ChEBI	ADRA2C	protein	P18825	UNIPROT	up-regulates activity	chemical activation			9606									9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258900	0.8
Quadazocine	chemical	CID:115077	PUBCHEM	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258418	0.8
CTNNB1	protein	P35222	UNIPROT	TCF7L2	protein	Q9NQB0	UNIPROT	up-regulates activity	binding			9606									20492721	t		FFerrentino	Hypophosphorylation of β-catenin and translocation into the nucleus leads to binding with members of the lymphoid-enhancer-binding factor/T-cell-specific transcription factor (LEF/TCF) family and activation of WNT target genesAs a member of LEF/TCF family, transcription factor 7 like 2 (Tcf7l2, formerly called Tcf4) is an important transcription factor triggering the downstream responsive genes of WNT signaling	SIGNOR-85757	0.897
LTB4R	protein	Q15722	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256691	0.252
TACR3	protein	P29371	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257267	0.428
ADCY10	protein	Q96PN6	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates quantity	chemical modification			9606									15385642	t		miannu	Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions.	SIGNOR-265008	0.8
MAFA	protein	Q8NHW3	UNIPROT	GLP1R	protein	P43220	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17149590	f		miannu	 the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA.	SIGNOR-254563	0.341
ANKRD26	protein	Q9UPS8	UNIPROT	PIDD1	protein	Q9HB75	UNIPROT	up-regulates activity	relocalization			9606	BTO:0004790								33350486	t		lperfetto	Here, we demonstrate that PIDD1 is recruited to mature centrosomes by the centriolar distal appendage protein ANKRD26.|We propose that PIDDosome activation can in both cases be promoted by an ANKRD26-dependent local increase in PIDD1 concentration close to the centrosome.	SIGNOR-266068	0.2
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Thr210	LSASTVLtAQESFSG	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276219	0.389
pazopanib hydrochloride	chemical	CHEBI:71217	ChEBI	SH2B3	protein	Q9UQQ2	UNIPROT	down-regulates activity	chemical inhibition			-1									17620431	t		miannu	Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. 	SIGNOR-259169	0.8
SP3	protein	Q02447	UNIPROT	PCYT1A	protein	P49585	UNIPROT	up-regulates quantity by expression	transcriptional regulation			7227	BTO:0001677								10744779	t		Luana	Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter	SIGNOR-266232	0.2
HTR3B	protein	O95264	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606		BTO:0000142							18761359	f		miannu	The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release. 	SIGNOR-264317	0.7
UBE3A	protein	Q05086	UNIPROT	MCM7	protein	P33993	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								9852095	t		miannu	The characterization of this interaction in turn led to the discovery that Mcm7 is a substrate for both E6-AP-dependent and -independent ubiquitination and is specifically targeted for degradation by the 26 S proteasome.	SIGNOR-272543	0.41
GNG3	protein	P63215	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									17419683	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt	SIGNOR-252685	0.357
WNK1	protein	Q9H4A3	UNIPROT	SLC12A6	protein	Q9UHW9	UNIPROT	down-regulates	phosphorylation	Thr1048	YQEKVHMtWTKDKYM	9606	BTO:0000938	BTO:0000142							19665974	t		gcesareni	We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases.	SIGNOR-187560	0.467
SMAD1	protein	Q15797	UNIPROT	GATA3	protein	P23771	UNIPROT	up-regulates quantity	transcriptional regulation			10090									22219353	t		Gianni	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268938	0.295
CSNK1E	protein	P49674	UNIPROT	APC	protein	P25054	UNIPROT	up-regulates activity	phosphorylation	Ser1279	SRCSSLSsLSSAEDE	9606	BTO:0000038								11487578	t		lperfetto	Apc can be phosphorylated by ck1epsilon at ser1279 and ser1392. Mutation of conserved serine residues in the beta-catenin regulatory motifs of APC interfered with both axin-dependent phosphorylation and phosphorylation by CKIepsilon and impaired the ability of APC to regulate beta-catenin.	SIGNOR-109660	0.596
PTPN6	protein	P29350	UNIPROT	JAK3	protein	P52333	UNIPROT	up-regulates	dephosphorylation			9606									11021818	t		gcesareni	The expression of shp-1 protein was associated with dephosphorylation of the jak3 kinase.	SIGNOR-82764	0.675
PHF2	protein	O75151	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									21532585	t		miannu	PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark.	SIGNOR-264519	0.2
TLE4	protein	Q04727	UNIPROT	PAX2/TLE4	complex	SIGNOR-C152	SIGNOR	form complex	binding			9606									16631587	t		miannu	Several Pax proteins are able to interact with groucho (TLE) family members. Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1.	SIGNOR-256360	0.469
AIRE	protein	O43918	UNIPROT	ICA1	protein	Q05084	UNIPROT	down-regulates quantity by repression	transcriptional regulation												22447927	t		lperfetto	Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression.	SIGNOR-268973	0.371
RNF183	protein	Q96D59	UNIPROT	ATP1B1	protein	P05026	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								31732153	t		miannu	RNF183 promotes the degradation of Na, K-ATPas.  We confirmed that RNF183 interacted with both α1 and β1 subunits; however, we found that RNF183 ubiquitinated only the β1 subunit, not the α1 subunit. 	SIGNOR-272218	0.2
MARCHF5	protein	Q9NX47	UNIPROT	SOD1	protein	P00441	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9534	BTO:0004055								19741096	t		lperfetto	Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SOD1 and attenuates mutant SOD1-induced reactive oxygen species generation	SIGNOR-272982	0.2
RASGEF1B	protein	Q0VAM2	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates	binding			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183832	0.385
RIN1	protein	Q13671	UNIPROT	ABL2	protein	P42684	UNIPROT	up-regulates	phosphorylation			9606		BTO:0000149							15886098	t	CrkL forms a constitutive complex with Abl, thus explaining the strong preference of Bcr-Abl for CrkL.	gcesareni	Rin1 binds to the abl sh3 and sh2 domains, and these inetractions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl	SIGNOR-136961	0.603
WDR62	protein	O43379	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								26297806	t		lperfetto	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.	SIGNOR-271726	0.247
BCORL1	protein	Q5H9F3	UNIPROT	CTBP1	protein	Q13363	UNIPROT	up-regulates activity	binding			9606	BTO:0002181								17379597	t		irozzo	BCoR-L1 also interacts with the CtBP corepressor through a CtBP-interacting motif in its amino terminus. Furthermore, BCoR-L1 is located on the E-cadherin promoter, a known CtBP-regulated promoter, and represses the E-cadherin promoter activity in a reporter assay.	SIGNOR-259193	0.448
AVEN	protein	Q9NQS1	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates activity	binding			-1									18571408	t		miannu	These data suggest that Aven overexpression can activate ATM and that Aven phosphorylation in a positive feedback loop enforces Aven activity, making it a more potent ATM activator.	SIGNOR-262638	0.392
ARID5B	protein	Q14865	UNIPROT	MYB	protein	P10242	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									29326336	f		miannu	We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F).	SIGNOR-256160	0.2
sapitinib	chemical	CHEBI:132986	ChEBI	SHC3	protein	Q92529	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000551								20145185	t		gcesareni	In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation.	SIGNOR-163733	0.8
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1899	SPTYSPTsPVYTPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120056	0.781
ANKRD11	protein	Q6UB99	UNIPROT	CORO1B	protein	Q9BR76	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000142							29274743	t		miannu	Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons. 	SIGNOR-266737	0.2
MYOD1	protein	P15172	UNIPROT	MYOD/E12E47	complex	SIGNOR-C127	SIGNOR	form complex	binding			10090		BTO:0001103							18094043	t		lperfetto	MyoD omodimers or heterodimers of MyoD plus E12 or E47 serve as transcription factor complexes that bind to CANNTG consensus sites in the promoter regions of genes, performing major functions in specification and differentiation of skeletl muscle precursor cells.	SIGNOR-241548	0.798
Phenelzine	chemical	CHEBI:8060	ChEBI	SLC6A3	protein	Q01959	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9537821	t		miannu	At the human dopamine transporter, sertraline and nomifensine were the most potent with KD's of 25±2 and 56±3, respectively. Except for these two compounds, most antidepressants were not potent at the human dopamine transporter. 	SIGNOR-258745	0.8
LRRC4C	protein	Q9HCJ2	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								19467332	t		miannu	A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles	SIGNOR-264050	0.374
PRKCB	protein	P05771	UNIPROT	ORAI1	protein	Q96D31	UNIPROT	down-regulates	phosphorylation	Ser30	TTSGSRRsRRRSGDG	9606									20534587	t		llicata	We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30.	SIGNOR-166044	0.2
MAP3K13	protein	O43283	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates	phosphorylation			9606									11726277	t		gcesareni	Lzk directly phosphorylated and activated mkk7.	SIGNOR-112349	0.566
PRKACA	protein	P17612	UNIPROT	RARA	protein	P10276	UNIPROT	down-regulates activity	phosphorylation	Ser369	YVRKRRPsRPHMFPK	9606									20215566	t		miannu	 Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity. 	SIGNOR-276282	0.378
PFDN5	protein	Q99471	UNIPROT	Prefoldin co-chaperone	complex	SIGNOR-C513	SIGNOR	form complex	binding			9606									32699605	t		miannu	The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6)	SIGNOR-270934	0.964
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr32	QSRPRSCtWPLQRPE										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249645	0.2
MAP3K8	protein	P41279	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates	phosphorylation	Ser248	SVQSDIWsMGLSLVE	9606									8131746	t		gcesareni	Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf	SIGNOR-36457	0.556
romidepsin	chemical	CHEBI:61080	ChEBI	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257994	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	KRT18	protein	P05783	UNIPROT	unknown	phosphorylation	Ser53	ISVSRSTsFRGGMGS		BTO:0000944								7523419	t		llicata	Ser-52 in K18 is not glycosylated and matches consensus sequences for phosphorylation by CAM kinase, S6 kinase and protein kinase C, and all these kinases can phosphorylate K18 in vitro predominantly at that site. Expression of K18 ser-52-->ala mutant in mammalian cells showed minimal phosphorylation but no distinguishable difference in filament assembly when compared with wild-type K18. In contrast, the ser-52 mutation played a clear but nonexclusive role in filament reorganization,	SIGNOR-250633	0.289
FCER1A	protein	P12319	UNIPROT	FCER1	complex	SIGNOR-C200	SIGNOR	form complex	binding			9606	BTO:0000830								16470226	t		Alessandro Palma	FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling.	SIGNOR-254959	0.668
CSNK2A1	protein	P68400	UNIPROT	MS4A1	protein	P11836	UNIPROT	unknown	phosphorylation	Ser289	PPQDQESsPIENDSS	9606									7678037	t		llicata	These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase erine threonine phosphorylation and may stimulate CKII activity in B cells.	SIGNOR-250916	0.311
PPP1CB	protein	P62140	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	dephosphorylation	Ser15	PSVEPPLsQETFSDL	9606									16501611	t			Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.	SIGNOR-248572	0.29
FGF2	protein	P09038	UNIPROT	HBB	protein	P68871	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									8142649	f	Regulation	miannu	Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production.	SIGNOR-251795	0.2
GDNF	protein	P39905	UNIPROT	RET	protein	P07949	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000142							9182803	t		gcesareni	A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling	SIGNOR-49094	0.907
GSK3B	protein	P49841	UNIPROT	SPI1	protein	P17947	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser41	EYYPYLSsDGESHSD	9606	BTO:0002181								33188146	t		miannu	We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7.	SIGNOR-277541	0.2
DOCK8	protein	Q8NF50	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor												28028151	t		lperfetto	Recently, DOCK8 was identified as a guanine-nucleotide exchange factor (GEF) for Cdc42 activation and has been associated with human mental retardation. 	SIGNOR-268412	0.756
PRKCA	protein	P17252	UNIPROT	GRIA2	protein	P42262	UNIPROT	unknown	phosphorylation	Ser717	GVARVRKsKGKYAYL	-1									8848293	t		lperfetto	Only two peptides containing Ser-662 and Ser-696 were found to be efficiently phosphorylated by protein kinase C (PKC). The peptide including Ser-696 was also phosphorylated by protein kinase G (PKG).	SIGNOR-248955	0.698
CYP11B2	protein	P19099	UNIPROT	cortisol	smallmolecule	CHEBI:17650	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000050							9814482	t		lperfetto	Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol.	SIGNOR-268676	0.8
MAP3K7	protein	O43318	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates	phosphorylation	Ser155	FPLRKTVsEPNLKLR	9606									16980613	t		lperfetto	We further show that emk and c-tak1 phosphorylate class iia hdacs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function	SIGNOR-149579	0.2
ATM	protein	Q13315	UNIPROT	BTRC	protein	Q9Y297	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser158	EFVEHLIsQMCHYQH	9606	BTO:0000093								33676897	t		miannu	ATM phosphorylates and stabilizes β-TrCP1 upon DNA damage.	SIGNOR-277549	0.304
TGFB1	protein	P01137	UNIPROT	BGLAP	protein	P02818	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11331591	f		gcesareni	Tgf-beta inhibited the expression of the cbfa1 and_ osteocalcin_ genes.	SIGNOR-107248	0.38
FZD4	protein	Q9ULV1	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates activity	binding			9606									12958364	t		amattioni	Endocytosis of frizzled 4 (fz4) in human embryonic kidney 293 cells was dependent on added wnt5a protein and was accomplished by the multifunctional adaptor protein beta-arrestin 2 (betaarr2), which was recruited to fz4 by binding to phosphorylated dvl2.	SIGNOR-100274	0.741
ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	ADP(3-)	smallmolecule	CHEBI:456216	ChEBI	up-regulates quantity	precursor of			9606									10101268	t		miannu	The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 	SIGNOR-269098	0.8
RIPK1	protein	Q13546	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates activity	binding			9606									20404851	t		lperfetto	Collectively, TRIF forms a multiprotein signaling complex along with TRAF6, TRADD, Pellino-1 and RIP1 for the activation of TAK1, which in turn activates the NF-_B and MAPK pathways.	SIGNOR-216325	0.647
FLNA	protein	P21333	UNIPROT	KCND2	protein	Q9NZV8	UNIPROT	up-regulates activity	binding			10116		BTO:0000232							11102480	t		Luisa	Filamin may function as a scaffold protein in the postsynaptic density, mediating a direct link between Kv4.2 and the actin cytoskeleton, and that this interaction is essential for the generation of appropriate Kv4.2 current densities.	SIGNOR-269003	0.36
PRKCG	protein	P05129	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser464	LLKHVTQsSRKLIRA	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-129316	0.326
cabozantinib	chemical	CHEBI:72317	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000184								26536165	t		miannu	Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. 	SIGNOR-262242	0.8
ITGA6	protein	P23229	UNIPROT	A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253179	0.813
CSK	protein	P41240	UNIPROT	ITCH	protein	Q96J02	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000007								16888620	t		gcesareni	CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro.	SIGNOR-245327	0.2
CARS1	protein	P49589	UNIPROT	Cys-tRNA(Cys)	smallmolecule	CHEBI:29152	ChEBI	up-regulates quantity	chemical modification			9606									11347887	t		miannu	Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine.	SIGNOR-270474	0.8
MRTFB	protein	Q9ULH7	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001260							21673106	t		gcesareni	Similarly, the myocd-related transcription factor (mrtf) family of proteins, mrtf-a and mrtf-b, are also involved in the transcriptional regulation of contractile gene markers as coactivators of srf.	SIGNOR-174316	0.2
ZNF423	protein	Q2M1K9	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates activity				10090	BTO:0000011								20200519	f			Ectopic expression of Zfp423 in non-adipogenic NIH 3T3 fibroblasts robustly activates expression of Pparg in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA (shRNA)-mediated reduction of Zfp423 expression in 3T3-L1 cells blunts preadipocyte Pparg expression and diminishes the ability of these cells to differentiate.	SIGNOR-255928	0.7
POU5F1	protein	Q01860	UNIPROT	Pluripotency	phenotype	SIGNOR-PH43	SIGNOR	up-regulates				9606	BTO:0001086								25126380	f		flangone	Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency. 	SIGNOR-242067	0.7
SMURF2	protein	Q9HAU4	UNIPROT	TGFBR2	protein	P37173	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0001538								11163210	t		miannu	Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways. 	SIGNOR-272939	0.577
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	PRC1	protein	O43663	UNIPROT	unknown	phosphorylation	Thr481	RRGLAPNtPGKARKL										9885575	t		llicata	We have shown that PRC1 is a good in vitro substrate for several CDKs, and that it is also phosphorylated in a cell cycle–dependent manner in vivo at Thr-481 (major mitosis. and Thr-470 (minor site), which are the in vitro phosphorylation sites.	SIGNOR-250746	0.351
HES1	protein	Q14469	UNIPROT	E2F1	protein	Q01094	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19891787	f		gcesareni	We earlier identified e2f-1 as a crucial transcription factor directly inhibited by hes-1.	SIGNOR-189061	0.2
GPR183	protein	P32249	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256715	0.393
EEF1A1	protein	P68104	UNIPROT	Ser-tRNA(Ser)	smallmolecule	CHEBI:29162	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269515	0.8
OPALIN	protein	Q96PE5	UNIPROT	Myelination	phenotype	SIGNOR-PH206	SIGNOR	up-regulates													18490449	f		SimoneGraziosi	Opalin protein is a type 1 transmembrane sialylglycoprotein and an oligodendrocyte-specific component of myelin membranes.	SIGNOR-269229	0.7
4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid	chemical	CHEBI:91366	ChEBI	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194518	0.8
MAPK1	protein	P28482	UNIPROT	PDE4D	protein	Q08499	UNIPROT	down-regulates	phosphorylation			9606									10828059	t	The effect has been demonstrated using Q08499-2	llicata	Long pde4d forms are inhibited by erk2 phosphorylation	SIGNOR-77574	0.36
CLCF1	protein	Q9UBD9	UNIPROT	CNTFR	protein	P26992	UNIPROT	up-regulates	binding			9606	BTO:0000938								10966616	t		gcesareni	Striking phenotypic differences between cntf- and cntfr-deficient mice suggest that cntfr serves as a receptor for a second, developmentally important ligand. We have identified this factor as a stable secreted complex of cardiotrophin-like cytokine (clc) and the soluble receptor cytokine-like factor-1 (clf).	SIGNOR-81376	0.691
RUVBL1	protein	Q9Y265	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270855	0.707
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	KLHL3	protein	Q9UH77	UNIPROT	up-regulates activity	phosphorylation	Ser433	PMNTRRSsVGVGVVE	-1									26435498	t	done	miannu	Consistent with the fact that S433 is a component of Akt and PKA phosphorylation motifs, in vitro kinase assay demonstrated that Akt and PKA can phosphorylate KLHL3 at S433, that was previously reported to be phosphorylated by PKC. 	SIGNOR-273825	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	DLC1	protein	Q96QB1	UNIPROT	unknown	phosphorylation	Ser766	VTRTRSLsACNKRVG	10116	BTO:0000443								16338927	t		gcesareni	We have demonstrated that Ser-322 is phosphorylated upon insulin stimulation of intact cells and that this site is directly phosphorylated in vitro by PKB and ribosomal S6 kinase, members of the AGC (protein kinases A, G, and C) family of insulin-stimulated protein kinases	SIGNOR-247997	0.2
17alpha-hydroxypregnenolone	smallmolecule	CHEBI:28750	ChEBI	17alpha-hydroxyprogesterone	smallmolecule	CHEBI:17252	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000050							2139411	t		lperfetto	The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione.	SIGNOR-268639	0.8
TTBK1	protein	Q5TCY1	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser515	SGDRSGYsSPGSPGT	9606	BTO:0000938								16923168	t	The effect has been demonstrated using P10636-8	lperfetto	Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation.	SIGNOR-148966	0.464
TNF	protein	P01375	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity				10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253491	0.2
FOS	protein	P01100	UNIPROT	AP1	complex	SIGNOR-C154	SIGNOR	form complex	binding			-1									3142692	t		irozzo	The c-Jun and c-fos proto-oncogenes encode proteins that form a complex which regulates transcription from promoters containing AP-1 activation elements. c-Jun has specific DNA binding activity, while c-Fos has homology to the putative DNA binding domain of c-Jun.	SIGNOR-256366	0.951
ISGF3 complex	complex	SIGNOR-C124	SIGNOR	EIF2AK2	protein	P19525	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27712625	f		miannu	The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum.	SIGNOR-260158	0.491
regorafenib	chemical	CHEBI:68647	ChEBI	RET	protein	P07949	UNIPROT	down-regulates activity	chemical inhibition			9606									26254357	t		miannu	A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF	SIGNOR-259181	0.8
quetiapine	chemical	CHEBI:8707	ChEBI	HTR2A	protein	P28223	UNIPROT	up-regulates activity	chemical activation			10090	BTO:0000331								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258532	0.8
farnesol	chemical	CHEBI:28600	ChEBI	UGT1A1	protein	P22309	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								21030469	t		Luana	Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation.	SIGNOR-258159	0.8
ACO2	protein	Q99798	UNIPROT	D-threo-isocitrate(3-)	smallmolecule	CHEBI:15562	ChEBI	up-regulates quantity	chemical modification			9606									24068518	t		miannu	Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained.	SIGNOR-266246	0.8
CDK4	protein	P11802	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Thr8	MSSILPFtPPIVKRL	9606									19114991	t		lpetrilli	In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity	SIGNOR-182983	0.748
PRKACA	protein	P17612	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser16	KELEKRAsGQAFELI	9606	BTO:0000782;BTO:0001271								8125092	t		gcesareni	Phosphorylation of either serine 16 or 63 is sufficient to inhibit stathmin in vitro. Phosphorylation at ser-63 reduces tubulin binding 10-fold and suppresses the mt polymerization inhibition activity.	SIGNOR-36370	0.313
NEK1	protein	Q96PY6	UNIPROT	VDAC1	protein	P21796	UNIPROT	down-regulates	phosphorylation	Ser193	DGTEFGGsIYQKVNK	9606									20230784	t		lperfetto	Nek1 phosphorylates vdac1 on ser193. Wild-type vdac1 assumes an open configuration, but closes and prevents cytochrome c efflux when phosphorylated by nek1. A vdac1-ser193ala mutant, which cannot be phosphorylated by nek1 under identical conditions, remains open and constitutively allows cytochrome c efflux.	SIGNOR-164222	0.436
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KA5	protein	O75582	UNIPROT	up-regulates	phosphorylation	Thr581	PDNQPLKtPCFTLHY	9606									18267068	t		lperfetto	Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth.	SIGNOR-249573	0.2
TPO	protein	P07202	UNIPROT	L-alanine zwitterion	smallmolecule	CHEBI:57972	ChEBI	up-regulates quantity	chemical modification			9606									28153798	t		scontino	The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines.	SIGNOR-267041	0.8
Glycine cleavage system	complex	SIGNOR-C437	SIGNOR	(6R)-5,10-methylenetetrahydrofolate(2-)	smallmolecule	CHEBI:15636	ChEBI	up-regulates quantity	chemical modification			9606									16051266	t		lperfetto	The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide.	SIGNOR-268239	0.8
BLVRA	protein	P53004	UNIPROT	biliverdin(2-)	smallmolecule	CHEBI:57991	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000759							7929092	t		lperfetto	This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. 	SIGNOR-275521	0.8
PCDH9	protein	Q9HC56	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-269035	0.2
GATA1	protein	P15976	UNIPROT	TAL1	protein	P17542	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									7632958	f		irozzo	Moreover, GATA-1 but not GATA-2 or GATA-3 was able to transactivate SCL promoter 1a in a T-cell environment. These results suggest that inactivity of SCL promoter 1a in T cells reflected the absence of GATA-1 rather than the presence of trans-dominant negative regulators.	SIGNOR-256047	0.777
ITK	protein	Q08881	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000782								20519342	t		gcesareni	In t cells, the predominant tec kinase is itk, which functions downstream of the t-cell receptor to regulate phospholipase c-gamma.	SIGNOR-165803	0.621
CSNK1D	protein	P48730	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	phosphorylation	Ser327	DPEMEEDsYDSFGEP	-1									9558331	t		llicata	In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites.	SIGNOR-250800	0.371
CDK2	protein	P24941	UNIPROT	CCP110	protein	O43303	UNIPROT	down-regulates activity	phosphorylation	Ser45	FHGVAILsPLLNIEK	-1									12361598	t		miannu	GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)	SIGNOR-265957	0.531
(S)-(-)-sulpiride	chemical	CHEBI:64119	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			10029									8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258733	0.8
SMAD3	protein	P84022	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								11331591	t		lperfetto	Tgf-beta inhibited the expression of the cbfa1 and osteocalcin genes, whose expression is controlled by cbfa1 in osteoblast-like cell lines. This inhibition was mediated by smad3, which interacts physically with cbfa1 and represses its transcriptional activity at the cbfa1-binding ose2 promoter sequence.	SIGNOR-235902	0.728
PLG	protein	P00747	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates activity	cleavage	Arg70	ESGLTEYrLVSINKS	-1									10978167	t		lperfetto	Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site.	SIGNOR-263572	0.62
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1626	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120176	0.321
MDM4	protein	O15151	UNIPROT	MDM4	protein	O15151	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1									12393902	t		miannu	Here we demonstrate that MdmX acts as a ubiquitin ligase in vitro, being capable of autoubiquitination, as well as mediating the ubiquitination of p53. 	SIGNOR-271390	0.2
cysteine	smallmolecule	CHEBI:15356	ChEBI	Cys-tRNA(Cys)	smallmolecule	CHEBI:29152	ChEBI	up-regulates quantity	precursor of			9606									11347887	t		miannu	Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine.	SIGNOR-270476	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	PDC	protein	P20941	UNIPROT	unknown	phosphorylation	Ser73	ERVSRKMsIQEYELI										11331285	t		llicata	In this study, we report that Pd was rapidly phosphorylated by Ca(2+)/calmodulin-dependent kinase II, resulting in 100-fold greater inhibition of Gbetagamma binding than cAMP-dependent protein kinase phosphorylation. Furthermore, Pd phosphorylation by Ca(2+)/calmodulin-dependent kinase II at Ser-54 and Ser-73 led to binding of the phosphoserine-binding protein 14-3-3.	SIGNOR-250637	0.311
MTCP1	protein	P56278	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271								10983986	t		miannu	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-81671	0.458
PRKCA	protein	P17252	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates activity	phosphorylation	Ser741	TKADKRRsVRIGSYI	9823	BTO:0004007								7539802	t		lperfetto	We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling.	SIGNOR-248898	0.51
TGFBR1	protein	P36897	UNIPROT	ZFYVE9	protein	O95405	UNIPROT	up-regulates activity	binding			9606									9865696	t		lperfetto	Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex	SIGNOR-62868	0.616
MAPK14	protein	Q16539	UNIPROT	EPS15	protein	P42566	UNIPROT	up-regulates	phosphorylation	Ser796	RSINKLDsPDPFKLN	9606									24269888	t		lperfetto	Tnf-_ induces phosphorylation of eps15 at ser-796eps15 is a substrate for p38_these results suggest an attractive model in which p38 phosphorylates both eps15 and egfr to trigger efficient endocytosis	SIGNOR-203315	0.351
MAPK1	protein	P28482	UNIPROT	RUNX1	protein	Q01196	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser249	DTRQIQPsPPWSYDQ	9606	BTO:0002181								16046550	t		miannu	We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 	SIGNOR-268218	0.2
GCSH	protein	P23434	UNIPROT	Glycine cleavage system	complex	SIGNOR-C437	SIGNOR	form complex	binding			9606									16051266	t		lperfetto	The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide.	SIGNOR-268241	0.728
SOCS6	protein	O14544	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates	ubiquitination			9606									21030588	t		miannu	Suppressor of cytokine signaling 6 (socs6) is a member of the socs family of e3 ubiquitin ligases that can interact with c-kit and suppress c-kit-dependent pathways. / we demonstrate that socs6 has ubiquitin ligase activity toward c-kit and regulates c-kit protein turnover in cells	SIGNOR-169145	0.665
MAPK3	protein	P27361	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser380	HQLFRGFsFVATGLM	9534	BTO:0001538								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252756	0.718
PRDM14	protein	Q9GZV8	UNIPROT	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001086								20953172	f		miannu	 We showed that PRDM14 regulates directly the expression of key pluripotency gene POU5F1 through its proximal enhancer.	SIGNOR-255067	0.609
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Thr522	SSPGSPGtPGSRSRT	9606		BTO:0000142							20308788	t	The effect has been demonstrated using P10636-8	lperfetto	Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in alzheimer's disease (ad). Gsk-3beta phosphorylated tau at many sites, with ser199, thr205, and ser396 being the most favorable sites in cells.	SIGNOR-164655	0.729
MAPK9	protein	P45984	UNIPROT	ELK3	protein	P41970	UNIPROT	down-regulates activity	phosphorylation												11042694	t		miannu	JNK binds to the J box in the middle of the protein, and binding is required for phosphorylation of the adjacent EXport motif. Both the binding and phosphorylation sites (the JEX element) are important for Net export.	SIGNOR-250138	0.328
GUCA2A	protein	Q02747	UNIPROT	GUCY2C	protein	P25092	UNIPROT	up-regulates	binding			9606									10845107	t		gcesareni	Guanylins activate two receptors, gc-c and ok-gc, which are expressed in intestine and/or kidney	SIGNOR-78096	0.763
NFE2L2	protein	Q16236	UNIPROT	MTHFD2	protein	P13995	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22789539	f		miannu	We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). 	SIGNOR-267359	0.2
TIGAR	protein	Q9NQ88	UNIPROT	beta-D-fructofuranose 2,6-bisphosphate(4-)	smallmolecule	CHEBI:58579	ChEBI	down-regulates quantity	chemical modification			9606									27803158	t		miannu	TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. TIGAR decreases glycolysis by functioning as a bisphosphatase that reduces levels of intracellular fructose-2,6-bisphosphate (Fru-2,6-P2) and 2,3-bisphosphoglycerate (7, 9), which are regulators of glycolysis.	SIGNOR-267364	0.8
ADAM17	protein	P78536	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	cleavage			10090									18344021	t		apalma	Two ADAMs have been implicated in the S2 cleavage of Notch. In Drosophila, ADAM10 ortholog Kuzbanian is the main protease mediating Notch processing [35–38]. In mouse cells in vitro, ADAM17, and not ADAM10, appears to be a protease responsible for Notch cleavage	SIGNOR-255370	0.729
MAPK1	protein	P28482	UNIPROT	NID1	protein	P14543	UNIPROT	unknown	phosphorylation	Ser333	YSVPSVLsPRRAATE	10090	BTO:0000944								22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262771	0.253
PAK4	protein	O96013	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	phosphorylation	Ser675	QDYKKRLsVELTSSL	9606									22173096	t		lperfetto	Pak4 interacts with and phosphorylates _-catenin on ser675, which promotes the tcf/lef transcriptional activity and stabilizes _-catenin through inhibition of its degradation.	SIGNOR-191557	0.291
LSM2	protein	Q9Y333	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270648	0.828
RPS6KB1	protein	P23443	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	down-regulates	phosphorylation	Thr491	PQQRNALtPTTIPDG	9606									18769144	t		lperfetto	Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively	SIGNOR-180784	0.2
DCC	protein	P43146	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity	binding			9606									29479476	t		miannu	The initial step of signaling inside the cell after netrin-1/DCC ligation is the binding of DCC cytoplasmic P3 motif to focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK). Here we report the crystal structure of P3/FAT complex. The helical P3 peptide interacts with a helix-swapped FAT dimer in a 2:2 ratio. Dimeric FAT binding is P3-specific and stabilized by a calcium ion. We propose that netrin-1/DCC engagement creates a small cluster of P3/FAT for FAK recruitment close to the cell membrane, which exerts a concerted effect with PIP2 for FAK signaling. Axon guidance assays confirm that this DCC/FAK complex is physiologically essential for netrin-1-induced chemoattraction. 	SIGNOR-268370	0.707
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1714	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273044	0.556
SEMA7A	protein	O75326	UNIPROT	PLXNC1	protein	O60486	UNIPROT	up-regulates	binding			9606									10520995	t		gcesareni	Plexin-c1 is a receptor for the gpi-anchored semaphorin sema7a. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro.	SIGNOR-71260	0.911
LYN	protein	P07948	UNIPROT	ACLY	protein	P53396	UNIPROT	up-regulates activity	phosphorylation	Tyr682	SRTTDGVyEGVAIGG	9606	BTO:0000007								32420483	t	done	miannu	 We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells.	SIGNOR-274103	0.2
SEC62	protein	Q99442	UNIPROT	Protein_translocation	phenotype	SIGNOR-PH176	SIGNOR	up-regulates													22375059	f		lperfetto	Silencing the SEC62 gene inhibits post-translational transport of small presecretory proteins into the human ER	SIGNOR-265280	0.7
RAF1	protein	P04049	UNIPROT	MAP2K2	protein	P36507	UNIPROT	up-regulates	phosphorylation	Ser222	VSGQLIDsMANSFVG	9606									8157000	t		gcesareni	To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1.	SIGNOR-262292	0.72
PRKACA	protein	P17612	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity	phosphorylation	Ser849	NMLNRRDsSASTISS	9606									10693759	t		lperfetto	Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3.	SIGNOR-75343	0.445
SHPK	protein	Q9UHJ6	UNIPROT	sedoheptulose 7-phosphate	smallmolecule	CHEBI:15721	ChEBI	up-regulates quantity	phosphorylation			9606									22682222	t		miannu	The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose	SIGNOR-267084	0.8
dothiepin	chemical	CHEBI:36798	ChEBI	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9537821	t		miannu	At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. 	SIGNOR-258878	0.8
ESR2	protein	Q92731	UNIPROT	SCN1A	protein	P35498	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938	BTO:0001264							22169964	f		miannu	17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice	SIGNOR-253472	0.2
TLN1	protein	Q9Y490	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257608	0.681
ATR	protein	Q13535	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Thr68	SSLETVStQELYSIP	9606	BTO:0000007								10973490	t		lperfetto	Atm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro.Substitution of thr68 with ala reduced the extent of phosphorylation and activation of chk2 in response to ir	SIGNOR-81442	0.855
CREB3	protein	O43889	UNIPROT	HERPUD1	protein	Q15011	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16940180	f		miannu	Luman/creb3 induces transcription of the endoplasmic reticulum (er) stress response protein herp through an er stress response element.	SIGNOR-149268	0.323
NR0B2	protein	Q15466	UNIPROT	NR5A2	protein	O00482	UNIPROT	down-regulates	binding			9606									12198243	t		gcesareni	Here we show that shp can interact with the liver x receptors lxralpha (nr1h3) and lxrbeta (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter	SIGNOR-92060	0.579
TLN1	protein	Q9Y490	UNIPROT	ITGB5	protein	P18084	UNIPROT	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257629	0.571
CSNK2A1	protein	P68400	UNIPROT	GTF2A1L	protein	Q9UNN4	UNIPROT	up-regulates activity	phosphorylation	Ser418	VEEDPLNsGDDVSEQ	-1									12107178	t		llicata	ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.	SIGNOR-250872	0.435
GLDN	protein	Q6ZMI3	UNIPROT	ANK3	protein	Q12955	UNIPROT	up-regulates quantity	relocalization			9606		BTO:0000227							19840192	t		miannu	Ankyrin-G is recruited to the nodes of Ranvier by gliomedin, which is produced by Schwann cells and accumulates in the perinodal extracellular matrix. As a ligand for neurofascin-186, gliomedin causes the nodal clustering of this cell adhesion molecule, which in turn recruits to the nodal plasma membrane an ankyrin-G protein network consisting of voltage-gated sodium or potassium channels (KCNQ2/3) and β4-spectrin. 	SIGNOR-266725	0.421
ITGB1BP1	protein	O14713	UNIPROT	Av/b8 integrin	complex	SIGNOR-C185	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257668	0.285
DRD2	protein	P14416	UNIPROT	GNB5	protein	O14775	UNIPROT	up-regulates activity	binding			9606									21303898	t		miannu	The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC	SIGNOR-264993	0.585
CAPN2	protein	P17655	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000590								25969760	t		lperfetto	Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase	SIGNOR-251613	0.289
ERBB2	protein	P04626	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates activity	phosphorylation	Tyr1139	TCSPQPEyVNQPDVR	-1									1706616	t			 Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2.	SIGNOR-251127	0.2
XAV939	chemical	CHEBI:62878	ChEBI	AXIN1	protein	O15169	UNIPROT	up-regulates				9606									19759537	f		gcesareni	Using a quantitative chemical proteomic approach, we discovered that xav939 stabilizes axin by inhibiting the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2	SIGNOR-188045	0.8
G1/S_transition	phenotype	SIGNOR-PH50	SIGNOR	DNA_replication	phenotype	SIGNOR-PH53	SIGNOR	up-regulates				9606									21524151	f		lperfetto	In addition to the successive phosphorylation of pRb by active Cyclin/Cdk complexes, other factors can also impact upon S-phase entry Subsequently, the initiation of replication requires the formation of a pre-initiation complex (pre-IC) that is initiated by phosphorylation of Mcm2-7 by CyclinE/Cdk2 and DDK (Dbf4- and Drf1-dependent kinase) and recruitment of Cdc45 onto the chromatin (Figure 1). This recruitment is thought to be the critical step for the activation of the Mcm2-7 helicase activity and replication initiation. Finally, unwinding of the chromatin enables DNA-polymerase _ to initiate DNA synthesis and DNA-polymerase _ to continue replication	SIGNOR-245489	0.7
CIT	protein	O14578	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates activity	phosphorylation	Thr19	KKRPQRAtSNVFAMF	-1									21457715	t		Giulio	Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation.	SIGNOR-260306	0.542
F2	protein	P00734	UNIPROT	Thrombin-Thrombomodulin	complex	SIGNOR-C316	SIGNOR	form complex	binding			9606		BTO:0000131							29880919	t		lperfetto	Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC).	SIGNOR-263550	0.903
PDPK1	protein	O15530	UNIPROT	TSSK3	protein	Q96PN8	UNIPROT	up-regulates activity	phosphorylation	Thr168	SHRELSQtFCGSTAY	-1									16336268	t		Manara	We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation.	SIGNOR-260786	0.264
neratinib	chemical	CHEBI:61397	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258255	0.8
CDK1	protein	P06493	UNIPROT	CDC25B	protein	P30305	UNIPROT	up-regulates	phosphorylation	Ser321	KCQRLFRsPSMPCSV	9606									20801879	t		gcesareni	Ser(321) is phosphorylated in mitosis by cdk1. The mitotic phosphorylation of ser(321) acts to maintain full activation of cdc25b by disrupting 14-3-3 binding to ser(323) and enhancing the dephosphorylation of ser(323) to block 14-3-3 binding to this site.	SIGNOR-167641	0.823
PRKDC	protein	P78527	UNIPROT	RPA2	protein	P15927	UNIPROT	unknown	phosphorylation	Ser33	GFGSPAPsQAEKKSR	-1									9139719	t		lperfetto	In this study, we show that efficient phosphorylation of HSSB-p34 by DNA-PK requires Ku as well as DNA. The DNA-PK phosphorylation sites in HSSB-p34 have been mapped at Thr-21 and Ser-33. Kinetic studies demonstrated that a phosphate residue is first incorporated at Thr-21 followed by the incorporation of a second phosphate residue at Ser-33.	SIGNOR-248971	0.598
MED28	protein	Q9H204	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266674	0.831
GSK3A	protein	P49840	UNIPROT	GRB14	protein	Q14449	UNIPROT	down-regulates activity	phosphorylation	Ser358	MHPYQGRsGCSSQSI	-1									28130417	t		lperfetto	Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3.	SIGNOR-264871	0.267
SYK	protein	P43405	UNIPROT	IKZF1	protein	Q13422	UNIPROT	up-regulates	phosphorylation	Ser364	GTPRSNHsAQDSAVE	9606	BTO:0001271								23071339	t		miannu	Syk phoshorylatesikarosat unique c-terminal serine phosphorylation sites s358 and s361, thereby augmenting its nuclear localization and sequence-specific dna binding activity. Mechanistically, we establish that syk-inducedikarosactivation is essential for its nuclear localization and optimal transcription factor function.	SIGNOR-199100	0.414
BRD7	protein	Q9NPI1	UNIPROT	SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270601	0.659
PHLPP2	protein	Q6ZVD8	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	dephosphorylation			9606	BTO:0001544								19261608	t			The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.	SIGNOR-248732	0.765
MAPK14	protein	Q16539	UNIPROT	FOXC1	protein	Q12948	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser272	SSLSSGSsPPGSLPS										31650548	t		lperfetto	P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation.	SIGNOR-275911	0.2
PRKAA1	protein	Q13131	UNIPROT	CPT1C	protein	Q8TCG5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21892142	f		gcesareni	In 2010, bungard et al., reported that ampk can target transcriptional regulation through phosphorylation of histone h2b on serine3681. Cells expressing a mutant h2b s36a blunted the induction of stress genes upregulated by ampk including p21 and cpt1c.	SIGNOR-176422	0.262
CHEK1	protein	O14757	UNIPROT	SYK	protein	P43405	UNIPROT	down-regulates	phosphorylation	Ser295	GIISRIKsYSFPKPG	9606									22585575	t		llicata	We found that chk1 phosphorylated the tumor suppressor spleen tyrosine kinase (l) (syk[l]) and identified the phosphorylation site at ser295. Furthermore, chk1 phosphorylation of syk(l) promoted its subsequent proteasomal degradation.	SIGNOR-197528	0.316
MYC	protein	P01106	UNIPROT	DKK1	protein	O94907	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17485441	f		gcesareni	C-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity	SIGNOR-245355	0.397
IKBKB	protein	O14920	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates	phosphorylation			9606									11158290	t		lperfetto	Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway.	SIGNOR-217403	0.865
THRA	protein	P10827	UNIPROT	RARB	protein	P10826	UNIPROT	up-regulates	binding			9606									15650024	t		gcesareni	Ee report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs	SIGNOR-133243	0.39
AML1-ETO	fusion protein	SIGNOR-FP1	SIGNOR	SPI1	protein	P17947	UNIPROT	down-regulates activity	binding			9606	BTO:0000318								18519037	t			We found that AML1-ETO is able to inhibit Sp1 transactivity. We also found that this inhibition of Sp1 transactivity by AML1-ETO is achieved by interaction between Sp1 and RUNT domain of AML1	SIGNOR-255671	0.2
MOV10	protein	Q9HCE1	UNIPROT	UPF1	protein	Q92900	UNIPROT	up-regulates activity	binding			9606									27016603	t		miannu	MOV10 has been shown to promote mRNA degradation by associating with UPF1, this activity requires the helicase activity of MOV10. 	SIGNOR-261139	0.535
FCAR	protein	P24071	UNIPROT	Phagocytosis	phenotype	SIGNOR-PH97	SIGNOR	up-regulates				9606									30766540	f		lperfetto	IgA-mediated immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst and cytokine release are mediated through FcalphaRI (CD89), an IgA-specific receptor that is expressed on monocytes, eosinophils, neutrophils and macrophages	SIGNOR-264861	0.7
GSK3B	protein	P49841	UNIPROT	NBR1	protein	Q14596	UNIPROT	down-regulates activity	phosphorylation	Thr586	HNTPVDVtPCMSPLP	-1									24879152	t		lperfetto	The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation|Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation. 	SIGNOR-261795	0.439
RFX1	protein	P22670	UNIPROT	HLA-DOB	protein	P13765	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								11823510	f	 	 	Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA. 	SIGNOR-254022	0.2
ILK	protein	Q13418	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA	-1									11313365	t		miannu	ILK Phosphorylates PKB/Akt on Serine 473 To become fully activated, PKB/Akt requires phosphorylation at two sites, threonine 308 and serine 473, in a phosphatidylinositol (PI) 3-kinase-dependent manner.	SIGNOR-250261	0.771
GMIP	protein	Q9P107	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260505	0.628
WDCP	protein	Q9H6R7	UNIPROT	MRE11	protein	P49959	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								30297404	t		miannu	PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11. 	SIGNOR-273733	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KA3	protein	P51812	UNIPROT	up-regulates	phosphorylation	Thr577	AENGLLMtPCYTANF	9606									10980595	t		lperfetto	We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway	SIGNOR-244696	0.2
CDK2	protein	P24941	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1497	EPGVERSsPSKCPSL	9606									10550055	t		gcesareni	However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci.	SIGNOR-72091	0.664
PPM1F	protein	P49593	UNIPROT	CAMK4	protein	Q16566	UNIPROT	down-regulates activity	dephosphorylation			9606									11726284	t		miannu	Calmodulin-dependent protein kinase phosphatase (CaMKP) dephosphorylates and concomitantly deactivates multifunctional Ca(2+)/calmodulin-dependent protein kinases , such as CaMKI, CaMKII, and CaMKIV.	SIGNOR-277157	0.355
CASP3	protein	P42574	UNIPROT	PSIP1	protein	O75475	UNIPROT	down-regulates	cleavage			9606	BTO:0001130								18708362	t		miannu	Ledgf/ p75 has a cooh-terminally truncated splice variant, p52 / during apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the nh2-terminal pwwp domain and failed to transactivate the hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of ledgf/p75	SIGNOR-180144	0.354
CDK1	protein	P06493	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	down-regulates activity	phosphorylation	Ser33	LRRSQRKsGSELPSI	-1									23901111	t		miannu	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. 	SIGNOR-276124	0.699
SIRT7	protein	Q9NRC8	UNIPROT	DDX21	protein	Q9NR30	UNIPROT	up-regulates activity	deacetylation	Lys600	HFKQSAEkLIEEKGA										28790157	t		lperfetto	Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21.	SIGNOR-275905	0.262
PLK1	protein	P53350	UNIPROT	BORA	protein	Q6PGQ7	UNIPROT	down-regulates	phosphorylation	Ser497	SSNIQMDsGYNTQNC	9606									18378770	t		gcesareni	Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp).	SIGNOR-178150	0.78
CTNNB1	protein	P35222	UNIPROT	CLDN2	protein	P57739	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0003569								14751232	f	 	lperfetto	Furthermore, claudin-2 promoter activity was found to be enhanced by the TCF-4/beta-catenin transcription complex.	SIGNOR-254114	0.312
PGR	protein	P06401	UNIPROT	KLK4	protein	Q9Y5K2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001248								19147544	f	 	miannu	 we have shown that K4.pPRE interacts directly with the PR to up-regulate KLK4 gene expression in T47D cells.	SIGNOR-254913	0.261
NEK10	protein	Q6ZWH5	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Tyr327	KKPLDGEyFTLQIRG	9606									32561851	t		miannu	 Here, we describe a function for NEK10 in the regulation of p53 transcriptional activity through tyrosine phosphorylation. NEK10 loss increases cellular proliferation by modulating the p53-dependent transcriptional output. NEK10 directly phosphorylates p53 on Y327, revealing NEK10's unexpected substrate specificity. A p53 mutant at this site (Y327F) acts as a hypomorph, causing an attenuated p53-mediated transcriptional response. 	SIGNOR-273881	0.259
DVL2	protein	O14641	UNIPROT	PLCB1	protein	Q9NQ66	UNIPROT	up-regulates activity				9606									19279717	t		areggio	Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin	SIGNOR-258979	0.271
PTPN2	protein	P17706	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates	dephosphorylation	Tyr996	EEAPEDLyKDFLTLE	9606	BTO:0000782								18840653	t		gcesareni	Vegfr2 contains several critical tyrosine residues that are autophosphorylated following activation. Our phosphorylation assays showed that tcptp was able to target specific tyrosines in vegfr2. The autophosphorylation sites tyr1054/1059 and tyr1214 were dephosphorylated by tcptp. Tyr996 was a tcptp target as well.	SIGNOR-181550	0.548
SRC	protein	P12931	UNIPROT	NOS2	protein	P35228	UNIPROT	up-regulates	phosphorylation	Tyr151	IEFVNQYyGSFKEAK	9606									19875457	t		llicata	We identify human inos residue tyr(1055) as a target for src-mediated phosphorylation. src kinase-mediated phosphorylation stabilizes inducible nitric-oxide synthase in normal cells and cancer cells.	SIGNOR-188974	0.668
GDF2	protein	Q9UK05	UNIPROT	ACVRL1	protein	P37023	UNIPROT	up-regulates	binding			9606									17068149	t		gcesareni	Finally, we demonstrate that bmp9 and bmp10 potently inhibit endothelial cell migration and growth, and stimulate endothelial expression of a panel of genes that was previously reported to be activated by the constitutively active form of alk1. Taken together, our results suggest that bmp9 and bmp10 are two specific alk1 ligands that may physiologically trigger the effects of alk1 on angiogenesis.	SIGNOR-150260	0.904
FLT3	protein	P36888	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity				10090									14981546	f			Immunoblot analysis indicated an increased level of Foxo3a phosphorylation on residue Thr32, as shown by the appearance of additional slower-migrating phospho-species immediately after induction of FLT3-ITD4 expression	SIGNOR-261523	0.315
NRF1	protein	Q16656	UNIPROT	BRK1	protein	Q8WUW1	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									23939472	f		miannu	We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons.	SIGNOR-261369	0.2
GCGR	protein	P47871	UNIPROT	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding			9606									12626323	t			Glucagon signals through its receptor on the cell surface (Fig.1). The binding of glucagon to the extracellular loops of the glucagon receptor results in conformational changes of the latter, leading to subsequent activation of the coupled G proteins. At least two classes of G proteins are known to be associated with and involved in the signal transduction of the glucagon receptor, namely Gsα and Gq. The activation of Gsα leads to activation of adenylate cyclase, increase in intracellular cAMP levels, and subsequent activation of protein kinase A (PKA).	SIGNOR-267715	0.49
48S_initiation_complex	complex	SIGNOR-C454	SIGNOR	MRNA_scanning	phenotype	SIGNOR-PH208	SIGNOR	up-regulates				9606									29401259	f		lperfetto	The 48S complex scans mRNA from 5′ to 3′ until it identifies an AUG start codon in an appropriate sequence context (Kozak consensus)	SIGNOR-269168	0.7
MC5R	protein	P33032	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257183	0.252
IPP complex	complex	SIGNOR-C380	SIGNOR	ACTB	protein	P60709	UNIPROT	up-regulates activity	relocalization												27590440	t		lperfetto	Apart from binding with integrins on the membrane, IPP complex can interact with the cytoskeleton as well as many signaling proteins inside the cell. Up to now, dozens of IPP complex-related proteins have been identified. One of these proteins is parvin that binds to F-actin, thus connecting ECM with cytoskeleton.17 In the following, we will discuss PINCH-interacting proteins and their roles.	SIGNOR-265768	0.356
TNF	protein	P01375	UNIPROT	TNFRSF1A	protein	P19438	UNIPROT	up-regulates activity	binding			9606									17151142	t		miannu	TNF-α has two distinct plasma membrane receptors known as p55 and p75. These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling	SIGNOR-253591	0.923
PTK2B	protein	Q14289	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates	phosphorylation	Tyr657	FGLGSRAyPHFCAFA	9606	BTO:0000007								19934023	t		gcesareni	We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657.	SIGNOR-161824	0.315
SEMA3B	protein	Q13214	UNIPROT	PLXNA4	protein	Q9HCM2	UNIPROT	up-regulates activity	binding			9606	BTO:0001176;BTO:0002036								25335892	t		miannu	We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin. 	SIGNOR-261810	0.649
CSNK2A2	protein	P19784	UNIPROT	MYCN	protein	P04198	UNIPROT	unknown	phosphorylation	Ser261	TSGEDTLsDSDDEDD	-1									1425701	t		llicata	Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263.	SIGNOR-251014	0.375
CSNK2A1	protein	P68400	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates activity	phosphorylation	Ser851	SLSSLNSsESDKDQD	10090	BTO:0000944								10671552	t		llicata	Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | Under these conditions, phosphorylation of the E-cadherin double mutant S853A/S855A was reduced by 25% as compared with wt E-cadherin. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion.	SIGNOR-250840	0.41
HSPA5	protein	P11021	UNIPROT	Chaperone-mediated protein folding	phenotype	SIGNOR-PH120	SIGNOR	up-regulates													28286085	f		lperfetto	The HSPA5 gene encodes the binding immunoglobulin protein (BiP), an Hsp70 family chaperone localized in the ER lumen.|When unfolded/misfolded proteins in the ER overwhelm the capacity of protein folding machinery, BiP can initiate the unfolded protein response (UPR), decrease unfolded/misfolded protein load, induce autophagy, and crosstalk with apoptosis machinery to assist in the cell survival decision. 	SIGNOR-265283	0.7
ABL1	protein	P00519	UNIPROT	RACK1	protein	P63244	UNIPROT	up-regulates	phosphorylation	Tyr52	LTRDETNyGIPQRAL	9606									19423701	t		lperfetto	Phosphorylation of rack1 on tyrosine 52 by c-abl is required for insulin-like growth factor i-mediated regulation of focal adhesion kinase.Tyrosine 52 is further shown to be phosphorylated by c-abl kinase, and the c-abl inhibitor sti571 disrupts fak interaction with rack1	SIGNOR-185649	0.2
ACE2	protein	Q9BYF1	UNIPROT	Receptor_mediated_ endocytosis	phenotype	SIGNOR-PH121	SIGNOR	up-regulates				9606									18554741	f		miannu	Endocytosis of the Receptor-Binding Domain of SARS-CoV Spike Protein Together With Virus Receptor ACE2. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells.	SIGNOR-260235	0.7
CSK	protein	P41240	UNIPROT	LYN	protein	P07948	UNIPROT	down-regulates	phosphorylation	Tyr508	YTATEGQyQQQP	9606	BTO:0000776								15626731	t		gcesareni	Lyn tyr507 kinase, csk, is recruited by pag, which targets lipid rafts by palmitoylation.Thus, our data suggest that il-6 treatment induces the translocation of cd45 to lipid rafts sequentially, followed by the association of cd45 with lyn and pag;dephosphorylation of lyn tyr507 and pag tyr314;lyn activation;and csk release from lipid rafts	SIGNOR-132912	0.517
EIF2B4	protein	Q9UI10	UNIPROT	EIF2S1	protein	P05198	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269127	0.864
ARHGDIA	protein	P52565	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	guanine nucleotide exchange factor			10116	BTO:0000526								20696765	t		miannu	Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays.RhoGDIα is required for Sema5A-induced Rac1 inactivation and inhibition of cell invasion in C6 glioma.	SIGNOR-268436	0.804
PIM1	protein	P11309	UNIPROT	FZR1	protein	Q9UM11	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000567								20663873	t		miannu	Pim-1 phosphorylates Cdh1 and impairs binding of this protein to another APC/C complex member, CDC27. These modifications inhibit Skp2 from degradation.Pim-1 Impairs Cdh1 and CDC27 Interaction and Phosphorylates Cdh1.	SIGNOR-259820	0.321
CDK1	protein	P06493	UNIPROT	PTPN2	protein	P17706	UNIPROT	unknown	phosphorylation	Ser304	LSPAFDHsPNKIMTE	9606									15030318	t		llicata	Our studies identify ser-304 as a major phosphorylation site in human tcptp, and the tc45 variant as a novel mitotic cdk substrate.	SIGNOR-123467	0.356
BAZ2B	protein	Q9UIF8	UNIPROT	H3C15	protein	Q71DI3	UNIPROT	down-regulates activity	binding			9606							acetylation:Lys15	ARKSTGGkAPRKQLA	31999386	t		miannu	The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation.	SIGNOR-266623	0.2
MAPK1	protein	P28482	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser87	AAAGPALsPVPPVVH	9606	BTO:0000567								10669763	t		lperfetto	Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation.	SIGNOR-74931	0.532
PHKA1	protein	P46020	UNIPROT	PHKG1	protein	Q16816	UNIPROT	down-regulates activity	binding			9606									10487978	t			Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.	SIGNOR-267405	0.68
BRK1	protein	Q8WUW1	UNIPROT	WAVE complex	complex	SIGNOR-C271	SIGNOR	form complex	binding			9606	BTO:0000567								15070726	t		lperfetto	Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex. 	SIGNOR-261875	0.842
AKT3	protein	Q9Y243	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation	Ser315	DFRSRTNsNASTVSG	9606									19188143	t		gcesareni	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-183648	0.697
Merimepodib	chemical	CID:153241	PUBCHEM	IMPDH2	protein	P12268	UNIPROT	down-regulates activity	chemical inhibition			9606									11288107	t		Federica	 These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation.	SIGNOR-261106	0.8
PKNOX1	protein	P55347	UNIPROT	SYP	protein	P08247	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20864515	f		miannu	 Prep1 overexpression in HepG2 liver cells upregulated SYP and SHP1 and inhibited insulin-induced IR and IRS1/2 phosphorylation and was accompanied by reduced glycogen content. 	SIGNOR-254923	0.2
UBE2E1	protein	P51965	UNIPROT	RNF167	protein	Q9H6Y7	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16314844	t		miannu	 Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop.	SIGNOR-271552	0.554
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	CIC	protein	Q96RK0	UNIPROT	down-regulates	phosphorylation	Ser173	PGKRRTQsLSALPKE	9606	BTO:0000848								21087211	t		gcesareni	Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)	SIGNOR-252778	0.2
PLK1	protein	P53350	UNIPROT	ERCC6L	protein	Q2NKX8	UNIPROT	up-regulates	relocalization			9606									17218258	t		lperfetto	Human pich was identified as an interaction partner and substrate of plk1. Our data indicate that plk1 prevents the association of pich with chromosome arms and restricts its localization to the kt/centromere region	SIGNOR-152136	0.875
AUTS2	protein	Q8WXX7	UNIPROT	ELMO2	protein	Q96JJ3	UNIPROT	up-regulates activity	binding			10090	BTO:0001909								25533347	t		miannu	Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development.  AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells.	SIGNOR-266819	0.273
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Thr325	TELEPLCtPVVTCTP	9606									12972619	t		lperfetto	In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity.	SIGNOR-251522	0.2
NKX2-5	protein	P52952	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21261500	f	 	 	Taken together, our results indicate that the expression of MEF2C in T-ALL cells is principally deregulated via activating leukemic transcription factors GFI1B or NKX2-5 and by escaping inhibitory developmental STAT5 signaling.	SIGNOR-253656	0.731
PRKCB	protein	P05771	UNIPROT	ITGB2	protein	P05107	UNIPROT	unknown	phosphorylation	Ser745	FEKEKLKsQWNNDNP	9606									11700305	t		lperfetto	Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. |	SIGNOR-249119	0.359
MAPK3	protein	P27361	UNIPROT	PTPN7	protein	P35236	UNIPROT	up-regulates activity	phosphorylation	Thr66	EPICSVNtPREVTLH	-1									16226275	t		lperfetto	First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|	SIGNOR-249476	0.68
IKBKB	protein	O14920	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser270	EFRPRSKsQSSSNCS	-1									12351658	t			IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.	SIGNOR-251289	0.644
MAPK1	protein	P28482	UNIPROT	PARP1	protein	P09874	UNIPROT	up-regulates	phosphorylation	Ser372	VAATPPPsTASAPAA	9606	BTO:0000938	BTO:0000142							16627622	t		esanto	Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation.	SIGNOR-146220	0.534
F2RL1	protein	P55085	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257232	0.341
GPC3	protein	P51654	UNIPROT	DPP4	protein	P27487	UNIPROT	down-regulates	binding			9606									17549790	t		miannu	The interaction occurred with both the glycosylated and unglycosylated forms of gpc3 and led to the inhibition of cd26 peptidase activity.	SIGNOR-155527	0.36
STX1A	protein	Q16623	UNIPROT	SNARE_complex 	complex	SIGNOR-C346	SIGNOR	form complex	binding			9606	BTO:0000938								30267828	t		miannu	The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells.	SIGNOR-263968	0.929
PPP2CA	protein	P67775	UNIPROT	CHEK1	protein	O14757	UNIPROT	down-regulates activity	dephosphorylation	Ser345	LVQGISFsQPTCPDH	9606									17015476	t			Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo.	SIGNOR-248615	0.474
SOX4	protein	Q06945	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0001545								24183681	f		miannu	These data demonstrate an HSC cell intrinsic role for Sox4 on proliferation induced by loss of C/EBPα.	SIGNOR-260133	0.7
PTTG1	protein	O95997	UNIPROT	Metastasis	phenotype	SIGNOR-PH107	SIGNOR	up-regulates activity				10090	BTO:0000093								22002306	f			Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling	SIGNOR-256535	0.7
CREB1	protein	P16220	UNIPROT	FST	protein	P19883	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								15130492	f		lperfetto	MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA	SIGNOR-251714	0.254
Verdinexor	chemical	CID:71492799	PUBCHEM	XPO1	protein	O14980	UNIPROT	down-regulates	chemical inhibition			9606									30541831	t		Simone Vumbaca	We show that KPT-335 inhibits XPO1-mediated nuclear export, leading to nuclear accumulation of RSV M protein and a reduction inRSV titers.	SIGNOR-261129	0.8
CDK1	protein	P06493	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Ser21	TPPSTALsPGKMSEA	9606			SIGNOR-C17						21059642	t	The effect has been demonstrated using Q01196-8	gcesareni	Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20).	SIGNOR-169318	0.347
PRKAA2	protein	P54646	UNIPROT	HIPK2	protein	Q9H2X6	UNIPROT	down-regulates activity	phosphorylation	Thr1116	AALGSTGtVAHLVAS										23871434	t	Phosphosite positions are derived from Figure S5	lperfetto	AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro	SIGNOR-275487	0.2
CDK1	protein	P06493	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	phosphorylation	Thr125	PEVLRPEtPRPVDIG	9606			SIGNOR-C17						17466630	t		gcesareni	Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle.	SIGNOR-154626	0.441
Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates activity	ubiquitination												18985065	t		lperfetto	Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding	SIGNOR-263265	0.763
PIK-75 Hydrochloride	chemical	CID:45265864	PUBCHEM	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206211	0.8
(S,S)-asenapine	chemical	CHEBI:71257	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258566	0.8
CSNK2A1	protein	P68400	UNIPROT	CACNA1S	protein	Q13698	UNIPROT	up-regulates activity	phosphorylation	Ser1575	PEICRTVsGDLAAEE	-1									20937870	t		miannu	 To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2. 	SIGNOR-263114	0.2
STXBP2	protein	Q15833	UNIPROT	STX11	protein	O75558	UNIPROT	up-regulates activity	binding			9606	BTO:0000782								28265073	t		lperfetto	Strikingly, addition of Munc18-2 substantially and selectively facilitates complete fusion mediated by lipid-anchored STX11 by promoting and stabilizing the assembly of SNARE complexes.	SIGNOR-261898	0.65
PIK3C3	protein	Q8NEB9	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates	binding			9606	BTO:0000567								20212113	t		lperfetto	Direct positive regulation of pten by the p85 subunit of phosphatidylinositol 3-kinase.Thus p85 regulates both p110-pi3k and pten-phosphatase enzymes through direct interaction	SIGNOR-164075	0.651
PIM1	protein	P11309	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation	Ser245	PSTSPRAsVTEESWL	9606	BTO:0001061								31730483	t		miannu	Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 	SIGNOR-276770	0.629
NOXA1	protein	Q86UR1	UNIPROT	NOX3	protein	Q9HBY0	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								20943948	t		lperfetto	Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation	SIGNOR-264711	0.618
CASP3	protein	P42574	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates	cleavage	Asp242	VRQKSEVdIVVSEDL	9606									11741536	t		gcesareni	Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis.	SIGNOR-112788	0.373
RAD51C	protein	O43502	UNIPROT	RAD51B/RAD51C	complex	SIGNOR-C65	SIGNOR	form complex	binding			9606									11751636	t		miannu	We show that two of them, rad51b and rad51c, are associated in a stable complex. Rad51b-rad51c complex has ssdna binding and ssdna-stimulated atpase activities.	SIGNOR-113388	0.645
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1920	SPTYSPTsPKYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269366	0.718
MAP3K20	protein	Q9NYL2	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates activity	phosphorylation			9606									11416147	t		gcesareni	We show here that members of the mixed-lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper kinase [DLK]) are expressed in neuronal cells and are likely to act between Rac1/Cdc42 and MKK4 and -7 in death signaling.	SIGNOR-243345	0.2
MAP3K7	protein	O43318	UNIPROT	TAB1	protein	Q15750	UNIPROT	up-regulates activity	phosphorylation	Ser456	HTQSSSSsSDGGLFR	9606	BTO:0000007								22216226	t		miannu	We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro. 	SIGNOR-276365	0.927
tRNA(Leu)	smallmolecule	CHEBI:29169	ChEBI	Leu-tRNA(Leu)	smallmolecule	CHEBI:16624	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270417	0.8
PECAM1	protein	P16284	UNIPROT	CD38	protein	P28907	UNIPROT	up-regulates activity	binding			9606									18626062	t		miannu	As a receptor, CD38 interacts with its ligand CD31 [15,16]. CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), is a 130 kDa type I transmembrane glycoprotein that consists of six extracellular immunoglobulin-like homology domains, a 19-residue transmembrane domain, and a 118-residue cytoplasmic tail	SIGNOR-264254	0.497
RANBP2	protein	P49792	UNIPROT	TNPO1	protein	Q92973	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								32161167	t		lperfetto	Nup358(806–1306), but not other regions, efficiently recruits importin β and transportin 1	SIGNOR-262111	0.467
ITGB1BP1	protein	O14713	UNIPROT	ITGB2	protein	P05107	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257649	0.318
resveratrol	chemical	CHEBI:27881	ChEBI	AHR	protein	P35869	UNIPROT	down-regulates activity	chemical inhibition			-1									9865727	t	 	 	Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor|These data demonstrate that resveratrol inhibits CYP1A1 expression in vitro, and that it does this by preventing the binding of the AHR to promoter sequences that regulate CYP1A1 transcription. 	SIGNOR-253640	0.8
HTR1B	protein	P28222	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257207	0.252
ARIH1	protein	Q9Y4X5	UNIPROT	EIF4E2	protein	O60573	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								14623119	t		miannu	Human homologue of Drosophila ariadne (HHARI) is a RING-IBR-RING domain protein identified through its ability to bind the human ubiquitin-conjugating enzyme, UbcH7. Thus, by promoting the ubiquitin-mediated degradation of 4EHP, HHARI may have a role in both protein degradation and protein translation.	SIGNOR-268848	0.665
MED31	protein	Q9Y3C7	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266668	0.7
PGD	protein	P52209	UNIPROT	NADP(3-)	smallmolecule	CHEBI:58349	ChEBI	down-regulates quantity	chemical modification			9606									34775382	t		miannu	6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule.	SIGNOR-268112	0.8
SPAST	protein	Q9UBP0	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates	cleavage			-1									15716377	f		Gianni	Using real-time imaging, we show that Spastin severs microtubules when added to permeabilized, cytosol-depleted cells stably expressing GFP-tubulin.	SIGNOR-269046	0.7
CDC14B	protein	O60729	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Thr698	KSIQATLtPSAMKSS	9606									20236090	t			Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3.	SIGNOR-248336	0.552
TRAF2	protein	Q12933	UNIPROT	BIRC3	protein	Q13489	UNIPROT	up-regulates	binding			9606									20385093	t		gcesareni	A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution.	SIGNOR-164785	0.888
SIN3B	protein	O75182	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	binding			9606	BTO:0001109								26181367	t		miannu	The present study shows that under bleomycin-induced stress, expression of Sin3B gets up-regulated and it gets recruited by p53 at its target promoters. Knockdown of Sin3B leads to impaired negative regulation of p53 target genes and thus exemplifies Sin3B as a critical player in down-regulation of p53 subset target genes.	SIGNOR-266776	0.511
BIRC3	protein	Q13489	UNIPROT	MAP3K14	protein	Q99558	UNIPROT	down-regulates	ubiquitination			9606									20682767	t		gcesareni	Ciap1/2 (cellular inhibitor of apoptosis 1 and 2) ubiquitinate nik for degradation.	SIGNOR-167298	0.635
HNRNPU	protein	Q00839	UNIPROT	NHLH2	protein	Q02577	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation												17174306	f		lperfetto	In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs.	SIGNOR-262286	0.3
D-106669	chemical	CID:16048654	PUBCHEM	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191256	0.8
PIK3CA	protein	P42336	UNIPROT	BTK	protein	Q06187	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000899								10201980	t		lperfetto	Activation of Btk occurs by transphosphorylation of tyrosine 551 in the catalytic domain, resulting in a dramatic increase in the catalytic activity of the kinase (11, 12, 13). This allows for autophosphorylation at tyrosine 223 in the SH3 domain (14). Both Lyn and Syk have been demonstrated to be involved in BCR-mediated Btk activation (11), but processes that drive colocalization of these kinases are ill-defined. Recently, it was suggested that phosphatidylinositol 3-kinase (PI3-K) is also involved in Btk activation	SIGNOR-249610	0.493
sorafenib tosylate	chemical	CHEBI:50928	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			-1									16757355	t		miannu	Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 	SIGNOR-259227	0.8
GPR35	protein	Q9HC97	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257112	0.2
CTSG	protein	P08311	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Phe59	GVTVETVfSVDEFSA	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263585	0.518
STK38	protein	Q15208	UNIPROT	RAB11FIP5	protein	Q9BXF6	UNIPROT	up-regulates activity	phosphorylation	Ser307	FTHKRTYsDEANQMR	10090		BTO:0000142							22445341	t		miannu	We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. 	SIGNOR-263035	0.2
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1882	SPTSPTYsPTTPKYS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120048	0.781
PTK6	protein	Q13882	UNIPROT	ARHGAP5	protein	Q13017	UNIPROT	up-regulates	phosphorylation	Tyr1109	KGYSDEIyVVPDDSQ	9606	BTO:0000150								18829532	t		lperfetto	Breast tumor kinase phosphorylates p190rhogap to regulate rho and ras and promote breast carcinoma growth, migration, and invasion. Brk phosphorylates p190 at the y(1105) residue both in vitro and in vivo, thereby promoting the association of p190 with p120rasgap (p120). As a consequence, brk stimulates p190 and attenuates p120 functions, leading to rhoa inactivation and ras activation, respectively.	SIGNOR-181452	0.2
NCK1	protein	P16333	UNIPROT	PAK1	protein	Q13153	UNIPROT	up-regulates activity	binding			10090	BTO:0002572								10026169	t		lperfetto	Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors.	SIGNOR-236512	0.697
CSNK2A1	protein	P68400	UNIPROT	DDHD1	protein	Q8NEL9	UNIPROT	down-regulates activity	phosphorylation	Ser711	NPAKEPTsVSENEGI	-1									11328814	t		miannu	Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity	SIGNOR-262977	0.2
KDM6A	protein	O15550	UNIPROT	HOXA9	protein	P31269	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24561908	t		miannu	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260025	0.33
naloxone	chemical	CHEBI:7459	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029									9262330	t		miannu	We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine.	SIGNOR-258661	0.8
GRK5	protein	P34947	UNIPROT	ADRB2	protein	P07550	UNIPROT	unknown	phosphorylation	Ser407	DSQGRNCsTNDSLL	-1									8662852	t			 we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). 	SIGNOR-251197	0.682
PRKACA	protein	P17612	UNIPROT	FRAT1	protein	Q92837	UNIPROT	down-regulates	phosphorylation	Ser188	RLQQRRGsQPETRTG	9606									16982607	t		lperfetto	Phosphorylation of ser188 by pka inhibited the ability of frat1 to activate beta-catenin-dependent transcription.	SIGNOR-149689	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser413	GLMQRSSsFPYTTKG	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-249678	0.397
N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide	chemical	CHEBI:63082	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3).	SIGNOR-257853	0.8
ANGPT1	protein	Q15389	UNIPROT	MYH2	protein	Q9UKX2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000222								26042050	f		lperfetto	Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein.	SIGNOR-241557	0.2
EIF2AK4	protein	Q9P2K8	UNIPROT	MARS1	protein	P56192	UNIPROT	down-regulates	phosphorylation	Ser662	NRAGMFVsKFFGGYV	9606									22106287	t		lperfetto	Here we demonstrate that aimp3 is released from mrs by uv irradiation-induced stress. Dissociation was induced by phosphorylation of mrs at ser662 by general control nonrepressed-2 (gcn2) following uv irradiation. Substitution of ser662 to asp (s662d) induced a conformational change in mrs and significantly reduced its interaction with aimp3. This mutant possessed significantly reduced mrs catalytic activity because of loss of trna(met) binding, resulting in down-regulation of global translation.	SIGNOR-177648	0.2
PRKCA	protein	P17252	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	unknown	phosphorylation	Ser473	PPSGTKKsKRGRGRP	9606									12529391	t		llicata	Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm.	SIGNOR-97279	0.2
GNAL	protein	P38405	UNIPROT	ADCY1	protein	Q08828	UNIPROT	up-regulates activity	binding			9606	BTO:0004032								21303898	t		miannu	D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum.	SIGNOR-264992	0.519
WNT1	protein	P04628	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131571	0.612
haloperidol	chemical	CHEBI:5613	ChEBI	HTR2B	protein	P41595	UNIPROT	down-regulates activity	chemical inhibition			10036	BTO:0000452								9459568	t		miannu	The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-	SIGNOR-258680	0.8
STK4	protein	Q13043	UNIPROT	MOB1A	protein	Q9H8S9	UNIPROT	up-regulates	phosphorylation	Thr12	FSSRSSKtFKPKKNI	9606									23431053	t		milica	Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity	SIGNOR-201306	0.896
PFKP	protein	Q01813	UNIPROT	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35.	SIGNOR-266473	0.8
TMLHE	protein	Q9NVH6	UNIPROT	3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine	smallmolecule	CHEBI:15786	ChEBI	up-regulates quantity	chemical modification			9606									11431483	t		miannu	Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. 	SIGNOR-269684	0.8
malonyl-CoA	smallmolecule	CHEBI:15531	ChEBI	CPT1A	protein	P50416	UNIPROT	down-regulates	binding			9606									17452323	t			Carnitine palmitoyltransferase 1 (CPT1) catalyzes the conversion of palmitoyl-CoA to palmitoylcarnitine in the presence of l-carnitine, thus facilitating the entry of fatty acids to mitochondria, in a process that is physiologically inhibited by malonyl-CoA	SIGNOR-267758	0.8
AGPAT5	protein	Q9NUQ2	UNIPROT	phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	up-regulates	chemical modification			9606									21173190	t		lperfetto	The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA). 	SIGNOR-267011	0.8
TREX complex	complex	SIGNOR-C444	SIGNOR	mRNA-nucleus_export	phenotype	SIGNOR-PH127	SIGNOR	up-regulates				9606									22928037	f		miannu	The conserved TREX complex, which contains UAP56, Aly, CIP29, and the multi-subunit THO complex, functions in mRNA export. 	SIGNOR-268514	0.7
MED20	protein	Q9H944	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266679	0.765
PAK2	protein	Q13177	UNIPROT	CASP7	protein	P55210	UNIPROT	down-regulates	phosphorylation	Thr173	FRGDRCKtLLEKPKL	9606	BTO:0000150								21555521	t		gcesareni	Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis.	SIGNOR-173663	0.357
PRKCA	protein	P17252	UNIPROT	PLCB3	protein	Q01970	UNIPROT	down-regulates	phosphorylation	Ser1105	LDRKRHNsISEAKMR	9606									9660757	t		gcesareni	These data establish that direct phosphorylation by pka of ser1105 in the putative g-box of plcbeta3 inhibits galphaq-stimulated plcbeta3 activity.	SIGNOR-58859	0.458
FOXO4	protein	P98177	UNIPROT	IDH1	protein	O75874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25648147	t		miannu	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260102	0.267
(D-Ala(2)-mephe(4)-gly-ol(5))enkephalin	chemical	CHEBI:272	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258783	0.8
TP53	protein	P04637	UNIPROT	TIGAR	protein	Q9NQ88	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001248								27803158	t		miannu	TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. TIGAR is the only known phosphatase glycolytic modulator regulated by TP53. The current study delineates the role of TIGAR in OXPHOS and glycolytic metabolic reprogramming in breast cancer. 	SIGNOR-267365	0.2
sphingosine 1-phosphate	smallmolecule	CHEBI:37550	ChEBI	LATS1	protein	O95835	UNIPROT	down-regulates				9606	BTO:0000007								22863277	f		milica	Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2.	SIGNOR-198550	0.8
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR1B	protein	P28222	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264284	0.8
MAPK14	protein	Q16539	UNIPROT	AKT2	protein	P31751	UNIPROT	up-regulates activity	phosphorylation	Ser474	RTHFPQFsYSASIRE	9606									12181443	f		lperfetto	We show [] that the kinase activity and s473 phosphorylation of akt induced by lpa and s1p requires both mitogen-activated protein (map) kinase kinase (mek) and p38 map kinase. [] among different stimuli tested, platelet-derived growth factor stimulates s473 phosphorylation of akt in a mek- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1?stimulated Akt s473 phosphorylation require p38 but not mek.	SIGNOR-91408	0.413
axitinib	chemical	CHEBI:66910	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258073	0.8
PPP2CA	protein	P67775	UNIPROT	HDAC4	protein	P56524	UNIPROT	up-regulates	dephosphorylation	Ser298	ACSSAPGsGPSSPNN	9606									18045992	t		lperfetto	Different signal-regulated serine/threonine kinases phosphorylate class ii histone deacetylases (hdacs) to promote nuclear export, cytosolic accumulation, and activation of gene transcriptionhere we show that hdac4 forms a complex with the pp2a holoenzyme c alpha, a alpha, b/pr55 alpha. In vitro and in vivo binding studies demonstrate that the n-terminus of hdac4 interacts with the catalytic subunit of pp2a. Hdac4 is dephosphorylated by pp2a	SIGNOR-159492	0.356
NRXN3	protein	Q9Y4C0	UNIPROT	NLGN2	protein	Q8NFZ4	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							22626547	t		miannu	 The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites	SIGNOR-265457	0.82
IL20RA	protein	Q9UHF4	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates				9606	BTO:0000782;BTO:0000876								12941475	f		gcesareni	Il-20 induces cheratin proliferation and stat-3 signal transduction pathway	SIGNOR-86269	0.565
WNT7A	protein	O00755	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity				10090		BTO:0000887;BTO:0001103							22944199	f		gcesareni	In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Here we report that cells expressing wnt1 will preferentially activate myf5 while cells expressing wnt7a will preferentially activate myod	SIGNOR-198922	0.356
HSPA5	protein	P11021	UNIPROT	EIF2AK3	protein	Q9NZJ5	UNIPROT	down-regulates activity	binding			9606									31226023	t		miannu	In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation.	SIGNOR-260164	0.715
PPP3CA	protein	Q08209	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates activity	dephosphorylation	Ser99	PFRGRSRsAPPNLWA	9606									10195903	t			Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 	SIGNOR-248695	0.451
PRKCB	protein	P05771	UNIPROT	KCNC4	protein	Q03721	UNIPROT	down-regulates	phosphorylation	Ser15	SSYRGRKsGNKPPSK	9606									9649584	t		gcesareni	This study investigated the molecular physiology of the nh2-terminal phosphorylation sites that regulate inactivation gating of an a-type k+ channel. The main results show that: (a) pkc acts on four phosphate acceptors (s8, s9, s15, and s21) within the inactivation domain because mutation of these residues to alanine is necessary and sufficient to remove the action of pkc on channel inactivation.	SIGNOR-58498	0.2
MAPKAPK3	protein	Q16644	UNIPROT	EEF2K	protein	O00418	UNIPROT	unknown	phosphorylation	Ser377	PPLLRPLsENSGDEN	-1									12171600	t		miannu	Identification of Ser-377 as the site on eEF2 kinase phosphorylated in vitro by MAPKAP-K2, MAPKAP-K3 and MAPKAP-K5. Maximal phosphorylation of eEF2 kinase by MAPKAP-K2 (Figure 5) or MAPKAP-K5 (results not shown) had no effect on its activity.	SIGNOR-249709	0.329
TRAF2	protein	Q12933	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates activity	binding			9606									10688666	t		lperfetto	Tnf receptor (tnfr) associated factor 2 (traf2), an adapter protein that couples tnfrs to the sapks and p38s, can activate ask1 in vivo and can interact in vivo with the amino- and carboxyl-terminal noncatalytic domains of the ask1 polypeptide	SIGNOR-75334	0.727
MRPS10	protein	P82664	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-267731	0.743
AKT1	protein	P31749	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates activity	phosphorylation	Ser262	TFRPRSSsNASSVST	10090	BTO:0004245								10217147	t			Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo.	SIGNOR-252569	0.755
SOX17	protein	Q9H6I2	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity				10090									33083751	f		SimoneGraziosi	Sox17 prevents beta-catenin activation by increasing its phosphorylation, particularly in WM lesions	SIGNOR-269268	0.674
SB 415286	chemical	CHEBI:91107	ChEBI	GSK3A	protein	P49840	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206751	0.8
UCK2	protein	Q9BZX2	UNIPROT	uridine 5'-monophosphate(2-)	smallmolecule	CHEBI:57865	ChEBI	up-regulates quantity	chemical modification												11306702	t		lperfetto	Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. 	SIGNOR-275860	0.8
ASPG	protein	Q86U10	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	up-regulates quantity	chemical modification			9606									24657844	t		miannu	Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia.	SIGNOR-267538	0.8
TEK	protein	Q02763	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	binding			9534									14665640	t		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242634	0.517
MEF2A	protein	Q02078	UNIPROT	Myoblast_fusion	phenotype	SIGNOR-PH98	SIGNOR	up-regulates				9606									19725819	f		areggio	In response to increases in intracellular Ca2+ levels, activated CaMKII translocates into the nucleus where it phosphorylates and deactivates HDAC4 which, as a result, dissociates from theDNA-binding domain of MEF2. This dissociation allows MEF2 to bind to its DNA-binding domain to activate transcription of the MEF2-dependent target gene products MyoD and myogenin	SIGNOR-255957	0.7
IGF1R	protein	P08069	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates	phosphorylation	Tyr1229	SSEDLSAyASISFQK	9606									17827393	t		gcesareni	Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K).	SIGNOR-157734	0.864
NTN1	protein	O95631	UNIPROT	UNC5	proteinfamily	SIGNOR-PF98	SIGNOR	up-regulates activity	binding			9606		BTO:0001484							25881791	t		miannu	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268183	0.849
MYC	protein	P01106	UNIPROT	BRD4	protein	O60885	UNIPROT	down-regulates activity				9606									32482868	t		lperfetto	Conversely, MYC inhibits BRD4's HAT activity, suggesting that MYC regulates its own transcription by limiting BRD4-mediated chromatin remodeling of its locus.	SIGNOR-262047	0.58
ZMYND8	protein	Q9ULU4	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001033								27477906	t		lperfetto	Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported	SIGNOR-262040	0.2
SLC36A2	protein	Q495M3	UNIPROT	glycine	smallmolecule	CHEBI:15428	ChEBI	up-regulates quantity	relocalization			9606									12748860	t		lperfetto	Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut.	SIGNOR-264738	0.8
CDC14A	protein	Q9UNH5	UNIPROT	WEE1	protein	P30291	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser123	EEGFGSSsPVKSPAA	9606	BTO:0000007								23051732	t		lperfetto	In particular, we found that Cdc14A inhibits Wee1 degradation through the dephosphorylation of Ser-123 and Ser-139 residues. 	SIGNOR-267469	0.562
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CCNF	protein	P41002	UNIPROT	up-regulates activity	phosphorylation	Ser577	TKRKRENsLQEDRGS	9606	BTO:0001938								28954236	t		miannu	AKT phosphorylation of cyclin F enhances its stability and promotes assembly into productive E3 ligase complexes. 	SIGNOR-266361	0.2
gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	GABA-B receptor	complex	SIGNOR-C336	SIGNOR	up-regulates activity	chemical activation			9606									18790874	t		miannu	Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS).	SIGNOR-264962	0.8
CD79B	protein	P40259	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates				9606	BTO:0000776								12324477	f		gcesareni	Bcr ligation resulted in p53 activation including its phosphorylation at ser15	SIGNOR-93526	0.314
EPHB2	protein	P29323	UNIPROT	RRAS	protein	P10301	UNIPROT	down-regulates activity	phosphorylation	Tyr66	DPTIEDSyTKICSVD	9606									10570155	t			Tyrosine 66 of R-Ras is phosphorylated by EphB2|. R-Ras, a small intracellular GTPase, regulates the binding of integrins to their ligands outside the cell. |Cells in which EphB2 is activated become poorly adherent to substrates coated with integrin ligands, and a tyrosine residue in the R-Ras effector domain is phosphorylated.	SIGNOR-251125	0.595
ABL1	protein	P00519	UNIPROT	MAP4K1	protein	Q92918	UNIPROT	up-regulates activity	phosphorylation	Tyr232	FLMTKSGyQPPRLKE	9606	BTO:0000007								11278340	t			C-Abl phosphorylates HPK1 in cytoplasm and stimulates HPK1 activity. the c-Abl phosphorylation site (YXXP) in HPK1 (Y232QPP; aa 232–235) is localized in HPK1-KD	SIGNOR-251429	0.387
ERRFI1	protein	Q9UJM3	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates	binding			10116									11003669	t		gcesareni	These data indicate that the gene 33 protein is a feedback inhibitor of ErbB-2 mitogenic function and a suppressor of ErbB-2 oncogenic activity. We propose that the gene 33 protein be renamed with the acronym RALT (receptor-associated late transducer)	SIGNOR-186198	0.66
PPP3CB	protein	P16298	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates				9606		BTO:0001103							11062529	f		gcesareni	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-84044	0.442
DPDPE	chemical	CHEBI:73356	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258792	0.8
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	CHEK1	protein	O14757	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									28138032	f		miannu	Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Ras–MEK signaling transcriptionally activates Chk1, which appears to sustain cancer cell growth by maintaining DNA damage levels below a threshold that would otherwise drive apoptosis.	SIGNOR-263069	0.2
MAPK3	protein	P27361	UNIPROT	GAB2	protein	Q9UQC2	UNIPROT	up-regulates	phosphorylation	Ser623	ALDFQPSsPSPHRKP	9606									15356145	t		lperfetto	Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623.	SIGNOR-128731	0.6
PHKG2	protein	P15735	UNIPROT	PYGL	protein	P06737	UNIPROT	up-regulates activity	phosphorylation	Ser15	QEKRRQIsIRGIVGV	9606	BTO:0002049								22225877	t			It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15	SIGNOR-267401	0.643
KDM3B	protein	Q7LBC6	UNIPROT	UCP1	protein	P25874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0005964								19194461	t		miannu	 We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. 	SIGNOR-266638	0.2
26S Proteasome	complex	SIGNOR-C307	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity	destabilization			10090	BTO:0003569								9233789	t			Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of beta-catenin turnover. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of beta-catenin.	SIGNOR-270947	0.39
TRIM28	protein	Q13263	UNIPROT	Aldolase	proteinfamily	SIGNOR-PF75	SIGNOR	down-regulates quantity by repression	transcriptional regulation			9606									17900823	f	inferred from family member	miannu	 We previously reported that ZNF224, a novel Krüppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. 	SIGNOR-270228	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	AR	protein	P10275	UNIPROT	down-regulates	phosphorylation	Ser516	VSRVPYPsPTCVKSE	9606	BTO:0001130								18511414	t		lperfetto	Map kinase-dependent phosphorylation at ar ser-515 was supported by the decrease in intensity of the slower migrating 23-kda band after treatment with both egf and increasing concentrations of the map kinase inhibitor, u0126	SIGNOR-244606	0.2
TGFB1	protein	P01137	UNIPROT	PAX8	protein	Q06710	UNIPROT	down-regulates activity	binding			9606									14623893	t		miannu	DNA Binding Activity of Pax8 to the NIS Promoter Is Reduced by Smad3. TGF-β decreases Pax8 DNA binding to the NIS promoter and also found a physical interaction between Pax8 and Smad3.	SIGNOR-251993	0.2
CHRM1	protein	P11229	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257130	0.376
AKT2	protein	P31751	UNIPROT	XIAP	protein	P98170	UNIPROT	up-regulates	phosphorylation	Ser87	VGRHRKVsPNCRFIN	9606									14645242	t		llicata	Here, we demonstrate that akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of xiap is also inhibited by akt.	SIGNOR-119492	0.43
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	NR3C1	protein	P04150	UNIPROT	down-regulates	phosphorylation	Ser134	ANLNRSTsVPENPKS	9606	BTO:0000731								24291004	t		lperfetto	Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus	SIGNOR-236216	0.2
EP300	protein	Q09472	UNIPROT	FLI1	protein	Q01543	UNIPROT	up-regulates	binding			9606									24058639	t		miannu	P300 promotes the interaction of fli1 with hdac1 and increases the dna binding ability of fli1 through deacetylation of lysine 380	SIGNOR-202682	0.296
PRKACA	protein	P17612	UNIPROT	LIPE	protein	Q05469	UNIPROT	down-regulates	phosphorylation	Ser855	EPMRRSVsEAALAQP	9606									9636039	t		gcesareni	Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase.	SIGNOR-58259	0.585
KIF3C	protein	O14782	UNIPROT	Minus-end directed microtubule movement	phenotype	SIGNOR-PH217	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272536	0.7
6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine	chemical	CHEBI:131165	ChEBI	CHEK2	protein	O96017	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206841	0.8
TRAF6	protein	Q9Y4K3	UNIPROT	TAB3	protein	Q8N5C8	UNIPROT	up-regulates activity	binding			9606									25290089	t		lperfetto	The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.	SIGNOR-205461	0.702
hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	GABA-A (a6-b2-d) receptor	complex	SIGNOR-C328	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000938								26136660	t		miannu	The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 	SIGNOR-264928	0.8
ASXL2	protein	Q76L83	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates activity	binding			9606									21047783	t		miannu	ASXL2, which does not bind HP1, promotes differentiation by binding to PPARγ and increasing the level of methylated H3K4, leading to the elevation of PPARγ activity. Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ. 	SIGNOR-260063	0.2
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	up-regulates activity	chemical activation			9606									15919192	t		miannu	Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1–4); five kainate receptor genes (GluR5–7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits.	SIGNOR-264696	0.8
IFNG	protein	P01579	UNIPROT	DIO	proteinfamily	SIGNOR-PF83	SIGNOR	down-regulates quantity by repression	transcriptional regulation			10116									9397972	f	inferred from family member	scontino	From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells grown in TSH-containing medium. These include TNF-a, IL-lb and INF-g but not TGF-b.	SIGNOR-267810	0.2
TP53	protein	P04637	UNIPROT	ABCB1	protein	P08183	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									10029407	f		miannu	 p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1.	SIGNOR-255435	0.602
GRK2	protein	P25098	UNIPROT	SNCG	protein	O76070	UNIPROT	down-regulates activity	phosphorylation	Ser124	EVAEEAQsGGD	-1									10852916	t			GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser124 dramatically inhibits γ-synuclein phosphorylation by GRK2	SIGNOR-251204	0.2
AKT1	protein	P31749	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	binding			9606									15048128	t		gcesareni	Pkb inhibits smad3 by preventing its phosphorylation, binding to smad4 and nuclear translocation. [...] Regulation of smad3 by pkb occurs through a kinase-activity-independent mechanism, resulting in a decrease in smad3-mediated transcription and protection of cells against tgf-beta-induced apoptosis.	SIGNOR-123606	0.643
arecoline	chemical	CHEBI:2814	ChEBI	CHRM3	protein	P20309	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258640	0.8
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity	transcriptional regulation			10090	BTO:0002314								24749067	f		gcesareni	We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration.	SIGNOR-252940	0.2
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser168	YREPLCLsPASSGSS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248678	0.613
ABL1	protein	P00519	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates activity	phosphorylation	Tyr394	QSQESEDySQPSTSS	9606									12110584	t		gcesareni	C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2.	SIGNOR-90512	0.705
FBXW7	protein	Q969H0	UNIPROT	MED13	protein	Q9UHV7	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007		SIGNOR-C135	SIGNOR-C406					23322298	t		miannu	The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association.	SIGNOR-266690	0.38
UBE2A	protein	P49459	UNIPROT	PCNA	protein	P12004	UNIPROT	up-regulates	ubiquitination	Lys164	AVVISCAkDGVKFSA	9606									12226657	t		gcesareni	Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18.	SIGNOR-92737	0.489
E2F1	protein	Q01094	UNIPROT	HSPA5	protein	P11021	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18840615	f		miannu	 we show that E2F1 represses GRP78/BIP at the transcriptional level, and this requires its DNA binding domain.	SIGNOR-253845	0.2
PRKG2	protein	Q13237	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Thr430	LEIIRGRtKQHGQFS	-1									35226996	t		miannu	Recombinant PKG II inhibited the epidermal growth factor (EGF)-induced activation of the EGF receptor via phosphorylating the T406 of the extracellular domain and blocked EGF-triggered proliferation of various cancer cells.	SIGNOR-277589	0.2
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2L6	protein	O14933	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271353	0.62
RPS6KA2	protein	Q15349	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606	BTO:0000007								10837486	t		lperfetto	We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites.	SIGNOR-249044	0.381
MAPK8	protein	P45983	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates				9606									15071501	f	JNK-mediated phosphorylation of 14-3-3 at Ser184 reduces its affinity for Bax.	gcesareni	We demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein.	SIGNOR-124012	0.542
ELF4	protein	Q99607	UNIPROT	LYZ	protein	P61626	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001271								14976184	f		miannu	Myeloid elf-1-like factor (mef) or elf4, which is a member of the ets transcription factor family, up-regulates the basal expression of lysozyme gene in epithelial cells and is constitutively localized in the nucleus	SIGNOR-122236	0.261
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1871	SPKYSPTsPKYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120224	0.321
NRF1	protein	Q16656	UNIPROT	RETREG3	protein	Q86VR2	UNIPROT	up-regulates				9606	BTO:0000934								23939472	f		lperfetto	We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. 	SIGNOR-261489	0.2
MAPK14	protein	Q16539	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity				9606		BTO:0000887;BTO:0001103							15466486	f		lperfetto	Here, we show that p38 activity facilitates myod and mef2 binding at a subset of late-activated promoters, and the binding of mef2d recruits pol ii.	SIGNOR-129702	0.463
TAOK2	protein	Q9UL54	UNIPROT	MAP2K6	protein	P52564	UNIPROT	up-regulates activity	phosphorylation	Ser207	ISGYLVDsVAKTIDA	9606	BTO:0000007								11279118	t		lperfetto	Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells	SIGNOR-106465	0.633
CDK1	protein	P06493	UNIPROT	USP9X	protein	Q93008	UNIPROT	up-regulates activity	phosphorylation	Ser2547	YEGSEEVsPPQTKDQ										32152317	t	Phosphosites were derived from Figure S1	lperfetto	Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. 	SIGNOR-275608	0.283
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR6	protein	P50406	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264295	0.8
IL10	protein	P22301	UNIPROT	IL1RN	protein	P18510	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20032313	f	 	miannu	 The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. 	SIGNOR-254793	0.601
GATA2	protein	P23769	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates activity				9606									20510530	t		fferrentino	GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis	SIGNOR-132949	0.378
ATM	protein	Q13315	UNIPROT	WRN	protein	Q14191	UNIPROT	unknown	phosphorylation	Ser1141	PEKAYSSsQPVISAQ	-1									10608806	t		llicata	We determined a general phosphorylation consensus sequence for ATM and identified putative in vitro targets by using glutathione S-transferase peptides as substrates. Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself.	SIGNOR-250577	0.821
ETFBKMT	protein	Q8IXQ9	UNIPROT	ETFB	protein	P38117	UNIPROT	down-regulates activity	methylation	Lys203	PNIMKAKkKKIEVIK	-1									25416781	t		miannu	 Accordingly, we found that METTL20-mediated methylation of ETFβ in vitro reduced its ability to receive electrons from the medium chain acyl-CoA dehydrogenase and the glutaryl-CoA dehydrogenase. In conclusion, the present study establishes METTL20 as the first human KMT localized to mitochondria and suggests that it may regulate cellular metabolism through modulating the interaction between its substrate ETFβ and dehydrogenases.	SIGNOR-269451	0.2
CDK3	protein	Q00526	UNIPROT	TFCP2	protein	Q12800	UNIPROT	down-regulates	phosphorylation	Ser309	SLGEGNGsPNHQPEP	9606									19237534	t		lperfetto	In vitro, lsf is phosphorylated by cyclin e/cyclin-dependent kinase 2 (cdk2), cyclin c/cdk2, and cyclin c/cdk3, predominantly on s309. Phosphorylation by cyclin c/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of lsf during g1 progression	SIGNOR-184164	0.267
MAPK1	protein	P28482	UNIPROT	MYO9B	protein	Q13459	UNIPROT	unknown	phosphorylation	Thr1346	RATGAALtPTEERRT	10090	BTO:0000944								22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262777	0.306
STK26	protein	Q9P289	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates	phosphorylation	Thr567	QGRDKYKtLRQIRQG	9606									19386264	t		lperfetto	Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. Mst4 phosphorylates the regulatory t567 residue of ezrin.	SIGNOR-185563	0.2
HTRA2	protein	O43464	UNIPROT	XIAP	protein	P98170	UNIPROT	down-regulates	binding			9606									11583623	t		gcesareni	Here we report that a serine protease called htra2/omi is released from mitochondria and inhibits the function of xiap by direct binding in a similar way to diablo.	SIGNOR-110834	0.702
SEMA5A	protein	Q13591	UNIPROT	PLXNB3	protein	Q9ULL4	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								15218527	t		miannu	Plexin-B3 is a functional receptor for semaphorin 5A. Here we show that plexin-B3 is a high-affinity receptor specific for Sema5A. We further demonstrate that plexin-B3 activation by Sema5A mediates functional responses in plexin-B3-expressing cells (either fibroblasts, epithelial and primary endothelial cells).	SIGNOR-268373	0.607
KREMEN2	protein	Q8NCW0	UNIPROT	LRP6	protein	O75581	UNIPROT	down-regulates	binding			9606									12050670	t		gcesareni	Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to block wnt/beta-catenin signalling. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane.	SIGNOR-88894	0.625
GMNN	protein	O75496	UNIPROT	CDT1	protein	Q9H211	UNIPROT	down-regulates activity	binding			9606	BTO:0002181								11125146	t			Here we show that geminin interacts tightly with Cdt1, a recently identified replication initiation factor necessary for MCM loading.	SIGNOR-261680	0.972
CCT8	protein	P50990	UNIPROT	TRiC	complex	SIGNOR-C539	SIGNOR	form complex	binding			9606									36185250	t		miannu	Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC).	SIGNOR-272862	0.756
PTPRK	protein	Q15262	UNIPROT	EGFR	protein	P00533	UNIPROT	unknown	dephosphorylation	Tyr1197	STAENAEyLRVAPQS	10029	BTO:0000246								16263724	t			RPTP-kappa also reduced epidermal growth factor-dependent EGFR tyrosine phosphorylation in CHO cells. Purified RPTP-kappa preferentially dephosphorylated EGFR tyrosines 1068 and 1173 in vitro.	SIGNOR-248723	0.602
BDKRB2	protein	P30411	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257344	0.2
LPAR1	protein	Q92633	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates	binding			9606									22863277	t		milica	Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription.	SIGNOR-198507	0.436
AXL	protein	P30530	UNIPROT	AXL	protein	P30530	UNIPROT	up-regulates activity	phosphorylation	Tyr821	QEPDEILyVNMDEGG	-1									9178760	t		llicata	Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins	SIGNOR-250592	0.2
GLE1	protein	Q53GS7	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262096	0.578
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	Calprotectin complex	complex	SIGNOR-C293	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0001044								16690079	t		miannu	S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization.	SIGNOR-262826	0.8
NUP85	protein	Q9BW27	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262093	0.722
RHO	protein	P08100	UNIPROT	GNAT1	protein	P11488	UNIPROT	up-regulates activity	binding			9606									8673138	t			We report that his affected descendants carry a missense mutation in the gene encoding the a subunit of rod transducin — the G-protein that couples rhodopsin to cGMP-phosphodiesterase in the phototransduction cascade.	SIGNOR-260007	0.785
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									12588998	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	lperfetto	Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro	SIGNOR-244275	0.2
copper(1+)	smallmolecule	CHEBI:49552	ChEBI	SOD3	protein	P08294	UNIPROT	up-regulates activity	chemical activation												1542024	t		lperfetto	Copper as a cofactor and regulator of copper,zinc superoxide dismutase	SIGNOR-272301	0.8
LFNG	protein	Q8NES3	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	glycosylation			9606		BTO:0000975							12486116	t	Fringe is a fucose-specific beta1,3-N-acetylglucosaminyltransferase that modifies O-fucose moieties on the epidermal growth factor-like (EGF) repeats of Notch.	gcesareni	We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1.	SIGNOR-96540	0.748
GSK3B	protein	P49841	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser104	FPPLNSVsPSPLMLL	9606									16076840	t		gcesareni	The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex.	SIGNOR-139316	0.347
DLGAP3	protein	O95886	UNIPROT	SHANK3	protein	Q9BYB0	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264594	0.2
DUSP3	protein	P51452	UNIPROT	PTK2	protein	Q05397	UNIPROT	down-regulates activity	dephosphorylation			9606									28759036	t		miannu	Deficiency in VHR/DUSP3, a suppressor of focal adhesion kinase, reveals its role in regulating cell adhesion and migration.|In vitro assays proved that recombinant VHR directly dephosphorylated FAK and paxillin.	SIGNOR-277033	0.333
MAPK1	protein	P28482	UNIPROT	ERF	protein	P50548	UNIPROT	up-regulates	phosphorylation	Ser246	RGGPEPLsPFPVSPL	9606									10330152	t		lperfetto	The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a).	SIGNOR-67524	0.578
CSNK2B	protein	P67870	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Ser99	HFAIAADsEAEQDSW	-1									8349691	t		llicata	These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1.	SIGNOR-251074	0.324
RNF146	protein	Q9NTX7	UNIPROT	BLZF1	protein	Q9H2G9	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								21478859	t		lperfetto	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 	SIGNOR-263340	0.419
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	PRDM1	protein	O75626	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269255	0.371
CSNK2A2	protein	P19784	UNIPROT	EEF1B2	protein	P24534	UNIPROT	unknown	phosphorylation	Ser106	DDIDLFGsDDEEESE	-1									8547318	t		llicata	EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent.	SIGNOR-250987	0.342
PRKCE	protein	Q02156	UNIPROT	GJA1	protein	P17302	UNIPROT	up-regulates	phosphorylation	Ser365	IVDQRPSsRASSRAS	9606									16474210	t		lperfetto	We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity.	SIGNOR-144461	0.451
RIPK1	protein	Q13546	UNIPROT	TAB3	protein	Q8N5C8	UNIPROT	up-regulates activity	binding			9606									19927120	t		lperfetto	Tab2 and tab3 activate the jun n-terminal kinase and nuclear factor-kappab pathways through the specific recognition of lys 63-linked polyubiquitin chains by its npl4 zinc-finger (nzf) domain.	SIGNOR-161787	0.557
RNF111	protein	Q6ZNA4	UNIPROT	SKI	protein	P12755	UNIPROT	down-regulates	ubiquitination			9606	BTO:0000150;BTO:0000551								18451154	t		gcesareni	On tgf-beta treatment, the e3 ubiquitin ligase arkadia mediates degradation of ski in a smad-dependent manner	SIGNOR-178598	0.577
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates activity				9606	BTO:0000093								8415704	f		miannu	PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site	SIGNOR-261507	0.2
RELA	protein	Q04206	UNIPROT	CD80	protein	P33681	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									12860928	f	 	 	Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. 	SIGNOR-253935	0.301
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	NMDA	proteinfamily	SIGNOR-PF56	SIGNOR	up-regulates activity	chemical activation			9606									24564659	t		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264692	0.8
MGRN1	protein	O60291	UNIPROT	TSG101	protein	Q99816	UNIPROT	up-regulates activity	monoubiquitination			9606	BTO:0000567								17229889	t		miannu	In the present study, we identified the first substrate of the Mahogunin E3 ubiquitin–protein ligase: TSG101, a key component of the endosomal sorting ESCRT machinery.We find that Mahogunin interacts with the ubiquitin E2 variant (UEV) domain of TSG101 via its PSAP motif and that it catalyzes monoubiquitylation of TSG101 both in vivo and in vitro.  Consistent with the results of the biochemical characterization and subcellular localization studies of Mahogunin, our functional studies provide direct evidence that Mahogunin plays an essential role in regulation of endosome-to-lysosome trafficking. We found that siRNA-mediated depletion of Mahogunin in HeLa cells causes enlargement and clustering of EEA1-positive endosomes and LAMP2-positive late endosomes/lysosomes (Figure 8B) and inhibits the endosomal trafficking of internalized EGF–EGFR complexes to lysosomes for degradation (Figures 9 and ​and10,10, A and B). These results are strikingly similar to the phenotypes that resulted from depletion of TSG101	SIGNOR-271635	0.506
POLR2F	protein	P61218	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606									12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266139	0.862
ESR1	protein	P03372	UNIPROT	OXT	protein	P01178	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									6153132	f		lperfetto	The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances.	SIGNOR-268546	0.439
UBE3A	protein	Q05086	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys135	AKRLKKEkVNVDIIN	-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. 	SIGNOR-272747	0.476
CSNK2A1	protein	P68400	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates activity	phosphorylation	Ser1124	LNTEEFSsESDMEES	9606	BTO:0000938								19064667	t		lperfetto	 We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275757	0.2
CDCA7L	protein	Q96GN5	UNIPROT	MAOB	protein	P27338	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20980443	f		miannu	 we identified two novel transcriptional repressors of MAO B, E2F-associated phosphoprotein (EAPP) and R1 (RAM2/CDCA7L/JPO2), that down-regulate MAO B via MAO B core promoter, which contains Sp1 sites.	SIGNOR-253768	0.293
MAPK6	protein	Q16659	UNIPROT	MAPK6	protein	Q16659	UNIPROT	up-regulates	phosphorylation	Ser189	YSHKGHLsEGLVTKW	9606									8621539	t		lperfetto	Ser189 of erk3, which corresponds to thr183, one of the activating phosphorylation sites of erk2, is autophosphorylated in vitro and phosphorylated in vivo.	SIGNOR-40097	0.2
MAPK10	protein	P53779	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates	phosphorylation	Thr743	VEVDAAVtPEERHLS	9606									24610780	t		lperfetto	Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. is regulated by jnk3 via phosphorylation of app at thr668	SIGNOR-204671	0.565
TBCK	protein	Q8TEA7	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				9606	BTO:0000142								33240423	f		miannu	TBCK included two types of alternatively spliced isoforms (long TBCK and short TBCK). Although there is a long way to go to fully understand the function of TBCK, recent research indicates that TBCK plays an important role in brain development. BCK deficiency would disturb activation of the mTOR complex 1 (mTORC1), thus, affecting the autophagy process and further leading to autophagosomal-lysosomal dysfunction	SIGNOR-266699	0.254
MED12	protein	Q93074	UNIPROT	CKM complex	complex	SIGNOR-C406	SIGNOR	form complex	binding			9606									23563140	t		miannu	The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation.	SIGNOR-266683	0.919
CSNK2A1	protein	P68400	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	phosphorylation	Thr155	DSTPPPGtRVRAMAI	-1									12628923	t		llicata	CK2 phosphoryl ates Thr155, which targets p53 to degradation by the Ub system.	SIGNOR-250968	0.654
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	lysine	smallmolecule	CHEBI:25094	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270405	0.8
MLL2 complex	complex	SIGNOR-C88	SIGNOR	H3C1	protein	P68431	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606									24680668	t		miannu	Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation.	SIGNOR-268798	0.2
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1693	SPTSPSYsPTSPSYS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248785	0.441
PRKDC	protein	P78527	UNIPROT	PRKAG1	protein	P54619	UNIPROT	up-regulates activity	phosphorylation	Ser192	KPEFMSKsLEELQIG	-1									31983282	t		miannu	PRKDC interacted with the AMPK complex and phosphorylated its nucleotide-sensing γ1 subunit PRKAG1/AMPKγ1 at Ser192 and Thr284, both events being significantly reduced upon the activation of the AMPK complex. Alanine substitutions of PRKDC phosphorylation sites in PRKAG1 reduced AMPK complex activation without affecting its nucleotide sensing capacity. 	SIGNOR-277503	0.2
BTF3	protein	P20290	UNIPROT	EPHB2	protein	P29323	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000584								17312387	f	 	 	In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis.	SIGNOR-253949	0.2
FBLIM1	protein	Q8WUP2	UNIPROT	FLNC	protein	Q14315	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								24165133	t		miannu	Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 	SIGNOR-266107	0.779
DDC	protein	P20711	UNIPROT	L-dopa	smallmolecule	CHEBI:15765	ChEBI	down-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Subsequently, L-DOPA is converted into 3,4-dihydroxyphenethylamine (dopamine) through decarboxylation by the enzyme L-3,4-dihydroxyphenylalanine decarboxylase (DOPA decarboxylase) in the pre-synaptic terminal	SIGNOR-263992	0.8
INS	protein	P01308	UNIPROT	COMT	protein	P21964	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000542								17612537	f	Regulation of expression	miannu	Catechol O-methyltransferase expression in granulosa cells was up-regulated by insulin, DHT, and ATRA. 	SIGNOR-251961	0.328
6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide	chemical	CHEBI:92401	ChEBI	HDAC4	protein	P56524	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257998	0.8
SLBP	protein	Q14493	UNIPROT	H2AC14	protein	Q99878	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265404	0.2
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	RB1	protein	P06400	UNIPROT	down-regulates activity	phosphorylation	Ser780	STRPPTLsPIPHIPR	9606	BTO:0000150								23336272	t		lperfetto	Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression.	SIGNOR-216988	0.858
PIM1	protein	P11309	UNIPROT	UHRF1	protein	Q96T88	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser311	S-->R	9606									28394343	t		miannu	Here we report that UHRF1 is a novel substrate of PIM1 kinase, which could be phosphorylated at Ser311 and therefore promoted to degradation. 	SIGNOR-277349	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser29	ATKAARKsAPSTGGV	9606									11278789	t	Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription.	miannu	 In the present study, ERK1, ERK2, or p38 kinase strongly phosphorylated H3 at serine 28 in vitro. JNK1 or JNK2 was able also to phosphorylate H3 at serine 28 in vitro but to a lesser degree. Histone H3 phosphorylation is related closely to chromatin remodeling and chromosome condensation. H3 phosphorylation at serine 28 is coupled with mitotic chromosome condensation in diverse mammalian cell lines.	SIGNOR-263068	0.2
DLG1	protein	Q12959	UNIPROT	Scribble_complex_DLG1-LLGL1_variant	complex	SIGNOR-C511	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270913	0.529
p38	proteinfamily	SIGNOR-PF16	SIGNOR	CDC25B	protein	P30305	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser101	ASESSLSsESSESSD	9606	BTO:0000567								21807946	t		miannu	 Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104).	SIGNOR-276350	0.2
BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	SMAD1	protein	Q15797	UNIPROT	up-regulates activity	phosphorylation	Ser465	HNPISSVs	9606									9136927	t		lperfetto	Here, we report that BMP receptors phosphorylate and activate Smad1 directly. Phosphorylation of Smad1 in vivo involves serines in the carboxy-terminal motif SSXS. These residues are phosphorylated directly by a BMP type I receptor in vitro	SIGNOR-217989	0.652
AKT2	protein	P31751	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates activity				9606	BTO:0000150								12697749	f		lperfetto	Our data indicate that akt2 inhibits cisplatin-induced jnk/p38 and bax activation through phosphorylation of ask1	SIGNOR-100591	0.413
RIMBP3	protein	Q9UFD9	UNIPROT	RIMS3	protein	Q9UJD0	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264370	0.289
ADRB1	protein	P08588	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257030	0.252
PIM3	protein	Q86V86	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606	BTO:0000007								16403219	t		miannu	Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.	SIGNOR-250396	0.353
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	EZH2	protein	Q15910	UNIPROT	down-regulates activity	phosphorylation	Ser21	CWRKRVKsEYMRLRQ	9606									16224021	t		lperfetto	Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3	SIGNOR-244259	0.2
SMO	protein	Q99835	UNIPROT	GNG3	protein	P63215	UNIPROT	up-regulates	binding			9606									16885213	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-148598	0.2
2-deoxy-alpha-D-ribose 1-phosphate	smallmolecule	CHEBI:11563	ChEBI	2-deoxy-D-ribose 5-phosphate	smallmolecule	CHEBI:16132	ChEBI	up-regulates quantity	precursor of			9606									17804405	t		miannu	Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses.	SIGNOR-267093	0.8
clozapine	chemical	CHEBI:3766	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			10116	BTO:0000529								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258515	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ZYX	protein	Q15942	UNIPROT	down-regulates	phosphorylation	Ser142	PQPREKVsSIDLEID	9606									17572661	t		lperfetto	Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus zyxin is a substrate of caspases, but akt phosphorylation fails to protect its proteolytic degradation	SIGNOR-244389	0.2
9-(1-anilinoethyl)-7-methyl-2-(4-morpholinyl)-4-pyrido[1,2-a]pyrimidinone	chemical	CHEBI:91428	ChEBI	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207278	0.8
PTPN1	protein	P18031	UNIPROT	STAT5B	protein	P51692	UNIPROT	down-regulates	dephosphorylation	Tyr699	TAKAVDGyVKPQIKQ	9606		BTO:0000149							10993888	t		gcesareni	A cytosolic protein-tyrosine phosphatase ptp1b specifically dephosphorylates and deactivates prolactin-activated stat5a and stat5b.	SIGNOR-82042	0.662
MAPKAPK2	protein	P49137	UNIPROT	BAG2	protein	O95816	UNIPROT	up-regulates	phosphorylation	Ser20	GRFCRSSsMADRSSR	9606	BTO:0000567								15271996	t		lperfetto	We provided definite evidence that mapkapk2 phosphorylates bag2 at ser 20 in vitro and in vivo. These results demonstrate that bag2 is a novel component of the p38 mapk signaling pathways.	SIGNOR-126953	0.373
acetylcholine	smallmolecule	CHEBI:15355	ChEBI	CHRM1	protein	P11229	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257468	0.8
HIRA complex 2	complex	SIGNOR-C462	SIGNOR	H3-3A	protein	P84243	UNIPROT	up-regulates quantity by stabilization	binding			9606									30285846	t		miannu	H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex.	SIGNOR-269440	0.2
SNRPB	protein	P14678	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270656	0.712
SKP2	protein	Q13309	UNIPROT	CCNE1	protein	P24864	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								10790373	t		miannu	 Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3. 	SIGNOR-272566	0.694
CDK4	protein	P11802	UNIPROT	CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	form complex	binding			9606									7736585	t		gcesareni	D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb,	SIGNOR-32301	0.964
CSKMT	protein	A8MUP2	UNIPROT	CS	protein	O75390	UNIPROT	down-regulates activity	methylation	Lys395	LLEQGKAkNPWPNVD										34929314	t		lperfetto	A mitochondrial matrix-located methyltransferase, methyltransferase-like protein 12 (METTL12), has been reported to methylate CS on the lysine 368 (K368) [15] and K395 residues [16] which are near the active site of CS. The methylation on K395 inhibits CS activity, which can be antagonized by its substrate oxaloacetate.	SIGNOR-267637	0.2
DRD2	protein	P14416	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256701	0.46
INO80	protein	Q9ULG1	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270853	0.736
FOXE1	protein	O00358	UNIPROT	TGFB3	protein	P10600	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									21177256	f	 	miannu	The MSX1 and TGF-β3 up-regulation in response to FOXE1 at both transcriptional and translational levels and the recruitment of FOXE1 to specific binding motifs, together with the transactivation of the promoters of these genes, indicate that MSX1 and TGF-β3 are direct FOXE1 targets.	SIGNOR-254174	0.357
NFYB	protein	P25208	UNIPROT	GFI1B	protein	Q5VTD9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19965638	f	 	miannu	HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. 	SIGNOR-254431	0.2
CSNK2A1	protein	P68400	UNIPROT	ABCF1	protein	Q8NE71	UNIPROT	unknown	phosphorylation	Ser109	KKLSVPTsDEEDEVP	9606									17894550	t		gcesareni	We demonstrate that abc50 is a phosphoprotein and is phosphorylated at two sites by ck2. These sites, ser-109 and ser-140, lie in the nterminal part of abc50 but are not required for the binding of abc50 to eif2.	SIGNOR-157933	0.2
CCNA1	protein	P78396	UNIPROT	Cell_growth	phenotype	SIGNOR-PH33	SIGNOR	up-regulates													15829981	f		lperfetto	Cyclin A1 contributes to G1 to S cell cycle progression in somatic cells. Cyclin A1 overexpression enhances S phase entry consistent with an oncogenic function. Finally, cyclin A1 might be a therapeutic target since its silencing inhibited leukemia cell growth.	SIGNOR-249637	0.7
PROX1	protein	Q92786	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates quantity by stabilization				9606									27476001	f		miannu	PROX1 is important to maintain HIF1α protein stability by inhibiting the proteasome activity after DAB2IP loss, since our immunoprecipitation data showed that knocking-down PROX1 could enhance the protein–protein interaction between HIF1α and ubiquitin in DAB2IP-deficient LAPC-4 and RWPE-1 KD cells. we found that knocking-down PROX1 could decrease HIF1α protein stability, because HIF1α protein degradation was significantly blocked by MG132 treatment in LAPC-4 and RWPE-1 KD cells	SIGNOR-254766	0.26
CDK9	protein	P50750	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser214	PTSSDPGsPFQMPAD	9606									19914168	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161666	0.325
ATP5IF1	protein	Q9UII2	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261400	0.2
CSNK2B	protein	P67870	UNIPROT	BRCA1	protein	P38398	UNIPROT	unknown	phosphorylation	Ser1572	ESGISLFsDDPESDP	-1									10403822	t		llicata	Subsequent studies showed that BRCA1 was phosphorylated in vitro by CK2. An analysis by site directed mutagenesis of BRCA1 showed that in vitro phosphorylation by CK2 required a serine at aa1572. These data implicate CK2 as a potential mediator of BRCA1 activity.	SIGNOR-251055	0.351
JAK3	protein	P52333	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000782								17259970	t		milica	Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity.	SIGNOR-152917	0.515
PRKCI	protein	P41743	UNIPROT	PARD6A	protein	Q9NPB6	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser345	RGDGSGFsL	9606	BTO:0002181								23249950	t		miannu	APKC associates and phosphorylates Par6 on S345. aPKC expression stabilizes Par6 protein levels. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation. 	SIGNOR-276432	0.86
carfilzomib	chemical	CHEBI:65347	ChEBI	PSMB5	protein	P28074	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000873								19348473	t		Luana	Carfilzomib selectively inhibits the CT-L activity of the 20S proteasome and displays equivalent potency against β5 and LMP7 with minimal cross reactivity to other protease classes.	SIGNOR-257818	0.8
C3	protein	P01024	UNIPROT	C5 convertase complex (C3bBbC3b)	complex	SIGNOR-C315	SIGNOR	form complex	binding			9606		BTO:0000089			cleavage:Arg748	ASHLGLArSNLDEDI			26489954	t	complement C3b fragment: PRO_0000005911	lperfetto	In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC).	SIGNOR-263480	0.2
(6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide	chemical	CHEBI:92629	ChEBI	HTR2B	protein	P41595	UNIPROT	up-regulates activity	chemical activation			10036	BTO:0000452								9459568	t		miannu	The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-	SIGNOR-258688	0.8
sapitinib	chemical	CHEBI:132986	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									20145185	t		gcesareni	In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation.	SIGNOR-163730	0.8
RET	protein	P07949	UNIPROT	ATF4	protein	P18848	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr114	TMPDDLLtTLDDTCD	9606	BTO:0002181								25795775	t		miannu	We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA. 	SIGNOR-276449	0.2
PCM1	protein	Q15154	UNIPROT	NEK2	protein	P51955	UNIPROT	up-regulates	relocalization			9606									15659651	t		miannu	Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1	SIGNOR-133337	0.4
GRK1	protein	Q15835	UNIPROT	RHO	protein	P08100	UNIPROT	up-regulates activity	phosphorylation	Ser343	TVSKTETsQVAPA	-1									8617805	t			That light-dependent phosphorylation of Rho is mediated primarily by RK. Addition of an inhibitory antibody against rhodopsin kinase (RK) lowered phosphorylation at Ser334, Ser338, and Ser343, without changing the ratio between phosphorylation sites. upon illumination, Ser334c, Ser338, and Ser343 are phosphorylated.	SIGNOR-251191	0.922
GADD45G	protein	O95257	UNIPROT	CDK11A	protein	Q9UQ88	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								26885618	t		lperfetto	Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58.	SIGNOR-273025	0.2
EP300	protein	Q09472	UNIPROT	CDX2/PAX6/P300	complex	SIGNOR-C33	SIGNOR	form complex	binding			9606									10506141	t		lperfetto	In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300.	SIGNOR-70960	0.458
ADORA2B	protein	P29275	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257240	0.301
MAP3K5	protein	Q99683	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000298								8974401	t		lperfetto	A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively.	SIGNOR-45366	0.616
NTRK2	protein	Q16620	UNIPROT	NTRK2	protein	Q16620	UNIPROT	unknown	phosphorylation	Tyr706	RDVYSTDyYRVGGHT	10090	BTO:0000944								10533983	t		miannu	TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785.	SIGNOR-250206	0.2
PPARG	protein	P37231	UNIPROT	GLS	protein	O94925	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0005871								33754076	f		Luana	Furthermore, the protein level of the rate-limiting enzyme GLS1 but not GLUD1, GOT1, or GPT2 was consistently reduced by PPARγ agonists	SIGNOR-268043	0.249
CSNK2A2	protein	P19784	UNIPROT	HDAC2	protein	Q92769	UNIPROT	up-regulates activity	phosphorylation	Ser422	IACDEEFsDSEDEGE	9606	BTO:0000567								12082111	t		llicata	HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2.	SIGNOR-251002	0.398
CDK1	protein	P06493	UNIPROT	LMNA	protein	P02545	UNIPROT	up-regulates	phosphorylation	Ser390	EEERLRLsPSPTSQR	9606									18815303	t		gcesareni	Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm	SIGNOR-181314	0.553
LTC4S	protein	Q16873	UNIPROT	leukotriene C4(2-)	smallmolecule	CHEBI:57973	ChEBI	up-regulates quantity	chemical modification			9606									27365393	t		miannu	Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4).	SIGNOR-277257	0.8
PRKAA1	protein	Q13131	UNIPROT	HIPK2	protein	Q9H2X6	UNIPROT	up-regulates activity	phosphorylation	Thr1114	APAALGStGTVAHLV	-1									23871434	t		miannu	These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J).	SIGNOR-276469	0.2
TP53	protein	P04637	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9122197	f		gcesareni	P53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis	SIGNOR-47541	0.743
ATM	protein	Q13315	UNIPROT	SMC1A	protein	Q14683	UNIPROT	up-regulates	phosphorylation	Ser957	ISQEEGSsQGEDSVS	9606									11877377	t		lperfetto	Here we report that smc1 is a component of the dna damage response network that functions as an effector in the atm/nbs1-dependent s-phase checkpoint pathway. Smc1 associates with brca1 and is phosphorylated in response to ir in an atm- and nbs1-dependent manner. Using mass spectrometry, we established that atm phosphorylates s957 and s966 of smc1 in vivo.	SIGNOR-115492	0.693
GXYLT1	protein	Q4G148	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	glycosylation			9606									22117070	t	Xylosylation in endoplasmic reticulum membrane	gcesareni	Activity on notch egf repeats was proven by in vitro xylosylation of a mouse notch1 fragment recombinantly produced in sf9 insect cells, a bacterially expressed egf repeat from mouse notch2 modified in vitro by rumi and gxylt2 and in vivo by co-expression of the enzyme with the notch1 fragment.	SIGNOR-177691	0.392
HES1	protein	Q14469	UNIPROT	ATOH1	protein	Q92858	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938								30030829	f		lperfetto	The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 	SIGNOR-265144	0.485
FBN1	protein	P35555	UNIPROT	FBLN5	protein	Q9UBX5	UNIPROT	down-regulates activity	binding			9606									19570982	t		miannu	Fibulin-4 and -5 are extracellular glycoproteins with essential non-compensatory roles in elastic fiber assembly. We have determined how they interact with tropoelastin, lysyl oxidase, and fibrillin-1, thereby revealing how they differentially regulate assembly. Both fibulins differentially bound N-terminal fibrillin-1, which strongly inhibited their binding to lysyl oxidase and tropoelastin. 	SIGNOR-252138	0.398
CDK1	protein	P06493	UNIPROT	PKN1	protein	Q16512	UNIPROT	up-regulates activity	phosphorylation	Ser562	LGTDSDSsPQKSSRD	9606	BTO:0000567								31981797	t		miannu	CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines.	SIGNOR-276831	0.411
APOBEC3F	protein	Q8IUX4	UNIPROT	Clearance_of_foreign intracellular_DNA	phenotype	SIGNOR-PH132	SIGNOR	up-regulates				9606									29367246	f		lperfetto	The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24).	SIGNOR-261327	0.7
CSNK2A2	protein	P19784	UNIPROT	GTF2A1L	protein	Q9UNN4	UNIPROT	up-regulates activity	phosphorylation	Ser423	LNSGDDVsEQDVPDL	-1									12107178	t		llicata	ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.	SIGNOR-250994	0.424
EP300	protein	Q09472	UNIPROT	PCK1	protein	P35558	UNIPROT	down-regulates quantity by destabilization	acetylation	Lys594	KEVEDIEkYLEDQVN	9606	BTO:0000007								21726808	t		lperfetto	Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 	SIGNOR-267604	0.526
PPP2CA	protein	P67775	UNIPROT	MAP3K7	protein	O43318	UNIPROT	down-regulates	dephosphorylation	Thr187	CDIQTHMtNNKGSAA	9606									17079228	t		gcesareni	Our results demonstrate that pp6 specifically down-regulates tak1 through dephosphorylation of thr-187 in the activation loop, which is likely important for suppressing inflammatory responses via tak1 signaling pathways.	SIGNOR-150369	0.334
PRKCZ	protein	Q05513	UNIPROT	PLA2G4A	protein	P47712	UNIPROT	up-regulates activity	phosphorylation	Thr376	GSKFFMGtVVKKYEE	9606	BTO:0006398								32559461	t		miannu	 To further evaluate cPLA2 as a candidate substrate for PKCζ, we developed a custom antibody recognizing the cPLA2 T376 phosphorylation site. Specificity was validated in both serum starved/stimulated samples	SIGNOR-277518	0.334
FBXO30	protein	Q8TB52	UNIPROT	Muscle_atrophy	phenotype	SIGNOR-PH40	SIGNOR	up-regulates				10090		BTO:0000887							24076600	f			 gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1)	SIGNOR-256489	0.7
WNT8A	protein	Q9H1J5	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131984	0.606
ERBB2	protein	P04626	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates activity	phosphorylation	Tyr1222	PAFDNLYyWDQDPPE	-1									1706616	t			 Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2.	SIGNOR-251130	0.2
SMARCD2	protein	Q92925	UNIPROT	Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270693	0.754
SMDT1	protein	Q9H4I9	UNIPROT	 MCU_MICU3_variant	complex	SIGNOR-C501	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270870	0.614
p38	proteinfamily	SIGNOR-PF16	SIGNOR	HNF4A	protein	P41235	UNIPROT	up-regulates	phosphorylation	Ser167	VLSRQITsPVSGING	9606									16351573	t		lperfetto	Our results indicate that p38 kinase-mediated ser158 phosphorylation is essential for augmentation of the dna binding and transactivation potential of hnf4alpha	SIGNOR-143046	0.2
PICALM	protein	Q13492	UNIPROT	CLTC	protein	Q00610	UNIPROT	up-regulates	binding			9606									16491119	t		miannu	Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro	SIGNOR-144683	0.738
ATOH1	protein	Q92858	UNIPROT	MUC2	protein	Q02817	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17000673	f		miannu	 This study confirms the importance of HATH1 for the development of intestinal secretory cells. The results further suggest that HATH1 is an important factor in the up-regulation of MUC2 expression that occurs in mucinous cancers and signet ring carcinomas.	SIGNOR-253755	0.2
FBXO22	protein	Q8NEZ5	UNIPROT	BSG	protein	P35613	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								28117675	t		miannu	FBXO22 mediates poly-ubiquitination and degradation of CD147. Classically, F-box protein together with Skp1 and Cullin 1 constitute Skp-Cullin-F box ubiquitin E3 ligase (SCFs)	SIGNOR-272787	0.438
WNK1	protein	Q9H4A3	UNIPROT	STK39	protein	Q9UEW8	UNIPROT	up-regulates	phosphorylation	Ser371	VRRVPGSsGHLHKTE	9606									16083423	t		gcesareni	Phosphorylation by WNK1 or WNK4 markedly increased SPAK and OSR1 activity. Phosphopeptide mapping studies demonstrated that WNK1 phosphorylated kinase-inactive SPAK and OSR1 at an equivalent residue located within the T-loop of the catalytic domain (Thr233 in SPAK, Thr185 in OSR1) and a serine residue located within a C-terminal non-catalytic region (Ser373 in SPAK, Ser325 in OSR1)	SIGNOR-253553	0.457
PLK1	protein	P53350	UNIPROT	MAP9	protein	Q49MG5	UNIPROT	up-regulates	phosphorylation	Ser289	SDENKENsFSADHVT	9606									20615875	t		lperfetto	We also demonstrate that asap is a novel substrate of plk1 phosphorylation and have identified serine 289 as the major phosphorylation site by plk1 in vivo. Asap phosphorylated on serine 289 is localized to centrosomes during mitosis, but this phosphorylation is not required for its plk1-dependent localization at the spindle poles. We show that phosphorylated asap on serine 289 contributes to spindle pole stability in a microtubule-dependent manner	SIGNOR-166564	0.28
RAB7A	protein	P51149	UNIPROT	NTRK1	protein	P04629	UNIPROT	down-regulates activity	binding			10116									16306406	t		Sara	Endogenous TrkA and Rab7 form a complex. Inhibition of Rab7 potentiates the signaling of TrkA in response to brief stimulations with NGF	SIGNOR-261305	0.485
IKK-complex	complex	SIGNOR-C14	SIGNOR	IKBKG	protein	Q9Y6K9	UNIPROT	down-regulates activity	phosphorylation	Ser85	ELLHFQAsQREEKEF	9606				SIGNOR-C14					17977820	t		lperfetto	In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I	SIGNOR-209784	0.928
GABA-A (a2-b1-g2) receptor	complex	SIGNOR-C331	SIGNOR	CRHR1	protein	P34998	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268601	0.282
(R)-adrenaline	smallmolecule	CHEBI:28918	ChEBI	ADRA1A	protein	P35348	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258458	0.8
EPN1	protein	Q9Y6I3	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates	relocalization			9606									19054389	t		gcesareni	Epsin 1 is involved in recruitment of ubiquitinated egf receptors into clathrin-coated pits this supports the contention that epsin 1 promotes endocytosis of the ubiquitinated egfr.	SIGNOR-182562	0.578
SIRT2	protein	Q8IXJ6	UNIPROT	PCK1	protein	P35558	UNIPROT	up-regulates quantity by stabilization	deacetylation	Lys70	EGILRRLkKYDNCWL	9606	BTO:0000007								21726808	t		lperfetto	Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 	SIGNOR-267599	0.438
MSL2	protein	Q9HCI7	UNIPROT	MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	form complex	binding			9606		BTO:0000567							16227571	t		miannu	We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. 	SIGNOR-263941	0.893
IRS2	protein	Q9Y4H2	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606									12850284	t		gcesareni	There was a high level of irs-2 expression and insulin-stimulated tyrosyl phosphorylation as early as embryonic day 15 with robust pi3k binding and activation	SIGNOR-103174	0.543
PSMD13	protein	Q9UNM6	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263348	0.881
TYK2	protein	P29597	UNIPROT	IFNAR1	protein	P17181	UNIPROT	up-regulates activity	phosphorylation	Tyr481	PSSSIDEyFSEQPLK	9606									7526154	t		lperfetto	In this report, we demonstrate that the alpha subunit of the type I IFN receptor (IFN-R) corresponds to the product of a previously cloned receptor subunit cDNA and, further, that the p135tyk2 tyrosine kinase directly binds and tyrosine phosphorylates this receptor subunit.These data support the hypothesis that the Tyk2 protein functions as part of a receptor complex to initiate intracellular signaling in response to type I IFNs	SIGNOR-246939	0.908
AMPK	complex	SIGNOR-C15	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	down-regulates activity	phosphorylation			10090	BTO:0002572								21460634	t		miannu	 AMP-activated protein kinase (AMPK), which is activated by LKB1/Strad/Mo25 upon high AMP levels, stimulates autophagy by inhibiting mTORC1.	SIGNOR-216418	0.449
TNF	protein	P01375	UNIPROT	PIK3CB	protein	P42338	UNIPROT	up-regulates				9606									10485710	f		gcesareni	Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k).	SIGNOR-70619	0.257
TSHR	protein	P16473	UNIPROT	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding			9606									25878058	t		scontino	The primary signal transduction pathway for TSH receptor is activation of adenylate cyclase via a Gαs G protein-coupled receptor.	SIGNOR-267136	0.649
SRC	protein	P12931	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	phosphorylation	Tyr81	WEVGSITyDTLSAQA	9606									32653904	t		miannu	Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS.	SIGNOR-277520	0.431
DIO	proteinfamily	SIGNOR-PF83	SIGNOR	3,3'-diiodothyronine	smallmolecule	CHEBI:35430	ChEBI	up-regulates quantity	small molecule catalysis			9606	BTO:0004055								12746313	t	inferred from family member	scontino	Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. 	SIGNOR-270307	0.8
SRC	protein	P12931	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr797	TLMSVPRyLPRPANP										31286874	t		lperfetto	Activated c-Src phosphorylated E-cadherin at the tyrosine 797 site to initiate RNF43-mediated E-cadherin ubiquitination at lysine 816 and subsequent degradation	SIGNOR-274048	0.747
SNCAIP	protein	Q9Y6H5	UNIPROT	SNCA	protein	P37840	UNIPROT	up-regulates activity	binding			9606									19224863	t		miannu	Synphilin-1 interacts in vivo with α-synuclein, and their coexpression promotes the formation of Lewy body-like inclusions	SIGNOR-272597	0.794
HTATSF1	protein	O43719	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270652	0.426
ULK3	protein	Q6PHR2	UNIPROT	GLI3	protein	P10071	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								19878745	t		Manara	We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro	SIGNOR-260799	0.543
ATM	protein	Q13315	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates activity	phosphorylation	Ser1981	SLAFEEGsQSTTISS	9606									21149446	t		gcesareni	In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible.	SIGNOR-170469	0.2
CSNK2A2	protein	P19784	UNIPROT	GTF2A1	protein	P52655	UNIPROT	up-regulates activity	phosphorylation	Ser280	VDGTGDTsSEEDEDE	-1									11278496	t		llicata	We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function.	SIGNOR-250995	0.382
DUSP4	protein	Q13115	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates activity	dephosphorylation	Thr202	HDHTGFLtEYVATRW	10116									7535768	t			Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK	SIGNOR-248715	0.696
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257907	0.8
Fanconi anemia ID complex	complex	SIGNOR-C302	SIGNOR	BRCA1	protein	P38398	UNIPROT	up-regulates													18985065	f		lperfetto	Once monoubiquitinated, the ID complex becomes associated with chromatin and is redistributed to DNA-damage sites, forming foci that are visible by immunofluorescence and colocalizing with other DNA-repair molecules, notably BRCA1, BRCA2 and γH2AX.	SIGNOR-263271	0.826
MLL-ENL	fusion protein	SIGNOR-FP7	SIGNOR	 Core Binding Factor complex	complex	SIGNOR-C214	SIGNOR	down-regulates quantity by repression	transcriptional regulation			9606									24449215	f		miannu	However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. 	SIGNOR-255971	0.2
ATG101	protein	Q9BSB4	UNIPROT	ATG13	protein	O75143	UNIPROT	up-regulates	binding			9606									19597335	t		gcesareni	Furthermore, atg101 is important for the stability and basal phosphorylation of atg13 and ulk1	SIGNOR-186989	0.958
HTR1B	protein	P28222	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257115	0.252
FBXW7	protein	Q969H0	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									15546612	t		lperfetto	Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.	SIGNOR-130706	0.633
ELF3	protein	P78545	UNIPROT	KRT4	protein	P19013	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								10773884	f	 	 	Interestingly, ELF3 suppressed basal keratin 4 promoter activity in both esophageal and cervical epithelial cancer cell lines, a novel result, while simultaneously activating the late-differentiation linked SPRR2A promoter.	SIGNOR-254291	0.289
TRIM63	protein	Q969Q1	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys262	DSDDALLkMTISQQE	-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). 	SIGNOR-272740	0.413
DRD1	protein	P21728	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257068	0.288
AKT1	protein	P31749	UNIPROT	PDE3B	protein	Q13370	UNIPROT	up-regulates	phosphorylation	Ser295	VIRPRRRsSCVSLGE	9606									10454575	t		esanto	Pde3b is a physiological substrate of akt and that akt-mediated phosphorylation of pde3b on serine-273 is important for insulin-induced activation of pde3b.	SIGNOR-252583	0.679
PML	protein	P29590	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606	BTO:0001271								15093545	f		gcesareni	The promyelocytic leukemia (pml) protein is a potent growth suppressor and proapototic factor	SIGNOR-256659	0.7
GGCX	protein	P38435	UNIPROT	F10	protein	P00742	UNIPROT	up-regulates activity	carboxylation	Glu56	KKGHLEReCMEETCS	-1									9538022	t		lperfetto	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263667	0.598
PDGFRB	protein	P09619	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			9606									7935391	t		fspada	A pathway leading to activation of the gtp-binding protein ras involves the adaptor molecule grb2. Here we show that tyr-716, a novel autophosphorylation site in the pdgf beta-receptor kinase insert, mediates direct binding of grb2 in vitro and in vivo.	SIGNOR-34765	0.666
STK11	protein	Q15831	UNIPROT	PRKAA2	protein	P54646	UNIPROT	up-regulates	phosphorylation	Thr172	SDGEFLRtSCGSPNY	9606				SIGNOR-C15					14614828	t		gcesareni	We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli	SIGNOR-119179	0.61
APC-c	complex	SIGNOR-C150	SIGNOR	PFKFB3	protein	Q16875	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000793								20080744	t		miannu	We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1, which also degrades cell-cycle proteins. 	SIGNOR-271435	0.2
FGFR1	protein	P11362	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates	phosphorylation	Tyr306	PSNHHAVyDVPPSVS	9606									12601080	t		lperfetto	Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas.	SIGNOR-98496	0.259
PTPN2	protein	P17706	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates activity	dephosphorylation	Tyr1054	FGLARDIyKDPDYVR	9606	BTO:0000007								18840653	t			We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well. 	SIGNOR-248399	0.548
SRC	protein	P12931	UNIPROT	DNM1	protein	Q05193	UNIPROT	up-regulates activity	phosphorylation	Tyr231	LLPLRRGyIGVVNRS	9606	BTO:0000007								9880482	t		lperfetto	Src-mediated tyrosine phosphorylation of dynamin is required for beta2-adrenergic receptor internalization and mitogen-activated protein kinase signalingHere we demonstrate that activation of beta2-adrenergic receptors (beta2-ARs) leads to c-Src-mediated tyrosine phosphorylation of dynamin, which is required for receptor internalization. Two tyrosine residues, Tyr231 and Tyr597, are identified as the major phosphorylation sites	SIGNOR-247124	0.621
HNF4A	protein	P41235	UNIPROT	G6PC1	protein	P35575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20577053	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-166355	0.2
ZAP70	protein	P43403	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	phosphorylation	Tyr492	ALGADDSyYTARSAG	9606									8756661	t		lperfetto	The data further support a model in which ZAP-70 is first phosphorylated by Lck at Tyr-493 to upregulate the catalytic activity of ZAP-70. This in turn per- mits additional phosphorylation of ZAP-70 mediated, in part, by autophosphorylation at sites including Tyr-292 and -492	SIGNOR-226624	0.2
PRKCB	protein	P05771	UNIPROT	PRKCB	protein	P05771	UNIPROT	up-regulates	phosphorylation	Thr642	TRQPVELtPTDKLFI	9606									17115692	t		lperfetto	The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif	SIGNOR-150865	0.2
CSNK2A1	protein	P68400	UNIPROT	WASF2	protein	Q9Y6W5	UNIPROT	down-regulates	phosphorylation	Ser488	YSDSEDDsSEFDEDD	9606									19012317	t		gcesareni	Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo.	SIGNOR-182358	0.2
CSNK1G1	protein	Q9HCP0	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation	Ser325	SSNASTIsGRLSPIM	-1									11980723	t		llicata	Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR	SIGNOR-250821	0.471
BCL3	protein	P20749	UNIPROT	NFKB2	protein	Q00653	UNIPROT	up-regulates	binding			9606									16713561	t		gcesareni	The cyclin d1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of bcl-3-associated nf-kappab p50 and p52.	SIGNOR-146768	0.554
KMT2C	protein	Q8NEZ4	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30385408	t		miannu	MLL3 enhances the transcription of PD-L1 and regulates anti-tumor immunity. We found that MLL3 bound to the enhancer of PD-L1.	SIGNOR-260040	0.2
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	GATA2	protein	P23769	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								25670854	t		miannu	GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. Substitution of threonine 176 to alanine in GATA2 inhibited binding with Fbw7, and the ubiquitylation and degradation of GATA2 by Fbw7 was suppressed. The CPD kinase, which mediates the phosphorylation of Thr(176), was cyclin B-cyclin-dependent kinase 1 (CDK1). 	SIGNOR-276885	0.343
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	HSPB8	protein	Q9UJY1	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser24	RRDPFRDsPLSSRLL	-1									18298377	t		miannu	Human small heat shock protein with molecular mass 22 kD (HSP22, HspB8) contains two Ser residues (Ser24 and Ser57) in consensus sequence RXS and is effectively phosphorylated by cAMP-dependent protein kinase in vitro. Mutation S24D did not affect, whereas mutations S57D or S24,57D prevented phosphorylation of HSP22 by cAMP-dependent protein kinase thus indicating that Ser57 is the primary site of phosphorylation. Phosphorylation (or mutation) of Ser57 (or Ser24 and Ser57) resulted in changes of the local environment of tryptophan residues and increased HSP22 susceptibility to chymotrypsinolysis. 	SIGNOR-276152	0.2
fentanyl	chemical	CHEBI:119915	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029									9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258938	0.8
FANCL	protein	Q9NW38	UNIPROT	FANCI	protein	Q9NVI1	UNIPROT	up-regulates activity	ubiquitination						SIGNOR-C300						18985065	t		lperfetto	Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding	SIGNOR-263266	0.837
ADAM12	protein	O43184	UNIPROT	SDC4	protein	P31431	UNIPROT	up-regulates	binding			9606		BTO:0000975							12509413	t		gcesareni	The adam12 cysteine-rich domain (radam12-cys) supports cell attachment using syndecan-4 as a primary cell surface receptor that subsequently triggers beta(1) integrin-dependent cell spreading, stress fiber assembly, and focal adhesion formation.	SIGNOR-96931	0.443
PTPRG	protein	P23470	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates activity	dephosphorylation	Tyr1054	FGLARDIyKDPDYVR	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254707	0.255
RPS6KA5	protein	O75582	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr37	PPGDYSTtPGGTLFS										12213813	t		lperfetto	In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E	SIGNOR-262991	0.658
PDK1	protein	Q15118	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	phosphorylation	Ser232	NRYGMGTsVERAAAS	-1									11485553	t		lperfetto	Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.	SIGNOR-109547	0.785
FLT3	protein	P36888	UNIPROT	FZD4	protein	Q9ULV1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15650056	f			Microarray analyses revealed higher mRNA expression of Frizzled-4, a receptor for Wnt ligands in 32D/Flt3-ITD cells. Findings were verified by quantitative realtime reverse transcription–polymerase chain reaction (RT-PCR) and on the protein level.	SIGNOR-260121	0.2
CSNK1A1	protein	P48729	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	phosphorylation	Ser45	GATTTAPsLSGKGNP	9606									20419129	t		lperfetto	Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome	SIGNOR-165022	0.783
FYN	protein	P06241	UNIPROT	DCBLD2	protein	Q96PD2	UNIPROT	up-regulates activity	phosphorylation	Tyr666	GQEVYHAyAEPLPIT	-1									23770091	t	done	miannu	Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding.	SIGNOR-273946	0.357
PAK5	protein	Q9P286	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser75	EIRSRHSsYPAGTED	9534	BTO:0000298								12897128	t		miannu	P21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Pak5 phosphorylates BAD Ser-112	SIGNOR-250247	0.2
EGFR	protein	P00533	UNIPROT	EPS15	protein	P42566	UNIPROT	up-regulates	phosphorylation	Tyr849	NFANFSAyPSEEDMI	9606									24269888	t		lperfetto	Earlier studies have shown that eps15 at tyr-849 is phosphorylated in egf-stimulated cells and partly controls the internalization of mono-ubiquitinated egfr via uim domains of eps15 [10]. It has also been shown that active egfr phosphorylates tyr-849 directly;	SIGNOR-203311	0.746
FAAP24	protein	Q9BTP7	UNIPROT	Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	form complex	binding			9606	BTO:0000567								17396147	t		lperfetto	This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo 	SIGNOR-263239	0.2
PDPK1	protein	O15530	UNIPROT	OXTR	protein	P30559	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								35104164	t		lperfetto	We found that Ser261 in OXTR was phosphorylated by protein kinase D1 (PKD1).|In HEK293A cells, the PKD1-mediated phosphorylation of OXTR promoted its binding to Gq protein and, in turn, OXTR-mediated phosphorylation of PKD1, indicating a positive feedback loop.	SIGNOR-268577	0.2
TNF	protein	P01375	UNIPROT	RIPK2	protein	O43353	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18647246	f		miannu	NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B.	SIGNOR-252409	0.361
CSNK2A1	protein	P68400	UNIPROT	PPP1R8	protein	Q12972	UNIPROT	up-regulates activity	phosphorylation	Ser204	KNSRVTFsEDDEIIN	-1									9407077	t		llicata	Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2.	SIGNOR-250930	0.482
DUSP3	protein	P51452	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	dephosphorylation	Tyr1016	DVVDADEyLIPQQGF	9606	BTO:0002552								21262974	t			We found that EGF receptor (EGFR) was a direct substrate of VHR and that overexpression of VHR down-regulated EGFR phosphorylation, particularly at Tyr-992 residue. Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR.	SIGNOR-248532	0.364
BDKRB1	protein	P46663	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257036	0.409
DLG3	protein	Q92796	UNIPROT	NMDA	proteinfamily	SIGNOR-PF56	SIGNOR	up-regulates activity	relocalization					BTO:0000227							32904533	t		lperfetto	DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses.	SIGNOR-266005	0.2
SIRT2	protein	Q8IXJ6	UNIPROT	PGAM1	protein	P18669	UNIPROT	up-regulates activity	deacetylation	Lys100	GGLTGLNkAETAAKH	9606									24786789	t		miannu	 Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2.	SIGNOR-266517	0.284
ALDOB	protein	P05062	UNIPROT	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266488	0.8
EGFR	protein	P00533	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1092	TFLPVPEyINQSVPK	10090	BTO:0002882								16122376	t	Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer	lperfetto	EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work	SIGNOR-236523	0.2
Laminin-5	complex	SIGNOR-C184	SIGNOR	A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	up-regulates activity	binding												8832392	t		lperfetto	The initial adhesion of PA-JEB and normal keratinocytes to laminin-1 and laminin-5, both ligands for alpha 6 beta 1 and alpha 6 beta 4, was similar. 	SIGNOR-253253	0.582
ROS	stimulus	SIGNOR-ST2	SIGNOR	ATF4	protein	P18848	UNIPROT	up-regulates				9606									19439225	f		lperfetto	Oxidative and ER stress conditions induce rapid and significant activation of ATF4 downstream of eIF2alpha phosphorylation, which is responsible for Redd1 expression	SIGNOR-253729	0.7
WLS	protein	Q5T9L3	UNIPROT	WNT3A	protein	P56704	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000007								20826466	t			WNT secretion requires its binding to the carrier protein wntless (WLS);	SIGNOR-256599	0.627
STK11	protein	Q15831	UNIPROT	STK11	protein	Q15831	UNIPROT	up-regulates activity	phosphorylation	Thr402	TEAAQLStKSRAEGR	9606	BTO:0000007;BTO:0000567								12805220	t		lperfetto	It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity.	SIGNOR-101852	0.2
WNT1	protein	P04628	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								21078818	t		gcesareni	Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.	SIGNOR-169648	0.822
PYHIN1	protein	Q6K0P9	UNIPROT	HDAC1	protein	Q13547	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001570								18247378	f		miannu	We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1.	SIGNOR-268495	0.296
GRK4	protein	P32298	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser366	EPIQMENsMGTLRTS	9606	BTO:0000007								11517230	t		gcesareni	...expression of GRK4Ž drastically increased the basal level of32P incorporation into B2R.[€]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation.	SIGNOR-247902	0.292
USF1	protein	P22415	UNIPROT	S100A6	protein	P06703	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11118618	f		miannu	 The results indicate that USF1 binds to an E-box sequence of the calcyclin gene promoter and enhances its transcription activity. 	SIGNOR-255598	0.2
CCP110	protein	O43303	UNIPROT	CETN1	protein	Q12798	UNIPROT	up-regulates activity	binding			9606									16760425	t		miannu	We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis.	SIGNOR-265966	0.497
SNAI2	protein	O43623	UNIPROT	VDR	protein	P11473	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000356								18485278	f		miannu	 We have shown here that the transcriptional repressor protein SLUG inhibits the expression of VDR in human breast cancer cells. 	SIGNOR-255177	0.382
malonyl-CoA	smallmolecule	CHEBI:15531	ChEBI	hexadecanoic acid	smallmolecule	CHEBI:15756	ChEBI	up-regulates quantity	precursor of			9606									15507492	t		miannu	Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the de novo biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH. 	SIGNOR-268090	0.8
ENPP1	protein	P22413	UNIPROT	Bone_mineralization	phenotype	SIGNOR-PH69	SIGNOR	up-regulates				9606									19049325	f		miannu	PC-1 and Tnap work together to produce normally mineralized bone matrix through the generation and hydrolysis of pyrophosphate.	SIGNOR-252195	0.7
MAPK1	protein	P28482	UNIPROT	UBTF	protein	P17480	UNIPROT	down-regulates	phosphorylation	Thr117	DFPKKPLtPYFRFFM	9606									11741541	t		lperfetto	Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna	SIGNOR-112805	0.402
PPM1D	protein	O15297	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates activity	dephosphorylation	Ser140	PKTDPSDsQTGLAEQ	9606									31959038	t		miannu	Increased expression of wildtype WIP1 reduces stability of p27 Kip1 while increased expression of similar amounts of phosphatase-dead WIP1 has no effect on p27 Kip1 protein stability.|We demonstrate that wildtype, but not phosphatase-dead WIP1, efficiently dephosphorylates p27 Kip1 Ser140 both in vitro and in cells and that this dephosphorylation is sensitive to the WIP1 specific inhibitor GSK 2830371.	SIGNOR-277109	0.263
ULK1	protein	O75385	UNIPROT	DENND3	protein	A2RUS2	UNIPROT	up-regulates activity	phosphorylation	Ser490	ELAPRNSsLRLTDTA	9606									25925668	t		lperfetto	ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12.	SIGNOR-264731	0.41
SHANK3	protein	Q9BYB0	UNIPROT	NMDA	proteinfamily	SIGNOR-PF56	SIGNOR	up-regulates quantity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264701	0.2
PRKCD	protein	Q05655	UNIPROT	BEST1	protein	O76090	UNIPROT	down-regulates activity	phosphorylation	Ser358	SAQFRRAsFMGSTFN	9606									19635817	t		Manara	We have identified a PKC phosphorylation site (S358) located in the C terminal region of hBest1 critical for channel rundown. Phosphorylation of this site by PKC activators and PP2A inhibitors reduces channel rundown.	SIGNOR-260880	0.2
CDK1	protein	P06493	UNIPROT	PTPN1	protein	P18031	UNIPROT	unknown	phosphorylation	Ser386	LRGAQAAsPAKGEPS	9606	BTO:0000567								8491187	t		llicata	Ptp1b is phosphorylated on ser386 by p34cdc2 in vivo.	SIGNOR-39233	0.517
PLK1	protein	P53350	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates	phosphorylation	Ser123	EEGFGSSsPVKSPAA	9606									16085715	t		gcesareni	Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp.	SIGNOR-139473	0.626
NPTX1	protein	Q15818	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates quantity				9606	BTO:0004168;BTO:0003227								31113871	f		lperfetto	We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control	SIGNOR-260412	0.2
MAPK8	protein	P45983	UNIPROT	JUNB	protein	P17275	UNIPROT	up-regulates activity	phosphorylation	Thr104	GVITTTPtPPGQYFY	10090									9889198	t		miannu	JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation. 	SIGNOR-250121	0.72
XRCC4	protein	Q13426	UNIPROT	Lig4-Xrcc4 complex	complex	SIGNOR-C354	SIGNOR	form complex	binding			-1									19837014	t		miannu	The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals. 	SIGNOR-264532	0.95
POU5F1	protein	Q01860	UNIPROT	EOMES	protein	O95936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086								17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254930	0.434
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CALM3	protein	P0DP25	UNIPROT	up-regulates	chemical activation			9606									10884684	t		miannu	Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘open’ conformations	SIGNOR-266333	0.8
CyclinD1/CDK6	complex	SIGNOR-C143	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser45	GATTTAPsLSGKGNP	-1									17208333	t		llicata	We showed that CCND1-CDK6 phosphorylates beta-catenin on serine 45 (S45). This phosphorylation creates a priming site for glycogen synthase kinase 3beta (GSK3beta) and is both necessary and sufficient to initiate the beta-catenin phosphorylation-degradation cascade.	SIGNOR-250647	0.641
CHIR 99021	chemical	CHEBI:91091	ChEBI	GSK3A	protein	P49840	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190997	0.8
TP53	protein	P04637	UNIPROT	BBC3	protein	Q9BXH1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001109								16151013	f		amattioni	Nuclear p53 caused expression of puma, which then displaced p53 from bcl-xl, allowing p53 to induce mitochondrial permeabilization.	SIGNOR-140245	0.683
MET	protein	P08581	UNIPROT	RANBP9	protein	Q96S59	UNIPROT	up-regulates	binding			9606									12147692	t		gcesareni	Our data suggest that ranbpm, functioning as an adaptor protein for the met tyrosine kinase domain, can augment the hgf-met signaling pathway.	SIGNOR-91028	0.537
ABL1	protein	P00519	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates	phosphorylation	Tyr386	YRARVANyQRDGPMC	9606									12950161	t		lperfetto	C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases	SIGNOR-86585	0.412
PLK4	protein	O00444	UNIPROT	TUBGCP6	protein	Q96RT7	UNIPROT	up-regulates activity	phosphorylation	Ser1437	RYPDSYEsMSEPPIA	-1									22302995	t		miannu	Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication.	SIGNOR-262907	0.691
LCK	protein	P06239	UNIPROT	SH2D2A	protein	Q9NP31	UNIPROT	up-regulates activity	phosphorylation	Tyr305	GEAPSNIyVEVEDEG	9606									18541536	t		miannu	 Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition.	SIGNOR-262890	0.597
THOC7	protein	Q6I9Y2	UNIPROT	TREX complex	complex	SIGNOR-C444	SIGNOR	form complex	binding			9606									33191911	t		miannu	The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56.	SIGNOR-268507	0.911
TFEB	protein	P19484	UNIPROT	HPS4	protein	Q9NQG7	UNIPROT	up-regulates quantity by expression	transcriptional regulation												32978159	f		lperfetto	Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14)	SIGNOR-276795	0.296
ZAP70	protein	P43403	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates activity	phosphorylation	Tyr113	SSFEEDDyESPNDDQ	9606	BTO:0000782								12817019	t		lperfetto	Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase.	SIGNOR-102507	0.798
Laminin-5	complex	SIGNOR-C184	SIGNOR	A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	up-regulates activity	binding												9790905	t		lperfetto	We propose that these alpha6 beta4/Ln-5 complexes may provide links between plasma membrane and basement membrane that resist mechanical stress and support epithelial integrity.	SIGNOR-253238	0.582
SEC24C	protein	P53992	UNIPROT	COPII vesicle	complex	SIGNOR-C370	SIGNOR	form complex	binding			9606	BTO:0000567								30605680	t		lperfetto	The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat	SIGNOR-265294	0.683
IGFBP5	protein	P24593	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates activity				10090	BTO:0000165								18762576	f			These findings suggest that IGFBP-5 promotes muscle cell differentiation by binding to and switching on the IGF-II auto-regulation loop.	SIGNOR-255940	0.7
PRKACA	protein	P17612	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates activity	phosphorylation	Thr369	DLINKKItPPFNPNV	-1									11096081	t		miannu	In this publication, we demonstrate that cAMP can activate Sgk and that this effect is mediated by PKA, which directly phosphorylates Thr369 in Sgk. 	SIGNOR-275972	0.3
EAF1	protein	Q96JC9	UNIPROT	ELL	protein	P55199	UNIPROT	up-regulates	binding			9606									16006523	t		miannu	Positive regulation of ell elongation activity depends on stable binding of eaf1 to the ell n terminus	SIGNOR-138516	0.841
MEF2C	protein	Q06413	UNIPROT	MECP2	protein	P51608	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20513142	f	 	 	Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression|In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5.	SIGNOR-254025	0.354
LCK	protein	P06239	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	phosphorylation	Tyr493	LGADDSYyTARSAGK	9606	BTO:0000661								7961936	t			We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck.	SIGNOR-251395	0.601
PPARGC1A	protein	Q9UBK2	UNIPROT	ARNTL	protein	O00327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17476214	t		miannu	Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. 	SIGNOR-268031	0.499
CCN4	protein	O95388	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA	10116									11782444	t			Here it is shown that WISP-1 can activate the antiapoptotic Akt/PKB signaling pathway.	SIGNOR-256269	0.2
tRNA(Gln)	smallmolecule	CHEBI:29168	ChEBI	Gln-tRNA(Gln)	smallmolecule	CHEBI:29166	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270393	0.8
STK39	protein	Q9UEW8	UNIPROT	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation	Thr100	TNTYYLQtFGHNTMD	9606	BTO:0000007								21321328	t		miannu	 We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A).	SIGNOR-276307	0.596
DNA polymerase epsilon	complex	SIGNOR-C377	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									10801849	f		lperfetto	HeLa pol epsilon was initially purified as a soluble factor that restored repair synthesis to cytosol-depleted, UV-irradiated permeabilized human fibroblasts (11). By reconstituting the nucleotide excision repair (NER) process from purified proteins, Shivji et al. (12) further showed that mammalian pol epsilon was the most efficient enzyme in performing gap-filling DNA synthesis during NER.	SIGNOR-265722	0.7
SLC2A3	protein	P11169	UNIPROT	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	up-regulates quantity	relocalization			9606									23506862	t		miannu	The SLC2A3 gene encoding GLUT3 was first cloned from a human fetal skeletal muscle cell line (Kayano et al., 1988). It shares ~64% sequence identity with SLC2A1. GLUT3 has a higher apparent affinity (lower Km) and a higher maximum turnover number for glucose than the other Class 1 GLUT proteins, and its principal physiological substrate is clearly D-glucose 	SIGNOR-267459	0.8
SRC	protein	P12931	UNIPROT	ARAF	protein	P10398	UNIPROT	up-regulates activity	phosphorylation	Tyr302	GYRDSGYyWEVPPSE	9534									9020159	t		lperfetto	A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation	SIGNOR-236459	0.466
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	TAOK1	protein	Q7L7X3	UNIPROT	up-regulates				9606									17396146	f		lperfetto	These findings indicate that TAO kinases are regulators of p38-mediated responses to DNA damage and are intermediates in the activation of p38 by ATM.	SIGNOR-226599	0.7
TH	protein	P07101	UNIPROT	tyrosine	smallmolecule	CHEBI:18186	ChEBI	down-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH).	SIGNOR-263990	0.8
PPP1CB	protein	P62140	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	dephosphorylation	Ser37	NVLSPLPsQAMDDLM	9606									16501611	t			Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.	SIGNOR-248573	0.29
VPS4A	protein	Q9UN37	UNIPROT	CHMP3	protein	Q9Y3E7	UNIPROT	up-regulates activity	cleavage			-1									30989108	t		Giorgia	Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission.	SIGNOR-260847	0.645
SLC5A5	protein	Q92911	UNIPROT	iodide	smallmolecule	CHEBI:16382	ChEBI	up-regulates activity	chemical activation			9606									14623893	t		miannu	Iodide is an essential element in thyroid physiology as a critical component of thyroxine and triiodothyronine molecules and a key regulator of thyroid gland function. The first step in iodide metabolism is represented by thyroid trapping, which is achieved by an active, energy-dependent transport process across the basolateral plasma membrane of the thyrocytes. The protein responsible for this process, the sodium/iodide symporter (NIS),1 is an intrinsic plasma membrane protein that mediates active transport of I- in the thyroid, lactating mammary gland, stomach, and salivary glands	SIGNOR-251996	0.8
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3Y2	protein	P0DPK5	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkATAWQAP	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269632	0.2
NR3C1	protein	P04150	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity				10090	BTO:0000944								11742987	f		gcesareni	Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1|Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. In NIH-3T3 fibroblasts, although glucocorticoids up-regulate the MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity. 	SIGNOR-251678	0.607
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	GATA1	protein	P15976	UNIPROT	up-regulates	phosphorylation	Ser310	QTRNRKAsGKGKKKR	9606									16107690	t		lperfetto	We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter.	SIGNOR-244267	0.2
PRKAA1	protein	Q13131	UNIPROT	PRPS1	protein	P60891	UNIPROT	down-regulates activity	phosphorylation	Ser180	GGAKRVTsIADRLNV	9606	BTO:0006038								29074724	t		lperfetto	We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production.	SIGNOR-265729	0.2
SYVN1	protein	Q86TM6	UNIPROT	CLU	protein	P10909	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0000298								17451556	t		miannu	We also report that the ER-associated ubiquitin ligase Hrd1/synoviolin can interact with, and ubiquitinate clusterin. The fact that cleaved endogenous clusterin appears, under certain conditions, to be subject to polyubiquitination (Figure 2C) and proteasomal degradation (1, 2) strongly suggests that it passed through the secretory pathway before reaching the cytosol.	SIGNOR-272629	0.325
LIMK1	protein	P53667	UNIPROT	CFL1	protein	P23528	UNIPROT	down-regulates	phosphorylation	Ser3	sGVAVSDG	9606									18079118	t		gcesareni	Our results suggest that limk1-mediated cofilin phosphorylation is required for accurate spindle orientation by stabilizing cortical actin networks during mitosis	SIGNOR-159885	0.808
ZAP70	protein	P43403	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	phosphorylation	Tyr292	DTLNSDGyTPEPARI	9606	BTO:0000782;BTO:0000776								8756661	t		lperfetto	The data further support a model in which ZAP-70 is first phosphorylated by Lck at Tyr-493 to upregulate the catalytic activity of ZAP-70. This in turn per- mits additional phosphorylation of ZAP-70 mediated, in part, by autophosphorylation at sites including Tyr-292 and -492	SIGNOR-43324	0.2
EP300	protein	Q09472	UNIPROT	SMAD7	protein	O15105	UNIPROT	up-regulates	acetylation	Lys70	GKAVRGAkGHHHPHP	9606									12408818	t		gcesareni	Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300	SIGNOR-95169	0.476
RNF146	protein	Q9NTX7	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates quantity	ubiquitination			9606	BTO:0000007								21799911	t			By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins.	SIGNOR-259998	0.515
SMARCB1	protein	Q12824	UNIPROT	Neural progenitor-specific SWI/SNF	complex	SIGNOR-C477	SIGNOR	form complex	binding			9606									25195934	t		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270618	0.852
FOXL2	protein	P58012	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606		BTO:0000975							16153597	f		miannu	We observed that foxl2 induces apoptosis in the ovarian cells unveiling a novel function of foxl2	SIGNOR-256643	0.7
LTBR	protein	P36941	UNIPROT	TRAF2	protein	Q12933	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								12571250	t		lperfetto	Endogenous association of traf2, traf3, ciap1, and smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis.	SIGNOR-97950	0.568
INSR	protein	P06213	UNIPROT	ADRB2	protein	P07550	UNIPROT	down-regulates activity	phosphorylation	Tyr354	LKAYGNGySSNGNTG	10029	BTO:0000246								8557631	t			Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors. 	SIGNOR-251302	0.385
CNR1	protein	P21554	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256724	0.52
SRC	protein	P12931	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates activity	phosphorylation	Tyr973	RLGNGVLyASVNPEY	-1									8940173	t		lperfetto	The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.	SIGNOR-247193	0.564
2-deoxy-D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:62877	ChEBI	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	precursor of			9606									25229427	t		miannu	Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase.	SIGNOR-267096	0.8
GNAL	protein	P38405	UNIPROT	ADCY5	protein	O95622	UNIPROT	up-regulates activity	binding			9606	BTO:0004032								21303898	t		miannu	D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum.	SIGNOR-264997	0.599
CDON	protein	Q4KMG0	UNIPROT	SPAG9	protein	O60271	UNIPROT	up-regulates activity	binding			9606	BTO:0000222								17074887	t		lperfetto	In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway.	SIGNOR-150282	0.477
PRKCB	protein	P05771	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates	phosphorylation	Thr143	RGKFKRPtLRRVRIS	9606									17010989	t		lperfetto	Pkc-betaii sensitizes cardiac myofilaments to ca2+ by phosphorylating troponin i on threonine-144.	SIGNOR-149957	0.2
STK4	protein	Q13043	UNIPROT	MOB1B	protein	Q7L9L4	UNIPROT	up-regulates	phosphorylation	Thr12	FGSRSSKtFKPKKNI	9606									21808241	t	MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors.	gcesareni	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction.	SIGNOR-175837	0.846
SRC	protein	P12931	UNIPROT	ANXA2	protein	P07355	UNIPROT	up-regulates	phosphorylation	Tyr24	HSTPPSAyGSVKAYT	9606									15302870	t		lperfetto	Translocation requires the presence of the annexin 2 binding partner p11 (s100a10) and the phosphorylation of annexin 2 at tyr23 through a src-like tyrosine kinase-dependent mechanism both in vitro and in vivo.	SIGNOR-127872	0.564
SMURF	proteinfamily	SIGNOR-PF29	SIGNOR	SMAD9	protein	O15198	UNIPROT	down-regulates	ubiquitination			9606									22298955	t	inferred from 70% family members	gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-270211	0.2
EPHA2	protein	P29317	UNIPROT	EPHA2	protein	P29317	UNIPROT	up-regulates activity	phosphorylation	Tyr594	TYVDPHTyEDPNQAV	9606									18387945	t		lperfetto	The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells.	SIGNOR-178173	0.2
EGFR	protein	P00533	UNIPROT	IKBKE	protein	Q14164	UNIPROT	up-regulates activity	phosphorylation	Tyr153	GEEGQSIyKLTDFGA	9606									27287717	t		miannu	EGFRL858R/T790M phosphorylates IKBKE at tyrosine residues. While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179. 	SIGNOR-277242	0.26
ALG2	protein	Q9H553	UNIPROT	alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol)	smallmolecule	CHEBI:133994	ChEBI	up-regulates quantity	chemical modification			9606									28575298	t		lperfetto	The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum.	SIGNOR-260419	0.8
ARHGEF25	protein	Q86VW2	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260544	0.829
CDC7	protein	O00311	UNIPROT	MCM7	protein	P33993	UNIPROT	up-regulates	phosphorylation			9606									21070963	t		gcesareni	We propose that phosphorylation of mcm4/6 s/tp sites, which are already phosphorylated in g1, allows initial mcm2-7 phosphorylation by ddk and initiation from the first origins of replication ( fig. 7ai ).	SIGNOR-169506	0.94
JAK2	protein	O60674	UNIPROT	EPOR	protein	P19235	UNIPROT	up-regulates activity	phosphorylation	Tyr368	SEHAQDTyLVLDKWL										12441334	t			JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2	SIGNOR-251348	0.806
(+)-pilocarpine	chemical	CHEBI:8207	ChEBI	CHRM1	protein	P11229	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258627	0.8
Noncanonical PRC1	complex	SIGNOR-C151	SIGNOR	UHRF1	protein	Q96T88	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000011								25533466	f		miannu	We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis.	SIGNOR-252250	0.271
motesanib	chemical	CHEBI:51098	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258253	0.8
perfluorononanoic acid	chemical	CHEBI:38397	ChEBI	PPARD	protein	Q03181	UNIPROT	up-regulates activity	chemical activation			-1									31332417	t		miannu	In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group.	SIGNOR-268756	0.8
PTP4A1	protein	Q93096	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates				9606									14643450	f		gcesareni	Cells overexpressing either prl-1 or prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity and significantly lower p21cip1/waf1 protein levels	SIGNOR-119418	0.2
DHCR7	protein	Q9UBM7	UNIPROT	cholesta-5,7-dien-3beta-ol	smallmolecule	CHEBI:17759	ChEBI	down-regulates quantity	chemical modification			9606									9634533	t		miannu	In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol D7 -reductase. This NADPH-dependent enzyme catalyzes the reduction of the D7 -diene bond in 7-DHC, to form cholesterol.	SIGNOR-267251	0.8
chlorpromazine	chemical	CHEBI:3647	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258371	0.8
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	BCR	protein	P11274	UNIPROT	down-regulates activity	phosphorylation	Tyr360	YSPRSFEdCGGGYTP	9606									9467953	t		Manara	Thus, we propose that the phosphorylation of tyrosine 328 and 360 within Bcr by Bcr-Abl will drastically interfere with Bcr's kinase role in either signal transduction or some other cellular mechanism.	SIGNOR-260828	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	SLC12A2	protein	P55011	UNIPROT	down-regulates activity	phosphorylation	Ser77	RPLGPTPsQSRFQVD	-1									24702155	t		miannu	 AMPK was found to directly phosphorylate a recombinant human-NKCC1 N-terminal fragment (1-293) with the phosphorylated site identified as S77. Mutation of Serine 77 to Alanine partially prevented the inhibitory effect of A-769662 on NKCC1 activity. In conclusion, AMPK can act to reduce NKCC1-mediated transport. 	SIGNOR-276630	0.2
PDGFRB	protein	P09619	UNIPROT	NCK1	protein	P16333	UNIPROT	up-regulates	binding			9606									10026169	t		esanto	Growth factor binding to receptor protein tyrosine kinases (r-ptks)1 induces their dimerization and trans-phosphorylation, creating docking sites for proteins containing sh2 and ptb protein interaction domains. Nck binds to the pdgf and egfr receptors (figure 3c).	SIGNOR-64737	0.622
CAMK2A	protein	Q9UQM7	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser571	PWPLRRTsAQGQPSP	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275771	0.383
SREBF1	protein	P36956	UNIPROT	PKM	protein	P14618	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20577053	t		gcesareni	Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk)	SIGNOR-166381	0.295
AKT1	protein	P31749	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation	Ser256	SPRRRAAsMDNNSKF	-1	BTO:0000318								10377430	t		lperfetto	Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export.	SIGNOR-236159	0.866
PRKCD	protein	Q05655	UNIPROT	PRKCD	protein	Q05655	UNIPROT	up-regulates	phosphorylation	Thr295	AEALNQVtQRASRRS	9606									19366211	t		gcesareni	These results implicate pkcdelta-thr(295) autophosphorylation as a lipid-dependent modification that links pkcdelta-thr(505) phosphorylation to src-dependent regulation of pkcdelta catalytic function.	SIGNOR-185283	0.2
P2RY13	protein	Q9BPV8	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257231	0.2
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	MAPK3	protein	P27361	UNIPROT	down-regulates	dephosphorylation			9606									12840032	t		lperfetto	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases	SIGNOR-264665	0.2
HOXA9	protein	P31269	UNIPROT	MYCN	protein	P04198	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000661								21261500	f	 	miannu	 HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. 	SIGNOR-254213	0.293
SMARCA4	protein	P51532	UNIPROT	Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	form complex	binding			10090	BTO:0001086								19279220	t		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270726	0.76
IL4	protein	P05112	UNIPROT	IL2RG	protein	P31785	UNIPROT	up-regulates	binding			9606									11418623	t		gcesareni	The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex	SIGNOR-108861	0.853
ABL2	protein	P42684	UNIPROT	GPX1	protein	P07203	UNIPROT	up-regulates activity	phosphorylation	Tyr98	EILNSLKyVRPGGGF	9606									12893824	t		lperfetto	GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress.	SIGNOR-104328	0.327
APC-c	complex	SIGNOR-C150	SIGNOR	KIF2C	protein	Q99661	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1									24510915	t		miannu	Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A). 	SIGNOR-266111	0.281
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr36	LPPGDYStTPGGTLF	9606									9465032	t		lperfetto	Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size.	SIGNOR-217086	0.753
N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]-2-pyridinyl]methanesulfonamide	chemical	CHEBI:91370	ChEBI	PTK2B	protein	Q14289	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206070	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity	phosphorylation	Ser641	RRSVKRNsTVDCNGV	9606	BTO:0000938								32611770	t		lperfetto	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275785	0.282
H2AC11	protein	P0C0S8	UNIPROT	SGO1	protein	Q5FBB7	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567				phosphorylation:Thr121	AVLLPKKtESHHKAK	phosphorylation:Thr346	LEEGVHLtPFRQKVS	24055156	t		lperfetto	The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl.|The centromeric localization of Sgo1 requires histone H2A phosphorylation at T120 (H2A-pT120) by the kinase Bub1.	SIGNOR-265262	0.2
FFAR4	protein	Q5NUL3	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257371	0.425
SP1	protein	P08047	UNIPROT	RLIM	protein	Q9NVW2	UNIPROT	up-regulates quantity by expression	transcriptional regulation												23650532	t		lperfetto	Thus, RLIM is a novel target of p53, and p53 exerts its inhibitory effect on RLIM expression by interfering with Sp1-mediated transcriptional activation on RLIM.|Although p53 does not directly bind to the RLIM promoter, it physically interacts with and prevents the binding of Sp1 to the RLIM promoter.	SIGNOR-268980	0.2
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1644	SPTSPSYsPTSPSYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203516	0.77
MAPK14	protein	Q16539	UNIPROT	NR3C1	protein	P04150	UNIPROT	up-regulates	phosphorylation	Ser211	PGKETNEsPWRSDLL	9606									15817653	t		llicata	We found serine 211 of the human gr to be a substrate for p38 mapk both in vitro and intracellularly. Mutation of this site to alanine greatly diminished gr-driven gene transcription and apoptosis.	SIGNOR-135198	0.49
APAF1	protein	O14727	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates activity	binding			9606									15829969	t		lperfetto	During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 .	SIGNOR-135381	0.953
SP3	protein	Q02447	UNIPROT	SLC19A3	protein	Q9BZV2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			7227	BTO:0001677								15217784	f		miannu	In transiently transfected Drosophila SL2 cells, both SP1 and SP3 transactivated the SLC19A3 minimal promoter in a dose-dependent manner and in combination demonstrated an additive stimulatory effect.	SIGNOR-255214	0.3
DMC1	protein	Q14565	UNIPROT	Synaptonemal_complex	complex	SIGNOR-C351	SIGNOR	up-regulates activity	binding			10090	BTO:0001275								10525529	t		miannu	The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process.	SIGNOR-264208	0.344
BHC complex	complex	SIGNOR-C353	SIGNOR	SYN1	protein	P17600	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								12032298	t		miannu	We show that BHC interacts with the promoter of the synapsin gene and mediates its RE1-dependent repression. BHC is recruited to the endogenous synapsin gene.	SIGNOR-264504	0.273
CDK12	protein	Q9NYV4	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1917	SPTSPTYsPTSPKYS	9606									22012619	t		miannu	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176825	0.775
ARHGEF10	protein	O15013	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260537	0.478
DRD3	protein	P35462	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256702	0.527
MTOR	protein	P42345	UNIPROT	MAF1	protein	Q9H063	UNIPROT	down-regulates	phosphorylation	Ser75	SPSRLSKsQGGEEEG	9606	BTO:0000567								20543138	t		fstefani	Maf1, a repressor that binds and inhibits pol iii, is phosphorylated in a mtor-dependent manner both in vitro and in vivo at serine 75	SIGNOR-166054	0.7
PIH1D2	protein	Q8WWB5	UNIPROT	R2SP co-chaperone	complex	SIGNOR-C517	SIGNOR	form complex	binding			9606									29844425	t		miannu	Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes.	SIGNOR-270937	0.48
RET	protein	P07949	UNIPROT	RET	protein	P07949	UNIPROT	unknown	phosphorylation	Tyr687	AQAFPVSySSSGARR	9534	BTO:0004055								8621380	t		lperfetto	Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map 	SIGNOR-248941	0.2
CLTB	protein	P09497	UNIPROT	AP-3/clathrin vescicle	complex	SIGNOR-C250	SIGNOR	form complex	binding			9606									23103167	t		lperfetto	Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors	SIGNOR-260671	0.76
STK38	protein	Q15208	UNIPROT	STK38	protein	Q15208	UNIPROT	up-regulates	phosphorylation	Ser281	NRRQLAFsTVGTPDY	9606	BTO:0000007								16314523	t		lperfetto	Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity.	SIGNOR-142514	0.2
PRKACA	protein	P17612	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	phosphorylation			10090	BTO:0000944								23644383	t		milica	Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381.	SIGNOR-236994	0.2
MYC	protein	P01106	UNIPROT	CUL1	protein	Q13616	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12835716	t		gcesareni	Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2	SIGNOR-102749	0.497
MAPK1	protein	P28482	UNIPROT	PCBP2	protein	Q15366	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser272	FSGIESSsPEVKGYW	9606	BTO:0000664								17475908	t		miannu	We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 	SIGNOR-262912	0.324
RPS6KB1	protein	P23443	UNIPROT	POLDIP3	protein	Q9BY77	UNIPROT	unknown	phosphorylation	Ser383	ELPRRVNsASSSNPP	9606									15341740	t		llicata	Here we identify skar as a novel and specific binding partner and substrate of s6k1 but not s6k2. We find that serines 383 and 385 of human skar are insulin-stimulated and rapamycin-sensitive s6k1 phosphorylation sites.	SIGNOR-128495	0.758
STAT3	protein	P40763	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000356								22693070	t		miannu	In summary, we report in this study that STAT1 expression is upregulated by nuclear EGFR, EGFRvIII and HER2, and that STAT3 synergizes with the three receptors to further enhance STAT1 expression. These novel findings establish a novel link between the mitogenic ErbB signaling pathway and the inflammatory pathway mediated by STAT1. The oncogenic transcription factor STAT3 binds to the STAT1 promoter and synergizes with nuclear EGFR to significantly enhance STAT1 gene expression. 	SIGNOR-263650	0.596
ATR	protein	Q13535	UNIPROT	DBF4	protein	Q9UBU7	UNIPROT	down-regulates	phosphorylation	Thr449	DDIRQNFtQLPLHKN	9606									22123827	t		lperfetto	Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication.	SIGNOR-177813	0.643
SH3BP1	protein	Q9Y3L3	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260514	0.387
IGF1	protein	P05019	UNIPROT	PPP3CB	protein	P16298	UNIPROT	up-regulates				10090									10448861	f		lperfetto	Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1.	SIGNOR-235825	0.267
(S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide	chemical	CID:6918848	PUBCHEM	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002428								31908417	t		miannu	The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs.	SIGNOR-262247	0.8
CDK2	protein	P24941	UNIPROT	EZH2	protein	Q15910	UNIPROT	up-regulates activity	phosphorylation	Thr416	EANSRCQtPIKMKPN	9606	BTO:0000007								23241245	t			Here, we demonstrate that the phosphorylation of EZH2 by cyclin-dependent kinases at Thr416 creates a docking site for the ForkHead-associated domain of NIPP1.	SIGNOR-255656	0.564
ADAM17	protein	P78536	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage			-1									9774383	t		lperfetto	By the use of gene disruption (knockout), we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. Our data suggest that TACE may be the alpha-secretase responsible for the majority of regulated alpha-cleavage in cultured cells. 	SIGNOR-262829	0.556
PTPN11	protein	Q06124	UNIPROT	MPZL1	protein	O95297	UNIPROT	down-regulates	dephosphorylation	Tyr263	NKSESVVyADIRKN	9606									10681522	t		gcesareni	In vitro, tyrosine-phosphorylated pzr was efficiently dephosphorylated by the full-length form of shp-2 but not by its sh2 domain-truncated form. The coexisting binding and dephosphorylation of pzr by shp-2 may function to terminate signal transduction initiated by pzr and shp-2 and to set a threshold for the signal transduction to be initiated.	SIGNOR-75220	0.538
PRKCD	protein	Q05655	UNIPROT	PTPRA	protein	P18433	UNIPROT	up-regulates activity	phosphorylation	Ser189	QAGSHSNsFRLSNGR	9606	BTO:0000017								11676480	t		lperfetto	In this process, PTPalpha Ser-180 and Ser-204 phosphorylation is critical for the induction of phosphatase activity, which is required for dephosphorylation of pp60(c-src). Taken together, we demonstrate the physical and functional association between PI 3-kinase, PKCdelta and PTPalpha in a signaling complex that mediates the antitumor activity of the somatostatin analogue TT-232.	SIGNOR-249113	0.333
ID2	protein	Q02363	UNIPROT	TCF4	protein	P15884	UNIPROT	down-regulates activity	binding			10090	BTO:0004058			SIGNOR-C129					9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241376	0.615
MCHR1	protein	Q99705	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257034	0.412
PRKCI	protein	P41743	UNIPROT	VIM	protein	P08670	UNIPROT	up-regulates activity	phosphorylation	Ser34	SRSYVTTsTRTYSLG	9606	BTO:0001033								33525953	t		miannu	Results suggest that aPKCs target multiple activation sites (Ser33/39/56) on Vimentin and therefore is essential for VIF dynamics regulation during the metastasis of prostate cancer cells.	SIGNOR-277623	0.2
PI3K	complex	SIGNOR-C156	SIGNOR	IRS1	protein	P35568	UNIPROT	down-regulates activity				9606									11160134	f		lperfetto	Ly294002 or wortmannin were used to determine whether pi 3-kinasedependent pathways mediate ser307 phosphorylation during insulin/igf-1 or TNF-alpha Stimulation. As expected, the pi-3 kinase inhibitors ly294002 or wortmannin inhibited activation of pkb/akt in insulin or igf-1 stimulated 3t3-l1 preadipocytes, but were without effect on erk1/2. these results suggest that elements of the pi 3-kinase cascade mediate insulin/igf-1stimulated phosphorylation of ser307	SIGNOR-252717	0.758
PPP2R5B	protein	Q15173	UNIPROT	KIF20A	protein	O95235	UNIPROT	up-regulates activity	dephosphorylation	Ser878	RILRSRRsPLLKSGP	9606	BTO:0000567								27939310	t		miannu	We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton. Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878. 	SIGNOR-262660	0.2
Laminin-5	complex	SIGNOR-C184	SIGNOR	A3/b1 integrin	complex	SIGNOR-C161	SIGNOR	up-regulates activity	binding												2032285	t		lperfetto	Epiligrin, a new cell adhesion ligand for integrin alpha 3 beta 1 in epithelial basement membranes.	SIGNOR-253252	0.526
DHFR	protein	P00374	UNIPROT	dihydrofolate(2-)	smallmolecule	CHEBI:57451	ChEBI	down-regulates quantity	chemical modification			9606									21876184	t		lperfetto	Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. 	SIGNOR-268257	0.8
PTPRG	protein	P23470	UNIPROT	BTK	protein	Q06187	UNIPROT	down-regulates activity	dephosphorylation	Tyr223	LKKVVALyDYMPMNA	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254694	0.265
BRAF	protein	P15056	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates activity	phosphorylation			9606									21900390	t		miannu	BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation.	SIGNOR-251988	0.779
MRPL14	protein	Q6P1L8	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262379	0.637
NECTIN2	protein	Q92692	UNIPROT	CD226	protein	Q15762	UNIPROT	up-regulates activity	binding			9606	BTO:0000914								15039383	t		lperfetto	CD226 (DNAM-1) is an adhesion molecule involved in NK and T cell-mediated cytotoxicity against certain tumors. Here, we have identified the human poliovirus receptor-related (PRR) family members CD155 [poliovirus receptor (PVR)] and CD112 (nectin-2/PRR-2) as the ligands for human CD226.	SIGNOR-261426	0.2
PLK1	protein	P53350	UNIPROT	USP16	protein	Q9Y5T5	UNIPROT	up-regulates activity	phosphorylation	Ser486	SEYEAEMsLQGEVNI	-1									26323689	t	done	miannu	Plk1 phosphorylates and activates Usp16. In vitro phosphorylation of Usp16 with single (S330A, S386A, or S486A) or collective 3A (S330A/S386A/S486A) mutation showed that Plk1 phosphorylated Usp16 at all three sites (Fig. S2 D).	SIGNOR-274017	0.35
SUGT1	protein	Q9Y2Z0	UNIPROT	Ndc80 complex	complex	SIGNOR-C361	SIGNOR	up-regulates activity	relocalization			9606	BTO:0000567								22869522	t		lperfetto	Here we identify Sgt1, a cochaperone for Hsp90, as a novel Plk1 substrate during mitosis|This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone with the MIS12 complex to stabilize this complex at the kinetochores and thus coordinates the recruitment of the NDC80 complex to form efficient microtubule-binding sites.	SIGNOR-265224	0.275
FGF8	protein	P55075	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002314	BTO:0000887;BTO:0001103							24209627	f		gcesareni	Loss of fgf signaling in fgf24 and fgf8 double-deficient zebrafish	SIGNOR-203148	0.347
POU2AF1	protein	Q16633	UNIPROT	POU2F1	protein	P14859	UNIPROT	up-regulates	binding			9606	BTO:0000776								12727885	t		miannu	Obf1 enhances transcriptional potential of oct1.	SIGNOR-100968	0.64
BRD2	protein	P25440	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	up-regulates activity	relocalization			9606	BTO:0001938								29018219	t		lperfetto	BRD2 is required to recruit 53BP1 to DSBs.|When BRD2 recruitment was blocked with shRNA or JQ1 (Fig. 3a and Supplementary Figure 3c) or a panel of BRD2 siRNAs (Supplementary Figure 3a), the recruitment of 53BP1 to DSBs was significantly delayed. 	SIGNOR-262035	0.272
Normorphine	chemical	CHEBI:7633	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258824	0.8
MYOD1	protein	P15172	UNIPROT	SMARCD3	protein	Q6STE5	UNIPROT	up-regulates	binding			9606									15870273	t		lperfetto	This suggests a novel mechanism by which myod interacts with the promoter indirectly via pbx-1 and recruits chromatin-remodeling enzymes, which then facilitate the binding of myod and other regulators. Demonstration of physical interactions between brg1 and myod and brg1 and pbx support this conclusion	SIGNOR-136130	0.555
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	CCT2	protein	P78371	UNIPROT	up-regulates	phosphorylation	Ser260	GSRVRVDsTAKVAEI	9606									21440620	t		lperfetto	Furthermore, both the s260a and s260d mutants showed a decreased folding capacity as compared to cells expressing the wild-type cct_ subunit ( fig.?_5e), suggesting that a cyclic phosphorylation of the s260 site by s6k1 is likely to be important for chaperonin function and that mutation of this site interferes with this process.	SIGNOR-252780	0.2
FYN	protein	P06241	UNIPROT	ACP1	protein	P24666	UNIPROT	up-regulates activity	phosphorylation	Tyr132	QLIIEDPyYGNDSDF	9534	BTO:0004055								9038134	t			We identify Tyr-131 as the major phosphorylation site and Tyr-132 as a minor site and the Src family PTKs Lck and Fyn as enzymes capable of phosphorylating these sites in vivo and in vitro. Both Tyr-131 and Tyr-132 are located next to the catalytic pocket of LMPTP, and especially, Tyr-131 seems to be important for the activity of LMPTP. Phosphorylation of Tyr-131 or Tyr-132, particularly the former, caused an increase in the activity of LMPTP. 	SIGNOR-251149	0.39
PTPN1	protein	P18031	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	dephosphorylation	Tyr1009	LDTSSVLyTAVQPNE	-1									7545675	t			Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides	SIGNOR-248416	0.679
C3	protein	P01024	UNIPROT	C3	protein	P01024	UNIPROT	up-regulates activity	cleavage	Arg748	ASHLGLArSNLDEDI	9606									26806831	t		lperfetto	 C3 autoactivates in a process known as “tick-over,” which is characterized by spontaneous hydrolysis of a reactive thiol-ester to generate C3(H2O). Although C3(H2O)Bb produces only relatively small amounts of C3b compared to the other C3 convertases, it nevertheless generates enough C3b to set the C3 convertase amplification loop in motion.	SIGNOR-263484	0.2
NR5A1	protein	Q13285	UNIPROT	STAR	protein	P49675	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19237537	t		miannu	The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes.	SIGNOR-271788	0.487
SLBP	protein	Q14493	UNIPROT	H2BS1	protein	P57053	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265384	0.2
PRKAA2	protein	P54646	UNIPROT	VASP	protein	P50552	UNIPROT	down-regulates	phosphorylation	Thr278	LARRRKAtQVGEKTP	9606			SIGNOR-C15						17082196	t		lperfetto	Pharmacological ampk inhibitors and activators and ampk mutants revealed that the kinase specifically targets residue thr-278 but not ser-157 or ser-239. Quantitative fluorescence-activated cell sorter analysis and serum response factor transcriptional reporter assays, which quantify the cellular f-/g-actin equilibrium, indicated that ampk-mediated vasp phosphorylation impaired actin stress fiber formation and altered cell morphology.	SIGNOR-150462	0.2
MAPK1	protein	P28482	UNIPROT	MED1	protein	Q15648	UNIPROT	up-regulates	phosphorylation	Thr1032	SSSNRPFtPPTSTGG	9606									16314496	t		fstefani	We demonstrate that erk phosphorylates trap220/med1 in vivo at two specific sites: threonine 1032 and threonine 1457. importantly, we found that erk phosphorylation significantly increases the stability and half-life of trap220/med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription.	SIGNOR-142458	0.362
F2RL1	protein	P55085	UNIPROT	ITGB4	protein	P16144	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21072196	f		miannu	 PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 	SIGNOR-254859	0.2
KLF16	protein	Q9BXK1	UNIPROT	SIN3A	protein	Q96ST3	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								11438660	t		miannu	detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.	SIGNOR-222460	0.476
tacrolimus (anhydrous)	chemical	CHEBI:61049	ChEBI	PPP3CB	protein	P16298	UNIPROT	down-regulates	chemical inhibition			9606									15276472	t		gcesareni	Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins.	SIGNOR-127242	0.8
IKBKE	protein	Q14164	UNIPROT	TANK	protein	Q92844	UNIPROT	down-regulates activity	phosphorylation	Ser208	DINRGAPsITSVTPR	9534	BTO:0000298								10759890	t		miannu	IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex	SIGNOR-262717	0.734
RXRB	protein	P28702	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates activity	binding			9606									10976919	t	inferred from family member	gcesareni	Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr	SIGNOR-267805	0.641
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	AKT1	protein	P31749	UNIPROT	down-regulates activity	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0002419								14633703	t		lperfetto	Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells	SIGNOR-264658	0.2
PRKCA	protein	P17252	UNIPROT	PLD2	protein	O14939	UNIPROT	up-regulates	phosphorylation	Thr252	LLYMCLEtGAISFVQ	9606									15979581	t		miannu	The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity	SIGNOR-138355	0.679
DYRK2	protein	Q92630	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser18	RRLLFACsPPPASQP	9606	BTO:0002181								34363019	t		miannu	Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. 	SIGNOR-276736	0.2
F2RL1	protein	P55085	UNIPROT	AREG	protein	P15514	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21072196	f		miannu	 PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 	SIGNOR-254855	0.2
MOS	protein	P00540	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser222	LIDSMANsFVGTRSY	10090									7731726	t		Manara	Our data indicate that Mos activated MEK1 in vitro as well as in vivo by phosphorylating Ser 222.	SIGNOR-260920	0.466
PP2	chemical	CHEBI:78331	ChEBI	SRC	protein	P12931	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0000142							11782488	t		gcesareni	Herbimycin a and pp2, specific inhibitors of src family kinases, both inhibited h2o2-mediated c-src and bmk1 activation.	SIGNOR-113776	0.8
TLN1	protein	Q9Y490	UNIPROT	A4/b1 integrin	complex	SIGNOR-C162	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257611	0.643
MEAF6	protein	Q9HAF1	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269301	0.738
GRIK5	protein	Q16478	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial.	SIGNOR-264946	0.8
CAMK1	protein	Q14012	UNIPROT	PPME1	protein	Q9Y570	UNIPROT	down-regulates activity	phosphorylation	Ser15	MHLGRLPsRPPLPGS	9606	BTO:0000007								24841198	t		lperfetto	CaMKI Is the Upstream Kinase for Phosphorylation of PME-1/Ser15|Our results also demonstrated that the phosphorylated levels of PME-1/Ser15 and CaMKI/Thr177 are inversely correlated with the phosphatase activity of SIK2·PP2A complex, further implying that the demethylase activity of phosphorylated PME-1/Ser15 may be higher than that of its unphosphorylated state.	SIGNOR-265747	0.404
PRKCA	protein	P17252	UNIPROT	ATP1A1	protein	P05023	UNIPROT	down-regulates activity	phosphorylation	Ser16	KYEPAAVsEQGDKKG	1792	BTO:0003069								14976217	t		miannu	Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit.	SIGNOR-262941	0.335
FBXO32	protein	Q969P5	UNIPROT	Muscle_atrophy	phenotype	SIGNOR-PH40	SIGNOR	up-regulates				10090									25096180	f			Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are increased transcriptionally in skeletal muscle under atrophy-inducing conditions, making them excellent markers of muscle atrophy	SIGNOR-252072	0.7
FLT3	protein	P36888	UNIPROT	NCOR2	protein	Q9Y618	UNIPROT	down-regulates activity	relocalization			10090									14982881	f			We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm.	SIGNOR-261538	0.26
RUNX3	protein	Q13761	UNIPROT	TIAL1	protein	Q01085	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002384								17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255088	0.2
CLK1	protein	P49759	UNIPROT	RBM17	protein	Q96I25	UNIPROT	up-regulates activity	phosphorylation	Ser62	IDLKRGGsSDDRQIV	9534	BTO:0001538								23519612	t		miannu	 In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 	SIGNOR-262712	0.324
PSMB6	protein	P28072	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606									29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263361	0.845
ATG4B	protein	Q9Y4P1	UNIPROT	MAP1LC3C	protein	Q9BXW4	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000007;BTO:0000567								15187094	t		lperfetto	Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16.	SIGNOR-125489	0.748
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PAK1	protein	Q13153	UNIPROT	down-regulates	phosphorylation			9606									14993270	t	inferred from 70% family members	gcesareni	Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation.	SIGNOR-270186	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	RPS6KA5	protein	O75582	UNIPROT	up-regulates	phosphorylation			9606									15568999	t	inferred from 70% family members	gcesareni	In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758.	SIGNOR-270076	0.2
MAPK15	protein	Q8TD08	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9606									12169099	t		gcesareni	Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation.	SIGNOR-91371	0.44
DUSP1	protein	P28562	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates activity	dephosphorylation			9606	BTO:0000567								12356755	t		gcesareni	Here we show that glucocorticoids synergistically enhance nthi-induced tlr2 expression via specific up-regulation of the mapk phosphatase-1 (mkp-1) that, in turn, leads to dephosphorylation and inactivation of p38 mapk, the negative regulator for tlr2 expression.	SIGNOR-93873	0.798
nitric oxide	smallmolecule	CHEBI:16480	ChEBI	ROS	stimulus	SIGNOR-ST2	SIGNOR	up-regulates				9606									35681445	f		lperfetto	The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment.	SIGNOR-272279	0.7
MYO9B	protein	Q13459	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260511	0.543
RIF1	protein	Q5UIP0	UNIPROT	G1/S_transition	phenotype	SIGNOR-PH50	SIGNOR	down-regulates				9606									15342490	f		miannu	This result would suggest that Rif1 acts in an intra-S-phase checkpoint pathway that is separate from the Nbs1 pathway. Although a role for human Rif1 at telomeres is not excluded, our data show that the primary function of Rif1 is in the DNA-damage response. Rif1 localizes to DSBs in an ATM- and 53BP1-dependent manner and functions in the intra-S-phase checkpoint that serves to slow down DNA synthesis when DNA damage has occurred.	SIGNOR-259060	0.7
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	TNNT3	protein	P45378	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136942	0.311
TNKS	protein	O95271	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									19759537	t		lperfetto	Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway.	SIGNOR-187972	0.766
EGFR	protein	P00533	UNIPROT	RGS16	protein	O15492	UNIPROT	up-regulates	phosphorylation	Tyr168	TLMEKDSyPRFLKSP	9606									12588871	t		gcesareni	Phosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr). We show here that endogenous rgs16 is phosphorylated after epidermal growth factor stimulation of mcf-7 cells.	SIGNOR-98267	0.425
N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide	chemical	CHEBI:94525	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257932	0.8
Immunoglobulin lambda-1 light chain	protein	P0DOX8	UNIPROT	BCR-Dl	complex	SIGNOR-C436	SIGNOR	form complex	binding			9606	BTO:0000776								20176268	t		scontino	Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes.	SIGNOR-268198	0.2
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr37	PPGDYSTtPGGTLFS	9823	BTO:0001840		SIGNOR-C3						23486913	t		lperfetto	These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation	SIGNOR-219262	0.924
STK39	protein	Q9UEW8	UNIPROT	SLC4A4	protein	Q9Y6R1	UNIPROT	down-regulates activity	phosphorylation			10090		BTO:0000988							21317537	t		lperfetto	WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression,	SIGNOR-264644	0.356
LYN	protein	P07948	UNIPROT	PAG1	protein	Q9NWQ8	UNIPROT	up-regulates activity	phosphorylation	Tyr387	SEEPEPDyEAIQTLN	9534									16920712	t		miannu	Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn.	SIGNOR-262893	0.714
DNAJC19	protein	Q96DA6	UNIPROT	TIM23 complex	complex	SIGNOR-C423	SIGNOR	form complex	binding												32074073	t		lperfetto	The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE.	SIGNOR-267694	0.67
CSNK2A1	protein	P68400	UNIPROT	PIAS1	protein	O75925	UNIPROT	up-regulates	phosphorylation	Ser466	VIDLTIDsSSDEEEE	9606									19217413	t		llicata	Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process.	SIGNOR-184039	0.337
MYCN	protein	P04198	UNIPROT	MEF2C	protein	Q06413	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000661								21261500	f		miannu	 HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. 	SIGNOR-254214	0.305
UCHL5	protein	Q9Y5K5	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	deubiquitination			9606									16027725	t		lperfetto	Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases	SIGNOR-232101	0.406
RUNX1	protein	Q01196	UNIPROT	SPI1	protein	P17947	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									23817177	f		irozzo	RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity.	SIGNOR-255709	0.675
DVL2	protein	O14641	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates activity	binding			9606									17529994	t		amattioni	Dix domain of dvl2 mediates dynamic polymerization, which is essential for the signaling activity of dvl2.	SIGNOR-155224	0.2
PTPN2	protein	P17706	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606									15780598	t		lperfetto	Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.	SIGNOR-93998	0.725
PTPN2	protein	P17706	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates activity	dephosphorylation	Tyr566	SLNQEDIyITTESLT	10029	BTO:0000246								12907755	t			PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 	SIGNOR-248394	0.298
CSNK1A1	protein	P48729	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates activity	binding			9606				SIGNOR-C110					19293931	t		gcesareni	In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)]	SIGNOR-184696	0.562
PLCG2	protein	P16885	UNIPROT	Macrophage_differentiation	phenotype	SIGNOR-PH99	SIGNOR	up-regulates				9606									24890514	f		apalma	Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-γ2 pathway	SIGNOR-255571	0.7
IL1B	protein	P01584	UNIPROT	ENPP1	protein	P22413	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									7479785	f		miannu	Interleukin 1 beta suppresses transforming growth factor-induced inorganic pyrophosphate (PPi) production and expression of the PPi-generating enzyme PC-1 in human chondrocytes. IL-1 beta may be an important regulator of mineralization in chondrocytes by inhibiting TGF beta-induced PPi production and PC-1 expression.	SIGNOR-252199	0.2
RAB38	protein	P57729	UNIPROT	AP-3 complex	complex	SIGNOR-C247	SIGNOR	up-regulates activity	relocalization			9606									23247405	t		lperfetto	Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes.	SIGNOR-260699	0.304
GTF2F2	protein	P13984	UNIPROT	TFIIF	complex	SIGNOR-C394	SIGNOR	form complex	binding			-1									18218714	t		lperfetto	Human general transcription factor IIF (TFIIF), a component of the transcription pre-initiation complex (PIC) associated with RNA polymerase II (Pol II), was characterized by size-exclusion chromatography (SEC), electrospray ionization mass spectrometry (ESI-MS), and chemical cross-linking. Recombinant TFIIF, composed of an equimolar ratio of alpha and beta subunits, was bacterially expressed, purified to homogeneity, and found to have a transcription activity similar to a natural one in the human in vitro transcription system. 	SIGNOR-266195	0.962
RASSF5	protein	Q8WWW0	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates activity	binding			9606									22195963	t		lperfetto	NORE1A can bind K-Ras.GTP through its RA domain and regulate the proapoptotic activity of MST1/2 kinases	SIGNOR-249586	0.681
NANOG	protein	Q9H9S0	UNIPROT	FOXA2	protein	Q9Y261	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003298								22795133	f		lperfetto	Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)	SIGNOR-253166	0.466
TP53	protein	P04637	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21524151	t		lperfetto	P53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting G1/S entry.	SIGNOR-173425	0.873
Naltrindole	chemical	CHEBI:81528	ChEBI	OPRD1	protein	P41143	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258817	0.8
CDH18	protein	Q13634	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265857	0.557
ATR	protein	Q13535	UNIPROT	RAD17	protein	O75943	UNIPROT	up-regulates activity	phosphorylation	Ser656	SASELPAsQPQPFSA	9606									11687627	t		lperfetto	Here we demonstrate that atr but not atm phosphorylates the human rad17 (hrad17) checkpoint protein on ser(635) and ser(645) in vitro.The rfc-related checkpoint protein rad17, a phosphorylation substrate of atr, is critical for atr-mediated checkpoint signaling and cell survival.	SIGNOR-111252	0.853
PPP2CA	protein	P67775	UNIPROT	KRT8	protein	P05787	UNIPROT	unknown	dephosphorylation	Ser432	SAYGGLTsPGLSYSL	9606	BTO:0000182								16554440	t			K8 Ser431-P is a physiologic substrate to PP2A during hyposmotic conditions and possibly other biologic contexts.	SIGNOR-248623	0.2
MMP13	protein	P45452	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272381	0.7
IRS1	protein	P35568	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9606		BTO:0000551							20966354	t		lperfetto	Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin.	SIGNOR-256170	0.758
CUDC-101	chemical	CID:24756910	PUBCHEM	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									20143778	t		miannu	By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively.	SIGNOR-262263	0.8
11-deoxycorticosterone	smallmolecule	CHEBI:16973	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								8282004	t		miannu	The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4).	SIGNOR-258713	0.8
ARHGAP6	protein	O43182	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260462	0.563
CSNK2A2	protein	P19784	UNIPROT	HDAC1	protein	Q13547	UNIPROT	up-regulates activity	phosphorylation	Ser423	CEEEFSDsEEEGEGG	9606	BTO:0000661								11602581	t		llicata	Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1.	SIGNOR-251000	0.407
PTPN2	protein	P17706	UNIPROT	STAT1	protein	P42224	UNIPROT	down-regulates activity	dephosphorylation	Tyr701	DGPKGTGyIKTELIS	9606									12138178	t			Upon interferon (IFN) stimulation, Stat1 becomes tyrosine phosphorylated and translocates into the nucleus, where it binds to DNA to activate transcription. The activity of Stat1 is dependent on tyrosine phosphorylation, and its inactivation in the nucleus is accomplished by a previously unknown protein tyrosine phosphatase (PTP). We have now purified a Stat1 PTP activity from HeLa cell nuclear extract and identified it as TC45, the nuclear isoform of the T-cell PTP (TC-PTP).	SIGNOR-248402	0.724
MAPK1	protein	P28482	UNIPROT	WWC1	protein	Q8IX03	UNIPROT	unknown	phosphorylation	Ser548	SSPSPPCsPLMADPL	9606		BTO:0000149							24269383	t		llicata	We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro.	SIGNOR-203286	0.271
SMAD1/4	complex	SIGNOR-C85	SIGNOR	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18854943	f		fferrentino	This Smad1/4 complex can directly interact with Shn-2 and C/EBP a on the PPAR g promoter thus, resulting in the transcriptional activation of PPAR g	SIGNOR-253551	0.29
SIM1	protein	P81133	UNIPROT	ARNT	protein	P27540	UNIPROT	down-regulates activity	binding			-1				SIGNOR-C125					9020169	t	2	miannu	SIM1 can inhibit AHR·ARNT binding to the XRE and can inhibit expression from an XRE-driven reporter gene indicates that SIM1 may act as negative regulator of transcription as well as a positive regulator. The above inhibitory effects may result from SIM1 competing with AHR for binding to ARNT, although we cannot exclude the possibility that SIM1 may also have other inhibitory effects of AHR·ARNT activity. In a similar fashion, SIM1 may act as a negative regulator of all ARNT-dependent genes.	SIGNOR-240756	0.545
125-L-serine-2-133-interleukin 2 (human reduced)	smallmolecule	SID:46508054	ChEBI	IL2RB	protein	P14784	UNIPROT	up-regulates activity	chemical activation			9606									18031103	t		miannu	Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response. 	SIGNOR-259389	0.8
MNAT1	protein	P51948	UNIPROT	CAK complex	complex	SIGNOR-C456	SIGNOR	form complex	binding			9606									30860024	t		lperfetto	CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 	SIGNOR-269320	0.946
FLT3	protein	P36888	UNIPROT	SIRT3	protein	Q9NTG7	UNIPROT	down-regulates activity	phosphorylation	Tyr226	KGLLLRLyTQNIDGL	-1									34289383	t		lperfetto	We also hypothesize that, besides activating ACAT1 through Y407 phosphorylation (Fan et al., 2016), FLT3 might simultaneously phosphorylate and regulate SIRT3. Our mutational studies on all of the seven tyrosine sites of SIRT3 revealed that purified rFLT3 directly phosphorylated purified rSIRT3 in an in vitro kinase assay, leading to decreased SIRT3 deacetylase activity that was assessed by ability to deacetylate K413 of mIDH2 (Figure 4H, first three samples in left, middle, and right panels), whereas replacement of Y226 completely abolished inhibition of SIRT3 by FLT3 (Figure 4H, right). 	SIGNOR-267631	0.2
AKT1	protein	P31749	UNIPROT	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000192								31435020	t	inferred from family member		K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization	SIGNOR-270267	0.498
AML1-ETO	fusion protein	SIGNOR-FP1	SIGNOR	PTPRC	protein	P08575	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0001271								22740448	f		miannu	Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced.	SIGNOR-255686	0.2
CDK2	protein	P24941	UNIPROT	ATRIP	protein	Q8WXE1	UNIPROT	up-regulates	phosphorylation	Ser224	APSVSHVsPRKNPSV	9606									17638878	t		lperfetto	Atrip is a cdk2 substrate, and cdk2-dependent phosphorylation of s224 regulates the ability of atr-atrip to promote cell cycle arrest in response to dna damage./ One possibility is s224 phosphorylation creates a binding site for another protein involved in the g2-m checkpoint response	SIGNOR-156928	0.563
4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide	chemical	CHEBI:94128	ChEBI	BCL2L1	protein	Q07817	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	The effect has been demonstrated using Q07817-1	gcesareni		SIGNOR-189153	0.8
MAP3K1	protein	Q13233	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates	phosphorylation	Thr275	LVDSKAKtRSAGCAA	9606									9312068	t		lperfetto	Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1	SIGNOR-51211	0.71
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									16308421	f	inferred from family member	gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-270252	0.2
MARK2	protein	Q7KZI7	UNIPROT	RAB11FIP2	protein	Q7L804	UNIPROT	up-regulates	phosphorylation	Ser227	QRLSSAHsMSDLSGS	9606		BTO:0000671							16775013	t		lperfetto	We identified the kinase that phosphorylated rab11-fip2 as mark2/emk1/par-1balpha (mark2), and recombinant mark2 phosphorylated rab11-fip2 only on serine 227. In calcium switch assays, cells expressing rab11-fip2(s227a) showed a defect in the timely reestablishment of p120-containing junctional complexes.	SIGNOR-147118	0.43
glutamine	smallmolecule	CHEBI:28300	ChEBI	Gln-tRNA(Gln)	smallmolecule	CHEBI:29166	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270394	0.8
belinostat	chemical	CHEBI:61076	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257745	0.8
SBDS	protein	Q9Y3A5	UNIPROT	EIF6	protein	P56537	UNIPROT	up-regulates				9606	BTO:0001271								21536732	f		miannu	Human sbds is an essential cofactor for the efl1 gtpase, and together they cooperate to directly catalyze the release of eif6 from mammalian pre-60s ribosomal subunits	SIGNOR-173536	0.532
VASP	protein	P50552	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606									18508258	f		miannu	Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance.	SIGNOR-268393	0.7
estrone	smallmolecule	CHEBI:17263	ChEBI	17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000056							16166196	t		lperfetto	A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis.	SIGNOR-268661	0.8
ECM	stimulus	SIGNOR-ST20	SIGNOR	Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259036	0.7
WNT6	protein	Q9Y6F9	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131891	0.613
AIP	protein	O00170	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates activity	transcriptional regulation			9606	BTO:0000093								21984905	t	 	 	The immunophilin-like protein XAP2 is a negative regulator of estrogen signaling through interaction with estrogen receptor α.	SIGNOR-253644	0.296
FPR1	protein	P21462	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256825	0.43
APC-c	complex	SIGNOR-C150	SIGNOR	PTTG1	protein	O95997	UNIPROT	down-regulates quantity by destabilization	ubiquitination												21596315	t		lperfetto	Complexed with the activator proteins CDC20 or CDH1 (Fang et al., 1998, Visintin et al., 1997), the APC/C recognizes, ubiquitinates, and targets for proteasomal degradation a multitude of cell cycle regulators containing KEN or D box degrons, including securin, cyclin A, and cyclin B.	SIGNOR-265049	0.553
MMP9	protein	P14780	UNIPROT	A2M	protein	P01023	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly702	YEMHGPEgLRVGFYE	-1									9344465	t		lperfetto	The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261781	0.471
PRKCA	protein	P17252	UNIPROT	DGKD	protein	Q16760	UNIPROT	down-regulates activity	phosphorylation	Ser66	MLTKQNNsFQRSKRR	9534									15228384	t		lperfetto	The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain.	SIGNOR-249265	0.373
CUL3	protein	Q13618	UNIPROT	TBCB	protein	Q99426	UNIPROT	down-regulates quantity	ubiquitination			10090	BTO:0000142								18680552	t		miannu	Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. 	SIGNOR-268945	0.247
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	NR4A1	protein	P22736	UNIPROT	down-regulates activity	phosphorylation	Ser351	GRRGRLPsKPKQPPD	9606	BTO:0000782								11274386	t		lperfetto	We show that akt interacts with nur77 and inactivates nur77 by phosphorylation at ser-350	SIGNOR-105927	0.2
CSNK2A1	protein	P68400	UNIPROT	RRN3	protein	Q9NYV6	UNIPROT	down-regulates	phosphorylation	Ser172	GDVDVSDsDDEDDNL	9606									18559419	t		llicata	Here we show that ck2 phosphorylates the transcription initiation factor tif-ia at serines 170 and 172 (ser170/172), and this phosphorylation triggers the release of tif-ia from pol i after transcription initiation.	SIGNOR-178943	0.206
CASP3	protein	P42574	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates activity	cleavage	Asp326	NSEEDEMdSGTMVRA	9534	BTO:0004055								11517310	t		lperfetto	In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus.	SIGNOR-109874	0.6
PRKDC	protein	P78527	UNIPROT	LIG4	protein	P49917	UNIPROT	down-regulates	phosphorylation	Thr650	HLKAPNLtNVNKISN	9606									15194694	t		lperfetto	Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability.	SIGNOR-125877	0.801
CENPN	protein	Q96H22	UNIPROT	CENP-A nucleosome	complex	SIGNOR-C321	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								20566683	t		miannu	CENP-C, like CENP-N, interacts directly and specifically with CENP-A nucleosomes. CENP-C and CENP-N bind to different sites on the same CENP-A nucleosomes. CENP-N also binds directly to CENP-A nucleosomes, thus providing additional CENP-A nucleosome contacts that reinforce the specificity of the centromere assembly process	SIGNOR-263705	0.9
SLIT2	protein	O94813	UNIPROT	ROBO2	protein	Q9HCK4	UNIPROT	up-regulates activity	binding			-1									16226035	t		miannu	This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation.	SIGNOR-268380	0.858
PPP3CB	protein	P16298	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates	relocalization			9606									11062529	t		gcesareni	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-84047	0.711
BMP4	protein	P12644	UNIPROT	BMPR2	protein	Q13873	UNIPROT	up-regulates	binding			9606				SIGNOR-C29					7673243	t		acerquone	We have isolated a cdna encoding a novel transmembrane serine/threonine kinase from human skin fibroblasts which we demonstrate here to be a type ii receptor that binds bmp-4. This receptor (brk-3) is distantly related to other known type ii receptors and is distinguished from them by an extremely long carboxyl-terminal sequence following the intracellular kinase domain.	SIGNOR-30697	0.772
vincaleukoblastine sulfate	chemical	CHEBI:9984	ChEBI	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	down-regulates activity	chemical inhibition			9606									15579115	t		miannu	Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. 	SIGNOR-259260	0.8
progesterone	smallmolecule	CHEBI:17026	ChEBI	11-deoxycorticosterone	smallmolecule	CHEBI:16973	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000048							25855791	t		lperfetto	Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively	SIGNOR-268631	0.8
FLT3	protein	P36888	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15626738	f			FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells	SIGNOR-261549	0.343
SIRT2	protein	Q8IXJ6	UNIPROT	PCK1	protein	P35558	UNIPROT	up-regulates quantity by stabilization	deacetylation	Lys71	GILRRLKkYDNCWLA	9606	BTO:0000007								21726808	t		lperfetto	Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 	SIGNOR-267601	0.438
MAPKAPK2	protein	P49137	UNIPROT	LSP1	protein	P33241	UNIPROT	unknown	phosphorylation	Ser204	KLIDRTEsLNRSIEK	-1									8995217	t		miannu	LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils	SIGNOR-250147	0.622
Vps34 Complex I	complex	SIGNOR-C242	SIGNOR	Autophagosome_formation	phenotype	SIGNOR-PH36	SIGNOR	up-regulates													30397185	f		lperfetto	PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively.	SIGNOR-260323	0.7
DOT1L	protein	Q8TEK3	UNIPROT	H3C1	protein	P68431	UNIPROT	unknown	methylation	Lys80	REIAQDFkTDLRFQS	9606									12123582	t		miannu	HDOT1L Is a Nucleosomal H3-K79-Specific HMTase. We identified a human DOT1-like (DOT1L) protein and demonstrated that this protein possesses intrinsic H3-K79-specific histone methyltransferase (HMTase) activity in vitro and in vivo. Furthermore, we found that K79 methylation level is regulated throughout the cell cycle. By using two different methods, we demonstrate that the K79 methylation level decreases during S phase, reaches its lowest level in G2, increases during M phase, and maintains at a high level during G1 phase.	SIGNOR-267141	0.2
SRC	protein	P12931	UNIPROT	CTNND1	protein	O60716	UNIPROT	up-regulates activity	phosphorylation	Tyr296	MGYDDLDyGMMSDYG	-1									11382764	t		lperfetto	Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302	SIGNOR-246500	0.92
LYPLA2	protein	O95372	UNIPROT	GAP43	protein	P17677	UNIPROT	down-regulates quantity by destabilization	deacetylation	Cys3	cCMRRTKQ	9606	BTO:0000567								21152083	t		miannu	Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution.we demonstrated that the reduction in the protein level was abrogated when cells were also treated with proteasome inhibitors (chloroquine, MG132 and lactacystin) which strongly suggest that GAP-43 deacylation is an early and necessary step for its later ubiquitination and degradation by the proteasome. In addition, it also suggests that acyl-protein thioesterase levels not only regulate palmitate turnover but also global protein turnover of GAP-43.	SIGNOR-266767	0.455
PRKD1	protein	Q15139	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser155	GRLKRERsMSENAVR										34010649	t		lperfetto	The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-275943	0.2
KAT2A	protein	Q92830	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269588	0.725
ITGB1	protein	P05556	UNIPROT	A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253180	0.813
GLIS1	protein	Q8NBF1	UNIPROT	WNT5A	protein	P41221	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32047936	t		miannu	GLIS1, a novel hypoxia-inducible transcription factor, promotes breast cancer cell motility via activation of WNT5A	SIGNOR-269040	0.25
HNF4A	protein	P41235	UNIPROT	LDLR	protein	P01130	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000398								21123766	f		miannu	 Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes.	SIGNOR-254454	0.354
RPS3A	protein	P61247	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262420	0.846
HAUS complex	complex	SIGNOR-C281	SIGNOR	NEDD1	protein	Q8NHV4	UNIPROT	up-regulates activity	relocalization			9606									19369198	t		lperfetto	We further found coprecipitation of HA-tagged NEDD1 [also called GCP-WD, a component of gamma-TuRC (12, 22)] with endogenous hDgt6|A link between augmin and gamma-TuRC is likely critical for these functions, because a gamma-TuRC mutant that attenuates interaction with augmin does not restore function in vivo	SIGNOR-262332	0.526
INSR	protein	P06213	UNIPROT	DOK1	protein	Q99704	UNIPROT	up-regulates activity	phosphorylation	Tyr362	DPKEDPIyDEPEGLA	10029	BTO:0000246								11551902	t			Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398. p62(dok) is a direct substrate for the IR tyrosine kinase and that phosphorylation at Tyr(362) and Tyr(398) plays an essential role for p62(dok) to interact with its effectors and negatively regulate the insulin signaling pathway.	SIGNOR-251307	0.542
KNL1	protein	Q8NG31	UNIPROT	KNL1 complex	complex	SIGNOR-C363	SIGNOR	form complex	binding												27881301	t		lperfetto	KNL1C (known as Spc105 complex in S. cerevisiae) contains the KNL1 and ZWINT subunits.	SIGNOR-265193	0.2
TP53	protein	P04637	UNIPROT	TBXAS1	protein	P24557	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									14586398	f	 	miannu	We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. 	SIGNOR-254086	0.2
ELOVL7	protein	A1L3X0	UNIPROT	palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	down-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267888	0.8
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DPB1	protein	P04440	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-253990	0.291
FHIT	protein	P49789	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	down-regulates				9606	BTO:0000551								16407838	f		miannu	Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis	SIGNOR-143706	0.252
SH2B2	protein	O14492	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	binding			9606		BTO:0000975							11498022	t		gcesareni	Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor. The aps adapter protein couples theinsulinreceptor to the phosphorylation of c-cbl and facilitates ligand-stimulated ubiquitination of theinsulinreceptor.	SIGNOR-109691	0.631
PDHX	protein	O00330	UNIPROT	GCG	protein	P01275	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001731								12783165	f		miannu	In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%. 	SIGNOR-254901	0.2
ZNF76	protein	P36508	UNIPROT	TCP1	protein	P17987	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10893243	t		Luana	The transcription from the minimalCcta promoter was up-regulated 3-fold by ZNF143 and 6-fold by ZNF76 when full-length proteins were co-expressed, indicating that both ZNF143 and ZNF76 can enhance Ccta transcription.	SIGNOR-266221	0.355
carfilzomib	chemical	CHEBI:65347	ChEBI	PSMB8	protein	P28062	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000873								19348473	t		Luana	Carfilzomib selectively inhibits the CT-L activity of the 20S proteasome and displays equivalent potency against β5 and LMP7 with minimal cross reactivity to other protease classes.	SIGNOR-257819	0.8
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	MYOD1	protein	P15172	UNIPROT	down-regulates	phosphorylation	Ser200	YSGDSDAsSPRSNCS	9606									21902831	t		lperfetto	Phosphorylation of myod at s200 is common to other cdks, such as the mitotic cyclin b/cdk1, which may prevent inappropriate myod accumulation during mitosis.	SIGNOR-216860	0.325
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264285	0.8
STAT3	protein	P40763	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0002314								25194572	f		lperfetto	STAT3 signaling controls satellite cell expansion and skeletal muscle repair	SIGNOR-245048	0.7
AKT1	protein	P31749	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606									21440011	t		lperfetto	Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs	SIGNOR-209647	0.866
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr307	IGPDNLPyVQILKTA	9606									8443592	t		lperfetto	Tyrosine residues 154 and 307, which are in the extracellular domain of transmembrane receptor isoforms and are in an unusual sequence context for tyrosine phosphorylation, were also phosphorylated.	SIGNOR-98630	0.2
YY1	protein	P25490	UNIPROT	TNFRSF10B	protein	O14763	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000848								34589486	t		miannu	Depletion of FKBP51 impairs the acetylation status of YY1 and interferes with its binding on the DR5 promoter. The lack of the repressor activity of YY1 increases DR5 transcription and sensitizes melanoma cell to TRAIL-induced apoptosis.	SIGNOR-268793	0.415
CCND1	protein	P24385	UNIPROT	CyclinD1/CDK6	complex	SIGNOR-C143	SIGNOR	form complex	binding			9606									8114739	t		lperfetto	Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells.	SIGNOR-250680	0.95
MAPK9	protein	P45984	UNIPROT	RRN3	protein	Q9NYV6	UNIPROT	down-regulates	phosphorylation	Thr200	IARYVPStPWFLMPI	9606									15805466	t		llicata	Inactivation is due to phosphorylation of tif-ia by c-jun n-terminal kinase (jnk) at a single threonine residue (thr 200). Phosphorylation at thr 200 impairs the interaction of tif-ia with pol i and the tbp-containing factor tif-ib/sl1, thereby abrogating initiation complex formation.	SIGNOR-134878	0.487
MMP2	protein	P08253	UNIPROT	LAMC2	protein	Q13753	UNIPROT	up-regulates activity	cleavage												9211848	t		lperfetto	Induction of Cell Migration by Matrix Metalloprotease-2 Cleavage of Laminin-5|MMP2 cleaved the Ln-5 gamma2 subunit at residue 587, exposing a putative cryptic promigratory site on Ln-5 that triggers cell motility. This altered form of Ln-5 is found in tumors and in tissues undergoing remodeling, but not in quiescent tissues. Cleavage of Ln-5 by MMP2 and the resulting activation of the Ln-5 cryptic site may provide new targets for modulation of tumor cell invasion and tissue remodeling.	SIGNOR-253240	0.449
1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	PRKCB	protein	P05771	UNIPROT	up-regulates activity	binding			9606									14967450	t	PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine.	lperfetto	The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified.	SIGNOR-242584	0.8
ETS2	protein	P15036	UNIPROT	SPARC	protein	P09486	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11175361	t		miannu	Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin	SIGNOR-259874	0.311
prednisone	chemical	CHEBI:8382	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									4344326	t	Bell's palsy	gcesareni		SIGNOR-251704	0.8
CDK4	protein	P11802	UNIPROT	FOXM1	protein	Q08050	UNIPROT	up-regulates	phosphorylation	Thr627	TPESWRLtPPAKVGG	9606									22094256	t		lperfetto	We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627)	SIGNOR-177263	0.609
MAPK8	protein	P45983	UNIPROT	ITCH	protein	Q96J02	UNIPROT	up-regulates activity	phosphorylation	Thr263	PSRPPPPtPRRPASV	9606	BTO:0000007								16446428	t		gcesareni	Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222	SIGNOR-249579	0.644
USP24	protein	Q9UPU5	UNIPROT	DDB2	protein	Q92466	UNIPROT	up-regulates	deubiquitination			9606									23159851	t		miannu	Usp24-mediated ddb2 deubiquitination prevents ddb2 degradation	SIGNOR-199731	0.691
BCL2	protein	P10415	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates				9606									1286168	f		lperfetto	Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis	SIGNOR-256637	0.7
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1913	SPKYSPTsPTYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120148	0.316
TICAM1	protein	Q8IUC6	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	binding			9606									20404851	t		lperfetto	TRIF also recruits the adaptor RIP1 through the distinct RIP homotypic interaction motif. RIP1 undergoes K63-linked polyubiquitination after stimulation by TLR3 agonists, and this modification is required for NF-_B activation.	SIGNOR-216313	0.723
RBBP8	protein	Q99708	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates activity	relocalization							SIGNOR-C295					24832651	t		lperfetto	DNA damage activates ATM and CHK2 kinases, which mediate phosphorylation of CtIP and BRCA1. Phosphorylated CtIP associates with BRCA1 and with the MRN complex leading to the recruitment of the BRCC complex at the site of DNA damage where HR is initiated.	SIGNOR-263203	0.836
P300/PCAF	complex	SIGNOR-C7	SIGNOR	SMAD2	protein	Q15796	UNIPROT	up-regulates	binding			9606	BTO:0000150								15009097	t		lperfetto	Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo.	SIGNOR-217230	0.617
SMAD2/SMAD4	complex	SIGNOR-C8	SIGNOR	SP1	protein	P08047	UNIPROT	up-regulates activity	binding			9606	BTO:0000552								11013220	t		irozzo	TGF-β induces the formation and nuclear translocation of a trimeric Smad complex, which in this case is likely to consist of one monomer each of Smad2, Smad3 and Smad4. Smad2 and Smad4 associate directly with Sp1 and co-activate the transcriptional activity of Sp1. 	SIGNOR-256288	0.584
NOG	protein	Q13253	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	down-regulates	binding			9606									22298955	t	Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function	lperfetto	Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmpby blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors	SIGNOR-217529	0.584
THRSP	protein	Q92748	UNIPROT	MID1IP1	protein	Q9NPA3	UNIPROT	down-regulates activity	binding			10029	BTO:0000457								20952657	t		miannu	In the current study, we have determined the crystal structure of mouse S14 to 2.65-Å resolution. The structure of S14 reveals a helical protein arranged as a symmetric dimer. Cultured cell experiments indicate that S14 can form heterodimers with MIG12, suggesting a mechanism through which S14 could modulate ACC activity and subsequently rates of fatty acid synthesis via heterodimer formation with MIG12.In the current study, we have shown that regulating the levels of S14∶MIG12 heterodimers regulates the ability of MIG12 to activate ACC. Increasing S14∶MIG12 heterodimers by the overexpression of S14 resulted in decreased ACC activity and polymerization, whereas decreasing S14∶MIG12 heterodimers by knockdown of S14 increased ACC activity and polymerization. 	SIGNOR-267113	0.49
PRMT1	protein	Q99873	UNIPROT	FUS	protein	P35637	UNIPROT	down-regulates activity	methylation			9606	BTO:0000567								30354839	t		lperfetto	PRMT1 catalyzes the arginine methylation of Fused in Sarcoma (FUS), an RNA-binding protein that interacts with RALY. We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels, thus reducing FUS methylation. It is known that mutations in the FUS nuclear localization signal (NLS) retain the protein to the cytosol, promote aggregate formation, and are associated with amyotrophic lateral sclerosis.	SIGNOR-262274	0.499
LRRK2	protein	Q5S007	UNIPROT	RAB8A	protein	P61006	UNIPROT	up-regulates activity	phosphorylation	Thr72	AGQERFRtITTAYYR	-1									32227113	t		lperfetto	In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease	SIGNOR-260267	0.337
NOG	protein	Q13253	UNIPROT	BMPR2	protein	Q13873	UNIPROT	down-regulates activity	binding			9031				SIGNOR-C29					12478285	t	Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function	lperfetto	Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors (PMID 22298955). Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors	SIGNOR-219225	0.572
LCK	protein	P06239	UNIPROT	CD3E	protein	P07766	UNIPROT	up-regulates activity	phosphorylation			10090									2470098	t			Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex.	SIGNOR-259930	0.679
SEC23A	protein	Q15436	UNIPROT	COPII vesicle	complex	SIGNOR-C370	SIGNOR	form complex	binding			9606	BTO:0000567								30605680	t		lperfetto	The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat	SIGNOR-265289	0.788
meloxicam	chemical	CHEBI:6741	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates activity	chemical inhibition			-1									9083488	t		miannu	Meloxicam (5),an NSAID in the enol−carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. This favorable therapeutic index has been confirmed in clinical trials. In subsequent studies we and others discovered that it possessed a selectivity profile for COX-2 superior to several other marketed NSAIDs.1 A comparison of 5 with piroxicam (6) revealed different inhibitory profiles for the two enzymes	SIGNOR-258609	0.8
CSF1R	protein	P07333	UNIPROT	CSF1R	protein	P07333	UNIPROT	down-regulates	phosphorylation	Tyr561	ESYEGNSyTFIDPTQ	9606	BTO:0001271								15297464	t		lperfetto	Csf-1-mediated wild-type (wt)-csf-1r phosphorylation was not markedly affected by sfk inhibition, indicating that lack of sfk binding is not responsible for diminished y559f phosphorylation. Unexpectedly, cells expressing y559f were hyperproliferative in response to csf-1. Hyperproliferation correlated with prolonged activation of akt, erk, and stat5 in the y559f mutant. Consistent with a defect in receptor negative regulation, c-cbl tyrosine phosphorylation and csf-1r/c-cbl co-association were almost undetectable in the y559f mutant. Furthermore, y559f underwent reduced multiubiquitination and delayed receptor internalization and degradation. In conclusion, we propose that tyr559 is a switch residue that functions in kinase regulation, signal transduction and, indirectly, receptor down-regulation.	SIGNOR-127622	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MAP2K1	protein	Q02750	UNIPROT	down-regulates activity	phosphorylation	Thr386	IGLNQPStPTHAAGV	9606	BTO:0000007								10567369	t		lperfetto	An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2	SIGNOR-244561	0.2
AURKC	protein	Q9UQB9	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									12588998	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.	SIGNOR-98361	0.2
SMO	protein	Q99835	UNIPROT	OPALIN	protein	Q96PE5	UNIPROT	up-regulates quantity	transcriptional regulation			10090									35082605	f	Non-canonical pathway (Gli1-indipendent): SMO/AMPK	SimoneGraziosi	We show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMPactivated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell.	SIGNOR-269225	0.2
FZD1	protein	Q9UP38	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates activity	binding			9606									22944199	t		amattioni	When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.	SIGNOR-253512	0.676
HIF1A	protein	Q16665	UNIPROT	Aldolase	proteinfamily	SIGNOR-PF75	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									8955077	f	inferred from family member	miannu	 we characterize hypoxia response elements in the promoters of the ALDA, ENO1, and Ldha genes. Our data establish that functional hypoxia-response elements consist of a pair of contiguous transcription factor binding sites at least one of which contains the core sequence 5'-RCGTG-3' and is recognized by HIF-1. These results provide further evidence that the coordinate transcriptional activation of genes encoding glycolytic enzymes which occurs in hypoxic cells is mediated by HIF-1.	SIGNOR-270229	0.344
HSD17B11	protein	Q8NBQ5	UNIPROT	testosterone	smallmolecule	CHEBI:17347	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000056							16166196	t		lperfetto	A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis.	SIGNOR-268666	0.8
CSNK2A1	protein	P68400	UNIPROT	EIF4G2	protein	P78344	UNIPROT	up-regulates activity	phosphorylation	Ser902	ETAEEEEsEEEAD	9606	BTO:0000007								29530922	t		miannu	DAP5(S902) is phosphorylated by CK2α. Phosphorylation of DAP5(S902) by CK2α is required for eIF2β binding. 	SIGNOR-266384	0.227
RPS6KA1	protein	Q15418	UNIPROT	PPP1R3A	protein	Q16821	UNIPROT	up-regulates activity	phosphorylation	Ser46	PQPSRRGsDSSEDIY	-1									10648825	t		lperfetto	The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates. 	SIGNOR-249036	0.416
sertindole	chemical	CHEBI:9122	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029									9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258843	0.8
CTF1	protein	Q16619	UNIPROT	LIFR	protein	P42702	UNIPROT	up-regulates	binding			9606									11834704	t		gcesareni	We conclude that gp130/lif receptor and et(a) receptor activation are essential for cardiac fibroblast growth by ct-1	SIGNOR-114758	0.721
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1647	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120180	0.321
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	SLC2A1	protein	P11166	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27692180	t		miannu	HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 	SIGNOR-267450	0.422
PRKCD	protein	Q05655	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Ser840	VRSAFTTsTVVRMHV	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249280	0.353
EIF2AK2	protein	P19525	UNIPROT	NLRP1 inflammasome	complex	SIGNOR-C224	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								22801494	t		miannu	Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. 	SIGNOR-263118	0.307
AGTR1	protein	P30556	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			9606									21289285	t		gcesareni	These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction.	SIGNOR-171760	0.506
mianserin	chemical	CHEBI:51137	ChEBI	HTR2B	protein	P41595	UNIPROT	down-regulates activity	chemical inhibition			10036	BTO:0000452								9459568	t		miannu	The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-	SIGNOR-258689	0.8
USP28	protein	Q96RU2	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates	deubiquitination			9606	BTO:0000150								17558397	t		esanto	Usp28, an ubiquitin-specific protease, binds to myc through an interaction with fbw7alpha, an f-box protein that is part of an scf-type ubiquitin ligase. Therefore, it stabilizes myc.	SIGNOR-155590	0.691
MAPK1	protein	P28482	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates activity	phosphorylation	Ser422	LSTPVVLsPGPQKP	10090	BTO:0000944								7889942	t		lperfetto	We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-235463	0.544
CREB5	protein	Q02930	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity	binding			9534	BTO:0000318								8378084	t		miannu	CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription	SIGNOR-219634	0.522
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT1	protein	P04628	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242704	0.28
RPS6KA5	protein	O75582	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									14625384	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-119237	0.2
MTOR	protein	P42345	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	up-regulates	phosphorylation			9606			SIGNOR-C3						17510057	t		gcesareni	In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size.	SIGNOR-154821	0.831
STAT1	protein	P42224	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates	binding			9606									16481475	t		lperfetto	Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease.	SIGNOR-217418	0.46
MYD88	protein	Q99836	UNIPROT	IRAK4	protein	Q9NWZ3	UNIPROT	up-regulates activity	binding			9606									12297423	t			Signaling between MyD88 and TRAF6 is mediated by members of the IL-1R-associated kinase (IRAK) family; however, the exact function of each IRAK protein remains controversial. IRAK-1 is required for the optimal transduction of IL-1R- and TLR-mediated signals, but IRAK-1 can be replaced by other IRAKs. Surprisingly, gene targeting studies show that the newest IRAK protein, IRAK-4, has an essential role in mediating signals initiated by IL-1R and TLR engagement.	SIGNOR-252097	0.945
ARHGAP30	protein	Q7Z6I6	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260486	0.376
CSNK2A1	protein	P68400	UNIPROT	HMGN1	protein	P05114	UNIPROT	down-regulates	phosphorylation	Ser7	sSAEGAAK	9606									10739259	t		gcesareni	Peptide mass and sequence analysis showed major and minor phosphorylation sites, respectively, at ser24 and ser28 in hmg-17, and ser20 and ser24 in hmg-14 a third phosphorylation site in hmg-14 was located at either ser6 or ser7phosphorylation of ser6 and ser7 may compromise the binding of hmgn1 protein to the binding domain of importin proteins, which in turn affects the nuclear transport and sub-cellular localization of hmgn1 protein. Protein kinase ck2 could potentially be an enzyme that regulates this process.	SIGNOR-76266	0.2
PRKCA	protein	P17252	UNIPROT	SNAP23	protein	O00161	UNIPROT	unknown	phosphorylation	Ser23	ITDESLEsTRRILGL	9606									12930825	t		lperfetto	Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion.	SIGNOR-249228	0.334
ULK2	protein	Q8IYT8	UNIPROT	HK1	protein	P19367	UNIPROT	up-regulates activity	phosphorylation	Ser364	TRLGVEPsDDDCVSV	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274041	0.2
CSNK2A1	protein	P68400	UNIPROT	HIF1A	protein	Q16665	UNIPROT	unknown	phosphorylation	Thr796	ESGLPQLtSYDCEVN	-1									17382325	t		llicata	These results implied that only Thr-796 was phosphorylated CK2. 	SIGNOR-250891	0.346
FOXA1	protein	P55317	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24875621	t		miannu	FOXA1 directly inhibits AR expression and thus the transcription of its target genes. FOXA1 inhibits AR gene expression in prostate cancer. oss of FOXA1 may lead to androgen-independent AR signaling and thus castration-resistant prostate cancer progression. Indeed, we have recently reported that FOXA1 is downregulated in CRPC	SIGNOR-251541	0.758
MAP2K2	protein	P36507	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity	phosphorylation			10090									11730323	t			Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs	SIGNOR-258995	0.735
testosterone	smallmolecule	CHEBI:17347	ChEBI	SRD5A1	protein	P18405	UNIPROT	up-regulates activity	chemical activation			9606									15861399	t		miannu	Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. 	SIGNOR-251532	0.8
PRKCA	protein	P17252	UNIPROT	KCNJ13	protein	O60928	UNIPROT	down-regulates	phosphorylation	Ser201	TRPSPLTsVRVSAVL	9606									18976636	t		gcesareni	After pharmacological pkc activation, kir7.1 currents were strongly inhibited. Co-application of pkc inhibitors attenuated this effect. Inactivation of pkc consensus sites also strongly attenuated the effect with a single site ((201)s) being essential for almost the total pkc sensitivity.	SIGNOR-181863	0.2
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser221	PRTSPIMsPRTSLAE	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248373	0.598
FANCM	protein	Q8IYD8	UNIPROT	TOPBP1	protein	Q92547	UNIPROT	up-regulates	relocalization			9606									20372056	t		gcesareni	The enzymatic activity of fan cm is then required to remodel and stabilize the fork to allow topbp1 access to activate atr , in a 9-1-1-independent manner.	SIGNOR-164765	0.43
AKT1	protein	P31749	UNIPROT	SKI	protein	P12755	UNIPROT	down-regulates	phosphorylation	Thr458	QPRKRKLtVDTPGAP	9606									19875456	t		llicata	The phosphorylation of ski at threonine 458 is induced by akt pathway activators including insulin, insulin-like growth factor-1, and hepatocyte growth factor. The phosphorylation of ski causes its destabilization and reduces ski-mediated inhibition of expression of another negative regulator of tgf-beta, smad7	SIGNOR-252527	0.343
ASH1L	protein	Q9NR48	UNIPROT	NTRK2	protein	Q16620	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000938								35210569	t		Gianni	Depletion of ASH1L decreases neurite outgrowth and decreases expression of the gene encoding the neurotrophin receptor TrkB whose signaling pathway is linked to neuronal morphogenesis.	SIGNOR-269058	0.2
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	SF3B1	protein	O75533	UNIPROT	unknown	phosphorylation	Thr313	HGSGWAEtPRTDRGG	9606									12105215	t		lperfetto	We indeed found that sap155-(223_322) and sap155-(1_491) are excellent substrates for in vitrophosphorylation by cyclin e-cdk2 as well as cyclin b-cdk1	SIGNOR-216717	0.354
GABRG2	protein	P18507	UNIPROT	GABA-A (a2-b1-g2) receptor	complex	SIGNOR-C331	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263755	0.622
MRAP	protein	Q8TCY5	UNIPROT	MC4R	protein	P32245	UNIPROT	down-regulates activity	binding			10029	BTO:0000246								19329486	t		miannu	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252362	0.504
MTOR	protein	P42345	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser636	SGDYMPMsPKSVSAP	10116									11287630	t		lperfetto	Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten	SIGNOR-106586	0.758
SEMA3B	protein	Q13214	UNIPROT	NRP2	protein	O60462	UNIPROT	up-regulates activity	binding			9606	BTO:0001176;BTO:0002036								25335892	t		miannu	Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction.	SIGNOR-261816	0.609
SREBF1	protein	P36956	UNIPROT	ACACA	protein	Q13085	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11994399	f		Luana	SREBP-1c–responsive genes include those for ATP citrate lyase (which produces acetyl-CoA) and acetyl-CoA carboxylase and fatty acid synthase (which together produce palmitate [C16:0]).	SIGNOR-267957	0.47
brimonidine	chemical	CHEBI:3175	ChEBI	ADRA2B	protein	P18089	UNIPROT	up-regulates activity	chemical activation			9606									9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258901	0.8
HAUS8	protein	Q9BT25	UNIPROT	HAUS complex	complex	SIGNOR-C281	SIGNOR	form complex	binding			9606	BTO:0000567								19369198	t		lperfetto	Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)	SIGNOR-262321	0.744
B4GALT1	protein	P15291	UNIPROT	UDP-D-galactose	smallmolecule	CHEBI:18307	ChEBI	down-regulates quantity	chemical modification			9606									16157350	t		miannu	Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 	SIGNOR-268467	0.8
CASP3	protein	P42574	UNIPROT	CASP6	protein	P55212	UNIPROT	up-regulates	cleavage			9606									9922454	t		amattioni	Caspase-3 is required for the activation of caspases 6	SIGNOR-64179	0.601
CSNK1A1L	protein	Q8N752	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation			9606									21606194	t		gcesareni	Ck1 also phosphorylates lrp6 at the second ser residue in the pppspxs motif ck1_ in the lrp5/e-cadherin/p120-catenin complex temporally coincides with p120-catenin phosphorylation in ser268. moreover, and considering the close similarity between the catalytic domains of ck1_ and ck1_, it is possible that ck1_ is indeed responsible for the phosphorylation at ser1420 and ser1430 in lrp5/6 that negatively affects wnt signaling by still not defined mechanisms	SIGNOR-173853	0.257
HIF1A	protein	Q16665	UNIPROT	KDM2B	protein	Q8NHM5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271567	0.2
Complement C1 complex	complex	SIGNOR-C309	SIGNOR	C2	protein	P06681	UNIPROT	up-regulates activity	cleavage	Arg243	KTKESLGrKIQIQRS										31331124	t		lperfetto	C1s subsequently activate serum proteins C4 and C2. C4 is cleaved to fragment C4a, which is an anaphylatoxin, and to fragment C4b, which is deposited on the adjacent surfaces. C2 is cleaved to a fragment C2b, and larger fragment C2a, which binds noncovalently to C4b on the target cell membrane. This forms the C4b2a complex	SIGNOR-263418	0.477
MEIS1	protein	O00470	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0001271								19109563	f		irozzo	These results show that MEIS1 expression is important for MLL-rearranged leukemias and suggest that MEIS1 promotes cell-cycle entry.Flow cytometric analysis of PI-stained nuclei showed that Meis1 knockdown led to a cell-cycle arrest in the G0/G1 phase.	SIGNOR-255859	0.7
FFAR2	protein	O15552	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257075	0.311
DNMT3A	protein	Q9Y6K1	UNIPROT	CDKN2C	protein	P42773	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									26350239	f		miannu	Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family	SIGNOR-261508	0.346
TDGF1	protein	P13385	UNIPROT	NODAL	protein	Q96S42	UNIPROT	up-regulates activity	binding			9606									19874624	t	Regulation	miannu	Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors.	SIGNOR-251937	0.648
MAPK1	protein	P28482	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Ser380	HQLFRGFsFVATGLM	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-219316	0.748
CSNK1A1	protein	P48729	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates	phosphorylation	Ser94	QISTIAEsEDSQESV	9606									9931297	t		lperfetto	Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement.	SIGNOR-64250	0.318
NRF1	protein	Q16656	UNIPROT	RETREG3	protein	Q86VR2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23939472	f		miannu	We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons.	SIGNOR-261367	0.2
CDK1	protein	P06493	UNIPROT	RANBP2	protein	P49792	UNIPROT	up-regulates activity	phosphorylation	Ser2280	LSPSKSerPAKLN	-1									26051540	t		irozzo	Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment.	SIGNOR-259121	0.452
AKT3	protein	Q9Y243	UNIPROT	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr235	QARKRKRtSIENRVR	9606	BTO:0004180								23041284	t		flangone	Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.	SIGNOR-242107	0.26
NAB2	protein	Q15742	UNIPROT	EGR3	protein	Q06889	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000414								20506119	f		miannu	Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop. 	SIGNOR-253887	0.501
LRRK2	protein	Q5S007	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates activity	phosphorylation	Thr825	LKISDFGtSKRLAGI	9606	BTO:0000007								28888991	t		miannu	LRRK2 phosphorylated ASK1 at Thr832 that is adjacent to Thr845, which serves as an autophosphorylation site. 	SIGNOR-277251	0.331
SALL4	protein	Q9UJQ4	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19440552	f		miannu	 Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex.	SIGNOR-255126	0.413
PRKCA	protein	P17252	UNIPROT	OCLN	protein	Q16625	UNIPROT	up-regulates activity	phosphorylation	Ser340	DKRFYPEsSYKSTPV	9615									11502742	t		lperfetto	Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X. 	SIGNOR-249105	0.371
SMURF	proteinfamily	SIGNOR-PF29	SIGNOR	TGFBR1	protein	P36897	UNIPROT	down-regulates activity	ubiquitination			9606									17317136	t		lperfetto	Recruitment of ww and hect domain e3-ubiquitin ligases smurf1 and 2 to induce type i receptor ubiquitination and subsequent receptor degradation	SIGNOR-253264	0.2
CTDSPL	protein	O15194	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	dephosphorylation	Ser206	SSSTYPHsPTSSDPG	9606	BTO:0000552								17085434	t			Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)	SIGNOR-248315	0.476
moclobemide	chemical	CHEBI:83531	ChEBI	MAOA	protein	P21397	UNIPROT	down-regulates activity	chemical inhibition			-1									21680183	t		Luana	Twenty-two pyrazoline derivatives were synthesized and tested for their human MAO (hMAO) inhibitory activity. Twelve molecules with unsubstituted ring A and substituted ring C (5–16) were found to be potent inhibitors of hMAO-A isoform with SIMAO-A in the order 103 and 104. 	SIGNOR-258314	0.8
CDK2	protein	P24941	UNIPROT	TK1	protein	P04183	UNIPROT	down-regulates	phosphorylation	Ser13	LPTVLPGsPSKTRGQ	9606									14697231	t		gcesareni	Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase.	SIGNOR-120372	0.301
OMG	protein	P23515	UNIPROT	LINGO1	protein	Q96FE5	UNIPROT	up-regulates	binding			9606	BTO:0000938								15694321	t		flangone	Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1...	SIGNOR-133640	0.484
PPARGC1A	protein	Q9UBK2	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates quantity by repression	transcriptional regulation			10090		BTO:0001103							20404331	f		lperfetto	In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB	SIGNOR-217978	0.371
CDX2	protein	Q99626	UNIPROT	FUT2	protein	Q10981	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000182;BTO:0000391								22547830	f		miannu	 We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. 	SIGNOR-254610	0.2
WASHC4	protein	Q2M389	UNIPROT	WASH complex	complex	SIGNOR-C258	SIGNOR	form complex	binding												23721880	t		lperfetto	The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53.	SIGNOR-261018	0.2
Phenylalanyl-tRNA synthetase	complex	SIGNOR-C473	SIGNOR	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									20223217	t		miannu	Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers.	SIGNOR-270437	0.8
GABA-A (a4-b1-g2) receptor	complex	SIGNOR-C333	SIGNOR	CRHR1	protein	P34998	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268603	0.242
STOML2	protein	Q9UJZ1	UNIPROT	OPA1	protein	O60313	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20359165	f		Giorgia	Of interest, induction of SLP-2 expression also resulted in significant increases in the levels of OPA-1 and mitofusin-2 (P < 0.05), both integral mitochondrial membrane proteins associated with mitochondrial fusion.	SIGNOR-260381	0.318
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	STMN1	protein	P16949	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000007								9731215	t	inferred from 70% family members	lperfetto	Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. 	SIGNOR-270182	0.2
CHEK2	protein	O96017	UNIPROT	XRCC1	protein	P18887	UNIPROT	up-regulates	phosphorylation	Thr284	APTRTPAtAPVPARA	9606									18971944	t		llicata	Chk2 formed a complex with xrcc1, the ber scaffold protein, and phosphorylated xrcc1 in vivo and in vitro at thr(284). our results are consistent with the phosphorylation of xrcc1 by atm-chk2 facilitating recruitment of downstream ber proteins to the initial damage recognition/excision step to promote ber.	SIGNOR-181816	0.531
MYOD1	protein	P15172	UNIPROT	VEGFA	protein	P15692	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0001103							18094043	t		lperfetto	We further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter.	SIGNOR-257598	0.401
CSNK2A1	protein	P68400	UNIPROT	PTPRC	protein	P08575	UNIPROT	up-regulates	phosphorylation	Ser1004	SEHDSDEsSDDDSDS	9606									10066810	t		gcesareni	Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein,	SIGNOR-65269	0.453
ATXN1	protein	P54253	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21315774	t		Luana	Overexpression of the CtBP2 protein enhanced the repression activity of the E-cadherin promoter in a dose-dependent manner, whereas overexpression of ataxin-1 increased the activity of the E-cadherin promoter in a dose-dependent manner 	SIGNOR-261577	0.351
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	S100A8	protein	P05109	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0001044								16690079	t		miannu	S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization.	SIGNOR-261935	0.8
VRK1	protein	Q99986	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9606									15378002	t		flangone	Vrk1 phosphorylates c-jun in ser63 and ser73 in vitro...VRK1 Activates c-jun dependent transcription	SIGNOR-127069	0.528
GSK3B	protein	P49841	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates	phosphorylation	Thr286	EEVDLACtPTDVRDV	9606									9832503	t		gcesareni	Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover.	SIGNOR-62265	0.776
CSNK2A1	protein	P68400	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates	phosphorylation	Thr350	PEVKKEEtLLDLDFD	9606	BTO:0000567								16945112	t		lperfetto	Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin.	SIGNOR-149314	0.2
ASH2L	protein	Q9UBL3	UNIPROT	Set1-Ash2 HMT complex	complex	SIGNOR-C352	SIGNOR	form complex	binding			9606	BTO:0000567								12670868	t		miannu	Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles.	SIGNOR-264479	0.909
PDK1	protein	Q15118	UNIPROT	PKN2	protein	Q16513	UNIPROT	up-regulates activity	phosphorylation	Thr816	GYGDRTStFCGTPEF	9606	BTO:0000007								10753910	t		miannu	PDK1 phosphorylates the PRKs at their conserved activation loop threonines (Thr-774 and Thr-816 for PRK1 and PRK2, respectively) both in vitro and in vivo.	SIGNOR-250265	0.344
cytidine	smallmolecule	CHEBI:17562	ChEBI	cytidine 5'-monophosphate(2-)	smallmolecule	CHEBI:60377	ChEBI	up-regulates quantity	precursor of												11306702	t		lperfetto	Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. 	SIGNOR-275857	0.8
MAPK14	protein	Q16539	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Ser65	FLMECRNsPVTKTPP	9606	BTO:0003316								11777913	t		miannu	4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E. 	SIGNOR-250097	0.444
GPIb-IX-V complex	complex	SIGNOR-C270	SIGNOR	FLNA	protein	P21333	UNIPROT	up-regulates activity	relocalization			9606									16293600	t		lperfetto	The cytoplasmic domain of GPIbα of the GPIb-IX-V complex binds to actin filaments through FLNa|This immediately means that clustering of the GPIb-IX-V complex and anchoring of FLNa to actin filaments by activation could also increase avidity, which could withstand high shear stress.	SIGNOR-261846	0.561
MAPK1	protein	P28482	UNIPROT	SPHK2	protein	Q9NRA0	UNIPROT	up-regulates	phosphorylation	Thr614	AFRLEPLtPRGVLTV	9606									17311928	t		llicata	Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1	SIGNOR-153383	0.431
CDK1	protein	P06493	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Thr252	PINGSPRtPRRGQNR	9606									1756735	t		lperfetto	The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2.	SIGNOR-21560	0.675
PAK3	protein	O75914	UNIPROT	SYN1	protein	P17600	UNIPROT	up-regulates activity	phosphorylation	Ser605	AGPTRQAsQAGPVPR	10116	BTO:0001009								12237306	t		miannu	Synapsin I is phosphorylated at Ser603 by p21-activated kinases. the Ser603 residue must be one of the pivotal sites for the release	SIGNOR-250246	0.339
LCK	protein	P06239	UNIPROT	CD3	complex	SIGNOR-C432	SIGNOR	up-regulates activity	phosphorylation			9606									8626561	t			The binding of Lck to the tyrosine-phosphorylated zeta chain of the TcR would serve to strengthen the interaction of the associated CD4 and the TcR complex, leading to increased avidity for the antigen-major histocompatibility protein complex	SIGNOR-252305	0.632
MAP3K14	protein	Q99558	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates	phosphorylation			9606				SIGNOR-C14					9520446	t		gcesareni	Activation of the transcription factor nf-kappab by inflammatory cytokines involves the successive action of nf-kappab-inducing kinase (nik) and two ikappab kinases, ikk-alpha and ikk-beta. Here we show that nik preferentially phosphorylates ikk-alpha over ikk-beta	SIGNOR-55949	0.701
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser679	SPDSMNAsRLSQPGQ	9606	BTO:0000007								10195894	t			Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.	SIGNOR-251277	0.2
TOMM5	protein	Q8N4H5	UNIPROT	TOM40 complex	complex	SIGNOR-C421	SIGNOR	form complex	binding			9606	BTO:0000567								18331822	t		lperfetto	The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex.	SIGNOR-267675	0.622
LTC4S	protein	Q16873	UNIPROT	leukotriene A4(1-)	smallmolecule	CHEBI:57463	ChEBI	down-regulates quantity	chemical modification			9606									27365393	t		miannu	Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4).	SIGNOR-277258	0.8
TLR4	protein	O00206	UNIPROT	TLR4	protein	O00206	UNIPROT	up-regulates	binding			9606									24352680	t		fstefani	Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain	SIGNOR-203484	0.2
MAPK3	protein	P27361	UNIPROT	NR3C2	protein	P08235	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser196	EKSPSVCsPLNMTSS	9606	BTO:0005043								22798426	t		miannu	 Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276102	0.358
CREB1	protein	P16220	UNIPROT	CYP19A1	protein	P11511	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000158								15955695	f		miannu	 In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro.	SIGNOR-253798	0.43
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TBX3	protein	O15119	UNIPROT	up-regulates activity	phosphorylation	Ser719	AEKEAATsELQSIQR	9606									25595898	t		lperfetto	We have identified TBX3 as a key substrate of AKT3 in melanomagenesis. we have identified the AKT3 target site at serine residue 720 in the TBX3 protein and show that this site is phosphorylated in vivo. the phosphorylation at S720 promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion.	SIGNOR-244353	0.2
EREG	protein	O14944	UNIPROT	ERBB3	protein	P21860	UNIPROT	up-regulates	binding			9606	BTO:0000150								22891299	t		gcesareni	For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4	SIGNOR-191785	0.576
HASPIN	protein	Q8TF76	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	phosphorylation	Thr4	tKQTARKS	9606									20705812	t		miannu	Here we show that phosphorylation of histone H3 threonine 3 (H3T3ph) by Haspin is necessary for CPC accumulation at centromeres and that the CPC subunit Survivin binds directly to H3T3ph.	SIGNOR-275428	0.2
JAK2	protein	O60674	UNIPROT	STAT6	protein	P42226	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000801								18852293	t		lperfetto	Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6.	SIGNOR-249532	0.658
Quadazocine	chemical	CID:115077	PUBCHEM	OPRD1	protein	P41143	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258419	0.8
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGB7	protein	Q9Y5F8	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265689	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	SIRT1	protein	Q96EB6	UNIPROT	up-regulates	phosphorylation	Ser540	HVSEDSSsPERTSPP	9606									19107194	t		lperfetto	We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells	SIGNOR-216841	0.488
CBM	complex	SIGNOR-C555	SIGNOR	T_cell_activation	phenotype	SIGNOR-PH73	SIGNOR	up-regulates				9606									35230873	f		miannu	The CBM complex not only induces a productive immune response in activated effector T cells but also controls peripheral tolerance by promoting the development and function of regulatory T (Treg) cells 	SIGNOR-276297	0.7
SGF29	protein	Q96ES7	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269572	0.2
MRGBP	protein	Q9NV56	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269296	0.775
PHKG1	protein	Q16816	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser602	INKKLDLsNVQSKCG	-1									8999860	t		miannu	Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules	SIGNOR-250285	0.318
BBC3	protein	Q9BXH1	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates	relocalization			9606	BTO:0000551								19439449	t		gcesareni	Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis.	SIGNOR-185671	0.504
MYC	protein	P01106	UNIPROT	GLS	protein	O94925	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001518								19219026	f		Luana	Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells. 	SIGNOR-268038	0.454
phosphatidylinositol bisphosphate	smallmolecule	CHEBI:37328	ChEBI	AKT1	protein	P31749	UNIPROT	up-regulates activity	chemical activation			9606									18249092	t		gcesareni	Furthermore, overall PKB activity, primarily consisting of cytosolic enzyme, was dependent upon levels of PI(3,4)P2, while only membrane-associated PKB activity was dependent upon PI(3,4,5)P3 levels. We conclude that PI(3,4,5)P3 and PI(3,4)P2 have distinct roles in determining PKB phosphorylation and activity. Thus, when investigating PI3K-PKB pathways, the importance of both lipids must be considered	SIGNOR-252432	0.8
SAR1A	protein	Q9NR31	UNIPROT	SEC24B	protein	O95487	UNIPROT	up-regulates quantity	binding							SIGNOR-C370					30605680	t		lperfetto	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 	SIGNOR-265300	0.737
AR	protein	P10275	UNIPROT	SERPINB5	protein	P36952	UNIPROT	down-regulates quantity by repression	transcriptional regulation												16304843	t	 	lperfetto	In addition, androgen receptor (AR) can recognize and bind to the ARE element, and then inhibit the activity of maspin promoter	SIGNOR-253685	0.412
nitric oxide	smallmolecule	CHEBI:16480	ChEBI	GUCY1A3-B2	complex	SIGNOR-C139	SIGNOR	up-regulates activity	chemical activation			9606									15036565	t		gcesareni	One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP)	SIGNOR-244113	0.8
PPP2R5C	protein	Q13362	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Thr55	DDIEQWFtEDPGPDE	9606	BTO:0001938								17245430	t			Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis. To investigate the molecular mechanisms, we have shown that the endogenous B56gamma protein level and association with p53 increase after DNA damage. Finally, we demonstrate that Thr55 dephosphorylation is required for B56gamma3-mediated inhibition of cell proliferation and cell transformation.	SIGNOR-268154	0.594
MAPK14	protein	Q16539	UNIPROT	ELAVL1	protein	Q15717	UNIPROT	up-regulates	phosphorylation	Thr118	SGLPRTMtQKDVEDM	9606									19528229	t		lperfetto	P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna.	SIGNOR-186135	0.538
RIPK1	protein	Q13546	UNIPROT	DAB2IP	protein	Q5VWQ8	UNIPROT	up-regulates activity	phosphorylation	Ser728	PSPARSSsYSEANEP	9913									17389591	t			We further show that RIP1 (the Ser/Thr protein kinase receptor-interacting protein) associates with the GAP domain of AIP1 and mediates TNF-induced AIP1 phosphorylation at Ser-604 and JNK/p38 activation as demonstrated by both overexpression and small interfering RNA knockdown of RIP1 in EC.	SIGNOR-259976	0.437
ALDH1A1	protein	P00352	UNIPROT	retinal	smallmolecule	CHEBI:15035	ChEBI	down-regulates quantity	chemical modification			9606									21621639	t		lperfetto	All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step.	SIGNOR-265122	0.8
DYRK1A	protein	Q13627	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates activity	phosphorylation	Ser293	PAPARPRsPSQTRKG	9606									16733250	t		lperfetto	Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins.	SIGNOR-146902	0.405
TTK	protein	P33981	UNIPROT	HSPA9	protein	P38646	UNIPROT	up-regulates	phosphorylation	Ser65	IDLGTTNsCVAVMEG	9606									17573779	t		lperfetto	Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin	SIGNOR-156181	0.2
NLGN3	protein	Q9NZ94	UNIPROT	NRXN1	protein	P58400	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264147	0.834
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr534	SRTPSLPtPPTREPK	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249349	0.729
TFE3	protein	P19532	UNIPROT	MYH9	protein	P35579	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								11467950	f		miannu	we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies.	SIGNOR-222504	0.2
TNF	protein	P01375	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253477	0.2
lenalidomide	chemical	CHEBI:63791	ChEBI	IKZF1	protein	Q13422	UNIPROT	down-regulates quantity by destabilization	chemical inhibition			9606									24328678	t		gcesareni	Members of the Ikaros family of transcription factors, specifically Ikaros and Aiolos (encoded by the genes IKZF1 and IKZF3 respectively), are recruited as protein substrates for CRL4CRBN in T cells in response to lenalidomide or pomalidomide treatment.	SIGNOR-236910	0.8
KLKB1	protein	P03952	UNIPROT	KNG1	protein	P01042	UNIPROT	up-regulates activity	cleavage	Arg389	PPGFSPFrSSRIGEI	9606		BTO:0000131			cleavage:Arg390	CTTKTSTrIVGGTNS			28966616	t		lperfetto	Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1).	SIGNOR-263548	0.772
RPS6KB2	protein	Q9UBS0	UNIPROT	TARBP2	protein	Q15633	UNIPROT	up-regulates activity	phosphorylation	Ser286	LRSCSLGsLGALGPA	-1									27407113	t		miannu	We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. 	SIGNOR-274069	0.341
ITGB2	protein	P05107	UNIPROT	AX/b2 integrin	complex	SIGNOR-C171	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253194	0.823
RPS6KA1	protein	Q15418	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates	phosphorylation	Ser1798	GQRKRLIsSVEDFTE	9606	BTO:0000007								15342917	t		lperfetto	The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1	SIGNOR-128634	0.76
mTORC1	complex	SIGNOR-C3	SIGNOR	MAF1	protein	Q9H063	UNIPROT	down-regulates	phosphorylation	Ser75	SPSRLSKsQGGEEEG	9606									20516213	t		lperfetto	The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly.	SIGNOR-217153	0.467
PTPN1	protein	P18031	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	9606	BTO:0000007								16582879	t			Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR	SIGNOR-248408	0.778
SIRT1	protein	Q96EB6	UNIPROT	ADAMTS5	protein	Q9UNA0	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21337390	f		miannu	 The inhibition of SIRT1 by siRNA induced OA-like gene expression changes, namely the significant down-regulation of aggrecan and up-regulation of COL10A1 and ADAMTS-5.	SIGNOR-255140	0.268
PKN1	protein	Q16512	UNIPROT	PGAM	proteinfamily	SIGNOR-PF78	SIGNOR	down-regulates	phosphorylation			9606	BTO:0000130								12189148	t	inferred from family member	llicata	Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity.	SIGNOR-270282	0.331
TERF2	protein	Q15554	UNIPROT	Shelterin complex	complex	SIGNOR-C306	SIGNOR	form complex	binding			9606	BTO:0000567								15383534	t		lperfetto	Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins.	SIGNOR-263317	0.801
MECP2	protein	P51608	UNIPROT	RBFOX1	protein	Q9NWB1	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000614								18511691	t		Luana	MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.	SIGNOR-264681	0.284
NOP10	protein	Q9NPE3	UNIPROT	TERT	protein	O14746	UNIPROT	up-regulates activity	binding												18680434	t		lperfetto	 Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity 	SIGNOR-263331	0.613
ABRAXAS1	protein	Q6UWZ7	UNIPROT	BRCA1-A complex	complex	SIGNOR-C296	SIGNOR	form complex	binding			9606	BTO:0000007								20656690	t		lperfetto	We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1. 	SIGNOR-263214	0.2
HMOX1	protein	P09601	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0004296								21037234	f		irozzo	In conclusion, AMPK stimulates HO-1 gene expression in human ECs via the Nrf2/antioxidant responsive element signaling pathway. The induction of HO-1 mediates the antiapoptotic effect of AMPK, and this may provide an important adaptive response to preserve EC viability during periods of metabolic stress.	SIGNOR-256302	0.7
TFAP2C	protein	Q92754	UNIPROT	CRABP2	protein	P29373	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002828								17187826	f	 	miannu	 Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. 	SIGNOR-255398	0.252
MARCHF8	protein	Q5T0T0	UNIPROT	HLA-DRB4	protein	P13762	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys254	FIYFRNQkGHSGLQP	9606									19117940	t		miannu	Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination.	SIGNOR-271407	0.2
17alpha-hydroxypregnenolone	smallmolecule	CHEBI:28750	ChEBI	dehydroepiandrosterone	chemical	CHEBI:28689	ChEBI	up-regulates quantity	precursor of			9606		BTO:0001363;BTO:0000050;BTO:0000056							17192295	t		lperfetto	THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones.	SIGNOR-268647	0.8
entinostat	chemical	CHEBI:132082	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257902	0.8
RNF168	protein	Q8IYW5	UNIPROT	H1-2	protein	P16403	UNIPROT	down-regulates	polyubiquitination			9606	BTO:0000815								30517763	t		miannu	ITCH biochemically antagonized RNF168 and RNF8 in polyubiquitination of histone H1.2 ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. Both RNF168 and RNF8 elicited higher Ubn levels of K46R-H1.2 compared to WT-H1.2, suggesting that Ubn of H1.2 by both E3 ligases occurs at a site apart from K46. 	SIGNOR-272927	0.2
ATF2	protein	P15336	UNIPROT	POLB	protein	P06746	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001025								10518804	f		miannu	 We identified the heterodimeric transcription factor ATF2/CREB as constitutively binding to the essential cAMP response element (CRE) site within the Ca2+-regulated DNA polymerase beta promoter and contributing to the activation of this promoter.	SIGNOR-253744	0.2
GAP43	protein	P17677	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	up-regulates				10116									26865625	f		miannu	Growth-associated protein 43 (GAP43), a protein kinase C (PKC)-activated phosphoprotein, is often implicated in axonal plasticity and regeneration. 	SIGNOR-266771	0.7
DBP	protein	Q10586	UNIPROT	CYP7A1	protein	P22680	UNIPROT	up-regulates quantity by expression	transcriptional regulation												8617210	f	 	lperfetto	While TEF stimulates transcription from the albumin promoter more potently than DBP, only DBP is capable of activating transcription efficiently from the cholesterol 7 alpha hydroxylase (C7alphaH) promoter.	SIGNOR-254121	0.37
KIT	protein	P10721	UNIPROT	SLA	protein	Q13239	UNIPROT	down-regulates activity	phosphorylation	Tyr258	KKSISLMyGGSKRKS	9534	BTO:0001538								24284075	t		miannu	Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity	SIGNOR-263141	0.2
CSNK2A1	protein	P68400	UNIPROT	FGF14	protein	Q92915	UNIPROT	up-regulates activity	phosphorylation	Ser230	VTPSKSTsASAIMNG	9606	BTO:0000938								26917740	t		lperfetto	 Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.	SIGNOR-275739	0.272
BDKRB1	protein	P46663	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256764	0.252
MAPK1	protein	P28482	UNIPROT	RGS19	protein	P49795	UNIPROT	up-regulates	phosphorylation	Ser151	EDYVSILsPKEVSLD	9606									15488168	t		gcesareni	Phosphorylation of gaip by erk2 were abrogated when serine at position 151 in the rgs domain was substituted by an alanine residue using site-directed mutagenesis. Furthermore, the lysosomal-autophagic pathway was not stimulated in s151a-gaip mutant-expressing cells when compared with wild-type gaip-expressing cells. These results demonstrate that the gtpase-activating protein activity of gaip is stimulated by erk2 phosphorylation.	SIGNOR-129883	0.488
PTPN1	protein	P18031	UNIPROT	BCR	protein	P11274	UNIPROT	down-regulates	dephosphorylation			9606									9566916	t	The effect has been demonstrated using P11274-1	gcesareni	These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo.	SIGNOR-56818	0.335
KIT	protein	P10721	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates	phosphorylation	Tyr703	DHAEAALyKNLLHSK	9606									10377264	t		miannu	Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr	SIGNOR-68643	0.2
CAMK2G	protein	Q13555	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity	phosphorylation	Ser641	RRSVKRNsTVDCNGV	9606	BTO:0000938								32611770	t		lperfetto	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275794	0.274
AREG	protein	P15514	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606		BTO:0001253							20513444	t	Amphiregulin is an autocrine growth factor	lperfetto	Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling.	SIGNOR-236356	0.764
dacomitinib	chemical	CHEBI:132268	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									23405260	t		gcesareni	The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor.	SIGNOR-200905	0.8
WNT7B	protein	P56706	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates	binding			9606									15923619	t		flangone	These studies point to an important interaction between wnt7b, lrp5, and fzd1 and fzd10.	SIGNOR-137937	0.661
 MCU_MICU3_variant	complex	SIGNOR-C501	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270873	0.8
EFNA3	protein	P52797	UNIPROT	EPHA3	protein	P29320	UNIPROT	up-regulates	binding			9606									9330863	t		gcesareni	The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells.	SIGNOR-52312	0.797
MECP2	protein	P51608	UNIPROT	SGK1	protein	O00141	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									16002417	t		Luana	These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress.	SIGNOR-264543	0.297
CDK5	protein	Q00535	UNIPROT	CLOCK	protein	O15516	UNIPROT	up-regulates	phosphorylation	Thr461	KIPTDTStPPRQHLP	9606									24235147	t		lperfetto	Cdk5 phosphorylates clock at the thr-451 and thr-461 residues in association with transcriptional activation of clock.	SIGNOR-203231	0.335
RXRA	protein	P19793	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates	binding			9606									10976919	t	inferred from 70% of family members	gcesareni	Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr).	SIGNOR-269877	0.714
PIK3R3	protein	Q92569	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								32606738	t		miannu	N this study, we aimed to explore the interaction of p55PIK with p53 and the role of p55PIK in regulating p53-dependent apoptosis in cancer cells. We found that p55PIK directly binds to the DBD domain of p53 via N24 domain. Moreover, the upregulation of p55PIK expression increases transcriptional levels of p53-dependent apoptosis-related genes including GADD45α, S100A9, MDM2 and AIP1. Furthermore, synthetic N24 translocated to nucleus can significantly inhibit cancer cell growth.	SIGNOR-261492	0.301
HIF1A	protein	Q16665	UNIPROT	PGK1	protein	P00558	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567;BTO:0000972								8089148	f	 	miannu	Hypoxia-inducible factor 1 (HIF-1) activates erythropoietin gene transcription in Hep3B cells subjected to hypoxia. HIF-1 activity is also induced by hypoxia in non-erythropoietin-producing cells, suggesting a more general regulatory role. We now report that RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 (1% O2, cobalt chloride, or desferrioxamine). Sequences from the ALDA, PFKL, and PGK1 genes containing HIF-1 binding sites mediated hypoxia-inducible transcription in transient expression assays.	SIGNOR-254424	0.482
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1871	SPKYSPTsPKYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120132	0.316
ADNP	protein	Q9H2P0	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	up-regulates				10090									12888219	f		miannu	Mouse ADNP was shown to be expressed at the time of neural tube closure, detected at E7.5 and increased on E9.5. Expression was augmented in the brain (E12.5), sustained throughout embryogenesis and regulated by VIP. In conclusion, ADNP is identified here as a new key gene essential for organogenesis in the developing embryo and may be implicated as a clinical target associated with proper neurodevelopment.	SIGNOR-266758	0.7
PPARGC1A	protein	Q9UBK2	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887;BTO:0001103							17609368	f		lperfetto	Furthermore, ampk directly phosphorylates pgc-1?, And this phosphorylation mediates an increase in pgc-1? Protein action on the pgc-1? Promoter.	SIGNOR-156783	0.2
DDX5	protein	P17844	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	binding			9606									15660129	t		miannu	The dead box protein p68: a novel transcriptional coactivator of the p53 tumour suppressor	SIGNOR-133341	0.691
YY1	protein	P25490	UNIPROT	ACTC1	protein	P68032	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									9171244	f		miannu	 Expression of YY1 inhibited cardiac alpha-actin promoter activity, whereas coexpression of Nkx-2.5 and SRF was able to partially reverse YY1 repression. 	SIGNOR-255616	0.2
OPHN1	protein	O60890	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates				9606	BTO:0000938								12932438	f		miannu	These results based on the immunodetection of the endogenous protein clearly show that OPHN1 colocalizes with F-actin in both neuronal and glial cells and suggest that OPHN-1 interacts with actin.	SIGNOR-268400	0.7
NMUR2	protein	Q9GZQ4	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256731	0.409
RUNX2	protein	Q13950	UNIPROT	ENPP1	protein	P22413	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004473								19049325	f		miannu	FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2.	SIGNOR-252192	0.346
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1927	SPKYSPTsPTYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269375	0.718
PTPN6	protein	P29350	UNIPROT	SYK	protein	P43405	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000782								10458769	t		miannu	We propose that shp1 can dephosphorylate sites in zap-70 and syk that are involved in coupling these kinases to downstream signaling cascades, including erk2 and elements of the il-2 gene.	SIGNOR-70234	0.726
PTPN22	protein	Q9Y2R2	UNIPROT	NLRP3	protein	Q96P20	UNIPROT	up-regulates activity	dephosphorylation			9606									28786745	t		miannu	Further, this explains how loss of PTPN22 and subsequent enhanced NLRP3 phosphorylation mediate a decrease in NLRP3 inflammasome activation.|Upon NLRP3 activation, PTPN22 dephosphorylates NLRP3 and thereby protects it from degradation, allowing robust inflammasome activity (summarized in Fig.S6).	SIGNOR-277056	0.364
PLK1	protein	P53350	UNIPROT	CLIP1	protein	P30622	UNIPROT	down-regulates activity	phosphorylation	Ser312	ASLKRSPsASSLSSM	-1									24451569	t		lperfetto	Plk1 phosphorylates CLIP-170 and regulates its binding to microtubules for chromosome alignment|Here, we show that phosphorylation at Ser312 in the third serine-rich region of CLIP-170 is increased during mitosis. Polo-like kinase 1 (Plk1) is responsible for this phosphorylation during the mitotic phase of dividing cells. In vitro analysis using a purified CLIP-170 N-terminal fragment showed that phosphorylation by Plk1 diminishes CLIP-170 binding to the MT ends	SIGNOR-264575	0.692
MAPK1	protein	P28482	UNIPROT	BCL3	protein	P20749	UNIPROT	up-regulates activity	phosphorylation	Ser454	PSPAPGGs	-1									28689659	t		miannu	Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA. 	SIGNOR-277361	0.487
HDAC3	protein	O15379	UNIPROT	FASN	protein	P49327	UNIPROT	up-regulates quantity by stabilization	deacetylation			9606	BTO:0000007								27758890	t			Overexpression of HA-HDAC3 decreased the acetylation level of endogenous FASN by 35% in HEK293T cells, while the expression of a catalytic inactive mutant HDAC3Y298H (38) failed to reduce FASN acetylation (Fig. 4C). Conversely, HDAC3 knockdown increased the acetylation level of endogenous FASN by >1.5-fold in HEK293T cells	SIGNOR-267367	0.2
CLOCK	protein	O15516	UNIPROT	CRY1	protein	Q16526	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f			Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253631	0.943
BRAF	protein	P15056	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates activity	phosphorylation	Ser465	TVGQRIGsGSFGTVY	9606									31929109	t		miannu	We previously identified that BRAFWT can autophosphorylate its P-loop (Ser-465/Ser-467) to inactivate itself in the absence of native substrate MEK	SIGNOR-277498	0.2
AKT3	protein	Q9Y243	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser253	APRRRAVsMDNSNKY										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249643	0.697
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	KHSRP	protein	Q92945	UNIPROT	down-regulates activity	phosphorylation	Ser193	GLPERSVsLTGAPES	9606									17177604	t		lperfetto	Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome.	SIGNOR-151216	0.2
AURKB	protein	Q96GD4	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	up-regulates activity	phosphorylation	Ser1342	GPLRGKTsGTEPADF	9606	BTO:0001938								28415769	t		lperfetto	Here we report for the first time that tumor suppressor p53-binding protein 1 (53BP1) is phosphorylated at serine 1342 (S1342) by Aurora kinase B both in vitro and in human cells, which is required for optimal recruitment of 53BP1 at kinetochores.	SIGNOR-264411	0.421
PFDN6	protein	O15212	UNIPROT	Prefoldin co-chaperone	complex	SIGNOR-C513	SIGNOR	form complex	binding			9606									32699605	t		miannu	The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6)	SIGNOR-270930	0.94
NRCAM	protein	Q92823	UNIPROT	ANK2	protein	Q01484	UNIPROT	up-regulates quantity	relocalization			10116		BTO:0000227							7961622	t		miannu	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266719	0.726
LAMA5	protein	O15230	UNIPROT	Laminin-10	complex	SIGNOR-C182	SIGNOR	form complex	binding												11821406	t		lperfetto	The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia.	SIGNOR-255317	0.738
CASP1	protein	P29466	UNIPROT	RNF31	protein	Q96EP0	UNIPROT	down-regulates activity	cleavage	Asp387	QPPSLVVdSRDAGIC	9606	BTO:0005111								32122970	t		miannu	We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death.	SIGNOR-272193	0.2
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2D3	protein	P61077	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271348	0.724
PRKCA	protein	P17252	UNIPROT	KCNJ1	protein	P48048	UNIPROT	down-regulates activity	phosphorylation	Thr193	KKRAKTItFSKNAVI	-1									22139477	t		miannu	The giant patch clamp together with site direct mutagenesis revealed that Thr-193 is the phosphorylation site on PKC that regulates the pH(i) sensitivity of ROMK1 channels. Mutation of PKC-induced phosphorylation sites (T193A) decreases the pH(i) sensitivity and increases the interaction of channel-PIP(2). 	SIGNOR-276389	0.2
CLK1	protein	P49759	UNIPROT	RBM17	protein	Q96I25	UNIPROT	up-regulates activity	phosphorylation	Ser266	QGLSTALsVEKTSKR	9534	BTO:0001538								23519612	t		miannu	 In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 	SIGNOR-262708	0.324
MSI1	protein	O43347	UNIPROT	NUMB	protein	P49757	UNIPROT	down-regulates	binding			9606									20477901	t	Inhibits translation	gcesareni	The study confirmed p21(cip1) and numb proteins as targets of musashi1, suggesting additionally p27(kip1) in cell-cycle regulation and jagged-1 in notch .	SIGNOR-165617	0.458
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	LATS2	protein	Q9NRM7	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0005907								25026211	t		miannu	CRL4 DCAF1 ubiquitylates and inhibits Lats.	SIGNOR-272230	0.2
PRKCG	protein	P05129	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	down-regulates	phosphorylation	Thr425	KKCLELFtELAEDKE	9606									24117238	t		lperfetto	Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_, and, more interestingly, this threonine residue set serves as a 'phosphorylation switch' for hsp90_ binding or release of pkc_. Moreover, phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity.	SIGNOR-202816	0.26
DZIP3	protein	Q86Y13	UNIPROT	H2AC18	protein	Q6FI13	UNIPROT	up-regulates activity	monoubiquitination	Lys119	IQAVLLPkKTESHHK	9606	BTO:0000007								18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271755	0.2
PRKAA1	protein	Q13131	UNIPROT	CRY1	protein	Q16526	UNIPROT	down-regulates	phosphorylation	Ser71	ANLRKLNsRLFVIRG	9606			SIGNOR-C15				phosphorylation:Ser71	ANLRKLNsRLFVIRG	21892142	t		gcesareni	Ampk was shown to regulate the stability of the core clock component cry1 though phosphorylation of cry1 ser71, which stimulates the direct binding of the fbox protein fbxl3 to cry1, targeting it for ubiquitin-mediated degradation	SIGNOR-176472	0.369
DUSP6	protein	Q16828	UNIPROT	MAPK8	protein	P45983	UNIPROT	down-regulates activity	dephosphorylation			9606									24861519	t		miannu	Our data demonstrate MKP-3 has differential substrate preference in astrocytes compared to other cells types, since it preferentially dephosphorylated p-JNK over p-ERK.|The main findings of our studies are (1) MKP-3 preferentially reduces p-JNK over p-ERK and p-p38 in primary astrocytes; (2) This MAPK modulation pattern in primary astrocytes significantly reduced NO and completely abolished IL-6 and TNF accumulation; and (3) These effects are specifically induced by MKP-3 since block-age of MKP-3 mRNA expression reversed its action on MAPKs and pro-inflammatory mediators in BV-2 microglia cells.	SIGNOR-277150	0.618
FYN	protein	P06241	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates	phosphorylation	Tyr523	REDSVLSyETVTQME	9606	BTO:0000938	BTO:0000142							18721130	t		llicata	Psd-95 is phosphorylated either by purified src/fyn kinases in vitro or by co-expression of constitutively active src/fyn in cos7 cells. psd-95 tyr(523) phosphorylation contributes to the post-ischaemic over-activation of nmda receptors.	SIGNOR-180449	0.58
U1 snRNP complex	complex	SIGNOR-C480	SIGNOR	RNA_splicing	phenotype	SIGNOR-PH201	SIGNOR	up-regulates				9606									30765414	f		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270687	0.7
STAT6	protein	P42226	UNIPROT	SLC26A4	protein	O43511	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24429829	f		miannu	 We then examined the ability of STAT6 to bind each of the N4 GAS motifs in vivo with a site-specific ChIP assay, the results of which showed that STAT6 interacted with only the N4 GAS motif that was functionally implicated in increasing the activity of the pendrin promoter following IL-4 treatment.	SIGNOR-255250	0.2
CSNK2A1	protein	P68400	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates activity	phosphorylation	Ser59	NKLFQYAsTDMDKVL	-1									8663403	t		llicata	We show that serine 59 located between the MADS and MEF2 domains of MEF2C is phosphorylated in vivo and can be phosphorylated in vitro by casein kinase-II (CKII). Phosphorylation of this site enhanced the DNA binding and transcriptional activity of MEF2C by increasing its DNA binding activity 5-fold.	SIGNOR-250914	0.338
PRKCZ	protein	Q05513	UNIPROT	WWC1	protein	Q8IX03	UNIPROT	unknown	phosphorylation	Ser978	KRPSSVKsLRSERLI	-1									15081397	t		lperfetto	PKCzeta phosphorylates KIBRA at serine 975 and 978	SIGNOR-249263	0.727
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDUFV1	protein	P49821	UNIPROT	up-regulates activity	phosphorylation	Thr383	HESCGQCtPCREGVD										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275602	0.2
CASP5	protein	P51878	UNIPROT	GSDMD	protein	P57764	UNIPROT	up-regulates activity	cleavage	Asp275	CLHNFLTdGVPAEGA	9606	BTO:0000007								26375003	t		lperfetto	 Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence |	SIGNOR-256418	0.609
CTNND1	protein	O60716	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates	binding			9606									22946057	t		gcesareni	We demonstrate that p120-catenin participates in the stimulation of rac1 activity, binding directly to this protein. In addition we show that vav2 also binds to p120-catenin and is required for rac1 activation and for beta-catenin translocation to the nucleus.Vav2 And rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by ck1 and inhibited by tyrosine phosphorylation by src or fyn	SIGNOR-198938	0.568
IKBKE	protein	Q14164	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Ser405	SHPLSLTsDQYKAYL	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178383	0.732
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	cleavage			-1									10579725	t		lperfetto	P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro	SIGNOR-256446	0.662
tetra-mu3-sulfido-tetrairon	chemical	CHEBI:49883	ChEBI	SDH	complex	SIGNOR-C400	SIGNOR	form complex	binding			9606									16143825	t		miannu	Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively.	SIGNOR-267733	0.8
PIP3	smallmolecule	CHEBI:16618	ChEBI	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	relocalization			10116									8645147	t			Activated hyperphosphorylated Akt-1 bound to Ptd Ins(3,4,5)P3 -containing vesicles in a similar manner to the inactive dephosphorylated enzyme	SIGNOR-254982	0.8
CCK	protein	P06307	UNIPROT	CCKAR	protein	P32238	UNIPROT	up-regulates	binding			9606									10368033	t		gcesareni	Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b	SIGNOR-68474	0.779
ABT-737	chemical	CID:11228183	PUBCHEM	BCL2	protein	P10415	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189159	0.8
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1910	TPTSPKYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273056	0.556
Corticotropin	protein	P01189-PRO_0000024969	UNIPROT	MC5R	protein	P33032	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268716	0.2
MAPK14	protein	Q16539	UNIPROT	DDIT3	protein	P35638	UNIPROT	up-regulates activity	phosphorylation	Ser82	STSQSPHsPDSSQSS	-1									8650547	t		miannu	CHOP, a member of the C/EBP family of transcription factors, mediates effects of cellular stress on growth and differentiation. It accumulates under conditions of stress and undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, CHOP is phosphorylated on these residues by p38 mitogen-activated protein kinase (MAP kinase).	SIGNOR-250096	0.593
MAPK1	protein	P28482	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation	Ser9	SGRPRTTsFAESCKP	10090	BTO:0002572								28646232	t		Gianni	We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels	SIGNOR-262524	0.39
SUFU	protein	Q9UMX1	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates activity	binding												15367681	t		lperfetto	Here we characterize structural and functional determinants of Su(fu) required for Gli regulation and show that Su(fu) contains at least two distinct domains: a highly conserved carboxy-terminal region required for binding to the amino-terminal ends of the Gli proteins and a unique amino-terminal domain that binds the carboxy-terminal tail of Gli1. While each domain is capable of binding to different Gli1 regions independently, interactions between Su(fu) and Gli1 at both sites are required for cytoplasmic tethering and repression of Gli1	SIGNOR-249591	0.948
PRKACA	protein	P17612	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation	Ser119	EILSRRPsYRKILND	10116	BTO:0001009								8336722	t		gcesareni	The degree of CREB phosphorylation, assessed with antiserum specific for CREB phosphorylated at Ser-133, correlated with the amount of PKA liberated. The time course of phosphorylation closely paralleled the nuclear entry of the catalytic subun	SIGNOR-166342	0.563
MRPS26	protein	Q9BYN8	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261447	0.691
PC	protein	P11498	UNIPROT	pyruvate	smallmolecule	CHEBI:15361	ChEBI	down-regulates quantity	chemical modification			9606									24363178	t		miannu	As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2)	SIGNOR-266554	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SPHK2	protein	Q9NRA0	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								17311928	t	inferred from 70% family members	llicata	Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1	SIGNOR-270154	0.2
MAPK1	protein	P28482	UNIPROT	DYRK1B	protein	Q9Y463	UNIPROT	up-regulates activity	phosphorylation	Ser421	YEPAARIsPLGALQH	-1									26346493	t		miannu	S421 resides within a Ser-Pro phosphoacceptor motif that is typical for ERK1/2 and recombinant ERK2 phosphorylated DYRK1B at S421 in vitro. 	SIGNOR-276937	0.376
SOCS3	protein	O14543	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	binding			9606									23115649	t		gcesareni	Irs-1 is the major signaling protein that socs3 targets to inhibit insulin signaling	SIGNOR-199361	0.73
PLK1	protein	P53350	UNIPROT	CCNB1	protein	P14635	UNIPROT	up-regulates activity	phosphorylation	Ser128	LVDTASPsPMETSGC	9606	BTO:0000567								11242082	t		lperfetto	Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation.	SIGNOR-105711	0.919
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	KRT8	protein	P05787	UNIPROT	unknown	phosphorylation												16554440	t	inferred from 70% family members	lperfetto	Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002).	SIGNOR-270003	0.2
BCL2L11	protein	O43521	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	down-regulates	binding			9606									15694340	t		gcesareni	Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly.	SIGNOR-133829	0.955
SUZ12/EZH2	complex	SIGNOR-C77	SIGNOR	SUZ12/EZH2/YY1	complex	SIGNOR-C102	SIGNOR	form complex	binding			10090	BTO:0000165;BTO:0002314								20887952	t		lperfetto	TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter.	SIGNOR-235577	0.766
DVL1	protein	O14640	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity	binding			9606				SIGNOR-C110					20837657	t		gcesareni	In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization.	SIGNOR-167957	0.606
FGD1	protein	P98174	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260551	0.705
CDK1	protein	P06493	UNIPROT	EP300	protein	Q09472	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1038	STSATQSsPAPGQSK	9606	BTO:0000551								24530506	t		miannu	In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels. 	SIGNOR-276457	0.413
LRIG1	protein	Q96JA1	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	binding			9606		BTO:0001253							15282549	t		gcesareni	We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.	SIGNOR-127298	0.572
POLR1D	protein	P0DPB6	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding												22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266146	0.89
fexofenadine	chemical	CHEBI:5050	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									19660947	t		Luana	 hERG activity was initially determined in a high throughput patch clamp screening assay (Ionworks)5 while a human H1 binding assay was used to determine H1 binding affinity.6 Selected results were confirmed in vitro using an IonWorks Quattro patch clamp assay and in vivo in the guinea pig.7, 8 Histamine H1activity was confirmed in vivo in the guinea pig.7	SIGNOR-257827	0.8
MFGE8	protein	Q08431	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity				9606									21901532	f		miannu	In an attempt to clarify the direct anti-inflammatory role of MFG-E8, we revealed a distinct signaling pathway where MFG-E8 activates suppressor of cytokine signaling (SOCS) 3 gene expression via STAT3 mediated pathway, which in turn served as a negative regulator for LPS induced TLR4 signaling by targeting NF-κB p65 component, thereby attenuating the down-stream signaling for TNF-α production	SIGNOR-260654	0.28
PLK1	protein	P53350	UNIPROT	CDC6	protein	Q99741	UNIPROT	up-regulates	phosphorylation	Thr37	SDAKLEPtNVQTVTC	9606									21041660	t		lperfetto	Binding between cdc6 and plk1 occurs through the polo-box domain of plk1, and cdc6 is phosphorylated by plk1 on t37. These results suggest that plk1-mediated phosphorylation of cdc6 promotes the interaction of cdc6 and cdk1, leading to the attenuation of cdk1 activity, release of separase, and subsequent anaphase progression.	SIGNOR-169184	0.584
PLAAT3	protein	P53816	UNIPROT	PPP2CB	protein	P62714	UNIPROT	down-regulates				9606									17374643	f		miannu	The alpha-isoform of the regulatory subunit a of protein phosphatase 2a (pr65alpha) as a new interaction partner of hrsl3 / we demonstrate that hrsl3 binds to the endogenous pr65alpha, thereby partially sequestering the catalytic subunit pr36 from the pr65 protein complex, and inhibiting pp2a catalytic activity.	SIGNOR-153775	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDE1	protein	Q9NXR1	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser282	RNLVYDQsPNRTGGP	9606	BTO:0000007								16682949	t	done	miannu	Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. 	SIGNOR-274083	0.525
ACSS1	protein	Q9NUB1	UNIPROT	acetate	smallmolecule	CHEBI:30089	ChEBI	down-regulates quantity	chemical modification												10843999	t		lperfetto	The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP.	SIGNOR-271830	0.8
MAPK1	protein	P28482	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser732	RRVRKLPsTTL	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252747	0.751
AKT1	protein	P31749	UNIPROT	BTK	protein	Q06187	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr495	EMRHRFQtQQLLEMC	9606	BTO:0003289								23754751	t		miannu	The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain. 	SIGNOR-276465	0.301
IKBKE	protein	Q14164	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Ser402	ISNSHPLsLTSDQYK	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178379	0.732
STAT6	protein	P42226	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates activity				10090									24948596	f			IL-4 was shown to inhibit lipid accumulation in adipose tissue by a mechanism that includes activation of Stat6, which suppresses PPARα transcriptional activity	SIGNOR-254682	0.529
MEF2D	protein	Q14814	UNIPROT	MYH7	protein	P12883	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								17111365	f	Regulation	miannu	Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner. 	SIGNOR-251957	0.342
C5 convertase complex (C3bBbC3b)	complex	SIGNOR-C315	SIGNOR	C5	protein	P01031	UNIPROT	up-regulates activity	cleavage	Arg751	HKDMQLGrLHMKTLL	9606		BTO:0000089							26489954	t		lperfetto	In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC).	SIGNOR-263482	0.538
AKT1	protein	P31749	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser315	DFRSRTNsNASTVSG										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249627	0.908
BMP7	protein	P18075	UNIPROT	UCP1	protein	P25874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18719589	f		fspada	Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways	SIGNOR-180354	0.44
MAPK7	protein	Q13164	UNIPROT	MAP2K5	protein	Q13163	UNIPROT	up-regulates	phosphorylation	Ser149	SNSLKKSsAELKKIL	9606		BTO:0000671							12628002	t		lperfetto	Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)	SIGNOR-99139	0.69
MET	protein	P08581	UNIPROT	MET	protein	P08581	UNIPROT	up-regulates	phosphorylation	Tyr1235	DMYDKEYySVHNKTG	9606									8302603	t		lperfetto	Previous work has shown that autophosphorylation of p190met enhances its enzymatic activity and that the major phosphorylation site is tyr1235, located in the catalytic domainonly the replacement of both tyr1234 and tyr1235 yielded a mutant which completely lost the ability to be activated by autophosphorylation	SIGNOR-37727	0.2
PPARGC1A	protein	Q9UBK2	UNIPROT	PCK2	protein	Q16822	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f		miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-255060	0.406
CHUK	protein	O15111	UNIPROT	CREBBP	protein	Q92793	UNIPROT	up-regulates	phosphorylation	Ser1382	MKSRFVDsGEMSESF	9606	BTO:0000551								17434128	t		lperfetto	Phosphorylation of cbp by ikkalpha promotes cell growth by switching the binding preference of cbp from p53 to nf-kappabhere, we show that ikkalpha phosphorylates cbp at serine 1382 and serine 1386 and consequently increases cbp's hat and transcriptional activities	SIGNOR-154329	0.533
PTPRB	protein	P23467	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates	dephosphorylation			9606									12840032	t		gcesareni	When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well	SIGNOR-103165	0.443
NR0B1	protein	P51843	UNIPROT	NR5A1	protein	Q13285	UNIPROT	down-regulates activity	binding			9606	BTO:0002588								19237537	t		miannu	The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes.	SIGNOR-271784	0.726
PIP3	smallmolecule	CHEBI:16618	ChEBI	AKT3	protein	Q9Y243	UNIPROT	up-regulates	chemical activation			9606									21779497	t		gcesareni	When active, pi3k converts phosphatidylinositol (4,5)-bisphosphate (pip2) into phosphatidylinositol (3,4,5)-trisphosphate (pip3). Pip3, in turn, binds the pleckstrin homology (ph) domain of akt/pkb, stimulating its kinase activity, resulting in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival.	SIGNOR-175250	0.8
PAFAH1B1	protein	P43034	UNIPROT	Neuron_migration	phenotype	SIGNOR-PH67	SIGNOR	up-regulates				9606									20133715	f		miannu	The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration.	SIGNOR-252169	0.7
GPR65	protein	Q8IYL9	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									27287411	t			GPR65 is playing a critical role in phagocytic cells that require high levels of V-ATPase activity to maintain phagosomal and lysosomal pH, and this activity aids in the direct clearance of enteric pathogens.	SIGNOR-272502	0.274
STK4	protein	Q13043	UNIPROT	TNNI3	protein	P19429	UNIPROT	unknown	phosphorylation	Thr129	ITEIADLtQKIFDLR	9606		BTO:0000671							18986304	t		llicata	Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143).	SIGNOR-182049	0.2
CREB1	protein	P16220	UNIPROT	IL10	protein	P22301	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10540320	f		miannu	Our data suggest that intracellular cAMP may directly affect expression of the immunoregulatory cytokine IL-10 in monocytic cells via activation of the eukaryotic transcription factors CREB-1 and ATF-1 and their binding to CRE1 and CRE4 in the upstream enhancer of the IL-10 promoter	SIGNOR-254522	0.442
ESR1	protein	P03372	UNIPROT	CRH	protein	P06850	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000614							8408641	t		lperfetto	Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.|Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro. 	SIGNOR-268721	0.348
SNRPG	protein	P62308	UNIPROT	U1 snRNP complex	complex	SIGNOR-C480	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270683	0.926
TGFB1	protein	P01137	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates	binding			9606									26194464	t		MARCO ROSINA	TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI).	SIGNOR-255030	0.847
EEF1A1P5	protein	Q5VTE0	UNIPROT	Pro-tRNA(Pro)	smallmolecule	CHEBI:29154	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269554	0.8
SP1	protein	P08047	UNIPROT	KLK3	protein	P07288	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001033								15708372	t	 	 	We characterized four Sp1/Sp3 binding sites in the proximal promoter of the PSA gene. In a luciferase assay, these sites contributed to the basal promoter activity in prostate cancer cells. In an electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we confirmed that Sp1 and Sp3 bind to these sites. Overexpression of wild-type Sp1 and Sp3 further upregulated the promoter activity, whereas overexpression of the Sp1 dominant-negative form or addition of mithramycin A significantly reduced the promoter activity and the endogenous mRNA level of PSA.	SIGNOR-253664	0.2
SLN	protein	O00631	UNIPROT	ATP2A2	protein	P16615	UNIPROT	down-regulates activity	binding			-1									23455424	t		lperfetto	The structure suggests a mechanism for selective Ca2+ loading and activation of SERCA, and provides new insight into how SLN and PLB inhibition arises from stabilization of this E1 intermediate state without bound Ca2+. 	SIGNOR-264779	0.52
SHH	protein	Q15465	UNIPROT	CP	protein	P00450	UNIPROT	down-regulates	binding			9606		BTO:0001253							9811851	t		gcesareni	Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms.	SIGNOR-61549	0.2
PRKACA	protein	P17612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606									18794113	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.	SIGNOR-180906	0.521
FAM8A1	protein	Q9UBU6	UNIPROT	SYVN1	protein	Q86TM6	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								28827405	t		miannu	FAM8A1 enhances binding of Herp to Hrd1, an interaction that is required for ERAD. Our findings support a model of Hrd1 complex formation, where the Hrd1 cytoplasmic domain and FAM8A1 have a central role in the assembly and activity of this ERAD machinery. A conserved Hrd1 cytoplasmic domain interacts with FAM8A1 and Herp	SIGNOR-261348	0.593
MACROD2	protein	A1Z1Q3	UNIPROT	ADP-D-ribose(2-)	smallmolecule	CHEBI:57967	ChEBI	up-regulates quantity	chemical modification			9606									32257385	t		miannu	MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins	SIGNOR-269840	0.8
THBS2	protein	P35442	UNIPROT	CD47	protein	Q08722	UNIPROT	up-regulates	binding			9606									8550562	t		gcesareni	We report here that iap is a receptor for the ts1 cbd and its vvm-containing peptides and that a function-blocking anti-iap mab inhibits the chemotactic response to ts1 and its cbd peptides in endothelial cells.	SIGNOR-39749	0.58
PDPK1	protein	O15530	UNIPROT	AHCYL1	protein	O43865	UNIPROT	down-regulates activity	phosphorylation	Ser68	RSLSRSIsQSSTDSY	9534									17635105	t		lperfetto	Residue 68 resides in a consensus phosphorylation site for PKD (Figure 1A) [22,23]. Interestingly, phosphorylation of Ser68 could allow for subsequent phosphorylation of Ser71, Ser74, Ser77 and Ser80 by CK1, for which the consensus phosphorylation site is pS/T-X-X-S/T| We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R	SIGNOR-249174	0.2
ITGB1BP1	protein	O14713	UNIPROT	ITGB3	protein	P05106	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257656	0.313
sulpiride	chemical	CHEBI:32168	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			-1									7576010	t		miannu	The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. When receptors were labeled with [lzs1]-NCQ-298, D2 and D3 receptors displayed similar potencies for sulpiride, a D2 receptor antagonist (Figure 3A, Table I). 	SIGNOR-258430	0.8
HSD17B1	protein	P14061	UNIPROT	estrone	smallmolecule	CHEBI:17263	ChEBI	up-regulates quantity	chemical modification			-1									8994190	t		Luana	Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues. 	SIGNOR-269758	0.8
putrescine	smallmolecule	CHEBI:17148	ChEBI	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									14617280	f		apalma	Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism	SIGNOR-255551	0.7
Shelterin complex	complex	SIGNOR-C306	SIGNOR	ATM	protein	Q13315	UNIPROT	down-regulates activity	binding												18680434	t		lperfetto	It is not yet clear how the presence of TRF2 at telomeres averts the activation of the ATM kinase.> In this regard, overexpression of TRF2can dampen the activation of the ATM kinase, even at nontelomeric sites of DNA damage (95). Furthermore, TRF2 can interact with the ATM kinase as well as with the Mre11 complex 	SIGNOR-263322	0.493
GABA-A (a3-b1-g2) receptor	complex	SIGNOR-C332	SIGNOR	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	relocalization			9606									18790874	t	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263812	0.8
HSBP1	protein	O75506	UNIPROT	WASH complex	complex	SIGNOR-C258	SIGNOR	up-regulates quantity	relocalization			9606	BTO:0000007								29844016	t		lperfetto	The Trimeric Coiled-Coil HSBP1 Protein Promotes WASH Complex Assembly at Centrosomes	SIGNOR-261007	0.2
COPS7B	protein	Q9H9Q2	UNIPROT	COP9 signalosome variant 2	complex	SIGNOR-C487	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270760	0.891
NTN4	protein	Q9HB63	UNIPROT	NEO1	protein	Q92859	UNIPROT	up-regulates activity	binding			9606		BTO:0001484							28245592	t		miannu	Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins.	SIGNOR-268170	0.553
CDKN1A	protein	P38936	UNIPROT	CDK1	protein	P06493	UNIPROT	down-regulates	binding			9606									15340381	t		gcesareni	P21 and p27 are key inhibitors of both cdk1 and cdk2.	SIGNOR-128442	0.876
BTRC	protein	Q9Y297	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys800	LNPILPPkAPAVSPL	9606	BTO:0000938								17283082	t		lperfetto	Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage.	SIGNOR-249578	0.657
FGF2	protein	P09038	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	up-regulates				9606									20974802	f	inferred from 70% of family members	gcesareni	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription.	SIGNOR-269908	0.2
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	precursor of			9606									22049910	t		miannu	Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia.	SIGNOR-266906	0.8
panobinostat	chemical	CHEBI:85990	ChEBI	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257752	0.8
IL2RG	protein	P31785	UNIPROT	JAK3	protein	P52333	UNIPROT	up-regulates	binding			9606	BTO:0000776								18445337	t		milica	Jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation.	SIGNOR-178491	0.736
GATA2	protein	P23769	UNIPROT	GATA1	protein	P15976	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12432220	f		irozzo	Closer examination revealed a cross-regulatory mechanism by which GATA-1 can control the expression of GATA-2 and vice versa, possibly via essential GATA binding sites in their cis-acting elements.In this model, GATA-2 activates GATA-1 gene expression, while GATA-1 represses GATA-2 gene expression. 	SIGNOR-256056	0.419
ZFYVE9	protein	O95405	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	binding			9606									9865696	t		lperfetto	We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex.	SIGNOR-62874	0.855
SIRT7	protein	Q9NRC8	UNIPROT	FBL	protein	P22087	UNIPROT	up-regulates activity	deacetylation	Lys102	GVFICRGkEDALVTK										30540930	t		lperfetto	Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206)	SIGNOR-275894	0.274
GGCX	protein	P38435	UNIPROT	F10	protein	P00742	UNIPROT	up-regulates activity	carboxylation	Glu54	EMKKGHLeRECMEET	-1									9538022	t		lperfetto	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263666	0.598
MAPK3	protein	P27361	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser636	SGDYMPMsPKSVSAP	9606									12510059	t		gcesareni	Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1.	SIGNOR-249409	0.696
POU5F1	protein	Q01860	UNIPROT	HLX	protein	Q14774	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086								17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254936	0.2
OSBPL3	protein	Q9H4L5	UNIPROT	RRAS	protein	P10301	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								18270267	t		miannu	We show that ORP3 interacts with R-Ras, a small GTPase regulating cell adhesion, spreading and migration. Gene silencing of ORP3 in HEK293 cells results in altered organization of the actin cytoskeleton, impaired cell-cell adhesion, enhanced cell spreading and an increase of beta1 integrin activity--effects similar to those of constitutively active R-Ras(38V).	SIGNOR-277221	0.416
AKT1	protein	P31749	UNIPROT	JAG1	protein	P78504	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									38402584	f		miannu	Jagged1 is upregulated by Akt upon activation by R-Ras. All three Akt isoforms influence Jagged1 expression in ECs, but Akt3 is the most prominent Akt isoform in this role, despite its low expression level compared with Akt1. Jagged1 then activates Notch to upregulate Hey1, Hes1, p21, p53, and Unc5b in adjacent cells. 	SIGNOR-277222	0.42
TMLHE	protein	Q9NVH6	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	down-regulates quantity	chemical modification			9606									11431483	t		miannu	Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. 	SIGNOR-269682	0.8
ROCK2	protein	O75116	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				9606									14701738	f		miannu	 Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively.	SIGNOR-261712	0.7
NFIL3	protein	Q16649	UNIPROT	NFIL3	protein	Q16649	UNIPROT	up-regulates activity	binding			-1									12805554	t		miannu	E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins	SIGNOR-224248	0.2
EIF3F	protein	O00303	UNIPROT	EIF3_complex	complex	SIGNOR-C401	SIGNOR	form complex	binding			-1									16920360	t		miannu	Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 	SIGNOR-266395	0.921
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1721	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273073	0.636
haloperidol	chemical	CHEBI:5613	ChEBI	SIGMAR1	protein	Q99720	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000793								17419803	t		Simone Vumbaca	These results suggest that haloperidol may irreversibly inactivate sigma-1 receptors in guinea pig and human cells, probably after metabolism to reduced haloperidol.	SIGNOR-261090	0.8
PRKD1	protein	Q15139	UNIPROT	ATP7B	protein	P35670	UNIPROT	up-regulates activity	phosphorylation	Ser1453	DDDGDKWsLLLNGRD	9606	BTO:0000599								21189263	t		lperfetto	ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking.	SIGNOR-272294	0.302
VHL	protein	P40337	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								16678111	t			Here we found that pVHL directly associates with and stabilizes p53 by suppressing Mdm2-mediated ubiquitination and nuclear export of p53.	SIGNOR-256594	0.464
NR3C1	protein	P04150	UNIPROT	PER1	protein	O15534	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19805059	t		miannu	GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription	SIGNOR-268050	0.272
PRKAA2	protein	P54646	UNIPROT	HIPK2	protein	Q9H2X6	UNIPROT	down-regulates activity	phosphorylation	Thr119	HNLMRRStVSLLDTY										23871434	t	Phosphosite positions are derived from Figure S5	lperfetto	AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro	SIGNOR-275485	0.2
CSNK1D	protein	P48730	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	down-regulates	phosphorylation			9606									15747065	t		gcesareni	Cki_/_ binds and phosphorylates lef-1, and this phosphorylation disrupts lef-1_-catenin interaction	SIGNOR-134494	0.253
ATM	protein	Q13315	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								10550055	t		gcesareni	Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner.	SIGNOR-72075	0.813
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1623	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273072	0.636
MARK1	protein	Q9P0L2	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser579	NVKSKIGsTENLKHQ	-1									10090741	t		miannu	We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. 	SIGNOR-250172	0.44
ATM	protein	Q13315	UNIPROT	NBN	protein	O60934	UNIPROT	up-regulates	phosphorylation	Ser278	VDTGITNsQTLIPDC	9606									10839544	t		lperfetto	We have identified two residues of nbs1, ser 278 and ser 343 that are phosphorylated in vitro by atm and whose modification in vivo is essential for the cellular response to dna damage. This response includes s-phase checkpoint activation, formation of the nbs1/mrel1/rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation.	SIGNOR-78025	0.852
SMAD7	protein	O15105	UNIPROT	BMPR1B	protein	O00238	UNIPROT	down-regulates				10090									10564272	f		gcesareni	We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2	SIGNOR-236864	0.687
L-isoprenaline	chemical	CHEBI:6257	ChEBI	ADRB3	protein	P13945	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257458	0.8
LIN7C	protein	Q9NUP9	UNIPROT	AMOT/MPP5/INADL/LIN7C	complex	SIGNOR-C27	SIGNOR	form complex	binding			9606									24366813	t		lperfetto	To gain a more detailed view on the organization of this cell polarity network linked to yap1 we included several proteins of the cell junction complex (amot, mpp5, lin7a),	SIGNOR-203491	0.67
POU5F1	protein	Q01860	UNIPROT	LEFTY1	protein	O75610	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001086								17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254938	0.515
GRB2	protein	P62993	UNIPROT	SOS2	protein	Q07890	UNIPROT	up-regulates	binding			9606									21779497	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.	SIGNOR-175180	0.876
ITGB1BP1	protein	O14713	UNIPROT	Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257657	0.283
CASP12	protein	Q6UXS9	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates	cleavage			9606	BTO:0000222								12097332	t		gcesareni	Caspase-12 specifically cleaves and activates procaspase-9 in cytosolic extracts. Results suggest that caspase-12 can activate caspase-9 without involvement of cytochromec.	SIGNOR-90318	0.2
TLN1	protein	Q9Y490	UNIPROT	AM/b2 integrin	complex	SIGNOR-C170	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257620	0.566
beta-Funaltrexamine	chemical	CHEBI:81527	ChEBI	OPRD1	protein	P41143	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258771	0.8
HIF1A	protein	Q16665	UNIPROT	PDK1	protein	Q15118	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003291								16517405	t		miannu	Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. 	SIGNOR-267444	0.484
UVB radiation	stimulus	SIGNOR-ST17	SIGNOR	EDN1	protein	P05305	UNIPROT	up-regulates				9606									9767234	f		miannu	UVB can stimulate the synthesis of IL-1, TNF-a and ET-1, and other cytokines by keratinocytes.	SIGNOR-252383	0.7
pentazocine	chemical	CHEBI:7982	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9262330	t		miannu	We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine.	SIGNOR-258659	0.8
PRKCB	protein	P05771	UNIPROT	CFLAR	protein	O15519	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser193	LQAAIQKsLKDPSNN	9606	BTO:0000664								19343040	t		miannu	 Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins. c-FLIP S193 phosphorylation is mediated by PKCa and PKCb.S193 phosphorylation increases the stability of the short c-FLIP proteins	SIGNOR-276146	0.2
NEDD4L	protein	Q96PU5	UNIPROT	SCNN1A	protein	P37088	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									15586017	t	Regulation of localization	miannu	The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane. 	SIGNOR-251948	0.767
MAPK1	protein	P28482	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	phosphorylation	Thr212	VIEPLPVtPTRDVAT	10116	BTO:0001260								15542607	t		lperfetto	We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal 	SIGNOR-249432	0.411
CSNK2A1	protein	P68400	UNIPROT	HMGA1	protein	P17096	UNIPROT	unknown	phosphorylation	Ser103	EGISQESsEEEQ	-1									2806554	t		llicata	Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells.	SIGNOR-250893	0.335
XIAP	protein	P98170	UNIPROT	CASP3	protein	P42574	UNIPROT	down-regulates activity	binding			9606									11583623	t		amattioni	Xiap is an endogenous inhibitor of caspase-3	SIGNOR-110837	0.938
MAPK14	protein	Q16539	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates activity	phosphorylation	Ser216	SGLYRSPsMPENLNR	-1									9543386	t		miannu	P38 binds and phosphorylates Cdc25B at serines 309 and 361, and Cdc25C at serine 216; phosphorylation of these residues is required for binding to 14-3-3 proteins.	SIGNOR-250091	0.449
PAK1	protein	Q13153	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	phosphorylation	Ser675	QDYKKRLsVELTSSL	9606									21822311	t		lperfetto	Pak1 directly phosphorylates _-catenin proteins at ser675 site and this leads to more stable and transcriptional active _-catenin	SIGNOR-175944	0.54
ECM	stimulus	SIGNOR-ST20	SIGNOR	A11/b1 integrin	complex	SIGNOR-C168	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259050	0.7
MAPK8IP1	protein	Q9UQF2	UNIPROT	MAP4K2	protein	Q12851	UNIPROT	down-regulates	binding			9606	BTO:0000007								10702297	t		gcesareni	DLK mutants were used to demonstrate that a DLK leucine zipper-leucine zipper interaction is necessary for DLK dimerization and to show that DLK dimerization mediated by the leucine zipper domain is prerequisite for DLK activity and subsequent activation of stress-activated protein kinase (SAPK).	SIGNOR-75385	0.2
bosutinib	chemical	CHEBI:39112	ChEBI	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	down-regulates activity	chemical inhibition			9606	BTO:0001056								23409026	t		miannu	Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. 	SIGNOR-259271	0.8
MCHR1	protein	Q99705	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256905	0.252
AKT1	protein	P31749	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates	phosphorylation	Ser1834	MLRRRMAsMQRTGVV	9606									16926151	t		lperfetto	We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity	SIGNOR-148983	0.685
LCK	protein	P06239	UNIPROT	IL2RB	protein	P14784	UNIPROT	unknown	phosphorylation	Tyr381	EIEACQVyFTYDPYS	-1									10214954	t			Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510.	SIGNOR-251375	0.629
SRC	protein	P12931	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates	phosphorylation	Tyr130	VLDVLKFyDSNTVKQ	9606									12215529	t		llicata	Pak2 became tyrosine phosphorylated in its n-terminal regulatory domain, where y130 was identified as the major phosphoacceptor site. Tyrosine phosphorylation-mediated superactivation of pak2 could be induced by overexpression of different src kinases or by inhibiting cellular tyrosine phosphatases with pervanadate and could be blocked by the src kinase inhibitor pp1 or by mutating the y130 residue.	SIGNOR-92460	0.542
PRKG2	protein	Q13237	UNIPROT	PTS	protein	Q03393	UNIPROT	up-regulates	phosphorylation	Ser19	AQVSRRIsFSASHRL	9606									10531334	t		gcesareni	Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps	SIGNOR-71751	0.508
Succinyl-CoA GTP variant	complex	SIGNOR-C399	SIGNOR	succinate(2-)	smallmolecule	CHEBI:30031	ChEBI	up-regulates quantity	chemical modification			9606									27487822	t		miannu	In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions.	SIGNOR-266270	0.8
EIF3_complex	complex	SIGNOR-C401	SIGNOR	EIF4G2	protein	P78344	UNIPROT	up-regulates activity	stabilization			9606									17581632	t		lperfetto	EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 	SIGNOR-269156	0.392
sphingosine 1-phosphate	smallmolecule	CHEBI:37550	ChEBI	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	down-regulates				9606	BTO:0000007								22863277	f	inferred from 70% of family members	milica	Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2.	SIGNOR-269864	0.8
3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	up-regulates quantity	precursor of			9606									24786789	t		miannu	Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle.	SIGNOR-266509	0.8
BMPR1B	protein	O00238	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates	phosphorylation	Ser462	GSPHNPIsSVS	9606									9335504	t		llicata	The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1.	SIGNOR-52662	0.628
PRKAA1	protein	Q13131	UNIPROT	DNMT1	protein	P26358	UNIPROT	down-regulates activity	phosphorylation	Ser714	DNIPEMPsPKKMHQG	-1									28143904	t		lperfetto	Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK decreased DNMT1 activity	SIGNOR-264783	0.2
PTPN1	protein	P18031	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	dephosphorylation			-1									10660596	t		lperfetto	Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein.	SIGNOR-74852	0.771
seliciclib	chemical	CHEBI:45307	ChEBI	TP53	protein	P04637	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206577	0.8
XRCC6	protein	P12956	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates	relocalization			9606									19133841	t		gcesareni	Ku and dna-pkcs only interact in the presence of dna and recruitment of dna-pkcs to sites of dna damage in vivo is ku-dependent. Inward translocation of ku allows dna-pkcs to interact with the extreme termini of the dna, allowing two dna-pkcs molecules to interact across the dsb in a so-called synaptic complex . This interaction stimulates the kinase activity of dna-pkcs, promoting phosphorylation in trans across the dsb (discussed in more detail below). Once assembled at the dna ends, the dna-pkcs-ku-dsb complex serves to tether the ends of the dsb together and protects the dna ends from nuclease attack.	SIGNOR-183276	0.939
RNF7	protein	Q9UBF6	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates activity	ubiquitination			9606									23136067	t		miannu	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 	SIGNOR-271447	0.334
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser172	LCLSPASsGSSASFI	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252316	0.635
N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine	chemical	CHEBI:92386	ChEBI	ADRA2B	protein	P18089	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258921	0.8
MAPK7	protein	Q13164	UNIPROT	MAP2K5	protein	Q13163	UNIPROT	up-regulates	phosphorylation	Ser142	AVSDSLPsNSLKKSS	9606		BTO:0000671							12628002	t		lperfetto	Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)	SIGNOR-99135	0.69
LCK	protein	P06239	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates	phosphorylation	Tyr204	HTGFLTEyVATRWYR	9606									17998336	t		gcesareni	The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1.	SIGNOR-159168	0.547
OTUB1	protein	Q96FW1	UNIPROT	UBE2N	protein	P61088	UNIPROT	down-regulates	binding			9606									21763684	t		gcesareni	The deubiquitinating enzyme otub1 suppresses rnf168 dependent ubiquitination by direct the e2 ligase ubc13	SIGNOR-175050	0.727
PTPN1	protein	P18031	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates activity	dephosphorylation	Tyr534	NFLMDNAyFCEADAK	10029									12907755	t			PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 	SIGNOR-248420	0.478
ABI1	protein	Q8IZP0	UNIPROT	WAVE complex	complex	SIGNOR-C271	SIGNOR	form complex	binding			9606	BTO:0000567								15070726	t		lperfetto	Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex. 	SIGNOR-261872	0.856
CTCF	protein	P49711	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12032779	f		miannu	 Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. 	SIGNOR-253827	0.637
lysophosphatidic acid	smallmolecule	CHEBI:132742	ChEBI	LPAR3	protein	Q9UBY5	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257530	0.8
PTP4A3	protein	O75365	UNIPROT	EZR	protein	P15311	UNIPROT	down-regulates activity	dephosphorylation	Thr567	QGRDKYKtLRQIRQG	9606	BTO:0001109								18078820	t			Here we report the identification of Ezrin as a specific and direct cellular substrate of PRL-3. In HCT116 colon cancer cell line, Ezrin was identified among the cellular proteins whose phosphorylation level decreased upon ectopic over-expression of wtPRL-3 but not of catalytically inactive PRL-3 mutants. Although PRL-3 over-expression in HCT116 cells appeared to affect Ezrin phosphorylation status at both tyrosine residues and Thr567, suppression of the endogenous protein by RNA interference pointed to Ezrin-Thr567 as the residue primarily affected by PRL-3 action. 	SIGNOR-248342	0.281
CSNK2A1	protein	P68400	UNIPROT	SLC9A5	protein	Q14940	UNIPROT	down-regulates activity	phosphorylation	Thr714	EESDSSEtEKEDDEG	-1									21296876	t		miannu	CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis	SIGNOR-276250	0.2
POLD3	protein	Q15054	UNIPROT	DNA polymerase delta 	complex	SIGNOR-C376	SIGNOR	form complex	binding			-1									12403614	t		lperfetto	Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme.	SIGNOR-265515	0.932
P2RY6	protein	Q15077	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256804	0.2
MAPK14	protein	Q16539	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates	phosphorylation	Ser389	ARIQAAAsTPTNATA	9606		BTO:0000142							17726008	t		gcesareni	However p38alfa also inactivates gsk3b by direct phosphorilation of the c-terminal residue ser389. this non-canonicl p38 mapk-dependent phosphorilation of gsk3b seems to occur primarily in the brain and thymocytes.	SIGNOR-157548	0.294
FUS	protein	P35637	UNIPROT	AGRN	protein	O00468	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			10090									28515487	f			This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease	SIGNOR-262807	0.276
EP300	protein	Q09472	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates quantity	acetylation			9606									22298955	t		gcesareni	Bmp-induced non-smad erk signaling pathway cooperatively regulates osteoblast differentiation, in part, through increasing the stability and transcriptional activity of runx2 or increasing runx2 acetylation by p300.	SIGNOR-195579	0.464
SF3a	complex	SIGNOR-C345	SIGNOR	Spliceosomal_snRNP_assembly	phenotype	SIGNOR-PH79	SIGNOR	up-regulates				9606									8349644	f		miannu	Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. 	SIGNOR-263950	0.7
MAPK1	protein	P28482	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser344	QDDDAPLsPMLYSSS	9606									18204439	t		lperfetto	Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation.	SIGNOR-160411	0.71
WNK1	protein	Q9H4A3	UNIPROT	SLC12A6	protein	Q9UHW9	UNIPROT	down-regulates	phosphorylation	Thr991	SAYTYERtLMMEQRS	9606	BTO:0000938	BTO:0000142							19665974	t		gcesareni	We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases.	SIGNOR-187564	0.467
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	TFCP2	protein	Q12800	UNIPROT	down-regulates	phosphorylation			9606									19237534	t	inferred from 70% family members	lperfetto	We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309.	SIGNOR-270110	0.2
WNT7A	protein	O00755	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity				10090		BTO:0000887;BTO:0001103							9753670	f		gcesareni	Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5	SIGNOR-60471	0.356
D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	3-phosphonato-D-glyceroyl phosphate(4-)	smallmolecule	CHEBI:57604	ChEBI	up-regulates quantity	precursor of			9606									11724794	t		miannu	GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion	SIGNOR-266496	0.8
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2NL	protein	Q5JXB2	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271370	0.2
BRCA1	protein	P38398	UNIPROT	ACACA	protein	Q13085	UNIPROT	down-regulates activity	binding			-1							phosphorylation: ser1263	FSDSPPQsPTFPEAG	16698035	t			ACCA binds BRCA1 when phosphorylated onSer1263, thus supporting a model in which controlof lipid synthesis would be mediated at least in part,viaphosphorylation of the Ser1263.	SIGNOR-267474	0.563
NFYB	protein	P25208	UNIPROT	GCH1	protein	P30793	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15496512	f		miannu	Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter.	SIGNOR-252233	0.2
ROCK1	protein	Q13464	UNIPROT	DPYSL2	protein	Q16555	UNIPROT	unknown	phosphorylation	Thr555	DNIPRRTtQRIVAPP	9534									10818093	t		lperfetto	We produced an antibody that specifically recognizes CRMP-2 phosphorylated at Thr-555. Using this antibody, we found that Rho-kinase phosphorylated CRMP-2 downstream of Rho in COS7 cells. 	SIGNOR-249042	0.431
Immune complexes	stimulus	SIGNOR-ST15	SIGNOR	FCGR2B	protein	P31994	UNIPROT	up-regulates activity				9606	BTO:0000801								25475856	f		lperfetto	Low affinity-activating Fcgamma receptors (FcgammaRs) that bind immune complexes are controlled by a single inhibitory receptor, FcgammaRIIb (CD32b).	SIGNOR-249522	0.7
TIMP3	protein	P35625	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates activity				10090	BTO:0005300								28709001	f			Hh signaling through FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. A pharmacological mimetic of TIMP3 blocked the conversion of FAPs into adipocytes	SIGNOR-255906	0.7
tRNA(Phe)	smallmolecule	CHEBI:29184	ChEBI	Phe-tRNA(Phe)	smallmolecule	CHEBI:29153	ChEBI	up-regulates quantity	precursor of			9606									20223217	t		miannu	Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers.	SIGNOR-270443	0.8
CH5132799	chemical	CID:49784945	PUBCHEM	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252648	0.8
seliciclib	chemical	CHEBI:45307	ChEBI	CDK5	protein	Q00535	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206574	0.8
CNKSR2	protein	Q8WXI2	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	binding			9606									14597674	t		gcesareni	We show cnk2 interacts with raf. cnk2 interacts with the gef domain of rlf and with both the regulatory and catalytic domains of raf. The raf interaction was also mapped to the carboxyl-terminal half of cnk2. Overexpression of cnk2 results in inhibition of the mapk signaling pathway.	SIGNOR-119039	0.758
GSK3B	protein	P49841	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr273	TTWTGSRtAPYTPNL	10090	BTO:0000944								25373906	t		miannu	In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region. 	SIGNOR-276440	0.408
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1951	SPGYSPTsPTYSLTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269341	0.718
EPHB2	protein	P29323	UNIPROT	NRCAM	protein	Q92823	UNIPROT	up-regulates activity	phosphorylation	Tyr1276	DGSFIGQySGKKEKE	9606	BTO:0000007								24023801	t		miannu	EphB receptors were found to induce phosphorylation of NrCAM on the tyrosine residue within the FIGQY ankyrin binding motif, inhibiting ankyrin recruitment. Furthermore, NrCAM phospho-FIGQY levels in the SC were decreased in EphB1/3 and EphB1/2/3 null mice and increased in mutant mice overexpressing constitutively active EphB2 kinase. 	SIGNOR-262863	0.303
thromboxane	smallmolecule	CHEBI:26995	ChEBI	TBXA2R	protein	P21731	UNIPROT	up-regulates activity	chemical activation												19747485	t			Thromboxane plays an essential role in hemostasis, regulating platelet aggregation and vessel tone. In humans, it signals through the TPalpha and TPbeta isoforms that are transcriptionally regulated by distinct promoters Prm1 and Prm3, respectively.	SIGNOR-254264	0.8
CDK5	protein	Q00535	UNIPROT	MEF2A	protein	Q02078	UNIPROT	down-regulates activity	phosphorylation	Ser408	SIKSEPIsPPRDRMT	9606	BTO:0004102								12691662	t		lperfetto	Cdk5-mediated inhibition of the protective effects of transcription factor mef2 in neurotoxicity-induced apoptosis.We have identified the prosurvival transcription factor mef2 as a direct nuclear target of cdk5. Cdk5 phosphorylates mef2 at a distinct serine in its transactivation domain to inhibit mef2 activity.	SIGNOR-100574	0.521
IRF3	protein	Q14653	UNIPROT	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates				9606									12692549	f		lperfetto	The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response.	SIGNOR-216316	0.7
CTSS	protein	P25774	UNIPROT	peptide antigen	smallmolecule	CHEBI:166824	ChEBI	up-regulates quantity	chemical modification			9606									31810556	t		scontino	Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol.	SIGNOR-267867	0.8
P4HA2	protein	O15460	UNIPROT	Collagen	proteinfamily	SIGNOR-PF103	SIGNOR	up-regulates quantity by stabilization	hydroxylation			9606									9211872	t		miannu	Prolyl 4-hydroxylase (proline hydroxylase, EC 1.14.11.2) catalyzes the hydroxylation of proline in -Xaa-Pro-Gly- triplets in collagens and other proteins with collagen-like sequences. The enzyme plays a central role in the synthesis of all collagens, as the 4-hydroxyproline residues formed in the reaction are essential for the folding of the newly synthesized collagen polypeptide chains into triple helical molecules. 	SIGNOR-269733	0.2
KIFC1	protein	Q9BW19	UNIPROT	Cell_migration	phenotype	SIGNOR-PH38	SIGNOR	up-regulates				9606									33361741	f		miannu	Kinesin Family Member C1 (KIFC1) Regulated by Centrosome Protein E (CENPE) Promotes Proliferation, Migration, and Epithelial-Mesenchymal Transition of Ovarian Cancer	SIGNOR-266115	0.7
ALPL	protein	P05186	UNIPROT	SPP1	protein	P10451	UNIPROT	down-regulates activity	dephosphorylation			10090									23427088	t		miannu	This result suggests that endogenous mouse TNAP dephosphorylates OPN in osteoblasts and that overexpressed human TNAP dephosphorylates OPN, compensating for the lack of endogenous TNAP in [Col1a1-Tnap +/\u2212 ;Alpl \u2212/\u2212 ] cells.	SIGNOR-277045	0.455
PRKACG	protein	P22612	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates	phosphorylation	Ser1177	TSRIRTQsFSLQERQ	9606									11729179	t		gcesareni	Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.	SIGNOR-112375	0.2
SNTG1	protein	Q9NSN8	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255994	0.462
NME1	protein	P15531	UNIPROT	KSR1	protein	Q8IVT5	UNIPROT	down-regulates	phosphorylation	Ser406	TRLRRTEsVPSDINN	9606									12105213	t		gcesareni	Autophosphorylated recombinant nm23-h1 phosphorylated ksr in vitro. Using site-directed mutagenesis, we found that nm23-h1 phosphorylated ksr serine 392, a 14-3-3-binding site, consistent with the recent identification of c-tak1 as a kinase for this site.	SIGNOR-90390	0.56
RIPK3	protein	Q9Y572	UNIPROT	PYGL	protein	P06737	UNIPROT	up-regulates	binding			9606									19632174	t		gcesareni	Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro.	SIGNOR-186939	0.505
CDK2	protein	P24941	UNIPROT	CCNO	protein	P22674	UNIPROT	up-regulates activity	phosphorylation	Ser81	PSAARGGsPLPGPAQ	9606	BTO:0000007								25364462	t		lperfetto	Phosphorylation of cyclin O, a novel cyclin family protein containing a cyclin-like domain, is involved in the activation of cyclin-dependent kinase 2|This activity was reduced in cells overexpressing cyclin O, in which the 81st serine had been replaced with alanine (S81A). These results suggest that cyclin O is a novel cyclin family protein that regulates CDK2 kinase activity, which is mediated by the phosphorylation of the 81st serine residue of cyclin O|CKD2 phosphorylates the 81st serine residue of cyclin O	SIGNOR-275615	0.466
MAPK1	protein	P28482	UNIPROT	ARRB1	protein	P49407	UNIPROT	down-regulates	phosphorylation	Ser412	EEEDGTGsPQLNNR	9606									15456867	t		gcesareni	Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation	SIGNOR-129585	0.717
IKBKE	protein	Q14164	UNIPROT	TANK	protein	Q92844	UNIPROT	down-regulates activity	phosphorylation	Ser257	PERPGILsPATSEAV	9534	BTO:0000298								10759890	t		miannu	IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex	SIGNOR-262719	0.734
UVB radiation	stimulus	SIGNOR-ST17	SIGNOR	cholesta-5,7-dien-3beta-ol	smallmolecule	CHEBI:17759	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0001253							30080183	t		lperfetto	Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin	SIGNOR-270563	0.7
RNF168	protein	Q8IYW5	UNIPROT	BLM	protein	P54132	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0001938								23708797	t		miannu	Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of RAP80. 	SIGNOR-272114	0.265
CSNK2A1	protein	P68400	UNIPROT	HMGN1	protein	P05114	UNIPROT	down-regulates	phosphorylation	Ser8	MPKRKVSsAEGAAKE	9606									10739259	t		gcesareni	Peptide mass and sequence analysis showed major and minor phosphorylation sites, respectively, at ser24 and ser28 in hmg-17, and ser20 and ser24 in hmg-14 a third phosphorylation site in hmg-14 was located at either ser6 or ser7phosphorylation of ser6 and ser7 may compromise the binding of hmgn1 protein to the binding domain of importin proteins, which in turn affects the nuclear transport and sub-cellular localization of hmgn1 protein. Protein kinase ck2 could potentially be an enzyme that regulates this process.	SIGNOR-76270	0.2
IGF1R	protein	P08069	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates	phosphorylation	Tyr1165	RDIYETDyYRKGGKG	9606									7493944	t		lperfetto	Insulin and insulin-like growth factor (IGF-I) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor.	SIGNOR-26586	0.2
DUSP1	protein	P28562	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates activity	dephosphorylation	Ser118	AELVRTDsPNFLCSV	9606									27031422	t		miannu	In a separate study, MKP-1 was shown to induce osteogenesis by dephosphorylating Ser125 on Runx2 isoform type II (37).|MKP-1 increases RUNX2 activity and downregulates MAPK, cyclin D1 in differentiated osteoblasts inducing growth arrest and mineralization.	SIGNOR-277143	0.362
MAPK1	protein	P28482	UNIPROT	LCK	protein	P06239	UNIPROT	up-regulates activity	phosphorylation	Ser59	EGSNPPAsPLQDNLV	9606	BTO:0000567								8618896	t		lperfetto	Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation.	SIGNOR-249412	0.564
Chaperone-mediated autophagy	phenotype	SIGNOR-PH118	SIGNOR	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	down-regulates quantity by destabilization				9606	BTO:0004424								26323688	t	inferred from family member		Our proteome analysis revealed that HK2 is a CMA substrate and that its degradation by CMA is regulated by glucose availability.	SIGNOR-270269	0.7
ATF4	protein	P18848	UNIPROT	NARS2	protein	Q96I59	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269423	0.2
3-iodo-L-tyrosine	smallmolecule	CHEBI:27847	ChEBI	L-tyrosine zwitterion	smallmolecule	CHEBI:58315	ChEBI	up-regulates quantity	precursor of			9606									28153798	t		scontino	MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide.	SIGNOR-267031	0.8
E2F4	protein	Q16254	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12110166	f		fspada	We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation	SIGNOR-90507	0.474
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Thr694	DSPSDGGtPGRMPPQ	9606									11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130.	SIGNOR-104707	0.843
STK11	protein	Q15831	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	up-regulates	phosphorylation			9606									14976552	t		lperfetto	We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli	SIGNOR-217472	0.595
ADCY2	protein	Q08462	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates quantity	chemical modification			9606									15385642	t		miannu	Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions.	SIGNOR-265004	0.8
PRKG1	protein	Q13976	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates	phosphorylation	Ser795	TASTRKVsLAPQANL	9606									10581361	t		lperfetto	Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function	SIGNOR-72724	0.521
FFAR1	protein	O14842	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257272	0.554
NFIA	protein	Q12857	UNIPROT	NEUROD1	protein	Q13562	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268890	0.288
NFIB	protein	O00712	UNIPROT	FOXO6	protein	A8MYZ6	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268881	0.2
MMP11	protein	P24347	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272356	0.7
PRKCA	protein	P17252	UNIPROT	SNAP23	protein	O00161	UNIPROT	unknown	phosphorylation	Thr24	TDESLEStRRILGLA	9606									12930825	t		lperfetto	Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion.	SIGNOR-249229	0.334
pipamperone	chemical	CHEBI:78549	ChEBI	HTR1D	protein	P28221	UNIPROT	down-regulates activity	chemical inhibition			10116	BTO:0000529								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258574	0.8
CDH4	protein	P55283	UNIPROT	CDH15	protein	P55291	UNIPROT	down-regulates quantity by repression				10090	BTO:0000165								18701479	f		lperfetto	Taken together, these data show that (a) R-cadherin decreases the expression of M-cadherin and (b) N-cadherin and M-cadherin only slightly accumulate at the cell contacts in R-cadherin–expressing myoblasts.	SIGNOR-253106	0.389
RET	protein	P07949	UNIPROT	RET	protein	P07949	UNIPROT	up-regulates	phosphorylation	Tyr905	DVYEEDSyVKRSQGR	9606									14711813	t		llicata	Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. taken together, the results suggest that phosphorylation of tyr981 is not obligatorily required for the catalytic activity but plays a supplementary role in initiating autophosphorylation of tyr905, which brings about the overall kinase activity.	SIGNOR-121165	0.2
GSK3B	protein	P49841	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Thr41	GIHSGATtTAPSLSG	-1									11955436	t			β-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)	SIGNOR-260016	0.856
PIAS4	protein	Q8N2W9	UNIPROT	STAT1	protein	P42224	UNIPROT	down-regulates	binding			9606									11248056	t		gcesareni	First, piasy interacts with stat1 both in vitro and in vivo. The in vivo piasy__stat1 interaction is dependent on cytokine stimulation. Second, piasy can inhibit stat1-mediated gene activation without blocking the dna binding activity of stat1.	SIGNOR-105723	0.543
KSR1	protein	Q8IVT5	UNIPROT	BRAF	protein	P15056	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								29433126	t		miannu	 In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. 	SIGNOR-273878	0.613
USP8	protein	P40818	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0000567								16120644	t		irozzo	Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells.	SIGNOR-259103	0.7
STK25	protein	O00506	UNIPROT	CCM2	protein	Q9BSQ5	UNIPROT	up-regulates	phosphorylation	Ser384	GRGIITDsFGRHRRA	9606	BTO:0001757								22782892	t		miannu	CCM2 can be phosphorylated by STK25, and the kinase activity of STK25 is required for death signaling. 	SIGNOR-263144	0.515
PEX2	protein	P28328	UNIPROT	UBE2D2	protein	P62837	UNIPROT	up-regulates activity	binding			-1									19687296	t		miannu	Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. 	SIGNOR-253025	0.595
GNRH1	protein	P01148	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								17202804	t		miannu	GnRH antagonizes testosterone activation of the human androgen receptor in SCL60 cells. Gonadotropin-Releasing Hormone Functionally Antagonizes Testosterone Activation of the Human Androgen Receptor in Prostate Cells through Focal Adhesion Complexes Involving Hic-5	SIGNOR-259267	0.473
GSK3B	protein	P49841	UNIPROT	MARK2	protein	Q7KZI7	UNIPROT	down-regulates activity	phosphorylation	Ser212	KLDTFCGsPPYAAPE	-1									18424437	t		miannu	MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase.	SIGNOR-276163	0.355
OAT	protein	P04181	UNIPROT	proline	smallmolecule	CHEBI:26271	ChEBI	up-regulates quantity	chemical modification			9606									14617280	t		miannu	Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC)	SIGNOR-256033	0.8
 p62_complex	complex	SIGNOR-C259	SIGNOR	Nuclear_pore_function	phenotype	SIGNOR-PH130	SIGNOR	up-regulates				10116									2050741	f		miannu	Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function.	SIGNOR-261261	0.7
FOXJ1	protein	Q92949	UNIPROT	TEKT1	protein	Q969V4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000939								23822649	t		miannu	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266936	0.373
RALA	protein	P11233	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Thr451	PIPKALGtPVLTPPT	10090									11689711	t		gcesareni	We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT.	SIGNOR-252984	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PDCD4	protein	Q53EL6	UNIPROT	down-regulates	phosphorylation	Ser457	RGRKRFVsEGDGGRL	9606									16357133	t		gcesareni	Our results show that akt specifically phosphorylates ser(67) and ser(457) residues of pdcd4 in vitro and in vivo. We further show that phosphorylation of pdcd4 by akt causes nuclear translocation of pdcd4.	SIGNOR-143098	0.2
MAPK1	protein	P28482	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates	phosphorylation	Ser2366	MEQGHFAsPDQNSML	9606									17623675	t		lperfetto	Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo.	SIGNOR-156895	0.478
PHGDH	protein	O43175	UNIPROT	3-phosphonatooxypyruvate(3-)	smallmolecule	CHEBI:18110	ChEBI	up-regulates activity	chemical modification			9606									25406093	t		lperfetto	PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG.	SIGNOR-268568	0.8
MAP3K1	protein	Q13233	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								17110930	t		Barakat	Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK	SIGNOR-274147	0.71
PTEN	protein	P60484	UNIPROT	DUSP1	protein	P28562	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11494141	f		miannu	Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 	SIGNOR-260053	0.331
POU5F1	protein	Q01860	UNIPROT	DLX5	protein	P56178	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254935	0.315
IFNGR1	protein	P15260	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates	binding			9606									15864272	t		gcesareni	The only type ii ifn, ifn-g, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2	SIGNOR-135952	0.691
MMP14	protein	P50281	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272382	0.7
ATM	protein	Q13315	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates activity	phosphorylation	Ser1893	PANLDSEsEHFFRCC	9606									21149446	t		gcesareni	In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible.	SIGNOR-170465	0.2
RET	protein	P07949	UNIPROT	ATF4	protein	P18848	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr119	LLTTLDDtCDLFAPL	9606	BTO:0002181								25795775	t		miannu	We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA. 	SIGNOR-276450	0.2
DAPK1	protein	P53355	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	binding			9606									15616583	t		gcesareni	Conversely, dapk promotes the cytoplasmic retention of erk, thereby inhibiting erk signaling in the nucleus.	SIGNOR-132610	0.55
furtrethonium	chemical	CHEBI:134764	ChEBI	CHRM3	protein	P20309	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258642	0.8
TACR2	protein	P21452	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257131	0.408
Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	up-regulates				10090	BTO:0001086								19279220	f		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270727	0.7
AKT1	protein	P31749	UNIPROT	FOXO6	protein	A8MYZ6	UNIPROT	down-regulates	phosphorylation			9606									18394876	t		lperfetto	The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity	SIGNOR-252582	0.635
RARA	protein	P10276	UNIPROT	OXT	protein	P01178	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									6153132	f		lperfetto	The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances.	SIGNOR-268548	0.256
FLT3	protein	P36888	UNIPROT	ZBTB16	protein	Q05516	UNIPROT	down-regulates activity				10090	BTO:0002181								14982881	f			We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm.	SIGNOR-261537	0.32
POLR1H	protein	Q9P1U0	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16373708	f	 	miannu	 ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells. 	SIGNOR-259908	0.2
XIAP	protein	P98170	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates quantity by destabilization	binding			-1									12620238	t		lperfetto	This paper reports the crystal structure of caspase-9 in an inhibitory complex with the third baculoviral iap repeat (bir3) of xiap at 2.4 a resolution. X-linked inhibitor-of-apoptosis protein (xiap) interacts with caspase-9 and inhibits its activity.	SIGNOR-98988	0.92
nutlin-3A	chemical	CID:11433190	PUBCHEM	MDM2	protein	Q00987	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194874	0.8
CDK6	protein	Q00534	UNIPROT	PRDX1	protein	Q06830	UNIPROT	down-regulates	phosphorylation	Thr90	CHLAWVNtPKKQGGL	9606									11986303	t		lperfetto	Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown).	SIGNOR-87113	0.2
PTK2	protein	Q05397	UNIPROT	PXN	protein	P49023	UNIPROT	up-regulates activity	binding			9606									15688067	t		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257732	0.912
ATF4	protein	P18848	UNIPROT	SARS1	protein	P49591	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269424	0.2
antigen	smallmolecule	CHEBI:59132	ChEBI	BCR-Dl	complex	SIGNOR-C436	SIGNOR	up-regulates activity	binding			9606	BTO:0000776								32323266	t		scontino	The recognition of antigen by the BCR initiates BCR signaling cascade.	SIGNOR-268205	0.8
PRKDC	protein	P78527	UNIPROT	MCC	protein	P23508	UNIPROT	up-regulates activity	phosphorylation	Ser120	LRSELSQsQHEVNED	9606	BTO:0001109								21779472	t		miannu	MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. 	SIGNOR-273531	0.2
YBX1	protein	P67809	UNIPROT	ABCB1	protein	P08183	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001023								17072343	f		miannu	 YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. 	SIGNOR-255614	0.393
p38	proteinfamily	SIGNOR-PF16	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Thr548	KKVAVVRtPPKSPSS	9606									21215781	t	The effect has been demonstrated using P10636-8	lperfetto	However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules	SIGNOR-171062	0.2
PRKCE	protein	Q02156	UNIPROT	GLS	protein	O94925	UNIPROT	up-regulates activity	phosphorylation	Ser314	RYVGKEPsGLRFNKL	9606	BTO:0002552								29515166	t		miannu	PKCε is the kinase that phosphorylates GAC at Ser314.	SIGNOR-277387	0.2
glucose	chemical	CHEBI:17234	ChEBI	PRKAA1	protein	Q13131	UNIPROT	down-regulates activity				10090	BTO:0000222								18477450	f			Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK).	SIGNOR-256136	0.8
nalbuphine	chemical	CHEBI:7454	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029									9262330	t		miannu	We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine.	SIGNOR-258658	0.8
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DRA	protein	P01903	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								11889043	f	 	 	Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment.	SIGNOR-254009	0.425
BRIP1	protein	Q9BX63	UNIPROT	BLM	protein	P54132	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000567								21240188	t		irozzo	In this work, FANCJ and BLM were found to interact physically and functionally in human cells and co-localize to nuclear foci in response to replication stress. The cellular level of BLM is strongly dependent upon FANCJ, and BLM is degraded by a proteasome-mediated pathway when FANCJ is depleted. 	SIGNOR-259186	0.642
AANAT	protein	Q16613	UNIPROT	N-acetylserotonin	smallmolecule	CHEBI:17697	ChEBI	up-regulates quantity	chemical modification			-1									22775292	t		miannu	Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS.	SIGNOR-265478	0.8
SEC61 complex	complex	SIGNOR-C368	SIGNOR	HSPA5	protein	P11021	UNIPROT	up-regulates activity	binding												33925740	t		lperfetto	This is where allosteric effectors of the Sec61 complex (BiP together with Sec62/Sec63 complex or TRAP complex) (Figure 2 and Figure 5) and auxiliary membrane protein insertases (EMC and TMCO1 complex) join the game	SIGNOR-265276	0.46
Sin3B_complex	complex	SIGNOR-C409	SIGNOR	H3-5	protein	Q6NXT2	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								21041484	t		miannu	We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin.	SIGNOR-266972	0.2
NEK9	protein	Q8TD19	UNIPROT	NEK9	protein	Q8TD19	UNIPROT	up-regulates	phosphorylation	Thr210	SEYSMAEtLVGTPYY	9606									14660563	t		lperfetto	A previous study (19) using the peptide substrate demonstrated that nek9 was able to phosphorylate in vitro the thr210 residue within the activation loop, thus indicating the potential ability of nek9 to autophosphorylate.Nek9 forms a stable, approximately 600-kda complex with fact in the interphase nuclei. Its active form is characterized by phosphorylation-dependent electrophoretic mobility shift and phosphorylation at a conserved residue within the activation loop (thr(210))	SIGNOR-119897	0.2
SLC24A2	protein	Q9UI40	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	down-regulates quantity	relocalization			9606									30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264389	0.8
AKT3	protein	Q9Y243	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates	phosphorylation	Ser428	GPQRERKsSSSSEDR	9606									10869359	t		gcesareni	We show that phosphorylation of b-raf by akt occurs at multiple residues within its aminoterminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity.	SIGNOR-78697	0.294
SORT1	protein	Q99523	UNIPROT	APOE	protein	P02649	UNIPROT	up-regulates quantity	binding			10029	BTO:0000246								23283348	t		miannu	Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms.	SIGNOR-273721	0.44
NEK7	protein	Q8TDX7	UNIPROT	EML4	protein	Q9HC35	UNIPROT	up-regulates activity	phosphorylation	Ser146	PQIRASPsPQPSSQP	-1									31409757	t	done	miannu	The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules. Together, these data support a model in which NEK6- and NEK7-dependent phosphorylation promotes the dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression.	SIGNOR-273884	0.277
CSNK2A1	protein	P68400	UNIPROT	α-Catenin	proteinfamily	SIGNOR-PF72	SIGNOR	down-regulates activity	phosphorylation			9606	BTO:0000527								19941816	t		miannu	We demonstrate here that egfr activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via ck2alpha-dependent phosphorylation of alpha-catenin at s641.	SIGNOR-265822	0.399
CHFR	protein	Q96EP1	UNIPROT	AURKA	protein	O14965	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									17442268	t		miannu	Chfr, a mitotic stress checkpoint, plays an important role in cell cycle progression, tumor suppression and the processes that require the E3 ubiquitin ligase activity mediated by the RING finger domain. Chfr stimulates the formation of polyubiquitin chains by ub-conjugating enzymes, and induces the proteasome-dependent degradation of a number of cellular proteins including Plk1 and Aurora A.	SIGNOR-271463	0.483
Cytoplasmic_Dynein	proteinfamily	SIGNOR-PF67	SIGNOR	Cilium_assembly	phenotype	SIGNOR-PH64	SIGNOR	up-regulates													16440056	f		lperfetto	A second cytoplasmic dynein complex, cytoplasmic dynein 2, has a role in intraflagellar transport (IFT), a process required for ciliary/flagellar assembly	SIGNOR-265022	0.7
PITX3	protein	O75364	UNIPROT	MTA1	protein	Q13330	UNIPROT	up-regulates activity	binding			9606	BTO:0000567			SIGNOR-C123					21368136	t	1	miannu	we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3.	SIGNOR-239770	0.33
RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000667								15866158	t			Induction of the p21WAF1/Cip1 gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-J_ protein to the p21 promoter.	SIGNOR-252033	0.346
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	DNM2	protein	P50570	UNIPROT	unknown	dephosphorylation			10116									20496096	t	inferred from 70% family members		CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII).	SIGNOR-269990	0.2
GTF2H5	protein	Q6ZYL4	UNIPROT	TFIIH	complex	SIGNOR-C457	SIGNOR	form complex	binding			9606									30860024	t		lperfetto	Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 	SIGNOR-269310	0.873
NFATC3	protein	Q12968	UNIPROT	TFF1	protein	P04155	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16219765	f		miannu	Overexpression of NFAT3 enhanced both ERalpha and ERbeta transcriptional activities in a ligand-independent manner and up-regulated downstream estrogen-responsive genes including pS2 and cathepsin D. Reduction of endogenous NFAT3 with NFAT3 small interfering RNA or overexpression of NFAT3 deletion mutants that lack the ER-binding sites reduced the NFAT3 coactivation of ERalpha and ERbeta.	SIGNOR-254639	0.2
PTPRK	protein	Q15262	UNIPROT	PROM1	protein	O43490	UNIPROT	down-regulates activity	dephosphorylation			-1									30947381	t		miannu	PTPRK dephosphorylates CD133, which is a stem cell marker; phosphorylated CD133 accelerates xenograft tumor growth of colon cancer cells through the activation of AKT, but the functional significance of this has remained elusive.|Together, these observations suggest that PTPRK suppresses CD133\u2010mediated colon cancer growth both in\u00a0vitro and in\u00a0vivo.	SIGNOR-277133	0.2
SUGT1	protein	Q9Y2Z0	UNIPROT	MIS12 complex	complex	SIGNOR-C362	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								22869522	t		lperfetto	Here we identify Sgt1, a cochaperone for Hsp90, as a novel Plk1 substrate during mitosis|This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone with the MIS12 complex to stabilize this complex at the kinetochores and thus coordinates the recruitment of the NDC80 complex to form efficient microtubule-binding sites.	SIGNOR-265223	0.307
progesterone	smallmolecule	CHEBI:17026	ChEBI	NR3C2	protein	P08235	UNIPROT	down-regulates activity	chemical inhibition			9534	BTO:0001538								8282004	t		miannu	The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4).	SIGNOR-258705	0.8
BAX	protein	Q07812	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	up-regulates				9606									21210296	f		gcesareni	Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c,(diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore.	SIGNOR-170969	0.526
Laminin-1	complex	SIGNOR-C183	SIGNOR	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates activity	binding												9361014	t		lperfetto	Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI.	SIGNOR-253254	0.539
Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	OXTR	protein	P30559	UNIPROT	up-regulates activity	binding			9606									11274341	t		lperfetto	The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation.| The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta.	SIGNOR-268545	0.2
SYK	protein	P43405	UNIPROT	IKZF1	protein	Q13422	UNIPROT	up-regulates	phosphorylation	Ser361	LAEGTPRsNHSAQDS	9606	BTO:0001271								23071339	t		miannu	Syk phoshorylatesikarosat unique c-terminal serine phosphorylation sites s358 and s361, thereby augmenting its nuclear localization and sequence-specific dna binding activity. Mechanistically, we establish that syk-inducedikarosactivation is essential for its nuclear localization and optimal transcription factor function.	SIGNOR-199096	0.414
dasatinib (anhydrous)	chemical	CHEBI:49375	ChEBI	SRC	protein	P12931	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258103	0.8
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	PPARGC1A	protein	Q9UBK2	UNIPROT	down-regulates				9606									20577053	f		gcesareni	Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner.	SIGNOR-252916	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CELF1	protein	Q92879	UNIPROT	up-regulates activity	phosphorylation	Ser28	GQVPRTWsEKDLREL	10090	BTO:0000165								18570922	t		miannu	CUG repeat binding protein, CUGBP1, is a key regulator of translation of proteins that are involved in muscle development and differentiation. In normal myoblasts, Akt kinase phosphorylates CUGBP1 at Ser28 and increases interactions of CUGBP1 with cyclin D1 mRNA. 	SIGNOR-262615	0.2
FYN	protein	P06241	UNIPROT	SCN5A	protein	Q14524	UNIPROT	down-regulates	phosphorylation	Tyr1495	TEEQKKYyNAMKKLG	9606									15831816	t		llicata	This study addresses the effects of the src family tyrosine kinase fyn on na(v)1.5 cardiac sodium channels. Sodium currents were acquired by whole cell recording on hek-293 cells transiently expressing na(v)1.5. Acute treatment of cells with insulin caused a depolarizing shift in steady-state inactivation, an effect eliminated by the src-specific tyrosine kinase inhibitor pp2 we provide evidence that this linker is a substrate for fyn in vitro, and that y1495 is a preferred phosphorylation site.	SIGNOR-135600	0.298
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CCNB1	protein	P14635	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189969	0.8
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	SUDS3	protein	Q9H7L9	UNIPROT	up-regulates activity	phosphorylation	Ser228	RTLNKLKsPKRPASP	9606	BTO:0000007								15489224	t		miannu	Cdk5/p35 phosphorylates mSds3 and regulates mSds3-mediated repression of transcription. the dimerization of the phosphorylation-deficient mutant of mSds3 (S228A) was not greatly enhanced by p35 when compared with wild type (Fig. 5D). This finding suggests that the phosphorylation of mSds3 by active Cdk5 increases the homodimerization potential of mSds3.	SIGNOR-262739	0.285
trametinib	chemical	CHEBI:75998	ChEBI	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates activity	chemical inhibition			9606	BTO:0001950								25487801	t		Luana	Inhibitors of MEK1/2 (trametinib) and/or ERK1/2 (selumetinib) had the strongest and most conserved inhibitory activities, suggesting that MEK1/2 and ERK1/2 may have unique capabilities as stand-alone or combinatorial therapies for MERS-CoV infections. 	SIGNOR-262312	0.8
SRC	protein	P12931	UNIPROT	CTTN	protein	Q14247	UNIPROT	down-regulates	phosphorylation	Tyr486	YPAEDSTyDEYENDL	9606									12601080	t		lperfetto	Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity	SIGNOR-98720	0.795
IL21R	protein	Q9HBE5	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates				9606	BTO:0000876	BTO:0000763;BTO:0001253							15667561	f		gcesareni	Interleukin 24 (il-24) is a new member of the il-10 family of cytokines and it signals through two heterodimeric receptors: il-20r1/il-20r2 and il-22r1/il-20r2. Upon binding to its receptors, il-24 induces rapid activation of stat-1 and stat-3 transcription factors,	SIGNOR-133379	0.594
NUF2	protein	Q9BZD4	UNIPROT	Ndc80 complex	complex	SIGNOR-C361	SIGNOR	form complex	binding												27881301	t		lperfetto	Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits	SIGNOR-265187	0.973
R547	chemical	CID:6918852	PUBCHEM	CCND1	protein	P24385	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206352	0.8
GSK3B	protein	P49841	UNIPROT	HDAC4	protein	P56524	UNIPROT	down-regulates	phosphorylation	Ser302	APGSGPSsPNNSSGS	9606									21118993	t		lperfetto	The double mutation of serines 298/302 into alanines, but also the sole mutation of serine 302, abolishes hdac4 phosphorylation by gsk3_we have shown that cells lacking gsk3_ are unable to degrade hdac4 after serum starvation	SIGNOR-170148	0.37
EEF2K	protein	O00418	UNIPROT	EEF2	protein	P13639	UNIPROT	down-regulates	phosphorylation	Thr59	GETRFTDtRKDEQER	9606									8386634	t		gcesareni	Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58.	SIGNOR-38556	0.781
CSNK2A1	protein	P68400	UNIPROT	CDC34	protein	P49427	UNIPROT	down-regulates activity	phosphorylation	Ser236	DDSGTEEs	9606									11546811	t		lperfetto	The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm.	SIGNOR-110403	0.403
glutamine	smallmolecule	CHEBI:28300	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264751	0.7
MECP2	protein	P51608	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates quantity by expression	post transcriptional regulation			10090	BTO:0000614								18511691	t		Luana	Interestingly, Creb1 was one of the activated MeCP2 targets that we validated by quantitative real-time RT-PCR (Fig. 1C), and using ChIP analysis we found that in vivo MeCP2 binds to the promoter region of Creb1, with significantly enhanced binding in MECP2-Tg samples compared to WT (p < 0.05) | In addition, Sst and CREB1 protein levels were increased in MECP2-Tg hypothalami compared to WT, indicating that MeCP2 indeed enhances expression of Sst and Creb1	SIGNOR-264682	0.548
Diisodecyl phthalate	chemical	CHEBI:34709	ChEBI	SLC5A5	protein	Q92911	UNIPROT	up-regulates quantity by expression				10116									16257484	f		miannu	DIDP, BBP and DOP stimulate NIS mRNA expression. Here, hNIS promoter construct (N3) was up-regulated 2.5-fold by DIDP, 2.6-fold by BBP and 2.4-fold by DOP in the presence of TSH. Likewise, these phthalates also enhanced rNIS endogenous mRNA expression, which increased ca. 2-fold after 48 h of treatment compared with the expression level generated by TSH only. At 72 h, mRNA content was unchanged.	SIGNOR-268742	0.8
PLK1	protein	P53350	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates	phosphorylation	Ser53	GHSTGEDsAFQEPDS	9606									15350223	t		gcesareni	Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp.	SIGNOR-128643	0.626
RIPK3	protein	Q9Y572	UNIPROT	RIPK3	protein	Q9Y572	UNIPROT	up-regulates activity	phosphorylation	Thr182	GSGEPGGtLGYLAPE	-1									29883609	t		miannu	This suggests that Thr182 is a likely auto-phosphorylation target and may be involved in RIP3 activity.	SIGNOR-277396	0.2
ATF4	protein	P18848	UNIPROT	DDIT3	protein	P35638	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									31226023	t		miannu	ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress.	SIGNOR-260170	0.809
GEMIN5	protein	Q8TEQ6	UNIPROT	SMN complex	complex	SIGNOR-C158	SIGNOR	form complex	binding												12065586	t		lperfetto	SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry.	SIGNOR-253119	0.737
WNT8B	protein	Q93098	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-132027	0.602
LLGL2	protein	Q6P1M3	UNIPROT	Scribble_complex_DLG3-LLGL2_variant	complex	SIGNOR-C504	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270883	0.56
ZNF239	protein	Q16600	UNIPROT	RBP3	protein	P10745	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12409453	f		miannu	 We have demonstrated that MOK2 can bind to the 8 bp present in the IRBP promoter and repress transcription from this promoter by competing with the CRX activator for DNA binding.	SIGNOR-255629	0.314
CSNK2A1	protein	P68400	UNIPROT	MAZ	protein	P56270	UNIPROT	up-regulates	phosphorylation	Ser460	PTAVGSLsGAEGVPV	9606	BTO:0000567								10448092	t		lperfetto	Site-specific mutagenesis of maz revealed that the serine residue at position 480 was the major site of phosphorylation by ckii both in vitro and in vivo. Phosphorylation of maz by ckii at this serine residue was required for maximum binding of maz to the pyrimidine-rich dna of the nuclease-hypersensitive element (nhe) in the 5'-end promoter region of the c-myc gene. Mutation of serine at position 480 to alanine eliminated the dna-binding activity of maz to this element.	SIGNOR-70082	0.459
NR3C1	protein	P04150	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity	transcriptional regulation			10090	BTO:0000011								8754811	f		ggiuliani	Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. The dose of DEX required to promote maximal expression of PPARg mRNA is approximately 10 nM, which is within the range of the Kd for the association of DEX with the glucocorticoid receptor in 3T3-L1 cells.	SIGNOR-255963	0.401
CLN8	protein	Q9UBY8	UNIPROT	PPP2CA	protein	P67775	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								30453012	t		miannu	CLN8 interacts with ceramide binding proteins PP2A and I2PP2A. We showed that the phosphorylation levels of several substrates of PP2A, namely Akt, S6 kinase, and GSK3β, were decreased in CLN8 disease patient fibroblasts. This reduction can be reversed by inhibiting PP2A phosphatase activity with cantharidin, suggesting a higher PP2A activity in CLN8-deficient cells. The phosphorylation levels of PP2A substrates are decreased in the absence of CLN8.	SIGNOR-265583	0.2
GNAI1	protein	P63096	UNIPROT	PLD2	protein	O14939	UNIPROT	down-regulates	binding			9606									9148895	t		gcesareni	The results of this study suggest that membrane phospholipase d activity can be negatively regulated via gi	SIGNOR-48256	0.312
PYGM	protein	P11217	UNIPROT	glycogen	smallmolecule	CHEBI:28087	ChEBI	down-regulates quantity	chemical modification			9606									3346228	t			Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267948	0.8
CEBPB	protein	P17676	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates													16319681	f		lperfetto	The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder.	SIGNOR-250572	0.7
MAPK8	protein	P45983	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates	phosphorylation	Ser168	SEMKYLGsPITTVPK	9606									20220133	t		gcesareni	Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset.	SIGNOR-164089	0.423
ADCY6	protein	O43306	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates quantity	chemical modification			9606									15385642	t		miannu	Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions.	SIGNOR-265001	0.8
DIABLO	protein	Q9NR28	UNIPROT	BIRC3	protein	Q13489	UNIPROT	down-regulates activity	binding			9606	BTO:0000007;BTO:0000891								10929712	t		amattioni	Diablo may promote apoptosis by binding to iaps and preventing them from inhibiting caspases.	SIGNOR-80225	0.785
JWOGUUIOCYMBPV-GMFLJSBRSA-N	chemical	CID:6918328	PUBCHEM	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257978	0.8
MAPKAPK5	protein	Q8IW41	UNIPROT	DNAJB1	protein	P25685	UNIPROT	up-regulates	phosphorylation	Ser149	TNVNFGRsRSAQEPA	9606									24309468	t		lperfetto	Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1.	SIGNOR-203456	0.44
FOXP2	protein	O15409	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000142							25232744	t		miannu	By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets.	SIGNOR-266834	0.325
NUP214	protein	P35658	UNIPROT	SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	up-regulates activity	relocalization			9606									12917407	t		lperfetto	We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import.	SIGNOR-217719	0.536
AKT2	protein	P31751	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates	phosphorylation	Thr440	EDRNRMKtLGRRDSS	9606									10869359	t		gcesareni	We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf	SIGNOR-78689	0.276
MAP2K6	protein	P52564	UNIPROT	STAT4	protein	Q14765	UNIPROT	up-regulates activity	phosphorylation	Ser721	PSDLLPMsPSVYAVL	10090	BTO:0000944								10961885	t			MKK6, phosphorylate STAT4 on serine 721. IL-12 induces STAT4 phosphorylation on serine 721 and that mutation of serine 721 interferes with STAT4 transcriptional activity. 	SIGNOR-251425	0.348
eIF4F_complex	complex	SIGNOR-C44	SIGNOR	Translational_regulation	phenotype	SIGNOR-PH202	SIGNOR	up-regulates				9606									30459806	f		gianni	The mRNA cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E), is involved in the recruitment of the ribosome to the mRNA cap structure, playing a central role in the regulation of translation initiation	SIGNOR-268530	0.7
CHUK	protein	O15111	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	down-regulates activity	phosphorylation	Ser432	KMPNTNGsIGHSPLS	9606	BTO:0000938								24614225	t		lperfetto	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204696	0.524
PAK2	protein	Q13177	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates activity	phosphorylation	Ser66	GVYATRSsAVRLRSS	-1									11895474	t		miannu	In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK. 	SIGNOR-250241	0.311
SRC	protein	P12931	UNIPROT	TGFA	protein	P01135	UNIPROT	up-regulates	cleavage			9606									17251915	t		lperfetto	Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network.	SIGNOR-235888	0.305
AMPK	complex	SIGNOR-C15	SIGNOR	CCNY	protein	Q8ND76	UNIPROT	up-regulates activity	phosphorylation	Ser326	SARKRSAsADNLTLP	9606									32723157	t		lperfetto	Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. |Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16	SIGNOR-273001	0.2
AKT1	protein	P31749	UNIPROT	PTPN1	protein	P18031	UNIPROT	down-regulates activity	phosphorylation	Ser50	RNRYRDVsPFDHSRI	10090	BTO:0000944								11579209	t		lperfetto	Phosphorylation of ptp1b at ser(50) by akt impairs its ability to dephosphorylate the insulin receptor.	SIGNOR-252542	0.733
NUMA1	protein	Q14980	UNIPROT	TUBA3E	protein	Q6PEY2	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116738	0.251
CTF1	protein	Q16619	UNIPROT	GCH1	protein	P30793	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12859689	f		miannu	CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. 	SIGNOR-252218	0.2
sorafenib tosylate	chemical	CHEBI:50928	ChEBI	RAF1	protein	P04049	UNIPROT	down-regulates activity	chemical inhibition			-1									16757355	t		miannu	This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant). 	SIGNOR-259228	0.8
ponatinib	chemical	CHEBI:78543	ChEBI	FGFR2	protein	P21802	UNIPROT	down-regulates activity	chemical inhibition			9606									23468082	t		miannu	Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. 	SIGNOR-259278	0.8
KIT	protein	P10721	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			9606					phosphorylation:Tyr703	DHAEAALyKNLLHSK			10377264	t		gcesareni	We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936.	SIGNOR-248283	0.635
PRKACA	protein	P17612	UNIPROT	ARFGEF1	protein	Q9Y6D6	UNIPROT	up-regulates activity	phosphorylation	Ser883	EIAGKKIsMKETKEL	9606	BTO:0000599								16467138	t		lperfetto	Within 20 min after addition of 8-Br-cAMP, BIG1 accumulated in nuclei, and this effect was blocked by protein kinase A (PKA) inhibitors H-89 and PKI, suggesting a dependence on PKA-catalyzed phosphorylation. |Mutant BIG1 (S883A) in which Ala replaced Ser-883, a putative PKA phosphorylation site, did not move to the nucleus with cAMP addition, whereas replacement with Asp (S883D) resulted in nuclear accumulation of BIG1 without or with cAMP exposure, consistent with the mechanistic importance of a negative charge at that site	SIGNOR-272146	0.2
MAPK3	protein	P27361	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Thr453	SGPIIIRtPTVGPNG	9606		BTO:0000887;BTO:0001260							14593115	t		gcesareni	We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription.	SIGNOR-248066	0.638
HDAC1	protein	Q13547	UNIPROT	Sin3B_complex	complex	SIGNOR-C409	SIGNOR	form complex	binding			9606	BTO:0000007								21041482	t		miannu	We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin.	SIGNOR-266968	0.787
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	INSIG2	protein	Q9Y5U4	UNIPROT	down-regulates quantity by repression				10090									21723501	f		miannu	MTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2.	SIGNOR-256211	0.2
SREBF1	protein	P36956	UNIPROT	ELOVL6	protein	Q9H5J4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								18226595	t		Luana	These data demonstrated that Elovl-6 is regulated directly and primarily by SREBP-1c.	SIGNOR-267943	0.464
CAMK2A	protein	Q9UQM7	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr548	KKVAVVRtPPKSPSS	9606	BTO:0000590								10090741	t		lperfetto	We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II.	SIGNOR-249315	0.578
ABL1	protein	P00519	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates	phosphorylation	Tyr78	RAIDFSPyLEPLGAP	9606	BTO:0000007								19563810	t		gcesareni	The y79 amino acid residue of c/ebpbeta was phosphorylated by c-abl or arg. The phosphorylation of c/ebpbeta resulted in an increased c/ebpbeta stability and a potentiation of c/ebpbeta transcription activation activity in cells	SIGNOR-186423	0.409
PTH	protein	P01270	UNIPROT	PTH2R	protein	P49190	UNIPROT	up-regulates	binding			9606		BTO:0000142;BTO:0000671							11861531	t		gcesareni	Pth was shown to efficiently activate the human type 2 pth receptor (pth2 receptor)	SIGNOR-115104	0.688
AP1	complex	SIGNOR-C154	SIGNOR	NFATC1	protein	O95644	UNIPROT	up-regulates activity	binding			9606	BTO:0000782								15928679	t			Activator protein 1 (AP1) proteins are the main transcriptional partners of NFAT during T-cell activation	SIGNOR-253004	0.649
CDK1	protein	P06493	UNIPROT	CHEK1	protein	O14757	UNIPROT	up-regulates	phosphorylation	Ser301	IQSNLDFsPVNSASS	9606									21765472	t		lperfetto	Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency	SIGNOR-175075	0.419
CDC7	protein	O00311	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates	phosphorylation	Ser13	ESFTMASsPAQRRRG	9606									16446360	t		gcesareni	In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2	SIGNOR-143984	0.961
AMER1	protein	Q5JTC6	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	binding			9606	BTO:0000007;BTO:0000038								21498506	t		lperfetto	We show that Amer1 binds directly to beta-catenin via a novel interaction motif, the REA repeats. This amino acid motif, including the core sequence arginine, glutamic acid and alanine, and this REA repeats mediate binding of Amer1 to the armadillo repeats of beta-catenin. The data suggest that Amer1 exerts its negative regulatory role in Wnt signaling by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the plasma membrane.	SIGNOR-217950	0.767
PPARG	protein	P37231	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity				9606	BTO:0000801								17681149	f		lperfetto	Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways	SIGNOR-249558	0.571
RAB6B	protein	Q9NRW1	UNIPROT	Synaptic_vesicle_exocytosis	phenotype	SIGNOR-PH160	SIGNOR	up-regulates				9534									20360680	f		miannu	We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles.	SIGNOR-266881	0.7
SRC	protein	P12931	UNIPROT	CTNND1	protein	O60716	UNIPROT	up-regulates activity	phosphorylation	Tyr112	PGQIVETyTEEDPEG	-1									11382764	t		lperfetto	Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302	SIGNOR-246480	0.92
PCSK7	protein	Q16549	UNIPROT	ETV6	protein	P41212	UNIPROT	down-regulates	phosphorylation			9606									12435397	t		gcesareni	In vivo p38-dependent phosphorylation reduced trans-repressional abilities of tel through ets-binding consensus site	SIGNOR-95622	0.2
PRKAA2	protein	P54646	UNIPROT	BAIAP2	protein	Q9UQB8	UNIPROT	down-regulates	phosphorylation	Ser366	KTLPRSSsMAAGLER	9606			SIGNOR-C15						19933840	t		lperfetto	Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction	SIGNOR-161810	0.2
NRF1	protein	Q16656	UNIPROT	SPAST	protein	Q9UBP0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22574173	f		miannu	 we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11. 	SIGNOR-254885	0.344
ITGA10	protein	O75578	UNIPROT	A10/b1 integrin	complex	SIGNOR-C167	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253185	0.678
POLR1H	protein	Q9P1U0	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16373708	f	 	miannu	 ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells. 	SIGNOR-259907	0.2
hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	GABA-A (a2-b1-g2) receptor	complex	SIGNOR-C331	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000938								26136660	t		miannu	The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 	SIGNOR-264921	0.8
SMARCD1	protein	Q96GM5	UNIPROT	SWI/SNF ACTL6A-ARID1A-SMARCA2 variant	complex	SIGNOR-C470	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269822	0.787
NEK6	protein	Q9HC98	UNIPROT	NUP98	protein	P52948	UNIPROT	down-regulates activity	phosphorylation	Ser839	TSRCLIKsPDRLADI	-1									21335236	t	done	miannu	To elucidate which of the identified sites can be targeted by CDK1/cyclin B1 and Nek6 in vitro (Figure S1D), we performed phosphorylation reactions using recombinant kinases and unlabeled ATP followed by phosphopeptide mapping (Table S1). MS analysis confirmed phosphorylation of S591 and S822 by Nek6 as well as phosphorylation of T529, T536, S595, S606, and T653 by CDK1. Phosphomimetic Mutants of Nup98 Show Defects in NPC Localization	SIGNOR-273893	0.321
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1619	SPSYSPTsPSYSPTS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248768	0.441
JUN	protein	P05412	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				10090									12553907	f			In contrast, c-Jun is required for the survival of liver tumor cells. Reduced tumor formation strictly correlated with high apoptotic indices in c-Jun-deficient tumors, suggesting that increased apoptosis in c-Jun-deficient liver tumors is the primary cause for impaired tumorigenesis.	SIGNOR-256560	0.7
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258012	0.8
CSNK2A1	protein	P68400	UNIPROT	ARNT	protein	P27540	UNIPROT	down-regulates	phosphorylation	Ser77	DKERFARsDDEQSSA	9606									16129408	t		gcesareni	Here, we show that arnt and alt arnt proteins are differentially phosphorylated by protein kinase ckii in vitro. Phosphorylation had an inhibitory effect on dna-binding to an e-box probe by alt arnt, but not arnt, homodimers. This inhibitory phosphorylation occurs through ser77.	SIGNOR-140034	0.345
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	RB1	protein	P06400	UNIPROT	down-regulates activity	phosphorylation	Thr826	LPTPTKMtPRSRILV	9606									9139732	t		lperfetto	We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein.	SIGNOR-216957	0.858
sunitinib	chemical	CHEBI:38940	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258290	0.8
MMP9	protein	P14780	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates	cleavage			9606									10652271	t		gcesareni	We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-_ (tgf-_), which constitutes a novel mechanism of tgf-_ activation.	SIGNOR-74461	0.611
FGF14	protein	Q92915	UNIPROT	SCN2A	protein	Q99250	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253429	0.384
MRPS30	protein	Q9NP92	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262342	0.703
alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	up-regulates quantity	precursor of			9606									12093795	t		miannu	Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis	SIGNOR-266577	0.8
SRC	protein	P12931	UNIPROT	SIRT2	protein	Q8IXJ6	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr104	RSPSTGLyDNLEKYH	9606	BTO:0000007								24996174	t		miannu	 In this study, we investigated the potential regulation of SIRT2 function by c-Src. We found that the protein levels of SIRT2 were decreased by c-Src, and subsequently rescued by the addition of a Src specific inhibitor, SU6656, or by siRNA-mediated knockdown of c-Src. The c-Src interacts with and phosphorylates SIRT2 at Tyr104. 	SIGNOR-263104	0.296
PRPF19	protein	Q9UMS4	UNIPROT	RPA2	protein	P15927	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0000567								24332808	t		miannu	PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). PRP19 ubiquitylates RPA and promotes ATRIP recruitment.	SIGNOR-272075	0.457
NMUR2	protein	Q9GZQ4	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256874	0.409
58131-57-0	chemical	CID:42640	PUBCHEM	MDM4	protein	O15151	UNIPROT	down-regulates activity	chemical inhibition			-1									21075910	t		miannu	Here we report the identification of a benzofuroxan derivative [7-(4-methylpiperazin-1-yl)-4-nitro-1-oxido-2,1,3-benzoxadiazol-1-ium, NSC207895] that could inhibit MDMX expression in cancer cells through a reporter-based drug screening. 	SIGNOR-262246	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	MITF	protein	O75030	UNIPROT	down-regulates quantity by destabilization	phosphorylation												10841026	t	inferred from 70% family members	lperfetto	More interestingly, ERK-dependent phosphorylation of MITF at Ser 73 is essential for MITF ubiquitinilation and degradation (87). Putting together all these findings, it can be proposed that MAPK activation inhibits melanogenesis due to an increased MITF degradation which is dependent on the MAPK-induced MITF phosphorylation and ubiquitinilation. In summary, although the phosphorylation of MITF at Ser73 increases its intrinsic transcriptional activity, this phosphorylation also targets MITF to the proteasome for its degradation. Consequently, the decrease in MITF levels leads to a down-regulation of melanogenic enzymes expression and to an inhibition of melanogenesis.	SIGNOR-270029	0.2
MUTYH	protein	Q9UIF7	UNIPROT	TOPBP1	protein	Q92547	UNIPROT	up-regulates	binding			9606	BTO:0000007								21615992	t		miannu	Binding of myh directly participates in atr and topbp1 activation in dna damage signaling, leading to apoptosis.	SIGNOR-173972	0.382
DYRK3	protein	O43781	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	down-regulates	phosphorylation			9606									23415227	t		lperfetto	When dyrk3 is active, it allows stress granule dissolution, releasing mtorc1 for signaling and promoting its activity by directly phosphorylating the mtorc1 inhibitor pras40	SIGNOR-217571	0.293
MIB1	protein	Q86YT6	UNIPROT	DAPK1	protein	P53355	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								12351649	t		miannu	Transient expression of DIP-1 in HeLa cells antagonizes the anti-apoptotic function of DAPK to promote a caspase-dependent apoptosis. These studies also demonstrate that DAPK is an in vitro and in vivo target for ubiquitination by DIP-1, thereby providing a mechanism by which DAPK activities can be regulated through proteasomal degradation.	SIGNOR-272602	0.448
HRAS	protein	P01112	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	binding			9606									9020159	t		lperfetto	We have examined whether the other two members of the Raf family, A-Raf and B-Raf, are regulated in a similar way to Raf-1. A-Raf behaves like Raf-1, being weakly activated by oncogenic Ras more strongly activated by oncogenic Src, and these signals synergize to give maximal activation. B-Raf by contrast is strongly activated by oncogenic Ras alone and is not activated by oncogenic Src.	SIGNOR-235786	0.934
CSNK2A1	protein	P68400	UNIPROT	CBX5	protein	P45973	UNIPROT	up-regulates	phosphorylation	Ser13	KRTADSSsSEDEEEY	9606									21245376	t		gcesareni	Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability.	SIGNOR-171703	0.354
VKORC1	protein	Q9BQB6	UNIPROT	vitamin K epoxide	smallmolecule	CHEBI:28371	ChEBI	down-regulates quantity	chemical modification			9606									31226734	t		lperfetto	The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form	SIGNOR-265900	0.8
CDR2	protein	Q01850	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates quantity by expression	transcriptional regulation												20383333	f		lperfetto	Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology	SIGNOR-252021	0.2
HRH2	protein	P25021	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257162	0.252
CSNK2A1	protein	P68400	UNIPROT	PML	protein	P29590	UNIPROT	down-regulates	phosphorylation	Ser518	PSTSKAVsPPHLDGP	9606	BTO:0000551								16873060	t		gcesareni	Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517.	SIGNOR-148306	0.347
Neurofibrillary tangle formation	phenotype	SIGNOR-PH58	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									11578751	f		lperfetto	Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death	SIGNOR-251641	0.7
RAC1	protein	P63000	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates	binding			9606									18423204	t		gcesareni	We show that rac1 activates jnk2 that in turn phosphorylates beta-catenin on critical residues and controls its nuclear translocation.	SIGNOR-178265	0.503
SCN5A	protein	Q14524	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606									27262167	t		miannu	Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential.	SIGNOR-253401	0.8
ARFGAP1	protein	Q8N6T3	UNIPROT	ARF1	protein	P84077	UNIPROT	up-regulates activity	gtpase-activating protein			-1									10102276	t			The ARFGAP molecule binds to switch 2 and helix α3 to orient ARF1 residues for catalysis, but it supplies neither arginine nor other amino acid side chains to the GTPase active site. 	SIGNOR-261915	0.858
BAZ2B	protein	Q9UIF8	UNIPROT	H3-2	protein	Q5TEC6	UNIPROT	down-regulates activity	binding			9606							acetylation:Lys15	ARKSTGGkAPRKQLA	31999386	t		miannu	The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation.	SIGNOR-266618	0.2
SP1	protein	P08047	UNIPROT	POR	protein	P16435	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0004428								8660656	f		miannu	Regulation of the NADPH-cytochrome P-450 oxidoreductase gene is controlled by both positive and negative regulatory elements, and, of the nine Sp1 consensus sites, the two proximal sites are sufficient to support basal transcription.	SIGNOR-255213	0.2
GATA1	protein	P15976	UNIPROT	GP6	protein	Q9HCN6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12377757	f	 	miannu	 We have determined that the GP6 sequence -191 to -39 represents the core promoter and that transcription is driven largely by GATA-1 (-176) and c-Ets-1 (-45) sites within this segment.	SIGNOR-254081	0.286
SPAG4	protein	Q9NPE6	UNIPROT	LINC complex	complex	SIGNOR-C303	SIGNOR	form complex	binding												24481844	t		lperfetto	LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM.	SIGNOR-263285	0.364
THRA	protein	P10827	UNIPROT	RARG	protein	P13631	UNIPROT	up-regulates	binding			9606									15650024	t		gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-133246	0.393
PRKACA	protein	P17612	UNIPROT	KCNN4	protein	O15554	UNIPROT	down-regulates activity	phosphorylation	Ser334	KHTRRKEsHAARRHQ	9606	BTO:0000007								25274816	t		miannu	Mutating the single PKA site (S334A) in human KCa3.1 abolished the PKA-dependent regulation. CaM-affinity chromatography showed that CaM binding to KCa3.1 was decreased by PKA-dependent phosphorylation of S334, and this regulation was absent in the S334A mutant.The results above indicate that PKA activation led to a phosphorylation event that inhibited KCa3.1 channel activity	SIGNOR-276855	0.2
PCSK5	protein	Q92824	UNIPROT	Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0001073								11690596	t		miannu	Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension.	SIGNOR-270334	0.2
RORC	protein	P51449	UNIPROT	ARNTL	protein	O00327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24737872	t		miannu	 As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression.	SIGNOR-268004	0.517
CDK2	protein	P24941	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Thr273	SPSVHPAtPISPGRA	9606	BTO:0002181								16046550	t	The effect has been demonstrated using Q01196-8	gcesareni	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-138940	0.2
HSPA1B	protein	P0DMV9	UNIPROT	PACRG	protein	Q96M98	UNIPROT	up-regulates quantity by stabilization	binding			-1									12150907	t		miannu	Our in vitro data suggest that CHIP competes with Hsp70 in binding to Parkin, probably via suppression of the ATPase activity of Hsc/Hsp70 (Figure 4E).In fact, it acts as an inhibitory factor that suppresses the ubiquitination of Pael-R mediated by Parkin in vitro, and Hsp70 enhances the efficiency of folding of overexpressed Pael-R in vivo.	SIGNOR-272891	0.2
MAPK3	protein	P27361	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser112	AIKVEPAsPPYYSEK	9606									11733495	t		gcesareni	Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells.	SIGNOR-179404	0.409
MSX2	protein	P35548	UNIPROT	SPEN	protein	Q96T58	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271;BTO:0000661								19835636	t		gcesareni	Furthermore, in addition to msx2, both tlx1 and nkx2-5 proteins interacted with notch-pathway repressors, spen/mint/sharp and tle1/grg1, representing a potential mechanism for (de)regulation.	SIGNOR-188572	0.494
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SREBF1	protein	P36956	UNIPROT	up-regulates	phosphorylation	Ser117	YPSMPAFsPGPGIKE	9606									10915800	t		lperfetto	Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo.	SIGNOR-244754	0.2
TSHB	protein	P01222	UNIPROT	TSH	complex	SIGNOR-C412	SIGNOR	form complex	binding			9606		BTO:0001379							8196184	t		scontino	TSH is a heterodimer composed of common alpha subunit and unique beta subunit encoded by genes located on different chromosomes. It is known that the expression of these subunit genes is regulated in different mechanism by several extracellular factors.	SIGNOR-267047	0.667
CEP41	protein	Q9BYV8	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								31885126	t		miannu	We performed these assays in HEK 293T cells and observed CEP41 binds HIF1α under both normoxic and hypoxic conditions. Of note, we found hypoxia induces more expression of HIF1α and increases its binding to CEP41 (Fig 8B and C). Hence, these results suggest CEP41 modulates the activation of HIF1α via a physical interaction	SIGNOR-269662	0.2
CACNA1B	protein	Q00975	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									20655485	t		miannu	The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release.	SIGNOR-265069	0.8
F2RL1	protein	P55085	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257300	0.38
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO4	protein	P98177	UNIPROT	down-regulates	phosphorylation	Ser197	APRRRAAsMDSSSKL	9606									16272144	t		lperfetto	Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression	SIGNOR-141416	0.2
RELA	protein	Q04206	UNIPROT	HDAC4	protein	P56524	UNIPROT	up-regulates	binding			9606									15988006	t		gcesareni	P65 and histone deacetylases 4 cooperate to inhibit the ability of mef2 factors to induce the klf2 promoter	SIGNOR-138368	0.322
MERTK	protein	Q12866	UNIPROT	MERTK	protein	Q12866	UNIPROT	up-regulates	phosphorylation	Tyr754	KIYSGDYyRQGRIAK	9606									8702477	t		gcesareni	By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain.	SIGNOR-42922	0.2
CRTC2	protein	Q53ET0	UNIPROT	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity	transcriptional regulation			9606									26652733	t	inferred from family member	miannu	Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-267788	0.283
clozapine	chemical	CHEBI:3766	ChEBI	HTR1E	protein	P28566	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258514	0.8
MAP2K4	protein	P45985	UNIPROT	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000298								8974401	t		lperfetto	A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively.	SIGNOR-236110	0.74
EFNA1	protein	P20827	UNIPROT	EPHA4	protein	P54764	UNIPROT	up-regulates	binding			9606									9576626	t		tpavlidou	Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity	SIGNOR-56907	0.817
DYRK1A	protein	Q13627	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation	Ser329	STISGRLsPIMTEQD	9606		BTO:0000887;BTO:0001103							11311120	t		lperfetto	The kinase dyrk1a phosphorylates the transcription factor fkhr at ser329 in vitro, a novel in vivo phosphorylation siteser(329) phosphorylation also decreases the ability of fkhr to stimulate gene transactivation and reduces the proportion of fkhr present in the nucleus	SIGNOR-106829	0.521
KIF1A	protein	Q12756	UNIPROT	Dense-core_vesicle_exocytosis	phenotype	SIGNOR-PH184	SIGNOR	up-regulates				10116									30021165	f		miannu	To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines	SIGNOR-266893	0.7
MAPK3	protein	P27361	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606									19723038	t		gcesareni	The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1	SIGNOR-187787	0.709
PTPN1	protein	P18031	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates activity	dephosphorylation	Tyr1235	DMYDKEYySVHNKTG	9606									18819921	t			Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases.	SIGNOR-248412	0.621
MAPK14	protein	Q16539	UNIPROT	ATF6	protein	P18850	UNIPROT	up-regulates activity	phosphorylation	Thr166	NKTENGLtPKKKIQV	10090	BTO:0002572								25135476	t		miannu	This observation not only confirms the specific role for IFN-γ-induced p38 MAPK-dependent phosphorylation of ATF6 at the T166 site but also indicates a connection between phosphorylation and proteolytic activation.	SIGNOR-276841	0.566
UBE2D2	protein	P62837	UNIPROT	UBR5	protein	O95071	UNIPROT	up-regulates activity	ubiquitination			-1									11714696	t		miannu	Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with gamma-H2AX nuclear foci in DNA breaks.	SIGNOR-272668	0.522
CDK2	protein	P24941	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser315	LPNNTSSsPQPKKKP	9606			SIGNOR-C83						24173284	t		lperfetto	The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A	SIGNOR-119379	0.867
AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	PTPN1	protein	P18031	UNIPROT	up-regulates activity	binding												16115959	t		lperfetto	N this study, we demonstrate an essential role for protein-tyrosine phosphatase (PTP)-1B in this process. In resting platelets, c-Src forms a complex with alphaIIbbeta3 and Csk, which phosphorylates c-Src tyrosine 529 to maintain c-Src autoinhibition. Fibrinogen binding to alphaIIbbeta3 triggers PTP-1B recruitment to the alphaIIbbeta3-c-Src-Csk complex in a manner that is dependent on c-Src and specific tyrosine (tyrosine 152 and 153) and proline (proline 309 and 310) residues in PTP-1B. Studies of PTP-1B-deficient mouse platelets indicate that PTP-1B is required for fibrinogen-dependent Csk dissociation from alphaIIbbeta3, dephosphorylation of c-Src tyrosine 529, and c-Src activation.	SIGNOR-261800	0.458
domperidone	chemical	CHEBI:31515	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258380	0.8
CSNK2A1	protein	P68400	UNIPROT	SMC3	protein	Q9UQE7	UNIPROT	unknown	phosphorylation	Ser1067	GDVEGSQsQDEGEGS	9606									18442975	t		gcesareni	Our data provide evidence that phosphorylation of a core cohesin subunit smc3 by atm plays an important role in dna damage response and suggest that a constitutive phosphorylation by ck2 may affect intra-s phase checkpoint by modulating smc3 phosphorylation by atm.	SIGNOR-178483	0.2
DUSP4	protein	Q13115	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	down-regulates activity	dephosphorylation			10116									7535768	t	inferred from 70% of family members		Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK	SIGNOR-269914	0.2
ATR	protein	Q13535	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates	phosphorylation	Thr2609	LTPMFVEtQASQGTL	9606									16908529	t		gcesareni	Finally, in vitro atr-mediated phosphorylation at the t2609 cluster was further confirmed by western blot analysis using phosphospecific antibodies against t2647 (fig. ?(Fig.7e),7e), suggesting that dna-pkcs could be the direct target of atr kinase.	SIGNOR-148722	0.316
RPS6KA3	protein	P51812	UNIPROT	WWC1	protein	Q8IX03	UNIPROT	up-regulates	phosphorylation	Ser947	CRLNRSDsDSSTLSK	9606		BTO:0000149							24269383	t		llicata	Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2.	SIGNOR-203302	0.2
CSNK1D	protein	P48730	UNIPROT	PER3	protein	P56645	UNIPROT	down-regulates quantity by destabilization	phosphorylation			10090									11865049	t		miannu	We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. 	SIGNOR-267998	0.712
ETS1	protein	P14921	UNIPROT	TBXAS1	protein	P24557	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14586398	f	 	miannu	We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. 	SIGNOR-254088	0.2
HDAC1	protein	Q13547	UNIPROT	FLI1	protein	Q01543	UNIPROT	up-regulates	deacetylation	Lys380	PTESSMYkYPSDISY	9606									24058639	t		miannu	Hdac1 interacts with fli1 and mediates its deacetylation / our previous studies have shown that pcaf-dependent acetylation of fli1 at lysine 380 decreases its protein stability / p300 promotes the interaction of fli1 with hdac1 and increases the dna binding ability of fli1 through deacetylation of lysine 380	SIGNOR-202689	0.2
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser682	SMNASRLsQPGQLMS	9606	BTO:0000007								10195894	t			Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.	SIGNOR-251278	0.2
MAPK8IP1	protein	Q9UQF2	UNIPROT	MAPK8	protein	P45983	UNIPROT	down-regulates	binding			9606									10490659	t	JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660).	gcesareni	These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins.	SIGNOR-70851	0.879
CACNA1G	protein	O43497	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			10090									33393208	t		miannu	Adult hippocampal neurogenesis plays an important role in neuronal plasticity and maintenance in mammals. Low-threshold voltage-gated T-type calcium channels produce calcium spikes that increase fast action potentials in newborn cells in the hippocampal dentate gyrus (DG)	SIGNOR-264032	0.8
PPP2R5C	protein	Q13362	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	binding			9606									16456541	t		gcesareni	B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk	SIGNOR-144325	0.491
canertinib	chemical	CHEBI:61399	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191012	0.8
SGK1	protein	O00141	UNIPROT	NDRG1	protein	Q92597	UNIPROT	up-regulates	phosphorylation	Thr366	GTRSRSHtSEGAHLD	9606	BTO:0000567								18787837	t		llicata	Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1.	SIGNOR-180829	0.588
TFIIE	complex	SIGNOR-C458	SIGNOR	TFIIH	complex	SIGNOR-C457	SIGNOR	up-regulates activity	relocalization			9606									31064989	t		lperfetto	The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur.	SIGNOR-269362	0.729
RPL7	protein	P18124	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262455	0.857
NPM1	protein	P06748	UNIPROT	CENPA	protein	P49450	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								19410544	t		miannu	Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURPA minority of NPM1 cofractionated with prenucleosomal CENP-A, consistent with only a small proportion of total NPM1 stably associated with CENP-A. The partial overlap of NPM1 and HJURP with each other supports their formation of distinct prenucleosomal complexes with CENP-A. it is also possible that NPM1 plays a non essential role in the assembly of CENP-A nucleosomes or the nucleophosmin paralogues NPM2 and NPM3 may compensate for the absence of NPM1.	SIGNOR-263708	0.547
ARID2	protein	Q68CP9	UNIPROT	SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270597	0.776
CELF4	protein	Q9BZC1	UNIPROT	TNNT2	protein	P45379	UNIPROT	up-regulates quantity	post transcriptional regulation			9606									11158314	f		miannu	We also demonstrated that CUG-binding protein (CUG-BP) binds a conserved CUG motif within a human cTNT MSE and positively regulates MSE-dependent exon inclusion. Alternative splicing of cardiac troponin T (cTNT) exon 5 undergoes a developmentally regulated switch such that exon inclusion predominates in embryonic, but not adult, striated muscle.	SIGNOR-264256	0.37
NCSTN	protein	Q92542	UNIPROT	APH1A	protein	Q96BI3	UNIPROT	up-regulates	binding			9606		BTO:0000142							12471034	t		gcesareni	We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch).	SIGNOR-96250	0.967
CAMK2A	protein	Q9UQM7	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates activity	phosphorylation	Thr642	RSVKRNStVDCNGVV	9606	BTO:0000938								32611770	t		lperfetto	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275786	0.282
AURKB	protein	Q96GD4	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	down-regulates activity	phosphorylation	Ser139	DARDLEMsKKVRRSY	-1									23901111	t		miannu	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. 	SIGNOR-276114	0.614
EPHB1	protein	P54762	UNIPROT	CASKIN1	protein	Q8WXD9	UNIPROT	up-regulates activity	phosphorylation	Tyr296	TKDYCNNyDLTSLNV	9534	BTO:0000298								23181695	t		miannu	EphB1 phosphorylates Caskin1 on tyrosine 296 and 336. Tyrosine phosphorylated Caskin1 then likely promotes reorganization of the actin cytoskeleton leading to spine formation. 	SIGNOR-262860	0.287
TWIST2	protein	Q8WVJ9	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003298								21931630	f	 	miannu	Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2.	SIGNOR-255592	0.484
CDK2	protein	P24941	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates	phosphorylation	Ser13	ESFTMASsPAQRRRG	9606									16446360	t		gcesareni	In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2	SIGNOR-144000	0.724
PPP1R1B	protein	Q9UD71	UNIPROT	PKA	proteinfamily	SIGNOR-PF17	SIGNOR	down-regulates activity	binding			9606	BTO:0000938								10604473	t		miannu	We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism.	SIGNOR-265087	0.484
PDE4DIP	protein	Q5VU43	UNIPROT	PRKAR2A	protein	P13861	UNIPROT	up-regulates	binding			9606									21569246	t		miannu	Mmgl acts as a dual-specific akap by anchoring pka regulatory isoforms r1a and r2a.	SIGNOR-173831	0.464
VKORC1L1	protein	Q8N0U8	UNIPROT	vitamin K epoxide	smallmolecule	CHEBI:28371	ChEBI	down-regulates quantity	chemical modification			9606									31226734	t		lperfetto	This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR)	SIGNOR-265906	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Ser276	VHPATPIsPGRASGM	9606									16046550	t	The effect has been demonstrated using Q01196-8	lperfetto	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-244711	0.2
thioridazine	chemical	CHEBI:9566	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029									9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258839	0.8
S100A9	protein	P06702	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	down-regulates				10090	BTO:0004730								18809714	f		miannu	We report here that up-regulation of S100A9 in myeloid precursors in cancer inhibits DC and macrophage differentiation and induces accumulation of MDSCs. This may represent a universal molecular mechanism of tumor-induced abnormalities in myeloid cells in cancer, directly linking inflammation and immune suppression.	SIGNOR-261932	0.7
SRC_kinase_family	proteinfamily	SIGNOR-PF32	SIGNOR	SLC24A2	protein	Q9UI40	UNIPROT	up-regulates quantity	phosphorylation	Tyr364	LAEELGSyGKLKYYD	9606	BTO:0000938								23431067	t		miannu	Src family kinase-mediated Tyr-365 phosphorylation of NCKX2 regulates its surface expression. PP2 facilitated the endocytosis of NCKX2 in both the somatodendritic and axonal compartments, suggesting that tyrosine phosphorylation of NCKX2 by SFK negatively regulates its endocytosis. Supporting this idea, activation of SFK enhanced the NCKX activity in the proximal dendrites of dentate granule cells (GCs). These results suggest that endocytosis of somatodendritic NCKX2 is regulated by SFK-dependent phosphorylation of Tyr-365.	SIGNOR-264387	0.2
CDC25C	protein	P30307	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates	dephosphorylation	Tyr15	EKIGEGTyGVVYKGR	9606									19574738	t		gcesareni	Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation by cdc25c	SIGNOR-186621	0.853
ATR	protein	Q13535	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates activity	phosphorylation	Thr1394	SQSDILTtQQRDTMQ	9606	BTO:0002181								11114888	t		llicata	Although no single mutation eliminated the GST–BRCA1 (1314–1863) electrophoretic mobility shift, a quadruple mutant (GST–BRCA14A) containing Ala substitutions at Ser 1387, Thr 1394, Ser 1423, and Ser 1457 showed no alteration in electrophoretic mobility after phosphorylation by ATR-containing immune complexes (Fig.2D). The total incorporation of 32Pi into the GST–BRCA14Asubstrate was reduced by 70% relative to that obtained with wild-type GST–BRCA1 (1314–1863), suggesting that these four residues account for most, but not all of the phosphorylation sites in this fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication.	SIGNOR-250583	0.792
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CDC6	protein	Q99741	UNIPROT	down-regulates activity	phosphorylation	Ser74	TPHLPPCsPPKQGKK	9606									9889196	t		lperfetto	Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2.	SIGNOR-217332	0.94
palmitoyl-CoA(4-)	smallmolecule	CHEBI:57379	ChEBI	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	precursor of			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267125	0.8
GNAS	protein	P63092	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001103;BTO:0001760							22179044	t		gcesareni	Notably, the fzd7 receptor complex was associated with g_?(s) and pi(3)k and these components were required for wnt7a to activate the akt/mtor growth pathway in myotubes. These data led us to hypothesize that g_?s Mediates the activation of pi3kinase following wnt7a binding to fzd7.	SIGNOR-191561	0.299
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO6	protein	A8MYZ6	UNIPROT	down-regulates	phosphorylation			9606									18394876	t		lperfetto	The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity	SIGNOR-66032	0.2
CRY2	protein	Q49AN0	UNIPROT	BMAL1/NPAS2	complex	SIGNOR-C431	SIGNOR	down-regulates activity	binding			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop.	SIGNOR-267972	0.892
MRPS2	protein	Q9Y399	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding		P82664	9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261449	0.733
MAPK1	protein	P28482	UNIPROT	MITF	protein	O75030	UNIPROT	down-regulates	phosphorylation	Ser180	PGSSAPNsPMAMLTL	9606									10673502	t	The effect has been demonstrated using O75030-9	gcesareni	The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation.	SIGNOR-75030	0.693
NMS	protein	Q5H8A3	UNIPROT	NMUR2	protein	Q9GZQ4	UNIPROT	up-regulates	binding			9606		BTO:0000142							15635449	t		gcesareni	Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus.	SIGNOR-133131	0.617
ACOT8	protein	O14734	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	chemical modification												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271809	0.8
PRKCB	protein	P05771	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser359	EERQTQRsKPQPAVP	9606									12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89205	0.549
PPP1CA	protein	P62136	UNIPROT	BRAF	protein	P15056	UNIPROT	up-regulates activity	dephosphorylation			9606									29335436	t		miannu	To address whether PP1\u03b1 activates B-Raf through these inhibitory sites, we made use of B-Raf protein mutants in which an individual inhibitory site, as well as all four sites (4A), were mutated to alanine.|We confirmed that GST-B-Raf was phosphorylated by ERK2 in vitro  xref  , mainly on S151 and T753 (Fig.\u00a0 xref ), and found that PP1\u03b1 dephosphorylated B-Raf on both ERK phosphorylation sites (Fig.\u00a0 xref ).	SIGNOR-277160	0.298
CSNK1A1	protein	P48729	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	up-regulates activity	binding			9606									22083140	t		lperfetto	In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)]	SIGNOR-227967	0.658
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser180	GSSASFIsDTFSPYT	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252327	0.635
trimethyl-[(5-methyl-2-furanyl)methyl]ammonium	chemical	CHEBI:94038	ChEBI	CHRM1	protein	P11229	UNIPROT	up-regulates activity	chemical activation			10029									9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258647	0.8
PRKCE	protein	Q02156	UNIPROT	TRPV1	protein	Q8NER1	UNIPROT	up-regulates activity	phosphorylation	Ser801	VPLLREAsARDRQSA	9534									14523239	t		lperfetto	We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. 	SIGNOR-249232	0.2
DUSP3	protein	P51452	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates activity	dephosphorylation	Tyr204	HTGFLTEyVATRWYR	9534	BTO:0004055								10224087	t			Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2	SIGNOR-248535	0.65
CAMK2A	protein	Q9UQM7	UNIPROT	ANKS1B	protein	Q7Z6G8	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000938								27477489	t		miannu	CaMKII-mediated displacement of AIDA-1 out of the postsynaptic density core. The present study indicates that CaMKII activation is necessary for the NMDA-induced movement of AIDA-1 out of the PSD core.	SIGNOR-264231	0.259
ALDOA	protein	P04075	UNIPROT	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266487	0.8
RPS6KA3	protein	P51812	UNIPROT	TH	protein	P07101	UNIPROT	up-regulates	phosphorylation	Ser40	GQGAPGPsLTGSPWP	9606									7901013	t	The effect has been demonstrated using P07101-3	gcesareni	Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax	SIGNOR-34682	0.271
NPTX1	protein	Q15818	UNIPROT	GRIA1	protein	P42261	UNIPROT	up-regulates activity	binding			10090	BTO:0000938								15115814	t		lperfetto	We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death. 	SIGNOR-261430	0.301
GALR2	protein	O43603	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257020	0.409
BAK1	protein	Q16611	UNIPROT	HTRA2	protein	O43464	UNIPROT	up-regulates				9606									21210296	f		gcesareni	Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore.	SIGNOR-170966	0.3
CSNK2A1	protein	P68400	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	unknown	phosphorylation	Ser263	PEIEDVGsDEEEEKK	9606	BTO:0000567								2492519	t		llicata	Both hsp 90 proteins are phosphorylated at two homologous sites. For the alpha protein, these sites correspond to serine 231 and serine 263. | Dephosphorylated hsp 90 is phosphorylated at both sites by casein kinase II from HeLa cells, calf thymus, or rabbit reticulocytes; no other hsp 90 residues were phosphorylated by casein kinase II in vitro.	SIGNOR-250900	0.547
ESRRA	protein	P11474	UNIPROT	CYP19A1	protein	P11511	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000154								15955695	f		miannu	 In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro.	SIGNOR-253794	0.358
GABRB3	protein	P28472	UNIPROT	GABA-A (a6-b3-d) receptor	complex	SIGNOR-C329	SIGNOR	form complex	binding			9606									18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263772	0.46
SOCS4	protein	Q8WXH5	UNIPROT	DAB1	protein	O75553	UNIPROT	down-regulates quantity by destabilization	binding			9534	BTO:0000298								24210661	t		miannu	SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1.	SIGNOR-272139	0.2
SLBP	protein	Q14493	UNIPROT	H2AC20	protein	Q16777	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265398	0.2
MED6	protein	O75586	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266677	0.844
IGF1R	protein	P08069	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates	phosphorylation	Tyr632	GRKGSGDyMPMSPKS	9606									17827393	t		gcesareni	Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K).	SIGNOR-157746	0.864
RPS6KA5	protein	O75582	UNIPROT	H2AW	protein	Q7L7L0	UNIPROT	up-regulates activity	phosphorylation	Ser2	sGRGKQGG	-1									15010469	t		miannu	We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1. Furthermore, we found that acetylation of histone H3 by the p300 and CREB-binding protein associated factor, PCAF, suppressed the kinase-dependent inhibition of transcription. These results suggest that acetylation of histones may stimulate transcription by suppressing an inhibitory phosphorylation by a kinase as MSK1.	SIGNOR-262942	0.2
MAPK1	protein	P28482	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates	phosphorylation	Thr581	PDNQPLKtPCFTLHY	9606		BTO:0000887							11940578	t		gcesareni	Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth.	SIGNOR-116489	0.6
CREBBP	protein	Q92793	UNIPROT	FBL	protein	P22087	UNIPROT	down-regulates activity	acetylation	Lys102	GVFICRGkEDALVTK										30540930	t		lperfetto	Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206)	SIGNOR-275898	0.274
TTF2	protein	Q9UNY4	UNIPROT	CDC5L	protein	Q99459	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000567								12927788	t		miannu	HLodestar/HuF2 associates with CDC5L in cell lysates and HeLa nuclear extracts. It is possible that during the cell division cycle, hLodestar/HuF2’s associates with transcription/splicing complexes in order to inhibit transcription/splicing prior to the start of mitosis and/or functions in stabilizing nuclear complexes containing splicing factors (e.g., the CDC5L complex) so that these are available for re-initiation of splicing at the end of mitosis when gene expression is re-established in cells.	SIGNOR-224460	0.443
MAPK14	protein	Q16539	UNIPROT	CASP3	protein	P42574	UNIPROT	down-regulates	phosphorylation	Ser150	FRGDRCRsLTGKPKL	9606	BTO:0000130								14970175	t		gcesareni	Consequently, p38-mapk can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response.	SIGNOR-122099	0.767
FCER1	complex	SIGNOR-C200	SIGNOR	SRC_kinase_family	proteinfamily	SIGNOR-PF32	SIGNOR	up-regulates				9606	BTO:0000830								16470226	f		Alessandro Palma	It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits	SIGNOR-254957	0.593
F2RL1	protein	P55085	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257408	0.433
SUZ12	protein	Q15022	UNIPROT	TWIST1	protein	Q15672	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001939								23836662	f	 	miannu	 We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes.	SIGNOR-254155	0.282
mTORC2	complex	SIGNOR-C2	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000132								21592956	t		lperfetto	Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1.	SIGNOR-251983	0.634
CDK2	protein	P24941	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates	phosphorylation	Thr160	GVPVRTYtHEVVTLW	9606									17361108	t		gcesareni	Our results demonstrate that cdk2 is capable of autophosphorylation at thr160.	SIGNOR-153636	0.2
NSF	protein	P46459	UNIPROT	SNAP25	protein	P60880	UNIPROT	down-regulates activity	binding			9606	BTO:0000938			SIGNOR-C346					16679567	t		miannu	NSF is an important regulator of SNARE assembly/disassembly. NSF binds to SNAP-25, while in complex with other SNAREs, and hydrolyzes adenosine triphosphate to disassemble the SNARE complex down to monomers	SIGNOR-263974	0.746
RUVBL2	protein	Q9Y230	UNIPROT	R2TP core co-chaperone	complex	SIGNOR-C515	SIGNOR	form complex	binding			9606									29662061	t		miannu	 Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90. 	SIGNOR-270929	0.8
GSK3B	protein	P49841	UNIPROT	PDX1	protein	P52945	UNIPROT	down-regulates quantity	phosphorylation	Ser61	LGALEQGsPPDISPY	10090	BTO:0000783;BTO:0002284								16407209	t			Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic beta-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity.	SIGNOR-255543	0.2
EP300	protein	Q09472	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									12690203	t		miannu	P53 is stabilized by the binding of p300 to the oncoprotein E1A, suggesting that p300 regulates p53 degradation. Purified p300 exhibited intrinsic ubiquitin ligase activity that was inhibited by E1A. In vitro, p300 with MDM2 catalyzed p53 polyubiquitination, whereas MDM2 catalyzed p53 monoubiquitination. E1A expression caused a decrease in polyubiquitinated but not monoubiquitinated p53 in cells. Thus, generation of the polyubiquitinated forms of p53 that are targeted for proteasome degradation requires the intrinsic ubiquitin ligase activities of MDM2 and p300.	SIGNOR-271418	0.909
PTPN6	protein	P29350	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr999	YASSNPEyLSASDVF	9606									10734133	t		flangone	Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1.	SIGNOR-75938	0.365
diethylstilbestrol	chemical	CHEBI:41922	ChEBI	ESR2	protein	Q92731	UNIPROT	up-regulates activity	chemical activation			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258597	0.8
SH2B3	protein	Q9UQQ2	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	binding			10090	BTO:0002882								18618018	t		miannu	 we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence. we identify a direct interaction between Lnk and the Mpl/JAK2 complex that regulates various HSC functions.	SIGNOR-260075	0.63
PPP2CA	protein	P67775	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	dephosphorylation	Ser473	RPHFPQFsYSASGTA	10090									15367694	t			Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes	SIGNOR-248627	0.889
Nalmefene	chemical	CHEBI:7457	ChEBI	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258810	0.8
NAIP	protein	Q13075	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	binding			9606	BTO:0000938								15280366	t		gcesareni	These results demonstrate that naip is distinct from the other iaps, both in demonstrating a ligand-dependent caspase-9 interaction and in demonstrating a distinct mechanism of inhibition.	SIGNOR-127193	0.471
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	CIITA	protein	P33076	UNIPROT	down-regulates	phosphorylation			9606									18245089	t	inferred from 70% family members	gcesareni	In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.	SIGNOR-270067	0.2
DRD2	protein	P14416	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256980	0.501
GTF2I	protein	P78347	UNIPROT	ARID3A	protein	Q99856	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								16738337	t		lperfetto	In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels.	SIGNOR-268533	0.358
arachidonic acid	smallmolecule	CHEBI:15843	ChEBI	PRKCA	protein	P17252	UNIPROT	up-regulates	chemical activation			9606									1357097	t		miannu	These results suggest that the activation of protein kinase c by both arachidonic acid and phorbol esters may play a role in the potentiation of glutamate exocytosis.	SIGNOR-17809	0.8
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR3C	protein	Q8WXA8	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264296	0.8
F9	protein	P00740	UNIPROT	F7	protein	P08709	UNIPROT	up-regulates activity	cleavage	Arg212	NASKPQGrIVGGKVC	9606		BTO:0000131							12524220	t		lperfetto	The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa.	SIGNOR-263522	0.529
LCK	protein	P06239	UNIPROT	SH2D2A	protein	Q9NP31	UNIPROT	up-regulates activity	phosphorylation	Tyr290	PDEPIAFyAMGRGSP	9606	BTO:0000782								18541536	t		miannu	 Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition.	SIGNOR-262889	0.597
MEN1	protein	O00255	UNIPROT	CDKN2C	protein	P42773	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15640349	f		irozzo	Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions.	SIGNOR-255888	0.502
GLI2	protein	P10070	UNIPROT	OLIG2	protein	Q13516	UNIPROT	up-regulates quantity	transcriptional regulation			9606									NBK6142	f		SimoneGraziosi	Therefore, Gli2 activity regulates the late phase of Olig2 gene expression in the ventral neuroepithelium and its subsequent production of OPC cells.	SIGNOR-269219	0.363
STUB1	protein	Q9UNE7	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	ubiquitination			9606									22298955	t		gcesareni	In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner	SIGNOR-195687	0.334
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Thr220	QSNYIPEtPPPGYIS	9606									19115199	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-183000	0.739
NANOGP8	protein	Q6NSW7	UNIPROT	BMP5	protein	P22003	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10900	BTO:0000667								23839044	f		Luana	Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun.	SIGNOR-266089	0.2
FBXW11	protein	Q9UKB1	UNIPROT	CLSPN	protein	Q9HAW4	UNIPROT	down-regulates	ubiquitination			9606									16885021	t		gcesareni	Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbetatrcp ubiquitin ligase.	SIGNOR-148438	0.352
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CALM1	protein	P0DP23	UNIPROT	up-regulates	chemical activation			9606									10884684	t		lperfetto	Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘open’ conformations	SIGNOR-78915	0.8
PTPRE	protein	P23469	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	10116	BTO:0000575								15738637	t			In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver.	SIGNOR-248444	0.289
DLG1	protein	Q12959	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	phosphorylation	Tyr493	LGADDSYyTARSAGK	9606	BTO:0000661								34960191	t		Barakat	Immunoblot analysis showed that phosphorylation of the activating ZAP70 kinase domain residue Tyr 493 was decreased in the DLG1 KD cells. Similarly, the Tyr 319 residue of ZAP70 and Tyr 83 residue of TCR- ζ also showed reduced phosphorylation.	SIGNOR-274142	0.513
RHEB	protein	Q15382	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				9606									19222999	t		lperfetto	Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1.	SIGNOR-232208	0.791
JAK3	protein	P52333	UNIPROT	SIGLEC10	protein	Q96LC7	UNIPROT	up-regulates	phosphorylation	Tyr667	ESQEELHyATLNFPG	9606									11733002	t		lperfetto	These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2	SIGNOR-112483	0.2
PAK4	protein	O96013	UNIPROT	MZF1	protein	P28698	UNIPROT	up-regulates activity	phosphorylation	Ser27	VMVKLEDsEEEGEAA	-1									30622337	t		miannu	 Here, we link ErbB2 activation to invasion via ErbB2-induced, SUMO-directed phosphorylation of a single serine residue, S27, of the transcription factor myeloid zinc finger-1 (MZF1).  Phosphorylation of MZF1-S27 is an early response to ErbB2 activation and results in increased transcriptional activity of MZF1.The phosphorylation of MZF1-S27 is preceded by poly-SUMOylation of K23, which can make S27 accessible to efficient phosphorylation by PAK4.	SIGNOR-277422	0.2
PLK4	protein	O00444	UNIPROT	TUBGCP6	protein	Q96RT7	UNIPROT	up-regulates activity	phosphorylation	Ser1249	HGHVSDAsISLGEPV	-1									22302995	t		miannu	Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication.	SIGNOR-262906	0.691
PRKCA	protein	P17252	UNIPROT	SLC6A9	protein	P48067-2	UNIPROT	down-regulates activity	phosphorylation	Thr590	PALLEHRtGRYAPTI	9823									21864610	t		miannu	We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 	SIGNOR-262921	0.337
MAPK11	protein	Q15759	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates	phosphorylation	Thr700	LSSNPLMtPDILGSS	9606	BTO:0000567								9687510	t		gcesareni	Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha	SIGNOR-59451	0.597
CSNK2A2	protein	P19784	UNIPROT	CLTB	protein	P09497	UNIPROT	unknown	phosphorylation	Ser13	GFFSSSEsGAPEAAE	-1									3128543	t		llicata	To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites.	SIGNOR-250984	0.312
NUP54	protein	Q7Z3B4	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262078	0.651
HNRNPA2B1	protein	P22626	UNIPROT	CDK5R1	protein	Q15078	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24792867	f		miannu	Hnrnpa2/b1 protein directly interacts with the r1 and r2 regions ofcdk5r13_-utr and displays a negative regulatory activity on its expression	SIGNOR-205023	0.2
IKBKB	protein	O14920	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser268	SDEFRPRsKSQSSSN	-1									12351658	t			IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.	SIGNOR-251288	0.644
ADRA1A	protein	P35348	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256955	0.281
BMPR1A	protein	P36894	UNIPROT	FAM83G	protein	A6ND36	UNIPROT	up-regulates activity	phosphorylation	Ser610	GPGPRRPsVASSVSE	9606									24554596	t		lperfetto	These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway.	SIGNOR-264765	0.383
JNJ-28312141 free base	chemical	CID:11676971	PUBCHEM	CSF1R	protein	P07333	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258228	0.8
KCNJ10	protein	P78508	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	up-regulates quantity	relocalization			9606									24561201	t		miannu	KCNJ10 encodes Kir4.1, a member of the K+ channel family known as inwardly rectifying K+ (Kir) channels. Kir4.1 channels may comprise either Kir4.1 homomers or Kir4.1/Kir5.1 heteromers	SIGNOR-269446	0.8
CSNK2A1	protein	P68400	UNIPROT	GTF2A1L	protein	Q9UNN4	UNIPROT	up-regulates activity	phosphorylation	Ser356	VDGSGDTsSNEEIGS	-1									12107178	t		llicata	ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.	SIGNOR-250870	0.435
PRKACA	protein	P17612	UNIPROT	PLCB3	protein	Q01970	UNIPROT	down-regulates	phosphorylation	Ser1105	LDRKRHNsISEAKMR	9606									10893237	t		llicata	These data indicate that pkc and pka act similarly in that they inhibit galpha(q)-stimulated plcbeta(3) as a result of phosphorylation of ser(1105).	SIGNOR-79148	0.263
PRKACA	protein	P17612	UNIPROT	MARK2	protein	Q7KZI7	UNIPROT	down-regulates activity	phosphorylation	Ser409	NPKQRRFsDQAAGPA	9606	BTO:0000007								25512381	t		miannu	Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409. 	SIGNOR-276870	0.2
RAF1	protein	P04049	UNIPROT	RAF1	protein	P04049	UNIPROT	unknown	phosphorylation	Thr268	PNVHMVStTLPVDSR	-1									8349614	t		lperfetto	Furthermore, we find that Thr268 is the predominant Raf-1 residue phosphorylated in in vitro autokinase assays.	SIGNOR-248917	0.2
CBX5	protein	P45973	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	binding			9606									19111658	t		miannu	A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing.	SIGNOR-265325	0.2
BCS1L	protein	Q9Y276	UNIPROT	Mitochondrial_biogenesis	phenotype	SIGNOR-PH32	SIGNOR	up-regulates				9606	BTO:0000567								18628306	f		lperfetto	We hypothesize a working model of the function of BCS1L and LETM1 in mitochondrial biogenesis (Fig. 8E). Because BCS1L is an AAA-ATPase, the following three functions are downstream targets: (1) respiratory chain assembly, (2) mitochondrial morphology maintenance and, (3) LETM1 complex formation. BCS1L functions directly in the formation of mitochondrial tubular networks, in addition to the assembly of the supercomplexes. LETM1 has a distinct role in maintenance of mitochondrial volume and shapes, which helps – in concert with BCS1L – to achieve the efficient assembly of the respiratory chains.	SIGNOR-262544	0.7
SNRPF	protein	P62306	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270631	0.791
PIM1	protein	P11309	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	phosphorylation	Ser276	SMQLRRPsDRELSEP	9606									19911008	t		llicata	In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276.	SIGNOR-189125	0.2
Set1-Ash2 HMT complex	complex	SIGNOR-C352	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606	BTO:0000567								12670868	t		miannu	 The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. 	SIGNOR-264484	0.2
procainamide	chemical	CHEBI:8428	ChEBI	ACHE	protein	P22303	UNIPROT	down-regulates activity	chemical inhibition			-1									9301662	t		miannu	With the aim of performing a rigorous test of the anti-AChE properties of our compounds, the kinetics of enzyme inhibition were studied in purified enzyme preparations. The inhibition data are shown in Table 1. Additionally, known competitive inhibitors of AChE (procainamide and edrophonium) were included in the study for comparative purposes.	SIGNOR-258668	0.8
REST	protein	Q13127	UNIPROT	REST-CoREST	complex	SIGNOR-C111	SIGNOR	form complex	binding			9606									20080105	t	1	miannu	Transcriptional repression of neural-specific genes in nonneuronal cells is dependent on the REST (RE1-silencing transcription factor)–CoREST complex.	SIGNOR-239217	0.761
acetate	smallmolecule	CHEBI:30089	ChEBI	acetyl-CoA(4-)	smallmolecule	CHEBI:57288	ChEBI	up-regulates quantity	precursor of												10843999	t		lperfetto	The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP.	SIGNOR-271824	0.8
MAPK8	protein	P45983	UNIPROT	CDC25B	protein	P30305	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser101	ASESSLSsESSESSD	9606	BTO:0000567								21807946	t		miannu	 Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104).	SIGNOR-276352	0.289
PDPK1	protein	O15530	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	up-regulates	phosphorylation	Thr228	HEGAVTHtFCGTIEY	9606									15209375	t		gcesareni	A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.	SIGNOR-126076	0.595
CBP/p300	complex	SIGNOR-C6	SIGNOR	MEF2C	protein	Q06413	UNIPROT	up-regulates	binding			9606									11062529	t		gcesareni	Cbp/p300 and pcaf are coactivators for myod and mef-2c during myogenic commitment and differentiation	SIGNOR-83840	0.703
PTPRG	protein	P23470	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	dephosphorylation	Tyr419	RLIEDNEyTARQGAK	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254725	0.312
CSNK1D	protein	P48730	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates	phosphorylation	Thr224	MSRFSSStEQSSASR	9606									22609948	t		lperfetto	Ck1_/__dependent phosphorylation of dvl2 at s143 and t224and that this event is critical to interact with plk1 in early stages of the cell cycle	SIGNOR-197551	0.519
SRGAP2	protein	O75044	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260516	0.569
CALM3	protein	P0DP25	UNIPROT	Calcineurin	complex	SIGNOR-C155	SIGNOR	up-regulates	binding			9606									11796223	t		miannu	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-266347	0.501
SAG	protein	P10523	UNIPROT	CUL5	protein	Q93034	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								25216516	t		miannu	Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation. 	SIGNOR-272844	0.421
RPEL1	protein	Q2QD12	UNIPROT	D-ribulose 5-phosphate	smallmolecule	CHEBI:17363	ChEBI	down-regulates quantity	chemical modification			9606									34775382	t		miannu	The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux.	SIGNOR-267066	0.8
promethazine	chemical	CHEBI:8461	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002126								18446005	t		Luana	We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells	SIGNOR-257788	0.8
testosterone	smallmolecule	CHEBI:17347	ChEBI	17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000975							27702664	t		lperfetto	The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively	SIGNOR-268667	0.8
PRKDC	protein	P78527	UNIPROT	TDP1	protein	Q9NUW8	UNIPROT	up-regulates	phosphorylation	Ser81	PKRQKSGsQEDLGWC	9606									19851285	t		lperfetto	Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk)	SIGNOR-188776	0.518
HDAC9	protein	Q9UKV0	UNIPROT	MEF2C	protein	Q06413	UNIPROT	down-regulates	binding			10090	BTO:0000165;BTO:0000222	BTO:0000887;BTO:0001103							15546868	t		lperfetto	Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner	SIGNOR-235642	0.618
PPARD	protein	Q03181	UNIPROT	SLC25A20	protein	O43772	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									19577614	f		miannu	 CACT is upregulated by PPARalpha and PPARdelta, probably by binding to a functional PPRE at position +45 to +57 relative to the transcription start site. The upregulation of CACT by PPARalpha and PPARdelta, which are both important for the regulation of fatty acid oxidation in tissues during fasting, may increase the import of acylcarnitine into the mitochondrial matrix during fasting.	SIGNOR-255048	0.309
PRKACA	protein	P17612	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser579	NVKSKIGsTENLKHQ	-1									12435421	t		miannu	Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly 	SIGNOR-250008	0.442
Sin3B_complex	complex	SIGNOR-C409	SIGNOR	H3C15	protein	Q71DI3	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								21041486	t		miannu	We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin.	SIGNOR-266974	0.2
ceramide 1-phosphate(2-)	smallmolecule	CHEBI:84404	ChEBI	PRKCA	protein	P17252	UNIPROT	up-regulates activity	chemical activation			9606									19948174	t		miannu	Here we demonstrate that C1P induces translocation of protein kinase C-alpha (PKC-alpha) from the soluble to the membrane fraction of bone marrow-derived macrophages. 	SIGNOR-268502	0.8
UBE3A	protein	Q05086	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									9497376	t		miannu	E6AP and E6 together provide the E3-ubiquitin protein ligase activity in the transfer of ubiquitin to p53. In vitro studies have shown that E6AP can form a high energy thiolester bond with ubiquitin and, in the presence of E6, transfer ubiquitin to p53. In this study we have addressed the role of E6AP in vivo in the degradation of p53. 	SIGNOR-272552	0.673
genistein	chemical	CHEBI:28088	ChEBI	ESR2	protein	Q92731	UNIPROT	up-regulates activity	chemical activation			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258599	0.8
RNF180	protein	Q86T96	UNIPROT	ZIC2	protein	O95409	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10116									18363970	t		miannu	Rinescan directly interact with Zic2. the ubiquitination of endogenous Zic2 was enhanced by Myc-Rines in rat neural stem cellline MNS70 cells. Rines-induced degradation of Zic2	SIGNOR-226303	0.381
AKT1	protein	P31749	UNIPROT	NQO1	protein	P15559	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr128	FIGEFAYtYAAMYDK	9606	BTO:0000007								31358653	t		miannu	Akt phosphorylates NQO1 on S40 and T128 residues. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase. 	SIGNOR-276869	0.379
MAPK3	protein	P27361	UNIPROT	DUSP1	protein	P28562	UNIPROT	up-regulates	phosphorylation	Ser364	LQSPITTsPSC	9606									10617468	t		lperfetto	Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein.	SIGNOR-73633	0.778
GNB3	protein	P16520	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Furthermore, this work suggested that the g subunits released upon gi activation activated phospholipase c (plc- ) to produce inositol 3-phosphate (ip3), which would subsequently increase intracellular ca2+ abundance.	SIGNOR-199135	0.2
MCF2L	protein	O15068	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260559	0.603
MAP3K7	protein	O43318	UNIPROT	RAB8A	protein	P61006	UNIPROT	up-regulates activity	phosphorylation	Thr72	AGQERFRtITTAYYR	-1									32227113	t		lperfetto	In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease	SIGNOR-260266	0.254
CDK6	protein	Q00534	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Ser672	TLYDRYSsPPASTTR	9606	BTO:0001938								11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus)	SIGNOR-104715	0.667
CCNA2	protein	P20248	UNIPROT	CyclinA2/CDK1	complex	SIGNOR-C420	SIGNOR	form complex	binding			9606									29870721	t		lperfetto	Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis. 	SIGNOR-267571	0.919
SPI1	protein	P17947	UNIPROT	ANXA1	protein	P04083	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19428102	f		miannu	Identification of annexin 1 as a PU.1 target gene in leukemia cells. PU.1 is a master regulator, and critical for the developmen tof a common progenitor for lymphoid-myeloid cell lineages in the hematopoietic system. From microarray analysis, we found that several genes including annexin 1 were markedly induced in K562PU.1KD cells. Annexin 1 is a calcium- and phospholipid-binding protein and increased expression leads to the constitutive activation of extracellular signal-regulated kinase (ERK)	SIGNOR-261688	0.2
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	WEE1	protein	P30291	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1									24817118	t		miannu	Casein kinase 1-mediated N-terminal Weee1 phosphorylation is required for interaction with the F-box protein β-TrCP.MS/MS spectra of human Wee1 identifying serine 212 as phosphorylated after incubation with recombinant CK1δ.	SIGNOR-276633	0.396
STK3	protein	Q13188	UNIPROT	MOB1B	protein	Q7L9L4	UNIPROT	up-regulates	phosphorylation	Thr12	FGSRSSKtFKPKKNI	9606									23431053	t		milica	Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity	SIGNOR-201290	0.809
UBQLN2	protein	Q9UHD9	UNIPROT	HNRNPA1	protein	P09651	UNIPROT	up-regulates quantity by stabilization	binding												25616961	t		lperfetto	Confirmation of binding of recombinant full-length hnRNPA1 and hnRNPU proteins with ubiquilin-2 by GST-pull-down assays|Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein 	SIGNOR-262270	0.471
S1PR2	protein	O95136	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			9606									22863277	t		gcesareni	Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2.	SIGNOR-198559	0.572
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser37	EDLTDELsLNKISAD	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276206	0.389
Motilin	smallmolecule	CHEBI:80269	ChEBI	MLNR	protein	O43193	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257542	0.8
SNRPE	protein	P62304	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270657	0.72
TGFBR2	protein	P37173	UNIPROT	ZFYVE9	protein	O95405	UNIPROT	up-regulates activity	binding			9606									9865696	t		lperfetto	Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex	SIGNOR-245093	0.551
FABP1	protein	P07148	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264455	0.7
ETFBKMT	protein	Q8IXQ9	UNIPROT	ETFB	protein	P38117	UNIPROT	down-regulates activity	methylation	Lys200	ATLPNIMkAKKKKIE	-1									25416781	t		miannu	 Accordingly, we found that METTL20-mediated methylation of ETFβ in vitro reduced its ability to receive electrons from the medium chain acyl-CoA dehydrogenase and the glutaryl-CoA dehydrogenase. In conclusion, the present study establishes METTL20 as the first human KMT localized to mitochondria and suggests that it may regulate cellular metabolism through modulating the interaction between its substrate ETFβ and dehydrogenases.	SIGNOR-269450	0.2
MED13	protein	Q9UHV7	UNIPROT	CKM complex	complex	SIGNOR-C406	SIGNOR	form complex	binding			9606									23563140	t		miannu	The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation.	SIGNOR-266684	0.794
CHUK	protein	O15111	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	down-regulates activity	phosphorylation	Ser439	SIGHSPLsLSAQSVM	9606	BTO:0000938								24614225	t		lperfetto	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204704	0.524
MAPK3	protein	P27361	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation	Ser301	SSSPNNLsPTGWSQP	9606									16407412	t		gcesareni	Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a.	SIGNOR-143696	0.622
HSD17B11	protein	Q8NBQ5	UNIPROT	17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000056							16166196	t		lperfetto	A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis.	SIGNOR-268664	0.8
AKT1	protein	P31749	UNIPROT	PALLD	protein	Q8WX93	UNIPROT	unknown	phosphorylation	Ser1118	VRRPRSRsRDSGDEN	9606									20471940	t		llicata	Akt1, but not akt2, phosphorylates palladin at ser507 in a domain that is critical for f-actin bundling.	SIGNOR-252510	0.417
ZNF774	protein	Q6NX45	UNIPROT	MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	up-regulates activity	binding			9606	BTO:0000578								31659254	t		miannu	Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription. 	SIGNOR-265558	0.25
F2RL3	protein	Q96RI0	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257312	0.2
CDK1	protein	P06493	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	unknown	phosphorylation	Ser696	EKNYALPsPATTEGG	9606									20169205	t		llicata	Cdc2 is the raptor ser696, thr706 kinase	SIGNOR-163849	0.395
RPL7A	protein	P62424	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262454	0.838
MAP2K1	protein	Q02750	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates	phosphorylation	Thr202	HDHTGFLtEYVATRW	9606									9677429	t	MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade.	gcesareni	The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells.	SIGNOR-59153	0.741
IL3RA	protein	P26951	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates				9606									15795318	f		gcesareni	We previously demonstrated that integrin-dependent adhesion activates stat5a, a well known target of il-3-mediated signaling	SIGNOR-134862	0.556
decanoic acid	chemical	CHEBI:30813	ChEBI	GPR84	protein	Q9NQS5	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257508	0.8
PTPN12	protein	Q05209	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation			-1									8454633	t		gcesareni	Intrinsic activity was demonstrated in vitro against a variety of phosphotyrosine-containing substrates including BIRK, the autophosphorylated cytoplasmic kinase domain of the insulin receptor beta subunit.	SIGNOR-39155	0.384
IL4R	protein	P24394	UNIPROT	JAK3	protein	P52333	UNIPROT	up-regulates				9606	BTO:0000776								7538655	f		gcesareni	The overlapping and distinct protein tyrosine phosphorylation and activation of the same jak1 kinase in t lymphocytes strongly suggests that il-4 and il-9 share the common signal transduction pathways.	SIGNOR-28399	0.662
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PCYT1A	protein	P49585	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000763							15788406	t	inferred from 70% family members	gcesareni	Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis.	SIGNOR-270028	0.2
SATB2	protein	Q9UPW6	UNIPROT	NR4A2	protein	P43354	UNIPROT	down-regulates quantity	transcriptional regulation			9606									31666685	t		gianni	Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development	SIGNOR-268930	0.3
S1PR2	protein	O95136	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates	binding			9606									22863277	t		gcesareni	Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2.	SIGNOR-198556	0.448
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates	relocalization			9606		BTO:0001103							11062529	t		gcesareni	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-84050	0.598
PPP2R1A	protein	P30153	UNIPROT	SGO1	protein	Q5FBB7	UNIPROT	up-regulates	binding			9606	BTO:0000567								16580887	t		miannu	Identification of subunits of protein phosphatase 2a (pp2a) as sgo1 binding proteins / pp2a is required for proper chromosome segregation and centromeric localization of sgo1 in hela cells	SIGNOR-145486	0.2
ATG10	protein	Q9H0Y0	UNIPROT	ATG12	protein	O94817	UNIPROT	up-regulates	binding			9606									18704115	t		gcesareni	Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein.	SIGNOR-180129	0.875
D-thyroxine	smallmolecule	CHEBI:30659	ChEBI	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0003736								6777394	t	inferred from family member	miannu	 The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response.	SIGNOR-267802	0.8
LAMTOR	complex	SIGNOR-C26	SIGNOR	RAGAC	complex	SIGNOR-C113	SIGNOR	up-regulates activity	relocalization			9606	BTO:0000007			SIGNOR-C3					20381137	t		lperfetto	We identify the trimeric Ragulator protein complex as a new component of the mTORC1 pathway that interacts with the Rag GTPases, is essential for localizing them and mTORC1 to the lysosomal surface, and is necessary for the activation of the mTORC1 pathway by amino acids.	SIGNOR-228155	0.874
CDK1	protein	P06493	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Ser367	GTQNPVSsPGMSQEL										26933062	t		lperfetto	Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis.	SIGNOR-276587	0.437
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Ser367	GTQNPVSsPGMSQEL										26933062	t		lperfetto	Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis.	SIGNOR-276590	0.398
ZEB1	protein	P37275	UNIPROT	EPCAM	protein	P16422	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000150;BTO:0000584								23667256	f		miannu	We found a similar ZEB1-dependent repression of EPCAM expression in human pancreatic and breast cancer cell lines, mediated through direct binding of ZEB1 to the EPCAM promoter.	SIGNOR-255622	0.443
Pentostatin	chemical	CID:439693	PUBCHEM	ADA	protein	P00813	UNIPROT	down-regulates activity	chemical inhibition			9606									2433905	t		miannu	2'-Chloropentostatin is a new inhibitor of adenosine deaminase isolated from the fermentation broth of an unidentified actinomycete, ATCC 39365. It contains the aglycone of coformycin, i.e. 3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-o1, coupled to the unusual carbohydrate, 2'-chloro-2'-deoxyribose. 2'-Chloropentostatin is a slightly weaker inhibitor of rat and human adenosine deaminases than coformycin, and considerably weaker than pentostatin. Unlike pentostatin, which appears to undergo a two-stage interaction with adenosine deaminase, 2'-chloropentostatin forms a single enzyme-inhibitor complex. The enzyme-inhibitor complex between adenosine deaminase and 2'-chloropentostatin was much more rapidly dissociable than the complex with pentostatin. 	SIGNOR-259261	0.8
CSNK2A1	protein	P68400	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	phosphorylation	Ser29	VSHWQQQsYLDSGIH	9606	BTO:0000007								12432063	t		llicata	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin	SIGNOR-250846	0.54
MAPK14	protein	Q16539	UNIPROT	MEF2A	protein	Q02078	UNIPROT	unknown	phosphorylation	Ser453	PRQEMGRsPVDSLSS	9606	BTO:0000938	BTO:0000887							12586839	t		lperfetto	Thr-312 and thr-319 are known phosphorylation sites important for the increased transcriptional activation of mef2a by p38 mapk. Ser-453 and ser-479 are phosphorylated in vitro but were not important functionally	SIGNOR-98228	0.646
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	RGCC	protein	Q9H4X1-2	UNIPROT	up-regulates activity	phosphorylation	Ser45	ERMKRRSsASVSDSS	9606	BTO:0000567								19162005	t		miannu	Akt phosphorylated GST-RGC-32 in vitro, and CDC2 was also able to phosphorylate RGC-32.  Akt failed to phosphorylate RGC-32 S45A-S47A mutant. These data indicate that Ser 45 and Ser 47 may be the RGC-32 phosphorylation sites for Akt kinase.	SIGNOR-262629	0.2
D-xylulose 5-phosphate(2-)	smallmolecule	CHEBI:57737	ChEBI	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	precursor of			9606									24929114	t		miannu	Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates.	SIGNOR-268141	0.8
FYN	protein	P06241	UNIPROT	PRKACA	protein	P17612	UNIPROT	up-regulates activity	phosphorylation	Tyr70	HKETGNHyAMKILDK	-1									30274258	t		miannu	We found that the Src family kinase Fyn phosphorylates the catalytic subunit of PKA (PKA-C) at Y69, thereby increasing PKA kinase activity. 	SIGNOR-277410	0.435
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									15994958	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-252808	0.2
CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	NAMPT	protein	P43490	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									19299583	t		miannu	 Here we report that both the rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and levels of NAD+ display circadian oscillations that are regulated by the core clock machinery in mice. Inhibition of NAMPT promotes oscillation of the clock gene Per2 by releasing CLOCK:BMAL1 from suppression by SIRT1. In turn, the circadian transcription factor CLOCK binds to and up-regulates Nampt, thus completing a feedback loop involving NAMPT/NAD+ and SIRT1/CLOCK:BMAL1. Transduction of Clock/Bmal1 into mouse embryonic fibroblasts appeared to up-regulate Nampt expression ∼1.6-fold (Fig. 3E). 	SIGNOR-268021	0.597
MAP2K1	protein	Q02750	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates				9606									18481201	f		gcesareni	Pd98059, a specific inhibitor of mek in addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation.	SIGNOR-178636	0.659
CSNK2A1	protein	P68400	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser273	AGTRRREsLGKKAKR	-1									9677319	t		llicata	CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin.	SIGNOR-250947	0.317
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GATA3	protein	P23771	UNIPROT	up-regulates activity	phosphorylation	Ser308	IKPKRRLsAARRAGT	9606	BTO:0000093								16109788	t		miannu	 PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469. 	SIGNOR-276042	0.2
LRP5	protein	O75197	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates activity	binding			9606									23209147	t		Gianni	The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization.	SIGNOR-262525	0.676
paliperidone	chemical	CHEBI:82978	ChEBI	HTR1E	protein	P28566	UNIPROT	down-regulates activity	chemical inhibition			9534	BTO:0000298								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258561	0.8
E2F1	protein	Q01094	UNIPROT	NOX4	protein	Q9NPH5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002195								18554521	f	 	lperfetto	Positive regulation of the NADPH oxidase NOX4 promoter in vascular smooth muscle cells by E2F	SIGNOR-254134	0.2
RAPGEF4	protein	Q8WZA2	UNIPROT	RAP1A	protein	P62834	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9534	BTO:0000298								10777494	t		miannu	Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.	SIGNOR-263954	0.786
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser713	GAEIVYKsPVVSGDT	9606									12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249320	0.754
ABL1	protein	P00519	UNIPROT	PLSCR1	protein	O15162	UNIPROT	unknown	phosphorylation	Tyr74	PVYNQPVyNQPVGAA	9606									11390389	t		Manara	Our data establish that the Abl SH3 domain binds to the N-terminal proline-rich segment of PLSCR1 and that ABL1 phosphorylates Tyr residues of the PLSCR1 polypeptide, most likely Tyr69 and Tyr74 within the tandem repeat sequence 	SIGNOR-260808	0.393
RPS23	protein	P62266	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262428	0.892
RAB6B	protein	Q9NRW1	UNIPROT	VPS13B	protein	Q7Z7G8	UNIPROT	up-regulates activity	binding			10116	BTO:0003102								25492866	t		miannu	Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization. 	SIGNOR-266870	0.2
PRKACA	protein	P17612	UNIPROT	AKAP12	protein	Q02952	UNIPROT	up-regulates activity	phosphorylation	Ser627	KKRVRRPsESDKEDE	-1									14657015	t		lperfetto	Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin.	SIGNOR-271841	0.2
IKBKB	protein	O14920	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation			9606			SIGNOR-C14						23332762	t		gcesareni	Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation.	SIGNOR-192614	0.266
PRKCD	protein	Q05655	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	phosphorylation	Ser498	RHRPLSRtQSSPLPQ	9606									18332134	t		Manara	In this report, we show that VEGF stimulates PKD-dependent phosphorylation of HDAC5 at Ser259/498residues in ECs, which leads to HDAC5 nuclear exclusion and myocyte enhancer factor-2 (MEF2) transcriptional activation.	SIGNOR-260876	0.359
DOK1	protein	Q99704	UNIPROT	ITGB4	protein	P16144	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257689	0.2
CSF1R	protein	P07333	UNIPROT	CSF1R	protein	P07333	UNIPROT	up-regulates	phosphorylation	Tyr809	DIMNDSNyIVKGNAR	9606	BTO:0001271								15297464	t		lperfetto	Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins.	SIGNOR-127618	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000130								16778989	t	inferred from 70% family members	gcesareni	Inhibitors of the erk1/2 pathway abrogated gm-csf-induced phosphorylation of ser345, while p38 mapk inhibitor abrogated tnf-alpha-induced phosphorylation of ser345.These results show that the ala-mutated p47phox acts as a dominant-negative inhibitor of endogenous p47phox and clearly indicate that phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells.	SIGNOR-270187	0.2
GSK3B	protein	P49841	UNIPROT	SFPQ	protein	P23246	UNIPROT	down-regulates	phosphorylation	Thr687	PRGMGPGtPAGYGRG	9606									20932480	t		lperfetto	We conclude that t687 is the primary site of threonine phosphorylation in psf. Gsk3 directly phosphorylates the splicing regulatory protein psf. In this phosphorylated form, psf is sequestered in a complex with trap150, precluding it from binding the ess1 sequence in cd45 alternatively spliced exons. Upon t?_Cell stimulation, reduced gsk3 activity leads to reduced psf phosphorylation, thereby releasing psf from trap150 and allowing it to participate in activation-induced cd45 exon skipping	SIGNOR-168389	0.351
PRKCA	protein	P17252	UNIPROT	IL2RA	protein	P01589	UNIPROT	unknown	phosphorylation	Thr271	RQRKSRRtI	9606	BTO:0000782								2303462	t		lperfetto	The interleukin-2 (il-2) receptor, the leukocyte-specific membrane glycoprotein, t200, and the class i major histocompatibility antigens (hla) have been identified as substrates for protein kinase c from these studies, it was concluded that ser-247 is the major site of phosphorylation in the il-2 receptor and that thr-250 is a minor site.	SIGNOR-22988	0.267
DUSP5	protein	Q16690	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	dephosphorylation			9606									20626350	t		gcesareni	The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues.	SIGNOR-166574	0.53
CDK2	protein	P24941	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser249	EGGKSGKsPRRRAAS	9606									17038621	t		lperfetto	Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1.	SIGNOR-252892	0.638
PRKCA	protein	P17252	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation	Ser43	FGYQRRAsDDGKLTD	9606									7935389	t		gcesareni	Pka can inhibit raf-1 function directly via phosphorylation of the raf-1 kinase domain	SIGNOR-34761	0.538
CTNNB1	protein	P35222	UNIPROT	TRRAP	protein	Q9Y4A5	UNIPROT	up-regulates	binding			9606									16510874	t		gcesareni	The beta-cat c-terminal activation domain associates with trrap/tip60 and mixed-lineage-leukemia (mll1/mll2) set1-type chromatin-modifying complexes in vitro, and we show that beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo.	SIGNOR-144966	0.561
EEF1A2	protein	Q05639	UNIPROT	Val-tRNA(Val)	smallmolecule	CHEBI:29164	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269539	0.8
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGA4	protein	Q9Y5G9	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265675	0.2
NPNT	protein	Q6UXI9	UNIPROT	Myoblast_fusion	phenotype	SIGNOR-PH98	SIGNOR	up-regulates				9606									23612709	f		miannu	The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 	SIGNOR-255458	0.7
TNKS2	protein	Q9H2K2	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates quantity by destabilization	ADP-ribosylation			9606									19759537	t		lperfetto	Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin.	SIGNOR-263378	0.693
DNAJC3	protein	Q13217	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								25329545	t		gcesareni	The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK	SIGNOR-246207	0.62
ASAP2	protein	O43150	UNIPROT	ARF1	protein	P84077	UNIPROT	up-regulates activity	gtpase-activating protein			-1									10022920	t		miannu	Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain.  In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6.  Pap protein exhibits Arf GAP activity in vitro. 	SIGNOR-269705	0.641
CCNT1	protein	O60563	UNIPROT	P-TEFb	complex	SIGNOR-C238	SIGNOR	form complex	binding			-1									34955012	t		lperfetto	Cyclin-dependent-kinases (CDKs) are members of the serine/threonine kinase family and are highly regulated by cyclins, a family of regulatory subunits that bind to CDKs. CDK9 represents one of the most studied examples of these transcriptional CDKs. CDK9 forms a heterodimeric complex with its regulatory subunit cyclins T1, T2 and K to form the positive transcription elongation factor b (P-TEFb). 	SIGNOR-267739	0.964
SP1	protein	P08047	UNIPROT	KRT16	protein	P08779	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000552								12954631	f	 	miannu	 these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter.	SIGNOR-253903	0.2
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1948	SPTSPGYsPTSPTYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203608	0.77
CDK4	protein	P11802	UNIPROT	PRDX1	protein	Q06830	UNIPROT	down-regulates	phosphorylation	Thr90	CHLAWVNtPKKQGGL	9606	BTO:0000567								11986303	t		lperfetto	Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown).	SIGNOR-87105	0.227
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Ser65	FLMECRNsPVTKTPP	9606									23486913	t		lperfetto	These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation	SIGNOR-217137	0.753
NLGN4Y	protein	Q8NFZ3	UNIPROT	NRXN3	protein	Q9Y4C0	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264163	0.2
ZAP70	protein	P43403	UNIPROT	LAT	protein	O43561	UNIPROT	up-regulates activity	phosphorylation	Tyr220	SLDGSREyVNVSQEL	9606									11368773	t		lperfetto	In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127.	SIGNOR-247030	0.762
JAK2	protein	O60674	UNIPROT	TET2	protein	Q6N021	UNIPROT	up-regulates activity	phosphorylation	Tyr1964	HETSEPTyLRFIKSL	-1									30944118	t		miannu	Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin. 	SIGNOR-277289	0.43
PTEN	protein	P60484	UNIPROT	SL1 complex	complex	SIGNOR-C464	SIGNOR	down-regulates quantity by destabilization													16055704	f		lperfetto	PTEN represses RNA Polymerase I transcription by disrupting the SL1 complex	SIGNOR-269645	0.282
FKBP15	protein	Q5T1M5	UNIPROT	ACTB	protein	P60709	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								19121306	t		Giulio	However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin.	SIGNOR-260595	0.2
chelerythrine	chemical	CHEBI:78373	ChEBI	BCL2L1	protein	Q07817	UNIPROT	down-regulates	chemical inhibition			9606									12702731	t		gcesareni	Chelerythrine inhibited the bclxl-bak bh3 peptide binding with ic50 of 1.5 micro m and displaced bax, a bh3-containing protein, from bclxl.	SIGNOR-100670	0.8
TAF2	protein	Q6P1X5	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263931	0.881
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser326	PPKMWKTsPDPSPVS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252335	0.635
TRPM6	protein	Q9BX84	UNIPROT	H2AC11	protein	P0C0S8	UNIPROT	down-regulates activity	phosphorylation	Ser2	sGRGKQGG	-1									15010469	t		miannu	We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1. 	SIGNOR-276008	0.2
DMC1	protein	Q14565	UNIPROT	SYCP3	protein	Q8IZU3	UNIPROT	up-regulates activity	binding			10090	BTO:0001275			SIGNOR-C351					10525529	t		miannu	The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process.	SIGNOR-264206	0.395
SPTAN1	protein	Q13813	UNIPROT	Membrane_blebbing	phenotype	SIGNOR-PH24	SIGNOR	up-regulates				9606									9624143	f	Cleaved by CASP3	amattioni	A-fodrin cleavage contributes to blebbing	SIGNOR-57897	0.7
GNRHR	protein	P30968	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257064	0.252
MAPK1	protein	P28482	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates activity	phosphorylation	Ser324	RDLELPLsPSLLGGP	10090	BTO:0000944								7889942	t		lperfetto	We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-235459	0.544
CSNK2A1	protein	P68400	UNIPROT	CDC37	protein	Q16543	UNIPROT	up-regulates activity	phosphorylation	Ser13	VWDHIEVsDDEDETH	-1									12930845	t		llicata	Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. | In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site. 	SIGNOR-250838	0.406
PRKCA	protein	P17252	UNIPROT	CSNK1D	protein	P48730	UNIPROT	up-regulates activity	phosphorylation	Thr176	ENKNLTGtARYASIN	-1									31096047	t		miannu	In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity.	SIGNOR-277450	0.2
MTOR	protein	P42345	UNIPROT	AKT1S1	protein	Q96B36	UNIPROT	down-regulates activity	phosphorylation	Ser212	EENGPPSsPDLDRIA	-1			SIGNOR-C3	SIGNOR-C3					18372248	t		lperfetto	In this study, we used two-dimensional phosphopeptide mapping in conjunction with mutational analysis to show that in addition to ser-183, mtorc1 also phosphorylates ser-212 and ser-221 in pras40 when assayed in vitro.	SIGNOR-178124	0.901
E2F1	protein	Q01094	UNIPROT	TFDP1	protein	Q14186	UNIPROT	up-regulates activity	binding			10029									8832394	t	2	miannu	The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3.	SIGNOR-240547	0.806
SGK1	protein	O00141	UNIPROT	NCSTN	protein	Q92542	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser437	FLRARNIsGVVLADH	9606	BTO:0000007								22590650	t		miannu	SGK1 directly bound to and phosphorylated NCT on Ser437, thereby promoting protein degradation.	SIGNOR-276415	0.345
PIGF	protein	Q07326	UNIPROT	PIGG	protein	Q5H8A4	UNIPROT	up-regulates quantity by stabilization	binding			10029	BTO:0000246								15632136	t		miannu	We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O.	SIGNOR-261358	0.63
AKT1	protein	P31749	UNIPROT	DAB2IP	protein	Q5VWQ8	UNIPROT	down-regulates activity	phosphorylation	Ser971	STRLRQQsSSSKGDS	9606									27858941	t		miannu	DAB2IP can be phosphorylated by RIP1 on Ser 604 within the PER domain, and by AKT1 on Ser 847 within the proline-rich domain. Although RIP1-mediated phosphorylation is stimulatory,40 a recent study reported that AKT-mediated phosphorylation inhibits DAB2IP functions	SIGNOR-254780	0.512
MYF6	protein	P23409	UNIPROT	DES	protein	P17661	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									8382796	t		lperfetto	Desmin, the muscle specific intermediate filament (IF) protein, is expressed at low levels in myoblasts and at the onset of differentiation its expression increases several fold. In an effort to explore the mechanism involved in the tissue-specific and developmentally regulated expression of desmin, we have isolated the mouse desmin gene.Co-transfection of myoD, myogenin, MRF4 and Myf5, with the desmin-CAT construct into 10T-1/2 cells demonstrated that all these factors could transactivate desmin gene expression	SIGNOR-241497	0.244
PARD6A	protein	Q9NPB6	UNIPROT	PARD6/SMURF1	complex	SIGNOR-C112	SIGNOR	form complex	binding			9606	BTO:0004183								15761148	t		lperfetto	The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT.	SIGNOR-227559	0.623
PRKCA	protein	P17252	UNIPROT	CSNK1D	protein	P48730	UNIPROT	up-regulates activity	phosphorylation	Ser53 	HPQLHIEsKIYKMMQ	-1									31096047	t		miannu	In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity.	SIGNOR-277451	0.2
GATA6	protein	Q92908	UNIPROT	RARB	protein	P10826	UNIPROT	up-regulates quantity by expression				9606	BTO:0000195								24317510	f		lperfetto	Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. 	SIGNOR-253154	0.297
ZNF91	protein	Q05481	UNIPROT	FCGR3B	protein	O75015	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002269								11470777	t		Luana	Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription.	SIGNOR-266215	0.2
NF1	protein	P21359	UNIPROT	HRAS	protein	P01112	UNIPROT	down-regulates activity				9606									19777070	t			NF1 negatively regulates Ras as an exchangefactor converting Ras-GTP to Ras-GDP by its GTPase-activating (Ras-GAP) domain.	SIGNOR-256067	0.807
FOXO3	protein	O43524	UNIPROT	FBXO32	protein	Q969P5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15109499	f		lperfetto	Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers.	SIGNOR-232174	0.451
SRC	protein	P12931	UNIPROT	BAIAP2L1	protein	Q9UHR4	UNIPROT	up-regulates activity	phosphorylation	Tyr163	YEHKEIEyVETVTSR	-1									21840312	t		miannu	Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility.	SIGNOR-263038	0.399
ARHGAP11B	protein	Q3KRB8	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260467	0.48
FLT3	protein	P36888	UNIPROT	FLT3	protein	P36888	UNIPROT	unknown	phosphorylation	Tyr955	ADAEEAMyQNVDGRV	10090	BTO:0001516								16627759	t		lperfetto	In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated.	SIGNOR-271923	0.2
MEF2C	protein	Q06413	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates				9606		BTO:0000887;BTO:0001103							10082551	f		lperfetto	During embryogenesis, the MEF2 genes are expressed throughout developing skeletal and cardiac muscle lineages, as well as in the nervous system (19, 42, 65, 68).MEF2C is the first member of the family to be expressed in developing muscle cell lineages, with transcripts appearing in precardiac cells by about embryonic day 7.75 and in skeletal muscle precursor cells within the myotome of the developing somites by embryonic day 8.5. Soon thereafter, the other MEF2 genes are expressed in overlapping patterns (19). After birth, the expression of MEF2A, -B, and -Dbecomes ubiquitous, whereas the expression of MEF2C becomes restricted to skeletal muscle, brain, and spleen	SIGNOR-219368	0.7
CDK1	protein	P06493	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Ser434	SFEPKIRsPRRFIGS	9606	BTO:0000567								9271440	t		gcesareni	The activation of p70s6k is associated with multiple phosphorylations at two sets of sites. The first set, s411, s418, t421, and s424, reside within the autoinhibitory domain, mutations of s371 abolished kinase activity. In mitotic hela cells, when the activity of cdc2 is high, s6k1 is phosphorylated at multiple ser/thr, pro (s/tp) sites, including ser(371), ser(411), thr(421), and ser(424).	SIGNOR-50607	0.392
INS	protein	P01308	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity				10116									15069075	f		lperfetto	The mechanism by which the phosphorylation of ser307 or ser318 inhibits irs-1 tyrosine phosphorylation is not known. Prolonged insulin-stimulation inhibits irs-1 binding to the phosphorylated npey motif in the juxta-membrane region of the irbeta -subunit.	SIGNOR-236625	0.67
PDPK1	protein	O15530	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	up-regulates	phosphorylation	Ser227	DHEKKAYsFCGTVEY	9606									19956600	t		gcesareni	We characterize two monoclonal antibodies raised against phosphorylated forms of the n- and c-terminal domain of rsk2 (p-s227 and p-t577, respectively). Using these two antibodies, we show that stress signals, such as uv light, induce phosphorylation and activation of the three rsks.	SIGNOR-161924	0.639
EEF1B complex	complex	SIGNOR-C460	SIGNOR	EEF1A1	protein	P68104	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. 	SIGNOR-269387	0.918
5-azacytidine	chemical	CHEBI:2038	ChEBI	DNMT1	protein	P26358	UNIPROT	down-regulates activity	chemical inhibition			9606									14585280	t		miannu	Both Azacitidine and Decitabine may also exert antitumor activity through induction of DNA hypomethylation, by forming a covalent complex with the major DNA methyltransferase (now termed DNMT1).Azacitidine and Decitabine effectively deplete the cell of functional DNA methylating activity, which results in profound hypomethylation after several rounds of DNA replication (Fig. 2). DNMT1 is considered a bona fide anticancer target at different levels 	SIGNOR-259293	0.8
DACH2	protein	Q96NX9	UNIPROT	MYOG	protein	P15173	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000165								17075071	t		Luana	We confirmed Dach2 is a Mgn transcriptional repressor that mediates HDAC-dependent regulation by (i) overexpressing Dach2 in myotubes harboring the 133-bp Mgn promoter and (ii) rescuing TSA-mediated Mgn repression by Dach2 knockdown.	SIGNOR-261579	0.376
L-tyrosine zwitterion	smallmolecule	CHEBI:58315	ChEBI	3-iodo-L-tyrosine	smallmolecule	CHEBI:27847	ChEBI	up-regulates quantity	precursor of			9606									16098474	t		scontino	TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. 	SIGNOR-266955	0.8
INTS4	protein	Q96HW7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	binding			9606									16239144	t		miannu	The Integrator Complex Can Directly Associate with the C-Terminal Domain of RNA Polymerase II Largest Subunit	SIGNOR-261185	0.523
RPS6KA5	protein	O75582	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									15994958	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-138483	0.2
AXIN1	protein	O15169	UNIPROT	SMAD7	protein	O15105	UNIPROT	down-regulates	binding			9606									16601693	t		gcesareni	Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia.	SIGNOR-145851	0.7
TEC	protein	P42680	UNIPROT	BMX	protein	P51813	UNIPROT	up-regulates activity	phosphorylation	Tyr216	SSTSLAQyDSNSKKI	9606	BTO:0000873								12573241	t		lperfetto	Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.The major phosphorylation sites were identified as conserved tyrosines, for Itk Y180 and for Bmx Y215, both sites being homologous to the Y223 site in Btk	SIGNOR-246647	0.337
LY-2157299	chemical	CHEBI:137064	ChEBI	TGFBR1	protein	P36897	UNIPROT	down-regulates	chemical inhibition			9606									18039567	t		gcesareni	Ly2157299, a new type i receptor tgf-beta kinase antagonist, was	SIGNOR-159354	0.8
CHEK2	protein	O96017	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates	phosphorylation	Thr288	SPDCDVKtDDSVVPC	9606									19151762	t		llicata	Phosphorylation at ttk/hmps1 thr288 is enhanced by chk2 in vitro and in vivo after ir	SIGNOR-242665	0.296
PLK1	protein	P53350	UNIPROT	TPT1	protein	P13693	UNIPROT	down-regulates	phosphorylation	Ser64	PEGEGTEsTVITGVD	9606									12167714	t		lperfetto	Plk phosphorylates tctp on two serine residues. These results suggest that phosphorylation decreases the microtubule-stabilizing activity of tctp and promotes the increase in microtubule dynamics that occurs after metaphase	SIGNOR-91348	0.705
TPO	protein	P07202	UNIPROT	diiodine	smallmolecule	CHEBI:17606	ChEBI	up-regulates quantity	chemical modification			9606									28153798	t		scontino	TPO is considered the key enzyme in thyroid hormonogenesis. It catalyzes the oxidation of iodide that is necessary for the iodinationof the TG tyrosyl residues (the organification reaction).	SIGNOR-266959	0.8
PRKACA	protein	P17612	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	down-regulates activity	phosphorylation	Ser491	SSTPQRSCsAAGLHRPR	10116	BTO:0002135								17023420	t			These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine.	SIGNOR-256112	0.401
CASP3	protein	P42574	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates	cleavage	Asp78	PNVVAARdVPEGMQN	9606									11741536	t		gcesareni	Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis.	SIGNOR-112800	0.373
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CKAP2	protein	Q8WWK9	UNIPROT	up-regulates	phosphorylation	Thr623	FKELKFLtPVRRSRR	9606									19369249	t		lperfetto	Among these, thr-622 was specifically phosphorylated by cdk1-cyclin b1 both in vitro and in vivo. these findings suggest that cdk1-cyclin b1-mediated phosphorylation of tmap is important for and contributes to proper regulation of microtubule dynamics and establishment of functional bipolar spindles during mitosis.	SIGNOR-216829	0.299
TFEB	protein	P19484	UNIPROT	SACM1L	protein	Q9NTJ5	UNIPROT	up-regulates quantity by expression	transcriptional regulation												30145926	f		lperfetto	Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 	SIGNOR-276801	0.2
AURKA	protein	O14965	UNIPROT	PARD3	protein	Q8TEW0	UNIPROT	up-regulates	phosphorylation	Ser962	SSRSGREsVSTASDQ	9606	BTO:0000938								19812038	t		llicata	Aurora a interacts directly with the atypical protein kinase c binding domain of par3 and phosphorylates it at serine 962. The phosphorylation of par3 at serine 962 contributes to its function in the establishment of neuronal polarity.	SIGNOR-188398	0.358
cyclosporin A	chemical	CHEBI:4031	ChEBI	PPP3CB	protein	P16298	UNIPROT	down-regulates	chemical inhibition			9606									15276472	t		gcesareni	Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins.	SIGNOR-127228	0.8
HJURP	protein	Q8NCD3	UNIPROT	CENPA	protein	P49450	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								19410544	t		miannu	Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURP. Recruitment of new CENP-A into nucleosomes at replicated centromeres is dependent on HJURP. Recognition by HJURP is mediated through the centromere targeting domain (CATD) of CENP-A, a region that we demonstrated previously to induce a unique conformational rigidity to both the subnucleosomal CENP-A heterotetramer and the corresponding assembled nucleosome. We propose HJURP to be a cell-cycle-regulated CENP-A-specific histone chaperone required for centromeric chromatin assembly.	SIGNOR-263707	0.958
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr18	EPPLSQEtFSDLWKL	9606									10656682	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-74839	0.784
lapatinib	chemical	CHEBI:49603	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150								22056878	t	Lapatinib (INN), used in the form of lapatinib ditosylate, (USAN) (Tykerb/Tyverb, GSK) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways.	gcesareni	In estrogen-receptor-negative cellular models showing coamplification of erbb2 and rara, simultaneous targeting of the corresponding gene products with combinations of lapatinib and atra causes synergistic growth inhibition, cyto-differentiation and apoptosis.	SIGNOR-177081	0.8
BACE2	protein	Q9Y5Z0	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Phe634	VHHQKLVfFAEDVGS	9606									10931940	t		lperfetto	BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating α- and β-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform.	SIGNOR-261773	0.561
WNT3A	protein	P56704	UNIPROT	FZD8	protein	Q9H461	UNIPROT	up-regulates	binding			9606									22653731	t		gcesareni	Structural basis of wnt recognition by frizzled.	SIGNOR-197638	0.79
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CDC25A	protein	P30304	UNIPROT	up-regulates	phosphorylation	Ser116	PQKLLGCsPALKRSH	9606									12411508	t		lperfetto	Mitotic stabilization of cdc25a reflects its phosphorylation on ser17 and ser115 by cyclin b-cdk1, modifications required to uncouple cdc25a from its ubiquitin-proteasome-mediated turnover.	SIGNOR-216761	0.843
MST1	protein	P26927	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates activity	phosphorylation	Ser226	LNPQWNEsFTFKLKP	9606	BTO:0002181								26414765	t		miannu	Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα. 	SIGNOR-277179	0.2
AKT2	protein	P31751	UNIPROT	ATP7A	protein	Q04656	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser1463	IVNYSRAsINSLLSD	10090									29301787	t		lperfetto	Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466	SIGNOR-272268	0.263
CTDSP2	protein	O14595	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	dephosphorylation	Ser214	PTSSDPGsPFQMPAD	9606	BTO:0000552								17085434	t			Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)	SIGNOR-248303	0.477
IL7	protein	P13232	UNIPROT	IL7R	protein	P16871	UNIPROT	up-regulates	binding			9606	BTO:0002314	BTO:0000887;BTO:0001103;BTO:0001760							20089933	t		milica	This receptor (il-7r) is a heterodimer consisting of the il-7r chain and the common cytokine ? -chain.	SIGNOR-163548	0.912
PTK2	protein	Q05397	UNIPROT	SH3GL1	protein	Q99961	UNIPROT	unknown	phosphorylation	Tyr315	QPSCKALyDFEPEND	9606									16054026	t		llicata	These results identified y315 of endophilin a2 as a major phosphorylation site by fak/src complex. tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp.	SIGNOR-139146	0.41
ACTB	protein	P60709	UNIPROT	Muscle cell-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C483	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex.	SIGNOR-270739	0.496
MAPK12/CARM1	complex	SIGNOR-C218	SIGNOR	SNTB1	protein	Q13884	UNIPROT	up-regulates activity	binding												29681515	t		apalma	Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated	SIGNOR-255978	0.376
CEBPB	protein	P17676	UNIPROT	GFER	protein	P55789	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								20690902	f		miannu	 In the present study, we investigated transcription of hHSS triggered by EGF (epidermal growth factor) and the role of C/EBPβ (CCAAT/enhancer-binding protein β) as a potential core factor responsible for hHSS transcription in HepG2 cells. The results show that EGF suppresses hHSS mRNA expression at early time points. Using a promoter deletion assay, we identified a proximal region (-358/-212) that is required for EGF suppression. Overexpression of C/EBPβ enhances EGF suppression of hHSS, and mutation of the C/EBPβ-binding site at -292/-279 or siRNA (short interfering RNA) interference abolishes EGF suppression.	SIGNOR-253772	0.2
FNTA	protein	P49354	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates activity				9606									24294527	t		lperfetto	Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials.	SIGNOR-242568	0.423
HDAC2	protein	Q92769	UNIPROT	TWIST1	protein	Q15672	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001939								23836662	f	 	miannu	 We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes.	SIGNOR-254154	0.389
SRC	protein	P12931	UNIPROT	NOXA1	protein	Q86UR1	UNIPROT	up-regulates	phosphorylation	Tyr110	RGHAAIDyTQLGLRF	9606									20943948	t		llicata	Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation.	SIGNOR-168545	0.419
MAPK8	protein	P45983	UNIPROT	BCL2L11	protein	O43521	UNIPROT	up-regulates activity	phosphorylation	Ser77	PGPFATRsPLFIFMR	10090									12818176	t		miannu	Mitochondrially localized JNKs but not their upstream activators MLKs or MKKs phosphorylated BIMEL at Ser65, potentiating its cytotoxicity without altering its subcellular distribution or integration into mitochondrial membranes. JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73	SIGNOR-250133	0.751
MAPK8	protein	P45983	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity	phosphorylation	Ser87	AAAGPALsPVPPVVH	9606									10567572	t		gcesareni	Jnk1-mediated phosphorylation of bcl-2 regulates starvation-induced autophagy.	SIGNOR-48038	0.564
SGCD	protein	Q92629	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255988	0.505
SRC	protein	P12931	UNIPROT	CTNND1	protein	O60716	UNIPROT	up-regulates activity	phosphorylation	Tyr96	QDHSHLLySTIPRMQ	-1									11382764	t		lperfetto	Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302	SIGNOR-246508	0.92
buprenorphine	chemical	CHEBI:3216	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258769	0.8
MAPK1	protein	P28482	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser363	TSRTPKDsPGIPPSA	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252754	0.751
AMPK	complex	SIGNOR-C15	SIGNOR	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation	Ser317	SHLASPPsLGEMQQL	9606									19584320	t		lperfetto	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-216491	0.469
PRKCD	protein	Q05655	UNIPROT	SHOC2	protein	Q9UQ13	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser297	GLRYNRLsAIPRSLA										29383184	t		lperfetto	PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8.	SIGNOR-275565	0.2
LSM4	protein	Q9Y4Z0	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270650	0.787
CDK19	protein	Q9BWU1	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2516	FLTPSPEsPDQWSSS	-1									25344755	t		lperfetto	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273135	0.307
KDR	protein	P35968	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9606									11278468	t		Gianni	These results demonstrate that activation of VEGFR-2 results in activation of PI3K and that activation of PI3K/S6kinase pathway, but not Ras/MAPK, is responsible for VEGFR-2-mediated cell growth.	SIGNOR-261916	0.553
CDK1	protein	P06493	UNIPROT	CREM	protein	Q03060	UNIPROT	down-regulates quantity	phosphorylation	Ser271	QGVVMAAsPGSLHSP	9606	BTO:0001033								21767532	t		miannu	In this report data is presented demonstrating that ICER is phosphorylated by the mitotic kinase cdk1. Phosphorylation of ICER on a discrete residue targeted ICER to be monoubiquitinated. Different from unphosphorylated, phosphorylated and polyubiquitinated ICER, monoubiquitinated ICER was found to be cytosolic. Taken together, these results hinted on a mechanism for the observed abnormal subcellular localization of ICER in human prostate tumors.	SIGNOR-276346	0.3
ARNTL2	protein	Q8WYA1	UNIPROT	CLOCK/BMAL2	complex	SIGNOR-C196	SIGNOR	form complex	binding												19605937	t	 	lperfetto	Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription	SIGNOR-253710	0.669
SHANK3	protein	Q9BYB0	UNIPROT	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	up-regulates quantity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264700	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Thr179	SSPDKRLtLSQIYEW	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-238813	0.397
BLVRA	protein	P53004	UNIPROT	bilirubin(2-)	smallmolecule	CHEBI:57977	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000759							7929092	t		lperfetto	This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. 	SIGNOR-275520	0.8
TAF8	protein	Q7Z7C8	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269573	0.545
Gluconeogenesis	phenotype	SIGNOR-PH35	SIGNOR	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	up-regulates				9606									12093795	t		miannu	Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis	SIGNOR-267958	0.7
CLOCK	protein	O15516	UNIPROT	PER2	protein	O15055	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f			Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253634	0.767
KDR	protein	P35968	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	binding			9606					phosphorylation:Tyr1175	AQQDGKDyIVLPISE			16835467	t		gcesareni	(vegfr) phosphorylated y1175 creates a binding site for phospholipase cgamma1 (plc-gamma1)	SIGNOR-147870	0.661
PAK2	protein	Q13177	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates activity	phosphorylation	Ser55	KPRHKIIsIFSGTEK	-1									10075701	t		miannu	Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197. 	SIGNOR-250229	0.2
H3C1	protein	P68431	UNIPROT	Nucleosome_H2A.Z.1 variant	complex	SIGNOR-C322	SIGNOR	form complex	binding			-1									24311584	t		miannu	In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined.	SIGNOR-263717	0.2
serine	smallmolecule	CHEBI:17822	ChEBI	Ser-tRNA(Ser)	smallmolecule	CHEBI:29162	ChEBI	up-regulates quantity	precursor of			9606									24095058	t		miannu	As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis	SIGNOR-270500	0.8
HOXD1	protein	Q9GZZ0	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001949								21501586	t		Luana	Consistently, ITGB1 promoter activity was decreased by HOXD1 knockdown in ECs. Furthermore, we identified the putative HOXD1-binding sites in the promoter region of ITGB1. Together, these findings suggest that HOXD1 plays a significant role in EC functions by regulating the expression of ITGB1.	SIGNOR-261648	0.2
AURKA	protein	O14965	UNIPROT	DLGAP5	protein	Q15398	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser627	VKLFSGLsVSSEGPS	9606									15987997	t		miannu	Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life.	SIGNOR-262649	0.741
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	KRT8	protein	P05787	UNIPROT	unknown	phosphorylation												16554440	t	inferred from 70% family members	lperfetto	Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002).	SIGNOR-270135	0.2
JAK1	protein	P23458	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	phosphorylation	Tyr701	DGPKGTGyIKTELIS	-1									7657660	t		lperfetto	Stat1 was phosphorylated at tyr 701 in jak immune complex kinase reaction. The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases.	SIGNOR-30905	0.783
ACO1	protein	P21399	UNIPROT	D-threo-isocitrate(3-)	smallmolecule	CHEBI:15562	ChEBI	up-regulates quantity	chemical modification			9606									24068518	t		miannu	Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained.	SIGNOR-266245	0.8
ATXN2L	protein	Q8WWM7	UNIPROT	MPL	protein	P40238	UNIPROT	down-regulates	binding			9606									11784712	t		miannu	A2d binds to cytokine receptors mpl and epo-r. A2d is associated with these unoccupied receptorsin vivo,and stimulation with tpo or epo causes the rapid dissociation of a2d from the activated receptor.	SIGNOR-113891	0.36
CHUK	protein	O15111	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser923	DELRDSDsVCDSGVE	10090	BTO:0000944		SIGNOR-C14	SIGNOR-C13					11297557	t		lperfetto	The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk.	SIGNOR-235434	0.737
PRKCZ	protein	Q05513	UNIPROT	MYH10	protein	P35580	UNIPROT	down-regulates	phosphorylation	Ser1937	RGGPISFsSSRSGRR	9606									16611744	t		lperfetto	After egf stimulation, apkc_ translocates from the nucleus to the cytoplasm (figure 3) and is therefore able to interact with myosin ii-b. apkc_ phosphorylates nmhc ii-b on ser1937, which is located on the nonhelical tailpiece, leading to filament disassembly at certain sites of the cell	SIGNOR-146100	0.272
GFI1	protein	Q99684	UNIPROT	CYP27B1	protein	O15528	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15947108	f	 	miannu	Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells.	SIGNOR-254205	0.2
phentolamine	chemical	CHEBI:8081	ChEBI	ADRA1D	protein	P25100	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258444	0.8
TRAF2	protein	Q12933	UNIPROT	BIRC2	protein	Q13490	UNIPROT	up-regulates activity	binding			9606									8548810	t		lperfetto	The c-iaps associate with traf1 and traf3	SIGNOR-39527	0.868
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1619	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-119992	0.781
PRKAA1	protein	Q13131	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation	Ser621	PKINRSAsEPSLHRA	9606			SIGNOR-C15						9091312	t		gcesareni	Ampk also phosphorylated full-length, kinase-defective raf-1 (k375m) to generate two [32p]phosphopeptides, one co-migrating with synthetic tryptic peptide containing phospho-ser621 and the other with phospho-ser259. The catalytic subunit of PKA also phosphorylated Ser621 in vitro, while its overexpression in intact cells resulted in increased phosphorylation of Ser621 and decreased activity of Raf-1. These results suggest that phosphorylation of Ser621 inactivates Raf-1, but do not prove that PKA is responsible for this in vivo.	SIGNOR-47148	0.348
KIF11	protein	P52732	UNIPROT	Spindle_assembly	phenotype	SIGNOR-PH60	SIGNOR	up-regulates				9606									21969468	f		lperfetto	The C-terminal fragment interferes with the TPX2–Eg5 interaction, relieving the inhibition of TPX2 on Eg5 and generating the observed spindle lengthening. According to this model, TPX2 and Eg5 should localize to microtubules in the spindle midzone.	SIGNOR-265098	0.7
LGALS3	protein	P17931	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	up-regulates quantity by stabilization				9606	BTO:0000664								21821001	f		miannu	Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells.	SIGNOR-261906	0.283
IL17R complex	complex	SIGNOR-C260	SIGNOR	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates activity				10090	BTO:0000944								8777726	f		lperfetto	3T3 cells were preincubated with an IL-17Rspecific antiserum and then assayed for NF-KB activation by HVS13. Preincubation with the IL-1 7R antiserum dramatically decreased the NF-KB activity induced by HVSl3 as compared with cells preincubated with an irrelevant rat antiserum (Figure 5C). This result indicated that the engagement of the IL-17R by its ligands induced NF-KB activity.	SIGNOR-261338	0.2
RAB9A	protein	P51151	UNIPROT	PLIN3	protein	O60664	UNIPROT	up-regulates activity													18195106	t		lperfetto	Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector	SIGNOR-253089	0.573
TYK2	protein	P29597	UNIPROT	DUSP3	protein	P51452	UNIPROT	up-regulates	phosphorylation	Tyr138	SPTLVIAyLMMRQKM	9606									17785772	t		lperfetto	Phosphorylation of vhr at tyr(138) was required for its phosphatase activity toward stat5. In addition, the src homology 2 domain of stat5 was required for the effective dephosphorylation of stat5 by vhr. The tyrosine kinase tyk2, which mediates the phosphorylation of stat5, was also responsible for the phosphorylation of vhr at tyr(138).	SIGNOR-157655	0.268
MDM2	protein	Q00987	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									23150757	t		lperfetto	Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity	SIGNOR-199371	0.968
TFE3	protein	P19532	UNIPROT	RRAGC	protein	Q9HB90	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276827	0.344
DIP2A	protein	Q14689	UNIPROT	SOD2	protein	P04179	UNIPROT	up-regulates activity	binding			10090	BTO:0000142								33781892	t		miannu	DIP2a is associated with SOD in the mitochondria of mouse brain. DIP2a knockout inhibited SOD activity. In this paper, we analyzed the interacting proteins of DIP2A by mass spectrum analysis and found that DIP2A was correlated with superoxide dismutase (SOD), SOD1 and SOD2. Knockout of DIP2A decreased SOD activity and increased the level of ROS in the mouse brain. 	SIGNOR-266592	0.2
KAT8	protein	Q9H7Z6	UNIPROT	NSL histone acetyltransferase	complex	SIGNOR-C413	SIGNOR	form complex	binding			9606	BTO:0000007								20018852	t		miannu	Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex.	SIGNOR-267160	0.638
COX7A2	protein	P14406	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267741	0.499
RAP1GDS1	protein	P52306	UNIPROT	RAP1B	protein	P61224	UNIPROT	up-regulates	binding			9606									21242305	t		miannu	Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob	SIGNOR-171552	0.423
EIF2AK2	protein	P19525	UNIPROT	NLRP3 inflammasome	complex	SIGNOR-C225	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								22801494	t		miannu	Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. 	SIGNOR-263119	0.331
FARSB	protein	Q9NSD9	UNIPROT	Phenylalanyl-tRNA synthetase	complex	SIGNOR-C473	SIGNOR	form complex	binding			9606									20223217	t		miannu	Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers.	SIGNOR-270435	0.994
AMPK	complex	SIGNOR-C15	SIGNOR	YAP1	protein	P46937	UNIPROT	down-regulates activity	phosphorylation	Ser94	RLRKLPDsFFKPPEP	9606	BTO:0002181								25751140	t		miannu	Moreover, AMPK directly phosphorylates YAP Ser 94, a residue essential for the interaction with TEAD, thus disrupting the YAP-TEAD interaction.	SIGNOR-277638	0.303
EIF3F	protein	O00303	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	deubiquitination			9606									21124883	t		gcesareni	The activated form of notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. The enzyme accounting for this deubiquitinase activity is eif3f, known so far as a translation initiation factor.	SIGNOR-254327	0.431
ATM	protein	Q13315	UNIPROT	EZH2	protein	Q15910	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser729	LFFDYRYsQADALKY	-1									24162653	t		miannu	Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is a new ATM kinase target, and ATM-mediated phosphorylation of EZH2 on Ser734 reduces protein stability. 	SIGNOR-276602	0.472
SMAD3	protein	P84022	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates activity	binding			10090									12524424	t		gcesareni	Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters	SIGNOR-241924	0.383
AURKB	protein	Q96GD4	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									10464286	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.	SIGNOR-70420	0.2
SMAD1/4	complex	SIGNOR-C85	SIGNOR	DLX5	protein	P56178	UNIPROT	up-regulates	transcriptional regulation			10090	BTO:0000165								12815054	f		ggiuliani	Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining 	SIGNOR-255789	0.308
zinc(2+)	chemical	CHEBI:29105	ChEBI	BRCA1-C complex	complex	SIGNOR-C299	SIGNOR	form complex	binding												25400280	t		lperfetto	The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2	SIGNOR-269478	0.8
HMGB2	protein	P26583	UNIPROT	GFI1B	protein	Q5VTD9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19965638	f	 	miannu	HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. 	SIGNOR-254429	0.2
JAK2	protein	O60674	UNIPROT	STAT4	protein	Q14765	UNIPROT	up-regulates	phosphorylation	Tyr693	TERGDKGyVPSVFIP	9606	BTO:0000782								16324152	t		gcesareni	Janus family tyrosine kinases jak2 and tyk2, which in turn phosphorylate stat4 on tyrosine 693. The p38 mitogen-activated protein kinase (mapk) signaling pathway is also activated in response to il-12, followed by phosphorylation of stat4 on serine 721, which is required for stat4 full transcriptional activity	SIGNOR-142736	0.664
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates	phosphorylation			9606									10197981	t		lperfetto	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3	SIGNOR-66778	0.739
ELOVL3	protein	Q9HB03	UNIPROT	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267893	0.8
RNF146	protein	Q9NTX7	UNIPROT	RNF146	protein	Q9NTX7	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								21799911	t			We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation.	SIGNOR-260006	0.2
TUT7	protein	Q5VYS8	UNIPROT	mRNA_polyadenylation	phenotype	SIGNOR-PH200	SIGNOR	down-regulates													25480299	f		lperfetto	Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. Consistently, purified TUT4/7 selectively recognize and uridylate RNAs with short A-tails (less than ∼ 25 nt) in vitro. PABPC1 antagonizes uridylation of polyadenylated mRNAs, contributing to the specificity for short A-tails. 	SIGNOR-268345	0.7
OXSR1	protein	O95747	UNIPROT	SLC12A2	protein	P55011	UNIPROT	up-regulates	phosphorylation	Thr203	HQHYYYDtHTNTYYL	9606									12145304	t		gcesareni	The secretory na-k-cl cotransporter nkcc1 is activated by secretagogues through a phosphorylation-dependent mechanism. three phosphoacceptor sites were identified in the n-terminal domain of the protein (at thr184, thr189, and thr202) none of these residues occurs in the context of strong consensus sites for known ser/thr kinases.	SIGNOR-90927	0.54
MAPK3	protein	P27361	UNIPROT	MED1	protein	Q15648	UNIPROT	up-regulates	phosphorylation	Thr1457	HSKSPAYtPQNLDSE	9606									12356758	t		lperfetto	Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase	SIGNOR-93993	0.267
PRKCA	protein	P17252	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates activity	phosphorylation	Ser185	SAYVGRLsARPKLKA	-1									15604283	t		miannu	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276025	0.2
CMA1	protein	P23946	UNIPROT	EDN1	protein	P05305	UNIPROT	up-regulates activity	cleavage	Tyr83	TPEHVVPyGLGSPRS	9606	BTO:0000830								9257865	t		miannu	Chymase from human mast cells selectively cleaved big endothelins (ETs) at the Tyr31-Gly32 bond and produced novel trachea-constricting 31-amino acid-length endothelins, ETs(1-31), without any further degradation products.	SIGNOR-256356	0.485
LCK	protein	P06239	UNIPROT	ACP1	protein	P24666	UNIPROT	up-regulates activity	phosphorylation	Tyr133	LIIEDPYyGNDSDFE	9534									9038134	t			In co-transfected COS cells, Lck and Fyn caused phosphorylation of LMPTP. Most of the phosphate was located at Tyr-131, and some was also located at Tyr-132. Site-directed mutagenesis showed that Tyr-131 is important for the catalytic activity of LMPTP, and that thiophosphorylation of Tyr-131, and to a lesser degree Tyr-132, is responsible for the activation.	SIGNOR-251367	0.361
SIK3	protein	Q9Y2K2	UNIPROT	CRTC2	protein	Q53ET0	UNIPROT	down-regulates activity	phosphorylation	Ser348	PSLQSSLsNPNLQAS	9606	BTO:0000567								16306228	t		lperfetto	We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression 	SIGNOR-249170	0.62
TFE3	protein	P19532	UNIPROT	WIPI1	protein	Q5MNZ9	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells	SIGNOR-276830	0.308
pazopanib	chemical	CHEBI:71219	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001949								18620382	t		Luana	Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively.	SIGNOR-257734	0.8
F2R	protein	P25116	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257293	0.414
GOT1	protein	P17174	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	down-regulates quantity	chemical modification			9606									26003525	t		miannu	Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and α-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer.	SIGNOR-268063	0.8
RAB6A	protein	P20340	UNIPROT	VPS13B	protein	Q7Z7G8	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								25492866	t		miannu	Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 Golgi Localization Is Mediated by Active RAB6 . COH1 Interacts with All Three Mammalian RAB6 Homologues	SIGNOR-269203	0.381
PROX1	protein	Q92786	UNIPROT	IFNG	protein	P01579	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20064070	f	 	 	Human PROX1 is involved in biologic functions closely tied to HIV infection, most notably as a negative regulator of interferon (IFN) gamma expression in T cells	SIGNOR-254506	0.262
PAX2	protein	Q02962	UNIPROT	Urogenital_tract	phenotype	SIGNOR-PH71	SIGNOR	up-regulates activity				10090									8575306	f			Pax-2 is required for multiple steps during the differentiation of intermediate mesoderm. In addition, Pax-2 mouse mutants provide an animal model for human hereditary kidney diseases.	SIGNOR-252301	0.7
GABA-A (a6-b2-d) receptor	complex	SIGNOR-C328	SIGNOR	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	relocalization			9606									18790874	t	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263816	0.8
KPNA6	protein	O60684	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	relocalization			9606									20454918	t		gcesareni	Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling.	SIGNOR-165343	0.2
FOXO6	protein	A8MYZ6	UNIPROT	FBXO32	protein	Q969P5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							21798082	f		lperfetto	Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome.	SIGNOR-236560	0.282
SRC	protein	P12931	UNIPROT	GAK	protein	O14976	UNIPROT	up-regulates activity	phosphorylation	Tyr412	KGDLDISyITSRIAV	-1									28135906	t		miannu	GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. Cyclin G-associated kinase (GAK) harbors a consensus phosphorylation motif (Y412) for c-Src; however, its physiological significance remains elusive. Here, we show that GAK is phosphorylated by c-Src not only at Y412 but also at Y1149.	SIGNOR-263197	0.278
AMPK	complex	SIGNOR-C15	SIGNOR	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation	Ser556	GLGCRLHsAPNLSDL	9606									19584320	t		lperfetto	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-216495	0.469
UQCRQ	protein	O14949	UNIPROT	Mitochondrial respiratory chain complex III	complex	SIGNOR-C279	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits	SIGNOR-262197	0.923
PTPRE	protein	P23469	UNIPROT	KCNB1	protein	Q14721	UNIPROT	down-regulates activity	dephosphorylation	Tyr128	YWGIDEIyLESCCQA	9606	BTO:0000007								10921884	t			Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon	SIGNOR-248450	0.362
FLT1	protein	P17948	UNIPROT	FLT1	protein	P17948	UNIPROT	up-regulates	phosphorylation	Tyr1333	DYNSVVLySTPPI	9606									9722576	t		lperfetto	Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor.	SIGNOR-59762	0.2
TRIM25	protein	Q14258	UNIPROT	MAVS	protein	Q7Z434	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys7	kTYKYICR	9606	BTO:0000007								22626058	t	K48	miannu	We report here that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling. 	SIGNOR-272041	0.762
HAUS6	protein	Q7Z4H7	UNIPROT	HAUS complex	complex	SIGNOR-C281	SIGNOR	form complex	binding			9606	BTO:0000567								19369198	t		lperfetto	Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)	SIGNOR-262320	0.889
SV2A	protein	Q7L0J3	UNIPROT	SYT1	protein	P21579	UNIPROT	up-regulates quantity	binding			9606	BTO:0000938								26903854	t		miannu	Recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. These cargoes are synaptophysin (for sybII) and SV2A (for synaptotagmin-1). SV2A Acts as an iTRAP to Direct Synaptotagmin-1 Retrieval to SVs.	SIGNOR-264116	0.552
SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	DPPA4	protein	Q7L190	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269235	0.592
MAPKAPK2	protein	P49137	UNIPROT	ZFP36	protein	P26651	UNIPROT	down-regulates activity	phosphorylation	Ser113	TELCRTFsESGRCRY	-1									14688255	t		miannu	We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated.	SIGNOR-250156	0.687
PP2CA_R1A_R2A 	complex	SIGNOR-C132	SIGNOR	DCK	protein	P27707	UNIPROT	down-regulates activity	dephosphorylation	Ser74	EFEELTMsQKNGGNV										24462681	t		lperfetto	Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation	SIGNOR-275804	0.2
DTL	protein	Q9NZJ0	UNIPROT	Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	up-regulates	binding			9606	BTO:0000567								27906959	t		miannu	Here, we identify human SDE2 as a new genome surveillance factor regulated by PCNA interaction. The cleaved SDE2 products need to be degraded by the CRL4CDT2 ubiquitin E3 ligase in a cell cycle- and DNA damage-dependent manner, and failure to degrade SDE2 impairs S phase progression and cellular survival. 	SIGNOR-272808	0.683
SRC	protein	P12931	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates	phosphorylation			9606									9096340	t		gcesareni	Expression of v-src, a transforming nonreceptor tyrosine kinase, results in ras activation, and ras function in nih 3t3 cells suppresses transformation by v-src, indicating that in these cells ras-dependent signaling pathways are required for v-src to exert its biological effects.	SIGNOR-47152	0.645
TFEB	protein	P19484	UNIPROT	PSAP	protein	P07602	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19556463	f	Figure 1	lperfetto	Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 	SIGNOR-276545	0.314
benazepril	chemical	CHEBI:3011	ChEBI	ACE	protein	P12821	UNIPROT	down-regulates activity	chemical inhibition			9606									16407508	t			Angiotensin-converting-enzyme inhibitors provide renal protection in patients with mild-to-moderate renal insufficiency (serum creatinine level, 3.0 mg per deciliter or less). We assessed the efficacy and safety of benazepril in patients without diabetes who had advanced renal insufficiency.	SIGNOR-253343	0.8
haloperidol	chemical	CHEBI:5613	ChEBI	HTR1D	protein	P28221	UNIPROT	down-regulates activity	chemical inhibition			10116									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258522	0.8
MAPK1	protein	P28482	UNIPROT	NDEL1	protein	Q9GZM8	UNIPROT	up-regulates activity	phosphorylation	Thr219	ASLSLPAtPVGKGTE	-1									12556484	t	done	miannu	In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites	SIGNOR-274076	0.292
28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	up-regulates				9606									27023846	f		miannu	Mitochondrial ribosomes (mitoribosomes) perform protein synthesis inside mitochondria, the organelles responsible for energy conversion and adenosine triphosphate production in eukaryotic cells. 	SIGNOR-261487	0.7
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	CEBPB	protein	P17676	UNIPROT	down-regulates activity	transcriptional regulation			9606									17139329	t		fferrentino	Phosphorylation of receptor-regulated SMADs (for example, SMAD1 or SMAD3) stimulates dimer formation with SMAD4 and translocation to the nucleus, where the SMADs regulate the transcription of target gene SMAD3 binds to C/EBPs and inhibits their transcriptional activity, including their ability to transactivate the Pparg2 promoter	SIGNOR-253538	0.561
ABT-737	chemical	CID:11228183	PUBCHEM	BCL2L1	protein	Q07817	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001271;BTO:0000776;BTO:0000785								17200714	t		gcesareni	A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells.	SIGNOR-151784	0.8
NFIX	protein	Q14938	UNIPROT	WNT5A	protein	P41221	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268889	0.2
DRD1	protein	P21728	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257391	0.267
NTRK1	protein	P04629	UNIPROT	NTRK1	protein	P04629	UNIPROT	up-regulates	phosphorylation	Tyr496	HIIENPQyFSDACVH	9606									9099755	t		gcesareni	In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785	SIGNOR-47167	0.2
SLC4A1	protein	P02730	UNIPROT	Ankyrin complex	complex	SIGNOR-C383	SIGNOR	form complex	binding			9606	BTO:0000424								22465511	t		lperfetto	The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) 	SIGNOR-266015	0.416
MDM2	protein	Q00987	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	ubiquitination			9606									23252402	t		gcesareni	Although the interaction between notch1 and mdm2 results in ubiquitination of notch1, this does not result in degradation of notch1, but instead leads to activation of the intracellular domain of notch1.	SIGNOR-200197	0.49
albuterol sulfate	chemical	CHEBI:2550	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-206682	0.8
GALR1	protein	P47211	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256687	0.448
sorafenib	chemical	CHEBI:50924	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258284	0.8
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation			9606		BTO:0000586							16293724	t		lperfetto	Because phosphorylation of β-catenin by GSK-3β leads to its rapid ubiquitination and subsequent degradation in the proteosome, inactivation of GSK-3β is often a prerequisite for stimulating the accumulation, nuclear translocation, and functional activity of β-catenin	SIGNOR-227893	0.892
TNFRSF13C	protein	Q96RJ3	UNIPROT	TRAF3	protein	Q13114	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000776;BTO:0000785								20889926	t		lperfetto	Activation of br3 induces recruitment and degradation of traf3.	SIGNOR-168199	0.749
MAP2K3	protein	P46734	UNIPROT	DYRK1B	protein	Q9Y463	UNIPROT	up-regulates	phosphorylation			9606		BTO:0000887;BTO:0001103							11980910	t		amattioni	Mkk3 enhanced mirk kinase activity. Mkk3 possibly activates mirk by phosphorylating it.	SIGNOR-86731	0.355
GSK3B	protein	P49841	UNIPROT	DPYSL3	protein	Q14195	UNIPROT	up-regulates activity	phosphorylation	Ser518	KGGTPAGsARGSPTR	10116									16611631	t		lperfetto	Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-146003	0.452
CDC42BPA	protein	Q5VT25	UNIPROT	LIMK2	protein	P53671	UNIPROT	up-regulates activity	phosphorylation	Thr505	NDRKKRYtVVGNPYW	9534	BTO:0004055								11340065	t		lperfetto	These results indicate that mrckalpha phosphorylates and activates lim kinases downstream of cdc42, which in turn regulates the actin cytoskeletal reorganization through the phosphorylation and inactivation of adf/cofilin.	SIGNOR-107584	0.403
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation			9606									21880741	t		miannu	Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.	SIGNOR-255463	0.635
ATM	protein	Q13315	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									11875057	t		gcesareni	In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization.	SIGNOR-115340	0.838
CDK5	protein	Q00535	UNIPROT	NDEL1	protein	Q9GZM8	UNIPROT	up-regulates activity	phosphorylation	Ser242	IPNGFGTsPLTPSAR	10090	BTO:0000142								12796778	t		llicata	Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function.	SIGNOR-250677	0.764
PPARA	protein	Q07869	UNIPROT	ACSL1	protein	P33121	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003204								17150915	f		miannu	 To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA.	SIGNOR-255044	0.533
MC3R	protein	P41968	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256748	0.293
MBOAT7	protein	Q96N66	UNIPROT	1-phosphatidyl-1D-myo-inositol	smallmolecule	CHEBI:16749	ChEBI	up-regulates quantity	chemical modification			-1									18772128	t		miannu	The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils.	SIGNOR-267248	0.8
LPAR1	protein	Q92633	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257200	0.409
TUBA8	protein	Q9NY65	UNIPROT	Neuron_migration	phenotype	SIGNOR-PH67	SIGNOR	up-regulates				9606	BTO:0000007								19185337	f		miannu	We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching.	SIGNOR-269729	0.7
GGCX	protein	P38435	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	carboxylation	Glu63	VQGNLEReCMEEKCS	10090		BTO:0001103							11133752	t		lperfetto	The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.	SIGNOR-263689	0.67
BZW2	protein	Q9Y6E2	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									31643092	f		miannu	WB showed that BZW2 silence significantly decreased p‐ERK protein level in Colo205 cells, whereas BZW2 overexpression upregulated p‐ERK protein expression in HCT116 cells (Figure 3a,b)	SIGNOR-261219	0.2
RAG2	protein	P55895	UNIPROT	MTOR	protein	P42345	UNIPROT	up-regulates	relocalization			9606									22790199	t		gcesareni	Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated.	SIGNOR-198245	0.271
clozapine	chemical	CHEBI:3766	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258368	0.8
PRKD1	protein	Q15139	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates	phosphorylation	Ser205	GVRRRRLsNVSLTGV	9606									10867018	t		llicata	Activation of the serine/threonine kinase, protein kinase d (pkd/pkc mu) via a phorbol ester/pkc-dependent pathway involves phosphorylation events. the second autophosphorylation site (ser(203)) lies in that region of the regulatory domain	SIGNOR-78676	0.2
CBX3	protein	Q13185	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	binding			9606							methylation:Lys10	RTKQTARkSTGGKAP	19111658	t		miannu	 A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 	SIGNOR-264494	0.2
mTORC1	complex	SIGNOR-C3	SIGNOR	NRBF2	protein	Q96F24	UNIPROT	up-regulates activity	phosphorylation	Ser113	AEDAEGQsPLSQKYS	9606									28059666	t		miannu	Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association.	SIGNOR-265876	0.2
tadalafil	chemical	CHEBI:71940	ChEBI	PDE5A	protein	O76074	UNIPROT	down-regulates activity	chemical inhibition			9606									21189023	t		Luana	All of the final compounds and intermediates synthesized were screened for in vitro tumor cell growth inhibition activity using the human MDA-MB-231 breast tumor cell line and for inhibition of recombinant human PDE5 at a single concentration of 10 μM. For compounds showing >60% inhibition, the IC50 was determined by testing a range of eight concentrations with quadruple replicates per concentration, tadalafil used as a positive control.| Conversely, tadalafil possessed a selectivity index of just 16.6 for PDE5 versus PDE11	SIGNOR-257887	0.8
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	PPP1R14B	protein	Q96C90	UNIPROT	up-regulates activity	phosphorylation	Thr57	VRRQGKVtVKYDRKE										10606530	t		lperfetto	Recombinant tagged PHI-1 was phosphorylated by protein kinase C at two sites, one a Ser and one a Thr; phosphorylation enhanced inhibitory potency 50-fold. 	SIGNOR-265740	0.2
TNIK	protein	Q9UKE5	UNIPROT	TCF7L2	protein	Q9NQB0	UNIPROT	up-regulates	phosphorylation	Ser177	QALKDARsPSPAHIV	9606	BTO:0000586								20530691	t		llicata	Here, we report that tnik is an activating kinase for tcf4 and essential for colorectal cancer growth. Tnik, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of tcf4.	SIGNOR-165946	0.535
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr70	RNSPVTKtPPRDLPT	9606	BTO:0002181			SIGNOR-C3					10942774	t		lperfetto	PHAS-I in adipocytes and HEK293 cells is phosphorylated in the following five sites, all of which conform to a (S/T)P motif (9, 10): Thr-36, Thr-45, Ser-64, Thr-69, and Ser-82. Thr-45 and Ser-64 flank the eIF4E-binding motif (7, 8), and phosphorylation of either site blocks eIF4E binding in vitro (10, 11). Insulin stimulates the phosphorylation of Thr-36, Thr-45, Ser-64, and Thr-69 in both fat cells and HEK293 cells, and incubating cells with rapamycin decreases the phosphorylation of these sites.Immunoprecipitated epitope-tagged mammalian target of rapamycin (mTOR) phosphorylated Thr-36/45. mTOR also phosphorylated Thr-69 and Ser-64 but only when purified immune complexes were incubated with the activating antibody, mTAb1.	SIGNOR-226710	0.924
TIM22 complex	complex	SIGNOR-C424	SIGNOR	Insertion into mitochondrial membrane	phenotype	SIGNOR-PH193	SIGNOR	up-regulates													32901109	f		lperfetto	The TIM22 complex is responsible for the translocation and insertion of hydrophobic membrane proteins, including mitochondrial carrier proteins and translocase subunits (Tim17, Tim22 and Tim23)	SIGNOR-267710	0.7
PRKCB	protein	P05771	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser304	GAPPRRSsIRNAHSI	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89186	0.549
SRC	protein	P12931	UNIPROT	GRIN2A	protein	Q12879	UNIPROT	up-regulates activity	phosphorylation	Tyr1267	PATGEQVyQQDWAQN	-1									10195142	t		lperfetto	To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain.	SIGNOR-247167	0.586
mTORC1	complex	SIGNOR-C3	SIGNOR	Autophagy	phenotype	SIGNOR-PH31	SIGNOR	down-regulates				9606									23863160	f		lperfetto	Historically, it was known that autophagy was switched off when mTORC1 was active and that inhibition of mTORC1 was a potent autophagy inducer.	SIGNOR-209922	0.7
PRKCD	protein	Q05655	UNIPROT	CXCR4	protein	P61073	UNIPROT	down-regulates activity	phosphorylation	Ser324	LTSVSRGsSLKILSK	9606									10521508	t		Manara	Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization.	SIGNOR-260898	0.2
TAF10	protein	Q12962	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269581	0.767
ARID1A	protein	O14497	UNIPROT	Brain-specific SWI/SNF SMARCA2 variant	complex	SIGNOR-C485	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270743	0.749
ECM	stimulus	SIGNOR-ST20	SIGNOR	A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259034	0.7
WNK1	protein	Q9H4A3	UNIPROT	WNK1	protein	Q9H4A3	UNIPROT	up-regulates	phosphorylation	Ser382	KRASFAKsVIGTPEF	9606									17190791	t		gcesareni	We finally establish that full-length wnk1, wnk2 and wnk3, but not wnk4, are capable of directly phosphorylating ser382 of wnk1 in vitro. This supports the notion that t-loop phosphorylation of wnk isoforms is controlled by trans-autophosphorylation.	SIGNOR-151675	0.2
anthra[1,9-cd]pyrazol-6(2H)-one	chemical	CHEBI:90695	ChEBI	MAPK8	protein	P45983	UNIPROT	down-regulates	chemical inhibition			9606									11717429	t		gcesareni	We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm).	SIGNOR-111983	0.8
EP300	protein	Q09472	UNIPROT	PCK1	protein	P35558	UNIPROT	down-regulates quantity by destabilization	acetylation	Lys71	GILRRLKkYDNCWLA	9606	BTO:0000007								21726808	t		lperfetto	Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 	SIGNOR-267603	0.526
RIPK1	protein	Q13546	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	binding			9606									21133840	t		simone vumbaca	RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of κB kinase) complex	SIGNOR-256022	0.533
PRKACA	protein	P17612	UNIPROT	KCNJ13	protein	O60928	UNIPROT	up-regulates	phosphorylation	Ser287	EICQRRTsYLPSEIM	9606									18976636	t		gcesareni	Pka activation induced an increase of kir7.1 currents. This effect was absent in mutant kir7.1 channels lacking pka consensus site (287)s	SIGNOR-181859	0.2
TNF	protein	P01375	UNIPROT	JAG2	protein	Q9Y219	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004914								14586405	f			We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues.	SIGNOR-253608	0.324
BRD3	protein	Q15059	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates activity	binding			9606	BTO:0003292								28045112	t		lperfetto	Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection.|Brd3 enhances p300-mediated acetylation of IRF3	SIGNOR-262044	0.322
bisphenol A	chemical	CHEBI:33216	ChEBI	AR	protein	P10275	UNIPROT	down-regulates activity	chemical inhibition			-1									31995776	t		miannu	This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . 	SIGNOR-268732	0.8
MAPK3	protein	P27361	UNIPROT	DUSP1	protein	P28562	UNIPROT	down-regulates	phosphorylation	Ser296	KQRRSIIsPNFSFMG	9606									16286470	t		lperfetto	The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain	SIGNOR-141605	0.778
KDM3A	protein	Q9Y4C1	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									16603237	t		miannu	Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. 	SIGNOR-276846	0.2
HARS1	protein	P12081	UNIPROT	alpha-aminoacyl-tRNA	smallmolecule	CHEBI:2651	ChEBI	up-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 	SIGNOR-270803	0.8
KDM3A	protein	Q9Y4C1	UNIPROT	H3-5	protein	Q6NXT2	UNIPROT	up-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									16603237	t		miannu	Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. 	SIGNOR-276847	0.2
CASP3	protein	P42574	UNIPROT	DFFB	protein	O76075	UNIPROT	up-regulates	cleavage			9606									9108473	t		gcesareni	Casp3_ cleaves the 45 kda subunit at two sites to generate an active factor that produces_ dna_ fragmentation	SIGNOR-47419	0.672
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	TNF	protein	P01375	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001103							20219869	f		apalma	Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6.	SIGNOR-255354	0.666
MAPK1	protein	P28482	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation	Ser418	TEERLPSsPVYEDAA	9606	BTO:0000938								20444238	t		gcesareni	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-165204	0.481
PTPN14	protein	Q15678	UNIPROT	CAV1	protein	Q03135	UNIPROT	down-regulates activity	dephosphorylation			9606									32152405	t		miannu	Finally, PTPN14 overexpression in B16F10 cells reduced the ability of CAV1 to induce metastasis in vivo.|Moreover, the CAV1 (Y14F) mutant protein was shown to co-immunoprecipitate with PTPN14 even in the absence of E-cadherin, and overexpression of PTPN14 reduced CAV1 phosphorylation on tyrosine 14, as well as suppressed CAV1 enhanced cell migration, invasion and Rac-1 activation in B16F10, metastatic colon [HT29 (US)] and breast cancer (MDA-MB-231) cell lines.	SIGNOR-277054	0.2
PDGFA	protein	P04085	UNIPROT	PDGFRA	protein	P16234	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0000763							11803579	t		gcesareni	Platelet-derived growth factors (pdgf) constitute a family of four gene products (pdgf-a-d) acting by means of two receptor tyrosine kinases, pdgfr alpha and beta. Three of the ligands (pdgf-a, -b, and -c) bind to pdgfr alpha with high affinity.	SIGNOR-114268	0.765
4-[4-(2-fluorophenyl)phenyl]-N-(4-hydroxyphenyl)butanamide	chemical	CHEBI:92949	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates	chemical inhibition			9606									15362850	t		gcesareni	In steady-state kinetics experiments, cmpd1 was observed to prevent the p38alpha-dependent phosphorylation (k(i)(app) = 330 nm) of the splice variant of mitogen-activated protein kinase-activated protein kinase 2 (mk2a) that contains a docking domain for p38alpha and p38beta	SIGNOR-128864	0.8
PLK1	protein	P53350	UNIPROT	PKMYT1	protein	Q99640	UNIPROT	down-regulates activity	phosphorylation	Ser426	CSLLLDSsLSSNWDD	-1									12738781	t		miannu	Here, we have shown that Plk1 is responsible for part of the phosphorylation of Myt1 during M phase. The kinase activity of human Myt1 is reported to be decreased during M phase, and the decreased activity correlates with hyperphosphorylated forms of Myt1 (35, 37). We then tested the ability of these mutant forms of Myt1 (GST fusion proteins), to serve as a substrate for Plk1 in vitro. Quantification of the result (Fig. 5C) showed that Ser-426 is the major phosphorylation site by Plk1 in vitro and Thr-495 the second major site.	SIGNOR-263096	0.707
CDK2	protein	P24941	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606			SIGNOR-C83						10428798	t		gcesareni	Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity.	SIGNOR-69718	0.491
alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	up-regulates quantity	precursor of			9606									32898648	t		miannu	Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P).	SIGNOR-267936	0.8
IKBKE	protein	Q14164	UNIPROT	IRF7	protein	Q92985	UNIPROT	up-regulates	phosphorylation	Ser472	TQREGVSsLDSSSLS	9606									10893229	t		gcesareni	In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3.	SIGNOR-79143	0.675
11-deoxycorticosterone	smallmolecule	CHEBI:16973	ChEBI	NR3C2	protein	P08235	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								8282004	t		miannu	The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4).	SIGNOR-258714	0.8
ethanolaminium(1+)	smallmolecule	CHEBI:57603	ChEBI	O-phosphonatoethanaminium(1-)	smallmolecule	CHEBI:58190	ChEBI	up-regulates quantity	precursor of												29928787	t		lperfetto	In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells.	SIGNOR-275638	0.8
DAPK1	protein	P53355	UNIPROT	MAP1B	protein	P46821	UNIPROT	up-regulates	binding			9606									18806760	t		gcesareni	Dapk-1 interacts with the microtubule-associated protein map1b, in particular in conditions of amino-acid starvation.	SIGNOR-181305	0.265
entacapone	chemical	CHEBI:4798	ChEBI	COMT	protein	P21964	UNIPROT	down-regulates activity	chemical inhibition			-1									7703232	t		miannu	Human soluble (S) and membrane-bound (MB) catechol O-methyltransferase (COMT, EC 2.1.1.6) enzymes have been expressed at sufficiently high levels in Escherichia coli and in baculovirus-infected insect cells to allow kinetic characterization of the enzyme forms. The use of tight-binding inhibitors such as entacapone enabled the estimation of actual enzyme concentrations and, thereby, comparison of velocity parameters, substrate selectivity, and regioselectivity of the methylation of both enzyme forms.	SIGNOR-258476	0.8
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	CSF2RB	protein	P32927	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0005248								8758906	t		irozzo	We demonstrated that Bcr-Abl co-immunoprecipitates with, and constitutively phosphorylates, the common βc,subunit of the interleukin 3 and granulocyte/macrophage-colony stimulating factor receptors.We demonstrate that Bcr-Abl interacts with the common βc subunit of the IL-3 family of receptors and phosphorylates it on tyrosine. 	SIGNOR-255814	0.2
MAPK3	protein	P27361	UNIPROT	ALOX5	protein	P09917	UNIPROT	up-regulates activity	phosphorylation	Ser272	CSLERQLsLEQEVQQ	9606	BTO:0000567								12670876	t		lperfetto	Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells.	SIGNOR-264441	0.335
ARHGEF25	protein	Q86VW2	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates	guanine nucleotide exchange factor			10090	BTO:0000165;BTO:0000222								16314529	t		gcesareni	Exogenous expression of geft promotes myogenesis ofc2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process.	SIGNOR-236885	0.829
POLA1	protein	P09884	UNIPROT	DNA polymerase alpha:primase complex	complex	SIGNOR-C262	SIGNOR	form complex	binding			-1									24043831	t		lperfetto	At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation 	SIGNOR-261343	0.979
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	DCX	protein	O43602	UNIPROT	unknown	phosphorylation	Ser306	GPMRRSKsPADSGND	9606									14741103	t		llicata	In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35.	SIGNOR-250658	0.415
PAK1	protein	Q13153	UNIPROT	ELF3	protein	P78545	UNIPROT	up-regulates	phosphorylation	Ser207	GTGASRSsHSSDSGG	9606	BTO:0000150								17491012	t		lperfetto	Phosphorylation-dependent regulation of stability and transforming potential of ets transcriptional factor ese-1 by p21-activated kinase 1. Pak1 selectively phosphorylates ese-1 at ser(207). Intriguingly, pak1 phosphorylation inactive mutant ese1-s207a is more unstable	SIGNOR-154743	0.469
cis-(z)-Flupenthixol	chemical	CHEBI:10454	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258715	0.8
somatostatin	smallmolecule	CHEBI:64628	ChEBI	SSTR5	protein	P35346	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257585	0.8
ADP	chemical	CHEBI:16761	ChEBI	P2RY1	protein	P47900	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257557	0.8
C1QA	protein	P02745	UNIPROT	Complement C1q	complex	SIGNOR-C308	SIGNOR	form complex	binding			-1									29449492	t		lperfetto	C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1).	SIGNOR-263390	0.628
ITGA3	protein	P26006	UNIPROT	A3/b1 integrin	complex	SIGNOR-C161	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253173	0.797
PRKACA	protein	P17612	UNIPROT	GYS1	protein	P13807	UNIPROT	unknown	phosphorylation	Ser8	MPLNRTLsMSSLPGL	-1									2117608	t		miannu	Phosphorylation of rabbit muscle glycogen synthase by cyclic AMP-dependent protein kinase has been shown to enhance subsequent phosphorylation by casein kinase I . phosphorylation at Ser7 is required for modification of Ser10 by casein kinase I. 	SIGNOR-249988	0.489
PRKCB	protein	P05771	UNIPROT	EEF1A1	protein	P68104	UNIPROT	up-regulates activity	phosphorylation	Ser53	AAEMGKGsFKYAWVL	10090									20923971	t		miannu	PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein.	SIGNOR-263167	0.2
CDK2	protein	P24941	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates activity	phosphorylation	Thr266	TDLDAVRtPEPLEEF		BTO:0000007								10593981	t		llicata	Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. 	SIGNOR-250736	0.711
THR	proteinfamily	SIGNOR-PF84	SIGNOR	RARG	protein	P13631	UNIPROT	up-regulates activity	binding			9606									15650024	t	inferred from family member	gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-267781	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	RRN3	protein	Q9NYV6	UNIPROT	down-regulates	phosphorylation	Ser635	DTHFRSPsSSVGSPP	9606									19815529	t		lperfetto	We show that ampk down-regulates rrna synthesis under glucose restriction by phosphorylating the rna polymerase i (pol i)-associated transcription factor tif-ia at a single serine residue (ser-635).	SIGNOR-216592	0.287
AURKA	protein	O14965	UNIPROT	LIMK1	protein	P53667	UNIPROT	up-regulates activity	phosphorylation	Ser307	DRSPGAGsLGSPASQ	-1									22214762	t		miannu	Here, we report a novel functional cooperativity between Aur-A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology. 	SIGNOR-276399	0.265
rRNA_transcription	phenotype	SIGNOR-PH145	SIGNOR	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	up-regulates													25901680	f		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262601	0.7
MYOCD	protein	Q8IZQ8	UNIPROT	ACTG2	protein	P63267	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19797053	f		miannu	 These results demonstrate the ability of MYOCD to discriminate among several juxtaposed CArG elements, presumably through its novel partnership with NKX3.1, to optimally transactivate the human ACTG2 promoter.	SIGNOR-254620	0.436
RPS29	protein	P62273	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262422	0.878
STK11	protein	Q15831	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	up-regulates activity	phosphorylation	Thr183	SDGEFLRtSCGSPNY	-1									14976552	t		lperfetto	We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP_activated protein kinase (AMPK).	SIGNOR-122721	0.581
PTPN2	protein	P17706	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									10734133	t		flangone	Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1.	SIGNOR-75918	0.604
AKT1	protein	P31749	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser694	QTSKRHDsDTFPELK	9606									20085797	t		lperfetto	We identify a novel akt phosphorylation site in brca1 at s694 which is responsive to activation of these signaling pathways. These data suggest akt phosphorylation of brca1 increases total protein expression by preventing proteasomal degradation	SIGNOR-163472	0.521
STK3	protein	Q13188	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	phosphorylation	Ser872	HQRCLAHsLVGTPNY	9606									23431053	t		milica	MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation	SIGNOR-201274	0.592
ITGAD	protein	Q13349	UNIPROT	AD/b2 integrin	complex	SIGNOR-C172	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253195	0.73
CREB1	protein	P16220	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001103							21902831	f		gcesareni	Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes.	SIGNOR-176533	0.293
PCGF2	protein	P35227	UNIPROT	UBE2I	protein	P63279	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								18211895	t		miannu	Based on this finding of interaction between MEL-18 and UBC9, we envisioned a mechanism in which MEL-18 bound to HSF2 inhibits its sumoylation by binding to and inhibiting the activity of UBC9 enzymes that approach HSF2.	SIGNOR-226248	0.591
SGK3	protein	Q96BR1	UNIPROT	FLII	protein	Q13045	UNIPROT	up-regulates	phosphorylation	Ser436	RLRRRKDsAQDDQAK	9606									19293151	t		lperfetto	Here we show that flii is an in vivo substrate of cisk that functions downstream of pi 3-kinase. Cisk can associate with flii and phosphorylate flii at residues ser(436) and thr(818).We demonstrate here that cisk can enhance er transcription, which is dependent on its kinase activity, and mutation of cisk phosphorylation sites on flii attenuates its activity as an er co-activator.	SIGNOR-184688	0.364
PPP3CB	protein	P16298	UNIPROT	PPP1R1A	protein	Q13522	UNIPROT	unknown	dephosphorylation	Ser67	LKSTLAMsPRQRKKM	10116									11278334	t			In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation.	SIGNOR-248379	0.383
SLC24A5	protein	Q71RS6	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264403	0.8
PRKCD	protein	Q05655	UNIPROT	HNRNPK	protein	P61978	UNIPROT	unknown	phosphorylation	Ser302	GRGGRGGsRARNLPL	9606									10329716	t		Manara	We have shown that PKCδ binds and phosphorylates K protein. These observations broaden the range of K protein interactions. PKCδ targets Ser302, which is located in the middle of what appears to be a highly interactive KI domain	SIGNOR-260877	0.35
NPFFR1	protein	Q9GZQ6	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256708	0.252
N-[4-[2-ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridinyl]benzamide	chemical	CHEBI:91360	ChEBI	MAPK11	protein	Q15759	UNIPROT	down-regulates activity	chemical inhibition			-1									16162000	t		miannu	A novel structural class of 4-phenyl-5-pyridyl-1,3-thiazoles was optimized as inhibitors of p38 MAP kinase and the proinflammatory cytokine TNF-α. it only significantly inhibited p38α (IC50 = 7.1 nM) and p38β (IC50 = 200 nM) in a concentration-dependent manner and was approximately 28 times more selective for p38α over p38β. 	SIGNOR-262222	0.8
STAT5A	protein	P42229	UNIPROT	PIM2	protein	Q9P1W9	UNIPROT	up-regulates quantity by expression	transcriptional regulation												16146838	t		lperfetto	The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells.	SIGNOR-249622	0.422
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259014	0.364
MRPL28	protein	Q13084	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262367	0.685
BCOR	protein	Q6W2J9	UNIPROT	HOXA5	protein	P20719	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									26847029	f		irozzo	Importantly, our results showed that BCOR is a repressor of HoxA cluster of genes (HoxA5, HoxA7 and HoxA9) in myeloid cells. Knock-down of HoxA5, HoxA7 and HoxA9 significantly decreased the clonogenic growth of Bcor mutant and wild type cells, demonstrating the Hox genes, as targets of BCOR, played an important role in mediating BCOR’s function in regulating myeloid cell proliferation.	SIGNOR-256012	0.2
DLL3	protein	Q9NYJ7	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								16140393	t		lperfetto	Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate.	SIGNOR-209738	0.47
GRSF1	protein	Q12849	UNIPROT	FASTKD5	protein	Q7L8L6	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									25683715	f		miannu	DHX30 siRNA treatment resulted in an increase of FASTKD2 levels, and FASTKD5 was increased in cells treated with siRNA for GRSF1.	SIGNOR-261224	0.378
CSNK2A1	protein	P68400	UNIPROT	CBX5	protein	P45973	UNIPROT	up-regulates	phosphorylation	Ser11	KTKRTADsSSSEDEE	9606									21245376	t		gcesareni	Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability.	SIGNOR-171695	0.354
CSNK1A1L	protein	Q8N752	UNIPROT	NFAT5	protein	O94916	UNIPROT	up-regulates activity	phosphorylation	Ser158	LLDNSRMsCQDEGCG	9606	BTO:0000567								18411282	t	done	miannu	However, the siRNA knockdown of CK1α1L significantly reduced the nuclear export of OREBP/TonEBP under hypotonic conditions (Fig. 5F). Taken together, these data suggest that CK1α1L is the kinase that phosphorylates Ser-158 in the regulation of OREBP/TonEBP export.	SIGNOR-274111	0.2
ITGAV	protein	P06756	UNIPROT	Av/b5 integrin	complex	SIGNOR-C178	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253207	0.763
PHA-848125	chemical	CID:16718576	PUBCHEM	CDK2	protein	P24941	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206151	0.8
EIF2AK2	protein	P19525	UNIPROT	EIF2S1	protein	P05198	UNIPROT	down-regulates activity	phosphorylation			9606									31226023	t		miannu	Besides PERK, eIF2α can also be phosphorylated by three other kinases: heme-regulated inhibitor kinase (HRI), general control nonderepressible 2 (GCN2), and PKR. PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. Together, these four eIF2α kinases and their convergent downstream signaling pathways are known as the integrated stress response (ISR)	SIGNOR-260168	0.717
JUN	protein	P05412	UNIPROT	RCAN1	protein	P53805	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									18641051	f		lperfetto	Taken together, our findings suggest that c-Jun, a transcription factor downstream of the JNK signaling pathway, up-regulates Adapt78 expression in response to TG-induced ER stress and contributes to protection against TG-induced cell death.	SIGNOR-253148	0.28
BCOR	protein	Q6W2J9	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				10090	BTO:0004850								26847029	f		irozzo	Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes.	SIGNOR-256011	0.7
ABL1	protein	P00519	UNIPROT	HDAC2	protein	Q92769	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr222	IGAGKGKyYAVNFPM	10116									25219501	t		Manara	C-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease.	SIGNOR-260928	0.289
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	ITGB4	protein	P16144	UNIPROT	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259003	0.2
FOS	protein	P01100	UNIPROT	AP1	complex	SIGNOR-C154	SIGNOR	form complex	binding			-1									2467839	t		irozzo	The protein products of the fos (Fos) and jun (Jun) proto-oncogenes have been shown to associate with a DNA element known as the transcription factor activator protein-1 (AP-1) binding site. Jun (previously known as the Fos-binding protein p39) and Fos form a protein complex in the nucleus. These data demonstrate a cooperative interaction between the protein products of two proto-oncogenes with a DNA element involved in transcriptional regulation.	SIGNOR-256362	0.951
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SOX2	protein	P48431	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000596								24942200	t		flangone	During neural fate specification, nuclear translocation of ERK1/2 is critical for its activation of Sox2 transcription. More-over, melatonin-induced Sox2 expression, through ERK1/ 2 activation, could locate between base pairs2719 and 1708 in the mouse Sox2 gene.	SIGNOR-241977	0.2
CDK1	protein	P06493	UNIPROT	SYN3	protein	O14994	UNIPROT	up-regulates	phosphorylation	Ser470	PQGQQPLsPQSGSPQ	9606									14732590	t		lperfetto	A rare, missense polymorphism, s470n, was identified in the synapsin iii gene and appeared more frequently in individuals with schizophrenia than in controls. Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action.	SIGNOR-121398	0.2
MCHR2	protein	Q969V1	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256938	0.252
TCL1B	protein	O95988	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271								10983986	t		gcesareni	In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation.	SIGNOR-81713	0.663
Non-erythrocytic spectrin	complex	SIGNOR-C385	SIGNOR	Cell_shape	phenotype	SIGNOR-PH182	SIGNOR	up-regulates				9606									24302288	f		lperfetto	Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell	SIGNOR-266033	0.7
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation			10090	BTO:0002572								20670887	t		lperfetto	Specifically as part of mTORC1, mTOR directly phosphorylates the ribosomal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2)phosphorylation of the 4E-BPs leads to their inhibition and release from eIF4E at the 5_ cap of mRNAs	SIGNOR-235745	0.753
NCOA1	protein	Q15788	UNIPROT	ASXL1	protein	Q8IXJ9	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								16606617	t		irozzo	We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation.Therefore, both the ability to bind SRC-1 and the autonomous activation of ASXL1 are required for its coactivator function. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR.	SIGNOR-255924	0.287
GDNF	protein	P39905	UNIPROT	Neural_tissue_regeneration	phenotype	SIGNOR-PH68	SIGNOR	up-regulates				10116									15212950	f		miannu	The glial cell line-derived neurotrophic factor (GDNF) is involved in the development and maintenance of neural tissues. In normal development, GDNF promotes survival of sympathetic, parasympathetic, and spinal motorneurons. It even promotes regeneration of spinal motor neurons after spinal cord injury.	SIGNOR-252170	0.7
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CDC6	protein	Q99741	UNIPROT	down-regulates activity	phosphorylation	Ser74	TPHLPPCsPPKQGKK	9606									10339564	t		lperfetto	Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction.	SIGNOR-217280	0.94
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	precursor of			9606									6698284	t		miannu	The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2).	SIGNOR-267339	0.8
TWIST1	protein	Q15672	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255526	0.494
ENPP1	protein	P22413	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	binding			9606									10615944	t		miannu	Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. PC-1 may inhibit the IR by interacting directly with a specific region in the IR alpha-subunit. 	SIGNOR-252190	0.397
MYH9	protein	P35579	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004953								32685004	t		miannu	Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo.	SIGNOR-269284	0.278
SIRT1	protein	Q96EB6	UNIPROT	FOXO1	protein	Q12778	UNIPROT	up-regulates activity	deacetylation			9606		BTO:0001103							22395773	t		lperfetto	SIRT1 controls the acetylation of FOXO transcription factors, which are important regulators of lipid and glucose metabolism as well as stress response. On the other hand, SIRT1 can also stimulate the gluconeogenic transcriptional program by deacetylating and activating FOXO1.	SIGNOR-253509	0.804
SIRT1	protein	Q96EB6	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates activity	deacetylation			10090		BTO:0001103							24003218	t		lperfetto	SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIRT1 activation has been reported to increase dramatically endurance exercise through the activation of PGC-1_ in muscle, which stimulates fatty acid oxidation	SIGNOR-217963	0.792
SKI	protein	P12755	UNIPROT	SMAD5	protein	Q99717	UNIPROT	down-regulates	binding			9606									12419246	t		gcesareni	Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad6	SIGNOR-95468	0.684
FYN	protein	P06241	UNIPROT	GRIN2A	protein	Q12879	UNIPROT	up-regulates activity	phosphorylation	Tyr1105	CSEVERTyLKTKSSS	-1									10195142	t		lperfetto	To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain.	SIGNOR-247151	0.724
STAT5A	protein	P42229	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates				9606	BTO:0001096								14530308	f		apalma	Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells	SIGNOR-256663	0.7
R547	chemical	CID:6918852	PUBCHEM	CDK2	protein	P24941	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206361	0.8
BMPR1B	protein	O00238	UNIPROT	STAMBP	protein	O95630	UNIPROT	up-regulates activity	phosphorylation	Ser247	GALSNSEsIPTIDGL	9534	BTO:0000298								11483516	t		llicata	BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads.	SIGNOR-250599	0.294
IRX1	protein	P78414	UNIPROT	NPTX1	protein	Q15818	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002392								20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 	SIGNOR-261655	0.258
IKBKB	protein	O14920	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	down-regulates activity	phosphorylation	Ser432	KMPNTNGsIGHSPLS	9606									24614225	t		lperfetto	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204724	0.529
MAPK1	protein	P28482	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Ser59	GGQESQPsPLALLAA	9606									11904305	t		gcesareni	Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1.	SIGNOR-116158	0.629
HNRNPU	protein	Q00839	UNIPROT	TNF	protein	P01375	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation												17174306	t		lperfetto	In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs.	SIGNOR-262281	0.2
lenalidomide	chemical	CHEBI:63791	ChEBI	CRBN	protein	Q96SW2	UNIPROT	up-regulates activity	chemical activation			9606									26131937	t		gcesareni	Lenalidomide, like thalidomide and pomalidomide, binds CRBN and induces degradation of specific substrates	SIGNOR-236891	0.8
CDK3	protein	Q00526	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates	phosphorylation	Ser63	GILARRPsYRKILKD	9606	BTO:0000527	BTO:0000142							18794154	t		lperfetto	Cyclin-dependent kinase 3-mediated activating transcription factor 1 phosphorylation enhances cell transformationwe found that cdk3 phosphorylates activating transcription factor 1 (atf1) at serine 63 and enhances the transactivation and transcriptional activities of atf1.	SIGNOR-180920	0.2
CDK1	protein	P06493	UNIPROT	RCC1	protein	P18754	UNIPROT	up-regulates activity	phosphorylation	Ser387	GQDEDAWsPVEMMGK	-1									15014043	t		miannu	We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. However, when both S2 and S11 were simultaneously mutated to As, the resulting 6His-RCC1S2,11A failed to be phosphorylated, whereas all of the other double mutants were phosphorylated (Fig. 1C). As expected, mutating all four sites to As (the 6His-RCC1S2,11,387A-T274A) also blocked phosphorylation (Fig. 1C).	SIGNOR-262703	0.518
HSPA2	protein	P54652	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates	binding			9606									12391142	t		gcesareni	Coimmunoprecipitation analysis revealed a physical interaction between endogenous hsp72 and ask1 in nih 3t3 cells exposed to mild heat shock. Hsp72 blocked both the homo-oligomerization of ask1 and ask1-dependent apoptosis.	SIGNOR-94565	0.2
MAPK3	protein	P27361	UNIPROT	SULT4A1	protein	Q9BR01	UNIPROT	down-regulates	phosphorylation	Thr11	SEAETPStPGEFESK	9606	BTO:0000938	BTO:0000142							20920535	t		gcesareni	The phosphorylation of sult4a1 allows interaction with pin1, which then promotes degradation of the sulfotransferase.	SIGNOR-168248	0.2
(-)-anisomycin	chemical	CHEBI:338412	ChEBI	MAPK13	protein	O15264	UNIPROT	up-regulates	chemical activation			9606									Other	t	CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb	gcesareni		SIGNOR-189696	0.8
RPS27L	protein	Q71UM5	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262445	0.785
CDK2	protein	P24941	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Thr179	PQSNIPEtPPPGYLS	9606									15241418	t		gcesareni	We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function	SIGNOR-126736	0.733
DLG4	protein	P78352	UNIPROT	NOS1	protein	P29475	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								11052931	t		miannu	Neuronal NOS, a Ca2+-activated form of NOS, can bind to PSD-95 through a class III PDZ domain interaction in which its own amino-terminal PDZ domain binds to a PDZ domain of PSD-95. PSD-95 may concentrate nNOS near the NMDA receptor at postsynaptic sites in these neurons.	SIGNOR-264227	0.726
IKBKB	protein	O14920	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	unknown	phosphorylation	Ser43	PAMLHLPsEQGAPET	9606			SIGNOR-C14	SIGNOR-C14					17977820	t		lperfetto	In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction.	SIGNOR-158655	0.962
DZIP3	protein	Q86Y13	UNIPROT	H2AZ1	protein	P0C0S5	UNIPROT	up-regulates activity	monoubiquitination	Lys121	IHKSLIGkKGQQKTV	9606									18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271748	0.2
Dihydromorphine	chemical	CHEBI:4575	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258786	0.8
TFAP2B	protein	Q92481	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	binding			9606									21556774	t		miannu	These data suggest that AP-2β enhances transactivation of p53 and regulates CRYAB transcription via p53. Further study demonstrated that AP-2β interacts with p53 and augments its protein stability. Taken together, our results indicate that AP-2β up-regulates the transcription of the CRYAB gene through stabilizing p53.	SIGNOR-255422	0.341
OGT	protein	O15294	UNIPROT	G6PD	protein	P11413	UNIPROT	up-regulates activity	glycosylation	Ser84	VADIRKQsEPFFKAT	9606	BTO:0000007								26399441	t		lperfetto	O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth|O-GlcNAcylation of G6PD activates enzyme activity|G6PD is dynamically modified by O-GlcNAc at serine 84|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 	SIGNOR-267582	0.267
PRKCZ	protein	Q05513	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Thr668	SYCGKRFtRSDELQR	9606		BTO:0000887;BTO:0001260							18258854	t		llicata	Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter.	SIGNOR-160770	0.498
PTPN6	protein	P29350	UNIPROT	VAV1	protein	P15498	UNIPROT	down-regulates activity	dephosphorylation			9606									30567306	t		miannu	SHP-1 dephosphorylates and inactivates the guanine exchange factor Vav1.	SIGNOR-277171	0.561
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257969	0.8
MAPK14	protein	Q16539	UNIPROT	NFATC4	protein	Q14934	UNIPROT	down-regulates activity	phosphorylation	Ser170	GGAFFSPsPGSSSLS	10029	BTO:0001131								11997522	t		miannu	P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity.	SIGNOR-250108	0.411
CDK2	protein	P24941	UNIPROT	HMGA1	protein	P17096	UNIPROT	down-regulates	phosphorylation	Ser36	PRKQPPVsPGTALVG	9606									17960875	t		gcesareni	Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation.	SIGNOR-158612	0.267
MEST	protein	Q5EB52	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	transcriptional regulation			9606									24827625	f		areggio	Our data demonstrate that Mest alleviated CCl4-induced collagen deposition in liver tissue and improved the condition of the liver in rats. Mest also significantly reduced the expression and distribution of β-catenin, α-SMA and Smad3 both in vivo and in vitro, in addition to the viability of HSCs in vitro.	SIGNOR-258982	0.253
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates activity	phosphorylation	Ser90	QHVRSHSsPASLQLG										26375055	t		lperfetto	We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity	SIGNOR-276522	0.265
phentolamine	chemical	CHEBI:8081	ChEBI	ADRA1B	protein	P35368	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258446	0.8
AXIN2	protein	Q9Y2T1	UNIPROT	APC	protein	P25054	UNIPROT	up-regulates	binding			9606		BTO:0000142;BTO:0000671;BTO:0000763							10911903	t		gcesareni	It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains.	SIGNOR-79944	0.833
STK4	protein	Q13043	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates													21512132	f		lperfetto	Mst1 plays a critical role in the regulation of programmed cell death and it has been implicated in PCa development. Interestingly, MST1 has been detected in AR-chromatin complexes, and forced expression of MST1 reduces AR binding to androgen-responsive elements along the PSA promoter. 	SIGNOR-151712	0.2
MBTD1	protein	Q05BQ5	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269303	0.416
AKT3	protein	Q9Y243	UNIPROT	BMI1	protein	P35226	UNIPROT	up-regulates activity	phosphorylation	Ser316	ANRPRKSsVNGSSAT										22505453	t		lperfetto	the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate	SIGNOR-249583	0.261
NUMA1	protein	Q14980	UNIPROT	TUBA8	protein	Q9NY65	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116826	0.2
KAR	proteinfamily	SIGNOR-PF57	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial.	SIGNOR-264940	0.8
GUCY1A2	protein	P33402	UNIPROT	GUCY1A2-B3	complex	SIGNOR-C138	SIGNOR	form complex	binding			9606									10977868	t		gcesareni	This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity	SIGNOR-243977	0.2
KAT2B	protein	Q92831	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269611	0.2
IRF2BPL	protein	Q9H1B7	UNIPROT	GNRH1	protein	P01148	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000938								17627301	t		miannu	EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.	SIGNOR-267154	0.429
GPR119	protein	Q8TDV5	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257366	0.252
nimodipine	chemical	CHEBI:7575	ChEBI	NR3C2	protein	P08235	UNIPROT	down-regulates activity	chemical inhibition			-1									18250364	t		Luana	Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression. 	SIGNOR-257765	0.8
suprofen	chemical	CHEBI:9362	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001061								18667313	t		Luana	Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2. 	SIGNOR-257808	0.8
COL21A1	protein	Q96P44	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	up-regulates activity	binding												35267698	t		lperfetto	Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23].	SIGNOR-272347	0.357
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR3A	protein	P46098	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264282	0.8
USF2	protein	Q15853	UNIPROT	CTSD	protein	P07339	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								9731700	f		miannu	Overexpression of cathepsin D (CD), a ubiquitous lysosomal protease, is closely associated with a poor clinical outcome for patients with breast cancer. Estrogen greatly induces transcription of the CD gene in estrogen receptor (ER)-positive breast cancer cells. These experiments suggest a model for ER stimulation of the CD promoter in which recruitment of USF-1/2 to the promoter is required for activation of transcription.	SIGNOR-255594	0.385
AVPR2	protein	P30518	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256754	0.57
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	tRNA(Pro)	smallmolecule	CHEBI:29177	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270427	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				10090									16982699	f			Protein kinase B (PKB/Akt) is an important modulator of insulin signaling, cell proliferation, and survival. Using small interfering RNA duplexes in nontransformed mammalian cells, we show that only Akt1 is essential for cell proliferation	SIGNOR-254353	0.7
CSNK2A3	protein	Q8NEV1	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates activity	phosphorylation	Ser1112	VPIAVGEsDFENLNT	9606	BTO:0000938								19064667	t		lperfetto	 We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275751	0.2
MUTYH	protein	Q9UIF7	UNIPROT	ATR	protein	Q13535	UNIPROT	up-regulates	binding			9606	BTO:0000007								21615992	t		miannu	Binding of myh directly participates in atr and topbp1 activation in dna damage signaling, leading to apoptosis.	SIGNOR-173966	0.252
MRPL3	protein	P09001	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262366	0.697
SRC	protein	P12931	UNIPROT	SPRY2	protein	O43597	UNIPROT	up-regulates	phosphorylation	Tyr55	AIRNTNEyTEGPTVV	9606									15564375	t		lperfetto	Activation of signalling by fibroblast growth factor receptor leads to phosphorylation of the signalling attenuator human sprouty 2 (hspry2) on residue y55. we show that hspry2 is a direct substrate for src family kinases, including src itself.Phosphorylation of hspry2 is required for hspry2 to inhibit activation of the extracellular signal-regulated kinase pathway.	SIGNOR-131189	0.548
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1892	TPKYSPTsPTYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269377	0.718
BMP7	protein	P18075	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	up-regulates	binding			9606									7644468	t		lperfetto	In transfected cos-1 cells, osteogenic protein (op)-1/bmp-7, and less efficiently bmp-4, bound to bmpr-ii. Bmpr-ii bound ligands only weakly alone, but the binding was facilitated by the presence of previously identified type i receptors for bmps. Binding of op-1/bmp-7 to bmpr-ii was also observed in nontransfected cell lines. Moreover, a transcriptional activation signal was transduced by bmpr-ii in the presence of type i receptors after stimulation by op-1/bmp-7.	SIGNOR-217520	0.77
PTK6	protein	Q13882	UNIPROT	KHDRBS1	protein	Q07666	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								10913193	t		gcesareni	Sik/brk is the first identified tyrosine kinase that can phosphorylate sam68 and regulate its activity within the nucleus, where it resides during most of the cell cycle	SIGNOR-80020	0.738
F2RL3	protein	Q96RI0	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257157	0.2
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270423	0.8
QRICH1	protein	Q2TAL8	UNIPROT	FARS2	protein	O95363	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269403	0.2
PSTPIP1	protein	O43586	UNIPROT	PTPN18	protein	Q99952	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								9422760	t		lperfetto	These data confirm the importance of these residues to the binding interaction, and they suggest that much of the COOH-terminal region of PTP HSCF may be required for highest affinity binding to PST PIP.|Because this protein-protein interaction appears to be required for the dephosphorylation of PST PIP phosphotyrosines (20), it may be a potentially important new mechanism for the regulation of the cytoskeleton.	SIGNOR-262594	0.582
CDK7	protein	P50613	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606									10949034	t		lperfetto	Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7.	SIGNOR-81170	0.423
DPF3	protein	Q92784	UNIPROT	Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270690	0.737
AKT1	protein	P31749	UNIPROT	RARG	protein	P13631	UNIPROT	up-regulates activity	phosphorylation	Ser371	YARRRRPsQPYMFPR	9606	BTO:0000093								31740618	t		miannu	S379 of RARγ is indispensable for the CLDN6-triggered cellular events. The most important finding of the present study is that the CLDN6/SFK/PI3K/AKT signaling controls the RARγ and ERα activities (Fig. 6).	SIGNOR-277492	0.444
IRX1	protein	P78414	UNIPROT	DKK3	protein	Q9UBP4	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002392								20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 	SIGNOR-261658	0.264
RLN2	protein	P04090	UNIPROT	RXFP2	protein	Q8WXD0	UNIPROT	up-regulates	binding			9606		BTO:0000142							11809971	t		gcesareni	Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway.	SIGNOR-114585	0.697
SLBP	protein	Q14493	UNIPROT	H3-5	protein	Q6NXT2	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265420	0.2
BCL2L11	protein	O43521	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								11997495	t		lperfetto	We have shown that the interaction of the bims and bimad isoforms with bax leads to a conformational change in this protein analogous to that triggered by the bh3-only protein bid.We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome.	SIGNOR-87280	0.825
MAPK14	protein	Q16539	UNIPROT	MEF2D	protein	Q14814	UNIPROT	up-regulates activity	phosphorylation			9606		BTO:0000887							18026121	t		lperfetto	Targeting of ash2l to specific genes is mediated by the transcriptional regulator mef2d. Furthermore, this interaction is modulated during differentiation through activation of the p38 mapk signaling pathway via phosphorylation of mef2d.	SIGNOR-159331	0.595
BICDL1	protein	Q6ZP65	UNIPROT	KIF1C	protein	O43896	UNIPROT	up-regulates activity	binding			-1									20360680	t		miannu	BICDR-1 interacts with the dynein/dynactin motor complex. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation. These results show that BICDR-1 regulates recruitment and/or activity of the anterograde kinesin motor Kif1C on Rab6 secretory carriers.	SIGNOR-266876	0.2
FZD5	protein	Q13467	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates activity	binding			9606									23151663	t		areggio	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. 	SIGNOR-258957	0.645
PAK6	protein	Q9NQU5	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates activity	phosphorylation	Ser186	RQRKRHKsDSISLSF	9606									23132866	t		miannu	We also showed that PAK6 phosphorylates Mdm2 on Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation.	SIGNOR-276427	0.2
3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	PKA	proteinfamily	SIGNOR-PF17	SIGNOR	up-regulates activity	chemical activation			9606									26687711	t			Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 	SIGNOR-258763	0.8
PPP1R3B	protein	Q86XI6	UNIPROT	GYS1	protein	P13807	UNIPROT	up-regulates	binding			9606		BTO:0000759							36551183	t		miannu	In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)	SIGNOR-271734	0.713
PGAM1	protein	P18669	UNIPROT	3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	down-regulates quantity	chemical modification			9606									24786789	t		miannu	Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle.	SIGNOR-266511	0.8
MRAP2	protein	Q96G30	UNIPROT	MC5R	protein	P33032	UNIPROT	down-regulates activity	binding			10029	BTO:0000246								19329486	t		miannu	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252369	0.517
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates	relocalization			9606		BTO:0001103							11062529	t		gcesareni	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-84056	0.386
BTC	protein	P35070	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606									14967450	t		gcesareni	Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4.	SIGNOR-121953	0.737
MN1	protein	Q10571	UNIPROT	MYBBP1A	protein	Q9BQG0	UNIPROT	up-regulates activity	binding			-1									12569362	t		irozzo	Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300.	SIGNOR-256021	0.2
Scribble_complex_DLG1-LLGL1_variant	complex	SIGNOR-C511	SIGNOR	Cell_polarity	phenotype	SIGNOR-PH213	SIGNOR	up-regulates				9606									23397623	f		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270914	0.7
SKI	protein	P12755	UNIPROT	EP300	protein	Q09472	UNIPROT	down-regulates	binding			9606				SIGNOR-C6					10575014	t		gcesareni	Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling.	SIGNOR-72664	0.2
KIF7	protein	Q2M1P5	UNIPROT	GLI2	protein	P10070	UNIPROT	up-regulates quantity by stabilization	binding			9606									19549984	t		lperfetto	Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling.	SIGNOR-209611	0.57
DNMT3B	protein	Q9UBC3	UNIPROT	DPP6	protein	P42658	UNIPROT	down-regulates quantity by repression	transcriptional regulation												23409053	t		lperfetto	Dnmt3b was responsible for transcriptional silencing of Dpp6 gene as depletion of Dnmt3b resulted in increased mRNA and protein expression of Dpp6.	SIGNOR-268963	0.334
DMD	protein	P11532	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255998	0.682
PTPN6	protein	P29350	UNIPROT	ROS1	protein	P08922	UNIPROT	down-regulates	dephosphorylation			9606									11266449	t		lperfetto	Overexpression of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation. We propose that shp-1 is an important downstream regulator of ros signaling.	SIGNOR-105922	0.375
N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide	chemical	CHEBI:94525	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257974	0.8
PTPRC	protein	P08575	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates activity	dephosphorylation	Tyr531	FTATEPQyQPGENL	9606	BTO:0000782								11909961	t			On the membrane SKAP55, via its phosphorylated Tyr-271, further binds the SH2 domain of Fyn to replace the low-affinity bound inhibitory site of the kinase. Consequently, CD45 may have transiently disassociated with the Tyr-232 residue of SKAP55 through dephosphorylation and simultaneously interacted with the released the phosphorylated inhibitory tyrosine residue of Fyn for dephosphorylation, resulting in activation of the Src family kinase Fyn and initiation of TCR-engaged signal transduction.	SIGNOR-248352	0.72
Angiotensin-1	protein	P01019-PRO_0000032457	UNIPROT	ACE	protein	P12821	UNIPROT	up-regulates activity	binding			9606									32201502	t		MIANNU	 Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I	SIGNOR-260231	0.2
CAPN1	protein	P07384	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates activity	cleavage	Lys76	YRLVSINkSSPLQKQ	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263560	0.383
IFNL1	protein	Q8IU54	UNIPROT	IFNLR1	protein	Q8IU57	UNIPROT	up-regulates	binding			9606									12469119	t		gcesareni	Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.	SIGNOR-96174	0.868
irinotecan	chemical	CHEBI:80630	ChEBI	TOP1	protein	P11387	UNIPROT	down-regulates activity	chemical inhibition			9606									15170677	t		miannu	Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin; CPT-11) is a widely used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I)	SIGNOR-259316	0.8
FGF11	protein	Q92914	UNIPROT	SCN9A	protein	Q15858	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253426	0.2
RANBP3	protein	Q9H6Z4	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	relocalization			9606									20704570	t		lperfetto	Importantly, PPM1A facilitates the interaction of dephosphorylated Smad2/3 with RanBP3, a nuclear export factor [75]. As a result, PPM1A-mediated dephosphorylation of Smad2/3 promotes nuclear export of Smad2/3 and shuts off TGF-_-induced anti-proliferative and transcriptional responses	SIGNOR-217625	0.447
RPS6KA3	protein	P51812	UNIPROT	CIC	protein	Q96RK0	UNIPROT	down-regulates	phosphorylation	Ser173	PGKRRTQsLSALPKE	9606	BTO:0000848								21087211	t		gcesareni	Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)	SIGNOR-169887	0.2
SLC25A12	protein	O75746	UNIPROT	aspartic acid	smallmolecule	CHEBI:22660	ChEBI	up-regulates quantity	relocalization			9606									12084073	t		miannu	Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. 	SIGNOR-265156	0.8
IL1A	protein	P01583	UNIPROT	FBN1	protein	P35555	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000452								9036927	f	Regulation	miannu	UVB irradiation (50 mJ) of cultured skin fibroblasts suppressed fibrillin mRNA by 50%, consistent with a direct effect of radiation. UVB irradiation (50 mJ) of cultured skin fibroblasts suppressed fibrillin mRNA by 50%, consistent with a direct effect of radiation. Addition to the cultured fibroblasts of several cytokines upregulated by UVB showed that IL-1alpha had no effect on fibrillin mRNA in unirradiated cells, but in irradiated cells, this cytokine enhanced the suppression of fibrillin mRNA. 	SIGNOR-251890	0.2
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1787	SPNYSPTsPSYSPTS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248779	0.441
PPM1D	protein	O15297	UNIPROT	CHEK1	protein	O14757	UNIPROT	down-regulates	dephosphorylation	Ser345	LVQGISFsQPTCPDH	9606									15870257	t		gcesareni	Ppm1d dephosphorylates chk1 phospho-ser 345	SIGNOR-135972	0.487
MAPK3	protein	P27361	UNIPROT	XPO5	protein	Q9HAV4	UNIPROT	down-regulates activity	phosphorylation	Thr345	GADSDVEtPSNFGKY	9606									27846390	t		lperfetto	Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. 	SIGNOR-262985	0.317
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	NFKBIA	protein	P25963	UNIPROT	up-regulates quantity by stabilization	cleavage			-1									9367996	t		lperfetto	The cell-death protease cpp32 (caspase-3) in vitro specifically cleaved chicken and human ikappab-alpha at a conserved asp-ser sequence.Therefore, cleavage of I_B-_ by a CPP32-like protease could create what is sometimes called a super-repressor form of I_B-_ (20). That is, cleavage by CPP32 would block the ability of I_B-_ to undergo signal-induced degradation by removing the sites of signal-induced ubiquitination and by likely disrupting the ability of I_B-_ to become phosphorylated at critical Ser residues.	SIGNOR-256456	0.433
STAG2	protein	Q8N3U4	UNIPROT	TNF	protein	P01375	UNIPROT	up-regulates				9606									14660624	f		miannu	Stag2 is able to enhance the activity of the tumor necrosis factor alpha, the cd69, and the human immunodeficiency virus long terminal repeat promoters in a nf-kappab-dependent manner.	SIGNOR-119988	0.2
Exocyst_EXOC6B variant	complex	SIGNOR-C491	SIGNOR	SNARE_complex 	complex	SIGNOR-C346	SIGNOR	up-regulates activity	binding			9606									30205058	t		miannu	The exocyst is a multisubunit protein complex that was first identified and characterized in budding yeast. This complex mediates the tethering of secretory vesicles to the plasma membrane prior to fusion mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Sec3 interacts with PI(4,5)P2 (red dots) in the plasma membrane. Its interaction with the t-SNARE protein Sso promotes the assembly of the Sso–Sec9 binary t-SNARE complex. 	SIGNOR-270792	0.427
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	MED13L	protein	Q71F56	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								23322298	t		miannu	The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association.	SIGNOR-266689	0.366
BIRC3	protein	Q13489	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0000007								21931591	t		miannu	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.	SIGNOR-272713	0.737
CYP17A1	protein	P05093	UNIPROT	17alpha-hydroxypregnenolone	smallmolecule	CHEBI:28750	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0001363;BTO:0000048;BTO:0000050							17192295	t		lperfetto	THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones.	SIGNOR-268652	0.8
IL10RB	protein	Q08334	UNIPROT	TYK2	protein	P29597	UNIPROT	up-regulates	binding			9606	BTO:0000801;BTO:0000776								10347215	t		milica	Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor ? Chain) and tyk2 (associated with the il-10 receptor ? Chain) and induces the activation of stat1, stat3, and, in some cells, stat5.	SIGNOR-68013	0.636
PPP1CA	protein	P62136	UNIPROT	MECOM	protein	Q03112	UNIPROT	down-regulates activity	dephosphorylation	Ser726	PLKMEPQsPGEVKKL										23858473	t	phosphorylation site remapping based on Fig 5	lperfetto	We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. 	SIGNOR-273430	0.2
PPARD	protein	Q03181	UNIPROT	TXN	protein	P10599	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001950								18048767	f		miannu	 Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs. 	SIGNOR-255052	0.2
MAP2K7	protein	O14733	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates	phosphorylation	Thr183	ACTNFMMtPYVVTRY	9606	BTO:0000007								9890973	t	phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif	gcesareni	Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway.	SIGNOR-63976	0.622
CDKN2A	protein	P42771	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0000176								7972006	f			Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation.	SIGNOR-259406	0.7
QRICH1	protein	Q2TAL8	UNIPROT	WARS1	protein	P23381	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269410	0.2
CTDSP2	protein	O14595	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation	Thr220	QSNYIPEtPPPGYIS	9606	BTO:0000007								17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248296	0.421
PPM1A	protein	P35813	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	dephosphorylation			9606									16931515	t		lpetrilli	In this study, we have found that ppm1a, a metal ion-dependent protein serine/threonine phosphatase, physically interacts with and dephosphorylates smad1 both in vitro and in vivo. considering the highly conserved nature of the sxs motif in all r-smads, we reasoned that ppm1a might also recognize the sxs motif in the bmp-activated smad1.	SIGNOR-149077	0.518
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	NANOG	protein	Q9H9S0	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269245	0.623
PRKCI	protein	P41743	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606	BTO:0000527								21419810	t		lperfetto	In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer	SIGNOR-172894	0.324
MAPK11	protein	Q15759	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates				9606									20551513	f		gcesareni	Mechanistic analysis revealed that the tak1-mkk3/6-p38 mapk axis phosphorylated runx2, promoting its association with the coactivator creb-binding protein (cbp), which is re-quired to regulate osteoblast genetic programs.	SIGNOR-166167	0.289
ARNT	protein	P27540	UNIPROT	CYP1A1	protein	P04798	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22387692	f	 	lperfetto	The miR-24-dependent down-regulation of ARNT decreased the expression of its downstream genes such as CYP1A1 and carbonic anhydrase IX. 	SIGNOR-253705	0.633
LYN	protein	P07948	UNIPROT	KCND3	protein	Q9UK17	UNIPROT	up-regulates activity	phosphorylation	Tyr108	GKLHYPRyECISAYD	9606	BTO:0000007								22198508	t		miannu	 These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels.	SIGNOR-276395	0.2
PDIA6	protein	Q15084	UNIPROT	ERN1	protein	O75460	UNIPROT	down-regulates activity				10090	BTO:0000944								24508390	t			A resident ER protein disulfide isomerase, PDIA6, limits the duration of IRE1α activity by direct binding to cysteine148 in the luminal domain of the sensor,	SIGNOR-256536	0.322
SATB1	protein	Q01826	UNIPROT	NUMB	protein	P49757	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000725								23563689	f		miannu	Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc	SIGNOR-224835	0.343
LPAR3	protein	Q9UBY5	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256747	0.252
PLK3	protein	Q9H4B4	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									20068231	t		gcesareni	Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.	SIGNOR-163274	0.2
JUN	protein	P05412	UNIPROT	KRT16	protein	P08779	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000552								12954631	f	 	miannu	 these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter.	SIGNOR-253905	0.271
TFE3	protein	P19532	UNIPROT	ATG16L1	protein	Q676U5	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells	SIGNOR-276807	0.269
BCL2L1	protein	Q07817	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				10090	BTO:0003328								9393856	f		fcortellessa	 Bcl-xL Expression Prevents Cytochrome c Redistribution and Subsequent Mitochondrial Depolarization during Apoptosis. Bcl-xL expression prevented both cytochrome c redistribution and mitochondrial membrane depolarization. In contrast, zVAD treatment could not prevent either cytochrome c redistribution or mitochondrial membrane depolarization in control transfectants withdrawn from IL-3. Thus, cytochrome c redistribution from mitochondria is an early apoptotic event that precedes mitochondrial membrane depolarization. Bcl-xL expression functions to inhibit both of these events. In at least some forms of cell death, the ability of Bcl-xL to regulate these mitochondrial events cannot be mimicked by caspase inhibition	SIGNOR-261683	0.7
IGF1R	protein	P08069	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates	phosphorylation	Tyr973	RLGNGVLyASVNPEY	-1									7493944	t		lperfetto	The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.	SIGNOR-246252	0.2
PRKACA	protein	P17612	UNIPROT	PARP1	protein	P09874	UNIPROT	up-regulates activity	phosphorylation	Ser782	YSLLRGGsDDSSKDP	9606	BTO:0001412								25069723	t		miannu	 In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain). 	SIGNOR-276652	0.2
ANK1	protein	P16157	UNIPROT	SLN	protein	O00631	UNIPROT	down-regulates activity	binding			9606									28487373	t		lperfetto	These results suggest that sAnk1 interacts with SLN both directly and in complex with SERCA1 and reduces SLN's inhibitory effect on SERCA1 activity.	SIGNOR-265930	0.26
1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	PRKCA	protein	P17252	UNIPROT	up-regulates activity	binding			9606									12629049	t			Activation of PKC depends on the availability of DAG,a signaling lipid that is tightly and dynamically regulated.	SIGNOR-251559	0.8
LPAR	proteinfamily	SIGNOR-PF2	SIGNOR	PCBP2	protein	Q15366	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser189	YRPKPSSsPVIFAGG	10090	BTO:0000665								17475908	t		miannu	All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells.	SIGNOR-262669	0.2
DLL1	protein	O00548	UNIPROT	NOTCH3	protein	Q9UM47	UNIPROT	up-regulates	binding			9606									11006133	t		gcesareni	These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors.	SIGNOR-82398	0.614
YAP1	protein	P46937	UNIPROT	FBXO32	protein	Q969P5	UNIPROT	down-regulates				9606	BTO:0000222;BTO:0002314	BTO:0000887;BTO:0001103							23038772	f		gcesareni	The downregulation of fbox32 expression by high yap activity in activated satellite cells may contribute to sustaining high levels of myod in activated satellite cells.	SIGNOR-199069	0.2
INPP5D	protein	Q92835	UNIPROT	PIP3	smallmolecule	CHEBI:16618	ChEBI	down-regulates quantity	chemical modification			9606									12421919	t		gcesareni	Two inositol phosphatases implicated in the degradation of PI(3, 4, 5)P3, namely the 5_ phosphatase Src homology 2 domain containing inositol polyphosphate phosphatase (SHIP) and the 3_ phosphatase and tensin homolog deleted on chromosome ten	SIGNOR-252428	0.8
CEBPA	protein	P49715	UNIPROT	PER2	protein	O15055	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22260161	f		apalma	We have previously shown that PER2 is a downstream CCAAT-enhancer-binding protein (C/EBP)-target gene, and its disruption might be involved in the initiation and progression of acute myelogenous leukemia (AML)	SIGNOR-256369	0.406
TLR2	protein	O60603	UNIPROT	TICAM2	protein	Q86XR7	UNIPROT	up-regulates activity	binding			10090									22664090	t		scontino	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266747	0.441
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr766	ALTSNQEyLDLSMPL	10116									19224897	t		lperfetto	This second-stage autophosphorylation occurs on y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of y463 in the juxtamembrane region, y766 in the c-terminal tail, and y585 in the kinase insert region (1). The third-stage autophosphorylation takes place on the second tyrosine in the activation loop (y654), resulting in an additional 10-fold increase in the intrinsic tyrosine kinase activity of fgfr1.	SIGNOR-236203	0.2
GSK3A	protein	P49840	UNIPROT	UNG	protein	P13051	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr60	AGQEEPGtPPSSPLS	9606	BTO:0000812						phosphorylation:Ser64	EPGTPPSsPLSAEQL	27875297	t		lperfetto	Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation 	SIGNOR-264887	0.2
MARCHF1	protein	Q8TCQ1	UNIPROT	HLA-DRB4	protein	P13762	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys254	FIYFRNQkGHSGLQP	9606									19117940	t		miannu	Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination.	SIGNOR-271409	0.2
TP53	protein	P04637	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10029407	f		miannu	 p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1.	SIGNOR-255430	0.592
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257935	0.8
TGFBR2	protein	P37173	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	binding			9606									19114990	t		lperfetto	in immunoprecipitation esperiments, the TGF _ RII receptor was found to be constitutively associated with p85, the regulatory subunity of PI3K	SIGNOR-217830	0.459
STAT6	protein	P42226	UNIPROT	CHI3L1	protein	P36222	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000801								20508200	f		lperfetto	Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation.	SIGNOR-249537	0.286
SPRY4	protein	Q9C004	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002058								20501643	f		miannu	When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. 	SIGNOR-253040	0.271
MMP23B	protein	O75900	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272367	0.7
GSK3B	protein	P49841	UNIPROT	LGALS3	protein	P17931	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21821001	f		miannu	Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells.	SIGNOR-261903	0.345
CDKN1A	protein	P38936	UNIPROT	CDK6	protein	Q00534	UNIPROT	down-regulates	binding			9606									7626805	t		gcesareni	P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases	SIGNOR-30030	0.859
NCSTN	protein	Q92542	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates	binding			9606									10993067	t	Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation	gcesareni	Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2.	SIGNOR-81936	0.939
ZW10	protein	O43264	UNIPROT	RZZ complex	complex	SIGNOR-C357	SIGNOR	form complex	binding			9606									20462495	t		lperfetto	The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico.	SIGNOR-265012	0.832
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	PLA2G4A	protein	P47712	UNIPROT	up-regulates	relocalization			9606									8027085	t		gcesareni	Cytosolic phospholipase a2 (cpla2) is a calcium-sensitive 85-kda enzyme that hydrolyzes arachidonic acid-containing membrane phospholipids to initiate the biosynthesis of eicosanoids and platelet-activating factor, potent inflammatory mediators. The calcium-dependent activation of the enzyme is mediated by an n-terminal c2 domain, which is responsible for calcium-dependent translocation of the enzyme to membranes and that enables the intact enzyme to hydrolyze membrane-resident substrates. cytosolic phospholipase a2 (cpla2) associates with natural membranes in response to physiological increases in ca2+, resulting in the selective hydrolysis of arachidonyl phospholipids.	SIGNOR-35874	0.8
HDAC1	protein	Q13547	UNIPROT	FSHR	protein	P23945	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									23086931	f	 	miannu	Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription. MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment. 	SIGNOR-254225	0.2
PHKG1	protein	Q16816	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser579	NVKSKIGsTENLKHQ	-1									8999860	t		miannu	Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules	SIGNOR-250284	0.318
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr463	MLAGVSEyELPEDPR	10116	BTO:0002809;BTO:0001009								8622701	t		lperfetto	In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1	SIGNOR-236179	0.2
MASP1	protein	P48740	UNIPROT	C4B	protein	P0C0L5	UNIPROT	up-regulates activity	cleavage	Arg756	KGQAGLQrALEILQE	-1									9087411	t		lperfetto	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263426	0.663
PTEN	protein	P60484	UNIPROT	PREX2	protein	Q70Z35	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								25829446	t		irozzo	Here, we used cell biology, biochemistry, and genetic approaches to show that PTEN suppresses cell movement by blocking PREX2 GEF–catalyzed activation of the GTPase RAC1. PTEN binds PREX2 and directly inhibits GEF activity.	SIGNOR-259190	0.606
MAP3K4	protein	Q9Y6R4	UNIPROT	MAP2K6	protein	P52564	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000298								9305639	t		lperfetto	These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1.	SIGNOR-50894	0.641
NLRC4 inflammasome	complex	SIGNOR-C223	SIGNOR	Pyroptosis	phenotype	SIGNOR-PH105	SIGNOR	up-regulates				9606									30166988	f		miannu	Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma.	SIGNOR-263122	0.7
SMARCC2	protein	Q8TAQ2	UNIPROT	SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270605	0.831
PTPN1	protein	P18031	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	dephosphorylation	Tyr771	ADIESSNyMAPYDNY	-1									7545675	t			Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides	SIGNOR-248415	0.679
PPP2CA	protein	P67775	UNIPROT	PREX2	protein	Q70Z35	UNIPROT	up-regulates activity	dephosphorylation	Ser1107	DTISNRDsYSDCNSN	9606	BTO:0000007								26438819	t		miannu	PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. 	SIGNOR-277184	0.2
CYP24A1	protein	Q07973	UNIPROT	calcitriol	smallmolecule	CHEBI:17823	ChEBI	down-regulates quantity	chemical modification												30080183	t		lperfetto	Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH).	SIGNOR-270572	0.8
TAB1	protein	Q15750	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	binding			9606									17299140	t		lperfetto	The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells.	SIGNOR-153031	0.927
UBE2D1	protein	P51668	UNIPROT	ZSWIM2	protein	Q8NEG5	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16522193	t		miannu	MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin. 	SIGNOR-271554	0.325
fluoxymesterone	chemical	CHEBI:5120	ChEBI	AR	protein	P10275	UNIPROT	up-regulates activity	chemical activation			9606									10077001	t		miannu	The anabolic steroids, oxandrolone and fluoxymesterone, have high inhibition constants for binding, yet induce the N/C interaction and stabilize AR at relatively low ligand concentrations and are AR agonists in vivo.	SIGNOR-259264	0.8
SYNE1	protein	Q8NF91	UNIPROT	LINC complex	complex	SIGNOR-C303	SIGNOR	form complex	binding												24481844	t		lperfetto	LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM.	SIGNOR-263287	0.56
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation			9606									18394876	t		lperfetto	The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity	SIGNOR-252834	0.908
 Core Binding Factor complex	complex	SIGNOR-C214	SIGNOR	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				10090									19813271	f			The core binding factor (CBF), consisting of a Runx protein and the CBFβ protein, is a transcription factor complex that is essential for emergence of the hematopoietic stem cell (HSC) from an endothelial cell stage. The hematopoietic defects observed in either Runx1 or CBFβ knockout mice underscore the necessity of this complex for definitive hematopoiesis.	SIGNOR-255740	0.7
LYL1	protein	P12980	UNIPROT	ANGPT2	protein	O15123	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22792348	f		miannu	Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation.	SIGNOR-198276	0.2
PRKDC	protein	P78527	UNIPROT	GOLPH3	protein	Q9H4A6	UNIPROT	up-regulates activity	phosphorylation	Thr143	ALKHVKEtQPPETVQ	-1	BTO:0000567								24485452	t			In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents	SIGNOR-253557	0.323
SUMO1	protein	P63165	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates	sumoylation	Lys65	QQCQAEAkCPKLLPC	9534									9756909	t		lperfetto	We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation.	SIGNOR-261788	0.771
RAC1	protein	P63000	UNIPROT	WAVE complex	complex	SIGNOR-C271	SIGNOR	up-regulates activity				9606									27871158	t		lperfetto	Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex	SIGNOR-261877	0.609
SRF	protein	P11831	UNIPROT	CNN1	protein	P51911	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887;BTO:0001260							21673106	f		gcesareni	In particular, high expression of vsmc-specific genes, such as smooth muscle -actin (sma), calponin1 (cnn), and sm22 (sm22) are associated with the contractile vsmc phenotype. Transcription of contractile genes is regulated by srf through a dna sequence motif known as the carg box (cc(a/t)6gg), which is present in the promoters of vsmc-specific genes.	SIGNOR-174358	0.371
TLR4	protein	O00206	UNIPROT	MYD88	protein	Q99836	UNIPROT	up-regulates activity	binding			10090									22664090	t		gcesareni	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-252065	0.761
SVIP	protein	Q8NHG7	UNIPROT	L3MBTL1	protein	Q9Y468	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								29018219	t		lperfetto	In response to DNA damage, VCP/p97, an ATPase which unfolds proteins, removes L3MBTL1 from H4K20me2, creating free H4K20me2 for 53BP1 to bind to (Fig. 3b).	SIGNOR-262060	0.2
MLL-AF9	fusion protein	SIGNOR-FP5	SIGNOR	CBFB	protein	Q13951	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24449215	f		irozzo	However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins.	SIGNOR-255852	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MAP2K4	protein	P45985	UNIPROT	down-regulates activity	phosphorylation	Ser80	IERLRTHsIESSGKL	9606	BTO:0002181								11707464	t		miannu	Akt (Protein Kinase B) Negatively Regulates SEK1 by Means of Protein Phosphorylation. In vitro and in vivo (32)P labeling indicated that Akt phosphorylated SEK1 on serine 78. The SEK1 mutant SEK1(S78A) was resistant to Akt-induced inhibition. 	SIGNOR-275980	0.2
CREB5	protein	Q02930	UNIPROT	TGFBR3	protein	Q03167	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		 BTO:0002818							21132541	f		miannu	 Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition),	SIGNOR-253811	0.2
PAK1	protein	Q13153	UNIPROT	PGAM1	protein	P18669	UNIPROT	down-regulates	phosphorylation	Ser118	QVKIWRRsYDVPPPP	9606	BTO:0000130								12189148	t	Activated pak1	gcesareni	Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity.	SIGNOR-91594	0.2
ANKRD11	protein	Q6UB99	UNIPROT	BDNF	protein	P23560	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000142							29274743	t		miannu	Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons. 	SIGNOR-266732	0.2
POLR1C	protein	O15160	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266136	0.876
ADRA2C	protein	P18825	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256699	0.457
FUBP1	protein	Q96AE4	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19637194	f		irozzo	In our analysis of FBP1 shRNA-transduced Hep3B cells, we found that p21 mRNA levels increase following FBP1 knockdown, suggesting that FBP1 functions as a repressor of p21. Our results identify the tumor suppressor p21 as the second direct FBP1 target gene in addition to the proto-oncogene c-myc.	SIGNOR-259125	0.2
PRKCG	protein	P05129	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Ser619	SLPKINRsASEPSLH	9606									8288587	t		gcesareni	Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation.	SIGNOR-37545	0.38
1-[2-[bis[4-(trifluoromethyl)phenyl]methoxy]ethyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid	chemical	CHEBI:93185	ChEBI	SLC6A1	protein	P30531	UNIPROT	down-regulates activity	chemical inhibition			-1									7851497	t		miannu	Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. 	SIGNOR-258480	0.8
BACE2	protein	Q9Y5Z0	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Phe635	HHQKLVFfAEDVGSN	9606									10931940	t		lperfetto	BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Aβ is produced from the Aβ precursor protein (APP) by two proteolytic events. A β-secretase activity cleaves APP at the N terminus of Aβ (β site) between amino acids Met-671 and Asp-672 |We show here that BACE2 cleaves APP at its β site and more efficiently at sites within the Aβ region of APP, after Phe-19 and Phe-20 of Aβ.	SIGNOR-261775	0.561
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	guanosine 5'-monophosphate	smallmolecule	CHEBI:17345	ChEBI	up-regulates quantity	precursor of			9606									6698284	t		miannu	The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2).	SIGNOR-268096	0.8
INSR	protein	P06213	UNIPROT	PTPN1	protein	P18031	UNIPROT	up-regulates activity	phosphorylation	Tyr153	SEDIKSYyTVRQLEL	-1									11506178	t		lperfetto	Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B	SIGNOR-249369	0.778
AKT1	protein	P31749	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity	phosphorylation	Ser695	EERMRMEsRRQATVS	-1									23264741	t		miannu	 Here we show that soluble growth factors enhance integrin signaling through Akt phosphorylation of FAK at Ser695 and Thr700. 	SIGNOR-276437	0.44
PRKAA1	protein	Q13131	UNIPROT	NOS2	protein	P35228	UNIPROT	down-regulates				9606	BTO:0000801	BTO:0000887							14985344	f		gcesareni	Ampk by insulin-sensitizing drugs markedly inactivates in- ducible nitric-oxide synthase (inos).	SIGNOR-120827	0.326
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	GYS1	protein	P13807	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136553	0.2
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	TRIM63	protein	Q969Q1	UNIPROT	up-regulates activity	transcriptional regulation			10090									PMC3619734	f		areggio	Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1induction.	SIGNOR-254990	0.2
CSNK2A1	protein	P68400	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates activity	phosphorylation	Ser1112	VPIAVGEsDFENLNT	9606	BTO:0000938								19064667	t		lperfetto	 We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275753	0.2
APEX1	protein	P27695	UNIPROT	CYP11B2	protein	P19099	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22652909	f		miannu	 We conclude that APEX1 is a novel transcriptional repressor of CYP11B2 and that differential APEX1 binding at -1651 of CYP11B2 results in altered gene expression. 	SIGNOR-253736	0.351
GSK1292263	chemical	CID:24996872	PUBCHEM	GPR119	protein	Q8TDV5	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257500	0.8
SRC	protein	P12931	UNIPROT	GRK2	protein	P25098	UNIPROT	up-regulates activity	phosphorylation	Tyr86	ARPLVEFyEEIKKYE	9606	BTO:0000007								16725308	t		miannu	Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq. 	SIGNOR-266306	0.2
CSNK2A1	protein	P68400	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates activity	phosphorylation	Ser1126	TEEFSSEsDMEESKE	9606	BTO:0000938								19064667	t		lperfetto	 We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275761	0.2
POLR2K	protein	P53803	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266141	0.798
PAX7	protein	P23759	UNIPROT	MLL2 complex	complex	SIGNOR-C88	SIGNOR	up-regulates	binding			9606	BTO:0002314	BTO:0000887;BTO:0001103							22863532	t		lperfetto	Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5.	SIGNOR-217712	0.31
CAMK2G	protein	Q13555	UNIPROT	GRIA1	protein	P42261	UNIPROT	up-regulates activity	phosphorylation	Ser849	FCLIPQQsINEAIRT										12609872	t		llicata	Direct phosphorylation of the GluR1 subunit of postsynaptic AMPA receptors by Ca(2+)/calmodulin-dependent protein kinase II (CaM-KII) is believed to be one of the major contributors to the enhanced strength of glutamatergic synapses in CA1 area of hippocampus during long-term potentiation. | Validity of the approach was confirmed by modeling, and silence analysis was applied then to the GluR1 AMPA receptor mutated at S831, the site phosphorylated by CaM-KII during long-term potentiation. Silence analysis indicates that a negative charge at S831 is a critical determinant for the enhanced channel function as a charge carrier. Silence and variance analyses, when applied to the same sets of data, were in agreement on the receptor regulation upon mutations.	SIGNOR-250698	0.614
CAMK2A	protein	Q9UQM7	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	up-regulates activity	phosphorylation	Ser772	LFKKIFPsLELNITD	9606	BTO:0004553								24614225	t		gianni	NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity.	SIGNOR-266433	0.311
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	TRIM63	protein	Q969Q1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								18612045	f		lperfetto	Transcriptional reporter assays performed in both HepG2 and C2C12 cells demonstrate that the MuRF1 promoter is highly responsive to dexamethasone-activated glucocorticoid receptor (GR) and FoxO1 individually, while co-overexpression of GR and FoxO1 leads to a dramatic synergistic increase in reporter activity	SIGNOR-252927	0.2
CAPN1	protein	P07384	UNIPROT	F2R	protein	P25116	UNIPROT	up-regulates activity	cleavage	Lys32	RARRPESkATNATLD	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus	SIGNOR-263559	0.383
DGC	complex	SIGNOR-C217	SIGNOR	GABA-A (a6-b2-d) receptor	complex	SIGNOR-C328	SIGNOR	up-regulates quantity	binding			9606	BTO:0000938;BTO:0002606								22626542	t		miannu	 In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses.	SIGNOR-265440	0.2
CSNK2A1	protein	P68400	UNIPROT	XRCC1	protein	P18887	UNIPROT	up-regulates	phosphorylation	Thr519	EDPYAGStDENTDSE	9606	BTO:0000567								15367657	t		lperfetto	Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523	SIGNOR-128897	0.404
PRKDC	protein	P78527	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates	phosphorylation	Thr2609	LTPMFVEtQASQGTL	9606									17189255	t		gcesareni	Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, we have reported here that atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster.	SIGNOR-151449	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SCN2A	protein	Q99250	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000938								32599005	t		lperfetto	For example, protein kinase A (PKA) and protein kinase C (PKC) have been shown to phosphorylate multiple serine residues on the interdomain I-II and III-IV linkers of Nav1.2, significantly reducing current and increasing firing thresholds 	SIGNOR-275749	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PPM1B	protein	O75688	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser195	MIQRVNGsLAVSRAL	9606	BTO:0000007								23756813	t		miannu	Here, we show that protein kinase A (PKA) phosphorylates the PP2Cβ, which was inhibited by PKA-specific inhibitor, H89. Mutation analysis of serine residues in PP2Cβ revealed that Ser-195 in PP2Cβ is phosphorylated by PKA. Importantly, PKA inhibition by H89 abrogated the Forskolin-induced destabilization of PP2Cβ against ubiquitin-dependent proteosomal degradation pathway.	SIGNOR-276494	0.2
ABCC8	protein	Q09428	UNIPROT	KATP channel	complex	SIGNOR-C274	SIGNOR	form complex	binding			9606									28842488	t		lperfetto	ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits.	SIGNOR-262056	0.641
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1619	SPSYSPTsPSYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269382	0.718
PTPRR	protein	Q15256	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Tyr187	HTGFLTEyVATRWYR	9534	BTO:0004055								11493009	t			Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL.|PTP-SL dephosphorylates the regulatory phosphotyrosine on the active loop of ERK1/2. Tyrosine dephosphorylation of ERK1/2 causes the inactivation of ERK1/2 and its retention in the cytoplasm	SIGNOR-248840	0.816
SRC	protein	P12931	UNIPROT	ENG	protein	P17813	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr612	LLTAALWyIYSHTRS	9606	BTO:0002828								25070888	t		miannu	We identified epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) as Src-activators that induce endoglin turnover following (612)YIY(614) phosphorylation. 	SIGNOR-276655	0.395
PTPN3	protein	P26045	UNIPROT	VCP	protein	P55072	UNIPROT	down-regulates activity	dephosphorylation	Tyr796	GGTGGSVyTEDNDDD	9606	BTO:0000007								10364224	t			Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs. 	SIGNOR-248460	0.491
NCL	protein	P19338	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by expression	post transcriptional regulation			9606									16508016	t	Regulation	miannu	Nucleolin binds human β-globin mRNA. A Nucleolin-Binding 3′ Untranslated Region Element Stabilizes β-Globin mRNA In Vivo	SIGNOR-251844	0.2
GSK3A	protein	P49840	UNIPROT	TSC2	protein	P49815	UNIPROT	up-regulates	phosphorylation			9606							phosphorylation:Ser1387	QPLSKSSsSPELQTL	20226003	t		gcesareni	Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation.	SIGNOR-164098	0.37
gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	GABA-A (a6-b3-d) receptor	complex	SIGNOR-C329	SIGNOR	up-regulates activity	chemical activation			9606									18790874	t	brain	lperfetto	Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS).	SIGNOR-263793	0.8
BECN1	protein	Q14457	UNIPROT	ZWINT	protein	O95229	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								23478334	t		lperfetto	We show that Beclin-1 interacts directly with Zwint-1-a component of the KMN (KNL-1/Mis12/Ndc80) complex-which is essential for kinetochore-microtubule interactions. This suggests that Beclin-1 acts downstream of the KMN complex to influence the recruitment of outer kinetochore proteins and promotes accurate kinetochore anchoring to the spindle during mitosis.	SIGNOR-265027	0.446
PCSK2	protein	P16519	UNIPROT	Corticotropin	protein	P01189-PRO_0000024969	UNIPROT	up-regulates quantity	cleavage												24631756	t		lperfetto	POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide	SIGNOR-268725	0.2
IKBKE	protein	Q14164	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates activity	phosphorylation			9606									15489227	t		miannu	Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro.	SIGNOR-217379	0.433
F2R	protein	P25116	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates	binding			9606									22318735	t		gcesareni	Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13).	SIGNOR-196009	0.376
CD79A	protein	P11912	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000776								12324477	f		gcesareni	Bcr ligation activated mitochondrial apoptotic pathways including down-regulation of bcl-x(l).	SIGNOR-93481	0.273
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-)	smallmolecule	CHEBI:58725	ChEBI	up-regulates quantity	precursor of			9606									21310273	t		miannu	GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans	SIGNOR-268097	0.8
HOXA7	protein	P31268	UNIPROT	TGM1	protein	P22735	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000667								11435435	f		miannu	Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes. 	SIGNOR-254474	0.2
BCL2L11	protein	O43521	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								15694340	t		lperfetto	Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1.	SIGNOR-133820	0.811
AMOT	protein	Q4VCS5	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates	relocalization			9606	BTO:0000567								21205866	t	AMOT proteins, a family of proteins including AMOT, AMOTL1, and AMOTL2, interact extensively with multiple TJ components and are important for maintaining TJ integrity and epithelial cell polarity.	gcesareni	Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition.	SIGNOR-175776	0.669
AMPK	complex	SIGNOR-C15	SIGNOR	SREBF1	protein	P36956	UNIPROT	down-regulates	phosphorylation	Ser396	TAVHKSKsLKDLVSA	9606									21459323	t		lperfetto	Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372	SIGNOR-216533	0.324
IL19	protein	Q9UHD0	UNIPROT	IL20RB	protein	Q6UXL0	UNIPROT	up-regulates	binding			9606									17208301	t		gcesareni	Il-19 signals only through the type i il-20r complex.	SIGNOR-151820	0.708
MTOR	protein	P42345	UNIPROT	MTOR	protein	P42345	UNIPROT	up-regulates activity	phosphorylation	Ser2481	TVPESIHsFIGDGLV	9606	BTO:0000782		SIGNOR-C2	SIGNOR-C2					10702316	t		lperfetto	We report here the identification of a FRAP autophosphorylation site. This site, Ser-2481, is located in a hydrophobic region near the conserved carboxyl-terminal FRAP tail. We demonstrate that the COOH-terminal tail is required for FRAP kinase activity and for signaling to the translational regulator p70(s6k) (ribosomal subunit S6 kinase).	SIGNOR-75394	0.2
PAX7	protein	P23759	UNIPROT	KMT2A	protein	Q03164	UNIPROT	up-regulates	binding			9606				SIGNOR-C89					22863532	t		miannu	Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5.	SIGNOR-198626	0.2
RPL37A	protein	P61513	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262462	0.816
RPS6KA3	protein	P51812	UNIPROT	HMGN1	protein	P05114	UNIPROT	unknown	phosphorylation	Ser7	sSAEGAAK	10090									12773393	t		lperfetto	The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 and HMG-14 at Ser6 after stimulation of primary embryonic fibroblasts by TPA or anisomycin.	SIGNOR-249215	0.371
D-fructofuranose 6-phosphate(2-)	smallmolecule	CHEBI:61527	ChEBI	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	precursor of			9606									21310273	t		miannu	GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans	SIGNOR-267813	0.8
TFE3	protein	P19532	UNIPROT	CLCN3	protein	P51790	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276813	0.2
CAMK1	protein	Q14012	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates activity	phosphorylation	Thr157	GIRKRPAtDDSSTQN	10090									23707388	t		Monia	We also demonstrate that i) CaMKI phosphorylates p27 at Thr157and Thr198 in human cells and at Thr170and Thr197in mouse cells to modulate its subcellular localization;	SIGNOR-261195	0.309
FERMT1	protein	Q9BQL6	UNIPROT	FBLIM1	protein	Q8WUP2	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								24165133	t		miannu	Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 	SIGNOR-266103	0.462
DTX1	protein	Q86Y01	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	ubiquitination			7227									22162134	t		lperfetto	The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch	SIGNOR-219269	0.773
2-[[2-[[2-[[2-[[2-amino-3-(4-hydroxyphenyl)-1-oxopropyl]amino]-1-oxoethyl]amino]-1-oxoethyl]amino]-1-oxo-3-phenylpropyl]amino]-4-methylpentanoic acid	chemical	CHEBI:91634	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258806	0.8
CDK5	protein	Q00535	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates	phosphorylation	Ser133	LPYSPVSsPQSSPRL	9606									22778263	t		lperfetto	Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity.	SIGNOR-198115	0.2
RORB	protein	Q92753	UNIPROT	ARNTL	protein	O00327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18418469	t		miannu	 RORβ and RORγ are also able to induce Bmal1 activity; however, RORα4 appears the most effective in inducing this activity. The ROREs in the Bmal1 promoter also bind ROR receptors. Overexpression of RORα1 and RORα4 induces Bmal1-promoter activity by interacting with these ROREs	SIGNOR-266852	0.492
SGCA	protein	Q16586	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255985	0.54
PRKCQ	protein	Q04759	UNIPROT	MSN	protein	P26038	UNIPROT	unknown	phosphorylation	Thr558	LGRDKYKtLRQIRQG	9606	BTO:0001545								9856983	t		lperfetto	By using mass spectroscopy and direct microsequencing of CNBr fragments of phospho-moesin, the phosphorylation site was identified as KYKT*LRQIR (where * indicates the phosphorylation site) (Thr558), which is conserved in the ERM family | Thus, PKC-theta is identified as a major kinase within cells with specificity for moesin and with activation under non-classical PKC conditions. It appears likely that this activity corresponds to a specific intracellular pathway controlling the function of moesin as well as other ERM proteins.	SIGNOR-249013	0.46
METTL3	protein	Q86U44	UNIPROT	UCK2	protein	Q9BZX2	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation												34430596	t		lperfetto	Furthermore, the m6A modification regulated by METTL3 led to UCK2 increased messenger RNA (mRNA) stability in melanoma cancer. Functional and mechanistic experiments indicated that UCK2 enhanced the metastasis of melanoma cancer cells through the WNT/β-catenin pathway.	SIGNOR-275862	0.2
PRKACA	protein	P17612	UNIPROT	CHKB	protein	Q9Y259	UNIPROT	up-regulates activity	phosphorylation	Ser39	TPKRRRAsSLSRDAE										27149373	t		lperfetto	Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. 	SIGNOR-275630	0.255
PAK1	protein	Q13153	UNIPROT	TBCB	protein	Q99426	UNIPROT	up-regulates	phosphorylation	Ser65	GVDDKFYsKLDQEDA	9606	BTO:0000150								15831477	t		lperfetto	P21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor b. Pak1 directly phosphorylated tcob in vitro and in vivo on serines 65 and 128 and colocalized with tcob on newly polymerized microtubules and on centrosomes. Pak1 phosphorylation is necessary for normal tcob function	SIGNOR-135464	0.46
INSR	protein	P06213	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	phosphorylation	Tyr1229	SSEDLSAyASISFQK	10029	BTO:0000246								7651388	t		lperfetto	Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir).	SIGNOR-236752	0.911
PTPN13	protein	Q12923	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									15611135	t		gcesareni	We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines.	SIGNOR-132559	0.263
zotepine	chemical	CHEBI:32316	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			9534									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258556	0.8
PRKACA	protein	P17612	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Thr169	FLPRHRDtGILDSIG	-1									2413024	t		miannu	Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-165	SIGNOR-250015	0.352
PAK2	protein	Q13177	UNIPROT	MYL12A	protein	P19105	UNIPROT	up-regulates activity	phosphorylation	Ser19	KRPQRATsNVFAMFD	-1									10047984	t		miannu	 In this study we report that gamma-PAK, which is activated by the GTP-binding proteins Cdc42 and Rac, catalyses phosphorylation of intact non-muscle myosin II and isolated recombinant RLC. Phosphopeptide maps and phosphoamino acid analysis revealed that gamma-PAK phosphorylates Ser-19 but does not phosphorylate Thr-18.Taken together, these data suggest that myosin II activation by the p21-activated family of kinases may be physiologically important in regulating cytoskeletal organization.	SIGNOR-263020	0.473
PELI3	protein	Q8N2H9	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates	ubiquitination			9606									17997719	t		gcesareni	These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4.	SIGNOR-159061	0.717
WNT7A	protein	O00755	UNIPROT	FZD7	protein	O75084	UNIPROT	up-regulates activity	binding			9606	BTO:0002314	BTO:0001103							23290138	t		apalma	Our previous work has demonstrated that ligation of Wnt7a to Fzd7 activates the planar cell polarity (PCP) pathway […] Therefore, we conclude that the Fzd7/Sdc4 co-receptor complex binds both Wnt7a and FN.	SIGNOR-255845	0.665
SOX9	protein	P48436	UNIPROT	CDX2	protein	Q99626	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15240568	f			SOX9 represses the expression of the CDX2 transcription factor, known to be mostly active in villus cells.	SIGNOR-253322	0.391
CDK1	protein	P06493	UNIPROT	KHDRBS1	protein	Q07666	UNIPROT	unknown	phosphorylation	Thr317	RGALVRGtPVRGAIT	9606									9315091	t		lperfetto	Phosphorylation of sam68 by purified cdc2.	SIGNOR-51275	0.516
AKT2	protein	P31751	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates	phosphorylation	Ser1834	MLRRRMAsMQRTGVV	9606									16926151	t		lperfetto	We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity	SIGNOR-148987	0.333
Unfolded_Proteins	stimulus	SIGNOR-ST22	SIGNOR	CREB3L1	protein	Q96BA8	UNIPROT	up-regulates				9606									16417584	f		miannu	Oasis (old astrocyte specifically induced substance) is an er stress transducer in astrocytes, a membrane-bound transcription factor that activates genes in the er stress response / when unfolded proteins accumulate in the er, oasis is cleaved at the membrane to release its cytoplasmic domain, which then enters the nucleus and activates target genes.	SIGNOR-143823	0.7
ATM	protein	Q13315	UNIPROT	CHEK1	protein	O14757	UNIPROT	up-regulates	phosphorylation	Ser317	ENVKYSSsQPEPRTG	9606									20068082	t		gcesareni	Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation.	SIGNOR-163106	0.84
PRSS1	protein	P07477	UNIPROT	F2RL1	protein	P55085	UNIPROT	up-regulates activity	cleavage	Arg36	TNRSSKGrSLIGKVD	-1									10978167	t		lperfetto	Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3. 	SIGNOR-263602	0.373
(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	ADRA2B	protein	P18089	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257454	0.8
CDKN2A	protein	Q8N726	UNIPROT	NPM1	protein	P06748	UNIPROT	down-regulates quantity by destabilization	binding			9606									14636574	t		gcesareni	The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division	SIGNOR-245077	0.57
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	unknown	phosphorylation			9606									21071439	t	inferred from 70% family members	lperfetto	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-270027	0.2
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9534	BTO:0000298								9482734	t		lperfetto	Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin	SIGNOR-227862	0.892
CDK1	protein	P06493	UNIPROT	FOXK2	protein	Q01167	UNIPROT	up-regulates	phosphorylation	Ser428	FAQSAPGsPLSSQPV	9606									20810654	t		gcesareni	We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis.	SIGNOR-167826	0.38
PYGB	protein	P11216	UNIPROT	glycogen	smallmolecule	CHEBI:28087	ChEBI	down-regulates quantity	chemical modification			9606									3346228	t			Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267395	0.8
NBEA	protein	Q8NFP9	UNIPROT	DLG3	protein	Q92796	UNIPROT	up-regulates activity	binding					BTO:0000227							23277425	t		lperfetto	Interestingly, a recent proteomic analysis (Lauks et al., 2012) revealed that Nbea binds SAP102, which interacts with glutamate receptors early in the biosynthetic route and regulates their targeting. This finding, along with the interaction of Nbea with the glycine receptor beta subunit (del Pino et al., 2011), further strengthens the notion that Nbea targets neurotransmitter receptors to synapses.	SIGNOR-266004	0.431
AMPK	complex	SIGNOR-C15	SIGNOR	EPM2A	protein	O95278	UNIPROT	up-regulates activity	phosphorylation			-1									18029386	t		miannu	Here, we provide evidence indicating that the formation of the laforin–malin complex is positively regulated by AMPK. We show that laforin, but not malin, can interact physically with the catalytic subunit of AMPK and that purified AMPK phosphorylates GST::laforin in vitro.	SIGNOR-271730	0.357
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	SIRT3	protein	Q9NTG7	UNIPROT	up-regulates activity	phosphorylation	Thr150	MVGAGIStPSGIPDF	9606	BTO:0001109								26141949	t		miannu	 Posttranscriptionally, SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by cyclin B1-CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3. 	SIGNOR-276922	0.295
PRKCA	protein	P17252	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates	phosphorylation	Ser742	GEKSFRRsVVGTPAY	9606									10197446	t		llicata	These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748.	SIGNOR-66670	0.421
Vps34 Complex II	complex	SIGNOR-C241	SIGNOR	Autophagosome_formation	phenotype	SIGNOR-PH36	SIGNOR	up-regulates													30397185	f		lperfetto	PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively.	SIGNOR-260324	0.7
GRIN2C	protein	Q14957	UNIPROT	GRIN1	protein	Q05586	UNIPROT	up-regulates activity	binding			10090	BTO:0004278								19477150	t		miannu	Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. These data are all consistent with a model in which NR1 and NR2C oligomerize, PKB phosphorylates S1096, and 14-3-3ε binds to phosphorylated NR2C thereby promoting NR2C-containing NMDA receptor surface expression in cerebellar granule cells. 	SIGNOR-262621	0.594
S100A8	protein	P05109	UNIPROT	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	up-regulates quantity by stabilization	binding			9606	BTO:0000876								16690079	t		miannu	Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner	SIGNOR-261937	0.2
LPAR4	protein	Q99677	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257325	0.2
ITGB1	protein	P05556	UNIPROT	A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253184	0.773
PPM1B	protein	O75688	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates activity	dephosphorylation			9606									23320500	t		miannu	Furthermore we show that PPM1B can directly dephosphorylate PPARgamma, both in intact cells and in vitro.|In addition PPM1B increases PPARγ-mediated transcription via dephosphorylation of Ser(112).|The serine/threonine phosphatase PPM1B (PP2Cbeta) selectively modulates PPARgamma activity.	SIGNOR-277073	0.379
HSD3B1	protein	P14060	UNIPROT	progesterone	smallmolecule	CHEBI:17026	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000048							2243100	t		lperfetto	Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens.	SIGNOR-268635	0.8
regorafenib	chemical	CHEBI:68647	ChEBI	DDR2	protein	Q16832	UNIPROT	down-regulates activity	chemical inhibition			9606									24756792	t		miannu	In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically.	SIGNOR-259208	0.8
CHD8	protein	Q9HCK8	UNIPROT	CCNE2	protein	O96020	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								19255092	t		miannu	In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells, finding out that CHD8 controls the expression of cyclin E2 (CCNE2) and thymidylate synthetase (TYMS), two genes expressed in the G1/S transition of the cell cycle. CHD8 was also able to co-activate the CCNE2 promoter in transient transfection experiments. Chromatin immunoprecipitation experiments demonstrated that CHD8 binds directly to the 5' region of both CCNE2 and TYMS genes. 	SIGNOR-268804	0.429
AMPK	complex	SIGNOR-C15	SIGNOR	NEDD4L	protein	Q96PU5	UNIPROT	up-regulates activity	phosphorylation	Ser795	VDLKPNGsEIMVTNE	-1									21501591	t		miannu	The AMP-activated protein kinase (AMPK) down-regulates the inward rectifier K+ channel Kir2.1. Expression of wild type Nedd4-2 or of Nedd4-2S795A lacking an AMPK phosphorylation consensus sequence downregulated Kir2.1 currents. The effect of wild type Nedd4-2 but not of Nedd4-2S795A was significantly augmented by additional coexpression of AMPK.	SIGNOR-276326	0.258
mTORC2	complex	SIGNOR-C2	SIGNOR	PRKCE	protein	Q02156	UNIPROT	up-regulates activity	phosphorylation	Thr710	TREEPVLtLVDEAIV	9606									21806543	t		miannu	In the present study, we have identified the mTORC2 subunit Sin1 as a direct binding partner of the PKC (protein kinase C) ε kinase domain and map the interaction to the central highly conserved region of Sin1. Exploiting the conformational dependence for PKC phosphorylation, we demonstrate that mTORC2 is essential for acute priming of PKC. 	SIGNOR-276347	0.324
MAPKAPK2	protein	P49137	UNIPROT	ELAVL1	protein	Q15717	UNIPROT	up-regulates	phosphorylation			9606									20626350	t		gcesareni	Mk2 and mk3 participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating the are-binding proteins ttp and hur, and by regulating eef2k	SIGNOR-166622	0.309
CLK4	protein	Q9HAZ1	UNIPROT	NR5A1	protein	Q13285	UNIPROT	up-regulates activity	phosphorylation	Ser203	EYPEPYAsPPQPGLP	9606	BTO:0000007								35592512	t	done	miannu	Immunoblotting analyses showed that the phosphorylation status of NR5A1 at Ser203 was attenuated by the CLK1/4 inhibitor.	SIGNOR-274117	0.2
MDH1	protein	P40925	UNIPROT	(S)-malate(2-)	smallmolecule	CHEBI:15589	ChEBI	down-regulates quantity	chemical modification			9606									24068518	t		miannu	Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle	SIGNOR-266283	0.8
CAMK2D	protein	Q13557	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser571	PWPLRRTsAQGQPSP	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275777	0.48
NFIA	protein	Q12857	UNIPROT	FOXO6	protein	A8MYZ6	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268875	0.2
EP300	protein	Q09472	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates	binding			9606			SIGNOR-C6						11062529	t		gcesareni	The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis.	SIGNOR-83846	0.73
CUX2	protein	O14529	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				10090									26221032	f		miannu	Genetic inactivation in mouse embryo fibroblasts or CUX2 knockdown in HCC38 cells delayed DNA repair and increased DNA damage. These results demonstrate that CUX2 functions as an accessory factor that stimulates the repair of oxidative DNA damage	SIGNOR-263958	0.7
ERG	protein	P11308	UNIPROT	ERG	protein	P11308	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001106								21536859	f	 	miannu	 We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer.	SIGNOR-253925	0.2
XAF1	protein	Q6GPH4	UNIPROT	BIRC2	protein	Q13490	UNIPROT	down-regulates	binding			9606									17613533	t		gcesareni	Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3.	SIGNOR-156843	0.426
entinostat	chemical	CHEBI:132082	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191481	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	THBD	protein	P07204	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15677570	f	 	miannu	We further show evidence suggesting that NF-κB inhibits TM expression indirectly by competition for the coactivator p300/CBP. 	SIGNOR-253909	0.2
HLA-G	protein	P17693	UNIPROT	LILRB1	protein	Q8NHL6	UNIPROT	up-regulates	binding			9606									15718280	t		gcesareni	Hla-g binds a limited repertoire of peptides and interacts with the inhibitory leukocyte ig-like receptors lir-1 and lir-2	SIGNOR-134180	0.763
CASP3	protein	P42574	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates activity	cleavage	Asp345	EEWEAQRdSHLGPHR	-1									10069390	t		lperfetto	Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.	SIGNOR-261756	0.466
NMDA	proteinfamily	SIGNOR-PF56	SIGNOR	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								11052931	t		miannu	Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor	SIGNOR-264801	0.2
TWIST1	protein	Q15672	UNIPROT	ILK	protein	Q13418	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255528	0.286
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1721	SPTSPSYsPTSPSYS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248823	0.849
MECP2	protein	P51608	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0004102								18952054	t		Luana	The interaction of MeCP2 with the 2BI3 and 2BI5 sites was strikingly reduced in neurons maintained in the presence of TTX (Fig. 2C). This result is consistent with the classical view of MeCP2 as a general transcriptional repressor, in that the reduced association leads to increased expression of NR2B.	SIGNOR-264685	0.358
ATM	protein	Q13315	UNIPROT	RPA2	protein	P15927	UNIPROT	up-regulates	phosphorylation	Thr21	YGGAGGYtQSPGGFG	9606									14872059	t		lperfetto	Replication protein a (rpa) is a single-stranded dna (ssdna) binding protein involved in various processes, including nucleotide excision repair and dna replication. The 32 kda subunit of rpa (rpa32) is phosphorylated in response to various dna-damaging agents, and two protein kinases, ataxia-telangiectasia mutated (atm) and the dna-dependent protein kinase (dna-pk) have been implicated in dna damage-induced phosphorylation of rpa32we show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro.	SIGNOR-121861	0.803
JWOGUUIOCYMBPV-GMFLJSBRSA-N	chemical	CID:6918328	PUBCHEM	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257914	0.8
PI-103	chemical	CHEBI:90524	ChEBI	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206166	0.8
ABL1	protein	P00519	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	phosphorylation	Tyr266	TDSIRDEyAFLQKKY	9606	BTO:0000793								29022905	t		miannu	In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation.	SIGNOR-277328	0.263
RHOA	protein	P61586	UNIPROT	FHL2	protein	Q14192	UNIPROT	up-regulates	relocalization			9606									11847121	t		gcesareni	Here, we show that stimulation of the rho pathway induces translocation of the transcriptional lim-only coactivator fhl2 to the nucleus and subsequent activation of fhl2- and androgen receptor-dependent genes.	SIGNOR-114071	0.355
EEF1A1P5	protein	Q5VTE0	UNIPROT	Tyr-tRNA(Tyr)	smallmolecule	CHEBI:29161	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269558	0.8
IL1RAP	protein	Q9NPH3	UNIPROT	TOLLIP	protein	Q9H0E2	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								10854325	t		lperfetto	Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) 	SIGNOR-251979	0.622
CALM1	protein	P0DP23	UNIPROT	GEM	protein	P55040	UNIPROT	up-regulates activity	binding			10116									14701738	t		miannu	Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells.	SIGNOR-261716	0.337
ponatinib	chemical	CHEBI:78543	ChEBI	LYN	protein	P07948	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000830								23539538	t		miannu	Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells	SIGNOR-259273	0.8
PHKA1	protein	P46020	UNIPROT	PHKA1	protein	P46020	UNIPROT	up-regulates activity	phosphorylation	Ser1007	TGIMQLKsEIKQVEF	-1									10487978	t		miannu	Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation)	SIGNOR-250280	0.2
ACP1	protein	P24666	UNIPROT	EPHA2	protein	P29317	UNIPROT	down-regulates activity	dephosphorylation	Tyr772	EDDPEATyTTSGGKI	-1									21538645	t		gcesareni	The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates	SIGNOR-246027	0.646
WNT5A	protein	P41221	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131841	0.749
MAPK3	protein	P27361	UNIPROT	FGFR1	protein	P11362	UNIPROT	down-regulates	phosphorylation	Ser777	SMPLDQYsPSFPDTR	9606									23405013	t		lperfetto	Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling	SIGNOR-200884	0.326
LPAR3	protein	Q9UBY5	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates	binding			9606									15856019	t		gcesareni	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13.	SIGNOR-135843	0.443
MAPK14	protein	Q16539	UNIPROT	TCF3	protein	P15923	UNIPROT	up-regulates activity	phosphorylation	Ser139	LNSPGPLsPSGMKGT	9606		BTO:0000887							15719023	t		lperfetto	Here we show that p38 mapk, whose activity is essential for myogenesis, regulates myod/e47 heterodimerization. Phosphorylation of e47 at ser140 by p38 induces myod/e47 association and activation of muscle-specific transcription	SIGNOR-134194	0.458
EIF1B	protein	O60739	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	down-regulates activity				9606									14600024	f		lperfetto	Binding of eIF1 to the 40S subunit would block access of the 60S	SIGNOR-269146	0.254
PRKACA	protein	P17612	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1223	SSSTRRSsEDLSAYA	9606		BTO:0000975							17360977	t		lperfetto	Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223	SIGNOR-236603	0.2
GAS2	protein	O43903	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates				9606									24706950	f		miannu	Previous work has shown that members of the growth-arrest-specific 2 (GAS2) family mediate the crosstalk between filamentous actin (F-actin) and MTs, but the molecular basis of this process remained unclear. By using fluorescence microscopy, we demonstrate that three members of this family, GAS2-like 1, GAS2-like 2 and GAS2-like 3 (G2L1, G2L2 and G2L3, also known as GAS2L1, GAS2L2 and GAS2L3, respectively) are differentially involved in mediating the crosstalk between F-actin and MTs. 	SIGNOR-273701	0.7
NR0B2	protein	Q15466	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates activity	binding			9606									17094771	t		miannu	SHP repressed C/EBPalpha (CCAAT/enhancer-binding protein alpha)-driven transcription of PEPCK through direct interaction with C/EBPalpha protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPalpha and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription.	SIGNOR-254831	0.273
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGA3	protein	Q9Y5H0	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265699	0.2
STXBP2	protein	Q15833	UNIPROT	STX11-VAMP8 SNARE complex	complex	SIGNOR-C273	SIGNOR	form complex	binding			9606	BTO:0000132								22767500	t		lperfetto	Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. 	SIGNOR-267727	0.56
TEK	protein	Q02763	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000222								26042050	f		lperfetto	the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein.	SIGNOR-241532	0.276
SMO	protein	Q99835	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates	phosphorylation			9606									23074268	t		gcesareni	Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion.	SIGNOR-199156	0.404
CREB3L1	protein	Q96BA8	UNIPROT	CREB3L1	protein	Q96BA8	UNIPROT	up-regulates activity	binding			-1									12805554	t		miannu	E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins	SIGNOR-224205	0.2
AUTS2	protein	Q8WXX7	UNIPROT	Polycomb repressive complex 1	complex	SIGNOR-C408	SIGNOR	down-regulates activity	binding			9606	BTO:0000007								25519132	t		miannu	We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2-mediated recruitment of P300 leads to gene activation.	SIGNOR-266814	0.361
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr522	SSPGSPGtPGSRSRT	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249347	0.729
PBK	protein	Q96KB5	UNIPROT	PRDX1	protein	Q06830	UNIPROT	up-regulates	phosphorylation	Ser32	QFKDISLsDYKGKYV	9606	BTO:0000782;BTO:0000848;BTO:0001286								20647304	t		lperfetto	We report that prx1 is newly discovered direct target of topk. Our results demonstrate that topk phosphorylation of prx1 at ser-32 inhibits uvb-induced apoptosis in rpmi7951 melanoma cells by increasing prx1 peroxidase activity and decreasing the intracellular accumulation of h2o2.	SIGNOR-166901	0.263
PRKCD	protein	Q05655	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser1101	GCRRRHSsETFSSTP	10029	BTO:0000246								15364919	t		lperfetto	Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101).	SIGNOR-249267	0.632
ZNF165	protein	P49910	UNIPROT	PMEPA1	protein	Q969W9	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000356								26567849	t		Luana	ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1.	SIGNOR-266094	0.275
TOMM70	protein	O94826	UNIPROT	HSPA1A	protein	P0DMV8	UNIPROT	up-regulates activity	binding			9534									12526792	t		miannu	The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting.	SIGNOR-261380	0.2
UBE2D2	protein	P62837	UNIPROT	TRIM22	protein	Q8IYM9	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								18656448	t		miannu	 It was found that TRIM22 underwent self-ubiquitylation in vitro in combination with the E2 enzyme UbcH5B and the ubiquitylation was dependent on its RING finger domain. Further evidences showed that TRIM22 could also be self-ubiquitylated in vivo. Importantly, TRIM22 was conjugated with poly-ubiquitin chains and stabilized by the proteasome inhibitor in 293T cells, suggesting that TRIM22 targeted itself for proteasomal degradation through the poly-ubiquitylation. We also found that TRIM22 was located in the nucleus, indicating that TRIM22 might function as a nuclear E3 ubiquitin ligase.	SIGNOR-271779	0.306
CDK2	protein	P24941	UNIPROT	CCP110	protein	O43303	UNIPROT	down-regulates activity	phosphorylation	Ser400	PINACELsPKGKEQA	-1									12361598	t		miannu	GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)	SIGNOR-265956	0.531
IL6	protein	P05231	UNIPROT	IL6R	protein	P08887	UNIPROT	up-regulates	binding			9606									15895091	t		gcesareni	We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model.	SIGNOR-137236	0.916
AKT1	protein	P31749	UNIPROT	DOCK6	protein	Q96HP0	UNIPROT	up-regulates activity	phosphorylation	Ser1194	GQRSRLAsMLDSDTE										23462102	t		lperfetto	Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching	SIGNOR-275666	0.382
leukotriene D4(1-)	smallmolecule	CHEBI:63166	ChEBI	CYSLTR2	protein	Q9NS75	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257476	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	TBC1D1	protein	Q86TI0	UNIPROT	down-regulates	phosphorylation	Ser237	RPMRKSFsQPGLRSL	9606									17995453	t		lperfetto	In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar	SIGNOR-216631	0.417
PIGBOS1	protein	A0A0B4J2F0	UNIPROT	ATF4	protein	P18848	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									31653868	f		miannu	We then confirmed via Western blot that TM treatment of PIGBOS-KD cells led to higher ATF4 and CHOP protein levels (Supplementary Fig. 13h). These data identified PIGBOS as a heretofore unknown mitochondrial regulator of UPR, and the only known microprotein linked to the regulation of cell stress or inter-organelle signaling. Upon UPR induction with TM, the loss of PIGBOS led to dramatic increases in the levels of all UPR target genes measured, indicating increased UPR signaling across all the branches (IRE1, PERK, and ATF6) (Fig. 6d and Supplementary Fig. 14a). Meanwhile, PIGBOS overexpressing cells showed the opposite effect, in which the UPR target genes showed less UPR activation, indicating a tunable modulation of ER stress by PIGBOS microprotein levels	SIGNOR-261041	0.2
PIM1	protein	P11309	UNIPROT	FLT3	protein	P36888	UNIPROT	up-regulates quantity	phosphorylation	Tyr591	SSDNEYFyVDFREYE	9606	BTO:0005720								24040307	t			Pim-1 Kinase Phosphorylates and Stabilizes 130 kDa FLT3 and Promotes Aberrant STAT5 Signaling in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication[...]Pim-1 inhibition also decreased phosphorylation of FLT3 at tyrosine 591 and of STAT5, and expression of Pim-1 itself, consistent with inhibition of the FLT3-ITD-STAT5 signaling pathway.	SIGNOR-259927	0.432
Pravadoline	chemical	CID:56463	PUBCHEM	PTGS2	protein	P35354	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206322	0.8
ALDH5A1	protein	P51649	UNIPROT	succinate(2-)	smallmolecule	CHEBI:30031	ChEBI	up-regulates quantity	chemical modification			9606									19300440	t		miannu	Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix.	SIGNOR-266617	0.8
PRKACG	protein	P22612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									10949026	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.	SIGNOR-81153	0.409
MRGPRX1	protein	Q96LB2	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256929	0.2
MAPK1	protein	P28482	UNIPROT	EPAS1	protein	Q99814	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser484	SSCSTPNsPEDYYTS	9606	BTO:0006155								35191554	t		miannu	The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells. 	SIGNOR-277585	0.252
Ggamma	proteinfamily	SIGNOR-PF3	SIGNOR	PCBP2	protein	Q15366	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser272	FSGIESSsPEVKGYW	10090	BTO:0000666								17475908	t		miannu	All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells.	SIGNOR-262670	0.2
MAPK3	protein	P27361	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606									19723038	t		gcesareni	The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1	SIGNOR-187779	0.709
CACNA2D3	protein	Q8IZS8	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									31746409	f		miannu	Overexpression of CACNA2D3 reduced proliferation and migration, but increased apoptosis and Ca2+ influx in Ishikawa and RL95-2 cells. 	SIGNOR-266855	0.7
EGFR	protein	P00533	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation			9606									14967450	t		lperfetto	The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation.	SIGNOR-121965	0.876
HNF4A	protein	P41235	UNIPROT	GK	protein	P32189	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18805788	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription	SIGNOR-181274	0.2
SRC	protein	P12931	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates	phosphorylation			9606									17991704	t		gcesareni	N attractive hypothesis consistent with our present data is that the gef responsible for rac activation in mce cells may be activated by src family kinase tyrosine phosphorylationour results present a novel mechanism by which the pi3k and src signaling cascades cooperate to activate rac and promote intestinal epithelial cell migration downstream of egfr.	SIGNOR-158954	0.599
ATP	smallmolecule	CHEBI:15422	ChEBI	ADP(3-)	smallmolecule	CHEBI:456216	ChEBI	up-regulates quantity	precursor of			9606									33961946	t		miannu	Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5′-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S).	SIGNOR-268079	0.8
SPAG9	protein	O60271	UNIPROT	ABL1	protein	P00519	UNIPROT	unknown	binding			9606	BTO:0000222		SIGNOR-C21						19470755	t		lperfetto	We report that abl associates with both cdo and jlp during myoblast differentiation	SIGNOR-185765	0.506
LPAR6	protein	P43657	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257120	0.2
N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methylpropanamide	chemical	CHEBI:91617	ChEBI	AR	protein	P10275	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190323	0.8
MAPK14	protein	Q16539	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates	phosphorylation	Thr299	AGLTPPTtPPHKANQ	9606		BTO:0000887							11741533	t		gcesareni	Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298	SIGNOR-112774	0.568
PRKCA	protein	P17252	UNIPROT	KIR3DL1	protein	P43629	UNIPROT	down-regulates activity	phosphorylation	Ser415	QRKITRPsQRPKTPP	-1									17911614	t		miannu	Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII.	SIGNOR-276080	0.2
JAK2	protein	O60674	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates	phosphorylation	Tyr718	IPERDSRySQPLHEE	9606									19287004	t		lperfetto	Previously we have shown that tyrosine 718 of ask1 when phosphorylated is critical for socs1 binding and socs1-mediated degradation of ask1we identified jak2 and shp2 as a tyr-718-specific kinase and phosphatase, respectively.	SIGNOR-184600	0.374
MAPK8	protein	P45983	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Ser307	TRRSRTEsITATSPA	9606									12510059	t		gcesareni	Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1.	SIGNOR-96936	0.767
R547	chemical	CID:6918852	PUBCHEM	CDK2	protein	P24941	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259793	0.8
olanzapine	chemical	CHEBI:7735	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258511	0.8
ROCK1	protein	Q13464	UNIPROT	KCNK3	protein	O14649	UNIPROT	up-regulates activity	phosphorylation	Ser393	GLMKRRSsV	9606									21838752	t		lperfetto	Task1 channels contain two putative rho kinase phosphorylation sites, ser(336) and ser(393) . Mutation of ser(393) rendered task1 channels insensitive to et(a) - or et(b)-mediated current inhibition. In contrast, removal of ser(336) selectively attenuated et(a) -dependent task1 regulation without affecting the et(b) pathway.	SIGNOR-176029	0.2
FBXW11	protein	Q9UKB1	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9606									10074433	t		gcesareni	We conclude that beta-trcp is a component of an e3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin. we found that the binding of beta-trcp to beta-catenin was direct.	SIGNOR-65429	0.734
EEF1A2	protein	Q05639	UNIPROT	His-tRNA(His)	smallmolecule	CHEBI:29155	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269531	0.8
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDUFA12	protein	Q9UI09	UNIPROT	up-regulates activity	phosphorylation	Thr120	HKFNVTGtPEQYVPY										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275596	0.2
ECSIT	protein	Q9BQ95	UNIPROT	MAVS	protein	Q7Z434	UNIPROT	up-regulates activity	binding			9606									22588174	t		Giorgia	ECSIT interacts with IPS-1|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation	SIGNOR-260371	0.439
ALK	protein	Q9UM73	UNIPROT	SHC3	protein	Q92529	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000785								12185581	t		gcesareni	Anaplastic lymphoma kinase (alk), which turned out to be one of these phosphoproteins, was constitutively activated and associated with the ptb domain of shcc in three neuroblastoma cells. In vitro kinase assay revealed that shcc is a potent substrate of the activated alk kinase. The alk gene locus was significantly amplified in both of these cell lines, suggesting that gene amplification leads to constitutive activation of the alk kinase, which results in hyperphosphorylation of shcc.	SIGNOR-91537	0.45
PRTN3	protein	P24158	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Asp62	VETVFSVdEFSASVL	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263593	0.381
PFAS	protein	O15067	UNIPROT	2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine	smallmolecule	CHEBI:147287	ChEBI	up-regulates quantity	chemical modification			9606									33179964	t		miannu	The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure.	SIGNOR-267311	0.8
GRM5	protein	P41594	UNIPROT	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							20055706	t		miannu	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264078	0.341
ZW10	protein	O43264	UNIPROT	NRZ complex	complex	SIGNOR-C358	SIGNOR	form complex	binding												25364732	t		lperfetto	NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay.	SIGNOR-265023	0.841
CCNC	protein	P24863	UNIPROT	CKM complex	complex	SIGNOR-C406	SIGNOR	form complex	binding			9606									23563140	t		miannu	The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation.	SIGNOR-266685	0.919
MAPK9	protein	P45984	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates	phosphorylation	Ser319	NSKYNAEsTERESQD	9606									18667537	t		llicata	This jnk phosphorylation of ps1 at ser(319)thr(320) enhances the stability of the ps1 c-terminal fragment that is necessary for gamma-secretase activity.	SIGNOR-179676	0.384
MAPK14	protein	Q16539	UNIPROT	MEF2A	protein	Q02078	UNIPROT	up-regulates	phosphorylation	Thr319	TPVVSVTtPSLPPQG	9606									9858528	t		lperfetto	We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a	SIGNOR-62784	0.646
JWOGUUIOCYMBPV-GMFLJSBRSA-N	chemical	CID:6918328	PUBCHEM	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257977	0.8
CDK2	protein	P24941	UNIPROT	SIRT2	protein	Q8IXJ6	UNIPROT	down-regulates	phosphorylation	Ser368	PNPSTSAsPKKSPPP	9606			SIGNOR-C16						18332217	t		llicata	We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2.	SIGNOR-177972	0.404
PAK1	protein	Q13153	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser74	VEIRSRHsSYPAGTE	9606									22096607	t		lperfetto	Bad is a pro-apoptotic member of the bcl-2 family of proteins, which can be phosphorylated on numerous sites to modulate binding to bcl-2 and 14-3-3 proteins and inhibit its pro-apoptotic activities. Together, these findings demonstrate that pak1 phosphorylates bad directly at s111, but phosphorylated s112 through raf-1. These two sites of bad serve as redundant regulatory sites for bcl-2 binding	SIGNOR-177271	0.341
orotidine 5'-phosphate(3-)	smallmolecule	CHEBI:57538	ChEBI	UMP	smallmolecule	CHEBI:16695	ChEBI	up-regulates quantity	precursor of			9606									2912371	t		miannu	Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase).	SIGNOR-267439	0.8
RUNX3	protein	Q13761	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002384								17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255098	0.252
sedoheptulose 7-phosphate	smallmolecule	CHEBI:15721	ChEBI	D-erythrose 4-phosphate(2-)	smallmolecule	CHEBI:16897	ChEBI	up-regulates quantity	precursor of			9606									19401148	t		miannu	Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 	SIGNOR-268135	0.8
IFNL3	protein	Q8IZI9	UNIPROT	IFNLR1	protein	Q8IU57	UNIPROT	up-regulates	binding			9606									12469119	t		gcesareni	Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.	SIGNOR-96243	0.843
CDK1	protein	P06493	UNIPROT	MAPK6	protein	Q16659	UNIPROT	up-regulates	phosphorylation	Ser705	TPSAMKSsPQIPHQT	9606			SIGNOR-C17						20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.	SIGNOR-164495	0.461
MAPK1	protein	P28482	UNIPROT	MRTFA	protein	Q969V6	UNIPROT	down-regulates	phosphorylation	Ser454	TGSTPPVsPTPSERS	9606									18694962	t	Translocation from Nuleus to Cytoplasm	gcesareni	Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization.	SIGNOR-179959	0.2
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	STK4	protein	Q13043	UNIPROT	up-regulates activity	cleavage	Asp326	NSEEDEMdSGTMVRA	9534	BTO:0004055								11517310	t		lperfetto	In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus.	SIGNOR-256444	0.6
GRK2	protein	P25098	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates activity	phosphorylation	Ser129	NEAYEMPsEEGYQDY	9606									10852916	t		llicata	We found that grk-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and pld2. These findings suggest that gpcrs may be able to indirectly stimulate pld2 activity via their ability to regulate grk-promoted phosphorylation of synuclein.	SIGNOR-78333	0.2
PRKCA	protein	P17252	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Thr678	RHIVRKRtLRRLLQE	9606									10816576	t		lperfetto	Biochemical and morphological analyses indicate that threonine-phosphorylated EGFR molecules undergo normal internalization, but instead of sorting to lysosomal degradation, they recycle back to the cell surfaceThe inhibitory effects of pkc are mediated by a single threonine residue (threonine 654) of egfr	SIGNOR-77421	0.591
GRIN1	protein	Q05586	UNIPROT	NMDA receptor_2B	complex	SIGNOR-C348	SIGNOR	form complex	binding			9606	BTO:0000938								12871085	t		miannu	The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits	SIGNOR-264122	0.716
HCRTR2	protein	O43614	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257350	0.252
2-[4-[3-[2-(trifluoromethyl)-9-thioxanthenylidene]propyl]-1-piperazinyl]ethanol	chemical	CHEBI:93235	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258729	0.8
KLHL3	protein	Q9UH77	UNIPROT	WNK1	protein	Q9H4A3	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000567								23387299	t		miannu	CUL3 assembles with BTB proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how a CUL3-KLHL3 complex might operate, we immunoprecipitated KLHL3 and found that it associated strongly with WNK isoforms and CUL3. These results suggest that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via its ability to interact with and ubiquitylate WNK isoforms. 	SIGNOR-272099	0.581
SRC	protein	P12931	UNIPROT	CTNND1	protein	O60716	UNIPROT	up-regulates activity	phosphorylation	Tyr228	YPGGSDNyGSLSRVT	-1									11382764	t		lperfetto	Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302	SIGNOR-246484	0.92
CDK2	protein	P24941	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates	phosphorylation	Ser577	RKPGLRRsPIKKVRK	9606			SIGNOR-C83						9840932	t		lperfetto	The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk5	SIGNOR-62353	0.711
SLC12A4	protein	Q9UP95	UNIPROT	chloride	smallmolecule	CHEBI:17996	ChEBI	down-regulates quantity	relocalization												21613606	t		lperfetto	Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12). 	SIGNOR-264636	0.8
AKT1	protein	P31749	UNIPROT	UPF1	protein	Q92900	UNIPROT	up-regulates activity	phosphorylation	Thr151	FCNGRGNtSGSHIVN	9606	BTO:0002181								35675814	t		miannu	AKT-Mediated UPF1 Phosphorylation at T151 Promotes UPF1 Helicase Activity	SIGNOR-277597	0.26
LCK	protein	P06239	UNIPROT	PRKCD	protein	Q05655	UNIPROT	up-regulates activity	phosphorylation	Tyr514	TFCGTPDyIAPEILQ	9534	BTO:0000298								11381116	t			The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2).	SIGNOR-251386	0.505
MAPK1	protein	P28482	UNIPROT	METTL3	protein	Q86U44	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser50	SPTFRSDsPVPTAPT	9606	BTO:0000007								33217317	t		miannu	 Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.	SIGNOR-265946	0.276
MED30	protein	Q96HR3	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266673	0.746
CASP1	protein	P29466	UNIPROT	NLRP1 inflammasome	complex	SIGNOR-C224	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256406	0.791
BLOC1S4	protein	Q9NUP1	UNIPROT	BLOC-1	complex	SIGNOR-C381	SIGNOR	form complex	binding			9606	BTO:0002946								22203680	t		lperfetto	We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter.	SIGNOR-265932	0.612
PTPN9	protein	P43378	UNIPROT	NSF	protein	P46459	UNIPROT	down-regulates	dephosphorylation	Tyr83	QEIEVSLyTFDKAKQ	9606									15322554	t		gcesareni	Our results suggest that the molecular mechanism by which ptp-meg2 promotes secretory vesicle fusion involves the local release of nsf from a tyrosine-phosphorylated, inactive state.	SIGNOR-128348	0.422
ADNP	protein	Q9H2P0	UNIPROT	ChAHP	complex	SIGNOR-C407	SIGNOR	form complex	binding			10090	BTO:0002896								29795351	t		miannu	Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. we have discovered ChAHP, a gene-regulatory complex that consists of the chromatin remodeller CHD4, the DNA-binding factor ADNP, and the heterochromatin proteins HP1β and HP1γ. By locally restricting access to DNA, ChAHP prevents endodermal gene transcription in mouse ES cells and during neuroectodermal differentiation. 	SIGNOR-266751	0.3
N-(1,3-benzodioxol-5-ylmethyl)-4-(4-benzofuro[3,2-d]pyrimidinyl)-1-piperazinecarbothioamide	chemical	CHEBI:91389	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189528	0.8
CHEK2	protein	O96017	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates activity	phosphorylation	Ser93	ARMMSTEsANSFTLI	9606	BTO:0002552								32187724	t		lperfetto	We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion.|CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, promoting autophagy via Beclin 1 release from Bcl‐2 sequestration	SIGNOR-264556	0.303
CSK	protein	P41240	UNIPROT	PECAM1	protein	P16284	UNIPROT	up-regulates activity	phosphorylation	Tyr713	KKDTETVySEVRKAV	9534	BTO:0001538								9624175	t		miannu	We demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances.	SIGNOR-262741	0.53
GTF2F2	protein	P13984	UNIPROT	GTF2F1	protein	P35269	UNIPROT	up-regulates activity	binding			9534									11278533	t		miannu	Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30. 	SIGNOR-261180	0.962
CDK1	protein	P06493	UNIPROT	CDC27	protein	P30260	UNIPROT	up-regulates	phosphorylation	Thr446	EGKISTItPQIQAFN	9606									14657031	t		lperfetto	Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation	SIGNOR-119877	0.692
PRKCA	protein	P17252	UNIPROT	CYTH2	protein	Q99418	UNIPROT	down-regulates activity	phosphorylation	Ser392	AARKKRIsVKKKQEQ	9606									10531036	t		lperfetto	ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'.	SIGNOR-249023	0.311
RNF111	protein	Q6ZNA4	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	ubiquitination			10090	BTO:0000165;BTO:0000222								17341133	t		gcesareni	Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblastsarkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling.	SIGNOR-236876	0.639
tofacitinib citrate	chemical	CHEBI:71197	ChEBI	JAK3	protein	P52333	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207311	0.8
TFAP2B	protein	Q92481	UNIPROT	CRYAB	protein	P02511	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21556774	t		miannu	Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53	SIGNOR-253637	0.2
EGFR	protein	P00533	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr373	ASDTDSSyCIPTAGM	9606									9890893	t		lperfetto	Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689).	SIGNOR-236408	0.751
GDP	smallmolecule	CHEBI:17552	ChEBI	GNAS	protein	Q5JWF2	UNIPROT	down-regulates	chemical inhibition			9606									17095603	t		gcesareni	Galfa subunits cycle between inactive (GDP-bound) and active (GTP-bound) states, and the lifetime of the active state is limited by GTP hydrolysis.	SIGNOR-253072	0.8
CHM	protein	P24386	UNIPROT	RABGGTB	protein	P53611	UNIPROT	down-regulates activity	binding			9606									18532927	t		miannu	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. 	SIGNOR-265571	0.758
DTX1	protein	Q86Y01	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates				9606	BTO:0000776								9528794	f		gcesareni	Our experiments indicate that deltex expression alone is suffcient to inhibit e47.	SIGNOR-56141	0.278
ROR2	protein	Q01974	UNIPROT	FLNA	protein	P21333	UNIPROT	up-regulates	binding			9606									18667433	t		gcesareni	Additionally, the association of ror2 with the actin-binding protein filamin a is required for wnt5a-induced jnk activation and polarized cell migration.	SIGNOR-179668	0.415
TRIM39	protein	Q9HCM9	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002552								23213260	t		miannu	Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation.	SIGNOR-272020	0.358
EFNA3	protein	P52797	UNIPROT	EPHA4	protein	P54764	UNIPROT	up-regulates	binding			9606									9330863	t		gcesareni	Eph receptors are activated by their ligands, which are membrane-anchored molecules	SIGNOR-52315	0.82
PPP3CB	protein	P16298	UNIPROT	KSR2	protein	Q6VAB6	UNIPROT	up-regulates activity	dephosphorylation	Ser313	TALHRSKsHEFQLGH	10090									19560418	t			These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3	SIGNOR-248382	0.262
JAK1	protein	P23458	UNIPROT	JAK3	protein	P52333	UNIPROT	up-regulates				9606									10825200	f		gcesareni	Syk activation required jak3, probably indirectly via activation of jak1.	SIGNOR-77551	0.515
PRKACA	protein	P17612	UNIPROT	ADD1	protein	P35611	UNIPROT	down-regulates activity	phosphorylation	Ser408	REKSKKYsDVEVPAS	-1									8810272	t		miannu	Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin.	SIGNOR-250329	0.316
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Thr8	MSSILPFtPPVVKRL	9606									19115199	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-183004	0.739
PTPN1	protein	P18031	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	dephosphorylation	Tyr419	RLIEDNEyTARQGAK	9606	BTO:0000007								11007774	t		gcesareni	Incubation of the inactivated c-Src with PTP1B results in a dose-dependent reactivation of c-Src tyrosine kinase activity. Incubation of c-Src with 2 or 10 g of PTP1B results in partial or full restoration of c-Src kinase activity, respectively. The activation is accompanied by dephosphorylation of c-Src, both of Tyr-419 and of Tyr-530	SIGNOR-245299	0.773
SMAD3	protein	P84022	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates activity	binding			10090	BTO:0000165								11711431	t		azuccotti	We show that the TGF-beta intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors.	SIGNOR-252071	0.72
HNF4A	protein	P41235	UNIPROT	ABCG8	protein	Q9H221	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000398								21123766	f		miannu	 these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α.	SIGNOR-254458	0.287
ZFPM1	protein	Q8IX07	UNIPROT	GATA2	protein	P23769	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21853041	t		miannu	GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1.	SIGNOR-256061	0.737
CAPN1	protein	P07384	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	cleavage			9606	BTO:0000590								25969760	t		lperfetto	Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains	SIGNOR-251584	0.341
HCFC1	protein	P51610	UNIPROT	Set1-Ash2 HMT complex	complex	SIGNOR-C352	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								12670868	t		miannu	Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles.	SIGNOR-264481	0.763
AMPK	complex	SIGNOR-C15	SIGNOR	SIRT7	protein	Q9NRC8	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr153	TLTHMSItRLHEQKL										27511885	t		lperfetto	Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.|These results strongly suggest that the phosphorylation status of SirT7 at T153 plays a crucial role in determining its subcellular distribution, degradation and binding to REGγ.	SIGNOR-275865	0.2
XL765	chemical	CHEBI:71958	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207872	0.8
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser268	VALPPGAsPQRSRSP	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252342	0.635
KAT5	protein	Q92993	UNIPROT	CHKA	protein	P35790	UNIPROT	up-regulates activity	acetylation	Lys247	MPFNKEPkWLFGTME	9606									34929314	t		lperfetto	Glucose deprivation induces the binding of choline kinase α2 (CHKα2) to lipid droplets, followed by a continuous PTMs to promote lipolysis of lipid droplets, which are in turn mediated by AMPK-dependent CHKα2 Serine 279 phosphorylation and KAT5-dependent CHKα2 Lysine 247 acetylation. 	SIGNOR-267648	0.2
INSIG1	protein	O15503	UNIPROT	SCAP	protein	Q12770	UNIPROT	down-regulates activity	binding			10029	BTO:0000246								12202038	t			Using coimmunoprecipitation and tandem mass spectrometry, we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER.	SIGNOR-267495	0.759
JAK2	protein	O60674	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates activity	phosphorylation	Tyr333	QRYRLVPyGNHSYLE	9606	BTO:0001535								34131122	t		miannu	Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation.	SIGNOR-277567	0.302
CSNK2A1	protein	P68400	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser290	GRIVARNsRKMAFRA	-1									9677319	t		llicata	CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin.	SIGNOR-250948	0.317
CAPN2	protein	P17655	UNIPROT	CDK5R1	protein	Q15078	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000590								25969760	t		lperfetto	Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain	SIGNOR-251610	0.545
CDKN2A	protein	P42771	UNIPROT	CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	down-regulates activity	binding			9606									8891723	t		lperfetto	The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb.	SIGNOR-217514	0.822
CDK1	protein	P06493	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	up-regulates	phosphorylation	Ser540	HVSEDSSsPERTSPP	9606			SIGNOR-C17						19107194	t		gcesareni	We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells	SIGNOR-182863	0.544
MAPK3	protein	P27361	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates	phosphorylation			9606									19346248	t		lperfetto	The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo.	SIGNOR-217556	0.393
KDM2B	protein	Q8NHM5	UNIPROT	Noncanonical PRC1	complex	SIGNOR-C151	SIGNOR	up-regulates activity	binding			10090	BTO:0000011								25533466	t		miannu	We show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. 	SIGNOR-252247	0.675
TADA2B	protein	Q86TJ2	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269571	0.762
PHF2	protein	O75151	UNIPROT	ARID5B	protein	Q14865	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								21532585	t		miannu	 We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity.	SIGNOR-264514	0.543
RPGRIP1	protein	Q96KN7	UNIPROT	RPGR	protein	Q92834	UNIPROT	down-regulates activity	binding			9606									20631154	t		miannu	The RPGR H98Q and F130C mutants exhibit compromised interaction with RPGRIP1, suggesting that RPGR–RPGRIP1 interaction may be an important determinant of RPGR activity. As RPGRIP1 appears to link RPGR to the cilium, it is possible that RPGR's effect on RAB8A function may occur in distinct subcellular compartments of photoreceptors and that RPGRIP1 and other interacting proteins may modulate targeting of RPGR to such compartments. 	SIGNOR-253031	0.738
FYN	protein	P06241	UNIPROT	DCBLD2	protein	Q96PD2	UNIPROT	up-regulates activity	phosphorylation	Tyr621	LQADSAEyAQPLVGG	-1									23770091	t	done	miannu	Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding.	SIGNOR-273941	0.357
ARHGAP29	protein	Q52LW3	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260484	0.533
PRKACA	protein	P17612	UNIPROT	FLNA	protein	P21333	UNIPROT	up-regulates	phosphorylation	Ser2152	TRRRRAPsVANVGSH	9606									15228085	t		gcesareni	Site-directed mutagenesis analysis indicated that serine 2152 is the unique substrate in the c-terminal region of abp for endogenously activated pka.	SIGNOR-126659	0.2
MAPK9	protein	P45984	UNIPROT	MAPK8IP3	protein	Q9UPT6	UNIPROT	up-regulates	phosphorylation	Thr286	SVPSAAVtPLNESLQ	9606									15767678	t		gcesareni	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134576	0.652
SKP2	protein	Q13309	UNIPROT	IDH1	protein	O75874	UNIPROT	down-regulates quantity by destabilization	ubiquitination										phosphorylation:Thr157	GKVEITYtPSDGTQK	34929314	t		lperfetto	During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome	SIGNOR-267625	0.2
MAPK14	protein	Q16539	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates	phosphorylation	Thr263	TTLSLPLtPESPNDP	9606		BTO:0000887							11741533	t		gcesareni	Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298	SIGNOR-112770	0.568
STK39	protein	Q9UEW8	UNIPROT	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation	Thr100	TNTYYLQtFGHNTMD	9606	BTO:0000007								21321328	t		miannu	We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity.	SIGNOR-263129	0.596
APOB	protein	P04114	UNIPROT	VLDL_assembly	phenotype	SIGNOR-PH62	SIGNOR	up-regulates				9606									23721961	f		miannu	Apolipoprotein B is a structural protein that is an integral component of chylomicrons, as well as very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) particles. In man, VLDL contains only ApoB100, the full length protein	SIGNOR-252115	0.7
PPP2CA	protein	P67775	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	dephosphorylation	Ser199	PRPEHTKsVYTRSVI	10116									18586681	t			Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation.	SIGNOR-248642	0.364
CSNK2A1	protein	P68400	UNIPROT	RNF7	protein	Q9UBF6	UNIPROT	up-regulates	phosphorylation	Thr10	DVEDGEEtCALASHS	9606	BTO:0000567								12748192	t		lperfetto	Ckbbp1 is phosphorylated in vivo and threonine to alanine mutation at residue 10 abrogates the phosphorylation of ckbbp1 observed in vivo, indicating that ckii is a major kinase that is responsible for in vivo phosphorylation of ckbbp1. As compared with the wild-type ckbbp1 or ckbbp1t10e (in which threonine 10 is replaced by glutamate), overexpression of nonphosphorylatable ckbbp1 (ckbbp1t10a) results in accumulation of ikappabalpha and p27kip1.	SIGNOR-101187	0.469
ruxolitinib	chemical	CHEBI:66919	ChEBI	JAK1	protein	P23458	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258276	0.8
CDK5	protein	Q00535	UNIPROT	DPYSL2	protein	Q16555	UNIPROT	down-regulates activity	phosphorylation	Ser522	PASSAKTsPAKQQAP	9606	BTO:0000938								25040932	t		lperfetto	Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition	SIGNOR-264838	0.642
PRKACA	protein	P17612	UNIPROT	NOXA1	protein	Q86UR1	UNIPROT	down-regulates	phosphorylation	Ser172	DQVQRRGsLPPRQVP	9606									20110267	t		llicata	We identified ser-282 as target of mapk and ser-172 as target of pkc and pka in vitro and in a transfected human embryonic kidney 293 (hek293) cell model using site directed mutagenesis and phosphopeptide mapping analysis. In hek293 cells, phosphorylation of these sites occurred at a basal level and down-regulated constitutive nox1 activity. I	SIGNOR-163663	0.329
RBX1	protein	P62877	UNIPROT	BAF250b E3 ligase	complex	SIGNOR-C522	SIGNOR	form complex	binding			9606	BTO:0000567								20086098	t		miannu	In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro	SIGNOR-271439	0.598
Av/b5 integrin	complex	SIGNOR-C178	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269027	0.7
STAT1	protein	P42224	UNIPROT	RELA	protein	Q04206	UNIPROT	down-regulates	binding			9606				SIGNOR-C13					16481475	t		gcesareni	Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease.	SIGNOR-144561	0.533
BAMBI	protein	Q13145	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates	binding			9606									2662247	t		gcesareni	Bmp-2 mediates phosphorylated smad1 (psmad1) or, with loss of bmprii, psmad3-dependent recruitment of disheveled (dvl) to promote rhoa-rac1 signaling necessary for motility.	SIGNOR-23037	0.498
GSK3B	protein	P49841	UNIPROT	FBXL21P	protein	Q9UKT6	UNIPROT	up-regulates activity	phosphorylation	Thr33	FYSSLNQtHTHTVLL	9606	BTO:0000007								32937135	t		lperfetto	GSK-3beta phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation.|These results show direct GSK-3beta phosphorylation of TCAP S157 and FBXL21 T33 sites.	SIGNOR-264851	0.2
palbociclib	chemical	CHEBI:85993	ChEBI	CCND1	protein	P24385	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189693	0.8
TLR5	protein	O60602	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24709011	f		miannu	These studies demonstrate a novel function of Toll-like receptor-5 (TLR5) in a human multiple myeloma (MM) cell line, KMS28BM. These cells express high levels of both TLR5 mRNA and protein. When cells were treated with the specific TLR5 ligand flagellin, proliferation was increased, and the secretion of IgG λ antibody and the expression of the pro-inflammatory cytokine IL-6 were increased via NF-κB activation through PI3K/AKT and p38 signaling.	SIGNOR-259868	0.481
DOK1	protein	Q99704	UNIPROT	ITGB8	protein	P26012	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257698	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GSTA4	protein	O15217	UNIPROT	up-regulates activity	phosphorylation	Ser189	QEYTVKLsNIPTIKR	9534									12646569	t		lperfetto	Mutational analysis show that the putative mitochondrial targeting signal resides within the C-terminal 20 amino acid residues of the protein and that the targeting signal requires activation by phosphorylation at the C-terminal-most protein kinase A (PKA) site at Ser-189 or protein kinase C (PKC) site at Thr-193. 	SIGNOR-264796	0.2
CSNK2B	protein	P67870	UNIPROT	OCLN	protein	Q16625	UNIPROT	unknown	phosphorylation	Thr404	HYETDYTtGGESCDE	9606									12804768	t		llicata	Mutagenesis of serine 407 to alanine resulted in reduced ability of the kinase to phosphorylate occludin. The threonine 403 to alanine mutant had a smaller effect but the double mutant (T403/S407A) was even less phosphorylated than either of the single mutants. These data are consistent with the claim that CK2 is the kinase in brain extracts responsible for phosphorylation of occludin.	SIGNOR-251080	0.426
SYK	protein	P43405	UNIPROT	TUBA4A	protein	P68366	UNIPROT	up-regulates activity	phosphorylation	Tyr432	MAALEKDyEEVGIDS	9606	BTO:0000776								9490415	t		lperfetto	Syk, Activated by Cross-linking the B-cell Antigen Receptor, Localizes to the Cytosol Where It Interacts with and Phosphorylates alpha-Tubulin on Tyrosine	SIGNOR-246626	0.335
MAPKAPK2	protein	P49137	UNIPROT	SRF	protein	P11831	UNIPROT	unknown	phosphorylation	Ser103	RGLKRSLsEMEIGMV	9606	BTO:0000567								10318869	t		llicata	Mk2 phosphorylates srf in vitro at ser-103	SIGNOR-67448	0.565
ETV6	protein	P41212	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15958056	f	Regulation of expression	miannu	Upon erythropoietin exposure, overexpressed TEL stimulated hemoglobin synthesis 	SIGNOR-251793	0.2
ARHGEF15	protein	O94989	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260541	0.537
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1675	SPSYSPTsPSYSPTS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248740	0.727
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1951	SPGYSPTsPTYSLTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120168	0.316
INSR	protein	P06213	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	phosphorylation	Tyr896	EPKSPGEyVNIEFGS	10029	BTO:0000246								7651388	t		lperfetto	Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir).	SIGNOR-236745	0.911
NAN 190	chemical	CHEBI:64131	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258855	0.8
LPCAT1	protein	Q8NF37	UNIPROT	acyl-CoA(4-)	chemical	CHEBI:58342	ChEBI	down-regulates quantity	chemical modification			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272763	0.8
CSNK2A1	protein	P68400	UNIPROT	USP7	protein	Q93009	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser18	KAGEQQLsEPEDMEM										22361354	t		lperfetto	We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53. 	SIGNOR-276530	0.38
MZF1	protein	P28698	UNIPROT	CCN2	protein	P29279	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25899830	f		miannu	we report the regulation of the CTGF and NOV genes by Myeloid Zinc Finger-1 (MZF-1), a hematopoietic transcription factor. We show the interaction of MZF-1 with the CTGF and NOV promoters in several cell types. Up-regulation of MZF-1 via calcitriol and vitamin A induces expression of CTGF and NOV, implicating a role for these vitamins in the functions of these two genes. Lastly, knockdown of MZF1 reduces levels of CTGF and NOV.	SIGNOR-226307	0.2
DLL1	protein	O00548	UNIPROT	PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	up-regulates activity	binding			9606	BTO:0000776								16140393	t		lperfetto	Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate.	SIGNOR-209741	0.2
SPOP	protein	O43791	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0005672								29160310	t		Barakat	Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumor-infiltrating lymphocytes (TILs) in mouse tumors and in primary human prostate cancer specimens.	SIGNOR-274978	0.332
ABL1	protein	P00519	UNIPROT	MYLK	protein	Q15746	UNIPROT	up-regulates	phosphorylation	Tyr846	DGGGSDRyGSLRPGW	9606		BTO:0000763							20861316	t		lperfetto	Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity	SIGNOR-168001	0.305
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation	Tyr1007	VLPQDKEyYKVKEPG	10090									11593427	t		irozzo	In this report, we show that Bcr–Abl forms a complex with Jak2, and induces tyrosine phosphorylation of Jak2; full phosphorylation requires the SH2 domain of Bcr–Abl. We found that Y1007 of Jak2 was phosphorylated in Bcr–Abl positive cells; phosphorylation of Jak2 Y1007 is known to be required for Jak2 kinase activation.	SIGNOR-255812	0.2
CD300LB	protein	A8K4G0	UNIPROT	TYROBP	protein	O43914	UNIPROT	up-regulates activity	binding			9534									20959446	t		lperfetto	The CD300b receptor is a non-classical activating receptor able to deliver signals by associating with the transmembrane adaptor protein DAP-12 and the intracellular mediator Grb-2.	SIGNOR-264834	0.692
XPA	protein	P23025	UNIPROT	Nucleotide-excision_repair	phenotype	SIGNOR-PH209	SIGNOR	up-regulates													24086043	f		lperfetto	The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275704	0.7
bilirubin(2-)	smallmolecule	CHEBI:57977	ChEBI	biliverdin(2-)	smallmolecule	CHEBI:57991	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000759							7929092	t		lperfetto	This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. 	SIGNOR-275522	0.8
amitriptyline	chemical	CHEBI:2666	ChEBI	CHRM5	protein	P08912	UNIPROT	down-regulates activity	chemical inhibition			10029									8100134	t		miannu	Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 	SIGNOR-258701	0.8
SRC	protein	P12931	UNIPROT	LRP1	protein	Q07954	UNIPROT	up-regulates activity	phosphorylation	Tyr4507	TNFTNPVyATLYMGG	9606	BTO:0000007								12789267	t		lperfetto	We recently observed that the ldl receptor-related protein 1 (lrp-1) is tyrosine phosphorylated in v-src-transformed cells.Of the four tyrosine residues present in the cytoplasmic domain of lrp-1, only tyr 63 is phosphorylated by v-src in vivo or in vitro. Using fibroblasts deficient in src, yes and fyn, we were able to show that there are multiple kinases present in the cell that can phosphorylate lrp-1. Tyrosine-phosphorylated lrp-1 associates with shc, a ptb and sh2 domain containing signaling protein that is involved in the activation of ras	SIGNOR-101535	0.402
CAMKK1	protein	Q8N5S9	UNIPROT	CAMK1	protein	Q14012	UNIPROT	up-regulates activity	phosphorylation	Thr177	DPGSVLStACGTPGY										8253780	t		llicata	Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase.	SIGNOR-250717	0.424
CDK1	protein	P06493	UNIPROT	NDEL1	protein	Q9GZM8	UNIPROT	up-regulates activity	phosphorylation	Ser242	IPNGFGTsPLTPSAR	-1									12556484	t	done	miannu	In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites	SIGNOR-274073	0.646
MAPK14	protein	Q16539	UNIPROT	ZNHIT1	protein	O43257	UNIPROT	up-regulates	phosphorylation	Thr103	AEGPNYLtACAGPPS	9606									17380123	t		llicata	Our results indicate that p38 mapk plays an important role in the regulation of p18hamlet half?life. In particular, p38 mapk activation is required for the accumulation of p18hamlet induced by dna damage?inducing Agents such as uv. We also showed that several sites that are phosphorylated by p38? In vitro are also important for p18hamlet protein stability in cells. the high conservation of thr103 as a phosphorylation site in p18hamlet proteins from different species (figure 1a), together with the in vitro phosphorylation experiments, suggested that this residue could be an important target for p38 mapk	SIGNOR-153899	0.319
ZNF804A	protein	Q7Z570	UNIPROT	CLIC2	protein	O15247	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								23434502	t		miannu	ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 	SIGNOR-269465	0.2
BUB1	protein	O43683	UNIPROT	H2AC11	protein	P0C0S8	UNIPROT	unknown	phosphorylation	Thr121	AVLLPKKtESHHKAK	9606									19965387	t		lperfetto	 the localization of hBub1 kinase usually defines the centromere-specific phosphorylation of H2A-T120. Accordingly, hSgo1 localized along the whole chromosome length in H2B-hBub1deltaN cells (Fig. 6D), indicating that H2A-pT120 plays a predominant role in defining shugoshin localization sites on the human chromosomes	SIGNOR-265261	0.2
STK11	protein	Q15831	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Ser380	EPDHYRYsDTTDSDP	9606									21779440	t		gcesareni	The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity	SIGNOR-161118	0.624
AURKA	protein	O14965	UNIPROT	TACC3	protein	Q9Y6A5	UNIPROT	unknown	phosphorylation	Ser552	GTSSFKEsALRKQSL	-1									26134678	t		lperfetto	In humans, Aurora-A phosphorylates TACC3 on three residues (S34, S552 and S558); these sites are conserved in Maskin and the S558 equivalent site is also present in D-TACC [26,27,30]. In mammalian cells, phosphorylation of S558 promotes accumulation of TACC3 on spindle MTs	SIGNOR-263698	0.934
PRKCZ	protein	Q05513	UNIPROT	MGluR	proteinfamily	SIGNOR-PF55	SIGNOR	up-regulates activity	phosphorylation			-1									15894802	t	inferred from family member	lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-270274	0.39
EPHB2	protein	P29323	UNIPROT	EPHB2	protein	P29323	UNIPROT	up-regulates activity	phosphorylation	Tyr602	IYIDPFTyEDPNEAV	-1									10572014	t			Our results demonstrate that autophosphorylation tyrosine 611 in the juxtamembrane region of chicken EphB2 is critical for the association of the Src SH2 domain.	SIGNOR-251124	0.2
NFYA	protein	P23511	UNIPROT	PHGDH	protein	O43175	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18378410	f		miannu	Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y.	SIGNOR-255209	0.2
RBM10	protein	P98175	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30403180	f		irozzo	In this study, we report that RBM10 acts as a tumor suppressor in osteosarcoma via the inhibition of cell growth, cell migration and invasion and the induction of cell apoptosis by inhibiting Bcl-2, activating caspase-3, and producing TNF-α. We also found that RBM10 overexpression significantly inhibited the expression of Bcl-2 and induced the expression of caspase-3 	SIGNOR-259151	0.2
PLK1	protein	P53350	UNIPROT	NEDD1	protein	Q8NHV4	UNIPROT	up-regulates activity	phosphorylation	Ser637	HSLLERYsVNEGLVA	9606	BTO:0000567						phosphorylation:Thr550	PPINGSStPNPKIAS	19509060	t		lperfetto	Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation.	SIGNOR-272991	0.604
ADNP	protein	Q9H2P0	UNIPROT	CTCF	protein	P49711	UNIPROT	down-regulates activity	relocalization			10090	BTO:0001086		SIGNOR-C407						31491387	t		miannu	These results argue against the simultaneous binding of CTCF and ADNP to the same genomic loci. Instead, they support a model in which ADNP counteracts stable association of CTCF with DNA at over 15,000 binding sites in the mouse genome.	SIGNOR-266755	0.206
naltrexone	chemical	CHEBI:7465	ChEBI	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258946	0.8
ABL2	protein	P42684	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates activity	phosphorylation	Tyr386	YRARVANyQRDGPMC	9606	BTO:0000093								12777400	t		lperfetto	C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases	SIGNOR-101310	0.345
FZD7	protein	O75084	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates	binding												22179044	t		apalma	In non-canonical Wnt signalling, Wnt proteins bind Fzd and glypican-4, to activate Dsh at the cell membrane, leading to activation of Rho and JNK	SIGNOR-255893	0.647
TFG	protein	Q92734	UNIPROT	SEC16B	protein	Q96JE7	UNIPROT	up-regulates	binding			9606									21478858	t		miannu	We identify tfg-1, a new conserved regulator of protein secretion that interacts directly with sec-16 and controls the export of cargoes from the endoplasmic reticulum in caenorhabditis elegans. Hydrodynamic studies indicate that tfg-1 forms hexamers that facilitate the co-assembly of sec-16 with copii subunits.	SIGNOR-173279	0.478
CSNK2B	protein	P67870	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Thr811	ADDSSSStSSDSLGG	-1									8349691	t		llicata	These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1.	SIGNOR-251075	0.324
CALM3	protein	P0DP25	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	up-regulates	binding			9606									9822657	t		miannu	The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk.	SIGNOR-266345	0.606
PRKAR2A	protein	P13861	UNIPROT	PRKACB	protein	P22694	UNIPROT	down-regulates activity	binding			9606									26687711	t			Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 	SIGNOR-258757	0.891
LPAR1	protein	Q92633	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257345	0.436
APPL1	protein	Q9UKG1	UNIPROT	STK11	protein	Q15831	UNIPROT	up-regulates	binding			9606		BTO:0000887							19520843	t		milica	In this study, we identified lkb1 as a new binding partner of appl1 and showed that the bar domain of appl1 is involved in this interaction.Here we show that in muscle cells adiponectin and metformin induce ampk activation by promoting appl1-dependent lkb1 cytosolic translocation. Appl1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances lkb1 cytosolic localization by anchoring this kinase in the cytosol.	SIGNOR-186065	0.323
CDK9	protein	P50750	UNIPROT	SUPT5H	protein	O00267	UNIPROT	up-regulates	phosphorylation	Thr806	TPHYGSQtPLHDGSR	9606									16427012	t		lperfetto	We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif	SIGNOR-143939	0.769
MAPK9	protein	P45984	UNIPROT	RXRA	protein	P19793	UNIPROT	down-regulates activity	phosphorylation	Ser260	NMGLNPSsPNDPVTN	9606									16551633	t		gcesareni	Under stress conditions, hyperphosphorylated by activated jnk on ser-56, ser-70, thr-82 and ser-260. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear rxralpha levels, via a multistep, jnk-dependent mechanism involving ser260, nuclear export, and proteasomal degradation.	SIGNOR-145301	0.249
GSK3B	protein	P49841	UNIPROT	NFE2L1	protein	Q14494	UNIPROT	down-regulates	phosphorylation	Ser379	SQDFLLFsPEVESLP	9606	BTO:0000938								23623971	t		lperfetto	Glycogen synthase kinase 3 regulates expression of nuclear factor-erythroid-2 related transcription factor-1 (nrf1) and inhibits pro-survival function of nrf1	SIGNOR-193450	0.409
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Ser952	DSRSHQNsPTELNKD	9606	BTO:0001938								11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130.	SIGNOR-104691	0.843
tryptophan	smallmolecule	CHEBI:27897	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264743	0.7
FUS	protein	P35637	UNIPROT	ADARB1	protein	P78563	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			10090		BTO:0001279							28515487	f			This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease	SIGNOR-262805	0.257
LRIG1	protein	Q96JA1	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates				9606									23723069	f		miannu	Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases, including erbb and met receptors, and promotes receptor degradation.	SIGNOR-202143	0.412
CFHR1	protein	Q03591	UNIPROT	CFH	protein	P08603	UNIPROT	down-regulates activity	binding			-1									27814381	t		lperfetto	 Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. |these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b	SIGNOR-263476	0.515
ZFPM1	protein	Q8IX07	UNIPROT	Megakaryocyte_differentiation 	phenotype	SIGNOR-PH103	SIGNOR	up-regulates activity				10090	BTO:0000725								22068055	f			We here use conditional removal of the GATA-1 and FOG-1 transcription factors to identify FOG-1 as required for the formation of all committed Mk- and E-lineage progenitors, whereas GATA-1 was observed to be specifically required for E-lineage commitment.	SIGNOR-259963	0.7
SCN4A	protein	P35499	UNIPROT	Action_potential 	phenotype	SIGNOR-PH82	SIGNOR	up-regulates				9606									26043074	f		miannu	The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons.	SIGNOR-253451	0.7
NHS	protein	Q6T4R5	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				9606									20332100	f		miannu	We demonstrate that NHS is essential for maintaining cell morphology through the regulation of actin cytoskeletal dynamics and suggest that an important mechanism of remodelling of the actin cytoskeleton during development would therefore be lost in patients with NHS.	SIGNOR-253565	0.7
NFIX	protein	Q14938	UNIPROT	SLIT1	protein	O75093	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268906	0.2
ER stress	stimulus	SIGNOR-ST9	SIGNOR	ATF4	protein	P18848	UNIPROT	up-regulates				9606									23205607	f		lperfetto	Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress	SIGNOR-253728	0.7
BRSK1	protein	Q8TDC3	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates activity	phosphorylation	Ser216	SGLYRSPsMPENLNR	9606	BTO:0000567								15150265	t		lperfetto	Overexpression of hssad1 resulted in an increased phosphorylation of cdc25c on ser-216 in vivo. Phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3	SIGNOR-107408	0.495
TGFBR1	protein	P36897	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000801								10973958	t		lperfetto	The pathway restricted (r)Smads (e.g. Smad1, 2, 3, and 5) are serine/threonine kinase activated proteins that interact in an unphosphorylated state with a TGF-b superfamily receptor. Upon ligand binding they are phosphorylated by the receptor and released.	SIGNOR-249549	0.819
PRKCH	protein	P24723	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000093								28939105	t		miannu	Protein kinase C-eta regulates Mcl-1 level via ERK1. knockdown of PKCη but not PKCα, -δ or -ε caused a significant decrease in ERK (extracellular signal-regulated kinase) phosphorylation. Knockdown of ERK1 but not ERK2 decreased Mcl-1 level, and the decrease in Mcl-1 caused by PKCη knockdown was restored by ERK1 overexpression. These results suggest that PKCη utilizes the ERK signaling pathway to protect against ubiquitin-mediated proteasomal degradation of Mcl-1.	SIGNOR-261910	0.484
UGP2	protein	Q16851	UNIPROT	UTP(4-)	smallmolecule	CHEBI:46398	ChEBI	down-regulates quantity	chemical modification			9606									8631325	t		miannu	UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi.	SIGNOR-267927	0.8
CDK1	protein	P06493	UNIPROT	RCC1	protein	P18754	UNIPROT	up-regulates activity	phosphorylation	Thr274	SNYHQLGtPGTESCF	-1									15014043	t		miannu	We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of hum an RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. However, when both S2 and S11 were simultaneously mutated to As, the resulting 6His-RCC1S2,11A failed to be phosphorylated, whereas all of the other double mutants were phosphorylated (Fig. 1C). As expected, mutating all four sites to As (the 6His-RCC1S2,11,387A-T274A) also blocked phosphorylation (Fig. 1C).	SIGNOR-262704	0.518
SMARCC1	protein	Q92922	UNIPROT	Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	form complex	binding			10090	BTO:0001086								19279220	t		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270724	0.739
PRKACB	protein	P22694	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser275	LSAFRRTsLAGGGRR	9606		BTO:0000887							20151718	t		miannu	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163768	0.276
CDK1	protein	P06493	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates	phosphorylation	Ser168	SEMKYLGsPITTVPK	9606									8119945	t		gcesareni	Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity.	SIGNOR-36279	0.853
RAP1A	protein	P62834	UNIPROT	AL/b2 integrin	complex	SIGNOR-C169	SIGNOR	up-regulates activity	binding			10090	BTO:0003104								12808052	t		lperfetto	The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity.	SIGNOR-253362	0.459
TCP1	protein	P17987	UNIPROT	TRiC	complex	SIGNOR-C539	SIGNOR	form complex	binding			9606									36185250	t		miannu	Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC).	SIGNOR-272863	0.741
E2F1	protein	Q01094	UNIPROT	DHFR	protein	P00374	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253853	0.517
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606									15486195	t	inferred from 70% family members	lperfetto	In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel	SIGNOR-270031	0.2
NEK6	protein	Q9HC98	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606	BTO:0000007								20595392	t	done	miannu	Our data also show that NEK6 interacts with STAT3, an oncogenic transcription factor, and phosphorylates STAT3 on Ser(727), which is important for transcriptional activation. These results demonstrate that NEK6 interacts with and phosphorylates STAT3, an event that could play an important role in oncogenesis. For the maximal activation of STAT3 signaling, phosphorylation of both Tyr705 and Ser727 is required. Phosphorylation of Tyr705 induces dimerization, nuclear translocation, and DNA binding of the STAT3 protein, whereas phosphorylation of Ser727 is important for transcriptional activation.	SIGNOR-273902	0.34
HP	protein	P00738	UNIPROT	HBB	protein	P68871	UNIPROT	down-regulates quantity	binding			9606									9315856	t	Regulation of binding	miannu	Haptoglobin forms a complex of extremely high affinity with Hb via a well-characterized globin site. Our results show that upon Hb-haptoglobin binding, the globin radical, loses its ability to be terminated by forming globin dimers.	SIGNOR-251815	0.764
ATG4B	protein	Q9Y4P1	UNIPROT	MAP1LC3B	protein	Q9GZQ8	UNIPROT	up-regulates	cleavage			9606	BTO:0000007;BTO:0000567								15187094	t		gcesareni	Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16.	SIGNOR-125449	0.796
EGFR	protein	P00533	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	phosphorylation	Tyr472	KLAEGSAyEEVPTSM	9606		BTO:0000142							1689310	t		llicata	We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation.	SIGNOR-20980	0.835
LMNA	protein	P02545	UNIPROT	SUN2	protein	Q9UH99	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								16380439	t		Sara	In the case of Sun2, there is some evidence that A-type lamins might contribute to Sun2 localization in the INM. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation. 	SIGNOR-261310	0.643
SLC8B1	protein	Q6J4K2	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization												23056385	t		lperfetto	This study focuses on NCLX, the recently discovered mitochondrial Na(+)/Ca(2+) exchanger that is linked to Ca(2+) signalling in MIN6 and primary β cells. Suppression either of NCLX expression, using a siRNA construct (siNCLX) or of its activity, by a dominant negative construct (dnNCLX), enhanced mitochondrial Ca(2+) influx and blocked efflux induced by glucose or by cell depolarization.	SIGNOR-275732	0.8
KDM5D	protein	Q9BY66	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	demethylation			9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-265336	0.2
CDK2	protein	P24941	UNIPROT	PGR	protein	P06401	UNIPROT	down-regulates	phosphorylation	Ser294	APMAPGRsPLATTVM	9606	BTO:0000150								10655479	t		miannu	Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26s proteasome	SIGNOR-74708	0.453
STAT3	protein	P40763	UNIPROT	CEBPD	protein	P49716	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									25787076	f		miannu	P-Stat3 stimulates C/EBPδ expression and activity, which increases myostatin and MAFbx/Atrogin-1 and MuRF-1. Both pathways result in protein losses in muscle.	SIGNOR-255334	0.596
perifosine	chemical	CHEBI:67272	ChEBI	AKT1	protein	P31749	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001130								14617782	t	Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation	gcesareni	Perifosine is an alkylphospholipid that targets the pleckstrin homology domain of akt and blocks its membrane translocation, hence preventing akt phosphorylation and activation	SIGNOR-252629	0.8
ULK3	protein	Q6PHR2	UNIPROT	GLI2	protein	P10070	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								19878745	t		Manara	We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro	SIGNOR-260798	0.606
CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	NANOS3	protein	P60323	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			9606									31320642	t		lperfetto	In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins	SIGNOR-268350	0.341
ZAP70	protein	P43403	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates	phosphorylation	Tyr113	SSFEEDDyESPNDDQ	9606									8702662	t		lperfetto	A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function	SIGNOR-42956	0.798
FZD3	protein	Q9NPG1	UNIPROT	NLK	protein	Q9UBE8	UNIPROT	up-regulates	binding			9606									20828404	t		gcesareni	Upon ligand binding, non-canonical wnt signaling controls tissue polarity and cell movement through the activation of rhoa, c-jun n-terminal kinase (jnk), and nemo-like kinase (nlk) signaling cascades.	SIGNOR-167862	0.36
MAGEL2	protein	Q9UJ55	UNIPROT	WASHC1	protein	A8K0Z3	UNIPROT	up-regulates activity	binding			9606									23452853	t		miannu	Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport.	SIGNOR-253515	0.2
PRKCA	protein	P17252	UNIPROT	ADD2	protein	P35612	UNIPROT	down-regulates	phosphorylation	Ser713	KKKFRTPsFLKKSKK	9606									9679146	t		gcesareni	Pkc phosphorylation of native and recombinant adducin inhibited actin capping measured using pyrene-actin polymerization and abolished activity of adducin in recruiting spectrin to ends and sides of actin filaments	SIGNOR-59299	0.2
CAMK1	protein	Q14012	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates activity	phosphorylation	Ser63	GILARRPsYRKILKD	-1									8663317	t		llicata	Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to Ser133 of CREB), which is essential for the activation, and not Ser72 (corresponding to Ser142 of CREB), which is a negative regulation site.	SIGNOR-250611	0.502
GLI2	protein	P10070	UNIPROT	Myelination	phenotype	SIGNOR-PH206	SIGNOR	up-regulates													NBK6142	f	Whilst shh signalling is required for ventral oligodendrogenesis in the entire central nervous system, Gli2 activity only regulates oligodendrocyte development in the ventral spinal cord. Gli3 plays a nonessential role in ventral oligodendrogenesis during normal development. 	SimoneGraziosi		SIGNOR-269214	0.7
PTPN12	protein	Q05209	UNIPROT	GIT2	protein	Q14161	UNIPROT	down-regulates	dephosphorylation	Tyr592	NSTPESDyDNTPNDM	9606									16317044	t		fspada	Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest.	SIGNOR-142719	0.352
MAPK13	protein	O15264	UNIPROT	EEF2K	protein	O00418	UNIPROT	down-regulates activity	phosphorylation	Ser359	GTEEKCGsPQVRTLS	9606		BTO:0000887;BTO:0001103							11500363	t		lperfetto	Sapk4/p38delta phosphorylated eef2k at ser359 in vitro, causing its inactivation.	SIGNOR-109703	0.56
KDM5C	protein	P41229	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264305	0.2
PHLPP1	protein	O60346	UNIPROT	PRKCA	protein	P17252	UNIPROT	down-regulates quantity	dephosphorylation	Ser657	QSDFEGFsYVNPQFV	9606	BTO:0000067								18162466	t		gcesareni	In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC alpha	SIGNOR-237043	0.253
RCOR1	protein	Q9UKL0	UNIPROT	CoREST-HDAC complex	complex	SIGNOR-C105	SIGNOR	form complex	binding			9606	BTO:0000567								11171972	t		miannu	Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function.	SIGNOR-222115	0.753
MKNK2	protein	Q9HBH9	UNIPROT	EIF4E	protein	P06730	UNIPROT	up-regulates	phosphorylation	Ser209	DTATKSGsTTKNRFV	9606									17724079	t		lperfetto	Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes.	SIGNOR-157537	0.578
GRIK1	protein	P39086	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial.	SIGNOR-264942	0.8
TFE3	protein	P19532	UNIPROT	GLA	protein	P06280	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276823	0.2
POU5F1	protein	Q01860	UNIPROT	CDX2	protein	Q99626	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254933	0.578
DEK	protein	P35659	UNIPROT	PRDX5	protein	P30044	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								19229864	f	 	lperfetto	We further demonstrated by ChIP analysis that knock-down of DEK caused hyperacetylation of histones around Prx VI promoter which is upregulated in our profile.	SIGNOR-254125	0.2
Brivanib alaninate	chemical	CID:11154925	PUBCHEM	FGFR1	protein	P11362	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190717	0.8
ERCC6	protein	Q03468	UNIPROT	B-WICH complex	complex	SIGNOR-C447	SIGNOR	form complex	binding			9606									21559432	t		miannu	The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 	SIGNOR-268822	0.304
CDK1	protein	P06493	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates	phosphorylation	Ser249	EGGKSGKsPRRRAAS	9606	BTO:0001130								18408765	t		gcesareni	Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1.	SIGNOR-178202	0.526
OSM	protein	P13725	UNIPROT	AHR	protein	P35869	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24127753	f		gcesareni	The il-6-type cytokine oncostatin m induces ahr expression in a stat3-ependent manner in human hepg2 hepatoma cells.	SIGNOR-202963	0.349
GTF3C4	protein	Q9UKN8	UNIPROT	TFIIIC	complex	SIGNOR-C392	SIGNOR	form complex	binding			9606									29378333	t		lperfetto	Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains	SIGNOR-266185	0.884
SSTR4	protein	P31391	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256959	0.252
MTCP1	protein	P56278	UNIPROT	AKT2	protein	P31751	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271								10983986	t		miannu	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-81674	0.431
HSBP1	protein	O75506	UNIPROT	HSF1	protein	Q00613	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								9649501	t		Monia	HSBP1 is nuclear-localized and interacts in vivo with the active trimeric state of HSF1 that appears during heat shock. During attenuation of HSF1 to the inert monomer, HSBP1 associates with Hsp70. HSBP1 negatively affects HSF1 DNA-binding activity, and overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1. HSF1 interacts with HSBP1 in vivo and is a nuclear localized protein.	SIGNOR-261181	0.686
NR0B2	protein	Q15466	UNIPROT	NR1I2	protein	O75469	UNIPROT	down-regulates	binding			9606									12805410	t		gcesareni	Our results suggest that shp is a negative regulator of pxr transcriptional activity. This conclusion derives from_ in vitro, cell culture, and_ in vivo_ experiments.	SIGNOR-101924	0.578
DNMT1	protein	P26358	UNIPROT	MBD2	protein	Q9UBB5	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000815								15618232	f	 	lperfetto	We then examined the levels of DNMT1 and methylated DNA-binding protein 2 (MBD2) expressions in these cells to determine whether this reduction in uPA expression is associated with changes in the DNA methylation machinery. Our results showed that ectopic expression of RAS induced DNMT1 expression and activity and inhibited MBD2 expression.	SIGNOR-254128	0.693
PTPN6	protein	P29350	UNIPROT	TRAF3	protein	Q13114	UNIPROT	down-regulates activity	dephosphorylation	Tyr446	SLYSQPFyTGYFGYK	9606	BTO:0002181								32779804	t		miannu	We identified a direct interaction between SHP‐1 and TRAF3; the association between these two proteins resulted in diminished recruitment of CK1ε to TRAF3 and inhibited its K63‐linked ubiquitination; SHP‐1 inhibited K63‐linked ubiquitination of TRAF3 by promoting dephosphorylation at Tyr116 and Tyr446.	SIGNOR-277526	0.2
PSMA5	protein	P28066	UNIPROT	XBP1	protein	P17861	UNIPROT	down-regulates quantity by destabilization	binding			-1									19941857	t	1	miannu	We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination.	SIGNOR-239213	0.308
ABL1	protein	P00519	UNIPROT	SRCIN1	protein	Q9C0H9	UNIPROT	unknown	phosphorylation	Tyr264	IYRKEPLyAAFPGSH	9606		BTO:0000142							23383002	t		llicata	Furthermore, we identify abl as the major tyrosine kinase that can trigger p140cap phosphorylation on these sequences.	SIGNOR-200854	0.2
PTPN11	protein	Q06124	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates quantity by stabilization	dephosphorylation			9606	BTO:0001963								19287004	t		miannu	In this study, we identified JAK2 and SHP2 as a Tyr-718-specific kinase and phosphatase, respectively.	SIGNOR-276144	0.374
LCK	protein	P06239	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr42	DSMKDEEyEQMVKEL										14534291	t		lperfetto	Loss of tyrosine kinase p56lck in Jurkat cells abolished NFkappaB activation and partially suppressed and delayed phosphorylation of Tyr-42 of IkappaB upon pervanadate treatment. |Transfection of these cells with wild type Lck but not with mutant Lck F394 followed by H/R induces the tyrosine phosphorylation of inhibitor of nuclear factor kappaB (IkappaBalpha) and transcriptional activation of NFkappaB, and these are inhibited by Lck inhibitors	SIGNOR-249374	0.567
TBK1	protein	Q9UHD2	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates activity	phosphorylation			9606									15489227	t		miannu	Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro.	SIGNOR-260157	0.578
ATM	protein	Q13315	UNIPROT	TOP2B	protein	Q02880	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1135	HDDSSSDsGTPSGPD	9606									32015321	t		miannu	Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation.ATM binds with and phosphorylates TOP2β at Ser1134 to promote its degradation by VM-26. 	SIGNOR-277510	0.422
JAK2	protein	O60674	UNIPROT	APOA1	protein	P02647	UNIPROT	up-regulates activity				9606									14668333	t		miannu	ApoA-I interactions with ABCA1 and lipid efflux to apoA-I were substantially impaired by inhibiting or abolishing JAK2, whereas ABCA1 protein levels were unaffected, and ABCA1 cholesterol translocase activity was only slightly reduced. The most likely explanation for these findings is that JAK2 promotes apolipoprotein interactions with ABCA1 or a closely proximal site, and this facilitates the removal of cellular lipids. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells	SIGNOR-252107	0.303
SIRT7	protein	Q9NRC8	UNIPROT	DDX21	protein	Q9NR30	UNIPROT	up-regulates activity	deacetylation	Lys18	LESDTAMkKGETLRK										28790157	t		lperfetto	Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21.	SIGNOR-275901	0.262
Host translation inhibitor nsp1	protein	P0DTD1-PRO_0000449619	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0002552								33188728	f		miannu	We present here data demonstrating that among all viral proteins, Nsp1 causes the most severe viability reduction in the cells of human lung origin. We found that introduction of Nsp1, but not other viral proteins, induced apoptosis in H1299 cells	SIGNOR-262506	0.7
CSNK1E	protein	P49674	UNIPROT	TRAF3	protein	Q13114	UNIPROT	up-regulates activity	phosphorylation	Tyr446	SLYSQPFyTGYFGYK	9606	BTO:0002181								32779804	t		miannu	We found that the interaction of CK1ε with TRAF3Y116F, TRAF3Y446F were markedly decreased compared with interactions with WT TRAF3 by Co‐IP (Figure 6C); as expected, TRAF3Y116F and TRAF3Y446F mutants exhibited reduced K63‐linked ubiquitination (Figure 6D). These data suggest that the phosphorylation of TRAF3 at Tyr 116 and Tyr 446 regulate CK1ε‐induced K63‐linked ubiquitination.	SIGNOR-277524	0.311
PRKACA	protein	P17612	UNIPROT	RAP1GAP	protein	P47736	UNIPROT	unknown	phosphorylation	Ser490	KSPTRKKsGPFGSRR	-1									1406653	t		miannu	We have localized two of the sites of phosphorylation in vitro by cAMP-dependent kinase to serine residues 490 and 499. raplGAP undergoes phosphorylation at specific sites in vivo, the effects of phosphorylation on raplGAP have remained elusive.	SIGNOR-250043	0.313
FZD2	protein	Q14332	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates				9606	BTO:0000222								10937998	f		fspada	Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma)	SIGNOR-80604	0.2
S1PR3	protein	Q99500	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257388	0.496
RARB	protein	P10826	UNIPROT	THRA	protein	P10827	UNIPROT	up-regulates	binding			9606									15650024	t		gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs	SIGNOR-133234	0.39
RPL5	protein	P46777	UNIPROT	TP73	protein	O15350	UNIPROT	up-regulates	binding			9606									25301064	t		miannu	We report that rpl5 and rpl11 can also enhance the transcriptional activity of a p53 homolog tap73	SIGNOR-205517	0.347
MAPK8	protein	P45983	UNIPROT	EIF4ENIF1	protein	Q9NRA8	UNIPROT	up-regulates	phosphorylation	Ser301	DAVLPEQsPGDFDFN	9606									22966201	t		llicata	Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress.	SIGNOR-198984	0.329
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser245	NQSMDTGsPAELSPT	9606		BTO:0000763;BTO:0000149							10197981	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-66759	0.739
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CDC6	protein	Q99741	UNIPROT	down-regulates activity	phosphorylation	Ser54	RVKALPLsPRKRLGD	9606									9889196	t		lperfetto	Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2.	SIGNOR-217328	0.94
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606									19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-252821	0.908
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1882	SPTSPTYsPTTPKYS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269380	0.718
PKN2	protein	Q16513	UNIPROT	MEFV	protein	O15553	UNIPROT	down-regulates activity	phosphorylation	Ser208	VRLRRNAsSAGRLQG	10090	BTO:0004732								27270401	t	no	miannu	PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. 	SIGNOR-275464	0.357
acetylcholine	smallmolecule	CHEBI:15355	ChEBI	CHRM5	protein	P08912	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257472	0.8
serotonin	smallmolecule	CHEBI:28790	ChEBI	3,4-dihydroxyphenylacetaldehyde	smallmolecule	CHEBI:27978	ChEBI	up-regulates quantity	precursor of			9606									31024440	t	brain	lperfetto	Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA).	SIGNOR-264188	0.8
PYGL	protein	P06737	UNIPROT	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	up-regulates quantity	chemical modification			9606									3346228	t		miannu	Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267393	0.8
MAPK8	protein	P45983	UNIPROT	PXN	protein	P49023	UNIPROT	up-regulates activity	phosphorylation	Ser178	PPLPGALsPLYGVPE	10116	BTO:0004316								12853963	t		miannu	JNK1 phosphorylates serine 178 on paxillin, a focal adhesion adaptor, both in vitro and in intact cells. NBT-II cells expressing the Ser 178 --> Ala mutant of paxillin (Pax(S178A)) formed focal adhesions and exhibited the limited movement associated with such contacts in both single-cell-migration and wound-healing assays. In contrast, cells expressing wild-type paxillin moved rapidly and retained close contacts as the predominant adhesion. 	SIGNOR-250129	0.699
DYRK1A	protein	Q13627	UNIPROT	CCNL2	protein	Q96S94	UNIPROT	unknown	phosphorylation	Ser330	LDGTSGFsPAPKLVE	9534	BTO:0000298								14623875	t		llicata	DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase. 	SIGNOR-251087	0.591
P-TEFb	complex	SIGNOR-C238	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0001545								19516275	f		miannu	Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) inhibits the positive transcription elongation factor b (P-TEFb), which is a key RNA polymerase II (Pol II) transcriptional regulator. In transfected cells, mutated NPM1 associated with, and sequestered, HEXIM1 in cytoplasm, resulting in higher transcription of RNA pol II target genes, among which were some positive regulators of cell-cycle progression such as cyclin D1 and anti-apoptotic proteins such as Mcl-1	SIGNOR-260136	0.7
TFIIIC	complex	SIGNOR-C392	SIGNOR	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	up-regulates activity	relocalization			9606	BTO:0000567								9308965	t		lperfetto	Transcription by RNA polymerase III (Pol III) requires multiple general initiation factors that, in isolated form, assemble onto the promoter in an ordered fashion. Here, it is shown that all components required for transcription of the VA1 and tRNA genes, including TFIIIB, TFIIIC, and RNA Pol III, can be coimmunopurified from a HeLa cell line that constantly expresses a FLAG epitope-tagged subunit of human RNA Pol III.	SIGNOR-266182	0.447
VPS39	protein	Q96JC1	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates activity	relocalization			9534									12941698	t		miannu	The data demonstrating binding of TLP to TGF-β and activin type II receptors and selective inhibition of Smad3/Smad4 complex formation by deregulated TLP suggest that TLP is involved in localizing these receptors and Smad4 to specific intracellular compartments, where it regulates formation of Smad3/Smad4 but not Smad2/Smad4 complexes.	SIGNOR-261377	0.324
CSNK2A1	protein	P68400	UNIPROT	CDC34	protein	P49427	UNIPROT	down-regulates activity	phosphorylation	Thr233	DDEDDSGtEES	9606									11546811	t		lperfetto	The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm.	SIGNOR-110407	0.403
CDON/SPAG9	complex	SIGNOR-C21	SIGNOR	MAP3K7	protein	O43318	UNIPROT	unknown	binding			10090	BTO:0000165;BTO:0000222;BTO:0002181								22337877	t		lperfetto	Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts	SIGNOR-235560	0.2
2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine	smallmolecule	CHEBI:44811	ChEBI	PTAFR	protein	P25105	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257567	0.8
DUSP9	protein	Q99956	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates	binding			9606									21908610	t	inferred from 70% of family members	gcesareni	Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein.	SIGNOR-269924	0.713
Set1-Ash2 HMT complex	complex	SIGNOR-C352	SIGNOR	H3C1	protein	P68431	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606	BTO:0000567								12670868	t		miannu	 The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. 	SIGNOR-264482	0.2
ATM	protein	Q13315	UNIPROT	EXO1	protein	Q9UQ84	UNIPROT	up-regulates	phosphorylation			9606									20019063	t		gcesareni	The phosphorylation of exo1 by atm appears to regulate the activity of exo1 following resection, allowing optimal rad51 loading and the completion of hr repair.	SIGNOR-162304	0.825
MAPK3	protein	P27361	UNIPROT	PTPRR	protein	Q15256	UNIPROT	up-regulates activity	phosphorylation	Thr361	EPFVSIPtPREKVAM										11493009	t		lperfetto	Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL.	SIGNOR-249477	0.656
FFAR2	protein	O15552	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256803	0.2
EP300	protein	Q09472	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	acetylation	Lys310	KRTYETFkSIMKKSP	9606	BTO:0002207								15152190	t		gcesareni	Using acetylation assays, p300 was found to effectively acetylate RelA/p65 across the amino-acid region containing 1€“317	SIGNOR-238778	0.814
MAPK8	protein	P45983	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser636	SGDYMPMsPKSVSAP	9606									12510059	t		gcesareni	Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1.	SIGNOR-96948	0.767
ZEB2	protein	O60315	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11430829	t		Luisa	 SIP 1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadh promoter.SIP1 induction resulted in the loss of cell-cell adhesion, in activation of invasion and in at random, multidirectional migration instead of unidirectional coherent migration (required in neurulation). 	SIGNOR-268950	0.503
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	AIM2 inflammasome	complex	SIGNOR-C222	SIGNOR	up-regulates activity													16037825	f		miannu	Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage	SIGNOR-263126	0.7
SYCP1	protein	Q15431	UNIPROT	Synaptonemal_complex	complex	SIGNOR-C351	SIGNOR	form complex	binding			9606									22394509	t		miannu	The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region.	SIGNOR-264197	0.675
ADORA2B	protein	P29275	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257039	0.296
ABL1	protein	P00519	UNIPROT	RAPH1	protein	Q70E73	UNIPROT	up-regulates activity	phosphorylation	Tyr456	NVYYGQDyRNKYKAP	-1									20417104	t		miannu	Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C).	SIGNOR-262607	0.289
PAK2	protein	Q13177	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates	phosphorylation	Ser619	PTPPKRSsSFREMDG	9606									18161990	t		lperfetto	The interaction of c-abl with the abl interactor protein abi2 is shown to be negatively regulated by phosphorylation of serines 637 and 638. These serines are adjacent to the pxxp motif (ptppkrs637s638sfr) that binds the sh3 domain of abi. phosphorylation of c-abl by pak2 inhibits the interaction between the sh3 domain of abi2 and the pxxp motif of c-abl.	SIGNOR-160219	0.424
RET	protein	P07949	UNIPROT	ATF4	protein	P18848	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr107	LGIDDLEtMPDDLLT	9606	BTO:0002181								25795775	t		miannu	We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA. 	SIGNOR-276448	0.2
ATM	protein	Q13315	UNIPROT	RASSF1	protein	Q9NS23	UNIPROT	up-regulates	phosphorylation	Ser135	EWETPDLsQAEIEQK	9606									19962312	t		llicata	We show that, upon dna damage, rassf1a is phosphorylated by atm on ser131 and is involved in the activation of both mst2 and lats1, leading to the stabilization of p73.	SIGNOR-161934	0.566
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Thr331	CTPVVTCtPSCTAYT	9606									12972619	t		lperfetto	In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity.	SIGNOR-251523	0.2
VCP	protein	P55072	UNIPROT	DDX58	protein	O95786	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys181	ALEKERNkFSELWIV	9606									26471729	t		lperfetto	Here, we report a new role for p97 with Npl4-Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG-I. The p97 complex is able to directly bind both non-ubiquitinated RIG-I and the E3 ligase RNF125, promoting K48-linked ubiquitination of RIG-I at residue K181. 	SIGNOR-261000	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PAPOLA	protein	P51003	UNIPROT	up-regulates activity	phosphorylation	Ser537	DNSMSVPsPTSATKT	10090	BTO:0000964								34048556	t		lperfetto	Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity.	SIGNOR-268341	0.2
PRKACA	protein	P17612	UNIPROT	PDE3A	protein	Q14432	UNIPROT	unknown	phosphorylation	Ser312	SKSHRRTsLPCIPRE	9606									16153182	t		llicata	Ser312 of pde3a was phosphorylated in an h-89-sensitive response to forskolin, indicative of phosphorylation by pka (camp-dependent protein kinase), but phosphorylation at this site did not stimulate 14-3-3 binding.	SIGNOR-140289	0.495
NPM1	protein	P06748	UNIPROT	CDKN2A	protein	Q8N726	UNIPROT	up-regulates activity	binding			10090									16199867	t		gcesareni	The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division	SIGNOR-245073	0.57
LPAR2	protein	Q9HBW0	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates	binding			9606									11093753	t		gcesareni	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. lpa2 also can couple to the gi/o, g12/13, and gqfamilies.	SIGNOR-84559	0.61
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRIA1	protein	P42261	UNIPROT	up-regulates activity	chemical activation			9606									30825796	t		miannu	In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses	SIGNOR-264616	0.8
CSNK1E	protein	P49674	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	up-regulates	phosphorylation			9606									12000790	t		lperfetto	We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms.	SIGNOR-227976	0.624
MLL1 complex	complex	SIGNOR-C89	SIGNOR	H3C1	protein	P68431	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606									24680668	t		miannu	Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation.	SIGNOR-268801	0.2
levomilnacipran	chemical	CHEBI:136040	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								18468895	t		Luana	Studies on a series of milnacipran analogs containing a heteroaromatic group as potent norepinephrine and serotonin transporter inhibitors	SIGNOR-257943	0.8
doramapimod	chemical	CHEBI:40953	ChEBI	TNF	protein	P01375	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190335	0.8
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	PDK1	protein	Q15118	UNIPROT	up-regulates quantity	transcriptional regulation			10090									16517405	t			We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. 	SIGNOR-267480	0.42
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	ABCB1	protein	P08183	UNIPROT	up-regulates activity	dephosphorylation	Ser667	SSLIRKRsTRRSVRG	9606	BTO:0000007								24333728	t			Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp	SIGNOR-272513	0.2
ATM	protein	Q13315	UNIPROT	SMURF2	protein	Q9HAU4	UNIPROT	up-regulates activity	phosphorylation	Ser384	KILRQELsQQQPQAG	10090	BTO:0002572								33097595	t		miannu	Using biochemical approaches and MS analysis, we show that upon the onset of the DNA-damage response, SMURF2 becomes phosphorylated at Ser384 by ataxia telangiectasia mutated (ATM) serine/threonine kinase, and this phosphorylation is required for its interaction with RNF20.	SIGNOR-277534	0.2
edoxaban	chemical	CHEBI:85973	ChEBI	F10	protein	P00742	UNIPROT	down-regulates activity	chemical inhibition			-1									20503967	t		Luana	Replacing the chloroindole P1 moiety of 100 with a 5-chloropyridin-2-yloxalamide group provided 101 (edoxaban, DU-176b). Compound 101 is a potent inhibitor of human FXa in vitro (FXa Ki = 0.56 nM), with >10 000-fold selectivity against relevant serine proteases, and demonstrated good anticoagulant activity (PT2× = 0.26 μM) and activity in various animal models of thrombosis, with minimal bleeding	SIGNOR-257845	0.8
N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide	chemical	CHEBI:95008	ChEBI	BCL2	protein	P10415	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207459	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	XPO5	protein	Q9HAV4	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000007								27846390	t	inferred from 70% family members	lperfetto	Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. 	SIGNOR-269999	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	CEBPA	protein	P49715	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000876								14701740	t	inferred from 70% family members	lperfetto	Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21.	SIGNOR-270066	0.2
MAPK3	protein	P27361	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates	phosphorylation	Ser641	DIKILIAsPSPTHIH	9606	BTO:0000567								18519666	t		lperfetto	We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_	SIGNOR-178731	0.688
CEBPB	protein	P17676	UNIPROT	TNFAIP6	protein	P98066	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									7876106	t	 	 	In cotransfection experiments, the C/EBP beta protein trans-activated 10-15-fold the cAspAT gene promoter in HepG2 cells.	SIGNOR-254055	0.307
PPP2CB	protein	P62714	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates activity	dephosphorylation	Thr216	RSSSSEStGTPSNPD	10090									11983168	t			cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216. Consistent with these data, cyclin G null cells have both Mdm2 that is hyperphosphorylated at T216 and markedly higher levels of p53 protein when compared to wild-type cells	SIGNOR-248593	0.374
CSNK1D	protein	P48730	UNIPROT	PSEN2	protein	P49810	UNIPROT	unknown	phosphorylation	Ser19	EVCDERTsLMSAESP	-1									8972483	t		llicata	In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. 	SIGNOR-250799	0.371
EXOSC1	protein	Q9Y3B2	UNIPROT	Exosome_Complex	complex	SIGNOR-C255	SIGNOR	form complex	binding			-1									24189234	t		miannu	The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 	SIGNOR-261381	0.958
WWP2	protein	O00308	UNIPROT	POU5F1	protein	Q01860	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								19274063	t		lperfetto	WWP2 promotes degradation of transcription factor OCT4 in human embryonic stem cells|Here, we report that human WWP2, an E3 ubiquitin (Ub)-protein ligase, interacts with OCT4 specifically through its WW domain and enhances Ub modification of OCT4 both in vitro and in vivo.	SIGNOR-268850	0.465
TUBA1C	protein	Q9BQE3	UNIPROT	Neuron_migration	phenotype	SIGNOR-PH67	SIGNOR	up-regulates				9606	BTO:0000007								19185337	f		miannu	We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching.	SIGNOR-269728	0.7
LCK	protein	P06239	UNIPROT	PIK3R1	protein	P27986	UNIPROT	down-regulates activity	phosphorylation	Tyr688	FAEPYNLySSLKELV	9534	BTO:0004055								9461588	t			 the regulatory p85 subunit of phosphatidylinositol 3-kinase is phosphorylated on tyrosine residues. We report that this phosphorylation event is readily catalyzed by the Abl and Lck protein-tyrosine kinases in vitro, by Bcr-Abl or a catalytically activated Lck-Y505F in co-transfected COS cells. we have mapped a major phosphorylation site to Tyr-688 in the C-terminal SH2 domain of p85. Tyrosine phosphorylation of p85 in vitro or in vivo was not associated with detectable change in the enzymatic activity of the phosphatidylinositol 3-kinase heterodimer, but correlated with a strong reduction in the binding of some, but not all, phosphoproteins to the SH2 domains of p85.	SIGNOR-251383	0.607
FST	protein	P19883	UNIPROT	MSTN	protein	O14793	UNIPROT	down-regulates activity	binding			10090									11459935	t		gcesareni	Binding of myostatin to Act RIIB could be inhibited by the activin-binding protein follistatin and, at higher concentrations, by the myostatin propeptide. T	SIGNOR-235150	0.751
BCL11A	protein	Q9H165	UNIPROT	HBG2	protein	P69892	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20712774	f	Regulation	miannu	BCL11A maintains silencing of gamma-globin expression in adult erythroid cells and functions as a direct transcriptional regulator of the fetal to adult hemoglobin switch in humans. we found that BCL11A plays a central role in the evolutionarily divergent globin gene switches of mammals. As a factor critical for gamma-globin gene silencing, BCL11A should be considered as a therapeutic target to increase HbF in a directed manner in beta-thalassemia patients.	SIGNOR-251775	0.46
CAMK2A	protein	Q9UQM7	UNIPROT	OPRM1	protein	P35372	UNIPROT	down-regulates	phosphorylation	Ser268	LKSVRMLsGSKEKDR	9606		BTO:0000671							10908300	t		gcesareni	The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization.	SIGNOR-79678	0.2
PRKG1	protein	Q13976	UNIPROT	TNNI3	protein	P19429	UNIPROT	up-regulates activity	phosphorylation	Ser24	APIRRRSsNYRAYAT	9606									15769444	t		lperfetto	Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.	SIGNOR-134644	0.366
CDK5	protein	Q00535	UNIPROT	PPP1CA	protein	P62136	UNIPROT	down-regulates activity	phosphorylation	Thr320	NPGGRPItPPRNSAK	9606									17202132	t		gcesareni	We observed that phosphorylation of protein phosphatase 1 (PP1) on Thr320 is reduced in brain extracts from Egr-1-/- mice, indicating that a kinase downstream of Egr-1 phosphorylates PP1. In HEK 293 cells co-transfected with PP1 and Cdk5, Cdk5 phosphorylates PP1. In vitro, Cdk5 purified from bovine brain phosphorylates bacterially expressed recombinant PP1	SIGNOR-151803	0.403
CSNK2A1	protein	P68400	UNIPROT	PTPN1	protein	P18031	UNIPROT	unknown	phosphorylation			-1									9600099	t		llicata	In this study, we demonstrate that HPTP1B are multiple phosphorylated on threonine and tyrosine as well as serine near its N-terminus by CKII and p60c-src in vitro.	SIGNOR-250941	0.448
CHUK	protein	O15111	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	down-regulates activity	phosphorylation	Ser444	PLSLSAQsVMEELNT	9606	BTO:0000938								24614225	t		lperfetto	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204712	0.524
BMAL1/NPAS2	complex	SIGNOR-C431	SIGNOR	CRY2	protein	Q49AN0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements.	SIGNOR-267968	0.892
ETF	complex	SIGNOR-C463	SIGNOR	FAD	smallmolecule	CHEBI:16238	ChEBI	down-regulates quantity	chemical modification			9606									33450351	t		miannu	ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a). 	SIGNOR-269454	0.8
NBR1	protein	Q14596	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	up-regulates	binding			9606									19250911	t		gcesareni	Nbr1 and p62 interact and form oligomers.	SIGNOR-184273	0.484
LNX1	protein	Q8TBB1	UNIPROT	ABCA1	protein	O95477	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1									22889411	t		miannu	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272902	0.243
KAT2B	protein	Q92831	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates	binding			9606									11062529	t		gcesareni	The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis.	SIGNOR-84032	0.554
CSNK2A1	protein	P68400	UNIPROT	GAP43	protein	P17677	UNIPROT	unknown	phosphorylation	Ser202	PPTETGEsSQAEENI	-1									1828073	t		llicata	Two serines located in the C-terminal end of neuromodulin, Ser-192 and Ser-193, were identified as the major casein kinase II phosphorylation sites. 	SIGNOR-250866	0.311
STK39	protein	Q9UEW8	UNIPROT	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation	Thr105	LQTFGHNtMDAVPKI	9606	BTO:0000007								21321328	t		miannu	We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity.	SIGNOR-263131	0.596
NUMA1	protein	Q14980	UNIPROT	TUBA1A	protein	Q71U36	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116640	0.408
4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide	chemical	CHEBI:94504	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191430	0.8
BRCA1-BARD1 complex	complex	SIGNOR-C297	SIGNOR	BRCA1-B complex	complex	SIGNOR-C298	SIGNOR	form complex	binding												25400280	t		lperfetto	Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation	SIGNOR-263217	0.766
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MEF2D	protein	Q14814	UNIPROT	up-regulates				9606	BTO:0000222	BTO:0000887;BTO:0001103							10896679	f		lperfetto	Two candidates that may function as mediators of pi3-k in the phosphorylation of mef2 proteins are pkb and big map kinase 1.	SIGNOR-244303	0.2
CDK2	protein	P24941	UNIPROT	ZBTB16	protein	Q05516	UNIPROT	down-regulates	phosphorylation	Thr282	RGKEGPGtPTRSSVI	9606	BTO:0001271								18246121	t		llicata	Here we show that the main cyclin-dependent kinase involved at the g(1) to s transition (cdk2) phosphorylates plzf at two consensus sites found within pest domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of plzf, which impairs plzf transcriptional repression ability and antagonizes its growth inhibitory effects.	SIGNOR-160630	0.286
SIK2	protein	Q9H0K1	UNIPROT	CDK5R1	protein	Q15078	UNIPROT	down-regulates	phosphorylation	Ser91	ENLKKSLsCANLSTF	9606									24561619	t		lperfetto	Sik2 phosphorylates p35 at ser 91, to trigger its ubiquitylation by pja2 and promote insulin secretion. _-cell knockout of sik2 leads to accumulation of p35 and impaired secretion	SIGNOR-204648	0.337
SLC2A4	protein	P14672	UNIPROT	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	up-regulates quantity	relocalization			9606									17403369	t			Skeletal muscle both stores glucose as glycogen and oxidizes it to produce energy following the transport step. The principal glucose transporter protein that mediates this uptake is GLUT4, which plays a key role in regulating whole body glucose homeostasis	SIGNOR-267291	0.8
TTL	protein	Q8NG68	UNIPROT	TUBA8	protein	Q9NY65	UNIPROT	down-regulates	tyrosination			9606									22020298	t		miannu	Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization	SIGNOR-176930	0.315
PRKCA	protein	P17252	UNIPROT	DGKZ	protein	Q13574	UNIPROT	unknown	phosphorylation	Ser265	SKKKKRAsFKRKSSK										9716136	t		lperfetto	Two isoforms of protein kinase C, but not others, regulate the localization of DGK-zeta. |The PSD in MARCKS is phosphorylated by PKC, which suggested that DGK-zeta may also be a substrate for PKC, and that this couldregulate its intracellular location.	SIGNOR-249010	0.518
PPP2CB	protein	P62714	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates	dephosphorylation	Ser62	LLPTPPLsPSRRSGL	9606									16987807	t		esanto	Phosphorylation at ser-62 by pro-directed kinases (p-k) is a prerequisite for gsk3-dependent phosphorylation of thr-58. This triggers binding of pin1, subsequently protein phosphatase 2a (pp2a)-dependent dephosphorylation of ser-62, and then recruitment of scf-fbw7 to the thr-58-phosphorylated myc. Scf-fbw7 polyubiquitinylates myc (branching through lys-48), leading to its proteasomal degradation.	SIGNOR-149726	0.28
CDK11B	protein	P21127	UNIPROT	EIF3F	protein	O00303	UNIPROT	unknown	phosphorylation	Thr119	GAARVIGtLLGTVDK	9606									19245811	t		lperfetto	Here, we identified a second eif3f phosphorylation site (thr119) by cdk11p46 during apoptosis.Thr119 is located in the mov34 domain of eif3f which is important for both the translational inhibitory function of eif3ffurther studies of how eif3f phosphorylation regulates its function will refine insights into the mechanism and regulation of translation initiation, apoptotic signaling, and tumorigenesis.	SIGNOR-184185	0.531
IL3RA	protein	P26951	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates	binding			9606									15795318	t		gcesareni	Indeed, only upon fibronectin adhesion is janus kinase 2 (jak2) recruited to the beta1 integrin-il-3r complex and triggers il-3r beta common phosphorylation, leading to the formation of docking sites for activated stat5a.	SIGNOR-134859	0.598
CASP1	protein	P29466	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates activity	cleavage	Asp345	EEWEAQRdSHLGPHR	-1									10069390	t		lperfetto	Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.	SIGNOR-261755	0.393
PRKCZ	protein	Q05513	UNIPROT	VIM	protein	P08670	UNIPROT	up-regulates activity	phosphorylation	Ser34	SRSYVTTsTRTYSLG	9606	BTO:0001033								33525953	t		miannu	Results suggest that aPKCs target multiple activation sites (Ser33/39/56) on Vimentin and therefore is essential for VIF dynamics regulation during the metastasis of prostate cancer cells.	SIGNOR-277622	0.2
LETM1	protein	O95202	UNIPROT	Mitochondrial_biogenesis	phenotype	SIGNOR-PH32	SIGNOR	up-regulates				9606	BTO:0000567								18628306	f		lperfetto	We hypothesize a working model of the function of BCS1L and LETM1 in mitochondrial biogenesis (Fig. 8E). Because BCS1L is an AAA-ATPase, the following three functions are downstream targets: (1) respiratory chain assembly, (2) mitochondrial morphology maintenance and, (3) LETM1 complex formation. BCS1L functions directly in the formation of mitochondrial tubular networks, in addition to the assembly of the supercomplexes. LETM1 has a distinct role in maintenance of mitochondrial volume and shapes, which helps – in concert with BCS1L – to achieve the efficient assembly of the respiratory chains.	SIGNOR-262545	0.7
AKT1	protein	P31749	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606									19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252522	0.908
Scribble_complex_DLG4-LLGL1_variant	complex	SIGNOR-C509	SIGNOR	Cell_polarity	phenotype	SIGNOR-PH213	SIGNOR	up-regulates				9606									23397623	f		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270906	0.7
PIM1	protein	P11309	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates activity	dephosphorylation	Ser683	QAQDRKLsTKEALDE	9606	BTO:0000007								24333728	t			Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp	SIGNOR-272511	0.449
DDB1	protein	Q16531	UNIPROT	DDB2/DDB1	complex	SIGNOR-C39	SIGNOR	form complex	binding			9606	BTO:0000567								9418871	t		miannu	Ddb was identified as a heterodimeric protein (48 and 127 kda) that binds to uv-damaged dna	SIGNOR-54093	0.936
CALM1	protein	P0DP23	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	down-regulates activity	binding			9606									11807557	t		miannu	Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias.	SIGNOR-253410	0.462
ziprasidone	chemical	CHEBI:10119	ChEBI	HTR2A	protein	P28223	UNIPROT	down-regulates activity	chemical inhibition			10090									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258500	0.8
MAPK3	protein	P27361	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								22802261	t		gcesareni	Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1	SIGNOR-198292	0.297
NAE	complex	SIGNOR-C131	SIGNOR	CUL7	protein	Q14999	UNIPROT	up-regulates activity	neddylation			9606									25504797	t		lperfetto	The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates.	SIGNOR-243172	0.463
EPHA8	protein	P29322	UNIPROT	EPHA8	protein	P29322	UNIPROT	up-regulates activity	phosphorylation	Tyr839	LAYGERPyWNMTNRD	9606	BTO:0000007								10498895	t			Tyr-615 and Tyr-838 are major autophosphorylation sites of the EphA8 receptor. phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for efficient phosphorylation at Tyr-615 as well as other major sites.	SIGNOR-251121	0.2
2,5-dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide	chemical	CHEBI:125569	ChEBI	PPARD	protein	Q03181	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001950								27489280	t		lperfetto	We performed reporter assays to examine the effect of NeoB on the transcriptional activity of specific nuclear hormone receptors, including PPARs, retinoic acid receptor (RAR), ER, and LXR, in uninfected Huh7-25 cells (Fig. 3A). NeoB did not have a significant effect [...] in contrast to the transcriptional repression by known antagonists as positive controls (GW6471, GSK0660, FH535, Ro41-5253, and 4-hydroxytamoxifen) (Fig. 3A)	SIGNOR-262014	0.8
NMDA receptor_2B	complex	SIGNOR-C348	SIGNOR	CAMK2A	protein	Q9UQM7	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								11052931	t		miannu	The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD	SIGNOR-264215	0.667
EPX	protein	P11678	UNIPROT	PRG2	protein	P13727	UNIPROT	up-regulates activity	post translational modification			9606	BTO:0000399								18694936	t		miannu	Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.	SIGNOR-261703	0.446
ARFGEF1	protein	Q9Y6D6	UNIPROT	ARF1	protein	P84077	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000599								14973189	t		lperfetto	Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) is an approximately 200-kDa brefeldin A-inhibited guanine nucleotide-exchange protein that preferentially activates ADP-ribosylation factor 1 (ARF1) and ARF3. 	SIGNOR-272147	0.584
MAPK11	protein	Q15759	UNIPROT	PIAS2	protein	O75928	UNIPROT	up-regulates activity	phosphorylation	Ser113	STSVTPHsPSSPVGS	9606	BTO:0000007								16713578	t		miannu	The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles	SIGNOR-262946	0.267
MAPK10	protein	P53779	UNIPROT	NFATC1	protein	O95644	UNIPROT	down-regulates	phosphorylation	Ser172	YRDPSCLsPASSLSS	9606									10652349	t	Translocation from Nucleus to Cytoplasm	esanto	We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats.	SIGNOR-74556	0.425
OGDC	complex	SIGNOR-C397	SIGNOR	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	down-regulates quantity	chemical modification			9606									15953811	t		miannu	The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH.	SIGNOR-266257	0.8
Orexin A	smallmolecule	CHEBI:80319	ChEBI	HCRTR2	protein	O43614	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257511	0.8
SYK	protein	P43405	UNIPROT	FCGR2A	protein	P12318	UNIPROT	up-regulates activity	phosphorylation	Tyr304	TDDDKNIyLTLPPND	-1									8756631	t		lperfetto	To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and pointFyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.	SIGNOR-246551	0.659
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	SREBF1	protein	P36956	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000599								10915800	t	inferred from 70% family members	lperfetto	Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo.	SIGNOR-270081	0.2
POLR2L	protein	P62875	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266171	0.861
GRK2	protein	P25098	UNIPROT	CLTB	protein	P09497	UNIPROT	unknown	phosphorylation	Ser205	LCDFNPKsSKQCKDV	9606									22704991	t		llicata	Moreover, we demonstrate that phosphorylation of ser204 in clcb is required for efficient endocytosis of a subset of gpcrs and identify g protein-coupled receptor kinase 2 (grk2) as a kinase that can phosphorylate clcb on ser204. Overexpression of clcb(s204a) specifically inhibits the endocytosis of those gpcrs whose endocytosis is grk2-dependent.	SIGNOR-197873	0.2
TP53	protein	P04637	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000801								24737129	f		simone vumbaca	We have identified a novel role for p53 that is specific to the regulation of several pro-inflammatory genes in human macrophages, including IL-6, IL-8 and CXCL1. Importantly, NF-κB co-activation is essential for this regulation	SIGNOR-255969	0.48
PTEN	protein	P60484	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	down-regulates activity	dephosphorylation			9606									33348808	t		miannu	GluN2B Y1472 site is dephosphorylated by PTEN .	SIGNOR-277165	0.301
AICA-Ribotide	chemical	CID:16760280	PUBCHEM	PRKAA2	protein	P54646	UNIPROT	up-regulates	chemical activation			9606	BTO:0000222	BTO:0000887;BTO:0001103;BTO:0001760							19491292	t		gcesareni	Aicar-induced ampk phosphorylation inhibits cell cycle transition, reducing differentiation of myoblasts into myotubes, through pgc-1alpha-foxo3a-p21.	SIGNOR-186055	0.8
MAPK1	protein	P28482	UNIPROT	NOX5	protein	Q96PH1	UNIPROT	up-regulates	phosphorylation	Ser544	RSVTMRKsQRSSKGS	9606									21297032	t	The effect has been demonstrated using Q96PH1-4	gcesareni	These results suggest that the mek/erk1/2 pathway is necessary but not sufficient to regulate the pma-dependent activation of nox5.	SIGNOR-171847	0.332
CREB1	protein	P16220	UNIPROT	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000759							14614508	f			HES-1 is a direct CREB target in vivo.	SIGNOR-254742	0.252
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606	BTO:0000007								16403219	t		miannu	Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.	SIGNOR-259423	0.2
LPAR6	protein	P43657	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257347	0.337
CAMK2A	protein	Q9UQM7	UNIPROT	DLGAP1	protein	O14490	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser356	KAMGDEDsGDSDTSP	-1									23143515	t		miannu	 CaMKIIα activated by the NMDA receptor phosphorylates GKAP Ser54 to induce polyubiquitination of GKAP. 	SIGNOR-276429	0.407
RPS26	protein	P62854	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262425	0.882
MIS12	protein	Q9H081	UNIPROT	MIS12 complex	complex	SIGNOR-C362	SIGNOR	form complex	binding			-1									27881301	t		lperfetto	 Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits 	SIGNOR-265190	0.857
GRM3	protein	Q14832	UNIPROT	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							20055706	t		miannu	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264083	0.333
CUL1	protein	Q13616	UNIPROT	SCF-SKP2	complex	SIGNOR-C136	SIGNOR	form complex	binding			9606									15340381	t		gcesareni	The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions.	SIGNOR-243557	0.943
2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol	chemical	CHEBI:93773	ChEBI	ARAF	protein	P10398	UNIPROT	down-regulates	chemical inhibition			9606									12970777	t		gcesareni	At drug concentrations around the reported ic(50) for the raf inhibitor l-779,450, it suppressed dna synthesis and induced apoptosis in hematopoietic fdc-p1 cells transformed to grow in response to either raf-1 or a-raf (fd/deltaraf-1:er and fd/deltaa-raf:er)	SIGNOR-100355	0.8
YWHAG	protein	P61981	UNIPROT	NEFL	protein	P07196	UNIPROT	down-regulates activity	binding			9606									23230147	t		miannu	These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments.	SIGNOR-252400	0.299
DLL1	protein	O00548	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	binding					BTO:0001103							12361602	t		apalma	When activated by its ligands (Delta and Jagged in vertebrates and Serrate in invertebrates), the intracellular portion of Notch is cleaved and translocates to the nucleus	SIGNOR-255368	0.625
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PIKFYVE	protein	Q9Y2I7	UNIPROT	up-regulates	phosphorylation	Ser307	PARNRSAsITNLSLD	9606		BTO:0000887							15546921	t		gcesareni	Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme.	SIGNOR-130920	0.2
PRKCA	protein	P17252	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser42	TRTYSLGsALRPSTS	-1									2500966	t		lperfetto	We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65.	SIGNOR-248881	0.289
BMX	protein	P51813	UNIPROT	RUFY1	protein	Q96T51	UNIPROT	up-regulates activity	phosphorylation	Tyr389	TKVELETyKQTRQGL	9534									11877430	t		miannu	 Etk interacts with RUFY1 through its SH3 and SH2 domains. RUFY1 is tyrosine-phosphorylated and appears to be a substrate of Etk. Phosphorylation of the two tyrosine residues, Tyr-281 and Tyr-292, located in the linker region of the two coiled-coil domains by Etk seems to be critical for RUFY1 targeting to the endosomes.	SIGNOR-262678	0.619
AKT2	protein	P31751	UNIPROT	ATP7A	protein	Q04656	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser1424	SYELPARsQIGQKSP	10090									29301787	t		lperfetto	Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466	SIGNOR-272269	0.263
SMARCD2	protein	Q92925	UNIPROT	Muscle cell-specific SWI/SNF ARID1B variant	complex	SIGNOR-C482	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270706	0.753
AKT2	protein	P31751	UNIPROT	PKP1	protein	Q13835	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser174	LRKGTLGsKGQKTTQ	-1									23444369	t		miannu	Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry.	SIGNOR-273492	0.27
CYP17A1	protein	P05093	UNIPROT	androst-4-ene-3,17-dione	smallmolecule	CHEBI:16422	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0001363;BTO:0000050;BTO:0000056							17192295	t		lperfetto	THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones.	SIGNOR-268654	0.8
MAPKAPK5	protein	Q8IW41	UNIPROT	EEF2K	protein	O00418	UNIPROT	unknown	phosphorylation	Ser377	PPLLRPLsENSGDEN	-1									12171600	t		miannu	Identification of Ser-377 as the site on eEF2 kinase phosphorylated in vitro by MAPKAP-K2, MAPKAP-K3 and MAPKAP-K5. Maximal phosphorylation of eEF2 kinase by MAPKAP-K2 (Figure 5) or MAPKAP-K5 (results not shown) had no effect on its activity.	SIGNOR-249708	0.298
RPS6KA3	protein	P51812	UNIPROT	HMGN2	protein	P05204	UNIPROT	down-regulates activity	phosphorylation	Ser29	QRRSARLsAKPAPPK	9606	BTO:0000567								11438671	t		lperfetto	We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets.	SIGNOR-249103	0.293
HMGB1	protein	P09429	UNIPROT	TLR4	protein	O00206	UNIPROT	up-regulates activity	binding			9606									20547845	t		gcesareni	Here we show that Toll-like receptor 4 (TLR4), a pivotal receptor for activation of innate immunity and cytokine release, is required for HMGB1-dependent activation of macrophage TNF release.	SIGNOR-252057	0.796
LPR5/6	complex	SIGNOR-C219	SIGNOR	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity	binding			9606									19107203	t	PPPSPxS motif in LRP6/5 must be phosphorylated.	miannu	These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence. binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin.	SIGNOR-256177	0.698
NCL	protein	P19338	UNIPROT	MYBL1	protein	P10243	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								10660576	t		miannu	We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity.	SIGNOR-221233	0.427
AMPK	complex	SIGNOR-C15	SIGNOR	ACACA	protein	Q13085	UNIPROT	down-regulates	phosphorylation	Ser80	LHIRSSMsGLHLVKQ	9606		BTO:0000887;BTO:0001103							12015362	t		lperfetto	Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed.	SIGNOR-216655	0.541
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	PPP3CA	protein	Q08209	UNIPROT	up-regulates	chemical activation			9606									22944199	t		lperfetto	Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell).	SIGNOR-198819	0.8
PDPK1	protein	O15530	UNIPROT	PDPK1	protein	O15530	UNIPROT	unknown	phosphorylation	Ser25	VVLCSCPsPSMVRTQ	9606									10455013	t		lperfetto	3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity	SIGNOR-236777	0.2
FOXM1	protein	Q08050	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606	BTO:0002181								26912724	t		miannu	Nuclear FoxM1 then directly interacted with nuclear β‐catenin, which released β‐catenin from ICAT and enhanced recruitment of β‐catenin to the promoter of Wnt target gene, hence increasing the expression of Wnt target gene.	SIGNOR-277211	0.534
SAR1A	protein	Q9NR31	UNIPROT	SEC24A	protein	O95486	UNIPROT	up-regulates quantity	binding							SIGNOR-C370					30605680	t		lperfetto	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 	SIGNOR-265303	0.747
iron-sulfur cluster	smallmolecule	CHEBI:30408	ChEBI	Mitochondrial respiratory chain complex III	complex	SIGNOR-C279	SIGNOR	up-regulates activity	chemical activation												26083061	t		lperfetto	Respiratory chain complexes I–III depend on Fe-S clusters for function	SIGNOR-262137	0.8
CACNA1G	protein	O43497	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606		BTO:0000227							30849329	f		miannu	Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]).	SIGNOR-264329	0.7
RAD21	protein	O60216	UNIPROT	APOB	protein	P04114	UNIPROT	down-regulates quantity	transcriptional regulation			9606									25575569	t			The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector.	SIGNOR-259974	0.2
PRKCA	protein	P17252	UNIPROT	IQGAP1	protein	P46940	UNIPROT	up-regulates	phosphorylation	Ser1443	DKMKKSKsVKEDSNL	9606									21349850	t		gcesareni	Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth.	SIGNOR-172235	0.261
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	KDM3B	protein	Q7LBC6	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273471	0.8
G6P	proteinfamily	SIGNOR-PF81	SIGNOR	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	down-regulates quantity	chemical modification			9606									12093795	t		miannu	Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis	SIGNOR-266571	0.8
PTPRO	protein	Q16827	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606									24708807	t		miannu	In addition, this group found that PTPRO dephosphorylated STAT3 at Y705 and S727 then attenuated STAT3 signalling.	SIGNOR-277062	0.385
CSNK2A1	protein	P68400	UNIPROT	MDC1	protein	Q14676	UNIPROT	up-regulates	phosphorylation	Thr455	TTERDSDtDVEEEEL	9606									18678890	t		gcesareni	The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites.	SIGNOR-179891	0.353
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1644	SPTSPSYsPTSPSYS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248748	0.727
KDR	protein	P35968	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	binding			9606	BTO:0001949								11278468	t		Gianni		SIGNOR-261917	0.483
MAP3K14	protein	Q99558	UNIPROT	G6PD	protein	P11413	UNIPROT	up-regulates activity	phosphorylation	Ser40	IFIIMGAsGDLAKKK	9606	BTO:0000007								33398181	t		miannu	Mass spectrometry identified four serine residues of G6PD phosphorylated by NIK (Extended Data Fig. 8f). All of these serines, except S278, are conserved between human and mouse G6PD proteins. In transfected cells, NIK stimulated G6PD activity, which was not affected by S8A or S486A mutation but abolished by S40A mutation (Extended Data Fig. 8g).	SIGNOR-277545	0.2
CSNK2A1	protein	P68400	UNIPROT	EIF5	protein	P55010	UNIPROT	up-regulates	phosphorylation	Ser390	KEAEEESsGGEEEDE	9606									16227438	t		gcesareni	We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2.	SIGNOR-141159	0.402
MSL2	protein	Q9HCI7	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	ubiquitination			9606	BTO:0002552								19033443	t		miannu	Here we describe MSL2, a novel E3 ligase for p53 that promotes ubiquitin-dependent cytoplasmic p53 localization. Unlike Mdm2 or most other p53 E3 ligases, MSL2-mediated p53 ubiquitination does not affect the stability of p53. Moreover, the MSL2-mediated effect on p53 is Mdm2-independent. Thus, our study identifies an important ubiquitin-ligase for modulating p53 subcellular localization. MSL2 ubiquitination of p53 is required for p53 cytoplasmic localization.	SIGNOR-271774	0.378
KAT2A	protein	Q92830	UNIPROT	PLCG1	protein	P19174	UNIPROT	down-regulates activity	acetylation												24870244	t		lperfetto	The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1alpha.	SIGNOR-275498	0.2
SRC	protein	P12931	UNIPROT	ARHGDIB	protein	P52566	UNIPROT	unknown	phosphorylation	Tyr24	ELDSKLNyKPPPQKS	9606									19321744	t		llicata	Studies confirmed that activated src kinase binds and phosphorylates rhogdi2 in vitro and vivo. Mutagenesis revealed that tyr-153 and, to a lesser degree, tyr-24 were the primary src phosphorylation sites. Phosphorylation decreased the amount of rac1 in rhogdi2 complexes and increased rhogdi2 association with cell membranes.	SIGNOR-184912	0.405
PKLR	protein	P30613	UNIPROT	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	down-regulates quantity	chemical modification			9606									15996096	t		miannu	Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A).	SIGNOR-266535	0.8
ATM	protein	Q13315	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates activity	phosphorylation	Ser395	SQESEDYsQPSTSSS	9606	BTO:0000971								17936559	t		gcesareni	Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation.	SIGNOR-158324	0.747
GAR1	protein	Q9NY12	UNIPROT	TERT	protein	O14746	UNIPROT	up-regulates activity	binding												18680434	t		lperfetto	A complex of four proteins (GAR1, NHP2, NOP10, and the putative pseudouridine synthase dyskerin) associates with snoRNAs to form small nucleolar ribonucleoprotein particles (snoRNPs), and the binding of this complex to the H/ACA domain of TERC may have a role in the biogenesis of the telomerase RNP	SIGNOR-263333	0.429
vincaleukoblastine sulfate	chemical	CHEBI:9984	ChEBI	TUBB	protein	P07437	UNIPROT	down-regulates activity	chemical inhibition			9606									15579115	t		miannu	Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. 	SIGNOR-259256	0.8
PRKACG	protein	P22612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606									10949026	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.	SIGNOR-81161	0.409
tRNA(Ser)	smallmolecule	CHEBI:29179	ChEBI	Ser-tRNA(Ser)	smallmolecule	CHEBI:29162	ChEBI	up-regulates quantity	precursor of			9606									24095058	t		miannu	As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis	SIGNOR-270499	0.8
DDIT4	protein	Q9NX09	UNIPROT	TSC2	protein	P49815	UNIPROT	up-regulates activity	binding			9606									21460850	t		miannu	 Redd1 is a negative regulator of mTOR, mediating dissociation of 14-3-3 from tuberous sclerosis complex (TSC)2, which allows formation of a TSC-TSC2 complex. 	SIGNOR-277469	0.626
GSTA1	protein	P08263	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0000018								29928434	f		irozzo	Accordingly, downregulation of GSTA1 suppressed tumor growth. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line.	SIGNOR-256296	0.7
FLT4	protein	P35916	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	down-regulates	phosphorylation	Tyr707	KGAMAATySALNRNQ	9606									12601080	t		llicata	Upon truncation of this c-terminal stretch, or mutation of the tyr-707 residue alone, autoinhibition is attenuated, and the kinase becomes constitutively active. Based on these findings we propose that phosphorylation of the tyr-707 represents a novel alternative regulatory mechanism for p90rsk activation.	SIGNOR-98708	0.2
BIX-02188	chemical	CID:66524294	PUBCHEM	MAP2K5	protein	Q13163	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190365	0.8
MTOR	protein	P42345	UNIPROT	UVRAG	protein	Q9P2Y5	UNIPROT	up-regulates activity	phosphorylation	Ser571	KGEDLVGsLNGGHAN	9606	BTO:0001938								26139536	t		miannu	MTOR phosphorylates UVRAG at serine 550 and serine 571	SIGNOR-276919	0.419
HES1	protein	Q14469	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19129776	t		gcesareni	HES1 binding to the promoter of the NC3C1 gene inhibits its expression and results in insufficient production of the encoded glucocorticoid receptor- rendering these cells resistant to treatment with dexamethasone	SIGNOR-251674	0.2
CDK1	protein	P06493	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates	phosphorylation	Ser1026	PQQGFFSsPSTSRTP	9606	BTO:0000017								8360196	t		gcesareni	Using a synthetic peptide corresponding to the sequence surrounding ser-1002, p34cdc2 was identified as a kinase capable of phosphorylating this serine residue. phosphorylation of the egf receptor by p34cdc2 was associated with a decrease in its tyrosine protein kinase activity.	SIGNOR-38313	0.435
CSNK1E	protein	P49674	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates activity	phosphorylation			6239									10517632	t		gcesareni	In addition, CKI bound to and increased the phosphorylation of dishevelled, a known component of the Wnt pathway	SIGNOR-244097	0.68
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates	phosphorylation	Ser511	RREERSLsAPGNLLT	9606									22778263	t		lperfetto	Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity	SIGNOR-198154	0.2
MARK1	protein	Q9P0L2	UNIPROT	MAP2	protein	P11137	UNIPROT	down-regulates activity	phosphorylation	Ser1710	HVTSKCGsLKNIRHR	-1									8631898	t		miannu	Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 	SIGNOR-250165	0.428
C1R	protein	P00736	UNIPROT	Complement C1 complex	complex	SIGNOR-C309	SIGNOR	form complex	binding			-1									29449492	t		lperfetto	The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases	SIGNOR-263395	0.692
LCK	protein	P06239	UNIPROT	DEF6	protein	Q9H4E7	UNIPROT	up-regulates activity	phosphorylation	Tyr133	NFLSEDKyPLIMVPD	9606									18976935	t		lperfetto	Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway|These results indicate that SLAT undergoes Lck-dependent phosphorylation on Tyr-144 and Tyr-133 upon TCR and CD28 stimulation.	SIGNOR-253367	0.515
DDX5	protein	P17844	UNIPROT	Microprocessor complex	complex	SIGNOR-C356	SIGNOR	up-regulates activity	binding												34936874	t		lperfetto	Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing. 	SIGNOR-275659	0.713
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO1	protein	Q12778	UNIPROT	down-regulates	relocalization			10090	BTO:0002572								18423396	t		lperfetto	Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation	SIGNOR-252351	0.2
iodide	smallmolecule	CHEBI:16382	ChEBI	3,5-diiodo-L-tyrosine	smallmolecule	CHEBI:15768	ChEBI	up-regulates quantity	precursor of			9606									16098474	t		scontino	TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. 	SIGNOR-266958	0.8
PHF12	protein	Q96QT6	UNIPROT	TLE5	protein	Q08117	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								11390640	t		miannu	We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE.	SIGNOR-266990	0.2
GHSR	protein	Q92847	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257322	0.252
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	CASP9	protein	P55211	UNIPROT	up-regulates activity	cleavage	Asp330	LRTFDQLdAISSLPT	9606	BTO:0001412								15657060	t		lperfetto	In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits.	SIGNOR-256440	0.622
GOT2	protein	P00505	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	up-regulates quantity	chemical modification			9606									31422819	t		miannu	This is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1).	SIGNOR-267514	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser221	DHEKKAYsFCGTVEY	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252741	0.754
ROCK1	protein	Q13464	UNIPROT	ARHGAP24	protein	Q8N264	UNIPROT	up-regulates activity	phosphorylation	Thr575	SNSCRSStTTCPEQD	9606									16862148	t		lperfetto	ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2).	SIGNOR-249299	0.444
TNF	protein	P01375	UNIPROT	DIO	proteinfamily	SIGNOR-PF83	SIGNOR	down-regulates quantity by repression	transcriptional regulation			10116									9397972	f	inferred from family member	scontino	From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y.	SIGNOR-270239	0.261
CTDSP1	protein	Q9GZU7	UNIPROT	NLI/Lmx1.1/Isl1 	complex	SIGNOR-C103	SIGNOR	form complex	binding			9606	BTO:0000007								9452425	t		lperfetto	Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas.	SIGNOR-236839	0.2
APP	protein	P05067	UNIPROT	Amyloid_fibril_formation	phenotype	SIGNOR-PH59	SIGNOR	up-regulates				9606									11578751	f		lperfetto	Neurodegeneration in Alzheimer's disease is a pathologic condition of cells rather than an accelerated way of aging. The senile plaques are generated by a deposition in the human brain of fibrils of the β-amyloid peptide (Aβ), a fragment derived from the proteolytic processing of the amyloid precursor protein (APP). Tau protein is the major component of paired helical filaments (PHFs), which form a compact filamentous network described as neurofibrillary tangles (NFTs).	SIGNOR-251638	0.7
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BC13	protein	Q99880	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRSRkESYSVYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271995	0.2
RBKS	protein	Q9H477	UNIPROT	D-ribofuranose	smallmolecule	CHEBI:47013	ChEBI	down-regulates quantity	chemical modification			9606									25749547	t		miannu	Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds.	SIGNOR-267072	0.8
proline	smallmolecule	CHEBI:26271	ChEBI	Pro-tRNA(Pro)	smallmolecule	CHEBI:29154	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270434	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	LRP6	protein	O75581	UNIPROT	up-regulates activity	phosphorylation	Thr1548	YAPSRRMtSVATAKG	-1									21406690	t		miannu	PKA phosphorylated LRP6, which enhanced the binding of Gα(s) to LRP6, its localization to the plasma membrane, and the production of cAMP in response to PTH. Only alteration of Thr1548 abolished the phosphorylation of LRP6C by PKA (Fig. 6B), and mass spectrometry analysis confirmed that Thr1548 was the PKA phosphorylation site in LRP6C (fig. S1).	SIGNOR-275416	0.2
HIRA	protein	P54198	UNIPROT	HIRA complex 1	complex	SIGNOR-C461	SIGNOR	form complex	binding			9606									30285846	t		miannu	H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex.	SIGNOR-269434	0.686
HDAC1	protein	Q13547	UNIPROT	SMAD7/HDAC1/E2F-1	complex	SIGNOR-C12	SIGNOR	form complex	binding			9606									23213415	t		gcesareni	Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes	SIGNOR-199958	0.641
MITF	protein	O75030	UNIPROT	TRPM1	protein	Q7Z4N2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									14744763	f		miannu	 Mice homozygously mutated in MITF showed a dramatic decrease in TRPM1 expression. Finally, the slope of TRPM1 induction by MITF was particularly steep compared with other MITF target genes, suggesting it is a sensitive indicator of MITF expression and correspondingly of melanocytic differentiation. 	SIGNOR-254588	0.437
CSNK2A2	protein	P19784	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates activity	phosphorylation	Thr59	EGYDELQtDGNRSSH	9606	BTO:0000567								11583622	t		llicata	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250979	0.289
PLK1	protein	P53350	UNIPROT	YY1	protein	P25490	UNIPROT	up-regulates	phosphorylation	Thr39	PVETIETtVVGEEEE	9606									23226345	t		lperfetto	More recently, we identified and mapped multiple phosphorylation sites in yy1, including, threonine 39, serine 118, serine 247, threonine 348 and threonine 378. The first kinase proven to phosphorylate yy1 in vivo was plk1, which phosphorylates threonine 39 during g2/m stage of the cell cycle [25]. Ck2_ is another kinase identified as constitutively phosphorylating yy1 at serine 118. This modification protects yy1 cleavage by caspase 7 during apoptosis	SIGNOR-200087	0.402
PAK2	protein	Q13177	UNIPROT	RPS6	protein	P62753	UNIPROT	unknown	phosphorylation	Ser242	SSLRASTsKSESSQK	-1									1985906	t		miannu	The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide.	SIGNOR-250234	0.313
PPP2CA	protein	P67775	UNIPROT	EIF4E	protein	P06730	UNIPROT	down-regulates	dephosphorylation	Ser209	DTATKSGsTTKNRFV	9606									20927323	t		tpavlidou	A recent study using genetically engineered mouse models has clearly shown that mnk-mediated eif4e phosphorylation is absolutely required for eif4e's oncogenic action. Taken together, we conclude that pp2a negatively regulates eif4e phosphorylation and eif4f complex assembly through dephosphorylation of mnk and eif4e, thus suggesting a novel mechanism by which pp2a exerts its tumor-suppressive function.	SIGNOR-168306	0.353
PTAFR	protein	P25105	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256932	0.2
RAB22A	protein	Q9UL26	UNIPROT	Early Endosome	complex	SIGNOR-C246	SIGNOR	form complex	binding			9606									19924646	t		lperfetto	The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 	SIGNOR-260621	0.464
PTPN11	protein	Q06124	UNIPROT	FGFR2	protein	P21802	UNIPROT	down-regulates activity	dephosphorylation			9606									23420874	t		miannu	In forming this heterotetrameric complex Grb2 inhibits both the dephosphorylation of FGFR2 by Shp2 and the phosphorylation of Shp2 by FGFR2 (XREF_FIG, respectively).|Knockdown of Grb2 elevates Shp2 phosphorylation (XREF_FIG), strongly suggesting that the inability of Shp2 to interact directly with the receptor in the presence of Grb2 prevents FGFR2 kinase activity toward Shp2.	SIGNOR-277030	0.607
CSNK2A1	protein	P68400	UNIPROT	CCAR2	protein	Q8N163	UNIPROT	up-regulates activity	phosphorylation	Thr454	AAEAAPPtQEAQGET	9606									24962073	t		lperfetto	CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. |In our results, CK2alpha affected the|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1	SIGNOR-267666	0.2
WNT5B	protein	Q9H1J7	UNIPROT	FZD6	protein	O60353	UNIPROT	up-regulates	binding			9606	BTO:0000551;BTO:0000848								16273260	t		gcesareni	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-141443	0.655
THOC6	protein	Q86W42	UNIPROT	TREX complex	complex	SIGNOR-C444	SIGNOR	form complex	binding			9606									33191911	t		miannu	The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56.	SIGNOR-268510	0.909
RPS6KA5	protein	O75582	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates activity	phosphorylation	Ser63	GILARRPsYRKILKD	9606									12414794	t		lperfetto	We find that activation of the c-jun promoter through the atf1 site requires phosphorylation of atf1 at serine 63. atf1 can be phosphorylated by mitogen- and stress-activated protein kinase 1 (msk1), which is activated by egf and erk1/2.	SIGNOR-95318	0.678
SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	OTX2	protein	P32243	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269240	0.476
NCK1	protein	P16333	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates activity	binding			9606									11494134	t		lperfetto	We also show that overexpression of nck could repress the phosphorylation of cbl by abl in vivo. Studies with nck mutants suggested that the nck sh2 domain is responsible for inhibiting the activity of abl toward both cbl and nck itself, most likely by competing with the abl sh2 for tyrosine-phosphorylated binding sites	SIGNOR-109672	0.409
GSK3A	protein	P49840	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates	phosphorylation	Ser243	PGETPPLsPIDMESQ	9606									1846781	t		lperfetto	Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity.	SIGNOR-21776	0.338
HNRNPA3	protein	P51991	UNIPROT	C9orf72	protein	Q96LT7	UNIPROT	down-regulates quantity				9606		BTO:0000142							27461252	f		lperfetto	Thus, reduced hnRNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci.	SIGNOR-262117	0.417
(1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid	chemical	CHEBI:94640	ChEBI	GRM2	protein	Q14416	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-193728	0.8
CDK2	protein	P24941	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates	phosphorylation	Thr235	SSSSPPGtPSPADAK	9606			SIGNOR-C83						22369944	t		fspada	Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity.	SIGNOR-196372	0.406
ATF4	protein	P18848	UNIPROT	DARS2	protein	Q6PI48	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269418	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9606	BTO:0001950								21561061	t		Luana	3b Induces Phosphorylation of c-Jun (Ser-63) throughActivation of the JNK Pathway.| An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP 	SIGNOR-260758	0.2
PRKCB	protein	P05771	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates activity	phosphorylation	Ser346	EWEAQRDsHLGPHRS	9606									14576165	t		lperfetto	A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis.	SIGNOR-249237	0.2
MTSS1	protein	O43312	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates	binding			9606									17845852	t		gcesareni	Mim is a shh-responsive gene that can potentiate gli transcriptional activity.MIM Appears to regulate target gene expression through its association with the gli complex	SIGNOR-157650	0.525
MAML1	protein	Q92585	UNIPROT	NOTCH3	protein	Q9UM47	UNIPROT	up-regulates	binding			9606									11101851	t		gcesareni	Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1.	SIGNOR-84838	0.781
SIAH2	protein	O43255	UNIPROT	AKAP1	protein	Q92667	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								18323779	t		miannu	Seven In-Absentia Homolog 2 (Siah2), an E3-ubiquitin ligase whose expression is induced in hypoxic conditions, formed a complex and degraded AKAP121. 	SIGNOR-272641	0.522
AMG 900	chemical	CID:24856041	PUBCHEM	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189492	0.8
PINK1	protein	Q9BXM7	UNIPROT	HTRA2	protein	O43464	UNIPROT	up-regulates	phosphorylation	Ser142	VPSPPPAsPRSQYNF	9606									17906618	t		gcesareni	Htra2 is phosphorylated on activation of the p38 pathway, occurring in a pink1-dependent mannerwe suggest that pink1-dependent phosphorylation of htra2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress.	SIGNOR-158052	0.627
PRKCA	protein	P17252	UNIPROT	UGT1A3	protein	P35503	UNIPROT	up-regulates activity	phosphorylation	Ser43	IDGSHWLsMREVLRE	-1									26094731	t	done	miannu	Curcumin and calphostin C suppressed the activity and phosphorylation of recombinant UGT1A3 expressed in Sf9 cells. These results indicate that UGT1A3 undergoes phosphorylation, which is required for its catalytic activity. Calphostin C is a highly specific protein kinase C (PKC) inhibitor, so three predicted PKC phosphorylation sites in UGT1A3 were examined. In conclusion, phosphorylation plays an important role in UGT1A3 activity, and the serine at site 43 in UGT1A3 is most likely a phosphorylation site.	SIGNOR-273823	0.2
PRKCA	protein	P17252	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates activity	phosphorylation	Ser821	ARDIKNDsNYVVKGN	9823									7539802	t		lperfetto	We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling.	SIGNOR-248897	0.51
VKORC1	protein	Q9BQB6	UNIPROT	vitamin K	smallmolecule	CHEBI:28384	ChEBI	down-regulates quantity	chemical modification			9606									31226734	t		lperfetto	This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR)	SIGNOR-265904	0.8
PDHX	protein	O00330	UNIPROT	INS	protein	P01308	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001731								12783165	f		miannu	In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%. 	SIGNOR-254902	0.293
FCN3	protein	O75636	UNIPROT	MASP2	protein	O00187	UNIPROT	up-regulates activity	binding												17204478	t		lperfetto	 In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2)	SIGNOR-263412	0.534
ULK1	protein	O75385	UNIPROT	ENO1	protein	P06733	UNIPROT	down-regulates activity	phosphorylation	Ser282	QLADLYKsFIKDYPV	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274029	0.2
CHUK	protein	O15111	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser36	RHDSGLDsMKDEEYE	9606	BTO:0000567		SIGNOR-C14						9346241	t		lperfetto	We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation	SIGNOR-52879	0.893
N-[3-[[5-Cyclopropyl-2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	chemical	CID:44465558	PUBCHEM	TBK1	protein	Q9UHD2	UNIPROT	down-regulates activity	chemical activation			10090	BTO:0001413								23099093	t		Federica	We herein describe the development of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines as potent inhibitors of TBK1/IKKɛ, with improved kinase selectivity and drug-like properties.	SIGNOR-261109	0.8
MEIS1	protein	O00470	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates				9606	BTO:0001271								19109563	f		irozzo	To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells.	SIGNOR-256648	0.7
GGCX	protein	P38435	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	carboxylation			9606									31226734	t		lperfetto	Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.	SIGNOR-265920	0.67
NOTCH2	protein	Q04721	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	down-regulates activity	binding			9606	BTO:0003960								31699119	t		miannu	 NOTCH2 attenuated the TRAF6-AKT signaling axis via an interaction between the NOTCH2 intracellular domain (N2ICD) and TRAF6, which inhibited epithelial-mesenchymal transition (EMT) and eventually suppressed NPC metastasis.	SIGNOR-265562	0.316
EDNRA	protein	P25101	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256923	0.425
Calprotectin complex	complex	SIGNOR-C293	SIGNOR	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	up-regulates quantity by stabilization	binding			9606	BTO:0000876								16690079	t		miannu	Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner	SIGNOR-262827	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PHF20	protein	Q9BVI0	UNIPROT	down-regulates	phosphorylation	Ser291	ELRRRKIsKGCEVPL	9606									22334668	t		llicata	Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function.	SIGNOR-196112	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	MTHFR	protein	P42898	UNIPROT	down-regulates activity	phosphorylation	Thr34	KDSSRCStPGLDPER	9606	BTO:0000007;BTO:0000567								24769206	t		miannu	We have demonstrated that MTHFR is phosphorylated on T34by CDK1/Cyclin B1 in vivo and this phosphorylation peaks duringmitosis and decreases its enzymatic activity. 	SIGNOR-263888	0.339
MPO-ANCA	complex	SIGNOR-C474	SIGNOR	thiocyanate	smallmolecule	CHEBI:18022	ChEBI	up-regulates quantity by expression	oxidation			9606		BTO:0000133							9922160	t		lperfetto	Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. The enzyme uses hydrogen peroxide to oxidize chloride (Cl-), bromide (Br-), iodide (I-), and the pseudohalide thiocyanate (SCN-) to their respective hypohalous acids.| Our results show that thiocyanate is an important substrate of myeloperoxidase in most environments and that hypothiocyanate is likely to contribute to leukocyte antimicrobial activity.	SIGNOR-270591	0.8
A-966492	chemical	CID:16666333	PUBCHEM	PARP1	protein	P09874	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205698	0.8
EPAS1	protein	Q99814	UNIPROT	HBA1	protein	P69905	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20534544	f	Regulation	miannu	We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2alpha, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. 	SIGNOR-251792	0.25
MADD	protein	Q8WXG6	UNIPROT	RAB3A	protein	P20336	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			10116		BTO:0000142							11809763	t		miannu	Rab3A, a member of the Rab3 small G protein family, regulates Ca(2+)-dependent exocytosis of neurotransmitter. The cyclical activation and inactivation of Rab3A are essential for the Rab3A action in exocytosis. GDP-Rab3A is activated to GTP-Rab3A by Rab3 GDP/GTP exchange protein (Rab3 GEP), and GTP-Rab3A is inactivated to GDP-Rab3A by Rab3 GTPase-activating protein (Rab3 GAP). 	SIGNOR-265579	0.407
FBXO11	protein	Q86XK2	UNIPROT	DTL	protein	Q9NZJ0	UNIPROT	down-regulates	binding			9606									23478441	t		miannu	We determined that the f-box protein fbxo11 interacts with cdt2,a dcaf protein that controls cell-cycle progression, and recruits cdt2 to the scf(fbxo11)complex to promote its proteasomal degradation.	SIGNOR-192325	0.561
GSK3A	protein	P49840	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser279	CGIQDTNsKKQSDTH	9606	BTO:0002181								33879767	t		miannu	We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation.	SIGNOR-277552	0.2
PRKD1	protein	Q15139	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates	phosphorylation	Ser155	FPLRKTVsEPNLKLR	9606	BTO:0000782								15623513	t		lperfetto	Protein kinase d1 (pkd1) was activated after tcr engagement, interacted with hdac7, and phosphorylated three serines (ser155, ser318, and ser448) at its n terminus, leading to its export from the nucleus.	SIGNOR-132894	0.492
EFNB2	protein	P52799	UNIPROT	EPHB3	protein	P54753	UNIPROT	up-regulates	binding			9606									9330863	t		gcesareni	Lerk-5 is a ligand for both elk and hek and induces receptor phosphorylation	SIGNOR-52583	0.879
GH1	protein	P01241	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001939								15665309	t		Luana	Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells	SIGNOR-261629	0.2
SP1	protein	P08047	UNIPROT	SLC5A8	protein	Q8N695	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20082847	t	 	 	Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription.	SIGNOR-254059	0.2
CPT1B	protein	Q92523	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	chemical modification			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267133	0.8
ATF2	protein	P15336	UNIPROT	FGF21	protein	Q9NSA1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0005787								25055037	f		miannu	 The increased production of reactive oxygen species, subsequent induction of p38 MAPK (mitogen-activated protein kinase) and activation of an ATF2 (activating transcription factor 2)-binding site at the proximal promoter region of the FGF21 gene was found to be a major mechanism linking mitochondrial dysfunction with enhanced FGF21 gene transcription in myogenic cells. 	SIGNOR-253743	0.354
PLG	protein	P00747	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates activity	cleavage	Lys76	YRLVSINkSSPLQKQ	-1									10978167	t		lperfetto	Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site.	SIGNOR-263574	0.62
PPP3CC	protein	P48454	UNIPROT	FLNA	protein	P21333	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser2152	TRRRRAPsVANVGSH	9606									16442073	t			Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation.	SIGNOR-248507	0.2
PPP2R5B	protein	Q15173	UNIPROT	CASP3	protein	P42574	UNIPROT	up-regulates	dephosphorylation	Ser150	FRGDRCRsLTGKPKL	9606	BTO:0000130								15569672	t		gcesareni	Dephosphorylation of caspase-3 at ser150 site by pp2a increased caspase-3 activity,which was essential to trigger apoptosis in neutrophils.	SIGNOR-131435	0.2
MTA1	protein	Q13330	UNIPROT	SNAI1	protein	O95863	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000812								18719363	f		miannu	 MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG.	SIGNOR-254596	0.477
GHRL	protein	Q9UBU3	UNIPROT	GHSR	protein	Q92847	UNIPROT	up-regulates	binding			9606									15070777	t		fspada	In contrast to wild-type mice, acute treatment of ghsr- mice with ghrelin stimulated neither gh release nor food intake, showing that the ghsr is a biologically relevant ghrelin receptor.	SIGNOR-123948	0.724
PRKCA	protein	P17252	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates activity	phosphorylation	Thr495	TGITRKKtFKEVANA	9606	BTO:0001853								24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251620	0.306
IRS1	protein	P35568	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates activity	binding			9606									20966354	t		lperfetto	Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin.	SIGNOR-168985	0.711
NEXMIF	protein	Q5QGS0	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0000938								27822498	f		miannu	Xpn regulates N-cadherin and β1-integrin expression at the transcriptional level in PC12 cells	SIGNOR-269661	0.2
PRKACA	protein	P17612	UNIPROT	KCNH2	protein	Q12809	UNIPROT	up-regulates	phosphorylation	Thr895	KLSFRRRtDKDTEQP	9606									10488078	t		lperfetto	Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a)	SIGNOR-70730	0.311
F2	protein	P00734	UNIPROT	F5	protein	P12259	UNIPROT	up-regulates activity	cleavage	Arg1046	HHAPLSPrTFHPLRS	-1									10026263	t		lperfetto	Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 	SIGNOR-263631	0.877
2-[[5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethanamine	chemical	CHEBI:93274	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9537821	t		miannu	Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 	SIGNOR-258880	0.8
CHUK	protein	O15111	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	up-regulates activity	phosphorylation	Ser422	RFHSLPFsLTKMPNT	9606	BTO:0000938								24614225	t		lperfetto	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204692	0.524
LNX2	protein	Q8N448	UNIPROT	NUMB	protein	P49757	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									26451611	t		miannu	Polyubiquitination of Human Numb by LNX2. The Zn-RING-Zn domain of LNX2 is a dimer and assumes a rigid elongated structure that undergoes autoubiquitination and undergoes N-terminal polyubiquitination. LNX2 can bind numb and induce its ubiquitination and subsequent proteasomal degradation	SIGNOR-272423	0.625
BRD4	protein	O60885	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1616	TPQSPSYsPTSPSYS	9606	BTO:0000150;BTO:0001271;BTO:0000785								22509028	t		llicata	We report that brd4 is an atypical kinase that binds to the carboxyl-terminal domain (ctd) of rna polymerase ii and directly phosphorylates its serine 2 (ser2) sites both in vitro and in vivo under conditions where other ctd kinases are inactive. our findings may provide a mechanistic basis for several functional studies that showed that loss of brd4 causes transcription termination and embryonic lethality	SIGNOR-197012	0.461
WDR24	protein	Q96S15	UNIPROT	GATOR2	complex	SIGNOR-C193	SIGNOR	form complex	binding			9606									23723239	t		miannu	Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5	SIGNOR-255302	0.907
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606									19819937	f			In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. 	SIGNOR-254355	0.7
dothiepin	chemical	CHEBI:36798	ChEBI	CHRM3	protein	P20309	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8100134	t		miannu	Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 	SIGNOR-258696	0.8
KMT2A	protein	Q03164	UNIPROT	SPI1	protein	P17947	UNIPROT	up-regulates quantity by expression	methylation			10090	BTO:0002884								22012064	t		irozzo	Furthermore, we show that both MLL and AML1/CBFβ are required for maintaining the H3K4-me3 mark at the PU.1 upstream regulatory element (URE) and promoter region, and for full PU.1 gene expression.	SIGNOR-255874	0.417
GSK3B	protein	P49841	UNIPROT	DCX	protein	O43602	UNIPROT	up-regulates activity	phosphorylation	Ser332	STPKSKQsPISTPTS	9606									21159948	t		lperfetto	Gsk3b phosphorylates dcx at the distinct site of ser327 and thereby contributes to dcx function in the restriction of axon branching. Together, our data define a jip3-regulated gsk3_/dcx signaling pathway that restricts axon branching in the mammalian brain.Gsk3_ induces the phosphorylation of dcx at ser327, which contributes to dcx function in the inhibition of axon branching and self-contact.	SIGNOR-170755	0.275
ULK2	protein	Q8IYT8	UNIPROT	PFKM	protein	P08237	UNIPROT	down-regulates activity	phosphorylation	Ser762	YEIDLDTsDHAHLEH	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274044	0.2
RNA helicases DDX5/DDX17	complex	SIGNOR-C34	SIGNOR	MYOD1	protein	P15172	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001103							17011493	t		miannu	We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod.	SIGNOR-149967	0.429
PHA-665752	chemical	CHEBI:90197	ChEBI	MET	protein	P08581	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258265	0.8
CSMD1	protein	Q96PZ7	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	binding			9606									22538441	t		miannu	CSMD1 co-immunoprecipitated with SMAD3, confirming our results that CSMD1 interacts with Smad3 in A375 cells. CSMD1 interacts with Smad3 and induces phosphorylation (p-Smad3). Phosphorylated Smad3 promotes Smad2 phosphorylation and Smad2/3/4 complex formation.	SIGNOR-265151	0.2
WNT3A	protein	P56704	UNIPROT	FZD1	protein	Q9UP38	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								21078818	t		gcesareni	Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have a complex and partially overlapping pattern of expression in different regions of the embryo, and many of them (fz1, 3, 7, 8 and 9) have specific expression in the epithelial somites as well as in the newly formed myotomes.	SIGNOR-169651	0.789
ATM	protein	Q13315	UNIPROT	BUB3	protein	O43684	UNIPROT	up-regulates activity	phosphorylation	Ser135	PCNAGTFsQPEKVYT	9606	BTO:0000567								35085551	t		miannu	Taken together, we highlight the functional significance of the crosstalk between the kinetochore-oriented signal and double-strand break repair pathways via ATM phosphorylation of Bub3 on Ser135.	SIGNOR-277582	0.319
PCDHA9	protein	Q9Y5H5	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606									16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-265662	0.2
Immune complexes	stimulus	SIGNOR-ST15	SIGNOR	FCGR1A	protein	P12314	UNIPROT	up-regulates activity				9606	BTO:0000801								18064051	f		lperfetto	Immune complexes bind to activating Fc receptors (FcR) and inhibitory FcRs that are expressed by innate immune effector cells such as basophils, mast cells, neutrophils, monocytes and macrophages, in which they trigger the indicated effector responses.	SIGNOR-249521	0.7
NRBF2	protein	Q96F24	UNIPROT	PIK3R4	protein	Q99570	UNIPROT	down-regulates activity	binding			9606	BTO:0001938				phosphorylation:Ser113;Ser120	AEDAEGQsPLSQKYS;SPLSQKYsPSTEKCL			28059666	t		miannu	NRBF2 S113 and S120 phosphorylation negatively regulates autophagy. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity. 	SIGNOR-265878	0.655
NDUFA8	protein	P51970	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added	SIGNOR-262159	0.816
NF1	protein	P21359	UNIPROT	ADCY5	protein	O95622	UNIPROT	up-regulates				9606	BTO:0000938								24431436	f		miannu	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-204140	0.273
MAPK1	protein	P28482	UNIPROT	FGFR1	protein	P11362	UNIPROT	down-regulates	phosphorylation	Ser777	SMPLDQYsPSFPDTR	9606									23405013	t		lperfetto	Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling	SIGNOR-200880	0.315
CDC73	protein	Q6P1J9	UNIPROT	PAF1C	complex	SIGNOR-C471	SIGNOR	form complex	binding			9606	BTO:0000567								20178742	t		miannu	Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A). 	SIGNOR-269836	0.931
NPFFR2	protein	Q9Y5X5	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256852	0.252
MAML3	protein	Q96JK9	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	binding			9606									12370315	t		gcesareni	We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors.	SIGNOR-254323	0.879
PTGFR	protein	P43088	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257193	0.409
SGK1	protein	O00141	UNIPROT	NEDD4L	protein	Q96PU5	UNIPROT	up-regulates	phosphorylation	Ser342	SSRLRSCsVTDAVAE	9606									11742982	t		lperfetto	Here we show by expression studies in xenopus laevis oocytes that the aldosterone-induced sgk1 kinase interacts with the ubiquitin protein ligase nedd4-2 in a py motif-dependent manner and phosphorylates nedd4-2 on ser444 and, to a lesser extent, ser338. Such phosphorylation reduces the interaction between nedd4-2 and enac, leading to elevated enac cell surface expression.	SIGNOR-113052	0.78
PSMD3	protein	O43242	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263353	0.891
VAV2	protein	P52735	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260582	0.741
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser174	LSPASSGsSASFISD	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248512	0.386
PRKCA	protein	P17252	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates	phosphorylation	Ser16	EKEAARRsRRIDRHL	9606		BTO:0000671							9166747	t		gcesareni	Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling.	SIGNOR-48677	0.418
PRKCA	protein	P17252	UNIPROT	LMNA	protein	P02545	UNIPROT	up-regulates activity	phosphorylation	Ser404	RSRGRASsHSSQTQG	-1									7925482	t		lperfetto	Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence.	SIGNOR-248904	0.369
OXSR1	protein	O95747	UNIPROT	SLC12A2	protein	P55011	UNIPROT	up-regulates	phosphorylation	Thr212	TNTYYLRtFGHNTMD	9606									12145304	t		gcesareni	Oxidative stress-responsive kinase-1 (osr1) is a known upstream regulator of n(k)ccs. these results suggest that, globally, osr1 is involved in the regulation of bp and renal tubular na(+) reabsorption mainly via the activation of nkcc1 and nkcc2.	SIGNOR-90931	0.54
RNF43	protein	Q68DV7	UNIPROT	FZD2	protein	Q14332	UNIPROT	up-regulates	relocalization			9606									23151663	t		gcesareni	Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation61 (see above), and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane	SIGNOR-199585	0.313
PPARGC1A	protein	Q9UBK2	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by repression	transcriptional regulation			10090		BTO:0001103							20404331	f		lperfetto	Capacity of PGC-1alpha and PGC-1beta to inhibit FoxO3 and NFkappaB actions and proteolysis helps explain how exercise prevents muscle atrophy.overexpression of PGC-1_ inhibits muscle wasting induced by denervation, starvation, and even caFoxO3 expression	SIGNOR-252969	0.568
YY2	protein	O15391	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								15087442	t		Luana	YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter.	SIGNOR-266212	0.402
GOLPH3	protein	Q9H4A6	UNIPROT	MTOR	protein	P42345	UNIPROT	up-regulates activity				9606	BTO:0000018;BTO:0005011								19553991	f			Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo.	SIGNOR-253554	0.338
INPP5D	protein	Q92835	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								24817116	t		lperfetto	Of note, SHIP1 was associated with TRAF6 in co-transfected HEK293T cells (Fig. 6A). Moreover, SHIP1 overexpression suppressed TRAF6 autoubiquitination in a dose-dependent manner	SIGNOR-261429	0.337
BRCA1	protein	P38398	UNIPROT	TFF1	protein	P04155	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000356;BTO:0001033								11244506	f	 	 	In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D. 	SIGNOR-253937	0.304
ADK	protein	P55263	UNIPROT	ADP(3-)	smallmolecule	CHEBI:456216	ChEBI	up-regulates quantity	chemical modification			9606									33961946	t		miannu	Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5′-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). 	SIGNOR-267841	0.8
CLK4	protein	Q9HAZ1	UNIPROT	MITF	protein	O75030	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr360	ILKASVDyIRKLQRE	9606	BTO:0002427								35092699	t	done	miannu	Mechanistically, wild type CLK4 (WT-CLK4) but not kinase-dead CLK4-K189R mutant phosphorylated MITF at Y360. This modification promoted its interaction with E3 ligase COP1 and its K63-linked ubiquitination at K308/K372, leading to sequestosome 1 recognition and autophagic degradation. 	SIGNOR-274116	0.2
WT1	protein	P19544	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0000738								25601757	f		irozzo	Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation.	SIGNOR-255705	0.7
WNT10B	protein	O00744	UNIPROT	FZD2	protein	Q14332	UNIPROT	up-regulates	binding			9606									12055200	t		fspada	Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 7	SIGNOR-89137	0.626
GSK3B	protein	P49841	UNIPROT	PPP1R2	protein	P41236	UNIPROT	up-regulates activity	phosphorylation	Thr73	MKIDEPStPYHSMMG	9913	BTO:0000142								11320080	t			Protein phosphatase 1 (PP1) is complexed with inhibitor 2 (I-2) in the cytosol. In rabbit muscle extract PP1.I-2 is activated upon preincubation with ATP/Mg. This activation is caused by phosphorylation of I-2 on Thr(72) by glycogen synthase kinase 3 (GSK3).	SIGNOR-251257	0.421
GDNF	protein	P39905	UNIPROT	FST	protein	P19883	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252188	0.27
beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266475	0.8
DIO1	protein	P49895	UNIPROT	iodide	smallmolecule	CHEBI:16382	ChEBI	up-regulates quantity	chemical modification			9606									34674502	t		scontino	Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3.	SIGNOR-266954	0.8
ZNF267	protein	Q14586	UNIPROT	MMP10	protein	P09238	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								16054593	t		Luana	Furthermore, ZNF267 binds to the MMP-10 promoter region as demonstrated by chromatin immunoprecipitation assays. In conclusion, our results suggest that ZNF267 as a negative transcriptional regulator of MMP-10 	SIGNOR-266211	0.401
GPR34	protein	Q9UPC5	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256967	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation	Thr227	PAPPEGAtPTSPVGH	9606	BTO:0000848	BTO:0001253							20959475	t		lperfetto	Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451).	SIGNOR-252954	0.704
T_cell_activation	phenotype	SIGNOR-PH73	SIGNOR	IFNG	protein	P01579	UNIPROT	up-regulates quantity				9606									10653850	f		miannu	IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement.	SIGNOR-260967	0.7
PRKCA	protein	P17252	UNIPROT	CFL1	protein	P23528	UNIPROT	down-regulates	phosphorylation	Ser24	DMKVRKSsTPEEVKK	9606	BTO:0001271								22855535	t		lperfetto	Pkc_ phosphorylates cofilin at ser-23 and/or ser-24 during degranulationthese results indicate that a novel pkc_-mediated phosphorylation event regulates cofilin by inhibiting its ability to depolymerize f-actin and bind to 14-3-3_, thereby promoting f-actin polymerization	SIGNOR-198482	0.2
INSR	protein	P06213	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Tyr27	GFDLDLTyIYPNIIA	-1									23995781	t		miannu	Our results show that the kinase region of IRβ subunit physically binds to PTEN and phosphorylates on Y27 and Y174. In the current study, we discovered that IR also downregulates PTEN through tyrosine phosphorylation and suggest that Y27 and 174 are the two key tyrosines.	SIGNOR-276470	0.455
MAOB	protein	P27338	UNIPROT	3-methoxytyramine	smallmolecule	CHEBI:1582	ChEBI	down-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO.	SIGNOR-264000	0.8
TNFSF4	protein	P23510	UNIPROT	TNFRSF4	protein	P43489	UNIPROT	up-regulates	binding			9606	BTO:0000007								9488716	t		gcesareni	Activation of nf-kappab in ox40-transfected hsb-2 cells was detected by electrophoretic mobility shift assay within 30 min after the binding of the ligand gp34.	SIGNOR-54927	0.919
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PDE4A	protein	P27815	UNIPROT	up-regulates activity	phosphorylation	Ser89	TRMSWPSsFHGTGTG	9534	BTO:0001538								12023945	t	done	miannu	Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5.	SIGNOR-273937	0.2
UPF3B	protein	Q9BZI7	UNIPROT	UPF1	protein	Q92900	UNIPROT	up-regulates activity	binding			-1									18066079	t		miannu	UPF2 and UPF3b increase UPF1 ATPase activity	SIGNOR-265247	0.957
TNF	protein	P01375	UNIPROT	TNFRSF1A	protein	P19438	UNIPROT	up-regulates activity	binding			9606									11502070	t		lperfetto	Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization.	SIGNOR-109716	0.923
PRKG2	protein	Q13237	UNIPROT	PLCB3	protein	Q01970	UNIPROT	down-regulates activity	phosphorylation	Ser26	VETLRRGsKFIKWDE	10116	BTO:0004576								11278298	t		lperfetto	PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG.	SIGNOR-249080	0.508
GAN	protein	Q9H2C0	UNIPROT	CUL3	protein	Q13618	UNIPROT	up-regulates activity	binding			10090	BTO:0000142								18680552	t		miannu	Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. 	SIGNOR-268944	0.658
RNF167	protein	Q9H6Y7	UNIPROT	VAMP3	protein	Q15836	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys66	QFETSAAkLKRKYWW	9606	BTO:0000007								23353890	t		miannu	Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains.	SIGNOR-272093	0.335
EGFR	protein	P00533	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates	phosphorylation	Tyr8	MPPYTVVyFPVRGRC	9606	BTO:0000150								19254954	t		llicata	Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly,	SIGNOR-184387	0.448
CDH1	protein	P12830	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	up-regulates activity	binding												18662541	t		lperfetto	In early mitosis, APC/C is activated through binding to Cdc20, and in late M, Cdc20 is replaced by Cdh1, the second activator of APC/C.	SIGNOR-274058	0.395
MC3R	protein	P41968	UNIPROT	GNAS	protein	P84996	UNIPROT	up-regulates activity				9606									22215617	t		lperfetto	We hypothesize that XLαs may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus.	SIGNOR-253068	0.528
Av/b1 integrin	complex	SIGNOR-C175	SIGNOR	TERT	protein	O14746	UNIPROT	up-regulates quantity by expression				10090									18757303	f		lperfetto	Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1.	SIGNOR-253274	0.325
PRKCA	protein	P17252	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Ser13	ITSAARRsYVSSGEM	-1									2155236	t		lperfetto	Glial fibrillary acidic protein (GFAP), the intermediate filament component of astroglial cells, can serve as an excellent substrate for both cAMP-dependent protein kinase and protein kinase C, in vitro. GFAP phosphorylated by each protein kinase does not polymerize, and the filaments that do polymerize tend to depolymerize after phosphorylation. Dephosphorylation of phospho-GFAP by phosphatase led to a recovery of the polymerization competence of GFAP. Most of the phosphorylation sites for cAMP-dependent protein kinase and protein kinase C on GFAP are the same, Ser-8, Ser-13, and Ser-34. cAMP-dependent protein kinase has one additional phosphorylation site, Thr-7.	SIGNOR-248860	0.374
MAPK1	protein	P28482	UNIPROT	MRTFA	protein	Q969V6	UNIPROT	down-regulates	phosphorylation	Ser454	TGSTPPVsPTPSERS	9606									22139079	t	Translocation from Nuleus to Cytoplasm	gcesareni	Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization.	SIGNOR-195153	0.2
PPM1A	protein	P35813	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	dephosphorylation	Thr423	PEQSKRStMVGTPYW	10116									18586681	t			Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop.	SIGNOR-248491	0.342
DDC	protein	P20711	UNIPROT	dopamine	smallmolecule	CHEBI:18243	ChEBI	up-regulates quantity	chemical modification			7955									23940784	t	brain	lperfetto	AADC is responsible for the decarboxylation step in the catecholamine and dopamine biosynthesis. Dopamine and serotonin can be synthesized by AADC from L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively [7]. A deficiency in AADC will lead to reduced biogenic monoamines, including dopamine, norepinephrine, epinephrine, and serotonin	SIGNOR-263986	0.8
DTX4	protein	Q9Y2E6	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	down-regulates	ubiquitination			9606	BTO:0000938								10531053	t		gcesareni	Nlrp4 negatively regulates type i interferon signaling by targeting the kinase tbk1 for degradation via the ubiquitin ligase dtx4	SIGNOR-71565	0.567
PTPN1	protein	P18031	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									22124607	t		lperfetto	Moreover, we reported that TCPTP knockdown in PTP1B deficient MEFS further enhanced IR activation, consistent with the two PTPs acting in a coordinated manner to attenuate insulin signalling .|Therefore, the inhibition of PTPs such as PTP1B that attenuate IR activation and signalling might be particularly effective in alleviating insulin resistance.|The prototypic family member PTP1B (encoded by PTPN1) dephosphorylates the IR beta subunit Y1162 and Y1163 activation loop autophosphorylation site to attenuate insulin signalling in vivo .	SIGNOR-276946	0.778
CDK2	protein	P24941	UNIPROT	NR3C1	protein	P04150	UNIPROT	up-regulates activity	phosphorylation	Ser211	PGKETNEsPWRSDLL	-1									9199329	t		lperfetto	Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.	SIGNOR-249427	0.296
NMDA receptor_2C	complex	SIGNOR-C349	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									30037851	t		miannu	NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS). 	SIGNOR-264220	0.8
NFKBIA	protein	P25963	UNIPROT	S100A6	protein	P06703	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								12859951	f		miannu	Transient expression of NF-kappaB (p65) increased S100A6 promoter activity and expression of inhibitor of NF-kappaB (IkappaBalpha) decreased TNFalpha-induced S100A6 promoter activity. 	SIGNOR-254804	0.2
PRKACA	protein	P17612	UNIPROT	CIITA	protein	P33076	UNIPROT	down-regulates activity	phosphorylation	Ser834	QELPGRLsFLGTRLT	9606	BTO:0000984								11416140	t		lperfetto	Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylationphosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription.	SIGNOR-108573	0.313
BAD	protein	Q92934	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203								23725574	f		irozzo	Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions.	SIGNOR-256259	0.7
PRKACA	protein	P17612	UNIPROT	SLC2A2	protein	P11168	UNIPROT	down-regulates activity	phosphorylation	Ser505	EFQKKSGsAHRPKAA	9534	BTO:0004055								8626492	t		miannu	GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity.	SIGNOR-250051	0.313
PDPK1	protein	O15530	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates	phosphorylation			9606									15175348	t		lperfetto	The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation.	SIGNOR-244938	0.275
3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	DIO	proteinfamily	SIGNOR-PF83	SIGNOR	up-regulates quantity by expression				9606									29892818	f	inferred from family member	scontino	Dio2 is a cAMP responsive gene. Thus, any signaling pathway or molecule that increases cAMP concentration will stimulate D2 activity.	SIGNOR-270243	0.8
MAP2K1	protein	Q02750	UNIPROT	ARRB2	protein	P32121	UNIPROT	up-regulates activity	phosphorylation	Thr382	EFDTNYAtDDDIVFE	9606	BTO:0000007								28169830	t			Here, we show that activation of serotonin 5-HT2C receptors, which engage Erk1/2 pathway via a _-arrestin-dependent mechanism, promotes MEK-dependent _-arrestin2 phosphorylation at Thr383	SIGNOR-252027	0.569
lysophosphatidic acid	smallmolecule	CHEBI:132742	ChEBI	LPAR6	protein	P43657	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257533	0.8
Odanacatib	chemical	CID:10152654	PUBCHEM	CTSK	protein	P43235	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-195007	0.8
EPC2	protein	Q52LR7	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269306	0.581
MAPK1	protein	P28482	UNIPROT	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation	Ser152	PASSVSSsPSPPFGH	9606									12050114	t		gcesareni	Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation.	SIGNOR-88716	0.361
AMPK	complex	SIGNOR-C15	SIGNOR	KCNA5	protein	P22460	UNIPROT	down-regulates activity	phosphorylation	Ser559	VQRKVSGsRGSFCKA	9606	BTO:0000007								30279167	t		miannu	Thus, AMPK directly phosphorylates the α subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559. 	SIGNOR-273736	0.296
SCN2A	protein	Q99250	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606									27262167	t		miannu	Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential.	SIGNOR-253404	0.8
KDM2B	protein	Q8NHM5	UNIPROT	UHRF1	protein	Q96T88	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000011								25533466	f		miannu	We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis.	SIGNOR-252245	0.288
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	Enolase	proteinfamily	SIGNOR-PF74	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f	inferred from family member	miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-270249	0.2
NOG	protein	Q13253	UNIPROT	BMPR1B	protein	O00238	UNIPROT	down-regulates activity	binding			9606									22298955	t		lperfetto	Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285)	SIGNOR-192802	0.584
EGFR	protein	P00533	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	phosphorylation	Tyr154	QLNDSAAyYLNDLDR	-1									33139573	t		miannu	RTKs directly phosphorylate Gαi on Y154, 155, and Y320.	SIGNOR-277227	0.44
dopamine	smallmolecule	CHEBI:18243	ChEBI	DRD1	protein	P21728	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257477	0.8
CD19	protein	P15391	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates activity				9606									10706702	f		lperfetto	CD19 is a coreceptor on B cells that enhances the increase in cytoplasmic calcium and ERK2 activation when coligated with the B cell Ag receptor.	SIGNOR-249609	0.398
JAK3	protein	P52333	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation	Tyr371	ADFAPEDySSFQHIR	9606	BTO:0001372								23263556	t		miannu	 Here we found that IL-7-Jak3 signals activated the transcription factor NFATc1 in DN thymocytes by phosphorylating Tyr371 in the regulatory region of NFATc1. 	SIGNOR-276435	0.391
PRKCA	protein	P17252	UNIPROT	HAND1	protein	O96004	UNIPROT	unknown	phosphorylation	Ser98	RLGRRKGsGPKKERR	9606									14636580	t		lperfetto	In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. 	SIGNOR-249243	0.292
bisphenol A	chemical	CHEBI:33216	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			-1									9751507	t		miannu	Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings. 	SIGNOR-268738	0.8
SIRT7	protein	Q9NRC8	UNIPROT	H3C15	protein	Q71DI3	UNIPROT	up-regulates activity	deacetylation	Lys37	APATGGVkKPHRYRP										30653310	t		lperfetto	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 	SIGNOR-275881	0.2
alvocidib hydrochloride	chemical	CHEBI:90998	ChEBI	CDK9	protein	P50750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192480	0.8
FER	protein	P16591	UNIPROT	PRKCD	protein	Q05655	UNIPROT	up-regulates activity	phosphorylation	Tyr374	ELKGRGEyFAIKALK	9606	BTO:0002548								33411917	t		miannu	We show that the tyrosine kinase FER alters PKCδ function by phosphorylating it on Y374, and that phospho-Y374-PKCδ prevents RAB5 release from nascent late endosomes, thereby inhibiting EGFR degradation and promoting the recycling of endosomal EGFR to the cell surface.	SIGNOR-277546	0.2
TNF	protein	P01375	UNIPROT	SCN4A	protein	P35499	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253481	0.26
PRKD1	protein	Q15139	UNIPROT	PAK4	protein	O96013	UNIPROT	up-regulates activity	phosphorylation	Ser474	KEVPRRKsLVGTPYW										24840177	t		lperfetto	When PKD3 was knocked-down using isoform-specific shRNA (PKD3-shRNA), PAK4 activity (judged by its phosphorylation status at the activation loop using the pS474-PAK4 antibody) was decreased 	SIGNOR-275930	0.255
PRKD2	protein	Q9BZL6	UNIPROT	SSH1	protein	Q8WYL5	UNIPROT	down-regulates activity	phosphorylation	Ser978	SPLKRSHsLAKLGSL										21832093	t		lperfetto	Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase	SIGNOR-275937	0.296
BLVRB	protein	P30043	UNIPROT	bilirubin(2-)	smallmolecule	CHEBI:57977	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000759							7929092	t		lperfetto	This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. 	SIGNOR-275523	0.8
MAP2K1	protein	Q02750	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates activity	phosphorylation			10090									11730323	t			Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs	SIGNOR-258993	0.739
ERBB2	protein	P04626	UNIPROT	ERBB3	protein	P21860	UNIPROT	up-regulates	binding			9606									12648465	t	Most breast, skin, lung, ovary, and gastrointestinal tract tumors express ErbB-3, and heterodimerization of this receptor with ErbB-2, may be involved in some cancers.	gcesareni	Although ErbB-2 binds no known ligand, when recruited into heterodimers it increases ligand binding affinity	SIGNOR-99569	0.569
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Phe634	VHHQKLVfFAEDVGS	-1									8943232	t		lperfetto	FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261770	0.502
EFNA2	protein	O43921	UNIPROT	EPHA8	protein	P29322	UNIPROT	up-regulates	binding			9606									9330863	t		gcesareni	The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. Therefore, eph receptors mediate signals that can override cell adhesion.	SIGNOR-52269	0.741
DAMPS	stimulus	SIGNOR-ST18	SIGNOR	TLRs	proteinfamily	SIGNOR-PF20	SIGNOR	up-regulates activity	binding			9606									25644504	t			The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs)	SIGNOR-252096	0.7
CEBPA	protein	P49715	UNIPROT	HSD11B1	protein	P28845	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19088256	t		lperfetto	Cotransfection with human CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPbeta-LAP expression vectors activated the HSD11B1 promoter with the strongest effect within the same region.	SIGNOR-268971	0.278
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr529	TPGSRSRtPSLPTPP	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249348	0.729
CCP110	protein	O43303	UNIPROT	CETN3	protein	O15182	UNIPROT	up-regulates activity	binding			9606									16760425	t		miannu	We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis.	SIGNOR-265968	0.43
DUSP10	protein	Q9Y6W6	UNIPROT	IRF3	protein	Q14653	UNIPROT	down-regulates activity	dephosphorylation			9606									26305722	t		miannu	The inactivation of IRF3 by MKP5 is dependent on MKP5 phosphatase activity or its binding to IRF3.|This is confirmed since MKP5 phosphatasedeficient mutant is unable to dephosphorylate IRF3 and MKP5 mutant lacking IRF3 binding motifs fails to suppress IRF3 nuclear translocation upon virus infection.	SIGNOR-277146	0.2
MYC	protein	P01106	UNIPROT	CDKN2A	protein	P42771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000785								20551174	f		lperfetto	In tissue culture, ectopic expression of Myc suppresses the cell cycle arrest that occurs in response to several anti-mitogenic signals such as transforming growth factor β (TGFβ), since Myc represses expression of the cyclin-dependent kinase inhibitors (CKIs) p15ink4b, p21cip1, and p57kip2 via interaction with Miz1	SIGNOR-267575	0.758
RUNX2	protein	Q13950	UNIPROT	SPP1	protein	P10451	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11331591	f		gcesareni	In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast	SIGNOR-107175	0.504
CIB1	protein	Q99828	UNIPROT	ITGA2B	protein	P08514	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								11756406	t		Gianni	The small GTPase Rac3 interacts with the integrin-binding protein CIB and promotes integrin alpha(IIb)beta(3)-mediated adhesion and spreading	SIGNOR-269061	0.485
AMPK	complex	SIGNOR-C15	SIGNOR	PLD1	protein	Q13393	UNIPROT	up-regulates	phosphorylation	Ser505	GSVKRVTsGPSLGSL	9606		BTO:0000887;BTO:0001103							20231899	t		lperfetto	Ampk-wild type (wt) stimulates pld activity, while ampk-dominant negative (dn) inhibits it. Ampk regulates pld1 activity through phosphorylation of the ser-505 and this phosphorylation is increased by the presence of amp.	SIGNOR-216643	0.245
NFIX	protein	Q14938	UNIPROT	ID3	protein	Q02535	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268885	0.2
GADD45A	protein	P24522	UNIPROT	CDK11A	protein	Q9UQ88	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								26885618	t		lperfetto	GADD45alpha inhibits CDK11p58 kinase activity|We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58.	SIGNOR-273023	0.2
CLU	protein	P10909	UNIPROT	COMMD1	protein	Q8N668	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0001321								20068069	t		miannu	CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation.	SIGNOR-271432	0.402
Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	GABA-A (a4-b2-d) receptor	complex	SIGNOR-C326	SIGNOR	up-regulates				9606									33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors	SIGNOR-268583	0.2
PMCH	protein	P20382	UNIPROT	MCHR1	protein	Q99705	UNIPROT	up-regulates	binding			9606	BTO:0000007								10421367	t		gcesareni	Here we show that the 353-amino-acid human orphan g-protein-coupled receptor slc-1 expressed in hek293 cells binds mch with sub-nanomolar affinity, and is stimulated by mch to mobilize intracellular ca2+ and reduce forskolin-elevated cyclic amp levels.	SIGNOR-69517	0.702
BRAP	protein	Q7Z569	UNIPROT	USP15	protein	Q9Y4E8	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								23105109	t		miannu	Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. 	SIGNOR-272029	0.27
PPP2CA	protein	P67775	UNIPROT	RACGAP1	protein	Q9H0H5	UNIPROT	down-regulates	dephosphorylation	Thr588	PEHQLLKtPSSSSLS	9606									18201571	t		gcesareni	We report here that (i) mgcracgap is phosphorylated by aurora b and cdk1, (ii) pp2a dephosphorylates aurora b and cdk1 phosphorylated sites and (iii) inhibition of pp2a abrogates mgcracgap/ect2 interaction. Therefore, pp2a may regulate cytokinesis by dephosphorylating mgcracgap and its interacting partners.	SIGNOR-160402	0.307
HNF1B	protein	P35680	UNIPROT	FXYD2	protein	P54710	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		 BTO:0000482							24204001	f		miannu	 Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT.	SIGNOR-254909	0.297
PJA2	protein	O43164	UNIPROT	PRKAR2A	protein	P13861	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								21423175	t		miannu	Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits	SIGNOR-271856	0.333
PRKCE	protein	Q02156	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates activity	phosphorylation	Ser876	QGLAERIsVL										12058027	t		lperfetto	Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.	SIGNOR-275959	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser296	SPSALSSsPNNLSPT	10090									15664191	t		lperfetto	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-244681	0.2
DYRK2	protein	Q92630	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser46	AMDDLMLsPDDIEQW										19965871	t		lperfetto	Phosphorylation of p53 at Ser-46 is indispensable for the commitment to apoptotic cell death. |Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. 	SIGNOR-275578	0.659
STK3	protein	Q13188	UNIPROT	STK3	protein	Q13188	UNIPROT	up-regulates	phosphorylation	Thr180	DTMAKRNtVIGTPFW	9606	BTO:0000150								20231902	t		gcesareni	Consistent with previous studies, sts alone induces mst2 cleavage and autophosphorylation of thr180, an indicator of mst2 activation, as well as apoptosis.	SIGNOR-164310	0.2
NR3C1	protein	P04150	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates activity	binding			9606									9162033	t		gcesareni	Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity.	SIGNOR-48516	0.526
GSK3B	protein	P49841	UNIPROT	PGR	protein	P06401	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser554	PDSEASQsPQYSFES	9606									23880761	t		miannu	Here, we have found that glycogen synthase kinase (GSK)-3β phosphorylation of progesterone receptor-A (PR-A) facilitates its ubiquitination. GSK-3β-mediated phosphorylation of serine 390 in PR-A regulates its subsequent ubiquitination and protein stability.	SIGNOR-276498	0.281
PRKACA	protein	P17612	UNIPROT	RASGRF1	protein	Q13972	UNIPROT	up-regulates	phosphorylation	Ser927	KEKYRRMsLASAGFP	9606	BTO:0000938								10601308	t		llicata	Phosphorylation of serine 916 of ras-grf1 contributes to the activation of exchange factor activity by muscarinic receptors.	SIGNOR-73202	0.501
TFIIF	complex	SIGNOR-C394	SIGNOR	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	up-regulates activity	relocalization			9606									18218714	t		lperfetto	Transcription processes in eukaryotes begin with the formation of a pre-initiation complex (PIC), composed of RNA polymerase II (Pol II) associated with five general transcription factors: TFIIB, TFIID, TFIIE, TFIIF, and TFIIH	SIGNOR-266199	0.724
MAML3	protein	Q96JK9	UNIPROT	NOTCH3	protein	Q9UM47	UNIPROT	up-regulates	binding			9606									12370315	t		gcesareni	We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors.	SIGNOR-94100	0.877
TFDP1	protein	Q14186	UNIPROT	TYMS	protein	P04818	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253861	0.411
POMC	protein	P01189	UNIPROT	MC3R	protein	P41968	UNIPROT	up-regulates activity	binding					BTO:0000614							17702843	t		lperfetto	Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases.	SIGNOR-253073	0.75
CTDSP2	protein	O14595	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	dephosphorylation	Ser195	PNSSYPNsPGSSSST	9606	BTO:0000552								17085434	t			Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)	SIGNOR-248301	0.477
4-[2-[(1R)-1-(N-(4-chlorophenyl)sulfonyl-2,5-difluoroanilino)ethyl]-5-fluorophenyl]butanoic acid	chemical	CHEBI:94983	ChEBI	PSEN1	protein	P49768	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0000142							18032377	t		gcesareni	We employed a combination of chimeric constructs and point mutants to identify structural determinants for ps1-selective inhibition by eln318463. Our studies identified amino acid residues leu(172), thr(281), and leu(282) in ps1 as necessary for ps1-selective inhibition by eln318463. These residues also contributed in part to the ps1-selective inhibition by bms299897.	SIGNOR-159344	0.8
ATM	protein	Q13315	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	down-regulates	phosphorylation	Ser560	LARLGCSsCLDYFTT	9606									18769144	t		lperfetto	Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively	SIGNOR-180751	0.413
glucose	chemical	CHEBI:17234	ChEBI	HK2	protein	P52789	UNIPROT	up-regulates quantity by stabilization				9606	BTO:0004424								26323688	t			Consistently, treatment of cells with 2-deoxy-d-glucose (2DG), which completely inhibits glucose metabolism, leads to HK2 degradation and cell death in combination with C43	SIGNOR-261323	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PEA15	protein	Q15121	UNIPROT	up-regulates activity	phosphorylation	Ser116	KDIIRQPsEEEIIKL	9606	BTO:0000007								12808093	t		lperfetto	Protein kinase b/akt binds and phosphorylates ped/pea-15, stabilizing its antiapoptotic action.	SIGNOR-244326	0.2
AMER1	protein	Q5JTC6	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								21304492	t		lperfetto	Knockdown of Amer1 reduces Wnt-induced LRP6 phosphorylation, Axin translocation to the plasma membrane and formation of LRP6 signalosomesThe generation of PtdIns(4,5)P2 in regions of receptor activity triggers the recruitment of Amer1 proteins, which in turn promote LRP6 phosphorylation by recruiting Axin/GSK3_ and CK1gamma to LRP6.	SIGNOR-24265	0.455
ACAT1	protein	P24752	UNIPROT	PDP1	protein	Q9P0J1	UNIPROT	down-regulates activity	acetylation												34289383	t		lperfetto	We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)	SIGNOR-267635	0.346
CDK1	protein	P06493	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates	phosphorylation	Ser83	QQQQQETsPRQQQQQ	9606	BTO:0001130								21799006	t		gcesareni	At first, the data show that cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins although ar was reported as substrates for cdk9 (5) as well as cdk1	SIGNOR-175692	0.547
SYNE3	protein	Q6ZMZ3	UNIPROT	LINC complex	complex	SIGNOR-C303	SIGNOR	form complex	binding												24481844	t		lperfetto	LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM.	SIGNOR-263284	0.529
CSNK1E	protein	P49674	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	phosphorylation	Ser400	SRDESTDsGLSMSSY	9606							phosphorylation:Ser127	PQHVRAHsSPASLQL 	24715453	t		milica	LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)	SIGNOR-230728	0.401
CDR2	protein	Q01850	UNIPROT	CENPE	protein	Q02224	UNIPROT	up-regulates quantity by expression	transcriptional regulation												20383333	f		lperfetto	Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology	SIGNOR-252020	0.2
AURKB	protein	Q96GD4	UNIPROT	INCENP	protein	Q9NQS7	UNIPROT	up-regulates	phosphorylation	Ser893	PRYHKRTsSAVWNSP	9606									12925766	t		gcesareni	Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites.	SIGNOR-118011	0.973
SMCR8	protein	Q8TEV9	UNIPROT	ULK1	protein	O75385	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								28195531	t			While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion.	SIGNOR-252029	0.406
PRKCB	protein	P05771	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Thr841	RSAFTTStVVRMHVG	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249286	0.36
TFEB	protein	P19484	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates quantity by expression	transcriptional regulation												28552616	t		lperfetto	As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes;	SIGNOR-276558	0.421
KCTD11	protein	Q693B1	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates activity													15249678	f	In absence of Hh	lperfetto	REN(KCTD11) seems to inhibit medulloblastoma growth by negatively regulating the Hedgehog pathway because it antagonizes the Gli-mediated transactivation of Hedgehog target genes, by affecting Gli1 nuclear transfer, and its growth inhibitory activity is impaired by Gli1 inactivation.	SIGNOR-249592	0.36
EPB41	protein	P11171	UNIPROT	4.1 complex	complex	SIGNOR-C386	SIGNOR	form complex	binding			9606									33187473	t		lperfetto	The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]	SIGNOR-266035	0.417
MRE11/RAD50/NBS1	complex	SIGNOR-C147	SIGNOR	BRCA1-C complex	complex	SIGNOR-C299	SIGNOR	form complex	binding												25400280	t		lperfetto	The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2	SIGNOR-263221	0.2
PTP4A3	protein	O75365	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates quantity by destabilization	dephosphorylation			9606									29266303	t		lperfetto	As expected, PRL3 clearly reduced PTEN phosphorylation at the tyrosine residue and PTEN protein in PRL3 overexpressing LO2 and HepG2 cell lines, with no significant changes in PRL3 (C104S) mutant cells.|PRL3 down-regulates PTEN expression, a negative regulator of the Akt pathway.11 Phosphorylation of PTEN at Tyr336 is required for maintenance of PTEN protein stability and prevention of PTEN degradation.17 We therefore speculated that PRL3 might dephosphorylate PTEN at tyrosine sites and consequently reduce the PTEN protein level.	SIGNOR-277010	0.301
AGRP	protein	O00253	UNIPROT	MC3R	protein	P41968	UNIPROT	down-regulates	binding			9606		BTO:0001253							9311920	t		gcesareni	Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r, melanocortin receptor subtypes implicated in weight regulation.	SIGNOR-51067	0.612
PRKG1	protein	Q13976	UNIPROT	CRIP2	protein	P52943	UNIPROT	unknown	phosphorylation	Ser104	RAEERKAsGPPKGPS	9534	BTO:0000298								10681529	t		lperfetto	 Cyclic GMP kinase I phosphorylated CRP2 at Ser-104, because the mutation to Ala completely prevented the in vivo phosphorylation.	SIGNOR-249038	0.462
CTBP1	protein	Q13363	UNIPROT	VDR	protein	P11473	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000356								18485278	f		miannu	 We have shown here that the transcriptional repressor protein SLUG inhibits the expression of VDR in human breast cancer cells. 	SIGNOR-255178	0.358
AMFR	protein	Q9UKV5	UNIPROT	GPI	protein	P06744	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								24810856	t		miannu	Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF.	SIGNOR-272177	0.546
MAPK8	protein	P45983	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates	phosphorylation	Thr743	VEVDAAVtPEERHLS	9606	BTO:0000793								24610780	t		lperfetto	Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1	SIGNOR-204679	0.7
GPR132	protein	Q9UNW8	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256945	0.2
CDK1	protein	P06493	UNIPROT	NIFK	protein	Q9BYG3	UNIPROT	up-regulates activity	phosphorylation	Thr238	QGPTPVCtPTFLERR	-1									16244663	t		miannu	The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1.	SIGNOR-262696	0.284
NR3C1	protein	P04150	UNIPROT	NFKBIA	protein	P25963	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									7569975	f		andrea cerquone perpetuini	Here it is shown that the synthetic glucocorticoid dexamethasone induces the transcription of the IKBc gene, which results in an increased rate of IKBa protein synthesis	SIGNOR-255688	0.334
PAX3	protein	P23760	UNIPROT	TBX2	protein	Q13207	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002267								25211658	t		lperfetto	We have recently found that a T-box gene family member, TBX2, is highly overexpressed in both ERMS and ARMS cells (Zhu et al, 2014). The regulation of TBX2 is uncharacterised in RMS cells, but is likely to link TBX2 expression to the known deregulation of signalling pathways in RMS. In melanoma cells, TBX2 is regulated by PAX3	SIGNOR-249596	0.354
beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	glycerone phosphate(2-)	smallmolecule	CHEBI:57642	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-268073	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	EP300	protein	Q09472	UNIPROT	up-regulates	phosphorylation	Ser1834	MLRRRMAsMQRTGVV	9606									16926151	t		lperfetto	We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity	SIGNOR-244236	0.2
NBN	protein	O60934	UNIPROT	MRE11/RAD50/NBS1	complex	SIGNOR-C147	SIGNOR	form complex	binding												17713585	t		lperfetto	The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50.	SIGNOR-251505	0.911
teniposide	chemical	CHEBI:75988	ChEBI	TOP2A	protein	P11388	UNIPROT	down-regulates activity	chemical inhibition			9606									1329225	t		miannu	Recognition of transient DNA breaks induced by teniposide, etoposide, and other podophyllotoxin analogues established not only that their site of activity was DNA but also that their cytotoxic effect was dose-dependent. Extensive investigation has further indicated that a primary mechanism of action of these agents involves inhibition of the catalytic activity of eukaryote topoisomerase II and, more important, the consequent stabilization of the normally transient covalent intermediate formed between the DNA substrate and the enzyme. 	SIGNOR-259329	0.8
ADRA1B	protein	P35368	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257190	0.409
ATR	protein	Q13535	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation			9606									23422745	t		gcesareni	The phosphorylation of atr and atm substrates, chk1, chk2, h2ax, and brca1 was significantly reduced or abrogated in mutant cells.	SIGNOR-201050	0.792
AKT1	protein	P31749	UNIPROT	SRPK2	protein	P78362	UNIPROT	up-regulates	phosphorylation	Thr492	PSHDRSRtVSASSTG	9606	BTO:0000938	BTO:0000142							19592491	t		lperfetto	Here we show that srpk2, a protein kinase specific for the serine/arginine (sr) family of splicing factors, triggers cell cycle progression in neurons and induces apoptosis through regulation of nuclear cyclin d1. Akt phosphorylates srpk2 on thr-492 and promotes its nuclear translocation leading to cyclin d1 up-regulation, cell cycle reentry, and neuronal apoptosis.	SIGNOR-186760	0.479
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	STK3	protein	Q13188	UNIPROT	down-regulates	phosphorylation	Thr117	IIRLRNKtLIEDEIA	9606	BTO:0000150								20231902	t		gcesareni	Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation.	SIGNOR-164298	0.2
SMAD1/5/8/SMAD4	complex	SIGNOR-C215	SIGNOR	RUNX2	protein	Q13950	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								15573378	t		ggiuliani	The Runx2 WT and deletion constructs (1 –495, 1–464, and 1–432) all physically interact with the BMP2 responsive Smad 1	SIGNOR-255834	0.579
CUL1	protein	Q13616	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606			SIGNOR-C5						10023660	t		lperfetto	These results indicate that the cul1/skp1/beta-trcp complex forms a ubiquitin ligase that mediates the degradation of beta-catenin.	SIGNOR-64499	0.58
EFNA3	protein	P52797	UNIPROT	EPHA7	protein	Q15375	UNIPROT	up-regulates	binding			9606									9330863	t		gcesareni	The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion	SIGNOR-52384	0.795
MAPK8	protein	P45983	UNIPROT	MAPK8IP1	protein	Q9UQF2	UNIPROT	unknown	phosphorylation	Ser29	FLGLHIAsPPNFRLT	9534	BTO:0000298								12756254	t		miannu	After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1.	SIGNOR-250125	0.879
PIK3CA	protein	P42336	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity				9606		BTO:0000150							19573809	f		lperfetto	However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth	SIGNOR-252634	0.811
PRKACA	protein	P17612	UNIPROT	PLIN1	protein	O60240	UNIPROT	down-regulates activity	phosphorylation	Ser220	KAKPSLLsRVGALTN	10090									11751901	t		miannu	PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.‚  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276)	SIGNOR-250028	0.482
MAPK3	protein	P27361	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser362	AAAHRKGsSSNEPSS										16055710	t		lperfetto	Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos	SIGNOR-262997	0.707
vitamin K epoxide	smallmolecule	CHEBI:28371	ChEBI	Reduced Vitamin K	smallmolecule	CHEBI:8784	ChEBI	up-regulates quantity	precursor of			9606									31226734	t		lperfetto	The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form	SIGNOR-265913	0.8
FGF14	protein	Q92915	UNIPROT	SCN10A	protein	Q9Y5Y9	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253441	0.2
Norzotepine	chemical	CID:10041551	PUBCHEM	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								20223878	t		Luana	These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity.	SIGNOR-257830	0.8
UBE2I	protein	P63279	UNIPROT	MBD4	protein	O95243	UNIPROT	up-regulates activity	sumoylation	Lys377	HLHTDILkRGSEMDN										31476572	t		lperfetto	MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro.	SIGNOR-275678	0.2
PLK1	protein	P53350	UNIPROT	SVIL	protein	O95425	UNIPROT	up-regulates activity	phosphorylation	Ser238	SFSGRDSsFTEVPRS	9606	BTO:0000007								23750008	t		miannu	PLK1 phosphorylates Ser238 of SVIL, which can promote the localization of SVIL to the central spindle and association with PRC1. Expression of a PLK1 phosphorylation site mutant, S238A-SVIL, inhibited myosin II activation at the equatorial cortex and induced aberrant furrowing. 	SIGNOR-273729	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	TSC2	protein	P49815	UNIPROT	down-regulates	phosphorylation	Ser1798	GQRKRLIsSVEDFTE	9606	BTO:0000007								15342917	t		lperfetto	The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1	SIGNOR-252801	0.2
MAPK1	protein	P28482	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser43	FGYQRRAsDDGKLTD	10090	BTO:0000944								15664191	t		lperfetto	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-249439	0.616
AP2B1	protein	P63010	UNIPROT	AP-2 complex	complex	SIGNOR-C245	SIGNOR	form complex	binding												31671891	t		lperfetto	 The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit	SIGNOR-260422	0.854
SMAD2/SMAD4	complex	SIGNOR-C8	SIGNOR	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606									22703233	f		lperfetto	Our results establish a novel biological role for TGFbeta signaling in controlling expression of genes characteristic for alternatively activated macrophages. We speculate that lack of TbetaRII signaling reduces the anti-inflammatory M2 phenotype of macrophages because of reduced expression of these products.	SIGNOR-249550	0.7
DAPK1	protein	P53355	UNIPROT	MYL12A	protein	P19105	UNIPROT	up-regulates activity	phosphorylation	Ser19	KRPQRATsNVFAMFD	9606	BTO:0000567								11485996	t		miannu	DAPK Phosphorylates Myosin II RLC in Vitro and in Vivo. Together these results show that similar to the conventional MLCKs, Ser-19 is the primary RLC residue phosphorylated by DAPK and that phosphorylation of Thr-18 is also possible.	SIGNOR-262842	0.278
LYN	protein	P07948	UNIPROT	YY1	protein	P25490	UNIPROT	down-regulates activity	phosphorylation	Tyr254	SPPDYSEyMTGKKLP	9606	BTO:0002181								26198631	t		miannu	In the case of Lyn overexpression, single mutations at either tyrosine 8, 254, or 383 severely reduced Lyn-mediated YY1 phosphorylation, suggesting that these three sites may be targets of Lyn in vivo (Fig. 3, A and B).	SIGNOR-276929	0.2
PRKCD	protein	Q05655	UNIPROT	PPP1R14B	protein	Q96C90	UNIPROT	up-regulates activity	phosphorylation	Thr57	VRRQGKVtVKYDRKE										10606530	t		lperfetto	Recombinant tagged PHI-1 was phosphorylated by protein kinase C at two sites, one a Ser and one a Thr; phosphorylation enhanced inhibitory potency 50-fold. 	SIGNOR-265739	0.2
TADA1	protein	Q96BN2	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269583	0.697
CDK1	protein	P06493	UNIPROT	LMNA	protein	P02545	UNIPROT	up-regulates	phosphorylation	Ser22	QASSTPLsPTRITRL	9606									18815303	t		gcesareni	Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm	SIGNOR-181310	0.553
WDR45	protein	Q9Y484	UNIPROT	ATG2A	protein	Q2TAZ0	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								28561066	t		miannu	WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation. 	SIGNOR-268483	0.538
TSPAN33	protein	Q86UF1	UNIPROT	ADAM10	protein	O14672	UNIPROT	up-regulates activity	binding			10116									30463011	t		Simone	Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11.	SIGNOR-261251	0.496
BAD	protein	Q92934	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	binding			9606	BTO:0002552								17000778	t		lperfetto	We also demonstrate that bad physically interacts with cytoplasmic p53. bad is able to direct p53 to the mitochondria and forms a p53/bad complex at the mitochondria. the mitochondrial p53/bad complex promotes apoptosis	SIGNOR-149815	0.335
Cyclopamine	chemical	CHEBI:4021	ChEBI	SMO	protein	Q99835	UNIPROT	down-regulates	chemical inhibition			9534	BTO:0000298								12414725	t		gcesareni	The steroidal alkaloid cyclopamine has both teratogenic and antitumor activities arising from its ability to specifically block cellular responses to vertebrate Hedgehog signaling. We show here, using photoaffinity and fluorescent derivatives, that this inhibitory effect is mediated by direct binding of cyclopamine to the heptahelical bundle of Smoothened (Smo)	SIGNOR-95270	0.8
HOXC11	protein	O43248	UNIPROT	S100B	protein	P04271	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17488478	t		Luana	HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells.	SIGNOR-261647	0.255
MLL3 complex	complex	SIGNOR-C446	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606									34156443	t		miannu	MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. 	SIGNOR-268811	0.2
F2R	protein	P25116	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257403	0.546
HDAC1	protein	Q13547	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	deacetylation			10090		BTO:0000887							24463822	t			Through the use of various pharmacological inhibitors to block HDAC activity, we demonstrate that class I HDACs are key regulators of FoxO and the muscle-atrophy program during both nutrient deprivation and skeletal muscle disuse.	SIGNOR-256485	0.377
JAK2	protein	O60674	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606	BTO:0000599								9575217	t		lperfetto	Activation of wild type stat3: il-6 treatment causes stat3 recruitment to receptor tyrosine phosphopeptides (gp130) where it is phosphorylated on tyrosine 705 (y) by jak kinase	SIGNOR-236463	0.812
AKT1	protein	P31749	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606									23552696	t		lperfetto	Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3beta (GSK3B). The AKT-mediated phosphorylation of glycogen synthase kinase 3b on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1	SIGNOR-245416	0.783
PHT-427	chemical	CID:44240850	PUBCHEM	PDPK1	protein	O15530	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001271								21715304	t		gcesareni	Consistent with the results described in figures 3c and and4a,4a, treatment of 32d/bcr-abl cells with the bcr-abl inhibitor imatinib, the pi3k inhibitor ly294002 or the akt/pdpk1 inhibitor pht-427 substantially reduced atf5 promoter-directed luciferase activity	SIGNOR-174612	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GRK1	protein	Q15835	UNIPROT	down-regulates activity	phosphorylation	Ser21	AFIAARGsFDGSSSQ	-1									15946941	t		miannu	 We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA.Phosphorylation of GRK1 and GRK7 by PKA reduces the ability of GRK1 and GRK7 to phosphorylate rhodopsin in vitro. 	SIGNOR-276034	0.2
APOA1	protein	P02647	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity				9606									14668333	f		miannu	ApoA-I Stimulates JAK2 Autophosphorylation. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells	SIGNOR-252108	0.303
HTR3E	protein	A5X5Y0	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606		BTO:0000142							18761359	f		miannu	The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release. 	SIGNOR-264318	0.7
dabrafenib	chemical	CHEBI:75045	ChEBI	NEK11	protein	Q8NG66	UNIPROT	down-regulates activity	chemical inhibition			-1									24720932	t		miannu	Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations	SIGNOR-259217	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CXCL8	protein	P10145	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19185596	f		miannu	S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. we have provided evidence that S protein induces IL-8 in PBMC in vitro and in THP-1 cells. The ability of S protein to increase IL-8 mRNA was mediated by activation of NF-κB possibly via TLR2 ligand and could be inhibited by the NF-κB inhibitor TPCK. The ability to detect elevated NF-κB transcription factor activity in the nucleus in response to S protein suggests that this most likely occurs by the mechanism of induction. Moreover increased secretion of IL-8 and IL-6 cytokines indicated that levels of proinflammatory mediators could be enhanced by S protein interaction with monocyte macrophages and could stimulate NK, neutrophil and monocyte migration to the site of infection.	SIGNOR-260974	0.634
DYRK1A	protein	Q13627	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates	phosphorylation	Thr310	VPPLPKVtPTKELQQ	9606		BTO:0000142							15262992	t		lperfetto	Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd	SIGNOR-126855	0.405
WASF3	protein	Q9UPY6	UNIPROT	Metastasis	phenotype	SIGNOR-PH107	SIGNOR	up-regulates activity				9534									17623672	f			We have also shown that Abl targets and phosphorylates four tyrosine residues in WAVE3 and that the Abl-dependent phosphorylation of WAVE3 is critical for the stimulation of lamellipodia formation and cell migration.	SIGNOR-259078	0.7
Survival Factors	stimulus	SIGNOR-ST8	SIGNOR	GRB2	protein	P62993	UNIPROT	up-regulates activity													19282669	f		lperfetto	Activation of receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs) by growth factors or mitogens leads to the recruitment of an adaptor protein Grb2 (growth factor receptor bound protein) and the guanine nucleotide exchange factor (SOS). The SOS activates Ras to recruit and activate Raf at the plasma membrane by phosphorylation at multiple sites. MEK1/2 is which then phosphorylated at two serine residues that subsequently phosphorylates ERK1/2 on both threonine and tyrosine. Activated ERK1/2 phosphorylates RSK and both RSK and ERK translocate to the nucleus where they activates multiple transcription factors ultimately resulting in effector protein synthesis and causing changes in cell proliferation and survival. ERK phosphorylation of MEK and possibly Raf can inactivate the pathway at those steps creating a negative feedback loop.	SIGNOR-250559	0.7
MAPK1	protein	P28482	UNIPROT	NR3C2	protein	P08235	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser287	SVKSPVSsPNNVTLR	9606	BTO:0005043								22798426	t		miannu	 Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276104	0.291
glycogen	smallmolecule	CHEBI:28087	ChEBI	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	up-regulates quantity	precursor of			9606									3346228	t			Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267397	0.8
OXGR1	protein	Q96P68	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257042	0.357
BBOX1	protein	O75936	UNIPROT	succinate(2-)	smallmolecule	CHEBI:30031	ChEBI	up-regulates quantity	chemical modification			9606									11802770	t		miannu	In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine.	SIGNOR-269700	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	HSPB8	protein	Q9UJY1	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser57	DWALPRLsSAWPGTL	-1									18298377	t		miannu	Human small heat shock protein with molecular mass 22 kD (HSP22, HspB8) contains two Ser residues (Ser24 and Ser57) in consensus sequence RXS and is effectively phosphorylated by cAMP-dependent protein kinase in vitro. Mutation S24D did not affect, whereas mutations S57D or S24,57D prevented phosphorylation of HSP22 by cAMP-dependent protein kinase thus indicating that Ser57 is the primary site of phosphorylation. Phosphorylation (or mutation) of Ser57 (or Ser24 and Ser57) resulted in changes of the local environment of tryptophan residues and increased HSP22 susceptibility to chymotrypsinolysis. 	SIGNOR-276151	0.2
PCDHAC1	protein	Q9H158	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-269037	0.2
IL10	protein	P22301	UNIPROT	IL10RA	protein	Q13651	UNIPROT	up-regulates	binding			9606	BTO:0000801;BTO:0000776								10347215	t		milica	Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling	SIGNOR-67964	0.911
IC-87114	chemical	CHEBI:90686	ChEBI	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206187	0.8
SHH	protein	Q15465	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates				9606	BTO:0002314								18662193	f		gcesareni	In addition, shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors myf-5 and myod, decreases the up-regulation of insulin-like growth factor (igf)-1 and reduces the number of myogenic satellite cells at injured site.	SIGNOR-179632	0.44
COL18A1	protein	P39060	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	down-regulates													17326328	f		lperfetto	There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3	SIGNOR-252269	0.7
PPP2CB	protein	P62714	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates	dephosphorylation			9606									8650155	t		gcesareni	These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity	SIGNOR-252636	0.487
CDK1	protein	P06493	UNIPROT	TOP1	protein	P11387	UNIPROT	up-regulates activity	phosphorylation	Ser394	SKDAKVPsPPPGHKW	-1									18408216	t		miannu	In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells.	SIGNOR-276157	0.358
TAF5L	protein	O75529	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269586	0.674
CENPI	protein	Q92674	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265213	0.756
messenger RNA	smallmolecule	CHEBI:33699	ChEBI	48S_initiation_complex	complex	SIGNOR-C454	SIGNOR	form complex	binding			9606									35489072	t		lperfetto	In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 	SIGNOR-269164	0.8
CDK11B	protein	P21127	UNIPROT	EIF3F	protein	O00303	UNIPROT	down-regulates	phosphorylation	Ser46	PAAAPASsSDPAAAA	9606									12446680	t		lperfetto	The interaction between cdk11p46 and eif3 p47 occurs in vitro and in vivo. In addition, cdk11 protein kinase isolated from cells undergoing apoptosis can phosphorylate eif3 p47in vitro, and serine phosphorylation of eif3 p47 occurs in cells during apoptosis.Purified recombinant cdk11p46 inhibited translation of a reporter gene in vitro in a dose-dependent manner.These data suggest that the function of the caspase-processed cdk11p110 isoform may be to inhibit translation during apoptosis. However, whether or not this inhibition of protein translation occurs in an eif3 p47-dependent or -independent manner remains to be clarified.	SIGNOR-95762	0.531
SAE1/SAE2 complex	complex	SIGNOR-C294	SIGNOR	FOS	protein	P01100	UNIPROT	down-regulates activity	sumoylation	Lys265	SISSMELkTEPFDDF	9606				SIGNOR-C154					16055711	t		lperfetto	We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. 	SIGNOR-263014	0.2
MAP3K5	protein	Q99683	UNIPROT	DAXX	protein	Q9UER7	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser176	TNAENTAsQSPRTRG	9606	BTO:0000567								19789335	t		lperfetto	we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1.	SIGNOR-109680	0.835
ketoconazole	chemical	CHEBI:47519	ChEBI	UGT1A1	protein	P22309	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								21030469	t		Luana	Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation.	SIGNOR-258060	0.8
PRPF4B	protein	Q13523	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Thr417	ISVDGLStPVVLSPG	9606		BTO:0000142;BTO:0000763							10799319	t		lperfetto	Activated hprp4 phosphorylates residue thr-417 on elk-1 resulting in elk-1 activation.	SIGNOR-77135	0.2
BST1	protein	Q10588	UNIPROT	nicotinic acid-adenine dinucleotide phosphate	smallmolecule	CHEBI:76072	ChEBI	up-regulates quantity	chemical modification			9606									18626062	t		miannu	The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR.	SIGNOR-264249	0.8
CDK7	protein	P50613	UNIPROT	E2F1	protein	Q01094	UNIPROT	down-regulates	phosphorylation	Ser403	PEEFISLsPPHEALD	9606									10428966	t		lperfetto	These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase. here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain.	SIGNOR-69776	0.506
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257942	0.8
SIRT5	protein	Q9NXA8	UNIPROT	SIRT3	protein	Q9NTG7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									31608237	f		Monia	In U2OS cells, SIRT5 silencing resulted in downregulation of SIRT1 and SIRT3 protein levels (Figures 4Ai,ii, compare bars 1 to 5). 	SIGNOR-261209	0.412
MECOM	protein	Q03112	UNIPROT	GATA1	protein	P15976	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000669								15889140	t		Luana	We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2 	SIGNOR-266061	0.325
PPM1D	protein	O15297	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	dephosphorylation	Thr68	SSLETVStQELYSIP	-1									16311512	t			 an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C.	SIGNOR-248318	0.59
IL1R1	protein	P14778	UNIPROT	IL1RAP	protein	Q9NPH3	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								10854325	t		lperfetto	Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) 	SIGNOR-251981	0.718
DLG4	protein	P78352	UNIPROT	Scribble_complex_DLG4-LLGL2_variant	complex	SIGNOR-C505	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270889	0.453
MLNR	protein	O43193	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256880	0.252
PRKAA2	protein	P54646	UNIPROT	CDC27	protein	P30260	UNIPROT	unknown	phosphorylation	Ser379	NALPRRSsRLFTSDS	9606			SIGNOR-C15						22137581	t		lperfetto	Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379, respectively) resulted in an almost complete loss of ampk phosphorylation in these proteins	SIGNOR-195106	0.265
C5AR2	protein	Q9P296	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	up-regulates quantity by expression													1847994	f		lperfetto	The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 	SIGNOR-263470	0.8
CSTF1	protein	Q05048	UNIPROT	CSTF complex	complex	SIGNOR-C441	SIGNOR	form complex	binding			9606									10669729	t		lperfetto	We therefore first identified regions of the CstF subunits, CstF-77, CstF-64, and CstF-50, required for interaction with each other. 	SIGNOR-268365	0.934
MAP3K7	protein	O43318	UNIPROT	NFKBIB	protein	Q15653	UNIPROT	down-regulates	phosphorylation			9606									9480845	t		gcesareni	Overexpression oftak1together with its activator protein,tak1binding protein 1 (tab1), induced thenucleartranslocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene.	SIGNOR-55719	0.494
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DPB1	protein	P04440	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								11889043	f	 	 	Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment.	SIGNOR-254007	0.291
FIP1L1	protein	Q6UN15	UNIPROT	PAPOLA	protein	P51003	UNIPROT	up-regulates	binding			9606									14749727	t		miannu	Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna.	SIGNOR-121700	0.782
ARHGEF28	protein	Q8N1W1	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260546	0.745
GGCX	protein	P38435	UNIPROT	SMAD7	protein	O15105	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									31539109	f		miannu	GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05).	SIGNOR-261233	0.2
CSMD1	protein	Q96PZ7	UNIPROT	C3	protein	P01024	UNIPROT	down-regulates quantity	binding			9606									28345259	t		miannu	CUB and sushi multiple domains 1 (CSMD1) is a relatively poorly studied large transmembrane protein of 390 kDa composed of 14 N-terminal CUB domains interspersed with complement control protein (CCP) domains followed by 15 consecutive CCP domains. The active domains of CSMD1 were then identified in CCP17-21, which were shown to interact with C4b and C3b and present these complement proteins for degradation by factor	SIGNOR-265148	0.2
AURKB	protein	Q96GD4	UNIPROT	RACGAP1	protein	Q9H0H5	UNIPROT	up-regulates activity	phosphorylation	Thr186	KREKRRStSRQFVDG	9606	BTO:0000567								14744859	t		llicata	It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1	SIGNOR-250590	0.772
DUSP5	protein	Q16690	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606									15713638	t		fstefani	Here we demonstrate that dusp5, an inducible nuclear phosphatase, interacts specifically with erk2 via a kinase interaction motif (kim) within its amino-terminal noncatalytic domain. This binding determines the substrate specificity of dusp5 in vivo, as it inactivates erk2 but not jun n-terminal protein kinase or p38 map kinase.	SIGNOR-134049	0.773
PRKACA	protein	P17612	UNIPROT	LIPE	protein	Q05469	UNIPROT	up-regulates activity	phosphorylation	Ser853	IAEPMRRsVSEAALA	10090	BTO:0000944								11581251	t		lperfetto	HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme	SIGNOR-249202	0.585
P2RY6	protein	Q15077	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256947	0.2
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser221	PRTSPIMsPRTSLAE	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248687	0.613
SMARCA2	protein	P51531	UNIPROT	SWI/SNF ACTL6A-ARID1A-SMARCA2 variant	complex	SIGNOR-C470	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269817	0.829
MRPS5	protein	P82675	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261441	0.732
TRIM22	protein	Q8IYM9	UNIPROT	TRIM22	protein	Q8IYM9	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								18656448	t		miannu	 Importantly, TRIM22 was conjugated with poly-ubiquitin chains and stabilized by the proteasome inhibitor in 293T cells, suggesting that TRIM22 targeted itself for proteasomal degradation through the poly-ubiquitylation. We also found that TRIM22 was located in the nucleus, indicating that TRIM22 might function as a nuclear E3 ubiquitin ligase.	SIGNOR-271780	0.2
TGFBI	protein	Q15582	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates activity	binding												26387839	t		lperfetto	 BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers	SIGNOR-253269	0.341
BLK	protein	P51451	UNIPROT	CGAS	protein	Q8N884	UNIPROT	down-regulates activity	phosphorylation	Tyr215	LLNTGSYyEHVKISA										30356214	t		lperfetto	DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS.	SIGNOR-275844	0.2
IRF7	protein	Q92985	UNIPROT	IFNA1	protein	P01562	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16612387	f		gcesareni	Ikkalfa can also phosphorylate and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production.	SIGNOR-146119	0.56
RAB1A	protein	P62820	UNIPROT	ULK1/Atg13/Fip200	complex	SIGNOR-C100	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								27334615	t		Giulio	Thus, these data show ULK1–Rab1a interaction in intact cells and reveal that this interaction is C9orf72 dependent.	SIGNOR-261283	0.382
MAPK8	protein	P45983	UNIPROT	PIN1	protein	Q13526	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser115	SQFSDCSsAKARGDL	9606	BTO:0002932								34048060	t		miannu	Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation.	SIGNOR-277562	0.276
TMED10	protein	P49755	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates	binding			9606									16641999	t		gcesareni	Here we report that tmp21, a member of the p24 cargo protein family, is a component of presenilin complexes and differentially regulates gamma-secretase cleavage	SIGNOR-146364	0.639
MAP3K5	protein	Q99683	UNIPROT	MAP2K3	protein	P46734	UNIPROT	up-regulates activity	phosphorylation			9534	BTO:0004055								8974401	t		lperfetto	ASK1 activated SEK1 and MKK3 up to 7.0- and 11.8-fold, respectively	SIGNOR-226672	0.582
ABT-737	chemical	CID:11228183	PUBCHEM	BCL2L1	protein	Q07817	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	The effect has been demonstrated using Q07817-1	gcesareni		SIGNOR-189171	0.8
fentanyl	chemical	CHEBI:119915	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258937	0.8
PPARGC1A	protein	Q9UBK2	UNIPROT	SOD2	protein	P04179	UNIPROT	up-regulates				10090									18074631	f		lperfetto	In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat.	SIGNOR-253395	0.383
COX5A	protein	P20674	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267751	0.796
tetra-mu3-sulfido-tetrairon	chemical	CHEBI:49883	ChEBI	BRCA1-B complex	complex	SIGNOR-C298	SIGNOR	form complex	binding												25400280	t		lperfetto	Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation	SIGNOR-269475	0.8
WNK1	protein	Q9H4A3	UNIPROT	STK39	protein	Q9UEW8	UNIPROT	up-regulates	phosphorylation	Thr231	TRNKVRKtFVGTPCW	9606	BTO:0000007	BTO:0000671							16083423	t		gcesareni	Phosphorylation by WNK1 or WNK4 markedly increased SPAK and OSR1 activity. Phosphopeptide mapping studies demonstrated that WNK1 phosphorylated kinase-inactive SPAK and OSR1 at an equivalent residue located within the T-loop of the catalytic domain (Thr233 in SPAK, Thr185 in OSR1) and a serine residue located within a C-terminal non-catalytic region (Ser373 in SPAK, Ser325 in OSR1)	SIGNOR-160846	0.457
PRKCB	protein	P05771	UNIPROT	PTPN11	protein	Q06124	UNIPROT	unknown	phosphorylation	Ser595	GLMQQQKsFR	9606									11781100	t		lperfetto	 In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta.	SIGNOR-249139	0.336
TNFSF13	protein	O75888	UNIPROT	TNFRSF17	protein	Q02223	UNIPROT	up-regulates	binding			9606	BTO:0000782								10973284	t		gcesareni	April is involved in stimulation of b and t cell function. April functions via binding to bcma and taci and competes with tall-i for receptor binding.	SIGNOR-81386	0.674
FOXO1	protein	Q12778	UNIPROT	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									16308421	f	inferred from family member	gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-267787	0.327
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PRKAA1	protein	Q13131	UNIPROT	down-regulates activity	phosphorylation			-1									16340011	t		gcesareni	It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase.	SIGNOR-252740	0.2
NUAK1	protein	O60285	UNIPROT	CASP6	protein	P55212	UNIPROT	down-regulates activity	phosphorylation	Ser257	TLVNRKVsQRRVDFC	-1									15273717	t		miannu	ARK5 negatively regulates procaspase-6 by phosphorylation at Ser257, leading to resistance to the FasL/Fas system.	SIGNOR-250209	0.497
STK3	protein	Q13188	UNIPROT	MOB1A	protein	Q9H8S9	UNIPROT	up-regulates	phosphorylation	Thr74	QINMLYGtITEFCTE	9606	BTO:0000007								18362890	t		gcesareni	These findings indicate that the phosphorylation of mob1 at thr74 by mst2 is essential to make a complex of mob1, mst2 and ndr1, and to fully activate ndr1	SIGNOR-177977	0.844
naloxone	chemical	CHEBI:7459	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258770	0.8
ARHGEF11	protein	O15085	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260538	0.899
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2Z	protein	Q9H832	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271313	0.687
tRNA(Asn)	smallmolecule	CHEBI:29172	ChEBI	Asn-tRNA(Asn)	smallmolecule	CHEBI:29265	ChEBI	up-regulates quantity	precursor of			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270467	0.8
SOS1	protein	Q07889	UNIPROT	NRAS	protein	P01111	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000938								11560935	t		lperfetto	Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras	SIGNOR-110566	0.771
amitriptyline	chemical	CHEBI:2666	ChEBI	CHRM3	protein	P20309	UNIPROT	down-regulates activity	chemical inhibition			10029									8100134	t		miannu	Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 	SIGNOR-258702	0.8
MECP2	protein	P51608	UNIPROT	GRIA2	protein	P42262	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									22262897	t		Luana	Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A.	SIGNOR-264684	0.33
idarubicin	chemical	CHEBI:42068	ChEBI	TOP2B	protein	Q02880	UNIPROT	down-regulates activity	chemical inhibition			9606									20824055	t		miannu	Topoisomerase II (Top2) is a nuclear enzyme involved in several metabolic processes of DNA. Chemotherapy agents that poison Top2 are known to induce persistent protein-mediated DNA double strand breaks (DSB). In this report, by using knock down experiments, we demonstrated that Top2α was largely responsible for the induction of γH2AX and cytotoxicity by the Top2 poisons idarubicin and etoposide in normal human cells. 	SIGNOR-259328	0.8
YY1	protein	P25490	UNIPROT	Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	up-regulates quantity by expression													17158804	t			YY1 REPO domain is necessary and sufficient for PcG transcriptional repression, Polycomb recruitment to DNA, and methylation of histone H3 on lysine 27	SIGNOR-253595	0.591
SP1	protein	P08047	UNIPROT	CDKN2B	protein	P42772	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11013220	f		irozzo	In this system, the basal transcription level from the p15Ink4B promoter was increased with increasing levels of Sp1, and Sp1 was required for transcriptional induction by Smads. Finally, inactivation of the Sp1 binding sites in the p15Ink4B promoter decreased the basal transcription level and TGF-β responsiveness.	SIGNOR-256289	0.543
SRC	protein	P12931	UNIPROT	G6PD	protein	P11413	UNIPROT	up-regulates activity	phosphorylation	Tyr112	NSYVAGQyDDAASYQ	-1									33686238	t		miannu	Here, we show that tyrosine kinase c-Src interacts with and phosphorylates G6PD at Tyr 112. This phosphorylation enhances catalytic activity of G6PD by dramatically decreasing its Km value and increasing its Kcat value for substrate glucose-6-phosphate.	SIGNOR-277550	0.278
ARP2/3	complex	SIGNOR-C146	SIGNOR	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates quantity	binding			9606	BTO:0000132								27871158	t		lperfetto	The Arp2/3 complex stimulates the assembly of actin filaments.	SIGNOR-261838	0.7
CDK1	protein	P06493	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Ser138	SLQLGAVsPGTLTPT										26933062	t		lperfetto	Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis.	SIGNOR-276589	0.437
IRF4	protein	Q15306	UNIPROT	IRF5	protein	Q13568	UNIPROT	down-regulates activity				9606	BTO:0000801								22378047	t		lperfetto	IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization.	SIGNOR-249560	0.433
CAPN1	protein	P07384	UNIPROT	CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	up-regulates activity	cleavage			9606	BTO:0000590								25969760	t		lperfetto	Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain	SIGNOR-251581	0.559
CSNK2A2	protein	P19784	UNIPROT	HSPH1	protein	Q92598	UNIPROT	down-regulates activity	phosphorylation	Ser509	PTEENEMsSEADMEC	-1									12558502	t		llicata	Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. | the phosphorylation of Hsp105 alpha at Ser(509) abolished the inhibitory activity of Hsp105 alpha in vitro.	SIGNOR-251008	0.332
SMAD6	protein	O43541	UNIPROT	TBX6	protein	O95947	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								19561075	t		miannu	Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase.	SIGNOR-272785	0.332
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation			9606									20630875	t	inferred from 70% family members	gcesareni	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress.	SIGNOR-269982	0.2
BTC	protein	P35070	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606									10209155	t		gcesareni	For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4	SIGNOR-67006	0.713
DAPK3	protein	O43293	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser166	SSRRRAIsETEENSD	9606									15001356	t		gcesareni	Zip kinase was able to phosphorylate mdm2 at ser166, a site previously reported to be modified by akt kinase, thus demonstrating that zip kinase is a bona fide mdm2-binding protein.	SIGNOR-123159	0.348
luminespib	chemical	CHEBI:83656	ChEBI	HSP90AB1	protein	P08238	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190041	0.8
SBDS	protein	Q9Y3A5	UNIPROT	EFL1	protein	Q7Z2Z2	UNIPROT	up-regulates	binding			9606	BTO:0001271								21536732	t		miannu	Sbds stimulates 60s-dependent gtp hydrolysis by efl1	SIGNOR-173533	0.2
FYN	protein	P06241	UNIPROT	JUP	protein	P14923	UNIPROT	up-regulates activity	phosphorylation	Tyr550	AAGTQQPyTDGVRME	10116									14517306	t			Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549 and that it phosphorylated Tyr133 with a much lower activity 	SIGNOR-251176	0.541
Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	PPARG	protein	P37231	UNIPROT	up-regulates				9606									29369787	t		miannu	Omega 3 fatty acids and fibrates are considered as natural and pharmacological ligands of PPARα, respectively, that reduce inflammation and arteriosclerosis in cardiovascular system	SIGNOR-256189	0.7
RBPJ	protein	Q06330	UNIPROT	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression	binding			9606	BTO:0000938								10520600	t		gcesareni	These results indicate that the two Hes genes are essential effectors for the Notch pathway and that neuronal differentiation is controlled by the pathway Notch-Hes1/Hes5-|Mash1.	SIGNOR-71168	0.584
canertinib	chemical	CHEBI:61399	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258200	0.8
PTPN12	protein	Q05209	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates activity	dephosphorylation	Tyr393	RLMTGDTyTAHAGAK	9534	BTO:0004055								11163214	t		lperfetto	Several experiments suggest that the pest-type ptps negatively regulate c-abl activity: c-abl was hyperphosphorylated in ptp-pest-deficient cells dephosphorylation of c-abl by pest-type ptp represents a novel mechanism by which c-abl activity is regulated.	SIGNOR-235568	0.449
2-acyl-sn-glycero-3-phospho-D-myo-inositol	smallmolecule	CHEBI:62746	ChEBI	1-phosphatidyl-1D-myo-inositol	smallmolecule	CHEBI:16749	ChEBI	up-regulates quantity	precursor of			-1									18772128	t		miannu	The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils.	SIGNOR-267245	0.8
CSNK1A1	protein	P48729	UNIPROT	FOXG1	protein	P55316	UNIPROT	up-regulates	phosphorylation	Ser19	MIPKSSFsINSLVPE	9606	BTO:0000938	BTO:0000142							17435750	t		llicata	Cki phosphorylation of ser 19 of foxg1 promotes nuclear import	SIGNOR-154386	0.2
MAPK9	protein	P45984	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Ser307	TRRSRTEsITATSPA	9606									14579029	t		gcesareni	Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632	SIGNOR-118881	0.698
DYRK1A	protein	Q13627	UNIPROT	MEF2D	protein	Q14814	UNIPROT	down-regulates activity	phosphorylation	Ser251	NKVIPAKsPPPPTHS	-1									34109727	t		miannu	Here, we uncovered that dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), a kinase critical in Down's syndrome pathogenesis, directly bound to and phosphorylated MEF2D at Ser251 in vitro. Phosphorylation of MEF2D by DYRK1A significantly increased MEF2D protein level but attenuated its transcriptional activity, which resulted in decreased transcriptions of MEF2D target genes.	SIGNOR-277565	0.421
ULK1	protein	O75385	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser227	VQQNMMNsASGPLPD	9606	BTO:0003491								34345207	t		miannu	Mechanistically, hypoxia stimulates ULK1 to translocate into nucleus, where it interacts with and phosphorylates yes-associated protein (YAP) at Ser227, resulting in YAP stabilization through blockade of ubiquitin-proteasome system (UPS), which in turn facilitates PKM2 transcription, glycolysis, cell proliferation in vitro as well as PDAC growth in mice.	SIGNOR-277570	0.2
S1PR3	protein	Q99500	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256933	0.2
IFI30	protein	P13284	UNIPROT	oligopeptide	smallmolecule	CHEBI:25676	ChEBI	down-regulates quantity	chemical modification			9606									31810556	t		scontino	Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol.	SIGNOR-267865	0.8
BRAF	protein	P15056	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity				9606									21900390	f		miannu	RAF, a cytoplasmic serine-threonine protein kinase, is a member of the RAS-RAF-MEK-ERK cell-signaling pathway [also known as the MAP kinase (MAPK) pathway], and it plays an essential role in mediating cellular differentiation, proliferation, senescence, and survival in response to extracellular cues. Raf phosphorylates and activates MAP-ERK kinase (MEK), which phosphorylates and activates extracellular signal-regulated kinase (ERK).	SIGNOR-260082	0.645
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	SLC25A13	protein	Q9UJS0	UNIPROT	up-regulates activity	chemical activation			9606									12084073	t		miannu	Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. 	SIGNOR-265153	0.8
CSNK1D	protein	P48730	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	phosphorylation	Ser400	SRDESTDsGLSMSSY	9606							phosphorylation:Ser127	PQHVRAHsSPASLQL 	24715453	t		milica	LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)	SIGNOR-230738	0.4
GSK3B	protein	P49841	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr66	NVNTKCItIPRSLDG	9606									18172167	t		lpetrilli	Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation.	SIGNOR-160318	0.502
SRC	protein	P12931	UNIPROT	PRKAA2	protein	P54646	UNIPROT	down-regulates activity	phosphorylation	Tyr179	TSCGSPNyAAPEVIS	9606	BTO:0002181								34673141	t		miannu	We show here that Src signaling leads to direct phosphorylation of the AMPK-α subunit on a novel site, tyrosine 179, resulting in suppression of AMPK-T172 phosphorylation and autophagy upon integrin-mediated cell adhesion.	SIGNOR-277573	0.26
PIM1	protein	P11309	UNIPROT	YWHAZ	protein	P63104	UNIPROT	up-regulates activity	phosphorylation	Ser64	SSWRVVSsIEQKTEG	9606	BTO:0001321								34697370	t		miannu	PIM1 phosphorylates the AR and 14-3-3 ζ and coordinates their interaction. PIM1 phosphorylation of the AR and 14-3-3 ζ enhances their interaction and shifts their occupancy on chromatin, resulting in 14-3-3 ζ co-regulation of AR, likely by recruiting other AR co-regulators such as hnRNPK and TRIM28. 	SIGNOR-277574	0.315
AKT1	protein	P31749	UNIPROT	HSF1	protein	Q00613	UNIPROT	up-regulates activity	phosphorylation	Thr527	PPKAKDPtVS	-1									35080342	t		miannu	Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9.	SIGNOR-277578	0.416
MAPK3	protein	P27361	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	up-regulates	phosphorylation	Ser227	DHEKKAYsFCGTVEY	9606									10980595	t		llicata	We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway	SIGNOR-81460	0.717
RTF1	protein	Q92541	UNIPROT	PAF1C	complex	SIGNOR-C471	SIGNOR	form complex	binding			9606	BTO:0000567								20178742	t		miannu	Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A). 	SIGNOR-269835	0.883
AKT1	protein	P31749	UNIPROT	HSF1	protein	Q00613	UNIPROT	up-regulates activity	phosphorylation	Thr142	DSVTKLLtDVQLMKG	-1									35080342	t		miannu	Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9.	SIGNOR-277579	0.416
PTPRR	protein	Q15256	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606	BTO:0001616								17360477	t			Here, we report identification of signal transducer and activator of transcription 3 (STAT3) as a substrate of PTPRT. Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position.	SIGNOR-248719	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	Chemoattraction_of_axon	phenotype	SIGNOR-PH197	SIGNOR	up-regulates				9606									15363394	f		miannu	In this study, we have identified CaMKII and CaN-PP1 as the downstream effectors of localized Ca2+ signals in mediating attractive and repulsive turning responses of growth cones, respectively. Local Ca2+ elevation activates CaMKII and CaN-PP1 for attraction and repulsion, respectively.	SIGNOR-268385	0.7
DDHD2	protein	O94830	UNIPROT	phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	down-regulates quantity	chemical modification			9606									22922100	t		miannu	Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 	SIGNOR-269649	0.8
INSR	protein	P06213	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	phosphorylation	Tyr1229	SSEDLSAyASISFQK	9606	BTO:0000443								12220227	t		lperfetto	Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions.	SIGNOR-235983	0.911
hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	GABA-A (a6-b3-d) receptor	complex	SIGNOR-C329	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000938								26136660	t		miannu	The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 	SIGNOR-264929	0.8
CSNK2A1	protein	P68400	UNIPROT	HMGN1	protein	P05114	UNIPROT	down-regulates	phosphorylation	Ser99	AGEKEAKsD	9606									10739259	t		lperfetto	Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.	SIGNOR-76278	0.2
STAT5A	protein	P42229	UNIPROT	DNMT3A	protein	Q9Y6K1	UNIPROT	up-regulates quantity	transcriptional regulation			9606									26059451	t			… these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells	SIGNOR-255631	0.332
KAT2A	protein	Q92830	UNIPROT	H3-4	protein	Q16695	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269596	0.2
AKT1	protein	P31749	UNIPROT	HSF1	protein	Q00613	UNIPROT	up-regulates activity	phosphorylation	Ser230	PKYSRQFsLEHVHGS	-1									35080342	t		miannu	Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9.	SIGNOR-277580	0.416
AKT1	protein	P31749	UNIPROT	HSF1	protein	Q00613	UNIPROT	up-regulates activity	phosphorylation	Ser326	SSVDTLLsPTALIDS	-1									35080342	t		miannu	Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9.	SIGNOR-277581	0.416
PAK4	protein	O96013	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr369	ESSSYGDtLLGLSDS	10090	BTO:0000575								35108418	t		miannu	PAK4 directly phosphorylated Nrf2 at T369, and it led to its nuclear export and proteasomal degradation, all of which impaired antioxidant responses in hepatocytes.	SIGNOR-277583	0.2
MAPK3	protein	P27361	UNIPROT	EPAS1	protein	Q99814	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser484	SSCSTPNsPEDYYTS	9606	BTO:0006155								35191554	t		miannu	The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells. 	SIGNOR-277584	0.263
ATR	protein	Q13535	UNIPROT	FANCA	protein	O15360	UNIPROT	up-regulates	phosphorylation	Ser1449	AAPDADLsQEPHLF	9606									19109555	t		lperfetto	The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site	SIGNOR-182953	0.58
PRKCA	protein	P17252	UNIPROT	PLD1	protein	Q13393	UNIPROT	up-regulates	phosphorylation	Ser2	sLKNEPRV	9606									10441128	t		gcesareni	Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells.	SIGNOR-69930	0.703
CDC14A	protein	Q9UNH5	UNIPROT	CDC25B	protein	P30305	UNIPROT	down-regulates activity	dephosphorylation			9606									20956543	t		lperfetto	Cdc14A inhibits Cdc25A and Cdc25B activity, the latter through direct binding and dephosphorylation ( ).|Together, these data indicate that Cdc14A dephosphorylates Cdc25B, inhibiting its catalytic activity.	SIGNOR-276968	0.577
ATM	protein	Q13315	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser31	ALRLLDSsQIVIISA	10090									11459832	t		lperfetto	Selective induction of e2f1 in response to dna damage, mediated by atm-dependent phosphorylation. We identify a site for atm/atr phosphorylation in the amino terminus of e2f1 and we show that this site is required for atm-mediated stabilization of e2f1. Finally, we also show that e2f1 is required for dna damaged induced apoptosis in mouse thymocytes.	SIGNOR-109416	0.667
CSNK2A1	protein	P68400	UNIPROT	DAXX	protein	Q9UER7	UNIPROT	up-regulates	phosphorylation	Ser739	EIIVLSDsD	9606									21474068	t		lperfetto	Daxx-sim is phosphorylated by ck2 kinase at residues s737 and s739. Phosphorylation promotes daxx-sim binding affinity toward sumo-1 over sumo-2/3, causing daxx preference for sumo-1 conjugation and interaction with sumo-1-modified factors.	SIGNOR-173109	0.332
GCHFR	protein	P30047	UNIPROT	GCH1	protein	P30793	UNIPROT	down-regulates activity	binding			9606									11361142	t		miannu	The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine	SIGNOR-252203	0.859
β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35.	SIGNOR-266465	0.8
FYN	protein	P06241	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation	Tyr427	ELFDDPSyVNVQNLD	9606	BTO:0000782								9710204	t		lperfetto	Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2.	SIGNOR-59631	0.721
MLL Fusion	fusion protein	SIGNOR-FP14	SIGNOR	MECOM	protein	Q03112	UNIPROT	up-regulates quantity by expression	methylation			10090	BTO:0001271								22553314	t		miannu	We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia.	SIGNOR-260107	0.2
MAPK3	protein	P27361	UNIPROT	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation	Ser152	PASSVSSsPSPPFGH	9606									12050114	t		gcesareni	Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk	SIGNOR-88728	0.36
prostaglandin E2	smallmolecule	CHEBI:15551	ChEBI	AKT1	protein	P31749	UNIPROT	up-regulates	chemical activation			9606									16293724	t		gcesareni	Pge2 also stimulated akt activity in a pi3k-dependent manner.	SIGNOR-141817	0.8
AKT1	protein	P31749	UNIPROT	LTB4R2	protein	Q9NPC1	UNIPROT	unknown	phosphorylation	Thr324	GGRSREGtMELRTTP	9606									22044535	t		llicata	Blt2 phosphorylation at thr355 by akt is necessary for blt2-mediated chemotaxis.	SIGNOR-252516	0.39
ARNT	protein	P27540	UNIPROT	FOS	protein	P01100	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21544813	f	 	lperfetto	Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC	SIGNOR-253696	0.291
PRKACA	protein	P17612	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Ser146	RPSQRHGsKYLATAS	-1									2413024	t		miannu	Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161	SIGNOR-250011	0.352
SOX6	protein	P35712	UNIPROT	HBG1	protein	P69891	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004911								20395365	f	Regulation	miannu	BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors.	SIGNOR-251810	0.306
MAP2K4	protein	P45985	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates activity	phosphorylation			9534	BTO:0000298								7839144	t		Luana	Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase.	SIGNOR-260722	0.574
Adenylate_cyclase	proteinfamily	SIGNOR-PF92	SIGNOR	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates quantity	chemical modification			9606									11376933	t		miannu	To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis.	SIGNOR-267844	0.8
MTOR	protein	P42345	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	up-regulates	phosphorylation			9606									23486913	t	mTORC1 phosphorylation of EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation.	gcesareni	These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway.	SIGNOR-201541	0.831
ERG	protein	P11308	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25277175	f		miannu	Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3.	SIGNOR-251554	0.287
CALM3	protein	P0DP25	UNIPROT	KIF1A	protein	Q12756	UNIPROT	up-regulates activity	binding			10116	BTO:0003102								30021165	t		miannu	To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines. we can conclude that TANC2 and liprin-α are enriched in dendritic spines and interact with various synaptic proteins. TANC2 and Liprin-α2 Act as Immobile Postsynaptic Posts Able to Recruit KIF1A in a Subset of Dendritic Spines	SIGNOR-266890	0.273
MEGF10	protein	Q96KG7	UNIPROT	Phagocytosis	phenotype	SIGNOR-PH97	SIGNOR	up-regulates				9606									28526325	f		miannu	Our results indicate that MEGF10 may be responsible for phagocytic activity targeted toward unwanted substances such as amyloid in cholinergic and glutamatergic neurons.	SIGNOR-265166	0.7
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1654	SPSYSPTsPSYSPTS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248738	0.727
HNF1B	protein	P35680	UNIPROT	AFP	protein	P02771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								7549116	f		miannu	 HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter in the HepG2 cells. 	SIGNOR-254638	0.324
8-(4-dibenzothiophenyl)-2-(4-morpholinyl)-1-benzopyran-4-one	chemical	CHEBI:91361	ChEBI	PRKDC	protein	P78527	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194865	0.8
RXRA	protein	P19793	UNIPROT	RAR	proteinfamily	SIGNOR-PF45	SIGNOR	up-regulates	binding			9606									1310351	t	inferred from 70% of family members	gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-269850	0.711
Naltriben	chemical	CID:5486827	PUBCHEM	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258424	0.8
bromocriptine	chemical	CHEBI:3181	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258366	0.8
MYOD1	protein	P15172	UNIPROT	MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	form complex	binding			9606		BTO:0001103							17194702	t		miannu	Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes	SIGNOR-151682	0.38
AKT1	protein	P31749	UNIPROT	PHB2	protein	Q99623	UNIPROT	down-regulates	binding			10090									15173318	t		lperfetto	Akt binds prohibitin 2 and relieves its repression of myod and muscle differentiation	SIGNOR-252541	0.5
CDK5	protein	Q00535	UNIPROT	STMN3	protein	Q9NZ72	UNIPROT	unknown	phosphorylation	Ser73	PESPMLSsPPKKKDT	-1									22577147	t		lperfetto	Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta	SIGNOR-264894	0.329
PRKCG	protein	P05129	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Thr841	RSAFTTStVVRMHVG	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249289	0.425
HCRTR1	protein	O43613	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257404	0.252
MRPS12	protein	O15235	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261457	0.671
arecoline	chemical	CHEBI:2814	ChEBI	CHRM4	protein	P08173	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258638	0.8
MTOR	protein	P42345	UNIPROT	PRKN	protein	O60260	UNIPROT	down-regulates activity	phosphorylation	Ser127	AVILHTDsRKDSPPA	9606	BTO:0002181								35191952	t		miannu	MTOR phosphorylates PARK2 at Ser127 Through biochemical, mutational, and genetic studies, we identified PARK2 as a mTORC1 substrate. mTORC1 phosphorylates PARK2 at Ser127, which blocks its cellular ubiquitination activity, thereby hindering its tumor suppressor effect on eIF4B's stability.	SIGNOR-277586	0.2
MAPK8	protein	P45983	UNIPROT	LAT	protein	O43561	UNIPROT	down-regulates	phosphorylation	Thr184	PSAPALStPGIRDSA	9606									15192708	t	The effect has been demonstrated using Q43561-2	gcesareni	Lat, an adapter protein essential for t-cell signaling, is phosphorylated at its thr 155 by erk in response to t-cell receptor stimulation. Thr 155 phosphorylation reduces the ability of lat to recruit plcgamma1 and slp76, leading to attenuation of subsequent downstream events such as [ca2+]i mobilization and activation of the erk pathway.Mutational analysis revealed that t155 but not t94 or t140 is the site of jnk-mediated phosphorylation (figure 2b). Erk also phosphorylated lat at t155 (figure 2c), whereas p38, which was able to phosphorylate atf2, failed to induce threonine phosphorylation of lat (figure 2d). These results indicate that lat is directly phosphorylated by erk and jnk at the same site, t155.	SIGNOR-125774	0.314
MAPK3	protein	P27361	UNIPROT	HDAC6	protein	Q9UBN7	UNIPROT	up-regulates	phosphorylation	Ser1035	DHQTPPTsPVQGTTP	9606									24089523	t		lperfetto	Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1	SIGNOR-202698	0.437
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SYN3	protein	O14994	UNIPROT	down-regulates activity	phosphorylation			9606									10571231	t		miannu	 Synapsins are exclusively localized to synaptic vesicles, which they coat as peripheral membrane proteins; they probably constitute one of the most abundant neuronal PKA substrates. Our study reveals an unexpectedly dynamic state of synapsins in nerve terminals: any changes in PKA or CaM Kinase I activity will modulate the amount of synapsin on synaptic vesicles. PKA Activation Triggers Synapsin Dissociation	SIGNOR-264110	0.2
ROBO3	protein	Q96MS0	UNIPROT	CFL1	protein	P23528	UNIPROT	up-regulates quantity by expression	post transcriptional regulation			-1									16226035	t		miannu	Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation.	SIGNOR-268379	0.2
ADORA1	protein	P30542	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257092	0.34
MAPK3	protein	P27361	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser235	MELLNEKsPSSQETH	-1									35216969	t		miannu	Screening the DEPTOR interactome identified that the association of USP-7 deubiquitinase with DEPTOR was dependent upon S235 phosphorylation. Inhibition of USP-7 activity resulted in DEPTOR polyubiquitination and degradation. A scansite search suggested that ERK1 may be responsible for S235 phosphorylation, which was confirmed through the use of inhibitors, ERK1 knockdown, and an in vitro kinase assay.	SIGNOR-277587	0.286
USP7	protein	Q93009	UNIPROT	DEPTOR	protein	Q8TB45	UNIPROT	up-regulates quantity by stabilization	deubiquitination			-1									35216969	t		miannu	Screening the DEPTOR interactome identified that the association of USP-7 deubiquitinase with DEPTOR was dependent upon S235 phosphorylation. Inhibition of USP-7 activity resulted in DEPTOR polyubiquitination and degradation. A scansite search suggested that ERK1 may be responsible for S235 phosphorylation, which was confirmed through the use of inhibitors, ERK1 knockdown, and an in vitro kinase assay.	SIGNOR-277588	0.2
BUB1B	protein	O60566	UNIPROT	MCC	complex	SIGNOR-C382	SIGNOR	form complex	binding			9606	BTO:0000567								25092294	t		miannu	The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. 	SIGNOR-265974	0.978
CDK5RAP2	protein	Q96SN8	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr743	VEVDAAVtPEERHLS	9606									15178331	t		Manara	The APPcyt is phosphorylated at Thr668 in vivo specifically in the brain. Cyclin‐dependent kinase 5 (Cdk5), a unique member of the Cdk family that is implicated in central nervous system development, participates in this phosphorylation. | In the present study, we demonstrate that APP phosphorylated at Thr668 is less vulnerable to cytoplasmic cleavage by caspase-3 and caspase-8.	SIGNOR-260818	0.2
SHH	protein	Q15465	UNIPROT	SMO	protein	Q99835	UNIPROT	up-regulates activity				10090									16885213	f		lperfetto	Binding of Hh to Ptch relieves the repression of Smo, allowing Smo to signal.	SIGNOR-148481	0.74
DPYD	protein	Q12882	UNIPROT	5-fluorouracil	chemical	CHEBI:46345	ChEBI	down-regulates quantity	chemical modification			9606									10499634	t		miannu	Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil.	SIGNOR-253987	0.8
LY96	protein	Q9Y6Y9	UNIPROT	HMGB1	protein	P09429	UNIPROT	up-regulates activity	binding			10090	BTO:0000801								25559892	t		gcesareni	Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2-deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling.	SIGNOR-252058	0.615
GADD45A	protein	P24522	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	binding			9606	BTO:0000782								15735649	t		gcesareni	Both phosphorylation of p38 ty323 and the activity of this phosphorylated species are inhibited by binding gadd45alpha, thus preventing these low-treshold signals from activating p38	SIGNOR-134333	0.474
KIF2B	protein	Q8N4N8	UNIPROT	Minus-end directed microtubule movement	phenotype	SIGNOR-PH217	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272534	0.7
leucine	smallmolecule	CHEBI:25017	ChEBI	Glutaminolysis	phenotype	SIGNOR-PH119	SIGNOR	up-regulates activity				9606	BTO:0000567								22749528	f		Luana	Leucine and Glutamine Activate Glutaminolysis and mTORC1	SIGNOR-268011	0.7
UTS2R	protein	Q9UKP6	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257252	0.268
cabazitaxel	chemical	CHEBI:63584	ChEBI	TUBB1	protein	Q9H4B7	UNIPROT	down-regulates activity	chemical inhibition			9606									21770474	t		miannu	Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization	SIGNOR-259341	0.8
PLK1	protein	P53350	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr197	ASTETYStPALLAPS	9606	BTO:0002181								35437307	t		miannu	We observed that PLK1 could significantly promote the ubiquitination and degradation of Smad4 wild type, Smad4 S171A, Smad4 S187A, Smad4 S191A, respectively, but PLK1-induced the ubiquitination and degradation of Smad4 T197A were obviously inhibited (Fig. 1M).	SIGNOR-277591	0.257
PRKAA1	protein	Q13131	UNIPROT	EGLN1	protein	Q9GZT9	UNIPROT	down-regulates activity	phosphorylation	Ser61	HKLVCQGsEGALGHG	9606	BTO:0000599								35538889	t		miannu	Mechanistically, AMPKα1 directly phosphorylated prolyl hydroxylase domain-containing (PHD)2 at serines 61 and 136, which suppressed PHD2-dependent hydroxylation of hypoxia-inducible factor (HIF)1α and subsequent regulation of hepatic hepcidin-related iron signalling.	SIGNOR-277592	0.382
PRKAA1	protein	Q13131	UNIPROT	EGLN1	protein	Q9GZT9	UNIPROT	down-regulates activity	phosphorylation	Ser136	AAAGGQGsAVAAEAE	9606	BTO:0000599								35538889	t		miannu	Mechanistically, AMPKα1 directly phosphorylated prolyl hydroxylase domain-containing (PHD)2 at serines 61 and 136, which suppressed PHD2-dependent hydroxylation of hypoxia-inducible factor (HIF)1α and subsequent regulation of hepatic hepcidin-related iron signalling.	SIGNOR-277593	0.382
MAPK3	protein	P27361	UNIPROT	NOXA1	protein	Q86UR1	UNIPROT	down-regulates	phosphorylation	Ser282	VGKQAPLsPGLPAMG	9606									20230789	t		lperfetto	Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity	SIGNOR-164231	0.271
2-oxoglutaric acid	smallmolecule	CHEBI:30915	ChEBI	OXGR1	protein	Q96P68	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257555	0.8
TFEB	protein	P19484	UNIPROT	GUSB	protein	P08236	UNIPROT	up-regulates quantity by expression	transcriptional regulation												28552616	t		lperfetto	Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants	SIGNOR-276553	0.252
SRC	protein	P12931	UNIPROT	AREG	protein	P15514	UNIPROT	up-regulates	cleavage			9606									17251915	t		lperfetto	Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network.	SIGNOR-236537	0.353
SRF	protein	P11831	UNIPROT	PLG	protein	P00747	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15514113	f		miannu	 We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1. 	SIGNOR-255226	0.249
SRC	protein	P12931	UNIPROT	CAPN2	protein	P17655	UNIPROT	up-regulates activity	phosphorylation	Tyr625	RSGTMNSyEMRKALE	-1									35697802	t		miannu	CAPN2 itself was a bone fide substrate of SRC that was primarily phosphorylated at Y625 by SRC and exhibited increased proteolysis activity upon phosphorylation.	SIGNOR-277598	0.505
MAPK14	protein	Q16539	UNIPROT	JDP2	protein	Q8WYK2	UNIPROT	unknown	phosphorylation	Thr148	VRTDSVKtPESEGNP	-1									12225289	t		miannu	Wild-type JDP2 exhibited efficient phosphorylation by the p38 kinase, the mutant JDP2 T%)A did not incorporate labelled Figure 5 JDP2 C-terminal domain is necessary but not sufficient for p38 phosphorylation (A) p38 phosphorylated JDP2 at Thr-148. Bacterially purified His-JDP2 (Wt) or His-JDP2 T148A (Ala) were incubated with bacterially purified activated p38 F327S [21] in the presence of [γ- 32P]ATP for 30 min. Proteins were resolved by SDS/PAGE (12 % gel), dried and exposed to autoradiography. (B) The JDP2 C-terminal domain is necessary but not sufficient for phosphorylation by p38 kinase. Bacterially purified GST fusion proteins with full-length JDP2 (Wt) C-terminally truncated JDP2 (∆C) and JDP2 C-terminal fragment (Dock) were used in an in vitro kinase assay as described in (A). A representative experiment is presented. (C) In vitro kinase assay using GST-JDP2 (JDP2wt), JDP2 ∆C and JDP2-Dock as substrates with either activated p38 or HA-JNK2 kinases. Protein mixtures were resolved by SDS/PAGE, fixed, dried and analysed by PhosphorImaging. The results represent meansS.E.M. from three independent experiments. phosphate in the presence of activated p38 kinase. This indicates that both p38 and JNK kinases are able to integrate stress signals to JDP2 Thr-148	SIGNOR-250100	0.388
PRKAA1	protein	Q13131	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	phosphorylation	Thr495	TGITRKKtFKEVANA	9606									24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251619	0.288
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	BCL2L11	protein	O43521	UNIPROT	up-regulates	phosphorylation	Ser104	FSFDTDRsPAPMSCD	9606									12591950	t		lperfetto	Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58)	SIGNOR-98384	0.2
IQGAP1	protein	P46940	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	binding												15695813	t		lperfetto	Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton. 	SIGNOR-261889	0.703
SRC	protein	P12931	UNIPROT	KCND3	protein	Q9UK17	UNIPROT	up-regulates activity	phosphorylation	Tyr108	GKLHYPRyECISAYD	9606	BTO:0000007								22198508	t		miannu	 These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels.	SIGNOR-276393	0.343
BID	protein	P55957	UNIPROT	CYCS	protein	P99999	UNIPROT	up-regulates activity				9606									9727492	f	Translocation from Mitochondria to Cytosol	lperfetto	TBID induces first the clustering of mitochondria around the nuclei and release of cytochrome c.	SIGNOR-59224	0.575
budesonide	chemical	CHEBI:3207	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									6958488	t	nasal polyposys	gcesareni		SIGNOR-251688	0.8
PRKD1	protein	Q15139	UNIPROT	KCNH2	protein	Q12809	UNIPROT	down-regulates activity	phosphorylation	Ser284	ASVRRASsADDIEAM	9606	BTO:0000007								29949809	t		miannu	Based on LC-MS results from in vivo and HEK293 cell experiments we chose four KV11.1 mutant candidates for further functional analysis. Ablation of the putative PKD phosphorylation site in the mutant S284A increased the maximal current indicating S284 as a main PKD target in KV11.1.	SIGNOR-277612	0.2
CyclinD1/CDK6	complex	SIGNOR-C143	SIGNOR	NDEL1	protein	Q9GZM8	UNIPROT	up-regulates activity	phosphorylation	Thr245	GFGTSPLtPSARISA	10090	BTO:0000142								12796778	t		llicata	Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function.	SIGNOR-250652	0.2
DZIP3	protein	Q86Y13	UNIPROT	H2AC14	protein	Q99878	UNIPROT	up-regulates activity	monoubiquitination	Lys119	IQAVLLPkKTESHHK	9606	BTO:0000007								18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271762	0.2
HDAC4	protein	P56524	UNIPROT	HOXB13	protein	Q92826	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19013255	f	 	miannu	 Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers.	SIGNOR-254232	0.265
MAPK8	protein	P45983	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Thr81	APAPAAPtPAAPAPA	9606									12531896	t		gcesareni	Wr1065 activates the jnk (c-jun n-terminal kinase), decreases complex formation between p53 and inactive jnk, and phosphorylates p53 at thr-81, a known site of phosphorylation by jnk.	SIGNOR-97405	0.79
BMP4	protein	P12644	UNIPROT	BMP4	protein	P12644	UNIPROT	up-regulates	binding			9606									11178121	t		lperfetto	Bmps are dimeric proteins with a single inter-chain disulfide bond. The dimeric conformation is anabsolute requirement for the biological action and interaction with receptors	SIGNOR-236169	0.2
ATP2B2	protein	Q01814	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	down-regulates quantity	relocalization			9606									30535804	t		lperfetto	ATP2B2 encodes the PMCA2 Ca(2+) pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca(2+) from the stereocilia to the endolymph.	SIGNOR-262585	0.8
CDK2	protein	P24941	UNIPROT	MCM3AP	protein	O60318	UNIPROT	up-regulates activity	phosphorylation	Ser508	FWHRKKIsPNKKPFS	10090	BTO:0000776								11526238	t		miannu	 To study the inducible regulation of GANP DNA-primase during cell activation, we examined phosphorylation induced by various kinds of kinases.We observed that the cell cycle-associated kinase Cdks induced phosphorylation of GANP in vitro. Examination of immunoprecipitates of Cdk2 from B cells revealed phosphorylation of GANP-PD at a consensus sequence of Cdk phosphorylation at Ser502 (S/T-P-X-K/R) (Fig. ​(Fig.1C1C Left; ref. 22).	SIGNOR-262734	0.2
KCNH2	protein	Q12809	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606									35442831	t		miannu	One such mechanism is operant in colorectal cancer (CRC) cells. On integrin-dependent CRC cell adhesion, the Kv11.1/β1 integrin complex recruits the PI3K p85 subunit, which stimulates AKT phosphorylation and thus regulates autophagy 	SIGNOR-277613	0.2
ITGB1	protein	P05556	UNIPROT	KCNH2	protein	Q12809	UNIPROT	up-regulates activity	binding			9606									35442831	t		miannu	One such mechanism is operant in colorectal cancer (CRC) cells. On integrin-dependent CRC cell adhesion, the Kv11.1/β1 integrin complex recruits the PI3K p85 subunit, which stimulates AKT phosphorylation and thus regulates autophagy 	SIGNOR-277614	0.2
EGFR	protein	P00533	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606	BTO:0000093	BTO:0000150							26918608	t		lperfetto	P85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation.	SIGNOR-252671	0.773
KDM4B	protein	O94953	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23435229	f		miannu	KDM4B enzymatic activity is required to enhance AR transcriptional activity	SIGNOR-254541	0.336
CSNK1G2	protein	P78368	UNIPROT	IRS4	protein	O14654	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser859	KDAASKPsGEGSFSK	9606	BTO:0002181								30026872	t		miannu	IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP).	SIGNOR-277615	0.2
RPS6KA1	protein	Q15418	UNIPROT	VASP	protein	P50552	UNIPROT	down-regulates	phosphorylation	Thr278	LARRRKAtQVGEKTP	9606	BTO:0000551								21423205	t		lperfetto	Rsk1 phosphorylated vasp on t278, a site regulating its binding to actin.	SIGNOR-172899	0.462
RNF185	protein	Q96GF1	UNIPROT	DVL2	protein	O14641	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			10090	BTO:0001957								24727453	t		miannu	The E3 ligase RNF185 negatively regulates osteogenic differentiation by targeting Dvl2 for degradation. Overexpression of RNF185 decreases the exogenous and endogenous level of Dvl2, promotes the ubiquitination and degradation of Dvl2 	SIGNOR-272173	0.479
RPS6KB1	protein	P23443	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser15	FSLLRGPsWDPFRDW	9606									19593530	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	lperfetto	Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk.	SIGNOR-186951	0.315
G3BP1	protein	Q13283	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates activity	binding			9606	 BTO:0001938;BTO:0000567 								25784705	t		SARA	PKR directly interacts with G3BP1 through the NTF2-like and PXXP domains of G3BP1. The recruitment of inactive PKR to SGs through this interaction correlates with its activation	SIGNOR-260981	0.312
KDM4C	protein	Q9H3R0	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	demethylation	Lys37	APSTGGVkKPHRYRP	9606									29207681	t		miannu	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 	SIGNOR-263868	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000763;BTO:0000149							10197981	t	inferred from 70% family members	gcesareni	Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus	SIGNOR-270005	0.2
KRT14	protein	P02533	UNIPROT	TNFRSF1A	protein	P19438	UNIPROT	down-regulates activity	binding			9606									11684708	t	Regulation	miannu	 TRADD specifically bound K18 and K14, type I (acidic) keratins. it is possible that epidermal K14 may function as an inhibitor of TNF–TNFR1 signaling through an association with TRADD.	SIGNOR-251906	0.268
INS	protein	P01308	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity				9606									10358076	f		lperfetto	Insulin disrupts irs-dependent transactivation by fkhr, and phosphorylation of ser-256 by pkb is necessary and sufficient to mediate this effect.	SIGNOR-252952	0.495
beta-Funaltrexamine	chemical	CHEBI:81527	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029									9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258772	0.8
NPNT	protein	Q6UXI9	UNIPROT	A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	up-regulates activity	binding			10090									22613833	t		lperfetto	The loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1-dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome.	SIGNOR-253344	0.668
ZNF804A	protein	Q7Z570	UNIPROT	STAT2	protein	P52630	UNIPROT	up-regulates activity	binding			9606	BTO:0005397								34364876	t		miannu	Together these results indicate the formation of ZNF804A:STAT2 protein complex and its translocation from the cytoplasm into the nucleus upon IFN stimulation, suggesting that it may function as a signal transducer that activates IFN-mediated gene expression programs.	SIGNOR-269460	0.2
RAC1	protein	P63000	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates activity	binding			9606									22252525	t		gcesareni	The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor.	SIGNOR-195414	0.645
PTPRG	protein	P23470	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	dephosphorylation	Tyr1172	ISLDNPDyQQDFFPK	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254700	0.494
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1913	SPKYSPTsPTYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269376	0.718
FZD1	protein	Q9UP38	UNIPROT	DVL3	protein	Q92997	UNIPROT	up-regulates activity	binding			9606									23151663	t		areggio	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. 	SIGNOR-258953	0.643
CKM complex	complex	SIGNOR-C406	SIGNOR	SMAD1	protein	Q15797	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser214	PTSSDPGsPFQMPAD	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-273148	0.346
GDNF	protein	P39905	UNIPROT	BIN1	protein	O00499	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252178	0.2
CILK1	protein	Q9UPZ9	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates	phosphorylation	Thr908	LPSGRPGtTGPAGAQ	9606				SIGNOR-C3					22356909	t		gcesareni	Our findings demonstrate an important role for ick in modulating the activity of mtorc1 through phosphorylation of raptor thr-908 and thus implicate a potential signaling mechanism by which ick regulates cell proliferation and division.	SIGNOR-196198	0.2
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1651	SPTSPSYsPTSPSYS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248749	0.727
NXF1	protein	Q9UBU9	UNIPROT	mRNA-nucleus_export	phenotype	SIGNOR-PH127	SIGNOR	up-regulates				9606									28831067	f		lperfetto	SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1.	SIGNOR-263298	0.7
RPS6KA5	protein	O75582	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	unknown	phosphorylation	Ser750	RRKMKKTsTSTETRS	9606									15568999	t		lperfetto	Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known.	SIGNOR-131399	0.2
KAT2B	protein	Q92831	UNIPROT	H3-5	protein	Q6NXT2	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269617	0.2
EPAS1	protein	Q99814	UNIPROT	KDM4C	protein	Q9H3R0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271585	0.2
IRS4	protein	O14654	UNIPROT	SSH1	protein	Q8WYL5	UNIPROT	up-regulates activity	binding			9606	BTO:0002181								25100728	t		miannu	Insulin Receptor Substrate-4 Binds to Slingshot-1 Phosphatase and Promotes Cofilin Dephosphorylation. In addition, IRS4 co-localized with SSH1 in F-actin-rich membrane protrusions in insulin-stimulated cells, which suggests that the association of IRS4 with SSH1 contributes to localized activation of cofilin in membrane protrusions.	SIGNOR-277617	0.316
MAPK3	protein	P27361	UNIPROT	RPS6KA4	protein	O75676	UNIPROT	up-regulates	phosphorylation			9606									9792677	t		lperfetto	Rsk-b is a p38alphamapk substrate, and activated by p38alphamapk and, more weakly, by erk1	SIGNOR-60998	0.567
IKBKE	protein	Q14164	UNIPROT	FAF1	protein	Q9UNN5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser556	EREAIRLsLEQALPP	9606	BTO:0002181								30472208	t		miannu	Upon virus infection, the kinase IKKɛ directly phosphorylates FAF1 at Ser556 and triggers FAF1 de-aggregation. Moreover, Ser556 phosphorylation promotes FAF1 lysosomal degradation, consequently relieving FAF1-dependent suppression of MAVS.	SIGNOR-277618	0.287
ASXL3	protein	Q9C0F0	UNIPROT	CBX5	protein	P45973	UNIPROT	down-regulates activity	binding			9606	BTO:0000972								25450400	t		miannu	Here, we showed that ASXL3 interacts with HP1α and LSD1, leading to transcriptional repression. 	SIGNOR-266763	0.254
HUWE1	protein	Q7Z6Z7	UNIPROT	MCL1	protein	Q07820	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000093								28939105	t		miannu	 Mule was identified as Mcl-1 ubiquitin ligase E3 to promote Mcl-1 degradation via the proteasomal pathway [46]. We found that knockdown of Mule (Fig. 4C) but not β-TRCP or FBXW7 (data not shown) prevented Mcl-1 downregulation caused by PKCη depletion.	SIGNOR-261909	0.517
CTNNA2	protein	P26232	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	binding			9606									23431053	t	In keratinocytes, YAP strongly interacts with a-catenin, and this interaction is mediated by 14-3-3.	gcesareni	The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation.	SIGNOR-201245	0.335
POMC	protein	P01189	UNIPROT	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258409	0.637
AKT3	protein	Q9Y243	UNIPROT	ADAR	protein	P55265	UNIPROT	down-regulates activity	phosphorylation	Thr1033	RLGERLRtMSCSDKI	-1									31095429	t		miannu	AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively	SIGNOR-276191	0.2
AKT2	protein	P31751	UNIPROT	ADAR	protein	P55265	UNIPROT	down-regulates activity	phosphorylation	Thr1033	RLGERLRtMSCSDKI	-1									31095429	t		miannu	AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively	SIGNOR-276192	0.2
GSK1059615	chemical	CHEBI:71955	ChEBI	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192774	0.8
MAPKAPK2	protein	P49137	UNIPROT	AATF	protein	Q9NY61	UNIPROT	up-regulates	phosphorylation	Thr366	FTVYRNRtLQKWHDK	9606									22909821	t		lperfetto	Upon genotoxic stress, aatf is phosphorylated by the checkpoint kinase mk2. Phosphorylation results in the release of aatf from cytoplasmic mrlc3 and subsequent nuclear translocation where aatf binds to the puma, bax and bak promoter regions to repress p53-driven expression of these pro-apoptotic genes.	SIGNOR-191935	0.332
CXCL12	protein	P48061	UNIPROT	CXCR4	protein	P61073	UNIPROT	up-regulates	binding			9606									11859124	t		gcesareni	To study the role of the sdf-1/cxcr4-chemokine/receptor system as a regulator of vertebrate development, we isolated and characterized a cdna encoding sdf-1 of the lower vertebrate xenopus laevis (xsdf-1). Recombinant xsdf-1 was produced in insect cells, purified, and functionally characterized. Although xsdf-1 is only 64-66% identical with its mammalian counterparts, it is indistinguishable from human (h)sdf-1alpha in terms of activating both x. laevis cxcr4 and hcxcr4. Thus, both xsdf-1 and hsdf-1alpha promoted cxcr4-mediated activation of heterotrimeric g(i2) in a cell-free system and induced release of intracellular calcium ions in and chemotaxis of intact lymphoblastic cells.	SIGNOR-115029	0.803
ESR1	protein	P03372	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates	binding			9606	BTO:0000150								16169518	t		gcesareni	Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k.	SIGNOR-140470	0.612
6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide	chemical	CHEBI:92401	ChEBI	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258004	0.8
CDK2	protein	P24941	UNIPROT	ID2	protein	Q02363	UNIPROT	down-regulates	phosphorylation	Ser5	sPVRSVRK	9606			SIGNOR-C16						9029153	t		lperfetto	Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_	SIGNOR-46397	0.445
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser362	TLKNKTEsSLLAKLE	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276200	0.389
AURKA	protein	O14965	UNIPROT	DLGAP5	protein	Q15398	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser725	CLSSERMsLPLLAGG	9606	BTO:0000007								15987997	t		miannu	Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life.	SIGNOR-262650	0.741
PLAGL1	protein	Q9UM63	UNIPROT	ABCC6	protein	O95255	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007;BTO:0000599								18850323	f		miannu	We identified ABCC6 as a target gene for transcriptional induction by PLAG1 and PLAGL1, transcription factors from the PLAG family of cell cycle progression-related DNA-binding proteins. Both these factors are shown to bind to the same single consensus-binding element in the ABCC6 proximal promoter in cell lines of hepatic and renal origin by reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation. PLAG-mediated ABCC6 transactivation may play an important role in determining the level of tissue-specific expression of this gene. The described mechanism can also find potential application in therapeutic interventions in forms of PXE related to impaired ABCC6 expression.	SIGNOR-254926	0.378
EP300	protein	Q09472	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	acetylation	Lys373	SSHLKSKkGQSTSRH	9606	BTO:0000567								11070080	t		gcesareni	P300 acetylates and activates the tumor suppressor p53 after dna damage.	SIGNOR-84070	0.909
SU11274	chemical	CID:9549297	PUBCHEM	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207123	0.8
GPR119	protein	Q8TDV5	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256911	0.252
NuA4 complex	complex	SIGNOR-C459	SIGNOR	Histone H2A	proteinfamily	SIGNOR-PF70	SIGNOR	down-regulates activity	acetylation			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269287	0.2
LPAR1	protein	Q92633	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			10090	BTO:0000944								15856019	t		milica	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13.	SIGNOR-236985	0.432
MAPK1	protein	P28482	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates	phosphorylation			9606									10197981	t		lperfetto	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3	SIGNOR-66738	0.711
CDK8	protein	P49336	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Ser208	DAGSPNLsPNPMSPA	9606									19914161	t		lpetrilli	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161553	0.547
PPP2CB	protein	P62714	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	down-regulates activity	dephosphorylation	Thr309	TMKTFCGtPEYLAPE	9606									18160256	t			Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248612	0.472
IKBKE	protein	Q14164	UNIPROT	TANK	protein	Q92844	UNIPROT	down-regulates activity	phosphorylation	Ser409	VFPPSITsRGDFLRH	9534	BTO:0000298								10759890	t		miannu	IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex	SIGNOR-262721	0.734
CSF2	protein	P04141	UNIPROT	HBG2	protein	P69892	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001571								2479426	f	Regulation of expression	miannu	Granulocyte-macrophage colony-stimulating factor reactivates fetal hemoglobin synthesis in erythroblast clones from normal adults.	SIGNOR-251776	0.2
STYX	protein	Q8WUJ0	UNIPROT	FBXW7	protein	Q969H0	UNIPROT	down-regulates activity	binding			9606									28007894	t			STYX acts as a direct inhibitor of FBXW7, affecting the cellular levels of its substrates. Furthermore, we find that levels of STYX and FBXW7 are anti-correlated in breast cancer patients,	SIGNOR-251663	0.353
GRHL2	protein	Q6ISB3	UNIPROT	ZEB1	protein	P37275	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000150								23814079	f		miannu	 we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc finger enhancer-binding protein 1 (ZEB1), which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells. 	SIGNOR-255624	0.444
ITGB1	protein	P05556	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253172	0.749
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	PRKCA	protein	P17252	UNIPROT	up-regulates	chemical activation			9606									9651347	t		gcesareni	Our results indicate that ca2+ ions not only anchor the protein to membrane surfaces but also induce conformational changes resulting in pkc activation.	SIGNOR-58506	0.8
DPYSL5	protein	Q9BPU6	UNIPROT	MAP2	protein	P11137	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								25040932	t		lperfetto	The studies on CRMP5 function show that, by interacting with tubulin and MAP2, this protein inhibits neurite growth especially at the dendritic level and restricts the promotional effect of CRMP2 on axon and dendrite growth	SIGNOR-264836	0.2
TARBP2	protein	Q15633	UNIPROT	RISC(DICER1/AGO2/TARBP2)	complex	SIGNOR-C32	SIGNOR	form complex	binding			9606									16142218	t		lperfetto	Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si_ or mi_riscs in mammalian cells, but it may also facilitate the cleavage of pre_mirnas by dicer.	SIGNOR-140229	0.901
COL3A1	protein	P02461	UNIPROT	ADGRG1	protein	Q9Y653	UNIPROT	up-regulates activity	binding												22238662	t			Using the N-terminal fragment of GPR56 (GPR56(N)) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N), the ligand binding domain.	SIGNOR-253979	0.2
DNA polymerase delta 	complex	SIGNOR-C376	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates													24035200	f		lperfetto	Analysis of the subcellular localization of Pol subunits in response to UV indicates that Pol delta3 is present at sites of DNA damage long before repair is complete, so that Pol delta3 is the form of Pol activity that is likely involved in gap filling reactions during DNA repair	SIGNOR-265721	0.7
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGB7	protein	Q9Y5F8	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265711	0.2
FOXA1	protein	P55317	UNIPROT	NFIX	protein	Q14938	UNIPROT	up-regulates	binding			9606		BTO:0001129							24801505	t		miannu	Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex.	SIGNOR-205082	0.341
spermidine	smallmolecule	CHEBI:16610	ChEBI	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									14617280	f		apalma	Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism	SIGNOR-255553	0.7
PDX1	protein	P52945	UNIPROT	SLC2A2	protein	P11168	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11309388	t			In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1.	SIGNOR-255540	0.538
FGR	protein	P09769	UNIPROT	ACO2	protein	Q99798	UNIPROT	unknown	phosphorylation	Tyr71	TLSEKIVyGHLDDPA	-1									17997986	t		miannu	Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations.	SIGNOR-262871	0.2
TRIM27	protein	P14373	UNIPROT	ULK1	protein	O75385	UNIPROT	down-regulates quantity	ubiquitination			10090									35670107	t			STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination	SIGNOR-270349	0.2
AURKA	protein	O14965	UNIPROT	KIF4A	protein	O95239	UNIPROT	up-regulates activity	phosphorylation	Thr799	PPKLRRRtFSLTEVR	-1									31881080	t		miannu	We show that Aurora A phosphorylates the condensin I-dependent pool of KIF4A and thus actively promotes chromosome congression from the spindle poles to the metaphase plate. In vitro kinase assays showed that recombinant KIF4A can be phosphorylated by Aurora A and that this activity is inhibited by the specific Aurora A inhibitor MLN8537 (Fig. 7 C). 	SIGNOR-265993	0.429
RPL23	protein	P62829	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262477	0.802
AMPK	complex	SIGNOR-C15	SIGNOR	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation	Ser638	FDFPKTPsSQNLLAL	9606									19584320	t		lperfetto	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-216499	0.469
NRCAM	protein	Q92823	UNIPROT	ANK3	protein	Q12955	UNIPROT	up-regulates quantity	relocalization			10116		BTO:0000227							7961622	t		miannu	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266720	0.711
MAPK3	protein	P27361	UNIPROT	CAPN2	protein	P17655	UNIPROT	up-regulates	phosphorylation	Ser50	GTLFQDPsFPAIPSA	9606									14993287	t		lperfetto	Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo.	SIGNOR-123083	0.547
CKM complex	complex	SIGNOR-C406	SIGNOR	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Ser208	DAGSPNLsPNPMSPA	9606									19914161	t		lpetrilli	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-273151	0.421
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Sec)	smallmolecule	CHEBI:29264	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269495	0.8
long-chain fatty acyl-CoA(4-)	smallmolecule	CHEBI:83139	ChEBI	arachidonoyl-CoA	smallmolecule	CHEBI:15514	ChEBI	up-regulates quantity	precursor of			9606									15189125	t		miannu	Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity.	SIGNOR-267903	0.8
PRKCA	protein	P17252	UNIPROT	NCF4	protein	Q15080	UNIPROT	up-regulates activity	phosphorylation	Thr154	LRRLRPRtRKVKSVS	9606	BTO:0000776								34264265	t		miannu	In murine and guinea pig neutrophils, PKCδ is required for the phosphorylation of p40phox, a subunit of the NADPH oxidase complex (Li et al., 2016; Someya et al., 1999). In particular, it mediates phosphorylation of the threonine 154 (T154) residue of p40phox, a key regulatory step in the activation of the NADPH oxidase complex in peripheral neutrophils and B cells, in both mice and humans. In conclusion, the EBV-B cells of patients with PKCδ deficiency have impaired ROS production, associated with lower levels of phosphorylation of the cytosolic NADPH oxidase subunit p40phox by PKCδ.	SIGNOR-277628	0.2
MAPK8IP3	protein	Q9UPT6	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates	binding			9606									15767678	t		gcesareni	The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.	SIGNOR-134561	0.652
MITF	protein	O75030	UNIPROT	OCA2	protein	Q04671	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000847								22234890	f		miannu	 the SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species.In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression.	SIGNOR-254556	0.362
STAT3	protein	P40763	UNIPROT	IL10	protein	P22301	UNIPROT	up-regulates	transcriptional regulation			9606									28713870	f		svumbaca	These data argue that, in TH2 cells, STAT3 is required for T cell IL-10 production, which in turn reinforces its own expression	SIGNOR-256234	0.783
PLK1	protein	P53350	UNIPROT	FBXO5	protein	Q9UKT4	UNIPROT	down-regulates	phosphorylation			9606									16439210	t		gcesareni	We propose that the balance of evi5 and polo-like kinase activities determines the timely accumulation of emi1 and cyclin, ensuring mitotic fidelity.	SIGNOR-142949	0.774
PPM1B	protein	O75688	UNIPROT	CDK9	protein	P50750	UNIPROT	unknown	dephosphorylation	Thr186	NSQPNRYtNRVVTLW	9606									18829461	t		gcesareni	Taken together, our data indicate that PPM1A and to some extent PPM1B are important negative regulators of P-TEFb function	SIGNOR-181396	0.382
CDK1	protein	P06493	UNIPROT	EEF1D	protein	P29692	UNIPROT	unknown	phosphorylation	Ser133	APQTQHVsPMRQVEP	9606									12551973	t		gcesareni	The sequence flanking ser-133 of ef-1delta completely matches the consensus phosphorylation site for a cellular protein kinase, cdc2, and in vitro kinase assays revealed that purified cdc2 phosphorylates ser-133 of ef-1delta.	SIGNOR-97733	0.368
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257972	0.8
SMAD7	protein	O15105	UNIPROT	ACVRL1	protein	P37023	UNIPROT	down-regulates				9606		BTO:0000975							12023024	f		gcesareni	Smad7, induced by alk1 activation, recruits pp1? To alk1 and thereby inhibits tgf-?/Alk1-induced smad1/5 phosphorylation in ecs.	SIGNOR-87673	0.554
CSNK1D	protein	P48730	UNIPROT	TOP2B	protein	Q02880	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1132	QNQHDDSsSDSGTPS	9606									32015321	t		miannu	Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation.CK1 binds with and phosphorylates TOP2β at Ser1130 to promote its degradation by VM-26. 	SIGNOR-277509	0.2
GSK3B	protein	P49841	UNIPROT	WT1	protein	P19544	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser208	GCHTPTDsCTGSQAL	9606									33184107	t		miannu	Glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box-/- WD repeat-containing protein 8.	SIGNOR-277540	0.289
MAPK8IP2	protein	Q13387	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates	binding			9606									10490659	t	These data demonstrated that JIP2 increases JNK activation by the MLK signaling pathway	gcesareni	These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins.	SIGNOR-70860	0.626
AKT2	protein	P31751	UNIPROT	AKT1S1	protein	Q96B36	UNIPROT	down-regulates activity	phosphorylation	Thr246	LPRPRLNtSDFQKLK	9606	BTO:0000007								12524439	t		gcesareni	1) PRAS40 was phosphorylated in vitro by purified Akt on the same site that was phosphorylated in insulin-treated cells; 2) activation of an inducible Akt was alone sufficient to stimulate the phosphorylation of PRAS40; and 3) cells lacking Akt1 and Akt2 exhibit a diminished ability to phosphorylate this protein	SIGNOR-248046	0.66
Osmotic_stress	stimulus	SIGNOR-ST28	SIGNOR	FUS	protein	P35637	UNIPROT	down-regulates activity	relocalization			9606	BTO:0000312								33172210	f			We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne	SIGNOR-262815	0.7
NSMCE1	protein	Q8WV22	UNIPROT	SMC5/6 	complex	SIGNOR-C374	SIGNOR	form complex	binding			-1									27427983	t		miannu	The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks	SIGNOR-265483	0.873
sphingosine 1-phosphate(1-)	smallmolecule	CHEBI:60119	ChEBI	S1PR5	protein	Q9H228	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257580	0.8
TEF	protein	Q10587	UNIPROT	NPPB	protein	P16860	UNIPROT	unknown	transcriptional regulation												15837525	f	 	 	In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription.	SIGNOR-253652	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	KLHL3	protein	Q9UH77	UNIPROT	up-regulates activity	phosphorylation	Ser433	PMNTRRSsVGVGVVE	-1									26435498	t	done	miannu	Consistent with the fact that S433 is a component of Akt and PKA phosphorylation motifs, in vitro kinase assay demonstrated that Akt and PKA can phosphorylate KLHL3 at S433, that was previously reported to be phosphorylated by PKC. 	SIGNOR-273824	0.2
MAPK1	protein	P28482	UNIPROT	KDM4B	protein	O94953	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser566	PTWKEPVsPMELTGP	9606	BTO:0001109								28945223	t		miannu	In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation. 	SIGNOR-276742	0.2
dopamine	smallmolecule	CHEBI:18243	ChEBI	DRD3	protein	P35462	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258716	0.8
PRKCE	protein	Q02156	UNIPROT	TRPV1	protein	Q8NER1	UNIPROT	up-regulates activity	phosphorylation	Ser502	YFLQRRPsMKTLFVD	9534	BTO:0000298								14523239	t		lperfetto	We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. 	SIGNOR-249230	0.2
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	COMMD1	protein	Q8N668	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001321								20068069	t		miannu	CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation.	SIGNOR-271430	0.444
MAML1	protein	Q92585	UNIPROT	CDK8	protein	P49336	UNIPROT	up-regulates	relocalization			9606									15546612	t		gcesareni	Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells.	SIGNOR-130718	0.58
RAD50	protein	Q92878	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	binding			9606	BTO:0000150								10426999	t		amattioni	Brca1 interacts in vitro and in vivo with hrad50. Brca1 is important for the cellular responses to dna damage that are mediated by the hrad50-hmre11-p95 complex.	SIGNOR-69701	0.779
PAK1	protein	Q13153	UNIPROT	ARPC1B	protein	O15143	UNIPROT	up-regulates	phosphorylation	Thr21	HAWNKDRtQIAICPN	9606									14749719	t		lperfetto	The formation of new branched actin filament networks at the cell cortex of migrating cells is choreographed by the actin-related protein (arp) 2/3 complex. Despite the fundamental role of the arp2/3 complex in actin nucleation and branching, upstream signals that control the functions of p41-arc, a putative regulatory component of the mammalian arp2/3 complex. Pak1 phosphorylation of p41-arc regulates its localization with the arp2/3 complex in the cortical nucleation regions of cells. Pak1 phosphorylates p41-arc on threonine 21	SIGNOR-121642	0.547
CSNK2A1	protein	P68400	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser214	LVRSREVsVDEGRAC	-1									9677319	t		llicata	CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin.	SIGNOR-250944	0.317
MAPK1	protein	P28482	UNIPROT	HNRNPH1	protein	P31943	UNIPROT	unknown	phosphorylation	Ser104	LKHTGPNsPDTANDG	10090	BTO:0000944								22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262776	0.2
afimoxifene	chemical	CHEBI:44616	ChEBI	ESR2	protein	Q92731	UNIPROT	down-regulates activity	chemical inhibition			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258596	0.8
STAT2	protein	P52630	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	binding			9606									17923090	t		lperfetto	We then examined STAT2 acetylation within the b-barrel DBD. A direct interaction between the STAT2-DBD (315485) and STAT1 was detected (Figure 6E) (Li et al., 1997).	SIGNOR-217957	0.534
MFF	protein	Q9GZY8	UNIPROT	Mitochondrial_fission	phenotype	SIGNOR-PH143	SIGNOR	up-regulates				9606									33610749	f		lperfetto	 These proteins include the classical mitochondrial fusion (MFN1, MFN2, and OPA1) and fission proteins (DRP1, MFF, FIS1, etc.) as well as several other proteins that are directly or indirectly involved in these processes (e.g. YME1L, OMA1, INF2, GDAP1, MIC13, etc.	SIGNOR-272983	0.7
SRC	protein	P12931	UNIPROT	SH3GL1	protein	Q99961	UNIPROT	unknown	phosphorylation	Tyr315	QPSCKALyDFEPEND	9606									16054026	t		llicata	These results identified y315 of endophilin a2 as a major phosphorylation site by fak/src complex. tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp.	SIGNOR-139154	0.625
BMP7	protein	P18075	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates				9606									18719589	f	induction of mitochondrial biogenesis	fspada	Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways	SIGNOR-180308	0.318
PPM1B	protein	O75688	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	dephosphorylation	Ser181	DQGSLCTsFVGTLQY	9606									18930133	t			PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation.	SIGNOR-248344	0.412
STXBP4	protein	Q6ZWJ1	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates activity	binding			-1									31782549	t			WW domain‐containing protein STXBP4 inhibits YAP activity via LATS1‐mediated phosphorylation.	SIGNOR-260013	0.2
CSNK2B	protein	P67870	UNIPROT	FGF14	protein	Q92915	UNIPROT	up-regulates activity	phosphorylation	Ser228	PGVTPSKsTSASAIM	9606	BTO:0000938								26917740	t		lperfetto	 Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.	SIGNOR-275744	0.273
PRC1	protein	O43663	UNIPROT	KIF23	protein	Q02241	UNIPROT	up-regulates activity	binding			9606									15297875	t		miannu	These data indicate that PRC1 binds to KIF4, MKLP1 and CENP-E during late mitosis; however, it apparently does not interact simultaneously with more than one of these motor proteins.	SIGNOR-265989	0.589
NR1H2	protein	P55055	UNIPROT	BHLHE40	protein	O14503	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									19032342	f		lperfetto	LXRα and LXRβ are potent positive regulators for hepatic Dec1	SIGNOR-253690	0.2
FLT3	protein	P36888	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15003515	f			Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site. 	SIGNOR-261520	0.293
CSNK2A1	protein	P68400	UNIPROT	EGR1	protein	P18146	UNIPROT	down-regulates activity	phosphorylation	Ser378	RICMRNFsRSDHLTT	10090	BTO:0000944								8662759	t		llicata	Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10.	SIGNOR-250856	0.477
ZEB2	protein	O60315	UNIPROT	MEOX2	protein	P50222	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20516212	t		Luisa	ZEB2 represses GAX transcription through multiple up- stream consensus binding sites. 	SIGNOR-268951	0.324
Condensin II	complex	SIGNOR-C342	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606									32445620	f		miannu	Human Condensin I and II Drive Extensive ATP-Dependent Compaction of Nucleosome-Bound DNA. the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction.	SIGNOR-263913	0.7
UBE2I	protein	P63279	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	sumoylation	Lys113	KNELKHVkYCQYAFD	9606									12621041	t		gcesareni	The mh1 domain of smad4 was shown to associate physically with ubc9, the ubiquitin carrier protein (e2) conjugating enzyme in sumoylation. In cultured cells, smad4 is modified by sumo-1 at the endogenous level. The sumoylation sites were identified as two evolutionarily conserved lysine residues, lys-113 and lys-159, in the mh1 domain. We found that the mutations at lys-113 and lys-159 did not alter the ability of smad4 to form a complex with smad2 and fast on the mix.2 promoter. Importantly, sumo-1 overexpression enhanced tgf-beta-induced transcriptional responses. These findings identify sumoylation as a unique mechanism to modulate smad4-dependent cellular responses	SIGNOR-98993	0.609
PIGG	protein	Q5H8A4	UNIPROT	PIGO	protein	Q8TEQ8	UNIPROT	up-regulates quantity by stabilization	binding			10029	BTO:0000246								15632136	t		miannu	We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O.	SIGNOR-261359	0.408
JAK2	protein	O60674	UNIPROT	STAP2	protein	Q9UGK3	UNIPROT	up-regulates activity	phosphorylation	Tyr310	LPNQEENyVTPIGDG		BTO:0000007								12540842	t		lperfetto	To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 80€“60% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2.	SIGNOR-249372	0.349
AKT2	protein	P31751	UNIPROT	P300/PCAF	complex	SIGNOR-C7	SIGNOR	up-regulates	phosphorylation			9606		BTO:0000887							17964260	t		lperfetto	Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300.	SIGNOR-217673	0.307
CTSB	protein	P07858	UNIPROT	BGLAP	protein	P02818	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly58	RYLYQWLgAPVPYPD	-1									9076588	t		miannu	This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 	SIGNOR-256318	0.335
TRIM33	protein	Q9UPN9	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates	binding			9606									16751102	t		gcesareni	The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. In human hematopoietic stem/progenitor cells, where tgfbeta inhibits proliferation and stimulates erythroid differentiation, tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses.	SIGNOR-146986	0.567
AKT1	protein	P31749	UNIPROT	HK1	protein	P19367	UNIPROT	up-regulates	binding			9606									16892082	t		gcesareni	The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects.	SIGNOR-252495	0.458
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	KAT2A	protein	Q92830	UNIPROT	up-regulates activity	phosphorylation	Thr272	LNYWKLEtPAQFRQR										24870244	t		lperfetto	Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT)	SIGNOR-275497	0.402
PLK1	protein	P53350	UNIPROT	CDC25B	protein	P30305	UNIPROT	up-regulates activity	phosphorylation												21640712	t		lperfetto	These data indicated that PLK1 phosphorylates CDC25B and that pre-phosphorylation of CDC25B by CDK1/CyclinB enhances its substrate properties for PLK1 in vitro	SIGNOR-267560	0.654
HECTD2	protein	Q5U5R9	UNIPROT	PIAS1	protein	O75925	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								26157031	t		miannu	We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model.	SIGNOR-272421	0.397
ATXN2	protein	Q99700	UNIPROT	DDX6	protein	P26196	UNIPROT	unknown	binding			9606									17392519	t		miannu	Ataxin-2 interacts with the dead/h-box rna helicase ddx6 / ddx6 is an essential component for the assembly of p-bodies/	SIGNOR-154158	0.587
CDK2	protein	P24941	UNIPROT	NR3C1	protein	P04150	UNIPROT	up-regulates activity	phosphorylation	Ser203	DLEFSSGsPGKETNE	-1									9199329	t		lperfetto	Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.	SIGNOR-249426	0.296
TGFBI	protein	Q15582	UNIPROT	A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	up-regulates activity	binding												26387839	t		lperfetto	 BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers	SIGNOR-253268	0.285
CAMK4	protein	Q16566	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser259	FPLRKTAsEPNLKVR	9606		BTO:0000887;BTO:0001103							12058061	t		lperfetto	Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs.	SIGNOR-236571	0.49
NF1	protein	P21359	UNIPROT	ADCY8	protein	P40145	UNIPROT	up-regulates				9606	BTO:0000938								24431436	f		miannu	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-204289	0.409
SLBP	protein	Q14493	UNIPROT	H2BC5	protein	P58876	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265378	0.2
CD38	protein	P28907	UNIPROT	OXT	protein	P01178	UNIPROT	up-regulates quantity	relocalization			10090									17287729	f		lperfetto	CD38 is critical for social behaviour by regulating oxytocin secretion|Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice.	SIGNOR-268544	0.375
M1_polarization	phenotype	SIGNOR-PH54	SIGNOR	IL1B	protein	P01584	UNIPROT	up-regulates				9606	BTO:0000801								32454942	f		miannu	Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ	SIGNOR-263825	0.7
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	DNM1L	protein	O00429	UNIPROT	up-regulates activity	dephosphorylation			9606									18838687	t	inferred from 70% family members		When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.	SIGNOR-269994	0.2
NFIB	protein	O00712	UNIPROT	NFIX	protein	Q14938	UNIPROT	up-regulates quantity	transcriptional regulation			10090									29106906	t		Gianni	We report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord.	SIGNOR-268869	0.429
RPA2	protein	P15927	UNIPROT	Nucleotide-excision_repair	phenotype	SIGNOR-PH209	SIGNOR	up-regulates													24086043	f		lperfetto	The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275706	0.7
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1931	SPTSPTYsPTSPKGS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273049	0.556
PLK3	protein	Q9H4B4	UNIPROT	VRK1	protein	Q99986	UNIPROT	up-regulates	phosphorylation	Ser342	DDGKLDLsVVENGGL	9606									19103756	t		llicata	Vrk1 does not phosphorylate plk3, but plk3 phosphorylates the c-terminal region of vrk1 in ser342. Vrk1 with substitutions in s342 is catalytically active but blocks golgi fragmentation, indicating that its specific phosphorylation is necessary for this process.	SIGNOR-182858	0.487
LARP4B	protein	Q92615	UNIPROT	Stress_granules	phenotype	SIGNOR-PH124	SIGNOR	up-regulates				9606									20573744	f		miannu	Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. 	SIGNOR-260939	0.7
POLA1	protein	P09884	UNIPROT	DNA_replication	phenotype	SIGNOR-PH53	SIGNOR	up-regulates				9606									19608746	f		lperfetto	Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase alpha (pol alpha), with chromatin.	SIGNOR-261275	0.7
MAPK12	protein	P53778	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser519	SGYSSPGsPGTPGSR	-1									9199504	t		miannu	Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective.	SIGNOR-250084	0.504
NOTCH1	protein	P46531	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								16990763	f		gcesareni	Other notch target genes identi__ed in the thymoma cell line were dtx1 (gene for deltex1), i__-202, i__-204, i__-d3, adam19 (meltrinb).24 a number of other genes have been reported as being notch targets, including notch1 itself,28 nrarp in xenopus embryos,29 bcl2 in thymoma cells,30 ccnd1 (gene for cyclin d1) in a kidney cell line,31 dkn1a (gene for cyclindependent kinase inhibitor 1a (p21, cip1)) in keratinocytes32 and tcf3 (gene for e2a).	SIGNOR-149730	0.266
DAPK3	protein	O43293	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates	phosphorylation	Ser20	KRPQRATsNVFAMFD	9606									19851336	t		lperfetto	More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.	SIGNOR-188789	0.501
GRM3	protein	Q14832	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening.	SIGNOR-264934	0.8
ATG13	protein	O75143	UNIPROT	RB1CC1	protein	Q8TDY2	UNIPROT	up-regulates	binding			9606									19225151	t		gcesareni	Atg13 directly binds fip200.	SIGNOR-184120	0.917
ELP5	protein	Q8TE02	UNIPROT	Elongator complex	complex	SIGNOR-C466	SIGNOR	form complex	binding			9606									28601220	t		miannu	Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer.	SIGNOR-269712	0.697
INPP5D	protein	Q92835	UNIPROT	SYK	protein	P43405	UNIPROT	down-regulates activity	dephosphorylation			9606									32323266	t		scontino	An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.	SIGNOR-268456	0.428
PRKACA	protein	P17612	UNIPROT	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	up-regulates	phosphorylation			10090	BTO:0000944								23644383	t	inferred from 70% of family members	milica	Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381.	SIGNOR-269863	0.2
OPRD1	protein	P41143	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256683	0.522
FBXL21P	protein	Q9UKT6	UNIPROT	TCAP	protein	O15273	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									32937135	t		lperfetto	FBXL21 is a clock-controlled E3 ligase modulating circadian periodicity via subcellular-specific CRYPTOCHROME degradation. How FBXL21 regulates tissue-specific circadian physiology and what mechanism operates upstream is poorly understood. Here we report the sarcomere component TCAP as a cytoplasmic substrate of FBXL21.	SIGNOR-264853	0.2
VHL	protein	P40337	UNIPROT	IREB2	protein	P48200	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0003781								15777842	t		miannu	We show here that IRP2 can interact with pVHL in co-transfection/co-immunoprecipitation assays. Furthermore, pVHL is able to promote the ubiquitination and the decay of transfected IRP2. 	SIGNOR-271421	0.366
PRKACA	protein	P17612	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	down-regulates activity	phosphorylation			10116									17023420	t			These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine.	SIGNOR-256111	0.387
CBFB	protein	Q13951	UNIPROT	 Core Binding Factor complex	complex	SIGNOR-C214	SIGNOR	form complex	binding			9606									12495904	t		irozzo	The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFβ, is essential for normal hematopoiesis	SIGNOR-255711	0.841
PRKDC	protein	P78527	UNIPROT	DCLRE1C	protein	Q96SD1	UNIPROT	up-regulates	phosphorylation	Ser516	SSTVAGGsQSPKLFS	9606									16600297	t		lperfetto	Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin	SIGNOR-145837	0.687
ITGB1BP1	protein	O14713	UNIPROT	ITGB4	protein	P16144	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257658	0.356
PRKAA1	protein	Q13131	UNIPROT	RBBP7	protein	Q16576	UNIPROT	up-regulates activity	phosphorylation	Ser314	LKLHTFEsHKDEIFQ	-1									28143904	t		lperfetto	AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity	SIGNOR-264784	0.2
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1944	GSTYSPTsPGYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120164	0.316
TOMM22	protein	Q9NS69	UNIPROT	TOM40 complex	complex	SIGNOR-C421	SIGNOR	form complex	binding			9606	BTO:0000567								18331822	t		lperfetto	The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex.	SIGNOR-267679	0.772
KCNJ3	protein	P48549	UNIPROT	KCNJ5/KCNJ3	complex	SIGNOR-C56	SIGNOR	form complex	binding			9606		BTO:0000562							22362083	t		miannu	The muscarinic k(+) channel (i (k,ach)) is a heterotetramer composed of girk1 (kir3.1) andgirk4(kir3.4) subunits of a g protein-coupled inwardly rectifying channel, and plays an important role in mediating electrical responses to the vagal stimulation in the heart.	SIGNOR-196202	0.482
GSK3B	protein	P49841	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr53	PPGSLSStPLSTPCS	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159466	0.26
RAF1	protein	P04049	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates	phosphorylation			9606									11018021	t	Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases.	lperfetto	The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins.	SIGNOR-244952	0.737
PRKACA	protein	P17612	UNIPROT	HMGN1	protein	P05114	UNIPROT	down-regulates activity	phosphorylation	Ser7	sSAEGAAK	9606									11438671	t		miannu	PKA preferentially phosphorylates serine 6 in human HMGN1. specific phosphorylation of the NBD of HMGN proteins serves to prevent the interaction of these proteins with their chromatin targets during mitosis.	SIGNOR-249993	0.311
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	down-regulates	dephosphorylation			9606									12840032	t	inferred from 70% of family members	lperfetto	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases	SIGNOR-269901	0.2
IL2RB	protein	P14784	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271;BTO:0000785								24737791	t		milica	In lymphocytes, binding of il-15 to the il-2/15rbg heterodimer induces jak1 activation that subsequently phosphorylates stat3 via the b-chain and jak3/stat5 activation via its g-chain	SIGNOR-204972	0.616
PML	protein	P29590	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates	binding			9606									15356634	t		gcesareni	Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome.	SIGNOR-128741	0.527
SLC12A5	protein	Q9H2X9	UNIPROT	chloride	smallmolecule	CHEBI:17996	ChEBI	down-regulates activity	relocalization			9606									26951057	t		miannu	As shown in Fig. 2, the intracellular Cl− concentration is regulated mainly by two cation-chloride cotransporters, NKCC1 and KCC2 [32]. NKCC1 imports Cl− whereas KCC2 extrudes intracellular Cl−. 	SIGNOR-264987	0.8
GRM8	protein	O00222	UNIPROT	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							20055706	t		miannu	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264081	0.428
OPRL1	protein	P41146	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256722	0.439
DACT1	protein	Q9NYF0	UNIPROT	DVL2	protein	O14641	UNIPROT	down-regulates	binding			9606									16446366	t		gcesareni	Dapper 1 antagonizes wnt signaling by promoting dishevelled degradation	SIGNOR-144053	0.783
MYC	protein	P01106	UNIPROT	HNRNPA1	protein	P09651	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20010808	t			We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2,	SIGNOR-268690	0.47
CSNK2B	protein	P67870	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	phosphorylation	Thr112	EGMQIPStQFDAAHP	9606									12432063	t		llicata	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin	SIGNOR-251067	0.587
ERRFI1	protein	Q9UJM3	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	binding			-1									18046415	t			The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2	SIGNOR-252076	0.66
PRKCE	protein	Q02156	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates activity	phosphorylation	Thr495	TGITRKKtFKEVANA	9606									24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251632	0.338
CTDSPL2	protein	Q05D32	UNIPROT	HBE1	protein	P02100	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20932329	f	Regulation of transcription	miannu	CTD small phosphatase like 2 (CTDSPL2) can increase ε- and γ-globin gene expression in K562 cells and CD34+ cells derived from umbilical cord blood.	SIGNOR-251779	0.2
YY1	protein	P25490	UNIPROT	SURF1	protein	Q15526	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10858544	f		miannu	 We show that although the Surf-1/Surf-2 promoter does not contain Myc binding sites (E-boxes), Myc over-expression, or the activation of a Myc-oestrogen receptor fusion protein, activates transcription in the Surf-1 direction and that this response to Myc requires a functional YY1 binding site. Our data suggest that the MAP kinase cascade is required for the stimulation of Surf-1 promoter activity and that the Myc-YY1 interaction mediates this response.	SIGNOR-254614	0.316
SRC	protein	P12931	UNIPROT	PDPK1	protein	O15530	UNIPROT	up-regulates	phosphorylation	Tyr376	DEDCYGNyDNLLSQF	9606									20643654	t		miannu	Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376	SIGNOR-166722	0.566
procaterol	chemical	CHEBI:135209	ChEBI	ADRB1	protein	P08588	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. 	SIGNOR-257864	0.8
FAS	protein	P25445	UNIPROT	DAXX	protein	Q9UER7	UNIPROT	up-regulates				9606									9743501	f		gcesareni	Fas activation induced daxx to interact with ask1	SIGNOR-60167	0.69
NFIX	protein	Q14938	UNIPROT	EPHA8	protein	P29322	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268910	0.2
CSNK2A1	protein	P68400	UNIPROT	CDC27	protein	P30260	UNIPROT	up-regulates	phosphorylation	Ser154	FLWSPFEsLCEIGEK	9606									21209074	t		lperfetto	We report here that phosphorylation of cdc27, a core subunit of apc, in response to tgf-
 signaling can facilitate the activation of apc.we have demonstrated that casein kinase ii (ckii) is involved in the phosphorylation of cdc27 in response to tgf-
 signaling.	SIGNOR-170872	0.387
MAPKAPK2	protein	P49137	UNIPROT	TH	protein	P07101	UNIPROT	up-regulates activity	phosphorylation	Ser40	GQGAPGPsLTGSPWP	-1									11359875	t		miannu	MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation.	SIGNOR-250150	0.498
CNOT6L	protein	Q96LI5	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	form complex	binding			9606									19558367	t		lperfetto	In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules.	SIGNOR-268311	0.805
PRKCA	protein	P17252	UNIPROT	PLA2G4A	protein	P47712	UNIPROT	up-regulates	phosphorylation			9606									16963226	t		gcesareni	Pkcalfa, but not pkcbeta, is the predominant cpkc isoenzyme required for cpla2 protein phosphorylation and maximal induction of cpla2 enzymatic activity.	SIGNOR-149406	0.557
GNA13	protein	Q14344	UNIPROT	ARHGEF1	protein	Q92888	UNIPROT	up-regulates activity	binding			9606									14607242	t			It turned out that RGS domain of p115RhoGEF is specific for Gα12 and Gα13, and does not bind Gαi, Gαs and Gαq (Kozasa et al., 1998). The binding of Gα13 but not Gα12 stimulated GEF activity for Rho	SIGNOR-256521	0.591
SP3	protein	Q02447	UNIPROT	CBS	protein	P35520	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12427542	f		miannu	We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter. 	SIGNOR-254813	0.2
DUSP1	protein	P28562	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Tyr187	HTGFLTEyVATRWYR	10116									7535768	t			We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively	SIGNOR-248465	0.799
PLK1	protein	P53350	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates	phosphorylation	Ser733	TVREQDQsFTALDWS	9606									18957422	t		lperfetto	Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma	SIGNOR-181798	0.349
CFH	protein	P08603	UNIPROT	CFB	protein	P00751	UNIPROT	down-regulates activity	binding			9606									19050261	t		miannu	As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity)	SIGNOR-252142	0.497
MAPK1	protein	P28482	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser519	SGYSSPGsPGTPGSR	9606	BTO:0000590								10737616	t		lperfetto	Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease.	SIGNOR-249416	0.553
PAK4	protein	O96013	UNIPROT	RAN	protein	P62826	UNIPROT	up-regulates	phosphorylation	Ser135	DRKVKAKsIVFHRKK	9606									20805321	t		lperfetto	We show that ran is a substrate for p21-activated kinase 4 (pak4) and that its phosphorylation on serine-135 increases during mitosis.Altogether, our findings strongly suggest that pak4-mediated phosphorylation of gdp- or gtp-bound ran modulates the assembly of complexes that are required at specific subcellular localizations for ran to carry out its functions during mitotic progression.	SIGNOR-167667	0.312
TGFB1	protein	P01137	UNIPROT	TAGLN	protein	Q01995	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20846954	f	Regulation	miannu	We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes. 	SIGNOR-251924	0.345
SNTA1	protein	Q13424	UNIPROT	NOS1	protein	P29475	UNIPROT	up-regulates	relocalization			9606		BTO:0001103							12456711	t		gcesareni	biochemical studies showed that the N-terminal PDZ domain of nNOS binds to a similar PDZ domain of syntrophin (Fig. 1), a dystrophin-associated protein	SIGNOR-236916	0.574
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	MYCN	protein	P04198	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269257	0.367
PPP4C	protein	P60510	UNIPROT	TRIM28	protein	Q13263	UNIPROT	down-regulates activity	dephosphorylation			9606									22732494	t		miannu	PP4 dephosphorylated pKAP1 in vitro.	SIGNOR-277163	0.365
ABL1	protein	P00519	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates activity	phosphorylation	Tyr30	FATTDDFyDDPCFDSP	9606	BTO:0000007								12415271	t			We have found that c-Abl can phosphorylate MyoD at a conserved N-terminal tyrosine (Tyr30) that is located within the transactivation domain. Mutation of Tyr30 to Phe does not interfere with the function of MyoD, but theTyr30Phe mutant becomes resistant to the inhibitory effect of DNA damage.	SIGNOR-253055	0.29
PRKCB	protein	P05771	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Ser840	VRSAFTTsTVVRMHV	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249279	0.36
WWTR1	protein	Q9GZV5	UNIPROT	TEAD4	protein	Q15561	UNIPROT	up-regulates	binding			9606									23431053	t	YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death.	gcesareni	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.	SIGNOR-201459	0.864
JAK2	protein	O60674	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000801								9575217	t		lperfetto	Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein	SIGNOR-249507	0.862
CHEK1	protein	O14757	UNIPROT	MDM4	protein	O15151	UNIPROT	down-regulates activity	phosphorylation	Ser342	SKLTHSLsTSDITAI	9606	BTO:0000971								16163388	t		llicata	MDMX is a direct substrate for Chk1 and Chk2 in vitro. Phosphorylation of MDMX leads to increased binding to MDM2 and more efficient ubiquitination, providing an explanation for the enhanced degradation of MDMX after DNA damage. | Western blot showed that Chk1 modified S342 and S367, but with strong preference for S342. 	SIGNOR-250770	0.536
KIF3A	protein	Q9Y496	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272531	0.7
AMPK	complex	SIGNOR-C15	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	down-regulates activity	phosphorylation			9606									23863160	t		lperfetto	AMPK inhibits mTORC1 through two means: first, through phosphorylation of TSC2 to activate its GAP (GTPase-activating protein) activity that converts Rheb into an inactive GDP-bound state, thus switching off mitogenic stimulation of mTORC1 [31], and, secondly, through phosphorylation of raptor at Ser722 and Ser792, which leads to 14-3-3 protein binding and mTORC1 inhibition	SIGNOR-209862	0.449
MAPK3	protein	P27361	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Thr573	AENGLLMtPCYTANF	9534	BTO:0001538								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252757	0.718
B-WICH complex	complex	SIGNOR-C447	SIGNOR	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								25883140	t		miannu	The chromatin-remodelling complex B-WICH, comprised of William syndrome transcription factor, the ATPase SNF2h and nuclear myosin, specifically activates RNA polymerase III transcription of the 5S rRNA and 7SL genes. 	SIGNOR-268841	0.2
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	NLRC4 inflammasome	complex	SIGNOR-C223	SIGNOR	up-regulates activity													16037825	f		miannu	Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage	SIGNOR-263124	0.7
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	MYB	protein	P10242	UNIPROT	up-regulates quantity	transcriptional regulation			9606	BTO:0005790								30335887	t			PML/RARa blocks the differentiation and promotes the proliferation of acute promyelocytic leukemia through activating MYB expression by transcriptional and epigenetic regulation mechanisms.	SIGNOR-259939	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser295	TKRRKSMsGASPKES	9606									23708659	t		lperfetto	Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.	SIGNOR-252776	0.2
ALYREF	protein	Q86V81	UNIPROT	TREX complex	complex	SIGNOR-C444	SIGNOR	form complex	binding			9606									33191911	t		miannu	The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56.	SIGNOR-268511	0.883
PIM1	protein	P11309	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606									16403219	t		lperfetto	All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death.	SIGNOR-249607	0.379
methysergide	chemical	CHEBI:584020	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9205951	t		miannu	The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively.	SIGNOR-258616	0.8
PLA2G4A	protein	P47712	UNIPROT	arachidonic acid	smallmolecule	CHEBI:15843	ChEBI	up-regulates	chemical modification			9606									6810878	t		acerquone	Alternatively, a phospholipase a2 may indeed deacylate the phosphatidylinositol, but the point of debate here is whether deacylation constitutes a significant component of the arachidonate liberation.	SIGNOR-25633	0.8
LCK	protein	P06239	UNIPROT	CD247	protein	P20963	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000782								8626561	t		amattioni	During tcr signaling, lck interacts with numerous molecules, including tcr-zeta. The binding of lck to the tyrosine-phosphorylated zeta chain of the tcr would serve to strengthen the interaction of the associated cd4 and the tcr complex, leading to increased avidity for the antigen-major histocompatibility protein complex.	SIGNOR-41361	0.755
AURKA	protein	O14965	UNIPROT	MAP9	protein	Q49MG5	UNIPROT	up-regulates	phosphorylation	Ser625	RKQKKRHsFLESEAL	9606									17925329	t		llicata	Asap is a novel substrate of the oncogenic mitotic kinase aurora-a: phosphorylation on ser625 is essential to spindle formation and mitosis.	SIGNOR-158210	0.333
GPC6	protein	Q9Y625	UNIPROT	PTCH1	protein	Q13635	UNIPROT	up-regulates activity	binding			9606									31756413	t		miannu	Based on results from in vitro experiments, we had previously proposed that GPC6 stimulates Hh signaling by interacting with Hh and Patched1 (Ptc1), and facilitating/stabilizing their interaction. 	SIGNOR-264031	0.358
ACOT4	protein	Q8N9L9	UNIPROT	succinyl-CoA(5-)	smallmolecule	CHEBI:57292	ChEBI	down-regulates quantity	chemical modification												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271807	0.8
UHMK1	protein	Q8TAS1	UNIPROT	SF1	protein	Q15637	UNIPROT	up-regulates	phosphorylation	Ser80	PPNPEDRsPSPEPIY	9606									16420481	t	The effect has been demonstrated using Q15637-2	gcesareni	Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding.	SIGNOR-143837	0.417
SMG1	protein	Q96Q15	UNIPROT	UPF1	protein	Q92900	UNIPROT	up-regulates	phosphorylation	Thr28	AELLGADtQGSEFEF	9606									23356578	t		lperfetto	Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively	SIGNOR-200793	0.971
EPO	protein	P01588	UNIPROT	EPOR	protein	P19235	UNIPROT	up-regulates	binding			10090									9442088	t		gcesareni	Binding of erythropoietin (epo) to the epo receptor (epor) initiates a signaling cascade resulting in tyrosine phosphorylation of several proteins and induction of ap-1 transcription factor(s).	SIGNOR-55300	0.873
MAPK3	protein	P27361	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	unknown	phosphorylation			9606									21071439	t		lperfetto	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-217577	0.393
Riluzole	chemical	CHEBI:8863	ChEBI	KCNN4	protein	O15554	UNIPROT	up-regulates activity	chemical activation			9606									18955585	t		Luana	Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. 	SIGNOR-258022	0.8
MAPK1	protein	P28482	UNIPROT	KLC1	protein	Q07866	UNIPROT	down-regulates	phosphorylation	Ser460	YKACKVDsPTVTTTL	9606									21385839	t		gcesareni	Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro.	SIGNOR-172638	0.274
ERG	protein	P11308	UNIPROT	ICAM1	protein	P05362	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22235125	f	 	miannu	 It has been shown that ERG is a positive regulator of several EC-restricted genes including VE-cadherin, endoglin, and von Willebrand factor, and a negative regulator of other genes such as interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1. 	SIGNOR-253917	0.2
TAOK	proteinfamily	SIGNOR-PF21	SIGNOR	STK4	protein	Q13043	UNIPROT	up-regulates	phosphorylation			9606									23431053	t		milica	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.	SIGNOR-230710	0.2
FST	protein	P19883	UNIPROT	GDF11	protein	O95390	UNIPROT	down-regulates activity	binding			10090									24627466	t		lperfetto	Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. |FST315-ΔHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function.	SIGNOR-251716	0.685
PRKCD	protein	Q05655	UNIPROT	ADRB2	protein	P07550	UNIPROT	down-regulates activity	phosphorylation	Ser261	TGHGLRRsSKFCLKE	-1									1848190	t		lperfetto	We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling.	SIGNOR-248854	0.358
UBE2G2	protein	P60604	UNIPROT	DIO2	protein	Q92813	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys237	VCIVQRQkIAYLGGK	9606		BTO:0001379							29892818	t		scontino	ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244.	SIGNOR-267483	0.2
LCK	protein	P06239	UNIPROT	PRKCD	protein	Q05655	UNIPROT	up-regulates activity	phosphorylation	Tyr334	MQDNSGTyGKIWEGS	9534	BTO:0000298								11381116	t			The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2).	SIGNOR-251385	0.505
CCP110	protein	O43303	UNIPROT	CALM3	protein	P0DP25	UNIPROT	up-regulates activity	binding			9606									16760425	t		miannu	We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis.	SIGNOR-266348	0.334
KIF21B	protein	O75037	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									28290984	f			In this study, we showed that KIF21B is a highly processive MT plus-end directed motor, which can potently induce pausing of MT plus ends. This activity depends on several regions of this large motor protein.	SIGNOR-272515	0.7
GSK3B	protein	P49841	UNIPROT	NACA	protein	E9PAV3	UNIPROT	down-regulates	phosphorylation	Thr2022	NIQENTQtPTVQEES	9606	BTO:0000007								15005626	t		gcesareni	Gsk3 beta-dependent phosphorylation of the alpha nac coactivator regulates its nuclear translocation and proteasome-mediated degradation.	SIGNOR-123262	0.2
PRKCE	protein	Q02156	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser558	VPTYESAsIRRFQEG	9606									15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation	SIGNOR-129308	0.316
PDHX	protein	O00330	UNIPROT	CDX2	protein	Q99626	UNIPROT	down-regulates activity	binding			9606	BTO:0000120								12783165	t		miannu	In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3.	SIGNOR-254904	0.2
ACTB	protein	P60709	UNIPROT	Brain-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C486	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270757	0.507
RNF139	protein	Q8WU17	UNIPROT	SREBF1	protein	P36956	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								20068067	t		miannu	Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner 	SIGNOR-271957	0.303
RUVBL2	protein	Q9Y230	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269291	0.727
XAV939	chemical	CHEBI:62878	ChEBI	CTNNB1	protein	P35222	UNIPROT	down-regulates				9606									19759537	f		amattioni	Xav939 selectively inhibits beta-catenin-mediated transcription. Xav939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex.	SIGNOR-188051	0.8
NTN3	protein	O00634	UNIPROT	NEO1	protein	Q92859	UNIPROT	up-regulates activity	binding			9606		BTO:0001484							28245592	t		miannu	Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins.	SIGNOR-268171	0.709
USF1	protein	P22415	UNIPROT	MYH9	protein	P35579	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								11467950	f		miannu	we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies.	SIGNOR-222554	0.2
SRF	protein	P11831	UNIPROT	TAGLN	protein	Q01995	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21673106	f		gcesareni	The contractile phenotype of smooth muscle (sm) cells is controlled by serum response factor (srf), which drives the expression of sm-specific genes including sm alpha-actin, sm22, and others.	SIGNOR-174393	0.423
CASP3	protein	P42574	UNIPROT	PTCH1	protein	Q13635	UNIPROT	down-regulates	cleavage	Asp1405	CPGYPETdHGLFEDP	9606									23074268	t		gcesareni	Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain.	SIGNOR-199111	0.327
MIPOL1	protein	Q8TD10	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity				9606									31609475	f		miannu	In our results, we also showed that re-expression of MIPOL1 is associated with suppression phosphorylation of AKT and p65, a subunit of NF-ҡB. This suggests that MIPOL1 may inhibit invasion by suppression of phosphorylation of AKT and p65 to further inhibit the expression of MMP-9	SIGNOR-261135	0.2
HDAC7	protein	Q8WUI4	UNIPROT	PLAG1	protein	Q6DJT9	UNIPROT	down-regulates	deacetylation			9606									16207715	t		miannu	Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.	SIGNOR-140950	0.258
ARHGAP33	protein	O14559	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260491	0.419
PRKCB	protein	P05771	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser328	QDAYRRNsVRFLQQR	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89201	0.549
N(6)-(1,2-dicarboxylatoethyl)-AMP(4-)	smallmolecule	CHEBI:57567	ChEBI	fumarate(2-)	smallmolecule	CHEBI:29806	ChEBI	up-regulates quantity	precursor of			9606									22812634	t		miannu	ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case	SIGNOR-266610	0.8
Ternatin	chemical	CID:5459184	PUBCHEM	EEF1A1	protein	P68104	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001109								26651998	t		Simone Vumbaca	Ternatins inhibit protein synthesis with potencies that correlate with their ability to block cell proliferation, and photo-ternatin 5 identified eEF1A as aplausible target.	SIGNOR-261126	0.8
FYN	protein	P06241	UNIPROT	GRIN2A	protein	Q12879	UNIPROT	up-regulates activity	phosphorylation	Tyr1387	GRCPSDPyKHSLPSQ	-1									10195142	t		lperfetto	To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain.	SIGNOR-247159	0.724
NEDD4	protein	P46934	UNIPROT	GUCD1	protein	Q96NT3	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								24743017	t		miannu	The E3 ligase NEDD4 regulates GUCD1 degradation. many polyubiquitinylated species of GUCD1 appeared as high molecular weight forms, suggesting that GUCD1 is degraded by the proteasome, after polyubiquitin chain formation, in the presence of NEDD4-1. 	SIGNOR-272846	0.43
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	BCR	protein	P11274	UNIPROT	down-regulates	phosphorylation	Tyr360	VSPSPTTyRMFRDKS	9606	BTO:0001271								8622703	t		lperfetto	We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrose 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr.	SIGNOR-40619	0.2
atomoxetine	chemical	CHEBI:127342	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			-1									9871604	t		miannu	The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2.	SIGNOR-259067	0.8
CCKAR	protein	P32238	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257361	0.435
RNF7	protein	Q9UBF6	UNIPROT	NF1	protein	P21359	UNIPROT	down-regulates activity	ubiquitination			9606									23136067	t		miannu	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 	SIGNOR-271453	0.252
PIM1	protein	P11309	UNIPROT	RP9	protein	Q8TA86	UNIPROT	unknown	phosphorylation	Ser212	KKRKHKSsKSNEGSD	-1									10931201	t		miannu	PAP-1 was phosphorylated in vitro by Pim-1, but not a kinase-negative Pim-1 mutant. The two serine residues of PAP-1 at amino acids 204 and 206 near the C-terminus were phosphorylated by Pim-1. PAP-1 is thus thought to be a target protein for Pim-1 kinase. 	SIGNOR-263029	0.2
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser217	AHYSPRTsPIMSPRT	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252330	0.635
aspartic acid	smallmolecule	CHEBI:22660	ChEBI	Asp-tRNA(Asp)	smallmolecule	CHEBI:29158	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270378	0.8
ERCC5	protein	P28715	UNIPROT	Nucleotide-excision_repair	phenotype	SIGNOR-PH209	SIGNOR	up-regulates													24086043	f		lperfetto	The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275709	0.7
MAPK1	protein	P28482	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates	phosphorylation	Ser2279	PVQPNPMsPQQHMLP	9606									17623675	t		lperfetto	Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo.	SIGNOR-156887	0.478
PRKACA	protein	P17612	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser284	AGGGRRIsDSHEDTG	9606									20151718	t		miannu	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163756	0.278
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2Z	protein	Q9H832	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271347	0.771
CSNK2A1	protein	P68400	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Ser330	SFRVRASsDGEGTMS	-1									8349691	t		llicata	These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1.	SIGNOR-250908	0.345
dopamine	smallmolecule	CHEBI:18243	ChEBI	3-methoxytyramine	smallmolecule	CHEBI:1582	ChEBI	up-regulates quantity	precursor of			9606									NBK536726	t	brain	lperfetto	Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO.	SIGNOR-264177	0.8
PPP2CB	protein	P62714	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	dephosphorylation	Ser181	DQGSLCTsFVGTLQY	9606									19607706	t			Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha|Chronic Ser 177/181 phosphorylation of IKKβ was due to UVB-induced inhibition of the catalytic subunit of the Ser-Thr phosphatase PP2A (PP2Ac)	SIGNOR-248580	0.262
RNF168	protein	Q8IYW5	UNIPROT	Histone H2A	proteinfamily	SIGNOR-PF70	SIGNOR	up-regulates quantity	ubiquitination			9606									31225475	t		miannu	L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.	SIGNOR-266784	0.2
PRKCA	protein	P17252	UNIPROT	PA2G4	protein	Q9UQ80	UNIPROT	unknown	phosphorylation	Ser363	ALLQSSAsRKTQKKK	9606									11325528	t		lperfetto	We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC.	SIGNOR-249089	0.441
KCNQ3	protein	O43525	UNIPROT	KCNQ2	protein	O43526	UNIPROT	up-regulates activity	binding			10116	BTO:0000938								9836639	t			The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current.	SIGNOR-268832	0.497
TRAF6	protein	Q9Y4K3	UNIPROT	CSNK2A1	protein	P68400	UNIPROT	up-regulates activity	binding			9606	BTO:0001370								29733298	t		miannu	Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways. 	SIGNOR-273656	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	T-reg_differentiation	phenotype	SIGNOR-PH91	SIGNOR	down-regulates				9606									23620016	f			In the current study, addition of ERK inhibitors suppressed IL-6-induced RORgammat expression and promoted TGF-beta-induced Foxp3 expression.	SIGNOR-254686	0.7
ETNK2	protein	Q9NVF9	UNIPROT	ethanolaminium(1+)	smallmolecule	CHEBI:57603	ChEBI	down-regulates quantity	chemical modification												36866238	t		lperfetto	Ethanolamine kinase 2 (ETNK2) is a protein-coding gene. Spondylometaphyseal dysplasia with cone-rod dystrophy is one of the diseases linked to the ETNKT2 gene. Glycerophospholipid biosynthesis and nuclear receptor meta-pathways are two of the ETNK2-related pathways. 	SIGNOR-275644	0.8
ACE2	protein	Q9BYF1	UNIPROT	Spike protein-ACE2	complex	SIGNOR-C240	SIGNOR	form complex	binding			9534	BTO:0001444								18554741	t		miannu	Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells.	SIGNOR-260288	0.2
HAUS5	protein	O94927	UNIPROT	HAUS complex	complex	SIGNOR-C281	SIGNOR	form complex	binding			9606	BTO:0000567								19369198	t		lperfetto	Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)	SIGNOR-262317	0.747
MC1R	protein	Q01726	UNIPROT	TNF	protein	P01375	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000552								19656324	f		miannu	Constitutive expression of MC1R in HaCaT keratinocytes inhibits basal and UVB-induced TNF-alpha production. the constitutive activity of MC1R results in elevated intracellular cAMP level, reduced NF-kappaB activity and decreased TNF-alpha transcription	SIGNOR-252375	0.294
BCAR1	protein	P56945	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	binding			9606									18321991	t		gcesareni	In this study, we show that, after tyrosine phosphorylation of p130cas mediated by integrin signaling, the phosphorylated p130cas is able to interact with phosphorylated smad3 and in turn prevent transcriptional activation by smad3	SIGNOR-161265	0.281
LPAR4	protein	Q99677	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257432	0.357
NPC	complex	SIGNOR-C263	SIGNOR	XPOT	protein	O43592	UNIPROT	up-regulates quantity	relocalization			9606									9660920	t		miannu	Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus.	SIGNOR-261394	0.448
ZNF165	protein	P49910	UNIPROT	SMURF2	protein	Q9HAU4	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000356								26567849	t		Luana	ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1.	SIGNOR-266095	0.271
EPHB2	protein	P29323	UNIPROT	ARHGEF15	protein	O94989	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr353	PLQDEPLyQTYRAAV	9606	BTO:0000007								21029865	t		miannu	 We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. EphB2 mediates phosphorylation of Ephexin5 at tyrosine-361	SIGNOR-262864	0.499
DRAM2	protein	Q6UX65	UNIPROT	ROCK1	protein	Q13464	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30755245	f		irozzo	Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors.	SIGNOR-259144	0.2
panobinostat	chemical	CHEBI:85990	ChEBI	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257750	0.8
CSNK2A1	protein	P68400	UNIPROT	RRN3	protein	Q9NYV6	UNIPROT	down-regulates	phosphorylation	Ser170	KEGDVDVsDSDDEDD	9606									18559419	t		llicata	Here we show that ck2 phosphorylates the transcription initiation factor tif-ia at serines 170 and 172 (ser170/172), and this phosphorylation triggers the release of tif-ia from pol i after transcription initiation.	SIGNOR-178939	0.206
TGFBI	protein	Q15582	UNIPROT	Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	up-regulates activity	binding												26387839	t		lperfetto	 BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers	SIGNOR-253270	0.417
CDK5	protein	Q00535	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates	phosphorylation	Ser83	QQQQQETsPRQQQQQ	9606	BTO:0001130								21799006	t		gcesareni	Cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins	SIGNOR-175696	0.381
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	HK2	protein	P52789	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27692180	t		miannu	HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 	SIGNOR-267453	0.312
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	GSN	protein	P06396	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000132								27871158	t		lperfetto	Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step.	SIGNOR-261844	0.8
MLL3 complex	complex	SIGNOR-C446	SIGNOR	H3-4	protein	Q16695	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606									34156443	t		miannu	MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. 	SIGNOR-268812	0.2
MAPK14	protein	Q16539	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser69	GPLAPPAsPGPFATR	10116									15486195	t		miannu	Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. 	SIGNOR-260442	0.326
4-fluoro-N-{2-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]ethyl}benzamide	chemical	CHEBI:64101	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258858	0.8
PBX4	protein	Q9BYU1	UNIPROT	FGF8	protein	P55075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003560								10026229	t		miannu	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 	SIGNOR-265806	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	KIFC1	protein	Q9BW19	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser6	sPLLEVKG	-1									24510915	t		miannu	 Tryptic digests of KIFC1 treated with CDK1/CYCLIN B were analyzed by LC-MS/MS revealing phosphorylation at Ser6 (Supplementary Fig S5B). These data indicate that phosphorylation by CDK1/CYLCIN B contributes to KIFC1 stability by protecting KIFC1 from APC/C-mediated ubiquitination and subsequent proteasomal degradation.	SIGNOR-266113	0.433
neratinib	chemical	CHEBI:61397	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258254	0.8
CDK1	protein	P06493	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	down-regulates activity	phosphorylation	Ser164	TSTPGRRsCFGFEGL	-1									23901111	t		miannu	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. 	SIGNOR-276120	0.699
Naltrindole	chemical	CHEBI:81528	ChEBI	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029									9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258818	0.8
PLK1	protein	P53350	UNIPROT	PKMYT1	protein	Q99640	UNIPROT	down-regulates activity	phosphorylation	Thr495	LLSLFEDtLDPT	-1									12738781	t		miannu	 Here, we have shown that Plk1 is responsible for part of the phosphorylation of Myt1 during M phase. The kinase activity of human Myt1 is reported to be decreased during M phase, and the decreased activity correlates with hyperphosphorylated forms of Myt1 (35, 37). We then tested the ability of these mutant forms of Myt1 (GST fusion proteins), to serve as a substrate for Plk1 in vitro. Quantification of the result (Fig. 5C) showed that Ser-426 is the major phosphorylation site by Plk1 in vitro and Thr-495 the second major site.	SIGNOR-263097	0.707
PRKCB	protein	P05771	UNIPROT	GSK3A	protein	P49840	UNIPROT	down-regulates	phosphorylation	Ser21	SGRARTSsFAEPGGG	9606									11884598	t		gcesareni	Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway.	SIGNOR-115718	0.333
WNT10A	protein	Q9GZT5	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131622	0.555
Spike protein-ACE2	complex	SIGNOR-C240	SIGNOR	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	up-regulates													17522231	f		lperfetto	These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins	SIGNOR-260711	0.2
UBE2I	protein	P63279	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates activity	sumoylation	Lys161	ALRPLVIkQEPREED	-1									12511558	t		miannu	C/EBPalpha interacts directly with the E2 SUMO-conjugating enzyme Ubc9 and can be SUMOylated in vitro using purified recombinant components. Our results indicate that SUMO modification of SC motifs provides a means to rapidly control higher order interactions among transcription factors and suggests that SUMOylation may be a general mechanism to limit transcriptional synergy.	SIGNOR-256334	0.2
CoV2 Spike protein-ACE2	complex	SIGNOR-C254	SIGNOR	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	up-regulates													17522231	f		lperfetto	These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins	SIGNOR-260756	0.2
PBRM1	protein	Q86U86	UNIPROT	S100A13	protein	Q99584	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000562							15601824	f		miannu	We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues.	SIGNOR-132431	0.457
FGFR1	protein	P11362	UNIPROT	FRS2	protein	Q8WU20	UNIPROT	up-regulates activity	phosphorylation			10116	BTO:0002809								9182757	t		fspada	In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.	SIGNOR-236944	0.863
RUVBL1	protein	Q9Y265	UNIPROT	R2SP co-chaperone	complex	SIGNOR-C517	SIGNOR	form complex	binding			9606									29844425	t		miannu	Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes.	SIGNOR-270939	0.517
CDK1	protein	P06493	UNIPROT	NUP98	protein	P52948	UNIPROT	down-regulates activity	phosphorylation	Ser612	LNNSNLFsPVNRDSE	9606									21335236	t		gcesareni	We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks.	SIGNOR-172217	0.408
MAPKAPK2	protein	P49137	UNIPROT	ZFP36	protein	P26651	UNIPROT	down-regulates activity	phosphorylation	Ser66	TSLVEGRsCGWVPPP	-1									14688255	t		miannu	We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated.	SIGNOR-250154	0.687
CHD4	protein	Q14839	UNIPROT	MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263844	0.809
Oxatomide	chemical	CHEBI:31943	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002126								18446005	t		Luana	We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells	SIGNOR-257791	0.8
CRH	protein	P06850	UNIPROT	KRT1	protein	P04264	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15787816	f	Regulation of expression	miannu	CRH also increased AP-1 binding activity, cell granularity, cytokeratin 1 and involucrin expression, and inhibited cytokeratin 14 expression.	SIGNOR-251882	0.2
HNF1A	protein	P20823	UNIPROT	AFP	protein	P02771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11314020	f	 	miannu	 We investigated AFP gene regulation in AFP-GC by an active transcription factor, HNF1 (hepatocyte nuclear factor 1) and a repressive transcription factor, ATBF1 (AT motif binding factor 1). CAT assays showed the direct inhibition of AFP gene expression by ATBF1.	SIGNOR-254435	0.336
NUMA1	protein	Q14980	UNIPROT	TUBB6	protein	Q9BUF5	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-117109	0.2
SSTR3	protein	P32745	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256820	0.428
ACE2	protein	Q9BYF1	UNIPROT	CoV2 Spike protein-ACE2	complex	SIGNOR-C254	SIGNOR	form complex	binding			9534	BTO:0001444								32155444	t		miannu	We report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2). Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV. 	SIGNOR-260740	0.2
BRCA1-C complex	complex	SIGNOR-C299	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates													25400280	f		lperfetto	The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2 	SIGNOR-263228	0.7
CDK5	protein	Q00535	UNIPROT	PIK3C3	protein	Q8NEB9	UNIPROT	down-regulates	phosphorylation	Thr159	DGSEPTKtPGRTSST	9606	BTO:0000938								20513426	t		llicata	Thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy cdk5/p25, a neuronal cdk shown to play a role in alzheimer's disease, can also phosphorylate thr159 of vps34.	SIGNOR-165772	0.365
TLN1	protein	Q9Y490	UNIPROT	AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257624	0.686
PRDM2	protein	Q13029	UNIPROT	HMOX1	protein	P09601	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8654390	f	2	miannu	We show that a portion of MTB-Zf, including an N-terminal zinc-finger domain, binds in vitro to MTE and that the transient coexpression of MTB-Zf cDNA leads to transativation of the heme-oxygenase-1 gene promoter.	SIGNOR-241047	0.2
SRC	protein	P12931	UNIPROT	AFAP1	protein	Q8N556	UNIPROT	unknown	phosphorylation	Tyr93	TSSLPEGyYEEAVPL	9534									9655255	t		lperfetto	In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110.	SIGNOR-246359	0.589
SRC	protein	P12931	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	phosphorylation	Tyr654	RNEGVATyAAAVLFR	9606									11279024	t		lperfetto	Beta-catenin is a good substrate of pp60c- src tyrosine kinase in vitro;this kinase modifies specifically tyr-86 and tyr-654,although consistently detected, this negative effect of tyr-86 phosphorylation on tbp binding was clearly less important than the positive effect observed after tyr-654 phosphorylation.	SIGNOR-106454	0.752
IL12A	protein	P29459	UNIPROT	IL12RB2	protein	Q99665	UNIPROT	up-regulates	binding			9606									11086056	t		gcesareni	Il-12r beta 2 plays an essential role in mediating the biological functions of il-12 in mice.	SIGNOR-84361	0.56
SIAH1	protein	Q8IUQ4	UNIPROT	HIPK2	protein	Q9H2X6	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002181								18536714	t		miannu	 Here we demonstrate that HIPK2 is an unstable protein that colocalizes and interacts with the E3 ubiquitin ligase Siah-1 in unstressed cells. Siah-1 knockdown increases HIPK2 stability and steady-state levels, whereas Siah-1 expression facilitates HIPK2 polyubiquitination, degradation and thereby inactivation. 	SIGNOR-276166	0.529
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1626	SPSYSPTsPSYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269379	0.718
PRKD1	protein	Q15139	UNIPROT	PTRH2	protein	Q9Y3E5	UNIPROT	up-regulates	phosphorylation	Ser87	GKVAAQCsHAAVSAY	9606									18703509	t		lperfetto	Overexpression of constitutively active pkd or pkd activation by treatment with phorbol 12-myristate 13-acetate results in phosphorylation of two serine residues (ser5 and ser87) in a form of bit1 that is confined to the cytoplasm and concomitantly increases the apoptotic activity of cytoplasmic bit1	SIGNOR-180089	0.305
CDK4	protein	P11802	UNIPROT	PELP1	protein	Q8IZL8	UNIPROT	up-regulates	phosphorylation	Ser991	PALPPPEsPPKVQPE	9606	BTO:0000150								20807815	t		llicata	Using site-directed mutagenesis and in vitro kinase assays, we identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we identified pelp1 as a novel substrate of cdks and found that cdk phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function.	SIGNOR-167774	0.36
EEF1A1	protein	P68104	UNIPROT	EEF1A:GTP:aa-tRNA	complex	SIGNOR-C493	SIGNOR	form complex	binding			9606									8722040	t		miannu	The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. 	SIGNOR-270809	0.2
NUMB	protein	P49757	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates	binding			9606									20940030	t		gcesareni	Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53	SIGNOR-168454	0.456
DDX5	protein	P17844	UNIPROT	HDAC1	protein	Q13547	UNIPROT	up-regulates	binding			9606									17369852	t		miannu	Wt p68 co-immunoprecipitates efficiently with hdac1, the k53r p68 does not / sumoylation is important for the interaction of p68 with hdac1 and for transcriptional repression by p68	SIGNOR-153715	0.401
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	RAD51	protein	Q06609	UNIPROT	up-regulates activity	phosphorylation	Tyr315	ETRICKIyDSPCLPE	9606	BTO:0002882								11684015	t		lperfetto	RAD51 is one of six mitotic human homologs of the E. coli RecA protein (RAD51-Paralogs) that play a central role in homologous recombination and repair of DNA double-strand breaks (DSBs).|Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance. 	SIGNOR-271707	0.2
GSK3B	protein	P49841	UNIPROT	CTNND1	protein	O60716	UNIPROT	unknown	phosphorylation	Ser252	MEGYRAPsRQDVYGP	-1									12885254	t			GSK3beta selectively phosphorylates p120 on S252 and T310 in Vitro	SIGNOR-251234	0.395
KLF6	protein	Q99612	UNIPROT	DLK1	protein	P80370	UNIPROT	down-regulates	transcriptional regulation			9606									15917248	f	Repression of dlk1 requires hdac3 deacetylase activity	fspada	We have identified krappel-like factor-6 (klf6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene delta-like 1 (dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation.	SIGNOR-210016	0.286
ATM	protein	Q13315	UNIPROT	CHEK1	protein	O14757	UNIPROT	up-regulates	phosphorylation	Ser345	LVQGISFsQPTCPDH	9606									20068082	t		gcesareni	Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation.	SIGNOR-163110	0.84
dexchlorpheniramine	chemical	CHEBI:4464	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7925364	t		miannu	The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum.	SIGNOR-258873	0.8
PPP2R1A	protein	P30153	UNIPROT	PPP2CA	protein	P67775	UNIPROT	up-regulates	binding			9606									16039140	t		miannu	Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme	SIGNOR-138883	0.957
IKBKE	protein	Q14164	UNIPROT	REL	protein	Q04864	UNIPROT	up-regulates	phosphorylation			9606				SIGNOR-C68					16888014	t		miannu	The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel.	SIGNOR-148620	0.362
CAMK1	protein	Q14012	UNIPROT	CAMK1	protein	Q14012	UNIPROT	up-regulates activity	phosphorylation	Thr177	DPGSVLStACGTPGY	-1									8253780	t		llicata	CaM kinase I was autophosphorylated in a Ca2+/CaM-dependent manner at a threonyl residue (Thr-177) which is located at a position equivalent to that of the threonyl residue (Thr-197) autophosphorylated in cAMP-dependent protein kinase.	SIGNOR-250612	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CCDC88A	protein	Q3V6T2	UNIPROT	unknown	phosphorylation	Ser1417	INRERQKsLTLTPTR	9606									16139227	t		llicata	Akt phosphorylates serine at position 1416 in girdin, and phosphorylated girdin accumulates at the leading edge of migrating cells.	SIGNOR-140216	0.2
Caspase 9 complex	complex	SIGNOR-C229	SIGNOR	CASP3	protein	P42574	UNIPROT	up-regulates activity	cleavage			9606									15657060	t		lperfetto	Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3.	SIGNOR-256448	0.622
PRKCA	protein	P17252	UNIPROT	DLX3	protein	O60479	UNIPROT	down-regulates activity	phosphorylation	Ser138	KPRTIYSsYQLAALQ	-1									11343707	t		lperfetto	Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3.	SIGNOR-249096	0.311
CEBPE	protein	Q15744	UNIPROT	LTF	protein	P02788	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								15588942	f		miannu	C/EBP_ interacts with C/EBP_ through the leucine-zipper–containing domain. C/EBP_ and C/EBP_ synergistically activate transcription of lactoferrin promoter	SIGNOR-225012	0.378
MAPK12	protein	P53778	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity	phosphorylation	Ser200	YSGDSDAsSPRSNCS	10090	BTO:0005930								20026657	t		miannu	 We determined that p38-gamma directly phosphorylated MyoD on Ser199 and Ser200, which results in enhanced occupancy of MyoD on the promoter of myogenin together with markedly decreased transcriptional activity. 	SIGNOR-276274	0.422
PPP2CB	protein	P62714	UNIPROT	ELF1	protein	P32519	UNIPROT	down-regulates activity	dephosphorylation	Thr231	CPKYIKWtQREKGIF	9606									18714041	t			Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response	SIGNOR-248591	0.2
RLN2	protein	P04090	UNIPROT	RXFP1	protein	Q9HBX9	UNIPROT	up-regulates	binding			9606		BTO:0000142							11809971	t		gcesareni	Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway	SIGNOR-114549	0.752
DLG2	protein	Q15700	UNIPROT	Scribble_complex_DLG2-LLGL1_variant	complex	SIGNOR-C510	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270909	0.485
PRTN3	protein	P24158	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Thr75	VLTGKLTtVFLPIVY	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263597	0.381
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	unknown	phosphorylation			9606									21071439	t	inferred from 70% family members	lperfetto	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-270150	0.401
ABL1	protein	P00519	UNIPROT	WASF3	protein	Q9UPY6	UNIPROT	up-regulates activity	phosphorylation	Tyr248	HASDVTDySYPATPN	9606	BTO:0000815								17623672	t			WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3.	SIGNOR-262300	0.565
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	ITGB2	protein	P05107	UNIPROT	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259023	0.2
GRM7	protein	Q14831	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening.	SIGNOR-264938	0.8
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	FOXP3	protein	Q9BZS1	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys356	AILEAPEkQRTLNEI	9606	BTO:0002181								27432879	t		miannu	The ubiquitination site of Foxp3 is Lys356	SIGNOR-277246	0.262
PDGFRB	protein	P09619	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	phosphorylation	Tyr320	RKDTKEIyTHFTCAT	-1									33139573	t		miannu	RTKs directly phosphorylate Gαi on Y154, 155, and Y320.	SIGNOR-277234	0.2
LPAR6	protein	P43657	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257004	0.2
ACVR1B	protein	P36896	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	phosphorylation			10090									14517293	t		gcesareni	ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway	SIGNOR-235157	0.795
PRKAA1	protein	Q13131	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation			9606			SIGNOR-C15						17900900	t		gcesareni	The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation	SIGNOR-252981	0.509
CDK3	protein	Q00526	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates activity	phosphorylation	Ser106	PLNSVSPsPLMLLHP										26202215	t		lperfetto	CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3	SIGNOR-273188	0.263
TRIM27	protein	P14373	UNIPROT	STK38L	protein	Q9Y2H1	UNIPROT	up-regulates activity	ubiquitination	Lys119	TGHIYAMkILRKSDM	10090									35670107	t	K11 corresponds to the 11th Lysine, which is in position 119 in the full length sequence	lperfetto	TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of the serine/threonine kinase 38-like (STK38L) kinase. In turn, STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination of ULK1	SIGNOR-270347	0.2
ARNTL	protein	O00327	UNIPROT	PPARA	protein	Q07869	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000759							16556735	t		miannu	We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. 	SIGNOR-268025	0.579
PPP1CA	protein	P62136	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	dephosphorylation	Ser469	AHEENPEsILDEHVQ	9606									17318175	t			The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 	SIGNOR-248554	0.338
sunitinib	chemical	CHEBI:38940	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									21423276	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-172917	0.8
IL1A	protein	P01583	UNIPROT	MC1R	protein	Q01726	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000847								9767234	f		miannu	MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression.	SIGNOR-252387	0.2
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	MAPK3	protein	P27361	UNIPROT	up-regulates	phosphorylation	Tyr204	HTGFLTEyVATRWYR	9606									9677429	t	MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade.	lperfetto	The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells.	SIGNOR-244806	0.2
GTP	smallmolecule	CHEBI:15996	ChEBI	GNAS	protein	P63092	UNIPROT	up-regulates	chemical activation			9606									17095603	t		gcesareni	Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis.	SIGNOR-150552	0.8
mTORC1	complex	SIGNOR-C3	SIGNOR	JMJD1C	protein	Q15652	UNIPROT	up-regulates activity	phosphorylation	Thr505	KFVSRPPtPKCVIDI	9606	BTO:0000007								32034158	t		miannu	We show that, by direct interaction with USF-1, JMJD1C is recruited to lipogenic promoters. We also show that JMJD1C is phosphorylated at T505 by mammalian target of rapamyci (mTOR) to be recruited to lipogenic genes in response to insulin/feeding. we detected phosphorylation of WT JMJD1C but not T505A mutant when we co-transfected JMJD1C constructs along with the mTORC1 in 293FT cells 	SIGNOR-265168	0.244
CDK1	protein	P06493	UNIPROT	RANGAP1	protein	P46060	UNIPROT	up-regulates	phosphorylation	Ser442	STFLAFPsPEKLLRL	9606			SIGNOR-C17						15037602	t		lperfetto	Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain.	SIGNOR-123520	0.472
CDC42BPA	protein	Q5VT25	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates	phosphorylation	Ser20	KRPQRATsNVFAMFD	9606									19851336	t		lperfetto	More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.	SIGNOR-188781	0.531
SLC9A9	protein	Q8IVB4	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265608	0.8
BIRC3	protein	Q13489	UNIPROT	RIPK1	protein	Q13546	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000815								18570872	t		miannu	 In this report, we show that cIAP1 and cIAP2 promote cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein. We demonstrate that AEG40730, a compound modeled on BIR-binding tetrapeptides, binds to cIAP1 and cIAP2, facilitates their autoubiquitination and proteosomal degradation, and causes a dramatic reduction in RIP1 ubiquitination. We show that cIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. 	SIGNOR-272637	0.737
CSNK2A1	protein	P68400	UNIPROT	DDIT3	protein	P35638	UNIPROT	down-regulates activity	phosphorylation	Ser15	FSFGTLSsWELEAWY	9606	BTO:0000567								12876286	t		llicata	CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites 	SIGNOR-250851	0.35
PATZ1	protein	Q9HBE1	UNIPROT	RNF4	protein	P78317	UNIPROT	down-regulates	binding			9606									10713105	t		miannu	In vitro and in vivo interaction between rnf4 and patz was demonstrated / patz acted as a transcriptional repressor, whereas its partner rnf4 behaved as a transcriptional activator./ the association of patz with rnf4 switches activation to repression	SIGNOR-75775	0.526
2-acyl-sn-glycero-3-phospho-D-myo-inositol	smallmolecule	CHEBI:62746	ChEBI	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	precursor of			-1									18772128	t		miannu	The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils.	SIGNOR-268105	0.8
ZBTB16	protein	Q05516	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				10090	BTO:0002882								9710637	f		fcortellessa	PLZF expression in 32DG/GM cells is associated with growth suppression and G1 arrest. 	SIGNOR-261685	0.7
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	MYC	protein	P01106	UNIPROT	up-regulates activity				9606									19855079	t		apalma	We demonstrate that in addition to blocking myeloid differentiation, PLZF-RARα also promotes proliferation/self-renewal via the aberrant regulation of cell cycle–associated genes such as c-Myc, providing a basis for studying the aberrant response of this leukemia subtype to retinoic acid.	SIGNOR-256374	0.2
PIM2	protein	Q9P1W9	UNIPROT	PFKFB3	protein	Q16875	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser478	TKKPRINsFEEHVAS	9606	BTO:0002181								33931981	t		miannu	We used biochemical methods to determine that PIM2 can directly bind and change the phosphorylation of PFKFB3 at Ser478 to enhance PFKFB3 protein stability through the ubiquitin-proteasome pathway.	SIGNOR-277554	0.2
PKM	protein	P14618	UNIPROT	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	down-regulates quantity	chemical modification			9606									15996096	t		miannu	Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A).	SIGNOR-266534	0.8
AKT3	protein	Q9Y243	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	up-regulates	phosphorylation			9606	BTO:0001454								19609947	t		lperfetto	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-217466	0.396
pentazocine	chemical	CHEBI:7982	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258766	0.8
PABPC1	protein	P11940	UNIPROT	EIF4E	protein	P06730	UNIPROT	up-regulates activity	binding			9606									30209168	t		miannu	The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling	SIGNOR-260968	0.799
JUN	protein	P05412	UNIPROT	CFI	protein	P05156	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10630630	f	 	miannu	 The production of CFI by Hep G2 cells was enhanced in a dose- and time-dependent fashion by 12-O-tetradecanoyl-1,2-phorbol 13-acetate (TPA), a potent PKC activator. The enhancement of the activity of transfected chimeric CAT constructs by TPA was abrogated by calphostin C and by pyrrolidine dithiocarbamate (an inhibitor of NF-kappaB and AP-1 transactivation). These results indicate that TPA regulation of CFI gene requires PKC signalling and is mediated by via a TPA response element (TRE) in the CFI promoter region located at -136/-130 and involves the transactivation of AP-1 and NF-kappaB transcription factors	SIGNOR-254787	0.2
entinostat	chemical	CHEBI:132082	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257963	0.8
NRP1	protein	O14786	UNIPROT	CoV2 spike protein-NRP1	complex	SIGNOR-C267	SIGNOR	form complex	binding			9606	BTO:0000007								other	t	 https://doi.org/10.1101/2020.06.07.137802	miannu	Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system To determine whether SARS-CoV-2 uses NRP1 for virus entry, we generated replication deficient lentiviruses pseudotyped with SARS-CoV-2 spike protein (S) that drive expression of green fluorescent protein (GFP) upon infection. When expressed alone, ACE2 rendered cells susceptible to infection (Fig. 1a). NRP1 alone allowed lower, yet detectable levels of infection, both in HEK-293T and in Caco2 cells (Fig. 1a,b), while cells transfected with plasmids encoding only TMPRSS2 were not infected (Fig. 1a). The co-expression of TMPRSS2 with either ACE2 or NRP1 potentiated the infection, with ACE2 together with TMPRSS2 being twice as efficient as NRP1 with TMPRSS2 (Fig. 1c)	SIGNOR-261672	0.2
ATP5F1A	protein	P25705	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261396	0.2
PHA-665752	chemical	CHEBI:90197	ChEBI	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206088	0.8
SSTR2	protein	P30874	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256684	0.563
CEP135	protein	Q66GS9	UNIPROT	SASS6	protein	Q6UVJ0	UNIPROT	up-regulates activity	binding			9606									23511974	t		miannu	 In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation.	SIGNOR-269676	0.616
WNT10B	protein	O00744	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates				9606									21872687	f		fspada	We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b	SIGNOR-176190	0.488
Tosedostat	chemical	CID:15547703	PUBCHEM	ANPEP	protein	P15144	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207372	0.8
PDCD1	protein	Q15116	UNIPROT	T cell exhaustion 	phenotype	SIGNOR-PH221	SIGNOR	up-regulates				9606	BTO:0000782								28286692	f		Barakat	Programmed cell death-1 (PD-1) is a major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores T-cell function and improves pathogen control and tumor eradication. Immunotherapy targeting the PD-1 inhibitory receptor pathway has demonstrated significant antitumor activity. 	SIGNOR-275413	0.7
RASGRF2	protein	O14827	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260575	0.535
GP1BA	protein	P07359	UNIPROT	GPIb-IX-V complex	complex	SIGNOR-C270	SIGNOR	form complex	binding			9606	BTO:0000132								16293600	t		lperfetto	The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1.	SIGNOR-261847	0.697
(2s)-1-{[5-(3-Methyl-1h-Indazol-5-Yl)pyridin-3-Yl]oxy}-3-Phenylpropan-2-Amine	chemical	CID:11314340	PUBCHEM	AKT1	protein	P31749	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258064	0.8
TLRs	proteinfamily	SIGNOR-PF20	SIGNOR	TICAM2	protein	Q86XR7	UNIPROT	up-regulates activity	binding			9606									20404851	t		lperfetto	These differences are explained by the discovery of TIR domain’containing adaptor molecules, including MyD88, TIRAP (Mal), TRIF and TRAM, which are recruited by distinct TLRs and activate distinct signaling pathways	SIGNOR-216307	0.2
GSK3A	protein	P49840	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates	phosphorylation	Ser137	PVSSPQSsPRLPRRP	9606									22778263	t		lperfetto	Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity.	SIGNOR-198130	0.272
EGFR	protein	P00533	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	phosphorylation	Tyr771	IGTAEPDyGALYEGR	9606									1689310	t		llicata	We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation.	SIGNOR-20984	0.835
RTKs	proteinfamily	SIGNOR-PF38	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity	phosphorylation			9606									30889378	t		miannu	The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs.	SIGNOR-259030	0.2
AHCYL1	protein	O43865	UNIPROT	PP1	proteinfamily	SIGNOR-PF54	SIGNOR	up-regulates activity	relocalization			10090		BTO:0000988							21317537	t		lperfetto	WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression,	SIGNOR-264645	0.2
MAPK13	protein	O15264	UNIPROT	PRKD1	protein	Q15139	UNIPROT	down-regulates	phosphorylation			9606									19135240	t		gcesareni	P38delta catalyzes an inhibitory phosphorylation of pkd1, thereby attenuating stimulated insulin secretion.	SIGNOR-183280	0.2
BMPR1B	protein	O00238	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	form complex	binding			9606									7791754	t		lperfetto	Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii).	SIGNOR-33431	0.541
NF1	protein	P21359	UNIPROT	ADCY9	protein	O60503	UNIPROT	up-regulates				9606	BTO:0000938								24431436	f		miannu	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-204354	0.31
CDC14A	protein	Q9UNH5	UNIPROT	WEE1	protein	P30291	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser123	EEGFGSSsPVKSPAA	9606									23051732	t		lperfetto	However, when both Ser-123 and Ser-139 were modified (2A), although Wee1 was still phosphorylated by Cdk1, treatment with active Cdc14A did not decrease the phosphorylation signal to any significant extent ( xref , lane 5), indicating that Cdc14A dephosphorylates Wee1 at Ser-123 and Ser-139 residues.|Our results indicate that Wee1 is a substrate of Cdc14 phosphatases in human cells and that by reversing specific Cdk1 phosphorylation, the Cdc14A isoform induces Wee1 stability, which in turn directly inhibits Cdk1 activity.	SIGNOR-276952	0.562
MAP2K7	protein	O14733	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates	phosphorylation	Thr221	AGTSFMMtPYVVTRY	9606									15911620	t		lperfetto	Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19).	SIGNOR-137609	0.564
CDC14A	protein	Q9UNH5	UNIPROT	WEE1	protein	P30291	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser139	YFLGSSFsPVRCGGP	9606									23051732	t		lperfetto	However, when both Ser 123 and Ser 139 were modified (2A), although Wee1 was still phosphorylated by Cdk1, treatment with active Cdc14A did not decrease the phosphorylation signal to any significant extent (XREF_FIG, lane 5), indicating that Cdc14A dephosphorylates Wee1 at Ser 123 and Ser 139 residues.|Our results indicate that Wee1 is a substrate of Cdc14 phosphatases in human cells and that by reversing specific Cdk1 phosphorylation, the Cdc14A isoform induces Wee1 stability, which in turn directly inhibits Cdk1 activity.	SIGNOR-276953	0.562
MAT2B	protein	Q9NZL9	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0001938								30942439	f		miannu	MAT2B Promotes Proliferation and Inhibits Apoptosis in Osteosarcoma by Targeting Epidermal Growth Factor Receptor and Proliferating Cell Nuclear Antigen	SIGNOR-261242	0.7
torin 2	chemical	CHEBI:90682	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									23436801	t	ATP-competitive inhibitor	gcesareni	Torin2, a second generation atp-competitive inhibitor that is potent and selective for mtor..	SIGNOR-201499	0.8
CDK2	protein	P24941	UNIPROT	PP1	proteinfamily	SIGNOR-PF54	SIGNOR	down-regulates activity	phosphorylation			9606									12202491	t		lperfetto	Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity	SIGNOR-264650	0.385
RELA	protein	Q04206	UNIPROT	B2M	protein	P61769	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12480693	f		miannu	 The nuclear factor kappa B (NF-kappa B) subunits p50 and p65 bind to the kappa B box and p65 transactivates beta(2)m. 	SIGNOR-254657	0.265
IFNL3	protein	Q8IZI9	UNIPROT	IL10RB	protein	Q08334	UNIPROT	up-regulates	binding			9606									12469119	t		gcesareni	Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.	SIGNOR-96246	0.842
PRKACA	protein	P17612	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	phosphorylation	Ser188	ARRGKKKsGCLVL	10090									12654918	t		miannu	PKA phosphorylates RhoA on Ser188. the addition of a negative charge to Ser188 is sufficient to diminish both RhoA activation and activity within the context of a cell. 	SIGNOR-250047	0.5
PDCD1	protein	Q15116	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity				9606	BTO:0000782								16227604	f		Barakat	Akt phosphorylation in cells stimulated by CD3/CD28/CTLA-4 or CD3/CD28/PD-1 aAPCs did not have detectable phosphorylated Akt at any time point, indicating that CTLA-4 and PD-1 signaling blocked rather than delayed Akt activation.	SIGNOR-275408	0.352
Calcineurin	complex	SIGNOR-C155	SIGNOR	MYOD1	protein	P15172	UNIPROT	up-regulates				9606		BTO:0001103							15829723	f		apalma	Calcineurin can activate the transcription factors myocyte enhancer factor-2 and MyoD, which leads to the subsequent induction of myogenin and muscle differentiation (22). In addition, inhibition of calcineurin prevents the initiation of early stages of muscle differentiation	SIGNOR-255103	0.268
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates	dephosphorylation			9606									18676376	t		lperfetto	Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes.	SIGNOR-252321	0.635
PLK2	protein	Q9NYY3	UNIPROT	FBXW7	protein	Q969H0	UNIPROT	down-regulates	phosphorylation	Ser176	KRKLDHGsEVRSFSL	9606									22399798	t		lperfetto	Plk2 regulates centriole duplication through phosphorylation-mediated degradation of fbxw7 (human cdc4).Plk2 phosphorylates fbxw7 on serine 176	SIGNOR-196448	0.497
GRM5	protein	P41594	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264348	0.7
MAP3K8	protein	P41279	UNIPROT	MAP2K2	protein	P36507	UNIPROT	up-regulates	phosphorylation	Ser222	VSGQLIDsMANSFVG	9606	BTO:0000007								15466476	t		lperfetto	Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases.	SIGNOR-129694	0.415
fumarate(2-)	smallmolecule	CHEBI:29806	ChEBI	(S)-malate(2-)	smallmolecule	CHEBI:15589	ChEBI	up-regulates quantity	precursor of			9606									30761759	t		miannu	Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors.	SIGNOR-266278	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Ser1064	SCPIKEDsFLQRYSS	9606	BTO:0000007								10347170	t		llicata	 We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. 	SIGNOR-250619	0.378
PMS1	protein	P54277	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates activity				10090									9500552	f			Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer	SIGNOR-257597	0.7
Integrator complex	complex	SIGNOR-C265	SIGNOR	JUNB	protein	P17275	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								25675981	f		lperfetto	The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes.	SIGNOR-261479	0.2
CDC7	protein	O00311	UNIPROT	ESCO1	protein	Q5FWF5	UNIPROT	down-regulates	phosphorylation			9606									23314252	t		gcesareni	We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases, cdc7-dbf4 and the gsk-3 homolog mck1.	SIGNOR-200397	0.442
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity	phosphorylation			10090	BTO:0002572								28646232	t	inferred from 70% family members	Gianni	We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels	SIGNOR-270068	0.2
SNRPA	protein	P09012	UNIPROT	U1 snRNP complex	complex	SIGNOR-C480	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270678	0.818
MED18	protein	Q9BUE0	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266672	0.876
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	T-reg_differentiation	phenotype	SIGNOR-PH91	SIGNOR	down-regulates				9606									21364186	f			Lowering the extent of costimulation of P2X in T cells diminishes the extent of ERK phosphorylation without affecting TCR-mediated nuclear translocation of NFAT (10). In Tregs, this mechanism would favor the stability of their transcriptional program through the stabilization of nuclear complexes of NFAT and Foxp3 (47).	SIGNOR-254687	0.7
LY-2157299	chemical	CHEBI:137064	ChEBI	TGFBR2	protein	P37173	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193778	0.8
RPS6KA3	protein	P51812	UNIPROT	WWC1	protein	Q8IX03	UNIPROT	up-regulates	phosphorylation	Thr929	STIIRSKtFSPGPQS	9606		BTO:0000149							24269383	t		llicata	Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2.	SIGNOR-203306	0.2
pictrelisib	chemical	CHEBI:65326	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0000149							21876152	t		gcesareni	Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed	SIGNOR-176301	0.8
PPARG	protein	P37231	UNIPROT	FABP4	protein	P15090	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000975							8943212	f		fspada	We report that insulin and a ppargamma ligand (thiazolidinedione (tzd)) stimulate in a synergistic manner the expression of an adipocyte-specific gene (ap2) in rat adipocytes and 3t3-l1 cells	SIGNOR-45294	0.673
Sin3B_complex	complex	SIGNOR-C409	SIGNOR	H3Y1	protein	P0DPK2	UNIPROT	down-regulates activity	binding			9606									21041487	t		miannu	We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin.	SIGNOR-266975	0.2
CTDSP1	protein	Q9GZU7	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	dephosphorylation	Ser214	PTSSDPGsPFQMPAD	9606	BTO:0000552								17085434	t			Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)	SIGNOR-248801	0.476
MAPK1	protein	P28482	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation	Ser405	KTQTPPVsPAPQPTE	9606	BTO:0000938								20444238	t		gcesareni	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-165200	0.481
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BANP	protein	Q8N9N5	UNIPROT	down-regulates activity	phosphorylation	Thr352	PSEPMMStPPPASEL	9606	BTO:0000567								26080397	t		miannu	ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68. 	SIGNOR-266204	0.2
SRC	protein	P12931	UNIPROT	BAIAP2L1	protein	Q9UHR4	UNIPROT	up-regulates activity	phosphorylation	Tyr274	SNVVRKDyDTLSKCS	-1									21840312	t		miannu	Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility.	SIGNOR-263039	0.399
CAPN3	protein	P20807	UNIPROT	GSK3A	protein	P49840	UNIPROT	up-regulates activity	cleavage			9606									25969760	t		lperfetto	Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase	SIGNOR-251606	0.2
SRC	protein	P12931	UNIPROT	GRIK2	protein	Q13002	UNIPROT	up-regulates activity	phosphorylation	Tyr590	RFSPYEWyNPHPCNP	9606	BTO:0000007								25201974	t		miannu	GluK2 binds to Src, and the tyrosine residue at position 590 (Y590) on GluK2 is a major site of phosphorylation by Src kinases. GluK2 phosphorylation at Y590 is responsible for increases in whole-cell currents and calcium influx in response to transient kainate stimulation.	SIGNOR-276850	0.381
MYOG	protein	P15173	UNIPROT	MYF6	protein	P23409	UNIPROT	up-regulates quantity by expression	transcriptional regulation					BTO:0001103							7739551	t		Simone Vumbaca	[...] confirming that myogenin binds to the E1 and E2 E boxes located in close proximity to the MRF4 transcription start site.	SIGNOR-255642	0.408
KDM6A	protein	O15550	UNIPROT	ELF4	protein	Q99607	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									29736013	t		miannu	Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase	SIGNOR-260031	0.283
ATM	protein	Q13315	UNIPROT	PVR	protein	P15151	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000914								21406724	f	 	 	The up-regulation of PVR expression involves DNA-damage response (DDR)-dependent pathways, because we found that pharmacologic inhibition of ATM and ATR kinases reduced PVR expression and that PVR was almost exclusively induced on cells expressing the DDR marker γH2AX.	SIGNOR-253927	0.253
GOLGA7	protein	Q7Z5G4	UNIPROT	NRAS	protein	P01111	UNIPROT	up-regulates activity	palmitoylation			9606	BTO:0000007								16000296	t		miannu	Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein.	SIGNOR-261354	0.405
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252826	0.908
PRKACA	protein	P17612	UNIPROT	TFAP2A	protein	P05549	UNIPROT	up-regulates	phosphorylation	Ser239	AEVQRRLsPPECLNA	9606									10037142	t		llicata	Recombinant ap-2 was phosphorylated in vitro by protein kinase a (pka) at ser239. Mutation of ser239 to ala abolished in vitro phosphorylation of ap-2 by pka, but not the dna binding activity of ap-2. Cotransfection studies showed that pka stimulated the effect of ap-2 on the apoe promoter, but not that of the s239a mutant.	SIGNOR-64955	0.2
KLF8	protein	O95600	UNIPROT	CTBP2	protein	P56545	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								10756197	t		miannu	Here we report the characterisation of KLF8/ZNF741/BKLF3 (KLF8). We demonstrate that this protein is able to bind CACCC-boxes in DNA and can repress gene expression by associating with CtBP co-repressors.	SIGNOR-236962	0.547
GSK3B	protein	P49841	UNIPROT	ZNF322	protein	Q6U7Q0	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser391	SEKGLELsPPHASEA	9606	BTO:0002552								28581525	t		lperfetto	CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction. 	SIGNOR-264891	0.2
HDAC1	protein	Q13547	UNIPROT	DNMT1	protein	P26358	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									23242655	f	 	 	Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells.	SIGNOR-254028	0.779
CEP192	protein	Q8TEP8	UNIPROT	AURKA	protein	O14965	UNIPROT	up-regulates activity	binding			9606									26012549	t		miannu	These findings demonstrated that Cep192 mediates the AurA-Plk1 interaction and that the formation of the Cep192-AurA-Plk1 complex could be important for activating AurA and Plk1.	SIGNOR-266406	0.787
CBX3	protein	Q13185	UNIPROT	NIPBL	protein	Q6KC79	UNIPROT	up-regulates activity	binding			9606									28167679	t		miannu	The heterochromatin protein HP1γ (also known as CBX3) recruits NIPBL to DNA double-strand breaks (DSBs) through the corresponding HP1-binding motif within the N-terminus.	SIGNOR-264524	0.447
CBLC	protein	Q9ULV8	UNIPROT	LRIG1	protein	Q96JA1	UNIPROT	down-regulates	ubiquitination			9606		BTO:0001253							15282549	t		gcesareni	Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation	SIGNOR-127292	0.2
JQ1	chemical	CHEBI:137113	ChEBI	BRD4	protein	O60885	UNIPROT	down-regulates activity	chemical inhibition			-1									20871596	t		lperfetto	Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. 	SIGNOR-261989	0.8
PLEKHG4	protein	Q58EX7	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260564	0.368
PLK1	protein	P53350	UNIPROT	DCTN1	protein	Q14203	UNIPROT	up-regulates	phosphorylation	Ser179	SASAGELsSSEPSTP	9606									20679239	t		lperfetto	Plk1-mediated phosphorylation of p150(glued) at ser-179 positively regulates its accumulation at the nuclear envelope during prophase.	SIGNOR-167281	0.539
JAK1	protein	P23458	UNIPROT	PTPN11	protein	Q06124	UNIPROT	up-regulates activity	phosphorylation	Tyr304	PNEPVSDyINANIIM	9534									8995399	t		lperfetto	Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2.	SIGNOR-236282	0.759
SRC	protein	P12931	UNIPROT	KCNJ1	protein	P48048	UNIPROT	down-regulates	phosphorylation	Tyr337	SKTKEGKyRVDFHNF	9606									12217858	t		gcesareni	Addition of active c-src and [32p]atp to the purified romk1 protein resulted in the phosphorylation of the romk1 protein. However, c-src did not phosphorylate r1y337a in which tyrosine residue 337 was mutated to alanine. Furthermore, phosphopeptide mapping identified two phosphopeptides from the trypsin-digested romk1 protein.	SIGNOR-92513	0.318
NFKBIA	protein	P25963	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates activity	binding			9606									9914500	t		lperfetto	In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon.	SIGNOR-64092	0.807
RPA1	protein	P27694	UNIPROT	BRIP1	protein	Q9BX63	UNIPROT	up-regulates activity	binding			9606									17596542	t		irozzo	Our data are consistent with a model in which FANCJ associates with RPA in a DNA damage-inducible manner and through the protein interaction RPA stimulates FANCJ helicase to better unwind duplex DNA substrates. These findings identify RPA as the first regulatory partner of FANCJ.	SIGNOR-259187	0.684
PI3K	complex	SIGNOR-C156	SIGNOR	PIP3	smallmolecule	CHEBI:16618	ChEBI	up-regulates quantity				9606									21798082	t		lperfetto	Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2).	SIGNOR-252722	0.8
SYK	protein	P43405	UNIPROT	SH3BP2	protein	P78314	UNIPROT	up-regulates activity	phosphorylation	Tyr174	YPTDNEDyEHDDEDD	9534									12709437	t		lperfetto	By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk.	SIGNOR-246587	0.569
IHH	protein	Q14623	UNIPROT	BMP2	protein	P12643	UNIPROT	up-regulates				9606									22298955	f		gcesareni	Ihh is found to be required for bmp-induced os-teogenesis of a limb-bud cell line in culture. Ihh sig-naling is directly required for the osteoblast lineage in developing long bones. Ihh functions in conjunction with other factors such as bmps to induce osteoblast differentiation. In vivo, ihh acts on potential progeni-tor cells to promote osteoblast differentiation and prevent chondrocyte differentiation.	SIGNOR-195609	0.533
EP300	protein	Q09472	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates activity	acetylation			9606	BTO:0003292								28045112	t		lperfetto	Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection.|Brd3 enhances p300-mediated acetylation of IRF3|Importantly, Brd3 promotes the recruitment of IRF3/p300 complex to the promoter of Ifnb1, and increases the acetylation of histone3/histone4 within the Ifnb1 promoter, leading to the enhancement of type I interferon production. 	SIGNOR-262045	0.2
HECTD3	protein	Q5T447	UNIPROT	MALT1	protein	Q9UDY8	UNIPROT	up-regulates quantity by stabilization	polyubiquitination			9606	BTO:0000007								23358872	t		miannu	HECTD3 promotes MALT1 ubiquitination with nondegradative polyubiquitin chains by direct interacting with the MALT1 through its N-terminal destruction of cyclin domain. HECTD3 does not target MALT1 for degradation but stabilize it. 	SIGNOR-272096	0.374
COP1	protein	Q8NHY2	UNIPROT	COP1	protein	Q8NHY2	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0001938								19805145	t		miannu	MTA1 destabilizes COP1 by promoting its autoubiquitination. in addition to polyubiquitination of its substrates, COP1 also catalyzes its autoubiquitination for degradation as a part of an autoregulatory mechanism	SIGNOR-271893	0.2
UBN2	protein	Q6ZU65	UNIPROT	HIRA complex 2	complex	SIGNOR-C462	SIGNOR	form complex	binding			9606									30285846	t		miannu	H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex.	SIGNOR-269436	0.382
F2RL1	protein	P55085	UNIPROT	CD44	protein	P16070	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254843	0.2
PRKD1	protein	Q15139	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser172	GQLVRNDsLWHRSDS	9606	BTO:0002181								34010649	t		miannu	PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-277559	0.2
frovatriptan	chemical	CHEBI:134991	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			-1									9986723	t		miannu	As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold).	SIGNOR-259074	0.8
CyclinD3/CDK6	complex	SIGNOR-C234	SIGNOR	PKM	protein	P14618	UNIPROT	down-regulates activity	phosphorylation	Ser37	MCRLDIDsPPITARN	9606	BTO:0000782								28607489	t		lperfetto	Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3–CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2.|Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity	SIGNOR-273032	0.263
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	SMAD3	protein	P84022	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0000298								11359933	t		miannu	Smad3 interacts with a RING finger protein, ROC1, through its C-terminal MH2 domain in a ligand-dependent manner. An E3 ubiquitin ligase complex ROC1-SCF(Fbw1a) consisting of ROC1, Skp1, Cullin1, and Fbw1a (also termed betaTrCP1) induces ubiquitination of Smad3. 	SIGNOR-272944	0.433
TTC3	protein	P53804	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000944								20059950	t		gcesareni	TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus	SIGNOR-252459	0.404
LSM-1231	chemical	CHEBI:91471	ChEBI	NTRK3	protein	Q16288	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258240	0.8
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser374	PSSDSLSsPTLLAL										16055710	t		lperfetto	Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos	SIGNOR-262998	0.2
MAP2K6	protein	P52564	UNIPROT	MAPK12	protein	P53778	UNIPROT	up-regulates	phosphorylation	Tyr185	ADSEMTGyVVTRWYR	9606									19230643	t		gcesareni	Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily . the p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms . p38mapks are activated by dual phosphorylation on a t-x-y motif in the activation loop through the action of map kinase kinases	SIGNOR-184138	0.644
SP3	protein	Q02447	UNIPROT	CADM1	protein	Q9BY67	UNIPROT	up-regulates quantity by expression	transcriptional regulation												18794147	f		lperfetto	Treatment with mithramycin A, an inhibitor of Sp1 or Sp3 binding, resulted in reduction of Cadm1 gene expression, therefore suggesting a potential role of Sp1/Sp3 in Cadm1 regulation.	SIGNOR-268959	0.273
TBK1	protein	Q9UHD2	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Thr404	NSHPLSLtSDQYKAY	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178420	0.817
CSNK2A1	protein	P68400	UNIPROT	IKZF1	protein	Q13422	UNIPROT	down-regulates	phosphorylation	Ser13	GQDMSQVsGKESPPV	9606	BTO:0001271								21750978	t		miannu	We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo	SIGNOR-174824	0.294
SMARCA2	protein	P51531	UNIPROT	SMARCC1	protein	Q92922	UNIPROT	up-regulates	binding			9606									10078207	t		miannu	The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.	SIGNOR-65432	0.908
PRKCA	protein	P17252	UNIPROT	LRRK1	protein	Q38SD2	UNIPROT	up-regulates activity	phosphorylation	Ser1064	NRKVTIYsFTGNQRN	-1									36040231	t		miannu	PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain. 	SIGNOR-276866	0.2
EZH2	protein	Q15910	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	down-regulates activity				10090									15520282	f			We report that Ezh2 expression was developmentally regulated in the myotome compartment of mouse somites and that its down-regulation coincided with activation of muscle gene expression and differentiation of satellite-cell-derived myoblasts	SIGNOR-255719	0.7
cholesterol	smallmolecule	CHEBI:16113	ChEBI	pregnenolone	smallmolecule	CHEBI:16581	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000048							33117906	t		lperfetto	The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme.	SIGNOR-268629	0.8
ARNTL	protein	O00327	UNIPROT	CRY2	protein	Q49AN0	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f			Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253627	0.931
PRKCA	protein	P17252	UNIPROT	ADD3	protein	Q9UEY8	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser693	KKKFRTPsFLKKNKK	-1									11895774	t		lperfetto	Results of in vitro experiments with recombinant alpha adducin demonstrated that PKC-phosphorylated adducin was proteolyzed by calpain more quickly than unphosphorylated adducin. | Phosphorylation of adducin by PKC may be a common mechanism for regulating adducin proteolysis by several proteases. | The antibody used in panel B is specific for the PKC-phosphorylated form of adducin. This antibody was raised against the phosphopeptide CKKFRTP[pS]FLKKNK, corresponding to amino acids 656-668 of human gamma adducin	SIGNOR-249143	0.339
AKT1	protein	P31749	UNIPROT	NQO1	protein	P15559	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser40	KGWEVVEsDLYAMNF	9606	BTO:0000007								31358653	t		miannu	Akt phosphorylates NQO1 on S40 and T128 residues. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase. 	SIGNOR-276868	0.379
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Lys)	smallmolecule	CHEBI:29185	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269490	0.8
MARCHF8	protein	Q5T0T0	UNIPROT	HLA-DRA	protein	P01903	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys244	FIIKGLRkSNAAERR	9606									19117940	t		miannu	Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination.	SIGNOR-271411	0.2
HACE1	protein	Q8IYU2	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									17694067	t		miannu	Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. 	SIGNOR-271405	0.313
TSSK3	protein	Q96PN8	UNIPROT	TSSK3	protein	Q96PN8	UNIPROT	up-regulates activity	phosphorylation	Ser166	PKSHRELsQTFCGST	-1									16336268	t		Manara	We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation.	SIGNOR-260785	0.2
Sincalide	smallmolecule	CID:9833444	PUBCHEM	CCKAR	protein	P32238	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257466	0.8
CSNK1E	protein	P49674	UNIPROT	CSNK1E	protein	P49674	UNIPROT	down-regulates activity	phosphorylation	Ser405	EVSRIPAsQTSVPFD	9606	BTO:0000007								10542239	t		llicata	Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T	SIGNOR-250809	0.2
TFEB	protein	P19484	UNIPROT	CTSD	protein	P07339	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19556463	f	Figure 1	lperfetto	Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 	SIGNOR-276537	0.445
MYOD1	protein	P15172	UNIPROT	RB1	protein	P06400	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									10373569	t		gcesareni	Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator.	SIGNOR-238532	0.403
FYN	protein	P06241	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates activity	phosphorylation	Tyr759	LYDVSRMyVDPSEIN	-1									7682059	t		lperfetto	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249340	0.556
STAT1	protein	P42224	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	binding			9606									19041276	t		lperfetto	Each STAT1 monomer becomes tyrosine phosphorylated at tyrosine 701 by the JAKs, dissociates from the receptor to form a STAT1-STAT1 homodimer which translocates to the nucleus	SIGNOR-249495	0.2
ESR1	protein	P03372	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000938								22169964	f		miannu	 In this study, quantitative real-time PCR analysis showed that the gene expression levels of TTX-S (Nav1.1 and Nav1.7) and TTX-R (Nav1.8 and Nav1.9) sodium channel subtypes were elevated in DRGs of αERKO and βERKO mice, whereas Nav1.6 mRNA decreased in αERKOs but showed no changes in βERKO mice	SIGNOR-253476	0.2
CDK5	protein	Q00535	UNIPROT	CRMP1	protein	Q14194	UNIPROT	up-regulates	phosphorylation	Ser522	PAPSAKSsPSKHQPP	9606	BTO:0000938								18003833	t		lperfetto	These findings suggest that sema3a-induced spine development is regulated by phosphorylation of crmp1 by cdk5. Introduction of crmp1-wt, but not crmp1-t509a/s522a, a crmp1 mutant that cannot be phosphorylated by cdk5, rescued the defect in sema3a responsiveness.	SIGNOR-159314	0.608
NUAK2	protein	Q9H093	UNIPROT	LATS1	protein	O95835	UNIPROT	down-regulates	phosphorylation	Ser464	NIPVRSNsFNNPLGN	9606									19927127	t		gcesareni	Phosphorylation at ser-464 by nuak1 and nuak2 leads to decreased protein level and is required to regulate cellular senescence and cellular ploidy	SIGNOR-161796	0.311
FOXA1	protein	P55317	UNIPROT	HSPA1B	protein	P0DMV9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								19486887	f	 	miannu	 The results showed overexpression of Foxa1 promoted the expression of HSP72, while Foxa1 depletion, induced by antisense oligonucleotides, decreased the expression of HSP72 in MCF-7 cells under normal and heat stress condition. 	SIGNOR-254165	0.2
PRKACA	protein	P17612	UNIPROT	GLIS2	protein	Q9BZE0	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000938								16537363	t		lperfetto	Protein kinase a (pka) and glycogen synthase kinase 3beta sequentially phosphorylate gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity	SIGNOR-145131	0.287
USP7	protein	Q93009	UNIPROT	UBA52	protein	P62987	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270823	0.722
PPARGC1A	protein	Q9UBK2	UNIPROT	Aldolase	proteinfamily	SIGNOR-PF75	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f	inferred from family member	miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-270226	0.258
MAPK1	protein	P28482	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser70	RDPVARTsPLQTPAA	9606	BTO:0000567								10669763	t		lperfetto	Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo.	SIGNOR-74919	0.532
HSPA1A	protein	P0DMV8	UNIPROT	NOD2	protein	Q9HC29	UNIPROT	up-regulates quantity by stabilization	binding			9606									24790089	t		miannu	The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease.	SIGNOR-252416	0.259
IRAK4	protein	Q9NWZ3	UNIPROT	IRAK4	protein	Q9NWZ3	UNIPROT	up-regulates activity	phosphorylation	Thr345	KFAQTVMtSRIVGTT	9606	BTO:0000876								24567333	t		lperfetto	We show irak4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues thr-342, thr-345, and ser-346 is required for full activity	SIGNOR-204661	0.2
GNA13	protein	Q14344	UNIPROT	ARHGEF12	protein	Q9NZN5	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								12024019	t			P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation.	SIGNOR-256519	0.764
GPR84	protein	Q9NQS5	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256983	0.252
PRKN	protein	O60260	UNIPROT	PACRG	protein	Q96M98	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									12150907	t		miannu	In this study, we found that CHIP promotes Parkin-mediated Pael-R ubiquitination and subsequent degradation. In vitro ubiquitination assays suggested that only a combination of both Parkin and its cofactor CHIP function as a ubiquitin ligase, which is able to sufficiently ubiquitinate Pael-R in vivo (Figure 6). 	SIGNOR-272889	0.2
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258016	0.8
L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	up-regulates quantity	precursor of			9606									26003525	t		miannu	Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and α-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer.	SIGNOR-267504	0.8
STAT6	protein	P42226	UNIPROT	KLF4	protein	O43474	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25934862	f		miannu	IL-4-induced macrophage polarization involves induction of STAT6 and KLF4 that induce each other and promote M2 polarization. 	SIGNOR-254519	0.353
CDK1	protein	P06493	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1497	EPGVERSsPSKCPSL	9606	BTO:0000150								10550055	t		gcesareni	However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci.	SIGNOR-72087	0.511
EGF	protein	P01133	UNIPROT	HBA1	protein	P69905	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									9168989	f	Regulation	miannu	We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin.	SIGNOR-251785	0.2
PRKCD	protein	Q05655	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	phosphorylation			9606									19363025	t		gcesareni	We identify protein kinase c-delta as the kinase responsible for h3t45ph in vitro and in vivo. Given the nucleosomal position of h3t45, we postulate that h3t45ph induces structural change within the nucleosome to facilitate dna nicking and/or fragmentation.	SIGNOR-265368	0.2
AKT1	protein	P31749	UNIPROT	EIF4B	protein	P23588	UNIPROT	up-regulates	phosphorylation	Ser422	RERSRTGsESSQTGT	9606									18836482	t		gcesareni	Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b.	SIGNOR-252520	0.404
CDON	protein	Q4KMG0	UNIPROT	CDON/BOC/PTCH1	complex	SIGNOR-C95	SIGNOR	form complex	binding			10090									21664576	t		lperfetto	Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands.	SIGNOR-209596	0.554
Mob1	proteinfamily	SIGNOR-PF42	SIGNOR	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	up-regulates activity	binding			9606									21084559	t		miannu	Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1.	SIGNOR-256186	0.941
PBRM1	protein	Q86U86	UNIPROT	SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270596	0.773
CASP3	protein	P42574	UNIPROT	GORASP1	protein	Q9BQQ3	UNIPROT	down-regulates quantity by destabilization	cleavage	Asp372	EFEVSFLdSPGAQAQ	9606	BTO:0000567								11815631	t		Giulio	Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage	SIGNOR-260603	0.405
CDK5	protein	Q00535	UNIPROT	STMN3	protein	Q9NZ72	UNIPROT	unknown	phosphorylation	Ser68	PSDLSPEsPMLSSPP	-1									22577147	t		lperfetto	Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta	SIGNOR-264893	0.329
somatostatin	smallmolecule	CHEBI:64628	ChEBI	SSTR3	protein	P32745	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257583	0.8
SENP1	protein	Q9P0U3	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates quantity by destabilization	desumoylation	Lys276	NVVYRDLkLENLMLD	10090	BTO:0002572								23884910	t		gcesareni	Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity.	SIGNOR-252736	0.284
PTPN11	protein	Q06124	UNIPROT	GAB2	protein	Q9UQC2	UNIPROT	down-regulates	dephosphorylation	Tyr614	KSTGSVDyLALDFQP	9606									15170389	t		gcesareni	Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2.	SIGNOR-124958	0.733
MAP2K5	protein	Q13163	UNIPROT	MAPK7	protein	Q13164	UNIPROT	up-regulates activity	phosphorylation	Tyr221	HQYFMTEyVATRWYR	9606	BTO:0000567								20667468	t		miannu	ERK5 is a member of the mitogen-activated protein kinase (MAPK) family that, after stimulation, is activated selectively by dual phosphorylation in the TEY motif by MAPK kinase 5 (MEK5). ERK5 is activated selectively by dual phosphorylation on Thr218 and Tyr220 in the TEY motif by its only upstream kinase, MEK5, a member of the MEK 	SIGNOR-259825	0.69
NFE2L2	protein	Q16236	UNIPROT	Metastasis	phenotype	SIGNOR-PH107	SIGNOR	up-regulates				9606	BTO:0000599								26194347	f		irozzo	Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes.	SIGNOR-259285	0.7
CDC25A	protein	P30304	UNIPROT	CDK6	protein	Q00534	UNIPROT	up-regulates activity	dephosphorylation	Tyr24	AEIGEGAyGKVFKAR	9606	BTO:0000007								23429262	t		lperfetto	Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs.	SIGNOR-267569	0.693
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser115	PAPSSFSsTSVSSLE	9606									15448698	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-129414	0.575
PTPN2	protein	P17706	UNIPROT	KDR	protein	P35968	UNIPROT	unknown	dephosphorylation	Tyr996	EEAPEDLyKDFLTLE	9606	BTO:0000007								18840653	t			We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well. 	SIGNOR-248398	0.548
EDNRA	protein	P25101	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257052	0.392
PCF11	protein	O94913	UNIPROT	CFII complex	complex	SIGNOR-C387	SIGNOR	form complex	binding			9606	BTO:0000567								30139799	t		lperfetto	Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1.	SIGNOR-266119	0.885
ADRA2C	protein	P18825	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256842	0.465
MAP3K1	protein	Q13233	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	phosphorylation			9606									9712898	t		lperfetto	The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, SEK1	SIGNOR-236376	0.717
NPAS1	protein	Q99742	UNIPROT	TH	protein	P07101	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003945								17457889	t	 	lperfetto	Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter.	SIGNOR-253702	0.255
MRPL35	protein	Q9NZE8	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262362	0.627
KLF4	protein	O43474	UNIPROT	TNF	protein	P01375	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000801								22378047	f		miannu	KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPARγ) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-κB activation.	SIGNOR-254520	0.338
SRC	protein	P12931	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates	phosphorylation	Tyr1165	RDIYETDyYRKGGKG	-1									7493944	t		lperfetto	The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.	SIGNOR-246264	0.564
SLC9A8	protein	Q9Y2E8	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265607	0.8
GNAI2	protein	P04899	UNIPROT	ADCY1	protein	Q08828	UNIPROT	down-regulates	binding			9606									8327893	t		gcesareni	Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required	SIGNOR-37973	0.579
LMX1A	protein	Q8TE12	UNIPROT	NLI/Lmx1.1/Isl1 	complex	SIGNOR-C103	SIGNOR	form complex	binding			9606	BTO:0000007								9452425	t		lperfetto	Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas.	SIGNOR-236812	0.345
F2RL1	protein	P55085	UNIPROT	TXNIP	protein	Q9H3M7	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	 PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 	SIGNOR-254857	0.2
GNAS	protein	P63092	UNIPROT	ADCY1	protein	Q08828	UNIPROT	up-regulates activity	binding			9606									17652154	t		gcesareni	Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR	SIGNOR-156958	0.612
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation	Ser119	EILSRRPsYRKILND	9606									8386317	t		miannu	CREB is phosphorylated on Ser133 by PKA (protein kinase A), promoting the recruitment of the co-activator proteins CBP (CREB-binding protein) and p300; this has been proposed to increase the transcription of CREB-dependent genes. 	SIGNOR-263653	0.2
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	BIRC6	protein	Q9NR09	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271352	0.418
RAB12	protein	Q6IQ22	UNIPROT	SLC36A4	protein	Q6YBV0	UNIPROT	down-regulates quantity by destabilization	relocalization			10090	BTO:0002572								23478338	t		lperfetto	We also found that Rab12 promotes constitutive degradation of PAT4 (proton‐coupled amino‐acid transporter 4|Rab12 regulates lysosomal localization or degradation of amino‐acid transporters. 	SIGNOR-264763	0.457
FZD3	protein	Q9NPG1	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	binding			9606									20828404	t		gcesareni	Upon ligand binding, non-canonical wnt signaling controls tissue polarity and cell movement through the activation of rhoa, c-jun n-terminal kinase (jnk), and nemo-like kinase (nlk) signaling cascades.	SIGNOR-167865	0.352
CDK9	protein	P50750	UNIPROT	SUPT5H	protein	O00267	UNIPROT	up-regulates	phosphorylation	Thr814	PLHDGSRtPAQSGAW	9606									16427012	t		lperfetto	We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif	SIGNOR-143943	0.769
RNF2	protein	Q99496	UNIPROT	Polycomb repressive complex 1	complex	SIGNOR-C408	SIGNOR	form complex	binding			9606									31608994	t		miannu	PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b	SIGNOR-266811	0.821
MAPK9	protein	P45984	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									20068231	t		gcesareni	Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.	SIGNOR-163262	0.686
CSNK2A1	protein	P68400	UNIPROT	WASF2	protein	Q9Y6W5	UNIPROT	down-regulates	phosphorylation	Ser482	RRIAVEYsDSEDDSS	9606									19012317	t		gcesareni	Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo.	SIGNOR-182350	0.2
TRAF6	protein	Q9Y4K3	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0000007								17135271	t			These data establish a signaling cascade in which regulated site-specific Lys-63-linked TRAF6 auto-ubiquitination is the critical upstream mediator of IKK.	SIGNOR-252099	0.2
CSNK2A1	protein	P68400	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	phosphorylation	Ser543	SIADMDFsALLSQIS	9606									10938077	t		llicata	We demonstrate that casein kinase II (CKII) interacts with p65 in vivo and can phosphorylate p65 at serine 529 in vitro. A CKII inhibitor (PD144795) inhibited TNFalpha-induced p65 phosphorylation in vivo. Furthermore, our results indicate that the association between IkappaBalpha and p65 inhibits p65 phosphorylation by CKII and that degradation of IkappaBalpha allows CKII to phosphorylate p65 to increase NF-kappaB transactivation potential. 	SIGNOR-250942	0.455
NPM1	protein	P06748	UNIPROT	HOXA9	protein	P31269	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30205049	t		miannu	In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation.	SIGNOR-260138	0.36
PRKCA	protein	P17252	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates				9606	BTO:0000599								15730925	f		irozzo	PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC.	SIGNOR-256660	0.7
FASN	protein	P49327	UNIPROT	NADP(3-)	smallmolecule	CHEBI:58349	ChEBI	up-regulates quantity	chemical modification			9606									15507492	t		miannu	Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the de novo biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH. 	SIGNOR-268087	0.8
HTR2A	protein	P28223	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257227	0.424
SLC35A2	protein	P78381	UNIPROT	UDP-D-galactose	smallmolecule	CHEBI:18307	ChEBI	up-regulates quantity	relocalization			9606									34384782	t		miannu	The CMP-sialic acid transporter SLC35A1 and UDP-galactose transporter SLC35A2 are two well-characterized nucleotide sugar transporters with distinctive substrate specificities. Nucleotide sugar transporters (NSTs) transport nucleotide sugars from the cytosol into the lumen of the endoplasmic reticulum or the Golgi apparatus, where the nucleotide sugars serve as substrates for protein glycosylation and glycosphingolipid synthesis. 	SIGNOR-268465	0.8
SMAD4	protein	Q13485	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11689553	t		lperfetto	Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter.	SIGNOR-251493	0.627
CSNK2A1	protein	P68400	UNIPROT	HES6	protein	Q96HZ4	UNIPROT	up-regulates activity	phosphorylation	Ser183	GPGDDLCsDLEEAPE	-1									12972610	t		llicata	Hes6 inhibits the interaction of Hes1 with its transcriptional corepressor Gro/TLE. Moreover, it promotes proteolytic degradation of Hes1. This effect is maximal when both Hes1 and Hes6 contain the WRPW motif and is reduced when Hes6 is mutated to eliminate a conserved site (Ser183) that can be phosphorylated by protein kinase CK2. 	SIGNOR-250890	0.513
WT1	protein	P19544	UNIPROT	RBM4	protein	Q9BWF3	UNIPROT	down-regulates	binding			9606									16934801	t		miannu	Wilm's tumor protein 1 (wt1), a protein implicated in various cancers and developmental disorders, consists of two major isoforms: wt1(-kts), a transcription factor, and wt1(+kts), a post-transcriptional regulator that binds to rna and can interact with splicing components. Here we show that wt1 interacts with the novel splicing regulator rbm4. / we conclude that the (+kts) form of wt1 is able to inhibit the effect of rbm4 on alternative splicing.	SIGNOR-149166	0.374
GSK3A	protein	P49840	UNIPROT	MCL1	protein	Q07820	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser159	NNTSTDGsLPSTPPP	9606	BTO:0000567								16543145	t			 MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). Glycogen Synthase Kinase-3 Regulates Mitochondrial Outer Membrane Permeabilization and Apoptosis by Destabilization of MCL-1. threonine 163, which represents the GSK-3 priming phosphorylation in this protein 	SIGNOR-251217	0.469
GSK3B	protein	P49841	UNIPROT	MAF	protein	O75444	UNIPROT	up-regulates	phosphorylation			9606									18042454	t		miannu	We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.	SIGNOR-159435	0.264
H2BC11	protein	P06899	UNIPROT	CENP-A nucleosome	complex	SIGNOR-C321	SIGNOR	form complex	binding			-1									23324462	t		miannu	 In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro.	SIGNOR-263699	0.2
LHX3	protein	Q9UBR4	UNIPROT	ISL1	protein	P61371	UNIPROT	up-regulates activity	binding			9606									9452425	t		miannu	The Lhx3-Isl1 C terminus interaction was dependent on the LIM domains of Lhx3. The combinatorial expression of the LIM homeodomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeodomain protein combinations in the specification of neuronal identity	SIGNOR-220169	0.606
SULT1E1	protein	P49888	UNIPROT	17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	up-regulates quantity	chemical modification			-1									7779757	t		Luana	HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM.	SIGNOR-269749	0.8
TAB3	protein	Q8N5C8	UNIPROT	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	up-regulates	binding			9606									25290089	t		lperfetto	The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.	SIGNOR-205449	0.373
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RXRA	protein	P19793	UNIPROT	down-regulates activity	phosphorylation	Ser260	NMGLNPSsPNDPVTN	9606									17604322	t		lperfetto	In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 	SIGNOR-244573	0.2
TACSTD2	protein	P09758	UNIPROT	CLDN7	protein	O95471	UNIPROT	up-regulates quantity	binding			9606	BTO:0001109								31177095	t	done	miannu	In summary, our findings provide evidence that Trop-2 is phosphorylated at Ser-322 by PKCα/δ and that this phosphorylation enhances cell motility and decreases claudin-7 localization to cellular borders.	SIGNOR-273822	0.403
CDK1	protein	P06493	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates activity	phosphorylation	Ser91	EGMGEEPsPFRGRSR										24677263	t		lperfetto	CDK1-mediated Bcl-2 serine 70 phosphorylation enhances its pro-apoptotic function, whereas CDK1-mediated Bad serine 128 phosphorylation promotes apoptosis. 	SIGNOR-267921	0.2
STAG2	protein	Q8N3U4	UNIPROT	RAD21	protein	O60216	UNIPROT	up-regulates quantity by stabilization	binding			9606									28430577	t		miannu	Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin	SIGNOR-261511	0.964
FLT4	protein	P35916	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates activity	phosphorylation	Tyr1230	RHSLAARyYNWVSFP	9606	BTO:0000394								12881528	t		lperfetto	Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail.	SIGNOR-104072	0.2
Palomid 529	chemical	CID:11998575	PUBCHEM	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-199120	0.8
CAD	protein	P27708	UNIPROT	Pyrimidine biosynthesis	phenotype	SIGNOR-PH187	SIGNOR	up-regulates activity				9606									15096496	f			The CPSase activity of CAD is the major locus of control of de novo pyrimidine biosynthesis	SIGNOR-267196	0.7
DLL1	protein	O00548	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	up-regulates	binding			9606									23111325	t		gcesareni	In this study, we demonstrate that dll1 can activate notch signaling mostly through notch2 receptor and can contribute to drug resistance to bortezomib, both in murine and human mm cells.	SIGNOR-199320	0.62
GRIK4	protein	Q16099	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial.	SIGNOR-264945	0.8
CTDSP1	protein	Q9GZU7	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	dephosphorylation	Ser206	SSSTYPHsPTSSDPG	9606	BTO:0000552								17085434	t			Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)	SIGNOR-248800	0.476
CTNNB1	protein	P35222	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity	binding												18316399	t		Simone Vumbaca	Together, these results suggest that B-Cat increases MyoD binding to E box elements	SIGNOR-255653	0.417
ARHGEF4	protein	Q9NR80	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260531	0.653
FKBP15	protein	Q5T1M5	UNIPROT	WIPF1	protein	O43516	UNIPROT	up-regulates activity	binding			9606									19121306	t		Giulio	However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin.	SIGNOR-260596	0.2
RTN4	protein	Q9NQC3	UNIPROT	LINGO1	protein	Q96FE5	UNIPROT	up-regulates	binding			9606	BTO:0000938								15694321	t		flangone	Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1,	SIGNOR-133752	0.654
WNT7A	protein	O00755	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131897	0.632
PSEN1	protein	P49768	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	cleavage			9606				SIGNOR-C98					10593990	t	Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface.	gcesareni	Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains.	SIGNOR-254308	0.79
IRAK1	protein	P51617	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Ser76	ISNKDQHsISYTLSR	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276134	0.758
CDK13	protein	Q14004	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	up-regulates activity	phosphorylation	Thr46	GGTLFSTtPGGTRII	9606	BTO:0001109								36882522	t		lperfetto	CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. 	SIGNOR-273113	0.2
SMAD1	protein	Q15797	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004058								12589053	f		lperfetto	Overexpression of smad6, a natural antagonist for smad1, blocked ppargamma expression and adipocytic differentiation induced by bmp2	SIGNOR-236227	0.265
ADAMTS5	protein	Q9UNA0	UNIPROT	ACAN	protein	P16112	UNIPROT	down-regulates quantity by destabilization	cleavage	Glu392	PRNITEGeARGSVIL	9606									9202061	t		lperfetto	Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374	SIGNOR-266985	0.757
KMT2A	protein	Q03164	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates quantity by stabilization	binding			9606									23817177	t		irozzo	RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity.	SIGNOR-255708	0.549
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	ACTL6B	protein	O94805	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136212	0.273
ARNT	protein	P27540	UNIPROT	TH	protein	P07101	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003945								17457889	f	 	lperfetto	Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter.	SIGNOR-253701	0.2
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CCND3	protein	P30281	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189975	0.8
Galanthamine hydrobromide	chemical	CID:121587	PUBCHEM	ACHE	protein	P22303	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192583	0.8
Y-27632	chemical	CHEBI:75393	ChEBI	ROCK1	protein	Q13464	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207890	0.8
PTEN	protein	P60484	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	dephosphorylation	Ser307	TRRSRTEsITATSPA	10090									25645159	t		miannu	In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser 307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon HCV infection occurred in a PTEN dependent manner.|In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser-307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon Hepatitis C virus infection occurred in a PTEN-dependent manner.	SIGNOR-277078	0.595
AURKA	protein	O14965	UNIPROT	WDR62	protein	O43379	UNIPROT	up-regulates activity	phosphorylation	Ser32	VPARRGQsSPPPAPP	-1									25501809	t		lperfetto	AURKA activity promotes WDR62 spindle localization|We next purified recombinant full-length WDR62 (GST–WDR62-FL) for in vitro kinase assays with active AURKA and demonstrated that WDR62 was a direct phosphorylation target of AURKA|In addition, our quantitative phosphoproteomic analysis of in-vitro-phosphorylated WDR62 identified S32 and S33 as significantly phosphorylated in the presence of active AURKA|Alanine replacement of the five putative phosphorylation sites (S32/S33/S49/T50/S52-AAAAA) of WDR62 attenuated interphase microtubule association induced by AURKA coexpression	SIGNOR-271712	0.359
CAMK2G	protein	Q13555	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser516	LSLTRGLsRTSMKPR	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275779	0.295
PTPN1	protein	P18031	UNIPROT	NTRK1	protein	P04629	UNIPROT	down-regulates activity	dephosphorylation			9606									28919207	t		miannu	PTP1B inactivation prevents TrkA exit from soma and causes receptor degradation, suggesting a " gate-keeper " mechanism that ensures targeting of inactive receptors to axons to engage with ligand.|We identify a gate keeping mechanism in which TrkA receptors, destined for transcytosis, are dephosphorylated in neuronal soma by the ER-resident tyrosine phosphatase, PTP1B.	SIGNOR-277081	0.385
IFNG	protein	P01579	UNIPROT	IFNGR1	protein	P15260	UNIPROT	up-regulates	binding			9606									12438563	t		gcesareni	Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (4345) is required for signal transduction	SIGNOR-95626	0.882
CDK6	protein	Q00534	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Ser276	VHPATPIsPGRASGM	9606									21059642	t	The effect has been demonstrated using Q01196-8	gcesareni	Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20).	SIGNOR-169334	0.598
ADRB2	protein	P07550	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256809	0.646
PTPN1	protein	P18031	UNIPROT	PTK6	protein	Q13882	UNIPROT	down-regulates activity	dephosphorylation	Tyr342	RLIKEDVyLSHDHNI	9606									29142193	t		miannu	Using a variety of PTEN mutant constructs, we show that protein phosphatase activity of PTEN targets PTK6, with efficiency similar to PTP1B, a phosphatase that directly dephosphorylates PTK6 Y342.	SIGNOR-277082	0.557
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MKNK2	protein	Q9HBH9	UNIPROT	up-regulates	phosphorylation			9606									9155017	t	inferred from 70% family members	gcesareni	Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity.	SIGNOR-270204	0.2
PDPK1	protein	O15530	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser222	LIDSMANsFVGTRSY	9606	BTO:0000007								15175348	t		lperfetto	In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation	SIGNOR-236633	0.274
MYO5A	protein	Q9Y4I1	UNIPROT	Dense-core_vesicle_exocytosis	phenotype	SIGNOR-PH184	SIGNOR	up-regulates				9606									21077886	f		miannu	 Myosin Va regulates exocytosis of large dense-core vesicles (LDCVs). interestingly, inhibition of myosin Va potentiates LDCV exocytosis to the same extent as F-actin depolymerization does, suggesting that myosin Va cooperates with the actin cytoskeleton to impede or control LDCV exocytosis	SIGNOR-269279	0.7
SOHLH2	protein	Q9NX45	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002181								22328502	t		Luana	Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression.	SIGNOR-266206	0.332
CDK9	protein	P50750	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Thr179	PQSNIPEtPPPGYLS	9606									19914161	t		lpetrilli	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161589	0.607
PPP2CA	protein	P67775	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Thr55	DDIEQWFtEDPGPDE	9606									17245430	t			A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55| In this study, we reported that the specific B regulatory subunits of PP2A B56gamma1 and B56gamma3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis	SIGNOR-248618	0.573
MAPK3	protein	P27361	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Thr739	SEGSGTAtPSALITT	9606		BTO:0000887;BTO:0001260							14593115	t		gcesareni	We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription.	SIGNOR-118936	0.638
PRKD1	protein	Q15139	UNIPROT	OSBP	protein	P22059	UNIPROT	down-regulates	phosphorylation	Ser240	TALQRSLsELESLKL	9606									21285358	t		gcesareni	Pkd attenuates the function of both cert and osbp by phosphorylation at their respective ser(132) and ser(240) residues (phosphorylation inhibition)	SIGNOR-171756	0.457
P2RY11	protein	Q96G91	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256788	0.357
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1896	SPTSPTYsPTSPVYT	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203584	0.77
Histone H2B	proteinfamily	SIGNOR-PF68	SIGNOR	Nucleosome	complex	SIGNOR-C371	SIGNOR	form complex	binding			-1									21812398	t		lperfetto	The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP.	SIGNOR-265310	0.2
TEK	protein	Q02763	UNIPROT	MYH2	protein	Q9UKX2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000222								26042050	f		lperfetto	the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein.	SIGNOR-241538	0.2
ERG	protein	P11308	UNIPROT	CLDN5	protein	O00501	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22235125	t		Luana	ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene.	SIGNOR-261596	0.225
NRG2	protein	O14511	UNIPROT	ERBB3	protein	P21860	UNIPROT	up-regulates	binding			9606	BTO:0000150								7514177	t		gcesareni	Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4	SIGNOR-26881	0.814
GOT2	protein	P00505	UNIPROT	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	down-regulates quantity	chemical modification			9606									31422819	t		miannu	This is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1).	SIGNOR-268057	0.8
SAFB	protein	Q15424	UNIPROT	FUS	protein	P35637	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000007								27731383	t	P35637:p.Pro525Leu (mutation disrupting interaction)		SAFB1 as well as Matrin3 to regulate splicing and ligand-mediated transcription| In addition, depletion of SAFB1 reduced FUS's localization to chromatin-bound fraction and splicing activity, suggesting SAFB1 could tether FUS to chromatin compartment thorough N-terminal DNA-binding motif.	SIGNOR-262821	0.371
PRKACB	protein	P22694	UNIPROT	GPKOW	protein	Q92917	UNIPROT	up-regulates activity	phosphorylation	Ser27	SFGFTRTsARRRLAD	-1									21880142	t		miannu	Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2. PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites.	SIGNOR-266311	0.311
VAC14	protein	Q08AM6	UNIPROT	FIG4	protein	Q92562	UNIPROT	up-regulates quantity by stabilization	binding			9534	BTO:0000298								20630877	t		miannu	Our data indentify a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J. our data are consistent with the notion that when associated with ArPIKfyve, Sac3 is stabilized and protected from degradation, whereas in the absence of associated ArPIKfyve, Sac3 remains unfolded and, hence, prone to rapid destruction.	SIGNOR-253534	0.919
PDHB	protein	P11177	UNIPROT	PDH	complex	SIGNOR-C402	SIGNOR	form complex	binding			9606									20160912	t		miannu	The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently.	SIGNOR-266547	0.934
AGRN	protein	O00468	UNIPROT	CHRNB3	protein	Q05901	UNIPROT	up-regulates activity	binding			9606	BTO:0002916								14502292	t		miannu	Treatment of muscle cells with neural agrin causes tyrosine phosphorylation of the AChR β subunit and induces AChR clustering by promoting anchoring of the receptor protein to postsynaptic cytoskeleton. Regulation of acetylcholine receptor clustering by the tumor suppressor APC. By showing a direct requirement for APC in AChR clustering, our present study suggests that the Wnt/β-catenin pathway may crosstalk with the agrin signaling cascade during the formation of mammalian neuromuscular junction.	SIGNOR-264260	0.2
MMP8	protein	P22894	UNIPROT	FGA	protein	P02671	UNIPROT	down-regulates quantity by destabilization	cleavage	Leu442	TSKGDKElRTGKEKV	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-8 20ADSGEGD a-chain | 442LRTGKEKV a-chain	SIGNOR-263626	0.2
SRC	protein	P12931	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates	phosphorylation	Tyr478	PPPPPPVyEPVSYHV	9606									15623525	t		lperfetto	Src phosphorylates ezrin at tyrosine 477 and induces a phosphospecific association between ezrin and a kelch-repeat protein family member	SIGNOR-132907	0.635
PIM1	protein	P11309	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606									18593906	t		fspada	Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42).	SIGNOR-252967	0.396
MAPK3	protein	P27361	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	phosphorylation	Thr277	GSRTAPYtPNLPHHQ	9606									12801888	t		llicata	Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4.	SIGNOR-101664	0.431
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000763;BTO:0000149							10197981	t	inferred from 70% family members	gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3.	SIGNOR-270142	0.2
GSK3B	protein	P49841	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates activity	phosphorylation	Ser404	SMRPDVSsPPSSSST	9606									18838540	t		gcesareni	We found hormone-dependent GR phosphorylation on serine 404 by GSK-3beta [ ]Cells expressing a GR that is incapable of GSK-3beta phosphorylation had a redirection of the global transcriptional response to hormone, including the activation of additional signaling pathways, in part due to the altered ability of unphosphorylatable GR to recruit transcriptional cofactors CBP/p300 and the p65 (RelA) subunit of NF-kappaB	SIGNOR-181541	0.521
Fostamatinib disodium	chemical	CID:25008120	PUBCHEM	SYK	protein	P43405	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206373	0.8
RETREG3	protein	Q86VR2	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606	BTO:0000934								23939472	f		lperfetto	We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. 	SIGNOR-261490	0.7
DRD2	protein	P14416	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257096	0.4
(S)-duloxetine	chemical	CHEBI:36795	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			-1									18387300	t		Luana	Selective inhibition of serotonin (5-HT) and noradrenaline (NA) reuptake (SNRI) has been shown to be an attractive dual pharmacology approach for the treatment of a number of diseases.1,2 For example, dual 5- HT/NA reuptake inhibitor duloxetine (1) has shown clinical efficacy in the treatment of depression, pain, and urinary incontinence.	SIGNOR-257776	0.8
SLBP	protein	Q14493	UNIPROT	H2AC12	protein	Q96KK5	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265402	0.2
PRKCA	protein	P17252	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates activity	phosphorylation	Ser746	RRSVRIGsYIERDVT	9823									7539802	t		lperfetto	We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling.	SIGNOR-248899	0.51
SCF-SKP2	complex	SIGNOR-C136	SIGNOR	IDH1	protein	O75874	UNIPROT	down-regulates quantity by destabilization	ubiquitination										phosphorylation:Thr157	GKVEITYtPSDGTQK	34929314	t		lperfetto	During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome	SIGNOR-267623	0.2
CD38	protein	P28907	UNIPROT	cyclic ADP-ribose	smallmolecule	CHEBI:31445	ChEBI	up-regulates quantity	chemical modification			9606									18626062	t		miannu	The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR.	SIGNOR-264244	0.8
CDK4	protein	P11802	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Thr8	MSSILPFtPPIVKRL	9606									15241418	t		lperfetto	We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity	SIGNOR-232138	0.748
serotonin(1+)	smallmolecule	CHEBI:350546	ChEBI	HTR2C	protein	P28335	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257523	0.8
PCSK7	protein	Q16549	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates				10090	BTO:0000165;BTO:0000222	BTO:0000887;BTO:0001103							14767066	f		lperfetto	Treatment with sb203580 significantly reduced this cooperation, consistent with the idea that p38 indirectly stimulates the transactivating activity of p65 through a mechanism involving cbp.	SIGNOR-235734	0.2
RELA	protein	Q04206	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000018								17350185	t		Luana	The IL-6 promoter was stimulated by NF-kB RelA protein. 	SIGNOR-266088	0.681
MAPK8	protein	P45983	UNIPROT	FOXO4	protein	P98177	UNIPROT	up-regulates	phosphorylation	Thr451	PIPKALGtPVLTPPT	9606									15538382	t		lperfetto	Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment.	SIGNOR-130381	0.597
PRKACA	protein	P17612	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates	phosphorylation	Thr686	QQKIRKYtMRRLLQE	9606									18799465	t		lperfetto	Pka directly phosphorylated erbb2 on thr-686, a highly conserved intracellular regulatory site that was required for the pka-mediated synergistic enhancement of neuregulin-induced erbb2-erbb3 activation and proliferation in scs.	SIGNOR-181191	0.379
AKT1	protein	P31749	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates activity	phosphorylation	Ser196	KLRRRFSsLHFMVEV	-1									9812896	t		lperfetto	Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity	SIGNOR-252581	0.768
MAPK9	protein	P45984	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates	phosphorylation	Thr320	SKYNAEStERESQDT	9606									18667537	t		llicata	This jnk phosphorylation of ps1 at ser(319)thr(320) enhances the stability of the ps1 c-terminal fragment that is necessary for gamma-secretase activity.	SIGNOR-179680	0.384
ERBB2	protein	P04626	UNIPROT	ERBB3	protein	P21860	UNIPROT	up-regulates	binding			9606									8816440	t	Most breast, skin, lung, ovary, and gastrointestinal tract tumors express ErbB-3, and heterodimerization of this receptor with ErbB-2, may be involved in some cancers.	gcesareni	Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3.	SIGNOR-43841	0.569
CD274	protein	Q9NZQ7	UNIPROT	PDCD1	protein	Q15116	UNIPROT	up-regulates	binding			9606	BTO:0000782								11015443	t		miannu	Pd-l1, was found to bind pd-1 specifically. The functional significance of this interaction has been demonstrated in t cell assays, in which engagement of pd-1 by pd-l1 leads to the inhibition of tcr-mediated lymphocyte proliferation and cytokine secretion.	SIGNOR-82604	0.935
CID 132010322	chemical	CID:132010322	PUBCHEM	BRD4	protein	O60885	UNIPROT	down-regulates activity	chemical inhibition			9606									31969702	t		Monia	ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4 	SIGNOR-261102	0.8
PTK7	protein	Q13308	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9606									23151663	t		gcesareni	Ptk7 has been strongly implicated in pcp and, like many pcp activators, is a negative regulator of beta-catenin-dependent wnt.	SIGNOR-199536	0.411
ELOVL6	protein	Q9H5J4	UNIPROT	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267894	0.8
GRB2	protein	P62993	UNIPROT	INPP5D	protein	Q92835	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								32323266	t		scontino	An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.	SIGNOR-268449	0.564
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1927	SPKYSPTsPTYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269344	0.718
ANXA1	protein	P04083	UNIPROT	FPR3	protein	P25089	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								15187149	t			We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2.	SIGNOR-259438	0.604
CSNK2A2	protein	P19784	UNIPROT	TCF7L2	protein	Q9NQB0	UNIPROT	up-regulates activity	phosphorylation	Ser58	ESETNQNsSSDSEAE	-1									11711551	t		llicata	We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. 	SIGNOR-251044	0.386
XXYLT1	protein	Q8NBI6	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606									22117070	t	Xylosylation in ER membrane	gcesareni	Xxylt1 acts on the xyl1,3glc-o-linked glycan of notch egf domains.	SIGNOR-177745	0.319
PINK1	protein	Q9BXM7	UNIPROT	MFN1	protein	Q8IWA4	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000793								20871098	f		Barakat	Ubiquitination of MFN-1 or MFN-2 was induced in untransfected cells and cells transfected with control siRNA. However, ubiquitination of MFN-1 and MFN-2 was significantly reduced when treated with either PINK1 siRNA combination. These results suggest that PINK1 is required for the ubiquitination of MFN-1 and MFN-2.	SIGNOR-274135	0.687
SLBP	protein	Q14493	UNIPROT	H2AC11	protein	P0C0S8	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265403	0.2
DMXL2	protein	Q8TDJ6	UNIPROT	RAB3GAP1	protein	Q15042	UNIPROT	up-regulates quantity	binding			10116		BTO:0000142							11809763	t		miannu	We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles.	SIGNOR-265582	0.557
ZAP70	protein	P43403	UNIPROT	LAT	protein	O43561	UNIPROT	up-regulates activity	phosphorylation	Tyr255	EEEGAPDyENLQELN	9606									11368773	t		lperfetto	In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127.	SIGNOR-247034	0.762
CBS	protein	P35520	UNIPROT	L-cystathionine dizwitterion	smallmolecule	CHEBI:58161	ChEBI	up-regulates quantity	chemical modification			9606									23981774	t		lperfetto	Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. 	SIGNOR-275830	0.8
ATM	protein	Q13315	UNIPROT	PIDD1	protein	Q9HB75	UNIPROT	up-regulates activity	phosphorylation	Thr788	DAETGFLtQSNLLSV	9606	BTO:0000567								22854598	t		miannu	ATM phosphorylates PIDD on Thr788 within the DD. This phosphorylation is necessary and sufficient for RAIDD binding and caspase-2 activation. Conversely, nonphosphorylatable PIDD fails to bind RAIDD or activate caspase-2, and engages prosurvival RIP1 instead. Thus, ATM phosphorylation of the PIDD DD enables a binary switch through which cells elect to survive or die upon DNA injury.	SIGNOR-262640	0.622
CDC14B	protein	O60729	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates activity	dephosphorylation			9606									18662541	t		lperfetto	Cdc14B activates APC/C Cdh1 after DNA damage in G2.|Importantly, after DNA damage, thein vivo phosphorylation of wild type Cdh1 - but not that of Cdh1 (4xA) - increased after Cdc14B silencing (XREF_FIG), indicating that in response to genotoxic stress, Cdc14B dephosphorylates Cdh1 on the four sites phosphorylated by Cdk2.	SIGNOR-277017	0.318
FYN	protein	P06241	UNIPROT	TGFB1I1	protein	O43294	UNIPROT	up-regulates activity	phosphorylation	Tyr60	SGDKDHLySTVCKPR	9534									10838081	t		miannu	Hic-5 is a CAKbeta-binding protein localized at focal adhesions. Here we show that overexpression of CAKbeta or Fyn, but not FAK, enhanced the tyrosine phosphorylation of coexpressed Hic-5 in COS-7 cells. The Y60F mutant of Hic-5 was not phosphorylated, and Hic-5 phosphorylated on tyrosine 60 was bound specifically to the SH2 domain of Csk. Specific phosphorylation of Hic-5 by CAKbeta and Fyn may activate a signaling pathway mediated by Hic-5.	SIGNOR-262875	0.347
TTBK1	protein	Q5TCY1	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser516	GDRSGYSsPGSPGTP	9606	BTO:0000938								16923168	t	The effect has been demonstrated using P10636-8	lperfetto	Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation.	SIGNOR-148970	0.464
SUN1	protein	O94901	UNIPROT	NUP153	protein	P49790	UNIPROT	up-regulates activity	binding			9606	BTO:0000567		SIGNOR-C303	SIGNOR-C263					28831067	t		lperfetto	The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export.	SIGNOR-263294	0.443
sabcomeline	chemical	CHEBI:134846	ChEBI	CHRM1	protein	P11229	UNIPROT	up-regulates activity	chemical activation			10116									9399977	t		miannu	 SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes	SIGNOR-258678	0.8
PTPN11	protein	Q06124	UNIPROT	PTK2	protein	Q05397	UNIPROT	down-regulates	dephosphorylation	Tyr577	YMEDSTYyKASKGKL	9606									16920701	t		gcesareni	Dca concomitantly and significantly increased association of tyrosine phosphatase shp2 with fak. Incubation of immunoprecipitated fak, in vitro, with glutathione-s-transferase-shp2 fusion protein resulted in tyrosine dephosphorylation of fak in a concentration-dependent manner.	SIGNOR-148926	0.72
KMT2D	protein	O14686	UNIPROT	MLL2 complex	complex	SIGNOR-C88	SIGNOR	form complex	binding			9606									24680668	t		miannu	The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation.	SIGNOR-204816	0.2
PD173955	chemical	CHEBI:49791	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258263	0.8
TGFB1	protein	P01137	UNIPROT	ITGA3	protein	P26006	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001596								1744142	f		lperfetto	TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way.	SIGNOR-253353	0.359
HSPA8	protein	P11142	UNIPROT	Chaperone-mediated autophagy	phenotype	SIGNOR-PH118	SIGNOR	up-regulates activity				-1									2799391	f			A 73-kilodalton (kD) intracellular protein was found to bind to peptide regions that target intracellular proteins for lysosomal degradation in response to serum withdrawal. This protein cross-reacted with a monoclonal antibody raised to a member of the 70-kD heat shock protein (hsp70) family, and sequences of two internal peptides of the 73-kD protein confirm that it is a member of this family.	SIGNOR-259991	0.7
KLC2	protein	Q9H0B6	UNIPROT	FYCO1	protein	Q9BQS8	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								25855459	t		Giulio	Interestingly, bead capture assays indicated that the middle part of FYCO1 (residues 585–1233) interacts directly with the KLC2 light chain of kinesin 1 (Fig. 3a and Extended Data Fig. 7a, b). Residues 735–773 of FYCO1 were found to be necessary for its kinesin-1 binding (Fig. 3c and Extended Data Fig. 7b, c), and FYCO1(Δ735–773)-positive LEs failed to translocate to the cell periphery (Extended Data Fig. 7e).	SIGNOR-260599	0.35
EGFR	protein	P00533	UNIPROT	HGS	protein	O14964	UNIPROT	up-regulates	phosphorylation	Tyr329	IDPELARyLNRNYWE	9606									12953068	t		lperfetto	We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation	SIGNOR-86689	0.622
CDK1	protein	P06493	UNIPROT	IREB2	protein	P48200	UNIPROT	down-regulates	phosphorylation	Ser157	LQKAGKLsPVKVQPK	9606			SIGNOR-C17						18574241	t		lperfetto	Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity	SIGNOR-179171	0.361
NOTCH3	protein	Q9UM47	UNIPROT	RBPJ	protein	Q06330	UNIPROT	up-regulates	binding			9606									11404076	t		gcesareni	Both notch 1 and notch 3 ics displace the co-repressor smrt from the dna-binding protein rbp-j kappa on the hes promoter. The latter observation suggests that both notch 3 ic and notch 1 ic can access rbp-j kappa in vivo, and that the difference in activation capacity instead stems from structural differences in the two ics when positioned on rbp-j kappa.	SIGNOR-86128	0.852
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser245	NQSMDTGsPAELSPT	9606		BTO:0000763							12193595	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-91730	0.739
PTAFR	protein	P25105	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257262	0.2
PRKCA	protein	P17252	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser34	SRSYVTTsTRTYSLG	-1									2500966	t		lperfetto	We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65.	SIGNOR-248880	0.289
PAK1	protein	Q13153	UNIPROT	SYN1	protein	P17600	UNIPROT	up-regulates activity	phosphorylation	Ser605	AGPTRQAsQAGPVPR	10116	BTO:0001009								12237306	t		miannu	Synapsin I is phosphorylated at Ser603 by p21-activated kinases. the Ser603 residue must be one of the pivotal sites for the release	SIGNOR-250235	0.355
MAPK14	protein	Q16539	UNIPROT	SIAH2	protein	O43255	UNIPROT	up-regulates	phosphorylation			9606									17003045	t		gcesareni	We show that siah2 is subject to phosphorylation by p38 mapk, which increases siah2-mediated degradation of phd3.	SIGNOR-149890	0.2
LTB4R2	protein	Q9NPC1	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256817	0.252
MAP4K1	protein	Q92918	UNIPROT	PSMD2	protein	Q13200	UNIPROT	up-regulates activity	phosphorylation	Ser361	ENNRFGGsGSQVDSA	-1									31843888	t	done	miannu	Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B). 	SIGNOR-273899	0.2
EPAS1	protein	Q99814	UNIPROT	KDM3A	protein	Q9Y4C1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271583	0.268
HSP90AB1	protein	P08238	UNIPROT	FLCN	protein	Q8NFG4	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								27353360	t		miannu	Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. 	SIGNOR-261418	0.2
RPS6KA3	protein	P51812	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									15994958	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-138475	0.2
CSNK2A2	protein	P19784	UNIPROT	RGS19	protein	P49795	UNIPROT	unknown	phosphorylation	Ser24	ADRPPSMsSHDTASP	-1									10760275	t		llicata	Phosphorylation was Mn(2+)-dependent, using both purified CK2 and CCVs. Ser-24 was identified as one of the phosphorylation sites. Our results establish that GAIP is phosphorylated and that only the membrane pool is phosphorylated, suggesting that GAIP can be regulated by phosphorylation events taking place at the level of clathrin-coated pits and vesicles.	SIGNOR-251033	0.333
GABA-A (a4-b2-d) receptor	complex	SIGNOR-C326	SIGNOR	CRHR1	protein	P34998	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268604	0.248
KDM5C	protein	P41229	UNIPROT	SCN2A	protein	Q99250	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									31691806	f		miannu	The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice.	SIGNOR-264313	0.336
IL5RA	protein	Q01344	UNIPROT	SOX4	protein	Q06945	UNIPROT	up-regulates activity	binding			10090	BTO:0003104								11498591	t		miannu	Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5–induced Sox4 activation.	SIGNOR-223010	0.429
PRKCB	protein	P05771	UNIPROT	KCNC4	protein	Q03721	UNIPROT	down-regulates	phosphorylation	Ser15	SSYRGRKsGNKPPSK	9606									7993631	t		gcesareni	We found that pkc specifically eliminates rapid inactivation of a cloned human a-type k+ channel (hkv3.4), converting this channel from a rapidly inactivating a type to a noninactivating delayed rectifier type.	SIGNOR-35622	0.2
PTPRJ	protein	Q12913	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	dephosphorylation	Tyr813	NSLFTPDyELLTEND	9606									28912580	t		miannu	These results support PTPRJ preferentially dephosphorylating Y813 and Y868 in JAK2.|We revealed that PTPRJ negatively regulates leptin signaling by dephosphorylating specific tyrosine residues (Y813 and Y868) in JAK2, the simultaneous phosphorylation of which plays a pivotal role in JAK2 activation.	SIGNOR-277093	0.329
CIT	protein	O14578	UNIPROT	KIF14	protein	Q15058	UNIPROT	up-regulates activity	binding			9606	BTO:0000565								16431929	t		miannu	We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase. 	SIGNOR-266424	0.713
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	STK3	protein	Q13188	UNIPROT	down-regulates	phosphorylation	Thr384	GTMKRNAtSPQVQRP	9606									20086174	t		lperfetto	We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2.	SIGNOR-244349	0.2
PIAS4	protein	Q8N2W9	UNIPROT	RPA2	protein	P15927	UNIPROT	up-regulates	phosphorylation	Ser8	MWNSGFEsYGSSSYG	9606									20016603	t		gcesareni	Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation	SIGNOR-162164	0.2
RAC1	protein	P63000	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0003009; BTO:0000018								22549160	f		irozzo	The small GTPase Rac1 regulates many cellular processes, including cytoskeletal reorganization, cell migration, proliferation, and survival. We found that silencing of Rac1 expression decreases NSCLC migration and proliferation [.]	SIGNOR-259088	0.7
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	RANGAP1	protein	P46060	UNIPROT	up-regulates	phosphorylation	Thr409	GQGEKSAtPSRKILD	9606									15037602	t		lperfetto	Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis. The m-phase kinase cyclin b/cdk1 phosphorylates rangap1 efficiently in vitro, and t409 phosphorylation correlates with nuclear accumulation of cyclin b1 in vivo.	SIGNOR-216789	0.446
ILK	protein	Q13418	UNIPROT	PPP1R14C	protein	Q8TAE6	UNIPROT	up-regulates activity	phosphorylation	Thr73	RHQQGKVtVKYDRKE	9606									12804574	t		lperfetto	Pka predominantly phosphorylated a site distinct from the inhibitory t73 in kepi. Integrin-linked kinase phosphorylated KEPI (T73) and this dramatically increased inhibition of PP1c	SIGNOR-101835	0.528
VAV3	protein	Q9UKW4	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260584	0.7
MARK1	protein	Q9P0L2	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser673	RVQSKIGsLDNITHV	-1									10090741	t		miannu	We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. 	SIGNOR-250175	0.44
UBE3A	protein	Q05086	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys126	DNEKDLVkLAKRLKK	-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. 	SIGNOR-272746	0.476
KLF11	protein	O14901	UNIPROT	HBG1	protein	P69891	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000664								10207080	f	Regulation	miannu	Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression. 	SIGNOR-251828	0.2
PTEN	protein	P60484	UNIPROT	NR5A1	protein	Q13285	UNIPROT	down-regulates activity	dephosphorylation			9606									27838257	t		miannu	The fact that SF-1 and PIP3 is robustly dephosphorylated by PTEN, yet SF-1 and PIP2 is resistant to phosphorylation by p110 PI3-kinases, suggests that nuclear proteins like SF-1 can help decouple PTEN signaling in the nucleus from p110 signaling.|We also showed that PTEN can dephosphorylate the SF-1 and PIP3 product of the IPMK reaction, and that PTEN inhibits SF-1 transcriptional activity.	SIGNOR-277117	0.259
PTEN	protein	P60484	UNIPROT	PFKP	protein	Q01813	UNIPROT	down-regulates activity	dephosphorylation	Ser386	AVRLRGRsFAGNLNT	9606									29038421	f		miannu	In addition, AKT phosphorylation and PFKP S386 phosphorylation and PFKP expression levels were inversely correlated with PTEN expression levels, suggesting that PTEN inhibits PFKP S386 phosphorylation and reduces PFKP stability through inhibition of AKT.|These results indicate that AKT activation resulted from PTEN loss or EGFR dependent PI3K activation induces PFKP upregulation.	SIGNOR-277118	0.2
NEDD4L	protein	Q96PU5	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	ubiquitination			9606									19917253	t		gcesareni	Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation	SIGNOR-161713	0.796
FOXO3	protein	O43524	UNIPROT	Cell_cycle_block	phenotype	SIGNOR-PH10	SIGNOR	up-regulates				9606	BTO:0000007								14976264	f		lperfetto	Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress	SIGNOR-217881	0.7
TRPM7	protein	Q96QT4	UNIPROT	ANXA1	protein	P04083	UNIPROT	up-regulates	phosphorylation	Ser5	sEFLKQAW	9606									24103589	t		lperfetto	Trpm7 was responsible for phosphorylation of the serine 5 (ser5) residue [29]. In 2009, the study focused on an association between anxa1 and trpm7 confirmed the presence of a trpm7/annexin a1/mg2_+ complex, suggesting a novel pathway in bradykinin signaling, dependent on pkc and c-src [30]. Even though that pathway is not fully characterized, the same team that discovered the ser5 phosphorylation of anxa1 also reported crucial relevance of this modification for anxa1 membrane binding and especially for the interaction between annexin a1 and its known partner, the calcium binding protein s100a11	SIGNOR-202804	0.561
PTPRR	protein	Q15256	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	dephosphorylation			9606									11711538	t		gcesareni	As shown, gst-ptp-sl dephosphorylated efficiently both erk2 and p38 wild typetogether, these results indicate that the defective association of the tyrosine phosphatase ptp-sl with erk2 d319n and p38 d316n mutations impairs the retention and inactivation in the cytosol of these map kinases by ptp-sl.	SIGNOR-111762	0.549
GRIA2	protein	P42262	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				-1									32527803	f		Luana	AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by naïve ones.	SIGNOR-265796	0.7
sertindole	chemical	CHEBI:9122	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			9534									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258547	0.8
N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide	chemical	CHEBI:94525	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194545	0.8
SRC	protein	P12931	UNIPROT	DAPK1	protein	P53355	UNIPROT	down-regulates activity	phosphorylation	Tyr491	CAAWHGYySVAKALC	9606	BTO:0002181								17803936	t		miannu	 Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation. 	SIGNOR-276073	0.277
FGF2	protein	P09038	UNIPROT	FGFR4	protein	P22455	UNIPROT	up-regulates	binding			9606									1385111	t		gcesareni	Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides.	SIGNOR-18564	0.812
GABRB3	protein	P28472	UNIPROT	GABA-A (a4-b3-d) receptor	complex	SIGNOR-C327	SIGNOR	form complex	binding			9606									18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263747	0.449
8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione	chemical	CHEBI:92539	ChEBI	ADRA1D	protein	P25100	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190642	0.8
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1696	SPSYSPTsPSYSPTS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248774	0.441
PABPC1	protein	P11940	UNIPROT	eIF4F_complex	complex	SIGNOR-C44	SIGNOR	up-regulates activity	binding			9606									30209168	t		miannu	The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling	SIGNOR-260943	0.82
TG	protein	P01266	UNIPROT	Thyroid_hormonogenesis	phenotype	SIGNOR-PH110	SIGNOR	up-regulates				9606		BTO:0004710							30886364	f		miannu	In humans, the thyroid hormones T3 and T4 are synthesized in the thyroid gland in a process that crucially involves the iodoglycoprotein thyroglobulin. The overall structure of thyroglobulin is conserved in all vertebrates. Upon thyroglobulin delivery from thyrocytes to the follicular lumen of the thyroid gland via the secretory pathway, multiple tyrosine residues can become iodinated to form mono-iodotyrosine (MIT) and/or di-iodotyrosine (DIT); however, selective tyrosine residues lead to preferential formation of T4 and T3 at distinct sites. 	SIGNOR-259915	0.7
DCAF7	protein	P61962	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002181; BTO:0003484								16887337	f		Giorgia	HAN11 and mDia1 repressed DYRK1A-dependent GLI1 transcriptional activity. The studies of SZ95 cells suggest that HAN11 reduces GLI1-dependent transcription by decreasing the nuclear pool of GLI1.	SIGNOR-260634	0.264
RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	Quiescence	phenotype	SIGNOR-PH25	SIGNOR	up-regulates				10090	BTO:0002314								22045613	f		gcesareni	Notch signaling is active in quiescent SCs. SC-specific deletion of recombining binding protein-J (RBP-J), a nuclear factor required for Notch signaling, resulted in the depletion of the SC pool and muscles that lacked any ability to regenerate in response to injury.	SIGNOR-244004	0.7
FBN1	protein	P35555	UNIPROT	MMP1	protein	P03956	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16442122	f	Regulation of expression	miannu	In this study we show that a fibrillin-1 fragment containing a EGFEPG sequence that conforms to a putative GxxPG elastin-binding protein (EBP) consensus sequence upregulates the expression and production of matrix metalloproteinase (MMP)-1 by up to ninefold in a cell culture system. Mutations in the gene for fibrillin-1 cause Marfan syndrome (MFS), a common hereditary disorder of connective tissue	SIGNOR-251887	0.354
EPHB2	protein	P29323	UNIPROT	RASA1	protein	P20936	UNIPROT	up-regulates	binding			9606									9233798	t		gcesareni	We have localized an in vitro rasgap-binding site to conserved tyrosine residues y604 and y610 in the juxtamembrane region of ephb2, and demonstrated that substitution of these amino acids abolishes ephrin-b1-induced signalling events in ephb2-expressing ng108-15 cells.	SIGNOR-50100	0.558
TSC22D3	protein	Q99576	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	relocalization			9606									20018851	t			GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells.	SIGNOR-256147	0.406
ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	P2RY11	protein	Q96G91	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257559	0.8
PTPRJ	protein	Q12913	UNIPROT	CBL	protein	P22681	UNIPROT	down-regulates activity				9606									19836242	f			Because c-CBL’s activation is achieved via tyrosine phosphorylation, we tested the effect of DEP-1 on modification of a major site of phosphorylation, namely tyro- sine 731. Upon DEP-1 overexpression, c-CBL displayed reduced phosphorylation on this site compared to control cells (Figure 7B). This result offers a mechanism by which DEP-1 affects EGFR trafficking: by dephosphorylating EGFR, and possibly also SRC family kinases involved in phosphoryla- tion of c-CBL [31, 32], DEP-1 reduces activation of c-CBL and its recruitment to the activated EGFR, hence inhibiting subsequent receptor internalization and degradation. 	SIGNOR-248839	0.33
PTGER4	protein	P35408	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256760	0.469
MYOD1	protein	P15172	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606		BTO:0001103							16275751	f		andrea cerquone perpetuini	Together, these results support the notion that Myf5 functions toward myoblast proliferation, whereas MyoD prepares myoblasts for efficient differentiation.	SIGNOR-255417	0.7
PDGFRB	protein	P09619	UNIPROT	PDGFRB	protein	P09619	UNIPROT	unknown	phosphorylation	Tyr751	SKDESVDyVPMLDMK	9606									2550144	t		llicata	We have identified two platelet-derived growth factor (pdgf)-dependent autophosphorylation sites in the beta subunit of the human pdgf receptor (pdgf-r). The major site of phosphorylation (tyr-857) corresponds to the major autophosphorylation site in many other tyrosine kinases. Tyr-751, which lies within the kinase insert region, is a second in vivo site and the major in vitro site.	SIGNOR-22993	0.2
PRKCZ	protein	Q05513	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Thr841	RSAFTTStVVRMHVG	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249291	0.377
SLC27A1	protein	Q6PCB7	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264463	0.7
EXOC1	protein	Q9NV70	UNIPROT	Exocyst_EXOC6 variant	complex	SIGNOR-C492	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270784	0.886
ITGA9	protein	Q13797	UNIPROT	A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253183	0.773
NDUFS5	protein	O43920	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 	SIGNOR-262179	0.815
WWTR1	protein	Q9GZV5	UNIPROT	LTBR	protein	P36941	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001615								22470139	f		miannu	Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation.	SIGNOR-255604	0.2
TRAF2	protein	Q12933	UNIPROT	MAP3K14	protein	Q99558	UNIPROT	down-regulates quantity by destabilization	binding			10090	BTO:0000785								15084608	t		lperfetto	We report here that one important mechanism of nik regulation is through its dynamic interaction with the tumor necrosis factor receptor-associated factor 3 (traf3). Traf3 physically associates with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome.	SIGNOR-124233	0.568
ROMO1	protein	P60602	UNIPROT	TIM23 complex	complex	SIGNOR-C423	SIGNOR	form complex	binding												32074073	t		lperfetto	The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE.	SIGNOR-267690	0.392
SMDT1	protein	Q9H4I9	UNIPROT	MCU_MICU1_variant	complex	SIGNOR-C500	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270866	0.622
MAF	protein	O75444	UNIPROT	MMP13	protein	P45452	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20067416	f		miannu	 MMP-13 gene expression is regulated primarily at the transcriptional level. In this study, we investigated the role of c-maf in regulating MMP-13 transcription. Using transient transfection system with an c-maf construct, and MMP-13 promoter-luciferase constructs with specific mutations in transcription factor binding sites, we found that c-maf can significantly enhance MMP-13 promoter activity via the AP-1 sitecv	SIGNOR-254560	0.254
BRK1	protein	Q8WUW1	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	down-regulates				9606									23939472	f		lperfetto	We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation. 	SIGNOR-261491	0.7
PCSK7	protein	Q16549	UNIPROT	DDB2	protein	Q92466	UNIPROT	down-regulates				9606									18806262	f	The phosphorylation of DDB2 by p38 promotes its ubiquitination	gcesareni	The data suggest that p38 mapk is involved in serine phosphorylation of ddb2, which may influence its ubiquitylation following irradiation.	SIGNOR-181278	0.2
PAK1	protein	Q13153	UNIPROT	BCL6	protein	P41182	UNIPROT	down-regulates activity	phosphorylation			9606									22723377	t		miannu	The transcriptional repressor B-cell lymphoma (BCL)-6 downregulates genes involved in cell-cycle progression and becomes inactivated following phosphorylation by the Rac1 GTPase-activated protein kinase PAK1.	SIGNOR-253930	0.2
PRKCA	protein	P17252	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	up-regulates	phosphorylation	Ser40	SREVFDFsQRRKEYE	9606									12198130	t		miannu	Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress	SIGNOR-91826	0.515
FOXO3	protein	O43524	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates quantity	transcriptional regulation												22848740	t			We show that FOXO3 binds and activates its own promoter via a positive autoregulatory feedback loop	SIGNOR-255757	0.2
NFE2L2	protein	Q16236	UNIPROT	TFB2M	protein	Q9H5Q4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15684387	f		lperfetto	Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC	SIGNOR-268996	0.253
KIT	protein	P10721	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates activity	phosphorylation	Tyr823	DIKNDSNyVVKGNAR	9606									12824176	t		lperfetto	Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth. / tyr-823 is the last tyrosine residue to be autophosphorylated	SIGNOR-102641	0.2
TRPV1	protein	Q8NER1	UNIPROT	PRKCB	protein	P05771	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								24920628	t		miannu	 In the present study, we report that the sensitivity of TRPV1 channels is determined by PKCβII. TRPV1 binds directly to PKCβII and subsequently activates PKCβII. Activated PKCβII then enhances the responsiveness of TRPV1 to thermal and chemical stimuli through a phosphorylation-dependent mechanism.	SIGNOR-276639	0.2
NFE2L2	protein	Q16236	UNIPROT	PGD	protein	P52209	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22789539	f		miannu	We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). 	SIGNOR-267355	0.285
TEK	protein	Q02763	UNIPROT	TEK	protein	Q02763	UNIPROT	up-regulates activity	phosphorylation	Tyr1102	MLEERKTyVNTTLYE	9606	BTO:0001176								20973951	t		miannu	This phosphorylation requires a kinase competent Tie2 as well as intact tyrosines 1100 and 1106 (Y1100 and Y1106) on the receptor. This suggests that Y1100 and Y1106 on Tie2 play a role in Grb14 mediated signal transduction downstream of this receptor.	SIGNOR-259834	0.2
TNF	protein	P01375	UNIPROT	DIO1	protein	P49895	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									9397972	f		scontino	From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y.	SIGNOR-267485	0.2
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606	BTO:0000007								14976264	f		lperfetto	Sirt1 inhibited foxo3's ability to induce cell death.	SIGNOR-256644	0.7
PIN1	protein	Q13526	UNIPROT	KLF10	protein	Q13118	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000018								23994618	t		miannu	RAF1 phosphorylates the Thr93 site of KLF10 in vivo. Since the phosphorylation of Thr93 enables KLF10 and PIN1 to bind, it seems likely that RAF-1 will have an effect on KLF10 stability that is similar to that of PIN1.PIN1 facilitates KLF10 protein degradation. (	SIGNOR-276503	0.2
CHEK1	protein	O14757	UNIPROT	ASF1A	protein	Q9Y294	UNIPROT	up-regulates activity	phosphorylation	Ser166	KLEDAESsNPNLQSL	9606	BTO:0002181								33503415	t		miannu	Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks.	SIGNOR-277620	0.424
XRCC5	protein	P13010	UNIPROT	DNA-PK	complex	SIGNOR-C107	SIGNOR	form complex	binding			9606	BTO:0002419								17308091	t		miannu	complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established	SIGNOR-226019	0.957
HTR7	protein	P34969	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257256	0.301
DUSP1	protein	P28562	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates activity	dephosphorylation			9606									20626350	t		lperfetto	The activity of MAPKs can be also regulated by a family of DUSPs (dual-specificity phosphatases)/MKPs (MAPK phosphatases), which dephosphorylate both phosphotyrosine and phosphothreonine residues MKPs 1, 4, 5 and 7 can dephosphorylate p38_ and p38_ in addition to JNK MAPKs. Importantly, some MKPs are transcriptionally up-regulated by stimuli that activate MAPK signalling, and are thought to play an important role limiting the extent of MAPK activation	SIGNOR-166571	0.798
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation	Thr455	ALGTPVLtPPTEAAS	9606	BTO:0000848	BTO:0001253							20959475	t		lperfetto	Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451).	SIGNOR-252956	0.704
XRCC6	protein	P12956	UNIPROT	DNA-PK	complex	SIGNOR-C107	SIGNOR	form complex	binding			9606	BTO:0002419								17308091	t		miannu	complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established	SIGNOR-226023	0.963
GSK3B	protein	P49841	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates activity	phosphorylation	Thr481	HVQRVLRtPGRQSPG	9606									10581160	t			Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP	SIGNOR-251222	0.917
ELANE	protein	P08246	UNIPROT	F5	protein	P12259	UNIPROT	down-regulates activity	cleavage	Ile536	RSLDRRGiQRAADIE	-1									9242537	t		lperfetto	Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity.	SIGNOR-263636	0.373
SLBP	protein	Q14493	UNIPROT	H2AC21	protein	Q8IUE6	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265406	0.2
OPRM1	protein	P35372	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257106	0.489
GDF6	protein	Q6KF10	UNIPROT	BMPR2	protein	Q13873	UNIPROT	up-regulates	binding			9606				SIGNOR-C29					16049014	t		gcesareni	We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins.	SIGNOR-139093	0.586
CSNK2A1	protein	P68400	UNIPROT	EIF3J	protein	O75822	UNIPROT	up-regulates activity	phosphorylation	Ser127	LKKLQEEsDLELAKE	9606	BTO:0000007								25887626	t		miannu	CK2 phosphorylates the eIF3j subunit at Ser127. CK2-phosphorylation of eIF3j triggers its association with the eIF3 complex.	SIGNOR-266402	0.331
APAF1	protein	O14727	UNIPROT	Apoptosome	complex	SIGNOR-C230	SIGNOR	form complex	binding			-1									10206961	t		lperfetto	 APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9. 	SIGNOR-256431	0.869
FGR	protein	P09769	UNIPROT	SDHA	protein	P31040	UNIPROT	unknown	phosphorylation	Tyr543	CGKISKLyGDLKHLK	-1									17997986	t		miannu	Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations.	SIGNOR-262872	0.2
TTK	protein	P33981	UNIPROT	HSPA9	protein	P38646	UNIPROT	up-regulates	phosphorylation	Thr62	VVGIDLGtTNSCVAV	9606									17573779	t		lperfetto	Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin	SIGNOR-156185	0.2
dasatinib (anhydrous)	chemical	CHEBI:49375	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258063	0.8
JAG1	protein	P78504	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	up-regulates	binding			9606									10551863	t	Binding Calcium-dependent.	gcesareni	Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch.	SIGNOR-72112	0.623
SPI1	protein	P17947	UNIPROT	CD14	protein	P08571	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12393465	f		apalma	In patients with t(8;21), expression of the cell surface markers CD11b, CD14, and CD64 was less in comparison to patients without t(8;21) (Figure 5B). CD14 and CD64 promoters have putative PU.1 binding sites but not AML1-, C/EBPα-, or MEF-binding sites suggesting that down-regulation of the function of PU.1 by AML1-ETO could possibly be an important step in progression toward leukemia.	SIGNOR-255696	0.403
MAP3K14	protein	Q99558	UNIPROT	CHUK	protein	O15111	UNIPROT	up-regulates activity	phosphorylation			9606									20651737	t		lperfetto	Once activated by autophosphorylation, nik activates ikkalpha, which in turn phosphorylates nf-kb2. This stimulates limited proteasome-mediated proteolysis of nf-kb2 to p52. Removal of the carboxy-terminal ankyrin repeats from nf-kb2 releases the p52/RELB heterodimer, allowing its translocation to the nucleus where it instigates the expression of nf-kb target genes.	SIGNOR-167060	0.684
AKT1	protein	P31749	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	phosphorylation	Ser127	PQHVRAHsSPASLQL	9606									12535517	t		gcesareni	One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73.	SIGNOR-252593	0.613
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser255	ELSPTTLsPVNHSLD	9606		BTO:0000763;BTO:0000149							10197981	t		lperfetto	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-244727	0.2
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr605	KDLVSCAyQVARGME	9606									12601080	t		lperfetto	Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways.	SIGNOR-98634	0.2
PTCD3	protein	Q96EY7	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding		Q9Y2Q9	9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261437	0.718
MAP3K7	protein	O43318	UNIPROT	KSR1	protein	Q8IVT5	UNIPROT	down-regulates	phosphorylation	Ser406	TRLRRTEsVPSDINN	9606									11741534	t		gcesareni	C-tak1 constitutively associates with mammalian ksr1 and phosphorylates serine 392 to confer 14-3-3 binding and cytoplasmic sequestration of ksr1 in unstimulated cells. In response to signal activation, the phosphorylation state of s392 is reduced, allowing the ksr1 complex to colocalize with activated ras and raf-1 at the plasma membrane	SIGNOR-112779	0.2
PPP2CA	protein	P67775	UNIPROT	TFCP2	protein	Q12800	UNIPROT	up-regulates	dephosphorylation	Ser291	TYVNNSPsPGFNSSH	9606									20682773	t		lperfetto	We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a	SIGNOR-167385	0.2
FGR	protein	P09769	UNIPROT	GLO1	protein	Q04760	UNIPROT	up-regulates activity	phosphorylation	Tyr136	GIAVPDVySACKRFE	-1									34838714	t		miannu	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276188	0.2
ITCH	protein	Q96J02	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	ubiquitination			9606									15350225	t		gcesareni	Itch promotes ubiquitination of smad2 and augments smad2 phosphorylation that requires an intact ligase activity of itch. Moreover, itch facilitates complex formation between tgf-beta receptor and smad2 and enhances tgf-beta-induced transcription.	SIGNOR-128647	0.464
IC-87114	chemical	CHEBI:90686	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206184	0.8
Laminin-1	complex	SIGNOR-C183	SIGNOR	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	up-regulates activity	binding												9361014	t		lperfetto	Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI.	SIGNOR-253255	0.527
NMUR1	protein	Q9HB89	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256894	0.409
CAMKK2	protein	Q96RR4	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	up-regulates	phosphorylation	Thr183	SDGEFLRtSCGSPNY	9606									21918180	t		gcesareni	Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli.	SIGNOR-176602	0.59
PRKAA1	protein	Q13131	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser214	GGKERPGsKEEVDED	-1									10090741	t		miannu	We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 	SIGNOR-275439	0.2
PRKCG	protein	P05129	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	phosphorylation	Ser1303	NKLRRQHsYDTFVDL	-1									11306676	t		lperfetto	These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels.	SIGNOR-249085	0.408
SYNE4	protein	Q8N205	UNIPROT	LINC complex	complex	SIGNOR-C303	SIGNOR	form complex	binding												24481844	t		lperfetto	LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM.	SIGNOR-263288	0.454
IL19	protein	Q9UHD0	UNIPROT	IL20RA	protein	Q9UHF4	UNIPROT	up-regulates	binding			9606	BTO:0000848								11564763	t		gcesareni	Il-19 signals only through the type i il-20r complex.	SIGNOR-110671	0.735
MRPL16	protein	Q9NX20	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262377	0.719
NOTCH1	protein	P46531	UNIPROT	RBPJ	protein	Q06330	UNIPROT	up-regulates	binding			9606									19165418	t		gcesareni	The intracellular part of the notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor rbp-j.	SIGNOR-183510	0.949
PRKCA	protein	P17252	UNIPROT	PLEK	protein	P08567	UNIPROT	up-regulates	phosphorylation	Ser117	ARKSTRRsIRLPETI	9606									8615792	t		gcesareni	To determine the role of pkc-dependent phosphorylation in pleckstrin function, we mapped the phosphorylation sites in vivo of wild-type and site-directed mutants of pleckstrin expressed in cos cells. Phosphorylation was found to occur almost exclusively on ser-113 and ser-117. Replacing all these sites with glycine decreased phosphorylation by > 90% and reduced pleckstrin's ability to inhibit phosphoinositide hydrolysis by as much as 80%.	SIGNOR-40048	0.284
RAD23B	protein	P54727	UNIPROT	RPA1	protein	P27694	UNIPROT	up-regulates activity	binding												24086043	t		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275698	0.557
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr199	VKKSIRDtPAKNAQK										11278991	t		llicata	Here, we identified that threonine 199 (Thr(199)) of NPM/B23 is the major phosphorylation target site of CDK2-cyclin E in vitro, and the same site is phosphorylated in vivo.|NPM/B23 binds specifically to unduplicated centrosomes and loses its centrosome binding activity when phosphorylated by CDK2-cyclin E	SIGNOR-250744	0.415
AMPK	complex	SIGNOR-C15	SIGNOR	HAT1	protein	O14929	UNIPROT	up-regulates activity	phosphorylation	Ser190	MWFIETAsFIDVDDE	-1									28143904	t		lperfetto	Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314	SIGNOR-264787	0.31
CNTN6	protein	Q9UQ52	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	relocalization			9606	BTO:0000938								15082708	t		gcesareni	Here, we establish that nb-3, a member of the f3/contactin family, acts as a novel notch ligand to participate in oligodendrocyte generation. Nb-3 triggers nuclear translocation of the notch intracellular domain and promotes oligodendrogliogenesis from progenitor cells and differentiation of oligodendrocyte precursor cells via deltex1.	SIGNOR-124151	0.572
PH 797804	chemical	CHEBI:82715	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206079	0.8
dabigatran	chemical	CHEBI:70752	ChEBI	F2	protein	P00734	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190314	0.8
CNTF	protein	P26441	UNIPROT	CNTFR	protein	P26992	UNIPROT	up-regulates	binding			9606									10966616	t		gcesareni	Ciliary neurotrophic factor (cntf) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, cntfr, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (lifr)	SIGNOR-81379	0.785
NFIB	protein	O00712	UNIPROT	ETV5	protein	P41161	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268880	0.2
DAPK1	protein	P53355	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606									17339337	t		gcesareni	A cell-free ser(20) phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser(20) kinases.Evaluation of these calcium calmodulin kinase superfamily members as candidate ser(20) kinases in vivo has shown that only chk1 or dapk-1 can stimulate p53 transactivation and induce ser(20) phosphorylation of p53.	SIGNOR-153487	0.575
XIAP	protein	P98170	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1									15749826	t		lperfetto	Xiap functions as ubiquitin ligase toward smac to inhibit apoptosis.	SIGNOR-134504	0.912
PPP2CA	protein	P67775	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	dephosphorylation	Thr308	KDGATMKtFCGTPEY	10090	BTO:0000944								15367694	t			Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes	SIGNOR-252614	0.889
ZHX1	protein	Q9UKY1	UNIPROT	ZMYND11	protein	Q15326	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								17127430	t		miannu	Corepressor BS69 interacts with ZHX1, a member of the ZHX family having zinc-fingers and homeoboxes. Although BS69 was originally found as a corepressor interacting with ZHX1, BS69 was also found to function as a transcriptional activator in HEK293 cells, in which the activation required the MYND domain of BS69. Co-transfection of BS69 with a mutant form of ZHX1, which cannot interact with BS69, led to increase the transcriptional activation of BS69, suggesting that transcriptional activation mediated by BS69 is suppressed by ZHX1.	SIGNOR-263898	0.505
AATK	protein	Q6ZMQ8	UNIPROT	CDK5R1	protein	Q15078	UNIPROT	up-regulates	binding			9606	BTO:0000007	BTO:0000142							14521924	t		gcesareni	Apoptosis-associated tyrosine kinase is a cdk5 activator p35 binding protein.	SIGNOR-118403	0.455
GATA2	protein	P23769	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity	transcriptional regulation			9606									19772889	t			These findings indicate that fatty marrow replacement in AA patients can be explained by downregulation of GATA-2 and overexpression of PPARgamma in MSCs. Decreased expression of GATA-2 might be responsible for the pathogenesis and development of the clinical features of the disease.	SIGNOR-259949	0.378
SAR1A	protein	Q9NR31	UNIPROT	SEC23B	protein	Q15437	UNIPROT	up-regulates quantity	binding							SIGNOR-C370					30605680	t		lperfetto	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 	SIGNOR-265298	0.685
Selinexor	chemical	CID:71481097	PUBCHEM	XPO1	protein	O14980	UNIPROT	down-regulates activity	chemical inhibition			9606									30510142	t		miannu	Selinexor (KPT-330) is a first-in-class selective inhibitor of nuclear export (C17H11F6N7O; see ref. 4; for its chemical structure). The drug binds and inhibits exportin XPO-1 that mediates nuclear export of proteins and mRNAs.	SIGNOR-262537	0.8
ER stress	stimulus	SIGNOR-ST9	SIGNOR	BID	protein	P55957	UNIPROT	up-regulates				9606									22492984	f		gcesareni	Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins	SIGNOR-196944	0.7
GSK3B	protein	P49841	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	up-regulates activity	phosphorylation	Thr57	LSSTPLStPCSSVPS	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159454	0.26
sorafenib	chemical	CHEBI:50924	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258285	0.8
CDK4	protein	P11802	UNIPROT	GATA4	protein	P43694	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser105	AYTPPPVsPRFSFPG	9606	BTO:0000567								21447557	t		miannu	Finally, CDK4 phosphorylated GATA4 directly, which promoted the degradation of GATA4 in cultured cells.	SIGNOR-276317	0.365
LRRK2	protein	Q5S007	UNIPROT	RAB5B	protein	P61020	UNIPROT	up-regulates activity	phosphorylation	Thr6	tARPNGQP	9606	BTO:0000567								25605758	t		miannu	 Using recombinant proteins, we show here that LRRK2 phosphorylates Rab5b at its Thr6 residue in in vitro kinase assays with mass spectrophotometry analysis. Phosphorylation of Rab5b by LRRK2 on the threonine residue was confirmed by western analysis using cells stably expressing LRRK2 G2019S. The phosphomimetic T6D mutant exhibited stronger GTPase activity than that of the wild-type Rab5b. In addition, phosphorylation of Rab5b by LRRK2 also exhibited GTPase activity stronger than that of the unphosphorylated Rab5b protein.	SIGNOR-276873	0.618
KAT6A/KAT6B	complex	SIGNOR-C54	SIGNOR	RUNX2	protein	Q13950	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271;BTO:0000785								11965546	t		lperfetto	Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation.	SIGNOR-217204	0.361
FGF12	protein	P61328	UNIPROT	SCN10A	protein	Q9Y5Y9	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253440	0.307
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	SFN	protein	P31947	UNIPROT	down-regulates	phosphorylation			9606									15071501	t	Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons	gcesareni	Here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein.Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-191	SIGNOR-269979	0.2
PPP1R9B	protein	Q96SB3	UNIPROT	SPATA13	protein	Q96N96	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								19151759	t		miannu	Here we show that Asef2, but not Asef, interacts with Neurabin2/Spinophilin, a scaffold protein that binds to Filamentous actin (F-actin). Neurabin2 is required for Asef2-induced filopodia formation. RNA interference experiments showed that Asef2, Neurabin2 and APC are involved in HGF-induced cell migration. Furthermore, knockdown of Neurabin2 resulted in the suppression of Asef2-induced filopodia formation.	SIGNOR-269174	0.496
HDAC4	protein	P56524	UNIPROT	MEF2D	protein	Q14814	UNIPROT	down-regulates	binding			9606									10737771	t		gcesareni	We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2.	SIGNOR-76237	0.68
SIK1	protein	P57059	UNIPROT	CRTC2	protein	Q53ET0	UNIPROT	down-regulates activity	phosphorylation	Ser70	RSSHYGGsLPNVNQI	9606	BTO:0000567								16306228	t		lperfetto	We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression 	SIGNOR-249169	0.63
RAB5C	protein	P51148	UNIPROT	EEA1	protein	Q15075	UNIPROT	up-regulates activity	binding			-1									12493736	t		Federica	The Rab5 effector early endosome antigen 1 (EEA1) is a parallel coiled coil homodimer with an N-terminal C(2)H(2) Zn(2+) finger and a C-terminal FYVE domain. Rab5 binds to independent sites at the N and C terminus of EEA1.|The results demonstrate that the C(2)H(2) Zn(2+) finger is both essential and sufficient for the N-terminal interaction with Rab5.	SIGNOR-261266	0.826
ZEB1	protein	P37275	UNIPROT	FBP1	protein	P09467	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000762								30616754	t		lperfetto	Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells|we confirmed DNA methylation in the promoter contributed to the decrease of FBP1 expression in lung cancer cells. We identified Zinc finger E-box-binding homeobox 1 (ZEB1) bond to FBP1 promoter to enhance DNA methylation in lung cancer cells. 	SIGNOR-267596	0.2
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	JAG1	protein	P78504	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20953350	f		gcesareni	Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip.	SIGNOR-254348	0.2
PTK6	protein	Q13882	UNIPROT	KHDRBS1	protein	Q07666	UNIPROT	unknown	phosphorylation	Tyr443	REHPYGRy	9606	BTO:0000567								16179349	t		lperfetto	We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal.	SIGNOR-249292	0.738
UBE2D1	protein	P51668	UNIPROT	TRIM65	protein	Q6PJ69	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0000567								24778252	t		miannu	Ubiquitination assays demonstrate that TRIM65 is an ubiquitin E3 ligase for TNRC6 proteins. The combination of overexpression and knockdown studies establishes that TRIM65 relieves miRNA-driven suppression of mRNA expression through ubiquitination and subsequent degradation of TNRC6. TRIM65 regulates ubiquitination and stability of TNRC6. (A) In vitro ubiquitination of TNRC6A by TRIM65 plus E1, E2 (UBCH5A, also known as UBE2D1), ATP, and HA-Ub. GST-tagged TRIM65 and mutant TRIM65 were purified from bacteria. TRIM65 regulates ubiquitination and stability of TNRC6. (A) In vitro ubiquitination of TNRC6A by TRIM65 plus E1, E2 (UBCH5A, also known as UBE2D1), ATP, and HA-Ub. GST-tagged TRIM65 and mutant TRIM65 were purified from bacteria. 	SIGNOR-272175	0.303
CDC42	protein	P60953	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates activity	binding			10090	BTO:0000142								8107774	t		gcesareni	A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways.	SIGNOR-248253	0.881
MTOR	protein	P42345	UNIPROT	ULK1	protein	O75385	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000007								21460634	t		lperfetto	mTORC1, which is often referred to as the gatekeeper to autophagy, is a key regulator of the Ulk1-Atg13-FIP200 kinase complex.11,14,25 Under nutrient-rich conditions, active mTORC1 associates with and inactivates the Ulk1-Atg13-FIP200 complex by phosphorylating Ulk1 and Atg13.	SIGNOR-183903	0.844
CAMK2D	protein	Q13557	UNIPROT	TPD52	protein	P55327	UNIPROT	unknown	phosphorylation	Ser176	KNSPTFKsFEEKVEN	9606									20946871	t		gcesareni	Here we demonstrate, using site-specific mutations, that ca(2+)-sensitive phosphorylation at serine 136 modulates the accumulation of d52 at the plasma membrane within 2 min of cell stimulation	SIGNOR-168550	0.2
ME1	protein	P48163	UNIPROT	(S)-malate(2-)	smallmolecule	CHEBI:15589	ChEBI	down-regulates quantity	chemical modification			9606									33064660	t		miannu	Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP.	SIGNOR-267717	0.8
NFX1	protein	Q12986	UNIPROT	TERT	protein	O14746	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17267499	f		miannu	NFX1-123 augments the activation of hTERT expression through interactions with PABPCs	SIGNOR-226015	0.505
Starvation	stimulus	SIGNOR-ST4	SIGNOR	SIRT1	protein	Q96EB6	UNIPROT	up-regulates activity				9606		BTO:0000759							15744310	f	AMPK pathway	Gianni	We show here that the Sir2 homologue, SIRT1—which modulates ageing in several species —controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1α. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting.	SIGNOR-261951	0.7
ADRA1B	protein	P35368	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257079	0.597
CDK1	protein	P06493	UNIPROT	CDC25A	protein	P30304	UNIPROT	up-regulates	phosphorylation	Ser116	PQKLLGCsPALKRSH	9606			SIGNOR-C17						12411508	t		lperfetto	Mitotic stabilization of cdc25a reflects its phosphorylation on ser17 and ser115 by cyclin b-cdk1, modifications required to uncouple cdc25a from its ubiquitin-proteasome-mediated turnover.	SIGNOR-95256	0.837
SGK3	protein	Q96BR1	UNIPROT	FLII	protein	Q13045	UNIPROT	up-regulates	phosphorylation	Thr818	LHRPRHAtVSRSLEG	9606									19293151	t		lperfetto	Here we show that flii is an in vivo substrate of cisk that functions downstream of pi 3-kinase. Cisk can associate with flii and phosphorylate flii at residues ser(436) and thr(818).We demonstrate here that cisk can enhance er transcription, which is dependent on its kinase activity, and mutation of cisk phosphorylation sites on flii attenuates its activity as an er co-activator.	SIGNOR-184692	0.364
ABL1	protein	P00519	UNIPROT	NCK1	protein	P16333	UNIPROT	up-regulates	phosphorylation	Tyr105	VDPGERLyDLNMPAY	9606									22327338	t		lperfetto	Activated c-abl reduces the amplitude of mitogen-activated protein kinases (erk1/2, jnks and p38) activation in a dose-dependent manner by a negative feedback mechanism. By analysis of the adaptor proteins nck1 and grb2 mutants we further show that the negative loop on p38 is mediated by c-abl phosphorylation at tyrosine 105 of the adaptor protein nck1	SIGNOR-196043	0.409
SRC	protein	P12931	UNIPROT	HNF4A	protein	P41235	UNIPROT	down-regulates	phosphorylation	Tyr286	LQIDDNEyAYLKAII	9606									22308320	t		lperfetto	Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function.	SIGNOR-195896	0.374
MAPK1	protein	P28482	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Ser447	GSPRTPVsPVKFSPG	9606									21035469	t		gcesareni	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-169154	0.578
PTK2	protein	Q05397	UNIPROT	ACTN4	protein	O43707	UNIPROT	up-regulates	phosphorylation	Tyr265	MTYVSSFyHAFSGAQ	9606									23454549	t		lperfetto	Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin	SIGNOR-192191	0.54
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	MYC	protein	P01106	UNIPROT	down-regulates quantity	ubiquitination			9606									20852628	t		gcesareni	We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it.	SIGNOR-243757	0.583
MMP12	protein	P39900	UNIPROT	FGA	protein	P02671	UNIPROT	down-regulates quantity by destabilization	cleavage	Leu433	REYHTEKlVTSKGDK	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain	SIGNOR-263624	0.2
MAPK3	protein	P27361	UNIPROT	CIITA	protein	P33076	UNIPROT	down-regulates	phosphorylation	Ser288	PDRPGSTsPFAPSAT	9606									18245089	t		gcesareni	In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.	SIGNOR-160617	0.348
SRC	protein	P12931	UNIPROT	VIL1	protein	P09327	UNIPROT	up-regulates activity	phosphorylation	Tyr256	LKAALKLyHVSDSEG	9606									15342783	t		lperfetto	These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton	SIGNOR-247433	0.37
TRiC	complex	SIGNOR-C539	SIGNOR	STAT3	protein	P40763	UNIPROT	up-regulates quantity by stabilization	binding			9606									36185250	t		miannu	Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC).	SIGNOR-272870	0.395
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates activity	phosphorylation			9606	BTO:0000007								10567369	t		lperfetto	An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2	SIGNOR-244858	0.747
RUNX2	protein	Q13950	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11331591	f		lperfetto	Together, these results suggest that the inhibition of cbfa1 transcription by TGF-_ requires both the presence of CBFA1 and CBFA1 binding to the cbfa1 promoter.	SIGNOR-235533	0.2
CNR2	protein	P34972	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256979	0.252
TGFb	proteinfamily	SIGNOR-PF5	SIGNOR	SNAI1	protein	O95863	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								29305973	t		miannu	Epithelial-mesenchymal transition (EMT) takes place, namely fibrosis, development and cancer. the process of EMT is integral to a number of physiological and disease states. TGF-β1 is a major effector of this process that activates various key transcription factors such as Snai1.	SIGNOR-265251	0.2
BABAM2	protein	Q9NXR7	UNIPROT	BRCA1-A complex	complex	SIGNOR-C296	SIGNOR	form complex	binding			9606	BTO:0000007								20656690	t		lperfetto	We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1. 	SIGNOR-263212	0.2
MAPK14	protein	Q16539	UNIPROT	CDX2	protein	Q99626	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser291	PVSSLQAsVPGSVPG	9606									16027724	t		miannu	ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation	SIGNOR-250094	0.425
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser362	TLKNKTEsSLLAKLE	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276201	0.2
CDK2	protein	P24941	UNIPROT	CDC6	protein	Q99741	UNIPROT	down-regulates activity	phosphorylation	Ser54	RVKALPLsPRKRLGD	9606			SIGNOR-C83						10339564	t		lperfetto	Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction.	SIGNOR-67544	0.94
N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide	chemical	CHEBI:91409	ChEBI	TYRO3	protein	Q06418	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190410	0.8
DCC	protein	P43146	UNIPROT	MYO10	protein	Q9HD67	UNIPROT	up-regulates activity	binding			10090	BTO:0000938								17237772	t		miannu	Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin.	SIGNOR-268281	0.672
1D-myo-inositol 1,4,5-trisphosphate	smallmolecule	CHEBI:16595	ChEBI	PRKCA	protein	P17252	UNIPROT	up-regulates	chemical activation			9606									18593525	t		gcesareni	The hrh1 predominantly couples to g?q/11 proteins, leading to the activation of phospholipase c (plc) and subsequent release of the second messengers inositol trisphosphate (ip3) and diacylglycerol (dag) followed by the activation of pkc and the release of [ca2+]i.	SIGNOR-179291	0.8
(1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid	chemical	CHEBI:94640	ChEBI	GRM3	protein	Q14832	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-193772	0.8
INS	protein	P01308	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates				10090									12530968	f		lperfetto	The forkhead transcription factor foxo1 is regulated by insulin via akt-dependent phosphorylation and nuclear exclusion.	SIGNOR-97392	0.745
quizartinib	chemical	CHEBI:90217	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									19754199	t			Compound 7 (AC220) (quizartinib) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models.	SIGNOR-255666	0.8
CCR3	protein	P51677	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates activity				9606	BTO:0000399								10706854	t			Activation of ERK2 and p38 by eotaxin is mediated through CCR3.	SIGNOR-256092	0.251
ADP	chemical	CHEBI:16761	ChEBI	PRPS1	protein	P60891	UNIPROT	down-regulates activity	chemical inhibition												29074724	t		lperfetto	PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP	SIGNOR-265736	0.8
Vincristine sulfate	chemical	CHEBI:79401	ChEBI	TUBB	protein	P07437	UNIPROT	down-regulates activity	chemical inhibition			9606									30599272	t		miannu	Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. 	SIGNOR-259251	0.8
GALR2	protein	O43603	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257296	0.252
LCK	protein	P06239	UNIPROT	VAV1	protein	P15498	UNIPROT	unknown	phosphorylation	Tyr174	EAEGDEIyEDLMRSE	-1									10669745	t			Lck recognizes preferentially the tyrosine residue of Vav located at position 174 and, with significantly less affinity, those present at positions 142 and 160. It is now clear that this posttranslational modification will be involved in the activation of Vav, in the regulation of the strength of the signals emanating from this molecule, and also in the negative regulation of its function.	SIGNOR-251391	0.776
MAP3K1	protein	Q13233	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser222	LIDSMANsFVGTRSY	10090	BTO:0000944								8131746	t		lperfetto	Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity.	SIGNOR-235564	0.645
FYN	protein	P06241	UNIPROT	JUP	protein	P14923	UNIPROT	down-regulates activity	phosphorylation	Tyr550	AAGTQQPyTDGVRME	10116									14517306	t			Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549 	SIGNOR-251177	0.541
CSNK2A1	protein	P68400	UNIPROT	CAV2	protein	P51636	UNIPROT	up-regulates activity	phosphorylation	Ser36	DPEKFADsDQDRDPH	9606	BTO:0001130								12743374	t		lperfetto	We show that caveolin-2 is phosphorylated in vivo at two serine residues and that the phosphorylation of caveolin-2 is necessary for its actions as a positive regulator of caveolin-1 during organelle biogenesis in prostate cancer cells. Mutation of the primary phosphorylation sites on caveolin-2, serine 23 and 36, reduces the number of plasmalemma-attached caveolae	SIGNOR-101110	0.325
citrate(3-)	smallmolecule	CHEBI:16947	ChEBI	D-threo-isocitrate(3-)	smallmolecule	CHEBI:15562	ChEBI	up-regulates quantity	precursor of			9606									24068518	t		miannu	Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained.	SIGNOR-266241	0.8
CSNK1E	protein	P49674	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates activity	phosphorylation	Thr59	EGYDELQtDGNRSSH	9606	BTO:0000567								11583622	t		llicata	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250806	0.35
GSK3B	protein	P49841	UNIPROT	CAP1	protein	Q01518	UNIPROT	up-regulates activity	phosphorylation	Ser308	SAPKPQTsPSPKRAT	9606		BTO:0000763							30123351	t		lperfetto	We found that GSK3 phosphorylates S307 and S309 by using inhibitors LiCl. Inhibition of GSK3beta can cause loss of cell polarity as well as accumulation of stress fibers. We propose that GSK3 regulates CAP1 through at least two mechanisms. First, GSK3 (and potentially other kinases) phosphorylate CAP1 at S309 and promote CAP1 localization to the cytosol. Second, phosphorylation at S309 affects protein-protein interactions with actin and cofilin. The loss of this phospho-regulation by GSK3 inhibition is expected to disrupt CAP1 function and actin dynamics.	SIGNOR-264822	0.256
PLCB1	protein	Q9NQ66	UNIPROT	GNA11	protein	P29992	UNIPROT	up-regulates	binding			9606									1322796	t		miannu	Plc-_1 stimulates hydrolysis of gq/11-bound gtp and acts as a gtpase-activating protein (gap) for its physiologic regulator, gq/11	SIGNOR-17239	0.607
LPCAT2	protein	Q7L5N7	UNIPROT	1,2-diacyl-sn-glycero-3-phosphocholine	chemical	CHEBI:57643	ChEBI	up-regulates quantity	chemical modification			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272764	0.8
PSME1	protein	Q06323	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	up-regulates activity	binding												35932807	t		lperfetto	While PA28alpha beta is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28gamma is well-known to not only promote peptidase activity but also proteolytic activity of proteasome. 	SIGNOR-275867	0.59
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1672	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273096	0.745
CCT4	protein	P50991	UNIPROT	TRiC	complex	SIGNOR-C539	SIGNOR	form complex	binding			9606									36185250	t		miannu	Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC).	SIGNOR-272866	0.737
PIN1	protein	Q13526	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	isomerization			9606	BTO:0000599								23720771	t		lperfetto	In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events	SIGNOR-265757	0.2
CEP290	protein	O15078	UNIPROT	RAB8A	protein	P61006	UNIPROT	up-regulates activity	binding			9606									18694559	t		miannu	CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CEP290 recruits Rab8a to centrosomes. Depletion of CEP290 results in a significant decrease of Rab8a at the centrosome and at the cilium, raising the possibility that CEP290 first recruits Rab8a through direct protein-protein interactions to the centrosome in cycling cells and later promotes ciliogenesis by allowing the entry of Rab8a into the cilium	SIGNOR-252146	0.732
MITF	protein	O75030	UNIPROT	TPSAB1	protein	Q15661	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000830								20513998	t		lperfetto	The transcription of tryptase gene in human mast cells is regulated by mi transcription factor |Using mutant constructs of tryptase promoter, we observed that two E-box (CANNTG) motifs including between -817 to -715 and -421 to -202 are able to involve in the transactivation of tryptase gene by MITF-A.	SIGNOR-251725	0.2
SAV1	protein	Q9H4B6	UNIPROT	STK3	protein	Q13188	UNIPROT	up-regulates	binding			9606									21084559	t	Sav1 interacts with Mst1/2 through the SARAH domains present in both Sav1 and Mst1/2.	gcesareni	Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst.	SIGNOR-169829	0.827
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1735	SPTSPSYsPTSPSYS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248824	0.849
CSNK2A1	protein	P68400	UNIPROT	CAV2	protein	P51636	UNIPROT	up-regulates activity	phosphorylation	Ser23	DDSYSHHsGLEYADP	9606	BTO:0001130								12743374	t		lperfetto	We show that caveolin-2 is phosphorylated in vivo at two serine residues and that the phosphorylation of caveolin-2 is necessary for its actions as a positive regulator of caveolin-1 during organelle biogenesis in prostate cancer cells. Mutation of the primary phosphorylation sites on caveolin-2, serine 23 and 36, reduces the number of plasmalemma-attached caveolae	SIGNOR-101106	0.325
ERG	protein	P11308	UNIPROT	ICAM2	protein	P13598	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10574717	f	 	miannu	The Ets family member Erg was found to be constitutively expressed in HUVEC, and TNF-(alpha) down-regulated Erg protein levels. Furthermore, an Erg cDNA transactivated the ICAM-2 promoter when transiently transfected into both HeLa cells and HUVEC. 	SIGNOR-253913	0.2
ATM	protein	Q13315	UNIPROT	ABRAXAS1	protein	Q6UWZ7	UNIPROT	up-regulates activity	phosphorylation	Ser404	MKGFGEYsRSPTF	9606	BTO:0000007								26778126	t			In this study, we demonstrate that ionizing radiation (IR)-induces ATM-dependent phosphorylation of serine 404 (S404) next to the pSPxF motif. Crystal structures of BRCT/Abraxas show that phosphorylation of S404 is important for extensive interactions through the N-terminal sequence outside the pSPxF motif and leads to formation of a stable dimer.	SIGNOR-255587	0.2
CAD	protein	P27708	UNIPROT	N-carbamoyl-L-aspartate(2-)	smallmolecule	CHEBI:32814	ChEBI	down-regulates quantity	chemical modification			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-267427	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	IL1RN	protein	P18510	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000130;BTO:0000876								20032313	f	 	miannu	 The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. 	SIGNOR-254794	0.339
SRC	protein	P12931	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates	phosphorylation	Tyr536	QKGQESEyGNITYPP	9606									14699166	t		llicata	Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells.	SIGNOR-120488	0.543
SMURF1	protein	Q9HCE7	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates activity	ubiquitination			9606	BTO:0002181								15817471	t	In the presence of smad6 or smad7 acting as adaptors	lperfetto	Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes.	SIGNOR-236096	0.735
3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	DIO	proteinfamily	SIGNOR-PF83	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0004055								12746313	t	inferred from family member	scontino	Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. 	SIGNOR-270246	0.8
NOXA1	protein	Q86UR1	UNIPROT	NOX1	protein	Q9Y5S8	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								20943948	t		lperfetto	Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation	SIGNOR-264710	0.743
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	NOS3	protein	P29474	UNIPROT	up-regulates activity	dephosphorylation	Thr495	TGITRKKtFKEVANA	9606	BTO:0001176								19036824	t		lperfetto	The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation	SIGNOR-264668	0.2
TEX10	protein	Q9NXF1	UNIPROT	Rix1 complex	complex	SIGNOR-C373	SIGNOR	form complex	binding			9606	BTO:0000007								22190735	t		miannu	LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes.	SIGNOR-265472	0.873
RPS6KA5	protein	O75582	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	unknown	phosphorylation	Ser752	KMKKTSTsTETRSSS	9606									15568999	t		lperfetto	Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known.	SIGNOR-131403	0.2
DOCK7	protein	Q96N67	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			10090	BTO:0000132								29187380	t		lperfetto	As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover.	SIGNOR-261887	0.525
STK3	protein	Q13188	UNIPROT	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	up-regulates	phosphorylation			9606									21808241	t	inferred from 70% of family members	gcesareni	Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2.	SIGNOR-269862	0.603
KDM3A	protein	Q9Y4C1	UNIPROT	H3C15	protein	Q71DI3	UNIPROT	up-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									16603237	t		miannu	Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. 	SIGNOR-276844	0.2
CSNK1A1	protein	P48729	UNIPROT	NFATC3	protein	Q12968	UNIPROT	down-regulates activity	phosphorylation	Thr210	FTLGSPLtSPGGSPG	9606	BTO:0001131								9630228	t		lperfetto	Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4.	SIGNOR-109776	0.571
ZNRF3	protein	Q9ULT6	UNIPROT	LRP6	protein	O75581	UNIPROT	down-regulates	ubiquitination			9606									23151663	t		gcesareni	Znrf3 is associated with the wnt receptor complex, and inhibits wnt by promoting the turnover of frizzled and lrp6. Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation, and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane.	SIGNOR-199656	0.642
GTF2E1	protein	P29083	UNIPROT	TFIIE	complex	SIGNOR-C458	SIGNOR	form complex	binding			9606									31064989	t		lperfetto	The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur.	SIGNOR-269360	0.94
CDK1	protein	P06493	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Ser394	TRQTPVDsPDDSTLS	9606	BTO:0000567								12586835	t		gcesareni	A physical interaction exists between cdc2 and s6k1, and this interaction is enhanced in mitotic cells. These results suggest that cdc2 provides a signal that triggers inactivation of s6k1 in mitosis, presumably serving to spare energy for costly mitotic processes at the expense of ribosomal protein synthesis.	SIGNOR-98211	0.392
PRKCB	protein	P05771	UNIPROT	SLC6A9	protein	P48067-2	UNIPROT	down-regulates activity	phosphorylation	Thr19	GAVPSEAtKRDQNLK	9823									21864610	t		miannu	We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 	SIGNOR-262925	0.2
TLE5	protein	Q08117	UNIPROT	ZNF503	protein	Q96F45	UNIPROT	down-regulates activity	binding			9534									19056829	t		miannu	 these results show that Grg5 can specifically interact with the C-terminus of Nolz1. these data suggest that Nolz1 functions as a repressor molecule, and that Grg5 interactions with Nolz1 serve to modulate Nolz1 repressor function. Mechanistically, Grg5 is known to modulate Grg co-repressor activity, raising the possibility that classical Grg proteins mediate Nolz1-dependent transcriptional repression. GalNolz1ΔC22 showed increased repressor activity compared with GalNolz1, consistent with the ability of Grg5 to modulate Nolz1 repressor function. 	SIGNOR-261192	0.2
gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	GABA-A (a2-b1-g2) receptor	complex	SIGNOR-C331	SIGNOR	up-regulates activity	chemical activation			9606									18790874	t	brain	lperfetto	Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS).	SIGNOR-263787	0.8
MAPK1	protein	P28482	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser616	DDGYMPMsPGVAPVP	9606									15001544	t		lperfetto	Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation.	SIGNOR-123173	0.667
RPL9	protein	P32969	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262452	0.858
SIRT2	protein	Q8IXJ6	UNIPROT	PGAM2	protein	P15259	UNIPROT	up-regulates activity	deacetylation	Lys100	GGLTGLNkAETAAKH	9606									24786789	t		miannu	 Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2.	SIGNOR-266518	0.2
PGM2	protein	Q96G03	UNIPROT	alpha-D-ribose 1-phosphate(2-)	smallmolecule	CHEBI:57720	ChEBI	down-regulates quantity	chemical modification			9606									17804405	t		miannu	Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase.	SIGNOR-267075	0.8
NFYA	protein	P23511	UNIPROT	OGG1	protein	O15527	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14688259	f		miannu	 these results demonstrate that MMS can up-regulate hOGG1 expression through the induction of the transcription factor, NF-YA, and increased transcription level of the hOGG1 gene correlates with an increase in enzyme activity providing functional protection from MMS.	SIGNOR-254817	0.268
AURKA	protein	O14965	UNIPROT	PIN1	protein	Q13526	UNIPROT	down-regulates activity	phosphorylation	Ser16	PGWEKRMsRSSGRVY	9606									23970419	t		llicata	Here, we found that aurora a can interact with and phosphorylate pin1 at ser16, which suppresses the g2/m function of pin1 by disrupting its binding ability and mitotic entry.	SIGNOR-202487	0.257
PRKAA1	protein	Q13131	UNIPROT	TBC1D1	protein	Q86TI0	UNIPROT	down-regulates	phosphorylation	Ser237	RPMRKSFsQPGLRSL	9606		BTO:0001760	SIGNOR-C15						17995453	t		gcesareni	In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar	SIGNOR-159048	0.404
SP4	protein	Q02446	UNIPROT	MAOB	protein	P27338	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11259630	f		miannu	Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2. 	SIGNOR-253869	0.2
IFNB1	protein	P01574	UNIPROT	IFNAR2	protein	P48551	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								11278538	t		lperfetto	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-219304	0.662
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1647	SPSYSPTsPSYSPTS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248770	0.441
SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	GDF3	protein	Q9NR23	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269250	0.454
ERCC4	protein	Q92889	UNIPROT	ERCC4/ERCC1	complex	SIGNOR-C50	SIGNOR	form complex	binding			9606									16338413	t		miannu	Human ercc1/xpf interaction domains reveals a complementary role for the two proteins in nucleotide excision repair.	SIGNOR-142992	0.952
AZD1480	chemical	CID:16659841	PUBCHEM	JAK1	protein	P23458	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190164	0.8
CSNK2A1	protein	P68400	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	down-regulates activity	phosphorylation	Ser891	TLSEEKNsECDPTPS	9606	BTO:0000567								31167143	t		miannu	Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations. 	SIGNOR-276728	0.2
PIM2	protein	Q9P1W9	UNIPROT	PKM	protein	P14618	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr454	RAPIIAVtRNPQTAR	9606									24142698	t		miannu	Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis	SIGNOR-267472	0.379
PRKCD	protein	Q05655	UNIPROT	FSCN1	protein	Q16658	UNIPROT	down-regulates activity	phosphorylation	Ser39	KVNASASsLKKKQIW	9606	BTO:0000931								8647875	t		lperfetto	Phosphorylation of human fascin inhibits its actin binding and bundling activities.	SIGNOR-248944	0.329
NDN	protein	Q99608	UNIPROT	CDKN2A	protein	P42771	UNIPROT	up-regulates				9606									24392140	f		lperfetto	In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity,	SIGNOR-253383	0.282
INSR	protein	P06213	UNIPROT	IRS2	protein	Q9Y4H2	UNIPROT	down-regulates activity	phosphorylation	Tyr632	YHPYPEDyGDIEIGS	-1									9195949	t			Tyr624 and Tyr628 are involved in the interaction between the IR and the KRLB domain of IRS-2, including tyrosine phosphorylation, and Tyr628 seems to be more important than Tyr624 in this process. the binding between the insulin receptor and the KRLB domain of IRS-2 results in tyrosine phosphorylation of the KRLB domain, and this leads to decreased binding of IRS-2 to the insulin receptor.	SIGNOR-251319	0.748
SOD3	protein	P08294	UNIPROT	hydrogen peroxide	smallmolecule	CHEBI:16240	ChEBI	up-regulates quantity	chemical modification			9606									29301787	t		lperfetto	Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD).	SIGNOR-272273	0.8
STK11	protein	Q15831	UNIPROT	MARK3	protein	P27448	UNIPROT	up-regulates activity	phosphorylation	Ser215	KLDTFCGsPPYAAPE	9606	BTO:0000568								12879020	t		lperfetto	Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211.	SIGNOR-104059	0.32
FGF14	protein	Q92915	UNIPROT	SCN1A	protein	P35498	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253421	0.369
ATM	protein	Q13315	UNIPROT	NBN	protein	O60934	UNIPROT	up-regulates	phosphorylation	Ser343	TTPGPSLsQGVSVDE	9606									10802669	t		gcesareni	We show that atm physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (s343a) does not completely complement radiosensitivity in nbs cells.	SIGNOR-77149	0.852
NME1	protein	P15531	UNIPROT	LPAR1	protein	Q92633	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001567								17671192	f		miannu	To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 	SIGNOR-255163	0.416
DAMPS	stimulus	SIGNOR-ST18	SIGNOR	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	up-regulates				9606									25720354	f		scontino	APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. 	SIGNOR-267856	0.7
SOD1	protein	P00441	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	down-regulates quantity	chemical modification			9606									29301787	t		lperfetto	Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD).	SIGNOR-272285	0.8
PTPRC	protein	P08575	UNIPROT	JAK1	protein	P23458	UNIPROT	down-regulates activity	dephosphorylation	Tyr1034	AIETDKEyYTVKDDR	10090									11201744	t			CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells 	SIGNOR-248355	0.466
CDK2	protein	P24941	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser36	HPGFDAEsYTFTVPR										23972993	t	For phosphorylated residues see Figure 7	lperfetto	Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP	SIGNOR-274049	0.441
PRKAA1	protein	Q13131	UNIPROT	ALDH2	protein	P05091	UNIPROT	up-regulates activity	phosphorylation	Thr356	GNPFDSKtEQGPQVD	10090	BTO:0000801								30375985	t		lperfetto	Further studies demonstrate that in the absence of LDLR, AMPK phosphorylates ALDH2 at threonine 356 and enables its nuclear translocation. Nuclear ALDH2 interacts with HDAC3 and represses transcription of a lysosomal proton pump protein ATP6V0E2, critical for maintaining lysosomal function, autophagy, and degradation of oxidized low-density lipid protein. 	SIGNOR-271863	0.2
PF-04691502	chemical	CID:25033539	PUBCHEM	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck;inhibitor of phosphorylation of AktT308 and AktS473	gcesareni		SIGNOR-205977	0.8
somatostatin	smallmolecule	CHEBI:64628	ChEBI	SSTR1	protein	P30872	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257581	0.8
PRKACA	protein	P17612	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Thr7	tSAARRSY	-1									2155236	t		miannu	GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments.	SIGNOR-249712	0.286
gamma-secretase	complex	SIGNOR-C98	SIGNOR	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000590								19958215	t		lperfetto	The production and accumulation of the beta amyloid protein (Abeta) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer's disease (AD). A multi-subunit enzyme complex, referred to as gamma (gamma) secretase, plays a pivotal role in the generation of Abeta from its parent molecule, the amyloid precursor protein (APP).	SIGNOR-251576	0.597
SESN2	protein	P58004	UNIPROT	GATOR2	complex	SIGNOR-C193	SIGNOR	down-regulates activity	binding			10090	BTO:0002572								25457612	t			We describe AMPK-independent mechanism of mTORC1 regulation by the Sestrins, in which the Sestrins inhibit mTORC1 localization to the lysosomes in a Rag-dependent manner through an interaction with GATOR2	SIGNOR-253560	0.708
EP300	protein	Q09472	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	acetylation	Lys28	LATKAARkSAPSTGG	9606			SIGNOR-C6						21131905	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	fspada	These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription.	SIGNOR-170266	0.2
SEC23IP	protein	Q9Y6Y8	UNIPROT	long-chain fatty acid anion	smallmolecule	CHEBI:57560	ChEBI	up-regulates quantity	chemical modification			9606									22922100	t		miannu	Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 	SIGNOR-269654	0.8
FGF10	protein	O15520	UNIPROT	FGFR2	protein	P21802	UNIPROT	up-regulates	binding			9606									9582367	t		gcesareni	Rfgf-10 bound the kgfr with high affinity comparable to that of kgf	SIGNOR-57380	0.89
AURKA	protein	O14965	UNIPROT	SPAG5	protein	Q96R06	UNIPROT	up-regulates activity	phosphorylation	Ser115	ISSTPKTsEEAVDPL	9606	BTO:0002181								25009111	t		miannu	We report here that Astrin acts as a mitotic phosphoprotein, and Aurora-A phosphorylates Astrin at Ser(115). The phosphorylation-deficient mutant Astrin S115A abnormally activates spindle assembly checkpoint and delays mitosis progression, decreases spindle stability, and induces chromosome misalignment. Mechanistic analyses reveal that Astrin phosphorylation mimicking mutant S115D, instead of S115A, binds and induces ubiquitination and degradation of securin, which sequentially activates Separase, an enzyme required for the separation of sister chromatids. 	SIGNOR-276648	0.525
BMP2	protein	P12643	UNIPROT	OMD	protein	Q99983	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16970923	f		miannu	Bmp-2 up regulates osad	SIGNOR-149562	0.316
ANKRD28	protein	O15084	UNIPROT	PPP1CC	protein	P36873	UNIPROT	up-regulates activity	binding			-1									17023142	t		lperfetto	Phosphatase Interactor Targeting K protein (PITK) was previously identified as a novel PP1 targeting subunit implicated in modulating the phosphorylation of the transcriptional regulator heterogeneous nuclear ribonucleoprotein K (hnRNP K)	SIGNOR-264794	0.456
PRKCZ	protein	Q05513	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser109	KSHSRQAsTDAGTAG	9606	BTO:0002181								25660024	t		miannu	 Yap and β-catenin are direct substrates of PKCζ.We show here that PKCζ suppresses intestinal stem cell function by promoting the downregulation of β-catenin and Yap through direct phosphorylation.Consistent with MS/MS analysis, mutation to alanine of these two sites completely abolished Yap phosphorylation by PKCζ. Interestingly, S109 and T110 sites were highly conserved among species (Figure S3B), which suggested an important role in Yap regulation. 	SIGNOR-276876	0.28
perfluorooctanoic acid	chemical	CHEBI:35549	ChEBI	PPARG	protein	P37231	UNIPROT	up-regulates activity	chemical activation			10090	BTO:0000011								16731579	t		miannu	Taken together, these data show that of the NRs studied, PPARα is the most likely target of PFOA and PFOS, although PPARγ is also activated to some extent.	SIGNOR-268788	0.8
INSR	protein	P06213	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	phosphorylation	Tyr941	EETGTEEyMKMDLGP	10116	BTO:0000443								7651388	t		lperfetto	All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10).	SIGNOR-235975	0.911
NF1	protein	P21359	UNIPROT	ADCY3	protein	O60266	UNIPROT	up-regulates				9606									24431436	f		miannu	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-204034	0.267
GLI1/GLI2	complex	SIGNOR-C450	SIGNOR	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000304								32766732	t	GLI2 and GLI1 heterodimerize via the Zn-finger domain	SimoneGraziosi	GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. | RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells	SIGNOR-269213	0.549
serotonin(1+)	smallmolecule	CHEBI:350546	ChEBI	HTR2B	protein	P41595	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257522	0.8
SLC11A1	protein	P49279	UNIPROT	M1_polarization	phenotype	SIGNOR-PH54	SIGNOR	up-regulates				9606									11909746	f			Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS)	SIGNOR-254037	0.7
PC	protein	P11498	UNIPROT	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	up-regulates quantity	chemical modification			9606									24363178	t		miannu	As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2)	SIGNOR-266552	0.8
CSNK1A1	protein	P48729	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	down-regulates activity	phosphorylation	Ser824	LVDKEHDsAEGSHTS	9606	BTO:0001109								28114302	t		miannu	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276511	0.378
PAX7/MLL1 complex	complex	SIGNOR-C90	SIGNOR	MYF5	protein	P13349	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002314	BTO:0000887;BTO:0001103							22863532	f		miannu	Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5.	SIGNOR-198638	0.508
3-iodo-L-tyrosine	smallmolecule	CHEBI:27847	ChEBI	3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	up-regulates quantity	precursor of			9606									28153798	t		scontino	The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines.	SIGNOR-268128	0.8
MAPKAPK5	protein	Q8IW41	UNIPROT	DNAJB1	protein	P25685	UNIPROT	up-regulates	phosphorylation	Ser151	VNFGRSRsAQEPARK	9606									24309468	t		lperfetto	Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1.	SIGNOR-203460	0.44
CDK1	protein	P06493	UNIPROT	PTTG2	protein	Q9NZH5	UNIPROT	up-regulates activity	phosphorylation	Ser165	LFQLGPPsPVKMPSP	9606	BTO:0000567								10656688	t		miannu	HPTTG is phosphorylated by Cdc2 at Ser165. we show that hPTTG is phosphorylated during mitosis. The direct phosphorylation of hPTTG by Cdc2 is interesting in itself since the substrates of this master mitotic kinase are supposed to play important roles in the initiation and progression of mitosis. 	SIGNOR-262700	0.296
PLD3	protein	Q8IV08	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								24336208	t		Monia	Furthermore, PLD3 can be co-immunoprecipitated with APP in cultured cells (Extended Data Figure 4). Together, these studies demonstrate that PLD3 plays a role in APP processing. Over-expression of PLD3 leads to a significant decrease in intracellular APP and extracellular Aβ42 and Aβ40, while knock-down of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a two-fold increased risk for LOAD and that PLD3 influences APP processing.	SIGNOR-261200	0.382
FBP1	protein	P09467	UNIPROT	HIF1A	protein	Q16665	UNIPROT	down-regulates activity	binding			9606									30616754	t		lperfetto	FBP1, but not FBP2, suppresses HIF-1a activity by directly binding to its inhibitory domain.	SIGNOR-267590	0.331
AR	protein	P10275	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates quantity by repression	binding			9606									9162033	t		lperfetto	Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity	SIGNOR-48513	0.526
AKT1	protein	P31749	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation	Ser119	EILSRRPsYRKILND	9606	BTO:0000007								9829964	t		gcesareni	When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner.	SIGNOR-252549	0.761
NFIL3	protein	Q16649	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				10090	BTO:0003104								10082541	f		lperfetto	NFIL3 inhibits apoptosis without affecting Bcl-xL expression.	SIGNOR-256618	0.7
BTK	protein	Q06187	UNIPROT	WAS	protein	P42768	UNIPROT	unknown	phosphorylation	Tyr291	AETSKLIyDFIEDQG	9606									10068673	t		llicata	These results indicate that btk phosphorylates wasp on its tyrosine 291	SIGNOR-86004	0.732
CDK2	protein	P24941	UNIPROT	ZBTB16	protein	Q05516	UNIPROT	down-regulates	phosphorylation	Ser197	SFGLSAMsPTKAAVD	9606	BTO:0001271								18246121	t		llicata	Here we show that the main cyclin-dependent kinase involved at the g(1) to s transition (cdk2) phosphorylates plzf at two consensus sites found within pest domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of plzf, which impairs plzf transcriptional repression ability and antagonizes its growth inhibitory effects.	SIGNOR-160626	0.286
GABA-A (a4-b3-d) receptor	complex	SIGNOR-C327	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000227							18790874	f	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263775	0.7
CSNK1E	protein	P49674	UNIPROT	ROR2	protein	Q01974	UNIPROT	up-regulates	phosphorylation			9606									15375164	t		gcesareni	We also show that ror2 is phosphorylated by ckiepsilon on serine/threonine residues.	SIGNOR-129117	0.271
MAPKAPK2	protein	P49137	UNIPROT	LPCAT2	protein	Q7L5N7	UNIPROT	up-regulates activity	phosphorylation	Ser34	PMVPRQAsFFPPPVP	10090	BTO:0002601								20663880	t		miannu	Mass spectrometry and mutagenesis analyses identified Ser34 of LPCAT2 as the phosphorylation site to enhance the catalytic activities. The experiments using inhibitors and siRNA against MAPK cascades demonstrated that LPCAT2 phosphorylation through LPS-TLR4 signaling may directly depend on MAPK-activated protein kinase 2 (MAPKAP kinase 2 or MK2).	SIGNOR-263077	0.2
FBXO22	protein	Q8NEZ5	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000356								29945959	t		lperfetto	FBXO22 elicits its antimetastatic effects by targeting SNAIL, a master regulator of EMT and breast cancer metastasis, for ubiquitin-mediated proteasomal degradation in a glycogen synthase kinase 3β phosphorylation-dependent manner. 	SIGNOR-273446	0.2
PRKCZ	protein	Q05513	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates activity	phosphorylation	Ser43	VETWQEGsLKASCLY	-1									15604283	t		miannu	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276016	0.2
SLC4A10	protein	Q6U841	UNIPROT	hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								23056253	t		miannu	The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pH(i)) and chloride concentration ([Cl(-)](i)) in neurons. 	SIGNOR-264687	0.8
CDH11	protein	P55287	UNIPROT	CTNNA1	protein	P35221	UNIPROT	unknown	binding			9606	BTO:0000150								10029089	t		miannu	Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin	SIGNOR-64859	0.467
ABL1	protein	P00519	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates	phosphorylation	Tyr686	IITEYCRyGDLVDYL	9606	BTO:0000150;BTO:0000527								19275932	t		gcesareni	These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis.	SIGNOR-184552	0.507
MACF1	protein	Q9UPN3	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates				9606	BTO:0000938								16815997	f		flangone	Macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane.	SIGNOR-147457	0.302
ANGPT1	protein	Q15389	UNIPROT	MYOG	protein	P15173	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000222								26042050	f		lperfetto	Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein.	SIGNOR-241554	0.26
prostaglandin D2(1-)	smallmolecule	CHEBI:57406	ChEBI	PTGDR	protein	Q13258	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257568	0.8
EPX	protein	P11678	UNIPROT	EPX	protein	P11678	UNIPROT	up-regulates activity	post translational modification			9606	BTO:0000399								18694936	t		miannu	Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.	SIGNOR-261706	0.2
ARHGAP8	protein	P85298	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260463	0.438
TPO	protein	P07202	UNIPROT	L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	up-regulates quantity	chemical modification			9606									28153798	t		scontino	The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines.	SIGNOR-267040	0.8
CHUK	protein	O15111	UNIPROT	TAX1BP1	protein	Q86VP1	UNIPROT	up-regulates activity	phosphorylation	Ser593	NYKELKRsLENPAER	10090	BTO:0002572								21765415	t	The effect has been demonstrated using Q86VP1-2	lperfetto	Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, But not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1).	SIGNOR-175058	0.39
APOA1	protein	P02647	UNIPROT	LCAT	protein	P04180	UNIPROT	up-regulates activity	binding			9606									19860440	t		miannu	Activation of LCAT by apolipoprotein (apo) A-I on nascent (discoidal) high density lipoproteins (HDL) is essential for formation of mature (spheroidal) HDL during the antiatherogenic process of reverse cholesterol transport. After attachment of LCAT to discoidal HDL, the helix 5/5 domains in apoA-I form amphipathic presentation tunnels for migration of hydrophobic acyl chains and amphipathic UC from the bilayer to the phospholipase A2-like and esterification active sites of LCAT, respectively. 	SIGNOR-252103	0.774
CDK7	protein	P50613	UNIPROT	XRN2	protein	Q9H0D6	UNIPROT	up-regulates activity	phosphorylation	Thr439	FTPSGILtPHALGSR	9606									26728557	t		Luana	CDKs and Xrn2 phosphorylation promote transcription termination. | Cdk7 phosphorylated Xrn2-Thr439 but was less efficient than Cdk9. | 	SIGNOR-259851	0.25
JAG2	protein	Q9Y219	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	binding			9606									10958687	t	inferred from 70% of family members	gcesareni	Binding of delta1, jagged1, and jagged2 to notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of notch2	SIGNOR-269935	0.628
ITGB4	protein	P16144	UNIPROT	PIK3CD	protein	O00329	UNIPROT	up-regulates	binding			9606									9428518	t		gcesareni	Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation.	SIGNOR-54700	0.2
ROS	stimulus	SIGNOR-ST2	SIGNOR	NFE2L2	protein	Q16236	UNIPROT	up-regulates				9606	BTO:0000018								22789539	f		miannu	Nrf2 is a master transcriptional activator of cytoprotective genes. It activates transcription in response to electrophiles and reactive oxygen species (ROS) (Itoh et al., 1997, Uruno and Motohashi, 2011). Under normal conditions, Nrf2 is constantly ubiquitinated by Keap1 and degraded by the proteasome. Exposure to the stimuli inactivates Keap1 and stabilizes Nrf2.	SIGNOR-267353	0.7
Viral_dsRNA	stimulus	SIGNOR-ST21	SIGNOR	DDX1	protein	Q92499	UNIPROT	up-regulates				10090									21703541	f		miannu	We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA.	SIGNOR-260190	0.7
AKT2	protein	P31751	UNIPROT	RALGAPA2	protein	Q2PPJ7	UNIPROT	down-regulates activity	phosphorylation	Ser696	TTVGRSFsLSWRSHP	10090				SIGNOR-C469					21148297	t		miannu	RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase	SIGNOR-269798	0.43
CFD	protein	P00746	UNIPROT	CFB	protein	P00751	UNIPROT	up-regulates activity	cleavage	Arg259	GPGEQQKrKIVLDPS	9606		BTO:0000089							26489954	t		lperfetto	The resulting proconvertase C3bB is subsequently cleaved by factor D (FD), generating the AP C3 convertase C3bBb	SIGNOR-263487	0.796
NME1	protein	P15531	UNIPROT	MMP2	protein	P08253	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001567								17671192	f		miannu	To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 	SIGNOR-255165	0.338
SPI1	protein	P17947	UNIPROT	MEIS1	protein	O00470	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26622774	f		miannu	 In the present study, PU.1 siRNA was demonstrated to efficiently inhibit the transcription level of oncogene MEIS1 in the human acute myeloid non-MLL leukemia U937 cell line. In addition, PU.1, as a positive regulator of MEIS1, performed a crucial role in maintaining cell proliferation. 	SIGNOR-256002	0.382
ARID3A	protein	Q99856	UNIPROT	Immunoglobulin mu heavy chain	protein	P0DOX6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								16738337	t		lperfetto	In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels.| Figure ​3 shows that both anti-Bright and anti-TFII-I precipitated the bf150 Bright binding site from the B-cell line but not from a T-cell line that contains but does not express the V1 gene.	SIGNOR-268532	0.2
Macrophage_activation	phenotype	SIGNOR-PH126	SIGNOR	IL18	protein	Q14116	UNIPROT	up-regulates quantity				9606	BTO:0000801								10653850	f		miannu	IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement.	SIGNOR-260964	0.7
MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606									27098840	f		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes.	SIGNOR-263859	0.7
GSK3B	protein	P49841	UNIPROT	AHR	protein	P35869	UNIPROT	up-regulates activity	phosphorylation	Ser693	PYKSEMDsMPYTQNF	9606	BTO:0000567								34198826	t		miannu	A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR.	SIGNOR-276663	0.253
SALL4	protein	Q9UJQ4	UNIPROT	HOXA9	protein	P31269	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001883								24051379	f		miannu	 In primary human AML cells, downregulation of SALL4 led to decreased HOXA9 expression and enhanced apoptosis. We found that SALL4 bound a specific region of the HOXA9 promoter in leukemic cells. SALL4 overexpression led to enhanced binding of histone activation markers at the HOXA9 promoter region, as well as increased HOXA9 expression in these cells. 	SIGNOR-255125	0.389
PAK1	protein	Q13153	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser38	SVPEFPLsPPKKKDL	9606									10913145	t		gcesareni	We find that, in vitro, pak1 phosphorylates op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays.	SIGNOR-79955	0.384
RPS4X	protein	P62701	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262447	0.847
PTPRF	protein	P10586	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	9606									10734133	t		gcesareni	Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product.	SIGNOR-76005	0.563
PHF3	protein	Q92576	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates activity	binding			9606	BTO:0000007						phosphorylation:Ser1594	GAMSPSYsPTSPAYE	34667177	t		miannu	PHF3 interacts with RNA polymerase II through the SPOC domain. PHF3 negatively regulates mRNA levels. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay. PHF3 SPOC preferentially binds RNA Pol II CTD phosphorylated on Serine-2	SIGNOR-266965	0.47
KRAS	protein	P01116	UNIPROT	PIK3CB	protein	P42338	UNIPROT	up-regulates	binding			9606									21779497	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k.	SIGNOR-175207	0.701
dimethyloxalylglycine	chemical	CHEBI:102218	ChEBI	EGLN1	protein	Q9GZT9	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000018								28900510	t		lperfetto	We treated the A549 cells with the following EGLN/PHD inhibitors: dimethyloxalyglycine (DMOG), CoCl2, inhibitors of dioxygenases, and BAY 85-3494 (BAY), a specific inhibitor of EGLNs with highest potency against EGLN1.	SIGNOR-261991	0.8
Riluzole	chemical	CHEBI:8863	ChEBI	KCNN3	protein	Q9UGI6	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								18955585	t		Luana	Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. 	SIGNOR-258019	0.8
PI3K	complex	SIGNOR-C156	SIGNOR	RAC1	protein	P63000	UNIPROT	up-regulates				9606									21779497	f		gcesareni	Pi3k can also activate rac, and this activation is involved in cytoskeleton reorganization.	SIGNOR-252707	0.528
BRCC3	protein	P46736	UNIPROT	BRCA1-A complex	complex	SIGNOR-C296	SIGNOR	form complex	binding			9606	BTO:0000007								20656690	t		lperfetto	We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1. 	SIGNOR-263213	0.925
CDK2	protein	P24941	UNIPROT	PRDX1	protein	Q06830	UNIPROT	down-regulates	phosphorylation	Thr90	CHLAWVNtPKKQGGL	9606	BTO:0000567								11986303	t		lperfetto	Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown).	SIGNOR-87101	0.256
carbamoyl phosphate(2-)	smallmolecule	CHEBI:58228	ChEBI	N-carbamoyl-L-aspartate(2-)	smallmolecule	CHEBI:32814	ChEBI	up-regulates quantity	precursor of			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-267422	0.8
FN1	protein	P02751	UNIPROT	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	up-regulates activity	binding			9606	BTO:0000664								12123670	t		lperfetto	We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1.	SIGNOR-253250	0.739
POLE	protein	Q07864	UNIPROT	DNA polymerase epsilon	complex	SIGNOR-C377	SIGNOR	form complex	binding			9606	BTO:0000567								10801849	t		lperfetto	Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon.	SIGNOR-265520	0.921
MAPK14	protein	Q16539	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity	phosphorylation	Thr56	FSSQPGHtPHPAASR	9606									16714293	t		gcesareni	Bcl-2 phosphorylation by p38 mapkin this study, we identify, by using mass spectrometry techniques and specific anti-phosphopeptide antibodies, ser(87) and thr(56) as the bcl-2 residues phosphorylated by p38 mapk and show that phosphorylation of these residues is always associated with a decrease in the antiapoptotic potential of bcl-2 protein.	SIGNOR-146786	0.339
PRKAA1	protein	Q13131	UNIPROT	TGFB1	protein	P01137	UNIPROT	down-regulates				9606		BTO:0000887							23324179	f		gcesareni	Amp-activated protein kinase inhibits tgf-__-, angiotensin ii-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition.	SIGNOR-200404	0.2
MAPK1	protein	P28482	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3	SIGNOR-161617	0.736
Halcinonide	chemical	CHEBI:31663	ChEBI	SMO	protein	Q99835	UNIPROT	up-regulates activity	chemical activation			10090									20439738	t		gcesareni	We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling.	SIGNOR-248265	0.8
ADRA2C	protein	P18825	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257094	0.412
NR0B2	protein	Q15466	UNIPROT	PCK2	protein	Q16822	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17094771	f		miannu	SHP repressed C/EBPalpha (CCAAT/enhancer-binding protein alpha)-driven transcription of PEPCK through direct interaction with C/EBPalpha protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPalpha and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription.	SIGNOR-254832	0.396
FES	protein	P07332	UNIPROT	BCR	protein	P11274	UNIPROT	down-regulates	phosphorylation	Tyr283	YQPYQSIyVGGMMEG	9606	BTO:0000007								8955135	t		lperfetto	In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1.	SIGNOR-45343	0.375
Av/b2 integrin	complex	SIGNOR-C176	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257715	0.619
PPM1D	protein	O15297	UNIPROT	ATM	protein	Q13315	UNIPROT	down-regulates activity	dephosphorylation	Ser1981	SLAFEEGsQSTTISS	9606									18265945	t		lperfetto	More recently, Shreeram et al.  have also shown that Wip1 dephosphorylates human ATM at Ser367 as well as Ser1981.|Thus, overexpression of Wip1 in an oncogenic context could contribute to tumor promotion by inhibiting both p53 and ATM functions.	SIGNOR-276954	0.504
AURKA	protein	O14965	UNIPROT	RASSF1	protein	Q9NS23	UNIPROT	down-regulates	phosphorylation	Ser207	TSVRRRTsFYLPKDA	9606									17563743	t		llicata	Aurora-a appears to phosphorylate rassf1a at threonine202 and/or serine203 that reside within the known microtubule-binding domain of rassf1a. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of rassf1a, disrupt rassf1a interactions with microtubules and abolish its ability to induce m-phase cell cycle arrest.	SIGNOR-155815	0.46
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	down-regulates	phosphorylation			9606									20086174	t	inferred from 70% of family members	lperfetto	We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2.	SIGNOR-269944	0.406
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1934	SPTYSPTsPKGSTYS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120252	0.321
PRKCZ	protein	Q05513	UNIPROT	HABP4	protein	Q5JVS0	UNIPROT	down-regulates activity	phosphorylation	Thr375	GRGARGGtRGGRGRI	9606	BTO:0004974								14699138	t		lperfetto	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249257	0.295
MEN1	protein	O00255	UNIPROT	HOXA9	protein	P31269	UNIPROT	up-regulates quantity by expression	methylation			9606	BTO:0004730								16415155	t		irozzo	Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus. 	SIGNOR-255894	0.491
EGFR	protein	P00533	UNIPROT	KCNJ4	protein	P48050	UNIPROT	up-regulates activity	phosphorylation	Tyr234	YMTQEGEyLPLDQRD	-1									21486282	t		miannu	These results demonstrate that the EGF receptor tyrosine kinase up-regulates the K(IR) 2.3 channel via phosphorylation of the Y234 residue of the WT protein. 	SIGNOR-276322	0.2
HDAC2	protein	Q92769	UNIPROT	MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263838	0.791
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CACNB1	protein	Q02641	UNIPROT	up-regulates activity	phosphorylation	Ser161	CEVGFIPsPVKLDSL	9534	BTO:0000298								16406008	t		miannu	Thus, Ser-447 on Ca(v)2.2 and Ser-161 and Ser-348 of Ca(v)beta1b appear to be both necessary and sufficient for ERK-dependent modulation of these channels. Together, our data strongly suggest that modulation of neuronal N-type VDCCs by ERK involves phosphorylation of Ca(v)2.2alpha1 and to a lesser extent possibly also Ca(v)beta subunits. On the basis of the evidence presented here, it is therefore suggested that ERK-dependent up-regulation of Cav2.2 channels is primarily mediated by phosphorylation of Ser-447 on the I–II loop of Cav2.2 and possibly also the two SP sites conserved on Cavβs.	SIGNOR-262966	0.2
N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide	chemical	CHEBI:91371	ChEBI	CDK2	protein	P24941	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206127	0.8
IKBKB	protein	O14920	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	unknown	phosphorylation	Ser31	QDVLGEEsPLGKPAM	9606			SIGNOR-C14	SIGNOR-C14					12657630	t			IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376. IKKβ mediates IKKγ phosphorylation under physiologic signaling conditions. IKKγ is chronically phosphorylated in cells expressing the HTLV1 Tax oncoprotein, which interfaces directly with the IκB kinase complex.both Tax and TNF induce phosphorylation of human IKKγ at Ser-31, Ser-43, and Ser-376.	SIGNOR-251285	0.962
PRKAA1	protein	Q13131	UNIPROT	KPNA2	protein	P52292	UNIPROT	up-regulates	phosphorylation	Ser105	QAARKLLsREKQPPI	9606			SIGNOR-C15						15342649	t		lperfetto	Ampk phosphorylated importin alpha1 on ser(105). Accordingly, expression of importin alpha1 proteins bearing k22r or s105a mutations failed to mediate the nuclear import of hur in intact cells. Our results point to importin alpha1 as a critical downstream target of ampk and key mediator of ampk-triggered hur nuclear import.	SIGNOR-128629	0.2
(6S)-5,6,7,8-tetrahydrofolate(2-)	smallmolecule	CHEBI:57453	ChEBI	(6R)-5,10-methylenetetrahydrofolate(2-)	smallmolecule	CHEBI:15636	ChEBI	up-regulates quantity	precursor of			9606									32439610	t		lperfetto	Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. 	SIGNOR-268225	0.8
LNX1	protein	Q8TBB1	UNIPROT	GRIN1	protein	Q05586	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1									22889411	t		miannu	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272901	0.292
PRKCA	protein	P17252	UNIPROT	NKX3-1	protein	Q99801	UNIPROT	up-regulates	phosphorylation	Ser48	RQGGRTSsQRQRDPE	9606	BTO:0001130								11980664	t		llicata	Phosphorylation of wild-type nkx3.1 decreased the apparent binding affinity of the protein for the consensus sequence by 3-fold relative to the nonphosphorylated protein (fig. 3) _ .	SIGNOR-86723	0.2
PPM1G	protein	O15355	UNIPROT	USP7	protein	Q93009	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser18	KAGEQQLsEPEDMEM										22361354	t		lperfetto	We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. |After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. 	SIGNOR-276531	0.525
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1665	SPTSPSYsPTSPSYS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248783	0.441
TJP1	protein	Q07157	UNIPROT	NHS	protein	Q6T4R5	UNIPROT	up-regulates activity	binding			10090									19447104	t		miannu	NHS-A is a novel interactor of ZO-1 and is expected to have a role at tight junctions. Its recruitment to these junctions is dependent upon their assembly.	SIGNOR-253567	0.2
CHEK2	protein	O96017	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser579	NVKSKIGsTENLKHQ	9606									21215781	t	The effect has been demonstrated using P10636-8	lperfetto	Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process	SIGNOR-171026	0.2
PRKAA1	protein	Q13131	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	up-regulates activity	phosphorylation	Ser433	PEKELPVsPGHRKTP	-1									31805502	t		miannu	MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected.	SIGNOR-277495	0.2
CDK1	protein	P06493	UNIPROT	TSC1	protein	Q92574	UNIPROT	down-regulates	phosphorylation	Thr1047	SSSSELStPEKPPHQ	9606	BTO:0000680;BTO:0001573;BTO:0001286		SIGNOR-C17						14551205	t		lperfetto	Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex	SIGNOR-118580	0.503
GRIN2A	protein	Q12879	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									20950656	t		lperfetto	In addition, neurons also possess unique systems for local Ca2+ signaling at synapses including; presynaptic voltage-gated Ca2+ channels coupled to the synaptic vesicle membrane fusion machinery [39]; postsynaptic excitatory glutamate receptor channels which flux either Na+ (AMPA receptors) or Ca2+ (NMDA receptors) [40] and [41]; and Ca2+-binding proteins	SIGNOR-251578	0.8
RAF1	protein	P04049	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates	binding			9606									11427728	t		gcesareni	Raf-1 interacts with the proapoptotic, stress-activated protein kinase ask1 (apoptosis signal-regulating kinase 1) in vitro and in vivo.	SIGNOR-109023	0.404
CD19	protein	P15391	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	binding			10090									10201980	t		lperfetto	Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase.	SIGNOR-249608	0.567
GDP	smallmolecule	CHEBI:17552	ChEBI	GNAS	protein	P63092	UNIPROT	down-regulates	chemical inhibition			9606									17095603	t		gcesareni	Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis.	SIGNOR-150549	0.8
GGCX	protein	P38435	UNIPROT	F10	protein	P00742	UNIPROT	up-regulates activity	carboxylation	Glu60	LERECMEeTCSYEEA	-1									9538022	t		lperfetto	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263669	0.598
DPP3	protein	Q9NY33	UNIPROT	Angiotensin-2	protein	P01019-PRO_0000032458	UNIPROT	down-regulates quantity by destabilization	cleavage			-1									34770898	t		miannu	Human dipeptidyl-peptidase III (hDPP III) is capable of specifically cleaving dipeptides from the N-terminal of small peptides with biological activity such as angiotensin II (Ang II, DRVYIHPF), and participates in blood pressure regulation, pain modulation, and the development of cancers in human biological activities. The binding of Ang II to hDPP III may lead to changes in the shape and size of subsite S1, an important catalytic site, so as to promote the decomposition of the substrate.	SIGNOR-268463	0.2
AGRP	protein	O00253	UNIPROT	MC2R	protein	Q01718	UNIPROT	down-regulates activity	binding			9606									20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and α, β, and γ melanocyte–stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268696	0.454
CSNK2A1	protein	P68400	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Thr502	TPGTGLGtSPALAGD	-1									8349691	t		llicata	These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1.	SIGNOR-250906	0.345
FLT3	protein	P36888	UNIPROT	PTPN6	protein	P29350	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15574429	f			Expression of FLT3/ITD induces down-regulation of SHP-1 expression and activity	SIGNOR-261532	0.374
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	Av/b2 integrin	complex	SIGNOR-C176	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259027	0.367
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	ABCB1	protein	P08183	UNIPROT	up-regulates activity	dephosphorylation	Ser667	SSLIRKRsTRRSVRG	9606	BTO:0000007								24333728	t			Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp	SIGNOR-272508	0.2
PRKAA1	protein	Q13131	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	up-regulates activity	phosphorylation	Ser408	GDMVQPLsPSQGQST	-1									31805502	t		miannu	MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected.	SIGNOR-277496	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser253	APRRRAVsMDNSNKY										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249646	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	ATG9A	protein	Q7Z3C6	UNIPROT	up-regulates activity	phosphorylation	Ser761	QSIPRSAsYPCAAPR	9606									25266655	t		miannu	Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK.	SIGNOR-266365	0.251
PRTN3	protein	P24158	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates activity	cleavage	Val72	GLTEYRLvSINKSSP	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263579	0.43
LRRK2	protein	Q5S007	UNIPROT	ARFGAP1	protein	Q8N6T3	UNIPROT	down-regulates	phosphorylation			9606									22423108	t		gcesareni	Arfgap1 is an lrrk2 kinase substrate whose gap activity is inhibited by lrrk2. The phosphorylation of arfgap1 by lrrk2 was subjected to mass spectrometry to determine the sites of phosphorylation. There was 95.3% coverage and serines(s155, s246, s284) and threonine (t189, t216, t292) are phosphorylated by lrrk2. Mutational analysis of these serine and threonine amino acids to alanine reveals that no single amino acid is the predominant phospho-amino acid.	SIGNOR-196732	0.598
RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	MYOD1	protein	P15172	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		BTO:0000165							10066785	t		lperfetto	Delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis	SIGNOR-219359	0.427
JDP2	protein	Q8WYK2	UNIPROT	ATF2	protein	P15336	UNIPROT	down-regulates activity	binding			9606									18671972	t		miannu	JDP2 dimerizes with other AP-1 proteins such as activating transcription factor-2 (ATF2) and Jun to repress transcription from promoters that contain a cyclic AMP-responsive element (CRE).	SIGNOR-226395	0.537
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258018	0.8
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270416	0.8
FOXO3	protein	O43524	UNIPROT	TRIM63	protein	Q969Q1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							21798082	f		lperfetto	Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome.	SIGNOR-236551	0.425
DUSP7	protein	Q16829	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	dephosphorylation			9606									20626350	t		gcesareni	The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues	SIGNOR-166577	0.654
ATM	protein	Q13315	UNIPROT	MDM4	protein	O15151	UNIPROT	down-regulates	phosphorylation	Ser403	DLAHSSEsQETISSM	9606									16943424	t		lperfetto	Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm.	SIGNOR-149300	0.725
PRKCA	protein	P17252	UNIPROT	HSPB8	protein	Q9UJY1	UNIPROT	up-regulates activity	phosphorylation	Ser14	PFSCHYPsRLRRDPF	9606		BTO:0000887							11342557	t		lperfetto	Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation	SIGNOR-107684	0.311
mono(2-ethylhexyl) phthalate	chemical	CHEBI:17243	ChEBI	PPARG	protein	P37231	UNIPROT	up-regulates activity	chemical activation			9606									19433246	t		miannu	Phthalates are true ligands of PPARs. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic.	SIGNOR-268747	0.8
CDK8	protein	P49336	UNIPROT	E2F1	protein	Q01094	UNIPROT	down-regulates	phosphorylation	Ser375	PVDEDRLsPLVAADS	9606									18794899	t		lperfetto	E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1.	SIGNOR-181078	0.497
PTPN6	protein	P29350	UNIPROT	NTRK1	protein	P04629	UNIPROT	down-regulates activity	dephosphorylation	Tyr681	DIYSTDYyRVGGRTM	10116							phosphorylation: tyr496	HIIENPQyFSDACVH	14662744	t			Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675. 	SIGNOR-248469	0.489
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser675	PVSGSPDsMNASRLS	9606	BTO:0000007								10195894	t			Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.	SIGNOR-251276	0.2
TRIP11	protein	Q15643	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates	binding			9606									9256431	t	inferred from family member	miannu	Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity.	SIGNOR-270295	0.432
PRKACA	protein	P17612	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser43	FGYQRRAsDDGKLTD	9534	BTO:0004055								12801936	t		miannu	Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259).	SIGNOR-250039	0.481
CSNK2A1	protein	P68400	UNIPROT	IKZF1	protein	Q13422	UNIPROT	down-regulates	phosphorylation	Ser295	LSDTPYDsSASYEKE	9606									21750978	t		miannu	We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo	SIGNOR-174828	0.294
CYSLTR1	protein	Q9Y271	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256740	0.2
SMAD7	protein	O15105	UNIPROT	SMURF2	protein	Q9HAU4	UNIPROT	up-regulates activity	relocalization			9606									21791611	t		lperfetto	One of the major mechanisms underlying the inhibitory effect of Smad7 on TGF-_ signaling operates through accelerating T_RI turnover by recruiting ubiquitin E3 ligases such as Smurf1 and Smurf2	SIGNOR-227556	0.865
HTR6	protein	P50406	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257340	0.35
STAT1	protein	P42224	UNIPROT	ISGF3 complex	complex	SIGNOR-C124	SIGNOR	form complex	binding			-1									8943351	t	2	miannu	The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3	SIGNOR-240606	0.672
MAPK14	protein	Q16539	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates	phosphorylation			9606									16932740	t	In this case, the phosphorylation of EGFR by p38 or a downstream kinase like MAPKAP-2, triggers receptor internalization.	gcesareni	In conclusion, the use of pharmacological agents suggests that p38 mapk is the enzyme involved in egfr phosphorylation, as well as internalization, following exposure of cells to various stress-inducing conditions.	SIGNOR-149089	0.521
EGFR	protein	P00533	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1016	DVVDADEyLIPQQGF	10090	BTO:0002882								16122376	t	Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer	lperfetto	EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work	SIGNOR-236527	0.2
PINK1	protein	Q9BXM7	UNIPROT	Ubiquitin	proteinfamily	SIGNOR-PF89	SIGNOR	up-regulates	phosphorylation	Ser65	DYNIQKEsTLHLVLR										24784582	t			Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential.	SIGNOR-270341	0.587
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9606									22083140	t		lperfetto	The role of apc is less clear, but it clearly binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex.	SIGNOR-227881	0.892
NUAK1	protein	O60285	UNIPROT	PPP1R12A	protein	O14974	UNIPROT	down-regulates	phosphorylation	Ser910	SLLGRSGsYSYLEER	9606									20354225	t		gcesareni	Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity.	SIGNOR-22572	0.522
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MAPK14	protein	Q16539	UNIPROT	down-regulates				9606	BTO:0000801								11842088	f		lperfetto	In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation.	SIGNOR-244665	0.2
CBLB	protein	Q13191	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates activity	ubiquitination			9606									15315962	t		miannu	KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. 	SIGNOR-260105	0.333
NatA	complex	SIGNOR-C415	SIGNOR	HIF1A	protein	Q16665	UNIPROT	down-regulates quantity by destabilization	acetylation			9606	BTO:0001282								12464182	t		miannu	In this report, we reveal an important function for ARD1 in mammalian cells as a protein acetyltransferase by direct binding to HIF-1alpha to regulate its stability. We present further evidence showing that ARD1-mediated acetylation enhances interaction of HIF-1alpha with pVHL and HIF-1alpha ubiquitination, suggesting that the acetylation of HIF-1alpha by ARD1 is critical to proteasomal degradation.	SIGNOR-267226	0.511
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser37	NVLSPLPsQAMDDLM	9606									10710310	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-75637	0.784
SYCE2	protein	Q6PIF2	UNIPROT	Synaptonemal_complex	complex	SIGNOR-C351	SIGNOR	form complex	binding			9606									22394509	t		miannu	The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region.	SIGNOR-264198	0.682
PRKCZ	protein	Q05513	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	phosphorylation	Ser144	GDVGALEsLRGNADL	9606									16287866	t		gcesareni	Inhibitor sensitivity and interactions with caspase 9 indicate that the predominant kinase that targets ser144 is the atypical protein kinase c isoform zeta (pkczeta).	SIGNOR-141629	0.354
RABGGTB	protein	P53611	UNIPROT	RAB3A	protein	P20336	UNIPROT	up-regulates activity	lipidation			9606	BTO:0000007								18532927	t		miannu	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional	SIGNOR-265575	0.642
PHLPP1	protein	O60346	UNIPROT	AKT2	protein	P31751	UNIPROT	down-regulates	dephosphorylation			9606									17386267	t		gcesareni	These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt / phlpp1 specifically modulates the phosphorylation of hdm2 and gsk-3alpha through akt2, whereas phlpp2 specifically modulates the phosphorylation of p27 through akt3	SIGNOR-153935	0.607
VEPH1	protein	Q14D04	UNIPROT	LATS1	protein	O95835	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000938								22055343	f	In the neuronal differentiation	lperfetto	Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r8	SIGNOR-177074	0.2
CHEK1	protein	O14757	UNIPROT	BLM	protein	P54132	UNIPROT	up-regulates	phosphorylation	Ser646	LKHERFQsLSFPHTK	9606									20719863	t		llicata	Hese results indicated that chk1-mediated phosphorylation on blm at ser(646) might be a determinant for regulating subnuclear localization and could act as a marker for the activation status of blm in response to dna damage.	SIGNOR-167534	0.772
RIMS3	protein	Q9UJD0	UNIPROT	CACNA1D	protein	Q01668	UNIPROT	up-regulates activity	binding			9606	BTO:0005822								28642685	t		miannu	Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells.	SIGNOR-264357	0.2
MAPK1	protein	P28482	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates	phosphorylation	Ser360	TEMDPTYsPAALPQS	9606									15568999	t		gcesareni	Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth.	SIGNOR-131311	0.6
PHLPP2	protein	Q6ZVD8	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0000527								15808505	t		gcesareni	Here, we identify a protein phosphatase, ph domain leucine-rich repeat protein phosphatase (phlpp), that specifically dephosphorylates the hydrophobic motif of akt (ser473 in akt1), triggering apoptosis and suppressing tumor growth.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt.	SIGNOR-252602	0.765
MTOR	protein	P42345	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Thr412	NQVFLGFtYVAPSVL	10090	BTO:0000944		SIGNOR-C3						17510057	t		lperfetto	mTORC1 catalyzes the phosphorylation of eIF4E binding protein-1 (4EBP1, also known as PHAS-I) and p70 S6 kinase 1 (S6K1)Phosphorylation of S6K1 at Thr-389	SIGNOR-235507	0.96
MAPK9	protein	P45984	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser69	GPLAPPAsPGPFATR										18174237	t		gcesareni	Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome.	SIGNOR-250136	0.622
AKT1S1	protein	Q96B36	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	form complex	binding			9606									25628925	t		lperfetto	Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)	SIGNOR-205597	0.795
UNC5A	protein	Q6ZN44	UNIPROT	Chemorepulsion_of_axon	phenotype	SIGNOR-PH198	SIGNOR	up-regulates				9606									30108487	f		miannu	Netrin binding to the receptor deleted in colorectal cancer (DCC) results in attractive responses, viahomodimerization of DCC (covered in detail in later sections), whereas heterodimerization between DCC and receptor uncoordinated locomotion 5 (UNC5) converts this attractive response into repulsion	SIGNOR-268182	0.7
PRKDC	protein	P78527	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates activity	phosphorylation	Thr2638	VAGQIRAtQQQHDFT	9606	BTO:0000773								12186630	t		lperfetto	 We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function.	SIGNOR-249159	0.2
CHKA	protein	P35790	UNIPROT	PLIN2	protein	Q99541	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr232	TKLHSRAyQQALSRV	9606	BTO:0000527								34929314	t		lperfetto	In addition, as a protein kinase, CHKalpha2 phosphorylates PLIN2 at Tyrosine 232 and PLIN3 at Tyrosine 251. Phosphorylated PLIN2 and PLIN3 are separated from lipid droplets and degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation and glioblastoma growth 	SIGNOR-267649	0.2
SP1	protein	P08047	UNIPROT	GP6	protein	Q9HCN6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001549								12359731	f	 	miannu	 Deletion analyses and site-directed mutagenesis identified Sp1(227), GATA(177), and Ets(48) sites as essential for GPVI expression. We show that transcription factors GATA-1, Fli-1, and Sp1 can bind to and activate this promoter.	SIGNOR-254159	0.2
TEC	protein	P42680	UNIPROT	BTK	protein	Q06187	UNIPROT	down-regulates activity	phosphorylation	Tyr223	LKKVVALyDYMPMNA	9606									12573241	t		lperfetto	Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the SH3 domain via a transphosphorylation mechanism, which for Bruton's tyrosine kinase (Btk) affects tyrosine 223.|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role	SIGNOR-246652	0.473
TNF	protein	P01375	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates activity				9606									23685857	f			Tumor necrosis factor α (TNF-α, also known as cachectin) is a strong pro-inflammatory cytokine which plays an important role in the immune system during inflammation, cell proliferation, differentiation and apoptosis	SIGNOR-258988	0.7
DUSP26	protein	Q9BV47	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	dephosphorylation	Ser37	NVLSPLPsQAMDDLM	9606									20562916	t			Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma|Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis	SIGNOR-248766	0.373
PRKCA	protein	P17252	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser51	LRPSTSRsLYASSPG	-1									2500966	t		lperfetto	We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65.	SIGNOR-248883	0.289
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser626	SLECDMEsIIRSELM	-1									17711846	t	done	miannu	Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626).	SIGNOR-274097	0.397
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	F3	protein	P13726	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001949								12744731	f		miannu	 In conclusion, NF-kappaB could be activated promptly after HUVEC incubated with TNF-alpha, then it was bound to TF promotor to start the TF transcription, TF mRNA expression was upregulated, that leaded to the increase of TF expression on the HUVEC surface and activated the coagulation cascade.	SIGNOR-254810	0.252
GSK3B	protein	P49841	UNIPROT	ARNTL	protein	O00327	UNIPROT	down-regulates	phosphorylation	Thr21	DFMSPGPtDLLSSSL	9606									20049328	t		lperfetto	Gsk3beta phosphorylates bmal1 specifically on ser 17 and thr 21 and primes it for ubiquitylation. In the absence of gsk3beta-mediated phosphorylation, bmal1 becomes stabilized and bmal1 dependent circadian gene expression is dampened.	SIGNOR-162790	0.392
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000567								19777442	t	inferred from 70% family members	gcesareni	Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells.	SIGNOR-270037	0.2
NAB2	protein	Q15742	UNIPROT	EGR1	protein	P18146	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000414								20506119	f		miannu	Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop. 	SIGNOR-253886	0.612
CASP3	protein	P42574	UNIPROT	Protein_degradation	phenotype	SIGNOR-PH96	SIGNOR	up-regulates				10090									25787076	f		miannu	The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice.	SIGNOR-255337	0.7
CDK1	protein	P06493	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	unknown	phosphorylation	Thr706	TTEGGSLtPVRDSPC	9606									20169205	t		llicata	Cdc2 is the raptor ser696, thr706 kinase	SIGNOR-163853	0.395
pemetrexed disodium	chemical	CHEBI:63722	ChEBI	ATIC	protein	P31939	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002058								14596699	t		miannu	Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). 	SIGNOR-259292	0.8
perfluorooctanoic acid	chemical	CHEBI:35549	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			-1									23764977	t		miannu	Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. 	SIGNOR-268762	0.8
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser104	GKGSQPPsPPSPAPS	9606									15448698	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-129402	0.575
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	NOTCH3	protein	Q9UM47	UNIPROT	down-regulates quantity	transcriptional regulation			10090									24749067	f		gcesareni	We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration.	SIGNOR-252941	0.2
TERF2IP	protein	Q9NYB0	UNIPROT	Shelterin complex	complex	SIGNOR-C306	SIGNOR	form complex	binding			9606	BTO:0000567								15383534	t		lperfetto	Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins.	SIGNOR-263319	0.827
WNT10A	protein	Q9GZT5	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131616	0.608
eribulin mesylate	chemical	CHEBI:70710	ChEBI	TUBA4A	protein	P68366	UNIPROT	down-regulates activity	chemical inhibition			9606									16940412	t		miannu	The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin.	SIGNOR-259344	0.8
PRKCA	protein	P17252	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates activity	phosphorylation	Ser686	WTETKKQsFKQTGEF	-1									1377674	t		lperfetto	Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC.	SIGNOR-248849	0.408
ACAT1	protein	P24752	UNIPROT	PDHA2	protein	P29803	UNIPROT	down-regulates activity	acetylation												34289383	t		lperfetto	We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)	SIGNOR-267634	0.2
DAB2IP	protein	Q5VWQ8	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									27858941	f		miannu	DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene	SIGNOR-254769	0.278
MAPK3	protein	P27361	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Ser59	GGQESQPsPLALLAA	9606									19318349	t		gcesareni	PKCalpha, which was activated in senescent cells by ROS strongly activated Erk1/2, and the SA-pErk1/2 in turn phosphorylated Sp1 on Ser(59). Sp1-enhanced transcription of p21(Sdi1) resulted in regulation of cellular senescence in primary human diploid fibroblast cells.	SIGNOR-248079	0.638
neratinib	chemical	CHEBI:61397	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194631	0.8
hydromorphone	chemical	CHEBI:5790	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000246								19282177	t		Luana	A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 	SIGNOR-258038	0.8
PI3K	complex	SIGNOR-C156	SIGNOR	BTK	protein	Q06187	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000899								10201980	t		lperfetto	Activation of Btk occurs by transphosphorylation of tyrosine 551 in the catalytic domain, resulting in a dramatic increase in the catalytic activity of the kinase (11, 12, 13). This allows for autophosphorylation at tyrosine 223 in the SH3 domain (14). Both Lyn and Syk have been demonstrated to be involved in BCR-mediated Btk activation (11), but processes that drive colocalization of these kinases are ill-defined. Recently, it was suggested that phosphatidylinositol 3-kinase (PI3-K) is also involved in Btk activation	SIGNOR-252709	0.463
TNF	protein	P01375	UNIPROT	SNAI2	protein	O43623	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20509143	f		miannu	 we show that TNFα treatment of human breast cancer cells up-regulates SLUG with a dependency on canonical NF-κB/HIF1α signaling, which is strongly enhanced by p53 inactivation.	SIGNOR-255152	0.313
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr498	KTPPAPKtPPSSGEP	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249351	0.729
SPX	protein	Q9BT56	UNIPROT	GALR3	protein	O60755	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								24517231	t		lperfetto	Coevolution of the spexin/galanin/kisspeptin family: Spexin activates galanin receptor type II and III.	SIGNOR-268575	0.354
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258010	0.8
CDK1	protein	P06493	UNIPROT	PTPN1	protein	P18031	UNIPROT	up-regulates activity	phosphorylation	Ser386	LRGAQAAsPAKGEPS	9606	BTO:0000567								23348582	t	phosphorylation site remapping based on mass spec table	lperfetto	Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B.|Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. 	SIGNOR-272970	0.517
PTPN11	protein	Q06124	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates activity	dephosphorylation			-1									19066472	t		miannu	Moreover, SHP-2 was strongly activated on G-CSF stimulation and specifically dephosphorylated p27(Kip1) in vitro.|Most importantly, we could illustrate that SHP-2 modulates p27 (Kip1) stability and contributes to p27 (Kip1)-mediated cell cycle progression.	SIGNOR-277168	0.286
DUSP26	protein	Q9BV47	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	dephosphorylation	Ser20	PLSQETFsDLWKLLP	9606									20562916	t		miannu	We found that dusp26 promotes the resistance of human neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to downregulate p53 tumor suppressor function in neuroblastoma cells. / we found that dusp26 binds to p53 and dephosphorylates p53 at ser20 and ser37.	SIGNOR-166258	0.373
2-methoxy-N-[3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]-6-quinazolinyl]prop-2-enyl]acetamide	chemical	CHEBI:91331	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191103	0.8
CDKN1A	protein	P38936	UNIPROT	RB1	protein	P06400	UNIPROT	up-regulates activity				9606									10439039	f		gcesareni	P21 may inhibit cell cycle progression by preventing the phosphorylation of prb.	SIGNOR-69925	0.704
EDNRA	protein	P25101	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256780	0.453
TAL1	protein	P17542	UNIPROT	ERG	protein	P11308	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001106								21536859	f	 	miannu	 We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer.	SIGNOR-253924	0.28
PAK3	protein	O75914	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Ser338	RPRGQRDsSYYWEIE	9606									9823899	t		llicata	The protein kinase pak3 positively regulates raf-1 activity through phosphorylation of serine 338.	SIGNOR-62043	0.535
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser14	LYSFFSPsPARKRHA	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276096	0.275
PES1	protein	O00541	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				10090	BTO:0002882								15169904	f		miannu	Pescadillo (PES1) and the upstream binding factor (UBF1) play a role in ribosome biogenesis, which regulates cell size, an important component of cell proliferation. We have investigated the effects of PES1 and UBF1 on the growth and differentiation of cell lines derived from 32D cells, an interleukin-3 (IL-3)-dependent murine myeloid cell line. Parental 32D cells and 32D IGF-IR cells (expressing increased levels of the type 1 insulin-like growth factor I [IGF-I] receptor [IGF-IR]) do not express insulin receptor substrate 1 (IRS-1) or IRS-2. 32D IGF-IR cells differentiate when the cells are shifted from IL-3 to IGF-I. Ectopic expression of IRS-1 inhibits differentiation and transforms 32D IGF-IR cells into a tumor-forming cell line. We found that PES1 and UBF1 increased cell size and/or altered the cell cycle distribution of 32D-derived cells but failed to make them IL-3 independent. PES1 and UBF1 also failed to inhibit the differentiation program initiated by the activation of the IGF-IR, which is blocked by IRS-1. 32D IGF-IR cells expressing PES1 or UBF1 differentiate into granulocytes like their parental cells. In contrast, PES1 and UBF1 can transform mouse embryo fibroblasts that have high levels of endogenous IRS-1 and are not prone to differentiation. Our results provide a model for one of the theories of myeloid leukemia, in which both a stimulus of proliferation and a block of differentiation are required for leukemia development.	SIGNOR-260078	0.7
CyclinD1/CDK6	complex	SIGNOR-C143	SIGNOR	TSC2	protein	P49815	UNIPROT	up-regulates activity	phosphorylation	Ser1217	MSLENPLsPFSSDIN	9606	BTO:0000007								32294430	t	done	miannu	We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452. 	SIGNOR-274101	0.415
DPF2	protein	Q92785	UNIPROT	Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	form complex	binding			10090	BTO:0001086								19279220	t		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270719	0.602
TBCK	protein	Q8TEA7	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				9606									23977024	f		miannu	Depletion of TBCK significantly inhibits cell proliferation, reduces cell size, and disrupts the organization of actin, but not microtubule.	SIGNOR-266701	0.7
(-)-anisomycin	chemical	CHEBI:338412	ChEBI	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates	chemical activation			9606									Other	t	CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb	gcesareni		SIGNOR-269916	0.8
TPO	protein	P07202	UNIPROT	3,5-diiodo-L-tyrosine	smallmolecule	CHEBI:15768	ChEBI	up-regulates quantity	chemical modification			9606									16098474	t		scontino	TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. 	SIGNOR-267030	0.8
PRKACA	protein	P17612	UNIPROT	NFATC1	protein	O95644	UNIPROT	down-regulates	phosphorylation	Ser269	PCNKRKYsLNGRQPP	9606									12351631	t		lperfetto	Here we show that overexpression of pka causes phosphorylation and cytoplasmic accumulation of nf-atc1 in direct opposition to calcineurin by phosphorylating ser-245, ser-269, and ser-294 in the conserved serine-proline repeat domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3)	SIGNOR-93535	0.357
nilotinib	chemical	CHEBI:52172	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258256	0.8
S1PR2	protein	O95136	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257401	0.572
PRKAA1	protein	Q13131	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser399	DNITLPPsQPSPTGG	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-249667	0.509
PRKACA	protein	P17612	UNIPROT	ARHGDIA	protein	P52565	UNIPROT	down-regulates	phosphorylation	Ser174	KGMLARGsYSIKSRF	9606									18768928	t		llicata	The results indicate that phosphorylation of gdi_ at ser174 by pka suppresses rhoa activity, providing a potential protective signaling mechanism for inflammatory injury.	SIGNOR-180576	0.364
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MXD1	protein	Q05195	UNIPROT	down-regulates	phosphorylation	Ser145	IERIRMDsIGSTVSS	9606									19526459	t		llicata	Here, we present evidence that akt inhibits mad1-mediated transcription repression by physical interaction with and phosphorylation of mad1.	SIGNOR-186130	0.2
RPS6KA4	protein	O75676	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser374	PSSDSLSsPTLLAL										16055710	t		lperfetto	Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos	SIGNOR-263000	0.401
FLT3	protein	P36888	UNIPROT	ID1	protein	P41134	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									18559972	f		apalma	In this study, we used specific tyrosine kinase inhibitors to identify critical target genes that are regulated by oncogenic tyrosine kinases. Using oligonucleotide microarrays, we identified genes that are either up- or down-regulated by selective small molecule inhibitors that target the ABL, PDGFβR, or FLT3 kinases. Genes induced by these inhibitors are presumably repressed by activated tyrosine kinases.Among these genes, we detected a 5- to 50-fold reduction in Id1 expression when the cancer cells were treated with inhibitors.	SIGNOR-255698	0.266
CSNK1D	protein	P48730	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	phosphorylation	Ser403	ESTDSGLsMSSYSVP	9606							phosphorylation:Ser127	PQHVRAHsSPASLQL 	24715453	t		milica	LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)	SIGNOR-230743	0.4
IRAK4	protein	Q9NWZ3	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Thr288	QCPVGFNtLAFPSMK	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276129	0.643
ATR	protein	Q13535	UNIPROT	KMT2A	protein	Q03164	UNIPROT	up-regulates	phosphorylation	Ser516	VHPPLPIsQSPENES	9606									4709074	t		lperfetto	Mll is phosphorylated at serine 516 by atr in response to genotoxic stress in the s phase, which disrupts its interaction with, and hence its degradation by, the scf(skp2) e3 ligase, leading to its accumulation.	SIGNOR-25151	0.284
CREBBP	protein	Q92793	UNIPROT	FBL	protein	P22087	UNIPROT	down-regulates activity	acetylation	Lys206	DLINLAKkRTNIIPV										30540930	t		lperfetto	Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206)	SIGNOR-275897	0.274
IL1B	protein	P01584	UNIPROT	IL1R1	protein	P14778	UNIPROT	up-regulates activity	binding			9606	BTO:0000801								24166242	t		lperfetto	Pro-IL-1beta, mIL-1beta and mIL-beta all bind to IL-1RI, which recruits the IL-1 receptor accessory protein (IL-1RAcP) as a co-receptor.	SIGNOR-249511	0.903
CSNK2A1	protein	P68400	UNIPROT	CALM1	protein	P0DP23	UNIPROT	down-regulates activity	phosphorylation	Thr118	TNLGEKLtDEEVDEM	-1									26675311	t		miannu	Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. 	SIGNOR-266355	0.432
Wnt	proteinfamily	SIGNOR-PF40	SIGNOR	LPR5/6	complex	SIGNOR-C219	SIGNOR	up-regulates activity	binding			9606									23209147	t		miannu	FZD and LRP5/6 transduce Wnt signal via engaging downstream cytoplasmic components, among which two scaffolding proteins, Dishevelled and Axin, have prominent roles.	SIGNOR-256174	0.802
HRH2	protein	P25021	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256920	0.359
CDK1	protein	P06493	UNIPROT	PLEC	protein	Q15149	UNIPROT	down-regulates	phosphorylation	Thr4539	GGLIEPDtPGRVPLD	9606	BTO:0000567		SIGNOR-C17						8626512	t		lperfetto	Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane.	SIGNOR-41319	0.396
CAMK2A	protein	Q9UQM7	UNIPROT	RIMS1	protein	Q86UR5	UNIPROT	up-regulates	phosphorylation	Ser288	NGKGALKsERKRVPK	9606	BTO:0000938	BTO:0000142							12871946	t		gcesareni	Two serine residues in rim1 (ser-241 and ser-287) and one serine residue in rim2 (ser-335) were required for 14-3-3 binding. Incubation with ca2+/calmodulin-dependent protein kinase ii greatly stimulated the interaction of recombinant n-terminal rim but not the s241/287a mutant with 14-3-3,	SIGNOR-103890	0.353
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258011	0.8
AXL	protein	P30530	UNIPROT	MLKL	protein	Q8NB16	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr376	DRVKSTAyLSPQELE	9606	BTO:0000007								31230815	t	done	miannu	TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6).	SIGNOR-274119	0.2
TNC	protein	P24821	UNIPROT	A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	up-regulates activity	binding			9606	BTO:0000801;BTO:0001336								24241034	t		lperfetto	Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed α9β1 integrins, a common receptor for osteopontin and tenascin-C.	SIGNOR-253312	0.415
Calcineurin	complex	SIGNOR-C155	SIGNOR	MEF2C	protein	Q06413	UNIPROT	up-regulates				9606		BTO:0001103							11062529	f		gcesareni	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-252309	0.38
SF1	protein	Q15637	UNIPROT	LHB	protein	P01229	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004467								19106114	f		miannu	 The human LHB promoter also contains low and high affinity SF1 binding sites. Mutation of these elements or depletion of endogenous SF1 impaired basal and ligand-induced transcription.	SIGNOR-254915	0.2
KAT2B	protein	Q92831	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	acetylation			9606									22120716	t		gcesareni	In earlier studies, we demonstrated that maml1 enhanced p300 acetyltransferase activity, which increased the acetylation of notch by p300.Acetylation controls notch stability and function in t-cell leukemia.	SIGNOR-254311	0.584
PRKCD	protein	Q05655	UNIPROT	KCNJ1	protein	P48048	UNIPROT	up-regulates activity				9606									8621594	t		lperfetto	To determine whether this channel is a substrate for PKA, ROMK tagged with the hemagglutinin epitope was transiently transfected into HEK293 cells. In vitro labeling of immunoprecipitated proteins from transfected cells showed that ROMK could be phosphorylated by PKA. | Taken together, these results provide strong evidence that direct phosphorylation of the channel polypeptide by PKA is involved in channel regulation and PKA-dependent phosphorylation is essential for ROMK channel activity.	SIGNOR-248943	0.311
EGLN3	protein	Q9H6Z9	UNIPROT	PKM	protein	P14618	UNIPROT	up-regulates activity	hydroxylation	Pro403	EELRRLApITSDPTE	9606	BTO:0000567								21620138	t			Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells.	SIGNOR-267476	0.447
ARHGAP20	protein	Q9P2F6	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260474	0.423
FOXP2	protein	O15409	UNIPROT	FOXP2	protein	O15409	UNIPROT	up-regulates activity	binding			-1									16407075	t		miannu	Our studies also reveal that the FOXP2 forkhead domain can form a domain-swapped dimer. The most surprising finding from these studies is that the FOXP2 forkhead domain can form a domain-swapped dimer. Disease-related mutations, sequence comparison, and biochemical analyses argue strongly that this domain swapping is a physiologically relevant function evolved in the P branch of FOX proteins.	SIGNOR-225738	0.2
CSNK1D	protein	P48730	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates	phosphorylation	Ser118	NQQESSDsGTSVSEN	9606									20708156	t		gcesareni	Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase.	SIGNOR-167497	0.351
SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0002586								12226744	f		irozzo	The hSNF5/INI1 gene encodes a member of the SWI/SNF chromatin remodelling complexes.Here, we show that the ectopic expression of wild-type hSNF5/INI1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into S phase of MRT cells.	SIGNOR-256298	0.7
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr237	KQEKTPKtPKGPSSV	9606									12058066	t		lperfetto	Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association.	SIGNOR-216749	0.418
LSM-1231	chemical	CHEBI:91471	ChEBI	NTRK1	protein	P04629	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258238	0.8
maraviroc	chemical	CHEBI:63608	ChEBI	CCL4L1	protein	Q8NHW4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194009	0.8
MARK1	protein	Q9P0L2	UNIPROT	MAP2	protein	P11137	UNIPROT	down-regulates activity	phosphorylation	Ser1802	SNVSSSGsINLLESP	-1									8631898	t		miannu	Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 	SIGNOR-250168	0.428
PIP3	smallmolecule	CHEBI:16618	ChEBI	MAPKAP1	protein	Q9BPZ7	UNIPROT	up-regulates activity	chemical activation			9606									26293922	t		gcesareni	PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation	SIGNOR-252429	0.8
SMURF2	protein	Q9HAU4	UNIPROT	SMAD7	protein	O15105	UNIPROT	down-regulates activity	ubiquitination			9606									18448069	t		lperfetto	The association of Smurf2 with Smad7 and its ubiquitination were inhibited by AIMP1, thereby protecting its autocatalytic degradation stimulated by Smad7.	SIGNOR-178501	0.865
TNIP1	protein	Q15025	UNIPROT	TRAF3	protein	Q13114	UNIPROT	down-regulates activity	binding												21885437	t		lperfetto	ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi. 	SIGNOR-275736	0.443
SRC	protein	P12931	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr407	IIDEEDTyTMPSTRD	9606									15735019	t		miannu	Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates	SIGNOR-150480	0.633
HCK	protein	P08631	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	down-regulates activity	phosphorylation	Tyr354	SSNQELIyEGRRLVL	9606	BTO:0002181								28618271	t		miannu	The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. 	SIGNOR-276726	0.2
romidepsin	chemical	CHEBI:61080	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257997	0.8
PRKCD	protein	Q05655	UNIPROT	HNRNPK	protein	P61978	UNIPROT	down-regulates	phosphorylation	Ser302	GRGGRGGsRARNLPL	9606									10329716	t		lperfetto	Ser302 is a major k protein site phosphorylated by pkcdelta in vitrothe ability of pkc_ to inducibly bind and phosphorylate k protein may serve not only to alter the activity of k protein itself, but k protein may also provide an avenue for pkc_ to engage in a cross-talk with other k protein molecular partners in response to specific changes in the extracellular environment	SIGNOR-67515	0.35
RAD51	protein	Q06609	UNIPROT	Synaptonemal_complex	complex	SIGNOR-C351	SIGNOR	up-regulates activity	binding			10090	BTO:0001275								10525529	t		miannu	The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process.	SIGNOR-264207	0.325
ARHGEF3	protein	Q9NR81	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260530	0.768
ILK	protein	Q13418	UNIPROT	PPP1R14A	protein	Q96A00	UNIPROT	up-regulates activity	phosphorylation	Thr38	QKRHARVtVKYDRRE	9606									12144526	t		miannu	Phosphopeptide mapping, phospho amino acid analysis and immunoblotting using phospho-specific antibodies indicated that ilk predominantly phosphorylated the site critical for potent inhibition, i.e. Thr(38) of cpi-17	SIGNOR-90828	0.531
AURKA	protein	O14965	UNIPROT	KNSTRN	protein	Q9Y448	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0001938								22535524	t		lperfetto	The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation.	SIGNOR-252052	0.264
ABL1	protein	P00519	UNIPROT	ABL1	protein	P00519	UNIPROT	up-regulates activity	phosphorylation	Tyr393	FGLSRLMtGDTYTAH	9606									10964922	t		Manara	We demonstrate here that autophosphorylation of ABL1 is intermolecular and stimulates Abl catalytic activity.	SIGNOR-260781	0.2
AKT2	protein	P31751	UNIPROT	ANKRD2	protein	Q9GZV1	UNIPROT	up-regulates	phosphorylation	Ser99	QERVRKTsLDLRREI	10090	BTO:0000165;BTO:0000222								21737686	t		llicata	In vitro and in vivo studies confirmed that akt phosphorylates ankrd2 at ser-99. moreover, the forced expression of a phosphorylation-defective mutant form of ankrd2 in c2c12 myoblasts promoted a faster differentiation program, implicating akt-dependent phosphorylation at ser-99 in the negative regulation of myogenesis in response to stress conditions.	SIGNOR-236978	0.425
IFNGR1	protein	P15260	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	binding			9606									23898330	t		lperfetto	In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation	SIGNOR-249505	0.703
SRC	protein	P12931	UNIPROT	PTPRA	protein	P18433	UNIPROT	up-regulates activity	phosphorylation	Tyr798	YIDAFSDyANFK	9606									7518772	t	The effect has been demonstrated using P18433-2	lperfetto	Transient overexpression of c-src together with rptp alpha in human embryonic kidney 293 cells increased phosphorylation of tyr789, suggesting that c-src may phosphorylate rptp alpha in vivo.	SIGNOR-111306	0.733
CREB1	protein	P16220	UNIPROT	PKM	protein	P14618	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16308421	f		gcesareni	In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1	SIGNOR-142103	0.252
SLC18A2	protein	Q05940	UNIPROT	dopamine	smallmolecule	CHEBI:18243	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								30465801	t		miannu	Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. 	SIGNOR-269190	0.8
ZAP70	protein	P43403	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation	Tyr323	DEPVADPyDQSFESR	10090	BTO:0000782								15735648	t		miannu	Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323.	SIGNOR-276030	0.457
FLT3	protein	P36888	UNIPROT	FLT3	protein	P36888	UNIPROT	up-regulates activity	phosphorylation	Tyr591	SSDNEYFyVDFREYE	10090	BTO:0001516								16627759	t		lperfetto	In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated.|This finding suggests that the combination of tyrosine residues 589 and 591 is required for activation of STAT-5 signaling pathways.	SIGNOR-271921	0.2
PTPN13	protein	Q12923	UNIPROT	NFKBIA	protein	P25963	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Tyr42	DSMKDEEyEQMVKEL	9606	BTO:0000007								11106428	t			Identification of IkappaBalpha as a substrate of Fas-associated phosphatase-1|A full-length FAP-1 protein preferentially dephosphorylates Tyr-42 of IkBa|Moreover, other studies have shown that tyrosine phosphorylation of IkBa on Tyr-42 (which occurs with Fas ligand binging) protected against inducible degradation both in vitro [30] and in vivo [38]	SIGNOR-248712	0.453
GATA1	protein	P15976	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0004475								19825991	f	 	miannu	Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors. 	SIGNOR-254189	0.413
EPHA8	protein	P29322	UNIPROT	EPHA8	protein	P29322	UNIPROT	up-regulates activity	phosphorylation	Tyr616	FYAEPHTyEEPGRAG	9606	BTO:0000007								10498895	t			Tyr-615 and Tyr-838 are major autophosphorylation sites of the EphA8 receptor. phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for efficient phosphorylation at Tyr-615 as well as other major sites.	SIGNOR-251120	0.2
1-[5-bromo-4-methyl-2-[[(2S)-2-morpholinyl]methoxy]phenyl]-3-(5-methyl-2-pyrazinyl)urea	chemical	CHEBI:124917	ChEBI	CHEK1	protein	O14757	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193787	0.8
HRH1	protein	P35367	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257425	0.434
METTL3	protein	Q86U44	UNIPROT	USP13	protein	Q92995	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation												36528756	t		lperfetto	Furthermore, N6-methyladenosine methyltransferase-like 3 (METTL3) mediated stabilization of USP13 mRNA that required the m6A reader IGF2BP2.	SIGNOR-275839	0.2
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation			9606									18593906	t		tpavlidou	Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene.	SIGNOR-259427	0.401
PKN1	protein	Q16512	UNIPROT	CDC25C	protein	P30307	UNIPROT	unknown	phosphorylation	Ser216	SGLYRSPsMPENLNR	9606	BTO:0000567								15791647	t		lperfetto	A role for PKN1 in mediating arsenite-induced G(2)/M delay was supported by the finding that expression of a constitutively active form of PKN1 (PKN1AF3) in HeLa cells delayed the mitotic entry of cell cycle. Further experiments indicate that PKN1 directly phosphorylated serine 216 (Ser216) in Cdc25C, which then facilitated association between Cdc25C and 14-3-3.	SIGNOR-249277	0.51
E2F1	protein	Q01094	UNIPROT	MUC4	protein	Q99102	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000584								22537161	f	 	lperfetto	Nicotine, IFN-γ and retinoic acid mediated induction of MUC4 in pancreatic cancer requires E2F1 and STAT-1 transcription factors and utilize different signaling cascades	SIGNOR-254133	0.2
BCL9	protein	O00512	UNIPROT	PYGO1	protein	Q9Y3Y4	UNIPROT	up-regulates	binding			9606	BTO:0000776								11955446	t		miannu	Here we report the identification of two segment polarity genes in drosophila, legless (lgs), and pygopus (pygo), and we show that their products are required for wnt signal transduction at the level of nuclear beta-catenin. Lgs encodes the homolog of human bcl9, and we provide genetic and molecular evidence that these proteins exert their function by physically linking pygo to beta-catenin.	SIGNOR-116577	0.903
Naltrindole	chemical	CHEBI:81528	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258816	0.8
SRF	protein	P11831	UNIPROT	PTGS2	protein	P35354	UNIPROT	up-regulates				9606									22225874	t		FFerrentino	Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy.	SIGNOR-255965	0.255
Cell-Cell_contact	stimulus	SIGNOR-ST13	SIGNOR	CDH1	protein	P12830	UNIPROT	up-regulates				9606									24532814	f		milica	Adherens junctions and the cadheriBeta-catenin complex have been found to activate the Hippo signaling pathway and inhibit cell growth. Cadherin-mediated stimulation of the Hippo signaling pathway requires cadherin ligation and the formation of a homophilic bond – consistent with a role in cell-cell contact – and works owing to phosphorylation of YAP by Lats and nuclear exclusion of YAP.	SIGNOR-230707	0.7
EVL	protein	Q9UI08	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606									18508258	f		miannu	Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance.	SIGNOR-268394	0.7
HNRNPH1	protein	P31943	UNIPROT	TERF2	protein	Q15554	UNIPROT	down-regulates quantity	post transcriptional regulation			10116	BTO:0001009								27117401	t		miannu	During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels.	SIGNOR-266807	0.342
(R)-(+)-sulpiride	chemical	CHEBI:64122	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029									8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258735	0.8
PRKACA	protein	P17612	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates activity	phosphorylation	Ser25	PGTASRPsSSRSYVT	-1									2500966	t		miannu	Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure.	SIGNOR-250066	0.313
HMGB2	protein	P26583	UNIPROT	POU2F1	protein	P14859	UNIPROT	up-regulates activity	binding			10090	BTO:0002910								7720710	t	2	miannu	HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins	SIGNOR-240151	0.311
MAP4K4	protein	O95819	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates	phosphorylation			9606									8824585	t		gcesareni	Hpk1 binds and phosphorylates mekk1 directly	SIGNOR-44040	0.538
CAMK1	protein	Q14012	UNIPROT	SYN1	protein	P17600	UNIPROT	down-regulates activity	phosphorylation	Ser9	NYLRRRLsDSNFMAN	-1									10571231	t		miannu	Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I 	SIGNOR-250615	0.579
bivalirudin	chemical	CHEBI:59173	ChEBI	F2	protein	P00734	UNIPROT	down-regulates activity	chemical inhibition			-1									1290488	t		miannu	These data demonstrate that hirulog-1 is a specific inhibitor of thrombin forms with high fibrinogen-procoagulant activities and that its Arg-3-Pro-4 bond is slowly cleaved by these thrombin forms.	SIGNOR-258346	0.8
MAPK14	protein	Q16539	UNIPROT	JUNB	protein	P17275	UNIPROT	up-regulates	phosphorylation	Ser79	QGSDTGAsLKLASSE	9606									15308641	t		lperfetto	These results clearly demonstrate that phosphorylation by p38 kinase is essential for the regulation of dmp1 transcription by junb and p300. phosphorylation of junb at ser-79 was found to be essential for its interaction with p300.	SIGNOR-127545	0.492
CPT1B	protein	Q92523	UNIPROT	O-palmitoyl-L-carnitine	smallmolecule	CHEBI:17490	ChEBI	up-regulates quantity	chemical modification			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267130	0.8
wortmannin	chemical	CHEBI:52289	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									7503989	t		gcesareni	Wortmannin inhibited the activity of partially purified pi3-kinase from calf thymus, as well as the pi3-kinase activity in anti-pi3-kinase p85 immunoprecipitates from rbl-2h3 cells, at a concentration as low as 1.0 nm and with ic50 values of 3.0 nm.	SIGNOR-26677	0.8
AURKB	protein	Q96GD4	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	down-regulates activity	phosphorylation	Ser33	LRRSQRKsGSELPSI	-1									23901111	t		miannu	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. 	SIGNOR-276116	0.614
CDK2	protein	P24941	UNIPROT	TPX2	protein	Q9ULW0	UNIPROT	down-regulates activity	phosphorylation	Thr72	NLQQAIVtPLKPVDN	-1									25688093	t		lperfetto	In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle	SIGNOR-265099	0.299
VAV1	protein	P15498	UNIPROT	PRKCQ	protein	Q04759	UNIPROT	up-regulates				9606	BTO:0000782								10725744	f		lperfetto	Vav synergizes with protein kinase c theta to mediate il-4 gene expression in response to cd28 costimulation in t cells	SIGNOR-75827	0.605
SLC25A1	protein	P53007	UNIPROT	D-threo-isocitrate(3-)	smallmolecule	CHEBI:15562	ChEBI	up-regulates quantity	relocalization			9606									29651165	t			SLC25A1, a mitochondrial carrier that promotes the flux of citrate/isocitrate across the mitochondria, in exchange for the entry of cytosolic malate	SIGNOR-267290	0.8
PRKACA	protein	P17612	UNIPROT	ACADVL	protein	P49748	UNIPROT	up-regulates activity	phosphorylation	Ser586	VVVLSRAsRSLSEGH	-1									19889959	t		lperfetto	As shown in Fig. 2C, an in vitro kinase assay carried out using PKA and a GST fusion protein containing the COOH-terminal 258 amino acids showed the protein to be efficiently phosphorylated in a time-dependent manner. |Furthermore, a phosphorylation-negative mutant (S586A) VLCAD shows reduced electron transfer activity and a strong dominant-negative effect on fatty acid beta-oxidation.	SIGNOR-264422	0.2
LATS1	protein	O95835	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	phosphorylation	Ser127	PQHVRAHsSPASLQL	9606									22658639	t		milica	In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus.	SIGNOR-197647	0.835
PRKCD	protein	Q05655	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser284	AGGGRRIsDSHEDTG	9606		BTO:0000562							17075052	t		gcesareni	The triple aspartic acid mutation shows greater distance between the two thick myosin filaments (affects the steric arrangement of the filament distances) in heart tissue. Mutation is cardioprotective during stress (ischemia-reprofusion injury) against apoptosis similar to isoproterenol treatment.	SIGNOR-150351	0.2
tyrosine	smallmolecule	CHEBI:18186	ChEBI	tyramine	smallmolecule	CHEBI:15760	ChEBI	up-regulates quantity	precursor of			9606									NBK536726	t	brain	lperfetto	Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain 	SIGNOR-264175	0.8
STK4	protein	Q13043	UNIPROT	MOB1B	protein	Q7L9L4	UNIPROT	up-regulates	phosphorylation	Thr12	FGSRSSKtFKPKKNI	9606									23431053	t		milica	Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity	SIGNOR-201314	0.846
S1PR5	protein	Q9H228	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256676	0.468
FFAR2	protein	O15552	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257188	0.468
NR3C1	protein	P04150	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates activity				10090	BTO:0000944								11742987	f		gcesareni	Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation.	SIGNOR-251677	0.523
EPHA3	protein	P29320	UNIPROT	EPHA3	protein	P29320	UNIPROT	up-regulates activity	phosphorylation	Tyr602	TYVDPHTyEDPTQAV	9606									11870224	t			Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3	SIGNOR-251116	0.2
ING2	protein	Q9H160	UNIPROT	AFP	protein	P02771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								14522900	f		miannu	 ING1b and ING2 also repressed the AFP promoter in Hep3B p53-null cell lines, and p53 coexpression enhanced this transcriptional repression. Suppression of AFP gene transcription by ING was strongly dependent on AT-motifs that bind to the hepatocyte nuclear factor 1 (HNF1) transcription factor. 	SIGNOR-254485	0.2
PARP1	protein	P09874	UNIPROT	SNAIL/RELA/PARP1	complex	SIGNOR-C198	SIGNOR	form complex	binding			9606									22223884	t		alessandro	Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin	SIGNOR-254528	0.496
CTNND1	protein	O60716	UNIPROT	CDH2	protein	P19022	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0003564								14610055	t		miannu	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 	SIGNOR-252125	0.726
DIS3L	protein	Q8TF46	UNIPROT	Exosome_Complex	complex	SIGNOR-C255	SIGNOR	form complex	binding			-1									24189234	t		miannu	The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 	SIGNOR-261391	0.908
BCL6	protein	P41182	UNIPROT	CD80	protein	P33681	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000776								12860928	f	 	 	Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. 	SIGNOR-253931	0.419
acetyl-CoA(4-)	smallmolecule	CHEBI:57288	ChEBI	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	precursor of			9606									19524112	t		miannu	The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA.	SIGNOR-267520	0.8
NFIB	protein	O00712	UNIPROT	ID3	protein	Q02535	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268879	0.253
MAP2K3	protein	P46734	UNIPROT	MAPK13	protein	O15264	UNIPROT	up-regulates activity	phosphorylation	Tyr182	ADAEMTGyVVTRWYR	9606	BTO:0000007								10066767	t	done	miannu	 p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.	SIGNOR-273949	0.59
CTTNBP2NL	protein	Q9P2B4	UNIPROT	STRN	protein	O43815	UNIPROT	up-regulates activity	binding			9606									23015759	t		miannu	Although CTTNBP2 and CTTNBP2NL are different in terms of tissue and subcellular distribution, our data indicate that, similar to CTTNBP2NL, CTTNBP2 associates with members of the striatin family, namely striatin and zinedin. Moreover, CTTNBP2 is critical for the distribution of striatin and zinedin in dendritic spines. The role of CTTNBP2 in the regulation of the synaptic distribution of striatin and zinedin suggests that CTTNBP2 regulates synaptic signaling through PP2A. 	SIGNOR-261702	0.665
CBL	protein	P22681	UNIPROT	CFLAR	protein	O15519	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606							phosphorylation:Ser2;Tyr182	sAEVIHQV;VQGAGTSyRNVLQAA	19597496	t	CFLAR has to be phosphorylated on Tyr211 and Ser4 by c-Abl and p38, respectively. This phosphorylation facilitated specific interaction between FLIPS and the ubiquitin E3 ligase c-Cbl	gcesareni	We therefore conclude that c-cbl is a e3 ubiquitin ligase for flips and that the interaction of flips with c-cbl requires phosphorylation of both ser4 and tyr211 of flips.This interaction triggered proteasomal degradation of FLIP(S), which promoted activation of caspase-8 and apoptosis.	SIGNOR-186998	0.2
MAPK1	protein	P28482	UNIPROT	NR3C2	protein	P08235	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser196	EKSPSVCsPLNMTSS	9606	BTO:0005043								22798426	t		miannu	 Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276107	0.291
P2RY11	protein	Q96G91	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257435	0.357
SPOP	protein	O43791	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								20463034	t		Gianni	RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins	SIGNOR-268861	0.692
PRKACA	protein	P17612	UNIPROT	GLI2	protein	P10070	UNIPROT	down-regulates	phosphorylation			9606									16885213	t		gcesareni	In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation	SIGNOR-148478	0.445
FGFR3	protein	P22607	UNIPROT	FGFR3	protein	P22607	UNIPROT	up-regulates activity	phosphorylation	Tyr760	TVTSTDEyLDLSAPF	9606	BTO:0000007								11294897	t		lperfetto	Ligand stimulation leads to autophosphorylation of fgfr3taken together, these results clearly implicate y724 in the activation of stat proteins by constitutively activated mutants of fgfr3 and suggest that both y724 and y760 are required for maximal stat activation.	SIGNOR-106742	0.2
JAG1	protein	P78504	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	binding			9606									10551863	t	Binding Calcium-dependent.	gcesareni	Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch.	SIGNOR-269936	0.628
HIF1A	protein	Q16665	UNIPROT	KDM4B	protein	O94953	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271569	0.265
MYF6	protein	P23409	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates				9606									8288123	f		miannu	The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers.	SIGNOR-37455	0.7
TCF4	protein	P15884	UNIPROT	MYOD/E2-2	complex	SIGNOR-C129	SIGNOR	form complex	binding			9606									16847330	t	2	miannu	The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation.	SIGNOR-241382	0.689
CDK1	protein	P06493	UNIPROT	USP1	protein	O94782	UNIPROT	up-regulates activity	phosphorylation	Ser313	ATSDTLEsPPKIIPK	-1									23116119	t		miannu	In this study, we show that Ser313 phosphorylation in USP1 is required for its interaction with UAF1 and for the stimulation of USP1's activity. We further demonstrated that CDK1 is responsible for Ser313 phosphorylation, and protein phosphatase treatment of USP1 can lead to inactivation of USP1/UAF1.	SIGNOR-276423	0.38
CYP2R1	protein	Q6VVX0	UNIPROT	calcidiol	smallmolecule	CHEBI:17933	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000759							30080183	t		lperfetto	Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. 	SIGNOR-270568	0.8
TFEB	protein	P19484	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	 Here we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via Ppargc1α and Ppar1α.	SIGNOR-276708	0.391
RPS6KA1	protein	Q15418	UNIPROT	ETV1	protein	P50549	UNIPROT	up-regulates activity	phosphorylation	Ser191	HRFRRQLsEPCNSFP	9606									12213813	t		lperfetto	Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation.	SIGNOR-249162	0.356
DZIP3	protein	Q86Y13	UNIPROT	H2AZ2	protein	Q71UI9	UNIPROT	up-regulates activity	monoubiquitination	Lys121	IHKSLIGkKGQQKTA	9606									18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271756	0.2
IGF1R	protein	P08069	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity				10090	BTO:0000165								11715022	f		lperfetto	we show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy.	SIGNOR-244403	0.398
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	MYC	protein	P01106	UNIPROT	up-regulates quantity	ubiquitination			9606									20852628	t		gcesareni	Here we show that SCF²-TrCP binds to Myc by means of a characteristic phosphodegron and ubiquitylates Myc; this results in enhanced Myc stability.	SIGNOR-243542	0.482
LCK	protein	P06239	UNIPROT	ACP1	protein	P24666	UNIPROT	up-regulates activity	phosphorylation	Tyr132	QLIIEDPyYGNDSDF	9534	BTO:0004055								9038134	t			In co-transfected COS cells, Lck and Fyn caused phosphorylation of LMPTP. Most of the phosphate was located at Tyr-131, and some was also located at Tyr-132. Site-directed mutagenesis showed that Tyr-131 is important for the catalytic activity of LMPTP, and that thiophosphorylation of Tyr-131, and to a lesser degree Tyr-132, is responsible for the activation.	SIGNOR-251366	0.361
PDGFRB	protein	P09619	UNIPROT	PTPN11	protein	Q06124	UNIPROT	up-regulates activity	phosphorylation	Tyr542	SKRKGHEyTNIKYSL	10090	BTO:0000944								8041791	t		miannu	Upon PDGF stimulation, SHPTP2 binds to the PDGFR and becomes tyrosine-phosphorylated. We have identified tyrosine-542 (pY542TNI) as the major in vivo site of SHPTP2 tyrosine phosphorylation. phosphorylation of SHPTP2 couples Grb2 to PDGFR in vivo, providing a mechanism for Ras activation by PDGFR and for positive signaling via SHPTP2 and Csw.	SIGNOR-250260	0.739
IRAK1	protein	P51617	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Ser76	ISNKDQHsISYTLSR	9606	BTO:0000007								12496252	t		lperfetto	In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation	SIGNOR-96739	0.758
APC-c	complex	SIGNOR-C150	SIGNOR	PPM1D	protein	O15297	UNIPROT	down-regulates quantity by destabilization	ubiquitination										phosphorylation:Ser40	PTAEEKPsPRRSLSQ	33309518	t		lperfetto	Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20)	SIGNOR-275492	0.318
CREBBP	protein	Q92793	UNIPROT	FBL	protein	P22087	UNIPROT	down-regulates activity	acetylation	Lys121	GESVYGEkRVSISEG										30540930	t		lperfetto	Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206)	SIGNOR-275899	0.274
JAK2	protein	O60674	UNIPROT	CSF2RA/CSF2RB	complex	SIGNOR-C212	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000801								8977526	t		irozzo	JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.	SIGNOR-256001	0.568
IGF2	protein	P01344	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates	binding			9606									9281335	t		fspada	Therefore, these results provide genetic evidence that the growth-promoting function of igf-ii during mouse embryogenesis is mediated in part by signaling through the insulin receptor.	SIGNOR-50719	0.707
CBP/p300	complex	SIGNOR-C6	SIGNOR	SMAD3	protein	P84022	UNIPROT	up-regulates activity	acetylation	Lys19	VKRLLGWkKGEQNGQ	9606	BTO:0000567;BTO:0002181;BTO:0000552								17074756	t		lperfetto	We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfb-dependent manner. the p300-dependent acetylation of smad3 was attenuated when lys19 was mutated, whereas mutation of lys20 had no effect, suggesting that lys19 is acetylated also in smad3.	SIGNOR-236126	0.682
CDK2	protein	P24941	UNIPROT	NFYA	protein	P23511	UNIPROT	up-regulates activity	phosphorylation	Ser326	FSPKEKDsPHMQDPN										12857729	t		llicata	Cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y. Cyclin A-cdk2 appears to associate with NF-Y both in vitro and in vivo. Furthermore, YA protein is phosphorylated in parallel with a cell cycle-dependent activation of cdk2 kinase and cyclin A expression. YA phosphorylation is unnecessary for heterotrimer formation with the YB-YC dimer. However, NF-Y containing a phosphorylation-deficient mutant form of YA, YA-aa, has its DNA binding activity impaired. \ To examine whether cdk2 phosphorylates the two serine residues at positions 320 and 326 in YA, we replaced either or both with alanine by site-directed mutagenesis. In a kinase assay using purified GST fusion proteins in vitro, cdk2 phosphorylated the wild type and both of the single-mutant proteins (YA-as and -sa), but not the double-mutant protein (YA-aa)	SIGNOR-250743	0.45
FGF6	protein	P10767	UNIPROT	FGFR2	protein	P21802	UNIPROT	up-regulates	binding			9606									8663044	t		gcesareni	The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors.	SIGNOR-42380	0.743
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DPA1	protein	P20036	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-253995	0.267
WNT7A	protein	O00755	UNIPROT	PRKACA	protein	P17612	UNIPROT	up-regulates activity				9606		BTO:0001103							21902831	f		gcesareni	Wnt1 and wnt7a stimulation of precursor cells activates protein kinase a (pka), which, through the phosphorylation of creb, induces the expression of the myogenic transcription factors myf5, myod and pax3, resulting in the myogenic commitment of embryonic precursors.	SIGNOR-176575	0.2
CTF1	protein	Q16619	UNIPROT	TH	protein	P07101	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12859689	f		miannu	CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. 	SIGNOR-252219	0.2
PRKACA	protein	P17612	UNIPROT	MAP2	protein	P11137	UNIPROT	down-regulates activity	phosphorylation	Ser1679	NVKSKIGsTDNIKYQ	9606	BTO:0000567								11029056	t		miannu	CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA	SIGNOR-250001	0.366
SRC	protein	P12931	UNIPROT	GSN	protein	P06396	UNIPROT	unknown	phosphorylation	Tyr651	ALGGKAAyRTSPRLK	-1									10210201	t		llicata	Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624.	SIGNOR-250783	0.576
threonine	smallmolecule	CHEBI:26986	ChEBI	Thr-tRNA(Thr)	smallmolecule	CHEBI:29163	ChEBI	up-regulates quantity	precursor of			9606									25824639	t		miannu	Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 	SIGNOR-270508	0.8
XL765	chemical	CHEBI:71958	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207881	0.8
JAK2	protein	O60674	UNIPROT	EZH2	protein	Q15910	UNIPROT	down-regulates	phosphorylation	Tyr641	KNEFISEyCGEIISQ	9606									24469040	t		lperfetto	Oncogenic y641 mutations in ezh2 prevent jak2/beta-trcp-mediated degradationbeta-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs beta-trcp-mediated ezh2 degradation.	SIGNOR-202711	0.551
CSNK2A1	protein	P68400	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	phosphorylation	Ser129	SGSPSDNsGAEEMEV	9606	BTO:0000007								21735093	t		gcesareni	CK2 hyperactivates AKT by phosphorylation at Ser129	SIGNOR-174691	0.379
Av/b1 integrin	complex	SIGNOR-C175	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269024	0.7
Norbinaltorphimine	chemical	CHEBI:81529	ChEBI	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258821	0.8
GART	protein	P22102	UNIPROT	2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine	smallmolecule	CHEBI:147287	ChEBI	down-regulates quantity	chemical modification			9606									33179964	t		miannu	The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner.	SIGNOR-267314	0.8
BIRC3	protein	Q13489	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								12525502	t		miannu	 Here we show that cIAP1 and cIAP2 are E3 ubiquitin-protein isopeptide ligases (ubiquitin ligases) for Smac. cIAPs stimulate Smac ubiquitination both in vivo and in vitro, leading to Smac degradation. cIAP1 and cIAP2 associate with overlapping but distinct subsets of E2 (ubiquitin carrier protein) ubiquitin-conjugating enzymes. The substrate-dependent E3 activity of cIAPs is mediated by their RING domains and is dependent on the specific interactions between cIAPs and Smac.	SIGNOR-271391	0.785
MAPK1	protein	P28482	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity	phosphorylation			10090	BTO:0002572								28646232	t		Gianni	We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels	SIGNOR-262521	0.325
ABL1	protein	P00519	UNIPROT	UBE3A	protein	Q05086	UNIPROT	down-regulates activity	phosphorylation	Tyr659	GDSHPVLyQSLKDLL	9606									23581475	t		Manara	Our results suggest that c-Abl protects p53 from HPV-E6-E6AP complex-mediated degradation by phosphorylating E6AP and impairing its E3 ligase activity	SIGNOR-260930	0.276
NADPH(4-)	smallmolecule	CHEBI:57783	ChEBI	NADP(3-)	smallmolecule	CHEBI:58349	ChEBI	up-regulates quantity	precursor of			9606									15507492	t		miannu	Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the de novo biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH. 	SIGNOR-268088	0.8
PRKD1	protein	Q15139	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates	phosphorylation	Ser486	RPLSRAQsSPAAPAS	9606									18617643	t		gcesareni	We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf.	SIGNOR-179430	0.492
MAML3	protein	Q96JK9	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	up-regulates	binding			9606									12370315	t		gcesareni	We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors.	SIGNOR-94097	0.744
SPI1	protein	P17947	UNIPROT	FCGR1A	protein	P12314	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12393465	f		apalma	In patients with t(8;21), expression of the cell surface markers CD11b, CD14, and CD64 was less in comparison to patients without t(8;21) (Figure 5B). CD14 and CD64 promoters have putative PU.1 binding sites but not AML1-, C/EBPα-, or MEF-binding sites suggesting that down-regulation of the function of PU.1 by AML1-ETO could possibly be an important step in progression toward leukemia.	SIGNOR-255697	0.539
CPS1	protein	P31327	UNIPROT	carbamoyl phosphate(2-)	smallmolecule	CHEBI:58228	ChEBI	up-regulates quantity	chemical modification			9606									15096496	t			CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules	SIGNOR-267192	0.8
PRKACA	protein	P17612	UNIPROT	VASP	protein	P50552	UNIPROT	unknown	phosphorylation	Ser239	GAKLRKVsKQEEASG	9606									12576312	t		miannu	Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro	SIGNOR-250063	0.487
CDK1	protein	P06493	UNIPROT	VCPIP1	protein	Q96JH7	UNIPROT	down-regulates activity	phosphorylation	Thr761	GPSSAPAtPTKAPYS										23500464	t		lperfetto	We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97. 	SIGNOR-265037	0.518
PRKAA1	protein	Q13131	UNIPROT	CYCS	protein	P99999	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887;BTO:0001103							17609368	f		gcesareni	Severalin vivostudies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochromec, uncoupling protein 3 (ucp-3)] (1518) and proteins involved in glucose uptake (glut4) (1820) are increased at the transcriptional level in skeletal muscle.	SIGNOR-156772	0.356
PEX14	protein	O75381	UNIPROT	PEX7	protein	O00628	UNIPROT	up-regulates activity	binding			-1									15798189	t		miannu	The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7.	SIGNOR-253028	0.887
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation	Ser939	SFRARSTsLNERPKS	10090	BTO:0000944								12150915	t		lperfetto	We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines.	SIGNOR-244369	0.2
SETD1B	protein	Q9UPS6	UNIPROT	MLL/SET subcomplex	complex	SIGNOR-C87	SIGNOR	form complex	binding			9606									24680668	t		miannu	Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation.	SIGNOR-268796	0.894
MTF1	protein	Q14872	UNIPROT	GCLC	protein	P48506	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15378601	f		miannu	 MRE-binding transcription factor-1 (MTF-1) is a highly conserved heavy metal-induced transcriptional activator. MTF-1 also activates transcription in response to oxidative stress and regulates the expression of several cytoprotective factor genes, including MT, gamma-glutamylcysteine synthetase, and Cu/Zn-superoxide dismutase.	SIGNOR-254599	0.29
PAK1	protein	Q13153	UNIPROT	ARHGEF2	protein	Q92974	UNIPROT	down-regulates	phosphorylation	Ser886	PVDPRRRsLPAGDAL	9606									19667072	t		gcesareni	We identify gef-h1 as a binding target and substrate for p21-activated kinase 1 (pak1), we show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules.	SIGNOR-187573	0.36
MRPL38	protein	Q96DV4	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262359	0.676
SF3B6	protein	Q9Y3B4	UNIPROT	SF3b	complex	SIGNOR-C442	SIGNOR	form complex	binding			9606									32140746	t		lperfetto	Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a).	SIGNOR-268408	0.858
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser519	SGYSSPGsPGTPGSR	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249343	0.729
ADRA2B	protein	P18089	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256714	0.439
KIRREL3	protein	Q8IZU9	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			10090	BTO:0004032								28381988	t		miannu	 We here report that, through its C-terminal PDZ domain-binding motif, Neph2 directly interacts with postsynaptic density (PSD)-95, an abundant excitatory postsynaptic scaffolding protein. Moreover, Neph2 protein is detected in the brain PSD fraction and interacts with PSD-95 in synaptosomal lysates. Functionally, loss of Neph2 in mice leads to age-specific defects in the synaptic connectivity of DG neurons.	SIGNOR-269079	0.382
SMARCD2	protein	Q92925	UNIPROT	Brain-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C486	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270753	0.775
CD36	protein	P16671	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264453	0.7
Parathyroid hormone-related peptide (1-36)	smallmolecule	CHEBI:80274	ChEBI	PTH1R	protein	Q03431	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257575	0.8
BIRC5	protein	O15392	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates	binding			9606									11069302	t		amattioni	Survivin (an inhibitor of apoptosis) phosphorylation on thr34 may regulate apoptosis at cell division via an interaction with caspase-9.	SIGNOR-84065	0.518
MAPK8	protein	P45983	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr71	IVADQTPtPTRFLKN	9606									7737130	t		gcesareni	Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro.	SIGNOR-32425	0.772
POU1F1	protein	P28069	UNIPROT	TSHB	protein	P01222	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001379							10931853	t		scontino	CBP and Pit-1 acted synergistically in TRH stimulation of the TSH-β promoter. The human TSH-β promoter contains three well defined Pit-1 DNA-binding sites.	SIGNOR-267205	0.45
PRKCA	protein	P17252	UNIPROT	NOS1	protein	P29475	UNIPROT	unknown				-1									1375933	t		lperfetto	We now report that NOS is stoichiometrically phosphorylated by cAMP dependent protein kinase, protein kinase C, and calcium/calmodulin-dependent protein kinase, with each kinase phosphorylating a different serine site on NOS.	SIGNOR-248848	0.491
CBX1	protein	P83916	UNIPROT	ChAHP	complex	SIGNOR-C407	SIGNOR	form complex	binding			10090	BTO:0002896								29795351	t		miannu	Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. In conclusion, CHD4, ADNP and HP1β/γ form a stable protein complex, which we refer to as ChAHP.	SIGNOR-266754	0.366
MAP3K11	protein	Q16584	UNIPROT	PIN1	protein	Q13526	UNIPROT	up-regulates	phosphorylation	Ser138	QKPFEDAsFALRTGE	9606									25519816	t		llicata	Here we demonstrate that mixed-lineage kinase 3 (mlk3), a map3k family member, phosphorylates pin1 on a ser138 site to increase its catalytic activity and nuclear translocation.	SIGNOR-205586	0.265
IKBKB	protein	O14920	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	down-regulates activity	phosphorylation	Ser436	TNGSIGHsPLSLSAQ	9606									24614225	t		lperfetto	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204728	0.529
N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide	chemical	CHEBI:91393	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194337	0.8
ROCK1	protein	Q13464	UNIPROT	ARHGAP35	protein	Q9NRY4	UNIPROT	down-regulates activity	phosphorylation	Ser1150	LERGRKVsIVSKPVL	9534	BTO:0000298								19103606	t		miannu	 these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells 	SIGNOR-276177	0.425
p38	proteinfamily	SIGNOR-PF16	SIGNOR	CDC25B	protein	P30305	UNIPROT	down-regulates activity	phosphorylation	Ser323	QRLFRSPsMPCSVIR	9606									11333986	t		lperfetto	P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteins phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3	SIGNOR-107412	0.2
(R)-carnitine	smallmolecule	CHEBI:16347	ChEBI	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	precursor of			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-268108	0.8
GLS	protein	O94925	UNIPROT	L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	down-regulates quantity	chemical modification			9606									22049910	t		miannu	Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia.	SIGNOR-260000	0.8
FSTL1	protein	Q12841	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity				9606	BTO:0001176;BTO:0002320								18718903	f		miannu	In this study, Fstl1 was shown to activate Akt signaling in cardiac myocytes and inhibit apoptosis. Thus, Fstl1 can function as a survival factor for both cardiac myocytes and endothelial cells via the activation of Akt signaling. 	SIGNOR-266604	0.393
PRKACA	protein	P17612	UNIPROT	NFATC1	protein	O95644	UNIPROT	down-regulates	phosphorylation	Ser245	PSTSPRAsVTEESWL	9606									12351631	t		lperfetto	Here we show that overexpression of pka causes phosphorylation and cytoplasmic accumulation of nf-atc1 in direct opposition to calcineurin by phosphorylating ser-245, ser-269, and ser-294 in the conserved serine-proline repeat domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3)	SIGNOR-93531	0.357
CyclinD3/CDK6	complex	SIGNOR-C234	SIGNOR	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Ser397	SMVGGERsPPRILPP	9606	BTO:0000007								21059642	t	The effect has been demonstrated using Q01196-8	gcesareni	Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20).	SIGNOR-273030	0.562
IRAK4	protein	Q9NWZ3	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Ser76	ISNKDQHsISYTLSR	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276127	0.643
CTTNBP2NL	protein	Q9P2B4	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				10116									23015759	f		miannu	Through alternative splicing, a single CTTNBP2 gene encodes three different transcripts, namely short (S), long (L), and intron forms. The interaction with cortactin is required for the function of CTTNBP2-S in dendritic spine formation because the CTTNBP2-S mutant, which no longer interacts with cortactin, is unable to rescue the spine defects resulting from CTTNBP2 knockdown. Thus CTTNBP2-S may control cortactin–F-actin cytoskeletons and regulate the formation and maintenance of dendritic spines in neurons.	SIGNOR-261694	0.7
THRAP3	protein	Q9Y2W1	UNIPROT	SFPQ	protein	P23246	UNIPROT	down-regulates	binding			9606									20932480	t		miannu	Here we demonstrate that in resting tcells psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. Upon tcell activation, reduced gsk3 activity leads to reduced psf phosphorylation, releasing psf from trap150 and allowing it to bind cd45 splicing regulatory elements and repress exon inclusion.	SIGNOR-168441	0.447
AXIN1	protein	O15169	UNIPROT	BMPR1A	protein	P36894	UNIPROT	down-regulates	ubiquitination			9606									22298955	t		gcesareni	Other proteins, such as the serine/threonine kinase fused (fu), can function in concert with the e3 ligase smurf to regulate ubiquitination and proteolysis of the bmp receptor	SIGNOR-195552	0.337
LZTR1	protein	Q8N653	UNIPROT	KRAS	protein	P01116	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								31337872	t		Gianni	We demonstrate that LZTR1 facilitates the polyubiquitination and degradation of RAS via the ubiquitin-proteasome pathway, leading to the inhibition of the RAS/MAPK signaling.	SIGNOR-269069	0.253
DYRK2	protein	Q92630	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser320	HQSLSLAsSPKGTIE	9606	BTO:0002181								34363019	t		miannu	Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases. 	SIGNOR-276734	0.2
citrate(3-)	smallmolecule	CHEBI:16947	ChEBI	D-threo-isocitrate(3-)	smallmolecule	CHEBI:15562	ChEBI	up-regulates quantity	precursor of			9606									24068518	t		miannu	Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained.	SIGNOR-266243	0.8
THBD	protein	P07204	UNIPROT	Thrombin-Thrombomodulin	complex	SIGNOR-C316	SIGNOR	form complex	binding			9606		BTO:0000131							29880919	t		lperfetto	Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC).	SIGNOR-267726	0.903
ITGA11	protein	Q9UKX5	UNIPROT	A11/b1 integrin	complex	SIGNOR-C168	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253187	0.694
ATR	protein	Q13535	UNIPROT	CREB1	protein	P16220	UNIPROT	down-regulates	phosphorylation	Ser107	SVDSVTDsQKRREIL	9606									15073328	t		lperfetto	Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potentialit is, therefore, likely that atm and atr regulate creb phosphorylation collectively in response to stress stimuli.	SIGNOR-124060	0.354
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606									19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-252823	0.908
MAPK3	protein	P27361	UNIPROT	ALOX5	protein	P09917	UNIPROT	up-regulates activity	phosphorylation	Ser664	QLPYYYLsPDRIPNS	9606	BTO:0000567								12670876	t		lperfetto	Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells.	SIGNOR-264440	0.335
TGFB1	protein	P01137	UNIPROT	SLC20A1	protein	Q8WUM9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000249								20930330	f		miannu	TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line.	SIGNOR-252202	0.2
DEF6	protein	Q9H4E7	UNIPROT	RAP1B	protein	P61224	UNIPROT	up-regulates activity	binding			9606	BTO:0000782								26483383	t		lperfetto	Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4(+) T cell adhesion.	SIGNOR-253366	0.2
PAK1	protein	Q13153	UNIPROT	PAK1	protein	Q13153	UNIPROT	up-regulates activity	phosphorylation	Ser199	PRPEHTKsVYTRSVI	9534									9032240	t		miannu	Cdc42 and Rac1 cause alpha-PAK autophosphorylation and kinase activation.	SIGNOR-250216	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ZNF322	protein	Q6U7Q0	UNIPROT	up-regulates activity	phosphorylation	Thr234	IVHKRVHtGEKPYKC	9606	BTO:0002552								31399647	t		miannu	We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A.	SIGNOR-276752	0.2
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CDC7	protein	O00311	UNIPROT	up-regulates activity	phosphorylation	Thr376	QVAPRAGtPGFRAPE										10846177	t		llicata	Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks.	SIGNOR-250725	0.604
ATF2	protein	P15336	UNIPROT	ST3GAL5	protein	Q9UNP4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002335								21699754	f		miannu	Our results identified the core promoter region in the hST3Gal V promoter and for the first time demonstrated that ATF2 binding to the CREB/ATF binding site at -143 is essential for transcriptional activation of hST3Gal V in VPA-induced ARPE-19 cells.	SIGNOR-253745	0.2
CTDSPL	protein	O15194	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	dephosphorylation	Ser195	PNSSYPNsPGSSSST	9606	BTO:0000552								17085434	t			Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)	SIGNOR-248314	0.476
nefazodone	chemical	CHEBI:7494	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			-1									9871604	t		miannu	Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. Nefazodone has similar affinities at hSERT, hNET, and hDAT, but has low potency	SIGNOR-259068	0.8
EGFR	protein	P00533	UNIPROT	SHC2	protein	P98077	UNIPROT	up-regulates	binding			9606									11350724	t		miannu	Shc exists in three different isoforms, p46shc, p52shc and p66shc which are tyrosine phosphorylated upon egf stimulation and bind to the activated egfr and grb2. Interestingly, while the 46 and 52 kda isoforms increase mitogenic signalling after egf stimulation and are able to transform nih3t3 cells (pelicci et al. 1992), p66shc has no transforming potential and negatively influences egf-induced c-fos transcription	SIGNOR-107750	0.598
AMER1	protein	Q5JTC6	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000007			SIGNOR-C110					21304492	t		gcesareni	Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6.	SIGNOR-171892	0.393
PER1	protein	O15534	UNIPROT	CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	down-regulates activity	binding			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop.	SIGNOR-267978	0.72
HSPA1A	protein	P0DMV8	UNIPROT	GSTA4	protein	O15217	UNIPROT	up-regulates activity	relocalization										phosphorylation:Thr193;Ser189	VKLSNIPtIKRFLEP;QEYTVKLsNIPTIKR	21929724	t		lperfetto	Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. |Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation	SIGNOR-264799	0.2
CDK1	protein	P06493	UNIPROT	STIM1	protein	Q13586	UNIPROT	down-regulates	phosphorylation	Ser668	IGEETDSsPGRKKFP	9606									19881501	t		gcesareni	Stim1 is phosphorylated during mitosis. Removal of ten mpm-2 recognition sites by truncation at amino acid 482 abolished mpm-2 recognition of mitotic stim1, and significantly rescued stim1 rearrangement and soce response in mitosis. We identified ser 486 and ser 668 as mitosis-specific phosphorylation sites, and stim1 containing mutations of these sites to alanine also significantly rescued mitotic soce.	SIGNOR-189017	0.353
IL1R1	protein	P14778	UNIPROT	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000801								9625767	t	inferred from 70% of family members	lperfetto	Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab	SIGNOR-269883	0.389
FOXO1	protein	Q12778	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				10090									12530968	f			�The present data provide a direct link between insulin signaling through Irs _ PI 3-kinase _ Akt and adipogenesis through Foxo1 phosphorylation. Inhibition of Foxo1 via phosphorylation appears to be required during the clonal expansion phase, and our data show that unrestrained Foxo1 activity prevents terminal differentiation.	SIGNOR-254981	0.7
NOS2	protein	P35228	UNIPROT	L-citrulline	smallmolecule	CID:9750	PUBCHEM	up-regulates				9606									7537672	f		apalma	Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the ammino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline	SIGNOR-255382	0.8
CLTB	protein	P09497	UNIPROT	AP-1/clathrin vescicle	complex	SIGNOR-C251	SIGNOR	form complex	binding			9606									23103167	t		lperfetto	Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors	SIGNOR-260677	0.76
IKBKE	protein	Q14164	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Ser396	NTVDLHIsNSHPLSL	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178371	0.732
SRC	protein	P12931	UNIPROT	PDPK1	protein	O15530	UNIPROT	up-regulates activity	phosphorylation	Tyr9	ARTTSQLyDAVPIQS	9606									11481331	t		lperfetto	Using site-directed mutants, we show that, although phosphorylation on tyr-373/376 is important for pdk1 activity, phosphorylation on tyr-9 has no effect on the activity of the kinase. Both of these residues can be phosphorylated by v-src tyrosine kinase in vitro, and co-expression of v-src leads to tyrosine phosphorylation and activation of pdk1.	SIGNOR-109533	0.566
NPY	protein	P01303	UNIPROT	NPY1R	protein	P25929	UNIPROT	up-regulates	binding			9606									9549761	t		gcesareni	Analogs of npy and pyy have been synthesized that contain a proline residue in position 34 of the molecule, i.e., [leu31, pro34]npy (fuhlendorff et al., 1990) or [pro34]pyy (grandt et al., 1994b), and are much more potent at y1 than y2receptors.	SIGNOR-56522	0.853
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	YBX1	protein	P67809	UNIPROT	up-regulates	phosphorylation	Ser102	NPRKYLRsVGDGETV	9606	BTO:0000150								19036157	t		lperfetto	We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue.	SIGNOR-252804	0.2
FLT3	protein	P36888	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity				10090	BTO:0001516								23246379	f		miannu	Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells.	SIGNOR-260081	0.547
AMPK	complex	SIGNOR-C15	SIGNOR	INSR	protein	P06213	UNIPROT	up-regulates	phosphorylation			9606		BTO:0000887							22207502	t		lperfetto	Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway.	SIGNOR-216619	0.309
GGCX	protein	P38435	UNIPROT	F10	protein	P00742	UNIPROT	up-regulates activity	carboxylation	Glu65	MEETCSYeEAREVFE	-1									9538022	t		lperfetto	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263670	0.598
SMAD1	protein	Q15797	UNIPROT	SMAD1/4	complex	SIGNOR-C85	SIGNOR	form complex	binding			9606									9436979	t		lperfetto	Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription.	SIGNOR-103615	0.655
Dynorphin B	chemical	CHEBI:80347	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258796	0.8
TGFBI	protein	Q15582	UNIPROT	Av/b5 integrin	complex	SIGNOR-C178	SIGNOR	up-regulates activity	binding												26387839	t		lperfetto	 BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers	SIGNOR-253271	0.349
DAGLA	protein	Q9Y4D2	UNIPROT	2-arachidonoylglycerol	smallmolecule	CHEBI:52392	ChEBI	up-regulates quantity	chemical modification			9606									26787883	t		miannu	Diacylglycerol lipases (DAGLα and DAGLβ) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. 	SIGNOR-264264	0.8
MMP13	protein	P45452	UNIPROT	FGA	protein	P02671	UNIPROT	down-regulates quantity by destabilization	cleavage	Ala20	VVGTAWTaDSGEGDF	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain 	SIGNOR-263612	0.2
p38	proteinfamily	SIGNOR-PF16	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation			9606	BTO:0001286								17254968	t	inferred from 70% family members	gcesareni	We show that prak activates p53 by direct phosphorylation.	SIGNOR-270126	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation			9606									21798082	t		lperfetto	Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b).	SIGNOR-252352	0.2
ERG	protein	P11308	UNIPROT	WNT1	protein	P04628	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001321								23913826	t		Luana	Interestingly, our data showed that ERG drastically induced Wnt ligand gene expression.	SIGNOR-261597	0.2
MTHFR	protein	P42898	UNIPROT	(6S)-5-methyltetrahydrofolate(2-)	smallmolecule	CHEBI:18608	ChEBI	up-regulates quantity	chemical modification			9606									10720211	t		lperfetto	Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine.	SIGNOR-268229	0.8
histamine	smallmolecule	CHEBI:18295	ChEBI	HRH1	protein	P35367	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257512	0.8
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRM8	protein	O00222	UNIPROT	up-regulates activity	chemical activation			9606									25042998	t		miannu	Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate	SIGNOR-264073	0.8
AGTR1	protein	P30556	UNIPROT	PAX2	protein	Q02962	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15569307	f			Ang II up-regulated Pax-2 gene expression via AT2R in IRPTC (immortalized rat renal proximal tubular cells)	SIGNOR-252294	0.259
PRKCB	protein	P05771	UNIPROT	CD5	protein	P06127	UNIPROT	unknown	phosphorylation	Thr434	MSFHRNHtATVRSHA	9606									11123317	t		lperfetto	Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. 	SIGNOR-249073	0.364
AKT1	protein	P31749	UNIPROT	ADARB1	protein	P78563	UNIPROT	down-regulates activity	phosphorylation	Thr553	LQGERLLtMSCSDKI	-1									31095429	t		miannu	AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively	SIGNOR-276194	0.2
NR3C1	protein	P04150	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									8639160	t		gcesareni	We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins	SIGNOR-251680	0.582
AKT1	protein	P31749	UNIPROT	MST1R	protein	Q04912	UNIPROT	up-regulates	phosphorylation	Ser1394	VRRPRPLsEPPRPT	9606									14505491	t		lperfetto	Akt/pkb phosphorylates ron ser-1394, thus providing a docking site for 14-3-3based on these results, we propose a mechanism based on msp-ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing	SIGNOR-252471	0.54
SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	TRIM71	protein	Q2Q1W2	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269239	0.299
TLN1	protein	Q9Y490	UNIPROT	ITGB6	protein	P18564	UNIPROT	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257631	0.571
DROSHA	protein	Q9NRR4	UNIPROT	Microprocessor complex	complex	SIGNOR-C356	SIGNOR	form complex	binding			9606	BTO:0000552								24581491	t		lperfetto	Microprocessor minimally comprises the ribonuclease DROSHA and its double-stranded RNA-binding partner DGCR8 (Denli et al., 2004; Gregory et al., 2004). Microprocessor recognizes pri-miRNA through the stem-loop (Zeng et al., 2005) and the stem-loop-ssRNA junction (Han et al., 2006), and cleaves both the 5′ and 3′ flanking segments to generate pre-miRNA.	SIGNOR-264848	0.922
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr529	TPGSRSRtPSLPTPP	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-251594	0.695
ISL1	protein	P61371	UNIPROT	NLI/Lmx1.1/Isl1 	complex	SIGNOR-C103	SIGNOR	form complex	binding			9606									9452425	t		miannu	Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas.	SIGNOR-220131	0.345
APC-c	complex	SIGNOR-C150	SIGNOR	AURKA	protein	O14965	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0004055								12023018	t		miannu	We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity.	SIGNOR-272612	0.42
DHX30	protein	Q7L2E3	UNIPROT	Stress_granules	phenotype	SIGNOR-PH124	SIGNOR	up-regulates				9606									25683715	f		miannu	DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. 	SIGNOR-261228	0.7
PRKD1	protein	Q15139	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	phosphorylation	Ser154	STLYRTQsSSNLAEL	9606	BTO:0000738								23129748	t		miannu	 PKD1 phosphorylates p85α to enhance its interaction with PTEN, leading to polarized PTEN activity, thereby regulating neutrophil migration. 	SIGNOR-276426	0.2
ACLY	protein	P53396	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity by destabilization	chemical modification			9606									19286649	t		miannu	ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor.	SIGNOR-268082	0.8
HOXC10	protein	Q9NYD6	UNIPROT	LAMB2	protein	P55268	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534	BTO:0000298								10835276	t		Luana	The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells.	SIGNOR-261645	0.2
piroxicam	chemical	CHEBI:8249	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates activity	chemical inhibition			-1									9083488	t		miannu	Meloxicam (5),an NSAID in the enol−carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. This favorable therapeutic index has been confirmed in clinical trials. In subsequent studies we and others discovered that it possessed a selectivity profile for COX-2 superior to several other marketed NSAIDs.1 A comparison of 5 with piroxicam (6) revealed different inhibitory profiles for the two enzymes	SIGNOR-258608	0.8
PRKACA	protein	P17612	UNIPROT	HAND1	protein	O96004	UNIPROT	unknown	phosphorylation	Ser98	RLGRRKGsGPKKERR	10116	BTO:0001556								14636580	t		miannu	In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function.	SIGNOR-249990	0.299
TNF	protein	P01375	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253480	0.261
ATF4	protein	P18848	UNIPROT	AARS2	protein	Q5JTZ9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269415	0.246
IGF1R	protein	P08069	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates activity	phosphorylation	Tyr1166	DIYETDYyRKGGKGL	-1									8940173	t		miannu	The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.	SIGNOR-246244	0.2
HIPK2	protein	Q9H2X6	UNIPROT	ZBTB4	protein	Q9P1Z0	UNIPROT	down-regulates activity	phosphorylation	Thr983	AAPPAPPtPPPPTLP	-1									19448668	t		miannu	The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4.	SIGNOR-262882	0.387
F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	down-regulates activity	relocalization			9606									27871158	t		lperfetto	Integrin αIIbβ3 is retained by the actin cytoskeleton in resting platelets but is released to the cell surface during platelet activation. 	SIGNOR-261864	0.7
PRKG1	protein	Q13976	UNIPROT	HRH1	protein	P35367	UNIPROT	down-regulates	phosphorylation	Ser398	WKRLRSHsRQYVSGL	9606		BTO:0000975							15107581	t	Translocation from Endosome to Lysosome	fspada	A specific pkg inhibitor inhibits h1r downregulation in cho cells (37). However, direct activation of pkg in these cells does not cause h1r down-regulation, indicating that more studies are required to clarify the role of pkg in h1r down-regulation.	SIGNOR-124360	0.2
DUSP1	protein	P28562	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates	dephosphorylation			9606									10617468	t	inferred from 70% of family members	gcesareni	The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1.	SIGNOR-269930	0.828
PRKCQ	protein	Q04759	UNIPROT	RAPGEF2	protein	Q9Y4G8	UNIPROT	up-regulates	phosphorylation	Ser960	KKRVRRSsFLNAKKL	9606	BTO:0000782								18796635	t		lperfetto	After t-cell activation, the direct phosphorylation of rapgef2 at ser960 by pkc- theta regulates rap1 activation as well as lfa-1 adhesiveness to icam-1. Pkc- theta and its effector rapgef2 are critical factors in tcr signaling to rap1	SIGNOR-181186	0.2
DYRK2	protein	Q92630	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser46	AMDDLMLsPDDIEQW	9606									17349958	t		llicata	Here, we demonstrate that the dual-specificity tyrosine-phosphorylation-regulated kinase 2 (dyrk2) directly phosphorylates p53 at ser46. these findings indicate that dyrk2 regulates p53 to induce apoptosis in response to dna damage.	SIGNOR-153544	0.659
GPR132	protein	Q9UNW8	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257341	0.397
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates activity	phosphorylation			9534	BTO:0004055								14993270	t		lperfetto	We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling.	SIGNOR-244862	0.747
MAPK7	protein	Q13164	UNIPROT	MEF2A	protein	Q02078	UNIPROT	up-regulates	phosphorylation	Thr312	QATQPLAtPVVSVTT	9606	BTO:0000567								10849446	t		lperfetto	We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo.	SIGNOR-236583	0.699
GRK5	protein	P34947	UNIPROT	ST13	protein	P50502	UNIPROT	up-regulates activity	phosphorylation	Ser346	AQNPANMsKYQSNPK	9606	BTO:0000007								21728385	t		miannu	An in vitro screen for novel GRK substrates revealed Hsp70 interacting protein (Hip) as a substrate. GRK5, but not GRK2, bound to and stoichiometrically phosphorylated Hip in vitro. The primary binding domain of GRK5 was mapped to residues 303-319 on Hip, while the major site of phosphorylation was identified to be Ser-346. GRK5 also bound to and phosphorylated Hip on Ser-346 in cells.we found that the phosphorylation of Ser-346 was required for proper agonist-induced internalization of the chemokine receptor CXCR4.	SIGNOR-262877	0.272
LPCAT2	protein	Q7L5N7	UNIPROT	acyl-CoA(4-)	chemical	CHEBI:58342	ChEBI	down-regulates quantity	chemical modification			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272767	0.8
TWIST2	protein	Q8WVJ9	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255502	0.2
PLK1	protein	P53350	UNIPROT	RAP1GAP	protein	P47736	UNIPROT	down-regulates	phosphorylation	Ser525	AGQKTPDsGHVSQEP	9606									25329897	t		lperfetto	Plk1 phosphorylates ser525 in conserved 524dsghvs529 degron of rap1gap and promotes its interaction with _-trcp. Together, these results further support a model in which plk1, but not cdk1 or gsk-3_-mediated phosphorylation of rap1gap is a prerequisite for mitotic degradation.	SIGNOR-205577	0.464
ELE1-RET	fusion protein	SIGNOR-FP10	SIGNOR	SHC1	protein	P29353	UNIPROT	up-regulates activity	binding			9606									16946010	t		miannu	RET/PTC is tumorigenic in thyroid follicular cells; it transforms thyroid cells in culture and gives rise to thyroid carcinomas in transgenic mice. effects of RET/PTC activation require signaling along the MAPK pathway and, more specifically, the presence of the functional BRAF kinase. all breakpoints in the RET gene occur within intron 11, leaving intact the TK domain of the receptor and enabling the RET/PTC oncoprotein to bind SHC via Y1062 and activate the RAS-RAF-MAPK cascade	SIGNOR-251985	0.2
SRC	protein	P12931	UNIPROT	ACLY	protein	P53396	UNIPROT	up-regulates activity	phosphorylation	Tyr227	KVDATADyICKVKWG	9606	BTO:0000007								32420483	t	done	miannu	 We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells.	SIGNOR-274108	0.268
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SLITRK1	protein	Q96PX8	UNIPROT	up-regulates activity	phosphorylation	Ser695	DCGSHSLsD	-1									19640509	t		miannu	In our studies, SICD was phosphorylated by PKA, PKC, and CK2, and association of SLITRK1 with 14-3-3 was regulated by phosphorylation at Ser695. Co-precipitation experiments demonstrated much greater recovery of 14-3-3 in SLITRK1 precipitates when wild-type or S695E was used, as compared with S695A, consistent with the results with purified peptides.	SIGNOR-273634	0.2
10-formyltetrahydrofolate(2-)	smallmolecule	CHEBI:57454	ChEBI	5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-)	smallmolecule	CHEBI:58467	ChEBI	up-regulates quantity	precursor of			9606									33179964	t		miannu	The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP.	SIGNOR-267324	0.8
STAT4	protein	Q14765	UNIPROT	LAMTOR5	protein	O43504	UNIPROT	up-regulates activity	binding			9606									22740693	t		miannu	It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4. here we first report that the transcription factor STAT4 plays a role in regulating S100A4 mediated by HBXIP in breast cancer.	SIGNOR-255247	0.332
DKC1	protein	O60832	UNIPROT	TERT	protein	O14746	UNIPROT	up-regulates activity	binding												18680434	t		lperfetto	 Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity 	SIGNOR-263332	0.809
CARM1	protein	Q86X55	UNIPROT	PAX7	protein	P23759	UNIPROT	up-regulates	methylation			10090	BTO:0002314	BTO:0001103							29681515	t		apalma	Carm1 specifically methylates Pax7 at multiple arginine residues in the N terminus of Pax7	SIGNOR-255898	0.433
WNT4	protein	P56705	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131835	0.635
PRKCZ	protein	Q05513	UNIPROT	ADD1	protein	P35611	UNIPROT	up-regulates	phosphorylation	Ser726	KKKFRTPsFLKKSKK	9606									8810272	t		gcesareni	These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc.	SIGNOR-43834	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr145	QGRKRRQtSMTDFYH	9606									16982699	t		gcesareni	Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt.	SIGNOR-244184	0.2
FFAR1	protein	O14842	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256942	0.2
DGC	complex	SIGNOR-C217	SIGNOR	GABA-A (a4-b1-g2) receptor	complex	SIGNOR-C333	SIGNOR	up-regulates quantity	binding			9606	BTO:0000938;BTO:0002606								22626542	t		miannu	 In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses.	SIGNOR-265435	0.2
RPL22L1	protein	Q6P5R6	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262498	0.725
RPS27A	protein	P62979	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262424	0.783
DUX4	protein	Q9UBX2	UNIPROT	PITX1	protein	P78337	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									17984056	t		Luana	DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1	SIGNOR-261590	0.312
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	TAL2	protein	Q16559	UNIPROT	up-regulates quantity by expression				10090									24816818	f		irozzo	These results demonstrate for the first time that atRA induces Tal2 expression in P19 cells, and suggest that TAL2 commits to the acquisition of neural fate in brain development.	SIGNOR-259087	0.8
HCK	protein	P08631	UNIPROT	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	up-regulates activity	phosphorylation	Tyr875	GLITTLHyPAPKRNK	9606									16912036	t		Manara	Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 	SIGNOR-260816	0.2
PTPN1	protein	P18031	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									16582879	t			Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR	SIGNOR-248410	0.778
PGM1	protein	P36871	UNIPROT	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	up-regulates quantity	chemical modification			9606									32898648	t		miannu	Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P).	SIGNOR-267929	0.8
PRKAA2	protein	P54646	UNIPROT	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606	BTO:0000007								11069105	t		miannu	AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells.  activation of PFK-2 was due to the phosphorylation of Ser466	SIGNOR-250323	0.429
TGFBR2	protein	P37173	UNIPROT	USP2	protein	O75604	UNIPROT	up-regulates activity	phosphorylation	Ser207	ENYGRKGsASQVPSQ	-1									29490279	t		miannu	Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1.	SIGNOR-273604	0.2
Dynorphin B	chemical	CHEBI:80347	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258797	0.8
EIF3D	protein	O15371	UNIPROT	EIF3_complex	complex	SIGNOR-C401	SIGNOR	form complex	binding			-1									16920360	t		miannu	Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 	SIGNOR-266397	0.928
PTH1R	protein	Q03431	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									23151663	t		gcesareni	Parathyroid hormone (pth) binding to its receptor pth1r induces association of the pthpth1r complex with lrp6and phosphorylation of pppsp sites by protein kinase_ a, which in turn triggers wnt.	SIGNOR-199533	0.345
POMC	protein	P01189	UNIPROT	MC4R	protein	P32245	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268710	0.771
DDX58	protein	O95786	UNIPROT	MAVS	protein	Q7Z434	UNIPROT	up-regulates activity	binding			9606									19052324	t		miannu	Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ.	SIGNOR-260139	0.935
TBK1	protein	Q9UHD2	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606									21329883	t		lperfetto	Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling.	SIGNOR-252608	0.417
olanzapine	chemical	CHEBI:7735	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			10116	BTO:0000529								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258510	0.8
DCK	protein	P27707	UNIPROT	G2/M_transition-checkpoint	phenotype	SIGNOR-PH146	SIGNOR	up-regulates	phosphorylation	Ser74											27879648	f		lperfetto	Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in order to activate the cell cycle G2/M checkpoint. 	SIGNOR-275806	0.7
SRC	protein	P12931	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000150								12869565	t		gcesareni	Activated src reduces the ability of pten to dephosphorylate phosphatidylinositols in micelles and promotes akt translocation to cellular plasma membranes but does not alter pten activity toward water-soluble phosphatidylinositols.	SIGNOR-103721	0.554
L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	precursor of			9913									11254391	t		miannu	Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate.	SIGNOR-266915	0.8
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	KDM6B	protein	O15054	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273461	0.8
CDC14A	protein	Q9UNH5	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates activity	dephosphorylation			9606									20956543	f		miannu	Cdc14A inhibits Cdc25A and Cdc25B activity, the latter through direct binding and dephosphorylation ( ).|Indeed, in vitro dephosphorylation of Cdk1-cyclin B1-phosphorylated Cdc25A by Cdc14A did not inhibit its catalytic activity (data not shown).|Taken together, our results suggest that at the G2/M transition Cdc14A acts on an unknown protein, which in turn inhibits Cdc25A phosphatase activity.	SIGNOR-277065	0.518
GSK3B	protein	P49841	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser33	QQQSYLDsGIHSGAT	9606			SIGNOR-C110						23151663	t		gcesareni	Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells.	SIGNOR-199504	0.856
RNF146	protein	Q9NTX7	UNIPROT	TNKS2	protein	Q9H2K2	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								21799911	t			We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation.	SIGNOR-260005	0.599
MYC	protein	P01106	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000150;BTO:0000782	BTO:0000887;BTO:0001260							11313917	f		amattioni	P27(kip1) gene is a target of transcriptional repression by c-myc.	SIGNOR-107032	0.549
ABL1	protein	P00519	UNIPROT	RAD52	protein	P43351	UNIPROT	up-regulates activity	phosphorylation	Tyr104	DLNNGKFyVGVCAFV	9606	BTO:0000007								12379650	t			C-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. he functional significance of c-Abl-dependent phosphorylation of Rad52 is underscored by our findings that cells that express the phosphorylation-resistant Rad52 mutant, in which tyrosine 104 is replaced by phenylalanine, exhibit compromised nuclear foci formation in response to IR. 	SIGNOR-251435	0.673
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	GFI1	protein	Q99684	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000498								31289136	t		miannu	GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation.	SIGNOR-277467	0.2
PPP2CA	protein	P67775	UNIPROT	ATM	protein	Q13315	UNIPROT	down-regulates activity	dephosphorylation	Ser1981	SLAFEEGsQSTTISS	9606									15510216	t			Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro. 	SIGNOR-248644	0.34
CHEK1	protein	O14757	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Thr507	KFRTKSRtWAGEKSK	9606									20068082	t		gcesareni	The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts);	SIGNOR-163154	0.852
CDC25A	protein	P30304	UNIPROT	DYRK2	protein	Q92630	UNIPROT	down-regulates activity	dephosphorylation			9606									34363019	t		miannu	Finally, DYRK2 is dephosphorylated by CDC25A, suggesting a feedback regulatory loop.|Notably, the co-expression of CDC25A inhibited the DYRK2 pro-apoptotic effect (Fig.\u00a06D), concurring with a possible inhibitory role on DYRK2 activity and further suggesting that the effect of DYRK2 was dependent on CDC25A.	SIGNOR-277098	0.2
mTORC1	complex	SIGNOR-C3	SIGNOR	TFEB	protein	P19484	UNIPROT	down-regulates activity	phosphorylation	Ser211	LVGVTSSsCPADLTQ	9606	BTO:0000567		SIGNOR-C3						22692423	t		gcesareni	Our data points to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. [...]Our study has revealed a specific role for phosphorylation of TFEB S211 in the negative regulation of the nuclear abundance of TFEB. This occurs through the promotion of 14-3-3 binding and the masking of the nearby NLS on TFEB.	SIGNOR-248274	0.371
PPP4C	protein	P60510	UNIPROT	PLK1	protein	P53350	UNIPROT	down-regulates activity	dephosphorylation	Ser137	LELCRRRsLLELHKR	9606									35546066	t		miannu	PPP4C dephosphorylated PLK1 at the S137 site, negatively regulating its activity in the DSB response in early embryonic cells.	SIGNOR-277076	0.426
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CDK4	protein	P11802	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189990	0.8
GSK3A	protein	P49840	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates	phosphorylation	Ser133	LPYSPVSsPQSSPRL	9606									22778263	t		lperfetto	Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity.	SIGNOR-198126	0.272
PTPN2	protein	P17706	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates activity	dephosphorylation	Tyr1234	RDMYDKEyYSVHNKT	9606									18819921	t			Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases.	SIGNOR-248387	0.479
STAT3	protein	P40763	UNIPROT	HSPA1B	protein	P0DMV9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19754877	f		miannu	 Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress.	SIGNOR-255241	0.2
RPS6KA3	protein	P51812	UNIPROT	FGFR1	protein	P11362	UNIPROT	down-regulates quantity	phosphorylation	Ser789	DTRSSTCsSGEDSVF	9606	BTO:0001938								24141780	t		miannu	 Both in vitro and in vivo experiments confirmed the interaction and we show that phosphorylated RSK2 binds to and phosphorylates serine 789 in the C-terminal tail of FGFR1.prevention of FGFR1 phosphorylation by inhibition of RSK2 activity or mutation of serine 789 to alanine reduced FGFR1 endocytosis and ubiquitination explaining mechanistically the prolonged signaling activity.	SIGNOR-276599	0.363
GAB2	protein	Q9UQC2	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271;BTO:0000785								24737791	t		milica	The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival	SIGNOR-204966	0.444
PTPN9	protein	P43378	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr999	YASSNPEyLSASDVF	9606									16679294	t		gcesareni	Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action	SIGNOR-146680	0.263
CDK2	protein	P24941	UNIPROT	UBTF	protein	P17480	UNIPROT	up-regulates activity	phosphorylation	Ser389	INKKQATsPASKKPA	10090	BTO:0000944		SIGNOR-C16						11698641	t		lperfetto	Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity	SIGNOR-235419	0.379
SIRT1	protein	Q96EB6	UNIPROT	FOXL2	protein	P58012	UNIPROT	down-regulates	deacetylation			9606									19010791	t		miannu	We find that foxl2 activity is repressed by the sirt1 deacetylase.	SIGNOR-182306	0.515
PDGFRB	protein	P09619	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	phosphorylation	Tyr154	QLNDSAAyYLNDLDR	-1									33139573	t		miannu	RTKs directly phosphorylate Gαi on Y154, 155, and Y320.	SIGNOR-277233	0.2
GSK3B	protein	P49841	UNIPROT	AKAP11	protein	Q9UKA4	UNIPROT	down-regulates activity	phosphorylation	Thr1136	AKEFAPAtPPSTPHN	9606	BTO:0000007								26088133	t		lperfetto	A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Using a combination of molecular and cellular approaches we show that GSK3beta phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3beta and its substrate beta-catenin in membrane ruffles.	SIGNOR-264816	0.379
EDN1	protein	P05305	UNIPROT	EDNRA	protein	P25101	UNIPROT	up-regulates	binding			9606									16597412	t		gcesareni	Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors.	SIGNOR-145759	0.877
KAT2B	protein	Q92831	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	acetylation	Lys19	VKRLLGWkKSAGGSG	9606			SIGNOR-C7						17074756	t		gcesareni	We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfbeta-dependent manner. Smad2 is also acetylated by p/caf. The acetylation of smad2 was significantly higher than that of smad3. Lys(19) in the mh1 domain was identified as the major acetylated residue in both the long and short isoform of smad2.....acetylation of the short isoform of smad2 improves its dna binding activity in vitro and enhances its association with target promoters in vivo, thereby augmenting its transcriptional activity	SIGNOR-150273	0.559
PIK3CA	protein	P42336	UNIPROT	TPM1	protein	P09493	UNIPROT	up-regulates activity	phosphorylation	Ser61	EDELDKYsEALKDAQ	-1									16094730	t		miannu	Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization. 	SIGNOR-263027	0.2
zotepine	chemical	CHEBI:32316	ChEBI	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			9606									20223878	t		Luana	These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity.	SIGNOR-257828	0.8
CDK4	protein	P11802	UNIPROT	FOXM1	protein	Q08050	UNIPROT	up-regulates	phosphorylation	Ser4	sPRRPLIL	9606									22094256	t		lperfetto	We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627)	SIGNOR-177251	0.609
PIM1	protein	P11309	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606									18593906	t		tpavlidou	Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene.	SIGNOR-179304	0.396
CYP11B1	protein	P15538	UNIPROT	corticosterone	smallmolecule	CHEBI:16827	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000048							33117906	t		lperfetto	The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone	SIGNOR-268682	0.8
PDP2	protein	Q9P2J9	UNIPROT	PDHA1	protein	P08559	UNIPROT	up-regulates activity	dephosphorylation			9606									20208177	t			Pyruvate dehydrogenase phosphatase (PDP) is a mitochondrial serine phosphatase that activates phosphorylated pyruvate dehydrogenase complex by dephosphorylation	SIGNOR-251665	0.644
CKM complex	complex	SIGNOR-C406	SIGNOR	Core mediator complex	complex	SIGNOR-C405	SIGNOR	down-regulates activity	binding			-1									23563140	t		miannu	We found that interaction of the CKM with Mediator's middle module interferes with CTD-dependent RNAPII binding to a previously unknown middle-module CTD-binding site and with the holoenzyme formation process. Taken together, our results reveal the basis for CKM repression, clarify the origin of the connection between CKM subunits and the CTD and suggest that a combination of competitive interactions and conformational changes that facilitate holoenzyme formation underlie the mechanism of transcription regulation by Mediator.	SIGNOR-266687	0.753
BTRC	protein	Q9Y297	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									10835356	t		miannu	Here we demonstrate that following IkappaB kinase (IkappaK)-mediated phosphorylation, the C-terminal domain of p105 (residues 918-934) serves as a recognition motif for the SCF(beta)(-TrCP) ubiquitin ligase.In vitro, SCF(beta)(-TrCP) specifically conjugates and promotes processing of phosphorylated p105. 	SIGNOR-272570	0.571
MAPK3	protein	P27361	UNIPROT	CTNND1	protein	O60716	UNIPROT	down-regulates activity	phosphorylation	Thr906	SLDNNYStPNERGDH	9615	BTO:0000837								32010791	t		miannu	 Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation. 	SIGNOR-277506	0.299
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGA9	protein	Q9Y5G4	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265700	0.2
zotepine	chemical	CHEBI:32316	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10116									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258558	0.8
PRKACA	protein	P17612	UNIPROT	SNAPIN	protein	O95295	UNIPROT	up-regulates activity	phosphorylation	Ser50	HVHAVREsQVELREQ										11283605	t		miannu	PKA-phosphorylation of Snapin significantly increases its binding to synaptosomal-associated protein-25 (SNAP-25). Mutation of Snapin serine 50 to aspartic acid (S50D) mimics this effect of PKA phosphorylation	SIGNOR-250053	0.311
TTL	protein	Q8NG68	UNIPROT	TUBA4A	protein	P68366	UNIPROT	down-regulates	tyrosination			9606									22020298	t		miannu	Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization	SIGNOR-176927	0.29
MAPK3	protein	P27361	UNIPROT	PPARA	protein	Q07869	UNIPROT	up-regulates activity	phosphorylation	Ser21	LEAGDLEsPLSEEFL	9606	BTO:0000599								10187842	t		lperfetto	We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution.	SIGNOR-249474	0.584
ZBTB14	protein	O43829	UNIPROT	ZBTB14	protein	O43829	UNIPROT	up-regulates activity	binding			9606									10080939	t		miannu	ZF5, which we have cloned as a transcriptional repressor on the mouse c-myc promoter, has the POZ domain at the amino-terminus and the Kruppel-type zinc finger domain at the carboxy-terminus. We demonstrated that the POZ domain has a function mediating homomeric protein-protein interaction and this interaction requires the zinc finger domain.	SIGNOR-220534	0.2
CCL11	protein	P51671	UNIPROT	CCR3	protein	P51677	UNIPROT	up-regulates activity	binding			9606	BTO:0000399								10706854	t			Eotaxin and other CC chemokines acting via CC chemokine receptor-3 (CCR3) are believed to play an integral role in the development of eosinophilic inflammation in asthma and allergic inflammatory diseases.	SIGNOR-256091	0.934
AKT1	protein	P31749	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation			10090	BTO:0002572								18423396	t		lperfetto	Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation.	SIGNOR-236206	0.866
RXRA	protein	P19793	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates activity	binding			9606									10976919	t	inferred from family member	gcesareni	Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr).	SIGNOR-267800	0.714
monoisononyl phthalate	chemical	CHEBI:132593	ChEBI	PPARD	protein	Q03181	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 	SIGNOR-268781	0.8
PCGF2	protein	P35227	UNIPROT	Polycomb repressive complex 1	complex	SIGNOR-C408	SIGNOR	form complex	binding			9606									31608994	t		miannu	PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b	SIGNOR-266813	0.767
AKT3	protein	Q9Y243	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606									19188143	t		gcesareni	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-183644	0.697
CASZ1	protein	Q86V15	UNIPROT	EGFL7	protein	Q9UHF1	UNIPROT	up-regulates quantity	transcriptional regulation			9606	BTO:0001176								24150064	t		miannu	 We have recently demonstrated that a novel transcriptional pathway involving activation of the Epidermal Growth Factor-like Domain 7 (Egfl7) gene by the transcription factor CASTOR (CASZ1) is required for blood vessel assembly and lumen morphogenesis.	SIGNOR-266858	0.438
MAX	protein	P61244	UNIPROT	MGA	protein	Q8IWI9	UNIPROT	up-regulates activity	binding			9606									7954804	t	2	miannu	the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences.	SIGNOR-240261	0.552
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	GATA2	protein	P23769	UNIPROT	down-regulates activity	phosphorylation	Ser401	QTRNRKMsNKSKKSK	9606	BTO:0000876								15837948	t	PI-3K/Akt-dependent manner.	lperfetto	We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity	SIGNOR-244271	0.2
N-hydroxy-2-[4-[[(1-methyl-3-indolyl)methylamino]methyl]-1-piperidinyl]-5-pyrimidinecarboxamide	chemical	CHEBI:94771	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193513	0.8
clofarabine	chemical	CHEBI:681569	ChEBI	RRM1	protein	P23921	UNIPROT	down-regulates activity	chemical inhibition			9606									1707752	t		miannu	Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate	SIGNOR-258357	0.8
CAMK2B	protein	Q13554	UNIPROT	PLCB3	protein	Q01970	UNIPROT	unknown	phosphorylation	Ser537	PSLEPQKsLGDEGLN										11325525	t		llicata	CaMK II phosphorylated PLCbeta3 but not PLCbeta1 in vitro. Phosphorylation occurred exclusively on 537Ser in the X-Y linker region of PLCbeta3. 537Ser was also phosphorylated in the basal state in cells and phosphorylation was enhanced by ionomycin treatment	SIGNOR-250689	0.509
USP6	protein	P35125	UNIPROT	MMP10	protein	P09238	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20418905	f		miannu	In this study we show that tre17 is sufficient to induce expression of mmp-9 and mmp-10, in a manner requiring its usp activity, but not its ability to bind arf6. Tre17 induces transcription of mmp-9 through activation of nuclear factor-kappab (nf-kappab), mediated in part by the gtpase rhoa and its effector kinase, rock.	SIGNOR-164943	0.2
ARNT	protein	P27540	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								21544813	f	 	lperfetto	Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC	SIGNOR-253697	0.554
P2RY10	protein	O00398	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256726	0.2
IL12A	protein	P29459	UNIPROT	IFNG	protein	P01579	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10653850	f		miannu	IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12	SIGNOR-260859	0.374
DHX9	protein	Q08211	UNIPROT	NUP98	protein	P52948	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								28221134	t		miannu	Here we report on the identification of the DExH/D-box helicase DHX9 as an intranuclear Nup98 binding partner. Various results, including in vitro assays, show that the FG/GLFG region of Nup98 binds to N- and C-terminal regions of DHX9 in an RNA facilitated manner. Importantly, binding of Nup98 stimulates the ATPase activity of DHX9, and a transcriptional reporter assay suggests Nup98 supports DHX9-stimulated transcription.	SIGNOR-260954	0.364
CyclinD3/CDK6	complex	SIGNOR-C234	SIGNOR	PKM	protein	P14618	UNIPROT	down-regulates activity	phosphorylation	Ser37	MCRLDIDsPPITARN	9606	BTO:0001106								28607489	t		miannu	We show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity, which was not further affected by pre-incubation with cyclin D3-CDK6 (Extended Data Fig. 3a, b). 	SIGNOR-276453	0.263
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser689	SQPGQLMsQPSTASN	9606									10195894	t			Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.	SIGNOR-251279	0.2
EPB41	protein	P11171	UNIPROT	DLG1	protein	Q12959	UNIPROT	up-regulates activity	relocalization			9615	BTO:0000837								12807908	t		lperfetto	Together, our results demonstrate that in addition to the N-terminal targeting domain, the alternatively spliced I3 insertion plays a critical role in recruiting hDlg to the lateral membrane in epithelial cells via its interaction with protein 4.1R.	SIGNOR-266011	0.485
ROCK1	protein	Q13464	UNIPROT	Brown_adipogenesis	phenotype	SIGNOR-PH27	SIGNOR	up-regulates				9606		BTO:0000887;BTO:0001103							22944199	f		gcesareni	Other g protein-mediated pathways are the planar cell polarity (pcp) pathway (shown in blue) leading to the activation of rac/rho, c-jun n-terminal kinase (jnk), and/or rho-associated kinase (rock). Jnk can induce jun, which, together with fos, forms the ap-1 early response transcription factor. Both pcp pathways have been implicated in cytoskeletal rearrangements	SIGNOR-198840	0.7
PTPN1	protein	P18031	UNIPROT	ACTN1	protein	P12814	UNIPROT	up-regulates	dephosphorylation	Tyr12	DSQQTNDyMQPEEDW	9606									16291744	t		gcesareni	Here we report that protein-tyrosine phosphatase 1b (ptp 1b) is an ?-Actinin phosphatase.	SIGNOR-141634	0.34
AMPK	complex	SIGNOR-C15	SIGNOR	PAK2	protein	Q13177	UNIPROT	unknown	phosphorylation	Ser20	APPVRMSsTIFSTGG	9606									22137581	t		lperfetto	Together, these results indicate that ampk phosphorylates endogenous ppp1r12c at s452 and pak2 at s20 in human cells.	SIGNOR-216612	0.244
PIP3	smallmolecule	CHEBI:16618	ChEBI	PDPK1	protein	O15530	UNIPROT	up-regulates activity	chemical activation			9606									19951971	t		lperfetto	PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain.	SIGNOR-249628	0.8
CDK5	protein	Q00535	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates activity	phosphorylation	Ser203	DLEFSSGsPGKETNE	9606									17440046	t		llicata	Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue 	SIGNOR-154401	0.459
CTH	protein	P32929	UNIPROT	hydrosulfide	smallmolecule	CHEBI:29919	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000671;BTO:0000759;BTO:0002688							19961860	t		lperfetto	 the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production.	SIGNOR-275819	0.8
ATF6	protein	P18850	UNIPROT	DDIT3	protein	P35638	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									31226023	t		miannu	Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network	SIGNOR-260180	0.646
Papain-like proteinase	protein	P0C6X9-PRO_0000037340	UNIPROT	IFNB1	protein	P01574	UNIPROT	down-regulates quantity by repression				9606	BTO:0000007								17761676	f		lperfetto	SARS-CoV PLpro domain inhibits activation of IFN-β promoter following engagement of TLR3 or RIG-I pathways independent of its protease activity	SIGNOR-260277	0.2
PTPN2	protein	P17706	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606	BTO:0000007								12612081	t			In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A substrate-trapping mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR beta-subunit in 293 cells.|IR β-subunit phosphorylated on tyrosine and specifically on tyrosines 1162 and 1163 could be coimmunoprecipitated with the TC48-D182A and TC45-D182A mutants but not the wild-type TC48 or TC45 in response to insulin	SIGNOR-248385	0.604
STAT1	protein	P42224	UNIPROT	S100A10	protein	P60903	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567;BTO:0002923								12645529	f		miannu	 IFN-gamma induced a rapid tyrosine phosphorylation and nuclear translocation of STAT1 protein, which is involved in the binding to the GAS-2 site in the p11 promoter by EMSA analysis. These data suggest that IFN-gamma-induced p11 expression is mediated through the binding of STAT1 to GAS sites in the p11 promoter. 	SIGNOR-255237	0.2
trichostatin A	chemical	CHEBI:46024	ChEBI	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258014	0.8
FOXA1	protein	P55317	UNIPROT	KRT7	protein	P08729	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002861								20043065	f	 	miannu	 These results suggest that FOXA1 induces not only KRT7 but also LOXL2 in a subset of poor prognostic ESCCs with metastatic lymph nodes. FOXA1 siRNA treatment of esophageal cancer cells reduced the mRNA level of both KRT7 and a stabilizer of epithelial-mesenchymal transition (EMT) regulator LOXL2, and that both FOXA1 and LOXL2 siRNAs reduced invasion and migration of ESCC cells. 	SIGNOR-254167	0.284
LYN	protein	P07948	UNIPROT	LYN	protein	P07948	UNIPROT	up-regulates activity	phosphorylation	Tyr397	RVIEDNEyTAREGAK	-1									8530369	t			Lyn is a member of the Src family of protein-tyrosine kinases that can readily undergo autophosphorylation in vitro. The site of autophosphorylation is Tyr397. Autophosphorylation results in a 17-fold increase in protein-tyrosine kinase activity. 	SIGNOR-251402	0.2
NFIX	protein	Q14938	UNIPROT	FOXO6	protein	A8MYZ6	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268887	0.2
BMP7	protein	P18075	UNIPROT	ACVR2A	protein	P27037	UNIPROT	up-regulates	binding			9606									9748228	t		fspada	We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes	SIGNOR-60237	0.76
ANGPT1	protein	Q15389	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000222								26042050	f		lperfetto	Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein.	SIGNOR-241529	0.268
OPRL1	protein	P41146	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257001	0.355
iodide	smallmolecule	CHEBI:16382	ChEBI	3-iodo-L-tyrosine	smallmolecule	CHEBI:27847	ChEBI	up-regulates quantity	precursor of			9606									16098474	t		scontino	TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. 	SIGNOR-268120	0.8
UNC5D	protein	Q6UXZ4	UNIPROT	DCC	protein	P43146	UNIPROT	down-regulates activity	binding			9606		BTO:0001484							25881791	t		miannu	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268167	0.567
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1619	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120172	0.321
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	tRNA(Lys)	smallmolecule	CHEBI:29185	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270403	0.8
SPOP	protein	O43791	UNIPROT	DAXX	protein	Q9UER7	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0002181								16524876	t		Gianni	These results suggest that SPOP/Cul3-ubiquitin ligase plays an essential role in the control of Daxx level and, thus, in the regulation of Daxx-mediated cellular processes, including transcriptional regulation and apoptosis.	SIGNOR-268858	0.497
HDAC11	protein	Q96DB2	UNIPROT	BRD2	protein	P25440	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								30089714	t		lperfetto	Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to β-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone-binding protein.	SIGNOR-262058	0.346
risperidone	chemical	CHEBI:8871	ChEBI	HTR1D	protein	P28221	UNIPROT	down-regulates activity	chemical inhibition			10116	BTO:0000529								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258527	0.8
AIMP2	protein	Q13155	UNIPROT	Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	form complex	binding			9606									32644155	t		miannu	In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes).	SIGNOR-270361	0.919
TAF3/TRF3	complex	SIGNOR-C23	SIGNOR	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates				10090	BTO:0000165								17704303	f		llicata	Here we report that differentiation of myoblast to myotubes involves the disruption of the canonical holo-TFIID and replacement by a novel TRF3/TAF3 (TBP-related factor 3/TATA-binding protein-associated factor 3) complex.	SIGNOR-237621	0.7
MAPK1	protein	P28482	UNIPROT	DUSP6	protein	Q16828	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser197	SATDSDGsPLSNSQP	9606									15632084	t		gcesareni	In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3.	SIGNOR-132971	0.901
FLNA	protein	P21333	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates	binding			9606	BTO:0000848								9006895	t		gcesareni	Sek-1 binds directly and specifically to the actin-binding protein abp-280. As a consequence, active sek-1 is capable of phosphorylating and activating in vitro added bacterial recombinant sapk.	SIGNOR-45887	0.507
N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide	chemical	CHEBI:91409	ChEBI	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190404	0.8
EGFR	protein	P00533	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	phosphorylation	Tyr1253	EGSFESRyQQPFEDF	9606		BTO:0000142							1689310	t		llicata	We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation.	SIGNOR-20976	0.835
MET	protein	P08581	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr925	DRSNDKVyENVTGLV	9606									16782899	t		llicata	Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain	SIGNOR-147203	0.475
ILK	protein	Q13418	UNIPROT	PPP1R12A	protein	O14974	UNIPROT	down-regulates activity	phosphorylation	Thr696	ARQSRRStQGVTLTD	-1									12030846	t		miannu	 MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition	SIGNOR-262886	0.566
GSK3B	protein	P49841	UNIPROT	RICTOR	protein	Q6R327	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr1695	EAEAVLAtPPKQPIV	9606	BTO:0002181								25897075	t		miannu	We show that this process is dependent on glycogen synthase kinase 3 (GSK3): GSK3 was associated with rictor and directly phosphorylated the Thr-1695 site in a putative CDC4 phospho-degron motif of rictor; mutation of this site impaired the interaction between rictor and FBXW7, decreased rictor ubiquitination, and increased rictor stability. 	SIGNOR-276898	0.419
ILK	protein	Q13418	UNIPROT	PPP1R12A	protein	O14974	UNIPROT	down-regulates	phosphorylation	Thr696	ARQSRRStQGVTLTD	9606									12030846	t		lperfetto	Mypt1 was phosphorylated by ilk and phosphorylation sites in the n- and c-terminal fragments of mypt1 were detected. From sequence analyses, three sites were identified: a primary site at thr(709), and two other sites at thr(695) and thr(495)	SIGNOR-87924	0.566
dicyclomine	chemical	CHEBI:4514	ChEBI	CHRM2	protein	P08172	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								2704370	t		miannu	In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 	SIGNOR-258388	0.8
KLF2	protein	Q9Y5W3	UNIPROT	HBE1	protein	P02100	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15947087	f	Regulation of expression	miannu	Our results show that KLF2 positively regulates the human (ε) and murine (Ey and βh1) embryonic globin genes at both E10.5 and E12.5, in the yolk sac, which is the site of primitive erythropoiesis. 	SIGNOR-251830	0.246
GSK3B	protein	P49841	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	form complex	binding			9606	BTO:0000586								9734785	t		lperfetto	Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level.	SIGNOR-227299	0.833
MARK4	protein	Q96L34	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser420	KHPTPGSsDPLIQPS	-1									21204788	t		miannu	AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 	SIGNOR-273936	0.429
STK4	protein	Q13043	UNIPROT	MOB1B	protein	Q7L9L4	UNIPROT	up-regulates	phosphorylation	Thr35	LLKHAEAtLGSGNLR	9606									23431053	t		milica	Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity	SIGNOR-201318	0.846
EGR1	protein	P18146	UNIPROT	TBXA2R	protein	P21731	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19747485	f			Collectively, data establish that regulated WT1 followed by sequential Egr1 and Sp1 binding to elements within Prm1 mediate repression and subsequent induction of TPα during differentiation into the megakaryocytic phenotype, shedding significant insights into factors regulating TPα expression therein.	SIGNOR-254253	0.263
PPM1F	protein	P49593	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	dephosphorylation	Ser57	KKDRFYRsILPGDKT	10116									11864573	t			The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX.	SIGNOR-248530	0.399
RET	protein	P07949	UNIPROT	DOK6	protein	Q6PKX4	UNIPROT	up-regulates	binding			9606		BTO:0000671							15286081	t		gcesareni	These data identify dok-6 as a novel dok-4/5-related adaptor molecule that may function in vivo to transduce signals that regulate ret-mediated processes such as axonal projection.	SIGNOR-127382	0.632
BDKRB2	protein	P30411	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257199	0.36
LEF1	protein	Q9UJU2	UNIPROT	FST	protein	P19883	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								24344199	t		lperfetto	We further demonstrate that Fst is a direct target of the WNT/β-catenin pathway. Activation and inactivation of β-catenin induced and inhibited Fst expression, respectively, in both C2C12 cells and mouse embryos. Specific TCF/LEF1 binding sites within the promoter and intron 1 region of the Fst gene were required for RSPO2 and WNT/β-catenin-induced Fst expression.	SIGNOR-251722	0.284
ATM	protein	Q13315	UNIPROT	RAD17	protein	O75943	UNIPROT	unknown	phosphorylation	Ser656	SASELPAsQPQPFSA	9606									10608806	t		lperfetto	We determined a general phosphorylation consensus sequence for atm and identified putative in vitro targets by using glutathione s-transferase peptides as substrates. Putative atm in vitro targets include p95/nibrin, mre11, brca1, rad17, pts, wrn, and atm (s440) itself.	SIGNOR-73524	0.841
GCG	protein	P01275	UNIPROT	GLP1R	protein	P43220	UNIPROT	up-regulates	binding			9606	BTO:0000776								7937318	t		gcesareni	In the present study we stably expressed the rat b-cell glp-i receptor in cho cells and studied binding characteristics and receptor activation utilizing the naturally occurring receptor agonist glp-i(7-36)-amide (glp-i), the proglucagon-derived glp-i-related peptide oxyntomodulin, the glp-i receptor agonist exendin-4, and the specific antagonist exendin	SIGNOR-34855	0.775
BRSK2	protein	Q8IWQ3	UNIPROT	WDR45	protein	Q9Y484	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0001938								28561066	t		miannu	WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes.	SIGNOR-268482	0.25
SIRT1	protein	Q96EB6	UNIPROT	SMAD7	protein	O15105	UNIPROT	down-regulates	deacetylation	Lys64	RAGCCLGkAVRGAKG	9606									17098745	t		gcesareni	Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells.	SIGNOR-150595	0.452
PF-5274857	chemical	CID:56956240	PUBCHEM	SMO	protein	Q99835	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206058	0.8
PRKCQ	protein	Q04759	UNIPROT	HABP4	protein	Q5JVS0	UNIPROT	down-regulates activity	phosphorylation	Thr375	GRGARGGtRGGRGRI	9606									14699138	t		lperfetto	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249256	0.307
GHSR	protein	Q92847	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257167	0.357
MAP4K1	protein	Q92918	UNIPROT	CARD11	protein	Q9BXL7	UNIPROT	up-regulates activity	phosphorylation	Ser556	TKMQPPRsRSSIMSI	-1									19706536	t		miannu	HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro.	SIGNOR-276259	0.507
CDK5	protein	Q00535	UNIPROT	NES	protein	P48681	UNIPROT	unknown	phosphorylation	Thr1299	GETLPDStPLGFYLR	10090									12832492	t		llicata	We identify nestin as a novel in vivo target for cdk5 and p35 kinase, a critical signaling determinant in development. Two cdk5-specific phosphorylation sites on nestin, Thr-1495 and Thr-316, were established, the latter of which was used as a marker for cdk5-specific phosphorylation in vivo. | Cdk5 activity is necessary for differentiation and the concomitant nestin reorganization in C2C12 myoblasts.	SIGNOR-250669	0.564
PRKACA	protein	P17612	UNIPROT	PSEN1	protein	P49768	UNIPROT	unknown	phosphorylation	Ser310	PEAQRRVsKNSKYNA	-1									14576165	t		miannu	PKA-mediated phosphorylation of PS1 is completely inhibited by mutation of Ser310.phosphorylation of Ser310 does not inhibit the caspase-mediated cleavage of PS1, and the biological function of this phosphorylation event remains to be determined in further experiments.	SIGNOR-250036	0.472
TRIM27	protein	P14373	UNIPROT	MAPK12	protein	P53778	UNIPROT	up-regulates				9606		BTO:0000671							12807881	f		miannu	We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38.	SIGNOR-102025	0.2
MAP2K7	protein	O14733	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates	phosphorylation	Thr183	ACTNFMMtPYVVTRY	9606									11062067	t	phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif	gcesareni	Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway.	SIGNOR-83744	0.622
prostaglandin H2(1-)	smallmolecule	CHEBI:57405	ChEBI	prostaglandin G2(1-)	smallmolecule	CHEBI:82629	ChEBI	up-regulates quantity	precursor of			-1									7592599	t		Luana	[14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2,	SIGNOR-269769	0.8
CDK1	protein	P06493	UNIPROT	PDCD1	protein	Q15116	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser261	PSGMGTSsPARRGSA	9606	BTO:0000007								36104103	t		miannu	We demonstrated that cyclin-dependent kinase 1-mediated phosphorylation of Ser261 residue primes PD-1 protein nucleus translocation and binding with FBW7.	SIGNOR-277605	0.2
IFNB1	protein	P01574	UNIPROT	MGMT	protein	P16455	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000711								17564708	f		miannu	 we observed that IFN-beta sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via induction of TP53. In this context, IFN-beta inactivates MGMT via p53 gene induction and enhances the therapeutic efficacy to TMZ.	SIGNOR-255438	0.365
NFIB	protein	O00712	UNIPROT	GAS6	protein	Q14393	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268882	0.2
KDM6A	protein	O15550	UNIPROT	SPI1	protein	P17947	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									29736013	t		miannu	Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase	SIGNOR-260036	0.255
CDK1	protein	P06493	UNIPROT	SLBP	protein	Q14493	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr62	RRPESFTtPEGPKPR	9606									18490441	t		lperfetto	Phosphorylation of threonine 61 by cyclin a/Cdk1 triggers degradation of stem-loop binding protein at the end of S phase	SIGNOR-265258	0.428
NANOG	protein	Q9H9S0	UNIPROT	PAX6	protein	P26367	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003298								22795133	f		lperfetto	Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)	SIGNOR-253164	0.448
MSH6	protein	P52701	UNIPROT	BLM	protein	P54132	UNIPROT	up-regulates	binding			9606			SIGNOR-C60						15064730	t		miannu	We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro	SIGNOR-123705	0.618
MIB1	protein	Q86YT6	UNIPROT	JAG1	protein	P78504	UNIPROT	up-regulates activity	ubiquitination			9606		BTO:0001253							18043734	t		lperfetto	Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum.	SIGNOR-159480	0.68
FGG	protein	P02679	UNIPROT	Fibrinogen	complex	SIGNOR-C311	SIGNOR	form complex	binding			-1									25427968	t		lperfetto	Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively).	SIGNOR-263393	0.75
IKBKE	protein	Q14164	UNIPROT	IRF1	protein	P10914	UNIPROT	down-regulates activity	phosphorylation	Ser221	VSPMPSTsEATTDED	9606	BTO:0000007								24396068	t		miannu	We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity. 	SIGNOR-276479	0.357
PSMD7	protein	P51665	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263349	0.902
SIRT3	protein	Q9NTG7	UNIPROT	CYP11A1	protein	P05108	UNIPROT	up-regulates quantity by stabilization	deacetylation	Lys149	KKSAAWKkDRVALNQ	9606	BTO:0002588								22585829	t		lperfetto	Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.|Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis.	SIGNOR-268718	0.2
EGFR	protein	P00533	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates	phosphorylation	Tyr4	yTVVYFPV	9606	BTO:0000150								19254954	t		llicata	Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly,	SIGNOR-184383	0.448
SRC	protein	P12931	UNIPROT	PRKCI	protein	P41743	UNIPROT	up-regulates	phosphorylation	Tyr334	RLFFVIEyVNGGDLM	9606									11713277	t		llicata	Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain.	SIGNOR-111928	0.512
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CDK4	protein	P11802	UNIPROT	down-regulates activity	chemical inhibition			-1									29901072	t		miannu	AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9.	SIGNOR-262221	0.8
PKI-402	chemical	CID:44187953	PUBCHEM	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206250	0.8
PKI-402	chemical	CID:44187953	PUBCHEM	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206256	0.8
SPI1	protein	P17947	UNIPROT	NAB2	protein	Q15742	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									16923394	f		miannu	PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation	SIGNOR-256039	0.312
CDK2	protein	P24941	UNIPROT	RUNX1	protein	Q01196	UNIPROT	down-regulates activity	phosphorylation	Ser276	VHPATPIsPGRASGM	9606			SIGNOR-C83						17015473	t	The effect has been demonstrated using Q01196-8	gcesareni	Previous studies have shown that phosphorylation of aml1, particularly at serines 276 and 303, affects its transcriptional activation. Here, we report that phosphorylation of aml1 serines 276 and 303 can be blocked in vivo by inhibitors of the cyclin-dependent kinases (cdks) cdk1 and cdk2. Furthermore, these residues can be phosphorylated in vitro by purified cdk1/cyclin b and cdk2/cyclin a.	SIGNOR-149976	0.2
GRIA1	protein	P42261	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								30825796	f		miannu	In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses	SIGNOR-264615	0.7
ECM	stimulus	SIGNOR-ST20	SIGNOR	A10/b1 integrin	complex	SIGNOR-C167	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259049	0.7
PSMA5	protein	P28066	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263364	0.863
CSNK2A2	protein	P19784	UNIPROT	CDC37	protein	Q16543	UNIPROT	up-regulates activity	phosphorylation	Ser13	VWDHIEVsDDEDETH	-1									12930845	t		llicata	Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. | In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site. 	SIGNOR-250982	0.503
MYC	protein	P01106	UNIPROT	PFK	proteinfamily	SIGNOR-PF79	SIGNOR	up-regulates quantity by expression	transcriptional regulation			10116									10823814	t			C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.	SIGNOR-267587	0.337
IL20	protein	Q9NYY1	UNIPROT	IL22RA1	protein	Q8N6P7	UNIPROT	up-regulates	binding			9606									11163236	t		gcesareni	An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis.	SIGNOR-151877	0.59
APOBEC3C	protein	Q9NRW3	UNIPROT	Clearance_of_foreign intracellular_DNA	phenotype	SIGNOR-PH132	SIGNOR	up-regulates				9606									29367246	f		lperfetto	The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24).	SIGNOR-261326	0.7
MXD1	protein	Q05195	UNIPROT	UBTF	protein	P17480	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000539								15282543	t		lperfetto	MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter. 	SIGNOR-269646	0.368
CSNK1A1	protein	P48729	UNIPROT	OSBP2	protein	Q969R2	UNIPROT	up-regulates activity	phosphorylation												30925160	t		lperfetto	CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.	SIGNOR-264877	0.2
JAK2	protein	O60674	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates activity	phosphorylation	Tyr341	GQRDSSYyWEIEASE	10090	BTO:0001482								8876196	t			 JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process.	SIGNOR-251362	0.6
CTH	protein	P32929	UNIPROT	pyruvate	smallmolecule	CHEBI:15361	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000671;BTO:0000759;BTO:0002688							19961860	t		lperfetto	 the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production.	SIGNOR-275820	0.8
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR2A	protein	P28223	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264293	0.8
PRKCE	protein	Q02156	UNIPROT	TRPV1	protein	Q8NER1	UNIPROT	up-regulates activity	phosphorylation	Ser821	YLRQFSGsLKPEDAE	9534	BTO:0000298								14523239	t		lperfetto	We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. 	SIGNOR-249233	0.2
4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one	chemical	CHEBI:94732	ChEBI	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	down-regulates	chemical inhibition			9606									18922779	t	inferred from 70% of family members	gcesareni	Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell.	SIGNOR-269884	0.8
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	Arg-tRNA(Arg)	smallmolecule	CHEBI:18366	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270366	0.8
AKT2	protein	P31751	UNIPROT	GSK3A	protein	P49840	UNIPROT	down-regulates	phosphorylation			9606									16023596	t		gcesareni	Activated pi3k/akt pathway results in inhibitory phosphorylation of gsk3	SIGNOR-138179	0.538
CUL4A	protein	Q13619	UNIPROT	ARIH1	protein	Q9Y4X5	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								24076655	t		miannu	Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin.	SIGNOR-268847	0.284
TFEB	protein	P19484	UNIPROT	HPS3	protein	Q969F9	UNIPROT	up-regulates quantity by expression	transcriptional regulation												32978159	f		lperfetto	Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14)	SIGNOR-276794	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser362	AAAHRKGsSSNEPSS	9606									8248197	t		gcesareni	We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling.	SIGNOR-252789	0.2
PPP1CC	protein	P36873	UNIPROT	IKZF1	protein	Q13422	UNIPROT	up-regulates	dephosphorylation			9606									21750978	t		miannu	Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway	SIGNOR-174865	0.336
MAPK1	protein	P28482	UNIPROT	NR5A1	protein	Q13285	UNIPROT	up-regulates activity	phosphorylation	Ser203	EYPEPYAsPPQPGLP	9534	BTO:0004055								10230405	t		lperfetto	Here we show that maximal SF-1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (Ser-203) located in a major activation domain (AF-1) of the protein. Moreover, phosphorylation-dependent SF-1 activation is likely mediated by the mitogen-activated protein kinase (MAPK) signaling pathway.	SIGNOR-249431	0.475
Cytoplasmic_Dynein	proteinfamily	SIGNOR-PF67	SIGNOR	Spindle_assembly	phenotype	SIGNOR-PH60	SIGNOR	up-regulates													16440056	f		lperfetto	The most abundant cytoplasmic dynein complex, cytoplasmic dynein 1, is involved in functions as diverse as spindle-pole organization and nuclear migration during mitosis, the positioning and functioning of the endoplasmic reticulum, the Golgi apparatus, and the nucleus, and also the minus-end-directed transport of vesicles, including endosomes and lysosomes, along microtubules and retrograde axonal transport in neurons.	SIGNOR-265059	0.7
ITGB1BP1	protein	O14713	UNIPROT	A3/b1 integrin	complex	SIGNOR-C161	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257641	0.757
MAPK8	protein	P45983	UNIPROT	NFE2	protein	Q16621	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser157	LNYSDAEsLELEGTE										19966288	t		lperfetto	Through use of different approaches including nano-scale proteomics, we show that activated-JNK, or Phospho-JNK (P-JNK), physically interacts with p45/NF-E2 and phosphorylates its Ser157 residue. This reaction leads to the poly-ubiquitination of p45/NF-E2 at one or more of six Lys residues, one of which being also a sumoylation site, and its degradation through the proteasome pathway. 	SIGNOR-275552	0.42
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser255	ELSPTTLsPVNHSLD	9606									19115199	t		gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-182996	0.739
CDC25C	protein	P30307	UNIPROT	CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	up-regulates activity	dephosphorylation	Tyr15	EKIGEGTyGVVYKGR	9606	BTO:0001938								10913154	t		lperfetto	Cyclin B-Cdc2 complexes are maintained in an inactive state until the end of G2 by phosphorylation of the Thr14/Tyr15 residues. Around the time of nuclear translocation of the complex, these residues are dephosphorylated, resulting in the formation of an active cyclin B-Cdc2 complex (2). As mentioned, this dephosphorylation occurs by a Cdc25 protein phosphatase. Three Cdc25 family members have been identified to date, A, B and C, the last one being the active one at the onset of mitosis. The activity of Cdc25C itself can be enhanced through phosphorylation by cyclin B-Cdc2 (9, 10). Therefore, activation of cyclin B-Cdc2 has been proposed to result in an autocatalytic feedback loop to ensure rapid activation of these complexes at the G2/M transition	SIGNOR-255037	0.839
ADORA1	protein	P30542	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256697	0.434
AMPK	complex	SIGNOR-C15	SIGNOR	MTOR	protein	P42345	UNIPROT	down-regulates activity				9606									30274374	f		miannu	AMPK inhibits the mTOR pathway through phosphorylation and activation of tuberous sclerosis protein 2 (TSC2) and causes direct activation of unc-51-like autophagy activating kinase 1 (ULK1) via phosphorylation of Ser555, thus promoting initiation of autophagy.	SIGNOR-260096	0.549
ILK	protein	Q13418	UNIPROT	PPP1R12A	protein	O14974	UNIPROT	down-regulates	phosphorylation	Thr710	DLQEAEKtIGRSRST	9606									12030846	t		lperfetto	Mypt1 was phosphorylated by ilk and phosphorylation sites in the n- and c-terminal fragments of mypt1 were detected. From sequence analyses, three sites were identified: a primary site at thr(709), and two other sites at thr(695) and thr(495). phosphorylation of the various sites indicated that thr695 was the major inhibitory site, thr709 had only a slight inhibitory effect	SIGNOR-87928	0.566
RAP1B	protein	P61224	UNIPROT	AL/b2 integrin	complex	SIGNOR-C169	SIGNOR	up-regulates activity	binding			10090	BTO:0003104								12808052	t		lperfetto	The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity.	SIGNOR-253363	0.42
SMAD8/SMAD4	complex	SIGNOR-C206	SIGNOR	RUNX2	protein	Q13950	UNIPROT	up-regulates	transcriptional regulation			9606									27563484	f		ggiuliani	Smad1/5/8-Smad4 complex transcribed Runx2 expression, as they complex with Runx2 to initiate other osteoblast gene expression.	SIGNOR-255784	0.477
MAPK8	protein	P45983	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity	phosphorylation	Ser87	AAAGPALsPVPPVVH	9606									18570871	t		gcesareni	Jnk1-mediated phosphorylation of bcl-2 regulates starvation-induced autophagy.	SIGNOR-179092	0.564
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	IDH1	protein	O75874	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr157	GKVEITYtPSDGTQK										34929314	t		lperfetto	During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome	SIGNOR-267621	0.273
CHEK1	protein	O14757	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser378	SKKGQSTsRHKKLMF	9606									15659650	t		lperfetto	Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage.	SIGNOR-217857	0.772
PRKCB	protein	P05771	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Thr373	TVLVKDStNRDSLDM	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-129296	0.289
FCER1	complex	SIGNOR-C200	SIGNOR	SRC_kinase_family	proteinfamily	SIGNOR-PF32	SIGNOR	up-regulates				9606	BTO:0000830								16470226	f		Alessandro Palma	It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits	SIGNOR-254963	0.593
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	MYBL2	protein	P10244	UNIPROT	up-regulates	phosphorylation	Thr494	TPLHRDKtPLHQKHA	9606									9840932	t		lperfetto	The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk4	SIGNOR-217264	0.708
CDK1	protein	P06493	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Ser214	SRSGLYRsPSMPENL	9606									8119945	t		gcesareni	Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity.	SIGNOR-36267	0.853
AMPK	complex	SIGNOR-C15	SIGNOR	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Thr101	IVLNKGKtIFRFSAT	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275769	0.325
YAP/TAZ	proteinfamily	SIGNOR-PF120	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606									23075495	f		miannu	YAP and TAZ are two main downstream effectors of the Hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis.	SIGNOR-277639	0.7
SMO	protein	Q99835	UNIPROT	MBP	protein	P02686	UNIPROT	up-regulates quantity	transcriptional regulation			10090									35082605	f	Non-canonical pathway (Gli1-indipendent): SMO/AMPK	SimoneGraziosi	We show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMPactivated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell.	SIGNOR-269226	0.2
CDK1	protein	P06493	UNIPROT	WAC	protein	Q9BTA9	UNIPROT	up-regulates activity	phosphorylation	Thr471	PIKPLIStPPVSSQP	9606	BTO:0000567								30021153	t		lperfetto	Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. 	SIGNOR-265034	0.2
MEF2D	protein	Q14814	UNIPROT	MYF6	protein	P23409	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165;BTO:0000222								7739551	t		lperfetto	Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis.	SIGNOR-238715	0.555
G3BP1	protein	Q13283	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates activity	binding			9606									25520508	t		miannu	We show that G3BP1 can activate effectors of the innate immune transcriptional program, culminating in enhanced expression of a set of cytokines. We demonstrate that a subset of PKR is recruited to SGs, that close-proximity interactions between G3BP1 and PKR complexes increase in response to stress and PKR activation, that once activated PKR no longer associates with SGs, and that the PXXP domain of G3BP1 is essential for PKR recruitment to SGs and PKR activation in cells. Together, these findings suggest that G3BP1 plays an important role in the recruitment of PKR to SGs and suggest that activation of PKR can take place at the SG. 	SIGNOR-260750	0.312
LIMS2	protein	Q7Z4I7	UNIPROT	IPP complex	complex	SIGNOR-C380	SIGNOR	form complex	binding												16493410	t		lperfetto	Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton.	SIGNOR-265764	0.649
dexmedetomidine	chemical	CHEBI:4466	ChEBI	ADRA2C	protein	P18825	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258908	0.8
CRH	protein	P06850	UNIPROT	CRHR2	protein	Q13324	UNIPROT	up-regulates activity	binding			9606									23504413	t		lperfetto	The actions of CRH are transduced through CRH receptors, which belong to the class II/secretin-like family of the G-protein coupled receptor (GPCR) superfamily (Martin et al. 2005). There are three types of CRH receptors – type 1 (CRHR1), type 2 (CRHR2) and type 3 (CRHR3). Among these, CRHR3 has not been identified in mammals. |CRH is a high-affinity ligand of CRHR1. It also binds to CRHR2, but with lower affinity	SIGNOR-268611	0.915
LMO2	protein	P25791	UNIPROT	TAL1	protein	P17542	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271								9020185	t		miannu	Transcriptional activity of tal1 in t cell acute lymphoblastic leukemia (t-all) requires rbtn1 or -2	SIGNOR-46161	0.923
SRC	protein	P12931	UNIPROT	CTTN	protein	Q14247	UNIPROT	down-regulates	phosphorylation	Tyr470	AYATEAVyESAEAPG	9606									12601080	t		lperfetto	Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity	SIGNOR-98716	0.795
PRKCD	protein	Q05655	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates activity	phosphorylation	Thr790	TRNDVAPtLMSVPRY	10029									27203386	t		Manara	Phosphorylation of E-cadherin at threonine 790 by protein kinase Cδ reduces β-catenin binding and suppresses the function of E-cadherin.	SIGNOR-260893	0.2
CDC25B	protein	P30305	UNIPROT	CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	up-regulates	dephosphorylation			9606									7880537	t		lperfetto	Cdc25 dephosphorylates cdc2/cdk1 within the activation loop of the kinase domain to achieve full activity of the cyclin-cdk complex	SIGNOR-217511	0.759
ERC1	protein	Q8IUD2	UNIPROT	CHUK	protein	O15111	UNIPROT	up-regulates	binding			9606				SIGNOR-C14					15218148	t		miannu	Elks likely functions by recruiting ikappabalpha to the ikk complex and thus serves a regulatory function for ikk activation.	SIGNOR-126430	0.573
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1735	SPTSPSYsPTSPSYS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248755	0.727
ADAM17	protein	P78536	UNIPROT	GP1BA	protein	P07359	UNIPROT	down-regulates activity	cleavage	Val466	ATSPTILvSATSLIT	9606	BTO:0000132								25297919	t		lperfetto	GPIbα is shed by metalloproteases such as ADAM17, a process that releases a soluble GPIbα fragment termed glycocalicin. ADAM17 cleaves within the GPIbα-based peptide (LRGV465LK) through a mechanism that is only partially understood [42]. GPIbα shedding has been shown to be constitutive but it can be increased by activation of protein kinases C (PKC) or inhibition of calmodulin [42, 43]. Shedding leads to decreased receptor density	SIGNOR-261861	0.288
CRP	protein	P02741	UNIPROT	CXCL8	protein	P10145	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004910								26961257	f		miannu	In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained.	SIGNOR-252143	0.492
atenolol	chemical	CHEBI:2904	ChEBI	ADRB2	protein	P07550	UNIPROT	down-regulates activity	chemical inhibition			10030	BTO:0000246								10079020	t		Luana	In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue	SIGNOR-258335	0.8
lisinopril	chemical	CHEBI:43755	ChEBI	ACE	protein	P12821	UNIPROT	down-regulates activity	chemical inhibition			-1									9187274	t		miannu	We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range.	SIGNOR-258611	0.8
SF3B4	protein	Q15427	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270666	0.764
MTOR	protein	P42345	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606			SIGNOR-C2						21157483	t		lperfetto	Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism	SIGNOR-170604	0.928
TNF	protein	P01375	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32446778	f	doi: 10.1016/j.cytogfr.2020.05.003 	miannu	Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α)	SIGNOR-260856	0.52
PRKCH	protein	P24723	UNIPROT	PTPN7	protein	P35236	UNIPROT	up-regulates activity	phosphorylation	Ser246	QYQEERRsVKHILFS	-1									16479000	t		miannu	HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. 	SIGNOR-276049	0.2
PLK4	protein	O00444	UNIPROT	TUBGCP6	protein	Q96RT7	UNIPROT	up-regulates activity	phosphorylation	Ser1465	PVDPQVQsAADETAV	-1									22302995	t		miannu	Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication.	SIGNOR-262908	0.691
BRAP	protein	Q7Z569	UNIPROT	BRAP	protein	Q7Z569	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								23105109	t		miannu	Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. 	SIGNOR-272027	0.2
STUB1	protein	Q9UNE7	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								14701756	t		miannu	CHIP mediates the ubiquitination of Smad1. we demonstrate that the coexpression of Smad1 and Smad4 with the CHIP protein results in the degradation of the Smad proteins through a ubiquitin-mediated process. 	SIGNOR-272948	0.334
NUP214	protein	P35658	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates	binding			9606				SIGNOR-C9					12917407	t		gcesareni	We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import.	SIGNOR-117644	0.531
coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	acyl-CoA(4-)	chemical	CHEBI:58342	ChEBI	up-regulates quantity	precursor of			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272769	0.8
SGK1	protein	O00141	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates	binding			9606									25790864	t		gcesareni	SGK1 is known to inhibit another intrinsic pathway, the Hedgehog pathway, through downregulation of SMO and the GLI transcription factor family	SIGNOR-251672	0.2
AKT2	protein	P31751	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates	phosphorylation	Ser428	GPQRERKsSSSSEDR	9606									10869359	t		gcesareni	We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf	SIGNOR-78685	0.276
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	up-regulates	phosphorylation			9606									12270934	t	inferred from 70% of family members	lperfetto	Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis.	SIGNOR-269913	0.2
NR4A1	protein	P22736	UNIPROT	HSD3B2	protein	P26439	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0005761								15666793	f		miannu	Herein we discuss the evidence that suggests a role for NURR1 (NR4A2) in the expression of CYP11B2 in the glomerulosa as well as in the dysregulation of CYP11B2 gene expression as is seen in aldosterone-producing adenoma (APA), a major cause of endocrine hypertension. NURR1 appears to be important for CYP11B2 transcription and is found at higher levels in glomerulosa and in APA.	SIGNOR-254866	0.373
NLRX1	protein	Q86UT6	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates activity	relocalization			9606	BTO:0002181								18219313	f		lperfetto	NLRX1 synergistically potentiated ROS production induced by tumour necrosis factor alpha, Shigella infection and double-stranded RNA, resulting in amplified NF-kappaB-dependent and JUN amino-terminal kinases-dependent signalling. We observed that NLRX1-positive cells showed increased p65 translocation as early as 15 min after infection, an effect that was maintained over time.	SIGNOR-260399	0.274
SEC63	protein	Q9UGP8	UNIPROT	SEC62	protein	Q99442	UNIPROT	up-regulates activity	binding			9606	BTO:0000599								23287549	t		lperfetto	Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62.	SIGNOR-265273	0.959
Host translation inhibitor nsp1	protein	P0C6X7-PRO_0000037309	UNIPROT	STAT1	protein	P42224	UNIPROT	down-regulates activity				9606	BTO:0000007								17715225	f		miannu	We mapped a strong inhibitory activity to SARS-CoV nonstructural protein 1 (nsp1) and show that expression of nsp1 significantly inhibited the activation of all three virus-dependent signaling pathways. We show that expression of nsp1 significantly inhibited IFN-dependent signaling by decreasing the phosphorylation levels of STAT1 while having little effect on those of STAT2, JAK1, and TYK2.	SIGNOR-262502	0.2
SREBF1	protein	P36956	UNIPROT	ELOVL	proteinfamily	SIGNOR-PF93	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								18226595	t		Luana	These data demonstrated that Elovl-6 is regulated directly and primarily by SREBP-1c.	SIGNOR-267944	0.466
ATP2A1	protein	O14983	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	down-regulates quantity	relocalization			9986									28487373	t		lperfetto	SERCA1, the sarco(endo)plasmic reticulum Ca2+-ATPase of skeletal muscle, is essential for muscle relaxation and maintenance of low resting Ca2+ levels in the myoplasm.	SIGNOR-265928	0.8
STK4	protein	Q13043	UNIPROT	SAV1	protein	Q9H4B6	UNIPROT	up-regulates				-1									16930133	t		lperfetto	In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav	SIGNOR-217833	0.882
YAP1	protein	P46937	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	up-regulates quantity by expression	transcriptional regulation					BTO:0001939							30224758	f		lperfetto	 By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 	SIGNOR-276565	0.2
ROCK1	protein	Q13464	UNIPROT	ARHGAP24	protein	Q8N264	UNIPROT	up-regulates activity	phosphorylation	Ser437	SGIVTNGsFSSSNAE	9606	BTO:0000007								16862148	t		lperfetto	ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2).	SIGNOR-249305	0.444
PRKCA	protein	P17252	UNIPROT	ADD1	protein	P35611	UNIPROT	up-regulates	phosphorylation	Ser726	KKKFRTPsFLKKSKK	9606	BTO:0000938	BTO:0000671							9679146	t		gcesareni	These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc.	SIGNOR-59229	0.2
PRKAA1	protein	Q13131	UNIPROT	GFPT1	protein	Q06210	UNIPROT	up-regulates	phosphorylation	Ser261	CNLSRVDsTTCLFPV	9606									17941647	t		gcesareni	Amp-activated protein kinase and calcium/calmodulin-dependent kinase ii were identified to phosphorylate specifically ser243 in vitro. Phosphorylation by these two kinases results in an increase of enzymatic activity by 1.4-fold. These findings suggest for the first time that hgfat1 may be regulated by kinases other than pka.	SIGNOR-158490	0.2
EEF1A1	protein	P68104	UNIPROT	His-tRNA(His)	smallmolecule	CHEBI:29155	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269511	0.8
NLGN1	protein	Q8N2Q7	UNIPROT	NRXN1	protein	Q9ULB1	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264144	0.835
SRC	protein	P12931	UNIPROT	GLO1	protein	Q04760	UNIPROT	up-regulates activity	phosphorylation	Tyr136	GIAVPDVySACKRFE	-1									34838714	t		miannu	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276189	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	ALOX5	protein	P09917	UNIPROT	up-regulates activity	phosphorylation	Ser272	CSLERQLsLEQEVQQ	9606	BTO:0000567								18978352	t		lperfetto	Phosphorylation of serine 271 on 5-lipoxygenase and its role in nuclear export|We report here that 5-LO is constitutively phosphorylated on Ser-271 in transfected NIH 3T3 cells. This residue is nested in a classical nuclear export sequence, and phosphorylated Ser-271 5-LO was exclusively found in the nucleus by immunofluorescence and by fractionation techniques|Nuclear export of 5-LO can also be induced by KN-93, an inhibitor of Ca2+/calmodulin-dependent kinase II, and the effects of SB 203,580 plus KN-93 are additive. Finally, HeLa cells, which lack nuclear 5-LO, also lack constitutive phosphorylation of Ser-271. Taken together, these results indicate that the phosphorylation of Ser-271 serves to inhibit the nuclear export of 5-LO.	SIGNOR-264408	0.2
TAOK3	protein	Q9H2K8	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	up-regulates	phosphorylation			9606									23431053	t	inferred from 70% of family members	gcesareni	In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2	SIGNOR-269949	0.295
ANXA1	protein	P04083	UNIPROT	FPR1	protein	P21462	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								15187149	t			We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2.	SIGNOR-259439	0.734
HIF1A	protein	Q16665	UNIPROT	EPO	protein	P01588	UNIPROT	up-regulates quantity by expression	transcriptional regulation												8663540	t	 	lperfetto	Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor that regulates hypoxia-inducible genes including the human erythropoietin (EPO) gene.	SIGNOR-253695	0.63
romidepsin	chemical	CHEBI:61080	ChEBI	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257992	0.8
IFNL1	protein	Q8IU54	UNIPROT	IL10RB	protein	Q08334	UNIPROT	up-regulates	binding			9606									12469119	t		gcesareni	Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.	SIGNOR-96177	0.6
TPP1	protein	O14773	UNIPROT	Telomere_maintenance	phenotype	SIGNOR-PH148	SIGNOR	up-regulates				9606									22101936	f		miannu	The mammalian shelterin component TPP1 has essential roles in telomere maintenance and, together with POT1, is required for the repression of DNA damage signaling at telomeres. 	SIGNOR-272723	0.7
mesulergine	chemical	CHEBI:73378	ChEBI	HTR2B	protein	P41595	UNIPROT	down-regulates activity	chemical inhibition			10036	BTO:0000452								9459568	t		miannu	The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-	SIGNOR-258686	0.8
TNK2	protein	Q07912	UNIPROT	TNK2	protein	Q07912	UNIPROT	up-regulates	phosphorylation	Tyr284	LPQNDDHyVMQEHRK	9606									14506255	t		llicata	Purified ack1 undergoes autophosphorylation, and autophosphorylation enhances kinase activity. We identified tyr284 in the activation loop of ack1 as the primary autophosphorylation site using mass spectrometry.	SIGNOR-118201	0.2
AM/b2 integrin	complex	SIGNOR-C170	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257713	0.459
reserpine	chemical	CHEBI:28487	ChEBI	SLC18A2	protein	Q05940	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000318								8643547	t		miannu	Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2.	SIGNOR-258490	0.8
CDK12	protein	Q9NYV4	UNIPROT	CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	form complex	binding			9606									22012619	t		miannu	We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells	SIGNOR-176789	0.941
ATM	protein	Q13315	UNIPROT	DCLRE1C	protein	Q96SD1	UNIPROT	up-regulates	phosphorylation	Ser503	NDEITDEsLENFPSS	9606									16874298	t		lperfetto	The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo	SIGNOR-148315	0.603
NFIX	protein	Q14938	UNIPROT	ROBO1	protein	Q9Y6N7	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268907	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation			10090	BTO:0002572								18423396	t		lperfetto	Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation	SIGNOR-252350	0.2
bosutinib	chemical	CHEBI:39112	ChEBI	SRC	protein	P12931	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258089	0.8
PTPN6	protein	P29350	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	dephosphorylation	Tyr530	FTSTEPQyQPGENL	9606									9261115	t			To determine whether the COOH-terminal or other phosphotyrosine residues within Src are subject to dephosphorylation by SHP-1, the effects of this phosphatase on Src tyrosine phosphorylation were initially examined using CNBr cleavage analysis. As illustrated in Fig.1 A, CNBr treatment of 32P-labeled human Src has been shown previously to yield phosphorylated cleavage fragments of about 31, 9.7, and 4.7 kDa, which, respectively, contain the Src NH2-terminal region encompassing the major sites for serine phosphorylation on Src, Ser-12 and Ser-17 (31-kDa fragment), the inhibitory tyrosine phosphorylation site, Tyr-530 (4.7-kDa fragment), and a key site for autophosphorylation on activated Src, Tyr-419 [} These observations, together with the finding of reduced Src activity in HEY cells expressing a dominant negative form of SHP-1, provide compelling evidence that SHP-1 functions include the positive regulation of Src activation. 	SIGNOR-248473	0.543
TRPV4	protein	Q9HBA0	UNIPROT	UCP1	protein	P25874	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000443								23021218	f		lperfetto	TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance.	SIGNOR-253096	0.291
SKP2	protein	Q13309	UNIPROT	DAB2IP	protein	Q5VWQ8	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									27858941	t		miannu	DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1	SIGNOR-254775	0.271
LRRK2	protein	Q5S007	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0000938								21658387	t		lperfetto	A knockdown experiment using intact cells also demonstrated LRRK2-mediated phosphorylation of Akt1 (Ser473), suggesting that Akt1 is a convincing candidate for the physiological substrate of LRRK2.	SIGNOR-174044	0.387
FBXW7	protein	Q969H0	UNIPROT	EGLN2	protein	Q96KS0	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								28036276	t		lperfetto	Mechanistically, we further show that FBW7, an E3 ligase complex component that is frequently downregulated in TNBC, negatively regulates EglN2 protein stability.	SIGNOR-261997	0.355
RARA	protein	P10276	UNIPROT	THRA	protein	P10827	UNIPROT	up-regulates	binding			9606									15650024	t		gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-133231	0.407
naratriptan	chemical	CHEBI:7478	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000567								10193663	t		Luana	This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues 	SIGNOR-258338	0.8
CAP1	protein	Q01518	UNIPROT	PTK2	protein	Q05397	UNIPROT	down-regulates activity				9606	BTO:0000567								30894654	f		lperfetto	In HeLa and metastatic breast cancer cells, depletion of CAP1 leads to activation of FAK and enhanced cell adhesion	SIGNOR-264824	0.2
GSK3B	protein	P49841	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Thr41	GIHSGATtTAPSLSG	9606	BTO:0000938	BTO:0000142	SIGNOR-C110						19303846	t		gcesareni	DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin.	SIGNOR-184789	0.856
PCM1	protein	Q15154	UNIPROT	CETN1	protein	Q12798	UNIPROT	up-regulates	relocalization			9606									12403812	t		miannu	Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome	SIGNOR-94947	0.418
PDXP	protein	Q96GD0	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates activity	dephosphorylation	Ser166	SSRRRAIsETEENSD	9606									33414453	t		miannu	Considering the roles of NF2 in actin dynamics and Mdm2 regulation  - , , , it is noteworthy to elucidate whether interaction of PLPP and CIN with NF2 modulates actin dynamics and Mdm2 degradation in neuronal excitability.|Recently, we have reported that PLPP and CIN dephosphorylates Mdm2 at S166 site in activity dependent manners, which inhibits Mdm2 mediated PSD95 degradation by facilitating Mdm2 ubiquitination 38.	SIGNOR-277151	0.2
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	PALB2	protein	Q86YC2	UNIPROT	up-regulates activity				9606	BTO:0001938								19369211	f		lperfetto	Consistent with the converging functions of the BRCA proteins in DNA repair, cells harboring mutations with abrogated BRCA1-PALB2 interaction resulted in defective homologous recombination (HR) repair. We propose that, via its direct interaction with PALB2, BRCA1 fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Our findings uncover PALB2 as the molecular adaptor between the BRCA proteins, and suggest that impaired HR repair is one of the fundamental causes for genomic instability and tumorigenesis observed in patients carrying BRCA1, BRCA2, or PALB2 mutations.	SIGNOR-244490	0.7
FBXW11	protein	Q9UKB1	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	ubiquitination			9606									14988407	t		gcesareni	We have identified scf(beta-trcp1), a ubiquitin (e3) ligase, as a critical determinant for the protein degradation of smad4 protein.	SIGNOR-123060	0.2
PLPPR1	protein	Q8TBJ4	UNIPROT	RASGEF1B	protein	Q0VAM2	UNIPROT	up-regulates activity	binding			9606									27058420	t		miannu	Oncogenic effects of imbalanced PRG3 are mediated via PRG3-RasGEF1 interaction and Ras activation. PRG3 interacts with RasGEF1 in vivo.We could further show that PRG3 executes the binding to RasGEF1 predominantly via its C-terminal domain (CT) and in the consequence causes Ras activation.	SIGNOR-261806	0.2
TFEB	protein	P19484	UNIPROT	IL24	protein	Q13007	UNIPROT	up-regulates quantity by expression	transcriptional regulation												32978159	f		lperfetto	Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14)	SIGNOR-276797	0.2
CDK5	protein	Q00535	UNIPROT	TRIM59	protein	Q8IWR1	UNIPROT	up-regulates activity	phosphorylation	Ser308	LIPKMKIsPKRMSCS										31488827	t		miannu	 Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis-trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation.	SIGNOR-272929	0.2
NPFFR2	protein	Q9Y5X5	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256709	0.252
dibutyl phthalate	chemical	CHEBI:535597	ChEBI	PPARA	protein	Q07869	UNIPROT	up-regulates activity	chemical activation			10116									33508418	t		miannu	Both in vitro and in vivo experiments have proved that DBP is a real activator of PPARα. he current study proves that plasticizer DBP has severe hepatotoxicity and could induce liver dysfunction even at normal doses after prolonged exposure. DBP might accumulate in the liver for a long time to activate PPARα/SREBP-1c/FAS/GPAT/AMPK and result in the accumulation of triglycerides and cholesterol in the liver.	SIGNOR-268748	0.8
SRC	protein	P12931	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr126	AKSVTCTySPALNKM	9606	BTO:0002181								25071020	t		miannu	We recently found that ISGylation of the p53 tumor suppressor is an important novel mechanism to control its stability. Here we identified that Isg15-dependent regulation of p53 can be enhanced by different oncogenes. We further show that the Src-mediated phosphorylation of p53 on Tyr126 and Tyr220 has a positive effect on p53 ISGylation by enhancing Herc5 binding.	SIGNOR-276668	0.54
SRC	protein	P12931	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates activity	phosphorylation	Tyr315	RADNDKEyLVLTLTK	9606	BTO:0002035								11948419	t		miannu	MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e).	SIGNOR-275981	0.554
MAPK11	protein	Q15759	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates	phosphorylation	Thr581	PDNQPLKtPCFTLHY	9606	BTO:0000567								9687510	t		gcesareni	Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha	SIGNOR-59447	0.597
choline	smallmolecule	CHEBI:15354	ChEBI	choline phosphate(1-)	smallmolecule	CHEBI:295975	ChEBI	up-regulates quantity	precursor of												27149373	t		lperfetto	Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes	SIGNOR-275633	0.8
KDM6A	protein	O15550	UNIPROT	HOXA7	protein	P31268	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24561908	t		miannu	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260024	0.278
EDNRA	protein	P25101	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001260							15475516	t		gcesareni	The response to endothelin-1 (et-1) consisted of two phases in both cell types. The initial, transient phase of contraction and phosphorylation of 20-kda myosin light chain (mlc20) was mediated additively by eta and etb receptors and initiated by galphaq-, ca2+/calmodulin-dependent activation of mlc kinase.	SIGNOR-129817	0.523
PTPN2	protein	P17706	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates activity	dephosphorylation	Tyr487	SLSNIDFyAQVSDIT	10029	BTO:0000246								12907755	t			PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 	SIGNOR-248392	0.298
clofarabine	chemical	CHEBI:681569	ChEBI	POLG2	protein	Q9UHN1	UNIPROT	down-regulates activity	chemical inhibition			9606									1707752	t		miannu	Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase.	SIGNOR-258362	0.8
JAK2	protein	O60674	UNIPROT	CTLA4	protein	P16410	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr201	SPLTTGVyVKMPPTE	9606									10842319	t			Janus Kinase 2 (Jak2) was directly associated with a box 1-like motif in the cytoplasmic tail of CTLA-4 molecule. Jak2 phosphorylated Y-165 residue in the cytoplasmic region of CTLA-4. It has been reported that phosphorylation and dephosphorylation of tyrosine residue Y-165 in the cytoplasmic region of CTLA-4 play an important role in its negative signaling and cell surface expression. Some signaling molecules such as Src homology 2 protein tyrosine phosphatase 2 (SHP-2) and the p85 subunit of phosphatidylinositol 3 kinase (PI3 kinase) associate with phosphorylated tyrosine residue Y-165, through Src homology 2 (SH2) domains. On the other hand, the adapter complex proteins, AP-2 and AP-50 interact with the same tyrosine residue when unphosphorylated, resulting in clathrin-mediated endocytosis of CTLA-4 molecules.	SIGNOR-251346	0.456
CAMK2G	protein	Q13555	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser571	PWPLRRTsAQGQPSP	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275780	0.295
PPARA	protein	Q07869	UNIPROT	CPT1A	protein	P50416	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003204								17150915	f		miannu	 To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA.	SIGNOR-255047	0.616
FGF2	protein	P09038	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates				9606									20974802	f		gcesareni	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription	SIGNOR-168989	0.599
GRB10	protein	Q13322	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	binding			10090	BTO:0001516								23246379	t			Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation	SIGNOR-255945	0.411
ERCC4/ERCC1	complex	SIGNOR-C50	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				-1									10542278	f		miannu	HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay.	SIGNOR-259064	0.7
PRKCA	protein	P17252	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser9	STRSVSSsSYRRMFG	-1									2500966	t		lperfetto	We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65.	SIGNOR-248876	0.289
AKT3	protein	Q9Y243	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	up-regulates	phosphorylation	Ser387	SKLMRSAsFNTDPYV	9606									23603119	t		lperfetto	Phosphorylation of argonaute 2 at serine-387 facilitates its localization to processing bodies. , akt3-mediated phosphorylation of ago2 is a molecular switch between target mrna cleavage and translational repression activities of ago2	SIGNOR-201918	0.434
GSK3B	protein	P49841	UNIPROT	PDX1	protein	P52945	UNIPROT	down-regulates quantity	phosphorylation	Ser272	LSASPQPsSVAPRRP	10090	BTO:0002284								19833727	t			We show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose	SIGNOR-255567	0.2
CHD2	protein	O14647	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity	binding												29962935	t		miannu	CHD2 also showed an interaction with MyoD, a master regulator of skeletal muscle differentiation, and together MyoD and CHD2 bind to myogenic gene promoters.	SIGNOR-264525	0.2
BMP7	protein	P18075	UNIPROT	BMPR2	protein	Q13873	UNIPROT	up-regulates	binding			9606				SIGNOR-C29					7644468	t		acerquone	In transfected cos-1 cells, osteogenic protein (op)-1/bmp-7, and less efficiently bmp-4, bound to bmpr-ii. Bmpr-ii bound ligands only weakly alone, but the binding was facilitated by the presence of previously identified type i receptors for bmps. Binding of op-1/bmp-7 to bmpr-ii was also observed in nontransfected cell lines. Moreover, a transcriptional activation signal was transduced by bmpr-ii in the presence of type i receptors after stimulation by op-1/bmp-7.	SIGNOR-30512	0.797
FYN	protein	P06241	UNIPROT	GRIN2A	protein	Q12879	UNIPROT	up-regulates activity	phosphorylation	Tyr1267	PATGEQVyQQDWAQN	-1									10195142	t		lperfetto	To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain.	SIGNOR-247155	0.724
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	FERMT1	protein	Q9BQL6	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser179	TASGSSVsPGLYSKT	9606	BTO:0000567								35469017	t		miannu	 CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry.	SIGNOR-276721	0.2
PTN	protein	P21246	UNIPROT	ALK	protein	Q9UM73	UNIPROT	up-regulates	binding			9606									11278720	t		gcesareni	We conclude from this series of experiments that ptn specifically binds to the alk orphan receptor as a high affinity ligand at least in part via the putative ligand binding domain described above.	SIGNOR-106411	0.564
FEZF2	protein	Q8TBJ5	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates quantity by repression	transcriptional regulation												23677067	f		lperfetto	FEZF2, a novel 3p14 tumor suppressor gene, represses oncogene EZH2 and MDM2 expression and is frequently methylated in nasopharyngeal carcinoma.	SIGNOR-268974	0.2
PSTPIP1	protein	O43586	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates				9606									11163214	f		lperfetto	Cytoskeletal protein pstpip1 directs the pest-type protein tyrosine phosphatase to the c-abl kinase to mediate abl dephosphorylationSeveral experiments suggest that the PEST-type PTPs negatively regulate c-Abl activity	SIGNOR-105035	0.616
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	LCK	protein	P06239	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000567								8618896	t	inferred from 70% family members	lperfetto	Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation.	SIGNOR-270177	0.2
GSK3A	protein	P49840	UNIPROT	IL17RA	protein	Q96F46	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr780	MVLTDPHtPYEEEQR	9606	BTO:0000007								26871944	t		miannu	Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation. 	SIGNOR-277206	0.2
TNF	protein	P01375	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252285	0.7
TLN1	protein	Q9Y490	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257609	0.603
PLK1	protein	P53350	UNIPROT	CENPQ	protein	Q7L2Z9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser255	SSQMKSMsTFIEEAY	9606	BTO:0000567								25670858	t		lperfetto	Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 	SIGNOR-265226	0.57
IKBKE	protein	Q14164	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation	Ser151	VLPSSKRsPSTATLS	9606	BTO:0001061								31730483	t		miannu	Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 	SIGNOR-276778	0.2
TET1	protein	Q8NFU7	UNIPROT	SLIT2	protein	O94813	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27708339	t		irozzo	Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9.	SIGNOR-259093	0.2
MAPK14	protein	Q16539	UNIPROT	EZH2	protein	Q15910	UNIPROT	up-regulates activity	phosphorylation			9606				SIGNOR-C77					21902831	t		lperfetto	P38 can phosphorylate the histone-lysine n-methyltransferase ezh2, the catalytic subunit of the polycomb repressive complex 2 (prc2), with phosphorylation of ezh2 necessary for prc2s association with the transcriptional repressor yy1 and subsequent chromatin remodelling.	SIGNOR-176548	0.381
proline	smallmolecule	CHEBI:26271	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264744	0.7
CCKAR	protein	P32238	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256763	0.267
EGR1	protein	P18146	UNIPROT	FCER2	protein	P06734	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003076								9300687	f	 	 	Thus, Egr-1 seems to control the expression of downstream target genes not only as a transcriptional activator, but also as a repressor molecule. In B cells, Egr-1 therefore plays a critical role in integrating the short-lived signal delivered by triggering of the Ag receptor into phenotypic changes, including repression of CD95 and CD23 transcription.	SIGNOR-254277	0.2
PPP2CA	protein	P67775	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	dephosphorylation	Ser473	RPHFPQFsYSASGTA	10090	BTO:0000944								15367694	t			Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes	SIGNOR-252606	0.889
POLR2B	protein	P30876	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266162	0.871
CDK5	protein	Q00535	UNIPROT	AMPH	protein	P49418	UNIPROT	unknown	phosphorylation	Ser285	NHTLAPAsPAPARPR	-1									11113134	t		llicata	Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. 	SIGNOR-250650	0.537
MAPK15	protein	Q8TD08	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser73	VGLLKLAsPELERLI	9606									12169099	t		gcesareni	Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation.	SIGNOR-91375	0.44
ARID5B	protein	Q14865	UNIPROT	GATA3	protein	P23771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									29326336	f		miannu	We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F).	SIGNOR-256158	0.341
ROCK1	protein	Q13464	UNIPROT	FHOD1	protein	Q9Y613	UNIPROT	up-regulates	phosphorylation	Thr1141	NRKSLRRtLKSGLGD	9606									18239683	t		lperfetto	Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres.	SIGNOR-160552	0.315
GGCX	protein	P38435	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	carboxylation	Glu86	ENTERTTeFWKQYVD	10090		BTO:0001103							11133752	t		lperfetto	The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.	SIGNOR-263696	0.67
CSNK2A1	protein	P68400	UNIPROT	CTDP1	protein	Q9Y5B0	UNIPROT	down-regulates activity	phosphorylation	Ser575	AGESLDQsMEEEEEE	9606	BTO:0000567								12591939	t		llicata	We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified 	SIGNOR-250844	0.381
COLGALT1	protein	Q8NBJ5	UNIPROT	COL4A1	protein	P02462	UNIPROT	up-regulates activity	glycosylation			-1									19075007	t			Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261155	0.375
Succinyl-CoA GTP variant	complex	SIGNOR-C399	SIGNOR	succinyl-CoA(5-)	smallmolecule	CHEBI:57292	ChEBI	down-regulates quantity	chemical modification			9606									27487822	t		miannu	In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions.	SIGNOR-266268	0.8
MLXIPL	protein	Q9NP71	UNIPROT	FAS	protein	P25445	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000759							15496471	t		Luana	The present study provides evidence for a direct and dominant role of ChREBP in the glucose regulation of two key liver lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS)	SIGNOR-267947	0.2
ZIC1	protein	Q15915	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates	relocalization			9606									11238441	t		lperfetto	Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels	SIGNOR-105491	0.385
CSNK1A1	protein	P48729	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates	phosphorylation			9606									11955435	t		gcesareni	In principle, pka, ck-1 and gsk3 can phosphorylate as many as 19 serine residues in gli3: fourpkasites, three primarygsk3sites, four primary ck-1 sites and eight secondary gsk3 and ck-1 sites	SIGNOR-116512	0.581
HBA1	protein	P69905	UNIPROT	TNF	protein	P01375	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000876								11901318	f	Regulation of expression	miannu	Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes.	SIGNOR-251753	0.2
CYP21A2	protein	P08686	UNIPROT	11-deoxycorticosterone	smallmolecule	CHEBI:16973	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000048							25855791	t		lperfetto	Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively	SIGNOR-268645	0.8
MAK	protein	P20794	UNIPROT	MAK	protein	P20794	UNIPROT	up-regulates activity	phosphorylation	Thr157	LRSQPPYtDYVSTRW	9606									21986944	t		Manara	We conclude that dual phosphorylation on the TDY motif is crucial for MAK activity, and that the autokinase activity is required for this phosphorylation	SIGNOR-260779	0.2
E	protein	P59637	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000661								16048439	f		Luana	Overexpression of SARS-CoV E protein in T-cells promoted apoptosis	SIGNOR-260208	0.7
GNA12	protein	Q03113	UNIPROT	RFFL	protein	Q8WZ73	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								22609986	f		miannu	LPA and Gα12 may upregulate the expression of an E3 ubiquitin ligase that catalyzes the polyubiquitination of PRR5L.	SIGNOR-271496	0.2
DEK	protein	P35659	UNIPROT	B-WICH complex	complex	SIGNOR-C447	SIGNOR	form complex	binding			9606									21559432	t		miannu	The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 	SIGNOR-268823	0.43
BRDT	protein	Q58F21	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	up-regulates quantity	binding			9606									33125143	t		lperfetto	It was revealed that eIF4EBP1 interacted with BRDT, a novel interacting protein. In addition, the present study further demonstrated that BRDT inhibitors PLX51107 and INCB054329 blocked the progression of RCC cells, along with suppressing eIF4EBP1 and c‑myc expression. 	SIGNOR-262049	0.2
AKT2	protein	P31751	UNIPROT	CHUK	protein	O15111	UNIPROT	up-regulates	phosphorylation	Thr23	EMRERLGtGGFGNVC	9606				SIGNOR-C14					19609947	t		gcesareni	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-187010	0.508
WNK3	protein	Q9BYP7	UNIPROT	SLC12A6	protein	Q9UHW9	UNIPROT	down-regulates activity	phosphorylation	Thr991	SAYTYERtLMMEQRS	9606									24043619	t		Manara	WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048. 	SIGNOR-260912	0.457
MAPK14	protein	Q16539	UNIPROT	ADAM17	protein	P78536	UNIPROT	up-regulates activity	phosphorylation	Thr735	KPFPAPQtPGRLQPA	10029	BTO:0000246								20188673	t		gcesareni	We show that p38 MAP kinase, which is activated in response to inflammatory or stress signals, directly activates TACE, a membrane-associated metalloprotease that is also known as ADAM17 and effects shedding in response to growth factors and Erk MAP kinase activation. p38alpha MAP kinase interacts with the cytoplasmic domain of TACE and phosphorylates it on Thr(735), which is required for TACE-mediated ectodomain shedding	SIGNOR-163970	0.416
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	TP73	protein	O15350	UNIPROT	down-regulates	phosphorylation	Thr86	AASASPYtPEHAASV	9606									12676926	t		lperfetto	Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86.	SIGNOR-216849	0.467
MAPK1	protein	P28482	UNIPROT	SCNN1G	protein	P51170	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr622	LGTQVPGtPPPKYNT	-1									11805112	t		lperfetto	Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.	SIGNOR-249448	0.367
E2F3	protein	O00716	UNIPROT	TFDP1	protein	Q14186	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								8832394	t	2	miannu	The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3.	SIGNOR-240553	0.729
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	down-regulates				9606									12244043	f		azuccotti	Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes	SIGNOR-254989	0.7
NR0B2	protein	Q15466	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates	binding			9606		BTO:0000975							11861507	t		gcesareni	Our results identify shp as an inhibitor of 4-oht agonist activity in rl95-2 human endometrial carcinoma cells that express endogenous er?. We conclude that shp does not decrease er expression, but rather it is the direct interaction of shp with er that inhibits er transcriptional activity.	SIGNOR-115033	0.633
8a	protein	Q7TFA0	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0001950								17597455	f		Luana	Open Reading Frame 8a of the Human Severe Acute Respiratory Syndrome Coronavirus Not Only Promotes Viral Replication but Also Induces Apoptosis	SIGNOR-260206	0.7
Factor FVIIa:TF	complex	SIGNOR-C319	SIGNOR	F10	protein	P00742	UNIPROT	up-regulates activity	binding			9606		BTO:0000131							32665005	t		lperfetto	During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury.	SIGNOR-263543	0.638
AMFR	protein	Q9UKV5	UNIPROT	MFN1	protein	Q8IWA4	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0000298								23427266	t		miannu	Gp78 induces ubiquitylation and proteasomal degradation of Mfn1 and Mfn2.	SIGNOR-272886	0.315
HNF1A	protein	P20823	UNIPROT	IGF1	protein	P05019	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10050749	t		lperfetto	Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α	SIGNOR-251720	0.306
NBEAL2	protein	Q6ZNJ1	UNIPROT	Platelet_morphogenesis	phenotype	SIGNOR-PH135	SIGNOR	up-regulates				9606	BTO:0000132								28082341	f		lperfetto	We compared platelet size and number of α-granules for two NBEAL2 and two GATA1-deficient patients and found reduced numbers of α-granules for all, with the defect being more pronounced for NBEAL2 deficiency. 	SIGNOR-261882	0.7
LRAT	protein	O95237	UNIPROT	retinol	smallmolecule	CHEBI:50211	ChEBI	down-regulates quantity	chemical modification			10090									18093970	t		lperfetto	We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis	SIGNOR-265110	0.8
NR1H3	protein	Q13133	UNIPROT	BHLHE40	protein	O14503	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									19032342	f		lperfetto	LXRα and LXRβ are potent positive regulators for hepatic Dec1	SIGNOR-253691	0.271
STMN3	protein	Q9NZ72	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	down-regulates quantity by destabilization	binding												22577147	t		lperfetto	 Stathmins can thus sequester free tubulin that may result in inhibiting microtubule growth and/or promoting microtubule collapse	SIGNOR-264896	0.7
SERPINC1	protein	P01008	UNIPROT	F12	protein	P00748	UNIPROT	down-regulates activity	cleavage												31030036	t		lperfetto	Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1	SIGNOR-264139	0.587
EFNA1	protein	P20827	UNIPROT	EPHA5	protein	P54756	UNIPROT	up-regulates	binding			9606									9576626	t		tpavlidou	Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity	SIGNOR-56910	0.804
CNTF	protein	P26441	UNIPROT	LIFR	protein	P42702	UNIPROT	up-regulates	binding			9606									10966616	t		gcesareni	Ciliary neurotrophic factor (cntf) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, cntfr, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (lifr)	SIGNOR-81382	0.732
PTPRB	protein	P23467	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606									10734133	t		gcesareni	Identification of tyrosine phosphatases that dephosphorylate the insulin receptor.	SIGNOR-75993	0.349
GRK2	protein	P25098	UNIPROT	SMO	protein	Q99835	UNIPROT	up-regulates	phosphorylation			9606									23074268	t		gcesareni	We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins	SIGNOR-199104	0.2
TSHB	protein	P01222	UNIPROT	SLC5A5	protein	Q92911	UNIPROT	up-regulates quantity by stabilization				9606									14623893	f		miannu	Uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane	SIGNOR-251994	0.39
UBE2G2	protein	P60604	UNIPROT	DIO2	protein	Q92813	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys244	KIAYLGGkGPFSYNL	9606		BTO:0001379							29892818	t		scontino	ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244.	SIGNOR-267484	0.2
TFIIH	complex	SIGNOR-C457	SIGNOR	Nucleotide-excision_repair	phenotype	SIGNOR-PH209	SIGNOR	up-regulates				9606									30860024	f		lperfetto	Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.	SIGNOR-269322	0.7
PPM1F	protein	P49593	UNIPROT	CAMK1	protein	Q14012	UNIPROT	down-regulates activity	dephosphorylation			9606									11726284	t		miannu	Calmodulin-dependent protein kinase phosphatase (CaMKP) dephosphorylates and concomitantly deactivates multifunctional Ca(2+)/calmodulin-dependent protein kinases , such as CaMKI, CaMKII, and CaMKIV.	SIGNOR-277111	0.475
CTNNB1	protein	P35222	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								15735151	f		gcesareni	Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation (fig 2?2),), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1	SIGNOR-134216	0.794
PHGDH	protein	O43175	UNIPROT	(R)-2-hydroxyglutarate(2-)	smallmolecule	CHEBI:15801	ChEBI	up-regulates activity	chemical modification												25406093	t		lperfetto	Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of alpha-ketoglutarate (AKG) to the oncometabolite d-2-hydroxyglutarate (d-2HG). 	SIGNOR-268572	0.8
PPARGC1A	protein	Q9UBK2	UNIPROT	CAV3	protein	P56539	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534	BTO:0001538								15199055	f	 	 	Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle.	SIGNOR-254261	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	AKT1S1	protein	Q96B36	UNIPROT	down-regulates activity	phosphorylation	Thr246	LPRPRLNtSDFQKLK	9606	BTO:0000007								12524439	t		gcesareni	Treatment of these cells with 4-hydroxytamoxifen stimulated the phosphorylation of wt PRAS40 but not the mutant PRAS40 in which Thr-246 was mutated. These results demonstrate that activation of Akt alone is sufficient to induce phosphorylation of PRAS40	SIGNOR-236929	0.2
PLK1	protein	P53350	UNIPROT	MRE11	protein	P49959	UNIPROT	down-regulates activity	phosphorylation	Ser649	EVIEVDEsDVEEDIF	9606	BTO:0001938								28512243	t		miannu	Plk1 phosphorylates Mre11 at S649.Mre11 phosphorylation at S649/S688 inhibits its binding to dsDNA and antagonizes the ATM signaling.	SIGNOR-265943	0.2
ROCK1	protein	Q13464	UNIPROT	FHOD1	protein	Q9Y613	UNIPROT	up-regulates	phosphorylation	Ser1137	RSRGNRKsLRRTLKS	9606									18239683	t		lperfetto	Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres.	SIGNOR-160548	0.315
MSX1	protein	P28360	UNIPROT	TBP	protein	P20226	UNIPROT	down-regulates activity	binding			-1									8700832	t	2	miannu	Msx-1 is a potent transcriptional repressor and that this activity is independent of its DNA binding function. Here we show that Msx-1 interacts directly with the TATA binding protein (TBP) but not with several other general transcription factors. This interaction is mediated by the Msx-1 homeodomain, specifically through residues in the N-terminal arm. These same N-terminal arm residues are required for repression by Msx-1, suggesting a functional relationship between TBP association and transcriptional repression.	SIGNOR-240401	0.406
NEU1	protein	Q99519	UNIPROT	ITGB4	protein	P16144	UNIPROT	down-regulates activity				9606	BTO:0000182								19151752	f		Giorgia	In HT-29 cells cultured with 10% fetal bovine serum (FBS), the phosphorylation of integrin β4 was significantly decreased in NEU1-overexpressing cells and the level seemed to be inversely correlated with the sialidase activity. These results suggest that NEU1 is involved in the regulation of integrin β4 phosphorylation probably through desialylation in colon cancer cells.	SIGNOR-260655	0.2
ELANE	protein	P08246	UNIPROT	AGT	protein	P01019	UNIPROT	up-regulates activity	cleavage	Phe41	DRVYIHPfHLVIHNE	-1									11747312	t		miannu	Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.	SIGNOR-256313	0.279
RNF111	protein	Q6ZNA4	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	ubiquitination			10090									17341133	t		lperfetto	Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling.	SIGNOR-235388	0.639
SEC23IP	protein	Q9Y6Y8	UNIPROT	SEC23B	protein	Q15437	UNIPROT	up-regulates activity	binding			10090	BTO:0000142								10400679	t		lperfetto	The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway.	SIGNOR-265306	0.354
THR	proteinfamily	SIGNOR-PF84	SIGNOR	RARB	protein	P10826	UNIPROT	up-regulates	binding			9606									15650024	t	inferred from family member	gcesareni	Ee report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs	SIGNOR-270314	0.2
BTK	protein	Q06187	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates activity	phosphorylation	Tyr1217	LNNQLFLyDTHQNLR	9606									11507089	t		lperfetto	These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2.	SIGNOR-109750	0.77
BCL2L11	protein	O43521	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates activity	binding			10090									12242151	t		lperfetto	We find short peptides representing the alpha-helical BH3 domains of BID or BIM are capable of inducing oligomerization of BAK and BAX to release cytochrome c.	SIGNOR-92939	0.825
SNRPD1	protein	P62314	UNIPROT	U1 snRNP complex	complex	SIGNOR-C480	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270684	0.905
INSR	protein	P06213	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	phosphorylation	Tyr1189	RDIYETDyYRKGGKG	-1									2449432	t		lperfetto	We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151;	SIGNOR-106514	0.2
PEX6	protein	Q13608	UNIPROT	Protein_localization_to_peroxisome	phenotype	SIGNOR-PH86	SIGNOR	up-regulates				9606									26476099	f			The Pex1 and Pex6 proteins are members of the AAA family of ATPases and are involved in peroxisome biogenesis.	SIGNOR-253617	0.7
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	BCL2L1	protein	Q07817	UNIPROT	down-regulates	phosphorylation	Thr47	GTESEMEtPSAINGN	9606									10617621	t		lperfetto	Sapk phosphorylates bcl-x(l) on threonine 47 (thr-47) and threonine 115 (thr-115) in vitro and in vivo. In contrast to wild-type bcl-x(l), a mutant bcl-x(l) with the two threonines substituted by alanines (ala-47, ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis	SIGNOR-73642	0.2
TGFB1	protein	P01137	UNIPROT	LPP	protein	Q93052	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887;BTO:0001260							22886954	f		miannu	Tgf-_1-induced lpp expression dependant on rho kinase during differentiation and migration of bone marrow-derived smooth muscle progenitor cells	SIGNOR-191768	0.333
PTPN2	protein	P17706	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	9606									10734133	t		flangone	Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1.	SIGNOR-75910	0.604
MAP3K21	protein	Q5TCX8	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser218	VSGQLIDsMANSFVG	9606									23319808	t		Manara	These experiments showed that MEK1 is phosphorylated by MLK4 on Ser217/221	SIGNOR-260767	0.2
DGC	complex	SIGNOR-C217	SIGNOR	NRXN2	protein	P58401	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							11470830	t		miannu	In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan.	SIGNOR-265449	0.285
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CDH1	protein	P12830	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr40	DAESYTFtVPRRHLE										23972993	t	For phosphorylated residues see Figure 7	lperfetto	Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP	SIGNOR-274052	0.419
PRKCB	protein	P05771	UNIPROT	LMNB1	protein	P20700	UNIPROT	unknown	phosphorylation	Ser395	LKLSPSPsSRVTVSR	-1									8034666	t		lperfetto	Beta II PKC-mediated phosphorylation of lamin B is confined to two sites, Ser395 and Ser405 | Comparative tryptic phosphopeptide mapping demonstrates that the beta II PKC site, Ser405, is a prominent target of mitotic lamin B phosphorylation in vivo. beta II PKC translocates to the nucleus during the G2/M phase of cell cycle concomitant with phosphorylation of Ser405, indicating a physiologic role for nuclear beta II PKC activation in mitotic lamin B phosphorylation in vivo. 	SIGNOR-248911	0.476
AKT1	protein	P31749	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Thr157	GIRKRPAtDDSSTQN	9606									18570873	t		gcesareni	Mtor may promote g1 progression in part through sgk1 activation and deregulate the cell cycle in cancers through both akt- and sgk-mediated p27 t157 phosphorylation and cytoplasmic p27 mislocalization.	SIGNOR-179109	0.845
BMPR1A	protein	P36894	UNIPROT	SMAD5/SMAD4	complex	SIGNOR-C205	SIGNOR	up-regulates activity	phosphorylation			10090									19620713	t		ggiuliani	The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17).	SIGNOR-255788	0.679
DTNB	protein	O60941	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255990	0.444
CAPN3	protein	P20807	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	cleavage			9606									25969760	t		lperfetto	Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains	SIGNOR-251605	0.331
NAE1	protein	Q13564	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606	BTO:0000938								25568892	f		lperfetto	Overexpression of AppBp1 in primary neurons induces apoptosis through the neddylation pathway	SIGNOR-256651	0.7
PRKAA1	protein	Q13131	UNIPROT	SREBF1	protein	P36956	UNIPROT	down-regulates activity	phosphorylation			9606			SIGNOR-C15						21892142	t		lperfetto	Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation	SIGNOR-176497	0.368
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MAPKAPK2	protein	P49137	UNIPROT	up-regulates	phosphorylation			9606									14967450	t	inferred from 70% family members	gcesareni	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-270206	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser197	APRRRAAsMDSSSKL	9606									16272144	t		lperfetto	Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression	SIGNOR-252828	0.908
MYOG	protein	P15173	UNIPROT	DES	protein	P17661	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								25653159	f		lperfetto	Ectopic expression of myogenin and a specific Mef2 isoform induced myogenic differentiation without activating endogenous MyoD expression. Under these conditions, the regulatory sequences of late gene loci were not in close proximity, and these genes were prematurely activated.	SIGNOR-241501	0.257
AKT1	protein	P31749	UNIPROT	CFLAR	protein	O15519	UNIPROT	down-regulates quantity	phosphorylation	Ser273	LLRDTFTsLGYEVQK	9606									19339247	t		gcesareni	TNFalpha enhanced FLIP(L) serine phosphorylation, which was increased by activated Akt-1. Serine 273, a putative Akt-1 phosphorylation site in FLIP(L), was critical for the activation-induced reduction of FLIP(L). Thus, these observations document a novel mechanism where by TNFalpha facilitates the reduction of FLIP(L) protein, which is dependent on the phosphatidylinositol 3-kinase/Akt signaling.	SIGNOR-252548	0.481
VEGFA	protein	P15692	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252275	0.7
PAX1	protein	P15863	UNIPROT	MEOX2	protein	P50222	UNIPROT	up-regulates activity	binding			-1									11423130	t		miannu	We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family.	SIGNOR-222232	0.419
SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	TDGF1	protein	P13385	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269236	0.624
NFIA	protein	Q12857	UNIPROT	GAS6	protein	Q14393	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268876	0.2
CDK1	protein	P06493	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Thr48	VCPDVPRtPVGKFLG	9606									10037602	t		gcesareni	Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity.	SIGNOR-64964	0.853
AKT1	protein	P31749	UNIPROT	SCYL1	protein	Q96KG9	UNIPROT	up-regulates activity	phosphorylation	Thr469	STRHRVLtSAFSRAT	9606	BTO:0000567								24769208	t		lperfetto	In previous work, we demonstrated that TEIF (transcriptional element-interacting factor) distributes in the centrosomes and regulates centrosome status under both physiologic and pathologic conditions.|A consensus motif for Akt phosphorylation (RHRVLT) proved to be involved in centrosomal TEIF localization, and the 469-threonine of this motif may be phosphorylated by Akt both in vitro and in vivo. Elimination of this phosphorylated site on TEIF caused reduced centrosome distribution and centrosome splitting or amplification. 	SIGNOR-265496	0.258
JAK2	protein	O60674	UNIPROT	EPOR	protein	P19235	UNIPROT	up-regulates activity	phosphorylation	Tyr456	PPHLKYLyLVVSDSG										12441334	t			JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2	SIGNOR-251351	0.806
CDK1	protein	P06493	UNIPROT	CEP55	protein	Q53EZ4	UNIPROT	down-regulates	phosphorylation	Ser425	NREKVAAsPKSPTAA	9606									16198290	t		lperfetto	Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis.	SIGNOR-140882	0.461
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PHKA2	protein	P46019	UNIPROT	down-regulates activity	phosphorylation			9606									10487978	t			Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.	SIGNOR-267408	0.2
PAK1	protein	Q13153	UNIPROT	ARHGDIA	protein	P52565	UNIPROT	down-regulates	phosphorylation	Ser101	LESFKKQsFVLKEGV	9606									15225553	t		lperfetto	Pak1 binds and phosphorylates rhogdi both in vitro and in vivo at ser101 and ser174. This resulted in dissociation of rac1-rhogdi, but not rhoa-rhogdi, complexes, as determined by in vitro assays of complexation and in vivo by coimmunoprecipitation analysis. We observed that cdc42-induced rac1 activation is inhibited by expression of pak1 autoinhibitory domain. The dissociation of rac1 from rhogdi and its subsequent activation stimulated by pdgf or egf is also attenuated by pak1 autoinhibitory domain, and this is dependent on the ability of rhogdi to be phosphorylated at ser101/174.	SIGNOR-126650	0.595
TWIST1	protein	Q15672	UNIPROT	FN1	protein	P02751	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003879								20646316	f		miannu	Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1.	SIGNOR-255521	0.422
vandetanib	chemical	CHEBI:49960	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258306	0.8
MAPK14	protein	Q16539	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates	phosphorylation	Ser266	SLPLTPEsPNDPKGS	9606		BTO:0000887							11741533	t		gcesareni	Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298	SIGNOR-112766	0.568
HHEX	protein	Q03014	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates activity				10090		BTO:0000089							26728554	f			Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal.	SIGNOR-256306	0.7
H2BC11	protein	P06899	UNIPROT	Nucleosome_H2A.Z.1 variant	complex	SIGNOR-C322	SIGNOR	form complex	binding			-1									24311584	t		miannu	In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined.	SIGNOR-263716	0.2
UFL1	protein	O94874	UNIPROT	H4C1	protein	P62805	UNIPROT	up-regulates activity	ubiquitination	Lys32	DNIQGITkPAIRRLA	9606	BTO:0000007;BTO:0001938								30886146	t		lperfetto	Here we report that UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation.	SIGNOR-265072	0.2
ATM	protein	Q13315	UNIPROT	CREB1	protein	P16220	UNIPROT	down-regulates	phosphorylation	Ser107	SVDSVTDsQKRREIL	9606									15073328	t		lperfetto	Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potential,	SIGNOR-124047	0.538
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	APBB1	protein	O00213	UNIPROT	unknown	phosphorylation			9606									14697653	t	inferred from 70% family members	lperfetto	Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved.	SIGNOR-270166	0.2
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	CDKN1B	protein	P46527	UNIPROT	up-regulates quantity	transcriptional regulation			10090									10783894	t		gcesareni	AFX transcriptionally activates p27kip1, resulting in increased protein levels.	SIGNOR-252928	0.2
SGK1	protein	O00141	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser214	GGKERPGsKEEVDED	9606									16982696	t		lperfetto	Second, sgk1 indirectly depolymerized mts through the phosphorylation of tau at ser214	SIGNOR-161288	0.336
NFE2L1	protein	Q14494	UNIPROT	NQO1	protein	P15559	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8962164	f		irozzo	These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2.	SIGNOR-256280	0.394
HIF1A	protein	Q16665	UNIPROT	CCL2	protein	P13500	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001496								17474992	t		lperfetto	These findings suggest that both MCP-1 and MCP-5 are HIF-1 target genes and that HIF-1α is involved in transcriptional induction of these two chemokines in astrocytes by hypoxia.	SIGNOR-251719	0.414
PRKCA	protein	P17252	UNIPROT	FLNC	protein	Q14315	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser2236	ERLGSFGsITRQQEG	10090	BTO:0000165								32444788	t		miannu	We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells. In vitro kinase assays combined with LC-MS confirmed hFLNc-S2233 as a substrate of Akt, whereas PKCα preferentially targeted S2236.	SIGNOR-262617	0.344
MAPK1	protein	P28482	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr70	RNSPVTKtPPRDLPT	9606	BTO:0000007								11691836	t		lperfetto	The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding 	SIGNOR-249394	0.649
FOXA1	protein	P55317	UNIPROT	LOXL2	protein	Q9Y4K0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002861								20043065	f	 	miannu	 These results suggest that FOXA1 induces not only KRT7 but also LOXL2 in a subset of poor prognostic ESCCs with metastatic lymph nodes. FOXA1 siRNA treatment of esophageal cancer cells reduced the mRNA level of both KRT7 and a stabilizer of epithelial-mesenchymal transition (EMT) regulator LOXL2, and that both FOXA1 and LOXL2 siRNAs reduced invasion and migration of ESCC cells. 	SIGNOR-254166	0.2
RPS8	protein	P62241	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262416	0.902
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CHUK	protein	O15111	UNIPROT	up-regulates	phosphorylation	Thr23	EMRERLGtGGFGNVC	9606				SIGNOR-C14					19609947	t		lperfetto	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-244210	0.2
PTEN	protein	P60484	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates activity	dephosphorylation	Thr383	HYRYSDTtDSDPENE	9606									22413754	t		miannu	Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites	SIGNOR-248545	0.2
TEAD1	protein	P28347	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21211055	f		gcesareni	Tead1 can regulate transcription of the foxo3a gene through the binding to the m-cat element, demonstrated with independent chip-pcr analysis, emsa and luciferase reporter system assay. The over-expression and inhibition analysis suggest that foxo3a was positively regulated by tead1.	SIGNOR-170976	0.31
PI-103	chemical	CHEBI:90524	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258266	0.8
CDK5	protein	Q00535	UNIPROT	TLN1	protein	Q9Y490	UNIPROT	up-regulates	phosphorylation	Ser425	TMLEDSVsPKKSTVL	9606									19363486	t		lperfetto	Cdk5 phosphorylated talin head at ser 425, inhibiting its binding to smurf1, thus preventing talin head ubiquitylation and degradation.	SIGNOR-185210	0.471
E2F4	protein	Q16254	UNIPROT	BIRC5	protein	O15392	UNIPROT	down-regulates quantity by repression	transcriptional regulation												18504435	t		lperfetto	This TGF-beta response is triggered through a Smad2/3-dependent hypophosphorylation of Rb and the subsequent association of the Rb/E2F4 repressive complex to CDE/CHR elements in the proximal region of the survivin promoter.	SIGNOR-271678	0.341
SETDB1/NLK/CHD7	complex	SIGNOR-C189	SIGNOR	PPARG	protein	P37231	UNIPROT	down-regulates activity				10090									21952300	f		FFerrentino	The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1). SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3-L1 cells	SIGNOR-253524	0.432
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	RANGAP1	protein	P46060	UNIPROT	up-regulates	phosphorylation	Ser428	EPAPVLSsPPPADVS	9606									15037602	t		lperfetto	Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain.	SIGNOR-216781	0.446
Degranulation	phenotype	SIGNOR-PH92	SIGNOR	TNF	protein	P01375	UNIPROT	up-regulates quantity				9606	BTO:0000830								24232182	f		apalma	Particularly, damage-activated mast cells almost instantly begin to secrete TNFa, histamine and tryptase and then initiate the de novo synthesis of other cytokines, such as interleukin (IL)6	SIGNOR-255347	0.7
TUBB	protein	P07437	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates	binding			9606									17429065	t		lpetrilli	Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin.	SIGNOR-154316	0.2
EN1	protein	Q05925	UNIPROT	FGF8	protein	P55075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0003560								10026229	t		miannu	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 	SIGNOR-265802	0.466
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BCL2	protein	P10415	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr56	FSSQPGHtPHPAASR	9606									10669763	t		lperfetto	The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87.	SIGNOR-244610	0.2
SCNN1A	protein	P37088	UNIPROT	CACNA1H	protein	O95180	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							30736831	t		miannu	This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues.	SIGNOR-269272	0.2
PAX3	protein	P23760	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							23384562	f		gcesareni	Direct molecular regulation of the myogenic determination gene myf5 by pax3, with modulation by six1/4 factors, is exemplified by the -111 kb-myf5 enhancer.	SIGNOR-200862	0.487
SETD2	protein	Q9BYW2	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								18158893	f		gcesareni	In response to hypoxia, foxo3a transcript levels accumulate in an hif1-dependent way, resulting in enhanced foxo3a activity.	SIGNOR-252986	0.2
NME1	protein	P15531	UNIPROT	NME1	protein	P15531	UNIPROT	up-regulates activity	phosphorylation	Ser44	GLKFMQAsEDLLKEH	9606	BTO:0000093								8245015	t		miannu	An acid-stable (nonhistidine) phosphorylation was identified on autophosphorylated purified recombinant Nm23 proteins and [32P]orthophosphate-labeled human breast carcinoma and murine melanoma Nm23. Phosphoamino acid analysis identified serine as the acid-stable phosphorylation and serine 44 as the major site of phosphorylation. The biological relevance of the novel phosphorylation identified herein is suggested by the direct correlation of in vivo Nm23 acid-stable phosphorylation levels, but not Nm23 NDPK activity, with suppression of tumor metastatic potential among control and nm23-1 transfected murine melanoma cells.	SIGNOR-250303	0.2
CBFB	protein	Q13951	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates quantity by stabilization	binding			10090	BTO:0002883								11179217	t			The RUNX genes encode the α subunit of the transcription factor PEBP2/CBF. The β subunit consists of the non-RUNX protein PEBP2β. We found that RUNX1/AML1, which is essential for hematopoiesis, is continuously subjected to proteolytic degradation mediated by the ubiquitin–proteasome pathway. When PEBP2β is present, however, the ubiquitylation of RUNX1 is abrogated and this causes a dramatic inhibition of RUNX1 proteolysis.	SIGNOR-255742	0.841
CRH	protein	P06850	UNIPROT	KRT14	protein	P02533	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15468147	t	Regulation	miannu	CRH stimulated the expression of cytokeratin 1 and involucrin, and inhibited cytokeratin 14 on both mRNA and protein levels.	SIGNOR-251899	0.2
CDK2	protein	P24941	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates activity	phosphorylation	Thr518	SMDNTPHtPTPFKNA										10593981	t		llicata	Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. 	SIGNOR-250740	0.711
MRPL2	protein	Q5T653	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262374	0.707
SART1	protein	O43290	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270623	0.746
ACSL1	protein	P33121	UNIPROT	palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	up-regulates quantity	chemical modification			9606									21242590	t		miannu	Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. On the other hand, overexpression of ACSL1 resulted in large increases in oleoyl-CoA synthesis and palmitoyl-CoA synthesis in SMC lysates (Fig. 4A).	SIGNOR-267877	0.8
MAP2K6	protein	P52564	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000298								8974401	t		lperfetto	A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively.	SIGNOR-236116	0.733
FNIP1	protein	Q8TF40	UNIPROT	HSP90AB1	protein	P08238	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								27353360	t		miannu	FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle. 	SIGNOR-261415	0.2
PRKCD	protein	Q05655	UNIPROT	PLSCR3	protein	Q9NRY6	UNIPROT	up-regulates	phosphorylation	Thr21	PPPPYPVtPGYPEPA	9606									16267027	t		gcesareni	Ad198-activated pkc-delta induces phosphorylation of mitochondrial pls3 at thr21;pls3 is a critical downstream effector of pkc-delta in ad198-induced apoptosis.	SIGNOR-140759	0.469
SRC	protein	P12931	UNIPROT	NDUFV2	protein	P19404	UNIPROT	up-regulates activity	phosphorylation	Tyr193	VQINDNYyEDLTAKD	9606	BTO:0001583								22823520	t		miannu	Phosphorylation-site analysis selects c-Src targets, including NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) at Tyr(193) of respiratory complex I and SDHA (succinate dehydrogenase A) at Tyr(215) of complex II. The phosphorylation of these sites by c-Src is supported by an in vivo assay using cells expressing their phosphorylation-defective mutants. 	SIGNOR-276419	0.329
WDR48	protein	Q8TAF3	UNIPROT	USP1	protein	O94782	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								18082604	t		lperfetto	 In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM).	SIGNOR-263274	0.945
HGF	protein	P14210	UNIPROT	MET	protein	P08581	UNIPROT	up-regulates	binding			9606									8380735	t		gcesareni	Hgf is the ligand for p190met, the receptor tyrosine kinase encoded by the met proto-oncogene.	SIGNOR-38429	0.927
EGFR	protein	P00533	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr869	LGAEEKEyHAEGGKV	9606	BTO:0000567								10653583	t	Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer	lperfetto	After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine.	SIGNOR-236487	0.2
PHF5A	protein	Q7RTV0	UNIPROT	SF3b	complex	SIGNOR-C442	SIGNOR	form complex	binding			9606									32140746	t		lperfetto	Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a).	SIGNOR-268409	0.906
KLF6	protein	Q99612	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates				9606									15917248	f		fspada	We have identified kr?ppel-like factor-6 (klf6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene delta-like 1 (dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation.	SIGNOR-137807	0.7
KLF6	protein	Q99612	UNIPROT	DLK1	protein	P80370	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15917248	f	Repression of Dlk1 requires HDAC3 deacetylase activity	fspada	We have identified kr?ppel-like factor-6 (klf6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene delta-like 1 (dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation.	SIGNOR-137836	0.286
ITCH	protein	Q96J02	UNIPROT	TRPV4	protein	Q9HBA0	UNIPROT	down-regulates activity	ubiquitination			9606	BTO:0000007								17110928	t		miannu	AIP4 ubiquitin ligase is involved in the ubiquitination of both TRPV4 and TRPC4.Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane.	SIGNOR-272625	0.385
POLR3G	protein	O15318	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266127	0.685
LRIG1	protein	Q96JA1	UNIPROT	ERBB3	protein	P21860	UNIPROT	down-regulates	ubiquitination			9606									16123311	t		gcesareni	We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.	SIGNOR-139951	0.446
LPAR3	protein	Q9UBY5	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257297	0.46
SIRT2	protein	Q8IXJ6	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								14522900	f	 	miannu	 In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity.	SIGNOR-254481	0.315
IRAK1	protein	P51617	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity	phosphorylation	Thr387	RTQTVRGtLAYLPEE	-1									11960013	t			In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4.	SIGNOR-251330	0.2
(+)-pilocarpine	chemical	CHEBI:8207	ChEBI	CHRM4	protein	P08173	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258628	0.8
ATF2	protein	P15336	UNIPROT	PLAT	protein	P00750	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								8647095	f	 	lperfetto	We suggest that the mechanism for the transcriptional down-regulation of t-PA by PMA in HT-1080 cells requires CREB-1 binding to the t-PACRE while ATF-2, by associating with the same site, plays a role in PMA-mediated induction of t-PA in HeLa cells.	SIGNOR-253724	0.2
ZAP70	protein	P43403	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation	Tyr349	EEPPDHQyYNDFPGK	9606	BTO:0000782								9710204	t		gcesareni	The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2).	SIGNOR-59647	0.664
ABL1	protein	P00519	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates activity	phosphorylation	Tyr315	ETRICKIyDSPCLPE	10090	BTO:0002883								11684015	t		gcesareni	Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance	SIGNOR-247599	0.764
BMP7	protein	P18075	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	up-regulates activity	binding			9606									7791754	t		fspada	 BMPR-II is a transmembrane serine/threonine kinase that binds BMP-2 and BMP-7 in association with multiple type I receptors, including BMPR-IA/Brk1, BMPR-IB, and ActR-I, which is also an activin type I receptor. 	SIGNOR-232216	0.77
DBH	protein	P09172	UNIPROT	noradrenaline	smallmolecule	CHEBI:33569	ChEBI	up-regulates quantity	chemical modification			10090									7961964	t	brain	lperfetto	Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway.	SIGNOR-264006	0.8
ERBB3	protein	P21860	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606									16729043	t		gcesareni	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146861	0.697
MBTPS1	protein	Q14703	UNIPROT	SREBF2	protein	Q12772	UNIPROT	up-regulates activity	cleavage			10029	BTO:0000246								10644685	t			We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2	SIGNOR-267496	0.579
H2BC11	protein	P06899	UNIPROT	Nucleosome_H3.1t variant	complex	SIGNOR-C325	SIGNOR	form complex	binding			-1									20498094	t		miannu	A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. 	SIGNOR-263727	0.2
CSNK1E	protein	P49674	UNIPROT	PER3	protein	P56645	UNIPROT	down-regulates activity	phosphorylation	Ser625	TAMLSLGsGISQCGY	9534	BTO:0000298								11865049	t		llicata	The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. 	SIGNOR-250816	0.734
MAP2K7	protein	O14733	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates activity	phosphorylation	Thr404	SSMSTEQtLASDTDS	-1									11062067	t			MKK7 also phosphorylates JNK2 alpha 2 at Thr-404 and Ser-407 in vitro. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7.	SIGNOR-251418	0.622
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates quantity by destabilization	cleavage	Gln711	PTYKFFEqMQN	-1									8943232	t		lperfetto	FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261790	0.502
HACD2	protein	Q6Y1H2	UNIPROT	FASN	protein	P49327	UNIPROT	up-regulates activity	chemical activation			9606									18554506	t			Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases,	SIGNOR-267761	0.2
CXCL8	protein	P10145	UNIPROT	ARDS	phenotype	SIGNOR-PH128	SIGNOR	up-regulates				9606									32446778	f		miannu	Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection	SIGNOR-261030	0.7
MUSK	protein	O15146	UNIPROT	DOK7	protein	Q18PE1	UNIPROT	up-regulates activity	phosphorylation	Tyr405	PTSLRAHyDTPRSLC	10090									20603078	t		miannu	Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes. 	SIGNOR-273846	0.746
SLC38A1	protein	Q9H2H9	UNIPROT	L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	up-regulates quantity	relocalization			9606									26724577	t			Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine.	SIGNOR-266912	0.8
SRC	protein	P12931	UNIPROT	ARHGAP35	protein	Q9NRY4	UNIPROT	up-regulates	phosphorylation	Tyr1105	RNEEENIySVPHDST	9606									9819392	t		lperfetto	Phosphorylation of y1105, but not the minor site, was modulated in vivo to a greater extent by overexpression of c-src than by the egf receptor and was efficiently catalyzed by c-src in vitro. Mutation of y1105 from tyr to phe resulted in complete loss of p-tyr-dependent complex formation, indicating that p-y1105 was the sole p-tyr residue mediating binding to p120	SIGNOR-61670	0.764
FBN1	protein	P35555	UNIPROT	EFEMP2	protein	O95967	UNIPROT	down-regulates activity	binding			9606									19570982	t	Regulation of binding	miannu	Fibulin-4 and -5 are extracellular glycoproteins with essential non-compensatory roles in elastic fiber assembly. Both fibulins differentially bound N-terminal fibrillin-1, which strongly inhibited their binding to lysyl oxidase and tropoelastin. 	SIGNOR-251860	0.402
ADAM9	protein	Q13443	UNIPROT	FGFR2	protein	P21802	UNIPROT	down-regulates quantity by destabilization	cleavage			9606	BTO:0000007								22632802	t		Giulio	Truncated FGFR2 was observed in cells transfected with wild-type ADAM9, but not in those with inactive mutant ADAM9 (Figure 5E). In line with this, cells transfected with wild-type ADAM9 showed reduced pErK1/2 in response to FGF2 as compared to controls or cells expressing mutant ADAM9.|Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9, hence protecting FGFR2 from ADAM9-mediated ectodomain shedding on the cell surface.	SIGNOR-260300	0.26
GSK3B	protein	P49841	UNIPROT	STAT2	protein	P52630	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser381	RKFNILTsNQKTLTP	9606	BTO:0002181								31843895	t		miannu	GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation.	SIGNOR-276763	0.293
belinostat	chemical	CHEBI:61076	ChEBI	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257741	0.8
GRIN2D	protein	O15399	UNIPROT	NMDA receptor_2D	complex	SIGNOR-C350	SIGNOR	form complex	binding			9606									12871085	t		miannu	The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits	SIGNOR-264127	0.649
CDK8	protein	P49336	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser195	PNSSYPNsPGSSSST	9606									19914168	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161626	0.392
AURKB	protein	Q96GD4	UNIPROT	CDCA2	protein	Q69YH5	UNIPROT	down-regulates activity	phosphorylation	Ser977	EPGKRRKsFCISTLA	9606	BTO:0000567								32938714	t	done	miannu	This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin.	SIGNOR-274004	0.459
CDK7	protein	P50613	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates activity	phosphorylation	Ser41	RTDALTSsPGRDLPP	9606									16899510	t		Luana	Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2.	SIGNOR-259849	0.304
SMC3	protein	Q9UQE7	UNIPROT	RAD21L Cohesin complex	complex	SIGNOR-C355	SIGNOR	form complex	binding			10090		BTO:0000534							21242291	t		miannu	RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21.	SIGNOR-264537	0.814
mTORC1	complex	SIGNOR-C3	SIGNOR	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Thr412	NQVFLGFtYVAPSVL	9606									15809305	t		lperfetto	Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size.	SIGNOR-217067	0.749
RPS6KA3	protein	P51812	UNIPROT	GSK3A	protein	P49840	UNIPROT	down-regulates activity	phosphorylation	Ser21	SGRARTSsFAEPGGG	9606	BTO:0000130								11583116	t		lperfetto	P90-rsk and akt may promote rapid phosphorylation/inactivation of glycogen synthase kinase 3 in chemoattractant-stimulated neutrophils. These reactions were monitored with a phosphospecific antibody that only recognized the alpha- or beta-isoforms of GSK-3 when these proteins were phosphorylated on serine residues 21 and 9, respectively.	SIGNOR-110827	0.268
AURKB	protein	Q96GD4	UNIPROT	KIF2C	protein	Q99661	UNIPROT	up-regulates	phosphorylation	Ser95	IQKQKRRsVNSKIPA	9606									17567953	t		lperfetto	Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres.	SIGNOR-155890	0.72
oxymetazoline	chemical	CHEBI:7862	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			9913		BTO:0000142							9632357	t		miannu	Benzylimidazolines may represent a class of 5-HT1D ligands that has yet to be exploited. On the basis of a previous report that the 2-(substituted-benzyl)imidazoline alpha-adrenergic agonist oxymetazoline (8) binds with high affinity at calf brain 5-HT1D receptors, we explored the structure-affinity relationships of a series of related derivatives.	SIGNOR-258927	0.8
DOT1L	protein	Q8TEK3	UNIPROT	MEIS1	protein	O00470	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20854876	f		irozzo	Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented.	SIGNOR-256143	0.411
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DOA	protein	P06340	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-253994	0.335
PLCB3	protein	Q01970	UNIPROT	1D-myo-inositol 1,4,5-trisphosphate(6-)	smallmolecule	CHEBI:203600	ChEBI	up-regulates quantity	chemical modification			9606									23994464	t		apalma	The first phase of this signal is likely mediated by phospholipase Cβ (PLCβ) enzymes leading to the generation of IP3 and concomitant release of Ca2+ from intracellular stores	SIGNOR-255018	0.8
DIO3	protein	P55073	UNIPROT	L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	down-regulates quantity	chemical modification			9606									12746313	t		scontino	Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144.	SIGNOR-266941	0.8
MAP2K4	protein	P45985	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates	phosphorylation			9606									10715136	t	Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif.	gcesareni	A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1).	SIGNOR-75792	0.732
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	SMAD3	protein	P84022	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0005493								10601313	t		lperfetto	JNK-mediated phosphorylation of Smad3 outside the -SSXS motif enhances Smad3 nuclear translocation and potentiates transcriptional activation independent of Smad3 phosphorylation by T_RI.	SIGNOR-236113	0.2
CAMKK2	protein	Q96RR4	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	up-regulates	phosphorylation	Thr483	KHIPSLAtVILVKTM	9606									22778263	t		lperfetto	It has been proposed that a major consequence of relief from autoinhibition is autophosphorylation of thr-482, a post-translational change that likely contributes to the increased autonomous activity of camkk2	SIGNOR-198107	0.2
CTSE	protein	P14091	UNIPROT	A2M	protein	P01023	UNIPROT	down-regulates quantity by destabilization	cleavage	Phe834	QLEASPAfLAVPVEK	-1									12631277	t		lperfetto	Disruption of structural and functional integrity of alpha 2-macroglobulin by cathepsin E|Analysis of the N-terminal amino-acid sequences of these proteins revealed that alpha 2M was selectively cleaved at the Phe811-Leu812 bond in about 100mer downstream of the bait region. 	SIGNOR-266977	0.388
MAPK9	protein	P45984	UNIPROT	H2AX	protein	P16104	UNIPROT	up-regulates	phosphorylation	Ser140	GKKATQAsQEY	9606									18158901	t		gcesareni	H2ax interacts with numerous proteins required for dna damage signaling and repair when phosphorylated on ser-140. Phosphorylation of ser-140 (h2ax139ph) in response to ionizing radiation is mediated by both atm and prkdc. Our data showed that h2ax is phosphorylated by uva-activated jnk.	SIGNOR-160210	0.2
JAK1	protein	P23458	UNIPROT	TYK2	protein	P29597	UNIPROT	up-regulates	phosphorylation	Tyr1054	AVPEGHEyYRVREDG	9606	BTO:0000667								30029643	t			Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated 	SIGNOR-256221	0.505
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates	relocalization			9606		BTO:0001103							11062529	t		gcesareni	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-252338	0.635
INSR	protein	P06213	UNIPROT	BLVRA	protein	P53004	UNIPROT	up-regulates activity	phosphorylation	Tyr291	LAEEIQKyCCSRK										15870194	t		lperfetto	Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK 	SIGNOR-275516	0.494
NFATC2	protein	Q13469	UNIPROT	PTGS2	protein	P35354	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21871017	t		miannu	 NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration	SIGNOR-264025	0.381
XAV939	chemical	CHEBI:62878	ChEBI	TNKS2	protein	Q9H2K2	UNIPROT	down-regulates activity	chemical inhibition			-1									20565110	t			We report two crystal structures of the PARP domain of human tankyrase-2 (TNKS2). Tankyrases are involved in fundamental cellular processes such as telomere homeostasis and Wnt signaling.	SIGNOR-259995	0.8
SIRT1	protein	Q96EB6	UNIPROT	SOD2	protein	P04179	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20089851	f	Regulation	miannu	SIRT1 deacetylates and activates the FOXOs under oxidative stress, thereby inducing Mn-SOD expression	SIGNOR-251763	0.507
MAPK1	protein	P28482	UNIPROT	NFATC4	protein	Q14934	UNIPROT	up-regulates	phosphorylation	Ser676	SNGRRKRsPTQSFRF	9606									15657420	t		esanto	We demonstrate that p90 ribosomal s6 kinase (rsk) is recruited to the nfat-dna transcription complex upon activation.Bound Rsk phosphorylates ser(676) and potentiates nfatc4 dna binding. Ser(676) is also targeted by the erk map kinase.	SIGNOR-133272	0.287
DNMT1	protein	P26358	UNIPROT	DNMT1/DNMT3B	complex	SIGNOR-C43	SIGNOR	form complex	binding			9606									12145218	t		miannu	We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation	SIGNOR-90839	0.783
EGR1	protein	P18146	UNIPROT	FAS	protein	P25445	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									9300687	f	 	 	Thus, Egr-1 seems to control the expression of downstream target genes not only as a transcriptional activator, but also as a repressor molecule. In B cells, Egr-1 therefore plays a critical role in integrating the short-lived signal delivered by triggering of the Ag receptor into phenotypic changes, including repression of CD95 and CD23 transcription.	SIGNOR-254278	0.278
CAMK2A	protein	Q9UQM7	UNIPROT	CAMK2A	protein	Q9UQM7	UNIPROT	down-regulates	phosphorylation	Thr306	LKGAILTtMLATRNF	9606									1324926	t		lperfetto	After removal of ca2+/calmodulin, the autonomous kinase undergoes a burst of inhibitory autophosphorylation at sites distinct from the autonomy site. Ca(2+)-independent autophosphorylation occurs within the calmodulin binding domain at thr305, thr306, and ser314	SIGNOR-17316	0.2
CCR1	protein	P32246	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity	phosphorylation			10090									20219869	t		areggio	The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. 	SIGNOR-255118	0.317
CRTC2	protein	Q53ET0	UNIPROT	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity	transcriptional regulation			9600	BTO:0000567								26652733	t	inferred from family member		Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-270253	0.283
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates	phosphorylation	Ser83	NKEKKAVsPLLLTTT	9606									11152499	t		tpavlidou	Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites.	SIGNOR-85769	0.2
PIAS1	protein	O75925	UNIPROT	SATB2	protein	Q9UPW6	UNIPROT	down-regulates activity	sumoylation	Lys350	PPIPRAVkPEPTNSS	9606	BTO:0000007								14701874	t		gianni	We found that SATB2 differs from the closely related thymocyte-specific protein SATB1 by modifications of two lysines with the small ubiquitive related modifier (SUMO), which are augmented specifically by the SUMO E3 ligase PIAS1.	SIGNOR-269112	0.564
IPO5	protein	O00410	UNIPROT	DSCAM	protein	O60469	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								30745319	t		miannu	DSCAM and DSCAML1 specifically interacted with the importin beta IPO5, whereas deletion of the identified NLSs abolished this specific interaction and suppressed nuclear translocation of the DSCAM/L1 ICDs in cell lines and cultured neurons. This suggests a direct role of IPO5 in the nuclear import of the DSCAM/L1 ICDs.	SIGNOR-264273	0.2
PDK3	protein	Q15120	UNIPROT	PDHA2	protein	P29803	UNIPROT	down-regulates	phosphorylation	Ser291	TYRYHGHsMSDPGVS	9606									16436377	t		miannu	Pdh2 was found to be very similar to pdh1 / in the mechanism of inactivation by phosphorylation of three sites;and (iv) in the phosphorylation of sites 1 and 2 by pdk3 / (ser-264 (site 1), ser-271 (site 2), and ser-203 (site 3)	SIGNOR-143974	0.544
NR3C1	protein	P04150	UNIPROT	IRAK3	protein	Q9Y616	UNIPROT	up-regulates quantity	transcriptional regulation			9606									25585690	t			We show that glucocorticoids and non-typeable Haemophilus influenzae synergistically upregulate IRAK-M expression via mutually and synergistically enhancing p65 and glucocorticoid receptor binding to the IRAK-M promoter	SIGNOR-259287	0.369
MAPK1	protein	P28482	UNIPROT	ARHGEF2	protein	Q92974	UNIPROT	up-regulates	phosphorylation	Thr679	PGVELLLtPREPALP	9606		BTO:0000671							19261619	t		gcesareni	Importantly tnf-alpha enhanced the erk pathway-dependent phosphorylation of thr-678 of gef-h1 that was key for activation.	SIGNOR-184469	0.364
CREB5	protein	Q02930	UNIPROT	RASGRP3	protein	Q8IV61	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		 BTO:0002815							21132541	f		miannu	 Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition),	SIGNOR-253808	0.2
F2RL1	protein	P55085	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257028	0.2
Pr3-ANCA	complex	SIGNOR-C475	SIGNOR	Neutrophil_activation	phenotype	SIGNOR-PH211	SIGNOR	up-regulates				9606		BTO:0000133							2161532	f		lperfetto	ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation. 	SIGNOR-270584	0.7
UNII-XH2662798I	chemical	CID:16156006	PUBCHEM	H3-3A	protein	P84243	UNIPROT	down-regulates				9606									20068082	f		gcesareni	Pf-00477736 also significantly enhances docetaxel efficacy in vitro and in vivo, in association with decreased cdc25c cytoplasmic phosphorylation (ser216) and histone h3 phosphorylation (ser10)(42).	SIGNOR-163130	0.8
MTOR	protein	P42345	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	up-regulates activity	phosphorylation	Thr228	HEGAVTHtFCGTIEY	-1									11733037	t		miannu	In vitro phosphorylation and activation of p70β by mTOR and PDK1. We observed that the replacement of either Thr241 or Thr401 to Ala in p70β1(T241A, T401A) severely decreased the kinase activity.	SIGNOR-250294	0.831
TNF	protein	P01375	UNIPROT	LZTR1	protein	Q8N653	UNIPROT	down-regulates quantity by destabilization				9606									16356934	f			Induction of Apoptosis by Staurosporine, TNFα, and TRAIL Induces Degradation of LZTR-1 by Caspase- and Proteasome-dependent Pathways	SIGNOR-253612	0.2
CSNK2A1	protein	P68400	UNIPROT	IGFBP3	protein	P17936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser140	APGNASEsEEDRSAG	9606	BTO:0000093								10650937	t		llicata	The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro | These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment.	SIGNOR-250904	0.344
MAPK3	protein	P27361	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates	phosphorylation	Ser70	RDPVARTsPLQTPAA	9606									10669763	t		gcesareni	Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association.	SIGNOR-74935	0.541
GSK3B	protein	P49841	UNIPROT	AREL1	protein	O15033	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr783	IAAPTHStLPTAHTC										27162139	t		lperfetto	These experiments suggested that GSK3beta phosphorylation of FIEL1 is required for PIAS4 targeting, and FIEL1 residues P779 and phosphorylated T783 are both required for PIAS4 interaction |FIEL1 T783A mutant overexpression completely failed to decrease PIAS4 protein level.	SIGNOR-275528	0.321
MAPK3	protein	P27361	UNIPROT	PDE4D	protein	Q08499	UNIPROT	down-regulates	phosphorylation	Ser715	YQSTIPQsPSPAPDD	9606									10828059	t	The effect has been demonstrated using Q08499-2	gcesareni	These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro.	SIGNOR-77578	0.255
PTCH1	protein	Q13635	UNIPROT	CCNB1	protein	P14635	UNIPROT	up-regulates	binding			9606									11331587	t	Type I noncanonical;P-cyclina B (CCNB).	gcesareni	In addition, we demonstrate that endogenous ptc1 and endogenous cyclin B1 interact in vivo. The findings reported here demonstrate that ptc1 participates in determining the subcellular localization of cyclin B1 and suggest a link between the tumor suppressor activity of ptc1 and the regulation of cell division. Thus, we propose that ptc1 participates in a G2/M checkpoint by regulating the localization of MPF.	SIGNOR-199147	0.671
RPS6KA4	protein	O75676	UNIPROT	H3-4	protein	Q16695	UNIPROT	unknown	phosphorylation	Ser29	ATKVARKsAPATGGV	10090									12773393	t		lperfetto	The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28	SIGNOR-249212	0.2
INSR	protein	P06213	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	phosphorylation	Tyr1361	SYEEHIPyTHMNGGK	-1									3166375	t		lperfetto	This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972	SIGNOR-233560	0.2
Monobutylphthalate	chemical	CHEBI:88522	ChEBI	AHR	protein	P35869	UNIPROT	up-regulates activity	chemical activation			-1									25081364	t		miannu	BBP affected hepatocellular carcinoma progression through the aryl hydrocarbon receptor (AhR) and that benzyl butyl phthalate (BBP) stimulated AhR at the cell surface, which then interacted with G proteins and triggered a downstream signaling cascade. BBP activated AhR through a nongenomic action involving G-protein signaling rather than the classical genomic AhR action.	SIGNOR-268791	0.8
NR3C1	protein	P04150	UNIPROT	HDAC1	protein	Q13547	UNIPROT	up-regulates	binding			10116									18762022	t			The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene	SIGNOR-253057	0.457
PPM1D	protein	O15297	UNIPROT	ATM	protein	Q13315	UNIPROT	down-regulates activity	dephosphorylation	Ser367	DTRSLEIsQSYTTTQ	9606									18265945	t		lperfetto	More recently, Shreeram et al.  have also shown that Wip1 dephosphorylates human ATM at Ser367 as well as Ser1981.|Thus, overexpression of Wip1 in an oncogenic context could contribute to tumor promotion by inhibiting both p53 and ATM functions.	SIGNOR-276955	0.504
BTRC	protein	Q9Y297	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys779	TKWMEHVkLERLKQV	9606	BTO:0000938								17283082	t		lperfetto	Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage.	SIGNOR-249576	0.657
LAT	protein	O43561	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9606									11368773	t		lperfetto	By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.	SIGNOR-252734	0.402
SSTR2	protein	P30874	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256963	0.359
MAPK1	protein	P28482	UNIPROT	DAZAP1	protein	Q96EP5	UNIPROT	down-regulates activity	phosphorylation	Thr269	FTSYIVStPPGGFPP	9606	BTO:0000007								16848763	t		miannu	Further experiments showed that DAZAP1 was phosphorylated stoichiometrically in vitro by ERK2 (extracellular-signal-regulated protein kinase 2) at two Thr-Pro sequences (Thr269 and Thr315), and that both sites became phosphorylated in HEK-293 (human embryonic kidney 293) cells in response to PMA or EGF (epidermal growth factor), or RAW 264.7 macrophages in response to LPS. Phosphorylation of the ARE-binding protein DAZAP1 by ERK2 induces its dissociation from DAZ	SIGNOR-262970	0.2
D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	D-erythrose 4-phosphate(2-)	smallmolecule	CHEBI:16897	ChEBI	up-regulates quantity	precursor of			9606									19401148	t		miannu	Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 	SIGNOR-268132	0.8
VRK2	protein	Q86Y07	UNIPROT	BANF1	protein	O75531	UNIPROT	down-regulates	phosphorylation	Thr2	tTSQKHRD	9606									16495336	t		lperfetto	Herein, we demonstrate that b1, vrk1, and vrk2 efficiently phosphorylate the extreme n' terminus of the baf protein. We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain	SIGNOR-144799	0.517
MAPK3	protein	P27361	UNIPROT	MCRIP1	protein	C9JLW8	UNIPROT	down-regulates activity	phosphorylation	Ser21	KRTSSPRsPPSSSEI	9606									25728771	t		lperfetto	When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation	SIGNOR-264773	0.2
EIF2AK1	protein	Q9BQI3	UNIPROT	EIF2S1	protein	P05198	UNIPROT	down-regulates	phosphorylation	Ser52	MILLSELsRRRIRSI	9606									3352609	t		lperfetto	The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases . The ser-51 mutant showed little covalent modification by the endogenous enzymes. Phosphorylation of the serine 51 residue in the alpha-subunit of translational initiation factor 2 in eukaryotes (eif2 alpha) impairs protein synthesis presumably by sequestering eif2b, a rate-limiting pentameric guanine nucleotide exchange protein which catalyzes the exchange of gtp for gdp in the eif2-gdp binary complex	SIGNOR-24543	0.886
PRKAA2	protein	P54646	UNIPROT	VASP	protein	P50552	UNIPROT	down-regulates	phosphorylation	Ser322	TTLPRMKsSSSVTTS	9606			SIGNOR-C15						21945940	t		lperfetto	Here we show that phosphorylation of vasp by ampk occurs at a novel site, serine 322, and that phosphorylation at this site alters actin filament binding. We also show that inhibition of ampk activity results in the accumulation of vasp at cell-cell adhesions and a concomitant increase in cell-cell adhesion.	SIGNOR-176642	0.2
GSK3B	protein	P49841	UNIPROT	CDX2	protein	Q99626	UNIPROT	unknown	phosphorylation	Ser283	RSVPEPLsPVSSLQA	-1									16027724	t			GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines)	SIGNOR-251227	0.389
AURKB	protein	Q96GD4	UNIPROT	SSU72	protein	Q9NP77	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser19	CSSNQNRsMEAHNIL										24149858	t		lperfetto	Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72. 	SIGNOR-275529	0.257
SNAI1	protein	O95863	UNIPROT	SNAIL/RELA/PARP1	complex	SIGNOR-C198	SIGNOR	form complex	binding			9606	BTO:0000452;BTO:0002625								22223884	t		alessandro	Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin	SIGNOR-254526	0.441
Enolase	proteinfamily	SIGNOR-PF74	SIGNOR	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	up-regulates quantity	chemical modification			9606									29767008	t		miannu	Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: α-enolase (ENO1) is present in almost all mature tissues; β-enolase (ENO3) exists primarily in muscle tissues; and γ-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits.	SIGNOR-266527	0.8
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1623	SPTSPSYsPTSPSYS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248747	0.727
PDK2	protein	Q15119	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates	phosphorylation	Ser293	TYRYHGHsMSDPGVS	-1									7782287	t		gcesareni	Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase.	SIGNOR-33137	0.667
SLITRK5	protein	O94991	UNIPROT	PTCH1	protein	Q13635	UNIPROT	down-regulates activity	binding			10090	BTO:0001593								34326333	t		miannu	 SLITRK5 interacts with SHH and PTCH1. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation.	SIGNOR-268438	0.2
CDC14A	protein	Q9UNH5	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Thr698	KSIQATLtPSAMKSS	9606									20236090	t			Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3.	SIGNOR-248832	0.627
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser245	NQSMDTGsPAELSPT	9606		BTO:0000763;BTO:0000149							10197981	t		lperfetto	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-244719	0.2
CNKSR1	protein	Q969H4	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	binding			9606									15845549	t		gcesareni	Here we demonstrate that the connector enhancer of ksr1, cnk1, mediates src-dependent tyrosine phosphorylation and activation of raf-1. Cnk1 binds preactivated raf-1 and activated src and forms a trimeric complex.	SIGNOR-135674	0.699
CDON	protein	Q4KMG0	UNIPROT	CDON/SPAG9	complex	SIGNOR-C21	SIGNOR	form complex	binding			9606	BTO:0000222								17074887	t		gcesareni	In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway.	SIGNOR-150279	0.477
NFE2L2	protein	Q16236	UNIPROT	Purine biosynthesis	phenotype	SIGNOR-PH186	SIGNOR	up-regulates				9606	BTO:0000018								22789539	f		miannu	Nrf2 promotes purine nucleotide synthesis and glutamine use in proliferating cells	SIGNOR-267352	0.7
PRKCA	protein	P17252	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser304	GAPPRRSsIRNAHSI	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89154	0.538
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	CELF6	protein	Q96J87	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001109								31534127	t		miannu	CELF6 is degraded by ubiquitin-dependent proteasome pathway. The cell cycle-dependent expression of CELF6 is mediated through the ubiquitin-proteasome pathway, SCF-β-TrCP recognizes a nonphospho motif in CELF6 and regulates its proteasomal degradation.	SIGNOR-269043	0.2
RFX1	protein	P22670	UNIPROT	ABL1	protein	P00519	UNIPROT	up-regulates	binding			9606									9583676	t		gcesareni	We show that rfxi and c-abl are in direct interaction, in vitro and in cell extracts, through the rfxi proline rich (pxxp) motif and the c-abl sh3 domain. Remarkably, this interaction significantly potentiates c-abl but not v-abl auto-kinase activity	SIGNOR-57516	0.2
naltrexone	chemical	CHEBI:7465	ChEBI	OPRD1	protein	P41143	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258936	0.8
OXSR1	protein	O95747	UNIPROT	SLC12A2	protein	P55011	UNIPROT	up-regulates	phosphorylation	Thr203	HQHYYYDtHTNTYYL	9606									16669787	t		miannu	We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1	SIGNOR-146513	0.54
PRKACA	protein	P17612	UNIPROT	LASP1	protein	Q14847	UNIPROT	down-regulates activity	phosphorylation	Ser146	MEPERRDsQDGSSYR	-1									12432067	t		miannu	Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146	SIGNOR-250074	0.311
ABL1	protein	P00519	UNIPROT	PTPN6	protein	P29350	UNIPROT	unknown	phosphorylation	Tyr564	SKHKEDVyENLHTKN	-1									12468540	t		gcesareni	Incorporation of Pmp at the 536 site led to 4-fold stimulation of the SHP-1 tyrosine phosphatase activity whereas incorporation at the 564 site led to no effect	SIGNOR-246240	0.423
MAPK1	protein	P28482	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Ser249	DTRQIQPsPPWSYDQ	9606									16046550	t	The effect has been demonstrated using Q01196-8	miannu	We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 	SIGNOR-138969	0.2
SERPINC1	protein	P01008	UNIPROT	LRP1	protein	Q07954	UNIPROT	up-regulates	binding			9606									8626456	t		gcesareni	In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp.	SIGNOR-41232	0.2
EHMT2	protein	Q96KQ7	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19822740	f	Regulation of transcription	miannu	 G9a activation of the βmaj globin gene was shown to be independent of G9a MT activity.	SIGNOR-251788	0.2
NTF4	protein	P34130	UNIPROT	NTRK2	protein	Q16620	UNIPROT	up-regulates	binding			9606									7679912	t		gcesareni	Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb.	SIGNOR-31644	0.939
BCL2	protein	P10415	UNIPROT	BECN1	protein	Q14457	UNIPROT	down-regulates	binding			9606									17643073	t		gcesareni	In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function.	SIGNOR-156941	0.731
SMARCC1	protein	Q92922	UNIPROT	SMARCE1	protein	Q969G3	UNIPROT	up-regulates quantity by stabilization				9606									20829358	f		miannu	We show that the mechanism of baf155-mediated stabilization of baf57 involves blocking its ubiquitination by preventing interaction with trip12, an e3 ubiquitin ligase.	SIGNOR-167869	0.894
CSNK2A1	protein	P68400	UNIPROT	GYS1	protein	P13807	UNIPROT	unknown	phosphorylation	Ser653	PSLSRHSsPHQSEDE	-1									2117608	t		llicata	With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action.	SIGNOR-250881	0.334
WWTR1	protein	Q9GZV5	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	binding			9606									21084559	t		gcesareni	Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal.	SIGNOR-169835	0.576
GABRA6	protein	Q16445	UNIPROT	GABA-A (a6-b3-d) receptor	complex	SIGNOR-C329	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263771	0.523
RPS6KA1	protein	Q15418	UNIPROT	RPS6	protein	P62753	UNIPROT	up-regulates	phosphorylation	Ser236	AKRRRLSsLRASTSK	9606									17360704	t		gcesareni	We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism.	SIGNOR-153622	0.608
SDHAF2	protein	Q9NX18	UNIPROT	SDHB	protein	P21912	UNIPROT	up-regulates	binding			9606									19628817	t		miannu	Sdh5 is required for sdh activity and stability / the sdh1-sdh5 interaction is likely to be functionally important because the sdh5_ mutant lacks sdh activity	SIGNOR-187239	0.637
Niflumic acid	chemical	CHEBI:34888	ChEBI	UGT1A1	protein	P22309	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								21030469	t		Luana	Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation.	SIGNOR-258062	0.8
AIP	protein	O00170	UNIPROT	TFF1	protein	P04155	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21984905	t		miannu	We show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells.	SIGNOR-259911	0.2
FLT3	protein	P36888	UNIPROT	CISH	protein	Q9NSE2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15769897	f			The STAT5 target gene CIS, a member of the suppressor of cytokine signaling (SOCS) protein family, was highly induced by Flt3-ITD	SIGNOR-261542	0.304
DRD2	protein	P14416	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256844	0.536
8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	chemical	CHEBI:93369	ChEBI	HTR1E	protein	P28566	UNIPROT	down-regulates activity	chemical inhibition			9534	BTO:0000298								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258541	0.8
MAPK3	protein	P27361	UNIPROT	ABI1	protein	Q8IZP0	UNIPROT	up-regulates	phosphorylation	Ser225	ARLGSQHsPGRTASL	9606									21419341	t		gcesareni	We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1.	SIGNOR-172881	0.431
MIB1	protein	Q86YT6	UNIPROT	JAG1	protein	P78504	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0000938								12530964	t		lperfetto	Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum.	SIGNOR-97388	0.68
CSF2RA	protein	P15509	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates				9606									7716810	f		gcesareni	A major pathway which mediates the effects of gm-csf on macrophages involves activation of the latent transcription factor stat5a via a janus kinase 2 (jak2)-dependent pathway.	SIGNOR-32220	0.576
CHEK1	protein	O14757	UNIPROT	TLK1	protein	Q9UKI8	UNIPROT	down-regulates	phosphorylation	Ser743	PHMRRSNsSGNLHMA	9606									12660173	t		llicata	Chk1 phosphorylates tlk1 on serine 695 (s695) these findings identify an unprecedented functional co- operation between atm and chk1 in propagation of a checkpoint response during s phase and suggest that, through transient inhibition of tlk kinases, the atm_chk1_tlk pathway may regulate processes involved in chromatin assembly.	SIGNOR-99653	0.442
JAK1	protein	P23458	UNIPROT	IFNGR1	protein	P15260	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000801								19041276	t		lperfetto	The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process.	SIGNOR-249488	0.691
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	NOXA1	protein	Q86UR1	UNIPROT	down-regulates activity	phosphorylation	Ser461	VPAGPRMsGAPGRLP	9606	BTO:0003250								20943948	t		lperfetto	On the other hand, our group has shown that protein kinase A (PKA) inhibits Nox1 activity in colon epithelial cells by phosphorylating NoxA1 at two distinct sites, Ser172 and Ser461	SIGNOR-264713	0.2
SRC	protein	P12931	UNIPROT	PLSCR1	protein	O15162	UNIPROT	up-regulates activity	phosphorylation	Tyr69	PVPNQPVyNQPVYNQ	9606									12871937	t		lperfetto	Plscr1 is phosphorylated by c-src, within the tandem repeat sequence 68vynqpvynqp77.|The EGF-mediated Interaction between PLSCR1 and Shc Requires Phosphorylation of Tyr69 and Tyr74 in PLSCR1	SIGNOR-103769	0.489
CHEK2	protein	O96017	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity	phosphorylation	Ser178	LFTQRQNsAPARMLS	9606									12676583	t		Manara	Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A	SIGNOR-260833	0.837
SF3B4	protein	Q15427	UNIPROT	SF3b	complex	SIGNOR-C442	SIGNOR	form complex	binding			9606									32140746	t		lperfetto	Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a).	SIGNOR-268406	0.916
3-iodo-L-tyrosine	smallmolecule	CHEBI:27847	ChEBI	L-alanine zwitterion	smallmolecule	CHEBI:57972	ChEBI	up-regulates quantity	precursor of			9606									28153798	t		scontino	The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a “donor” onto a DIT residue called an “acceptor”. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines.	SIGNOR-268123	0.8
FBP2	protein	O00757	UNIPROT	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	down-regulates quantity	chemical modification			9606									30616754	t		lperfetto	FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle	SIGNOR-267612	0.8
LOX	protein	P28300	UNIPROT	EFEMP2	protein	O95967	UNIPROT	up-regulates activity	binding			9606									19570982	t		miannu	Fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking.	SIGNOR-252135	0.578
pazopanib	chemical	CHEBI:71219	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258261	0.8
BMPR1A	protein	P36894	UNIPROT	FAM83G	protein	A6ND36	UNIPROT	up-regulates activity	phosphorylation	Ser616	PSVASSVsEEYFEVR	-1									24554596	t		lperfetto	These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway.	SIGNOR-264767	0.383
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1766	SPSYSPTsPSYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269381	0.718
MSX1	protein	P28360	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		BTO:0001103							15192231	f		gcesareni	We found that msx1 and h1b bind to a key regulatory element of myod, a central regulator of skeletal muscle differentiation, where they induce repressed chromatin.	SIGNOR-125765	0.438
ATM	protein	Q13315	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606	BTO:0001938								15254178	t		lperfetto	Although the stabilization of p53 was apparently concordant with its phosphorylation on N-terminal serine residues in HFFF-2 cells, it did not require the phosphorylation of Ser15 or Ser20 by ATM, a cellular kinase known to phosphorylate and promote the stabilization of p53 in response to DNA damage.	SIGNOR-126757	0.838
vorinostat	chemical	CHEBI:45716	ChEBI	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257917	0.8
CSNK1E	protein	P49674	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	phosphorylation	Ser403	ESTDSGLsMSSYSVP	9606							phosphorylation:Ser127	PQHVRAHsSPASLQL 	24715453	t		milica	LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)	SIGNOR-230733	0.401
PRKCA	protein	P17252	UNIPROT	PDE3A	protein	Q14432	UNIPROT	up-regulates	phosphorylation	Ser465	VRRDRSTsIKLQEAP	9606									19261611	t		llicata	Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding.	SIGNOR-184460	0.2
DNM1	protein	Q05193	UNIPROT	SYP	protein	P08247	UNIPROT	up-regulates activity	binding			9606									10823955	t		miannu	The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca2+-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling. 	SIGNOR-264119	0.34
DOK1	protein	Q99704	UNIPROT	Av/b5 integrin	complex	SIGNOR-C178	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257692	0.298
PRKACA	protein	P17612	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser273	AGTRRREsLGKKAKR	-1									9677319	t		miannu	Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII). Incubation of Rad with PKA decreases GTP binding by 60-70%, but this effect seems to be independent of phosphorylation, as it is observed with the Ser273-->Ala mutant of Rad containing a mutation at the site of PKA phosphorylation.	SIGNOR-250048	0.346
F2	protein	P00734	UNIPROT	F5	protein	P12259	UNIPROT	up-regulates activity	cleavage	Arg737	LAAALGIrSFRNSSL	-1									10026263	t		lperfetto	Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 	SIGNOR-263632	0.877
DYRK2	protein	Q92630	UNIPROT	KATNA1	protein	O75449	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr133	HGNRPSTtVRVHRSS	9606	BTO:0000007								19287380	t		miannu	DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d). 	SIGNOR-262849	0.524
GSK3B	protein	P49841	UNIPROT	MITF	protein	O75030	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0001583								21873430	t		miannu	 Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186.	SIGNOR-276356	0.446
CBX3	protein	Q13185	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	binding			9606							methylation:Lys10	RTKQTARkSTGGKAP	19111658	t		miannu	 A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 	SIGNOR-264496	0.2
DLL4	protein	Q9NR61	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18339870	f		gcesareni	Dll4 down-regulates vascular endothelial growth factor (vegf) receptor 2 and nrp1 expression and inhibits vegf function	SIGNOR-178026	0.489
AMER1	protein	Q5JTC6	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	up-regulates activity	relocalization			9606									21304492	t		lperfetto	Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6.	SIGNOR-227991	0.633
PIK3CA	protein	P42336	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity				9606		BTO:0000150							12167717	f		lperfetto	PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473,	SIGNOR-236353	0.811
PPP1CC	protein	P36873	UNIPROT	AHCYL1	protein	O43865	UNIPROT	unknown	dephosphorylation	Ser68	RSLSRSIsQSSTDSY	10090									17635105	t			Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1.	SIGNOR-248498	0.2
PTK2B	protein	Q14289	UNIPROT	PTK2B	protein	Q14289	UNIPROT	up-regulates	phosphorylation	Tyr402	CSIESDIyAEIPDET	9606									15105428	t		llicata	Overexpression of pyk2 alone led to its spontaneous activation and tyrosine phosphorylation, resulting in activation of stat5b, indicated by the reporter gfp-stat5b. These effects were completely dependent upon tyr(402), the autophosphorylation site of pyk2, which allows recruitment of src family members for further activating phosphorylations at other sites on pyk2.	SIGNOR-124339	0.2
NQO1	protein	P15559	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0000849								20226854	f		irozzo	More importantly, our results also indicate that NF-kappaB p50 correlates with the expression of NQO1 and mediates its role in the proliferation of melanoma cells.	SIGNOR-256264	0.7
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CDKN1B	protein	P46527	UNIPROT	up-regulates	phosphorylation	Ser10	NVRVSNGsPSLERMD	9606									10831586	t		lperfetto	Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.	SIGNOR-244622	0.2
ABCA13	protein	Q86UQ4	UNIPROT	cholesterol	smallmolecule	CHEBI:16113	ChEBI	up-regulates quantity	relocalization			9606									33478937	t		miannu	ATP-binding cassette subfamily A member 13 (ABCA13) is predicted to be the largest ABC protein, consisting of 5058 amino acids and a long N-terminal region. Mutations in the ABCA13 gene were reported to increase the susceptibility to schizophrenia, bipolar disorder, and major depression.Here, we examined the biochemical activity of ABCA13 using HEK293 cells transfected with mouse ABCA13. The expression of ABCA13 induced the internalization of cholesterol and gangliosides from the plasma membrane to intracellular vesicles. These findings suggest that ABCA13 accelerates cholesterol internalization by endocytic retrograde transport in neurons and that loss of this function is associated with the pathophysiology of psychiatric disorders.	SIGNOR-265158	0.8
ARHGEF12	protein	Q9NZN5	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260539	0.902
PLK1	protein	P53350	UNIPROT	TNKS	protein	O95271	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser978	VVSASLIsPASTPSC	9606	BTO:0000567								21818122	t		miannu	Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends. 	SIGNOR-276242	0.439
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269629	0.2
PRKCA	protein	P17252	UNIPROT	LRP1	protein	Q07954	UNIPROT	up-regulates	phosphorylation	Ser4520	GGHGSRHsLASTDEK	9606									15272003	t		lperfetto	Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc.	SIGNOR-127207	0.2
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGA9	protein	Q9Y5G4	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265678	0.2
MAPKAPK5	protein	Q8IW41	UNIPROT	MAPK4	protein	P31152	UNIPROT	up-regulates	phosphorylation	Ser186	YSHKGYLsEGLVTKW	9606									1319925	t		lperfetto	This is due to mk5-dependent phosphorylation and only this retarded erk4 species is both phosphorylated on ser(186) and co-immunoprecipitates with wild-type mk5. We conclude that binding between erk4 and mk5 facilitates phosphorylation of ser(186) and stabilization of the erk4-mk5 complex.	SIGNOR-17069	0.614
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1665	SPTSPSYsPTSPSYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203524	0.77
CAMK2A	protein	Q9UQM7	UNIPROT	TH	protein	P07101	UNIPROT	up-regulates	phosphorylation	Ser19	KGFRRAVsELDAKQA	9606		BTO:0000142							1680128	t		llicata	This increase in ser19 phosphorylation was associated with enhanced th activity and was due, in part, to glutamate-receptor-mediated calcium influx and possibly calcium/calmodulin-dependent protein kinase ii (camkii) activation.	SIGNOR-20912	0.259
PTPRZ1	protein	P23471	UNIPROT	ALK	protein	Q9UM73	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000785								17681947	t		gcesareni	Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation.	SIGNOR-157227	0.561
SRC	protein	P12931	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates	phosphorylation	Tyr1337	QVFYNSEyGELSEPS	9606									20431062	t		lperfetto	Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk.	SIGNOR-165043	0.491
2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione	chemical	CHEBI:74947	ChEBI	CRBN	protein	Q96SW2	UNIPROT	up-regulates activity	chemical activation			9606									20223979	t		gcesareni	We identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks	SIGNOR-234786	0.8
1124329-14-1	chemical	CID:56973724	PUBCHEM	TTK	protein	P33981	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190137	0.8
HTR2C	protein	P28335	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257295	0.409
HTR1A	protein	P08908	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256693	0.472
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	AKT2	protein	P31751	UNIPROT	up-regulates				9606	BTO:0000150								12554767	f		gcesareni	Treatment of cells with estradiol resulted in phosphorylation of akt and a 9-fold increase in akt activity in 10 min.	SIGNOR-97798	0.8
DAMPS	stimulus	SIGNOR-ST18	SIGNOR	AIM2	protein	O14862	UNIPROT	up-regulates activity													16037825	f		lperfetto	Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage	SIGNOR-256419	0.7
RPL6	protein	Q02878	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262456	0.869
KISS1R	protein	Q969F8	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256893	0.409
NME1	protein	P15531	UNIPROT	FZD1	protein	Q9UP38	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001567								17671192	f		miannu	To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 	SIGNOR-255162	0.2
LEF1	protein	Q9UJU2	UNIPROT	ALX4	protein	Q9H161	UNIPROT	up-regulates quantity by expression	binding			10090	BTO:0003952								11696550	t		miannu	Alx4 Stably Interacts with LEF-1. LEF-1 enhances Alx4 binding to DNA, suggesting that both interaction with LEF-1 and DNA binding are required to mediate its effects on the N-CAM promoter.	SIGNOR-254547	0.457
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	up-regulates quantity	precursor of			9606									12746313	t		scontino	Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144.	SIGNOR-266940	0.8
PTPN2	protein	P17706	UNIPROT	SHC1	protein	P29353	UNIPROT	down-regulates activity	dephosphorylation	Tyr349	EEPPDHQyYNDFPGK	9606									9488479	t		llicata	However, TC45 inhibited the EGF-induced association of p52Shc with Grb2, which was attributed to the ability of the PTP to recognize specifically p52Shc phosphorylated on Y239. These results indicate that TC45 recognizes not only selected substrates in a cellular context but also specific sites within substrates and thus may regulate discrete signaling events.	SIGNOR-248397	0.553
CAMK4	protein	Q16566	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser498	RPLSRTQsSPLPQSP	9606		BTO:0000887;BTO:0001103							12058061	t		lperfetto	Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs.	SIGNOR-236575	0.49
ATF4	protein	P18848	UNIPROT	NLRP1 inflammasome	complex	SIGNOR-C224	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									26086088	t		miannu	Transcription Factor ATF4 Induces NLRP1 Inflammasome Expression During Endoplasmic Reticulum Stress. Here we report that expression of NLRP1, a core inflammasome component, is specifically up-regulated during severe ER stress conditions in human cell lines. Both IRE1α and PERK, but not the ATF6 pathway, modulate NLRP1 gene expression. Furthermore, using mutagenesis, chromatin immunoprecipitation and CRISPR-Cas9-mediated genome editing technology, we demonstrate that ATF4 transcription factor directly binds to NLRP1 promoter during ER stress.	SIGNOR-260354	0.286
BCL3	protein	P20749	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16384933	f		gcesareni	One mechanism by which this inhibition occurs is through bcl-3-mediated induction of the p53 inhibitor hdm2. Both stable and transient overexpression of bcl-3 leads to increased hdm2 expression, and small interfering rna (sirna)-mediated knockdown of bcl-3 blocks expression of hdm2. ( articolo-abstract)	SIGNOR-143403	0.291
PRKDC	protein	P78527	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	unknown	phosphorylation	Thr7	tQDQPMEE	9606	BTO:0000567								2507541	t		lperfetto	Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha.	SIGNOR-248888	0.438
Caspase 8 complex	complex	SIGNOR-C231	SIGNOR	CASP3	protein	P42574	UNIPROT	up-regulates activity	cleavage			9606									21295084	t		amattioni	Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction.	SIGNOR-256452	0.713
EAPP	protein	Q56P03	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23542036	f		miannu	 We show here that EAPP stimulates the MDR1 promoter resulting in higher PGP levels. Independently of EAPP, E2F1 also increases the activity of the MDR1 promoter. 	SIGNOR-253842	0.2
IKBKB	protein	O14920	UNIPROT	DOK1	protein	Q99704	UNIPROT	up-regulates	phosphorylation	Ser439	EPGTATGsGIKSHNS	9606									15574499	t		amattioni	Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility.	SIGNOR-131447	0.255
TP53	protein	P04637	UNIPROT	SCO2	protein	O43819	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27692180	t		miannu	P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.	SIGNOR-267463	0.626
MAPKAPK2	protein	P49137	UNIPROT	ZFP36	protein	P26651	UNIPROT	down-regulates activity	phosphorylation	Ser60	RLPGRSTsLVEGRSC	-1									14688255	t		miannu	We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated.	SIGNOR-250155	0.687
PIAS1	protein	O75925	UNIPROT	FHL1	protein	Q13642	UNIPROT	down-regulates	sumoylation	Lys144	GTGSFFPkGEDFYCV	9606									17509614	t		gcesareni	Pias1 (the protein inhibitor of activated stat1) interacts with kyot2 directly and attenuates kyot2-mediated transcriptional repression. We demonstrate that kyot2 is modified by sumoylation at two lysine residues, k144 and k171. Sumoylation of the transfected kyot2 is enhanced by pias1	SIGNOR-154801	0.259
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH1	protein	P12830	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265841	0.8
RPL31	protein	P62899	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262469	0.858
ACVR1B	protein	P36896	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	phosphorylation			10090									14517293	t		gcesareni	ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway	SIGNOR-235160	0.73
HSPA5	protein	P11021	UNIPROT	ATF6	protein	P18850	UNIPROT	down-regulates activity	binding			9606									31226023	t		miannu	Similar to PERK and IRE1, ATF6 is activated by ER stress-induced dissociation from GRP78	SIGNOR-260179	0.816
KDM2A	protein	Q9Y2K7	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates	demethylation			9606									20080798	t		lperfetto	Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation.	SIGNOR-217415	0.471
SCHEMBL14517914	chemical	CID:10016910	PUBCHEM	CHEK2	protein	O96017	UNIPROT	down-regulates	chemical inhibition			9606									20068082	t		gcesareni	Xl844 (exelixis) a potent atp-competitive inhibitor of chk1 (ki, 2.2nm) and chk2 (ki, 0.07nm).	SIGNOR-163234	0.8
RNF126	protein	Q9BV68	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								23418353	t		miannu	RNF126 and Rabring7 associate with the EGFR through a ubiquitin-binding zinc finger domain and both E3 ubiquitin ligases promote ubiquitylation of EGFR. In HeLa cells depleted of either RNF126 or Rabring7 the EGFR is retained in a late endocytic compartment and is inefficiently degraded.	SIGNOR-272103	0.334
HTR1D	protein	P28221	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257116	0.252
CSNK2A1	protein	P68400	UNIPROT	ERCC3	protein	P19447	UNIPROT	down-regulates activity	phosphorylation	Ser751	FGTMSSMsGADDTVY	-1									15549133	t		miannu	Phosphorylation of S751 by CKII inhibits 5′ incision.	SIGNOR-276013	0.2
masitinib	chemical	CHEBI:63450	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258246	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	AR	protein	P10275	UNIPROT	down-regulates	phosphorylation	Ser215	SGRAREAsGAPTSSK	9606	BTO:0000938								17470458	t		lperfetto	The work presented here is the first demonstration that phosphorylation at s215 and s792 by akt regulates ligand binding, and the subcellular distribution of the receptor	SIGNOR-244140	0.2
zolpidem	chemical	CHEBI:10125	ChEBI	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	up-regulates activity	chemical activation			9606		BTO:0000227							18790874	t	brain	lperfetto	The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005).	SIGNOR-263802	0.8
SLC27A4	protein	Q6P1M0	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264465	0.7
ADSS2	protein	P30520	UNIPROT	N(6)-(1,2-dicarboxylatoethyl)-AMP(4-)	smallmolecule	CHEBI:57567	ChEBI	up-regulates quantity	chemical modification			9606									10496970	t		miannu	Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 	SIGNOR-267347	0.8
AKT3	protein	Q9Y243	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates	phosphorylation	Ser119	EILSRRPsYRKILND	9606									9829964	t		gcesareni	When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp.	SIGNOR-62257	0.475
TTK	protein	P33981	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates	phosphorylation	Thr68	SSLETVStQELYSIP	9606									15618221	t		lperfetto	Ttk/hmps1 directly phosphorylates chk2 on thr-68 in vitro.ablation of ttk expression using small interfering rna results not only in reduced chk2 thr-68 phosphorylation, but also in impaired growth arrest. Our results are consistent with a model in which ttk functions upstream from chk2 in response to dna damage	SIGNOR-132665	0.296
CSNK2A1	protein	P68400	UNIPROT	XRCC1	protein	P18887	UNIPROT	up-regulates	phosphorylation	Ser518	GEDPYAGsTDENTDS	9606									20471329	t		lperfetto	Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523	SIGNOR-165423	0.404
ACADM	protein	P11310	UNIPROT	Fatty_acid_oxidation	phenotype	SIGNOR-PH129	SIGNOR	up-regulates				9606	BTO:0001370								28974683	f		lperfetto	This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation	SIGNOR-261265	0.7
CBX5	protein	P45973	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	binding			9606							methylation:Lys10	RTKQTARkSTGGKAP	19111658	t		miannu	 A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 	SIGNOR-264490	0.2
tolazoline	chemical	CHEBI:28502	ChEBI	ADRA2C	protein	P18825	UNIPROT	down-regulates activity	chemical inhibition			9606									9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258914	0.8
PRKACA	protein	P17612	UNIPROT	PHKA2	protein	P46019	UNIPROT	down-regulates activity	phosphorylation			9606									10487978	t			Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.	SIGNOR-267410	0.307
PHLPP2	protein	Q6ZVD8	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0001544								19261608	t			The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.	SIGNOR-248728	0.765
CHUK	protein	O15111	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser32	LLDDRHDsGLDSMKD	9606	BTO:0000567		SIGNOR-C14						9346241	t		lperfetto	We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation	SIGNOR-52875	0.893
ATR	protein	Q13535	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates activity	phosphorylation	Ser1423	AVLEQHGsQPSNSYP	9606	BTO:0000773								11278964	t		lperfetto	Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion.	SIGNOR-106436	0.792
THOC1	protein	Q96FV9	UNIPROT	TREX complex	complex	SIGNOR-C444	SIGNOR	form complex	binding			9606									33191911	t		miannu	The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56.	SIGNOR-268508	0.913
MAPKAPK2	protein	P49137	UNIPROT	YWHAZ	protein	P63104	UNIPROT	down-regulates activity	phosphorylation	Ser58	VVGARRSsWRVVSSI	9606	BTO:0000007								12861023	t		miannu	We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. Mutation analysis showed that MAPKAPK2 phosphorylated 14-3-3zeta at Ser-58. S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1.	SIGNOR-250151	0.609
EGFR	protein	P00533	UNIPROT	ERBB3	protein	P21860	UNIPROT	up-regulates	phosphorylation	Tyr1289	CPASEQGyEEMRAFQ	9606	BTO:0000150								7929151	t		lperfetto	The erbb3 protein which possesses little or no intrinsic protein tyrosine kinase activiity is phosphorylated by the activated egf receptor protein tyrosine kinase on tyrosine residues within the yxxm sequence motif. These phosphorylated tyrosine residues interact with the p85 regulatory subunit of pi 3-kinase, which could result in the activation of the p110 catalytic subunit via a conformational mechanism.	SIGNOR-34752	0.654
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Ser367	GTQNPVSsPGMSQEL	9606									21364637	t		miannu	JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells	SIGNOR-277644	0.2
MACF1	protein	Q9UPN3	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity				9606	BTO:0000938								16815997	f		lperfetto	In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes.	SIGNOR-228000	0.411
NFKB1	protein	P19838	UNIPROT	THBD	protein	P07204	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17211835	f		miannu	Blocking the transcriptional activation of NF-kappaB prevented the TNFalpha-induced downregulation of TM.	SIGNOR-254811	0.2
IRS1	protein	P35568	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	binding			10116		BTO:0001103							21798082	t		lperfetto	Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate (pip2).	SIGNOR-175668	0.806
CAD	protein	P27708	UNIPROT	glutamine	smallmolecule	CHEBI:28300	ChEBI	down-regulates quantity	chemical modification			9606									24332717	t			In animals, the first three reactions of the pathway are catalyzed by CAD, an 
240 kDa multifunctional protein that combines glutamine-dependent carbamyl phosphate synthetase (GLNCPSase), aspartate transcarbamylase (ATCase), and dihydroorotase (DHOase) activities	SIGNOR-267199	0.8
IFNB1	protein	P01574	UNIPROT	IFNAR1	protein	P17181	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								11278538	t		lperfetto	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-219301	0.862
ELP3	protein	Q9H9T3	UNIPROT	Elongator complex	complex	SIGNOR-C466	SIGNOR	form complex	binding			9606									28601220	t		miannu	Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer.	SIGNOR-269710	0.8
GATA1	protein	P15976	UNIPROT	SPTA1	protein	P02549	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10037687	f	Regulation of expression	miannu	GATA-1 and CACCC-related Proteins Are Both Major Activators of the Human Erythroid β-Spectrin Gene Promoter	SIGNOR-251928	0.387
LYN	protein	P07948	UNIPROT	CASP8	protein	Q14790	UNIPROT	down-regulates activity	phosphorylation	Tyr380	TDSEEQPyLEMDLSS										18086677	t		lperfetto	The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. 	SIGNOR-272979	0.317
N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide	chemical	CHEBI:91371	ChEBI	CDK7	protein	P50613	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206136	0.8
NEK6	protein	Q9HC98	UNIPROT	NUP98	protein	P52948	UNIPROT	down-regulates activity	phosphorylation	Ser608	VLKNLNNsNLFSPVN	-1									21335236	t	done	miannu	To elucidate which of the identified sites can be targeted by CDK1/cyclin B1 and Nek6 in vitro (Figure S1D), we performed phosphorylation reactions using recombinant kinases and unlabeled ATP followed by phosphopeptide mapping (Table S1). MS analysis confirmed phosphorylation of S591 and S822 by Nek6 as well as phosphorylation of T529, T536, S595, S606, and T653 by CDK1. Phosphomimetic Mutants of Nup98 Show Defects in NPC Localization	SIGNOR-273892	0.321
RUNX2	protein	Q13950	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	binding			9606									20740684	t	Accumulated Runx2 suppressed Notch1 transcriptional activity by dissociating the Notch1-IC-RBP-Jk complex	gcesareni	Runx2 is an inhibitor of the notch1 signaling pathway during normal osteoblast differentiation. The n-terminal domain of runx2 was crucial to the binding and inhibition of the the n-terminus of the notch1 intracellular domain.	SIGNOR-167627	0.39
GSK3B	protein	P49841	UNIPROT	CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	down-regulates quantity by destabilization	phosphorylation			9606					phosphorylation:Ser9	SGRPRTTsFAESCKP 			23552696	t		lperfetto	Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1	SIGNOR-245432	0.606
QRICH1	protein	Q2TAL8	UNIPROT	TARS2	protein	Q9BW92	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269407	0.2
SRC	protein	P12931	UNIPROT	ACLY	protein	P53396	UNIPROT	up-regulates activity	phosphorylation	Tyr252	EAYPEEAyIADLDAK	9606	BTO:0000007								32420483	t	done	miannu	 We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells.	SIGNOR-274109	0.268
Av/b8 integrin	complex	SIGNOR-C185	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257730	0.568
PAS complex	complex	SIGNOR-C190	SIGNOR	1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate)(5-)	smallmolecule	CHEBI:85342	ChEBI	up-regulates quantity	chemical modification			-1									17556371	t		miannu	Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. we demonstrate a central function for each component of the core protein machinery for PtdIns(3,5)P2 synthesis and turnover in the formation/detachment (or maturation) of transport vesicle intermediates from early endosomes.	SIGNOR-253531	0.8
ACP3	protein	P15309	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	down-regulates quantity	chemical modification			-1									18940592	t		Luana	Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord.	SIGNOR-269740	0.8
IRAK1	protein	P51617	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606									15465816	t		gcesareni	Irak1 can directly use stat3 as a substrate and cause stat3 serine 727 phosphorylation.	SIGNOR-129685	0.567
POMC	protein	P01189	UNIPROT	MC3R	protein	P41968	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268705	0.75
FLT3	protein	P36888	UNIPROT	IDH2	protein	P48735	UNIPROT	down-regulates activity	phosphorylation	Tyr107	SALATQKySVAVKCA	9606	BTO:0001545								34289383	t		lperfetto	FLT3 promotes mIDH2 acetylation through Y107 phosphorylation of mIDH2 that enhances ACAT1 recruitment,	SIGNOR-267632	0.433
XXYLT1	protein	Q8NBI6	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	binding			9606									22117070	t	Xylosylation in ER membrane	gcesareni	Xxylt1 acts on the xyl1,3glc-o-linked glycan of notch egf domains.	SIGNOR-254333	0.319
MLH1	protein	P40692	UNIPROT	MLH1/PMS2	complex	SIGNOR-C59	SIGNOR	form complex	binding			9606									10542278	t		miannu	Hmlh1 and hpms2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hmutl_	SIGNOR-71771	0.747
CSNK2A2	protein	P19784	UNIPROT	GTF2A1L	protein	Q9UNN4	UNIPROT	up-regulates activity	phosphorylation	Ser418	VEEDPLNsGDDVSEQ	-1									12107178	t		llicata	ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.	SIGNOR-250993	0.424
PPP2R5A	protein	Q15172	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates	binding			9606									9774674	t		gcesareni	In this report, we show that another wd-40 repeat protein, the balpha subunit of protein phosphatase 2a, associates with the cytoplasmic domain of type i tgf-beta receptors..[..] Furthermore, balpha enhances the growth inhibition activity of tgf-beta in a receptor-dependent manner	SIGNOR-60743	0.264
4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[4-methyl-6-(4-morpholinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-pyridinone	chemical	CHEBI:91454	ChEBI	INSR	protein	P06213	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190446	0.8
MAPK1	protein	P28482	UNIPROT	SMAD3	protein	P84022	UNIPROT	unknown	phosphorylation	Ser204	NHSMDAGsPNLSPNP	9606									19914168	t		lpetrilli	In contrast, ERK2 phosphorylated all four Smad1 residues almost evenly, while showing a preference for S204 over S208 and S213 in Smad3	SIGNOR-161698	0.736
HCRTR2	protein	O43614	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257124	0.252
PTPN6	protein	P29350	UNIPROT	LCK	protein	P06239	UNIPROT	down-regulates activity	dephosphorylation	Tyr394	RLIEDNEyTAREGAK	9606									11294838	t		lperfetto	We demonstrate that shp-1 dephosphorylates the lymphoid-specific src family kinase lck at tyr-394. Because phosphorylation of tyr-394 activates lck, the fact that shp-1 specifically dephosphorylates this site suggests that shp-1 is a negative regulator of lck.	SIGNOR-106604	0.596
TGFBR2	protein	P37173	UNIPROT	TGFBR2	protein	P37173	UNIPROT	down-regulates activity	phosphorylation	Ser416	SVDDLANsGQVGTAR	9606									9155023	t		lperfetto	Tbetarii kinase is regulated intricately by autophosphorylation on at least three serine residues. Phosphorylation of ser416 inhibits receptor function.	SIGNOR-48412	0.2
UBXN2B	protein	Q14CS0	UNIPROT	AURKA	protein	O14965	UNIPROT	down-regulates activity	binding			6239									23649807	t		lperfetto	The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.|We found that UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 from embryonic extracts	SIGNOR-265042	0.309
SGK3	protein	Q96BR1	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser664	GARQRALsAVSVLTS	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275768	0.279
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates activity	chemical activation			10116	BTO:0000759								2158622	t	inferred from family member	miannu	We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 	SIGNOR-267808	0.8
SHH	protein	Q15465	UNIPROT	PTCH2	protein	Q9Y6C5	UNIPROT	down-regulates activity	binding			9606		BTO:0001253							9811851	t		lperfetto	Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH.	SIGNOR-217776	0.796
TGFBR1	protein	P36897	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates activity	binding			9606		BTO:0002181							18758450	t		lperfetto	Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis.	SIGNOR-236119	0.439
SRR	protein	Q9GZT4	UNIPROT	pyruvate	smallmolecule	CHEBI:15361	ChEBI	up-regulates quantity	chemical modification			10090		BTO:0000142							12393813	t		lperfetto	High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media.	SIGNOR-268268	0.8
CDK4	protein	P11802	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Thr179	PQSNIPEtPPPGYLS	9606									15241418	t		lperfetto	We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity	SIGNOR-232146	0.748
FGD5	protein	Q6ZNL6	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260555	0.2
ATR	protein	Q13535	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates activity	phosphorylation	Ser1457	SEKAVLTsQKSSEYP	9606	BTO:0000773								11278964	t		lperfetto	Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion.	SIGNOR-106440	0.792
MAPK14	protein	Q16539	UNIPROT	SUZ12/EZH2	complex	SIGNOR-C77	SIGNOR	up-regulates	phosphorylation			9606									21902831	t		lperfetto	P38 can phosphorylate the histone-lysine n-methyltransferase ezh2, the catalytic subunit of the polycomb repressive complex 2 (prc2), with phosphorylation of ezh2 necessary for prc2s association with the transcriptional repressor yy1 and subsequent chromatin remodelling.	SIGNOR-217676	0.381
CHKA	protein	P35790	UNIPROT	choline phosphate(1-)	smallmolecule	CHEBI:295975	ChEBI	up-regulates quantity	chemical modification												27149373	t		lperfetto	Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes	SIGNOR-275636	0.8
PLK1	protein	P53350	UNIPROT	HASPIN	protein	Q8TF76	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000567								24413556	t		miannu	Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis.	SIGNOR-275421	0.2
CSNK2A1	protein	P68400	UNIPROT	WASF2	protein	Q9Y6W5	UNIPROT	down-regulates	phosphorylation	Ser497	EFDEDDWsD	9606									19012317	t		gcesareni	Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo.	SIGNOR-182362	0.2
PPP1CA	protein	P62136	UNIPROT	NR3C1	protein	P04150	UNIPROT	up-regulates activity	dephosphorylation			9606									32585168	t		miannu	The current study assessed whether PP1\u03b1 can stimulate GR function and tested two different hypotheses: First, that PP1\u03b1 regulates GR activity through suppression of MDM2 activity by dephosphorylating it at Ser166, thereby reducing the MDM2-mediated ubiquitination of GR and the subsequent proteasomal degradation of the receptor, as shown for the MR and AR ( xref ; xref ); and second, that PP1\u03b1 directly dephosphorylates the GR at a particular site to relieve functional repression as demonstrated for PP2A and PP5 ( xref ; xref ; xref ).|The involvement of GR-Ser211 phosphorylation supports the assumption that altered subcellular trafficking is a mechanism less likely contributing to the PP1\u03b1-dependent GR activation.	SIGNOR-277161	0.295
TNFRSF1A	protein	P19438	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates				9606	BTO:0000567								11672426	f		lperfetto	Conversely, only activation of the TNFR1 could stimulate mitogen-activated protein kinase (MAPK) or p38 MAPK activities in a time-dependent manner.	SIGNOR-226637	0.38
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	GTF2I	protein	P78347	UNIPROT	up-regulates	phosphorylation			9606									10648599	t	inferred from 70% family members	lperfetto	Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation.	SIGNOR-270169	0.2
acetylsalicylic acid	chemical	CHEBI:15365	ChEBI	PTGS1	protein	P23219	UNIPROT	down-regulates	chemical inhibition			9606									11809688	t		gcesareni	Nsaids inhibit cyclooxygenase (cox) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which nsaids exert their antitumorigenic effects.	SIGNOR-114377	0.8
RPS6KA3	protein	P51812	UNIPROT	TH	protein	P07101	UNIPROT	up-regulates	phosphorylation	Ser71	RFIGRRQsLIEDARK	9606									12421349	t	The effect has been demonstrated using P07101-3	gcesareni	Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax	SIGNOR-95487	0.271
CAMKK1	protein	Q8N5S9	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	up-regulates	phosphorylation	Thr183	SDGEFLRtSCGSPNY	9606									21918180	t		gcesareni	Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli.	SIGNOR-176598	0.473
NFIX	protein	Q14938	UNIPROT	NEUROD4	protein	Q9HD90	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268905	0.2
HSP90AA1	protein	P07900	UNIPROT	PAFAH1B1	protein	P43034	UNIPROT	up-regulates quantity by stabilization	binding			9606									20133715	t		miannu	The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability.	SIGNOR-252168	0.501
DPYD	protein	Q12882	UNIPROT	uracil	smallmolecule	CHEBI:17568	ChEBI	down-regulates quantity	chemical modification												10499634	t			Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil.	SIGNOR-253988	0.8
DGC	complex	SIGNOR-C217	SIGNOR	GABA-A (a4-b3-d) receptor	complex	SIGNOR-C327	SIGNOR	up-regulates quantity	binding			9606	BTO:0000938;BTO:0002606								22626542	t		miannu	 In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses.	SIGNOR-265437	0.2
MTA1	protein	Q13330	UNIPROT	MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263854	0.811
NUMA1	protein	Q14980	UNIPROT	TUBD1	protein	Q9UJT1	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-117159	0.2
SEC61 complex	complex	SIGNOR-C368	SIGNOR	SEC62	protein	Q99442	UNIPROT	up-regulates activity	binding												33925740	t		lperfetto	This is where allosteric effectors of the Sec61 complex (BiP together with Sec62/Sec63 complex or TRAP complex) (Figure 2 and Figure 5) and auxiliary membrane protein insertases (EMC and TMCO1 complex) join the game	SIGNOR-265275	0.739
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PHF2	protein	O75151	UNIPROT	up-regulates activity	phosphorylation	Ser899	RSKKRKGsDDAPYSP	9606	BTO:0000007								21532585	t		miannu	PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h).	SIGNOR-264511	0.2
TCF4	protein	P15884	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20459685	f	 	miannu	 Cd2+ reduced the interaction of beta-catenin with AJ components (E-cadherin, alpha-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling. 	SIGNOR-255389	0.252
SAE1/SAE2 complex	complex	SIGNOR-C294	SIGNOR	JUN	protein	P05412	UNIPROT	down-regulates activity	sumoylation	Lys254	MESQERIkAERKRMR	9606	BTO:0000567			SIGNOR-C154					16055711	t		lperfetto	We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. 	SIGNOR-263005	0.257
NEUROG3	protein	Q9Y4Z2	UNIPROT	NEUROD4	protein	Q9HD90	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19028584	f		miannu	Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated.	SIGNOR-254631	0.249
KDM6A	protein	O15550	UNIPROT	HOXC4	protein	P09017	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24561908	t		miannu	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260030	0.444
GALR2	protein	O43603	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256741	0.425
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1675	SPSYSPTsPSYSPTS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248773	0.441
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation	Ser9	SGRPRTTsFAESCKP										26088133	t		lperfetto	Interestingly, GSK3beta can be released from the multienzyme complex in response to PKA phosphorylation on serine 9, which suppresses GSK3beta activity.	SIGNOR-264819	0.2
AKT1	protein	P31749	UNIPROT	STK4	protein	Q13043	UNIPROT	down-regulates	phosphorylation	Thr120	IIRLRNKtLTEDEIA	9606									19940129	t		llicata	Akt interacts with mst1 and phosphorylates a highly conserved residue threonine 120 of mst1, which leads to inhibition of its kinase activity and nuclear translocation as well as the autophosphorylation of thr(183).	SIGNOR-252507	0.406
PTPN11	protein	Q06124	UNIPROT	GRB7	protein	Q14451	UNIPROT	up-regulates activity	dephosphorylation			9606									20142421	t		miannu	Dephosphorylation of Grb7 was blocked by the SHP inhibitor NSC-87877 (Zhan et al., 2009), supporting the specificity of SHP-2 in dephosphorylating Grb7.|Nuclear SHP-2 mediates the formation of an EGF induced complex of Grb7, HuR, and CRM1.|Using the \u03ba\u2013opioid receptor (OR [KOR]) as a model, we demonstrate that EGF activates nuclear SHP-2 (Src homology region 2\u2013containing tyrosine phosphatase), which dephosphorylates Grb7 in the nucleus.	SIGNOR-277169	0.446
MTA2	protein	O94776	UNIPROT	MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263853	0.814
PRKACA	protein	P17612	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates	phosphorylation	Ser813	DIYSRRLsQETGLEI	9606									1716180	t		lperfetto	Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response.	SIGNOR-21324	0.466
NUAK1	protein	O60285	UNIPROT	PPP1R12A	protein	O14974	UNIPROT	down-regulates	phosphorylation	Ser472	AGVTRSAsSPRLSSS	9606									20354225	t		gcesareni	Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity.	SIGNOR-164751	0.522
glycine	smallmolecule	CHEBI:15428	ChEBI	GLRA1	protein	P23415	UNIPROT	up-regulates activity	chemical activation			9606		BTO:0001175;BTO:0001279;BTO:0000146							18721822	t		miannu	The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. 	SIGNOR-264980	0.8
TAB2	protein	Q9NYJ8	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	binding			9606									14670075	t		lperfetto	Our results indicate that two distinct TAK1 complexes are present in cells. One comprises TAK1 complexed with TAB1 and TAB2, and the other TAK1 complexed with TAB1 and TAB3. Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1 in human epithelial KB cells or bacterial lipopolysaccharide in RAW264.7 macrophages	SIGNOR-120268	0.934
WT1	protein	P19544	UNIPROT	REN	protein	P00797	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18496514	t			Here, we show that a splice variant of the Wilms' tumor protein lacking three amino acids WT1(-KTS) suppresses renin gene transcription	SIGNOR-252296	0.433
A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269008	0.7
MAPK8	protein	P45983	UNIPROT	NR4A1	protein	P22736	UNIPROT	down-regulates	phosphorylation	Ser95	TSSSSATsPASASFK	9606									17023523	t		llicata	We also identified the exact phosphorylation site of jnk to be serine 95 at the n terminus of tr3, around which a classical jnk phosphorylation motif exists. Furthermore, we demonstrated that tr3 phosphorylation by jnk coincided with its ubiquitination and degradation, resulting in the loss of its mitogenic activity.	SIGNOR-149998	0.515
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr234	SFKKQEKtPKTPKGP	9606									11278991	t		lperfetto	We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication.	SIGNOR-216674	0.415
AKT1	protein	P31749	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation	Thr1462	GLRPRGYtISDSAPS	10090	BTO:0000944								12150915	t		lperfetto	We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines.	SIGNOR-235515	0.811
SNRPC	protein	P09234	UNIPROT	U1 snRNP complex	complex	SIGNOR-C480	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270679	0.899
HYDIN	protein	Q4G0P3	UNIPROT	GATA4	protein	P43694	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001086								32376282	t		miannu	HYDIN promotes expression of Gata4 in cardiomyocyte differentiation. HYDIN functions as a positive regulator of human cardiomyocyte differentiation and promotes expression of cardiac contractile genes in hESC cells. This is mediated through GATA4, a critical transcription factor in heart development. Cardiac-specific Hydin knockdown in vivo leads to Gata4 downregulation and enhanced atrial septal defect (ASD) risk in mice. GATA4 is a fundamental TF in embryonic heart development and cardiac differentiation, and reduction in GATA4 function results in a diverse range of CHDs	SIGNOR-265479	0.2
TOR1AIP1	protein	Q5JTV8	UNIPROT	VIM	protein	P08670	UNIPROT	up-regulates activity	binding			9606	BTO:0000452								16361107	t		Sara	Co-immune precipitation studies revealed association between vimentin and torsinA in a complex. these studies suggest that mutant torsinA interferes with cytoskeletal events involving vimentin, possibly by restricting movement of these particles/filaments, and hence may affect development of neuronal pathways in the brain.	SIGNOR-261313	0.2
SRC	protein	P12931	UNIPROT	HNF4A	protein	P41235	UNIPROT	down-regulates	phosphorylation	Tyr288	IDDNEYAyLKAIIFF	9606									22308320	t		lperfetto	Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function.	SIGNOR-195900	0.374
PTPN6	protein	P29350	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates	dephosphorylation			9606									18508557	t		gcesareni	Stat3 may also be a substrate of shp1	SIGNOR-178699	0.47
OTX2	protein	P32243	UNIPROT	BEST1	protein	O76090	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									20530484	f		miannu	 BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. 	SIGNOR-255186	0.359
C8A	protein	P07357	UNIPROT	Membrane attack complex	complex	SIGNOR-C313	SIGNOR	form complex	binding			-1									30552328	t		lperfetto	The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer	SIGNOR-263445	0.579
PRKCD	protein	Q05655	UNIPROT	CXCR4	protein	P61073	UNIPROT	down-regulates activity	phosphorylation	Ser339	GKRGGHSsVSTESES	9606									10521508	t		Manara	Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization.	SIGNOR-260901	0.2
CYSLTR1	protein	Q9Y271	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257019	0.357
MAPK1	protein	P28482	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates	phosphorylation	Ser21	PMSSHLQsPPHAPSS	9606	BTO:0000876								14701740	t		lperfetto	Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21.	SIGNOR-120566	0.361
gamma-secretase	complex	SIGNOR-C98	SIGNOR	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	cleavage			9606									25610395	t		lperfetto	The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a γ-secretase substrate. γ-Secretase performs the subsequent cleavage at S3, releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 family of DNA binding proteins. 	SIGNOR-209717	0.665
PTGER2	protein	P43116	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256756	0.409
XL765	chemical	CHEBI:71958	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207869	0.8
LTF	protein	P02788	UNIPROT	iron(3+)	smallmolecule	CHEBI:29034	ChEBI	up-regulates quantity	relocalization			9606									11747454	t			Lactoferrin (Lf), a major iron-binding protein in human milk, has been suggested to have multiple biological roles such as facilitating iron absorption, modulating the immune system, embryonic development, and cell proliferation.	SIGNOR-272473	0.8
STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	MAP1LC3B	protein	Q9GZQ8	UNIPROT	down-regulates activity	phosphorylation	Thr50	QLPVLDKtKFLVPDH	-1									31857374	t	done	miannu	LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1).	SIGNOR-273905	0.2
AP2A2	protein	O94973	UNIPROT	AP-2 complex	complex	SIGNOR-C245	SIGNOR	form complex	binding												31671891	t		lperfetto	 The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit	SIGNOR-260423	0.85
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	FERMT2	protein	Q96AC1	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser175	GPLITPGsGSIYSSP	9606	BTO:0000567								35469017	t		miannu	 CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry.	SIGNOR-276716	0.2
CSNK2A1	protein	P68400	UNIPROT	DDIT3	protein	P35638	UNIPROT	down-regulates activity	phosphorylation	Ser30	EDLQEVLsSDENGGT	9606	BTO:0000567								12876286	t		llicata	CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites 	SIGNOR-250852	0.35
SRC	protein	P12931	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Tyr537	CKNVVPLyDLLLEML	9606	BTO:0000150;BTO:0000567								9500442	t		tpavlidou	Although the molecular mechanisms underlying ligand-independent activation of era are not completely understood, phosphorylation of a serine residue in af1 has been implicated in the response to epidermal growth factor. Era is also a target for tyrosine phosphorylation, anda single tyrosine residue located immediately adjacent to af2 has been identified as a substrate for src-family tyrosine kinases.	SIGNOR-55857	0.77
TNF	protein	P01375	UNIPROT	LPL	protein	P06858	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16106106	f	Regulation	miannu	TNF-α and IL-6 inhibit lipoprotein lipase	SIGNOR-251855	0.401
ML240	chemical	CHEBI:143014	ChEBI	VCP	protein	P55072	UNIPROT	down-regulates activity	chemical inhibition			-1									23316025	t		Monia	Inhibition of p97 by ML240 and ML241 is ATP competitive. To determine the mechanism by which ML240 and ML241 inhibited p97 ATPase, we evaluated rates of ATP hydrolysis at different concentrations of ATP. ML240 and ML241 inhibited p97competitively with respect to ATP with a Kivalues of 0.22 mm and 0.35 mm respectively.	SIGNOR-261066	0.8
PDPK1	protein	O15530	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser221	DHEKKAYsFCGTVEY	9534	BTO:0000298								10480933	t		miannu	90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1.	SIGNOR-252763	0.642
MAPK12	protein	P53778	UNIPROT	SNTA1	protein	Q13424	UNIPROT	up-regulates	phosphorylation	Ser193	GWDSPPAsPLQRQPS	9606									10212242	t		lperfetto	Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates.	SIGNOR-67061	0.655
CDC14B	protein	O60729	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	dephosphorylation	Ser315	LPNNTSSsPQPKKKP	9606									10644693	t			The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53|. Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34Cdc2/clb phosphorylation site (p53-phosphor-Ser315)|Earlier studies showed that Ser315 phosphorylation increases the sequence-specific DNA binding capacity of p53, suggesting that Ser315 phosphorylation is an activating modification	SIGNOR-248332	0.338
GNAI1	protein	P63096	UNIPROT	ADCY1	protein	Q08828	UNIPROT	down-regulates activity	binding			9606									19703466	t			GTP-bound, active WT Gαi1 acts to inhibit AC, resulting in a decreased concentration of intracellular cAMP.	SIGNOR-256498	0.533
INSR	protein	P06213	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	phosphorylation	Tyr992	DGPLGPLyASSNPEY	-1									3166375	t		lperfetto	This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972	SIGNOR-106522	0.2
MAVS	protein	Q7Z434	UNIPROT	IKBKE	protein	Q14164	UNIPROT	up-regulates activity	binding			9606									25636800	t		miannu	After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively. 	SIGNOR-260144	0.826
KDM4C	protein	Q9H3R0	UNIPROT	H3-4	protein	Q16695	UNIPROT	down-regulates activity	demethylation	Lys37	APATGGVkKPHRYRP	9606									29207681	t		miannu	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 	SIGNOR-263866	0.2
E2F1	protein	Q01094	UNIPROT	CTNND2	protein	Q9UQB3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001033								21106062	f		miannu	Coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression.	SIGNOR-251876	0.2
JAK2	protein	O60674	UNIPROT	LEPR	protein	P48357	UNIPROT	up-regulates activity	phosphorylation	Tyr1141	SKKTFASyMPQFQTC	9606	BTO:0000007								11018044	t		miannu	LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. 	SIGNOR-263494	0.766
FUBP1	protein	Q96AE4	UNIPROT	TNFSF10	protein	P50591	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19637194	f		irozzo	FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In addition, mRNA levels of the death ligands tumor necrosis factor (TNF) α and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) were significantly increased.	SIGNOR-259129	0.2
PXN	protein	P49023	UNIPROT	Cell_migration	phenotype	SIGNOR-PH38	SIGNOR	up-regulates				9606									18650496	f	VEGF pathway	Gianni	Through the interactions of its multiple protein-protein binding modules, many of which are regulated by phosphorylation, paxillin serves as a platform for the recruitment of numerous regulatory and structural proteins that together control the dynamic changes in cell adhesion, cytoskeletal reorganization and gene expression that are necessary for cell migration and survival.	SIGNOR-261944	0.7
Mitochondrial Fe-S Cluster Assembly Complex	complex	SIGNOR-C276	SIGNOR	iron-sulfur cluster	smallmolecule	CHEBI:30408	ChEBI	up-regulates quantity	chemical modification			-1									27519411	t		lperfetto	As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry.	SIGNOR-262129	0.8
EMX1	protein	Q04741	UNIPROT	NRP1	protein	O14786	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									26534986	t		Luana	EMX1 activates the transcription of Nrp1 in vitro.	SIGNOR-261593	0.2
TAF12	protein	Q16514	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269580	0.746
4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	chemical	CHEBI:49868	ChEBI	PLK1	protein	P53350	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190281	0.8
PRKACA	protein	P17612	UNIPROT	RAP1GAP	protein	P47736	UNIPROT	unknown	phosphorylation	Ser499	PFGSRRSsAIGIENI	-1									1406653	t		miannu	We have localized two of the sites of phosphorylation in vitro by cAMP-dependent kinase to serine residues 490 and 499. raplGAP undergoes phosphorylation at specific sites in vivo, the effects of phosphorylation on raplGAP have remained elusive.	SIGNOR-250044	0.313
ACAT1	protein	P24752	UNIPROT	ME1	protein	P48163	UNIPROT	up-regulates activity	acetylation	Lys337	KIWLVDSkGLIVKGR										31735643	t		lperfetto	PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. 	SIGNOR-275571	0.251
GOT2	protein	P00505	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	down-regulates quantity	chemical modification			9606									31422819	t		miannu	This is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1).	SIGNOR-268060	0.8
IRF1	protein	P10914	UNIPROT	SOCS2	protein	O14508	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22291912	f		miannu	 SOCS2 induction by LPS was dependent on the type I IFN regulated transcription factors IRF1 and IRF3 as shown by using silencing RNAs for IRFs. 	SIGNOR-254494	0.316
EEF1A1	protein	P68104	UNIPROT	Lys-tRNA(Lys)	smallmolecule	CHEBI:16047	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269502	0.8
CDK6	protein	Q00534	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates	phosphorylation	Ser10	NVRVSNGsPSLERMD	9606									16160006	t		gcesareni	Phosphorylation on ser-10 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.p27(kip1) was phosphorylated by v-cyclin-cdk6 predominantly on ser10, which enhances its cytoplasmic localization.	SIGNOR-140401	0.85
Survival Factors	stimulus	SIGNOR-ST8	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates				9606	BTO:0000938								9346240	f		lperfetto	Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death MachineryAkt phosphorylates BAD in vitro and in vivo, and blocks the BAD-induced death of primary neurons in a site-specific manner.	SIGNOR-209693	0.7
PRKACA	protein	P17612	UNIPROT	HMGCR	protein	P04035	UNIPROT	down-regulates activity	phosphorylation	Ser872	SHMIHNRsKINLQDL	10116									2369897	t		miannu	The intact, 100 kd microsomal enzyme and the 53 kd catalytic fragment of rat HMG-CoA reductase are both phosphorylated and inactivated by the AMP-activated protein kinase. this site is highly phosphorylated in intact liver under these conditions (Ser872 in the human enzyme).	SIGNOR-249992	0.338
HES1	protein	Q14469	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								14614508	f			Overexpression of HES-1 fully repressed PPAR-g even in the presence of the ACREB inhibitor, showing that HES-1 acts downstream of CREB	SIGNOR-254743	0.251
CPSF3	protein	Q9UKF6	UNIPROT	CPSF complex	complex	SIGNOR-C53	SIGNOR	form complex	binding			9606	BTO:0000007								19224921	t		lperfetto	The CPSF complex consists of five subunits, named CPSF160, CPSF100, Fip1, CPSF73, and CPSF30.	SIGNOR-268333	0.878
CSNK2A1	protein	P68400	UNIPROT	PPP1R1B	protein	Q9UD71	UNIPROT	up-regulates activity	phosphorylation	Ser45	LFRLSEHsSPEEEAS	-1									2557337	t		llicata	Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase	SIGNOR-250928	0.346
MAPK8IP3	protein	Q9UPT6	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates	binding			9606									10629060	t		gcesareni	These data demonstrate that jip3 interacts with proteins that can form a mapk signaling module, including jnk, mkk7, and mlk3	SIGNOR-73906	0.691
MYH9	protein	P35579	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	up-regulates activity	binding			9606	BTO:0004953								32685004	t		miannu	Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo.	SIGNOR-269285	0.257
KDM4C	protein	Q9H3R0	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									29207681	t		miannu	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 	SIGNOR-263869	0.2
GSK3B	protein	P49841	UNIPROT	GRB14	protein	Q14449	UNIPROT	down-regulates activity	phosphorylation	Ser358	MHPYQGRsGCSSQSI	-1									28130417	t		lperfetto	Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3.	SIGNOR-264868	0.328
CDK1	protein	P06493	UNIPROT	NDUFA12	protein	Q9UI09	UNIPROT	up-regulates activity	phosphorylation	Thr142	QEWIPPStPYK										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275587	0.2
HMGA2	protein	P52926	UNIPROT	SCNN1A	protein	P37088	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0001003								11390395	f	Regulation of expression	miannu	Expression of endogenous alpha-ENaC gene in salivary Pa-4 cells is suppressed by an ectopic HMGI-C overexpression.	SIGNOR-251946	0.2
diisononyl phthalate	chemical	CHEBI:35459	ChEBI	OXER1	protein	Q8TDS5	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). 	SIGNOR-268773	0.8
PRKCA	protein	P17252	UNIPROT	HABP4	protein	Q5JVS0	UNIPROT	down-regulates activity	phosphorylation	Thr375	GRGARGGtRGGRGRI	9606	BTO:0004974								14699138	t		lperfetto	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249252	0.293
PTPN11	protein	Q06124	UNIPROT	GAB1	protein	Q13480	UNIPROT	down-regulates activity	dephosphorylation	Tyr659	VADERVDyVVVDQQK	9606									11323411	t			These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro.	SIGNOR-248675	0.952
IKBKB	protein	O14920	UNIPROT	BCL10	protein	O95999	UNIPROT	up-regulates activity	phosphorylation	Ser141	SRSNSDEsNFSEKLR	9606	BTO:0000007								16818229	t		miannu	Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling.	SIGNOR-276293	0.765
TG101209	chemical	CHEBI:90304	ChEBI	RET	protein	P07949	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207269	0.8
7a	protein	P59635	UNIPROT	Cell_cycle_block	phenotype	SIGNOR-PH10	SIGNOR	up-regulates				9606	BTO:0000007								16303160	f		Luana	Expression of SARS-CoV ORF7a block cell cycle arrest in G0/G1	SIGNOR-260207	0.7
PDE3A	protein	Q14432	UNIPROT	ATP2A2	protein	P16615	UNIPROT	down-regulates activity	binding			9606		BTO:0000199							25593322	t		lperfetto	Regulation of sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) activity by phosphodiesterase 3A (PDE3A) in human myocardium: phosphorylation-dependent interaction of PDE3A1 with SERCA2.|PDE3A co-localized with PLB, SERCA2, and an AKAP18 variant|our studies show that PDE3-selective inhibition (but not PDE4 inhibition) potentiates the phosphorylation of PLB by endogenous PKA and stimulation of SERCA2 activity and Ca2+ uptake in SR-enriched vesicles prepared from human myocardium.	SIGNOR-262051	0.348
NOTCH1	protein	P46531	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	up-regulates				9606									22298955	f		gcesareni	Similar synergy is found in notch and bmp crosstalk: activating notch signaling enhanced bmp-induced alp activity and formation of calcified nodules in vitro.	SIGNOR-114592	0.361
DDIT3	protein	P35638	UNIPROT	ANKRD1	protein	Q15327	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0003324								19299913	f	 	lperfetto	Promoter deletion and reporter analysis revealed that hypoxia transcriptionally activates a GADD153 promoter through the AP-1 element in neonatal cardiomyocytes. Ectopic overexpression of GADD153 resulted in the downregulation of CARP expression.	SIGNOR-254122	0.277
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1724	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269334	0.718
ELF2	protein	Q15723	UNIPROT	VCP	protein	P55072	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								18544453	f	 	 	These findings indicate that ELF2 transactivates VCP promoter through binding to two motifs, with a predominant contribution of the upstream one.	SIGNOR-254283	0.369
ARF6	protein	P62330	UNIPROT	PIP4K2A	protein	P48426	UNIPROT	up-regulates activity				10116	BTO:0003102								14565977	t		miannu	Effects of ARF6 upon Axonogenesis Are Mediated by Phosphatidyl-inositol-4-phosphate 5-Kinase α. activated ARF6 stimulates the lipid-modifying enzyme PI(4)P 5-Kinase, leading to local increases in plasma membrane PIP2 and changes in actin dynamics. Alternatively, activation of Rac1 by upstream Rac1 activators or indirectly by ARF6-GTP results in stimulation of actin polymerization. 	SIGNOR-264911	0.345
AM/b2 integrin	complex	SIGNOR-C170	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269019	0.7
ATP13A1	protein	Q9HD20	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				9606	BTO:0004093								29650961	f	doi.org/10.1101/185272	francesca	Loss of ATP13A3 led to marked inhibition of serum-stimulated proliferation of BOECs, and increased apoptosis in serum-deprived conditions	SIGNOR-261217	0.7
SRC	protein	P12931	UNIPROT	CBLC	protein	Q9ULV8	UNIPROT	up-regulates	phosphorylation	Tyr341	SEEQLQLyWAMDSTF	9606									20525694	t		gcesareni	Phosphorylation of a critical tyrosine (tyr-341) in the linker region of cbl-c by src or a phosphomimetic mutation of this tyrosine (y341e) is sufficient to increase the e3 activity of cbl-c.	SIGNOR-165862	0.551
DYRK2	protein	Q92630	UNIPROT	SIAH2	protein	O43255	UNIPROT	up-regulates	phosphorylation	Ser28	PQPQHTPsPAAPPAA	9606									22878263	t		llicata	In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis.	SIGNOR-198725	0.42
MAPK12	protein	P53778	UNIPROT	Satellite_cells_self-renewal	phenotype	SIGNOR-PH100	SIGNOR	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002314	BTO:0001103							29681515	f		apalma	[...] we observed a significant diminution in the number of symmetric satellite stem cell (YFP–) divisions in p38 gamma siRNA-treated fibers, suggesting that p38 gamma is required for symmetric stem cell maintenance. Thus, loss of p38gamma greatly skewed the ratio of asymmetric to symmetric satellite stem cell divisions to favor asymmetric divisions and myogenic commitment at the expense of self-renewal	SIGNOR-255902	0.7
PPP1R1B	protein	Q9UD71	UNIPROT	PPP1CC	protein	P36873	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								10604473	t		miannu	DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚ 	SIGNOR-264958	0.579
PRKCA	protein	P17252	UNIPROT	FBXW7	protein	Q969H0	UNIPROT	down-regulates activity	phosphorylation	Ser18	KRRRTGGsLRGNPSS	9606	BTO:0000567								28850619	t		miannu	Here, we report that Fbw7α, the only Fbw7 isoform detected in eggs, is phosphorylated by PKC (protein kinase C) at a key residue (S18) in a manner coincident with Fbw7α inactivation.	SIGNOR-277249	0.352
FBXW7	protein	Q969H0	UNIPROT	MED13L	protein	Q71F56	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007		SIGNOR-C135						23322298	t		miannu	The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association.	SIGNOR-266688	0.366
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	NFATC4	protein	Q14934	UNIPROT	up-regulates	phosphorylation			9606									15657420	t	inferred from 70% family members	lperfetto	The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity.	SIGNOR-270160	0.2
NLGN4Y	protein	Q8NFZ3	UNIPROT	NRXN1	protein	P58400	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264148	0.2
ID2	protein	Q02363	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates activity	binding			10090	BTO:0004058			SIGNOR-C127					9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241140	0.603
CDC14B	protein	O60729	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates	dephosphorylation	Ser705	TPSAMKSsPQIPHQT	9606									20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis.	SIGNOR-164479	0.552
metformin	chemical	CHEBI:6801	ChEBI	PRKAA1	protein	Q13131	UNIPROT	up-regulates activity				10116									11602624	f		gcesareni	Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin€™s inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation	SIGNOR-241952	0.8
CDK3	protein	Q00526	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates activity	phosphorylation	Ser104	FPPLNSVsPSPLMLL										26202215	t		lperfetto	CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3	SIGNOR-273189	0.263
PPARGC1A	protein	Q9UBK2	UNIPROT	OTC	protein	P00480	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f		miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-255056	0.2
MAPK11	protein	Q15759	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates	phosphorylation			9606									20820849	t		gcesareni	Smads can also be phosphorylated in the linker region most prominently by the action of mitogen-activated protein (map) kinaseslinker region phosphorylation can prevent nuclear translocation of smads and inhibit tgf-_ signalling, potentially leading to oncogenesis.	SIGNOR-167848	0.36
FZD8	protein	Q9H461	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606	BTO:0000971								21078818	t		amattioni	Ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane domain receptor Frizzled (Fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (LRP5/6) to activate Wnt–Beta-catenin signaling.	SIGNOR-169638	0.745
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MYB	protein	P10242	UNIPROT	down-regulates	phosphorylation	Ser532	KIKQEVEsPTDKSGN	9606	BTO:0000661								8960373	t		lperfetto	Functional analysis of phosphorylation at serine 532 of human c-myb by map kinase. expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532. Our data suggest that the mapk-dependent state of phosphorylation modifies the cellular function of c-myb by modulating its interaction with a putative inhibitory factor	SIGNOR-244569	0.2
sulindac	chemical	CHEBI:9352	ChEBI	RXRA	protein	P19793	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001109								20541701	t		Luana	NSAID Sulindac and Its Analogs Bind RXRα and Inhibit RXRα-dependent AKT Signaling	SIGNOR-257847	0.8
SYK	protein	P43405	UNIPROT	HCLS1	protein	P14317	UNIPROT	up-regulates	phosphorylation	Tyr397	EDEPEGDyEEVLEPE	9606	BTO:0000776								9104825	t		llicata	Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis.	SIGNOR-47342	0.652
PLIN3	protein	O60664	UNIPROT	IGF2R	protein	P11717	UNIPROT	up-regulates activity	relocalization			9534	BTO:0004055								9590177	t		lperfetto	TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi.	SIGNOR-253092	0.715
ZNF322	protein	Q6U7Q0	UNIPROT	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									24550733	t		lperfetto	Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays revealed that Zfp322a binds to Pou5f1 and Nanog promoters and regulates their transcription.	SIGNOR-264900	0.2
POMC	protein	P01189	UNIPROT	CDKN2A	protein	P42771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11830546	f		miannu	The expression of the melanoma susceptibility gene product p16 is increased after UVR both in epidermally derived cell lines and in human skin. the increased expression of p16 after exposure to suberythemal doses of UVR is potentiated by α-MSH, a ligand for MC1R, and this effect is mimicked by cAMP, the intracellular mediator of α-MSH signaling via the MC1 receptor.	SIGNOR-252377	0.27
bosutinib	chemical	CHEBI:39112	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190696	0.8
BLOC1S3	protein	Q6QNY0	UNIPROT	BLOC-1	complex	SIGNOR-C381	SIGNOR	form complex	binding			9606									22203680	t		lperfetto	We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter.	SIGNOR-265934	0.705
PRKAA1	protein	Q13131	UNIPROT	EEF2K	protein	O00418	UNIPROT	down-regulates activity	phosphorylation	Ser78	SSGSPANsFHFKEAW	-1									14709557	t		miannu	AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase	SIGNOR-250314	0.473
PPP1CB	protein	P62140	UNIPROT	IKZF1	protein	Q13422	UNIPROT	up-regulates	dephosphorylation			9606									21750978	t		miannu	Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway	SIGNOR-174862	0.268
PAK3	protein	O75914	UNIPROT	TNNI3	protein	P19429	UNIPROT	unknown	phosphorylation	Ser150	TLRRVRIsADAMMQA	9606		BTO:0000887							12242269	t		llicata	Importantly, cardiac troponin i was found to be phosphorylated at serine 149 of human cardiac troponin i, representing a novel phosphorylation site. These findings suggest a novel mechanism of modulating the calcium sensitivity of cardiac muscle contraction.	SIGNOR-92990	0.2
EIF4E	protein	P06730	UNIPROT	Translational_regulation	phenotype	SIGNOR-PH202	SIGNOR	up-regulates				9606									30459806	f		gianni	The mRNA cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E), is involved in the recruitment of the ribosome to the mRNA cap structure, playing a central role in the regulation of translation initiation	SIGNOR-268529	0.7
EGFR	protein	P00533	UNIPROT	GSTP1	protein	P09211	UNIPROT	up-regulates	phosphorylation	Tyr199	AFLASPEyVNLPING	9606	BTO:0000150								19254954	t		llicata	Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly,	SIGNOR-184379	0.448
AR	protein	P10275	UNIPROT	CLK3	protein	P49761	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001321								16281084	f	 	 	 After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes.	SIGNOR-253672	0.2
IL2RB	protein	P14784	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271;BTO:0000785								24737791	t		milica	The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival	SIGNOR-204975	0.538
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates	chemical inhibition			9606									17891169	t		fspada	Hydroxamate derivatives are the most powerful category of hdaci, active on class i and ii hdac,especially on hdac1 and hdac2. In the study reported here, we described the anti-leukaemic properties of itf2357, a recently synthesized, orally active hydroxamate derivative.	SIGNOR-157857	0.8
CAMK2D	protein	Q13557	UNIPROT	SCN5A	protein	Q14524	UNIPROT	down-regulates	phosphorylation	Ser516	LSLTRGLsRTSMKPR	9606									22514276	t		miannu	A stable interaction between ?(C)-camkii and the intracellular loop between domains 1 and 2 of na(v)1.5 was observed. This region was also phosphorylated by ?(C)-camkii, specifically at the ser-516 and thr-594 sites.Wild-type (wt) and phosphomutant hna(v)1.5 were co-expressed with gfp-?(C)-camkii in hek293 cells, and i(na) was recorded. As observed in myocytes, camkii shifted wt i(na) availability to a more negative membrane potential and enhanced accumulation of i(na) into an intermediate inactivated state, but these effects were abolished by mutating either of these sites to non-phosphorylatable ala residues.	SIGNOR-197058	0.48
RPS4Y1	protein	P22090	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262446	0.2
ME2	protein	P23368	UNIPROT	NADPH(4-)	smallmolecule	CHEBI:57783	ChEBI	up-regulates quantity	chemical modification			9606									24769394	t		miannu	The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle	SIGNOR-267054	0.8
malonyl-CoA	smallmolecule	CHEBI:15531	ChEBI	CPT1C	protein	Q8TCG5	UNIPROT	down-regulates activity	binding			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267116	0.8
MAPK14	protein	Q16539	UNIPROT	PIAS2	protein	O75928	UNIPROT	up-regulates activity	phosphorylation	Ser113	STSVTPHsPSSPVGS	9606	BTO:0000007								16713578	t		miannu	The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles	SIGNOR-262948	0.322
PTPN12	protein	Q05209	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	dephosphorylation	Tyr1008	LPQDKEYyKVKEPGE	9606	BTO:0003892								11731619	t			PTP-PEST-Containing Lysates from EGF-Treated HC11 Cells Dephosphorylate JAK2 More Efficiently than Lysates from Control Cells|phospho-JAK2-specific rabbit polyclonal antiserum (44-426, BioSource Technologies, Inc., Camarillo, CA) which recognizes Tyr1007/1008 in the activation site 	SIGNOR-248658	0.384
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	MAPT	protein	P10636	UNIPROT	up-regulates	dephosphorylation	Ser579	NVKSKIGsTENLKHQ	9606		BTO:0000142							20308788	t	The effect has been demonstrated using P10636-8	lperfetto	Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro.	SIGNOR-164663	0.2
PTPRF	protein	P10586	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									10734133	t		gcesareni	Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product.	SIGNOR-76013	0.563
GSK3A	protein	P49840	UNIPROT	NIFK	protein	Q9BYG3	UNIPROT	up-regulates activity	phosphorylation	Thr234	TVDSQGPtPVCTPTF	-1									16244663	t		miannu	The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1.	SIGNOR-262697	0.2
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2U	protein	Q5VVX9	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271337	0.532
PRKAA2	protein	P54646	UNIPROT	EEF2K	protein	O00418	UNIPROT	down-regulates activity	phosphorylation	Ser78	SSGSPANsFHFKEAW	-1									14709557	t		miannu	AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase	SIGNOR-250321	0.48
lapatinib	chemical	CHEBI:49603	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193627	0.8
AURKA	protein	O14965	UNIPROT	ALDH1A1	protein	P00352	UNIPROT	up-regulates activity	phosphorylation	Thr493	YTEVKTVtVKISQKN	-1									28193222	t		miannu	AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species. 	SIGNOR-276749	0.381
TFIIH	complex	SIGNOR-C457	SIGNOR	NR5A1	protein	Q13285	UNIPROT	up-regulates	phosphorylation	Ser203	EYPEPYAsPPQPGLP	9606									17901130	t		llicata	In conclusion, our results indicate that cdk7, as part of the cak complex and tfiih, phosphorylates sf1 at s203 followed by increased transcriptional activity of sf1	SIGNOR-269355	0.2
Spike protein-ACE2	complex	SIGNOR-C240	SIGNOR	Receptor_mediated_ endocytosis	phenotype	SIGNOR-PH121	SIGNOR	up-regulates				9606									18554741	f		miannu	Endocytosis of the Receptor-Binding Domain of SARS-CoV Spike Protein Together With Virus Receptor ACE2. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells.	SIGNOR-260289	0.7
CoV2 Spike protein-ACE2	complex	SIGNOR-C254	SIGNOR	Receptor_mediated_ endocytosis	phenotype	SIGNOR-PH121	SIGNOR	up-regulates				9606									32221306	f		miannu	We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease.	SIGNOR-260743	0.7
CoV2 spike protein-NRP1	complex	SIGNOR-C267	SIGNOR	Receptor_mediated_ endocytosis	phenotype	SIGNOR-PH121	SIGNOR	up-regulates				10090	BTO:0000108								33082293	t		Luana	NRP mediates entry of nanoparticles coated with SARS-CoV-2 (SARS-2) S–derived CendR peptides into cultured cells, olfactory epithelium, and the central nervous system of mice.	SIGNOR-262316	0.7
SND1	protein	Q7KZF4	UNIPROT	IGFBP3	protein	P17936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23878061	f		irozzo	Therefore, we concluded that SND1 could affect SMMC-7721 cells proliferation by regulating IGFBP3 expression and IGF signaling pathway.	SIGNOR-259140	0.2
FGF12	protein	P61328	UNIPROT	SCN9A	protein	Q15858	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253424	0.2
CoV2 Spike protein-ACE2	complex	SIGNOR-C254	SIGNOR	Membrane_fusion	phenotype	SIGNOR-PH122	SIGNOR	up-regulates				9606									32231345	f	doi.org/10.1101/2020.03.09.983247	miannu	Unlike SARS-CoV, live SARS-CoV-2-infected cells were found to form typical syncytium, suggesting that SARS-CoV-2 may mainly utilize the plasma membrane fusion pathway to enter and replicate inside host cells. Consistently, in the cell-cell fusion system, SARS-CoV-2 S protein could effectively mediate the formation of syncytium between the effector cell and the target cell in the absence of an exogenous proteolytic enzyme, e.g., trypsin, while SARS-CoV S protein could not. Actually, the plasma membrane fusion pathway is more efficient than the endosomal membrane fusion pathway for most viruses because the latter is more prone to activating the host cell antiviral immunity.	SIGNOR-260741	0.7
CoV2 Spike protein-ACE2	complex	SIGNOR-C254	SIGNOR	Membrane_fusion	phenotype	SIGNOR-PH122	SIGNOR	up-regulates				9606									32221306	f		miannu	We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease.	SIGNOR-260744	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation			10090									14981546	t		miannu	Phosphorylation of Foxo proteins through FLT3-ITD signaling promotes their translocation from the nucleus into the cytoplasm, which requires the presence of conserved Akt phosphorylation sites in Forkhead transcription factors and PI3K activity.	SIGNOR-261526	0.2
Calcineurin	complex	SIGNOR-C155	SIGNOR	FLNA	protein	P21333	UNIPROT	down-regulates	dephosphorylation	Ser2152	TRRRRAPsVANVGSH	9606									16442073	t		gcesareni	We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells	SIGNOR-252339	0.27
DOK1	protein	Q99704	UNIPROT	AE/b7 integrin	complex	SIGNOR-C186	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257696	0.329
SRC	protein	P12931	UNIPROT	GSN	protein	P06396	UNIPROT	unknown	phosphorylation	Tyr465	VPVPTNLyGDFFTGD	-1									10210201	t		llicata	Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624.	SIGNOR-250784	0.576
DYRK1A	protein	Q13627	UNIPROT	DYRK1A	protein	Q13627	UNIPROT	up-regulates	phosphorylation	Tyr319	CQLGQRIyQYIQSRF	9606									10910078	t		lperfetto	Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site	SIGNOR-79760	0.2
ATF1	protein	P18846	UNIPROT	EGR1	protein	P18146	UNIPROT	up-regulates quantity by expression	transcriptional regulation												10391889	t		lperfetto	Phosphorylated CREB and ATF1 then bind to the CRE of the egr-1 promoter and cause a stress-dependent transcriptional activation of this gene.	SIGNOR-271686	0.279
CD19	protein	P15391	UNIPROT	VAV1	protein	P15498	UNIPROT	up-regulates activity	binding			10090									25673924	t		lperfetto	CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades.	SIGNOR-242897	0.713
CHEK1	protein	O14757	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Thr18	EPPLSQEtFSDLWKL	9606									15659650	t		lperfetto	CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37	SIGNOR-217803	0.772
DOK1	protein	Q99704	UNIPROT	AM/b2 integrin	complex	SIGNOR-C170	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257682	0.301
CDK1	protein	P06493	UNIPROT	KAT7	protein	O95251	UNIPROT	up-regulates	phosphorylation	Thr88	QQQPTPVtPKKYPLR	9606									18250300	t		lperfetto	Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate.	SIGNOR-160747	0.363
TERB2	protein	Q8NHR7	UNIPROT	Cohesin complex	complex	SIGNOR-C304	SIGNOR	up-regulates activity	relocalization						SIGNOR-C305						27025256	t		lperfetto	Terb1 and Sun1 are two key proteins linking the meiotic telomeres to the NE. Terb1 participates in telomere fortification by recruiting cohesins to the site	SIGNOR-263306	0.2
ASTN1	protein	O14525	UNIPROT	Neuron_migration	phenotype	SIGNOR-PH67	SIGNOR	up-regulates				9606	BTO:0000142								28506896	f		miannu	The role of astrotactin and Brinp proteins has been partially characterized, with ASTN1 and ASTN2 demonstrated to facilitate glial-guided neuronal migration during brain development	SIGNOR-269815	0.7
CSNK2A1	protein	P68400	UNIPROT	CARD9	protein	Q9H257	UNIPROT	down-regulates	phosphorylation	Thr531	NTTGSDNtDTEGS	9606									17936701	t		lperfetto	Pvhl acts as an adaptor to promote the inhibitory phosphorylation of the nf-kappab agonist card9 by ck2. The card9 c terminus contains multiple serine and threonine residues that resemble ck2 phosphorylation sites. Mass spectrometry analysis of myc-card9 recovered from hela cells revealed that these sites, including t531 and t533, were phosphorylated in vivo	SIGNOR-158414	0.352
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	tRNA(Ile)	smallmolecule	CHEBI:29174	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270419	0.8
SPRY4	protein	Q9C004	UNIPROT	MMP9	protein	P14780	UNIPROT	down-regulates activity				9606	BTO:0002058								20501643	f		miannu	When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. 	SIGNOR-253037	0.271
PTPN5	protein	P54829	UNIPROT	FYN	protein	P06241	UNIPROT	down-regulates	dephosphorylation	Tyr420	RLIEDNEyTARQGAK	9606	BTO:0000938	BTO:0000671							11983687	t		lperfetto	Wild-type step(61) dephosphorylates fyn at tyr(420) but not at tyr(531). These results suggest that step regulates the activity of fyn by specifically dephosphorylating the regulatory tyr(420) and may be one mechanism by which fyn activity is decreased within psds.	SIGNOR-86791	0.543
FLNA	protein	P21333	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates quantity by stabilization	binding			9606									11706047	t		lperfetto	We conclude that FLNa is essential in cells that express it for stabilizing orthogonal actin networks suitable for locomotion. 	SIGNOR-261851	0.7
PRKACB	protein	P22694	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606									10949026	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136.	SIGNOR-81145	0.403
MSC	protein	O60682	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates activity	binding			9606	BTO:0000776								9584154	t	2	miannu	ABF-1 contains a transcriptional repression domain and is capable of inhibiting the transactivation capability of E47 in mammalian cells.	SIGNOR-241315	0.475
estriol	smallmolecule	CHEBI:27974	ChEBI	ESR2	protein	Q92731	UNIPROT	up-regulates activity	chemical activation			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258585	0.8
RHEB	protein	Q15382	UNIPROT	MTOR	protein	P42345	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								20006481	t		lperfetto	Rheb stimulates the phosphorylation of mtor and plays an essential role in regulation of s6k and 4ebp1 in response to nutrients and cellular energy status.	SIGNOR-162006	0.949
PTK2B	protein	Q14289	UNIPROT	ASAP1	protein	Q9ULH1	UNIPROT	down-regulates activity	phosphorylation	Tyr323	QLQGNKEyGSEKKGY	9606	BTO:0000007								12771146	t		miannu	The tyrosine kinase Pyk2 regulates Arf1 activity by phosphorylation and inhibition of the Arf-GTPase-activating protein ASAP1. Pyk2 directly phosphorylates ASAP1 on tyrosine residues in vitro and increases ASAP1 tyrosine phosphorylation when co-expressed in HEK293T cells.Phosphorylation of tyrosine 308 and 782 affects the phosphoinositide binding profile of ASAP1, and fluorimetric Arf-GTPase assays with purified proteins revealed an inhibition of ASAP1 GTPase-activating protein activity by Pyk2-mediated tyrosine phosphorylation.	SIGNOR-263186	0.469
ASDURF	protein	L0R819	UNIPROT	PAQosome co-chaperone complex	complex	SIGNOR-C516	SIGNOR	form complex	binding			9606									30484152	t		miannu	The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92. 	SIGNOR-270922	0.2
WAS	protein	P42768	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								20498093	t		lperfetto	Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes.	SIGNOR-261001	0.804
SRC	protein	P12931	UNIPROT	MMP14	protein	P50281	UNIPROT	unknown	phosphorylation	Tyr573	GTPRRLLyCQRSLLD	9606									17389600	t		llicata	We show that mt1-mmp is phosphorylated on the unique tyrosine residue located within this cytoplasmic sequence (tyr(573)) and that this phosphorylation requires the kinase src. accordingly, overexpression of a nonphosphorylable mt1-mmp mutant (y573f) blocked sphingosine-1-phosphate-induced migration of human umbilical vein endothelial cells and ht-1080 (human fibrosarcoma) cells and failed to stimulate migration of cells lacking the enzyme (bovine aortic endothelial cells).	SIGNOR-154006	0.448
PRKACA	protein	P17612	UNIPROT	APOBEC3G	protein	Q9HC16	UNIPROT	up-regulates	phosphorylation	Thr32	PILSRRNtVWLCYEV	9606									18836454	t		llicata	Here we show that pka binds and specifically phosphorylates a3g at thr32 in vitro and in vivo. This phosphorylation event reduces the binding of a3g to vif and its subsequent ubiquitination and degradation, and thus promotes a3g antiviral activity.	SIGNOR-181526	0.329
DSCAML1	protein	Q8TD84	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	down-regulates				9606	BTO:0000938								30745319	f		miannu	Nuclear DSCAM and DSCAML1 impair neurite outgrowth. this demonstrates that enhanced nuclear translocation of the DSCAM and DSCAML1 ICDs profoundly impairs neurite outgrowth and development of primary cortical neurons	SIGNOR-264275	0.7
CRADD	protein	P78560	UNIPROT	Caspase-2 PIDDosome	complex	SIGNOR-C292	SIGNOR	form complex	binding			9606									20158568	t		miannu	The PIDDosome consists of the proteins PIDD, RAIDD and caspase-2. 	SIGNOR-262642	0.921
IRF3	protein	Q14653	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000801								27337441	t		lperfetto	Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation	SIGNOR-251721	0.418
SLBP	protein	Q14493	UNIPROT	H2AC1	protein	Q96QV6	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265401	0.2
GSK3B	protein	P49841	UNIPROT	AHR	protein	P35869	UNIPROT	up-regulates activity	phosphorylation	Ser689	SQEFPYKsEMDSMPY	9606	BTO:0000567								34198826	t		miannu	A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR.	SIGNOR-276660	0.253
ritonavir	chemical	CHEBI:45409	ChEBI	CYP3A4	protein	P08684	UNIPROT	down-regulates activity	chemical inhibition			-1									18285471	t		Luana	Ritonavir is the most potent and efficacious inhibitor of cytochrome P4503A (CYP3A	SIGNOR-257769	0.8
ADAM10	protein	O14672	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates activity	cleavage			9606									26284334	t		miannu	The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. 	SIGNOR-259845	0.352
NUP98-HOXA9	fusion protein	SIGNOR-FP15	SIGNOR	PBX3	protein	P40426	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17442773	f		miannu	Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. PBX3, a member of the PBX family of TALE homeobox genes, is upregulated in both NUP98‐HOXA9–transduced adult and cord blood CD34+ cells (Table 3).	SIGNOR-261504	0.2
YAP1	protein	P46937	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates	binding			9606									14765127	t	Regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation.	gcesareni	Here we show that the endogenous yes-associated protein (yap), a mediator of src/yes signaling, interacts with the native runx2 protein, an osteoblast-related transcription factor, and suppresses runx2 transcriptional activity in a dose-dependent manner.	SIGNOR-121803	0.461
NLGN2	protein	Q8NFZ4	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								18923512	t	brain	lperfetto	Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.	SIGNOR-264193	0.751
ADSS1	protein	Q8N142	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	down-regulates quantity	chemical modification			9606									10496970	t		miannu	Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 	SIGNOR-267346	0.8
CEBPB	protein	P17676	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity	transcriptional regulation			10090									7557387	t		Andrea Cerquone Perpetuini	 Induction of C/EBP beta DNA-binding activity in NIH-3T3 beta 2 cells exposed to dexamethasone in the presence of insulin and fetal bovine serum activates the expression of an adipocyte-specific nuclear hormone receptor, PPAR gamma, that stimulates the conversion of these fibroblasts into committed preadipocytes	SIGNOR-255730	0.719
PRKAR2B	protein	P31323	UNIPROT	PRKACB	protein	P22694	UNIPROT	down-regulates activity	binding			9606									26687711	t			Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 	SIGNOR-258758	0.89
CSNK2A1	protein	P68400	UNIPROT	PPP1R1B	protein	Q9UD71	UNIPROT	up-regulates activity	phosphorylation	Ser102	NLNENQAsEEEDELG	-1									2557337	t		llicata	Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase	SIGNOR-250927	0.346
seliciclib	chemical	CHEBI:45307	ChEBI	CCNA2	protein	P20248	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206559	0.8
ROCK1	protein	Q13464	UNIPROT	RND3	protein	P61587	UNIPROT	up-regulates	phosphorylation	Ser11	RRASQKLsSKSIMDP	9606									15775972	t		lperfetto	We show that rock phosphorylates endogenous rhoe at serine 11 upon cell stimulation with platelet-derived growth factor. Phosphorylation has no effect on rhoe binding to rock i, but instead increases rhoe protein stability.	SIGNOR-134703	0.731
MAPK1	protein	P28482	UNIPROT	TNKS1BP1	protein	Q9C0C2	UNIPROT	unknown	phosphorylation	Thr131	KEEPPPLtPPARCAA	10090	BTO:0000944								22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262782	0.2
PRKACB	protein	P22694	UNIPROT	TENT2	protein	Q6PIY7	UNIPROT	down-regulates activity	phosphorylation	Ser116	LSGERRYsMPPLFHT	9606									31057087	t		miannu	We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. 	SIGNOR-259403	0.2
RANBP3	protein	Q9H6Z4	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	relocalization			9606									19289081	t		lperfetto	RanBP3 directly recognizes dephosphorylated Smad2/3, which results from the activity of nuclear Smad phosphatases, and mediates nuclear export of Smad2/3 in a Ran-dependent manner.	SIGNOR-232116	0.398
TNFRSF17	protein	Q02223	UNIPROT	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	up-regulates				9606									10903733	f	inferred from 70% of family members	miannu	Overexpression of bcma activates jnk	SIGNOR-269887	0.295
Hypoxia	stimulus	SIGNOR-ST25	SIGNOR	EGLN3	protein	Q9H6Z9	UNIPROT	down-regulates				9606									24990963	f		lperfetto	There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization	SIGNOR-262002	0.7
beta-alanine	smallmolecule	CHEBI:16958	ChEBI	GLRA1	protein	P23415	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9009272	t		miannu	For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system.	SIGNOR-258581	0.8
SEC24D	protein	O94855	UNIPROT	COPII vesicle	complex	SIGNOR-C370	SIGNOR	form complex	binding			9606	BTO:0000567								30605680	t		lperfetto	The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat	SIGNOR-265291	0.68
regorafenib	chemical	CHEBI:68647	ChEBI	FGFR2	protein	P21802	UNIPROT	down-regulates activity	chemical inhibition			9606									26254357	t		miannu	A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF	SIGNOR-259178	0.8
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	IGFBP5	protein	P24593	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136601	0.317
AKT2	protein	P31751	UNIPROT	PPIF	protein	P30405	UNIPROT	up-regulates activity	phosphorylation	Ser31	LPAARACsKGSGDPS	9606	BTO:0002004								25650317	t		miannu	In turn, mitochondrial Akt2 phosphorylates Ser31 in cyclophilin D (CypD), a regulator of organelle functions. Akt2-phosphorylated CypD supports mitochondrial bioenergetics and opposes tumor cell death, conferring resistance to PI3K therapy.	SIGNOR-276875	0.2
oxymetazoline	chemical	CHEBI:7862	ChEBI	ADRA1A	protein	P35348	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258462	0.8
CDK1	protein	P06493	UNIPROT	DDX3X	protein	O00571	UNIPROT	down-regulates	phosphorylation	Thr323	GCHLLVAtPGRLVDM	9606			SIGNOR-C17						16280325	t		lperfetto	Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis.	SIGNOR-141569	0.301
SIRT4	protein	Q9Y6E7	UNIPROT	GLUD2	protein	P49448	UNIPROT	down-regulates activity	glycosylation			9606									16959573	t		miannu	We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity.	SIGNOR-268559	0.486
CSNK2A1	protein	P68400	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	up-regulates	phosphorylation			9606									15747065	t		gcesareni	Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex. Ck1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays.	SIGNOR-134500	0.308
UBE2D2	protein	P62837	UNIPROT	PDZRN3	protein	Q9UPQ7	UNIPROT	up-regulates activity	binding			9534	BTO:0000298								17576800	t		miannu	Our initial tests of various E2s showed that the RING domain of PDZRN3 exhibits ubiquitin ligase activity in the presence of E1 and the UbcH5 family of E2 enzymes (Fig. 3 A). Consistent with this finding, GST pull-down assays showed that PDZRN3 directly interacts with the UbcH5B ubiquitin conjugating enzyme (Fig. 3 B). 	SIGNOR-271663	0.393
SRC	protein	P12931	UNIPROT	LASP1	protein	Q14847	UNIPROT	up-regulates activity	phosphorylation	Tyr171	IPTSAPVyQQPQQQP	9606	BTO:0000132								19718473	t		lperfetto	Integrin-dependent translocation of LASP-1 to the cytoskeleton of activated platelets correlates with LASP-1 phosphorylation at tyrosine 171 by Src-kinase	SIGNOR-271706	0.256
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation			9606									20974802	t	inferred from 70% family members	gcesareni	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6.	SIGNOR-270024	0.2
PRKCD	protein	Q05655	UNIPROT	C5AR1	protein	P21730	UNIPROT	down-regulates	phosphorylation	Ser334	SVVRESKsFTRSTVD	9606									12464600	t		gcesareni	Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation.	SIGNOR-96067	0.2
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1882	SPTSPTYsPTTPKYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273052	0.556
RAR	proteinfamily	SIGNOR-PF45	SIGNOR	THRA	protein	P10827	UNIPROT	up-regulates	binding			9606									15650024	t	inferred from 70% family members	gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-269955	0.2
DNM2	protein	P50570	UNIPROT	VAV1	protein	P15498	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000584								23537630	t			Disruption of the Dyn2-Vav1 interaction targets Vav1 to the lysosome for degradation via an interaction with the cytoplasmic chaperone Hsc70, resulting in a dramatic reduction of Vav1 protein stability.	SIGNOR-259080	0.501
SHC1	protein	P29353	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	up-regulates activity				10090	BTO:0000944								17673906	f	inferred from 70% of family members	lperfetto	We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases.	SIGNOR-269903	0.2
SLC16A2	protein	P36021	UNIPROT	L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	down-regulates quantity	relocalization			9606									28153798	t		scontino	T4 and T3 are released from the thyroid cell through transporters present at the basolateral plasma membrane of thyrocytes (Fig. 1). The most important transporter known to be responsible for thyroid hormone transport is the SLC16A2 monocarboxylate transporter 8 (MCT8), which can promote both uptake and efflux of TH and is involved in the release of TH from the thyroid gland.	SIGNOR-267140	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	SH2B2	protein	O14492	UNIPROT	unknown	phosphorylation	Ser598	SARSRSNsAERLLEA	10090									16141217	t			Serine 588 of APS is a newly identified target for protein kinase B in intact cells and in vitro. The precise function of this PKB-mediated phosphorylation event is not entirely clear but may be responsible for regulating cellular localization and will be the subject of future investigation.	SIGNOR-251487	0.2
SMAD2/SMAD4	complex	SIGNOR-C8	SIGNOR	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11689553	f		irozzo	To identify this pathway, we analyzed TGF-β-responsive elements in the human c-myc promoter and found that Smad proteins directly bound to an element in the c-myc promoter and suppressed c-myc promoter activity.	SIGNOR-256291	0.649
AMG 900	chemical	CID:24856041	PUBCHEM	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189495	0.8
CAMK2G	protein	Q13555	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser259	FPLRKTAsEPNLKVR	9606									11114197	t		gcesareni	Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.	SIGNOR-85098	0.403
P2RY13	protein	Q9BPV8	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256749	0.2
MAPK1	protein	P28482	UNIPROT	DUSP1	protein	P28562	UNIPROT	down-regulates	phosphorylation	Ser296	KQRRSIIsPNFSFMG	9606									16286470	t		lperfetto	The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain	SIGNOR-141593	0.799
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser274	ASPQRSRsPSPQPSS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248520	0.386
INTS3	protein	Q68E01	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261485	0.89
PI3K	complex	SIGNOR-C156	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation			9606		BTO:0001103							15829723	t		apalma	IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt.	SIGNOR-255106	0.785
1D-myo-inositol 1,4,5-trisphosphate	smallmolecule	CHEBI:16595	ChEBI	GSN	protein	P06396	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000132								12788695	t		lperfetto	We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations.	SIGNOR-261840	0.8
SMAD3	protein	P84022	UNIPROT	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	up-regulates				9606									30017632	f		miannu	Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. 	SIGNOR-260432	0.7
NR4A3	protein	Q92570	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0000815;BTO:0002552								30455429	f		miannu	NR4A3 exhibits p53-independent anti-proliferative functions. Ectopic expression of NR4A3 inhibits the growth of MDA-MB-231 and H1299 cancer cell lines.	SIGNOR-256201	0.7
PRKACA	protein	P17612	UNIPROT	RGS10	protein	O43665	UNIPROT	down-regulates activity	phosphorylation	Ser176	QTAAKRAsRIYNT	9606									11443111	t		lperfetto	We report in this study the acute functional regulation of rgs10 thru the specific and inducible phosphorylation of rgs10 protein at serine 168 by camp-dependent kinase a. This phosphorylation nullifies the rgs10 activity at the plasma membrane, which controls the g protein-dependent activation of the inwardly rectifying potassium channel.	SIGNOR-109173	0.34
MAPK8	protein	P45983	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser69	GPLAPPAsPGPFATR	9606									18174237	t		gcesareni	Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome.	SIGNOR-160323	0.751
NFE2L2	protein	Q16236	UNIPROT	SOD1	protein	P00441	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22493435	t		miannu	BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2	SIGNOR-254653	0.42
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PLA2G4A	protein	P47712	UNIPROT	up-regulates	phosphorylation			9606									8381049	t	inferred from 70% family members	gcesareni	Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane.	SIGNOR-270096	0.2
GABA-A (a4-b1-g2) receptor	complex	SIGNOR-C333	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000227							18790874	f	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263779	0.7
TRiC	complex	SIGNOR-C539	SIGNOR	CDC20	protein	Q12834	UNIPROT	up-regulates quantity by stabilization	binding			9606									36185250	t		miannu	Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC).	SIGNOR-272869	0.538
SATB2	protein	Q9UPW6	UNIPROT	BCL11B	protein	Q9C0K0	UNIPROT	down-regulates quantity	transcriptional regulation			9606									31666685	t		gianni	Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development	SIGNOR-268931	0.511
LATS1	protein	O95835	UNIPROT	AMOT	protein	Q4VCS5	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser175	QGHVRSLsERLMQMS										24101513	t		lperfetto	Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130	SIGNOR-275843	0.539
MAPK1	protein	P28482	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation			9606									20974802	t		gcesareni	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription.	SIGNOR-169001	0.307
ATM	protein	Q13315	UNIPROT	NBN	protein	O60934	UNIPROT	up-regulates	phosphorylation	Ser397	EQKFRMLsQDAPTVK	9606									10839545	t		lperfetto	We have identified two residues of nbs1, ser 278 and ser 343 that are phosphorylated in vitro by atm and whose modification in vivo is essential for the cellular response to dna damage. This response includes s-phase checkpoint activation, formation of the nbs1/mrel1/rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation.	SIGNOR-78030	0.852
HOXA9	protein	P31269	UNIPROT	IGF1	protein	P05019	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25252870	f		miannu	Hoxa9bound directly to the putative promoter and a dnase-hypersensitive region in the first intron of the igf1 gene. Transcription rates of the igf1 gene paralleledhoxa9activity	SIGNOR-205308	0.2
perfluorooctane-1-sulfonic acid	chemical	CHEBI:39421	ChEBI	ESR2	protein	Q92731	UNIPROT	up-regulates activity	chemical activation			-1									23764977	t		miannu	Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. 	SIGNOR-268763	0.8
RUBCNL	protein	Q9H714	UNIPROT	STX17	protein	P56962	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								30704899	t		miannu	Under nutrient-rich conditions, mTORC1 phosphorylates Pacer at serine157 to disrupt the association of Pacer with Stx17 and the HOPS complex and thus abolishes Pacer-mediated autophagosome maturation. These results demonstrate that mTORC1-mediated Pacer phosphorylation at S157 inhibits autophagosome maturation by disrupting the association of Pacer with Stx17 and the HOPS complex	SIGNOR-273684	0.2
lenvatinib	chemical	CHEBI:85994	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191454	0.8
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine	chemical	CHEBI:91451	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206382	0.8
Cytosolic DNA	stimulus	SIGNOR-ST30	SIGNOR	POLR3A	protein	O14802	UNIPROT	up-regulates				9606	BTO:0000007								19631370	t		miannu	These results suggest that RNA Pol-III is a cytosolic DNA sensor involved in innate immune responses. Here we show that the cytosolic poly(dA-dT) DNA is converted into 5′-ppp RNA to induce IFN-β through the RIG-I pathway. Biochemical purification led to the identification of DNA-dependent RNA polymerase III (Pol-III) as the enzyme responsible for synthesizing 5′-ppp RNA from the poly(dA-dT) template. Inhibition of RNA Pol-III prevents IFN-β induction by transfection of DNA or infection with DNA viruses. 	SIGNOR-265564	0.7
PTCHD1	protein	Q96NR3	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates quantity	binding			10090		BTO:0000142							29118110	t		miannu	Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus	SIGNOR-266652	0.2
BRAF	protein	P15056	UNIPROT	EEF1A1	protein	P68104	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser21	GHVDSGKsTTTGHLI	-1									22378069	t		miannu	Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf. 	SIGNOR-276404	0.266
Sincalide	smallmolecule	CID:9833444	PUBCHEM	CCKBR	protein	P32239	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257467	0.8
GNG12	protein	Q9UBI6	UNIPROT	PLCE1	protein	Q9P212	UNIPROT	up-regulates	binding			9606									17251915	t		gcesareni	In the non-canonical wntpathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor	SIGNOR-152612	0.2
LEF1	protein	Q9UJU2	UNIPROT	IL4	protein	P05112	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000782								18579517	f			We identified a high affinity LEF-1-binding site in the negative regulatory element of the IL-4 promoter. Knockdown LEF-1 expression by LEF-1-specific small interfering RNA resulted in an increase in the IL-4 mRNA expression	SIGNOR-254504	0.358
PPP4C	protein	P60510	UNIPROT	HDAC3	protein	O15379	UNIPROT	down-regulates activity	dephosphorylation	Ser424	DHDNDKEsDVEI	9606									15805470	t			Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.|Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4(c). 	SIGNOR-248548	0.387
KLC1	protein	Q07866	UNIPROT	TOR1A	protein	O14656	UNIPROT	up-regulates activity	binding			10116									14970196	t		Monia	We identified the light chain subunit (KLC1) of kinesin-I as an interacting partner for torsinA, with binding occurring between the tetratricopeptide repeat domain of KLC1 and the carboxyl-terminal region of torsinA. Coimmunoprecipitation analysis demonstrated that wildtype torsinA and kinesin-I form a complex in vivo. These studies suggest that wild-type torsinA undergoes anterograde transport along microtubules mediated by kinesin and may act as a molecular chaperone regulating kinesin activity and/or cargo binding.	SIGNOR-261172	0.401
HRH3	protein	Q9Y5N1	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256689	0.412
ARHGEF25	protein	Q86VW2	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates	guanine nucleotide exchange factor			10090	BTO:0000165;BTO:0000222								16314529	t		lperfetto	Exogenous expression of geft promotes myogenesis of c2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process.	SIGNOR-235391	0.656
MAPK8	protein	P45983	UNIPROT	KRT8	protein	P05787	UNIPROT	up-regulates	phosphorylation	Ser74	TVNQSLLsPLVLEVD	9606									11788583	t		lperfetto	Kinase assays showed that c-jun n-terminal kinase (jnk) was also activated with activation kinetics corresponding to that of k8 phosphorylation. Furthermore, k8 was also phosphorylated on ser-73 by jnk in vitro. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.	SIGNOR-114083	0.383
TAOK	proteinfamily	SIGNOR-PF21	SIGNOR	STK3	protein	Q13188	UNIPROT	up-regulates	phosphorylation			9606									23431053	t		milica	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.	SIGNOR-230713	0.2
DIABLO	protein	Q9NR28	UNIPROT	BIRC5	protein	O15392	UNIPROT	down-regulates	binding			9606									10929711	t		gcesareni	Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. mitochondrial survivin associated with smac/diablo, delaying its release.	SIGNOR-80212	0.586
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2Q1	protein	Q7Z7E8	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271372	0.415
SRGAP1	protein	Q7Z6B7	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260515	0.541
MYCBP2	protein	O75592	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001321								32814769	t		miannu	 We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. 	SIGNOR-267147	0.425
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PTPRR	protein	Q15256	UNIPROT	up-regulates activity	phosphorylation												11493009	t	inferred from 70% family members	lperfetto	Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL.	SIGNOR-270147	0.2
CSNK2A1	protein	P68400	UNIPROT	RGS19	protein	P49795	UNIPROT	unknown	phosphorylation	Ser24	ADRPPSMsSHDTASP	-1									10760275	t		llicata	Phosphorylation was Mn(2+)-dependent, using both purified CK2 and CCVs. Ser-24 was identified as one of the phosphorylation sites. Our results establish that GAIP is phosphorylated and that only the membrane pool is phosphorylated, suggesting that GAIP can be regulated by phosphorylation events taking place at the level of clathrin-coated pits and vesicles.	SIGNOR-250943	0.334
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGA12	protein	O60330	UNIPROT	up-regulates activity	binding			9606									16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265676	0.2
SIN3B	protein	O75182	UNIPROT	Sin3B_complex	complex	SIGNOR-C409	SIGNOR	form complex	binding			9606	BTO:0000007								21041482	t		miannu	We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin.	SIGNOR-266967	0.757
PRKCD	protein	Q05655	UNIPROT	ADD2	protein	P35612	UNIPROT	unknown	phosphorylation	Ser713	KKKFRTPsFLKKSKK	-1									8810272	t		lperfetto	Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites for PKC.	SIGNOR-248952	0.288
N-(cyanomethyl)-4-[2-[4-(4-morpholinyl)anilino]-4-pyrimidinyl]benzamide	chemical	CHEBI:91407	ChEBI	JAK2	protein	O60674	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191247	0.8
ATM	protein	Q13315	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates	phosphorylation	Ser239	DPMTQDGsQPMDTNM	9606									22588298	t		llicata	On genotoxic stress, atm phosphorylates bmps-activated smad1 in the nucleus on s239, which disrupts smad1 interaction with protein phosphatase ppm1a, leading to enhanced activation and upregulation of smad1.	SIGNOR-197533	0.2
SRC	protein	P12931	UNIPROT	VCL	protein	P18206	UNIPROT	down-regulates activity	phosphorylation	Tyr1133	WVRKTPWyQ	9534									15229287	t		lperfetto	The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail.	SIGNOR-247428	0.752
VAMP3	protein	Q15836	UNIPROT	LE-TGN SNARE	complex	SIGNOR-C157	SIGNOR	form complex	binding			9606	BTO:0000567								18195106	t		lperfetto	We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport	SIGNOR-253082	0.716
CAMK2A	protein	Q9UQM7	UNIPROT	PTTG1	protein	O95997	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser87	PLKQKQPsFSAKKMT	9606	BTO:0000567								24781523	t		miannu	CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase	SIGNOR-276381	0.314
OS9	protein	Q13438	UNIPROT	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								17932042	t		miannu	Here we report that OS-9, a ubiquitously expressed endoplasmic reticulum (ER)-associated protein, interacts with the cytosolic N-terminal tail of TRPV4.Thus, OS-9 regulates the secretory transport of TRPV4 and appears to protect TRPV4 subunits from the precocious ubiquitination and ER-associated degradation. Our data suggest that OS-9 functions as an auxiliary protein for TRPV4 maturation.	SIGNOR-261064	0.382
MAPK3	protein	P27361	UNIPROT	CIITA	protein	P33076	UNIPROT	up-regulates	phosphorylation	Ser280	TVHGLPTsPDRPGST	9606	BTO:0000782;BTO:0000801								17095509	t		gcesareni	We found that in these cells, lipopolysaccharide stimulates the expression of mhc ii genes via the activation of erk1/2, which is mediated by toll-like receptor 4. Erk1/2 then phosphorylates the serine at position 357, which is located in a degron of ciita isoform 1 that leads to its monoubiquitylation.	SIGNOR-150545	0.348
SHANK2	protein	Q9UPX8	UNIPROT	Postsynaptic density assembly	phenotype	SIGNOR-PH163	SIGNOR	up-regulates				9606	BTO:0000938								28179641	f		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. 	SIGNOR-264606	0.7
TGFB1	protein	P01137	UNIPROT	KRT1	protein	P04264	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16258965	f	Regulation	miannu	TGFβ1 and TGFβ2 induce loss of epithelial morphology, cytokeratin, and membrane-associated Zonula Occludens-1 and increase the smooth muscle markers calponin and caldesmon	SIGNOR-251884	0.2
NTRK2	protein	Q16620	UNIPROT	FRS3	protein	O43559	UNIPROT	up-regulates activity	phosphorylation	Tyr417	EPPRQLNyIQVELKG	9606									11432792	t		miannu	The tyrosine phosphoryla tion of FRS2/SNT2 was stimulated dependently on the TrkB activation. to explore the possibility that tyrosine residues 417 and 455 on FRS2/SNT2 function as the binding sites for Shp2, we coexpressed Y417F or Y455F phenylalanine mutants and the Y417/455F double phenylalanine mutant of Myc/Histagged FRS2/SNT2 with TrkB. The active TrkB induced somewhat reduced tyrosine phosphorylation of all of the phenylalanine mutants of FRS2/SNT2 in comparison with tyrosine phosphorylation of the wild type 	SIGNOR-250202	0.584
TCAP	protein	O15273	UNIPROT	TTN	protein	Q8WZ42	UNIPROT	up-regulates activity	binding			9606		BTO:0001103							32937135	t		lperfetto	TCAP, a core sarcomeric component capping the titin proteins, was identified as a positive hit (Figure 1A). TCAP is a small (19 kDa), highly abundant cytoplasmic protein expressed exclusively in skeletal muscle and the heart (Valle et al., 1997). TCAP interacts with titin through its N-terminal beta sheet to anchor titin to the Z-disc 	SIGNOR-264854	0.905
Phenylalanyl-tRNA synthetase	complex	SIGNOR-C473	SIGNOR	Phe-tRNA(Phe)	smallmolecule	CHEBI:29153	ChEBI	up-regulates quantity	chemical modification			9606									20223217	t		miannu	Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers.	SIGNOR-270442	0.8
KDM2B	protein	Q8NHM5	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000011								25533466	f		miannu	We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis.	SIGNOR-252246	0.2
EPB41	protein	P11171	UNIPROT	NUMA1	protein	Q14980	UNIPROT	up-regulates activity	relocalization			9606									23870127	t		lperfetto	These results indicate that 4.1 proteins recruit NuMA and dynein to the anaphase cell cortex through their conserved CTD (Figure 2I).	SIGNOR-266012	0.55
PRRX1	protein	P54821	UNIPROT	MAFK	protein	O60675	UNIPROT	down-regulates activity	binding			-1									11036080	t		miannu	Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.	SIGNOR-221932	0.277
FANCD2	protein	Q9BXW9	UNIPROT	D1-D2-G-X3 complex	complex	SIGNOR-C301	SIGNOR	form complex	binding			9606	BTO:0000567								18212739	t		lperfetto	These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). 	SIGNOR-263255	0.736
NEIL2	protein	Q969S2	UNIPROT	Base-excision_repair	phenotype	SIGNOR-PH222	SIGNOR	up-regulates													23545420	f		lperfetto	The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1).	SIGNOR-275719	0.7
RPN1	protein	P04843	UNIPROT	OPRM1	protein	P35372	UNIPROT	up-regulates	binding			9606									19289571	t		miannu	Ribophorin i (rpni), a component of the oligosaccharide transferase complex, could directly interact with mor. Rpni can be shown to participate in mor export by the intracellular retention of the receptor after small interfering rna knockdown of endogenous rpni.	SIGNOR-184651	0.255
MAPK12	protein	P53778	UNIPROT	KRT8	protein	P05787	UNIPROT	up-regulates	phosphorylation	Ser74	TVNQSLLsPLVLEVD	9606									11788583	t		lperfetto	Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.	SIGNOR-114067	0.2
RCHY1	protein	Q96PM5	UNIPROT	POLH	protein	Q9Y253	UNIPROT	down-regulates activity	monoubiquitination	Lys682	SAVSHQGkRNPKSPL	9606									21791603	t		miannu	Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709).	SIGNOR-272730	0.563
PAK1	protein	Q13153	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser38	SVPEFPLsPPKKKDL	9606									19162178	t		gcesareni	The hgf-induced wave2 transport, lamellipodia formation, stathmin/op18 phosphorylation at ser38 and binding to kinesin-wave2 complex, but not stathmin/op18 phosphorylation at ser25 and microtubule growth, were abrogated by pak1 inhibitor ipa-3	SIGNOR-183503	0.384
NPTX1	protein	Q15818	UNIPROT	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	up-regulates activity	binding			10090	BTO:0000938								15115814	t	inferred from family member	lperfetto	We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death. 	SIGNOR-270235	0.343
PLCB1	protein	Q9NQ66	UNIPROT	1D-myo-inositol 1,4,5-trisphosphate	smallmolecule	CHEBI:16595	ChEBI	up-regulates quantity	chemical modification			-1									23880553	t		miannu	Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate.	SIGNOR-256497	0.8
RAD52	protein	P43351	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates													27649245	f		lperfetto	Homologous recombination (HR) plays an important role in maintaining genomic integrity. It is responsible for repair of the most harmful DNA lesions, DNA double-strand breaks and inter-strand DNA cross-links. HR function is also essential for proper segregation of homologous chromosomes in meiosis, maintenance of telomeres, and resolving stalled replication forks. Defects in HR often lead to genetic diseases and cancer. Rad52 is one of the key HR proteins, which is evolutionarily conserved from yeast to humans| in mammals, Rad52 knockouts showed no significant DNA repair or recombination phenotype. |These new findings indicate an important backup role for Rad52, which complements the main HR mechanism in mammals.	SIGNOR-251507	0.7
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Ser397	SMVGGERsPPRILPP	9606									21059642	t	The effect has been demonstrated using Q01196-8	lperfetto	Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20).	SIGNOR-216912	0.347
clonidine	chemical	CHEBI:46631	ChEBI	ADRA2A	protein	P08913	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258905	0.8
lysophosphatidic acids	smallmolecule	CHEBI:32957	ChEBI	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	down-regulates				10090	BTO:0002572								22863277	f	inferred from 70% of family members	milica	Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2.	SIGNOR-269868	0.8
FYN	protein	P06241	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates	phosphorylation	Tyr420	RLIEDNEyTARQGAK	9606									22080863	t		lperfetto	Previously, we reported that sfks can serve as bona fide substrates for tcptp and that tcptp dephosphorylates the y418 activation loop autophosphorylation site (corresponding to y394 in lck and y417 in fyn) to inactivate sfks	SIGNOR-177109	0.2
ENG	protein	P17813	UNIPROT	GDF2	protein	Q9UK05	UNIPROT	up-regulates activity	binding			9606	BTO:0003767								21737454	t		miannu	Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays.	SIGNOR-276656	0.74
IKBKE	protein	Q14164	UNIPROT	TANK	protein	Q92844	UNIPROT	down-regulates activity	phosphorylation	Ser406	CQAVFPPsITSRGDF	9534	BTO:0000298								10759890	t		miannu	IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex	SIGNOR-262720	0.734
SLC5A5	protein	Q92911	UNIPROT	iodide	smallmolecule	CHEBI:16382	ChEBI	up-regulates quantity	relocalization			10116									28192058	t		scontino	Active iodide (I-) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+/I- symporter (NIS). In the thyroid, NIS-mediated I- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis. 	SIGNOR-266960	0.8
MAPK8	protein	P45983	UNIPROT	CDT1	protein	Q9H211	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser491	GSCCTIMsPGEMEKH	9606	BTO:0000567								21930785	t		miannu	 We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2. 	SIGNOR-276360	0.378
N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonyl-1-piperazinyl)-1-piperidinyl]anilino]-4-pyrimidinyl]-2-imidazo[1,2-a]pyridinyl]-2-methoxybenzamide	chemical	CHEBI:91401	ChEBI	IGF1R	protein	P08069	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192880	0.8
RUNX1	protein	Q01196	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606									19334039	f		lperfetto	AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability.	SIGNOR-249631	0.7
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	CEBPD	protein	P49716	UNIPROT	down-regulates	binding			9606									12524424	t		fspada	C/ebpbeta and c/ebpdelta were found to physically interact with smad3 and smad4, and smad3 cooperated with smad4 and tgf-beta signaling to repress the transcriptional activity of c/ebps.	SIGNOR-97120	0.328
sorafenib tosylate	chemical	CHEBI:50928	ChEBI	RET	protein	P07949	UNIPROT	down-regulates activity	chemical inhibition			-1									16757355	t		miannu	Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 	SIGNOR-259229	0.8
Wnt	proteinfamily	SIGNOR-PF40	SIGNOR	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606									15578921	t	inferred from 70% family members	gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-269960	0.2
SMURF1	protein	Q9HCE7	UNIPROT	SMAD7	protein	O15105	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0000298								11278251	t		miannu	Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7. 	SIGNOR-272941	0.877
CCL2	protein	P13500	UNIPROT	CCR2	protein	P41597	UNIPROT	up-regulates activity	binding			9606									20219869	t		areggio	The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. 	SIGNOR-255113	0.783
PLK3	protein	Q9H4B4	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606	BTO:0000452								11447225	t		lperfetto	Upon exposure of cells to hydrogen peroxide (h(2)o(2)) phosphorylation of p53 was rapidly induced in human fibroblast gm00637, and this phosphorylation occurred on serine 9, serine 15, serine 20, but not on serine 392. In addition, h(2)o(2)-induced phosphorylation of p53 was followed by induction of p21, suggesting functional activation of p53. Ectopic expression of a plk3 dominant negative mutant, plk3(k52r), in gm00637 cells suppressed h(2)o(2)-induced serine 20 phosphorylation. Taken together, our studies strongly suggest that the oxidative stress-induced activation of p53 is at least in part mediated by plk3.	SIGNOR-109239	0.695
AMOT/MPP5/INADL/LIN7C	complex	SIGNOR-C27	SIGNOR	SMAD4	protein	Q13485	UNIPROT	up-regulates	binding			9606									9748228	t		fspada	Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2	SIGNOR-210096	0.2
sitaxentan	chemical	CHEBI:135736	ChEBI	EDNRA	protein	P25101	UNIPROT	down-regulates activity	chemical inhibition			-1									9171878	t		miannu	Discovery of TBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist.The optimal compound discovered during these studies, 15q (TBC11251), binds competitively to human ETA receptors with a Ki of 0.43 +/- 0.03 nM and an IC50 of 1.4 nM (IC50 for ETB = 9800 nM). This compound inhibits ET-1-induced stimulation of phosphoinositide turnover with a Ki of 0.686 nM and a pA2 of 8.0.	SIGNOR-258610	0.8
FANCD2	protein	Q9BXW9	UNIPROT	Fanconi anemia ID complex	complex	SIGNOR-C302	SIGNOR	form complex	binding			9606	BTO:0000007								17412408	t		lperfetto	Immunoprecipitation of HA-FLAG-tagged FANCI expressed in 293T cells with antibodies against either HA or FLAG, but not MYC, resulted in coimmunoprecipitation of endogenous FANCD2|The FANCI protein associates with FANCD2 and, together, as the FANCI-FANCD2 (ID) complex, localize to chromatin in response to DNA damage.	SIGNOR-263268	0.955
RUBCN	protein	Q92622	UNIPROT	PIK3C3	protein	Q8NEB9	UNIPROT	down-regulates	binding			9606									19270693	t		gcesareni	The run or cysteine-rich domain of rubicon appears to be inhibitory to the binding of rubicon to beclin 1 and vps34	SIGNOR-184547	0.2
MAX	protein	P61244	UNIPROT	MXD3	protein	Q9BW11	UNIPROT	up-regulates activity	binding			9606									7954804	t	2	miannu	the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences.	SIGNOR-240393	0.479
CRHR1	protein	P34998	UNIPROT	Corticotropin	protein	P01189-PRO_0000024969	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001073							23504413	f		lperfetto	CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981).	SIGNOR-268613	0.2
THEM4	protein	Q5T1C6	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates	binding			9606									11598301	t		gcesareni	Here, we describe a protein partner for pkbalpha termed ctmp, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of pkbalpha at the plasma membrane. Binding of ctmp reduces the activity of pkbalpha by inhibiting phosphorylation on serine 473 and threonine 308.	SIGNOR-111003	0.687
MARK2	protein	Q7KZI7	UNIPROT	ARHGEF2	protein	Q92974	UNIPROT	down-regulates	phosphorylation	Ser886	PVDPRRRsLPAGDAL	9606									22072711	t	The effect has been demonstrated using Q92974-2	gcesareni	We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation	SIGNOR-177096	0.518
PRKACA	protein	P17612	UNIPROT	CAPN2	protein	P17655	UNIPROT	down-regulates	phosphorylation	Thr370	GNWRRGStAGGCRNY	9606									11909964	t		llicata	Activation of m-calpain (calpain ii) by epidermal growth factor is limited by protein kinase a phosphorylation of m-calpain.These Data point to a novel mechanism of negative control of calpain activation, direct phosphorylation by pka.	SIGNOR-116248	0.265
ABL1	protein	P00519	UNIPROT	DDB2	protein	Q92466	UNIPROT	down-regulates	phosphorylation			9606									12107171	t		miannu	C-abl might act as a negative regulator of uv-ddb by phosphorylating ddb2	SIGNOR-90446	0.47
RUNX1	protein	Q01196	UNIPROT	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002580								34902205	t		lperfetto	RUNX1 transactivates BCR-ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia.	SIGNOR-272145	0.2
VDR	protein	P11473	UNIPROT	CYP3A4	protein	P08684	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12147248	f		miannu	Expression of cytochrome P450 3A4 (CYP3A4) is induced by 1,25-dihydroxyvitamin D(3)(1,25(OH)(2)D(3)) in Caco-2 cells. However, since a typical vitamin D responsive element has not been found in the 5(')-flanking region of the CYP3A4 gene, the mechanism of 1,25(OH)(2)D(3)-induced CYP3A4 mRNA expression is poorly understood. In the present study, we demonstrated that vitamin D receptor (VDR) is a critical factor for the induction using the antisense oligonucleotide technique.	SIGNOR-255600	0.414
ECM	stimulus	SIGNOR-ST20	SIGNOR	Av/b2 integrin	complex	SIGNOR-C176	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259054	0.7
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	FOXM1	protein	Q08050	UNIPROT	up-regulates	phosphorylation	Thr611	ETLPISStPSKSVLP	9606									19737929	t		lperfetto	A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity	SIGNOR-216837	0.753
CDC14A	protein	Q9UNH5	UNIPROT	IREB2	protein	P48200	UNIPROT	up-regulates activity	dephosphorylation	Ser157	LQKAGKLsPVKVQPK	9606									18574241	t			IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis. 	SIGNOR-248829	0.356
IL22	protein	Q9GZX6	UNIPROT	IL10RB	protein	Q08334	UNIPROT	up-regulates	binding			9606									17208301	t		gcesareni	See table 2	SIGNOR-151880	0.684
MAPK14	protein	Q16539	UNIPROT	ZFP36	protein	P26651	UNIPROT	down-regulates activity	phosphorylation			10029	BTO:0005787								25815583	t			TTP appears to be a p38α/β MAPK target and pretreating skeletal muscle with a p38α/β MAPK inhibitor reduces TTP phosphorylation.	SIGNOR-253596	0.365
FYN	protein	P06241	UNIPROT	DCBLD2	protein	Q96PD2	UNIPROT	up-regulates activity	phosphorylation	Tyr565	KKKTEGTyDLPYWDR	-1									23770091	t	done	miannu	Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding.	SIGNOR-273945	0.357
MAPK3	protein	P27361	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser221	DHEKKAYsFCGTVEY	9534									9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-252758	0.718
CASP1	protein	P29466	UNIPROT	Caspase 1 complex	complex	SIGNOR-C220	SIGNOR	form complex	binding								cleavage:Asp119	PAPQAVQdNPAMPTS			7721861	t		lperfetto	The interleukin-1 beta-converting enzyme is a heterodimeric cysteine protease that is produced as a 45-kDa precursor. The full-length precursor form of the enzyme was expressed in Escherichia coli as insoluble inclusion bodies. Following solubilization and refolding of the 45-kDa protein, autoproteolytic conversion to a heterodimeric form containing 10- and 20-kDa subunits was observed.	SIGNOR-256386	0.2
MAPK9	protein	P45984	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser73	VGLLKLAsPELERLI	9606	BTO:0000938								12040039	t		gcesareni	Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Jnk2/3 activity selectively targets c-jun.	SIGNOR-88212	0.881
ARHGAP30	protein	Q7Z6I6	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260487	0.435
SDC3	protein	O75056	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	binding			10090	BTO:0002314								20696709	t		gcesareni	Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-€“converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size.	SIGNOR-244072	0.389
ABL1	protein	P00519	UNIPROT	RAD9A	protein	Q99638	UNIPROT	up-regulates	phosphorylation	Tyr28	SRIGDELyLEPLEDG	9606									11971963	t		gcesareni	C-abl phosphorylates the rad9 bcl-2 homology 3 domain (tyr-28) in vitro and in cells exposed to dna-damaging agents. The results also demonstrate that c-abl-mediated phosphorylation of rad9 induces binding of rad9 to the antiapototic bcl-x(l) protein	SIGNOR-86186	0.491
CHEK1	protein	O14757	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser293	GSTKRRKsMSGASPK	9606									20068082	t		gcesareni	The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216).	SIGNOR-163146	0.852
IL18	protein	Q14116	UNIPROT	IL18R1	protein	Q13478	UNIPROT	up-regulates	binding			9606									9792649	t		gcesareni	Acpl was required for il-18 responsiveness in terms of nf?B Induction and jnk activation	SIGNOR-60991	0.829
PRKAA1	protein	Q13131	UNIPROT	PIAS1	protein	O75925	UNIPROT	up-regulates activity	phosphorylation	Ser510	SPVSRTPsLPAVDTS	9606									27256105	t		Luana	Mechanically, we found that AMPKα1 directly phosphorylated protein inhibitor of activated STAT-1 (PIAS1), the SUMO E3-ligase of Runx2, at serine 510, to promote its SUMO E3-ligase activity. Finally, mutation of protein inhibitor of activated STAT-1 at serine 510 suppressed m	SIGNOR-259866	0.2
ACTG1	protein	P63261	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates quantity	binding			9606									28233384	t		lperfetto	Here, we report the highest resolution, cryo-EM structures of actin filaments with bound ATP analog β,γ-imidoadenosine 5′-triphosphate (AMPPNP) (3.1 Å) and ADP with inorganic phosphate (ADP-Pi) (3.1 Å) as well as a 3.6-Å resolution structure of the ADP filament. These structures of the three well-characterized nucleotide states of actin monomers and filaments 	SIGNOR-261878	0.7
HMGCS2	protein	P54868	UNIPROT	acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	down-regulates quantity	chemical modification												29597274	t		lperfetto	Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis	SIGNOR-267658	0.8
BCR	protein	P11274	UNIPROT	YWHAZ	protein	P63104	UNIPROT	unknown	phosphorylation	Thr232	LTLWTSDtQGDEAEA	-1									16045749	t		llicata	We show here that BCR interacts with at least five isoforms of 14-3-3 in vivo and phosphorylates 14-3-3tau on Ser233 and to a lesser extent 14-3-3zeta on Thr233	SIGNOR-250595	0.336
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1619	SPSYSPTsPSYSPTS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248735	0.727
dacomitinib	chemical	CHEBI:132268	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205936	0.8
PINK1	protein	Q9BXM7	UNIPROT	HIF3A	protein	Q9Y2N7	UNIPROT	down-regulates activity	phosphorylation	Thr12	LQRARSTtELRKEKS	9606	BTO:0000793								27551449	t	Parkinson	miannu	Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of IPAS at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur. 	SIGNOR-263090	0.355
CYP21A2	protein	P08686	UNIPROT	17alpha-hydroxyprogesterone	smallmolecule	CHEBI:17252	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000050							25855791	t		lperfetto	Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively	SIGNOR-268643	0.8
PTPN5	protein	P54829	UNIPROT	GRIA2	protein	P42262	UNIPROT	down-regulates activity	dephosphorylation			9606									21883219	t		miannu	One study showed that stimulation of the metabotrophic glutamate receptor mGluR5 leads to a STEP mediated tyrosine dephosphorylation of GluA2 and internalization of GluA1 and GluA2, although the tyrosine residue on GluA2 that is dephosphorylated by STEP remains unidentified.	SIGNOR-277040	0.423
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1619	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269351	0.718
RRM2B	protein	Q7LG56	UNIPROT	RRM1	protein	P23921	UNIPROT	up-regulates activity	binding			9606	BTO:0001061								14583450	t		miannu	Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3.	SIGNOR-259366	0.932
Mob1	proteinfamily	SIGNOR-PF42	SIGNOR	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	binding			9606									21084559	t	Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases.	gcesareni	Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1.	SIGNOR-269957	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CARHSP1	protein	Q9Y2V2	UNIPROT	unknown	phosphorylation	Ser52	TRRTRTFsATVRASQ	9606		BTO:0000671							15910284	t		lperfetto	These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf	SIGNOR-137430	0.2
sirolimus	chemical	CHEBI:9168	ChEBI	mTORC1	complex	SIGNOR-C3	SIGNOR	down-regulates	chemical inhibition			-1									17350953	t		lperfetto	Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kDa FK506- and rapamycin-binding protein (FKBP12, or FKBP) and the FKBP-rapamycin binding (FRB) domain of the mammalian target of rapamycin (mTOR) kinase. The resulting ternary complex has been used to conditionally perturb protein function, and one such method involves perturbation of a protein of interest through its mislocalization.	SIGNOR-219385	0.8
XBP1	protein	P17861-2	UNIPROT	Unfolded_Proteins	stimulus	SIGNOR-ST22	SIGNOR	down-regulates				9606									15598891	f		miannu	ATF6 and XBP1 are transcription factors activated specifically in response to endoplasmic reticulum (ER) stress. Three cis-acting elements capable of binding to ATF6, XBP1 or both have been identified to date, namely ER stress-response element (ERSE), unfolded protein response element (UPRE) and ERSE-II. ERSE controls the expression of ER-localized molecular chaperones such as BiP that can refold unfolded proteins in the ER; transcription from ERSE is fully activated by ATF6 even in the absence of XBP1. In contrast, transcription from UPRE depends solely on XBP1 and it has been suggested that UPRE may control the expression of components of the ER-associated degradation system that can degrade unfolded proteins in the ER. 	SIGNOR-260186	0.7
PRKCQ	protein	Q04759	UNIPROT	HSF1	protein	Q00613	UNIPROT	up-regulates	phosphorylation			9606									23352416	t		gcesareni	At the same time, ea causes pkc?-Mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence.	SIGNOR-200576	0.355
FOXP1	protein	Q9H334	UNIPROT	KLK3	protein	P07288	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001321								18640093	f	 	 	Notably, we demonstrate that FOXP1 directly interacts with AR and negatively regulates AR signaling ligand-dependently, as exemplified by the transcriptional repression of PSA gene regulated by androgen-dependent FOXP1 recruitment on its enhancer region.	SIGNOR-253660	0.278
PLK1	protein	P53350	UNIPROT	RACGAP1	protein	Q9H0H5	UNIPROT	up-regulates	phosphorylation	Ser214	AVDQGNEsIVAKTTV	9606									19468302	t		llicata	Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex.	SIGNOR-185754	0.658
ECM	stimulus	SIGNOR-ST20	SIGNOR	AL/b2 integrin	complex	SIGNOR-C169	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259051	0.7
S	protein	P59594	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9534	BTO:0001444								16310778	f		Luana	We demonstrated that the adenovirus-mediated over-expression of SARS-CoV spike (S) protein and its C-terminal domain (S2) induce apoptosis in Vero E6 cells in a time- and dosage-dependent manner	SIGNOR-260219	0.7
N	protein	P59595	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9534	BTO:0001538								15294014	f		Luana	In the present paper, we show that SARS-CoV N is capable of inducing apoptosis of COS-1 monkey kidney cells in the absence of growth factors by down-regulating ERK (extracellular-signal-regulated kinase), up-regulating JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) pathways, and affecting their downstream effectors.	SIGNOR-260204	0.7
N	protein	P59595	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9534	BTO:0001538								17453707	f		Luana	SARS-CoV Nucleocapsid Protein Induced Apoptosis of COS-1 Mediated by the Mitochondrial Pathway	SIGNOR-260205	0.7
N	protein	P59595	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000161								16845612	f		Luana	Co-transfection of M and N enhances the induction of apoptosis by M or N alone, which also suggests that the structural proteins of SARS-CoV may play an important role not only in the process of invasion but also in the pathogenetic process in cells.	SIGNOR-260199	0.7
M	protein	P59596	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000161								16845612	f		Luana	Co-transfection of M and N enhances the induction of apoptosis by M or N alone, which also suggests that the structural proteins of SARS-CoV may play an important role not only in the process of invasion but also in the pathogenetic process in cells.	SIGNOR-260198	0.7
3a	protein	P59632	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates activity				9534									15958670	f		Luana	These results indicated that the 3a protein induced apoptosis in Vero E6 cells.	SIGNOR-260195	0.7
3b	protein	P59633	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates activity				9534									16965829	f		Luana	Over-expression of severe acute respiratory syndrome coronavirus 3b protein induces both apoptosis and necrosis in Vero E6 cells	SIGNOR-260194	0.7
6	protein	P59634	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9534									18708124	f		Luana	A SARS-CoV protein, ORF-6, induces caspase-3 mediated, ER stress and JNK-dependent apoptosis	SIGNOR-260203	0.7
7a	protein	P59635	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000018								15564512	f		Luana	7a induces apoptosis via a caspase-dependent pathway and in cell lines derived from different organs, including lung, kidney, and liver. | The overexpression of HA-tagged 7a (7a-HA) induces apoptosis in 293T (human kidney epithelial) cells, as evidenced by an increase in caspase-3 protease activity, a hallmark of apoptosis, which is comparable to that caused by the overexpression of BAX, a proapoptotic member of the Bcl-2 family	SIGNOR-260197	0.7
7a	protein	P59635	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9534	BTO:0001444								17686858	f		Luana	Cells expressing the ORF7a or ORF7b protein undergo apoptosis.	SIGNOR-260209	0.7
NFE2L2	protein	Q16236	UNIPROT	NQO1	protein	P15559	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8962164	f		irozzo	These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2.	SIGNOR-256279	0.503
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRIK5	protein	Q16478	UNIPROT	up-regulates activity	chemical activation			9606									27586965	t		miannu	Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors	SIGNOR-264474	0.8
3-phosphonatooxypyruvate(3-)	smallmolecule	CHEBI:18110	ChEBI	3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	up-regulates quantity	precursor of			9606									25406093	t		lperfetto	PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG.	SIGNOR-268566	0.8
EGFR	protein	P00533	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	relocalization			9606									11823423	t	Cbl binds directly to Tyr1045 receptors	gcesareni	Consistent with a negative role for c-Cbl, here we report that defective Tyr1045 of EGFR, an inducible c-Cbl docking site, enhances the mitogenic response to EGF	SIGNOR-114701	0.882
LARP1	protein	Q6PKG0	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity	binding			9606	BTO:0002181								28650797	t		SARA	LARP1-mTORC1 interaction occurs through direct protein-protein contacts. phosphorylated LARP1 facilitates mTORC1-dependent phosphorylation of S6K1 and 4EBP1 on the LARP1-containing mRNPs by scaffolding mTORC1.	SIGNOR-260993	0.307
7b	protein	Q7TFA1	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9534	BTO:0001444								17686858	f		Luana	Cells expressing the ORF7a or ORF7b protein undergo apoptosis.	SIGNOR-260210	0.7
AR	protein	P10275	UNIPROT	NRAS	protein	P01111	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001321								16281084	f	 	 	 After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes.	SIGNOR-253676	0.287
STK11	protein	Q15831	UNIPROT	STK11	protein	Q15831	UNIPROT	up-regulates activity	phosphorylation	Thr336	KDRWRSMtVVPYLED	9606	BTO:0000007;BTO:0000567								12805220	t		lperfetto	It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity.	SIGNOR-101844	0.2
CKM complex	complex	SIGNOR-C406	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR										18418385	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	lperfetto	However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo.	SIGNOR-273172	0.2
GPHA2	protein	Q96T91	UNIPROT	TSHR	protein	P16473	UNIPROT	up-regulates	binding			9606									12045258	t		gcesareni	Recombinant a2/b5 heterodimeric glycoproteins, purified using cation exchange and size fractionation chromatography, activated human tsh receptors, but not lh and fsh receptors, and showed high affinity to tsh receptors in a radioligand receptor assay	SIGNOR-88614	0.528
PRKCA	protein	P17252	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Ser141	MASQKRPsQRHGSKY	-1									2413024	t		lperfetto	MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 	SIGNOR-248869	0.503
SRC	protein	P12931	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	phosphorylation	Tyr1474	GSSNGHVyEKLSSIE	-1									11483655	t		lperfetto	We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases	SIGNOR-247180	0.577
TRIM41	protein	Q8WV44	UNIPROT	PRKCE	protein	Q02156	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								17893151	t		miannu	RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. The RINCK-mediated ubiquitination is likely to be polyubiquitination, because the ubiquitinated PKCβII was detected as a high molecular weight smear. 	SIGNOR-271668	0.2
CTDP1	protein	Q9Y5B0	UNIPROT	CDK1	protein	P06493	UNIPROT	down-regulates activity	dephosphorylation			9606									26653855	t		miannu	Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression.|We can not exclude that, in addition to S90 and S453, other Cdk1 phosphorylation sites in Gwl are dephosphorylated by Fcp1; nevertheless, assaying S67-Ensa kinase activity of V5-GwlS90A and V5-GwlS453A mutant proteins, isolated from transfected and prometaphase arrested HeLa cells, revealed that both mutants had significantly reduced S67-Ensa kinase activity compared to V5-GwlWT (XREF_FIG).|We show here that activation of PP2A-B55, a major mitosis exit phosphatase, required the phosphatase Fcp1 downstream Cdk1 inactivation in human cells.	SIGNOR-277141	0.339
C5AR1	protein	P21730	UNIPROT	Chemotaxis	phenotype	SIGNOR-PH93	SIGNOR	up-regulates				9606									9108406	f		lperfetto	We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro.	SIGNOR-263460	0.7
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606									12840032	t		lperfetto	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)	SIGNOR-264664	0.2
MYOD1	protein	P15172	UNIPROT	CCND3	protein	P30281	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									10373569	t		gcesareni	Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator.	SIGNOR-238526	0.383
GPR34	protein	Q9UPC5	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256688	0.252
CTDP1	protein	Q9Y5B0	UNIPROT	WEE1	protein	P30291	UNIPROT	up-regulates activity	dephosphorylation			9606									27670139	t		miannu	At mitosis exit, Fcp1 promoted inhibitory Cdk1 phosphorylation by dephosphorylating Wee1, and ubiquitin dependent cyclin B degradation by dephosphorylating Cdc20 and USP44.|This lead us to hypothesize that, during prolonged mitosis in AMCDs treated cancer cells, progressive Fcp1 induced Wee1 reactivation might lead to progressive loss of Cdk1 activity that weakens the SAC to a point in which the mitotic state could not be sustained .	SIGNOR-277142	0.392
PPM1G	protein	O15355	UNIPROT	ATM	protein	Q13315	UNIPROT	down-regulates activity	dephosphorylation			9606									22361354	t		miannu	After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. |ATM Dependent Downregulation of USP7 and HAUSP by PPM1G Activates p53 Response to DNA Damage.|DNA Damage Leads to ATM Dependent USP7S Dephosphorylation by PPM1G.	SIGNOR-277158	0.309
PPM1F	protein	P49593	UNIPROT	LATS1	protein	O95835	UNIPROT	down-regulates activity	dephosphorylation	Thr1079	EHAFYEFtFRRFFDD	9606									30863499	t		lperfetto	POPX2 is capable of dephosphorylating LATS1 at Thr1079 (Figure xref ), which is a residue critical for LATS1 activity.|POPX2 might negatively regulate the activities of MST1 and LATS1 through dephosphorylation.|We found that POPX2 could dephosphorylate LATS1 on Threonine-1079, leading to inactivation of LATS1 kinase.	SIGNOR-276989	0.2
tamsulosin	chemical	CHEBI:9398	ChEBI	ADRA1D	protein	P25100	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258471	0.8
SLC6A4	protein	P31645	UNIPROT	serotonin	smallmolecule	CHEBI:28790	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000132								17506858	t		miannu	Serotonin (5HT) is a platelet-stored vasoconstrictor. Altered concentrations of circulating 5HT are implicated in several pathologic conditions, including hypertension. The actions of 5HT are mediated by different types of receptors and terminated by a single 5HT transporter (SERT). Therefore, SERT is a major mechanism that regulates plasma 5HT levels to prevent vasoconstriction and thereby secure a stable blood flow.	SIGNOR-263952	0.8
MYOD1	protein	P15172	UNIPROT	PJA1	protein	Q8NG27	UNIPROT	up-regulates quantity	transcriptional regulation			10090									28067271	t			... chromatin immunoprecipitation (ChIP) analysis showed MYOD binds to a site upstream the Pja1 promoter preferentially in C2C12 cells induced to differentiate (Fig. 2c). In addition, over-expression of MyoD in human fibroblasts is sufficient to up-regulate Pja1 expression	SIGNOR-255718	0.2
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser315	LPNNTSSsPQPKKKP	9606									14640983	t		lperfetto	We used non-radioactive electrophoretic mobility shift assays to show that c-terminal phosphorylation of p53 protein by cdk2/cyclin a on ser315 or by pkc on ser378 can efficiently stimulate p53 binding to dna in vitro.	SIGNOR-217300	0.803
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1878	SPKYSPTsPTYSPTT	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273085	0.745
LMNA	protein	P02545	UNIPROT	Membrane_blebbing	phenotype	SIGNOR-PH24	SIGNOR	up-regulates													23401537	f		lperfetto	Mammalian lamin meshworks consist of two types of lamin proteins, A type and B type, and it has been reported that nuclear blebs are enriched in A-type lamins. 	SIGNOR-83706	0.7
EGLN3	protein	Q9H6Z9	UNIPROT	PK	proteinfamily	SIGNOR-PF80	SIGNOR	up-regulates activity	hydroxylation			9606	BTO:0000567								21620138	t	inferred from family member		Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells.	SIGNOR-270290	0.447
EGFR	protein	P00533	UNIPROT	MUC1	protein	P15941	UNIPROT	up-regulates activity	phosphorylation	Tyr1229	SSTDRSPyEKVSAGN	9606	BTO:0000150								11483589	t		lperfetto	We also show that the activated egf-r phosphorylates the muc1 cytoplasmic tail on tyrosine at a yekv motif that functions as a binding site for the c-src sh2 domain. The results demonstrate that egf-r-mediated phosphorylation of muc1 induces binding of muc1 to c-src in cells	SIGNOR-109538	0.596
PHF21A	protein	Q96BD5	UNIPROT	KDM1A	protein	O60341	UNIPROT	down-regulates activity	binding			-1									16140033	t		miannu	BHC80 Inhibits LSD1 Demethylase Activity In Vitro. in contrast to CoREST, which is a positive regulator of LSD1 activity, the in vitro evidence presented above suggests that BHC80 may function to inhibit LSD1 activity.	SIGNOR-264505	0.704
HMGB1	protein	P09429	UNIPROT	HOXD9	protein	P28356	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								8890171	t		miannu	We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain.ƒ‚‚ The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.	SIGNOR-236956	0.34
JAK1	protein	P23458	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates	phosphorylation			9606									21576360	t			When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita	SIGNOR-256247	0.783
AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	Receptor_mediated_ endocytosis	phenotype	SIGNOR-PH121	SIGNOR	up-regulates													17522231	f		lperfetto	These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins	SIGNOR-260704	0.7
DHPS	protein	P49366	UNIPROT	EIF5A	protein	P63241	UNIPROT	up-regulates activity	post translational modification			-1									32142284	t		miannu	Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation. 	SIGNOR-266374	0.932
ABL2	protein	P42684	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Tyr292	RLGHCHTyWAVSEEL	9606	BTO:0000007								30842273	t		miannu	The data in this study show that IRF3 is physically associated with c-Abl in vivo and directly binds to c-Abl in vitro. IRF3 is phosphorylated by c-Abl and c-Abl-related kinase, Arg, mainly at Y292.	SIGNOR-277441	0.2
DYRK1A	protein	Q13627	UNIPROT	LIN52	protein	Q52LA3	UNIPROT	up-regulates activity	phosphorylation	Ser28	FEKLDRAsPDLWPEQ	9606	BTO:0001583								21498570	t		miannu	Here we report that DYRK1A can specifically phosphorylate LIN52 on serine residue 28, and that this phosphorylation is required for DREAM assembly. 	SIGNOR-262846	0.668
Myog/SWI/SNF complex	complex	SIGNOR-C94	SIGNOR	MYOG	protein	P15173	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001103							17194702	t		miannu	Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle	SIGNOR-151697	0.633
LCK	protein	P06239	UNIPROT	CD28	protein	P10747	UNIPROT	up-regulates	phosphorylation	Tyr191	SRLLHSDyMNMTPRR	9606	BTO:0000782;BTO:0001271								8992971	t		lperfetto	We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor	SIGNOR-45524	0.745
EP300	protein	Q09472	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates quantity	acetylation			9606									20851880	t		gcesareni	These results indicate that Erk signaling increases Runx2 stability and transcriptional activity, partly via increasing p300 protein levels and histone acetyltransferase activity and subsequently increasing Runx2 acetylation by p300	SIGNOR-167966	0.464
EN2	protein	P19622	UNIPROT	FGF8	protein	P55075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									10026229	t		miannu	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression.	SIGNOR-265775	0.428
IL4R	protein	P24394	UNIPROT	IRS2	protein	Q9Y4H2	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000782;BTO:0000801;BTO:0000876	BTO:0000887;BTO:0000763;BTO:0001260							12704343	t		milica	Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2.	SIGNOR-100771	0.575
SRGAP3	protein	O43295	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606									32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260518	0.547
HCRTR2	protein	O43614	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256872	0.267
CSNK2A2	protein	P19784	UNIPROT	CTDP1	protein	Q9Y5B0	UNIPROT	down-regulates activity	phosphorylation	Ser575	AGESLDQsMEEEEEE	9606	BTO:0000567								12591939	t		llicata	We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified 	SIGNOR-250985	0.381
CCNA1	protein	P78396	UNIPROT	WT1	protein	P19544	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19082485	f		irozzo	This study identified WT1 as a repressed target of cyclin A1 and suggests that the suppression of WT1 in cyclin A1-overexpressing leukemias might play a role in the growth and suppression of apoptosis in these leukemic cells.	SIGNOR-255905	0.399
DOK4	protein	Q8TEW6	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001103;BTO:0000671							12730241	t		gcesareni	Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells.	SIGNOR-100999	0.552
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270375	0.8
JAG2	protein	Q9Y219	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			10090	BTO:0000165;BTO:0000222								9315665	t		gcesareni	Immunohistochemistry revealed coexpression of jagged2 and notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human jagged2 with murine c2c12 myoblasts inhibited myogenic differentiation, accompanied by increased notch1 and the appearance of a novel 115-kda notch1 fragment. Exposure of c2c12 cells to jagged2 led to increased amounts of notch mrna as well as mrnas for a second notch receptor, notch3, and a second notch ligand, jagged1. Constitutively active forms of notchl in c2c12 cells also induced increased levels of the same set of mrnas, suggesting positive feedback control of these genes initiated by binding of jagged2 to notch1.	SIGNOR-236922	0.608
PRKACA	protein	P17612	UNIPROT	LCK	protein	P06239	UNIPROT	unknown	phosphorylation	Ser42	TLLIRNGsEVRDPLV	-1									8506364	t		miannu	Ser-42 can be phosphorylated by either protein kinase A or protein kinase C	SIGNOR-249999	0.334
CHMP4A	protein	Q9BY43	UNIPROT	ESCRT-III	complex	SIGNOR-C379	SIGNOR	form complex	binding			-1									26775243	t		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission.	SIGNOR-265529	0.696
MECOM	protein	Q03112	UNIPROT	GATA2	protein	P23769	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000565								15889140	t		Luana	Evi1 directly binds to the promoter region of GATA-2 and thus enhances the GATA-2 transcription.	SIGNOR-266062	0.368
PLCE1	protein	Q9P212	UNIPROT	1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	up-regulates	chemical modification			9606									17251915	t		gcesareni	Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases.	SIGNOR-152771	0.8
RAC1	protein	P63000	UNIPROT	ROCK1	protein	Q13464	UNIPROT	up-regulates activity	binding			9606									27571105	t		areggio	Although there are other activators of PCP, Wnt5a can activate the PCP pathway by forming a complex with Fzd and Ror2 receptors, activating DVL, which in turn activates Rho-family small GTPases, including RhoA and Rac, and their downstream effectors, Rho-associated protein kinase (ROCK), the actin-binding protein, Filamin A and c-Jun N-terminal protein kinase (JNK)	SIGNOR-258972	0.414
CREBBP	protein	Q92793	UNIPROT	DDX21	protein	Q9NR30	UNIPROT	down-regulates activity	acetylation	Lys18	LESDTAMkKGETLRK										28790157	t		lperfetto	Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21.	SIGNOR-275902	0.247
IGF1R	protein	P08069	UNIPROT	CRK	protein	P46108	UNIPROT	down-regulates activity	phosphorylation	Tyr221	GGPEPGPyAQPSVNT	10090	BTO:0000944								9480911	t			On activation of the IGF-I receptor, Crk-II binds to phosphorylated tyrosine residues, especially in the juxtamembrane region. As a result of this binding, the IGF-I receptor kinase phosphorylates Tyr-221 of Crk-II, resulting in a change in intramolecular folding and binding of the SH2 domain to the phosphorylated Tyr-221, which causes rapid disassociation of the Crk-II-IGF-I receptor complex.	SIGNOR-251273	0.711
PRKN	protein	O60260	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. 	SIGNOR-272749	0.2
CSNK2A1	protein	P68400	UNIPROT	MYCN	protein	P04198	UNIPROT	unknown	phosphorylation	Ser263	GEDTLSDsDDEDDEE	-1									1425701	t		llicata	Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263.	SIGNOR-250921	0.458
CTNNB1	protein	P35222	UNIPROT	AFF3	protein	P51826	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26214578	f		irozzo	We demonstrate that AFF3 is a new target of Wnt/β-catenin pathway involved in ACC, acting on transcription and RNA splicing.	SIGNOR-259192	0.287
PPP2CA	protein	P67775	UNIPROT	TRPM8	protein	Q7Z2W7	UNIPROT	down-regulates activity	dephosphorylation	Ser9	SFRAARLsMRNRRND	9606	BTO:0000007								20110357	t	done	miannu	Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity.	SIGNOR-273794	0.2
APOE	protein	P02649	UNIPROT	MAPT	protein	P10636	UNIPROT	up-regulates activity	binding												7566652	t		lperfetto	Isoform specific interactions of ApoE have been shown with the microtubule-associated protein tau, which forms the neurofibrillary tangle in this disease.|Phosphorylation of serine262 in domain I of tau decreases tau binding to microtubules and also abolishes binding by ApoE3. 	SIGNOR-262588	0.586
WNK4	protein	Q96J92	UNIPROT	STK39	protein	Q9UEW8	UNIPROT	up-regulates activity	phosphorylation	Thr231	TRNKVRKtFVGTPCW										16990453	t		lperfetto	Vitari et al. (76) and Moriguchi et al. (52) demonstrated that WNK4 bound and phosphorylated PASK at Thr-233 and Ser-373 in mammalian cells.| this phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1	SIGNOR-264640	0.521
C1D	protein	Q13901	UNIPROT	NR1D1	protein	P20393	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								9405624	t	2	miannu	SUN-CoR is a protein involved in transcriptional repression by nuclear hormone receptors. The C terminus of SUN-CoR interacts with TR and RevErb in vitro and associates with RevErb in cells, SUN-CoR potentiates repression by both receptors in cells, and the N terminus of SUN-CoR contains an intrinsic repression domain.	SIGNOR-241272	0.318
GIGYF1	protein	O75420	UNIPROT	EIF4E2/GIGYF1 complex	complex	SIGNOR-C256	SIGNOR	form complex	binding			9606									30917308	t		lperfetto	4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression	SIGNOR-261011	0.627
NOX1	protein	Q9Y5S8	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	up-regulates quantity	chemical modification			9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264721	0.8
AXIN1	protein	O15169	UNIPROT	RNF111	protein	Q6ZNA4	UNIPROT	up-regulates	binding			9606									16601693	t		gcesareni	Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia.	SIGNOR-145845	0.626
MSH release-inhibiting hormone	smallmolecule	CID:56842142	PUBCHEM	MC4R	protein	P32245	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257538	0.8
PRKACA	protein	P17612	UNIPROT	GSK3A	protein	P49840	UNIPROT	down-regulates	phosphorylation	Ser21	SGRARTSsFAEPGGG	9606									11035810	t		gcesareni	Phosphorylation of ser21 and inactivation of glycogen synthase kinase 3 by protein kinase a.	SIGNOR-83221	0.378
MAPK1	protein	P28482	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser112	AIKVEPAsPPYYSEK	9606									11733495	t		gcesareni	Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells.	SIGNOR-112544	0.47
STK11	protein	Q15831	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									17108107	t		gcesareni	We show that lkb1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 ser15 (previously shown to be phosphorylated by amp-dependent kinase) and p53 ser392	SIGNOR-150830	0.747
DIP2A	protein	Q14689	UNIPROT	acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	up-regulates quantity	chemical modification			-1									30672040	t		miannu	 In this paper, we summarized the conservation of gene sequences and protein domains of DIP2 family members and predicted that they may have a similar functional role in acetyl-coenzyme A (acetyl-CoA) synthesis. We then used the most characterized member, disconnected interacting protein 2 homolog A (DIP2A), for further study. DIP2A is a cytoplasmic protein that is preferentially localized to mitochondria, and its acetyl-CoA synthetase activity has been demonstrated in vitro. Furthermore, the level of acetyl-CoA in HEK293 cells overexpressing DIP2A was increased, which is consistent with its metabolically related function.	SIGNOR-266590	0.8
PSENEN	protein	Q9NZ42	UNIPROT	RYK	protein	P34925	UNIPROT	up-regulates	cleavage			9606									19000841	t		gcesareni	Ryk activity is modulated through cleavage of its icd by gamma-secretase	SIGNOR-182145	0.2
CDK1	protein	P06493	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0003918								19917720	t		lperfetto	Cyclin-Dependent Kinase 1-Mediated Bcl-xL/Bcl-2 Phosphorylation Acts as a Functional Link Coupling Mitotic Arrest and Apoptosis|These findings suggest a model whereby a switch in the duration of CDK1 activation, from transient during mitosis to sustained during mitotic arrest, dramatically increases the extent of Bcl-xL/Bcl-2 phosphorylation, resulting in inactivation of their antiapoptotic function. Thus, phosphorylation of antiapoptotic Bcl-2 proteins acts as a sensor for CDK1 signal duration and as a functional link coupling mitotic arrest to apoptosis.	SIGNOR-267986	0.554
CSNK2A1	protein	P68400	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	phosphorylation	Ser330	MEEDSYDsFGEPSYP	-1									9558331	t		llicata	In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites.	SIGNOR-250934	0.311
VCAM1	protein	P19320	UNIPROT	A4/b1 integrin	complex	SIGNOR-C162	SIGNOR	up-regulates activity	binding			9606									12123670	t		lperfetto	We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1.	SIGNOR-253241	0.662
CKM complex	complex	SIGNOR-C406	SIGNOR	H3C1	protein	P68431	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR										18418385	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	lperfetto	However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo.	SIGNOR-273170	0.2
PIM3	protein	Q86V86	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606	BTO:0000007								16403219	t		miannu	Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.	SIGNOR-250399	0.353
RNF144A	protein	P50876	UNIPROT	PRKDC	protein	P78527	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								24979766	t		miannu	We show that RNF144A induces ubiquitination of DNA-PKcs in vitro and in vivo and promotes its degradation.	SIGNOR-272213	0.548
SUN1	protein	O94901	UNIPROT	MAJIN	protein	Q3KP22	UNIPROT	up-regulates activity	binding			9606	BTO:0000007		SIGNOR-C303	SIGNOR-C305					33015044	t		lperfetto	In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | It will be of great interest to test this hypothesis to fully understand the mechanisms of stable telomere–NE connection and telomere movement along the NE driven by the LINC complex.	SIGNOR-263300	0.2
CTNND1	protein	O60716	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000414								14610055	t		miannu	P120 regulates E-cadherin turnover at the cell membrane. Because direct binding of p120 to E-cadherin is required, it is possible that p120 binding blocks the interaction of an unknown binding partner (or event) that targets E-cadherin for degradation	SIGNOR-252123	0.945
SNW1	protein	Q13573	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606	BTO:0000222	BTO:0000887							10713164	t		gcesareni	Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip.	SIGNOR-75788	0.584
C1QBP	protein	Q07021	UNIPROT	KRT1	protein	P04264	UNIPROT	up-regulates activity	binding			9606									14691569	t	Regulation of binding	miannu	Cytokeratin 1 binds to both gC1qR and u-PAR. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored.	SIGNOR-251881	0.382
HES1	protein	Q14469	UNIPROT	RCAN1	protein	P53805	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000667								15866158	t			Increased Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, an endogenous Calcineurin inhibitor, through a HES-1-dependent mechanism .... Chromatin immunoprecipitation (ChIP) analysis of keratinocytes overexpressing HES-1 showed that this protein can bind to the HES binding sites present in both distal and proximal promoters	SIGNOR-252026	0.2
ULK1	protein	O75385	UNIPROT	SEC23B	protein	Q15437	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser186	SCEGISKsYVFRGTK	9606	BTO:0000007								30596474	t		lperfetto	Here, we show that the F-box protein FBXW5 targets SEC23B, a component of COPII, for proteasomal degradation and that this event limits the autophagic flux in the presence of nutrients. In response to starvation, ULK1 phosphorylates SEC23B on Serine 186, preventing the interaction of SEC23B with FBXW5 and, therefore, inhibiting SEC23B degradation.	SIGNOR-265285	0.2
BRCA1	protein	P38398	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0002572								19074868	t		gcesareni	The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation	SIGNOR-252435	0.521
NR3C1	protein	P04150	UNIPROT	NR4A1	protein	P22736	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15591535	f		gcesareni	Our data suggest a mechanism for transrepression between two nuclear receptors, gr and ngfi-b.	SIGNOR-132251	0.329
F2RL2	protein	O00254	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257146	0.2
PDPK1	protein	O15530	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Thr252	HDGTVTHtFCGTIEY	9606									9445476	t		gcesareni	A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.	SIGNOR-55306	0.714
VRK2	protein	Q86Y07	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates	phosphorylation	Ser31	PQDELDFsILFDYEY	9606									23105117	t		gcesareni	We demonstrate that vrk2 directly interacts and phosphorylates nfat1 in ser-32 within its n-terminal transactivation domain.	SIGNOR-199263	0.376
MEFV	protein	O15553	UNIPROT	Pyrin inflammasome	complex	SIGNOR-C226	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256413	0.598
FGFR4	protein	P22455	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	phosphorylation	Tyr701	DGPKGTGyIKTELIS	9606	BTO:0000007								10918587	t			Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. 	SIGNOR-251141	0.355
MAPK1	protein	P28482	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									19914168	t		lpetrilli	Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3	SIGNOR-161706	0.736
CSNK2B	protein	P67870	UNIPROT	CDC34	protein	P49427	UNIPROT	unknown	phosphorylation	Ser222	EVEEEADsCFGDDED	9606	BTO:0000567								11546811	t		llicata	CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm. 	SIGNOR-251058	0.357
GSK3B	protein	P49841	UNIPROT	MCL1	protein	Q07820	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser159	NNTSTDGsLPSTPPP	10090	BTO:0003328								16543145	t			MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1.	SIGNOR-251242	0.515
PAX7	protein	P23759	UNIPROT	PAX7/MLL1 complex	complex	SIGNOR-C90	SIGNOR	form complex	binding			9606	BTO:0002314	BTO:0000887;BTO:0001103							22863532	t		miannu	Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5.	SIGNOR-198632	0.2
CCNB1	protein	P14635	UNIPROT	CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	form complex	binding			9606									25603287	t		lperfetto	The central mitotic kinase, cyclin-dependent kinase-1 (human cdk1 is present through all stages of the cell cycle, but its activity is cell-cycle regulated by phosphorylation/dephosphorylation and cyclin binding.Cdk1-cyclin b phosphorylates ser/thr residues directly preceding pro; thus, it is classified as a proline-directed kinase.	SIGNOR-205590	1
SRC	protein	P12931	UNIPROT	TRIM25	protein	Q14258	UNIPROT	up-regulates activity	phosphorylation	Tyr278	NSKFDTIyQILLKKK	9606	BTO:0002181								30100205	t		miannu	Here, we demonstrated that TRIM25 interacted with c-Src and underwent tyrosine phosphorylation by c-Src kinase upon viral infection and the phosphorylation is required for the complete activation of RIG-I signaling. Analysis using a c-Src inhibitor and TRIM25 mutant, in which tyrosine 278 is substituted by phenylalanine (Y278F), suggested that the phosphorylation positively regulates K63-linked polyubiquitination of RIG-I and subsequent antiviral signaling. 	SIGNOR-277405	0.274
Endothelin-1	smallmolecule	CHEBI:80240	ChEBI	EDNRB	protein	P24530	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257483	0.8
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates	phosphorylation	Tyr86	VADIDGQyAMTRAQR	9606	BTO:0001271								17318191	t		lperfetto	Bcr_abl_mediated phosphorylation of y86 could induce a conformational change of __catenin impairing its binding to axin	SIGNOR-153435	0.2
MECOM	protein	Q03112	UNIPROT	DNMT3A	protein	Q9Y6K1	UNIPROT	up-regulates activity	binding												21695170	t		lperfetto	The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA|Here we show that EVI1 physically interacts with DNA methyltransferases 3a and 3b (Dnmt3a/b), which are the only de novo DNA methyltransferases identified to date in mouse and man, and that it forms an enzymatically active protein complex that induces de novo DNA methylation in vitro. 	SIGNOR-273432	0.299
INPP5D	protein	Q92835	UNIPROT	PLCG2	protein	P16885	UNIPROT	down-regulates activity	dephosphorylation			9606	BTO:0000776								32323266	t		scontino	An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.	SIGNOR-268455	0.317
WT1	protein	P19544	UNIPROT	PAX2	protein	Q02962	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090		BTO:0000671							7720589	t			A marked increase in WT1 protein levels coincided precisely with down-regulation of the Pax-2 gene in the individual precursor cells of the visceral glomerular epithelium, suggesting a direct effect of the WT1 repressor protein on Pax-2 regulatory elements. To examine whether WT1 could directly repress Pax-2 transcription, binding of WT1 to three high affinity sites in the 5' untranslated Pax-2 leader sequence was demonstrated by DNAseI footprinting analysis	SIGNOR-252298	0.618
STK16	protein	O75716	UNIPROT	STK16	protein	O75716	UNIPROT	unknown	phosphorylation	Tyr198	AQRCTISyRAPELFS	-1									18184589	t		Manara	Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition.	SIGNOR-260805	0.2
DGCR8	protein	Q8WYQ5	UNIPROT	RNF168	protein	Q8IYW5	UNIPROT	up-regulates activity	binding			9606	BTO:0002181								34188037	t		miannu	 Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs. 	SIGNOR-277309	0.2
GSK3A	protein	P49840	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser509	GVHSPMAsSGNTGNH	9606	BTO:0000093								17574025	t		miannu	GSK3 Phosphorylates SRC-3 on S505.In this report, we identified GSK3 as a kinase that phosphorylates SRC-3 on S505 and demonstrated that this phosphorylation modulates SRC-3 transcriptional function and turnover. 	SIGNOR-276067	0.2
PRKAA1	protein	Q13131	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	down-regulates activity	phosphorylation			9606			SIGNOR-C15	SIGNOR-C3					21460634	t		lperfetto	Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2.	SIGNOR-173035	0.674
DNM2	protein	P50570	UNIPROT	GJB2	protein	P29033	UNIPROT	down-regulates	binding			9606									25263585	t		miannu	This study identifies dynamin 2 (dyn2) as a cx26 interactor in yeast and mammalian cells / we demonstrate that dyn2 regulates cx26 endocytosis and ubiquitination	SIGNOR-205372	0.335
EGFR	protein	P00533	UNIPROT	ERBB3	protein	P21860	UNIPROT	up-regulates	phosphorylation	Tyr1276	GGGPGGDyAAMGACP	9606	BTO:0000150								7929151	t		lperfetto	The erbb3 protein which possesses little or no intrinsic protein tyrosine kinase activiity is phosphorylated by the activated egf receptor protein tyrosine kinase on tyrosine residues within the yxxm sequence motif. These phosphorylated tyrosine residues interact with the p85 regulatory subunit of pi 3-kinase, which could result in the activation of the p110 catalytic subunit via a conformational mechanism.	SIGNOR-34748	0.654
PHKG1	protein	Q16816	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser622	KHVPGGGsVQIVYKP	-1									8999860	t		miannu	Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules	SIGNOR-250286	0.318
PLK1	protein	P53350	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates	phosphorylation	Ser740	SFTALDWsWLQTEEE	9606									18957422	t		lperfetto	Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma	SIGNOR-181802	0.349
Apoptosome	complex	SIGNOR-C230	SIGNOR	CASP3	protein	P42574	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000567								9390557	t		lperfetto	Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade.	SIGNOR-256472	0.731
RPS6KA1	protein	Q15418	UNIPROT	RPS6	protein	P62753	UNIPROT	up-regulates	phosphorylation	Ser235	IAKRRRLsSLRASTS	9606									17360704	t		gcesareni	We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism.	SIGNOR-153618	0.608
RAB6C	protein	Q9H0N0	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				10116									25492866	f		miannu	Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons	SIGNOR-266875	0.7
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	A10/b1 integrin	complex	SIGNOR-C167	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259021	0.457
NEK1	protein	Q96PY6	UNIPROT	VHL	protein	P40337	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser168	RCLQVVRsLVKPENY	9606	BTO:0000007								23255108	t		miannu	Nek1 phosphorylates Von Hippel-Lindau tumor suppressor to promote its proteasomal degradation and ciliary destabilization. Mutation of pVHL at S-168 increases protein stability. 	SIGNOR-276434	0.26
CSNK2A2	protein	P19784	UNIPROT	AQP4	protein	P55087	UNIPROT	down-regulates activity	phosphorylation	Ser316	EKKGKDQsGEVLSSV	9615									11742978	t		llicata	We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII.	SIGNOR-250976	0.344
SLBP	protein	Q14493	UNIPROT	H2BE1	protein	A0A2R8Y619	UNIPROT	up-regulates quantity by expression	translation regulation			9606									19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265380	0.2
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DQB1	protein	P01920	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-253992	0.277
MAPK3	protein	P27361	UNIPROT	KRT8	protein	P05787	UNIPROT	unknown	phosphorylation	Ser432	SAYGGLTsPGLSYSL										16554440	t		lperfetto	Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002).	SIGNOR-249468	0.429
SOS1	protein	Q07889	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									25624485	t	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.	gcesareni	Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts 	SIGNOR-122075	0.821
ATR	protein	Q13535	UNIPROT	ATRIP	protein	Q8WXE1	UNIPROT	up-regulates	phosphorylation	Ser72	TLASQALsQCPAAAR	9606									15451423	t		lperfetto	When dna is damaged, the atr-atrip complex is recruited to chromatin and is activated to transduce the checkpoint signal, but the precise kinase activation mechanism remains unknown. Here, we show that atrip is phosphorylated in an atr-dependent manner after genotoxic stimuli. The serine 68 and 72 residues are important for the phosphorylation in vivo and are required exclusively for direct modification by atr in vitro.	SIGNOR-129473	0.873
dolichyl beta-D-mannosyl phosphate	smallmolecule	CHEBI:17624	ChEBI	Protein_glycosylation	phenotype	SIGNOR-PH144	SIGNOR	up-regulates													21384228	f		lperfetto	Dolichol has a well defined role as a lipid carrier for the glycan precursor in the early stages of N‐linked protein glycosylation, which is assembled in the endoplasmic reticulum of all eukaryotic cells.	SIGNOR-262568	0.7
SRC	protein	P12931	UNIPROT	VCL	protein	P18206	UNIPROT	down-regulates activity	phosphorylation	Tyr100	QMLQSDPySVPARDY	9534									15229287	t		lperfetto	The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail.	SIGNOR-247424	0.752
RPS6KA4	protein	O75676	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates	phosphorylation	Ser119	EILSRRPsYRKILND	9606	BTO:0000782								17668895	t		gcesareni	Msk1 and msk2 directly phosphorilate and activete transcription factors such as creb1, atf1 msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation.	SIGNOR-157158	0.588
ARAP2	protein	Q8WZ64	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260454	0.439
MLL-AF4	fusion protein	SIGNOR-FP4	SIGNOR	CBFB	protein	Q13951	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24449215	f		irozzo	However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins.	SIGNOR-255856	0.2
Naltriben	chemical	CID:5486827	PUBCHEM	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258426	0.8
GSK3B	protein	P49841	UNIPROT	CDX2	protein	Q99626	UNIPROT	unknown	phosphorylation	Ser291	PVSSLQAsVPGSVPG	-1									16027724	t			GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines)	SIGNOR-251229	0.389
ETS1	protein	P14921	UNIPROT	MUC4	protein	Q99102	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001861								19757157	t	 	lperfetto	Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level.	SIGNOR-254098	0.2
KDM4C	protein	Q9H3R0	UNIPROT	KDM1A	protein	O60341	UNIPROT	up-regulates activity	binding			9606	BTO:0001033								29207681	t		miannu	JMJD2C was found to be co-localized with AR and LSD1 in the epithelium of prostate carcinoma and normal prostate cells. For the detailed mechanism, JMJD2C, AR and LSD1 assembled on the chromatin to remove the methyl groups from mono-, di- and trimethylated H3K9. Importantly, JMJD2C specifically removed the demethylation of the trimethyl H3K9 marks and modulated the transcriptional activity of AR. Moreover, JMJD2C cooperated with LSD1 and activated AR-mediated gene expression via decreasing H3K9me3 at the promoter of AR targeting genes KLK2 and PSA.	SIGNOR-263880	0.2
CAMK2B	protein	Q13554	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	up-regulates	phosphorylation	Thr183	SDGEFLRtSCGSPNY	9606	BTO:0000567			SIGNOR-C15					15980064	t		gcesareni	These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo.	SIGNOR-138360	0.2
FLT3	protein	P36888	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity				9606									30552988	f		miannu	Oncogenic, constitutively active mutants of FLT3 are known to be expressed in acute myeloid leukemia and to correlate with poor prognosis. Activation of the receptor mediates cell survival, cell proliferation and differentiation of cells. Several of the signal transduction pathways downstream of FLT3 have been shown to include various members of the SRC family of kinases (SFKs). They are involved in regulating the activity of RAS/ERK pathways through the scaffolding protein GAB2 and the adaptor protein SHC.	SIGNOR-260132	0.297
GSK3B	protein	P49841	UNIPROT	SREBF1	protein	P36956	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr426	TEVEDTLtPPPSDAG	9606	BTO:0000567								16825193	t		lperfetto	The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding	SIGNOR-236649	0.499
SIRT1	protein	Q96EB6	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity				9606	BTO:0000007								14976264	f		lperfetto	Sirt1 inhibited foxo3's ability to induce cell death.	SIGNOR-252995	0.909
SIRT5	protein	Q9NXA8	UNIPROT	GLS	protein	O94925	UNIPROT	up-regulates activity	binding			9606	BTO:0006301								30910998	t		Monia	Immunoprecipitation assays of interaction between GLS and SIRT5 in HepG2 cells infected with lentivirus containing empty or BAG3 construct. Ectopic BAG3 expression decreases the interaction between GLS and SIRT5. It has been reported that SIRT5 is responsible for desuccinylation of GLS35, immunoprecipitation (IP) was then performed.	SIGNOR-261207	0.461
levomethadone	chemical	CHEBI:136003	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258807	0.8
vasopressin	smallmolecule	CHEBI:9937	ChEBI	AVPR1B	protein	P47901	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257462	0.8
IL7	protein	P13232	UNIPROT	IL2RG	protein	P31785	UNIPROT	up-regulates	binding			9606									11418623	t		gcesareni	The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, il-15, il-2, il21	SIGNOR-108864	0.699
MAPKAPK2	protein	P49137	UNIPROT	PLK1	protein	P53350	UNIPROT	up-regulates	phosphorylation	Ser326	LTIPPRFsIAPSSLD	9606									18695677	t		llicata	Here, we have identified mk2 as a major plk1 kinase toward ser326, whose phosphorylation is critical to recruit ?-Tubulin to centrosomes and subsequent establishment of functional bipolar spindles. To our knowledge, this is the first direct evidence to demonstrate that the essential function of plk1 in centrosome maturation and bipolar spindle formation is controlled by its upstream kinase.	SIGNOR-179968	0.356
PHLPP2	protein	Q6ZVD8	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	down-regulates activity	dephosphorylation	Ser472	RPHFPQFsYSASGRE	9606	BTO:0001544								19261608	t			The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.	SIGNOR-248731	0.671
ABL2	protein	P42684	UNIPROT	ABL2	protein	P42684	UNIPROT	up-regulates	phosphorylation	Tyr261	GLVTTLHyPAPKCNK	9606									15735735	t		lperfetto	The results show that arg is stabilized in response to 0.1 mm h2o2 by autophosphorylation of y-261, consistent with involvement of the arg kinase function in regulating arg levels. The results further demonstrate that c-abl-mediated phosphorylation of arg on y-261 similarly confers arg stabilization	SIGNOR-134400	0.2
GRK5	protein	P34947	UNIPROT	ADRB2	protein	P07550	UNIPROT	unknown	phosphorylation	Ser411	RNCSTNDsLL	-1									8662852	t			 we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). 	SIGNOR-251198	0.682
PPARG	protein	P37231	UNIPROT	UCP1	protein	P25874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								32991581	t	brain	lperfetto	NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,	SIGNOR-263985	0.55
PRKACA	protein	P17612	UNIPROT	CHCHD3	protein	Q9NX63	UNIPROT	unknown	phosphorylation	Thr11	TTSTRRVtFEADENE	-1									17242405	t		miannu	Identification of ChChd3 as a novel substrate of the cAMP-dependent protein kinase (PKA) using an analog-sensitive catalytic subunit. we used the recombinant GST-ChChd3 for an in vitro kinase assays to determine whether in vitro phosphorylation by PKA was direct. Fig. 6 demonstrates that PKA directly phosphorylates recombinant Chchd3 with a stoichiometry of 0.3 mol of phosphate incorporated per mol of ChChd3. Although three potential PKA phosphorylation sites exist in ChChd3, Thr10 represents the most likely site to be phosphorylated. 	SIGNOR-263116	0.2
PTEN	protein	P60484	UNIPROT	HCLS1	protein	P14317	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11494141	f		miannu	Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 	SIGNOR-260052	0.2
EIF2S1	protein	P05198	UNIPROT	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	up-regulates				9606									11381086	f		miannu	Translation initiation is inhibited in cells exposed to different stressful conditions. The phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) plays an important role in this stereotyped response, and is mediated by distinct kinases that are activated by specific stress signals. When phosphorylated on serine 51, eIF2α binds to and inhibits the guanine nucleotide exchange factor, eIF2B. The latter is required for the formation of the eukaryotic translational preinitiation complexes, and its sequestration in an inactive complex with phosphorylated eIF2α inhibits the initiation step of protein synthesis. 	SIGNOR-260625	0.7
MRPL32	protein	Q9BYC8	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262339	0.697
ROCK1	protein	Q13464	UNIPROT	ARHGAP24	protein	Q8N264	UNIPROT	up-regulates activity	phosphorylation	Ser573	ENSNSCRsSTTTCPE	9606	BTO:0000007								16862148	t		lperfetto	ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2).	SIGNOR-249302	0.444
NF1	protein	P21359	UNIPROT	KRAS	protein	P01116	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								32697994	t		miannu	Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS.	SIGNOR-273661	0.711
INS	protein	P01308	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000011								11279134	f		lperfetto	The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin	SIGNOR-235619	0.504
5,15-Diphenyl-21H,23H-porphine	chemical	CID:10895852	PUBCHEM	STAT3	protein	P40763	UNIPROT	down-regulates activity	chemical inhibition			9606									26260587	t		gcesareni	15-DPP is an effective STAT3 inhibitor and blocks IL10-mediated signalling in macrophages leading to altered regulation of CNV	SIGNOR-238549	0.8
ELOVL	proteinfamily	SIGNOR-PF93	SIGNOR	palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	down-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267901	0.8
INSR	protein	P06213	UNIPROT	ADRB2	protein	P07550	UNIPROT	down-regulates activity	phosphorylation	Tyr141	AITSPFKyQSLLTKN	10029	BTO:0000246								8557631	t			Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors. 	SIGNOR-251300	0.385
CDK1	protein	P06493	UNIPROT	RAD9A	protein	Q99638	UNIPROT	up-regulates activity	phosphorylation	Ser328	VLPSISLsPGPQPPK	9606	BTO:0000567								12734188	t		lperfetto	Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9.	SIGNOR-101047	0.37
CTDSP1	protein	Q9GZU7	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	dephosphorylation	Ser213	NLSPNPMsPAHNNLD	9606	BTO:0000007								17035229	t			SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248793	0.408
PNMT	protein	P11086	UNIPROT	adrenaline	smallmolecule	CHEBI:33568	ChEBI	up-regulates quantity	chemical modification			9606									7961964	t	brain	lperfetto	In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline).	SIGNOR-264007	0.8
MYCN	protein	P04198	UNIPROT	ABCB1	protein	P08183	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000793;BTO:0002104								7923112	f		miannu	 Decreased expression of the N-myc oncogene in neuroblastoma cell lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, was paralleled by down-regulation of MRP gene expression, contrasting with increased expression of the MDR1 gene. 	SIGNOR-254616	0.378
IL6	protein	P05231	UNIPROT	IL6R	protein	P08887	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001103							23663276	t		milica	In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal.	SIGNOR-202030	0.916
RANBP3	protein	Q9H6Z4	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	relocalization			9606									19289081	t		gcesareni	Ranbp3 directly recognizes dephosphorylated smad2/3, which results from the activity of nuclear smad phosphatases, and mediates nuclear export of smad2/3 in a ran-dependent manner	SIGNOR-184608	0.398
MYCT1	protein	Q8N699	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30283340	f		miannu	MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. 	SIGNOR-261734	0.2
sabcomeline	chemical	CHEBI:134846	ChEBI	CHRM4	protein	P08173	UNIPROT	up-regulates activity	chemical activation			10116									9399977	t		miannu	 SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes	SIGNOR-258675	0.8
POLR2C	protein	P19387	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266163	0.877
PRKCZ	protein	Q05513	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates	phosphorylation			9606									17183360	t		lperfetto	Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k)	SIGNOR-217370	0.476
IL12A	protein	P29459	UNIPROT	IL12B	protein	P29460	UNIPROT	up-regulates	binding			9606									7527811	t		fspada	However, a proper conformation required for high affinity binding is achieved only when p40 is associated with a p35 subunit or another p40 subunit. When p40 is associated with a p35 subunit, the heterodimer acts as an agonist mediating biologic activity. However, when p40 associates with another p40, the homodimer behaves as an antagonist in vitro	SIGNOR-27619	0.842
MFNG	protein	O00587	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	up-regulates	binding			9606									11346656	t		gcesareni	These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch (30, 31). It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2.	SIGNOR-107708	0.674
ITGB1BP1	protein	O14713	UNIPROT	Av/b5 integrin	complex	SIGNOR-C178	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257661	0.288
PRKCB	protein	P05771	UNIPROT	PRKCB	protein	P05771	UNIPROT	up-regulates activity	phosphorylation	Ser661	QNEFAGFsYTNPEFV	9606									17115692	t		lperfetto	The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif	SIGNOR-150861	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Ser13	ITSAARRsYVSSGEM	-1									7822264	t		llicata	On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II.	SIGNOR-250626	0.438
creatine	smallmolecule	CHEBI:16919	ChEBI	CKB	protein	P12277	UNIPROT	up-regulates activity	chemical activation			9606									18502307	t		miannu	Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 	SIGNOR-265809	0.8
SMARCC1	protein	Q92922	UNIPROT	Neural progenitor-specific SWI/SNF	complex	SIGNOR-C477	SIGNOR	form complex	binding			9606									25195934	t		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270617	0.82
STK11	protein	Q15831	UNIPROT	MARK2	protein	Q7KZI7	UNIPROT	up-regulates activity	phosphorylation	Thr208	TFGNKLDtFCGSPPY	-1									18424437	t		miannu	MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase.	SIGNOR-276165	0.569
KEAP1	protein	Q14145	UNIPROT	CUL3	protein	Q13618	UNIPROT	up-regulates activity	binding			9534	BTO:0001538								15983046	t		miannu	Keap1 is a BTB-Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 targets its substrate, the Nrf2 transcription factor, for ubiquitination and subsequent degradation by the 26 S proteasome.  The N-terminal BTB domain and central linker region of Keap1 bind Cul3, whereas the C-terminal Kelch domain of Keap1 binds Nrf2 via residues located within loops that extend out from the bottom of the Kelch domain	SIGNOR-268925	0.949
CERK	protein	Q8TCT0	UNIPROT	ceramide 1-phosphate(2-)	smallmolecule	CHEBI:84404	ChEBI	up-regulates quantity	chemical modification			9606									34202192	t		miannu	Another relevant enzyme is Ceramide kinase (CerK), which phosphorylates Cer to produce Ceramide 1-phosphate (C1P). 	SIGNOR-268499	0.8
RB1	protein	P06400	UNIPROT	ANP32A	protein	P39687	UNIPROT	down-regulates activity	binding			9606					phosphorylation:Thr826	LPTPTKMtPRSRILV			15716273	t			We further demonstrate that pp32-Rb interaction inhibits the apoptotic activity of pp32 and stimulates proliferation.	SIGNOR-259083	0.2
CYP1B1	protein	Q16678	UNIPROT	4-hydroxy-17beta-estradiol	smallmolecule	CHEBI:62845	ChEBI	up-regulates quantity	chemical modification			9606	BTO:0000093								8790407	t		Luana	These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens.	SIGNOR-269754	0.8
GABA-A (a4-b3-d) receptor	complex	SIGNOR-C327	SIGNOR	CRHR1	protein	P34998	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268605	0.254
MAPKAPK2	protein	P49137	UNIPROT	TCF3	protein	P15923	UNIPROT	up-regulates	phosphorylation			9606									20626350	t		gcesareni	Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2	SIGNOR-166643	0.498
PPP2CA	protein	P67775	UNIPROT	CILK1	protein	Q9UPZ9	UNIPROT	down-regulates	dephosphorylation	Tyr159	SKPPYTDyVSTRWYR	9606									15988018	t		lperfetto	In addition, mass spectrometry showed that pp2a treatment completely abolished the dually phosphorylated form, leaving only the singly phosphorylated form (data not shown). We conclude that a portion of ick in unstimulated and asynchronized hek293t cells is dually phosphorylated on the tdy motif.	SIGNOR-138432	0.2
RPS6KA1	protein	Q15418	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser153	SWTRVFQsWWDRNLG	9606	BTO:0000007								10837486	t		lperfetto	We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites.	SIGNOR-249045	0.404
FADD	protein	Q13158	UNIPROT	CASP8	protein	Q14790	UNIPROT	up-regulates activity	binding			9606									11717445	t		amattioni	Fadd recruits caspase-8 through homotypic interactions of death-effector domains (deds), leading to caspase-8 activation and apoptosis. In turn, fadd recruits the zymogen form of the apoptosis-initiating protease caspase-8, through homophilic interaction of death effector domains.	SIGNOR-112061	0.929
Naloxone benzoylhydrazone	chemical	CID:9601084	PUBCHEM	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258422	0.8
ITGB3	protein	P05106	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257718	0.652
NELFA	protein	Q9H3P2	UNIPROT	NELF	complex	SIGNOR-C521	SIGNOR	form complex	binding			9606									18628398	t		miannu	The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. 	SIGNOR-271401	0.882
PSMB7	protein	Q99436	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263360	0.855
PRTN3	protein	P24158	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates activity	cleavage	Pro48	RSFLLRNpNDKYEPF	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263577	0.43
PRKCD	protein	Q05655	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates	phosphorylation	Thr890	GQVERFEtVGMEAAT	9606									12361954	t		fspada	This interaction, which does not seem to involve a classical phosphotyrosine sh2-mediated binding, however, significantly enhances the interaction of stat3 and the il-6 receptor subunit glycoprotein (gp) 130, which is the initial step for stat3 activation by il-6. Expression of a dominant negative pkcdelta or depletion of the endogenous pkcdelta by phorbol 12-myristate 3-acetate treatment abrogates the association of stat3 with gp130. At the same time, pkcdelta is recruited to gp130 via association with stat3, which may facilitate its phosphorylation on the gp130 receptor. Finally, we identified thr-890, a putative pkc phosphorylation site on gp130, to be critical for the effect of pkcdelta. Our data indicate that pkcdelta plays important regulatory roles in il-6 signaling.	SIGNOR-94012	0.339
EIF4E2/GIGYF2 complex	complex	SIGNOR-C257	SIGNOR	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	down-regulates				9606	BTO:0000568								22751931	f		lperfetto	A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|m4EHP and/or GIGYF2 proteins repress translation.	SIGNOR-261013	0.7
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	transfer RNA	smallmolecule	CHEBI:17843	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-266143	0.8
AKT3	protein	Q9Y243	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	up-regulates	phosphorylation	Ser387	SKLMRSAsFNTDPYV	9606									18476811	t		lperfetto	Phosphorylation of argonaute 2 at serine-387 facilitates its localization to processing bodies, akt3-mediated phosphorylation of ago2 is a molecular switch between target mrna cleavage and translational repression activities of ago2	SIGNOR-178416	0.434
MKNK1	protein	Q9BUB5	UNIPROT	SPRY2	protein	O43597	UNIPROT	down-regulates	phosphorylation	Ser121	VSSGSRSsTRTSTSS	9606									19864419	t		llicata	The spry2/nedd4 association involves the ww domains of nedd4 and requires phosphorylation of the mnk2 kinase sites, ser(112) and ser(121), on spry2. mnk2 silencing decreased spry2-nedd4 interactions and also augmented the ability of spry2 to inhibit fibroblast growth factor signaling. endogenous and overexpressed nedd4 polyubiquitinate spry2 via lys(48) on ubiquitin and decrease its stability.	SIGNOR-188893	0.509
PTPN2	protein	P17706	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates activity	dephosphorylation	Tyr1059	DIYKDPDyVRKGDAR	9606	BTO:0000007								18840653	t			We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well. 	SIGNOR-248400	0.548
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates activity	phosphorylation	Tyr101	EGLSMGNyIGLINRI	-1									16373505	t		Manara	PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR.	SIGNOR-260782	0.2
HTR4	protein	Q13639	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257309	0.252
CSNK2A1	protein	P68400	UNIPROT	MRE11	protein	P49959	UNIPROT	up-regulates activity	phosphorylation	Ser558	AEQMANDsDDSISAA	-1									28436950	t		miannu	Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689.	SIGNOR-265896	0.2
MAPK1	protein	P28482	UNIPROT	DUSP16	protein	Q9BY84	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser446	TNKLCQFsPVQELSE	9534									15689616	t		lperfetto	Phosphorylation of Ser-446 determines stability of MKP-7.|We also determined that MKP-7 phosphorylated at Ser-446 has a longer half-life than unphosphorylated form of the wild type protein, as does a phospho-mimic mutant of MKP-7. These results indicate that activation of the ERK pathway strongly blocks JNK activation through stabilization of MKP-7 mediated by phosphorylation.	SIGNOR-249389	0.802
MMP20	protein	O60882	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272365	0.7
AKAP11	protein	Q9UKA4	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity	binding			9606	BTO:0000007				phosphorylation:Thr1136	AKEFAPAtPPSTPHN			26088133	t		lperfetto	A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Using a combination of molecular and cellular approaches we show that GSK3beta phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3beta and its substrate beta-catenin in membrane ruffles.	SIGNOR-264817	0.379
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BC1	protein	Q96A08	UNIPROT	down-regulates activity	monoubiquitination	Lys36	KKRKRTRkESYSIYI	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271992	0.2
TGFBR1	protein	P36897	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	unknown	phosphorylation	Ser160	SSTFDALsPSPAIPS	9606									23166821	t		llicata	We show that phosphorylation of _np63_ at s66/68 in response to ultraviolet (uv) irradiation is mediated by alk5	SIGNOR-199781	0.2
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2W	protein	Q96B02	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271340	0.676
MYC	protein	P01106	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	binding			9606									11804592	t		gcesareni	Through its direct interaction with smads, c-myc binds to the sp1-smad complex on the promoter of the p15(ink4b) gene, thereby inhibiting the tgf-beta-induced transcriptional activity of sp1 and smad/sp1-dependent transcription of the p15(ink4b) gene. These results suggest that oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads.	SIGNOR-114284	0.673
HCK	protein	P08631	UNIPROT	RAPGEF1	protein	Q13905	UNIPROT	up-regulates	phosphorylation	Tyr504	APIPSVPyAPFAAIL	9606									24396067	t		llicata	We also showed that ctla-4 receptor signaling mediates tyrosine phosphorylation in the c3g protein, and that this is required for augmented activation of rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (lfa-1). ctla-4 signaling leads to phosphorylation of c3g tyrosine 504. the src family member hck phosphorylates c3g downstream of ctla-4.	SIGNOR-203613	0.512
LAMA4	protein	Q16363	UNIPROT	Laminin-9	complex	SIGNOR-C180	SIGNOR	form complex	binding												10809728	t		lperfetto	Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. 	SIGNOR-253223	0.485
GDF11	protein	O95390	UNIPROT	ACVR2B	protein	Q13705	UNIPROT	up-regulates	binding			9606									12414726	t		gcesareni	Here we demonstrate using genetic and biochemical studies that actriib and its subfamily receptor, actriia, cooperatively mediate the gdf11 signal in patterning the axial vertebrae, and that gdf11 binds to both actriia and actriib, and induces phosphorylation of smad2	SIGNOR-95309	0.646
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	UNG	protein	P13051	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								20870715	t		miannu	Using reconstituted CRL4(DCAF1) and CRL4(DCAF1-Vpr) E3 ubiquitin ligases in vitro reveals that UNG2 ubiquitination (ubiquitylation) is facilitated by Vpr. Co-expression of DCAF1 and Vpr causes down-regulation of UNG2 in a proteasome-dependent manner, with Vpr mutants that are defective in UNG2 or DCAF1 binding abrogating this effect.	SIGNOR-271905	0.382
SATB1	protein	Q01826	UNIPROT	SPARC	protein	P09486	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000664								17343824	f		miannu	 In this study, a SATB1 eukaryotic expression plasmid was transfected into the human erythroleukemia K562 cell line and individual clones that stably over-expressed the SATB1 protein were isolated. Microarray analysis revealed that hundreds of genes were either up- or down-regulated in the SATB1 over-expressing K562 cell lines. One of these was the extra-cellular matrix glycoprotein, SPARC (human secreted protein acidic and rich in cysteine). siRNA knock-down of SATB1 also reduced SPARC expression, which was consistent with elevated SPARC levels in the SATB1 over-expressing cell line. 	SIGNOR-255128	0.2
MAPK1	protein	P28482	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser362	AAAHRKGsSSNEPSS										16055710	t		lperfetto	Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos	SIGNOR-262996	0.784
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	down-regulates quantity by destabilization	chemical inhibition			9606									19029980	t			Retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation.	SIGNOR-259926	0.8
COL1A1	protein	P02452	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	up-regulates activity	binding												35267698	t		lperfetto	Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23].	SIGNOR-272346	0.623
PLK1	protein	P53350	UNIPROT	GTSE1	protein	Q9NYZ3	UNIPROT	up-regulates	phosphorylation	Ser435	RSIRRRDsCLNSKTK	9606									20577264	t		lperfetto	In this study, we show that g2 and s-phase-expressed 1 (gtse1) protein, a negative regulator of p53, is required for g2 checkpoint recovery and that plk1 phosphorylation of gtse1 at ser 435 promotes its nuclear localization, and thus shuttles p53 out of the nucleus to lead to its degradation during the recovery.	SIGNOR-166417	0.725
SRC	protein	P12931	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr861	PIGNQHIyQPVGKPD	9606	BTO:0000195								17289681	t	The effect has been demonstrated using P34152-3	gcesareni	We propose that fak/c-src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on fak tyr-861 by src and subsequent reorganization of f-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress.	SIGNOR-152971	0.633
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1654	SPSYSPTsPSYSPTS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248771	0.441
CREB1	protein	P16220	UNIPROT	MITF	protein	O75030	UNIPROT	up-regulates quantity by expression	transcriptional regulation												10841026	t		lperfetto	Therefore, the molecular steps linking cAMPto melanogenesis up-regulation appear currently better elucidated. cAMP activates PKA, and PKA phosphorylates and activates CREB which, when activated, binds to the CRE domain present in the microphthalmia promoter,thereby up-regulating its transcription.	SIGNOR-249619	0.62
IKBKB	protein	O14920	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser345	RPASVDGsPVSPSTN	-1									12351658	t			IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.	SIGNOR-251295	0.644
PIK3R1	protein	P27986	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	form complex	binding			9606									19805105	t		miannu	Phosphoinositol 3- kinase alpha (PI3Kα) is a heterodimeric enzyme formed by a catalytic subunit (p110α, encoded by PIK3CA) and one of several regulatory subunits (a major one being p85α, encoded by PI3KR1).	SIGNOR-255300	0.934
CDK1	protein	P06493	UNIPROT	KRT8	protein	P05787	UNIPROT	up-regulates	phosphorylation	Ser432	SAYGGLTsPGLSYSL	9606									9524113	t		lperfetto	With regard to k8 phosphorylation at ser-431, it increases dramatically upon stimulation of cells with epidermal growth factor (egf) or after mitotic arrest and is the major k8 phosphorylated residue after incubating k8 immunoprecipitates with mitogen-activated protein or cdc2 kinases.	SIGNOR-56054	0.25
TACR1	protein	P25103	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257423	0.408
FOXS1	protein	O43638	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9913									18288644	t		Luana	Fkhl18 suppressed the transcriptional activity of FoxO3a and FoxO4.	SIGNOR-261610	0.2
TAL1	protein	P17542	UNIPROT	Erythrocyte_differentiation 	phenotype	SIGNOR-PH104	SIGNOR	up-regulates activity				10090	BTO:0004911								29713515	f			The truncated form TAL1-s is required for erythroid progenitors differentiation, while the full-length protein TAL1-l is required for megakaryocytic differentiation of progenitor cells.	SIGNOR-259970	0.7
MMP15	protein	P51511	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272383	0.7
PRKCA	protein	P17252	UNIPROT	LRP1	protein	Q07954	UNIPROT	up-regulates	phosphorylation	Thr4460	GFQHQRMtNGAMNVE	9606									15272003	t		lperfetto	Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc.	SIGNOR-127215	0.2
IQSEC2	protein	Q5JU85	UNIPROT	GRIA1	protein	P42261	UNIPROT	up-regulates quantity	relocalization			9606		BTO:0000142							27009485	t		miannu	BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.	SIGNOR-264912	0.2
COL4A1	protein	P02462	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	up-regulates activity	binding			9606	BTO:0000664								12123670	t		lperfetto	We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1.	SIGNOR-253242	0.481
CEBPB	protein	P17676	UNIPROT	SFTPD	protein	P35247	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001910								11912209	t	 	 	Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.	SIGNOR-254045	0.254
STAT6	protein	P42226	UNIPROT	ALOX15	protein	P16050	UNIPROT	up-regulates				9606	BTO:0000018								12517954	f	 	lperfetto	IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300.	SIGNOR-254101	0.335
RPL24	protein	P83731	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262475	0.84
GATA4	protein	P43694	UNIPROT	TDO2	protein	P48775	UNIPROT	down-regulates quantity by repression	transcriptional regulation				BTO:0000575								19003156	t		lperfetto	GATA4 inhibits expression of the tryptophan oxygenase gene by binding to the TATA box in fetal hepatocytes.	SIGNOR-268994	0.255
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	ABCB1	protein	P08183	UNIPROT	up-regulates activity	dephosphorylation	Ser671	RKRSTRRsVRGSQAQ	9606	BTO:0000007								24333728	t			Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp	SIGNOR-272509	0.2
PRKCA	protein	P17252	UNIPROT	ADRA1B	protein	P35368	UNIPROT	down-regulates activity	phosphorylation	Ser410	RKDSLDDsGSCLSGS	9534	BTO:0000298								9353340	t		lperfetto	 Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response. 	SIGNOR-248988	0.399
ACVR2B	protein	Q13705	UNIPROT	ACVR1B	protein	P36896	UNIPROT	up-regulates activity	phosphorylation	Thr206	VQRTVARtIVLQEII	9606									8622651	t		miannu	Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB.	SIGNOR-235146	0.677
nitric oxide	smallmolecule	CHEBI:16480	ChEBI	DNM1L	protein	O00429	UNIPROT	up-regulates activity													33850055	f		lperfetto	Upon viral infection, DDAH2 relocated to mitochondria, where it induced the production of nitric oxide (NO) and the activation of dynamin-related protein 1 (Drp1)	SIGNOR-275650	0.8
NRG1	protein	Q02297	UNIPROT	ERBB3	protein	P21860	UNIPROT	up-regulates	binding			9606		BTO:0000887							7477375	t		gcesareni	The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4 direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.	SIGNOR-26061	0.868
ATF2	protein	P15336	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates													22685333	f		Luana	ATF2 contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death.	SIGNOR-261324	0.7
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	precursor of			9606									21310273	t		miannu	GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans	SIGNOR-267814	0.8
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	WWC1	protein	Q8IX03	UNIPROT	up-regulates	phosphorylation	Thr929	STIIRSKtFSPGPQS	9606		BTO:0000149							24269383	t		llicata	Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2.	SIGNOR-252810	0.2
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	G6PC1	protein	P35575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16308421	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-252921	0.2
TOMM70	protein	O94826	UNIPROT	TOM40 complex	complex	SIGNOR-C421	SIGNOR	form complex	binding			9606	BTO:0000567								18331822	t		lperfetto	The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex.	SIGNOR-267677	0.2
NDUFB4	protein	O95168	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4	SIGNOR-262167	0.788
D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	5-phospho-α-D-ribose 1-diphosphate	smallmolecule	CHEBI:58017	ChEBI	up-regulates quantity	precursor of			9606									16939420	t		miannu	PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP.	SIGNOR-267080	0.8
WDR5	protein	P61964	UNIPROT	HMT	complex	SIGNOR-C19	SIGNOR	form complex	binding			9606									17500065	t		lperfetto	The evolutionarily conserved hdpy-30, ash2l, rbbp5, and wdr5 likely constitute a subcomplex that is shared by all human set1-like hmt complexes.	SIGNOR-154766	0.889
FBXW7	protein	Q969H0	UNIPROT	GATA3	protein	P23771	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								24820417	t		miannu	Fbw7 promotes degradation of GATA3 in a Thr-156-dependent manner. 	SIGNOR-276635	0.411
NFE2	protein	Q16621	UNIPROT	HBD	protein	P02042	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000426								16287851	f	Regulation of expression	miannu	NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells.	SIGNOR-251843	0.365
CSNK1A1	protein	P48729	UNIPROT	BHLHE40	protein	O14503	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser243	GSDTDTDsGYGGESE	9606	BTO:0002181								25202122	t		miannu	CK1α-mediated phosphorylation of DEC1 on a conserved degron is required for DEC1 degradation. 	SIGNOR-276851	0.2
EPS15	protein	P42566	UNIPROT	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	up-regulates quantity by stabilization	binding												24789820	t		lperfetto	Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth	SIGNOR-260713	0.679
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1899	SPTYSPTsPVYTPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120236	0.321
D-ribulose 5-phosphate	smallmolecule	CHEBI:17363	ChEBI	D-xylulose 5-phosphate(2-)	smallmolecule	CHEBI:57737	ChEBI	up-regulates quantity	precursor of			9606									34775382	t		miannu	The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux.	SIGNOR-267062	0.8
MEN1	protein	O00255	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates	binding			9606									11526476	t		lperfetto	Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner.	SIGNOR-217406	0.433
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1672	SPTSPSYsPTSPSYS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248820	0.849
GGCX	protein	P38435	UNIPROT	PROC	protein	P04070	UNIPROT	up-regulates activity	carboxylation			9606									28125048	t		lperfetto	Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z	SIGNOR-265925	0.553
lysophosphatidylserine 14:0(1-)	chemical	CHEBI:72402	ChEBI	GPR174	protein	Q9BXC1	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257503	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	PEA15	protein	Q15121	UNIPROT	up-regulates	phosphorylation	Ser116	KDIIRQPsEEEIIKL	9606									15916534	t		gcesareni	Pea-15 is a phosphoprotein containing a ser-104 phosphorylated by protein kinase c and a ser-116 phosphorylated by camkii (calcium/calmodulin-dependent protein kinase ii) or akt. Phosphorylation of ser-104 is implicated in the regulation of glucose metabolism, while phosphorylation at ser-116 is required for pea-15 recruitment to the disc (death-initiation signalling complex)	SIGNOR-137614	0.2
CTNNB1	protein	P35222	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	up-regulates activity	binding			9606									21078818	t		gcesareni	Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors.	SIGNOR-169632	0.914
PDPK1	protein	O15530	UNIPROT	PKN2	protein	Q16513	UNIPROT	up-regulates	phosphorylation	Thr816	GYGDRTStFCGTPEF	9606									10753910	t		miannu	It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively)	SIGNOR-76710	0.691
FGF13	protein	Q92913	UNIPROT	SCN2A	protein	Q99250	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253427	0.273
MRPL46	protein	Q9H2W6	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262350	0.632
CXCL10	protein	P02778	UNIPROT	ARDS	phenotype	SIGNOR-PH128	SIGNOR	up-regulates				9606									32446778	f		miannu	Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection	SIGNOR-261031	0.7
SB 203580	chemical	CHEBI:90705	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000567								10702313	t		gcesareni	Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme.	SIGNOR-75389	0.8
RET	protein	P07949	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr577	YMEDSTYyKASKGKL	9606									21454698	t		gcesareni	The identification of focal adhesion kinase (fak) as a direct substrate for ret kinase revealed (i) a ret-fak transactivation mechanism consisting of direct phosphorylation of fak tyr-576/577 by ret and a reciprocal phosphorylation of ret by fak, which crucially is able to rescue the kinase-impaired ret k758m mutant and (ii) that fak binds ret via its ferm domain. Interestingly, this interaction is abolished upon ret phosphorylation, indicating that ret binding to the ferm domain of fak is a priming step for ret-fak transactivation.	SIGNOR-173017	0.622
HMGB1	protein	P09429	UNIPROT	HOXB3	protein	P14651	UNIPROT	up-regulates activity	binding			-1									8890171	t		miannu	We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.	SIGNOR-219902	0.301
GOT1	protein	P17174	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	chemical modification			9606									26003525	t		miannu	Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and α-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer.	SIGNOR-267505	0.8
PPP2CA	protein	P67775	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	dephosphorylation	Ser57	KKDRFYRsILPGDKT	10116									18586681	t			Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation.	SIGNOR-248641	0.364
SKIL	protein	P12757	UNIPROT	SMAD5	protein	Q99717	UNIPROT	down-regulates	binding			9606				SIGNOR-C85					12419246	t		gcesareni	Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad8.	SIGNOR-95474	0.459
SIRT7	protein	Q9NRC8	UNIPROT	H3C15	protein	Q71DI3	UNIPROT	up-regulates activity	deacetylation	Lys38	PATGGVKkPHRYRPG										30653310	t		lperfetto	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 	SIGNOR-275887	0.2
metformin	chemical	CHEBI:6801	ChEBI	NDUFS1	protein	P28331	UNIPROT	down-regulates activity	chemical inhibition			9606									24843020	t		Federica	 In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration	SIGNOR-261080	0.8
ATP5F1D	protein	P30049	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261402	0.2
CDC14A	protein	Q9UNH5	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	dephosphorylation	Ser315	LPNNTSSsPQPKKKP	9606									10644693	t			The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53|. Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34Cdc2/clb phosphorylation site (p53-phosphor-Ser315)|Earlier studies showed that Ser315 phosphorylation increases the sequence-specific DNA binding capacity of p53, suggesting that Ser315 phosphorylation is an activating modification	SIGNOR-248828	0.41
entinostat	chemical	CHEBI:132082	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257962	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606	BTO:0000567								12853467	t		gcesareni	These findings suggest that PKB-dependent binding of 14-3-3s to phospho-Ser483 of cardiac PFK-2 mediates the stimulation of glycolysis by growth factor.	SIGNOR-248031	0.2
PPP2CA	protein	P67775	UNIPROT	MKNK1	protein	Q9BUB5	UNIPROT	down-regulates	dephosphorylation	Thr250	NSCTPITtPELTTPC	9606									20927323	t		gcesareni	Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e.	SIGNOR-168310	0.492
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PPP1R1B	protein	Q9UD71	UNIPROT	up-regulates activity	phosphorylation	Thr34	MIRRRRPtPAMLFRL	9606	BTO:0000938								10604473	t		miannu	DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚ 	SIGNOR-264956	0.2
AKT3	protein	Q9Y243	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606									10949026	t		gcesareni	Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155.	SIGNOR-81122	0.522
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PDCD4	protein	Q53EL6	UNIPROT	down-regulates	phosphorylation	Ser67	KRRLRKNsSRDSGRG	9606	BTO:0000007	BTO:0001253							18296647	t		gcesareni	Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.	SIGNOR-160982	0.2
PTPN2	protein	P17706	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000527								11514572	t		gcesareni	Tc45 dephosphorylated delta egfr in u87mg glioblastoma cells and inhibited mitogen-activated protein kinase erk2 and phosphatidylinositol 3-kinase signaling. In contrast, the substrate-trapping tc45-d182a mutant, which is capable of forming stable complexes with tc45 substrates, suppressed the activation of erk2 but not phosphatidylinositol 3-kinase. The activation results in reduced egfr phosphorylation after egf stimulation. Introduction of the alpha(1) cytoplasmic domain peptide into cells induces phosphatase activation and inhibits egf-induced cell proliferation and anchorage-independent growth of malignant cells.	SIGNOR-109804	0.62
RIMBP2	protein	O15034	UNIPROT	RIMS2	protein	Q9UQ26	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264366	0.549
PKN3	protein	Q6P5Z2	UNIPROT	ARHGAP18	protein	Q8N392	UNIPROT	up-regulates activity	phosphorylation	Ser156	QKRVETVsQTLRKKN	-1									33092266	t		lperfetto	We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA.|These results support our data from phosphoproteomic screen and suggest that ARHGAP18 can be phosphorylated by PKN3 on Thr154, Ser156 and Thr158.	SIGNOR-264571	0.2
CDK1	protein	P06493	UNIPROT	ORC1	protein	Q13415	UNIPROT	up-regulates	phosphorylation	Ser273	VAFSEITsPSKRSQP	9606									11931757	t		lperfetto	Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.	SIGNOR-116325	0.621
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RCAN1	protein	P53805	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000165								12063245	t	inferred from 70% family members	lperfetto	Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. 	SIGNOR-270149	0.2
F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	LATS1	protein	O95835	UNIPROT	down-regulates				9606									23450633	f		gcesareni	Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism.	SIGNOR-201522	0.7
PLK1	protein	P53350	UNIPROT	AXIN2	protein	Q9Y2T1	UNIPROT	up-regulates activity	phosphorylation	Ser311	SDALTDDsMSMTDSS	9606	BTO:0001061								26438599	t		miannu	Plk1 phosphorylates axin2 at Ser311. 	SIGNOR-277180	0.499
ADRA1D	protein	P25100	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257191	0.409
CCT129202	chemical	CID:16202152	PUBCHEM	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190877	0.8
PK	proteinfamily	SIGNOR-PF80	SIGNOR	HIF-1 complex	complex	SIGNOR-C418	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								21620138	t	inferred from family member		PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements,	SIGNOR-270311	0.399
PTEN	protein	P60484	UNIPROT	PINK1	protein	Q9BXM7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11494141	f		miannu	Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 	SIGNOR-260056	0.484
GLI2	protein	P10070	UNIPROT	PTCH1	protein	Q13635	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002572								16571352	f		lperfetto	Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1.	SIGNOR-209632	0.703
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									24743741	f			Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases.	SIGNOR-257606	0.7
vorinostat	chemical	CHEBI:45716	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257916	0.8
INSR	protein	P06213	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	phosphorylation	Tyr580	LRKTRDQyLMWLTQK	9534	BTO:0000298								8385099	t			The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor.	SIGNOR-252691	0.601
CDK6	protein	Q00534	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Ser266	QYLGSIAsPSVHPAT	9606	BTO:0002181								16046550	t	The effect has been demonstrated using Q01196-8.	gcesareni	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-138957	0.598
NPC2	protein	P61916	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates activity				9606									21084287	f		Giorgia	Here we show that NPC2 deficiency in human fibroblasts confers their activation. The activation phenomenon was not limited to fibroblasts as it was also observed in aortic smooth muscle cells upon silencing NPC2 gene by siRNA. The molecular mechanism responsible for activation of NPC2-null cells was shown to be a sustained phosphorylation of ERK 1/2 mitogen-activated protein kinase (MAPK), which fulfills both the sufficient and necessary fibroblast activation criteria. All of these findings highlight a novel mechanism where NPC2 by negatively regulating ERK 1/2 MAPK phosphorylation may efficiently suppress development of maladaptive tissue remodeling and inflammation.	SIGNOR-260660	0.357
SELE	protein	P16581	UNIPROT	ITGAL	protein	P20701	UNIPROT	up-regulates				9606	BTO:0000130								23994464	f		apalma	This deceleration is due to the expression of E-selectins on the inflamed endothelium which provides increased number of binding sites for PSGL-1 and also triggers an intermediate-affinity conformational state of the beta2-integrin LFA-1 on neutrophils.	SIGNOR-255968	0.417
ROCK1	protein	Q13464	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Ser13	ITSAARRsYVSSGEM	-1									12686604	t		lperfetto	We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro.	SIGNOR-100181	0.316
EIF3F	protein	O00303	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	deubiquitination	Lys1759	CGVLLSRkRRRQHGQ	9606									21124883	t		gcesareni	The activated form of notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. The enzyme accounting for this deubiquitinase activity is eif3f, known so far as a translation initiation factor.	SIGNOR-170158	0.431
TIMM23	protein	O14925	UNIPROT	TIM23 complex	complex	SIGNOR-C423	SIGNOR	form complex	binding												32074073	t		lperfetto	The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE.	SIGNOR-267697	0.634
CREBL2	protein	O60519	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000011								21728997	f		Luana	 Accordingly, the results of QPCR and immunoblot analysis showed that during adipogenesis, both the mRNA (Figures 4D and 4E) and protein (Figure 4F) levels of PPARγ , as well as C/EBPα, in 3T3-L1 preadipocytes transfected with either siCREBL2-1 or siCREBL2-2 were significantly decreased compared with the control (P < 0.05), suggesting that knockdown of CREBL2 protein suppress 3T3-L1 preadipocyte differentiation via inhibition of PPARγ and C/EBPα expression.	SIGNOR-261573	0.2
MBD2	protein	Q9UBB5	UNIPROT	CHD4	protein	Q14839	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000776								23071088	f	 	lperfetto	MBD2 and multiple domains of CHD4 are required for transcriptional repression by Mi-2/NuRD complexes	SIGNOR-254102	0.616
RUNX3	protein	Q13761	UNIPROT	HSPD1	protein	P10809	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002384								17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255086	0.2
Starvation	stimulus	SIGNOR-ST4	SIGNOR	AMPK	complex	SIGNOR-C15	SIGNOR	up-regulates				9606	BTO:0001760								20810907	f		lperfetto	L6 myotubes were incubated in serum-containing or serum-free medium for 3 h. Levels of phosphorylated AMPK, Akt, and ATM were greater in serum-starved cells than in control cells.	SIGNOR-209894	0.7
NFYC	protein	Q13952	UNIPROT	NFY	complex	SIGNOR-C1	SIGNOR	form complex	binding			9606	BTO:0000801;BTO:0000876								9885213	t		lperfetto	Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding.	SIGNOR-63019	0.966
IKBKB	protein	O14920	UNIPROT	PFKFB3	protein	Q16875	UNIPROT	down-regulates activity	phosphorylation	Ser269	QGRIGGDsGLSSRGK	-1									27585591	t		miannu	IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3.We demonstrate that IKKβ directly interacts with and phosphorylates 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase isoform 3 (PFKFB3), a major driver of aerobic glycolysis, at Ser269 upon glutamine deprivation to inhibit its activity, thereby down-regulating aerobic glycolysis when glutamine levels are low. 	SIGNOR-277278	0.295
TOPORS	protein	Q9NS56	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	ubiquitination			9606					phosphorylation:Ser718	KDRDGYEsSYRRRTL 			19473992	t		lperfetto	Plk1-mediated phosphorylation of topors regulates p53 stabilityherein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation.	SIGNOR-185848	0.473
CBX7	protein	O95931	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000196								19706751	f		miannu	 We confirmed by coimmunoprecipitation that CBX7 physically interacts with the HDAC2 protein and is able to inhibit its activity. Then, we showed that both these proteins bind the E-cadherin promoter and that CBX7 up-regulates E-cadherin expression. 	SIGNOR-253767	0.394
CSNK2A1	protein	P68400	UNIPROT	PDCD5	protein	O14737	UNIPROT	up-regulates	phosphorylation	Ser119	NRRKVMDsDEDDDY	9606									19616514	t		lperfetto	Programmed cell death 5 (pdcd5), a protein involved in cell death and down-regulated in different forms of human tumors. Pdcd5 is phosphorylated in vitro by both ck2alpha subunit and by the ck2 holoenzyme at a residue, s118, which is found phosphorylated in vivo. Transfection of the non-phosphorylatable mutant (s118a) impairs the pdcd5 acceleration of either doxorubimicin- or uv-induced apoptosis in u2os cells	SIGNOR-187106	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Ser1166	QKGSHQIsLDNPDYQ	9606	BTO:0000007								10347170	t		llicata	 We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. 	SIGNOR-250624	0.378
LCK	protein	P06239	UNIPROT	DEF6	protein	Q9H4E7	UNIPROT	up-regulates activity	phosphorylation	Tyr210	SMAIHEVyQELIQDV	-1									12923183	t			In vitro kinase assays indeed demonstrated that Lck can phosphorylate wild-type IBP but not the Y210F mutant. IBP Binds PI(3,4,5)P3 upon Phosphorylation by Lck	SIGNOR-251372	0.515
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	KDM5D	protein	Q9BY66	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273473	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	SCNN1G	protein	P51170	UNIPROT	down-regulates quantity by destabilization	phosphorylation			-1									11805112	t	inferred from 70% family members	lperfetto	Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.	SIGNOR-270061	0.2
ruxolitinib	chemical	CHEBI:66919	ChEBI	JAK3	protein	P52333	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258278	0.8
PAK2	protein	Q13177	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Thr93	GHITTTPtPTQFLCP	9606	BTO:0000848								21177766	t		lperfetto	P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)	SIGNOR-170776	0.272
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Ser138	SLQLGAVsPGTLTPT										26933062	t		lperfetto	Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis.	SIGNOR-276592	0.398
ETF	complex	SIGNOR-C463	SIGNOR	FADH2	smallmolecule	CHEBI:17877	ChEBI	up-regulates quantity	chemical modification			9606									33450351	t		miannu	ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a). 	SIGNOR-269455	0.8
SMAD2	protein	Q15796	UNIPROT	SMAD2/STAT3/EP300	complex	SIGNOR-C203	SIGNOR	form complex	binding			9606									26194464	t		MARCO ROSINA	Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes.	SIGNOR-255023	0.555
dasatinib (anhydrous)	chemical	CHEBI:49375	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191301	0.8
PPP1CB	protein	P62140	UNIPROT	NF2	protein	P35240	UNIPROT	up-regulates	dephosphorylation	Ser518	DTDMKRLsMEIEKEK	9606									18071304	t		lperfetto	When serine 518 is dephosphorylated by the myosin phosphatase mypt-1-pp1?, The tumor suppressor function of merlin is activated, inhibiting the ras signaling pathway and leading to growth arrest	SIGNOR-159836	0.386
MAPK10	protein	P53779	UNIPROT	STMN2	protein	Q93045	UNIPROT	down-regulates	phosphorylation	Ser62	ELILKPPsPISEAPR	9606									11718727	t		gcesareni	We demonstrate that purified scg10 can be phosphorylated by two subclasses of mitogen-activated protein (map) kinases, c-jun n-terminal/stress-activated protein kinase (jnk/sapk) and p38 map kinase;jnk3/sapkbeta phosphorylation occurs at ser-62 and ser-73, residues that result in reduced microtubule-destabilizing activity for scg10.	SIGNOR-112110	0.455
RNF7	protein	Q9UBF6	UNIPROT	PMAIP1	protein	Q13794	UNIPROT	down-regulates activity	ubiquitination			9606									23136067	t		miannu	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 	SIGNOR-271446	0.399
EGFR	protein	P00533	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates activity	phosphorylation	Tyr1248	PTAENPEyLGLDVPV	9606	BTO:0000356								12354693	t		llicata	Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR. | In summary, c-erbB-2 up-regulation switches on the cell migration program by modulating the time course of PLC-gamma1 activation. 	SIGNOR-251094	0.595
RIMBP2	protein	O15034	UNIPROT	RIMS1	protein	Q86UR5	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264361	0.517
belinostat	chemical	CHEBI:61076	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257747	0.8
DZIP3	protein	Q86Y13	UNIPROT	H2AJ	protein	Q9BTM1	UNIPROT	up-regulates activity	monoubiquitination	Lys119	IQAVLLPkKTESQKT	9606	BTO:0000007								18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271763	0.2
SMAD3	protein	P84022	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000782								22740686	f		lperfetto	PD-1 also inhibited phosphorylation of the transcription factor Smad3, which increased its activity. These events induced additional inhibitory checkpoints in the cell cycle by increasing the abundance of the G(1) phase inhibitor p15(INK4) and repressing the Cdk-activating phosphatase Cdc25A	SIGNOR-245445	0.549
TRIM13	protein	O60858	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								21333377	t		miannu	Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT.  We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro. 	SIGNOR-271852	0.359
CERT1	protein	Q9Y5P4	UNIPROT	ceramide	smallmolecule	CHEBI:17761	ChEBI	up-regulates quantity	relocalization			9606									18184806	t		miannu	In mammalian cells, ceramide is synthesized in the endoplasmic reticulum and transferred to the Golgi apparatus for conversion to sphingomyelin. Ceramide transport occurs in a nonvesicular manner and is mediated by CERT, a cytosolic 68-kDa protein with a C-terminal steroidogenic acute regulatory protein-related lipid transfer (START) domain. The CERT START domain efficiently transfers natural D-erythro-C16-ceramide, but not lipids with longer (C20) amide-acyl chains. 	SIGNOR-268496	0.8
CSNK2A1	protein	P68400	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser299	KMAFRAKsKSCHDLS	-1									9677319	t		llicata	CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin.	SIGNOR-250946	0.317
FOXA1	protein	P55317	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									19127412	f		miannu	Overexpression of foxa1 promoted apoptosis	SIGNOR-256642	0.7
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR1F	protein	P30939	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264297	0.8
CPT1A	protein	P50416	UNIPROT	(R)-carnitine	smallmolecule	CHEBI:16347	ChEBI	down-regulates quantity	chemical modification			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267120	0.8
CREB1	protein	P16220	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				10090		BTO:0000142							17584923	f		Luana	These findings, together with studies in Aplysia and Drosophila, strongly suggest that CREB is an evolutionary conserved component of the molecular cascade of events leading to memory consolidation.	SIGNOR-265773	0.7
GAS7	protein	O60861	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23840221	f		miannu	Downregulation of gas7 using short-hairpin rna decreased the expression of runx2, a master regulator of osteogenesis, and its target genes (alkaline phosphatase, type i collagen, osteocalcin, and osteopontin).	SIGNOR-202242	0.2
BDKRB2	protein	P30411	UNIPROT	Vascular_Permeability	phenotype	SIGNOR-PH140	SIGNOR	up-regulates				9606									28966616	f		lperfetto	BK binds receptor B2 (B2R) and triggers inflammation, edema, and symptoms of anaphylaxis.	SIGNOR-263540	0.7
SPC24	protein	Q8NBT2	UNIPROT	Ndc80 complex	complex	SIGNOR-C361	SIGNOR	form complex	binding												27881301	t		lperfetto	Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits	SIGNOR-265185	0.938
MAPK3	protein	P27361	UNIPROT	ERBB4	protein	Q15303	UNIPROT	down-regulates activity	phosphorylation	Ser1051	NRSEIGHsPPPAYTP	9606	BTO:0000007								31053301	t		miannu	We also identified Ser-1026 as an ErbB4-specific ERK target site in the CYT-1 region. Moreover, double mutations (Thr-674/Ser-1026 to Ala) significantly upregulated ErbB4 activation, indicating that Thr-674 and Ser-1026 are cooperatively involved in negative feedback regulation. 	SIGNOR-277449	0.514
CKM complex	complex	SIGNOR-C406	SIGNOR	SMAD3	protein	P84022	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									19914161	t		lpetrilli	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-273147	0.421
PRKAB1	protein	Q9Y478	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates	phosphorylation	Ser1177	TSRIRTQsFSLQERQ	9606			SIGNOR-C15						11729179	t		gcesareni	Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.	SIGNOR-112367	0.2
MAP3K7	protein	O43318	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	phosphorylation	Thr178	LKICDFGtACDIQTH	-1									20538596	t		lperfetto	Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation.	SIGNOR-227536	0.2
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	SHOC2	protein	Q9UQ13	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								30865892	t		miannu	Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation.	SIGNOR-277444	0.2
phosphatidylinositol bisphosphate	smallmolecule	CHEBI:37328	ChEBI	CAPZA1	protein	P52907	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000132								12788695	t		lperfetto	We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations.	SIGNOR-261843	0.8
NFATC1	protein	O95644	UNIPROT	IL4	protein	P05112	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8668213	t		lperfetto	Recombinant NFAT1 can mediate transcription of the interleukin-2, interleukin-4, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor promoters in T cells, suggesting that NFAT1 contributes to the CsA-sensitive transcription of these genes during the immune response.	SIGNOR-254498	0.531
SRC	protein	P12931	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Tyr86	VADIDGQyAMTRAQR	9606	BTO:0000038								11279024	t		lperfetto	beta-catenin is a good substrate of pp60c- srctyrosine kinase in vitro;this kinase modifies specifically tyr-86 and tyr-654although consistently detected, this negative effect of tyr-86 phosphorylation on tbp binding was clearly less important than the positive effect observed after tyr-654 phosphorylation.	SIGNOR-106458	0.752
PIAS4	protein	Q8N2W9	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates	binding			9606				SIGNOR-C9					12904571	t		gcesareni	Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity.	SIGNOR-104541	0.539
RET	protein	P07949	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates	phosphorylation	Tyr182	TDDEMTGyVATRWYR	9606									7535770	t		gcesareni	Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme.	SIGNOR-28063	0.338
AE/b7 integrin	complex	SIGNOR-C186	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257727	0.464
LIF	protein	P15018	UNIPROT	LIFR	protein	P42702	UNIPROT	up-regulates	binding			9606									16051226	t		gcesareni	Lif binds at low-affinity to lifr, the structure of which is closely related to that of gp130 (42). Lifr then becomes heterodimerized with gp130 to form the high-affinity and signaling-competent complex (43). Osm utilizes this type of heterodimer, i.e. the lifr/gp130 complex (43, 44).	SIGNOR-139102	0.751
naloxone	chemical	CHEBI:7459	ChEBI	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258941	0.8
SRC	protein	P12931	UNIPROT	CTNND1	protein	O60716	UNIPROT	up-regulates activity	phosphorylation	Tyr280	HRFHPEPyGLEDDQR	-1									11382764	t		lperfetto	Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302	SIGNOR-246492	0.92
CDK1	protein	P06493	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	up-regulates	phosphorylation	Thr269	GGKRSRLtPVSPESS	9606			SIGNOR-C17						20974803	t		gcesareni	Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis.	SIGNOR-169016	0.349
FZD2	protein	Q14332	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates activity	binding			9606									23151663	t		areggio	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. 	SIGNOR-258959	0.636
SPAG9	protein	O60271	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	unknown	binding			10090	BTO:0000165;BTO:0000222;BTO:0002181		SIGNOR-C21						22337877	t		lperfetto	Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts	SIGNOR-235545	0.363
HNRNPA1	protein	P09651	UNIPROT	TRA2B	protein	P62995	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000586								31311954	t		lperfetto	HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells.	SIGNOR-262280	0.683
CDK2	protein	P24941	UNIPROT	CCP110	protein	O43303	UNIPROT	down-regulates activity	phosphorylation	Ser372	PSPEPSMsPKMHRRR	-1									12361598	t		miannu	GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B)	SIGNOR-265962	0.531
SET	protein	Q01105	UNIPROT	PPP2CA	protein	P67775	UNIPROT	down-regulates	binding			9606									21806989	t		miannu	Here we report that both the amino terminal fragment (i(2ntf);aa 1-175) and the carboxy terminal fragment (i(2ctf);aa 176-277) of i(2)(pp2a) inhibit pp2a by binding to its catalytic subunit pp2ac	SIGNOR-175719	0.547
PPP2CA	protein	P67775	UNIPROT	AKT2	protein	P31751	UNIPROT	down-regulates activity	dephosphorylation	Ser474	RTHFPQFsYSASIRE	10090	BTO:0000944								15367694	t			Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes	SIGNOR-248631	0.736
PLPPR1	protein	Q8TBJ4	UNIPROT	RASGEF1A	protein	Q8N9B8	UNIPROT	up-regulates activity	binding			9606	BTO:0002036								27058420	t		miannu	Oncogenic effects of imbalanced PRG3 are mediated via PRG3-RasGEF1 interaction and Ras activation. PRG3 interacts with RasGEF1 in vivo.We could further show that PRG3 executes the binding to RasGEF1 predominantly via its C-terminal domain (CT) and in the consequence causes Ras activation.	SIGNOR-261807	0.2
CDK5	protein	Q00535	UNIPROT	PEBP1	protein	P30086	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr42	DELGKVLtPTQVKNR	9606	BTO:0000007								25104559	t		miannu	 Here, we demonstrate that RKIP is a substrate of cyclin-dependent kinase 5 (CDK5) in neurons and that the phosphorylation of RKIP at T42 causes the release of Raf-1. Moreover, T42 phosphorylation promotes the exposure and recognition of the target motif "KLYEQ" in the C-terminus of RKIP by chaperone Hsc70 and the subsequent degradation of RKIP via chaperone-mediated autophagy (CMA). 	SIGNOR-276672	0.344
RNF128	protein	Q8TEB7	UNIPROT	CD83	protein	Q01151	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys192	LPVTSPNkHLGLVTP	9606	BTO:0000007								19542455	t		miannu	In this study, we show that GRAIL can down-modulate the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. GRAIL-mediated down-modulation of CD83 is dependent on an intact GRAIL extracellular protease-associated domain and an enzymatically active cytosolic RING domain, and proceeds via the ubiquitin-dependent 26S proteosome pathway. Ubiquitin modification of lysine residues K168 and K183, but not K192, in the cytoplasmic domain of CD83 was shown to be necessary for GRAIL-mediated degradation of CD83.	SIGNOR-271849	0.359
PRKX	protein	P51817	UNIPROT	PKD1	protein	P98161	UNIPROT	up-regulates	phosphorylation	Ser4166	EPLPSRSsRGSKVSP	9606									17980165	t		lperfetto	The possibility of functional interactions between pkd1-encoded polycystin-1 and prkx was suggested by the renal co-distribution of prkx and polycystin-1 and the binding and phosphorylation of the c-terminal of polycystin-1 by prkx at s4166 in vitro. Taken together these results suggest that prkx can reverse the abnormalities in epithelial adhesion, migration and morphogenesis associated with pkd1 inhibition and cyst formation in adpkd.	SIGNOR-158852	0.26
MEF2A	protein	Q02078	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity	binding			9606		BTO:0000887;BTO:0001103							9418854	t		lperfetto	Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis.	SIGNOR-54086	0.733
CSNK2A1	protein	P68400	UNIPROT	SPTBN1	protein	Q01082	UNIPROT	down-regulates	phosphorylation	Thr2159	NGATEQRtSSKESSP	9606	BTO:0000938								17088250	t		miannu	We show here that the short c-terminal splice variant of betaii-spectrin (betaiisigma2) is a substrate for phosphorylation. In vitro, protein kinase ck2 phosphorylates ser-2110 and thr-2159 / phosphorylation of ?II?2 C-terminal fragment inhibits its interaction with ?II N-terminal fragment.	SIGNOR-150471	0.339
PPP5C	protein	P53041	UNIPROT	ABCB1	protein	P08183	UNIPROT	down-regulates activity	dephosphorylation	Ser667	SSLIRKRsTRRSVRG	9606	BTO:0000007								24333728	t			Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp	SIGNOR-272506	0.2
SRC	protein	P12931	UNIPROT	DDR2	protein	Q16832	UNIPROT	up-regulates	phosphorylation	Tyr740	RNLYSGDyYRIQGRA	9606									16186108	t		gcesareni	Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues.	SIGNOR-140763	0.388
ASIP	protein	P42127	UNIPROT	MC3R	protein	P41968	UNIPROT	down-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268703	0.526
PRKCD	protein	Q05655	UNIPROT	PRKCD	protein	Q05655	UNIPROT	up-regulates	phosphorylation	Ser645	LNEKARLsYSDKNLI	9606									15731106	t		gcesareni	Taken together, our results demonstrate that serine 643 of pkc-delta is a major autophosphorylation site, and phosphorylation of this site plays an important role in controlling its enzymatic activity and biological function. The enzymatic activity of pkc-deltas643a mutant as measured by phosphorylating the pkc-delta pseudosubstrate region-derived substrate was also reduced more than 70% in comparison to that of pkc-deltawt.	SIGNOR-134207	0.2
SYK	protein	P43405	UNIPROT	BLNK	protein	Q8WV28	UNIPROT	up-regulates	phosphorylation	Tyr178	LLEDEADyVVPVEDN	9606	BTO:0000776								12456653	t		llicata	The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex.	SIGNOR-96040	0.799
LSM-1231	chemical	CHEBI:91471	ChEBI	NTRK2	protein	Q16620	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-258239	0.8
GUCY1B1	protein	Q02153	UNIPROT	GUCY1A3-B3	complex	SIGNOR-C140	SIGNOR	form complex	binding			9606									10977868	t		gcesareni	This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity	SIGNOR-243986	0.2
TIMP2	protein	P16035	UNIPROT	LRP2	protein	P98164	UNIPROT	up-regulates quantity	binding			10116	BTO:0001860								28659595	t		miannu	We show that megalin/LRP-2 acts as an endocytic receptor for proMMP-2:TIMP-2 complex. We found that RAP, an antagonist of the LDL receptor family18, competed with binding of proMMP-2:TIMP-2 complex onto rat BN16 epithelial cells.	SIGNOR-265254	0.2
HTR2C	protein	P28335	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257013	0.301
COP9 signalosome variant 1	complex	SIGNOR-C489	SIGNOR	26S Proteasome	complex	SIGNOR-C307	SIGNOR	up-regulates activity	binding			9606									26497135	t		miannu	The COP9 signalosome (CSN) and the proteasomal LID are conserved macromolecular complexes composed of at least eight subunits with molecular weights of approximately 350 kDa. CSN and LID are part of the ubiquitin–proteasome pathway and cleave isopeptide linkages of lysine side chains on target proteins. CSN cleaves the isopeptide bond of ubiquitin-like protein Nedd8 from cullins, whereas the LID cleaves ubiquitin from target proteins sentenced for degradation. The evolutionary conserved ubiquitin proteasome pathway (UPP) mediates degradation of intracellular proteins in all eukaryotes. This essential process requires three protein complexes: E3 ubiquitin ligases as e.g., cullin-RING ligases (CRLs), CSN and the 26S proteasome.	SIGNOR-270795	0.328
Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	DVL1	protein	O14640	UNIPROT	up-regulates activity	binding			9606									22944199	t		amattioni	When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.	SIGNOR-253124	0.2
IGF1R	protein	P08069	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	binding			-1									7541045	t		lperfetto	In our present work, we show that both IRS-1 and SHC interact directly with the juxtamembrane region of the IGFIR in a phosphotyrosine-dependent manner. |We propose a model in which IGFIR autophosphorylation of Tyr-950 forms a direct binding site for the amino-terminal receptor binding domains of SHC and IRS-1. This interaction is presumed to facilitate tyrosine phosphorylation of SHC on Tyr-317 leading to GRB2/SOS interaction	SIGNOR-262587	0.726
RPLP1	protein	P05386	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262450	0.819
RALBP1	protein	Q15311	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260513	0.564
GSK3B	protein	P49841	UNIPROT	NR1D1	protein	P20393	UNIPROT	up-regulates	phosphorylation	Ser59	FPPSPTGsLTQDPAR	9606									16484495	t		llicata	We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock.	SIGNOR-144570	0.286
FGB	protein	P02675	UNIPROT	Platelet_aggregation	phenotype	SIGNOR-PH81	SIGNOR	up-regulates													16418530	f		lperfetto	In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation.	SIGNOR-253374	0.7
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	Calcineurin	complex	SIGNOR-C155	SIGNOR	up-regulates	chemical activation			9606									22944199	t		lperfetto	Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell).	SIGNOR-252320	0.8
CACNA1E	protein	Q15878	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606		BTO:0000227							30849329	f		miannu	Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. 	SIGNOR-264327	0.7
MST1	protein	P26927	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates	phosphorylation	Thr183	DTMAKRNtVIGTPFW	9606									11805089	t		llicata	We directly show that okadaic acid induces phosphorylation in the activation loop of mst, and, once phosphorylated, mst is rapidly translocated to the nucleus. when thr183 in mst1 was mutated to ala, no band could be detected by oa treatment,2 indicating that thr183 was the site of phosphorylation.	SIGNOR-114289	0.54
EGR1	protein	P18146	UNIPROT	COL7A1	protein	Q02388	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21931594	f	Regulation	miannu	Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1)	SIGNOR-251920	0.2
BMAL1/NPAS2	complex	SIGNOR-C431	SIGNOR	PER1	protein	O15534	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements.	SIGNOR-267970	0.704
PTK2	protein	Q05397	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr861	PIGNQHIyQPVGKPD	9606		BTO:0000671							15694384	t		llicata	Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925.	SIGNOR-133849	0.2
TAF12	protein	Q16514	UNIPROT	ATF7	protein	P17544	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								15735663	t		miannu	We show that overexpression of hsTAF12 potentiates ATF7-induced transcriptional activation through direct interaction with ATF7, suggesting that TAF12 is a functional partner of ATF7.	SIGNOR-225249	0.531
CHEK1	protein	O14757	UNIPROT	AURKB	protein	Q96GD4	UNIPROT	up-regulates	phosphorylation	Ser331	HPWVRANsRRVLPPS	9606									17276342	t		lperfetto	Chk1 phosphorylates aurora-b and enhances its catalytic activity in vitro.	SIGNOR-152926	0.367
DSCAML1	protein	Q8TD84	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								30745319	t		miannu	Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels.	SIGNOR-264278	0.2
ADSL	protein	P30566	UNIPROT	fumarate(2-)	smallmolecule	CHEBI:29806	ChEBI	up-regulates quantity	chemical modification			9606									22812634	t		miannu	ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case	SIGNOR-266606	0.8
PAF1C	complex	SIGNOR-C471	SIGNOR	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								20178742	t		miannu	HPAF1C Independently and Cooperatively (with SII) Stimulates Transcription Elongation. Direct Interactions of hPAF1C with Pol II and SII Are Required for Its Intrinsic and Synergistic Effects on Chromatin Transcription.	SIGNOR-269837	0.439
AXIN2	protein	Q9Y2T1	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates activity	binding			9606		BTO:0000142;BTO:0000671;BTO:0000763		SIGNOR-C110					10911903	t		gcesareni	It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains.	SIGNOR-79950	0.825
PRKAA1	protein	Q13131	UNIPROT	PDHA1	protein	P08559	UNIPROT	up-regulates activity	phosphorylation	Ser295	RYHGHSMsDPGVSYR	-1									33022274	t		miannu	AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex	SIGNOR-276837	0.2
NOTCH1	protein	P46531	UNIPROT	CD44	protein	P16070	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001454								10933396	f		gcesareni	Activation of notch1 signaling in dp thymocytes and thymoma cell lines results in the upregulation of cd25 and cd44 expression	SIGNOR-80333	0.428
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CFI	protein	P05156	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10630630	f	 	miannu	 The production of CFI by Hep G2 cells was enhanced in a dose- and time-dependent fashion by 12-O-tetradecanoyl-1,2-phorbol 13-acetate (TPA), a potent PKC activator. The enhancement of the activity of transfected chimeric CAT constructs by TPA was abrogated by calphostin C and by pyrrolidine dithiocarbamate (an inhibitor of NF-kappaB and AP-1 transactivation). These results indicate that TPA regulation of CFI gene requires PKC signalling and is mediated by via a TPA response element (TRE) in the CFI promoter region located at -136/-130 and involves the transactivation of AP-1 and NF-kappaB transcription factors	SIGNOR-254786	0.2
SH3GLB1	protein	Q9Y371	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	binding			9606									11894095	t		gcesareni	Cbl rapidly recruits cin85 (cbl-interacting protein of 85k;ref. 6) and endophilins (regulatory components of clathrin-coated vesicles) to form a complex with activated egf receptors, thus controlling receptor internalization.	SIGNOR-115826	0.377
ARHGEF6	protein	Q15052	UNIPROT	Cell_migration	phenotype	SIGNOR-PH38	SIGNOR	up-regulates				9606	BTO:0000599								23776207	f		lperfetto	Expression of the phospho-mimicking ACAP4 mutant promotes ARF6-dependent cell migration.	SIGNOR-272237	0.7
D-xylulose 5-phosphate(2-)	smallmolecule	CHEBI:57737	ChEBI	sedoheptulose 7-phosphate	smallmolecule	CHEBI:15721	ChEBI	up-regulates quantity	precursor of			9606									24929114	t		miannu	Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates.	SIGNOR-268143	0.8
NUAK2	protein	Q9H093	UNIPROT	WDR45	protein	Q9Y484	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0001938								28561066	t		miannu	WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes.	SIGNOR-268481	0.265
CSNK1D	protein	P48730	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	phosphorylation	Thr1479	SSSSTKGtYFPAILN	9606									35487243	t		miannu	Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493	SIGNOR-275402	0.2
(-)-anisomycin	chemical	CHEBI:338412	ChEBI	FOS	protein	P01100	UNIPROT	up-regulates	chemical activation			9606									Other	t	CellSignaling	gcesareni		SIGNOR-189626	0.8
ADIPOR2	protein	Q86V24	UNIPROT	APPL1	protein	Q9UKG1	UNIPROT	up-regulates	binding			9606									16622416	t		milica	Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin.	SIGNOR-146215	0.735
MAPK3	protein	P27361	UNIPROT	ERBB4	protein	Q15303	UNIPROT	down-regulates activity	phosphorylation	Thr699	TELVEPLtPSGTAPN	9606	BTO:0000007								31053301	t		miannu	We also identified Ser-1026 as an ErbB4-specific ERK target site in the CYT-1 region. Moreover, double mutations (Thr-674/Ser-1026 to Ala) significantly upregulated ErbB4 activation, indicating that Thr-674 and Ser-1026 are cooperatively involved in negative feedback regulation. 	SIGNOR-277448	0.514
GADL1	protein	Q6ZQY3	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	down-regulates quantity	chemical modification			9606									22718265	t		miannu	Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate α-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of α-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce γ-aminobutyric acid (GABA), β-alanine and hypotaurine, respectively; these amine products play important role in living organisms.	SIGNOR-267545	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606									11108261	t		lperfetto	Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt.	SIGNOR-244255	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Ser393	NLQIRETsLDTKSVS	-1									7822264	t		llicata	On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II.	SIGNOR-250629	0.438
PRKAA1	protein	Q13131	UNIPROT	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSSN	10116									11069105	t			AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells. AMPK-mediated PFK-2 activation is likely to be involved in the stimulation of heart glycolysis during ischaemia.	SIGNOR-260012	0.452
IRF5	protein	Q13568	UNIPROT	IL10	protein	P22301	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000801								22025054	f		lperfetto	IRF5 is directly recruited to gene promoters associated with the M1 phenotype (including Il12b), but it represses Il10, probably also by binding to an ISRE in the gene promoter	SIGNOR-249509	0.436
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	iodide	smallmolecule	CHEBI:16382	ChEBI	up-regulates quantity	precursor of			9606									12746313	t		scontino	Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144.	SIGNOR-266946	0.8
ACE2	protein	Q9BYF1	UNIPROT	AGT	protein	P01019	UNIPROT	up-regulates activity	cleavage	Pro40	GDRVYIHpFHLVIHN	-1									11815627	t		miannu	The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus. 	SIGNOR-256315	0.75
LYST	protein	Q99698	UNIPROT	RAB5C	protein	P51148	UNIPROT	down-regulates activity	binding			7227									33725482	t		lperfetto	Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment	SIGNOR-266003	0.2
MARCHF5	protein	Q9NX47	UNIPROT	MFN1	protein	Q8IWA4	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								20103533	t		Barakat	MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion.|Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate.	SIGNOR-274133	0.2
CHFR	protein	Q96EP1	UNIPROT	CHFR	protein	Q96EP1	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								17442268	t		miannu	In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell.  USP7 mediates deubiquitination of Chfr.	SIGNOR-271461	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	MLXIPL	protein	Q9NP71	UNIPROT	down-regulates	phosphorylation			10116									21892142	t		lperfetto	AMPK has also been suggested to phosphorylate the glucose-sensitive transcription factor ChREBP89 which dictates expression of an overlapping lipogenic gene signature with Srebp1	SIGNOR-216561	0.406
CAMK2A	protein	Q9UQM7	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Ser768	DEAYVMAsVDNPHVC	9606	BTO:0000007								10347170	t		llicata	 We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. 	SIGNOR-250625	0.378
ESPL1	protein	Q14674	UNIPROT	RAD21	protein	O60216	UNIPROT	down-regulates quantity by destabilization	cleavage			9606									15737063	t		lperfetto	In order to segregate sister chromatids to opposite poles in anaphase, cohesin has to be removed from chromosomes. In budding yeast, the prevalent mode of cohesin removal is by proteolytic cleavage of the Scc1 subunit at the onset of anaphase by the endopeptidase separase 	SIGNOR-275537	0.772
WNT2B	protein	Q93097	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131777	0.615
FYN	protein	P06241	UNIPROT	KIRREL1	protein	Q96J84	UNIPROT	up-regulates activity	phosphorylation	Tyr605	MKDPTNGyYNVRAHE	9606	BTO:0000007								18258597	t		miannu	Here we have characterized Neph1, another SD component, as a novel substrate of SFK. Fyn interacts with and phosphorylates the cytoplasmic domain of Neph1 in vitro and in intact cells. Both tyrosine 637 and 638 of Neph1 are crucial for Neph1-Grb2 binding.	SIGNOR-262745	0.2
IMP	smallmolecule	CHEBI:17202	ChEBI	5'-xanthylic acid	smallmolecule	CHEBI:15652	ChEBI	up-regulates quantity	precursor of			9606									19480389	t		miannu	IMPDH controls the gateway to guanine nucleotides, making it an “enzyme of consequence” for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS).	SIGNOR-267333	0.8
MASP2	protein	O00187	UNIPROT	C4B	protein	P0C0L5	UNIPROT	up-regulates activity	cleavage	Arg756	KGQAGLQrALEILQE	-1									17204478	t		lperfetto	MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a).	SIGNOR-263425	0.793
FYN	protein	P06241	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates activity	phosphorylation	Tyr420	RLIEDNEyTARQGAK	-1									9425276	t			Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn.	SIGNOR-251167	0.2
L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	SAICAR(4-)	smallmolecule	CHEBI:58443	ChEBI	up-regulates quantity	precursor of			9606									33179964	t		miannu	The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS).	SIGNOR-267320	0.8
CDK12	protein	Q9NYV4	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1948	SPTSPGYsPTSPTYS	9606									22012619	t		miannu	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176841	0.775
Hexocyclium	chemical	CHEBI:5707	ChEBI	CHRM4	protein	P08173	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								2704370	t		miannu	In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 	SIGNOR-258398	0.8
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1616	TPQSPSYsPTSPSYS	-1									17157258	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248767	0.441
CDK2	protein	P24941	UNIPROT	RAD9A	protein	Q99638	UNIPROT	unknown	phosphorylation	Ser328	VLPSISLsPGPQPPK	9606			SIGNOR-C83						23028682	t		llicata	The forced activation of cyclin a-cdk2 in these cells by the overexpression of cyclin a,triggered rad9 phosphorylation at serine 328 and thereby promoted the interaction of rad9 with bcl-xl and the subsequent initiation of the apoptotic program.	SIGNOR-199020	0.41
PTGES	protein	O14684	UNIPROT	prostaglandin E2	smallmolecule	CHEBI:15551	ChEBI	up-regulates quantity	chemical modification			9606									21983014	t			The mPGES-1, one of three PGE2 synthases, is barely basally expressed, but is inducible by different stimuli and frequently co-expressed with COX-2. COX-2, mPGES-1 and PGE2 are enhanced during pain, inflammatory processes and in several cancer cells	SIGNOR-254263	0.8
RET	protein	P07949	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates	phosphorylation	Thr180	RHTDDEMtGYVATRW	9606									17548358	t		gcesareni	Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme.	SIGNOR-155377	0.338
HOXA9	protein	P31269	UNIPROT	PIM1	protein	P11309	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001412								17327400	t		Luana	Thus Pim1 appears to be a direct transcriptional target of HOXA9 and a mediator of its antiapoptotic and proproliferative effects in early cells. 	SIGNOR-261632	0.2
GRPR	protein	P30550	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606	BTO:0000189								17251915	t		gcesareni	Gastrin-releasing peptide receptors (grpr) are coupled primarily to galfaq, and are highly expressed in many cancers, including small-cell lung cancer	SIGNOR-152679	0.503
PTPRJ	protein	Q12913	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr999	YASSNPEyLSASDVF	9606									10734133	t		gcesareni	These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase.	SIGNOR-76100	0.309
DPP10	protein	Q8N608	UNIPROT	KCND2	protein	Q9NZV8	UNIPROT	up-regulates activity	relocalization			9534	BTO:0000298								15454437	t		Luisa	Coexpression of DPP10 changes the subcellular localization of Kv4.2 expressed in COS-7 cells by promoting surface trafficking.DPP10 accelerates Kv4.2 inactivation at high and low voltages	SIGNOR-269006	0.55
IKBKE	protein	Q14164	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	phosphorylation	Ser468	AVFTDLAsVDNSEFQ	9606				SIGNOR-C13					15489227	t		gcesareni	Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro.	SIGNOR-129939	0.45
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1647	SPSYSPTsPSYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269370	0.718
PRKCD	protein	Q05655	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates activity	phosphorylation	Thr495	TGITRKKtFKEVANA	9606	BTO:0001853								24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251631	0.551
CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	VWF	protein	P04275	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000394								20658528	t	 	lperfetto	We also show that major circadian transcriptional regulators CLOCK and Bmal1 directly regulate the activity of vWF promoter and that lack of Bmal1 results in upregulation of vWF both at mRNA and protein level. Here we report a direct regulation of vWF expression in endothelial cells by biological clock gene Bmal1. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype.	SIGNOR-253703	0.33
ROBO	proteinfamily	SIGNOR-PF14	SIGNOR	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									15916964	t		lperfetto	Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities	SIGNOR-137635	0.2
PPP1CA	protein	P62136	UNIPROT	CCND3	protein	P30281	UNIPROT	up-regulates	dephosphorylation	Thr283	QGPSQTStPTDVTAI	9606									16331257	t		lperfetto	These results support the hypothesis that pp1 constitutively keeps cyclin d3 in a stable, dephosphorylated state	SIGNOR-142884	0.248
PALB2	protein	Q86YC2	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates	binding			9606									19423707	t		miannu	We propose that both palb2 chromatin association and its oligomerization serve to secure the brca2 x rad51 repair machinery at the sites of dna damage.	SIGNOR-185656	0.745
CDKN2B	protein	P42772	UNIPROT	CDK4	protein	P11802	UNIPROT	down-regulates	binding			9606		BTO:0000763							9042862	t		gcesareni	We present evidence that the different subcellular location of p15 and p27 ensures the prior access of p15 to cdk4. In the cell, p15 is localized mostly in the cytoplasm, whereas p27 is nuclear. p15 prevails over p27 or a p27 construct consisting of the cdk inhibitory domain tagged with a nuclear localization signal. However, when p15 and p27 are forced to reside in the same subcellular location, either the cytoplasm or the nucleus, p15 no longer prevents p27 from binding to cdk4. These properties allow p15 and p27 to coordinately inhibit cdk4 and cdk2.	SIGNOR-46758	0.875
(R)-adrenaline	smallmolecule	CHEBI:28918	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates	chemical activation			9606									22863277	t		gcesareni	In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function.	SIGNOR-198501	0.8
3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one	chemical	CHEBI:91346	ChEBI	AKT2	protein	P31751	UNIPROT	down-regulates activity	chemical inhibition												25309440	t		lperfetto	Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway.	SIGNOR-262011	0.8
MAPK12	protein	P53778	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation			9606									10085140	t		gcesareni	Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target	SIGNOR-65589	0.522
DIP2A	protein	Q14689	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates activity	acetylation			10090	BTO:0000142								31600191	t		miannu	DIP2A binds to cortactin and modulates cortactin acetylation. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin.	SIGNOR-266589	0.2
Thrombin	smallmolecule	CHEBI:9574	ChEBI	F2RL3	protein	Q96RI0	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257487	0.8
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates	phosphorylation	Tyr966	QICKGMEyLGTKRYI	9606	BTO:0000007								20304997	t		lperfetto	Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity	SIGNOR-236290	0.2
romidepsin	chemical	CHEBI:61080	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257990	0.8
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr46	GGTLFSTtPGGTRII	9823	BTO:0001840		SIGNOR-C3						23486913	t		lperfetto	These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation	SIGNOR-219266	0.924
MAPK3	protein	P27361	UNIPROT	ARRB1	protein	P49407	UNIPROT	down-regulates	phosphorylation	Ser412	EEEDGTGsPQLNNR	9606									15456867	t		gcesareni	Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation	SIGNOR-129589	0.705
SMAD6	protein	O43541	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates activity	binding			9606									9892110	t		lperfetto	SMAD6 functions as a negative regulator of the TGFB and BMP signaling pathways by interacting with other SMADs and/or TBRI.	SIGNOR-64079	0.73
SHH	protein	Q15465	UNIPROT	GLI2	protein	P10070	UNIPROT	up-regulates activity				9606	BTO:0001593								16880529	f		lperfetto	Finally, Sonic hedgehog (Shh) stimulates BMP-2 promoter activity and osteoblast differentiation, and the effects of Shh are mediated by Gli2.	SIGNOR-148349	0.72
IRF5	protein	Q13568	UNIPROT	TNF	protein	P01375	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21240265	f		miannu	Among the genes with differences in expression in the M1 and M2 subsets are those regulated by IRF5, including IL12A, IL12B, IL23A, IL1B, TNF, CCL3(encoding MIP-1α), RANTES, CD1A, CD40, CD86 and CCR7	SIGNOR-254518	0.465
BTK	protein	Q06187	UNIPROT	BMX	protein	P51813	UNIPROT	up-regulates	phosphorylation	Tyr216	SSTSLAQyDSNSKKI	9606									12573241	t		lperfetto	Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism.	SIGNOR-98028	0.34
tRNA(Ile)	smallmolecule	CHEBI:29174	ChEBI	Ile-tRNA(Ile)	smallmolecule	CHEBI:29160	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270425	0.8
PAK6	protein	Q9NQU5	UNIPROT	SYNJ1	protein	O43426	UNIPROT	up-regulates activity	phosphorylation			-1									22371566	t		miannu	We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. 	SIGNOR-263022	0.2
SCAP	protein	Q12770	UNIPROT	SREBF1	protein	P36956	UNIPROT	up-regulates activity	binding			10029									12242332	t		miannu	Insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis.	SIGNOR-256210	0.716
MAPK14	protein	Q16539	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	phosphorylation	Ser208	DAGSPNLsPNPMSPA	9606	BTO:0001939								15520018	t		miannu	Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways.	SIGNOR-250112	0.553
GSK3B	protein	P49841	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates	phosphorylation	Ser129	ICPSLPYsPVSSPQS	9606									22778263	t		lperfetto	Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity.	SIGNOR-198134	0.276
MAPK1	protein	P28482	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Ser567	DSSRFPMsPRPDSVH	10029	BTO:0000246								15379552	t		lperfetto	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-249398	0.584
AKAP11	protein	Q9UKA4	UNIPROT	PKA	proteinfamily	SIGNOR-PF17	SIGNOR	down-regulates activity	binding												26088133	t		lperfetto	A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). 	SIGNOR-264818	0.434
ULK2	protein	Q8IYT8	UNIPROT	PRKAA2	protein	P54646	UNIPROT	down-regulates	phosphorylation			9606				SIGNOR-C15					21460634	t		miannu	We could prove that ulk1-mediated phosphorylation of ampk reduced its level of phosphorylation at t172 of the _-subunit and hence interferes with its catalytic activity. I	SIGNOR-173089	0.309
RELA	protein	Q04206	UNIPROT	SNAIL/RELA/PARP1	complex	SIGNOR-C198	SIGNOR	form complex	binding			9606	BTO:0000452;BTO:0002625								22223884	t		alessandro	Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin	SIGNOR-254527	0.453
PTK2B	protein	Q14289	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates	phosphorylation	Tyr657	FGLGSRAyPHFCAFA	9606	BTO:0000007								18483407	t		gcesareni	We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657.	SIGNOR-178648	0.315
PRKACA	protein	P17612	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser304	SLLKKRDsFRTPRDS	9606									20151718	t		miannu	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163760	0.278
CAV1	protein	Q03135	UNIPROT	SLC1A3	protein	P43003	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								26690923	t		miannu	EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. 	SIGNOR-264808	0.2
NFATC2	protein	Q13469	UNIPROT	MYOF	protein	Q9NZM1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001103							23612709	f		miannu	Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin 	SIGNOR-255465	0.2
DDX1	protein	Q92499	UNIPROT	DDX21	protein	Q9NR30	UNIPROT	up-regulates activity	binding			10090									21703541	t		miannu	We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA.	SIGNOR-260191	0.327
DBP	protein	Q10586	UNIPROT	ALDOB	protein	P05062	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								8383844	f		miannu	 Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators	SIGNOR-253833	0.2
vitamin K	smallmolecule	CHEBI:28384	ChEBI	Reduced Vitamin K	smallmolecule	CHEBI:8784	ChEBI	up-regulates quantity	precursor of			9606									31226734	t		lperfetto	This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR)	SIGNOR-265915	0.8
ESR1	protein	P03372	UNIPROT	MYC	protein	P01106	UNIPROT	unknown	transcriptional regulation			9606	BTO:0000356								11517191	f	 	 	ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression	SIGNOR-253941	0.718
PIM1	protein	P11309	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606									18593906	t		tpavlidou	Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene.	SIGNOR-252966	0.396
epinastine	chemical	CHEBI:51032	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002126								18446005	t		Luana	We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells	SIGNOR-257779	0.8
GSK3B	protein	P49841	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates	phosphorylation	Thr226	GSSGSLStSSSSSPP	9606							phosphorylation:Ser237	SSPPGTPsPADAKAP	22369944	t		fspada	However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs.	SIGNOR-210129	0.469
ZNF217	protein	O75362	UNIPROT	CoREST-HDAC complex	complex	SIGNOR-C105	SIGNOR	form complex	binding			9606	BTO:0000567								11171972	t		miannu	Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function.	SIGNOR-222118	0.552
TALDO1	protein	P37837	UNIPROT	sedoheptulose 7-phosphate	smallmolecule	CHEBI:15721	ChEBI	down-regulates quantity	chemical modification			9606									19401148	t		miannu	Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 	SIGNOR-267089	0.8
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270380	0.8
CTNND2	protein	Q9UQB3	UNIPROT	ERBIN	protein	Q96RT1	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								11821434	t		miannu	We characterized the interactions between the Erbin PDZ domain and both ARVCF and δ-catenin in vitro and in vivo. endogenous δ-catenin and Erbin co-localized in and co-immunoprecipitated from neurons. These results suggest that δ-catenin and ARVCF may function to mediate the association of Erbin with the junctional cadherin-catenin complex.	SIGNOR-252120	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	POU5F1	protein	Q01860	UNIPROT	down-regulates	phosphorylation			9606									23024368	t	inferred from 70% family members	gcesareni	Phosphorylation of this site downregulates nanog, sox2, rex1 and upregulates bmp4, gata6, ddlx5.	SIGNOR-270185	0.2
PAX3-FOXO1	fusion protein	SIGNOR-FP12	SIGNOR	FGFR4	protein	P22455	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25211658	t		miannu	Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA.	SIGNOR-251569	0.2
ETV2	protein	O00321	UNIPROT	FLI1	protein	Q01543	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24727028	f		miannu	We have identified a novel positive feed-forward regulatory loop in which etv2 activates expression of genes involved in vasculogenesis, including fli1.	SIGNOR-203272	0.2
ABL2	protein	P42684	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates	phosphorylation	Tyr231	NANGEAVyCKFHYKT	9606									12950161	t		lperfetto	C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases	SIGNOR-86680	0.345
romidepsin	chemical	CHEBI:61080	ChEBI	HDAC1	protein	Q13547	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257996	0.8
MT-ND4	protein	P03905	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4	SIGNOR-262146	0.779
vitamin D	smallmolecule	CHEBI:27300	ChEBI	calcidiol	smallmolecule	CHEBI:17933	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000759							30080183	t		lperfetto	Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. 	SIGNOR-270567	0.8
GDNF	protein	P39905	UNIPROT	DCX	protein	O43602	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization.	SIGNOR-252172	0.353
9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone	chemical	CID:71748056	PUBCHEM	TEC	protein	P42680	UNIPROT	down-regulates activity	chemical inhibition			-1									24556163	t		miannu	This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine 	SIGNOR-262235	0.8
EIF3_complex	complex	SIGNOR-C401	SIGNOR	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	down-regulates activity				9606									15703437	f		lperfetto	EIF3 and, to some extent, eIF1A have been implicated in preventing reassociation of free 40S and 60S subunits and in dissociation of empty 80S ribosomes	SIGNOR-269149	0.407
PPP2CA	protein	P67775	UNIPROT	FCAR	protein	P24071	UNIPROT	up-regulates activity	dephosphorylation	Ser284	LTFARTPsVCK	-1									30766540	t		lperfetto	Furthermore, FcalphaRI activation is induced by protein phosphatase 2A (PP2A) after it dephosphorylates a single serine residue (S263) in the FcalphaRI intracellular tail	SIGNOR-264858	0.328
PTAFR	protein	P25105	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257436	0.387
KIT	protein	P10721	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates activity	phosphorylation	Tyr570	INGNNYVyIDPTQLP	9606									12824176	t		lperfetto	Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth./ Tyr-568 and tyr-570 are significantly phosphorylated	SIGNOR-102637	0.2
3-(2-Carboxyethyl)-4,6-dichloro-1H-indole-2-carboxylic acid	chemical	CID:446916	PUBCHEM	GPR17	protein	Q13304	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257502	0.8
GATA2	protein	P23769	UNIPROT	GATA2	protein	P23769	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27545880	f		irozzo	GATA-2 phosphorylation facilitates GATA-2 chromatin occupancy at GATA-2 target genes. GATA-2 stimulates GATA2 transcription through positive autoregulation	SIGNOR-256090	0.2
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	chemical	CHEBI:95082	ChEBI	BRD2	protein	P25440	UNIPROT	down-regulates activity	chemical inhibition			-1									24015967	t		Gianni	This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation	SIGNOR-262202	0.8
trimethyl-[(5-methyl-2-furanyl)methyl]ammonium	chemical	CHEBI:94038	ChEBI	CHRM2	protein	P08172	UNIPROT	up-regulates activity	chemical activation			10029									9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258649	0.8
DOCK4	protein	Q8N1I0	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			10090	BTO:0001976								32009906	t		miannu	DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia. 	SIGNOR-266823	0.568
MAPK3	protein	P27361	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates	phosphorylation	Ser295	PARPRSPsQTRKGPP	9606		BTO:0000142							15262992	t		lperfetto	Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2.	SIGNOR-126871	0.277
S1PR3	protein	Q99500	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257263	0.377
DOK1	protein	Q99704	UNIPROT	Av/b2 integrin	complex	SIGNOR-C176	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257684	0.301
ESR1	protein	P03372	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000356								11517191	f	 	 	ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression	SIGNOR-253940	0.491
cholesterol	smallmolecule	CHEBI:16113	ChEBI	SOAT1	protein	P35610	UNIPROT	up-regulates activity	chemical activation			9606		BTO:0000759							31848472	t		miannu	Excess cholesterol is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT; also known as SOAT) to cholesteryl esters	SIGNOR-265159	0.8
TBX21	protein	Q9UL17	UNIPROT	IL4	protein	P05112	UNIPROT	down-regulates	transcriptional regulation			9606	BTO:0000782								17541280	f			IL-4 gene transcription is inhibited by T-bet via the suppression of its promoter activity, independently of IFN-gamma. T-bet facilitates Th1 differentiation through not only upregulation of IFN-gamma, but also downregulation of IL-4 gene transcription	SIGNOR-254496	0.493
lysophosphatidic acids	smallmolecule	CHEBI:32957	ChEBI	GNB3	protein	P16520	UNIPROT	up-regulates	chemical activation			9606									17251915	t		gcesareni	Lpa through galfai and gbetagamma subunits also activates phosphatidylinositol 3-kinase (pi3k), which results in the stimulation of the akt survival pathway and increased protein translation by the activation of the mammalian target of rapamycin (mtor) pathway.	SIGNOR-152759	0.8
NAD(1-)	smallmolecule	CHEBI:57540	ChEBI	SIRT1	protein	Q96EB6	UNIPROT	up-regulates activity	binding			9606									10693811	t		gcesareni	Here we show that yeast and mouse Sir2 proteins are nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases	SIGNOR-238539	0.8
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Ser307	TRRSRTEsITATSPA	9606		BTO:0000887							11160134	t		lperfetto	Thus, at least three kinases mediate phosphorylation of ser307, including jnk, serine kinases in the pi 3-kinase cascade that are activated byinsulinor igf-1, and mek1-sensitive kinase cascades during tnf-alfa stimulation.	SIGNOR-244784	0.2
PLXNB3	protein	Q9ULL4	UNIPROT	FSCN1	protein	Q16658	UNIPROT	up-regulates activity				10090	BTO:0000526								21706053	f		miannu	Sema5A regulates the phosphorylation states of fascin-1 through plexin-B3. 	SIGNOR-268374	0.342
LRP6	protein	O75581	UNIPROT	LPR5/6	complex	SIGNOR-C219	SIGNOR	form complex	binding			9606									27821587	t		miannu	Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are co-receptors for Wnt ligands.	SIGNOR-256175	0.38
AURKB	protein	Q96GD4	UNIPROT	CHMP4C	protein	Q96CF2	UNIPROT	up-regulates	phosphorylation	Ser214	ARRSRAAsSQRAEEE	9606									22724069	t		lperfetto	Moreover, we find that the cpc's catalytic subunit, aurora b kinase, phosphorylates one of the three human snf7 paralogues-chmp4c-in its c-terminal tail, a region known to regulate its ability to form polymers and associate with membranes. Phosphorylation at these sites appears essential for chmp4c function because their mutation leads to cytokinesis defects. The introduction of the s214a and s215a mutations together with s210a almost completely abolished aurora b phosphorylation	SIGNOR-197971	0.483
MAPK7	protein	Q13164	UNIPROT	MAP2K5	protein	Q13163	UNIPROT	up-regulates	phosphorylation	Ser137	QHSSPAVsDSLPSNS	9606		BTO:0000671							12628002	t		lperfetto	Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)	SIGNOR-99131	0.69
AGO2	protein	Q9UKV8	UNIPROT	RISC(DICER1/AGO2/TARBP2)	complex	SIGNOR-C32	SIGNOR	form complex	binding			9606									16142218	t		lperfetto	Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si_ or mi_riscs in mammalian cells, but it may also facilitate the cleavage of pre_mirnas by dicer.	SIGNOR-140220	0.902
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	DDX3X	protein	O00571	UNIPROT	down-regulates	phosphorylation	Thr323	GCHLLVAtPGRLVDM	9606									16280325	t		lperfetto	Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis.	SIGNOR-216872	0.345
IL10RA	protein	Q13651	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000801								26260587	t		lperfetto	IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes.	SIGNOR-249545	0.42
FZD4	protein	Q9ULV1	UNIPROT	DVL3	protein	Q92997	UNIPROT	up-regulates activity	binding			9606									27096005	t		areggio	Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin.	SIGNOR-258961	0.57
apigenin	chemical	CHEBI:18388	ChEBI	CYP2C9	protein	P11712	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189802	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Thr573	AENGLLMtPCYTANF	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-250558	0.2
MFGE8	protein	Q08431	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates activity				10116	BTO:0000801								19020771	f		Giorgia	In our current study, we have shown that after LPS-stimulation, MFG-E8-mediated apoptotic cell phagocytosis suppresses various ERK1/2, p38, JNK, and NFκB activation, resulting in a lower TNF-α release. We also explored whether MFG-E8 helps to suppress the proinflammatory pathway within RPMs. We hence incubated the macrophages with apoptotic cells and stimulated them with LPS and examined the activation of MAP kinase and NFkB pathways after the exogenous addition of recombinant MFG-E8 (rMFG-E8). While apoptotic cells alone had no effect on these pathways, the addition of rMFG-E8 to apoptotic cells prior to phagocytosis and LPS stimulation had a marked suppressive effect on all of the investigated pathways, particularly on the p38 and NFκB pathways that play a key role in the cytokine response of macrophages	SIGNOR-260652	0.2
PRKCA	protein	P17252	UNIPROT	KCNQ2	protein	O43526	UNIPROT	up-regulates quantity	phosphorylation	Ser558	SKRKFKEsLRPYDVM	10029	BTO:0000246								12754513	t		lperfetto	Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. | These results suggest that Ser534 and 541 are key sites for PKC phosphorylation, although we have not ruled out the possibility that other PKC sites are involved in this process.	SIGNOR-249210	0.329
MUL1	protein	Q969V5	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates quantity by destabilization	ubiquitination	Lys284	LENLMLDkDGHIKIT	9606									22410793	t		gcesareni	The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability.	SIGNOR-252460	0.488
CSNK2A1	protein	P68400	UNIPROT	CARD9	protein	Q9H257	UNIPROT	down-regulates activity	phosphorylation	Thr533	TGSDNTDtEGS	9606									17936701	t		miannu	PVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2	SIGNOR-257601	0.352
STOM	protein	P27105	UNIPROT	SLC2A1	protein	P11166	UNIPROT	down-regulates activity	binding			9606									10562431	t		Giulio	Similar to the results obtained in the RBC, Glut1 and stomatin immunoprecipitated with each other in lysates of Clone 9 cells. The above results suggest that stomatin is closely associated with Glut1 in the plasma membrane and that overexpression of stomatin results in a depression in the basal rate of glucose transport.	SIGNOR-261278	0.543
MAP2K5	protein	Q13163	UNIPROT	MAPK7	protein	Q13164	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0005787	BTO:0001103							23612709	t		miannu	The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 	SIGNOR-255453	0.69
GABARAP	protein	O95166	UNIPROT	GPHN	protein	Q9NQX3	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								25882190	t		miannu	The GABA(A)R-associated protein GABARAP was found to bind to the gamma2 subunit of GABA(A)Rs. Here we show that GABARAP interacts with gephyrin in both biochemical assays and transfected cells. Our data indicate that GABARAP-gephyrin interactions are not important for postsynaptic GABA(A)R anchoring but may be implicated in receptor sorting and/or targeting mechanisms. 	SIGNOR-264971	0.579
GNAS	protein	P63092	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	down-regulates				-1									10224115	f		miannu	G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics.	SIGNOR-256524	0.7
POU5F1	protein	Q01860	UNIPROT	ZFP42	protein	Q96MM3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001086								17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254944	0.479
MRPL20	protein	Q9BYC9	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262373	0.723
FZD4	protein	Q9ULV1	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates activity	binding			9606									25902418	t		areggio	Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain.	SIGNOR-258967	0.694
PP2	chemical	CHEBI:78331	ChEBI	SRC	protein	P12931	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0001760							12351660	t		gcesareni	Treatment of l6 cells with pp2 or su6656, specific inhibitors of src family kinases, and transient transfection of dominant-inhibitory src inhibited the formation of myotubes and expression of myogenin.	SIGNOR-93549	0.8
SHC1	protein	P29353	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity				10090	BTO:0000944								17673906	f		lperfetto	We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases.	SIGNOR-242628	0.709
FGR	protein	P09769	UNIPROT	SDHA	protein	P31040	UNIPROT	unknown	phosphorylation	Tyr604	YKVRIDEyDYSKPIQ	-1									17997986	t		miannu	Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations.	SIGNOR-262873	0.2
FZR1	protein	Q9UM11	UNIPROT	PFKFB3	protein	Q16875	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000793								20080744	t		miannu	We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1, which also degrades cell-cycle proteins. Cdh1 promotes PFKFB3 degradation in the nucleus.	SIGNOR-271436	0.266
Inflammation	phenotype	SIGNOR-PH12	SIGNOR	ARDS	phenotype	SIGNOR-PH128	SIGNOR	up-regulates				9606									32446778	f		miannu	The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm.	SIGNOR-261036	0.7
EIF2AK3	protein	Q9NZJ5	UNIPROT	EIF2AK3	protein	Q9NZJ5	UNIPROT	up-regulates	phosphorylation	Tyr619	NKVDDCNyAIKRIRL	9606									17998206	t		lperfetto	We show that perk is capable of autophosphorylating on tyrosine residues in vitro and in vivo. We further show that tyrosine 615, which is embedded in a highly conserved region of the kinase domain of perk, is essential for autocatalytic activity.	SIGNOR-159156	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	FERMT2	protein	Q96AC1	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser180	PGSGSIYsSPGLYSK	9606	BTO:0000567								35469017	t		miannu	 CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry.	SIGNOR-276715	0.2
TET2	protein	Q6N021	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0000738								25601757	f		irozzo	Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation.	SIGNOR-255704	0.7
MRPS27	protein	Q92552	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261446	0.684
PPARA	protein	Q07869	UNIPROT	SLC25A20	protein	O43772	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									19577614	f		miannu	 CACT is upregulated by PPARalpha and PPARdelta, probably by binding to a functional PPRE at position +45 to +57 relative to the transcription start site. The upregulation of CACT by PPARalpha and PPARdelta, which are both important for the regulation of fatty acid oxidation in tissues during fasting, may increase the import of acylcarnitine into the mitochondrial matrix during fasting.	SIGNOR-255049	0.505
PRKCZ	protein	Q05513	UNIPROT	PIAS4	protein	Q8N2W9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser18	MVMSFRVsDLQMLLG										27162139	t		lperfetto	In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFbeta signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCzeta and GSK3beta. Specifically, PKCzeta phosphorylation of PIAS4 and GSK3beta phosphorylation of FIEL1 are both essential for the degradation of PIAS4.|These experiments suggested that PKCzeta is an authentic regulator of PIAS4 protein stability; Q21 and phosphorylated S18 of PIAS4 are both required for FIEL1 interaction.	SIGNOR-275513	0.501
KRN-633	chemical	CID:9549295	PUBCHEM	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193582	0.8
UBE3A	protein	Q05086	UNIPROT	RAD23B	protein	P54727	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0000298								10373495	t		miannu	 Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP.  E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B.	SIGNOR-272551	0.413
Glutaminolysis	phenotype	SIGNOR-PH119	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				9606	BTO:0000567								22749528	f		Luana	Glutaminolysis Is Required for the Activation of mTORC1 by Leucine and Glutamine	SIGNOR-268007	0.7
IARS1	protein	P41252	UNIPROT	Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	form complex	binding			9606									32644155	t		miannu	In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes).	SIGNOR-270354	0.2
18-hydroxycorticosterone	smallmolecule	CHEBI:16485	ChEBI	aldosterone	smallmolecule	CHEBI:27584	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000048							33117906	t		lperfetto	The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone	SIGNOR-268686	0.8
ACTL6A	protein	O96019	UNIPROT	Neural progenitor-specific SWI/SNF	complex	SIGNOR-C477	SIGNOR	form complex	binding			9606									25195934	t		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270620	0.805
TAF1	protein	P21675	UNIPROT	GTF2A1	protein	P52655	UNIPROT	up-regulates activity	phosphorylation	Ser281	DGTGDTSsEEDEDEE	9606									11278496	t		lperfetto	TAFII 250 Phosphorylates Human Transcription Factor IIA on Serine Residues Important for TBP Binding and Transcription ActivityAdditional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels	SIGNOR-246634	0.662
TBX3	protein	O15119	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									25595898	f		miannu	AKT phosphorylation potentiates the ability of TBX3 to repress the transcription of the E-cadherin gene	SIGNOR-223537	0.421
TRIM23	protein	P36406	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								28871090	t		miannu	TRIM23 interacts with TBK1 and p62. TRIM23 GTPase activates TBK1 to phosphorylate p62. Biochemical characterization showed that TRIM23 binds with its C-terminal ARF domain to the N-terminal KD of TBK1, and that GTP hydrolysis activity of the ARF stimulates TBK1-mediated phosphorylation of p62 at S403 in its ubiquitin-associated (UBA) domain, which was shown to promote cargo recruitment and autophagic flux	SIGNOR-266654	0.534
DLG5	protein	Q8TDM6	UNIPROT	Scribble_complex_DLG5-LLGL1_variant	complex	SIGNOR-C508	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270901	0.315
DDX28	protein	Q9NUL7	UNIPROT	Stress_granules	phenotype	SIGNOR-PH124	SIGNOR	up-regulates				9606									25683715	f		miannu	DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. 	SIGNOR-261229	0.7
PDPK1	protein	O15530	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Thr308	KDGATMKtFCGTPEY	10116		BTO:0000142							10226025	t		lperfetto	Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown.	SIGNOR-244421	0.736
HCRTR2	protein	O43614	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257216	0.425
ALDH1A2	protein	O94788	UNIPROT	retinal	smallmolecule	CHEBI:15035	ChEBI	down-regulates quantity	chemical modification			9606									21621639	t		lperfetto	All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step.	SIGNOR-265125	0.8
PBK	protein	Q96KB5	UNIPROT	ULK1	protein	O75385	UNIPROT	down-regulates activity	phosphorylation	Ser469	IRRSGSTsPLGFARA	9606	BTO:0002181								31378785	t		miannu	We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1. 	SIGNOR-277474	0.2
GRK7	protein	Q8WTQ7	UNIPROT	GRK7	protein	Q8WTQ7	UNIPROT	unknown	phosphorylation	Ser490	YAKDIAEiDDFSEVR	9606									15946941	t		Manara	In the absence of PKA, GRK1 and GRK7 are autophosphorylated | The mutants, S490A-GRK7 and S490E-GRK7, do not undergo autophosphorylation, indicating that Ser490 is the only autophosphorylation site in GRK7	SIGNOR-260838	0.2
GMIP	protein	Q9P107	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260507	0.491
MAPK8	protein	P45983	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									7824938	t		gcesareni	Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain.	SIGNOR-33914	0.772
GRIN1	protein	Q05586	UNIPROT	NMDA receptor_2C	complex	SIGNOR-C349	SIGNOR	form complex	binding			9606	BTO:0000938								12871085	t		miannu	The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits	SIGNOR-264124	0.594
EFEMP2	protein	O95967	UNIPROT	ELN	protein	P15502	UNIPROT	up-regulates activity	binding			9606									19570982	t		miannu	Fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking.	SIGNOR-252136	0.575
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates	dephosphorylation			9606									18676376	t	inferred from 70% family members	lperfetto	Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes.	SIGNOR-269988	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	MMP13	protein	P45452	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003858								12734180	f		miannu	The suppressive effect of IGF-1 and OP-1 on MMP-13 expression was due in part to down-regulation of the expression of pro-inflammatory cytokines and the activity of their intermediate molecules, including NF-kappaB and AP-1 factors. 	SIGNOR-254800	0.315
GSK3B	protein	P49841	UNIPROT	MYOCD	protein	Q8IZQ8	UNIPROT	down-regulates activity	phosphorylation	Ser459	TSSSPPIsPASSDLS	9606	BTO:0000007								16141410	t			In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity	SIGNOR-251243	0.406
TBX21	protein	Q9UL17	UNIPROT	IL10	protein	P22301	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000782								20154735	f		azuccotti	Similarly, an increase in IL-10 expression was observed in mice deficient for the TH1 cell-specific transcription factor T-bet (also known as TBX21) that were infected with M.tuberculosis, suggesting that T-bet might have a role in the negative regulation of IL-10 expression by TH1 cells	SIGNOR-254524	0.46
TEAD1	protein	P28347	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							21527258	f		gcesareni	We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor.	SIGNOR-173445	0.326
POU2AF1	protein	Q16633	UNIPROT	POU2F2	protein	P09086	UNIPROT	up-regulates	binding			9606	BTO:0000776								8654375	t		miannu	We have shown previously that both octamer binding transcription factors, namely the ubiquitous oct-1 and the b cell-specific oct-2a protein, can be enhanced in transcriptional activity by their association with the b cell-specific coactivator protein bob1, also calledobf-1or oca-b.	SIGNOR-42278	0.579
ARHGAP39	protein	Q9C0H5	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260494	0.48
TEK	protein	Q02763	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	binding			9606					phosphorylation:Tyr1102	MLEERKTyVNTTLYE			14665640	t		gcesareni	Our results identified a novel interaction between Tie2 with the adapter molecule ShcA and suggested that this interaction may play a role in the regulation of migration and three-dimensional organization of endothelial cells induced by angiopoietin-1. Furthermore, Tyr-1101 of Tie2 was identified as the primary binding site for the SH2 domain of ShcA. 	SIGNOR-242573	0.562
CYP2D6	protein	P10635	UNIPROT	dopamine	smallmolecule	CHEBI:18243	ChEBI	up-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain 	SIGNOR-263996	0.8
Histone H2A	proteinfamily	SIGNOR-PF70	SIGNOR	Nucleosome	complex	SIGNOR-C371	SIGNOR	form complex	binding			-1									21812398	t		lperfetto	The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP.	SIGNOR-265309	0.2
PTPN1	protein	P18031	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates	dephosphorylation	Tyr1234	RDMYDKEyYSVHNKT	9606									18819921	t		gcesareni	Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion.	SIGNOR-181323	0.621
USF2	protein	Q15853	UNIPROT	FMR1	protein	Q06787	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001363; BTO:0000142							11058604	f		miannu	 We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs.	SIGNOR-254883	0.274
SMARCA4	protein	P51532	UNIPROT	Muscle cell-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C483	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex.	SIGNOR-270738	0.864
CTNNB1	protein	P35222	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity				9606									16510874	f		Luana	Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro. Chromatin immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp.	SIGNOR-260448	0.2
POLR2H	protein	P52434	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding												22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266149	0.908
PPP2CA	protein	P67775	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	dephosphorylation			9606									19061640	t		gcesareni	In the absence of the wt apc protein, phosphorylated beta-catenin is rapidly dephosphorylated by serine/threonine protein phosphatase 2a (pp2a). phosphorylated beta-catenin associated with the wild-type apc protein is recruited to the scf(beta-trcp) complex, ubiquitin conjugated, and degraded.	SIGNOR-182637	0.439
BARD1	protein	Q99728	UNIPROT	BRCA1-BARD1 complex	complex	SIGNOR-C297	SIGNOR	form complex	binding												25400280	t		lperfetto	 Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks.	SIGNOR-263223	0.785
TFE3	protein	P19532	UNIPROT	CTSA	protein	P10619	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276815	0.2
MMP3	protein	P08254	UNIPROT	SPP1	protein	P10451	UNIPROT	up-regulates activity	cleavage												25545242	t		lperfetto	In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA.	SIGNOR-253320	0.656
CBL	protein	P22681	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									19450681	t		lperfetto	Tyrosine y1001, which when phosphorylated upon met activation, is involved in cbl recruitment, allowing receptor ubiquitination and down regulation	SIGNOR-185680	0.72
CREB1	protein	P16220	UNIPROT	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity	transcriptional regulation			9606									26652733	t	inferred from family member	miannu	Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-267786	0.2
CTNNB1	protein	P35222	UNIPROT	SOX2	protein	P48431	UNIPROT	down-regulates activity	binding			9606	BTO:0000093								24291232	t		flangone	The interaction between Sox2 and _-catenin provides a novel mechanism underlying the functional dichotomy of BC cells, which carries potential therapeutic implications.	SIGNOR-241994	0.697
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ARHGEF2	protein	Q92974	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000567								18211802	t	inferred from 70% family members	gcesareni	Activates rhoa and as a result regulates actin assembly.	SIGNOR-270138	0.2
WNT9B	protein	O14905	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									20093360	t		gcesareni	We find that wnt9b binds to a different part of the lrp6 extracellular domain	SIGNOR-163552	0.615
NR3C1	protein	P04150	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates activity				10090									11742987	f		gcesareni	The MAP kinase p38 is also a target for negative regulation by glucocorticoids	SIGNOR-251675	0.49
PAK1	protein	Q13153	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Ser338	RPRGQRDsSYYWEIE	9606									18775988	t		gcesareni	P21-activated protein kinases (paks) are serine/threonine protein kinases that phosphorylate raf-1 at ser-338 and ser-339.	SIGNOR-180808	0.584
PTPN2	protein	P17706	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates	dephosphorylation	Tyr1234	RDMYDKEyYSVHNKT	9606									18819921	t		gcesareni	We have identified ptp1b and tcptp as negative regulators of the hepatocyte growth factor receptor, the met receptor-tyrosine kinase. In vivo, loss of ptp1b or tcptp enhances hepatocyte growth factor-mediated phosphorylation of met.	SIGNOR-181331	0.479
AKT1	protein	P31749	UNIPROT	CLK2	protein	P49760	UNIPROT	up-regulates	phosphorylation	Thr127	RRRRRSRtFSRSSSQ	9606	BTO:0000567								20682768	t		lperfetto	Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva	SIGNOR-167340	0.398
MAPKAPK2	protein	P49137	UNIPROT	ALOX5	protein	P09917	UNIPROT	up-regulates activity	phosphorylation	Ser272	CSLERQLsLEQEVQQ	-1									11844797	t		miannu	Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). when stimulated with only exogenous arachidonic acid, activity for the S271A mutant was significantly lower as compared with wild type 5-LO. 	SIGNOR-250143	0.525
GSK3B	protein	P49841	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr46	GGTLFSTtPGGTRII	9606		BTO:0000671							18701453	t		lperfetto	We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation.	SIGNOR-236660	0.373
MAPK7	protein	Q13164	UNIPROT	MEF2A	protein	Q02078	UNIPROT	up-regulates	phosphorylation	Ser355	SALQGFNsPGMLSLG	9606	BTO:0000567								10849446	t		lperfetto	We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo.	SIGNOR-236587	0.699
ATM	protein	Q13315	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1423	AVLEQHGsQPSNSYP	9606	BTO:0000150								10550055	t		lperfetto	Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint.	SIGNOR-72052	0.813
BMP4	protein	P12644	UNIPROT	MRTFA	protein	Q969V6	UNIPROT	up-regulates				9606									21673106	f		gcesareni	These results demonstrate that mrtf-a is essential for the bmp4-mediated induction of pri-mir-143/145 and mature mir-143/145, whereas tgf- -mediated induction of mir-143/145 requires myocd. Mrtf-a is primarily localized in the cytoplasm in unstimulated cells;upon stimulation with bmp4, mrtf-a translocates into the nucleus to promote changes in gene expression.	SIGNOR-174124	0.2
ERBB2	protein	P04626	UNIPROT	BBC3	protein	Q9BXH1	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr152	ADDLNAQyERRRQEE	9606	BTO:0000093								24236056	t		miannu	HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. 	SIGNOR-276472	0.286
CDK2	protein	P24941	UNIPROT	ORC2	protein	Q13416	UNIPROT	up-regulates	phosphorylation	Thr116	LASELAKtPQKSVSF	9606			SIGNOR-C83						11931757	t		lperfetto	We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.	SIGNOR-116364	0.744
CAMK2B	protein	Q13554	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	up-regulates	phosphorylation	Ser362	FYTLNGSsVDSQPQS	9606									24614225	t		lperfetto	Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity.	SIGNOR-25334	0.2
TRIM28	protein	Q13263	UNIPROT	ALDOA	protein	P04075	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17900823	f		miannu	 We previously reported that ZNF224, a novel Krüppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. 	SIGNOR-255628	0.2
PTPN13	protein	Q12923	UNIPROT	TRIP6	protein	Q15654	UNIPROT	down-regulates activity	dephosphorylation	Tyr55	PLPSEQCyQAPGGPE	10090	BTO:0002572								17591779	t			PTPL1/FAP-1 negatively regulates TRIP6 function in lysophosphatidic acid-induced cell migration.|Here we further demonstrate that a switch from c-Src-mediated phosphorylation to PTPL1/Fas-associated phosphatase-1-dependent dephosphorylation serves as an inhibitory feedback control mechanism of TRIP6 function in LPA-induced cell migration. PTPL1 dephosphorylates phosphotyrosine 55 of TRIP6 in vitro and inhibits LPA-induced tyrosine phosphorylation of TRIP6 in cells. 	SIGNOR-248713	0.444
ABL1	protein	P00519	UNIPROT	MYLK	protein	Q15746	UNIPROT	up-regulates	phosphorylation	Tyr464	QEGSIEVyEDAGSHY	9606		BTO:0000763							20861316	t		lperfetto	We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity	SIGNOR-167993	0.305
GSK3A	protein	P49840	UNIPROT	STMN3	protein	Q9NZ72	UNIPROT	up-regulates activity	phosphorylation	Ser60	SFEVILKsPSDLSPE	-1									22577147	t		lperfetto	Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta	SIGNOR-264883	0.254
CSNK1D	protein	P48730	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606									10734067	t		gcesareni	Here we show that the direct association between a p53 n-terminal peptide and mdm2 is disrupted by phosphorylation of the peptide on thr(18) but not by phosphorylation at other n-terminal sites, including ser(15) and ser(37). Thr(18) was phosphorylated in vitro by casein kinase (ck1).	SIGNOR-75889	0.559
TLRs	proteinfamily	SIGNOR-PF20	SIGNOR	TLRs	proteinfamily	SIGNOR-PF20	SIGNOR	up-regulates activity	binding			9606									24352680	t		lperfetto	Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain	SIGNOR-216301	0.2
PRKACA	protein	P17612	UNIPROT	AKAP13	protein	Q12802	UNIPROT	down-regulates	phosphorylation	Ser1565	LSPFRRHsWGPGKNA	9606									15229649	t		llicata	Elevation of the cellular concentration of camp activates the pka holoenzyme anchored to akap-lbc, which phosphorylates the anchoring protein on the serine 1565. This phosphorylation event induces the recruitment of 14-3-3, which inhibits the rho-gef activity of akap-lbc.	SIGNOR-126723	0.337
TFE3	protein	P19532	UNIPROT	CTSD	protein	P07339	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276816	0.287
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	CARHSP1	protein	Q9Y2V2	UNIPROT	unknown	phosphorylation	Ser52	TRRTRTFsATVRASQ	9606		BTO:0000671							15910284	t		lperfetto	These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf	SIGNOR-252814	0.2
SERPINE1	protein	P05121	UNIPROT	Fibrinolysis	phenotype	SIGNOR-PH6	SIGNOR	down-regulates				9606									19387897	f		miannu	Plasma PAI-1 levels robustly fluctuate in a circadian manner and consequently contribute to hypofibrinolysis during the early morning. The circadian expression of PAI-1 gene is thought to be directly regulated by the circadian clock proteins such as CLOCK and BMAL1/BMAL2 which drive the endogenous biological clock. Plasma PAI-1 levels are increased in the beginning of the active phase in both diurnal humans and in nocturnal rodents, suggesting that the rhythmic PAI-1 expression is commonly indispensable for organisms. 	SIGNOR-267984	0.7
NFE2L2	protein	Q16236	UNIPROT	GSTA1	protein	P08263	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24024136	t		irozzo	In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).	SIGNOR-256278	0.35
NDUFC1	protein	O43677	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 	SIGNOR-262173	0.782
MET	protein	P08581	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr577	YMEDSTYyKASKGKL	9606									16782899	t		llicata	Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain	SIGNOR-147195	0.475
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Phe709	ENPTYKFfEQMQN	-1									8943232	t		lperfetto	FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261777	0.502
SLBP	protein	Q14493	UNIPROT	H3Y2	protein	P0DPK5	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265416	0.2
CAMTA1	protein	Q9Y6Y1	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606	BTO:0005397								21385898	f		irozzo	Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma.	SIGNOR-259100	0.7
DNMT3B	protein	Q9UBC3	UNIPROT	GSTM2	protein	P28161	UNIPROT	down-regulates quantity by repression	transcriptional regulation												21246532	f		lperfetto	Knockdown of Sp1 in normal lung cells reduced GST-M2 expression, and silencing of DNMT-3b increased GST-M2 expression in lung cancer cells.	SIGNOR-271687	0.334
PHB2	protein	Q99623	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates	binding			10090	BTO:0000165	BTO:0000887							15173318	t		lperfetto	Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation.	SIGNOR-235843	0.372
MMP2	protein	P08253	UNIPROT	PZP	protein	P20742	UNIPROT	down-regulates quantity by destabilization	cleavage	Thr718	PYVPQLGtYNVIPLN	-1									9344465	t		lperfetto	The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261796	0.335
clotrimazole	chemical	CHEBI:3764	ChEBI	KCNN4	protein	O15554	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9730970	t		miannu	IK was blocked by the classical inhibitors of the Gardos channel charybdotoxin (IC50 28 nM) and clotrimazole (IC50 153 nM) as well as by nitrendipine (IC50 27 nM), Stichodactyla toxin (IC50 291 nM), margatoxin (IC50 459 nM), miconazole (IC50 785 nM), econazole (IC50 2.4 microM), and cetiedil (IC50 79 microM). Finally, 1-ethyl-2-benzimidazolinone, an opener of the T84 cell IK channel, activated hIK with an EC50 of 74 microM.	SIGNOR-258832	0.8
NEIL3	protein	Q8TAT5	UNIPROT	Base-excision_repair	phenotype	SIGNOR-PH222	SIGNOR	up-regulates													23545420	f		lperfetto	The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1).	SIGNOR-275720	0.7
PPP1CB	protein	P62140	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	dephosphorylation	Ser217	YTRTGSEsPKVCSDQ	9606									17318175	t			The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 	SIGNOR-248569	0.2
MTA1/DJ1 complex 	complex	SIGNOR-C123	SIGNOR	TH	protein	P07101	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000793								21368136	f	1	miannu	we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3.	SIGNOR-239773	0.468
PCSK6	protein	P29122	UNIPROT	VWF	protein	P04275	UNIPROT	up-regulates activity	cleavage												8218226	t		Giorgia	Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine	SIGNOR-260367	0.298
PRL	protein	P01236	UNIPROT	KRT5	protein	P13647	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20103718	f	Regulation	miannu	PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes.	SIGNOR-251903	0.267
PYG	proteinfamily	SIGNOR-PF96	SIGNOR	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	up-regulates quantity	chemical modification			9606									3346228	t		miannu	Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267954	0.8
CDK6	protein	Q00534	UNIPROT	CyclinD3/CDK6	complex	SIGNOR-C234	SIGNOR	form complex	binding												8114739	t		lperfetto	Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells.	SIGNOR-273028	0.933
MAPK1	protein	P28482	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser214	PTSSDPGsPFQMPAD	9606									19914168	t		lpetrilli	Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3	SIGNOR-161694	0.59
L-cystathionine dizwitterion	smallmolecule	CHEBI:58161	ChEBI	L-cysteine zwitterion	smallmolecule	CHEBI:35235	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000671;BTO:0000759;BTO:0002688							19961860	t		lperfetto	 the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production.	SIGNOR-275813	0.8
SRC	protein	P12931	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	phosphorylation	Tyr530	FTSTEPQyQPGENL	9606									8755732	t		lperfetto	Rapid digestion of pp60c-src tyrosine kinase (src TK) in combination with electrospray ionization mass spectrometry enabled the determination of the time course for autophosphorylation of three tyrosine sites (Y338, Y419, and Y530) and a correlation with src TK activity. Here, conditions were identified which promoted essentially complete autophosphorylation of y530. Phosphorylation of y530 was directly correlated to a decrease in tyrosine kinase activity	SIGNOR-43315	0.2
MDH1	protein	P40925	UNIPROT	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	up-regulates quantity	chemical modification			9606									24068518	t		miannu	Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle	SIGNOR-266285	0.8
CSNK1D	protein	P48730	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Thr18	EPPLSQEtFSDLWKL	9606									10606744	t		gcesareni	Protein kinase ck1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15.	SIGNOR-73270	0.559
NR3C1	protein	P04150	UNIPROT	CEBPD	protein	P49716	UNIPROT	up-regulates quantity	transcriptional regulation			10090	BTO:0000011								10649448	t		gcesareni	We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPδ; C/EBPδ then binds to PPARγ2 promoter and transactivates PPARγ2 gene expression.	SIGNOR-253061	0.321
TNFRSF25	protein	Q93038	UNIPROT	TRADD	protein	Q15628	UNIPROT	up-regulates	binding			9606									14585074	t		amattioni	Dr3 induces apoptosis by tradd-mediated recruitment of fadd and caspase-8	SIGNOR-100480	0.729
MAPK1	protein	P28482	UNIPROT	STK11	protein	Q15831	UNIPROT	down-regulates activity	phosphorylation	Ser428	SSKIRRLsACKQQ	9606									25846811	t		lperfetto	Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK.	SIGNOR-209876	0.411
ULK2	protein	Q8IYT8	UNIPROT	ENO1	protein	P06733	UNIPROT	down-regulates activity	phosphorylation	Ser115	ANAILGVsLAVCKAG	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274038	0.2
IKBKG	protein	Q9Y6K9	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	form complex	binding			10090			SIGNOR-C14	SIGNOR-C14					19666475	t		lperfetto	Proinflammatory NF-kappaB activation requires the IkappaB (inhibitor of NF-kappaB) kinase (IKK) complex that contains two catalytic subunits named IKKalpha and IKKbeta and a regulatory subunit named NF-kappaB essential modulator (NEMO).	SIGNOR-209762	0.928
BRCA1	protein	P38398	UNIPROT	HSPA5	protein	P11021	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000093								18776923	f		miannu	 We report here that glucose-regulated protein (GRP)-78, a critical regulator of the unfolded protein response (UPR), is a novel downstream target of BRCA1. We showed that overexpression of wild-type BRCA1 suppressed the expression of GRP78, whereas expression of mutant BRCA1 gene or targeted inhibition of endogenous BRCA1 using small-interfering RNA (siRNA) enhanced GRP78 expression.	SIGNOR-253761	0.2
MCF2L	protein	O15068	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260560	0.74
HTR1D	protein	P28221	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257208	0.252
NDUFC2	protein	O95298	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 	SIGNOR-262174	0.802
lysophosphatidic acid	smallmolecule	CHEBI:132742	ChEBI	LPAR2	protein	Q9HBW0	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257529	0.8
ITCH	protein	Q96J02	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates	ubiquitination			9606									20818436	t		gcesareni	The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation. we demonstrate that the hedgehog transcription factor gli1 is targeted by numb for itch-dependent ubiquitination, which suppresses hedgehog signals, thus arresting growth and promoting cell differentiation	SIGNOR-167838	0.559
CDK5	protein	Q00535	UNIPROT	HTT	protein	P42858	UNIPROT	up-regulates	phosphorylation	Ser1179	LTNPPSLsPIRRKGK	9606	BTO:0000938								17611284	t		lperfetto	Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage.	SIGNOR-156836	0.46
RNF220	protein	Q5VTB9	UNIPROT	SIN3B	protein	O75182	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								20170641	t		miannu	Here we identify RNF220 (RING finger protein 220) as a novel ubiquitin ligase for Sin3B. RNF220 specifically interacts with Sin3B both in vitro and in vivo. Sin3B can be regulated by the ubiquitin-proteasome system. Co-expression of RNF220 promotes the ubiquitination and proteasomal degradation of Sin3B. 	SIGNOR-271943	0.439
SALL4	protein	Q9UJQ4	UNIPROT	ABCA3	protein	Q99758	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21526180	f		miannu	 we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples	SIGNOR-255121	0.286
CASP1	protein	P29466	UNIPROT	NLRP3 inflammasome	complex	SIGNOR-C225	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256409	0.754
TEAD1	protein	P28347	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165;BTO:0000222	BTO:0000887;BTO:0001103;BTO:0001760							20153295	f		lperfetto	We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor.	SIGNOR-235849	0.275
WWTR1	protein	Q9GZV5	UNIPROT	TEAD1	protein	P28347	UNIPROT	up-regulates	binding			9606									23431053	t	YAP/TAZ mainly bind to the transcription factors TEAD1?????_?4 to regulate genes involved in cell proliferation and cell death.	gcesareni	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead1?_?_?4.	SIGNOR-192768	0.862
PTPN22	protein	Q9Y2R2	UNIPROT	LCK	protein	P06239	UNIPROT	down-regulates	dephosphorylation	Tyr394	RLIEDNEyTAREGAK	9606	BTO:0000007								16461343	t		gcesareni	Native ptpn22 dephosphorylated lck at its activating tyrosine residues tyr-394.	SIGNOR-144341	0.741
DNMT3B	protein	Q9UBC3	UNIPROT	IL32	protein	P24001	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000018								20889550	f	 	lperfetto	A virus or dsRNA in human PBMCs from healthy volunteers. We demonstrate that the NF-κB and CREB pathways play key roles in the activation of IL-32 production in response to influenza virus infection in A549 human lung epithelial cells.|Overexpression assays combined with RNA interference show that DNA methyltransferases DNMT1 and DNMT3b are critical for IL32 promoter methylation and gene silencing before viral infection. 	SIGNOR-254127	0.2
DUSP16	protein	Q9BY84	UNIPROT	MTOR	protein	P42345	UNIPROT	down-regulates activity	dephosphorylation			9606									25077541	t		miannu	MKP7 represses mTOR function.|These results suggest that MKP7 could directly dephosphorylate pmTOR and pPRAS40 and forming complexes with these two proteins ( xref ).	SIGNOR-277067	0.278
AKT2	protein	P31751	UNIPROT	PKP1	protein	Q13835	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr189	NRYSFYStCSGQKAI	-1									23444369	t		miannu	Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry.	SIGNOR-273493	0.27
CBL	protein	P22681	UNIPROT	SORBS2	protein	O94875	UNIPROT	down-regulates	ubiquitination			9606									12475393	t		gcesareni	Cbl-argbp2 complex mediates ubiquitination and degradation of c-abl	SIGNOR-96325	0.527
Sumanirole maleate	chemical	CID:9818478	PUBCHEM	DRD2	protein	P14416	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-207594	0.8
ELP1	protein	O95163	UNIPROT	Elongator complex	complex	SIGNOR-C466	SIGNOR	form complex	binding			9606									28601220	t		miannu	Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer.	SIGNOR-269708	0.2
PPP2R1A	protein	P30153	UNIPROT	PP2CA_R1A_R2A 	complex	SIGNOR-C132	SIGNOR	form complex	binding			9606									23454242	t		gcesareni	[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity.	SIGNOR-243427	0.921
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser413	GLMQRSSsFPYTTKG	-1									17711846	t	done	miannu	Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626).	SIGNOR-274098	0.397
GRK2	protein	P25098	UNIPROT	FPR1	protein	P21462	UNIPROT	down-regulates activity	phosphorylation	Thr331	LTEDSTQtSDTATNS	-1									7836371	t		gcesareni	Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation.	SIGNOR-249676	0.2
PTEN	protein	P60484	UNIPROT	ABI1	protein	Q8IZP0	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser216	VPNDYMTsPARLGSQ	9606									32673396	t		lperfetto	After dephosphorylation by PTEN, Abi1 is degraded by calpains.|We demonstrate that PTEN dephosphorylation of Abi1 at Y213 and S216 results in Abi1 degradation through the calpain pathway.	SIGNOR-276949	0.243
TP53BP1	protein	Q12888	UNIPROT	H4C1	protein	P62805	UNIPROT	unknown	binding			9606									17190600	t		gcesareni	Here we demonstrate that this link occurs through direct binding of 53bp1 and crb2 to histone h4.	SIGNOR-151654	0.2
STUB1	protein	Q9UNE7	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. 	SIGNOR-272752	0.431
VRK2	protein	Q86Y07	UNIPROT	BANF1	protein	O75531	UNIPROT	down-regulates	phosphorylation	Ser4	sQKHRDFV	9606									16495336	t		gcesareni	We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell	SIGNOR-144795	0.517
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	KDM5C	protein	P41229	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273468	0.8
TFE3	protein	P19532	UNIPROT	GBA	protein	P04062	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276822	0.2
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1623	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273047	0.556
RPS6KB1	protein	P23443	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser270	EFRPRSKsQSSSNCS	9606		BTO:0000975;BTO:0001760;BTO:0000142							9312143	t		lperfetto	Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites.	SIGNOR-51216	0.781
MAPK1	protein	P28482	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates	phosphorylation	Thr581	PDNQPLKtPCFTLHY	9606									18267068	t		gcesareni	Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth.	SIGNOR-160787	0.6
5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine	chemical	CID:11617559	PUBCHEM	CSF1R	protein	P07333	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258119	0.8
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	TP53	protein	P04637	UNIPROT	down-regulates activity	dephosphorylation	Ser15	PSVEPPLsQETFSDL	9606									16501611	t		lperfetto	Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.	SIGNOR-264670	0.2
SPTAN1	protein	Q13813	UNIPROT	Non-erythrocytic spectrin	complex	SIGNOR-C385	SIGNOR	form complex	binding			9606									24302288	t		lperfetto	Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell	SIGNOR-266026	0.556
SIRT7	protein	Q9NRC8	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	deacetylation	Lys37	APSTGGVkKPHRYRP										30653310	t		lperfetto	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 	SIGNOR-275878	0.2
SLC9A4	protein	Q6AI14	UNIPROT	hydron	chemical	CHEBI:15378	ChEBI	down-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265594	0.8
MAP2K6	protein	P52564	UNIPROT	PAK6	protein	Q9NQU5	UNIPROT	up-regulates	phosphorylation	Tyr566	KSLVGTPyWMAPEVI	9606									15550393	t		llicata	Moreover, pak6 was directly activated by mkk6, and mutation of tyrosine 566 in a consensus mkk6 site (threonine-proline-tyrosine, tpy) in the activation loop of the pak6 kinase domain prevented activation by mkk6.	SIGNOR-130975	0.2
NatA	complex	SIGNOR-C415	SIGNOR	CHEK2	protein	O96017	UNIPROT	down-regulates activity	acetylation			9606	BTO:0001109								21351257	t		miannu	The human protein N(α)-terminal acetyltransferase A complex (hNatA), composed of the catalytic hNaa10p (hArd1) and auxiliary hNaa15p (hNat1/NATH/Tubedown) subunits, was reported to be important for cell survival and growth of various types of cancer.  lack of acetylation by hNatA activated H2A.X and Chk2 in both HCT116 cell lines independent of TP53 status (Fig. 6). 	SIGNOR-267228	0.2
DLAT	protein	P10515	UNIPROT	PDH	complex	SIGNOR-C402	SIGNOR	form complex	binding			9606									20160912	t		miannu	The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently.	SIGNOR-266546	0.85
DYRK1A	protein	Q13627	UNIPROT	DYRK1A	protein	Q13627	UNIPROT	up-regulates activity	phosphorylation	Ser529	SNSGRARsDPTHQHR	9606	BTO:0001938								17229891	t		llicata	In the present study, we show that DYRK1A autophosphorylates, via an intramolecular mechanism, on Ser-520, in the PEST domain of the protein. | Instead, we demonstrate that this phosphorylation allows the binding of 14-3-3beta, which in turn stimulates the catalytic activity of DYRK1A.	SIGNOR-251090	0.2
KCNS3	protein	Q9BQ31	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			10029	BTO:0000246								10484328	t		miannu	We describe the cloning and characterization of the first human members, hKv9.1 and hKv9.3, of the electrically silent delayed-rectifying-like K+ channel subfamily.	SIGNOR-269448	0.8
RBPJ	protein	Q06330	UNIPROT	RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	form complex	binding			9606									21873209	t		lperfetto	When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects.	SIGNOR-209702	0.949
DHODH	protein	Q02127	UNIPROT	orotate	smallmolecule	CHEBI:30839	ChEBI	up-regulates quantity	chemical modification			9606									30449682	t		miannu	OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway	SIGNOR-267433	0.8
EPHA3	protein	P29320	UNIPROT	EPHA3	protein	P29320	UNIPROT	up-regulates activity	phosphorylation	Tyr779	EDDPEAAyTTRGGKI	9606									11870224	t			Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3	SIGNOR-251117	0.2
NF1	protein	P21359	UNIPROT	ADCY6	protein	O43306	UNIPROT	up-regulates				9606	BTO:0000938								24431436	f		miannu	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-204195	0.266
O-phosphoethanolamine	smallmolecule	CHEBI:17553	ChEBI	GABARAP	protein	O95166	UNIPROT	up-regulates	chemical activation			9606									16303767	t		gcesareni	Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme)	SIGNOR-142011	0.8
SNRPD2	protein	P62316	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270636	0.831
PLK1	protein	P53350	UNIPROT	LRRK1	protein	Q38SD2	UNIPROT	up-regulates activity	phosphorylation	Ser1817	GDSIADVsIMYSEEL	9606	BTO:0000567								26192437	t	phosphosite is derived from Fig 2	lperfetto	Here we show that LRRK1 is a PLK1 substrate that is phosphorylated on Ser 1790. PLK1 phosphorylation is required for CDK1-mediated activation of LRRK1 at the centrosomes	SIGNOR-275467	0.351
PTPN11	protein	Q06124	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	dephosphorylation	Tyr740	TGESDGGyMDMSKDE	-1									7545675	t			Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides	SIGNOR-248667	0.739
FOXD2	protein	O60548	UNIPROT	PRKAR1A	protein	P10644	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000661								12621056	t		Luana	Elevating the amounts of FOXD2 expression vector up to 12-fold relative to the RIα1b reporter construct demonstrated that maximal induction of the RIα1b promoter by FOXD2 was at least 5.8-fold	SIGNOR-261605	0.2
NARS1	protein	O43776	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270458	0.8
CKM complex	complex	SIGNOR-C406	SIGNOR	CCNH	protein	P51946	UNIPROT	down-regulates activity	phosphorylation	Ser304	YEDDDYVsKKSKHEE	9606									10993082	t		lperfetto	Cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity	SIGNOR-273141	0.447
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Thr)	smallmolecule	CHEBI:29180	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269497	0.8
LHX3	protein	Q9UBR4	UNIPROT	CGA	protein	P01215	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001379							10931853	t		scontino	Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). P-Lim binds to CBP in TRH-dependent manner on this site and that these proteins synergistically activate the human α-GSU promoter during TRH stimulation. 	SIGNOR-267207	0.397
AKT2	protein	P31751	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser253	APRRRAVsMDNSNKY										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249640	0.742
NFATC2	protein	Q13469	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606	BTO:0000776								11163226	f		scontino	In this study, the roles of NFATc1 and NFATc2 in T and B cells were examined. These results further characterize NFAT as a transcription factor family that plays a critical role in the regulation of lymphocyte effector differentiation.	SIGNOR-270538	0.7
DRAP1	protein	Q14919	UNIPROT	NC2 complex	complex	SIGNOR-C108	SIGNOR	form complex	binding			9606	BTO:0000567								18838386	t		miannu	NC2_ co-fractionated with NC2_ only in the low molecular weight complex (fractions 86–94) and an NC2_ antibody co-immunoprecipitated NC2_ (but not GCN5) in these fractions, which thus contain the classical NC2 complex	SIGNOR-226402	0.775
RBL2	protein	Q08999	UNIPROT	RAD50	protein	Q92878	UNIPROT	up-regulates activity	binding			9606	BTO:0004784								16600870	t		lperfetto	We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells. 	SIGNOR-265029	0.308
GGCX	protein	P38435	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	carboxylation	Glu76	CSFEEAReVFENTER	10090		BTO:0001103							11133752	t		lperfetto	The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.	SIGNOR-263694	0.67
PRKCA	protein	P17252	UNIPROT	TRPM4	protein	Q8TD43	UNIPROT	up-regulates	phosphorylation	Ser1152	SERLKRTsQKVDLAL	9606									15590641	t		gcesareni	Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites.	SIGNOR-132247	0.2
IFIH1	protein	Q9BYX4	UNIPROT	MAVS	protein	Q7Z434	UNIPROT	up-regulates activity	binding			9606									19052324	t		miannu	Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ.	SIGNOR-260140	0.808
PTPRJ	protein	Q12913	UNIPROT	FLT3	protein	P36888	UNIPROT	down-regulates activity	dephosphorylation			9606									21262971	t		miannu	Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro.|The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation.	SIGNOR-277092	0.504
TGFBR1	protein	P36897	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity				9606									19726546	t		lperfetto	Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity.	SIGNOR-227499	0.625
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	precursor of			9606									29084849	t		miannu	Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7.	SIGNOR-268072	0.8
CSNK2A1	protein	P68400	UNIPROT	CCNF	protein	P41002	UNIPROT	down-regulates activity	phosphorylation	Ser621	GYEGDQEsEGEKEGD	9606									29021214	t		miannu	We determined that casein kinase II (CK2) can phosphorylate Ser621 and thereby regulate the E3 ligase activity of the SCF(cyclin F) complex.	SIGNOR-266373	0.252
UNC13B	protein	O14795	UNIPROT	Synaptic_vesicle_exocytosis	phenotype	SIGNOR-PH160	SIGNOR	up-regulates				9606	BTO:0000938								31679900	f		miannu	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle. MUNC13 is proposed to tether synaptic vesicles by bridging between vesicle and plasma membrane via its C2C-domain and C1/C2B-domains	SIGNOR-264386	0.7
CDK5	protein	Q00535	UNIPROT	HTRA2	protein	O43464	UNIPROT	up-regulates	phosphorylation	Ser400	IHKVILGsPAHRAGL	9606									21701498	t		lperfetto	Here we report that cyclin-dependent kinase-5 (cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating htra2 at s400.We have shown previously that phosphomimetic mutants of htra2 at s400 result in increased proteolytic activity and contribute to enhanced resistance to mitochondrial stress	SIGNOR-174598	0.468
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr18	EPPLSQEtFSDLWKL	9606	BTO:0000567								10673501	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-75025	0.784
PIK3CG	protein	P48736	UNIPROT	TPM2	protein	P07951	UNIPROT	up-regulates activity	phosphorylation	Ser61	EDEVEKYsESVKEAQ	-1									16094730	t		miannu	Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization. 	SIGNOR-263028	0.34
CSNK2A1	protein	P68400	UNIPROT	RANGAP1	protein	P46060	UNIPROT	up-regulates	phosphorylation	Ser358	AKVLASLsDDEDEEE	9606									16428860	t		lperfetto	Phosphorylation of rangap1 stabilizes its interaction with ran and ranbp1. Serine-358 (358s) was identified as the major phosphorylation site. Experiments using purified recombinant kinase and specific inhibitors such as drb and apigenin strongly suggest that casein kinase ii (ck2) is the responsible kinase	SIGNOR-143948	0.314
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	GRB10	protein	Q13322	UNIPROT	up-regulates	phosphorylation			9606									15952796	t	inferred from 70% family members	lperfetto	Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation	SIGNOR-270178	0.2
EGFR	protein	P00533	UNIPROT	SPRED1	protein	Q7Z699	UNIPROT	down-regulates activity	phosphorylation	Ser105	KFGLTFQsPADARAF	9606	BTO:0000007								32697994	t		miannu	We show that oncogenic EGFR(L858R) signaling leads to the phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. The structural, biochemical, and biological results provide new mechanistic insights about how SPRED1 interacts with neurofibromin and regulates active KRAS levels in normal and pathologic conditions.	SIGNOR-273638	0.276
CDK1	protein	P06493	UNIPROT	CDC23	protein	Q9UJX2	UNIPROT	up-regulates	phosphorylation	Thr565	NQGETPTtEVPAPFF	9606									14657031	t		lperfetto	Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation	SIGNOR-119821	0.621
bradykinin	smallmolecule	CHEBI:3165	ChEBI	BDKRB1	protein	P46663	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257464	0.8
CDK7	protein	P50613	UNIPROT	CDK11B	protein	P21127	UNIPROT	up-regulates activity	phosphorylation	Thr595	GSPLKAYtPVVVTLW	9606	BTO:0000567								16327805	t		gcesareni	We conclude that CDK7 phsphorylates Cdk11, dependent on the conserved Thr219 residue in the CDK11 T loop, and it is therefore likely to be a genuine Cdk11 activating kinase	SIGNOR-245871	0.34
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser519	SGYSSPGsPGTPGSR	9606	BTO:0000590								12226093	t	The effect has been demonstrated using P10636-8	lperfetto	Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease.	SIGNOR-92603	0.754
CASP8	protein	Q14790	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									14585074	f		amattioni	Downstream of caspase-8 activation, apoptosis induction takes place	SIGNOR-90612	0.7
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	XPO5	protein	Q9HAV4	UNIPROT	down-regulates activity	phosphorylation	Ser416	GFPSKTDsPSCEYSR	9606	BTO:0000007								27846390	t		lperfetto	Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. 	SIGNOR-262980	0.2
SRC	protein	P12931	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates activity	phosphorylation	Tyr188	SFVGTLQyLAPELLE	9606				SIGNOR-C14					12707358	t		lperfetto	These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation.	SIGNOR-100784	0.369
TACR3	protein	P29371	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257438	0.287
LYN	protein	P07948	UNIPROT	LPXN	protein	O60711	UNIPROT	up-regulates activity	phosphorylation	Tyr72	NIQELNVySEAQEPK	9606	BTO:0000007								17640867	t		miannu	Of a total of 11 tyrosine sites in LPXN, we mutated Tyr(22), Tyr(72), Tyr(198), and Tyr(257) to phenylalanine and demonstrated that LPXN was phosphorylated by Lyn only at Tyr(72) and that this tyrosine site is proximal to the LD3 domain. We further show that LPXN suppressed the secretion of interleukin-2 by BCR-activated A20 B cells and that this inhibition was abrogated in the Y72F LPXN mutant, indicating that the phosphorylation of Tyr(72) is critical for the biological function of LPXN.	SIGNOR-262892	0.385
CSNK2A1	protein	P68400	UNIPROT	MYH9	protein	P35579	UNIPROT	up-regulates	phosphorylation	Ser1943	RKGAGDGsDEEVDGK	9606	BTO:0000150								17567956	t		gcesareni	In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)	SIGNOR-155987	0.347
MTSS1	protein	O43312	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates	binding			9606									16280553	t		lperfetto	Mim-b binds and activates rac via its irsp53/mim domain	SIGNOR-141573	0.2
PIM2	protein	Q9P1W9	UNIPROT	PK	proteinfamily	SIGNOR-PF80	SIGNOR	down-regulates activity	phosphorylation			9606	BTO:0000007								24142698	t			Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis	SIGNOR-268148	0.379
IFNW1	protein	P05000	UNIPROT	IFNAR1	protein	P17181	UNIPROT	up-regulates	binding			9606									11278538	t		gcesareni	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-105979	0.719
MLL-AF9	fusion protein	SIGNOR-FP5	SIGNOR	 Core Binding Factor complex	complex	SIGNOR-C214	SIGNOR	down-regulates quantity by repression	transcriptional regulation			9606									24449215	f		miannu	However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. 	SIGNOR-255970	0.2
PRKCB	protein	P05771	UNIPROT	TYR	protein	P14679	UNIPROT	up-regulates	phosphorylation	Ser527	DYHSLYQsHL	9606	BTO:0000848								10347209	t		llicata	We conclude that pkc-beta activates tyrosinase directly by phosphorylating serine residues at positions 505 and 509 in the cytoplasmic domain of this melanosome-associated protein. our results strongly suggest that direct phosphorylation of tyrosinase by pkc-_ leads to its activation.	SIGNOR-67870	0.421
PPP2CA	protein	P67775	UNIPROT	AKT2	protein	P31751	UNIPROT	down-regulates activity	dephosphorylation	Ser474	RTHFPQFsYSASIRE	9606									18160256	t			Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248632	0.736
PRKCB	protein	P05771	UNIPROT	PRKCB	protein	P05771	UNIPROT	unknown	phosphorylation	Ser16	PPSEGEEsTVRFARK	-1									2377895	t		lperfetto	Thus four peptides containing six major sites of intrapeptide autophosphorylation of protein kinase C have been identified. | Phosphoamino acid analyses indicated that only the NH2-terminal peptide contained phosphoserine. The modified residue was determined to be Ser16	SIGNOR-248863	0.2
DOK1	protein	Q99704	UNIPROT	AD/b2 integrin	complex	SIGNOR-C172	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257685	0.301
RPS6KA1	protein	Q15418	UNIPROT	MXD1	protein	Q05195	UNIPROT	down-regulates	phosphorylation	Ser145	IERIRMDsIGSTVSS	9606									18451027	t		lperfetto	In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway	SIGNOR-178586	0.32
MAPK8	protein	P45983	UNIPROT	OSBP2	protein	Q969R2	UNIPROT	up-regulates activity	phosphorylation												30925160	t		lperfetto	CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.	SIGNOR-264876	0.2
MAPK14	protein	Q16539	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606									15879307	t		gcesareni	Conversely, constitutively active mkk6 induced p38 mapk activation that recapitulated the effects of polyphenols by inducing eralpha phosphorylation and downstream activation of akt, and enos. The key role of eralpha ser-118 phosphorylation was confirmed in enos-transfected cos-7 cells	SIGNOR-136950	0.609
RIPK3	protein	Q9Y572	UNIPROT	MLKL	protein	Q8NB16	UNIPROT	up-regulates activity	phosphorylation	Ser358	ELRKTQTsMSLGTTR	-1									24012422	t		gianni	MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays	SIGNOR-266439	0.742
EGFR	protein	P00533	UNIPROT	PIK3C2B	protein	O00750	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000017								10805725	t		gcesareni	The n-terminal region of pi3k-c2beta was found to selectively interact with the egf receptor in vitro, suggesting that it mediates the association of this pi3k with the receptor.	SIGNOR-77195	0.451
MAP3K5	protein	Q99683	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates activity	phosphorylation	Thr813	GDNVLINtYSGVLKI	9606									17937911	t		lperfetto	Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling.	SIGNOR-158423	0.2
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser168	YREPLCLsPASSGSS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248509	0.386
CRX	protein	O43186	UNIPROT	RS1	protein	O15537	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18927113	f		miannu	Our in vitro and in vivo results indicate that two CRE sites in the minimal RS1 promoter region control retinal RS1 expression and establish CRX as a key factor driving this expression.	SIGNOR-253822	0.338
MSH release-inhibiting hormone	smallmolecule	CID:56842142	PUBCHEM	MC3R	protein	P41968	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257537	0.8
TRiC	complex	SIGNOR-C539	SIGNOR	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	up-regulates quantity by stabilization	binding			9606									36185250	t		miannu	Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC).	SIGNOR-272868	0.2
MAP3K1	protein	Q13233	UNIPROT	FADD	protein	Q13158	UNIPROT	down-regulates activity	phosphorylation	Ser194	QNRSGAMsPMSWNSD	9606									15001534	t		gcesareni	The results clearly show that fadd phosphorylation at ser194 affects functions both upstream and downstream of the mekk1/mkk7/jnk1 pathway and is closely associated with chemosensitivity in prostate cancer cells	SIGNOR-123168	0.482
EFNA2	protein	O43921	UNIPROT	EPHA7	protein	Q15375	UNIPROT	up-regulates	binding			9606									9330863	t		gcesareni	The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion.	SIGNOR-52206	0.799
IKBKB	protein	O14920	UNIPROT	DOK1	protein	Q99704	UNIPROT	up-regulates	phosphorylation	Ser450	SHNSALYsQVQKSGA	9606									15574499	t		amattioni	Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility.	SIGNOR-131556	0.255
PRLHR	protein	P49683	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257089	0.278
RNF2	protein	Q99496	UNIPROT	Noncanonical PRC1	complex	SIGNOR-C151	SIGNOR	form complex	binding			10090									25533466	t		miannu	 inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR.	SIGNOR-255277	0.573
tolazoline	chemical	CHEBI:28502	ChEBI	ADRA2B	protein	P18089	UNIPROT	down-regulates activity	chemical inhibition			9606									9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258913	0.8
ARHGAP40	protein	Q5TG30	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260497	0.383
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TBC1D4	protein	O60343	UNIPROT	unknown	phosphorylation	Thr642	QFRRRAHtFSHPPSS	9606									16880201	t		llicata	14-3-3 proteins interact with as160 in an insulin- and akt-dependent manner via an akt phosphorylation site, thr-642.	SIGNOR-148342	0.2
PELP1	protein	Q8IZL8	UNIPROT	NR3C1	protein	P04150	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18682536	t		gcesareni	MNAR functionally interacts with both NH2- and COOH-terminal GR domains to modulate transactivation	SIGNOR-251681	0.534
GNAI3	protein	P08754	UNIPROT	ADCY1	protein	Q08828	UNIPROT	down-regulates	binding			9606									8327893	t		gcesareni	Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required	SIGNOR-38029	0.578
TPH2	protein	Q8IWU9	UNIPROT	5-hydroxy-L-tryptophan	smallmolecule	CHEBI:17780	ChEBI	up-regulates quantity	chemical modification			9606									31024440	t	brain	lperfetto	In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)].	SIGNOR-264012	0.8
ID3	protein	Q02535	UNIPROT	MYOD/E2-2	complex	SIGNOR-C129	SIGNOR	down-regulates activity	binding			10090									9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241155	0.458
CSNK2A1	protein	P68400	UNIPROT	HOXB7	protein	P09629	UNIPROT	down-regulates activity	phosphorylation	Ser133	IYPWMRSsGTDRKRG	10090	BTO:0002882								11290787	t		llicata	Thus, we concluded that CKII can phosphorylate HOXB7 in vitro and that this phosphorylation occurs at both of the CKII target sites, S133 and T204. | Wild-type HOXB7 inhibited the differentiation of 32D cells, whereas mutations in the Pbx-binding pentapeptide motif or the DNA-binding homeodomain, as well as internal deletions of the N-terminal unique region, blocked this effect. Interestingly, mutations eliminating two target sites for casein kinase II, the glutamate-rich C terminus, or the first 14 amino acids of HOXB7, led to enhanced 32D differentiation. 	SIGNOR-250896	0.35
PTPRZ1	protein	P23471	UNIPROT	ARHGAP35	protein	Q9NRY4	UNIPROT	down-regulates activity	dephosphorylation	Tyr1105	RNEEENIySVPHDST	10090	BTO:0000601								16513268	t			Protein tyrosine phosphatase receptor type Z is involved in hippocampus-dependent memory formation through dephosphorylation at Y1105 on p190 RhoGAP| Furthermore, Ptprz selectively dephosphorylated pY1105 of p190 RhoGAP in vitro, and the tyrosine phosphorylation at Y1105 controls p190 RhoGAP activity in vivo.	SIGNOR-248451	0.427
BMP4	protein	P12644	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	up-regulates	binding			9606		BTO:0001253							7673243	t		lperfetto	We have isolated a cdna encoding a novel transmembrane serine/threonine kinase from human skin fibroblasts which we demonstrate here to be a type ii receptor that binds bmp-4. This receptor (brk-3) is distantly related to other known type ii receptors and is distinguished from them by an extremely long carboxyl-terminal sequence following the intracellular kinase domain.	SIGNOR-217535	0.847
CTNND2	protein	Q9UQB3	UNIPROT	CDH5	protein	P33151	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0001109								14610055	t		miannu	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 	SIGNOR-252132	0.321
CHUK	protein	O15111	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	phosphorylation	Ser536	SGDEDFSsIADMDFS	9606	BTO:0000876		SIGNOR-C14	SIGNOR-C13					15611276	t		lperfetto	Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta.	SIGNOR-132568	0.841
PIAS1	protein	O75925	UNIPROT	STAT1	protein	P42224	UNIPROT	down-regulates	binding			9606		BTO:0000887;BTO:0001103							23663276	t		milica	Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna.	SIGNOR-202039	0.786
INSR	protein	P06213	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr589	SHDSEENyVPMNPNL	10090	BTO:0000944								10978177	t			HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin	SIGNOR-251315	0.492
HABP4	protein	Q5JVS0	UNIPROT	MEF2C	protein	Q06413	UNIPROT	down-regulates activity	binding			10116									15862299	t		llicata	MEF2C DNA-binding activity is inhibited through its interaction with the regulatory protein Ki-1/57.	SIGNOR-238283	0.344
P4HB	protein	P07237	UNIPROT	ERN1	protein	O75460	UNIPROT	down-regulates activity	binding												32149426	t		lperfetto	The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity. 	SIGNOR-275573	0.44
MAPK8	protein	P45983	UNIPROT	EIF4ENIF1	protein	Q9NRA8	UNIPROT	up-regulates	phosphorylation	Ser693	ASITSMLsPSFTPTS	9606									22966201	t		llicata	Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress.	SIGNOR-199000	0.329
FLT3	protein	P36888	UNIPROT	PIM1	protein	P11309	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15498859	f			 Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells.	SIGNOR-261519	0.432
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1724	SPSYSPTsPSYSPTS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248743	0.727
GRPR	protein	P30550	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257247	0.271
PTPN1	protein	P18031	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates	dephosphorylation	Tyr1008	LPQDKEYyKVKEPGE	9606									15780598	t		lperfetto	JAK2 and STAT3 are dephosphorylated by PTP1B in vitro	SIGNOR-133852	0.79
HMGB1	protein	P09429	UNIPROT	HOXB1	protein	P14653	UNIPROT	up-regulates activity	binding			-1									8890171	t		miannu	We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.	SIGNOR-219853	0.301
ROCK1	protein	Q13464	UNIPROT	MPRIP	protein	Q6WCQ1	UNIPROT	down-regulates	phosphorylation			9606									17761936	t		gcesareni	Enhanced rho kinase activity induces endothelial barrier dysfunction by a contractile mechanism via inactivation of myosin phosphatase (mp)..	SIGNOR-157593	0.302
PRKACA	protein	P17612	UNIPROT	THOP1	protein	P52888	UNIPROT	up-regulates activity	phosphorylation	Ser643	KVGMDYRsCILRPGG	-1									10969067	t		miannu	PKA phosphorylation is suggested to play a regulatory role in EP24.15 enzyme activity. Mutation analysis of each putative PKA site, in vitro phosphorylation, and phosphopeptide mapping indicated serine 644 as the phosphorylation site. The most dramatic change upon PKA phosphorylation was a substrate-specific, 7-fold increase in both K(m) and k(cat) for GnRH.	SIGNOR-250060	0.311
CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	BHLHE40	protein	O14503	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									19032342	f	 	lperfetto	DEC1 (BHLHB2/Stra13/Sharp2)-a basic helix-loop-helix transcription factor-is known to be involved in various biological phenomena including clock systems and metabolism. In the clock systems, Dec1 expression is dominantly up-regulated by CLOCK : BMAL1 heterodimer, and it exhibits circadian rhythm in the suprachiasmatic nucleus (SCN)-the central circadian pacemaker-and other peripheral tissues.	SIGNOR-253707	0.652
CASP8	protein	Q14790	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	cleavage	Asp326	YDPEMEEdSYDSFGE	-1									10069390	t		lperfetto	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261744	0.338
FES	protein	P07332	UNIPROT	FES	protein	P07332	UNIPROT	up-regulates	phosphorylation	Tyr713	REEADGVyAASGGLR	9606									8663427	t		llicata	Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kda phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. Cnbr cleavage analysis of fes isolated from 32po4-labeled 293t cells showed that tyr-713 and tyr-811 are also autophosphorylated in vivo. . Mutagenesis of tyr-713 reduced both autophosphorylation of tyr-811 and transphosphorylation of bcr, a recently identified fes substrate, supporting a major regulatory role for tyr-713.	SIGNOR-42655	0.2
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270396	0.8
DAPK1	protein	P53355	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates	phosphorylation	Thr119	LSRRLKVtGDLFDIM	9606									19395874	t		gcesareni	We found that DAPk phosphorylates Beclin 1 on T119, a critical residue within its BH3 domain, and thus promotes Beclin 1 dissociation from Bcl-X(L) and autophagy induction. Here we report that T119 phosphorylation also reduces the interaction between Beclin 1 and Bcl-2, in line with the high degree of structural homology between the BH3 binding pockets of Bcl-2 and Bcl-X(L) proteins.	SIGNOR-185589	0.72
RPS6KB1	protein	P23443	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser167	GGRERLAsTNDKGSM	9606									7838153	t		gcesareni	Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii.	SIGNOR-34117	0.583
PRKCA	protein	P17252	UNIPROT	PTGIR	protein	P43119	UNIPROT	unknown	phosphorylation	Ser328	TPLSQLAsGRRDPRA	9606	BTO:0000007								9722557	t		lperfetto	These results indicate that PKC-dependent phosphorylation is of critical importance to homologous regulation of hIP. Ser-328 is a primary site for PKC phosphorylation of hIP.	SIGNOR-249011	0.328
MTOR	protein	P42345	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	up-regulates activity	phosphorylation	Ser370	TRQTPVDsPDDTALS	-1									11733037	t		miannu	In vitro phosphorylation and activation of p70β by mTOR and PDK1. replacement of Ser383 to Gly (S383G) reduced but still retained nearly half of the kinase activity of the wild-type.	SIGNOR-250293	0.831
SRC	protein	P12931	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr397	SVSETDDyAEIIDEE	9606									15735019	t		miannu	Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates	SIGNOR-150476	0.633
JAK2	protein	O60674	UNIPROT	STAP2	protein	Q9UGK3	UNIPROT	up-regulates activity	phosphorylation	Tyr250	PFLLDEDyEKVLGYV		BTO:0000007								12540842	t		lperfetto	To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 80€“60% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2.	SIGNOR-249371	0.349
GRK6	protein	P43250	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser373	SMGTLRTsISVERQI	9606	BTO:0000007								11517230	t			Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251205	0.292
SH3RF1	protein	Q7Z6J0	UNIPROT	MAP3K12	protein	Q12852	UNIPROT	up-regulates	binding			9606	BTO:0000938								11416147	t		gcesareni	One explanation as provided by our model is that mlk3 and dlk interact indirectly via posh with mutual activation when both are wild-type the multidomain protein posh binds to the constitutively active form of rac1, which is known to regulate the activity of mlks, while jip1 binds to mlks and additional components of the jnk pathway and appears to be capable of activating mlks	SIGNOR-108577	0.384
TP53	protein	P04637	UNIPROT	AIFM2	protein	Q9BRQ8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12135761	t		miannu	The p53 tumor suppressor protein induces cell cycle arrest or apoptosis in response to cellular stresses. We have identified PRG3 (p53-responsive gene 3), which is induced specifically under p53-dependent apoptotic conditions in human colon cancer cells, and encodes a novel polypeptide of 373 amino acids with a predicted molecular mass of 40.5 kDa. these results support the hypothesis that the expression of the PRG3 gene in cells undergoing p53‐dependent apoptosis involves direct activation of its promoter by p53.	SIGNOR-261808	0.482
JAK2	protein	O60674	UNIPROT	IFNGR1	protein	P15260	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000801								23898330	t		lperfetto	In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation	SIGNOR-249490	0.703
KLF3	protein	P57682	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates	transcriptional regulation			9606									18391014	f		fspada	We find that c/ebpalpha is derepressed in klf3 and ctbp knockout fibroblasts and adipocytes from klf3 knockout mice.	SIGNOR-210117	0.305
HAX1	protein	O00165	UNIPROT	ATP2A2	protein	P16615	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18971376	f	 	miannu	 HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels.	SIGNOR-254222	0.38
CAMK2A	protein	Q9UQM7	UNIPROT	HOMER3	protein	Q9NSC5	UNIPROT	down-regulates activity	phosphorylation	Ser176	ERLKKMLsEGSVGEV	-1									18480293	t		miannu	Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation	SIGNOR-262686	0.2
phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	pyruvate	smallmolecule	CHEBI:15361	ChEBI	up-regulates quantity	precursor of			9606									15996096	t		miannu	Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A).	SIGNOR-266532	0.8
IFNG	protein	P01579	UNIPROT	RIPK2	protein	O43353	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18647246	f		miannu	NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B.	SIGNOR-252410	0.286
HACD	proteinfamily	SIGNOR-PF86	SIGNOR	ELOVL	proteinfamily	SIGNOR-PF93	SIGNOR	up-regulates activity	binding												18554506	t		miannu	Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle.	SIGNOR-267915	0.2
SLRP 	proteinfamily	SIGNOR-PF31	SIGNOR	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									21949456	t			Proteoglycans are ubiquitous in connective tissue, and muscle ECM is no exception. A number of PGsare present in muscle ECM, and many belong to the family of small leucine-rich proteoglycans (SLRPs).	SIGNOR-255345	0.7
pipamperone	chemical	CHEBI:78549	ChEBI	HTR1B	protein	P28222	UNIPROT	down-regulates activity	chemical inhibition			10116		BTO:0001311							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258573	0.8
ACACB	protein	O00763	UNIPROT	malonyl-CoA	smallmolecule	CHEBI:15531	ChEBI	up-regulates quantity	chemical modification			9606									20952656	t		miannu	ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA	SIGNOR-267110	0.8
PRKCZ	protein	Q05513	UNIPROT	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation	Ser840	VRSAFTTsTVVRMHV	-1									15894802	t		lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249284	0.377
RPS6KB1	protein	P23443	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser527	RFRKRTHsAGTSPTI	9606	BTO:0000007								16914728	t		lperfetto	Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites.	SIGNOR-148903	0.781
IRX1	protein	P78414	UNIPROT	EGR1	protein	P18146	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002392								20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 	SIGNOR-261661	0.2
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1672	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273071	0.636
acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	malonyl-CoA	smallmolecule	CHEBI:15531	ChEBI	up-regulates quantity	precursor of			9606									20952656	t		miannu	ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA	SIGNOR-267108	0.8
GATA3	protein	P23771	UNIPROT	CEBPB	protein	P17676	UNIPROT	down-regulates	binding			10090									15632071	t		fspada	In the present study, we demonstrate that both gata-2 and gata-3 form protein complexes with ccaat/enhancer binding protein alpha (c/ebpalpha) and c/ebpbeta, members of a family of transcription factors that are integral to adipogenesis. []the interaction between gata and c/ebp factors is critical for the ability of gata to suppress adipocyte differentiation.	SIGNOR-132952	0.36
ABL1	protein	P00519	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Tyr219	SIQGHNDyMCPATNQ	9606	BTO:0000150								20101225	t		gcesareni	Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes.	SIGNOR-163562	0.459
GPT2	protein	Q8TD30	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	chemical modification			9606									11863375	t			Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2	SIGNOR-266925	0.8
adapalene	chemical	CHEBI:31174	ChEBI	RARB	protein	P10826	UNIPROT	up-regulates activity	chemical activation			9606		BTO:0000404							30836068	t		miannu	Adapalene, the third-generation synthetic retinoid,selectively bound to specific RAR, thus activating genes responsible forcellular differentiation. It showed greatest affinity for subtypes RARβindermalfibroblasts (Kd value 34 nM) and RARγin the epidermis (Kdvalue 130 nM)	SIGNOR-258487	0.8
LPCAT1	protein	Q8NF37	UNIPROT	1,2-diacyl-sn-glycero-3-phosphocholine	chemical	CHEBI:57643	ChEBI	up-regulates quantity	chemical modification			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272760	0.8
MET-enkephalin	smallmolecule	CHEBI:6618	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257554	0.8
SEMA3B	protein	Q13214	UNIPROT	NRP1	protein	O14786	UNIPROT	up-regulates activity	binding			9606									25335892	t		miannu	Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction.	SIGNOR-261814	0.748
GDF6	protein	Q6KF10	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	up-regulates	binding			9606									16049014	t		lperfetto	We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins.	SIGNOR-217526	0.595
PDPK1	protein	O15530	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Thr308	KDGATMKtFCGTPEY	9606	BTO:0000567								15718470	t		gcesareni	Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase.	SIGNOR-252612	0.736
MAPK1	protein	P28482	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates	phosphorylation	Ser360	TEMDPTYsPAALPQS	9606									9687510	t		gcesareni	Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth.	SIGNOR-59435	0.6
AIMP1	protein	Q12904	UNIPROT	SMURF2	protein	Q9HAU4	UNIPROT	up-regulates activity	binding			9606									18448069	t		lperfetto	Here, we report that AIMP1 negatively regulates TGF-_ signaling via stabilization of Smurf2.	SIGNOR-227470	0.399
TWIST1	protein	Q15672	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255511	0.294
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser315	LPNNTSSsPQPKKKP	10116	BTO:0001009								12064478	t		llicata	 the present study it is shown that in apoptotic PC12 cells the levels of p53 and Cdk5 increase concomitantly. Further, Cdk5/p25 effectively phosphorylates recombinant p53 in vitro. Transient transfection of Cdk5/p25 into cells results in an increase in p53 levels, as well as the expression of the p53-responsive genes p21 and Bax. Furthermore, evidence is provided that increased Cdk5 activity increases p53 transcriptional activity significantly, suggesting that p53 is modulated in situ by Cdk5. 	SIGNOR-250674	0.57
ethanol	chemical	CHEBI:16236	ChEBI	GlyR	proteinfamily	SIGNOR-PF62	SIGNOR	up-regulates activity	chemical activation			8355	BTO:0000964								8700149	t	inferred from family member	miannu	Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations.	SIGNOR-267794	0.8
PRKAA1	protein	Q13131	UNIPROT	PFKFB3	protein	Q16875	UNIPROT	up-regulates	phosphorylation	Ser461	NPLMRRNsVTPLASP	9606	BTO:0000876	BTO:0000671	SIGNOR-C15						12065600	t		llicata	Ipfk-2 was phosphorylated on the homologous serine (ser-461) and activated by ampk in vitro.	SIGNOR-89760	0.384
afimoxifene	chemical	CHEBI:44616	ChEBI	ESR1	protein	P03372	UNIPROT	down-regulates activity	chemical inhibition			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258595	0.8
CSNK2A1	protein	P68400	UNIPROT	IKZF1	protein	Q13422	UNIPROT	down-regulates	phosphorylation	Thr23	ESPPVSDtPDEGDEP	9606	BTO:0001271								21750978	t		miannu	We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo	SIGNOR-174836	0.294
KDM6A	protein	O15550	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	demethylation	Lys28	LATKAARkSAPATGG	9606									24561908	t	This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions.	miannu	Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation.	SIGNOR-260017	0.2
PHLPP1	protein	O60346	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates	binding			9606									23431053	t		gcesareni	Here, we report that phlpp1 is a binding protein for mst1 and it modulates the hippo pathway by dephosphorylating mst1 at the inhibitory thr(387) of mst1.	SIGNOR-201262	0.3
7alpha,25-dihydroxycholesterol	smallmolecule	CHEBI:37623	ChEBI	GPR183	protein	P32249	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257504	0.8
4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide	chemical	CHEBI:94506	ChEBI	CCNE1	protein	P24864	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193543	0.8
MAPK1	protein	P28482	UNIPROT	RUNX1	protein	Q01196	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser276	VHPATPIsPGRASGM	9606	BTO:0002181								16046550	t		miannu	We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 	SIGNOR-268221	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MAP3K11	protein	Q16584	UNIPROT	down-regulates	phosphorylation	Ser674	PGRERGEsPTTPPTP	9606	BTO:0000938								12458207	t		lperfetto	Negative regulation of mixed lineage kinase 3 by protein kinase b/akt leads to cell survivalthe expression of activated akt1 inhibits mlk3-mediated cell death in a manner dependent on serine 674 phosphorylation.	SIGNOR-96062	0.2
(S)-adrenaline	smallmolecule	CHEBI:40751	ChEBI	ADRA1A	protein	P35348	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258454	0.8
HIVEP2	protein	P31629	UNIPROT	SSTR2	protein	P30874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001976								10207097	t		Luana	Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain.	SIGNOR-261617	0.423
HBB	protein	P68871	UNIPROT	APOB	protein	P04114	UNIPROT	up-regulates quantity by stabilization				9606									8611031	f	Regulation of binding	miannu	Hemoglobin induced apolipoprotein B crosslinking in low-density lipoprotein peroxidation. Crosslinked apo B was shown to resist lysosomal degradation, thereby causing accumulation of oxidized LDL in macrophages	SIGNOR-251754	0.279
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	GSK3A	protein	P49840	UNIPROT	down-regulates	phosphorylation	Ser21	SGRARTSsFAEPGGG	9606									11035810	t		gcesareni	In response to insulin, gsk3a inhibited by phosphorylation at ser-21 by pkb/akt1;phosphorylation at this site causes a conformational change, preventing access of substrates to the active site.	SIGNOR-83217	0.2
FCN2	protein	Q15485	UNIPROT	MASP2	protein	O00187	UNIPROT	up-regulates activity	binding												17204478	t		lperfetto	 In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2)	SIGNOR-263413	0.628
α-Catenin	proteinfamily	SIGNOR-PF72	SIGNOR	JUP	protein	P14923	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000586								21598020	t		miannu	Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14	SIGNOR-265819	0.2
CDK5	protein	Q00535	UNIPROT	NES	protein	P48681	UNIPROT	unknown	phosphorylation	Thr315	AENSRLQtPGGGSKT	10090	BTO:0000165								12832492	t		llicata	We identify nestin as a novel in vivo target for cdk5 and p35 kinase, a critical signaling determinant in development. Two cdk5-specific phosphorylation sites on nestin, Thr-1495 and Thr-316, were established, the latter of which was used as a marker for cdk5-specific phosphorylation in vivo. | Cdk5 activity is necessary for differentiation and the concomitant nestin reorganization in C2C12 myoblasts.	SIGNOR-250670	0.564
RNF146	protein	Q9NTX7	UNIPROT	CASC3	protein	O15234	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									21478859	t		lperfetto	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 	SIGNOR-263339	0.266
HACD	proteinfamily	SIGNOR-PF86	SIGNOR	very long-chain 2,3-trans-enoyl CoA(4-)	smallmolecule	CHEBI:83728	ChEBI	up-regulates quantity	chemical modification			9606									18554507	t		miannu	Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle.	SIGNOR-267918	0.8
CDKN2A	protein	P42771	UNIPROT	CDK6	protein	Q00534	UNIPROT	down-regulates	binding			9606									8891723	t		miannu	The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb.	SIGNOR-44557	0.866
PTPN22	protein	Q9Y2R2	UNIPROT	CD247	protein	P20963	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000007								16461343	t		amattioni	T cell signaling is negatively regulated by the activity of protein-tyrosine phosphatases. Native ptpn22 dephosphorylated tcrzeta in vitro and in cells.	SIGNOR-144337	0.458
NEDD4L	protein	Q96PU5	UNIPROT	NF2	protein	P35240	UNIPROT	up-regulates activity	ubiquitination	Lys396	QITEEEAkLLAQKAA	9606									33058421	t		miannu	Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2-patient-derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1-NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti-mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control.	SIGNOR-263662	0.264
Unfolded_Proteins	stimulus	SIGNOR-ST22	SIGNOR	ERP44	protein	Q9BS26	UNIPROT	up-regulates				9606									11847130	f		miannu	Like many ER folding factors, ERp44 transcripts are induced by agents that cause the accumulation of unfolded proteins in the ER.	SIGNOR-261047	0.7
CDK1	protein	P06493	UNIPROT	TSC1	protein	Q92574	UNIPROT	unknown	phosphorylation	Thr1047	SSSSELStPEKPPHQ	9606	BTO:0000680;BTO:0001573;BTO:0001286								14551205	t		llicata	In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain.	SIGNOR-117339	0.503
CTDSP1	protein	Q9GZU7	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	dephosphorylation			9606									16882717	t		lpetrilli	In human cells, rnai-mediated depletion of scp1 and scp2 increases the extent and duration of smad1 phosphorylation in response to bmp, the transcriptional action of smad1, and the strength of endogenous bmp gene responses. The present identification of the scp family as smad c-terminal phosphatases sheds light on the events that attenuate smad signaling and reveals unexpected links to the essential phosphatases that control rna polymerase ii in eukaryotes.	SIGNOR-148396	0.476
SHANK1	protein	Q9Y566	UNIPROT	ACTN1	protein	P12814	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264583	0.277
KCNIP4	protein	Q6PIL6	UNIPROT	KCND2	protein	Q9NZV8	UNIPROT	up-regulates activity	relocalization			8355	BTO:0000964								24811166	t		Luisa	KChIP4 increased the current amplitude of Kv4.2, decelerated the inactivation, and accelerated the recovery from inactivation of Kv4.2. KChIP.is known to promote the translocation of Kv4.2 from the endoplasmic reticulum or Golgi to the cell surface 	SIGNOR-269004	0.765
TERF2	protein	Q15554	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	down-regulates				10116									27117401	f		miannu	During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes.	SIGNOR-266805	0.7
C1S	protein	P09871	UNIPROT	Complement C1 complex	complex	SIGNOR-C309	SIGNOR	form complex	binding			-1									29449492	t		lperfetto	The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases	SIGNOR-263394	0.692
MCF2	protein	P10911	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260556	0.744
CSNK2A1	protein	P68400	UNIPROT	NOL3	protein	O60936	UNIPROT	up-regulates activity	phosphorylation	Thr149	SEAVQSGtPEEPEPE	9606	BTO:0000007								12191471	t		miannu	Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm.	SIGNOR-262837	0.328
NFATC2	protein	Q13469	UNIPROT	IL4	protein	P05112	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								11956291	f			IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production	SIGNOR-254502	0.525
PDPK2P	protein	Q6A1A2	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	phosphorylation			9606									15505410	t		gcesareni	Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (pdk) 1 and pdk2.	SIGNOR-129965	0.2
PRKCE	protein	Q02156	UNIPROT	RAB11A	protein	P62491	UNIPROT	unknown	phosphorylation	Ser177	TEIYRIVsQKQMSDR	-1									22188018	t		miannu	 This report shows for the first time that Rab11 is differentially phosphorylated by distinct PKC isoenzymes and that this post-translational modification might be a regulatory mechanism of intracellular trafficking.Our results demonstrate that classical PKC (PKCα and PKCβII but not PKCβI) directly phosphorylate Rab11 in vitro. In addition, novel PKCε and PKCη but not PKCδ isoenzymes also phosphorylate Rab11. Mass spectrometry analysis revealed that Ser 177 is the Rab11 residue to be phosphorylated in vitro by either PKCβII or PKCε. 	SIGNOR-263170	0.273
CUL9	protein	Q8IWT3	UNIPROT	FERMT1	protein	Q9BQL6	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								35469017	t		miannu	M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2.	SIGNOR-276718	0.2
SIK2	protein	Q9H0K1	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates quantity	phosphorylation	Ser794	QHLRLSTsSGRLLYA										24841198	t		lperfetto	SIK2 is known to attenuate insulin signaling by phosphorylating IRS-1/Ser789	SIGNOR-265745	0.586
NF1	protein	P21359	UNIPROT	Adenylate_cyclase	proteinfamily	SIGNOR-PF92	SIGNOR	up-regulates				9606	BTO:0000938								24431436	f		miannu	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-267847	0.409
RPS6KA5	protein	O75582	UNIPROT	RPS6KA5	protein	O75582	UNIPROT	up-regulates activity	phosphorylation	Ser381	GYSFVAPsILFKRNA	9606									15568999	t		lperfetto	Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro.	SIGNOR-131395	0.2
TUBGCP3	protein	Q96CW5	UNIPROT	g-TuRC complex	complex	SIGNOR-C282	SIGNOR	form complex	binding			-1									31862189	t		lperfetto	Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.”	SIGNOR-262327	0.771
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Ser1044	YPFVRTGsPRRIQLS	9606									11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. site-directed mutagenesis of s1044 to an alanine resulted in the specific loss of d5 when this mutant was ectopically expressed in t98g cells and labelled by [32p]orthophosphate (figure 4b), proving that phosphorylation of s1044 gave rise to the tryptic phosphopeptide d5: tgspr.	SIGNOR-104660	0.843
CDK9	protein	P50750	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser195	PNSSYPNsPGSSSST	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161569	0.325
PLK1	protein	P53350	UNIPROT	OPTN	protein	Q96CV9	UNIPROT	up-regulates	phosphorylation	Ser177	SSGSSEDsFVEIRMA	9606									22365832	t		lperfetto	Here we show that at mitotic entry, plk1 phosphorylates optineurin (optn) at serine 177 and that this dissociates optn from the golgi-localized gtpase rab8, inducing its translocation into the nucleus.	SIGNOR-196367	0.52
EGLN3	protein	Q9H6Z9	UNIPROT	ADRB2	protein	P07550	UNIPROT	up-regulates quantity by stabilization	hydroxylation	Pro395	VGHQGTVpSDNIDSQ	9606	BTO:0000007								19584355	t		lperfetto	We further show that the interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. Under hypoxic conditions, receptor hydroxylation and subsequent ubiquitylation decrease dramatically, thus attenuating receptor degradation and down-regulation.	SIGNOR-262007	0.323
EFNA1	protein	P20827	UNIPROT	EPHA1	protein	P21709	UNIPROT	up-regulates	binding			9606									9330863	t		gcesareni	The eph family receptors and ligands.	SIGNOR-51932	0.825
SP3	protein	Q02447	UNIPROT	KLK3	protein	P07288	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001033								15708372	t	 	 	We characterized four Sp1/Sp3 binding sites in the proximal promoter of the PSA gene. In a luciferase assay, these sites contributed to the basal promoter activity in prostate cancer cells. In an electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we confirmed that Sp1 and Sp3 bind to these sites. Overexpression of wild-type Sp1 and Sp3 further upregulated the promoter activity, whereas overexpression of the Sp1 dominant-negative form or addition of mithramycin A significantly reduced the promoter activity and the endogenous mRNA level of PSA.	SIGNOR-253665	0.2
PRKCA	protein	P17252	UNIPROT	MBD4	protein	O95243	UNIPROT	up-regulates activity	phosphorylation	Ser262	SGFVQSDsKRESVCN										23195996	t		lperfetto	 Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12]	SIGNOR-275672	0.2
PPM1A	protein	P35813	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation			9606									16751101	t		lperfetto	Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.	SIGNOR-217628	0.655
EGFR	protein	P00533	UNIPROT	NCK2	protein	O43639	UNIPROT	up-regulates	binding			9606									10026169	t		esanto	Growth factor binding to receptor protein tyrosine kinases (r-ptks)1 induces their dimerization and trans-phosphorylation, creating docking sites for proteins containing sh2 and ptb protein interaction domains. Nck binds to the pdgf and egfr receptors (figure 3c).	SIGNOR-64731	0.408
PRKCA	protein	P17252	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Ser295	FKLGGRDsRSGSPMA	-1									2413024	t		lperfetto	MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 	SIGNOR-248875	0.503
CDC14B	protein	O60729	UNIPROT	USP9X	protein	Q93008	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser2547	YEGSEEVsPPQTKDQ										32152317	t	Phosphosites were derived from Figure S1	lperfetto	Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. 	SIGNOR-275613	0.2
R547	chemical	CID:6918852	PUBCHEM	CCNB1	protein	P14635	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206349	0.8
UNC5	proteinfamily	SIGNOR-PF98	SIGNOR	DCC	protein	P43146	UNIPROT	down-regulates activity	binding			9606		BTO:0001484							25881791	t		miannu	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268168	0.2
BLOC-1	complex	SIGNOR-C381	SIGNOR	serotonin	smallmolecule	CHEBI:28790	ChEBI	up-regulates quantity	relocalization			9606									23805129	t		lperfetto	The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules 	SIGNOR-265999	0.8
CDK5	protein	Q00535	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	phosphorylation	Thr212	VIEPLPVtPTRDVAT	9534	BTO:0004055								11604394	t		lperfetto	Our previous work revealed that the neuronal p35/Cdk5 kinase associates with Pak1 in a RacGTP-dependent manner, causing hyperphosphorylation and down-regulation of Pak1 kinase activity. We have now demonstrated direct phosphorylation of Pak1 on threonine 212 by the p35/Cdk5 kinase.	SIGNOR-249328	0.519
GSK3B	protein	P49841	UNIPROT	BCL2L12	protein	Q9HB09	UNIPROT	up-regulates	phosphorylation	Ser156	SESPRPCsLPIRPCY	9606	BTO:0000527								22262180	t		lperfetto	Gsk3b phosphorylates bcl2l12 at s156. Ectopic expression of gfp-fused bcl2l12 or bcl2l12a in u87mg cells leads to repression of apoptotic markers and protects against staurosporine (sts) insults, indicating an antiapoptotic role for both bcl2l12 and bcl2l12a. In contrast, no anti-apoptotic ability was seen in bcl2l12(s156a)	SIGNOR-195512	0.346
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation			9606		BTO:0001103							21798082	t		lperfetto	Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b).	SIGNOR-252841	0.908
LRP6	protein	O75581	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	relocalization			9606									16890161	t		amattioni	The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism.	SIGNOR-148668	0.829
NR1I3	protein	Q14994	UNIPROT	UGT1A1	protein	P22309	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18172616	f	 	miannu	 This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities.	SIGNOR-254438	0.459
SSH1	protein	Q8WYL5	UNIPROT	CORO1B	protein	Q9BR76	UNIPROT	up-regulates activity	dephosphorylation	Ser2	sFRKVVRQ	9606									17350576	t			Coronin 1B inhibits filament nucleation by Arp2/3 complex and this inhibition is attenuated by phosphorylation of Coronin 1B at Serine 2, a site targeted by SSH1L. Coronin 1B also directs SSH1L to lamellipodia where SSH1L likely regulates Cofilin activity via dephosphorylation	SIGNOR-248763	0.458
MRAP2	protein	Q96G30	UNIPROT	MC3R	protein	P41968	UNIPROT	down-regulates activity	binding			10029	BTO:0000246								19329486	t		miannu	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252367	0.52
TLN1	protein	Q9Y490	UNIPROT	A10/b1 integrin	complex	SIGNOR-C167	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257616	0.576
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270415	0.8
PAK2	protein	Q13177	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates activity	phosphorylation	Ser73	SAVRLRSsVPGVRLL	-1									11895474	t		miannu	In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK. 	SIGNOR-250243	0.311
PIAS1	protein	O75925	UNIPROT	RPA2	protein	P15927	UNIPROT	up-regulates	sumoylation			9606									20016603	t		gcesareni	Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair	SIGNOR-162153	0.2
CKM complex	complex	SIGNOR-C406	SIGNOR	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation			-1									25344755	t		lperfetto	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273158	0.379
PRKCA	protein	P17252	UNIPROT	ADD1	protein	P35611	UNIPROT	up-regulates	phosphorylation	Ser726	KKKFRTPsFLKKSKK	9606									8810272	t		gcesareni	These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc.	SIGNOR-43744	0.2
HSP90AB1	protein	P08238	UNIPROT	FLCN	protein	Q8NFG4	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								27353360	t		miannu	Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. 	SIGNOR-261417	0.2
AKT2	protein	P31751	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates activity	phosphorylation	Ser186	RQRKRHKsDSISLSF	9606	BTO:0000093								11504915	t		lperfetto	Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.. Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186.	SIGNOR-109736	0.542
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2M	protein	P61081	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271366	0.689
MMP13	protein	P45452	UNIPROT	FGB	protein	P02675	UNIPROT	down-regulates quantity by destabilization	cleavage	Arg124	LQQERPIrNSVDELN	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain 	SIGNOR-263615	0.2
PLCB2	protein	Q00722	UNIPROT	superoxide	smallmolecule	CHEBI:18421	ChEBI	up-regulates quantity													23994464	f		apalma	The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release	SIGNOR-255013	0.8
KASH5	protein	Q8N6L0	UNIPROT	LINC complex	complex	SIGNOR-C303	SIGNOR	form complex	binding												24481844	t		lperfetto	LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM.	SIGNOR-263290	0.2
MAPK8	protein	P45983	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									7737130	t		gcesareni	Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro.	SIGNOR-32421	0.772
Anthra[2,1-d]thiazol-2-ylamine	chemical	CID:90872293	PUBCHEM	KCNN1	protein	Q92952	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								18955585	t		Luana	Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. 	SIGNOR-258023	0.8
KAT2B	protein	Q92831	UNIPROT	H3Y1	protein	P0DPK2	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkATAWQAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269614	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	HOMER	proteinfamily	SIGNOR-PF59	SIGNOR	down-regulates activity	phosphorylation			-1									18480293	t		miannu	Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation	SIGNOR-264699	0.405
SP1	protein	P08047	UNIPROT	GGH	protein	Q92820	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									31739835	t		miannu	Overexpression of Sp1 led to enhanced GGH promoter activity and GGH mRNA expression in allele-specific manners. These findings suggested that Sp1 acted as a positive regulator of human GGH transcription through the rs3758149 polymorphism in CEM/C1 cells.	SIGNOR-261350	0.2
MYF5	protein	P13349	UNIPROT	DES	protein	P17661	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								8382796	t		lperfetto	Desmin, the muscle specific intermediate filament (IF) protein, is expressed at low levels in myoblasts and at the onset of differentiation its expression increases several fold. In an effort to explore the mechanism involved in the tissue-specific and developmentally regulated expression of desmin, we have isolated the mouse desmin gene.Co-transfection of myoD, myogenin, MRF4 and Myf5, with the desmin-CAT construct into 10T-1/2 cells demonstrated that all these factors could transactivate desmin gene expression	SIGNOR-241494	0.243
MLL3 complex	complex	SIGNOR-C446	SIGNOR	H3C1	protein	P68431	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606									34156443	t		miannu	MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. 	SIGNOR-268810	0.2
LATS2	protein	Q9NRM7	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates activity	phosphorylation	Thr178	VYHYRINtASDGKLY	-1									23852372	t		miannu	 Inhibition of c-Abl by Lats2 was mediated through Lats2 interaction with and phosphorylation of c-Abl.  Lats2 phosphorylates c-Abl at Thr197 in vitro.	SIGNOR-276497	0.369
MAP3K6	protein	O95382	UNIPROT	MAP3K6	protein	O95382	UNIPROT	up-regulates activity	phosphorylation	Thr806	GITPCTEtFTGTLQY	9606									17210579	t		Manara	These results suggested that the induction of ASK2 phosphorylation in the presence of ASK1 is the consequence of autophosphorylation of ASK2. ASK1 thus appears to not only support the effective protein expression but also confer the kinase activity to ASK2.	SIGNOR-260774	0.2
TLN1	protein	Q9Y490	UNIPROT	Av/b2 integrin	complex	SIGNOR-C176	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257622	0.64
FILIP1L	protein	Q4L180	UNIPROT	FLNC	protein	Q14315	UNIPROT	down-regulates quantity by destabilization	binding			10090	BTO:0000165								32444788	t		miannu	We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells.	SIGNOR-262618	0.254
tRNA(Pro)	smallmolecule	CHEBI:29177	ChEBI	Pro-tRNA(Pro)	smallmolecule	CHEBI:29154	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270433	0.8
DOCK3	protein	Q8IZD9	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260548	0.642
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	METTL1	protein	Q9UBP6	UNIPROT	down-regulates	phosphorylation	Ser27	YYRQRAHsNPMADHT	9606	BTO:0000007;BTO:0000567								15861136	t		gcesareni	Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro.	SIGNOR-252800	0.2
FHL2	protein	Q14192	UNIPROT	SPHK1	protein	Q9NYA1	UNIPROT	down-regulates activity	binding			10090		BTO:0000562							16888242	t		llicata	FHL2/SLIM3 decreases cardiomyocyte survival by inhibitory interaction with sphingosine kinase-1.	SIGNOR-237775	0.433
TIP-LINK complex	complex	SIGNOR-C291	SIGNOR	LHFPL5	protein	Q8TAF8	UNIPROT	up-regulates activity	binding			10090		BTO:0000630							23217710	t		lperfetto	 We conclude that the transmembrane and membrane proximal CR domain of PCDH15 mediate interaction with TMHS.|Based on the interdependence of PCDH15 and TMHS for their efficient localization to stereocilia, we reasoned that interaction between the two proteins might regulate their effective cell surface transport.	SIGNOR-262580	0.417
RET	protein	P07949	UNIPROT	ATF4	protein	P18848	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr115	MPDDLLTtLDDTCDL	9606	BTO:0002181								25795775	t		miannu	We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA. 	SIGNOR-276447	0.2
tadalafil	chemical	CHEBI:71940	ChEBI	PDE11A	protein	Q9HCR9	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000815								21189023	t		Luana	All of the final compounds and intermediates synthesized were screened for in vitro tumor cell growth inhibition activity using the human MDA-MB-231 breast tumor cell line and for inhibition of recombinant human PDE5 at a single concentration of 10 μM. For compounds showing >60% inhibition, the IC50 was determined by testing a range of eight concentrations with quadruple replicates per concentration, tadalafil used as a positive control.| Conversely, tadalafil possessed a selectivity index of just 16.6 for PDE5 versus PDE11	SIGNOR-257888	0.8
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2K	protein	P61086	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271367	0.749
EGR1	protein	P18146	UNIPROT	Monocyte_differentiation 	phenotype	SIGNOR-PH101	SIGNOR	up-regulates				9606	BTO:0001412								1864967	f		irozzo	Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression. Taken together, the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes.	SIGNOR-256088	0.7
CDK1	protein	P06493	UNIPROT	KIF11	protein	P52732	UNIPROT	up-regulates	phosphorylation	Thr926	LDIPTGTtPQRKSYL	9606									9235942	t		lperfetto	The kinesin-related motor hseg5 is essential for centrosome separation, and its association with centrosomes appears to be regulated by phosphorylation of tail residue threonine 927 by the p34(cdc2) protein kinase.Phosphorylation also enhanced the specific binding of p150(glued) to the tail domain of hseg5 in vitro	SIGNOR-50169	0.658
PTPRC	protein	P08575	UNIPROT	LYN	protein	P07948	UNIPROT	down-regulates activity	dephosphorylation	Tyr397	RVIEDNEyTAREGAK	10090	BTO:0000776								10415030	t			CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)	SIGNOR-248353	0.651
GNGT1	protein	P63211	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606									12507995	t		gcesareni	Therefore, we conclude that in vivo, g beta gamma activates pi3k gamma by a mechanism assigning specific roles for both pi3k gamma subunits, i.e., membrane recruitment is mediated via the noncatalytic p101 subunit, and direct stimulation of g beta gamma with p110 gamma contributes to activation of pi3k gamma.	SIGNOR-96831	0.465
RAB21	protein	Q9UL25	UNIPROT	Early Endosome	complex	SIGNOR-C246	SIGNOR	form complex	binding			9606									19924646	t		lperfetto	The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 	SIGNOR-260620	0.4
BZW2	protein	Q9Y6E2	UNIPROT	ATF4	protein	P18848	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									31643092	f		miannu	Subsequent research reveals that BZW2 induces ATF4 translation which is a pro‐oncogenic transcription factor	SIGNOR-261222	0.424
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates activity	phosphorylation	Tyr293	HRIDGKTyVIKRVKY	-1									16373505	t		Manara	PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR.	SIGNOR-260784	0.2
PLEKHG6	protein	Q3KR16	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260568	0.302
TWIST1	protein	Q15672	UNIPROT	PFDN4	protein	Q9NQP4	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255532	0.2
CTNNB1	protein	P35222	UNIPROT	KLF4	protein	O43474	UNIPROT	up-regulates activity	binding			10090									24482235	t		flangone	The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes.	SIGNOR-242100	0.674
BTF3	protein	P20290	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000584								17312387	f	 	 	In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis.	SIGNOR-253948	0.254
TGFb	proteinfamily	SIGNOR-PF5	SIGNOR	TGFBR2	protein	P37173	UNIPROT	up-regulates activity	binding			9606									22326956	t		miannu	TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family.	SIGNOR-256178	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	ABCB1	protein	P08183	UNIPROT	up-regulates activity	dephosphorylation	Ser683	QAQDRKLsTKEALDE	9606	BTO:0000007								24333728	t			Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp	SIGNOR-272510	0.2
GRN	protein	P28799	UNIPROT	TNFRSF1A	protein	P19438	UNIPROT	down-regulates	binding			9606									21393509	t		gcesareni	Collectively, these findings demonstrate that pgrn is a ligand of tnfr, an antagonist of tnf signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice.	SIGNOR-172684	0.506
IRAK4	protein	Q9NWZ3	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Thr133	KLPTDNQtKKPETYL	9606	BTO:0000130								17217339	t		lperfetto	Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation.	SIGNOR-152023	0.39
LCK	protein	P06239	UNIPROT	MED28	protein	Q9H204	UNIPROT	up-regulates	phosphorylation	Tyr64	ASLVSQDyVNGTDQE	9606									16899217	t		gcesareni	Y64 of magicin is phosphorylated by lck creating a sh2-grb2 binding motif	SIGNOR-148704	0.451
PTGER3	protein	P43115	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257111	0.273
CHEK2	protein	O96017	UNIPROT	BLM	protein	P54132	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr182	SHFVRVStAQKSKKG	9606	BTO:0002181								26028025	t		miannu	We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges. 	SIGNOR-276908	0.543
SCNN1G	protein	P51170	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606									26772908	t		miannu	The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity.	SIGNOR-269277	0.8
SYK	protein	P43405	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates	phosphorylation	Tyr125	VDPDNEAyEMPSEEG	9606		BTO:0000975;BTO:0000142							11744621	t		llicata	Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers.	SIGNOR-113061	0.511
MAPK15	protein	Q8TD08	UNIPROT	MAPK15	protein	Q8TD08	UNIPROT	up-regulates	phosphorylation	Tyr177	EDQAVTEyVATRWYR	9606									16336213	t		lperfetto	Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif.Our results suggest that the activity of erk8 in transfected hek-293 cells depends on the relative rates of erk8 autophosphorylation	SIGNOR-142973	0.2
SH3GLB1	protein	Q9Y371	UNIPROT	BAK1	protein	Q16611	UNIPROT	up-regulates				9606	BTO:0000567								16227588	f		gcesareni	Here, we provide evidence that bif-1 plays a regulatory role in apoptotic activation of not only bax but also bak and appears to be involved in suppression of tumorigenesis. while bif-1 did not directly interact with bak, it heterodimerized with bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the bax conformational change.	SIGNOR-141163	0.2
SCF-SKP2	complex	SIGNOR-C136	SIGNOR	E2F1	protein	Q01094	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0001938								10559858	t		miannu	P45 SKP2 binds to a specific domain of E2F-1. We propose a model in which an SCFSKP2-dependent ubiquitination pathway contributes to the timely ubiquitination and degradation of E2F-1 in the S/G2 phases of the cell cycle.	SIGNOR-272557	0.39
NLGN2	protein	Q8NFZ4	UNIPROT	NRXN2	protein	Q9P2S2	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264156	0.824
MAPK1	protein	P28482	UNIPROT	PFAS	protein	O15067	UNIPROT	up-regulates	phosphorylation	Thr619	GQGDAPPtPLPTPVD	9606									32485148	t		miannu	T619 in PFAS is required to mediate ERK2-dependent purine synthesis stimulation. We demonstrate that ERK2, but not ERK1, phosphorylates the purine synthesis enzyme PFAS (phosphoribosylformylglycinamidine synthase) at T619 in cells to stimulate de novo purine synthesis. The expression of nonphosphorylatable PFAS (T619A) decreases purine synthesis, RAS-dependent cancer cell-colony formation, and tumor growth. Thus, ERK2-mediated PFAS phosphorylation facilitates the increase in nucleic acid synthesis required for anabolic cell growth and proliferation.	SIGNOR-267306	0.2
LHX4	protein	Q969G2	UNIPROT	POU1F1	protein	P28069	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10029	BTO:0000246								15998782	t		Luana	We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression.	SIGNOR-266056	0.53
GPT2	protein	Q8TD30	UNIPROT	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	down-regulates quantity	chemical modification			9606									11863375	t			Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2	SIGNOR-266926	0.8
IFNAR1	protein	P17181	UNIPROT	IFNAR	complex	SIGNOR-C243	SIGNOR	form complex	binding			9606									11278538	t		miannu	The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. 	SIGNOR-260332	0.903
GPR132	protein	Q9UNW8	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257187	0.2
GABA-A (a6-b1-g2) receptor	complex	SIGNOR-C334	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000227							18790874	f	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263780	0.7
TLR2	protein	O60603	UNIPROT	TICAM1	protein	Q8IUC6	UNIPROT	up-regulates activity	binding			10090									22664090	t		scontino	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266746	0.628
TFEB	protein	P19484	UNIPROT	NDUFA13	protein	Q9P0J0	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4).	SIGNOR-276701	0.2
HCK	protein	P08631	UNIPROT	HCK	protein	P08631	UNIPROT	up-regulates activity	phosphorylation	Tyr411	RVIEDNEyTAREGAK	9606	BTO:0000007								10934191	t			Hck transiently expressed in human embryonic kidney 293T cells was found to be phosphorylated at Tyr-29 and Tyr-388, proving that Hck can also undergo autophosphorylation at both sites in vivo. autophosphorylation of Tyr-29 contributes significantly to the activation of Hck.	SIGNOR-251266	0.2
DYRK1A	protein	Q13627	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Ser330	RLSPIMAsTELDEVQ	9606									19188143	t		lperfetto	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition.	SIGNOR-106833	0.367
DVL1	protein	O14640	UNIPROT	DAAM1	protein	Q9Y4D1	UNIPROT	up-regulates activity	binding			9606									19365405	t		gcesareni	B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1.	SIGNOR-185271	0.724
furtrethonium	chemical	CHEBI:134764	ChEBI	CHRM2	protein	P08172	UNIPROT	up-regulates activity	chemical activation			10029									9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258643	0.8
VPS72	protein	Q15906	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269290	0.66
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2D4	protein	Q9Y2X8	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271341	0.725
PRKCA	protein	P17252	UNIPROT	INSR	protein	P06213	UNIPROT	unknown	phosphorylation	Ser1062	AVKTVNEsASLRERI	-1									7926007	t		lperfetto	Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites.	SIGNOR-248905	0.354
DNMT3A	protein	Q9Y6K1	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606									27639498	f		irozzo	The DNA methyltransferase 3 genes (DNMT3A and DNMT3B) encode methyltransferases that catalyze the addition of a methyl group to the cytosine residue of CpG dinucleotide; therefore they play an essential role in DNA methylation and gene silencing regulatory processes. DNMT3A function is involved in hematopoietic stem cells (HSCs) renewal and myeloid differentiation.	SIGNOR-255714	0.7
PSME3	protein	P61289	UNIPROT	SIRT7	protein	Q9NRC8	UNIPROT	down-regulates quantity by destabilization	binding												27511885	t		lperfetto	Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.|These results strongly suggest that the phosphorylation status of SirT7 at T153 plays a crucial role in determining its subcellular distribution, degradation and binding to REGγ.	SIGNOR-275866	0.2
MRPL22	protein	Q9NWU5	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262371	0.678
IKBKB	protein	O14920	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	unknown	phosphorylation			9606									16046471	t		lperfetto	Rela is phosphorylated at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) .we now present evidence that suggests that the upstream kinase ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. .Ikkbeta Plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. .	SIGNOR-217427	0.865
PRKCA	protein	P17252	UNIPROT	PEA15	protein	Q15121	UNIPROT	down-regulates	phosphorylation	Ser104	TKLTRIPsAKKYKDI	9606		BTO:0000149							15917297	t		miannu	Pea-15 is phosphorylated on two ser residues, ser104 and ser116. Protein kinase c (pkc) phosphorylates ser104 / we report that phosphorylation of pea-15 blocks its interaction with erk1/2 in vitro and in vivo and that phosphorylation of both ser104 and ser116 is required for this effect.	SIGNOR-137841	0.392
DAMPS	stimulus	SIGNOR-ST18	SIGNOR	MEFV	protein	O15553	UNIPROT	up-regulates activity													16037825	f		lperfetto	Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage	SIGNOR-256422	0.7
GSK3B	protein	P49841	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	phosphorylation	Ser1490	AILNPPPsPATERSH	9606			SIGNOR-C110						16341017	t		gcesareni	Glycogen synthase kinase 3 (gsk3), which is known for its inhibitory role in wnt through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of lrp6. We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.	SIGNOR-143041	0.787
GLI3	protein	P10071	UNIPROT	MYCN	protein	P04198	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000150;BTO:0000551								19860666	f		gcesareni	Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. .Hedgehog Signals induce cellular proliferation through upregulation of n-myc, cyclin d/e, and foxm1.	SIGNOR-188881	0.365
BTF3	protein	P20290	UNIPROT	IRAG1	protein	Q9Y6F6	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000584								17312387	f	 	 	In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis.	SIGNOR-253946	0.2
CSNK1A1	protein	P48729	UNIPROT	EIF2B5	protein	Q13144	UNIPROT	unknown	phosphorylation	Ser469	DGEFSDDsGADQEKD	9606	BTO:0000007								11500362	t		llicata	 The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1. All five sites are phosphorylated in the eIF2B complex in vivo. | A phosphopeptide corresponding to this region was identified in Asp‐N digests of eIF2Bϵ phosphorylated in vitro by CK1, suggesting that Ser461 or Ser464 may be phosphorylated by this kinase in vivo.	SIGNOR-250788	0.328
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CDKN1C	protein	P49918	UNIPROT	down-regulates	phosphorylation	Ser282	FFAKRKRsAPEKSSG	9606	BTO:0000150								23421998	t		lperfetto	Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination	SIGNOR-201042	0.2
CHFR	protein	Q96EP1	UNIPROT	PBK	protein	Q96KB5	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								24012691	t		miannu	CHFR ubiquitinates and degrades TOPK. Our in vivo ubiquitination assays revealed that the polyubiquitination of TOPK occurs only in the presence of full length CHFR but not with the ΔRING or Δcysteine-rich domain deletion mutants (Fig. 2a).	SIGNOR-271471	0.352
PHF12	protein	Q96QT6	UNIPROT	TLE6	protein	Q9H808	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								11390640	t		miannu	We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE.	SIGNOR-266991	0.2
Upf-EJC	complex	SIGNOR-C367	SIGNOR	Nonsense-mediated mRNA decay	phenotype	SIGNOR-PH175	SIGNOR	up-regulates				9606	BTO:0000567								17803942	t		miannu	The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1. the hUpf complex communicates with the EJC and triggers NMD in the cytoplasm.	SIGNOR-265239	0.7
DAB2IP	protein	Q5VWQ8	UNIPROT	NRAS	protein	P01111	UNIPROT	down-regulates activity	gtpase-activating protein			9606									27858941	t		miannu	The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP.	SIGNOR-254747	0.472
PRKACA	protein	P17612	UNIPROT	TAL1	protein	P17542	UNIPROT	up-regulates	phosphorylation	Ser172	NRVKRRPsPYEMEIT	9606									22310283	t		llicata	The phosphorylation of serine 172 of tal1 specifically destabilizes tal1 interaction with histone demethylase lsd1 and, therefore, leads to the activation of the certain tal1 target genes in differentiated erythroid cells or t-cell leukemia.	SIGNOR-195983	0.2
PI3K	complex	SIGNOR-C156	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000830								15526160	t		miannu	C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo.	SIGNOR-254951	0.283
ATXN2L	protein	Q8WWM7	UNIPROT	DDX6	protein	P26196	UNIPROT	unknown	binding			9606									23209657	t		miannu	Ataxin-2-like associates with known interaction partners of ataxin-2, the rna helicase ddx6	SIGNOR-199948	0.556
UCHL3	protein	P15374	UNIPROT	UBA52	protein	P62987	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270827	0.792
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	Citric_Acid_Cycle	phenotype	SIGNOR-PH191	SIGNOR	up-regulates				9606									15953811	f		miannu	A branch-point metabolite α-ketoglutarate is generated in the TCA cycle during the oxidation of carbohydrates and fatty acids and by glutamate dehydrogenase during the oxidative deamination of glutamate. The enzymes that form the mitochondrial α-ketoglutarate– dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme system of the tricarboxylic acid cycle, might mediate the interaction of these processes.	SIGNOR-267821	0.7
SFPQ	protein	P23246	UNIPROT	TH	protein	P07101	UNIPROT	down-regulates quantity by repression	transcriptional regulation												20938049	t		lperfetto	It has been reported that DJ-1 is a neuroprotective transcriptional co-activator that sequesters a transcriptional co-repressor polypyrimidine tract-binding protein-associated splicing factor (PSF) from the TH gene promoter.	SIGNOR-271697	0.2
PPP3CC	protein	P48454	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates activity	dephosphorylation	Ser99	PFRGRSRsAPPNLWA	9606	BTO:0000007								10195903	t			Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 	SIGNOR-248529	0.372
MAPK8	protein	P45983	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates activity	phosphorylation	Ser62	LLPTPPLsPSRRSGL	9606	BTO:0000007;BTO:0000567								10551811	t		lperfetto	The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71.	SIGNOR-236018	0.574
HOXA10	protein	P31260	UNIPROT	EMX2	protein	Q04743	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15494461	f		miannu	EMSA demonstrated HOXA10-Pbx2 binding as a heterodimer to an enhancer of the EMX2 gene, a known target of HOXA10 regulation.	SIGNOR-254465	0.325
EIF2S1	protein	P05198	UNIPROT	HBG2	protein	P69892	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24714526	f		miannu	Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy.	SIGNOR-251818	0.2
MAPK13	protein	O15264	UNIPROT	EEF2K	protein	O00418	UNIPROT	down-regulates activity	phosphorylation	Ser396	TFDSLPSsPSSATPH	-1									11500363	t		miannu	 eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. eEF2K[S359A] was phosphorylated (presumably at Ser396) by the high concentrations of SAPK4/p38 used in this experiment. However, the inhibition of eEF2K under these conditions was reduced from 82% in the wild-type enzyme to 19% in eEF2K[S359A]	SIGNOR-250089	0.56
GTF2I	protein	P78347	UNIPROT	KDM1A	protein	O60341	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								12493763	t		lperfetto	We identify a new family of HDAC1,2-associated complexes containing BHC110. Moreover, we define the polypeptide composition of a novel member of this family containing the candidate gene for X-linked mental retardation XFIM and the initiator-binding protein TFII-I.	SIGNOR-268539	0.415
MYC	protein	P01106	UNIPROT	PPAT	protein	Q06203	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003291								18628958	t		miannu	 PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria. 	SIGNOR-267381	0.2
NFX1	protein	Q12986	UNIPROT	SIN3A	protein	Q96ST3	UNIPROT	up-regulates activity	binding			9606	BTO:0004117								18505829	t		miannu	we investigated the mechanism of NFX1-91 repression of the hTERT promoter and demonstrated that NFX1-91 interacts with the corepressor mSin3A/HDAC to maintain the deacetylated status at the hTERT promoter, thus providing a mechanism by which NFX1-91 represses hTERT expression.	SIGNOR-226360	0.381
STAT3	protein	P40763	UNIPROT	SMAD2/STAT3/EP300	complex	SIGNOR-C203	SIGNOR	form complex	binding			9606									26194464	t		MARCO ROSINA	Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes.	SIGNOR-255024	0.567
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr18	EPPLSQEtFSDLWKL	9606	BTO:0000776								17339337	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-153483	0.784
ADCY7	protein	P51828	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates quantity	chemical modification			9606									15385642	t		miannu	Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions.	SIGNOR-265007	0.8
GABRA6	protein	Q16445	UNIPROT	GABA-A (a6-b2-d) receptor	complex	SIGNOR-C328	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263768	0.521
DAB2IP	protein	Q5VWQ8	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates activity	binding			9606									27858941	t		miannu	DAB2IP also mediates recruitment of PP2A to ASK1, binding both proteins through its C2 domain; this favors removal of the inhibitory S967 phosphorylation and further activation of ASK1	SIGNOR-254748	0.835
PRKCA	protein	P17252	UNIPROT	HAND1	protein	O96004	UNIPROT	unknown	phosphorylation	Thr107	PKKERRRtESINSAF	9606	BTO:0000007								14636580	t		lperfetto	In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. 	SIGNOR-249244	0.292
MELK	protein	Q14680	UNIPROT	MELK	protein	Q14680	UNIPROT	up-regulates	phosphorylation	Ser356	DIKSNNWsLEDVTAS	9606									16216881	t		lperfetto	We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase.	SIGNOR-140998	0.2
MAP2K7	protein	O14733	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates	phosphorylation			9606									11062067	t	Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif	gcesareni	Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)these results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway.	SIGNOR-83732	0.564
valrubicin	chemical	CHEBI:135876	ChEBI	TOP2A	protein	P11388	UNIPROT	down-regulates activity	chemical inhibition			9606									16019763	t		miannu	Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a semi-synthetic derivative of the anthracycline doxorubicin. Valrubicin inhibits the incorporation of nucleosides into nucleic acids, causing extensive chromosomal damage and cell-cycle arrest in the G2 phase. Its principal metabolites inhibit topoisomerase II, thus arresting DNA synthesis.	SIGNOR-259383	0.8
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1784	TPTSPNYsPTSPSYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203556	0.77
L3MBTL2	protein	Q969R5	UNIPROT	RNF168	protein	Q8IYW5	UNIPROT	down-regulates quantity	binding			9606									31225475	t		miannu	L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.	SIGNOR-266788	0.248
PRKCA	protein	P17252	UNIPROT	RHO	protein	P08100	UNIPROT	unknown	phosphorylation	Ser338	DEASATVsKTETSQV	-1									9099669	t		lperfetto	Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343.	SIGNOR-248967	0.451
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CDC6	protein	Q99741	UNIPROT	down-regulates activity	phosphorylation	Ser54	RVKALPLsPRKRLGD	9606									10339564	t		lperfetto	Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction.	SIGNOR-217276	0.94
BMPR1A	protein	P36894	UNIPROT	SMAD5	protein	Q99717	UNIPROT	up-regulates activity	phosphorylation			9606									19620713	t		lperfetto	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-255261	0.676
PRKCA	protein	P17252	UNIPROT	TACSTD2	protein	P09758	UNIPROT	down-regulates activity	phosphorylation	Ser322	GELRKEPsL	9606	BTO:0001109								31177095	t	done	miannu	 Analyses using HCT116 cells expressing WT Trop-2 (HCT116/WT) or Trop-2 alanine-substituted at Ser-303 (HCT116/S303A) or Ser-322 (HCT116/S322A) revealed that Trop-2 is phosphorylated at Ser-322. sing protein kinase C (PKC) inhibitors and PKC-specific siRNAs, we found that PKCα and PKCδ are responsible for Trop-2 phosphorylation. 	SIGNOR-273821	0.2
DYRK1B	protein	Q9Y463	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates	phosphorylation	Ser10	NVRVSNGsPSLERMD	10090									15546868	t		lperfetto	Mirk phosphorylates p27 at ser-10, thus stabilizing p27 and blocking its nuclear export and degradation	SIGNOR-235805	0.363
RBM7	protein	Q9Y580	UNIPROT	P-TEFb	complex	SIGNOR-C238	SIGNOR	up-regulates activity	relocalization			9606	BTO:0000007								30824372	t		miannu	Here, we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) transcription and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb) via its release from the inhibitory 7SK small nuclear ribonucleoprotein (7SK snRNP). these findings establish that RBM7 binds 7SK snRNP and that genotoxic stress activates P-TEFb by relocating it from 7SK snRNP to the CTD of Pol II.	SIGNOR-261182	0.2
DGC	complex	SIGNOR-C217	SIGNOR	GABA-A (a4-b2-d) receptor	complex	SIGNOR-C326	SIGNOR	up-regulates quantity	binding			9606	BTO:0000938;BTO:0002606								22626542	t		miannu	 In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses.	SIGNOR-265436	0.2
CDK5	protein	Q00535	UNIPROT	HTR6	protein	P50406	UNIPROT	down-regulates activity	phosphorylation	Ser350	ERQASLAsPSLRTSH	10090	BTO:0000942								32047117	t		lperfetto	Cdk5 phosphorylates the 5-HT6R on serine 350 (Ser350)|This suggests that the 5-HT6R is unable to interact with GPRIN1 when it is phosphorylated by Cdk5.	SIGNOR-264407	0.382
FUS	protein	P35637	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates quantity	post transcriptional regulation			10090		BTO:0000142							32118033	t		lperfetto	These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.|As seen in Figure 7 (top panel), both PSD-95 Q1-Q2 and Shank1a GQ probes pulled down endogenous FUS, whereas their M2 mutants did not, indicating that the GQ structure is sufficient for recognition.	SIGNOR-262103	0.274
PTEN	protein	P60484	UNIPROT	PIK3CA	protein	P42336	UNIPROT	down-regulates activity				9606									18794881	f		lperfetto	The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)).	SIGNOR-209856	0.723
ESR1	protein	P03372	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								15808510	t		gcesareni	Ikkalpha in conjunction with eralpha and aib1/src-3, is important in activating the transcription of estrogen-responsive genes, including cyclin d1.	SIGNOR-135053	0.746
AKAP9	protein	Q99996	UNIPROT	TRIP10	protein	Q15642	UNIPROT	up-regulates activity	binding			9606	BTO:0000182;BTO:0000666								27039663	t		Giulio	Mechanistically, AKAP-9 interacted with cdc42 interacting protein 4 (CIP4) and regulated its expression. CIP4 levels were interrelated to the AKAP-9 level in CRC cells. Functionally, AKAP-9 was essential for TGF-β1-induced epithelial-mesenchymal transition of CRC cells, and CIP4 played a critical role in mediating the function of AKAP-9. Importantly, CIP4 expression was significantly up-regulated in human CRC tissues.|Co-immunoprecipitation assay revealed that AKAP-9 and CIP4 physically interacted with each other in Lovo and HT29 cells (Fig. 4B and C).	SIGNOR-260303	0.528
TFEB	protein	P19484	UNIPROT	NDUFS4	protein	O43181	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4).	SIGNOR-276705	0.248
PRKCA	protein	P17252	UNIPROT	EDF1	protein	O60869	UNIPROT	down-regulates activity	phosphorylation	Thr91	GRQSKGLtQKDLATK	9606	BTO:0001949								10816571	t		lperfetto	EDF-1 was phosphorylated in vitro by PKC in the presence of Ca2+ and phospholipids | This results shows that introduction of a single negative charge by phosphorylation at Thr-91 inhibited CaM-EDF-1 interactions.	SIGNOR-249041	0.305
ITGAL	protein	P20701	UNIPROT	AKAP9	protein	Q99996	UNIPROT	up-regulates activity	binding			9606	BTO:0001945								16339516	t		Giulio	However, association of CG-NAP/AKAP450 was signifi-cantly enhanced at 37°C in LFA-1-activated cells triggered toundergo motility. Taken together, our findings provide the first definitiveevidence that the protein CG-NAP/AKAP450 is a key scaffoldingcomponent of the multimolecular complex assembled in T cellsupon LFA cross-linking and is functionally indispensable for cellpolarity and migration induced by this integrin.	SIGNOR-260304	0.2
BMPR2	protein	Q13873	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	form complex	binding			9606									7791754	t		lperfetto	Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii).	SIGNOR-33443	0.611
CDC42BPB	protein	Q9Y5S2	UNIPROT	MSN	protein	P26038	UNIPROT	up-regulates activity	phosphorylation	Thr558	LGRDKYKtLRQIRQG	9606									10947843	t		Manara	In this study, we have shown that MRCKb phosphorylated moesin at Thr-558 | We have shown that the phosphorylation is important to the formation of ®lopodia, and that MRCK may regulate this formation through the phosphorylation of ERM proteins at the tip of ®lopodia.	SIGNOR-260802	0.2
MAPK8	protein	P45983	UNIPROT	MAPK8IP1	protein	Q9UQF2	UNIPROT	unknown	phosphorylation	Ser15	GLGGGAAsPPAASPF	9534	BTO:0000298								12756254	t		miannu	After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1.	SIGNOR-250123	0.879
MSH release-inhibiting hormone	smallmolecule	CID:56842142	PUBCHEM	MC5R	protein	P33032	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257539	0.8
ABL1	protein	P00519	UNIPROT	RAD52	protein	P43351	UNIPROT	up-regulates activity	phosphorylation	Tyr104	DLNNGKFyVGVCAFV	9606	BTO:0000007								12379650	t		gcesareni	We show here that c-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. Importantly, the very same site of Rad52 is phosphorylated on exposure of cells to ionizing radiation (IR).	SIGNOR-247661	0.673
EIF1	protein	P41567	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	up-regulates activity	relocalization			9606									20921384	t		lperfetto	Genetic and biochemical studies have revealed several eukaryotic factors involved in selecting the correct initiation codon (3–6). Further analyses pointed toward eukaryotic initiation factor 1 (eIF1) as the key mediator of this process (7–10). eIF1 binds near the P-site of the small ribosomal subunit (11); this binding is thought to lead to an open conformation of the preinitiation complex favoring scanning	SIGNOR-269143	0.54
MAP3K5	protein	Q99683	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates activity	phosphorylation	Thr842	CTETFTGtLQYMAPE	9606									17937911	t		lperfetto	Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling.	SIGNOR-158431	0.2
NMDA receptor_2A	complex	SIGNOR-C347	SIGNOR	CTTN	protein	Q14247	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000142								14684878	t		miannu	Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors.	SIGNOR-266599	0.285
PRKCD	protein	Q05655	UNIPROT	MGluR	proteinfamily	SIGNOR-PF55	SIGNOR	up-regulates activity	phosphorylation			-1									15894802	t	inferred from family member	lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-270275	0.404
HRH1	protein	P35367	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257163	0.2
NLGN3	protein	Q9NZ94	UNIPROT	NRXN1	protein	Q9ULB1	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264142	0.834
PRKCH	protein	P24723	UNIPROT	MCL1	protein	Q07820	UNIPROT	up-regulates quantity by stabilization				9606									28939105	f		miannu	The results of our present study show that PKCη positively regulates the anti-apoptotic Bcl-2 family protein Mcl-1 by preventing its degradation via the proteasomal pathway involving Mcl-1 ubiquitin ligase Mule.	SIGNOR-261908	0.2
pentazocine	chemical	CHEBI:7982	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258935	0.8
sonidegib	chemical	CHEBI:90863	ChEBI	SMO	protein	Q99835	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000527								21679342	t		gcesareni	Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date.	SIGNOR-174593	0.8
HSPA1B	protein	P0DMV9	UNIPROT	NOD2	protein	Q9HC29	UNIPROT	up-regulates quantity by stabilization	binding			9606									24790089	t		miannu	The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease.	SIGNOR-252417	0.2
PI4KA	protein	P42356	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									10101268	t		miannu	The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 	SIGNOR-269096	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000938								8387505	t	inferred from 70% family members	lperfetto	The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases	SIGNOR-270002	0.2
MAPK3	protein	P27361	UNIPROT	TAL1	protein	P17542	UNIPROT	down-regulates	phosphorylation	Ser122	DGRMVQLsPPALAAP	9606									11904294	t		gcesareni	We report here that the important proangiogenic stimulus hypoxia stimulates phosphorylation, ubiquitination, and proteasomal breakdown of tal1 in endothelial cells. A specific serine in the putative transactivation domain of the protein, ser122, is preferentially phosphorylated by mapk in vitro.	SIGNOR-116153	0.364
NMBR	protein	P28336	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257422	0.409
clozapine	chemical	CHEBI:3766	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258513	0.8
HOXA13	protein	P31271	UNIPROT	EPHA7	protein	Q15375	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000942								21829694	t		Luana	Analysis of normalized luciferase expression confirmed that wt HOXA13 regulates gene expression through the EphA7 cis-regulatory DNA element	SIGNOR-261631	0.296
P2RY12	protein	Q9H244	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256991	0.2
N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide	chemical	CHEBI:91393	ChEBI	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194343	0.8
MAPK1	protein	P28482	UNIPROT	MED1	protein	Q15648	UNIPROT	up-regulates	phosphorylation	Thr1457	HSKSPAYtPQNLDSE	9606									16314496	t		fstefani	We demonstrate that erk phosphorylates trap220/med1 in vivo at two specific sites: threonine 1032 and threonine 1457. importantly, we found that erk phosphorylation significantly increases the stability and half-life of trap220/med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription.	SIGNOR-142462	0.362
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CCL2	protein	P13500	UNIPROT	up-regulates	transcriptional regulation			9606	BTO:0000801								20086235	f			Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2)	SIGNOR-254509	0.567
KDM4C	protein	Q9H3R0	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									29207681	t		miannu	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 	SIGNOR-263865	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	FERMT1	protein	Q9BQL6	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser174	LESSPTAsGSSVSPG	9606	BTO:0000567								35469017	t		miannu	CDK1–cyclin B1 mediates KIND1 and KIND2 phosphorylation at mitotic entry . MS of KIND1 and KIND2 immunoprecipitates from STLC-arrested HeLa cells confirmed the phosphorylation of KIND1-S179 and KIND2-S181 and revealed phosphorylation of closely adjacent serine residues (KIND1: SSphS174GphS176PVphS179PGLYSK; KIND2: GphS175GphS177IYphS180phS181PGLYSK), although to a weaker extent (Supplementary Table 2).	SIGNOR-276719	0.2
MKRN1	protein	Q9UHC7	UNIPROT	CDKN2A	protein	Q8N726	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002552								23104211	t		miannu	Biochemical analyses confirmed that MKRN1 targets p14ARF for ubiquitination and subsequent proteasome-dependent degradation.The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro.	SIGNOR-272036	0.375
GABRD	protein	O14764	UNIPROT	GABA-A (a6-b3-d) receptor	complex	SIGNOR-C329	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263773	0.394
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	RPTOR	protein	Q8N122	UNIPROT	up-regulates	phosphorylation	Ser719	PCTPRLRsVSSYGNI	9606				SIGNOR-C3					18722121	t		llicata	Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity	SIGNOR-252772	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	COPS6	protein	Q7L5N1	UNIPROT	up-regulates	phosphorylation	Ser60	DHWIRMRsQEGRPVQ	9606									23095642	t		llicata	Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6.	SIGNOR-199254	0.2
TNF	protein	P01375	UNIPROT	SCN11A	protein	Q9UI33	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253483	0.2
BID	protein	P55957	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates	binding			9606									10629050	t		amattioni	Bid, a bh3-domain-only protein which interacts with bax, was able to trigger a conformational change in bax.	SIGNOR-73902	0.818
CUL3	protein	Q13618	UNIPROT	KCTD10	protein	Q9H3F6	UNIPROT	up-regulates activity	binding			9606									19782033	t		miannu	 BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.	SIGNOR-264234	0.508
TEK	protein	Q02763	UNIPROT	MYOG	protein	P15173	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000222								26042050	f		lperfetto	the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein.	SIGNOR-241535	0.248
OPA3	protein	Q9H6K4	UNIPROT	Mitochondrial_fission	phenotype	SIGNOR-PH143	SIGNOR	up-regulates				9606									20372962	f		lperfetto	Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation|Together, these results indicate that OPA3, as an integral MOM protein, has a crucial role in mitochondrial fission, and provides a direct link between mitochondrial morphology and optic atrophy.	SIGNOR-272988	0.7
RPS6KA1	protein	Q15418	UNIPROT	MITF	protein	O75030	UNIPROT	down-regulates	phosphorylation	Ser409	HGLSLIPsTGLCSPD	9606									10673502	t	The effect has been demonstrated using O75030-9	gcesareni	The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert.	SIGNOR-75034	0.419
MAP3K3	protein	Q99759	UNIPROT	WDR62	protein	O43379	UNIPROT	up-regulates quantity by stabilization	binding												30566428	t		lperfetto	Specifically, we demonstrate that MEKK3 interacts with WDR62 to stabilize WDR62 and regulates JNK activity in a synergic way. On the other hand, JNK activity also regulates the phosphorylation of WDR62 at T1053 in a feedback loop which facilities the recruitment of FBW7 degradation of WDR62 	SIGNOR-271714	0.2
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	up-regulates quantity	precursor of			9606									1400883	t		scontino	The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production.	SIGNOR-266943	0.8
TP53	protein	P04637	UNIPROT	NFKB2	protein	Q00653	UNIPROT	up-regulates	binding			9606									16990795	t		gcesareni	P52 cooperates with p53 to regulate other known p53 target genes.	SIGNOR-149811	0.437
SRC	protein	P12931	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr869	LGAEEKEyHAEGGKV	9606	BTO:0000452								11983694	t		lperfetto	In summary, this study describes a novel mechanism for metal-induced egfr transactivation, which is likely to be mediated by src through the phosphorylation site of tyr-845 on egfr. emanating from a variety of growth factor receptors, including egfry845 (e-e-k-e-y845-h-a-e)	SIGNOR-235921	0.609
GRP	protein	P07492	UNIPROT	GRPR	protein	P30550	UNIPROT	up-regulates	binding			9606									17251915	t		gcesareni	Indeed, many potent mitogens such as thrombin, lysophosphatidic acid (lpa), gastrin-releasing peptide (grp), endothelin and prostaglandins stimulate cell proliferation by acting on their cognate gpcrs in various cell types.	SIGNOR-152676	0.777
ZDHHC9	protein	Q9Y397	UNIPROT	NRAS	protein	P01111	UNIPROT	up-regulates activity	palmitoylation			9606	BTO:0000007								16000296	t		miannu	Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein.	SIGNOR-261355	0.415
PTPN2	protein	P17706	UNIPROT	JAK1	protein	P23458	UNIPROT	down-regulates activity	dephosphorylation			9606									15780598	t		lperfetto	Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.	SIGNOR-134620	0.758
ROCK1	protein	Q13464	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Ser38	LGPGTRLsLARMPPP	-1									12686604	t		lperfetto	We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro.	SIGNOR-100188	0.316
OFD1	protein	O75665	UNIPROT	IFT88	protein	Q13099	UNIPROT	up-regulates activity	binding			9606	BTO:0001086								20230748	t	Regulation of binding	miannu	Ofd1 acts at the distal centriole to build distal appendages, recruit Ift88, and stabilize centriolar microtubules at a defined length.	SIGNOR-251973	0.423
phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	long-chain fatty acid anion	smallmolecule	CHEBI:57560	ChEBI	up-regulates quantity	precursor of			9606									22922100	t		miannu	Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 	SIGNOR-269658	0.8
Host translation inhibitor nsp1	protein	P0C6X7-PRO_0000037309	UNIPROT	IRF7	protein	Q92985	UNIPROT	down-regulates activity				9606									17715225	f		miannu	SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7.	SIGNOR-262504	0.2
PPP1R9A	protein	Q9ULJ8	UNIPROT	ARHGEF2	protein	Q92974	UNIPROT	up-regulates activity	binding			10090	BTO:0001976								15996550	t		miannu	The Rho Family GEF Lfc Interacts with Neurabin and Spinophilin. Neurabin and spinophilin are homologous protein phosphatase 1 and actin binding proteins that regulate dendritic spine function. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc	SIGNOR-269177	0.347
TBC1D4	protein	O60343	UNIPROT	SLC2A4	protein	P14672	UNIPROT	down-regulates				9606									12637568	f		gcesareni	These findings strongly indicate that insulin-stimulated phosphorylation of as160 is required for glut4 translocation and that this phosphorylation signals translocation through inactivation of the rab gap function.	SIGNOR-99303	0.655
CSNK2A2	protein	P19784	UNIPROT	IL16	protein	Q14005	UNIPROT	up-regulates activity	phosphorylation	Ser743	MPLQPNAsLNEEEGT	-1									12450396	t		llicata	We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. | Thus, we confirm that the N-terminal (42SLNEE46) sequence of pro-IL-16 is in fact a site for protein kinase CK2 phosphorylation.	SIGNOR-251009	0.331
TFE3	protein	P19532	UNIPROT	ATP6V0D2	protein	Q8N8Y2	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276810	0.2
ETS2	protein	P15036	UNIPROT	IBSP	protein	P21815	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11175361	t		miannu	Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin	SIGNOR-259873	0.2
CDK1	protein	P06493	UNIPROT	CC2D1A	protein	Q6P1N0	UNIPROT	up-regulates activity	phosphorylation	Ser208	PASTPTYsPAPTQPA				SIGNOR-C17						20171170	t	nucleus	lperfetto	We identified the Ser208 residue of Aki1 as a cyclin B1–Cdk1 phosphorylation site. Furthermore, cyclin B1–Cdk1 inhibitor treatment was shown to attenuate the level of Aki1 in complex with Scc1, suggesting that Aki1 phosphorylation by cyclin B1–Cdk1 contributes to Aki1–Scc1 complex formation. 	SIGNOR-268297	0.2
PRKACA	protein	P17612	UNIPROT	VASP	protein	P50552	UNIPROT	unknown	phosphorylation	Thr278	LARRRKAtQVGEKTP	-1									8182057	t		miannu	The vasodilator-stimulated phosphoprotein (VASP) is a major substrate for cAMP-dependent- (cAK) and cGMP-dependent protein kinase (cGK) in human platelets and other cardiovascular cells.‚  three VASP phosphorylation sites are phosphorylated by cAK and cGK. Thr, Ser I, and Ser 2 correspond to Thr278, Ser157, Ser239 of the VASP protein, respectively	SIGNOR-250065	0.487
RPL10L	protein	Q96L21	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262500	0.773
CSNK2A2	protein	P19784	UNIPROT	TCF7L2	protein	Q9NQB0	UNIPROT	up-regulates activity	phosphorylation	Ser59	SETNQNSsSDSEAER	-1									11711551	t		llicata	We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. 	SIGNOR-251045	0.386
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	Asp-tRNA(Asp)	smallmolecule	CHEBI:29158	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270374	0.8
SGK1	protein	O00141	UNIPROT	NEDD4L	protein	Q96PU5	UNIPROT	down-regulates activity	phosphorylation			9606									15586017	t	Regulation of localization	miannu	The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane. 	SIGNOR-251949	0.78
TCL1A	protein	P56279	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271								10983986	t		miannu	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-81680	0.823
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TBC1D4	protein	O60343	UNIPROT	unknown	phosphorylation	Ser588	RMRGRLGsVDSFERS	10090	BTO:0000011								11994271	t		gcesareni	To determine directly whether AS160 was a substrate for Akt, we examined the phosphorylation of recombinant AS160, as well as mutant forms with Ser-588, Thr-642, or both converted to Ala, by recombinant Akt 1.	SIGNOR-245268	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Thr8	MSSILPFtPPVVKRL	9606		BTO:0000763							12193595	t		lperfetto	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity	SIGNOR-244735	0.2
estramustine	chemical	CHEBI:4868	ChEBI	MAP2	protein	P11137	UNIPROT	down-regulates activity	chemical inhibition			-1									1647395	t		miannu	Estramustine is a novel anti-microtubule drug shown to bind MAP-1 and MAP-2 (microtubule-associated proteins) in vitro. In this paper we have shown that estramustine specifically binds MAP-1A in Du 145a cells, resulting in disruption of MAP-1A microtubules and inhibition of type IV collagenase secretion.	SIGNOR-259298	0.8
MCHR1	protein	Q99705	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256762	0.272
CSNK1A1	protein	P48729	UNIPROT	SNCA	protein	P37840	UNIPROT	up-regulates	phosphorylation	Ser87	KTVEGAGsIAAATGF	9606	BTO:0000938								10617630	t		lperfetto	In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes.	SIGNOR-73799	0.379
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-183620	0.2
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	down-regulates activity				9606	BTO:0002882								11684015	f		lperfetto	BCR/ABL Tyrosine Kinase Enhances Expression of RAD51 by Stimulation of STAT5-Mediated Transactivation and Inhibition of Caspase-3-Dependent Degradation|	SIGNOR-271705	0.2
PRKACA	protein	P17612	UNIPROT	GPKOW	protein	Q92917	UNIPROT	up-regulates activity	phosphorylation	Ser27	SFGFTRTsARRRLAD	-1									21880142	t		miannu	PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites.	SIGNOR-266309	0.311
CSNK2A1	protein	P68400	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates activity	phosphorylation	Ser49	HKAELQGsDEDEHVR	-1									9461343	t		llicata	Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity. 	SIGNOR-250923	0.311
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	VCP	protein	P55072	UNIPROT	up-regulates	phosphorylation	Ser746	AMRFARRsVSDNDIR	9606	BTO:0000150								16551632	t		llicata	Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I	SIGNOR-145288	0.2
SUFU	protein	Q9UMX1	UNIPROT	GLI2	protein	P10070	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								20463034	t		Gianni	We show that loss of suppressor of fused (Sufu; an inhibitory effector for Gli proteins) results in destabilization of Gli2 and Gli3 full-length activators but not of their C-terminally processed repressors, whereas overexpression of Sufu stabilizes them.	SIGNOR-268867	0.907
GNB/GNG	complex	SIGNOR-C202	SIGNOR	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates													23994464	t		apalma	Similar to PLCβ activation, PI3K-activation by neutrophil GPCRs also occurs primarily through Gβγ subunits, through the unique PI3Kγ isoform which is directly activated by Gβγ dimers	SIGNOR-255010	0.468
GABA-A (a2-b1-g2) receptor	complex	SIGNOR-C331	SIGNOR	CRHR2	protein	Q13324	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268590	0.2
TP53	protein	P04637	UNIPROT	CTSD	protein	P07339	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10029407	f		miannu	 p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1.	SIGNOR-255434	0.372
CHD2	protein	O14647	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				10090									26895424	f		miannu	We show in mouse cells that the cNHEJ-dependent fusion of chromosomes containing uncapped telomeres requires the activity of CHD2. Together, these findings argue that the chromatin response mediated by CHD2 is triggered by the presence of DSBs and promotes repair of these lesions by the canonical KU-dependent NHEJ pathway.	SIGNOR-264529	0.7
MAPK3	protein	P27361	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates	phosphorylation	Ser523	GVSDVPTsPTLQRPT	9606									16705159	t	16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling.	lperfetto	We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner	SIGNOR-146747	0.502
BCL6	protein	P41182	UNIPROT	LITAF	protein	Q99732	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001518								23795761	f		miannu	 BCL6 silencing increased LITAF expression, and chromatin immunoprecipitation and luciferase reporter assays demonstrated a direct transcriptional repression of LITAF by BCL6.	SIGNOR-253758	0.36
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	Lys-tRNA(Lys)	smallmolecule	CHEBI:16047	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270406	0.8
tubastatin A	chemical	CHEBI:94186	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207450	0.8
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DMB	protein	P28068	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								11889043	f	 	 	Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment.	SIGNOR-254016	0.373
Glycine cleavage system	complex	SIGNOR-C437	SIGNOR	carbon dioxide	smallmolecule	CHEBI:16526	ChEBI	up-regulates quantity	chemical modification			9606									16051266	t		lperfetto	The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide.	SIGNOR-268244	0.8
PPP2CA	protein	P67775	UNIPROT	RACGAP1	protein	Q9H0H5	UNIPROT	down-regulates	dephosphorylation	Ser387	ETGLYRIsGCDRTVK	9606									18201571	t		gcesareni	We report here that (i) mgcracgap is phosphorylated by aurora b and cdk1, (ii) pp2a dephosphorylates aurora b and cdk1 phosphorylated sites and (iii) inhibition of pp2a abrogates mgcracgap/ect2 interaction. Therefore, pp2a may regulate cytokinesis by dephosphorylating mgcracgap and its interacting partners.	SIGNOR-160398	0.307
COL3A1	protein	P02461	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									21949456	t			Collagen is the major structural protein in skeletal muscle ECM;... type III collagen appears to be more evenly distributed between endomysium and epimysium	SIGNOR-254664	0.7
PTX3	protein	P26022	UNIPROT	CFH	protein	P08603	UNIPROT	up-regulates activity	binding			9606									19050261	t		miannu	Our findings identify PTX3 as a unique FH ligand in that it can bind both of the two hot-spots of FH, namely SCR7 and SCR19-20 and indicate that PTX3 participates in the localization of functionally active FH. PTX3 binds FH without interfering with its complement inhibitory function. Therefore PTX3 may contribute to focusing FH regulatory action, prevent excessive complement activation, and thus exert an important function in the control of inflammation in response to tissue injury.	SIGNOR-252140	0.408
PRKACA	protein	P17612	UNIPROT	TRIM71	protein	Q2Q1W2	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser3	sFPETDFQ	-1									31160797	t		miannu	 These observations suggested that LINK-A expression potentially inhibits PKA phosphorylation/activity and PKA-mediated phosphorylation of TRIM71 at Ser3.	SIGNOR-277454	0.2
MAPK12	protein	P53778	UNIPROT	EEF2K	protein	O00418	UNIPROT	unknown	phosphorylation	Ser396	TFDSLPSsPSSATPH	-1									12171600	t		miannu	We have also shown that JNK11, JNK22 and SAPK3 p38 phosphorylate eEF2 kinase very poorly at Ser-396	SIGNOR-250137	0.334
CDK2	protein	P24941	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates	phosphorylation	Thr444	NSLTPKStPVKTLPF	9606			SIGNOR-C83						9840932	t		lperfetto	The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk3	SIGNOR-62357	0.711
GAST	protein	P01350	UNIPROT	SLC4A2	protein	P04920	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000269							22228178	f	 	 	Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation.	SIGNOR-254251	0.281
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	up-regulates quantity	precursor of			9606									26003525	t		miannu	Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and α-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer.	SIGNOR-267507	0.8
PTGFR	protein	P43088	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257082	0.426
GSK3B	protein	P49841	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates activity	phosphorylation	Ser243	PGETPPLsPIDMESQ	9606	BTO:0000007								16023596	t		lperfetto	The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance	SIGNOR-235892	0.7
SP1	protein	P08047	UNIPROT	ENG	protein	P17813	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002741								21146604	f		miannu	 In hepatic stellate cells, TGF-β1 upregulates endoglin expression most likely via the ALK5 pathway and requires the SP1 transcription factor.	SIGNOR-255201	0.2
FGR	protein	P09769	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	down-regulates activity	phosphorylation	Tyr374	PLPPAPAyLSSPLAL	9606	BTO:0000007								23131831	t		miannu	Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation. 	SIGNOR-276368	0.332
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr145	QGRKRRQtSMTDFYH	9606									20307683	t		lperfetto	Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellshere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo	SIGNOR-259424	0.2
GTF2I	protein	P78347	UNIPROT	USF2	protein	Q15853	UNIPROT	up-regulates activity	binding			9606									21282467	t		lperfetto	TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription	SIGNOR-268537	0.355
AKT3	protein	Q9Y243	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									10949026	t		gcesareni	Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155.	SIGNOR-81118	0.522
SYK	protein	P43405	UNIPROT	LAT2	protein	Q9GZY6	UNIPROT	up-regulates activity	phosphorylation	Tyr233	EEDGEPDyVNGEVAA	10090	BTO:0001930								14722116	t		miannu	Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases.	SIGNOR-273577	0.576
EGFR	protein	P00533	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates activity	phosphorylation	Tyr370	SLEISQSyTTTQRES	-1									25601159	t		miannu	Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks.	SIGNOR-276872	0.41
BABAM2	protein	Q9NXR7	UNIPROT	BRCC ubiquitin ligase complex	complex	SIGNOR-C295	SIGNOR	form complex	binding			9606	BTO:0000007								14636569	t		lperfetto	These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer	SIGNOR-263209	0.2
MAPK3	protein	P27361	UNIPROT	SOS1	protein	Q07889	UNIPROT	down-regulates	phosphorylation	Ser1178	IMSKHLDsPPAIPPR	9606									8816480	t		gcesareni	In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1	SIGNOR-43947	0.621
PLCG1	protein	P19174	UNIPROT	SOS1	protein	Q07889	UNIPROT	up-regulates	binding			9606									10913276	t		gcesareni	We provide evidence that sos1, a p21ras-specific guanine nucleotide exchange factor, directly binds to the sh3 domain of plc-gamma1, and that the sh3 domain of plc-gamma1 is involved in sos1-mediated p21ras activation.	SIGNOR-80024	0.632
PIAS1	protein	O75925	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	sumoylation	Lys276	NVVYRDLkLENLMLD	10090	BTO:0002572								23884910	t		gcesareni	Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity.	SIGNOR-252735	0.387
CSNK2A1	protein	P68400	UNIPROT	WASF2	protein	Q9Y6W5	UNIPROT	down-regulates	phosphorylation	Ser484	IAVEYSDsEDDSSEF	9606									19012317	t		gcesareni	Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo.	SIGNOR-182354	0.2
AKT1	protein	P31749	UNIPROT	KHSRP	protein	Q92945	UNIPROT	down-regulates activity	phosphorylation	Ser193	GLPERSVsLTGAPES	9606									17177604	t		lperfetto	Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome.	SIGNOR-252497	0.692
SLC27A2	protein	O14975	UNIPROT	fatty acyl-CoA	smallmolecule	CHEBI:37554	ChEBI	up-regulates quantity	chemical modification			9606									10198260	t		lperfetto	Very-long-chain acyl-CoA synthetases (VLCS) activate very-long-chain fatty acids (VLCFA) containing 22 or more carbons to their CoA derivatives. 	SIGNOR-260415	0.8
PTTG1	protein	O95997	UNIPROT	TIMP2	protein	P16035	UNIPROT	down-regulates quantity				9606									19351864	f		miannu	Suppressing PTTG expression by siRNA decreased cell motility in both PTTG-HA/EC9706 and KYSE150 cells. By using mass spectrometric analysis, we identified that PTTG up-regulated S100A4 and galectin-1 secretion and down-regulated tissue inhibitor of metalloproteinase-2 secretion to the culture media.	SIGNOR-255069	0.2
CBL	protein	P22681	UNIPROT	EPHA2	protein	P29317	UNIPROT	down-regulates quantity by destabilization	binding			9606									12496371	t		miannu	In our present study, we demonstrate that ligand-mediated stimulation causes EphA2 to be internalized and degraded. The mechanism of this response involves ligand-mediated autophosphorylation of EphA2, which promotes an association between EphA2 and the c-Cbl adaptor protein. We also show that c-Cbl promotes stimulation-dependent EphA2 degradation. 	SIGNOR-272590	0.622
ZFYVE9	protein	O95405	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	relocalization			9606									20515759	t		lperfetto	Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor.	SIGNOR-165786	0.905
CDK1	protein	P06493	UNIPROT	NDUFB6	protein	O95139	UNIPROT	up-regulates activity	phosphorylation	Thr5	tPDEKLRL										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275589	0.2
MAPKAPK2	protein	P49137	UNIPROT	TSC2	protein	P49815	UNIPROT	unknown	phosphorylation	Ser1254	TALYKSLsVPAASTA	9606									12582162	t		llicata	Both in vitro and in vivo experiments demonstrate that the p38-activated kinase mk2 (also known as mapkapk2) is directly responsible for the phosphorylation of ser(1210).	SIGNOR-98201	0.645
RNF31	protein	Q96EP0	UNIPROT	NR0B1	protein	P51843	UNIPROT	up-regulates quantity by stabilization	monoubiquitination			9606	BTO:0002588								19237537	t		miannu	RNF31 promotes monoubiquitination of DAX-1 in an RBR domain-dependent manner. In conclusion, our results suggest that the major DAX-1 modification observed in different experimental settings is likely to be monoubiquitination at one or more lysine residues (multiubiquitination) possibly located within the LBD of DAX-1. RNF31 stabilizes endogenous DAX-1. 	SIGNOR-271786	0.449
AKT1	protein	P31749	UNIPROT	VIM	protein	P08670	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser39	TTSTRTYsLGSALRP	9606									20856200	t		llicata	The binding of akt (tail region) to vim (head region) results in vim ser39 phosphorylation enhancing the ability of vim to induce motility and invasion while protecting vim from caspase-induced proteolysis.	SIGNOR-252511	0.632
CDK1	protein	P06493	UNIPROT	GORASP1	protein	Q9BQQ3	UNIPROT	down-regulates activity	phosphorylation	Ser274	DPLPGPGsPSHSAPD	10116	BTO:0000951								15834132	t		miannu	Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. Phosphorylation of Ser-277 is also dramatically increased during mitosis, however this is mediated by Cdk1 and not by ERK. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events. 	SIGNOR-262840	0.705
olanzapine	chemical	CHEBI:7735	ChEBI	HTR2A	protein	P28223	UNIPROT	down-regulates activity	chemical inhibition			10090	BTO:0000331								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258506	0.8
PRKCA	protein	P17252	UNIPROT	ITGB4	protein	P16144	UNIPROT	down-regulates	phosphorylation	Ser1494	TLTRDYNsLTRSEHS	9606									15121854	t		lperfetto	Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures	SIGNOR-124498	0.51
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser721	PVVSGDTsPRHLSNV	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-251592	0.695
FZD5	protein	Q13467	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates				9606									10937998	f		fspada	Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma)	SIGNOR-80607	0.2
motesanib	chemical	CHEBI:51098	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194560	0.8
AURKB	protein	Q96GD4	UNIPROT	SKA3	protein	Q8IX90	UNIPROT	up-regulates activity	phosphorylation	Ser159	SPRSPQLsDFGLERY	-1									22371557	t		miannu	Aurora B directly phosphorylated Ska1 and Ska3 in vitro, and expression of phosphomimetic mutants of Ska1 and Ska3 impaired Ska KT recruitment and formation of stable KT-MT fibers (K-fibers), disrupting mitotic progression. We propose that Aurora B phosphorylation antagonizes the interaction between the Ska complex and the KMN network, thereby controlling Ska recruitment to KTs and stabilization of KT-MT attachments.	SIGNOR-262661	0.466
PCM1	protein	Q15154	UNIPROT	PCNT	protein	O95613	UNIPROT	up-regulates	relocalization			9606									12403812	t		miannu	Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome	SIGNOR-95117	0.675
WNT9A	protein	O14904	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-132076	0.626
PLK1	protein	P53350	UNIPROT	CENPU	protein	Q71F23	UNIPROT	down-regulates	phosphorylation	Ser77	TFDPPLHsTAIYADE	9606									17081991	t		lperfetto	S77 and t78 of pbip1 are important for plk1-dependent pbip1 phosphorylation and degradation. Here, we demonstrate that a pbd-binding protein, pbip1, is crucial for recruiting plk1 to the interphase and mitotic kinetochores. Unprecedentedly, plk1 phosphorylated pbip1 at t78. Later in mitosis, plk1 also induced pbip1 degradation in a t78-dependent manner, thereby enabling itself to interact with other components critical for proper kinetochore functions	SIGNOR-150453	0.731
EDNRB	protein	P24530	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257428	0.411
FAAP100	protein	Q0VG06	UNIPROT	Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	form complex	binding			9606	BTO:0000567								17396147	t		lperfetto	This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo 	SIGNOR-263244	0.2
ABL1	protein	P00519	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates activity	phosphorylation	Tyr686	IITEYCRyGDLVDYL	-1									19275932	t		miannu	C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis. 	SIGNOR-276142	0.507
PLK1	protein	P53350	UNIPROT	NUDC	protein	Q9Y266	UNIPROT	up-regulates activity	phosphorylation	Ser326	QHPEMDFsKAKFN	9606	BTO:0000567								12852857	t		lperfetto	Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites.	SIGNOR-103407	0.719
TSHB	protein	P01222	UNIPROT	TSHR	protein	P16473	UNIPROT	up-regulates	binding			9606									12045258	t		gcesareni	Two novel human glycoprotein hormonelike genes, alpha2 (a2) and beta5 (b5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners.	SIGNOR-88653	0.712
USP5	protein	P45974	UNIPROT	UBB	protein	P0CG47	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270821	0.756
PTPN12	protein	Q05209	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	9606	BTO:0000567	BTO:0000887;BTO:0001103							8454633	t		gcesareni	Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190.	SIGNOR-39147	0.384
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr199	VKKSIRDtPAKNAQK	9606									12058066	t		lperfetto	However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation.	SIGNOR-216845	0.418
SALL4	protein	Q9UJQ4	UNIPROT	CECR2	protein	Q9BXF3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002572								33144328	t		miannu	SALL4 activates Cecr2 by directly binging to its promotor region and CECR2 in turn promotes reprogramming through forming a SMARCA1-contained chromatin remodeling complex with its DTT domain. 	SIGNOR-263893	0.2
CNOT4	protein	O95628	UNIPROT	RBM15	protein	Q96T37	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								26575292	t		miannu	We demonstrate that RBM15 is methylated by protein arginine methyltransferase 1 (PRMT1) at residue R578, leading to its degradation via ubiquitylation by an E3 ligase (CNOT4). 	SIGNOR-271466	0.367
ANP32A	protein	P39687	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								12522243	t			PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation.	SIGNOR-259082	0.282
YARS1	protein	P54577	UNIPROT	Tyr-tRNA(Tyr)	smallmolecule	CHEBI:29161	ChEBI	up-regulates quantity	chemical modification			9606									16429158	t		miannu	YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr	SIGNOR-270522	0.8
VARS1	protein	P26640	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									30755602	t		miannu	Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 	SIGNOR-270529	0.8
GSK3A	protein	P49840	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates	phosphorylation			9606									16023596	t		gcesareni	Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.	SIGNOR-138592	0.338
AKT1	protein	P31749	UNIPROT	TKT	protein	P29401	UNIPROT	up-regulates activity	phosphorylation	Thr382	GCATRNRtVPFCSTF	9606	BTO:0000567								24981175	t		lperfetto	Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis. 	SIGNOR-265101	0.287
IQGAP1	protein	P46940	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	binding												15695813	t		lperfetto	Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton. 	SIGNOR-261888	0.805
WNT3A	protein	P56704	UNIPROT	FZD2	protein	Q14332	UNIPROT	up-regulates	binding			9606									19910923	t		gcesareni	It was also shown that wnt5a inhibits the beta-catenin pathway by competing with wnt3a for binding to fz2, and that the impairment of clathrin-mediated internalization does not affect this wnt5a inhibitory action.	SIGNOR-189117	0.744
NUP98	protein	P52948	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262098	0.692
GSK3B	protein	P49841	UNIPROT	PHLPP1	protein	O60346	UNIPROT	down-regulates	phosphorylation	Ser1359	VPRPHVQsVLLTPQD	9606									19797085	t		llicata	In addition, we show that the beta-trcp-mediated degradation requires phosphorylation of phlpp1 by casein kinase i and glycogen synthase kinase 3beta (gsk-3beta), and activation of the phosphatidylinositol 3-kinase/akt pathway suppresses the degradation of phlpp1 by inhibiting the gsk-3beta activity.	SIGNOR-188330	0.36
Papain-like proteinase	protein	P0C6X7-PRO_0000037311	UNIPROT	IRF3	protein	Q14653	UNIPROT	down-regulates activity	binding			9606									17761676	t		lperfetto	PLpro interacts with IRF-3, and inhibits the phosphorylation and nuclear translocation of IRF-3, thereby disrupting the activation of type I IFN responses through either Toll-like receptor 3 or retinoic acid inducible gene I/melanoma differentiation-associated gene 5 pathways.	SIGNOR-260276	0.2
CDK2	protein	P24941	UNIPROT	SMAD3	protein	P84022	UNIPROT	unknown	phosphorylation	Ser208	DAGSPNLsPNPMSPA	-1									15241418	t		llicata	Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. We propose that under physiological conditions, phosphorylation of Smad3 by CDK inhibits its transcriptional activity, contributing to a decreased level of p15 and an increased level of c-Myc, thus facilitating cell cycle progression from G1 to S phase.	SIGNOR-250750	0.733
PTPN12	protein	Q05209	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr999	YASSNPEyLSASDVF	9606	BTO:0000567	BTO:0000887;BTO:0001103							8454633	t		gcesareni	Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190.	SIGNOR-39159	0.384
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	CDC25B	protein	P30305	UNIPROT	up-regulates	phosphorylation	Thr355	NKRRRSVtPPEEQQE	9606									23708659	t		lperfetto	Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.	SIGNOR-252779	0.2
LRIG1	protein	Q96JA1	UNIPROT	ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	down-regulates	ubiquitination			9606									16123311	t	inferred from 70% of family members	gcesareni	We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.	SIGNOR-269872	0.727
N-(6-fluoro-1H-indazol-5-yl)-6-methyl-2-oxo-4-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyridine-5-carboxamide	chemical	CHEBI:91332	ChEBI	ROCK2	protein	O75116	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								19740074	t		miannu	We also observed that several ROCK (Rho kinase) inhibitors such as Y-27632 and H-1152, suppressed LRRK2 with similar potency to which they inhibited ROCK2. In contrast, GSK429286A, a selective ROCK inhibitor, did not significantly inhibit LRRK2.	SIGNOR-262230	0.8
dopamine	smallmolecule	CHEBI:18243	ChEBI	noradrenaline	smallmolecule	CHEBI:33569	ChEBI	up-regulates quantity	precursor of			10090									7961964	t	brain	lperfetto	Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway.	SIGNOR-264182	0.8
RAPGEF5	protein	Q92565	UNIPROT	NRAS	protein	P01111	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183738	0.414
ITGB1	protein	P05556	UNIPROT	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253178	0.913
QSOX2	protein	Q6ZRP7	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									18034316	f		miannu	 a pro-apoptotic member of the QSOX superfamily, QSOXN, was described (Wittke et al. 2003). QSOXN was shown to sensitize neuroblastoma cells to INFγ-induced apoptosis, by still unknown mechanisms. In this context, absence of QSOX in fetal epithelia may prevent apoptosis.	SIGNOR-261365	0.7
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	RXRG	protein	P48443	UNIPROT	up-regulates activity	chemical activation			9606									17132853	t		miannu	The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 	SIGNOR-256193	0.8
PLEKHA7	protein	Q6IQ23	UNIPROT	PDZD11	protein	Q5EBL8	UNIPROT	up-regulates activity	binding			10116	BTO:0003618								30463011	t		Simone	Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. The PLEKHA7-PDZD11 Complex Clusters ADAM10 at Junctions through Tspan33	SIGNOR-261253	0.39
Dynorphin A	smallmolecule	CHEBI:4727	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257552	0.8
C6	protein	P13671	UNIPROT	Membrane attack complex	complex	SIGNOR-C313	SIGNOR	form complex	binding			-1									30552328	t		lperfetto	The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer	SIGNOR-263442	0.48
SEC13	protein	P55735	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262091	0.585
MMP13	protein	P45452	UNIPROT	COL2A1	protein	P02458	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly906	EGPPGPQgLAGQRGI	9606									8609233	t		miannu	Although it appears that MMP-1 and MMP-13 both cleave type II collagen initially at the same site, MMP-13 affects a secondary cleavage to produce a 1/4-size collagen fragment with an NH2 terminus three amino acids removed from the primary cleavage site.The present work has demonstrated expression of MMP-13 in human osteoarthritic cartilage and shown that MMP-13 has significant type II collagen degrading activity.	SIGNOR-256340	0.561
mono(2-ethylhexyl) phthalate	chemical	CHEBI:17243	ChEBI	PPARD	protein	Q03181	UNIPROT	up-regulates activity	chemical activation			9606									19433246	t		miannu	Phthalates are true ligands of PPARs. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic.	SIGNOR-268746	0.8
FLT3	protein	P36888	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	phosphorylation	Tyr427	ELFDDPSyVNVQNLD	9606									10482988	t		miannu	Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. 	SIGNOR-251148	0.434
CDK9	protein	P50750	UNIPROT	NCOA2	protein	Q15596	UNIPROT	up-regulates activity	phosphorylation	Ser493	LSPRHRMsSPGVAGS	9606	BTO:0000801								29170386	t			Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties.	SIGNOR-256098	0.248
AKT1	protein	P31749	UNIPROT	PDCD4	protein	Q53EL6	UNIPROT	down-regulates	phosphorylation	Ser67	KRRLRKNsSRDSGRG	9606									17053147	t		gcesareni	Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.	SIGNOR-252496	0.448
GABRD	protein	O14764	UNIPROT	GABA-A (a4-b3-d) receptor	complex	SIGNOR-C327	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263749	0.389
PHIP	protein	Q8WWQ0	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	binding			9534	BTO:0001538								12242307	t		miannu	We have recently reported the isolation of a PH domain-interacting protein, PHIP, which selectively binds to the IRS-1 PH domain and is stably associated with IRS-1 in mammalian cells. Here we demonstrate that overexpression of PHIP in fibroblasts enhances insulin-induced transcriptional responses in a mitogen-activated protein kinase-dependent manner. 	SIGNOR-266962	0.527
PTPN1	protein	P18031	UNIPROT	ROS1	protein	P08922	UNIPROT	down-regulates	dephosphorylation	Tyr2114	RDIYKNDyYRKRGEG	9606									17416557	t		gcesareni	In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products.	SIGNOR-154203	0.38
PRKAA1	protein	Q13131	UNIPROT	SIRT7	protein	Q9NRC8	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr153	TLTHMSItRLHEQKL										27511885	t		lperfetto	Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.|These results strongly suggest that the phosphorylation status of SirT7 at T153 plays a crucial role in determining its subcellular distribution, degradation and binding to REGγ.	SIGNOR-275864	0.2
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1920	SPTYSPTsPKYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120152	0.316
MAPK1	protein	P28482	UNIPROT	PTPRR	protein	Q15256	UNIPROT	up-regulates activity	phosphorylation	Thr361	EPFVSIPtPREKVAM										11493009	t		lperfetto	Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL.	SIGNOR-249438	0.816
Unfolded_Proteins	stimulus	SIGNOR-ST22	SIGNOR	HSPA5	protein	P11021	UNIPROT	down-regulates				9606									31226023	f		miannu	In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation.	SIGNOR-260163	0.7
AMER1	protein	Q5JTC6	UNIPROT	APC	protein	P25054	UNIPROT	up-regulates	relocalization			9606									23151663	t		gcesareni	Apc membrane recruitment protein 1 (amer1;alsoknownas wtx)	SIGNOR-199375	0.726
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	CDC25C	protein	P30307	UNIPROT	up-regulates	binding			9606									14592972	t		lperfetto	Pp1 recognizes cdc25 directly by interacting with a pp1-binding motif in the cdc25 n-terminus.	SIGNOR-264654	0.2
IKK-complex	complex	SIGNOR-C14	SIGNOR	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression				9606									22056382	f			Tnf-α enhanced the transcriptional activity of a classical Notch target gene via Ikk2 by inducing histone H3 phosphorylation	SIGNOR-253586	0.2
UBE3A	protein	Q05086	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	down-regulates activity	ubiquitination			9606	BTO:0000007								28559284	t			Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A	SIGNOR-270946	0.312
BIK	protein	Q13323	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	down-regulates	binding			9606									7478623	t		gcesareni	We have identified a novel cellular protein, bik, that interacts with the cellular survival-promoting proteins, bcl-2 and bcl-xl in transient transfection assays, bik promotes cell death in a manner similar to the death-promoting members of the bcl-2 family, bax and bak.	SIGNOR-26453	0.801
NFIA	protein	Q12857	UNIPROT	ID3	protein	Q02535	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268873	0.2
SLC36A2	protein	Q495M3	UNIPROT	proline	smallmolecule	CHEBI:26271	ChEBI	up-regulates quantity	relocalization			9606									12748860	t		lperfetto	Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut.	SIGNOR-264742	0.8
ATR	protein	Q13535	UNIPROT	USP28	protein	Q96RU2	UNIPROT	up-regulates activity	phosphorylation	Ser67	DERVKEPsQDTVATE										31938050	t		lperfetto	Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity.|Representative immunoblots of n = 3. C Immunoblotting of total and phosphorylated USP28 at serine 67 and 714 in A431 cells exposed to indicated concentrations of CPPD for 6 h.	SIGNOR-275850	0.2
L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	up-regulates quantity	precursor of			9606									32041144	t		miannu	Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce γ-aminobutyric acid (GABA), which exhibits several well-known physiological functions.	SIGNOR-267553	0.8
MAPKAPK2	protein	P49137	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser166	SSRRRAIsETEENSD	9606									15688025	t		gcesareni	Hdm2 phosphorylation by mapkap kinase 2 enhances hdm2 activity and promote the degradation of p53.	SIGNOR-133560	0.371
CHMP4C	protein	Q96CF2	UNIPROT	ESCRT-III	complex	SIGNOR-C379	SIGNOR	form complex	binding			-1									26775243	t		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission.	SIGNOR-265528	0.631
NEDD4	protein	P46934	UNIPROT	SPRY2	protein	O43597	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									19864419	t		miannu	Endogenous and overexpressed Nedd4 polyubiquitinate Spry2 via Lys(48) on ubiquitin and decrease its stability. 	SIGNOR-271425	0.398
PTPRD	protein	P23468	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606	BTO:0000938								27225731	f		miannu	LAR (for leukocyte common antigen-related) is a family of receptor protein tyrosine phosphatases (LAR-RPTPs) with three known members: LAR/PTPRF, PTPδ/PTPRD, and PTPσ/PTPRS. In mammals, LAR-RPTPs have been shown to regulate dendrite and excitatory synapse development and maintenance	SIGNOR-264089	0.7
linifanib	chemical	CHEBI:91435	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193660	0.8
PAX6	protein	P26367	UNIPROT	CDX2/PAX6/P300	complex	SIGNOR-C33	SIGNOR	form complex	binding			9606									10506141	t		lperfetto	In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300.	SIGNOR-70963	0.476
TNKS	protein	O95271	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates quantity by destabilization				9606	BTO:0000007								19759537	t			Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway.	SIGNOR-261249	0.523
ZNF304	protein	Q9HCX3	UNIPROT	CDKN2A	protein	Q8N726	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000391								24623306	t		Luana	Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells.	SIGNOR-266098	0.307
NR3C1	protein	P04150	UNIPROT	NR4A3	protein	Q92570	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15591535	f		gcesareni	We now show that the other nur factors, nurr1 and nor-1, are also subject to antagonism by gr and that this transrepression appears to involve direct protein-protein interactions between the dbds of gr and nur factors.	SIGNOR-132309	0.295
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	LASP1	protein	Q14847	UNIPROT	unknown	phosphorylation	Tyr171	IPTSAPVyQQPQQQP	9606	BTO:0000664								24913448	t	phosphorylation blocks localization at focal adhesion sites and induces binding to CRLK	lperfetto	LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia|We demonstrate that LASP1 is specifically phosphorylated by BCR-ABL at tyrosine-171 in CML patients	SIGNOR-271703	0.2
FFAR1	protein	O14842	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257071	0.311
DCAF7	protein	P61962	UNIPROT	DYRK1A	protein	Q13627	UNIPROT	up-regulates activity	binding			9534	BTO:0000298								14593110	t		Giorgia	Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. HAN11 might target DYRKs to cytosolic locations for regulation of specific cellular functions.	SIGNOR-260630	0.734
STAT1	protein	P42224	UNIPROT	SOCS3	protein	O14543	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19643666	t		lperfetto	Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways.	SIGNOR-249565	0.666
PRKCH	protein	P24723	UNIPROT	GSK3A	protein	P49840	UNIPROT	down-regulates	phosphorylation	Ser21	SGRARTSsFAEPGGG	9606									11884598	t		gcesareni	Furthermore, several pkc isotypes phosphorylate gsk-3 in vitro and in vivo. in the presence of atp, several isoforms (?, ___, _, ?, And of pkc phosphorylated both gsk-3? At ser 21 and gsk-3_ at ser 9	SIGNOR-115730	0.326
PRKACA	protein	P17612	UNIPROT	ABCA1	protein	O95477	UNIPROT	up-regulates activity	phosphorylation	Ser2054	GGNKRKLsTAMALIG	10090	BTO:0000801								12196520	t		miannu	Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins.	SIGNOR-250327	0.485
AMPK	complex	SIGNOR-C15	SIGNOR	RPTOR	protein	Q8N122	UNIPROT	down-regulates	phosphorylation	Ser722	PRLRSVSsYGNIRAV	10090			SIGNOR-C15	SIGNOR-C3					18439900	t		lperfetto	These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK	SIGNOR-263046	0.501
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGC5	protein	Q9Y5F6	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265705	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	TP53BP1	protein	Q12888	UNIPROT	down-regulates activity	phosphorylation	Ser1678	ITSEEERsPAKRGRK	-1									30685087	t		lperfetto	Nuclear import of 53BP1 is required for proper localization of 53BP1 and maintenance of genome integrity. 53BP1 has a classical bipartite nuclear localization signal (NLS) of sequence 1666-GKRKLITSEEERSPAKRGRKS-1686. Ser1678 within the 53BP1 NLS can be phosphorylated by CDK1/cyclin B, and a phosphomimetic substitution of Ser1678 with aspartate has been shown to negatively regulate nuclear import of 53BP1.	SIGNOR-264444	0.562
ZNF462	protein	Q96JM2	UNIPROT	PBX1	protein	P40424	UNIPROT	down-regulates activity	binding			9534	BTO:0000298								17353115	t		miannu	We demonstrated that ZFPIP is expressed in embryonic female genital tract but also in other PBX1 expression domains such as the developing head and the limb buds. We further showed that ZFPIP is able to bind physically and in vivo to PBX1 and moreover, that it prevents the binding of HOXA9/PBX complexes to their consensus DNA site. We suggest that ZFPIP is a new type of PBX1 partner that could participate in PBX1 function during several developmental pathways.	SIGNOR-264477	0.314
oligopeptide	smallmolecule	CHEBI:25676	ChEBI	peptide antigen	smallmolecule	CHEBI:166824	ChEBI	up-regulates quantity	precursor of			9606									31810556	t		scontino	While peptides loaded onto MHC class I molecules are 8–11 amino acid residues long (a restriction based on the size and conformation of the peptide-binding groove of MHC class I molecules), peptides translocated by TAP can be significantly longer. These peptides will be trimmed to the correct length by ERAP-1.	SIGNOR-267770	0.8
TBK1	protein	Q9UHD2	UNIPROT	TNIP1	protein	Q15025	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser123	PPSSGTSsEFEVVTP										36574265	t		lperfetto	TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1	SIGNOR-275734	0.383
CSNK2B	protein	P67870	UNIPROT	EIF5	protein	P55010	UNIPROT	up-regulates activity	phosphorylation	Ser390	KEAEEESsGGEEEDE	9606	BTO:0001938								11861906	t		llicata	Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis.	SIGNOR-251070	0.387
MAP2K1	protein	Q02750	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity	phosphorylation			10090	BTO:0000011								12270934	t		lperfetto	MEK1 as indicated by extensive phosphorylation of ERK1 and ERK2 during the initial 2 h of adipogenesis.	SIGNOR-235352	0.741
PRKD1	protein	Q15139	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	phosphorylation	Thr112	EGMQIPStQFDAAHP	9606	BTO:0001130								19141652	t		lperfetto	This study provides evidence that pkd1 interacts with and phosphorylates beta-catenin at thr(112) and thr(120) we postulate that pkd1 phosphorylation is required to maintain _-catenin transcription activity.	SIGNOR-183384	0.398
SGK1	protein	O00141	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606	BTO:0000007								11154281	t		lperfetto	Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis.	SIGNOR-252988	0.787
SDHD	protein	O14521	UNIPROT	SDH	complex	SIGNOR-C400	SIGNOR	form complex	binding			9606									16143825	t		miannu	Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively.	SIGNOR-266274	0.925
beta-Funaltrexamine	chemical	CHEBI:81527	ChEBI	OPRM1	protein	P35372	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258773	0.8
tRNA(Arg)	smallmolecule	CHEBI:29171	ChEBI	Arg-tRNA(Arg)	smallmolecule	CHEBI:18366	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270369	0.8
PRKACA	protein	P17612	UNIPROT	KCNN2	protein	Q9H2S1	UNIPROT	down-regulates	phosphorylation	Ser464	QAIHQLRsVKMEQRK	9606									16513649	t		llicata	Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization	SIGNOR-145028	0.2
EGFR	protein	P00533	UNIPROT	SCAMP3	protein	O14828	UNIPROT	up-regulates activity	phosphorylation	Tyr41	QYATLDVyNPFETRE	-1									9658162	t		miannu	In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation	SIGNOR-262858	0.408
SOHLH1	protein	Q5JUK2	UNIPROT	ZP1	protein	P60852	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								16690745	t		Luana	Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.	SIGNOR-266077	0.2
NCOA4	protein	Q13772	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates	binding			9606									10347167	t		miannu	Identification of ara70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma. / ppargamma and ara70 interact in the absence of the ppargamma ligand 15-deoxy-delta12,14-prostaglandin j2, although the addition of exogenous ligand enhances this interaction.	SIGNOR-67687	0.461
2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[8-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]octyl]acetamide	chemical	CID:121427831	PUBCHEM	BRD3	protein	Q15059	UNIPROT	down-regulates quantity	chemical inhibition			9606									29764999	t		Monia	DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells	SIGNOR-261096	0.8
fosinoprilat	chemical	CHEBI:116962	ChEBI	ACE	protein	P12821	UNIPROT	down-regulates activity	chemical inhibition			-1									9187274	t		miannu	We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range.	SIGNOR-258613	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	CAD	protein	P27708	UNIPROT	down-regulates activity	phosphorylation	Ser1406	GAGGRRLsSFVTKGY	-1									17485345	t		miannu	The multifunctional protein CAD initiates de novo pyrimidine biosynthesis in mammalian cells. CAD is activated by MAP kinase (Erk1/2) just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. MAP kinase phosphorylates Thr456, while PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation. 	SIGNOR-267442	0.2
PRKG1	protein	Q13976	UNIPROT	PLCB3	protein	Q01970	UNIPROT	down-regulates activity	phosphorylation	Ser1105	LDRKRHNsISEAKMR	10116	BTO:0004576								11278298	t		lperfetto	PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG.	SIGNOR-249077	0.522
citrate(3-)	smallmolecule	CHEBI:16947	ChEBI	PFK	proteinfamily	SIGNOR-PF79	SIGNOR	down-regulates activity	binding			9606									31751601	t		miannu	Once in the cytoplasm, citrate is able to inhibit phosphofructokinase 1 (PFK1) [4], the enzyme that is in charge of the “committed” step in glycolysis and converts fructose-6-phosphate to fructose-1, 6-bisphosphate (Fig. 1). In addition, citrate can inhibit PFK2, a bifunctional enzyme that regulates the rates of glycolysis and gluconeogenesis. Thus, a high level of citrate can lead to the reduction of glycolysis by directly inhibiting PFK1 and PFK2 and indirectly inhibiting PK. 	SIGNOR-267579	0.8
NCOA2	protein	Q15596	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates activity	binding			9606									24239470	t		miannu	The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis	SIGNOR-251531	0.898
PRKCA	protein	P17252	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Thr373	TVLVKDStNRDSLDM	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-129276	0.392
RASSF1	protein	Q9NS23	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates	binding			9606									21808241	t	Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage	milica	Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization.	SIGNOR-175793	0.801
CSNK2A1	protein	P68400	UNIPROT	HDAC2	protein	Q92769	UNIPROT	up-regulates activity	phosphorylation	Ser422	IACDEEFsDSEDEGE	9606	BTO:0000567								12082111	t		llicata	HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2.	SIGNOR-250887	0.608
PAX6	protein	P26367	UNIPROT	CTNND2	protein	Q9UQB3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									16973151	f	Indirect:regulation of expression	miannu	In Pax6 mutant embryos, delta-catenin expression was severely reduced in the optic vesicle neural ectoderm, in the ventricular zone of the neocortex and in the external granule layer of the cerebellum. We identified a Pax6 binding site in delta-catenin promoter that is conserved between mice and humans and which is effectively bound by Pax6 in vitro. Our results suggest that Pax6 regulates delta-catenin expression during CNS development in mice.	SIGNOR-251878	0.387
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	HNF4G	protein	Q14541	UNIPROT	down-regulates quantity by repression				9606									9792724	f		miannu	Retinoic acid mediates down-regulation of the alpha-fetoprotein gene through decreased expression of hepatocyte nuclear factors. The levels of HNF1 and HNF4 mRNA were also decreased following RA treatment.	SIGNOR-254444	0.8
AKT1	protein	P31749	UNIPROT	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser483	IRRPRNYsVGSRPLK	9606	BTO:0000567	BTO:0000562							12853467	t		lperfetto	These findings suggest that pkb-dependent binding of 14-3-3s to phospho-ser483 of cardiac pfk-2 mediates the stimulation of glycolysis by growth factor.	SIGNOR-252464	0.643
BECN1	protein	Q14457	UNIPROT	Vps34 Complex I	complex	SIGNOR-C242	SIGNOR	form complex	binding			-1									30397185	t		lperfetto	PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively.	SIGNOR-260315	0.935
HSPA9	protein	P38646	UNIPROT	MVD	protein	P53602	UNIPROT	down-regulates activity	binding			9534									12646231	t		miannu	Mortalin binds to mevalonate pyrophosphate decarboxyl ase in mammalian cell. Mot-2 inactivates MPD resulting in decreased amounts of the steady state Ras protein.	SIGNOR-265890	0.348
SPDEF	protein	O95238	UNIPROT	MMP9	protein	P14780	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003160								22761428	f		miannu	 Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. 	SIGNOR-255218	0.369
ROBO	proteinfamily	SIGNOR-PF14	SIGNOR	CDC25B	protein	P30305	UNIPROT	down-regulates	phosphorylation	Ser323	QRLFRSPsMPCSVIR	9606	BTO:0000567;BTO:0000938	BTO:0000142							15150265	t		lperfetto	P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteinsphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3	SIGNOR-124843	0.2
PRKACA	protein	P17612	UNIPROT	ADD1	protein	P35611	UNIPROT	down-regulates activity	phosphorylation	Ser481	KEDGHRTsTSAVPNL	-1									8810272	t		miannu	Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin.	SIGNOR-250331	0.316
TLR9	protein	Q9NR96	UNIPROT	TIRAP	protein	P58753	UNIPROT	up-regulates activity	binding			10090									22664090	t		scontino	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266748	0.452
PTPN6	protein	P29350	UNIPROT	ZAP70	protein	P43403	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000782								10458769	t		miannu	We propose that shp1 can dephosphorylate sites in zap-70 and syk that are involved in coupling these kinases to downstream signaling cascades, including erk2 and elements of the il-2 gene.	SIGNOR-70237	0.569
4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone	chemical	CHEBI:91395	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258210	0.8
Nucleosome_H3.3 variant	complex	SIGNOR-C339	SIGNOR	Transcritpional_activation	phenotype	SIGNOR-PH205	SIGNOR	down-regulates				9606									15623580	f		lperfetto	All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage.	SIGNOR-273457	0.7
SP4	protein	Q02446	UNIPROT	CRX	protein	O43186	UNIPROT	up-regulates activity	binding			9606									15781457	t		miannu	Sp4 directly binds Crx. Sp4 and Sp1 produce much higher levels of transcriptional activation when co-transfected with Crx, they may additionally act by directly increasing the rate of transcriptional initiation by the general transcriptional apparatus through their activation domains.	SIGNOR-225333	0.396
MLL-AF4	fusion protein	SIGNOR-FP4	SIGNOR	RUNX1	protein	Q01196	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24449215	f		irozzo	However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins.	SIGNOR-255855	0.2
MMP2	protein	P08253	UNIPROT	DCN	protein	P07585	UNIPROT	down-regulates quantity by destabilization	cleavage	Ser240	ISRVDAAsLKGLNNL	-1									9148753	t		miannu	Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.	SIGNOR-256350	0.682
PPP3CB	protein	P16298	UNIPROT	DNM2	protein	P50570	UNIPROT	unknown	dephosphorylation	Ser764	LQSASSHsPTPQRRP	10116									20496096	t			CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII).	SIGNOR-248363	0.254
CEBPA	protein	P49715	UNIPROT	Mast-Cell_diff	phenotype	SIGNOR-PH117	SIGNOR	down-regulates activity				10090	BTO:0000725								23990620	f			Notably, enforced overexpression of C/EBP-α in BMCPs results in exclusive differentiation into basophils, whereas conditional deletion of C/EBP-α in these same cells promotes mast cell differentiation,1 suggesting that C/EBP-α is an essential “switch factor” for basophil lineage choice	SIGNOR-259967	0.7
MTA1	protein	Q13330	UNIPROT	EPHA2	protein	P29317	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001211								22184117	f	 	miannu	 The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1). we observe that inactivation of endogenous HIC1 through RNA interference in normal breast epithelial cells results in the up-regulation of EphA2 and is correlated with increased cellular migration. chromatin immunoprecipitation (ChIP) and sequential ChIP experiments demonstrate that endogenous HIC1 proteins are bound, together with the MTA1 corepressor, to the EphA2 promoter in WI38 cells. 	SIGNOR-254242	0.292
IRAK4	protein	Q9NWZ3	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity	phosphorylation	Ser376	GSSPSQSsMVARTQT	-1									11960013	t			In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4.	SIGNOR-251328	0.672
RBP2	protein	P50120	UNIPROT	all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	up-regulates quantity	relocalization			9606									31963453	t		lperfetto	Either acting on the producing cell (autocrine signaling) or the receiving cell (paracrine signaling), RA is transferred into the nucleus by Cellular retinoic acid-binding protein 2 (CRABP2) [18]. Once inside the nucleus, RA binds to specific nuclear transcription factors named Retinoic acid receptors (RARs)	SIGNOR-265130	0.8
TGFB1	protein	P01137	UNIPROT	COL4A1	protein	P02462	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000764								20846954	f	Regulation	miannu	We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes. 	SIGNOR-251922	0.376
H4C1	protein	P62805	UNIPROT	Nucleosome	complex	SIGNOR-C371	SIGNOR	form complex	binding			-1									21812398	t		lperfetto	The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP.	SIGNOR-265311	0.2
GNG12	protein	Q9UBI6	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606	BTO:0000586								16293724	t		gcesareni	We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin.	SIGNOR-141795	0.373
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	BHLHE40	protein	O14503	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002181								25202122	t		miannu	 During unperturbed cell cycles, DEC1 is a highly unstable protein that is targeted for proteasome-dependent degradation by the SCF(βTrCP) ubiquitin ligase in cooperation with CK1. 	SIGNOR-276853	0.351
CERS5	protein	Q8N5B7	UNIPROT	ceramide	smallmolecule	CHEBI:17761	ChEBI	up-regulates quantity	chemical modification			9606									26887952	t	done	miannu	 Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity. 	SIGNOR-273996	0.8
IKBKB	protein	O14920	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates activity	phosphorylation			10090	BTO:0002572;BTO:0000801		SIGNOR-C14						21232017	t		lperfetto	Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation	SIGNOR-235400	0.92
ELAVL3	protein	Q14576	UNIPROT	ANK3	protein	Q12955	UNIPROT	down-regulates quantity	post transcriptional regulation			9606	BTO:0000938								29614249	t		miannu	NElavl (composed of Elavl2, Elavl3, and Elavl4) proteins are the RNA-binding proteins that is specifically expressed in neurons, regulate the alternative splicing of target RNAs, and promote neuronal differentiation and maturation. Here, we found that the alternative splicing of AnkyrinG exon 34 was misregulated in the cerebella of Elavl3-/- mice. AnkyrinG is an essential factor for the formation of neuronal polarity and is required for normal neuronal functions. 	SIGNOR-266861	0.253
LYN	protein	P07948	UNIPROT	CD79B	protein	P40259	UNIPROT	up-regulates activity	phosphorylation	Tyr196	GMEEDHTyEGLDIDQ	-1									9531288	t			Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b	SIGNOR-251398	0.665
SRC	protein	P12931	UNIPROT	LRP1	protein	Q07954	UNIPROT	up-regulates	phosphorylation	Tyr4473	VEIGNPTyKMYEGGE	9606									18381291	t		lperfetto	The observation that the wild type protein was phosphorylated to a higher level than the y4473f mutant again indicates that phosphorylation of the tyr4473 residue by v-src is occurring in these cellsmutation of tyr4473 to alanine, which abolishes snx17 binding, resulted in impaired receptor recycling and reduced amounts of the mature form of lrp1 on the cell surface	SIGNOR-178159	0.402
PRKG1	protein	Q13976	UNIPROT	PPP1R17	protein	O96001	UNIPROT	up-regulates	phosphorylation	Thr119	KKPRRKDtPALHMSP	9606	BTO:0001011								10051666	t		miannu	 Recombinant human G-substrate was phosphorylated efficiently by cGMP-dependent protein kinase exclusively at Thr residues, and it was recognized by antibodies specific for rabbit phospho-G-substrate. The amino acid sequences surrounding the sites of phosphorylation in G-substrate are related to those around Thr-34 and Thr-35 of the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and inhibitor-1, respectively, two potent inhibitors of protein phosphatase 1. 	SIGNOR-263147	0.646
CORT	protein	O00230	UNIPROT	SSTR4	protein	P31391	UNIPROT	up-regulates	binding			9606	BTO:0000938								11011067	t		gcesareni	Cortistatin is known to bind all five cloned somatostatin receptors and share many pharmacological and functional properties with somatostatin including the depression of neuronal activity.	SIGNOR-82493	0.636
DGC	complex	SIGNOR-C217	SIGNOR	GABA-A (a6-b1-g2) receptor	complex	SIGNOR-C334	SIGNOR	up-regulates quantity	binding			9606	BTO:0000938;BTO:0002606								22626542	t		miannu	 In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses.	SIGNOR-265439	0.2
RPS6KB1	protein	P23443	UNIPROT	MTOR	protein	P42345	UNIPROT	down-regulates activity	phosphorylation	Thr2446	NKRSRTRtDSYSAGQ	9606									15905173	t		lperfetto	Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain	SIGNOR-102051	0.96
NTRK2	protein	Q16620	UNIPROT	SHC3	protein	Q92529	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000142							9507002	t		gcesareni	Our present study established that n-shc and sck are expressed in a region-specific manner in the brain and that n-shc is a higher affinity adapter molecule than sck for trka and trkb receptors	SIGNOR-55864	0.744
SP3	protein	Q02447	UNIPROT	SLC9A3	protein	P48764	UNIPROT	up-regulates quantity by expression	transcriptional regulation			7227	BTO:0001677								16464174	f	 	 	Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity	SIGNOR-254271	0.2
PIAS1	protein	O75925	UNIPROT	SATB2	protein	Q9UPW6	UNIPROT	down-regulates activity	sumoylation	Lys233	YKKYKKIkVERVERE	9606									14701874	t		gianni	We found that SATB2 differs from the closely related thymocyte-specific protein SATB1 by modifications of two lysines with the small ubiquitive related modifier (SUMO), which are augmented specifically by the SUMO E3 ligase PIAS1.	SIGNOR-268932	0.564
CHUK	protein	O15111	UNIPROT	NCOR2	protein	Q9Y618	UNIPROT	down-regulates	phosphorylation	Ser2407	AKVSGRPsSRKAKSP	9606			SIGNOR-C14						15494311	t	Translocation from Nucleus to Cytoplasm	gcesareni	Nf-kappab transcription requires ikkalpha to phosphorylate smrt on chromatin, stimulating the exchange of corepressor for coactivator complexes. Ikk directly phosphorylates smrt to stimulate nuclear export. Ikkalpha orchestrates smrt derepression, a prerequisite for nf-kappab transcription and survival.	SIGNOR-129956	0.426
NFATC1	protein	O95644	UNIPROT	MYH7	protein	P12883	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								17111365	f	Regulation	miannu	Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner. 	SIGNOR-251956	0.278
FGF13	protein	Q92913	UNIPROT	SCN9A	protein	Q15858	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253423	0.366
MECP2	protein	P51608	UNIPROT	GAMT	protein	Q14353	UNIPROT	up-regulates quantity by expression	post transcriptional regulation			10090	BTO:0000614								18511691	t		Luana	MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.	SIGNOR-264678	0.284
Cyclopamine	chemical	CHEBI:4021	ChEBI	SMO	protein	Q99835	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001757								12202832	t		gcesareni	We investigate the therapeutic efficacy of the Hh pathway antagonist cyclopamine in preclinical models of medulloblastoma, the most common malignant brain tumor in children. Cyclopamine treatment of murine medulloblastoma cells blocked proliferation in vitro and induced changes in gene expression consistent with initiation of neuronal differentiation and loss of neuronal stem cell-like character.	SIGNOR-174432	0.8
TGFBI	protein	Q15582	UNIPROT	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	up-regulates activity				10090	BTO:0004093								25786978	t		lperfetto	First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs.	SIGNOR-253284	0.36
NCOA3	protein	Q9Y6Q9	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								15808510	f		gcesareni	Ikkalpha in conjunction with eralpha and aib1/src-3, is important in activating the transcription of estrogen-responsive genes, including cyclin d1.	SIGNOR-135056	0.489
MAPK1	protein	P28482	UNIPROT	TFCP2	protein	Q12800	UNIPROT	down-regulates	phosphorylation	Ser309	SLGEGNGsPNHQPEP	9606									19237534	t		lperfetto	We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309.	SIGNOR-184172	0.34
OGG1	protein	O15527	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				10090									26221032	f		miannu	Cut repeats from the CUX1 protein were recently shown to stimulate 8-oxoguanine DNA glycosylase 1 (OGG1), an enzyme that removes oxidized purines from DNA and introduces a single strand break through its apurinic/apyrimidinic lyase activity to initiate base excision repair.	SIGNOR-263959	0.7
RAD51AP1	protein	Q96B01	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									17996711	f		miannu	Homologous recombination (HR) repairs chromosome damage and is indispensable for tumor suppression in humans. RAD51 mediates the DNA strand-pairing step in HR. RAD51 associated protein 1 (RAD51AP1) is a RAD51-interacting protein whose function has remained elusive. Biochemical and cytological results show that RAD51AP1 functions at a step subsequent to the assembly of the RAD51-ssDNA nucleoprotein filament. Purified RAD51AP1 binds both dsDNA and a D loop structure and, only when able to interact with RAD51, greatly stimulates the RAD51-mediated D loop reaction.	SIGNOR-261961	0.7
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	GAB2	protein	Q9UQC2	UNIPROT	up-regulates	phosphorylation			9606									15356145	t	inferred from 70% family members	lperfetto	Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623.	SIGNOR-270000	0.2
CTSD	protein	P07339	UNIPROT	BGLAP	protein	P02818	UNIPROT	down-regulates quantity by destabilization	cleavage	Ala92	DHIGFQEaYRRFYGP	-1									9076588	t		miannu	This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 	SIGNOR-256319	0.318
RNA helicases DDX5/DDX17	complex	SIGNOR-C34	SIGNOR	NFAT5	protein	O94916	UNIPROT	up-regulates activity	binding			9606	BTO:0000815								22266867	t	done	miannu	In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. 	SIGNOR-274112	0.36
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CDCA7	protein	Q9BWT1	UNIPROT	down-regulates	phosphorylation	Thr163	SRRPRRRtFPGVASR	9606									23166294	t		llicata	The prosurvival kinase akt phosphorylates cdca7 at threonine 163, promoting binding to 14-3-3, dissociation from myc, and sequestration to the cytoplasm. we have mapped the domains of interaction and have discovered that akt phosphorylates cdca7 near this contact region, leading to loss of its association with myc, binding to 14-3-3 proteins, and exclusion from the nucleus.	SIGNOR-199776	0.2
1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methyl-1-piperazinyl)anilino]-2-prop-2-enyl-3-pyrazolo[3,4-d]pyrimidinone	chemical	CHEBI:91414	ChEBI	WEE1	protein	P30291	UNIPROT	down-regulates	chemical inhibition			9606									20068082	t		gcesareni	Mk-1775 (merck). This wee1 inhibitor (ic50, 5.2nm) potentiates the activity of dna-damaging agents (e.g., gemcitabine, cisplatin, carboplatin) in vitro and in vivo, particularly in p53-negative cancers	SIGNOR-163173	0.8
HNF1B	protein	P35680	UNIPROT	UMOD	protein	P07911	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18846391	f	 	miannu	 UMOD transcription is activated by the transcription factor HNF1B.	SIGNOR-254441	0.375
CSNK2A1	protein	P68400	UNIPROT	BRCA1	protein	P38398	UNIPROT	unknown	phosphorylation	Ser1572	ESGISLFsDDPESDP	-1									10403822	t		llicata	 Subsequent studies showed that BRCA1 was phosphorylated in vitro by CK2. An analysis by site directed mutagenesis of BRCA1 showed that in vitro phosphorylation by CK2 required a serine at aa1572. These data implicate CK2 as a potential mediator of BRCA1 activity.	SIGNOR-250832	0.379
CSNK2A2	protein	P19784	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Ser112	KRAGGEEsQFEMDI	9606	BTO:0000007								9806882	t		lperfetto	The kinase is quite distinct from casein kinase 2, which also phosphorylates Ser-111 of 4E-BP1. The possible importance of these kinases in the phosphorylation of 4E-BP1 in fat cells is discussed. It is suggested that the phosphorylation of Ser-111 might be a priming event that facilitates the subsequent phosphorylation of Thr-36, Thr-45, Ser-64 and Thr69 by a rapamycin-sensitive process that initiates the dissociation of 4E-BP1 from eIF4E and hence the formation of the eIF4F complex.	SIGNOR-249334	0.338
TUFM	protein	P49411	UNIPROT	ATG5	protein	Q9H1Y0	UNIPROT	down-regulates activity	binding			9606									33113344	t		miannu	PINK1 interacts with the autophagy effector TUFm and phosphorylates TUFm at Ser222. These results indicated that p222-hTUFm sequestered more monomer Atg5 and reduced the conjugated Atg5-Atg12 complex to subdue mitophagy.	SIGNOR-266383	0.436
MAPK1	protein	P28482	UNIPROT	PPP1R9B	protein	Q96SB3	UNIPROT	unknown	phosphorylation	Ser15	GPGGPLRsASPHRSA	9606									15728359	t		lperfetto	We have identified three sites phosphorylated by ERK2 (Ser-15 and Ser-205) and cyclin-dependent PK 5 (Cdk5) (Ser-17), within the actin-binding domain of spinophilin.	SIGNOR-249435	0.476
cortisol	smallmolecule	CHEBI:17650	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								8282004	t		miannu	The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4).	SIGNOR-258708	0.8
KIF3A	protein	Q9Y496	UNIPROT	Minus-end directed microtubule movement	phenotype	SIGNOR-PH217	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272538	0.7
LYN	protein	P07948	UNIPROT	YY1	protein	P25490	UNIPROT	down-regulates activity	phosphorylation	Tyr8	MASGDTLyIATDGSE	9606	BTO:0002181								26198631	t		miannu	In the case of Lyn overexpression, single mutations at either tyrosine 8, 254, or 383 severely reduced Lyn-mediated YY1 phosphorylation, suggesting that these three sites may be targets of Lyn in vivo (Fig. 3, A and B).	SIGNOR-276930	0.2
ZBTB43	protein	O43298	UNIPROT	BDP1	protein	A6H8Y1	UNIPROT	unknown	binding			9606									16542149	t		miannu	The zinc finger protein ZNF297B interacts with BDP1, a subunit of TFIIIB. Due to the essential role of BDP1 in Pol III transcription, we propose that ZNF297B may also regulate these transcriptional pathways.	SIGNOR-225852	0.466
PRKCE	protein	Q02156	UNIPROT	PRKCE	protein	Q02156	UNIPROT	down-regulates	phosphorylation	Ser729	QEEFKGFsYFGEDLM	9606									11964154	t		llicata	Protein kinase-inactive mutants of pkcepsilon were not phosphorylated at ser(729) in cells, and phosphorylation of this site leads to dephosphorylation of the activation-loop thr(566)	SIGNOR-117324	0.2
SMAD3/PIAS3	complex	SIGNOR-C204	SIGNOR	STAT3	protein	P40763	UNIPROT	down-regulates				9606									26194464	t		mrosina	In summary, the TGF-b/IL-6/TCR-pERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation	SIGNOR-255036	0.632
MIOS	protein	Q9NXC5	UNIPROT	GATOR2	complex	SIGNOR-C193	SIGNOR	form complex	binding			9606									23723239	t		miannu	Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5	SIGNOR-255301	0.944
NEDD4L	protein	Q96PU5	UNIPROT	SCN3A	protein	Q9NY46	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000938								23778145	t		miannu	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 	SIGNOR-253464	0.287
ALDOC	protein	P09972	UNIPROT	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266489	0.8
PTPRH	protein	Q9HD43	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606									10734133	t		gcesareni	These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase	SIGNOR-76076	0.273
PSMB1	protein	P20618	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263356	0.863
LYN	protein	P07948	UNIPROT	HCLS1	protein	P14317	UNIPROT	unknown	phosphorylation	Tyr222	MEAPTTAyKKTTPIE	-1									10066823	t			HS1 was shown to undergo a process of sequential phosphorylation both in vitro and in vivo, which is synergistically mediated by Syk and Src family protein-tyrosine kinases and essential for B cell antigen receptor-mediated apoptosis. We have now identified tyrosine 222 as the HS1 residue phosphorylated by the Src family protein kinases c-Fgr and Lyn	SIGNOR-251399	0.702
MED8	protein	Q96G25	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266659	0.792
metformin	chemical	CHEBI:6801	ChEBI	CRTC2	protein	Q53ET0	UNIPROT	down-regulates				9606									20577053	f		gcesareni	It has been proposed that metformin stimulates crtc2 phosphorylation in response to metabolic signals such as energy stress through the lkb1-ampk/sik1 pathways, which promotes binding to 14-3-3 proteins, thereby sequestering crtc2 from the nucleus to the cytoplasm	SIGNOR-166361	0.8
KMT2C	protein	Q8NEZ4	UNIPROT	MLL3 complex	complex	SIGNOR-C446	SIGNOR	form complex	binding			9606									34156443	t		miannu	MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. 	SIGNOR-268809	0.2
PPP3CC	protein	P48454	UNIPROT	KSR2	protein	Q6VAB6	UNIPROT	up-regulates activity	dephosphorylation	Ser198	IRTHLSQsPRVPSKC	10090									19560418	t			These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3	SIGNOR-248525	0.262
MAPK1	protein	P28482	UNIPROT	KDM4B	protein	O94953	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr1065	AKRPRVGtPLATEDS	9606	BTO:0001109								28945223	t		miannu	In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation. 	SIGNOR-276744	0.2
FYN	protein	P06241	UNIPROT	DCC	protein	P43146	UNIPROT	up-regulates activity	phosphorylation	Tyr1420	TEDSANVyEQDDLSE	10090	BTO:0001909								15557120	t		miannu	Fyn tyrosine kinase, but not Src, regulates the phosphorylation of DCC in N1E-115 neuroblastoma cells.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1. these results show that DCC is phosphorylated by Fyn, but not Src, in N1E-115 cells, and that tyrosines 1261 and 1418 are the major phosphorylation sites of Fyn in vivo.	SIGNOR-268176	0.554
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								29953871	f		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. 	SIGNOR-264953	0.7
CDK1	protein	P06493	UNIPROT	NPM1	protein	P06748	UNIPROT	down-regulates activity	phosphorylation	Thr237	KQEKTPKtPKGPSSV	9606									14670079	t		gcesareni	We further demonstrate that phospho-mkk1/mkk2 antibodies recognize npm on the c-terminal region, which is phosphorylated by cdc2 (cell division control kinase-2) during g2/m-phase. biochemical and immunocytochemistry analyses verified that the phospho-mkk1/mkk2 antibodies cross-reacted with npm that was phosphorylated at thr234 and thr237 during g2/m-phase, which are the same sites that are targeted by cdc2 (cell division cycle protein-2) during mitosis.	SIGNOR-120334	0.534
RELA	protein	Q04206	UNIPROT	IEX-1L	protein	O75353	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9703517	f		gcesareni	Transcription factors of the nuclear factor-kappab/rel (nf-kappab) family may be important in cell survival by regulating unidentified, anti-apoptotic genes. One such gene that protects cells from apoptosis induced by fas or tumor necrosis factor type alpha (tnf), iex-1l, is described here.	SIGNOR-59542	0.2
EZH2	protein	Q15910	UNIPROT	HOXA9	protein	P31269	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20565746	t		miannu	These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression.	SIGNOR-260068	0.406
PRKACA	protein	P17612	UNIPROT	PJA2	protein	O43164	UNIPROT	up-regulates activity	phosphorylation	Thr389	RVITQREtENNQMTS	-1									21423175	t		miannu	In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h).	SIGNOR-276325	0.2
ATP7A	protein	Q04656	UNIPROT	SOD3	protein	P08294	UNIPROT	up-regulates activity				10090									29301787	t		lperfetto	Copper transporter ATP7A (copper-transporting/ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide.	SIGNOR-272267	0.684
mTORC1	complex	SIGNOR-C3	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606		BTO:0001103							15829723	f		apalma	Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction	SIGNOR-256064	0.7
CAMK2A	protein	Q9UQM7	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Thr574	VDNIRSAtPEALAFV	9606	BTO:0000938	BTO:0000142							12486117	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-96628	0.38
PPP5C	protein	P53041	UNIPROT	ABCB1	protein	P08183	UNIPROT	down-regulates activity	dephosphorylation	Ser661	SSNDSRSsLIRKRST	9606	BTO:0000007								24333728	t			Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp	SIGNOR-272505	0.2
TRAF7	protein	Q6Q0C0	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									15001576	f		miannu	Overexpression of traf7 induced caspase-dependent apoptosis.	SIGNOR-256666	0.7
HHIP	protein	Q96QV1	UNIPROT	SHH	protein	Q15465	UNIPROT	down-regulates activity	binding			10090									10050855	t		lperfetto	Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal.	SIGNOR-65078	0.893
NMDA receptor_2B	complex	SIGNOR-C348	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									30037851	t		miannu	NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS). 	SIGNOR-264219	0.8
LPAR	proteinfamily	SIGNOR-PF2	SIGNOR	GNA12	protein	Q03113	UNIPROT	up-regulates	binding			10090	BTO:0000944								15856019	t	inferred from 70% family members	milica	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13.	SIGNOR-269968	0.2
LCK	protein	P06239	UNIPROT	CCDC50	protein	Q8IVM0	UNIPROT	down-regulates activity	phosphorylation	Tyr304	SSHKGFHyKH	9606	BTO:0000567								19059208	t		miannu	We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling.	SIGNOR-262855	0.2
naproxen	chemical	CHEBI:7476	ChEBI	PTGS1	protein	P23219	UNIPROT	down-regulates activity	chemical inhibition			-1									9057869	t		miannu	Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). 	SIGNOR-258603	0.8
CNR1	protein	P21554	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity				9606	BTO:0002036								25012566	f		lperfetto	We subsequently analyzed whether Gαo modulates the cellular activities of Necdin. Notably, expression of Gαo significantly augmented Necdin-mediated cellular responses, such as proliferation and differentiation. Moreover, activation of type 1 cannabinoid receptor (CB1R), a Gi/oα-coupled receptor, augmented cell growth suppression, which was mediated by Gαo and Necdin in U87MG cells containing CB1R, Gαo, and Necdin as normal components.	SIGNOR-253389	0.444
CSNK2A1	protein	P68400	UNIPROT	SSRP1	protein	Q08945	UNIPROT	down-regulates activity	phosphorylation	Ser688	KRRRSEDsEEEELAS	9606									15659405	t		llicata	CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity.	SIGNOR-250961	0.689
FN1	protein	P02751	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates				9606									20457810	f		fspada	We conclude that, by interacting with fibronectin, pref-1 activates integrin downstream signaling to activate mek/erk and to inhibit adipocyte differentiation.	SIGNOR-165350	0.589
2'-deoxyguanosine	smallmolecule	CHEBI:17172	ChEBI	2'-deoxyguanosine 5'-monophosphate(2-)	smallmolecule	CHEBI:57673	ChEBI	up-regulates quantity	precursor of												20637175	t		lperfetto	Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis	SIGNOR-275812	0.8
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates activity	phosphorylation	Tyr293	HRIDGKTyVIKRVKY	9606	BTO:0001282								16373505	t			PKR autophosphorylates on Y101, Y162, and Y293. The introduction of the Y293F mutation causes significant defects in PKR autophosphorylation and eIF2α phosphorylation, providing evidence for a critical function of this phosphorylated residue.	SIGNOR-251114	0.2
PIM1	protein	P11309	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates													16146838	f		lperfetto	The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells.	SIGNOR-256657	0.7
MARK1	protein	Q9P0L2	UNIPROT	MAP2	protein	P11137	UNIPROT	down-regulates activity	phosphorylation	Ser1679	NVKSKIGsTDNIKYQ	-1									8631898	t		miannu	Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 	SIGNOR-250164	0.428
TP53	protein	P04637	UNIPROT	SIAH1	protein	Q8IUQ4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								20181957	t		miannu	P53 directly induces the expression of Siah-1 and in turn formation of a unique SCF-like complex (SCF(TBL1)) comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin β-like 1 (TBL1), and APC	SIGNOR-271953	0.382
POU5F1	protein	Q01860	UNIPROT	DKK1	protein	O94907	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086								17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254934	0.358
TTI1	protein	O43156	UNIPROT	mTORC2	complex	SIGNOR-C2	SIGNOR	up-regulates quantity by stabilization	binding			9606	BTO:0000007								20427287	t		miannu	MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. 	SIGNOR-272004	0.643
DLG3	protein	Q92796	UNIPROT	Scribble_complex_DLG3-LLGL2_variant	complex	SIGNOR-C504	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270885	0.495
PRKCE	protein	Q02156	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606		BTO:0001253							16418226	t		gcesareni	Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation.	SIGNOR-143832	0.409
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRIK1	protein	P39086	UNIPROT	up-regulates activity	chemical activation			9606									27586965	t		miannu	Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors	SIGNOR-264470	0.8
IKBKE	protein	Q14164	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser644	GLDFNFDsLISTQNV	9606	BTO:0000150;BTO:0000551								23691078	t		lperfetto	Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation.	SIGNOR-252949	0.418
IKZF1	protein	Q13422	UNIPROT	Lymphopoiesis	phenotype	SIGNOR-PH111	SIGNOR	up-regulates activity				9606	BTO:0000725								25085254	f			The Ikaros family of DNA binding proteins are critical regulators of lymphocyte differentiation. In multipotent hematopoietic progenitors, Ikaros supports transcriptional priming of genes promoting lymphocyte differentiation.	SIGNOR-259958	0.7
pentazocine	chemical	CHEBI:7982	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258934	0.8
PTPRA	protein	P18433	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates	dephosphorylation	Tyr530	FTSTEPQyQPGENL	9606	BTO:0000938								7691597	t		gcesareni	Endogenous pp60c-src kinase activity is enhanced in the rptp alpha-transfected cells, which may be due to direct dephosphorylation of the regulatory tyr residue at position 527 in pp60c-src by rptp alpha.	SIGNOR-32014	0.733
WNT3A	protein	P56704	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								21078818	t		gcesareni	We demonstrate here that prototype canonical Wnt3a and noncanonical Wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-LRP5/6 and Ror1/2, respectively-through a common mechanism that involves their Wnt-dependent coupling to the Frizzled (Fzd) coreceptor and recruitment of shared components, including dishevelled (Dvl), axin, and glycogen synthase kinase 3 (GSK3)	SIGNOR-169654	0.626
icariin	chemical	CHEBI:78420	ChEBI	PDE5A	protein	O76074	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193363	0.8
MAPK1	protein	P28482	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates	phosphorylation	Ser780	DSLDSRLsPPAGLFT	9606		BTO:0000975							10194762	t		lperfetto	Gh treatment of chinese hamster ovary cells stably transfected with the gh receptor (choa cells) led to rapid and transient activation of both stat5a and erk1 and erk2. these observations show, for the first time, direct physical interaction between erk and stat5a and also clearly identify serine 780 as a target for erk.	SIGNOR-66239	0.751
Scribble_complex_DLG5-LLGL1_variant	complex	SIGNOR-C508	SIGNOR	Cell_polarity	phenotype	SIGNOR-PH213	SIGNOR	up-regulates				9606									23397623	f		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270902	0.7
RNF123	protein	Q5XPI4	UNIPROT	CBX5	protein	P45973	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									23077635	t		miannu	In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation.	SIGNOR-272035	0.2
Fibrin	complex	SIGNOR-C317	SIGNOR	PLAT	protein	P00750	UNIPROT	up-regulates				9606		BTO:0000131							1447176	f		lperfetto	The presence of fibrin greatly accelerates the activation of plasminogen by tPA and hence can exert a regulatory influence over plasminogen activation 	SIGNOR-263536	0.2
ITGA4	protein	P13612	UNIPROT	A4/b7 integrin	complex	SIGNOR-C187	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253293	0.852
MAPK1	protein	P28482	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr522	SSPGSPGtPGSRSRT	9606									10737616	t		lperfetto	Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease.	SIGNOR-249417	0.553
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1951	SPGYSPTsPTYSLTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120080	0.781
PRKAA2	protein	P54646	UNIPROT	ULK1	protein	O75385	UNIPROT	up-regulates	phosphorylation	Ser317	SHLASPPsLGEMQQL	9606			SIGNOR-C15						21205641	t		gcesareni	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-170859	0.483
PTPRG	protein	P23470	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates activity	dephosphorylation	Tyr730	DMKPGVSyVVPTKAD	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254710	0.2
SMARCE1	protein	Q969G3	UNIPROT	Brain-specific SWI/SNF SMARCA2 variant	complex	SIGNOR-C485	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270744	0.783
CDK2	protein	P24941	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Thr821	KISEGLPtPTKMTPR	9606			SIGNOR-C83						9139732	t		miannu	We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein.	SIGNOR-47895	0.879
CSNK2B	protein	P67870	UNIPROT	CTDP1	protein	Q9Y5B0	UNIPROT	down-regulates activity	phosphorylation	Ser575	AGESLDQsMEEEEEE	9606	BTO:0000567								12591939	t		llicata	We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified 	SIGNOR-251063	0.332
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ZNF322	protein	Q6U7Q0	UNIPROT	up-regulates activity	phosphorylation	Ser224	EKSYRHRsAFIVHKR	9606	BTO:0002552								31399647	t		miannu	We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A.	SIGNOR-276755	0.2
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1875	SPTSPKYsPTSPTYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii	SIGNOR-203568	0.77
CAMK2D	protein	Q13557	UNIPROT	CEACAM1	protein	P13688	UNIPROT	up-regulates	phosphorylation	Thr457	CFLHFGKtGRASDQR	9606		BTO:0000149							24302721	t		lperfetto	Camkiid specifically phosphorylates thr-457 on ceacam1-sf, which in turn regulates the process of lumen formation via apoptosis of the central acinar cells.	SIGNOR-203402	0.2
DIABLO	protein	Q9NR28	UNIPROT	BIRC3	protein	Q13489	UNIPROT	down-regulates quantity	binding			9606									14960576	t		amattioni	Smac/diablo selectively causes the rapid degradation of c-iap1 and c-iap2 in hela cells. Smac binding to c-iap via its n-terminal iap-binding motif is the prerequisite for this effect	SIGNOR-121886	0.785
terazosin	chemical	CHEBI:9445	ChEBI	ADRA1B	protein	P35368	UNIPROT	down-regulates activity	chemical inhibition			9606		BTO:0001260							9379432	t		miannu	Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication	SIGNOR-258669	0.8
RNF31	protein	Q96EP0	UNIPROT	CASP1	protein	P29466	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0005111								32122970	t		miannu	HOIP forms a constitutive interaction with caspase-1 and mediates the linear ubiquitination of the CARD pro-domain. Upon engagement of apoptosis, caspase-1 and caspase-8 cleave HOIP at Asp-348 and Asp-387, limiting the ability of LUBAC to ubiquitinate substrates. 	SIGNOR-272191	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	SOS1	protein	Q07889	UNIPROT	down-regulates	phosphorylation			9606									8816480	t	inferred from 70% family members	gcesareni	In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1	SIGNOR-270112	0.2
PLK3	protein	Q9H4B4	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Ser370	TSVTPDVsDNEPDHY	9606									20940307	t		gcesareni	Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis	SIGNOR-168469	0.342
CHEK1	protein	O14757	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser366	PGGSRAHsSHLKSKK	9606	BTO:0001321								15659650	t		lperfetto	Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage.	SIGNOR-217853	0.772
SRC	protein	P12931	UNIPROT	FHIT	protein	P49789	UNIPROT	up-regulates activity	phosphorylation	Tyr114	FHRNDSIyEELQKHD	-1									15835917	t		lperfetto	The human tumor suppressor Fhit is a homodimeric histidine triad (HIT) protein of 147 amino acids which has Ap3A hydrolase activity. We have recently discovered that Fhit is phosphorylated in vivo and is phosphorylated in vitro by Src kinaseMALDI-TOF and HPLC-ESI tandem mass spectrometry of intact Fhit and proteolytic peptides of Fhit demonstrated that Fhit is phosphorylated on Y114 on either one or both subunitsThe decreases in the values of Km and kcat for the phosphorylated forms in comparison to those of unphosphorylated Fhit favor the formation and lifetime of the Fhit_Ap3A complex, which may enhance the tumor suppressor activity of Fhit.	SIGNOR-247134	0.479
STK11	protein	Q15831	UNIPROT	SIK1	protein	P57059	UNIPROT	up-regulates	phosphorylation	Thr182	KSGEPLStWCGSPPY	9606									14976552	t		lperfetto	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122784	0.566
CAMK2A	protein	Q9UQM7	UNIPROT	SYNGAP1	protein	Q96PV0	UNIPROT	up-regulates activity	phosphorylation	Ser779	FMARGLNsSMDMARL	-1									14970204	t		miannu	Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. The Major Phosphorylation Sites, Serines 764/765, 1058, and 1123, All Contribute to Regulation of GAP Activity of synGAP by CaMKII	SIGNOR-262689	0.439
tamsulosin	chemical	CHEBI:9398	ChEBI	ADRA1B	protein	P35368	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258470	0.8
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRM5	protein	P41594	UNIPROT	up-regulates activity	chemical activation			9606									25042998	t		miannu	Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate	SIGNOR-264070	0.8
CTNNB1	protein	P35222	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									18697834	f		Simone Vumbaca	 we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells.	SIGNOR-255654	0.7
ABL2	protein	P42684	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates activity	phosphorylation	Tyr686	IITEYCRyGDLVDYL	-1									19275932	t		miannu	C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis. 	SIGNOR-276140	0.308
KIF5C	protein	O60282	UNIPROT	Organelle_transport	phenotype	SIGNOR-PH159	SIGNOR	up-regulates				9606	BTO:0000938								9438838	f		miannu	The kinesin superfamily of proteins plays a major role in this complex organelle transport. Kinesin is primarily associated with anterogradely transported membranous organelles in nerve axons. KIF5B and HsuKHC are expressed ubiquitously in many tissues, whereas KIF5A, KIF5C, and HsnKHC are specific to nerve tissue.	SIGNOR-264066	0.7
SPI1	protein	P17947	UNIPROT	ITGAM	protein	P11215	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12393465	f		apalma	CD11b is regulated by PU.1 and its promoter contains putative binding sites of AML1. In this case AML1-ETO interaction and down-regulation of important myeloid transcription factors like PU.1 and AML1 could explain the lower CD11b expression	SIGNOR-255661	0.565
N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	chemical	CHEBI:91418	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258111	0.8
PRKCE	protein	Q02156	UNIPROT	OCLN	protein	Q16625	UNIPROT	up-regulates	phosphorylation	Thr404	HYETDYTtGGESCDE	9606	BTO:0000195	BTO:0000671							21545357	t		lperfetto	Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions.	SIGNOR-173635	0.2
saxagliptin	chemical	CHEBI:71272	ChEBI	DPP4	protein	P27487	UNIPROT	down-regulates activity	chemical inhibition			9606									19149538	t		Luana	Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched.	SIGNOR-257813	0.8
PTPRJ	protein	Q12913	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	dephosphorylation	Tyr1021	PNEGDNDyIIPLPDP	9606									12062403	t			Primary sequence determinants responsible for site-selective dephosphorylation of the PDGF beta-receptor by the receptor-like protein tyrosine phosphatase DEP-1|DEP-1 dephosphorylation of original and chimeric phospho-peptides spanning the preferred pY1021	SIGNOR-248704	0.564
GPR132	protein	Q9UNW8	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257275	0.2
Caspase 1 complex	complex	SIGNOR-C220	SIGNOR	IL1B	protein	P01584	UNIPROT	up-regulates activity	cleavage	Asp27	DDLFFEAdGPKQMKC	-1									1919001	t		lperfetto	IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta. 	SIGNOR-256375	0.796
AURKB	protein	Q96GD4	UNIPROT	ARHGEF2	protein	Q92974	UNIPROT	down-regulates activity	phosphorylation	Ser960	SRLSPPHsPRDFTRM	9606	BTO:0000567								17488622	t		miannu	The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity.	SIGNOR-276062	0.253
SRC	protein	P12931	UNIPROT	CNKSR1	protein	Q969H4	UNIPROT	up-regulates activity	phosphorylation	Tyr665	KEQNRELySEGLGAW										26319181	t		lperfetto	We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. 	SIGNOR-275920	0.485
MTNR1B	protein	P49286	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256850	0.427
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	UBTF	protein	P17480	UNIPROT	down-regulates	phosphorylation			9606									11741541	t	inferred from 70% family members	lperfetto	Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna	SIGNOR-270080	0.2
POMC	protein	P01189	UNIPROT	MC4R	protein	P32245	UNIPROT	up-regulates activity	binding			9606									20694162	t		miannu	α-MSH can activate both melanocortin 4 receptors (MC4R) and melanocortin 1 receptors (MC1R)	SIGNOR-252373	0.771
PRKG1	protein	Q13976	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser82	RALSRQLsSGVSEIR	9606									19593530	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	lperfetto	Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization	SIGNOR-186788	0.278
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1675	SPSYSPTsPSYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269374	0.718
3-isobutyl-1-methyl-7H-xanthine	smallmolecule	CHEBI:34795	ChEBI	CEBPA	protein	P49715	UNIPROT	up-regulates				9606									11279134	f		fspada	The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin	SIGNOR-209992	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	TSC1	protein	Q92574	UNIPROT	up-regulates	phosphorylation			9606									19584320	t		lperfetto	Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity.	SIGNOR-216487	0.41
PRKCZ	protein	Q05513	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	up-regulates activity	phosphorylation	Thr305	TDAATMKtFCGTPEY	9606	BTO:0000007								9512493	t		lperfetto	The activation of PKBbeta and PKBgamma by PDK1 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma). PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides. The activation of PKBgamma and its phosphorylation at Thr305 was triggered by insulin-like growth factor-1 in 293 cells.	SIGNOR-248996	0.529
ABL1	protein	P00519	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	phosphorylation	Tyr934	PAHASDEiYEIMQKC	9606									19275932	t		Manara	C-Abl phosphorylates three tyrosine residues on PDGFR-β (Y686, Y934, Y970) | These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis.	SIGNOR-260931	0.507
CDC42BPA	protein	Q5VT25	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates	phosphorylation	Thr19	KKRPQRAtSNVFAMF	9606									19851336	t		lperfetto	More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.	SIGNOR-188785	0.531
CSF3	protein	P09919	UNIPROT	CSF3R	protein	Q99062	UNIPROT	up-regulates	binding			9606									16492764	t		gcesareni	The gcsf:gcsf-r complex formed a 2:2 stoichiometry by means of a cross-over interaction between the ig-like domains of gcsf-r and gcsf. the ig-like domain cross-over structure necessary for gcsf-r activation is consistent with previously reported thermodynamic and mutational analyses.	SIGNOR-144743	0.758
CUL3	protein	Q13618	UNIPROT	ARIH1	protein	Q9Y4X5	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								24076655	t		miannu	Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin.	SIGNOR-268846	0.319
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Thr548	KKVAVVRtPPKSPSS	9606									21215781	t	The effect has been demonstrated using P10636-8	lperfetto	However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules	SIGNOR-251601	0.695
SMAD5/SMAD4	complex	SIGNOR-C205	SIGNOR	RUNX2	protein	Q13950	UNIPROT	up-regulates	transcriptional regulation			10090	BTO:0000165								11073979	f		ggiuliani	As shown in Fig. 8A, overexpression of Smad5 by itself induced Runx2 expression even in the absence of BMP-2 (lane 5). Western blot analysis also confirmed the induced level of Runx2 protein in C2C12-Sm5 cells (Fig. 8B)	SIGNOR-255783	0.583
CNR1	protein	P21554	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257346	0.252
PAK1	protein	Q13153	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates activity	phosphorylation			9606									12876277	t		lperfetto	We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation.	SIGNOR-244924	0.563
FOXO4	protein	P98177	UNIPROT	TRIM63	protein	Q969Q1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							21798082	f		lperfetto	Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome.	SIGNOR-236557	0.346
PHKA1	protein	P46020	UNIPROT	PHKA1	protein	P46020	UNIPROT	up-regulates activity	phosphorylation	Ser985	SNVSPAIsIHEIGAV	-1									10487978	t		miannu	Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation)	SIGNOR-250282	0.2
FOXO1	protein	Q12778	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				10090									12530968	f			�The present data provide a direct link between insulin signaling through Irs _ PI 3-kinase _ Akt and adipogenesis through Foxo1 phosphorylation. Inhibition of Foxo1 via phosphorylation appears to be required during the clonal expansion phase, and our data show that unrestrained Foxo1 activity prevents terminal differentiation.	SIGNOR-254977	0.7
NFASC	protein	O94856	UNIPROT	ANK3	protein	Q12955	UNIPROT	up-regulates quantity	relocalization			10116		BTO:0000227							7961622	t		miannu	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266717	0.736
Non-structural protein 10	protein	P0C6X7-PRO_0000037317	UNIPROT	MT-CO2	protein	P00403	UNIPROT	down-regulates activity	binding			9606									16157265	t		lperfetto	This result suggests that the nsp10 protein could affect the activities of NADH and cytochrome oxidase II via a direct interaction while being involved in viral replication.	SIGNOR-260254	0.2
LPAR2	protein	Q9HBW0	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257257	0.252
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	BRAF	protein	P15056	UNIPROT	down-regulates	phosphorylation	Ser428	GPQRERKsSSSSEDR	9606									10869359	t		lperfetto	We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf	SIGNOR-244160	0.2
SMARCB1	protein	Q12824	UNIPROT	Brain-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C486	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270755	0.833
ITGB4	protein	P16144	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257720	0.57
PRKACA	protein	P17612	UNIPROT	STK38	protein	Q15208	UNIPROT	down-regulates activity	phosphorylation	Ser11	TGSTPCSsMSNHTKE	-1									22142472	t		miannu	GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively.  Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress.	SIGNOR-276390	0.299
CDK1	protein	P06493	UNIPROT	DNMT1	protein	P26358	UNIPROT	up-regulates	phosphorylation	Ser154	AKPEPSPsPRITRKS	9606									21565170	t		gcesareni	We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5	SIGNOR-173677	0.305
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CDC25C	protein	P30307	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0001938								10913154	t		lperfetto	Cyclin B-Cdc2 complexes are maintained in an inactive state until the end of G2 by phosphorylation of the Thr14/Tyr15 residues. Around the time of nuclear translocation of the complex, these residues are dephosphorylated, resulting in the formation of an active cyclin B-Cdc2 complex (2). As mentioned, this dephosphorylation occurs by a Cdc25 protein phosphatase. Three Cdc25 family members have been identified to date, A, B and C, the last one being the active one at the onset of mitosis. The activity of Cdc25C itself can be enhanced through phosphorylation by cyclin B-Cdc2 (9, 10). Therefore, activation of cyclin B-Cdc2 has been proposed to result in an autocatalytic feedback loop to ensure rapid activation of these complexes at the G2/M transition	SIGNOR-251510	0.839
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	NOS2	protein	P35228	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001103							20219869	f		apalma	Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6.	SIGNOR-255353	0.447
carbachol	chemical	CHEBI:3385	ChEBI	CHRM1	protein	P11229	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258620	0.8
CDK11A	protein	Q9UQ88	UNIPROT	PAK1	protein	Q13153	UNIPROT	up-regulates activity	phosphorylation	Ser174	TPAVPPVsEDEDDDD										19520772	t		lperfetto	CDK11p58 phosphorylation of PAK1 Ser174 promotes DLC2 binding and roles on cell cycle progression|We show that PAK1 is a substrate of CDK11p58 and can be strongly activated upon phosphorylation.	SIGNOR-273026	0.392
ATP	smallmolecule	CHEBI:15422	ChEBI	PRKAG1	protein	P54619	UNIPROT	down-regulates	chemical inhibition			9606				SIGNOR-C15					21399626	t		gcesareni	Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive	SIGNOR-172822	0.8
ATM	protein	Q13315	UNIPROT	WRAP53	protein	Q9BUR4	UNIPROT	up-regulates activity	phosphorylation	Ser64	PVAGSAVsQELREGD	9606	BTO:0001938								27715493	t	done	miannu	Here, we show that in response to various types of DNA damage, including IR and UV, WRAP53β is phosphorylated on serine residue 64 by ATM with a time-course that parallels its accumulation at DNA lesions. Interestingly, recruitment of phosphorylated WRAP53β (pWRAP53βS64) to sites of such DNA damage promotes its interaction with γH2AX at these locations. 	SIGNOR-273511	0.345
CDC7	protein	O00311	UNIPROT	RAD18	protein	Q9NS91	UNIPROT	unknown	phosphorylation	Ser434	IQEVLSSsESDSCNS	9606									21098111	t		llicata	Although the cdc7/rad18 interaction and phosphorylation at s434 are induced by dna damage, s434 was also observed to be phosphorylated basally	SIGNOR-170049	0.503
PAX7-FOXO1	fusion protein	SIGNOR-FP11	SIGNOR	PDGFA	protein	P04085	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25211658	t		miannu	Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA.	SIGNOR-251567	0.2
P2RY11	protein	Q96G91	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257386	0.357
CDK1	protein	P06493	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Ser434	SFEPKIRsPRRFIGS	9606									12586835	t		gcesareni	The activation of p70s6k is associated with multiple phosphorylations at two sets of sites. The first set, s411, s418, t421, and s424, reside within the autoinhibitory domain, mutations of s371 abolished kinase activity. In mitotic hela cells, when the activity of cdc2 is high, s6k1 is phosphorylated at multiple ser/thr, pro (s/tp) sites, including ser(371), ser(411), thr(421), and ser(424).	SIGNOR-98215	0.392
ANAPC2	protein	Q9UJX6	UNIPROT	DVL1	protein	O14640	UNIPROT	down-regulates	binding			9606									19805045	t		gcesareni	We now report that the anaphase-promoting complex (apc/c) recognizes a d-box motif of dvl and ubiquitylates dvl on a highly conserved lysine residue.We now report that expression of the apc/c subunit anapc2 activates the apc/c-dependent degradation of dvl by disrupting canonical wnt signaling.	SIGNOR-188393	0.241
C1QC	protein	P02747	UNIPROT	Complement C1q	complex	SIGNOR-C308	SIGNOR	form complex	binding			-1									29449492	t		lperfetto	C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1).	SIGNOR-263389	0.557
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270400	0.8
PLK3	protein	Q9H4B4	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser73	VGLLKLAsPELERLI	9606									17804415	t		gcesareni	Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun.	SIGNOR-157725	0.379
BMPR1B	protein	O00238	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates	phosphorylation	Ser463	SPHNPISsVS	9606									9335504	t		llicata	The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1.	SIGNOR-52666	0.628
SLBP	protein	Q14493	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265417	0.2
TLN1	protein	Q9Y490	UNIPROT	ITGB4	protein	P16144	UNIPROT	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257627	0.484
STX16	protein	O14662	UNIPROT	LE-TGN SNARE	complex	SIGNOR-C157	SIGNOR	form complex	binding			9606	BTO:0000567								18195106	t		lperfetto	We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport	SIGNOR-253079	0.798
pazopanib hydrochloride	chemical	CHEBI:71217	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates activity	chemical inhibition			-1									17620431	t		miannu	The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. 	SIGNOR-259168	0.8
PPP1R8	protein	Q12972	UNIPROT	EZH2	protein	Q15910	UNIPROT	up-regulates activity	binding			9606							phosphorylation:Thr416	EANSRCQtPIKMKPN	23241245	t			Recruited NIPP1 enables the net phosphorylation of EZH2 by inhibiting its dephosphorylation by PP1.	SIGNOR-255665	0.367
SMAD4	protein	Q13485	UNIPROT	SMAD4/JUN	complex	SIGNOR-C10	SIGNOR	form complex	binding			9606									9312063	t		gcesareni	Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter.	SIGNOR-50589	0.663
IKBKE	protein	Q14164	UNIPROT	CDK2AP1	protein	O14519	UNIPROT	unknown	phosphorylation	Ser46	LSDYGPPsLGYTQGT	-1									22427660	t		lperfetto	CDK2AP1 is phosphorylated at a conserved Ser-46 site in the N-terminal "intrinsically disordered" region by IkappaB kinase epsilon.	SIGNOR-264780	0.2
PPP2CA	protein	P67775	UNIPROT	PTTG1	protein	O95997	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser89	KQKQPSFsAKKMTEK	9606	BTO:0000567								24781523	t		miannu	CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase	SIGNOR-276380	0.301
JAK3	protein	P52333	UNIPROT	JAK3	protein	P52333	UNIPROT	down-regulates	phosphorylation	Tyr981	LPLDKDYyVVREPGQ	9606									9391116	t		gcesareni	We found that jak3 is autophosphorylated on multiple sites including y980 and y981. Compared with the activity of wild-type (wt) jak3, mutant y980f demonstrated markedly decreased kinase activity, and optimal phosphorylation of jak3 on other sites was dependent on y980 phosphorylation. The mutant y980f also exhibited reduced phosphorylation of its substrates, gammac and stat5a. In contrast, mutant y981f had greatly increased kinase activity, whereas the double mutant, yy980/981ff, had intermediate activity.	SIGNOR-53594	0.2
PRKD3	protein	O94806	UNIPROT	GIT1	protein	Q9Y2X7	UNIPROT	unknown	phosphorylation	Ser46	RSLGRHIsIVKHLRH	9606									22893698	t		lperfetto	We propose that phosphorylation of git1 on serine 46 by pkd3 represents a molecular switch by which git1 localization, paxillin trafficking, and cellular protrusive activity are regulated.	SIGNOR-191839	0.37
TP53	protein	P04637	UNIPROT	PMAIP1	protein	Q13794	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14500851	f		gcesareni	P53 has the ability to activate transcription of various proapoptotic genes, including those encoding members of the bcl-2 family, such as the bh-3 only proteins bax, noxa, and puma pmaip1 may thus represent a mediator of tp53-dependent apoptosis.	SIGNOR-118048	0.691
CKM complex	complex	SIGNOR-C406	SIGNOR	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation			-1									25344755	t		lperfetto	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273159	0.379
Laminin-5	complex	SIGNOR-C184	SIGNOR	A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	up-regulates activity	binding												12123670	t		lperfetto	We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1.	SIGNOR-253219	0.529
ARHGEF9	protein	O43307	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260534	0.828
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRM3	protein	Q14832	UNIPROT	up-regulates activity	chemical activation			9606									25042998	t		miannu	Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate	SIGNOR-264075	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	PTTG1	protein	O95997	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser31	LKLGSGPsIKALDGR	9606	BTO:0000567								24781523	t		miannu	CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase	SIGNOR-276382	0.314
PTPN13	protein	Q12923	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	dephosphorylation			9606									19307596	t		miannu	Mechanistically, RIL suppresses Src activation through interacting with Src and PTPL1, allowing PTPL1 dependent dephosphorylation of Src at the activation loop.|Our results reveal a novel Src inactivation cycle in which reversion-induced LIM preferentially recognizes active Src and facilitates PTPL1-mediated inactivation of Src.	SIGNOR-277125	0.521
SKI	protein	P12755	UNIPROT	SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	down-regulates activity	binding			9606									12793438	t		lperfetto	The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway	SIGNOR-253301	0.764
STUB1	protein	Q9UNE7	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	ubiquitination			9606									14701756	t		gcesareni	These results suggest that chip can interact with the smad1/smad4 proteins and block bmp signal transduction through the ubiquitin-mediated degradation of smad proteins.	SIGNOR-120731	0.334
LRSAM1	protein	Q6UWE0	UNIPROT	TSG101	protein	Q99816	UNIPROT	down-regulates quantity	monoubiquitination			9606	BTO:0000007								15256501	t		miannu	Tal increases ubiquitylation of Tsg101 and affects its solubility in a RING- and PTAP-dependent manner.  Tal-mediated ubiquitylation of Tsg101 inactivates this sorting function and concomitantly translocates Tsg101 from relatively insoluble membrane subdomains. Presumably, the coordinated action of Tal and a deubiquitylation enzyme (DUB) enables recycling of Tsg101 and reloading of cargo.	SIGNOR-271509	0.543
TTK	protein	P33981	UNIPROT	USP16	protein	Q9Y5T5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr554	EVLTSSPtRNLNGAY	9606	BTO:0002181								28380042	t		miannu	 Usp16 is a TTK phosphorylation substrate. 	SIGNOR-277351	0.378
CDK1	protein	P06493	UNIPROT	UBA1	protein	P22314	UNIPROT	up-regulates	phosphorylation	Ser4	sPLSKKRR	9606									9099746	t		lperfetto	Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Each serine residue was independently mutated to an alanine and analyzed by two-dimensional electrophoresis;only serine 4 was phosphorylated. Disruption of the basic amino acids within the nls resulted in loss of exclusive nuclear localization and a 90-95% decrease in the phosphorylation of ha1-e1	SIGNOR-47162	0.414
GTF2H1	protein	P32780	UNIPROT	TFIIH	complex	SIGNOR-C457	SIGNOR	form complex	binding			9606									30860024	t		lperfetto	Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 	SIGNOR-269316	0.902
CHAMP1	protein	Q96JM3	UNIPROT	MAD2L2	protein	Q9UI95	UNIPROT	up-regulates activity	binding			9606									21063390	t		miannu	Here, we report a novel regulator for accurate chromosome segregation, chromosome alignment-maintaining phosphoprotein (CAMP). We identified CAMP as a MAD2L2-interacting protein. Spindle localization of MAD2L2 was abrogated by CAMP depletion (Supplementary Figure S2A)	SIGNOR-264904	0.512
PYCARD	protein	Q9ULZ3	UNIPROT	AIM2 inflammasome	complex	SIGNOR-C222	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256401	0.79
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	SP3	protein	Q02447	UNIPROT	up-regulates	phosphorylation			9606									17685427	t	inferred from 70% family members	gcesareni	Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73.	SIGNOR-270053	0.2
raloxifene	chemical	CHEBI:8772	ChEBI	ESR1	protein	P03372	UNIPROT	down-regulates activity	chemical inhibition			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258582	0.8
NR3C1	protein	P04150	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000011								11279134	f		lperfetto	The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin	SIGNOR-250561	0.401
EIF2B2	protein	P49770	UNIPROT	EIF2S1	protein	P05198	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269125	0.794
GNB3	protein	P16520	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606									14668344	t		gcesareni	Expression of the g__ sequestrant, _-transducin, inhibits both ras activation and membrane translocation of _-arrestin1, suggesting that g__ dimers from g_i2 and g_q activate different effectors to coordinately regulate the pi 3-kinase/akt pathway. , these data indicate that _-thrombin stimulates rapid pi 3-kinase activity and akt phosphorylation by the g__ dimers released from a ptx-sensitive g protein.	SIGNOR-120264	0.374
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DMA	protein	P28067	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-253993	0.334
DDHD2	protein	O94830	UNIPROT	long-chain fatty acid anion	smallmolecule	CHEBI:57560	ChEBI	up-regulates quantity	chemical modification			9606									22922100	t		miannu	Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 	SIGNOR-269652	0.8
RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	DUSP1	protein	P28562	UNIPROT	up-regulates quantity	transcriptional regulation			10090		BTO:0001103							17158101	f		Andrea	Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis	SIGNOR-255744	0.279
FGF11	protein	Q92914	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253414	0.256
PPARGC1A	protein	Q9UBK2	UNIPROT	COX5B	protein	P10606	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000443								23021218	f		lperfetto	PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). 	SIGNOR-253099	0.333
RPL37	protein	P61927	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262463	0.829
Erythrocytic spectrin	complex	SIGNOR-C384	SIGNOR	Cell_shape	phenotype	SIGNOR-PH182	SIGNOR	up-regulates				9606									24302288	f		lperfetto	Spectrin is multifunctional, and spectrin-based networks are important for maintaining the shape and mechanical properties of erythrocytes.	SIGNOR-266032	0.7
COX5B	protein	P10606	UNIPROT	Oxidative_phosphorylation	phenotype	SIGNOR-PH78	SIGNOR	up-regulates				10090									23021218	f		lperfetto	PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). 	SIGNOR-253102	0.7
ABCA7	protein	Q8IZY2	UNIPROT	Phagocytosis	phenotype	SIGNOR-PH97	SIGNOR	up-regulates				9606									27472885	f		miannu	 Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD.	SIGNOR-265175	0.7
PDP1	protein	Q9P0J1	UNIPROT	PDHA1	protein	P08559	UNIPROT	up-regulates activity	dephosphorylation			9606									20208177	t			Pyruvate dehydrogenase phosphatase (PDP) is a mitochondrial serine phosphatase that activates phosphorylated pyruvate dehydrogenase complex by dephosphorylation	SIGNOR-251664	0.722
PRKDC	protein	P78527	UNIPROT	JUN	protein	P05412	UNIPROT	unknown	phosphorylation	Ser249	LSPIDMEsQERIKAE	-1									8464713	t		lperfetto	Here, we show that the DNA-PK modifies c-Jun in vitro and that serine residue 249 (Ser-249) is required for phosphorylation to occur. This residue corresponds to one of three sites of c-Jun that are phosphorylated in vivo and which negatively regulate c-Jun DNA binding in vitro. However, we find that phosphorylation of c-Jun by the DNA-PK does not interfere with DNA binding, indicating that phosphorylation at other sites is required for this effect.	SIGNOR-248934	0.415
MRPS25	protein	P82663	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261448	0.692
monoisononyl phthalate	chemical	CHEBI:132593	ChEBI	OXER1	protein	Q8TDS5	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 	SIGNOR-268778	0.8
NUMA1	protein	Q14980	UNIPROT	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	up-regulates	binding			9606									11956313	t			Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-256541	0.2
PEX6	protein	Q13608	UNIPROT	PEX1	protein	O43933	UNIPROT	up-regulates activity	binding			10029									12717447	t			Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions.	SIGNOR-253615	0.654
risperidone	chemical	CHEBI:8871	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10116									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258525	0.8
IL6ST	protein	P40189	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates				9606		BTO:0000887;BTO:0001103							23663276	t		milica	Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects.	SIGNOR-202036	0.662
MAPK10	protein	P53779	UNIPROT	MAPK8IP3	protein	Q9UPT6	UNIPROT	up-regulates	phosphorylation	Thr265	GQSSAAAtPSTTGTK	9606									15767678	t		gcesareni	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134529	0.738
LTB4R	protein	Q15722	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257086	0.409
MTOR	protein	P42345	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	up-regulates activity	phosphorylation	Ser863	LTQSAPAsPTNKGVH	9606	BTO:0000007		SIGNOR-C3	SIGNOR-C3					19864431	t		lperfetto	Our data that insulin-stimulated raptor ser863 phosphorylation requires kinase-active mtorc1 and displays rapamycin sensitivity in intact cells, together with the data of wang et al. (67) that mtor phosphorylates raptor ser863 in vitro, strongly suggest that mtor itself mediates raptor ser863 phosphorylation. / strikingly, raptor ser863 phosphorylation is absolutely required for raptor ser859 and ser855 phosphorylation. These data suggest that mtorc1 activation leads to raptor multisite phosphorylation and that raptor ser863 phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation	SIGNOR-188924	0.989
BRAF	protein	P15056	UNIPROT	MAP2K2	protein	P36507	UNIPROT	up-regulates	phosphorylation	Ser222	VSGQLIDsMANSFVG	9606		BTO:0000142							8668348	t		gcesareni	We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l.	SIGNOR-42664	0.739
CSNK2A2	protein	P19784	UNIPROT	PPP1R2	protein	P41236	UNIPROT	up-regulates activity	phosphorylation	Ser122	RIQEQESsGEEDSDL	-1									8288648	t		llicata	Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action.	SIGNOR-251021	0.311
RUNX2	protein	Q13950	UNIPROT	COL1A2	protein	P08123	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11331591	f		gcesareni	In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast	SIGNOR-107166	0.439
MSI2	protein	Q96DH6	UNIPROT	NUMB	protein	P49757	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001271								21084860	f		miannu	Msi2 was shown to be upregulated in blast crisis cml and to negatively regulate expression ofnumb.	SIGNOR-169848	0.431
ATM	protein	Q13315	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Ser19	SHGSSACsQPHGSVT	9606	BTO:0000007								10973490	t		lperfetto	Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir	SIGNOR-81391	0.83
UTS2R	protein	Q9UKP6	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256779	0.252
pimozide	chemical	CHEBI:8212	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258841	0.8
TGFBR2	protein	P37173	UNIPROT	USP2	protein	O75604	UNIPROT	up-regulates activity	phosphorylation	Ser225	SRVPEIIsPTYRPIG	-1									29490279	t		miannu	Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1.	SIGNOR-273603	0.2
ABL1	protein	P00519	UNIPROT	JUN	protein	P05412	UNIPROT	unknown	phosphorylation	Tyr170	LHSEPPVyANLSNFN	9606									10637231	t		gcesareni	After phosphorylation of c-Jun by Abl on Tyr170, both proteins interacted via the SH2 domain of Abl	SIGNOR-245370	0.542
GAS2L1	protein	Q99501	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates				9606									24706950	f		miannu	Previous work has shown that members of the growth-arrest-specific 2 (GAS2) family mediate the crosstalk between filamentous actin (F-actin) and MTs, but the molecular basis of this process remained unclear. By using fluorescence microscopy, we demonstrate that three members of this family, GAS2-like 1, GAS2-like 2 and GAS2-like 3 (G2L1, G2L2 and G2L3, also known as GAS2L1, GAS2L2 and GAS2L3, respectively) are differentially involved in mediating the crosstalk between F-actin and MTs. 	SIGNOR-273700	0.7
PRKCA	protein	P17252	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser118	GEAAEPGsPTAAEGE	-1									8034575	t		lperfetto	Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | We conclude that the primary phosphorylation site is Ser116 |	SIGNOR-248907	0.72
clomipramine	chemical	CHEBI:47780	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9537821	t		miannu	Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 	SIGNOR-258876	0.8
PTPN9	protein	P43378	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates activity	dephosphorylation			10029	BTO:0000246								12907755	t			Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR	SIGNOR-248505	0.319
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Tyr)	smallmolecule	CHEBI:29182	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269499	0.8
GRPR	protein	P30550	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256774	0.252
SMO	protein	Q99835	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates	binding			10090	BTO:0002572								16885213	t		gcesareni	We found that Smo, by virtue of what appears to be constitutive activity, activates all members of the G(i) family but does not activate members of the G(s), G(q), and G(12) families. The activation is suppressed by cyclopamine and other inhibitors of Hedgehog signaling and is enhanced by the Smo agonist purmorphamine.	SIGNOR-148487	0.496
PPM1D	protein	O15297	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser15	PSVEPPLsQETFSDL	9606									18265945	t		lperfetto	Dephosphorylation of p53 at serine 15 by Wip1 also contributes to p53 degradation, as does dephosphorylation of Mdm2, which stabilizes Mdm2, an E3 ubiquitin ligase specific for p53 [ xref ].	SIGNOR-276943	0.576
AMOT/MPP5/INADL/LIN7C	complex	SIGNOR-C27	SIGNOR	YAP1	protein	P46937	UNIPROT	down-regulates	binding			10090									21145499	t		milica	Because we found that multiple domains of taz/yap interacted with multiple components of the crumbs complex, which include pals1, lin7c, patj, and the crumbs regulator amot, we propose that this multifactoral interaction serves to ensure that assembly of the hippo pathway and efficient phosphorylation of taz/yap is coupled only by the assembly of the crumbs complex, rather than by any single component.	SIGNOR-170364	0.363
MAPK3	protein	P27361	UNIPROT	LAT	protein	O43561	UNIPROT	down-regulates	phosphorylation	Thr184	PSAPALStPGIRDSA	9606									15192708	t	The effect has been demonstrated using O43561-2	gcesareni	Lat, an adapter protein essential for t-cell signaling, is phosphorylated at its thr 155 by erk in response to t-cell receptor stimulation. Thr 155 phosphorylation reduces the ability of lat to recruit plcgamma1 and slp76, leading to attenuation of subsequent downstream events such as [ca2+]i mobilization and activation of the erk pathway.	SIGNOR-125770	0.31
BRAF	protein	P15056	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates activity	phosphorylation	Ser467	GQRIGSGsFGTVYKG	9606									31929109	t		miannu	We previously identified that BRAFWT can autophosphorylate its P-loop (Ser-465/Ser-467) to inactivate itself in the absence of native substrate MEK	SIGNOR-277499	0.2
EFNB1	protein	P98172	UNIPROT	EPHB4	protein	P54760	UNIPROT	up-regulates	binding			9606									9330863	t		tpavlidou	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52580	0.745
SMC6	protein	Q96SB8	UNIPROT	SMC5/6 	complex	SIGNOR-C374	SIGNOR	form complex	binding			-1									27427983	t		miannu	The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks	SIGNOR-265482	0.896
ROCK2	protein	O75116	UNIPROT	LPP	protein	Q93052	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22886954	f		miannu	Inactivation of rho kinase (rok) with rok inhibitors significantly inhibited lpp mrna expression	SIGNOR-191765	0.267
MAML1	protein	Q92585	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates	binding			9606									16530044	t		gcesareni	Maml-1 is preassociated with other components of the transcriptional machinery, such as p300	SIGNOR-145057	0.635
CDC25C	protein	P30307	UNIPROT	CDK1	protein	P06493	UNIPROT	up-regulates activity	dephosphorylation	Tyr15	EKIGEGTyGVVYKGR	9606									24643073	t		lperfetto	At the onset of mitosis, the protein phosphatase Cdc25C activates the Cdc2 and cyclin B1 complex by removing the inhibitory phosphate groups from Thr 14 and Tyr 15 on Cdc2.|Dephosphorylation of Tyr15 of Cdc2 is catalyzed by Cdc25C phosphatases, and this reaction is believed to be the rate limited step for the entrance into mitosis .	SIGNOR-276944	0.853
GRK2	protein	P25098	UNIPROT	OXTR	protein	P30559	UNIPROT	down-regulates activity	phosphorylation			9534	BTO:0000298								16179383	t		miannu	Recent experiments in COS-7 cells transfected with OTR have demonstrated that a rapid GRK2-mediated phosphorylation of the agonist-occupied OTR is a key first step leading to its desensitization, and that it precedes and is required for β-arrestin-dependent internalization	SIGNOR-270329	0.2
TGFB1	protein	P01137	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11331591	f		lperfetto	Tgf-b caused a 50% reduction of cbfa1 mrna.	SIGNOR-235998	0.352
BUB1	protein	O43683	UNIPROT	BUB1	protein	O43683	UNIPROT	up-regulates activity	phosphorylation	Ser969	FTAKCETsGFQCVEM	-1									26658523	t		miannu	 Conversely, Bub1 is an active kinase regulated by intra-molecular phosphorylation at the P+1 loop. 	SIGNOR-277186	0.2
SMC2	protein	O95347	UNIPROT	Condensin II	complex	SIGNOR-C342	SIGNOR	form complex	binding			9606									32445620	t		miannu	The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction.	SIGNOR-263908	0.812
ACD	protein	Q96AP0	UNIPROT	RPA3	protein	P35244	UNIPROT	down-regulates activity	binding						SIGNOR-C306						18680434	t		lperfetto	The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA	SIGNOR-263329	0.2
ZIC1	protein	Q15915	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates				9606	BTO:0002181								11238441	f		fspada	Moreover, gli proteins were translocated to cell nuclei by coexpressed zic proteins, and both proteins regulated each others transcriptional activity.In Nih3t3 and 293t cells, both gli1 and gli3 proteins were located predominantly in the cytoplasm (fig. 2, c, d, h, k, l, and p). Coexpression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels (fig. 2, e and m).	SIGNOR-105494	0.385
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser345	PLVSDEKsSELIITD	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276198	0.389
FOXL2	protein	P58012	UNIPROT	CYP11A1	protein	P05108	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21862621	f	 	miannu	We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation.	SIGNOR-254177	0.4
ceritinib	chemical	CHEBI:78432	ChEBI	ALK	protein	Q9UM73	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002058								24670165	t		miannu	Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.	SIGNOR-259263	0.8
PRKCA	protein	P17252	UNIPROT	PTPN6	protein	P29350	UNIPROT	down-regulates	phosphorylation	Ser591	DKEKSKGsLKRK	9606									15269224	t		llicata	Protein kinase calpha therefore critically and negatively regulates shp-1 function, forming part of a mechanism to retain shp-1 in a basal active state through interaction with its sh2 domains, and phosphorylating its c-terminal ser591 upon cellular activation	SIGNOR-126876	0.371
TP53	protein	P04637	UNIPROT	HR	protein	O43593	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15489903	f		miannu	 P53 may downregulate HR through multiple mechanisms including the reported associations with the Rad51 and Rad54 recombinases, and the BLM and WRN helicases. 	SIGNOR-255436	0.348
RPS6KA5	protein	O75582	UNIPROT	H3-4	protein	Q16695	UNIPROT	unknown	phosphorylation	Ser29	ATKVARKsAPATGGV	10090									12773393	t		lperfetto	The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28	SIGNOR-249214	0.2
EPGN	protein	Q6UW88	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606	BTO:0001801								16469638	t		gcesareni	They both bind to betacellulin and the heparin-binding ligand, hb-egf, as well as to two low-affinity ligands, epiregulin and epigen.	SIGNOR-144399	0.404
PRKD1	protein	Q15139	UNIPROT	PPP1R14A	protein	Q96A00	UNIPROT	up-regulates activity	phosphorylation	Thr38	QKRHARVtVKYDRRE	9606									32471307	t		lperfetto	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.	SIGNOR-249260	0.2
PLK1	protein	P53350	UNIPROT	G6PD	protein	P11413	UNIPROT	up-regulates activity	phosphorylation	Thr406	AVYTKMMtKKPGMFF	9606	BTO:0000007								29138396	t		lperfetto	We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules.|the kinase domain of Plk1 phosphorylates T406, T466 of G6PD	SIGNOR-267580	0.354
lidocaine	chemical	CHEBI:6456	ChEBI	SCN2A	protein	Q99250	UNIPROT	down-regulates activity	chemical inhibition			10116									1658608	t		miannu	This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. 	SIGNOR-258354	0.8
EP300	protein	Q09472	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates	binding			9606									11796223	t		lperfetto	Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription.	SIGNOR-232159	0.73
Factor VIIIa-IXa	complex	SIGNOR-C320	SIGNOR	F10	protein	P00742	UNIPROT	up-regulates activity	cleavage			10090		BTO:0000131							25769543	t		lperfetto	The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin.	SIGNOR-263538	0.553
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Ser221	DHEKKAYsFCGTVEY	9606	BTO:0000007								20048145	t		lperfetto	Herein, we demonstrate that the n-terminal kinase domain (ntk) of rsk1 is necessary for interactions with pkarialpha. Substitution of the activation loop phosphorylation site (ser-221) in the ntk with the negatively charged asp residue abrogated the association between rsk1 and pkarialpha.	SIGNOR-252785	0.599
QRICH1	protein	Q2TAL8	UNIPROT	EARS2	protein	Q5JPH6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269402	0.2
BLK	protein	P51451	UNIPROT	BCR-Mk	complex	SIGNOR-C433	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000776								32323266	t		scontino	The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases.	SIGNOR-268208	0.633
PPP2CB	protein	P62714	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates	dephosphorylation	Thr216	RSSSSEStGTPSNPD	9606									11983168	t		fstefani	Cyclin g also binds in vivo and in vitro to mdm2 and markedly stimulates the ability of pp2a to dephosphorylate mdm2 at t216. Our data imply that the function of cyclin g is to serve as a negative regulator of p53 by activating mdm2 through dephosphorylation.	SIGNOR-86736	0.374
HRH1	protein	P35367	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256778	0.2
PI3K	complex	SIGNOR-C156	SIGNOR	PIK3CB	protein	P42338	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								14665640	t		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-252719	0.623
CSNK1A1	protein	P48729	UNIPROT	LGALS3	protein	P17931	UNIPROT	up-regulates	phosphorylation	Ser6	sLHDALSG	9606	BTO:0000150								15121858	t		llicata	These results indicate that phosphorylation of gal-3 promotes its nuclear export after apoptotic stimuli through enhanced nuclear export.	SIGNOR-124583	0.312
Nalmefene	chemical	CHEBI:7457	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258812	0.8
RPS6KA1	protein	Q15418	UNIPROT	CCT2	protein	P78371	UNIPROT	up-regulates	phosphorylation	Ser260	GSRVRVDsTAKVAEI	9606									21440620	t		lperfetto	Furthermore, both the s260a and s260d mutants showed a decreased folding capacity as compared to cells expressing the wild-type cct_ subunit ( fig.?_5e), suggesting that a cyclic phosphorylation of the s260 site by s6k1 is likely to be important for chaperonin function and that mutation of this site interferes with this process.	SIGNOR-172986	0.251
NAE1	protein	Q13564	UNIPROT	NAE	complex	SIGNOR-C131	SIGNOR	form complex	binding			9606									25504797	t		lperfetto	the NEDD8 E1-activating enzyme (NAE) is a heterodimer of APPBP1 and UBA3 corresponding to the N-terminal and C-terminal of the single polypeptide of the ubiquitin E1 respectively	SIGNOR-242907	0.965
phosphatidylinositol bisphosphate	smallmolecule	CHEBI:37328	ChEBI	WASL	protein	O00401	UNIPROT	up-regulates activity	chemical activation			9606									10219243	t		lperfetto	In the presence of Cdc42 and PI(4,5)P2, the potency of N-WASP was increased to a level approaching that of GST-VCA, suggesting that N-WASP was fully activated by the two molecules.	SIGNOR-261870	0.8
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2N	protein	P61088	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271354	0.753
miR-495	mirna	URS000075C517_9606	RNAcentral	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606									19219026	t		Luana	Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells. 	SIGNOR-268044	0.4
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	MYOM1	protein	P52179	UNIPROT	down-regulates activity	phosphorylation	Ser618	ARLKSRPsAPWTGQI	-1									9029142	t		miannu	 This interaction is regulated by phosphorylation of Ser482 in the linker between myomesin domains My4 and My5. Myomesin phosphorylation at this site by cAMP-dependent kinase and similar or identical activities in muscle extracts block the association with titin. 	SIGNOR-263156	0.2
MBTPS1	protein	Q14703	UNIPROT	CREB3L1	protein	Q96BA8	UNIPROT	up-regulates	cleavage			9606									16417584	t		miannu	Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes	SIGNOR-143785	0.554
ETS1	protein	P14921	UNIPROT	GFI1	protein	Q99684	UNIPROT	down-regulates activity	binding			9606	BTO:0002181								17213822	t	 	miannu	Co-immunoprecipitation analyses and glutathione-S-transferase pull-down assays revealed that ETS1 bound directly to GFI1 via its Ets domain, and GFI1 bound to ETS1 via its zinc-finger domain. Luciferase (Luc) assays using artificial reporters showed that GFI1 repressed ETS1-mediated transcriptional activation and ETS1 repressed GFI1-mediated transcriptional activation, in a dose-dependent manner. 	SIGNOR-254202	0.437
PCC	complex	SIGNOR-C414	SIGNOR	propionyl-CoA(4-)	smallmolecule	CHEBI:57392	ChEBI	down-regulates quantity	chemical modification			9606									15890657	t		miannu	Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively.	SIGNOR-267184	0.8
STAT2	protein	P52630	UNIPROT	ISGF3 complex	complex	SIGNOR-C124	SIGNOR	form complex	binding			-1									8943351	t	2	miannu	The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3	SIGNOR-240603	0.726
ZNF503	protein	Q96F45	UNIPROT	GATA3	protein	P23771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									28258171	f		Monia	Intriguingly, ZPO2/ZNF503 levels were higher in breast cancer samples with WT GATA3 than in those with mutated GATA3 (Fig. 1B). We found that Zpo2 down-regulated GATA3 levels, whereas shRNA-mediated Zpo2 knockdown enhanced GATA3 expression	SIGNOR-261189	0.26
CDC14B	protein	O60729	UNIPROT	SKP2	protein	Q13309	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser64	SNLGHPEsPPRKRLK	9606									18239684	t			The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1).	SIGNOR-248333	0.364
SOX2	protein	P48431	UNIPROT	ABCC6	protein	O95255	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21531766	f		miannu	 ID4-mediated SOX2 induction enhanced ABCC3 and ABCC6 expression through direct transcriptional regulation, indicating that ID4 regulates the chemoresistance of iGSCs by promoting SOX2-mediated induction of ABC transporters. 	SIGNOR-255182	0.287
ERCC8	protein	Q13216	UNIPROT	RAD23B	protein	P54727	UNIPROT	up-regulates activity													24086043	f		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275693	0.536
AURKA	protein	O14965	UNIPROT	MBD3	protein	O95983	UNIPROT	up-regulates	phosphorylation	Ser85	RQRVRYDsSNQVKGK	9606	BTO:0000567								12354758	t		llicata	These results suggest that the biochemical changes of mbd3 may be intimately related to the targeting of mbd3 to centrosomes. aurora-a phosphorylates mbd3	SIGNOR-93697	0.289
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation			9606									12110590	t	inferred from 70% family members	gcesareni	Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway.	SIGNOR-270073	0.2
clomipramine	chemical	CHEBI:47780	ChEBI	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9537821	t		miannu	At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. 	SIGNOR-258874	0.8
ING1	protein	Q9UK53	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001938								15662138	f		miannu	Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. 	SIGNOR-254490	0.494
MAPK8	protein	P45983	UNIPROT	MAPK8IP3	protein	Q9UPT6	UNIPROT	up-regulates	phosphorylation	Thr275	TTGTKSNtPTSSVPS	9606									15767678	t		gcesareni	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134545	0.715
SPOP	protein	O43791	UNIPROT	PDX1	protein	P52945	UNIPROT	down-regulates quantity	ubiquitination			10090	BTO:0000783								20811152	t		Gianni	Pdx1 C terminus-interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation.	SIGNOR-268859	0.331
RET	protein	P07949	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr576	RYMEDSTyYKASKGK	9606									21454698	t		gcesareni	The identification of focal adhesion kinase (fak) as a direct substrate for ret kinase revealed (i) a ret-fak transactivation mechanism consisting of direct phosphorylation of fak tyr-576/577 by ret and a reciprocal phosphorylation of ret by fak, which crucially is able to rescue the kinase-impaired ret k758m mutant and (ii) that fak binds ret via its ferm domain. Interestingly, this interaction is abolished upon ret phosphorylation, indicating that ret binding to the ferm domain of fak is a priming step for ret-fak transactivation.	SIGNOR-173013	0.622
VRK3	protein	Q8IV63	UNIPROT	BANF1	protein	O75531	UNIPROT	down-regulates activity	phosphorylation	Ser4	sQKHRDFV	-1									25899223	t		lperfetto	Although VRK3 has been regarded as a genuine pseudokinase from structural and biochemical studies, recent reports suggest that VRK3 acts as an active kinase as well as a signaling scaffold in cells. Here, we demonstrate that VRK3 phosphorylates the nuclear envelope protein barrier-to-autointegration factor (BAF) on Ser4.|Ectopic expression of VRK3 induces the translocation of BAF from the nucleus to the cytoplasm. I	SIGNOR-264564	0.506
LCK	protein	P06239	UNIPROT	ITK	protein	Q08881	UNIPROT	up-regulates	phosphorylation	Tyr512	RFVLDDQyTSSTGTK	-1									9312162	t			Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. The major site of Lck phosphorylation on Itk was mapped to the conserved tyrosine (Tyr511) in the activation loop of the Itk kinase domain. 	SIGNOR-251380	0.534
AKT2	protein	P31751	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	up-regulates	phosphorylation			9606	BTO:0001454								19609947	t		lperfetto	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-217463	0.438
RPS6KA1	protein	Q15418	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606	BTO:0000848								18246127	t		lperfetto	To understand the mechanisms underlying B-RAF effects on cell survival we initially analysed the Bcl-2 family protein, Bad, that is phosphorylated by RSK1 at the inhibitory serine-75 residue in a MEK-dependent manner in melanoma cells	SIGNOR-160635	0.404
IL1B	protein	P01584	UNIPROT	CTSK	protein	P43235	UNIPROT	up-regulates quantity by expression	transcriptional regulation												11920402	f		lperfetto	This is supported by our finding that inflammatory cytokines such as IL-1b and TNFa increase the expres- sion of cathepsin K mRNA 􏰌6–8-fold and increase the secretion of the mature enzyme.	SIGNOR-253316	0.34
MAPK1	protein	P28482	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Ser208	DAGSPNLsPNPMSPA	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3	SIGNOR-161613	0.736
IL1RN	protein	P18510	UNIPROT	IL1R1	protein	P14778	UNIPROT	down-regulates activity	binding			9606									2876877	t		Gianni	Homozygous truncating mutations result in lack of secreted interleukin-1–receptor antagonist protein, which inhibits the proinflammatory cytokines interleukin-1α and interleukin-1β	SIGNOR-262302	0.894
RAC1	protein	P63000	UNIPROT	PAK	proteinfamily	SIGNOR-PF13	SIGNOR	up-regulates activity	binding			10090	BTO:0000142								8107774	t		gcesareni	A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways.	SIGNOR-248256	0.781
GSK2126458	chemical	CID:25167777	PUBCHEM	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192895	0.8
PPP2CA	protein	P67775	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	dephosphorylation	Thr32	QSRPRSCtWPLQRPE	9606									20110348	t		gcesareni	Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a.	SIGNOR-252974	0.411
MYCBP2	protein	O75592	UNIPROT	TSC	complex	SIGNOR-C101	SIGNOR	down-regulates	ubiquitination			10116	BTO:0001009								14559897	t		Monia	Pam Interacts with the Tuberin-Hamartin Complex—To examine the in vivo association of tuberin and Pam, we performed co-immunoprecipitation experiments in PC12 cells and rat embryonic brain. Immunoprecipitation of tuberin using an anti-tuberin antibody followed by immunoblot analysis showed that endogenous Pam co-immunoprecipitates with tuberin in PC12 cells and embryonic rat brain. Pam Homolog HIW Modulates Tsc1
Tsc2 Activity in Drosophila. The enhancement of Tsc1Tsc2 phenotype by the removal of the hiw gene indicates that hiw negatively regulates Tsc1
Tsc2 activity in Drosophila eye. Taken together, it is probable that Pam may function as an E3 ligase for tuberin and regulate the ubiquitination and proteasomal degradation of the tuberinhamartin complex particularly in the CNS	SIGNOR-261202	0.321
CCNO	protein	P22674	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								25364462	t		lperfetto	Phosphorylation of cyclin O, a novel cyclin family protein containing a cyclin-like domain, is involved in the activation of cyclin-dependent kinase 2|This activity was reduced in cells overexpressing cyclin O, in which the 81st serine had been replaced with alanine (S81A). These results suggest that cyclin O is a novel cyclin family protein that regulates CDK2 kinase activity, which is mediated by the phosphorylation of the 81st serine residue of cyclin O	SIGNOR-275616	0.466
TGFBR2	protein	P37173	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates activity	phosphorylation	Tyr424	GQVGTARyMAPEVLE	-1									9169454	t		lperfetto	Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor.	SIGNOR-48867	0.2
ITCH	protein	Q96J02	UNIPROT	BCL10	protein	O95999	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000661								15082780	t		miannu	The HECT domain ubiquitin ligases NEDD4 and Itch promote ubiquitination and degradation of Bcl10, thus downmodulating NF-kappa B activation. 	SIGNOR-271414	0.28
CDK5	protein	Q00535	UNIPROT	DLC1	protein	Q96QB1	UNIPROT	up-regulates activity	phosphorylation	Ser642	DSFGSLPsPKELSSF	9606	BTO:0002181								25452387	t		miannu	The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. 	SIGNOR-276444	0.2
PTPN12	protein	Q05209	UNIPROT	PTK2B	protein	Q14289	UNIPROT	down-regulates activity	dephosphorylation	Tyr402	CSIESDIyAEIPDET	10116									11337490	t			Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-PEST-mediated dephosphorylation|CAKbeta was found to be a substrate for PTP-PEST. Both the major autophosphorylation site of CAKbeta (Tyr(402)) and activation loop tyrosine residues, Tyr(579) and Tyr(580), were targeted for dephosphorylation by PTP-PEST. Dephosphorylation of CAKbeta by PTP-PEST dramatically inhibited CAKbeta kinase activity.	SIGNOR-248662	0.562
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029									9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258846	0.8
EEF1A2	protein	Q05639	UNIPROT	Tyr-tRNA(Tyr)	smallmolecule	CHEBI:29161	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269538	0.8
PAX3	protein	P23760	UNIPROT	FGFR4	protein	P22455	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25211658	t			FGFR4 is a transcriptional target of PAX3 and the PAX3-FOXO1 fusion protein found in ARMS.	SIGNOR-251572	0.374
TIGIT	protein	Q495A1	UNIPROT	ARRB2	protein	P32121	UNIPROT	up-regulates activity	binding			9606	BTO:0000914								24817116	t		lperfetto	With TIGIT/PVR engagement, cytoplasmic TIGIT was phosphorylated at Tyr-225 and Tyr-231 residues. Phosphorylated Tyr-225 recruits adaptor protein beta arrestin 2|TIGIT/PVR signaling mediates suppression of IFN- gamma production via the NF-kappaB pathway. We identified a new adaptor β-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells.	SIGNOR-261482	0.2
ARID1A	protein	O14497	UNIPROT	Neural progenitor-specific SWI/SNF	complex	SIGNOR-C477	SIGNOR	form complex	binding			9606									25195934	t		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270611	0.801
SRMS	protein	Q9H3Y6	UNIPROT	DOK1	protein	Q99704	UNIPROT	unknown	phosphorylation			9606	BTO:0000007								23822091	t		lperfetto	These data indicate that ectopically‐expressed GFP‐SRMS interacts with and mediates the phosphorylation of overexpressed GFP‐Dok1.	SIGNOR-264569	0.424
MED16	protein	Q9Y2X0	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266671	0.782
GOT1	protein	P17174	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	up-regulates quantity	chemical modification			9606									26003525	t		miannu	Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and α-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer.	SIGNOR-267506	0.8
MAPK14	protein	Q16539	UNIPROT	SLC9A1	protein	P19634	UNIPROT	up-regulates	phosphorylation	Ser723	VITIDPAsPQSPESV	9606									11604491	t		llicata	Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728.	SIGNOR-111039	0.552
MAPK3	protein	P27361	UNIPROT	SREBF2	protein	Q12772	UNIPROT	up-regulates	phosphorylation	Ser432	NQNVLLMsPPASDSG	9606									14988395	t		lperfetto	Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity.	SIGNOR-123049	0.4
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	Av/b6 integrin	complex	SIGNOR-C179	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259008	0.344
ECM	stimulus	SIGNOR-ST20	SIGNOR	A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259047	0.7
NEK6	protein	Q9HC98	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates activity	phosphorylation	Ser377	PPFNPNVsGPNDLRH	-1									12023960	t		miannu	The present study is the first report of a protein kinase (NEK6) capable of phosphorylating the hydrophobic motif of SGK1, although our data suggest that NEK6 may not mediate this reaction in cells. Nevertheless, the phosphorylation of the hydrophobic motif of SGK1in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1. Ser377 and Ser422of SGK1, and the CDK7 T-loop peptide, which are phosphorylated by NEK6.	SIGNOR-250296	0.344
linagliptin	chemical	CHEBI:68610	ChEBI	DPP4	protein	P27487	UNIPROT	down-regulates activity	chemical inhibition			9606									18052023	t		Luana	Herein, we report the discovery of the novel, potent, and selective DPP-4 inhibitor 1 (BI 1356)9 originating from the class of xanthines (Chart 1)	SIGNOR-257764	0.8
SLC34A1	protein	Q06495	UNIPROT	phosphate(3-)	smallmolecule	CHEBI:18367	ChEBI	up-regulates quantity	relocalization			9606		BTO:0000671							20335586	t		lperfetto	Genetic analysis revealed a homozygous in-frame duplication of 21 bp in SLC34A1, which encodes the renal sodium-inorganic phosphate cotransporter NaPi-IIa,	SIGNOR-270576	0.8
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DMB	protein	P28068	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-253999	0.373
CHEK2	protein	O96017	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser37	NVLSPLPsQAMDDLM	9606									10656682	t		gcesareni	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-74831	0.784
SCRIB	protein	Q14160	UNIPROT	Scribble_complex_DLG2-LLGL1_variant	complex	SIGNOR-C510	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270908	0.532
SEC31B	protein	Q9NQW1	UNIPROT	COPII vesicle	complex	SIGNOR-C370	SIGNOR	form complex	binding			9606	BTO:0000567								30605680	t		lperfetto	The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat	SIGNOR-265287	0.656
PRKCA	protein	P17252	UNIPROT	LRP1	protein	Q07954	UNIPROT	up-regulates	phosphorylation	Ser4523	GSRHSLAsTDEKREL	9606									15272003	t		lperfetto	Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc.	SIGNOR-127211	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ARHGAP26	protein	Q9UNA1	UNIPROT	unknown	phosphorylation			-1									9525907	t	inferred from 70% family members	miannu	In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling.	SIGNOR-270170	0.2
NDUFB8	protein	O95169	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1	SIGNOR-262171	0.814
PRKCQ	protein	Q04759	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	up-regulates activity	phosphorylation	Ser716	HILERFGsLTMDGGL	9606									31792381	t			TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation	SIGNOR-272472	0.2
MDM4	protein	O15151	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by stabilization				9606									15735705	f		lperfetto	Mdm2 and mdmx function as cellular regulators of the p53 tumor suppressor protein. Intriguingly, the activities of these proteins are interdependent;mdmx stabilizes mdm2, enabling its activities towards p53	SIGNOR-134391	0.72
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH20	protein	Q9HBT6	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265837	0.8
GAPDH	protein	P04406	UNIPROT	3-phosphonato-D-glyceroyl phosphate(4-)	smallmolecule	CHEBI:57604	ChEBI	up-regulates quantity	chemical modification			9606									11724794	t		miannu	GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion	SIGNOR-266494	0.8
CSNK2A1	protein	P68400	UNIPROT	NKX2-5	protein	P52952	UNIPROT	up-regulates activity	phosphorylation	Ser164	FKQQRYLsAPERDQL	9534	BTO:0004055								9858576	t		llicata	Mutational analysis and in vitro kinase assays suggested that this 40-kDa Csx/Nkx2.5 kinase is a catalytic subunit of casein kinase II (CKII) that phosphorylates the serine residue between the first and second helix of the homeodomain. This CKII site is phosphorylated in vivo. CKII-dependent phosphorylation of the homeodomain increased Csx/Nkx2. 5 DNA binding. Serine-to-alanine mutation at the CKII phosphorylation site reduced transcriptional activity when the carboxyl-terminal repressor domain was deleted.	SIGNOR-250924	0.338
SLBP	protein	Q14493	UNIPROT	H2AJ	protein	Q9BTM1	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265412	0.2
CTNNB1	protein	P35222	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	up-regulates activity	binding			9606									23151663	t		gcesareni	Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus.	SIGNOR-199378	0.914
FLT1	protein	P17948	UNIPROT	PHACTR1	protein	Q9C0D0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21939755	f		miannu	Recently, we identified a new Vascular Endothelial Growth Factor (VEGF)-A(165)-induced gene Phactr-1, (Phosphatase Actin Regulator-1). We found that neuropilin-1 (NRP-1) and VEGF-R1 depletion inhibited Phactr-1 mRNA expression while NRP-2 and VEGF-R2 depletion had no effect.	SIGNOR-260060	0.264
ROCK1	protein	Q13464	UNIPROT	RDX	protein	P35241	UNIPROT	unknown	phosphorylation	Thr573	RQIRQGNtKQRIDEF	-1									9456324	t		lperfetto	 A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kc€“phosphorylated C-rad as T564-phosphorylated C-rad.	SIGNOR-248995	0.666
NPTX1	protein	Q15818	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates activity	relocalization			10090									23069675	t		lperfetto	Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential	SIGNOR-261439	0.2
PIM1	protein	P11309	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation	Thr338	VPVKSRKtTLEQPPS	9606	BTO:0001061								31730483	t		miannu	Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 	SIGNOR-276775	0.629
CAMK2A	protein	Q9UQM7	UNIPROT	CD44	protein	P16070	UNIPROT	up-regulates activity	phosphorylation	Ser706	LNGEASKsQEMVHLV	9606	BTO:0000452								11463356	t		lperfetto	In previous studies we have demonstrated that a key control point for this receptor is the phosphorylation of CD44 on a conserved cytoplasmic serine residue, Ser(325). This modification is not required for efficient ligand binding, but is an essential component of CD44-dependent cell migration on a hyaluronan substratum. We demonstrate here that cd44 is phosphorylated to high stoichiometry in resting cells and that ca(2+)/calmodulin-dependent protein kinase ii is a cd44 ser(325) kinase.	SIGNOR-109502	0.2
5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine	chemical	CID:11617559	PUBCHEM	CSF1R	protein	P07333	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259743	0.8
KAT6A	protein	Q92794	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	acetylation	Lys382	QSTSRHKkLMFKTEG	9606	BTO:0001271		SIGNOR-C54						23431171	t		miannu	We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression	SIGNOR-201486	0.657
PKNOX1	protein	P55347	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								20864515	f		miannu	 Prep1 overexpression in HepG2 liver cells upregulated SYP and SHP1 and inhibited insulin-induced IR and IRS1/2 phosphorylation and was accompanied by reduced glycogen content. 	SIGNOR-254924	0.2
BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	SMAD1	protein	Q15797	UNIPROT	up-regulates	phosphorylation	Ser465	HNPISSVs	9606									9136927	t		lperfetto	Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro	SIGNOR-249648	0.652
FANCD2	protein	Q9BXW9	UNIPROT	BRCA2	protein	P51587	UNIPROT	up-regulates activity	binding			9606	BTO:0005035				phosphorylation:Ser331	KSKGRASsSGNQESS			19861535	t		lperfetto	Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction	SIGNOR-263238	0.806
ANGPTL1	protein	O95841	UNIPROT	TEK	protein	Q02763	UNIPROT	up-regulates	binding			9606									15284220	t		gcesareni	In experiments with human endothelial cell lines, ang3 was identified as an antagonist of tie2 and ang4 was identified as an agonist of tie2.	SIGNOR-127354	0.521
PTK2	protein	Q05397	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	phosphorylation	Tyr427	ELFDDPSyVNVQNLD	9606									9566877	t		Luana	 In vitro, FAK directly phosphorylated Shc Tyr-317 to promote Grb2 binding. FAK can associate and directly phosphorylate Shc at Tyr-317 to promote Grb2 binding and low-level signaling to ERK2.	SIGNOR-259854	0.661
MTOR	protein	P42345	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser616	DDGYMPMsPGVAPVP	10116									11287630	t		lperfetto	Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten	SIGNOR-106582	0.758
OXTR	protein	P30559	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256936	0.252
CHEK1	protein	O14757	UNIPROT	ERRFI1	protein	Q9UJM3	UNIPROT	down-regulates activity	phosphorylation	Ser251	RRLRRSHsGPAGSFN	-1									22505024	t		miannu	 Our results suggest that Chk1 phosphorylates Mig-6 on Ser 251, resulting in the inhibition of Mig-6, and that Chk1 acts as a positive regulator of EGF signalling. This is a novel function of Chk1.	SIGNOR-276411	0.331
PLK2	protein	Q9NYY3	UNIPROT	CENPJ	protein	Q9HC77	UNIPROT	up-regulates	phosphorylation	Ser589	EQAADEIsFSSNSSF	9606									20531387	t		lperfetto	Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle.	SIGNOR-165999	0.561
AKT2	protein	P31751	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Thr24	LPRPRSCtWPLPRPE	9606									10377430	t		lperfetto	Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus.	SIGNOR-252872	0.757
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO4	protein	P98177	UNIPROT	up-regulates	phosphorylation			9606									17900900	t		lperfetto	The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation	SIGNOR-216484	0.336
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser37	EDLTDELsLNKISAD	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276207	0.2
MSN	protein	P26038	UNIPROT	MSN/PDZD8	complex	SIGNOR-C61	SIGNOR	form complex	binding			9606									21549406	t		miannu	These results demonstrated that both human moesin and its newly identified binding partner, pdzd8 had similar effects on host mt networks, suggesting that they are likely to function as part of a stable mt regulatory complex.	SIGNOR-173647	0.324
MAPK10	protein	P53779	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates				9606									15071501	f		gcesareni	Demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria; these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins.	SIGNOR-124001	0.263
WWC1	protein	Q8IX03	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates activity				9606	BTO:0000007								20159598	f	Hippo pathway	Gianni	These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis.	SIGNOR-261954	0.455
TRIM23	protein	P36406	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0003682								19176615	t		miannu	 We show here that the upregulation of NF-kappaB by UL144 is dependent upon cellular tripartite motif 23 (TRIM23) protein. We propose a mechanism by which UL144 activates NF-kappaB through a direct interaction with the cellular protein TRIM23 in a complex containing TRAF6. we propose that TRIM23 mediates TRAF6 autoubiquitination in the presence of UL144, resulting in the virally controlled activation of NF-κB stimulation at early times of HCMV infection. 	SIGNOR-266655	0.319
FGFR1	protein	P11362	UNIPROT	CTTN	protein	Q14247	UNIPROT	down-regulates	phosphorylation	Tyr446	GTEPEPVySMEAADY	9606									12601080	t		lperfetto	Cortactin, which is an actin-binding protein that also plays a role in actin cytoskeleton dynamics (45), was phosphorylated on tyr-446 in our assay (by fgfr1).Phosphorylation of these residues attenuates the f-actin cross-linking activity	SIGNOR-98618	0.318
RPS6KA4	protein	O75676	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	unknown	phosphorylation			10090									12773393	t		lperfetto	The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28	SIGNOR-265355	0.2
SRC	protein	P12931	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates activity	phosphorylation	Tyr502	TTANVVYyVGENVVN	9606									12637538	t		lperfetto	Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation.	SIGNOR-247328	0.421
PRKDC	protein	P78527	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates activity	phosphorylation	Ser3205	TPLPEDNsMNVDQDG	9606	BTO:0000773								12186630	t		lperfetto	 We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function.	SIGNOR-249157	0.2
WWP1	protein	Q9H0M0	UNIPROT	TP73	protein	O15350	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								25071155	t		miannu	WWP1 in complex with WWP2 specifically regulates ΔNp73.  In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73. 	SIGNOR-272232	0.287
AKT1	protein	P31749	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation			9606									22798428	t		gcesareni	Akt negatively regulates the raf and gsk-3 kinases and the cell cycle regulatory transcription factor fkhr.	SIGNOR-252531	0.687
SIRT7	protein	Q9NRC8	UNIPROT	RAN	protein	P62826	UNIPROT	down-regulates activity	deacetylation	Lys37	HLTGEFEkKYVATLG										31075303	t	Ran ID inferred from sequence: KRHLTGEFEKKYVATLGVEV	lperfetto	N this study, we demonstrated that SIRT7 interacts with a small GTPase, Ras-related nuclear antigen (Ran), and deacetylates Ran at K37. |The nuclear export by CRM1 requires an interaction with the small GTPase Ras-related nuclear antigen (Ran), which cycles between GTP- and GDP-bound states. The binding of Ran GTP to CRM1 in the nucleus increases the affinity of CRM1 for cargo proteins [[18], [19], [20]]. Interestingly, Ran is a lysine-acetylated protein	SIGNOR-275849	0.2
PF-03814735	chemical	CID:49830590	PUBCHEM	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205950	0.8
H4C1	protein	P62805	UNIPROT	BRD4	protein	O60885	UNIPROT	up-regulates activity	relocalization			9606					acetylation:Lys21;Lys17	GGAKRHRkVLRDNIQ;GLGKGGAkRHRKVLR			27991587	t		lperfetto	BRD4 interacts with acetylated nucleosomes via both its BD1 and BD2 domains. Our results indicate that BRD4-BD1 binds to nucleosomes through the acetylated histone H4 tail and does not additionally interact with DNA.	SIGNOR-262065	0.2
prednisone	chemical	CHEBI:8382	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									3930339	t	ulcerative colitis	gcesareni		SIGNOR-251702	0.8
MRE11/RAD50/NBS1	complex	SIGNOR-C147	SIGNOR	Mitotic_checkpoint	phenotype	SIGNOR-PH28	SIGNOR	up-regulates													17713585	f		lperfetto	The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs).|Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein--nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB.	SIGNOR-251503	0.7
LYN	protein	P07948	UNIPROT	CD19	protein	P15391	UNIPROT	up-regulates	phosphorylation	Tyr531	HEEDADSyENMDNPD	9606									10933394	t		llicata	Experiments with purified proteins demonstrated that cd19-y513 was lyn's initial phosphorylation and binding site. This led to processive phosphorylation of cd19-y482, which recruited a second lyn molecule, allowing for transphosphorylation and amplification of lyn activation.	SIGNOR-80294	0.765
DDX21	protein	Q9NR30	UNIPROT	B-WICH complex	complex	SIGNOR-C447	SIGNOR	form complex	binding			9606									21559432	t		miannu	The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 	SIGNOR-268824	0.421
PTPN11	protein	Q06124	UNIPROT	α-Catenin	proteinfamily	SIGNOR-PF72	SIGNOR	down-regulates activity	dephosphorylation			9606									16767162	t		miannu	Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals.	SIGNOR-265824	0.41
CSNK1A1	protein	P48729	UNIPROT	YWHAZ	protein	P63104	UNIPROT	down-regulates activity	phosphorylation	Thr232	LTLWTSDtQGDEAEA	9606	BTO:0000007								9360956	t		llicata	This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins. | We have now shown that in vivo phosphorylation of 14-3-3 zeta at the CKIalpha site (Thr-233) negatively regulates its binding to c-Raf, and may be important in Raf-mediated signal transduction. 	SIGNOR-250796	0.56
EGFR	protein	P00533	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates	phosphorylation	Tyr354	LMLRLQDyEEKTKKA	9606	BTO:0000017								15647376	t		lperfetto	Ezrin was initially identified as a substrate for tyrosine phosphorylation by egfr (bretscher, 1989) and phosphorylation of residues y145 and y353 were detected to high stoichiometry after egf treatment . Phosphorylation of ezrin at y353 has been delineated to signal survival during epithelial cell differentiation via the phosphatidylinositol 3-kinase (pi3k)/akt pathway.	SIGNOR-133215	0.546
MEF2A	protein	Q02078	UNIPROT	MYH10	protein	P35580	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0001103							15728583	t		lperfetto	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238763	0.323
PRKCI	protein	P41743	UNIPROT	NUMB	protein	P49757	UNIPROT	down-regulates	phosphorylation			9606									17609107	t		esanto	Numb is regulated by phosphorylation since the protein is released from ccss and no longer binds integrins when phosphorylated by atypical protein kinase c (apkc).	SIGNOR-156765	0.761
PDK4	protein	Q16654	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates	phosphorylation	Ser300	SMSDPGVsYRTREEI	-1									7782287	t		gcesareni	Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase.	SIGNOR-33201	0.674
CIITA	protein	P33076	UNIPROT	HLA-DRB1	protein	P01911	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002417								10886240	f	 	 	These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma.	SIGNOR-253976	0.516
L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	precursor of			9606									29084849	t		miannu	Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7.	SIGNOR-267529	0.8
SOX6	protein	P35712	UNIPROT	CEBPA	protein	P49715	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26893351	t			We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST	SIGNOR-255824	0.297
PPARG	protein	P37231	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates				10090		BTO:0004300							16150867	f		lperfetto	Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor	SIGNOR-256229	0.7
CCKAR	protein	P32238	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256906	0.267
CCND1	protein	P24385	UNIPROT	CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	form complex	binding			9606									7736585	t		gcesareni	D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb,	SIGNOR-32298	0.964
ADAMTS4	protein	O75173	UNIPROT	ACAN	protein	P16112	UNIPROT	down-regulates quantity by destabilization	cleavage	Glu392	PRNITEGeARGSVIL	9606									9202061	t		lperfetto	Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE373	SIGNOR-266984	0.759
PTPRJ	protein	Q12913	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									10734133	t		gcesareni	Ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase.	SIGNOR-76096	0.309
CIITA	protein	P33076	UNIPROT	HLA-DMA	protein	P28067	UNIPROT	up-regulates quantity by expression	transcriptional regulation												9300700	f	 	 	The class II transactivator (CIITA) is a highly specific transcription factor that activates only genes known to be involved in the class II MHC processing pathway, including class II MHC, invariant chain, and HLA-DMA/B genes.	SIGNOR-254004	0.413
CDK2	protein	P24941	UNIPROT	CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	form complex	binding			9606									19665013	t		lperfetto	The eukaryotic cell cycle is controlled by different cyclins and their associated kinases (murray and hunt, 1993). In mammalian cells, levels of cycline and its associated kinase, cdk2, rise in late g1/early s-phase when dna replication is initiated	SIGNOR-187457	0.931
nitrendipine	chemical	CHEBI:7582	ChEBI	KCNN4	protein	O15554	UNIPROT	down-regulates activity	chemical inhibition			9606									9730970	t		miannu	IK was blocked by the classical inhibitors of the Gardos channel charybdotoxin (IC50 28 nM) and clotrimazole (IC50 153 nM) as well as by nitrendipine (IC50 27 nM), Stichodactyla toxin (IC50 291 nM), margatoxin (IC50 459 nM), miconazole (IC50 785 nM), econazole (IC50 2.4 microM), and cetiedil (IC50 79 microM). Finally, 1-ethyl-2-benzimidazolinone, an opener of the T84 cell IK channel, activated hIK with an EC50 of 74 microM.	SIGNOR-258831	0.8
CDK1	protein	P06493	UNIPROT	RAB1A	protein	P62820	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000567								1902553	t		Giulio	We now present biochemical evidence for a mitosis-specific p34cdc2 phosphorylation of RablAp and Rab4p.We also show that the distribution of RablAp and Rab4p between cytosolic and membrane-bound forms is different in interphase and mitotic cells.	SIGNOR-261284	0.506
EGFR	protein	P00533	UNIPROT	ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	up-regulates	binding			9606									11279155	t	inferred from 70% of family members	gcesareni	These results demonstrate that egfr-erbb2 oligomers are potent activators of mapk and akt, and this signaling does not require egfr kinase activity	SIGNOR-269876	0.655
TBR1	protein	Q16650	UNIPROT	AUTS2	protein	Q8WXX7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000142							20615956	t		miannu	Tbr1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism.	SIGNOR-266836	0.367
CFH	protein	P08603	UNIPROT	CRP	protein	P02741	UNIPROT	down-regulates activity	binding			9606	BTO:0004910								26961257	t		miannu	In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained.	SIGNOR-252145	0.568
CAMK2A	protein	Q9UQM7	UNIPROT	CLCN3	protein	P51790	UNIPROT	up-regulates activity	phosphorylation	Ser109	ERHRRINsKKKESAW										14754994	t		lperfetto	Identification of an N-terminal amino acid of the CLC-3 chloride channel critical in phosphorylation-dependent activation of a CaMKII-activated chloride current|The N-terminus of CLC-3, which contains a CaMKII consensus sequence, was phosphorylated by CaMKII in vitro, and mutation of the serine at position 109 (S109A) abolished the CaMKII-dependent Cl(-) conductance, indicating that this residue is important in the gating of CLC-3 at the plasma membrane.	SIGNOR-275863	0.345
CDK1	protein	P06493	UNIPROT	NUP210	protein	Q8TEM1	UNIPROT	up-regulates activity	phosphorylation	Ser1881	SPPSGLWsPAYASH	-1									8672508	t		miannu	 In vitro phosphorylation of GST fusion protein containing the carboxyl-terminal domain of gp210 by cyclin B-p34cdc2 protein kinase generates a phosphopeptide that comigrates with a mitosis-specific phosphopeptide. Ser1880 Is the Mitotic Phosphorylation Site of Gp210. 	SIGNOR-262699	0.529
ATM	protein	Q13315	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1542	EEQQLEEsGPHDLTE	9606	BTO:0000150								10550055	t		lperfetto	The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm	SIGNOR-72072	0.813
KLF2	protein	Q9Y5W3	UNIPROT	RELN	protein	P78509	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21530336	t		Luana	KLF2 transactivates the reelin promoter in K562 cells.	SIGNOR-266048	0.2
TSC1	protein	Q92574	UNIPROT	RHEB	protein	Q15382	UNIPROT	down-regulates activity	binding			9606									20006481	t		lperfetto	Tsc1 and tsc2 proteins, which together inhibit rheb through the gap activity of tsc2.	SIGNOR-162096	0.909
TBK1	protein	Q9UHD2	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Ser396	NTVDLHIsNSHPLSL	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178399	0.817
TAP1	protein	Q03518	UNIPROT	oligopeptide	smallmolecule	CHEBI:25676	ChEBI	down-regulates quantity	relocalization			9606									31810556	t		scontino	Following cytosolic proteolysis, antigenic peptides are recruited to the ER and translocated to its lumen by the Transporter associated with Antigen Processing (TAP).	SIGNOR-267778	0.8
A4/b1 integrin	complex	SIGNOR-C162	SIGNOR	JAG1	protein	P78504	UNIPROT	up-regulates quantity by expression				10090									25786978	f		lperfetto	First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs.	SIGNOR-253287	0.307
MAPK3	protein	P27361	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser104	FPPLNSVsPSPLMLL	9606									18372406	t		gcesareni	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity	SIGNOR-178141	0.692
PLK1	protein	P53350	UNIPROT	WDCP	protein	Q9H6R7	UNIPROT	up-regulates activity	phosphorylation	Ser686	RSDVFRDsFSHSPGA	9606	BTO:0000007								30297404	t		miannu	PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11. we performed in vitro kinase assays followed by mass spectrometry and found that two sites (S686 and S695) in this cluster were phosphorylated. Thus, all of these results are in agreement that this cluster is phosphorylated by PLK1.	SIGNOR-273730	0.2
PTPRA	protein	P18433	UNIPROT	VPS33B	protein	Q9H267	UNIPROT	down-regulates activity	dephosphorylation			9606									18474358	t		lperfetto	Here, we report that VPS33B, a host protein involved in vesicle trafficking, is dephosphorylated by PtpA leading to a block of phagosome maturation by M. tuberculosis.|These data suggest that M. tuberculosis PtpA inhibits phagosome maturation.To assess the role of VPS33B in phagosome maturation, we attenuated the expression of endogenous VPS33B expression in THP-1 cells using a siRNA based approach.	SIGNOR-277015	0.2
SIRT7	protein	Q9NRC8	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	deacetylation	Lys37	APATGGVkKPHRYRP										30653310	t		lperfetto	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 	SIGNOR-275876	0.2
PLK1	protein	P53350	UNIPROT	BRCA2	protein	P51587	UNIPROT	down-regulates activity	phosphorylation	Ser193	AEVDPDMsWSSSLAT	9606	BTO:0001938								12815053	t		lperfetto	M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1	SIGNOR-102486	0.556
ARHGAP4	protein	P98171	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260460	0.456
TERF1	protein	P54274	UNIPROT	Shelterin complex	complex	SIGNOR-C306	SIGNOR	form complex	binding			9606									15383534	t		lperfetto	Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins.	SIGNOR-263316	0.743
PTPN1	protein	P18031	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	10090	BTO:0000944								11579209	t		lperfetto	Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor.	SIGNOR-235499	0.778
AKT1	protein	P31749	UNIPROT	TENT2	protein	Q6PIY7	UNIPROT	down-regulates activity	phosphorylation	Ser116	LSGERRYsMPPLFHT	9606	BTO:0000007								31057087	t		miannu	We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. 	SIGNOR-259405	0.2
CSNK2A1	protein	P68400	UNIPROT	CERS6	protein	Q6ZMG9	UNIPROT	up-regulates activity	phosphorylation	Ser346	DRSDIESsSDEEDSE	9606	BTO:0000007								26887952	t		miannu	Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue. 	SIGNOR-273992	0.2
CRX	protein	O43186	UNIPROT	BEST1	protein	O76090	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									18849347	f		miannu	 Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity.	SIGNOR-253815	0.377
RRAGC	protein	Q9HB90	UNIPROT	RAGBC	complex	SIGNOR-C115	SIGNOR	form complex	binding			9606									20381137	t		gcesareni	Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant	SIGNOR-228173	0.783
SIRT7	protein	Q9NRC8	UNIPROT	H3-2	protein	Q5TEC6	UNIPROT	up-regulates activity	deacetylation	Lys37	APATGGVkKPHRYRP										30653310	t		lperfetto	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 	SIGNOR-275877	0.2
MECP2	protein	P51608	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000452								19820693	f		Luana	We show that MeCP2 cooperates with HIPK2 in induction of apoptosis and that Ser 80 phosphorylation is required together with the DNA binding of MeCP2. | We found increased cell death in each of the tested cell lines not only, as expected, when HIPK2 was overexpressed but also with MeCP2 alone. When both proteins were expressed together, the number of dead cells increased in an additive manner. 	SIGNOR-264550	0.7
CSNK2A1	protein	P68400	UNIPROT	SNAI1	protein	O95863	UNIPROT	up-regulates	phosphorylation	Ser92	VAELTSLsDEDSGKG	9606									19923321	t		lperfetto	Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively.	SIGNOR-161775	0.354
PRKCD	protein	Q05655	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	phosphorylation	Thr46	PHRYRPGtVALREIR	9606									19363025	t		gcesareni	We identify protein kinase c-delta as the kinase responsible for h3t45ph in vitro and in vivo. Given the nucleosomal position of h3t45, we postulate that h3t45ph induces structural change within the nucleosome to facilitate dna nicking and/or fragmentation.	SIGNOR-185144	0.2
ULK1	protein	O75385	UNIPROT	PRKAA2	protein	P54646	UNIPROT	down-regulates	phosphorylation			9606				SIGNOR-C15					21460634	t		gcesareni	Here we report that ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. Thus, we propose that ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of ampk by ulk1 represents a negative feedback circuit.	SIGNOR-173050	0.483
RABGEF1	protein	Q9UJ41	UNIPROT	RAB5A	protein	P20339	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			10090									27411398	t		lperfetto	AP-1/sigma1A-ArfGAP1-Rabex-5 complex formation leads to more endosomal Rabex-5 and enhanced, Rab5GTP-stimulated Vps34 PI3-kinase activity, which is essential for multivesicular body endosome formation.	SIGNOR-260707	0.921
zolmitriptan	chemical	CHEBI:10124	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			9606									10193663	t		Luana	This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues 	SIGNOR-258341	0.8
NFATC2	protein	Q13469	UNIPROT	MEF2D	protein	Q14814	UNIPROT	up-regulates	binding			9606									11796223	t		lperfetto	Upon dephosphorylation by calcineurin, nfatc2, also referred to as nfatp/nfat1, translocates to the nucleus where it directly associates with mef2a and -d. Nfatc2 stimulates mef2-dependent transcription by facilitating recruitment of the p300 coactivator to mef2-response elements.	SIGNOR-117589	0.564
CUL1	protein	Q13616	UNIPROT	SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	form complex	binding			9606									10023660	t		gcesareni	The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin.	SIGNOR-64502	0.884
P2RY4	protein	P51582	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257122	0.2
venlafaxine	chemical	CHEBI:9943	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606									20378347	t		Luana	The cycloalkanol ethylamine scaffold was successfully utilized in the discovery and development of dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitors (SNRIs).1 Drugs such as venlafaxine (1) and duloxetine (2) possessing norepinephrine reuptake inhibition, either selectively or in combination with serotonin reuptake inhibition were approved for major depressive disorder (MDD).	SIGNOR-257836	0.8
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	EEF2K	protein	O00418	UNIPROT	down-regulates activity	phosphorylation	Ser366	SPQVRTLsGSRPPLL	9606									11500364	t		lperfetto	We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity	SIGNOR-252775	0.2
WWP2	protein	O00308	UNIPROT	EGR2	protein	P11161	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								19651900	t		lperfetto	The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell death by catalyzing EGR2 ubiquitination|AIP2 interacts with and promotes ubiquitin-mediated degradation of EGR2, a zinc finger transcription factor that has been found to regulate Fas ligand (FasL) expression during activation-induced T-cell death.	SIGNOR-268849	0.379
FBXO11	protein	Q86XK2	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	neddylation	Lys320	SSSPQPKkKPLDGEY	9606									17098746	t		miannu	Fbxo11 promotes the neddylation of p53 and inhibits its transcriptional activity / we found that fbxo11 also neddylates p53 on two lysines, lys-320 and lys-321	SIGNOR-150669	0.658
CSNK2A1	protein	P68400	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser32	LLDDRHDsGLDSMKD										10398585	t		lperfetto	Serine 32 and serine 36 of IkappaBalpha are directly phosphorylated by protein kinase CKII in vitro|Phosphorylation of IkappaBalpha at serine 32 (S32) and serine 36 (S36) is necessary for this stimuli-induced degradation	SIGNOR-249332	0.566
TNFRSF1B	protein	P20333	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity													17151142	f			[...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation	SIGNOR-253601	0.306
eribulin mesylate	chemical	CHEBI:70710	ChEBI	Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	down-regulates activity	chemical inhibition			9606									16940412	t		miannu	The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin.	SIGNOR-259444	0.8
TUBGCP6	protein	Q96RT7	UNIPROT	g-TuRC complex	complex	SIGNOR-C282	SIGNOR	form complex	binding			-1									31862189	t		lperfetto	Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.”	SIGNOR-262330	0.775
TSC22D3	protein	Q99576	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates activity	binding			9606	BTO:0000007								11468175	t			GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits.	SIGNOR-253299	0.364
PHF2	protein	O75151	UNIPROT	H3-4	protein	Q16695	UNIPROT	down-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									21532585	t		miannu	PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark.	SIGNOR-264520	0.2
Ku-0063794	chemical	CHEBI:85572	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0000887;BTO:0001260							20884880	t		gcesareni	Sgk-1 activation in response to stretch is blocked by insulin-like growth factor (igf)-1 receptor inhibitor and mammalian target of rapamycin complex (mtorc)2 inhibitor (ku-0063794) but not mtorc1 inhibitor (rapamycin).	SIGNOR-168188	0.8
SETBP1	protein	Q9Y6X0	UNIPROT	HOXA9	protein	P31269	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001271								22566606	f		miannu	Setbp1 activates hoxa9 and hoxa10 expression in myeloid progenitors	SIGNOR-197321	0.432
MAP1LC3A	protein	Q9H492	UNIPROT	ATG3	protein	Q9NT62	UNIPROT	up-regulates	binding			9606									22170151	t		gcesareni	Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe.	SIGNOR-191543	0.85
SGK2	protein	Q9HBY8	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606									11154281	t		lperfetto	Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 	SIGNOR-249132	0.512
PRKCB	protein	P05771	UNIPROT	PRKCB	protein	P05771	UNIPROT	unknown	phosphorylation	Thr17	PSEGEEStVRFARKG	-1									2377895	t		lperfetto	Thus four peptides containing six major sites of intrapeptide autophosphorylation of protein kinase C have been identified. | Phosphoamino acid analyses indicated that only the NH2-terminal peptide contained phosphoserine. The modified residue was determined to be Ser16	SIGNOR-248868	0.2
MAPK3	protein	P27361	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity	phosphorylation			10090	BTO:0002572								28646232	t		Gianni	We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels	SIGNOR-262520	0.356
TEK	protein	Q02763	UNIPROT	TEK	protein	Q02763	UNIPROT	up-regulates activity	phosphorylation	Tyr992	LSRGQEVyVKKTMGR	-1									11513602	t		lperfetto	Isoelectric focusing electrophoresis and mass spectrometric analysis of a tie2 autophosphorylation time course showed that tyr992 on the putative activation loop was phosphorylated first followed by tyr1108 in the c-terminal tail autophosphorylation of tie2 to produce ptie2 resulted in a 100-fold increase in kcat and a 460-fold increase in kcat/km.	SIGNOR-109790	0.2
SF3B3	protein	Q15393	UNIPROT	SF3b	complex	SIGNOR-C442	SIGNOR	form complex	binding			9606									32140746	t		lperfetto	Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a).	SIGNOR-268405	0.929
HACD3	protein	Q9P035	UNIPROT	FASN	protein	P49327	UNIPROT	up-regulates activity	chemical activation			9606									18554506	t			Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases,	SIGNOR-267762	0.2
HRK	protein	O00198	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	down-regulates	binding			9606									9130713	t		gcesareni	Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1.	SIGNOR-47797	0.622
FYN	protein	P06241	UNIPROT	ITCH	protein	Q96J02	UNIPROT	down-regulates activity	phosphorylation	Tyr420	QFNQRFIyGNQDLFA	10090	BTO:0002417								16387660	t		gcesareni	Tyrosine phosphorylation of Itch appears to reduce its interaction with its substrate JunB. The turnover of JunB is accelerated in Fyn-deficient T cells, which is further reconstituted by Itch Tyr371 mutation	SIGNOR-245332	0.373
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation	Tyr1007	VLPQDKEyYKVKEPG	-1									9111318	t			Multiple autophosphorylation sites on Jak2, including Y1007 and Y1008. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop.	SIGNOR-251357	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CACNB1	protein	Q02641	UNIPROT	up-regulates activity	phosphorylation	Ser348	IVYIKITsPKVLQRL	9534	BTO:0000298								16406008	t		miannu	Thus, Ser-447 on Ca(v)2.2 and Ser-161 and Ser-348 of Ca(v)beta1b appear to be both necessary and sufficient for ERK-dependent modulation of these channels. Together, our data strongly suggest that modulation of neuronal N-type VDCCs by ERK involves phosphorylation of Ca(v)2.2alpha1 and to a lesser extent possibly also Ca(v)beta subunits. On the basis of the evidence presented here, it is therefore suggested that ERK-dependent up-regulation of Cav2.2 channels is primarily mediated by phosphorylation of Ser-447 on the I–II loop of Cav2.2 and possibly also the two SP sites conserved on Cavβs.	SIGNOR-262965	0.2
EIF2B3	protein	Q9NR50	UNIPROT	EIF2S3	protein	P41091	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269136	0.724
CSNK2A1	protein	P68400	UNIPROT	ANP32B	protein	Q92688	UNIPROT	up-regulates	phosphorylation	Thr244	GEKRKREtDDEGEDD	9606									19130553	t		gcesareni	Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna	SIGNOR-183158	0.235
GGCX	protein	P38435	UNIPROT	F2	protein	P00734	UNIPROT	up-regulates activity	carboxylation	Glu72	CSYEEAFeALESSTA	-1									10556651	t		lperfetto	We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 	SIGNOR-263683	0.655
CAMK2A	protein	Q9UQM7	UNIPROT	SLN	protein	O00631	UNIPROT	down-regulates activity	phosphorylation	Thr5	tRELFLNF	10116									23455424	t		lperfetto	SLN is also phosphorylated by CaMKII at Thr 5, and a phosphorylation mimic (Thr5Glu mutation) abolishes the inhibitory function of ectopically expressed SLN in adult rat ventricular myocytes| Thr 5 interacts with SERCA Trp 932, and phosphorylation at this site would cause a steric clash that destabilizes binding 	SIGNOR-264778	0.243
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1651	SPTSPSYsPTSPSYS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248818	0.849
PRKACG	protein	P22612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									10230396	t		gcesareni	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.	SIGNOR-67392	0.409
RUNX1	protein	Q01196	UNIPROT	GP1BA	protein	P07359	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17725493	f	 	miannu	 We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. 	SIGNOR-254195	0.376
RPL19	protein	P84098	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262479	0.879
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1864	SPKYSPTsPKYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120040	0.781
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	NR5A2	protein	O00482	UNIPROT	up-regulates activity	phosphorylation	Ser510	LPEIRAIsMQAEEYL	9606	BTO:0000093								16109788	t		miannu	 PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469. 	SIGNOR-276041	0.2
ATM	protein	Q13315	UNIPROT	NOP53	protein	Q9NZM5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser233	ARLHTKPsQAPAVEV	9606	BTO:0000007								27829214	t		miannu	PICT-1 S233 and T289 were identified as the key phosphorylation sites in this pathway, as mutating both to alanine abolished UVB-induced increase of PICT-1 phosporylation. Inhibition of PIKKs or ATM (with wortmannin and KU55933, respectively) prevented the agglomeration and degradation of PICT-1, suggesting that ATM is a key regulator of PICT-1. 	SIGNOR-273506	0.2
HMGA1	protein	P17096	UNIPROT	KITLG	protein	P21583	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								15378028	f	 	miannu	Human KIT ligand promoter is positively regulated by HMGA1 in breast and ovarian cancer cells.	SIGNOR-254426	0.335
VARS1	protein	P26640	UNIPROT	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									30755602	t		miannu	Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 	SIGNOR-270528	0.8
KIFC1	protein	Q9BW19	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									33361741	f		miannu	Kinesin Family Member C1 (KIFC1) Regulated by Centrosome Protein E (CENPE) Promotes Proliferation, Migration, and Epithelial-Mesenchymal Transition of Ovarian Cancer	SIGNOR-266114	0.7
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	ATF2	protein	P15336	UNIPROT	up-regulates activity	binding			9606									10085140	t		lperfetto	Here we report that the transcription factor atf-2 (also called cre-bp1) is bound by a hetero-oligomer of smad3 and smad4 upon tgf-beta stimulation. Both of these actions are shown to be responsible for the synergistic stimulation of ATF-2 trans-activating capacity.	SIGNOR-65583	0.581
1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester	chemical	CHEBI:92418	ChEBI	CHRM1	protein	P11229	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258636	0.8
lurasidone	chemical	CHEBI:70735	ChEBI	HTR2A	protein	P28223	UNIPROT	down-regulates activity	chemical inhibition			10030									20404009	t		Luana	Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 
2C receptors.	SIGNOR-259465	0.8
CSNK2A2	protein	P19784	UNIPROT	HMGA1	protein	P17096	UNIPROT	unknown	phosphorylation	Ser103	EGISQESsEEEQ	-1									2806554	t		llicata	Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells.	SIGNOR-251005	0.333
PRKCD	protein	Q05655	UNIPROT	HMGA1	protein	P17096	UNIPROT	down-regulates	phosphorylation	Ser64	PRGRPKGsKNKGAAK	9606									10617144	t		fspada	In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64	SIGNOR-73610	0.267
STAT5A	protein	P42229	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0004408								15353555	f		miannu	Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors.	SIGNOR-255682	0.7
KANK1	protein	Q14678	UNIPROT	BAIAP2	protein	Q9UQB8	UNIPROT	down-regulates activity	binding			10090	BTO:0000944								19171758	t		miannu	In this study, we report that Kank disrupts the function of active Rac1 through IRSp53. The binding between IRSp53 and Kank inhibits the association of active Rac1 with IRSp53 rather than the association of active cdc42 with IRSp53. Kank inhibits the formation of lamellipodia and membrane ruffles induced by active Rac1 in NIH3T3 cells. Kank interacts with IRSp53 through their coiled-coil domains. Kank affected the interaction between IRSp53 and Rac1 and partially affected that between IRSp53 and cdc42 (Fig. 3). 	SIGNOR-265553	0.348
MAPK1	protein	P28482	UNIPROT	DUSP1	protein	P28562	UNIPROT	up-regulates	phosphorylation	Ser359	SALSYLQsPITTSPS	9606									10617468	t		lperfetto	Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein.	SIGNOR-73621	0.799
SNW1	protein	Q13573	UNIPROT	NCOR2	protein	Q9Y618	UNIPROT	down-regulates	binding			9606	BTO:0000222	BTO:0000887							10713164	t		gcesareni	We present evidence that skip interacts with the cbf1 corepressor complex and that skip has a role in orchestrating the conversion of cbf1 from an smrt-hdac-tethered transcriptional repressor to a notchic-tethered activation complex.	SIGNOR-75785	0.574
COL1A2	protein	P08123	UNIPROT	A1/b1 integrin	complex	SIGNOR-C159	SIGNOR	up-regulates activity	binding			9606	BTO:0000664								12123670	t		lperfetto	We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1.	SIGNOR-253248	0.457
MEIS1	protein	O00470	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	down-regulates				9606	BTO:0000725								14701735	f		irozzo	Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function.	SIGNOR-255865	0.7
FES	protein	P07332	UNIPROT	BCR	protein	P11274	UNIPROT	down-regulates activity	phosphorylation	Tyr177	ADAEKPFyVNVEFHH	9606	BTO:0000007								8955135	t			Mutagenesis of BCR Tyr-177 to Phe completely abolished FES-induced BCR binding to the GRB2 SH2 domain, identifying Tyr-177 as an additional phosphorylation site for FES. Co-expression of BCR and FES in human 293T cells stimulated the tyrosine autophosphorylation of FES. By contrast, tyrosine phosphorylation of BCR by FES suppressed BCR serine/threonine kinase activity toward the 14-3-3 protein and BCR substrate, BAP-1.	SIGNOR-251136	0.375
GDP	smallmolecule	CHEBI:17552	ChEBI	PRPS1	protein	P60891	UNIPROT	down-regulates activity	chemical inhibition												29074724	t		lperfetto	PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP	SIGNOR-265738	0.8
S100A4	protein	P26447	UNIPROT	MYH9	protein	P35579	UNIPROT	down-regulates activity	binding			10090	BTO:0005138								16707441	t		miannu	Our results show that S100A4 regulates cell polarization during directed motility by affecting the localization of protrusions through interactions with myosin-IIA, with S100A4 expressing cells displaying few side protrusions and extensive forward protrusions during chemotaxis compared with control cells. The mechanisms by which these antibodies and S100A4 increase protrusive activity and promote cellular motility are not well understood, but the observation that S100A4 can inhibit the actin-activated ATPase of myosin-IIA (34) suggests that S100A4 could function as a myosin-IIA inhibitor in vivo. 	SIGNOR-269282	0.428
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr45	PGGTLFStTPGGTRI	10090	BTO:0002572		SIGNOR-C3						20670887	t		lperfetto	Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation	SIGNOR-167184	0.924
RPS6KA1	protein	Q15418	UNIPROT	CIC	protein	Q96RK0	UNIPROT	down-regulates	phosphorylation	Ser173	PGKRRTQsLSALPKE	9606	BTO:0000848								21087211	t		gcesareni	Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)	SIGNOR-169883	0.2
GGCX	protein	P38435	UNIPROT	vitamin K epoxide	smallmolecule	CHEBI:28371	ChEBI	up-regulates activity	chemical modification			9606									31226734	t		lperfetto	GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form.	SIGNOR-265917	0.8
AKT1	protein	P31749	UNIPROT	TARBP2	protein	Q15633	UNIPROT	up-regulates activity	phosphorylation	Ser286	LRSCSLGsLGALGPA	-1									27407113	t		miannu	We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. 	SIGNOR-274067	0.2
NFIA	protein	Q12857	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									32991581	t	brain	lperfetto	NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,	SIGNOR-263982	0.249
CCL25	protein	O15444	UNIPROT	ACKR4	protein	Q9NPB9	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								23341447	t		Luana	 In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines.	SIGNOR-268418	0.65
PRKG1	protein	Q13976	UNIPROT	RYR1	protein	P21817	UNIPROT	unknown	phosphorylation	Ser2843	KKKTRKIsQSAQTYD	-1									8380342	t		lperfetto	Automated Edman sequence analysis of the major phosphopeptide obtained from PK-A and PK-G phosphorylation and one phosphopeptide obtained from PK-CaM phosphorylation yielded the sequence KISQTAQTYDPR (residues 2841€“2852) with serine 2843 as phosphorylation site	SIGNOR-248918	0.399
SRC	protein	P12931	UNIPROT	FCRL3	protein	Q96P31	UNIPROT	up-regulates activity	phosphorylation	Tyr650	PMELEPMySNVNPGD	-1									12051764	t		miannu	Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2.	SIGNOR-274008	0.2
AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	FGA	protein	P02671	UNIPROT	up-regulates activity	binding			9606	BTO:0000132								16418530	t		lperfetto	In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation.	SIGNOR-253359	0.562
ALDH1A2	protein	O94788	UNIPROT	all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	up-regulates quantity	chemical modification			9606									21621639	t		lperfetto	All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step.	SIGNOR-265126	0.8
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	tRNA(Met)	smallmolecule	CHEBI:29173	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270395	0.8
6-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine	chemical	CHEBI:40629	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189347	0.8
RPS6KA5	protein	O75582	UNIPROT	H3-4	protein	Q16695	UNIPROT	unknown	phosphorylation	Ser11	TKQTARKsTGGKAPR	10090									12773393	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	lperfetto	The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28	SIGNOR-249213	0.2
PDPK1	protein	O15530	UNIPROT	SGK2	protein	Q9HBY8	UNIPROT	up-regulates activity	phosphorylation	Thr193	EPEDTTStFCGTPEY										10548550	t		miannu	SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB.	SIGNOR-250277	0.581
FCRL3	protein	Q96P31	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	binding			-1									12051764	t		miannu	Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2.	SIGNOR-274012	0.372
MAPK8	protein	P45983	UNIPROT	RXRA	protein	P19793	UNIPROT	down-regulates activity	phosphorylation	Ser260	NMGLNPSsPNDPVTN	9606									16551633	t		gcesareni	Under stress conditions, hyperphosphorylated by activated jnk on ser-56, ser-70, thr-82 and ser-260. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear rxralpha levels, via a multistep, jnk-dependent mechanism involving ser260, nuclear export, and proteasomal degradation.	SIGNOR-145297	0.442
RPL36	protein	Q9Y3U8	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262464	0.848
SEC16A	protein	O15027	UNIPROT	COPII vesicle	complex	SIGNOR-C370	SIGNOR	form complex	binding			9606	BTO:0000567								30605680	t		lperfetto	The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat	SIGNOR-265293	0.717
GSK3A	protein	P49840	UNIPROT	MAF	protein	O75444	UNIPROT	up-regulates	phosphorylation			9606									18042454	t		miannu	We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.	SIGNOR-159358	0.2
KDM6A	protein	O15550	UNIPROT	HOXC6	protein	P09630	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24561908	t		miannu	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260028	0.263
ABL2	protein	P42684	UNIPROT	CRK	protein	P46108	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000149							15886098	t		amattioni	Abl2 kinase activity toward crk leads to increased phosphorylation of crk, inhibiting this cytoskeletal regulator by promoting intramolecular over intermolecular associations.	SIGNOR-136958	0.684
ESR1	protein	P03372	UNIPROT	SCN10A	protein	Q9Y5Y9	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938	BTO:0001264							22169964	f		miannu	17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice	SIGNOR-253470	0.294
PRKCA	protein	P17252	UNIPROT	GRIA2	protein	P42262	UNIPROT	unknown	phosphorylation	Ser683	TKEFFRRsKIAVFDK	-1									8848293	t		lperfetto	Only two peptides containing Ser-662 and Ser-696 were found to be efficiently phosphorylated by protein kinase C (PKC). The peptide including Ser-696 was also phosphorylated by protein kinase G (PKG).	SIGNOR-248954	0.698
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Phe635	HHQKLVFfAEDVGSN	-1									10605825	t		lperfetto	In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D.	SIGNOR-261774	0.502
MYOG	protein	P15173	UNIPROT	FBXO32	protein	Q969P5	UNIPROT	down-regulates activity	binding			9534									19631210	t		llicata	Myogenin had a MAFbx-recognition motif and interacted with MAFbx. MAFbx activated polyubiquitination of myogenin. The results of this study suggest that MAFbx functions as an F-box protein for ubiquitination of myogenin.	SIGNOR-237854	0.527
PPARGC1A	protein	Q9UBK2	UNIPROT	COX4I1	protein	P13073	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000443								23021218	f		lperfetto	PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). 	SIGNOR-253098	0.41
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1766	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120120	0.316
PLK4	protein	O00444	UNIPROT	TUBGCP6	protein	Q96RT7	UNIPROT	up-regulates activity	phosphorylation	Ser1060	HGHVSDAsIRVGENV	-1									22302995	t		miannu	Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication.	SIGNOR-262900	0.691
PLCG1	protein	P19174	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates				9606									17562871	f		gcesareni	We propose that the association of plcgamma1 with complexes containing git1 and beta-pix is essential for its role in integrin-mediated cell spreading and motility. As a component of this complex, plcgamma1 is also involved in the activation of cdc42 and rac1.	SIGNOR-155747	0.518
NAE	complex	SIGNOR-C131	SIGNOR	CUL3	protein	Q13618	UNIPROT	up-regulates activity	neddylation			9606									25504797	t		lperfetto	The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates.	SIGNOR-243157	0.591
F12	protein	P00748	UNIPROT	F11	protein	P03951	UNIPROT	up-regulates activity	cleavage			9606		BTO:0000131							8427954	t		lperfetto	Activation of factor XI in plasma is dependent on factor XII | Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided.	SIGNOR-263519	0.472
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1944	GSTYSPTsPGYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269383	0.718
PIM1	protein	P11309	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr145	QGRKRRQtSMTDFYH	9606									20307683	t		lperfetto	Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellshere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo	SIGNOR-164642	0.494
MAPKAPK3	protein	Q16644	UNIPROT	RCSD1	protein	Q6JBY9	UNIPROT	down-regulates activity	phosphorylation	Ser244	PPLRRSPsRTEKQEE	-1									15850461	t		miannu	Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263082	0.496
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1717	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120108	0.316
IFNG	protein	P01579	UNIPROT	IFNGR1	protein	P15260	UNIPROT	up-regulates activity	binding			9606	BTO:0000801								23898330	t		lperfetto	In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation	SIGNOR-249484	0.882
HSPB1	protein	P04792	UNIPROT	CASP3	protein	P42574	UNIPROT	down-regulates				9606									10544189	f		gcesareni	Hsp27 overexpression delays poly(adp-ribose)polymerase cleavage and procaspase-3 activation.	SIGNOR-71869	0.583
SMARCC1	protein	Q92922	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	form complex	binding			9606									15627498	t		miannu	We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers.	SIGNOR-132933	0.858
APEX1	protein	P27695	UNIPROT	Base-excision_repair	phenotype	SIGNOR-PH222	SIGNOR	up-regulates													23545420	f		lperfetto	An essential role of BER has been documented by inactivating functions of proteins in the common steps of BER. Thus, the major AP-endonuclease in mammalian cells, APE1, is essential for survival, as shown using knockout mice (Friedberg and Meira 2006). APE1 (also called HAP1 and Apex) carries both an AP-endonuclease activity and a redox function required for activation of several transcription factors	SIGNOR-275721	0.7
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CEBPB	protein	P17676	UNIPROT	up-regulates	phosphorylation	Thr235	SSSSPPGtPSPADAK	9606									17601773	t		lperfetto	Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity.	SIGNOR-217312	0.345
PAK1	protein	Q13153	UNIPROT	DYNLL1	protein	P63167	UNIPROT	down-regulates	phosphorylation	Ser88	VAILLFKsG	9606		BTO:0000149							18084006	t		lperfetto	Dlc1 phosphorylation on ser(88) by p21-activated kinase 1 (pak1), a signaling nodule, promotes mammalian cell survival by regulating its interaction with bim and the stability of bim. Here we discovered that phosphorylation of ser(88), which juxtapose each other at the interface of the dlc dimer, disrupts dlc1 dimer formation and consequently impairs its interaction with bim	SIGNOR-159995	0.385
PCSK1	protein	P29120	UNIPROT	IAPP	protein	P10997	UNIPROT	up-regulates activity	cleavage	Lys72	VGSNTYGkRNAVEVL	-1									10931181	t		lperfetto	The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule	SIGNOR-261782	0.457
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PDE11A	protein	Q9HCR9	UNIPROT	up-regulates activity	phosphorylation	Ser162	RALLRKAsSLPPTTA	-1									18312413	t		miannu	The N-terminus has two phosphorylation sites for cyclic nucleotide monophosphate-dependent protein kinases (Ser117, Ser168). Phosphorylation of both by cAMP-dependent protein kinase decreased the EC50 value for cGMP from 72 to 23 μm. Effect of phosphorylations at Ser117 and Ser162. Here, serine phosphorylation by the catalytic subunit of cAK, albeit not known whether at position 117, 162 or both, increased cGMP affinity about threefold.	SIGNOR-276179	0.2
UBE2G2	protein	P60604	UNIPROT	DIO	proteinfamily	SIGNOR-PF83	SIGNOR	down-regulates quantity by destabilization	ubiquitination			9606		BTO:0001379							29892818	t	inferred from family member	scontino	ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244.	SIGNOR-270244	0.2
MAPK8	protein	P45983	UNIPROT	AIMP1	protein	Q12904	UNIPROT	down-regulates	phosphorylation	Ser140	KKEKKQQsIAGSADS	9606									20510162	t		llicata	We further demonstrated that serine-140 residue of aimp1 was phosphorylated by jnk and alanine mutation of serine-140 suppressed lps-induced cell surface altogether, these results suggest that aimp1 is phosphorylated by jnk through tlr-myd88 pathway and lose the regulatory activity for er retention of gp96expression of gp96.	SIGNOR-165763	0.486
PPM1D	protein	O15297	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates activity	dephosphorylation			9606									23907458	t		miannu	Activating dephosphorylation of RUNX2 by Wip1 increases its transcriptional activity on the Bax promoter.	SIGNOR-277110	0.456
ULK1	protein	O75385	UNIPROT	FBP1	protein	P09467	UNIPROT	down-regulates activity	phosphorylation	Ser88	LVMNMLKsSFATCVL	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274031	0.2
ATP8B1	protein	O43520	UNIPROT	ATP2B2	protein	Q01814	UNIPROT	up-regulates				9606		BTO:0000630							19478059	f		lperfetto	Consequently ATP8B1 deficiency, with a secondary disturbance of membrane lipid asymmetry, likely inhibits PMCA2 activity and affects the efficiency of mechanotransduction.	SIGNOR-262584	0.2
RPS7	protein	P62081	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262417	0.81
UBE2D2	protein	P62837	UNIPROT	VPS18	protein	Q9P253	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16203730	t		miannu	VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4. 	SIGNOR-271549	0.325
SLC4A8	protein	Q2Y0W8	UNIPROT	hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								26136660	t		miannu	Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. In neurons, bicarbonate transport is mainly mediated by members of the SLC4A family of proteins. While the Na+-independent anion-exchanger SLC4A3 lowers the intraneuronal bicarbonate concentration, the Na+-dependent anion exchangers SLC4A8 (NDCBE) and SLC4A10 (NCBE) use the sodium gradient to accumulate bicarbonate in exchange of chloride	SIGNOR-264918	0.8
HIF1A	protein	Q16665	UNIPROT	KDM5A	protein	P29375	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271565	0.277
CDK5	protein	Q00535	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606	BTO:0000938								17591690	t		gcesareni	Here, we demonstrate for the first time that cdk5 interacts with p53 and increases its stability through posttranslational regulation, leading to accumulation of p53, particularly in the nucleus. We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 in vitro,	SIGNOR-156414	0.722
ALOX15	protein	P16050	UNIPROT	15(S)-HETE	smallmolecule	CHEBI:15558	ChEBI	up-regulates quantity	chemical modification			9606									12517954	t	 	lperfetto	In A549 cells activation of 15-LOX by IL-4 required the coactivation of histone acetyltransferases CREB-binding protein/p300 and led to a sizable production of 15(S)-HETE	SIGNOR-254094	0.8
MAML1	protein	Q92585	UNIPROT	RBPJ	protein	Q06330	UNIPROT	up-regulates	binding			9606									11101851	t		gcesareni	Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes0	SIGNOR-84919	0.87
LRRK2	protein	Q5S007	UNIPROT	MSN	protein	P26038	UNIPROT	up-regulates activity	phosphorylation	Thr558	LGRDKYKtLRQIRQG	9606									8537411	t		lperfetto	This led to the discovery that moesin, a protein which anchors the actin cytoskeleton to the plasma membrane, is efficiently phosphorylated by lrrk2, at thr558. Moesin phosphorylation could be essential to support the cytoskeletal changes accompanying this process.	SIGNOR-39433	0.569
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FAS	protein	P25445	UNIPROT	down-regulates				9606									15004527	f		gcesareni	Akt may serve to stimulate certain proteins (e.g., Ikk) involved in the prevention of apoptosis such as nf-kb as well as repress other proteins normally involved in the induction of apoptosis such as the forkhead transcription factors (fkhr, now know as foxo3), creb, glycogen synthetase-3 kinase-beta (gsk-3beta), fas, caspase-9 and cell cycle inhibitors such as p27	SIGNOR-123239	0.2
ADCK5	protein	Q3MIX3	UNIPROT	SOX9	protein	P48436	UNIPROT	up-regulates activity	phosphorylation	Ser181	YQPRRRKsVKNGQAE										32277958	t		lperfetto	Here we investigated the mechanism of ADCK5 involved in regulating invasion and migration of lung cancer cells, and showed that ADCK5 might regulate the expression of tumor oncogene human pituitary tumor transforming gene-1 (PTTG1) by phosphorylating transcription factor SOX9|Mutagenesis of potential serine phosphorylation sites on SOX9 indicated that serine 181 might be required to maintain transcription activation of SOX9 as well as increase PTTG1 levels.	SIGNOR-264567	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates activity	phosphorylation	Thr346	TGENAGQtPMNINPQ										26375055	t		lperfetto	We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity	SIGNOR-276525	0.265
DUSP4	protein	Q13115	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates activity	dephosphorylation	Tyr204	HTGFLTEyVATRWYR	10116									7535768	t			Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK	SIGNOR-248716	0.696
MMP26	protein	Q9NRE1	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272370	0.7
F12	protein	P00748	UNIPROT	GPIb-IX-V complex	complex	SIGNOR-C270	SIGNOR	up-regulates activity	binding			9606	BTO:0000132								25297919	t		lperfetto	Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1.	SIGNOR-261856	0.448
ATM	protein	Q13315	UNIPROT	FBXW7	protein	Q969H0	UNIPROT	up-regulates activity	phosphorylation	Ser26	LRGNPSSsQVDEEQM	9606	BTO:0002137								26774286	t			In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7	SIGNOR-259942	0.438
MAPK3	protein	P27361	UNIPROT	MCRIP1	protein	C9JLW8	UNIPROT	down-regulates activity	phosphorylation	Thr30	PSSSEIFtPAHEENV	9606									25728771	t		lperfetto	When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation	SIGNOR-264772	0.2
GSK3B	protein	P49841	UNIPROT	DPYSL2	protein	Q16555	UNIPROT	down-regulates activity	phosphorylation	Thr514	SVTPKTVtPASSAKT	9606							phosphorylation:Ser522	PASSAKTsPAKQQAP	25040932	t		lperfetto	Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition	SIGNOR-264840	0.713
RBX1	protein	P62877	UNIPROT	NFKB1	protein	P19838	UNIPROT	up-regulates	ubiquitination			9606			SIGNOR-C5						11295495	t		gcesareni	The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk.	SIGNOR-106781	0.426
CFAP53	protein	Q96M91	UNIPROT	ODAD4	protein	Q96NG3	UNIPROT	up-regulates activity	binding			10090		BTO:0000379							33347437	t		miannu	CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B).	SIGNOR-265543	0.2
PTPRJ	protein	Q12913	UNIPROT	RET	protein	P07949	UNIPROT	down-regulates	dephosphorylation	Tyr1062	TWIENKLyGMSDPNW	9606									16778204	t		gcesareni	Ptprj expression induces dephosphorylation of the ret(c634r) and, probably via an indirect mechanism, ret/ptc1 oncoproteins on two key ret autophosphorylation sites (tyr1062 and tyr905). in line with this finding, adoptive ptprj expression reduced the oncogenic activity of ret	SIGNOR-147161	0.281
STX11	protein	O75558	UNIPROT	STX11-SNAP23 SNARE complex	complex	SIGNOR-C272	SIGNOR	form complex	binding			9606	BTO:0000132								22767500	t		lperfetto	Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. 	SIGNOR-261894	0.735
BAIAP2	protein	Q9UQB8	UNIPROT	ENAH	protein	Q8N8S7	UNIPROT	up-regulates activity	binding			9606	BTO:0000452								11696321	t		miannu	We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia.	SIGNOR-268423	0.551
L-serine	chemical	CHEBI:17115	ChEBI	PK	proteinfamily	SIGNOR-PF80	SIGNOR	up-regulates activity	chemical activation			9606									23064226	t	inferred from family member		We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation.	SIGNOR-270286	0.8
NKX2-5	protein	P52952	UNIPROT	LYL1	protein	P12980	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19608273	f	 	 	Sequence analysis of the LYL1 promoter region revealed potential binding sites for transcription factors HOXA10, LMO2 and NKX2-5. Overexpression analysis, reporter gene assays and chromatin immuno-precipitation confirmed their activating impact on LYL1 expression. In conclusion, we identified multiple mechanisms which activate LYL1 in leukemic cells, including structural genomic alterations, namely microdeletion or amplification, together with the involvement of prominent oncogenic transcription factors.	SIGNOR-253655	0.319
PTPN6	protein	P29350	UNIPROT	ACTG1	protein	P63261	UNIPROT	down-regulates	dephosphorylation	Tyr218	DIKEKLCyVALDFEQ	9606	BTO:0000776								12646642	t		gcesareni	Our data suggest that shp-1 plays a pivotal role in reorganization of cytoskeletal architecture inducing actin dephosphorylation. These results clearly demonstrate the direct interaction of shp-1 with actin	SIGNOR-99565	0.2
lurasidone	chemical	CHEBI:70735	ChEBI	ADRA2A	protein	P08913	UNIPROT	down-regulates activity	chemical inhibition			10030	BTO:0000246								20404009	t		Luana	Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 
2C receptors.	SIGNOR-257842	0.8
PTGER2	protein	P43116	UNIPROT	GNAS	protein	P63092	UNIPROT	up-regulates	binding			9606									16293724	t		gcesareni	Pge2 receptors are coupled to the g protein gs, which causes accumulation of cyclic adenosine monophosphate (camp) and activates protein kinase a (pka), we confirmed that pge2 treatment or transfection of cells with the active catalytic subunit of pka also stimulated the activity of a camp-responsive-elementdriven reporter gene (cre-luc).	SIGNOR-141597	0.409
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	ABI1	protein	Q8IZP0	UNIPROT	up-regulates	phosphorylation			9606									21419341	t	inferred from 70% family members	gcesareni	We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1.	SIGNOR-270048	0.2
IL17A	protein	Q16552	UNIPROT	IL17R complex	complex	SIGNOR-C260	SIGNOR	up-regulates activity	binding			9606	BTO:0001946								32024054	t		lperfetto	Importantly, IL-17 was involved in increased collagen production in cardiac fibroblasts in response to HG, with both subunits of the IL-17RA and IL-17RC heterodimer complex being important to mediating this response.	SIGNOR-261337	0.799
SRC	protein	P12931	UNIPROT	ACLY	protein	P53396	UNIPROT	up-regulates activity	phosphorylation	Tyr682	SRTTDGVyEGVAIGG	9606	BTO:0000007								32420483	t	done	miannu	 We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells.	SIGNOR-274106	0.268
ESR1	protein	P03372	UNIPROT	SCN11A	protein	Q9UI33	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938	BTO:0001264							22169964	f		miannu	17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice	SIGNOR-253471	0.2
SMG1	protein	Q96Q15	UNIPROT	UPF1	protein	Q92900	UNIPROT	up-regulates	phosphorylation	Ser1107	SQIDVALsQDSTYQG	9606									23356578	t		lperfetto	Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively	SIGNOR-200789	0.971
PTPN1	protein	P18031	UNIPROT	IGF1R	protein	P08069	UNIPROT	down-regulates activity	dephosphorylation			9606									11884589	t		lperfetto	Ptp-1b can regulate igf-ir kinase activity and function and that loss of ptp-1b can enhance igf-i-mediated cell survival, growth, and motility in transformed cells.	SIGNOR-115709	0.855
MAP2K4	protein	P45985	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates	phosphorylation	Tyr185	TNFMMTPyVVTRYYR	9606		BTO:0000149;BTO:0001129							22730327	t		gcesareni	Mkk4, which activates p38gamma, p38delta, and jnk2 to phosphorylate p53 on ser-33 and cause a transient g(1) arrest. A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)	SIGNOR-197998	0.716
AKT1	protein	P31749	UNIPROT	KDM5A	protein	P29375	UNIPROT	up-regulates activity	phosphorylation	Ser225	TRRVKTQsESGDVSR	-1									27292631	t		miannu	We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment.	SIGNOR-274060	0.309
GSK3A	protein	P49840	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates	phosphorylation	Ser249	LSPIDMEsQERIKAE	9606									1846781	t		lperfetto	Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity.	SIGNOR-21780	0.338
MAX	protein	P61244	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates	binding			9606									8425218	t		esanto	In vivo transactivation assays suggest that myc-max and mad-max complexes have opposing functions in transcription and that max plays a central role in this network of transcription factors	SIGNOR-39137	0.731
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	NHEJ1	protein	Q9H9Q4	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Thr181	LIRDRLKtEPFEENS	9606	BTO:0000567								25661488	t		miannu	Here we report that Akt phosphorylates XLF (XRCC4 like factor, also called NHEJ1) at T181, to dissociate XLF from the XRCC4 (X-ray repair cross-complementing protein 4)/DNA ligase IV (LIG4) complex and subsequently triggers XLF cytoplasmic translocation, leading to XLF ubiquitination by SCFβ-TRCP in a CKI-dependent manner.	SIGNOR-276882	0.329
TP53	protein	P04637	UNIPROT	MLH1	protein	P40692	UNIPROT	up-regulates quantity	transcriptional regulation			9606									15781865	t			.... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron.	SIGNOR-257605	0.595
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000007								12747827	t		lperfetto	Our data demonstrate that the TOS motif functions as a docking site for the mTOR/raptor complex, which is required for multisite phosphorylation of 4E-BP1, eIF4E release from 4E-BP1, and cell growth.	SIGNOR-236678	0.753
CTNNB1	protein	P35222	UNIPROT	CCN4	protein	O95388	UNIPROT	up-regulates quantity	transcriptional regulation			10116	BTO:0002409								10716946	t			This study identifies WISP-1 as a beta-catenin-regulated gene that can contribute to tumorigenesis. The promoter of WISP-1 was cloned and shown to be activated by both Wnt-1 and beta-catenin expression.	SIGNOR-256270	0.2
CARM1	protein	Q86X55	UNIPROT	RUNX1	protein	Q01196	UNIPROT	down-regulates activity	methylation	Arg223	PAPTPNPrASLNHST	9606	BTO:0000725								24332853	t		miannu	We have found that PRMT4 is highly expressed in HSPCs, where it functions as an inhibitor of myeloid differentiation (Figure 7G). In these cells, PRMT4 methylates RUNX1 at R223, promoting the assembly of a DPF2-containing transcriptional co-repressive complex, and repressing transcription at the miR-223 locus.	SIGNOR-261967	0.286
PAWR	protein	Q96IZ0	UNIPROT	WT1	protein	P19544	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								8943350	t	2	miannu	We identified par-4 (for prostate apoptosis response) as a WT1-interacting protein that itself functions as a transcriptional repressor. Functionally, par-4 inhibited transcription activated by WT1	SIGNOR-240596	0.515
BCL2L1	protein	Q07817	UNIPROT	VDAC1	protein	P21796	UNIPROT	down-regulates activity	binding												10365962	t		lperfetto	The anti-apoptotic protein Bcl-x(L) closes VDAC by binding to it directly	SIGNOR-249614	0.584
NOTCH1	protein	P46531	UNIPROT	BCL11B	protein	Q9C0K0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								22577461	f		miannu	E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r.	SIGNOR-197449	0.403
CDK2	protein	P24941	UNIPROT	MCM4	protein	P33991	UNIPROT	down-regulates activity	phosphorylation	Thr110	PRSGVRGtPVRQRPD	9606	BTO:0000567		SIGNOR-C83						12714602	t		lperfetto	We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a.	SIGNOR-100889	0.758
POMC	protein	P01189	UNIPROT	MC5R	protein	P33032	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268715	0.758
FYN	protein	P06241	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates activity	phosphorylation	Tyr28	SLNQSSGyRYGTDPT	-1									9425276	t			Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn.	SIGNOR-251168	0.2
GSK3B	protein	P49841	UNIPROT	ARHGAP31	protein	Q2M1Z3	UNIPROT	up-regulates activity	phosphorylation	Thr789	PPAPPPPtPLEESTP	10090	BTO:0000944								17158447	t		miannu	We show that GSK-3alpha and -beta interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation. 	SIGNOR-262879	0.307
CDK4	protein	P11802	UNIPROT	RUNX3	protein	Q13761	UNIPROT	down-regulates	phosphorylation	Ser356	SSSGGDRsPTRMLAS	9606			SIGNOR-C18						19351720	t		llicata	Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation.	SIGNOR-185120	0.41
3-phosphonato-D-glyceroyl phosphate(4-)	smallmolecule	CHEBI:57604	ChEBI	3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa.	SIGNOR-266499	0.8
UBE2N	protein	P61088	UNIPROT	UBE2V1	protein	Q13404	UNIPROT	up-regulates activity	binding			9606									20551964	t		lperfetto	Ubc13, the partner of rnf8 and rnf168, usually cooperates with an e2-like protein, uev1 (also known as ube2v1) or mms2 (also known as ube2v2), for the synthesis of lys63-linked polyubiquitin chains.	SIGNOR-166177	0.849
BRCA1	protein	P38398	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates activity				9606	BTO:0000356;BTO:0001033								11244506	f	 	 	The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-alpha] in human breast and prostate cancer cell lines.	SIGNOR-253974	0.745
FYN	protein	P06241	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	unknown	phosphorylation	Tyr1336	RFMDGSPyAHMFEMS	9606	BTO:0000007								11024032	t			Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed.	SIGNOR-251173	0.76
CHUK	protein	O15111	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000093								18490760	t		gcesareni	Insulin activation of mtor requires akt in a manner that involves ikkalpha, preferentially to ikkbeta, and tsc2 phosphorylation	SIGNOR-178664	0.301
AKT1	protein	P31749	UNIPROT	PDE3B	protein	Q13370	UNIPROT	up-regulates activity	phosphorylation	Ser318	CKIFRRPsLPCISRE	10090	BTO:0000011								10454575	t		gcesareni	PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B.	SIGNOR-252554	0.679
afimoxifene	chemical	CHEBI:44616	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258594	0.8
GPER1	protein	Q99527	UNIPROT	1D-myo-inositol 1,4,5-trisphosphate	smallmolecule	CHEBI:16595	ChEBI	up-regulates				9606									19549922	f		gcesareni	Gpr30 also stimulates the pi3k pathway, elevating cellular pip3 levels, which is also predicted to activate nr5a receptors by direct binding of pip3 to the ligand binding domain .	SIGNOR-186206	0.8
HLX	protein	Q14774	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20008130	t		Luana	In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.	SIGNOR-261623	0.2
amisulpride	chemical	CHEBI:64045	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258365	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									22021368	f		apalma	In normal hematopoiesis, AML1 suppresses NF-κB signaling and thus may contribute to inhibition of excessive proliferation of hematopoietic cells.	SIGNOR-255692	0.7
TEK	protein	Q02763	UNIPROT	TEK	protein	Q02763	UNIPROT	down-regulates activity	phosphorylation	Tyr897	GACEHRGyLYLAIEY	-1									11080633	t		lperfetto	The Tie2 nucleotide binding loop is in an inhibitory conformation, which is not seen in other kinase structures, while its activation loop adopts an activated-like conformation in the absence of phosphorylation. Tyr-897, located in the N-terminal domain, may negatively regulate the activity of Tie2 by preventing dimerization of the kinase domains or by recruiting phosphatases when it is phosphorylated.	SIGNOR-246662	0.2
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	AQP4	protein	P55087	UNIPROT	down-regulates activity	phosphorylation	Ser180	TIFASCDsKRTDVTG	-1									19761816	t		miannu	Taken together this data shows that AQP4 in gliomas is the target of PKC phosphorylation, and albeit significantly phosphorylated at rest, phosphorylation can be further enhanced by PKC activation.This data suggests that in gliomas water permeability through AQP4 is under the regulation of PKC via phosphorylation of S180.	SIGNOR-276260	0.2
ASPA	protein	P45381	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	up-regulates quantity	chemical modification			9606									17194761	t		miannu	N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain.	SIGNOR-267528	0.8
HTR7	protein	P34969	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257168	0.284
carfilzomib	chemical	CHEBI:65347	ChEBI	PSMB1	protein	P20618	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000898								17591945	t		miannu	Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM.	SIGNOR-259307	0.8
PRKG1	protein	Q13976	UNIPROT	ENAH	protein	Q8N8S7	UNIPROT	down-regulates activity	phosphorylation			9606									15066263	t		miannu	 Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts. PKG may preferentially phosphorylate sites of Ena/VASP proteins that reduce or inactivate these proteins. Inactivated Ena/VASP proteins dissociate from actin filaments, allowing capping proteins to bind and block monomer addition to plus ends, resulting in filament retraction. 	SIGNOR-268288	0.308
PLK4	protein	O00444	UNIPROT	TUBGCP6	protein	Q96RT7	UNIPROT	up-regulates activity	phosphorylation	Ser392	VSGASPEsISSLLSE	-1									22302995	t		miannu	Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication.	SIGNOR-262909	0.691
SF3A1	protein	Q15459	UNIPROT	SF3a	complex	SIGNOR-C345	SIGNOR	form complex	binding			9606	BTO:0000567								8349644	t		miannu	Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. 	SIGNOR-263948	0.973
PRMT5	protein	O14744	UNIPROT	HOXA9	protein	P31269	UNIPROT	up-regulates activity	methylation	Arg140	KPEPLSArRGDCPTL	9606	BTO:0000007								22269951	t		lperfetto	Hoxa9 methylation by prmt5 is essential for endothelial cell expression of leukocyte adhesion molecules. / prmt5 is a critical coactivator component in a newly defined, hoxa9-containing transcription complex./ Hoxa9 is methylated on arg140 by prmt5.	SIGNOR-195526	0.474
PLK1	protein	P53350	UNIPROT	SUGT1	protein	Q9Y2Z0	UNIPROT	up-regulates activity	phosphorylation	Ser331	VKRAMNKsFMESGGT	9606									22869522	t		lperfetto	Plk1 phosphorylates Sgt1 at the kinetochores to promote timely kinetochore-microtubule attachment|Plk1 is required for the kinetochore localization of Sgt1 and phosphorylates serine 331 of Sgt1 at the kinetochores. This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone 	SIGNOR-265222	0.448
ACP1	protein	P24666	UNIPROT	EPHA2	protein	P29317	UNIPROT	down-regulates activity	dephosphorylation	Tyr588	QLKPLKTyVDPHTYE	-1									21538645	t		gcesareni	The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates	SIGNOR-246035	0.646
RPL10A	protein	P62906	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262489	0.843
PSMC6	protein	P62333	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263370	0.85
PDHX	protein	O00330	UNIPROT	PDH	complex	SIGNOR-C402	SIGNOR	form complex	binding			9606									20160912	t		miannu	The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently.	SIGNOR-266543	0.809
MAPK1	protein	P28482	UNIPROT	TWIST1	protein	Q15672	UNIPROT	up-regulates	phosphorylation	Ser68	GGGDEPGsPAQGKRG	9606	BTO:0000007;BTO:0000150								21502402	t		gcesareni	We identified the serine 68 (s68) as a major phosphorylation site of twist1 by mass spectrometry and with specific antibodies. This s68 is phosphorylated by p38, jnk and erk1/2 in vitro, and its phosphorylation levels positively correlate with twist1 protein levels in hek293 and breast cancer cells.	SIGNOR-173401	0.31
AKT1	protein	P31749	UNIPROT	FSTL1	protein	Q12841	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18718903	f		miannu	Akt1 Overexpression in Skeletal Muscle Increases Capillary Vessel Formation and Up-regulates Fstl1 Expression	SIGNOR-266605	0.393
PHC1	protein	P78364	UNIPROT	Polycomb repressive complex 1	complex	SIGNOR-C408	SIGNOR	form complex	binding			9606									31608994	t		miannu	PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b	SIGNOR-266809	0.812
TAF1	protein	P21675	UNIPROT	GTF2A1	protein	P52655	UNIPROT	up-regulates activity	phosphorylation	Ser316	VEEEPLNsEDDVSDE	9606									11278496	t		lperfetto	Taf(ii) 250 phosphorylates human transcription factor iia on serine residues important for tbp binding and transcription activity.	SIGNOR-105688	0.662
BTK	protein	Q06187	UNIPROT	GTF2I	protein	P78347	UNIPROT	up-regulates activity	phosphorylation	Tyr248	EESEDPDyYQYNIQA	9534	BTO:0004055								11373296	t		lperfetto	These residues, tyr248, tyr357, and tyr462, were also found to be the major sites for btk-dependent phosphorylation of bap/tfii-i in vivo. Residues tyr357 and tyr462 are contained within the loop regions of adjacent helix-loop-helix-like repeats within bap/tfii-i. Mutation of either tyr248, tyr357, or tyr462 to phenylalanine reduced transcription from a c-fos promoter relative to wild-type bap/tfii-i in transfected cos-7 cells, consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation.	SIGNOR-108338	0.532
ADRB1	protein	P08588	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256758	0.507
AKT1	protein	P31749	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates	phosphorylation	Ser188	RKRHKSDsISLSFDE	9606		BTO:0000671							15169778	t		lperfetto	Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188)	SIGNOR-124953	0.804
CHRM2	protein	P08172	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256964	0.332
diazepam	chemical	CHEBI:49575	ChEBI	GABA-A (a5-b1-g2) receptor	complex	SIGNOR-C335	SIGNOR	up-regulates activity	chemical activation			9606		BTO:0000227							18790874	t	brain	lperfetto	The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5. 	SIGNOR-263799	0.8
TNFRSF1A	protein	P19438	UNIPROT	TRAF2	protein	Q12933	UNIPROT	up-regulates				9606									10795740	t			We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation	SIGNOR-256251	0.826
HNRNPH1	protein	P31943	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates quantity by expression	post transcriptional regulation			9606	BTO:0000938								9858532	t		lperfetto	HnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells.	SIGNOR-261273	0.296
RET	protein	P07949	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates	phosphorylation	Tyr204	HTGFLTEyVATRWYR	9606									16153436	t		gcesareni	We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).	SIGNOR-140298	0.443
ID2	protein	Q02363	UNIPROT	TCF12	protein	Q99081	UNIPROT	down-regulates activity	binding			10090	BTO:0004058			SIGNOR-C128					9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241131	0.567
RPL11	protein	P62913	UNIPROT	TP73	protein	O15350	UNIPROT	up-regulates	binding			9606									25301064	t		miannu	We report that rpl5 and rpl11 can also enhance the transcriptional activity of a p53 homolog tap73	SIGNOR-205514	0.366
CyclinD3/CDK6	complex	SIGNOR-C234	SIGNOR	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser40	ASAAGGLsPVTNLTV	9606	BTO:0000017								28192398	t		miannu	We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation. 	SIGNOR-277343	0.615
ARID1B	protein	Q8NFD5	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	form complex	binding			9606									15627498	t		lperfetto	We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers.	SIGNOR-241713	0.779
CSNK2A1	protein	P68400	UNIPROT	SP1	protein	P08047	UNIPROT	down-regulates activity	phosphorylation	Thr579	GDGIHDDtAGGEEGE	9606									9153193	t		llicata	Casein kinase II-mediated phosphorylation of the C terminus of Sp1 decreases its DNA binding activity. | Mutation of a consensus CKII site at amino acid 579, within the second zinc finger, eliminates phosphorylation of this site and the CKII-mediated inhibition of Sp1 binding.	SIGNOR-250954	0.346
CHUK	protein	O15111	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates	phosphorylation	Thr286	EEVDLACtPTDVRDV	9606									16103118	t		gcesareni	Ikkalpha regulates subcellular localization and proteolysis of cyclin d1 by phosphorylation of cyclin d1 at thr286.	SIGNOR-139570	0.389
ULK2	protein	Q8IYT8	UNIPROT	FBP1	protein	P09467	UNIPROT	down-regulates activity	phosphorylation	Ser88	LVMNMLKsSFATCVL	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274039	0.2
TCEA1	protein	P23193	UNIPROT	UBR5	protein	O95071	UNIPROT	up-regulates	binding			9606									21127351	t		miannu	We show that the e3 ubiquitin ligase ubr5 associates with the cdk9 subunit of positive transcription elongation factor b to mediate its polyubiquitination in human cells. Tfiis also binds ubr5 to stimulate cdk9 polyubiquitination.	SIGNOR-170258	0.364
UNG	protein	P13051	UNIPROT	5-fluorouracil	chemical	CHEBI:46345	ChEBI	down-regulates quantity by destabilization	chemical modification			9606									27875297	t		lperfetto	Uracil N-glycosylase 2 (UNG2), the nuclear isoform of UNG, catalyzes the removal of uracil or 5-fluorouracil lesions that accumulate in DNA following treatment with the anticancer agents 5-fluorouracil and 5-fluorodeoxyuridine (floxuridine), a 5-fluorouracil metabolite. By repairing these DNA lesions before they can cause cell death, UNG2 promotes cancer cell survival and is therefore critically involved in tumor resistance to these agents. 	SIGNOR-264888	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	CFTR	protein	P13569	UNIPROT	down-regulates activity	phosphorylation	Ser737	EPLERRLsLVPDSEQ	9606									19095655	t		Luana	AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions	SIGNOR-250350	0.396
TWIST1	protein	Q15672	UNIPROT	GDF15	protein	Q99988	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255527	0.282
EFNA5	protein	P52803	UNIPROT	EPHA4	protein	P54764	UNIPROT	up-regulates	binding			9606									9330863	t		tpavlidou	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52473	0.943
CDK1	protein	P06493	UNIPROT	LIG1	protein	P18858	UNIPROT	up-regulates activity	phosphorylation	Ser76	EEEDEALsPAKGQKP	9606	BTO:0000567								12851383	t		lperfetto	We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner.	SIGNOR-103242	0.371
MAPK1	protein	P28482	UNIPROT	ESPL1	protein	Q14674	UNIPROT	down-regulates	phosphorylation	Ser1126	IAPSTNSsPVLKTKP	9606									11747808	t		lperfetto	Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro	SIGNOR-113130	0.28
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	RB1	protein	P06400	UNIPROT	down-regulates activity	phosphorylation	Ser788	PIPHIPRsPYKFPSS	-1									9139732	t		llicata	In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB.	SIGNOR-250759	0.858
ULK2	protein	Q8IYT8	UNIPROT	FBP1	protein	P09467	UNIPROT	down-regulates activity	phosphorylation	Ser63	HLYGIAGsTNVTGDQ	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274040	0.2
PRKCA	protein	P17252	UNIPROT	STXBP1	protein	P61764	UNIPROT	unknown	phosphorylation	Ser306	VSQEVTRsLKDFSSS	-1									12519779	t		lperfetto	Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation.	SIGNOR-249182	0.386
NLK	protein	Q9UBE8	UNIPROT	TCF7L2	protein	Q9NQB0	UNIPROT	down-regulates quantity	phosphorylation			9606	BTO:0000007								16714285	t		miannu	NLK Augments the Ubiquitylation Activity of NARF against TCF/LEF. ctivation of NLK induced by unknown ligands leads to the phosphorylation of TCF/LEF. NARF then acts on TCF/LEF as an E3 ubiquitin-ligase and, together with E1 and E2 ubiquitylation enzymes, catalyze the ubiquitylation of TCF/LEF. Finally, ubiquitylated TCF/LEF is degraded by the 26 S proteasome.	SIGNOR-271597	0.763
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PLN	protein	P26678	UNIPROT	down-regulates activity	phosphorylation	Thr17	SAIRRAStIEMPQQA	10090	BTO:0003265								19696029	t			Akt interacts with and phosphorylates PLN at Thr(17), the Ca(2+)-calmodulin-dependent kinase IIdelta site, whereas silencing Akt signaling, through the knock-out of phosphatidylinositol-dependent kinase-1, resulted in reduced phosphorylation of PLN at Thr(17).	SIGNOR-252035	0.2
FOXS1	protein	O43638	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9913	BTO:0004577								18288644	t		Luana	Fkhl18 suppressed the transcriptional activity of FoxO3a and FoxO4.	SIGNOR-261611	0.2
EDNRB	protein	P24530	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257379	0.56
BMPR1A	protein	P36894	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity				10090									19620713	f		ggiuliani	The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17).	SIGNOR-255785	0.301
MAPK9	protein	P45984	UNIPROT	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation	Ser164	FGHSAAVsPTFMPRS	9606	BTO:0000782								12151396	t		gcesareni	Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro.	SIGNOR-91075	0.346
LCK	protein	P06239	UNIPROT	CD3G	protein	P09693	UNIPROT	up-regulates activity	phosphorylation			10090									2470098	t			Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex.	SIGNOR-259928	0.541
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	USP37	protein	Q86T82	UNIPROT	up-regulates activity	phosphorylation	Ser628	MVNSCITsPSTPSKK	9606	BTO:0000007;BTO:0000567								21596315	t		lperfetto	There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity	SIGNOR-265046	0.51
AKT2	protein	P31751	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLPRPE	10090	BTO:0000944								11313479	t			Phosphorylation of AFX by PKB occurs in the nucleus. Phosphorylation of S193 reduces the rate of nuclear import. PKB-mediated phosphorylation of AFX, therefore, attenuates the import of the transcription factor, which shifts the localization of the protein from the nucleus to the cytoplasm and results in the inhibition of AFX transcriptional activity.	SIGNOR-251491	0.593
INSR	protein	P06213	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	phosphorylation	Tyr1185	FGMTRDIyETDYYRK	-1									2449432	t		lperfetto	We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151;	SIGNOR-106510	0.2
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser12	LASDFAFsPPPGGGG	-1									31306665	t		lperfetto	Recently, Liu et al. [3] identified CyclinE/CDK2 to be the kinase phosphorylating OCT4 on serine 12 (S12), serine 355 (S355) and threonine 322 (T322) by elegantly combining genetics and biochemistry. Knockout of all five G1 cyclins (D1, D2, D3, E1 and E2) in mESCs (coined Q-KO cells) and consequent inactivation of CDK2/4/ 6 leads to perturbation of the pluripotent state and to the adaption of the trophectoderm cell fate. This was attributed to reduced phosphorylation of OCT4 (as well as SOX2 and NANOG) leading to an increase of protein turnover [3].	SIGNOR-264438	0.325
EGFR	protein	P00533	UNIPROT	EPB41	protein	P11171	UNIPROT	down-regulates	phosphorylation	Tyr660	RLDGENIyIRHSNLM	9606									1647028	t		lperfetto	The phosphorylation site has been localized to the 8-kda domain, which has one tyrosine, tyrosine-418. The 8-kda region is required for the assembly of the spectrin/actin complex, and phosphorylation by egfr reduced the ability of protein 4.1 to promote the assembly of the spectrin/actin/protein 4.1 ternary complex	SIGNOR-20452	0.409
SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	CCND1	protein	P24385	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12138206	f		irozzo	INI1/hSNF5 is a component of the ATP-dependent chromatin remodeling hSWI/SNF complex [.]. Our data suggest that one of the mechanisms by which INI1/hSNF5 exerts its tumor suppressor function is by mediating the cell cycle arrest due to the direct recruitment of HDAC activity to the cyclin D1 promoter thereby causing its repression and G(0)-G(1) arrest. These results together indicate that cyclin D1 is a direct target for repression by INI1/hSNF5.	SIGNOR-256293	0.481
N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide	chemical	CHEBI:91399	ChEBI	CDK7	protein	P50613	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207087	0.8
ULK2	protein	Q8IYT8	UNIPROT	HK1	protein	P19367	UNIPROT	up-regulates activity	phosphorylation	Ser124	NIVHGSGsQLFDHVA	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274042	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	RBBP7	protein	Q16576	UNIPROT	up-regulates activity	phosphorylation	Ser314	LKLHTFEsHKDEIFQ	-1									28143904	t		lperfetto	AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity	SIGNOR-264789	0.261
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	STK11	protein	Q15831	UNIPROT	down-regulates activity	phosphorylation			9606									25846811	t	inferred from 70% family members	lperfetto	Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK.	SIGNOR-270071	0.2
EIF2B2	protein	P49770	UNIPROT	Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269140	0.739
S100A9	protein	P06702	UNIPROT	TLR4	protein	O00206	UNIPROT	up-regulates activity	binding			9606									28137827	t		miannu	RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells. S100A9 binds to TLR4 and induces signaling pathways,promoting leukemic cell differentiation and proliferation arrest. Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-kB.	SIGNOR-261918	0.527
SMAD6	protein	O43541	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates activity	binding			9606									20663871	t		lperfetto	The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation.	SIGNOR-167160	0.73
NAD(1-)	smallmolecule	CHEBI:57540	ChEBI	NADH	smallmolecule	CHEBI:16908	ChEBI	up-regulates quantity	precursor of			9606									28139779	t		miannu	Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP.	SIGNOR-268113	0.8
MAPK14	protein	Q16539	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates	phosphorylation	Ser7	sPAPLSPL	9606									22128155	t		gcesareni	Ogether, our results suggest that p38 phosphorylation of foxo3a on ser-7 is essential for its nuclear relocalization in response to doxorubicin	SIGNOR-177927	0.513
SGK1	protein	O00141	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606	BTO:0000007								11154281	t		lperfetto	Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis.	SIGNOR-252987	0.787
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr664	EGGWMEDyDYVHLQG	9606									11604500	t		lperfetto	The loss of activity in the cas-f668/f670 mutant is consistent with the notion that src, once initially bound by its sh3 domain, phosphorylates the tyr668/670 site to further stabilize its interaction by sh2 binding.	SIGNOR-111056	0.797
IL6	protein	P05231	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity				10116		BTO:0001103							23869758	f		andrea cerquone perpetuini	IL-6 induced dose-dependent increase in satellite cell proliferation by activating the JAK2/STAT3/cyclin D1 pathway.Treatment with 1 ng/ml IL-6 for 3 h significantly increased p-STAT3+/MyoD+ cell numbers by 44% compared to control media only .	SIGNOR-255415	0.748
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	MCL1	protein	Q07820	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000150								18676833	t	inferred from 70% family members	fstefani	We then showed that erk could phosphorylate mcl-1 at two consensus residues, thr 92 and 163, which is required for the association of mcl-1 and pin1, resulting in stabilization of mcl-1.	SIGNOR-270042	0.2
CSNK2A1	protein	P68400	UNIPROT	SPIB	protein	Q01892	UNIPROT	down-regulates	phosphorylation	Ser37	KHSSYPDsEGAPDSL	9606									10618498	t		lperfetto	Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability	SIGNOR-73891	0.44
lurasidone	chemical	CHEBI:70735	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10030									20404009	t		Luana	In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype.	SIGNOR-259463	0.8
NFY	complex	SIGNOR-C1	SIGNOR	TOP2A	protein	P11388	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25328138	t		lperfetto	The expression of human TOP2A is controlled by its promoter region that contains two GC boxes and five CCAAT boxes. NF-Y recognizes and binds to the ICBs. This binding of NF-Y to the TOP2A promoter can be promoted by HMGB1/2 and inhibited by pRb.	SIGNOR-242526	0.275
MAGEC2	protein	Q9UBF1	UNIPROT	TRIM28	protein	Q13263	UNIPROT	up-regulates activity	binding			9606	BTO:0000594								28394358	t		lperfetto	In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28. 	SIGNOR-267593	0.52
LRRK2	protein	Q5S007	UNIPROT	LRRK2	protein	Q5S007	UNIPROT	down-regulates	phosphorylation	Thr1491	DYHFVNAtEESDALA	9606	BTO:0000938								19824698	t		lperfetto	We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. eduction in the gtp-bound form of lrrk2 caused by t1491d mutation might have lowered the kinase activity, implicating the autophosphorylation of the roc domain in a negative feedback regulation of the kinase activity of lrrk2.	SIGNOR-188425	0.2
PHA-680632	chemical	CID:11249084	PUBCHEM	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206097	0.8
CSNK2A1	protein	P68400	UNIPROT	IP6K2	protein	Q9UHH9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser347	RPEVVLDsDAEDLED	9606	BTO:0000007								21262846	t		miannu	CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation.	SIGNOR-273624	0.257
UHMK1	protein	Q8TAS1	UNIPROT	PIMREG	protein	Q9BSJ6	UNIPROT	up-regulates	phosphorylation	Ser131	GAQKGSGsPTHSLSQ	9606									23419774	t		lperfetto	Cats is a substrate of kis and mapped the phosphorylation site to cats serine 131 (s131). Kis enhances the transcriptional repressor activity of cats	SIGNOR-192702	0.2
TP53	protein	P04637	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000142							8242752	t		lperfetto	The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents.	SIGNOR-37145	0.873
FIP1L1	protein	Q6UN15	UNIPROT	CPSF complex	complex	SIGNOR-C53	SIGNOR	form complex	binding			9606									14749727	t		miannu	Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna.	SIGNOR-121649	0.897
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser175	SPASSGSsASFISDT	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252343	0.635
SGK2	protein	Q9HBY8	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606	BTO:0000007								11154281	t		lperfetto	Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis.	SIGNOR-252991	0.514
THRA	protein	P10827	UNIPROT	RAR	proteinfamily	SIGNOR-PF45	SIGNOR	up-regulates	binding			9606									15650024	t	inferred from 70% of family members	gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-269851	0.407
SRC	protein	P12931	UNIPROT	YY1	protein	P25490	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0002181								26198631	t		miannu	YY1 phosphorylation is mediated by Src family kinases.	SIGNOR-276940	0.288
L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	L-asparagine zwitterion	smallmolecule	CHEBI:58048	ChEBI	up-regulates quantity	precursor of			9606									29084849	t		miannu	Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7.	SIGNOR-268069	0.8
DYRK1A	protein	Q13627	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates	phosphorylation			9606		BTO:0000142							19383720	t		gcesareni	Dyrk1a physically interacts with the nicd inducing its phosphorylation in the ankyrin domain, thereby attenuating notch .	SIGNOR-254313	0.406
CEP290	protein	O15078	UNIPROT	Cilium_assembly	phenotype	SIGNOR-PH64	SIGNOR	up-regulates				9606									18694559	f		miannu	CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110	SIGNOR-252147	0.7
ATM	protein	Q13315	UNIPROT	XRCC6	protein	P12956	UNIPROT	up-regulates activity	phosphorylation	Ser33	ASGDYKYsGRDSLIF	9606	BTO:0001546								26337656	t	done	miannu	 Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks.	SIGNOR-274021	0.703
CAMK2A	protein	Q9UQM7	UNIPROT	HSF1	protein	Q00613	UNIPROT	up-regulates activity	phosphorylation	Ser230	PKYSRQFsLEHVHGS		BTO:0000664								11447121	t		llicata	Ser230 is located in the regulatory domain of HSF1, and promotes the magnitude of the inducible transcriptional activity. Ser230 lies within a consensus site for calcium/calmodulin-dependent protein kinase II (CaMKII), and CaMKII overexpression enhances both the level of in vivo Ser230 phosphorylation and transactivation of HSF1. The importance of Ser230 was further established by the S230A HSF1 mutant showing markedly reduced activity relative to wild-type HSF1 when expressed in hsf1(-/-) cells.	SIGNOR-250631	0.49
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9606									16288293	f		miannu	Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2.	SIGNOR-251550	0.7
SYK	protein	P43405	UNIPROT	FCGR2A	protein	P12318	UNIPROT	up-regulates activity	phosphorylation	Tyr281	LEETNNDyETADGGY	-1									8756631	t		lperfetto	To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and pointFyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.	SIGNOR-247590	0.659
P2RY10	protein	O00398	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257121	0.2
AURKC	protein	Q9UQB9	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									14583461	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.	SIGNOR-118898	0.2
ATR	protein	Q13535	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser31	ALRLLDSsQIVIISA	10090	BTO:0001372								11459832	t		lperfetto	These results thus suggest that this serine 31 residue is indeed an atm/atr phosphorylation site and in fact is the major site for atm/atr-mediated phosphorylation within e2f1. Thus, it is possible that the atm/atr-mediated phosphorylation inhibits the binding and function of skp2 and thus prevents the normal degradation of e2f1	SIGNOR-109420	0.384
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	DCX	protein	O43602	UNIPROT	unknown	phosphorylation	Ser332	STPKSKQsPISTPTS	9606									14741103	t		llicata	In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35.	SIGNOR-250667	0.415
ESR1	protein	P03372	UNIPROT	SCN1A	protein	P35498	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938	BTO:0001264							22169964	f		miannu	17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice	SIGNOR-253468	0.271
CDK2	protein	P24941	UNIPROT	GRK2	protein	P25098	UNIPROT	down-regulates	phosphorylation	Ser670	KMKNKPRsPVVELSK	9606									20080565	t		gcesareni	We report that grk2 protein levels are transiently down-regulated during the g2/m transition by a mechanism involving cdk2-mediated phosphorylation of grk2 at serine670, which triggers binding to the prolyl-isomerase pin1 and subsequent degradation.	SIGNOR-163279	0.2
SRC	protein	P12931	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates	phosphorylation	Tyr242	FFQQQMIyDSPPSRA	9606									19881549	t		lperfetto	Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis	SIGNOR-236314	0.693
CSNK1A1	protein	P48729	UNIPROT	ERG	protein	P11308	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser39	EMTASSSsDYGQTSK	-1									26344095	t		miannu	Using in vitro kinase assays, we further demonstrated that deletion of degron 1 largely abolished CKI-mediated phosphorylation of ERG (Figure S5B), indicating that serine residues within degron 1 are the major CKI phosphorylation sites.	SIGNOR-276935	0.2
PRKCA	protein	P17252	UNIPROT	EIF4G1	protein	Q04637	UNIPROT	up-regulates activity	phosphorylation	Ser1185	RTPATKRsFSKEVEE	9606	BTO:0000007								21576361	t		miannu	Phospho-proteomic and mutational analyses revealed that eIF4G1 is a substrate for PKCα at Ser1186. 	SIGNOR-276327	0.261
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	carbamoyl phosphate(2-)	smallmolecule	CHEBI:58228	ChEBI	up-regulates quantity	precursor of			9606									15096496	t			CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules	SIGNOR-267191	0.8
(-)-anisomycin	chemical	CHEBI:338412	ChEBI	JUND	protein	P17535	UNIPROT	up-regulates	chemical activation			9606									Other	t	CellSignaling	gcesareni		SIGNOR-189672	0.8
TNF	protein	P01375	UNIPROT	SCN3A	protein	Q9NY46	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253485	0.2
PRKAA2	protein	P54646	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates	phosphorylation	Ser177	AKELDQGsLCTSFVG	9606				SIGNOR-C14					21673972	t		lperfetto	These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes	SIGNOR-174401	0.259
mTORC2	complex	SIGNOR-C2	SIGNOR	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606									21157483	t		lperfetto	Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism	SIGNOR-217004	0.634
EEF1G	protein	P26641	UNIPROT	EEF1B complex	complex	SIGNOR-C460	SIGNOR	form complex	binding			9606									23699257	t		lperfetto	An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. The requirement for a guanine nucleotide exchange factor, the eEF1B complex, which in metazoans is composed of the subunits α, δ, and γ (also called eEF1B, eEF1D, and eEF1G, respectively)	SIGNOR-269391	0.981
PRKG1	protein	Q13976	UNIPROT	HRH1	protein	P35367	UNIPROT	down-regulates	phosphorylation	Ser398	WKRLRSHsRQYVSGL	9606		BTO:0000975							10101032	t	Translocation from Endosome to Lysosome	fspada	Ser396 and ser398 are also potential phosphorylation sites for capk, cgmp-dependent protein kinase, and camk ii. Elevation of intracellular camp content has been shown to attenuate histamine-induced accumulation of ip in c6 glioma cells (peakman and hill, 1994) and in ddt1 mf-2 smooth muscle cells (sipma et al., 1995	SIGNOR-66019	0.2
PAS complex	complex	SIGNOR-C190	SIGNOR	1-phosphatidyl-1D-myo-inositol 3-phosphate	smallmolecule	CHEBI:17283	ChEBI	down-regulates quantity	chemical modification			-1									18950639	t		miannu	PtdIns(3,5)P2 is synthesized from PtdIns(3)P through the action of mammalian PIKfyve or the yeast counterpart Fab1, both sole enzymes for PtdIns(3,5)P2 synthesis. PIKfyve and Fab1, in turn, are activated by the orthologous proteins, mammalian ArPIKfyve and yeast Vac14, to upregulate intracellular PtdIns(3,5)P2 production. PtdIns(3,5)P2 turnover is catalyzed, at least in part, by mammalian Sac3 or its yeast counterpart Fig4	SIGNOR-253533	0.8
GOLPH3	protein	Q9H4A6	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				9606									19553991	f			Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo.	SIGNOR-253555	0.3
TCF4	protein	P15884	UNIPROT	CNTNAP2	protein	Q9UHC6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22777675	f	 	miannu	 we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays.	SIGNOR-255390	0.336
GOT2	protein	P00505	UNIPROT	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	up-regulates quantity	chemical modification			9606									31422819	t		miannu	This is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1).	SIGNOR-267517	0.8
HAUS2	protein	Q9NVX0	UNIPROT	HAUS complex	complex	SIGNOR-C281	SIGNOR	form complex	binding			9606	BTO:0000567								19369198	t		lperfetto	Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)	SIGNOR-262323	0.813
XCL1	protein	P47992	UNIPROT	XCR1	protein	P46094	UNIPROT	up-regulates	binding			9606		BTO:0000763							10518929	t		gcesareni	Scm-1 showed a high-affinity binding to xcr1 with a kd of 10 nm and induced vigorous chemotaxis and calcium mobilization in xcr1-transfected murine l1.2 cells.	SIGNOR-71164	0.779
WNT10B	protein	O00744	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131628	0.58
CAMK2A	protein	Q9UQM7	UNIPROT	ETS1	protein	P14921	UNIPROT	down-regulates	phosphorylation	Ser257	DSFESIEsYDSCDRL	9606	BTO:0000782								12475968	t		lperfetto	Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition	SIGNOR-96334	0.313
CSNK1A1	protein	P48729	UNIPROT	ERG	protein	P11308	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser38	TEMTASSsSDYGQTS	-1									26344095	t		miannu	Using in vitro kinase assays, we further demonstrated that deletion of degron 1 largely abolished CKI-mediated phosphorylation of ERG (Figure S5B), indicating that serine residues within degron 1 are the major CKI phosphorylation sites.	SIGNOR-276936	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO4	protein	P98177	UNIPROT	down-regulates	phosphorylation	Thr32	QSRPRSCtWPLPRPE	9606									16272144	t		lperfetto	Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression	SIGNOR-141424	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CASP9	protein	P55211	UNIPROT	down-regulates activity	phosphorylation	Ser196	KLRRRFSsLHFMVEV	9606	BTO:0000938								10529400	t		lperfetto	Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9BAD phosphorylation by Akt is an essential step for growth factor-mediated inhibition of caspase activation	SIGNOR-71480	0.2
RIT1	protein	Q92963	UNIPROT	BRAF	protein	P15056	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								23791108	t			It is possible that RIT1 interacts with RAF1 and that gain-of-function mutations in RIT1 and RAF1 exert similar effects in heart development.	SIGNOR-251650	0.53
BRCA1-BARD1 complex	complex	SIGNOR-C297	SIGNOR	BRCA1-BARD1 complex	complex	SIGNOR-C297	SIGNOR	up-regulates activity	ubiquitination			-1									12485996	t		lperfetto	Auto‐ubiquitylation stimulates the ubiquitin ligase activity of BRCA1/BARD1|Secondly, BRCA1/BARD1 catalyses the formation of multiple polyubiquitin chains on itself. Remarkably, this auto‐polyubiquitylation potentiates the E3 ubiquitin ligase activity of the BRCA1/BARD1 complex >20‐fold. 	SIGNOR-263233	0.785
TACR1	protein	P25103	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256776	0.2
SUB1	protein	P53999	UNIPROT	REST-CoREST	complex	SIGNOR-C111	SIGNOR	up-regulates activity	binding			9606									20080105	t	1	miannu	We have found that PC4 directly interacts with the REST–CoREST complex. we found that there was a substantial reduction of REST–CoREST complex on the SCN2 promoter upon PC4 silencing in 293T cells.	SIGNOR-239325	0.324
MRPL13	protein	Q9BYD1	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262380	0.739
NT5E	protein	P21589	UNIPROT	adenosine	smallmolecule	CHEBI:16335	ChEBI	up-regulates quantity	chemical modification			-1									31461341	t		Luana	Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine.	SIGNOR-269742	0.8
IL6ST	protein	P40189	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	binding			9606									9126968	t		milica	Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase.	SIGNOR-250574	0.352
ID1	protein	P41134	UNIPROT	TCF4	protein	P15884	UNIPROT	down-regulates activity	binding			10090	BTO:0004058			SIGNOR-C129					9242638	t	2	miannu	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241385	0.648
CBX3	protein	Q13185	UNIPROT	ChAHP	complex	SIGNOR-C407	SIGNOR	form complex	binding			10090	BTO:0002896								29795351	t		miannu	Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. In conclusion, CHD4, ADNP and HP1β/γ form a stable protein complex, which we refer to as ChAHP.	SIGNOR-266753	0.416
MAP3K20	protein	Q9NYL2	UNIPROT	MAP3K20	protein	Q9NYL2	UNIPROT	up-regulates	phosphorylation	Thr161	ASRFHNHtTHMSLVG	9606									15342622	t		gcesareni	Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation.	SIGNOR-128577	0.2
ACTB	protein	P60709	UNIPROT	Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270698	0.483
SCN3A	protein	Q9NY46	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606									27262167	t		miannu	Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential.	SIGNOR-253409	0.8
NTRK1	protein	P04629	UNIPROT	NTRK1	protein	P04629	UNIPROT	up-regulates	phosphorylation	Tyr681	DIYSTDYyRVGGRTM	9606									9099755	t		gcesareni	In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785	SIGNOR-47179	0.2
IL10	protein	P22301	UNIPROT	SCN3A	protein	Q9NY46	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									23357618	f		miannu	Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α.	SIGNOR-253504	0.2
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	CDC25A	protein	P30304	UNIPROT	up-regulates	ubiquitination			9606									15340381	t		lperfetto	Scfb-trcp has recently been shown to degrade phosphorylated cdc25a in the s and g2 phases.	SIGNOR-217178	0.493
SIRT1	protein	Q96EB6	UNIPROT	XPA	protein	P23025	UNIPROT	up-regulates activity	deacetylation	Lys215	QENREKMkQKKFDKK	9606									30327428	t		miannu	SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR	SIGNOR-258986	0.526
NUP133	protein	Q8WUM0	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262089	0.735
bortezomib	chemical	CHEBI:52717	ChEBI	PSMD2	protein	Q13200	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000898								21504411	t		miannu	Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma.	SIGNOR-259313	0.8
IRS2	protein	Q9Y4H2	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			10090	BTO:0004087								24811175	t		lperfetto	Insulin receptor substrate 1 (IRS-1) and IRS-2 are cytoplasmic adaptor proteins that mediate the activation of signaling pathways in response to ligand stimulation of upstream cell surface receptors. Despite sharing a high level of homology and the ability to activate PI3K, only Irs-2 positively regulates aerobic glycolysis in mammary tumor cells.	SIGNOR-252696	0.693
DCAF7	protein	P61962	UNIPROT	DYRK1B	protein	Q9Y463	UNIPROT	up-regulates activity	binding			9534	BTO:0000298								14593110	t		miannu	Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. HAN11 might target DYRKs to cytosolic locations for regulation of specific cellular functions.	SIGNOR-260631	0.752
TNFSF10	protein	P50591	UNIPROT	TNFRSF10B	protein	O14763	UNIPROT	up-regulates	binding			9606									15766588	t		gcesareni	Tumour necrosis factor-related apoptosis inducing ligand (trail) receptor 2 (trail-r2) also known as tnfrsf10b (tumour necrosis factor receptor (tnfr) super family 10b) or killer/dr5, a member of the tnfr family, is a promising candidate tumour suppressor gene at 8p21-22.	SIGNOR-134524	0.932
RELA	protein	Q04206	UNIPROT	PCK2	protein	Q16822	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		BTO:0000759							20137375	f	 	miannu	 NF-kappaB p65 was shown to inhibit transcription of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme in gluconeogenesis in the liver	SIGNOR-255072	0.27
GABA-A (a5-b1-g2) receptor	complex	SIGNOR-C335	SIGNOR	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	relocalization			9606									18790874	t	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263815	0.8
valrubicin	chemical	CHEBI:135876	ChEBI	TOP2B	protein	Q02880	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000096								16019763	t		miannu	Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a semi-synthetic derivative of the anthracycline doxorubicin. Valrubicin inhibits the incorporation of nucleosides into nucleic acids, causing extensive chromosomal damage and cell-cycle arrest in the G2 phase. Its principal metabolites inhibit topoisomerase II, thus arresting DNA synthesis.	SIGNOR-259384	0.8
DLGAP2	protein	Q9P1A6	UNIPROT	SHANK1	protein	Q9Y566	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264589	0.745
E2F1	protein	Q01094	UNIPROT	HDAC1	protein	Q13547	UNIPROT	up-regulates	binding			9606									23213415	t		gcesareni	Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes	SIGNOR-199952	0.638
CDK1	protein	P06493	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates	phosphorylation	Ser200	YSGDSDAsSPRSNCS	9606			SIGNOR-C17						21902831	t		gcesareni	Phosphorylation of myod at s200 is common to other cdks, such as the mitotic cyclin b/cdk1, which may prevent inappropriate myod accumulation during mitosis.	SIGNOR-176505	0.372
SUN1	protein	O94901	UNIPROT	LINC complex	complex	SIGNOR-C303	SIGNOR	form complex	binding												24481844	t		lperfetto	LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM.	SIGNOR-263282	0.508
SPI1	protein	P17947	UNIPROT	TAL1	protein	P17542	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								16298389	t		irozzo	PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity.By expressing a mutant protein containing only the ETS domain of PU.1 in human erythroleukemic HEL cells, we demonstrated that PU.1 mediates the transcriptional repression activity of the silencer. Our data clearly demonstrate that PU.1 mediates TAL-1 silencer activity	SIGNOR-256048	0.452
EDN1	protein	P05305	UNIPROT	MC1R	protein	Q01726	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9767234	f		miannu	MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression.	SIGNOR-252386	0.358
DOLK	protein	Q9UPQ8	UNIPROT	dolichyl beta-D-mannosyl phosphate	smallmolecule	CHEBI:17624	ChEBI	up-regulates quantity	chemical modification			-1									16923818	t		lperfetto	Dolichol kinase (DK) catalyzes the CTP-dependent phosphorylation of dolichol in the biosynthesis de novo and possibly the recycling of dolichyl monophosphate in yeast and mammals.	SIGNOR-262567	0.8
RPS28	protein	P62857	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262423	0.895
TAB3	protein	Q8N5C8	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	binding			9606									14670075	t		lperfetto	We have identified a new binding partner of the tgfbeta (transforming growth factor-beta)-activated protein kinase (tak1), termed tab.two distinct tak1 complexes are present in cells. One comprises tak1 complexed with tab1 and tab2, and the other tak1 complexed with tab1 and tab3 (tak1-binding protein-3). Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1.	SIGNOR-120325	0.826
CAV1	protein	Q03135	UNIPROT	SLC1A1	protein	P43005	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								26690923	t		miannu	EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. 	SIGNOR-264807	0.2
BMP15	protein	O95972	UNIPROT	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	up-regulates	binding			9606		BTO:0000975							16446785	t		lperfetto	Here we have performed a detailed in situ hybridization analysis of the spatial and temporal expression patterns of the bmp ligands (bmp-2, -3, -3b, -4, -6, -7, -15), receptors (bmpr-ia, -ib, -ii), and bmp antagonist, follistatin, in rat ovaries over the normal estrous cycle.	SIGNOR-217538	0.529
MAPK1	protein	P28482	UNIPROT	RORA	protein	P35398	UNIPROT	down-regulates	phosphorylation	Thr183	PGEAEPLtPTYNISA	9606									17512500	t	The effect has been demonstrated using P35398-4	gcesareni	We identified the extracellular signal-regulated kinase 2 (erk-2) as roralpha4 phosphorylating kinase in vitro. The primary sequence of roralpha4 contains an erk-2 recognition motif (p-l-t(128)-p) within the hinge domain, and mutation of thr-128 to ala prevents roralpha4 phosphorylation by erk. The roralpha4-t128a mutant exhibits an increased dna-binding affinity, an increased transcriptional activity	SIGNOR-154914	0.263
D-threo-isocitrate(3-)	smallmolecule	CHEBI:15562	ChEBI	IDH1	protein	O75874	UNIPROT	up-regulates activity	chemical activation			9606									32943735	t			Wild-type IDH1 and IDH2 catalyze the reaction by converting isocitrate and NADP+ into α-KG and CO2 with the concomitant generation of NADPH in the cytosol and mitochondrial matrix	SIGNOR-267369	0.8
PAM16	protein	Q9Y3D7	UNIPROT	TIM23 complex	complex	SIGNOR-C423	SIGNOR	form complex	binding												32074073	t		lperfetto	The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE.	SIGNOR-267699	0.671
Aflibercept	chemical	SID:134445687	ChEBI	VEGFB	protein	P49765	UNIPROT	down-regulates activity	chemical inhibition			9606									22813448	t		miannu	Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor. 	SIGNOR-259387	0.8
MYOD1	protein	P15172	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates				10090									7791789	f		lperfetto	The upregulation of p21 occurred at the levels of mrna and protein,	SIGNOR-235831	0.412
IL31RA	protein	Q8NI17	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates	binding			9606									18926762	t		gcesareni	Il-31 can activate janus kinase (jak) 1 and jak2 signaling molecules after binding to its receptor complex.	SIGNOR-161430	0.391
SREBF1	protein	P36956	UNIPROT	ACLY	protein	P53396	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11994399	f		Luana	SREBP-1c–responsive genes include those for ATP citrate lyase (which produces acetyl-CoA) and acetyl-CoA carboxylase and fatty acid synthase (which together produce palmitate [C16:0]).	SIGNOR-267956	0.475
alvocidib	chemical	CHEBI:47344	ChEBI	CDK4	protein	P11802	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258172	0.8
CDX2	protein	Q99626	UNIPROT	MUC2	protein	Q02817	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534	BTO:0004055								12559945	t	 	 	COS-7 cells were transiently transfected with a CDX1 or CDX2 expression construct and then used for the luciferase assay, reverse transcription-polymerase chain reaction, and electrophoretic mobility shift assay (EMSA). The CDX2 expression construct activated the MUC2 promoter and increased the endogenous MUC2 mRNA level, while the CDX1 one did not.	SIGNOR-253966	0.2
HDAC1	protein	Q13547	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates	binding			9606									15713663	t		gcesareni	Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5.	SIGNOR-134059	0.685
O-phosphonato-L-serine(2-)	smallmolecule	CHEBI:57524	ChEBI	3-phosphonatooxypyruvate(3-)	smallmolecule	CHEBI:18110	ChEBI	up-regulates quantity	precursor of			3702									30034403	t		lperfetto	Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction.	SIGNOR-268564	0.8
Ribonucleotide reductase	complex	SIGNOR-C233	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									14583450	f		miannu	Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2.	SIGNOR-259365	0.7
MAPK14	protein	Q16539	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	phosphorylation	Ser727	TDNLLPMsPEEFDEV	9606									17502367	t		lperfetto	All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).	SIGNOR-154779	0.709
PTPN18	protein	Q99952	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Tyr1196	GAVENPEyLTPQGGA	9606	BTO:0000007								25081058	t		lperfetto	PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop.	SIGNOR-262596	0.658
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1714	SPTSPSYsPTSPSYS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248786	0.441
DOK1	protein	Q99704	UNIPROT	ITGB6	protein	P18564	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257693	0.2
CASP7	protein	P55210	UNIPROT	Caspase 7 complex	complex	SIGNOR-C232	SIGNOR	form complex	binding								cleavage:Asp206	SGPINDTdANPRYKI			11701129	t		lperfetto	The quaternary structure of caspase-7 comprises two closely associated heterodimers, with each heterodimer consisting of a large and a small subunit. 	SIGNOR-256394	0.2
CDC42	protein	P60953	UNIPROT	BAIAP2	protein	Q9UQB8	UNIPROT	up-regulates activity	binding			9606	BTO:0000452								11696321	t		miannu	We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia.	SIGNOR-268424	0.857
PRKAA1	protein	Q13131	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606			SIGNOR-C15						15866171	t		gcesareni	Ampk activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate ampk-dependent cell-cycle arrest	SIGNOR-135960	0.458
PTGER1	protein	P34995	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257194	0.409
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	GRIN2C	protein	Q14957	UNIPROT	up-regulates activity	phosphorylation	Ser1081	GSRPRHAsLPSSVAE	10090	BTO:0004278								19477150	t		miannu	Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. These data are all consistent with a model in which NR1 and NR2C oligomerize, PKB phosphorylates S1096, and 14-3-3ε binds to phosphorylated NR2C thereby promoting NR2C-containing NMDA receptor surface expression in cerebellar granule cells. 	SIGNOR-262620	0.2
CSNK1E	protein	P49674	UNIPROT	TCF3	protein	P15923	UNIPROT	up-regulates	phosphorylation			9606									11524435	t		gcesareni	Tcf3 is a substrate for both glycogen synthase kinase (gsk) 3 and casein kinase (ck) 1epsilon, and phosphorylation of tcf3 by ckiepsilon stimulates its binding to beta-catenin, an effect reversed by gsk3.	SIGNOR-110056	0.2
BTK	protein	Q06187	UNIPROT	DAPP1	protein	Q9UN19	UNIPROT	up-regulates activity	phosphorylation	Tyr139	KVEEPSIyESVRVHT		BTO:0000776								10880360	t		lperfetto	Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins.	SIGNOR-249313	0.658
NBEAL2	protein	Q6ZNJ1	UNIPROT	Platelet_alpha_granule_formation	phenotype	SIGNOR-PH136	SIGNOR	up-regulates				9606	BTO:0000132								28082341	f		lperfetto	We compared platelet size and number of α-granules for two NBEAL2 and two GATA1-deficient patients and found reduced numbers of α-granules for all, with the defect being more pronounced for NBEAL2 deficiency. 	SIGNOR-261883	0.7
MTA2	protein	O94776	UNIPROT	FSHR	protein	P23945	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001238								23086931	f	 	miannu	Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription. MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment. 	SIGNOR-254226	0.251
MAPK1	protein	P28482	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates	relocalization			9606									18596912	t		fspada	The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform	SIGNOR-179400	0.47
[4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone	chemical	CHEBI:91441	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258233	0.8
IRS1	protein	P35568	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			10116		BTO:0001103							21798082	t		lperfetto	Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate (pip2).	SIGNOR-252694	0.758
CDK7	protein	P50613	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates	phosphorylation	Ser516	VSRVPYPsPTCVKSE	9606									21157430	t		acerquone	Here, we show that the transcription factor tfiih, via its cdk7 kinase, phosphorylates the androgen receptor (ar) at position ar/s515. Strikingly, this phosphorylation is a key step for an accurate transactivation that includes the cyclic recruitment of the transcription machinery, the mdm2 e3 ligase, the subsequent ubiquitination of ar at the promoter of target genes and its degradation by the proteasome machinery	SIGNOR-170599	0.384
PDPK1	protein	O15530	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Thr308	KDGATMKtFCGTPEY	9606							phosphorylation:Ser473	RPHFPQFsYSASGTA	12167717	t		gcesareni	Together, these results suggest a mechanism in which 3' phosphoinositide lipid-dependent translocation of pkb to the plasma membrane promotes serine 473 phosphorylation, which is, in turn, necessary for pdk1-mediated phosphorylation of threonine 308 and, consequentially, full pkb activation.	SIGNOR-91354	0.736
PTPRB	protein	P23467	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr999	YASSNPEyLSASDVF	9606									10734133	t		gcesareni	Identification of tyrosine phosphatases that dephosphorylate the insulin receptor.	SIGNOR-76001	0.349
BTF3	protein	P20290	UNIPROT	SSPN	protein	Q14714	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000584								17312387	f	 	 	In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis.	SIGNOR-253951	0.2
clofarabine	chemical	CHEBI:681569	ChEBI	POLG	protein	P54098	UNIPROT	down-regulates activity	chemical inhibition			9606									1707752	t		miannu	Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase.	SIGNOR-258361	0.8
ZBTB32	protein	Q9Y2Y4	UNIPROT	ZBTB16/ZBTB32	complex	SIGNOR-C80	SIGNOR	form complex	binding			9606									10572087	t		miannu	We show that fazf is a transcriptional repressor and it readily forms heterodimers with plzf.	SIGNOR-72380	0.368
palbociclib	chemical	CHEBI:85993	ChEBI	CDK6	protein	Q00534	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205707	0.8
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2L5	protein	A0A1B0GUS4	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271365	0.2
WNT6	protein	Q9Y6F9	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates				9606									21872687	f		fspada	We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b	SIGNOR-176193	0.475
FHIT	protein	P49789	UNIPROT	AKT2	protein	P31751	UNIPROT	down-regulates				9606	BTO:0000551								16407838	f		miannu	Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis	SIGNOR-143703	0.252
ATF6	protein	P18850	UNIPROT	XBP1	protein	P17861-2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									31226023	t		miannu	Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network	SIGNOR-260184	0.677
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	THRB	protein	P10828	UNIPROT	down-regulates activity	phosphorylation			9606									12809513	t	inferred from 70% family members	llicata	We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay.	SIGNOR-270016	0.2
CDK1	protein	P06493	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Thr48	VCPDVPRtPVGKFLG	9606									8119945	t		gcesareni	Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity.	SIGNOR-36271	0.853
KDM4B	protein	O94953	UNIPROT	BBC3	protein	Q9BXH1	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001109								28073943	f		miannu	 JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. 	SIGNOR-263732	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	FH	protein	P07954	UNIPROT	up-regulates activity	phosphorylation	Ser75	YGAQTVRsTMNFKIG	-1									28628081	t		miannu	Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes.	SIGNOR-266313	0.2
MET	protein	P08581	UNIPROT	GLMN	protein	Q92990	UNIPROT	down-regulates	relocalization			9606									11571281	t		gcesareni	Significantly, nonphosphorylated hgf receptor prevents fap68 from stimulating p70s6k. fap68 binding to met requires the last 30 amino acids of the c-terminal tail, which are unique to the hgf receptor.	SIGNOR-110726	0.336
EIF5	protein	P55010	UNIPROT	EIF5B	protein	O60841	UNIPROT	up-regulates activity	relocalization			9606									30211544	t		lperfetto	 eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC.	SIGNOR-269122	0.741
CDK1	protein	P06493	UNIPROT	EPN1	protein	Q9Y6I3	UNIPROT	down-regulates activity	phosphorylation	Ser382	FSDPWGGsPAKPSTN	10029	BTO:0000246								10764745	t		miannu	Phosphorylation of POB1 and Epsin by p34cdc2 kinase. Their phosphorylation sites (Ser411 of POB1 and Ser357 of Epsin) were determined. Phosphorylated Epsin and EpsinS357D formed a complex with α-adaptin less efficiently than wild type Epsin. 	SIGNOR-262723	0.328
Shikonin	chemical	CHEBI:81068	ChEBI	PKM	protein	P14618	UNIPROT	down-regulates activity	chemical inhibition			9606									21516121	t		lperfetto	Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2.	SIGNOR-262008	0.8
PRKCA	protein	P17252	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser371	AHSSHLKsKKGQSTS	-1									9571186	t		lperfetto	Here, we demonstrate that cotransfection of p53 with either PKC alpha or PKC zeta increases p53's transcriptional activity. Mutagenesis of p53 indicates that serine 371 is the major site for phosphorylation by PKC alpha in vitro.	SIGNOR-248999	0.448
CASK	protein	O14936	UNIPROT	Exocytosis	phenotype	SIGNOR-PH157	SIGNOR	up-regulates				9606	BTO:0000938								11036064	f		miannu	As neurexins have been proposed to function in neuronal cell adhesion, it is possible that they define specific sites at the plasma membrane and that Mint complexes and Mint1-CASK complexes on neurexin are involved in the localized recruitment of Munc18 to the sites of exocytosis. In support of this hypothesis, both CASK and Mint1 have been reported to be localized at synapses	SIGNOR-264044	0.7
PPP2CA	protein	P67775	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	down-regulates activity	dephosphorylation	Thr305	TDAATMKtFCGTPEY	10090									15367694	t			Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes	SIGNOR-248654	0.725
PRKG2	protein	Q13237	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates activity	phosphorylation	Ser553	KNAHAKAsRTSSKHK	9606	BTO:0002181								21177494	t		miannu	 PKGII directly phosphorylated and stimulated SHP-1 activity	SIGNOR-276288	0.2
MITF	protein	O75030	UNIPROT	MLANA	protein	Q16655	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000848								12819038	f		miannu	 The results of the present work demonstrate that the essential melanocyte-specific transcription factor MITF regulates expression of the genes encoding the melanoma tumor markers MLANA and SILV. MITF up- or down-regulation is seen to correspondingly modulate expression of MLANA and SILV in parallel directions, at both mRNA and protein levels.	SIGNOR-254590	0.484
Ub:HECT_E3 	complex	SIGNOR-C518	SIGNOR	Protein_ubiquitination	phenotype	SIGNOR-PH214	SIGNOR	up-regulates				9606									34199813	f		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. 	SIGNOR-271382	0.7
ARRY-520	chemical	CID:44224257	PUBCHEM	KIF11	protein	P52732	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189891	0.8
MECP2	protein	P51608	UNIPROT	DLX5	protein	P56178	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									19195802	f	 	 	Expression of DLX5 is controlled by MECP2, and defect in MECP2 induced an over-expression of DLX5 in lymphocytes as well as in the brain	SIGNOR-254034	0.388
MAPK1	protein	P28482	UNIPROT	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation	Ser164	FGHSAAVsPTFMPRS	9606									12050114	t		gcesareni	Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation.	SIGNOR-88724	0.361
PPP2R5B	protein	Q15173	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates	dephosphorylation	Ser70	RDPVARTsPLQTPAA	9606									18845789	t		gcesareni	Pp2a directly interacts with the bh4 domain of bcl2 as a docking site to potentially bridge pp2a to bcl2's flexible loop domain containing the target serine 70 phosphorylation site.	SIGNOR-181559	0.305
DYRK1A	protein	Q13627	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000142							19383720	t		gcesareni	Dyrk1a physically interacts with the nicd inducing its phosphorylation in the ankyrin domain, thereby attenuating notch .	SIGNOR-185494	0.406
ADARB1	protein	P78563	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates activity	binding			9606	BTO:0000661								19605474	t		miannu	Both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation. 	SIGNOR-266359	0.47
MAPK3	protein	P27361	UNIPROT	DUSP1	protein	P28562	UNIPROT	up-regulates	phosphorylation	Ser359	SALSYLQsPITTSPS	9606									10617468	t		lperfetto	Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein.	SIGNOR-73629	0.778
CBLB	protein	Q13191	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			9606	BTO:0000661								8626404	t		lperfetto	Here we show that in unstimulated Jurkat cells Cbl is co-immunoprecipitated with monoclonal antibody against Grb2.	SIGNOR-236051	0.583
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1864	SPKYSPTsPKYSPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269385	0.718
SIRT7	protein	Q9NRC8	UNIPROT	FBL	protein	P22087	UNIPROT	up-regulates activity	deacetylation	Lys205	RDLINLAkKRTNIIP										30540930	t		lperfetto	Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206)	SIGNOR-275892	0.274
Diprenorphine	chemical	CHEBI:4650	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9262330	t		miannu	We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine.	SIGNOR-258662	0.8
CDK9	protein	P50750	UNIPROT	NCOA2	protein	Q15596	UNIPROT	up-regulates activity	phosphorylation	Ser487	GQPTSMLsPRHRMSP	9606	BTO:0000801								29170386	t			Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties.	SIGNOR-256097	0.248
UIMC1	protein	Q96RL1	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	binding			9606	BTO:0000150								17525342	t		gcesareni	Rap80 specifically recruits brca1 to dna damage sites and functions with brca1 in g2/m checkpoint control	SIGNOR-155201	0.907
AMPK	complex	SIGNOR-C15	SIGNOR	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation	Ser8	MPLNRTLsMSSLPGL	-1									22233421	t		miannu	Recombinant muscle GYS1 (glycogen synthase 1) and recombinant liver GYS2 were phosphorylated by recombinant AMPK (AMP-activated protein kinase) in a time-dependent manner and to a similar stoichiometry. The phosphorylation site in GYS2 was identified as Ser7, which lies in a favourable consensus for phosphorylation by AMPK. Phosphorylation of GYS1 or GYS2 by AMPK led to enzyme inactivation by decreasing the affinity for both UDP-Glc (UDP-glucose) [assayed in the absence of Glc-6-P (glucose-6-phosphate)] and Glc-6-P (assayed at low UDP-Glc concentrations). 	SIGNOR-263102	0.479
PPM1D	protein	O15297	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	down-regulates activity	dephosphorylation	Ser227	DHEKKAYsFCGTVEY	10090									15206906	t			RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity	SIGNOR-248320	0.369
ATG12	protein	O94817	UNIPROT	Autophagosome_formation	phenotype	SIGNOR-PH36	SIGNOR	up-regulates				4932									23321721	f		lperfetto	Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation	SIGNOR-219396	0.7
PHKG1	protein	Q16816	UNIPROT	PYG	proteinfamily	SIGNOR-PF96	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0002049								22225877	t			It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15	SIGNOR-267960	0.671
MED4	protein	Q9NPJ6	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266675	0.811
AREG	protein	P15514	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606									10085134	t	Amphiregulin is an autocrine growth factor	gcesareni	The epidermal growth factor receptor (EGFR) mediates the actions of a family of bioactive peptides that include epidermal growth factor (EGF) and amphiregulin (AR)	SIGNOR-65576	0.764
(2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide	chemical	CHEBI:131158	ChEBI	APP	protein	P05067	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206850	0.8
LHX4	protein	Q969G2	UNIPROT	POU1F1	protein	P28069	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15998782	f		miannu	 We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression. 	SIGNOR-254558	0.53
PAX7	protein	P23759	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates quantity by destabilization				10090									17548510	f		Simone Vumbaca	Previously, we showed that Pax7 overexpression in adult primary myoblasts down-regulates MyoD and prevents myogenin induction, inhibiting myogenesis. We show that Pax7 prevents muscle differentiation independently of its transcriptional activity, affecting MyoD function. [...] Pax7 expression affects MyoD protein stability	SIGNOR-255637	0.618
furtrethonium	chemical	CHEBI:134764	ChEBI	CHRM4	protein	P08173	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258644	0.8
PARP1	protein	P09874	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	relocalization			9606									17891139	t		miannu	We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus.	SIGNOR-261321	0.577
CSNK1A1	protein	P48729	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates activity	phosphorylation	Ser75	LGYEPEGsASPTPPY	-1									17318175	t		lperfetto	Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling.	SIGNOR-249189	0.776
PTPN12	protein	Q05209	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									10734133	t		gcesareni	Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190.	SIGNOR-75902	0.384
LPAR2	protein	Q9HBW0	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257056	0.61
SF3b	complex	SIGNOR-C442	SIGNOR	Spliceosomal_snRNP_assembly	phenotype	SIGNOR-PH79	SIGNOR	up-regulates				9606									32140746	f		lperfetto	The SF3b complex is an intrinsic component of the functional U2 small nuclear ribonucleoprotein (snRNP). As U2 snRNP enters nuclear pre-mRNA splicing, SF3b plays key roles in recognizing the branch point sequence (BPS) and facilitating spliceosome assembly and activation. 	SIGNOR-268414	0.7
PDPK1	protein	O15530	UNIPROT	SGK3	protein	Q96BR1	UNIPROT	up-regulates	phosphorylation	Thr320	AISDTTTtFCGTPEY	9606									16790420	t		llicata	Full-length sgk3 contains a complete phox homology (px) domain that targets the protein to endosomes. Both a functional px domain and pi3k activation are necessary for phosphorylation of sgk3 at two regulatory sites (thr-320 and ser-486) and subsequent induction of kinase activity. Pdk1 phosphorylates endosome-associated sgk3 at thr-320	SIGNOR-147213	0.472
PRKCA	protein	P17252	UNIPROT	HNRNPA1	protein	P09651	UNIPROT	down-regulates	phosphorylation	Ser95	RAVSREDsQRPGAHL	9606									7727389	t		gcesareni	A survey of seven protein kinases showed that a1 was heavily phosphorylated by protein kinase c (pkc) and also was phosphorylated by casein kinase iiamino acid sequencing revealed that these sites were ser95, ser192, and ser199;phosphorylation at ser192 was more abundant than at ser95 and ser199. Phosphorylation by pkc inhibited the strand annealing activity of a1.	SIGNOR-32291	0.2
CENPK	protein	Q9BS16	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265212	0.714
RB1	protein	P06400	UNIPROT	E2F1	protein	Q01094	UNIPROT	down-regulates activity	binding			9606									8255752	t		amattioni	E2f binds rb. E2f activation domain is the target for rb-induced repression. Rb can silence the 57 residue e2f activation domain. Rb can mask e2f residues involved in the activation process, possibly by mimicking a component of the transcriptional machinery	SIGNOR-37305	0.918
FOXO3	protein	O43524	UNIPROT	DIO	proteinfamily	SIGNOR-PF83	SIGNOR	up-regulates quantity by expression	transcriptional regulation												20978344	f	inferred from family member		Forkhead box O3 (FoxO3) was identified as a key molecule inducing D2 expression and thereby increasing intracellular T3 production. Accordingly, FoxO3-depleted primary myoblasts also had a differentiation deficit that could be rescued by high levels of T3.	SIGNOR-270245	0.35
glutamine	smallmolecule	CHEBI:28300	ChEBI	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				9606	BTO:0000567								27126896	f		Luana	 Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation.	SIGNOR-268012	0.8
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser280	RSPSPQPsSHVAPQD	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248522	0.386
GUCY1A2-B2	complex	SIGNOR-C137	SIGNOR	3',5'-cyclic GMP	smallmolecule	CHEBI:16356	ChEBI	up-regulates quantity	chemical modification			9606									10977868	t		gcesareni	Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types	SIGNOR-244090	0.8
TRAF2	protein	Q12933	UNIPROT	BIRC2	protein	Q13490	UNIPROT	up-regulates activity	binding			9606	BTO:0000459								18621737	t		lperfetto	Through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2.	SIGNOR-179449	0.868
MAPK14	protein	Q16539	UNIPROT	RPS6KA4	protein	O75676	UNIPROT	up-regulates	phosphorylation	Ser196	EEKERTFsFCGTIEY	9606	BTO:0000567								10806207	t		llicata	Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity.	SIGNOR-77204	0.586
CDKN2A	protein	P42771	UNIPROT	CDK4	protein	P11802	UNIPROT	down-regulates	binding			9606				SIGNOR-C18					8891723	t		miannu	The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks, cdk4 and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb.	SIGNOR-44554	0.902
BIRC2	protein	Q13490	UNIPROT	RIPK2	protein	O43353	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0000007								21931591	t		miannu	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.	SIGNOR-272712	0.637
DVL3	protein	Q92997	UNIPROT	CSNK1E	protein	P49674	UNIPROT	up-regulates	binding			9606									10535959	t		gcesareni	Ckiepsilon was in a complex with axin and other downstream components of the wnt pathway, including dishevelled.	SIGNOR-71759	0.653
BTK	protein	Q06187	UNIPROT	BTK	protein	Q06187	UNIPROT	up-regulates	phosphorylation	Tyr551	RYVLDDEyTSSVGSK	9606	BTO:0000776								8630736	t		lperfetto	Overexpression of btk with a src family kinase increases tyrosine phosphorylation and catalytic activity of btk. This occurs by transphosphorylation at y551 in the btk catalytic domain and the enhancement of btk autophosphorylation at a second site. We mapped the major btk autophosphorylation site to y223 within the sh3 domain	SIGNOR-41480	0.2
FOXN3	protein	O00409	UNIPROT	PIM2	protein	Q9P1W9	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002552								24403608	t		Luana	CHES1/FOXN3 regulates cell proliferation by repressing PIM2 and protein biosynthesis.	SIGNOR-261607	0.301
SMAD3	protein	P84022	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16766264	f		irozzo	This protection is conferred by Smad3’s ability to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 promoter.	SIGNOR-256294	0.2
4-methylumbelliferone	chemical	CHEBI:17224	ChEBI	UGT1A1	protein	P22309	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								21030469	t		Luana	Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation.	SIGNOR-258057	0.8
SL-327	chemical	CHEBI:92211	ChEBI	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates	chemical inhibition			9606	BTO:0000938	BTO:0000142							11160424	t		lperfetto	The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity	SIGNOR-244955	0.8
FRAT2	protein	O75474	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity	binding			-1									11738041	t		gcesareni	The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation.	SIGNOR-244030	0.682
FYN	protein	P06241	UNIPROT	IFITM3	protein	Q01628	UNIPROT	up-regulates quantity	phosphorylation	Tyr20	NSGQPPNyEMLKEEH	10090	BTO:0000452								24627473	t		miannu	We determined that both mouse and human IFITM3 are phosphorylated by the protein-tyrosine kinase FYN on tyrosine 20 (Tyr(20)). Phosphorylation of IFITM3 on Tyr20 Leads to Plasma Membrane Accumulation.	SIGNOR-266304	0.464
MYOD1	protein	P15172	UNIPROT	SMARCA4	protein	P51532	UNIPROT	up-regulates	binding			9606				SIGNOR-C92					17194702	t		miannu	Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes	SIGNOR-151685	0.544
PHLPP1	protein	O60346	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	dephosphorylation	Ser338	RPRGQRDsSYYWEIE	10090									24530606	t		gcesareni	PHLPP1 and PHLPP2 dephosphorylate RAF1 to reduce its signaling, increase the invasive and migratory activities of CRC cells, and activate the epithelial-mesenchymal transition. In Apc(Min) mice, loss of PHLPP1 promotes tumor progression.	SIGNOR-237449	0.275
ROCK1	protein	Q13464	UNIPROT	ARHGAP35	protein	Q9NRY4	UNIPROT	down-regulates activity	phosphorylation	Ser1236	PKPKPRPsITKATWE	9534	BTO:0000298								19103606	t		miannu	 these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells 	SIGNOR-276176	0.425
CDK4	protein	P11802	UNIPROT	RASSF1	protein	Q9NS23	UNIPROT	down-regulates	phosphorylation	Ser207	TSVRRRTsFYLPKDA	9606			SIGNOR-C18						18071316	t		llicata	This skp2-dependent destruction of rassf1a requires phosphorylation of the latter on serine-203 by cyclin d-cyclin-dependent kinase 4.	SIGNOR-159849	0.419
belinostat	chemical	CHEBI:61076	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257956	0.8
9-cis-retinoic acid	chemical	CHEBI:50648	ChEBI	RXRB	protein	P28702	UNIPROT	up-regulates activity	chemical activation			9606									18321241	t		miannu	Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma).	SIGNOR-259238	0.8
NDUFB9	protein	Q9Y6M9	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1	SIGNOR-262172	0.802
CSNK1E	protein	P49674	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates	phosphorylation	Ser143	FHPNVSSsHENLEPE	9606									22609948	t		lperfetto	We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle	SIGNOR-197063	0.68
BCOR	protein	Q6W2J9	UNIPROT	Noncanonical PRC1	complex	SIGNOR-C151	SIGNOR	form complex	binding			10090									25533466	t		miannu	 inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR.	SIGNOR-255276	0.562
Tert-butyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate	chemical	CID:46907787	PUBCHEM	BRD2	protein	P25440	UNIPROT	down-regulates activity	chemical inhibition			9606									30080437	t		Simone Vumbaca	Through the integrative analyses of ChIP-seq and CAGE data, we elucidate the involvement of BRD2 in gene regulation upon BET inhibition by JQ1 in H23 cells.	SIGNOR-261124	0.8
KDM5D	protein	Q9BY66	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264309	0.2
CDH1	protein	P12830	UNIPROT	CTNNA1	protein	P35221	UNIPROT	up-regulates	binding			9606									24336504	t		milica	Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm.	SIGNOR-203468	0.673
SLC9A5	protein	Q14940	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265604	0.8
EIF3_complex	complex	SIGNOR-C401	SIGNOR	EIF4G1	protein	Q04637	UNIPROT	up-regulates activity	stabilization			9606									17581632	t		lperfetto	EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 	SIGNOR-269155	0.625
vandetanib	chemical	CHEBI:49960	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258308	0.8
EEF1A2	protein	Q05639	UNIPROT	Trp-tRNA(Trp)	smallmolecule	CHEBI:29159	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269537	0.8
CD40	protein	P25942	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606	BTO:0000782;BTO:0000776								19904719	f		fstefani	Cd40 has been found to be essential in mediating a broad variety of immune and inflammatory responses including t cell-dependent immunoglobulin class switching, memory b cell development	SIGNOR-189109	0.7
PLK1	protein	P53350	UNIPROT	PINX1	protein	Q96BK5	UNIPROT	down-regulates	phosphorylation	Ser226	ATGKDVEsYLQPKAK	9606									20573420	t		lperfetto	Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation.	SIGNOR-166325	0.37
UBE3A	protein	Q05086	UNIPROT	PSMD7	protein	P51665	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								28559284	t		lperfetto	Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits.	SIGNOR-265134	0.275
PTPN11	protein	Q06124	UNIPROT	PDCD1	protein	Q15116	UNIPROT	down-regulates activity	dephosphorylation			9606									32437509	t		miannu	Related to the latter notion, we recently showed that SHP2 dephosphorylates PD-1 to disassemble the PD-1:SHP2 complex ( xref ).	SIGNOR-277052	0.645
DNA polymerase delta 	complex	SIGNOR-C376	SIGNOR	DNA_replication	phenotype	SIGNOR-PH53	SIGNOR	up-regulates				9534	BTO:0004055								12930972	f		lperfetto	Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA).	SIGNOR-265513	0.7
PJA2	protein	O43164	UNIPROT	PRKAR1B	protein	P31321	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								21423175	t		miannu	Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits	SIGNOR-271857	0.2
PLCG1	protein	P19174	UNIPROT	ITPRIPL1	protein	Q6GPH6	UNIPROT	up-regulates				9606	BTO:0000938								21368195	f		gcesareni	Recruitment of g protein also can activate phospholipase c (plc) that in turn increases inositol triphosphate (ip3) levels and induces ca2+ release from internal stores	SIGNOR-172500	0.2
GSK3B	protein	P49841	UNIPROT	MACF1	protein	Q9UPN3	UNIPROT	down-regulates activity	phosphorylation	Ser7222	FRSRGRRsKPSSRAA	9606	BTO:0004905								21295697	t		lperfetto	We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules.	SIGNOR-264426	0.446
MAPK3	protein	P27361	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation	Thr739	SEGSGTAtPSALITT	9606									11904305	t		gcesareni	Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. sa-perk1/2 activates the transcription factor, sp1, via ser59 phosphorylation downstream of pkc_, leading to transcription of p21sdi1 and resulting in replicative senescence of hdf cells.	SIGNOR-116174	0.638
APH1A	protein	Q96BI3	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates	binding			9606		BTO:0000142							12297508	t	Gamma secretase subunit that leads to PS1/PS2 eterodimer complex stabilisation.	gcesareni	By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.	SIGNOR-93262	0.946
CDC25B	protein	P30305	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates activity	dephosphorylation			9606									26474275	t		miannu	CDC25B is also able to dephosphorylate and activate CDK2-Cyclin A and CDK2-Cyclin E complexes [ xref \u2013 xref ].	SIGNOR-277140	0.757
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270383	0.8
CDK1	protein	P06493	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	down-regulates activity	phosphorylation	Ser126	NPEAESSsKEGELDA	-1									23901111	t		miannu	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. 	SIGNOR-276115	0.699
RPS6KA3	protein	P51812	UNIPROT	TH	protein	P07101	UNIPROT	up-regulates	phosphorylation	Ser40	GQGAPGPsLTGSPWP	9606									12421349	t	The effect has been demonstrated using P07101-3	gcesareni	Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax	SIGNOR-95483	0.271
TCL1B	protein	O95988	UNIPROT	AKT2	protein	P31751	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271								10983986	t		gcesareni	In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation.	SIGNOR-81716	0.545
SRC	protein	P12931	UNIPROT	ARAF	protein	P10398	UNIPROT	up-regulates	phosphorylation	Tyr301	LGYRDSGyYWEVPPS	9534	BTO:0004055								9020159	t		lperfetto	A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation. Activation of Raf-1 and A-Raf by Src requires tyrosine phosphorylation at residues 340 and 341 in Raf-1 and 301 and 302 in A-Raf.	SIGNOR-236037	0.466
PIH1D1	protein	Q9NWS0	UNIPROT	R2TP core co-chaperone	complex	SIGNOR-C515	SIGNOR	form complex	binding			9606									29662061	t		miannu	 Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90. 	SIGNOR-270926	0.838
PRKCA	protein	P17252	UNIPROT	NPHS1	protein	O60500	UNIPROT	up-regulates activity	phosphorylation	Thr1125	QWTGERDtQSSTVST	9606	BTO:0000007								21321125	t		llicata	Binding of _-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by pkc_.	SIGNOR-172056	0.2
FBXO22	protein	Q8NEZ5	UNIPROT	BSG	protein	P35613	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007;BTO:0003227;BTO:0005816								28117675	t		lperfetto	F-Box Protein FBXO22 Mediates Polyubiquitination and Degradation of CD147 to Reverse Cisplatin Resistance of Tumor Cells	SIGNOR-273452	0.438
CREB1	protein	P16220	UNIPROT	PKM	protein	P14618	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20577053	f		gcesareni	In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1	SIGNOR-166346	0.252
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1878	SPKYSPTsPTYSPTT	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203572	0.77
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1738	SPSYSPTsPSYSPTS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248813	0.849
Complement C1 complex	complex	SIGNOR-C309	SIGNOR	C4B	protein	P0C0L5	UNIPROT	up-regulates activity	cleavage	Arg679	EKTTRKKrNVNFQKA	-1									9087411	t		lperfetto	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263424	0.63
TAF8	protein	Q7Z7C8	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263927	0.866
TGFB1	protein	P01137	UNIPROT	MYOG	protein	P15173	UNIPROT	down-regulates				10090									14739161	f		lperfetto	Tgf-beta was shown to inhibit myogenin and mef2d expression and myotube formation in c2c12.	SIGNOR-235728	0.261
4-{[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]amino}benzoic acid	chemical	CHEBI:64210	ChEBI	RARB	protein	P10826	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								19058965	t		Luana	Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes. 	SIGNOR-258035	0.8
HOXB8	protein	P17481	UNIPROT	PBX1	protein	P40424	UNIPROT	up-regulates activity	binding			9606	BTO:0001545								11571641	t		miannu	the ability of HoxB8 to heterodimerizes with endogenous Pbx proteins on DNA alters gene transcription in a manner that prevents progression through an intrinsic genetic differentiation program. In conjunction with Pbx, HoxB8 could alter transcription of Pbx target genes by direct or indirect mechanisms.	SIGNOR-223153	0.513
CSNK2A1	protein	P68400	UNIPROT	PPP1R8	protein	Q12972	UNIPROT	up-regulates activity	phosphorylation	Thr161	LGLPEEEtELDNLTE	-1									9407077	t		llicata	Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2.	SIGNOR-250931	0.482
THR	proteinfamily	SIGNOR-PF84	SIGNOR	RARG	protein	P13631	UNIPROT	up-regulates	binding			9606									15650024	t	inferred from family member	gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-270315	0.2
Opsonization	phenotype	SIGNOR-PH150	SIGNOR	Membrane attack complex	complex	SIGNOR-C313	SIGNOR	up-regulates				-1									30552328	f		lperfetto	CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers	SIGNOR-263455	0.7
AURKA	protein	O14965	UNIPROT	NEDD9	protein	Q14511	UNIPROT	up-regulates activity	phosphorylation	Ser296	PVARRHQsLSPNHPP	9606	BTO:0000093								16184168	t		miannu	HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins.	SIGNOR-262654	0.588
acetylcholine	smallmolecule	CHEBI:15355	ChEBI	CHRM4	protein	P08173	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258633	0.8
U2AF2	protein	P26368	UNIPROT	U2AF1/U2AF2	complex	SIGNOR-C78	SIGNOR	form complex	binding			9606									8647433	t		miannu	The splicing factor u2af (u2 snrnp auxiliary factor) is a heterodimer with subunits of 65 and 35 kd (u2af65 and u2af35).	SIGNOR-41948	0.2
HCFC1	protein	P51610	UNIPROT	NSL histone acetyltransferase	complex	SIGNOR-C413	SIGNOR	form complex	binding			9606	BTO:0000007								20018852	t		miannu	Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex.	SIGNOR-267165	0.587
SGK3	protein	Q96BR1	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606	BTO:0000007								12054501	t		lperfetto	Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction	SIGNOR-249166	0.453
AMPK	complex	SIGNOR-C15	SIGNOR	CDC27	protein	P30260	UNIPROT	unknown	phosphorylation	Ser379	NALPRRSsRLFTSDS	9606									22137581	t		lperfetto	Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379, respectively) resulted in an almost complete loss of ampk phosphorylation in these proteins	SIGNOR-216434	0.274
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	BIRC6	protein	Q9NR09	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271318	0.388
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr387	RPGPGTLyDVPRERV	10090									12972425	t		lperfetto	Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs	SIGNOR-246413	0.797
CCL11	protein	P51671	UNIPROT	CCR3	protein	P51677	UNIPROT	up-regulates	binding			9606									24702154	t			Eotaxin (CCL11) is a specific ligand for CCR3 and serves as a potent chemoattractant for eosinophils	SIGNOR-254356	0.934
sirolimus	chemical	CHEBI:9168	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									17350953	t		gcesareni	Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kda fk506- and rapamycin-binding protein (fkbp12, or fkbp) and the fkbp-rapamycin binding (frb) domain of the mammalian target of rapamycin (mtor) kinase. autophagy is negatively regulated by the mammalian target of rapamycin (mtor) and can be induced in all mammalian cell types by the mtor inhibitor rapamycin.	SIGNOR-153608	0.8
MACROD2	protein	A1Z1Q3	UNIPROT	2''-O-acetyl-ADP-D-ribose(2-)	smallmolecule	CHEBI:83767	ChEBI	down-regulates quantity	chemical modification			9606									32257385	t		miannu	MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins	SIGNOR-269839	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CDKN1B	protein	P46527	UNIPROT	down-regulates	binding			9606									23400686	t		gcesareni	Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1.	SIGNOR-200875	0.2
CTDSP2	protein	O14595	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	dephosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248295	0.399
EEF1A1P5	protein	Q5VTE0	UNIPROT	Met-tRNA(Met)	chemical	CHEBI:16635	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269544	0.8
IL21R	protein	Q9HBE5	UNIPROT	JAK3	protein	P52333	UNIPROT	up-regulates	binding			9606	BTO:0000776								12093291	t		gcesareni	Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5	SIGNOR-90269	0.54
PRKCD	protein	Q05655	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser373	SMGTLRTsISVERQI	9606	BTO:0000007								11517230	t		lperfetto	In addition, we found a protein kinase C-dependent phosphorylation of Ser(346) that was mutually exclusive with the basal phosphorylation at Ser(348) and therefore may be implicated in differential regulation of B2 receptor activation. Functional analysis of receptor mutants revealed that a low phosphorylation stoichiometry is sufficient to initiate receptor sequestration while a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation.	SIGNOR-249108	0.305
JAG1	protein	P78504	UNIPROT	NOTCH3	protein	Q9UM47	UNIPROT	up-regulates	binding			9606									18660822	t	Binding Calcium-dependent	gcesareni	Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch.	SIGNOR-179625	0.628
GRM6	protein	O15303	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening.	SIGNOR-264937	0.8
leukotriene A4(1-)	smallmolecule	CHEBI:57463	ChEBI	leukotriene C4(2-)	smallmolecule	CHEBI:57973	ChEBI	up-regulates quantity	precursor of			9606									27365393	t		miannu	Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4).	SIGNOR-277260	0.8
PIM1	protein	P11309	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates activity	phosphorylation			9606									25280219	t			FLT3-ITD kinase may regulate c-MYC through STAT5-induced enhancement of PIM kinases (Choudhary et al., 2009), which can modulate c-MYC stability and activity via phosphorylation (van der Lugt et al., 1995s). This is supported by the observation that FLT3-ITD CD34+ cells showed higher PIM activity compared to cells expressing FLT3-WT, indicated by increased expression of the PIM targets including p-BAD (Ser112), p-4EBP1 (Thr37/46), and p-c-MYC (Ser62) (Figure 6C); and by the observation that siRNA-mediated inhibition of PIM1, but not PIM2, expression resulted in significantly decreased p-c-MYC (Ser62), c-MYC, and SIRT1 expression in MV4-11 cells	SIGNOR-261557	0.685
DPF2	protein	Q92785	UNIPROT	RUNX1	protein	Q01196	UNIPROT	down-regulates activity	binding			9606									24332853	t		miannu	 The interaction between RUNX1 and DPF2 is dependent on the RUNX1 methylation status	SIGNOR-261966	0.2
GSK3A	protein	P49840	UNIPROT	PKD2	protein	Q13563	UNIPROT	unknown	phosphorylation	Ser76	AGAAASPsPPLSSCS	9606	BTO:0000007	BTO:0000671							16551655	t		llicata	We report the identification of a new phosphorylation site for pc2 within its n-terminal domain (ser(76)) and demonstrate that this residue is phosphorylated by glycogen synthase kinase 3 (gsk3).	SIGNOR-145306	0.2
Sin3B_complex	complex	SIGNOR-C409	SIGNOR	H3C1	protein	P68431	UNIPROT	down-regulates activity	binding			9606									21041485	t		miannu	We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin.	SIGNOR-266973	0.2
KHSRP	protein	Q92945	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates quantity by expression	post transcriptional regulation			-1									9858532	t		lperfetto	We show here that this component of the DCS complex is hnRNP H and that, like hnRNP F and KSRP, hnRNP H is needed for src N1 splicing in vitro.	SIGNOR-261274	0.275
CACNA1H	protein	O95180	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606		BTO:0000142							30736831	t		miannu	Certain types of sensory neurons express Cav3.2 calcium channels [12, 13] These channels belong to the family of low-voltage gated T-type calcium channels 	SIGNOR-269278	0.8
MAP3K7	protein	O43318	UNIPROT	RAB1A	protein	P62820	UNIPROT	up-regulates activity	phosphorylation	Thr75	AGQERFRtITSSYYR	-1									27482120	t		miannu	TAK1 preferentially phosphorylates the inactive (GDP-bound) state of Rab1. Phosphorylation of Rab1 disrupts interaction with GDP dissociation inhibitor 1 (GDI1), but not guanine exchange factor (GEF) or GTPase-activating protein (GAP) enzymes, and is exclusive to membrane-localized Rab1, suggesting phosphorylation may stimulate Rab1 membrane association. Furthermore, we found phosphorylation of Rab1 at T75 to be essential for Rab1 function. 	SIGNOR-277270	0.2
AKT2	protein	P31751	UNIPROT	PDK1	protein	Q15118	UNIPROT	up-regulates activity	phosphorylation	Thr346	APRPRVEtSRAVPLA	-1									27505672	t		miannu	 Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. 	SIGNOR-277271	0.383
AKT1	protein	P31749	UNIPROT	PDK1	protein	Q15118	UNIPROT	up-regulates activity	phosphorylation	Thr346	APRPRVEtSRAVPLA	-1									27505672	t		miannu	 Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. 	SIGNOR-277272	0.619
PPM1D	protein	O15297	UNIPROT	MDM4	protein	O15151	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser403	DLAHSSEsQETISSM										33309518	t		lperfetto	PPM1D also inhibits p53 activity by dephosphorylating Ser395 and stabilizing MDM2 and by dephosphorylating Ser403 on MDMX	SIGNOR-275491	0.444
GSK3B	protein	P49841	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser184	GKTTTTNsKREEKLF	9606	BTO:0002548								27572267	t		miannu	We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP.	SIGNOR-277275	0.311
GSK3B	protein	P49841	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr180	QVLSGKTtTTNSKRE	9606	BTO:0002548								27572267	t		miannu	We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP.	SIGNOR-277276	0.311
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	CD274	protein	Q9NZQ7	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002548								27572267	t		miannu	We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP.	SIGNOR-277277	0.2
AKT1	protein	P31749	UNIPROT	MITF	protein	O75030	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser516	KTSSRRSsMSMEETE	9606	BTO:0002181								27702651	t		miannu	We found that AKT phosphorylates MITF at S510. Phosphorylated MITF S510 enhances its affinity to TP53 and promotes CDKN1A expression. Phosphorylation of MITF by AKT induces its degradation	SIGNOR-277281	0.453
IL23R	protein	Q5VWK5	UNIPROT	STAT4	protein	Q14765	UNIPROT	up-regulates				9606	BTO:0000782								12023369	f		gcesareni	Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12.	SIGNOR-87838	0.575
MCHR2	protein	Q969V1	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257334	0.409
RPS6KB1	protein	P23443	UNIPROT	PIP5K1C	protein	O60331	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser555	RYRRRTQsSGQDGRP										27780861	t		miannu	Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. These data suggest that S6K1-mediated PIPKIγ90 phosphorylation regulates cell migration and invasion by controlling PIPKIγ90 degradation.	SIGNOR-277283	0.2
PDCD1	protein	Q15116	UNIPROT	DNM1L	protein	O00429	UNIPROT	down-regulates activity				9606	BTO:0000782								34535949	f		Barakat	Mechanistically, we provided evidence that PD1 signaling downregulates Drp1 activating phosphorylation on Ser616 (and consequently mitochondrial fragmentation) via the inhibition of ERK1/2 and mTOR kinases.	SIGNOR-275406	0.2
GSK3B	protein	P49841	UNIPROT	GLI2	protein	P10070	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser820	VSSAYTVsRRSSGIS	9606	BTO:0000007								16611981	t		lperfetto	The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3.	SIGNOR-148472	0.544
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MDM2	protein	Q00987	UNIPROT	up-regulates activity	phosphorylation	Ser166	SSRRRAIsETEENSD	9606									15169778	t		lperfetto	Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation.	SIGNOR-244296	0.2
NEK2	protein	P51955	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr194	EEKLFNVtSTLRINT	10090	BTO:0000584								34315872	t		miannu	NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. 	SIGNOR-277315	0.2
IL4	protein	P05112	UNIPROT	IL13RA1	protein	P78552	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0000801;BTO:0000876	BTO:0000887;BTO:0000763;BTO:0001260							12704343	t		milica	It is now known that this alternate receptor is a heterodimer, the type ii il-4 receptor or the il-13 receptor, which is comprised of IL-4R And IL-13R1.	SIGNOR-100759	0.772
MAPK3	protein	P27361	UNIPROT	SOS1	protein	Q07889	UNIPROT	down-regulates	phosphorylation	Ser1167	ESAPAESsPSKIMSK	9606									8816480	t		gcesareni	In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1	SIGNOR-43943	0.621
TRIM47	protein	Q96LD4	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	down-regulates quantity	ubiquitination			10090	BTO:0000575								29291351	t		gianni	CYLD is progressively degraded upon interaction with the E3 ligase TRIM47 in proportion to NASH severity	SIGNOR-266443	0.2
SMAD1	protein	Q15797	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates	binding			9606									22298955	t		gcesareni	Smad1 interacts with runx2 on the promoter of target genes and controls osteoblast gene expression and differentiation	SIGNOR-195642	0.554
CCNT1	protein	O60563	UNIPROT	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15546612	f		gcesareni	Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells.	SIGNOR-130634	0.2
JAK2	protein	O60674	UNIPROT	ARHGEF1	protein	Q92888	UNIPROT	up-regulates	phosphorylation	Tyr738	WDQEAQIyELVAQTV	9606									20098430	t		gcesareni	We found that angiotensin ii activates arhgef1 through a previously undescribed mechanism in which jak2 phosphorylates tyr738 of arhgef1	SIGNOR-163557	0.332
CDK5	protein	Q00535	UNIPROT	DPYSL3	protein	Q14195	UNIPROT	up-regulates activity	phosphorylation	Thr509	PVFDLTTtPKGGTPA	9606									16611631	t		lperfetto	Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-145967	0.588
GNAI1	protein	P63096	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	down-regulates				-1									10224115	f			G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics.	SIGNOR-256523	0.7
UBE2I	protein	P63279	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates activity	sumoylation	Lys254	MESQERIkAERKRMR	9606				SIGNOR-C154					16055711	t		lperfetto	We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. 	SIGNOR-263001	0.43
TCF3	protein	P15923	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								22577461	f		miannu	E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r.	SIGNOR-197523	0.438
CDK14	protein	O94921	UNIPROT	CCNY	protein	Q8ND76	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser73	STIFLSKsQTDVREK	9606	BTO:0000599								24794231	t		lperfetto	Phosphorylation of cyclin Y by CDK14 induces its ubiquitination and degradation|Phosphorylation of CCNY at Serines 71 and 73 creates a putative phospho-degron that controls its association with an SCF complex	SIGNOR-273007	0.824
PAK1	protein	Q13153	UNIPROT	VIM	protein	P08670	UNIPROT	unknown	phosphorylation	Ser56	SRSLYASsPGGVYAT	9606		BTO:0000887;BTO:0001260							15766329	t		llicata	In the present study, pak1 was able to phosphorylate vimentin on ser-56 in vitro.	SIGNOR-134520	0.2
3-phenanthryl hydrogen sulfate	chemical	CHEBI:37459	ChEBI	DRD3	protein	P35462	UNIPROT	down-regulates activity	chemical inhibition			-1									7576010	t		miannu	The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1.	SIGNOR-258438	0.8
CDK1	protein	P06493	UNIPROT	PIK3C3	protein	Q8NEB9	UNIPROT	down-regulates	phosphorylation	Thr159	DGSEPTKtPGRTSST	9606									20513426	t		llicata	We show that vps34 is phosphorylated on thr159 by cdk1, thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy	SIGNOR-165768	0.431
MYOG	protein	P15173	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates activity						BTO:0001103							7532173	f		Simone Vumbaca	These results suggest that at least initially, the muscle-forming regions contained cells with myogenic potential, and that this potential is lost in the myogenin mutants as development proceeds.	SIGNOR-255644	0.7
SNCA	protein	P37840	UNIPROT	VAMP2	protein	P63027	UNIPROT	down-regulates quantity	binding			9606	BTO:0000938								31110017	t		miannu	The normal function of the small presynaptic protein α-synuclein (α-syn) is of exceptional interest, not only in the context of neurodegeneration, but also as a cytosolic regulator of neurotransmission. we show that α-syn-VAMP2 interactions are necessary for α-syn-induced synaptic attenuation. Our data connect divergent views and suggest a unified model of α-syn function. the data indicate that α-syn–VAMP2 binding is essential for α-syn function and advocate an “interlocking model” where α-syn multimers on the SV surface interact with VAMP2 on adjacent SVs, helping to maintain physiologic SV clustering.	SIGNOR-264104	0.41
CDK1	protein	P06493	UNIPROT	HMGA1	protein	P17096	UNIPROT	down-regulates	phosphorylation	Ser36	PRKQPPVsPGTALVG	9606									17960875	t		gcesareni	Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation.	SIGNOR-158604	0.392
CSNK2A1	protein	P68400	UNIPROT	SEC63	protein	Q9UGP8	UNIPROT	up-regulates activity	phosphorylation	Ser576	VSDKGSDsEEEETNR	9606	BTO:0000599								23287549	t		lperfetto	Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62.	SIGNOR-265267	0.295
IKBKB	protein	O14920	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser274	RSKSQSSsNCSNPIS	-1									12351658	t			IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.	SIGNOR-251291	0.644
RAB6A	protein	P20340	UNIPROT	VPS13B	protein	Q7Z7G8	UNIPROT	up-regulates activity	binding			10116	BTO:0003102								25492866	t		miannu	Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization. 	SIGNOR-266869	0.381
PAK2	protein	Q13177	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates	phosphorylation	Ser141	TVKQKYLsFTPPEKD	9606	BTO:0000007								16204230	t		gcesareni	Pak2 is autophosphorylated at eight sites;ser-141 and ser-165 in the regulatory domain and thr-402 in the activation loop are identified as key sites in activation of the protein kinase.	SIGNOR-140907	0.2
HES1	protein	Q14469	UNIPROT	NEUROG2	protein	Q9H2A3	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938								30030829	f		lperfetto	The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 	SIGNOR-265142	0.325
HCRTR1	protein	O43613	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257128	0.252
PICALM	protein	Q13492	UNIPROT	CLTCL1	protein	P53675	UNIPROT	up-regulates	binding			9606	BTO:0001271;BTO:0000785								16491119	t		miannu	Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro	SIGNOR-144733	0.717
PRKAA1	protein	Q13131	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates activity	phosphorylation	Ser408	GPLPRAPsISTVEPK	9606									26190112	t		Luana	AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency.	SIGNOR-259863	0.339
MED27	protein	Q6P2C8	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266662	0.8
NOL9	protein	Q5SY16	UNIPROT	Rix1 complex	complex	SIGNOR-C373	SIGNOR	form complex	binding			9606	BTO:0000007								22190735	t		miannu	LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes.	SIGNOR-265470	0.789
MYCN	protein	P04198	UNIPROT	SIRT2	protein	Q8IXJ6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000931								23175188	f		miannu	Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. 	SIGNOR-255145	0.385
MIB2	protein	Q96AX9	UNIPROT	RIPK1	protein	Q13546	UNIPROT	down-regulates activity	polyubiquitination	Lys377	NEPSLQSkLQDEANY	9606	BTO:0000815								29642005	t		miannu	Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation.  We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. MIB2 Ubiquitylates RIPK1 at Lysines K377 and K634	SIGNOR-272662	0.299
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser213	QNIPAHYsPRTSPIM	9606									11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248516	0.386
ULK2	protein	Q8IYT8	UNIPROT	PFKM	protein	P08237	UNIPROT	down-regulates activity	phosphorylation	Ser74	EATWESVsMMLQLGG	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274043	0.2
SMAD1	protein	Q15797	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	binding			9606			SIGNOR-C85						21454478	t		lperfetto	Upon ligand binding, the specific heteromeric transmembrane serine/threonine kinase receptor complexes undergo phosphorylation/activation and subsequently phosphorylate the two ser residues in the c-terminal sxs motif of specific r-smads, smad1/5/8 for bmp pathway and smad2/3 for tgf-_/activin signaling. The activated r-smads then associate with co-smad, smad4. The heteromeric complexes translocate into the nucleus, where they bind to dna directly or indirectly to regulate the transcription of specific genes.	SIGNOR-172990	0.655
MORF4L1	protein	Q9UBU8	UNIPROT	Sin3B_complex	complex	SIGNOR-C409	SIGNOR	form complex	binding			9606	BTO:0000007								21041482	t		miannu	We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. our data suggest that the tethering of HDAC1, as part of this complex, to these loci promotes histone deacetylation within the coding region and prevents uncontrolled RNAP II progression at transcribed loci.	SIGNOR-266966	0.796
CyclinD3/CDK6	complex	SIGNOR-C234	SIGNOR	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Ser21	TPPSTALsPGKMSEA	9606									21059642	t	The effect has been demonstrated using Q01196-8	gcesareni	Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20).	SIGNOR-273031	0.562
LRRFIP1	protein	Q32MZ4	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000944								14522076	t		Luana	GC-binding factor 2 (GCF2) is a transcriptional repressor that decreases activity of the epidermal growth factor receptor (EGFR) and other genes. |Deletion mutants of GCF2 revealed that amino acids 429–528 are required for both DNA binding and repression of the EGFR promoter. 	SIGNOR-266057	0.298
resveratrol	chemical	CHEBI:27881	ChEBI	SIRT1	protein	Q96EB6	UNIPROT	up-regulates activity	chemical activation			-1									12939617	t		gcesareni	We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53	SIGNOR-238786	0.8
bortezomib	chemical	CHEBI:52717	ChEBI	PSMB1	protein	P20618	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000898								21504411	t		miannu	Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma.	SIGNOR-259306	0.8
UBA2	protein	Q9UBT2	UNIPROT	SAE1/SAE2 complex	complex	SIGNOR-C294	SIGNOR	form complex	binding			-1									15660128	t		lperfetto	E1 enzymes facilitate conjugation of ubiquitin and ubiquitin-like proteins through adenylation, thioester transfer within E1, and thioester transfer from E1 to E2 conjugating proteins. Structures of human heterodimeric Sae1/Sae2-Mg.ATP and Sae1/Sae2-SUMO-1-Mg.ATP complexes were determined at 2.2 and 2.75 A resolution, respectively.	SIGNOR-263004	0.815
N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-)	smallmolecule	CHEBI:143788	ChEBI	(6S)-5,6,7,8-tetrahydrofolate(2-)	smallmolecule	CHEBI:57453	ChEBI	up-regulates quantity	precursor of			9606									33179964	t		miannu	The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner.	SIGNOR-268103	0.8
CLK1	protein	P49759	UNIPROT	PTPN1	protein	P18031	UNIPROT	up-regulates activity	phosphorylation	Ser50	RNRYRDVsPFDHSRI	9606									10480872	t		gcesareni	The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation.	SIGNOR-70563	0.353
GSK3B	protein	P49841	UNIPROT	MACF1	protein	Q9UPN3	UNIPROT	down-regulates activity	phosphorylation	Ser7314	KSASRPGsRAGSRAG	9606	BTO:0004905								21295697	t		lperfetto	We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules.	SIGNOR-264431	0.446
SYK	protein	P43405	UNIPROT	SYK	protein	P43405	UNIPROT	up-regulates activity	phosphorylation	Tyr323	STVSFNPyEPELAPW	9606	BTO:0000776								9820500	t		lperfetto	These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520	SIGNOR-246605	0.2
SMAD1	protein	Q15797	UNIPROT	SMAD6	protein	O43541	UNIPROT	up-regulates quantity	transcriptional regulation			10090									22219353	t		Gianni	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268935	0.56
dactolisib	chemical	CHEBI:71952	ChEBI	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000848								21803746	t	ATP-competitive inhibitor of PI3K and mTOR	gcesareni	While the pi3k inhibitors, ly294002 or wortmannin, in the presence of plx4032 were individually inactive against pprm cell lines (fig. S4), the dual pi3k and mtorc1/2 inhibitor bez235 was highly specific (vs. parental lines) and potent in growth-inhibiting pprm cell lines	SIGNOR-175712	0.8
SEC61 complex	complex	SIGNOR-C368	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization												33925740	t		lperfetto	The Sec61 complex in the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER and provides a conduit for Ca2+ ions from the ER lumen to the cytosol. 	SIGNOR-265284	0.8
MMP20	protein	O60882	UNIPROT	ACAN	protein	P16112	UNIPROT	down-regulates quantity by destabilization	cleavage			-1									10922468	t		lperfetto	Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|It has been suggested that MMPs play a role in the hydrolysis of COMP and, therefore, compromise the integrity of the cartilage ECM structure leading to the ultimate loss of joint function	SIGNOR-266981	0.491
EEF1A1P5	protein	Q5VTE0	UNIPROT	Trp-tRNA(Trp)	smallmolecule	CHEBI:29159	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269557	0.8
MBTPS1	protein	Q14703	UNIPROT	CREB3L2	protein	Q70SY1	UNIPROT	up-regulates	cleavage			9606	BTO:0000938	BTO:0000142							17178827	t		miannu	Bbf2h7 is cleaved by s1p in response to er stress / cleaved fragments of the bbf2h7 n-terminal portion containing the bzip domain translocate into nuclei	SIGNOR-151309	0.544
BACE2	protein	Q9Y5Z0	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates activity	cleavage	Phe634	VHHQKLVfFAEDVGS	9606									10931940	t		lperfetto	BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Aβ is produced from the Aβ precursor protein (APP) by two proteolytic events. A β-secretase activity cleaves APP at the N terminus of Aβ (β site) between amino acids Met-671 and Asp-672 |We show here that BACE2 cleaves APP at its β site and more efficiently at sites within the Aβ region of APP, after Phe-19 and Phe-20 of Aβ.	SIGNOR-261772	0.561
CSMD1	protein	Q96PZ7	UNIPROT	C4B	protein	P0C0L5	UNIPROT	down-regulates quantity	binding			9606									28345259	t		miannu	CUB and sushi multiple domains 1 (CSMD1) is a relatively poorly studied large transmembrane protein of 390 kDa composed of 14 N-terminal CUB domains interspersed with complement control protein (CCP) domains followed by 15 consecutive CCP domains. The active domains of CSMD1 were then identified in CCP17-21, which were shown to interact with C4b and C3b and present these complement proteins for degradation by factor	SIGNOR-265149	0.2
MAPK1	protein	P28482	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser195	PNSSYPNsPGSSSST	9606									9335504	t		llicata	In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1	SIGNOR-52678	0.59
MAPK8	protein	P45983	UNIPROT	ITCH	protein	Q96J02	UNIPROT	up-regulates activity	phosphorylation	Ser273	RPASVNGsPSATSES	9606	BTO:0000007								16446428	t		gcesareni	Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222	SIGNOR-249580	0.644
HLA-DRA	protein	P01903	UNIPROT	Membrane_fusion	phenotype	SIGNOR-PH122	SIGNOR	up-regulates				9606	BTO:0000776								21178476	f		scontino	Fusion with a B cell requires a ternary complex of gHgLgp42. Fusion is triggered by an interaction between gp42 and HLA class II.	SIGNOR-266630	0.7
CDKN2B	protein	P42772	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				10090	BTO:0001056								14681685	f			The Ink4b gene (Cdkn2b) encodes p15Ink4b, a cyclin-dependent kinase inhibitor. It has been implicated in playing a role in the development of acute myeloid leukemia (AML) in man, since it is hypermethylated with high frequency. We provide evidence that the gene is a tumor suppressor for myeloid leukemia in mice.	SIGNOR-259407	0.7
FLT3	protein	P36888	UNIPROT	FLT3	protein	P36888	UNIPROT	unknown	phosphorylation	Tyr726	KEHNFSFyPTFQSHP	10090	BTO:0001516								16627759	t		lperfetto	In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated.	SIGNOR-271922	0.2
AKT1	protein	P31749	UNIPROT	SH3RF1	protein	Q7Z6J0	UNIPROT	down-regulates	phosphorylation	Ser304	KNTKKRHsFTSLTMA	9606									17535800	t		miannu	We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac, as does phosphomimetic s304d and s304e mutation of posh.	SIGNOR-252501	0.402
LYN	protein	P07948	UNIPROT	CD19	protein	P15391	UNIPROT	up-regulates	phosphorylation	Tyr500	TSLGSQSyEDMRGIL	9606									10933394	t		llicata	Experiments with purified proteins demonstrated that cd19-y513 was lyn's initial phosphorylation and binding site. This led to processive phosphorylation of cd19-y482, which recruited a second lyn molecule, allowing for transphosphorylation and amplification of lyn activation.	SIGNOR-80290	0.765
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT3	protein	P56703	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242730	0.283
GSK3B	protein	P49841	UNIPROT	STK38	protein	Q15208	UNIPROT	down-regulates activity	phosphorylation	Ser6	sTPCSSMS	-1									22142472	t		miannu	GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively.  Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress.	SIGNOR-276392	0.281
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser171	PLCLSPAsSGSSASF	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248510	0.386
LRFN4	protein	Q6PJG9	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606	BTO:0000938								21736948	f		miannu	The SALM (synaptic adhesion-like molecule) family of adhesion molecules, also known as Lrfn, belongs to the superfamily of leucine-rich repeat (LRR)-containing adhesion molecules. Proteins of the SALM family, which includes five known members (SALMs 1-5), have been implicated in the regulation of neurite outgrowth and branching, and synapse formation and maturation.SALM3 and SALM5, but not other SALMs, possess synaptogenic activity, inducing presynaptic differentiation in contacting axons.	SIGNOR-264092	0.7
CCNE1	protein	P24864	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates	binding			9606									23437375	t		gcesareni	Our results suggest that ad-induced cyclin e activates cdk2 that targets the transcriptional repressor prb/cyclin e activates the cdk2 kinase necessary for the actual initiation of dna replication	SIGNOR-201506	0.954
EGLN2	protein	Q96KS0	UNIPROT	ADSL	protein	P30566	UNIPROT	up-regulates activity	hydroxylation	Pro24	LASRYASpEMCFVFS	9606	BTO:0000007								31729379	t		miannu	ADSL is hydroxylated by EglN2 on Proline 24. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels	SIGNOR-266613	0.2
DLX5	protein	P56178	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22298955	f		gcesareni	Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme , indicat-ing that dlx5 can work as an upstream gene of runx2.	SIGNOR-195576	0.5
WNT2B	protein	Q93097	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors andinitiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131780	0.584
GADD45B	protein	O75293	UNIPROT	CDK11A	protein	Q9UQ88	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								26885618	t		lperfetto	Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58.	SIGNOR-273024	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9606									17158707	t		lperfetto	The JNK-mediated phosphorylation of both Ser63 and Ser73 within the transactivation domain of c-Jun (Table _(Table1)1) potentiates its transcriptional activity	SIGNOR-53784	0.2
SIN3A	protein	Q96ST3	UNIPROT	MECP2/SIN3A/HDAC complex	complex	SIGNOR-C360	SIGNOR	form complex	binding			9606	BTO:0000567								9620804	t		Luana	We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases.	SIGNOR-267737	0.825
CUL1	protein	Q13616	UNIPROT	RNF7	protein	Q9UBF6	UNIPROT	up-regulates activity	binding			9606									10851089	t		miannu	SAG was found to be the second family member of Rbx (RING box protein) or ROC (Regulator of cullins) or Hrt that is a component of SCF E3 ubiquitin ligase. Indeed, like ROC1/Rbx1/Hrt1, SAG binds to Cul1 and SAG-Cul1 complex has ubiquitin ligase activity to promote poly-ubiquitination of E2/Cdc34. 	SIGNOR-271444	0.851
NUP62	protein	P37198	UNIPROT	TUBG1	protein	P23258	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								24107630	t		Simone	Furthermore, we found interactions and co-localization with γ-tubulin and SAS-6. Our results also point to a potential role of Nup62 in targeting gamma-tubulin and SAS-6 to the centrioles.	SIGNOR-261257	0.2
GSK3A	protein	P49840	UNIPROT	FCAR	protein	P24071	UNIPROT	down-regulates activity	phosphorylation	Ser284	LTFARTPsVCK	10090	BTO:0001516								30766540	t		lperfetto	GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state. 	SIGNOR-264856	0.2
RPS6KA5	protein	O75582	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	phosphorylation			9606									10464286	t		gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-265348	0.2
EDNRA	protein	P25101	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			9606		BTO:0000671							10199825	t		gcesareni	We studied the ability of et receptors to activate galfa13 using an assay for g protein alfa-chain activation that is based on the fact that an activated (gtp-bound) alfa-chain is resistant to trypsinization compared with an inactive (gdp-bound) alfa-chain.	SIGNOR-66856	0.543
PAK4	protein	O96013	UNIPROT	SNAI2	protein	O43623	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser254	SKTFSRMsLLHKHEE	-1									29849120	t		miannu	PAK4 bound and directly phosphorylated Slug at two previously unknown sites, S158 and S254, which resulted in its stabilization. 	SIGNOR-277394	0.2
STOML2	protein	Q9UJZ1	UNIPROT	ATP	smallmolecule	CHEBI:15422	ChEBI	up-regulates quantity				9606									20359165	f		Giorgia	In addition, mitochondrial and whole-cell ATP levels in resting SLP-2hi T cells were significantly higher than those in SLP-2lo T cells (P < 0.05) (Fig. 7d). Such an increase in ATP levels in SLP-2hi T cells correlated with increased resistance to depletion of mitochondrial ATP with oligomycin	SIGNOR-260384	0.8
AHSA1	protein	O95433	UNIPROT	GCH1	protein	P30793	UNIPROT	up-regulates activity	binding			9606	BTO:0001519								16696853	t		miannu	The interaction of GCH1 with Aha1 may recruit GCH1 into the eNOS/Hsp90 complex so as to support local changes in nitric oxide production by endothelial cells.	SIGNOR-252213	0.301
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	PIN1	protein	Q13526	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								19151708	f		lperfetto	Previously, we have shown that commitment of the C2C12 cells to the osteoblastic lineage occurs around 24h after BMP treatment, when the osteoblast specific transcription factor Cbfa1 and the novel osteoblast related genes Tcf7 and Hey1 become regulated	SIGNOR-254342	0.2
ITGA2	protein	P17301	UNIPROT	A2/b1 integrin	complex	SIGNOR-C160	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253171	0.749
PPARD	protein	Q03181	UNIPROT	HSD11B2	protein	P80365	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001975								15591138	f		miannu	 Peroxisome proliferator-activated receptor delta suppresses 11beta-hydroxysteroid dehydrogenase type 2 gene expression in human placental trophoblast cells.	SIGNOR-255050	0.319
TKT	protein	P29401	UNIPROT	D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	down-regulates quantity	chemical modification			9606									24929114	t		miannu	Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates.	SIGNOR-267086	0.8
ARRB2	protein	P32121	UNIPROT	ADRB1	protein	P08588	UNIPROT	down-regulates activity	binding			-1									2163110	t			The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors	SIGNOR-256502	0.481
CDKN2C	protein	P42773	UNIPROT	CDK4	protein	P11802	UNIPROT	down-regulates	binding			9606									8891723	t		miannu	The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb.	SIGNOR-44598	0.866
DUSP5	protein	Q16690	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates	dephosphorylation			9606									10224087	t	inferred from 70% of family members	gcesareni	Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway	SIGNOR-269932	0.773
TNF	protein	P01375	UNIPROT	SERPINA3	protein	P01011	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002600								11027208	f		miannu	We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. 	SIGNOR-254809	0.2
ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9606									17306385	t		miannu	Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase 	SIGNOR-256168	0.773
GTF3C5	protein	Q9Y5Q8	UNIPROT	TFIIIC	complex	SIGNOR-C392	SIGNOR	form complex	binding			9606									29378333	t		lperfetto	Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains	SIGNOR-266184	0.91
TNPO1	protein	Q92973	UNIPROT	FUS	protein	P35637	UNIPROT	up-regulates activity	relocalization			-1									23056579	t		lperfetto	The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1).	SIGNOR-262101	0.661
CAMK4	protein	Q16566	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser16	KELEKRAsGQAFELI	9606									7925472	t		gcesareni	Serine 16 of oncoprotein 18 is a major cytosolic target for the ca2+/calmodulin-dependent kinase-gr.	SIGNOR-34743	0.468
MMP8	protein	P22894	UNIPROT	FGA	protein	P02671	UNIPROT	down-regulates quantity by destabilization	cleavage	Ala20	VVGTAWTaDSGEGDF	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-8 20ADSGEGD a-chain | 442LRTGKEKV a-chain	SIGNOR-263625	0.2
EEF1A2	protein	Q05639	UNIPROT	Arg-tRNA(Arg)	smallmolecule	CHEBI:18366	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269525	0.8
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	MBL2	protein	P11226	UNIPROT	up-regulates activity	binding												17204478	t		lperfetto	 In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2)	SIGNOR-263405	0.7
PLCE1	protein	Q9P212	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									11022047	t		gcesareni	The presence of a rasgef motif in the n terminus of plcepsilon suggests that plcepsilon can activate ras by acting as an exchange factor by promoting the exchange of gtp for bound gdp.	SIGNOR-82859	0.56
ATOH1	protein	Q92858	UNIPROT	HES6	protein	Q96HZ4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17826772	f		miannu	Electrophoretic mobility shift assays and luciferase assays show that ATOH1 activates HES6 transcription through binding to three clustered E boxes of its promoter.	SIGNOR-253754	0.452
CCL5	protein	P13501	UNIPROT	CCR1	protein	P32246	UNIPROT	up-regulates	binding			9606									10734056	t			RANTES interacts with specific cell surface receptors, which are coupled to pertussis toxin-sensitive guanine nucleotide regulatory proteins (G protein) to activate effectors such as phospholipase C (PLC), ion channels, phospholipase D, and protein kinase C. In addition to the CCR1 receptor, RANTES activates several members of the CC subfamily of chemokine receptors including CCR3, CCR4, and CCR5	SIGNOR-254367	0.764
HAUS6	protein	Q7Z4H7	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates				9606	BTO:0000567								19029337	f		miannu	FAM29A interacts with the NEDD1-gamma-tubulin complex and recruits this complex to the spindle, which, in turn, promotes MT polymerization. 	SIGNOR-261420	0.7
IL1R1	protein	P14778	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000801								9625767	t		lperfetto	Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab	SIGNOR-249515	0.2
GSK3B	protein	P49841	UNIPROT	PSEN1	protein	P49768	UNIPROT	down-regulates activity	phosphorylation	Ser353	SHLGPHRsTPESRAA	9606	BTO:0000007		SIGNOR-C110						17360711	t		gcesareni	We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin.	SIGNOR-153627	0.605
HNF4A	protein	P41235	UNIPROT	G6P	proteinfamily	SIGNOR-PF81	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									16308421	f	inferred from family member	gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-270255	0.26
MAPK14	protein	Q16539	UNIPROT	AKT2	protein	P31751	UNIPROT	down-regulates activity				9606									20626350	f		lperfetto	On the other hand, p38 alfa may negatively modulate akt activity, indipendently of pi3k by regulating the interaction between caveolin 1 and pp2a through a mechanism dependent on cell attachment.	SIGNOR-166591	0.413
PGAM2	protein	P15259	UNIPROT	2-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58289	ChEBI	up-regulates quantity	chemical modification			9606									24786789	t		miannu	Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle.	SIGNOR-266515	0.8
FLT3	protein	P36888	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0001516								12796379	t			FLT3-ITDs induced a strong activation of STAT5. FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation. 	SIGNOR-261516	0.594
BCL2L11	protein	O43521	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates activity	binding			9606									17289999	t		lperfetto	Contrary to the direct-activation model, we show that Bax and Bak can mediate apoptosis without discernable association with the putative BH3-only activators (Bim, Bid, and Puma), even in cells with no Bim or Bid and reduced Puma. Our results indicate that BH3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding Bax and Bak	SIGNOR-152986	0.825
CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	NANOS2	protein	P60321	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			9606									31320642	t		lperfetto	In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins	SIGNOR-268349	0.492
SP1	protein	P08047	UNIPROT	CD34	protein	P28906	UNIPROT	up-regulates quantity by expression	transcriptional regulation			7227									10989198	t		lperfetto	Activation of the CD34 promoter by Sp1 requires the presence of a binding domain at -48 bp as well as the 5' untranslated region, which also binds Sp1	SIGNOR-241481	0.267
TOMM20	protein	Q15388	UNIPROT	TOM40 complex	complex	SIGNOR-C421	SIGNOR	form complex	binding			9606	BTO:0000567								18331822	t		lperfetto	The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex.	SIGNOR-267678	0.693
NUP98-HOXA9	fusion protein	SIGNOR-FP15	SIGNOR	EP300	protein	Q09472	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								28630438	t		miannu	NUP98-HOXA9 has an activator-repressor role in transcriptional regulation driven by p300 and HDAC1 interactions. The chromosomal translocation t(7;11)(p15, p15), encoding the fusion protein NUP98-HOXA9 (NHA9), is a rare poor risk cytogenetic event in AML associated with a particularly poor prognosis.In summary, NHA9 deregulates the expression of key leukemic genes, including MEIS1-HOXA9-PBX3 complex, through the enhancer binding and the direct interaction of the fusion protein with HDAC and p300 transcriptional regulators. 	SIGNOR-261497	0.2
WNT5B	protein	Q9H1J7	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131882	0.622
RIPK3	protein	Q9Y572	UNIPROT	GLUD1	protein	P00367	UNIPROT	up-regulates	binding			9606									19632174	t		gcesareni	Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro.	SIGNOR-187314	0.426
PTGS2	protein	P35354	UNIPROT	episterol ester	smallmolecule	CHEBI:52393	ChEBI	down-regulates quantity	chemical modification			9606									19126760	t		miannu	After biosynthesis, 2-AG is partially degraded by postsynaptic COX-2, and partly released to the extracellular space. 	SIGNOR-264270	0.8
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Ser214	SRSGLYRsPSMPENL	9606									10864927	t		lperfetto	Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b.	SIGNOR-216765	0.839
TLN1	protein	Q9Y490	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			10090	BTO:0000132			SIGNOR-C167					19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257593	0.79
ACVR1	protein	Q04771	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates activity	phosphorylation	Ser463	SPHNPISsVS	10090									9748228	t		gcesareni	Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif, and also regulated Smad5 and Smad8 phosphorylation.	SIGNOR-247674	0.69
INS	protein	P01308	UNIPROT	RHOQ	protein	P17081	UNIPROT	up-regulates				9606									12687004	f		gcesareni	Exo70 translocates to the plasma membrane in response to insulin through the activation of tc10, where it assembles a multiprotein complex that includes sec6 and sec8	SIGNOR-100483	0.291
CSNK1A1	protein	P48729	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates	phosphorylation	Ser100	ESEDSQEsVDSVTDS	9606									9931297	t		lperfetto	Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement.	SIGNOR-64258	0.318
MASP1	protein	P48740	UNIPROT	C4A	protein	P0C0L4	UNIPROT	up-regulates activity	cleavage	Arg756	KGQAGLQrALEILQE	-1									9087411	t		lperfetto	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263435	0.59
PLK1	protein	P53350	UNIPROT	TPT1	protein	P13693	UNIPROT	down-regulates	phosphorylation	Ser46	TEGNIDDsLIGGNAS	9606									12167714	t		lperfetto	Plk phosphorylates tctp on two serine residues. These results suggest that phosphorylation decreases the microtubule-stabilizing activity of tctp and promotes the increase in microtubule dynamics that occurs after metaphase	SIGNOR-91344	0.705
Class I MHC:Antigen	complex	SIGNOR-C426	SIGNOR	Cytotoxic_T-lymphocyte_activation	phenotype	SIGNOR-PH195	SIGNOR	up-regulates				9606									31810556	f		scontino	High-affinity peptide/MHC class I complexes that successfully pass the aforementioned “quality controls” will be transported through the Golgi apparatus to the cell membrane to elicit antigen-specific CD8+ T cell responses.	SIGNOR-267875	0.7
CDC16	protein	Q13042	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	form complex	binding												16896351	t		lperfetto	The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex.	SIGNOR-252006	0.918
MDM2	protein	Q00987	UNIPROT	EID1	protein	Q9Y6B2	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0001938								11073989	t		miannu	Degradation of EID-1 occurs via ubiquitin-dependent proteolysis and correlates with MDM2 binding. These results are consistent with a model wherein destruction of EID-1 is linked to its ability to interact with MDM2 via either p300 or pRB.	SIGNOR-272582	0.434
H2BC11	protein	P06899	UNIPROT	Nucleosome_H2A.Z.2 variant	complex	SIGNOR-C323	SIGNOR	form complex	binding			-1									24311584	t		miannu	In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined.	SIGNOR-263710	0.2
SMOC1	protein	Q9H4F8	UNIPROT	SPARC	protein	P09486	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20359165	f		lperfetto	The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells	SIGNOR-260401	0.411
STAT1	protein	P42224	UNIPROT	MMP13	protein	P45452	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000249								17179173	f		miannu	IFNgamma, through its receptor, activates STAT1, which binds with CBP/p300 coactivator, sequesters it from the cell system, and thus inhibits transcriptional induction of the MMP13 gene in chondrocytes.	SIGNOR-255235	0.295
CDC73	protein	Q6P1J9	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	binding			9606									16630820	t		gcesareni	Parafibromin/hyrax activates wnt/wg target gene transcription by direct association with beta-catenin/armadillo	SIGNOR-146282	0.683
CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	MTA1	protein	Q13330	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									24089055	t	 	lperfetto	Here we provide genetic and biochemical evidence that metastasis-associated protein 1 (MTA1), a widely upregulated gene product in human cancers, is an integral component of the circadian molecular machinery. | The CLOCK-BMAL1 heterodimer activates MTA1 transcription through a conserved E-box element at its promoter. MTA1, in turn, interacts with and recruits CLOCK-BMAL1 at its own and CRY1 promoters and promotes their transcription.	SIGNOR-253718	0.2
PRKCE	protein	Q02156	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr52	HKHKHEMtLKFGPAR	9606	BTO:0000848;BTO:0001286								22304920	t		lperfetto	Pkc_ phosphorylation of atf2 on thr52. Pkc_ promotes oncogenic functions of atf2 in the nucleus while blocking its apoptotic function at mitochondria	SIGNOR-195761	0.292
PTPN1	protein	P18031	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates	dephosphorylation	Tyr1235	DMYDKEYySVHNKTG	9606									18819921	t		gcesareni	Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion.	SIGNOR-181327	0.621
Dynorphin A	smallmolecule	CHEBI:4727	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258795	0.8
GEM	protein	P55040	UNIPROT	CACNB2	protein	Q08289	UNIPROT	down-regulates activity	binding			9606									14701738	t		miannu	 Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively.	SIGNOR-261720	0.2
GGCX	protein	P38435	UNIPROT	F2	protein	P00734	UNIPROT	up-regulates activity	carboxylation	Glu57	EVRKGNLeRECVEET	-1									10556651	t		lperfetto	We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 	SIGNOR-263677	0.655
PPP6C	protein	O00743	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	up-regulates activity	dephosphorylation	Ser834	GSHTSGQsNGRDHQA	9606	BTO:0001109								28114302	t		miannu	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276514	0.335
GRK5	protein	P34947	UNIPROT	SNCB	protein	Q16143	UNIPROT	down-regulates activity	phosphorylation	Ser118	LMEPEGEsYEDPPQE	-1									10852916	t			GRK5 prefers alpha-synuclein as a substrate. GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser118 practically abolishes β-synuclein phosphorylation by both GRK2 and GRK5	SIGNOR-251203	0.326
PLK1	protein	P53350	UNIPROT	NEDD1	protein	Q8NHV4	UNIPROT	up-regulates activity	phosphorylation	Thr382	PRSINTDtLSKETDS	9606	BTO:0000567								19509060	t		lperfetto	Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation.	SIGNOR-272993	0.604
IRX1	protein	P78414	UNIPROT	RALGPS1	protein	Q5JS13	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed.	SIGNOR-261668	0.2
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2E1	protein	P51965	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271359	0.582
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DQA1	protein	P01909	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-253991	0.29
MLL-AF4	fusion protein	SIGNOR-FP4	SIGNOR	RUNX1	protein	Q01196	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24449215	f		miannu	However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions.	SIGNOR-260126	0.2
triprolidine	chemical	CHEBI:84116	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			10029									7925364	t		miannu	The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum.	SIGNOR-258870	0.8
CLK3	protein	P49761	UNIPROT	USP13	protein	Q92995	UNIPROT	up-regulates activity	phosphorylation	Tyr708	EPLTMPGyGGAASAG	9606	BTO:0003911								32453420	t	done	miannu	CLK3 directly phosphorylated USP13 at Y708, which promoted its binding to c-Myc, thereby preventing Fbxl14-mediated c-Myc ubiquitination and activating the transcription of purine metabolic genes.	SIGNOR-274122	0.2
KRAS	protein	P01116	UNIPROT	MAP4K5	protein	Q9Y4K4	UNIPROT	up-regulates				9606	BTO:0001271								9949177	f		fstefani	Bcr-abl_mediated ras activation is crucial for the ability of bcr-abl to activate gckr and is consistent with the previously known requirement for ras in bcr-abl_induced sapk activation how ras activates gckr remains enigmatic.	SIGNOR-64262	0.2
PRKCE	protein	Q02156	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	phosphorylation	Ser139	EEWTRHGsFVNKPTR	10090	BTO:0000944								12052829	t		lperfetto	Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms.	SIGNOR-263048	0.2
selumetinib	chemical	CHEBI:90227	ChEBI	MAP2K1	protein	Q02750	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258280	0.8
RPL30	protein	P62888	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262470	0.873
PBX1	protein	P40424	UNIPROT	MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	form complex	binding			9606		BTO:0001103							17194702	t		miannu	Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes	SIGNOR-151700	0.419
HBA1	protein	P69905	UNIPROT	AHSP	protein	Q9NZD4	UNIPROT	down-regulates activity				9606									2545495	f	Regulation	miannu	EDRF is rapidly inactivated by hemoglobin and superoxide.	SIGNOR-251751	0.771
CHEK1	protein	O14757	UNIPROT	E2F6	protein	O75461	UNIPROT	down-regulates activity	phosphorylation	Ser12	RPARKLPsLLLDPTE	-1									23954429	t		miannu	 the checkpoint kinase Chk1 phosphorylates E2F6 leading to its dissociation from promoters. 	SIGNOR-266370	0.557
FLT1	protein	P17948	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	phosphorylation	Tyr154	QLNDSAAyYLNDLDR	-1									33139573	t		miannu	RTKs directly phosphorylate Gαi on Y154, 155, and Y320.	SIGNOR-277230	0.26
CSNK2A1	protein	P68400	UNIPROT	PSEN2	protein	P49810	UNIPROT	unknown	phosphorylation	Ser9	LTFMASDsEEEVCDE	-1									8972483	t		llicata	In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. 	SIGNOR-250937	0.311
AURKA	protein	O14965	UNIPROT	TACC3	protein	Q9Y6A5	UNIPROT	unknown	phosphorylation	Ser34	PEVTGRSsVLRVSQK	-1									26134678	t		lperfetto	To address whether the phosphorylation state of TACC3 influenced Aurora-A binding and activation, we generated TACC3 variants in which all three Aurora-A phosphorylation sites (S34, S552 and S558)| The SA mutant had strongly reduced levels of phosphorylation compared to the individual mutations|	SIGNOR-263697	0.934
PAK1	protein	Q13153	UNIPROT	TBCB	protein	Q99426	UNIPROT	up-regulates	phosphorylation	Ser128	VRSFLKRsKLGRYNE	9606	BTO:0000150								15831477	t		lperfetto	P21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor b. Pak1 directly phosphorylated tcob in vitro and in vivo on serines 65 and 128 and colocalized with tcob on newly polymerized microtubules and on centrosomes. Pak1 phosphorylation is necessary for normal tcob function	SIGNOR-135460	0.46
levomethadone	chemical	CHEBI:136003	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258808	0.8
MAST3	protein	O60307	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates	binding			9606									15951562	t		miannu	Pten binds to and is phosphorylated by mast kinases./ Pdz domain-mediated binding to pten facilitates its phosphorylation by mast kinases / pdz domain binding increases pten protein stability.	SIGNOR-138077	0.586
MAPK1	protein	P28482	UNIPROT	SMAD3	protein	P84022	UNIPROT	unknown	phosphorylation	Ser204	NHSMDAGsPNLSPNP	9606				SIGNOR-C9					15241418	t		llicata	We found that ser 203 and ser 207 were phosphorylated by map kinase and that thr 178 was phosphorylated mostly by cdk and to a lesser extent by map kinase	SIGNOR-126744	0.736
CDK2	protein	P24941	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Ser214	SRSGLYRsPSMPENL	9606			SIGNOR-C16						20530684	t		gcesareni	The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry.	SIGNOR-165872	0.748
MAPK14	protein	Q16539	UNIPROT	HBA1	protein	P69905	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20162623	f	Indirect:regulation	miannu	Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). 	SIGNOR-251838	0.2
ATF4	protein	P18848	UNIPROT	EPRS1	protein	P07814	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269419	0.2
CDK1	protein	P06493	UNIPROT	PRDX1	protein	Q06830	UNIPROT	down-regulates	phosphorylation	Thr90	CHLAWVNtPKKQGGL	9606									11986303	t		lperfetto	Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.	SIGNOR-87097	0.359
PRKACA	protein	P17612	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser362	AAAHRKGsSSNEPSS	9534									1545828	t		miannu	Human c-Fos protein is phosphorylated in vitro by PKA. phosphorylation of Fos occurs at serine residue 362. Modification of the Fos protein by phosphorylation with PKA then allows it to act as a regulator of its own synthesis by downregulating fos gene expression at a transcriptional level	SIGNOR-250356	0.5
CSNK2B	protein	P67870	UNIPROT	CD163	protein	Q86VB7	UNIPROT	up-regulates activity	phosphorylation	Ser1085	RQRLAVSsRGENLVH	-1									11298324	t		llicata	Interaction of CD163 with the regulatory subunit of casein kinase II (CKII) and dependence of CD163 signaling on CKII and protein kinase C. | Inhibition studies using specific kinase inhibitors reveal that both CKII and PKC are involved in the CD163 signaling mechanism resulting in the secretion of proinflammatory cytokines. 	SIGNOR-251056	0.311
CUDC-907	chemical	CID:54575456	PUBCHEM	HDAC1	protein	Q13547	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191157	0.8
MAPK1	protein	P28482	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Thr573	AENGLLMtPCYTANF	9606	BTO:0000567								9687510	t		lperfetto	Thus, MAPK1/ERK1 and MAPK2/ERK2 activate three closely related protein kinases known as MAPK_activated protein kinases_1a, _1b and _1c (MAPKAP_K1a/b/c; also known as RSK1/2/3)	SIGNOR-59363	0.748
mTORC1	complex	SIGNOR-C3	SIGNOR	ULK1/Atg13/Fip200	complex	SIGNOR-C100	SIGNOR	down-regulates activity	phosphorylation			9606									23863160	t		lperfetto	Several studies published simultaneously illustrated that the equivalent mammalian ULK1Atg13FIP200 complex was also negatively regulated by mTORC1 in an analogous manner [17,18,24]. In mammalian cells, amino acid starvation or rapamycin treatment causes dephosphorylation of both Atg13 and ULK1, indicating that an mTORC1 input regulates the ULK1Atg13FIP200 complex mTORC1 modulates the kinase activity of ULK1 directly, with rapamycin treatment of cells leading to enhanced ULK1 kinase activity, whereas Rheb overexpression causes a decrease in ULK1 kinase activity	SIGNOR-209904	0.561
PLEKHG3	protein	A1L390	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260585	0.362
PPP4C	protein	P60510	UNIPROT	NDEL1	protein	Q9GZM8	UNIPROT	down-regulates activity	dephosphorylation	Thr219	ASLSLPAtPVGKGTE	9606									18347064	t			Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation|PP4c selectively dephosphorylates NDEL1 at Cdk1 sites. We also demonstrate that PP4c negatively regulates Cdk1 activity at the centrosome.|We next examined the ability of PP4c to dephosphorylate a Cdk1 phosphorylation site, phospho-T219	SIGNOR-248550	0.406
SARS1	protein	P49591	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								24940000	t			Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation.	SIGNOR-259368	0.2
SRC	protein	P12931	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	phosphorylation	Tyr701	DGPKGTGyIKTELIS	9606		BTO:0000763							14978237	t		lperfetto	The tyr701 phosphorylation of signal transducer and activator of transcription 1 (stat1) induced by interferon-gamma (ifn-gamma) and 12-o-tetradecanoylphorbol 13-acetate (tpa) was inhibited by the protein kinase c (pkc) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the src kinase inhibitor pp2. An association between c-src and stat1 was increased by ifn-gamma and tpa, indicating the direct phosphorylation of stat1 by pkc-dependent c-src activation.	SIGNOR-235696	0.577
ANO6	protein	Q4KMQ2	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity				10090									24663380	f		francesca	Ano6 deficiency significantly reduces ERK/AKT phosphorylation. Our data have also shown that Ano6-KD significantly attenuates ERK phosphorylation, which is implicated in the regulation of cancer cell proliferation by Ano1, suggesting that Ano6 is potentially involved in regulating myoblast proliferation through the ERK signaling pathway.	SIGNOR-261214	0.2
APC-c	complex	SIGNOR-C150	SIGNOR	CCNB1	protein	P14635	UNIPROT	down-regulates quantity by destabilization	ubiquitination												21596315	t		lperfetto	Complexed with the activator proteins CDC20 or CDH1 (Fang et al., 1998, Visintin et al., 1997), the APC/C recognizes, ubiquitinates, and targets for proteasomal degradation a multitude of cell cycle regulators containing KEN or D box degrons, including securin, cyclin A, and cyclin B.	SIGNOR-265051	0.607
STK11	protein	Q15831	UNIPROT	PRMT5	protein	O14744	UNIPROT	up-regulates activity	phosphorylation	Thr144	VLTNHIHtGHHSSMF	-1									30289978	t		miannu	We found that PRMT5 is a bona fade substrate for LKB1. We identified T132, 139 and 144 residues, located in the TIM-Barrel domain of PRMT5, as target sites for LKB1 phosphorylation. The point mutation of PRMT5 T139/144 to A139/144 drastically decreased its methyltransferase activity, due probably to the loss of its interaction with regulatory proteins such as MEP50, pICln and RiOK1. 	SIGNOR-277412	0.2
MAPK14	protein	Q16539	UNIPROT	F3	protein	P13726	UNIPROT	down-regulates	phosphorylation	Ser290	GQSWKENsPLNVS	9606									23195225	t		lperfetto	We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. Our current study has identified p38_ as a major kinase, responsible for the phosphorylation of ser258 within the cytoplasmic domain of tf	SIGNOR-199868	0.296
GGCX	protein	P38435	UNIPROT	F10	protein	P00742	UNIPROT	up-regulates activity	carboxylation	Glu69	CSYEEAReVFEDSDK	-1									9538022	t		lperfetto	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263672	0.598
TRADD	protein	Q15628	UNIPROT	BIRC2	protein	Q13490	UNIPROT	up-regulates activity	binding			9606	BTO:0000007;BTO:0001412;BTO:0000567								8943045	t		amattioni	The recruitment of TRAF2 and c-IAP1 to TNF-R1 is TNF-dependent, is mediated by TRADD. N-terminal domain of tradd may become accessible to traf2, thereby permitting recruitment of the traf2/ciap1 heterocomplex.	SIGNOR-45134	0.687
COL1A2	protein	P08123	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									21949456	t			Collagen is the major structural protein in skeletal muscle ECM;...Several studies suggest that perimysial collagen is predominantly type I	SIGNOR-254663	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	S1PR1	protein	P21453	UNIPROT	up-regulates activity	phosphorylation	Thr236	RTRSRRLtFRKNISK	9606									11583630	t		lperfetto	Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis	SIGNOR-110845	0.2
panobinostat	chemical	CHEBI:85990	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257751	0.8
NEU1	protein	Q99519	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates activity				9606									19151752	f		Giorgia	One of the major molecular changes by NEU1 was decreased sialylation of integrin beta4, assessed by PNA- and MAL-II-lectin blotting of immunoprecipitates with anti-integrin beta4 antibody. The desialylation was accompanied by decreased phosphorylation of the integrin followed by attenuation of focal adhesion kinase and Erk1/2 pathway.	SIGNOR-260656	0.252
RAB5A	protein	P20339	UNIPROT	Early Endosome	complex	SIGNOR-C246	SIGNOR	form complex	binding			9606									19924646	t		lperfetto	The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 	SIGNOR-260616	0.535
DYNLL1	protein	P63167	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260501	0.276
GTF2H4	protein	Q92759	UNIPROT	TFIIH	complex	SIGNOR-C457	SIGNOR	form complex	binding			9606									30860024	t		lperfetto	Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 	SIGNOR-269315	0.908
MAPK3	protein	P27361	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	phosphorylation	Thr8	MSSILPFtPPVVKRL	9606									12193595	t		lperfetto	We show that phosphorylation of Smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (ERK1) increases the amount of Smad2 protein and leads to enhanced transcriptional activity.[] A site of ERK-dependent phosphorylation on Smad2 was located to Thr8	SIGNOR-227514	0.739
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates quantity by destabilization	cleavage	Asp683	HHGVVEVdAAVTPEE	-1									8943232	t		lperfetto	The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261765	0.502
CDK7	protein	P50613	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser392	FKTEGPDsD	9606									9315650	t		llicata	The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase.	SIGNOR-51292	0.47
Calprotectin complex	complex	SIGNOR-C293	SIGNOR	AGER	protein	Q15109	UNIPROT	up-regulates activity	binding			9606									28137827	t		miannu	RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33	SIGNOR-262825	0.339
SL-327	chemical	CHEBI:92211	ChEBI	MAP2K5	protein	Q13163	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000938	BTO:0000142							11160424	t		gcesareni	The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity.	SIGNOR-104933	0.8
RGMA	protein	Q96B86	UNIPROT	NEO1	protein	Q92859	UNIPROT	down-regulates activity	binding			10090									18485097	t		miannu	Netrin-1-neogenin interactions mediate chemoattractive axon guidance, while RGMa-neogenin interactions repel axons. 	SIGNOR-268388	0.78
imatinib	chemical	CHEBI:45783	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258226	0.8
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	Muscle_atrophy	phenotype	SIGNOR-PH40	SIGNOR	up-regulates				10090	BTO:0001103								15109499	f		gcesareni	Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.	SIGNOR-252932	0.7
CSNK2A1	protein	P68400	UNIPROT	EEF1B2	protein	P24534	UNIPROT	unknown	phosphorylation	Ser112	GSDDEEEsEEAKRLR	-1									8547318	t		llicata	EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent.	SIGNOR-250855	0.349
RAP1GDS1	protein	P52306	UNIPROT	RAP1A	protein	P62834	UNIPROT	up-regulates	binding			9606									21242305	t		miannu	Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob	SIGNOR-171482	0.43
PRRX1	protein	P54821	UNIPROT	SRF	protein	P11831	UNIPROT	up-regulates	binding			9606	BTO:0000567								9334314	t		miannu	The human homeodomain proteinphox1interacts functionally with serum response factor (srf) to impart serum responsive transcriptional activity to srf-binding sites in a hela cell cotransfection assay.	SIGNOR-52657	0.453
PTPN2	protein	P17706	UNIPROT	KRAS	protein	P01116	UNIPROT	down-regulates activity	dephosphorylation			9606									33122197	t		miannu	Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling.	SIGNOR-277039	0.279
Tiospirone	chemical	CID:55752	PUBCHEM	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029									9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258863	0.8
IL6R	protein	P08887	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates	binding			9606									23663276	t		milica	In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal.	SIGNOR-202033	0.74
TNF	protein	P01375	UNIPROT	SCN10A	protein	Q9Y5Y9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004102								26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253484	0.28
PTPN2	protein	P17706	UNIPROT	STAT5A	protein	P42229	UNIPROT	down-regulates activity	dephosphorylation			9606									15780598	t		lperfetto	Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.	SIGNOR-133547	0.723
NR3C1	protein	P04150	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates	binding			9606									8878484	t		fspada	We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter.	SIGNOR-44376	0.546
BMS 794833	chemical	CID:44155856	PUBCHEM	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190422	0.8
CTDSPL	protein	O15194	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	dephosphorylation	Ser213	NLSPNPMsPAHNNLD	9606	BTO:0000007								17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248308	0.398
MAP3K3	protein	Q99759	UNIPROT	RCAN1	protein	P53805	UNIPROT	up-regulates	phosphorylation	Ser167	FLISPPAsPPVGWKQ	9606	BTO:0000782								16126726	t		gcesareni	Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation	SIGNOR-138945	0.46
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser197	APRRRAAsMDSSSKL	9606									16272144	t		lperfetto	Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression	SIGNOR-252853	0.908
UMPS	protein	P11172	UNIPROT	orotate	smallmolecule	CHEBI:30839	ChEBI	down-regulates quantity	chemical modification			9606									2912371	t		miannu	Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase).	SIGNOR-267436	0.8
ITPR1	protein	Q14643	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	chemical modification			9606									24646566	t		miannu	The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell.	SIGNOR-256238	0.8
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CALM2	protein	P0DP24	UNIPROT	up-regulates	chemical activation			9606									10884684	t		miannu	Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘open’ conformations	SIGNOR-266317	0.8
DVL1P1	protein	P54792	UNIPROT	PRKCB	protein	P05771	UNIPROT	up-regulates	binding			9606									23151663	t		gcesareni	Taken together, these results suggest that site-specific dvl2 phosphorylation is required for dvl2 association with pkc_. This interaction is likely to be one of the mechanisms essential for wnt3a-dependent neurite outgrowth.	SIGNOR-199457	0.2
RAMAC	protein	Q9BTL3	UNIPROT	RNMT	protein	O43148	UNIPROT	up-regulates activity	binding			9606									27422871	t		lperfetto	Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM. 	SIGNOR-268344	0.2
EDA	protein	Q92838	UNIPROT	EDAR	protein	Q9UNE0	UNIPROT	up-regulates	binding			9606									18304980	t		gcesareni	Ultimately, in mammals, eda-a1 and eda-a2 trimers each bind a different receptor, edar and xedar, respectively, through their trimerized tnf domain.	SIGNOR-161109	0.742
RPS6KA3	protein	P51812	UNIPROT	HMGN2	protein	P05204	UNIPROT	down-regulates activity	phosphorylation	Ser25	KDEPQRRsARLSAKP	9606	BTO:0000567								11438671	t		lperfetto	We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets.	SIGNOR-249102	0.293
FBXW7	protein	Q969H0	UNIPROT	DAB2IP	protein	Q5VWQ8	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									27858941	t		miannu	DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1	SIGNOR-254774	0.332
SCN3A	protein	Q9NY46	UNIPROT	Action_potential 	phenotype	SIGNOR-PH82	SIGNOR	up-regulates				9606									26043074	f		miannu	The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons.	SIGNOR-253455	0.7
ELOC	protein	Q15369	UNIPROT	H1-1	protein	Q02539	UNIPROT	up-regulates	phosphorylation	Ser183	KPKKVAKsPAKAKAV	9606	BTO:0000567								20551309	t		lperfetto	Our results also show the potential function of p-tefb phosphorylation of h1, namely, to increase h1 dissociation from actively transcribed dna. P-tefb preferentially phosphorylates the ser-183 phosphorylation site of histone h1.1	SIGNOR-166120	0.2
TAB1	protein	Q15750	UNIPROT	JNK	proteinfamily	SIGNOR-PF15	SIGNOR	up-regulates	binding			9606									25290089	t		lperfetto	The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.	SIGNOR-205437	0.393
SP1	protein	P08047	UNIPROT	MAOB	protein	P27338	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11259630	f		miannu	Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2. 	SIGNOR-253868	0.277
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258591	0.8
BRCA2	protein	P51587	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates activity	binding			9606									17515904	t			We suggest that interactions of the BRCA2 C-terminal region with RAD51 may facilitate efficient nucleation of RAD51 multimers on DNA and thereby stimulate recombination-mediated repair.	SIGNOR-259905	0.945
F2	protein	P00734	UNIPROT	F5	protein	P12259	UNIPROT	up-regulates activity				9606		BTO:0000131							29880919	t		lperfetto	Thrombin also activates the cofactors FVIII (to FVIIIa) and FV (to FVa) and activates platelets such that they provide a procoagulant membrane surface to which these proteins then bind	SIGNOR-263530	0.877
MAPK14	protein	Q16539	UNIPROT	ELAVL1	protein	Q15717	UNIPROT	up-regulates	phosphorylation			9606									19528229	t		gcesareni	P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna.	SIGNOR-186138	0.538
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates	phosphorylation	Thr676	NQMQPDTtSVVKDSQ	9606									19120698	t		llicata	Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity	SIGNOR-183026	0.2
RUNX1	protein	Q01196	UNIPROT	HHEX	protein	Q03014	UNIPROT	up-regulates quantity	transcriptional regulation			9606									28213513	t			We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML.	SIGNOR-256305	0.275
MAP3K2	protein	Q9Y2U5	UNIPROT	MAP2K5	protein	Q13163	UNIPROT	up-regulates	phosphorylation			9606									12912994	t		gcesareni	Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5.	SIGNOR-104634	0.751
AKT1	protein	P31749	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	down-regulates activity	phosphorylation	Ser571	RMRSRSRsFSRHRSC	9606		BTO:0000759							17554339	t		lperfetto	Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1alpha At ser570 Is required for akt to inhibit recruitment of pgc-1alpha To chromatin.	SIGNOR-252502	0.459
PPP5C	protein	P53041	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates activity	dephosphorylation	Thr838	GINPCTEtFTGTLQY	9606	BTO:0000567								11689443	t		lperfetto	Pp5 directly dephosphorylated an essential phospho-threonine residue within the kinase domain of ask1 and thereby inactivated ask1 activity in vitro and in vivo.	SIGNOR-111301	0.584
MAPK3	protein	P27361	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Thr331	CTPVVTCtPSCTAYT								phosphorylation:Ser374;Ser362	PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS	16055710	t		lperfetto	Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos	SIGNOR-263008	0.707
MET	protein	P08581	UNIPROT	MET	protein	P08581	UNIPROT	up-regulates	phosphorylation	Tyr1234	RDMYDKEyYSVHNKT	9606									8302603	t		lperfetto	Previous work has shown that autophosphorylation of p190met enhances its enzymatic activity and that the major phosphorylation site is tyr1235, located in the catalytic domainonly the replacement of both tyr1234 and tyr1235 yielded a mutant which completely lost the ability to be activated by autophosphorylation	SIGNOR-37723	0.2
GATA1	protein	P15976	UNIPROT	ZNF268	protein	Q14587	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001271								22235304	f		miannu	Here we found that gata-1, a master regulator of erythropoiesis, repressed the promoter activity and transcription of znf268	SIGNOR-195410	0.38
BTRC	protein	Q9Y297	UNIPROT	PDCD4	protein	Q53EL6	UNIPROT	down-regulates	ubiquitination			9606	BTO:0000007	BTO:0001253							18296647	t		gcesareni	Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.	SIGNOR-160985	0.435
PIP3	smallmolecule	CHEBI:16618	ChEBI	ZFYVE1	protein	Q9HBF4	UNIPROT	up-regulates	chemical activation			9606									18725538	t		gcesareni	Dfcp1 contains two fyve domains (thus explaining its pi(3)p binding)	SIGNOR-180527	0.8
SLC12A2	protein	P55011	UNIPROT	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	relocalization			9606									26951057	t		miannu	As shown in Fig. 2, the intracellular Cl− concentration is regulated mainly by two cation-chloride cotransporters, NKCC1 and KCC2 [32]. NKCC1 imports Cl− whereas KCC2 extrudes intracellular Cl−. 	SIGNOR-264986	0.8
EPHA3	protein	P29320	UNIPROT	CRK	protein	P46108	UNIPROT	up-regulates	binding			9606	BTO:0000007								11870224	t		lperfetto	Our results suggest that recruitment of crkii and activation of rho signalling are responsible for epha3-mediated cell rounding, blebbing and de-adhesion, and that ephrin-a5-mediated receptor clustering and epha3 tyrosine kinase activity are essential for this response	SIGNOR-115335	0.609
MAPK3	protein	P27361	UNIPROT	DUSP6	protein	Q16828	UNIPROT	down-regulates	phosphorylation	Ser159	DGSCSSSsPPLPVLG	9606									15632084	t		amattioni	Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3	SIGNOR-132975	0.849
GSK3B	protein	P49841	UNIPROT	XIAP	protein	P98170	UNIPROT	up-regulates activity	phosphorylation	Thr180	WPDYAHLtPRELASA	9606	BTO:0002181								29678905	t		miannu	 We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAPT180A) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in Xenopus embryos. 	SIGNOR-277390	0.403
KAT2A	protein	Q92830	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	binding			9606	BTO:0000150		SIGNOR-C7						15009097	t		gcesareni	Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo.	SIGNOR-123315	0.342
PTPRE	protein	P23469	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Thr185	HDHTGFLtEYVATRW	9606									12754301	t		llicata	The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling|These enzymes are joined by the large family of dual-specificity phosphatases, which are structurally similar to tyrosine phosphatases but which can dephosphorylate both residues of the activation loop	SIGNOR-248449	0.398
CREB1	protein	P16220	UNIPROT	MUC4	protein	Q99102	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001861								19757157	f	 	lperfetto	Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level.	SIGNOR-254091	0.2
MC4R	protein	P32245	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257270	0.254
TP53	protein	P04637	UNIPROT	ETS1	protein	P14921	UNIPROT	down-regulates activity	binding			9606									14586398	t	 	miannu	We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. We show that ets-1 and p53 associate physically in vitro and in vivo and that their interaction, rather than a direct binding of p53 to the TXSA promoter, is required for transcriptional repression of TXSA by wild-type p53.	SIGNOR-254087	0.547
SMURF2	protein	Q9HAU4	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates activity	ubiquitination			9606									17317136	t		lperfetto	Recruitment of ww and hect domain e3-ubiquitin ligases smurf1 and 2 to induce type i receptor ubiquitination and subsequent receptor degradation;	SIGNOR-153423	0.698
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	PPM1J	protein	Q5JR12	UNIPROT	down-regulates	phosphorylation			9606									18553930	t	inferred from 70% family members	gcesareni	Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells.	SIGNOR-269981	0.2
UBR4	protein	Q5T4S7	UNIPROT	TRPV5	protein	Q9NQA5	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0003913								23747339	t		miannu	Cytomix induced interaction between TRPV5 and UBR4 (Ubiquitin recoginition 4), an E3 ubiquitin ligase; knockdown of UBR4 with small interfering RNAs prevented cytomix-induced degradation of TRPV5.  UBR4/p600 ubiquitin ligase is responsible for TRPV5 ubiquitination and proteasomal degradation in response to cytomix 	SIGNOR-272117	0.248
YAP1	protein	P46937	UNIPROT	CDC6	protein	Q99741	UNIPROT	up-regulates quantity by expression	transcriptional regulation					BTO:0001939							30224758	f		lperfetto	 By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 	SIGNOR-276564	0.273
MAPK3	protein	P27361	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates	phosphorylation	Ser294	DPRQAQSsPPWSYDQ	9606									19801668	t		llicata	In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation.	SIGNOR-188343	0.547
PAX7	protein	P23759	UNIPROT	MLL1 complex	complex	SIGNOR-C89	SIGNOR	up-regulates	binding			9606	BTO:0002314	BTO:0000887;BTO:0001103							22863532	t		lperfetto	Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5.	SIGNOR-217716	0.2
FBXO44	protein	Q9H4M3	UNIPROT	BRCA1	protein	P38398	UNIPROT	down-regulates quantity by destabilization	binding			-1									23086937	t		miannu	The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation. The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro.	SIGNOR-272037	0.376
CYCS	protein	P99999	UNIPROT	Oxidative_phosphorylation	phenotype	SIGNOR-PH78	SIGNOR	up-regulates				10090									23021218	f		lperfetto	PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). 	SIGNOR-253100	0.7
Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	CDKN2A	protein	Q8N726	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22469984	t		irozzo	The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a	SIGNOR-259360	0.345
BST1	protein	Q10588	UNIPROT	cyclic ADP-ribose	smallmolecule	CHEBI:31445	ChEBI	up-regulates quantity	chemical modification			9606									18626062	t		miannu	The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR.	SIGNOR-264248	0.8
AURKB	protein	Q96GD4	UNIPROT	NINL	protein	Q9Y2I6	UNIPROT	up-regulates	phosphorylation	Ser448	QGYRERLsLLRSEVE	9606									20864540	t		lperfetto	Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability.	SIGNOR-168049	0.255
PTPN2	protein	P17706	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									30230471	f		lperfetto	In keeping with the overall improvement in insulin sensitivity we found that insulin-induced IR Y1162/Y1163 tyrosine phosphorylation and activation and downstream PI3K/AKT signaling in the liver (as monitored by AKT Ser-473 phosphorylation) were dramatically enhanced by POMC TCPTP deficiency (Figure 4h).|This would suggest that TCPTP deletion, or decreased TCPTP in POMC neurons in response to feeding, represses HGP by enhancing IR signaling and permitting POMC neurons to be activated by insulin.	SIGNOR-276957	0.604
PPM1A	protein	P35813	UNIPROT	STING1	protein	Q86WV6	UNIPROT	down-regulates activity	dephosphorylation	Ser358	VPSTSTMsQEPELLI	9606									25815785	t		lperfetto	Collectively, our findings suggest that the overexpression of PPM1A antagonizes the STING- and TBK1-induced type I interferon signaling pathway.|First, PPM1A directly dephosphorylated STING, likely via its S358 site (Figs.|Moreover, our study demonstrates that while TBK1 enhances STING aggregation in a kinase activity-dependent manner, PPM1A suppresses STING aggregation by dephosphorylating both STING and TBK1.	SIGNOR-276958	0.2
CGP-42112A	chemical	CHEBI:147302	ChEBI	AGTR2	protein	P50052	UNIPROT	down-regulates activity	chemical inhibition			-1									32278693	t		Luana	CGP42112A is an angiotensin AT2 (Angiotensin receptor 2) receptor agonist that may alleviate the virus-induced lung injury	SIGNOR-262311	0.8
PTPN6	protein	P29350	UNIPROT	SH3BP2	protein	P78314	UNIPROT	down-regulates	dephosphorylation			9606									16649996	t		gcesareni	Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling	SIGNOR-146508	0.551
CSNK1E	protein	P49674	UNIPROT	CSNK1E	protein	P49674	UNIPROT	down-regulates activity	phosphorylation	Ser323	RMGQLRGsATRALPP	9606	BTO:0000007								10542239	t		llicata	Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T	SIGNOR-250807	0.2
CTDP1	protein	Q9Y5B0	UNIPROT	MASTL	protein	Q96GX5	UNIPROT	down-regulates activity	dephosphorylation	Ser90	DALALSKsPFIVHLY	9606									26653855	t		lperfetto	Taken together, these data suggest that Fcp1 bound and dephosphorylated Gwl at S90 and S453, and possibly at other Cdk1 dependent sites, during mitosis exit and that Fcp1 catalyzed dephosphorylation lowered Gwl activity towards Ensa and ARPP19, allowing PP2A-B55 to autoactivate.|Together, these data indicate that Fcp1 dependent dephosphorylation greatly reduces S67-Ensa kinase activity of Gwl and that, downstream inactivation of Cdk1, Fcp1 deficit substantially blunts inactivation of Gwl.	SIGNOR-276972	0.446
LMO3	protein	Q8TAP4	UNIPROT	NHLH2	protein	Q02577	UNIPROT	up-regulates activity	binding			9606									21573214	t		miannu	 Here we found that LMO3 forms a complex with HEN2 and acts as an upstream mediator for transcription of Mash1 in neuroblastoma.	SIGNOR-254827	0.421
MAOA	protein	P21397	UNIPROT	(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000142							20493079	t		Luana	The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied.	SIGNOR-269745	0.8
PTPRJ	protein	Q12913	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	dephosphorylation	Tyr419	RLIEDNEyTARQGAK	9606									22898603	t		lperfetto	In addition, our work further reveals that above a threshold expression level, DEP-1 can also dephosphorylate Src Y418 and attenuate downstream signaling and biologic responses, consistent with the quiescent behavior of confluent endothelial cells that express the highest levels of endogenous DEP-1.	SIGNOR-276978	0.622
SRC	protein	P12931	UNIPROT	WNK4	protein	Q96J92	UNIPROT	down-regulates activity	phosphorylation	Tyr1115	PVWMNYSySSLCLSS	9606	BTO:0002181								25805816	t		miannu	Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4. 	SIGNOR-276895	0.2
ATM	protein	Q13315	UNIPROT	PNKP	protein	Q96T60	UNIPROT	up-regulates	phosphorylation	Ser114	EETRTPEsQPDTPPG	9606									21824916	t		lperfetto	We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro.	SIGNOR-176008	0.476
PTPN1	protein	P18031	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	dephosphorylation			9606									18253097	t		lperfetto	The protein tyrosine phosphatase, PTP1B, is known to negatively regulate EGF-induced signaling in several cell types by dephosphorylating the epidermal growth factor receptor (EGFR).|Together, these findings provide evidence that PTP1B plays a role in the negative regulation of EGFR signaling in rat corneal endothelial cells, at least at the level of Tyr992 phosphorylation.	SIGNOR-276981	0.751
STK17A	protein	Q9UEE5	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606	BTO:0000776								17339337	t		gcesareni	Genetic and biochemical studies have shown that ser20 phosphorylation in the transactivation domain of p53 mediates p300-catalyzed dna-dependent p53 acetylation and b-cell tumor suppression. a cell-free ser20 phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser20 kinases.	SIGNOR-153532	0.291
PIAS4	protein	Q8N2W9	UNIPROT	RPA2	protein	P15927	UNIPROT	up-regulates	phosphorylation	Ser4	sGFESYGS	9606									20016603	t		gcesareni	Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation	SIGNOR-162160	0.2
PPM1D	protein	O15297	UNIPROT	CHEK1	protein	O14757	UNIPROT	down-regulates activity	dephosphorylation	Ser345	LVQGISFsQPTCPDH	9606									18265945	t		lperfetto	Because Chk1 phosphorylates and activates p53, the inhibition of Chk1 by Wip1 also places Wip1 in a negative feedback regulatory loop for p53 .|In vitro phosphatase assays showed that Wip1 dephosphorylated Chk1 at Ser345, but not Ser317.	SIGNOR-276986	0.487
PPM1F	protein	P49593	UNIPROT	CHEK1	protein	O14757	UNIPROT	down-regulates activity	dephosphorylation	Ser317	ENVKYSSsQPEPRTG	9606									31944151	t		lperfetto	As a result, inactivation of Chk1 by POPX2 leads to impaired G1S checkpoint activation and cells are able to proceed from G1 to S phase despite DNA damage.|We also determined that POPX2 can dephosphorylate Chk1Ser317 and -Ser345 and is a potential regulator of Chk1 function in the cell.	SIGNOR-276987	0.2
MAPK1	protein	P28482	UNIPROT	ALOX5	protein	P09917	UNIPROT	up-regulates activity	phosphorylation	Ser664	QLPYYYLsPDRIPNS	9606	BTO:0000567								12670876	t		lperfetto	Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells.	SIGNOR-264409	0.391
EXOC3	protein	O60645	UNIPROT	Exocyst_EXOC6B variant	complex	SIGNOR-C491	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270778	0.933
PTPN13	protein	Q12923	UNIPROT	EFNB1	protein	P98172	UNIPROT	up-regulates activity	dephosphorylation			9606									23811940	t		lperfetto	Loss of PTPN13 function increases EFNB1 phosphorylation, enhances EFNB1 's interaction with ERBB1 and correlates with potentiated ERK1/2 activation.|Moreover, acquisition of PTPN13 loss-of-function mutations or its decreased expression (due to HPV infection or epigenetic silencing) may further enhance ERBB1 and EFNB1 mediated signals.	SIGNOR-277002	0.697
PTPRO	protein	Q16827	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	dephosphorylation	Tyr419	RLIEDNEyTARQGAK	9606									25301722	t		lperfetto	SRC activation triggered by loss of PTPRO leads to c-CBL degradation.|These data corroborate that PTPRO directly dephosphorylates SRC at Y416.	SIGNOR-277004	0.434
DUSP6	protein	Q16828	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation			9606									20638106	t		lperfetto	Dual-specificity phosphatase six (DUSP6, MKP3, or PYST1) dephosphorylates phosphotyrosine and phosphothreonine residues on ERK-2 (MAPK1) to inactivate the ERK-2 kinase.	SIGNOR-277006	0.901
GSK3B	protein	P49841	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr46	GGTLFSTtPGGTRII	9606									23584478	t		lperfetto	Glycogen synthase kinase-3_ positively regulates protein synthesis and cell proliferation through the regulation of translation initiation factor 4E-binding protein 1We found that GSK-3_ phosphorylates and inactivates 4E-BP1, thereby increasing eIF4E-dependent protein synthesis.	SIGNOR-201699	0.373
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CCNE1	protein	P24864	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189978	0.8
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	MPO-ANCA	complex	SIGNOR-C474	SIGNOR	up-regulates quantity				9606		BTO:0000133							15972951	f		lperfetto	In the early phase, LPS enhanced anti-MPO IgG-induced glomerular neutrophil accumulation. |using bacterial lipopolysaccharide (LPS) as the proinflammatory stimulus.	SIGNOR-270586	0.7
UDP-D-galactose	smallmolecule	CHEBI:18307	ChEBI	lactose	smallmolecule	CHEBI:17716	ChEBI	up-regulates quantity	precursor of			9606									16157350	t		miannu	Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 	SIGNOR-268471	0.8
CTNNB1	protein	P35222	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	up-regulates activity	binding			9606	BTO:0000782								15735151	t		gcesareni	Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1	SIGNOR-134219	0.914
CSNK2A2	protein	P19784	UNIPROT	KIF1C	protein	O43896	UNIPROT	unknown	phosphorylation	Ser1092	PRMRRQRsAPDLKES	-1									10559254	t		llicata	Serine 1092 was a substrate for the protein kinase casein kinase II in vitro, and inhibition of casein kinase II in cells diminished the association of KIF1C with 14-3-3gamma. Our data thus suggest that KIF1C can form dimers and is associated with proteins of the 14-3-3 family.	SIGNOR-251010	0.314
CHUK	protein	O15111	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	down-regulates activity	phosphorylation	Ser436	TNGSIGHsPLSLSAQ	9606	BTO:0000938								24614225	t		lperfetto	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204700	0.524
ESR1	protein	P03372	UNIPROT	F12	protein	P00748	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								9794469	f	 	miannu	 Transcription of the FXII gene is stimulated by estrogens through specific interaction of the estrogen receptor alpha (ER alpha) with an estrogen response element present on FXII promoter. 	SIGNOR-254072	0.2
FBXO32	protein	Q969P5	UNIPROT	Protein_degradation	phenotype	SIGNOR-PH96	SIGNOR	up-regulates				10090									20871233	f			Atrogin-1, but not MuRF-1, was induced at both the gene and protein level as ApcMin/+ mice aged from 3 to 6 months of age, going from a pre-cachectic to a cachectic state. Atrogin-1 mRNA and protein levels were also elevated in ApcMin/+ mice when we over-expressed IL-6 in the circulation. 	SIGNOR-255341	0.7
STK38	protein	Q15208	UNIPROT	STK38	protein	Q15208	UNIPROT	up-regulates	phosphorylation	Thr74	SAHARKEtEFLRLKR	9606									12493777	t		lperfetto	We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo	SIGNOR-96687	0.2
P2RY2	protein	P41231	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257145	0.2
L-dopa	smallmolecule	CHEBI:15765	ChEBI	dopamine	smallmolecule	CHEBI:18243	ChEBI	up-regulates quantity	precursor of			9606									NBK536726	t	brain	lperfetto	Subsequently, L-DOPA is converted into 3,4-dihydroxyphenethylamine (dopamine) through decarboxylation by the enzyme L-3,4-dihydroxyphenylalanine decarboxylase (DOPA decarboxylase) in the pre-synaptic terminal	SIGNOR-264174	0.8
CD3G	protein	P09693	UNIPROT	CD3	complex	SIGNOR-C432	SIGNOR	form complex	binding			9606									12507424	t		miannu	The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.	SIGNOR-255296	0.634
PPM1G	protein	O15355	UNIPROT	SRSF3	protein	P84103	UNIPROT	down-regulates activity	dephosphorylation			9606									34290239	t		miannu	Here, we found that the PPM1G regulated SRSF3, and high levels of PPM1G decreased SRSF3 activity in HCC cells.|PPM1G interacted with SRSF3 and dephosphorylated SRSF3.	SIGNOR-277048	0.2
CDK4	protein	P11802	UNIPROT	MEF2D	protein	Q14814	UNIPROT	down-regulates	binding			9606			SIGNOR-C18						21902831	t		gcesareni	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-176524	0.283
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Thr41	GIHSGATtTAPSLSG	9606									23151663	t		lperfetto	Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells.	SIGNOR-227866	0.892
PP2Ca_R1A_Bd	complex	SIGNOR-C134	SIGNOR	RAF1	protein	P04049	UNIPROT	up-regulates activity	dephosphorylation	Ser259	SQRQRSTsTPNVHMV	9606	BTO:0000007								16239230	t		gcesareni	... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259.	SIGNOR-243538	0.496
TGFBR1	protein	P36897	UNIPROT	SERPINE1	protein	P05121	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									28520219	f		miannu	The transforming growth factor-β pathway is the major driver of fibrotic response. Plasminogen activator inhibitor-1 (PAI-1) is a crucial downstream target of this pathway. Transforming growth factor-β positively regulates PAI-1 gene expression via two main pathways including Smad-mediated canonical and non-canonical pathways.	SIGNOR-260590	0.444
IL12A	protein	P29459	UNIPROT	IL12RB1	protein	P42701	UNIPROT	up-regulates	binding			9606	BTO:0000782								12023369	t		gcesareni	Like il-12, il-23 binds to the il-12r subunit il-12rbeta1.	SIGNOR-87677	0.553
CDK1	protein	P06493	UNIPROT	USP24	protein	Q9UPU5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2047	QRVSDQNsPVLPKKS	9606	BTO:0000018								27991932	t		lperfetto	 Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604.	SIGNOR-275604	0.2
WNT5A	protein	P41221	UNIPROT	FZD5	protein	Q13467	UNIPROT	up-regulates	binding			9606									9054360	t		gcesareni	These results identify hfz5 as a receptor for wnt-5a.	SIGNOR-46897	0.826
GALR2	protein	O43603	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256884	0.425
IMP	smallmolecule	CHEBI:17202	ChEBI	GDP	smallmolecule	CHEBI:17552	ChEBI	up-regulates quantity	precursor of												10496970	t		miannu	Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP.	SIGNOR-268130	0.8
ANAPC4	protein	Q9UJX5	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	form complex	binding												16896351	t		lperfetto	The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex.	SIGNOR-252004	0.899
LYN	protein	P07948	UNIPROT	PAG1	protein	Q9NWQ8	UNIPROT	up-regulates activity	phosphorylation	Tyr417	LVPKENDyESISDLQ	9534									16920712	t		miannu	Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn.	SIGNOR-262899	0.714
ATG4B	protein	Q9Y4P1	UNIPROT	GABARAP	protein	O95166	UNIPROT	up-regulates activity	cleavage			-1									16303767	t		lperfetto	In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly	SIGNOR-141929	0.856
HNRNPH2	protein	P55795	UNIPROT	TERF2	protein	Q15554	UNIPROT	down-regulates quantity	post transcriptional regulation			10116	BTO:0001009								27117401	t		miannu	During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels.	SIGNOR-266806	0.34
DAB2IP	protein	Q5VWQ8	UNIPROT	PIK3R1	protein	P27986	UNIPROT	down-regulates activity	binding			9606									27858941	t		miannu	DAB2IP binds the p85 subunit of PI3K through its PR domain and prevents PI3K-p85 relocation from the cytoplasm to the membrane, a necessary step for PI3K activation and signaling to AKT. Notably, DAB2IP reinforces this inhibitory effect by directly binding AKT.2	SIGNOR-254757	0.286
RRAGB	protein	Q5VZM2	UNIPROT	RAGBC	complex	SIGNOR-C115	SIGNOR	form complex	binding			9606									20381137	t		gcesareni	Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant	SIGNOR-228176	0.783
HNF1B	protein	P35680	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								9671480	t	2	miannu	The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays.	SIGNOR-241320	0.311
RNF41	protein	Q9H4P4	UNIPROT	ERBB3	protein	P21860	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								12411582	t		miannu	Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3	SIGNOR-272599	0.679
HBB	protein	P68871	UNIPROT	EDN1	protein	P05305	UNIPROT	down-regulates activity				9606									8573884	f	Regulation of localization	miannu	Hb inhibitory activity toward ET-1 production might be related to Hb mediated endothelial oxidative injury.	SIGNOR-251766	0.279
AMPK	complex	SIGNOR-C15	SIGNOR	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates activity	phosphorylation	Thr178	NHNHRIRtNPAIVKT	10090		BTO:0001103							17609368	t		gcesareni	AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter	SIGNOR-228642	0.483
GSK3A	protein	P49840	UNIPROT	GPSM3	protein	Q9Y4H4	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser35	STTRPWRsAPPSPPP	9606	BTO:0000876								22843681	t		lperfetto	Co-immunoprecipitation of endogenous GPSM3 and 14-3-3 proteins from the human monocytic cell line THP-1 suggests basal phosphorylation of GPSM3 at serine 35 as potentially mediated by GSK3alpha. The GPSM3/14-3-3 interaction is seen to stabilize GPSM3 from degradation and also support the nuclear exclusion of both proteins. 	SIGNOR-264863	0.2
ZBTB20	protein	Q9HC78	UNIPROT	AFP	protein	P02771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								23776228	t		miannu	Zinc finger and BTB domain-containing 20 (ZBTB20), a member of BTB/POZ family, functions in neurogenesis and represses α-fetoprotein gene transcription in liver.	SIGNOR-266867	0.453
NMDA receptor_2A	complex	SIGNOR-C347	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264132	0.7
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser23	ARKRHAPsPEPAVQG	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276092	0.275
GSK3B	protein	P49841	UNIPROT	DPYSL5	protein	Q9BPU6	UNIPROT	up-regulates activity	phosphorylation	Thr516	TPLADTPtRPVTRHG	9606	BTO:0000938								25040932	t		lperfetto	The T516 phosphorylation was achieved by the glycogen synthase kinase-3beta (GSK-3beta), which can phosphorylate the wildtype protein but not the non-phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin-binding property of CRMP5. Therefore, CRMP5-induced growth inhibition is dependent on T516 phosphorylation through the GSK-3beta pathway.	SIGNOR-264835	0.406
PTPN6	protein	P29350	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	9606									10734133	t		flangone	Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1.	SIGNOR-75926	0.365
TET1	protein	Q8NFU7	UNIPROT	HOXA9	protein	P31269	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27708339	t		irozzo	Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9.	SIGNOR-259094	0.312
fulvestrant	chemical	CHEBI:31638	ChEBI	ESR2	protein	Q92731	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000150								12113237	t		miannu	Fulvestrant (Faslodex, formerly ICI 182,780) is a potent steroidal antiestrogen that mediates its effects by estrogen receptor downregulation.	SIGNOR-259304	0.8
F2RL1	protein	P55085	UNIPROT	RAB3A	protein	P20336	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254836	0.2
LMX1B	protein	O60663	UNIPROT	LMX1B/SFPQ/PSPC1 complex	complex	SIGNOR-C106	SIGNOR	form complex	binding			10090									23308148	t		miannu	LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo.	SIGNOR-223966	0.35
ULK3	protein	Q6PHR2	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								19878745	t		Manara	We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro. | Our data suggest that serine/threonine kinase ULK3 is involved in the SHH pathway as a positive regulator of GLI proteins.	SIGNOR-260797	0.662
DNMT3A	protein	Q9Y6K1	UNIPROT	CDKN2B	protein	P42772	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									26350239	f		miannu	Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family	SIGNOR-261509	0.355
BAX	protein	Q07812	UNIPROT	CYCS	protein	P99999	UNIPROT	up-regulates				9606									18097445	f		gcesareni	This process of mitochondrial outer membrane permeabilization (momp) results in the release of cycs.it is commonly thought that bax and bak form pores in membranes	SIGNOR-160039	0.687
LYN	protein	P07948	UNIPROT	CASP8	protein	Q14790	UNIPROT	down-regulates activity	phosphorylation	Tyr448	TILTEVNyEVSNKDD										18086677	t		lperfetto	The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. 	SIGNOR-272980	0.317
SRC	protein	P12931	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates activity	phosphorylation	Tyr900	EHAPAEMyDIMKTCW	9606									12878163	t		lperfetto	C-src phosphorylates tyr900 in the second part of the kinase domain of c-kit.	SIGNOR-103999	0.395
TEAD1	protein	P28347	UNIPROT	MSLN	protein	Q13421	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17909009	f	 	miannu	 The presence of TEF-1 was required for MSLN protein overexpression as determined by TEF-1 knockdown experiments.	SIGNOR-255395	0.286
SETD1B	protein	Q9UPS6	UNIPROT	H3-4	protein	Q16695	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606									32546567	t		miannu	SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks.	SIGNOR-265577	0.2
RPS6	protein	P62753	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262418	0.882
JUN	protein	P05412	UNIPROT	DDIT3	protein	P35638	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									19299913	f	 	lperfetto	Promoter deletion and reporter analysis revealed that hypoxia transcriptionally activates a GADD153 promoter through the AP-1 element in neonatal cardiomyocytes. Ectopic overexpression of GADD153 resulted in the downregulation of CARP expression.	SIGNOR-254123	0.596
CLU	protein	P10909	UNIPROT	SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	up-regulates activity	binding			9606	BTO:0001321								20068069	t		miannu	CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation.	SIGNOR-271429	0.318
ECM	stimulus	SIGNOR-ST20	SIGNOR	A3/b1 integrin	complex	SIGNOR-C161	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259044	0.7
CDC25A	protein	P30304	UNIPROT	FOXO1	protein	Q12778	UNIPROT	up-regulates activity	dephosphorylation			9606									21670150	t		miannu	In this study, we revealed that Cdc25A enhances Foxo1 stability by dephosphorylating Cdk2, and Foxo1 was shown to directly regulate transcription of the metastatic factor MMP1.	SIGNOR-277139	0.319
KMT2E	protein	Q8IZD2-8	UNIPROT	NCR2	protein	O95944	UNIPROT	up-regulates activity	binding			9606	BTO:0000737								23958951	t		miannu	We identify natural cytotoxicity receptor NKp44 (NKp44L), a novel isoform of the mixed-lineage leukemia-5 protein, as a cellular ligand for NKp44. Unlike the other MLL family members, NKp44L is excluded from the nucleus, but expressed at the cell-surface level; its subcellular localization is being associated with the presence of a specific C-terminal motif. Strikingly, NKp44L has not been detected on circulating cells isolated from healthy individuals, but it is expressed on a large panel of the tumor and transformed cells. 	SIGNOR-260042	0.52
CEBPA	protein	P49715	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								8075306	f	 	 	Transactivation by the CCAAT/enhancer binding protein alpha of the wild-type and mutated factor IX promoter (-192 to +38) resulted in an approximately four-fold and approximately two-fold, respectively, increase of CAT activity	SIGNOR-254040	0.291
GSK3B	protein	P49841	UNIPROT	MAML1	protein	Q92585	UNIPROT	down-regulates	phosphorylation			9606									19740771	t		gcesareni	We found that gsk3beta inhibits maml1 transcriptional activity by directly targeting the n-terminal domain of maml1	SIGNOR-187896	0.2
dacomitinib	chemical	CHEBI:132268	ChEBI	ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	down-regulates	chemical inhibition			9606									23405260	t	inferred from 70% of family members	gcesareni	The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor.	SIGNOR-269871	0.8
GRM5	protein	P41594	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening.	SIGNOR-264936	0.8
AKT1	protein	P31749	UNIPROT	FANCA	protein	O15360	UNIPROT	unknown	phosphorylation	Ser1149	CLRSRDPsLMVDFIL	-1									11855836	t			FANCA is phosphorylated at Ser1149 by Akt. The biological significance of FANCA phosphorylation and its regulation by Akt remains unclear at this time.	SIGNOR-252567	0.471
TRAF6	protein	Q9Y4K3	UNIPROT	ULK1	protein	O75385	UNIPROT	up-regulates quantity by stabilization	ubiquitination			9606	BTO:0000007								23524951	t		lperfetto	AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. 	SIGNOR-273000	0.532
OXTR	protein	P30559	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606									30739093	t		miannu	OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq).	SIGNOR-270332	0.533
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	FOXO4	protein	P98177	UNIPROT	up-regulates	phosphorylation	Ser230	PEGATPTsPVGHFAK	9606	BTO:0000848	BTO:0001253							20959475	t		lperfetto	Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451).	SIGNOR-168754	0.2
MAP4K3	protein	Q8IVH8	UNIPROT	MAP4K3	protein	Q8IVH8	UNIPROT	up-regulates	phosphorylation	Ser170	ATIAKRKsFIGTPYW	9606									20227368	t		gcesareni	We identify a transautophosphorylation site in the map4k3 kinase activation segment (ser170) that is required for map4k3 activity and its activation of mtorc1 signaling.	SIGNOR-164103	0.2
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	ID2	protein	Q02363	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18025157	f			Also comparable with ID1, RARα, RXR, PML, PLZF-RARα, and RARα/RXR did not transactivate the ID2 promoter, whereas PML-RARα did. Together, these data show that like ID1, ID2 may also be transactivated by PML-RARα without direct DNA binding of the fusion protein.	SIGNOR-255727	0.2
LRRK1	protein	Q38SD2	UNIPROT	CLIP1	protein	P30622	UNIPROT	up-regulates activity	phosphorylation	Thr1430	EMFGHWAtNCNDDET										25413345	t	Phosphosite positions are derived from Figure 1	lperfetto	LRRK1 phosphorylates CLIP-170 at Thr1384, located in its C-terminal zinc knuckle motif, and this promotes the association of CLIP-170 with dynein-dynactin complexes.	SIGNOR-275469	0.409
4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine	chemical	CHEBI:91419	ChEBI	CDK1	protein	P06493	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190176	0.8
ESR1	protein	P03372	UNIPROT	SCN9A	protein	Q15858	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938	BTO:0001264							22169964	f		miannu	17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice	SIGNOR-253469	0.2
ATG4B	protein	Q9Y4P1	UNIPROT	GABARAPL2	protein	P60520	UNIPROT	up-regulates activity	cleavage			-1									16303767	t		lperfetto	In mammals, at least three atg8 homologs, lc3, gabarap, and gate-16, have been identified (fig. 1a), all of which have structural ubiquitin folds (1416). In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly	SIGNOR-141932	0.838
EGLN3	protein	Q9H6Z9	UNIPROT	BCL2L11	protein	O43521-1	UNIPROT	up-regulates quantity by stabilization	hydroxylation	Pro67	PQGPLAPpASPGPFA	9606									31375625	t		lperfetto	EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance|EglN3 Hydroxylates BIM-EL at the Proline67/70 Residues	SIGNOR-262003	0.257
HCRTR2	protein	O43614	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256729	0.252
CCL7	protein	P80098	UNIPROT	Macrophage_activation	phenotype	SIGNOR-PH126	SIGNOR	up-regulates				10090									32283152	f		miannu	The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages.	SIGNOR-260850	0.7
BDKRB2	protein	P30411	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256695	0.357
DIAPH1	protein	O60610	UNIPROT	CDH4	protein	P55283	UNIPROT	up-regulates activity				9606	BTO:0000815								22820501	t		lperfetto	Taken together, data obtained from MCF10A cells were consistent with the idea that Rho signaling to Dia1 and profilin-1 was essential for R-cadherin adherens junction formation.	SIGNOR-253110	0.2
TGFBR1	protein	P36897	UNIPROT	VPS39	protein	Q96JC1	UNIPROT	up-regulates activity	binding			9534									12941698	t		miannu	TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling.	SIGNOR-261375	0.2
DAPK3	protein	O43293	UNIPROT	MYL12B	protein	O14950	UNIPROT	up-regulates	phosphorylation	Thr19	KKRPQRAtSNVFAMF	9606									12429016	t		gcesareni	Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge.	SIGNOR-95524	0.526
MAPKAPK2	protein	P49137	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation			9606									17292828	t		amattioni	Mk2 was required for the degradation of cdc25a. Mk2 phosphorylates cdc25a in vitro. Phosphorylation of cdc25a in vivo has been shown to facilitate its ubiquitin-mediated proteolysis	SIGNOR-152996	0.372
PIK3C3	protein	Q8NEB9	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	relocalization			9606									10698680	t		lperfetto	One of the best characterized targets of pi3k lipid products is the protein kinase akt or protein kinase b (pkb). In quiescent cells, pkb resides in the cytosol in a low-activity conformation. Upon cellular stimulation, pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1).	SIGNOR-252632	0.446
ziprasidone	chemical	CHEBI:10119	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029									9760039	t		miannu	Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3).	SIGNOR-258833	0.8
MAPK3	protein	P27361	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates	phosphorylation	Thr43	KVTTVVAtPGQGPDR	9606	BTO:0000150;BTO:0000680								16039586	t		lperfetto	Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin.	SIGNOR-138898	0.299
MBTPS1	protein	Q14703	UNIPROT	SREBF1	protein	P36956	UNIPROT	up-regulates activity	cleavage			10029	BTO:0000246								10644685	t			We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2	SIGNOR-267497	0.544
UBE3A	protein	Q05086	UNIPROT	SIPA1L1	protein	O43166	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									12036950	t		miannu	 the purified E6AP enhanced the ubiquitination and degradation of E6TP1 in the presence of E6 in vitro. Additionally, the expression of a dominant-negative E6AP mutant (C833A) in cells inhibited the E6-induced degradation of E6TP1. These findings demonstrate that the E6-induced decrease in the levels of E6TP1 protein involves the E6AP-mediated ubiquitination followed by proteasome-dependent degradation.	SIGNOR-272608	0.374
SP1	protein	P08047	UNIPROT	SLC9A3	protein	P48764	UNIPROT	up-regulates quantity by expression	transcriptional regulation			7227	BTO:0001677								16464174	f	 	 	Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity	SIGNOR-254270	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	up-regulates				9606									20640476	f		lperfetto	The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes.	SIGNOR-209929	0.7
EEF1A2	protein	Q05639	UNIPROT	Leu-tRNA(Leu)	smallmolecule	CHEBI:16624	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269533	0.8
MAPK3	protein	P27361	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser106	PLNSVSPsPLMLLHP	9606	BTO:0000567								17615152	t		gcesareni	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity	SIGNOR-156864	0.692
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	Macrophage_differentiation	phenotype	SIGNOR-PH99	SIGNOR	up-regulates				9606									24890514	f		apalma	The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ∼5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation	SIGNOR-255573	0.7
FASN	protein	P49327	UNIPROT	Lipogenesis	phenotype	SIGNOR-PH30	SIGNOR	up-regulates				9606									20373869	f		lperfetto	Fatty acid synthase (FASN) is a key enzyme involved in neoplastic lipogenesis	SIGNOR-242874	0.7
PCSK5	protein	Q92824	UNIPROT	Neurophysin 1	protein	P01178-PRO_0000020496	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0001073								11690596	t		miannu	Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension.	SIGNOR-270336	0.2
CDK1	protein	P06493	UNIPROT	WAC	protein	Q9BTA9	UNIPROT	up-regulates activity	phosphorylation	Thr244	AETHSSStPVQHPIK	9606	BTO:0000567								30021153	t		lperfetto	Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. 	SIGNOR-265032	0.2
CSNK2A2	protein	P19784	UNIPROT	SPIB	protein	Q01892	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser129	PYPSPVLsEEEDLPL	9606	BTO:0000567								10618498	t		llicata	Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo	SIGNOR-251039	0.311
FLT3	protein	P36888	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates activity	phosphorylation	Tyr88	KGSLPEFyYRPPRPP	10090	BTO:0001516								28522571	t		lperfetto	FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin-dependent kinase inhibitor p27 Kip1 in acute myeloid leukemia|P27Kip1 (p27) can prevent cell proliferation by inactivating cyclin-dependent kinases. This function is impaired upon phosphorylation of p27 at tyrosine residue 88.	SIGNOR-269208	0.295
ZSTK-474	chemical	CHEBI:90545	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252646	0.8
PCDH19	protein	Q8TAB3	UNIPROT	GABA-A	proteinfamily	SIGNOR-PF61	SIGNOR	up-regulates quantity by stabilization	binding			10116	BTO:0003102								29360992	t		miannu	Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons. 	SIGNOR-267216	0.2
PRKACA	protein	P17612	UNIPROT	AANAT	protein	Q16613	UNIPROT	up-regulates activity	phosphorylation	Thr31	PSCQRRHtLPASEFR	-1									11336675	t		miannu	AANAT1201 is phosphorylated at Thr-31 by PKA, it binds to 14-3-3. regulation is achieved by binding to 14-3-3, which structurally modulates the substrate binding sites, leading to measurable effects on the affinity of AANAT for its substrates with an accompanying increase in activity at low substrate concentrations. 	SIGNOR-250325	0.325
MC3R	protein	P41968	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257298	0.252
HAUS6	protein	Q7Z4H7	UNIPROT	NEDD1	protein	Q8NHV4	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								19029337	t		miannu	FAM29A recruits NEDD1 to spindle MTs. Ectopically expressed NEDD1 and FAM29A interact with each other. 	SIGNOR-261421	0.807
UCK2	protein	Q9BZX2	UNIPROT	cytidine 5'-monophosphate(2-)	smallmolecule	CHEBI:60377	ChEBI	up-regulates quantity	chemical modification												11306702	t		lperfetto	Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. 	SIGNOR-275861	0.8
FBXW7	protein	Q969H0	UNIPROT	ZNF322	protein	Q6U7Q0	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002552						phosphorylation:Ser391;Ser396	SEKGLELsPPHASEA;ELSPPHAsEASQMS	28581525	t		lperfetto	CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction. 	SIGNOR-264898	0.2
AKT1	protein	P31749	UNIPROT	CCT2	protein	P78371	UNIPROT	unknown	phosphorylation	Ser260	GSRVRVDsTAKVAEI	9606									19332537	t		llicata	Furthermore, ha-tagged akt can phosphorylate gst-cct_ protein in vitro	SIGNOR-184922	0.2
SMURF	proteinfamily	SIGNOR-PF29	SIGNOR	SMAD5	protein	Q99717	UNIPROT	down-regulates	ubiquitination			9606									22298955	t	inferred from 70% family members	gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-270213	0.2
DOK7	protein	Q18PE1	UNIPROT	CRKL	protein	P46109	UNIPROT	up-regulates activity	binding			10090	BTO:0000165								20603078	t		miannu	Here, we identify two tyrosine residues in Dok-7 that are phosphorylated by Agrin stimulation, and show that two proteins, Crk and Crk-L, are recruited to these phosphorylation sites in Dok-7.	SIGNOR-273848	0.351
AKT1	protein	P31749	UNIPROT	CARD11	protein	Q9BXL7	UNIPROT	up-regulates activity	phosphorylation	Ser644	NLMFRKFsLERPFRP	-1									24548923	t		miannu	Here we show that Akt-mediated NF-κB activation is mediated at least in part through direct phosphorylation of the adaptor protein Carma1, which we previously demonstrated could interact with Akt in a TCR ligation-dependent manner. The putative Akt phosphorylation sites in Carma1 are distinct from known PKC consensus sites. Mutation of S551, S637 and S645 in Carma1 to non-phosphorylatable residues decreased phosphorylation of GST-Carma1-linker construct by Akt in vitro. 	SIGNOR-276255	0.538
EP300	protein	Q09472	UNIPROT	MN1	protein	Q10571	UNIPROT	up-regulates	binding			9606									12569362	t		miannu	Our results indicate that mn1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate rar/rxr-mediated transcription through interaction with p160 and p300.	SIGNOR-97899	0.348
GTF2H2	protein	Q13888	UNIPROT	TFIIH	complex	SIGNOR-C457	SIGNOR	form complex	binding			9606									30860024	t		lperfetto	Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 	SIGNOR-269311	0.861
MECP2	protein	P51608	UNIPROT	SST	protein	P61278	UNIPROT	up-regulates quantity by expression	post transcriptional regulation			10090									18511691	t		Luana	MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.	SIGNOR-264676	0.302
CASP3	protein	P42574	UNIPROT	GORASP1	protein	Q9BQQ3	UNIPROT	down-regulates quantity by destabilization	cleavage	Asp317	VSGISLLdNSNASVW	9606	BTO:0000567								11815631	t		Giulio	Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage	SIGNOR-260602	0.405
MAP3K7	protein	O43318	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	up-regulates	phosphorylation			9606									11460167	t		lperfetto	Tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a	SIGNOR-217445	0.717
PPP3CC	protein	P48454	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser268	VALPPGAsPQRSRSP	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248519	0.386
PDPK1	protein	O15530	UNIPROT	SGK2	protein	Q9HBY8	UNIPROT	up-regulates	phosphorylation			9606									15209375	t		gcesareni	One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.	SIGNOR-126177	0.581
(S)-malate(2-)	smallmolecule	CHEBI:15589	ChEBI	pyruvate	smallmolecule	CHEBI:15361	ChEBI	up-regulates quantity	precursor of			9606									33064660	t		miannu	Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP.	SIGNOR-267721	0.8
SUFU	protein	Q9UMX1	UNIPROT	GLIS2	protein	Q9BZE0	UNIPROT	down-regulates	relocalization			9606	BTO:0001130								16316410	t		gcesareni	Negative regulation of gli1 and gli2 activator function by suppressor of fused through multiple mechanisms.Together, these observations reveal that su(fu) regulates the activity of gli1 and gli2 through distinct cytoplasmic and nuclear mechanisms.	SIGNOR-142608	0.269
SOX4	protein	Q06945	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	down-regulates				9606	BTO:0001271								24183681	f		apalma	Collectively, our experiments identified the oncogene Sox4 as a factor mediating increased serial-replating ability and blocked differentiation of Cebpa-deficient progenitors.	SIGNOR-255676	0.7
PRKCZ	protein	Q05513	UNIPROT	MARK2	protein	Q7KZI7	UNIPROT	down-regulates	phosphorylation	Thr596	RGVSSRStFHAGQLR	9606									15084291	t		lperfetto	Hpar-1b is phosphorylated by apkc on threonine 595 importantly, phosphorylation of hpar-1b on t595 negatively regulates the kinase activity and plasma membrane localization of hpar-1b in vivo.	SIGNOR-124217	0.269
NARS2	protein	Q96I59	UNIPROT	tRNA(Asn)	smallmolecule	CHEBI:29172	ChEBI	down-regulates quantity	chemical modification			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270461	0.8
AURKA	protein	O14965	UNIPROT	WDR62	protein	O43379	UNIPROT	up-regulates activity	phosphorylation	Ser33	PARRGQSsPPPAPPI	-1									25501809	t		lperfetto	AURKA activity promotes WDR62 spindle localization|We next purified recombinant full-length WDR62 (GST–WDR62-FL) for in vitro kinase assays with active AURKA and demonstrated that WDR62 was a direct phosphorylation target of AURKA|In addition, our quantitative phosphoproteomic analysis of in-vitro-phosphorylated WDR62 identified S32 and S33 as significantly phosphorylated in the presence of active AURKA|Alanine replacement of the five putative phosphorylation sites (S32/S33/S49/T50/S52-AAAAA) of WDR62 attenuated interphase microtubule association induced by AURKA coexpression	SIGNOR-271713	0.359
PIK3CA	protein	P42336	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates				9606									21779497	f		gcesareni	Pi3k can also activate rac, and this activation is involved in cytoskeleton reorganization.	SIGNOR-175238	0.551
E2F1	protein	Q01094	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253855	0.508
PKN1	protein	Q16512	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates	phosphorylation			9606									17251915	t		gcesareni	At the same time, rho signals to c-jun n-terminal kinase (jnk) and p38 through rock and protein kinase n (pkn), leading to the transcriptional regulation of jun	SIGNOR-152765	0.385
CSNK2A1	protein	P68400	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates	phosphorylation	Ser288	PESEDEEsYDTESEF	9606	BTO:0000782								8622692	t		llicata	Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation.	SIGNOR-40506	0.566
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	up-regulates quantity	precursor of			9606									8755651	t		scontino	Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5’-position) to yield T3	SIGNOR-266948	0.8
RIPK1	protein	Q13546	UNIPROT	FAS	protein	P25445	UNIPROT	up-regulates activity	binding			9606									18545270	t		lperfetto	The death domain of the rip1 kinase binds to death receptors such as fas that is required for caspase 8 activation and apoptosis	SIGNOR-177949	0.637
MAPK8IP2	protein	Q13387	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates	binding			9606									9733513	t		gcesareni	Thus, both jip1 and jip2 selectively bind the mapkk isoform mkk7.	SIGNOR-59944	0.668
GLUD1	protein	P00367	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	chemical modification			9913									11254391	t			Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate.	SIGNOR-266916	0.8
KLF8	protein	O95600	UNIPROT	HBB	protein	P68871	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000944								10756197	t		Luana	These results establish KLF8 as a CACCC-box binding protein that associates with CtBP and represses transcription.	SIGNOR-266052	0.2
IGF1R	protein	P08069	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates	phosphorylation			9606									21798082	t		gcesareni	Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor.	SIGNOR-175665	0.864
BIRC3	protein	Q13489	UNIPROT	BIRC2	protein	Q13490	UNIPROT	up-regulates activity	binding			9606									23070005	t		amattioni	Ligand-stimulated aggregation of receptor complexes causes recruitment of multiple traf2 trimers, which in turn leads to cIAP1 or cIAP2 dimerization.	SIGNOR-199088	0.473
EP300	protein	Q09472	UNIPROT	MAML1	protein	Q92585	UNIPROT	up-regulates	acetylation			9606									17300219	t		gcesareni	The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin. Furthermore, p300 acetylates maml1 and evolutionarily conserved lysine residues in the maml1 n-terminus are direct substrates for p300-mediated acetylation.	SIGNOR-153035	0.635
TXK	protein	P42681	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates	phosphorylation	Tyr145	PVEDDADyEPPPSND	9606	BTO:0000782								10660534	t		lperfetto	Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function	SIGNOR-74848	0.717
GABA-A	proteinfamily	SIGNOR-PF61	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000227							18790874	f		miannu	Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS).	SIGNOR-264970	0.7
MDK	protein	P21741	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	up-regulates	binding			9606									18469519	t		gcesareni	We showed that mk binds to the notch2 receptor in hacat keratinocytes. We further found that mk activates notch2	SIGNOR-161427	0.469
MAPK7	protein	Q13164	UNIPROT	KLF4	protein	O43474	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23612709	f		miannu	The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 	SIGNOR-255455	0.442
L-ornithine	smallmolecule	CHEBI:15729	ChEBI	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates activity													25386178	f		apalma	In general, M2 type macrophages act as anti-inflammatory cells via diversion of arginine away from NOS or via the synthesis of downstream products derived from the ornithine that is generated via arginase	SIGNOR-256075	0.7
ponatinib	chemical	CHEBI:78543	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206277	0.8
CDK2	protein	P24941	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	down-regulates	phosphorylation	Thr491	PQQRNALtPTTIPDG	9606									18769144	t		lperfetto	Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively	SIGNOR-180767	0.249
SIRT7	protein	Q9NRC8	UNIPROT	H3-5	protein	Q6NXT2	UNIPROT	up-regulates activity	deacetylation	Lys19	TGGKAPRkQLATKAA										22722849	t		lperfetto	SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. 	SIGNOR-275873	0.2
FYN	protein	P06241	UNIPROT	BCR-Dl	complex	SIGNOR-C436	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000776								32323266	t		scontino	The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases.	SIGNOR-268216	0.619
bromocriptine	chemical	CHEBI:3181	ChEBI	DRD3	protein	P35462	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258722	0.8
PPP1R1B	protein	Q9UD71	UNIPROT	PP1	proteinfamily	SIGNOR-PF54	SIGNOR	down-regulates activity	binding			9606	BTO:0000938								10604473	t	inferred from 70% of family members	miannu	DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚ 	SIGNOR-269869	0.674
PTPRB	protein	P23467	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates	dephosphorylation	Tyr1356	YVHVNATyVNVKCVA	9606									21454675	t		gcesareni	Receptor-type protein tyrosine phosphatase beta (rptp-beta) directly dephosphorylates and regulates hepatocyte growth factor receptor (hgfr/met) function.	SIGNOR-173004	0.371
ALDH5A1	protein	P51649	UNIPROT	4-oxobutanoate	smallmolecule	CHEBI:57706	ChEBI	down-regulates quantity	chemical modification			9606									19300440	t		miannu	Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix.	SIGNOR-266616	0.8
PRKACA	protein	P17612	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates	phosphorylation	Ser17	DASQRRRsLEPAENV	9606									11804588	t		llicata	Pka activated src both in vitro and in vivo by phosphorylating src on serine 17	SIGNOR-114277	0.367
APC	protein	P25054	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	form complex	binding			9606									9734785	t		lperfetto	Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level.	SIGNOR-227296	0.846
SPOP	protein	O43791	UNIPROT	INF2	protein	Q27J81	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								28448495	t		miannu	SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J). 	SIGNOR-272798	0.2
SMARCB1	protein	Q12824	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	form complex	binding			9606									15627498	t		miannu	We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers.	SIGNOR-132930	0.894
nintedanib	chemical	CHEBI:85164	ChEBI	FGFR2	protein	P21802	UNIPROT	down-regulates activity	chemical inhibition			-1									18559524	t		Luana	In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers.	SIGNOR-257806	0.8
LLGL2	protein	Q6P1M3	UNIPROT	Scribble_complex_DLG5-LLGL2_variant	complex	SIGNOR-C506	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270891	0.471
FYN	protein	P06241	UNIPROT	PTPRF	protein	P10586	UNIPROT	up-regulates activity	phosphorylation			9534									12496362	t			LAR PTPase domain 2 was tyrosine phosphorylated by Fyn tyrosine kinase. we confirmed that LAR dephosphorylated the phosphorylated tyrosine residues of Lck and Fyn, and tyrosine residue(s) in LAR PTPase D2 was phosphorylated by Fyn to supply Fyn SH2 binding site. 	SIGNOR-251180	0.405
SUZ12	protein	Q15022	UNIPROT	SUZ12/EZH2	complex	SIGNOR-C77	SIGNOR	form complex	binding			9606									16712789	t		miannu	Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2.	SIGNOR-146764	0.96
ASTN2	protein	O75129	UNIPROT	ASTN1	protein	O14525	UNIPROT	down-regulates quantity	binding			9606	BTO:0000007								20573900	t		miannu	Biochemical and flow cytometry experiments show that ASTN2 forms a complex with ASTN1 and regulates surface expression of ASTN1. Coexpression with ASTN2 reduces the cell surface localization of ASTN1. 	SIGNOR-269813	0.2
AKT1	protein	P31749	UNIPROT	TERT	protein	O14746	UNIPROT	up-regulates	phosphorylation	Ser227	GARRRGGsASRSLPL	9606									10224060	t		gcesareni	Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins.	SIGNOR-67313	0.722
RUNX1	protein	Q01196	UNIPROT	ELANE	protein	P08246	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004850								14594802	f		miannu	We find that LEF-1 and CBFalpha co-activate ELA2 expression.	SIGNOR-254553	0.325
ENSA	protein	O43768	UNIPROT	PPP2R2D	protein	Q66LE6	UNIPROT	down-regulates activity	binding			-1					phosphorylation:Ser67	KGQKYFDsGDYNMAK			21164014	t		gcesareni	We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry.	SIGNOR-243735	0.76
CSNK2A1	protein	P68400	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000661								15818404	t		lperfetto	Akt/pkb ser129 is phosphorylated by ck2 in vitro and in vivo;(4) such a phosphorylation of activated akt/pkb correlates with a further increase in catalytic activity.	SIGNOR-244400	0.379
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ARHGAP31	protein	Q2M1Z3	UNIPROT	up-regulates activity	phosphorylation	Thr789	PPAPPPPtPLEESTP	9534	BTO:0000298								16024771	t		miannu	CdGAP interacts with and is phosphorylated by ERK-1 and RSK-1 in vitro. A putative DEF (docking for ERK FXFP) domain located in the proline-rich region of CdGAP is required for efficient binding and phosphorylation by ERK1/2. We identify Thr776 as an in vivo target site of ERK1/2 and as an important regulatory site of CdGAP activity. Together, these data suggest that CdGAP is a novel substrate of ERK1/2 and mediates cross talk between the Ras/mitogen-activated protein kinase pathway and regulation of Rac1 activity.	SIGNOR-263057	0.2
TOMM6	protein	Q96B49	UNIPROT	TOM40 complex	complex	SIGNOR-C421	SIGNOR	form complex	binding			9606	BTO:0000567								18331822	t		lperfetto	The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex.	SIGNOR-267676	0.622
GPAA1	protein	O43292	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32432756	f		miannu	GPAA1 may contribute to the malignant progression of childhood ALL via activating c-myc. Luciferase reporter gene assay demonstrated that overexpression of c-myc remarkably attenuated the Luciferase activity of the wild-type GPAA1 vector without attenuating that of the mutant vector or empty vector, further demonstrating that GPAA1 can be targeted by c-myc. 	SIGNOR-261240	0.2
MAPK3	protein	P27361	UNIPROT	WWC1	protein	Q8IX03	UNIPROT	unknown	phosphorylation	Ser548	SSPSPPCsPLMADPL	9606		BTO:0000149							24269383	t		llicata	We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro.	SIGNOR-203290	0.273
PIAS1	protein	O75925	UNIPROT	FHL1	protein	Q13642	UNIPROT	down-regulates	sumoylation	Lys300	PRGPGLVkAPVWWPM	9606									17509614	t		gcesareni	Pias1 (the protein inhibitor of activated stat1) interacts with kyot2 directly and attenuates kyot2-mediated transcriptional repression. We demonstrate that kyot2 is modified by sumoylation at two lysine residues, k144 and k171. Sumoylation of the transfected kyot2 is enhanced by pias1	SIGNOR-154805	0.259
RUNX3	protein	Q13761	UNIPROT	ING4	protein	Q9UNL4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002384								17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255096	0.2
CCKAR	protein	P32238	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257303	0.441
IFNGR2/INFGR1	complex	SIGNOR-C142	SIGNOR	JAK2	protein	O60674	UNIPROT	up-regulates activity	binding			9606	BTO:0000801								23898330	t		lperfetto	In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation	SIGNOR-249506	0.695
ID1	protein	P41134	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	binding			9606	BTO:0004136								26084673	t		apalma	We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation;	SIGNOR-255658	0.341
TLR4	protein	O00206	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates activity	phosphorylation			9606									28137827	t		miannu	Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation.	SIGNOR-261928	0.427
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1647	SPSYSPTsPSYSPTS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248737	0.727
TGFBR1	protein	P36897	UNIPROT	PIK3R2	protein	O00459	UNIPROT	up-regulates	binding			9606									9435577	t		lperfetto	These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells.	SIGNOR-227531	0.349
EIF3I	protein	Q13347	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates	binding			9606									9774674	t		gcesareni	Another receptor-associated protein is trip-1, which interacts with and is phosphorylated by tbrii and contains five wd-40 repeats. The association of wd-40 repeat proteins may then allow them to play a role in signaling by the serine/threonine kinase receptors.	SIGNOR-60700	0.329
Neuronal AP-3	complex	SIGNOR-C445	SIGNOR	Platelet_dense_granule_formation	phenotype	SIGNOR-PH181	SIGNOR	up-regulates				9606	BTO:0000132								12019270	f		miannu	BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton.	SIGNOR-268523	0.7
PLEKHG4B	protein	Q96PX9	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260565	0.288
CDK1	protein	P06493	UNIPROT	TSC1	protein	Q92574	UNIPROT	down-regulates	phosphorylation	Ser584	ETSIFTPsPCKIPPP	9606	BTO:0000680;BTO:0001573;BTO:0001286		SIGNOR-C17						14551205	t		lperfetto	Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex	SIGNOR-118576	0.503
CLASP1	protein	Q7Z460	UNIPROT	CLIP1	protein	P30622	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								15631994	t		lperfetto	CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. 	SIGNOR-265091	0.715
POLR1A	protein	O95602	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding												22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266152	0.836
MAPK13	protein	O15264	UNIPROT	EEF2K	protein	O00418	UNIPROT	down-regulates	phosphorylation	Ser359	GTEEKCGsPQVRTLS	9606									18337751	t		gcesareni	The phosphorylation of eef2k at ser359 is of particular interest. First, the phosphorylation of this site strongly decreases the activity of eef2k even at high calcium concentrations (knebel et al, 2001), that is, desensitizes eef2k to the activating effects of elevated ca2+ levels. third, although p38 map kinase (also termed sapk4 can phosphorylate ser359 in vitro (knebel et al, 2001), this enzyme is not known to be active basally or to be regulated by amino acids.	SIGNOR-177986	0.56
KRAS	protein	P01116	UNIPROT	TCF3	protein	P15923	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000776								9528794	t		gcesareni	Our results are consistent with a model in which notch and deltex act on e47 by inhibiting signaling through ras.	SIGNOR-56144	0.317
PRKACA	protein	P17612	UNIPROT	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSS	-1									12853467	t		miannu	PFK-2 that was phosphorylated on Ser466, but not Ser483, by PKA did not bind to 14-3-3s‚ 	SIGNOR-250025	0.453
U50488	chemical	CHEBI:73358	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029									9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258826	0.8
MAPK3	protein	P27361	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity	phosphorylation			9606									19143636	t		lperfetto	Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor.	SIGNOR-209859	0.393
SMOC1	protein	Q9H4F8	UNIPROT	COL1A2	protein	P08123	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20359165	f		lperfetto	The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells	SIGNOR-260404	0.2
CSNK1D	protein	P48730	UNIPROT	PSEN2	protein	P49810	UNIPROT	unknown	phosphorylation	Ser7	sDSEEEVC	-1									8972483	t		llicata	In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. 	SIGNOR-250803	0.371
BUB1	protein	O43683	UNIPROT	CENPE	protein	Q02224	UNIPROT	up-regulates activity	relocalization												11402067	t		lperfetto	Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity	SIGNOR-252016	0.824
WNT9A	protein	O14904	UNIPROT	CHRNA1	protein	P02708	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000887							22309736	t		gcesareni	We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles.	SIGNOR-195972	0.2
SIGMAR1	protein	Q99720	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	up-regulates quantity by stabilization	stabilization			9606	BTO:0000815								29117944	t		Barakat	We propose that Sigma1 is a ligand-operated scaffolding protein that promotes the stability, processing, assembly, and trafficking of specific proteins in the secretory pathway of cancer cells. In support of this hypothesis, we found that siRNA-mediated knockdown of Sigma1 resulted in a significant decrease in PD-L1 protein levels in triple-negative MDA-MB-231 breast cancer and androgen-independent PC3 prostate cancer cells	SIGNOR-274974	0.2
CDK2	protein	P24941	UNIPROT	SF3B1	protein	O75533	UNIPROT	up-regulates	phosphorylation	Thr244	GRAKGSEtPGATPGS	9606			SIGNOR-C16						12105215	t		gcesareni	To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313	SIGNOR-90434	0.354
LYL1	protein	P12980	UNIPROT	ERG	protein	P11308	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21536859	f	 	miannu	 We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer.	SIGNOR-253923	0.2
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	BIRC2	protein	Q13490	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								16510124	t		miannu	Since Fbxo7 is one component of the SCF complex, we tried to determine whether overexpression of Fbxo7 could promote cIAP1 ubiquitination in the hope to reveal functional aspects of the cIAP1–Fbxo7 interaction. cIAP1-Flag was co-expressed with or without Fbxo7 in 293T cells. In conclusion, our results show that overexpression of Fbxo7 promotes the ubiquitination of cIAP1.	SIGNOR-271553	0.313
F12	protein	P00748	UNIPROT	KLKB1	protein	P03952	UNIPROT	up-regulates activity	cleavage	Arg390	CTTKTSTrIVGGTNS	9606		BTO:0000131							28966616	t		lperfetto	FXIIa activates two serine proteinases, factor XI (FXI) and plasma prekallikrein (PK) that drive the coagulation and kallikrein–kinin systems, respectively	SIGNOR-263518	0.588
Melanin-concentrating hormone	smallmolecule	CHEBI:80254	ChEBI	MCHR1	protein	Q99705	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257540	0.8
PPP2CA	protein	P67775	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates activity	dephosphorylation	Thr216	RSSSSEStGTPSNPD	10090									11983168	t			cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216. Consistent with these data, cyclin G null cells have both Mdm2 that is hyperphosphorylated at T216 and markedly higher levels of p53 protein when compared to wild-type cells	SIGNOR-248636	0.431
GSK3A	protein	P49840	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	phosphorylation	Thr312	TMKTFCGtPEYLAPE	10090	BTO:0005655								23142783	t		gcesareni	GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function.	SIGNOR-252455	0.621
UBE2N	protein	P61088	UNIPROT	TRIM63	protein	Q969Q1	UNIPROT	up-regulates activity	ubiquitination			-1									19240029	t		miannu	We used MuRF1 as the E3 as it functions with all these E2s to ubiquitinate one of its typical substrates, troponin I Although UbcH1 and UbcH13/Uev1a support ubiquitination of troponin I by MuRF1, these E2s do not support ubiquitination of S5a, unlike Class I E2s.	SIGNOR-272737	0.518
MAP1B	protein	P46821	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates quantity by stabilization	binding			9606	BTO:0000938								10649507	t		lperfetto	MAP1B is a microtubule-associated phosphoprotein that is particularly highly expressed in developing neurons. 	SIGNOR-264844	0.7
JAG2	protein	Q9Y219	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	up-regulates	binding			9606									10958687	t		gcesareni	Binding of delta1, jagged1, and jagged2 to notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of notch2	SIGNOR-81367	0.619
DYRK1A	protein	Q13627	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates	phosphorylation	Ser262	LRIAKTPsPPEEPSP	9606		BTO:0000142							15262992	t		lperfetto	Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd	SIGNOR-126839	0.405
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	MCM3	protein	P25205	UNIPROT	up-regulates	phosphorylation	Thr722	EEMPQVHtPKTADSQ	9606									21965652	t		lperfetto	In this study, we demonstrate that mcm3 is a substrate of cyclin e/cdk2 and can be phosphorylated by cyclin e/cdk2 at thr-722.	SIGNOR-216694	0.62
BBC3	protein	Q9BXH1	UNIPROT	MCL1	protein	Q07820	UNIPROT	down-regulates	binding			9606									15694340	t		gcesareni	Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.	SIGNOR-133817	0.742
NDC1	protein	Q9BTX1	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262073	0.515
GRM4	protein	Q14833	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening.	SIGNOR-264935	0.8
PPP2R2A	protein	P63151	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates	binding			9606									9774674	t		lperfetto	In this report, we show that another WD-40 repeat protein, the B_ subunit of protein phosphatase 2A, associates with the cytoplasmic domain of type I TGF-_ receptors. [...] We therefore conclude that B_ specifically and directly associates with the type I receptor cytoplasmic domain in vitro.	SIGNOR-227517	0.515
PIM2	protein	Q9P1W9	UNIPROT	PKM	protein	P14618	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr454	RAPIIAVtRNPQTAR	9606									24142698	t		Manara	Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels.	SIGNOR-260905	0.379
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	IREB2	protein	P48200	UNIPROT	down-regulates	phosphorylation	Ser157	LQKAGKLsPVKVQPK	9606									18574241	t		lperfetto	Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity	SIGNOR-216888	0.361
PRKACA	protein	P17612	UNIPROT	CA9	protein	Q16790	UNIPROT	up-regulates	phosphorylation	Thr443	RRQHRRGtKGGVSYR	9606									22037869	t		llicata	Here, we report that thr443 phosphorylation at the intracellular domain of ca ix by protein kinase a (pka) is critical for its activation in hypoxic cells, with the fullest activity of ca ix also requiring dephosphorylation of ser448.	SIGNOR-176973	0.2
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259017	0.374
DOK1	protein	Q99704	UNIPROT	A4/b7 integrin	complex	SIGNOR-C187	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257697	0.329
PLK1	protein	P53350	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser2439	SFLSGEPsQADVQPL	9606	BTO:0000552								31597699	t		miannu	As shown in Fig. S4D, the C-terminal NOTCH1 fragment was readily phosphorylated by PLK1. Additionally, when the two putative phosphorylation sites, Ser-1791 and Ser-2349, were replaced by Ala, WT NOTCH1-IC but not the mutant was efficiently phosphorylated (Fig. S4E). We found that mutation of Ser-1791/2349 promotes NOTCH1-IC stabilization (Fig. S4F).	SIGNOR-277490	0.411
ITSN1	protein	Q15811	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates	binding			9606									15824104	t		gcesareni	Full-length intersectin-l exhibited little ability to stimulate nucleotide exchange on cdc42	SIGNOR-135377	0.842
BMS-754807	chemical	CHEBI:88339	ChEBI	IGF1R	protein	P08069	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190497	0.8
DHODH	protein	Q02127	UNIPROT	coenzyme Q10	smallmolecule	CHEBI:46245	ChEBI	down-regulates quantity	chemical modification			9606									30449682	t		miannu	OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway	SIGNOR-267431	0.8
P2RY1	protein	P47900	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256943	0.2
Guanabenz	chemical	CHEBI:5553	ChEBI	ADRA2C	protein	P18825	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258911	0.8
HNuRF	complex	SIGNOR-C448	SIGNOR	EN1	protein	Q05925	UNIPROT	up-regulates quantity by expression				9606									14609955	f		miannu	Human NURF (hNURF) is enriched in brain, and we demonstrate that it regulates human Engrailed, a homeodomain protein that regulates neuronal development in the mid-hindbrain. Furthermore, we show that hNURF potentiates neurite outgrowth in cell culture. Taken together, our data suggess a role for an ISWI complex in neuronal growth. ) ChIP assays localize hNURF specifically to engrailed-1 (en-1) and engrailed-2 (en-2) promoters.	SIGNOR-268839	0.322
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	NCOA3	protein	Q9Y6Q9	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000093								17574025	t		miannu	We identified SCFFbw7α as an E3 ligase that binds to SRC-3 in an S505 phosphorylation-dependent manner (Figure 4Ci) and that is responsible for the further ubiquitination of SRC-3 (Figure 4A). 	SIGNOR-276066	0.301
GSK3B	protein	P49841	UNIPROT	CTPS1	protein	P17812	UNIPROT	down-regulates activity	phosphorylation	Ser575	SDRSGSSsPDSEITE	9606	BTO:0000007								17681942	t		miannu	We found that low serum conditions increased phosphorylation of endogenous CTPS1 and this phosphorylation was inhibited by the glycogen synthase kinase 3 (GSK3) inhibitor indirubin-3'-monoxime and GSK3beta short interfering RNAs, demonstrating the involvement of GSK3 in phosphorylation of endogenous human CTPS1. Separating tryptic peptides from [(32)P]orthophosphate-labeled cells and analyzing the phosphopeptides by mass spectrometry identified Ser-574 and Ser-575 as phosphorylated residues. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity. 	SIGNOR-276069	0.2
BTRC	protein	Q9Y297	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								16371461	t		lperfetto	Phosphorylated gli3 can bind beta-trcp directly both in vitro and in vivo, resulting in polyubiquitination of gli3 and processing through proteasome activity	SIGNOR-143171	0.657
ROCK1	protein	Q13464	UNIPROT	RDX	protein	P35241	UNIPROT	up-regulates activity	phosphorylation	Thr564	AGRDKYKtLRQIRQG	10090	BTO:0005065								9456324	t		lperfetto	 A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kc€“phosphorylated C-rad as T564-phosphorylated C-rad. | In this study, we found that the T564 phosphorylation of radixin markedly suppressed its head-to-tail association. This suggests that the T564-phosphorylation of radixin (and probably also the phosphorylation of ezrin T567 and moesin T558) keeps them open and active.	SIGNOR-248994	0.666
TRAF2	protein	Q12933	UNIPROT	TICAM1	protein	Q8IUC6	UNIPROT	up-regulates	polyubiquitination			9606									20047764	t		miannu	Here, we show that the TRAF family proteins directly bind TICAM-1 and demonstrate that TRAF2 and TRAF6 bind different sites of the N-terminal TICAM-1 and accelerate its polyubiquitination. we speculate that polyubiquitination of TICAM-1 by TRAF2 and TRAF6 is required for TICAM-1 to induce IRF-3 and NF-κB activation. This is supported by the observation that polyubiquitination of TICAM-1 was required for TRAF3-binding to TICAM-1	SIGNOR-271427	0.442
WNT4	protein	P56705	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates				9606		BTO:0000887;BTO:0001103							9753670	f		gcesareni	Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm.	SIGNOR-60373	0.318
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser14	LYSFFSPsPARKRHA	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276089	0.292
STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	LATS1	protein	O95835	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000007								15688006	t	Two of these, S909 and T1079, were required for Lats1 activation.	milica	Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1.	SIGNOR-270217	0.2
(4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester	chemical	CHEBI:103931	ChEBI	ADRA1D	protein	P25100	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258464	0.8
CSNK2A1	protein	P68400	UNIPROT	CTNNA1	protein	P35221	UNIPROT	down-regulates	phosphorylation	Ser641	TPEELDDsDFETEDF	9606	BTO:0000527								19941816	t		gcesareni	We demonstrate here that egfr activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via ck2alpha-dependent phosphorylation of alpha-catenin at s641.	SIGNOR-161847	0.398
AKT1	protein	P31749	UNIPROT	VCP	protein	P55072	UNIPROT	up-regulates	phosphorylation	Ser748	RFARRSVsDNDIRKY	9606	BTO:0000150								16551632	t		llicata	Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I	SIGNOR-252493	0.523
OPRD1	protein	P41143	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256962	0.279
RNF8	protein	O76064	UNIPROT	BLM	protein	P54132	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0001938								23708797	t		miannu	Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of . 	SIGNOR-272115	0.343
MAPK1	protein	P28482	UNIPROT	RPS6KA1	protein	Q15418	UNIPROT	up-regulates activity	phosphorylation	Thr573	AENGLLMtPCYTANF	9534	BTO:0004055								9430688	t		lperfetto	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-219328	0.748
MARCHF5	protein	Q9NX47	UNIPROT	FIS1	protein	Q9Y3D6	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									16874301	t		Barakat	MITOL associates with and ubiquitinates mitochondrial fission protein hFis1. (A) Ubiquitination of hFis1 by MITOL. Thus, MITOL may control the protein expression level of hFis1 through the ubiquitin–proteasome pathway.	SIGNOR-274141	0.2
MAP1LC3B	protein	Q9GZQ8	UNIPROT	NBR1	protein	Q14596	UNIPROT	down-regulates	binding			9606	BTO:0000007								19250911	t		gcesareni	We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1.	SIGNOR-184252	0.574
CDK5	protein	Q00535	UNIPROT	STXBP2	protein	Q15833	UNIPROT	down-regulates	phosphorylation	Thr572	IGSSHILtPTRFLDD	9606	BTO:0000938								17716669	t		lperfetto	It was shown that munc18 inhibition of neuronal syntaxin 1 can be overcome by cdk5 phosphorylation, indicating that structural change disrupts the syntaxin-munc18 interaction.	SIGNOR-157528	0.2
CDK1	protein	P06493	UNIPROT	UBXN2B	protein	Q14CS0	UNIPROT	down-regulates activity	phosphorylation	Ser56	PKATVFKsPRTPPQR										23500464	t		lperfetto	At mitosis, Cdc2 kinase phosphorylates p47 on Serine-140 and p37 on Serine-56 and Threonine-59, respectively. The phosphorylated p47 and p37 are unable to bind to Golgi membranes, resulting in mitotic inhibition of the p97/p47 and the p97/p37 pathways, respectively.	SIGNOR-265040	0.2
FGFR3	protein	P22607	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	phosphorylation	Tyr701	DGPKGTGyIKTELIS	9606	BTO:0000007								10918587	t			Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. 	SIGNOR-251138	0.657
NCBP3	protein	Q53F19	UNIPROT	mRNA-nucleus_export	phenotype	SIGNOR-PH127	SIGNOR	up-regulates				9606									26382858	f		lperfetto	The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. 	SIGNOR-268362	0.7
PRKAB1	protein	Q9Y478	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	form complex	binding			9606									16054041	t		gcesareni	Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits.	SIGNOR-139164	0.865
PPP2CA	protein	P67775	UNIPROT	PP2Ca_R1A_Bd 	complex	SIGNOR-C133	SIGNOR	form complex	binding			9606									23454242	t		gcesareni	[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity.	SIGNOR-243442	0.827
PROK1	protein	P58294	UNIPROT	PROKR1	protein	Q8TCW9	UNIPROT	up-regulates	binding			9606									12054613	t		gcesareni	The present study demonstrates that eg-vegf/prokineticin 1 and a peptide closely related to eg-vegf, prokineticin 2, are cognate ligands of two orphan g-protein-coupled receptors designated zaq (=eg-vegf/pk-r1) and i5e (=eg-vegf/pk-r2)	SIGNOR-89084	0.424
DCTPP1	protein	Q9H773	UNIPROT	dCMP 3'-end residue	smallmolecule	CHEBI:53119	ChEBI	up-regulates quantity by expression	chemical modification			10116									31377845	t		lperfetto	Our data indicate that DCTPP1 is crucially involved in the provision of dCMP for thymidylate biosynthesis, introducing a new player in the regulation of pyrimidine dNTP levels and the maintenance of genomic integrity	SIGNOR-261333	0.8
HAT1	protein	O14929	UNIPROT	H4C1	protein	P62805	UNIPROT	down-regulates activity	acetylation	Lys6	kGGKGLGK	-1									11585814	t		lperfetto	During nucleosome assembly in vivo, newly synthesized histone H4 is specifically diacetylated on lysines 5 and 12 within the H4 NH(2)-terminal tail domain. The highly conserved "K5/K12" deposition pattern of acetylation is thought to be generated by the Hat1 histone acetyltransferase, which in vivo is found in the HAT-B complex.	SIGNOR-264791	0.2
EGR1	protein	P18146	UNIPROT	COL10A1	protein	Q03692	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21931594	f	Regulation	miannu	Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1)	SIGNOR-251921	0.2
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	NMDA receptor_2A	complex	SIGNOR-C347	SIGNOR	up-regulates activity	chemical activation			9606									12871085	t		miannu	The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate	SIGNOR-264128	0.8
PRKD1	protein	Q15139	UNIPROT	RIN1	protein	Q13671	UNIPROT	unknown	phosphorylation	Ser292	QLLRRESsVGYRVPA	9606									21209314	t		llicata	Here, we report the identification of serine 292 in rin1 as an in vivo pkd phosphorylation site. we demonstrate that phosphorylation at serine 292 controls rin1-mediated inhibition of cell migration by modulating the activation of abl kinases.	SIGNOR-170877	0.413
PHLPP2	protein	Q6ZVD8	UNIPROT	PRKCA	protein	P17252	UNIPROT	down-regulates quantity	dephosphorylation	Ser657	QSDFEGFsYVNPQFV	9606	BTO:0000067								18162466	t		gcesareni	In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC alpha	SIGNOR-237051	0.256
NOD2	protein	Q9HC29	UNIPROT	RIPK2	protein	O43353	UNIPROT	up-regulates activity	binding			9606									17355968	t		miannu	The function of NOD2 could be to recruit RICK at the plasma membrane to form an active complex able to activate part of the NF-κB pathway. NOD2 induces a membrane recruitment of RICK that is dependent on a CARD-CARD interaction.	SIGNOR-252402	0.757
CDC42BPA	protein	Q5VT25	UNIPROT	MYL2	protein	P10916	UNIPROT	up-regulates activity	phosphorylation	Ser19	GANSNVFsMFEQTQI		BTO:0000567								9418861	t		llicata	These approximately 190-kDa myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs) preferentially phosphorylate nonmuscle myosin light chain at serine 19, which is known to be crucial for activating actin-myosin contractility.	SIGNOR-250723	0.635
SMARCD1	protein	Q96GM5	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	form complex	binding			9606									15627498	t		miannu	We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers.	SIGNOR-132939	0.881
MAPK1	protein	P28482	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates	phosphorylation	Ser530	DGPPSPRsPVIGSEV	9606	BTO:0001271								15093545	t	The effect has been demonstrated using P29590-4	gcesareni	We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3).	SIGNOR-124056	0.366
wortmannin	chemical	CHEBI:52289	ChEBI	PIK3C3	protein	Q8NEB9	UNIPROT	down-regulates	chemical inhibition			9534	BTO:0001444								22253445	t		lperfetto	From these results, we conclude that LY294002 and wortmannin inhibit SARS pseudovirus entry by targeting PI4KB and that PI4KB is involved in SARS-CoV S-mediated entry into VeroE6 cells.	SIGNOR-260730	0.8
T_cell_activation	phenotype	SIGNOR-PH73	SIGNOR	IFNG	protein	P01579	UNIPROT	up-regulates quantity				9606	BTO:0002417								32454942	f		miannu	 interferon gamma- (IFNγ-) and interleukin-17- (IL-17-) secreting CD4+ T cells are believed to be the pathogenic initiators of MS [22], and in MS patients, the increased production of either IFNγ or IL-17 is associated with pathology 	SIGNOR-263818	0.7
pazopanib hydrochloride	chemical	CHEBI:71217	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-200809	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	ARMC10	protein	Q8N2F6	UNIPROT	up-regulates activity	phosphorylation	Ser45	LGIRSSKsAGALEEG	9606									30631047	t		miannu	We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Moreover, ARMC10 overexpression was sufficient to promote mitochondrial fission, whereas ARMC10 knockout prevented AMPK-mediated mitochondrial fission. These results demonstrate that ARMC10 is an effector of AMPK that participates in dynamic regulation of mitochondrial fission and fusion.	SIGNOR-266413	0.2
PRKACA	protein	P17612	UNIPROT	AICDA	protein	Q9GZX7	UNIPROT	unknown	phosphorylation	Thr27	WAKGRREtYLCYVVK	9606									18417471	t		llicata	We have found using sf9 insect cells to overexpress human gst-aid that a small fraction of the enzyme is phosphorylated at ser38 and thr27 and at two residues not reported previously, ser41 and ser43	SIGNOR-178248	0.329
zaleplon	chemical	CHEBI:10102	ChEBI	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	up-regulates activity	chemical activation			9606		BTO:0000227							18790874	t	brain	lperfetto	The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005).	SIGNOR-263804	0.8
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	PTCH1	protein	Q13635	UNIPROT	down-regulates activity	cleavage	Asp1405	CPGYPETdHGLFEDP	9606									12907805	t		lperfetto	Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain.	SIGNOR-256438	0.327
IRF9	protein	Q00978	UNIPROT	ISGF3 complex	complex	SIGNOR-C124	SIGNOR	form complex	binding			-1									8943351	t	2	miannu	The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3	SIGNOR-240600	0.865
BMPR1A	protein	P36894	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates	phosphorylation			9606									19620713	t		gcesareni	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-187181	0.721
TNFSF13B	protein	Q9Y275	UNIPROT	TNFRSF13B	protein	O14836	UNIPROT	up-regulates	binding			9606									10956646	t		gcesareni	Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys.	SIGNOR-81360	0.774
ADORA2B	protein	P29275	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256910	0.516
FZD5	protein	Q13467	UNIPROT	DVL3	protein	Q92997	UNIPROT	up-regulates activity	binding			9606									23151663	t		areggio	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling. 	SIGNOR-258963	0.626
atomoxetine	chemical	CHEBI:127342	ChEBI	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			-1									9871604	t		miannu	The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2.	SIGNOR-259071	0.8
Dinaciclib	chemical	CID:46926350	PUBCHEM	CDK2	protein	P24941	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191325	0.8
PDGFRB	protein	P09619	UNIPROT	CRK	protein	P46108	UNIPROT	up-regulates	binding			9606									10733900	t		amattioni	Crk could bind to both pdgf alpha- and beta-receptors in vivo	SIGNOR-75884	0.591
STK4	protein	Q13043	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation			9606									18394876	t		gcesareni	The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1	SIGNOR-253002	0.673
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2E3	protein	Q969T4	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271364	0.593
LPAR	proteinfamily	SIGNOR-PF2	SIGNOR	GNAI1	protein	P63096	UNIPROT	up-regulates	binding			9606									12393875	t	inferred from 70% family members	gcesareni	We conclude that lpa(1) receptors couple to a g(i)-phosphoinositide 3-kinase-tiam1 pathway to activate rac.	SIGNOR-269964	0.2
NCSTN	protein	Q92542	UNIPROT	gamma-secretase	complex	SIGNOR-C98	SIGNOR	form complex	binding			9606									25610395	t		lperfetto	-Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2)	SIGNOR-209711	0.964
NR1D1	protein	P20393	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates				10090	BTO:0000011								12821652	f		miannu	Mutations of the 5' or 3' half-sites of the response element totally abrogated PPARgamma binding and transcriptional activation, identifying this site as a novel type of functional PPARgamma response element. Finally, ectopic expression of Rev-Erbalpha in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARgamma ligand rosiglitazone. These results identify Rev-Erbalpha as a target gene of PPARgamma in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation.	SIGNOR-268023	0.7
CSNK2A1	protein	P68400	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Thr366	ASSSTSVtPDVSDNE	-1									12297295	t		llicata	We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366). 	SIGNOR-250940	0.667
SARS1	protein	P49591	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									24095058	t		miannu	As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis	SIGNOR-270497	0.8
CEBPA	protein	P49715	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates				10090	BTO:0000011								25451943	f		gcesareni	Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) ² plays an essential role.	SIGNOR-250562	0.7
ROCK2	protein	O75116	UNIPROT	Actin_cytoskeleton_reorganization	phenotype	SIGNOR-PH84	SIGNOR	up-regulates				9606									14701738	f		miannu	 Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively.	SIGNOR-261722	0.7
CTBP1	protein	Q13363	UNIPROT	CDKN2A	protein	P42771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									23303449	f		irozzo	Our findings suggest an important role of CtBP1 in the transcriptional control of p16INK4a and Brca1[.]. Additionally, the inhibitor of cyclin-dependent protein kinases (CDKs), p16INK4a, whose loss has been related to the pathogenesis of melanoma, was repressed by CtBP1 as well.	SIGNOR-259195	0.423
ROCK1	protein	Q13464	UNIPROT	MYL12B	protein	O14950	UNIPROT	up-regulates	phosphorylation	Ser20	KRPQRATsNVFAMFD	9606									12185584	t		lperfetto	Here we found that rho-kinase has an activity for mrlc diphosphorylation at both threonine 18 and serine 19 in nonmuscle cells using sequential column chromatographies.	SIGNOR-91542	0.609
CSNK2A2	protein	P19784	UNIPROT	PTPRC	protein	P08575	UNIPROT	up-regulates activity	phosphorylation	Ser1004	SEHDSDEsSDDDSDS	9606	BTO:0000661								10066810	t		llicata	Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment. 	SIGNOR-251029	0.445
CRKL	protein	P46109	UNIPROT	MAP4K1	protein	Q92918	UNIPROT	up-regulates	binding			9606	BTO:0000782								9891069	t	HPK1 phosphorylated CrkL mainly on serine and weakly on threonine	gcesareni	We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk.	SIGNOR-63991	0.57
GSK3B	protein	P49841	UNIPROT	TOP2A	protein	P11388	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1361	SPPKTKTsPKLSNKE	9606	BTO:0003492								21254166	t		miannu	 This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361.	SIGNOR-276301	0.355
GSK3B	protein	P49841	UNIPROT	DEK	protein	P35659	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr67	KKKVERLtMQVSSLQ	9606	BTO:0002181								21282377	t		miannu	 These data suggest that the E3 ligase SCFFbxw7-α degrades p-DEK in a GSK-3β–dependent manner.Therefore, the phosphorylation of DEK by GSK-3β is a crucial step to mediate Tpm RNA splicing.	SIGNOR-276303	0.412
DAMPS	stimulus	SIGNOR-ST18	SIGNOR	AP-1/clathrin vescicle	complex	SIGNOR-C251	SIGNOR	up-regulates				9606									25720354	f		scontino	APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. 	SIGNOR-267854	0.7
INSR	protein	P06213	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	binding			9606									11075717	t		gcesareni	The npxy motif around 960-tyr residue of the insulin receptor binds to the n-terminal ptb domain of shc.	SIGNOR-84251	0.698
RPS6KA1	protein	Q15418	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									14625384	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-119221	0.2
PTPRC	protein	P08575	UNIPROT	SKAP1	protein	Q86WV1	UNIPROT	up-regulates activity	dephosphorylation	Tyr232	EEEKEETyDDIDGFD	9606	BTO:0000661								11909961	t			Mutational analysis demonstrated the pivotal role of Tyr-232 in SKAP55 in the association with CD45. In Jurkat cells, anti-CD3 antibody stimulation promoted SKAP55 tyrosine phosphorylation and translocation from the cytoplasm to the membrane. Overexpression of SKAP55 in these cells induced transcriptional activation of the IL-2 promoter, while mutant SKAP55-Y232F totally suppressed the promoter activity. Furthermore, overexpression of SKAP55-Y232F also caused the tyrosine hyperphosphorylation of Fyn with a decreased kinase activity. Thus, SKAP55 is an essential adapter to couple CD45 with the Src family kinases for dephosphorylation and, thus, positively regulates TCR signaling.	SIGNOR-248360	0.367
doxorubicin	chemical	CHEBI:28748	ChEBI	ABCC1	protein	P33527	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002206								9647783	t		Simone Vumbaca	Unconjugated Dox and Dau failed to inhibit the transport of LTC4, whereas 30 microM GS-Dox or GS-Dau conjugates completely inhibited the transport.	SIGNOR-261085	0.8
G6PD	protein	P11413	UNIPROT	NADP(3-)	smallmolecule	CHEBI:58349	ChEBI	down-regulates quantity	chemical modification			9606									24769394	t		miannu	G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress	SIGNOR-268125	0.8
PRKCD	protein	Q05655	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates activity	phosphorylation	Ser167	LFPSFIHsQKRNPQT	9935									24211614	t		Manara	Endothelin-1 stimulates catalase activity through the PKCδ-mediated phosphorylation of serine 167.	SIGNOR-260904	0.27
CTSD	protein	P07339	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates quantity by destabilization	cleavage	Glu637	QKLVFFAeDVGSNKG	-1									8943232	t		lperfetto	FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261768	0.502
SRC	protein	P12931	UNIPROT	HNRNPK	protein	P61978	UNIPROT	down-regulates	phosphorylation	Tyr236	FYDETYDyGGFTMMF	9606									12052863	t		lperfetto	We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown).	SIGNOR-88911	0.609
metoprolol	chemical	CHEBI:6904	ChEBI	ADRB1	protein	P08588	UNIPROT	down-regulates activity	chemical inhibition			10030	BTO:0000246								10079020	t		Luana	In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue	SIGNOR-258337	0.8
BIRC3	protein	Q13489	UNIPROT	TRAF2	protein	Q12933	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									18997794	t		lperfetto	Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3.	SIGNOR-182131	0.888
ADRA2A	protein	P08913	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256977	0.405
POU2F1	protein	P14859	UNIPROT	MYH2	protein	Q9UKX2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0001103							15728583	t		lperfetto	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238757	0.2
ATM	protein	Q13315	UNIPROT	DCLRE1C	protein	Q96SD1	UNIPROT	up-regulates	phosphorylation	Ser516	SSTVAGGsQSPKLFS	9606									16874298	t		lperfetto	The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo	SIGNOR-148319	0.603
KDM6A	protein	O15550	UNIPROT	FLI1	protein	Q01543	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									29736013	t		miannu	Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase	SIGNOR-260034	0.2
RBP4	protein	P02753	UNIPROT	retinol	smallmolecule	CHEBI:50211	ChEBI	up-regulates quantity	relocalization			9606									31963453	t		lperfetto	In the blood, serum retinol travels in association with Retinol-binding protein 4 (RBP4)	SIGNOR-265106	0.8
4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid	chemical	CHEBI:91366	ChEBI	AURKA	protein	O14965	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258250	0.8
RUNX2	protein	Q13950	UNIPROT	MMP13	protein	P45452	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15564063	f		miannu	 Increased expression of RUNX2 in OA cartilage may contribute to increased expression of MMP-13. FGF2, which is present in OA synovial fluid, activated RUNX2 via the MEK/ERK pathway and increased MMP-13 expression. 	SIGNOR-255078	0.486
FOXA1	protein	P55317	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								16331276	f		miannu	We identified a foxa1 binding site within the brca1-responsive element of the p27(kip1) promoter and showed that foxa1 activated the promoter alone and in conjunction with brca1.	SIGNOR-142940	0.327
PTPN2	protein	P17706	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	9606									1373652	t		gcesareni	The question of whether protein tyrosine phosphatases (ptpases) dephosphorylate a multiply phosphorylated peptide in a random or ordered manner was investigated using the synthetic triphosphotyrosyl peptide trdiy(p)etdy(p)y(p)rk, corresponding to the major sites of autophosphorylation of the insulin receptor, as a substrate for four purified ptpases.	SIGNOR-18018	0.604
KDM6B	protein	O15054	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	demethylation			9606									24561908	t	This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions.	miannu	Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation.	SIGNOR-265361	0.2
DUSP2	protein	Q05923	UNIPROT	MAPK4	protein	P31152	UNIPROT	down-regulates activity	dephosphorylation			9606									28252035	t		miannu	DUSP2 can dephosphorylate both ERK3 and ERK4 when expressed in mammalian cells.|Finally, we demonstrate that DUSP2 inhibits ERK3 and ERK4 mediated activation of MK5.	SIGNOR-277068	0.36
CEBPB	protein	P17676	UNIPROT	IL10	protein	P22301	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12493739	f		miannu	The C/EBP5 motif, which is located between the TATA-box and the translation start point, is essential for the C/EBP-mediated constitutive and most of the cAMP-stimulated expression as its mutation nearly abolished IL-10 promoter activity. Our results suggest a dominant role of C/EBP transcription factors relative to CREB/ATF in tissue-specific and differentiation-dependent IL-10 transcription	SIGNOR-254523	0.364
SQSTM1	protein	Q13501	UNIPROT	WDFY3	protein	Q8IZQ1	UNIPROT	up-regulates quantity	binding			9606	BTO:0000452								20168092	t		miannu	 We show here that p62 is required to recruit the large phosphoinositide-binding protein ALFY to cytoplasmic p62 bodies generated upon amino acid starvation or puromycin-treatment. ALFY, as well as p62, is required for formation and autophagic degradation of cytoplasmic ubiquitin-positive inclusions. 	SIGNOR-266792	0.581
GATA4	protein	P43694	UNIPROT	HAMP	protein	P81172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								21609320	f	 	miannu	 Co-transfection of a GATA-4 expression vector with a hepcidin promoter reporter construct enhanced hepcidin promoter transcriptional activity. 	SIGNOR-254196	0.2
MAPKAPK2	protein	P49137	UNIPROT	ETV1	protein	P50549	UNIPROT	down-regulates activity	phosphorylation	Ser216	PMYQRQMsEPNIPFP	452646									11551945	t		miannu	MK2 phosphorylates ER81 in vitro within its central inhibitory domain, and overexpression of MK2 leads to increased in vivo phosphorylation of ER81. Two serine residues, ER81 amino acids 191 and 216, were identified as MK2 phosphorylation sites. MK2 suppresses basal ER81-dependent transcription	SIGNOR-250146	0.595
RPL39L	protein	Q96EH5	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262491	0.715
ALK	protein	Q9UM73	UNIPROT	ALK	protein	Q9UM73	UNIPROT	up-regulates activity	phosphorylation	Tyr1278	FGMARDIyRASYYRK	-1									15938644	t		llicata	ALK SelectiVely Phosphorylates the First Tyrosine in Its A-Loop Peptide.	SIGNOR-250575	0.2
NGF	protein	P01138	UNIPROT	NGFR	protein	P08138	UNIPROT	up-regulates	binding			9606	BTO:0000007								10764727	t		gcesareni	The low affinity neurotrophin receptor p75ntr can mediate cell survival as well as cell death of neural cells by ngf and other neurotrophins.	SIGNOR-76832	0.831
LRP5	protein	O75197	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates quantity by destabilization	relocalization			9606									11336703	t		lperfetto	Lrp-5, a close homolog of lrp-6 (hey et al., 1998), functions as a coreceptor for wnt proteins in mammalian cells and that it can transduce the canonical wnt signals, at least in part by binding and recruiting axin to membranes	SIGNOR-227930	0.672
MAPK8	protein	P45983	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606	BTO:0002923								23255093	t		lperfetto	Transfection of the cells with sirna specific for jnk1 revealed that jnk silencing reduced serine727 phosphorylation of stat3,	SIGNOR-235704	0.585
PPP1CA	protein	P62136	UNIPROT	PFN1	protein	P07737	UNIPROT	up-regulates	dephosphorylation	Ser138	MASHLRRsQY	9606									22479341	t		lperfetto	Knockdown of the catalytic subunit of pp1 (pp1c_), but not pp2a (pp2ac_), increased ps137-pfn1 levels. Pp1c_ binds pfn1 in cultured cells, and this interaction was increased by a phosphomimetic mutation of pfn1 at ser-137 (s137d). Together, these data define pp1 as the principal phosphatase for ser-137 of pfn1	SIGNOR-196816	0.248
RAB38	protein	P57729	UNIPROT	BLOC-2	complex	SIGNOR-C252	SIGNOR	up-regulates activity	relocalization			9606									23247405	t		lperfetto	Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes.	SIGNOR-260697	0.363
RPL21	protein	P46778	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262478	0.85
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH18	protein	Q13634	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265835	0.8
GATA2	protein	P23769	UNIPROT	GATA1	protein	P15976	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21853041	f		miannu	GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1.	SIGNOR-256062	0.419
CREBBP	protein	Q92793	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	acetylation			9606			SIGNOR-C6						16382138	t		gcesareni	Rela is also acetylated at several sites by p300 and cbp	SIGNOR-143396	0.874
CDK1	protein	P06493	UNIPROT	RCC1	protein	P18754	UNIPROT	up-regulates activity	phosphorylation	Ser11	KRIAKRRsPPADAIP	-1									15014043	t		miannu	Human RCC1 is phosphorylated on Ser 2 and Ser 11 in mitosis by Cdc2 kinase. We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation.	SIGNOR-262702	0.518
RPEL1	protein	Q2QD12	UNIPROT	D-xylulose 5-phosphate(2-)	smallmolecule	CHEBI:57737	ChEBI	up-regulates quantity	chemical modification			9606									34775382	t		miannu	The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux.	SIGNOR-267069	0.8
EFNA5	protein	P52803	UNIPROT	EPHA2	protein	P29317	UNIPROT	up-regulates	binding			9606									9330863	t		gcesareni	Members of the epha subfamily of receptor tyrosine kinases and their ephrin-a ligands have been implicated in the guidance of retinal axons along the anterior-posterior axis of the chick optic tectum.	SIGNOR-52467	0.919
AKT2	protein	P31751	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates	phosphorylation	Thr567	QGRDKYKtLRQIRQG	9606									15531580	t		llicata	Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression	SIGNOR-130260	0.384
SMARCD3	protein	Q6STE5	UNIPROT	Muscle cell-specific SWI/SNF ARID1B variant	complex	SIGNOR-C482	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270705	0.751
RPL29	protein	P47914	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262471	0.855
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates	relocalization			9606									11062529	t		gcesareni	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-84041	0.613
TNF	protein	P01375	UNIPROT	NOD2	protein	Q9HC29	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18647246	f		miannu	NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B.	SIGNOR-252407	0.428
CHRNA7	protein	P36544	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	binding												27167578	t			Here, we demonstrate a role for α7 nAChR/G protein interaction in the activation of the small (monomeric) RhoA GTPase leading to cytoskeletal changes during neurite growth. Treatment of PC12 cells with the α7 nAChR agonist choline or PNU-282987 was associated with an increase in RhoA activity and an inhibition in neurite growth.	SIGNOR-253985	0.2
CDK1	protein	P06493	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Ser249	DTRQIQPsPPWSYDQ	9606									16046550	t	The effect has been demonstrated using Q01196-8.	gcesareni	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-138908	0.347
SELENOS	protein	Q9BQE4	UNIPROT	DERL1	protein	Q9BUN8	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								15215856	t		miannu	VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97.	SIGNOR-261370	0.2
IKBKB	protein	O14920	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser923	DELRDSDsVCDSGVE	9606	BTO:0000459			SIGNOR-C13					10469655	t		lperfetto	Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway.	SIGNOR-70465	0.848
RTKs	proteinfamily	SIGNOR-PF38	SIGNOR	A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	up-regulates activity	phosphorylation			9606									30889378	t		miannu	The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs.	SIGNOR-259032	0.2
FES	protein	P07332	UNIPROT	FES	protein	P07332	UNIPROT	up-regulates	phosphorylation	Tyr811	RPSFSTIyQELQSIR	9606									8663427	t		llicata	Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kda phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. Cnbr cleavage analysis of fes isolated from 32po4-labeled 293t cells showed that tyr-713 and tyr-811 are also autophosphorylated in vivo. . Mutagenesis of tyr-713 reduced both autophosphorylation of tyr-811 and transphosphorylation of bcr, a recently identified fes substrate, supporting a major regulatory role for tyr-713.	SIGNOR-42659	0.2
ZSTK-474	chemical	CHEBI:90545	ChEBI	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207938	0.8
CHIR-98014	chemical	CID:53396311	PUBCHEM	GSK3B	protein	P49841	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190988	0.8
PPARA	protein	Q07869	UNIPROT	ARNTL	protein	O00327	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									16556735	t		miannu	We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. 	SIGNOR-268024	0.579
FYN	protein	P06241	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	unknown	phosphorylation	Tyr1109	FDEIELAyRRRPPRS	-1									11024032	t			Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro.	SIGNOR-251171	0.76
CDH8	protein	P55286	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265870	0.665
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PDE3B	protein	Q13370	UNIPROT	up-regulates activity	phosphorylation	Ser295	VIRPRRRsSCVSLGE	10090	BTO:0000944								10454575	t			PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B	SIGNOR-251483	0.2
GSK3B	protein	P49841	UNIPROT	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	down-regulates				9606		BTO:0001103							15829723	f		apalma	GSK-3beta is a serine/threonine kinase that can block translation that is initiated by eukaryotic initiation factor-2B (24) and may thereby reduce protein synthesis.	SIGNOR-255110	0.7
RAD18	protein	Q9NS91	UNIPROT	PCNA	protein	P12004	UNIPROT	up-regulates	ubiquitination			9606									19706603	t		gcesareni	Rad5 interacts with the e3 ligase rad18, which is initially required to monoubiquitinate pcna	SIGNOR-187705	0.84
MAP2K1	protein	Q02750	UNIPROT	CEBPA	protein	P49715	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000011								12270934	f		lperfetto	We further show that activation of mek1 significantly enhances the transactivation of the c/ebpalpha minimal promoter during the early phase of the differentiation process.	SIGNOR-235325	0.266
PIP3	smallmolecule	CHEBI:16618	ChEBI	WIPI1	protein	Q5MNZ9	UNIPROT	up-regulates	chemical activation			9606									22082875	t		gcesareni	We identified the human wipi protein family and found that wipi-1 specifically binds ptdins(3)p, accumulates at the phagophore and becomes a membrane protein of generated autophagosomes.	SIGNOR-177169	0.8
RPS6KA5	protein	O75582	UNIPROT	NR4A1	protein	P22736	UNIPROT	unknown	phosphorylation	Ser351	GRRGRLPsKPKQPPD	9606	BTO:0000007								16223362	t		lperfetto	In the present paper, we have re-examined the phosphorylation of Nur77 on Ser354. Using a combination of cell-permeable kinase inhibitors and mouse knockin mutations, we show that Nur77 is phosphorylated by RSK in response to mitogenic stimulation of cells. Phosphorylation of Nur77 on Ser354 did not, however, appear to affect the transcriptional activity of Nur77, or its ability to bind 14-3-3 proteins in vivo.	SIGNOR-249296	0.391
ATM	protein	Q13315	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606	BTO:0000552								15254178	t		lperfetto	Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. We next aimed to identify novel factors that control damage-induced p53 phosphorylation in a keratinocyte model system, and discovered that the epithelial stem cell marker _Np63_ is a novel ATM regulator that controls p53 Serine-15 phosphorylation through transcription of the ATM kinase.	SIGNOR-126753	0.838
TLK1	protein	Q9UKI8	UNIPROT	RAD9A	protein	Q99638	UNIPROT	up-regulates	phosphorylation	Ser328	VLPSISLsPGPQPPK	9606									18940270	t		llicata	Tlk1b phosphorylates hrad9 at s328 after the induction of dsb, occupancy of rad9 adjacent to the break increased during repair while that of asf1 decreased, and the effect was more pronounced in tlk1b-overexpressing cells. We propose that following genotoxic stress, tlk1/1b is first recruited to the dsb in a complex with rad9. It then exchanges with asf1 to promote nucleosomes eviction at the dsb and access of the repair machinery to unencumbered dna.	SIGNOR-181748	0.462
PIM1	protein	P11309	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation	Ser151	VLPSSKRsPSTATLS	9606	BTO:0001061								31730483	t		miannu	Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 	SIGNOR-276779	0.629
MYCT1	protein	Q8N699	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0000670;BTO:0000738								30283340	f		miannu	Overexpression of MYCT1 Inhibits Proliferation and Induces Apoptosis in Human Acute Myeloid Leukemia HL-60 and KG-1a Cells in vitro and in vivo	SIGNOR-261728	0.7
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	KHSRP	protein	Q92945	UNIPROT	down-regulates	binding			9606									17177604	t		gcesareni	Akt phosphorylates ksrp at a unique serine residue, creating a functional binding site for the molecular chaperone 14-3-3. As a consequence, akt activation impairs ksrp ability to interact with the exoribonucleolytic complex exosome and, in turn, to promote rapid mrna decay.	SIGNOR-151212	0.2
3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	3-phosphonatooxypyruvate(3-)	smallmolecule	CHEBI:18110	ChEBI	up-regulates quantity	precursor of			9606									25406093	t		lperfetto	PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG.	SIGNOR-268565	0.8
PIK-90	chemical	CID:6857685	PUBCHEM	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206232	0.8
CYP24A1	protein	Q07973	UNIPROT	calcitetrol	smallmolecule	CHEBI:47799	ChEBI	up-regulates quantity	chemical modification												30080183	t		lperfetto	Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH).	SIGNOR-270571	0.8
TGFB1	protein	P01137	UNIPROT	ENG	protein	P17813	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002741								21146604	f		miannu	 In hepatic stellate cells, TGF-β1 upregulates endoglin expression most likely via the ALK5 pathway and requires the SP1 transcription factor.	SIGNOR-255202	0.7
ZNF140	protein	P52738	UNIPROT	FCGR3B	protein	O75015	UNIPROT	down-regulates quantity by repression	transcriptional regulation				BTO:0002269								11470777	t		Luana	Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription.	SIGNOR-266214	0.2
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Asn)	smallmolecule	CHEBI:29172	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269482	0.8
ERN1	protein	O75460	UNIPROT	XBP1	protein	P17861-2	UNIPROT	up-regulates quantity by expression	post transcriptional regulation			9606									31226023	t		miannu	Upon activation by oligomerization and autophosphorylation, the cytosolic RNase domain of IRE1 mediates an unconventional splicing of the mRNA of X-box-binding protein 1 (XBP1). The spliced and frameshifted transcript encodes XBP1S, a bZIP transcription factor inducing the expression of numerous UPR effector genes that enhance ER folding capacity.	SIGNOR-260183	0.638
CCAR2	protein	Q8N163	UNIPROT	SUV39H1	protein	O43463	UNIPROT	down-regulates activity	binding												26158765	t		lperfetto	Besides SIRT1, CCAR2 inhibits the activity of the histone-modifying enzymes SUV39H1 and HDAC3 [9, 10], thus playing an important role in chromatin structure regulation.	SIGNOR-267664	0.354
[5-fluoro-1-(4-isopropylbenzylidene)-2-methylinden-3-yl]acetic acid	chemical	CHEBI:59660	ChEBI	RXRA	protein	P19793	UNIPROT	down-regulates activity	chemical inhibition			9606									20541701	t		Luana	NSAID Sulindac and Its Analogs Bind RXRα and Inhibit RXRα-dependent AKT Signaling	SIGNOR-258031	0.8
CSNK1E	protein	P49674	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates	phosphorylation	Thr50	FSTTPGGtRIIYDRK	9606	BTO:0000150								24247720	t		lperfetto	Mechanistic investigations showed that ck1_ interacted with and phosphorylated 4e-bp1 at two novel sites t41 and t50, which were essential for 4e-bp1 inactivation along with increased mrna translation and cell proliferation.	SIGNOR-203276	0.2
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	WIPI2	protein	Q9Y4P8	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								30898011	t		miannu	Here we show that WIPI2/ATG18B (WD repeat domain, phosphoinositide interacting 2), an autophagy-related (ATG) protein that plays a critical role in autophagosome biogenesis, is a direct substrate of CUL4-RING ubiquitin ligases (CRL4s)	SIGNOR-272302	0.2
PRKACG	protein	P22612	UNIPROT	PHKA2	protein	P46019	UNIPROT	down-regulates activity	phosphorylation			9606									10487978	t			Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.	SIGNOR-267414	0.307
PRKCB	protein	P05771	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser38	SVPEFPLsPPKKKDL	9606	BTO:0001271								7637391	t		gcesareni	Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation.	SIGNOR-30357	0.2
prostaglandin E2(1-)	smallmolecule	CHEBI:606564	ChEBI	CTNNB1	protein	P35222	UNIPROT	up-regulates				9606	BTO:0000725								23645839	f		apalma	Prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion	SIGNOR-255685	0.8
TNF	protein	P01375	UNIPROT	GCH1	protein	P30793	UNIPROT	up-regulates activity				9606									9204951	f		miannu	The de novo synthesis of 6-BH4 depends on the induction of GTP-CH-1, e.g., by tumor necrosis factor-alpha (TNF alpha). 	SIGNOR-252210	0.25
MAP2K1	protein	Q02750	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser304	LSSYGMDsRPPMAIF	-1									8226933	t			MEK1 and MEK2 can also be activated by autophosphorylation. Tyrosine 304 may be a candidate for the autophosphorylation site in MEK1. 	SIGNOR-251415	0.2
SPP1	protein	P10451	UNIPROT	Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	up-regulates	binding			9606									10835423	t		gcesareni	Among others, vitronectin (vn)1- (11, 13, 14) and osteopontin (opn)-coated (15-20) substrates have been shown to support cell adhesion via avb3.	SIGNOR-77910	0.605
GSK3B	protein	P49841	UNIPROT	MUC1	protein	P15941	UNIPROT	down-regulates activity	phosphorylation	Ser1227	PPSSTDRsPYEKVSA		BTO:0000567								9819408	t		lperfetto	GSK3beta binds directly to an STDRSPYE site in MUC1 and phosphorylates the serine adjacent to proline. Phosphorylation of MUC1 by GSK3beta decreases binding of MUC1 to beta-catenin in vitro and in vivo.	SIGNOR-249356	0.469
CDK1	protein	P06493	UNIPROT	CSNK2A1	protein	P68400	UNIPROT	up-regulates	phosphorylation	Thr360	SGISSVPtPSPLGPL	9606	BTO:0000527								19941816	t		gcesareni	It has been shown that the c-terminal domains of ck2? Are phosphorylated by cdc2 and interact with the peptidyl-prolyl isomerase pin1 in a cell cycle-dependent manner	SIGNOR-161843	0.361
SERPINE1	protein	P05121	UNIPROT	F12	protein	P00748	UNIPROT	down-regulates activity	binding			9606		BTO:0000131							26707513	t		lperfetto	C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1). 	SIGNOR-263516	0.311
sunitinib	chemical	CHEBI:38940	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates	chemical inhibition			9606									20185585	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-163956	0.8
PRKDC	protein	P78527	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	unknown	phosphorylation	Thr5	tQTQDQPM	9606	BTO:0000567								2507541	t		lperfetto	Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha.	SIGNOR-248887	0.438
MAPK1	protein	P28482	UNIPROT	ABI1	protein	Q8IZP0	UNIPROT	up-regulates	phosphorylation	Ser225	ARLGSQHsPGRTASL	9606									21419341	t		gcesareni	We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1.	SIGNOR-172877	0.421
RARB	protein	P10826	UNIPROT	RXRA	protein	P19793	UNIPROT	up-regulates	binding			9606									1310351	t		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16519	0.666
CSNK2A1	protein	P68400	UNIPROT	HDAC1	protein	Q13547	UNIPROT	up-regulates	phosphorylation	Ser421	IACEEEFsDSEEEGE	9606									11602581	t		gcesareni	Human hdac1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, ser(421) and ser(423), were unambiguously identified. Loss of phosphorylation at ser(421) and ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of hdac1.	SIGNOR-111011	0.61
CRTC2	protein	Q53ET0	UNIPROT	NR3C1	protein	P04150	UNIPROT	up-regulates activity	binding			9606									26652733	t			We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR).	SIGNOR-256101	0.299
MAP3K7	protein	O43318	UNIPROT	MAP3K14	protein	Q99558	UNIPROT	up-regulates activity	phosphorylation												10094049	t		lperfetto	The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway|Activated TAK1 phosphorylates NIK, which stimulates IKK-alpha activity. Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway.	SIGNOR-262833	0.544
SRC	protein	P12931	UNIPROT	HCN4	protein	Q9Y3Q4	UNIPROT	up-regulates	phosphorylation	Tyr531	RRQYQEKyKQVEQYM	9606									17977941	t		fspada	These results demonstrate that src tyrosine kinase enhances hcn4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics. The tyrosine residue that mediates most of src s actions on hcn4 channels is tyr531.	SIGNOR-158707	0.38
SKP2	protein	Q13309	UNIPROT	IDH2	protein	P48735	UNIPROT	down-regulates quantity by destabilization	ubiquitination										phosphorylation:Thr197	GTFKMVFtPKDGSGV	34929314	t		lperfetto	During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome	SIGNOR-267626	0.2
PRKCG	protein	P05129	UNIPROT	CD5	protein	P06127	UNIPROT	unknown	phosphorylation	Thr434	MSFHRNHtATVRSHA	9606									11123317	t		lperfetto	Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. 	SIGNOR-249072	0.348
AKT3	protein	Q9Y243	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	down-regulates	phosphorylation			9606	BTO:0000150								20231902	t	inferred from 70% of family members	gcesareni	Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation.	SIGNOR-269941	0.274
CDK1	protein	P06493	UNIPROT	TERT	protein	O14746	UNIPROT	up-regulates activity	phosphorylation	Thr249	AAPEPERtPVGQGSW	9606	BTO:0000567								32214089	t		miannu	Here we report that hTERT is phosphorylated at threonine 249 during mitosis by the serine/threonine kinase CDK1.These observations indicate that phosphorylation at threonine 249 regulates hTERT RdRP and contributes to cancer progression in a telomere independent manner.	SIGNOR-277517	0.33
DCC	protein	P43146	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity	binding			9606									15494734	t		miannu	Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling.	SIGNOR-268371	0.707
PPIF	protein	P30405	UNIPROT	ATP5PO	protein	P48047	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								32814770	t		lperfetto	We here hypothesized that CypD phosphorylation on its residue S191 induces its translocation and binding to the OSCP to favor mPTP opening. 	SIGNOR-264881	0.2
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Thr41	GIHSGATtTAPSLSG	-1									11955436	t			β-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC)	SIGNOR-260015	0.892
SRC	protein	P12931	UNIPROT	EMD	protein	P50402	UNIPROT	down-regulates	phosphorylation	Tyr59	SSSAASSySFSDLNS	9606	BTO:0000567	BTO:0000887							19789182	t		llicata	Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf	SIGNOR-188308	0.463
MBOAT7	protein	Q96N66	UNIPROT	acyl-CoA	smallmolecule	CHEBI:17984	ChEBI	down-regulates quantity	chemical modification			-1									18772128	t		miannu	The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils.	SIGNOR-267244	0.8
TEK	protein	Q02763	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9534	BTO:0004055								14665640	t		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-252728	0.483
FGF11	protein	Q92914	UNIPROT	SCN3A	protein	Q9NY46	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								20679355	t		miannu	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253446	0.2
(2S)-2-[[2-(2,3-dihydro-1H-inden-5-yloxy)-9-[(4-phenylphenyl)methyl]-6-purinyl]amino]-3-phenyl-1-propanol	chemical	CHEBI:94469	ChEBI	ARFGAP3	protein	Q9NP61	UNIPROT	down-regulates activity	chemical inhibition			-1									26152429	t		lperfetto	Here we present structure-activity relationship (SAR) studies of QS11 analogs in two assays: direct inhibition of enzymatic activity of purified ARFGAP1 protein and cellular activation of the Wnt/β-catenin pathway. The results confirm the direct inhibition of ARFGAP1 by QS11, and also suggest the presence of other potential cellular targets of QS11	SIGNOR-261980	0.8
Protocadherin_alpha	proteinfamily	SIGNOR-PF100	SIGNOR	Protocadherin_beta	proteinfamily	SIGNOR-PF102	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								15347688	t		miannu	We analyzed the expression of CNR/Pcdhalpha and Pcdhgamma in HEK293T cells and found that they formed a protein complex and that Pcdhgamma enhanced the surface expression of CNR/Pcdhalpha. This enhanced surface expression was confirmed by flow cytometry analysis and by marking cell surface proteins with biotin. The enhancement was observed using different combinations of CNR/Pcdhalpha and Pcdhgamma proteins. The surface expression activity was enhanced by the extracellular domains of the proteins, which could bind each other. Their cytoplasmic domains also had binding activity and influenced their localization. Their protein-protein interaction was also detected in extracts of mouse brain and two neuroblastoma cell lines. Thus, interactions between CNR/Pcdhalpha and Pcdhgamma regulate their surface expression and contribute to the combinatorial diversity of cell recognition proteins in the brain.	SIGNOR-269036	0.2
NEB	protein	P20929	UNIPROT	WASL	protein	O00401	UNIPROT	up-regulates	binding			9606									21798082	t		gcesareni	Igf1-akt signaling, by inhibiting gsk3b, allows the interaction of n-wasp with the unphosphorylated nebulin;the consequent recruitment of n-wasp to the z-disk promotes actin nucleation and elongation of actin filaments.	SIGNOR-175671	0.36
PCDHA4	protein	Q9UN74	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-265665	0.2
CYP24A1	protein	Q07973	UNIPROT	propan-2-ol	smallmolecule	CHEBI:17824	ChEBI	up-regulates quantity	chemical modification												30080183	t		lperfetto	Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH).	SIGNOR-270574	0.8
Ub:RING_E3	complex	SIGNOR-C519	SIGNOR	Protein_ubiquitination	phenotype	SIGNOR-PH214	SIGNOR	up-regulates				9606									34199813	f		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. 	SIGNOR-271383	0.7
CSNK2A1	protein	P68400	UNIPROT	CLTB	protein	P09497	UNIPROT	unknown	phosphorylation	Ser11	DFGFFSSsESGAPEA	-1									3128543	t		llicata	To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites.	SIGNOR-250842	0.313
KANSL2	protein	Q9H9L4	UNIPROT	NSL histone acetyltransferase	complex	SIGNOR-C413	SIGNOR	form complex	binding			9606	BTO:0000007								20018852	t		miannu	Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex.	SIGNOR-267163	0.655
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1644	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273067	0.636
DUSP4	protein	Q13115	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606									8626452	t		fstefani	Here we characterize a new map kinase phosphatase, mkp-2, that is induced in human peripheral blood t cells with phorbol 12-myristate 13-acetate and is expressed in a variety of nonhematopoietic tissues as well. We show that the in vivo substrate specificities of individual phosphatases are unique. Pac1, mkp-2, and mkp-1 recognize erk and p38, erk and jnk, and erk, p38, and jnk, respectively.	SIGNOR-40926	0.752
ULK3	protein	Q6PHR2	UNIPROT	ULK3	protein	Q6PHR2	UNIPROT	up-regulates activity	phosphorylation	Ser464	DKEGLSEsVRSSCTL	9606									20643644	t		Manara	We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. 	SIGNOR-260796	0.2
PDCD1	protein	Q15116	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates activity				9606	BTO:0000782								22740686	f		Barakat	MEK1/2 was phosphorylated and activated upon activation of T cells through TCR-CD3 and CD28, which resulted in phosphorylation of its downstream target ERK1/2, as determined by Western blotting analysis with an antibody specific for ERK1/2 phosphorylated at Thr202 and Tyr204, markers of activation. PD-1 substantially inhibited the activation of MEK1/2 and ERK1/2 	SIGNOR-275411	0.266
perfluorohexanesulfonic acid	chemical	CHEBI:132448	ChEBI	ESR2	protein	Q92731	UNIPROT	up-regulates activity	chemical activation			-1									23764977	t		miannu	Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. 	SIGNOR-268764	0.8
RIPK3	protein	Q9Y572	UNIPROT	MLKL	protein	Q8NB16	UNIPROT	up-regulates activity	phosphorylation	Ser360	RKTQTSMsLGTTREK	-1									24012422	t		gianni	MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays	SIGNOR-266440	0.742
PIK3CA	protein	P42336	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity				9606	BTO:0000938								9346240	f		lperfetto	Growth factors can promote cell survival by activating the phosphatidylinositide-3'-OH kinase and its downstream target, the serine-threonine kinase Akt	SIGNOR-236428	0.811
TLN1	protein	Q9Y490	UNIPROT	A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257613	0.61
MCHR1	protein	Q99705	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257235	0.276
GSK3B	protein	P49841	UNIPROT	SPAG5	protein	Q96R06	UNIPROT	up-regulates	phosphorylation	Ser974	EESLAEMsIMTTELQ	9606									18055457	t		lperfetto	Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta	SIGNOR-159574	0.274
MDN1	protein	Q9NU22	UNIPROT	PELP1	protein	Q8IZL8	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000567								27814492	t		miannu	MDN1 Is Physically and Functionally Associated with the Mammalian PELP1 Complex. To more specifically determine a function of mammalian MDN1 in the subnuclear distribution of PELP1-containing pre-60S-particles, we examined PELP1 localization in control cells or cells depleted from MDN1. Importantly, in the absence of MDN1, PELP1 became sequestered in enlarged nucleoli, indicating that MDN1 is involved in the nucleolar release of PELP1-containing pre-60S ribosomes	SIGNOR-261357	0.385
PTPRC	protein	P08575	UNIPROT	PRKCD	protein	Q05655	UNIPROT	down-regulates activity	dephosphorylation			9606									11124968	t		lperfetto	Taken together, these data indicate that CD45 inhibits PMA dependent PKCdelta activation by impeding PMA dependent PKCdelta tyrosine phosphorylation.|reduction in CD45 expression caused the duration of peak PMA-induced MEK and extracellular signal-regulated kinase (ERK) 1/2 activity to increase from 5 min to 30 min while leading to a 4-fold increase in PMA-dependent PKCdelta activation.	SIGNOR-277028	0.301
CSNK1D	protein	P48730	UNIPROT	ZNF322	protein	Q6U7Q0	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser396	ELSPPHAsEASQMS	9606	BTO:0002552								28581525	t		lperfetto	CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction. 	SIGNOR-264892	0.2
WWP2	protein	O00308	UNIPROT	SLC11A2	protein	P49281	UNIPROT	down-regulates quantity	ubiquitination			10029	BTO:0000246								18776082	t		lperfetto	Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2|This promotes DMT1 ubiquitination and degradation by WWP2.	SIGNOR-268852	0.304
lovastatin	chemical	CHEBI:40303	ChEBI	HMGCR	protein	P04035	UNIPROT	down-regulates activity	chemical inhibition			-1									1597859	t		miannu	A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). 	SIGNOR-258351	0.8
PTGER3	protein	P43115	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256859	0.433
MAPK14	protein	Q16539	UNIPROT	RBSN	protein	Q9H1K0	UNIPROT	up-regulates	phosphorylation			9606									16138080	t		gcesareni	We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes.	SIGNOR-140146	0.2
PRMT1	protein	Q99873	UNIPROT	CNBP	protein	P62633	UNIPROT	down-regulates	methylation	Arg25	ECPTGGGrGRGMRSR	9606									24726729	t		miannu	Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding	SIGNOR-204958	0.376
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	RPTOR	protein	Q8N122	UNIPROT	up-regulates	phosphorylation	Ser721	TPRLRSVsSYGNIRA	9606				SIGNOR-C3					18722121	t		llicata	Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity	SIGNOR-252774	0.2
IGF1R	protein	P08069	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates	phosphorylation	Tyr612	TLHTDDGyMPMSPGV	9606									17827393	t		gcesareni	Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K).	SIGNOR-157742	0.864
PRKD1	protein	Q15139	UNIPROT	CFL1	protein	P23528	UNIPROT	down-regulates activity	phosphorylation	Ser3	sGVAVSDG										19329994	t		lperfetto	PKD1 regulates cofilin S3-phosphorylation|Both, oxidative stress as well as RhoA activation enhanced cofilin phosphorylation at S3, implicating an increased inhibition due to PKD1-mediated signalling events 	SIGNOR-275944	0.341
Caspase 1 complex	complex	SIGNOR-C220	SIGNOR	GSDMD	protein	P57764	UNIPROT	up-regulates activity	cleavage	Asp275	CLHNFLTdGVPAEGA	9606	BTO:0000007								26375003	t		lperfetto	 Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence |	SIGNOR-256415	0.634
STAT1	protein	P42224	UNIPROT	TAP1	protein	Q03518	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15778351	f		miannu	 We also show that this cytokine-dependent expression of TAP1 transcripts depends on STAT1 and IFN regulatory factor-2 (IRF-2), but not on IRF-1, and provide evidence that IRF-2 constitutively binds to the TAP1 gene promoter and enhances TAP1 promoter activity. We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested. 	SIGNOR-254531	0.277
RET	protein	P07949	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Tyr315	TFCGTPEyLAPEVLE	9606	BTO:0000944								15994200	t		lperfetto	The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity	SIGNOR-252619	0.329
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1868	SPTSPKYsPTSPKYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273037	0.556
PCSK7	protein	Q16549	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates				10090	BTO:0000165;BTO:0000222	BTO:0000887;BTO:0001103							14767066	f		lperfetto	The levels of ikb_? Where reduced in cells overexpressing mkk6 [] these results indicated that mkk6 was able to promote the degradation of the NF-kappaB inhibitor, in a p38-dependent manner.	SIGNOR-235837	0.2
CXCL1	protein	P09341	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates				9606									16885213	f		gcesareni	The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i).	SIGNOR-148454	0.2
CDK2	protein	P24941	UNIPROT	CDC6	protein	Q99741	UNIPROT	down-regulates activity	phosphorylation	Ser54	RVKALPLsPRKRLGD	9606			SIGNOR-C83						9889196	t		lperfetto	Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2.	SIGNOR-63891	0.94
D-thyroxine	smallmolecule	CHEBI:30659	ChEBI	THRB	protein	P10828	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0003736								6777394	t		miannu	 The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response.	SIGNOR-258401	0.8
EIF3_complex	complex	SIGNOR-C401	SIGNOR	Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	up-regulates activity	stabilization			9606									17581632	t		lperfetto	EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 	SIGNOR-269154	0.621
PTPN12	protein	Q05209	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	dephosphorylation	Tyr419	RLIEDNEyTARQGAK	10090									18482983	t			we identify SHP-2 and PTP-PEST as negative regulators of c-Src kinase | Inactivation of catalytically active c-Src kinase by the phosphatases SHP-2 or PTP-PEST by dephosphorylation of the tyrosine residue Tyr-416 within the c-Src kinase domain prevents the phosphorylation of villin	SIGNOR-248659	0.545
PRKDC	protein	P78527	UNIPROT	PRKDC	protein	P78527	UNIPROT	up-regulates	phosphorylation	Ser2056	VQSYSYSsQDPRPAT	9606									17189255	t		llicata	Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, in addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair.	SIGNOR-151445	0.2
embelin	chemical	CHEBI:4778	ChEBI	XIAP	protein	P98170	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001271								28704451	t		lperfetto	Targeting of X-linked inhibitor of apoptosis protein and PI3-kinase/AKT signaling by embelin suppresses growth of leukemic cells.	SIGNOR-262013	0.8
PMPCB	protein	O75439	UNIPROT	PINK1	protein	Q9BXM7	UNIPROT	down-regulates quantity by destabilization	cleavage			9606	BTO:0000007								22354088	t		miannu	Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy.	SIGNOR-261363	0.346
AMPK	complex	SIGNOR-C15	SIGNOR	NOS3	protein	P29474	UNIPROT	down-regulates activity	phosphorylation	Thr495	TGITRKKtFKEVANA	9606	BTO:0001853								24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251618	0.266
ARHGEF10	protein	O15013	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260535	0.505
LLGL2	protein	Q6P1M3	UNIPROT	Scribble_complex_DLG2-LLGL2_variant	complex	SIGNOR-C503	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270879	0.548
CASP3	protein	P42574	UNIPROT	Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	form complex	binding								cleavage:Asp28	IHGSESMdSGISLDN			15115390	t		lperfetto	Caspases are expressed as inactive proenzymes of 30−50 kDa that include an amino-terminal domain of variable length and sequence that is followed by two domains of conserved sequences:  a large subunit (approximately 20 kDa, designated p17 in caspase-3) and a small carboxy-terminal subunit (approximately 10 kDa, designated p12 in caspase-3). Activation is accomplished by proteolytic cleavage between these domains and subsequent assembly of heterotetramers that contain two copies each of the large and small subunits but lack the amino-terminal domains.	SIGNOR-256387	0.2
CSNK2A1	protein	P68400	UNIPROT	AIP	protein	O00170	UNIPROT	unknown	phosphorylation	Ser43	FHYRTLHsDDEGTVL	9534									12361709	t		llicata	Protein kinase CK2 (CK2) was identified as the 45-kDa kinase from COS 1 cell or liver extracts that was responsible for phosphorylation of serine 43 in the XAP2 peptide 39-57. Loss of phosphorylation at any or all of the serine residues did not significantly affect the ability of XAP2-FLAG to bind to the murine AhR in rabbit reticulocyte lysate or Hsp90 in COS-1 cells.	SIGNOR-250824	0.311
TLN1	protein	Q9Y490	UNIPROT	AX/b2 integrin	complex	SIGNOR-C171	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257621	0.482
UBE4B	protein	O95155	UNIPROT	PTTG1	protein	O95997	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									15611659	t		miannu	We further demonstrate that Ufd2 directly and efficiently ubiquitylates securin in vitro and is required for securin polyubiquitylation in vivo. This is the first description of a physiologic substrate for Ufd2, establishing this E4 enzyme as an important regulator of chromosome condensation and separation during mitosis in human cells. 	SIGNOR-271523	0.2
SETDB2	protein	Q96T68	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	methylation	Lys 10	RTKQTARkSTGGKAP	9606	BTO:0000007								20404330	t		miannu	 Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression.	SIGNOR-263894	0.2
NLK	protein	Q9UBE8	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	down-regulates quantity	phosphorylation			9606	BTO:0000007								16714285	t		miannu	NLK Augments the Ubiquitylation Activity of NARF against TCF/LEF. ctivation of NLK induced by unknown ligands leads to the phosphorylation of TCF/LEF. NARF then acts on TCF/LEF as an E3 ubiquitin-ligase and, together with E1 and E2 ubiquitylation enzymes, catalyze the ubiquitylation of TCF/LEF. Finally, ubiquitylated TCF/LEF is degraded by the 26 S proteasome.	SIGNOR-271596	0.751
RAD23B	protein	P54727	UNIPROT	TFIIH	complex	SIGNOR-C457	SIGNOR	up-regulates activity	binding												24086043	t		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275696	0.559
SOD1	protein	P00441	UNIPROT	DERL1	protein	Q9BUN8	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								18519638	t	P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)		 Various proteins involved in ERAD have been identified recently (Meusser et al. 2005). Among them, components of the retro-translocation machinery including ATPase p97, its cofactors Ufd1 and Npl4, and the ER membrane proteins Derlin-1 and VIMP are of key importance to ERAD function |Here we show that SOD1(mut) specifically interacted with Derlin-1, a component of endoplasmic reticulum (ER)-associated degradation (ERAD) machinery and triggered ER stress through dysfunction of ERAD.	SIGNOR-262785	0.438
AMPD1	protein	P23109	UNIPROT	adenosine 5'-monophosphate	smallmolecule	CHEBI:16027	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0001103							1631143	t		miannu	AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells. 	SIGNOR-269772	0.8
MAPK1	protein	P28482	UNIPROT	ERF	protein	P50548	UNIPROT	up-regulates	phosphorylation	Ser251	PLSPFPVsPLAGPGS	9606									10330152	t		lperfetto	The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a).	SIGNOR-67528	0.578
ACVR1B	protein	P36896	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by stabilization				9606									2920215	f	Regulation	miannu	Activin, also named FSH-releasing protein, was previously shown to induce hemoglobin accumulation in K562 cells and potentiate the proliferation and differentiation of CFU-E in human bone marrow cultures.	SIGNOR-251768	0.2
sorafenib	chemical	CHEBI:50924	ChEBI	RAF1	protein	P04049	UNIPROT	down-regulates	chemical inhibition			9606									21654832	t		gcesareni	Inhibition of map kinases mek, jnk, p38, and multikinases (braf, craf, vegfp by sorafenib) in wm-115 and m14 human melanoma cell lines led to either significant reduction or complete inhibition of the plk-1 protein expression.	SIGNOR-174039	0.8
TGFBR2	protein	P37173	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates activity	phosphorylation	Ser172	SLDRPFIsEGTTLKD	9606									8576253	t		lperfetto	Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta	SIGNOR-246728	0.709
PRKCA	protein	P17252	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser214	LVRSREVsVDEGRAC	-1									9677319	t		lperfetto	Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases.	SIGNOR-249000	0.292
DVL1	protein	O14640	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606									17569865	t		amattioni	The scaffold protein dishevelled (dvl) is required for lrp6 phosphorylation and aggregation. We propose that wnts induce coclustering of receptors and dvl in lrp6-signalosomes, which in turn triggers lrp6 phosphorylation to promote axin recruitment and beta-catenin stabilization.	SIGNOR-156072	0.697
SMAD7	protein	O15105	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates activity	binding			9606									20663871	t		lperfetto	The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation.	SIGNOR-167163	0.781
IRAK4	protein	Q9NWZ3	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Ser78	NKDQHSIsYTLSRAQ	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276126	0.643
RASGEF1C	protein	Q8N431	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates	binding			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-161505	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	DNMT1	protein	P26358	UNIPROT	down-regulates activity	phosphorylation	Ser714	DNIPEMPsPKKMHQG	-1									28143904	t		lperfetto	Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK decreased DNMT1 activity	SIGNOR-264788	0.291
BIRC2	protein	Q13490	UNIPROT	RIPK4	protein	P57078	UNIPROT	up-regulates activity	polyubiquitination		lys145	9606	BTO:0000007								21931591	t		miannu	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation.	SIGNOR-272708	0.361
PTPN1	protein	P18031	UNIPROT	STAT6	protein	P42226	UNIPROT	down-regulates activity	dephosphorylation			9606									22156494	t		miannu	Phosphorylated STAT6 may also serve as a cytoplasmic substrate for PTP1B since overexpression of PTP1B leads to STAT6 dephosphorylation and the suppression of STAT6 transcriptional activity, whereas PTP1B deficiency increases IL-4-induced STAT6 signaling in B-cells.	SIGNOR-277122	0.333
MMP7	protein	P09237	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272374	0.7
LHFPL5	protein	Q8TAF8	UNIPROT	Hair cells mechanotransduction channel	complex	SIGNOR-C290	SIGNOR	up-regulates activity	binding			10090		BTO:0000630							23217710	t		lperfetto	Here we show that TMHS is an auxiliary subunit of the hair cells mechanotransduction channel.|TMHS belongs to the tetraspan family. It binds to PCDH15, controls the assembly of the hair cells mechanotransduction machinery, regulates the properties of their mechanotransduction channels, and is required for adaptation.	SIGNOR-262574	0.426
EEF1A2	protein	Q05639	UNIPROT	Lys-tRNA(Lys)	smallmolecule	CHEBI:16047	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269522	0.8
5-aza-2'-deoxycytidine	chemical	CHEBI:50131	ChEBI	DNMT1	protein	P26358	UNIPROT	down-regulates activity	chemical inhibition			9606									14585280	t		miannu	Both Azacitidine and Decitabine may also exert antitumor activity through induction of DNA hypomethylation, by forming a covalent complex with the major DNA methyltransferase (now termed DNMT1).Azacitidine and Decitabine effectively deplete the cell of functional DNA methylating activity, which results in profound hypomethylation after several rounds of DNA replication (Fig. 2). DNMT1 is considered a bona fide anticancer target at different levels 	SIGNOR-259294	0.8
regorafenib	chemical	CHEBI:68647	ChEBI	TEK	protein	Q02763	UNIPROT	down-regulates activity	chemical inhibition			9606									24756792	t		miannu	In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically.	SIGNOR-259213	0.8
NEUROD1	protein	Q13562	UNIPROT	MGAT5B	protein	Q3V5L5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001976								21771782	f		miannu	 By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression.	SIGNOR-253825	0.254
CAMK2A	protein	Q9UQM7	UNIPROT	NCOR2	protein	Q9Y618	UNIPROT	down-regulates	phosphorylation	Ser2426	ASGDRPPsVSSVHSE	9606									22888005	t		lperfetto	We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation.	SIGNOR-191773	0.2
KCNB2	protein	Q92953	UNIPROT	VAPB	protein	O95292	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000007								29941597	t		lperfetto	Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions.	SIGNOR-262123	0.2
CAMK2B	protein	Q13554	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser16	KELEKRAsGQAFELI	9606	BTO:0000661								9686569	t		gcesareni	Stimulation via cd2 activated multiple signal transduction pathways, resulting in phosphorylation of distinct sites of stathmin. Ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells.	SIGNOR-59358	0.495
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	FOS	protein	P01100	UNIPROT	up-regulates	phosphorylation			9606	BTO:0001950								21561061	t		Luana	3b Augments c-Fos Levels by Activating the ERK Pathway. | Higher c-Fos levels were observed in 3b-expressing cells than in GFP-expressing control cells	SIGNOR-260762	0.2
TALDO1	protein	P37837	UNIPROT	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	up-regulates quantity	chemical modification			9606									19401148	t		miannu	Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (‚Äúdihydroxyacetone‚Äù) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 	SIGNOR-267091	0.8
IKBKE	protein	Q14164	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates	phosphorylation	Ser727	TDNLLPMsPEEFDEV	9606									17502367	t		gcesareni	All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).	SIGNOR-154775	0.411
SB 505124	chemical	CHEBI:100922	ChEBI	ACVR1B	protein	P36896	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206736	0.8
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	MBD4	protein	O95243	UNIPROT	up-regulates activity	phosphorylation	Ser262	SGFVQSDsKRESVCN										23195996	t		lperfetto	 Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12]	SIGNOR-275674	0.2
RHEB	protein	Q15382	UNIPROT	MTOR	protein	P42345	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								15854902	t		lperfetto	Rheb binds and regulates the mTOR kinase.	SIGNOR-135770	0.949
RARS1	protein	P54136	UNIPROT	Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	form complex	binding			9606									32644155	t		miannu	In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes).	SIGNOR-270357	0.2
UCHL5	protein	Q9Y5K5	UNIPROT	SMAD7	protein	O15105	UNIPROT	up-regulates	binding			9606									16027725	t		gcesareni	Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases.	SIGNOR-138879	0.649
PI3K	complex	SIGNOR-C156	SIGNOR	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9606	BTO:0000876	BTO:0001103							19436055	f		apalma	Low pM concentrations of GM-CSF mediate βc Ser585 phosphorylation, leading to 14-3-3 binding, PI-3 kinase activation, and hemopoietic cell survival, whereas at concentrations of 10 pM or more, GM-CSF mediates βc Tyr577 phosphorylation, Shc recruitment, and PI-3 kinase activation, thereby promoting both survival and proliferation.	SIGNOR-255576	0.7
GTF2H1	protein	P32780	UNIPROT	E2F1	protein	Q01094	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr433	DCDFGDLtPLDF	-1									10428966	t			TFIIH-mediated phosphorylation of E2F-1 plays a role in triggering E2F-1 degradation during S phase. E2F-1 activation domain interacts with a kinase activity which phosphorylates two sites, Ser403 and Thr433, within the activation domain. We demonstrate that TFIIH is responsible for the E2F-1 phosphorylation observed in cell extracts and that endogenous E2F-1 interacts in vivo with p62, a component of TFIIH, during S phase. 	SIGNOR-251260	0.445
SNX9	protein	Q9Y5X1	UNIPROT	DNM1	protein	Q05193	UNIPROT	up-regulates	binding			9606	BTO:0000567								15703209	t		miannu	Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes.	SIGNOR-133892	0.781
5-hydroxy-L-tryptophan	smallmolecule	CHEBI:17780	ChEBI	serotonin	smallmolecule	CHEBI:28790	ChEBI	up-regulates quantity	precursor of			9606									31024440	t	brain	lperfetto	In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT	SIGNOR-264186	0.8
NBEAL2	protein	Q6ZNJ1	UNIPROT	VWF	protein	P04275	UNIPROT	up-regulates				9606	BTO:0000132								28082341	f		lperfetto	Recent in vitro megakaryopoiesis studies using HSCs from GPS patients with NBEAL2 mutations showed normal MK differentiation with defective proplatelet formation and reduced α-granule proteins such as von Willebrand factor (VWF), thrombospondin and P-selectin.	SIGNOR-261884	0.276
MRPS15	protein	P82914	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261455	0.73
TAF9	protein	Q16594	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269582	0.515
CBLB	protein	Q13191	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	ubiquitination			9606	BTO:0000007								11375397	t		lperfetto	Cbl proteins function as ubiquitin protein ligases for the activated epidermal growth factor receptor and, thus, negatively regulate its activity.	SIGNOR-236519	0.748
PPM1F	protein	P49593	UNIPROT	PAK2	protein	Q13177	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000150;BTO:0000093								20016286	t		gcesareni	Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity.	SIGNOR-162149	0.264
PRKCA	protein	P17252	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser320	QRSRKRLsQDAYRRN	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89162	0.538
MAPK1	protein	P28482	UNIPROT	PPARA	protein	Q07869	UNIPROT	up-regulates activity	phosphorylation	Ser12	ESPLCPLsPLEAGDL	9606	BTO:0000599								10187842	t		lperfetto	We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution.	SIGNOR-249433	0.559
WNT2	protein	P09544	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131727	0.608
EREG	protein	O14944	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606		BTO:0001253							20513444	t	Epiregulin may be a mediator of localized cell proliferation	gcesareni	Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling.	SIGNOR-165782	0.889
CD38	protein	P28907	UNIPROT	nicotinic acid-adenine dinucleotide phosphate	smallmolecule	CHEBI:76072	ChEBI	up-regulates quantity	chemical modification			9606									18626062	t		miannu	The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR.	SIGNOR-264245	0.8
IRF3	protein	Q14653	UNIPROT	IFNB1	protein	P01574	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								16699525	t		lperfetto	Similarly, exogenous expression of wild-type Pin1 suppressed TLR3-mediated, IRF3-dependent activation of the IFN-beta promoter and reduced IFN-beta secretion in culture supernatants	SIGNOR-252257	0.653
ATP	smallmolecule	CHEBI:15422	ChEBI	P2RX7	protein	Q99572	UNIPROT	up-regulates	chemical activation			9606									18827222	t		mrosina	Pericellular ATP activates P2XRs on the T cell in an autocrine fashion (step 4) and perhaps also P2X7 receptors on the APC in a paracrine fashion resulting in IL-1beta processing and release (step 5).	SIGNOR-254965	0.8
PLK1	protein	P53350	UNIPROT	BORA	protein	Q6PGQ7	UNIPROT	down-regulates	phosphorylation	Thr501	QMDSGYNtQNCGSNI	9606									18521620	t		gcesareni	Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp).	SIGNOR-178807	0.78
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	USP9X	protein	Q93008	UNIPROT	up-regulates activity	phosphorylation	Ser2547	YEGSEEVsPPQTKDQ										32152317	t	Phosphosites were derived from Figure S1	lperfetto	Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. 	SIGNOR-275612	0.273
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr36	LPPGDYStTPGGTLF	10090	BTO:0002572		SIGNOR-C3						20670887	t		lperfetto	Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation	SIGNOR-167180	0.924
EXOSC2	protein	Q13868	UNIPROT	Exosome_Complex	complex	SIGNOR-C255	SIGNOR	form complex	binding			-1									24189234	t		miannu	The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 	SIGNOR-261387	0.948
MAPK3	protein	P27361	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Ser381	CIPTAGMsPSRSNTI	10029	BTO:0000246								15379552	t		lperfetto	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-249459	0.618
AP3S1	protein	Q92572	UNIPROT	AP-3 complex	complex	SIGNOR-C247	SIGNOR	form complex	binding			9606									21097499	t		lperfetto	Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)	SIGNOR-260680	0.884
dothiepin	chemical	CHEBI:36798	ChEBI	CHRM2	protein	P08172	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8100134	t		miannu	Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 	SIGNOR-258699	0.8
AIP	protein	O00170	UNIPROT	TFF1	protein	P04155	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000093								21984905	t	 	 	In this study, we show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells.	SIGNOR-253643	0.2
PAK1	protein	Q13153	UNIPROT	PGAM	proteinfamily	SIGNOR-PF78	SIGNOR	down-regulates	phosphorylation			9606	BTO:0000130								12189148	t	Activated pak1|inferred from family member	gcesareni	Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity.	SIGNOR-270283	0.2
AKT2	protein	P31751	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLPRPE	9606									16272144	t		gcesareni	FOXO4 transcription factor, also referred to AFX, contains three putative phosphorylation motif sites for protein kinase B (PKB), Thr32, Ser197, and Ser262, and it is proposed that phosphorylated FOXO4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression.[...]These results indicate that phosphorylation at Thr32 and Ser197 is indispensable, whereas that at Ser262 is not critical, for regulation of the nuclear localization and transcriptional activity of FOXO4	SIGNOR-248055	0.593
NFIL3	protein	Q16649	UNIPROT	PER1	protein	O15534	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11316793	t		miannu	E4BP4, a basic leucine zipper transcription factor, contains a DNA-binding domain closely related to DBP, HLF, and TEF, which are PAR proteins. Here, we show that the phase of e4bp4 mRNA rhythm is opposite to that of the dbp, hlf, and tef rhythms in the suprachiasmatic nucleus (SCN), the mammalian circadian center, and the liver. The protein levels of E4BP4 and DBP also fluctuate in almost the opposite phase. All PAR proteins activate, whereas E4BP4 suppresses the mPer1 promoter through the same sequence	SIGNOR-268056	0.354
RBPJ	protein	Q06330	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									15866158	t			Induction of the p21WAF1/Cip1 gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-J_ protein to the p21 promoter.	SIGNOR-252032	0.313
GLI1	protein	P08151	UNIPROT	MYCN	protein	P04198	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150;BTO:0000551								19860666	f		gcesareni	GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin	SIGNOR-188872	0.412
TP53INP2	protein	Q8IXH6	UNIPROT	MAP1LC3A	protein	Q9H492	UNIPROT	up-regulates	binding			9606									19056683	t		gcesareni	Tp53inp2 is a scaffold protein that recruits lc3 and/or lc3-related proteins to the autophagosome membrane by interacting with the transmembrane protein vmp1	SIGNOR-182614	0.416
XIAP	protein	P98170	UNIPROT	CASP9	protein	P55211	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								9545235	t		lperfetto	IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspasesThese findings demonstrate that IAPs can suppress different apoptotic pathways by inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis	SIGNOR-56484	0.92
GSK3B	protein	P49841	UNIPROT	STAT2	protein	P52630	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr385	ILTSNQKtLTPEKGQ	9606	BTO:0002181								31843895	t		miannu	GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation.	SIGNOR-276765	0.293
MOB1A	protein	Q9H8S9	UNIPROT	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	up-regulates	binding			9606									21084559	t	Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases.	gcesareni	Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1	SIGNOR-269866	0.94
a7/b1 integrin	complex	SIGNOR-C126	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269007	0.7
VHL	protein	P40337	UNIPROT	DAB2	protein	P98082	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000037								15824735	f		miannu	 three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL. 	SIGNOR-255602	0.2
HSP90AB1	protein	P08238	UNIPROT	NOD2	protein	Q9HC29	UNIPROT	up-regulates quantity by stabilization	binding			9606									23019338	t		miannu	Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation. 	SIGNOR-252415	0.326
quetiapine	chemical	CHEBI:8707	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			10116	BTO:0000529								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258535	0.8
NME1	protein	P15531	UNIPROT	NME1	protein	P15531	UNIPROT	unknown	phosphorylation	Ser122	NIIHGSDsVESAEKE	-1									8810265	t		miannu	For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown. 	SIGNOR-250301	0.2
LAT	protein	O43561	UNIPROT	PIK3R2	protein	O00459	UNIPROT	up-regulates activity	binding			9606					phosphorylation:Tyr161;Tyr200	DDYHNPGyLVVLPDS;SMESIDDyVNVPESG			11368773	t		lperfetto	By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.	SIGNOR-246055	0.2
SRC	protein	P12931	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1110	GSVQNPVyHNQPLNP	9606									8845374	t		lperfetto	The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site.	SIGNOR-44243	0.609
KCNC2	protein	Q96PR1	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			9606									11506885	t		miannu	Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height	SIGNOR-265585	0.8
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr37	PPGDYSTtPGGTLFS	9606	BTO:0000007		SIGNOR-C3						12747827	t		lperfetto	Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo.	SIGNOR-101119	0.924
XIAP	protein	P98170	UNIPROT	RIPK4	protein	P57078	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0000007								21931591	t		miannu	In this study, we report that in addition to RIP1 and RIP2, also RIP3 and RIP4 directly interact with XIAP, cIAP1 and cIAP2. When comparing the ability of these IAPs to directly conjugate RIP1–RIP4 with ubiquitin chains, we found that cIAP1 was the most effective E3 and was capable of ubiquitinating all four RIPs in the presence of the E2 component UbcH5a. On the contrary, XIAP was only capable of inducing weak ubiquitination of RIP4.	SIGNOR-272716	0.338
FOXJ1	protein	Q92949	UNIPROT	EFHC1	protein	Q5JVL4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000939								23822649	t		miannu	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266934	0.364
3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea	chemical	CHEBI:91362	ChEBI	AURKC	protein	Q9UQB9	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192814	0.8
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1626	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120088	0.316
tiagabine	chemical	CHEBI:9586	ChEBI	SLC6A1	protein	P30531	UNIPROT	down-regulates activity	chemical inhibition			-1									7851497	t		miannu	Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. 	SIGNOR-258477	0.8
DGC	complex	SIGNOR-C217	SIGNOR	GABA-A (a6-b3-d) receptor	complex	SIGNOR-C329	SIGNOR	up-regulates quantity	binding			9606									22626542	t		miannu	 In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses.	SIGNOR-265441	0.2
SIRT7	protein	Q9NRC8	UNIPROT	H3-2	protein	Q5TEC6	UNIPROT	up-regulates activity	deacetylation	Lys19	TGGKAPRkQLATKAA										22722849	t		lperfetto	SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. 	SIGNOR-275871	0.2
AREL1	protein	O15033	UNIPROT	MTX2	protein	O75431	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								34584540	t		lperfetto	Therefore, these results implied that AREL1 ubiquitinates and promotes the degradation of MTX2.	SIGNOR-267674	0.2
AKT2	protein	P31751	UNIPROT	MTOR	protein	P42345	UNIPROT	up-regulates				9606		BTO:0000887;BTO:0001103							12782654	f		gcesareni	It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor.	SIGNOR-101324	0.625
CDK2	protein	P24941	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser263	CKLFDSPsLCSSSTR	9606									17110335	t		gcesareni	We show here that dna-responsive checkpoints activate pp2a/b56delta phosphatase complexes to dephosphorylate cdc25 at a site distinct from ser287 (t138), the phosphorylation of which is required for 14-3-3 release.	SIGNOR-150839	0.824
PRKG1	protein	Q13976	UNIPROT	GABRR1	protein	P24046	UNIPROT	unknown	phosphorylation	Ser444	QRKSQRSsYVSMRID	-1									12175859	t		miannu	Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The 1 IC-loop does not have consensus sequences for PKG, but we found that this enzyme phosphorylated the same sites as PKA: S422, S423 (Fig. 5A).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation	SIGNOR-262757	0.322
PTPRK	protein	Q15262	UNIPROT	ZNRF3	protein	Q9ULT6	UNIPROT	up-regulates activity	dephosphorylation			9606	BTO:0003009								31934854	t			We show that PTPRK acts via the transmembrane E3 ubiquitin ligase ZNRF3, a negative regulator of Wnt signaling promoting Wnt receptor degradation, which is also expressed in the organizer.	SIGNOR-260110	0.363
HIPK2	protein	Q9H2X6	UNIPROT	PAX6	protein	P26367	UNIPROT	up-regulates activity	phosphorylation	Thr281	QRRQASNtPSHIPIS	9606	BTO:0001938								16407227	t			HIPK2 phosphorylates the activation domain of Pax6, which augments Pax6 transactivation by enhancing its interaction with p300. Mass spectrometric analysis identified three Pax6 phosphorylation sites as threonines 281, 304, and 373. 	SIGNOR-251269	0.476
MAPK8	protein	P45983	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates activity	phosphorylation	Ser112	AIKVEPAsPPYYSEK	9606									9030579	t		llicata	The a/b domain of human ppargamma1 was phosphorylated in vivo, and this was abolished either by mutation of serine 84 to alanine (s84a) or coexpression of a phosphoprotein phosphatase. In vitro, this domain was phosphorylated by erk2 and jnk, and this was markedly reduced in the s84a mutant. Thus, phosphorylation of a mitogen-activated protein kinase site in the a/b region of ppargamma inhibits both ligand-independent and ligand-dependent transactivation functions.	SIGNOR-46518	0.543
BAG5	protein	Q9UL15	UNIPROT	PRKN	protein	O60260	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								15603737	t		Monia	Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity Immunoprecipitation (IP) of GFP-parkin resulted in the coimmunoprecipitation of both Hsp70 and BAG5 or BAG5(DARA) (Figure 4A). Furthermore, IP of GFP-parkin resulted in the coimmunoprecipitation of BAG5 or BAG5 (DARA) in the absence of overexpressed Hsp70. Taken together, these data demonstrate that BAG5 can directly inhibit parkin-mediated autoubiquitinylation independently of Hsp70.	SIGNOR-261198	0.2
LCK	protein	P06239	UNIPROT	LCP2	protein	Q13094	UNIPROT	unknown	phosphorylation	Tyr423	NSLNEEWyVSYITRP	-1									8702662	t			Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro	SIGNOR-251381	0.744
CLTC	protein	Q00610	UNIPROT	AP-3/clathrin vescicle	complex	SIGNOR-C250	SIGNOR	form complex	binding			9606									23103167	t		lperfetto	Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors	SIGNOR-260670	0.735
RNF5	protein	Q99942	UNIPROT	MAVS	protein	Q7Z434	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys362	RAGMVPSkVPTSMVL	9606	BTO:0000007								20483786	t		miannu	In this study, we showed that the E3 ubiquitin ligase RING-finger protein 5 (RNF5) interacted with VISA at mitochondria in a viral infection-dependent manner. Domain mapping experiments indicated that the C-terminal transmembrane domain of VISA was required for its interaction with RNF5. RNF5 targeted VISA at K362 and K461 for K48-linked ubiquitination and degradation after viral infection, whereas knockdown of RNF5 reversed virus-induced downregulation of VISA at the early phase. 	SIGNOR-271488	0.468
PTPRK	protein	Q15262	UNIPROT	EGFR	protein	P00533	UNIPROT	unknown	dephosphorylation	Tyr1092	TFLPVPEyINQSVPK	10029	BTO:0000246								16263724	t			RPTP-kappa also reduced epidermal growth factor-dependent EGFR tyrosine phosphorylation in CHO cells. Purified RPTP-kappa preferentially dephosphorylated EGFR tyrosines 1068 and 1173 in vitro.	SIGNOR-248722	0.602
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT9B	protein	O14905	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242739	0.28
GSK3B	protein	P49841	UNIPROT	HSF1	protein	Q00613	UNIPROT	down-regulates activity	phosphorylation	Ser303	RVKEEPPsPPQSPRV	-1									8940068	t			Ser-303 is phosphorylated by glycogen synthase kinase 3 (GSK3) through a mechanism dependent on primary phosphorylation of Ser-307 by MAPK. Secondary phosphorylation of Ser-303 by GSK3 may thus repress the activity of HSF-1, and its requirement for priming by MAPK phosphorylation of Ser-307 provides a potential link between the MAPK cascade and HSF-1. 	SIGNOR-251216	0.539
dexmedetomidine	chemical	CHEBI:4466	ChEBI	ADRA2A	protein	P08913	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258906	0.8
MAP2K2	protein	P36507	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates activity	phosphorylation			10090									11730323	t			Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs	SIGNOR-258997	0.73
MELK	protein	Q14680	UNIPROT	EZH2	protein	Q15910	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser220	RPPRKFPsDKIFEAI	9606	BTO:0002030								31434700	t		miannu	We observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination. 	SIGNOR-277480	0.334
PRKD1	protein	Q15139	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates activity	phosphorylation	Ser259	FPLRKTAsEPNLKVR	9534	BTO:0004055								15367659	t		lperfetto	Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes.	SIGNOR-249270	0.532
PAX7/MLL2 complex	complex	SIGNOR-C91	SIGNOR	MYF5	protein	P13349	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002314	BTO:0000887;BTO:0001103							22863532	f		miannu	Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5.	SIGNOR-198641	0.508
P-TEFb	complex	SIGNOR-C238	SIGNOR	MLLT3	protein	P42568	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606	BTO:0000007								17135274	t		miannu	Phosphorylation of Af9 and Enl by P-TEFb promotes their proteolysis	SIGNOR-266800	0.687
TBP	protein	P20226	UNIPROT	LIN28B	protein	Q6ZN17	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								23494474	f		miannu	We conclude that the oncoprotein HBXIP as a co-activator of TF II D transactivates Lin28B promoter via directly binding to TBP to upregulate the expression of Lin28B in promotion of proliferation of breast cancer cells, in which Lin28B maintains the high level of HBXIP through suppressing miR-520b in a feedback manner. 	SIGNOR-255252	0.252
PAK2	protein	Q13177	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Thr8	MTAKMETtFYDDALN	9606	BTO:0000848								21177766	t		lperfetto	P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)	SIGNOR-170768	0.272
CSNK2A1	protein	P68400	UNIPROT	SAT1	protein	P21673	UNIPROT	unknown	phosphorylation	Ser146	FYKRRGAsDLSSEEG	-1									8954982	t		llicata	Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149.	SIGNOR-250949	0.33
FGF2	protein	P09038	UNIPROT	ALPL	protein	P05186	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004473								19049325	f		miannu	FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2.	SIGNOR-252194	0.385
DIABLO	protein	Q9NR28	UNIPROT	BIRC5	protein	O15392	UNIPROT	down-regulates	binding			9606									17546047	t		gcesareni	Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. mitochondrial survivin associated with smac/diablo, delaying its release.	SIGNOR-155364	0.586
GAS2L3	protein	Q86XJ1	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates				9606									24706950	f		miannu	Previous work has shown that members of the growth-arrest-specific 2 (GAS2) family mediate the crosstalk between filamentous actin (F-actin) and MTs, but the molecular basis of this process remained unclear. By using fluorescence microscopy, we demonstrate that three members of this family, GAS2-like 1, GAS2-like 2 and GAS2-like 3 (G2L1, G2L2 and G2L3, also known as GAS2L1, GAS2L2 and GAS2L3, respectively) are differentially involved in mediating the crosstalk between F-actin and MTs. 	SIGNOR-273702	0.7
MELK	protein	Q14680	UNIPROT	MELK	protein	Q14680	UNIPROT	up-regulates	phosphorylation	Thr167	NKDYHLQtCCGSLAY	9606									16216881	t		gcesareni	We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.	SIGNOR-141022	0.2
TESK1	protein	Q15569	UNIPROT	TESK1	protein	Q15569	UNIPROT	up-regulates activity	phosphorylation	Ser220	EPLAVVGsPYWMAPE	-1									10207045	t		Manara	These results suggest that autophosphorylation of Ser-215 is an important step to positively regulate the kinase activity of TESK1.	SIGNOR-260825	0.2
AKT1	protein	P31749	UNIPROT	BTK	protein	Q06187	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser51	FERGRRGsKKGSIDV	9606	BTO:0003289								23754751	t		miannu	The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain. 	SIGNOR-276466	0.301
GSK1059615	chemical	CHEBI:71955	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252667	0.8
LARP7	protein	Q4G0J3	UNIPROT	HEXIM1	protein	O94992	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								30824372	t		Monia	To investigate whether LARP7 is part of the known 7SK RNP implicated in the regulation of transcription, co‐immunoprecipitation studies were performed using the nuclear extracts of HeLa cells (Fig 3A, lanes 1–4). Antibodies against LARP7, CDK9 and HEXIM1 efficiently precipitated 7SK RNA, whereas no RNA was found in the control (Fig 3A, lower panel, lanes 1–4). Interestingly, HEXIM1, CDK9, CYCT1 and LARP7 were present in all immunopurifications, as determined by mass spectrometry of silver‐stained gels (Fig 3A; data not shown) and western blotting. In conclusion, these experiments show that LARP7 negatively regulates not only viral but also cellular POLII class genes through the 7SK P‐TEFb system.	SIGNOR-261183	0.708
SOSTDC1	protein	Q6X4U4	UNIPROT	WNT10B	protein	O00744	UNIPROT	down-regulates activity				10090									22829579	f		lperfetto	Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells.	SIGNOR-242698	0.391
CD79A	protein	P11912	UNIPROT	BCR-Mk	complex	SIGNOR-C433	SIGNOR	form complex	binding			9606	BTO:0000776								32323266	t		scontino	BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition.	SIGNOR-268188	0.641
PDX1	protein	P52945	UNIPROT	NKX6-1	protein	P78426	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11309388	t			In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1.	SIGNOR-255542	0.481
N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide	chemical	CHEBI:91399	ChEBI	CDK2	protein	P24941	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258087	0.8
ELOVL	proteinfamily	SIGNOR-PF93	SIGNOR	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267902	0.8
phenylalanine	smallmolecule	CHEBI:28044	ChEBI	Phe-tRNA(Phe)	smallmolecule	CHEBI:29153	ChEBI	up-regulates quantity	precursor of			9606									20223217	t		miannu	Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers.	SIGNOR-270444	0.8
CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	down-regulates quantity by destabilization	chemical modification			9606									31320642	t		lperfetto	CCR4-NOT is a conserved multiprotein complex which regulates eukaryotic gene expression principally via shortening of poly(A) tails of messenger RNA or deadenylation. |The poly(A) tails at 3′ ends of eukaryotic mRNAs are crucial for their cytoplasmic stability and to enhance the initiation of translation. Newly synthesized metazoan mRNAs possess long poly(A) tails1, and following export to the cytoplasm the tails are reported to be ~60–80 nucleotides on average at steady state2. Poly(A) tails are also important for translational efficiency at the embryonic stage2 and the length of the poly(A) tail was reported to be correlated with translational efficiency3. The multisubunit CCR4-NOT complex is principally responsible for efficient processive shortening of poly(A) tails, or deadenylation, in addition to other function	SIGNOR-268312	0.8
LEF1	protein	Q9UJU2	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							16936075	f	The other members of the Lef1 HMGB1 protein super-family, Tcf1 and Tcf3, were also expressed in the PSM and the newly formed somites, although at a lower level than was Lef1.	gcesareni	Furthermore, we show that direct activation is mediated by binding of the tcf-lef/ - catenin complex to the myf5 epaxial enhancer and to a newly identified element upstream of this enhancer.	SIGNOR-149170	0.255
CACNA1A	protein	O00555	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									30849329	t		miannu	Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]).	SIGNOR-264323	0.8
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	DYSF	protein	O75923	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136497	0.351
SMAD5	protein	Q99717	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	phosphorylation			9606									20957627	t		gcesareni	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.	SIGNOR-168737	0.659
5-(1H-indol-3-ylmethyl)-3-methyl-2-sulfanylidene-4-imidazolidinone	chemical	CHEBI:91658	ChEBI	RIPK1	protein	Q13546	UNIPROT	down-regulates	chemical inhibition			9606									19524513	t		gcesareni	The interaction between rip1 and rip3 is abolished by the rip1 kinase inhibitor necrostatin-1.	SIGNOR-186075	0.8
AURKB	protein	Q96GD4	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser278	QKVAERRsSPLLRRK	9606									22865920	t		lperfetto	We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions	SIGNOR-198650	0.261
GHSR	protein	Q92847	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257054	0.357
SHMT2	protein	P34897	UNIPROT	(6R)-5,10-methylenetetrahydrofolate(2-)	smallmolecule	CHEBI:15636	ChEBI	up-regulates quantity	chemical modification			9606									32439610	t		lperfetto	Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. 	SIGNOR-268227	0.8
TGFB1	protein	P01137	UNIPROT	LPL	protein	P06858	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000801								11742878	f	Regulation of expression	miannu	TGF-β1 inhibited gene expression and cell surface activity of LPL. TGF-β1 did not have an effect on LPL activity when it was added directly to the LPL activity assay (data not shown); however, as shown in the Table, TGF-β1 significantly reduced LPL mRNA by 55.0%	SIGNOR-251847	0.268
PTPN9	protein	P43378	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1189	RDIYETDyYRKGGKG	9606									16679294	t		gcesareni	Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action	SIGNOR-146672	0.263
CSNK2A1	protein	P68400	UNIPROT	PPP1R2	protein	P41236	UNIPROT	up-regulates	phosphorylation	Ser122	RIQEQESsGEEDSDL	9606									9405437	t		gcesareni	Recombinant inh2 was phosphorylated by kinases in cytosols prepared from g1 and s phase cells. The amount of inh2 kinase attributed to casein kinase 2, based on inhibition by heparin, increased 2.6-fold from g1 to s phase	SIGNOR-53861	0.311
RPS6KA5	protein	O75582	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates	phosphorylation			9606									12628924	t		lperfetto	Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276.	SIGNOR-217424	0.604
CSNK2A1	protein	P68400	UNIPROT	PRPF3	protein	O43395	UNIPROT	up-regulates	phosphorylation	Thr494	TEAVQDPtKVEAHVR	9606									17932117	t		lperfetto	Our findings provide new insights into the biology of hprp3p and suggest that the loss of hprp3p phosphorylation at thr494 is a key step for initiating thr494met aberrant interactions within u4/u6 snrnp complex and that these are likely linked to the rp18 phenotype.	SIGNOR-158319	0.2
PRKACA	protein	P17612	UNIPROT	SPTBN1	protein	Q01082	UNIPROT	down-regulates activity	phosphorylation	Thr2159	NGATEQRtSSKESSP	-1									17088250	t		miannu	Short C-terminal splice variant of betaII-spectrin (betaIISigma2) is a substrate for phosphorylation. protein kinase A phosphorylates Thr-2159. Mammalian alphaII- and betaII-spectrin subunits form dimers that associate head to head with high affinity to form tetramers In vitro, protein kinase A phosphorylation of an active fragment of betaIISigma2 greatly reduced its interaction with alphaII-spectrin at the tetramerization site.	SIGNOR-250054	0.336
FGG	protein	P02679	UNIPROT	FN1	protein	P02751	UNIPROT	down-regulates activity	binding			9606									2243140	t	Regulation	miannu	Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a).	SIGNOR-251970	0.534
HIF1A	protein	Q16665	UNIPROT	KDM5C	protein	P41229	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271564	0.262
STK4	protein	Q13043	UNIPROT	Mob1	proteinfamily	SIGNOR-PF42	SIGNOR	up-regulates	phosphorylation			9606									21808241	t	MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors.	gcesareni	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction.	SIGNOR-269856	0.896
KLF4	protein	O43474	UNIPROT	SRF	protein	P11831	UNIPROT	down-regulates	binding			9606		BTO:0000887;BTO:0001260							21673106	t		gcesareni	Klf4 antagonizes contractile gene expression through diverse mechanisms including (i) inhibiting the binding of srf-myocd or srf-mrtfs to the carg box by direct association with srf.	SIGNOR-174258	0.377
TSC2	protein	P49815	UNIPROT	TSC	complex	SIGNOR-C101	SIGNOR	form complex	binding			9606									12172553	t		lperfetto	TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR).	SIGNOR-217913	0.933
CC2D1A	protein	Q6P1N0	UNIPROT	RAD21	protein	O60216	UNIPROT	up-regulates activity	binding												20171170	t	centrosome	lperfetto	Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. | In the centrosome, it regulates spindle pole localization of the cohesin subunit Scc1, thereby mediating centriole cohesion during mitosis.	SIGNOR-268294	0.2
SF3B1	protein	O75533	UNIPROT	SF3b	complex	SIGNOR-C442	SIGNOR	form complex	binding			9606									32140746	t		lperfetto	Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a).	SIGNOR-268403	0.937
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	RPS6KA3	protein	P51812	UNIPROT	up-regulates	phosphorylation			9606									10980595	t	inferred from 70% family members	llicata	We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway	SIGNOR-270014	0.2
CDK1	protein	P06493	UNIPROT	RAD9A	protein	Q99638	UNIPROT	up-regulates activity	phosphorylation	Ser336	PGPQPPKsPGPHSEE	9606	BTO:0000567								12734188	t		lperfetto	Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9.	SIGNOR-101051	0.37
RORA	protein	P35398	UNIPROT	PCP4	protein	P48539	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001011								19381306	t		miannu	RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. 	SIGNOR-266848	0.2
P2RY10	protein	O00398	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257287	0.2
UHMK1	protein	Q8TAS1	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates	phosphorylation	Ser10	NVRVSNGsPSLERMD	9606									10831586	t		lperfetto	Hkis is a nuclear protein that binds the c-terminal domain of p27(kip1) and phosphorylates it on s10 in vitro and in vivo, promoting its nuclear export to the cytoplasm.Phosphorylation at serine 10, a major phosphorylation site of p27(kip1), increases its protein stability	SIGNOR-77705	0.377
MAPK3	protein	P27361	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation			9606									7618106	t		lperfetto	The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation	SIGNOR-29923	0.582
PTK2	protein	Q05397	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr577	YMEDSTYyKASKGKL	9606		BTO:0000671							15694384	t		llicata	Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925.	SIGNOR-133845	0.2
F11	protein	P03951	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	cleavage			9606		BTO:0000131							20110423	t		lperfetto	Factor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX.|The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets.	SIGNOR-263537	0.462
FOXO3	protein	O43524	UNIPROT	GALT	protein	P07902	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		 BTO:0000975							17975019	f	 	miannu	Our finding that FOXO3 regulates the expression of Galt and enhances its transcriptional activity indicates that it is the repression of FOXO3 by PRL acting through RS that prevents Galt expression in the ovary and causes follicular death.	SIGNOR-254186	0.2
SRC	protein	P12931	UNIPROT	EPHA2	protein	P29317	UNIPROT	up-regulates activity	phosphorylation	Tyr594	TYVDPHTyEDPNQAV	9606									24457997	t		gcesareni	SRC phosphorylates EPHA2 on Tyr594|. It is therefore likely that this phosphorylation site is included in the binding motif of an additional signalling molecule required for cell transformation.	SIGNOR-246104	0.43
3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	THRB	protein	P10828	UNIPROT	up-regulates activity	chemical activation			10116	BTO:0000759								2158622	t		miannu	We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 	SIGNOR-258384	0.8
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	up-regulates quantity	precursor of			9606									34674502	t		scontino	Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule. 	SIGNOR-267042	0.8
POLR2J2	protein	Q9GZM3	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606									9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266174	0.2
HLX	protein	Q14774	UNIPROT	EGR1	protein	P18146	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003980								20008130	t		Luana	In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.	SIGNOR-261621	0.265
MAPK1	protein	P28482	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser214	PTSSDPGsPFQMPAD	9606									9335504	t		llicata	In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1	SIGNOR-52691	0.59
GSK3B	protein	P49841	UNIPROT	PSEN1	protein	P49768	UNIPROT	down-regulates activity	phosphorylation	Ser357	PHRSTPEsRAAVQEL	9606	BTO:0000007		SIGNOR-C110						17360711	t		gcesareni	We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin.	SIGNOR-153631	0.605
OGDC	complex	SIGNOR-C397	SIGNOR	NADH	smallmolecule	CHEBI:16908	ChEBI	up-regulates quantity	chemical modification			9606									15953811	t		miannu	The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH.	SIGNOR-266259	0.8
ADRB2	protein	P07550	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256952	0.412
TNKS2	protein	Q9H2K2	UNIPROT	TERF1	protein	P54274	UNIPROT	down-regulates activity	ADP-ribosylation			-1									11739745	t		lperfetto	Tankyrase 2 poly(ADP-ribosyl)ated itself and TRF1. Overexpression of tankyrase 2 in the nucleus released endogenous TRF1 from telomeres.	SIGNOR-263376	0.567
CSNK2A1	protein	P68400	UNIPROT	TTI1	protein	O43156	UNIPROT	down-regulates	phosphorylation	Ser828	DVADGNVsDFDNEEE	9606									23263282	t		lperfetto	Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1	SIGNOR-200240	0.2
PRKAA1	protein	Q13131	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation	Ser259	SQRQRSTsTPNVHMV	9606			SIGNOR-C15						11971957	t		gcesareni	Mutation of serine 259 increased the basal raf-1 activity and rendered it largely resistant to inhibition by pka.	SIGNOR-86133	0.348
SIRT7	protein	Q9NRC8	UNIPROT	FBL	protein	P22087	UNIPROT	up-regulates activity	deacetylation	Lys121	GESVYGEkRVSISEG										30540930	t		lperfetto	Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206)	SIGNOR-275895	0.274
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	NCOR1	protein	O75376	UNIPROT	down-regulates	phosphorylation	Ser1450	TVRSRHTsVVSSGPS	9606	BTO:0001271								23940660	t		lperfetto	Akt-induced phosphorylation of n-cor at serine 1450 contributes to its misfolded conformational dependent loss (mcdl) in acute myeloid leukemia of the m5 subtype.	SIGNOR-244318	0.2
Caspase 1 complex	complex	SIGNOR-C220	SIGNOR	IL1B	protein	P01584	UNIPROT	up-regulates activity	cleavage	Asp116	DNEAYVHdAPVRSLN	-1									1919001	t		lperfetto	IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta. 	SIGNOR-256376	0.796
perfluorodecanoic acid	chemical	CHEBI:35546	ChEBI	PPARD	protein	Q03181	UNIPROT	up-regulates activity	chemical activation			-1									31332417	t		miannu	In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group.	SIGNOR-268758	0.8
Neurokinin B	smallmolecule	CHEBI:80312	ChEBI	TACR3	protein	P29371	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257588	0.8
CREBBP	protein	Q92793	UNIPROT	FBL	protein	P22087	UNIPROT	down-regulates activity	acetylation	Lys205	RDLINLAkKRTNIIP										30540930	t		lperfetto	Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206)	SIGNOR-275896	0.274
PRKAA1	protein	Q13131	UNIPROT	EEF2K	protein	O00418	UNIPROT	up-regulates activity	phosphorylation	Ser398	DSLPSSPsSATPHSQ	-1									14709557	t		miannu	Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398. phosphorylation of eEF2 kinase at Ser-398 leads to an increase in its activity.	SIGNOR-250157	0.473
IRAK1	protein	P51617	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Ser78	NKDQHSIsYTLSRAQ	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276133	0.758
TGFB2	protein	P61812	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates	binding			9606									1310899	t		gcesareni	A cdna encoding the tgf-beta type ii receptor protein has been isolated by an expression cloning strategy. The cloned cdna, when transfected into cos cells, leads to overexpression of an approximately 80 kd protein that specifically binds radioiodinated tgf-beta 1. Excess tgf-beta 1 competes for binding of radioiodinated tgf-beta 1 in a dose-dependent manner and is more effective than tgf-beta 2.	SIGNOR-16690	0.744
UPF2	protein	Q9HAU5	UNIPROT	Upf-EJC	complex	SIGNOR-C367	SIGNOR	form complex	binding			9606	BTO:0000567								17803942	t		miannu	The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1	SIGNOR-265238	0.972
MAPK8	protein	P45983	UNIPROT	APP	protein	P05067	UNIPROT	up-regulates	phosphorylation	Thr743	VEVDAAVtPEERHLS	9606	BTO:0000793								12917434	t		lperfetto	Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1	SIGNOR-117852	0.7
sapitinib	chemical	CHEBI:132986	ChEBI	ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	down-regulates	chemical inhibition			9606	BTO:0000551								20145185	t	AZD8931 has a unique pharmacologic profile providing equipotent EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models.	gcesareni	In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation.	SIGNOR-269874	0.8
MAPK3	protein	P27361	UNIPROT	ETV6	protein	P41212	UNIPROT	down-regulates	phosphorylation	Ser213	DNMIRRLsPAERAQG	10090									15060146	t		miannu	Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation.	SIGNOR-123656	0.323
COL6A1	protein	P12109	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									21949456	t			Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present.	SIGNOR-254673	0.7
CEBPB	protein	P17676	UNIPROT	C3	protein	P01024	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									25617152	t		Gianni	CCAAT/enhancer binding protein β directly regulates the expression of the complement component 3 gene in neural cells: implications for the pro-inflammatory effects of this transcription factor	SIGNOR-261927	0.262
APH1B	protein	Q8WW43	UNIPROT	NCSTN	protein	Q92542	UNIPROT	up-regulates	binding			9606		BTO:0000142							12297508	t		gcesareni	By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.These data indicate that maph-1 is probably a functional component of the gamma-secretase complex	SIGNOR-93307	0.939
CASP3	protein	P42574	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									14585074	f		amattioni	Caspase-3 is responsible for apoptosis execution	SIGNOR-89244	0.7
Raltegravir	chemical	CID:54671008	PUBCHEM	UGT1A1	protein	P22309	UNIPROT	down-regulates activity	chemical inhibition			9606									21030469	t		Luana	Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation.	SIGNOR-258162	0.8
PJA2	protein	O43164	UNIPROT	PRKAR1A	protein	P10644	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								21423175	t		miannu	Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits	SIGNOR-271855	0.387
MAML3	protein	Q96JK9	UNIPROT	NOTCH4	protein	Q99466	UNIPROT	up-regulates	binding			9606									12370315	t		esanto	Whereas maml1 and maml2 functioned efficiently as coactivators with each of the notch receptors to transactivate a notch target hes1 promoter construct, maml3 functioned more efficiently with icn4 than with other forms of icn.	SIGNOR-94103	0.862
BTC	protein	P35070	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606									23382875	t		gcesareni	Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4.	SIGNOR-200813	0.737
RUNX3	protein	Q13761	UNIPROT	ELANE	protein	P08246	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004850								14594802	f		miannu	We find that LEF-1 and CBFalpha co-activate ELA2 expression.	SIGNOR-254554	0.2
PRKD3	protein	O94806	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	up-regulates activity	phosphorylation	Ser498	RPLSRTQsSPLPQSP										18692497	t		lperfetto	Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].	SIGNOR-275928	0.268
MRPS17	protein	Q9Y2R5	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606	BTO:0000934								25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261453	0.2
PRKD2	protein	Q9BZL6	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser155	GRLKRERsMSENAVR										34010649	t		lperfetto	The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-275947	0.2
CHKA	protein	P35790	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	binding			9606	BTO:0000093								21822308	t		miannu	We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. CHKA is required for maximum EGF-dependent cell growth in mammary epithelium-derived cell lines	SIGNOR-266352	0.413
PRKAA2	protein	P54646	UNIPROT	PLD1	protein	Q13393	UNIPROT	up-regulates	phosphorylation	Ser505	GSVKRVTsGPSLGSL	9606		BTO:0000887;BTO:0001103	SIGNOR-C15						20231899	t		gcesareni	Ampk-wild type (wt) stimulates pld activity, while ampk-dominant negative (dn) inhibits it. Ampk regulates pld1 activity through phosphorylation of the ser-505 and this phosphorylation is increased by the presence of amp.	SIGNOR-164293	0.2
CKB	protein	P12277	UNIPROT	N-phosphocreatine	smallmolecule	CHEBI:17287	ChEBI	up-regulates quantity	chemical modification			9606									18502307	t		miannu	Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 	SIGNOR-265787	0.8
MYOF	protein	Q9NZM1	UNIPROT	Myoblast_fusion	phenotype	SIGNOR-PH98	SIGNOR	up-regulates				10090									16280346	f			These data support a role for myoferlin in the maturation of myotubes and the formation of large myotubes that arise from the fusion of myoblasts to multinucleate myotubes	SIGNOR-255973	0.7
GATA3	protein	P23771	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates	transcriptional regulation			9606									15632071	f		fspada	Constitutive expression of both gata-2 and gata-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor gamma (ppargamma) promoter and suppression of its basal activity	SIGNOR-210025	0.356
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRIK3	protein	Q13003	UNIPROT	up-regulates activity	chemical activation			9606									27586965	t		miannu	Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors	SIGNOR-264472	0.8
SMARCE1	protein	Q969G3	UNIPROT	Muscle cell-specific SWI/SNF ARID1B variant	complex	SIGNOR-C482	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270704	0.832
PRKCA	protein	P17252	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates activity	phosphorylation	Ser706	ARIIGEKsFRRSVVG										12058027	t		lperfetto	Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.	SIGNOR-275955	0.371
PPP2R1B	protein	P30154	UNIPROT	PPP2CA	protein	P67775	UNIPROT	up-regulates activity	binding			9606									19114990	t		lperfetto	Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity	SIGNOR-217872	0.941
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser280	RSPSPQPsSHVAPQD	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248377	0.598
48S_initiation_complex	complex	SIGNOR-C454	SIGNOR	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	up-regulates activity	binding			9606									35489072	t		lperfetto	In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 	SIGNOR-269169	0.2
UTS2R	protein	Q9UKP6	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257051	0.268
MAPK1	protein	P28482	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	up-regulates activity	phosphorylation	Ser65	PCSSVPSsPSFCAPS	9606	BTO:0000567								11416124	t		miannu	In the present study, we provide the first evidence that MafA is phosphorylated and that its biological properties strongly rely upon phosphorylation of serines 14 and 65, two residues located in the transcriptional activating domain within a consensus for phosphorylation by mitogen-activated protein kinases and which are conserved among Maf proteins. These residues are phosphorylated by ERK2 but not by p38, JNK, and ERK5 in vitro. 	SIGNOR-275977	0.34
F2R	protein	P25116	UNIPROT	FOSL1	protein	P15407	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254848	0.2
TNKS	protein	O95271	UNIPROT	AXIN2	protein	Q9Y2T1	UNIPROT	down-regulates quantity by destabilization	ADP-ribosylation			9606	BTO:0000007								19759537	t		lperfetto	Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin.	SIGNOR-263381	0.765
Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	DVL1	protein	O14640	UNIPROT	up-regulates	binding												19279717	t		apalma	After binding of Wnt to the receptor complex, the signal is transduced to cytoplasmic phosphoprotein Dishevelled (Dsh/Dvl), and studies have uncovered that Dsh can directly interact with Fz	SIGNOR-255892	0.2
STAT5A	protein	P42229	UNIPROT	HBA1	protein	P69905	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000574								9168989	f	Regulation	miannu	We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin.	SIGNOR-251787	0.2
NUAK1	protein	O60285	UNIPROT	LATS1	protein	O95835	UNIPROT	down-regulates	phosphorylation	Ser464	NIPVRSNsFNNPLGN	9606									19927127	t		lperfetto	Moreover, we show that nuak1 phosphorylates lats1 at s464 and this has a role in controlling its stabilitycells that constitutively express nuak1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator lats1	SIGNOR-161792	0.397
ATM	protein	Q13315	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates activity	phosphorylation	Ser395	SQESEDYsQPSTSSS	-1									12383858	t		gcesareni	Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation.	SIGNOR-94268	0.747
AHCYL1	protein	O43865	UNIPROT	PAPOLB	protein	Q9NRJ5	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								19224921	t		lperfetto	Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner.	SIGNOR-268331	0.2
SOD1	protein	P00441	UNIPROT	ER stress	stimulus	SIGNOR-ST9	SIGNOR	up-regulates				10090									18519638	f	P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)		SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK	SIGNOR-262788	0.7
SGK3	protein	Q96BR1	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606	BTO:0000007								16543730	t		lperfetto	Phosphorylation of GSK3 by PKB or SGK1 inhibits GSK3 activity|estern blotting using an antibody specific for the PKB/SGK1 consensus phosphorylation site in GSK3a/beta (serine 21 and 9 respectively) revealed an increase in GSK3a/beta phosphorylation in human embryonic kidney 293 (HEK293) cells overexpressing wild type SGK1, constitutively active SGK1, but not catalytically inactive SGK1.|The effect of SGK1 was mimicked by PKB and SGK3.	SIGNOR-249167	0.453
SMURF1	protein	Q9HCE7	UNIPROT	BMPR2	protein	Q13873	UNIPROT	down-regulates	ubiquitination			9606									22298955	t		gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-195654	0.542
Brain-specific SWI/SNF SMARCA2 variant	complex	SIGNOR-C485	SIGNOR	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	up-regulates				9606		BTO:0000143							25195934	f		miannu	The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. 	SIGNOR-270750	0.7
LPAR1	protein	Q92633	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates	binding			9606									20331961	t		milica	The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits).	SIGNOR-164679	0.436
HSP90AB1	protein	P08238	UNIPROT	CBLL1	protein	Q75N03	UNIPROT	up-regulates quantity	binding			9606	BTO:0000007								31952268	t		miannu	By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. 	SIGNOR-271475	0.2
FOXO3	protein	O43524	UNIPROT	NOTCH3	protein	Q9UM47	UNIPROT	down-regulates quantity	transcriptional regulation			10090									24749067	f		gcesareni	We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration.	SIGNOR-244079	0.312
COP1	protein	Q8NHY2	UNIPROT	DCX DET1-COP1	complex	SIGNOR-C24	SIGNOR	form complex	binding			9606									17452440	t		lperfetto	Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes	SIGNOR-154514	0.2
KANSL3	protein	Q9P2N6	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates				9606									26243146	f		miannu	Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. 	SIGNOR-267169	0.7
BMP2	protein	P12643	UNIPROT	BMP2	protein	P12643	UNIPROT	up-regulates	binding			9606		BTO:0000887							11178121	t		lperfetto	Bmps are dimeric proteins with a single interchain disulfide bond. The dimeric conformation is an absolute requirement for the biological action and interaction with receptors	SIGNOR-236166	0.2
OPRK1	protein	P41145	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257105	0.319
TNIK	protein	Q9UKE5	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	phosphorylation	Thr322	SNVNRNStIENTRRH	9606	BTO:0002181								21690388	t		miannu	Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation. 	SIGNOR-276334	0.2
GDF5	protein	P43026	UNIPROT	ID3	protein	Q02535	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004291								16716349	f	Regulation	miannu	 GDF5 induces ID1 and ID3 in HUVSMC by a smad-dependent, MAPK-independent pathway. GDF5 binds to specific receptors, thereby inducing phosphorylation and translocation of smad1 to the nucleus where it is involved in the regulation of transcription. 	SIGNOR-251872	0.2
RPS6KA1	protein	Q15418	UNIPROT	RPS6	protein	P62753	UNIPROT	up-regulates	phosphorylation	Ser244	LRASTSKsESSQK	9606									21233202	t		lperfetto	In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity	SIGNOR-171247	0.608
AKT2	protein	P31751	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLPRPE	10090	BTO:0000944								11313479	t			Phosphorylation of AFX by PKB occurs in the nucleus. Phosphorylation of S193 reduces the rate of nuclear import. PKB-mediated phosphorylation of AFX, therefore, attenuates the import of the transcription factor, which shifts the localization of the protein from the nucleus to the cytoplasm and results in the inhibition of AFX transcriptional activity.	SIGNOR-252873	0.757
p38	proteinfamily	SIGNOR-PF16	SIGNOR	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation			9606									10085140	t	inferred from 70% family members	gcesareni	Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target	SIGNOR-270124	0.2
PBX1	protein	P40424	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								21746878	t		miannu	We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.	SIGNOR-267241	0.271
ABL2	protein	P42684	UNIPROT	ABL2	protein	P42684	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr261	GLVTTLHyPAPKCNK	-1									15735735	t		miannu	The results show that Arg is stabilized in response to 0.1 mM H2O2 by autophosphorylation of Y-261, consistent with involvement of the Arg kinase function in regulating Arg levels. The results further demonstrate that c-Abl-mediated phosphorylation of Arg on Y-261 similarly confers Arg stabilization.. These findings indicate that abrogation of the Arg kinase function by the Y261F mutation is dependent on phosphorylation of the Y-439 site.	SIGNOR-276033	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GATA4	protein	P43694	UNIPROT	up-regulates activity	phosphorylation	Ser262	IKPQRRLsASRRVGL	9606	BTO:0000093								16109788	t		miannu	 PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469. 	SIGNOR-276043	0.2
PLK3	protein	Q9H4B4	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Ser73	VSTQELYsIPEDQEP	-1									16481012	t		miannu	Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity. 	SIGNOR-276051	0.644
mTORC2	complex	SIGNOR-C2	SIGNOR	mTORC2	complex	SIGNOR-C2	SIGNOR	up-regulates activity	phosphorylation			10090	BTO:0000944								20022946	t		lperfetto	These data suggest that mTORC1- and likely mTORC2-associated mTOR Ser-2481 autophosphorylation directly monitors intrinsic mTORC-specific catalytic activity	SIGNOR-235484	0.678
PRKCA	protein	P17252	UNIPROT	TP73	protein	O15350	UNIPROT	up-regulates activity	phosphorylation	Ser388	VPQPLVDsYRQQQQL	9606									19158275	t		miannu	Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388. 	SIGNOR-276235	0.2
NDUFA2	protein	O43678	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24].	SIGNOR-262154	0.856
CSNK2A1	protein	P68400	UNIPROT	STX1A	protein	Q16623	UNIPROT	up-regulates	phosphorylation	Ser14	ELRTAKDsDDDDDVA	9606									11846792	t		lperfetto	In this report, we show that syntaxin-1a is phosphorylated in vitro by cki on thr21. Casein kinase ii (ckii) has been shown previously to phosphorylate syntaxin-1a in vitro and we have identified ser14 as the ckii phosphorylation site. the phosphorylation of syntaxin-1a by ckii enhances its capacity to associate with synaptotagmin [21]. Therefore, phosphorylation of ser14 by ckii suggests an important role for this residue in regulating the interaction between syntaxin-1a and synaptotagmin	SIGNOR-114840	0.374
mTORC2	complex	SIGNOR-C2	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Thr479	FSYSASGtA	9606	BTO:0000093								24670654	t		gcesareni	Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation	SIGNOR-252454	0.634
INHA	protein	P05111	UNIPROT	TGFBR3	protein	Q03167	UNIPROT	down-regulates	binding			9606									10746731	t		gcesareni	Type iii tgf-beta receptor, betaglycan, can function as an inhibin co-receptor with actrii. Betaglycan binds inhibin with high affinity and enhances binding in cells co-expressing actrii and betaglycan. ability of betaglycan to facilitate inhibin antagonism of activin	SIGNOR-76470	0.578
AMPK	complex	SIGNOR-C15	SIGNOR	CSNK1E	protein	P49674	UNIPROT	up-regulates activity	phosphorylation	Ser389	RGAPANVsSSDLTGR	-1									17525164	t		miannu	AMPK enhances mPer2 degradation and CKIɛ activity by phosphorylating Ser-389 of CKIɛ. One of the regulators of the period length is casein kinase Iepsilon (CKIepsilon), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKIepsilon, resulting in increased CKIepsilon activity and degradation of mPer2. 	SIGNOR-276064	0.266
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	MAPK3	protein	P27361	UNIPROT	up-regulates	phosphorylation			9606									12270934	t		lperfetto	Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis.	SIGNOR-244798	0.2
CSNK1E	protein	P49674	UNIPROT	PER2	protein	O15055	UNIPROT	down-regulates quantity by destabilization	phosphorylation			-1									17525164	t		miannu	AMPK enhances mPer2 degradation and CKIɛ activity by phosphorylating Ser-389 of CKIɛ. One of the regulators of the period length is casein kinase Iepsilon (CKIepsilon), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKIepsilon, resulting in increased CKIepsilon activity and degradation of mPer2. 	SIGNOR-276065	0.898
LYN	protein	P07948	UNIPROT	SLAMF1	protein	Q13291	UNIPROT	unknown	phosphorylation	Tyr327	ETNSITVyASVTLPE	9606									15315965	t		llicata	Cd150-mediated akt phosphorylation required syk and sh2d1a, was negatively regulated by lyn and btk, but was ship independent. Lyn directly phosphorylated y327 in cd150, but the akt pathway did not depend on cd150 tyrosine phosphorylation and cd150-shp-2 association.	SIGNOR-127997	0.306
AKT1	protein	P31749	UNIPROT	YWHAZ	protein	P63104	UNIPROT	unknown	phosphorylation	Ser58	VVGARRSsWRVVSSI	9606	BTO:0000007								11956222	t		llicata	Ese data indicate that pkb/akt phosphorylates ser-58 on 14-3-3zeta both in vitro and in intact cells. The functional relevance of this phosphorylation remains to be determined.	SIGNOR-116587	0.659
PPP2CA	protein	P67775	UNIPROT	MAP2K2	protein	P36507	UNIPROT	down-regulates	dephosphorylation			9606									20626350	t		gcesareni	In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a.	SIGNOR-166652	0.47
mono(2-ethylhexyl) phthalate	chemical	CHEBI:17243	ChEBI	PPARG	protein	P37231	UNIPROT	up-regulates activity	chemical activation			-1									16326050	t		miannu	Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast	SIGNOR-268751	0.8
CEBPA	protein	P49715	UNIPROT	SFTPD	protein	P35247	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001910								11912209	t	 	 	Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.	SIGNOR-254042	0.262
MKNK1	protein	Q9BUB5	UNIPROT	EIF4E	protein	P06730	UNIPROT	up-regulates	phosphorylation			9606									9878069	t		gcesareni	Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e.	SIGNOR-62936	0.771
TRADD	protein	Q15628	UNIPROT	TRAF2	protein	Q12933	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								27383048	t		miannu	Upon stimulation with TNFα, TNFR1 recruits TRADD, which provides a scaffold for the assembly of complex I at the plasma membrane by binding with RIP1, TRAF2 and cIAP. 	SIGNOR-42980	0.865
RNF139	protein	Q8WU17	UNIPROT	INSIG2	protein	Q9Y5U4	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								20068067	t		miannu	Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner 	SIGNOR-271956	0.448
TNKS	protein	O95271	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates quantity by destabilization	ADP-ribosylation			9606									19759537	t		lperfetto	Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin.	SIGNOR-263379	0.766
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRIA3	protein	P42263	UNIPROT	up-regulates activity	chemical activation			9606									30825796	t		miannu	In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses	SIGNOR-264610	0.8
creatine	smallmolecule	CHEBI:16919	ChEBI	CKB	protein	P12277	UNIPROT	up-regulates activity	chemical activation			9606									18502307	t		miannu	Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 	SIGNOR-265783	0.8
ethanol	chemical	CHEBI:16236	ChEBI	GLRA1	protein	P23415	UNIPROT	up-regulates activity	chemical activation			8355	BTO:0000964								8700149	t		miannu	Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations.	SIGNOR-258495	0.8
SRC	protein	P12931	UNIPROT	HNRNPK	protein	P61978	UNIPROT	down-regulates	phosphorylation	Tyr230	QPYDPNFyDETYDYG	9606									12052863	t		lperfetto	We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown).	SIGNOR-88903	0.609
RACK1	protein	P63244	UNIPROT	LARP4B	protein	Q92615	UNIPROT	up-regulates activity	binding			9606	BTO:0005238								20573744	t		miannu	Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex. 	SIGNOR-260941	0.2
MAPK11	protein	Q15759	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20162623	f	Indirect:regulation	miannu	Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). 	SIGNOR-251833	0.2
NMUR2	protein	Q9GZQ4	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257402	0.252
PTPN6	protein	P29350	UNIPROT	CTTN	protein	Q14247	UNIPROT	down-regulates activity	dephosphorylation	Tyr421	RLPSSPVyEDAASFK	9606									34088320	t		lperfetto	Shp1 interacts with cortactin and reduces cortactin phosphorylation at tyrosine 421; 3.|induction of Shp1-cortactin complex formation impairs cortactin scaffolding-activity and negatively affects invadopodia behaviour; 4.	SIGNOR-277003	0.2
HIF1A	protein	Q16665	UNIPROT	Epithelial-mesenchymal_transition	phenotype	SIGNOR-PH45	SIGNOR	up-regulates				9606	BTO:0001033								27476001	f		miannu	Our present study reveals that DAB2IP prevents EMT and metastasis of prostate cancer through targeting PROX1 gene transcription and destabilizing HIF1α protein, which provides a new insight into mechanism that DAB2IP regulates EMT and PCa metastasis. 	SIGNOR-254768	0.7
SP1	protein	P08047	UNIPROT	CACNA1G	protein	O43497	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									23868804	t		miannu	 Consistent with this, Sp1 over-expression enhanced promoter activity while siRNA-mediated Sp1 silencing significantly decreased the level of CaV 3.1 protein and reduced the amplitude of whole-cell T-type Ca(2+) currents expressed in the N1E-115 cells. These results provide new insights into the molecular mechanisms that control CaV 3.1 channel expression.	SIGNOR-264034	0.264
PPP1R9B	protein	Q96SB3	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates				10090	BTO:0001976								15996550	f		miannu	Neurabin and spinophilin are preferentially expressed in neurons, where they are highly localized to dendritic spines via an interaction with F-actin. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc	SIGNOR-269179	0.7
LAT	protein	O43561	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	binding			9606					phosphorylation:Tyr161;Tyr200	DDYHNPGyLVVLPDS;SMESIDDyVNVPESG			11368773	t		lperfetto	By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.	SIGNOR-246050	0.416
motesanib	chemical	CHEBI:51098	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258252	0.8
CSNK1A1	protein	P48729	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates activity	phosphorylation	Ser129	NEAYEMPsEEGYQDY	9606									10617630	t		lperfetto	In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2.| together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of alpha-synuclein could affect its binding to membranes.	SIGNOR-73795	0.379
RPGR	protein	Q92834	UNIPROT	RAB8A	protein	P61006	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									20631154	t		miannu	 PGR interacts with the small GTPase RAB8A, which participates in cilia biogenesis and maintenance. We show that RPGR primarily associates with the GDP-bound form of RAB8A and stimulates GDP/GTP nucleotide exchange. RPGR functions as a GEF for RAB8A and RPGR–RAB8A association may facilitate ciliary trafficking.	SIGNOR-253030	0.44
RPS6KA3	protein	P51812	UNIPROT	KCNK3	protein	O14649	UNIPROT	up-regulates activity	phosphorylation	Ser393	GLMKRRSsV	9606									21357689	t		gcesareni	The chaperone protein, 14-3-3, binds to a critical phosphorylated serine in the channel c termini of k2p3.1 and k2p9.1 (ser(393) and ser(373), respectively) and overcomes retention in the endoplasmic reticulum by ?COP. We sought to identify the kinase responsible for phosphorylation of the terminal serine in human and rat variants of k2p3.1 and k2p9.1. Adopting a bioinformatic approach, three candidate protein kinases were identified: camp-dependent protein kinase, ribosomal s6 kinase, and protein kinase c.	SIGNOR-172470	0.2
SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269254	0.834
Class I MHC:Antigen	complex	SIGNOR-C426	SIGNOR	T_cell_activation	phenotype	SIGNOR-PH73	SIGNOR	up-regulates				9606									31810556	f		scontino	High-affinity peptide/MHC class I complexes that successfully pass the aforementioned “quality controls” will be transported through the Golgi apparatus to the cell membrane to elicit antigen-specific CD8+ T cell responses.	SIGNOR-267775	0.7
HNF4A	protein	P41235	UNIPROT	CYP27A1	protein	Q02318	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								11867220	f		miannu	 Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells.	SIGNOR-255198	0.307
CAMK2G	protein	Q13555	UNIPROT	RYR1	protein	P21817	UNIPROT	unknown	phosphorylation	Ser2843	KKKTRKIsQSAQTYD										8380342	t		llicata	Phosphorylation of serine 2843 in ryanodine receptor-calcium release channel of skeletal muscle by cAMP-, cGMP- and CaM-dependent protein kinase.	SIGNOR-250704	0.403
Substance P	smallmolecule	CHEBI:80308	ChEBI	TACR1	protein	P25103	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257586	0.8
PRKCA	protein	P17252	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates	phosphorylation	Ser741	TKADKRRsVRIGSYI	9606									7539802	t		miannu	Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity	SIGNOR-28601	0.51
MAP3K7	protein	O43318	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	phosphorylation	Thr187	CDIQTHMtNNKGSAA	-1									20538596	t		lperfetto	Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation.	SIGNOR-227540	0.2
CBX3	protein	Q13185	UNIPROT	H3-4	protein	Q16695	UNIPROT	up-regulates activity	binding			9606							methylation:Lys10	RTKQTARkSTGGKAP	19111658	t		miannu	 A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 	SIGNOR-264495	0.2
WNT5A	protein	P41221	UNIPROT	Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	up-regulates activity	binding												18697834	t		Simone Vumbaca	Wnt1, Wnt3a and Wnt5a all induced a statistically greater degree of proliferation than control cells	SIGNOR-255651	0.828
dopamine	smallmolecule	CHEBI:18243	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258717	0.8
NFKB1	protein	P19838	UNIPROT	TRAF1	protein	Q13077	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9733516	f		gcesareni	Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2	SIGNOR-59954	0.543
KIF19	protein	Q2TAC6	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272532	0.7
WDR62	protein	O43379	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates activity	relocalization			10090									30566428	t		lperfetto	In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis	SIGNOR-271718	0.573
FZD5	protein	Q13467	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates				9606									10937998	f		fspada	Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma)	SIGNOR-80610	0.2
PTPRG	protein	P23470	UNIPROT	BMX	protein	P51813	UNIPROT	down-regulates activity	dephosphorylation	Tyr40	LTKTNLSyYEYDKMK	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254693	0.263
KAT5	protein	Q92993	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates	acetylation	Lys2054	LLKNGANkDMQNNRE	9606									17636029	t		gcesareni	This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60.	SIGNOR-156919	0.424
NPY	protein	P01303	UNIPROT	Food intake	phenotype	SIGNOR-PH152	SIGNOR	down-regulates				9606	BTO:0000614								10195157	f		miannu	Neuropeptide Y (NPY) stimulates food intake and promotes weight gain, whereas melanocortins have the opposite effect. 	SIGNOR-263505	0.7
SEPTIN12	protein	Q8IYM1	UNIPROT	SEPTIN6	protein	Q14141	UNIPROT	down-regulates	binding			9606	BTO:0000567								18047794	t		miannu	Sept12 interacts with sept6 and this interaction alters the filament structure of sept6 in hela cells.	SIGNOR-159537	0.2
UBE4B	protein	O95155	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002552								21317885	t		miannu	We show that ubiquitination factor E4B (UBE4B), an E3 and E4 ubiquitin ligase, physically interacts with p53 and Hdm2 (also known as Mdm2 in mice). UBE4B promotes p53 polyubiquitination and degradation and inhibits p53-dependent transactivation and apoptosis. 	SIGNOR-271907	0.405
HARS1	protein	P12081	UNIPROT	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									10430027	t		miannu	Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 	SIGNOR-270488	0.8
POU2F1	protein	P14859	UNIPROT	MYH1	protein	P12882	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0001103							15728583	t		lperfetto	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238760	0.2
N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide	chemical	CHEBI:63082	ChEBI	ADRB3	protein	P13945	UNIPROT	up-regulates activity	chemical activation			10030									20590599	t		Luana	Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3).	SIGNOR-257855	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	GABRB2	protein	P47870	UNIPROT	up-regulates activity	phosphorylation	Ser472	SRLRRRAsQLKITIP	9606	BTO:0000007								12818177	t		miannu	 Here we report that Akt phosphorylates, both in vitro and in vivo, the type A gamma-aminobutyric acid receptor (GABA(A)R), the principal receptor mediating fast inhibitory synaptic transmission in the mammalian brain. Akt-mediated phosphorylation increases the number of GABA(A)Rs on the plasma membrane surface, thereby increasing the receptor-mediated synaptic transmission in neurons. These results identify the GABA(A)R as a novel substrate of Akt, thereby linking Akt to the regulation of synaptic strength. 	SIGNOR-262619	0.2
CDK1	protein	P06493	UNIPROT	KIF4A	protein	O95239	UNIPROT	up-regulates activity	phosphorylation	Thr1161	FFNPVCAtPNSKILK	9606									29771379	t		miannu	Identification of Cdk phosphorylation of Kif4A at T1161 in early mitosis. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization. 	SIGNOR-265994	0.502
IKBKG	protein	Q9Y6K9	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates activity	binding			9606			SIGNOR-C14	SIGNOR-C14					20300203	t		lperfetto	The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation	SIGNOR-164512	0.962
GSK3B	protein	P49841	UNIPROT	MACF1	protein	Q9UPN3	UNIPROT	down-regulates activity	phosphorylation	Ser7230	KPSSRAAsPTRSSSS	9606	BTO:0004905								21295697	t		lperfetto	We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules.	SIGNOR-264428	0.446
WNT5B	protein	Q9H1J7	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates				9606									19577541	f		fspada	Wnt5b additionally appears to be a potent enhancer of adipogenic capacity by stimulation of ppargamma	SIGNOR-186625	0.256
UMPS	protein	P11172	UNIPROT	orotidine 5'-phosphate(3-)	smallmolecule	CHEBI:57538	ChEBI	down-regulates quantity	chemical modification			9606									18020427	t		miannu	Orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) catalyzes the Mg2+-dependent condensation of orotic acid (OA) with PRPP (5-alpha-d-phosphorylribose 1-diphosphate) to yield diphosphate (PPi) and the nucleotide OMP (orotidine 5'-monophosphate).	SIGNOR-253581	0.8
MMP2	protein	P08253	UNIPROT	A2M	protein	P01023	UNIPROT	down-regulates quantity by destabilization	cleavage	Arg719	VMGRGHArLVHVEEP	-1									9344465	t		lperfetto	The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261739	0.62
PTPN1	protein	P18031	UNIPROT	GAB1	protein	Q13480	UNIPROT	down-regulates activity	dephosphorylation			9606									23521888	t		lperfetto	Since Gab1 is negatively regulated by PTP1B, a part of the retinal neuroprotective effect we have observed previously in PTP1B deficient mice could be contributed by Gab1 as well.|The results indicate that PTP1B completely dephosphorylated Gab1 and the mutant protein failed to dephosphorylate Gab1 (Figure\u00a0 xref C).	SIGNOR-276965	0.389
EIF2AK1	protein	Q9BQI3	UNIPROT	HBA1	protein	P69905	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19946423	f	Regulation of expression	miannu	Translation of α- and β-globin is tightly controlled by eIF2 and downregulated by HRI.	SIGNOR-251781	0.2
MAPK8	protein	P45983	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation	Thr455	ALGTPVLtPPTEAAS	9606									15538382	t		lperfetto	Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment.	SIGNOR-252965	0.704
SRC	protein	P12931	UNIPROT	ARHGAP5	protein	Q13017	UNIPROT	up-regulates activity	phosphorylation	Tyr1109	KGYSDEIyVVPDDSQ	-1									9819392	t		miannu	 Phosphotyrosine (p-Tyr)-dependent and -independent mechanisms of p190 RhoGAP-p120 RasGAP interaction: Tyr 1105 of p190, a substrate for c-Src, is the sole p-Tyr mediator of complex formation. Phosphorylation of Y1105, but not the minor site, was modulated in vivo to a greater extent by overexpression of c-Src than by the EGF receptor and was efficiently catalyzed by c-Src in vitro, indicating that Y1105 is a selective and preferential target of c-Src both in vitro and in vivo.	SIGNOR-276170	0.591
FLT1	protein	P17948	UNIPROT	GLO1	protein	Q04760	UNIPROT	up-regulates activity	phosphorylation	Tyr136	GIAVPDVySACKRFE	-1									34838714	t		miannu	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276190	0.2
CHKB	protein	Q9Y259	UNIPROT	choline phosphate(1-)	smallmolecule	CHEBI:295975	ChEBI	up-regulates quantity	chemical modification												27149373	t		lperfetto	Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes	SIGNOR-275634	0.8
POLR2M	protein	Q6EEV4	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266175	0.463
CDC14A	protein	Q9UNH5	UNIPROT	WEE1	protein	P30291	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser139	YFLGSSFsPVRCGGP	9606	BTO:0000007								23051732	t		lperfetto	In particular, we found that Cdc14A inhibits Wee1 degradation through the dephosphorylation of Ser-123 and Ser-139 residues. 	SIGNOR-267470	0.562
GSK3B	protein	P49841	UNIPROT	USF1	protein	P22415	UNIPROT	up-regulates activity	phosphorylation	Thr153	EALLGQAtPPGTGQF	9606									21873430	t		miannu	 Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186.	SIGNOR-276355	0.291
RBBP7	protein	Q16576	UNIPROT	MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263848	0.831
MAPK3	protein	P27361	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates activity	phosphorylation	Thr202	HDHTGFLtEYVATRW										1712480	t		lperfetto	Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.|	SIGNOR-249471	0.2
MAPK3	protein	P27361	UNIPROT	TFCP2	protein	Q12800	UNIPROT	down-regulates	phosphorylation	Ser309	SLGEGNGsPNHQPEP	9606									19237534	t		lperfetto	We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309.	SIGNOR-184180	0.2
THBS1	protein	P07996	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	down-regulates													17326328	f		lperfetto	There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3	SIGNOR-252271	0.7
DNMT3A	protein	Q9Y6K1	UNIPROT	CDKN2A	protein	P42771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									26350239	f		miannu	Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family	SIGNOR-255809	0.388
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates						BTO:0001103							12361602	f		apalma	Taken together, these results show that Notch-1 activity promotes myogenic cell proliferation and that attenuation of Notch-1 activity by its antagonist Numb causes cells to exit from the cell cycle, express MRFs, and undergo myogenic differentiation.	SIGNOR-255376	0.7
CDC7	protein	O00311	UNIPROT	MCM4	protein	P33991	UNIPROT	up-regulates	phosphorylation			9606									21070963	t		gcesareni	Activation of the eukaryotic replicative dna helicase, the mcm2-7 complex, requires phosphorylation by cdc7/dbf4 (dbf4-dependent kinase or ddk), which, in turn, depends on prior phosphorylation of mcm2-7 by an unknown kinase (or kinases).we propose that the resulting mec1 modification of mcm4 and mcm6 further activates ddk phosphorylation of mcm2-7 ( fig. 7aii ).	SIGNOR-169453	0.957
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Thr33	KFKNEDLtDELSLNK	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276205	0.2
Nucleosome_H2A.Z.2 variant	complex	SIGNOR-C323	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606									24311584	f		miannu	In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression.	SIGNOR-263714	0.7
ITGB2	protein	P05107	UNIPROT	Av/b2 integrin	complex	SIGNOR-C176	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253204	0.651
XAV939	chemical	CHEBI:62878	ChEBI	AXIN2	protein	Q9Y2T1	UNIPROT	up-regulates				9606									19759537	f		gcesareni	Using a quantitative chemical proteomic approach, we discovered that xav939 stabilizes axin by inhibiting the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2	SIGNOR-188048	0.8
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	YBX1	protein	P67809	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								16797541	t		miannu	Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions.  FBX33 recruits Skp-1/Cul1 to YB-1	SIGNOR-271606	0.327
RAF1	protein	P04049	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser218	VSGQLIDsMANSFVG	9606									10359597	t		lperfetto	Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 active raf phosphorylates mek phospholpeptide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf.	SIGNOR-235987	0.737
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Ser214	TVLTAQEsFSGSLGH	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276217	0.2
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Thr46	NKISADTtDNSGTVN	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276218	0.389
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser168	YREPLCLsPASSGSS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248364	0.598
PER2	protein	O15055	UNIPROT	SNAI2	protein	O43623	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001939								23836662	f	 	miannu	 PER2 Suppresses TWIST1 and SLUG Transcription by Recruiting EZH2, SUZ12, and HDAC2.	SIGNOR-254147	0.2
Camostat mesylate	chemical	CID:5284360	PUBCHEM	TMPRSS2	protein	O15393	UNIPROT	down-regulates activity	chemical inhibition			9606									32142651	t		Monia	Ndeed, the clinically proven serine protease inhibitor camostat mesylate, which is active against TMPRSS2 (Kawase et al., 2012), partially blocked SARS-2-S-driven entry into Caco-2 (Figure S3 B) and Vero-TMPRSS2 cells, efficiently blocked 2019-nCoV-S-driven entry into Caco-2 (TMPRSS2+) but not 293T (TMPRSS2- 110 ) cells while the CatB/L inhibitor E64d had the opposite effect 	SIGNOR-261098	0.8
EEF1A1	protein	P68104	UNIPROT	Arg-tRNA(Arg)	smallmolecule	CHEBI:18366	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269505	0.8
MAPK3	protein	P27361	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates activity	phosphorylation	Ser151	VARSNPKsPQKPIVR	9606	BTO:0000848								21478863	t			We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction	SIGNOR-259921	0.629
YWHAH	protein	Q04917	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	binding			9606									12042314	t		miannu	14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue.	SIGNOR-109771	0.479
AKT1	protein	P31749	UNIPROT	PFKFB3	protein	Q16875	UNIPROT	up-regulates	phosphorylation	Ser461	NPLMRRNsVTPLASP	9606									15896703	t		gcesareni	We also found that AMP activated protein kinase and protein kinases A, B, and C catalyzed the phosphorylation of Ser-460 of HBP1, and that in addition both isoforms are phosphorylated at a second, as yet undetermined site by protein kinase C. However, none of the phosphorylations had any effect on the intrinsic kinetic characteristics of either enzymatic activity, and neither did point mutation (mimicking phosphorylation), deletion, and alternative-splice modification of the HBP1 carboxy-terminal region. Instead, these phosphorylations and mutations decreased the sensitivity of the 6PF2K to a potent allosteric inhibitor, phosphoenolpyruvate, which appears to be the major regulatory mechanism.	SIGNOR-252477	0.439
CAMK2G	protein	Q13555	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	phosphorylation	Ser1071	SFLQRYSsDPTGALT	9606	BTO:0000017								1309762	t		llicata	The mechanism of desensitization of kinase activity can be accounted for, in part, by the EGF-stimulated phosphorylation of the receptor at Ser1046/7, a substrate for the multifunctional calmodulin-dependent protein kinase II in vitro. Mutation of Ser1046/7 by replacement with Ala residues blocks desensitization of the EGF receptor protein-tyrosine kinase activity. 	SIGNOR-250695	0.369
VKORC1	protein	Q9BQB6	UNIPROT	Reduced Vitamin K	smallmolecule	CHEBI:8784	ChEBI	up-regulates quantity	chemical modification			9606									31226734	t		lperfetto	This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR)	SIGNOR-265905	0.8
BAZ2B	protein	Q9UIF8	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	binding			9606							acetylation:Lys15	ARKSTGGkAPRKQLA	31999386	t		miannu	The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation.	SIGNOR-266622	0.2
ABL1	protein	P00519	UNIPROT	MUC1	protein	P15941	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr1243	NGGSSLSyTNPAVAA	9606									16888623	t		Manara	The results demonstrate that ABL1 phosphorylates MUC1 on Tyr-60 and forms a complex with MUC1 by binding of the ABL1 SH2 domain to the pTyr-60 site. 	SIGNOR-260830	0.468
MAPK1	protein	P28482	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Ser276	VHPATPIsPGRASGM	9606									16046550	t	The effect has been demonstrated using Q01196-8	miannu	We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 	SIGNOR-138985	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	XPO5	protein	Q9HAV4	UNIPROT	down-regulates activity	phosphorylation	Ser497	GSLCSVFsPSFVQWE	9606	BTO:0000007								27846390	t		lperfetto	Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. 	SIGNOR-262983	0.2
TDRD3	protein	Q9H7E2	UNIPROT	SNRPN	protein	P63162	UNIPROT	unknown	binding			-1									15955813	t		miannu	 the TDRD3 GST-Tudor protein interacted strongly with methylated SmB/B′ and SmD but not with SmE. These results suggest that the Tudor domains of SMN and SPF30 likely interact with assembled snRNPs, whereas the Tudor domain of TDRD3 might bind unassembled methylated Sm proteins.	SIGNOR-253518	0.2
IFNA1	protein	P01562	UNIPROT	IFNAR	complex	SIGNOR-C243	SIGNOR	up-regulates activity	binding			9606									11278538	t		miannu	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-260334	0.63
MARK2	protein	Q7KZI7	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser355	EADLPEPsEKQPAAA	-1									10090741	t		miannu	We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 	SIGNOR-275436	0.695
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	GSTA4	protein	O15217	UNIPROT	up-regulates activity	phosphorylation	Thr193	VKLSNIPtIKRFLEP	9534									12646569	t		lperfetto	Mutational analysis show that the putative mitochondrial targeting signal resides within the C-terminal 20 amino acid residues of the protein and that the targeting signal requires activation by phosphorylation at the C-terminal-most protein kinase A (PKA) site at Ser-189 or protein kinase C (PKC) site at Thr-193. 	SIGNOR-264795	0.2
ARHGEF19	protein	Q8IW93	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260543	0.62
SIM1	protein	P81133	UNIPROT	AHR-ARNT	complex	SIGNOR-C125	SIGNOR	down-regulates activity	binding			-1									9020169	t	2	miannu	SIM1 can inhibit AHR·ARNT binding to the XRE and can inhibit expression from an XRE-driven reporter gene indicates that SIM1 may act as negative regulator of transcription as well as a positive regulator. The above inhibitory effects may result from SIM1 competing with AHR for binding to ARNT, although we cannot exclude the possibility that SIM1 may also have other inhibitory effects of AHR·ARNT activity. In a similar fashion, SIM1 may act as a negative regulator of all ARNT-dependent genes.	SIGNOR-240811	0.42
SIRT7	protein	Q9NRC8	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	deacetylation	Lys38	PSTGGVKkPHRYRPG										30653310	t		lperfetto	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 	SIGNOR-275884	0.2
TGFB2	protein	P61812	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252283	0.7
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	HEY2	protein	Q9UBP5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12548545	f		gcesareni	SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.	SIGNOR-254338	0.2
PRKACA	protein	P17612	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates quantity	phosphorylation	Ser980	VHAPRRCsDGGAHGY	9606									10693759	t		lperfetto	Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3.	SIGNOR-75359	0.445
U2AF2	protein	P26368	UNIPROT	ZRSR2/U2AF2	complex	SIGNOR-C81	SIGNOR	form complex	binding			9606									9237760	t		miannu	Recognition of a functional 3' splice site in pre-mrna splicing requires a heterodimer of the proteins u2af65/u2af35.	SIGNOR-50173	0.77
palbociclib	chemical	CHEBI:85993	ChEBI	CCND2	protein	P30279	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205701	0.8
FASLG	protein	P48023	UNIPROT	FAS	protein	P25445	UNIPROT	up-regulates activity	binding			9606									14965271	t		lperfetto	Fas (CD95) is activated by its natural ligand FasL	SIGNOR-216292	0.9
PRKAA2	protein	P54646	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	up-regulates	phosphorylation			9606			SIGNOR-C15						20647423	t		gcesareni	Ampk recruitment and h2b ser36 phosphorylation colocalized within genes activated by ampk-dependent pathways, both in promoters and in transcribed regions.	SIGNOR-166905	0.2
GGCX	protein	P38435	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	carboxylation	Glu53	RYNSGKLeEFVQGNL	10090		BTO:0001103							11133752	t		lperfetto	The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.	SIGNOR-263686	0.67
SIX1	protein	Q15475	UNIPROT	MYOG	protein	P15173	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							9826681	f		gcesareni	We have demonstrated by studies of transgenic mice the importance of the mef3 motif present in the myogeninpromoter for its activation and have characterized the mef3 binding activity as consisting of two skeletal-muscle specific members of the six family, six1 and six4.	SIGNOR-62104	0.454
DAPK3	protein	O43293	UNIPROT	DAPK3	protein	O43293	UNIPROT	up-regulates	phosphorylation	Thr265	KDPKRRMtIAQSLEH	9606									15611134	t		gcesareni	Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates.	SIGNOR-132467	0.2
NDUFA9	protein	Q16795	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)	SIGNOR-262160	0.823
JUN	protein	P05412	UNIPROT	GCH1	protein	P30793	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16149046	f		miannu	Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2.	SIGNOR-252225	0.2
vitamin K epoxide	smallmolecule	CHEBI:28371	ChEBI	VKORC1L1	protein	Q8N0U8	UNIPROT	up-regulates activity	chemical activation			9606									31226734	t		lperfetto	The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form	SIGNOR-265914	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	IRX2	protein	Q9BZI1	UNIPROT	up-regulates activity	phosphorylation			-1									15133517	t	inferred from 70% family members	miannu	To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target.	SIGNOR-270193	0.2
CDK7	protein	P50613	UNIPROT	RARA	protein	P10276	UNIPROT	unknown	phosphorylation	Ser77	EIVPSPPsPPPLPRI	9606									11955452	t		llicata	Thus, we demonstrate that the cdk7 kinase of tfiih phosphorylates the nuclear receptor, then allowing ligand-dependent control of the activation of the hormone-responsive genes.	SIGNOR-116582	0.526
STIP1	protein	P31948	UNIPROT	HSP90AB1	protein	P08238	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								27353360	t		miannu	Hsp90 chaperone cycle is tightly regulated by another group of proteins referred to as ‘co-chaperones'. Their stability does not depend on Hsp90 function but they interact with distinct Hsp90 conformational states, providing directionality to the Hsp90 cycle4. Furthermore, certain co-chaperones, such as HOP and Cdc37p50 inhibit the Hsp90 chaperone cycle, assisting in delivery of distinct sets of client proteins (steroid hormone receptors and kinases, respectively) to the Hsp90 chaperone machine.	SIGNOR-261412	0.848
NLGN4Y	protein	Q8NFZ3	UNIPROT	NRXN2	protein	P58401	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264158	0.2
AKT1	protein	P31749	UNIPROT	HNRNPA1	protein	P09651	UNIPROT	down-regulates	phosphorylation	Ser199	SQRGRSGsGNFGGGR	9606									18562319	t		gcesareni	Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199.	SIGNOR-252519	0.423
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser374	PSSDSLSsPTLLAL	9606									12972619	t		lperfetto	In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity.	SIGNOR-251524	0.2
TOPBP1	protein	Q92547	UNIPROT	BRCA1-B complex	complex	SIGNOR-C298	SIGNOR	form complex	binding												25400280	t		lperfetto	Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation	SIGNOR-263218	0.661
CAPN2	protein	P17655	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Thr45	LIGKVDGtSHVTGKG	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263582	0.301
IRX1	protein	P78414	UNIPROT	PHYHIPL	protein	Q96FC7	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 	SIGNOR-261659	0.2
WIF1	protein	Q9Y5W5	UNIPROT	WNT8A	protein	Q9H1J5	UNIPROT	down-regulates	binding			9606									10201374	t		gcesareni	Here we describe wnt-inhibitory factor-1 (wif-1), a secreted protein that binds to wnt proteins and inhibits their activities.	SIGNOR-66892	0.542
DIP2A	protein	Q14689	UNIPROT	SOD1	protein	P00441	UNIPROT	up-regulates activity	binding			10090	BTO:0000142								33781892	t		miannu	DIP2a is associated with SOD in the mitochondria of mouse brain. DIP2a knockout inhibited SOD activity. In this paper, we analyzed the interacting proteins of DIP2A by mass spectrum analysis and found that DIP2A was correlated with superoxide dismutase (SOD), SOD1 and SOD2. Knockout of DIP2A decreased SOD activity and increased the level of ROS in the mouse brain. 	SIGNOR-266591	0.2
CTNNA1	protein	P35221	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	binding			9606									23431053	t		milica	The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation.	SIGNOR-201173	0.359
CAMK2A	protein	Q9UQM7	UNIPROT	ITPKA	protein	P23677	UNIPROT	up-regulates	phosphorylation	Thr311	EHAQRAVtKPRYMQW	9606	BTO:0000938	BTO:0000975;BTO:0000142							9155020	t		lperfetto	D-myo-inositol 1,4,5-trisphosphate 3-kinase a is activated by receptor activation through a calcium:calmodulin-dependent protein kinase ii phosphorylation mechanism. the phosphorylated residue was thr311.	SIGNOR-48387	0.334
KIT	protein	P10721	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	phosphorylation	Tyr701	DGPKGTGyIKTELIS	-1									21135090	t			KIT is responsible for the permanent phosphorylation of all three STAT proteins. STAT1, -3, and -5 were phosphorylated on their activation-specific Tyr701, Tyr704, and Tyr694, respectively, following KIT stimulation.	SIGNOR-251365	0.714
IL22RA1	protein	Q8N6P7	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates	binding			9606									15120645	t		gcesareni	Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain.	SIGNOR-124489	0.504
UBE2I	protein	P63279	UNIPROT	SOX6	protein	P35712	UNIPROT	down-regulates activity	sumoylation	Lys404	VSPTGIkNEKRGTS	9606									16442531	t			We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity.	SIGNOR-256129	0.374
SMURF2	protein	Q9HAU4	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	ubiquitination			9606		BTO:0000007							11016919	t		lperfetto	The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway.	SIGNOR-236133	0.77
GSK3B	protein	P49841	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by repression	phosphorylation	Ser76	SNLQRMGsSESTDSG	9606	BTO:0000567								20348946	t		lperfetto	Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a	SIGNOR-164742	0.319
ITGB3	protein	P05106	UNIPROT	Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253206	0.912
Terfenadine	chemical	CHEBI:9453	ChEBI	KCNH2	protein	Q12809	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9395068	t		miannu	We have previously shown that terfenadine can inhibit both Kv1.5 and HERG with its effects on HERG being approximately 10‐fold more potent	SIGNOR-258673	0.8
PTPRJ	protein	Q12913	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates	dephosphorylation			9606									12771128	t		gcesareni	A dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation.	SIGNOR-101282	0.47
MAP3K8	protein	P41279	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity				10090	BTO:0000776; BTO:0000801								16484370	f			Mitogen-activated protein 3 kinase Tpl2, levels of which are markedly reduced in nfkb1(-/-) cells, is required for extracellular signal-regulated kinase (ERK) activation in bone marrow-derived macrophages and B cells stimulated with diverse TLR ligands	SIGNOR-256078	0.363
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000763;BTO:0000149							10197981	t	inferred from 70% family members	gcesareni	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3.	SIGNOR-270015	0.2
SRC	protein	P12931	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr42	DSMKDEEyEQMVKEL	9606									9792645	t		llicata	C-src phosphorylates IkappaB On tyrosine 42|NF-kappaB is sequestered in the cytosol by IkappaBalpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation.	SIGNOR-60879	0.675
PDE2A	protein	O00408	UNIPROT	PRKACA	protein	P17612	UNIPROT	down-regulates activity	binding												36476859	t		lperfetto	We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice. 	SIGNOR-275730	0.375
(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	ADRA1D	protein	P25100	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258457	0.8
ATM	protein	Q13315	UNIPROT	XPA	protein	P23025	UNIPROT	unknown	phosphorylation	Ser173	VKKNPHHsQWGDMKL	-1									16540648	t		llicata	Kinase phosphorylation assays were done with synthesized short peptides (20-mer) with the sequences at Ser173 and Ser196 of XPA, respectively. Both peptides seemed to be good substrates for DNA-PK, ATR ( Fig. 2D), and ATM (data not shown).	SIGNOR-250579	0.61
PTPRG	protein	P23470	UNIPROT	PRKCD	protein	Q05655	UNIPROT	up-regulates activity	dephosphorylation	Tyr313	SSEPVGIyQGFEKKT	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254716	0.2
HRAS	protein	P01112	UNIPROT	PIK3CD	protein	O00329	UNIPROT	up-regulates	binding			9606									21779497	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k	SIGNOR-175192	0.65
ADK	protein	P55263	UNIPROT	adenosine	smallmolecule	CHEBI:16335	ChEBI	down-regulates quantity	chemical modification			9606									33961946	t		miannu	Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5′-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). 	SIGNOR-267838	0.8
TRIP11	protein	Q15643	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates	binding			9606									9256431	t	inferred from 70% of family members	miannu	Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity.	SIGNOR-269879	0.432
AURKA	protein	O14965	UNIPROT	NDEL1	protein	Q9GZM8	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser251	LTPSARIsALNIVGD	10090									17060449	t		miannu	Here, we show that Aurora-A phosphorylates NDEL1 at Ser251 at the beginning of mitotic entry. Interestingly, NDEL1 phosphorylated by Aurora-A was rapidly downregulated thereafter by ubiquitination-mediated protein degradation. 	SIGNOR-263159	0.587
REST	protein	Q13127	UNIPROT	SCN2A	protein	Q99250	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								10449787	f		miannu	We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity.	SIGNOR-220698	0.297
SNAP91	protein	O60641	UNIPROT	SYT1	protein	P21579	UNIPROT	up-regulates quantity	binding			9606	BTO:0000938								26903854	t		miannu	 the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval.  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. 	SIGNOR-264114	0.618
CDK5	protein	Q00535	UNIPROT	PPP1R1A	protein	Q13522	UNIPROT	unknown	phosphorylation	Ser67	LKSTLAMsPRQRKKM	10116									11278334	t		lperfetto	In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation.	SIGNOR-249194	0.381
ASNS	protein	P08243	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	chemical modification			9606									29084849	t		miannu	Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7.	SIGNOR-267535	0.8
ACVR1B	protein	P36896	UNIPROT	TDP2	protein	O95551	UNIPROT	up-regulates activity	phosphorylation	Thr88	PKTYVDLtNEETTDS	9606	BTO:0000007								18039968	t		miannu	 ALK4 phosphorylated TTRAP in vitro (Fig. 6A). The band migrating at the position of TTRAP was excised and analyzed by LC-MS/MS. One TTRAP peptide was phosphorylated either on T88 and T92, or on T92 only (Fig. 6B).	SIGNOR-262611	0.285
STK25	protein	O00506	UNIPROT	PDCD10	protein	Q9BUL8	UNIPROT	unknown	phosphorylation	Ser39	ELERVNLsAAQTLRA	9606									19370760	t		llicata	Stk25 phosphorylates ccm3 at serine 39 and threonine 43	SIGNOR-185388	0.791
beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	glycerone phosphate(2-)	smallmolecule	CHEBI:57642	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-268074	0.8
5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide	chemical	CID:73755145	PUBCHEM	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259808	0.8
nitric oxide	smallmolecule	CHEBI:16480	ChEBI	M1_polarization	phenotype	SIGNOR-PH54	SIGNOR	up-regulates													24669294	f		apalma	While investigating the factors that regulate macrophage arginine metabolism, Mills and colleagues found that macrophages activated in mouse strains with Th1 and Th2 backgrounds differed qualitatively in their ability to respond to the classic stimuli IFN-γ or lipopolysaccharide (LPS) or both and defined an important metabolic difference in the pathway: M1 macrophages made the toxic nitric oxide (NO), whereas M2 macrophages made the trophic polyamines	SIGNOR-255556	0.7
FGFR3	protein	P22607	UNIPROT	PTEN	protein	P60484	UNIPROT	unknown	phosphorylation	Tyr240	RREDKFMyFEFPQPL	9606	BTO:0000527								22891331	t		llicata	Fgfrs phosphorylate pten at tyrosine 240	SIGNOR-191797	0.437
KCNB2	protein	Q92953	UNIPROT	VAPA	protein	Q9P0L0	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000007								29941597	t		lperfetto	Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions.	SIGNOR-262124	0.2
MAPK14	protein	Q16539	UNIPROT	EEA1	protein	Q15075	UNIPROT	up-regulates activity	phosphorylation	Thr1392	CSAKNALtPSSKKPV	10090	BTO:0002572								16138080	t		lperfetto	We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes	SIGNOR-140082	0.47
PKN1	protein	Q16512	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser170	SFKLSGFsFKKNKKE	9534	BTO:0000298								8557118	t		lperfetto	PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163.	SIGNOR-248939	0.372
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	BIRC3	protein	Q13489	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9916987	f		gcesareni	The iaps have been shown to be induced by nf-kappab or v-rel in multiple cell lines and conversely, hiap1 and hiap2 have been shown to activate nf-kappab possibly forming a positive feed-back loop.	SIGNOR-64103	0.672
ANKLE2	protein	Q86XL3	UNIPROT	VRK1	protein	Q99986	UNIPROT	down-regulates				9606									22770216	f		miannu	Lem4 inhibits the activity of baf's kinase vrk-1 during mitotic exit	SIGNOR-198103	0.79
adenosine	smallmolecule	CHEBI:16335	ChEBI	ADORA1	protein	P30542	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257446	0.8
iron-sulfur cluster	smallmolecule	CHEBI:30408	ChEBI	D-threo-isocitrate(3-)	smallmolecule	CHEBI:15562	ChEBI	up-regulates quantity	precursor of												26083061	t		lperfetto	Mitochondrial aconitase and succinate dehydrogenase were among the earliest mammalian Fe-S proteins identified.|The enzymatic activity of both proteins depends on the presence of intact Fe-S clusters	SIGNOR-262132	0.8
PSPH	protein	P78330	UNIPROT	O-phosphonato-L-serine(2-)	smallmolecule	CHEBI:57524	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000142							12213811	t		lperfetto	Human phosphoserine phosphatase (HPSP) regulates the levels of glycine and d-serine, the putative co-agonists for the glycine site of the NMDA receptor in the brain. |Phosphoserine phosphatase (PSP)1 is an important enzyme in the phosphorylated pathway of serine biosynthesis, which contributes a major portion of the endogenous l-serine|he enzymatic reaction of PSP is Mg2+-dependent and results in the dephosphorylation of phospho-l-serine with the formation of a phosphoenzyme intermediate, which is subsequently autodephosphorylated. The resulting product, l-serine, is not only a precursor for the biosynthesis of glycine but also an uncompetitive inhibitor for the enzymatic reaction of PSP	SIGNOR-268570	0.8
PPARG	protein	P37231	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	down-regulates quantity by repression				9606	BTO:0000801								17681149	f		lperfetto	Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways	SIGNOR-249555	0.599
CILK1	protein	Q9UPZ9	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates	phosphorylation			9606									22356909	t		lperfetto	Our findings demonstrate an important role for ick in modulating the activity of mtorc1 through phosphorylation of raptor thr-908 and thus implicate a potential signaling mechanism by which ick regulates cell proliferation and division.	SIGNOR-217562	0.2
IYD	protein	Q6PHW0	UNIPROT	3-iodo-L-tyrosine	smallmolecule	CHEBI:27847	ChEBI	down-regulates quantity	chemical modification			9606									28153798	t		scontino	MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide.	SIGNOR-267032	0.8
ACTL6A	protein	O96019	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	form complex	binding			9606									15627498	t		miannu	We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers.	SIGNOR-132916	0.846
MTOR	protein	P42345	UNIPROT	MAF1	protein	Q9H063	UNIPROT	down-regulates	phosphorylation	Ser75	SPSRLSKsQGGEEEG	9606			SIGNOR-C3						20516213	t		fstefani	The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly.	SIGNOR-165799	0.7
SMAD1/5/8	proteinfamily	SIGNOR-PF35	SIGNOR	SMAD4	protein	Q13485	UNIPROT	up-regulates	binding			9606			SIGNOR-C85						21454478	t	inferred from 70% family members	lperfetto	Upon ligand binding, the specific heteromeric transmembrane serine/threonine kinase receptor complexes undergo phosphorylation/activation and subsequently phosphorylate the two ser residues in the c-terminal sxs motif of specific r-smads, smad1/5/8 for bmp pathway and smad2/3 for tgf-_/activin signaling. The activated r-smads then associate with co-smad, smad4. The heteromeric complexes translocate into the nucleus, where they bind to dna directly or indirectly to regulate the transcription of specific genes.	SIGNOR-269952	0.2
KLF7	protein	O75840	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534	BTO:0004055								14729953	f		miannu	KLF7 stimulates p21WAF1/Cip1 transcription	SIGNOR-224624	0.274
STK4	protein	Q13043	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	phosphorylation	Thr1041	EHAFYEFtFRRFFDD	9606									23431053	t		milica	MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation	SIGNOR-201302	0.62
RXRB	protein	P28702	UNIPROT	RARB	protein	P10826	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									1310351	f		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16680	0.65
SH3RF1	protein	Q7Z6J0	UNIPROT	MAP3K10	protein	Q02779	UNIPROT	up-regulates	binding			9606	BTO:0000938								12514131	t		gcesareni	Taken together, these findings support a model in which apoptotic stimuli or posh overexpression induce direct association between posh and inactive mlks.	SIGNOR-97003	0.362
NMUR2	protein	Q9GZQ4	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257126	0.271
RBM10	protein	P98175	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0001938								30403180	f		irozzo	Cell apoptosis is an important event in cancer progression. Overexpression of RBM10 dramatically induced U2OS cell apoptosis compared with negative control cells.	SIGNOR-259150	0.7
LYN	protein	P07948	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates activity	phosphorylation	Tyr753	ERDINSLyDVSRMYV	-1									7682059	t		lperfetto	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249383	0.603
L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	beta-alanine zwitterion	smallmolecule	CHEBI:57966	ChEBI	up-regulates quantity	precursor of			9606									22718265	t		miannu	Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate α-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of α-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce γ-aminobutyric acid (GABA), β-alanine and hypotaurine, respectively; these amine products play important role in living organisms.	SIGNOR-267544	0.8
doramapimod	chemical	CHEBI:40953	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190332	0.8
CAPN2	protein	P17655	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Gly71	FSASVLTgKLTTVFL	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263581	0.301
PI3K	complex	SIGNOR-C156	SIGNOR	Chemotaxis	phenotype	SIGNOR-PH93	SIGNOR	up-regulates													23994464	f		apalma	The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release	SIGNOR-255012	0.7
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates	phosphorylation	Thr258	DMKETKYtVDKRFGM	9606									11152499	t		tpavlidou	We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity.	SIGNOR-85777	0.2
PTPN11	protein	Q06124	UNIPROT	IRF8	protein	Q02556	UNIPROT	down-regulates activity	dephosphorylation			9606									27769062	t		miannu	We found that Bcr-abl-induced, Shp2 dependent dephosphorylation of Icsbp impaired repression of GAS2 by this transcription factor.	SIGNOR-277173	0.361
SMAD2	protein	Q15796	UNIPROT	SMURF2	protein	Q9HAU4	UNIPROT	up-regulates activity	binding			9606									11389444	t		lperfetto	We show that in the presence of TGF-beta signalling, Smad2 interacts through its proline-rich PPXY motif with the tryptophan-rich WW domains of Smurf2, a recently identified E3 ubiquitin ligases.Thus, stimulation by TGF-beta can induce the assembly of a Smad2-Smurf2 ubiquitin ligase complex that functions to target substrates for degradation.	SIGNOR-108490	0.77
RHOA	protein	P61586	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates activity	phosphorylation	Thr567	QGRDKYKtLRQIRQG	9606	BTO:0000132								35267019	t		miannu	Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. 	SIGNOR-268429	0.751
MRAP	protein	Q8TCY5	UNIPROT	MC2R	protein	Q01718	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								19329486	t		miannu	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor.	SIGNOR-252360	0.756
NAE	complex	SIGNOR-C131	SIGNOR	CUL5	protein	Q93034	UNIPROT	up-regulates activity	neddylation			9606									25504797	t		lperfetto	The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates.	SIGNOR-243166	0.622
PFDN6	protein	O15212	UNIPROT	URI1 prefoldin co-chaperone	complex	SIGNOR-C514	SIGNOR	form complex	binding			9606									30484151	t		miannu	In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR95	SIGNOR-270918	0.629
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR4	protein	Q13639	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264294	0.8
ABR	protein	Q12979	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260525	0.482
PPARGC1A	protein	Q9UBK2	UNIPROT	APOA5	protein	Q6Q788	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								16891307	f		miannu	 Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 	SIGNOR-255058	0.286
BECN1	protein	Q14457	UNIPROT	Autophagosome_formation	phenotype	SIGNOR-PH36	SIGNOR	up-regulates				9606		BTO:0001623							20921139	f		miannu	Autophagy initiation signaling requires both the ULK1 kinase and the BECLIN 1–VPS34 core complex to generate autophagosomes, double-membraned vesicles that transfer cellular contents to lysosomes.	SIGNOR-219545	0.7
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	SF3B1	protein	O75533	UNIPROT	up-regulates	phosphorylation	Thr248	GSETPGAtPGSKIWD	9606									12105215	t		lperfetto	To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptides. Three phosphorylation sites were identified as thr244, thr248, and thr313	SIGNOR-216666	0.354
ACTB	protein	P60709	UNIPROT	SWI/SNF ACTL6A-ARID1A-SMARCA2 variant	complex	SIGNOR-C470	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269826	0.488
FYN	protein	P06241	UNIPROT	DLG2	protein	Q15700	UNIPROT	up-regulates activity	phosphorylation	Tyr348	TRPPEPVySTVNKLC	-1									13129934	t		miannu	 Recombinant PSD-93 was phosphorylated by Fyn in vitro, and Tyr-384 was identified as a major phosphorylation site. In COS7 cells, exogenously expressed PSD-93 was phosphorylated, dependent on its membrane localization. In addition, tyrosine-phosphorylated PSD-93 was able to bind to Csk, a negative regulator of Src family kinases, in vitro as well as in a brain lysate. 	SIGNOR-262874	0.375
MAPK14	protein	Q16539	UNIPROT	CFLAR	protein	O15519	UNIPROT	up-regulates	phosphorylation			9606									19597496	t	There are three isoforms of cellular FLIP (c-FLIP): FLIPL, FLIPS and FLIPR	gcesareni	Here we demonstrate that m. tuberculosis?induced Tnf triggered reactive oxygen species?dependent Activation of ask1 and the tyrosine kinase c-abl (a000161) in mouse macrophages and that flips was phosphorylated on tyr211 and ser4 by c-abl and p38, respectively.	SIGNOR-187001	0.381
EGFR	protein	P00533	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr472	EPIQEANyVPMTPGT	9606	BTO:0000527;BTO:0000017								9890893	t		lperfetto	Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689).	SIGNOR-236412	0.751
JAK2	protein	O60674	UNIPROT	BRD4	protein	O60885	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr97	VKLNLPDyYKIIKTP	9606	BTO:0002181								34290255	t		miannu	JAK2 induces tyrosine phosphorylation of BRD4 at Y97/Y98, resulting in BRD4 stabilization. 	SIGNOR-277313	0.331
ROCK1	protein	Q13464	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates	phosphorylation	Thr232	YSSNSGPtRREDKFM	9606									15793569	t		llicata	In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues.	SIGNOR-134855	0.643
UPF3B	protein	Q9BZI7	UNIPROT	Upf-EJC	complex	SIGNOR-C367	SIGNOR	form complex	binding			9606	BTO:0000567								17803942	t		miannu	The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1	SIGNOR-265236	0.961
MAPK3	protein	P27361	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	up-regulates	phosphorylation			9606									19282669	t		gcesareni	Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.	SIGNOR-184583	0.717
EXOC1	protein	Q9NV70	UNIPROT	Exocyst_EXOC6B variant	complex	SIGNOR-C491	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270776	0.864
CSNK1A1	protein	P48729	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation	Ser97	TIAESEDsQESVDSV	9606									9931297	t		lperfetto	Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement.	SIGNOR-64254	0.318
EIF2AK1	protein	Q9BQI3	UNIPROT	EIF2S1	protein	P05198	UNIPROT	down-regulates activity	phosphorylation			9606									24714526	t		miannu	HRI is an intracellular heme sensor that coordinates heme and globin synthesis in erythropoiesis by inhibiting protein synthesis of globins and heme biosynthetic enzymes during heme deficiency. HRI is a heme-regulated kinase that phosphorylates the α-subunit of eIF2 in heme deficiency, impairing another round of translational initiation and thereby inhibiting translation.	SIGNOR-251817	0.886
FYN	protein	P06241	UNIPROT	ACP1	protein	P24666	UNIPROT	up-regulates activity	phosphorylation	Tyr133	LIIEDPYyGNDSDFE	9534	BTO:0004055								9038134	t			We identify Tyr-131 as the major phosphorylation site and Tyr-132 as a minor site and the Src family PTKs Lck and Fyn as enzymes capable of phosphorylating these sites in vivo and in vitro. Both Tyr-131 and Tyr-132 are located next to the catalytic pocket of LMPTP, and especially, Tyr-131 seems to be important for the activity of LMPTP. Phosphorylation of Tyr-131 or Tyr-132, particularly the former, caused an increase in the activity of LMPTP. 	SIGNOR-251150	0.39
PTPN13	protein	Q12923	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr999	YASSNPEyLSASDVF	9606									15611135	t		gcesareni	We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines.	SIGNOR-132563	0.263
BMPR1B	protein	O00238	UNIPROT	SMAD5	protein	Q99717	UNIPROT	up-regulates				10090	BTO:0000165								10564272	f		lperfetto	We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2	SIGNOR-235625	0.667
PSMD2	protein	Q13200	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606									29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263344	0.887
FLNA	protein	P21333	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates activity				9606									18667433	f		areggio	Additionally, the association of Ror2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration. 	SIGNOR-258973	0.488
PI-103	chemical	CHEBI:90524	ChEBI	PIK3C2B	protein	O00750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206160	0.8
UMPS	protein	P11172	UNIPROT	5-phospho-α-D-ribose 1-diphosphate	smallmolecule	CHEBI:58017	ChEBI	down-regulates quantity	chemical modification			9606									2912371	t		miannu	Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase).	SIGNOR-267437	0.8
BIRC2	protein	Q13490	UNIPROT	BIRC2	protein	Q13490	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567								14960576	t		lperfetto	Ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria.	SIGNOR-121877	0.2
MAPK14	protein	Q16539	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									20068231	t		gcesareni	Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.	SIGNOR-163246	0.786
SOCS1	protein	O15524	UNIPROT	STAT1	protein	P42224	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16628196	f		miannu	SOCS1, which is another inducible gene, not only blocks STAT1 activation but also inhibits STAT1-dependent TLR3, IRF-7, and MIP-1α. 	SIGNOR-255229	0.623
RFPL4A	protein	A6NLU0	UNIPROT	CCNB1	protein	P14635	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10029	BTO:0000246								12525704	t		miannu	We conclude that, like many RING-finger containing proteins, RFPL4 is an E3 ubiquitin ligase. The specificity of its expression and these interactions suggest that RFPL4 targets cyclin B1 for proteasomal degradation, a key aspect of oocyte cell cycle control during meiosis and the crucial oocyte-to-embryo transition to mitosis. 	SIGNOR-271476	0.325
RICTOR	protein	Q6R327	UNIPROT	mTORC2	complex	SIGNOR-C2	SIGNOR	form complex	binding			9606									25628925	t		lperfetto	Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)	SIGNOR-205624	0.828
DYRK2	protein	Q92630	UNIPROT	PSMC4	protein	P43686	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr25	LSVSRPQtGLSFLGP										26655835	t		lperfetto	Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation.	SIGNOR-275845	0.289
MEF2C	protein	Q06413	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	up-regulates				-1									23001426	f		Luana	 In brain, MEF2C is essential for early neurogenesis, neuronal migration, and differentiation. 	SIGNOR-265800	0.7
Protocadherin_beta	proteinfamily	SIGNOR-PF102	SIGNOR	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-269039	0.2
ATM	protein	Q13315	UNIPROT	ATM	protein	Q13315	UNIPROT	unknown	phosphorylation	Ser440	SPLLMILsQLLPQQR	-1									10608806	t		llicata	Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself.	SIGNOR-250576	0.2
PTPRS	protein	Q13332	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606	BTO:0000938								27225731	f		miannu	LAR (for leukocyte common antigen-related) is a family of receptor protein tyrosine phosphatases (LAR-RPTPs) with three known members: LAR/PTPRF, PTPδ/PTPRD, and PTPσ/PTPRS. In mammals, LAR-RPTPs have been shown to regulate dendrite and excitatory synapse development and maintenance	SIGNOR-264091	0.7
SSTR4	protein	P31391	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256680	0.482
CDK4	protein	P11802	UNIPROT	KAT2A	protein	Q92830	UNIPROT	up-regulates activity	phosphorylation	Ser372	EEIYGANsPIWESGF										24870244	t		lperfetto	Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT)	SIGNOR-275494	0.367
DYRK2	protein	Q92630	UNIPROT	DPYSL3	protein	Q14195	UNIPROT	up-regulates activity	phosphorylation	Thr509	PVFDLTTtPKGGTPA	9606									16611631	t		lperfetto	Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-145979	0.373
STAT6	protein	P42226	UNIPROT	SOCS1	protein	O15524	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17093501	t		lperfetto	We found that IL-4, like IFN-gamma, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent.	SIGNOR-249570	0.624
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	TSPYL2	protein	Q9H2G4	UNIPROT	up-regulates activity	phosphorylation	Ser20	RRLSSSEsPQRDPPP	9606	BTO:0000567								11395479	t		llicata	We observed that a CDA1 mutant with the two consensus CDK phosphorylation sites abolished (S20A and T340A) disabled its capacity to inhibit cell growth, indicating that these sites are important for the function of this protein. Furthermore, we showed that these sites are phosphorylated by cyclin/CDKs in vitro, suggesting that these kinases may regulate CDA1 function in vivo. 	SIGNOR-250752	0.345
Immune complexes	stimulus	SIGNOR-ST15	SIGNOR	FCGR3A	protein	P08637	UNIPROT	up-regulates activity				9606	BTO:0000801								17558411	f		lperfetto	After binding their antibody ligands, FcgRI and FcgRIII deliver activating signals through an association with the FcRg-chain (FcRg), a transmembrane adaptor protein with an immuno-receptor tyrosine-based activation motif in its cytoplasmic domain.	SIGNOR-249523	0.7
AKT1	protein	P31749	UNIPROT	STK4	protein	Q13043	UNIPROT	down-regulates	phosphorylation	Thr387	TMKRRDEtMQPAKPS	9606									23431053	t		gcesareni	Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt.	SIGNOR-252537	0.406
PRKCA	protein	P17252	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser27	TASRPSSsRSYVTTS	-1									2500966	t		lperfetto	We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65.	SIGNOR-248879	0.289
WNT5A	protein	P41221	UNIPROT	FZD2	protein	Q14332	UNIPROT	up-regulates activity	binding			9606									19008118	t		FFerrentino	Perhaps through Wnt5a acting via FZD2, might also inhibit adipocyte differentiation.	SIGNOR-253520	0.757
PRKAA1	protein	Q13131	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser626	SLECDMEsIIRSELM	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-249687	0.509
AURKB	protein	Q96GD4	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates	phosphorylation	Ser73	SAVRLRSsVPGVRLL	9606									12458200	t		llicata	By identifying eight aurora-b phosphorylation sites on vimentin in vitro, we have demonstrated that vimentin-ser-72 is an in vitrophosphorylation site of aurora-b. in vitro analyses revealed that aurora-b phosphorylates vimentin at approximately 2 mol phosphate/mol of substrate for 30 min and that this phosphorylation dramatically inhibits vimentin filament formation.	SIGNOR-96057	0.397
AKT1	protein	P31749	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18423396	f		fspada	Moreover, expression of p27(kip1), an inhibitor of the cell cycle, was down regulated in an akt1/pkbalpha-specific manner during adipocytedifferentiation.	SIGNOR-178269	0.845
SRC	protein	P12931	UNIPROT	MPZL1	protein	O95297	UNIPROT	up-regulates	phosphorylation	Tyr263	NKSESVVyADIRKN	9606									11751924	t		lperfetto	Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr	SIGNOR-113410	0.481
WNK1	protein	Q9H4A3	UNIPROT	STK39	protein	Q9UEW8	UNIPROT	up-regulates	phosphorylation	Ser371	VRRVPGSsGHLHKTE	9606	BTO:0000007	BTO:0000671							18270262	t		gcesareni	Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1).	SIGNOR-160842	0.457
SKI	protein	P12755	UNIPROT	SMAD2/SMAD4	complex	SIGNOR-C8	SIGNOR	down-regulates activity	binding			9606	BTO:0000848								12793438	t		lperfetto	The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway	SIGNOR-253300	0.771
CDK2	protein	P24941	UNIPROT	PGR	protein	P06401	UNIPROT	unknown	phosphorylation	Ser213	SGAPVKPsPQAAAVE	9606									11110801	t		llicata	In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676).	SIGNOR-84984	0.453
METTL3	protein	Q86U44	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007;BTO:0000567								27117702	t		miannu	Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells. 	SIGNOR-265955	0.2
ANKRD11	protein	Q6UB99	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				10090		BTO:0000142							29274743	f		miannu	We showed that ANKRD11 regulates dendrite outgrowth, arborization, and spine formation via Trkb transcription and activation of its downstream effectors in the developing mouse brain. 	SIGNOR-266733	0.7
FLT3	protein	P36888	UNIPROT	PTPN11	protein	Q06124	UNIPROT	up-regulates activity	binding			10090	BTO:0002882				phosphorylation:Tyr599	VDFREYEyDLKWEFP			16684964	t		gcesareni	Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation.	SIGNOR-245057	0.54
NT5E	protein	P21589	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	down-regulates quantity	chemical modification			-1									31461341	t		Luana	Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine.	SIGNOR-269743	0.8
CRYGS	protein	P22914	UNIPROT	Maintenance_of_lens_transparency	phenotype	SIGNOR-PH65	SIGNOR	up-regulates				9606									10521291	f			The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification. 	SIGNOR-253625	0.7
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH11	protein	P55287	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265829	0.8
CCT239065	chemical	CID:44131523	PUBCHEM	BRAF	protein	P15056	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190907	0.8
TAL1	protein	P17542	UNIPROT	TSG101	protein	Q99816	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								17229889	t		miannu	These data suggest that Tal mediates polyubiquitylation of the lysine residues in the VPS28-binding region of TSG101, leading to subsequent degradation of TSG101.	SIGNOR-271636	0.2
IKBKB	protein	O14920	UNIPROT	TSC1	protein	Q92574	UNIPROT	down-regulates	phosphorylation	Ser511	DSPFYRDsLPGSQRK	9606	BTO:0000150								17693255	t		gcesareni	Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression.	SIGNOR-157300	0.627
STAT3	protein	P40763	UNIPROT	KRT17	protein	Q04695	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000667								21796151	f		miannu	 IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms.	SIGNOR-255234	0.262
FBXO21	protein	O94952	UNIPROT	EID1	protein	Q9Y6B2	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								26085330	t		miannu	SCFFBXO21 ubiquitylates and thereby targets EID1 for degradation.We have now applied this approach to an uncharacterized human F-box protein, FBXO21, which serves as the substrate-recognition subunit of a SKP1-CUL1-F-box protein (SCF)-type E3, thereby identifying EID1 (EP300-interacting inhibitor of differentiation 1) as a candidate substrate.Over-expression of FBXO21 resulted in the down-regulation of EID1, whereas disruption of the FBXO21 gene with the CRISPR/Cas9 system stabilized EID1 and led to its accumulation in both the cytoplasm and nucleus. An in vitro ubiquitylation assay showed that EID1 is a direct substrate of SCF(FBXO)	SIGNOR-272429	0.423
oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	precursor of			9606									26003525	t		miannu	Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and α-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer.	SIGNOR-267503	0.8
PRKCA	protein	P17252	UNIPROT	PLEK	protein	P08567	UNIPROT	up-regulates	phosphorylation	Ser117	ARKSTRRsIRLPETI	9606									7559487	t		gcesareni	To determine the role of pkc-dependent phosphorylation in pleckstrin function, we mapped the phosphorylation sites in vivo of wild-type and site-directed mutants of pleckstrin expressed in cos cells. Phosphorylation was found to occur almost exclusively on ser-113 and ser-117. Replacing all these sites with glycine decreased phosphorylation by > 90% and reduced pleckstrin's ability to inhibit phosphoinositide hydrolysis by as much as 80%.	SIGNOR-28884	0.284
MAPK11	protein	Q15759	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates activity				9606	BTO:0001255								12839928	f		miannu	Activation of p38 MAPK is required for arsenite-induced apoptosis and MEK1,2 dephosphorylation in human skin fibroblasts. Our data suggest the presence of a continuous negative feedback from p38α and p38β to MEK1,2 as simultaneous inhibition of p38α and p38β isoforms in normal quiescent cells resulted in accumulation of phosphorylated MEK1,2 (Fig. 2A) ⇓ . This negative regulation of MEK1,2 in normal cells could be considered a means to control MEK1,2-mediated proliferation and expression of transformation-related genes. 	SIGNOR-263512	0.457
lanreotide	chemical	CHEBI:135901	ChEBI	SSTR5	protein	P35346	UNIPROT	up-regulates activity	chemical activation			9606									26416534	t		miannu	Lanreotide Autogel (known as lanreotide Depot in the USA) is a synthetic octapeptide analog of somatostatin with a longer half-life than the native molecule and with selectivity for somatostatin receptor (SSTR) 2 and, to a lesser extent, SSTR 5	SIGNOR-259243	0.8
HCK	protein	P08631	UNIPROT	ELMO1	protein	Q92556	UNIPROT	up-regulates	phosphorylation	Tyr18	AIEWPGAyPKLMEID	9606									15952790	t		llicata	We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts.	SIGNOR-138142	0.59
1-acyl-sn-glycerol 3-phosphate(2-)	smallmolecule	CHEBI:57970	ChEBI	phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	up-regulates quantity	precursor of			9606									21173190	t		lperfetto	The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA). 	SIGNOR-267016	0.8
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	RUNX1	protein	Q01196	UNIPROT	down-regulates activity	phosphorylation	Ser276	VHPATPIsPGRASGM	9606									17015473	t	The effect has been demonstrated using Q01196-8	lperfetto	Previous studies have shown that phosphorylation of aml1, particularly at serines 276 and 303, affects its transcriptional activation. Here, we report that phosphorylation of aml1 serines 276 and 303 can be blocked in vivo by inhibitors of the cyclin-dependent kinases (cdks) cdk1 and cdk2. Furthermore, these residues can be phosphorylated in vitro by purified cdk1/cyclin b and cdk2/cyclin a.	SIGNOR-217340	0.2
CSNK2B	protein	P67870	UNIPROT	SORT1	protein	Q99523	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser825	KSGYHDDsDEDLLE	10090	BTO:0003449								25805502	t		miannu	 Phosphorylation of Ser-825 is required for insulin to induce Sort1 in AML12 cells. LC-MS/MS analysis further revealed that serine phosphorylation of Sort1 protein was required for insulin induction of Sort1 in a casein kinase 2-dependent manner and that inhibition of PI3K signaling or prevention of Sort1 phosphorylation accelerated proteasome-dependent Sort1 degradation. 	SIGNOR-273636	0.2
SCNN1G	protein	P51170	UNIPROT	CACNA1H	protein	O95180	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							30736831	t		miannu	This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues.	SIGNOR-269274	0.2
FLT3	protein	P36888	UNIPROT	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	up-regulates activity				9606	BTO:0002144								28194038	f	inferred from family member		FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity	SIGNOR-270268	0.267
PPM1A	protein	P35813	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates	dephosphorylation			9606									16751101	t		lpetrilli	Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.	SIGNOR-146919	0.655
CDK4	protein	P11802	UNIPROT	FOXM1	protein	Q08050	UNIPROT	up-regulates	phosphorylation	Thr611	ETLPISStPSKSVLP	9606									22094256	t		lperfetto	We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627)	SIGNOR-177255	0.609
CDON	protein	Q4KMG0	UNIPROT	MAP3K7	protein	O43318	UNIPROT	unknown	binding			10090			SIGNOR-C21						22337877	t		lperfetto	Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts	SIGNOR-235554	0.2
RARB	protein	P10826	UNIPROT	OXT	protein	P01178	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									6153132	f		lperfetto	The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances.	SIGNOR-268549	0.2
HK3	protein	P52790	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor.	SIGNOR-266447	0.8
WNT7A	protein	O00755	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131900	0.585
PPP1CA	protein	P62136	UNIPROT	PREX2	protein	Q70Z35	UNIPROT	up-regulates activity	dephosphorylation	Ser1107	DTISNRDsYSDCNSN	9606	BTO:0000007								26438819	t		miannu	PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. 	SIGNOR-277183	0.2
clobetasol	chemical	CHEBI:205919	ChEBI	SMO	protein	Q99835	UNIPROT	up-regulates activity	chemical activation			10090									20439738	t		gcesareni	We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling.	SIGNOR-248212	0.8
Hypoxia	stimulus	SIGNOR-ST25	SIGNOR	NPTX1	protein	Q15818	UNIPROT	up-regulates				10090	BTO:0000938								15115814	f		lperfetto	We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death. 	SIGNOR-261431	0.7
SERPINA1	protein	P01009	UNIPROT	LRP1	protein	Q07954	UNIPROT	up-regulates	binding			9606									8626456	t		gcesareni	In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp	SIGNOR-41180	0.328
ATM	protein	Q13315	UNIPROT	NBN	protein	O60934	UNIPROT	up-regulates	phosphorylation	Ser343	TTPGPSLsQGVSVDE	9606									10608806	t		lperfetto	In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage.	SIGNOR-73432	0.852
NR1I3	protein	Q14994	UNIPROT	CYP2B6	protein	P20813	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19702527	f		miannu	 Human CYP2B6 is closely regulated by constitutive androstane receptor (CAR/NR1I3) which can activate CYP2B6 expression upon ligand binding.	SIGNOR-254863	0.485
IQSEC2	protein	Q5JU85	UNIPROT	GRIA4	protein	P48058	UNIPROT	up-regulates quantity	relocalization			9606		BTO:0000142							27009485	t		miannu	BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.	SIGNOR-264915	0.2
ETS1	protein	P14921	UNIPROT	BAX	protein	Q07812	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002181								17213822	f	 	miannu	 Our results suggest that the interaction between ETS1 and GFI1 facilitates their binding to specific sites on the Bax promoter and represses Bax expression in vivo.	SIGNOR-254204	0.2
tRNA(Asn)	smallmolecule	CHEBI:29172	ChEBI	Asn-tRNA(Asn)	smallmolecule	CHEBI:29265	ChEBI	up-regulates quantity	precursor of			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270459	0.8
CIITA	protein	P33076	UNIPROT	MYOG	protein	P15173	UNIPROT	down-regulates	binding			9606		BTO:0001103							28163303	t		apalma	During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function	SIGNOR-255111	0.2
GAPDHS	protein	O14556	UNIPROT	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	down-regulates quantity	chemical modification			9606									11724794	t		miannu	GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion	SIGNOR-266498	0.8
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser721	PVVSGDTsPRHLSNV	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249346	0.729
RAB14	protein	P61106	UNIPROT	RUFY1	protein	Q96T51	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								20534812	t		Giulio	Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.	SIGNOR-261279	0.615
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation			9606									14662762	t	inferred from 70% family members	lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-270039	0.2
STK11	protein	Q15831	UNIPROT	SIK3	protein	Q9Y2K2	UNIPROT	up-regulates	phosphorylation	Thr221	TPGQLLKtWCGSPPY	9606									14976552	t		lperfetto	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122835	0.466
pazopanib hydrochloride	chemical	CHEBI:71217	ChEBI	FGF1	protein	P05230	UNIPROT	down-regulates activity	chemical inhibition			-1									17620431	t		miannu	Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. 	SIGNOR-259166	0.8
PRKACA	protein	P17612	UNIPROT	SREBF1	protein	P36956	UNIPROT	down-regulates	phosphorylation	Ser338	IEKRYRSsINDKIIE	9606									16381800	t		llicata	Sterol regulatory element-binding protein 1 is negatively modulated by pka phosphorylation. ser338 of srebp-1a and ser314 of srebp-1c are pka phosphorylation sites.	SIGNOR-143392	0.2
TRIP12	protein	Q14669	UNIPROT	RNF168	protein	Q8IYW5	UNIPROT	down-regulates activity	ubiquitination			9606	BTO:0001938								22884692	t		miannu	Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1. 	SIGNOR-266783	0.478
KDM4C	protein	Q9H3R0	UNIPROT	JAG1	protein	P78504	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23698634	f		miannu	The expression of KDM4C gene was increased in spheres from colorectal cancer (CRC) cells and the knockdown (KD) of KDM4C eliminated colonosphere formation. KDM4C KD decreased the expression of JAG1 gene, and the downregulation of JAG1 gene recapitulated the impaired colonosphere formation. 	SIGNOR-254542	0.2
DUX4	protein	Q9UBX2	UNIPROT	HEY1	protein	Q9Y5J3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24278031	f		miannu	 HEY1, a repressor of myogenesis, is activated by DUX4 through a MaLR promoter.	SIGNOR-253840	0.278
Urotensin II	smallmolecule	CHEBI:80244	ChEBI	UTS2R	protein	Q9UKP6	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257590	0.8
Vincristine sulfate	chemical	CHEBI:79401	ChEBI	FN1	protein	P02751	UNIPROT	down-regulates activity	chemical inhibition			9606									30599272	t		miannu	Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. 	SIGNOR-259252	0.8
PRKCD	protein	Q05655	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser163	KRFSFKKsFKLSGFS	-1									8422248	t		lperfetto	These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III.	SIGNOR-248927	0.469
KAT6A/KAT6B	complex	SIGNOR-C54	SIGNOR	TP53	protein	P04637	UNIPROT	up-regulates	acetylation	Lys120	FLHSGTAkSVTCTYS	9606	BTO:0001271								23431171	t		lperfetto	We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression	SIGNOR-217194	0.492
ATM	protein	Q13315	UNIPROT	SIAH1	protein	Q8IUQ4	UNIPROT	down-regulates	phosphorylation	Ser19	GTSKCPPsQRVPALT	9606									18536714	t		llicata	Disruption of the hipk2-siah-1 complex is mediated by the atm/atr pathway and involves atm/atr-dependent phosphorylation of siah-1 at ser 19.	SIGNOR-177945	0.314
MAPK1	protein	P28482	UNIPROT	TPPP	protein	O94811	UNIPROT	down-regulates activity	phosphorylation	Ser160	GVTKAISsPTVSRLT	-1									17693641	t		miannu	 Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP.	SIGNOR-262928	0.363
MAPK3	protein	P27361	UNIPROT	EWSR1	protein	Q01844	UNIPROT	unknown	phosphorylation	Thr79	QPPTGYTtPTAPQAY	9606									19076070	t		lperfetto	Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2.	SIGNOR-182782	0.268
MASP2	protein	O00187	UNIPROT	C4A	protein	P0C0L4	UNIPROT	up-regulates activity	cleavage	Arg679	EKTTRKKrNVNFQKA	-1									17204478	t		lperfetto	MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a).	SIGNOR-263431	0.793
MTX2	protein	O75431	UNIPROT	SAM complex	complex	SIGNOR-C422	SIGNOR	form complex	binding												31387448	t		lperfetto	The SAM complex of the outer membrane mediates insertion of β-barrel proteins into the outer membrane. hSam50 associates with MTX1 and MTX2. 	SIGNOR-267682	0.727
ITGB1	protein	P05556	UNIPROT	A4/b1 integrin	complex	SIGNOR-C162	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253176	0.803
CDK2	protein	P24941	UNIPROT	CCNE1	protein	P24864	UNIPROT	down-regulates	phosphorylation	Thr395	PLPSGLLtPPQSGKK	9606									19561641	t		gcesareni	Phosphorylation of threonine 395 has been linked to the proteasome-mediated degradation of full length cyclin e	SIGNOR-186418	0.954
SRP54	protein	P61011	UNIPROT	SRPRB	protein	Q9Y5M8	UNIPROT	up-regulates activity	binding			-1									30649417	t		miannu	The multi-domain SRP GTPase SRP54 recognizes the signal with its M domain and establishes the targeting complex consisting of its NG domain bound to the homologous NG domain of the SRP receptor SRα at a proximal ribosome binding site.	SIGNOR-261165	0.812
MAPK9	protein	P45984	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Tyr612	TLHTDDGyMPMSPGV	9606									14579029	t		gcesareni	Map kinases and mtor mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632	SIGNOR-118873	0.698
CSNK2A1	protein	P68400	UNIPROT	OTUD5	protein	Q96G74	UNIPROT	up-regulates activity	phosphorylation	Ser177	EVGAGYNsEDEYEAA	-1									22245969	t		miannu	Here we show that phosphorylation of the human deubiquitinase DUBA (OTUD5) at a single residue, Ser177, is both necessary and sufficient to activate the enzyme. Treatment with CK2 could activate DUBA purified from E. coli, and this activity was associated with a species monophosphorylated at Ser177 (Fig. 1d).	SIGNOR-265872	0.2
CHEK1	protein	O14757	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates activity	phosphorylation	Ser331	KSKGRASsSGNQESS	9606	BTO:0005035								19861535	t		lperfetto	In this study, we report a novel phosphorylation site serine 331 (S331) of FANCD2, the pivotal downstream player of the Fanconi anemia pathway. Phosphorylation of S331 is important for its DNA damage-inducible monoubiquitylation, resistance to DNA cross-linkers, and in vivo interaction with FANCD1/BRCA2.|In vitro and in vivo experiments show that phosphorylation of S331 is mediated by CHK1,	SIGNOR-263252	0.604
DNMT1	protein	P26358	UNIPROT	FOXP3	protein	Q9BZS1	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000775								32905139	t		Gianni	Our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35)	SIGNOR-269053	0.503
LCK	protein	P06239	UNIPROT	ZAP70	protein	P43403	UNIPROT	unknown	phosphorylation	Tyr69	ERQLNGTyAIAGGKA	9606	BTO:0000661								7961936	t			We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck.	SIGNOR-251396	0.601
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	TSC2	protein	P49815	UNIPROT	up-regulates activity	phosphorylation	Ser1217	MSLENPLsPFSSDIN	9606	BTO:0000007								32294430	t	done	miannu	We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452. 	SIGNOR-274099	0.481
DIABLO	protein	Q9NR28	UNIPROT	BIRC2	protein	Q13490	UNIPROT	down-regulates quantity	binding			9606	BTO:0000567								14960576	t		amattioni	Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells.	SIGNOR-121883	0.891
CACNA2D3	protein	Q8IZS8	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606									31746409	f		miannu	Overexpression of CACNA2D3 reduced proliferation and migration, but increased apoptosis and Ca2+ influx in Ishikawa and RL95-2 cells. 	SIGNOR-266854	0.7
CD79A	protein	P11912	UNIPROT	BCR-Ml	complex	SIGNOR-C434	SIGNOR	form complex	binding			9606	BTO:0000776								32323266	t		scontino	BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition.	SIGNOR-268192	0.641
TFEB	protein	P19484	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Notably, TFEB regulates genes involved in several steps of lipid catabolism, which occur in different cellular compartments, such as the transport of fatty acid chains across the plasma membrane (for example, Cd36 and Fabps), and the β-oxidation of FFA in mitochondria (for example, Cpt1, Crat, Acadl, Acads and Hdad) and in peroxisomes (Cyp4a genes). 	SIGNOR-276707	0.287
STAT5A	protein	P42229	UNIPROT	IRF5	protein	Q13568	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000801								25506346	t		lperfetto	The GM-CSF receptor forms a dodecamer structure and recruits JAK2, leading to the activation of STAT5, extracellular signal-regulated kinase (ERK), V-Akt murine thymoma viral oncogene homolog 1 (AKT), and the nuclear translocation of NF-kappaB and IRF5	SIGNOR-249508	0.292
WNK1	protein	Q9H4A3	UNIPROT	WNK1	protein	Q9H4A3	UNIPROT	up-regulates	phosphorylation	Ser382	KRASFAKsVIGTPEF	9606	BTO:0000007	BTO:0000671							18270262	t		gcesareni	We demonstrate that wnk1 is rapidly activated and phosphorylated at multiple residues after exposure of cells to hyperosmotic conditions and that activation is mediated by the phosphorylation of its t-loop ser382 residue, possibly triggered by a transautophosphorylation reaction.	SIGNOR-160850	0.2
PRKCQ	protein	Q04759	UNIPROT	PTPN6	protein	P29350	UNIPROT	down-regulates activity	phosphorylation	Ser591	DKEKSKGsLKRK	9606	BTO:0000914								35258455	t		miannu	SHP-1 phosphorylation is mediated through PKC-θ. Here, we show that phosphorylation of SHP-1 in NK cells on the S591 residue by PKC-θ promotes the inhibited SHP-1 'folded' state. Silencing PKC-θ maintains SHP-1 in the active conformation, reduces NK cell activation and cytotoxicity, and promotes tumor progression in vivo.	SIGNOR-277590	0.2
GCG	protein	P01275	UNIPROT	LATS1	protein	O95835	UNIPROT	up-regulates				9606									23075495	f		gcesareni	On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz.	SIGNOR-199202	0.276
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation	Tyr637	KFGSLDTyLKKNKNC	9606	BTO:0000007								19364823	t	16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition.	lperfetto	Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2.	SIGNOR-235885	0.2
KDM6B	protein	O15054	UNIPROT	IRF4	protein	Q15306	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000801								22025054	t		lperfetto	JMJD3 seems to function by controlling expression of the transcription factor IRF4, which in turn is required for M2 polarization of macrophages in vitro and in vivo. Although this pathway is strongly supported by genetic.	SIGNOR-249540	0.435
PRKCB	protein	P05771	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser315	AHSIHQRsRKRLSQD	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89193	0.549
MAP3K7	protein	O43318	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								17110930	t		Barakat	Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK	SIGNOR-274146	0.629
FASN	protein	P49327	UNIPROT	malonyl-CoA	smallmolecule	CHEBI:15531	ChEBI	down-regulates quantity	chemical modification			9606									15507492	t			Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the de novo biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH. 	SIGNOR-267212	0.8
ULK1	protein	O75385	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	down-regulates activity	phosphorylation			9606				SIGNOR-C15					21460634	t		lperfetto	Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity.	SIGNOR-173047	0.552
SIK1	protein	P57059	UNIPROT	CRTC2	protein	Q53ET0	UNIPROT	down-regulates activity	phosphorylation	Ser348	PSLQSSLsNPNLQAS	9606	BTO:0000567								16306228	t		lperfetto	We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression 	SIGNOR-249168	0.63
STK11	protein	Q15831	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates	phosphorylation	Thr109	QWARLLQtSNITKSE	9606									20400510	t		esanto	Lkb1 suppresses p21-activated kinase-1 (pak1) by phosphorylation of thr109 in the p21-binding domain.	SIGNOR-164814	0.249
lysophosphatidylserine 14:0(1-)	chemical	CHEBI:72402	ChEBI	GPR34	protein	Q9UPC5	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257505	0.8
POU3F4	protein	P49335	UNIPROT	POU3F3	protein	P20264	UNIPROT	up-regulates activity	binding			-1									9105675	t		miannu	POU proteins (Brain-1, Brain-2, Brain-4 and SCIP) serve as transcriptional transactivators. if they were to form homomeric and heteromeric complexes with each other, depending on the particular combination, they might have different DNA-binding specificities and, thus, activate different genes.	SIGNOR-220127	0.318
PRKAA1	protein	Q13131	UNIPROT	UCP3	protein	P55916	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887;BTO:0001103							17609368	f		gcesareni	Severalin vivostudies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochromec, uncoupling protein 3 (ucp-3)] (1518) and proteins involved in glucose uptake (glut4) (1820) are increased at the transcriptional level in skeletal muscle.	SIGNOR-156831	0.336
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	alpha-aminoacyl-tRNA	smallmolecule	CHEBI:2651	ChEBI	up-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 	SIGNOR-270796	0.8
STAT3	protein	P40763	UNIPROT	FBXO32	protein	Q969P5	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									22669242	f		miannu	Thus we infected C2C12 myofibers with a recombinant adenovirus expressing a mutant, constitutively activated STAT3 (cSTAT3) known to possess increased DNA binding/transcriptional activity. Consistent with wasting, atrogin-1 expression was also markedly increased (Fig. 3A). Thus STAT3 activation is by itself sufficient to induce muscle fiber wasting in cell culture.	SIGNOR-255331	0.286
PCCA	protein	P05165	UNIPROT	PCC	complex	SIGNOR-C414	SIGNOR	form complex	binding			9606									15890657	t		miannu	Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. 	SIGNOR-267182	0.887
CSNK1E	protein	P49674	UNIPROT	PER3	protein	P56645	UNIPROT	down-regulates quantity by destabilization	phosphorylation			10090									11865049	t		miannu	We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. 	SIGNOR-267996	0.734
MRPL4	protein	Q9BYD3	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262357	0.73
AKT1	protein	P31749	UNIPROT	MAP3K11	protein	Q16584	UNIPROT	down-regulates	phosphorylation	Ser674	PGRERGEsPTTPPTP	9606	BTO:0000938								12458207	t		lperfetto	Negative regulation of mixed lineage kinase 3 by protein kinase b/akt leads to cell survivalthe expression of activated akt1 inhibits mlk3-mediated cell death in a manner dependent on serine 674 phosphorylation.	SIGNOR-252592	0.409
MAPK8	protein	P45983	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates	phosphorylation	Thr69	SRDPVARtSPLQTPA	9606									10567572	t		gcesareni	G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2..	SIGNOR-72361	0.564
zotepine	chemical	CHEBI:32316	ChEBI	DRD4	protein	P21917	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258555	0.8
A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9606									9428518	t		miannu	Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation.	SIGNOR-259033	0.405
MYD88	protein	Q99836	UNIPROT	IRAK4	protein	Q9NWZ3	UNIPROT	up-regulates activity	binding			9606	BTO:0000776								17548806	t		lperfetto	St2825 interfered with recruitment of irak1 and irak4 by myd88, causing inhibition of il-1beta-mediated activation of nf-kappab transcriptional activity.	SIGNOR-155385	0.945
GNB1	protein	P62873	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity													15345719	f			In this study, we investigated the possible role of the Gβγ heterodimer in signaling Gi-induced Src activation	SIGNOR-251107	0.459
AMP	smallmolecule	CHEBI:456215	ChEBI	ETF	complex	SIGNOR-C463	SIGNOR	form complex	binding			9606									33450351	t		miannu	Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors.	SIGNOR-269468	0.8
UBE2E2	protein	Q96LR5	UNIPROT	RNF19B	protein	Q6ZMZ0	UNIPROT	up-regulates activity	binding			9606	BTO:0000914								16709802	t		miannu	We demonstrated that both UbcH7 and UbcH8 bind to full-length NKLAM.  We demonstrated decreased protein expression and enhanced ubiquitination of URKL-1 in the presence of NKLAM. These data indicate that NKLAM is a RING finger protein that binds Ubcs and 	SIGNOR-271592	0.484
PRKCA	protein	P17252	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates activity	phosphorylation	Ser153	SMTDFYHsKRRLIFS	9606									16055744	t		lperfetto	Binding of calmodulin to the carboxy-terminal region of p21 induces nuclear accumulation via inhibition of protein kinase c-mediated phosphorylation of ser153| When phosphorylated at Ser153, p21 is located at the cytoplasm and disrupts stress fibers.	SIGNOR-139302	0.385
KAT2A	protein	Q92830	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269602	0.2
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	STAT2	protein	P52630	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002181								31843895	t		miannu	 These results demonstrate that the interaction between STAT2 and FBXW7 is involved in the SCF complex containing cullin 1 and RBX1.	SIGNOR-276766	0.291
PTPRA	protein	P18433	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	dephosphorylation	Tyr530	FTSTEPQyQPGENL	10090	BTO:0000944								10698938	t			Protein tyrosine phosphatase alpha (PTPalpha) is believed to dephosphorylate physiologically the Src proto-oncogene at phosphotyrosine (pTyr)527, a critical negative-regulatory residue. It thereby activates Src, and PTPalpha overexpression neoplastically transforms NIH 3T3 cells.	SIGNOR-248438	0.733
CSNK2A1	protein	P68400	UNIPROT	FGF14	protein	Q92915	UNIPROT	up-regulates activity	phosphorylation	Ser228	PGVTPSKsTSASAIM	9606	BTO:0000938								26917740	t		lperfetto	 Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.	SIGNOR-275738	0.272
CCNK	protein	O75909	UNIPROT	CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	form complex	binding			9606									22012619	t		miannu	We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells	SIGNOR-176783	0.941
PRKACA	protein	P17612	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser259	SQRQRSTsTPNVHMV	9534	BTO:0004055								12801936	t		miannu	Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259).	SIGNOR-250041	0.481
PHLPP1	protein	O60346	UNIPROT	AKT2	protein	P31751	UNIPROT	down-regulates activity	dephosphorylation	Ser474	RTHFPQFsYSASIRE	9606	BTO:0001544								19261608	t			The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.	SIGNOR-248328	0.607
MAP3K21	protein	Q5TCX8	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	phosphorylation	Ser222	LIDSMANsFVGTRSY	9606									23319808	t		Manara	These experiments showed that MEK1 is phosphorylated by MLK4 on Ser217/221	SIGNOR-260768	0.2
ASXL1	protein	Q8IXJ9	UNIPROT	NCOA1	protein	Q15788	UNIPROT	up-regulates activity	binding			9606									16606617	t		irozzo	We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR.	SIGNOR-255931	0.287
MYF5	protein	P13349	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates				9606									8288123	f		miannu	The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers.	SIGNOR-37409	0.7
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser519	SGYSSPGsPGTPGSR	9606									17078951	t	The effect has been demonstrated using P10636-8	lperfetto	Here, we found that prephosphorylation by pka promotes gsk-3beta-catalyzed tau phosphorylation at thr181, ser199, ser202, thr205, thr217, thr231, ser396 and ser422	SIGNOR-150360	0.729
CDK1	protein	P06493	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Thr67	LSILSGGtPKRCLDL	9606			SIGNOR-C17						10864927	t		gcesareni	Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b.	SIGNOR-78432	0.853
TP53	protein	P04637	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									16151013	t	Nuclear p53	lperfetto	Bid is a p53 primary-response gene.	SIGNOR-140248	0.499
D1-D2-G-X3 complex	complex	SIGNOR-C301	SIGNOR	RAD51	protein	Q06609	UNIPROT	up-regulates activity	relocalization			9606									23438602	t		lperfetto	We examined the effect of XRCC3 depletion on redistribution of RAD51 upon IR damage|Interestingly, cells expressing the XRCC3 S225A phosphomutant showed compromised chromatin loading of RAD51 upon IR damage (Fig. 4G) while the nuclear and cytosolic fractions of RAD51 were largely unchanged|It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation.	SIGNOR-263259	0.682
NAIP	protein	Q13075	UNIPROT	NLRC4 inflammasome	complex	SIGNOR-C223	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256403	0.52
ZAP70	protein	P43403	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates	phosphorylation	Tyr128	DGEDDGDyESPNEEE	9606	BTO:0000782								8702662	t		lperfetto	A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function	SIGNOR-42960	0.798
GRM8	protein	O00222	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264351	0.7
GOT2	protein	P00505	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	down-regulates quantity	chemical modification			9606									31422819	t		miannu	This is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and α-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1).	SIGNOR-268058	0.8
PI3K	complex	SIGNOR-C156	SIGNOR	superoxide	smallmolecule	CHEBI:18421	ChEBI	up-regulates quantity													23994464	f		apalma	The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release	SIGNOR-255011	0.8
S1PR1	protein	P21453	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256856	0.482
MAPK3	protein	P27361	UNIPROT	STK11	protein	Q15831	UNIPROT	down-regulates activity	phosphorylation	Ser428	SSKIRRLsACKQQ	9606									25846811	t		lperfetto	Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK.	SIGNOR-209880	0.398
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	MARK3	protein	P27448	UNIPROT	down-regulates	phosphorylation	Ser96	KTQLNPTsLQKLFRE	9606									15319445	t		gcesareni	Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1.	SIGNOR-259432	0.2
PP2CA_R1A_R2A 	complex	SIGNOR-C132	SIGNOR	MASTL	protein	Q96GX5	UNIPROT	down-regulates activity	dephosphorylation	Thr194	NMMDILTtPSMAKPR	9606	BTO:0002181								24391510	t		miannu	We demonstrate that PP2A/B55 is required for Gwl dephosphorylation at the essential Cdk site Thr194.Gwl phosphorylation by CycA/Cdk2 in vitro. Flag WT and Thr194A Gwl was transiently expressed and purified from asynchronous HEK 293T cells and incubated with recombinant CycA/Cdk2, following treatment with alkaline phosphatase (aPh) in the indicated samples. The proteins were analysed by immuno-blotting with anti-Gwl and Gwl pThr194 antibodies	SIGNOR-276615	0.481
MEF2D	protein	Q14814	UNIPROT	MYH1	protein	P12882	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0001103							15728583	t		lperfetto	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238751	0.347
ADRA2A	protein	P08913	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257093	0.481
olanzapine	chemical	CHEBI:7735	ChEBI	HTR1F	protein	P30939	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258512	0.8
L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	N(6)-(1,2-dicarboxylatoethyl)-AMP(4-)	smallmolecule	CHEBI:57567	ChEBI	up-regulates quantity	precursor of												10496970	t		miannu	Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP.	SIGNOR-268131	0.8
ID1	protein	P41134	UNIPROT	CASK	protein	O14936	UNIPROT	unknown	binding			9606									15694377	t		miannu	We identified a novel CASK-interacting protein, inhibitor of differentiation 1 (Id1)	SIGNOR-225149	0.415
PP2CA_R1A_R2A 	complex	SIGNOR-C132	SIGNOR	PPME1	protein	Q9Y570	UNIPROT	up-regulates activity	dephosphorylation	Ser15	MHLGRLPsRPPLPGS	9606	BTO:0000007								24841198	t		lperfetto	The results subsequently revealed that phosphorylated PME-1/Ser15 is dephosphorylated by SIK2·PP2A (Fig. 5G). |Our results also demonstrated that the phosphorylated levels of PME-1/Ser15 and CaMKI/Thr177 are inversely correlated with the phosphatase activity of SIK2·PP2A complex, further implying that the demethylase activity of phosphorylated PME-1/Ser15 may be higher than that of its unphosphorylated state.	SIGNOR-265752	0.815
ATM	protein	Q13315	UNIPROT	DBF4	protein	Q9UBU7	UNIPROT	down-regulates	phosphorylation	Ser502	FSTDNSGsQPKQKSD	9606									22123827	t		lperfetto	Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication.	SIGNOR-177793	0.385
TNKS	protein	O95271	UNIPROT	PSMF1	protein	Q92530	UNIPROT	down-regulates quantity by destabilization	ADP-ribosylation			9606	BTO:0000007								23622245	t		lperfetto	We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31.	SIGNOR-263387	0.479
MCUB	protein	Q9NWR8	UNIPROT	MCU_MICUB_variant	complex	SIGNOR-C499	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270863	0.2
CSNK2A1	protein	P68400	UNIPROT	DDHD1	protein	Q8NEL9	UNIPROT	down-regulates activity	phosphorylation	Ser92	SDENYDFsSAESGSS	-1									11328814	t		miannu	Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity	SIGNOR-262973	0.2
PTPRF	protein	P10586	UNIPROT	LRRC4B	protein	Q9NT99	UNIPROT	up-regulates activity	binding			9606									19467332	t		miannu	The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively.	SIGNOR-264049	0.602
PTPRC	protein	P08575	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	dephosphorylation			9606									24252238	t		miannu	Src homology-2 (SH2) containing tyrosine phosphatase and CD45 tyrosine phosphatase play a major role in modulating JAK-STAT pathway. SH2 containing tyrosine phosphatases include SHP1 and SHP2 (shatterproof 1 & 2). Their SH2 domains allow attachment to the phospho-tyrosine residues present on activated receptors, JAKs or STAT proteins, leading to dephosphorylation of the substrates. 	SIGNOR-255679	0.484
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1924	SPTSPKYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273063	0.636
PRKAA1	protein	Q13131	UNIPROT	MFF	protein	Q9GZY8	UNIPROT	up-regulates activity	phosphorylation	Ser155	GRLKRERsMSENAVR	9606									26816379	t		gcesareni	A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission.	SIGNOR-245953	0.2
BTK	protein	Q06187	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates	phosphorylation	Tyr759	LYDVSRMyVDPSEIN	9606	BTO:0000776								11606584	t		gcesareni	By measuring the ability of human plcgamma2 to restore calcium responses to the b-cell receptor stimulation or oxidative stress in a b-cell line (dt40) deficient in plcgamma2, we have demonstrated that two tyrosine residues, tyr(753) and tyr(759), were important for the plcgamma2 signaling function.Of the two kinases that previously have been proposed to phosphorylate plcgamma2, btk, and syk, purified btk had much greater ability to phosphorylate recombinant plcgamma2 in vitro, whereas syk efficiently phosphorylated adapter protein blnk.	SIGNOR-111073	0.77
PTPN21	protein	Q16825	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates	dephosphorylation	Tyr530	FTSTEPQyQPGENL	9606									15143158	t		gcesareni	Ptpd1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (egf) signaling.	SIGNOR-124774	0.628
C3 convertase complex (C3bBb)	complex	SIGNOR-C314	SIGNOR	C3	protein	P01024	UNIPROT	up-regulates activity	cleavage	Arg671	QPAARRRrSVQLTEK	9606		BTO:0000089							26489954	t		lperfetto	In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC).	SIGNOR-263477	0.903
SMAD2/SMAD4	complex	SIGNOR-C8	SIGNOR	CDKN2B	protein	P42772	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11013220	f		irozzo	Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β.	SIGNOR-256287	0.588
POU5F1	protein	Q01860	UNIPROT	SOX17	protein	Q9H6I2	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003298								22795133	f		lperfetto	Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)	SIGNOR-253167	0.628
LYN	protein	P07948	UNIPROT	PAG1	protein	Q9NWQ8	UNIPROT	up-regulates activity	phosphorylation	Tyr317	EEEISAMySSVNKPG	9534									16920712	t		miannu	Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn.	SIGNOR-262898	0.714
NDUFA6	protein	P56556	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24].	SIGNOR-262157	0.828
SKP2	protein	Q13309	UNIPROT	MYBL2	protein	P10244	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								10871850	t		miannu	P19Skp1 and Cul-1 bind to the F-box protein p45Skp2 to form a complex (SCF) that functions as E3 ubiquitin ligase.We show that B-Myb physically and functionally interacts with components of the Cdc34-SCFp45Skp2 ubiquitin pathway and propose that B-Myb degradation may be required for controlling the correct alternation of events during progression through the cell division cycle.	SIGNOR-272572	0.386
BUB3	protein	O43684	UNIPROT	MCC	complex	SIGNOR-C382	SIGNOR	form complex	binding			9606	BTO:0000567								25092294	t		miannu	The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. 	SIGNOR-265975	0.965
PTPN11	protein	Q06124	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity				9606									11085989	f		miannu	We show here that leptin can activate ERK signaling in thehypothalamus and that this stimulation is likely to occur viatwo pathways, both involving SHP-2.We have shown above that SHP-2 is a positive mediator of ERK activation by ObRb and that this requires both the phosphatase activity and tyrosine phosphorylation of SHP-2. Furthermore,Tyr-985 is required for maximal ERK phosphorylation. 	SIGNOR-263500	0.862
Mitochondrial respiratory chain complex III	complex	SIGNOR-C279	SIGNOR	Respiratory electron transport chain	phenotype	SIGNOR-PH141	SIGNOR	up-regulates													30030361	f		lperfetto	The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA).	SIGNOR-262139	0.7
KDM5B	protein	Q9UGL1	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	demethylation			9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-265335	0.2
MAPK1	protein	P28482	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates activity	phosphorylation	Ser255	HATSGALsPAKDCGS	9606	BTO:0000567								9535909	t		lperfetto	These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.	SIGNOR-249401	0.595
THPO	protein	P40225	UNIPROT	MPL	protein	P40238	UNIPROT	up-regulates	binding			9606									11784712	t		miannu	Thrombopoietin(tpo) controls the formation of megakaryocytes and platelets from hematopoietic stem cells via activation of the c-mplreceptorand multiple downstream signal transduction pathways.	SIGNOR-113955	0.774
PTEN	protein	P60484	UNIPROT	KIF11	protein	P52732	UNIPROT	up-regulates activity	dephosphorylation	Thr926	LDIPTGTtPQRKSYL	9606									27492783	t		lperfetto	PTEN significantly reduces EG5 phosphorylation at Thr926 (XREF_FIG), suggesting PTEN may target this EG5 site for dephosphorylation.	SIGNOR-277000	0.467
NSMCE3	protein	Q96MG7	UNIPROT	NSMCE1	protein	Q8WV22	UNIPROT	up-regulates activity	binding			-1									20864041	t		miannu	MAGE-G1 enhances NSE1 ubiquitin ligase activity in vitro. 	SIGNOR-265489	0.2
MDM2	protein	Q00987	UNIPROT	KAT5	protein	Q92993	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0001938								11927554	t		miannu	Furthermore, we provide evidence that Mdm2, the ubiquitin ligase of the p53 tumour suppressor, interacts physically with Tip60 and induces its ubiquitylation and proteasome-dependent degradation.	SIGNOR-272613	0.639
SNRPD1	protein	P62314	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270635	0.813
CDK4	protein	P11802	UNIPROT	BRCA1	protein	P38398	UNIPROT	down-regulates	phosphorylation	Ser632	LVVSRNLsPPNCTEL	9606	BTO:0000150		SIGNOR-C18						17334399	t		lperfetto	In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo.	SIGNOR-153450	0.651
pazopanib	chemical	CHEBI:71219	ChEBI	FGFR1	protein	P11362	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001949								18620382	t		Luana	Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively.	SIGNOR-257735	0.8
FGF6	protein	P10767	UNIPROT	FGFR4	protein	P22455	UNIPROT	up-regulates	binding			9606									1385111	t		gcesareni	Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides.	SIGNOR-18570	0.722
CTNNB1	protein	P35222	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity	binding			9606		BTO:0000887							18316399	t		gcesareni	We showed that beta-catenin interacts directly with myod, a basic helix-loop-helix transcription factor essential for muscle differentiation and enhances its binding to e box elements and transcriptional activity.	SIGNOR-161113	0.417
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	RAD51	protein	Q06609	UNIPROT	down-regulates quantity by destabilization	cleavage			9606	BTO:0002882								11684015	t		lperfetto	The RAD51 protein has been shown to be a substrate for caspase-3|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin	SIGNOR-271708	0.478
PTEN	protein	P60484	UNIPROT	CREB1	protein	P16220	UNIPROT	down-regulates activity	dephosphorylation	Ser119	EILSRRPsYRKILND	10090	BTO:0002572								21385900	t			Our study demonstrates that PTEN can dephosphorylate CREB at Ser133 and that PTEN protein phosphatase activity is required for CREB dephosphoryation.|Moreover, we use both in vitro and in vivo experiments to show PTEN can dephosphorylate CREB in a phosphatase-dependent manner, suggesting that CREB is a substrate of PTEN nuclear phosphatase. Loss of Pten results in an elevated RNA level of multiple CREB transcriptional targets and increased cell proliferation, which can be reversed by a nonphosphorylatable CREB mutant or knockdown of CREB. These data reveal a mechanism for PTEN modulation of CREB-mediated gene transcription and cell growth.	SIGNOR-248543	0.449
TRAF2	protein	Q12933	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	ubiquitination	Lys158	ALIHRDLkPPNLLLV	9606	BTO:0000007								20038579	t		lperfetto	Tumor necrosis factor receptor-associated factors 2 and 6 (traf2 and -6) act as the ubiquitin e3 ligases to mediate lys63-linked tak1 polyubiquitination at the lys158 residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment.	SIGNOR-162638	0.579
SMARCD3	protein	Q6STE5	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity	binding			-1									22068056	t		lperfetto	We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/SNF core to muscle genes.	SIGNOR-238289	0.555
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGA10	protein	Q9Y5H3	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265682	0.2
OPRL1	protein	P41146	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257209	0.359
COPS6	protein	Q7L5N1	UNIPROT	COP9 signalosome variant 1	complex	SIGNOR-C489	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270768	0.928
CRP	protein	P02741	UNIPROT	GCH1	protein	P30793	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004602								17942113	f		miannu	The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH(4), were significantly inhibited by CRP. 	SIGNOR-252216	0.282
SCNN1B	protein	P51168	UNIPROT	CACNA1H	protein	O95180	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							30736831	t		miannu	This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues.	SIGNOR-269273	0.2
ABRAXAS1	protein	Q6UWZ7	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	binding			9606									17525340	t		gcesareni	Full length abraxas binds the brct-repeats of brca1the rap80-abraxas complex may help recruit brca1 to dna damage sites in part through recognition of ubiquitinated proteins	SIGNOR-155144	0.2
BAG5	protein	Q9UL15	UNIPROT	HSPA1A	protein	P0DMV8	UNIPROT	down-regulates activity	binding			9606	BTO:0000142								15603737	t		Monia	Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction.	SIGNOR-261196	0.742
tiotropium	chemical	CHEBI:90960	ChEBI	CHRM2	protein	P08172	UNIPROT	down-regulates activity	chemical inhibition			-1									8441333	t		miannu	A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors.	SIGNOR-258484	0.8
CSNK2A2	protein	P19784	UNIPROT	PTPRC	protein	P08575	UNIPROT	up-regulates activity	phosphorylation	Ser1001	SKESEHDsDESSDDD	9606	BTO:0000661								10066810	t		llicata	Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment. 	SIGNOR-251032	0.445
GSK3B	protein	P49841	UNIPROT	MYOCD	protein	Q8IZQ8	UNIPROT	down-regulates activity	phosphorylation	Ser626	DQTNVLSsTFLSPQC	9606	BTO:0000007								16141410	t			In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity	SIGNOR-251247	0.406
HCK	protein	P08631	UNIPROT	CSF3R	protein	Q99062	UNIPROT	up-regulates activity	phosphorylation	Tyr787	LTPSPKSyENLWFQA	-1									9790917	t			Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling. the ability of Hck to phosphorylate the G-CSF-R in vitro, both Y728 and Y763 fit the Src consensus phosphorylation site. we investigated the activation of Hck by the G-CSF-R in intact cells as well as in vitro. These studies revealed recruitment of Hck to activated G-CSF-R, mediated by direct binding via its SH2 domain to multiple phosphotyrosines of the receptor. In addition, we show that Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling.	SIGNOR-251264	0.393
PRKCD	protein	Q05655	UNIPROT	PRKCD	protein	Q05655	UNIPROT	unknown	phosphorylation	Ser503	KENIFGEsRASTFCG	9606									19366211	t		llicata	This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop.	SIGNOR-185299	0.2
ibuprofen	chemical	CHEBI:5855	ChEBI	PTGS1	protein	P23219	UNIPROT	down-regulates activity	chemical inhibition			-1									9544212	t		miannu	 The IC50 values for two benchmark compounds were determined for comparison. The marketed NSAID ibuprofen was a modestly selective COX-1 inhibitor, while Searle's SC-5766614 was a highly selective (>100-fold) COX-2 inhibitor, results consistent with literature reports.	SIGNOR-258883	0.8
HIPK2	protein	Q9H2X6	UNIPROT	HMGA1	protein	P17096	UNIPROT	down-regulates	phosphorylation	Thr53	KEPSEVPtPKRPRGR	9606									17960875	t		gcesareni	Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation.	SIGNOR-158620	0.508
NTRK2	protein	Q16620	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates	binding			9606	BTO:0000938								9648856	t		gcesareni	All these data suggest the involvement of fyn in the neurotrophin signal transduction pathways downstream of trkb. We investigated whether fyn is involved in the trk-dependent signal transduction pathways of neurotrophin. The fyn-src homology domain 2 (sh2) was observed to associate in vitro with the intracellular domain of trkb (icd-trkb).	SIGNOR-58424	0.389
PLK1	protein	P53350	UNIPROT	ATXN10	protein	Q9UBB4	UNIPROT	down-regulates	phosphorylation	Ser77	QVENLASsLQLITEC	9606									21857149	t		lperfetto	Phosphorylation of ataxin-10 by polo-like kinase 1 is required for cytokinesis. Plk1 phosphorylates ataxin-10 at s77 and t82 in vitro. we found that ataxin-10 is ubiquitinated, and is subject to proteasome-dependent degradation, which is delayed in the 2a mutant. We propose a model in which plk1 phosphorylation of ataxin-10 influences its degradation and cytokinesis	SIGNOR-176122	0.361
DVL1	protein	O14640	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	binding			9606	BTO:0000007								18347071	t		gcesareni	In this study, we discovered two novel interactions between dvl and c-jun and between dvl and beta-catenin in the nucleus that mediate the formation of a dvlc-junbeta-catenintcf functional complex.	SIGNOR-178038	0.472
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	IL18	protein	Q14116	UNIPROT	up-regulates activity	cleavage	Asp71	PLFEDMTdSDCRDNA	9606	BTO:0001370								9334240	t		lperfetto	We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products.	SIGNOR-256378	0.497
AATK	protein	Q6ZMQ8	UNIPROT	STK39	protein	Q9UEW8	UNIPROT	down-regulates				9606									17267545	f		gcesareni	Taken together, our data are consistent with aatyk1 indirectly inhibiting the spak/wnk4 activation of the cotransporter by scaffolding an inhibitory phosphatase in proximity to a stimulatory kinase.	SIGNOR-152921	0.348
RIPK1	protein	Q13546	UNIPROT	CASP8	protein	Q14790	UNIPROT	up-regulates activity	binding			9606									21525013	t		amattioni	Degradation of ciaps triggers the release of receptor interacting protein kinase (ripk1) from tnf receptor i (tnfr1) to form a caspase-8 activating complex	SIGNOR-173432	0.907
EDNRB	protein	P24530	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257053	0.425
MAPK1	protein	P28482	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606									16282323	t		lperfetto	Erk phosphorylation serves as a signal for bim ubiquitination and proteasomal degradation	SIGNOR-141584	0.705
diarsenic trioxide	chemical	CHEBI:30621	ChEBI	PIN1	protein	Q13526	UNIPROT	down-regulates activity	chemical inhibition			9606									30093655	t			Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1’s active site	SIGNOR-259923	0.8
BRAF	protein	P15056	UNIPROT	EEF1A1	protein	P68104	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr88	ETSKYYVtIIDAPGH	-1									22378069	t		miannu	Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf. 	SIGNOR-276405	0.266
SGK1	protein	O00141	UNIPROT	NR3C1	protein	P04150	UNIPROT	up-regulates activity	phosphorylation	Ser203	DLEFSSGsPGKETNE	9606									23650397	t		gcesareni	SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|Having demonstrated that SGK1 mediates the cortisol-induced increase in GR phosphorylation at the S203 and S211 phospho-sites, which enhance GR nuclear translocation, but not at the S226 site, which inhibits nuclear translocation	SIGNOR-251669	0.474
maraviroc	chemical	CHEBI:63608	ChEBI	CCL3	protein	P10147	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193928	0.8
EGR1	protein	P18146	UNIPROT	SLC4A2	protein	P04920	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000269							22228178	f	 	 	Cellular and molecular experiments indicated that AE2 expression promoted proliferation of colon cancer cells. In addition, we found that transcription factor EGR1 underlies AE2 upregulation and the AE2 sequester p16INK4a (P16) in the cytoplasm of colon cancer cells	SIGNOR-254250	0.2
methyltestosterone	chemical	CHEBI:27436	ChEBI	AR	protein	P10275	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								17202804	t		miannu	GnRH antagonizes testosterone activation of the human androgen receptor in SCL60 cells. Gonadotropin-Releasing Hormone Functionally Antagonizes Testosterone Activation of the Human Androgen Receptor in Prostate Cells through Focal Adhesion Complexes Involving Hic-5	SIGNOR-259266	0.8
GSK3B	protein	P49841	UNIPROT	USF1	protein	P22415	UNIPROT	up-regulates activity	phosphorylation	Ser186	APRTHPYsPKSEAPR	9606	BTO:0001583								21873430	t		miannu	 Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186.	SIGNOR-276354	0.291
MAP3K5	protein	Q99683	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates	phosphorylation			9606									11959862	t		amattioni	Activation of mkk7 by ask1	SIGNOR-117264	0.576
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1714	SPTSPSYsPTSPSYS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248822	0.849
PTPN1	protein	P18031	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates	dephosphorylation	Tyr42	DSMKDEEyEQMVKEL	9606									8940099	t		gcesareni	Ptp1b is able to dephosphorylate phosphorylated-tyr-42 on ikappabalpha	SIGNOR-45004	0.36
lysophosphatidic acid	smallmolecule	CHEBI:132742	ChEBI	LPAR5	protein	Q9H1C0	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257532	0.8
AURKA	protein	O14965	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser106	SQKTYQGsYGFRLGF	9606									23201157	t		gcesareni	Ser-106 phosphorylation of p53 decreases its interaction with mdm2 and prolongs the half-life of p53	SIGNOR-199939	0.771
PFN1	protein	P07737	UNIPROT	CDH4	protein	P55283	UNIPROT	up-regulates activity				9606	BTO:0000815								22820501	t		lperfetto	Taken together, data obtained from MCF10A cells were consistent with the idea that Rho signaling to Dia1 and profilin-1 was essential for R-cadherin adherens junction formation.	SIGNOR-253111	0.343
NAA25	protein	Q14CX7	UNIPROT	NatB 	complex	SIGNOR-C416	SIGNOR	form complex	binding			9606									18570629	t		miannu	In the present study we present the components of hNatB (human NatB complex). It consists of the Nat3p homologue hNAT3 (human N-acetyltransferase 3) and the Mdm20p homologue hMDM20 (human mitochondrial distribution and morphology 20). They form a stable complex and in vitro display sequence-specific N(alpha)-acetyltransferase activity on a peptide with the N-terminus Met-Asp-. 	SIGNOR-267231	0.9
ROCK1	protein	Q13464	UNIPROT	PFN1	protein	P07737	UNIPROT	down-regulates	phosphorylation	Ser138	MASHLRRsQY	9606									22479341	t		lperfetto	We previously identified pfn1 as a huntingtin aggregation inhibitor, and others have implicated it as a tumor-suppressor. Rho-associated kinase (rock) directly phosphorylates pfn1 at ser-137 to prevent its binding to polyproline sequences. This negatively regulates its anti-aggregation activity.	SIGNOR-196820	0.276
PINK1	protein	Q9BXM7	UNIPROT	LETM1	protein	O95202	UNIPROT	up-regulates activity	phosphorylation	Thr192	ILNGHSLtRRERRQF	-1									29123128	t		lperfetto	Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro.|Phosphorylated LETM1 or the phospho-mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria. 	SIGNOR-262540	0.367
MAP3K7	protein	O43318	UNIPROT	PTPN3	protein	P26045	UNIPROT	unknown	phosphorylation	Ser359	PAMRRSLsVEHLETK	9606									9341175	t		gcesareni	Mutation of ser359 and ser853 to alanine significantly reduced the association between 14-3-3beta and ptph1. Furthermore, association of ptph1 and 14-3-3beta was detected in several cell lines and was regulated in response to extracellular signals	SIGNOR-52781	0.267
NOXA1	protein	Q86UR1	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity				9606									19879762	t		lperfetto	BH3-only proteins containing only a single BH domain and including Puma, Noxa, Bid and Bad as well as other factors are particularly important for such neutralisation, binding and regulating the anti-apoptotic Bcl-2 proteins to promote apoptosis	SIGNOR-209684	0.2
AKAP5	protein	P24588	UNIPROT	PRKACA	protein	P17612	UNIPROT	up-regulates activity	relocalization			10116									10939335	t			In this report, we demonstrate that glutamate receptors and PKA are recruited into a macromolecular signaling complex through direct interaction between the MAGUK proteins, PSD-95 and SAP97, and AKAP79/150	SIGNOR-261292	0.541
HCRTR1	protein	O43613	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256733	0.252
vatalanib	chemical	CHEBI:90620	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207642	0.8
CTNNA3	protein	Q9UI47	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000586								21598020	t		miannu	Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14	SIGNOR-265493	0.747
DYRK1B	protein	Q9Y463	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates	phosphorylation	Thr288	VDLACTPtDVRDVDI	9606	BTO:0000567								17046823	t		lperfetto	Further, we found that not only gsk-3beta but also dyrk1b modulates cyclin d1 subcellular localization by the phosphorylation of thr(288). These results suggest that dif-3 induces degradation of cyclin d1 through the gsk-3beta- and dyrk1b-mediated threonine phosphorylation in hela cells	SIGNOR-150126	0.422
CAMK2B	protein	Q13554	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates	phosphorylation	Ser727	TDNLLPMsPEEFDEV	9606									17502367	t		gcesareni	All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).	SIGNOR-154771	0.38
MN1	protein	Q10571	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	down-regulates				10090									17494859	f		irozzo	MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment.	SIGNOR-256016	0.7
FZR1	protein	Q9UM11	UNIPROT	TK1	protein	P04183	UNIPROT	down-regulates quantity by destabilization	binding			-1									14701726	t		miannu	We show that hTK1 is degraded via a ubiquitin-proteasome pathway in mammalian cells and that anaphase-promoting complex/cyclosome (APC/C) activator Cdh1 is not only a necessary but also a rate-limiting factor for mitotic degradation of hTK1. By in vitro ubiquitinylation assays, we demonstrated that hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif. 	SIGNOR-272945	0.347
D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	3-phosphonato-D-glyceroyl phosphate(4-)	smallmolecule	CHEBI:57604	ChEBI	up-regulates quantity	precursor of			9606									11724794	t		miannu	GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion	SIGNOR-266493	0.8
PAK3	protein	O75914	UNIPROT	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation	Ser714	EGVRNIKsMWEKGNV	9606		BTO:0000887;BTO:0001260							20858431	t		gcesareni	We investigated the effects of phosphorylation by p(21)-activated kinase 3 (pak) and calmodulin on the 22 kda c-terminal fragment of caldesmon (cad22). We substituted the major pak sites, ser-672 and ser-702, with either alanine or aspartic acid to mimic nonphosphorylated and constitutively phosphorylated states of caldesmon, respectively. Phosphorylation at these sites weakened ca(2+)-calmodulin binding further and reduced the inhibitory activity of cad22 in the absence of ca(2+)-calmodulin.	SIGNOR-167976	0.2
KANSL1	protein	Q7Z3B3	UNIPROT	Chromosome_segregation	phenotype	SIGNOR-PH44	SIGNOR	up-regulates				9606	BTO:0000567								26243146	f		miannu	Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. 	SIGNOR-267172	0.7
SOST	protein	Q9BQB4	UNIPROT	WNT3A	protein	P56704	UNIPROT	down-regulates				9606									19874086	f	Interacts with LRP4 (via the extracellular domain);the interaction facilitates the Wnt signaling. Interacts with LRP5 (via the first two YWTD-EGF repeat domains);the interaction inhibits Wnt-mediated signaling.	gcesareni	It has been shown that both sclerostin and dkk1 act physiologically as downstream mole-cules of bmp signaling to inhibit canonical wnt sig-naling and therefore negatively regulate bone mass	SIGNOR-188964	0.568
ziprasidone	chemical	CHEBI:10119	ChEBI	HTR1E	protein	P28566	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258503	0.8
SMURF2	protein	Q9HAU4	UNIPROT	STAMBP	protein	O95630	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								14755250	t		miannu	RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome.	SIGNOR-272951	0.546
WDFY3	protein	Q8IZQ1	UNIPROT	GABARAP	protein	O95166	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000567								24668264	t		miannu	 Here, we show that ALFY binds selectively to LC3C and the GABARAPs through a LIR in its WD40 domain. Binding of ALFY to GABARAP is indispensable for its recruitment to LC3B-positive structures and, thus, for the clearance of certain p62 structures by autophagy.	SIGNOR-266796	0.682
PRKAA2	protein	P54646	UNIPROT	TSC1	protein	Q92574	UNIPROT	up-regulates	phosphorylation			9606			SIGNOR-C15						14651849	t		gcesareni	Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity.	SIGNOR-119541	0.532
SMARCA2	protein	P51531	UNIPROT	Brain-specific SWI/SNF SMARCA2 variant	complex	SIGNOR-C485	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270742	0.804
RIMBP3B	protein	A6NNM3	UNIPROT	RIMS3	protein	Q9UJD0	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264374	0.267
RLF	protein	Q13129	UNIPROT	RIT1	protein	Q92963	UNIPROT	up-regulates activity	binding			9606									10545207	t		miannu	Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors.	SIGNOR-220799	0.313
MTOR	protein	P42345	UNIPROT	TFEB	protein	P19484	UNIPROT	down-regulates activity	phosphorylation	Ser142	AGNSAPNsPMAMLHI	9606	BTO:0000007								22343943	t			Here, we have used an mTORC1 in-vitro kinase assay and a phosphoantibody to demonstrate that serine S142, which we previously found to be phosphorylated by ERK2, is also phosphorylated by mTOR and that this phosphorylation has a crucial role in controlling TFEB subcellular localization and activity.	SIGNOR-255310	0.492
MAPK3	protein	P27361	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr74	ARTSPLQtPAAPGAA	9606									10669763	t		gcesareni	The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro.	SIGNOR-74943	0.541
UMPS	protein	P11172	UNIPROT	orotidine 5'-phosphate(3-)	smallmolecule	CHEBI:57538	ChEBI	up-regulates quantity	chemical modification			9606									2912371	t		miannu	Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase).	SIGNOR-267438	0.8
MAPK1	protein	P28482	UNIPROT	NCOA6	protein	Q14686	UNIPROT	up-regulates activity	phosphorylation	Ser884	NKDVTLTsPLLVNLL	-1									11773444	t		miannu	 In vitro phosphorylation studies with His-tagged TRBP (795–931) suggested that S884 can be phosphorylated by MAPK (ERK2) in vitro (Fig. 10A).Analysis of in vitro and in vivo receptor interactions with TRBP suggested that S884 allowed selective interactions for ERβ, TR, and RXR vs. ERα. 	SIGNOR-265882	0.2
CDK5	protein	Q00535	UNIPROT	TPPP	protein	O94811	UNIPROT	down-regulates activity	phosphorylation	Ser160	GVTKAISsPTVSRLT	-1									17693641	t		miannu	 Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP.	SIGNOR-262931	0.414
CAMK1	protein	Q14012	UNIPROT	NUMB	protein	P49757	UNIPROT	down-regulates	phosphorylation	Ser276	EQLARQGsFRGFPAL	9606									17022975	t		esanto	Based on experiments using numb mutants, both the initial phosphorylation of ser(264) and the subsequent phosphorylation of ser(283) are sufficient to abolish the binding of numb to ap-2.	SIGNOR-149993	0.34
PDE6G	protein	P18545	UNIPROT	PDE6A	protein	P16499	UNIPROT	down-regulates activity	binding			9606									20940301	t			Both PDE6C-A and PDE6C-B were potently and similarly inhibited by both Pγ subunits, with Ki values ranging from 33 to 46 pm (Fig. 5). The inhibition analysis revealed no significant differences between PDE6C-A and PDE6C-B	SIGNOR-260010	0.861
regorafenib	chemical	CHEBI:68647	ChEBI	FRK	protein	P42685	UNIPROT	down-regulates activity	chemical inhibition			9606									24756792	t		miannu	In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically.	SIGNOR-259207	0.8
TUT4	protein	Q5TAX3	UNIPROT	mRNA_polyadenylation	phenotype	SIGNOR-PH200	SIGNOR	down-regulates													25480299	f		lperfetto	Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells.	SIGNOR-268355	0.7
CDK2	protein	P24941	UNIPROT	PGR	protein	P06401	UNIPROT	unknown	phosphorylation	Ser554	PDSEASQsPQYSFES	9606									11110801	t		llicata	In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676).	SIGNOR-84992	0.453
NUP35	protein	Q8NFH5	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262080	0.616
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	RPS19	protein	P39019	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000007								16266891	t		gcesareni	The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay.	SIGNOR-259412	0.2
PIM2	protein	Q9P1W9	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates													16146838	f		lperfetto	The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells.	SIGNOR-256575	0.7
acetoacetyl-CoA	smallmolecule	CHEBI:15345	ChEBI	(3S)-3-hydroxy-3-methylglutaryl-CoA(5-)	smallmolecule	CHEBI:43074	ChEBI	up-regulates quantity	precursor of												29597274	t		lperfetto	Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis	SIGNOR-267652	0.8
PERP	protein	Q96FX8	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity	ubiquitination			9606									25860612	t			We identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling	SIGNOR-255843	0.2
PKN1	protein	Q16512	UNIPROT	MEFV	protein	O15553	UNIPROT	down-regulates activity	phosphorylation	Ser208	VRLRRNAsSAGRLQG	10090	BTO:0004732								27270401	t	no	miannu	PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. 	SIGNOR-275462	0.394
PAX3-FOXO1	fusion protein	SIGNOR-FP12	SIGNOR	IGF2	protein	P01344	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25211658	t		miannu	Insulin-like growth factor is required for RMS cell growth and IGF2 is expressed in an autocrine manner by the tumour cells. The IGF2 locus shows a loss of imprinting in both ERMS and ARMS tumours and expression of PAX3-FOXO1 can induce the upregulation of IGF2, thus enhancing the activation of IGF signalling pathway in ARMS	SIGNOR-251573	0.2
NCAPG	protein	Q9BPX3	UNIPROT	Condensin I	complex	SIGNOR-C341	SIGNOR	form complex	binding			9606									32445620	t		miannu	The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction.	SIGNOR-263902	0.961
MAP3K1	protein	Q13233	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	phosphorylation	Thr261	LVDSIAKtRDAGCRP	9606									9712898	t		lperfetto	The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1	SIGNOR-236380	0.717
FABP5	protein	Q01469	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264459	0.7
SMURF1	protein	Q9HCE7	UNIPROT	UVRAG	protein	Q9P2Y5	UNIPROT	down-regulates activity	ubiquitination	Lys559	DTSLDFSkENKKKGE	9606	BTO:0000007								30686098	t		miannu	Here we report that UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. However, the deubiquitinase ZRANB1 specifically cleaves SMURF1-induced K29 and K33-linked polyubiquitin chains from UVRAG, thereby increasing the binding of UVRAG to RUBCN and inhibiting autophagy flux. 	SIGNOR-273653	0.2
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0001412								8394219	f			We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death. 	SIGNOR-255722	0.7
FUS	protein	P35637	UNIPROT	MATR3	protein	P43243	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000007								27731383	t	P35637:p.Pro525Leu (mutation disrupting interaction)		Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates. 	SIGNOR-262822	0.5
MPG	protein	P29372	UNIPROT	PPP2CA	protein	P67775	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			-1									25207814	t		miannu	Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac.	SIGNOR-271930	0.2
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Trp)	smallmolecule	CHEBI:29181	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269498	0.8
MAPK14	protein	Q16539	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606		BTO:0001103							15824134	f		Andrea	Inhibition of p38 / MAPKs (a) promotes exit from the cell cycle, (b) prevents differentiation, and (c) insulates the cell from most external stimuli allowing the satellite cell to maintain a quiescent state. Activation of satellite cells and p38 / MAPKs occurs concomitantly, providing further support that these MAPKs function as a molecular switch for satellite cell activation	SIGNOR-255745	0.7
ACP1	protein	P24666	UNIPROT	EPHA2	protein	P29317	UNIPROT	down-regulates activity	dephosphorylation	Tyr960	GHQKRIAySLLGLKD	-1									21538645	t		gcesareni	The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates	SIGNOR-246023	0.646
LRRK1	protein	Q38SD2	UNIPROT	CDK5RAP2	protein	Q96SN8	UNIPROT	up-regulates activity	phosphorylation	Ser140	SLAEAGGsEIQRVKE	9606	BTO:0000567								26192437	t		lperfetto	Interestingly, LRRK1 in turn phosphorylates CDK5RAP2(Cep215), a human homologue of Drosophila Centrosomin (Cnn), in its gamma-tubulin-binding motif, thus promoting the interaction of CDK5RAP2 with gamma-tubulin. LRRK1 phosphorylation of CDK5RAP2 Ser 140 is necessary for CDK5RAP2-dependent microtubule nucleation.	SIGNOR-275468	0.52
MDM2	protein	Q00987	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000038								26718225	t		miannu	 Here, we found that nuclear EGFR induced phosphorylation of PPARγ at Tyr-74 leading to PPARγ ubiquitination and degradation by mouse double minute 2 (MDM2) ubiquitin ligase. 	SIGNOR-277191	0.398
FLT1	protein	P17948	UNIPROT	FLT1	protein	P17948	UNIPROT	up-regulates	phosphorylation	Tyr1327	CCSPPPDyNSVVLYS	9606									9722576	t		lperfetto	Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor.	SIGNOR-59758	0.2
ABL1	protein	P00519	UNIPROT	WASL	protein	O00401	UNIPROT	up-regulates activity	phosphorylation	Tyr175	EITTNRFyGPQVNNI	-1									16199863	t			Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation.	SIGNOR-251436	0.566
propionic acid	chemical	CHEBI:30768	ChEBI	FFAR3	protein	O14843	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257490	0.8
PRKACA	protein	P17612	UNIPROT	CFTR	protein	P13569	UNIPROT	down-regulates activity	phosphorylation	Ser737	EPLERRLsLVPDSEQ	9606									19095655	t		Luana	AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.	SIGNOR-21316	0.466
Nucleosome_H3.1 variant	complex	SIGNOR-C324	SIGNOR	Transcritpional_activation	phenotype	SIGNOR-PH205	SIGNOR	down-regulates				9606									15623580	f		lperfetto	All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage.	SIGNOR-273458	0.7
PIK3R1	protein	P27986	UNIPROT	PIK3CD	protein	O00329	UNIPROT	up-regulates activity	binding			9534									14665640	t		lperfetto	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242643	0.821
MLNR	protein	O43193	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256737	0.252
PTPN22	protein	Q9Y2R2	UNIPROT	ZAP70	protein	P43403	UNIPROT	down-regulates activity	dephosphorylation	Tyr493	LGADDSYyTARSAGK	9606									16461343	t			In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22.	SIGNOR-248838	0.693
RPL18A	protein	Q02543	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262480	0.816
ELOVL2	protein	Q9NXB9	UNIPROT	palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	down-regulates quantity	chemical modification			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267890	0.8
F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	Platelet_morphogenesis	phenotype	SIGNOR-PH135	SIGNOR	up-regulates				9606	BTO:0000132								27871158	f		lperfetto	Each step in platelet shape change involves the participation of a variety of actin filament-related proteins that are highly concentrated in platelets (Fig. 1). In resting human platelets, the actin filaments from the core to the membrane skeleton are tightly bound to the plasma membrane by GP1b/IX-filamin A complexes 	SIGNOR-261839	0.7
MAPK1	protein	P28482	UNIPROT	NDE1	protein	Q9NXR1	UNIPROT	up-regulates activity	phosphorylation	Ser239	FRRGLDDsTGGTPLT	9606	BTO:0000007								12556484	t		lperfetto	Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro. In the case of Nudel, the phosphorylation sites were also located in the S/TP motifs. Detailed mutagenesis study indicated that T219, S242, and T245 were phosphorylated by Cdc2, while T219 and T245 were phosphorylated by Erk2.|Phosphorylation of Nudel in M phase appears to positively modulate dynein motor activity. Both phosphorylated and unphosphorylated forms of Nudel were transported by dynein (Fig. 7 and 9 and data not shown), indicating that neither of them inactivated the dynein motor. On the other hand, both phospho-Nudel and Nudelpmt5 bound Lis1 more strongly than Nudel or Nudelmt5 did 	SIGNOR-249421	0.382
MAPK3	protein	P27361	UNIPROT	SREBF1	protein	P36956	UNIPROT	up-regulates activity	phosphorylation	Ser117	YPSMPAFsPGPGIKE	9606	BTO:0000599								10915800	t		lperfetto	Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo.	SIGNOR-80096	0.455
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr583	RRPPGLEyCYNPSHN	10116	BTO:0002809;BTO:0001009								8622701	t		lperfetto	In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1	SIGNOR-236183	0.2
PIK3CA	protein	P42336	UNIPROT	PIP3	smallmolecule	CHEBI:16618	ChEBI	up-regulates quantity	chemical modification			9606									24647478	t	AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring	miannu	Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks.	SIGNOR-65409	0.8
IL6R	protein	P08887	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates	binding			9606	BTO:0000785								11238858	t		gcesareni	Part of the receptor for interleukin 6. Binds to il6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with il6st. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis.	SIGNOR-105504	0.74
L-arginine	chemical	CHEBI:16467	ChEBI	ARG1	protein	P05089	UNIPROT	up-regulates					BTO:0000801	BTO:0001103							25386178	f		apalma	In mammalian cells, arginine can be catabolized by four classes of enzymes (Figure ​(Figure1):1): NOS, arginase, arginine decarboxylase (ADC), and arginine:glycine amidinotransferase (AGAT)	SIGNOR-255555	0.8
ULK1	protein	O75385	UNIPROT	RB1CC1	protein	Q8TDY2	UNIPROT	up-regulates	phosphorylation			9606									19597335	t		gcesareni	Ulk1 and ulk2 are the kinase phosphorylating their binding proteins atg13 and fip200. Atg13 directly binds fip200 and mediates the interaction between fip200 and ulks.	SIGNOR-186992	0.911
ARHGEF25	protein	Q86VW2	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates	guanine nucleotide exchange factor			10090									16314529	t		gcesareni	Exogenous expression of geft promotes myogenesis ofc2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process.	SIGNOR-236882	0.605
CBLB	protein	Q13191	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity				9606	BTO:0004175								27773928	f		miannu	We have also shown that the E3 ubiquitin ligase Cbl-b is crucial for activation of the p53 pathway through ubiquitinating and promoting degradation of Siva1, the E3 ubiquitin ligase targeting ARF, a positive regulator of p53. On the basis of our data presented in the study, we propose the model (Figure 2i) that Cbl-b negatively regulates Siva1 by ubiquitination and subsequent degradation of Siva1, which is followed by stabilization of ARF. This in turn downregulates MDM2, thereby promoting the induction of p53 and activation of its downstream targets.	SIGNOR-261320	0.2
AKT1	protein	P31749	UNIPROT	TARBP2	protein	Q15633	UNIPROT	up-regulates activity	phosphorylation	Ser283	ILSLRSCsLGSLGAL	-1									27407113	t		miannu	We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. In vitro kinase assays demonstrated that TRBP-D3 can be phosphorylated by S6K1, S6K2, but also AKT1 (Figure ​(Figure1C),1C), 	SIGNOR-274064	0.2
CRBN	protein	Q96SW2	UNIPROT	SALL4	protein	Q9UJQ4	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									32071327	t		miannu	Thalidomide-induced teratogenicity is dependent on its binding to cereblon (CRBN), the substrate receptor of the Cul4A-DDB1-CRBN-RBX1 E3 ubiquitin ligase complex. Thalidomide binding to CRBN elicits subsequent ubiquitination and proteasomal degradation of CRBN neosubstrates including SALL4, a transcription factor of which polymorphisms phenocopy thalidomide-induced limb defects in humans. 	SIGNOR-272206	0.2
ARID1A	protein	O14497	UNIPROT	Muscle cell-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C483	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex.	SIGNOR-270729	0.78
IKBKB	protein	O14920	UNIPROT	TSC1	protein	Q92574	UNIPROT	down-regulates	phosphorylation	Ser511	DSPFYRDsLPGSQRK	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression.	SIGNOR-183692	0.627
ABL1	protein	P00519	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates	phosphorylation			9606									10212258	t		gcesareni	C-abl phosphorylates rad51 in vitro and in vivo. In assays using purified components, phosphorylation of rad51 by c-abl enhances complex formation between rad51 and rad52, which cooperates with rad51 in recombination and repair	SIGNOR-67069	0.764
WNT5A	protein	P41221	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates				9606				SIGNOR-C110					21078818	f		gcesareni	We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3).	SIGNOR-169663	0.488
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	TP73	protein	O15350	UNIPROT	down-regulates	phosphorylation	Thr86	AASASPYtPEHAASV	9606									12676926	t		lperfetto	Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86.	SIGNOR-216702	0.515
Upadacitinib	chemical	CID:58557659	PUBCHEM	JAK1	protein	P23458	UNIPROT	down-regulates activity	binding			9606									33240390	t			Upadacitinib (ABT-494) is another selective inhibitor of JAK1 undergoing clinical trials to determine its benefit for several inflammatory diseases	SIGNOR-272504	0.8
CSNK2B	protein	P67870	UNIPROT	CSNK2B	protein	P67870	UNIPROT	unknown	phosphorylation	Ser2	sSSEEVSW	9606									1939094	t		llicata	Phosphorylation of the beta subunit of casein kinase II in human A431 cells. Identification of the autophosphorylation site | Cleavage of the beta subunit, that had been autophosphorylated in vitro, at tryptophan 9 and tryptophan 12 using N-chlorosuccinimide demonstrated that the autophosphorylation site is located near the amino terminus of the protein, most likely at serine 2 and serine 3.	SIGNOR-251062	0.2
HNRNPU	protein	Q00839	UNIPROT	HEXIM1	protein	O94992	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation												17174306	f		lperfetto	In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs.	SIGNOR-262283	0.249
SLC27A5	protein	Q9Y2P5	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264466	0.7
MAP3K7	protein	O43318	UNIPROT	MAP2K6	protein	P52564	UNIPROT	up-regulates activity	phosphorylation			9606									21902831	t		lperfetto	Tak1 can phosphorylate and activate map kinase kinase 3/6 (mkk3/6), and numerous studies have demonstrated a requirement for mkk3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner.	SIGNOR-236145	0.753
MSX1	protein	P28360	UNIPROT	DLX5	protein	P56178	UNIPROT	down-regulates activity	binding			10090	BTO:0000946								9111364	t	2	miannu	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240987	0.398
INTS10	protein	Q9NVR2	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261473	0.772
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	NMDA receptor_2C	complex	SIGNOR-C349	SIGNOR	up-regulates activity	chemical activation			9606									12871085	t		miannu	The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate	SIGNOR-264130	0.8
AP3B1	protein	O00203	UNIPROT	AP-3 complex	complex	SIGNOR-C247	SIGNOR	form complex	binding			9606									21097499	t		lperfetto	Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)	SIGNOR-260681	0.908
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	THBD	protein	P07204	UNIPROT	up-regulates quantity by expression				9606									22406829	f		miannu	In carcinomas the expression of thrombomodulin (TM) is inversely correlated with tumour progression and metastasis. The expression of TM is negatively regulated by NF-?B- and GSK3-?-dependent signalling pathways and positively regulated by retinoic acid and transcription factor Sp1 in PrEC, LNCaP and PC-3 cells, but not in DU-145 cells.	SIGNOR-255217	0.8
CDK1	protein	P06493	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser105	TGAGAAGsPAQQHAH	9606	BTO:0000567								26183396	t		miannu	In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system.	SIGNOR-276927	0.261
prostaglandin E2	smallmolecule	CHEBI:15551	ChEBI	GNG12	protein	Q9UBI6	UNIPROT	up-regulates	chemical activation			9606									16293724	t		gcesareni	Although pge2 promotes nucleotide exchange on gas and subsequent dissociation of gtp-bound gas from gbg subunits.	SIGNOR-141820	0.8
WWTR1	protein	Q9GZV5	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	binding			9606									21084559	t		lperfetto	Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal.	SIGNOR-232098	0.536
oxymetazoline	chemical	CHEBI:7862	ChEBI	ADRA1D	protein	P25100	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258460	0.8
INS	protein	P01308	UNIPROT	GATA2	protein	P23769	UNIPROT	down-regulates				9606	BTO:0000876								15837948	f		fspada	We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity	SIGNOR-135617	0.321
ZDHHC2	protein	Q9UIJ5	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	palmitoylation	Cys5	cIVTTKKY	9606									23836932	t			Plasma membrane targeting of DHHC2 palmitoyltransferase rapidly recruited PSD-95 to the plasma membrane and proved essential for postsynaptic nanodomain formation.	SIGNOR-261290	0.389
PTK6	protein	Q13882	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr165	PSPATDLyQVPPGPG	9606									22084245	t		lperfetto	Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 crk-associated substrate. Tyrosine residues 165 and 664 of p130cas were both phosphorylated by ptk6 in vitro	SIGNOR-177238	0.584
PTPN1	protein	P18031	UNIPROT	EPOR	protein	P19235	UNIPROT	down-regulates activity	dephosphorylation			9606									14527337	t		lperfetto	In vivo interaction between EPO-R and PTP1B suggested that PTP1B dephosphorylates the EPO-R intracellularly.|Protein tyrosine phosphatase 1B participates in the down-regulation of erythropoietin receptor signalling.	SIGNOR-276994	0.471
PTPN13	protein	Q12923	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	dephosphorylation			9606									17638892	t		miannu	Finally, we report that PTPL1 expression is sufficient to block the IRS-1/phosphatidylinositol 3-kinase/Akt signaling pathway, to inhibit the insulin-like growth factor-I effect on cell survival, and to induce apoptosis.|We first show by complementary approaches that PTPL1 specifically dephosphorylates insulin receptor substrate-1 (IRS-1) in vitro and in cellulo.	SIGNOR-277053	0.48
GIT1	protein	Q9Y2X7	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates activity	binding			9606	BTO:0000599								23325602	t		miannu	We found both MAT2B variants interact with GIT1. MAT2B directly promoted binding of GIT1 and ERK2 to MEK1. MAT2B and GIT1 interact and are overexpressed in most human liver and colon cancer specimens. 	SIGNOR-261245	0.401
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr548	KKVAVVRtPPKSPSS	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-251596	0.695
MAPK3	protein	P27361	UNIPROT	IRX2	protein	Q9BZI1	UNIPROT	up-regulates activity	phosphorylation	Ser317	TPQGSRTsPGAPPPA	-1									15133517	t		miannu	To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target.	SIGNOR-263060	0.2
STAT5A	protein	P42229	UNIPROT	M1_polarization	phenotype	SIGNOR-PH54	SIGNOR	up-regulates				9606									22025054	f		lperfetto	The activation of receptors for both GM-CSF and IFN-g stimulates the Jak kinaseSTAT transcription factor pathway, and an ISRE in the Irf5 promoter can bind STAT1 and STAT2, which suggests a possible mechanism for IRF5 expression induced by GM-CSF and IFN-g. Consequently, high expression of IRF5 results in polarization of the macrophage phenotype toward M1.	SIGNOR-249510	0.7
CDK8	protein	P49336	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	phosphorylation	Ser187	NSHPFPHsPNSSYPN	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-189129	0.392
ERN1	protein	O75460	UNIPROT	TRAF2	protein	Q12933	UNIPROT	up-regulates activity	binding			10090									18519638	t	P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction)		 Activated IRE1 has been demonstrated to recruit TRAF2 and ASK1 on the ER membrane and thus to activate ASK1|ASK1 was found to associate with IRE1 only in the presence of TRAF2 and SOD1mut (Fig. 4B), suggesting that SOD1mut induces formation of an IRE1–TRAF2–ASK1 complex on the ER membrane and thus activates ASK1 by triggering ER stress-induced IRE1 activation.	SIGNOR-262790	0.667
FFAR4	protein	Q5NUL3	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257246	0.252
FYN	protein	P06241	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates	phosphorylation	Tyr323	DEPVADPyDQSFESR	9606									15735648	t		fstefani	T cell src family kinases and zap70 activate p38 by phosphorylating tyr323.	SIGNOR-134293	0.466
CAMK2G	protein	Q13555	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates activity	phosphorylation	Ser63	GILARRPsYRKILKD										8663317	t		llicata	Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to Ser133 of CREB), which is essential for the activation, and not Ser72 (corresponding to Ser142 of CREB), which is a negative regulation site.	SIGNOR-250692	0.303
MAPK1	protein	P28482	UNIPROT	AHNAK	protein	Q09666	UNIPROT	unknown	phosphorylation	Thr694	LPDMSVKtPKISMPD	10090									22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262768	0.259
NRAS	protein	P01111	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	relocalization			9606									21779497	t	Translocation from Cytosol to Membrane	gcesareni	The raf family of proteins (raf-1, a-raf, and b-raf) bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.	SIGNOR-175231	0.865
MYC	protein	P01106	UNIPROT	HK2	protein	P52789	UNIPROT	up-regulates quantity	transcriptional regulation			9606									17785433	t			Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration.	SIGNOR-259986	0.379
telmisartan	chemical	CHEBI:9434	ChEBI	AGTR1	protein	P30556	UNIPROT	down-regulates activity	chemical inhibition			9606									9878991	t		miannu	Telmisartan is a nonpeptide angiotensin II receptor antagonist which selectively and insurmountably inhibits the angiotensin II AT1 receptor subtype without affecting other receptor systems involved in cardiovascular regulation.	SIGNOR-259072	0.8
PPP1CC	protein	P36873	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0002419								14633703	t			Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells	SIGNOR-252605	0.392
MAPK1	protein	P28482	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates	phosphorylation	Thr235	SSSSPPGtPSPADAK	9606									19723873	t		gcesareni	Phosphorylation of cebpb at thr(235) peaked at 16 hours in il-1beta-stimulated cells. The mek inhibitor u0126 inhibited this phosphorylation and reduced mmp-1 gene induction.	SIGNOR-187798	0.705
VEGFD	protein	O43915	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates	binding			9606									9435229	t		gcesareni	Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors.	SIGNOR-55065	0.2
NHLH2	protein	Q02577	UNIPROT	MAOA	protein	P21397	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000142							22169038	f		miannu	SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter	SIGNOR-254829	0.409
ESR2	protein	Q92731	UNIPROT	TGFA	protein	P01135	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000356								11517191	f	 	 	ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression	SIGNOR-253944	0.262
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates activity	phosphorylation	Ser189	DEEFREPsTGKTCLP	-1									19661060	t		miannu	 We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.	SIGNOR-276233	0.2
moclobemide	chemical	CHEBI:83531	ChEBI	MAOB	protein	P27338	UNIPROT	down-regulates activity	chemical inhibition			-1									21680183	t		Luana	Twenty-two pyrazoline derivatives were synthesized and tested for their human MAO (hMAO) inhibitory activity. Twelve molecules with unsubstituted ring A and substituted ring C (5–16) were found to be potent inhibitors of hMAO-A isoform with SIMAO-A in the order 103 and 104. 	SIGNOR-258315	0.8
PRKCD	protein	Q05655	UNIPROT	SMPD1	protein	P17405	UNIPROT	up-regulates	phosphorylation	Ser510	DGNYSGSsHVVLDHE	9606									17303575	t		lperfetto	Activation of acid sphingomyelinase by protein kinase cdelta-mediated phosphorylation. Phosphorylation of ser(508) proved to be an indispensable step for asmase activation and membrane translocation in response to pma	SIGNOR-153276	0.259
ROCK1	protein	Q13464	UNIPROT	ADD1	protein	P35611	UNIPROT	up-regulates	phosphorylation	Thr480	TKEDGHRtSTSAVPN	9606		BTO:0000671							10209029	t		lperfetto	Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480	SIGNOR-66996	0.384
FFAR4	protein	Q5NUL3	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257313	0.252
SDC3	protein	O75056	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates activity	binding			10090	BTO:0002314								20696709	t		gcesareni	Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-€“converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size.	SIGNOR-254329	0.392
MAPK12	protein	P53778	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	down-regulates activity	phosphorylation	Thr1609	LGPYEAVtPLTKAAD	-1									24703952	t		lperfetto	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK 	SIGNOR-264448	0.2
FLCN	protein	Q8NFG4	UNIPROT	RRAGD	protein	Q9NQL2	UNIPROT	up-regulates activity	gtpase-activating protein			9606	BTO:0000007								24095279	t			The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur	SIGNOR-256504	0.675
PPP3CA	protein	Q08209	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	dephosphorylation	Ser637	VPVARKLsAREQRDC	9606									18838687	t			When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.	SIGNOR-248676	0.28
EPHB1	protein	P54762	UNIPROT	NRCAM	protein	Q92823	UNIPROT	up-regulates activity	phosphorylation	Tyr1276	DGSFIGQySGKKEKE	9606	BTO:0000007								24023801	t		miannu	EphB receptors were found to induce phosphorylation of NrCAM on the tyrosine residue within the FIGQY ankyrin binding motif, inhibiting ankyrin recruitment. Furthermore, NrCAM phospho-FIGQY levels in the SC were decreased in EphB1/3 and EphB1/2/3 null mice and increased in mutant mice overexpressing constitutively active EphB2 kinase. 	SIGNOR-262862	0.423
atropine	chemical	CHEBI:16684	ChEBI	CHRM3	protein	P20309	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								2704370	t		miannu	In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 	SIGNOR-258391	0.8
SRC	protein	P12931	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates	phosphorylation	Tyr478	PPPPPPVyEPVSYHV	9606									22397367	t		lperfetto	Ezrin, a member of the erm family of proteins, is frequently over-expressed in human breast cancers, and is required for motility and invasion of epithelial cells. In particular, ezrin phosphorylation on y477 by src is specific to ezrin within the erm family, and is required for hgf-induced scattering of epithelial cells.	SIGNOR-196443	0.635
3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one	chemical	CHEBI:91346	ChEBI	AKT1	protein	P31749	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000782								25336630	t		miannu	 stimulations were performed in the presence or absence of Akt inhibitor VIII, which selectively inhibits Akt1/Akt2 activity. 	SIGNOR-262227	0.8
KCNQ3	protein	O43525	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	up-regulates quantity	relocalization			9606									19298256	t		miannu	KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations.	SIGNOR-265984	0.8
GSK3B	protein	P49841	UNIPROT	EIF2B1	protein	Q14232	UNIPROT	down-regulates	binding			9606									21798082	t		gcesareni	Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b).	SIGNOR-175436	0.2
873837-23-1	chemical	CID:46930994	PUBCHEM	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190467	0.8
PRKCA	protein	P17252	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Ser249	GLSLSRFsWGAEGQR	-1									2413024	t		lperfetto	MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 	SIGNOR-248872	0.503
AKT1	protein	P31749	UNIPROT	MAP2K4	protein	P45985	UNIPROT	down-regulates	phosphorylation	Ser80	IERLRTHsIESSGKL	9606	BTO:0000007								11707464	t		lperfetto	Akt phosphorylated sek1 on serine 78.	SIGNOR-236494	0.58
rRNA_transcription	phenotype	SIGNOR-PH145	SIGNOR	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	up-regulates													25901680	f		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262602	0.7
IL1B	protein	P01584	UNIPROT	IL1R1	protein	P14778	UNIPROT	up-regulates	binding			9606		BTO:0001253							9625767	t		gcesareni	Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab).	SIGNOR-58122	0.903
CSNK1D	protein	P48730	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates	phosphorylation			9606									20708156	t		gcesareni	Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase.	SIGNOR-167520	0.351
IFNB1	protein	P01574	UNIPROT	IFNAR1	protein	P17181	UNIPROT	up-regulates	binding			9606									11278538	t		gcesareni	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-104663	0.862
NKX2-2	protein	O95096	UNIPROT	ERMN	protein	Q8TAM6	UNIPROT	up-regulates quantity by expression	transcriptional regulation												21221725	t		lperfetto	Further study revealed that Nkx2.2 could bind JN promoter and its overexpression increase the promoter activity of JN.	SIGNOR-268965	0.252
PPP1CA	protein	P62136	UNIPROT	AURKA	protein	O14965	UNIPROT	down-regulates	dephosphorylation			9606									11551964	t		gcesareni	Pp1 is shown to dephosphorylate active stk15 and abolish its activity in vitro.	SIGNOR-110411	0.446
PRKG1	protein	Q13976	UNIPROT	SEPTIN3	protein	Q9UH03	UNIPROT	up-regulates activity	phosphorylation	Ser91	SQVSRKAsSWNREEK	-1									15107017	t		miannu	Mutation of Ser-91 to Ala in recombinant Sept3 also abolished PKG phosphorylation, confirming that Ser-91 is the major site in vitro. Therefore Sept3 is phosphorylated on Ser-91 in nerve terminals and its phosphorylation may contribute to the regulation of its subcellular localization in neurons.	SIGNOR-263183	0.2
succinyl-CoA(5-)	smallmolecule	CHEBI:57292	ChEBI	succinate(2-)	smallmolecule	CHEBI:30031	ChEBI	up-regulates quantity	precursor of			9606									27487822	t		miannu	In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions.	SIGNOR-266265	0.8
CTDSP1	protein	Q9GZU7	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation	Thr220	QSNYIPEtPPPGYIS	9606	BTO:0000007								17035229	t			SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248794	0.493
MAPK3	protein	P27361	UNIPROT	ADAM17	protein	P78536	UNIPROT	up-regulates	phosphorylation	Thr735	KPFPAPQtPGRLQPA	9606									12058067	t		gcesareni	Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated sheddingwe show that extracellular signal-regulated kinase (erk) acts as an intermediate in protein kinase c-regulated trka cleavage. We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (tace) is phosphorylated by erk at threonine 735. In addition, we show that erk and tace associate. This association is favored by erk activation and by the presence of threonine 735. In contrast to the erk route, the p38 mapk was able to stimulate trka cleavage in cells devoid of tace activity, indicating that other proteases are also involved in trka shedding.	SIGNOR-89625	0.37
MAML2	protein	Q8IZL2	UNIPROT	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12386158	f		gcesareni	Similarly, maml1 and maml2 amplified notch ligand (both jagged2 and delta1)-induced transcription of the hes-1 gene, whereas maml3 displayed little effect.	SIGNOR-94276	0.379
alectinib	chemical	CHEBI:90936	ChEBI	ALK	protein	Q9UM73	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190961	0.8
aminoglutethimide	chemical	CHEBI:2654	ChEBI	CYP19A1	protein	P11511	UNIPROT	down-regulates activity	chemical inhibition			-1									19470632	t		Luana	 A new naturally occurring relatively common alteration of enzyme structure at T201M increases enzyme activity and reduces the inhibitory effect of aminoglutethimide.	SIGNOR-257824	0.8
DUSP3	protein	P51452	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates activity	dephosphorylation	Tyr1221	SPAFDNLyYWDQDPP	9606	BTO:0002552								21262974	t			Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. | We found that VHR decreased ErbB2 phosphorylation in vitro and in a cellular context, and the dephosphorylation of ErbB2 was more evident at Tyr-877 and Tyr-1221 than those at Tyr-1139 and Tyr-1248 (supplemental Fig. S1). Our data indicated that VHR was a cellular PTP against EGFR and ErbB2. 	SIGNOR-248534	0.271
CENPK	protein	Q9BS16	UNIPROT	SOX6	protein	P35712	UNIPROT	up-regulates activity	binding			10029	BTO:0000246								10996314	t		miannu	Here we report the cloning of a novel cDNA, termed Solt, from a mouse testis cDNA library. Its gene product, Solt, interacts with the leucine zipper region of SoxLZ/Sox6. In transient transfection assays with SoxLZ/Sox6 containing the transactivation domain of herpes simplex virus VP16, the expression of a luciferase reporter gene under the control of a promoter containing a synthetic cis element that is bound by the HMG box of SoxLZ/Sox6 was poorly enhanced in the presence of Solt.	SIGNOR-221820	0.483
PPP2CB	protein	P62714	UNIPROT	PRKCB	protein	P05771	UNIPROT	down-regulates activity	dephosphorylation	Thr500	WDGVTTKtFCGTPDY	10116									8749392	t			 Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme. 	SIGNOR-248585	0.457
NTRK1	protein	P04629	UNIPROT	NTRK1	protein	P04629	UNIPROT	up-regulates	phosphorylation	Tyr680	RDIYSTDyYRVGGRT	9606									9099755	t		gcesareni	In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785	SIGNOR-47175	0.2
FYN	protein	P06241	UNIPROT	AGAP2	protein	Q99490	UNIPROT	up-regulates	phosphorylation	Tyr1038	ESWIRAKyEQLLFLA	9606									16841086	t		llicata	We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival.	SIGNOR-147932	0.444
CAMK2B	protein	Q13554	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser571	PWPLRRTsAQGQPSP	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275774	0.394
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser326	PPKMWKTsPDPSPVS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248692	0.613
SH3GL3	protein	Q99963	UNIPROT	Endocytosis	phenotype	SIGNOR-PH123	SIGNOR	up-regulates				9606									25517094	f		miannu	Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. 	SIGNOR-263884	0.7
PLK1	protein	P53350	UNIPROT	TNKS	protein	O95271	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr839	DTQGRNStPLHLAAG	9606	BTO:0000567								21818122	t		miannu	Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends. 	SIGNOR-276245	0.439
AKT1	protein	P31749	UNIPROT	PFKFB2	protein	O60825	UNIPROT	unknown	phosphorylation	Ser483	IRRPRNYsVGSRPLK	9606	BTO:0000567								12853467	t			14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling.	SIGNOR-252575	0.643
EEF1B complex	complex	SIGNOR-C460	SIGNOR	EEF1A2	protein	Q05639	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. 	SIGNOR-269388	0.715
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates	chemical activation			9606	BTO:0000150								17478088	t		gcesareni	Oestrogen receptors (er)alpha and beta modify the expression of genes involved in cell growth, proliferation and differentiation through binding to oestrogen response elements (eres) located in a number of gene promoters.	SIGNOR-154660	0.8
S1PR3	protein	Q99500	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256790	0.2
WDR18	protein	Q9BV38	UNIPROT	Rix1 complex	complex	SIGNOR-C373	SIGNOR	form complex	binding			9606	BTO:0000007								22190735	t		miannu	LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes.	SIGNOR-265471	0.866
DIABLO	protein	Q9NR28	UNIPROT	BIRC3	protein	Q13489	UNIPROT	down-regulates activity	binding			9606	BTO:0000007;BTO:0000891								10929711	t		amattioni	Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity.	SIGNOR-80209	0.785
AKT1	protein	P31749	UNIPROT	CARD11	protein	Q9BXL7	UNIPROT	up-regulates activity	phosphorylation	Ser652	LERPFRPsVTSVGHV	-1									24548923	t		miannu	Here we show that Akt-mediated NF-κB activation is mediated at least in part through direct phosphorylation of the adaptor protein Carma1, which we previously demonstrated could interact with Akt in a TCR ligation-dependent manner. The putative Akt phosphorylation sites in Carma1 are distinct from known PKC consensus sites. Mutation of S551, S637 and S645 in Carma1 to non-phosphorylatable residues decreased phosphorylation of GST-Carma1-linker construct by Akt in vitro. 	SIGNOR-276256	0.538
CSNK2A1	protein	P68400	UNIPROT	EIF2S2	protein	P20042	UNIPROT	up-regulates	phosphorylation	Ser2	sGDEMIFD	9606	BTO:0000567								16225457	t		lperfetto	The n-terminal domain of the human eif2beta subunit and the ck2 phosphorylation sites are required for its function. These results suggest that ser2 and ser67 contribute to the important role of the n-terminal region of eif2beta for its function in mammals.	SIGNOR-140994	0.355
ERBB2	protein	P04626	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	relocalization			9606									14967450	t		gcesareni	All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor	SIGNOR-121968	0.845
MAPK10	protein	P53779	UNIPROT	BCL2L11	protein	O43521	UNIPROT	up-regulates activity	phosphorylation	Ser59	GDSCPHGsPQGPLAP	10090									12818176	t		miannu	JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity. 	SIGNOR-250130	0.677
PLK3	protein	Q9H4B4	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates activity	phosphorylation	Ser129	NEAYEMPsEEGYQDY	9606									19889641	t		lperfetto	Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation.	SIGNOR-189053	0.324
atropine	chemical	CHEBI:16684	ChEBI	CHRM2	protein	P08172	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								2704370	t		miannu	In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 	SIGNOR-258392	0.8
CSNK2A2	protein	P19784	UNIPROT	SCN2A	protein	Q99250	UNIPROT	up-regulates activity	phosphorylation	Ser1112	VPIAVGEsDFENLNT	9606	BTO:0000938								19064667	t		lperfetto	 We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275754	0.2
PRKG2	protein	Q13237	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	phosphorylation	Ser712	SDKRRPPsAELYSNA	9606	BTO:0000498								29935031	t		miannu	PKG II inhibited PDGFRβ activation in gastric cancer via phosphorylating Ser712 of this RTK.	SIGNOR-277401	0.276
STOM	protein	P27105	UNIPROT	4.1 complex	complex	SIGNOR-C386	SIGNOR	form complex	binding			9606	BTO:0000424								33187473	t		lperfetto	The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16]	SIGNOR-266040	0.357
SLC6A3	protein	Q01959	UNIPROT	dopamine	smallmolecule	CHEBI:18243	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								30465801	t		miannu	Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. 	SIGNOR-269196	0.8
PRKG2	protein	Q13237	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Thr143	RCFTRKYtLPPGVDP	9606									19593530	t	11383510: to test the hypothesis that cGK could inhibit platelet aggregation by phosphorylating Hsp27 and interfering with the MAPKAP kinase phosphorylation of Hsp27, the known MAPKAP kinase 2-phosphorylation sites (Ser15, Ser78, and Ser82) as well as Thr143 were replaced by negatively charged amino acids, which are considered to mimic phosphate groups, and tested in actin polymerization experiments. Mimicry at the MAPKAP kinase 2 phosphorylation sites led to mutants with a stimulating effect on actin polymerization	lperfetto	Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization	SIGNOR-186947	0.2
vorapaxar	chemical	CHEBI:82702	ChEBI	F2R	protein	P25116	UNIPROT	down-regulates activity	chemical inhibition			-1									18447380	t		Luana	The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. 	SIGNOR-257792	0.8
MRPL21	protein	Q7Z2W9	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262372	0.699
LMTK2	protein	Q8IWU2	UNIPROT	PPP1CA	protein	P62136	UNIPROT	down-regulates activity	phosphorylation	Thr320	NPGGRPItPPRNSAK	9606									12393858	t		gcesareni	Kpi-2 kinase domain phosphorylated protein phosphatase-1 (pp1c) at thr(320), which attenuated pp1c activity.	SIGNOR-94631	0.589
CDK5	protein	Q00535	UNIPROT	CDK5R1	protein	Q15078	UNIPROT	down-regulates	phosphorylation	Thr138	PAVTSAGtPKRVIVQ	9606									18326489	t		lperfetto	P35 phosphorylation by cdk5 interferes with the microtubule-binding and polymerizing activities of p35. Using a mutational approach, we found that only phosphorylation at thr-138, one of the two residues primarily phosphorylated in vivo, inhibits the polymerizing activity	SIGNOR-177967	0.942
NFATC1	protein	O95644	UNIPROT	PTGS2	protein	P35354	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21871017	t		miannu	 NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration	SIGNOR-264026	0.323
IFNAR	complex	SIGNOR-C243	SIGNOR	CCL2	protein	P13500	UNIPROT	up-regulates quantity by expression				10090									32283152	f		miannu	The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages.	SIGNOR-260851	0.322
WASHC3	protein	Q9Y3C0	UNIPROT	WASH complex	complex	SIGNOR-C258	SIGNOR	form complex	binding												23721880	t		lperfetto	The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53.	SIGNOR-261017	0.2
NXF1	protein	Q9UBU9	UNIPROT	RBM15/NXF1	complex	SIGNOR-C67	SIGNOR	form complex	binding			9606									17001072	t		miannu	Rbm15 binds to nxf1 and the two proteins cooperate in stimulating rte-mediated mrna export and expression.	SIGNOR-149880	0.503
CSNK2A1	protein	P68400	UNIPROT	RPS6KA4	protein	O75676	UNIPROT	up-regulates activity	phosphorylation	Ser324	PFRPQIRsELDVGNF	9606	BTO:0002181								19933278	t		miannu	Here we report that the CK2 protein kinase, which contributes to NF-kappaB activation following UV radiation in a p38-dependent manner, physically interacts with MSK2 but not MSK1 and that CK2 inhibition specifically impairs UV-induced MSK2 kinase activation. A putative site of CK2 phosphorylation was mapped to MSK2 residue Ser(324) and when substituted to alanine (S324A) also compromised MSK2 activity.Serine 324 is required for UV-induced MSK2 activation and for autophosphorylation at MSK2-Ser196. 	SIGNOR-276268	0.284
IFNAR1	protein	P17181	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	phosphorylation			9606									21631354	t		miannu	These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity 	SIGNOR-260435	0.331
PPP1CA	protein	P62136	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	down-regulates	dephosphorylation			9606									12840032	t	inferred from 70% of family members	fstefani	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases	SIGNOR-269906	0.2
NDFIP1	protein	Q9BT67	UNIPROT	NEDD4	protein	P46934	UNIPROT	up-regulates activity	relocalization			9606	BTO:0002181								26363003	t		SARA	Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2.	SIGNOR-260997	0.608
FOXO3	protein	O43524	UNIPROT	FASLG	protein	P48023	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10102273	f		gcesareni	Within the nucleus, fkhrl1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the fas ligand gene.	SIGNOR-66035	0.697
INHBA	protein	P08476	UNIPROT	ACVR2B	protein	Q13705	UNIPROT	up-regulates activity	binding			9606									8622651	t		gcesareni	Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB.	SIGNOR-235142	0.778
ADORA1	protein	P30542	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256976	0.398
SRC	protein	P12931	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr627	KGDKQVEyLDLDLDS	9606	BTO:0000007								19881549	t		lperfetto	Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis	SIGNOR-236302	0.693
Core mediator complex	complex	SIGNOR-C405	SIGNOR	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	up-regulates activity	binding			9606									25693131	t		miannu	The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most non-coding RNA genes and is globally regulated by Mediator — a large, conformationally flexible protein complex with a variable subunit composition (for example, a four-subunit cyclin-dependent kinase 8 module can reversibly associate with it). Because of its direct and extensive interactions with Pol II, Mediator regulates multiple stages of Pol II transcription (for example, initiation and re-initiation). Mediator interactions with the super elongation complex (SEC) also seem to be important for its regulation of Pol II elongation.	SIGNOR-266682	0.341
EEF1A1	protein	P68104	UNIPROT	Asn-tRNA(Asn)	smallmolecule	CHEBI:29265	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269506	0.8
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257985	0.8
TFIIH	complex	SIGNOR-C457	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									30860024	f		lperfetto	Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.	SIGNOR-269323	0.7
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	LDHB	protein	P07195	UNIPROT	up-regulates quantity	transcriptional regulation			9606									7673128	t		lperfetto	Deletional and mutational analysis of the function of mouse LDH-reporter fusion gene constructs in transient transfection assays defined three domains, between -41 and -84 base pairs upstream of the transcription initiation site, which were crucial for oxygen-regulated expression. The most important of these, although not capable of driving hypoxic induction in isolation, had the consensus of a hypoxia-inducible factor 1 (HIF-1) site, and cross-competed for the binding of HIF-1 with functionally active Epo and phosphoglycerate kinase-1 sequences	SIGNOR-267653	0.361
PARD6/SMURF1	complex	SIGNOR-C112	SIGNOR	RHOA	protein	P61586	UNIPROT	down-regulates	ubiquitination			9606									15761148	t		lperfetto	The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT.	SIGNOR-227492	0.662
CRHR1	protein	P34998	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding												22869609	t		lperfetto	Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3	SIGNOR-268619	0.289
MYOG	protein	P15173	UNIPROT	ITGA7	protein	Q13683	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									8798472	t		lperfetto	Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development.	SIGNOR-241521	0.287
SCN9A	protein	Q15858	UNIPROT	Action_potential 	phenotype	SIGNOR-PH82	SIGNOR	up-regulates				9606									26043074	f		miannu	The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons.	SIGNOR-253449	0.7
ZMIZ1	protein	Q9ULJ6	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									26522984	t		miannu	The N-terminal domain (NTD) of Zmiz1 is important for driving Myc transcription and proliferation […] Zmiz1 directly interacted with Notch1 via a tetratricopeptide repeat domain at a special class of Notch-regulatory sites.	SIGNOR-263939	0.371
FGD4	protein	Q96M96	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260554	0.604
PRKCD	protein	Q05655	UNIPROT	MEP1B	protein	Q16820	UNIPROT	down-regulates quantity	phosphorylation	Ser687	KKYRERMsSNRPNLT	9534	BTO:0001538								12941954	t		miannu	These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.	SIGNOR-263171	0.311
MAPK12	protein	P53778	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity	phosphorylation	Ser201	SGDSDASsPRSNCSD	10090	BTO:0005930								20026657	t		miannu	 We determined that p38-gamma directly phosphorylated MyoD on Ser199 and Ser200, which results in enhanced occupancy of MyoD on the promoter of myogenin together with markedly decreased transcriptional activity. Phosphorylation of MyoD by p38-γ directs the assembly of a repressive transcriptional complex at the Myogenin promoter.	SIGNOR-276273	0.422
2-(2-amino-3-methoxyphenyl)chromen-4-one	chemical	CHEBI:77954	ChEBI	MAP2K2	protein	P36507	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000938	BTO:0000142							11160424	t		gcesareni	The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity.	SIGNOR-104921	0.8
PEX26	protein	Q7Z412	UNIPROT	PEX6	protein	Q13608	UNIPROT	up-regulates activity	binding			10029									12717447	t			Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions.	SIGNOR-253614	0.773
RXRB	protein	P28702	UNIPROT	NR1H2	protein	P55055	UNIPROT	up-regulates	binding			9606									14993927	t		gcesareni	We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active.	SIGNOR-123094	0.681
N-(4-methoxyphenyl)sulfonyl-N-[2-[2-(1-oxido-4-pyridin-1-iumyl)ethenyl]phenyl]acetamide	chemical	CHEBI:91440	ChEBI	PLK1	protein	P53350	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193309	0.8
PAK2	protein	Q13177	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates	phosphorylation	Ser618	APTPPKRsSSFREMD	9606									18161990	t		lperfetto	The interaction of c-abl with the abl interactor protein abi2 is shown to be negatively regulated by phosphorylation of serines 637 and 638. These serines are adjacent to the pxxp motif (ptppkrs637s638sfr) that binds the sh3 domain of abi. phosphorylation of c-abl by pak2 inhibits the interaction between the sh3 domain of abi2 and the pxxp motif of c-abl.	SIGNOR-160215	0.424
AKT2	protein	P31751	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000007								17386266	t		lperfetto	Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity.	SIGNOR-236705	0.568
CDK1	protein	P06493	UNIPROT	SIRT2	protein	Q8IXJ6	UNIPROT	down-regulates	phosphorylation	Ser368	PNPSTSAsPKKSPPP	9606									17488717	t		gcesareni	Here, we demonstrate that sirt2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1. Overexpression of sirt2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation.	SIGNOR-154681	0.423
(-)-anisomycin	chemical	CHEBI:338412	ChEBI	JUNB	protein	P17275	UNIPROT	up-regulates	chemical activation			9606									Other	t	CellSignaling;phospho-JunB (Thr102/Thr104) (D3C6) Rabbit mAb #8053	gcesareni		SIGNOR-189644	0.8
regorafenib	chemical	CHEBI:68647	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates activity	chemical inhibition			9606									24756792	t		miannu	In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically.	SIGNOR-259209	0.8
MAP2K4	protein	P45985	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates activity	phosphorylation	Tyr185	TSFMMTPyVVTRYYR	-1									11062067	t			Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1).	SIGNOR-251419	0.74
NHS	protein	Q6T4R5	UNIPROT	ABI2	protein	Q9NYB9	UNIPROT	up-regulates activity	binding			9606		BTO:0000723							20332100	t		miannu	NHS may preferentially bind one or more Abi's in vivo, and it is also likely that specificity is governed by spatiotemporal expression of both proteins. Abi2 is highly expressed in the lens and plays a pivotal role in the development of the anterior and posterior sutures. This suggests that an NHS–Abi2 interaction may be physiologically important for lens development and that null mutations in the NHS gene could cause congenital cataract by disruption of this interaction and the actin cytoskeleton.	SIGNOR-253579	0.2
TNFRSF1B	protein	P20333	UNIPROT	TRAF1	protein	Q13077	UNIPROT	up-regulates	binding			9606									8069916	t		gcesareni	Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2.	SIGNOR-33133	0.709
CD19	protein	P15391	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			10090	BTO:0000776								25673924	t		lperfetto	CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades.	SIGNOR-252670	0.502
GRK2	protein	P25098	UNIPROT	FPR1	protein	P21462	UNIPROT	down-regulates activity	phosphorylation	Thr334	DSTQTSDtATNSTLP	-1									7836371	t			Phosphorylation of the FPR carboxyl terminus by GRK2 is the result of a high affinity interaction and proceeds in a hierarchical manner. sequential mechanism of phosphorylation beginning with residues 328 and/or 329, followed by residues 331 and/or 332, and finally residues 334 through 339. Attenuation of receptor-mediated signal amplification in response to external stimuli, an essential step in the balance of cellular activation, may be mediated by receptor phosphorylation. 	SIGNOR-251451	0.2
RHOA	protein	P61586	UNIPROT	PKN2	protein	Q16513	UNIPROT	up-regulates activity	binding			10090	BTO:0004732								27270401	t	no	miannu	PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. 	SIGNOR-275466	0.826
PRKACA	protein	P17612	UNIPROT	EEF2K	protein	O00418	UNIPROT	up-regulates activity	phosphorylation	Ser366	SPQVRTLsGSRPPLL	-1									11171059	t		miannu	EEF-2K can be phosphorylated in vitro by cAMP-dependent protein kinase (PKA) and that this induces significant Ca(2+)/calmodulin (CaM)-independent eEF-2K activity. sites of phosphorylation were Ser-365 and Ser-499	SIGNOR-250354	0.31
MAPK13	protein	O15264	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser38	SVPEFPLsPPKKKDL	9606	BTO:0000782								8325880	t		gcesareni	Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase.	SIGNOR-25826	0.389
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	iodide	smallmolecule	CHEBI:16382	ChEBI	up-regulates quantity	precursor of			9606									8755651	t		scontino	Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5’-position) to yield T3	SIGNOR-266950	0.8
HTR4	protein	Q13639	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257242	0.255
10-formyltetrahydrofolate(2-)	smallmolecule	CHEBI:57454	ChEBI	(6S)-5,6,7,8-tetrahydrofolate(2-)	smallmolecule	CHEBI:57453	ChEBI	up-regulates quantity	precursor of			9606									11381136	t		miannu	The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR.	SIGNOR-267302	0.8
WDR5	protein	P61964	UNIPROT	NSL histone acetyltransferase	complex	SIGNOR-C413	SIGNOR	form complex	binding			9606	BTO:0000007								20018852	t		miannu	Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex.	SIGNOR-267157	0.648
MAPK3	protein	P27361	UNIPROT	PCBP2	protein	Q15366	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser173	MLETLSQsPPKGVTI	9606	BTO:0000664								17475908	t		miannu	We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 	SIGNOR-262914	0.329
PAX2/TLE4	complex	SIGNOR-C152	SIGNOR	WT1	protein	P19544	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0002295								16631587	t			Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1.	SIGNOR-252291	0.46
CDK2	protein	P24941	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Thr8	MSSILPFtPPIVKRL	9606									15241418	t		gcesareni	We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function	SIGNOR-126740	0.733
SLC4A3	protein	P48751	UNIPROT	hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	down-regulates quantity	relocalization			9606	BTO:0000938								26136660	t		miannu	Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. In neurons, bicarbonate transport is mainly mediated by members of the SLC4A family of proteins. While the Na+-independent anion-exchanger SLC4A3 lowers the intraneuronal bicarbonate concentration, the Na+-dependent anion exchangers SLC4A8 (NDCBE) and SLC4A10 (NCBE) use the sodium gradient to accumulate bicarbonate in exchange of chloride	SIGNOR-264917	0.8
UBAP2L	protein	Q14157	UNIPROT	RNF2	protein	Q99496	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								25185265	t		Sara	UBAP2L associates with BMI1 and RNF2. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex	SIGNOR-261316	0.357
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	Calcineurin	complex	SIGNOR-C155	SIGNOR	up-regulates activity	chemical activation			9606									21880741	t		miannu	Except for nfat5, nfatc1c4 are activated upon a rise in intracellular ca2+, which stimulates the serine/threonine phosphatase activity of calcineurin the ca2+-calcineurin signal is the most important signal for regulating nfat activation, but the signal that leads to ca2+ influx during neural tube differentiation is still unclear.	SIGNOR-255462	0.8
TRIP11	protein	Q15643	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates activity	binding			9606									9256431	t	inferred from family member	miannu	Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity.	SIGNOR-267803	0.432
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CSNK2A1	protein	P68400	UNIPROT	up-regulates	phosphorylation	Ser362	ISSVPTPsPLGPLAG	9606	BTO:0000527								19941816	t		lperfetto	Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity	SIGNOR-244521	0.2
MMP21	protein	Q8N119	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272389	0.7
REST	protein	Q13127	UNIPROT	HCN1	protein	O60741	UNIPROT	down-regulates quantity by repression	transcriptional regulation				BTO:0000938								21905079	t		lperfetto	Levels of NRSF and its physical binding to the Hcn1 gene were augmented after SE, resulting in repression of HCN1 expression and HCN1-mediated currents (I(h) ), and reduced I(h) -dependent resonance in hippocampal CA1 pyramidal cell dendrites.	SIGNOR-268970	0.2
vorinostat	chemical	CHEBI:45716	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257949	0.8
DRD3	protein	P35462	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256845	0.431
WNT8B	protein	Q93098	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-132024	0.609
DOT1L	protein	Q8TEK3	UNIPROT	H3-4	protein	Q16695	UNIPROT	unknown	methylation	Lys80	REIAQDFkTDLRFQS	9606									12123582	t		miannu	HDOT1L Is a Nucleosomal H3-K79-Specific HMTase. We identified a human DOT1-like (DOT1L) protein and demonstrated that this protein possesses intrinsic H3-K79-specific histone methyltransferase (HMTase) activity in vitro and in vivo. Furthermore, we found that K79 methylation level is regulated throughout the cell cycle. By using two different methods, we demonstrate that the K79 methylation level decreases during S phase, reaches its lowest level in G2, increases during M phase, and maintains at a high level during G1 phase.	SIGNOR-267142	0.2
GPR119	protein	Q8TDV5	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257153	0.252
CSNK2B	protein	P67870	UNIPROT	SET	protein	Q01105-2	UNIPROT	down-regulates	phosphorylation	Ser9	SAPAAKVsKKELNSN	9606	BTO:0000938	BTO:0000142							23374587	t	The effect has been demonstrated using Q01105-2	miannu	Ckii-mediated phosphorylation at ser9 hinders nuclear import of set	SIGNOR-200806	0.248
MCL1	protein	Q07820	UNIPROT	BAX	protein	Q07812	UNIPROT	down-regulates	binding			9606									17289999	t		gcesareni	Which of the multiple pro-survival proteins that can bind Bax (fig. S15A) can functionally restrain it? Mcl-1 must, because neutralizing Mcl-1 by enforced Noxa expression rendered MEFs containing only Bax (Bak KO cells) sensitive to the Bad BH3 mimetic ABT-737 (Fig. 4A), which inactivates Bcl-2, Bcl-xL, and Bcl-w	SIGNOR-151787	0.724
ER stress	stimulus	SIGNOR-ST9	SIGNOR	BCL2L11	protein	O43521	UNIPROT	up-regulates				9606									22492984	f		gcesareni	Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins	SIGNOR-196941	0.7
vadimezan	chemical	CHEBI:75934	ChEBI	NQO1	protein	P15559	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191397	0.8
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser14	LYSFFSPsPARKRHA	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276085	0.283
GRIA3	protein	P42263	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								30825796	f		miannu	In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses	SIGNOR-264613	0.7
ATF3	protein	P18847	UNIPROT	GDF15	protein	Q99988	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15670751	t	 	lperfetto	In addition, DIM increased the expression of NAG-1 as well as activating transcription factor 3 (ATF3), and the induction of ATF3 was earlier than that of NAG-1. The DIM treatment increased luciferase activity of NAG-1 in HCT-116 cells transfected with NAG-1 promoter construct. The results suggest that I3C represses cell proliferation through up-regulation of NAG-1 and that ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells.	SIGNOR-253725	0.439
SMARCE1	protein	Q969G3	UNIPROT	Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270691	0.832
NUP98 Fusion	fusion protein	SIGNOR-FP16	SIGNOR	CDK6	protein	Q00534	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32344427	f		miannu	NUP98-fusion proteins directly regulate leukemia-associated gene expression programs in AML. CDK6 expression is under direct transcriptional control of NUP98-fusions and NUP98-fusion AML is particularly sensitive to CDK6 inhibition.	SIGNOR-261505	0.2
IKBKB	protein	O14920	UNIPROT	BCL10	protein	O95999	UNIPROT	up-regulates activity	phosphorylation	Ser136	ATNNLSRsNSDESNF	9606	BTO:0000007								16818229	t		miannu	Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling.	SIGNOR-276290	0.765
CCIN	protein	Q13939	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates				9606	BTO:0001277								11090452	t		miannu	The results suggest that the affinity of calicin to F-actin allows targeting of calicin at the subacrosomal space of round spermatids, and that its ability to form homomultimers contributes to the formation of a rigid calyx.	SIGNOR-268503	0.7
CoREST-HDAC complex	complex	SIGNOR-C105	SIGNOR	SCN2A	protein	Q99250	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								16140033	f		lperfetto	This suggests that the HDACs in the LSD1 complex are likely to function upstream of CoREST/LSD1, generating a hypoacetylated histone substrate, which can then be better recognized by CoREST/LSD1. Further supporting this model, we found that inhibition of HDAC activity by TSA resulted in derepression of two LSD1 target genes, the human neuronal-specific sodium channel (SCN) genes, SCNA2 and SCNA3 (Figure 1H).	SIGNOR-268541	0.277
VEPH1	protein	Q14D04	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000938								22055343	f	In the neuronal differentiation	lperfetto	Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9	SIGNOR-177077	0.2
AR	protein	P10275	UNIPROT	TMPRSS2	protein	O15393	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24505269	t		miannu	Recurrent gene fusion between the androgen-regulated gene TMPRSS2 and members of the ETS transcription factor family, most commonly ERG, are present in about 50% of prostate cancer cases. Presence of this fusion gene is a critical event in the development of prostate cancer. the more aggressive phenotype that arises with the presence of TMPRSS2-ERG at least in part is caused by changes in the tumor stroma.	SIGNOR-251545	0.595
NMBR	protein	P28336	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			9606	BTO:0001130;BTO:0000551								11313903	t		gcesareni	These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways.	SIGNOR-107028	0.252
IDH2	protein	P48735	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	chemical modification			9606									26178471	t		lperfetto	Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG)	SIGNOR-261827	0.8
HNF1A	protein	P20823	UNIPROT	ALDOB	protein	P05062	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									8383844	f		miannu	 Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators	SIGNOR-253834	0.317
MYT1L	protein	Q9UL68	UNIPROT	HES1	protein	Q14469	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0002572								28379941	t		miannu	ChIP–seq experiments showed that 80% of Myt1l targets, including the transcription factor Hes1, were co-bound by the repressive Sin3b–HDAC1 complex early during reprogramming	SIGNOR-266775	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	SH2B2	protein	O14492	UNIPROT	up-regulates activity	phosphorylation	Ser598	SARSRSNsAERLLEA	10090									16141217	t		gcesareni	This study identifies APS as a novel physiological substrate for PKB and the first serine phosphorylation site on APS	SIGNOR-248042	0.2
RCOR1	protein	Q9UKL0	UNIPROT	REST	protein	Q13127	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								10449787	t		miannu	We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity.	SIGNOR-220618	0.761
PAK2	protein	Q13177	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates activity	phosphorylation	Ser141	TVKQKYLsFTPPEKD	-1									10075701	t		miannu	Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197. 	SIGNOR-250228	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPS6KA3	protein	P51812	UNIPROT	up-regulates	phosphorylation			9606									19282669	t		lperfetto	Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.	SIGNOR-244699	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CDCA5	protein	Q96FF9	UNIPROT	up-regulates activity	phosphorylation	Ser79	AVQSPRRsPRISFFL	9606	BTO:0000567								20551060	t		miannu	Phosphorylation and activation of cell division cycle associated 5 by mitogen-activated protein kinase play a crucial role in human lung carcinogenesis. Our data suggest that transactivation of CDCA5 and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation, and that the selective suppression of the ERK-CDCA5 pathway could be a promising strategy for cancer therapy.	SIGNOR-262969	0.2
GTP	smallmolecule	CHEBI:15996	ChEBI	Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	form complex	binding			9606									32955564	t		lperfetto	In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3.	SIGNOR-269118	0.8
ABL1	protein	P00519	UNIPROT	RAPH1	protein	Q70E73	UNIPROT	up-regulates activity	phosphorylation	Tyr513	GKQLYMNyQEALKRT	-1									20417104	t		miannu	Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C).	SIGNOR-262608	0.289
ACLY	protein	P53396	UNIPROT	citrate(3-)	smallmolecule	CHEBI:16947	ChEBI	down-regulates quantity by destabilization	chemical modification			9606									19286649	t		miannu	ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor.	SIGNOR-267101	0.8
BCL10	protein	O95999	UNIPROT	CBM	complex	SIGNOR-C555	SIGNOR	form complex	binding			9606									15122200	t		miannu	CARMA1, the adaptor protein BCL-10 (B-cell lymphoma 10) and the caspase-like protein MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) form a signalling complex that has a key role in antigen-receptor-mediated activation of the nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK) pathways.	SIGNOR-276294	0.827
PRKACA	protein	P17612	UNIPROT	ITGA4	protein	P13612	UNIPROT	up-regulates activity	phosphorylation	Ser1021	QEENRRDsWSYINSK	9606	BTO:0000782								11533025	t		lperfetto	PKA phosphorylationin vitro blocks the binding of the alpha4 tail to paxillin. A mutation that mimics alpha4 phosphorylation disrupts paxillin binding and promotes cell spreading	SIGNOR-110119	0.47
MDGA2	protein	Q7Z553	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606									26206665	f		miannu	MDGA2 acts as a novel tumour suppressor in gastric cancer through inhibiting cell proliferation, suppressing G1–S cell cycle transition and inducing cell apoptosis.	SIGNOR-264239	0.7
TP53INP1	protein	Q96A56	UNIPROT	GABARAPL2	protein	P60520	UNIPROT	up-regulates	binding			9606									22421968	t		gcesareni	In this work, we show that tp53inp1 is also able to interact with atg8-family proteins and to induce autophagy-dependent cell death. mammalian cells contain multiple atg8 orthologs belonging to three subfamilies: microtubule-associated protein 1 light chain 3, -aminobutyric acid receptor-associated protein (gabarap) and -aminobutyric acid receptor-associated protein like 2 (gabarapl2).	SIGNOR-196667	0.388
CASP3	protein	P42574	UNIPROT	RAD51	protein	Q06609	UNIPROT	down-regulates quantity by destabilization	cleavage			9606	BTO:0002882								11684015	t		lperfetto	The RAD51 protein has been shown to be a substrate for caspase-3|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin	SIGNOR-271709	0.478
FZD5	protein	Q13467	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	binding			9606									18077588	t		areggio	Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction.	SIGNOR-258966	0.727
NMBR	protein	P28336	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257248	0.271
MAP3K5	protein	Q99683	UNIPROT	ZNF622	protein	Q969S3	UNIPROT	up-regulates	phosphorylation	Ser314	WCNEKGKsFYSTEAV	9606									21771788	t		gcesareni	Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis.	SIGNOR-175113	0.501
HDAC1	protein	Q13547	UNIPROT	HSPA5	protein	P11021	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19417144	f	 	miannu	 We show the involvement of HDAC1 in the negative regulation of the Grp78 promoter not only by its induction in the presence of the HDAC inhibitors trichostatin A and MS-275 but also by exogenous overexpression and small interfering RNA knockdown of specific HDACs.	SIGNOR-254227	0.264
AP1G2	protein	O75843	UNIPROT	NEDD4	protein	P46934	UNIPROT	up-regulates activity	binding			9606	BTO:0001950								18772139	t		miannu	Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination. 	SIGNOR-272636	0.41
KATNAL2	protein	Q8IYT4	UNIPROT	TUBE1	protein	Q9UJT0	UNIPROT	down-regulates quantity by destabilization	binding			10090	BTO:0001363								29136647	t		miannu	KATNAL2 does not sever microtubules composed of α- and β-tubulin but does interact with δ- and ε-tubulin	SIGNOR-267176	0.2
ITCH	protein	Q96J02	UNIPROT	CFLAR	protein	O15519	UNIPROT	down-regulates quantity	ubiquitination			10090									16469705	t		gcesareni	Depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation.	SIGNOR-245307	0.601
CDK2	protein	P24941	UNIPROT	CCDC6	protein	Q16204	UNIPROT	up-regulates	phosphorylation	Ser244	QPVSAPPsPRDISME	9606									14712216	t		amattioni	Serine 244 phosphorylation is required for h4 apoptotic function.	SIGNOR-121198	0.2
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser64	EPGTPPSsPLSAEQL	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276090	0.292
CSNK2A1	protein	P68400	UNIPROT	ACACA	protein	Q13085	UNIPROT	unknown	phosphorylation	Ser29	GSVSEDNsEDEISNL	-1									2900140	t		llicata	These results show that casein kinase-2 phosphorylates site 6 exclusively 	SIGNOR-250823	0.311
PLK1	protein	P53350	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Thr12	DLSGRELtIDSIMNK	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276202	0.389
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates activity	phosphorylation	Thr12	DLSGRELtIDSIMNK	-1									26119734	t		miannu	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276203	0.2
MLLT3	protein	P42568	UNIPROT	SCNN1A	protein	P37088	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0005545								20159978	f	Regulation	miannu	AF9/MLLT3 contributes to the regulation of the gene encoding the epithelial sodium channel alpha, ENaCalpha, in renal tubular cells. Specifically, increases in AF9 protein lead to a reduction in ENaCalpha expression and changes in AF9 activity appear to be an important component of aldosterone signaling in the kidney.	SIGNOR-251944	0.276
MAPK10	protein	P53779	UNIPROT	MAPK8IP3	protein	Q9UPT6	UNIPROT	up-regulates	phosphorylation	Thr275	TTGTKSNtPTSSVPS	9606									15767678	t		gcesareni	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134533	0.738
PLK1	protein	P53350	UNIPROT	TOP2A	protein	P11388	UNIPROT	up-regulates	phosphorylation	Ser1525	PIKYLEEsDEDDLF	9606									18171681	t		llicata	Plk1 phosphorylates ser(1337) and ser(1524) of topoiialpha plk1-associated phosphorylation is essential for the functions of topoiialpha in mitosis	SIGNOR-160237	0.493
HLTF	protein	Q14527	UNIPROT	OCA2	protein	Q04671	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000847								22234890	f	 	miannu	The SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species.In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression.	SIGNOR-254425	0.36
MAPK1	protein	P28482	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates activity	phosphorylation	Ser151	VARSNPKsPQKPIVR	9606	BTO:0000848								21478863	t			We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction	SIGNOR-259920	0.612
ATM	protein	Q13315	UNIPROT	UCHL3	protein	P15374	UNIPROT	up-regulates activity	phosphorylation	Ser75	EEEEKIKsQGQDVTS										27941124	t		lperfetto	The deubiquitinase UCHL3 is phosphorylated and activated by ATM. UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2. |Mutation of S75 (S75A) abolished the pSQ/TQ signal, suggesting that S75 is a major ATM phosphorylation site following DNA damage	SIGNOR-275910	0.336
MAPK9	protein	P45984	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates	phosphorylation	Ser168	SEMKYLGsPITTVPK	9606									20220133	t		gcesareni	Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset.	SIGNOR-164093	0.384
INSR	protein	P06213	UNIPROT	GYS1	protein	P13807	UNIPROT	up-regulates activity				9606		BTO:0000887;BTO:0001103							10909964	f		lperfetto	In skeletal muscle, insulin activates glycogen synthase by reducing phosphorylation at both NH2- and COOH-terminal sites of the enzyme and by elevating the levels of glucose-6-phosphate, an allosteric activator of glycogen synthase.	SIGNOR-236803	0.374
BMP4	protein	P12644	UNIPROT	BMPR1A	protein	P36894	UNIPROT	up-regulates	binding												26330344	t		fferrentino	BMP interacts with specific receptors on the cell surface, BMP receptor types 1 and 2 (BMPr1 and BMPr2).	SIGNOR-253548	0.887
PTPN9	protein	P43378	UNIPROT	GHR	protein	P10912	UNIPROT	down-regulates	dephosphorylation			9606									12907755	t		fspada	Using ghr hyper-phosphorylated by elk kinase, we have identified tc-ptp, ptp- , pyst-2, sap1, meg-2, ptp1b, and ptph1 as having substrate specificity for this receptor. In addition, we have shown that these same ptps (or rather their nonmutated counterparts) can dephosphorylate the ghr.	SIGNOR-104577	0.319
ATM	protein	Q13315	UNIPROT	DBF4	protein	Q9UBU7	UNIPROT	down-regulates	phosphorylation	Ser539	GLITINSsQEHLTVQ	9606									22123827	t		lperfetto	Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication.	SIGNOR-177797	0.385
IGF1	protein	P05019	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates	binding			9606									19029956	t		lperfetto	At the cellular level, the ligands IGF1, IGF2 and insulin bind to various members of the insulin receptor (IR) - IGF1 receptor (IGF1R) family.	SIGNOR-182484	0.955
PSEN1	protein	P49768	UNIPROT	gamma-secretase	complex	SIGNOR-C98	SIGNOR	up-regulates	cleavage			9606									10593990	t	Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface.	lperfetto	Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains.	SIGNOR-217743	0.956
acetylsalicylic acid	chemical	CHEBI:15365	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates	chemical inhibition			9606									11809688	t		gcesareni	Nsaids inhibit cyclooxygenase (cox) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which nsaids exert their antitumorigenic effects.	SIGNOR-114380	0.8
VCP	protein	P55072	UNIPROT	UFD1	protein	Q92890	UNIPROT	up-regulates activity	binding			9606									20442859	t		miannu	These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes.	SIGNOR-252424	0.2
F2RL2	protein	O00254	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257409	0.357
IKZF3	protein	Q9UKT9	UNIPROT	B_cell_maturation	phenotype	SIGNOR-PH15	SIGNOR	up-regulates activity				10090	BTO:0004731								14718515	f			Here we show that the Ikaros family member, Aiolos, is specifically required for the generation of these plasma cells. Failure to generate high affinity plasma cells in the BM and to sustain serum antibody titers is apparent after both primary and secondary immunization of Aiolos−/− mice with a range of hapten concentrations.	SIGNOR-259952	0.7
GRID1	protein	Q9ULK0	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial.	SIGNOR-264951	0.8
VAV1	protein	P15498	UNIPROT	GRAP	protein	Q13588	UNIPROT	up-regulates	binding			9606									7809090	t		gcesareni	Here we report that both in cell extracts and within intact mammalian cells vav binds to grb2 (sem-5/ash/drk), an adaptor molecule which plays a key role in ras activation.	SIGNOR-33840	0.302
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	up-regulates				9606									25720354	f		scontino	APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. 	SIGNOR-267857	0.7
Av/b1 integrin	complex	SIGNOR-C175	SIGNOR	POU5F1	protein	Q01860	UNIPROT	up-regulates quantity by expression				10090									18757303	f		lperfetto	Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1.	SIGNOR-253272	0.341
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SMN complex	complex	SIGNOR-C158	SIGNOR	up-regulates quantity by stabilization	phosphorylation			9606	BTO:0000007								19103745	t		lperfetto	PKA increases SMN complex formation and SMN stability.	SIGNOR-253122	0.2
YAP1	protein	P46937	UNIPROT	MYF6	protein	P23409	UNIPROT	down-regulates				9606	BTO:0000222;BTO:0002314	BTO:0000887;BTO:0001103							23038772	f		gcesareni	Myf6 (mrf4) is repressed by hyap1 s127a overexpression.	SIGNOR-199075	0.2
DACH1	protein	Q9UI36	UNIPROT	Six1/Dach	complex	SIGNOR-C122	SIGNOR	form complex	binding			10090									14628042	t		llicata	The phosphatase function of Eya switches the function of Six1-Dach from repression to activation,	SIGNOR-238026	0.615
CD163	protein	Q86VB7	UNIPROT	hb:hp	complex	SIGNOR-C149	SIGNOR	down-regulates quantity by destabilization	binding			9606									11854029	t		miannu	CD163 was identified as the endocytic receptor binding hemoglobin (Hb) in complex with the plasma protein haptoglobin (Hp). This specific receptor-ligand interaction leading to removal from plasma of the Hp-Hb complex-but not free Hp or Hb-now explains the depletion of circulating Hp in individuals with increased intravascular hemolysis. 	SIGNOR-251823	0.735
PIAS3	protein	Q9Y6X2	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	binding			9606									14691252	t		lperfetto	We have further shown that PIAS3, Smad3, and p300 can form a ternary complex, which is significantly increased by TGF-_ treatment. Taken together, these results suggest that PIAS3 stimulates Smad transcriptional activity through formation of a complex with Smad proteins and p300/CBP.	SIGNOR-217725	0.58
CDK2	protein	P24941	UNIPROT	SF3B1	protein	O75533	UNIPROT	up-regulates	phosphorylation	Thr248	GSETPGAtPGSKIWD	9606			SIGNOR-C16						12105215	t		gcesareni	To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptides. Three phosphorylation sites were identified as thr244, thr248, and thr313	SIGNOR-90438	0.354
DPYD	protein	Q12882	UNIPROT	thymine	smallmolecule	CHEBI:17821	ChEBI	down-regulates quantity	chemical modification												10499634	t			Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil.	SIGNOR-253989	0.8
PRKACA	protein	P17612	UNIPROT	GNA13	protein	Q14344	UNIPROT	down-regulates activity	phosphorylation	Thr203	ILLARRPtKGIHEYD	9534									12399457	t		miannu	PKA directly phosphorylates Galpha(13). Galpha(13)-T203A mutant (in COS-7 cells) could not be phosphorylated by PKA. PKA blocks Rho activation by phosphorylation of Galpha(13) Thr(203).	SIGNOR-249985	0.373
SRC	protein	P12931	UNIPROT	PTK2B	protein	Q14289	UNIPROT	up-regulates	phosphorylation	Tyr402	CSIESDIyAEIPDET	9606									15695828	t		llicata	These data indicate that pyk2 activation via phosphorylation at tyr-402 requires ?V?3 Ligation and src activity.	SIGNOR-133870	0.607
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation			9606									12510059	t	inferred from 70% family members	gcesareni	Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1.	SIGNOR-270132	0.2
CDK5R1	protein	Q15078	UNIPROT	CDK5	protein	Q00535	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								10604467	t			Cyclin-dependent kinase 5 (Cdk5) is required for proper development of the mammalian central nervous system. To be activated, Cdk5 has to associate with its regulatory subunit, p35. We have found that p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's disease. This accumulation correlates with an increase in Cdk5 kinase activity. Unlike p35, p25 is not readily degraded, and binding of p25 to Cdk5 constitutively activates Cdk5, changes its cellular location and alters its substrate specificity.	SIGNOR-268153	0.942
RAC1	protein	P63000	UNIPROT	BAIAP2	protein	Q9UQB8	UNIPROT	up-regulates	binding			9606									11130076	t		gcesareni	Here we demonstrate that irsp53, a substrate for insulin receptor with unknown function, is the 'missing link' between rac and wave. Activated rac binds to the amino terminus of irsp53, and carboxy-terminal src-homology-3 domain of irsp53 binds to wave to form a trimolecular complex.	SIGNOR-85302	0.728
CDK1	protein	P06493	UNIPROT	PTHLH	protein	P12272	UNIPROT	down-regulates	phosphorylation	Thr121	YKEQPLKtPGKKKKG	9606									10373465	t		lperfetto	Phosphorylation at the cyclin-dependent kinases site (thr85) of parathyroid hormone-related protein negatively regulates its nuclear localization	SIGNOR-68544	0.2
RPS6KA5	protein	O75582	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser383	IHFWSTLsPIAPRSP	9606	BTO:0000150	BTO:0000975							11145955	t		gcesareni	Phosphorylation on ser383 and ser389 of elk-1 by mapk enhances this basal binding but, most importantly, elk-1 exhibits new interactions with p300.	SIGNOR-85514	0.2
Daunorubicin hydrochloride	chemical	CHEBI:31456	ChEBI	TOP2B	protein	Q02880	UNIPROT	down-regulates activity	chemical inhibition			9606									1963303	t		miannu	DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives. 	SIGNOR-259323	0.8
fulvestrant	chemical	CHEBI:31638	ChEBI	ESR1	protein	P03372	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000150								12113237	t		miannu	Fulvestrant (Faslodex, formerly ICI 182,780) is a potent steroidal antiestrogen that mediates its effects by estrogen receptor downregulation.	SIGNOR-259305	0.8
TRPV4	protein	Q9HBA0	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000443								23021218	f		lperfetto	TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance.	SIGNOR-253095	0.2
BRCA2	protein	P51587	UNIPROT	D1-D2-G-X3 complex	complex	SIGNOR-C301	SIGNOR	form complex	binding			9606	BTO:0000567								18212739	t		lperfetto	These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). 	SIGNOR-263256	0.793
CDK9	protein	P50750	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser206	SSSTYPHsPTSSDPG	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161573	0.325
MAPK1	protein	P28482	UNIPROT	KHDRBS1	protein	Q07666	UNIPROT	up-regulates	phosphorylation	Thr84	TVGGPAPtPLLPPSA	9606									12478298	t		lperfetto	In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites	SIGNOR-96418	0.652
STX10	protein	O60499	UNIPROT	LE-TGN SNARE	complex	SIGNOR-C157	SIGNOR	form complex	binding			9606	BTO:0000567								18195106	t		lperfetto	We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport	SIGNOR-253080	0.754
CHFR	protein	Q96EP1	UNIPROT	PLK1	protein	P53350	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									17442268	t		miannu	Chfr, a mitotic stress checkpoint, plays an important role in cell cycle progression, tumor suppression and the processes that require the E3 ubiquitin ligase activity mediated by the RING finger domain. Chfr stimulates the formation of polyubiquitin chains by ub-conjugating enzymes, and induces the proteasome-dependent degradation of a number of cellular proteins including Plk1 and Aurora A.	SIGNOR-271464	0.481
UBE2O	protein	Q9C0C9	UNIPROT	SMAD6	protein	O43541	UNIPROT	down-regulates	ubiquitination	Lys173	LLLEQELkTVTYSLL	9606									23455153	t		gcesareni	We showed that ube2o functions as an e2-e3 hybrid to monoubiquitinate smad6 at lysine 174	SIGNOR-192255	0.477
GPR183	protein	P32249	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256994	0.2
TAOK1	protein	Q7L7X3	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates	phosphorylation			9606									23431053	t		gcesareni	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.	SIGNOR-201324	0.375
ABL1	protein	P00519	UNIPROT	ATR	protein	Q13535	UNIPROT	up-regulates	phosphorylation	Tyr291	DTDQLKLyEEPLSKL	9606									20798688	t		lperfetto	C-abl can phosphorylate atr on y291 and y310 and this phosphorylation appears to have a positive role in atr activation under genotoxic stress.	SIGNOR-167632	0.582
F2RL3	protein	Q96RI0	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256915	0.2
SRC	protein	P12931	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates	phosphorylation	Tyr833	EQCEYLSyDASQWEF	9606									20431062	t		lperfetto	Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk.	SIGNOR-165051	0.491
BCOR	protein	Q6W2J9	UNIPROT	HDAC3	protein	O15379	UNIPROT	up-regulates activity	binding			9606									10898795	t		miannu	BCoR can interact w Because HDACs appear to be involved in repression by an increasing number of transcriptional repressors, we tested whether BCoR can associate with HDACs. BCoR can interact with HDAC1, HDAC3, and HDAC-B/5 more strongly than with HDAC-A/4, HDAC-C, HDAC-D, and HDAC-E. 	SIGNOR-252237	0.317
CARD11	protein	Q9BXL7	UNIPROT	BCL10	protein	O95999	UNIPROT	up-regulates	binding			9606									12356734	t		gcesareni	Card11 cooperates with bcl10 in a card domain-dependent manner.;These results implicate card11 in factor- specific activation of nf-kappab	SIGNOR-93869	0.841
MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	NOTCH2	protein	Q04721	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000578								31659254	t		miannu	Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription. 	SIGNOR-265561	0.275
AGPAT3	protein	Q9NRZ7	UNIPROT	1-acyl-sn-glycerol 3-phosphate(2-)	smallmolecule	CHEBI:57970	ChEBI	down-regulates quantity	chemical modification			9606									21173190	t		lperfetto	The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA). 	SIGNOR-267009	0.8
Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	up-regulates				9606									33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors	SIGNOR-268579	0.2
1-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-2-methoxyphenyl)-3-(1-(thiazol-2-yl)ethyl)urea	chemical	CID:9869779	PUBCHEM	CSF1R	protein	P07333	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258126	0.8
CDK1	protein	P06493	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates	phosphorylation	Ser55	TSRSLYAsSPGGVYA	9606									7983050	t		llicata	These results strongly suggest that cdc2 kinase is the kinase which phosphorylates vimentin ser55 in the entire cytoplasm during mitosis and that the appearance of immunoreactivities with antibody 4a4 in cell staining indeed reflect the vimentin phosphorylation by cdc2 kinase. immunofluorescent evidence using antibody 4a4 and biochemical analysis using vimentin ser55 peptide showed that the degree of disassembly of vimentin filament of various cell types at early mitotic phase correlated well with the amount of mitotically activated cdc2 kinase.	SIGNOR-35492	0.369
IDH2	protein	P48735	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	chemical modification			9606									29090344	t		miannu	Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases. 	SIGNOR-253134	0.8
RIMS3	protein	Q9UJD0	UNIPROT	RAB3C	protein	Q96E17	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								31679900	t		miannu	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264380	0.262
Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	CDKN2A	protein	P42771	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22469984	t		irozzo	The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a	SIGNOR-256122	0.345
ICAM1	protein	P05362	UNIPROT	ITGAX	protein	P20702	UNIPROT	up-regulates	binding			9606									7679388	t		gcesareni	Using assays to quantify cd11c-mediated cell adhesion, we demonstrate that cd11c recognizes icam-2 and vcam-1. The cd11c-binding site on vcam-1 appears to be different from that used by the integrin alpha4.	SIGNOR-31388	0.667
ABT-737	chemical	CID:11228183	PUBCHEM	BCL2L2	protein	Q92843	UNIPROT	down-regulates	chemical inhibition			9606									17200714	t		gcesareni	A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells.	SIGNOR-151790	0.8
CSNK1E	protein	P49674	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation	Ser1430	LGYVPHPsSLSGSLP	9606									16513652	t		gcesareni	We find that ckiepsilon binds to lrp5 and lrp6 in vitro and in vivo and identify three ckiepsilon-specific phosphorylation sites in lrp6. Two of the identified phosphorylation sites, ser1420 and ser1430, influence wnt signaling in vivo,	SIGNOR-145053	0.266
NRXN3	protein	Q9HDB5	UNIPROT	NLGN2	protein	Q8NFZ4	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							22626546	t		miannu	 The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites	SIGNOR-265456	0.82
BMPR2	protein	Q13873	UNIPROT	ACVR1	protein	Q04771	UNIPROT	up-regulates	binding			9606									7791754	t		gcesareni	Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.	SIGNOR-33434	0.701
PRKACA	protein	P17612	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	phosphorylation	Ser552	QDTQRRTsMGGTQQQ	9606									16476742	t		lperfetto	In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin	SIGNOR-144478	0.459
VAV1	protein	P15498	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			9606	BTO:0001271								9209406	t		gcesareni	Recently, we have shown that the proto-oncogene vav product (vav) is also tyrosine-phosphorylated by treatment with gm-csf and epo and is constitutively associated with the sh3 domain of grb2/ash in ut-7.	SIGNOR-49362	0.671
TFDP1	protein	Q14186	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253862	0.492
FBN1	protein	P35555	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity				9606									17242066	f	Regulation	miannu	Fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling. 	SIGNOR-251889	0.374
PTPRJ	protein	Q12913	UNIPROT	PLCG1	protein	P19174	UNIPROT	down-regulates	dephosphorylation			9606									11259588	t		miannu	Cd148 can dephosphorylate lat and plc?1 In vitro. / plc?1 Undergoes inducible tyrosine phosphorylation following tcr stimulation (46), and this phosphorylation is required to stimulate its catalytic activity	SIGNOR-105790	0.376
GRK1	protein	Q15835	UNIPROT	GRK1	protein	Q15835	UNIPROT	down-regulates activity	phosphorylation	Thr492	QDVGAFStVKGVAFD	-1									1527025	t			The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase.	SIGNOR-251188	0.2
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Cys)	smallmolecule	CHEBI:29167	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269484	0.8
MAPK1	protein	P28482	UNIPROT	LIMA1	protein	Q9UHB6	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser362	PVHPKPLsPDSRASS	9606	BTO:0001033								23188829	t		miannu	Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover.	SIGNOR-263054	0.2
L-serine zwitterion	smallmolecule	CHEBI:33384	ChEBI	L-cystathionine dizwitterion	smallmolecule	CHEBI:58161	ChEBI	up-regulates quantity	precursor of			9606									23981774	t		lperfetto	Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. 	SIGNOR-275827	0.8
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	ITGB7	protein	P26010	UNIPROT	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259009	0.2
CDK1	protein	P06493	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	down-regulates	phosphorylation	Ser728	VVKQEQLsPKKKENN	9606			SIGNOR-C17						22163316	t		gcesareni	We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase.	SIGNOR-195233	0.377
IRF9	protein	Q00978	UNIPROT	STAT2	protein	P52630	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								9242679	t		lperfetto	Coimmunoprecipitation assays demonstrate p48 association with STAT2 but not STAT1.The studies demonstrate the in vivo existence of a STAT2.p48 complex and a distinct STAT2.STAT1 complex after IFN-alpha stimulation. Data suggest that distinct bipartite complexes STAT2.p48 and STAT2.STAT1 translocate to the nucleus and associate on the DNA target site as ISGF3.	SIGNOR-217806	0.919
CKM complex	complex	SIGNOR-C406	SIGNOR	SMAD1	protein	Q15797	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser195	PNSSYPNsPGSSSST	9606									19914168	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-273152	0.346
CAMKK1	protein	Q8N5S9	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Thr308	KDGATMKtFCGTPEY										10833263	t		llicata	Protein kinase B (PKB) was recently reported to be activated on the phosphorylation of Thr(308) by Ca(2+)/calmodulin-dependent protein kinase kinase alpha (CaM-kinase kinase alpha), suggesting that PKB was regulated through not only the phosphoinositide 3-kinase pathway but also the Ca(2+)/calmodulin protein kinase pathway.	SIGNOR-252609	0.387
PRKACA	protein	P17612	UNIPROT	GMFB	protein	P60983	UNIPROT	up-regulates activity	phosphorylation	Ser83	QHDDGRVsYPLCFIF	-1									9030586	t		miannu	Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82.	SIGNOR-249983	0.311
PTK2	protein	Q05397	UNIPROT	ATP2B4	protein	P23634-6	UNIPROT	up-regulates activity	phosphorylation	Tyr1176	LDGEVTPyANTNNNA	9606									12540962	t		miannu	 Results of co-immunoprecipitation, treatment with tyrosine kinase inhibitors and integrin inhibition experiments suggest that FAK is responsible for PMCA4b tyrosine phosphorylation during platelet activation. equence analysis indicates that Y(1176) is a likely substrate for focal adhesion kinase (FAK), while Y(1122) is not located in a tyrosine phosphorylation motif.	SIGNOR-263194	0.2
superoxide	smallmolecule	CHEBI:18421	ChEBI	SOD2	protein	P04179	UNIPROT	up-regulates activity	precursor of			9606									29301787	t		lperfetto	Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD).	SIGNOR-272284	0.8
CTLA4	protein	P16410	UNIPROT	T cell exhaustion 	phenotype	SIGNOR-PH221	SIGNOR	up-regulates				9606	BTO:0000782								26086965	f		Barakat	 Both PD-1 and CTLA-4 inhibited the activity of Akt, a crucial molecular in regulating glucose metabolism of T cells by elevating glucose transporter 1 expression and glycolysis, suggesting that glucose metabolism may contribute to T-cell exhaustion	SIGNOR-275415	0.7
cyclosporin A	chemical	CHEBI:4031	ChEBI	PPP3CA	protein	Q08209	UNIPROT	down-regulates	chemical inhibition			9606									15276472	t		gcesareni	Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins.	SIGNOR-127225	0.8
PTPN1	protein	P18031	UNIPROT	NTRK2	protein	Q16620	UNIPROT	down-regulates activity	dephosphorylation	Tyr707	DVYSTDYyRVGGHTM	9606									26214522	t		Luana	Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling	SIGNOR-264553	0.388
CILK1	protein	Q9UPZ9	UNIPROT	CILK1	protein	Q9UPZ9	UNIPROT	up-regulates	phosphorylation	Tyr159	SKPPYTDyVSTRWYR	9606									15988018	t		lperfetto	Ick is activated by dual phosphorylation of the tdy motif. Phosphorylation of tyr-159 in the tdy motif requires ick autokinase activity	SIGNOR-138424	0.2
ITGA6	protein	P23229	UNIPROT	A6/b4 integrin	complex	SIGNOR-C174	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253199	0.761
CAPN2	protein	P17655	UNIPROT	CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	up-regulates activity	cleavage			9606	BTO:0000590								25969760	t		lperfetto	Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain	SIGNOR-251608	0.551
9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone	chemical	CID:71748056	PUBCHEM	JAK3	protein	P52333	UNIPROT	down-regulates activity	chemical inhibition			-1									24556163	t		miannu	This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine 	SIGNOR-262234	0.8
PRKACA	protein	P17612	UNIPROT	LASP1	protein	Q14847	UNIPROT	up-regulates activity	phosphorylation	Ser99	KNKGKGFsVVADTPE	-1									12432067	t		miannu	Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146	SIGNOR-250075	0.311
MAPK3	protein	P27361	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates	phosphorylation	Ser643	KILIASPsPTHIHKE	9606	BTO:0000567								18519666	t		lperfetto	We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_	SIGNOR-178735	0.688
MAP3K8	protein	P41279	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates	phosphorylation	Ser244	GTHYSVQsDIWSMGL	9606									8131746	t		gcesareni	Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf	SIGNOR-36453	0.556
Interferon-type-I	proteinfamily	SIGNOR-PF50	SIGNOR	IFITMs	proteinfamily	SIGNOR-PF49	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									25599080	f		miannu	The IFITM (interferon-induced transmembrane) proteins comprise a family of interferon-induced antiviral cell-intrinsic restriction factors with high constitutive expression in many cells, including barrier epithelial cells. As their names imply, the expression of human IFITM1, IFITM2, and IFITM3 is also strongly upregulated by both type I and type II interferons	SIGNOR-260220	0.2
CAPN1	protein	P07384	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Phe59	GVTVETVfSVDEFSA	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263580	0.301
CSNK2A1	protein	P68400	UNIPROT	PTPRC	protein	P08575	UNIPROT	up-regulates	phosphorylation	Ser1001	SKESEHDsDESSDDD	9606									10066810	t		gcesareni	Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein,	SIGNOR-65281	0.453
ELK1	protein	P19419	UNIPROT	MUC4	protein	Q99102	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001861								19757157	t	 	lperfetto	Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level.	SIGNOR-254096	0.2
SPI1	protein	P17947	UNIPROT	B-Lymphocyte_diff	phenotype	SIGNOR-PH113	SIGNOR	up-regulates activity				10090									10203717	f			PU.1 regulates the expression of several genes, including those encoding immunoglobulins, receptors and enzymes. The expression of these genes is crucial for macrophage and B-cell differentiation and for the functional activity of neutrophils.	SIGNOR-259955	0.7
STK3	protein	Q13188	UNIPROT	LATS1	protein	O95835	UNIPROT	up-regulates	phosphorylation	Ser909	HQRCLAHsLVGTPNY	9606	BTO:0000007								15688006	t	Two of these, S909 and T1079, were required for Lats1 activation.	milica	Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1.	SIGNOR-133544	0.603
ROCK1	protein	Q13464	UNIPROT	ARHGAP24	protein	Q8N264	UNIPROT	up-regulates activity	phosphorylation	Ser574	NSNSCRSsTTTCPEQ	9606	BTO:0000007								16862148	t		lperfetto	ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2).	SIGNOR-249303	0.444
SMAD1	protein	Q15797	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				10090	BTO:0002729								23993924	f		flangone	Engagement of BMP4-mediated signaling in adult mouse ovary-derived OSCs cultured in vitro drives differentiation of these cells into IVD oocytes through Smad1/5/8 activation and transcriptional up-regulation of key meiosis-initiating genes.	SIGNOR-255259	0.7
DNMT1	protein	P26358	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001570								23242655	f	 	 	Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells.	SIGNOR-254027	0.41
DOK1	protein	Q99704	UNIPROT	ITGB1	protein	P05556	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257669	0.32
AURKB	protein	Q96GD4	UNIPROT	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates	phosphorylation	Ser239	QKVAERRsSPLLRRK	9606									22865920	t		lperfetto	We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions	SIGNOR-198654	0.266
DIO2	protein	Q92813	UNIPROT	L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	down-regulates quantity	chemical modification			9606									8755651	t		scontino	Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5’-position) to yield T4	SIGNOR-266949	0.8
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2N	protein	P61088	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271320	0.85
AP-2 complex	complex	SIGNOR-C245	SIGNOR	SYNJ1	protein	O43426	UNIPROT	up-regulates activity	binding			10116									15496985	t		Giorgia	Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs	SIGNOR-260396	0.5
PPP2CA	protein	P67775	UNIPROT	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	dephosphorylation	Ser394	EDAVHEDsGDEDGED	9606									30050113	t		miannu	In contrast, in the present work, PPP2CA reduced HDAC2 S394 phosphorylation.|We postulated that PPP2CA would negatively regulate phospho dependent HDAC2 activity.	SIGNOR-277049	0.285
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GNMT	protein	Q14749	UNIPROT	unknown	phosphorylation	Ser10	DSVYRTRsLGVAAEG	-1									12697024	t		miannu	 Activation of cAMP-dependent protein kinase by dibutyryl-cAMP, reported to cause GNMT phosphorylation under cell-free conditions, also had little effect on hepatocytic AdoMet and AdoHcy levels. Phosphorylation of GNMT would thus seem to play no role in regulation of the intracellular AdoMet/AdoHcy ratio, but could be involved in other GNMT functions, such as the binding of folates or aromatic hydrocarbons. The amino acid sequence surrounding Ser-10 (Val-Tyr-Arg-Thr-Arg-SerLeu-Gly-Val-Ala-Ala) could possibly qualify as a recognition site for AMPK as well as for PKA [32], the latter enzyme being capable of phosphorylating GNMT in intact hepatocytes (present study) as well as under cell-free conditions	SIGNOR-263151	0.2
PTK2B	protein	Q14289	UNIPROT	SNCA	protein	P37840	UNIPROT	unknown	phosphorylation	Tyr125	VDPDNEAyEMPSEEG	9534	BTO:0000298								12096713	t		lperfetto	The present report demonstrates that the protein tyrosine kinase Pyk2/RAFTK is involved in cell stress-induced tyrosine phosphorylation of alpha S. Hyperosmotic stress induced tyrosine phosphorylation of alpha S via Pyk2/RAFTK at tyrosine residue 125.	SIGNOR-249151	0.32
TFEB	protein	P19484	UNIPROT	FABP3	protein	P05413	UNIPROT	up-regulates quantity by expression	transcriptional regulation												32978159	f		lperfetto	On the contrary, proteins increasing the most included those degraded by autophagy (e.g., SQSTM1/p62 and GABARAPL2	SIGNOR-276790	0.2
TNF	protein	P01375	UNIPROT	SCN3A	protein	Q9NY46	UNIPROT	up-regulates activity				10090									26112872	f		miannu	TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels.	SIGNOR-253494	0.2
MAPK1	protein	P28482	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	unknown	phosphorylation			9606									21071439	t		lperfetto	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-217574	0.387
LCK	protein	P06239	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	phosphorylation	Tyr319	TSVYESPySDPEELK	10090	BTO:0000782								10037717	t			 the protein tyrosine kinase (PTK) ZAP-70 is rapidly phosphorylated on several tyrosine residues, presumably by two mechanisms: an autophosphorylation and a trans-phosphorylation by the Src-family PTK Lck. we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function	SIGNOR-251393	0.601
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1787	SPNYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120124	0.316
axitinib	chemical	CHEBI:66910	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150								21297102	t		gcesareni	Inhibitors for fgf (azd4547), vegf, or pdgf receptors (axitinib), but not that for tgf receptor (ly364947), significantly decreased the abundance of (pcna) in endothelial cells.	SIGNOR-171869	0.8
THR	proteinfamily	SIGNOR-PF84	SIGNOR	RARB	protein	P10826	UNIPROT	up-regulates activity	binding			9606									15650024	t	inferred from family member	gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs	SIGNOR-267780	0.2
MAPK9	protein	P45984	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser38	SVPEFPLsPPKKKDL	9606									20630875	t		gcesareni	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress.	SIGNOR-166698	0.259
BCL10	protein	O95999	UNIPROT	NFKB1	protein	P19838	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14695475	f		Barakat	The adaptor protein Bcl10 promotes activation of NF-κB transcription factors through paracaspase- and UBC13-dependent ubiquitination of NEMO.	SIGNOR-274145	0.507
CSNK1E	protein	P49674	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	phosphorylation	Ser403	ESTDSGLsMSSYSVP	9606							phosphorylation:Ser127	PQHVRAHsSPASLQL	23431053	t		milica	Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by Casein Kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ	SIGNOR-201170	0.401
PPM1D	protein	O15297	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates activity	dephosphorylation			9606									19713933	t		lperfetto	In addition, wip1 can dephosphorylate atm, as well as other components of the dna damage checkpoint, such as p38.	SIGNOR-187770	0.456
STAT3	protein	P40763	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0003298	BTO:0001103							30029643	f			In summary, our results indicate IL-15 can stimulate the proliferation of FAPs through Jak-STAT pathway.	SIGNOR-256256	0.7
9-cis-retinoic acid	chemical	CHEBI:50648	ChEBI	RARB	protein	P10826	UNIPROT	up-regulates activity	chemical activation			9606									18321241	t		miannu	Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma).	SIGNOR-259235	0.8
PRKAA1	protein	Q13131	UNIPROT	RRN3	protein	Q9NYV6	UNIPROT	down-regulates	phosphorylation	Ser635	DTHFRSPsSSVGSPP	9606			SIGNOR-C15						19815529	t		llicata	We show that ampk down-regulates rrna synthesis under glucose restriction by phosphorylating the rna polymerase i (pol i)-associated transcription factor tif-ia at a single serine residue (ser-635).	SIGNOR-188403	0.2
PAICS	protein	P22234	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	down-regulates quantity	chemical modification			9606									33179964	t		miannu	The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS).	SIGNOR-267321	0.8
ATM	protein	Q13315	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	unknown	phosphorylation	Ser25	PCLIIEDsQPESQVL	9606									12697768	t		llicata	To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1	SIGNOR-100641	0.869
CDK3	protein	Q00526	UNIPROT	CABLES1	protein	Q8TDN4	UNIPROT	unknown	phosphorylation	Ser273	PGQGGSTsAFEQLQR	9534									11733001	t		miannu	P70ik3-1 is phosphorylated by either cyclin A/cdk3 or cyclin E/cdk3 reconstituted in COS7 cells. Accordingly, we can conclude that in COS7 cells, Ser274 in p70ik3-1 is phosphorylated by endogenous kinases other than cdk5 (Fig. 4), at least one of which is cdk3 as shown in this work. Currently, however, the question of how ik3-1 function is modified by its cdk3-mediated phosphorylation of Ser274 remains to be adressed.	SIGNOR-250679	0.494
MAPK3	protein	P27361	UNIPROT	PGR	protein	P06401	UNIPROT	down-regulates	phosphorylation	Ser294	APMAPGRsPLATTVM	9606	BTO:0000150								10655479	t		gcesareni	Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation.	SIGNOR-74716	0.543
RUNX2	protein	Q13950	UNIPROT	COL1A1	protein	P02452	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11331591	f	Osteoblast-like cell lines	lpetrilli	In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast differentiation, including alkaline phosphatase, a1 and a2 collagen, osteopontin and osteoprotegerin ligand.	SIGNOR-107163	0.465
MEN1	protein	O00255	UNIPROT	MLL-ENL	fusion protein	SIGNOR-FP7	SIGNOR	up-regulates activity	binding			10090	BTO:0004730								16239140	t		irozzo	We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...].	SIGNOR-255866	0.2
TAL1	protein	P17542	UNIPROT	UBE2H	protein	P62256	UNIPROT	up-regulates quantity by expression	transcriptional regulation												20028976	t		lperfetto	Tal1 expression activated UBE2H expression, whereas Tal1 knock-down reduced UBE2H expression and ubiquitin transfer activity.|Binding of Tal1 to UBE2H was confirmed by chromatin immunoprecipitation.	SIGNOR-269000	0.333
BIRC7	protein	Q96CA5	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	down-regulates	binding			9606	BTO:0000848								15485396	t		gcesareni	These results suggest that ml-iap might regulate apoptosis by sequestering smac and preventing it from antagonizing xiap-mediated caspases, rather than by direct caspases.	SIGNOR-129869	0.688
MIB2	protein	Q96AX9	UNIPROT	RIPK1	protein	Q13546	UNIPROT	down-regulates activity	polyubiquitination	Lys634	KVYQMLQkWVMREGI	9606	BTO:0000815								29642005	t		miannu	Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation.  We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. MIB2 Ubiquitylates RIPK1 at Lysines K377 and K634	SIGNOR-272663	0.299
PDPK1	protein	O15530	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	phosphorylation			9606									21798082	t		lperfetto	Positive feedback involves mtorc2, which phosphorylates akt at serine 473, a phosphorylation required for maximum activation of akt in addition to phosphorylation at threonine 308 by pdk1.	SIGNOR-244396	0.736
PTPRE	protein	P23469	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	10116	BTO:0000575								15738637	t			In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver.	SIGNOR-248446	0.289
HIPK2	protein	Q9H2X6	UNIPROT	MECP2	protein	P51608	UNIPROT	up-regulates activity	phosphorylation	SeR80	AVPEASAsPKQRRSI	9606	BTO:0000007								19820693	t		Luana	Here, we identify the homeodomain-interacting protein kinase 2 (HIPK2) as a kinase that binds MeCP2 and phosphorylates it at Ser 80 in vitro and in vivo.	SIGNOR-264549	0.491
IGF1R	protein	P08069	UNIPROT	PDPK1	protein	O15530	UNIPROT	up-regulates	phosphorylation	Tyr373	SEDDEDCyGNYDNLL	-1									20044479	t		lperfetto	IGF-1R Directly Interacts with and Phosphorylates PDK1 in Vitro	SIGNOR-236548	0.348
clomipramine	chemical	CHEBI:47780	ChEBI	SLC6A3	protein	Q01959	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9537821	t		miannu	At the human dopamine transporter, sertraline and nomifensine were the most potent with KD's of 25±2 and 56±3, respectively. Except for these two compounds, most antidepressants were not potent at the human dopamine transporter. 	SIGNOR-258875	0.8
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Ser65	FLMECRNsPVTKTPP	9606	BTO:0000007								12747827	t		lperfetto	Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e.	SIGNOR-236690	0.753
STOML2	protein	Q9UJZ1	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21746876	f		Giorgia	We performed real-time RT-PCR to measure the levels of PGC-1alpha mRNA and found that these were increased in SLP-2hi cells (Fig. 3h), supporting the idea that upregulation of SLP-2 expression is associated with an increase in the expression of mitochondrially targeted genes.	SIGNOR-260379	0.2
WNK3	protein	Q9BYP7	UNIPROT	SLC12A4	protein	Q9UP95	UNIPROT	down-regulates activity	phosphorylation												21613606	t		lperfetto	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264627	0.478
FHL1	protein	Q13642	UNIPROT	RBPJ	protein	Q06330	UNIPROT	down-regulates	binding			9606									9418910	t	With differential splicing resulting in deletion of an exon, KyoT2 lacked two LIM domains from the C terminus and had a frameshift in the last exon, creating the RBP-J-binding region in the C terminus	gcesareni	It was demonstrated by emsa that kyot2 can form a complex with dna-bound rbp-j, but the dna-binding affinity of the kyot2rbp-j complex is greatly weakened and it exists mostly dissociated from dna	SIGNOR-54277	0.669
PPP3CA	protein	Q08209	UNIPROT	DNM2	protein	P50570	UNIPROT	unknown	dephosphorylation	Ser764	LQSASSHsPTPQRRP	10116									20496096	t			CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII).	SIGNOR-248677	0.269
ABCA7	protein	Q8IZY2	UNIPROT	APP	protein	P05067	UNIPROT	down-regulates quantity	relocalization			9606		BTO:0000142							27472885	f		miannu	 Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD.	SIGNOR-265176	0.417
MYC	protein	P01106	UNIPROT	CCND2	protein	P30279	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									7526316	t		gcesareni	C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation.	SIGNOR-27446	0.464
GNGT1	protein	P63211	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606	BTO:0000938								16537363	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt	SIGNOR-252687	0.4
PNCK	protein	Q6P2M8	UNIPROT	EIF4G3	protein	O43432	UNIPROT	up-regulates	phosphorylation	Ser1156	NTFMRGGsSKDLLDN	9606									22514323	t		lperfetto	Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by camki-mediated phosphorylation of ser1156 in eukaryotic initiation factor eif4gii (4gii).	SIGNOR-197190	0.2
ERRFI1	protein	Q9UJM3	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates activity	binding			-1									18046415	t			The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2	SIGNOR-252077	0.73
EGFR	protein	P00533	UNIPROT	CALM1	protein	P0DP23	UNIPROT	down-regulates	phosphorylation	Tyr100	FDKDGNGyISAAELR	9606									3415247	t		lperfetto	Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.	SIGNOR-24778	0.414
PJA1	protein	Q8NG27	UNIPROT	EZH2	protein	Q15910	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000165								28067271	t			Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2	SIGNOR-255664	0.502
GRB2	protein	P62993	UNIPROT	GAB2	protein	Q9UQC2	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271;BTO:0000785								24737791	t		milica	The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival	SIGNOR-204969	0.908
Fibrinolysis	phenotype	SIGNOR-PH6	SIGNOR	Fibrin	complex	SIGNOR-C317	SIGNOR	down-regulates				9606		BTO:0000131							1447176	f		lperfetto	The fibrinolytic system is sequentially composed of plasminogen activation and fibrin degradation [1, 2]. Three distinct inhibitors of the fibrinolytic system that differently regulate these two steps are plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin (α2AP) and thrombin activatable fibrinolysis inhibitor (TAFI) [3]. PAI-1 limits the amount of free tissue-type plasminogen activator (tPA) both in plasma and on vascular endothelial cells (VECs), and regulates plasminogen activation potential to dissolve fibrin	SIGNOR-263532	0.7
GUCA2B	protein	Q16661	UNIPROT	GUCY2C	protein	P25092	UNIPROT	up-regulates	binding			9606									10845107	t		gcesareni	Guanylins activate two receptors, gc-c and ok-gc, which are expressed in intestine and/or kidney.	SIGNOR-78120	0.605
GATA1	protein	P15976	UNIPROT	GFI1B	protein	Q5VTD9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19965638	f		miannu	HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. 	SIGNOR-254430	0.517
tandutinib	chemical	CHEBI:90237	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258299	0.8
RNF19A	protein	Q9NV58	UNIPROT	SNCAIP	protein	Q9Y6H5	UNIPROT	up-regulates quantity	ubiquitination			9606	BTO:0000007								12750386	t		miannu	Ubiquitylation of synphilin-1 by Dorfin. A, synphilin-1 is ubiquitylated in HEK293 cells. Several lines of evidence have suggested that derangements in the ubiquitin-proteasome protein degradation pathway may have a prominent role in the pathogenesis of PD (5). Our present study shows that Dorfin, an E3 ubiquityl ligase, is colocalized with ubiquitin in LBs of PD and physically binds to ubiquitylate synphilin-1, which is known to be a major component of LBs	SIGNOR-271455	0.465
GRK2	protein	P25098	UNIPROT	OPRM1	protein	P35372	UNIPROT	down-regulates activity	phosphorylation	Ser358	EFCIPTSsNIEQQNS	9606	BTO:0000007								12123746	t		gcesareni	These results suggest that two C-terminal amino acids, Ser(355) and Thr(357), are required for short-term homologous desensitization and agonist-induced phosphorylation of mu-opioid receptors expressed in HEK 293 cells	SIGNOR-249661	0.2
COX4I1	protein	P13073	UNIPROT	Mitochondrial respiratory chain complex IV	complex	SIGNOR-C280	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 	SIGNOR-267744	0.745
SMURF2	protein	Q9HAU4	UNIPROT	SMAD5	protein	Q99717	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001593	BTO:0000140							22298955	t		lperfetto	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-153420	0.725
AKT2	protein	P31751	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000150								10576742	t		lperfetto	Akt (protein kinase b), a member of a different signaling pathway that also regulates these responses, interacted with raf and phosphorylated this protein at a highly conserved serine residue in its regulatory domain in vivo. This phosphorylation of raf by akt inhibited activation of the raf-mek-erk signaling pathway and shifted the cellular response in a human breast cancer cell line from cell cycle arrest to proliferation.	SIGNOR-235678	0.431
GSK3B	protein	P49841	UNIPROT	CEBPA	protein	P49715	UNIPROT	up-regulates activity	phosphorylation	Thr230	GHPTPPPtPVPSPHP	10090	BTO:0000944								10567568	t			Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes.	SIGNOR-251232	0.387
UBR2	protein	Q8IWV8	UNIPROT	RECQL4	protein	O94761	UNIPROT	up-regulates	binding			9606	BTO:0000567								15317757	t		miannu	The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells	SIGNOR-128214	0.546
MAPK14	protein	Q16539	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								10085140	t		lperfetto	On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38.	SIGNOR-65593	0.786
AURKB	protein	Q96GD4	UNIPROT	NINL	protein	Q9Y2I6	UNIPROT	up-regulates	phosphorylation	Ser585	RLPKNRHsPSWSPDG	9606									20864540	t		lperfetto	Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability.	SIGNOR-168053	0.255
TRHR	protein	P34981	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606		BTO:0001379							23248581	t		scontino	TRH receptors are textbook calcium-mobilizing receptors: they are coupled to Gq and G11, which activate phospholipase Cβ (PLCβ).	SIGNOR-267202	0.468
nisoxetine	chemical	CHEBI:73410	ChEBI	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								18487050	t		Luana	For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428. 	SIGNOR-257797	0.8
CSNK2A1	protein	P68400	UNIPROT	GTF2A1L	protein	Q9UNN4	UNIPROT	up-regulates activity	phosphorylation	Ser423	LNSGDDVsEQDVPDL	-1									12107178	t		llicata	ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.	SIGNOR-250873	0.435
KARS1	protein	Q15046	UNIPROT	Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	form complex	binding			9606									32644155	t		miannu	In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes).	SIGNOR-270353	0.2
CPI-0610 carboxylic acid	chemical	CID:67815062	PUBCHEM	BRD4	protein	O60885	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0004479								26815195	t		Monia	Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).	SIGNOR-261101	0.8
CSNK2A1	protein	P68400	UNIPROT	PTGES3	protein	Q15185	UNIPROT	up-regulates	phosphorylation	Ser113	WKDWEDDsDEDMSNF	9606									15040786	t		gcesareni	Several lines of evidence suggest that a cpges-activating protein kinase is ck-ii (casein kinase ii). Recombinant cpges was phosphorylated directly by and associated with ck-ii in vitro, resulting in marked reduction of the k m for the substrate pgh2.	SIGNOR-123594	0.36
SLC38A9	protein	Q8NBW4	UNIPROT	leucine	smallmolecule	CHEBI:25017	ChEBI	up-regulates quantity	relocalization			9606									29053970	t			SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins	SIGNOR-255313	0.8
MYCT1	protein	Q8N699	UNIPROT	CCNE2	protein	O96020	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30283340	f		miannu	MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. 	SIGNOR-261733	0.2
AURKB	protein	Q96GD4	UNIPROT	INCENP	protein	Q9NQS7	UNIPROT	up-regulates	phosphorylation	Thr892	KPRYHKRtSSAVWNS	9606									12925766	t		gcesareni	Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites.	SIGNOR-118019	0.973
JUN	protein	P05412	UNIPROT	GLS	protein	O94925	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									28111979	t		Luana	The transcription factor c-Jun can directly bind to the GLS gene promoter and enhance expression	SIGNOR-268035	0.358
PRKCD	protein	Q05655	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser616	DDGYMPMsPGVAPVP	9606									15143153	t		gcesareni	These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling.	SIGNOR-124737	0.632
GSK3B	protein	P49841	UNIPROT	NEFH	protein	P12036	UNIPROT	down-regulates	phosphorylation	Ser503	GGEEETKsPPAEEAA	9606									12130654	t		lperfetto	Gsk3beta was shown to phosphorylate at ser-493 in vitro by phosphopeptide mapping and site-directed mutagenesis, and in vivo in hek293 cells. The role of ser-493 phosphorylation is also a question to be addressed in the future. Because the e-segment appears to be involved in filament formation (27, 42), phosphorylation in that region may also play a regulatory role in filament formation. Secondary structure prediction suggests that phosphorylation of ser-493 in combination with following the pro residue interrupts _-helix of the e-segment	SIGNOR-90668	0.308
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2B	protein	P63146	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271334	0.746
GGCX	protein	P38435	UNIPROT	F2	protein	P00734	UNIPROT	up-regulates activity	carboxylation	Glu69	EETCSYEeAFEALES	-1									10556651	t		lperfetto	We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 	SIGNOR-263682	0.655
MAPK8	protein	P45983	UNIPROT	MAPK8IP3	protein	Q9UPT6	UNIPROT	up-regulates	phosphorylation	Thr265	GQSSAAAtPSTTGTK	9606									15767678	t		gcesareni	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134541	0.715
AURKB	protein	Q96GD4	UNIPROT	CDCA2	protein	Q69YH5	UNIPROT	down-regulates activity	phosphorylation	Ser981	RRKSFCIsTLANTKA	9606	BTO:0000567								32938714	t	done	miannu	This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin.	SIGNOR-274001	0.459
MET	protein	P08581	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr589	SHDSEENyVPMNPNL	9606	BTO:0000018								10734310	t		miannu	Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF.	SIGNOR-250288	0.661
PLK1	protein	P53350	UNIPROT	USP16	protein	Q9Y5T5	UNIPROT	up-regulates activity	phosphorylation	Ser330	ILKAFGNsTEKLDEE	-1									26323689	t	done	miannu	Plk1 phosphorylates and activates Usp16. In vitro phosphorylation of Usp16 with single (S330A, S386A, or S486A) or collective 3A (S330A/S386A/S486A) mutation showed that Plk1 phosphorylated Usp16 at all three sites (Fig. S2 D).	SIGNOR-274016	0.35
SRC	protein	P12931	UNIPROT	CELF2	protein	O95319	UNIPROT	up-regulates activity	phosphorylation	Tyr63	LKELFEPyGAVYQIN	-1									17855367	t		miannu	Site-directed mutagenesis of putative tyrosine phosphorylation sites in CUGBP2 identified tyrosine 39 as a c-Src target, and a CUGBP2 with a mutated tyrosine 39 displayed an attenuated ability to bind COX-2 mRNA. 	SIGNOR-263195	0.327
FOXO1	protein	Q12778	UNIPROT	SMURF1	protein	Q9HCE7	UNIPROT	up-regulates quantity	transcriptional regulation			10090	BTO:0000165								15125842	t			The IGF-1/PI3K/Akt pathway, which has been shown to induce hypertrophy, prevents induction of requisite atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1. Moreover, the mechanism for this inhibition involves Akt-mediated inhibition of the FoxO family of transcription factors;	SIGNOR-256258	0.251
WWTR1	protein	Q9GZV5	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001615								22470139	f		miannu	Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation.	SIGNOR-255606	0.2
Riluzole	chemical	CHEBI:8863	ChEBI	KCNN1	protein	Q92952	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								18955585	t		Luana	Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. 	SIGNOR-258021	0.8
KDM4C	protein	Q9H3R0	UNIPROT	H2AX	protein	P16104	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									29207681	f		miannu	Knockdown of JMJD2C gene led to the up-regulation of basal γ-H2AX expression. and γ-H2AX together with its phosphorylated C-terminal (Sre residues 139–140, γ-H2AX) are crucial for DNA repair	SIGNOR-263872	0.2
imatinib methanesulfonate	chemical	CHEBI:31690	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck;VIRAL ABL	gcesareni		SIGNOR-193387	0.8
lysine	smallmolecule	CHEBI:25094	ChEBI	Lys-tRNA(Lys)	smallmolecule	CHEBI:16047	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270410	0.8
phosphatidylinositol bisphosphate	smallmolecule	CHEBI:37328	ChEBI	GSN	protein	P06396	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000132								12788695	t		lperfetto	We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations.	SIGNOR-261841	0.8
FYN	protein	P06241	UNIPROT	SLAMF1	protein	Q13291	UNIPROT	up-regulates activity	phosphorylation	Tyr327	ETNSITVyASVTLPE	9534	BTO:0000298								11806999	t			All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327. 	SIGNOR-251183	0.647
PAS complex	complex	SIGNOR-C190	SIGNOR	Multivesicular_body_assembly	phenotype	SIGNOR-PH83	SIGNOR	up-regulates				9606									17556371	f		miannu	Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. We further demonstrate a key function for each of the three proteins in the biogenesis of ECV/MVB transport intermediates from early endosomes.	SIGNOR-253532	0.7
PRKCA	protein	P17252	UNIPROT	ADAP1	protein	O75689	UNIPROT	unknown	phosphorylation	Ser87	AARARFEsKVPSFYY	-1									12893243	t		lperfetto	The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ 	SIGNOR-249223	0.322
manganese(2+)	chemical	CHEBI:29035	ChEBI	BRCA1-C complex	complex	SIGNOR-C299	SIGNOR	form complex	binding												25400280	t		lperfetto	The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2	SIGNOR-269476	0.8
APC	protein	P25054	UNIPROT	ODC1	protein	P11926	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12112318	t	 	 	 APC-dependent regulation of ornithine decarboxylase in human colon tumor cells|Upon induction of APC expression, ODC promoter activity and RNA levels were suppressed	SIGNOR-253670	0.271
zotepine	chemical	CHEBI:32316	ChEBI	HTR1D	protein	P28221	UNIPROT	down-regulates activity	chemical inhibition			10116	BTO:0000529								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258550	0.8
ATM	protein	Q13315	UNIPROT	CCDC6	protein	Q16204	UNIPROT	up-regulates	phosphorylation	Thr434	TPPPSPNtQTPVQPP	9606	BTO:0000551								23108047	t		miannu	Phosphorylation of ccdc6 at thr434 by atm during dna damage response prevents fbxw7-mediated ccdc6 degradation.	SIGNOR-199276	0.278
MAPK14	protein	Q16539	UNIPROT	H3C1	protein	P68431	UNIPROT	unknown	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									20626350	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	The p38 mapk pathway can positevely regulate nf-kb activity by different mechanisms, including chromatin remodelling through ser10 phosphorylation of histone h3 at nf-kb dependent promoters such as il-8 and mcp or by impinging on ikk or the p65 subunit in a direct or indirect manner.	SIGNOR-166602	0.2
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser315	DFRSRTNsNASTVSG										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-252845	0.908
DNAJC6	protein	O75061	UNIPROT	HSPA8	protein	P11142	UNIPROT	up-regulates activity	relocalization												24789820	t		lperfetto	Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane.	SIGNOR-260719	0.879
ADRA2C	protein	P18825	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256978	0.403
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	UNG	protein	P13051	UNIPROT	up-regulates activity	phosphorylation	Ser12	KTLYSFFsPSPARKR	9606	BTO:0000567								18079698	t		miannu	We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14.	SIGNOR-276098	0.267
DRAM2	protein	Q6UX65	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30755245	f		irozzo	Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors.	SIGNOR-259142	0.2
GRIK2	protein	Q13002	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial.	SIGNOR-264943	0.8
IRF2BPL	protein	Q9H1B7	UNIPROT	PDYN	protein	P01213	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000938								17627301	t		miannu	EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.	SIGNOR-267156	0.266
CARS1	protein	P49589	UNIPROT	alpha-aminoacyl-tRNA	smallmolecule	CHEBI:2651	ChEBI	up-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 	SIGNOR-270805	0.8
AKT2	protein	P31751	UNIPROT	SRSF5	protein	Q13243	UNIPROT	up-regulates activity	phosphorylation	Ser86	GRGRGRYsDRFSSRR	10116									15684423	t		miannu	Here we show that Akt2 kinase phosphorylated SRp40 in vivo and in vitro. Mutation of Ser86 on SRp40 blocked in vitro phosphorylation. 	SIGNOR-262633	0.371
SLC34A2	protein	O95436	UNIPROT	EGF	protein	P01133	UNIPROT	down-regulates				9606	BTO:0000195	BTO:0000763							11171583	f		miannu	In vivo and in vitro studies showed that egf treatment decreased intestinal napi-iib mrna abundance by _50%, suggesting possible transcriptional regulation.	SIGNOR-105161	0.36
MAPK1	protein	P28482	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Ser434	SFEPKIRsPRRFIGS	9606									7545671	t		gcesareni	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-28796	0.578
4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide	chemical	CHEBI:91447	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194919	0.8
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation			9606									21798082	t		gcesareni	Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b).	SIGNOR-252843	0.908
MAP1LC3A	protein	Q9H492	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	up-regulates	binding			9606									19250911	t		gcesareni	Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation.	SIGNOR-184198	0.784
FLT1	protein	P17948	UNIPROT	FLT1	protein	P17948	UNIPROT	up-regulates	phosphorylation	Tyr1242	ATSMFDDyQGDSSTL	9606									9722576	t		lperfetto	Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor.	SIGNOR-59754	0.2
HSF2	protein	Q03933	UNIPROT	HSPA6	protein	P17066	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12813038	f	 	miannu	These experiments suggest that HSF2 is involved in the stress response, but unlike the ubiquitous HSF1 operates in a cell-line specific manner through differential expression of alternatively spliced isoforms. Curiously, HSF2A could not be activated by heat shock in cells deficient in functional HSF1 and required the expression of HSF1 for heat induction of the hsp70B gene in cells. 	SIGNOR-254478	0.345
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	IL16	protein	Q14005	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000782								14768064	t	inferred from 70% family members	lperfetto	The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 in antigen receptor-, sdf1alpha- and il-2-activated t cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response.	SIGNOR-270168	0.2
1-[2-[(diphenylmethylene)amino]oxyethyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid	chemical	CHEBI:92744	ChEBI	SLC6A1	protein	P30531	UNIPROT	down-regulates activity	chemical inhibition			-1									7851497	t		miannu	Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. 	SIGNOR-258479	0.8
CDS2	protein	O95674	UNIPROT	CDP-diacylglycerol(2-)	smallmolecule	CHEBI:58332	ChEBI	up-regulates	chemical modification			9606									25375833	t		lperfetto	CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA).	SIGNOR-267020	0.8
CIC	protein	Q96RK0	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	up-regulates activity	binding			10090		BTO:0000142							32229723	t		miannu	Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified the BRG1-containing mSWI/SNF complex whose function is necessary for transcriptional repression by CIC. CIC interacts with mSWI/SNF complex during neurogenesis. CIC tethers SIN3-HDAC corepressor complex and mSWI/SNF complex to VGF promoter during neurogenesis.	SIGNOR-269207	0.273
mTORC1	complex	SIGNOR-C3	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity	phosphorylation			10090	BTO:0000944								18372248	t		lperfetto	We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competition. We also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1.	SIGNOR-235518	0.83
SOS1	protein	Q07889	UNIPROT	NRAS	protein	P01111	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									21779497	t		lperfetto	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.	SIGNOR-175259	0.771
ZNF804A	protein	Q7Z570	UNIPROT	BIRC3	protein	Q13489	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								23434502	t		miannu	ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 	SIGNOR-269467	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	HNF4A	protein	P41235	UNIPROT	down-regulates	phosphorylation	Ser303	DPDAKGLsDPGKIKR	9606									12740371	t		lperfetto	Here we demonstrate that ampk directly phosphorylates hnf4 and represses its transcriptional activity. Ampk-mediated phosphorylation of hnf4 on serine 304 had a 2-fold effect	SIGNOR-216511	0.312
AMOT	protein	Q4VCS5	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates	relocalization			9606									23431053	t	AMOT proteins, a family of proteins including AMOT, AMOTL1, and AMOTL2, interact extensively with multiple TJ components and are important for maintaining TJ integrity and epithelial cell polarity.	gcesareni	Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms.	SIGNOR-201132	0.669
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation	Thr1462	GLRPRGYtISDSAPS	10090	BTO:0000944								12150915	t		lperfetto	We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines.	SIGNOR-244365	0.2
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGA6	protein	Q9Y5G7	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265694	0.2
PPP2CA	protein	P67775	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Thr185	HDHTGFLtEYVATRW	10116									7780739	t			Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts. 	SIGNOR-248625	0.604
ZSTK-474	chemical	CHEBI:90545	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207944	0.8
FAS	protein	P25445	UNIPROT	RASSF1	protein	Q9NS23	UNIPROT	up-regulates				9606									22830020	f		gcesareni	It was also shown that the fas active receptor induces rassf1a to compete with raf1 in binding to mst2, thus promoting the formation of a lats1 complex.	SIGNOR-198435	0.26
PKNOX1	protein	P55347	UNIPROT	PBX1	protein	P40424	UNIPROT	up-regulates activity	binding			-1									9482740	t	2	miannu	we show that Pbx proteins exist as stable heterodimers with a novel homeodomain protein, Prep1. Here we show that Prep1-Pbx interaction presents novel structural features: it is independent of DNA binding and of the integrity of their respective homeodomains, and requires sequences in the N-terminal portions of both proteins. The Prep1-Pbx protein-protein interaction is essential for DNA-binding activity.	SIGNOR-241212	0.733
MYO3A	protein	Q8NEV4	UNIPROT	MYO3A	protein	Q8NEV4	UNIPROT	down-regulates activity	phosphorylation	Thr908	INLAKGDtGEATRHA	9534									24214986	t		Manara	We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919) | Thus, the phosphorylation sites in loop 2 (Thr-908 and Thr-919) are likely responsible for the down-regulation of MYO3A motor activity observed in our current and previous work	SIGNOR-260923	0.2
androst-4-ene-3,17-dione	smallmolecule	CHEBI:16422	ChEBI	testosterone	smallmolecule	CHEBI:17347	ChEBI	up-regulates quantity	precursor of			9606		BTO:0001363							16166196	t		lperfetto	A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis.	SIGNOR-268665	0.8
PIK3AP1	protein	Q6ZUJ8	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606	BTO:0000801								22187458	t		gcesareni	This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Therefore, bcap is an essential activator of the pi3k pathway downstream of tlr signaling, providing a brake to limit potentially pathogenic excessive tlr responses.	SIGNOR-191664	0.394
Phagocytosis	phenotype	SIGNOR-PH97	SIGNOR	TGFB1	protein	P01137	UNIPROT	up-regulates quantity					BTO:0000801								22933625	f		apalma	Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype	SIGNOR-255444	0.7
KMN network	complex	SIGNOR-C366	SIGNOR	Chromosome_segregation	phenotype	SIGNOR-PH44	SIGNOR	up-regulates				9606	BTO:0000567								18007590	f		lperfetto	Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis.	SIGNOR-265220	0.7
PKN1	protein	Q16512	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser159	KKKKKRFsFKKSFKL	9534	BTO:0000298								8557118	t		lperfetto	PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163.	SIGNOR-248937	0.372
PRKACA	protein	P17612	UNIPROT	PACSIN2	protein	Q9UNF0	UNIPROT	down-regulates activity	phosphorylation	Ser313	ADLNRTLsRREKKKA	9606	BTO:0000007								31801866	t	done	miannu	PKCα phosphorylates PACSIN2 at serine 313 in the linker region and decreases its membrane binding and tubulation activities. Phosphorylation of PACSIN2 at S313 negatively regulated protein interaction between NS5A and core, which affected viral assembly	SIGNOR-273799	0.2
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC1	protein	O95644	UNIPROT	up-regulates	dephosphorylation			9606									21880741	t		gcesareni	Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.	SIGNOR-252323	0.821
CSNK2A1	protein	P68400	UNIPROT	IL16	protein	Q14005	UNIPROT	up-regulates activity	phosphorylation	Ser743	MPLQPNAsLNEEEGT	-1									12450396	t		llicata	We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. | Thus, we confirm that the N-terminal (42SLNEE46) sequence of pro-IL-16 is in fact a site for protein kinase CK2 phosphorylation.	SIGNOR-250905	0.331
ADCYAP1	protein	P18509	UNIPROT	VIPR1	protein	P32241	UNIPROT	up-regulates	binding			9606									11897681	t		gcesareni	Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip).	SIGNOR-116066	0.807
SCF-SKP2	complex	SIGNOR-C136	SIGNOR	CDKN1B	protein	P46527	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000567						phosphorylation:Thr187	NAGSVEQtPKKPGLR	10559916	t		lperfetto	SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27|We conclude that the stable interaction of p27 with SKP2 is highly specific and dependent upon phosphorylation of p27 on T187.	SIGNOR-267557	0.683
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	down-regulates	phosphorylation	Ser1112	LLEDGSEsPAKRICP	9606	BTO:0001938								11157749	t		gcesareni	When expressed in u2os cells, the phosphorylation-deficient mutant p130(delta)(cdk4), in which the cdk4 specific sites were mutated to alanine residues, imposed a more sustained g1 arrest than a constitutively active prb(delta)(cdk), known to repress all cellular e2f activity	SIGNOR-104656	0.843
MAPK1	protein	P28482	UNIPROT	UBAP2L	protein	Q14157	UNIPROT	unknown	phosphorylation	Thr844	IPFPTPTtPLTGRDG	10090									22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262774	0.2
MFF	protein	Q9GZY8	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	relocalization			9606									21149567	t		gcesareni	Mff functions as an essential factor in mitochondrial recruitment of Drp1.	SIGNOR-245957	0.621
MAP3K7	protein	O43318	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	up-regulates activity	phosphorylation			9606									21232017	t		lperfetto	Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. 	SIGNOR-209759	0.717
WNT9B	protein	O14905	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-132114	0.592
WWTR1	protein	Q9GZV5	UNIPROT	BAK1	protein	Q16611	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001615								22470139	f		miannu	Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation.	SIGNOR-255605	0.2
Laminin-1	complex	SIGNOR-C183	SIGNOR	a7/b1 integrin	complex	SIGNOR-C126	SIGNOR	up-regulates activity	binding												1839357	t		lperfetto	By using specific proteolytically derived fragments of laminin, it was determined that the alpha 7 beta 1 complex binds selectively to the E8 region, which represents part of the long arm of laminin. 	SIGNOR-253257	0.539
CHEK1	protein	O14757	UNIPROT	E2F6	protein	O75461	UNIPROT	down-regulates activity	phosphorylation	Ser52	EDNVQYVsMRKALKV	-1									23954429	t		miannu	 the checkpoint kinase Chk1 phosphorylates E2F6 leading to its dissociation from promoters. 	SIGNOR-266371	0.557
STK4	protein	Q13043	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates activity	phosphorylation	Thr183	DTMAKRNtVIGTPFW	9534	BTO:0004055								12223493	t		lperfetto	Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationWe define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity.	SIGNOR-247577	0.2
prostaglandin E2(1-)	smallmolecule	CHEBI:606564	ChEBI	PTGER4	protein	P35408	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257572	0.8
ADP	chemical	CHEBI:16761	ChEBI	P2RY13	protein	Q9BPV8	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257561	0.8
(+)-pilocarpine	chemical	CHEBI:8207	ChEBI	CHRM2	protein	P08172	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258629	0.8
REN	protein	P00797	UNIPROT	ATP6AP2	protein	O75787	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0000142;BTO:0000671;BTO:0001260							12045255	t		gcesareni	We report the expression cloning of the human renin receptor complementary dna encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin i and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of map kinases erk1 and erk2	SIGNOR-88416	0.78
CUDC-101	chemical	CID:24756910	PUBCHEM	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191145	0.8
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser172	LCLSPASsGSSASFI	9606									11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248366	0.598
SMURF1	protein	Q9HCE7	UNIPROT	PADI4	protein	Q9UM07	UNIPROT	unknown	ubiquitination			-1									20804422	t		miannu	Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay.	SIGNOR-272689	0.2
RBKS	protein	Q9H477	UNIPROT	D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	up-regulates quantity	chemical modification			9606									25749547	t		miannu	Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds.	SIGNOR-267073	0.8
CBLB	protein	Q13191	UNIPROT	PIK3R2	protein	O00459	UNIPROT	down-regulates activity	ubiquitination			9606	BTO:0000661								11087752	t		miannu	Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. it can be postulated that Cbl-b, as an E3 Ub ligase, may play a general role in functional regulation of its target proteins through ubiquitination in a protein degradation-independent manner.	SIGNOR-271424	0.48
GXYLT2	protein	A0PJZ3	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	binding			9606									22117070	t	Xylosylation in ER membrane.	gcesareni	Recently, we have shown (28) that two members of the human glycosyltransferase 8 family (gt8) (29), gxylt1 and gxylt2 (glucoside-xylosyltransferase 1/2), are able to transfer the first alfa1,3-linked xylose to o-glucosylated mammalian notch egf repeats.	SIGNOR-254314	0.391
AKT1	protein	P31749	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	phosphorylation	Ser552	QDTQRRTsMGGTQQQ	9606									17287208	t		lperfetto	Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo.	SIGNOR-252499	0.799
MLL-ENL	fusion protein	SIGNOR-FP7	SIGNOR	RUNX1	protein	Q01196	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									24449215	f		irozzo	However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins.	SIGNOR-255853	0.2
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1672	SPTSPSYsPTSPSYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203528	0.77
MAPK14	protein	Q16539	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser33	LPENNVLsPLPSQAM	9606	BTO:0000093								17535811	t		lperfetto	P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.	SIGNOR-155242	0.765
ING3	protein	Q9NXR8	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269294	0.668
FYN	protein	P06241	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates activity	phosphorylation	Tyr731	QQIDSCTyEAMYNIQ	9606									9890970	t		lperfetto	Fyn associates with cbl and phosphorylates tyrosine 731 in cbl, a binding site for phosphatidylinositol 3-kinasecbl represents a substrate for src-like kinases that are activated in response to the engagement of cell surface receptors, and that src-like kinases are responsible for the phosphorylation of a tyrosine residue in cbl that may regulate activation of phosphatidylinositol 3-kinase	SIGNOR-63968	0.804
CSNK2A1	protein	P68400	UNIPROT	EEF1B2	protein	P24534	UNIPROT	unknown	phosphorylation	Ser106	DDIDLFGsDDEEESE	-1									8547318	t		llicata	EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent.	SIGNOR-250854	0.349
PRKACA	protein	P17612	UNIPROT	SOX9	protein	P48436	UNIPROT	up-regulates	phosphorylation	Ser181	YQPRRRKsVKNGQAE	9606									15889150	t		llicata	We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta.	SIGNOR-137085	0.445
CAMTA1	protein	Q9Y6Y1	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0005397								21385898	f		irozzo	Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma.	SIGNOR-259099	0.7
IKBKE	protein	Q14164	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation	Ser644	GLDFNFDsLISTQNV	9606									23691078	t		lperfetto	Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation.	SIGNOR-202054	0.418
PTPN12	protein	Q05209	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates activity	dephosphorylation			10090									11163214	t		gcesareni	Several experiments suggest that the PEST-type PTPs negatively regulate c-Abl activity: c-Abl was hyperphosphorylated in PTP-PEST-deficient cells; disruption of the c-Abl-PSTPIP1-PEST-type PTP ternary complex by overexpression of PSTPIP1 mutants increased c-Abl phosphotyrosine content	SIGNOR-246222	0.449
CHUK	protein	O15111	UNIPROT	FOXA2	protein	Q9Y261	UNIPROT	down-regulates	phosphorylation	Ser107	AGMGPHLsPSLSPLG	9606									22196886	t		lperfetto	Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression	SIGNOR-195312	0.2
Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	up-regulates activity				9606									18350175	f	inferred from family member		The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase.	SIGNOR-270310	0.7
Serdemetan	chemical	CID:11609586	PUBCHEM	MDM2	protein	Q00987	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193504	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	SMAD4	protein	Q13485	UNIPROT	up-regulates	phosphorylation			9606									12801888	t	inferred from 70% family members	llicata	Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4.	SIGNOR-270107	0.2
clozapine	chemical	CHEBI:3766	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10116		BTO:0000601							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258517	0.8
VRK2	protein	Q86Y07	UNIPROT	BANF1	protein	O75531	UNIPROT	down-regulates	phosphorylation	Thr3	tSQKHRDF	9606									16495336	t		gcesareni	We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell	SIGNOR-144803	0.517
WNK3	protein	Q9BYP7	UNIPROT	SLC12A6	protein	Q9UHW9	UNIPROT	down-regulates activity	phosphorylation	Ser96	IEDLSQNsITGEHSQ	9606									24043619	t		Manara	WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048. 	SIGNOR-260911	0.457
RPS6KA4	protein	O75676	UNIPROT	RPS6KA4	protein	O75676	UNIPROT	up-regulates	phosphorylation	Ser196	EEKERTFsFCGTIEY	9606		BTO:0001253							17429437	t		gcesareni	Ser-343 and ser-196 are autophosphorylated by the c-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain.	SIGNOR-154324	0.2
PTPN6	protein	P29350	UNIPROT	IL2RB	protein	P14784	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000782								9520455	t		gcesareni	We have found that il-2 induces association of shp-1 with the il-2 receptor complex, and that once shp-1 is recruited to the activated receptor it is able to decrease tyrosine phosphorylation of il-2rbeta and the associated tyrosine kinases jak1 and jak3.	SIGNOR-55989	0.51
IL6ST	protein	P40189	UNIPROT	T_cell_activation	phenotype	SIGNOR-PH73	SIGNOR	up-regulates				9606									32234467	f		miannu	Interleukin-6 (IL-6) is an important member of the cytokine network and plays a central role in acute inflammation. IL-6 binds to its receptor IL-6R to form a complex, and then binds to the membrane protein gp130 to initiate intracellular signal transduction. IL-6 is the terminal helper factor of cytotoxic T lymphocyte (CTL), which can induce CTL activity and make immature thymocytes develop into CTL. In addition, IL-6 is a pro-inflammatory regulator of T cells.	SIGNOR-261028	0.7
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	relocalization			10090	BTO:0002572								18423396	t		lperfetto	Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation.	SIGNOR-252852	0.908
tacrolimus (anhydrous)	chemical	CHEBI:61049	ChEBI	PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	down-regulates	chemical inhibition			9606									15276472	t	inferred from 70% of family members	gcesareni	Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins.	SIGNOR-269893	0.8
RAB1A	protein	P62820	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								27479033	t		Giulio	Hemagglutinin (HA)-Rab1A is associated with mTOR and Raptor, not Rictor (Figure S2A), and is bound more with Myc-Raptor than Myc-mTOR (Figures S2B and S2C).|Rab1A Is an mTORC1 Activator and a Colorectal Oncogene	SIGNOR-261286	0.321
NMDA	proteinfamily	SIGNOR-PF56	SIGNOR	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								11052931	t		miannu	Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor	SIGNOR-264704	0.2
ADAM17	protein	P78536	UNIPROT	TGFA	protein	P01135	UNIPROT	up-regulates activity	cleavage			9606									26284334	t		miannu	ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF	SIGNOR-259841	0.503
STAT3	protein	P40763	UNIPROT	PLK1	protein	P53350	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22108192	t		lperfetto	Stat3 directly activated transcription of PLK1 in esophageal cancer cells and mouse embryonic fibroblast cell NIH3T3.	SIGNOR-271690	0.312
PRKCA	protein	P17252	UNIPROT	GFPT1	protein	Q06210	UNIPROT	down-regulates activity	phosphorylation	Ser205	AVGTRRGsPLLIGVR	-1									10806197	t		lperfetto	Phosphorylation of human glutamine:fructose-6-phosphate amidotransferase by cAMP-dependent protein kinase at serine 205 blocks the enzyme activity.	SIGNOR-249040	0.311
PRKCA	protein	P17252	UNIPROT	NPHS1	protein	O60500	UNIPROT	up-regulates activity	phosphorylation	Thr1120	EYEESQWtGERDTQS	9606	BTO:0000007								21321125	t		llicata	Binding of _-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by pkc_.	SIGNOR-178695	0.2
TG101209	chemical	CHEBI:90304	ChEBI	JAK3	protein	P52333	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207266	0.8
SETD2	protein	Q9BYW2	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	trimethylation	Lys37	APATGGVkKPHRYRP	9606									16118227	t		Gianni	Our results suggest that HYPB HMTase may coordinate histone methylation and transcriptional regulation in mammals and open perspective for the further study of the potential roles of HYPB protein in hematopoiesis and pathogenesis of HD.	SIGNOR-269071	0.2
SELENOS	protein	Q9BQE4	UNIPROT	VCP	protein	P55072	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								15215856	t		miannu	VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97.	SIGNOR-261371	0.2
CSNK1A1	protein	P48729	UNIPROT	CTPS2	protein	Q9NRF8	UNIPROT	down-regulates	phosphorylation	Ser568	LSSSDRYsDASDDSF	9606									20739275	t		gcesareni	Hctps2 ser(568) was phosphorylated by casein kinase 1 both in vitro and in vivo. Mutation of ser(568) (s568a) significantly increased hctps2 activity, demonstrating that ser(568) is a major inhibitory phosphorylation site.	SIGNOR-167623	0.2
PIK3C3	protein	Q8NEB9	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates				9606									10698680	f		acerquone	Pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1)	SIGNOR-75376	0.446
ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	ADP(3-)	smallmolecule	CHEBI:456216	ChEBI	up-regulates quantity	precursor of			9606									19286649	t		miannu	ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor.	SIGNOR-268084	0.8
CDK1	protein	P06493	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates	phosphorylation	Ser394	TRQTPVDsPDDSTLS	9606									9271440	t		gcesareni	Interestingly, phosphorylation at several ser/thr residues within the c-terminal autoinhibitory tail appears to either activate or inhibit s6k1, depending on the cell cycle phase. phosphorylation of those residues (featured by the thr-421/ser-424 site) during mitosis pursued by cdk1 inactivates s6k1 we then assessed the phosphorylation status of the mitosis-specific inhibitory residue of s6k1, thr-421/ser-424, which is targeted by mitotic cdk1.	SIGNOR-50603	0.392
BMAL1/NPAS2	complex	SIGNOR-C431	SIGNOR	CRY1	protein	Q16526	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements.	SIGNOR-267967	0.891
RPS6KA1	protein	Q15418	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser374	PSSDSLSsPTLLAL										16055710	t		lperfetto	Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos	SIGNOR-262999	0.545
CDKN1A	protein	P38936	UNIPROT	CDK3	protein	Q00526	UNIPROT	down-regulates	binding			9606									7626805	t		gcesareni	P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. We have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases.	SIGNOR-29954	0.663
PHF2	protein	O75151	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									21532585	t		miannu	PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark.	SIGNOR-264521	0.2
NFIB	protein	O00712	UNIPROT	WNT5A	protein	P41221	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268883	0.2
metformin	chemical	CHEBI:6801	ChEBI	NR0B2	protein	Q15466	UNIPROT	up-regulates quantity by expression				9606									17909097	f		gcesareni	As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells	SIGNOR-158068	0.8
LYL1	protein	P12980	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21261500	f		miannu	TAL1 and LYL1 are two leukemic members of the bHLH family of transcription factors. TAL1 and LYL1 activate expression of MEF2C	SIGNOR-254208	0.345
PTPN5	protein	P54829	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates	binding			9606	BTO:0000938								23932588	t	A study conducted by Zhang et al. showed that STEP is significantly less efficient than PTPSL and HePTP at dephosphorylating p38a.	gcesareni	First [] step prevents upstream activating kinases from promiscuously binding and activating p38a. Second, by blocking access to the mapk insert pocket, through the stepcat interaction, step can prevent the binding of allosteric signaling molecules that induce autoactivation of p38a.	SIGNOR-194829	0.478
PRKCA	protein	P17252	UNIPROT	CTPS1	protein	P17812	UNIPROT	up-regulates	phosphorylation	Ser462	TLFQTKNsVMRKLYG	9606									17463002	t		llicata	These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity.	SIGNOR-154617	0.2
PEA15	protein	Q15121	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates				9606									11702783	f	inferred from 70% of family members	gcesareni	Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase.	SIGNOR-269925	0.862
NME1	protein	P15531	UNIPROT	NME1	protein	P15531	UNIPROT	unknown	phosphorylation	Ser120	GRNIIHGsDSVESAE	-1									8810265	t		miannu	For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown. 	SIGNOR-250300	0.2
CyclinD/CDK4	complex	SIGNOR-C18	SIGNOR	TSC2	protein	P49815	UNIPROT	up-regulates activity	phosphorylation	Ser1452	LPSSSPRsPSGLRPR	9606	BTO:0000007								32294430	t	done	miannu	We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452. 	SIGNOR-274100	0.481
GABA-A (a2-b1-g2) receptor	complex	SIGNOR-C331	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000227							18790874	f	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263777	0.7
GOLGA2	protein	Q08379	UNIPROT	GORASP1	protein	Q9BQQ3	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000567								16489344	t		Giulio	Previous studies have implicated the GM130–GRASP65 complex in diverse Golgi functions. Therefore, GM130–GRASP65 interactions are required for Golgi ribbon formation.|A surprising clue came from the observation that GM130 was required for stability of GRASP65. 	SIGNOR-260601	0.875
PRKCD	protein	Q05655	UNIPROT	TRIM28	protein	Q13263	UNIPROT	down-regulates	phosphorylation	Ser473	SGVKRSRsGEGEVSG	9606									18590578	t		gcesareni	This work demonstrates that tif1beta is phosphorylated on ser473, the alteration of which is dynamically associated with cell cycle progression and functionally linked to transcriptional regulation. Phosphorylation of tif1beta/ser473 is mediated by the pkcdelta pathway and is closely linked to cell proliferation. Phosphorylation of tif1beta/ser473 coincides with the induction of cell cycle gene cyclin a2 at the s-phase. Promoter of cyclin a2 gene is occupied by tif1beta and such occupancy is inversely correlated with ser473 phosphorylation. Non-phosphorylated tif1beta/ser473 allowed greater tif1beta association with the regulatory regions and the consequent repression of these genes.	SIGNOR-179250	0.2
STUB1	protein	Q9UNE7	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								14701756	t		miannu	We demonstrate that the coexpression of Smad1 and Smad4 with the CHIP protein results in the degradation of the Smad proteins through a ubiquitin-mediated process. 	SIGNOR-272947	0.405
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	GSK3B	protein	P49841	UNIPROT	up-regulates activity	phosphorylation	Tyr216	RGEPNVSyICSRYYR	9606		BTO:0001253							15020233	t		lperfetto	In vitro kinase assay was carried out using a recombinant human active mek1 and we found that gsk-3beta was phosphorylated on tyr(216) by this kinase in a dose- and time-dependent manner. Further, the pretreatment of fibroblasts with u0126 inhibited serum-induced nuclear translocation of gsk-3beta. These results suggested that mek1/2 induces tyrosine phosphorylation of gsk-3beta and this cellular event might induce nuclear translocation of gsk-3beta.	SIGNOR-244780	0.2
CALM3	protein	P0DP25	UNIPROT	EEF2K	protein	O00418	UNIPROT	up-regulates	binding			9606									11015200	t		miannu	The calmodulin-binding region is located between amino acids 51 and 96	SIGNOR-266337	0.472
KDM5A	protein	P29375	UNIPROT	RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	down-regulates	binding			7227	BTO:0000782								20231316	t		lperfetto	In this study, we show that the histone demethylase kdm5a associated with rbp-j protein and is essential for notch/rbp-j target gene silencing in vitro.	SIGNOR-219250	0.393
MAP4K1	protein	Q92918	UNIPROT	MAP3K11	protein	Q16584	UNIPROT	up-regulates	phosphorylation	Ser281	WHKTTQMsAAGTYAW	9606									11053428	t		gcesareni	Hpk1 also phosphorylated mlk-3 activation loop in vitro, and ser281 was found to be the major phosphorylation site, indicating that hpk1 also activates mlk-3 via phosphorylation of the kinase activation loop.	SIGNOR-83415	0.555
TP53	protein	P04637	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates activity	binding			9606									19007744	t	Cytosolic p53	lperfetto	Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis	SIGNOR-99712	0.739
RISC(DICER1/AGO2/TARBP2)	complex	SIGNOR-C32	SIGNOR	NcRNA_processing	phenotype	SIGNOR-PH95	SIGNOR	up-regulates				9606									23661684	f		lperfetto		SIGNOR-255323	0.7
pazopanib	chemical	CHEBI:71219	ChEBI	CSF1R	protein	P07333	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001949								18620382	t		Luana	Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively.	SIGNOR-257740	0.8
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates activity	chemical activation			10116	BTO:0000759								2158622	t	inferred from 70% of family members	miannu	We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 	SIGNOR-269881	0.8
TLR4	protein	O00206	UNIPROT	MAP3K8	protein	P41279	UNIPROT	up-regulates activity				10090									16484370	f			Our findings indicate that the Tpl2/MEK/ERK signaling module is a master regulator of ERK-dependent gene expression downstream of TLRs in different hemopoietic cells	SIGNOR-256083	0.399
TAL1	protein	P17542	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000661								21261500	f		miannu	TAL1 and LYL1 are two leukemic members of the bHLH family of transcription factors. TAL1 and LYL1 activate expression of MEF2C	SIGNOR-254209	0.336
MAPK1	protein	P28482	UNIPROT	CIITA	protein	P33076	UNIPROT	down-regulates	phosphorylation	Ser288	PDRPGSTsPFAPSAT	9606									18245089	t		gcesareni	Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. ... Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.	SIGNOR-160613	0.443
CREB1	protein	P16220	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	binding			9606									15126506	t		lperfetto	We provide evidence that the acetyltransferase creb-binding protein (cbp) binds foxo resulting in acetylation of foxo. This acetylation inhibits foxo transcriptional activity	SIGNOR-252894	0.53
ITGA7	protein	Q13683	UNIPROT	a7/b1 integrin	complex	SIGNOR-C126	SIGNOR	form complex	binding			9606	BTO:0000222;BTO:0002319								10199978	t		lperfetto	The alpha7beta1 integrin is a laminin receptor on the surface of skeletal myoblasts and myofibers. Alternative forms of both the alpha7 and beta1 chains are expressed in a developmentally regulated fashion during myogenesis. These different alpha7beta1 isoforms localize at specific sites on myofibers and appear to have distinct functions in skeletal muscle.	SIGNOR-241508	0.764
IL21	protein	Q9HBE4	UNIPROT	IL21R	protein	Q9HBE5	UNIPROT	up-regulates	binding			9606									16424177	t		gcesareni	Il-21 mediates its biological effects via the il-21r in conjunction with the common receptor gamma-chain that is also shared by members of the il-2 family	SIGNOR-143849	0.898
glutaryl-CoA(5-)	smallmolecule	CHEBI:57378	ChEBI	glutarate(2-)	smallmolecule	CHEBI:30921	ChEBI	up-regulates quantity	precursor of												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271815	0.8
CDK9	protein	P50750	UNIPROT	TP53	protein	P04637	UNIPROT	unknown	phosphorylation	Ser33	LPENNVLsPLPSQAM	9606									16552184	t		llicata	Here, we report for the first time that cyclin dependent kinase 9, whose well-known substrate is rna polymerase ii, can also phosphorylate p53. Specifically, ser33 on the n-terminus and, ser315 and ser392 on the c-terminus of p53 were found to be phosphorylated. The precise biological role of this phosphorylation remains to be elucidated.	SIGNOR-145315	0.551
perfluorodecanoic acid	chemical	CHEBI:35546	ChEBI	AR	protein	P10275	UNIPROT	down-regulates activity	chemical inhibition			-1									23764977	t		miannu	Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. 	SIGNOR-268770	0.8
MTOR	protein	P42345	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0000132		SIGNOR-C2						21592956	t		lperfetto	Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1.	SIGNOR-217869	0.928
RNF8	protein	O76064	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates				9606									31225475	f		miannu	L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.	SIGNOR-266790	0.7
P2RY2	protein	P41231	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	up-regulates activity	demethylation			9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-265342	0.2
BRIP1	protein	Q9BX63	UNIPROT	BRCA1-B complex	complex	SIGNOR-C298	SIGNOR	form complex	binding												25400280	t		lperfetto	Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation	SIGNOR-263219	0.661
SDC4	protein	P31431	UNIPROT	FN1/SDC4	complex	SIGNOR-C210	SIGNOR	form complex	binding												23290138	t		apalma	We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells	SIGNOR-255286	0.7
RPL36A	protein	P83881	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262492	0.818
PPP2CA	protein	P67775	UNIPROT	RPS3	protein	P23396	UNIPROT	down-regulates	dephosphorylation	Ser6	sKKRKFVA	9606									15950189	t		lperfetto	We identified that pp2a interacts with wild-type rps3, but not with mutants (s6a/t221a) (fig. 8), and that it associates with the n-terminal region of rps3 (fig. 2). From our results presented here, we conclude that pp2a is involved in the dephosphorylation of phosphorylated rps3 by pkc
, and that serine 6 on the n-terminal region of rps3 appears to mediate the pp2a recruitment.	SIGNOR-137963	0.402
aloxistatin	chemical	CHEBI:101381	ChEBI	CTSL	protein	P07711	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								32142651	t		miannu	Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines.	SIGNOR-260282	0.8
BAX	protein	Q07812	UNIPROT	VDAC1	protein	P21796	UNIPROT	up-regulates activity	binding												10365962	t		lperfetto	The recombinant pro-apoptotic proteins Bax and Bak accelerate the opening of VDAC	SIGNOR-249613	0.574
MOB1B	protein	Q7L9L4	UNIPROT	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	up-regulates	binding			9606									21084559	t	Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases.	gcesareni	Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1.	SIGNOR-269865	0.918
CSNK2A1	protein	P68400	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	unknown	phosphorylation	Ser661	GAEVYSDsEDDVLSS	9606									19236849	t		llicata	We demonstrate that sirt1 is a substrate for protein kinase ck2 both in vitro and in vivo. Both, deletion construct analyses and serine-to-alanine mutations identified sirt1 ser-659 and ser-661 as major ck2 phosphorylation sites that are phosphorylated in vivo as well.	SIGNOR-184155	0.627
PPP2CA	protein	P67775	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates	dephosphorylation			9606									12840032	t	inferred from 70% of family members	gcesareni	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).	SIGNOR-269918	0.634
MAPK14	protein	Q16539	UNIPROT	DLX5	protein	P56178	UNIPROT	up-regulates activity	phosphorylation	Ser34	MHHPSQEsPTLPESS	10090									18056716	t		ggiuliani	We show that Dlx5 is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-34 and Ser-217 are the sites phosphorylated by p38	SIGNOR-255792	0.296
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	TOB1	protein	P50616	UNIPROT	down-regulates	phosphorylation			9606									12050114	t	inferred from 70% family members	gcesareni	Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation.	SIGNOR-270210	0.2
IKBKB	protein	O14920	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser312	TESITATsPASMVGG	-1									12351658	t			IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.	SIGNOR-251293	0.644
MSX2	protein	P35548	UNIPROT	DLX5	protein	P56178	UNIPROT	down-regulates activity	binding			10090	BTO:0000947								9111364	t	2	miannu	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240990	0.553
TAOK1	protein	Q7L7X3	UNIPROT	STK3	protein	Q13188	UNIPROT	up-regulates	phosphorylation			9606									23431053	t		gcesareni	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.	SIGNOR-201321	0.302
MOB1A	protein	Q9H8S9	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	binding			9606									21084559	t	Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases.	gcesareni	Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1	SIGNOR-169755	0.862
PPP2CA	protein	P67775	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates	dephosphorylation	Thr32	QSRPRSCtWPLQRPE	9606									20110348	t		gcesareni	Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a.	SIGNOR-163684	0.411
ATRX	protein	P46100	UNIPROT	Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	up-regulates activity	binding			9606									25417162	t		lperfetto	ATRX is a required specificity determinant for PRC2 targeting and function.	SIGNOR-241890	0.343
CALM1	protein	P0DP23	UNIPROT	PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	up-regulates	binding			9606									11796223	t	inferred from 70% of family members	gcesareni	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-269892	0.762
IL1RAP	protein	Q9NPH3	UNIPROT	IL1R1	protein	P14778	UNIPROT	up-regulates	binding			9606									12530978	t		gcesareni	Here we report that the soluble form of the il-1 receptor accessory protein (acp) increases the affinity of binding of human il-1alpha and il-1beta to the soluble human type ii il-1 receptor by approximately 100-fold,	SIGNOR-97396	0.718
CDK5	protein	Q00535	UNIPROT	GRIN2A	protein	Q12879	UNIPROT	up-regulates activity	phosphorylation	Ser1232	SGHFTMRsPFKCDAC	10116	BTO:0000938								11675505	t		llicata	Here, we demonstrate that cyclin dependent kinase-5 (Cdk5) associates with and phosphorylates NR2A subunits at Ser-1232 in vitro and in intact cells. Moreover, we show that roscovitine, a selective Cdk5 inhibitor, blocks both long-term potentiation induction and NMDA-evoked currents in rat CA1 hippocampal neurons. These results suggest that Cdk5 plays a key role in synaptic transmission and plasticity through its up-regulation of NMDARs.	SIGNOR-250666	0.541
(R)-adrenaline	smallmolecule	CHEBI:28918	ChEBI	LATS2	protein	Q9NRM7	UNIPROT	up-regulates				9606									23075495	f		gcesareni	On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz.	SIGNOR-199199	0.8
ZNF804A	protein	Q7Z570	UNIPROT	PIK3AP1	protein	Q6ZUJ8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								23434502	t		miannu	ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 	SIGNOR-269463	0.2
AGRP	protein	O00253	UNIPROT	MC1R	protein	Q01726	UNIPROT	down-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268699	0.454
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	NFY	complex	SIGNOR-C1	SIGNOR	up-regulates activity	binding			9606	BTO:0000972								18025157	t			We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein.	SIGNOR-255747	0.2
ZAP70	protein	P43403	UNIPROT	GAB2	protein	Q9UQC2	UNIPROT	up-regulates activity	phosphorylation	Tyr614	KSTGSVDyLALDFQP	9606	BTO:0000782								11572860	t		lperfetto	In the present study, we found that gab2 is phosphorylated by zap-70, associates with the tcr signaling complex, and acts as an inhibitory adaptor molecule via recruitment of shp-2 following tcr ligation.	SIGNOR-110731	0.473
FYN	protein	P06241	UNIPROT	TRIO	protein	O75962	UNIPROT	up-regulates activity	phosphorylation	Tyr2681	LLNPNYIyDVPPEFV	-1									23230270	t		miannu	Here, we demonstrate that Trio is phosphorylated by Src family kinases in the embryonic rat cortex in response to netrin-1. In vitro, Trio was predominantly phosphorylated at Tyr(2622) by the Src kinase Fyn. 	SIGNOR-273855	0.2
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1784	TPTSPNYsPTSPSYS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248790	0.441
NFIB	protein	O00712	UNIPROT	NFIX	protein	Q14938	UNIPROT	up-regulates quantity	transcriptional regulation			10090									29106906	t		Gianni	We report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord.	SIGNOR-268870	0.429
SLC6A3	protein	Q01959	UNIPROT	dopamine	smallmolecule	CHEBI:18243	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								30465801	t		miannu	Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. 	SIGNOR-269189	0.8
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates activity	phosphorylation	Ser162	FDIVSRGsTADLDGL	-1									19661060	t		miannu	Activation of the TRPV4 ion channel is enhanced by phosphorylation. TRPV4 is phosphorylated in response to activation of PKC. We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.	SIGNOR-276229	0.2
Pac-1	chemical	CID:135421197	PUBCHEM	CASP3	protein	P42574	UNIPROT	up-regulates activity	chemical activation			-1									16936720	t		lperfetto	Here we report the identification of a small molecule (PAC-1) that directly activates procaspase-3 to caspase-3 in vitro and induces apoptosis in cancerous cells isolated from primary colon tumors in a manner directly proportional to the concentration of procaspase-3 inside these cells. W	SIGNOR-262016	0.8
MAPK1	protein	P28482	UNIPROT	SREBF1	protein	P36956	UNIPROT	up-regulates	phosphorylation	Ser117	YPSMPAFsPGPGIKE	9606									10915800	t		llicata	Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo.	SIGNOR-80092	0.415
MAPK14	protein	Q16539	UNIPROT	JUNB	protein	P17275	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10330170	f		gcesareni	Moreover, in addition to jnk, erk5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements.	SIGNOR-67535	0.492
SRC	protein	P12931	UNIPROT	GSN	protein	P06396	UNIPROT	up-regulates	phosphorylation	Tyr465	VPVDPATyGQFYGGD	9606									10210201	t		lperfetto	Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently	SIGNOR-67014	0.576
PTH1R	protein	Q03431	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding												28363951	t		lperfetto	This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11.	SIGNOR-270550	0.279
MED17	protein	Q9NVC6	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266669	0.827
ARRB1	protein	P49407	UNIPROT	KIF3A	protein	Q9Y496	UNIPROT	up-regulates	binding			9606									18497258	t		gcesareni	Kif3a is essential for shh-mediated signaling in mammalian systems (5), and we identified kif3a as a arr1 binding partner in a proteomics screen (18). To test whether arrs, smo, and kif3a might work in concert.	SIGNOR-178672	0.532
PTK2	protein	Q05397	UNIPROT	TRIO	protein	O75962	UNIPROT	up-regulates activity	phosphorylation	Tyr2796	KDNFDSFySEVAELG	9534									12551902	t		lperfetto	A FAK phosphorylation site, tyrosine residue 2737, was identified in subdomain I of the Trio kinase domain. Additionally, in vitro phosphorylation assays and in vivo co-expression studies indicated that Trio enhances FAK kinase activity.	SIGNOR-249188	0.487
8-Hydroxy-7-(6-sulfo-naphthalen-2-ylazo)-quinoline-5-sulfonic acid	chemical	CID:92577	PUBCHEM	DUSP26	protein	Q9BV47	UNIPROT	down-regulates activity	chemical inhibition			-1									19233143	t		lperfetto	Phosphatase activity of dual-specificity protein phosphatase 26 (DUSP26) was decreased by the inhibitor in a dose-dependent manner. Kinetic studies with NSC-87877 and DUSP26 revealed a competitive inhibition.	SIGNOR-261979	0.8
PHKG2	protein	P15735	UNIPROT	PYG	proteinfamily	SIGNOR-PF96	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0002049								22225877	t		miannu	It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15	SIGNOR-267962	0.651
SMURF1	protein	Q9HCE7	UNIPROT	BMPR1A	protein	P36894	UNIPROT	down-regulates	ubiquitination			9606									17317136	t		gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-153399	0.645
SOX17/POU5F1	complex	SIGNOR-C451	SIGNOR	PIM2	protein	Q9P1W9	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269249	0.2
CSNK2B	protein	P67870	UNIPROT	EIF5	protein	P55010	UNIPROT	up-regulates activity	phosphorylation	Ser174	DKENGSVsSSETPPP	9606	BTO:0001938								11861906	t		llicata	Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis.	SIGNOR-251068	0.387
CFL1	protein	P23528	UNIPROT	Axonal_growth_cone_formation	phenotype	SIGNOR-PH199	SIGNOR	down-regulates				9606									16226035	f		miannu	This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation.	SIGNOR-268382	0.7
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO1	protein	Q12778	UNIPROT	up-regulates	phosphorylation			9606									18394876	t		lperfetto	The energy sensor AMP-activated protein kinase (AMPK) has been shown to directly phosphorylate FoxO factors at six regulatory sites that are distinct from the Akt phosphorylation sites, resulting in FoxO activation.	SIGNOR-216478	0.354
PDPK1	protein	O15530	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	up-regulates activity	phosphorylation	Thr228	HEGAVTHtFCGTIEY	-1									11733037	t		miannu	 Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities.	SIGNOR-250273	0.595
TCAP	protein	O15273	UNIPROT	Sarcomere_organization	phenotype	SIGNOR-PH165	SIGNOR	up-regulates activity	binding			9606		BTO:0001103							9804419	t		lperfetto	The giant muscle protein titin (connectin) is essential in the temporal and spatial control of the assembly of the highly ordered sarcomeres (contractile units) of striated muscle. 	SIGNOR-264855	0.7
PLK1	protein	P53350	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007;BTO:0001914								23887393	t		gcesareni	Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency	SIGNOR-243522	0.549
WWTR1	protein	Q9GZV5	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates				9606									23075495	f		gcesareni	Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis.	SIGNOR-256668	0.7
CDC14B	protein	O60729	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Ser684	IGIPQFHsPVGSPLK	9606									20236090	t			Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3.	SIGNOR-248334	0.552
ZMYND8	protein	Q9ULU4	UNIPROT	SNAI2	protein	O43623	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									27477906	t		lperfetto	Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported	SIGNOR-262038	0.2
PHLPP1	protein	O60346	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0000527								15808505	t		gcesareni	Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth.	SIGNOR-135005	0.752
Aflibercept	chemical	SID:134445687	ChEBI	VEGFA	protein	P15692	UNIPROT	down-regulates activity	chemical inhibition			9606									22813448	t		miannu	Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor. 	SIGNOR-259386	0.8
FOXO3	protein	O43524	UNIPROT	TSC22D3	protein	Q99576	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001482								15705665	t			We have analyzed the promoter of human gilz (glucocorticoid-induced leucine zipper), a dexamethasone-inducible gene that is involved in regulating apoptosis, and identified six glucocorticoid (GC)-responsive elements and three Forkhead responsive elements (FHREs).	SIGNOR-255950	0.406
Phenylalanyl-tRNA synthetase	complex	SIGNOR-C473	SIGNOR	tRNA(Phe)	smallmolecule	CHEBI:29184	ChEBI	down-regulates quantity	chemical modification			9606									20223217	t		miannu	Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers.	SIGNOR-270438	0.8
RIT2	protein	Q99578	UNIPROT	POU4F1	protein	Q01851	UNIPROT	up-regulates activity	binding			9606	BTO:0000934								12934100	t		miannu	we describe the evidence for a functional interaction between Brn-3a and Rin and demonstrate the role of Rin in modulating the activation of the Brn-3a regulated egr-1 promoter by the N-terminal domain of Brn-3a.	SIGNOR-224546	0.542
BRK1	protein	Q8WUW1	UNIPROT	WRC complex	complex	SIGNOR-C191	SIGNOR	form complex	binding			9606									21107423	t		miannu	WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems	SIGNOR-253570	0.859
ADIPOQ	protein	Q15848	UNIPROT	ADIPOR1	protein	Q96A54	UNIPROT	up-regulates	binding			9606									16622416	t		milica	Two adiponectin receptors, adipor1 and adipor2, have recently been identified.	SIGNOR-146170	0.666
DEAF1	protein	O75398	UNIPROT	HTR1A	protein	P08908	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									14507979	f	 	lperfetto	Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism.	SIGNOR-254124	0.45
DKK1	protein	O94907	UNIPROT	KREMEN1	protein	Q96MU8	UNIPROT	up-regulates	binding			9606									12050670	t		gcesareni	Dkk1 has been shown to inhibitwnt by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to blockwnt/betBeta-catenin. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of thewntreceptor lrp6 from the plasma membrane.	SIGNOR-88838	0.832
MTOR	protein	P42345	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation	Thr390	DSKFTRQtPVDSPDD	9606									11914378	t			Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain,[…] Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings.	SIGNOR-255841	0.553
paroxetine	chemical	CHEBI:7936	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9537821	t		miannu	Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 	SIGNOR-258739	0.8
USP6	protein	P35125	UNIPROT	MMP9	protein	P14780	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20418905	f		miannu	In this study we show that tre17 is sufficient to induce expression of mmp-9 and mmp-10, in a manner requiring its usp activity, but not its ability to bind arf6. Tre17 induces transcription of mmp-9 through activation of nuclear factor-kappab (nf-kappab), mediated in part by the gtpase rhoa and its effector kinase, rock.	SIGNOR-164946	0.334
2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid	chemical	CID:135461425	PUBCHEM	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		miannu	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here.	SIGNOR-259707	0.8
CSNK2A1	protein	P68400	UNIPROT	L1CAM	protein	P32004	UNIPROT	unknown	phosphorylation	Ser1181	GEYRSLEsDNEEKAF	10116	BTO:0000142								8592152	t		llicata	Serine to alanine substitutions in these peptides indicate that the CKII phosphorylation site is at Ser1,181. | Finally, in vivo radiolabeling indicates that Ser1,181 is phosphorylated in newborn rat brain. These data show that CKII is associated with and able to phosphorylate L1.	SIGNOR-250913	0.468
PKCtheta/Nfix	complex	SIGNOR-C121	SIGNOR	MEF2A	protein	Q02078	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000165								20178747	t		llicata	In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A.	SIGNOR-238022	0.344
AURKB	protein	Q96GD4	UNIPROT	NINL	protein	Q9Y2I6	UNIPROT	up-regulates	phosphorylation	Ser185	WDSEDFGsPQKSCSP	9606									20864540	t		lperfetto	Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability.	SIGNOR-168045	0.255
GPR17	protein	Q13304	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256971	0.2
INTS4	protein	Q96HW7	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261467	0.755
lapatinib	chemical	CHEBI:49603	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258234	0.8
PIAS1	protein	O75925	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates	sumoylation			9606									15028714	t		lperfetto	These data demonstrate that pias1 protein positively modulates tgf-beta responses as a sumo e3 ligase for smad4	SIGNOR-123462	0.403
MYC	protein	P01106	UNIPROT	Enolase	proteinfamily	SIGNOR-PF74	SIGNOR	up-regulates quantity	transcriptional regulation			10116									10823814	t	inferred from family member		C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.	SIGNOR-270247	0.423
TFAP4	protein	Q01664	UNIPROT	NFIA	protein	Q12857	UNIPROT	up-regulates activity	binding			9606	BTO:0001109								19505873	t		miannu	We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads.	SIGNOR-226586	0.27
PDK4	protein	Q16654	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates	phosphorylation	Ser300	SMSDPGVsYRTREEI	9606									17474719	t		gcesareni	In mammals, pdhc is tightly regulated by phosphorylation-dephosphorylation of three serine residues in the thiamin-dependent pyruvate dehydrogenase (e1) component. In vivo, inactivation of human pdhc correlates mostly with phosphorylation of serine 264, which is located at the entrance of the substrate channel leading to the active site of e1.	SIGNOR-154656	0.674
leukotriene B4(1-)	smallmolecule	CHEBI:57461	ChEBI	LTB4R	protein	Q15722	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257534	0.8
EGFR	protein	P00533	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates	phosphorylation	Tyr447	SEELDENyVPMNPNS	9606	BTO:0000527;BTO:0000017								9890893	t		lperfetto	Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689).	SIGNOR-236420	0.751
RNF146	protein	Q9NTX7	UNIPROT	TNKS	protein	O95271	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								21799911	t			We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation.	SIGNOR-260004	0.713
NCK1	protein	P16333	UNIPROT	WASL	protein	O00401	UNIPROT	up-regulates	binding			9606									11340081	t		gcesareni	Nck and cdc42 activate n-wasp by redundant mechanisms.	SIGNOR-107634	0.772
4E2RCat	chemical	CID:2287236	PUBCHEM	EIF4E	protein	P06730	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000414								21507972	t		miannu	Characterization of 4E2RCat, an inhibitor of eIF4E-eIF4G interaction. Herein we describe a molecule from this screen that prevents the interaction between eIF4E (the cap-binding protein) and eIF4G (a large scaffolding protein), inhibiting cap-dependent translation. This inhibitor significantly decreased human coronavirus 229E (HCoV-229E) replication, reducing the percentage of infected cells and intra- and extracellular infectious virus titers. 	SIGNOR-260187	0.8
FFAR4	protein	Q5NUL3	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257045	0.252
Varespladib	chemical	CID:155815	PUBCHEM	PLA2G1B	protein	P04054	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207633	0.8
ITGB1BP1	protein	O14713	UNIPROT	AL/b2 integrin	complex	SIGNOR-C169	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257650	0.318
NLGN3	protein	Q9NZ94	UNIPROT	NRXN3	protein	Q9HDB5	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264167	0.82
CAMK2D	protein	Q13557	UNIPROT	KCNQ1	protein	P51787	UNIPROT	down-regulates activity	phosphorylation	Ser484	PHFMRTNsFAEDLDL										29410121	t		lperfetto	CaMKII regulates KCNQ1 at S484 during sustained β-AR stimulation to inhibit IKs. The ability of CaMKII to inhibit IKs may contribute to arrhythmogenicity during HF.	SIGNOR-275479	0.2
ACVR1B	protein	P36896	UNIPROT	TDP2	protein	O95551	UNIPROT	up-regulates activity	phosphorylation	Thr92	VDLTNEEtTDSTTSK	9606	BTO:0000007								18039968	t		miannu	 ALK4 phosphorylated TTRAP in vitro (Fig. 6A). The band migrating at the position of TTRAP was excised and analyzed by LC-MS/MS. One TTRAP peptide was phosphorylated either on T88 and T92, or on T92 only (Fig. 6B).We tested in vivo phosphorylation of Strep-TTRAP by co-expression with mouse Alk4 in HEK293T cells, and affinity-purified TTRAP. In this preparation TTRAP-specific peptides were reproducibly found in both the singly (T92) and doubly phosphorylated form (T88/T92). mutant TTRAPT88A,T92A is not able to rescue the TtrapMO phenotype, suggesting that phosphorylation of Ttrap on Thr88 and Thr92 is essential for Ttrap function.	SIGNOR-262612	0.285
DYRK1A	protein	Q13627	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity	SIGNOR-183677	0.321
FCER1G	protein	P30273	UNIPROT	FCER1G/FCER1G	complex	SIGNOR-C199	SIGNOR	form complex	binding			9606	BTO:0000830								16470226	t		Alessandro Palma	FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling.	SIGNOR-254961	0.2
MTR	protein	Q99707	UNIPROT	(6S)-5-methyltetrahydrofolate(2-)	smallmolecule	CHEBI:18608	ChEBI	down-regulates quantity	chemical modification			9606									10520212	t		lperfetto	Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels.	SIGNOR-253144	0.8
PIK-90	chemical	CID:6857685	PUBCHEM	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206229	0.8
HK1	protein	P19367	UNIPROT	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor.	SIGNOR-266455	0.8
CHUK	protein	O15111	UNIPROT	NFKB2	protein	Q00653	UNIPROT	up-regulates activity	phosphorylation	Ser870	KEDSAYGsQSVEQEA	10090	BTO:0000785								15084608	t		lperfetto	Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52.	SIGNOR-124230	0.784
26S Proteasome	complex	SIGNOR-C307	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity	destabilization			10090	BTO:0003569								9233789	t			Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of beta-catenin turnover. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of beta-catenin.	SIGNOR-270340	0.39
CDK2	protein	P24941	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates	phosphorylation	Ser249	EGGKSGKsPRRRAAS	9606									17038621	t		lperfetto	Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1.	SIGNOR-150028	0.638
PROC	protein	P04070	UNIPROT	F5	protein	P12259	UNIPROT	down-regulates activity	cleavage	Arg334	KNCPKKTrNLKKITR	-1									7989361	t		lperfetto	The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. 	SIGNOR-263628	0.583
LONP2	protein	Q86WA8	UNIPROT	TYSND1	protein	Q2T9J0	UNIPROT	down-regulates quantity by destabilization	cleavage			9606	BTO:0000567								22002062	t		miannu	Self-cleavage of Tysnd1 in the active oligomer most likely inactivates its protease activity. Subsequently, the cleaved products are degraded by PsLon and removed from the Tysnd1 oligomer. 	SIGNOR-261054	0.646
atomoxetine	chemical	CHEBI:127342	ChEBI	SLC6A3	protein	Q01959	UNIPROT	down-regulates activity	chemical inhibition			-1									9871604	t		miannu	The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2.	SIGNOR-259070	0.8
NFIB	protein	O00712	UNIPROT	EPHA4	protein	P54764	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268901	0.2
ELL	protein	P55199	UNIPROT	ELL/ICE1	complex	SIGNOR-C48	SIGNOR	form complex	binding			9606	BTO:0001271								22195968	t		miannu	The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes.	SIGNOR-193458	0.554
HES1	protein	Q14469	UNIPROT	ASCL1	protein	P50553	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000931								11054669	f		miannu	 Our data show that functional sympathetic neuronal differentiation of neuroblastoma cells is associated with transient activation of HES-1 and down-regulation of HASH-1 expression.	SIGNOR-254824	0.453
Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	PAX7	protein	P23759	UNIPROT	down-regulates quantity by repression	transcriptional regulation												20887952	t			The results presented above demonstrate a signal-dependent interaction between p38a, YY1, and EZH2 on the chromatin of the Pax7 regulatory elements that coincides with p38-mediated repression of Pax7 at early stages of myoblast differentiation.	SIGNOR-253598	0.376
AXIN1	protein	O15169	UNIPROT	RNF111	protein	Q6ZNA4	UNIPROT	up-regulates	binding			9606									14657019	t		gcesareni	Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia.	SIGNOR-119660	0.626
HOXA9	protein	P31269	UNIPROT	MSI2	protein	Q96DH6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20805843	f		gcesareni	Nup98-hoxa9 oncogene binds the putative element at 5.7 kb upstream of transcription start site to trigger the upregulated expression of musashi2 gene (b). The elevated level of musashi2 leads to the downregulation of numb, by binding to the 3' utr of numb mrna to inhibit translation	SIGNOR-167725	0.44
Brivanib alaninate	chemical	CID:11154925	PUBCHEM	FGFR3	protein	P22607	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190723	0.8
BMPR1B	protein	O00238	UNIPROT	SMAD5	protein	Q99717	UNIPROT	up-regulates activity	phosphorylation			9606									19620713	t		lperfetto	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-255260	0.667
PDGFRB	protein	P09619	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates activity	phosphorylation	Tyr763	DMKGDVKyADIESSN	9823									10391677	t		miannu	Activation of the beta-receptor for platelet-derived growth factor (PDGF) by its ligand leads to autophosphorylation on a number of tyrosine residues. Here we show that Tyr763 in the kinase insert region is a novel autophosphorylation site, which after phosphorylation binds the protein tyrosine phosphatase SHP-2. 	SIGNOR-250258	0.2
SEPTIN7	protein	Q16181	UNIPROT	CENPE	protein	Q02224	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								18460473	t		lperfetto	These findings reveal a key role for the SEPT7-CENP-E interaction in the distribution of CENP-E to the kinetochore and achieving chromosome alignment. We propose that SEPT7 forms a link between kinetochore distribution of CENP-E and the mitotic spindle checkpoint.	SIGNOR-252040	0.2
oxotremorine M	chemical	CHEBI:38322	ChEBI	CHRM4	protein	P08173	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258657	0.8
SRC	protein	P12931	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates activity	phosphorylation	Tyr251	LQFPGAVyGTDGCPV										29844931	t		lperfetto	As a result, we established that Src was able to directly phosphorylate caspase-9 at tyrosine 251, leading to elevated caspase-9 activity.	SIGNOR-272998	0.383
dothiepin	chemical	CHEBI:36798	ChEBI	CHRM1	protein	P11229	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8100134	t		miannu	Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 	SIGNOR-258697	0.8
KCNJ5	protein	P48544	UNIPROT	KCNJ5/KCNJ3	complex	SIGNOR-C56	SIGNOR	form complex	binding			9606		BTO:0000562							22362083	t		miannu	The muscarinic k(+) channel (i (k,ach)) is a heterotetramer composed of girk1 (kir3.1) andgirk4(kir3.4) subunits of a g protein-coupled inwardly rectifying channel, and plays an important role in mediating electrical responses to the vagal stimulation in the heart.	SIGNOR-196205	0.482
EP300	protein	Q09472	UNIPROT	XBP1	protein	P17861-2	UNIPROT	up-regulates quantity by stabilization	acetylation			9606	BTO:0000007								20955178	t		miannu	P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR. 	SIGNOR-260429	0.289
UNC5	proteinfamily	SIGNOR-PF98	SIGNOR	Chemorepulsion_of_axon	phenotype	SIGNOR-PH198	SIGNOR	up-regulates				9606									30108487	f		miannu	Netrin binding to the receptor deleted in colorectal cancer (DCC) results in attractive responses, viahomodimerization of DCC (covered in detail in later sections), whereas heterodimerization between DCC and receptor uncoordinated locomotion 5 (UNC5) converts this attractive response into repulsion	SIGNOR-268177	0.7
PAX6	protein	P26367	UNIPROT	PCSK1	protein	P29120	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									19034419	f	 	miannu	 PAX6 can bind to the promoter and directly upregulate production of prohormone convertase (PC)1/3, an enzyme essential for conversion of proinsulin to insulin. 	SIGNOR-254900	0.34
CAMK1	protein	Q14012	UNIPROT	EIF4G3	protein	O43432	UNIPROT	unknown	phosphorylation	Ser1156	NTFMRGGsSKDLLDN	9606									14507913	t		llicata	Endogenous eIF4GII immunoprecipitated from HEK293T cells was phosphorylated by CaMKI, in vitro as was a recombinant fragment of eIF4GII encompassing the central and C-terminal regions. The latter phosphorylation occurred with favorable kinetics (Km = 1 microm; kcat = 1.8 s-1) at a single site, Ser1156, located in a segment of eIF4GII aligning with the phosphoregion of eIF4GI. Phosphopeptide mapping and back phosphorylation experiments revealed [Ca2+]i-dependent, CaMKI site-specific, eIF4GII phosphorylation in vivo.	SIGNOR-250613	0.486
MTR	protein	Q99707	UNIPROT	methionine	smallmolecule	CHEBI:16811	ChEBI	up-regulates quantity	chemical modification			9606									10520212	t		lperfetto	Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels.	SIGNOR-253143	0.8
LYN	protein	P07948	UNIPROT	PPP1R8	protein	Q12972	UNIPROT	down-regulates activity	phosphorylation	Tyr264	FAFSGGLyGGLPPTH	-1									11104670	t			Tyrosine phosphorylation of NIPP1 by Lyn was abolished by the Tyr-264 to Asp mutation.	SIGNOR-251405	0.317
LCK	protein	P06239	UNIPROT	CD5	protein	P06127	UNIPROT	up-regulates activity	phosphorylation	Tyr487	DNSSDSDyDLHGAQR	9606	BTO:0000782								11298344	t		lperfetto	Tyrosine phosphorylation of cd5 requires lck activity. We propose that t cell activation mediates cd5 tyrosine phosphorylation at residues y429 and y463 mainly through the activation of lck	SIGNOR-106803	0.558
PAX5	protein	Q02548	UNIPROT	PRDM1	protein	O75626	UNIPROT	down-regulates quantity	transcriptional regulation			10090									9120274	t		Gianni	Overexpression of BSAP reduced Blimp-1 expression in CH12.LX.A2 clones but not in MPC11 clones. In addition, overexpression of BSAP in CH12.LX.A2 cells suppressed spontaneous appearance of cells with high Syndecan-1 expression and high amounts of intracytosolic as well as secreted Ig synthesi	SIGNOR-269085	0.518
H4C1	protein	P62805	UNIPROT	Nucleosome_H3.1t variant	complex	SIGNOR-C325	SIGNOR	form complex	binding			-1									20498094	t		miannu	A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. 	SIGNOR-263726	0.2
DISC1	protein	Q9NRI5	UNIPROT	KIF5B	protein	P33176	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								17202468	t		miannu	We identified Kinesin-1, a microtubule-dependent and plus-end directed motor, as a DISC1-interacting molecule. Our results show that DISC1 links Kinesin-1 to the NUDEL/LIS1/14-3-3ε complex, serves as the cargo receptor, and regulates the transport of the complex to axons, leading to axon elongation. DISC1 directly interacted with kinesin heavy chain of Kinesin-1. Kinesin-1 interacted with the NUDEL/LIS1/14-3-3ε complex through DISC1	SIGNOR-252161	0.2
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270408	0.8
PRKCA	protein	P17252	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser359	EERQTQRsKPQPAVP	9606	BTO:0000130								12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89170	0.538
PITX2	protein	Q99697	UNIPROT	TBX1	protein	O43435	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20129917	f	Regulation	miannu	 Pitx2 activated Tbx4, Tbx15, and Mga and repressed Tbx1, Tbx2, Tbx5, and Tbx6 expression.	SIGNOR-251870	0.432
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	CYP26A1	protein	O43174	UNIPROT	up-regulates activity	chemical activation			9606									31963453	t		lperfetto	Cytochrome P450 (CYP) subfamily 26 of enzymes degrade the excess of RA to avoid detrimental effects [17]. Among the three subtypes (CYP26A1, CYP26B1, and CYP26C1), CYP26A1 is particularly important during embryonic development	SIGNOR-265138	0.8
ARAF	protein	P10398	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates	phosphorylation	Ser222	LIDSMANsFVGTRSY	9606	BTO:0000567								8621729	t		lperfetto	Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling|The immunoprecipitates were assayed for GST-MEK1 activation. D, activation of MEK1 by A-Raf requires the presence of serine residue 218 and 222.	SIGNOR-235944	0.728
tacedinaline	chemical	CHEBI:90195	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-258007	0.8
VEGFA	protein	P15692	UNIPROT	DLL4	protein	Q9NR61	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22426001	f		gcesareni	Activation triggered by vegf-a (also known as vegf) has been shown to induce expression of thenotchligand dll4 in angiogenic vessels.	SIGNOR-196736	0.487
DKK1	protein	O94907	UNIPROT	WNT3A	protein	P56704	UNIPROT	down-regulates				9606									19874086	f	Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6.	gcesareni	It has been shown that both sclerostin and dkk1 act physiologically as downstream molecules of bmp signaling to inhibit canonical wnt signaling and therefore negatively regulate bone mass.	SIGNOR-188961	0.725
STMN1	protein	P16949	UNIPROT	TTL	protein	Q8NG68	UNIPROT	down-regulates	binding			9606									23624152	t		miannu	Stathmin depresses ttl tubulin tyrosination activityin vitro.	SIGNOR-193465	0.4
ERG	protein	P11308	UNIPROT	TDRD1	protein	Q9BXT4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003215								23319146	f	 	miannu	 In the prostate cancer cell line VCaP, downregulation of ERG by shRNA lead to a lower expression level of TDRD1 and resulted in a decreased activity of the TDRD1 promoter.	SIGNOR-254067	0.2
KIF5A	protein	Q12840	UNIPROT	Organelle_transport	phenotype	SIGNOR-PH159	SIGNOR	up-regulates				9606	BTO:0000938								9438838	f		miannu	The kinesin superfamily of proteins plays a major role in this complex organelle transport. Kinesin is primarily associated with anterogradely transported membranous organelles in nerve axons. KIF5B and HsuKHC are expressed ubiquitously in many tissues, whereas KIF5A, KIF5C, and HsnKHC are specific to nerve tissue.	SIGNOR-264067	0.7
IL3	protein	P08700	UNIPROT	IL3RA	protein	P26951	UNIPROT	up-regulates	binding			9606									1465408	t		fspada	These results show the generation of an il-3 analog with increased biological and binding activities and support a model where the c terminus of il-3 interacts with the alpha chain of the il-3 receptor, making this region a useful focus for the development of more potent il-3 agonists or antagonists	SIGNOR-19538	0.884
PEA15	protein	Q15121	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	down-regulates				9606									11702783	f	inferred from 70% of family members	gcesareni	Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase.	SIGNOR-269904	0.2
FOXO3	protein	O43524	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									14981546	f			Induction of Foxo3a phosphorylation by FLT3-ITD receptors in Ba/F3 cells correlates with the suppression of Foxo-target genes p27Kip1 and the proapoptotic Bcl-2 family member Bim	SIGNOR-261528	0.763
PAK1	protein	Q13153	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates	phosphorylation			9606									15037762	t		gcesareni	Kinases targeted sequentially to the neck, cla4/pak and cdc5/polo, are responsible for stepwise phosphorylation and down-regulation of swe1.	SIGNOR-123528	0.303
ITK	protein	Q08881	UNIPROT	CD28	protein	P10747	UNIPROT	up-regulates activity	phosphorylation	Tyr191	SRLLHSDyMNMTPRR										8992971	t			EMT can phosphorylate all four tyrosines of the CD28 tail. in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor.	SIGNOR-251336	0.677
DMTF1	protein	Q9Y222	UNIPROT	EGR1	protein	P18146	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004532								19816943	t		Luana	 Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. 	SIGNOR-261584	0.2
SYK	protein	P43405	UNIPROT	LAT2	protein	Q9GZY6	UNIPROT	up-regulates activity	phosphorylation	Tyr136	EDDDANSyENVLICK	10090	BTO:0001930								14722116	t		miannu	Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases.	SIGNOR-273576	0.576
PAPOLB	protein	Q9NRJ5	UNIPROT	mRNA_polyadenylation	phenotype	SIGNOR-PH200	SIGNOR	up-regulates				9606									19224921	f		lperfetto	Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner.	SIGNOR-268326	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	STK4	protein	Q13043	UNIPROT	down-regulates	phosphorylation	Thr120	IIRLRNKtLTEDEIA	9606									19940129	t		llicata	Akt interacts with mst1 and phosphorylates a highly conserved residue threonine 120 of mst1, which leads to inhibition of its kinase activity and nuclear translocation as well as the autophosphorylation of thr(183).	SIGNOR-161829	0.2
YY1	protein	P25490	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates activity	binding			9606	BTO:0000664								12913000	t			Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex [..] both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling.	SIGNOR-254305	0.607
LRRK2	protein	Q5S007	UNIPROT	SH3GL2	protein	Q99962	UNIPROT	down-regulates	phosphorylation	Ser75	LSMINTMsKIRGQEK	9606									22998870	t		gcesareni	We show that lrrk2 affects synaptic endocytosis by phosphorylating endophilin-a1 at s75.	SIGNOR-192072	0.484
ARHGAP23	protein	Q9P227	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260479	0.529
IFNAR	complex	SIGNOR-C243	SIGNOR	JAK1	protein	P23458	UNIPROT	up-regulates activity	binding			9606									15120645	t		miannu	Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48).	SIGNOR-260147	0.727
AURKB	protein	Q96GD4	UNIPROT	CENPA	protein	P49450	UNIPROT	unknown	phosphorylation	Ser7	sRKPEAPR	9606	BTO:0000567								11756469	t		llicata	CENP-A–GST constructs were prepared in which Ser7 was mutated to alanine or glutamic acid. Phosphorylation of these proteins by Aurora B was reduced by 50%, demonstrating that Ser7 is a kinase substrate | Therefore, under the short term induction conditions used in these experiments, we can conclude that CENP-A Ser7 mutations do not grossly interfere with kinetochore formation, spindle assembly, or cell cycle progression.	SIGNOR-250585	0.815
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	ROCK1	protein	Q13464	UNIPROT	up-regulates	cleavage			9606									11283607	t		gcesareni	Rock i is cleaved by casp3 at a conserved detd1113/g sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity.	SIGNOR-256460	0.724
SNAI2	protein	O43623	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000150								20509143	f		miannu	 SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. 	SIGNOR-255154	0.433
CSNK2A1	protein	P68400	UNIPROT	XPC	protein	Q01831	UNIPROT	up-regulates activity	phosphorylation	Ser94	VIKDEALsDGDDLRD	9606	BTO:0000552								29660033	t		miannu	CK2 kinase mediates XPC phosphorylation at serine 94, and also promotes recruitment of ubiquitinated XPC to the chromatin after UVB irradiation.	SIGNOR-277389	0.2
NGEF	protein	Q8N5V2	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260562	0.661
phenylalanine	smallmolecule	CHEBI:28044	ChEBI	GCHFR	protein	P30047	UNIPROT	down-regulates activity	chemical inhibition			9606									11361142	t		miannu	The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine	SIGNOR-252205	0.8
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser740	SFTALDWsWLQTEEE	9606			SIGNOR-C14	SIGNOR-C14					10195894	t		lperfetto	Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response	SIGNOR-236048	0.2
PI4K2A	protein	Q9BTU6	UNIPROT	CLSPN	protein	Q9HAW4	UNIPROT	down-regulates	phosphorylation	Ser984	ALALCSGsFPTDKEE	9606									18082599	t		gcesareni	These results indicate that plx1 phosphorylates claspin on s934, which is relatively close to the plx1-docking site at t906. Human claspin also contains a serine at position 984 in a homologous sequence	SIGNOR-159937	0.2
PPP2CA	protein	P67775	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates	dephosphorylation			9606									12840032	t		gcesareni	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).	SIGNOR-103162	0.632
crizotinib	chemical	CHEBI:64310	ChEBI	ALK	protein	Q9UM73	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258101	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser259	FPLRKTAsEPNLKVR	9606									21892142	t		lperfetto	Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)	SIGNOR-216596	0.316
NEK2	protein	P51955	UNIPROT	GAS2L1	protein	Q99501	UNIPROT	up-regulates activity	phosphorylation	Ser352	HPRSRRYsGDSDSSA	9606									32289147	t		miannu	Nek2A mediates G2/M phosphorylation of GAS2L1. GAS2L1 and its Ser352 phosphorylation are required for proper spindle organization and chromosome segregation. 	SIGNOR-273683	0.2
ABL1	protein	P00519	UNIPROT	PSMA7	protein	O14818	UNIPROT	down-regulates	phosphorylation	Tyr153	QTDPSGTyHAWKANA	9606									16678104	t		lperfetto	Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised	SIGNOR-146585	0.406
Blood vessel damage	stimulus	SIGNOR-ST26	SIGNOR	VWF	protein	P04275	UNIPROT	up-regulates				9606									NBK559062	f		lperfetto	Exposed VWF bound to collagen from vascular injury and endothelial damage adheres to the GPIb receptor on platelets to initiate signaling pathways for platelet activation, the next step in primary hemostasis. VW|VWF released by Weibel-Palade bodies or alpha-granules can enter circulation or accumulate in the subendothelial matrix binding to collagen through its A3 domain. Once exposed under high shear stress conditions in the arterial circulation, VWF can bind to platelets via its A1 domain. 	SIGNOR-261862	0.7
glutaryl-CoA(5-)	smallmolecule	CHEBI:57378	ChEBI	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	precursor of												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271812	0.8
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	GRM5	protein	P41594	UNIPROT	up-regulates activity	phosphorylation			-1									15894802	t	inferred from 70% family members	lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-269972	0.2
Neurophysin 1	protein	P01178-PRO_0000020496	UNIPROT	Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	up-regulates quantity	binding			9606	BTO:0000427								9511957	t		miannu	 Neurophysins I and II (NPI and NPII) serve in the neurosecretory granules of the posterior pituitary as carrier proteins for the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively, until the latter are released into blood. 	SIGNOR-270351	0.2
EFNA1	protein	P20827	UNIPROT	EPHA8	protein	P29322	UNIPROT	up-regulates	binding			9606									9576626	t		gcesareni	Ephrins are cell-surface tethered guidance cues that bind to eph receptor tyrosine kinases in trans on opposing cells.	SIGNOR-56968	0.811
E2F1	protein	Q01094	UNIPROT	SERPINB5	protein	P36952	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001938								20197383	f	 	lperfetto	Importantly, we show that E2F1-mediated upregulation of maspin is enhanced by chemotherapeutic drugs, and inhibition of maspin expression significantly impairs the ability of E2F1 to promote chemotherapy-induced apoptosis. Summarily, our data indicate that maspin is an important effector of E2F1-induced chemosensitization.	SIGNOR-254135	0.2
PRKACA	protein	P17612	UNIPROT	HAND1	protein	O96004	UNIPROT	down-regulates activity	phosphorylation	Ser109	KERRRTEsINSAFAE	10116	BTO:0001556								14636580	t		miannu	In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function.	SIGNOR-249989	0.299
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	TRPC5	protein	Q9UL62	UNIPROT	down-regulates activity	phosphorylation	Ser794	SGGARAKsKSVSFNL	9606	BTO:0000007								21734191	t		miannu	We show that TRPC5 channels may become directly phosphorylated by PKA at serine residues 794 and 796, and that this phosphorylation abolishes the receptor-operated nonselective cation current mediated by TRPC5 channels in HEK-293 cells. 	SIGNOR-276340	0.2
PRKACA	protein	P17612	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Ser266	FGYGGRAsDYKSAHK	-1									2413024	t		miannu	Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-163	SIGNOR-250013	0.352
serotonin(1+)	smallmolecule	CHEBI:350546	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257518	0.8
SIRT7	protein	Q9NRC8	UNIPROT	DDB1	protein	Q16531	UNIPROT	down-regulates activity	deacetylation												28886238	t		lperfetto	Here, we show that DDB1 is acetylated and acetylation promotes DDB1 binding to CUL4. We also identify nucleolar sirtuin 7 (SIRT7) as a major deacetylase that negatively regulates DDB1-CUL4 interaction. 	SIGNOR-275900	0.364
SKP2	protein	Q13309	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates	ubiquitination			9606									15314162	t		gcesareni	We found that skp2, the f-box component of scfskp2, physically interacted with smad4 at the physiological levels. Several cancer-derived unstable mutants exhibited significantly increased binding to skp2, which led to their increased ubiquitination and accelerated proteolysis. These results suggest an important role for the scfskp2 complex in switching cancer mutants of smad4 to undergo polyubiquitination-dependent degradation.	SIGNOR-127964	0.406
MAVS	protein	Q7Z434	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	binding			9606									25636800	t		miannu	Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. 	SIGNOR-260143	0.794
GGCX	protein	P38435	UNIPROT	F10	protein	P00742	UNIPROT	up-regulates activity	carboxylation	Glu47	RANSFLEeMKKGHLE	-1									9538022	t		lperfetto	This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39).	SIGNOR-263665	0.598
LSM-1231	chemical	CHEBI:91471	ChEBI	JAK2	protein	O60674	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258237	0.8
3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide	chemical	CHEBI:91433	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-195543	0.8
GFPT1	protein	Q06210	UNIPROT	Protein_glycosylation	phenotype	SIGNOR-PH144	SIGNOR	up-regulates				9606									21310273	f		miannu	 GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. 	SIGNOR-267820	0.7
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	Thermogenesis 	phenotype	SIGNOR-PH192	SIGNOR	up-regulates				9606									24692351	f		scontino	TH plays a significant role in energy expenditure through both central and peripheral actions. TH maintains basal metabolic rate, facilitates adaptive thermogenesis, modulates appetite and food intake, and regulates body weight.	SIGNOR-267492	0.7
R2SP co-chaperone	complex	SIGNOR-C517	SIGNOR	PPFIA2	protein	O75334	UNIPROT	up-regulates quantity by stabilization	binding			9606									29844425	t		miannu	Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. Remarkably, R2SP is required for liprin-α2 expression and for the assembly of liprin-α2 complexes, indicating that R2SP functions in quaternary protein folding.	SIGNOR-270942	0.2
PARD6A	protein	Q9NPB6	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates				9606									23151663	f		gcesareni	In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58.	SIGNOR-199530	0.618
PTPN12	protein	Q05209	UNIPROT	PTK2B	protein	Q14289	UNIPROT	down-regulates activity	dephosphorylation	Tyr580	YIEDEDYyKASVTRL	10116									11337490	t			Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-PEST-mediated dephosphorylation|CAKbeta was found to be a substrate for PTP-PEST. Both the major autophosphorylation site of CAKbeta (Tyr(402)) and activation loop tyrosine residues, Tyr(579) and Tyr(580), were targeted for dephosphorylation by PTP-PEST. Dephosphorylation of CAKbeta by PTP-PEST dramatically inhibited CAKbeta kinase activity.	SIGNOR-248664	0.562
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	MYLPF	protein	Q96A32	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136726	0.341
GSK3B	protein	P49841	UNIPROT	EIF2B4	protein	Q9UI10	UNIPROT	down-regulates	binding			9606									21798082	t		gcesareni	Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b).	SIGNOR-175572	0.2
ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			9606									14967450	t		miannu	All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor	SIGNOR-256162	0.2
EEF2K	protein	O00418	UNIPROT	EEF2	protein	P13639	UNIPROT	down-regulates	phosphorylation	Thr59	GETRFTDtRKDEQER	9606									2261989	t		gcesareni	Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58.	SIGNOR-22928	0.781
CYP11B2	protein	P19099	UNIPROT	11-deoxycortisol	smallmolecule	CHEBI:28324	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000050							9814482	t		lperfetto	Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol.	SIGNOR-268677	0.8
AP-3 complex	complex	SIGNOR-C247	SIGNOR	Platelet_dense_granule_formation	phenotype	SIGNOR-PH181	SIGNOR	up-regulates				9606	BTO:0000132								12019270	f		lperfetto	BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton.	SIGNOR-265942	0.7
MLL-ENL	fusion protein	SIGNOR-FP7	SIGNOR	AEP complex	complex	SIGNOR-C117	SIGNOR	up-regulates activity	binding			9606	BTO:0005261								19956800	t		irozzo	Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription.	SIGNOR-255878	0.2
HCK	protein	P08631	UNIPROT	HCK	protein	P08631	UNIPROT	up-regulates	phosphorylation	Tyr411	RVIEDNEyTAREGAK	9606	BTO:0000007								10934191	t		gcesareni	Tyr(416) is the autophosphorylation site in the activation loop. Autophosphorylation of tyr(416) is required for hck activation.	SIGNOR-80340	0.2
MET	protein	P08581	UNIPROT	GSK3B	protein	P49841	UNIPROT	up-regulates activity	phosphorylation	Tyr56	DRPQEVSyTDTKVIG	9606	BTO:0000972								30711629	t		miannu	 MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells. 	SIGNOR-277428	0.313
nalbuphine	chemical	CHEBI:7454	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000246								19282177	t		Luana	A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 	SIGNOR-258041	0.8
PSEN1	protein	P49768	UNIPROT	gamma-secretase	complex	SIGNOR-C98	SIGNOR	up-regulates	cleavage			9606									10497236	t	Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface.	lperfetto	Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains.	SIGNOR-217746	0.956
RAD23B	protein	P54727	UNIPROT	Protein_degradation	phenotype	SIGNOR-PH96	SIGNOR	up-regulates				9606									16401726	f		miannu	The XPCB domain of Rad23 binds Png1, which in turn facilitates the substrate recognition of Rad23. Through interactions with Ub chains and the proteasome mediated by the UBA and UBL domains in Rad23, Rad23 facilitates substrate transfer to the proteasome. 	SIGNOR-261062	0.7
HECTD3	protein	Q5T447	UNIPROT	CASP8	protein	Q14790	UNIPROT	down-regulates activity	polyubiquitination	Lys231	KVYQMKSkPRGYCLI	9606	BTO:0000007								24287696	t		miannu	HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 ubiquitinates caspase-8 with K63-linked polyubiquitin chains at K215.	SIGNOR-272077	0.342
Volasertib	chemical	CID:10461508	PUBCHEM	PLK1	protein	P53350	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190290	0.8
SMARCD2	protein	Q92925	UNIPROT	SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270603	0.715
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	E2F1	protein	Q01094	UNIPROT	up-regulates activity	phosphorylation			9606									23616010	t		lperfetto	Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1.	SIGNOR-233526	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	MFN2	protein	O95140	UNIPROT	up-regulates activity	phosphorylation	Ser442	AEEIRRLSVLVDDYQ	10090	BTO:0004578								20303493	t		Barakat	Mitofusin 2 (Mfn2) is an important suppressor of vascular smooth muscle cell (VSMC) proliferation. It contains a protein kinase A (PKA) phosphorylation site at serine 442 (S442) and can be phosphorylated by PKA	SIGNOR-274137	0.2
PRKAA1	protein	Q13131	UNIPROT	CRTC2	protein	Q53ET0	UNIPROT	down-regulates	phosphorylation	Ser170	PSALNRTsSDSALHT	9606			SIGNOR-C15						21892142	t		gcesareni	Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation	SIGNOR-176426	0.528
MAP2K3	protein	P46734	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates activity	phosphorylation			9534	BTO:0000298								7839144	t		Luana	Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase.	SIGNOR-260723	0.715
SMARCD1	protein	Q96GM5	UNIPROT	SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270604	0.811
PRKACA	protein	P17612	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	phosphorylation	Ser633	WRRKRKEsSNTDSAG	9606	BTO:0001853								24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251616	0.373
SMO	protein	Q99835	UNIPROT	ARRB2	protein	P32121	UNIPROT	up-regulates	binding			9606									23074268	t	The binding occours if Smo is phosphorylated	gcesareni	Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2	SIGNOR-199153	0.647
ZAP70	protein	P43403	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation	Tyr350	EPPDHQYyNDFPGKE	9606	BTO:0000782								9710204	t		gcesareni	The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2).	SIGNOR-59651	0.664
4,4'-sulfonyldiphenol	chemical	CHEBI:34372	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			-1									31995776	t		miannu	This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . 	SIGNOR-268730	0.8
PTK2B	protein	Q14289	UNIPROT	TGFB1I1	protein	O43294	UNIPROT	up-regulates activity	phosphorylation	Tyr60	SGDKDHLySTVCKPR	9534									10838081	t		miannu	Hic-5 is a CAKbeta-binding protein localized at focal adhesions. Here we show that overexpression of CAKbeta or Fyn, but not FAK, enhanced the tyrosine phosphorylation of coexpressed Hic-5 in COS-7 cells. The Y60F mutant of Hic-5 was not phosphorylated, and Hic-5 phosphorylated on tyrosine 60 was bound specifically to the SH2 domain of Csk. Specific phosphorylation of Hic-5 by CAKbeta and Fyn may activate a signaling pathway mediated by Hic-5.	SIGNOR-262876	0.734
CLOCK	protein	O15516	UNIPROT	BMAL1/NPAS2	complex	SIGNOR-C431	SIGNOR	form complex	binding			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements.	SIGNOR-267965	0.518
3-phosphonato-D-glyceroyl phosphate(4-)	smallmolecule	CHEBI:57604	ChEBI	3-phosphonato-D-glycerate(3-)	smallmolecule	CHEBI:58272	ChEBI	up-regulates quantity	precursor of			9606									16051738	t		miannu	Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa.	SIGNOR-266500	0.8
HDAC2	protein	Q92769	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates	binding			9606									15713663	t		gcesareni	Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5.	SIGNOR-134062	0.482
NTN1	protein	O95631	UNIPROT	DCC	protein	P43146	UNIPROT	up-regulates activity	binding			9606		BTO:0001484							25881791	t		miannu	DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the immunoglobulin superfamily. It was originally identified as a prognostic tumor marker and then subsequently found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other important cellular processes. 	SIGNOR-268162	0.907
CDK1	protein	P06493	UNIPROT	RAP1GAP	protein	P47736	UNIPROT	unknown	phosphorylation	Ser484	SLIVPGKsPTRKKSG	9606									1406653	t		lperfetto	Two of the sites of phosphorylation by cyclic amp (camp)-dependent kinase were localized to serine residues 490 and 499, and one site of phosphorylation by p34cdc2 was localized to serine 484.	SIGNOR-18735	0.457
HNF1A	protein	P20823	UNIPROT	SLCO1B3	protein	Q9NPD5	UNIPROT	up-regulates quantity by expression	transcriptional regulation												16741617	t		lperfetto	Farnesoid X receptor, hepatocyte nuclear factors 1alpha and 3beta are essential for transcriptional activation of the liver-specific organic anion transporter-2 gene.|This study demonstrated that the transcription of the LST-2 gene is regulated by three transcription factors, FXR, HNF1alpha, and HNF3beta.	SIGNOR-268988	0.254
LFNG	protein	Q8NES3	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	up-regulates	binding			9606									11346656	t	Fucosylation	gcesareni	These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch. It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2.	SIGNOR-107702	0.685
NTN1	protein	O95631	UNIPROT	ACTB	protein	P60709	UNIPROT	up-regulates quantity	post transcriptional regulation			443947	BTO:0001036								16980963	t		miannu	Netrin-1 induces β-actin translation driven by its 3’UTR.	SIGNOR-268161	0.285
MAPK3	protein	P27361	UNIPROT	STMN2	protein	Q93045	UNIPROT	down-regulates activity	phosphorylation	Ser62	ELILKPPsPISEAPR	10116	BTO:0000142								9525956	t		lperfetto	SCG10, a growth cone-enriched MT-destabilizing protein, has been recently characterized as an in vitro substrate for various serine/threonine kinases including PKA, MAP kinase, and CDK (19). We have found that SCG10 is phosphorylated in vivo in developing rat brain.| The sites for MAP kinase phosphorylation were identified as Ser-62 and Ser-73 of SCG10|By expressing a series of phosphorylation site mutants, we showed that the MT-destabilizing effect of SCG10 could be modulated. While the nonphosphorylatable mutant showed higher activity than the wild-type protein, the activity of the mutant in which phosphorylation on all four sites was mimicked by an aspartate residue was greatly reduced. These data suggest that the nonphosphorylated state of SCG10 represents the most active form of the protein.	SIGNOR-249115	0.359
SLC35A1	protein	P78382	UNIPROT	sialic acid	smallmolecule	CHEBI:26667	ChEBI	up-regulates quantity	relocalization			9606									34384782	t		miannu	The CMP-sialic acid transporter SLC35A1 and UDP-galactose transporter SLC35A2 are two well-characterized nucleotide sugar transporters with distinctive substrate specificities. Nucleotide sugar transporters (NSTs) transport nucleotide sugars from the cytosol into the lumen of the endoplasmic reticulum or the Golgi apparatus, where the nucleotide sugars serve as substrates for protein glycosylation and glycosphingolipid synthesis. 	SIGNOR-268466	0.8
PLK3	protein	Q9H4B4	UNIPROT	HIF1A	protein	Q16665	UNIPROT	down-regulates	phosphorylation	Ser657	ETTSATSsPYRDTQS	9606	BTO:0000567								18519666	t		lperfetto	Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditionsplk3 can potentially inhibit hif-1_ by physical interaction and direct phosphorylation	SIGNOR-178743	0.355
CDH24	protein	Q86UP0	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265862	0.531
FFAR4	protein	Q5NUL3	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256916	0.252
CDK1	protein	P06493	UNIPROT	KIFC1	protein	Q9BW19	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser6	sPLLEVKG	-1									24510915	t		miannu	We confirmed that CDK1 phosphorylates Ser6 (Supplementary Fig S5B) and demonstrated that KIFC1 displays CDK1-mediated resistance to ubiquitination by the APC/C (Fig S5C).	SIGNOR-277294	0.47
SMO	protein	Q99835	UNIPROT	ARRB2	protein	P32121	UNIPROT	up-regulates	binding			9606									15618519	t	The binding occours if Smo is phosphorylated	gcesareni	Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2	SIGNOR-132759	0.647
ANGPT4	protein	Q9Y264	UNIPROT	TEK	protein	Q02763	UNIPROT	up-regulates	binding			9606	BTO:0004980	BTO:0000763							15284220	t		gcesareni	In experiments with human endothelial cell lines, ang3 was identified as an antagonist of tie2 and ang4 was identified as an agonist of tie2.	SIGNOR-127351	0.688
RPS6KA5	protein	O75582	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									15994958	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-138479	0.2
ALDH1A3	protein	P47895	UNIPROT	all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	up-regulates quantity	chemical modification			9606									21621639	t		lperfetto	All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step.	SIGNOR-265129	0.8
SDC4	protein	P31431	UNIPROT	DVL1	protein	O14640	UNIPROT	up-regulates	binding			9606									23151663	t		gcesareni	Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1.	SIGNOR-199632	0.363
IRF7	protein	Q92985	UNIPROT	Interferon-type-I	proteinfamily	SIGNOR-PF50	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									16612387	f		miannu	Ikkalfa can also phosphorylate and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production.	SIGNOR-263128	0.2
TRH	protein	P20396	UNIPROT	TRHR	protein	P34981	UNIPROT	up-regulates activity	binding			9606		BTO:0001379							27515033	t		scontino	When TRH reaches the pars distalis of the pituitary, it regulates cells that express TRH receptor-1 (TRH-R1), such as the thyrotrophs. These cell types are subject to a multifactorial regulation that determines the extent and specificity of their response to TRH.	SIGNOR-267200	0.753
CSNK2A1	protein	P68400	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Ser129	SGSPSDNsGAEEMEV	9606									15818404	t		gcesareni	Akt/pkb ser129 is phosphorylated by ck2 in vitro and in vivo;(4) such a phosphorylation of activated akt/pkb correlates with a further increase in catalytic activity.	SIGNOR-135203	0.379
F3	protein	P13726	UNIPROT	Factor FVIIa:TF	complex	SIGNOR-C319	SIGNOR	form complex	binding			9606		BTO:0000131							32665005	t		lperfetto	During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury.	SIGNOR-263556	0.932
F2	protein	P00734	UNIPROT	F2RL3	protein	Q96RI0	UNIPROT	up-regulates	binding			9606									22318735	t		gcesareni	Thrombin activates platelets by binding and cleaving protease-activated receptors 1 and 4 (par1 and par4).	SIGNOR-196003	0.683
chlorphenamine	chemical	CHEBI:52010	ChEBI	HRH3	protein	Q9Y5N1	UNIPROT	down-regulates activity	chemical inhibition			-1									12781173	t		Luana	Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine.	SIGNOR-257897	0.8
SMO	protein	Q99835	UNIPROT	TIAM1	protein	Q13009	UNIPROT	up-regulates	binding			9606	BTO:0000785								23074268	t		gcesareni	This latter work suggested that inactive smo prevents rac1 activation by interacting with the rac guanine nucleotide exchange factor (gef) t-lymphoma invasion and metastasis 1 (tiam1). This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1	SIGNOR-199192	0.271
FASN	protein	P49327	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	chemical modification			9606									15507492	t		miannu	Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the de novo biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH. 	SIGNOR-268086	0.8
MAPK1	protein	P28482	UNIPROT	NCOA1	protein	Q15788	UNIPROT	up-regulates	phosphorylation	Ser395	PSVNPSIsPAHGVAR	9606									10660621	t		lperfetto	Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene.	SIGNOR-74876	0.371
Viral_replication	stimulus	SIGNOR-ST23	SIGNOR	Viral_dsRNA	stimulus	SIGNOR-ST21	SIGNOR	up-regulates				9606									31226023	f		miannu	Double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. 	SIGNOR-260587	0.7
SF1	protein	Q15637	UNIPROT	EWSR1	protein	Q01844	UNIPROT	down-regulates	binding			9606									9660765	t		miannu	Here we report that zfm1 also interacts withews / overexpression of zfm1 in hepg2 cells represses the transactivation of reporter gene expression driven by gal4-ews-ntd fusion protein and this repression correlates with zfm1 binding to ews.	SIGNOR-58928	0.427
UBE2D3	protein	P61077	UNIPROT	ZSWIM2	protein	Q8NEG5	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16522193	t		miannu	MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin. 	SIGNOR-271557	0.337
CIB2	protein	O75838	UNIPROT	AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	up-regulates activity	binding			9606									35408910	t		miannu	So far, two integrins have been found to interact with CIB2: αIIbβ3 is expressed by platelets and megakaryocytes and, apparently, a common target for all CIB family members, at odds with α7Bβ1D, which seems to be CIB2-specific and is expressed in skeletal muscles.	SIGNOR-269669	0.2
TXNIP	protein	Q9H3M7	UNIPROT	DDIT4	protein	Q9NX09	UNIPROT	up-regulates quantity by stabilization	binding			9606									21460850	t		miannu	 In the present study, we identify TXNIP that inhibits mTOR activity by binding to and stabilizing Redd1 protein. 	SIGNOR-277470	0.523
MAPK3	protein	P27361	UNIPROT	BAG3	protein	O95817	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser377	PVPCPPPsPGPSAVP	9606	BTO:0002181								34215846	t		miannu	We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCFFBXO22. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377.	SIGNOR-277318	0.317
HRAS	protein	P01112	UNIPROT	GATA2	protein	P23769	UNIPROT	up-regulates activity	phosphorylation	Ser192	PSTTGAAsPASSSAG	9606									25056917	f			Oncogenic Ras enhanced S192-dependent GATA-2 phosphorylation, nuclear foci localization, and transcriptional activation. These studies define a mechanism that controls a key regulator of hematopoiesis and a dual mode of impairing GATA-2-dependent genetic networks: mutational disruption of chromatin occupancy yielding insufficient GATA-2, and oncogenic Ras-mediated amplification of GATA-2 activity	SIGNOR-259945	0.364
SFRP1	protein	Q8N474	UNIPROT	Wnt	proteinfamily	SIGNOR-PF40	SIGNOR	down-regulates	binding			9606	BTO:0000782								10347172	t		gcesareni	Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling.	SIGNOR-262527	0.787
CSTF3	protein	Q12996	UNIPROT	CSTF complex	complex	SIGNOR-C441	SIGNOR	form complex	binding			9606									10669729	t		lperfetto	We therefore first identified regions of the CstF subunits, CstF-77, CstF-64, and CstF-50, required for interaction with each other. 	SIGNOR-268367	0.954
ERG	protein	P11308	UNIPROT	ADAMTS1	protein	Q9UHI8	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								19396168	f	 	miannu	 ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression. 	SIGNOR-253910	0.2
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1948	SPTSPGYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273086	0.745
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1868	SPTSPKYsPTSPKYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273087	0.745
RBM42	protein	Q9BTD8	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270645	0.313
MAPK14	protein	Q16539	UNIPROT	PTPN7	protein	P35236	UNIPROT	down-regulates activity	phosphorylation	Ser93	ALQRQPPsPKQLEEE	-1									10206983	t		miannu	The noncatalytic N terminus of HePTP binds Erk and p38 and is phosphorylated at Ser-72 and Thr-45 by these kinases. the N terminus of HePTP binds Erk and p38 but may release them upon phosphorylation.it is clear that phosphorylation of HePTP at Thr-45 and/or Ser-72 is not required for inhibition of MAP kinase. Rather, it seems that phosphorylation has the opposite effect, namely to lessen the inhibitory effect of HePTP. 	SIGNOR-250109	0.584
TAF1C	protein	Q15572	UNIPROT	SL1 complex	complex	SIGNOR-C464	SIGNOR	form complex	binding			9606									30693017	t		lperfetto	SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation.	SIGNOR-269564	0.797
SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	CDKN2A	protein	P42771	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18332116	f		irozzo	HSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15INK4b and p16INK4a, but not of p14ARF.Reexpression of hSNF5 in MRT cells overcomes epigenetic silencing and mediates transcriptional activation of p15INK4b and p16INK4a	SIGNOR-256299	0.359
TP53BP2	protein	Q13625	UNIPROT	PPP1R14A	protein	Q96A00	UNIPROT	down-regulates	binding			9606									8549741	t		gcesareni	The phosphorylase phosphatase activity of pp1 was inhibited by p53bp2 at nanomolar concentrations.	SIGNOR-39666	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	EPCAM	protein	P16422	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11505407	f	 	miannu	 The current results provide the first insights into the regulation of EpCAM expression, which is regulated negatively by TNFalpha and TPA through the activation of NF-kappaB. The repression may rely on the competition of NF-kappaB for p300/CBP histone acetyl transferase activity, because the overexpression of p300 reverts TNFalpha effects.	SIGNOR-254790	0.287
MAPK1	protein	P28482	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates				9606	BTO:0000130								16709866	f		gcesareni	The role of members of the arrestin family to mediate kinase activation is also a well-established phenomenon, including activation of members of the src family, erk1/2, and jnk3. Activation often includes the recruitment and interaction of arrestins with upstream mapks (ask1, mek3, mkk3, and mek kinase-2).	SIGNOR-146751	0.326
CSNK2A1	protein	P68400	UNIPROT	CDC34	protein	P49427	UNIPROT	down-regulates activity	phosphorylation	Ser222	EVEEEADsCFGDDED	9606	BTO:0000567								11546811	t		lperfetto	The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm.	SIGNOR-110395	0.403
INS	protein	P01308	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates quantity by destabilization				9606									17360977	f		lperfetto	Research has focused on insulin receptor substrate (IRS)-1 as a locus for insulin resistance. Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signal. Insulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223	SIGNOR-236737	0.67
MAPK10	protein	P53779	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Ser63	KNSDLLTsPDVGLLK	9606									20395206	t		gcesareni	With epidermal growth factor treatment, overexpression of erk8 in jb6 cl41 cells caused an increased phosphorylation of c-jun at ser(63) and ser(73), resulting in increased activator protein-1 transactivation.	SIGNOR-164800	0.883
SLC2A5	protein	P22732	UNIPROT	D-fructofuranose	smallmolecule	CHEBI:37721	ChEBI	up-regulates quantity	relocalization			9606									28083649	t			Although increased dietary fructose consumption is associated with metabolic impairments, the mechanisms and regulation of intestinal fructose absorption are poorly understood. GLUT5 is considered to be the main intestinal fructose transporter.	SIGNOR-267493	0.8
H2AC4	protein	P04908	UNIPROT	Nucleosome_H3.3 variant	complex	SIGNOR-C339	SIGNOR	form complex	binding			9606									15776021	t		miannu	Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes.	SIGNOR-263874	0.2
PTPN11	protein	Q06124	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	dephosphorylation	Tyr1179	GLENGLNyIDLDLVK	9606									10660596	t		gcesareni	The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling.	SIGNOR-74856	0.893
PTPRG	protein	P23470	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	dephosphorylation	Tyr999	YASSNPEyLSASDVF	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254703	0.373
MYOD1	protein	P15172	UNIPROT	MYOG	protein	P15173	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		lperfetto	We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by myod and other regulatory proteins.	SIGNOR-135984	0.436
POT1	protein	Q9NUX5	UNIPROT	POT1/ACD	complex	SIGNOR-C64	SIGNOR	form complex	binding			9606									17237768	t		miannu	We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme.	SIGNOR-152324	0.88
PAK1	protein	Q13153	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser305	IKRSKKNsLALSLTA	9606		BTO:0000149							12374744	t		lperfetto	Pak1 directly phosphorylated the activation function-2 domain of the er at the n-terminal residue ser305, and its mutation to ala (s305a) abolished the pak1-mediated phosphorylation and transactivation functions of the er	SIGNOR-94206	0.55
CDK1	protein	P06493	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Ser811	IYISPLKsPYKISEG	9606									1756735	t		gcesareni	The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2.	SIGNOR-21556	0.675
LTBR	protein	P36941	UNIPROT	B_cell_maturation	phenotype	SIGNOR-PH15	SIGNOR	up-regulates				9606									17633025	f		lperfetto	The lymphotoxin-beta receptor (ltbetar, tnfrsf3) signaling pathway activates gene transcription programs and cell death important in immune development and host defense.	SIGNOR-156899	0.7
NSMCE3	protein	Q96MG7	UNIPROT	SMC5/6 	complex	SIGNOR-C374	SIGNOR	form complex	binding			-1									27427983	t		miannu	The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks	SIGNOR-265485	0.2
aclidinium	chemical	CHEBI:65346	ChEBI	CHRM3	protein	P20309	UNIPROT	down-regulates activity	chemical inhibition			9606									19653626	t		Luana	This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects.	SIGNOR-258151	0.8
CTNNB1	protein	P35222	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates activity	binding			10090	BTO:0003346								16847334	t			Oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain	SIGNOR-256072	0.555
LPAR2	protein	Q9HBW0	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256927	0.252
dopamine	smallmolecule	CHEBI:18243	ChEBI	DRD3	protein	P35462	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								1975644	t		miannu	Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells.	SIGNOR-258377	0.8
FZD1	protein	Q9UP38	UNIPROT	CEBPA	protein	P49715	UNIPROT	down-regulates				9606	BTO:0000222								10937998	f		fspada	Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma)	SIGNOR-80595	0.2
ESR2	protein	Q92731	UNIPROT	OXT	protein	P01178	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									6153132	f		lperfetto	The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances.	SIGNOR-268547	0.489
cyclosporin A	chemical	CHEBI:4031	ChEBI	Calcineurin	complex	SIGNOR-C155	SIGNOR	down-regulates	chemical inhibition			10116		BTO:0001103							15829723	t		apalma	On one hand, inhibition of calcineurin with cyclosporin A (CsA) significantly reduced the growth of both the slow/type I soleus muscle and fast/type II plantaris muscle in normal, ambulatory rats	SIGNOR-255102	0.8
MMP2	protein	P08253	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272387	0.7
SRC	protein	P12931	UNIPROT	PLSCR1	protein	O15162	UNIPROT	up-regulates activity	phosphorylation	Tyr74	PVYNQPVyNQPVGAA	9606									12871937	t		lperfetto	Plscr1 is phosphorylated by c-src, within the tandem repeat sequence 68vynqpvynqp77.|The EGF-mediated Interaction between PLSCR1 and Shc Requires Phosphorylation of Tyr69 and Tyr74 in PLSCR1	SIGNOR-103773	0.489
FNTB	protein	P49356	UNIPROT	MRAS	protein	O14807	UNIPROT	up-regulates activity				9606									24294527	t		lperfetto	Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials.	SIGNOR-242562	0.276
R547	chemical	CID:6918852	PUBCHEM	CDK2	protein	P24941	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258273	0.8
RNF4	protein	P78317	UNIPROT	NFYC	protein	Q13952	UNIPROT	up-regulates activity	binding			9606									15496512	t		miannu	Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter.	SIGNOR-252231	0.2
ESR1	protein	P03372	UNIPROT	GREB1	protein	Q4ZG55	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000356								17666587	f	 	miannu	 Long-range activation of GREB1 by estrogen receptor via three distal consensus estrogen-responsive elements in breast cancer cells. . GREB1 (gene regulated by estrogen in breast cancer 1) is an ER target gene that regulates estrogen-induced proliferation in breast cancer cells. 	SIGNOR-254074	0.703
ATM	protein	Q13315	UNIPROT	NBN	protein	O60934	UNIPROT	up-regulates	phosphorylation	Ser615	VPESSKIsQENEIGK	9606									10839545	t		lperfetto	In vivo, nbs was phosphorylated on many serine residues, of which s343, s397 and s615 were phosphorylated by atm in vitro. Reconstituting nbs cells with a mutant form of nbs that cannot be phosphorylated at selected, atm-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation.	SIGNOR-78034	0.852
SDC4	protein	P31431	UNIPROT	DVL3	protein	Q92997	UNIPROT	up-regulates	binding			9606									23151663	t		gcesareni	Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1.	SIGNOR-199638	0.249
IGF1R	protein	P08069	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates	phosphorylation	Tyr1179	GLENGLNyIDLDLVK	9606									17827393	t		gcesareni	Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K).	SIGNOR-157730	0.864
APC-c	complex	SIGNOR-C150	SIGNOR	CCNA2	protein	P20248	UNIPROT	down-regulates quantity by destabilization	ubiquitination												21596315	t		lperfetto	Complexed with the activator proteins CDC20 or CDH1 (Fang et al., 1998, Visintin et al., 1997), the APC/C recognizes, ubiquitinates, and targets for proteasomal degradation a multitude of cell cycle regulators containing KEN or D box degrons, including securin, cyclin A, and cyclin B.	SIGNOR-265050	0.539
CDK4	protein	P11802	UNIPROT	MEF2C	protein	Q06413	UNIPROT	down-regulates	binding			9606			SIGNOR-C18						21902831	t		gcesareni	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-176518	0.287
MAPK1	protein	P28482	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr57	NFDFVTEtPLEGDFA	9606									19364816	t		lperfetto	We have shown that erk2 interacts with and phosphorylates p21cip1, promoting p21cip1_ubiquitination. We identified two erk2 phosphorylation sites, thr57 and ser130, in p21cip1_and showed that phosphorylation of these residues increases p21cip1_cytoplasmic distribution and proteasome-dependent degradation.	SIGNOR-185219	0.373
CSNK1A1	protein	P48729	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser79	QRMGSSEsTDSGFCL	9606									20348946	t		lperfetto	Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a	SIGNOR-164734	0.338
SMAD1	protein	Q15797	UNIPROT	HAND1	protein	O96004	UNIPROT	up-regulates quantity	transcriptional regulation			10090									22219353	t		Gianni	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268936	0.2
CHUK	protein	O15111	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser923	DELRDSDsVCDSGVE	9606	BTO:0000567			SIGNOR-C13					10469655	t		lperfetto	All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391).	SIGNOR-70449	0.737
PGK2	protein	P07205	UNIPROT	3-phosphonato-D-glyceroyl phosphate(4-)	smallmolecule	CHEBI:57604	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa.	SIGNOR-266503	0.8
TNF	protein	P01375	UNIPROT	ARDS	phenotype	SIGNOR-PH128	SIGNOR	up-regulates				9606									32446778	f		miannu	Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection	SIGNOR-261034	0.7
TP53	protein	P04637	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									7566157	t		gcesareni	The p21 gene is under the transcriptional control of p53 (ref. 5), suggesting that p21 might promote p53-dependent cell cycle arrest or apoptosis. p21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. p53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting g1/s entry.	SIGNOR-29248	0.873
SPRY4	protein	Q9C004	UNIPROT	CD82	protein	P27701	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002058								20501643	f		miannu	When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. 	SIGNOR-253039	0.2
BTK	protein	Q06187	UNIPROT	ITK	protein	Q08881	UNIPROT	up-regulates	phosphorylation	Tyr180	ETVVIALyDYQTNDP	9606									12573241	t		lperfetto	Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanismthe major phosphorylation sites were identified as conserved tyrosines, for itk y180	SIGNOR-98036	0.474
IL1B	protein	P01584	UNIPROT	LPL	protein	P06858	UNIPROT	down-regulates activity				9606									1572904	f	Regulation	miannu	IL-1 beta also depressed adipoconversion, inhibited markedly LPL activity, and partially reduced GPDH activity. 	SIGNOR-251856	0.294
MMP9	protein	P14780	UNIPROT	HAPLN1	protein	P10915	UNIPROT	down-regulates quantity by destabilization	cleavage	His31	LDHDRAIhIQAENGP	-1									7694569	t		miannu	Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.	SIGNOR-256328	0.348
AREL1	protein	O15033	UNIPROT	SEPTIN4	protein	O43236	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									23479728	t		lperfetto	Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists	SIGNOR-267670	0.2
PVR	protein	P15151	UNIPROT	TIGIT	protein	Q495A1	UNIPROT	up-regulates activity	binding			9606									30591568	t		lperfetto	Poliovirus receptor (PVR/CD155) is a ligand of the paired NK receptors, DNAM-1 (activating) and TIGIT (inhibiting). NK cells can kill cancer cells expressing PVR via the DNAM-1-mediated activating signaling (11,12). 	SIGNOR-261425	0.867
BCL3	protein	P20749	UNIPROT	CTCF	protein	P49711	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004298								21912613	f		miannu	 In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription.	SIGNOR-253757	0.306
dovitinib; bis(lactic acid)	chemical	CID:56973714	PUBCHEM	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191421	0.8
GABRD	protein	O14764	UNIPROT	GABA-A (a6-b2-d) receptor	complex	SIGNOR-C328	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263770	0.399
ASIP	protein	P42127	UNIPROT	MC1R	protein	Q01726	UNIPROT	down-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268698	0.734
CSNK2A1	protein	P68400	UNIPROT	SSB	protein	P05455	UNIPROT	up-regulates	phosphorylation	Ser366	GKKTKFAsDDEHDEH	9606									18257391	t		gcesareni	Prior studies indicate that hla is activated by phosphorylation of serine-366 by protein kinase ck2, neutralizing a negative effect of a short basic motif (sbm)	SIGNOR-160761	0.342
TRADD	protein	Q15628	UNIPROT	FADD	protein	Q13158	UNIPROT	up-regulates activity	binding			9606									18545270	t		lperfetto	Tradd recruits fadd	SIGNOR-177958	0.774
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	EGFR	protein	P00533	UNIPROT	down-regulates	phosphorylation	Thr693	RELVEPLtPSGEAPN	9606									10816576	t		lperfetto	It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation.	SIGNOR-244529	0.2
MAPK1	protein	P28482	UNIPROT	NR4A2	protein	P43354	UNIPROT	up-regulates	phosphorylation	Ser126	SVYYKPSsPPTPTTP	9606	BTO:0000938	BTO:0000142							17681692	t		llicata	We have shown that erk2 is a kinase to phosphorylate nurr1 on multiple sites. S126 and t132, which are located near af1 core of nurr1, are dominant sites phosphorylated by erk2. reporter gene assays show that nurr1delta124-133/t185a, an erk2 phospho-site mutant form, could not further increase its transcriptional activity on th promoter, suggesting that nurr1 phosphorylation by erk2 may regulate its transcriptional activity on th promoter.	SIGNOR-157167	0.405
FGFR1	protein	P11362	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates	phosphorylation	Tyr128	SKAQQGLyQVPGPSP	9606									11019781	t		lperfetto	Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas.	SIGNOR-82760	0.259
MAPK3	protein	P27361	UNIPROT	BCL6	protein	P41182	UNIPROT	down-regulates	phosphorylation	Ser343	KSDCQPNsPTESCSS	9606	BTO:0000782;BTO:0000785								9649500	t		gcesareni	Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway.	SIGNOR-58493	0.416
ALDOA	protein	P04075	UNIPROT	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C.	SIGNOR-266479	0.8
GALP	protein	Q9UBC7	UNIPROT	GALR2	protein	O43603	UNIPROT	up-regulates	binding			9606									10601261	t		gcesareni	Galp is therefore an endogenous ligand that preferentially binds the galr2 receptor	SIGNOR-73143	0.443
masitinib	chemical	CHEBI:63450	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258245	0.8
SMAD2	protein	Q15796	UNIPROT	SMAD2/SMAD4	complex	SIGNOR-C8	SIGNOR	form complex	binding			9606					phosphorylation:Ser465;Ser467	SPSVRCSsMS;SVRCSSMs			11274206	t		gcesareni	the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4	SIGNOR-235188	0.708
EREG	protein	O14944	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606	BTO:0000150								9419975	t	Epiregulin may be a mediator of localized cell proliferation	gcesareni	Chemical cross-linking experiments showed that [125i]epiregulin directly bound to each of egfr and erbb-4 but not to erbb-2 and erbb-3. remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling.	SIGNOR-54351	0.889
HTR2A	protein	P28223	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257137	0.591
AKT3	protein	Q9Y243	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252877	0.697
ERBB3	protein	P21860	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606									16729043	t		gcesareni	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146870	0.332
ME1	protein	P48163	UNIPROT	pyruvate	smallmolecule	CHEBI:15361	ChEBI	up-regulates quantity	chemical modification			9606									33064660	t		miannu	Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP.	SIGNOR-267723	0.8
N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide	chemical	CHEBI:94793	ChEBI	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	lperfetto		SIGNOR-244820	0.8
NEDD4L	protein	Q96PU5	UNIPROT	SCN9A	protein	Q15858	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000938								23778145	t		miannu	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 	SIGNOR-253458	0.341
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1924	SPTSPKYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273088	0.745
IFTAP	protein	Q86VG3	UNIPROT	BTF3	protein	P20290	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								18433331	t		lperfetto	Furthermore, we co-immunoprecipitated HEPIS with BTF3, a component of the RNA pol II initiation complex, and observed reduced proliferation of HeLa cells transfected with the HEPIS gene. 	SIGNOR-260252	0.2
ITGB4	protein	P16144	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606									9428518	t		gcesareni	Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation.	SIGNOR-54703	0.2
FBXW11	protein	Q9UKB1	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9606									9784611	t		gcesareni	 we conclude that beta-trcp is a component of an e3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin.We Found that the binding of beta-trcp to beta-catenin was direct	SIGNOR-60751	0.734
TNFRSF11A	protein	Q9Y6Q6	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates activity				9606									10075662	f		miannu	RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation. 	SIGNOR-253047	0.262
ITGB1BP1	protein	O14713	UNIPROT	AX/b2 integrin	complex	SIGNOR-C171	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257652	0.318
PPP2CB	protein	P62714	UNIPROT	PRKCB	protein	P05771-2	UNIPROT	down-regulates activity	dephosphorylation	Thr641	TRHPPVLtPPDQEVI	10116									8749392	t			 Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme. 	SIGNOR-248587	0.457
NFY	complex	SIGNOR-C1	SIGNOR	CCNB1	protein	P14635	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165	BTO:0000887;BTO:0001103							10362252	f		lperfetto	In conclusion, our data demonstrate that nf-y is required for cyclin b1 promoter activity.	SIGNOR-235834	0.363
SRSF11	protein	Q05519	UNIPROT	LRP8	protein	Q14114	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation			10090									31269452	t		miannu	We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling.	SIGNOR-269670	0.2
MAPK14	protein	Q16539	UNIPROT	MEF2A	protein	Q02078	UNIPROT	unknown	phosphorylation	Ser408	SIKSEPIsPPRDRMT	9606	BTO:0000938	BTO:0000887							12586839	t		lperfetto	A p38 mapk-induced phosphopeptide with no mapk consensus the phosphorylation site is identified as ser-408	SIGNOR-98224	0.646
CAMK1	protein	Q14012	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser259	FPLRKTAsEPNLKVR	9606		BTO:0000887							11114197	t		gcesareni	Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.	SIGNOR-85018	0.43
PRKCD	protein	Q05655	UNIPROT	DAP3	protein	P51398	UNIPROT	up-regulates	phosphorylation	Thr237	ITRVRNAtDAVGIVL	9606									18227431	t		amattioni	Dap3 is phosphorylated by protein kinase cdelta on thr237. Dap3 was originally identified as a pro-apoptotic protein. The mutation of the phosphorylation site thr237 to alanine reversed the cell death caused by the wild-type dap3	SIGNOR-160488	0.2
BCOR	protein	Q6W2J9	UNIPROT	BCL6	protein	P41182	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								10898795	t		miannu	In this study we have shown that BCoR interacts with BCL-6 and potentiates transcriptional repression by BCL-6 with striking specificity.	SIGNOR-252235	0.882
1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone	chemical	CHEBI:93753	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252657	0.8
NANOG	protein	Q9H9S0	UNIPROT	DNMT1	protein	P26358	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003298								22795133	t		lperfetto	Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation	SIGNOR-253157	0.445
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation	Ser259	SQRQRSTsTPNVHMV	9606	BTO:0000222	BTO:0000887;BTO:0001760							10576741	t		gcesareni	The stage-specific inhibitory action of Akt correlated with its stage-specific ability to form a complex with Raf, suggesting the existence of differentially expressed mediators of an inhibitory Akt-Raf complex.	SIGNOR-72669	0.2
CDK5	protein	Q00535	UNIPROT	EPRS1	protein	P07814	UNIPROT	down-regulates	phosphorylation	Ser886	LSQSSDSsPTRNSEP	9606	BTO:0000801								21220307	t		lperfetto	Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation	SIGNOR-171138	0.2
HDAC1	protein	Q13547	UNIPROT	VDR	protein	P11473	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000356								18485278	f		miannu	 We have shown here that the transcriptional repressor protein SLUG inhibits the expression of VDR in human breast cancer cells. 	SIGNOR-255179	0.393
NKX2-1	protein	P43699	UNIPROT	SFTPB	protein	P07988	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004299								18003659	f	 	miannu	TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription.	SIGNOR-254172	0.486
CSNK1A1	protein	P48729	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	phosphorylation			9606									16341017	t		gcesareni	We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.	SIGNOR-143037	0.534
DCN	protein	P07585	UNIPROT	FBN1	protein	P35555	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0000951								17200203	f	Regulation	miannu	Decorin Induces Fibrillin-1 Protein Expression in NRK Cells via IGF-IR. we report a novel mechanism of action that involves two key molecules: decorin, a small leucine-rich proteoglycan, and the IGF-IR. These two players, together with the downstream signaling pathway evoked by decorin-mediated activation of the receptor, lead to an enhanced translation of fibrillin-1 and its deposition in the extracellular environment both in vitro and in vivo. 	SIGNOR-251893	0.578
MAPK3	protein	P27361	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606	BTO:0001271	BTO:0000671							14551213	t		gcesareni	The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1	SIGNOR-118600	0.709
MAP2K1	protein	Q02750	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates activity	phosphorylation	Tyr187	HTGFLTEyVATRWYR	9606	BTO:0003807								11971971	t		lperfetto	Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.	SIGNOR-235937	0.739
TTM complex	complex	SIGNOR-C305	SIGNOR	Shelterin complex	complex	SIGNOR-C306	SIGNOR	up-regulates activity	relocalization			9606	BTO:0000007								33015044	t		lperfetto	The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1	SIGNOR-263308	0.2
ETF1	protein	P62495	UNIPROT	Translation release factor ERF1-ERF3	complex	SIGNOR-C494	SIGNOR	form complex	binding			9606									29735640	t		miannu	Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex. 	SIGNOR-270813	0.972
AKT1	protein	P31749	UNIPROT	YBX1	protein	P67809	UNIPROT	up-regulates	phosphorylation	Ser102	NPRKYLRsVGDGETV	9606	BTO:0000150								15806160	t		lperfetto	Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102	SIGNOR-252475	0.576
VPS13B	protein	Q7Z7G8	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				10116									25492866	f		miannu	Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons	SIGNOR-266872	0.7
MC4R	protein	P32245	UNIPROT	GNAS	protein	P84996	UNIPROT	up-regulates activity				9606									22215617	t		lperfetto	We hypothesize that XLαs may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus.	SIGNOR-253067	0.501
3-[(2-Bromo-4,5-dimethoxyphenyl)methyl]-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one	chemical	CID:44436444	PUBCHEM	ACHE	protein	P22303	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001239								17888667	t		Luana	AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE.	SIGNOR-257760	0.8
GFI1	protein	Q99684	UNIPROT	BAX	protein	Q07812	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002181								17213822	f	 	miannu	 Our results suggest that the interaction between ETS1 and GFI1 facilitates their binding to specific sites on the Bax promoter and represses Bax expression in vivo.	SIGNOR-254203	0.2
125-L-serine-2-133-interleukin 2 (human reduced)	smallmolecule	SID:46508054	ChEBI	IL2RG	protein	P31785	UNIPROT	up-regulates activity	chemical activation			9606									18031103	t		miannu	Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response. 	SIGNOR-259390	0.8
ABL1	protein	P00519	UNIPROT	WASL	protein	O00401	UNIPROT	unknown	phosphorylation	Tyr175	EITTNRFyGPQVNNI	10090									16199863	t		gcesareni	Mutation of both tyrosines 175 and 256 to phenylalanine was required to abolish Abl-mediated phosphorylation of N-WASP in the presence of Grb2 [€] suggesting that phosphorylation at tyrosine 175 is not critical for comet tail formation by Shigella	SIGNOR-247666	0.566
DLG3	protein	Q92796	UNIPROT	Scribble_complex_DLG3-LLGL1_variant	complex	SIGNOR-C507	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270897	0.519
Hexocyclium	chemical	CHEBI:5707	ChEBI	CHRM3	protein	P20309	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								2704370	t		miannu	In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 	SIGNOR-258397	0.8
ACOT8	protein	O14734	UNIPROT	glutaryl-CoA(5-)	smallmolecule	CHEBI:57378	ChEBI	down-regulates quantity	chemical modification												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271814	0.8
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CCND1	protein	P24385	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189972	0.8
TP53	protein	P04637	UNIPROT	CRYAB	protein	P02511	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21556774	t		miannu	Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53	SIGNOR-253638	0.483
risperidone	chemical	CHEBI:8871	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258840	0.8
PRKG1	protein	Q13976	UNIPROT	GTF2I	protein	P78347	UNIPROT	up-regulates	phosphorylation	Ser784	GVPFRRPsTFGIPRL	9606		BTO:0000671							12082086	t		lperfetto	G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells	SIGNOR-89853	0.554
CAMKK2	protein	Q96RR4	UNIPROT	PRKAA2	protein	P54646	UNIPROT	up-regulates	phosphorylation	Thr172	SDGEFLRtSCGSPNY	9606	BTO:0000567			SIGNOR-C15					15980064	t		gcesareni	These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo.	SIGNOR-138364	0.606
AARS1	protein	P49588	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									32314272	t		miannu	Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N).	SIGNOR-270448	0.8
KIF13A	protein	Q9H1H9	UNIPROT	Early Endosome	complex	SIGNOR-C246	SIGNOR	up-regulates	relocalization			9606									30404817	t		lperfetto	Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis.	SIGNOR-260703	0.299
aliskiren	chemical	CHEBI:601027	ChEBI	REN	protein	P00797	UNIPROT	down-regulates activity	chemical inhibition			9606									18307734	t		Luana	Aliskiren has a low bioavailality (between 2.6 and 5.0%) compensated by its high potency to inhibit renin (IC50: 0.6 nmol/L) and a long plasma half-life (23–36 h)	SIGNOR-257771	0.8
UV stress	stimulus	SIGNOR-ST7	SIGNOR	KRT14	protein	P02533	UNIPROT	up-regulates				9606									11875647	f		miannu	UVB increases keratin 5 and keratin 14 expression through direct activation of the EGF receptor in SVHK.	SIGNOR-251900	0.7
REST	protein	Q13127	UNIPROT	BDNF	protein	P23560	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21832040	f		miannu	 HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK).	SIGNOR-255075	0.433
ENAH	protein	Q8N8S7	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				9606									18508258	f		miannu	Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance.	SIGNOR-268392	0.7
THOC2	protein	Q8NI27	UNIPROT	TREX complex	complex	SIGNOR-C444	SIGNOR	form complex	binding			9606									33191911	t		miannu	The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56.	SIGNOR-268509	0.941
pyruvate	smallmolecule	CHEBI:15361	ChEBI	(S)-lactate	smallmolecule	CHEBI:16651	ChEBI	up-regulates quantity	precursor of			9606									24929216	t		lperfetto	Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase.	SIGNOR-267655	0.8
RIPK1	protein	Q13546	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	up-regulates activity	binding			9606				SIGNOR-C14					16603398	t		lperfetto	Interestingly, polyubiquitinated rip1 recruits ikk through the binding between the polyubiquitin chains and nemo, a regulatory subunit of the ikk complex. Mutations of nemo that disrupt its polyubiquitin binding also abolish ikk activation.	SIGNOR-145858	0.912
INSR	protein	P06213	UNIPROT	DOK4	protein	Q8TEW6	UNIPROT	up-regulates				9606		BTO:0000887;BTO:0001103;BTO:0000671							12730241	f		gcesareni	Irs5/dok4 and irs6/dok5 represent two new signaling proteins with potential roles in insulin and igf-1 action.	SIGNOR-101005	0.377
CHEK2	protein	O96017	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser364	PLLSRMGsLRAPVDE	9606									12717439	t		lperfetto	We report that checkpoint kinase 2 (chk2) regulates e2f-1 activity in response to the dna-damaging agent etoposide. A chk2 consensus phosphorylation site in e2f-1 is phosphorylated in response to dna damage	SIGNOR-100898	0.5
CHEK2	protein	O96017	UNIPROT	SOD1	protein	P00441	UNIPROT	up-regulates activity	phosphorylation	Ser99	KDGVADVsIEDSVIS	4932									24647101	t			ROS signaling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to the promoters and regulates the expression of oxidative resistance and repair genes.	SIGNOR-262795	0.384
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									19819937	f			In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. 	SIGNOR-254354	0.7
STAT3	protein	P40763	UNIPROT	VEGFA	protein	P15692	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12545153	t		luana	Stat3 directly regulated the promoter of the VEGF gene. Blockade of activated Stat3 by ectopic expression of dominant-negative Stat3 significantly inhibited VEGF expression, and the growth and metastasis of human pancreatic cancer cells. 	SIGNOR-259456	0.779
AKT1	protein	P31749	UNIPROT	RANBP3	protein	Q9H6Z4	UNIPROT	unknown	phosphorylation	Ser126	VKRERTSsLTQFPPS	9606									18280241	t		llicata	Akt regulates ranbp3 phosphorylation in vitro and in vivo	SIGNOR-252504	0.367
TNFRSF17	protein	Q02223	UNIPROT	MAPK11	protein	Q15759	UNIPROT	up-regulates				9606									10903733	f		miannu	Overexpression of bcma activates the p38 mapk	SIGNOR-79495	0.2
WNT6	protein	Q9Y6F9	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates				9606									9753670	f		gcesareni	Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm.	SIGNOR-60415	0.315
MAPK3	protein	P27361	UNIPROT	MAGEA11	protein	P43364	UNIPROT	up-regulates	phosphorylation	Ser174	ESPSPPQsPQEESFS	9606	BTO:0000848								19828458	t		llicata	Mage-11 ser-174 appears to be a post-translational regulatory site phosphorylated by erk1, based on the inhibitory effect of the s174a mutation in the context of shorter ar nh2-terminal fragments (19), and the greater transcriptional activity of gal-mage-11 fusion proteins containing the s174d phosphomimetic.	SIGNOR-188466	0.304
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser167	GGRERLAsTNDKGSM	9606	BTO:0000150								7838153	t		gcesareni	Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii.	SIGNOR-252807	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser16	KELEKRAsGQAFELI	9606	BTO:0000661								16982419	t		gcesareni	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16.	SIGNOR-149640	0.376
arachidonic acid	smallmolecule	CHEBI:15843	ChEBI	FOS	protein	P01100	UNIPROT	up-regulates				9606									15878913	f		miannu	 AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription.	SIGNOR-255392	0.8
PCDHAC1	protein	Q9H158	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-269032	0.2
P2RY1	protein	P47900	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257339	0.401
UCHL5	protein	Q9Y5K5	UNIPROT	TGFBR1	protein	P36897	UNIPROT	up-regulates quantity by stabilization	binding			9606									17052192	t		gcesareni	Smad7 can act as an adaptor able to recruit uch37 to the type i tgf-beta receptor. Consequently, uch37 dramatically up-regulates tgf-beta-dependent gene expression by de-ubiquitinating and stabilizing the type i tgf-beta receptor.	SIGNOR-150135	0.484
ADNP	protein	Q9H2P0	UNIPROT	MAP1LC3B	protein	Q9GZQ8	UNIPROT	up-regulates activity	binding			10116		BTO:0000601							24365867	t		miannu	Here, we show for the first time that hippocampal ADNP deficiency paralleled reduced beclin1 expression which, in turn, parallels increased tauopathy and cell death. We now show that ADNP directly interacts with LC3B, implicating the requirement of a healthy ADNP system for the apoptotic/autophagy processes.	SIGNOR-266759	0.378
NUMB	protein	P49757	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates						BTO:0001103							12361602	t		apalma	Therefore, these genetic data further support the hypothesis that activation of Notch-1 promotes a less committed myogenic phenotype and that the attenuation of Notch-1 activity by Numb promotes progression along the myogenic lineage toward a myoblast cell fate.	SIGNOR-255375	0.791
spironolactone	chemical	CHEBI:9241	ChEBI	NR3C2	protein	P08235	UNIPROT	down-regulates activity	chemical inhibition			-1									18038968	t		Luana	Results of the RALES trial (Randomized Aldactone Evaluation Study) demonstrated that the published MR antagonist spironolactone, added to standard therapy, reduced mortality due to all causes by 30% as well as reduced hospitalizations and improved cardiac function in patients with severe heart failure.2	SIGNOR-257762	0.8
TP53	protein	P04637	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates	binding			9606									14963330	t		gcesareni	Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program	SIGNOR-121895	0.743
AKT2	protein	P31751	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation	Thr24	LPRPRSCtWPLPRPE	9606									10377430	t		lperfetto	Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus.	SIGNOR-68656	0.645
RASGEF1A	protein	Q8N9B8	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183826	0.402
ABL1	protein	P00519	UNIPROT	PTPN6	protein	P29350	UNIPROT	up-regulates activity	phosphorylation	Tyr564	SKHKEDVyENLHTKN	9606	BTO:0001412								8692915	t			The SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites. The functional significance of the c-Abl-SHPTP1 interaction is supported by the demonstration that, like c-Abl, SHPTP1 regulates the induction of Jun kinase activity following DNA damage. 	SIGNOR-251433	0.423
POU5F1	protein	Q01860	UNIPROT	BMP4	protein	P12644	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086								17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254932	0.486
PPP1CC	protein	P36873	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	dephosphorylation	Ser75	LGYEPEGsASPTPPY	9606									17318175	t			The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 	SIGNOR-248494	0.272
RPS6KA3	protein	P51812	UNIPROT	CENPE	protein	Q02224	UNIPROT	up-regulates activity				9606	BTO:0000567								20383198	f		lperfetto	We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions.	SIGNOR-252037	0.2
linifanib	chemical	CHEBI:91435	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates activity	chemical inhibition			-1									16648571	t		Gianni	ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families	SIGNOR-262207	0.8
E2F1	protein	Q01094	UNIPROT	SMAD7/HDAC1/E2F-1	complex	SIGNOR-C12	SIGNOR	form complex	binding			9606									23213415	t		gcesareni	Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes	SIGNOR-199955	0.445
PRKCA	protein	P17252	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	phosphorylation	Ser1303	NKLRRQHsYDTFVDL	-1									11306676	t		lperfetto	These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels.	SIGNOR-249083	0.482
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr179	GGPAQDIyQVPPSAG	10090									12972425	t		lperfetto	Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs	SIGNOR-246389	0.797
WWTR1	protein	Q9GZV5	UNIPROT	NKX2-1	protein	P43699	UNIPROT	up-regulates	binding			9606		BTO:0000887							16397409	t		gcesareni	Taz also binds to the transcription factor ttf-1 that is involved in formation and differentiation of the lungs and respiratory epithelia, and stimulates the production of pulmonary surfactant.	SIGNOR-143472	0.435
ZMYND8	protein	Q9ULU4	UNIPROT	CD44	protein	P16070	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001033								27477906	t		lperfetto	Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported	SIGNOR-262039	0.2
CASP1	protein	P29466	UNIPROT	Pyrin inflammasome	complex	SIGNOR-C226	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256412	0.725
p38	proteinfamily	SIGNOR-PF16	SIGNOR	NFATC4	protein	Q14934	UNIPROT	down-regulates	phosphorylation	Ser170	GGAFFSPsPGSSSLS	9606									11997522	t		lperfetto	Phosphorylation of nfatc4 by p38 mitogen-activated protein kinasesthe p38 map kinase phosphorylates multiple residues, including ser(168) and ser(170), in the nfat homology domain of nfatc4. Replacement of ser(168,170) with ala promotes nuclear localization of nfatc4 and increases nfat-mediated transcription activity.	SIGNOR-87397	0.2
PDGFRB	protein	P09619	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates	phosphorylation	Tyr771	ADIESSNyMAPYDNY	9606									1314164	t		llicata	Mutagenesis studies show that tyr740 and 751 are involved in the pdgf-stimulated binding of phosphatidylinositol (pi) 3 kinase, and tyr771 is required for efficient binding of gap, the gtpase activator of ras.	SIGNOR-16892	0.2
PRKG2	protein	Q13237	UNIPROT	LASP1	protein	Q14847	UNIPROT	unknown	phosphorylation	Ser146	MEPERRDsQDGSSYR	9606									12571245	t		lperfetto	Recombinant human LASP was phosphorylated by cGMP- and cAMP-dependent protein kinase (cAK) in vitro. Cotransfection of PtK-2 cells with LASP and cGK confirmed phosphorylation of LASP in vivo. Studies with human LASP mutants identified serine 146 as a specific phosphorylation site for cGK and cAK in vivo. LASP is an actin-binding protein, and the phospho-LASP-mimicking mutant S146D showed reduced binding affinity for F-actin in cosedimentation experiments.	SIGNOR-249197	0.348
NOTCH1	protein	P46531	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606									18342499	f		flangone	Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages	SIGNOR-241998	0.7
INSR	protein	P06213	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr627	KGDKQVEyLDLDLDS	10090	BTO:0000944								10978177	t			HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin	SIGNOR-251316	0.492
MYCT1	protein	Q8N699	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30283340	f		miannu	MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. 	SIGNOR-261730	0.2
RPS6KA3	protein	P51812	UNIPROT	NR4A1	protein	P22736	UNIPROT	unknown	phosphorylation	Ser351	GRRGRLPsKPKQPPD	9606	BTO:0000007								16223362	t		lperfetto	In the present paper, we have re-examined the phosphorylation of Nur77 on Ser354. Using a combination of cell-permeable kinase inhibitors and mouse knockin mutations, we show that Nur77 is phosphorylated by RSK in response to mitogenic stimulation of cells. Phosphorylation of Nur77 on Ser354 did not, however, appear to affect the transcriptional activity of Nur77, or its ability to bind 14-3-3 proteins in vivo.	SIGNOR-249295	0.477
NF2	protein	P35240	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	binding			9606									24012335	t	The opposite changes in Lats/YAP and Mst1/2 phosphorylation upon loss of NF2 therefore argue against the generally assumed linear model in which NF2 signals through activation of Mst1/2	flangone	As expected, the nf2-/- fc-912 cells were defective in lats1/2 phosphorylation (figure s2e-f). Subcellular fractionation revealed a significant increase of endogenous lats1/2 in the cytoplasmic relative to the membrane fraction in the nf2-/- fc-912 schwann cells compared to the nf2+/+ fh-912 schwann cells (figure 2e). This localization defect was rescued by re-expression of nf2	SIGNOR-202607	0.716
KIF1C	protein	O43896	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272517	0.7
COL6A6	protein	A6NMZ7	UNIPROT	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									21949456	t			Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present.	SIGNOR-254677	0.7
CDK5	protein	Q00535	UNIPROT	CORO1A	protein	P31146	UNIPROT	up-regulates activity	phosphorylation	Thr424	AAPEASGtPSSDAVS	9606	BTO:0001588								26823173	t		lperfetto	We here show that phosphorylation of coronin 1 on Thr(418/424) by cyclin-dependent kinase (CDK) 5 activity was responsible for coronin 1-G_s association and the modulation of cAMP production. Together these results show an essential role for CDK5 activity in promoting the coronin 1-dependent cAMP/PKA pathway.	SIGNOR-245187	0.293
NTNG2	protein	Q96CW9	UNIPROT	LRRC4	protein	Q9HBW1	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								19467332	t		miannu	The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively.	SIGNOR-264048	0.724
clenbuterol	chemical	CHEBI:174690	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. 	SIGNOR-257861	0.8
imatinib	chemical	CHEBI:45783	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates activity	chemical inhibition			9606									22045730	t			Recently, imatinib, an inhibitor of several tyrosine kinases, including c-abl, c-kit and PDGFRs, was demonstrated to ameliorate dystrophic phenotypes in mdx mice by suppressing the phosphorylation of PDGFRa	SIGNOR-254378	0.8
venlafaxine	chemical	CHEBI:9943	ChEBI	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			9615									20378347	t		Luana	The cycloalkanol ethylamine scaffold was successfully utilized in the discovery and development of dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitors (SNRIs).1 Drugs such as venlafaxine (1) and duloxetine (2) possessing norepinephrine reuptake inhibition, either selectively or in combination with serotonin reuptake inhibition were approved for major depressive disorder (MDD).	SIGNOR-257835	0.8
PPP1CC	protein	P36873	UNIPROT	CASP2	protein	P42575	UNIPROT	up-regulates activity	dephosphorylation	Ser164	STDTVEHsLDNKDGP	-1									19531356	t		llicata	nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2.	SIGNOR-248503	0.2
PP121	chemical	CHEBI:50915	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252655	0.8
CSNK1D	protein	P48730	UNIPROT	BACE1	protein	P56817	UNIPROT	unknown	phosphorylation	Ser498	DDFADDIsLLK	9606	BTO:0000007								11278841	t		llicata	Here, we report that BACE can be phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1. Phosphorylation exclusively occurs after full maturation of BACE by propeptide cleavage and complex N-glycosylation. | After reinternalization, BACE wild type as well as BACE S498D are efficiently retrieved from early endosomal compartments and further targeted to later endosomal compartments and/or the trans-Golgi network. In contrast, nonphosphorylatable BACE S498A is retained within early endosomes. 	SIGNOR-250797	0.374
PPP1CC	protein	P36873	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	dephosphorylation	Ser469	AHEENPEsILDEHVQ	9606									17318175	t			The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 	SIGNOR-248497	0.272
EIF2AK3	protein	Q9NZJ5	UNIPROT	EIF2S1	protein	P05198	UNIPROT	down-regulates activity	phosphorylation	Ser52	MILLSELsRRRIRSI	9606									30070006	t		gcesareni	The integrated stress response is characterized by the phosphorylation of eukaryotic initiation factor-2α (eIF2α) on serine 51 by one out of four specific kinases (EIF2AK1 to 4)	SIGNOR-246153	0.757
CUL1	protein	Q13616	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001271		SIGNOR-C5						12835716	t		lperfetto	Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2	SIGNOR-102725	0.627
hydromorphone	chemical	CHEBI:5790	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000246								19282177	t		Luana	A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 	SIGNOR-258143	0.8
GABRG2	protein	P18507	UNIPROT	GABA-A (a5-b1-g2) receptor	complex	SIGNOR-C335	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263767	0.634
PRKG1	protein	Q13976	UNIPROT	LASP1	protein	Q14847	UNIPROT	down-regulates activity	phosphorylation	Ser146	MEPERRDsQDGSSYR	9606									12571245	t		lperfetto	Studies with human lasp mutants identified serine 146 as a specific phosphorylation site for cgk and cak in vivo. Lasp is an actin-binding protein, and the phospho-lasp-mimicking mutant s146d showed reduced binding affinity for f-actin in cosedimentation experiments.	SIGNOR-97946	0.366
NRF1	protein	Q16656	UNIPROT	TFB2M	protein	Q9H5Q4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15684387	f		lperfetto	Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC	SIGNOR-268997	0.54
etorphine	chemical	CHEBI:4912	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10029									9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258804	0.8
NUP155	protein	O75694	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262082	0.745
MAPKAPK2	protein	P49137	UNIPROT	RCSD1	protein	Q6JBY9	UNIPROT	down-regulates activity	phosphorylation	Ser179	RRFRRSQsDCGELGD	-1									15850461	t		miannu	Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263079	0.491
N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-(2,6-dimethoxyphenoxy)ethanamine	chemical	CHEBI:64098	ChEBI	ADRA1D	protein	P25100	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258467	0.8
GSK3B	protein	P49841	UNIPROT	EIF2B5	protein	Q13144	UNIPROT	down-regulates activity	phosphorylation	Ser535	ESEQSMDsEEPDSRG	-1									12133000	t			The largest (epsilon) subunit of eIF2B is a substrate for glycogen synthase kinase (GSK)-3 in vitro, and phosphorylation by GSK3 inhibits the activity of eIF2B. The site of phosphorylation has previously been identified as Ser(535). 	SIGNOR-251236	0.561
MAPK1	protein	P28482	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser294	QLSKWPGsPTSRSSD	9606									18204439	t		lperfetto	Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation.	SIGNOR-160407	0.71
ARNTL	protein	O00327	UNIPROT	VWF	protein	P04275	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000394								20658528	t	 	lperfetto	We also show that major circadian transcriptional regulators CLOCK and Bmal1 directly regulate the activity of vWF promoter and that lack of Bmal1 results in upregulation of vWF both at mRNA and protein level. Here we report a direct regulation of vWF expression in endothelial cells by biological clock gene Bmal1. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype.	SIGNOR-253704	0.331
SLC38A9	protein	Q8NBW4	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				9606	BTO:0000007								29053970	f			Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters.	SIGNOR-255311	0.469
VEGFA	protein	P15692	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates				9606									16301830	f			VEGF as a key mediator of angiogenesis in cancer.	SIGNOR-256597	0.7
GSK3B	protein	P49841	UNIPROT	NR1D1	protein	P20393	UNIPROT	up-regulates	phosphorylation	Ser55	CPTYFPPsPTGSLTQ	9606									16484495	t		llicata	We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock.	SIGNOR-144566	0.286
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	BCL2L11	protein	O43521	UNIPROT	up-regulates	phosphorylation	Ser118	DKSTQTPsPPCQAFN	9606									12591950	t		lperfetto	Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58)	SIGNOR-98388	0.2
RPL17	protein	P18621	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262482	0.751
GGCX	protein	P38435	UNIPROT	F2	protein	P00734	UNIPROT	up-regulates activity	carboxylation	Glu75	EEAFEALeSSTATDV	-1									10556651	t		lperfetto	We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 	SIGNOR-263684	0.655
PRKCD	protein	Q05655	UNIPROT	PRKCD	protein	Q05655	UNIPROT	up-regulates	phosphorylation	Thr141	EDEAKFPtMNRRGAI	9606									19366211	t		llicata	This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. a t141d substitution markedly increases basal lipid-independent pkcdelta activity;	SIGNOR-185279	0.2
SYVN1	protein	Q86TM6	UNIPROT	HMGCR	protein	P04035	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			10090	BTO:0000944								14593114	t		miannu	In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols.	SIGNOR-272594	0.579
CSNK1A1L	protein	Q8N752	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	phosphorylation	Ser45	GATTTAPsLSGKGNP	9606									12000790	t		gcesareni	We show that a complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45).	SIGNOR-87430	0.491
CPS1	protein	P31327	UNIPROT	glutamine	smallmolecule	CHEBI:28300	ChEBI	down-regulates quantity	chemical modification			9606									15096496	t			CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules	SIGNOR-267198	0.8
p38	proteinfamily	SIGNOR-PF16	SIGNOR	FOXC1	protein	Q12948	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser272	SSLSSGSsPPGSLPS										31650548	t		lperfetto	P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation.	SIGNOR-275912	0.2
MAP2K3	protein	P46734	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation	Thr180	RHTDDEMtGYVATRW	9606									8622669	t		lperfetto	Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases.	SIGNOR-40349	0.715
SLC36A2	protein	Q495M3	UNIPROT	alanine	smallmolecule	CHEBI:16449	ChEBI	up-regulates quantity	relocalization			9606									12748860	t		lperfetto	Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut.	SIGNOR-264740	0.8
HDAC1	protein	Q13547	UNIPROT	SERPINB5	protein	P36952	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001570								18247378	t		miannu	We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1.	SIGNOR-268494	0.423
MAPK3	protein	P27361	UNIPROT	XPO5	protein	Q9HAV4	UNIPROT	down-regulates activity	phosphorylation	Ser497	GSLCSVFsPSFVQWE	9606									27846390	t		lperfetto	Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. 	SIGNOR-262982	0.317
TRIB3	protein	Q96RU7	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity	binding			9606	BTO:0000007	BTO:0000759							12791994	t		llicata	TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase.	SIGNOR-237850	0.603
AKT1	protein	P31749	UNIPROT	IRAK1	protein	P51617	UNIPROT	down-regulates activity	phosphorylation	Thr100	LRARDIItAWHPPAP	9606	BTO:0000007								11976320	t		gcesareni	CaMKKc and Akt overexpression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-kappaB activation.	SIGNOR-252551	0.394
CSNK2B	protein	P67870	UNIPROT	ATF4	protein	P18848	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser215	IKEEDTPsDNDSGIC	9606	BTO:0000567								23123191	t		miannu	By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form. 	SIGNOR-276424	0.2
fludrocortisone	chemical	CHEBI:50885	ChEBI	NR3C2	protein	P08235	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								8282004	t		miannu	The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4).	SIGNOR-258706	0.8
MLL2 complex	complex	SIGNOR-C88	SIGNOR	PAX7/MLL2 complex	complex	SIGNOR-C91	SIGNOR	form complex	binding			9606	BTO:0002314	BTO:0000887;BTO:0001103							22863532	t		miannu	Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5.	SIGNOR-198623	0.2
Starvation	stimulus	SIGNOR-ST4	SIGNOR	AMPK	complex	SIGNOR-C15	SIGNOR	up-regulates				9606									23000343	f		lperfetto	Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activationSTARV	SIGNOR-209796	0.7
MAPK3	protein	P27361	UNIPROT	NCOA1	protein	Q15788	UNIPROT	up-regulates	phosphorylation	Thr1179	NYGTNPGtPPASTSP	9606									12163482	t		lperfetto	Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein	SIGNOR-91143	0.271
FGD3	protein	Q5JSP0	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260553	0.633
F7	protein	P08709	UNIPROT	F10	protein	P00742	UNIPROT	up-regulates activity	binding			9606		BTO:0000131	SIGNOR-C319						29880919	t		lperfetto	TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively.	SIGNOR-263545	0.52
IL27	protein	Q8NEV9	UNIPROT	IL27RA	protein	Q6UWB1	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0000876								14764690	t		gcesareni	Wsx-1 and glycoprotein 130 constitute a signal-transducing receptor for il-27.	SIGNOR-121799	0.701
BMP2	protein	P12643	UNIPROT	SHH	protein	Q15465	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19855020	f		gcesareni	On the other hand, bmp activity negatively regulates shh transcription and a bmp-shh nega-tive-feedback loop serves to confine shh expression during limb development.	SIGNOR-188853	0.532
TET1	protein	Q8NFU7	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27121319	t		irozzo	We also found that TET1 directly binds to the promoter region of PTEN and activates its transcription through demethylation of CpG islands	SIGNOR-259096	0.382
FOXO4	protein	P98177	UNIPROT	IDH1	protein	O75874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25648147	t		miannu	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260091	0.267
PRKACA	protein	P17612	UNIPROT	ITPR1	protein	Q14643	UNIPROT	down-regulates activity	phosphorylation	Ser1598	RNAARRDsVLAASRD	-1									12529267	t		miannu	IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site. 	SIGNOR-249996	0.537
pralatrexate	chemical	CHEBI:71223	ChEBI	TYMS	protein	P04818	UNIPROT	down-regulates activity	chemical inhibition			9606									23409799	t		miannu	Pralatrexate is a small molecule with a chemical formula C23H23N7O5 and a molecular weight of 477.48 g/mol (Box 1). It competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase.	SIGNOR-259352	0.8
SIRT1	protein	Q96EB6	UNIPROT	CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	down-regulates activity	binding												19299583	t	 	lperfetto	Using Per2:luciferase transcriptional reporter assays in HEK293 cells (Fig. 2C-E; S2), we show that inhibition of NAMPT by FK866 led to a significant increase in the CLOCK:BMAL1-driven transcription of the Per2:luciferase reporter (Fig. 2C), indicating that reduced NAMPT-mediated NAD+ biosynthesis released CLOCK:BMAL1 from the SIRT1-dependent suppression.	SIGNOR-253722	0.772
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	ID2	protein	Q02363	UNIPROT	down-regulates	phosphorylation	Ser5	sPVRSVRK	9606									9029153	t		lperfetto	Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_	SIGNOR-216698	0.445
MAPK14	protein	Q16539	UNIPROT	CASP8	protein	Q14790	UNIPROT	down-regulates	phosphorylation	Ser347	FTGLKCPsLAGKPKV	9606	BTO:0000130								14970175	t		amattioni	P38-mapk can directly phosphorylate and inhibit the activities of caspase-8	SIGNOR-122103	0.567
NDUFB1	protein	O75438	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4	SIGNOR-262162	0.766
CTBP1	protein	Q13363	UNIPROT	UBE2D3	protein	P61077	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000356								21044962	f		miannu	 knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene.	SIGNOR-255174	0.2
1-phospho-alpha-D-glucuronic acid	smallmolecule	CHEBI:681	ChEBI	DRD3	protein	P35462	UNIPROT	up-regulates activity	chemical activation			-1									7576010	t		miannu	The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1.Similarly, the affinities of D3 receptors for quinpirole and dopamine were much higher than the affinities of D:! receptors for the agonists in the presence of Gpp(NH)p and NaCl when [1251]-NCQ-298 was used to label receptors; however, when Gpp(NH)p and NaCl were not present, and when [12sI]-7-OH-PIPAT was used, receptors bound quinpirole and dopamine with nearly equal affinities (Table 1). 	SIGNOR-258434	0.8
DDIT3	protein	P35638	UNIPROT	PPP1R15A	protein	O75807	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									31226023	t		miannu	ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress.	SIGNOR-260173	0.468
CDK1	protein	P06493	UNIPROT	CDC27	protein	P30260	UNIPROT	up-regulates	phosphorylation	Ser426	TQPNINDsLEITKLD	9606									14657031	t		lperfetto	Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation	SIGNOR-119873	0.692
ZMYM2	protein	Q9UBW7	UNIPROT	NANOG	protein	Q9H9S0	UNIPROT	down-regulates activity	binding			10090		BTO:0004593							31363497	t		miannu	 In this work, we identified ZMYM2/ZFP198, which physically associates with NANOG as a key negative regulator of NANOG-mediated reprogramming of both epiblast stem cells and somatic cells.	SIGNOR-269802	0.304
PTGER4	protein	P35408	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257032	0.318
TNF	protein	P01375	UNIPROT	MPO-ANCA	complex	SIGNOR-C474	SIGNOR	up-regulates				10090		BTO:0000133							15972951	f		lperfetto	Second, LPS-mediated aggravation of anti-MPO IgG-induced glomerulonephritis was attenuated, but not prevented, by pretreatment with neutralizing anti-TNF-α antibodies.	SIGNOR-270588	0.2
4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide	chemical	CHEBI:94506	ChEBI	CCNA2	protein	P20248	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193537	0.8
P2RY2	protein	P41231	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256759	0.357
MAML1	protein	Q92585	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates	binding			9606									16510869	t		gcesareni	Unexpectedly, however, emerging evidence implicate maml proteins as exciting key transcriptional co-activators in other signal transduction pathways including: muscle differentiation and myopathies (mef2c), tumor suppressor pathway (p53) and colon carcinoma survival (beta-catenin).	SIGNOR-144913	0.404
SP1	protein	P08047	UNIPROT	ATP2C1	protein	P98194	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000667								15955096	f		miannu	 when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter. 	SIGNOR-255194	0.2
GDNF	protein	P39905	UNIPROT	GCH1	protein	P30793	UNIPROT	up-regulates activity				9606									12358777	f		miannu	GDNF can support the function of primary dopaminergic neurones by triggering activation of GTP-cyclohydrolase I (GTPCH I), a key enzyme in catecholamine biosynthesis. GTPCH I mRNA levels in primary dopaminergic neurones were not altered by GDNF treatment, suggesting that the mode of action for that up-regulation is not directly connected to the regulation of GTPCH I transcription	SIGNOR-252221	0.282
GTF2I	protein	P78347	UNIPROT	KDM1A	protein	O60341	UNIPROT	up-regulates activity	relocalization			9606									21282467	t		lperfetto	Moreover, the inhibitory effect of TFII-I on transcription is mediated by its ability to recruit corepressor complexes, including histone deacetylase 3 (HDAC3) (25, 133), histone H3K4-specific demethylase LSD1 (48), and components of the polycomb repressor complex 	SIGNOR-268540	0.415
MAP4K1	protein	Q92918	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates				9606									10224067	f		gcesareni	These studies establish that hpk1 acts as an upstream activator for the tak1-sek-jnk1 module in relaying the tgf-_ signal into the nuclei in 293t cells.	SIGNOR-67321	0.536
PLK1	protein	P53350	UNIPROT	RACGAP1	protein	Q9H0H5	UNIPROT	up-regulates	phosphorylation	Ser157	GSILSDIsFDKTDES	9606									19468302	t		llicata	Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex.	SIGNOR-185746	0.658
ERN1	protein	O75460	UNIPROT	OS9	protein	Q13438	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18417469	f		miannu	Here we characterize the function in ER quality control of two proteins derived from alternative splicing of the OS-9 gene. OS-9.1 and OS-9.2 are ubiquitously expressed in human tissues and are amplified in tumors. They are transcriptionally induced upon activation of the Ire1/Xbp1 ER-stress pathway. 	SIGNOR-261063	0.435
DYDC1	protein	Q8WWB3	UNIPROT	Acrosome_assembly	phenotype	SIGNOR-PH156	SIGNOR	up-regulates				9606									19545932	f		miannu	Knockdown of Dydc1 blocks spermatogenesis and acrosome biogenesis	SIGNOR-263881	0.7
MAPK3	protein	P27361	UNIPROT	SCNN1B	protein	P51168	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr615	QALPIPGtPPPNYDS	-1									11805112	t		lperfetto	Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.	SIGNOR-249447	0.282
PTGER3	protein	P43115	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257203	0.252
PDPK1	protein	O15530	UNIPROT	PDPK1	protein	O15530	UNIPROT	up-regulates activity	phosphorylation	Ser241	SKQARANsFVGTAQY	9606									11481331	t		miannu	In terms of the modulation of PDK1 activity by reversible phosphorylation, five pS sites have been identified on PDK1 in vivo, but only one of these sites, Ser-241 in the activation loop of PDK1, is essential for activity. It seems likely that PDK1 autophosphorylates itself on this residue.	SIGNOR-250268	0.2
MTOR	protein	P42345	UNIPROT	DAP	protein	P51397	UNIPROT	down-regulates activity	phosphorylation	Ser3	DQEWESPsPPKPTVF	9606									20537536	t		miannu	 A critical step in autophagy induction comprises the inactivation of a key negative regulator of the process, the Ser/Thr kinase mammalian target of rapamycin (mTOR). Here we identify death-associated protein 1 (DAP1) as a novel substrate of mTOR that negatively regulates autophagy. Mapping of the phosphorylation sites and analysis of phosphorylation mutants indicated that DAP1 is functionally silenced in growing cells through mTOR-dependent phosphorylations on Ser3 and Ser51. 	SIGNOR-259813	0.405
CDK1	protein	P06493	UNIPROT	PAPOLA	protein	P51003	UNIPROT	up-regulates activity	phosphorylation	Ser537	DNSMSVPsPTSATKT	10090	BTO:0000964								34048556	t		lperfetto	Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity.	SIGNOR-268338	0.261
CSNK1A1	protein	P48729	UNIPROT	AGO2	protein	Q9UKV8	UNIPROT	down-regulates activity	phosphorylation	Ser834	GSHTSGQsNGRDHQA	9606	BTO:0001109								28114302	t		miannu	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276509	0.378
PDK1	protein	Q15118	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates	phosphorylation	Ser232	NRYGMGTsVERAAAS	-1									7782287	t		gcesareni	Sites 1, 2, and 3 in the E1 mutants were phosphorylated either individually or in the presence of the other sites by the dihydrolipoamide acetyltransferase-protein X-E1 kinase indicating a site-independent mechanism of phosphorylation.	SIGNOR-32977	0.785
CLTA	protein	P09496	UNIPROT	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	form complex	binding			9606									24789820	t		lperfetto	AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly. 	SIGNOR-260667	0.755
LCK	protein	P06239	UNIPROT	LAT	protein	O43561	UNIPROT	up-regulates	phosphorylation	Tyr200	SMESIDDyVNVPESG	9606	BTO:0000782								16938345	t		gcesareni	Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation.	SIGNOR-149182	0.749
CYP11B1	protein	P15538	UNIPROT	11-deoxycorticosterone	smallmolecule	CHEBI:16973	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000048							33117906	t		lperfetto	The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone	SIGNOR-268683	0.8
WASHC1	protein	A8K0Z3	UNIPROT	WASH complex	complex	SIGNOR-C258	SIGNOR	form complex	binding												23721880	t		lperfetto	The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53.	SIGNOR-261020	0.2
ERG	protein	P11308	UNIPROT	EPB41L3	protein	Q9Y2J2	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20860828	f	 	miannu	EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression.	SIGNOR-253918	0.2
MSH2	protein	P43246	UNIPROT	MSH2/MSH6	complex	SIGNOR-C60	SIGNOR	form complex	binding			9606									15064730	t		miannu	The human msh2/6 complex is essential for mismatch recognition during the repair of replication errors.	SIGNOR-123702	0.803
H2AC4	protein	P04908	UNIPROT	Nucleosome_H3.1 variant	complex	SIGNOR-C324	SIGNOR	form complex	binding			-1									21812398	t		miannu	The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 	SIGNOR-263719	0.2
PRKCI	protein	P41743	UNIPROT	LLGL2	protein	Q6P1M3	UNIPROT	up-regulates activity	phosphorylation	Ser653	LKKSLRQsFRRMRRS	9615	BTO:0000837								12725730	t		miannu	This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner.	SIGNOR-263180	0.709
PRKCE	protein	Q02156	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates activity	phosphorylation	Ser710	GEKSFRRsVVGTPAY										12058027	t		lperfetto	Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.	SIGNOR-275960	0.2
BMS-265246	chemical	CID:5329775	PUBCHEM	CDK2	protein	P24941	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190434	0.8
CSNK2A1	protein	P68400	UNIPROT	SLK	protein	Q9H2G2	UNIPROT	down-regulates	phosphorylation	Ser348	SDLSIASsEEDKLSQ	9606									16837460	t		gcesareni	Slk down-regulation by v-src is indirect and is accompanied by slk hyperphosphorylation on serine residues. Deletion analysis revealed that casein kinase ii (ck2) sites at position 347/348 are critical for v-src-dependent modulation of slk activity.	SIGNOR-147883	0.2
ANK2	protein	Q01484	UNIPROT	DCTN4	protein	Q9UJW0	UNIPROT	up-regulates quantity	relocalization			10090		BTO:0001103							19109891	t		miannu	We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4.	SIGNOR-266713	0.609
TYMS	protein	P04818	UNIPROT	(6R)-5,10-methylenetetrahydrofolate(2-)	smallmolecule	CHEBI:15636	ChEBI	down-regulates quantity	chemical modification			9606									21876188	t		lperfetto	In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR.	SIGNOR-268231	0.8
MET	protein	P08581	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr194	ALEKKSNyEVLEKDV	9606									16782899	t		gcesareni	Here we report that fak directly interacts with the hepatocyte growth factor receptor c-met. Phosphorylation of c-met at tyr-1349 and, to a lesser extent, tyr-1356 is required for its interaction with the band 4.1 and ezrin/radixin/moesin homology domain (ferm domain) of fak. met-fak interaction leads to fak activation and subsequent contribution to hepatocyte growth factor-induced cell motility and cell invasion.	SIGNOR-147179	0.475
JAK2	protein	O60674	UNIPROT	SLC6A8	protein	P48029	UNIPROT	down-regulates activity	relocalization			443947	BTO:0000964								22407360	t		miannu	Janus-activated kinase-2 (JAK2) participates in the regulation of the Na⁺-coupled glucose transporter SGLT1 and the Na⁺-coupled amino acid transporter SLC6A19. JAK2 is a novel regulator of the creatine transporter SLC6A8, which downregulates the carrier, presumably by interference with carrier protein insertion into the cell membrane.	SIGNOR-265807	0.2
SLA	protein	Q13239	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9534	BTO:0001538								24284075	t		miannu	 In this report, we show that SLAP associates with both wild-type and oncogenic c-Kit (c-Kit-D816V). The association involves the SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitylation which, in turn, is followed by receptor degradation	SIGNOR-263143	0.2
KRAS	protein	P01116	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606									21779497	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism.	SIGNOR-175204	0.907
UHMK1	protein	Q8TAS1	UNIPROT	SF1	protein	Q15637	UNIPROT	up-regulates	phosphorylation	Ser82	NPEDRSPsPEPIYNS	9606									23175611	t	The effect has been demonstrated using Q15637-2	gcesareni	Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding.	SIGNOR-199797	0.417
CSNK2A1	protein	P68400	UNIPROT	SLITRK1	protein	Q96PX8	UNIPROT	up-regulates activity	phosphorylation	Ser695	DCGSHSLsD	-1									19640509	t		miannu	In our studies, SICD was phosphorylated by PKA, PKC, and CK2, and association of SLITRK1 with 14-3-3 was regulated by phosphorylation at Ser695. Co-precipitation experiments demonstrated much greater recovery of 14-3-3 in SLITRK1 precipitates when wild-type or S695E was used, as compared with S695A, consistent with the results with purified peptides.	SIGNOR-273633	0.2
MBD5	protein	Q9P267	UNIPROT	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606									20700456	f		miannu	The human proteins MBD5 and MBD6 associate with heterochromatin but they do not bind methylated DNA.Our data suggest that MBD5 and MBD6 are unlikely to be methyl-binding proteins, yet they may contribute to the formation or function of heterochromatin. One isoform of MBD5 is highly expressed in oocytes, which suggests a possible role in epigenetic reprogramming after fertilization.	SIGNOR-266773	0.7
CRTC2	protein	Q53ET0	UNIPROT	TSC22D3	protein	Q99576	UNIPROT	up-regulates quantity	transcriptional regulation			9606									26652733	t			CRTC2 knockdown attenuates glucocorticoid-responsive GILZ mRNA expression in HeLa cells	SIGNOR-256109	0.2
EFNB1	protein	P98172	UNIPROT	EPHB3	protein	P54753	UNIPROT	up-regulates	binding			9606									9330863	t		gcesareni	The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion.	SIGNOR-52517	0.754
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CDK7	protein	P50613	UNIPROT	up-regulates activity	phosphorylation	Thr170	GSPNRAYtHQVVTRW	-1									11113184	t		lperfetto	Activating phosphorylation of CDK7 by CDC2 and CDK2. The ability of pure CDK2-cyclin A to activate CDK7 in T170-dependent fashion (Fig. ​(Fig.3C,3C, lane 2) strongly suggested a direct phosphorylation mechanism. Tryptic phosphopeptide mapping confirmed that both CDK2-cyclin A (Fig. ​(Fig.4A)4A) and CDC2-cyclin B (Fig. ​(Fig.4D)4D) phosphorylated CDK7 on both S164 and T170. 	SIGNOR-270806	0.629
PRKCA	protein	P17252	UNIPROT	CFLAR	protein	O15519	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser193	LQAAIQKsLKDPSNN	9606	BTO:0000664								19343040	t		miannu	 Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins. c-FLIP S193 phosphorylation is mediated by PKCa and PKCb.S193 phosphorylation increases the stability of the short c-FLIP proteins	SIGNOR-276147	0.2
Saracatinib	chemical	CID:10302451	PUBCHEM	SRC	protein	P12931	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206691	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	CDK18	protein	Q07002	UNIPROT	up-regulates activity	phosphorylation	Ser14	KNFKRRFsLSVPRTE										28361970	t		lperfetto	We previously revealed that PCTK3 is activated by two pathways: interaction with cytoplasmic cyclin A and phosphorylation at Ser-12 by protein kinase A (PKA)12. Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro. 	SIGNOR-264559	0.2
FST	protein	P19883	UNIPROT	INHBA	protein	P08476	UNIPROT	down-regulates activity	binding			10090	BTO:0005787								24627466	t		lperfetto	Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. |FST315-ΔHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function.	SIGNOR-251715	0.84
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Ser214	SRSGLYRsPSMPENL	9606	BTO:0000150								20530684	t		lperfetto	The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry.	SIGNOR-216721	0.598
NAB2	protein	Q15742	UNIPROT	TNFSF10	protein	P50591	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000782								22128144	f	 	miannu	 In the present study, we investigated the molecular basis for the differential regulation of TRAIL in helped versus helpless CD8(+) T cells by comparing their transcriptional profiles, and have identified a transcriptional corepressor, NGFI-A binding protein 2 (Nab2), that is selectively induced in helped CD8(+) T cells. Enforced expression of Nab2 prevents TRAIL induction after restimulation of primary helpless CD8(+) T cells, and expression of a dominant-negative form of Nab2 in helped CD8(+) T cells impairs their secondary proliferative response that is reversible by TRAIL blockade. 	SIGNOR-253893	0.2
CSNK2A1	protein	P68400	UNIPROT	MDC1	protein	Q14676	UNIPROT	up-regulates	phosphorylation	Thr378	ESQAGSDtDVEEGKA	9606									18678890	t		gcesareni	The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites.	SIGNOR-179887	0.353
NKD1	protein	Q969G9	UNIPROT	DVL3	protein	Q92997	UNIPROT	down-regulates	binding			9606									20858476	t		gcesareni	Naked (nkd)1 and nkd2 are mammalian homologs of drosophila naked cuticle, which negatively regulates canonical wnt signaling by binding dishevelled. various reports using cell culture assays indicate that nkd-mediated wnt antagonism involves dvl degradation	SIGNOR-167984	0.696
OPTN	protein	Q96CV9	UNIPROT	NEFL	protein	P07196	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									22194658	f	same result in PC12 cell 	miannu	SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA.	SIGNOR-259881	0.271
INSR	protein	P06213	UNIPROT	PTPN1	protein	P18031	UNIPROT	up-regulates activity	phosphorylation	Tyr66	LHQEDNDyINASLIK	-1									11506178	t		lperfetto	Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B	SIGNOR-249370	0.778
EGFR	protein	P00533	UNIPROT	SOX2	protein	P48431	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19882665	f		miannu	We show that egfr-mediated signaling promotes sox2 expression, which in turn binds to the egfr promoter and directly upregulates egfr expression.	SIGNOR-189033	0.494
DAB1	protein	O75553	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606		BTO:0000142							22394407	t		lperfetto	The induction of disabled-1 (dab-1) tyrosine phosphorylation, and the subsequent activation of src family kinases, were found to be essential steps for the activation of notch-1 signaling by reelin	SIGNOR-196438	0.388
POLR2A	protein	P24928	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266160	0.864
UQCR10	protein	Q9UDW1	UNIPROT	Mitochondrial respiratory chain complex III	complex	SIGNOR-C279	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits	SIGNOR-262199	0.925
HRAS	protein	P01112	UNIPROT	BRAF	protein	P15056	UNIPROT	up-regulates	binding			10090	BTO:0000944								7706312	t		lperfetto	Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes.	SIGNOR-235478	0.873
PRKCA	protein	P17252	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates activity	phosphorylation	Ser166	LGARAKEsLDLRAHL	-1									11121119	t		lperfetto	In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Overphosphorylation of troponin I reduced its affinity for troponin C, as measured by isothermal titration microcalorimetry. Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation.	SIGNOR-249069	0.349
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2V2	protein	Q15819	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271369	0.455
diethylstilbestrol	chemical	CHEBI:41922	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258598	0.8
MEN1	protein	O00255	UNIPROT	MLL-AF4	fusion protein	SIGNOR-FP4	SIGNOR	up-regulates activity	binding			10090	BTO:0004730								16239140	t		irozzo	We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...].	SIGNOR-255868	0.2
LCK	protein	P06239	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates				9606									17998336	f		gcesareni	The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1.	SIGNOR-159164	0.564
Cap-binding complex	complex	SIGNOR-C440	SIGNOR	PUM3	protein	Q15397	UNIPROT	down-regulates quantity by repression	post transcriptional regulation			9606									31320643	t		lperfetto	In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins	SIGNOR-268352	0.2
PRKACA	protein	P17612	UNIPROT	NOS1	protein	P29475	UNIPROT	unknown	phosphorylation			-1									1375933	t		miannu	NOS is stoichiometrically phosphorylated by PKA, PKC, and CaMK, with each enzyme predominantly phosphorylating a distinct serine. CPT-CAMP has no effect on NOS activity	SIGNOR-250021	0.326
CLASP1	protein	Q7Z460	UNIPROT	MAPRE1	protein	Q15691	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								15631994	t		lperfetto	CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. 	SIGNOR-265094	0.593
CDK9	protein	P50750	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									19914168	t		lpetrilli	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161678	0.607
SRC	protein	P12931	UNIPROT	SPTAN1	protein	Q13813	UNIPROT	up-regulates	phosphorylation	Tyr1176	AVQQQEVyGMMPRDE	9606									11971983	t		llicata	Using mutagenesis on recombinant peptides, we identified the residue y1176 located in the calpain cleavage site of alpha ii-spectrin, near the sh3 domain, as an in vitro substrate for src kinase and lmw-ptp a. phosphorylation of this residue decreases spectrin sensitivity to calpain in vitro.	SIGNOR-86718	0.543
very long-chain (R)-3-hydroxyacyl-CoA(4-)	smallmolecule	CHEBI:85440	ChEBI	very long-chain 2,3-trans-enoyl CoA(4-)	smallmolecule	CHEBI:83728	ChEBI	up-regulates quantity	precursor of			9606									18554507	t		miannu	Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle.	SIGNOR-267916	0.8
CIITA	protein	P33076	UNIPROT	HLA-DRB5	protein	Q30154	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002417								10886240	f	 	 	These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma.	SIGNOR-254013	0.447
CDK1	protein	P06493	UNIPROT	MAP4	protein	P27816	UNIPROT	down-regulates	phosphorylation	Ser787	KAPEKRAsPSKPASA	9606									10791892	t		gcesareni	Ser787 in the proline-rich region of human map4 is a critical phosphorylation site that reduces its activity to promote tubulin polymerization. Phosphorylation on ser-787 negatively regulates map4 activity to promote microtubule assembly.	SIGNOR-77087	0.512
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	BLM	protein	P54132	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser175	SFVTPPQsHFVRVST	9606	BTO:0002181								26028025	t		miannu	We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.	SIGNOR-276910	0.422
TGFB1	protein	P01137	UNIPROT	ANKH	protein	Q9HCJ1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20930330	f		miannu	TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line.	SIGNOR-252201	0.2
regorafenib	chemical	CHEBI:68647	ChEBI	TAP1	protein	Q03518	UNIPROT	down-regulates activity	chemical inhibition			9606									26254357	t		miannu	 It is suggested that in vitro, regorafenib is an inhibitor of ABCB1 and ABCG2, but not a substrate, and that its active metabolites, M2 (N-Oxide metabolite) and M5 (N-Oxide/N-desmethyl metabolite), are substrates of ABCB1 and ABCG3	SIGNOR-259204	0.8
SMAD1/5/8/SMAD4	complex	SIGNOR-C215	SIGNOR	DLX5	protein	P56178	UNIPROT	up-regulates	transcriptional regulation			10090	BTO:0000165								12815054	f		ggiuliani	Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining	SIGNOR-255837	0.321
SH2B2	protein	O14492	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	binding			9606		BTO:0000975							11498022	t		lperfetto	APS couples c-Cbl to the insulin receptor, resulting in ubiquitination of the insulin receptor.	SIGNOR-109694	0.604
TFEB	protein	P19484	UNIPROT	NDUFA1	protein	O15239	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4).	SIGNOR-276700	0.2
ATP5F1B	protein	P06576	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261397	0.2
PIP3	smallmolecule	CHEBI:16618	ChEBI	PDPK1	protein	O15530	UNIPROT	up-regulates activity	chemical activation			-1									9094314	t		gcesareni	We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1)	SIGNOR-243274	0.8
CSNK2A1	protein	P68400	UNIPROT	IKZF1	protein	Q13422	UNIPROT	down-regulates	phosphorylation	Ser101	GSHRDQGsSALSGVG	9606									21750978	t		miannu	We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo	SIGNOR-174820	0.294
CDK1	protein	P06493	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	down-regulates activity	phosphorylation	Ser139	DARDLEMsKKVRRSY	-1									23901111	t		miannu	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. 	SIGNOR-276125	0.699
PAFAH1B1	protein	P43034	UNIPROT	Cerebral_cortex_development	phenotype	SIGNOR-PH66	SIGNOR	up-regulates				9606									23973156	f		miannu	LIS1, the first gene to be identified as involved in a neuronal migration disease, is a dosage-sensitive gene whose proper levels are required for multiple aspects of cortical development. Deletions in LIS1 result in a severe brain malformation, known as lissencephaly, whereas duplications delay brain development. LIS1 affects the proliferation of progenitors, spindle orientation and interkinetic nuclear movement in the ventricular zone, as well as nucleokinesis and migration of neurons.	SIGNOR-252165	0.7
FGFR1	protein	P11362	UNIPROT	ACAT1	protein	P24752	UNIPROT	up-regulates activity	phosphorylation	Tyr407	HALKQGEyGLASICN	9606	BTO:0002552								27867011	t		lperfetto	Treatment with the FGFR1 inhibitor TKI258 in FGFR1-expressing H1299 cells led to decreased Y407 phosphorylation of ACAT1 in the mitochondrial fraction, where both ACAT1 and a fraction of FGFR1 were detected|Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity,	SIGNOR-264423	0.2
dacomitinib	chemical	CHEBI:132268	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									23405260	t		gcesareni	The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor.	SIGNOR-200902	0.8
BMS-740808	chemical	CID:6914623	PUBCHEM	F10	protein	P00742	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190488	0.8
Exocyst_EXOC6 variant	complex	SIGNOR-C492	SIGNOR	SNARE_complex 	complex	SIGNOR-C346	SIGNOR	up-regulates activity	binding			9606									30205058	t		miannu	The exocyst is a multisubunit protein complex that was first identified and characterized in budding yeast. This complex mediates the tethering of secretory vesicles to the plasma membrane prior to fusion mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Sec3 interacts with PI(4,5)P2 (red dots) in the plasma membrane. Its interaction with the t-SNARE protein Sso promotes the assembly of the Sso–Sec9 binary t-SNARE complex. 	SIGNOR-270793	0.443
adapalene	chemical	CHEBI:31174	ChEBI	RARG	protein	P13631	UNIPROT	up-regulates activity	chemical activation			9606									30836068	t		miannu	Adapalene, the third-generation synthetic retinoid,selectively bound to specific RAR, thus activating genes responsible forcellular differentiation. It showed greatest affinity for subtypes RARβ in dermal fibroblasts (Kd value 34 nM) and RARγ in the epidermis (Kdvalue 130 nM)	SIGNOR-258488	0.8
PRKD1	protein	Q15139	UNIPROT	ATP7B	protein	P35670	UNIPROT	up-regulates activity	phosphorylation	Ser481	ILAKSPQsTRAVAPQ	9606	BTO:0000599								21189263	t		lperfetto	ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking.	SIGNOR-272293	0.302
DNAJC14	protein	Q6Y2X3	UNIPROT	ROS	stimulus	SIGNOR-ST2	SIGNOR	down-regulates				9606									15525720	f		lperfetto	Mutations in the gene encoding DJ-1 have also been linked to familial Parkinson€™s disease. Other studies have suggested that DJ-1 protects cells from oxidative damage, and mutations in DJ-1 may therefore contribute to in- creased levels of oxidative stress.	SIGNOR-249698	0.7
PRKCI	protein	P41743	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates activity	phosphorylation	Thr495	TGITRKKtFKEVANA	9606									24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251635	0.2
HNRNPA1	protein	P09651	UNIPROT	Alternative_Splicing_Regulation	phenotype	SIGNOR-PH204	SIGNOR	up-regulates				9606									17371836	f			We demonstrate that Sam68 binds the mRNA for Bcl-x and affects its alternative splicing	SIGNOR-268687	0.7
TOM40 complex	complex	SIGNOR-C421	SIGNOR	Insertion into mitochondrial membrane	phenotype	SIGNOR-PH193	SIGNOR	up-regulates													18423394	f		lperfetto	The sorting and assembly pathway of outer membrane proteins involves three machineries: the translocase of the outer membrane (TOM complex) the sorting and assembly machinery (SAM complex) and the MDM complex (mitochondrial distribution and morphology).	SIGNOR-267688	0.7
HRAS	protein	P01112	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation	Ser63	KNSDLLTsPDVGLLK	10116	BTO:0000452								1749429	t		lperfetto	Expression of oncogenic ha-ras augments transactivation by c-jun and stimulates its phosphorylation. Here we describe the mapping of the ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-jun activity and for cooperation with ha-ras in ocogenic transformation.	SIGNOR-236682	0.516
NKX3-1	protein	Q99801	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16697957	t		miannu	Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events.	SIGNOR-251547	0.518
CSNK2A1	protein	P68400	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	up-regulates	phosphorylation			9606									2861485	t		gcesareni	Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex.CK1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays.	SIGNOR-23958	0.308
perfluorooctanoic acid	chemical	CHEBI:35549	ChEBI	PPARA	protein	Q07869	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000150								35370244	t		miannu	Detailed in vitro studies on the effects of perfluorooctanoic acid (PFOA) have demonstrated that activation of peroxisome proliferator-activated receptor α (PPARα) is a key process by which PFOA affects the malignancy of estrogen receptor α (ERα)-positive breast cancer cells. 	SIGNOR-268753	0.8
NCOR1	protein	O75376	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22395773	t		FFerrentino	In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription.	SIGNOR-253507	0.696
TFAP2D	protein	Q7Z6R9	UNIPROT	ST8SIA2	protein	Q92186	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9031									24462686	t		lperfetto	We use chromatin immunoprecipitation and gel shift assays to demonstrate direct interaction between AP-2 and the ST8SIA2 promoter.|We show that ST8SIA2 is induced by AP-2δ overexpression in chick retina. We use chromatin immunoprecipitation and gel shift assays to demonstrate direct interaction between AP-2δ and the ST8SIA2 promoter.	SIGNOR-268992	0.344
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270367	0.8
EGLN2	protein	Q96KS0	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	hydroxylation			9606									24990963	t		lperfetto	Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase.|Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a. 	SIGNOR-261998	0.292
CHEK1	protein	O14757	UNIPROT	MDM4	protein	O15151	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser367	PDCRRTIsAPVVRPK	9606									18356162	t		lperfetto	The chk1 and chk2 kinases have also been shown to phosphorylate ser367, leading to 14-3-3 binding (34_36, 38, 44). In both cases, the outcome differed: in chk1-mediated phosphorylation, mdmx was translocated to the cytoplasm;in chk2-mediated phosphorylation, mdmx was degraded (34_36, 38, 44). It is possible that the damage response is mediated through additional phosphorylation sites other than ser367 and that, depending on the type of damage, certain sites will be modified, leading to different outcomes.	SIGNOR-178067	0.536
SP1	protein	P08047	UNIPROT	NDUFV1	protein	P49821	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000931								17786189	f		miannu	 Sp1 role in the regulation of complex I subunits, was demonstrated by the ability of the Sp1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, Sp1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin.	SIGNOR-255206	0.2
HDAC1	protein	Q13547	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001570								23242655	f	 	 	Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells.	SIGNOR-254029	0.644
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	estrone	smallmolecule	CHEBI:17263	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000056							16166196	t		lperfetto	A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis.	SIGNOR-268662	0.8
PIP3	smallmolecule	CHEBI:16618	ChEBI	PDPK1	protein	O15530	UNIPROT	up-regulates activity	relocalization			9606									21798082	t		lperfetto	Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation.	SIGNOR-175253	0.8
AKT1	protein	P31749	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser82	RALSRQLsSGVSEIR	9606									19593530	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	lperfetto	First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.	SIGNOR-252526	0.682
SLC9A6	protein	Q92581	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265605	0.8
p38	proteinfamily	SIGNOR-PF16	SIGNOR	CDC25B	protein	P30305	UNIPROT	down-regulates activity	phosphorylation	Ser375	ARVLRSKsLCHDEIE	9606									11333986	t		lperfetto	P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteins phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3	SIGNOR-107416	0.2
FZR1	protein	Q9UM11	UNIPROT	ANLN	protein	Q9NQW6	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000567								16040610	t		miannu	 Ubiquitination of anillin required a destruction-box and was mediated by Cdh1, an activator of APC/C. Overexpression of Cdh1 reduced the levels of anillin, whereas inactivation of APC/C(Cdh1) increased the half-life of anillin.	SIGNOR-272654	0.269
DCTN6	protein	O00399	UNIPROT	PLK1	protein	P53350	UNIPROT	up-regulates activity	binding			9534	BTO:0004055				phosphorylation:Thr186	KTMKGSStPVKN			23455152	t		lperfetto	Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin‐dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo‐like kinase 1 (Plk1) at kinetochores. 	SIGNOR-264798	0.382
GRK3	protein	P35626	UNIPROT	CCR5	protein	P51681	UNIPROT	down-regulates activity	phosphorylation	Ser342	ASSVYTRsTGEQEIS	9534	BTO:0000298								10085131	t		gcesareni	Phosphoamino acid analysis revealed that RANTES-induced CCR5 phosphorylation selectively occurs on serine residues. Our findings with receptor mutants indicate that serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5.	SIGNOR-249675	0.2
DNAJC11	protein	Q9NVH1	UNIPROT	Mitochondrial_biogenesis	phenotype	SIGNOR-PH32	SIGNOR	up-regulates				10090	BTO:0000312								25111180	f			Homozygous mutant mice developed locomotion defects, muscle weakness, spasticity, limb tremor, leucopenia, thymic and splenic hypoplasia, general wasting and early lethality. Neuropathological analysis showed severe vacuolation of the motor neurons in the spinal cord, originating from dilatations of the endoplasmic reticulum and notably from mitochondria that had lost their proper inner membrane organization. T	SIGNOR-261147	0.7
2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide	chemical	CHEBI:91353	ChEBI	MAP2K2	protein	P36507	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191024	0.8
celecoxib	chemical	CHEBI:41423	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190928	0.8
SMARCE1	protein	Q969G3	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	form complex	binding			9606									15627498	t		miannu	We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers.	SIGNOR-132942	0.88
ketanserin	chemical	CHEBI:6123	ChEBI	HTR2B	protein	P41595	UNIPROT	down-regulates activity	chemical inhibition			10036	BTO:0000452								9459568	t		miannu	The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-	SIGNOR-258685	0.8
RPIA	protein	P49247	UNIPROT	D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	up-regulates quantity	chemical modification			9606									34775382	t		miannu	The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux.	SIGNOR-267070	0.8
SNRPE	protein	P62304	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270630	0.827
OPTN	protein	Q96CV9	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				10090	BTO:0005118								22194658	f	same result in PC12 cell 	miannu	SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA.	SIGNOR-259876	0.7
SOS1	protein	Q07889	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									23132018	t		lperfetto	The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras.	SIGNOR-39237	0.888
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation			9606		BTO:0001260							10514499	t	inferred from 70% family members	lperfetto	Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin.	SIGNOR-270162	0.2
CTDSP2	protein	O14595	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	dephosphorylation	Ser206	SSSTYPHsPTSSDPG	9606	BTO:0000552								17085434	t			Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)	SIGNOR-248302	0.477
EIF2AK3	protein	Q9NZJ5	UNIPROT	EIF2S1	protein	P05198	UNIPROT	down-regulates activity	phosphorylation	Ser52	MILLSELsRRRIRSI	9606									25660019	t		Manara	We now demonstrate a major role for Rheb in inhibiting protein synthesis by enhancing the phosphorylation of eIF2α by protein kinase-like ER kinase (PERK).	SIGNOR-260874	0.757
EIF3_complex	complex	SIGNOR-C401	SIGNOR	43S_pre_initiation_complex	complex	SIGNOR-C453	SIGNOR	form complex	binding			9606									35489072	t		lperfetto	In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 	SIGNOR-269162	0.663
sunitinib	chemical	CHEBI:38940	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000776								20185585	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-163938	0.8
CSNK1D	protein	P48730	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	up-regulates	phosphorylation			9606									12000790	t		lperfetto	We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45 . This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/mscomplex of axin and casein kinase i (cki) induces betBeta-catenin phosphorylation at a single site: serine 45 (s45)	SIGNOR-227970	0.519
STK4	protein	Q13043	UNIPROT	FOXO1	protein	Q12778	UNIPROT	up-regulates	phosphorylation	Ser212	SSAGWKNsIRHNLSL	9606	BTO:0000782	BTO:0001253							22898666	t		gcesareni	Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1.	SIGNOR-191847	0.582
CREB1	protein	P16220	UNIPROT	SNAI2	protein	O43623	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15955695	f		miannu	 In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro.	SIGNOR-253791	0.286
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BAG3	protein	O95817	UNIPROT	up-regulates activity	phosphorylation	Thr285	GSPARSStPLHSPSP	9606	BTO:0000016								27659916	t		miannu	ERK-dependent phosphorylation of BIS following H2O2 treatment.	SIGNOR-274071	0.2
ASNS	protein	P08243	UNIPROT	L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	down-regulates quantity	chemical modification			9606									29084849	t		miannu	Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7.	SIGNOR-267531	0.8
CHAF1B	protein	Q13112	UNIPROT	MGMT	protein	P16455	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								15657354	f		miannu	 Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT.	SIGNOR-254570	0.299
Erythrocytic spectrin	complex	SIGNOR-C384	SIGNOR	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates	binding			9606									24302288	t		lperfetto	Spectrin is a member of the F-actin-crosslinking protein superfamily. 	SIGNOR-266030	0.7
2-(Decan-2-ylamino)ethyl 4-aminobenzoate	chemical	CID:50729	PUBCHEM	TOP2A	protein	P11388	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000664								18258442	t		Luana	As shown in Table 1 all of the bisanthrapyrazoles inhibited the decatenation activity of human topoisomerase IIα in the low micromolar concentration range	SIGNOR-257768	0.8
SYDE2	protein	Q5VT97	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260522	0.375
CSNK2A2	protein	P19784	UNIPROT	PPP1R2	protein	P41236	UNIPROT	up-regulates activity	phosphorylation	Ser87	GDDEDACsDTEATEA	-1									8288648	t		llicata	Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action.	SIGNOR-251022	0.311
ATP5PB	protein	P24539	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261401	0.2
PRKCA	protein	P17252	UNIPROT	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates activity	phosphorylation	Ser162	FDIVSRGsTADLDGL	9606									19661060	t		Manara	We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.	SIGNOR-260886	0.357
LRRC4	protein	Q9HBW1	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								19467332	t		miannu	A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles	SIGNOR-264051	0.436
HPS6	protein	Q86YV9	UNIPROT	BLOC-2	complex	SIGNOR-C252	SIGNOR	form complex	binding			9606									15030569	t		lperfetto	Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS8	SIGNOR-260690	0.772
GADD45A	protein	P24522	UNIPROT	CDK1	protein	P06493	UNIPROT	down-regulates	binding			9606				SIGNOR-C17					10362260	t		gcesareni	Gadd45 has now been found to directly inhibit the activity of cdc2/cyclin b1 complex	SIGNOR-68221	0.699
AP3M2	protein	P53677	UNIPROT	Neuronal AP-3	complex	SIGNOR-C445	SIGNOR	form complex	binding			9606	BTO:0000938								19497727	t		miannu	Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) 	SIGNOR-268520	0.738
SMC3	protein	Q9UQE7	UNIPROT	MXD1	protein	Q05195	UNIPROT	down-regulates activity	binding			9534	BTO:0000318								9528857	t	2	miannu	We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions.	SIGNOR-241278	0.3
P2RY14	protein	Q15391	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257210	0.2
DEPTOR	protein	Q8TB45	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	form complex	binding			9606									25628925	t		lperfetto	Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)	SIGNOR-205600	0.718
PDPK1	protein	O15530	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	up-regulates activity	phosphorylation	Ser370	TRQTPVDsPDDTALS	-1									11733037	t		miannu	 Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities.	SIGNOR-250371	0.595
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates	phosphorylation	Thr331	CTPVVTCtPSCTAYT	9606									12972619	t		lperfetto	In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity.	SIGNOR-252353	0.784
cabazitaxel	chemical	CHEBI:63584	ChEBI	TUBA4A	protein	P68366	UNIPROT	down-regulates activity	chemical inhibition			9606									21770474	t		miannu	Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization	SIGNOR-259340	0.8
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser579	NVKSKIGsTENLKHQ	9606									21215781	t	The effect has been demonstrated using P10636-8	lperfetto	Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process	SIGNOR-171042	0.729
RNF152	protein	Q8N8N0	UNIPROT	RRAGA	protein	Q7L523	UNIPROT	down-regulates activity	polyubiquitination			9606	BTO:0000007								25936802	t		miannu	 Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases. 	SIGNOR-272222	0.73
RPTOR	protein	Q8N122	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	form complex	binding			9606									25628925	t		lperfetto	Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)	SIGNOR-205627	0.858
3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	Fatty_Acid_Biosynthesis	phenotype	SIGNOR-PH190	SIGNOR	up-regulates				9606		BTO:0000759							24692351	f		scontino	TH stimulates both lipolysis and lipogenesis, although the direct action is lipolysis with lipogenesis thought to be stimulated to restore fat stores. Fatty acids produced from TH-induced lipolysis are the substrate for the increase in thermogenesis.	SIGNOR-267488	0.7
LAMA2	protein	P24043	UNIPROT	DGC	complex	SIGNOR-C217	SIGNOR	form complex	binding			9606									15117830	t		apalma	The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink).	SIGNOR-255984	0.425
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	TFCP2	protein	Q12800	UNIPROT	down-regulates	phosphorylation	Ser309	SLGEGNGsPNHQPEP	9606									19237534	t		lperfetto	In vitro, lsf is phosphorylated by cyclin e/cyclin-dependent kinase 2 (cdk2), cyclin c/cdk2, and cyclin c/cdk3, predominantly on s309. Phosphorylation by cyclin c/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of lsf during g1 progression	SIGNOR-216713	0.2
CAMK2B	protein	Q13554	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	phosphorylation	Thr472	ICALRHLtSRHQEAE	9606	BTO:0000938								24117889	t		lperfetto	Camkii represses transcriptionally active _-catenin to mediate acute ethanol neurodegeneration and can phosphorylate _-catenincamkii can directly phosphorylate _-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human _-catenin at t332, t472, and s552.	SIGNOR-202833	0.294
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2D1	protein	P51668	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271311	0.827
FOXL2	protein	P58012	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19010791	f		miannu	Foxl2 can directly activate the transcription of sirt1	SIGNOR-182300	0.515
MAPK8	protein	P45983	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser130	SGEQAEGsPGGPGDS	9606									12058028	t		gcesareni	The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro.	SIGNOR-89440	0.659
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr57	NFDFVTEtPLEGDFA	9606									19364816	t		lperfetto	We have shown that erk2 interacts with and phosphorylates p21cip1, promoting p21cip1_ubiquitination. We identified two erk2 phosphorylation sites, thr57 and ser130, in p21cip1_and showed that phosphorylation of these residues increases p21cip1_cytoplasmic distribution and proteasome-dependent degradation.	SIGNOR-244513	0.2
NEDD4	protein	P46934	UNIPROT	AP1G2	protein	O75843	UNIPROT	up-regulates activity	monoubiquitination			9606	BTO:0001950								18772139	t		miannu	Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination. 	SIGNOR-272634	0.41
A11/b1 integrin	complex	SIGNOR-C168	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269017	0.7
ADRB1	protein	P08588	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256901	0.377
RAB2A	protein	P61019	UNIPROT	TRIP11	protein	Q15643	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								25473115	t		Sara	Vesicle-associated Rab2 then mediates attachment to the Rab2 binding site within the central coiled-coil region of GMAP-210, bringing the vesicle into closer proximity to the target membrane. GMAP-210 function in vivo is dependent upon its ability to tether membranes, which is mediated exclusively by the amino-terminal ALPS motif. Binding to Rab2 is also important for GMAP-210 function, although it is dispensable for tethering per se. 	SIGNOR-261300	0.405
ATG14	protein	Q6ZNE5	UNIPROT	PIK3C3	protein	Q8NEB9	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								19270693	t		lperfetto	Characterization of the new proteins revealed that atg14l enhances vps34 lipid kinase activity and upregulates autophagy,	SIGNOR-235448	0.878
SMURF1	protein	Q9HCE7	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates activity	ubiquitination			9606									12738770	t		lperfetto	Smurf1 interacts directly with Cbfa1 and mediates Cbfa1 degradation in a ubiquitin- and proteasome-dependent manner.	SIGNOR-236083	0.518
UCHL5	protein	Q9Y5K5	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	deubiquitination			9606									16027725	t		gcesareni	Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases	SIGNOR-138876	0.386
DOK1	protein	Q99704	UNIPROT	Av/b8 integrin	complex	SIGNOR-C185	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257699	0.2
3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol	chemical	CHEBI:94691	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258300	0.8
CDK2	protein	P24941	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Thr187	NAGSVEQtPKKPGLR	9606									17409098	t		gcesareni	Ubiquitination and subsequent degradation play a critical role in regulating the levels of p27 during cell cycle progression. Here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3).	SIGNOR-154188	0.949
KRAS	protein	P01116	UNIPROT	CARM1	protein	Q86X55	UNIPROT	down-regulates activity				9606	BTO:0000304								27840030	f		lperfetto	Interestingly, overexpression of KRASG12V (an activating mutant) in BxPC-3 cells, a PDAC cell line carrying wild-type KRAS, led to a 40% decrease of CARM1 protein and consequent hypomethylation or activation of MDH1|These observations indicate that KRAS suppresses CARM1-mediated MDH1 methylation, contributing to Gln metabolism in pancreatic cancer.	SIGNOR-267640	0.275
TRIM27	protein	P14373	UNIPROT	MAPK11	protein	Q15759	UNIPROT	up-regulates				9606		BTO:0000671							12807881	f		miannu	We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38.	SIGNOR-102022	0.2
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	MLH1/PMS2	complex	SIGNOR-C59	SIGNOR	up-regulates				-1									10542278	f		miannu	HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay.	SIGNOR-259062	0.7
RNF167	protein	Q9H6Y7	UNIPROT	VAMP3	protein	Q15836	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys77	KYWWKNCkMWAIGIT	9606	BTO:0000007								23353890	t		miannu	Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains.	SIGNOR-272095	0.335
ziprasidone	chemical	CHEBI:10119	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			10116									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258502	0.8
EIF3_complex	complex	SIGNOR-C401	SIGNOR	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	up-regulates activity	binding			9606									16920360	t		miannu	EIF3 binds 40S and inhibits the association of 60S. Structural analysis suggests that eIF3 performs this scaffolding function by binding to the 40S subunit on its solvent-exposed surface rather than on its interface with the 60S subunit, where the decoding sites exist. This location of eIF3 seems ideally suited for its other proposed regulatory functions, including reinitiating translation on polycistronic mRNAs and acting as a receptor for protein kinases that control protein synthesis.	SIGNOR-266401	0.597
JMJD1C	protein	Q15652	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	demethylation	Lys10	RTKQTARkSTGGKAP	9606									32034158	t		miannu	We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state.	SIGNOR-265169	0.2
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PTPN11	protein	Q06124	UNIPROT	down-regulates activity	phosphorylation	Thr73	YGGEKFAtLAELVQY	9606	BTO:0002181								25802336	t		miannu	 We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity. 	SIGNOR-276893	0.2
ABL1	protein	P00519	UNIPROT	ABL1	protein	P00519	UNIPROT	up-regulates activity	phosphorylation	Tyr393	RLMTGDTyTAHAGAK	9606									11781820	t		lperfetto	Phosphorylation of tyr412 can occur autocatalytically by a trans-mechanism and cause activation of otherwise inactive c-abl, suggesting a positive feedback loop on c-abl activity.	SIGNOR-113659	0.2
HAUS1	protein	Q96CS2	UNIPROT	HAUS complex	complex	SIGNOR-C281	SIGNOR	form complex	binding			9606	BTO:0000567								19369198	t		lperfetto	Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)	SIGNOR-262319	0.799
oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	up-regulates quantity	precursor of			9606									24632615	t		miannu	Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine.	SIGNOR-266555	0.8
KDM4C	protein	Q9H3R0	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates activity	binding			9606	BTO:0001033								29207681	t		miannu	JMJD2C was found to be co-localized with AR and LSD1 in the epithelium of prostate carcinoma and normal prostate cells. For the detailed mechanism, JMJD2C, AR and LSD1 assembled on the chromatin to remove the methyl groups from mono-, di- and trimethylated H3K9. Importantly, JMJD2C specifically removed the demethylation of the trimethyl H3K9 marks and modulated the transcriptional activity of AR. Moreover, JMJD2C cooperated with LSD1 and activated AR-mediated gene expression via decreasing H3K9me3 at the promoter of AR targeting genes KLK2 and PSA.	SIGNOR-263879	0.2
GSK3B	protein	P49841	UNIPROT	MAP3K4	protein	Q9Y6R4	UNIPROT	down-regulates	binding			9606									17726008	t		gcesareni	Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways	SIGNOR-157541	0.374
PRKCA	protein	P17252	UNIPROT	HSPB8	protein	Q9UJY1	UNIPROT	up-regulates	phosphorylation	Ser14	PFSCHYPsRLRRDPF	9606									22721717	t		lperfetto	Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation	SIGNOR-197940	0.311
CSNK2A1	protein	P68400	UNIPROT	VAMP4	protein	O75379	UNIPROT	up-regulates	phosphorylation	Ser30	RNLLEDDsDEEEDFF	9606									14608369	t		gcesareni	The r-snare vamp4, which contains a dileucine motif, binds to the ap-1 or the ggas. Serine 20 and leucines 25,26 are essential for this binding. Ap-1 association with vamp4 is enhanced when serine 30 is phosphorylated by casein kinase 2. This phosphorylation-dependent modulation of ap-1 binding is mediated by pacs-1 (phosphofurin acidic cluster sorting protein). Ablation of both the dileucine motif and serine 30 results in a dramatic mislocalization of vamp4 in the regulated secretory pathway.	SIGNOR-119090	0.457
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1787	SPNYSPTsPSYSPTS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248746	0.727
Cytoplasmic_Dynein	proteinfamily	SIGNOR-PF67	SIGNOR	Microtubule-based_movement	phenotype	SIGNOR-PH170	SIGNOR	up-regulates													16440056	f		lperfetto	Dyneins are large multi-subunit protein complexes that undertake a wide range of roles within the cell. They are adenosine triphosphate (ATP)–driven, microtubule minus-end-directed molecular motors that can be divided, based on function, into two classes: axonemal and cytoplasmic dyneins	SIGNOR-265019	0.7
PRKCA	protein	P17252	UNIPROT	CASR	protein	P41180	UNIPROT	down-regulates	phosphorylation	Thr888	FKVAARAtLRRSNVS	9606									21135065	t		llicata	Casr(t888) is a protein kinase c (pkc) phosphorylation site in the receptor's intracellular domain that has previously been identified as a critical negative regulator of casr downstream signaling in vitro, thus, casr(t888) represents a functionally important, inhibitory phosphorylation site that contributes to the control of pth secretion.	SIGNOR-170334	0.358
MLST8	protein	Q9BVC4	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	form complex	binding			9606									25628925	t		lperfetto	Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8)	SIGNOR-205609	0.882
pevonedistat	chemical	CHEBI:145535	ChEBI	UBE2F	protein	Q969M7	UNIPROT	down-regulates quantity	chemical inhibition			9606	BTO:0001109								19360080	t		Monia	MLN4924 is a potent and selective inhibitor of NEDD8-activating enzyme; A single dose of MLN4924 resulted in a dose- and time-dependent decrease of NEDD8–cullin levels as early as 30 min after administration of compound	SIGNOR-261067	0.8
DYRK1B	protein	Q9Y463	UNIPROT	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates	phosphorylation	Ser240	KVAERRSsPLLRRKD	10090	BTO:0000165;BTO:0000222	BTO:0000887;BTO:0001103							15546868	t		lperfetto	Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner	SIGNOR-235813	0.2
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	GSK3B	protein	P49841	UNIPROT	up-regulates activity	dephosphorylation	Ser9	SGRPRTTsFAESCKP										26088133	t		lperfetto	Anchored PP1 may relieve PKA-mediated inhibition of GSK3beta by dephosphorylating Ser-9, providing bi-directional control of AKAP220 complex formation in response to cAMP.	SIGNOR-264820	0.2
CASP2	protein	P42575	UNIPROT	Caspase-2 PIDDosome	complex	SIGNOR-C292	SIGNOR	form complex	binding			9606									20158568	t		miannu	The PIDDosome consists of the proteins PIDD, RAIDD and caspase-2. 	SIGNOR-262641	0.858
PIK-93	chemical	CID:6852167	PUBCHEM	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206241	0.8
DUSP6	protein	Q16828	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	dephosphorylation			9606									22521266	t		gcesareni	Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase).	SIGNOR-252903	0.44
PYGM	protein	P11217	UNIPROT	glycogen	smallmolecule	CHEBI:28087	ChEBI	down-regulates quantity	chemical modification			9606									3346228	t			Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267389	0.8
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Thr143	AVSPGTLtPTGVVSG										26933062	t		lperfetto	Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis.	SIGNOR-276591	0.398
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	CASP9	protein	P55211	UNIPROT	down-regulates	phosphorylation	Thr125	PEVLRPEtPRPVDIG	9606									17466630	t		lperfetto	Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle.	SIGNOR-216884	0.431
MASP2	protein	O00187	UNIPROT	C4A	protein	P0C0L4	UNIPROT	up-regulates activity	cleavage	Gly1446	TPLQLFEgRRNRRRR	-1									17204478	t		lperfetto	MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a).	SIGNOR-263437	0.793
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	KMT5A	protein	Q9NQR1	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser100	SKIYSYMsPNKCSGM	9606									20966048	t		lperfetto	First, we found that pr-set7 is phosphorylated at ser 29 (s29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinb complex, s29 phosphorylation also functions to stabilize pr-set7 by directly inhibiting its interaction with the anaphase-promoting complex (apc), an e3 ubiquitin ligase.	SIGNOR-216856	0.2
CDK2	protein	P24941	UNIPROT	PRKAR1A	protein	P10644	UNIPROT	up-regulates	phosphorylation	Ser83	DSREDEIsPPPPNPV	9606			SIGNOR-C16						16582606	t		gcesareni	In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue.	SIGNOR-145577	0.349
WWTR1	protein	Q9GZV5	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates	binding			9606									22153608	t		gcesareni	Kmp also enhanced the association of taz with ppar_, thereby suppressing the gene transcription of ppar_ targets and resulting in diminished adipocyte differentiation.	SIGNOR-195215	0.317
SPI1	protein	P17947	UNIPROT	IRF8	protein	Q02556	UNIPROT	up-regulates activity	binding			9606	BTO:0001413								11483597	t		miannu	We found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP.	SIGNOR-222880	0.613
PIN1	protein	Q13526	UNIPROT	XPO5	protein	Q9HAV4	UNIPROT	down-regulates activity	isomerization			9606							phosphorylation:Ser416;Ser497;Thr345	GFPSKTDsPSCEYSR;GSLCSVFsPSFVQWE;GADSDVEtPSNFGKY	27846390	t		lperfetto	Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. 	SIGNOR-263015	0.2
KAT6A	protein	Q92794	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	acetylation	Lys120	FLHSGTAkSVTCTYS	9606	BTO:0001271		SIGNOR-C54						23431171	t		miannu	We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression	SIGNOR-201482	0.657
PRKCA	protein	P17252	UNIPROT	SPAG1	protein	Q07617	UNIPROT	unknown	phosphorylation	Ser326	VERDLKNsEAASETQ	-1									11517287	t		lperfetto	In-vitro incubation with [_-32P]ATP showed that HSD-3.8 protein can be phosphorylated by PKC. The phosphate is probably linked to the serine residue presenting the sequence X LysXX SerX.	SIGNOR-249109	0.311
PDGFRA	protein	P16234	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	phosphorylation	Tyr419	RLIEDNEyTARQGAK	9606									15489898	t		gcesareni	The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells.	SIGNOR-247984	0.468
MAPK1	protein	P28482	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Ser454	YVPMNPNsPPRQHSS	10029									15379552	t		lperfetto	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-249396	0.584
FBXW11	protein	Q9UKB1	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates	ubiquitination	Lys21	EGPRDGLkKERLLDD	9606									7479976	t		gcesareni	Here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha.	SIGNOR-26573	0.521
IL4R	protein	P24394	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000801								23124025	t		lperfetto	Although the receptor-associated tyrosine kinases Jak2 and Tyk2 are activated after the recruitment of IL-13 to its receptor (containing IL-4R and IL-13R1), IL-4 stimulates Jak1 activation.	SIGNOR-249529	0.705
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1721	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273098	0.745
DET1	protein	Q7L5Y6	UNIPROT	DCX DET1-COP1	complex	SIGNOR-C24	SIGNOR	form complex	binding			9606									17452440	t		lperfetto	Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes	SIGNOR-154508	0.787
TGFBR1	protein	P36897	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	unknown	phosphorylation	Ser68	FLEQPICsVQPIDLN	9606									23166821	t		llicata	We show that phosphorylation of _np63_ at s66/68 in response to ultraviolet (uv) irradiation is mediated by alk5	SIGNOR-199785	0.2
PHF10	protein	Q8WUB8	UNIPROT	Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	form complex	binding			10090	BTO:0001086								19279220	t		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270716	0.622
TP53	protein	P04637	UNIPROT	CBP/p300	complex	SIGNOR-C6	SIGNOR	up-regulates	binding			9606									10207072	t		gcesareni	Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo.	SIGNOR-66956	0.909
CXCL1	protein	P09341	UNIPROT	GLI2	protein	P10070	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16885213	f		gcesareni	The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i).	SIGNOR-148457	0.2
MARK2	protein	Q7KZI7	UNIPROT	ARHGEF2	protein	Q92974	UNIPROT	down-regulates	phosphorylation	Ser960	SRLSPPHsPRDFTRM	9606									22072711	t	The effect has been demonstrated using Q92974-2	gcesareni	We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation	SIGNOR-177100	0.518
CBX4	protein	O00257	UNIPROT	ZEB2	protein	O60315	UNIPROT	down-regulates quantity by destabilization	sumoylation	Lys391	QTGLLKIkTEPLDFN	9534									16061479	t		Luisa	Pc2 can act directly as an E3 ligase for SIP1 sumoylation.SIP1 sumoylation having a negative effect on its repression of E-cadherin transcription. 	SIGNOR-268955	0.336
brimonidine	chemical	CHEBI:3175	ChEBI	ADRA2A	protein	P08913	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258902	0.8
3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide	chemical	CHEBI:92223	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189168	0.8
PTGER2	protein	P43116	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256899	0.252
NELFE	protein	P18615	UNIPROT	NELF	complex	SIGNOR-C521	SIGNOR	form complex	binding			9606									18628398	t		miannu	The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. 	SIGNOR-271400	0.901
RNF128	protein	Q8TEB7	UNIPROT	ARHGDIA	protein	P52565	UNIPROT	up-regulates quantity by stabilization	polyubiquitination			9606	BTO:0000661								17114425	t		miannu	We found that RhoGDIα and RhoGDIβ are ubiquitin E3 substrates of GRAIL. GRAIL uses nonlysine 48-ubiquitin linkage in polyubiquitinating RhoGDI. GRAIL was subsequently demonstrated to bind and ubiquitinate RhoGDI, although GRAIL-mediated ubiquitination of RhoGDI did not result in proteosomal degradation. Our data suggest that ubiquitination of RhoGDI by GRAIL does not result in proteolytic degradation. In fact, GRAIL activity appeared to increase RhoGDI stability.	SIGNOR-271622	0.27
SMAD5	protein	Q99717	UNIPROT	GATA3	protein	P23771	UNIPROT	up-regulates quantity	transcriptional regulation			10090									22219353	t		Gianni	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268943	0.315
THR	proteinfamily	SIGNOR-PF84	SIGNOR	RARA	protein	P10276	UNIPROT	up-regulates activity	binding			9606									15650024	t	inferred from family member	gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-267779	0.2
COPII vesicle	complex	SIGNOR-C370	SIGNOR	Vesicle_transport	phenotype	SIGNOR-PH172	SIGNOR	up-regulates				9606									30605680	f		lperfetto	Coat protein complex (COP) II vesicles export newly synthesized secretory proteins from the endoplasmic reticulum (ER)	SIGNOR-265297	0.7
YWHAG	protein	P61981	UNIPROT	GEM	protein	P55040	UNIPROT	up-regulates quantity by stabilization	binding			9534									14701738	t		miannu	In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase	SIGNOR-261713	0.269
PLG	protein	P00747	UNIPROT	Fibrinolysis	phenotype	SIGNOR-PH6	SIGNOR	up-regulates				9606									1447176	f		lperfetto	The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme 	SIGNOR-263535	0.7
PRSS2	protein	P07478	UNIPROT	F2RL1	protein	P55085	UNIPROT	up-regulates activity	cleavage	Lys34	QGTNRSSkGRSLIGK	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263606	0.2
SMARCB1	protein	Q12824	UNIPROT	Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270697	0.851
ABL1	protein	P00519	UNIPROT	PTPN6	protein	P29350	UNIPROT	unknown	phosphorylation	Tyr564	SKHKEDVyENLHTKN	9606	BTO:0001412								8692915	t		gcesareni	Treatment with ionizing radiation is associated with c-Abl-dependent tyrosine phosphorylation of SHPTP1. The results demonstrate that the SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites.	SIGNOR-246231	0.423
CDK1	protein	P06493	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates activity	phosphorylation	Ser90	QHVRSHSsPASLQLG										26375055	t		lperfetto	We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity	SIGNOR-276518	0.261
Nucleosome_H2A.Z.1 variant	complex	SIGNOR-C322	SIGNOR	Transcritpional_activation	phenotype	SIGNOR-PH205	SIGNOR	down-regulates				9606									15623580	f		lperfetto	All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage.	SIGNOR-273455	0.7
EEF1A1P5	protein	Q5VTE0	UNIPROT	Leu-tRNA(Leu)	smallmolecule	CHEBI:16624	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269553	0.8
SRC	protein	P12931	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr259	ASVDSSLyNLPRSYS	9606	BTO:0000007								19881549	t		lperfetto	Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis	SIGNOR-236310	0.693
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	ROR2	protein	Q01974	UNIPROT	down-regulates activity	phosphorylation	Ser864	PKPSSHHsGSGSTST	9606									21078818	t		gcesareni	We identify ror2 ser 864 as a critical residue phosphorylated by gsk3 and required for noncanonical receptor activation by wnt5a, analogous to the priming phosphorylation of low-density receptor-related protein 6 (lrp6) in response to wnt3a.	SIGNOR-228026	0.338
crizotinib	chemical	CHEBI:64310	ChEBI	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191136	0.8
GATA6	protein	Q92908	UNIPROT	CYP11A1	protein	P05108	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002850								15284005	f	 	miannu	The transcription factor GATA6, which regulates the promoter activity of CYP17 and CYP11A, was increased in the PCOS compared to normal theca cells. 	SIGNOR-254197	0.332
AKT3	protein	Q9Y243	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr32	QSRPRSCtWPLQRPE										19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249642	0.697
SRC	protein	P12931	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates activity	phosphorylation	Tyr234	AQPEQDEyDIPRHLL	10090									12972425	t		lperfetto	Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs	SIGNOR-246397	0.797
PTPN1	protein	P18031	UNIPROT	PTPN1	protein	P18031	UNIPROT	down-regulates activity	dephosphorylation	Tyr152	ISEDIKSyYTVRQLE	-1									11506178	t			Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions.	SIGNOR-248424	0.2
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	TLR4	protein	O00206	UNIPROT	up-regulates activity				9606	BTO:0000801								19946286	f		lperfetto	The lipopolysaccharide (LPS) of Gram negative bacteria is a wellknown inducer of the innate immune response1. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common pattern in structurally diverse LPS molecules.	SIGNOR-249516	0.7
FLT1	protein	P17948	UNIPROT	FLT1	protein	P17948	UNIPROT	up-regulates	phosphorylation	Tyr1213	GSSDDVRyVNAFKFM	9606									11583921	t		tpavlidou	Vegfr-1 mutated at y1213, y1242, and y1333 were constructed and expressed in pae cells, to the same level as that of pae/vegfr-1 cells. The mutated vegfr-1 y1213f expressed in pae cells was kinase inactive.	SIGNOR-110850	0.2
CSNK2A1	protein	P68400	UNIPROT	CARD9	protein	Q9H257	UNIPROT	down-regulates activity	phosphorylation	Thr531	NTTGSDNtDTEGS	9606									17936701	t			PVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2.	SIGNOR-266900	0.352
NOTCH1	protein	P46531	UNIPROT	SNW1	protein	Q13573	UNIPROT	up-regulates	binding			9606									10713164	t		gcesareni	SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.	SIGNOR-75782	0.584
PTK6	protein	Q13882	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	phosphorylation	Tyr315	TFCGTPEyLAPEVLE	9606	BTO:0000150	BTO:0001129							20606012	t		gcesareni	Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6.	SIGNOR-166506	0.454
LMO2	protein	P25791	UNIPROT	ANGPT2	protein	O15123	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22792348	f		miannu	Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation.	SIGNOR-198249	0.338
CDK2	protein	P24941	UNIPROT	ID3	protein	Q02535	UNIPROT	down-regulates	phosphorylation	Ser5	sPVRGCYE	9606									9372912	t		lperfetto	We now show that an analogous cell-cycle-regulated phosphorylation of id3 alters the specificity of id3 for abrogating both e-box-dependent bhlh homo- or heterodimer complex formation in vitro and e-box-dependent reporter gene function in vivo._	SIGNOR-53306	0.348
NEU1	protein	Q99519	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0003554								32164705	f		miannu	Our data showed that NEU1 inhibited cancer cell proliferation, induced apoptosis, and suppressed tumor formation both in vitro and in vivo, by disrupting interaction of FN and integrin β1 and inhibiting the Akt signaling pathway. 	SIGNOR-260657	0.7
E2F1	protein	Q01094	UNIPROT	TLR3	protein	O15455	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									22310660	f	 	lperfetto	Together, these data indicated that E2F1 suppresses TLR3 transcription, but during immune stimulation, Rb is upregulated to block the inhibitory effect of E2F1 on TLR3, highlighting a role of Rb-E2F1 axis in the innate immune response in epithelial cells.	SIGNOR-254136	0.2
UFD1	protein	Q92890	UNIPROT	AMFR	protein	Q9UKV5	UNIPROT	up-regulates activity	binding												17681147	t		miannu	Here we show that Ufd1 directly interacts with gp78 and functions as a cofactor. Ufd1 enhances the E3 activity of gp78, accelerates the ubiquitination and degradation of reductase, and eventually promotes receptor-mediated uptake of low-density lipoprotein.	SIGNOR-252425	0.2
PLK1	protein	P53350	UNIPROT	CEP55	protein	Q53EZ4	UNIPROT	up-regulates	phosphorylation	Ser436	PTAALNEsLVECPKC	9606									16198290	t		lperfetto	Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. s425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436...enabling it to relocate to the midbody to function in mitotic exit and cytokinesis.	SIGNOR-140898	0.57
GRK2	protein	P25098	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser375	GTLRTSIsVERQIHK	9606	BTO:0000007								11517230	t			Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251446	0.2
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1889	SPTTPKYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273103	0.745
PLEKHA7	protein	Q6IQ23	UNIPROT	TSPAN33	protein	Q86UF1	UNIPROT	up-regulates activity	binding			10116	BTO:0003618								30463011	t		Simone	Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11.	SIGNOR-261250	0.409
PAK2	protein	Q13177	UNIPROT	MKNK1	protein	Q9BUB5	UNIPROT	down-regulates activity	phosphorylation	Ser39	RRGRATDsLPGKFED	9606	BTO:0000007								15234964	t		miannu	Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk. When 293T cells are subjected to apoptotic induction by hydrogen peroxide, Mnk1 is phosphorylated at both Thr(22) and Ser(27). These results indicate a role for Pak2 in the down-regulation of translation initiation in apoptosis by phosphorylation of Mnk1.	SIGNOR-250221	0.43
ARAF	protein	P10398	UNIPROT	MAP2K2	protein	P36507	UNIPROT	up-regulates	phosphorylation			9606									21779497	t		gcesareni	Active raf phosphorylates mek.	SIGNOR-175142	0.742
KDM5B	protein	Q9UGL1	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	demethylation	Lys5	kQTARKST	9606									30246379	t		miannu	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264304	0.2
CDK12	protein	Q9NYV4	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1941	SPKGSTYsPTSPGYS	9606									22012619	t		miannu	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176837	0.775
ABCC4	protein	O15439	UNIPROT	BLOC-1	complex	SIGNOR-C381	SIGNOR	up-regulates activity	binding			9606	BTO:0000132								23805129	t		lperfetto	The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). 	SIGNOR-265996	0.2
CSNK2A2	protein	P19784	UNIPROT	SAT1	protein	P21673	UNIPROT	unknown	phosphorylation			-1									8954982	t		llicata	Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149.	SIGNOR-251036	0.329
GSK3B	protein	P49841	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr37	PPGDYSTtPGGTLFS	9606		BTO:0000671							18701453	t		lperfetto	We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation.	SIGNOR-236026	0.373
HPN	protein	P05981	UNIPROT	F7	protein	P08709	UNIPROT	up-regulates activity	cleavage	Arg212	NASKPQGrIVGGKVC	-1									7814421	t		lperfetto	Hepsin, a putative membrane-associated serine protease, activates human factor VII and initiates a pathway of blood coagulation on the cell surface leading to thrombin formation|In contrast, an activation cleavage site factor VII mutant, R152E factor VII, was not cleaved by hepsin-transfected cells, suggesting that factor VII and S344A factor VII were activated on these cells by cleavage of the Arg152-Ile153 peptide bond. I	SIGNOR-263638	0.353
dehydroepiandrosterone	chemical	CHEBI:28689	ChEBI	androst-5-ene-3beta,17beta-diol	smallmolecule	CHEBI:2710	ChEBI	up-regulates quantity	precursor of			9606		BTO:0001363							30943210	t		lperfetto	Testicular 17betaHSD3 converts DHEA to androstenediol and androstenedione to testosterone	SIGNOR-268659	0.8
CAMK4	protein	Q16566	UNIPROT	HDAC4	protein	P56524	UNIPROT	down-regulates activity	phosphorylation	Ser467	RPLGRTQsAPLPQNA		BTO:0001938								11470791	t		llicata	CaMKIV phosphorylates HDAC4 in vitro and promotes its nuclear-cytoplasmic shuttling in vivo. | Thus, CaMKIV can phosphorylate HDAC4 at Ser-467 and/or Ser-632 in vitro. | Collectively, our results suggest that CaMKIV reverses the transcriptional repression activity of HDAC4 by stimulating the mobilization of HDAC4 out of the nucleus.	SIGNOR-250711	0.603
CBL	protein	P22681	UNIPROT	PIK3R1	protein	P27986	UNIPROT	down-regulates	ubiquitination			9606	BTO:0000782								11526404	t		lperfetto	Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner.	SIGNOR-110060	0.68
TGFB1	protein	P01137	UNIPROT	CDK2	protein	P24941	UNIPROT	down-regulates				9606				SIGNOR-C16					10611320	f		gcesareni	Tgf-beta treatment resulted in the specific inactivation of cyclin cdk2 complexes caused by absence of the activating thr(160) phosphorylation on cdk2.	SIGNOR-73537	0.286
PRKCA	protein	P17252	UNIPROT	SDC2	protein	P34741	UNIPROT	unknown	phosphorylation	Ser187	DLGERKPsSAAYQKA	-1									9244383	t		lperfetto	We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198.	SIGNOR-248973	0.378
SLC9A2	protein	Q9UBY0	UNIPROT	hydron	chemical	CHEBI:15378	ChEBI	down-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265592	0.8
PPM1B	protein	O75688	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	dephosphorylation	Ser177	AKELDQGsLCTSFVG	9606									18930133	t			PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation.	SIGNOR-248343	0.412
CDK1	protein	P06493	UNIPROT	CDC7	protein	O00311	UNIPROT	up-regulates	phosphorylation	Thr376	QVAPRAGtPGFRAPE	9606									10846177	t		gcesareni	Hucdc7 and ask proteins can also be phosphorylated by cdks in vitro. Among four possible cdk phosphorylation sites of hucdc7, replacement of thr-376, corresponding to the activating threonine of cdk, with alanine (t376a mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue.	SIGNOR-78311	0.551
TBR1	protein	Q16650	UNIPROT	FOXP2	protein	O15409	UNIPROT	up-regulates activity	binding			9606									25232744	t		miannu	We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. 	SIGNOR-266831	0.573
RAF1	protein	P04049	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606									15849194	t	Ser112 corresponds to EIRSRHSsYPAGTED	lperfetto	Raf-1 protects cells from apoptosis, independently of its signals to MEK and ERK, by translocating to the mitochondria where it binds Bcl-2 and displaces BAD|Upon phosphorylation by Pak1, Raf-1 translocates to mitochondria and phosphorylates BAD at Ser-112.	SIGNOR-81165	0.644
85375-15-1	chemical	CID:6917797	PUBCHEM	SLC6A11	protein	P48066	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206990	0.8
NTN4	protein	Q9HB63	UNIPROT	UNC5	proteinfamily	SIGNOR-PF98	SIGNOR	up-regulates activity	binding			9606		BTO:0001484							25881791	t		miannu	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268184	0.596
palbociclib	chemical	CHEBI:85993	ChEBI	CDK4	protein	P11802	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205704	0.8
PRKCA	protein	P17252	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser66	GVYATRSsAVRLRSS	-1									2500966	t		lperfetto	We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65.	SIGNOR-248884	0.289
DAB2	protein	P98082	UNIPROT	LRP6	protein	O75581	UNIPROT	down-regulates	binding			9606									22491013	t		gcesareni	Wnt stimulation induces the casein kinase 2 (ck2)-dependent phosphorylation of lrp6 at s1579, promoting its binding to dab2 and internalization with clathrin.	SIGNOR-196925	0.509
RPS6KB1	protein	P23443	UNIPROT	EIF4B	protein	P23588	UNIPROT	up-regulates	phosphorylation	Ser422	RERSRTGsESSQTGT	9606									15071500	t		gcesareni	S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.	SIGNOR-123997	0.768
CYCS	protein	P99999	UNIPROT	Apoptosome	complex	SIGNOR-C230	SIGNOR	form complex	binding			-1									10206961	t		lperfetto	 APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9. 	SIGNOR-256430	0.831
ATM	protein	Q13315	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates activity	phosphorylation	Ser2996	QECKRNLsDIDQSFN	9606									21149446	t		gcesareni	In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible.	SIGNOR-170473	0.2
CHEK2	protein	O96017	UNIPROT	RASGRF1	protein	Q13972	UNIPROT	down-regulates	phosphorylation	Ser287	PITHDDVsSIFLNSE	9606									17110335	t		miannu	During interphase, cdc25 is inhibited by ser287 phosphorylation (xenopus cdc25;ser 216 in human cdc25c) and this inhibitory phosphorylation is maintained by dna-responsive checkpoints / s287 is targeted by many kinases, including chk1, chk2, ctak-1, pka, p38 and mapkap kinase-2 suggesting that phosphorylation of this site may integrate multiple signaling inputs.	SIGNOR-150843	0.378
PRKCB	protein	P05771	UNIPROT	MEP1B	protein	Q16820	UNIPROT	down-regulates quantity	phosphorylation	Ser687	KKYRERMsSNRPNLT	9534									12941954	t		miannu	These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.	SIGNOR-263173	0.2
2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid	chemical	CID:135461425	PUBCHEM	FGFR1	protein	P11362	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258183	0.8
SRC	protein	P12931	UNIPROT	TXK	protein	P42681	UNIPROT	up-regulates activity	phosphorylation	Tyr420	RYVLDDEyVSSFGAK	9606									11353545	t		lperfetto	We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association.	SIGNOR-247346	0.354
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	RRN3	protein	Q9NYV6	UNIPROT	up-regulates	phosphorylation	Ser44	LENDFFNsPPRKTVR	9606									15004009	t		lperfetto	Cdk2/cyclin e-mediated phosphorylation at ser 44 activates tif-ia	SIGNOR-216682	0.485
SAE1/SAE2 complex	complex	SIGNOR-C294	SIGNOR	MBD4	protein	O95243	UNIPROT	up-regulates activity	sumoylation	Lys215	TSTHLLLkEDEGVDD										31476572	t		lperfetto	MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro.	SIGNOR-275680	0.2
AKT2	protein	P31751	UNIPROT	PKP1	protein	Q13835	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr171	RGTLRKGtLGSKGQK	-1									23444369	t		miannu	Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry.	SIGNOR-273488	0.27
PKI-402	chemical	CID:44187953	PUBCHEM	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206259	0.8
RET	protein	P07949	UNIPROT	DOK1	protein	Q99704	UNIPROT	up-regulates	binding			9606									12087092	t		amattioni	Dok proteins directly associate with tyrosine 1062 of ret and could be its substrates. Phosphorylation of dok1 is necessary for interaction with ras-gap in vitro and in vivo. Dok1 is a negative regulator for the ras/erk signaling pathway activated by ret.	SIGNOR-90158	0.595
MBD4	protein	O95243	UNIPROT	CYP27B1	protein	O15528	UNIPROT	up-regulates quantity by expression	transcriptional regulation												23195996	t		lperfetto	 Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12]	SIGNOR-275682	0.386
MBD4	protein	O95243	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates													23195996	f		lperfetto	The base excision repair DNA N-glycosylase MBD4 (also known as MED1), an interactor of the DNA mismatch repair protein MLH1, plays a central role in the maintenance of genomic stability of CpG sites by removing thymine and uracil from G:T and G:U mismatches, respectively. 	SIGNOR-275683	0.7
MBD4	protein	O95243	UNIPROT	Base-excision_repair	phenotype	SIGNOR-PH222	SIGNOR	up-regulates													23195996	f		lperfetto	The base excision repair DNA N-glycosylase MBD4 (also known as MED1), an interactor of the DNA mismatch repair protein MLH1, plays a central role in the maintenance of genomic stability of CpG sites by removing thymine and uracil from G:T and G:U mismatches, respectively. 	SIGNOR-275684	0.7
UVB radiation	stimulus	SIGNOR-ST17	SIGNOR	DDB1	protein	Q16531	UNIPROT	up-regulates													24086042	f		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein).	SIGNOR-275685	0.7
GNAO1	protein	P09471	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	down-regulates				-1									10224115	f			G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics.	SIGNOR-256525	0.7
RNF8	protein	O76064	UNIPROT	H2AC11	protein	P0C0S8	UNIPROT	up-regulates	ubiquitination			9606									20551964	t		gcesareni	Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist.	SIGNOR-166174	0.2
PYY	protein	P10082	UNIPROT	NPY5R	protein	Q15761	UNIPROT	up-regulates	binding			9606									11825645	t		esanto	Maml3 forms complexes in vivo with icn and csl and functiosn as transcriptional coactivators for notch signaling.	SIGNOR-114749	0.629
NOX1	protein	Q9Y5S8	UNIPROT	ROS	stimulus	SIGNOR-ST2	SIGNOR	up-regulates				9606									17237347	t		lperfetto	Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS).	SIGNOR-264714	0.7
TGFBR1	protein	P36897	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity				9606									19726546	t		lperfetto	Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity.	SIGNOR-227496	0.284
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser383	IHFWSTLsPIAPRSP	9606									7889942	t		gcesareni	Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-252083	0.2
PRKCD	protein	Q05655	UNIPROT	ELAVL1	protein	Q15717	UNIPROT	up-regulates	phosphorylation	Ser318	GDKILQVsFKTNKSH	9606									20086103	t		lperfetto	Tandem phosphorylation of serines 221 and 318 by protein kinase cdelta coordinates mrna binding and nucleocytoplasmic shuttling of hurstabilization of mrna by the ubiquitous rna binding protein human antigen r (hur), a member of the embryonic lethal abnormal vision (elav) protein family, requires canonical binding to au-rich element (are)-bearing target mrna and export of nuclear hur-mrna complexes to the cytoplasm. In human mesangial cells (hmc) both processes are induced by angiotensin ii (angii) via protein kinase cdelta (pkcdelta)-triggered serine phosphorylation of hur.	SIGNOR-163528	0.622
phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	MAPK1	protein	P28482	UNIPROT	up-regulates	chemical activation			9606		BTO:0000887;BTO:0001103							20231899	t		gcesareni	In addition, extracellular signal-regulated kinase (erk) is stimulated by ampk-induced pld1 activation through the formation of phosphatidic acid (pa), which is a product of pld	SIGNOR-164289	0.8
CHRM2	protein	P08172	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256828	0.377
glycogen	smallmolecule	CHEBI:28087	ChEBI	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	up-regulates quantity	precursor of			9606									3346228	t			Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267391	0.8
TFAP4	protein	Q01664	UNIPROT	HDAC1	protein	Q13547	UNIPROT	up-regulates activity	binding			9606	BTO:0001109								19505873	t		miannu	We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads.	SIGNOR-226590	0.286
ROCK1	protein	Q13464	UNIPROT	ARHGAP24	protein	Q8N264	UNIPROT	up-regulates	phosphorylation			9606									16862148	t		acerquone	Rock phosphorylates filgap, and this phosphorylation stimulates its racgap activity and is a requirement for filgap-mediated bleb formation	SIGNOR-148262	0.444
NOTCH1	protein	P46531	UNIPROT	PIN1	protein	Q13526	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19151708	f		gcesareni	Notch1 directly induces transcription of pin1	SIGNOR-183458	0.393
PRKCZ	protein	Q05513	UNIPROT	STK11	protein	Q15831	UNIPROT	up-regulates	phosphorylation	Ser307	IRQIRQHsWFRKKHP	9606		BTO:0000887;BTO:0001103;BTO:0001260							19414597	t		llicata	Here, we have identified s307 as a novel phosphorylation site in lkb1 and provide evidence that, in multiple cell types, phosphorylation of this site by protein kinase c ? (pkc-?) Induces nucleocytoplasmic transport of lkb1.	SIGNOR-185640	0.326
ITGAX	protein	P20702	UNIPROT	AX/b2 integrin	complex	SIGNOR-C171	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253193	0.823
MYC	protein	P01106	UNIPROT	ST3GAL1	protein	Q11201	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22547830	f	 	 	We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. 	SIGNOR-253961	0.2
ERCC6	protein	Q03468	UNIPROT	RAD23B	protein	P54727	UNIPROT	up-regulates activity													24086043	f		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275694	0.469
Thrombin-Thrombomodulin	complex	SIGNOR-C316	SIGNOR	PROC	protein	P04070	UNIPROT	up-regulates activity	cleavage			9606		BTO:0000131							29880919	t		lperfetto	Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC).	SIGNOR-263526	0.708
ACTB	protein	P60709	UNIPROT	Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	form complex	binding			10090	BTO:0001086								19279220	t		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270717	0.476
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates													25309941	f			Following GSK3β activation, NF-κB is translocated from the cytoplasm to the nucleus and binds transcriptional sites with CBP leading to an increase in the transcription of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6). 	SIGNOR-255489	0.7
TGFB3	protein	P10600	UNIPROT	TGFB3	protein	P10600	UNIPROT	up-regulates	binding			9606									16885528	t		gcesareni	The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge	SIGNOR-148611	0.2
NLGN3	protein	Q9NZ94	UNIPROT	NRXN2	protein	P58401	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264157	0.825
RNF31	protein	Q96EP0	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0000007								24469399	t		miannu	Involvement of Gln271 and Asp275 of NEMO in LUBAC-mediated linear polyubiquitination.vHOIP NZF1 also recognizes NEMO, and this recognition is involved in linear polyubiquitination of NEMO. Linear chains conjugated to NEMO are recognized by NEMO in trans on another IKK complex, thereby inducing multimerization of the IKK complex and trans autophosphorylation of IKK2.	SIGNOR-272052	0.844
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	STAT5A	protein	P42229	UNIPROT	up-regulates	phosphorylation			9606		BTO:0000975							10194762	t	inferred from 70% family members	gcesareni	Serine 780 is the only substrate in full-length stat5a for active erk	SIGNOR-270004	0.2
GATA1	protein	P15976	UNIPROT	NBEAL2	protein	Q6ZNJ1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000132								28082341	f		lperfetto	In conclusion, we herein show a long-distance regulatory region with GATA1 binding sites as being a strong enhancer for NBEAL2 expression.	SIGNOR-261881	0.385
CNTNAP2	protein	Q9UHC6	UNIPROT	CNTN1	protein	Q12860	UNIPROT	up-regulates activity	relocalization			10090	BTO:0001221								11069942	t		Gianni	These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr.	SIGNOR-269074	0.49
HDAC5	protein	Q9UQL6	UNIPROT	MEF2C	protein	Q06413	UNIPROT	down-regulates	binding			9606									11062529	t		gcesareni	The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis.	SIGNOR-84026	0.684
PPP2CA	protein	P67775	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	dephosphorylation	Ser12	KSKPKDAsQRRRSLE	9606	BTO:0001938								18069897	t		gcesareni	We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC	SIGNOR-247970	0.442
DDX5	protein	P17844	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates	binding			10090	BTO:0000165								17960593	t		miannu	P68 (ddx5) interacts with runx2 and regulates osteoblast differentiation. / p68 is a novel co-activator for runx2	SIGNOR-236974	0.466
DLGAP5	protein	Q15398	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								9115257	t		miannu	SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.	SIGNOR-264213	0.401
SGK1	protein	O00141	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Ser315	DFRSRTNsNASTVSG	9606									11154281	t		lperfetto	We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. However, sgk and akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on fkhrl1. While both kinases can phosphorylate thr-32, sgk displays a marked preference for ser-315 whereas akt favors ser-253.	SIGNOR-236607	0.787
ATG12/5/16L1	complex	SIGNOR-C109	SIGNOR	Autophagosome_formation	phenotype	SIGNOR-PH36	SIGNOR	up-regulates				-1									23321721	f		lperfetto	Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation	SIGNOR-226702	0.7
CDH15	protein	P55291	UNIPROT	CDON	protein	Q4KMG0	UNIPROT	up-regulates activity	binding			9606									12634428	t		lperfetto	Cdo binds promyogenic cadherins form complexes with n- and m-cadherin.	SIGNOR-99250	0.477
ACIN1	protein	Q9UKV3	UNIPROT	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606									10490026	f	Cleaved by CASP3	amattioni	Acinus induces apoptotic chromatin condensation after cleavage by caspase-3 without inducing dna fragmentation.	SIGNOR-70797	0.7
125-L-serine-2-133-interleukin 2 (human reduced)	smallmolecule	SID:46508054	ChEBI	IL2RA	protein	P01589	UNIPROT	up-regulates activity	chemical activation			9606									18031103	t		miannu	Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response. 	SIGNOR-259388	0.8
MAPK3	protein	P27361	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates activity	phosphorylation	Ser255	HATSGALsPAKDCGS	9606									9535909	t		lperfetto	These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.	SIGNOR-249465	0.626
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									15916964	t		lperfetto	Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities	SIGNOR-137627	0.2
regorafenib	chemical	CHEBI:68647	ChEBI	MAPK11	protein	Q15759	UNIPROT	down-regulates activity	chemical inhibition			9606									24756792	t		miannu	In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically.	SIGNOR-259211	0.8
MAPK8	protein	P45983	UNIPROT	SFN	protein	P31947	UNIPROT	down-regulates	phosphorylation	Ser186	FHYEIANsPEEAISL	9606									15071501	t	JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8	gcesareni	Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-187.	SIGNOR-124016	0.346
GRB14	protein	Q14449	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates activity	binding												24535599	t		lperfetto	Growth factor receptor-bound protein 14 (Grb14) interacts with insulin receptor (IR) through the between PH and SH2 (BPS) domain. Grb14-IR complex formation is initiated by insulin stimulation, and the binding event results in the inhibition of insulin signalling.	SIGNOR-264873	0.75
MGluR	proteinfamily	SIGNOR-PF55	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264690	0.7
TRAF2	protein	Q12933	UNIPROT	MAP3K14	protein	Q99558	UNIPROT	up-regulates activity	binding			9606									9020361	t		lperfetto	NIK binds to Traf2 and stimulates NF-kappaB activity.	SIGNOR-46215	0.568
5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid	chemical	CHEBI:76223	ChEBI	PTGS2	protein	P35354	UNIPROT	down-regulates activity	chemical inhibition			-1									22091869	t		Luana	 Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2. 	SIGNOR-258324	0.8
ACP1	protein	P24666	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	dephosphorylation	Tyr530	FTSTEPQyQPGENL	10090									19088431	t			LMWPTP dephosphorylated pY(527)-Src and pY(416)-Src in vitro, with greater specificity for pY(527)Src. Activation of LMWPTP produced strong activation of Src mediated by fast dephosphorylation of pY(527)-Src, followed by slower deactivation of this kinase via dephosphorylation of pY(416)Src.	SIGNOR-248454	0.451
NAT8L	protein	Q8N9F0	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	chemical modification			9606									19524112	t		miannu	The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA.	SIGNOR-267524	0.8
FUBP1	protein	Q96AE4	UNIPROT	BIK	protein	Q13323	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19637194	f		irozzo	FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In particular, elevated expression of the Bcl-2 family members Bik and Noxa was detected. 	SIGNOR-259127	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	TH	protein	P07101	UNIPROT	up-regulates	phosphorylation			9606									7901013	t	inferred from 70% family members	gcesareni	In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11	SIGNOR-270055	0.2
PRKCD	protein	Q05655	UNIPROT	ADRA2A	protein	P08913	UNIPROT	up-regulates activity	phosphorylation	Ser247	RRTRVPPsRRGPDAV	10029	BTO:0000246								11732925	t		lperfetto	Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling.	SIGNOR-249126	0.512
EFL1	protein	Q7Z2Z2	UNIPROT	EIF6	protein	P56537	UNIPROT	up-regulates				9606	BTO:0001271								21536732	f		miannu	Human sbds is an essential cofactor for the efl1 gtpase, and together they cooperate to directly catalyze the release of eif6 from mammalian pre-60s ribosomal subunits	SIGNOR-173492	0.2
NAALAD2	protein	Q9Y3Q0	UNIPROT	N-acetyl-L-aspartate(2-)	smallmolecule	CHEBI:16953	ChEBI	up-regulates quantity	chemical modification			9606									10085079	t		miannu	The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated.	SIGNOR-267543	0.8
TFDP1	protein	Q14186	UNIPROT	RRM1	protein	P23921	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253866	0.287
CCL19	protein	Q99731	UNIPROT	ACKR4	protein	Q9NPB9	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								23341447	t		Luana	 In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines.	SIGNOR-268416	0.65
MYCT1	protein	Q8N699	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates activity				9606									30283340	f		miannu	Herein, we observed that overexpression of MYCT1 induced apoptosis in HL-60 and KG-1a cells, and upregulated Bax, downregulated Bcl-2, and enhanced cleavage of caspase-3 and -9. Similar proapoptotic role of MYCT1 was also found in the AML cell xenografts. These results suggest that MYCT1 affects AML cell apoptosis by modulating the endogenous apoptotic pathways.	SIGNOR-261943	0.2
1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	PRKCD	protein	Q05655	UNIPROT	up-regulates activity	binding			9606									14967450	t	PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine.	lperfetto	The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified.	SIGNOR-242587	0.8
MMP2	protein	P08253	UNIPROT	A2M	protein	P01023	UNIPROT	down-regulates quantity by destabilization	cleavage	Gly702	YEMHGPEgLRVGFYE	-1									9344465	t		lperfetto	The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261780	0.62
CDK1	protein	P06493	UNIPROT	HMGA1	protein	P17096	UNIPROT	down-regulates	phosphorylation	Thr53	KEPSEVPtPKRPRGR	9606									17960875	t		gcesareni	Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation.	SIGNOR-158608	0.392
ATM	protein	Q13315	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606	BTO:0002552								17967874	t		gcesareni	The increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15.	SIGNOR-158636	0.838
PI-103	chemical	CHEBI:90524	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252651	0.8
EIF2AK1	protein	Q9BQI3	UNIPROT	EIF2S1	protein	P05198	UNIPROT	up-regulates	phosphorylation	Ser49	IEGMILLsELSRRRI	9606									10563826	t		lperfetto	The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases present in the reticulocyte lysate. These findings support the hypothesis that the serine 48 residue is required for high-affinity interaction between eif2 alpha(p) and eif2b.	SIGNOR-72152	0.886
EGFR	protein	P00533	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									14967450	t		lperfetto	The egf-r coimmunoprecipitated with p85 alpha	SIGNOR-252672	0.773
AMPK	complex	SIGNOR-C15	SIGNOR	HDAC4	protein	P56524	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000938	BTO:0000887							21565617	t		lperfetto	We show here that in liver, class iia hdacs (hdac4, 5, and 7) are phosphorylated and excluded from the nucleus by ampk family kinases.	SIGNOR-216658	0.275
RHOBTB1	protein	O94844	UNIPROT	PDE5A	protein	O76074	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								30896450	t		miannu	RhoBTB1 augmented the cGMP response to nitric oxide by restraining the activity of phosphodiesterase 5 (PDE5) by acting as a substrate adaptor delivering PDE5 to the Cullin-3 E3 Ring ubiquitin ligase complex for ubiquitination inhibiting PDE5.	SIGNOR-272312	0.2
EXOC7	protein	Q9UPT5	UNIPROT	SLC2A4	protein	P14672	UNIPROT	up-regulates				9606									12687004	f		gcesareni	So, the exocyst might have a crucial role in the targeting of the glut4 vesicle to the plasma membrane, perhaps directing the vesicle to the precise site of fusion	SIGNOR-100242	0.53
RNF138	protein	Q8WVD3	UNIPROT	LEF1	protein	Q9UJU2	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								16714285	t		miannu	Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome. 	SIGNOR-271595	0.311
MAPK3	protein	P27361	UNIPROT	HSPB8	protein	Q9UJY1	UNIPROT	up-regulates activity	phosphorylation	Thr87	GVPAEGRtPPPFPGE	9606		BTO:0000887							11342557	t		lperfetto	Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation	SIGNOR-107680	0.346
oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	citrate(3-)	smallmolecule	CHEBI:16947	ChEBI	up-regulates quantity	precursor of			9606									3013232	t		miannu	Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond.	SIGNOR-266237	0.8
MAPK1	protein	P28482	UNIPROT	TPR	protein	P12270	UNIPROT	up-regulates	phosphorylation	Thr2214	GGRSVPTtPLQVAAP	9606									18794356	t		miannu	Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore.	SIGNOR-181026	0.382
TGFB2	protein	P61812	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates	binding			9606									11157754	t		gcesareni	We show that tbetarii-b, an alternatively spliced variant of the tgf-beta type ii receptor, is a tgf-beta2 binding receptor, which mediates signalling via the smad pathway in the absence of any tgf-beta type iii receptor	SIGNOR-104795	0.744
BCAR1	protein	P56945	UNIPROT	PKN3	protein	Q6P5Z2	UNIPROT	up-regulates activity	binding			10090	BTO:0002572								30422386	t		lperfetto	Taken together, the data suggest that p130Cas expression induces PKN3 activation and this activation is independent of p130Cas–PKN3 interaction.	SIGNOR-264573	0.2
PRKCA	protein	P17252	UNIPROT	RAF1	protein	P04049	UNIPROT	unknown	phosphorylation	Ser499	VKSRWSGsQQVEQPT	9606									12551925	t		gcesareni	For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1.	SIGNOR-97644	0.538
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine	chemical	CHEBI:91451	ChEBI	RAF1	protein	P04049	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206385	0.8
ESR2	protein	Q92731	UNIPROT	SCN11A	protein	Q9UI33	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938	BTO:0001264							22169964	f		miannu	17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice	SIGNOR-253475	0.2
FXN	protein	Q16595	UNIPROT	Mitochondrial Fe-S Cluster Assembly Complex	complex	SIGNOR-C276	SIGNOR	form complex	binding			-1									27519411	t		lperfetto	As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry.	SIGNOR-262125	0.783
GPHN	protein	Q9NQX3	UNIPROT	GABA-A	proteinfamily	SIGNOR-PF61	SIGNOR	up-regulates quantity by stabilization	binding			10116	BTO:0000938								21994384	t		miannu	 we demonstrate that GABA(A)Rs and gephyrin are intimately associated at inhibitory synapses in cultured rat neurons. Our results suggest that the direct binding of gephyrin to residues 360-375 of the α1 subunit and its modulation are likely to be important determinants for the stabilization of GABA(A)Rs at synaptic sites, thereby modulating the strength of synaptic inhibition.	SIGNOR-264964	0.2
TLN1	protein	Q9Y490	UNIPROT	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257612	0.744
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Thr41	GIHSGATtTAPSLSG	9606	BTO:0000938	BTO:0000142							19303846	t		lperfetto	GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation	SIGNOR-227878	0.892
P2RY2	protein	P41231	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257233	0.2
CHMP2A	protein	O43633	UNIPROT	Viral_budding	phenotype	SIGNOR-PH125	SIGNOR	up-regulates				-1									30989108	f		miannu	ESCRT-III has been proposed to assemble inside the membrane neck formed at a late stage of a budding vesicle or an enveloped virus. The membrane neck needs to be constricted to proceed to membrane fission, thereby splitting the vesicle or virus from the cellular membrane. CHMP2A and CHMP3 are engaged late in ESCRT-III assembly, recruit VPS4 (31, 42), and block Snf7 (CHMP4) polymerization	SIGNOR-260844	0.7
KLF4	protein	O43474	UNIPROT	HSPA8	protein	P11142	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165;BTO:0003292								18379898	f		miannu	 The results showed the upregulation of the HSP73 constitutive expression by KLF4 overexpression in both C2C12 cells and murine RAW264.7 macrophages; in response to heat stress, however, few changes were observed in the levels of HSP73 by KLF4 overexpression. 	SIGNOR-254544	0.2
RABEP1	protein	Q15276	UNIPROT	RAB5A	protein	P20339	UNIPROT	up-regulates	binding			9606									11452015	t		miannu	We have previously shown that rab5, which regulates various steps of transport along the early endocytic pathway, is activated by a complex consisting of rabex-5, a rab5 nucleotide exchange factor, and the effector rabaptin-5.	SIGNOR-109352	0.927
PRKCD	protein	Q05655	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation	Ser727	NTIDLPMsPRTLDSL	9606									16418226	t		gcesareni	Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation.	SIGNOR-143828	0.578
CDK2	protein	P24941	UNIPROT	CCNE1	protein	P24864	UNIPROT	down-regulates	phosphorylation	Ser387	LSEQNRAsPLPSGLL	9606									19561641	t		gcesareni	Phosphorylation of threonine 395 has been linked to the proteasome-mediated degradation of full length cyclin e	SIGNOR-186414	0.954
SRC	protein	P12931	UNIPROT	ARRB1	protein	P49407	UNIPROT	down-regulates	phosphorylation	Tyr54	YLKERRVyVTLTCAF	9606									17456551	t		lperfetto	Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors.	SIGNOR-154564	0.67
OTUB1	protein	Q96FW1	UNIPROT	ESR1	protein	P03372	UNIPROT	down-regulates activity	deubiquitination												19383985	t		lperfetto	OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity.|We show that OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells.	SIGNOR-276529	0.526
MAPK1	protein	P28482	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates	phosphorylation			9606									18596912	t		lbriganti	The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform	SIGNOR-210182	0.47
USF2	protein	Q15853	UNIPROT	MYH9	protein	P35579	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								11467950	f		miannu	we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies.	SIGNOR-222608	0.2
ANKRD11	protein	Q6UB99	UNIPROT	GAP43	protein	P17677	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0000142							29274743	t		miannu	Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons. 	SIGNOR-266736	0.2
FLT3	protein	P36888	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation			9606									26049753	f			SIRT1 protein but not mRNA expression is increased in CD34+ cells from FLT3-ITD positive AML patients compared to FLT3 wild-type AML patients	SIGNOR-261555	0.358
flumazenil	chemical	CHEBI:5103	ChEBI	GABA-A (a4-b1-g2) receptor	complex	SIGNOR-C333	SIGNOR	up-regulates activity	chemical activation			9606		BTO:0000227							18790874	t	brain	lperfetto	Receptors containing the alpha4 or alpha6 subunits, together with beta and gamma2, do not bind the traditional BZ agonists, including zolpidem, but demonstrate high affinity for some ligands, notably the imidazobenzodiazepines such as flumazenil and Ro15-4513, or bretazenil	SIGNOR-263807	0.8
TRAF3	protein	Q13114	UNIPROT	IL10	protein	P22301	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									16306937	f		miannu	TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10), but is dispensable for expression of pro-inflammatory cytokines.	SIGNOR-256077	0.337
perfluorononanoic acid	chemical	CHEBI:38397	ChEBI	AR	protein	P10275	UNIPROT	down-regulates activity	chemical inhibition			-1									23764977	t		miannu	Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner. 	SIGNOR-268769	0.8
ESCRT-III	complex	SIGNOR-C379	SIGNOR	Cytoskeleton_organization	phenotype	SIGNOR-PH89	SIGNOR	up-regulates				9606									26775243	f		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit.	SIGNOR-265535	0.7
PTPN1	protein	P18031	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates	dephosphorylation	Tyr530	FTSTEPQyQPGENL	9606									12857726	t		gcesareni	The tyrosine kinase pp60c-src has also been identified as a good substrate of ptp1b leading to an activation of this kinase (27).	SIGNOR-103607	0.773
PRKCG	protein	P05129	UNIPROT	STXBP1	protein	P61764	UNIPROT	unknown	phosphorylation	Ser306	VSQEVTRsLKDFSSS	-1									12519779	t		lperfetto	Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation.	SIGNOR-249184	0.394
orotate	smallmolecule	CHEBI:30839	ChEBI	orotidine 5'-phosphate(3-)	smallmolecule	CHEBI:57538	ChEBI	up-regulates quantity	precursor of			9606									2912371	t		miannu	Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase).	SIGNOR-267434	0.8
TNFRSF1A	protein	P19438	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates				10090	BTO:0000165								17151142	f		lperfetto	These results indicate that TNF-alpha regulates myogenesis and muscle regeneration as a key activator of p38.	SIGNOR-235370	0.38
dexamethasone	chemical	CHEBI:41879	ChEBI	CEBPD	protein	P49716	UNIPROT	up-regulates quantity by expression				9606									8754811	f		fspada	The differentiation of 3t3 preadipocytes into adipocytes is accompanied by a transient induction of c/ebpbeta and c/ebpdelta expression in response to treatment of the cells with methylisobutylxanthine (mix) and dexamethasone (dex), respectively	SIGNOR-43254	0.8
HDAC1	protein	Q13547	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates	binding			9606		BTO:0000887							11684023	t		gcesareni	Interaction of myod with hdac1 in undifferentiated myoblasts mediates repression of muscle-specific gene expression.	SIGNOR-111243	0.563
GOPC	protein	Q9HD26	UNIPROT	ADRB1	protein	P08588	UNIPROT	down-regulates	relocalization			9606									15358775	t		miannu	Overexpression of cal reduces surface expression of beta1ar. Interaction with cal promotes retention of beta1ar within the cell	SIGNOR-128791	0.349
SLC25A13	protein	Q9UJS0	UNIPROT	glutamic acid	smallmolecule	CHEBI:18237	ChEBI	down-regulates quantity	relocalization			9606									12084073	t		miannu	Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. 	SIGNOR-265155	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	AMOTL1	protein	Q8IY63	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser793	SSLRPARsVPSIAAA	9606	BTO:0000007								25373897	t		miannu	 we show that AMPK directly phosphorylates S793 of AMOTL1. AMPK activation stabilizes and increases AMOTL1 steady-state protein levels, contributing to YAP inhibition. 	SIGNOR-263105	0.2
MAPK3	protein	P27361	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	up-regulates	phosphorylation	Thr577	AENGLLMtPCYTANF	9606									10980595	t		llicata	We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway	SIGNOR-81464	0.717
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	ATF4	protein	P18848	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								11238952	t		miannu	Here we show that the F-box protein betaTrCP, the receptor component of the SCF E3 ubiquitin ligase responsible for IkappaBalpha and beta-catenin degradation, is colocalized in the nucleus with ATF4, a member of the ATF-CREB bZIP family of transcription factors, and controls its stability. ATF4 ubiquitination in HeLa cells is enhanced in the presence of betaTrCP. 	SIGNOR-272580	0.334
paliperidone	chemical	CHEBI:82978	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10116		BTO:0000601							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258565	0.8
PLK1	protein	P53350	UNIPROT	CLIP1	protein	P30622	UNIPROT	up-regulates	phosphorylation	Ser195	LTKTASEsISNLSEA	9606									20664522	t		gcesareni	Furthermore, we provide evidence that plk1 phosphorylation of clip-170 at s195 enhances its association with ck2	SIGNOR-167172	0.692
SIK2	protein	Q9H0K1	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	phosphorylation	Ser1490	AILNPPPsPATERSH	9606	BTO:0006293								35277657	t		miannu	Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/β-catenin signaling pathway activation.	SIGNOR-275399	0.2
PPAT	protein	Q06203	UNIPROT	5-phospho-beta-D-ribosylaminium(1-)	smallmolecule	CHEBI:58681	ChEBI	up-regulates quantity	chemical modification			9606									8106516	t			Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed”	SIGNOR-267190	0.8
HSPA1A	protein	P0DMV8	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates	binding			9606									21730050	t		gcesareni	Interestingly, FKBP51 forms complexes in mitochondria with the glucocorticoid receptor and the Hsp90/Hsp70-based chaperone heterocomplex	SIGNOR-251668	0.618
BKM120	chemical	CHEBI:71954	ChEBI	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190386	0.8
RUNX2	protein	Q13950	UNIPROT	ELANE	protein	P08246	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004850								14594802	f		miannu	We find that LEF-1 and CBFalpha co-activate ELA2 expression.	SIGNOR-254552	0.259
PIEZO1	protein	Q92508	UNIPROT	Hair cells mechanotransduction channel	complex	SIGNOR-C290	SIGNOR	form complex	binding			10090		BTO:0000630							23217710	t		lperfetto	The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012).	SIGNOR-262571	0.398
CSNK2B	protein	P67870	UNIPROT	CDC34	protein	P49427	UNIPROT	unknown	phosphorylation	Ser231	FGDDEDDsGTEES	9606	BTO:0000567								11546811	t		llicata	CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm. 	SIGNOR-251059	0.357
ARNT	protein	P27540	UNIPROT	CYP1A1	protein	P04798	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17012224	t		miannu	Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1.	SIGNOR-259910	0.633
MAPK14	protein	Q16539	UNIPROT	RBSN	protein	Q9H1K0	UNIPROT	up-regulates	phosphorylation	Ser215	ESLSTHTsPSQSPNS	9606									16138080	t		lperfetto	We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes	SIGNOR-140143	0.2
GNAI2	protein	P04899	UNIPROT	TNFAIP8	protein	O95379	UNIPROT	up-regulates activity	binding			9606									20607800	t			TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation	SIGNOR-256492	0.2
CCNA1	protein	P78396	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0001884								15829981	f		miannu	SiRNA mediated silencing of cyclin A1 in highly cyclin A1 expressing ML1 leukemic cells significantly slowed S phase entry, decreased proliferation and inhibited colony formation. 	SIGNOR-255734	0.7
PDK3	protein	Q15120	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	phosphorylation	Ser300	SMSDPGVsYRTREEI	-1									11486000	t		lperfetto	Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes.	SIGNOR-109651	0.866
1038915-60-4	chemical	CID:24958200	PUBCHEM	PARP2	protein	Q9UGN5	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194402	0.8
LRRK2	protein	Q5S007	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation			9606									22303461	t		gcesareni	Lrrk2 directly phosphorylates tubulin-associated tau, but not free tau;(iii) lrrk2 phosphorylates tau at thr181 as one of the target sites;. furthermore, we revealed that lrrk2-mediated phosphorylation of tau reduces its tubulin-binding ability.	SIGNOR-195756	0.545
HRAS	protein	P01112	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9534	BTO:0004055								8052307	t		lperfetto	In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k	SIGNOR-252689	0.84
GSK3B	protein	P49841	UNIPROT	EIF2B3	protein	Q9NR50	UNIPROT	down-regulates	binding			9606									21798082	t		gcesareni	Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b).	SIGNOR-175520	0.264
RBPJ	protein	Q06330	UNIPROT	MAML3	protein	Q96JK9	UNIPROT	up-regulates	binding			9606									21873209	t		gcesareni	When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects.	SIGNOR-176200	0.872
GSK3A	protein	P49840	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser49	CHRLPPGsLSSTPLS	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159381	0.2
GEMIN7	protein	Q9H840	UNIPROT	SMN complex	complex	SIGNOR-C158	SIGNOR	form complex	binding												12065586	t		lperfetto	SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry.	SIGNOR-253121	0.812
PTPN12	protein	Q05209	UNIPROT	WAS	protein	P42768	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000782								14707117	t		gcesareni	Furthermore, we demonstrate that pstpip serves as a scaffold protein between ptp-pest and wasp and allows ptp-pest to dephosphorylate wasp. This finding suggests a possible mechanism for ptp-pest to directly modulate actin remodeling through the pstpip-wasp interaction.	SIGNOR-121136	0.456
TSC	complex	SIGNOR-C101	SIGNOR	RHEB	protein	Q15382	UNIPROT	down-regulates activity	gtpase-activating protein			9606									15340059	t		lperfetto	Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb.	SIGNOR-235895	0.914
SRC	protein	P12931	UNIPROT	ANXA1	protein	P04083	UNIPROT	up-regulates	phosphorylation	Tyr21	IENEEQEyVQTVKSS	9606									24103589	t		lperfetto	The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf	SIGNOR-202796	0.398
SMN complex	complex	SIGNOR-C158	SIGNOR	Spliceosomal_snRNP_assembly	phenotype	SIGNOR-PH79	SIGNOR	up-regulates				9606									9323129	f		lperfetto	These findings suggest a role for SMN and SIP1 in spliceosomal snRNP biogenesis and function and provide a likely molecular mechanism for the cause of SMA	SIGNOR-253123	0.7
CUL5	protein	Q93034	UNIPROT	DAB1	protein	O75553	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0000298								24210661	t		miannu	SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1.	SIGNOR-272140	0.332
LCK	protein	P06239	UNIPROT	ZAP70	protein	P43403	UNIPROT	unknown	phosphorylation	Tyr178	EEAERKLySGAQTDG	9606	BTO:0000661								7961936	t			We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck.	SIGNOR-251392	0.601
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	CASP6	protein	P55212	UNIPROT	up-regulates	cleavage			9606									9922454	t		amattioni	Caspase-3 is required for the activation of caspases 6	SIGNOR-256467	0.601
pimozide	chemical	CHEBI:8212	ChEBI	STAT5A	protein	P42229	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001545								23264850	t		miannu	We have identified the psychotropic drug pimozide as an effective inhibitor of STAT5 function. Pimozide inhibits the tyrosine phosphorylation of STAT5, leading to the death of AML cells through the induction of apoptosis.	SIGNOR-260125	0.8
PAX7	protein	P23759	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18854138	f		lperfetto	Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts.	SIGNOR-181624	0.618
TRPC6	protein	Q9Y210	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									12032305	t			Members of the transient receptor potential channel (TRPC) family have been characterized as molecular substrates mediating receptor-activated cation influx	SIGNOR-253339	0.8
SOX2/POU5F1	complex	SIGNOR-C73	SIGNOR	SOX2	protein	P48431	UNIPROT	up-regulates quantity by expression	transcriptional regulation												31583686	t		SimoneGraziosi	Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6).	SIGNOR-269253	0.834
INSR	protein	P06213	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates activity	phosphorylation	Tyr612	TLHTDDGyMPMSPGV	10116									11416002	t		lperfetto	All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells	SIGNOR-235971	0.911
SYVN1	protein	Q86TM6	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									29731393	t		miannu	NRF2 is negatively regulated by three E3 ubiquitin ligase complexes: the KEAP1-CUL3-RBX1 complex, the β-TrCP-SKP1-CUL1-RBX1 complex, and HRD1. 	SIGNOR-267360	0.2
CSNK2A1	protein	P68400	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates	phosphorylation	Thr236	VEKFKDNtIPDKVKK	9606									15064744	t		lperfetto	Inhibition of protein kinase ck2 enzyme activity in vivo resulted in an enhanced nuclear localization of cdc25c. Thus, phosphorylation of cdc25c at threonine 236 is an important signal for the retention of cdc25c in the cytoplasm	SIGNOR-123713	0.307
AKT1	protein	P31749	UNIPROT	P300/PCAF	complex	SIGNOR-C7	SIGNOR	up-regulates	phosphorylation			9606		BTO:0000887							17964260	t		lperfetto	Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300.	SIGNOR-217670	0.597
apraclonidine	chemical	CHEBI:2788	ChEBI	ADRA2C	protein	P18825	UNIPROT	up-regulates activity	chemical activation			-1									8784451	t		miannu	 we describe full details of our studies with 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline (AGN 193080, 3), a potent, selective α2 adrenoceptor agonist that does not cross the blood−brain barrier.	SIGNOR-258498	0.8
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide	chemical	CHEBI:125619	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207779	0.8
CH5132799	chemical	CID:49784945	PUBCHEM	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190943	0.8
MAOB	protein	P27338	UNIPROT	(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000142							20493079	t		Luana	The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied.	SIGNOR-269747	0.8
LRRK2	protein	Q5S007	UNIPROT	LRRK2	protein	Q5S007	UNIPROT	up-regulates	phosphorylation	Thr2035	GIKTSEGtPGFRAPE	9606	BTO:0000938								20595391	t		lperfetto	Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2.	SIGNOR-166474	0.2
WNK1	protein	Q9H4A3	UNIPROT	SYT2	protein	Q8N9I0	UNIPROT	up-regulates activity	phosphorylation	Thr199	ETKVHRKtLNPAFNE	9606	BTO:0000007								15350218	t		miannu	Endogenous WNK1 and Syt2 coimmunoprecipitate and colocalize on a subset of secretory granules in INS-1 cells. Phosphorylation by WNK1 increases the amount of Ca2+ required for Syt2 binding to phospholipid vesicles; mutation of threonine 202, a WNK1 phosphorylation site, partially prevents this change. These findings suggest that phosphorylation of Syts by WNK1 can regulate Ca2+ sensing and the subsequent Ca2+-dependent interactions mediated by Syt C2 domains. . In contrast, WNK1 phosphorylated Syt2 on T202 and T386 within the C2 domains (Figure 6B). 	SIGNOR-263049	0.623
NEUROG3	protein	Q9Y4Z2	UNIPROT	NEUROD1	protein	Q13562	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19028584	f		miannu	Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated.	SIGNOR-254630	0.448
PRKDC	protein	P78527	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0001949								18439899	t		gcesareni	DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform	SIGNOR-252447	0.745
LEF1	protein	Q9UJU2	UNIPROT	CEBPA	protein	P49715	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19620402	f		miannu	We have identified LEF-1 as a decisive transcription factor in granulopoiesis controlling proliferation and granulocytic differentiation by direct activation of its target gene, C/EBPalpha.	SIGNOR-254551	0.356
MAPK1	protein	P28482	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser245	NQSMDTGsPAELSPT	9606		BTO:0000763							12193595	t		gcesareni	We show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity.	SIGNOR-91714	0.711
DUSP1	protein	P28562	UNIPROT	MAPK9	protein	P45984	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000782								8626452	t		fstefani	We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. the dual specific phosphatases pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively.	SIGNOR-40879	0.671
MAPK1	protein	P28482	UNIPROT	MAPKAPK5	protein	Q8IW41	UNIPROT	up-regulates	phosphorylation	Thr182	IDQGDLMtPQFTPYY	9606	BTO:0000567								9628874	t		gcesareni	Activated following phosphorylation at thr-182 by p38-alpha/mapk14, p38-beta/mapk11, erk2/mapk1, erk3/mapk6, and erk4/mapk4.	SIGNOR-58127	0.492
p38	proteinfamily	SIGNOR-PF16	SIGNOR	CDC25C	protein	P30307	UNIPROT	down-regulates activity	phosphorylation	Ser216	SGLYRSPsMPENLNR	9606									11333986	t		lperfetto	P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteins phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3	SIGNOR-107420	0.2
PIP3	smallmolecule	CHEBI:16618	ChEBI	WDR45B	protein	Q5MNZ6	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0001938								28561066	t		miannu	All WIPI members fold into seven-bladed β-propeller proteins that bind PtdIns3P and co-localize at nascent autophagosomes.	SIGNOR-268476	0.8
FGF18	protein	O76093	UNIPROT	FGFR2	protein	P21802	UNIPROT	up-regulates	binding			9606									8663044	t		tpavlidou	Fgfs bind and activate high-affinity receptor tyrosine kinases. The cloning of fgf receptors (fgfrs) has identified four distinct genes	SIGNOR-42368	0.719
MAPK1	protein	P28482	UNIPROT	ETV6	protein	P41212	UNIPROT	down-regulates	phosphorylation	Ser213	DNMIRRLsPAERAQG	10090	BTO:0000944								15060146	t		miannu	Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation.	SIGNOR-260086	0.323
GSK3A	protein	P49840	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	phosphorylation	Ser1490	AILNPPPsPATERSH	9606									35487243	t		miannu	Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493	SIGNOR-275398	0.616
N-(1,3-benzodioxol-5-ylmethyl)-4-(4-benzofuro[3,2-d]pyrimidinyl)-1-piperazinecarbothioamide	chemical	CHEBI:91389	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189525	0.8
ESR1	protein	P03372	UNIPROT	CYP19A1	protein	P11511	UNIPROT	down-regulates quantity by repression	transcriptional regulation												11973645	t		lperfetto	By binding to S1, ERalpha down-regulates the aromatase promoter activity.	SIGNOR-271683	0.534
vitamin K epoxide	smallmolecule	CHEBI:28371	ChEBI	VKORC1L1	protein	Q8N0U8	UNIPROT	up-regulates activity	chemical activation			9606									31226734	t		lperfetto	This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR)	SIGNOR-265916	0.8
CDK5	protein	Q00535	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates	phosphorylation	Ser129	ICPSLPYsPVSSPQS	9606									22778263	t		lperfetto	Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity.	SIGNOR-198111	0.2
4-(4-fluoronaphthalen-1-yl)-6-isopropylpyrimidin-2-amine	chemical	CID:196968	PUBCHEM	HTR2B	protein	P41595	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206658	0.8
CDK5RAP2	protein	Q96SN8	UNIPROT	MAD2L1	protein	Q13257	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19282672	t		Giulio	These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter	SIGNOR-260313	0.313
ABL1	protein	P00519	UNIPROT	BTK	protein	Q06187	UNIPROT	unknown	phosphorylation	Tyr223	LKKVVALyDYMPMNA	9606	BTO:0000567								12445832	t		gcesareni	In this report we describe for the first time that c-Abl and Btk physically interact and that c-Abl can phosphorylate tyrosine 223 in the SH3 domain of Btk	SIGNOR-245278	0.342
ATF3	protein	P18847	UNIPROT	PCLAF	protein	Q15004	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23593430	f		gcesareni	P15(paf) is a direct transcriptional target of atf3	SIGNOR-201850	0.2
MAPK14	protein	Q16539	UNIPROT	MAPKAPK2	protein	P49137	UNIPROT	up-regulates activity	phosphorylation	Ser272	SNHGLAIsPGMKTRI	9606	BTO:0000130								14499342	t		lperfetto	Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils.	SIGNOR-118036	0.758
PPARGC1A	protein	Q9UBK2	UNIPROT	ESRRA	protein	P11474	UNIPROT	up-regulates activity				10090									18074631	f		lperfetto	The PGC1 transcriptional coactivators are major regulators of several crucial aspects of energy metabolism. PGC1alpha controls many aspects of oxidative metabolism, including mitochondrial biogenesis and respiration through the coactivation of many nuclear receptors, and factors outside the nuclear receptor family. ERRalpha, NRF1 and NRF2 are key targets of the PGC1s in mitochondrial biogenesis.	SIGNOR-253392	0.921
SIRT1	protein	Q96EB6	UNIPROT	2''-O-acetyl-ADP-D-ribose(2-)	smallmolecule	CHEBI:83767	ChEBI	up-regulates quantity	chemical modification			9606									18662546	t		miannu	The SIRT1 catalytic reaction involves the breakdown of one NAD+ molecule for each deacetylated acetyl lysine and the generation of nicotinamide and O-acetyl-ADP-ribose. 	SIGNOR-267963	0.8
SMAD3	protein	P84022	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									14993291	f		gcesareni	Smad3 is required for both tgf-beta-induced repression of c-myc and subsequent growth arrest in keratinocytes	SIGNOR-123087	0.673
PKN1	protein	Q16512	UNIPROT	PGAM1	protein	P18669	UNIPROT	down-regulates	phosphorylation	Ser23	WNLENRFsGWYDADL	9606	BTO:0000130								12189148	t		llicata	Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity.	SIGNOR-91606	0.257
PER2	protein	O15055	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606									22260161	f		apalma	We have previously shown that PER2 is a downstream CCAAT-enhancer-binding protein (C/EBP)-target gene, and its disruption might be involved in the initiation and progression of acute myelogenous leukemia (AML)	SIGNOR-256371	0.7
KDM5B	protein	Q9UGL1	UNIPROT	SOX2	protein	P48431	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000815								31776402	t		lperfetto	Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes.	SIGNOR-273450	0.315
EPHB3	protein	P54753	UNIPROT	EPHB3	protein	P54753	UNIPROT	up-regulates activity	phosphorylation	Tyr614	VYIDPFTyEDPNEAV	-1									9674711	t			Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions. a single amino acid substitution (Y614F) clearly reduces the phosphotyrosine content of HEK2 and abrogates its ability to bind rasGAP, Crk and Fyn indicating that this residue functions as major phosphorylation and multi-docking site. 	SIGNOR-251126	0.2
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	GRB10	protein	Q13322	UNIPROT	up-regulates	binding			9606									15722337	t		miannu	The interaction of phosphorylated grb10 with 14-3-3 may lead to the translocation of grb10 back to the cytosol	SIGNOR-134198	0.2
CEP43	protein	O95684	UNIPROT	MAPRE1	protein	Q15691	UNIPROT	up-regulates	relocalization			9606									16314388	t		miannu	Fop also binds to eb1 and is required for localizing eb1 to the centrosome	SIGNOR-142400	0.2
NGFR	protein	P08138	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									14699954	f		amattioni	Neurotrophin binding to p75ntr has also been shown to induce apoptosis	SIGNOR-256655	0.7
TLR9	protein	Q9NR96	UNIPROT	TICAM1	protein	Q8IUC6	UNIPROT	up-regulates activity	binding			10090									22664090	t		scontino	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266749	0.451
PGLS	protein	O95336	UNIPROT	6-O-phosphono-D-glucono-1,5-lactone	smallmolecule	CHEBI:16938	ChEBI	down-regulates quantity	chemical modification			9606									31586547	t		miannu	The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG).	SIGNOR-267057	0.8
PAX3	protein	P23760	UNIPROT	MEOX2	protein	P50222	UNIPROT	up-regulates activity	binding			-1									11423130	t		miannu	We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family.	SIGNOR-222238	0.413
MAML1	protein	Q92585	UNIPROT	CCNT1	protein	O60563	UNIPROT	up-regulates	relocalization			9606									15546612	t		gcesareni	Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells.	SIGNOR-130712	0.2
ULK1/Atg13/Fip200	complex	SIGNOR-C100	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	down-regulates activity	phosphorylation			9606									23863160	t		lperfetto	Raptor phosphorylation by ULK1 was sufficient to completely block Rheb-induced mTORC1 activity in cells as well as mTORC1 kinase activity invitro	SIGNOR-209910	0.561
levomilnacipran	chemical	CHEBI:136040	ChEBI	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								18468895	t		Luana	Studies on a series of milnacipran analogs containing a heteroaromatic group as potent norepinephrine and serotonin transporter inhibitors	SIGNOR-257946	0.8
HOXC13	protein	P31276	UNIPROT	FOXN1	protein	O15353	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21191399	f		miannu	Hoxc13-dependent activation of foxn1 is part of a regulatory cascade controlling the expression of terminal differentiation markers.	SIGNOR-170850	0.543
CEBPA	protein	P49715	UNIPROT	STAR	protein	P49675	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003697								18583320	t	 	 	Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells.	SIGNOR-254043	0.342
TYK2	protein	P29597	UNIPROT	TYK2	protein	P29597	UNIPROT	up-regulates activity	phosphorylation	Tyr1055	VPEGHEYyRVREDGD	9606	BTO:0000452								8702790	t		lperfetto	These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055The K930R mutant, bearing a mutation in the ATP binding site, is catalytically inactive (Fig. 3B, lanes 5 and 6). This protein is not basally phosphorylated, while the wt and the Y1054F/Y1055F proteins are (Fig. 3A), suggesting that autophosphorylation is responsible for the basal level of phosphorylation.	SIGNOR-43092	0.2
ANKRD26	protein	Q9UPS8	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				10090									21669876	f		lperfetto	Ankrd26 gene disruption enhances adipogenesis of mouse embryonic fibroblasts.	SIGNOR-266071	0.7
MAPK8	protein	P45983	UNIPROT	APLP2	protein	Q06481	UNIPROT	up-regulates	phosphorylation	Thr736	VEVDPMLtPEERHLN	9606									14970211	t		lperfetto	Phosphorylation at the thr(668) residue of app (with respect to the numbering conversion for the app 695 isoform) and the thr(736) residue of aplp2 (with respect to the numbering conversion for the aplp2 763 isoform) in their cytoplasmic domains acts as a molecular switch for their protein-protein interaction and is implicated in neural function(s) and/or alzheimer's disease pathogenesis. Here we demonstrate that both app and aplp2 can be phosphorylated by jnk at the thr(668) and thr(736) residues, respectively, in response to cellular stress.	SIGNOR-122196	0.37
NR2C2	protein	P49116	UNIPROT	LHCGR	protein	P22888	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534	BTO:0000318								10644740	t		Luana	Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription.	SIGNOR-266217	0.2
SYK	protein	P43405	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates activity	phosphorylation	Tyr783	EGRNPGFyVEANPMP	9606									8657103	t		lperfetto	Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771.	SIGNOR-246576	0.764
RET	protein	P07949	UNIPROT	DOK4	protein	Q8TEW6	UNIPROT	up-regulates	binding			9606	BTO:0000938								11470823	t		gcesareni	We identified two new family members, dok-4 and dok-5, that can directly associate with y1062 of c-ret dok-4 and dok-5 enhance c-ret-dependent activation of mitogen-activated protein kinase	SIGNOR-109513	0.557
F2RL3	protein	Q96RI0	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257245	0.2
tri-mu-sulfido-mu3-sulfido-triiron	chemical	CHEBI:21137	ChEBI	SDH	complex	SIGNOR-C400	SIGNOR	form complex	binding			9606									16143825	t		miannu	Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively.	SIGNOR-267734	0.8
KIF7	protein	Q2M1P5	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates quantity by stabilization	binding			10090									19549984	t		lperfetto	Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling.	SIGNOR-209608	0.607
SMC3	protein	Q9UQE7	UNIPROT	MXD3	protein	Q9BW11	UNIPROT	down-regulates activity	binding			9534	BTO:0000318								9528857	t	2	miannu	We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions.	SIGNOR-241281	0.3
GNG2	protein	P59768	UNIPROT	GNB1	protein	P62873	UNIPROT	up-regulates activity	binding												10696571	t			GNG2 dissociates from the activated receptor, bound with GNB1 as stable dimer.	SIGNOR-251106	0.938
SP2	protein	Q02086	UNIPROT	IRF1	protein	P10914	UNIPROT	up-regulates activity	binding			9606	BTO:0000552								19482358	t		miannu	Sp2 could be also able to interact with IRF-1 and this interaction is also observed on DNA indicating that by this way Sp2 is able to modulate IRF-1 transcriptional activity.	SIGNOR-226478	0.345
regorafenib	chemical	CHEBI:68647	ChEBI	RTKs	proteinfamily	SIGNOR-PF38	SIGNOR	down-regulates activity	chemical inhibition			9606									24756792	t		miannu	In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically.	SIGNOR-259453	0.8
canagliflozin	chemical	CHEBI:73274	ChEBI	SLC5A2	protein	P31639	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190850	0.8
IL4R	protein	P24394	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000801								18852293	t		lperfetto	Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6.	SIGNOR-249530	0.608
SYK	protein	P43405	UNIPROT	SLC4A1	protein	P02730	UNIPROT	up-regulates	phosphorylation	Tyr8	MEELQDDyEDMMEEN	9606									10942405	t		llicata	Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites.	SIGNOR-80792	0.462
AKT1	protein	P31749	UNIPROT	ATXN1	protein	P54253	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser775	ATRKRRWsAPESRKL	9606	BTO:0000567								12757707	t			Interaction of Ataxin-1 and 14-3-3 Requires Akt Phosphorylation at S776. 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation.	SIGNOR-252561	0.42
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	MTOR	protein	P42345	UNIPROT	down-regulates activity	phosphorylation	Ser2448	RSRTRTDsYSAGQSV	9606									15905173	t		lperfetto	Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain	SIGNOR-137251	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	PDHA1	protein	P08559	UNIPROT	up-regulates activity	phosphorylation	Ser314	IQEVRSKsDPIMLLK	-1									33022274	t		miannu	In vitro kinase assay revealed that PDHA could be readily phosphorylated by active AMPK complex in a dose-dependent manner (Figure 6C). 	SIGNOR-276836	0.257
GMPS	protein	P49915	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	binding			9606									24462112	t		miannu	In response to genotoxic stress or nucleotide deprivation, gmps becomes nuclear and facilitates p53 stabilization by promoting its transfer from mdm2 to a gmps-usp7 deubiquitylation complex.	SIGNOR-204409	0.387
EEF2	protein	P13639	UNIPROT	Translational_regulation	phenotype	SIGNOR-PH202	SIGNOR	up-regulates				9606									30082469	f		gianni	… several key regulators of nervous system translation, including eukaryotic initiation factor 2α (eIF2α), the mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1), and the eukaryotic elongation factor 2 (eEF2). These pathways regulate the overall rate of protein synthesis in neurons and have selective effects on the translation of specific messenger RNAs (mRNAs	SIGNOR-268628	0.7
CYC-116	chemical	CID:6420138	PUBCHEM	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191221	0.8
AP-3/clathrin vescicle	complex	SIGNOR-C250	SIGNOR	Early Endosome	complex	SIGNOR-C246	SIGNOR	up-regulates activity	relocalization			9606									23144738	t		lperfetto	Rabip4' colocalized with AP-3 on a tubular subdomain of early endosomes and the extent of colocalization was increased by a dominant negative rab4 mutant. Knock-down of AP-3 had an ever more dramatic effect and caused accumulation of lysosomes in protrusions at the plasma membrane. The most peripheral lysosomes were localized beyond microtubules, within the cortical actin network. Our results uncover a novel function for AP-3 and rabip4' in regulating lysosome positioning through an interorganellar pathway.	SIGNOR-260712	0.2
HPX	protein	P02790	UNIPROT	HBB	protein	P68871	UNIPROT	down-regulates activity				9606									20617898	f	Regulation	miannu	The endogenous molecule hemoglobin and its derivative heme are often released into tissue compartments where there is infection in the presence of degrading blood. We found that hemoglobin synergizes with multiple TLR agonists to induce high levels of tumor necrosis factor and interleukin-6 from macrophages and that this synergy is independent of TLR4 and MyD88. In contrast, heme synergized with some but not all TLR agonists studied. Furthermore, the synergy of both hemoglobin and heme with lipopolysaccharide was suppressed by hemopexin, a plasma heme-binding protein. 	SIGNOR-251811	0.484
ITLN1	protein	Q8WWA0	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity				9606									35186726	f			ITLN1 increases Akt phosphorylation in adipocytes, osteoblasts, and mesenchymal cells. |n mesenchymal stem cells, ITLN1 also leads to Akt-mediated proliferation, resistance to oxidative stress, and secretion of proangiogenic factors	SIGNOR-272499	0.32
DIABLO	protein	Q9NR28	UNIPROT	CASP9	protein	P55211	UNIPROT	up-regulates				9606									10929711	f		gcesareni	Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity.	SIGNOR-80215	0.726
PKI-402	chemical	CID:44187953	PUBCHEM	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206253	0.8
PDHA2	protein	P29803	UNIPROT	PDH	complex	SIGNOR-C402	SIGNOR	form complex	binding			9606									20160912	t		miannu	The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently.	SIGNOR-267832	0.656
JUN	protein	P05412	UNIPROT	MMP13	protein	P45452	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20338993	f		miannu	 The activated c-Jun protein has been proven to activate binding to the MMP-13 promoter and also upregulate the amount of MMP-13.	SIGNOR-254539	0.404
SNAI2	protein	O43623	UNIPROT	HPGD	protein	P15428	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004078								17575121	f		miannu	 the Slug protein, but not ZEB1, binds to the PGDH promoter and represses transcription. 	SIGNOR-255172	0.267
EGFR	protein	P00533	UNIPROT	VAV2	protein	P52735	UNIPROT	up-regulates	phosphorylation	Tyr159	HDLGEDIyDCVPCED	9606									12454019	t		miannu	To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor.	SIGNOR-95976	0.61
RNF4	protein	P78317	UNIPROT	KDM5C	protein	P41229	UNIPROT	up-regulates activity	sumoylation			9606									33859667	t		SaraGualdi	Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015).	SIGNOR-271576	0.2
MYD88	protein	Q99836	UNIPROT	DHX36	protein	Q9H2U1	UNIPROT	up-regulates activity	binding			9606	BTO:0002042								20696886	t		miannu	 We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing.	SIGNOR-260956	0.504
ACTB	protein	P60709	UNIPROT	Early Endosome	complex	SIGNOR-C246	SIGNOR	up-regulates				9606	BTO:0000007								19121306	f		lperfetto	However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin.	SIGNOR-260610	0.311
MTHFD1	protein	P11586	UNIPROT	(6R)-5,10-methenyltetrahydrofolate	smallmolecule	CHEBI:57455	ChEBI	up-regulates quantity	chemical modification			-1									18767138	t		lperfetto	Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate	SIGNOR-268249	0.8
SMARCC2	protein	Q8TAQ2	UNIPROT	Muscle cell-specific SWI/SNF ARID1B variant	complex	SIGNOR-C482	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270708	0.829
MSTN	protein	O14793	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity				9606									19357233	f		miannu	In the current study, it was demonstrated that myostatin inhibits activation of Akt, in both myoblasts and myotubes.	SIGNOR-255339	0.506
PRKCZ	protein	Q05513	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	phosphorylation	Ser323	MVGGKPGsFRVRASS	9606									15069075	t		gcesareni	Thus, pkc-zeta might promote feedback ir/irs-1 complex formation and irs-1 tyrosine phosphorylation through phosphorylation of ser318.	SIGNOR-123738	0.716
SP1	protein	P08047	UNIPROT	CYP27A1	protein	Q02318	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11867220	f		miannu	 Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells.	SIGNOR-255199	0.325
N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide	chemical	CHEBI:91409	ChEBI	AXL	protein	P30530	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190401	0.8
2-cyclopentyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid	chemical	CHEBI:95066	ChEBI	SGK2	protein	Q9HBY8	UNIPROT	down-regulates activity	chemical inhibition			-1									18794135	t		lperfetto	GSK650394 quantitatively inhibits the activity of SGK1 and SGK2 in a scintillation proximity assay.	SIGNOR-262018	0.8
2-[(3-bromo-5-tert-butyl-4-hydroxyphenyl)methylidene]propanedinitrile	chemical	CHEBI:93757	ChEBI	IGF1R	protein	P08069	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189368	0.8
U0126	chemical	CHEBI:90693	ChEBI	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates	chemical inhibition			9606									9873633	t		lperfetto	The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2.	SIGNOR-244958	0.8
CAPN2	protein	P17655	UNIPROT	GSK3A	protein	P49840	UNIPROT	up-regulates activity	cleavage			9606									25969760	t		lperfetto	Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase	SIGNOR-251612	0.2
PRKCE	protein	Q02156	UNIPROT	OCLN	protein	Q16625	UNIPROT	up-regulates	phosphorylation	Thr438	LYKRNFDtGLQEYKS	9606									21545357	t		lperfetto	Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions.	SIGNOR-173643	0.2
L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	THRA	protein	P10827	UNIPROT	up-regulates activity	chemical activation			10116	BTO:0000759								2158622	t		miannu	We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 	SIGNOR-258382	0.8
CCL1	protein	P22362	UNIPROT	CCR8	protein	P51685	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0000785								12645948	t		gcesareni	Ccl1 activates the mapk pathway in ccr8-transfected cho cells.	SIGNOR-99401	0.716
SENP1	protein	Q9P0U3	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates	desumoylation			9606									17981124	t		miannu	Sumo-specific protease 1 is essential for stabilization of hif1alpha during hypoxia / our results support a model in which sumoylated hif1_ is unstable but can be stabilized when sumo is removed by senp1	SIGNOR-158891	0.331
RHAG	protein	Q02094	UNIPROT	Ankyrin complex	complex	SIGNOR-C383	SIGNOR	form complex	binding			9606	BTO:0000424								22465511	t		lperfetto	The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) 	SIGNOR-266020	0.413
LCK	protein	P06239	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Tyr537	CKNVVPLyDLLLEML	9606	BTO:0000150;BTO:0000567								9500442	t		gcesareni	On the basis of these data and other reports describing the structure and activity of y537 mutations, as well as knowledge of the three-dimensional structure of the her ligand binding domain, we propose an alternate model wherein y537f mutation favors an open pocket conformation, affecting the estrogen binding kinetics and stability of the hormone-bound, transcriptionally active closed pocket conformation.	SIGNOR-55853	0.391
SIRT4	protein	Q9Y6E7	UNIPROT	GLUD1	protein	P00367	UNIPROT	down-regulates activity	glycosylation			9606									16959573	t		miannu	We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. 	SIGNOR-267828	0.604
PEX14	protein	O75381	UNIPROT	PEX5	protein	P50542	UNIPROT	up-regulates activity	binding			-1									15798189	t		miannu	The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7.	SIGNOR-253027	0.931
SMURF2	protein	Q9HAU4	UNIPROT	SMAD5	protein	Q99717	UNIPROT	down-regulates	ubiquitination			9606									22298955	t		gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-193378	0.725
NR3C1	protein	P04150	UNIPROT	KAT2B	protein	Q92831	UNIPROT	up-regulates activity	relocalization												32917954	t		SimoneGraziosi	NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase 	SIGNOR-269233	0.529
TBX2	protein	Q13207	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									24470334	f			TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells	SIGNOR-251562	0.7
VAV2	protein	P52735	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									10982832	t		miannu	Vav2 activates rac1 / vav2 is an exchange factor for rho family gtpases.	SIGNOR-81645	0.752
RET	protein	P07949	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates	phosphorylation			9606									16153436	t		lperfetto	We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).	SIGNOR-244643	0.443
MLF1	protein	P58340	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates				9606									15861129	f		miannu	Mlf1 induces p53-dependent cell cycle arrest	SIGNOR-135943	0.294
PRKCA	protein	P17252	UNIPROT	RHO	protein	P08100	UNIPROT	unknown	phosphorylation	Ser343	TVSKTETsQVAPA	-1									11910029	t		lperfetto	Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343.	SIGNOR-249148	0.451
MAPK1	protein	P28482	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation			-1									8929531	t		lperfetto	The rapid phosphorylation of bad following il-3 connects a proximal survival signal with the bcl-2 family, modulating this checkpoint for apoptosis.phosphorylatedBAD is bound to 14-3-3 within the cytosol, while only nonphosphorylated BAD is heterodimerized with membrane-bound BCL-XL.	SIGNOR-44858	0.438
PDK2	protein	Q15119	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	phosphorylation	Ser293	TYRYHGHsMSDPGVS	-1									11485553	t		lperfetto	Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.	SIGNOR-109563	0.667
MAP4K2	protein	Q12851	UNIPROT	PSMD2	protein	Q13200	UNIPROT	up-regulates activity	phosphorylation	Ser361	ENNRFGGsGSQVDSA	-1									31843888	t	done	miannu	Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B). 	SIGNOR-273900	0.2
GSK3B	protein	P49841	UNIPROT	DPYSL3	protein	Q14195	UNIPROT	up-regulates activity	phosphorylation	Thr509	PVFDLTTtPKGGTPA	10116									16611631	t		lperfetto	Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-146011	0.452
VARS1	protein	P26640	UNIPROT	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									30755602	t		miannu	Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 	SIGNOR-270527	0.8
IGF2	protein	P01344	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates activity	binding			9606									22810696	t		lperfetto	These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients.	SIGNOR-251495	0.816
RABEP1	protein	Q15276	UNIPROT	RABGEF1	protein	Q9UJ41	UNIPROT	up-regulates	binding			9606									11452015	t		miannu	We show that rabaptin-5 increases the exchange activity of rabex-5 on rab5.	SIGNOR-109395	0.941
FOXO3	protein	O43524	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000007								14976264	f		lperfetto	Sirt1 inhibited foxo3's ability to induce cell death.	SIGNOR-217887	0.7
MAPK9	protein	P45984	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Thr69	SVIVADQtPTPTRFL	9606									7737130	t		gcesareni	Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro.	SIGNOR-32429	0.686
IFNG	protein	P01579	UNIPROT	RFX5	protein	P48382	UNIPROT	up-regulates activity				9606	BTO:0000567								9177217	f	2	miannu	Transcriptional Activation by the RFX5 Activation Domain Is IFN-_-Inducible in HeLa Cells.	SIGNOR-241368	0.287
BCL2L1	protein	Q07817	UNIPROT	BAK1	protein	Q16611	UNIPROT	down-regulates	binding			9606									17289999	t		gcesareni	Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax	SIGNOR-152983	0.735
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	GRK7	protein	Q8WTQ7	UNIPROT	down-regulates activity	phosphorylation	Ser23	YLQARKPsDCDSKEL	-1									15946941	t	done	miannu	PKA Phosphorylates GRK7 on Ser23 and Ser36. Phosphorylation by PKA inhibits GRK7 activity	SIGNOR-274081	0.2
GATA1	protein	P15976	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									27858941	f		miannu	DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene	SIGNOR-254771	0.406
LRIG3	protein	Q6UXM1	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates				9606									23723069	f		miannu	Lrig3 opposes lrig1 negative regulatory activity and stabilizes erbb receptors.	SIGNOR-202183	0.284
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	BAD	protein	Q92934	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000938								15231831	t		lperfetto	Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant.	SIGNOR-256455	0.517
4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone	chemical	CHEBI:91395	ChEBI	FGFR3	protein	P22607	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258105	0.8
MAPK14	protein	Q16539	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606	BTO:0003316								10781582	t		lperfetto	Serine 15 phosphorylation of p53 leads to a stabilization of p53 by reducing its interaction with murine double minute 2, a negative regulatory partner[...]These results strongly suggest that both ERKs and p38 kinase have a direct role in UVB-induced phosphorylation of p53 at serine 15 in vivo.	SIGNOR-226614	0.765
BRSK1	protein	Q8TDC3	UNIPROT	WEE1	protein	P30291	UNIPROT	unknown	phosphorylation	Ser642	KKMNRSVsLTIY	-1									15150265	t		llicata	HsSAD1 protein produced in Sf9 cells phosphorylated the GST-fused human wild-type Wee1A fragment but not its S642A mutant produced inEscherichia coli (Fig. 2). The kinase-dead hsSAD1 mutant (K59A) failed to phosphorylate the wild-type Wee1A fragment.	SIGNOR-250601	0.45
6alpha-methylprednisolone	chemical	CHEBI:6888	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									6749443	t	bronchial ashma	gcesareni		SIGNOR-251696	0.8
PRKCA	protein	P17252	UNIPROT	NOXO1	protein	Q8NFA2	UNIPROT	up-regulates	phosphorylation	Thr346	AIQSRCCtVTRRALE	9606									23957209	t		llicata	Phosphorylation of thr341 allows noxo1 to sufficiently interact with noxa1, an interaction that participates in nox1 activation.	SIGNOR-202482	0.2
SRC_kinase_family	proteinfamily	SIGNOR-PF32	SIGNOR	KLF16	protein	Q9BXK1	UNIPROT	up-regulates activity	phosphorylation	Tyr10	AAVACVDyFAADVLM										22203677	t		lperfetto	Phosphorylation of KLF16 was confirmed by in vivo (32)P incorporation and controlled by a Y10F site-directed mutant. Inhibition of Src-type tyrosine kinase signaling as well as the nonphosphorylatable Y10F mutation disrupted KLF16-mediated gene silencing, demonstrating that its function is regulatable rather than constitutive.	SIGNOR-275586	0.2
Av/b6 integrin	complex	SIGNOR-C179	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269028	0.7
CSNK2A1	protein	P68400	UNIPROT	IGF2R	protein	P11717	UNIPROT	unknown	phosphorylation	Ser2484	LVSFHDDsDEDLLHI	9606									8318012	t		lperfetto	The two sites phosphorylated by ck ii in vivo and in vitro are ser82 and ser157.	SIGNOR-37835	0.486
TSC2	protein	P49815	UNIPROT	RHEB	protein	Q15382	UNIPROT	down-regulates activity	gtpase-activating protein			9606		BTO:0000142							15340059	t		lperfetto	Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb.	SIGNOR-128432	0.92
SOHLH1	protein	Q5JUK2	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates quantity by expression	transcriptional regulation				BTO:0002181								22328502	t		Luana	Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression.	SIGNOR-266205	0.355
ACVR2A	protein	P27037	UNIPROT	ACVR1B	protein	P36896	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000007								12682303	t		acerquone	In this complex, the actrii??/Iib kinase phosphorylates alk4 within a glycine- and serine-rich region called the gs domain, and this phosphorylation event activates the alk4 kinase	SIGNOR-99995	0.672
FFAR4	protein	Q5NUL3	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256773	0.252
PDE2A	protein	O00408	UNIPROT	PKA	proteinfamily	SIGNOR-PF17	SIGNOR	down-regulates activity	binding												36476859	t		lperfetto	We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice. 	SIGNOR-275731	0.392
MDC1	protein	Q14676	UNIPROT	RNF8	protein	O76064	UNIPROT	up-regulates	relocalization			9606									18678647	t		gcesareni	Rnf8 relocalizes to dna damage sites via a phospho-dependent interaction with mdc1	SIGNOR-179820	0.749
TRIM8	protein	Q9BZR9	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	polyubiquitination	Lys158	ALIHRDLkPPNLLLV										22084099	t	K63	miannu	These results suggest that TRIM8 could mediate K63-linked polyubiquitination of TAK1 at residue K158.These results suggest that TRIM8 is involved in TNFα- and IL-1β–induced NF-κB activation by mediating K63-linked TAK1 polyubiquitination and subsequent activation.	SIGNOR-271890	0.349
ARHGEF5	protein	Q12774	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260533	0.6
MTF1	protein	Q14872	UNIPROT	SOD1	protein	P00441	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15378601	f		miannu	 MRE-binding transcription factor-1 (MTF-1) is a highly conserved heavy metal-induced transcriptional activator. MTF-1 also activates transcription in response to oxidative stress and regulates the expression of several cytoprotective factor genes, including MT, gamma-glutamylcysteine synthetase, and Cu/Zn-superoxide dismutase.	SIGNOR-254601	0.291
1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea	chemical	CHEBI:91327	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207302	0.8
RBX1	protein	P62877	UNIPROT	DCX DET1-COP1	complex	SIGNOR-C24	SIGNOR	form complex	binding			9606									17452440	t		lperfetto	Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes	SIGNOR-154511	0.864
CDK2	protein	P24941	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Thr8	MSSILPFtPPIVKRL	9606									15241418	t		lperfetto	We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity,	SIGNOR-217734	0.733
AMPK	complex	SIGNOR-C15	SIGNOR	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates	phosphorylation	Ser358	WPLSRTRsEPLPPSA	9606									21892142	t		lperfetto	Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs).	SIGNOR-216558	0.281
CDK1	protein	P06493	UNIPROT	PAPOLA	protein	P51003	UNIPROT	up-regulates activity	phosphorylation	Ser545	PTSATKTsPLNSSGS	10090	BTO:0000964								34048556	t		lperfetto	Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity.	SIGNOR-268339	0.261
IL6ST	protein	P40189	UNIPROT	IL6ST	protein	P40189	UNIPROT	up-regulates activity	phosphorylation	Ser661	NVPDPSKsHIAQWSP	-1									8511589	t		lperfetto	The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130.	SIGNOR-238625	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation	Thr24	LPRPRSCtWPLPRPE	-1	BTO:0000318								10377430	t		lperfetto	Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export.	SIGNOR-252347	0.2
ASIP	protein	P42127	UNIPROT	ATRN	protein	O75882	UNIPROT	up-regulates	binding			9606		BTO:0001253							11137996	t		gcesareni	Attractin is a low-affinity receptor for agouti protein, but not agrp, in vitro and in vivo.	SIGNOR-85496	0.401
CHM	protein	P24386	UNIPROT	RABGGTA	protein	Q92696	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								18532927	t		miannu	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. 	SIGNOR-265570	0.76
SLC24A1	protein	O60721	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264400	0.8
MAPK3	protein	P27361	UNIPROT	SP3	protein	Q02447	UNIPROT	up-regulates	phosphorylation	Ser73	CSKIGPPsPGDDEEE	9606									17685427	t		gcesareni	Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73.	SIGNOR-157276	0.304
EFNA2	protein	O43921	UNIPROT	EPHA5	protein	P54756	UNIPROT	up-regulates	binding			9606									10072375	t		tpavlidou	Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8)	SIGNOR-65416	0.812
AMPK	complex	SIGNOR-C15	SIGNOR	EEF2K	protein	O00418	UNIPROT	up-regulates	phosphorylation	Ser398	DSLPSSPsSATPHSQ	9606									22669845	t		lperfetto	In response to genotoxic stress, eef2k was activated by ampk (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eef2k phosphorylated eef2 and induced a temporary ribosomal slowdown at the stage of elongation	SIGNOR-216503	0.403
CSNK2A1	protein	P68400	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	unknown	phosphorylation	Ser659	FHGAEVYsDSEDDVL	9606									19236849	t		llicata	We demonstrate that sirt1 is a substrate for protein kinase ck2 both in vitro and in vivo. Both, deletion construct analyses and serine-to-alanine mutations identified sirt1 ser-659 and ser-661 as major ck2 phosphorylation sites that are phosphorylated in vivo as well.	SIGNOR-184151	0.627
IFNB1	protein	P01574	UNIPROT	IFNAR2	protein	P48551	UNIPROT	up-regulates	binding			9606									11278538	t		gcesareni	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-105934	0.662
FARP2	protein	O94887	UNIPROT	SOD2	protein	P04179	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19276662	f	Regulation of expression	miannu	FIR induced the expression of IAP1, IAP2, XIAP Survivin, MnSOD, TNFalpha, pAKT and IL-1alpha	SIGNOR-251761	0.2
FYN	protein	P06241	UNIPROT	LCP2	protein	Q13094	UNIPROT	down-regulates	phosphorylation			9606									9047237	t		lperfetto	P59fyn_phosphorylated slp-76 at intermediate levels but, significantly, this phosphorylation failed to induce vav?SLP-76 complex formation	SIGNOR-46851	0.745
EIF4E2	protein	O60573	UNIPROT	EIF4E2/GIGYF1 complex	complex	SIGNOR-C256	SIGNOR	form complex	binding			9606									30917308	t		lperfetto	4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression	SIGNOR-261010	0.627
LTBP1	protein	Q14766	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates activity	binding			9606	BTO:0003247								8432736	t		lperfetto	Together these data form strong support for the hypothesis that the LTBP plays an essential role in the activation of latent TGF-b in heterotypic cultures.	SIGNOR-235754	0.623
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	FCN3	protein	O75636	UNIPROT	up-regulates activity	binding			-1									11907111	t		lperfetto	H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates.	SIGNOR-263406	0.7
CSNK2A1	protein	P68400	UNIPROT	ABCF1	protein	Q8NE71	UNIPROT	unknown	phosphorylation	Ser140	AALIQDQsEEEEEEE	9606									17894550	t		gcesareni	We demonstrate that abc50 is a phosphoprotein and is phosphorylated at two sites by ck2. These sites, ser-109 and ser-140, lie in the nterminal part of abc50 but are not required for the binding of abc50 to eif2.	SIGNOR-157937	0.2
ACP1	protein	P24666	UNIPROT	EPHA2	protein	P29317	UNIPROT	down-regulates activity	dephosphorylation	Tyr594	TYVDPHTyEDPNQAV	-1									21538645	t		gcesareni	The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates	SIGNOR-246039	0.646
MTOR	protein	P42345	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser307	TRRSRTEsITATSPA	9606		BTO:0000671							9335553	t		lperfetto	These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling.	SIGNOR-52700	0.758
OLIG1	protein	Q8TAK6	UNIPROT	OLIG2	protein	Q13516	UNIPROT	up-regulates				9606	BTO:0000938								25206819	f		miannu	During central nervous system development, olig1 assists olig2 in formation of the motor neuron progenitor domain (pmn), the area responsible for generation of motor neurons and oligodendrocytes	SIGNOR-205304	0.31
PTPRC	protein	P08575	UNIPROT	JAK1	protein	P23458	UNIPROT	down-regulates activity	dephosphorylation	Tyr1035	IETDKEYyTVKDDRD	10090									11201744	t			CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells 	SIGNOR-248356	0.466
IL6	protein	P05231	UNIPROT	GCH1	protein	P30793	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12859689	f		miannu	CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. 	SIGNOR-252220	0.268
CDK1	protein	P06493	UNIPROT	PPP1R13L	protein	Q8WUF5	UNIPROT	up-regulates activity	phosphorylation	Ser84	EPFGSRGsPRKAATD	9606									30105797	t	done	miannu	Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53. 	SIGNOR-273585	0.52
lysophosphatidic acid	smallmolecule	CHEBI:132742	ChEBI	LPAR1	protein	Q92633	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257528	0.8
PRKD1	protein	Q15139	UNIPROT	PRKD1	protein	Q15139	UNIPROT	unknown	phosphorylation	Ser742	GEKSFRRsVVGTPAY	-1									10867018	t		lperfetto	The last two autophosphorylation sites (Ser(744) and Ser(748)) are located in the activation loop but are only phosphorylated in the isolated PKD-catalytic domain and not in the full-length PKD; they may affect enzyme catalysis but are not involved in the activation of wild-type PKD by phorbol ester. | These results indicate that neither of the activation loop serines is involved in PDBu-induced activation but that they may be involved in catalysis or in maintaining the conformation of the enzyme prot	SIGNOR-249047	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	CREB1	protein	P16220	UNIPROT	down-regulates	phosphorylation	Ser142	RKILNDLsSDAPGVP	9606									9668047	t		gcesareni	Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer.	SIGNOR-59137	0.576
PRKACA	protein	P17612	UNIPROT	KCNJ12	protein	Q14500	UNIPROT	down-regulates activity	phosphorylation	Ser431	QRPYRREsEI	9534									11181181	t		miannu	Phosphorylation of the Kir2.2 C terminus by protein kinase A inhibited the association with SAP97.‚ 	SIGNOR-249998	0.286
enalaprilat (anhydrous)	chemical	CHEBI:4786	ChEBI	ACE	protein	P12821	UNIPROT	down-regulates activity	chemical inhibition			10116									7527095	t		miannu	The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. 	SIGNOR-258429	0.8
GDNF	protein	P39905	UNIPROT	PDPK1	protein	O15530	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252186	0.2
CDON/SPAG9	complex	SIGNOR-C21	SIGNOR	ABL1	protein	P00519	UNIPROT	unknown	binding			9606									19470755	t		lperfetto	We report that abl associates with both cdo and jlp during myoblast differentiation	SIGNOR-217019	0.501
perfluorooctane-1-sulfonic acid	chemical	CHEBI:39421	ChEBI	PPARA	protein	Q07869	UNIPROT	up-regulates activity	chemical activation			10090	BTO:0000011								16731579	t		miannu	Human, mouse, and rat PPARα were activated by PFOA isomers and PFOS.	SIGNOR-268789	0.8
DHRS9	protein	Q9BPW9	UNIPROT	retinal	smallmolecule	CHEBI:15035	ChEBI	up-regulates quantity	chemical modification			9606									21621639	t		lperfetto	Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11	SIGNOR-265117	0.8
BCL2L1	protein	Q07817	UNIPROT	BAK1	protein	Q16611	UNIPROT	down-regulates	binding			9606									9463381	t		amattioni	Bcl-xl bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim)	SIGNOR-55549	0.735
AKT1	protein	P31749	UNIPROT	TP53RK	protein	Q96S44	UNIPROT	up-regulates	phosphorylation	Ser250	RLRGRKRsMVG	9606									17712528	t		gcesareni	Here we show that such an activation of prpk is mediated by another kinase, akt/pkb, which phosphorylates prpk at ser250.	SIGNOR-252503	0.301
ICAM4	protein	Q14773	UNIPROT	Ankyrin complex	complex	SIGNOR-C383	SIGNOR	form complex	binding			9606	BTO:0000424								22465511	t		lperfetto	The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) 	SIGNOR-266019	0.341
PSMA6	protein	P60900	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606									29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263368	0.825
CHUK	protein	O15111	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation	Ser644	GLDFNFDsLISTQNV	9606			SIGNOR-C14						15084260	t		gcesareni	Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation.	SIGNOR-124203	0.553
PTPN6	protein	P29350	UNIPROT	KIT	protein	P10721	UNIPROT	down-regulates	binding			9606									9528781	t		miannu	Shp-1 binds and negatively modulates the c-kit receptor by interaction with tyrosine 569 in the c-kit juxtamembrane domain.	SIGNOR-56104	0.557
ROCK1	protein	Q13464	UNIPROT	MYL9	protein	P24844	UNIPROT	up-regulates activity	phosphorylation	Ser20	KRPQRATsNVFAMFD	-1									21457715	t		Giulio	Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation.	SIGNOR-260307	0.633
RAF1	protein	P04049	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser118	GRELRRMsDEFVDSF	9606									17535812	t		lperfetto	The activation of several major anti-apoptotic signaling pathways correlates with an increase in the phosphorylation of bad on ser-112, ser-136, and ser-155. These phosphorylation events result in bad inactivation through sequestration by 14-3-3 proteins	SIGNOR-155293	0.644
WNT3A	protein	P56704	UNIPROT	FBN1	protein	P35555	UNIPROT	up-regulates quantity by stabilization				10090									17943183	f	Regulation	miannu	Wnt3a markedly stimulated matrix assembly of microfibrillar proteins, including Fbn-1, by cultured fibroblasts, suggesting that Wnts contribute to increased microfibrillar matrices in Tsk skin.Wnt3a stimulates Fbn-1 matrix formation.	SIGNOR-251894	0.277
DUSP6	protein	Q16828	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	down-regulates	dephosphorylation			9606									12840032	t	inferred from 70% of family members	gcesareni	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).	SIGNOR-269926	0.901
STAG	proteinfamily	SIGNOR-PF52	SIGNOR	Cohesin complex	complex	SIGNOR-C304	SIGNOR	form complex	binding												28430577	t		lperfetto	Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin	SIGNOR-263314	0.915
CSNK1A1	protein	P48729	UNIPROT	TP53	protein	P04637	UNIPROT	unknown	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606									20041275	t		llicata	Our data support the concept that non-primed phosphorylation of p53 by ck1 is an isoform-specific reaction preferentially affecting s20	SIGNOR-162648	0.58
SIRT1	protein	Q96EB6	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	deacetylation	Lys14	VKEGWLHkRGEYIKT	10090		BTO:0000562							21775285	t		gcesareni	We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation.	SIGNOR-252456	0.62
TTM complex	complex	SIGNOR-C305	SIGNOR	Cohesin complex	complex	SIGNOR-C304	SIGNOR	up-regulates activity	relocalization												27025256	t		lperfetto	Terb1 and Sun1 are two key proteins linking the meiotic telomeres to the NE. Terb1 participates in telomere fortification by recruiting cohesins to the site	SIGNOR-263307	0.2
CEBPB	protein	P17676	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates													11884404	f		fferrentino	Overexpression and ribozyme-mediated targeting of transcriptional coactivators CREB-binding protein and p300 revealed their indispensable roles in adipocyte differentiation through the regulation of peroxisome proliferator-activated receptor gamma.	SIGNOR-250564	0.7
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	PLA2G4A	protein	P47712	UNIPROT	up-regulates	relocalization			9606									9430701	t		gcesareni	Cytosolic phospholipase a2 (cpla2) is a calcium-sensitive 85-kda enzyme that hydrolyzes arachidonic acid-containing membrane phospholipids to initiate the biosynthesis of eicosanoids and platelet-activating factor, potent inflammatory mediators. The calcium-dependent activation of the enzyme is mediated by an n-terminal c2 domain, which is responsible for calcium-dependent translocation of the enzyme to membranes and that enables the intact enzyme to hydrolyze membrane-resident substrates. cytosolic phospholipase a2 (cpla2) associates with natural membranes in response to physiological increases in ca2+, resulting in the selective hydrolysis of arachidonyl phospholipids.	SIGNOR-54943	0.8
MAPK14	protein	Q16539	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									8702807	f		gcesareni	This result suggests that the p38mapk cascade could be involved in the negative regulation of cyclin d1 transcription and thus antagonize the mitogen-dependent stimulation of cyclin d1 transcription mediated, at least in part, by the p42/p44mapk cascade.	SIGNOR-43096	0.439
CDK7	protein	P50613	UNIPROT	TP53	protein	P04637	UNIPROT	unknown	phosphorylation	Ser33	LPENNVLsPLPSQAM	9606									9372954	t		llicata	We have mapped a major site of phosphorylation by cak to ser-33 of p53 and have demonstrated as well that p53 is phosphorylated at this site in vivo.	SIGNOR-53311	0.47
PIM3	protein	Q86V86	UNIPROT	PSMD2	protein	Q13200	UNIPROT	up-regulates activity	phosphorylation	Ser361	ENNRFGGsGSQVDSA	-1									31843888	t	done	miannu	Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B). 	SIGNOR-273897	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Ser621	PKINRSAsEPSLHRA	9606									9091312	t		lperfetto	Ampk also phosphorylated full-length, kinase-defective raf-1 (k375m) to generate two [32p]phosphopeptides, one co-migrating with synthetic tryptic peptide containing phospho-ser621 and the other with phospho-ser259	SIGNOR-216616	0.302
glyburide	chemical	CHEBI:5441	ChEBI	CFTR	protein	P13569	UNIPROT	down-regulates activity	chemical inhibition			10090	BTO:0000944								1281220	t		miannu	The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 microM, respectively.	SIGNOR-258344	0.8
AKT2	protein	P31751	UNIPROT	STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	down-regulates	phosphorylation			9606	BTO:0000150								20231902	t	inferred from 70% of family members	gcesareni	Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation.	SIGNOR-269937	0.265
ITCH	protein	Q96J02	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates	ubiquitination			9606		BTO:0001253							10940313	t		gcesareni	Itch binds to the n-terminal portion of the notch intracellular domain via its ww domains and promotes ubiquitination of notch through its hect ubiquitin ligase domain.	SIGNOR-254331	0.629
PTPN1	protein	P18031	UNIPROT	TYK2	protein	P29597	UNIPROT	down-regulates activity	dephosphorylation			9606									15780598	t		lperfetto	Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.	SIGNOR-134564	0.631
NEK7	protein	Q8TDX7	UNIPROT	KIF14	protein	Q15058	UNIPROT	up-regulates activity	phosphorylation	Ser56	NDDPLLRsAGKVRDI	9606	BTO:0000565								28630147	t		miannu	Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). 	SIGNOR-266416	0.38
STAT5A	protein	P42229	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0000830								20535135	f		miannu	Specifically, SCF-induced activation of JAK2 in human mast cells has been shown to activate STAT5 and STAT6. STAT5 contributes to mast cell homeostasis, by mediating proliferation, survival, and mediator release. 	SIGNOR-256233	0.7
neuropeptide FF receptor agonist	smallmolecule	CHEBI:141000	ChEBI	NPFFR1	protein	Q9GZQ6	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257549	0.8
DNA polymerase gamma	complex	SIGNOR-C378	SIGNOR	DNA_replication	phenotype	SIGNOR-PH53	SIGNOR	up-regulates				-1									19837034	f		lperfetto	DNA Pol gamma, in contrast to the many nuclear DNA polymerases (DNAPs) that have specialized functions, is solely responsible for DNA replication and repair in mitochondria. 	SIGNOR-265720	0.7
ZBED1	protein	O96006	UNIPROT	RPS6	protein	P62753	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								17220279	t		Luana	HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid.	SIGNOR-266082	0.2
torkinib	chemical	CHEBI:90679	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258269	0.8
GSK3B	protein	P49841	UNIPROT	BLM	protein	P54132	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser175	SFVTPPQsHFVRVST	9606	BTO:0002181								26028025	t		miannu	We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.	SIGNOR-276911	0.262
HCK	protein	P08631	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates activity	phosphorylation	Tyr1253	EGSFESRyQQPFEDF	-1									7682059	t		lperfetto	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249360	0.666
MRAP	protein	Q8TCY5	UNIPROT	MC3R	protein	P41968	UNIPROT	down-regulates activity	binding			10029	BTO:0000246								19329486	t		miannu	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252366	0.487
UHMK1	protein	Q8TAS1	UNIPROT	MBP	protein	P02686	UNIPROT	down-regulates	phosphorylation	Ser299	GRDSRSGsPMARR	9606		BTO:0000142							16401070	t		lperfetto	Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of mbp as the unique site phosphorylated by kis. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1.	SIGNOR-143485	0.2
BTC	protein	P35070	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606		BTO:0000142							22232668	t		gcesareni	For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4	SIGNOR-195347	0.713
U0126.EtOH	chemical	CHEBI:90692	ChEBI	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	lperfetto		SIGNOR-244961	0.8
ABL1	protein	P00519	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation	Tyr1007	VLPQDKEyYKVKEPG	-1									11593427	t		gcesareni	Jak2 peptide substrate studies indicated that the Bcr-Abl and Abl tyrosine kinases specifically phosphorylated Y1007 of Jak2 but only poorly phosphorylated Y1008. Phosphorylation of Y1007 of Jak2 is known to be critical for its tyrosine kinase activation.	SIGNOR-245365	0.42
VAPB	protein	O95292	UNIPROT	VAPB-PTPIP51 complex	complex	SIGNOR-C275	SIGNOR	form complex	binding			10116		BTO:0000142							30841933	t		lperfetto	Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction.	SIGNOR-262118	0.626
IL17B	protein	Q9UHF5	UNIPROT	IL17RB	protein	Q9NRM6	UNIPROT	up-regulates	binding			9606	BTO:0000130	BTO:0000975;BTO:0000142;BTO:0000671							10749887	t		gcesareni	Here we report on the discovery of a novel il-17 homolog (il-17b), together with the identification of a novel cell surface receptor that specifically binds to it. We detail the molecular cloning, tissue distribution, and expression of both il-17b and il-17br, describe thein vivo activity of il-17b, and demonstrate binding to il-17br.	SIGNOR-76544	0.743
HP	protein	P00738	UNIPROT	hb:hp	complex	SIGNOR-C149	SIGNOR	form complex	binding			9606									11854029	t		miannu	CD163 was identified as the endocytic receptor binding hemoglobin (Hb) in complex with the plasma protein haptoglobin (Hp). This specific receptor-ligand interaction leading to removal from plasma of the Hp-Hb complex-but not free Hp or Hb-now explains the depletion of circulating Hp in individuals with increased intravascular hemolysis.	SIGNOR-255283	0.2
GTF2F1	protein	P35269	UNIPROT	GTF2F1	protein	P35269	UNIPROT	down-regulates	phosphorylation	Ser385	GGSSRGNsRPGTPSA	9606									10428810	t		gcesareni	We show that tfiifalpha possesses a serine/threonine kinase activity, allowing an autophosphorylation of the two residues at position serine 385 and threonine 389. Mutation analysis strongly suggests that autophosphorylation of both sites regulates the transcription elongation process.	SIGNOR-69767	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates	phosphorylation	Ser37	YLDSGIHsGATTTAP	9606									20419129	t		lperfetto	Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta.	SIGNOR-165026	0.2
Neuronal AP-3	complex	SIGNOR-C445	SIGNOR	AP-3/clathrin vescicle	complex	SIGNOR-C250	SIGNOR	form complex	binding			9606									23103167	t		miannu	Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors	SIGNOR-268525	0.386
DAXX	protein	Q9UER7	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates	binding			9606									23405218	t		gcesareni	The optimal function of mdm2 requires daxx, which stabilizes mdm2 through the deubiquitinase hausp/usp7 and also directly promotes mdm2's ubiquitin ligase activity towards p53.	SIGNOR-200892	0.66
PPP2CA	protein	P67775	UNIPROT	DDHD1	protein	Q8NEL9	UNIPROT	unknown	dephosphorylation	Ser727	TIPSPVTsPVLSRRH	-1									11328814	t		miannu	Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity	SIGNOR-262976	0.2
AARS1	protein	P49588	UNIPROT	Ala-tRNA(Ala)	smallmolecule	CHEBI:17732	ChEBI	up-regulates quantity	chemical modification			9606									32314272	t		miannu	Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N).	SIGNOR-270447	0.8
DCK	protein	P27707	UNIPROT	2'-deoxyadenosine 5'-monophosphate(2-)	smallmolecule	CHEBI:58245	ChEBI	up-regulates quantity	chemical modification												20637175	t		lperfetto	Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis	SIGNOR-275808	0.8
PRKACA	protein	P17612	UNIPROT	VIM	protein	P08670	UNIPROT	down-regulates activity	phosphorylation	Ser7	sSSSYRRM	-1									2500966	t		miannu	Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure.	SIGNOR-250071	0.313
TMED5	protein	Q9Y3A6	UNIPROT	TMED10	protein	P49755	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								19948005	t		Sara	P28 forms hetero-oligomeric complexes with p23. p23 is a major determinant for efficient targeting of p28 to the ERGIC	SIGNOR-261298	0.584
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	AQP2	protein	P41181	UNIPROT	up-regulates activity	phosphorylation	Ser256	REVRRRQsVELHSPQ	9615	BTO:0000837								12194985	t		lperfetto	For Ser-256 in AQP2, this hypothesis is in line with data from Zeleninaet al. (35), who showed that in isolated rat inner medulla prostaglandin E2 induces internalization of AQP2 without decreasing the amount of PKA-phosphorylated AQP2.|Phosphorylation of Ser-256 Is Necessary and Sufficient for Localization of AQP2 in the Apical Plasma Membrane	SIGNOR-264563	0.2
MAP4K3	protein	Q8IVH8	UNIPROT	PRKCQ	protein	Q04759	UNIPROT	up-regulates	phosphorylation	Thr538	LGDAKTNtFCGTPDY	9606	BTO:0000782								21983831	t		llicata	We report that the kinase glk (map4k3) directly activated pkc-? During tcr signaling.	SIGNOR-176744	0.388
EGFR	protein	P00533	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates	phosphorylation	Tyr406	DASSQDCyDIPRAFP	9606	BTO:0000527;BTO:0000017								9890893	t		lperfetto	Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689).	SIGNOR-236396	0.751
SEMA3A	protein	Q14563	UNIPROT	NRP1	protein	O14786	UNIPROT	down-regulates	binding			9606									10196546	t		gcesareni	Semaphorins a and e act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors.	SIGNOR-66661	0.911
AKT1	protein	P31749	UNIPROT	STK3	protein	Q13188	UNIPROT	down-regulates	phosphorylation	Thr117	IIRLRNKtLIEDEIA	9606	BTO:0000150								20231902	t		gcesareni	Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation.	SIGNOR-252509	0.363
CDK5	protein	Q00535	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates	phosphorylation	Ser75	NSSDTVTsPQRAGPL	9606	BTO:0000938								10544291	t		llicata	These results present compelling evidence that cdk5/p35 kinase is responsible for the novel phosphorylation of c-src at ser75 in neuronal cells, raising the intriguing possibility that c-src acts as an effector of cdk5/p35 kinase during neuronal development.	SIGNOR-71950	0.398
AMPK	complex	SIGNOR-C15	SIGNOR	CFTR	protein	P13569	UNIPROT	down-regulates activity	phosphorylation	Ser768	LQARRRQsVLNLMTH	9606									19095655	t		Luana	AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions	SIGNOR-72708	0.396
NOS1	protein	P29475	UNIPROT	nitric oxide	smallmolecule	CHEBI:16480	ChEBI	up-regulates quantity	chemical modification			9606									21890489	t		gcesareni	Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates	SIGNOR-243957	0.8
TTBK1	protein	Q5TCY1	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser739	GSIDMVDsPQLATLA	9606	BTO:0000938								16923168	t	The effect has been demonstrated using P10636-8	lperfetto	Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation.	SIGNOR-148978	0.464
ATR	protein	Q13535	UNIPROT	RBBP8	protein	Q99708	UNIPROT	up-regulates	phosphorylation	Thr859	WEVGFPStQTCMERG	9606									23273981	t		llicata	Characterization of this site using phospho-specific antibodies and mutational analysis reveals that it is phosphorylated by atr and is required for binding of ctip to chromatin and subsequent processive resection.	SIGNOR-200245	0.6
RXRB	protein	P28702	UNIPROT	THRB	protein	P10828	UNIPROT	up-regulates	binding			9606									10976919	t		gcesareni	Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr	SIGNOR-81455	0.623
GOT1	protein	P17174	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	down-regulates quantity	chemical modification			9606									26003525	t		miannu	Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and α-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer.	SIGNOR-268062	0.8
SMAD7	protein	O15105	UNIPROT	SMURF	proteinfamily	SIGNOR-PF29	SIGNOR	up-regulates activity	relocalization			9606									19352540	t		lperfetto	Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway.	SIGNOR-253258	0.895
selumetinib	chemical	CHEBI:90227	ChEBI	MAP2K2	protein	P36507	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258281	0.8
ROCK2	protein	O75116	UNIPROT	SH3GL2	protein	Q99962	UNIPROT	down-regulates	phosphorylation	Thr14	KKQFHKAtQKVSEKV	9606									16164598	t		llicata	We identified the phosphorylation site of endophilin a1 at thr-14 endophilin t14d inhibited egf receptor internalization. Furthermore, phosphorylation of endophilin by rho-kinase inhibited the binding to cin85.	SIGNOR-140466	0.414
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine	chemical	CHEBI:91451	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258098	0.8
PRKCA	protein	P17252	UNIPROT	HMGN2	protein	P05204	UNIPROT	down-regulates	phosphorylation	Ser25	KDEPQRRsARLSAKP	9606									10739259	t		lperfetto	Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.	SIGNOR-76320	0.293
APOB	protein	P04114	UNIPROT	LDL_assembly	phenotype	SIGNOR-PH63	SIGNOR	up-regulates				9606									23721961	f		miannu	Apolipoprotein B is a structural protein that is an integral component of chylomicrons, as well as very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) particles. 	SIGNOR-252116	0.7
MAP3K1	protein	Q13233	UNIPROT	MAP2K7	protein	O14733	UNIPROT	up-regulates	phosphorylation	Ser271	ISGRLVDsKAKTRSA	9606									9312068	t		lperfetto	Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1	SIGNOR-51207	0.71
MTOR	protein	P42345	UNIPROT	ATG13	protein	O75143	UNIPROT	down-regulates	phosphorylation			9606									19211837	t		gcesareni	Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2.	SIGNOR-183965	0.638
CDX2	protein	Q99626	UNIPROT	LCT	protein	P09848	UNIPROT	up-regulates quantity by expression	transcriptional regulation												9148757	t	 	 	By electrophoretic mobility-shift assay it was shown that the factor Cdx-2 (a homoeodomain-protein related to caudal) binds to a TTTAC sequence in the CE-LPH1. Furthermore it was demonstrated that Cdx-2 is able to activate reporter gene transcription by binding to CE-LPH1.	SIGNOR-253964	0.371
RBPJ	protein	Q06330	UNIPROT	GTF2A2	protein	P52657	UNIPROT	up-regulates	binding			9606									9620850	t	Inhibits transcription	gcesareni	Rbp interacts with two transcriptional coactivators: dtafii110, a subunit of tfiid, and tfiia to repress transcription. The domain of dtafii110 targeted by rbp is the same domain that interacts with tfiia	SIGNOR-57832	0.2
PRKCA	protein	P17252	UNIPROT	RHO	protein	P08100	UNIPROT	unknown	phosphorylation	Ser338	DEASATVsKTETSQV	-1									11910029	t		lperfetto	Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343.	SIGNOR-249147	0.451
AKT1	protein	P31749	UNIPROT	ACAP1	protein	Q15027	UNIPROT	unknown	phosphorylation	Ser554	SIRPRPGsLRSKPEP	9606									16256741	t		llicata	Akt phosphorylates s554 in acap1	SIGNOR-252483	0.497
11-deoxycortisol	smallmolecule	CHEBI:28324	ChEBI	cortisol	smallmolecule	CHEBI:17650	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000050							9814482	t		lperfetto	Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol.	SIGNOR-268675	0.8
RXRB	protein	P28702	UNIPROT	NR2F2	protein	P24468	UNIPROT	up-regulates	binding			9606									10900149	t		gcesareni	Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site.	SIGNOR-79452	0.278
antigen	smallmolecule	CHEBI:59132	ChEBI	BCR-Mk	complex	SIGNOR-C433	SIGNOR	up-regulates activity	binding			9606	BTO:0000776								32323266	t		scontino	The recognition of antigen by the BCR initiates BCR signaling cascade.	SIGNOR-268202	0.8
R547	chemical	CID:6918852	PUBCHEM	CDK4	protein	P11802	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206364	0.8
15(S)-HETE	smallmolecule	CHEBI:15558	ChEBI	PPARG	protein	P37231	UNIPROT	up-regulates activity	chemical activation			9606									12517954	t	 	lperfetto	15(S)-HETE is a ligand for PPARγ in IL-4-stimulated A549 cells	SIGNOR-254095	0.8
HDAC1	protein	Q13547	UNIPROT	YY1	protein	P25490	UNIPROT	down-regulates activity	deacetylation			-1									11486036	t		miannu	Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs.	SIGNOR-268835	0.789
SYCP2	protein	Q9BX26	UNIPROT	Synaptonemal_complex	complex	SIGNOR-C351	SIGNOR	form complex	binding			9606									22394509	t		miannu	The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region.	SIGNOR-264199	0.646
EFTUD2	protein	Q15029	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270639	0.79
SRC	protein	P12931	UNIPROT	FCRL3	protein	Q96P31	UNIPROT	up-regulates activity	phosphorylation	Tyr692	HEELTVLySELKKTH	-1									12051764	t		miannu	Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2.	SIGNOR-274007	0.2
ELP1	protein	O95163	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates				9606									12058026	f		gcesareni	Ikap efficiently and specifically enhanced jnk activation induced by ectopic expression of mekk1 and ask1, upstream activators of jnk	SIGNOR-89334	0.2
EGFR	protein	P00533	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								7518560	t		lperfetto	Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc).	SIGNOR-235721	0.921
BCL2L1	protein	Q07817	UNIPROT	BECN1	protein	Q14457	UNIPROT	down-regulates	binding			9606									17446862	t		gcesareni	The anti-apoptotic proteins bcl-2 and bcl-x(l) bind and inhibit beclin-1, an essential mediator of autophagy.	SIGNOR-154480	0.916
TNFSF15	protein	O95150	UNIPROT	TNFRSF25	protein	Q93038	UNIPROT	up-regulates	binding			9606									14585074	t		amattioni	The ligand of dr3 is tl1a	SIGNOR-103078	0.768
INSR	protein	P06213	UNIPROT	GRB7	protein	Q14451	UNIPROT	up-regulates	binding			9606									10803466	t		gcesareni	Insulin induces the ir-grb7 interaction in cells expressing physiological levels of the proteins, suggesting that grb7 is implicated in insulin signaling.	SIGNOR-77153	0.428
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr548	KKVAVVRtPPKSPSS	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249325	0.754
MAP3K14	protein	Q99558	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	up-regulates	phosphorylation			9606									9520446	t		lperfetto	Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176.Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa.	SIGNOR-217433	0.712
FASN	protein	P49327	UNIPROT	long-chain fatty acid anion	smallmolecule	CHEBI:57560	ChEBI	up-regulates quantity	chemical modification			9606									15507492	t			Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the de novo biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH. 	SIGNOR-267208	0.8
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NME1	protein	P15531	UNIPROT	up-regulates	phosphorylation	Ser120	GRNIIHGsDSVESAE	9606									18234856	t		lperfetto	Application of this approach to the discovery of cdk1-cyclin b substrates yielded identification of >70 substrates and phosphorylation sites. Many of these sites are known to be phosphorylated in vivo, but most of the proteins have not been characterized as cdk1-cyclin b substrates.	SIGNOR-216825	0.275
SP1	protein	P08047	UNIPROT	SOD2	protein	P04179	UNIPROT	up-regulates quantity by expression	transcriptional regulation												10669635	f		lperfetto	These results suggest that PMA stimulates transcription of the Mn-SOD gene through an increase in Sp1 expression and thus implicate Sp1 as an effector mediating the PKC-signaling pathway elicited by extracellular signals.	SIGNOR-271693	0.409
MAPK14	protein	Q16539	UNIPROT	RPS6KA4	protein	O75676	UNIPROT	up-regulates	phosphorylation	Ser360	PRIFQGYsFVAPSIL	9606	BTO:0000567								10806207	t		llicata	Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity.	SIGNOR-77216	0.586
EIF2B5	protein	Q13144	UNIPROT	EIF2S1	protein	P05198	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269123	0.834
FOXL2	protein	P58012	UNIPROT	CYP19A1	protein	P11511	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21862621	f	 	miannu	We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation.	SIGNOR-254179	0.515
RB1	protein	P06400	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates	binding			9606									8242749	t		gcesareni	A domain in the c-terminus of rb, outside of the a/b pocket, binds to the atp-binding lobe of the c-abl tyrosine kinase, resulting in kinase inhibition.	SIGNOR-37139	0.551
CD38	protein	P28907	UNIPROT	NMN(+)	smallmolecule	CHEBI:14648	ChEBI	down-regulates quantity	chemical modification			9606									18626062	t		miannu	CD38 is also able to catalyze the degradation of the NAD precursor nicotinamide mono-nucleotide (NMN) into nicotinamide	SIGNOR-264252	0.8
SMAD6	protein	O43541	UNIPROT	NR2C2	protein	P49116	UNIPROT	down-regulates	binding			9606									11737269	t		lperfetto	Smad6 interacts with tak1 and tab1, and smad7 with tab1	SIGNOR-112636	0.2
6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine	chemical	CHEBI:131165	ChEBI	CDK2	protein	P24941	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206835	0.8
ILK	protein	Q13418	UNIPROT	PPP1R12A	protein	O14974	UNIPROT	down-regulates activity	phosphorylation	Thr710	DLQEAEKtIGRSRST	-1									12030846	t		miannu	 MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition	SIGNOR-262885	0.566
MTOR	protein	P42345	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Ser434	SFEPKIRsPRRFIGS	10090	BTO:0002572								12782654	t		lperfetto	S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation.	SIGNOR-101332	0.96
VARLITINIB	chemical	CID:42642648	PUBCHEM	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189903	0.8
PKMYT1	protein	Q99640	UNIPROT	CDK1	protein	P06493	UNIPROT	down-regulates	phosphorylation	Tyr15	EKIGEGTyGVVYKGR	9606	BTO:0000567								9001210	t	Preference on the part of Myt1Hu for the cyclin-bound form of Cdc2	lperfetto	Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory.	SIGNOR-45729	0.739
TWIST2	protein	Q8WVJ9	UNIPROT	ICAM1	protein	P05362	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002590								17487558	f		miannu	 Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells	SIGNOR-255514	0.2
HRAS	protein	P01112	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606									9727023	t		gcesareni	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k we show here, however, that in vivo there are marked quantitative differences in the ability of ki- and ha-ras to activate raf-1 and phosphoinositide 3 kinase. the mechanism of raf-1 activation is complex, but it is clear that one important role of ras is to recruit raf-1 to the plasma membrane where a series of events is initiated that ultimately leads to full raf-1 activation. These events include tyrosine, serine, and threonine phosphorylation plus interactions with ras, phospholipids, 14-3-3 proteins and their associated proteins, and possibly dimerization.	SIGNOR-59816	0.813
9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone	chemical	CID:71748056	PUBCHEM	BTK	protein	Q06187	UNIPROT	down-regulates activity	chemical inhibition			-1									24556163	t		miannu	BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling and cellular assays to develop a potent, selective, and irreversible BTK kinase inhibitor, QL47, which covalently modifies Cys481. QL47 inhibits BTK kinase activity with an IC50 of 7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with an EC50 of 475 nM, and inhibits phosphorylation of a downstream effector PLCγ2 (Tyr759) with an EC50 of 318 nM. 	SIGNOR-262238	0.8
PDK4	protein	Q16654	UNIPROT	PDHA2	protein	P29803	UNIPROT	down-regulates	phosphorylation	Ser291	TYRYHGHsMSDPGVS	9606		BTO:0000887;BTO:0001103							14966024	t		gcesareni	Pyruvate dehydrogenase (pdh) activity (pdha) controls the entry of carbohydrate into the tricarboxylic cycle and is regulated by pdh kinase (pdk), which phosphorylates and inactivates the enzyme, and pdh phosphatase, which dephosphorylates the enzyme to the active form	SIGNOR-121936	0.528
PDXP	protein	Q96GD0	UNIPROT	CFL1	protein	P23528	UNIPROT	down-regulates activity	dephosphorylation	Ser3	sGVAVSDG	-1									15580268	t			Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics|Cofilin is a key regulator of actin cytoskeletal dynamics whose activity is controlled by phosphorylation of a single serine residue. We report the biochemical isolation of chronophin (CIN), a unique cofilin-activating phosphatase of the haloacid dehalogenase (HAD) superfamily.	SIGNOR-248764	0.46
LRRK2	protein	Q5S007	UNIPROT	SH3GL2	protein	Q99962	UNIPROT	down-regulates	phosphorylation			9606									22998870	t		miannu	We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association.	SIGNOR-192075	0.484
KAT5	protein	Q92993	UNIPROT	SRSF2	protein	Q01130	UNIPROT	down-regulates	acetylation	Lys52	IPRDRYTkESRGFAF	9606									21157427	t		miannu	In this study, we provide the first evidence that the acetyltransferase tip60 acetylates srsf2 on its lysine 52 residue inside the rna recognition motif, and promotes its proteasomal degradation.	SIGNOR-170594	0.48
MDH1	protein	P40925	UNIPROT	NAD(1-)	smallmolecule	CHEBI:57540	ChEBI	down-regulates quantity	chemical modification			9606									24068518	t		miannu	Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle	SIGNOR-268099	0.8
EGFR	protein	P00533	UNIPROT	SCAMP3	protein	O14828	UNIPROT	unknown	phosphorylation	Tyr41	QYATLDVyNPFETRE	-1									9658162	t		llicata	SCAMP3 Is Tyrosine Phosphorylated by EGFR in Vitro	SIGNOR-251096	0.408
(2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide	chemical	CHEBI:91449	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252658	0.8
PPP4C	protein	P60510	UNIPROT	CDK1	protein	P06493	UNIPROT	down-regulates activity	dephosphorylation			9606									18347064	t		miannu	PP4c efficiently dephosphorylates Cdk1 sites of NDEL1 but does not dephosphorylate the Aurora A site.|We also found that PP4c negatively regulates Cdk1 activity in interphase.	SIGNOR-277162	0.407
FYN	protein	P06241	UNIPROT	PGD	protein	P52209	UNIPROT	up-regulates activity	phosphorylation	Tyr481	GTVSSSSyNA	9606									30824700	t		lperfetto	6PGD is phosphorylated at tyrosine (Y) 481 by Src family kinase Fyn. This phosphorylation enhances 6PGD activity by increasing its binding affinity to NADP+ and therefore activates the PPP for NADPH and ribose-5-phosphate, which consequently detoxifies intracellular reactive oxygen species (ROS) and accelerates DNA synthesis. 	SIGNOR-265758	0.2
NEK2	protein	P51955	UNIPROT	NEK2	protein	P51955	UNIPROT	down-regulates	phosphorylation	Ser241	RRIPYRYsDELNEII	9606									17197699	t		gcesareni	Enzymatic activity, inhibited;	SIGNOR-151767	0.2
TRAF1	protein	Q13077	UNIPROT	TRAF2	protein	Q12933	UNIPROT	up-regulates	binding			9606									8069916	t		gcesareni	Traf1 and traf2 can form homo- and heterotypic dimers.	SIGNOR-34768	0.618
TLR4	protein	O00206	UNIPROT	Interferon_Production	phenotype	SIGNOR-PH16	SIGNOR	up-regulates				9606									20596954	f		fstefani	Regulation of toll-like receptor signaling in the innate immunity.	SIGNOR-166488	0.7
Vicriviroc Malate	chemical	CID:10218922	PUBCHEM	CCR5	protein	P51681	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207657	0.8
POLR3B	protein	Q9NW08	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266132	0.858
F2R	protein	P25116	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256875	0.375
MECP2	protein	P51608	UNIPROT	MECP2/SIN3A/HDAC complex	complex	SIGNOR-C360	SIGNOR	form complex	binding			10116									9620804	t		Luana	We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases.	SIGNOR-265070	0.689
GDF6	protein	Q6KF10	UNIPROT	BMPR1A	protein	P36894	UNIPROT	up-regulates	binding			9606									16049014	t		gcesareni	We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10.	SIGNOR-139090	0.59
PRKACA	protein	P17612	UNIPROT	AURKA	protein	O14965	UNIPROT	up-regulates activity	phosphorylation	Thr288	APSSRRTtLCGTLDY	-1									11039908	t		miannu	Aurora2 is regulated by phosphorylation. phosphorylation occurs on a conserved residue, Threonine 288, within the activation loop of the catalytic domain of the kinase and results in a significant increase in the enzymatic activity. Threonine 288 resides within a consensus motif for the cAMP dependent kinase and can be phosphorylated by PKA in vitro.	SIGNOR-250337	0.49
CDS2	protein	O95674	UNIPROT	phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	down-regulates quantity	chemical modification			9606									25375833	t		lperfetto	CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA).	SIGNOR-267021	0.8
anthra[1,9-cd]pyrazol-6(2H)-one	chemical	CHEBI:90695	ChEBI	MAPK10	protein	P53779	UNIPROT	down-regulates	chemical inhibition			9606									11717429	t		gcesareni	We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). To determine whether jnk activity is required for stress-induced translocation of bax to the mitochondria, we examined the effect of sp600125, a jnk inhibitor.	SIGNOR-111980	0.8
RAE1	protein	P78406	UNIPROT	NUP98	protein	P52948	UNIPROT	up-regulates activity	binding			9606									16036565	t		miannu	Nup98 is a major interacting partner of Rae1 and known to beinvolved in mRNA export.	SIGNOR-260868	0.882
CREB1	protein	P16220	UNIPROT	NR2F6	protein	P10588	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15955695	f		miannu	 In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro.	SIGNOR-253793	0.268
RAD51	protein	Q06609	UNIPROT	BRCC ubiquitin ligase complex	complex	SIGNOR-C295	SIGNOR	form complex	binding			9606	BTO:0000007								14636569	t		lperfetto	These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer	SIGNOR-263206	0.743
N-(3-methoxy-5-methyl-2-pyrazinyl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]-3-pyridinesulfonamide	chemical	CHEBI:94573	ChEBI	EDNRA	protein	P25101	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207902	0.8
AKT1	protein	P31749	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates activity	phosphorylation	Ser365	GQRDRSSsAPNVHIN	9606									10869359	t			Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo	SIGNOR-251471	0.47
TRAF6	protein	Q9Y4K3	UNIPROT	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	down-regulates quantity	ubiquitination			9606	BTO:0000007								28980855	t	inferred from family member		The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation.	SIGNOR-270271	0.2
CDK1	protein	P06493	UNIPROT	DUT	protein	P33316-2	UNIPROT	up-regulates quantity	phosphorylation	Ser11	SEETPAIsPSKRARP	-1									8631817	t		miannu	DUTPase Is Phosphorylated at a Consensus Cyclin-dependent Protein Kinase Site: in Vitro Phosphorylation of Ser-11 by p34cdc2. It is conceivable that the exclusive phosphorylation of DUT-N may play a role in nuclear targeting of this protein. Taken a step further, Ser-11 may confer the ability of DUT-N to localize in specific regions of the nucleus where the dUTPase function is required. The Ser-11 Ala mutant should aid in the testing of these hypotheses.	SIGNOR-262693	0.393
RCHY1	protein	Q96PM5	UNIPROT	POLH	protein	Q9Y253	UNIPROT	down-regulates activity	monoubiquitination	Lys694	SPLACTNkRPRPEGM	9606									21791603	t		miannu	Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709).	SIGNOR-272732	0.563
CDH23	protein	Q9H251	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265861	0.292
F2RL3	protein	Q96RI0	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates	binding			9606									22318735	t		gcesareni	Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13).	SIGNOR-196012	0.463
TFAP4	protein	Q01664	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates activity	binding			9606	BTO:0001109								19505873	t		miannu	We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads.	SIGNOR-226593	0.365
HDAC3	protein	O15379	UNIPROT	SMAD7	protein	O15105	UNIPROT	up-regulates	binding			9606									23213415	t		gcesareni	We show here that smad7 can form a complex with endogenous histone deacetylase proteins hdac-1 and hdac-3 in nih 3t3 mouse fibroblast cells	SIGNOR-199967	0.348
ATM	protein	Q13315	UNIPROT	RNF40	protein	O75150	UNIPROT	up-regulates	phosphorylation			9606									21763684	t		gcesareni	E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm.	SIGNOR-175003	0.455
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates				9606									18481201	f		lperfetto	Pd98059, a specific inhibitor of mek in addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation.	SIGNOR-244877	0.618
DNER	protein	Q8NFT8	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606	BTO:0000938								15965470	t		gcesareni	Dner binds to notch1 at cell-cell contacts and activates notch signaling in vitro.	SIGNOR-138346	0.439
ROCK1	protein	Q13464	UNIPROT	DES	protein	P17661	UNIPROT	unknown	phosphorylation	Thr76	LRASRLGtTRTPSSY	9606	BTO:0000971								10574968	t		lperfetto	We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin	SIGNOR-249031	0.321
PRKCB	protein	P05771	UNIPROT	SDC2	protein	P34741	UNIPROT	unknown	phosphorylation	Ser187	DLGERKPsSAAYQKA	-1									9244383	t		lperfetto	We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198.	SIGNOR-248974	0.333
CAMK2B	protein	Q13554	UNIPROT	CYLD	protein	Q9NQC7	UNIPROT	up-regulates	phosphorylation	Ser772	LFKKIFPsLELNITD	9606									24614225	t		lperfetto	Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity.	SIGNOR-91403	0.2
SMURF2	protein	Q9HAU4	UNIPROT	SMAD1/5/8	proteinfamily	SIGNOR-PF35	SIGNOR	down-regulates	ubiquitination			9606									22298955	t	inferred from 70% of family members	gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-269845	0.778
UBE3A	protein	Q05086	UNIPROT	PSMD2	protein	Q13200	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								28559284	t		lperfetto	Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits.	SIGNOR-265133	0.28
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3-5	protein	Q6NXT2	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269634	0.2
NFKB1	protein	P19838	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	form complex	binding			9606									9450761	t		gcesareni	Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna	SIGNOR-55375	0.699
SOCS1	protein	O15524	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606									24890514	f		apalma	Socs1 associates with CSF-1R pTyr-697 and pTyr721 binding sites to inhibit proliferation by an unknown mechanism	SIGNOR-255575	0.7
GAB2	protein	Q9UQC2	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									24737791	t		milica	The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival	SIGNOR-252677	0.5
SOCS1	protein	O15524	UNIPROT	IFNG	protein	P01579	UNIPROT	down-regulates				9606									21628332	f		lperfetto	SOCS1 inhibits macrophage responses to IFN-g, and SOCS1-deficient mice develop symptoms of severe systemic autoimmune and inflammatory disease.	SIGNOR-249571	0.538
USP1	protein	O94782	UNIPROT	DGCR8	protein	Q8WYQ5	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0002181								34188037	t		miannu	 Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs. 	SIGNOR-277308	0.2
GSK3B	protein	P49841	UNIPROT	PHLPP1	protein	O60346	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr1363	HVQSVLLtPQDEFFI	9606	BTO:0002181								19797085	t		miannu	We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity. 	SIGNOR-276264	0.36
CHEK2	protein	O96017	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Thr383	GETSLMRtLCGTPTY	9606	BTO:0000007								11901158	t		gcesareni	Phosphorylation of thr-68 by the ataxia telangiectasia-mutated is necessary for efficient activation of chk2 when cells are exposed to ionizing radiation. By an unknown mechanism, this initial event promotes additional autophosphorylation events including modifications of thr-383 and thr-387	SIGNOR-116127	0.2
PRKACA	protein	P17612	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser726	DTSPRHLsNVSSTGS	-1									12435421	t		miannu	Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly 	SIGNOR-250009	0.442
DOK1	protein	Q99704	UNIPROT	Av/b6 integrin	complex	SIGNOR-C179	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257694	0.2
Caspase 8 complex	complex	SIGNOR-C231	SIGNOR	CASP6	protein	P55212	UNIPROT	up-regulates	cleavage			9606									9727491	t		gcesareni	Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them.	SIGNOR-256466	0.722
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PPARG	protein	P37231	UNIPROT	down-regulates activity	relocalization			9606									18596912	t	inferred from 70% family members	lperfetto	The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform	SIGNOR-270008	0.2
WNK4	protein	Q96J92	UNIPROT	SLC12A3	protein	P55017	UNIPROT	down-regulates activity													22342722	f		lperfetto	Evidences from early studies using Xenopus oocytes and mammalian cells indicate that WNK4 inhibits NCC and PHAII-causing mutations relieve the inhibition	SIGNOR-264632	0.598
CDH17	protein	Q12864	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265856	0.694
PIK3C3	protein	Q8NEB9	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates activity	binding			10090									19270693	t		lperfetto	The beclin 1-vps34 interaction regulates autophagy.	SIGNOR-184521	0.934
CASP8AP2	protein	Q9UKL3	UNIPROT	NFKB1	protein	P19838	UNIPROT	up-regulates	binding			9606				SIGNOR-C13					22075988	t		gcesareni	In addition, both cleavage products of c-flip turned out to be inducers of nf-kb activity by binding to the ikk complex.	SIGNOR-177104	0.248
N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide	chemical	CHEBI:91399	ChEBI	CDK2	protein	P24941	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207084	0.8
LYN	protein	P07948	UNIPROT	FCGR2A	protein	P12318	UNIPROT	up-regulates activity	phosphorylation	Tyr304	TDDDKNIyLTLPPND	-1									8756631	t		lperfetto	Phosphorylation of FcgammaRIIa/c by Lyn is clearly dependent on the presence of Y-298, since all mutants lacking this residue are not phosphorylated by this PTK. This result suggests that Y-298 might be the only tyrosine residue of FcgammaRIIa/c phos- phorylated by Lyn.	SIGNOR-249379	0.591
SGK3	protein	Q96BR1	UNIPROT	GSK3A	protein	P49840	UNIPROT	down-regulates activity	phosphorylation	Ser21	SGRARTSsFAEPGGG	9606	BTO:0000007								16543730	t		lperfetto	Phosphorylation of GSK3 by PKB or SGK1 inhibits GSK3 activity|estern blotting using an antibody specific for the PKB/SGK1 consensus phosphorylation site in GSK3a/beta (serine 21 and 9 respectively) revealed an increase in GSK3a/beta phosphorylation in human embryonic kidney 293 (HEK293) cells overexpressing wild type SGK1, constitutively active SGK1, but not catalytically inactive SGK1.|The effect of SGK1 was mimicked by PKB and SGK3.	SIGNOR-249165	0.361
Scribble_complex_DLG2-LLGL1_variant	complex	SIGNOR-C510	SIGNOR	Cell_polarity	phenotype	SIGNOR-PH213	SIGNOR	up-regulates				9606									23397623	f		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270910	0.7
PBK	protein	Q96KB5	UNIPROT	ULK1	protein	O75385	UNIPROT	down-regulates activity	phosphorylation	Ser495	GVLARKMsLGGGRPY	9606	BTO:0002181								31378785	t		miannu	We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1. 	SIGNOR-277473	0.2
UVRAG	protein	Q9P2Y5	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								17106237	t		lperfetto	UVRAG interacts with Beclin 1, leading to activation of autophagy and thereof inhibition of tumorigenesis.	SIGNOR-150825	0.857
ESR1	protein	P03372	UNIPROT	ESR2	protein	Q92731	UNIPROT	up-regulates	binding			9606									10022879	t		tpavlidou	It was recently shown that er? And er? Could form a heterodimer complex both in vitro and in vivo	SIGNOR-64427	0.506
ALPL	protein	P05186	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	dephosphorylation			9606									24646911	t		miannu	TNAP dephosphorylates overphosphorylated tau once it is released upon neuronal death.	SIGNOR-277097	0.2
PLK1	protein	P53350	UNIPROT	MAD1L1	protein	Q9Y6D9	UNIPROT	up-regulates activity	phosphorylation	Thr680	SKMQLLEtEFSHTVG	-1									18922800	t		miannu	These findings indicate mechanistic roles contributed by protein phosphorylation and Plk1 to the SAC activity of Mad1.Here, we have studied the phosphorylation of Mad1 and mapped using liquid chromatography-tandem mass spectrometry several phosphorylated amino acids in this protein. One phosphorylated residue, Thr680, was characterized to be important for the kinetochore localization of Mad1 and its SAC function. 	SIGNOR-276173	0.441
PHKG1	protein	Q16816	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser669	DFKDRVQsKIGSLDN	-1									8999860	t		miannu	Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules	SIGNOR-250287	0.318
NUAK1	protein	O60285	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									21317932	t		gcesareni	Here we showed that in the presence of wild-type lkb1, nuak1 directly interacts with and phosphorylates p53 in vitro and in vivo.	SIGNOR-172008	0.527
DVL3	protein	Q92997	UNIPROT	FRAT1	protein	Q92837	UNIPROT	up-regulates	binding			9606	BTO:0000567	BTO:0000671							12556519	t		gcesareni	These results indicate that cki epsilon-dependent phosphorylation of dvl enhances the formation of a complex of dvl-1 with frat-1 and that this complex leads to the activation of the wnt signaling pathway.	SIGNOR-97877	0.435
SRC	protein	P12931	UNIPROT	MYLK	protein	Q15746	UNIPROT	up-regulates	phosphorylation	Tyr464	QEGSIEVyEDAGSHY	9606									11113114	t		gcesareni	Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity.	SIGNOR-85005	0.427
NUMB	protein	P49757	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates				9606									20940030	f		gcesareni	Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53.	SIGNOR-168457	0.531
ZAP70	protein	P43403	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates	phosphorylation	Tyr423	NSLNEEWyVSYITRP	9606	BTO:0000782								8702662	t		lperfetto	A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function	SIGNOR-42972	0.798
PTPN12	protein	Q05209	UNIPROT	PTK2B	protein	Q14289	UNIPROT	down-regulates activity	dephosphorylation	Tyr579	RYIEDEDyYKASVTR	9606									11337490	t		lperfetto	Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-pest-mediated dephosphorylation. / dephosphorylation of tyr402 and tyr579/580 by ptp-pest	SIGNOR-107502	0.562
PRKCA	protein	P17252	UNIPROT	MARCKS	protein	P29966	UNIPROT	down-regulates activity	phosphorylation	Ser170	SFKLSGFsFKKNKKE	-1									1560845	t		gcesareni	Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin	SIGNOR-249670	0.72
pazopanib	chemical	CHEBI:71219	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001949								18620382	t		Luana	Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively.	SIGNOR-257737	0.8
EIF2S2	protein	P20042	UNIPROT	Ternary_GTP_eIF2_tRNA_complex	complex	SIGNOR-C452	SIGNOR	form complex	binding			9606									32955564	t		lperfetto	In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3.	SIGNOR-269115	0.954
CTSG	protein	P08311	UNIPROT	F2R	protein	P25116	UNIPROT	down-regulates activity	cleavage	Phe43	ATLDPRSfLLRNPND	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263562	0.577
FCHO2	protein	Q0JRZ9	UNIPROT	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	up-regulates quantity by stabilization	binding												24789820	t		lperfetto	Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth	SIGNOR-260717	0.558
RET	protein	P07949	UNIPROT	RET	protein	P07949	UNIPROT	up-regulates	phosphorylation	Tyr900	FGLSRDVyEEDSYVK	9606									16928683	t		gcesareni	Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation	SIGNOR-148992	0.2
CSNK2A1	protein	P68400	UNIPROT	DNMT3A	protein	Q9Y6K1	UNIPROT	down-regulates activity	phosphorylation	Ser390	LFPVCHDsDESDTAK	-1									25066127	t		miannu	This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin.	SIGNOR-276650	0.2
N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide	chemical	CHEBI:91439	ChEBI	IKBKE	protein	Q14164	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190792	0.8
FBXW7	protein	Q969H0	UNIPROT	NOTCH4	protein	Q99466	UNIPROT	down-regulates	ubiquitination			9606									11585921	t		gcesareni	We show here that the f-box/wd40 repeat protein sel-10 negatively regulates notch receptor activity by targeting the intracellular domain of notch receptors for ubiquitin-mediated protein degradation. in conclusion, hsel-10 physically associates with mouse notch4(int-3) through the wd40 domain, whereas the f-box domain is not required for this interaction.	SIGNOR-110955	0.514
TFEB	protein	P19484	UNIPROT	HEXA	protein	P06865	UNIPROT	up-regulates quantity by expression	transcriptional regulation												19556463	f	Figure 1	lperfetto	Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 	SIGNOR-276541	0.312
PRKCQ	protein	Q04759	UNIPROT	CARD11	protein	Q9BXL7	UNIPROT	down-regulates activity	phosphorylation	Ser893	SPRLSRAsFLFGQLL	-1									35230873	t		miannu	PKCθ-catalyzed CARD11 Ser893 phosphorylation impairs CBM complex formation	SIGNOR-276298	0.767
NFX1	protein	Q12986	UNIPROT	HLA-DRA	protein	P01903	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									7964459	t		Luana	A novel cysteine-rich sequence-specific DNA-binding protein interacts with the conserved X-box motif of the human major histocompatibility complex class II genes via a repeated Cys-His domain and functions as a transcriptional repressor	SIGNOR-266224	0.407
CASP6	protein	P55212	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates activity	cleavage	Asp333	DTVAENDdGGFSEEW	-1									10069390	t		lperfetto	Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.	SIGNOR-261753	0.379
ERBB2	protein	P04626	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates activity	phosphorylation	Tyr1023	DLVDAEEyLVPQQGF	9606									1706616	t			Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2.	SIGNOR-251129	0.2
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2H	protein	P62256	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271328	0.747
diisononyl phthalate	chemical	CHEBI:35459	ChEBI	monoisononyl phthalate	chemical	CHEBI:132593	ChEBI	up-regulates quantity	precursor of			-1									33125036	t		miannu	The primary metabolite of DiNP is monoisononyl-phthalate (MiNP) and the secondary metabolites include three oxidative derivatives of DiNP, which have been identified mainly in urine: mono-oxoisononyl phthalate (MOINP or oxo-MiNP), mono-carboxyisooctyl phthalate (MCIOP, MCOP or cx-MiNP), and mono-hydroxyisononyl phthalate (MHINP or OH-MiNP).	SIGNOR-268771	0.8
ACAT1	protein	P24752	UNIPROT	IDH2	protein	P48735	UNIPROT	down-regulates activity	acetylation	Lys413	VESGAMTkDLAGCIH	9606	BTO:0001545								34289383	t		lperfetto	Mitochondrial acetyltransferase ACAT1 and deacetylase SIRT3 are responsible for acetylation and deacetylation, respectively, at K413 of mIDH2|K413 acetylation inhibits mIDH2 by simultaneously attenuating dimer formation from monomers and destabilizing dimers for conversion to monomers	SIGNOR-267627	0.291
CSNK1D	protein	P48730	UNIPROT	PER1	protein	O15534	UNIPROT	down-regulates quantity by destabilization	phosphorylation			9606									11165242	t		miannu	Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2). 	SIGNOR-268001	0.799
GSK3A	protein	P49840	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	up-regulates activity	phosphorylation	Thr57	LSSTPLStPCSSVPS	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159377	0.2
VX-745	chemical	CHEBI:90528	ChEBI	MAPK11	protein	Q15759	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207684	0.8
NANOG	protein	Q9H9S0	UNIPROT	GATA6	protein	Q92908	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003298								22795133	f		lperfetto	Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)	SIGNOR-253160	0.473
AKT1	protein	P31749	UNIPROT	TBC1D4	protein	O60343	UNIPROT	unknown	phosphorylation	Thr642	QFRRRAHtFSHPPSS	9606									16880201	t		llicata	14-3-3 proteins interact with as160 in an insulin- and akt-dependent manner via an akt phosphorylation site, thr-642.	SIGNOR-252494	0.756
F2R	protein	P25116	UNIPROT	LATS1/2	proteinfamily	SIGNOR-PF43	SIGNOR	down-regulates				9606	BTO:0000007								22972936	f	inferred from 70% of family members	milica	Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase.	SIGNOR-269860	0.2
CEBPA	protein	P49715	UNIPROT	Granulocyte_differentiation	phenotype	SIGNOR-PH102	SIGNOR	up-regulates activity				10090	BTO:0000725								19706798	f			Conditional cebpa deficiency in adult mice blocks the transition from common myeloid progenitors (CMP) to granulocyte monocyte progenitors (GMP) resulting in the accumulation of myeloid blasts	SIGNOR-259966	0.7
INTS12	protein	Q96CB8	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261470	0.741
NFE2L2	protein	Q16236	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22493435	t		miannu	BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2	SIGNOR-254651	0.439
GSK3B	protein	P49841	UNIPROT	H1-5	protein	P16401	UNIPROT	up-regulates	phosphorylation	Thr11	TAPAETAtPAPVEKS	9606	BTO:0000567								19136008	t		lperfetto	We found that threonine 10 of h1.5 can be phosphorylated by glycogen synthase kinase-3 in vitro. We have generated an antiserum specific for human h1.5 phosphorylated at threonine 10. Immunofluorescence labeling of hela cells with this antiserum revealed that the phosphorylation at this site appears in prometaphase and disappears in telophase, and that this hyperphosphorylated form of h1.5 is mainly chromatin-bound in metaphase when chromatin condensation is maximal.	SIGNOR-183325	0.2
3-isobutyl-1-methylxanthine	chemical	CHEBI:48518	ChEBI	CEBPB	protein	P17676	UNIPROT	up-regulates quantity by expression				9606									8754811	f		fspada	The differentiation of 3t3 preadipocytes into adipocytes is accompanied by a transient induction of c/ebpbeta and c/ebpdelta expression in response to treatment of the cells with methylisobutylxanthine (mix) and dexamethasone (dex), respectively	SIGNOR-43310	0.8
PDPK1	protein	O15530	UNIPROT	AKT2	protein	P31751	UNIPROT	up-regulates activity	phosphorylation	Thr309	SDGATMKtFCGTPEY	9606		BTO:0000887;BTO:0001103;BTO:0001760							9512493	t		lperfetto	The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma)	SIGNOR-236785	0.718
CHRM3	protein	P20309	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257224	0.371
Immune complexes	stimulus	SIGNOR-ST15	SIGNOR	FCAR	protein	P24071	UNIPROT	up-regulates activity	relocalization												12768205	f		lperfetto	Both monomeric and dimeric IgA can bind to FcalphaRI, and monomeric or dimeric IgA immune complexes can activate phagocytosis and other immune responses through the clustering of FcalphaRI	SIGNOR-264859	0.7
PTPN1	protein	P18031	UNIPROT	CAV1	protein	Q03135	UNIPROT	unknown	dephosphorylation	Tyr14	VDSEGHLyTVPIREQ	-1									16388599	t			The scaffolding protein caveolin-1 is also a participant in these pathways and is specifically phosphorylated on tyrosine 14, when these pathways are activated. Here, we provide evidence that PTP1B can efficiently catalyze the removal of the phosphoryl group from phosphocaveolin-1.	SIGNOR-248430	0.554
PRKCB	protein	P05771	UNIPROT	ICOSLG	protein	O75144	UNIPROT	up-regulates activity	phosphorylation	Ser285	RDRCLQHsYAGAWAV	9606	BTO:0000567								24837102	t	done	miannu	PKCα and PKCβ are required for phosphorylation of ICOSL and ICOSL-mediated cytokine induction 	SIGNOR-273797	0.2
ruxolitinib	chemical	CHEBI:66919	ChEBI	JAK1	protein	P23458	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206667	0.8
GARS1	protein	P41250	UNIPROT	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									24898252	t		miannu	Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 	SIGNOR-270480	0.8
ALK	protein	Q9UM73	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000785								12185581	t		gcesareni	Anaplastic lymphoma kinase (alk), which turned out to be one of these phosphoproteins, was constitutively activated and associated with the ptb domain of shcc in three neuroblastoma cells. In vitro kinase assay revealed that shcc is a potent substrate of the activated alk kinase. The alk gene locus was significantly amplified in both of these cell lines, suggesting that gene amplification leads to constitutive activation of the alk kinase, which results in hyperphosphorylation of shcc.	SIGNOR-91534	0.467
PRKCA	protein	P17252	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser163	KRFSFKKsFKLSGFS	-1									8422248	t		lperfetto	These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III.	SIGNOR-248928	0.72
EIF3A	protein	Q14152	UNIPROT	EIF3_complex	complex	SIGNOR-C401	SIGNOR	form complex	binding			-1									16920360	t		miannu	Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 	SIGNOR-266400	0.918
PASK	protein	Q96RG2	UNIPROT	EEF1A1	protein	P68104	UNIPROT	unknown	phosphorylation			9606	BTO:0000567								17595531	t		gcesareni	Kinase assays, mass spectrometry and site-directed mutagenesis revealed PASKIN auto-phosphorylation as well as eEF1A1 target phosphorylation mainly but not exclusively at Thr432.	SIGNOR-245862	0.381
PTGS2	protein	P35354	UNIPROT	prostaglandin G2(1-)	smallmolecule	CHEBI:82629	ChEBI	up-regulates quantity	chemical modification			-1									7592599	t		Luana	[14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2,	SIGNOR-269770	0.8
RPS6KA2	protein	Q15349	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates	phosphorylation	Ser32	LLDDRHDsGLDSMKD	9606									20385620	t		gcesareni	Rsk2 is activated by treatment with tumor necrosis factor-alfa (tnf-alfa) and directly phosphorylates ikbalfa at ser-32, leading to ikbalfa degradation.	SIGNOR-164790	0.271
2-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine	chemical	CID:49830260	PUBCHEM	VCP	protein	P55072	UNIPROT	down-regulates activity	chemical inhibition			-1									23316025	t		Luana	Inhibition of p97 by ML240 and ML241 is ATP competitive. To determine the mechanism by which ML240 and ML241 inhibited p97 ATPase, we evaluated rates of ATP hydrolysis at different concentrations of ATP. ML240 and ML241 inhibited p97competitively with respect to ATP with a Kivalues of 0.22 mm and 0.35 mm respectively.	SIGNOR-261093	0.8
MAPK1	protein	P28482	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates activity	phosphorylation	Ser383	IHFWSTLsPIAPRSP	10090	BTO:0000944								7889942	t		lperfetto	We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-235455	0.544
E2F1	protein	Q01094	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22832221	f		gcesareni	Brca1/e2f1/ctipbinding to atm promoter activates atm transcription.	SIGNOR-198470	0.667
DIABLO	protein	Q9NR28	UNIPROT	XIAP	protein	P98170	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								10929711	t		amattioni	Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity.	SIGNOR-80218	0.912
ketanserin	chemical	CHEBI:6123	ChEBI	SLC18A1	protein	P54219	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000318								8643547	t		miannu	Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2.	SIGNOR-258493	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	KCNJ2	protein	P63252	UNIPROT	down-regulates activity	phosphorylation	Ser425	PRPLRREsEI	-1									19843922	t	done	miannu	KCNJ2 encodes Kir2.1, a pore-forming subunit of the cardiac inward rectifier current, I(K1). This PKA-simulated catecholaminergic stimulation caused marked reduction of outward I(K1) compared with Kir2.1-WT. PKA-induced reduction in I(K1) was eliminated by mutating the phosphorylation site at serine 425 (S425N).	SIGNOR-273779	0.2
STAT5A	protein	P42229	UNIPROT	FOXP3	protein	Q9BZS1	UNIPROT	up-regulates				9606									18270368	t			We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cell	SIGNOR-254365	0.496
CD3	complex	SIGNOR-C432	SIGNOR	NCK1	protein	P16333	UNIPROT	up-regulates activity	relocalization			9606									12110186	t			We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck.	SIGNOR-259935	0.344
entinostat	chemical	CHEBI:132082	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257961	0.8
ULK2	protein	Q8IYT8	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	down-regulates	phosphorylation			9606									21460634	t		lperfetto	We could prove that ulk1-mediated phosphorylation of ampk reduced its level of phosphorylation at t172 of the _-subunit and hence interferes with its catalytic activity. I	SIGNOR-217487	0.306
AKT1	protein	P31749	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates activity	phosphorylation	Ser87	FIFMRRSsLLSRSSS	9606									16282323	t		lperfetto	Recombinant Akt could directly phosphorylate a GST-Bim(EL) fusion protein and identified the Akt phosphorylation site in the Bim(EL) domain as Ser(87). Further, we demonstrated that cytokine stimulation promotes Bim(EL) binding to 14-3-3 proteins. Finally, we show that mutation of Ser(87) dramatically increases the apoptotic potency of Bim(EL).	SIGNOR-252487	0.586
PIP3	smallmolecule	CHEBI:16618	ChEBI	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	relocalization			9606		BTO:0001130							23633519	t		lperfetto	Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring.	SIGNOR-236490	0.8
D-serine	smallmolecule	CHEBI:16523	ChEBI	NMDA receptor_2B	complex	SIGNOR-C348	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0002609								12393813	t		lperfetto	D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically 	SIGNOR-268278	0.8
PRKDC	protein	P78527	UNIPROT	NR3C1	protein	P04150	UNIPROT	unknown	phosphorylation	Ser508	QQATTGVsQETSENP	-1									9038175	t		lperfetto	Phosphorylation of the GR fusion protein by DNA-PK mapped to a single site, Ser-527. This site occurs adjacent the GR nuclear localization sequence between the DNA and ligand binding domains of GR, and thus its phosphorylation, if confirmed, has the potential to affect receptor function in vivo.	SIGNOR-248965	0.355
SIRT2	protein	Q8IXJ6	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates	deacetylation			9606		BTO:0000887;BTO:0001103							12887892	t		gcesareni	Sir2-mediated deacetylation of myod can be expected to inhibit its transcriptional capabilities.	SIGNOR-104251	0.385
AURKB	protein	Q96GD4	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	phosphorylation	Thr284	CPGRDRRtEEENLRK	9606									20959462	t		llicata	Importantly, the aurora b-mediated phosphorylation on ser(269) or thr(284) significantly compromises p53 transcriptional activity.	SIGNOR-168749	0.708
TTK	protein	P33981	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates	phosphorylation	Thr735	DTEWRSVtLPRDLQS	9606									18794806	t		lperfetto	Ttk phosphorylation of thr735 was associated with partial inhibition of nuclear targeting of c-abl.	SIGNOR-181064	0.284
CASP1	protein	P29466	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	cleavage	Asp326	YDPEMEEdSYDSFGE	-1									10069390	t		lperfetto	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261747	0.325
4-(3-chloro-2-fluorophenoxy)-1-[[6-(2-thiazolylamino)-2-pyridinyl]methyl]-1-cyclohexanecarboxylic acid	chemical	CHEBI:125340	ChEBI	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194411	0.8
ATM	protein	Q13315	UNIPROT	SMC1A	protein	Q14683	UNIPROT	up-regulates activity	phosphorylation	Ser966	GEDSVSGsQRISSIY	9606	BTO:0005521								11877376	t			Atm phosphorylates Smc1 on serines 957 and 966 in vitro and in vivo, and expression of an Smc1 protein mutated at these phosphorylation sites abrogates the ionizing irradiation-induced S phase cell cycle checkpoint	SIGNOR-255589	0.693
1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea	chemical	CHEBI:91327	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207299	0.8
SETBP1	protein	Q9Y6X0	UNIPROT	HOXA10	protein	P31260	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001271								22566606	f		miannu	Setbp1 activates hoxa9 and hoxa10 expression in myeloid progenitors	SIGNOR-197318	0.352
IKBKB	protein	O14920	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser36	RHDSGLDsMKDEEYE										11815618	t		lperfetto	Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. The phosphorylation of I_Balpha on Ser32 and Ser36 is initiated by an IkapapB kinase (IKK) complex that includes a catalytic heterodimer composed of I_B kinase 1 (IKK-1) and IkapapB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator.	SIGNOR-249366	0.92
PRKCD	protein	Q05655	UNIPROT	PTPRA	protein	P18433	UNIPROT	up-regulates activity	phosphorylation	Ser213	PLLARSPsTNRKYPP	9606									11676480	t		lperfetto	In this process, PTPalpha Ser-180 and Ser-204 phosphorylation is critical for the induction of phosphatase activity, which is required for dephosphorylation of pp60(c-src). Taken together, we demonstrate the physical and functional association between PI 3-kinase, PKCdelta and PTPalpha in a signaling complex that mediates the antitumor activity of the somatostatin analogue TT-232.	SIGNOR-249114	0.333
FUS	protein	P35637	UNIPROT	SHANK1	protein	Q9Y566	UNIPROT	up-regulates quantity	post transcriptional regulation			10090		BTO:0000142							32118033	t		lperfetto	These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.|As seen in Figure 7 (top panel), both PSD-95 Q1-Q2 and Shank1a GQ probes pulled down endogenous FUS, whereas their M2 mutants did not, indicating that the GQ structure is sufficient for recognition.	SIGNOR-262104	0.2
MAP2K1	protein	Q02750	UNIPROT	MAPK1	protein	P28482	UNIPROT	up-regulates activity	phosphorylation	Thr185	HDHTGFLtEYVATRW	9606	BTO:0003807								11971971	t		lperfetto	Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.	SIGNOR-236447	0.739
NRAS	protein	P01111	UNIPROT	ARAF	protein	P10398	UNIPROT	up-regulates	binding			9606									21779497	t		gcesareni	The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.	SIGNOR-175216	0.828
PRKD1	protein	Q15139	UNIPROT	RTKN	protein	Q9BST9	UNIPROT	up-regulates activity	phosphorylation	Ser448	QALAKQGsLYHEMAI										22228765	t	Phosphosite positions are derived from Figure 2	lperfetto	Here, we show that rhotekin, an effector of RhoA GTPase, is a novel substrate of PKD. We identified Ser-435 in rhotekin as the potential site targeted by PKD in vivo. Expression of a phosphomimetic S435E rhotekin mutant resulted in an increase of endogenous active RhoA GTPase levels. Phosphorylation of rhotekin by PKD2 modulates the anchoring of the RhoA in the plasma membrane.	SIGNOR-275511	0.364
mRNA_capping	phenotype	SIGNOR-PH178	SIGNOR	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates quantity by stabilization	chemical modification			9606									19224921	f		lperfetto	Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation. 	SIGNOR-268317	0.7
AKT2	protein	P31751	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates	phosphorylation	Ser119	EILSRRPsYRKILND	9606									9829964	t		gcesareni	Creb is a nuclear target for activation via the growth factor-dependent ser/thr kinase akt/pkb. When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp.	SIGNOR-62253	0.493
CASP9	protein	P55211	UNIPROT	CASP3	protein	P42574	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000567								9390557	t		lperfetto	Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade.	SIGNOR-53582	0.622
EXOC5	protein	O00471	UNIPROT	Exocyst_EXOC6B variant	complex	SIGNOR-C491	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270780	0.917
NTRK2	protein	Q16620	UNIPROT	NTRK2	protein	Q16620	UNIPROT	up-regulates activity	phosphorylation	Tyr516	PVIENPQyFGITNSQ	10090	BTO:0000944								10533983	t		miannu	TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc	SIGNOR-250204	0.2
RELN	protein	P78509	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				10090									17584923	f		Luana	Reln, encoding an extracellular signaling molecule essential for neuronal lamination and synaptic plasticity	SIGNOR-265772	0.7
COL2A1	protein	P02458	UNIPROT	A10/b1 integrin	complex	SIGNOR-C167	SIGNOR	up-regulates activity	binding			9606	BTO:0000249								25169886	t		lperfetto	Isolation, cloning, and sequence analysis of the integrin subunit alpha10, a beta1-associated collagen binding integrin expressed on chondrocytes.	SIGNOR-253347	0.469
ATR	protein	Q13535	UNIPROT	XPC	protein	Q01831	UNIPROT	up-regulates	binding			9606									23422745	t		gcesareni	Atrand atm physically interacted with xpc and promptly localized to the uv damage sites.	SIGNOR-201112	0.49
CENPE	protein	Q02224	UNIPROT	MAD2L1	protein	Q13257	UNIPROT	up-regulates activity				10090									12925705	f		lperfetto	CENP-E is required for efficient recruitment of BubR1, Mad1, and Mad2 to attached and newly unattached kinetochores	SIGNOR-252045	0.785
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606	BTO:0000938								29953871	f		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. 	SIGNOR-264955	0.7
SLC36A1	protein	Q7Z2H8	UNIPROT	glycine	smallmolecule	CHEBI:15428	ChEBI	up-regulates quantity	relocalization			9606									12748860	t		lperfetto	Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut.	SIGNOR-264737	0.8
PML	protein	P29590	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates	binding			9606									15356634	t		gcesareni	Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome.	SIGNOR-128735	0.529
TMC2	protein	Q8TDI7	UNIPROT	Hair cells mechanotransduction channel	complex	SIGNOR-C290	SIGNOR	form complex	binding			10090		BTO:0000630							23217710	t		lperfetto	The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012).	SIGNOR-262570	0.404
bortezomib	chemical	CHEBI:52717	ChEBI	PSMD1	protein	Q99460	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000898								21504411	t		miannu	Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma.	SIGNOR-259312	0.8
CREB5	protein	Q02930	UNIPROT	STAT1	protein	P42224	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		 BTO:0002817							21132541	f		miannu	 Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition),	SIGNOR-253810	0.2
CTDSP2	protein	O14595	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	dephosphorylation	Ser208	DAGSPNLsPNPMSPA	9606	BTO:0000007								17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248294	0.399
copper(1+)	smallmolecule	CHEBI:49552	ChEBI	SOD2	protein	P04179	UNIPROT	up-regulates activity	chemical activation												1542024	t		lperfetto	Copper as a cofactor and regulator of copper,zinc superoxide dismutase	SIGNOR-272300	0.8
PRKCA	protein	P17252	UNIPROT	HRH1	protein	P35367	UNIPROT	down-regulates	phosphorylation	Thr478	CNENFKKtFKRILHI	9606		BTO:0000975							15107581	t	Translocation from Endosome to Lysosome	fspada	The peptide p10-t478a (thr478 to alanine) was not phosphorylated by pkc, indicating that thr478 can be phosphorylated by pkc.	SIGNOR-124356	0.2
CDK7	protein	P50613	UNIPROT	NR5A1	protein	Q13285	UNIPROT	up-regulates	phosphorylation	Ser203	EYPEPYAsPPQPGLP	9606									17901130	t		llicata	In conclusion, our results indicate that cdk7, as part of the cak complex and tfiih, phosphorylates sf1 at s203 followed by increased transcriptional activity of sf1	SIGNOR-157952	0.376
TUBE1	protein	Q9UJT0	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates				9606									28347630	f		miannu	Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation	SIGNOR-267178	0.7
GPR84	protein	Q9NQS5	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257099	0.252
CCKAR	protein	P32238	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257035	0.254
HCK	protein	P08631	UNIPROT	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	up-regulates activity	phosphorylation	Tyr798	VSRNAAEyLLSSGIN	9606									16912036	t		Manara	Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 	SIGNOR-260812	0.2
GRK3	protein	P35626	UNIPROT	CCR5	protein	P51681	UNIPROT	down-regulates activity	phosphorylation	Ser336	QEAPERAsSVYTRST	9534	BTO:0000298								10085131	t			Serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. CCR5 phosphorylation and desensitization through a GRK-mediated mechanism	SIGNOR-251463	0.2
MYO10	protein	Q9HD67	UNIPROT	Axonal_growth_cone_formation	phenotype	SIGNOR-PH199	SIGNOR	up-regulates				9606									27580874	f		miannu	Myosin X is required for filopodia formation and extension. myosin X functions as an antiparallel dimer in cells with a unique geometry optimized for movement on actin bundles. Myosin X facilitates initiation and elongation of filopodia, which implies favouring formation of parallel bundled F-actin filaments.	SIGNOR-268284	0.7
TOX2	protein	Q96NM4	UNIPROT	TBX21	protein	Q9UL17	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002181								25352127	t		Luana	We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET).	SIGNOR-266097	0.299
PTPN12	protein	Q05209	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1190	DIYETDYyRKGGKGL	-1									10734133	t		gcesareni	Interestingly, all PTPs that were tested could completely dephosphorylate the receptor, given sufficient time, including a negative control (PTP-PEST) that failed to bind IRK as a trapping mutant.	SIGNOR-262291	0.384
MLNR	protein	O43193	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257016	0.409
CDK8	protein	P49336	UNIPROT	E2F1	protein	Q01094	UNIPROT	down-regulates	phosphorylation	Ser375	PVDEDRLsPLVAADS	9606									22945643	t		lperfetto	Cdk8 regulates e2f1 transcriptional activity through s375 phosphorylation. 	SIGNOR-198934	0.497
PPP2CA	protein	P67775	UNIPROT	PRKCD	protein	Q05655	UNIPROT	down-regulates activity	dephosphorylation	Ser664	QSAFAGFsFVNPKFE	9606									11959144	t			PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex	SIGNOR-248639	0.385
MAPK1	protein	P28482	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1724	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120112	0.316
BCOR	protein	Q6W2J9	UNIPROT	HDAC1	protein	Q13547	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								10898795	t		miannu	BCoR can interact w Because HDACs appear to be involved in repression by an increasing number of transcriptional repressors, we tested whether BCoR can associate with HDACs. BCoR can interact with HDAC1, HDAC3, and HDAC-B/5 more strongly than with HDAC-A/4, HDAC-C, HDAC-D, and HDAC-E. 	SIGNOR-252236	0.385
TAOK3	protein	Q9H2K8	UNIPROT	STK3	protein	Q13188	UNIPROT	up-regulates	phosphorylation			9606									23431053	t		gcesareni	In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2	SIGNOR-201333	0.295
SCN4A	protein	P35499	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606									27262167	t		miannu	Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential.	SIGNOR-253405	0.8
RPS6KA5	protein	O75582	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Ser29	ATKAARKsAPSTGGV	9606									18508628	t	Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription.	gcesareni	In addition to ser10, msk was also found to phosphorylate a second site on h3, ser28 (75). It should be noted that while both ser10 and ser28 in h3 are extensively phosphorylated during mitosis, this is independent of msks and is catalysed by aurora kinases. In contrast, msks only phosphorylate a small proportion of the total cellular histone h3 in response to mitogens or stress. The spatial distribution of ser10 and ser28 phosphorylation is very tightly regulated in cells. In vitro, msk1 will phosphorylate one histone h3 molecule on both ser10 and ser28. Surprisingly it has been shown that in cells msk phosphorylates either ser10 or ser28 but not both on individual nucleosomes.	SIGNOR-178708	0.2
NEK9	protein	Q8TD19	UNIPROT	NEK9	protein	Q8TD19	UNIPROT	up-regulates	phosphorylation	Ser944	GQQVGMHsKGTQTAK	9606									21454704	t		lperfetto	We find that the interaction of lc8 with nek9 depends on a (k/r)xtqt motif adjacent to the nek9 c-terminal coiled coil motif, results in nek9 multimerization, and increases the rate of nek9 autoactivation. Lc8 binding to nek9 is regulated by nek9 activity through the autophosphorylation of ser(944), a residue immediately n-terminal to the (k/r)xtqt motif.	SIGNOR-173026	0.2
3-isobutyl-1-methylxanthine	chemical	CHEBI:48518	ChEBI	CEBPA	protein	P49715	UNIPROT	up-regulates				9606									11279134	f		fspada	The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin	SIGNOR-106478	0.8
PRKCZ	protein	Q05513	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser320	QRSRKRLsQDAYRRN	9606									12056906	t		lperfetto	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89268	0.402
PELI2	protein	Q9HAT8	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates	ubiquitination			9606									17997719	t		gcesareni	These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4.	SIGNOR-159058	0.772
vincaleukoblastine sulfate	chemical	CHEBI:9984	ChEBI	TUBA1A	protein	Q71U36	UNIPROT	down-regulates activity	chemical inhibition			9606									15579115	t		miannu	Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. 	SIGNOR-259255	0.8
CSNK2A1	protein	P68400	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Thr88	KHLVALYtRDEHFAI	-1									8349691	t		llicata	These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1.	SIGNOR-250911	0.345
mifepristone	chemical	CHEBI:50692	ChEBI	NR3C1	protein	P04150	UNIPROT	down-regulates activity	chemical inhibition			9534	BTO:0001538								8282004	t		miannu	The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4).	SIGNOR-258709	0.8
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	GAP43	protein	P17677	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									26865625	t		miannu	 In this study, we demonstrated for the first time that growth-associated protein 43 (GAP43), a well known growth cone protein that promotes axonal regeneration, can be induced in rat brain astrocytes by the proinflammatory endotoxin lipopolysaccharide via both nuclear factor-κB and signal transducer and activator of transcription 3-mediated transcriptional activation.	SIGNOR-266770	0.2
KIFC1	protein	Q9BW19	UNIPROT	Epithelial-mesenchymal_transition	phenotype	SIGNOR-PH45	SIGNOR	up-regulates				9606									33361741	f		miannu	Kinesin Family Member C1 (KIFC1) Regulated by Centrosome Protein E (CENPE) Promotes Proliferation, Migration, and Epithelial-Mesenchymal Transition of Ovarian Cancer	SIGNOR-266117	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PALLD	protein	Q8WX93	UNIPROT	unknown	phosphorylation	Ser1118	VRRPRSRsRDSGDEN	9606									20471940	t		llicata	Akt1, but not akt2, phosphorylates palladin at ser507 in a domain that is critical for f-actin bundling.	SIGNOR-165497	0.2
MARCHF9	protein	Q86YJ5	UNIPROT	HLA-DQA1	protein	P01909	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001522								19457934	t		miannu	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. 	SIGNOR-271538	0.2
CEBPG	protein	P53567	UNIPROT	LTF	protein	P02788	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								15588942	f		miannu	C/EBP_ interacts with C/EBP_ through the leucine-zipper–containing domain. C/EBP_ and C/EBP_ synergistically activate transcription of lactoferrin promoter	SIGNOR-225015	0.2
DVL1	protein	O14640	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity	binding			9534	BTO:0004055								10196136	t		lperfetto	We have recently found that Dvl-1 directly binds to Axin and that the binding of Dvl-1 to Axin does not affect the interaction of GSK-3beta with Axin. It is possible that the binding of Dvl to Axin induces the structural change of the Axin complex; therefore GSK-3beta does not effectively phosphorylate Axin. This is the first demostration showing that Dvl inhibits the function of GSK-3beta directly.	SIGNOR-227917	0.701
PTPN2	protein	P17706	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates	dephosphorylation	Tyr1214	VCDPKFHyDNTAGIS	9606									18840653	t		gcesareni	Vegfr2 contains several critical tyrosine residues that are autophosphorylated following activation. Our phosphorylation assays showed that tcptp was able to target specific tyrosines in vegfr2. The autophosphorylation sites tyr1054/1059 and tyr1214 were dephosphorylated by tcptp. Tyr996 was a tcptp target as well.	SIGNOR-181546	0.548
EIF1B	protein	O60739	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	up-regulates activity	relocalization			9606									20921384	t		lperfetto	Genetic and biochemical studies have revealed several eukaryotic factors involved in selecting the correct initiation codon (3–6). Further analyses pointed toward eukaryotic initiation factor 1 (eIF1) as the key mediator of this process (7–10). eIF1 binds near the P-site of the small ribosomal subunit (11); this binding is thought to lead to an open conformation of the preinitiation complex favoring scanning	SIGNOR-269145	0.474
EGFR	protein	P00533	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates	phosphorylation	Tyr659	VADERVDyVVVDQQK	9606	BTO:0000527;BTO:0000017								9890893	t		lperfetto	Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689).	SIGNOR-236404	0.751
E2F1	protein	Q01094	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23542036	f		miannu	We show here that EAPP stimulates the MDR1 promoter resulting in higher PGP levels. Independently of EAPP, E2F1 also increases the activity of the MDR1 promoter. 	SIGNOR-253841	0.2
PTAFR	protein	P25105	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257329	0.2
RPS6KB1	protein	P23443	UNIPROT	CAD	protein	P27708	UNIPROT	up-regulates	phosphorylation	Ser1859	PPRIHRAsDPGLPAE	9606									23429703	t		lperfetto	Mtorc1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein s6 kinase 1 (s6k1), which directly phosphorylates s1859 on cad, the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mtorc1 thus stimulates the production of new nucleotides to accommodate an increase in rna and dna synthesis.	SIGNOR-201117	0.381
8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	chemical	CHEBI:93369	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258538	0.8
NLRP3	protein	Q96P20	UNIPROT	NLRP3 inflammasome	complex	SIGNOR-C225	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256410	0.738
SLC2A3	protein	P11169	UNIPROT	glucose	chemical	CHEBI:17234	ChEBI	up-regulates quantity	relocalization			9606									23506862	t		miannu	GLUThe SLC2A3 gene encoding GLUT3 was first cloned from a human fetal skeletal muscle cell line (Kayano et al., 1988). It shares ~64% sequence identity with SLC2A1. GLUT3 has a higher apparent affinity (lower Km) and a higher maximum turnover number for glucose than the other Class 1 GLUT proteins, and its principal physiological substrate is clearly D-glucose T1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells.	SIGNOR-267461	0.8
MMP1	protein	P03956	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272377	0.7
CNKSR1	protein	Q969H4	UNIPROT	RASSF1	protein	Q9NS23	UNIPROT	up-regulates	binding			9606									22830020	t		gcesareni	Cnk1 binds to rassf1a and promotes apoptosis through a pathway that requires rassf1a and mst kinases.	SIGNOR-198432	0.412
MAP2K6	protein	P52564	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation	Tyr182	TDDEMTGyVATRWYR	9534									8622669	t		lperfetto	These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase	SIGNOR-40427	0.733
SMURF	proteinfamily	SIGNOR-PF29	SIGNOR	TGFBR2	protein	P37173	UNIPROT	down-regulates activity	ubiquitination			9606									22298955	t		lperfetto	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-253265	0.2
2-(2-amino-3-methoxyphenyl)chromen-4-one	chemical	CHEBI:77954	ChEBI	MAPK7	protein	Q13164	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0000142							11782488	t		gcesareni	Bmk1 activation by h2o2 was inhibited by both pd98059 and u0126, which were reported to inhibit mek5 as well as mek1/2.	SIGNOR-113773	0.8
UPF2	protein	Q9HAU5	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606		BTO:0000142							31636381	f		miannu	Our data indicate that proper synaptic plasticity and cognitive function requires UPF2. 	SIGNOR-265235	0.7
YWHAE	protein	P62258	UNIPROT	NEFL	protein	P07196	UNIPROT	down-regulates activity	binding			9606									23230147	t		miannu	These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments.	SIGNOR-252398	0.28
CREB1	protein	P16220	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0002572								14593102	f		lperfetto	Expression of constitutively active CREB strongly activated C/EBPbeta promoter-reporter genes, induced expression of endogenous C/EBPbeta, and caused adipogenesis in the absence of the hormonal inducers normally required	SIGNOR-250573	0.578
PRKCA	protein	P17252	UNIPROT	KCNQ2	protein	O43526	UNIPROT	up-regulates activity	phosphorylation	Ser551	CVMRFLVsKRKFKES	10029	BTO:0000246								12754513	t		lperfetto	Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. | These results suggest that Ser534 and 541 are key sites for PKC phosphorylation, although we have not ruled out the possibility that other PKC sites are involved in this process.	SIGNOR-249209	0.329
RASGEF1C	protein	Q8N431	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates	binding			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-161508	0.2
CCL25	protein	O15444	UNIPROT	CCR9	protein	P51686	UNIPROT	up-regulates	binding			9606									11159507	t		gcesareni	Ccr9 is a specific receptor for the beta-chemokine teck/ccl25.	SIGNOR-104902	0.798
MAPK14	protein	Q16539	UNIPROT	ELK3	protein	P41970	UNIPROT	up-regulates	phosphorylation	Ser363	LSPVAPLsPARLQGP	9606									9130707	t		gcesareni	Tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387. Mutation of these sites to alanine severely reduces c-fos sre-dependent transcription mediated by sap-1a and p38 map kinase.	SIGNOR-47685	0.386
SIK2	protein	Q9H0K1	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Ser794	QHLRLSTsSGRLLYA	9606									12624099	t		lperfetto	Sik2 could phosphorylate ser(794) of human irs-1	SIGNOR-99059	0.586
AURKB	protein	Q96GD4	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									14583461	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.	SIGNOR-118890	0.2
CAMK2D	protein	Q13557	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser1985	DSVTRATsDNLQVRG										28882890	t	Phosphosite is derived from Figure 2	lperfetto	C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation| Of 19 native NaV1.5 phosphorylation sites identified, two C-terminal phosphoserines at positions 1938 and 1989 showed increased phosphorylation in the CaMKIIδc-Tg compared with the WT ventricles. 	SIGNOR-275783	0.48
NEDD4L	protein	Q96PU5	UNIPROT	SCN1A	protein	P35498	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000938								23778145	t		miannu	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 	SIGNOR-253457	0.296
PRKACA	protein	P17612	UNIPROT	RYR2	protein	Q92736	UNIPROT	up-regulates activity	phosphorylation	Ser2808	YNRTRRIsQTSQVSV	-1									14532276	t		miannu	PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure	SIGNOR-250079	0.458
MAPK1	protein	P28482	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	up-regulates	phosphorylation			9606									19282669	t		gcesareni	Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.	SIGNOR-161518	0.715
YARS1	protein	P54577	UNIPROT	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									16429158	t		miannu	YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr	SIGNOR-270520	0.8
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1717	SPSYSPTsPSYSPTS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248742	0.727
AHR	protein	P35869	UNIPROT	CYP1A1	protein	P04798	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17012224	t		miannu	Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1.	SIGNOR-259909	0.673
GSK3A	protein	P49840	UNIPROT	ANKRD28	protein	O15084	UNIPROT	down-regulates activity	phosphorylation	Ser1007	INRYTNTsKTVSFEA	-1							phosphorylation:Ser1011	TNTSKTVsFEALPIM	17023142	t		lperfetto	We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K	SIGNOR-264792	0.2
LGALS3	protein	P17931	UNIPROT	MCL1	protein	Q07820	UNIPROT	up-regulates quantity by stabilization				9606	BTO:0000664								21821001	f		miannu	Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells.	SIGNOR-261905	0.257
MMP12	protein	P39900	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272357	0.7
TLR4	protein	O00206	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation			9606									28137827	t		miannu	Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation.	SIGNOR-263652	0.427
NEK6	protein	Q9HC98	UNIPROT	PSMD2	protein	Q13200	UNIPROT	up-regulates activity	phosphorylation	Ser361	ENNRFGGsGSQVDSA	-1									31843888	t	done	miannu	Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B). 	SIGNOR-273894	0.2
NOTCH1	protein	P46531	UNIPROT	NFKB1	protein	P19838	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								11591772	f		lperfetto	Nf-kappab activity is regulated by notch-1 via transcriptional control of nf-kappab.	SIGNOR-110963	0.385
PTPRO	protein	Q16827	UNIPROT	VCP	protein	P55072	UNIPROT	down-regulates activity	dephosphorylation			9606									23533167	t		miannu	An important aspect of this study is that tyrosine dephosphorylation of VCP by PTPRO sensitizes HepG2 cells to Doxorubicin, a chemotherapeutic drug commonly used for a variety of cancers.	SIGNOR-277063	0.433
RPS3	protein	P23396	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262421	0.889
TAOK3	protein	Q9H2K8	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates	phosphorylation			9606									23431053	t		gcesareni	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2	SIGNOR-192762	0.287
CCND1	protein	P24385	UNIPROT	HDAC2	protein	Q92769	UNIPROT	up-regulates	binding			9606									15713663	t		gcesareni	Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5.	SIGNOR-134053	0.482
DMTF1	protein	Q9Y222	UNIPROT	BCL3	protein	P20749	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004532								19816943	f		Luana	 Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. 	SIGNOR-261583	0.2
DYRK2	protein	Q92630	UNIPROT	CARHSP1	protein	Q9Y2V2	UNIPROT	unknown	phosphorylation	Ser30	TPRSRERsPSPLRGN	9606		BTO:0000671							15910284	t		lperfetto	Dyrk2 (dual-specificity tyrosine-phosphorylated and -regulated protein kinase 2) phosphorylated crhsp24 at ser30, ser32 and ser41 in vitro, and ser41 was identified as a site phosphorylated in cells.	SIGNOR-137474	0.263
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	ACIN1	protein	Q9UKV3	UNIPROT	up-regulates	cleavage			9606									10490026	t		amattioni	Induces apoptotic chromatin condensation after activation by casp3	SIGNOR-256449	0.612
FLT3	protein	P36888	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates				9606	BTO:0000222;BTO:0001946	BTO:0000887;BTO:0001103							23704355	f		gcesareni	Here we report the identification of flt3l (fms-like tyrokine kinase 3 ligand) signaling as a novel regulator of skeletal myogenesis	SIGNOR-202105	0.7
SMO	protein	Q99835	UNIPROT	GNB1	protein	P62873	UNIPROT	up-regulates	binding			9606									16885213	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-148537	0.357
AURKA	protein	O14965	UNIPROT	FAF1	protein	Q9UNN5	UNIPROT	down-regulates activity	phosphorylation	Ser291	DVHMVSDsDGDDFED	9606									18790738	t		llicata	This study reports that aurora-a (aur-a) phosphorylates fas-associated factor-1 (faf1) at ser-289 and ser-29 our findings support the negative feedback regulation of aur-a via phosphorylation of the death-promoting protein, faf1	SIGNOR-180891	0.2
ARF6	protein	P62330	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				10116	BTO:0003102								14565977	f		miannu	ARNO and ARF6 regulate axonal elongation and branching through downstream activation of phosphatidylinositol 4-phosphate 5-kinase alpha	SIGNOR-264908	0.7
MMP25	protein	Q9NPA2	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272392	0.7
GDF5	protein	P43026	UNIPROT	ID1	protein	P41134	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004291								16716349	f	Regulation	miannu	 GDF5 induces ID1 and ID3 in HUVSMC by a smad-dependent, MAPK-independent pathway. GDF5 binds to specific receptors, thereby inducing phosphorylation and translocation of smad1 to the nucleus where it is involved in the regulation of transcription. 	SIGNOR-251871	0.285
beta-D-fructofuranose 2,6-bisphosphate	smallmolecule	CHEBI:28602	ChEBI	PFKM	protein	P08237	UNIPROT	up-regulates activity	binding			9606									19454274	t			The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux	SIGNOR-267267	0.8
CDK2	protein	P24941	UNIPROT	FZR1	protein	Q9UM11	UNIPROT	down-regulates activity	phosphorylation	Ser163	KSQKLLRsPRKPTRK										12560341	t		llicata	 A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus. 	SIGNOR-250733	0.733
CSNK2A2	protein	P19784	UNIPROT	GTF2A1	protein	P52655	UNIPROT	up-regulates activity	phosphorylation	Ser281	DGTGDTSsEEDEDEE	-1									11278496	t		llicata	We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function.	SIGNOR-250996	0.382
CSNK2A1	protein	P68400	UNIPROT	CARD9	protein	Q9H257	UNIPROT	down-regulates activity	phosphorylation	Thr533	TGSDNTDtEGS	9606									17936701	t			PVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2.	SIGNOR-269111	0.352
seliciclib	chemical	CHEBI:45307	ChEBI	CCNB1	protein	P14635	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206562	0.8
CSNK2A2	protein	P19784	UNIPROT	FGF14	protein	Q92915	UNIPROT	up-regulates activity	phosphorylation	Ser228	PGVTPSKsTSASAIM	9606	BTO:0000938								26917740	t		lperfetto	 Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.	SIGNOR-275740	0.312
873837-23-1	chemical	CID:46930994	PUBCHEM	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190470	0.8
LPAR5	protein	Q9H1C0	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257284	0.333
PRKACB	protein	P22694	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser284	AGGGRRIsDSHEDTG	9606		BTO:0000887							20151718	t		miannu	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163772	0.276
CDK4	protein	P11802	UNIPROT	MYOG	protein	P15173	UNIPROT	down-regulates	binding			9606			SIGNOR-C18						21902831	t		gcesareni	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-176530	0.336
CHRM3	protein	P20309	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257018	0.56
Phenylalanyl-tRNA synthetase	complex	SIGNOR-C473	SIGNOR	diphosphate(3-)	smallmolecule	CHEBI:33019	ChEBI	up-regulates quantity	chemical modification			9606									20223217	t		miannu	Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers.	SIGNOR-270440	0.8
AKT1	protein	P31749	UNIPROT	MVD	protein	P53602	UNIPROT	up-regulates activity	phosphorylation	Ser96	LARKRRNsRDGDPLP	10090									25378391	t		miannu	Akt modulated the pathway by phosphorylating mevalonate diphosphate decarboxylase (MDD) at Ser96. These data suggest that Akt regulates Rac1 activity by directly phosphorylating MDD at Ser96, which augments Rac1 geranylgeranylation. 	SIGNOR-265891	0.2
CHEK2	protein	O96017	UNIPROT	FOXM1	protein	Q08050	UNIPROT	up-regulates	phosphorylation	Ser376	PLLPRVSsYLVPIQF	9606	BTO:0001938								17101782	t		lperfetto	Chk2 mediates stabilization of the foxm1 transcription factor to stimulate expression of dna repair genesthis phosphorylation of foxm1 on serine residue 361 caused increased stability of the foxm1 protein	SIGNOR-150746	0.71
RBPJ	protein	Q06330	UNIPROT	CIR1	protein	Q86X95	UNIPROT	up-regulates	binding			9606									9874765	t		amattioni	In the mechanism of cbf1-mediated repression, cbf1 binds to a unique corepressor cir. Targeting of cir to cbf1 is an important component of repression. Cir binds to histone deacetylase and to sap30 and serves as a linker between cbf1 and the histone deacetylase complex.	SIGNOR-62932	0.66
AKT1	protein	P31749	UNIPROT	AKT1S1	protein	Q96B36	UNIPROT	down-regulates activity	phosphorylation	Thr246	LPRPRLNtSDFQKLK	9606	BTO:0000007								12524439	t		gcesareni	Treatment of these cells with 4-hydroxytamoxifen stimulated the phosphorylation of wt PRAS40 but not the mutant PRAS40 in which Thr-246 was mutated. These results demonstrate that activation of Akt alone is sufficient to induce phosphorylation of PRAS40	SIGNOR-252544	0.775
HSP90AA1	protein	P07900	UNIPROT	PPP5C	protein	P53041	UNIPROT	up-regulates	binding			9606									15577939	t		miannu	Hsp90 causes substantial activation of ppp5 by competing for tpr_phosphatase domain contacts and allowing access to the catalytic site.	SIGNOR-131564	0.762
PRKCA	protein	P17252	UNIPROT	PLD1	protein	Q13393	UNIPROT	up-regulates	phosphorylation	Ser561	PRKFSKFsLYKQLHR	9606									10441128	t		gcesareni	Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells.	SIGNOR-69934	0.703
EIF5B	protein	O60841	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	down-regulates activity	binding			9606									30211544	t		lperfetto	 eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC.	SIGNOR-269121	0.607
HSP90AA1	protein	P07900	UNIPROT	FLCN	protein	Q8NFG4	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								27353360	t			Here we show that the stability of the tumour suppressor folliculin (FLCN) depends on the chaperone function of Hsp90.	SIGNOR-256505	0.31
9-cis-retinoic acid	chemical	CHEBI:50648	ChEBI	RAR	proteinfamily	SIGNOR-PF45	SIGNOR	up-regulates activity	chemical activation			9606									18321241	t		miannu	Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma).	SIGNOR-259241	0.8
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	RPS6	protein	P62753	UNIPROT	up-regulates	phosphorylation	Ser235	IAKRRRLsSLRASTS	9606									17360704	t		gcesareni	We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism.	SIGNOR-252813	0.2
PRKACA	protein	P17612	UNIPROT	TPH1	protein	P17752	UNIPROT	up-regulates activity	phosphorylation	Ser58	RKSKRRNsEFEIFVD	-1									9109552	t		miannu	The activation of tryptophan hydroxylase by protein kinase A is mediated by the phosphorylation of serine-58 within the regulatory domain of the enzyme.	SIGNOR-250062	0.356
N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-6-quinazolinyl]-2-propenamide	chemical	CHEBI:91467	ChEBI	ERBB4	protein	Q15303	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189945	0.8
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264752	0.7
JUN	protein	P05412	UNIPROT	AP1	complex	SIGNOR-C154	SIGNOR	form complex	binding			9606									1904542	t		irozzo	The proteins encoded by the proto-oncogenes c-fos and c-jun (Fos and Jun, respectively) form a heterodimeric complex that regulates transcription by interacting with the DNA-regulatory element known as the activator protein 1 (AP-1) binding site.	SIGNOR-256363	0.951
G3BP2	protein	Q9UN86	UNIPROT	Stress_granules	phenotype	SIGNOR-PH124	SIGNOR	up-regulates				9606									23279204	f		SARA	G3BP1 and G3BP2 form homo‐ and hetero‐multimers to induce SGs	SIGNOR-260983	0.7
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser399	DNITLPPsQPSPTGG	9606	BTO:0000007								17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-249668	0.397
PRKAA1	protein	Q13131	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Thr179	SSPDKRLtLSQIYEW	9606	BTO:0000007								17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-252980	0.509
POU5F1	protein	Q01860	UNIPROT	GATA4	protein	P43694	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									22795133	f		lperfetto	Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)	SIGNOR-253161	0.513
α-Catenin	proteinfamily	SIGNOR-PF72	SIGNOR	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates				9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265814	0.7
paliperidone	chemical	CHEBI:82978	ChEBI	HTR2A	protein	P28223	UNIPROT	down-regulates activity	chemical inhibition			10090		BTO:0000331							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258564	0.8
PPP1R9B	protein	Q96SB3	UNIPROT	PP1	proteinfamily	SIGNOR-PF54	SIGNOR	up-regulates activity	binding			9606	BTO:0000938								10194355	t		miannu	In the present study, the interaction between PP1 and spinophilin, a neuronal protein that targets PP1 to dendritic spines, has been characterized. . These studies support the notion that spinophilin functions in vivo as a neuronal PP1 targeting subunit by directing the enzyme to postsynaptic densities and regulating its activity toward physiological substrates.	SIGNOR-269178	0.764
MRE11	protein	P49959	UNIPROT	MRE11/RAD50/NBS1	complex	SIGNOR-C147	SIGNOR	form complex	binding												17713585	t		lperfetto	The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50.	SIGNOR-251504	0.2
NLGN2	protein	Q8NFZ4	UNIPROT	NRXN3	protein	Q9HDB5	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								18923512	t	brain	lperfetto	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264171	0.82
iron-sulfur cluster	smallmolecule	CHEBI:30408	ChEBI	PRIM2	protein	P49643	UNIPROT	up-regulates activity	chemical activation												26083061	t		lperfetto	Human DNA primase, are Fe-S proteins. The loss of an iron-sulfur cluster in RAD3 helicase results in a failure to unwind DNA1 	SIGNOR-262134	0.8
ZAP70	protein	P43403	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation	Tyr427	ELFDDPSyVNVQNLD	9606	BTO:0000782								9710204	t		gcesareni	The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2).	SIGNOR-59659	0.664
TLR4	protein	O00206	UNIPROT	TIRAP	protein	P58753	UNIPROT	up-regulates	binding			9606									11544529	t		fstefani	Mal (myd88-adapter-like) is required for toll-like receptor-4 signal transduction.	SIGNOR-110337	0.772
AMPK	complex	SIGNOR-C15	SIGNOR	NAMPT	protein	P43490	UNIPROT	up-regulates quantity				10090									18477450	f		gcesareni	Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt	SIGNOR-238824	0.276
CREB1	protein	P16220	UNIPROT	NR2F1	protein	P10589	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000152								15955695	f		miannu	 In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro.	SIGNOR-253792	0.275
CTSS	protein	P25774	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													11920402	f		lperfetto	Cathepsins K and S have been implicated in various aspects of extracellular matrix degradation and inflammatory responses. 	SIGNOR-253319	0.7
WASHC2C	protein	Q9Y4E1	UNIPROT	WASH complex	complex	SIGNOR-C258	SIGNOR	form complex	binding												23721880	t		lperfetto	The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53.	SIGNOR-261016	0.2
SLC24A4	protein	Q8NFF2	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			9606									30173760	t		miannu	K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 	SIGNOR-264397	0.8
EGFR	protein	P00533	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			9606									24697349	t			Adaptor protein Grb2 binds phosphotyrosines in the epidermal growth factor (EGF) receptor (EGFR) and thereby links receptor activation to intracellular signaling cascades.	SIGNOR-267725	0.921
PIPP	smallmolecule	CID:24755493	PUBCHEM	LRP6	protein	O75581	UNIPROT	up-regulates				9606									18772438	f		gcesareni	Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. In turn, ptdins (4,5)p2 regulated phosphorylation of lrp6 at thr1479 and ser1490	SIGNOR-180797	0.8
RPS6KB1	protein	P23443	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser82	RALSRQLsSGVSEIR	9606									19593530	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	lperfetto	Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk.	SIGNOR-186959	0.315
GFPT1	protein	Q06210	UNIPROT	2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-)	smallmolecule	CHEBI:58725	ChEBI	up-regulates quantity	chemical modification			9606									21310273	t		miannu	GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans	SIGNOR-267817	0.8
WNT10B	protein	O00744	UNIPROT	FZD5	protein	Q13467	UNIPROT	up-regulates	binding			9606									12055200	t		fspada	Inhibition of adipogenesis by wnt10b is likely mediated by‚ wnt‚ receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 8	SIGNOR-210164	0.604
TAGAP	protein	Q8N103	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260524	0.376
NFKB1	protein	P19838	UNIPROT	BMP4	protein	P12644	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000018								17350185	t		Luana	 The effect of TNF-alpha on the Bmp4 promoter is mediated through NF-kB.	SIGNOR-266086	0.2
JAK3	protein	P52333	UNIPROT	JAK3	protein	P52333	UNIPROT	up-regulates	phosphorylation	Tyr785	NSLISSDyELLSDPT	9606									18250158	t		lperfetto	The phosphorylation of wt jak3 and y980f/y981f/y785f mutant jak3 is presumably mediated through autophosphorylation at distinct jak3 sites within this model systemhosphorylation of jak3 on y785 has been reported to create a binding site for the adaptor protein sh2b-beta	SIGNOR-160660	0.2
3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione	chemical	CHEBI:91368	ChEBI	PRKCA	protein	P17252	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191490	0.8
SNS-314 Mesylate	chemical	CID:24995523	PUBCHEM	AURKC	protein	Q9UQB9	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207105	0.8
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	FERMT2	protein	Q96AC1	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser177	LITPGSGsIYSSPGL	9606	BTO:0000567								35469017	t		miannu	CDK1–cyclin B1 mediates KIND1 and KIND2 phosphorylation at mitotic entry . MS of KIND1 and KIND2 immunoprecipitates from STLC-arrested HeLa cells confirmed the phosphorylation of KIND1-S179 and KIND2-S181 and revealed phosphorylation of closely adjacent serine residues (KIND1: SSphS174GphS176PVphS179PGLYSK; KIND2: GphS175GphS177IYphS180phS181PGLYSK), although to a weaker extent (Supplementary Table 2).	SIGNOR-276713	0.2
IL17RA	protein	Q96F46	UNIPROT	IL17R complex	complex	SIGNOR-C260	SIGNOR	form complex	binding			9606	BTO:0001946								32024054	t		lperfetto	Importantly, IL-17 was involved in increased collagen production in cardiac fibroblasts in response to HG, with both subunits of the IL-17RA and IL-17RC heterodimer complex being important to mediating this response.	SIGNOR-261335	0.531
TAOK2	protein	Q9UL54	UNIPROT	MAP2K6	protein	P52564	UNIPROT	up-regulates activity	binding			9606									10497253	t		lperfetto	Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7.	SIGNOR-70950	0.633
ARPC1A	protein	Q92747	UNIPROT	ARP2/3	complex	SIGNOR-C146	SIGNOR	form complex	binding			9606									12479800	t			The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc	SIGNOR-251515	0.872
POU5F1	protein	Q01860	UNIPROT	FOXA2	protein	Q9Y261	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003298								22795133	f		lperfetto	Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D)	SIGNOR-253165	0.438
TAF1	protein	P21675	UNIPROT	GTF2A1	protein	P52655	UNIPROT	up-regulates activity	phosphorylation	Ser280	VDGTGDTsSEEDEDE	9606									11278496	t		lperfetto	TAFII 250 Phosphorylates Human Transcription Factor IIA on Serine Residues Important for TBP Binding and Transcription ActivityAdditional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels	SIGNOR-246630	0.662
PFDN1	protein	O60925	UNIPROT	Prefoldin co-chaperone	complex	SIGNOR-C513	SIGNOR	form complex	binding			9606									32699605	t		miannu	The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6)	SIGNOR-270932	0.948
CSNK2A1	protein	P68400	UNIPROT	SET	protein	Q01105-2	UNIPROT	down-regulates	phosphorylation	Ser9	SAPAAKVsKKELNSN	9606	BTO:0000938	BTO:0000142							23374587	t	The effect has been demonstrated using Q01105-2	miannu	Ckii-mediated phosphorylation at ser9 hinders nuclear import of set	SIGNOR-200798	0.372
RELA	protein	Q04206	UNIPROT	CBP/p300	complex	SIGNOR-C6	SIGNOR	up-regulates	binding			9606									10207072	t		lperfetto	Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo.	SIGNOR-217655	0.844
BAX	protein	Q07812	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates activity	binding			9606									10629050	t	Following Bid-induced conformational change	lperfetto	Following bid-induced conformational change, bax oligomerizes and inserts tightly within the outer mitochondrial membrane. The integration of bax in the outer mitochondrial membrane is followed by cytochrome crelease	SIGNOR-73895	0.2
SRC	protein	P12931	UNIPROT	PBK	protein	Q96KB5	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr272	DFDDEAYyAALGTRP	9606	BTO:0000038								27016416	t		miannu	Phosphorylation of TOPK at Y74, Y272 by Src increases the stability of TOPK and promotes tumorigenesis of colon	SIGNOR-277217	0.404
AKT1	protein	P31749	UNIPROT	KDM5A	protein	P29375	UNIPROT	up-regulates activity	phosphorylation	Thr1225	SRRPRLEtILSLLVS	-1									27292631	t		miannu	We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment.	SIGNOR-274063	0.309
taurine	smallmolecule	CHEBI:15891	ChEBI	GlyR	proteinfamily	SIGNOR-PF62	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000007								9009272	t	inferred from family member	miannu	For each mutant GlyR we examined the agonist efficacies of taurine and beta-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where beta-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human alpha-1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and beta-alanine act as full agonists of huma nalpha-1 GlyRs when expressed in this system.	SIGNOR-267793	0.8
DSN1	protein	Q9H410	UNIPROT	MIS12 complex	complex	SIGNOR-C362	SIGNOR	form complex	binding			-1									27881301	t		lperfetto	 Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits 	SIGNOR-265189	0.898
MLNR	protein	O43193	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257222	0.252
PRDM1	protein	O75626	UNIPROT	Pluripotency	phenotype	SIGNOR-PH43	SIGNOR	up-regulates													31583686	f		SimoneGraziosi	SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation. 	SIGNOR-269263	0.7
A10/b1 integrin	complex	SIGNOR-C167	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257709	0.539
dexamethasone	chemical	CHEBI:41879	ChEBI	SCNN1A	protein	P37088	UNIPROT	up-regulates				9606	BTO:0000018								10722699	f	Regulation of expression	miannu	Dexamethasone induces α-ENaCmRNA expression in lung epithelial A549 cells	SIGNOR-251945	0.8
CDK1	protein	P06493	UNIPROT	NSFL1C	protein	Q9UNZ2	UNIPROT	down-regulates activity	phosphorylation	Ser140	AVERVTKsPGETSKP	9606									12810701	t		lperfetto	Now, we have found that p47, which mainly localizes to the nucleus during interphase, is phosphorylated on serine-140 by cdc2 at mitosis. The phosphorylated p47 does not bind to golgi membranes.	SIGNOR-102350	0.33
TNPO1	protein	Q92973	UNIPROT	NUP153	protein	P49790	UNIPROT	up-regulates activity	relocalization												29970603	t		lperfetto	TNPO1 only mediates the nuclear import of a subset of proteins.|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import	SIGNOR-262100	0.514
C8G	protein	P07360	UNIPROT	Membrane attack complex	complex	SIGNOR-C313	SIGNOR	form complex	binding			-1									30552328	t		lperfetto	The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer	SIGNOR-263446	0.588
ABL1	protein	P00519	UNIPROT	RB1	protein	P06400	UNIPROT	unknown	phosphorylation	Tyr805	RIPGGNIyISPLKSP	9606	BTO:0001271								16158058	t		llicata	Rb-induced apoptosis is compromised by abl-catalysed phosphorylation of rb at y805.	SIGNOR-140396	0.551
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MDM2	protein	Q00987	UNIPROT	up-regulates activity	phosphorylation	Ser188	RKRHKSDsISLSFDE	9606									15169778	t		lperfetto	Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188)	SIGNOR-244300	0.2
IL6R	protein	P08887	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation			9606									23869758	t		miannu	On binding of IL-6 to its receptor IL-6R, JAK2 is phosphorylated, then STAT3 is phosphorylated by JAK2	SIGNOR-254405	0.552
ponatinib	chemical	CHEBI:78543	ChEBI	RIPK3	protein	Q9Y572	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000661								25801024	t		Federica	Discovery of ponatinib as the first-in-class dual inhibitor of RIPK1 and RIPK3	SIGNOR-261083	0.8
ICI D1694	chemical	CHEBI:5847	ChEBI	TYMS	protein	P04818	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206403	0.8
SRC	protein	P12931	UNIPROT	ENO1	protein	P06733	UNIPROT	up-regulates	phosphorylation	Tyr44	SGASTGIyEALELRD	9606									24841372	t		lperfetto	The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways	SIGNOR-205092	0.419
PRKCD	protein	Q05655	UNIPROT	ITGB2	protein	P05107	UNIPROT	up-regulates activity	phosphorylation	Thr758	NPLFKSAtTTVMNPK	9606	BTO:0000782								11700305	t		lperfetto	We identify catalytic domain fragments of protein kinase c (pkc) delta and pkcbetai/ii as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin cd18 chain. The sites phosphorylated in vitro were identified as ser-745 and thr-758. Pkc-mediated phosphorylation of cd18 after cell stimulation could lead to the recruitment of 14-3-3 proteins to the activated integrin, which may play a role in regulating its adhesive state or ability to signal.	SIGNOR-111495	0.334
AKT1	protein	P31749	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser197	APRRRAAsMDSSSKL	10090	BTO:0004245								10217147	t			Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo.	SIGNOR-252861	0.908
PRKACA	protein	P17612	UNIPROT	PDE4B	protein	Q07343	UNIPROT	up-regulates activity	phosphorylation	Ser56	NLQLPPLsQRQSERA	9534	BTO:0000298								12441002	t		miannu	PKA-mediated phosphorylation of Ser-56 in UCR1 of PDE4B4 leads to activation of this long isoform	SIGNOR-250024	0.587
GGCX	protein	P38435	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	carboxylation	Glu61	EFVQGNLeRECMEEK	10090		BTO:0001103							11133752	t		lperfetto	The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.	SIGNOR-263688	0.67
IL4R	protein	P24394	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates				9606									7538655	f		lperfetto	We demonstrate that il4r triggering induced the tyrosine phosphorylation of jak3	SIGNOR-34756	0.705
MLL-AF4	fusion protein	SIGNOR-FP4	SIGNOR	MLLT3	protein	P42568	UNIPROT	down-regulates quantity	relocalization			9606	BTO:0000567								14603337	t		irozzo	The AF4–AF9 interaction is maintained by the MLL–AF4 fusion protein, and expression of the MLL–AF4 fusion can alter the subnuclear localization of AF9. This fusion does, however, contain the AF9 interaction domain we have identified. These findings imply that the interaction that we have characterized plays an important role in MLL leukemogenesis. Furthermore, we show that MLL–AF4 does interact with AF9 and has the ability to misdirect AF9 expression from the AF4 body to alternative foci within the nucleolus.	SIGNOR-255857	0.2
RAB10	protein	P61026	UNIPROT	Early Endosome	complex	SIGNOR-C246	SIGNOR	form complex	binding			9606									19924646	t		lperfetto	The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 	SIGNOR-260618	0.399
NR3C1	protein	P04150	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates quantity	transcriptional regulation			10090									22848740	t		miannu	We show that FOXO3 is an immediate early glucocorticoid receptor (GR) target, whose transcription is even further enhanced by conditions that mimic metabolic stress.	SIGNOR-255759	0.426
CRYAA	protein	P02489	UNIPROT	CRYBB2	protein	P43320	UNIPROT	up-regulates activity	binding			9606									22982024	t		miannu	Aberrant protein interactions can lead to aggregation and insolubilization, such as occurs during cataract formation. Deamidation, a prevalent age-related modification in the lens of the eye, decreases stability of the major lens proteins, crystallins. Deamidation did not disrupt specific αA/βB2 interactions but favored aggregation before complex formation with αA. We conclude that deamidation contributes to cataract formation through destabilization of crystallins before they can be rescued by α-crystallin.	SIGNOR-252155	0.2
SLIT1	protein	O75093	UNIPROT	GPC1	protein	P35052	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000142							10364234	t		gcesareni	Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis.	SIGNOR-68327	0.39
MAPK14	protein	Q16539	UNIPROT	MKNK1	protein	Q9BUB5	UNIPROT	up-regulates activity	phosphorylation	Thr250	NSCTPITtPELTTPC	9606									9155017	t		lperfetto	Mnk1, but not mnk2, also binds strongly to the stress-activated kinase, p38. Erk and p38 phosphorylate MNK1 and Mnk2.	SIGNOR-48342	0.656
ERBB2	protein	P04626	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates activity	phosphorylation	Tyr1248	PTAENPEyLGLDVPV	-1									1706616	t			 Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2.	SIGNOR-251128	0.2
RHOA	protein	P61586	UNIPROT	ROCK1	protein	Q13464	UNIPROT	up-regulates activity	binding			9606									25010901	t		gcesareni	Rho-associated coiled-coil containing kinases (ROCK) were originally identified as effectors of the RhoA small GTPase	SIGNOR-196740	0.804
MAML1	protein	Q92585	UNIPROT	H4C1	protein	P62805	UNIPROT	down-regulates activity	acetylation			9606									17300219	t		gcesareni	We speculated that maml1, in addition to recruiting p300, might directly interact with histones to facilitate histone acetylation. We had observed acetylation of the histones h3 and h4.	SIGNOR-153041	0.2
CENPX	protein	A8MT69	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265201	0.2
LY294002	chemical	CHEBI:65329	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606	BTO:0000222	BTO:0000887;BTO:0001103							10896679	t		gcesareni	Here we show that inhibition of pi3-k activity by the pharmacological agent ly294002 affects early processes of myoblast differentiation including the transcriptional activation of myogenin.	SIGNOR-252647	0.8
SLC9A5	protein	Q14940	UNIPROT	hydron	chemical	CHEBI:15378	ChEBI	down-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265595	0.8
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	G6PC1	protein	P35575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18805788	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-252922	0.2
ERCC6	protein	Q03468	UNIPROT	NEIL1	protein	Q96FI4	UNIPROT	up-regulates activity	binding			9606									19179336	t	Regulation	miannu	CSB stimulates NEIL1 incision activity in vitro, and CSB and NEIL1 co-immunoprecipitate and co-localize in HeLa cells.	SIGNOR-251931	0.352
APC-c	complex	SIGNOR-C150	SIGNOR	CLSPN	protein	Q9HAW4	UNIPROT	down-regulates quantity by destabilization	ubiquitination												18662541	t		lperfetto	Claspin Is Degraded in G0 and G1 via the APC/CCdh1 Ubiquitin Ligase	SIGNOR-274056	0.263
GOPC	protein	Q9HD26	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates	binding			9606									21311563	t		gcesareni	Npist binds beclin 1 by a ccd	SIGNOR-171896	0.539
IGF2	protein	P01344	UNIPROT	IGF2R	protein	P11717	UNIPROT	up-regulates	binding			9606									11867533	t		fspada	Insulin-like growth factor ii receptor (igf2r) is a multifunctional cell surface receptor implicated in tumour suppression. Its growth inhibitory activity has been associated with an ability to bind igf-ii.	SIGNOR-115250	0.752
WNT11	protein	O96014	UNIPROT	FZD3	protein	Q9NPG1	UNIPROT	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131634	0.643
UHRF1	protein	Q96T88	UNIPROT	ABCB1	protein	P08183	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0005192								20037778	f	 	miannu	 we find UHRF1 plays an important role in inhibiting MDR1 promoter activity by directly binding to the MDR1 promoter. Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter, which is facilitated by recruitment of HDAC1 to the MDR1 promoter.	SIGNOR-254224	0.2
NRTN	protein	Q99748	UNIPROT	RET	protein	P07949	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000142							9182803	t		gcesareni	A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling	SIGNOR-49122	0.705
CSNK2A2	protein	P19784	UNIPROT	HDAC2	protein	Q92769	UNIPROT	up-regulates activity	phosphorylation	Ser394	EDAVHEDsGDEDGED	9606	BTO:0000567								12082111	t		llicata	HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2.	SIGNOR-251001	0.398
sirolimus	chemical	CHEBI:9168	ChEBI	CD80	protein	P33681	UNIPROT	down-regulates quantity by repression				9606									18652845	f		miannu	Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells.	SIGNOR-255475	0.8
UGP2	protein	Q16851	UNIPROT	UDP-alpha-D-glucose(2-)	chemical	CHEBI:58885	ChEBI	up-regulates quantity	chemical modification			9606									8631325	t		miannu	UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi.	SIGNOR-267928	0.8
LAMB3	protein	Q13751	UNIPROT	Laminin-5	complex	SIGNOR-C184	SIGNOR	form complex	binding												9211848	t		lperfetto	Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2.	SIGNOR-253236	0.633
tamoxifen	chemical	CHEBI:41774	ChEBI	GPER1	protein	Q99527	UNIPROT	up-regulates	chemical activation			9606									15539556	t		gcesareni	The finding that the antiestrogens tamoxifen and ici 182,780, and an environmental estrogen, ortho,para-dichlorodiphenyldichloroethylene (o,p'-dde), have high binding affinities to the receptor and mimic the actions of e2 has important implications for both the development and treatment of estrogen-dependent breast cancer.	SIGNOR-130395	0.8
MAP2K6	protein	P52564	UNIPROT	CRK	protein	P46108	UNIPROT	up-regulates	phosphorylation			9606									8663074	t		gcesareni	Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub-family of the mitogen-activated protein kinase superfamily.	SIGNOR-42384	0.2
PLK1	protein	P53350	UNIPROT	CENPQ	protein	Q7L2Z9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser248	DLDILHNsSQMKSMS	9606	BTO:0000567								25670858	t		lperfetto	Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 	SIGNOR-265227	0.57
ENY2	protein	Q9NPA8	UNIPROT	SAGA complex	complex	SIGNOR-C465	SIGNOR	form complex	binding			9606									34811519	t		lperfetto	Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module	SIGNOR-269577	0.574
PRKCA	protein	P17252	UNIPROT	VCL	protein	P18206	UNIPROT	unknown	phosphorylation	Ser1113	VREAEAAsIKIRTDA	-1									11741957	t		lperfetto	PKC Phosphorylates Serines 1033 and 1045 in Helix H5	SIGNOR-249129	0.399
CSNK2A1	protein	P68400	UNIPROT	TELO2	protein	Q9Y4R8	UNIPROT	down-regulates	phosphorylation	Ser487	AQLAGSDsDLDSDDE	9606									23263282	t		lperfetto	Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. ere, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2)	SIGNOR-200202	0.2
STK11	protein	Q15831	UNIPROT	MARK3	protein	P27448	UNIPROT	up-regulates activity	phosphorylation	Thr211	TVGGKLDtFCGSPPY	9606	BTO:0000568								12879020	t		lperfetto	Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211.	SIGNOR-104063	0.32
etorphine	chemical	CHEBI:4912	ChEBI	OPRD1	protein	P41143	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258802	0.8
Pyrin inflammasome	complex	SIGNOR-C226	SIGNOR	Caspase 1 complex	complex	SIGNOR-C220	SIGNOR	up-regulates activity	cleavage												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256383	0.2
NHLH2	protein	Q02577	UNIPROT	ASCL1	protein	P50553	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21573214	f		miannu	Overexpression of both LMO3 and HEN2 induced expression of Mash1, suggesting that they might function as a transcriptional activator for Mash1.	SIGNOR-254823	0.243
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser326	PPKMWKTsPDPSPVS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248378	0.598
tRNA(His)	smallmolecule	CHEBI:29178	ChEBI	His-tRNA(His)	smallmolecule	CHEBI:29155	ChEBI	up-regulates quantity	precursor of			9606									10430027	t		miannu	Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 	SIGNOR-270491	0.8
Caspase 8 complex	complex	SIGNOR-C231	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									14585074	f		amattioni	Downstream of caspase-8 activation, apoptosis induction takes place	SIGNOR-256549	0.7
dasatinib (anhydrous)	chemical	CHEBI:49375	ChEBI	SRC	protein	P12931	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191304	0.8
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	MAML3	protein	Q96JK9	UNIPROT	up-regulates	binding			9606									12370315	t		flangone	Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages	SIGNOR-254346	0.2
CSNK2A1	protein	P68400	UNIPROT	FKBP4	protein	Q02790	UNIPROT	down-regulates activity	phosphorylation	Thr143	EFKGEDLtEEEDGGI	-1									9405642	t		llicata	Thr-143 in the hinge I region was identified as the major phosphorylation site for CK2. | Most importantly, CK2-phosphorylated FKBP52 did not bind to HSP90	SIGNOR-250865	0.348
SYNE2	protein	Q8WXH0	UNIPROT	LINC complex	complex	SIGNOR-C303	SIGNOR	form complex	binding												24481844	t		lperfetto	LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM.	SIGNOR-263283	0.529
Matrine	chemical	CHEBI:6700	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-194316	0.8
Complement C1 complex	complex	SIGNOR-C309	SIGNOR	C4A	protein	P0C0L4	UNIPROT	up-regulates activity	cleavage	Arg756	KGQAGLQrALEILQE	-1									9087411	t		lperfetto	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263436	0.63
POLR2L	protein	P62875	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606									12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266142	0.83
RAD21	protein	O60216	UNIPROT	Cohesin complex	complex	SIGNOR-C304	SIGNOR	form complex	binding												28430577	t		lperfetto	Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin	SIGNOR-263311	0.966
CSNK2A2	protein	P19784	UNIPROT	CASQ2	protein	O14958	UNIPROT	unknown	phosphorylation	Ser385	DDDDDDNsDEEDNDD	-1									1985907	t		llicata	Both cardiac and skeletal muscle calsequestrins were phosphorylated by casein kinase II, but cardiac calsequestrin was phosphorylated to a higher stoichiometry and at least 50 times more rapidly. The site of rapid phosphorylation of cardiac calsequestrin was localized to the distinct COOH terminus, where a cluster of three closely spaced serine residues are found (S378DEESN-DDSDDDDE-COOH).	SIGNOR-250980	0.382
CDKN1B	protein	P46527	UNIPROT	CDK1	protein	P06493	UNIPROT	down-regulates	binding			9606									15340381	t		gcesareni	P21 and p27 are key inhibitors of both cdk1 and cdk2.	SIGNOR-128445	0.676
IRF4	protein	Q15306	UNIPROT	IL4	protein	P05112	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								11956291	f			IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production	SIGNOR-254501	0.541
TCF7L2	protein	Q9NQB0	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates activity	transcriptional regulation												20492721	f		FFerrentino	These findings suggested that miR-210 could promote adipogenesis by repressing WNT signaling through targeting Tcf7l2.	SIGNOR-253519	0.7
SRSF7	protein	Q16629	UNIPROT	NXF1	protein	Q9UBU9	UNIPROT	up-regulates	binding			9606									18364396	t		miannu	9g8 and srp20 also enhance the tap rna-binding activity	SIGNOR-161338	0.656
DTX1	protein	Q86Y01	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	ubiquitination			9606									11153911	t		gcesareni	The human Deltex (DTX1) gene encodes a cytoplasmic protein that functions as a positive regulator of the Notch signaling pathway.	SIGNOR-85942	0.773
CHEK2	protein	O96017	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates activity	phosphorylation	Ser364	PLLSRMGsLRAPVDE	9606									12717439	t		Manara	Therefore, Chk2 phosphorylates and activates E2F-1 in response to DNA damage, resulting in apoptosis. | These results suggest that the Ser 364 site is phosphorylated by Chk2 and that anti-P-Ser 364 recognises the phosphorylated site in E2F-1.	SIGNOR-260822	0.5
CTSG	protein	P08311	UNIPROT	SERPIND1	protein	P05546	UNIPROT	down-regulates activity	cleavage	Val458	QATTVTTvGFMPLST	-1									2318847	t		miannu	Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC.	SIGNOR-256509	0.455
SERPINC1	protein	P01008	UNIPROT	F10	protein	P00742	UNIPROT	down-regulates activity	cleavage												31030036	t		lperfetto	Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1	SIGNOR-264138	0.872
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2Q1	protein	Q7Z7E8	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271338	0.436
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	MDM2	protein	Q00987	UNIPROT	up-regulates activity	phosphorylation	Ser186	RQRKRHKsDSISLSF	9606									11504915	t		lperfetto	Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186.	SIGNOR-244292	0.2
migalastat	chemical	CHEBI:135923	ChEBI	GLA	protein	P06280	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0003676								10866822	t		Federica	1-Deoxygalactonojirimycin was the most potent inhibitor of a-Gal A with an IC50 value of 0.04mm.	SIGNOR-261076	0.8
MAPK3	protein	P27361	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates activity	phosphorylation	Ser62	LLPTPPLsPSRRSGL	-1									32482868	t		lperfetto	ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation 	SIGNOR-236250	0.696
NTRK2	protein	Q16620	UNIPROT	NTRK2	protein	Q16620	UNIPROT	up-regulates activity	phosphorylation	Tyr702	FGMSRDVySTDYYRV	10090	BTO:0000944								10533983	t		miannu	TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc	SIGNOR-250205	0.2
UVB radiation	stimulus	SIGNOR-ST17	SIGNOR	calciol	smallmolecule	CHEBI:28940	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0001253							30080183	t		lperfetto	Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin	SIGNOR-270562	0.7
CD19	protein	P15391	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			10090	BTO:0000899								10201980	t		lperfetto	Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase.	SIGNOR-252669	0.502
NR4A3	protein	Q92570	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									30455429	f		miannu	Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax.	SIGNOR-259398	0.7
SREBF2	protein	Q12772	UNIPROT	NPC1L1	protein	Q9UHC9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21123766	f		miannu	Our results showed a positive correlation between changes in NPC1L1 and changes in both SREBP-2 and HNF-4α mRNA expression, a finding that supports the notion that these transcription factors stimulate intestinal NPC1L1 expression. 	SIGNOR-254452	0.583
Integrator complex	complex	SIGNOR-C265	SIGNOR	NcRNA_processing	phenotype	SIGNOR-PH95	SIGNOR	up-regulates				9606									26220997	f		lperfetto	 In vivo knockdown and rescue experiments confirmed that the 3′ end processing of HVS pre-miRNAs also depends on Integrator activity. Interaction between Integrator and HVS primary miRNA (pri-miRNA) substrates that contain only the miRNA 3′ box was confirmed by coimmunoprecipitation and an in situ proximity ligation assay (PLA)	SIGNOR-261475	0.7
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	NUP153	protein	P49790	UNIPROT	unknown	phosphorylation			9606									19767751	t	inferred from 70% family members	llicata	These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport.	SIGNOR-270159	0.2
SMAD3	protein	P84022	UNIPROT	CDKN2B	protein	P42772	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								23032366	f		lperfetto	PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A.	SIGNOR-245441	0.545
SST	protein	P61278	UNIPROT	SSTR4	protein	P31391	UNIPROT	up-regulates	binding			9606									10433861	t		gcesareni	The five receptor subtypes bind the natural SST peptides, SST-14 and SST-28, with low nanomolar affinity.	SIGNOR-82496	0.77
SOD1	protein	P00441	UNIPROT	VDAC1	protein	P21796	UNIPROT	down-regulates activity	binding			10090		BTO:0001279							20797535	t	P00441:p.Gly38Arg (mutation causing interaction)		Misfolded Mutant SOD1 Directly Inhibits VDAC1 Conductance in a Mouse Model of Inherited ALS|With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane. 	SIGNOR-262798	0.437
BCL11A	protein	Q9H165	UNIPROT	HBG2	protein	P69892	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004408								29606353	t		Gianni	Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching.	SIGNOR-269066	0.46
PPP2CA	protein	P67775	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	dephosphorylation	Thr68	SSLETVStQELYSIP	9606	BTO:0001023								16596250	t			Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation. 	SIGNOR-248617	0.442
topotecan	chemical	CHEBI:63632	ChEBI	TOP1MT	protein	Q969P6	UNIPROT	down-regulates activity	chemical inhibition			9606									11166732	t		miannu	Topotecan is a topoisomerase I inhibitor which is currently evaluated as an adjuvant agent for malignant glioma.	SIGNOR-259318	0.8
RLIM	protein	Q9NVW2	UNIPROT	ZFP42	protein	Q96MM3	UNIPROT	down-regulates quantity by destabilization	ubiquitination												22596162	t		lperfetto	RNF12 causes ubiquitination and proteasomal degradation of REX1, and Rnf12 knockout embryonic stem cells show an increased level of REX1.	SIGNOR-269002	0.343
ATG3	protein	Q9NT62	UNIPROT	GABARAP	protein	O95166	UNIPROT	up-regulates activity	binding			-1									16303767	t		lperfetto	Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme)	SIGNOR-141868	0.842
MYC	protein	P01106	UNIPROT	SIRT1	protein	Q96EB6	UNIPROT	up-regulates quantity by stabilization				9606									26049753	f			Overexpression of c-MYC resulted in SIRT1 deubiquitination, whereas c-MYC knockdown led to decrease in SIRT1 protein stability and expression.	SIGNOR-261558	0.59
DAXX	protein	Q9UER7	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates	binding			9606									9743501	t		gcesareni	Daxx was found to activate the jnk kinase kinase ask1, and overexpression of a kinase-deficient ask1 mutant inhibited fas- and daxx-induced apoptosis and jnk activation.	SIGNOR-60164	0.835
SLC9A1	protein	P19634	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265600	0.8
TRIB3	protein	Q96RU7	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	binding			9606	BTO:0000007	BTO:0000759							12791994	t		llicata	TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase.	SIGNOR-252644	0.603
CHMP2B	protein	Q9UQN3	UNIPROT	ESCRT-III	complex	SIGNOR-C379	SIGNOR	form complex	binding			-1									26775243	t		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission.	SIGNOR-265530	0.67
RPS6KB1	protein	P23443	UNIPROT	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606									2846551	t		gcesareni	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-23757	0.249
FLT3	protein	P36888	UNIPROT	SPI1	protein	P17947	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									14592841	f			This data confirms that PU.1 is a downstream target of activated C/EBPα and is suppressed in FLT3/ITD-expressing cells as a result of C/EBPα suppression.	SIGNOR-261530	0.611
SDCBP	protein	O00560	UNIPROT	SOX4	protein	Q06945	UNIPROT	up-regulates activity	binding			10090	BTO:0003104								11498591	t		miannu	Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5–induced Sox4 activation.	SIGNOR-223089	0.554
TP53	protein	P04637	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									24212651	f		miannu	P53 is a nuclear transcription factor with a pro-apoptotic function	SIGNOR-255678	0.7
EXOC5	protein	O00471	UNIPROT	Exocyst_EXOC6 variant	complex	SIGNOR-C492	SIGNOR	form complex	binding			9606									26240175	t		miannu	The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 	SIGNOR-270788	0.94
STK4	protein	Q13043	UNIPROT	TNNI3	protein	P19429	UNIPROT	unknown	phosphorylation	Thr143	RGKFKRPtLRRVRIS	9606		BTO:0000671							18986304	t		llicata	Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143).	SIGNOR-182053	0.2
dutasteride	chemical	CHEBI:521033	ChEBI	ESR2	protein	Q92731	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-191445	0.8
VCP	protein	P55072	UNIPROT	DERL1	protein	Q9BUN8	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								15215856	t		miannu	VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97.	SIGNOR-261372	0.879
alvocidib	chemical	CHEBI:47344	ChEBI	CDK2	protein	P24941	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191532	0.8
CEP152	protein	O94986	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								26297806	t		lperfetto	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.	SIGNOR-271724	0.283
TUBA3C	protein	P0DPH7	UNIPROT	Neuron_migration	phenotype	SIGNOR-PH67	SIGNOR	up-regulates				9606	BTO:0000007								19185337	f		miannu	We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching.	SIGNOR-269724	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	HK1	protein	P19367	UNIPROT	up-regulates	binding			9606									16892082	t		gcesareni	The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects.	SIGNOR-148675	0.2
NFE2L2	protein	Q16236	UNIPROT	KRT16	protein	P08779	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18629308	f		miannu	 When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression.	SIGNOR-254645	0.2
resiquimod	chemical	CHEBI:36706	ChEBI	TLR8	protein	Q9NR97	UNIPROT	up-regulates activity	chemical activation			9606									15661881	t		miannu	Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively.	SIGNOR-259247	0.8
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	precursor of			9606									22049910	t			Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia.	SIGNOR-266907	0.8
CHUK	protein	O15111	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates	phosphorylation	Ser857	PPYNRAVsLDSPVSV	9606	BTO:0000551								22505454	t		gcesareni	Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites.	SIGNOR-196953	0.403
N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide	chemical	CHEBI:91371	ChEBI	CDK4	protein	P11802	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206130	0.8
PTPN6	protein	P29350	UNIPROT	JAK1	protein	P23458	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000150;BTO:0001271;BTO:0000785;BTO:0000661;BTO:0003076								14624462	t		gcesareni	We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation.	SIGNOR-119197	0.631
CSNK2A1	protein	P68400	UNIPROT	MS4A1	protein	P11836	UNIPROT	unknown	phosphorylation	Thr250	KEEVVGLtETSSQPK	9606	BTO:0000776								7678037	t		llicata	These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase erine threonine phosphorylation and may stimulate CKII activity in B cells.	SIGNOR-250917	0.311
INVS	protein	Q9Y283	UNIPROT	DVL1	protein	O14640	UNIPROT	down-regulates	ubiquitination			9606									15852005	t		gcesareni	Inversin inhibits the canonical wnt pathway by targeting cytoplasmic dishevelled (dsh or dvl1) for degradation	SIGNOR-135766	0.631
TLE5	protein	Q08117	UNIPROT	SIX3	protein	O95343	UNIPROT	down-regulates activity	binding			-1									12441302	t		lperfetto	Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. AES abrogates SIX3- and SIX6-induced phenotypes	SIGNOR-234586	0.2
ETS1	protein	P14921	UNIPROT	SLC26A3	protein	P40879	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								7935445	f	 	miannu	 Ets-1 activates the DRA promoter in B cells.	SIGNOR-254085	0.2
AKT1	protein	P31749	UNIPROT	CARD11	protein	Q9BXL7	UNIPROT	up-regulates activity	phosphorylation	Ser652	LERPFRPsVTSVGHV	-1									24548923	t		miannu	Akt phosphorylates S637 and S645 in the linker region of Carma1 	SIGNOR-276620	0.538
CDS1	protein	Q92903	UNIPROT	CDP-diacylglycerol(2-)	smallmolecule	CHEBI:58332	ChEBI	up-regulates	chemical modification			9606									25375833	t		lperfetto	CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA).	SIGNOR-267017	0.8
ERAP1	protein	Q9NZ08	UNIPROT	peptide antigen	smallmolecule	CHEBI:166824	ChEBI	up-regulates quantity	chemical modification			9606									31810556	t		scontino	While peptides loaded onto MHC class I molecules are 8–11 amino acid residues long (a restriction based on the size and conformation of the peptide-binding groove of MHC class I molecules), peptides translocated by TAP can be significantly longer. These peptides will be trimmed to the correct length by ERAP-1.	SIGNOR-267772	0.8
CSNK2A1	protein	P68400	UNIPROT	YWHAQ	protein	P27348	UNIPROT	down-regulates activity	phosphorylation	Ser232	LTLWTSDsAGEECDA	9606									25862939	t		lperfetto	The neuroprotective effect of 14-3-3theta against rotenone toxicity is dependent on the inhibition of the pro-apoptotic factor Bax|Phosphorylation at S232 induced by rotenone is reduced by casein kinase inhibitors, and is not dependent on alphasyn.| The S232D mutant partially reduced the ability of 14-3-3theta to inhibit Bax activation in response to rotenone. Based on these findings, we propose that phosphorylation of 14-3-3s at serine 232 contributes to the neurodegenerative process in PD.	SIGNOR-264405	0.354
MORF4L2	protein	Q15014	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269300	0.663
CDK1	protein	P06493	UNIPROT	ESPL1	protein	Q14674	UNIPROT	down-regulates	phosphorylation	Ser1126	IAPSTNSsPVLKTKP	9606									11747808	t		lperfetto	Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro	SIGNOR-113126	0.59
CDKN2A	protein	P42771	UNIPROT	CDK6	protein	Q00534	UNIPROT	down-regulates	binding			9606									16161044	t		gcesareni	In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm.	SIGNOR-140412	0.866
vatalanib	chemical	CHEBI:90620	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207645	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	LRRC7	protein	Q96NW7	UNIPROT	unknown	phosphorylation	Ser1439	IQTKGQRsMDGYPEQ										11160423	t		llicata	In contrast, phosphorylation of densin-180 by CaMKII at serine-1397 only slightly decreases its affinity for CaMKII. The specific interaction of densin-180 with holoenzymes of CaMKII containing only alpha-subunit and the increased affinity of CaMKII for densin-180 after autophosphorylation suggest that densin-180 may be involved in localization of activated CaMKII synthesized in dendrites.	SIGNOR-250634	0.437
PRL	protein	P01236	UNIPROT	KRT14	protein	P02533	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000667								20103718	f	Regulation	miannu	PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes.	SIGNOR-251902	0.286
CUDC-907	chemical	CID:54575456	PUBCHEM	HDAC10	protein	Q969S8	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191206	0.8
SMURF1	protein	Q9HCE7	UNIPROT	DAB2IP	protein	Q5VWQ8	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									27858941	t		miannu	DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1	SIGNOR-254776	0.265
WNT1	protein	P04628	UNIPROT	PRKACA	protein	P17612	UNIPROT	up-regulates activity				9606		BTO:0001103							21902831	f		gcesareni	Wnt1 and wnt7a stimulation of precursor cells activates protein kinase a (pka), which, through the phosphorylation of creb, induces the expression of the myogenic transcription factors myf5, myod and pax3, resulting in the myogenic commitment of embryonic precursors.	SIGNOR-176572	0.27
capecitabine	chemical	CHEBI:31348	ChEBI	TYMS	protein	P04818	UNIPROT	down-regulates activity	chemical inhibition			9606									15866500	t		miannu	These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to TS inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). 	SIGNOR-259354	0.8
U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	RNA_splicing	phenotype	SIGNOR-PH201	SIGNOR	up-regulates				9606									30765414	f		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270676	0.7
MAPK7	protein	Q13164	UNIPROT	PML	protein	P29590	UNIPROT	down-regulates	phosphorylation			9606	BTO:0001271								20832753	t		gcesareni	We found that bmk1 interacted with promyelocytic leukemia protein (pml), and inhibited its tumor-suppressor function through phosphorylation.	SIGNOR-167947	0.487
mTORC1	complex	SIGNOR-C3	SIGNOR	GRB10	protein	Q13322	UNIPROT	up-regulates	phosphorylation			9606									21659604	t		lperfetto	The adaptor protein grb10 was identified as an mtorc1 substrate that mediates the phosphoinositide 3-kinase.	SIGNOR-217063	0.366
ADSS2	protein	P30520	UNIPROT	IMP	smallmolecule	CHEBI:17202	ChEBI	down-regulates quantity	chemical modification			9606									10496970	t		miannu	Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 	SIGNOR-267343	0.8
PPP2CA	protein	P67775	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	up-regulates activity	dephosphorylation	Ser358	WPLSRTRsEPLPPSA	9606									18339811	t			Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. 	SIGNOR-248648	0.322
MAPK14	protein	Q16539	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser383	IHFWSTLsPIAPRSP	9606	BTO:0000150	BTO:0000975							11145955	t		tpavlidou	Subsequent studies with dominant negative elk-1, wild type, and variant gal4-elk-1 fusion proteins confirmed that phosphorylation of elk-1 at serines 383 and 389 in the c-terminal region of elk-1 is an important downstream target associated with activation of an sre by e2. Both e2 (er?-Dependent) and growth factors (er?-Independent) activated the sre in breast cancer cells via the ras/mapk pathway	SIGNOR-85510	0.505
AKT1	protein	P31749	UNIPROT	SH2B2	protein	O14492	UNIPROT	unknown	phosphorylation	Ser598	SARSRSNsAERLLEA	10090									16141217	t			Serine 588 of APS is a newly identified target for protein kinase B in intact cells and in vitro. The precise function of this PKB-mediated phosphorylation event is not entirely clear but may be responsible for regulating cellular localization and will be the subject of future investigation.	SIGNOR-252577	0.409
GSK3B	protein	P49841	UNIPROT	RXRA	protein	P19793	UNIPROT	up-regulates activity	phosphorylation	Ser78	PMGPHSMsVPTTPTL	9606	BTO:0000007								29137318	t		miannu	GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis. 	SIGNOR-277371	0.279
prednisone	chemical	CHEBI:8382	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									9753485	t	Crohn's Disease	gcesareni		SIGNOR-251703	0.8
PTPN1	protein	P18031	UNIPROT	ROS1	protein	P08922	UNIPROT	down-regulates	dephosphorylation	Tyr2110	FGLARDIyKNDYYRK	9606									17416557	t		gcesareni	In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products.	SIGNOR-154199	0.38
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH10	protein	Q9Y6N8	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265828	0.8
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC3	protein	Q12968	UNIPROT	up-regulates	dephosphorylation			9606									21880741	t		gcesareni	Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.	SIGNOR-252312	0.559
EP300	protein	Q09472	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates	acetylation			9606		BTO:0000887	SIGNOR-C6						10944526	t		gcesareni	Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.	SIGNOR-81053	0.667
BIRC3	protein	Q13489	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	ubiquitination	Lys377	NEPSLQSkLQDEANY	9606									16603398	t		amattioni	In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein.	SIGNOR-145855	0.737
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	MYBL2	protein	P10244	UNIPROT	up-regulates	phosphorylation	Thr487	SQKVVVTtPLHRDKT	9606									9840932	t		lperfetto	The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk2	SIGNOR-217260	0.708
NFE2L3	protein	Q9Y4A8	UNIPROT	NQO1	protein	P15559	UNIPROT	down-regulates quantity by repression	transcriptional regulation												15385560	f		lperfetto	Nrf3 negatively regulates antioxidant-response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene.	SIGNOR-268975	0.346
SLX4	protein	Q8IY92	UNIPROT	ERCC4	protein	Q92889	UNIPROT	up-regulates	binding			9606				SIGNOR-C50					24726326	t		miannu	Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair.	SIGNOR-204890	0.746
MAPK8	protein	P45983	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates	phosphorylation	Ser38	SVPEFPLsPPKKKDL	9606									20630875	t		gcesareni	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress.	SIGNOR-166694	0.323
CDK4	protein	P11802	UNIPROT	FOXM1	protein	Q08050	UNIPROT	up-regulates	phosphorylation			9606									22094256	t		tpavlidou	We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1, thereby maintain expression of g1/s phase genes, suppress the levels of reactive oxygen species (ros), and protect cancer cells from senescence.	SIGNOR-177266	0.609
SYK	protein	P43405	UNIPROT	SYK	protein	P43405	UNIPROT	up-regulates activity	phosphorylation	Tyr525	ALRADENyYKAQTHG	9606									9820500	t		lperfetto	These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520	SIGNOR-246617	0.2
POLR2K	protein	P53803	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	form complex	binding												22260999	t		lperfetto	In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1). 	SIGNOR-266150	0.856
SRC	protein	P12931	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates	phosphorylation	Tyr1161	FGMTRDIyETDYYRK	9606									8940173	t		lperfetto	Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor	SIGNOR-45122	0.564
LCK	protein	P06239	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	phosphorylation	Tyr493	LGADDSYyTARSAGK	-1									8756661	t		lperfetto	these data suggest that phosphorylation of ZAP-70 is initiated by a heterologous trans-phosphorylation of ZAP-70 by Lck on Tyr- 493.	SIGNOR-226628	0.601
PIAS1	protein	O75925	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	up-regulates	sumoylation			9606									20016603	t		gcesareni	Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation.	SIGNOR-162156	0.507
Org 27569	chemical	CID:44828492	PUBCHEM	CNR1	protein	P21554	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-195097	0.8
GSK690693	chemical	CHEBI:90677	ChEBI	AKT3	protein	Q9Y243	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193006	0.8
RND1	protein	Q92730	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates	binding			9606									17251915	t		gcesareni	In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor	SIGNOR-152811	0.328
PCDHA3	protein	Q9Y5H8	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-265668	0.2
hydrosulfide	smallmolecule	CHEBI:29919	ChEBI	Vasodilation	phenotype	SIGNOR-PH223	SIGNOR	up-regulates													26539823	f		lperfetto	We have recently shown, that in arterial (HAEC) end venular (HUVEC) endothelial cells, GPBAR1 agonism increases the expression/ activity of cystathione-γ-liase (CSE, CTH, EC 4.4.1), a key enzyme in the “trans-sulfuration pathway” that generates hydrogen sulfide (H2S), a vasodilatory agent 	SIGNOR-275831	0.7
heme	smallmolecule	CHEBI:30413	ChEBI	FBXO22	protein	Q8NEZ5	UNIPROT	up-regulates activity	chemical activation			9606									31257023	t			Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22.	SIGNOR-259332	0.8
PI4KB	protein	Q9UBF8	UNIPROT	phosphatidylinositol 4-phosphate	smallmolecule	CHEBI:37530	ChEBI	up-regulates quantity	chemical modification			9534									22253445	t		lperfetto	Interestingly, we found that PI4P, the product of PI4KB catalysis, creates a lipid microenvironment that is required for SARS-CoV S-mediated entry.	SIGNOR-260732	0.8
PAK4	protein	O96013	UNIPROT	PAK4	protein	O96013	UNIPROT	up-regulates activity	phosphorylation	Ser474	KEVPRRKsLVGTPYW	10090	BTO:0000944								11668177	t		lperfetto	Here we demonstrate that PAK4 is frequently overexpressed in human tumor cell lines of various tissue origins. We also have identified serine (Ser-474) as the likely autophosphorylation site in the kinase domain of PAK4 in vivo. Mutation of this serine to glutamic acid (S474E) results in constitutive activation of the kinase.	SIGNOR-235867	0.2
HLX	protein	Q14774	UNIPROT	CDKN1C	protein	P49918	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003980								20008130	t		Luana	In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.	SIGNOR-261620	0.2
CDK1	protein	P06493	UNIPROT	NUP98	protein	P52948	UNIPROT	down-regulates activity	phosphorylation	Thr670	IAKPIPQtPESAGNK	9606									21335236	t		gcesareni	We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks.	SIGNOR-172225	0.408
HOXB8	protein	P17481	UNIPROT	PBX3	protein	P40426	UNIPROT	up-regulates activity	binding			9606	BTO:0001545								11571641	t		miannu	the ability of HoxB8 to heterodimerizes with endogenous Pbx proteins on DNA alters gene transcription in a manner that prevents progression through an intrinsic genetic differentiation program. In conjunction with Pbx, HoxB8 could alter transcription of Pbx target genes by direct or indirect mechanisms.	SIGNOR-223149	0.497
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Thr312	ISYDIPPtPGNTYQI	9606									15379552	t		lperfetto	Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597)	SIGNOR-129196	0.2
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	TAOK2	protein	Q9UL54	UNIPROT	up-regulates				9606									17396146	f		lperfetto	These findings indicate that TAO kinases are regulators of p38-mediated responses to DNA damage and are intermediates in the activation of p38 by ATM.	SIGNOR-226602	0.7
TRIM38	protein	O00635	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								22323536	t		miannu	As an E3 ligase, TRIM38 bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6. 	SIGNOR-272009	0.441
KIF4A	protein	O95239	UNIPROT	PRC1	protein	O43663	UNIPROT	up-regulates activity	binding			9606									15297875	t		miannu	 These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins	SIGNOR-265988	0.585
PTPN2	protein	P17706	UNIPROT	WASL	protein	O00401	UNIPROT	down-regulates	dephosphorylation	Tyr256	RETSKVIyDFIEKTG	9606									16293614	t		gcesareni	Similarly, the t cell phosphatase has a 30-fold lower kcat/km toward autoinhibited p-n-wasp than toward the isolated p-gbd, and again this effect is largely reversed by that cdc42	SIGNOR-141652	0.293
HIF-1 complex	complex	SIGNOR-C418	SIGNOR	BID	protein	P55957	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									27692180	t		miannu	HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 	SIGNOR-267457	0.2
DLGAP3	protein	O95886	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								9115257	t		miannu	SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.	SIGNOR-264211	0.748
PTPN6	protein	P29350	UNIPROT	PKM	protein	P14618	UNIPROT	down-regulates activity	dephosphorylation	Tyr105	FASDPILyRPVAVAL	9606									26959741	t		lperfetto	SHP-1 dephosphorylates PKM2 at Y105 to inhibit nuclear function of PKM2 and determines the efficacy of targeted drugs.|SHP-1 directly dephosphorylated PKM2 at Y105 and further decreased the proliferative activity of PKM2; similar effects were found in sorafenib-treated hepatocellular carcinoma cells.|SHP-1 dephosphorylates p-PKM2Y105 and further affects the nucleus-related cell proliferation.	SIGNOR-276997	0.2
CADPS2	protein	Q86UW7	UNIPROT	SNAP25	protein	P60880	UNIPROT	up-regulates activity	binding			9606	BTO:0000938			SIGNOR-C346					24363652	t		miannu	 CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1	SIGNOR-264339	0.269
PRKACA	protein	P17612	UNIPROT	TBXA2R	protein	P21731	UNIPROT	unknown	phosphorylation	Ser331	STRPRSLsLQPQLTQ	9606									12147288	t		llicata	Ser-331 was found to be involved in pka-mediated phosphorylation.	SIGNOR-90976	0.47
OST-B complex	complex	SIGNOR-C536	SIGNOR	Protein_glycosylation	phenotype	SIGNOR-PH144	SIGNOR	up-regulates				9606									31831667	t		miannu	Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. 	SIGNOR-272056	0.7
GSK3B	protein	P49841	UNIPROT	MYOCD	protein	Q8IZQ8	UNIPROT	down-regulates activity	phosphorylation	Ser455	HFGSTSSsPPISPAS	9606	BTO:0000007								16141410	t			In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity	SIGNOR-251244	0.406
AURKB	protein	Q96GD4	UNIPROT	RACGAP1	protein	Q9H0H5	UNIPROT	up-regulates activity	phosphorylation	Ser387	ETGLYRIsGCDRTVK	9606	BTO:0000567								12689593	t		lperfetto	We also report that aurora b phosphorylates mgcracgap on serine residues and that this modification induces latent gap activity toward rhoa in vitro.	SIGNOR-100569	0.772
PRKCH	protein	P24723	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates activity	phosphorylation	Thr495	TGITRKKtFKEVANA	9606	BTO:0001853								24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251634	0.2
CYSLTR1	protein	Q9Y271	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257225	0.379
nocodazole	chemical	CHEBI:34892	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194838	0.8
OGDHL	protein	Q9ULD0	UNIPROT	OGDC	complex	SIGNOR-C397	SIGNOR	form complex	binding			9606									15953811	t		miannu	The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH.	SIGNOR-267833	0.642
MRPL36	protein	Q9P0J6	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262361	0.71
TAOK2	protein	Q9UL54	UNIPROT	STK3	protein	Q13188	UNIPROT	up-regulates	phosphorylation			9606									23431053	t		gcesareni	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.	SIGNOR-201327	0.278
PRKCZ	protein	Q05513	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606									14657655	t		gcesareni	Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent.	SIGNOR-119889	0.579
AP-2 complex	complex	SIGNOR-C245	SIGNOR	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	form complex	binding			9606									24789820	t		lperfetto	AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly. 	SIGNOR-260663	0.624
CBLB	protein	Q13191	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									10542134	t		miannu	Here we describe that overexpression of cbl-b, a homologue of the c-cbl protooncogene, inhibits EGFR-induced apoptosis in MDA-MB-468 breast cancer cells. Overexpression of cbl-b results in a shortened duration of EGFR activation upon EGF stimulation. This is demonstrated by decreased amounts of phosphorylated EGFR as well as by inhibition of multiple downstream signaling pathways. The inhibition of signaling by cbl-b results from increased ubiquitination and degradation of the activated EGFR. 	SIGNOR-272934	0.748
MAPK8	protein	P45983	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation			9606									14967141	t		gcesareni	Jnk phosphorylates bad at threonine 201, thereby inhibiting bad association with the antiapoptotic molecule bcl-x(l)	SIGNOR-121940	0.672
PRKCA	protein	P17252	UNIPROT	GPM6A	protein	P51674	UNIPROT	up-regulates activity	phosphorylation	Thr10	ENMEEGQtQKGCFEC	10116	BTO:0001009								12359212	t		miannu	In summary, a CNS neuron-specific membrane glycoprotein, M6a, could act as a novel NGF-gated Ca2+ channel through the phosphorylation with PKC and augments [Ca2+]i in M6a-S cells.	SIGNOR-263163	0.328
FABP3	protein	P05413	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264457	0.7
AMBRA1	protein	Q9C0C7	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates activity	binding			9606		BTO:0000459							20921139	t		lperfetto	we show that the BECLIN 1-VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2.	SIGNOR-168252	0.779
TBX2	protein	Q13207	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates activity	binding			9606									24470334	t			We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity.	SIGNOR-251560	0.316
GATA1	protein	P15976	UNIPROT	Megakaryocyte_differentiation 	phenotype	SIGNOR-PH103	SIGNOR	up-regulates activity				10090									12032775	f			Studies involving point mutants of GATA-1 have shown that a direct physical interaction between GATA-1 and FOG-1 is essential for normal human erythroid and megakaryocyte maturation in vivo.	SIGNOR-259961	0.7
ESR1	protein	P03372	UNIPROT	SCN5A	protein	Q14524	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000093	BTO:0001264							24493753	f		miannu	The effects of β-oestradiol (E2), the biologically active form of oestrogen, are classically mediated by two types of oestrogen receptor (ER): ERα and ERβ. E2 has both non-genomic and genomic effects upon VGSC expression/activity; and (ii) transcriptionally, E2 (via ERα) downregulates functional VGSC (nNav1.5) expression in BCa cells.	SIGNOR-253467	0.2
CYP19A1	protein	P11511	UNIPROT	androst-4-ene-3,17-dione	smallmolecule	CHEBI:16422	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000975							27702664	t		lperfetto	The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively	SIGNOR-268672	0.8
ATM	protein	Q13315	UNIPROT	TAOK1	protein	Q7L7X3	UNIPROT	up-regulates	phosphorylation	Thr643	EELNKRQtQKDLEHA	9606									17396146	t		gcesareni	The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells.	SIGNOR-154171	0.394
CYCS	protein	P99999	UNIPROT	APAF1	protein	O14727	UNIPROT	up-regulates activity	binding			9606									15829969	t		lperfetto	During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9.	SIGNOR-135384	0.786
ABL1	protein	P00519	UNIPROT	APBB1	protein	O00213	UNIPROT	up-regulates	phosphorylation	Tyr547	VQKFQVYyLGNVPVA	9606									15031292	t		lperfetto	The c-abl tyrosine kinase phosphorylates the fe65 adaptor protein to stimulate fe65/amyloid precursor protein nuclear signaling. Here, we show that active c-abl stimulates app/fe65-mediated gene transcription and that this effect is mediated by phosphorylation of fe65 on tyrosine 547 within its second ptb domain.	SIGNOR-123476	0.425
CSNK1E	protein	P49674	UNIPROT	CTNND1	protein	O60716	UNIPROT	down-regulates	phosphorylation	Ser268	PQVRVGGsSVDLHRF	9606	BTO:0000782								3133391	t		gcesareni	Moreover, in response to wnt3a, p120-catenin is phosphorylated at ser268, a modification dependent on ck1epsilon activity, which disrupts its interaction with e-cadherin and, subsequently, with lrp5/6, promoting the release of ck1epsilon/p120-catenin from the wnt receptor complex.	SIGNOR-24443	0.292
SLC9A1	protein	P19634	UNIPROT	hydron	chemical	CHEBI:15378	ChEBI	down-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265591	0.8
MOG	protein	Q16653	UNIPROT	Myelination	phenotype	SIGNOR-PH206	SIGNOR	up-regulates													33290135	f		SimoneGraziosi	Myelin oligodendrocyte glycoprotein (MOG) is a nervous system protein expressed by oligodendrocytes to constitute the myelin sheath.	SIGNOR-269232	0.7
CSNK2A1	protein	P68400	UNIPROT	GYS1	protein	P13807	UNIPROT	unknown	phosphorylation	Ser649	VPPSPSLsRHSSPHQ	-1									2117608	t		llicata	With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action.	SIGNOR-250880	0.334
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline	chemical	CHEBI:94782	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190919	0.8
RBX1	protein	P62877	UNIPROT	NFKB2	protein	Q00653	UNIPROT	up-regulates	ubiquitination			9606			SIGNOR-C5						14676825	t		gcesareni	Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase.	SIGNOR-120342	0.285
CSNK2A1	protein	P68400	UNIPROT	SEC63	protein	Q9UGP8	UNIPROT	up-regulates activity	phosphorylation	Ser574	EEVSDKGsDSEEEET	9606									23287549	t		lperfetto	Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62.	SIGNOR-265269	0.295
IRS1	protein	P35568	UNIPROT	PIK3CB	protein	P42338	UNIPROT	up-regulates activity	binding			10090		BTO:0000887							14623899	t		lperfetto	As shown previously, IRS-1 was required for insulin-stimulated phosphorylation of Akt in 32D cells, which is consistent with the binding and activation of PI3K by IRS-1 during insulin stimulation	SIGNOR-236618	0.712
MZF1	protein	P28698	UNIPROT	CCN3	protein	P48745	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25899830	f		miannu	we report the regulation of the CTGF and NOV genes by Myeloid Zinc Finger-1 (MZF-1), a hematopoietic transcription factor. We show the interaction of MZF-1 with the CTGF and NOV promoters in several cell types. Up-regulation of MZF-1 via calcitriol and vitamin A induces expression of CTGF and NOV, implicating a role for these vitamins in the functions of these two genes. Lastly, knockdown of MZF1 reduces levels of CTGF and NOV.	SIGNOR-226356	0.2
MAPK14	protein	Q16539	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser33	LPENNVLsPLPSQAM	9606	BTO:0000093								10581258	t		lperfetto	P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.	SIGNOR-72699	0.765
MMP1	protein	P03956	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272354	0.7
CSNK2A1	protein	P68400	UNIPROT	SSRP1	protein	Q08945	UNIPROT	down-regulates activity	phosphorylation	Ser510	SSSNEGDsDRDEKKR	9606	BTO:0000007								15659405	t		llicata	CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity.	SIGNOR-250959	0.689
nitric oxide	smallmolecule	CHEBI:16480	ChEBI	GUCY1A3-B3	complex	SIGNOR-C140	SIGNOR	up-regulates activity	chemical activation			9606									15036565	t		gcesareni	One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP)	SIGNOR-243967	0.8
SNCA	protein	P37840	UNIPROT	ER stress	stimulus	SIGNOR-ST9	SIGNOR	up-regulates				9606									12666095	f		lperfetto	Furthermore, mutant isoforms of alpha-synuclein more readily oligomerize, and it has been suggested that its tendency to aggregate into misfolded structures may confer toxic properties to the protein.	SIGNOR-249702	0.7
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAP2K1	protein	Q02750	UNIPROT	down-regulates activity	phosphorylation	Thr286	VEGDAAEtPPRPRTP	10090	BTO:0000944								11684694	t		llicata	Phosphorylation of MEK1 by cdk5/p35 down-regulates the mitogen-activated protein kinase pathway. | suggesting that Thr286 in MEK1 is a site of cdk5/p35 phosphorylation that inhibits MEK1 activity.	SIGNOR-250653	0.478
PAK2	protein	Q13177	UNIPROT	PAK2	protein	Q13177	UNIPROT	up-regulates activity	phosphorylation	Thr402	PEQSKRStMVGTPYW	-1									10075701	t		miannu	Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites	SIGNOR-250230	0.2
PRKCD	protein	Q05655	UNIPROT	TNNI3	protein	P19429	UNIPROT	up-regulates activity	phosphorylation	Ser24	APIRRRSsNYRAYAT	9606									18550549	t		gcesareni	Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144.	SIGNOR-178884	0.276
PELI3	protein	Q8N2H9	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates				9606									12874243	f		gcesareni	Pellino3 leads to activation of c-jun and elk-1, but not nf-kappab	SIGNOR-103989	0.282
KAT6A/KAT6B	complex	SIGNOR-C54	SIGNOR	RUNX1	protein	Q01196	UNIPROT	up-regulates	binding			9606	BTO:0000801;BTO:0001271;BTO:0000876								11742995	t		lperfetto	The activation domain of aml1 is required for its interaction with moz / moz activates aml1_mediated transcription	SIGNOR-217201	0.418
tRNA(Cys)	smallmolecule	CHEBI:29167	ChEBI	Cys-tRNA(Cys)	smallmolecule	CHEBI:29152	ChEBI	up-regulates quantity	precursor of			9606									11347887	t		miannu	Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine.	SIGNOR-270475	0.8
MAP1LC3B	protein	Q9GZQ8	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	up-regulates	binding			9606									17580304	t		gcesareni	Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation.	SIGNOR-156356	0.832
MAPKAPK2	protein	P49137	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation	Ser119	EILSRRPsYRKILND	9606									8887554	t		lperfetto	We show that mapkap kinase-2 phosphorylates creb at ser133 in vitro.	SIGNOR-44384	0.679
IL6	protein	P05231	UNIPROT	AMPK	complex	SIGNOR-C15	SIGNOR	up-regulates				10090									23531613	f			AMPK phosphorylation was increased nearly fourfold (Fig. 2C) with the high dose of IL-6 	SIGNOR-255338	0.248
PGM1	protein	P36871	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	up-regulates quantity	chemical modification			9606									32898648	t		miannu	Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P).	SIGNOR-267930	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	GABBR1	protein	Q9UBS5	UNIPROT	down-regulates	phosphorylation	Ser868	ITRGEWQsEAQDTMK	9606	BTO:0000938	BTO:0000142							20643921	t		gcesareni	Nmda-dependent internalization of gabab receptors requires activation of ca2+/calmodulin-dependent protein kinase ii (camkii), which associates with gabab receptors in vivo and phosphorylates serine 867 (s867) in the intracellular c terminus of the gabab1 subunit.	SIGNOR-166846	0.239
AXIN1	protein	O15169	UNIPROT	MAP3K4	protein	Q9Y6R4	UNIPROT	up-regulates	binding			9606	BTO:0000007								12878610	t		gcesareni	Mekk4, also binds to axin in vivo and mediates axin-induced jnk activation.	SIGNOR-104003	0.43
GSK3B	protein	P49841	UNIPROT	MYOCD	protein	Q8IZQ8	UNIPROT	down-regulates activity	phosphorylation	Ser630	VLSSTFLsPQCSPQH	9606	BTO:0000007								16141410	t			In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity	SIGNOR-251248	0.406
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	JAK2	protein	O60674	UNIPROT	down-regulates	phosphorylation	Ser523	GVSDVPTsPTLQRPT	9534	BTO:0004055								16705159	t	16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling.	lperfetto	We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner	SIGNOR-244553	0.2
MAPK1	protein	P28482	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates	phosphorylation	Ser36	PSEGRQPsPSPSPTE	9606	BTO:0001271								15093545	t	The effect has been demonstrated using P29590-4	gcesareni	We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3).	SIGNOR-124240	0.366
RET	protein	P07949	UNIPROT	AFAP1L2	protein	Q8N4X5	UNIPROT	up-regulates activity	phosphorylation	Tyr54	SSSSDEEyIYMNKVT	9606	BTO:0000007								19060924	t		miannu	RET/PTC induced robust tyrosine phosphorylation of XB130, which promoted its subsequent association with the p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase). We identified tyrosine 54 of XB130 as the major target of RET/PTC-mediated phosphorylation and a critical binding site for the SH2 domains of p85alpha.	SIGNOR-263192	0.338
AKT2	protein	P31751	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606									10949026	t		gcesareni	Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155.	SIGNOR-81114	0.504
USP9X	protein	Q93008	UNIPROT	SMN1	protein	Q16637	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0000007								23112048	t		lperfetto	Ubiquitin-specific Protease 9x Deubiquitinates and Stabilizes the Spinal Muscular Atrophy Protein-Survival Motor Neuron	SIGNOR-253113	0.285
glutamine	smallmolecule	CHEBI:28300	ChEBI	Glutaminolysis	phenotype	SIGNOR-PH119	SIGNOR	up-regulates activity				9606	BTO:0000567								22749528	f		Luana	Leucine and Glutamine Activate Glutaminolysis and mTORC1	SIGNOR-268009	0.7
PDPK1	protein	O15530	UNIPROT	SGK3	protein	Q96BR1	UNIPROT	up-regulates activity	phosphorylation	Thr320	AISDTTTtFCGTPEY										10548550	t		miannu	SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB.	SIGNOR-250279	0.472
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	MMP9	protein	P14780	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15536164	f	 	miannu	 Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG. 	SIGNOR-254798	0.429
FOXM1	protein	Q08050	UNIPROT	SLC27A2	protein	O14975	UNIPROT	up-regulates quantity by expression				9606									31949772	f		lperfetto	FOXM1 as a prognostic biomarker promotes endometrial cancer progression via transactivation of SLC27A2 expression.	SIGNOR-260414	0.2
BRCA1-BARD1 complex	complex	SIGNOR-C297	SIGNOR	BRCA1-A complex	complex	SIGNOR-C296	SIGNOR	form complex	binding			9606	BTO:0000007								20656690	t		lperfetto	We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1. 	SIGNOR-263216	0.763
mTORC2	complex	SIGNOR-C2	SIGNOR	ELP1	protein	O95163	UNIPROT	up-regulates activity	phosphorylation	Ser1174	SETSSVVsGSEMSGK										29925953	t		lperfetto	Human ELP1 S1174 phosphorylation was triggered by insulin treatment, as shown by the specific phosphorylated (p)ELP1 (S1174) antibody, and addition of a phosphorylation-mutant variant of the ELP1 protein (ELP1(S1174A)) to ELP1-depleted BRAFV600E melanoma cells failed to rescue cell survival |In line with these findings, mTORC2 activity, but not mTORC1, was required for the insulin-induced phosphorylation of Elp1 S1174	SIGNOR-275542	0.2
PRKAA1	protein	Q13131	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Ser413	GLMQRSSsFPYTTKG	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-252976	0.509
GEM	protein	P55040	UNIPROT	ROCK2	protein	O75116	UNIPROT	down-regulates activity	binding			9606									14701738	t		miannu	 Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively.	SIGNOR-261711	0.294
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1889	SPTTPKYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273053	0.556
SGK3	protein	Q96BR1	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser484	KRRKRMSsGTEECGE	9606	BTO:0000938								33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275767	0.279
TRIP12	protein	Q14669	UNIPROT	NAE1	protein	Q13564	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1				SIGNOR-C131					18627766	t		miannu	Our data suggest that that TRIP12 promotes degradation of APP-BP1 by catalyzing its ubiquitination, which in turn modulates the neddylation pathway.	SIGNOR-266780	0.443
CDK1	protein	P06493	UNIPROT	MASTL	protein	Q96GX5	UNIPROT	up-regulates activity	phosphorylation	Thr194	NMMDILTtPSMAKPR	8355									22354989	t		gcesareni	We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop	SIGNOR-243414	0.492
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1924	SPTSPKYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273038	0.556
PRC1	protein	O43663	UNIPROT	Spindle_assembly	phenotype	SIGNOR-PH60	SIGNOR	up-regulates				9606									15297875	f		miannu	 These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins	SIGNOR-265987	0.7
HOXB1	protein	P14653	UNIPROT	OTX2	protein	P32243	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000946								9556594	t		Luana	Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively	SIGNOR-261633	0.278
SGK1	protein	O00141	UNIPROT	MAP3K3	protein	Q99759	UNIPROT	down-regulates activity	phosphorylation	Ser337	DPRGRLRsADSENAL	9606									12761205	t		lperfetto	Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 2	SIGNOR-101216	0.2
ACVR1	protein	Q04771	UNIPROT	ACVR1/BMPR2	complex	SIGNOR-C30	SIGNOR	form complex	binding			9606									7791754	t		lperfetto	Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.	SIGNOR-33287	0.701
CDK12	protein	Q9NYV4	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1875	SPTSPKYsPTSPTYS	9606									22012619	t		miannu	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176801	0.775
CDX2	protein	Q99626	UNIPROT	TFF3	protein	Q07654	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534	BTO:0004055								17182120	t	 	 	The transcription of human TFF3 reporter genes was significantly up-regulated by the transient overexpression of CDX2 in COS-7 cells and AGS gastric cells.	SIGNOR-253967	0.402
CDK5	protein	Q00535	UNIPROT	CDK5R1	protein	Q15078	UNIPROT	down-regulates	phosphorylation	Ser8	MGTVLSLsPSYRKAT	9606									18326489	t		lperfetto	When overexpressed with cdk5, a large fraction of the double mutant p35(s8a/t138a) co-sedimented with microtubules (fig. 5b), further supporting the idea that the phosphorylation at these two residues by cdk5 is inhibitory to the microtubule association.	SIGNOR-177963	0.942
JUN	protein	P05412	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									9878062	f		lperfetto	Functional data suggest that c-Jun is not merely a target for activation by many of the extracellular stimuli, but that it plays a role in mediating the cellular response. In the case of growth control, three lines of evidence suggest that the transcription factor AP-1, which is composed of Fos–Jun and Jun–Jun dimers, mediates cell proliferation in response to external growth signals in the form of peptide growth factors.	SIGNOR-233467	0.7
NPM1	protein	P06748	UNIPROT	FBXW7	protein	Q969H0	UNIPROT	up-regulates quantity	binding			10090	BTO:0002572								18625840	t		gcesareni	We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7 , a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabili- zation of Fbw7	SIGNOR-245084	0.496
CH5132799	chemical	CID:49784945	PUBCHEM	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190949	0.8
EYA3	protein	Q99504	UNIPROT	H2AX	protein	P16104	UNIPROT	down-regulates	dephosphorylation	Tyr143	ATQASQEy	9606									20965415	t		gcesareni	Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3.	SIGNOR-168927	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SOS1	protein	Q07889	UNIPROT	down-regulates activity	phosphorylation	Ser1132	TLPHGPRsASVSSIS	9534	BTO:0004055								8816480	t		lperfetto	In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1	SIGNOR-244580	0.2
ANAPC1	protein	Q9H1A4	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	form complex	binding												16896351	t		lperfetto	The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex.	SIGNOR-252001	0.876
LRRC4	protein	Q9HBW1	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000142							25526788	f		miannu	LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway.	SIGNOR-264054	0.361
SRC	protein	P12931	UNIPROT	BCKDK	protein	O14874	UNIPROT	up-regulates activity	phosphorylation	Tyr246	RRLCEHKyGNAPRVR	9606	BTO:0001615								32238881	t		lperfetto	Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells. 	SIGNOR-275583	0.2
silodosin	chemical	CHEBI:135929	ChEBI	ADRA1A	protein	P35348	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206914	0.8
CDK2	protein	P24941	UNIPROT	UBE2A	protein	P49459	UNIPROT	up-regulates	phosphorylation	Ser120	LDEPNPNsPANSQAA	9606									11953320	t		llicata	Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity.	SIGNOR-116508	0.381
EGR1	protein	P18146	UNIPROT	COL4A1	protein	P02462	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21931594	f	Regulation	miannu	Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1)	SIGNOR-251917	0.2
RIPK2	protein	O43353	UNIPROT	RIPK2	protein	O43353	UNIPROT	up-regulates activity	phosphorylation	Ser176	KWRMMSLsQSRSSKS	9606									16824733	t		amattioni	In summary, our results indicate that s176 is a regulatory autophosphorylation site for rip2 and that s176 phosphorylation can be used to monitor the activation state of rip2.	SIGNOR-229701	0.2
CEBPA	protein	P49715	UNIPROT	FTO	protein	Q9C0B1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								24877091	f		lperfetto	CCAAT/Enhancer-Binding Protein 𝛼 Is a Crucial	SIGNOR-261805	0.352
CSNK2B	protein	P67870	UNIPROT	USO1	protein	O60763	UNIPROT	up-regulates activity	phosphorylation	Ser942	EEEDELEsGDQEDED	-1									10931861	t		llicata	Phosphorylation is mediated by casein kinase II (CKII) or a CKII-like kinase. | Serine 941 in the Acidic Domain of p115 Is Essential for Reassembly of Golgi Cisternae 	SIGNOR-251082	0.341
BAK1	protein	Q16611	UNIPROT	BAK1	protein	Q16611	UNIPROT	up-regulates	binding			9606									11175253	t		amattioni	Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux	SIGNOR-105203	0.2
APOA1	protein	P02647	UNIPROT	cholesterol	smallmolecule	CHEBI:16113	ChEBI	up-regulates				9606									20642861	t		miannu	ApoA-I increases cholesterol release in mature human adipocytes.	SIGNOR-252104	0.8
CDK1	protein	P06493	UNIPROT	GOLGA2	protein	Q08379	UNIPROT	down-regulates	phosphorylation	Ser37	REYQQRNsPGVPTGA	9606									9753325	t		lperfetto	Cdc2 kinase directly phosphorylates the cis-golgi matrix protein gm130 and is required for golgi fragmentation in mitosis. Mitotic fragmentation of the golgi apparatus can be largely explained by disruption of the interaction between gm130 and the vesicle-docking protein p115. Here we identify a single serine (ser-25) in gm130 as the key phosphorylated target and cdc2 as the responsible kinase	SIGNOR-60281	0.66
GNG2	protein	P59768	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity													15345719	f			In this study, we investigated the possible role of the Gβγ heterodimer in signaling Gi-induced Src activation	SIGNOR-251108	0.443
TAOK2	protein	Q9UL54	UNIPROT	MAP2K3	protein	P46734	UNIPROT	up-regulates activity	binding			-1									10497253	t		lperfetto	Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7.	SIGNOR-70947	0.654
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	CITED1	protein	Q99966	UNIPROT	up-regulates	binding			9606									9660950	t		lperfetto	The transcriptional coactivator cpb/p300 associates with nf-kappa b p65 through two sites, an n-terminal domain that interacts with the c-terminal region of unphosphorylated p65, and a second domain that only interacts with p65 phosphorylated on serine 276.	SIGNOR-216331	0.2
EIF2S1	protein	P05198	UNIPROT	ATF4	protein	P18848	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24714526	f		miannu	Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy.	SIGNOR-251820	0.627
DNM2	protein	P50570	UNIPROT	MYO1C	protein	O00159	UNIPROT	up-regulates	binding			9606									17257598	t		miannu	Dynamin bind directly to the sh3 domain of myo1e / an intriguing possibility is that binding of dynamin and synaptojanin to myo1e tail may activate motor activity since it has been demonstrated that myo1e atpase activity is autoinhibited by its sh3 domain	SIGNOR-152910	0.362
CREB1	protein	P16220	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								17668895	f		gcesareni	Phosphorylation of creb by msk has been linked to the of nur77, nor1 and c-fos downstream of mapkin various cell types	SIGNOR-157151	0.65
TEAD1	protein	P28347	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22286761	f		gcesareni	Yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor.	SIGNOR-195534	0.275
PRDM14	protein	Q9GZV8	UNIPROT	Pluripotency	phenotype	SIGNOR-PH43	SIGNOR	up-regulates													31583686	f		SimoneGraziosi	SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation. 	SIGNOR-269261	0.7
palmitoyl-CoA(4-)	smallmolecule	CHEBI:57379	ChEBI	O-palmitoyl-L-carnitine	smallmolecule	CHEBI:17490	ChEBI	up-regulates quantity	precursor of			9606									14517221	t		miannu	Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C).	SIGNOR-267123	0.8
UBE2A	protein	P49459	UNIPROT	PCNA	protein	P12004	UNIPROT	up-regulates	ubiquitination	Lys164	AVVISCAkDGVKFSA	9606									19706603	t		gcesareni	Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18.	SIGNOR-187761	0.489
PRKG1	protein	Q13976	UNIPROT	TRPC3	protein	Q13507	UNIPROT	down-regulates	phosphorylation	Ser251	KNDYRKLsMQCKDFV	9606	BTO:0000007								14983059	t		gcesareni	There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712.	SIGNOR-122978	0.417
AKT1	protein	P31749	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser104	FPPLNSVsPSPLMLL	9606									11108261	t		lperfetto	Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt.	SIGNOR-84963	0.757
EXTL1	protein	Q92935	UNIPROT	SHH	protein	Q15465	UNIPROT	down-regulates	binding			9606		BTO:0000142							15614771	t		gcesareni	A study in mice suggests that ext1 proteins might negatively regulate shh signaling by synthesizing hspgs, which sequester the ligand	SIGNOR-132606	0.299
GLS2	protein	Q9UI32	UNIPROT	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	chemical modification			9606									22049910	t		miannu	Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia.	SIGNOR-266911	0.8
PRKACA	protein	P17612	UNIPROT	AANAT	protein	Q16613	UNIPROT	up-regulates activity	phosphorylation	Ser205	HPFLRRNsGC	-1									11336675	t		miannu	AANAT1–207 was phosphorylated in vitro at both PKA sites, Thr-31 and Ser-205. regulation is achieved by binding to 14-3-3, which structurally modulates the substrate binding sites, leading to measurable effects on the affinity of AANAT for its substrates with an accompanying increase in activity at low substrate concentrations. 	SIGNOR-250324	0.325
SRC	protein	P12931	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr742	HMVQTNHyQVSGYPG	9606	BTO:0000195								17289681	t	The effect has been demonstrated using P34152-3	gcesareni	We propose that fak/c-src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on fak tyr-861 by src and subsequent reorganization of f-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress.	SIGNOR-152967	0.633
SKP2	protein	Q13309	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates	ubiquitination			9606									15998794	t		gcesareni	Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase.	SIGNOR-138490	0.763
MAPK8	protein	P45983	UNIPROT	CDC25B	protein	P30305	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser103	ESSLSSEsSESSDAG	9606	BTO:0000567								21807946	t		miannu	 Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104).	SIGNOR-276351	0.289
DZIP3	protein	Q86Y13	UNIPROT	H2AW	protein	Q7L7L0	UNIPROT	up-regulates activity	monoubiquitination	Lys119	IQAVLLPkKTESHHK	9606	BTO:0000007								18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271757	0.2
N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide	chemical	CHEBI:94793	ChEBI	MAP2K1	protein	Q02750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189930	0.8
BRCA1-B complex	complex	SIGNOR-C298	SIGNOR	G1/S_transition_checkpoint	phenotype	SIGNOR-PH147	SIGNOR	up-regulates													25400280	f		lperfetto	Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation	SIGNOR-263225	0.7
SMAD4	protein	Q13485	UNIPROT	SMAD1/4	complex	SIGNOR-C85	SIGNOR	form complex	binding			9606									9436979	t		lperfetto	Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription.	SIGNOR-103618	0.655
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	NEK2	protein	P51955	UNIPROT	down-regulates	dephosphorylation			9606									17283141	t		lperfetto	Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1	SIGNOR-264667	0.2
MICU2	protein	Q8IYU8	UNIPROT	MCU_MICUB_variant	complex	SIGNOR-C499	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270860	0.645
POT1/ACD	complex	SIGNOR-C64	SIGNOR	Shelterin complex	complex	SIGNOR-C306	SIGNOR	form complex	binding			9606									15383534	t		lperfetto	Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins.	SIGNOR-263318	0.856
RPRD1B	protein	Q9NQG5	UNIPROT	CCNB1	protein	P14635	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004953								30518842	t		lperfetto	These results indicated that CREPT regulates the Cyclin B1 expression via directly targeting its promoter region during transcription.	SIGNOR-265500	0.2
CDC14B	protein	O60729	UNIPROT	SIRT2	protein	Q8IXJ6	UNIPROT	unknown	dephosphorylation	Ser368	PNPSTSAsPKKSPPP	9606									17488717	t			Here, we demonstrate that SIRT2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1, and dephosphorylated by the phosphatases CDC14A and CDC14B. Overexpression of SIRT2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation|Additionally, we found that SIRT2, like other Cdk1 targets, can be dephosphorylated by the phosphatases CDC14A and CDC14B. In contrast to a published report (8), we did not observe any degradation of SIRT2 by the 26 S proteasome in response to CDC14B overexpression|However, we cannot exclude the possibility that phosphorylation of serine 368 might affect the activity of SIRT2 on other unidentified acetylated substrates. 	SIGNOR-248338	0.415
KMT2A	protein	Q03164	UNIPROT	KAT8	protein	Q9H7Z6	UNIPROT	up-regulates	binding			9606									15960975	t		miannu	Mll1 and mof can form a stable complex in vivo / given that an interaction of dmof with msl1 through its zinc finger is essential for correct targeting of mof to the male x chromosome	SIGNOR-138245	0.465
ADAMTS13	protein	Q76LX8	UNIPROT	VWF	protein	P04275	UNIPROT	down-regulates activity	cleavage			9606									23020315	t		miannu	Proteolytic degradation of VWF by ADAMTS-13 downregulates the proinflammatory potential of VWF. 	SIGNOR-251966	0.619
N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide	chemical	CHEBI:95008	ChEBI	BCL2L1	protein	Q07817	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	The effect has been demonstrated using Q07817-1	gcesareni		SIGNOR-207462	0.8
CSNK2A1	protein	P68400	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Ser24	GYLRKPKsMHKRFFV	-1									8349691	t		llicata	These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1.	SIGNOR-250907	0.345
MAPK1	protein	P28482	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation			9606									10197981	t		lperfetto	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3	SIGNOR-66749	0.736
IKBKE	protein	Q14164	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Ser386	ARVGGASsLENTVDL	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178367	0.732
PRKCG	protein	P05129	UNIPROT	STXBP1	protein	P61764	UNIPROT	down-regulates activity	phosphorylation	Ser313	SLKDFSSsKRMNTGE	9913	BTO:0000259								12519779	t		lperfetto	Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation.	SIGNOR-249187	0.394
LCK	protein	P06239	UNIPROT	IL2RB	protein	P14784	UNIPROT	unknown	phosphorylation	Tyr387	VYFTYDPySEEDPDE	-1									10214954	t			Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510.	SIGNOR-251377	0.629
PRKAA1	protein	Q13131	UNIPROT	SCN5A	protein	Q14524	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr101	IVLNKGKtIFRFSAT	9606	BTO:0002181								30759345	t		miannu	AMPK was found to phosphorylate Nav1.5 at threonine (T) 101, which then regulates the interaction between Nav1.5 and the autophagic adaptor protein, microtubule-associated protein 1 light chain 3 (LC3), by exposing the LC3-interacting region adjacent to T101 in Nav1.5.	SIGNOR-277432	0.2
CDK5R1	protein	Q15078	UNIPROT	CDK5	protein	Q00535	UNIPROT	up-regulates	binding			9606									15013773	t		miannu	In brain, p35 or p25 exists with and activates cdk5	SIGNOR-123387	0.942
MAPK1	protein	P28482	UNIPROT	STIM1	protein	Q13586	UNIPROT	up-regulates	phosphorylation	Ser575	LVEKLPDsPALAKKA	9606	BTO:0000222								22298426	t		gcesareni	The netrin-2-mediated nfatc3 activation was coincident with robust interactions between cdo and stim1 in myoblasts and the erk-mediated stim1 phosphorylation at serine 575	SIGNOR-192788	0.359
ABCA1	protein	O95477	UNIPROT	MEGF10	protein	Q96KG7	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								17205124	t		miannu	ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level. 	SIGNOR-265164	0.339
PP2CA_R1A_R2A 	complex	SIGNOR-C132	SIGNOR	AKT1	protein	P31749	UNIPROT	down-regulates activity	dephosphorylation	Thr308	KDGATMKtFCGTPEY	10090	BTO:0000944								18042541	t		gcesareni	Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B).	SIGNOR-252613	0.671
SMUG1	protein	Q53HV7	UNIPROT	Base-excision_repair	phenotype	SIGNOR-PH222	SIGNOR	up-regulates													23545420	f		lperfetto	The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1).	SIGNOR-275712	0.7
TUBB	protein	P07437	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	binding			9606									17429065	t		lperfetto	Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin.	SIGNOR-232113	0.2
BCORL1	protein	Q5H9F3	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								17379597	t		irozzo	BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor.	SIGNOR-259114	0.494
MAP3K6	protein	O95382	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity	phosphorylation	Tyr182	RHTDDEMtGYVATRW	9534									8622669	t		Manara	These data indicate that MKK6 phosphorylates p38 MAP kinase on Thr-180 and Tyr-182, the sites of phosphorylation that activate p38 MAP kinase	SIGNOR-260916	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	B2M	protein	P61769	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12480693	f		miannu	 The nuclear factor kappa B (NF-kappa B) subunits p50 and p65 bind to the kappa B box and p65 transactivates beta(2)m. 	SIGNOR-254658	0.349
MYF6	protein	P23409	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	up-regulates activity						BTO:0001103							7532173	f		Simone Vumbaca	Finally, MRF4 may be responsible for the final myogenic events of the fully differentiated myofiber	SIGNOR-255645	0.7
4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide	chemical	CHEBI:91447	ChEBI	RAF1	protein	P04049	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194922	0.8
DYRK2	protein	Q92630	UNIPROT	SIAH2	protein	O43255	UNIPROT	up-regulates	phosphorylation	Ser16	PSANKPCsKQPPPQP	9606									22878263	t		llicata	In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis.	SIGNOR-198721	0.42
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates activity	phosphorylation	Thr451	KRTRSKGtLRYMSPE	9606	BTO:0000567								11337501	t		lperfetto	Taken together, our findings support the idea that binding of pkr to dsrna increases autophosphorylation in the activation loop of the kinase domain (fig. 9). Because dsrna binding promotes dimerization, this would facilitate trans-autophosphorylation of thr-446 and thr-451 by the two kinase moieties in a pkr dimer	SIGNOR-107511	0.2
VASP	protein	P50552	UNIPROT	Axonal_growth_cone_formation	phenotype	SIGNOR-PH199	SIGNOR	up-regulates				9606									18508258	f		miannu	Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance.	SIGNOR-268390	0.7
PRKCZ	protein	Q05513	UNIPROT	YWHAB	protein	P31946	UNIPROT	down-regulates activity	phosphorylation	Thr143	SGDNKQTtVSNSQQA	9534	BTO:0004055								10620507	t		lperfetto	Our results with the 14-3-3 mutants indirectly imply a new phosphorylation site, 130Ser (and to a lesser extent 141Thr), in 14-3-3b that regulates the association}dissociation of 14-3-3b and PKC-f.	SIGNOR-249035	0.375
PPP1CC	protein	P36873	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	dephosphorylation	Thr495	TGITRKKtFKEVANA	9606	BTO:0001176								19036824	t			The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation	SIGNOR-248501	0.2
PLK1	protein	P53350	UNIPROT	CDC25C	protein	P30307	UNIPROT	up-regulates	phosphorylation	Ser198	SDELMEFsLKDQEAK	9606									11897663	t		lperfetto	The nuclear accumulation of active m-phase promoting factor (mpf) during prophase is thought to be essential for coordinating m-phase events in vertebrate cells. The protein phosphatase cdc25c, an activator of mpf, enters the nucleus to keep mpf active in the nucleus during prophase. these results suggest that plk1 phosphorylates cdc25c on ser198 and regulates nuclear translocation of cdc25c during prophase.	SIGNOR-115993	0.796
PRKCA	protein	P17252	UNIPROT	VCL	protein	P18206	UNIPROT	unknown	phosphorylation	Ser1101	NAQNLMQsVKETVRE	-1									11741957	t		lperfetto	PKC Phosphorylates Serines 1033 and 1045 in Helix H5	SIGNOR-249128	0.399
AURKB	protein	Q96GD4	UNIPROT	KNL1	protein	Q8NG31	UNIPROT	down-regulates	phosphorylation	Ser60	KKNSRRVsFADTIKV	9606									20471944	t		lperfetto	To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant).	SIGNOR-165506	0.2
Vincristine sulfate	chemical	CHEBI:79401	ChEBI	TUBB4A	protein	P04350	UNIPROT	down-regulates activity	chemical inhibition			9606									30599272	t		miannu	Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. 	SIGNOR-259250	0.8
PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	MAPT	protein	P10636	UNIPROT	up-regulates	dephosphorylation	Thr522	SSPGSPGtPGSRSRT	9606		BTO:0000142							20308788	t	The effect has been demonstrated using P10636-8	lperfetto	Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro.	SIGNOR-164671	0.2
BCLAF1	protein	Q9NYF8	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17938203	f		Luana	These results demonstrate that Btf positively regulates TP53 expression through CPE-TP53. 	SIGNOR-261568	0.423
ACD	protein	Q96AP0	UNIPROT	RPA1	protein	P27694	UNIPROT	down-regulates activity	binding						SIGNOR-C306						18680434	t		lperfetto	The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA	SIGNOR-263328	0.2
AKT2	protein	P31751	UNIPROT	BRAF	protein	P15056	UNIPROT	down-regulates	phosphorylation	Ser364	FGQRDRSsSAPNVHI	9606									10869359	t		gcesareni	We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf	SIGNOR-78681	0.276
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	IL18	protein	Q14116	UNIPROT	up-regulates activity	cleavage	Asp76	MTDSDCRdNAPRTIF	9606	BTO:0001370								9334240	t		lperfetto	Involvement of caspase-1 and caspase-3 in the production and processing of mature human interleukin 18 in monocytic THP.1 cells.|Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products.	SIGNOR-256379	0.497
ADAM17	protein	P78536	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	cleavage			10090									23729744	t		apalma	Receptor–ligand engagement triggers a second NECD cleavage (S2 cleavage) by a metalloproteinase ADAM (known as Kuzbanian in Drosophila melanogaster)	SIGNOR-255371	0.729
CSNK2A2	protein	P19784	UNIPROT	MYCN	protein	P04198	UNIPROT	unknown	phosphorylation	Ser263	GEDTLSDsDDEDDEE	-1									1425701	t		llicata	Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263.	SIGNOR-251015	0.375
AMPK	complex	SIGNOR-C15	SIGNOR	GBF1	protein	Q92538	UNIPROT	down-regulates	phosphorylation	Thr1337	GKIHRSAtDADVVNS	9606									18063581	t		lperfetto	These results indicate that gbf1 is a novel ampk substrate and that the ampk-mediated phosphorylation of gbf1 at thr(1337) has a critical role, presumably by attenuating the function of gbf1, in the disassembly of the golgi apparatus induced under stress conditions that lower the intracellular atp concentration.	SIGNOR-216588	0.2
SRC	protein	P12931	UNIPROT	FHOD1	protein	Q9Y613	UNIPROT	up-regulates activity	phosphorylation	Tyr99	REMLEGFyEEISKGR	10090									24331927	t		miannu	Our results show that only Src can efficiently phosphorylate FHOD1 at Y99 to enable the downstream activation by ROCK. 	SIGNOR-276612	0.312
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser37	YLDSGIHsGATTTAP	9606									11955436	t		lperfetto	Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC).	SIGNOR-227901	0.892
PTPN2	protein	P17706	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates	dephosphorylation			9606									15592458	t		gcesareni	Here, we report that the 45-kda variant of the protein tyrosine phosphatase tcptp (tc45) can recognize delta egfr as a cellular substrate	SIGNOR-132316	0.62
GSK3A	protein	P49840	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates	phosphorylation	Ser641	YRYPRPAsVPPSPSL	9606		BTO:0000887;BTO:0001103							14593110	t		gcesareni	Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase	SIGNOR-118927	0.422
RPS6KA5	protein	O75582	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates	phosphorylation			9606									20626350	t		gcesareni	Msk (mitogen- and stress-activated kinase) 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf- b isoform p65 and stat (signal transducer and activator of transcription) 1 and 3	SIGNOR-166664	0.393
TGFBR1	protein	P36897	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation			10090	BTO:0005065								17673906	t		lperfetto	We now report that upon TGF-_ stimulation, T_RI phosphorylates ShcA on serine and, to a lesser degree, on tyrosine to activate Erk MAP kinases.	SIGNOR-227503	0.529
GSK3B	protein	P49841	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation	Ser129	QKRREILsRRPSYRK	10116									12162494	t			GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant 	SIGNOR-251233	0.683
ERBB2	protein	P04626	UNIPROT	MSI1	protein	O43347	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20443831	f		gcesareni	We investigated the possibilities that erbb2 may regulate downstream mediators of notch1 signaling to induce musashi1 (which enhances notch1 signaling).	SIGNOR-165195	0.269
VWF	protein	P04275	UNIPROT	F8	protein	P00451	UNIPROT	up-regulates quantity by stabilization				9606									32644488	f		lperfetto	VWF plays a crucial role in hemostasis through platelet adhesion facilitation and coagulation factor VIII stabilization	SIGNOR-261865	0.782
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	MAPK1	protein	P28482	UNIPROT	up-regulates activity	phosphorylation	Thr185	HDHTGFLtEYVATRW	9606	BTO:0003807								11971971	t		lperfetto	Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.	SIGNOR-244792	0.2
PRKCD	protein	Q05655	UNIPROT	NCF4	protein	Q15080	UNIPROT	up-regulates activity	phosphorylation	Thr154	LRRLRPRtRKVKSVS	9606	BTO:0000738								9804763	t		lperfetto	P40(phox) is phosphorylated on threonine 154 and serine 315 during activation of the phagocyte NADPH oxidase. Implication of a protein kinase c-type kinase in the phosphorylation process.	SIGNOR-249012	0.361
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	MDM2	protein	Q00987	UNIPROT	up-regulates	phosphorylation	Ser186	RQRKRHKsDSISLSF	9606	BTO:0000785								18467333	t		gcesareni	Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt.	SIGNOR-259434	0.2
WWP1	protein	Q9H0M0	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates	ubiquitination			9606									15221015	t		gcesareni	Similar to smurfs, wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, wwp1 inhibited phosphorylation of smad2 induced by tgf-beta. Wwp1 thus negatively regulates tgf-beta signaling in cooperation with smad7	SIGNOR-126581	0.513
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates activity	phosphorylation	Ser105	TGAGAAGsPAQQHAH										26375055	t		lperfetto	We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity	SIGNOR-276524	0.265
IRX1	protein	P78414	UNIPROT	ANPEP	protein	P15144	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed.	SIGNOR-261663	0.2
ID1	protein	P41134	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	binding			9606	BTO:0004136								26084673	t		apalma	We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation;	SIGNOR-255942	0.341
DUSP9	protein	Q99956	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606									21908610	t		gcesareni	In addition, although mutation of ser-58 to either alanine or glutamic acid does not affect the intrinsic catalytic activity of dusp9/mkp-4, phospho-mimetic (ser-58 to glu) substitution inhibits both the interaction of dusp9/mkp-4 with erk2 and p38? In vivo and its ability to dephosphorylate and inactivate these map kinases.	SIGNOR-176586	0.686
PHLPP2	protein	Q6ZVD8	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0000527								15808505	t		gcesareni	Here, we identify a protein phosphatase, ph domain leucine-rich repeat protein phosphatase (phlpp), that specifically dephosphorylates the hydrophobic motif of akt (ser473 in akt1), triggering apoptosis and suppressing tumor growth.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt.	SIGNOR-135046	0.765
MMP19	protein	Q99542	UNIPROT	ACAN	protein	P16112	UNIPROT	down-regulates quantity by destabilization	cleavage			-1									10922468	t		lperfetto	Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|It has been suggested that MMPs play a role in the hydrolysis of COMP and, therefore, compromise the integrity of the cartilage ECM structure leading to the ultimate loss of joint function	SIGNOR-266980	0.409
PRKDC	protein	P78527	UNIPROT	LIG4	protein	P49917	UNIPROT	down-regulates	phosphorylation	Ser672	CVMSGTDsQPKPDLE	9606									15194694	t		lperfetto	Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability.	SIGNOR-125873	0.801
SMARCD3	protein	Q6STE5	UNIPROT	SWI/SNF ACTL6A-ARID1A-SMARCA2 variant	complex	SIGNOR-C470	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269820	0.748
NR1D1	protein	P20393	UNIPROT	ARNTL	protein	O00327	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21881539	f	 	lperfetto	Concomitant attenuation of NR1D1 downregulation (-2.4-fold compared with -4.1-fold in placebo; P=0.04), a transcriptional repressor of ARNTL, supported the view that ramipril might modulate glucose homeostasis pathways involving the NR1D1 ARNTL axis.	SIGNOR-253719	0.659
GSK3A	protein	P49840	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr53	PPGSLSStPLSTPCS	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159394	0.2
CENPA	protein	P49450	UNIPROT	CENP-A nucleosome	complex	SIGNOR-C321	SIGNOR	form complex	binding			-1									23324462	t		miannu	 In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro.	SIGNOR-263702	0.2
Multiaminoacyl-tRNA synthetase	complex	SIGNOR-C472	SIGNOR	ATP(4-)	smallmolecule	CHEBI:30616	ChEBI	down-regulates quantity	chemical modification			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270428	0.8
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(His)	smallmolecule	CHEBI:29178	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269488	0.8
ATM	protein	Q13315	UNIPROT	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates	phosphorylation	Ser1407	KSQNSQEsTADESED	9606									12086603	t		lperfetto	These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint	SIGNOR-90117	0.782
GNB1	protein	P62873	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606	BTO:0000938								16537363	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt	SIGNOR-145119	0.545
SFPQ	protein	P23246	UNIPROT	TOP1	protein	P11387	UNIPROT	up-regulates	binding			9606									9756848	t		miannu	We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i	SIGNOR-60563	0.379
monoisononyl phthalate	chemical	CHEBI:132593	ChEBI	PPARA	protein	Q07869	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 	SIGNOR-268780	0.8
AKT1	protein	P31749	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation			9606									21798082	t		lperfetto	Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b).	SIGNOR-175288	0.908
CDK2	protein	P24941	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser294	RAANLWPsPLMIKRS	9606	BTO:0000150								23390529	t		lperfetto	The pi3k/akt pathway is necessary to activate cdk2, which phosphorylates eralphaser294, and mediates the binding between pin1 and eralpha	SIGNOR-200867	0.491
PRKCA	protein	P17252	UNIPROT	NOXA1	protein	Q86UR1	UNIPROT	down-regulates	phosphorylation	Ser172	DQVQRRGsLPPRQVP	9606	BTO:0000007								20110267	t		llicata	Phosphorylation of nadph oxidase activator 1 (noxa1) on serine 282 by map kinases and on serine 172 by protein kinase c and protein kinase a prevents nox1 hyperactivation.	SIGNOR-163667	0.294
IGF1R	protein	P08069	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates	phosphorylation	Tyr941	EETGTEEyMKMDLGP	9606									17827393	t		gcesareni	Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K).	SIGNOR-157754	0.864
bisphenol A	chemical	CHEBI:33216	ChEBI	TPO	protein	P07202	UNIPROT	down-regulates activity	chemical inhibition			-1									17379648	t		miannu	Half-maximal inhibition of TPO by BPA and F21388 occurred at 174 and 37.5 mol/liter in the guaiacol assay.	SIGNOR-268786	0.8
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	H3C1	protein	P68431	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									17643117	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation.	SIGNOR-259409	0.2
CDK1	protein	P06493	UNIPROT	BCL2L11	protein	O43521	UNIPROT	up-regulates activity	phosphorylation	Ser104	FSFDTDRsPAPMSCD	9606									22071694	t		lperfetto	Furthermore, active recombinant Cdk1/cyclin B1 phosphorylates BimEL and BimL in vitro and Serine 44 on BimL has been identified as a Cdk1 phosphorylation site. Collectively, these results suggest that Cdk1/cyclin B1-dependent hyper-phosphorylation of Bim during prolonged mitotic arrest is an important cell death signal.	SIGNOR-267985	0.416
PROK2	protein	Q9HC23	UNIPROT	PROKR2	protein	Q8NFJ6	UNIPROT	up-regulates	binding			9606									12024206	t		gcesareni	We have cloned two closely related receptors for pk1 and pk2. These receptors, named prokineticin receptor 1 and 2 (pkr1 and pkr2)	SIGNOR-87919	0.654
CHEK2	protein	O96017	UNIPROT	PSME3	protein	P61289	UNIPROT	up-regulates activity	phosphorylation	Ser247	EKIKRPRsSNAETLY	9606	BTO:0001938								25361978	t		miannu	REGγ interacts with DBC1 and is phosphorylated by Chk2.	SIGNOR-273611	0.355
ABL1	protein	P00519	UNIPROT	PRDX2	protein	P32119	UNIPROT	down-regulates activity	phosphorylation	Tyr193	NVDDSKEyFSKHN	-1									20178744	t		miannu	Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.	SIGNOR-276280	0.289
KAR	proteinfamily	SIGNOR-PF57	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								15919192	f		miannu	Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1–4); five kainate receptor genes (GluR5–7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits.	SIGNOR-264693	0.7
Fibrinogen	complex	SIGNOR-C311	SIGNOR	Fibrin	complex	SIGNOR-C317	SIGNOR	form complex	cleavage			9606		BTO:0000131							18544683	t		lperfetto	A fibrin clot is the final product of the blood clotting cascade. Thrombin catalyzes release of fibrinopeptide A from fibrinogen to create fibrin monomers, which then aggregate to protofibrils. Proteolytic release of fibrinopeptide B by thrombin permits lateral protofibril aggregation, resulting in a three-dimensional fibrin gel.|Fibrin clots were formed as described for turbidity experiments, in which the fibrinogen, calcium, and polyP (when included) were preincubated for 15 minutes before adding thrombin. 	SIGNOR-263551	0.2
CSNK1D	protein	P48730	UNIPROT	DCK	protein	P27707	UNIPROT	up-regulates activity	phosphorylation	Ser74	EFEELTMsQKNGGNV										20637175	t		lperfetto	We showed that recombinant CKI delta phosphorylated several residues of bacterially overexpressed dCK: Ser-74, but also Ser-11, Ser-15, and Thr-72. Phosphorylation of dCK by CKI delta correlated with increased activity reaching at least 4-fold. Site-directed mutagenesis demonstrated that only Ser-74 phosphorylation was involved in dCK activation by CKI delta,	SIGNOR-275799	0.346
PCBD1	protein	P61457	UNIPROT	HNF1B	protein	P35680	UNIPROT	up-regulates activity	binding			9606		 BTO:0000482							24204001	t		miannu	 Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT.	SIGNOR-254910	0.598
PRKCD	protein	Q05655	UNIPROT	NFE2L2	protein	Q16236	UNIPROT	up-regulates activity	phosphorylation	Ser40	SREVFDFsQRRKEYE	-1									12198130	t		lperfetto	Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription.	SIGNOR-249161	0.378
ELF1	protein	P32519	UNIPROT	CD68	protein	P34810	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000801								12676954	f	 	 	Band shift experiments show that PU.1 associates with the -89 site whereas, Elf-1 preferentially binds the -106 Ets binding site and enhances CD68 activity in vitro.	SIGNOR-254282	0.2
PRKACA	protein	P17612	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates	phosphorylation	Ser857	PPYNRAVsLDSPVSV	9606									15383283	t		gcesareni	Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites.	SIGNOR-129349	0.34
TPI1	protein	P60174	UNIPROT	D-glyceraldehyde 3-phosphate(2-)	smallmolecule	CHEBI:59776	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa).	SIGNOR-266492	0.8
SKI	protein	P12755	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	binding			9606									10575014	t		lperfetto	Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling.	SIGNOR-232123	0.716
hydrogen peroxide	smallmolecule	CHEBI:16240	ChEBI	ROS	stimulus	SIGNOR-ST2	SIGNOR	up-regulates				9606									35681445	f		lperfetto	The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment.	SIGNOR-272278	0.7
NCOA1	protein	Q15788	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates	binding			9606		BTO:0000149							12954634	t		miannu	Ncoa-1/src-1 is an essential coactivator of stat5 that binds to the fdl motif in the alpha-helical region of the stat5 transactivation domain.	SIGNOR-100258	0.414
CIITA	protein	P33076	UNIPROT	HLA-A	protein	P04439	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								10329350	f	 	 	Transfection of CIITA in JEG-3 cells also upregulated functional HLA-B and HLA-C expression.	SIGNOR-254020	0.499
FOXO3	protein	O43524	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									14976264	f		lperfetto	Sirt1 inhibited foxo3's ability to induce cell death.	SIGNOR-256645	0.7
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser750	QTEEEEHsCLEQAS	9606			SIGNOR-C14	SIGNOR-C14					10195894	t		lperfetto	Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response	SIGNOR-66352	0.2
POGLUT1	protein	Q8NBL1	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	glycosylation			9606									22872643	t	O-glycosilation	gcesareni	O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus.	SIGNOR-254319	0.591
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH24	protein	Q86UP0	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265840	0.8
UBE2D2	protein	P62837	UNIPROT	TRIM5	protein	Q9C035	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								18312418	t		miannu	Here, we show that TRIM5alpha functions as a RING-finger-type E3 ubiquitin ligase both in vitro and in vivo and ubiquitinates itself in cooperation with the E2 ubiquitin-conjugating enzyme UbcH5B. 	SIGNOR-271670	0.469
MAD2L1BP	protein	Q15013	UNIPROT	TRIP13	protein	Q15645	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								25092294	t		miannu	We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4). 	SIGNOR-265971	0.483
PRKCB	protein	P05771	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Ser497	ATVKSRWsGSQQVEQ	9606									8288587	t		gcesareni	Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. the sites of pkc-mediated raf-1 phosphorylation are deduced to be ser497 and ser619.	SIGNOR-37474	0.42
GSK3B	protein	P49841	UNIPROT	MAF	protein	O75444	UNIPROT	down-regulates	phosphorylation			9606									18042454	t		miannu	We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.	SIGNOR-159438	0.264
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser413	GLMQRSSsFPYTTKG	10090									22848740	t			When AMPK is stimulated, pre-existing FOXO3 becomes reverted toward an active form.	SIGNOR-255756	0.397
CyclinD1/CDK6	complex	SIGNOR-C143	SIGNOR	TSC2	protein	P49815	UNIPROT	up-regulates activity	phosphorylation	Ser1452	LPSSSPRsPSGLRPR	9606	BTO:0000007								32294430	t	done	miannu	We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452. 	SIGNOR-274102	0.415
CDK5	protein	Q00535	UNIPROT	APP	protein	P05067	UNIPROT	unknown	phosphorylation	Thr743	VEVDAAVtPEERHLS	10116	BTO:0000938								10936190	t		llicata	In vitro, active cyclin-dependent kinase 5 (Cdk5) phosphorylated the cytoplasmic domain of APP at Thr(668). Treatment of mature neurons with an antisense oligonucleotide to Cdk5 suppressed Cdk5 expression and significantly diminished the level of phosphorylated APP. The expression of APP was unaffected in antisense-treated neurons. These results indicate that in neurons APP is phosphorylated by Cdk5, and that this may play a role in its localization.	SIGNOR-250651	0.584
DUSP5	protein	Q16690	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates	dephosphorylation			9606									10224087	t		gcesareni	Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway	SIGNOR-67358	0.751
CSNK2A3	protein	Q8NEV1	UNIPROT	FGF14	protein	Q92915	UNIPROT	up-regulates activity	phosphorylation	Ser230	VTPSKSTsASAIMNG	9606	BTO:0000938								26917740	t		lperfetto	 Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.	SIGNOR-275743	0.272
SRSF11	protein	Q05519	UNIPROT	APOE	protein	P02649	UNIPROT	up-regulates quantity by stabilization	post transcriptional regulation			10090									31269452	t		miannu	We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling.	SIGNOR-269671	0.2
SRC	protein	P12931	UNIPROT	CDH5	protein	P33151	UNIPROT	down-regulates activity	phosphorylation	Tyr731	PYDTLHIyGYEGSES	10029	BTO:0000246								16027153	t		lperfetto	cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity.	SIGNOR-246466	0.585
4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide	chemical	CHEBI:94506	ChEBI	CDK2	protein	P24941	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193549	0.8
SOX6	protein	P35712	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0003298								26893351	t			In adipocytes, in addition to the direct regulation of PPARγ andC/EBP expression, we showed that SOX6 inhibitsWNT signaling by binding to β-catenin, potentially leading to its degradation	SIGNOR-255825	0.64
TNPO1	protein	Q92973	UNIPROT	PER1	protein	O15534	UNIPROT	up-regulates activity	relocalization			9606									29377895	t		lperfetto	The non-classical nuclear import carrier Transportin 1 modulates circadian rhythms through its effect on PER1 nuclear localization	SIGNOR-262102	0.272
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH15	protein	P55291	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265832	0.8
PD173074	chemical	CHEBI:63448	ChEBI	FGFR3	protein	P22607	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205728	0.8
PPP2CA	protein	P67775	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Thr185	HDHTGFLtEYVATRW	9606	BTO:0004419								12840032	t		lperfetto	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).Mapk activity is tightly regulated by phosphorylation and dephosphorylation. The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase	SIGNOR-103159	0.604
1-phosphatidyl-1D-myo-inositol 5-phosphate(3-)	smallmolecule	CHEBI:57795	ChEBI	SPOP	protein	O43791	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								18218622	t		Gianni	Taken together, these data define a novel mechanism whereby the phosphoinositide PI5P leads to stimulation of Cul3-SPOP ubiquitin ligase activity and also implicate PIPKIIbeta as a key regulator of this signaling pathway through its association with the Cul3-SPOP complex.	SIGNOR-268863	0.8
P2RY12	protein	Q9H244	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256855	0.377
RELA	protein	Q04206	UNIPROT	IL1B	protein	P01584	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20975042	t		svumbaca	In addition, we show that the transcription of IL1B depends on a positively acting p65/c-Rel/ikbb complex	SIGNOR-256237	0.537
ADRB3	protein	P13945	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256753	0.605
SLC18A2	protein	Q05940	UNIPROT	dopamine	smallmolecule	CHEBI:18243	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								30465801	t		miannu	Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. 	SIGNOR-269197	0.8
entinostat	chemical	CHEBI:132082	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257903	0.8
PAK1	protein	Q13153	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation	Ser418	TEERLPSsPVYEDAA	9606									21079800	t		gcesareni	Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis.	SIGNOR-169694	0.695
TIMM22	protein	Q9Y584	UNIPROT	TIM22 complex	complex	SIGNOR-C424	SIGNOR	form complex	binding			9606	BTO:0000007								32901109	t		lperfetto	Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK).	SIGNOR-267706	0.665
PRKACA	protein	P17612	UNIPROT	CDK16	protein	Q00536	UNIPROT	down-regulates	phosphorylation	Ser153	SRRLRRVsLSEIGFG	9606		BTO:0000142							22184064	t		llicata	Here, we report that cdk16 is activated by membrane-associated cyclin y (ccny). Treatment of transfected human cells with the protein kinase a (pka) activator forskolin blocked, while kinase inhibition promoted, ccny-dependent targeting of cdk16-green fluorescent protein (gfp) to the cell membrane. Ccny binding to cdk16 required a region upstream of the kinase domain and was found to be inhibited by phosphorylation of serine 153, a potential pka phosphorylation site.	SIGNOR-191623	0.319
ECM	stimulus	SIGNOR-ST20	SIGNOR	A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	up-regulates				9606									30889378	t		miannu	Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions	SIGNOR-259046	0.7
SP7	protein	Q8TDD2	UNIPROT	IFITM5	protein	A6NNB3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23530031	f	 	miannu	Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation.	SIGNOR-254219	0.374
IKBKB	protein	O14920	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser531	RTHSAGTsPTITHQK	-1									12351658	t			IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.	SIGNOR-251297	0.644
PLK4	protein	O00444	UNIPROT	NEDD1	protein	Q8NHV4	UNIPROT	up-regulates activity	phosphorylation	Ser325	PTTVNKRsVNVNAAS										33351100	t		lperfetto	We found that PLK4-mediated phosphorylation of NEDD1 at its S325 amino acid residue directly promotes both NEDD1 binding to SAS-6 and recruiting SAS-6 to the centrosome. |Collectively, our results demonstrate that PLK4-regulated NEDD1 facilitates initiation of the cartwheel assembly and of daughter centriole biogenesis in mammals.	SIGNOR-272996	0.577
TP53	protein	P04637	UNIPROT	NDRG1	protein	Q92597	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15377670	f		miannu	We isolated a p53-regulated gene named ndrg1 (n-myc down-regulated gene 1). Its expression is induced by dna damage in a p53-dependent fashion.	SIGNOR-129183	0.509
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	HES1	protein	Q14469	UNIPROT	up-regulates quantity	transcriptional regulation			9606	BTO:0001938								24300895	f			These data indicate that basal NFκB activity at the conserved +26/+34 site of the HES1 gene promotes its expression, and that glucocorticoids can silence HES1 by inhibiting this activity.	SIGNOR-253063	0.2
MAPK8	protein	P45983	UNIPROT	RCSD1	protein	Q6JBY9	UNIPROT	down-regulates activity	phosphorylation	Ser68	GQNGEEKsPPNASHP	-1									15850461	t		miannu	CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263085	0.291
SRC	protein	P12931	UNIPROT	CACNA1C	protein	Q13936	UNIPROT	up-regulates activity	phosphorylation	Tyr2217	ELQDSRVyVSSL	9606	BTO:0000007								17942635	t		miannu	Cotransfection of human embryonic kidney (HEK)-293 cells with hCa(v)1.2b and c-Src resulted in tyrosine phosphorylation of the calcium channel, which was prevented by nitration of tyrosine residues by peroxynitrite. Whole cell calcium currents were reduced by 58 + 5% by the Src kinase inhibitor PP2 and 64 + 6% by peroxynitrite. 	SIGNOR-276081	0.455
SRC	protein	P12931	UNIPROT	CDCP1	protein	Q9H5V8	UNIPROT	unknown	phosphorylation	Tyr734	KDNDSHVyAVIEDTM	9606									14739293	t		lperfetto	Phosphorylation of gp140 and p80 are mediated by Src family kinases at multiple Tyr residues including Tyr(734).	SIGNOR-246457	0.545
PTGIR	protein	P43119	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256949	0.252
MYC	protein	P01106	UNIPROT	SFRP1	protein	Q8N474	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004896; BTO:0004300								17485441	f		gcesareni	c-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity	SIGNOR-245360	0.365
AKT1	protein	P31749	UNIPROT	ATG4B	protein	Q9Y4P1	UNIPROT	up-regulates activity	phosphorylation	Ser34	WILGRKYsIFTEKDE	9606	BTO:0000586								29165041	t		lperfetto	In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells.| In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity.	SIGNOR-275834	0.316
NDUFB2	protein	O95178	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1	SIGNOR-262165	0.775
FBXW8	protein	Q8N3Y1	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates quantity by destabilization	binding			10090	BTO:0002572								23142081	t		miannu	Defective IRS-1 degradation was due to attenuated expression and phosphorylation of the ubiquitin ligase substrate-targeting subunit, Fbw8. mTORC2 stabilizes Fbw8 by phosphorylation at Ser86, allowing the insulin-induced translocation of Fbw8 to the cytosol where it mediates IRS-1 degradation. 	SIGNOR-271939	0.473
KDR	protein	P35968	UNIPROT	KDR	protein	P35968	UNIPROT	up-regulates	phosphorylation	Tyr951	RFRQGKDyVGAIPVD	9606	BTO:0000801;BTO:0000876								17658244	t		gcesareni	Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability.	SIGNOR-157097	0.2
GPSM3	protein	Q9Y4H4	UNIPROT	GNAI1	protein	P63096	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								22843681	t		lperfetto	GPSM3 acts through its two GoLoco motifs to exert GDP dissociation inhibitor activity over Galpha(i) subunits|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET.	SIGNOR-264864	0.468
PTPN6	protein	P29350	UNIPROT	CASP8	protein	Q14790	UNIPROT	up-regulates activity	dephosphorylation	Tyr448	TILTEVNyEVSNKDD	9606									18086677	t			Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis. 	SIGNOR-248478	0.361
ACSL1	protein	P33121	UNIPROT	hexadecanoic acid	smallmolecule	CHEBI:15756	ChEBI	down-regulates quantity	chemical modification			9606									21242590	t		miannu	Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. On the other hand, overexpression of ACSL1 resulted in large increases in oleoyl-CoA synthesis and palmitoyl-CoA synthesis in SMC lysates (Fig. 4A).	SIGNOR-267878	0.8
CDK19	protein	Q9BWU1	UNIPROT	PAK1	protein	Q13153	UNIPROT	unknown	phosphorylation	Ser174	TPAVPPVsEDEDDDD	9606									19520772	t		llicata	Here, we identified p21 activated kinase 1 (pak1) as a new cdk11(p58) substrate and we mapped a new phosphorylation site of ser174 on pak1	SIGNOR-185000	0.337
CAMK2A	protein	Q9UQM7	UNIPROT	NOX5	protein	Q96PH1	UNIPROT	unknown	phosphorylation	Thr540	KRLSRSVtMRKSQRS	-1									21642394	t		miannu	In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475.	SIGNOR-276330	0.2
DNMT3B	protein	Q9UBC3	UNIPROT	DPP6	protein	P42658	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000596								23409053	t		lperfetto	In the absence of Dnmt3b, Dnmt3a was associated with Dpp6 gene promoter and regulated its expression and methylation in P19 cells.	SIGNOR-268964	0.334
PKN1	protein	Q16512	UNIPROT	MARCKS	protein	P29966	UNIPROT	down-regulates activity	phosphorylation	Ser159	KKKKKRFsFKKSFKL	-1									8557118	t		gcesareni	PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163.	SIGNOR-243199	0.372
HAP1	protein	P54257	UNIPROT	KIF5C	protein	O60282	UNIPROT	up-regulates activity	binding			9606									31757889	t		miannu	 HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C in vitro 	SIGNOR-264062	0.411
GGCX	protein	P38435	UNIPROT	F2	protein	P00734	UNIPROT	up-regulates activity	carboxylation	Glu49	RRANTFLeEVRKGNL	-1									10556651	t		lperfetto	We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 	SIGNOR-263675	0.655
MARCHF1	protein	Q8TCQ1	UNIPROT	HLA-DRB3	protein	P79483	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys254	FIYFRNQkGHSGLQP	9606									19117940	t		miannu	Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination.	SIGNOR-271410	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	VCP	protein	P55072	UNIPROT	up-regulates	phosphorylation	Ser352	AATNRPNsIDPALRR	9606	BTO:0000150								16551632	t		llicata	Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I	SIGNOR-145284	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-183612	0.2
spiperone	chemical	CHEBI:9233	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029									9550290	t		miannu	Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists.	SIGNOR-258894	0.8
CAMK2A	protein	Q9UQM7	UNIPROT	NOX5	protein	Q96PH1	UNIPROT	unknown	phosphorylation	Ser544	RSVTMRKsQRSSKGS	-1									21642394	t		miannu	In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475.	SIGNOR-276331	0.2
ADORA2B	protein	P29275	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256767	0.495
Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	up-regulates				9606									30397315	f		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270713	0.7
PLK1	protein	P53350	UNIPROT	STK38	protein	Q15208	UNIPROT	down-regulates activity	phosphorylation	Thr183	TLLMKKDtLTEEETQ	9606	BTO:0000567								26057687	t		miannu	Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis. 	SIGNOR-276913	0.321
PPP1CA	protein	P62136	UNIPROT	PREX1	protein	Q8TCU6	UNIPROT	up-regulates activity	dephosphorylation	Ser1165	DSGHDTMsYRDSYSE	9606									22242915	t		lperfetto	MS analysis of wild-type P-Rex1 and a PP1\u03b1-binding-deficient mutant revealed that endogenous PP1\u03b1 dephosphorylates P-Rex1 on at least three residues, Ser834, Ser1001 and Ser1165.|The phosphatase activity of PP1\u03b1 is required for P-Rex1 activation.	SIGNOR-277023	0.2
CDK20	protein	Q8IZL9	UNIPROT	CILK1	protein	Q9UPZ9	UNIPROT	up-regulates	phosphorylation	Thr157	IRSKPPYtDYVSTRW	9606									15988018	t		lperfetto	Recombinant cak1p phosphorylates thr-157 in the tdy motif of recombinant ick and activates its activity in vitro.	SIGNOR-138420	0.2
RASGEF1A	protein	Q8N9B8	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates	binding			9606									19201597	t		gcesareni	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183823	0.411
CDK1	protein	P06493	UNIPROT	NDUFB6	protein	O95139	UNIPROT	up-regulates activity	phosphorylation	Ser55	NKFLENKsPWRKMVH										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275590	0.2
NOD2	protein	Q9HC29	UNIPROT	ATG16L1	protein	Q676U5	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								19898471	t		miannu	By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease.	SIGNOR-252405	0.751
RXRA	protein	P19793	UNIPROT	RARB	protein	P10826	UNIPROT	up-regulates	binding			9606									1310351	t		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16668	0.666
MAP3K10	protein	Q02779	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates	phosphorylation	Thr355	NFSSSPStPVGSPQG	9606									19801649	t		llicata	Mlk2 inhibits e47 transactivation activity on the trkb promote	SIGNOR-161544	0.2
FYN	protein	P06241	UNIPROT	NOX4	protein	Q9NPH5	UNIPROT	down-regulates activity	phosphorylation	Tyr566	LSNQNNSyGTRFEYN	-1									27525436	t		miannu	We found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation.	SIGNOR-277273	0.274
KDM4B	protein	O94953	UNIPROT	TP53I3	protein	Q53FA7	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001109								28073943	f		miannu	 JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. 	SIGNOR-263731	0.2
N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide	chemical	CHEBI:91371	ChEBI	CDK5	protein	Q00535	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206133	0.8
PDGFRB	protein	P09619	UNIPROT	PDGFRB	protein	P09619	UNIPROT	up-regulates	phosphorylation	Tyr1009	LDTSSVLyTAVQPNE	9606									1396585	t		llicata	These data show that tyrosine phosphorylation of plc-gamma is dependent on autophosphorylation of the pdgf beta-receptor at tyr1009 and tyr1021.	SIGNOR-18575	0.2
SPI1	protein	P17947	UNIPROT	EGR2	protein	P11161	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									16923394	f		miannu	PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation	SIGNOR-256040	0.38
DYNLL2	protein	Q96FJ2	UNIPROT	AMBRA1	protein	Q9C0C7	UNIPROT	down-regulates	binding			9606									20921139	t		gcesareni	The beclin 1 vps34 complex is tethered to the cytoskeleton through an interaction between the beclin 1 interacting protein ambra1 and dynein light chains 1/2	SIGNOR-168289	0.438
NME1	protein	P15531	UNIPROT	CCN2	protein	P29279	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									17671192	f		miannu	To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 	SIGNOR-255160	0.2
CAMK2A	protein	Q9UQM7	UNIPROT	HOMER3	protein	Q9NSC5	UNIPROT	down-regulates activity	phosphorylation	Ser120	ARLAREKsQDGGELT	-1									18480293	t		miannu	Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation	SIGNOR-262684	0.2
ATM	protein	Q13315	UNIPROT	KHSRP	protein	Q92945	UNIPROT	up-regulates	phosphorylation	Ser274	MILIQDGsQNTNVDK	9606									21329876	t		lperfetto	The atm kinase directly binds to and phosphorylates ksrp, leading to enhanced interaction between ksrp and pri-mirnas and increased ksrp activity in mirna processing	SIGNOR-172123	0.435
CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	CRY2	protein	Q49AN0	UNIPROT	up-regulates quantity by expression	transcriptional regulation												22750052	f		lperfetto	Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins.	SIGNOR-253680	0.927
HRAS	protein	P01112	UNIPROT	BRAF	protein	P15056	UNIPROT	up-regulates	binding			9606									18098337	t		lperfetto	BRAF kinase is a downstream target of KRAS and activates the MAPK pathway.	SIGNOR-160043	0.873
ASIP	protein	P42127	UNIPROT	MC5R	protein	P33032	UNIPROT	down-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268713	0.515
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257970	0.8
TCF3	protein	P15923	UNIPROT	CR2	protein	P20023	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11739509	f	 	miannu	We have previously described the presence of an intronic element that is required for both cell- and stage-specific expression of CR2. In this study, we report the identification of a cell type-specific repressor element within the proximal promoter. By supershift analysis this element binds members of the basic helix-loop-helix family of proteins, in particular E2A gene products. Mutational analysis demonstrates that binding of E2A proteins is critical for functioning of this repressor. Thus, E2A activity is key not only for early B cell development, but also for controlling CR2 expression, a gene expressed only during later stages of ontogeny.	SIGNOR-255387	0.285
CCKBR	protein	P32239	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257412	0.487
PAX3	protein	P23760	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000222								18854138	f		gcesareni	Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts.	SIGNOR-181621	0.494
PCSK1	protein	P29120	UNIPROT	Corticotropin	protein	P01189-PRO_0000024969	UNIPROT	up-regulates quantity	cleavage												24631756	t		lperfetto	POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide	SIGNOR-268724	0.2
EGFR	protein	P00533	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	phosphorylation	Tyr320	RKDTKEIyTHFTCAT	-1									33139573	t		miannu	RTKs directly phosphorylate Gαi on Y154, 155, and Y320.	SIGNOR-277228	0.44
XL-647	chemical	CID:10458325	PUBCHEM	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									22722787	t	XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with EGFR-activating mutations.	gcesareni	Xl647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (egfr), vascular endothelial growth factor receptor 2, her2 and ephrin type-b receptor 4 (ephb4).	SIGNOR-197959	0.8
GGCX	protein	P38435	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	carboxylation	Glu54	YNSGKLEeFVQGNLE	10090		BTO:0001103							11133752	t		lperfetto	The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.	SIGNOR-263687	0.67
S100A9	protein	P06702	UNIPROT	Calprotectin complex	complex	SIGNOR-C293	SIGNOR	form complex	binding												9867828	t			Using the two-hybrid system we analyzed the dimerization of MRP8 (S100A8) and MRP14 (S100A9), two S100 proteins expressed in myeloid cells. It is reported that the MRP8-MRP14 heteromer is the clearly preferred complex in both man and mouse.	SIGNOR-262828	0.716
JUN	protein	P05412	UNIPROT	Monocyte_differentiation 	phenotype	SIGNOR-PH101	SIGNOR	up-regulates				10090	BTO:0000725								17041602	f		miannu	These results show that restoration of c-Jun expression rescues the myelomonocytic differentiation block in preleukemic PU.1-knockdown bone marrow cells, suggesting that c-Jun is a critical downstream target in PU.1-knockdown HSCs.	SIGNOR-256066	0.7
UBR5	protein	O95071	UNIPROT	SOX2	protein	P48431	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys115	YKYRPRRkTKTLMKK	9606	BTO:0002428								30894683	t		miannu	We identified UBR5 as a major ubiquitin E3 ligase that induces SOX2 degradation through ubiquitinating SOX2 at lysine 115.	SIGNOR-277446	0.258
GSK3B	protein	P49841	UNIPROT	TCAP	protein	O15273	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser157	GALRRSLsRSMSQEA	9606									32937135	t		lperfetto	GSK-3beta phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation.|These results show direct GSK-3beta phosphorylation of TCAP S157 and FBXL21 T33 sites.	SIGNOR-264852	0.2
SRC	protein	P12931	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Tyr373	ASDTDSSyCIPTAGM	9606									19881549	t		lperfetto	Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis	SIGNOR-236318	0.693
CHMP6	protein	Q96FZ7	UNIPROT	ESCRT-III	complex	SIGNOR-C379	SIGNOR	form complex	binding			-1									26775243	t		miannu	The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission.	SIGNOR-265526	0.662
SMAD2/STAT3/EP300	complex	SIGNOR-C203	SIGNOR	RORC	protein	P51449	UNIPROT	up-regulates				9606									26194464	t		MARCO ROSINA	Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes.	SIGNOR-255026	0.439
TGFB1	protein	P01137	UNIPROT	CDK4	protein	P11802	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		BTO:0000763							8402878	f		gcesareni	Here we show that tgf beta 1 induces suppression of cdk4 synthesis in g1 in mink lung epithelial cells.	SIGNOR-39045	0.286
tiotropium	chemical	CHEBI:90960	ChEBI	CHRM3	protein	P20309	UNIPROT	down-regulates activity	chemical inhibition			-1									8441333	t		miannu	A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors.	SIGNOR-258486	0.8
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1882	SPTSPTYsPTTPKYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203576	0.77
AMPK	complex	SIGNOR-C15	SIGNOR	HIPK2	protein	Q9H2X6	UNIPROT	down-regulates activity	phosphorylation	Thr119	HNLMRRStVSLLDTY										23871434	t	Phosphosite positions are derived from Figure S5	lperfetto	AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro	SIGNOR-275482	0.251
PKM	protein	P14618	UNIPROT	pyruvate	smallmolecule	CHEBI:15361	ChEBI	up-regulates quantity	chemical modification			9606									15996096	t		miannu	Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A).	SIGNOR-266536	0.8
CDC7	protein	O00311	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates	phosphorylation	Ser5	sESFTMAS	9606									19647517	t		lperfetto	Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry	SIGNOR-187396	0.961
RIMBP3C	protein	A6NJZ7	UNIPROT	RIMS1	protein	Q86UR5	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264362	0.267
HCRTR1	protein	O43613	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256876	0.252
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	LATS1	protein	O95835	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0005907								25026211	t		miannu	CRL4 DCAF1 ubiquitylates and inhibits Lats.	SIGNOR-272229	0.368
tolcapone	chemical	CHEBI:63630	ChEBI	COMT	protein	P21964	UNIPROT	down-regulates activity	chemical inhibition			9606									9681662	t		Simone Vumbaca	Entacapone and tolcapone were powerful inhibitors of COMT and their IC50 estimates were 151 and 773 nM (P=0.008), respectively, in the liver; consistent results were obtained with the other tissues.	SIGNOR-261091	0.8
GATA1	protein	P15976	UNIPROT	KLF1	protein	Q13351	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									8195185	f		irozzo	Regulation of the Erythroid Kruppel-like Factor (EKLF) Gene Promoter by the Erythroid Transcription Factor GATA-l.Accordingly,we have also demonstrated that GATA-2, like GATA-1, is able to activate the EKLF promoter in NIH3T3.	SIGNOR-256051	0.517
MDFI	protein	Q99750	UNIPROT	MYOG	protein	P15173	UNIPROT	down-regulates activity	binding			10090	BTO:0000944								8797820	t	2	miannu	We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals.	SIGNOR-240493	0.382
PPP2CA	protein	P67775	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates	dephosphorylation	Thr450	TAQMITItPPDQDDS	9606									11839802	t		gcesareni	Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2a and dephosphorylation of akt and glycogen synthase kinase 3 beta	SIGNOR-114767	0.889
TNFRSF17	protein	Q02223	UNIPROT	MAPK12	protein	P53778	UNIPROT	up-regulates				9606									10903733	f		miannu	Overexpression of bcma activates the p38 mapk	SIGNOR-79498	0.2
motesanib	chemical	CHEBI:51098	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258251	0.8
PRKCQ	protein	Q04759	UNIPROT	MGluR	proteinfamily	SIGNOR-PF55	SIGNOR	up-regulates activity	phosphorylation			-1									15894802	t	inferred from family member	lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-270273	0.294
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	MYOD1	protein	P15172	UNIPROT	down-regulates	phosphorylation	Ser200	YSGDSDAsSPRSNCS	9606									21902831	t		lperfetto	Cyclin e/cdk2 can phosphorylate myod at serine 200, which causes ubiquitination and degradation of this transcription factor during g1, preventing its accumulation and a commitment to differentiation.	SIGNOR-216706	0.538
RABGEF1	protein	Q9UJ41	UNIPROT	RAB5A	protein	P20339	UNIPROT	up-regulates	binding			9606									11452015	t		miannu	We have previously shown that rab5, which regulates various steps of transport along the early endocytic pathway, is activated by a complex consisting of rabex-5, a rab5 nucleotide exchange factor, and the effector rabaptin-5.	SIGNOR-109398	0.921
JUN	protein	P05412	UNIPROT	Cell_migration	phenotype	SIGNOR-PH38	SIGNOR	up-regulates				9606									23151663	f		amattioni	Planar cell polarity (PCP) signalling is prominently involved in the regulation of cell polarity, cell motility and morphogenetic movements, throught the activation of JUN transcription factor.	SIGNOR-229760	0.7
FZR1	protein	Q9UM11	UNIPROT	UBE2S	protein	Q16763	UNIPROT	up-regulates activity	binding			9606									19822757	t		lperfetto	Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity	SIGNOR-265081	0.749
afatinib	chemical	CHEBI:61390	ChEBI	ErbB receptor family	proteinfamily	SIGNOR-PF36	SIGNOR	down-regulates activity	chemical inhibition			9606	BTO:0000150								22418700	t		gcesareni	Afatinib is an oral, erbb family blocker, which covalently binds and irreversibly blocks all kinase-competent erbb family members.	SIGNOR-259442	0.8
INTS8	protein	Q75QN2	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261472	0.732
AKT2	protein	P31751	UNIPROT	PKP1	protein	Q13835	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser118	EPDNRRFsSYSQMEN	-1									23444369	t		miannu	Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry.	SIGNOR-273486	0.27
TGFA	protein	P01135	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252281	0.7
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDUFA12	protein	Q9UI09	UNIPROT	up-regulates activity	phosphorylation	Thr142	QEWIPPStPYK										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275595	0.2
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGB5	protein	Q9Y5G0	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265692	0.2
H3C1	protein	P68431	UNIPROT	CPC	complex	SIGNOR-C554	SIGNOR	up-regulates quantity	binding			9606	BTO:0000567								24413556	t		miannu	Histone modifications coordinate the chromatin localization of key regulatory factors in mitosis. For example, mitotic phosphorylation of Histone H3 threonine-3 (H3T3ph) by Haspin creates a binding site for the chromosomal passenger complex (CPC).	SIGNOR-275422	0.2
MAPK3	protein	P27361	UNIPROT	NUP50	protein	Q9UKX7	UNIPROT	down-regulates activity	phosphorylation	Ser315	TQSKPVSsPFPTKPL	9606									19767751	t		llicata	Erk phosphorylates nup50 at ser221 and ser315 phosphorylation of nup50 reduces affinity for importin-beta	SIGNOR-187378	0.2
KIT	protein	P10721	UNIPROT	GRB7	protein	Q14451	UNIPROT	up-regulates activity	binding			9606	BTO:0000567				phosphorylation:Tyr936	SESTNHIySNLANCS 			10377264	t		gcesareni	We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936.	SIGNOR-248291	0.566
IRAK1	protein	P51617	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								8837778	t		lperfetto	Il-1 treatment of 293 cells induces the association of traf6 with irak.	SIGNOR-44234	0.911
NFYB	protein	P25208	UNIPROT	SOX18	protein	P35713	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								18496767	f		miannu	 co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells	SIGNOR-254819	0.2
PRKCA	protein	P17252	UNIPROT	INSR	protein	P06213	UNIPROT	unknown	phosphorylation	Thr1362	YEEHIPYtHMNGGKK	-1									8463287	t		lperfetto	Therefore, the present study directly identifies threonine 1336 in the HIR as a phosphorylation site for insulin and PMA.	SIGNOR-248933	0.354
MLH1	protein	P40692	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates activity				10090									9500552	f			Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer	SIGNOR-257595	0.7
TAF5	protein	Q15542	UNIPROT	TFIID	complex	SIGNOR-C343	SIGNOR	form complex	binding			9606									27096372	t		miannu	The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences.	SIGNOR-263929	0.893
pazopanib	chemical	CHEBI:71219	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001949								18620382	t		Luana	Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively.	SIGNOR-257738	0.8
ERBB4	protein	Q15303	UNIPROT	PIK3CD	protein	O00329	UNIPROT	up-regulates	binding			9606									16729043	t		gcesareni	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146885	0.381
MORF4L1	protein	Q9UBU8	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269299	0.75
EXOSC8	protein	Q96B26	UNIPROT	Exosome_Complex	complex	SIGNOR-C255	SIGNOR	form complex	binding			-1									24189234	t		miannu	The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 	SIGNOR-261384	0.911
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	NDUFB6	protein	O95139	UNIPROT	up-regulates activity	phosphorylation	Thr5	tPDEKLRL										24746669	t		lperfetto	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 	SIGNOR-275597	0.251
C1QB	protein	P02746	UNIPROT	Complement C1q	complex	SIGNOR-C308	SIGNOR	form complex	binding			-1									29449492	t		lperfetto	C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1).	SIGNOR-263388	0.629
MYC	protein	P01106	UNIPROT	PFKM	protein	P08237	UNIPROT	up-regulates quantity	transcriptional regulation			10116									10823814	t			C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.	SIGNOR-259988	0.334
ITGB3BP	protein	Q13352	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265206	0.744
AURKB	protein	Q96GD4	UNIPROT	PLEKHG6	protein	Q3KR16	UNIPROT	up-regulates	phosphorylation	Thr544	SPSTRPStPSLEGSQ	9606									24482237	t		lperfetto	In this study we report that aurora b-mediated phosphorylation of myogef at thr-544 creates a docking site for plk1, leading to the localization and activation of myogef at the central spindle.	SIGNOR-204534	0.257
cyclosporin A	chemical	CHEBI:4031	ChEBI	Calcineurin	complex	SIGNOR-C155	SIGNOR	down-regulates	chemical inhibition			9606									15276472	t		gcesareni	Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins.	SIGNOR-252307	0.8
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	SERPINE1	protein	P05121	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9606191	f		lperfetto	Here we report the identification of smad3/smad4 binding sequences, termed caga boxes, within the promoter of the human pai-1 gene.	SIGNOR-57776	0.575
AXIN1	protein	O15169	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	up-regulates	binding			9606									10829020	t		gcesareni	We found that in contrast to axin, dvl2 activation of jnk does not require mekk1.	SIGNOR-77591	0.529
MAP3K3	protein	Q99759	UNIPROT	MAP2K5	protein	Q13163	UNIPROT	up-regulates	phosphorylation			9606									12912994	t		gcesareni	Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5.	SIGNOR-104637	0.706
CDH12	protein	P55289	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265852	0.488
ULK3	protein	Q6PHR2	UNIPROT	ULK3	protein	Q6PHR2	UNIPROT	up-regulates activity	phosphorylation	Ser384	RLLAALEvASAAMAK	9606									20643644	t		Manara	We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. 	SIGNOR-260795	0.2
lisuride	chemical	CHEBI:51164	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9550290	t		miannu	Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists.	SIGNOR-258886	0.8
LPAR2	protein	Q9HBW0	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256784	0.372
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser531	GSRSRTPsLPTPPTR	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-251589	0.695
USP8	protein	P40818	UNIPROT	BACE1	protein	P56817	UNIPROT	up-regulates quantity	deubiquitination			9606	BTO:0003704								27302062	t			Here, we report that RNAi-mediated depletion of USP8 reduced levels of both ectopically expressed and endogenous BACE1 in H4 human neuroglioma cells. Moreover, USP8 depletion increased BACE1 ubiquitination, promoted BACE1 accumulation in the early endosomes and late endosomes/lysosomes, and decreased levels of BACE1 in the recycling endosomes.	SIGNOR-266905	0.462
IMPDH2	protein	P12268	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	binding			9606	BTO:0001616								30518405	t		miannu	We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. There is evidence that IMPDH2 interacts with the pleckstrin homology domain of PKB/AKT in the regulation of GTP biosynthesis.	SIGNOR-260961	0.394
TRAF6	protein	Q9Y4K3	UNIPROT	HK2	protein	P52789	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								28980855	t			The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation.	SIGNOR-260003	0.2
dapagliflozin	chemical	CHEBI:85078	ChEBI	SLC5A2	protein	P31639	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191289	0.8
TP53	protein	P04637	UNIPROT	PMAIP1	protein	Q13794	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10807576	f	Nuclear p53	amattioni	Expression of noxa was dependent on p53. Noxa represent a mediator of p53-dependent apoptosis.	SIGNOR-76152	0.691
agomelatine	chemical	CHEBI:134990	ChEBI	HTR2C	protein	P28335	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189474	0.8
MAPK3	protein	P27361	UNIPROT	NUP153	protein	P49790	UNIPROT	unknown	phosphorylation	Thr388	VYFKPSLtPSGEFRK	9606									19767751	t		llicata	These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport.	SIGNOR-188147	0.4
NR5A1	protein	Q13285	UNIPROT	STAR	protein	P49675	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19022561	f		miannu	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 	SIGNOR-254869	0.487
PRKCE	protein	Q02156	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates	phosphorylation	Ser710	GEKSFRRsVVGTPAY	9606									12058027	t		miannu	In cells transfected with pkc? Or pkc? The phosphorylation of ser876 was markedly more pronounced than the phosphorylation of ser706/ser710 / the phosphorylation of ser706/ser710 in pkd2 reflects the activation of the kinase.	SIGNOR-89415	0.2
TFCP2	protein	Q12800	UNIPROT	TF	protein	P02787	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20796026	f		miannu	Ectopic expression of CP2 led to increased transferrin expression at both the mRNA and protein levels, whereas knockdown of CP2 down-regulated transferrin mRNA and protein expression.	SIGNOR-255429	0.2
MAP3K1	protein	Q13233	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates activity	phosphorylation			10090	BTO:0000944								8131746	t		lperfetto	Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity.	SIGNOR-244881	0.645
ASXL1	protein	Q8IXJ9	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				10090									26470845	f		lperfetto	Consistently, our results show that ASXL1 mutations are associated with lower expression levels of p15INK4B and a proliferative advantage of hematopoietic progenitors in primary bone marrow cells, and that depletion of ASXL1 in multiple cell lines results in resistance to growth inhibitory signals.	SIGNOR-241614	0.7
BMS-265246	chemical	CID:5329775	PUBCHEM	CDK1	protein	P06493	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190431	0.8
PCDHA6	protein	Q9UN73	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-265666	0.2
TUBGCP2	protein	Q9BSJ2	UNIPROT	g-TuRC complex	complex	SIGNOR-C282	SIGNOR	form complex	binding			-1									31862189	t		lperfetto	Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.”	SIGNOR-262326	0.796
p38	proteinfamily	SIGNOR-PF16	SIGNOR	CDT1	protein	Q9H211	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser491	GSCCTIMsPGEMEKH	9606	BTO:0000567								21930785	t		miannu	 We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2. 	SIGNOR-276363	0.2
PRKCA	protein	P17252	UNIPROT	RHO	protein	P08100	UNIPROT	unknown	phosphorylation	Thr336	GDDEASAtVSKTETS	-1									9099669	t		lperfetto	Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343.	SIGNOR-248969	0.451
CRBN	protein	Q96SW2	UNIPROT	Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	form complex	binding			9606									22649780	t		gcesareni	The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors	SIGNOR-234805	0.78
CSNK1D	protein	P48730	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	phosphorylation	Ser45	GATTTAPsLSGKGNP	9606									12000790	t		gcesareni	However, ckiepsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the -catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated cki as a candidate s45-kinase in several assays, both in vitro and in vivo.	SIGNOR-87441	0.61
AR	protein	P10275	UNIPROT	TMPRSS2	protein	O15393	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20308527	t		lperfetto	We demonstrate that CHD8 directly associates with AR and that CHD8 and AR simultaneously localize to the TMPRSS2 enhancer after androgen treatment. In the LNCaP cell line, reduction of CHD8 levels by small interfering RNA treatment severely diminishes androgen-dependent activation of the TMPRSS2 gene. We demonstrate that the recruitment of AR to the TMPRSS2 promoter in response to androgen treatment requires CHD8	SIGNOR-253686	0.595
FOXJ3	protein	Q9UPW0	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								19914232	t		Luana	Foxj3 transcriptionally activates Mef2c and regulates adult skeletal muscle fiber type identity.	SIGNOR-261606	0.322
TLX3	protein	O43711	UNIPROT	ETS1	protein	P14921	UNIPROT	down-regulates activity	binding			9606	BTO:0002504								22516263	t		irozzo	We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement. 	SIGNOR-259098	0.371
AKT2	protein	P31751	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation			9606									21620960	t		lperfetto	Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity.	SIGNOR-252866	0.757
FLT3	protein	P36888	UNIPROT	ACAT1	protein	P24752	UNIPROT	up-regulates activity	phosphorylation	Tyr407	HALKQGEyGLASICN	9606	BTO:0001545								34289383	t	in mitochondria	lperfetto	We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1) 	SIGNOR-267628	0.2
EGFR	protein	P00533	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1197	STAENAEyLRVAPQS	10090	BTO:0002882								16122376	t	Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer	lperfetto	EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work	SIGNOR-235951	0.2
FOXJ1	protein	Q92949	UNIPROT	SPAG6	protein	O75602	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000939								23822649	t		miannu	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266935	0.46
PTPN13	protein	Q12923	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates activity	dephosphorylation			9606									19734941	t		miannu	Since a previous report showed PTPN13 may dephosphorylate ErbB2 directly, we also examined levels of phospho-ErbB2 (tyr 1248), and we also observed a small effect in the presence of wild-type PTPN13 (XREF_FIG).|The fact that both ErbB2 and H-RasV12 were potentiated by PTPN13 loss and PTPN13 inhibited MAP kinase signaling downstream of multiple oncogenes (ErbB2, EGFR, H-RasV12), suggest that the phosphatase target that inhibits MAP kinase signaling may not only be limited to ErbB2 tyrosine 1248.	SIGNOR-277087	0.339
SIRT6	protein	Q8N6T7	UNIPROT	TNF	protein	P01375	UNIPROT	up-regulates	deacetylation	Lys20	AEEALPKkTGGPQGS	9606									23552949	t		gcesareni	Sirt6 regulates tnf-alfa secretion through hydrolysis of long-chain fatty acyl lysine	SIGNOR-201662	0.321
luminespib	chemical	CHEBI:83656	ChEBI	HSP90AA1	protein	P07900	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190038	0.8
LCK	protein	P06239	UNIPROT	PRKCD	protein	Q05655	UNIPROT	up-regulates activity	phosphorylation	Tyr313	SSEPVGIyQGFEKKT	9534	BTO:0000298								11381116	t			The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2).	SIGNOR-251384	0.505
Sitagliptin phosphate monohydrate	chemical	CID:11591741	PUBCHEM	DPP4	protein	P27487	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206923	0.8
SRC	protein	P12931	UNIPROT	MMP3	protein	P08254	UNIPROT	up-regulates activity													23967200	f			C-Src-induced STAT3 activation regulates MMP3 levels	SIGNOR-251109	0.348
DAGLB	protein	Q8NCG7	UNIPROT	episterol ester	smallmolecule	CHEBI:52393	ChEBI	up-regulates quantity	chemical modification			9606									26787883	t		miannu	Diacylglycerol lipases (DAGLα and DAGLβ) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. 	SIGNOR-264265	0.8
SOX9	protein	P48436	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000849								19273910	f		miannu	 Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. 	SIGNOR-255190	0.383
MEN1	protein	O00255	UNIPROT	RELA	protein	Q04206	UNIPROT	down-regulates	binding			9606				SIGNOR-C13					11526476	t		miannu	Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner.	SIGNOR-110067	0.475
HMGA2	protein	P52926	UNIPROT	E4F1	protein	Q66K89	UNIPROT	down-regulates	binding			9606									14645522	t		miannu	Here we show that hmga2 associates with the e1a-regulated transcriptional repressor p120(e4f), interfering with p120(e4f) binding to the cyclin a promoter	SIGNOR-119537	0.378
MK-8245	chemical	CID:24988881	PUBCHEM	SCD	protein	O00767	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194420	0.8
SRC	protein	P12931	UNIPROT	GlyR	proteinfamily	SIGNOR-PF62	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000938	BTO:0000142;BTO:0000671							11882681	t	inferred from family member	gcesareni	These findings indicate that glyr function is upregulated by ptks and this modulation is dependent on the tyrosine-413 residue of the beta subunit.	SIGNOR-270262	0.274
Collagen	proteinfamily	SIGNOR-PF103	SIGNOR	ECM_synthesis	phenotype	SIGNOR-PH8	SIGNOR	up-regulates				9606									35268340	f		miannu	The extracellular matrix is a structure composed of many molecules, including fibrillar (types I, II, III, V, XI, XXIV, XXVII) and non-fibrillar collagens (mainly basement membrane collagens: types IV, VIII, X), non-collagenous glycoproteins (elastin, laminin, fibronectin, thrombospondin, tenascin, osteopontin, osteonectin, entactin, periostin) embedded in a gel of negatively charged water-retaining glycosaminoglycans (GAGs) such as non-sulfated hyaluronic acid (HA) and sulfated GAGs which are linked to a core protein to form proteoglycans (PGs). 	SIGNOR-269732	0.7
A10/b1 integrin	complex	SIGNOR-C167	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269016	0.7
RPS11	protein	P62280	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262441	0.882
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser531	GSRSRTPsLPTPPTR	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249344	0.729
58131-57-0	chemical	CID:42640	PUBCHEM	MDM4	protein	O15151	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194856	0.8
SMAD7	protein	O15105	UNIPROT	STRAP	protein	Q9Y3F4	UNIPROT	up-regulates	binding			9606									10757800	t		gcesareni	Strap recruits smad7 to the activated type i receptor and forms a complex	SIGNOR-76771	0.593
CSNK1A1	protein	P48729	UNIPROT	NFATC3	protein	Q12968	UNIPROT	down-regulates activity	phosphorylation	Ser215	PLTSPGGsPGGCPGE	9606	BTO:0001131								9630228	t		lperfetto	Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4.	SIGNOR-109781	0.571
RASSF6	protein	Q6ZTQ3	UNIPROT	STK3	protein	Q13188	UNIPROT	down-regulates	binding			9606									22830020	t		gcesareni	When rassf 6 is bound to mst2, rassf 6 inhibits mst2 activity, thus, inhibiting its role in the hippo pathway.	SIGNOR-198463	0.646
adenosine	smallmolecule	CHEBI:16335	ChEBI	ADORA2B	protein	P29275	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257448	0.8
GRK2	protein	P25098	UNIPROT	PDE6G	protein	P18545	UNIPROT	up-regulates activity	phosphorylation	Thr62	PGMEGLGtDITVICP	9606	BTO:0000007								12624098	t		gcesareni	Mutation of Thr-62 (to Ala) in PDEgamma produced a GRK2 phosphorylation-resistant mutant that was less effective in associating with GRK2 in response to epidermal growth factor and did not potentiate the stimulation of p42/p44 mitogen-activated protein kinase by this growth factor.	SIGNOR-247823	0.2
TGFBI	protein	Q15582	UNIPROT	A4/b1 integrin	complex	SIGNOR-C162	SIGNOR	up-regulates activity				10090	BTO:0004093								25786978	t		lperfetto	First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs.	SIGNOR-253283	0.339
MAPK1	protein	P28482	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates	phosphorylation	Ser405	KTQTPPVsPAPQPTE	9606	BTO:0000938								21079800	t		gcesareni	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-169674	0.481
SNAI2	protein	O43623	UNIPROT	UBE2D3	protein	P61077	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000356								21044962	f		miannu	 knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene.	SIGNOR-255173	0.2
SRC	protein	P12931	UNIPROT	GLRB	protein	P48167	UNIPROT	up-regulates	phosphorylation	Tyr435	RDFELSNyDCYGKPI	9606	BTO:0000938	BTO:0000142;BTO:0000671							11882681	t		gcesareni	These findings indicate that glyr function is upregulated by ptks and this modulation is dependent on the tyrosine-413 residue of the beta subunit.	SIGNOR-115705	0.274
SMAD4	protein	Q13485	UNIPROT	SMAD1/5/8/SMAD4	complex	SIGNOR-C215	SIGNOR	form complex	binding			9606									9436979	t		lperfetto	Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription.	SIGNOR-255833	0.2
MMP24	protein	Q9Y5R2	UNIPROT	ECM	stimulus	SIGNOR-ST20	SIGNOR	down-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272391	0.7
KPNB1	protein	Q14974	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates	relocalization			9606									10846168	t		gcesareni	Here we show that the isolated smad 3 mh1 domain displays significant specific binding to importin beta. we propose that activation of all of the pathway-specific smad proteins (smads 1, 2, 3, 5, 8, and 9) exposes the conserved nls motif, which then binds directly to importin beta and triggers nuclear translocation.	SIGNOR-78191	0.502
AKT1	protein	P31749	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity	phosphorylation			9606									17130464	t	Translocation from Cytoplasm to Nucleus	lperfetto	Phosphorylation of pras40-thr246 by pkb/akt, and pras40-ser183 and pras40-ser221 by mtorc1 results in dissociation from mtorc1, and its binding to 14-3-3 proteins.	SIGNOR-252540	0.72
MAPK3	protein	P27361	UNIPROT	METTL3	protein	Q86U44	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser525	YGMIERLsPGTRKIE	9606	BTO:0000007								33217317	t		miannu	 Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.	SIGNOR-265947	0.274
EGF	protein	P01133	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	binding			9606									12297050	t		lperfetto	Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase.	SIGNOR-186159	0.948
MYLK	protein	Q15746	UNIPROT	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation	Ser744	GLKVGVSsRINEWLT	9606									20536391	t		gcesareni	Phosphorylation of caldesmon by myosin light chain kinase increases its binding affinity for phosphorylated myosin filaments.	SIGNOR-166049	0.627
tRNA(Trp)	smallmolecule	CHEBI:29181	ChEBI	Trp-tRNA(Trp)	smallmolecule	CHEBI:29159	ChEBI	up-regulates quantity	precursor of			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 	SIGNOR-270515	0.8
PPP1CA	protein	P62136	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0002419								14633703	t			Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells	SIGNOR-252603	0.436
CSNK2A1	protein	P68400	UNIPROT	NPHP1	protein	O15259	UNIPROT	up-regulates	phosphorylation	Ser123	EEEEESEsEDSEDSG	9606									16308564	t		lperfetto	Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting.	SIGNOR-142347	0.2
UHRF2	protein	Q96PU4	UNIPROT	CCNE1	protein	P24864	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9534	BTO:0000298								21952639	t		miannu	We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1.	SIGNOR-271886	0.337
DPF2	protein	Q92785	UNIPROT	ESRRA	protein	P11474	UNIPROT	down-regulates activity	binding			10090	BTO:0000165								25713408	t	1	miannu	DPF2 directly bound to ERRalpha and suppressed the transactivation function of nuclear receptors such as androgen receptor. DPF2 was recruited to ERR target gene promoters in myoblast cells, and knockdown of DPF2 derepressed the level of mRNA expressed by target genes of ERRalpha. These results show that DPF2 acts as a nuclear receptor-selective co-repressor for ERRalpha by associating with both acetylated histone H3 and HDAC1.	SIGNOR-239539	0.2
GSK3B	protein	P49841	UNIPROT	SREBF1	protein	P36956	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr426	TEVEDTLtPPPSDAG	9606	BTO:0000007								19126544	t		lperfetto	Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1.	SIGNOR-236667	0.499
TTK	protein	P33981	UNIPROT	MAD2L1	protein	Q13257	UNIPROT	up-regulates activity	phosphorylation												18541701	t		lperfetto	Mps1 is an upstream component of the spindle assembly checkpoint, which, in human cells, is required for checkpoint activation in response to spindle damage but not apparently during an unperturbed mitosis. Mps1 also recruits Mad1 and Mad2 to kinetochores.|Thus, in human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2.	SIGNOR-252036	0.736
AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	oligopeptide	smallmolecule	CHEBI:25676	ChEBI	up-regulates quantity	relocalization			9606									25720354	t		scontino	APCs cell surface receptors facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. It is in these compartments that internalized antigen proteolysis and peptide–MHC class II complex formation takes place.	SIGNOR-267861	0.8
PRKACA	protein	P17612	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates	phosphorylation	Ser795	TASTRKVsLAPQANL	9606									1716180	t		lperfetto	Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response.	SIGNOR-21320	0.466
WNT1	protein	P04628	UNIPROT	FZD1	protein	Q9UP38	UNIPROT	up-regulates activity	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131568	0.69
SRC	protein	P12931	UNIPROT	KCNA3	protein	P22001	UNIPROT	up-regulates	phosphorylation	Tyr499	EGEEQSQyMHVGSCQ	9606									11812778	t		gcesareni	The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties.	SIGNOR-114645	0.316
GPI	protein	P06744	UNIPROT	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P.	SIGNOR-266462	0.8
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	AFP	protein	P02771	UNIPROT	down-regulates quantity by repression				9606									9792724	f		miannu	In this report, we show a distinctive effect of all-trans-retinoic acid (RA) in Hep3B cells. RA caused a marked decrease in AFP transcripts.	SIGNOR-254443	0.8
dopamine	smallmolecule	CHEBI:18243	ChEBI	DRD5	protein	P21918	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257481	0.8
RPA4	protein	Q13156	UNIPROT	Nucleotide-excision_repair	phenotype	SIGNOR-PH209	SIGNOR	up-regulates													24086043	f		lperfetto	The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275708	0.7
NMDA receptor_2D	complex	SIGNOR-C350	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									30037851	t		miannu	NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS). 	SIGNOR-264221	0.8
NFE2L2	protein	Q16236	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	down-regulates				9606	BTO:0000599								26194347	f		irozzo	Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes.	SIGNOR-256652	0.7
CD28	protein	P10747	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			9606									7737275	t		fspada	In this study, we demonstrate that the co-stimulatory antigen cd28 binds to grb-2 by means of a cytoplasmic pymnm motif, which is the same motif bound by pi 3-kinase.	SIGNOR-32509	0.691
ARHGAP22	protein	Q7Z5H3	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606									32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260476	0.546
SMC1A	protein	Q14683	UNIPROT	Cohesin complex	complex	SIGNOR-C304	SIGNOR	form complex	binding												28430577	t		lperfetto	Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin	SIGNOR-263313	0.878
HRAS	protein	P01112	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606									8052307	t		gcesareni	In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k	SIGNOR-35878	0.922
Vincristine sulfate	chemical	CHEBI:79401	ChEBI	MMP10	protein	P09238	UNIPROT	down-regulates activity	chemical inhibition			9606									30599272	t		miannu	Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. 	SIGNOR-259253	0.8
3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea	chemical	CHEBI:91362	ChEBI	AURKC	protein	Q9UQB9	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001109;BTO:0000018								19567821	t		miannu	The protein kinases, Aurora A, B, and C have critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. GSK1070916, is a novel ATP competitive inhibitor that is highly potent and selective for Aurora B/C kinases. 	SIGNOR-262226	0.8
CDK13	protein	Q14004	UNIPROT	CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	form complex	binding			9606									22012619	t		miannu	We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells	SIGNOR-176844	0.914
GNG3	protein	P63215	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									16537363	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt	SIGNOR-252684	0.357
AKT3	protein	Q9Y243	UNIPROT	STK4	protein	Q13043	UNIPROT	down-regulates	phosphorylation	Thr387	TMKRRDEtMQPAKPS	9606									23431053	t		gcesareni	Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt.	SIGNOR-201129	0.264
Dinaciclib	chemical	CID:46926350	PUBCHEM	CDK1	protein	P06493	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191322	0.8
NR3C1	protein	P04150	UNIPROT	CEBPA	protein	P49715	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000746								27777311	t			We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα	SIGNOR-256116	0.467
WT1	protein	P19544	UNIPROT	AREG	protein	P15514	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10490105	t		lperfetto	The Wilms Tumor Suppressor WT1 Encodes a Transcriptional Activator of amphiregulin	SIGNOR-251745	0.405
ACACA	protein	Q13085	UNIPROT	Food intake	phenotype	SIGNOR-PH152	SIGNOR	down-regulates				9606	BTO:0003336								25343030	f		miannu	Leptin exerts an inhibitory effect on AMPK in the hypothalamus, thereby stimulating ACC and subsequently suppressing food intake.	SIGNOR-263509	0.7
OGA	protein	O60502	UNIPROT	PFK	proteinfamily	SIGNOR-PF79	SIGNOR	up-regulates activity	deglycosylation			9606									26399441	t		lperfetto	Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 	SIGNOR-267609	0.2
RET	protein	P07949	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	binding			9606									8183561	t		gcesareni	We have shown that the sh2 domain of the adaptor protein shc coimmunoprecipitates with all the ret.	SIGNOR-36902	0.642
GSK3A	protein	P49840	UNIPROT	BCL3	protein	P20749	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser402	LSASPSSsPSQSPPR	9606	BTO:0000007								15469820	t		miannu	In this report, we show that BCL-3 is a substrate for the protein kinase GSK3 and that GSK3-mediated BCL-3 phosphorylation, which is inhibited by Akt activation, targets its degradation through the proteasome pathway.	SIGNOR-276011	0.401
CLK1	protein	P49759	UNIPROT	PTPN1	protein	P18031	UNIPROT	up-regulates activity	phosphorylation	Ser243	DKRKDPSsVDIKKVL	-1									10480872	t		llicata	The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. 	SIGNOR-250774	0.353
ETNK2	protein	Q9NVF9	UNIPROT	O-phosphonatoethanaminium(1-)	smallmolecule	CHEBI:58190	ChEBI	up-regulates quantity	chemical modification												36866238	t		lperfetto	Ethanolamine kinase 2 (ETNK2) is a protein-coding gene. Spondylometaphyseal dysplasia with cone-rod dystrophy is one of the diseases linked to the ETNKT2 gene. Glycerophospholipid biosynthesis and nuclear receptor meta-pathways are two of the ETNK2-related pathways. 	SIGNOR-275643	0.8
AKT1	protein	P31749	UNIPROT	MDM4	protein	O15151	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser367	PDCRRTIsAPVVRPK	9606									18356162	t		lperfetto	We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2.	SIGNOR-252517	0.524
PPP2CA	protein	P67775	UNIPROT	TRPM8	protein	Q7Z2W7	UNIPROT	down-regulates activity	dephosphorylation	Thr17	MRNRRNDtLDSTRTL	9606	BTO:0000007								20110357	t	done	miannu	Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity.	SIGNOR-273793	0.2
trametinib	chemical	CHEBI:75998	ChEBI	MAP2K2	protein	P36507	UNIPROT	down-regulates activity	chemical inhibition			9606									26347206	t		miannu	Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation. 	SIGNOR-259448	0.8
CSNK2A2	protein	P19784	UNIPROT	PTPRC	protein	P08575	UNIPROT	up-regulates activity	phosphorylation	Ser1009	DESSDDDsDSEEPSK	9606	BTO:0000661								10066810	t		llicata	Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment. 	SIGNOR-251031	0.445
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser315	DFRSRTNsNASTVSG	9606									19951971	t		lperfetto	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-252822	0.908
AKT1	protein	P31749	UNIPROT	MASTL	protein	Q96GX5	UNIPROT	up-regulates activity	phosphorylation	Thr299	QSRKRLAtSSASSQS	9606	BTO:0002181								32123010	t		miannu	Here, we report that AKT phosphorylates MASTL at residue T299, which plays a critical role in its activation.	SIGNOR-277515	0.2
LRIG3	protein	Q6UXM1	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates				9606									23723069	f		miannu	Lrig3 opposes lrig1 negative regulatory activity and stabilizes erbb receptors.	SIGNOR-202180	0.311
COP1	protein	Q8NHY2	UNIPROT	ACACA	protein	Q13085	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								16794074	t		miannu	TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).	SIGNOR-271598	0.2
ABL1	protein	P00519	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates activity	phosphorylation	Tyr315	ETRICKIyDSPCLPE	9606									10212258	t		Manara	Tyrosine Phosphorylation of Rad51 by ABL1 Enhances the Interaction between Rad51 and Rad52 | our studies of Rad51·Rad52 complex formation in vitro and in vivo suggest that the ATM and ABL1-mediated signaling is likely to promote repair given the biochemical evidence that Rad51 acts in concert with Rad52 in homologous recombination	SIGNOR-260777	0.764
GUCY1A2-B3	complex	SIGNOR-C138	SIGNOR	3',5'-cyclic GMP	smallmolecule	CHEBI:16356	ChEBI	up-regulates quantity	chemical modification			9606									10977868	t		gcesareni	Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types	SIGNOR-244093	0.8
RAC1	protein	P63000	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates				9606									21712438	f		gcesareni	Hypertonicity activates p38 via a rac1-osm-mekk3-mkk3-p38 pathway.	SIGNOR-174602	0.517
GPR174	protein	Q9BXC1	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257029	0.2
FLT3	protein	P36888	UNIPROT	FLT3	protein	P36888	UNIPROT	up-regulates	phosphorylation	Tyr591	SSDNEYFyVDFREYE	9606									11971190	t		lperfetto	Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation	SIGNOR-117575	0.2
EIF6	protein	P56537	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	up-regulates quantity	binding			9606									10085284	t		lperfetto	The beta4 integrin interactor p27(BBP/eIF6) is an essential nuclear matrix protein involved in 60S ribosomal subunit assembly.	SIGNOR-269151	0.504
SOX6	protein	P35712	UNIPROT	HBG2	protein	P69892	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004911								20395365	f	Regulation	miannu	BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors.	SIGNOR-251808	0.317
MID1	protein	O15344	UNIPROT	HMG20B	protein	Q9P0W2	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								28760657	t		miannu	The E3 ubiquitin ligase MID1/TRIM18 promotes atypical ubiquitination of the BRCA2-associated factor 35, BRAF35. MID1 is implicated in BRAF35 ubiquitination promoting atypical poly-ubiquitination via K6-, K27- and K29-linkages. We found that MID1 depletion alters BRAF35 localization in these structures and increases BRAF35 stability affecting its cytoplasmic abundance	SIGNOR-272317	0.247
CSNK2A1	protein	P68400	UNIPROT	CALM1	protein	P0DP23	UNIPROT	down-regulates activity	phosphorylation	Ser102	KDGNGYIsAAELRHV	-1									26675311	t		miannu	Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. 	SIGNOR-266354	0.432
alogliptin	chemical	CHEBI:72323	ChEBI	DPP4	protein	P27487	UNIPROT	down-regulates activity	chemical inhibition			-1									22475866	t		Luana	Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization.	SIGNOR-258333	0.8
BAX	protein	Q07812	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	up-regulates	relocalization			9606									14585074	t	Translocation from Mitochondria to Cytosol	amattioni	Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi	SIGNOR-87109	0.526
GABA-A (a6-b1-g2) receptor	complex	SIGNOR-C334	SIGNOR	CRHR1	protein	P34998	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268607	0.264
WNK3	protein	Q9BYP7	UNIPROT	SLC12A7	protein	Q9Y666	UNIPROT	down-regulates activity	phosphorylation												21613606	t		lperfetto	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264630	0.465
PRKCA	protein	P17252	UNIPROT	MYL9	protein	P24844	UNIPROT	down-regulates	phosphorylation	Ser3	sKRAKAKT	9606									22136066	t		lperfetto	Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity	SIGNOR-192792	0.282
frovatriptan	chemical	CHEBI:134991	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			-1									9986723	t		miannu	As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold).	SIGNOR-259073	0.8
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	CEBPA	protein	P49715	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000011								12270934	f		lperfetto	We further show that activation of mek1 significantly enhances the transactivation of the c/ebpalpha minimal promoter during the early phase of the differentiation process.	SIGNOR-244773	0.2
CDK2	protein	P24941	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Thr179	PQSNIPEtPPPGYLS	9606									19114991	t		lpetrilli	In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity	SIGNOR-182971	0.733
VAV1	protein	P15498	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			7227									23525006	t			We identify the GTP exchange factor (GEF) Vav as a key regulator of Rac activity downstream of RTKs in a developmentally regulated cell migration event	SIGNOR-259081	0.755
PMF1	protein	Q6P1K2	UNIPROT	MIS12 complex	complex	SIGNOR-C362	SIGNOR	form complex	binding			-1									27881301	t		lperfetto	 Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits 	SIGNOR-265192	0.829
Serum	stimulus	SIGNOR-ST3	SIGNOR	PRKAA2	protein	P54646	UNIPROT	down-regulates				9606									19584320	f		miannu	Ampk is activated under conditions of low energy charge and typically inhibits anabolic reactions and promotes catabolism	SIGNOR-186644	0.7
CREB1	protein	P16220	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				10090		BTO:0000763							20660310	f		Luana	Beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state	SIGNOR-261288	0.7
Brivanib alaninate	chemical	CID:11154925	PUBCHEM	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190726	0.8
MAPK8	protein	P45983	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation	Thr451	PIPKALGtPVLTPPT	9606									15538382	t		lperfetto	Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment.	SIGNOR-252964	0.704
ELAVL1	protein	Q15717	UNIPROT	ADAM10	protein	O14672	UNIPROT	up-regulates quantity	post transcriptional regulation			9606									19221430	t		miannu	Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure	SIGNOR-266862	0.2
BMPR1A	protein	P36894	UNIPROT	BMPR1B	protein	O00238	UNIPROT	up-regulates	binding			9606									10712517	t		gcesareni	Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors	SIGNOR-75649	0.474
DAXX	protein	Q9UER7	UNIPROT	AIRE	protein	O43918	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								20185822	t	1	miannu	The interaction between AIRE and DAXX has been validated by in vivo coimmunoprecipitation analysis and colocalization study in mammalian cells. The interaction has been further confirmed by showing in transactivation assays that DAXX exerts a strong repressive role on the transcriptional activity of AIRE.	SIGNOR-239287	0.34
BCL2L2	protein	Q92843	UNIPROT	BAX	protein	Q07812	UNIPROT	down-regulates	binding			9606									17452531	t		gcesareni	Bcl-w may protect largely via its ability to associate with bax because it could efficiently protect xem from tbid and bid, bad, hrk, and bmf bh3 peptides	SIGNOR-154518	0.469
LY294002	chemical	CHEBI:65329	ChEBI	PIK3C3	protein	Q8NEB9	UNIPROT	down-regulates	chemical inhibition			9534	BTO:0001444								22253445	t		lperfetto	From these results, we conclude that LY294002 and wortmannin inhibit SARS pseudovirus entry by targeting PI4KB and that PI4KB is involved in SARS-CoV S-mediated entry into VeroE6 cells.	SIGNOR-260731	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	NOS3	protein	P29474	UNIPROT	up-regulates	phosphorylation	Ser1177	TSRIRTQsFSLQERQ	9606									11729179	t		lperfetto	Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.	SIGNOR-216445	0.266
ABI1	protein	Q8IZP0	UNIPROT	WRC complex	complex	SIGNOR-C191	SIGNOR	form complex	binding			9606									21107423	t		miannu	WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems	SIGNOR-253571	0.841
LSM-1231	chemical	CHEBI:91471	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258236	0.8
Immunoglobulin mu heavy chain	protein	P0DOX6	UNIPROT	BCR-Mk	complex	SIGNOR-C433	SIGNOR	form complex	binding			9606	BTO:0000776								32323265	t		scontino	An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs.	SIGNOR-268187	0.2
NXPH1	protein	P58417	UNIPROT	NRXN1	protein	P58400	UNIPROT	up-regulates	binding			9606	BTO:0000938								9856994	t		gcesareni	Purification of neurexin ialpha revealed that it is tightly complexed to a secreted glycoprotein called neurexophilin 1	SIGNOR-62699	0.565
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	MYBL2	protein	P10244	UNIPROT	up-regulates	phosphorylation	Thr444	NSLTPKStPVKTLPF	9606									9840932	t		lperfetto	The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk3	SIGNOR-217256	0.708
CHEK2	protein	O96017	UNIPROT	SOD1	protein	P00441	UNIPROT	up-regulates activity	phosphorylation	Ser60	DNTAGCTsAGPHFNP	4932									24647101	t			ROS signaling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to the promoters and regulates the expression of oxidative resistance and repair genes.	SIGNOR-262794	0.384
THAP12	protein	O43422	UNIPROT	EIF2S1	protein	P05198	UNIPROT	unknown	phosphorylation	Ser52	MILLSELsRRRIRSI	-1									10542257	t		lperfetto	The mammalian kinases PKR and HRI and the yeast kinase GCN2 specifically phosphorylate Ser-51 on the alpha subunit of the translation initiation factor eIF2. 	SIGNOR-249029	0.2
1-phosphatidyl-1D-myo-inositol(1-)	smallmolecule	CHEBI:57880	ChEBI	1-phosphatidyl-1D-myo-inositol 4-phosphate	smallmolecule	CHEBI:17526	ChEBI	up-regulates quantity	precursor of			9606									10101268	t		miannu	The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 	SIGNOR-269097	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser588	QTLSDSLsGSSLYST	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-249685	0.397
Clinofibrate	chemical	CHEBI:31412	ChEBI	HMGCR	protein	P04035	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191085	0.8
DLGAP3	protein	O95886	UNIPROT	SHANK1	protein	Q9Y566	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264592	0.791
PRKCD	protein	Q05655	UNIPROT	DAB2	protein	P98082	UNIPROT	unknown	phosphorylation	Ser24	QAAPKAPsKKEKKKG	9534	BTO:0004055								10542228	t		lperfetto	We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function.	SIGNOR-249028	0.3
CALM2	protein	P0DP24	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	down-regulates activity	binding			9606	BTO:0000938								11807557	t		miannu	Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias.	SIGNOR-266330	0.46
DRAM2	protein	Q6UX65	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30755245	f		irozzo	DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression.	SIGNOR-259147	0.2
FHIT	protein	P49789	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates				9606	BTO:0000551								16407838	f		miannu	Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis	SIGNOR-143700	0.382
SRC	protein	P12931	UNIPROT	KRT19	protein	P08727	UNIPROT	unknown	phosphorylation	Tyr391	LEGQEDHyNNLSASK	9606									21049038	t		llicata	Human k19 tyrosine 391 is phosphorylated, potentially by src kinase, and is the first well-defined tyrosine phosphorylation site of any keratin protein.	SIGNOR-169273	0.294
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	BEX1	protein	Q9HBH7	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser102	KLREKQLsHSLRAVS	10116	BTO:0001009								16498402	t		miannu	Phosphorylation of Bex1 in Ser105 by the serine–threonine kinase AKT stabilizes Bex1 and protects it from proteasomal degradation	SIGNOR-262614	0.2
BZW2	protein	Q9Y6E2	UNIPROT	EIF2S1	protein	P05198	UNIPROT	up-regulates activity	binding			9606									31643092	t		miannu	BZW2, as an evolutionary highly conserved protein, interacts with eIF2 and eIF3 and promotes ternary complex formation in vitro	SIGNOR-261220	0.255
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation			10090	BTO:0002572								18423396	t		lperfetto	Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation	SIGNOR-252836	0.908
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CASP9	protein	P55211	UNIPROT	down-regulates activity	phosphorylation	Ser196	KLRRRFSsLHFMVEV	-1									9812896	t			Akt phosphorylated recombinant Casp9 in vitro on serine-196 and inhibited its protease activity.	SIGNOR-251473	0.2
MAPK14	protein	Q16539	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser310	LYNFMCNsSCVGGMN	-1									30301786	t		miannu	P38α phosphorylates and destabilizes p63.	SIGNOR-277414 	0.313
UBE2I	protein	P63279	UNIPROT	PLAG1	protein	Q6DJT9	UNIPROT	down-regulates	sumoylation	Lys263	CNVSVPIkDELLPVM	9606									15208321	t		miannu	Sumoylation decreases the transcriptional activity of plag1 / plag1 is sumoylated at 2 specific lysine residues (lys-244 and lys-263)	SIGNOR-126048	0.281
TNKS2	protein	Q9H2K2	UNIPROT	RNF146	protein	Q9NTX7	UNIPROT	up-regulates activity				9606	BTO:0000007								21478859	f		lperfetto	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 	SIGNOR-263337	0.599
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1735	SPTSPSYsPTSPSYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii	SIGNOR-203544	0.77
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PDE4A	protein	P27815	UNIPROT	up-regulates activity	phosphorylation	Ser145	ATSQRREsFLYRSDS	9534	BTO:0001538								12023945	t		miannu	Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms.	SIGNOR-275985	0.2
ERG	protein	P11308	UNIPROT	EPB41L4B	protein	Q9H329	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20860828	f	 	miannu	EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression.	SIGNOR-253919	0.2
PRKCG	protein	P05129	UNIPROT	ARHGEF7	protein	Q14155	UNIPROT	up-regulates	phosphorylation	Ser761	DSLGRRSsLSRLEPS	9606									25009260	t		lperfetto	Pkc_ directly phosphorylates _pix at ser583 and indirectly at ser340 in cells. herefore, we propose that pkc_ positively modulates dopamine release through _2pix phosphorylation. The pkc_-_pix-cdc42/rac1 phosphorylation axis may provide a new therapeutic target for the treatment of parkinsonian syndrome	SIGNOR-205238	0.2
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	DCX	protein	O43602	UNIPROT	unknown	phosphorylation	Thr326	TSSSQLStPKSKQSP	9606									14741103	t		llicata	In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35.	SIGNOR-250659	0.415
PSMA7	protein	O14818	UNIPROT	XBP1	protein	P17861	UNIPROT	down-regulates quantity by destabilization	binding			-1									19941857	t	1	miannu	We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination.	SIGNOR-239042	0.321
PTPN1	protein	P18031	UNIPROT	PTK2	protein	Q05397	UNIPROT	down-regulates activity	dephosphorylation	Tyr397	SVSETDDyAEIIDEE	9534	BTO:0004055								16291744	t			The focal adhesion kinase (FAK) is a key regulator of cell migration. Phosphorylation at Tyr-397 activates FAK |The dephosphorylation at Tyr-397 in FAK triggered by wild-type alpha-actinin and PTP 1B caused a significant increase in cell migration.	SIGNOR-248431	0.354
CDK1	protein	P06493	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1191	GELSRSPsPFTHTHL	9606	BTO:0000551								19683496	t		gcesareni	However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci.	SIGNOR-187599	0.511
GATA2	protein	P23769	UNIPROT	SPI1	protein	P17947	UNIPROT	down-regulates activity	binding			9606	BTO:0000664								10411939	t		irozzo	Here we demonstrate that a region of the PU.1 Ets domain (the winged helix–turn–helix wing) interacts with the conserved carboxyl-terminal zinc finger of GATA-1 and GATA-2 and that GATA proteins inhibit PU.1 transactivation of critical myeloid target genes.	SIGNOR-256071	0.596
IRF5	protein	Q13568	UNIPROT	M1_polarization	phenotype	SIGNOR-PH54	SIGNOR	up-regulates				9606									22378047	f		lperfetto	IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization.	SIGNOR-249562	0.7
REL	protein	Q04864	UNIPROT	REL/RELA	complex	SIGNOR-C68	SIGNOR	form complex	binding			9606		BTO:0000671							9056676	t		miannu	Tnf-alpha induces the formation of a specific kappab binding complex, mainly composed of nf-kappab subunits rela and c-rel.	SIGNOR-46945	0.66
LFNG	protein	Q8NES3	UNIPROT	DLL3	protein	Q9NYJ7	UNIPROT	up-regulates	binding			9606									10934472	t		gcesareni	We find that mammalian lunatic fringe (lfng) inhibits jagged1-mediated signalling and potentiates delta1-mediated signalling through notch1.	SIGNOR-80524	0.461
NFE2L2	protein	Q16236	UNIPROT	NQO1	protein	P15559	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24024136	t		irozzo	In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).	SIGNOR-256275	0.503
ITGB1BP1	protein	O14713	UNIPROT	A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257646	0.757
N-[(4-chlorophenyl)methyl]-2-[(2R,6S)-5,12-dioxo-2-phenyl-1-oxa-4-azacyclododec-8-en-6-yl]acetamide	chemical	CHEBI:94175	ChEBI	SHH	protein	Q15465	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000527								21679342	t		gcesareni	More recently, robotnikinin was identified as a compound that binds to shh and blocks its ability to induce pathway activity at the level of ptch.	SIGNOR-174429	0.8
UBE2D1	protein	P51668	UNIPROT	MGRN1	protein	O60291	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								17229889	t		miannu	Our in vivo and in vitro ubiquitylation studies demonstrate that the binding of TSG101 to Mahogunin targets the substrate TSG101 for ubiquitylation by Mahogunin E3 ligase in cooperation with its cognate E2 enzyme Ubc5a	SIGNOR-271637	0.473
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	MXD1	protein	Q05195	UNIPROT	down-regulates	phosphorylation	Ser145	IERIRMDsIGSTVSS	9606									18451027	t		lperfetto	In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway	SIGNOR-252811	0.2
ATM	protein	Q13315	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	unknown	phosphorylation	Ser784	GVEKCSDsQSWEDIA	9606									12697768	t		llicata	To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1	SIGNOR-100653	0.869
FER	protein	P16591	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates	phosphorylation	Tyr225	PTSSKDNyLGGTSTI	9606	BTO:0001130								23906537	t		lperfetto	Fer is required for il-6 mediated ar activation by phosphorylating ar tyrosine 223 and binding via its sh2 domain.	SIGNOR-194749	0.262
WDCP	protein	Q9H6R7	UNIPROT	KIF2A	protein	O00139	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								30297404	t		miannu	PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11. 	SIGNOR-273732	0.2
SRC	protein	P12931	UNIPROT	CHRNA7	protein	P36544	UNIPROT	down-regulates	phosphorylation	Tyr442	KILEEVRyIANRFRC	9606	BTO:0000938								16251431	t		lperfetto	Alpha7 neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and src-family kinasesmutant alpha7 nachrs lacking cytoplasmic loop tyrosine residues because of alanine replacement of tyr-386 and tyr-442 were more active than wild-type receptorsexpression of active src reduced _7 nachr activity	SIGNOR-141311	0.2
MCM	complex	SIGNOR-C268	SIGNOR	DNA_replication	phenotype	SIGNOR-PH53	SIGNOR	up-regulates				9606									19946136	f			The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication.	SIGNOR-261678	0.7
MT-ND5	protein	P03915	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1	SIGNOR-262148	0.761
CSNK2A1	protein	P68400	UNIPROT	SLC9A5	protein	Q14940	UNIPROT	down-regulates activity	phosphorylation	Ser712	EEEESDSsETEKEDD	-1									21296876	t		miannu	CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis	SIGNOR-276249	0.2
IRF4	protein	Q15306	UNIPROT	CD68	protein	P34810	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000801								12676954	f	 	 	However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element.	SIGNOR-254284	0.303
BID	protein	P55957	UNIPROT	BAK1	protein	Q16611	UNIPROT	up-regulates	binding			9606									11175253	t		amattioni	Activated tbid results in an allosteric activation of bak	SIGNOR-105210	0.815
DRD1	protein	P21728	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256796	0.476
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	BIN1	protein	O00499	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136399	0.282
SOCS1	protein	O15524	UNIPROT	JAK1	protein	P23458	UNIPROT	down-regulates	binding			9606									23663276	t		milica	Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna.	SIGNOR-202042	0.721
LHB	protein	P01229	UNIPROT	LHCGR	protein	P22888	UNIPROT	up-regulates	binding			9606									10446903	t		gcesareni	Hcg is a heterodimeric glycoprotein hormone, consisting of a common? -subunit and a hormone-specific ?-Subunit (2). It binds to the lh receptor (lhr).	SIGNOR-70028	0.671
YY2	protein	O15391	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								15087442	t		Luana	YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter.	SIGNOR-266213	0.591
NEK1	protein	Q96PY6	UNIPROT	ATRIP	protein	Q8WXE1	UNIPROT	up-regulates activity	binding												28426283	t		lperfetto	It was reported that NEK1 associates with ATR/ATRIP and primes it for activation in response to a variety of genotoxic agents	SIGNOR-275842	0.287
SLC9A4	protein	Q6AI14	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265603	0.8
DRD4	protein	P21917	UNIPROT	GNB5	protein	O14775	UNIPROT	up-regulates activity	binding			9606									21303898	t		miannu	The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC	SIGNOR-264995	0.437
SIRT1	protein	Q96EB6	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	deacetylation			9606	BTO:0000007								14976264	t		lperfetto	Sirt1 inhibited foxo3's ability to induce cell death.	SIGNOR-122408	0.909
LSM-1988	chemical	CHEBI:92015	ChEBI	PARP1	protein	P09874	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189394	0.8
afatinib	chemical	CHEBI:61390	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189356	0.8
mTORC2	complex	SIGNOR-C2	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0000182;BTO:0000018								15718470	t		lperfetto	The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1	SIGNOR-217008	0.634
(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one	chemical	CHEBI:125500	ChEBI	OPRD1	protein	P41143	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258775	0.8
SCF-FBW7	complex	SIGNOR-C135	SIGNOR	FOXM1	protein	Q08050	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0002181								26912724	t		miannu	GSK3 phosphorylates FoxM1 on serine 474 which induces FoxM1 ubiquitination mediated by FBXW7.	SIGNOR-277209	0.31
FOSL2	protein	P15408	UNIPROT	FOSL1	protein	P15407	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004603								13679379	t		Luana	Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription. 	SIGNOR-261602	0.381
AAAS	protein	Q9NRG9	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262067	0.529
IRX2	protein	Q9BZI1	UNIPROT	CXCL10	protein	P02778	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003885								26560478	f		Luana	Our results imply that the IRX2 transcription factor might represent a novel metastasis associated protein that acts as a negative regulator of cellular motility and as a repressor of chemokine expression. 	SIGNOR-266042	0.2
ITGB4	protein	P16144	UNIPROT	PIK3CB	protein	P42338	UNIPROT	up-regulates	binding			9606									9428518	t		gcesareni	Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation.	SIGNOR-54615	0.2
IDH1	protein	O75874	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	chemical modification			9606									26178471	t		lperfetto	Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG)	SIGNOR-261828	0.8
FHIT	protein	P49789	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates				9606	BTO:0000551								15313915	f		miannu	We found that this synergistic inhibition of tumor cell growth corresponded with the fhit-mediated inactivation of mdm2, which thereby blocked the association of mdm2 with p53, thus stabilizing the p53 protein.	SIGNOR-127915	0.487
ABL1	protein	P00519	UNIPROT	ROBO1	protein	Q9Y6N7	UNIPROT	down-regulates	phosphorylation	Tyr1073	PSGQPTPyATTQLIQ	9606									10892742	t		gcesareni	Abl functions to antagonize robo signaling both abl and ena can directly bind to robo's cytoplasmic domain.	SIGNOR-78993	0.588
RAD51C	protein	O43502	UNIPROT	XRCC3	protein	O43542	UNIPROT	up-regulates activity	relocalization			9606									23438602	f		lperfetto	It is likely that the recruitment of RAD51C to the sites of DNA lesions can promote XRCC3 phosphorylation and activate the DNA damage response pathway(s) in the S and G2 phases. 	SIGNOR-263260	0.652
TP73	protein	O15350	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									17700533	f		miannu	Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death. 	SIGNOR-255473	0.7
NUP93	protein	Q8N1F7	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262081	0.711
FCAR	protein	P24071	UNIPROT	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates				9606	BTO:0000130;BTO:0000801;BTO:0000876;BTO:0000399								30766540	f		lperfetto	IgA-mediated immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst and cytokine release are mediated through FcalphaRI (CD89), an IgA-specific receptor that is expressed on monocytes, eosinophils, neutrophils and macrophages	SIGNOR-264862	0.7
CTSG	protein	P08311	UNIPROT	C3	protein	P01024	UNIPROT	up-regulates activity	cleavage	Arg748	ASHLGLArSNLDEDI	9606	BTO:0001412								1861080	t		miannu	Plasma membrane elastase and cathepsin G from U937 cells cleave C3 into C3a- and C3b-like fragments; further incubation leads to C3c- and C3dg-like fragments, as judged from SDS-PAGE analysis of the digests. Sequencing of the C3b-like fragment purified by reverse phase chromatography indicates that initial cleavage of C3 by purified cathepsin G occurs at two positions in the amino-terminal part of the alpha-chain, at a Arg-Ser bond located between residues 748 and 749 and at a Leu-Asp bond between residues 751 and 752. These proteases are, thus, able to generate, on the U937 surface, active fragments of C3, which are likely to be involved in cell-protein and cell-cell interactions.	SIGNOR-256347	0.582
NDN	protein	Q99608	UNIPROT	PIAS1	protein	O75925	UNIPROT	down-regulates quantity by destabilization	binding			9606									24911587	t		lperfetto	Necdin bound to PIAS1 central domains that are highly conserved among PIAS family proteins and suppressed PIAS1-dependent sumoylation of the substrates STAT1 and PML (promyelocytic leukemia protein). Remarkably, necdin promoted degradation of PIAS1 via the ubiquitin-proteasome pathway. In transfected HEK293A cells, amino- and carboxyl-terminally truncated mutants of PIAS1 bound to necdin but failed to undergo necdin-dependent ubiquitination.	SIGNOR-253387	0.301
RBM15	protein	Q96T37	UNIPROT	RBM15/NXF1	complex	SIGNOR-C67	SIGNOR	form complex	binding			9606									17001072	t		miannu	Rbm15 binds to nxf1 and the two proteins cooperate in stimulating rte-mediated mrna export and expression.	SIGNOR-149883	0.503
MYC	protein	P01106	UNIPROT	FUT3	protein	P21217	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22547830	f		miannu	 We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. 	SIGNOR-254612	0.256
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	17beta-estradiol 3-sulfate(1-)	smallmolecule	CHEBI:136582	ChEBI	up-regulates quantity	precursor of			-1									7779757	t		Luana	HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM.	SIGNOR-269750	0.8
CDK8	protein	P49336	UNIPROT	NOTCH1	protein	P46531	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr2511	VPEHPFLtPSPESPD	-1									25344755	t		lperfetto	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273178	0.534
CASP3	protein	P42574	UNIPROT	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606		BTO:0000142							10200555	f		amattioni	Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation	SIGNOR-66860	0.7
RPS6KA4	protein	O75676	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates	phosphorylation			9606									20626350	t		gcesareni	Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1.	SIGNOR-166661	0.599
EFNA1	protein	P20827	UNIPROT	EPHA3	protein	P29320	UNIPROT	up-regulates	binding			9606									9330863	t		gcesareni	Transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells.	SIGNOR-52005	0.811
APOA5	protein	Q6Q788	UNIPROT	LPL	protein	P06858	UNIPROT	up-regulates activity	binding			9606									21773006	t	Regulation	miannu	Apo A5 binds to and enhances the activity of lipoprotein lipase (LPL) enzyme	SIGNOR-251845	0.708
TRAF7	protein	Q6Q0C0	UNIPROT	MAP3K3	protein	Q99759	UNIPROT	up-regulates	binding			9606									15001576	t		miannu	Traf7 specifically interacts with and activates mekk3.	SIGNOR-123221	0.498
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Ser362	AAAHRKGsSSNEPSS										16055710	t		lperfetto	Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos	SIGNOR-262995	0.2
PRKCD	protein	Q05655	UNIPROT	TNNI3	protein	P19429	UNIPROT	down-regulates	phosphorylation	Thr143	RGKFKRPtLRRVRIS	9606									18550549	t		gcesareni	Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144.	SIGNOR-178888	0.276
SSTR5	protein	P35346	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256690	0.474
PP2CA_R1A_R2A 	complex	SIGNOR-C132	SIGNOR	DOCK6	protein	Q96HP0	UNIPROT	down-regulates activity	phosphorylation	Ser1194	GQRSRLAsMLDSDTE										23462102	t		lperfetto	Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching	SIGNOR-275668	0.2
GNG3	protein	P63215	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance.	SIGNOR-199141	0.2
GSK2126458	chemical	CID:25167777	PUBCHEM	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192892	0.8
NDC80	protein	O14777	UNIPROT	Ndc80 complex	complex	SIGNOR-C361	SIGNOR	form complex	binding												27881301	t		lperfetto	Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits	SIGNOR-265188	0.966
CDK2	protein	P24941	UNIPROT	PGR	protein	P06401	UNIPROT	unknown	phosphorylation	Ser25	PPSPEVGsPLLCRPA	9606									11110801	t		llicata	In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676).	SIGNOR-84988	0.453
CSTF2	protein	P33240	UNIPROT	CSTF complex	complex	SIGNOR-C441	SIGNOR	form complex	binding			9606									10669729	t		lperfetto	We therefore first identified regions of the CstF subunits, CstF-77, CstF-64, and CstF-50, required for interaction with each other. 	SIGNOR-268366	0.927
ATF4	protein	P18848	UNIPROT	WARS1	protein	P23381	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269429	0.2
TRAF2	protein	Q12933	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	ubiquitination	Lys377	NEPSLQSkLQDEANY	10090	BTO:0002572;BTO:0000801								21232017	t		lperfetto	Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2.	SIGNOR-235407	0.891
ACVR1	protein	Q04771	UNIPROT	SMAD1	protein	Q15797	UNIPROT	up-regulates activity	phosphorylation	Ser465	HNPISSVs	9534									9748228	t			ALK2 receptor specifically interacts with and phosphorylates Smad1 protein. ALK2 Activates Smad1 and Induces BMP-specific Signals. Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif	SIGNOR-251439	0.69
ERBB3	protein	P21860	UNIPROT	PIK3CB	protein	P42338	UNIPROT	up-regulates	binding			9606									16729043	t		gcesareni	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146864	0.5
DVL1	protein	O14640	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	down-regulates activity	binding			9606									20837657	t		lperfetto	In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization.	SIGNOR-227911	0.701
TRIM65	protein	Q6PJ69	UNIPROT	ARHGAP35	protein	Q9NRY4	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0003172								31332286	t		miannu	Ubiquitin ligase TRIM65 promotes colorectal cancer metastasis by targeting ARHGAP35 for protein degradation	SIGNOR-272256	0.2
MAPKAPK5	protein	Q8IW41	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation			9606	BTO:0001286								17254968	t		gcesareni	Furthermore, we show that prak activates p53 by direct phosphorylation. We propose that phosphorylation of p53 by prak following activation of p38 mapk by ras plays an important role in ras-induced senescence and tumor suppression.	SIGNOR-152850	0.752
CRIPAK	protein	Q8N1N5	UNIPROT	PAK1	protein	Q13153	UNIPROT	up-regulates	binding			9606	BTO:0000150	BTO:0000149							16278681	t		gcesareni	We further found that cripak interacted with pak1 through the n-terminal regulatory domain and inhibited pak1 kinase in both in vitro and in vivo assays.	SIGNOR-141467	0.425
VAV1	protein	P15498	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	binding			9606	BTO:0000782								9200440	t		gcesareni	Hese data imply that c-cbl is a molecular adapter that regulates the function of vav	SIGNOR-49188	0.68
GSK3B	protein	P49841	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser33	LPENNVLsPLPSQAM	9606									11483158	t			Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity.	SIGNOR-251258	0.717
AKT1	protein	P31749	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	binding			9606									23400686	t		gcesareni	Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1.	SIGNOR-252534	0.845
KLF14	protein	Q8TD94	UNIPROT	TGFBR2	protein	P37173	UNIPROT	down-regulates quantity by repression	transcriptional regulation												19088080	f		lperfetto	Mechanistically, KLF14 represses the TGFbetaRII promoter via a co-repressor complex containing mSin3A and HDAC2.	SIGNOR-271696	0.2
2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[8-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]octyl]acetamide	chemical	CID:121427831	PUBCHEM	BRD4	protein	O60885	UNIPROT	down-regulates quantity	chemical inhibition			9606									29764999	t		Monia	DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells	SIGNOR-261094	0.8
SRGAP3	protein	O43295	UNIPROT	RAC2	protein	P15153	UNIPROT	down-regulates				9606									12447388	f		miannu	Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo.	SIGNOR-95921	0.533
PRKAA1	protein	Q13131	UNIPROT	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Ser555	RALSNSVsNMGLSES	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-249681	0.509
WNK1	protein	Q9H4A3	UNIPROT	STK39	protein	Q9UEW8	UNIPROT	up-regulates	phosphorylation	Thr231	TRNKVRKtFVGTPCW	9606									17190791	t		gcesareni	Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1).	SIGNOR-151671	0.457
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	MBP	protein	P02686	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000142							16401070	t	inferred from 70% family members	lperfetto	Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence.	SIGNOR-270100	0.2
BRCA1-BARD1 complex	complex	SIGNOR-C297	SIGNOR	BRCC ubiquitin ligase complex	complex	SIGNOR-C295	SIGNOR	form complex	binding			9606	BTO:0000007								14636569	t		lperfetto	These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer	SIGNOR-263208	0.828
EGR1	protein	P18146	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000574								7565762	f		miannu	 TPA induced EGR1 binding to the -69/+20 promoter sequences over a time course which correlated with increased MDR1 promoter activity and increased steady-state MDR1 RNA levels. These data suggest a role for EGR1 in modulating MDR1 promoter activity in hematopoietic cells.	SIGNOR-253871	0.374
CSNK1D	protein	P48730	UNIPROT	GJA1	protein	P17302	UNIPROT	up-regulates activity	phosphorylation	Ser328	GQAGSTIsNSHAQPF	10116	BTO:0000067								12270943	t		lperfetto	We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation).	SIGNOR-249330	0.587
NEUROG1	protein	Q92886	UNIPROT	NEUROD2	protein	Q15784	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000596								10814830	t		Luana	Based on these results, we concluded that the transactivation of the NDRF gene by ngn1 is mediated through the E4 box, suggesting that the E4 box and its binding bHLH protein(s) may play an important role in the transcriptional regulation of the NDRF gene.	SIGNOR-266235	0.282
BRCA1-BARD1 complex	complex	SIGNOR-C297	SIGNOR	FANCD2	protein	Q9BXW9	UNIPROT	up-regulates activity	ubiquitination			9606	BTO:0003323								12485996	t		lperfetto	The major genetic evidence supporting ubiquitin ligase function for BRCA1 in vivo comes from studies on the FANCD2 protein. Whereas in wild‐type cells the FANCD2 protein co‐localizes with BRCA1 in nuclear foci and becomes monoubiquitylated in response to DNA damage, HCC1937 cells, which encode a mutated form of BRCA1, are largely defective for both monoubiquitylation of FANCD2 and foci formation	SIGNOR-263237	0.699
MAPK3	protein	P27361	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									12955074	t		gcesareni	Mutant p53 is constitutively phosphorylated at serine 15 in uv-induced mouse skin tumors: involvement of erk1/2 map kinase.	SIGNOR-100270	0.697
PRKACA	protein	P17612	UNIPROT	IGF2R	protein	P11717	UNIPROT	unknown	phosphorylation	Ser2347	TTCCRRSsNVSYKYS	9606									8318012	t		lperfetto	Pka phosphorylates the cytoplasmic mpr 300 domain at ser20 and at a non-identified site,	SIGNOR-37839	0.2
SEC24B	protein	O95487	UNIPROT	COPII vesicle	complex	SIGNOR-C370	SIGNOR	form complex	binding			9606	BTO:0000567								30605680	t		lperfetto	The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat	SIGNOR-265290	0.708
Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269026	0.7
PPP3CA	protein	Q08209	UNIPROT	NFATC4	protein	Q14934	UNIPROT	up-regulates	dephosphorylation			9606									21880741	t		gcesareni	Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.	SIGNOR-176379	0.56
STAT3	protein	P40763	UNIPROT	Fibrosis	phenotype	SIGNOR-PH90	SIGNOR	up-regulates				9606									30029643	f			Taken together, our data show IL-15 can enhance the collagen deposition in vivo after muscle damage and this process can be prevented by blocking Jak-STAT pathway.	SIGNOR-256257	0.7
E2F1	protein	Q01094	UNIPROT	CCNE1	protein	P24864	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000972								14618416	f		miannu	 To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 	SIGNOR-253854	0.67
MAPK3	protein	P27361	UNIPROT	SOS1	protein	Q07889	UNIPROT	down-regulates	phosphorylation			9606									7478566	t		gcesareni	For example, inactivation of sos through phosphorylation by the downstream mapk	SIGNOR-26338	0.621
NR0B2	protein	Q15466	UNIPROT	NR1H2	protein	P55055	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000195								12198243	f		gcesareni	Here we show that shp can interact with the liver x receptors lxr? (nr1h3) and lxr? (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter. T	SIGNOR-91901	0.472
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC7	protein	Q8WUI4	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257927	0.8
ANXA3	protein	P12429	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates activity				9606	BTO:0000018								27995049	f		miannu	We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells. 	SIGNOR-262210	0.2
ABL1	protein	P00519	UNIPROT	PSTPIP1	protein	O43586	UNIPROT	unknown	phosphorylation	Tyr345	PERNEGVyTAIAVQE	9606									11163214	t		Manara	PSTPIP1 was phosphorylated by ABL1, and growth factor–induced PSTPIP1 phosphorylation was diminished in Abl null fibroblasts.	SIGNOR-260809	0.616
GATA1	protein	P15976	UNIPROT	HBG2	protein	P69892	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004911								20395365	f	Regulation	miannu	BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors.	SIGNOR-251804	0.388
GNG2	protein	P59768	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606									17419683	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt.	SIGNOR-154255	0.455
CSNK1E	protein	P49674	UNIPROT	PER3	protein	P56645	UNIPROT	down-regulates activity	phosphorylation	Ser622	ILSTAMLsLGSGISQ	9534	BTO:0000298								11865049	t		llicata	The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. 	SIGNOR-250815	0.734
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	CDK9	protein	P50750	UNIPROT	up-regulates	dephosphorylation	Ser175	FGLARAFsLAKNSQP	9606									21533037	t		lperfetto	Protein phosphatase-1 activates cdk9 by dephosphorylating ser175	SIGNOR-264671	0.2
6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine	chemical	CHEBI:131165	ChEBI	CHEK1	protein	O14757	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206838	0.8
CH5132799	chemical	CID:49784945	PUBCHEM	PIK3C2B	protein	O00750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190940	0.8
TFAP2A	protein	P05549	UNIPROT	CRYAB	protein	P02511	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21556774	t		miannu	Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53	SIGNOR-253636	0.263
BIRC2	protein	Q13490	UNIPROT	RIPK1	protein	Q13546	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000815								18570872	t		miannu	 In this report, we show that cIAP1 and cIAP2 promote cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein. We demonstrate that AEG40730, a compound modeled on BIR-binding tetrapeptides, binds to cIAP1 and cIAP2, facilitates their autoubiquitination and proteosomal degradation, and causes a dramatic reduction in RIP1 ubiquitination. We show that cIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. 	SIGNOR-272638	0.76
ethanol	chemical	CHEBI:16236	ChEBI	SLC44A2	protein	Q8IWA5	UNIPROT	up-regulates quantity				9606	BTO:0003065								21367571	f		lperfetto	Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it 	SIGNOR-260407	0.8
TBK1	protein	Q9UHD2	UNIPROT	STAT6	protein	P42226	UNIPROT	up-regulates	phosphorylation	Ser407	PIQLQALsLPLVVIV	9606									22000020	t		gcesareni	We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing.	SIGNOR-176771	0.661
DUSP6	protein	Q16828	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606									12840032	t		gcesareni	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).	SIGNOR-103146	0.901
Cy3-bifunctional dye zwitterion	chemical	CHEBI:37990	ChEBI	ADRB1	protein	P08588	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. 	SIGNOR-257859	0.8
EIF3J	protein	O75822	UNIPROT	EIF3_complex	complex	SIGNOR-C401	SIGNOR	form complex	binding			-1									16920360	t		miannu	Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 	SIGNOR-266391	0.776
MAPK8	protein	P45983	UNIPROT	BCL2L11	protein	O43521	UNIPROT	up-regulates	phosphorylation			9606									18498746	t		gcesareni	Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf).	SIGNOR-178686	0.751
HSPA8	protein	P11142	UNIPROT	RNF5	protein	Q99942	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								21148293	t		miannu	JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. JB12 drives Hsc70 to associate with CFTR and the RMA1 E3 complex	SIGNOR-271493	0.397
APBA1	protein	Q02410	UNIPROT	CASK	protein	O14936	UNIPROT	up-regulates activity	binding			9534									11036064	t		miannu	Interaction with Munc18 increases Mint1 binding to CASK.	SIGNOR-264041	0.846
NR3C1	protein	P04150	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000746								27777311	f			We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα.	SIGNOR-256117	0.472
BMP2	protein	P12643	UNIPROT	SMAD5	protein	Q99717	UNIPROT	up-regulates				9606									22298955	f		gcesareni	Neogenin, a transmembranous protein, was re-ported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation	SIGNOR-195564	0.688
MAPK3	protein	P27361	UNIPROT	MKNK1	protein	Q9BUB5	UNIPROT	up-regulates activity	phosphorylation			-1									9155018	t			These results indicate that MNK1 is a novel class of protein kinase that is activated through both the ERK and p38 MAP kinase signaling pathways	SIGNOR-253012	0.556
DIABLO	protein	Q9NR28	UNIPROT	XIAP	protein	P98170	UNIPROT	down-regulates quantity	binding			9606	BTO:0000007;BTO:0000567								14523016	t		amattioni	Smac3, a novel Smac/DIABLO splicing variant, accelerates XIAP auto-ubiquitination and destruction	SIGNOR-118411	0.912
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	MAPK1	protein	P28482	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000443								12270934	t		lperfetto	Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis.	SIGNOR-244795	0.2
MDH2	protein	P40926	UNIPROT	NADH	smallmolecule	CHEBI:16908	ChEBI	up-regulates quantity	chemical modification			9606									24068518	t		miannu	Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle	SIGNOR-266288	0.8
SMARCB1	protein	Q12824	UNIPROT	Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	form complex	binding			10090	BTO:0001086								19279220	t		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270725	0.756
CREB1	protein	P16220	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates activity	binding			9606									15126506	t		lperfetto	We provide evidence that the acetyltransferase creb-binding protein (cbp) binds foxo resulting in acetylation of foxo. This acetylation inhibits foxo transcriptional activity	SIGNOR-124711	0.313
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	BCR	protein	P11274	UNIPROT	down-regulates activity	phosphorylation	Tyr177	ADAEKPFyVNVEFHH	9606									8622703	t		lperfetto	We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrosine 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr.	SIGNOR-40611	0.2
PTPN6	protein	P29350	UNIPROT	NTRK1	protein	P04629	UNIPROT	down-regulates activity	dephosphorylation	Tyr680	RDIYSTDyYRVGGRT	10116							phosphorylation: tyr496	HIIENPQyFSDACVH	14662744	t			Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675. 	SIGNOR-248468	0.489
NTRK1	protein	P04629	UNIPROT	SH2B1	protein	Q9NRF2	UNIPROT	up-regulates	binding			9606	BTO:0000938								15082760	t		lperfetto	The adapter protein sh2-b has been shown to bind to activated nerve growth factor (ngf) receptor trka and has been implicated in ngf-induced neuronal differentiation and the survival of sympathetic neurons.	SIGNOR-124198	0.523
PP121	chemical	CHEBI:50915	ChEBI	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206295	0.8
(2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol	chemical	CHEBI:94701	ChEBI	RRM2	protein	P31350	UNIPROT	down-regulates activity	chemical inhibition			-1									7048062	t		miannu	In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. 2-F-araATP was a potent inhibitor of ribonucleotide reductase	SIGNOR-258405	0.8
TAOK3	protein	Q9H2K8	UNIPROT	TAOK3	protein	Q9H2K8	UNIPROT	up-regulates activity	phosphorylation	Thr181	PANSFVGtPYWMAPE	9534	BTO:0004055								10559204	t		lperfetto	These data indicate that JIK is indeed the protein kinase present in the immune complex responsible for autophosphorylation and for the phosphorylation of the exogenous substrate. Moreover, our observations suggest that JIK (A181F183) acts as the catalytically inactive mutant of JIK, which is no longer able to potently undergo autophosphorylation and dramatically phosphorylate MBP, as compared with the wild type JIK.	SIGNOR-246298	0.2
PPP2CA	protein	P67775	UNIPROT	ELF1	protein	P32519	UNIPROT	down-regulates activity	dephosphorylation	Thr231	CPKYIKWtQREKGIF	9606									18714041	t			Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response	SIGNOR-248634	0.2
DUSP23	protein	Q9BVJ7	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates activity	dephosphorylation			9606									27281782	t		miannu	In particular, DUSP23 can dephosphorylate and inactivate MAPK3 ( xref ).|In particular, DUSP23 can dephosphorylate and inactivate MAPK3.	SIGNOR-277103	0.315
HCK	protein	P08631	UNIPROT	ADAM15	protein	Q13444	UNIPROT	unknown	phosphorylation	Tyr715	LVMLGASyWYRARLH	9606									11741929	t		llicata	Hck, and to a lesser extent lck, phosphorylated the adam15 cytoplasmic domain in vitro in immune complex kinase assays.	SIGNOR-112927	0.362
TNKS2	protein	Q9H2K2	UNIPROT	CASC3	protein	O15234	UNIPROT	down-regulates quantity by destabilization	ADP-ribosylation			9606									21478859	t		lperfetto	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 	SIGNOR-263382	0.2
haloperidol	chemical	CHEBI:5613	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9760039	t		miannu	Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects.	SIGNOR-258838	0.8
RBL2	protein	Q08999	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates quantity	transcriptional regulation			10090									10801445	f		gcesareni	Furthermore, muscle cells overexpressing p130 had reduced levels of the muscle-promoting factor MyoD. In addition, p130 repressed the transactivation capacity of MyoD, an effect abolished by co-transfection of pRb	SIGNOR-241943	0.379
Wnt	proteinfamily	SIGNOR-PF40	SIGNOR	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity by stabilization													17081971	f			The central player in the canonical Wnt cascade is β-catenin, a cytoplasmic protein whose stability is regulated by the destruction complex.	SIGNOR-256240	0.2
IL22RA1	protein	Q8N6P7	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates				9606									12087100	f		gcesareni	Il-22 also induced serine phosphorylation of stat3 on ser(727).	SIGNOR-90162	0.638
CALM3	protein	P0DP25	UNIPROT	PP2B	proteinfamily	SIGNOR-PF18	SIGNOR	up-regulates	binding			9606									11796223	t	inferred from 70% of family members	miannu	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-269891	0.66
STAT3	protein	P40763	UNIPROT	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606									10347215	f		lperfetto	The data presented this far show that the JAK-STAT signaling pathway and specifically Stat3 and Jak1 are required for induction of IL-10-dependent anti-inflammatory and developmental responses in macrophages.	SIGNOR-249547	0.7
2-(hydroxymethyl)-4-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)phenol	chemical	CHEBI:64064	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			10030									20590599	t		Luana	The affinity measurements (log KD values of −5.73, −9.26 and −6.33 for β1, β2 and β3, respectively), show that salmeterol has high affinity for the β2-adrenoceptor. 	SIGNOR-257852	0.8
SMO	protein	Q99835	UNIPROT	GNAT2	protein	P19087	UNIPROT	up-regulates	binding			9606									16885213	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-148534	0.264
PRDM16	protein	Q9HAZ2	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates	binding			9606	BTO:0000222	BTO:0000887;BTO:0001103							18719582	t	_activating its transcriptional function	fspada	Prdm16 stimulates brown adipogenesis by binding to ppar-gamma (peroxisome-proliferator-activated receptor-gamma) and activating its transcriptional function	SIGNOR-180298	0.483
NOTCH2	protein	Q04721	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates	binding			9606									9528794	t		gcesareni	In an effort to identify processes that regulate e47, and potentially b-cell development, we found that activated notch1 and notch2 effectively inhibit e47 activity.	SIGNOR-56222	0.277
vilanterol	chemical	CHEBI:75037	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			10030									20462258	t		Luana	A series of saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for β2, β1, and β3 agonist activity in CHO cells. | Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo	SIGNOR-257843	0.8
AEP complex	complex	SIGNOR-C117	SIGNOR	HOXA9	protein	P31269	UNIPROT	up-regulates quantity by expression				9606									20854876	f		irozzo	Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented.	SIGNOR-255879	0.418
RAD23B	protein	P54727	UNIPROT	ERCC5	protein	P28715	UNIPROT	up-regulates activity	binding												24086043	t		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275702	0.625
PFKL	protein	P17858	UNIPROT	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35.	SIGNOR-266468	0.8
MAPK3	protein	P27361	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606	BTO:0000567								17615152	t		gcesareni	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.	SIGNOR-156868	0.692
Hypoxia	stimulus	SIGNOR-ST25	SIGNOR	KDM4B	protein	O94953	UNIPROT	up-regulates				9606									30759871	f		miannu	The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. KDM4 enzymes are generally over-expressed in cancers, making them compelling targets for study and therapeutic inhibition. One of these family members, KDM4B, is especially interesting due to its regulation by multiple cellular stimuli, including DNA damage, steroid hormones, and hypoxia.	SIGNOR-263735	0.7
ABL1	protein	P00519	UNIPROT	VAV1	protein	P15498	UNIPROT	up-regulates	phosphorylation			9606	BTO:0001271								11790798	t		gcesareni	Thus, the c-terminal tail of vav serves as a direct substrate of bcr-abl in vitro.	SIGNOR-114091	0.41
IDH1	protein	O75874	UNIPROT	2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	up-regulates quantity	chemical modification			9606									29090344	t		miannu	Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases. 	SIGNOR-253135	0.8
CHD8	protein	Q9HCK8	UNIPROT	MAP2	protein	P11137	UNIPROT	down-regulates quantity	transcriptional regulation			10090									32839322	t		Gianni	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268916	0.2
CREB1	protein	P16220	UNIPROT	PLAT	protein	P00750	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001282								8647095	f	 	lperfetto	We suggest that the mechanism for the transcriptional down-regulation of t-PA by PMA in HT-1080 cells requires CREB-1 binding to the t-PACRE while ATF-2, by associating with the same site, plays a role in PMA-mediated induction of t-PA in HeLa cells.	SIGNOR-253732	0.268
CEBPA	protein	P49715	UNIPROT	SPI1	protein	P17947	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									14592841	t			Activation of C/EBPα induces PU.1 expression, cell cycle arrest, and differentiation in 32D cells expressing FLT3/ITD	SIGNOR-261531	0.544
SYK	protein	P43405	UNIPROT	SH3BP2	protein	P78314	UNIPROT	up-regulates activity	phosphorylation	Tyr183	HDDEDDSyLEPDSPE	9534	BTO:0004055								12709437	t		lperfetto	By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk	SIGNOR-246592	0.569
BRD4	protein	O60885	UNIPROT	P-TEFb	complex	SIGNOR-C238	SIGNOR	up-regulates activity	binding			9606									16109377	t		miannu	Binding of Brd4 to Core P-TEFb Is Essential for Transcription.	SIGNOR-266411	0.62
PPP2CA	protein	P67775	UNIPROT	DOCK6	protein	Q96HP0	UNIPROT	down-regulates activity	phosphorylation	Ser1194	GQRSRLAsMLDSDTE										23462102	t		lperfetto	Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching	SIGNOR-275669	0.2
ASTN2	protein	O75129	UNIPROT	Neuron_migration	phenotype	SIGNOR-PH67	SIGNOR	up-regulates				9606	BTO:0000142								28506896	f		miannu	The role of astrotactin and Brinp proteins has been partially characterized, with ASTN1 and ASTN2 demonstrated to facilitate glial-guided neuronal migration during brain development	SIGNOR-269814	0.7
PRKAR2A	protein	P13861	UNIPROT	PRKAR2A	protein	P13861	UNIPROT	up-regulates activity	phosphorylation	Ser99	SRFNRRVsVCAETYN	-1									6293815	t		miannu	 RII subunit containing the 'autophosphorylation' site (Ser-95)	SIGNOR-250073	0.2
TH	protein	P07101	UNIPROT	L-dopa	smallmolecule	CHEBI:15765	ChEBI	up-regulates quantity	chemical modification			9606									NBK536726	t	brain	lperfetto	Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH).	SIGNOR-263991	0.8
2-(2-amino-3-methoxyphenyl)chromen-4-one	chemical	CHEBI:77954	ChEBI	MAP2K2	protein	P36507	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205746	0.8
Tubulin	proteinfamily	SIGNOR-PF46	SIGNOR	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates				9606									28347630	f		miannu	Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation	SIGNOR-266827	0.7
AKT2	protein	P31751	UNIPROT	MYO5A	protein	Q9Y4I1	UNIPROT	up-regulates activity	phosphorylation	Thr1650	PTGLRKRtSSIADEG	10090	BTO:0000944								17515613	t		miannu	Here we identify an Akt consensus phosphorylation motif in the actin-based motor protein myosin 5a and show that insulin stimulation leads to phosphorylation of myosin 5a at serine 1650. This Akt-mediated phosphorylation event enhances the ability of myosin 5a to interact with the actin cytoskeleton.Taken together, these data indicate that myosin 5a is a newly identified direct substrate of Akt2 and, upon insulin stimulation, phosphorylated myosin 5a facilitates anterograde movement of GLUT4 vesicles along actin to the cell surface.	SIGNOR-262632	0.435
NF1	protein	P21359	UNIPROT	Adenylate_cyclase	proteinfamily	SIGNOR-PF92	SIGNOR	up-regulates				9606	BTO:0000938								24431436	f		miannu	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-267846	0.409
SGK1	protein	O00141	UNIPROT	NR3C1	protein	P04150	UNIPROT	up-regulates activity	phosphorylation	Ser211	PGKETNEsPWRSDLL	9606									23650397	t		gcesareni	SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|Having demonstrated that SGK1 mediates the cortisol-induced increase in GR phosphorylation at the S203 and S211 phospho-sites, which enhance GR nuclear translocation, but not at the S226 site, which inhibits nuclear translocation	SIGNOR-251670	0.474
DDIT3	protein	P35638	UNIPROT	TRIB3	protein	Q96RU7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002183								18940792	f		miannu	Exogenous CHOP expression enhanced the TRB3 gene induction by amino acid deprivation. 	SIGNOR-253839	0.591
EGFR	protein	P00533	UNIPROT	HGS	protein	O14964	UNIPROT	up-regulates activity	phosphorylation	Tyr334	ARYLNRNyWEKKQEE	9606									12953068	t		lperfetto	We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation	SIGNOR-100246	0.622
BTG2	protein	P78543	UNIPROT	SOD1	protein	P00441	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								22493435	f		miannu	BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2	SIGNOR-254650	0.2
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr45	PGGTLFStTPGGTRI	9606	BTO:0000007;BTO:0000443		SIGNOR-C3						17510057	t		lperfetto	In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size.	SIGNOR-154814	0.924
N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide	chemical	CHEBI:91336	ChEBI	AURKB	protein	Q96GD4	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258304	0.8
AURKB	protein	Q96GD4	UNIPROT	KIF20A	protein	O95235	UNIPROT	down-regulates activity	phosphorylation	Ser878	RILRSRRsPLLKSGP	9606	BTO:0000567								27939310	t		miannu	We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton. Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878. 	SIGNOR-262659	0.772
CSNK2A1	protein	P68400	UNIPROT	MYH9	protein	P35579	UNIPROT	up-regulates	phosphorylation	Ser1943	RKGAGDGsDEEVDGK	9606									22123909	t		gcesareni	In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)	SIGNOR-177818	0.347
CADPS2	protein	Q86UW7	UNIPROT	STX1A	protein	Q16623	UNIPROT	up-regulates activity	binding			9606	BTO:0000938			SIGNOR-C346					24363652	t		miannu	 CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1	SIGNOR-264337	0.364
ANXA3	protein	P12429	UNIPROT	CASP3	protein	P42574	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001109;BTO:0000038								30998268	f		miannu	ANXA3 depletion promoted cell apoptosis and upregulated c‐caspase 3 expression in HCT116/Ox and SW480/Ox cells with or without Ox, which is consistent with findings from a preliminary study by Yan et al	SIGNOR-262209	0.266
SIRT7	protein	Q9NRC8	UNIPROT	H3-5	protein	Q6NXT2	UNIPROT	up-regulates activity	deacetylation	Lys37	TPSTCGVkPHRYRPG										30653310	t		lperfetto	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 	SIGNOR-275879	0.2
alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	up-regulates quantity	precursor of			9606									32898648	t		miannu	Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P).	SIGNOR-267935	0.8
AKT2	protein	P31751	UNIPROT	PKP1	protein	Q13835	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr166	LYCDPRGtLRKGTLG	-1									23444369	t		miannu	Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry.	SIGNOR-273491	0.27
IL23A	protein	Q9NPF7	UNIPROT	IL12RB1	protein	P42701	UNIPROT	up-regulates	binding			9606									12023369	t		gcesareni	Like il-12, il-23 binds to the il-12r subunit il-12rbeta1.	SIGNOR-87739	0.631
MBP	protein	P02686	UNIPROT	Myelination	phenotype	SIGNOR-PH206	SIGNOR	up-regulates													31066630	f		SimoneGraziosi	Myelin basic protein (MBP) is essential for the compaction of the two adjacent cytoplasmic membrane surfaces into the major dense line of myelin.	SIGNOR-269230	0.7
IL17A	protein	Q16552	UNIPROT	IL17RA	protein	Q96F46	UNIPROT	up-regulates	binding			9606	BTO:0000782								9367539	t		gcesareni	Binding studies suggest that recombinant hil-17 binds to the hil-17r with low affinity. Monoclonal antibodies (mabs) generated against the hil-17r were able to block the il-17-induced production of cytokine from human foreskin fibroblast (hff) cells.	SIGNOR-53249	0.922
DAPK3	protein	O43293	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr145	QGRKRRQtSMTDFYH	-1									15001356	t		llicata	ZIP kinase phosphorylates p21(WAF1) at Thr145 and alanine-substituted mutations in the p21(WAF1) phosphorylation site alter its ability to be phosphorylated by ZIP kinase. | Transfected ZIPK can promote the phosphorylation of p21(WAF1) at Thr145 in vivo and can increase the half-life of p21(WAF1)	SIGNOR-251085	0.321
PRKCA	protein	P17252	UNIPROT	NOX5	protein	Q96PH1	UNIPROT	up-regulates	phosphorylation	Ser536	GRGSKRLsRSVTMRK	9606									24505490	t		llicata	A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498.	SIGNOR-204546	0.2
KDM1A	protein	O60341	UNIPROT	BHC complex	complex	SIGNOR-C353	SIGNOR	form complex	binding			9606	BTO:0000567; BTO:0000007								15325272	t		miannu	BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells	SIGNOR-264501	0.796
EPO	protein	P01588	UNIPROT	HBA1	protein	P69905	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000574								9168989	f	Regulation	miannu	We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin.	SIGNOR-251786	0.326
AMPK	complex	SIGNOR-C15	SIGNOR	FOXO3	protein	O43524	UNIPROT	up-regulates activity	phosphorylation	Thr179	SSPDKRLtLSQIYEW	-1									17711846	t	done	miannu	Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626).	SIGNOR-274094	0.397
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	TSC1	protein	Q92574	UNIPROT	down-regulates	phosphorylation			9606									15851026	t		lperfetto	Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin.	SIGNOR-244761	0.2
TNFSF11	protein	O14788	UNIPROT	Osteoclast_differentiation	phenotype	SIGNOR-PH76	SIGNOR	up-regulates				9606									17572386	f		miannu	Osteoclasts are fully differentiated, multi-nucleated cells originating from the hematopoietic monocyte-macrophage linage. RANKL, a member of the tumor necrosis factor (TNF) superfamily, and its receptor RANK are essential regulators of osteoclast maturation and activation	SIGNOR-253044	0.7
ACD	protein	Q96AP0	UNIPROT	POT1/ACD	complex	SIGNOR-C64	SIGNOR	form complex	binding			9606									17237768	t		miannu	We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme.	SIGNOR-152318	0.88
IRAK4	protein	Q9NWZ3	UNIPROT	IRAK1	protein	P51617	UNIPROT	up-regulates activity	phosphorylation	Thr387	RTQTVRGtLAYLPEE	-1									11960013	t			In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4.	SIGNOR-251329	0.672
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRIA1	protein	P42261	UNIPROT	up-regulates activity	chemical activation			10090									15115814	t		lperfetto	AMPA glutamate receptor subunit (GluR1)	SIGNOR-261432	0.8
CREB1	protein	P16220	UNIPROT	PK	proteinfamily	SIGNOR-PF80	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									20577053	f		gcesareni	In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1	SIGNOR-268145	0.252
IFNW1	protein	P05000	UNIPROT	IFNAR2	protein	P48551	UNIPROT	up-regulates	binding			9606									11278538	t		gcesareni	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-105982	0.751
KLF15	protein	Q9UIH9	UNIPROT	RHO	protein	P08100	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								15277472	f		miannu	 KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. 	SIGNOR-253817	0.276
SIRT1	protein	Q96EB6	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates activity	deacetylation												24870244	t		lperfetto	The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1alpha.	SIGNOR-275499	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	EPM2A	protein	O95278	UNIPROT	up-regulates activity	phosphorylation	Ser25	PELLVVGsRPELGRW	9606	BTO:0000007								21728993	t		miannu	In the present study, we demonstrate that laforin is a phosphoprotein, as indicated by two-dimensional electrophoresis, and we identify Ser(25) as the residue involved in this modification. We also show that Ser(25) is phosphorylated both in vitro and in vivo by AMPK. 	SIGNOR-276338	0.357
nintedanib	chemical	CHEBI:85164	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates activity	chemical inhibition			-1									18559524	t		Luana	In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers.	SIGNOR-257805	0.8
EP300	protein	Q09472	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	acetylation	Lys382	QSTSRHKkLMFKTEG	9606	BTO:0000567								11070080	t		gcesareni	P300 acetylates and activates the tumor suppressor p53 after dna damage.	SIGNOR-84074	0.909
SATB1	protein	Q01826	UNIPROT	CD52	protein	P31358	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000664								17343824	f		miannu	We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 	SIGNOR-255131	0.2
PFDN4	protein	Q9NQP4	UNIPROT	Prefoldin co-chaperone	complex	SIGNOR-C513	SIGNOR	form complex	binding			9606									32699605	t		miannu	The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6)	SIGNOR-270933	0.94
PRKCA	protein	P17252	UNIPROT	NOX5	protein	Q96PH1	UNIPROT	up-regulates	phosphorylation	Ser544	RSVTMRKsQRSSKGS	9606									24505490	t		llicata	A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498.	SIGNOR-204550	0.2
FBXO32	protein	Q969P5	UNIPROT	MYOD1	protein	P15172	UNIPROT	down-regulates quantity by destabilization	binding			10090	BTO:0000165								19319192	t		miannu	We previously showed that the level of MAFbx protein increased in skeletal muscle during aging and/or food deprivation. Immunoprecipitation of the SCFMAFbx complexes from mouse atrophic muscles exhibited ubiquitination activity by using MyoD as substrate. Food deprivation and oxidative stress–induced atrophy increase polyubiquitination by the SCFMAFbx pathway and degradation of MyoD by the proteasome	SIGNOR-271802	0.577
CSNK2A1	protein	P68400	UNIPROT	MAPK9	protein	P45984	UNIPROT	unknown	phosphorylation	Ser407	STEQTLAsDTDSSLD	9606									11062067	t		lperfetto	The phosphorylation of thr-404 and ser-407 is not increased in response to other agonists that activate mkk7 and sapk1/jnk, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as ck2, which also phosphorylates thr-404 and ser-407 in vitro.	SIGNOR-83711	0.222
PRKCA	protein	P17252	UNIPROT	CORO1B	protein	Q9BR76	UNIPROT	down-regulates	phosphorylation	Ser2	sFRKVVRQ	9606									16027158	t		lperfetto	We have identified serine 2 (ser-2) on coronin 1b as the major residue phosphorylated by pkc in vivo.In this work, we show that coronin 1b interacts in vivo with the arp2/3 complex and that this interaction is inhibited by pkc phosphorylation.	SIGNOR-138733	0.329
CREB5	protein	Q02930	UNIPROT	LY96	protein	Q9Y6Y9	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		 BTO:0002813							21132541	f		miannu	 Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition),	SIGNOR-253806	0.2
GSK3B	protein	P49841	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates activity	phosphorylation	Ser43	QTPSKPAsADGHRGP	9606	BTO:0002181								33388549	t		miannu	 Concurrently, ROCK1 was able to phosphorylate GSK-3β at Ser9, which phosphorylated Src at Ser51 and Ser492 residues, leading to Src inactivation 	SIGNOR-277543	0.392
PMS2	protein	P54278	UNIPROT	MLH1/PMS2	complex	SIGNOR-C59	SIGNOR	form complex	binding			9606									10542278	t		miannu	Hmlh1 and hpms2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hmutl_	SIGNOR-71777	0.747
PAK2	protein	Q13177	UNIPROT	NF2	protein	P35240	UNIPROT	down-regulates	phosphorylation	Ser518	DTDMKRLsMEIEKEK	9606									18071304	t		lperfetto	Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth,	SIGNOR-159768	0.491
AGTR1	protein	P30556	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606									32201502	f		MIANNU	Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis.	SIGNOR-260233	0.7
EPHB2	protein	P29323	UNIPROT	SYNJ1	protein	O43426	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000938								15821731	t		lperfetto	Ephb2 causes tyrosine phosphorylation in the proline-rich domain of synaptojanin 1, and inhibits both the interaction with endophilin and the 5'-phosphatase activity of synaptojanin 1	SIGNOR-135274	0.55
PKI-402	chemical	CID:44187953	PUBCHEM	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252654	0.8
NEK2	protein	P51955	UNIPROT	SGO1	protein	Q5FBB7	UNIPROT	up-regulates	phosphorylation	Ser507	TDLCFLNsPIFKQKK	9606									17621308	t		lperfetto	Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507)	SIGNOR-156882	0.2
MTOR	protein	P42345	UNIPROT	EIF4EBP2	protein	Q13542	UNIPROT	down-regulates	phosphorylation			9606									23100465	t		gcesareni	Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2).	SIGNOR-199258	0.651
MTA1	protein	Q13330	UNIPROT	MTA1/DJ1 complex 	complex	SIGNOR-C123	SIGNOR	form complex	binding			9606									21368136	t	1	miannu	We found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3.	SIGNOR-239739	0.333
CAMK2B	protein	Q13554	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Thr594	LHGKKNStVDCNGVV	9606									33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275775	0.394
DNMT3A	protein	Q9Y6K1	UNIPROT	CDKN2D	protein	P55273	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									26350239	f		miannu	Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family	SIGNOR-261510	0.2
FBXW11	protein	Q9UKB1	UNIPROT	CHUK	protein	O15111	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								10321728	t		miannu	We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo. 	SIGNOR-272545	0.416
NME1	protein	P15531	UNIPROT	NME1	protein	P15531	UNIPROT	unknown	phosphorylation	Ser125	HGSDSVEsAEKEIGL	-1									8810265	t		miannu	For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown. 	SIGNOR-250198	0.2
BRSK2	protein	Q8IWQ3	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	up-regulates	phosphorylation	Thr183	SDGEFLRtSCGSPNY	9606									21918180	t		gcesareni	Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli.	SIGNOR-176594	0.294
CSNK2A2	protein	P19784	UNIPROT	XRCC1	protein	P18887	UNIPROT	up-regulates activity	phosphorylation	Thr519	EDPYAGStDENTDSE	9606	BTO:0000567								15367657	t		llicata	XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1.	SIGNOR-251051	0.473
HDAC5	protein	Q9UQL6	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates	deacetylation			9606									22298955	t		gcesareni	Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation	SIGNOR-195606	0.47
YWHAQ	protein	P27348	UNIPROT	PRKD1	protein	Q15139	UNIPROT	down-regulates				-1									10092600	f		lperfetto	14-3-3tau strongly down-regulates pkcmu kinase activity in vitro	SIGNOR-65951	0.332
LTK	protein	P29376	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000938								9223670	t		gcesareni	Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85.	SIGNOR-49528	0.375
PAX7	protein	P23759	UNIPROT	Skeletal_muscle_differentiation	phenotype	SIGNOR-PH1	SIGNOR	down-regulates				9606		BTO:0001103;BTO:0002314							22493066	f		lperfetto	Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells	SIGNOR-219371	0.7
valsartan	chemical	CHEBI:9927	ChEBI	AGTR1	protein	P30556	UNIPROT	down-regulates activity	chemical inhibition			9606									8577935	t		miannu	The binding characteristics of the angiotensin AT1 receptor antagonist valsartan were investigated in different animal species and tissues.	SIGNOR-258489	0.8
NRAS	protein	P01111	UNIPROT	BRAF	protein	P15056	UNIPROT	up-regulates activity	binding			9606									21779497	t		lperfetto	The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.	SIGNOR-175219	0.849
JAK2	protein	O60674	UNIPROT	GTF2I	protein	P78347	UNIPROT	up-regulates activity	phosphorylation	Tyr248	EESEDPDyYQYNIQA	10090	BTO:0000944								11313464	t		lperfetto	Jak2 activates tfii-i and regulates its interaction with extracellular signal-regulated kinase the interaction between tfii-i and erk, which is essential for its activity, can be regulated by jak2 through phosphorylation of tfii-i at tyrosine 248	SIGNOR-235313	0.333
TRIM24	protein	O15164	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates	binding			9606	BTO:0001130								19909775	t		miannu	We found that trim24/transcriptional intermediary factor 1alpha (tif1alpha), which is known as a ligand-dependent nuclear receptor co-regulator, interacts with ar and enhances transcriptional activity of ar	SIGNOR-189113	0.405
MAPT	protein	P10636	UNIPROT	Neurofibrillary tangle formation	phenotype	SIGNOR-PH58	SIGNOR	down-regulates				9606									11578751	f		lperfetto	Tau is a multifunctional microtubule-associated protein that plays major roles in the assembly of microtubules, the stabilization of microtubules against dynamic instability, and in bridging these polymers with other cytoskeletal filaments 43, 44, 45, 46 and 47. In normal brain, the equilibrium between phosphorylations and dephosphorylations of tau modulates the stability of the cytoskeleton and consequently axonal morphology. The earliest modification found in Alzheimer brains consists of hyperphosphorylations on tau by the action of different protein kinase and phosphatase systems that appear to lead to structural and conformational changes in this protein, thus affecting its binding with tubulin and the capacity to promote microtubule assembly	SIGNOR-251639	0.7
SP1	protein	P08047	UNIPROT	ASNS	protein	P08243	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								11867623	t		Luana	Sp1 and Sp3 Activate Transcription Driven by the AS Promoter	SIGNOR-268019	0.2
GSK3B	protein	P49841	UNIPROT	MACF1	protein	Q9UPN3	UNIPROT	down-regulates activity	phosphorylation	Ser7234	RAASPTRsSSSASQS	9606	BTO:0004905								21295697	t		lperfetto	We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules.	SIGNOR-264429	0.446
AXIN1	protein	O15169	UNIPROT	AXIN1	protein	O15169	UNIPROT	up-regulates activity	binding			9606									17529994	t		amattioni	The axin dix domain has a novel structural fold largely composed of beta-strands that engage in head-to-tail self-interaction to form filaments in the crystal	SIGNOR-155218	0.2
PML	protein	P29590	UNIPROT	ZFYVE9	protein	O95405	UNIPROT	up-regulates	binding			9606									15356634	t		gcesareni	Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome.	SIGNOR-128744	0.555
MAPK3	protein	P27361	UNIPROT	MKNK2	protein	Q9HBH9	UNIPROT	up-regulates	phosphorylation			9606									9155017	t		gcesareni	Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity.	SIGNOR-48355	0.495
WZ4002	chemical	CHEBI:61400	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207827	0.8
COPS5	protein	Q92905	UNIPROT	SMAD4	protein	Q13485	UNIPROT	down-regulates	ubiquitination			9606									11818334	t		gcesareni	We report a novel mechanism of smad4 degradation. Jab1 interacts directly with smad4 and induces its ubiquitylation for degradation	SIGNOR-114697	0.444
EGR1	protein	P18146	UNIPROT	CYP2B6	protein	P20813	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18303024	f		miannu	 The CYP2B6 enzyme metabolizes commonly used therapeutics and also activates pro-drugs. The CAR directly binds to the distal enhancer element of the CYP2B6 promoter, which is essential in converging to its drug-sensing function onto promoter activity. However, this binding alone is not sufficient to activate the CYP2B6 promoter; the promoter requires EGR1 to enable CAR to activate the CYP2B6 promoter.	SIGNOR-253874	0.261
PDP1	protein	Q9P0J1	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	dephosphorylation			9606									16510868	t		lpetrilli	We show that the mammalian pdps are important in dephosphorylation of bmp-activated smad1 but not tgf-beta-activated smad2 or smad3. Thus, pdps specifically inactivate smads in the bmp/dpp pathway. [...] These observations suggest that pdp1 and pdp2 are important for dephosphorylation of smad1.	SIGNOR-144876	0.245
BIRC2	protein	Q13490	UNIPROT	CASP2	protein	P42575	UNIPROT	down-regulates	binding			9606									16701639	t		gcesareni	However, among hiap1, hiap2 and xiap, only hiap2 binds and inhibits caspase-2.	SIGNOR-146738	0.512
PLK1	protein	P53350	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates	phosphorylation	Ser53	GHSTGEDsAFQEPDS	9606									16085715	t		gcesareni	Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp.	SIGNOR-139477	0.626
AURKB	protein	Q96GD4	UNIPROT	CDCA5	protein	Q96FF9	UNIPROT	down-regulates activity	phosphorylation	Ser83	PRRSPRIsFFLEKEN	-1									23901111	t		miannu	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion. 	SIGNOR-276119	0.614
CASP1	protein	P29466	UNIPROT	AIM2 inflammasome	complex	SIGNOR-C222	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256400	0.783
NR0B2	protein	Q15466	UNIPROT	HNF4A	protein	P41235	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									10594021	f		gcesareni	Here we show that shp inhibits transactivation by the orphan receptor hepatocyte nuclear factor 4 (hnf-4) and the retinoid x receptor (rxr) by at least two mechanisms shp also competes with coactivators for binding to ligand-activated rxr, and based on the ligand-dependent interaction with other nuclear receptors, it is likely that coactivator competition is a general feature of shp-mediated repression.	SIGNOR-73032	0.439
AKT1	protein	P31749	UNIPROT	SP7	protein	Q8TDD2	UNIPROT	up-regulates	phosphorylation			9606									21777568	t		gcesareni	We found that Akt phosphorylates Osterix and that Akt activation increases protein stability, osteogenic activity and transcriptional activity of Osterix. We also found that BMP-2 increases the protein level of Osterix in an Akt activity-dependent manner.	SIGNOR-195549	0.435
BLM	protein	P54132	UNIPROT	UIMC1	protein	Q96RL1	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								23708797	t		miannu	Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of . 	SIGNOR-272116	0.334
ENOBOSARM	chemical	CID:11326715	PUBCHEM	AR	protein	P10275	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-195892	0.8
PHKG2	protein	P15735	UNIPROT	PYGM	protein	P11217	UNIPROT	up-regulates activity	phosphorylation	Ser15	QEKRKQIsVRGLAGV	9606	BTO:0002049								22225877	t			It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15	SIGNOR-267400	0.543
HDAC4	protein	P56524	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates	deacetylation			9606									16613856	t		gcesareni	Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation.	SIGNOR-146122	0.54
GUCY1A1	protein	Q02108	UNIPROT	GUCY1A3-B3	complex	SIGNOR-C140	SIGNOR	form complex	binding			9606									10977868	t		gcesareni	This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity	SIGNOR-243983	0.2
LCK	protein	P06239	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates	phosphorylation	Tyr759	LYDVSRMyVDPSEIN	9606									12181444	t		gcesareni	In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme.	SIGNOR-91477	0.538
RNF139	protein	Q8WU17	UNIPROT	SREBF2	protein	Q12772	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000007								20068067	t		miannu	Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner 	SIGNOR-271958	0.491
mTORC2	complex	SIGNOR-C2	SIGNOR	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Ser436	INQSTLPsQQNRFPD	9606	BTO:0002036								34343821	t		miannu	Here we report the ability of mTORC2 to directly phosphorylate YAP at serine 436 (Ser436) positively regulating YAP activity.	SIGNOR-277569	0.285
TRAF2	protein	Q12933	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates activity	binding			9606									9774977	t		lperfetto	Traf2 is a strong activator of ask1	SIGNOR-60747	0.727
UBE2V1	protein	Q13404	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								11057907	t		lperfetto	We find that traf6, a ring domain protein, functions together with ubc13/uev1a to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (k63) of ubiquitin	SIGNOR-83603	0.687
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser692	GQLMSQPsTASNSLP	9606									10195894	t			Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.	SIGNOR-251280	0.2
PTPN11	protein	Q06124	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates	dephosphorylation	Tyr896	EPKSPGEyVNIEFGS	9606									7515062	t		gcesareni	The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling.	SIGNOR-27028	0.893
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide	chemical	CHEBI:125619	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9550290	t		miannu	Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists.	SIGNOR-258887	0.8
JAK2	protein	O60674	UNIPROT	EPOR	protein	P19235	UNIPROT	up-regulates activity	phosphorylation	Tyr489	DGPYSNPyENSLIPA										12441334	t			JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2	SIGNOR-251354	0.806
PRKD1	protein	Q15139	UNIPROT	CTTN	protein	Q14247	UNIPROT	down-regulates	phosphorylation	Ser298	EKLAKHEsQQDYSKG	9606									20363754	t		lperfetto	Pkd phosphorylates cortactin in vitro and in vivo at serine 298 thereby generating a 14-3-3 binding motif. In vitro, a phosphorylation-deficient cortactin-s298a protein accelerated vca-arp-cortactin-mediated synergistic actin polymerization and showed reduced f-actin binding	SIGNOR-164756	0.433
JAK1	protein	P23458	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	10090									26260587	t		lperfetto	IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes.	SIGNOR-249546	0.793
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	CSF2RA/CSF2RB	complex	SIGNOR-C212	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0005248								8758906	t		irozzo	We demonstrated that Bcr-Abl co-immunoprecipitates with, and constitutively phosphorylates, the common βc,subunit of the interleukin 3 and granulocyte/macrophage-colony stimulating factor receptors.We demonstrate that Bcr-Abl interacts with the common βc subunit of the IL-3 family of receptors and phosphorylates it on tyrosine.	SIGNOR-255999	0.2
IRAK4	protein	Q9NWZ3	UNIPROT	PELI2	protein	Q9HAT8	UNIPROT	up-regulates	phosphorylation			9606									12860405	t		gcesareni	Pellino2 is one of the firstsubstrates identified for irak1 andirak4.	SIGNOR-103717	0.622
CCL2	protein	P13500	UNIPROT	CCR4	protein	P51679	UNIPROT	up-regulates activity	binding			9606									17160712	t		gcesareni	CCR2 and CCR4 are two cell surface receptors that bind CCL2	SIGNOR-237555	0.479
nilutamide	chemical	CHEBI:7573	ChEBI	AR	protein	P10275	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194649	0.8
MAP2K2	protein	P36507	UNIPROT	MAPK3	protein	P27361	UNIPROT	up-regulates	phosphorylation	Tyr204	HTGFLTEyVATRWYR	9606		BTO:0000142							1411546	t		gcesareni	The primary structure of mek, a protein kinase that phosphorylates the erk gene product	SIGNOR-19244	0.73
TYK2	protein	P29597	UNIPROT	ISGF3 complex	complex	SIGNOR-C124	SIGNOR	up-regulates activity	phosphorylation			9606									15120645	t		miannu	Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48).	SIGNOR-260148	0.72
PRKAA1	protein	Q13131	UNIPROT	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser466	PVRMRRNsFTPLSSS	9606		BTO:0000562	SIGNOR-C15						11069105	t		gcesareni	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-84061	0.452
NONO	protein	Q15233	UNIPROT	NONO/SFPQ	complex	SIGNOR-C62	SIGNOR	form complex	binding			9606	BTO:0000017								9756848	t		miannu	We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i	SIGNOR-60475	0.695
TRIO	protein	O75962	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260579	0.678
MAP4K1	protein	Q92918	UNIPROT	LCP2	protein	Q13094	UNIPROT	down-regulates activity	phosphorylation	Ser376	PRKQLSESSDDDYDD	9606	BTO:0000661								17353368	t		Barakat	The serine/threonine kinase HPK-1 phosphorylates serine 376 of SLP-76 and induces the interaction with 14-3-3 proteins	SIGNOR-274153	0.769
ATM	protein	Q13315	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates activity	phosphorylation	Ser429	KEESVESsLPLNAIE	9606	BTO:0000007								19816404	t		lperfetto	These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination	SIGNOR-188412	0.747
NUP98	protein	P52948	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262074	0.692
NOG	protein	Q13253	UNIPROT	BMP7	protein	P18075	UNIPROT	down-regulates activity	binding			-1									12478285	t			We report the crystal structure of the antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors.	SIGNOR-256484	0.858
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation			9606									7618106	t		lperfetto	The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation	SIGNOR-252081	0.2
KAT5	protein	Q92993	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								21936881	t		llicata	Tip60 regulates myoblast differentiation by enhancing the transcriptional activity of MyoD via their physical interactions.	SIGNOR-237675	0.372
PRKCB	protein	P05771	UNIPROT	TFEB	protein	P19484	UNIPROT	up-regulates activity	phosphorylation	Ser467	KASSRRSsFSMEEGD	10090	BTO:0000968								23599343	t			This occurs following PKCβ phosphorylation of TFEB on three serine residues located in its last 15 amino acids. This post-translational modification stabilizes and increases the activity of this transcription factor.	SIGNOR-255316	0.337
DUSP7	protein	Q16829	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606	BTO:0000150	BTO:0001253							9788880	t		gcesareni	Pyst2 preferentially dephosphorylates and inactivates p42 map kinase in vitro and in vivo	SIGNOR-60871	0.788
MAPK12	protein	P53778	UNIPROT	NUP62	protein	P37198	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser272	SGTSTTTsTAATATA	9606	BTO:0000007								30401435	t		miannu	We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). 	SIGNOR-277416	0.2
SNX5	protein	Q9Y5X3	UNIPROT	DOCK1	protein	Q14185	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								18596235	t		miannu	SNX5 Is a Novel Binding Partner of the DHR1 Domain of DOCK180. In summary, we found that DOCK180 regulates transport of CI-MPR via SNX5 binding. 	SIGNOR-269441	0.354
PRKDC	protein	P78527	UNIPROT	DCLRE1C	protein	Q96SD1	UNIPROT	up-regulates	phosphorylation	Ser503	NDEITDEsLENFPSS	9606									16874298	t		lperfetto	Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin	SIGNOR-148327	0.687
SIRT1	protein	Q96EB6	UNIPROT	SMAD7	protein	O15105	UNIPROT	down-regulates	deacetylation	Lys70	GKAVRGAkGHHHPHP	9606									17098745	t		gcesareni	Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells.	SIGNOR-150599	0.452
PFDN2	protein	Q9UHV9	UNIPROT	URI1 prefoldin co-chaperone	complex	SIGNOR-C514	SIGNOR	form complex	binding			9606									30484151	t		miannu	In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR96	SIGNOR-270919	0.724
JARID2	protein	Q92833	UNIPROT	MYOG	protein	P15173	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002267								23435416	t		lperfetto	JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells|Addition of Differentiation Media (DM) to human myoblasts was associated with the induction of MYOG, MYOD and MYL1 and a decrease in JARID2 RNA expression|Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3 lysine 27 in the promoter regions of MYOG and MYL1 and that the interaction of JARID2 at these promoters is dependent upon EED, a core component of the Polycomb Repressive Complex 2 (PRC2). Therefore JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS	SIGNOR-249599	0.2
SMARCB1	protein	Q12824	UNIPROT	SMARCA4	protein	P51532	UNIPROT	up-regulates activity	binding			9606									10078207	t		miannu	The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.	SIGNOR-65438	0.942
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	ETV1	protein	P50549	UNIPROT	up-regulates activity	phosphorylation	Ser191	HRFRRQLsEPCNSFP	9606									12213813	t		lperfetto	Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation.	SIGNOR-252768	0.2
DUSP4	protein	Q13115	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Tyr187	HTGFLTEyVATRWYR	10116									7535768	t			Dephosphorylation and Inactivation of ERKs|A single protein kinase, MEK, activates ERK2 by phosphorylating threonine 183 and tyrosine 185	SIGNOR-248718	0.752
Histone H2A	proteinfamily	SIGNOR-PF70	SIGNOR	Nucleosome_H3.1 variant	complex	SIGNOR-C324	SIGNOR	form complex	binding			-1									21812398	t		miannu	The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 	SIGNOR-267756	0.2
KIF2C	protein	Q99661	UNIPROT	Minus-end directed microtubule movement	phenotype	SIGNOR-PH217	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272535	0.7
PRKACA	protein	P17612	UNIPROT	KCNH2	protein	Q12809	UNIPROT	up-regulates	phosphorylation	Ser1137	EGPTRRLsLPGQLGA	9606									10488078	t		lperfetto	Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a)	SIGNOR-70718	0.311
ATM	protein	Q13315	UNIPROT	PPM1G	protein	O15355	UNIPROT	up-regulates activity	phosphorylation	Ser183	GTGEEPGsQGLNGEA	-1									26324325	t			ATM indeed mediated PPM1G phosphorylation at S183, and mutation of this residue (S183A) abrogated detection with the phospho-specific antibody	SIGNOR-255591	0.309
IL1B	protein	P01584	UNIPROT	SCNN1A	protein	P37088	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0005760								15755725	f	Regulation of transcription	miannu	Interleukin-1beta decreases expression of the epithelial sodium channel alpha-subunit in alveolar epithelial cells via a p38 MAPK-dependent signaling pathway.	SIGNOR-251947	0.2
KCNJ11	protein	Q14654	UNIPROT	KATP channel	complex	SIGNOR-C274	SIGNOR	form complex	binding			9606									28842488	t		lperfetto	ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits.	SIGNOR-262055	0.653
PLK1	protein	P53350	UNIPROT	ZMYM2	protein	Q9UBW7	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser303	QKQPGVDsLSPVASL										25855382	t		lperfetto	PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant	SIGNOR-275559	0.386
EDNRA	protein	P25101	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257165	0.421
CDK2	protein	P24941	UNIPROT	MCM4	protein	P33991	UNIPROT	down-regulates activity	phosphorylation	Ser32	RSEDARSsPSQRRRG	9606	BTO:0000567		SIGNOR-C83						12714602	t		lperfetto	We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a.	SIGNOR-100881	0.758
DLX2	protein	Q07687	UNIPROT	MSX2	protein	P35548	UNIPROT	down-regulates activity	binding			10090									9111364	t	2	miannu	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240911	0.4
WWC1	protein	Q8IX03	UNIPROT	STK3	protein	Q13188	UNIPROT	up-regulates activity				9606	BTO:0000007								20159598	f	Hippo pathway	Gianni	These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis.	SIGNOR-261953	0.376
PGD	protein	P52209	UNIPROT	D-ribulose 5-phosphate	smallmolecule	CHEBI:17363	ChEBI	up-regulates quantity	chemical modification			9606									34775382	t		miannu	6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule.	SIGNOR-267061	0.8
ELF1	protein	P32519	UNIPROT	FCER1A	protein	P12319	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000732								11971001	f	 	 	Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1|These up-regulating effects of PU.1 and YY1 with GATA-1 were inhibited by overexpression of Elf-1, indicating that Elf-1 serves as a repressor for the alpha-chain gene expression	SIGNOR-254287	0.2
SRC	protein	P12931	UNIPROT	FXN	protein	Q16595	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr118	EDLADKPyTFEDYDV	9606	BTO:0000007								25948553	t		lperfetto	We found that frataxin can be phosphorylated by Src. Phosphorylation occurs primarily on Y118 and promotes frataxin ubiquitination, a signal for degradation.	SIGNOR-275585	0.2
BUB1	protein	O43683	UNIPROT	MAD1L1	protein	Q9Y6D9	UNIPROT	up-regulates activity	relocalization												11402067	t		lperfetto	Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity	SIGNOR-252017	0.717
SNRNP200	protein	O75643	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270624	0.773
CRHR1	protein	P34998	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding												22869609	t		lperfetto	Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3	SIGNOR-268618	0.432
TP53	protein	P04637	UNIPROT	NR4A3	protein	Q92570	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									30455429	t		miannu	We showed that p53 directly bound the promoter of NR4A3 gene and induced its transcription. p53 transactivates the NR4A3 promoter in H1299 cells. 	SIGNOR-256200	0.268
RNF170	protein	Q96K19	UNIPROT	ITPR1	protein	Q14643	UNIPROT	down-regulates activity	polyubiquitination			9606	BTO:0000567								21610068	t		miannu	In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound.	SIGNOR-271913	0.442
CSF2	protein	P04141	UNIPROT	CSF2RA	protein	P15509	UNIPROT	up-regulates	binding			9606									10572088	t		gcesareni	We have determined the nmr structure of a ligand-binding domain of the granulocyte colony-stimulating factor (g-csf) receptor comparisons between the spectra of the 15n-labelled domain with and without g-csf indicate that the major ligand-recognition site is on the fg loop just upstream of the wsxws sequence.	SIGNOR-72458	0.851
OTUD5	protein	Q96G74	UNIPROT	TRAF3	protein	Q13114	UNIPROT	down-regulates activity	deubiquitination			9606	BTO:0000007								17991829	t		miannu	TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63-linked polyubiquitin chains. DUBA selectively cleaved the lysine-63-linked polyubiquitin chains on TRAF3, resulting in its dissociation from the downstream signaling complex containing TANK-binding kinase 1. 	SIGNOR-265873	0.767
FCAR	protein	P24071	UNIPROT	Cytokine_production	phenotype	SIGNOR-PH166	SIGNOR	up-regulates				9606	BTO:0000130;BTO:0000801;BTO:0000876;BTO:0000399								30766540	f		lperfetto	IgA-mediated immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst and cytokine release are mediated through FcalphaRI (CD89), an IgA-specific receptor that is expressed on monocytes, eosinophils, neutrophils and macrophages	SIGNOR-264860	0.7
NEK2	protein	P51955	UNIPROT	NEK2	protein	P51955	UNIPROT	down-regulates	phosphorylation	Thr179	FAKTFVGtPYYMSPE	9606									17197699	t		gcesareni	Enzymatic activity, inhibited;	SIGNOR-151771	0.2
phosphatidylglycerol(1-)	smallmolecule	CHEBI:60523	ChEBI	CRLS1	protein	Q9UJA2	UNIPROT	up-regulates activity	chemical activation			10090									16678169	t		lperfetto	The mitochondrial phospholipid cardiolipin is synthesized from cytidinediphosphate-diacylglycerol and phosphatidylglycerol, a process catalyzed by the enzyme cardiolipin synthase.	SIGNOR-267029	0.8
ARIH1	protein	Q9Y4X5	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002181								33879767	t		miannu	We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation.	SIGNOR-277553	0.2
PIN4	protein	Q9Y237	UNIPROT	rRNA_transcription	phenotype	SIGNOR-PH145	SIGNOR	up-regulates				9606	BTO:0000567								12860119	f		lperfetto	Par14 is a pre-rRNA processing factor involved in mammalian ribosome biogenesis, Par14 deficiency slowed cell growth (Fig. 3A) and reduced the production of 18 and 28 S rRNAs 	SIGNOR-265755	0.7
TP53	protein	P04637	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates				9606									15073170	f		gcesareni	Rather, p53 expression stimulates the serine/threonine kinase ribosomal s6 kinase 1 (rsk1), which in turn phosphorylates the p65 subunit of nf-kb.	SIGNOR-252816	0.366
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	HDAC4	protein	P56524	UNIPROT	up-regulates activity	phosphorylation			-1									30661366	t		miannu	 In vitro kinase assays have established that Ser584 and Ser265/266 are phosphorylated by protein kinase A (PKA). Overexpression of site-specific HDAC4 mutants (S584A, S265/266A) in HEK 293T cells, followed by HDAC activity assays, revealed the mutants to be less active than the wild-type protein. 	SIGNOR-277424	0.2
CDK1	protein	P06493	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	down-regulates	phosphorylation			9606									8114697	t		lperfetto	P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well	SIGNOR-244847	0.473
NME2	protein	P22392	UNIPROT	KCNN4	protein	O15554	UNIPROT	up-regulates	phosphorylation	His358	FRQVRLKhRKLREQV	9606									17157250	t		lperfetto	Ndpk-b directly binds and activates kca3.1 by phosphorylating histidine 358 in the carboxyl terminus of kca3.1	SIGNOR-151130	0.431
PRKCQ	protein	Q04759	UNIPROT	PKCtheta/Nfix	complex	SIGNOR-C121	SIGNOR	form complex	binding			10090	BTO:0000165								20178747	t		llicata	In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A.	SIGNOR-238019	0.2
PTEN	protein	P60484	UNIPROT	SP1	protein	P08047	UNIPROT	down-regulates activity	dephosphorylation			9606									21603612	t		miannu	Moreover, PTEN downregulates p75NTR expression by decreasing DNA-binding activity of Sp1 .|PTEN dephosphorylates the Sp1 transcription factor , the phosphorylation status of which directly impacts its ability to bind to some DNA promoter regions , .	SIGNOR-277119	0.432
STAT5A	protein	P42229	UNIPROT	FOXP3	protein	Q9BZS1	UNIPROT	up-regulates				9606									18270368	t			We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cell	SIGNOR-254301	0.496
TWIST2	protein	Q8WVJ9	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002590								17487558	f		miannu	 Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells	SIGNOR-255513	0.282
BCKDK	protein	O14874	UNIPROT	BCKDHA	protein	P12694	UNIPROT	down-regulates	phosphorylation	Ser337	TYRIGHHsTSDDSSA	9606		BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000671							3947057	t		gcesareni	Phosphorylation sites and inactivation of branched-chain alpha-ketoacid dehydrogenase isolated from rat heart, bovine kidney, and rabbit liver, kidney, heart, brain, and skeletal muscle.	SIGNOR-25084	0.593
AURKAIP1	protein	Q9NWT8	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261461	0.645
EGFR	protein	P00533	UNIPROT	CALM3	protein	P0DP25	UNIPROT	down-regulates	phosphorylation	Tyr100	FDKDGNGyISAAELR	9606									3415247	t		miannu	Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.	SIGNOR-266335	0.39
EGFR	protein	P00533	UNIPROT	STAT5A	protein	P42229	UNIPROT	up-regulates	binding			9606									16729043	t		gcesareni	We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5.Egf stimulation and subsequent phosphorylation of egfr at tyrosine y978, y998 and y869 would then subsequently lead to recruitment and activation of stat5.	SIGNOR-146852	0.818
LAMC1	protein	P11047	UNIPROT	Laminin-9	complex	SIGNOR-C180	SIGNOR	form complex	binding												10809728	t		lperfetto	Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. 	SIGNOR-253225	0.528
MAGOH	protein	P61326	UNIPROT	Exon junction complex	complex	SIGNOR-C369	SIGNOR	form complex	binding			-1									16923391	t		miannu	 The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. 	SIGNOR-265243	0.95
MAPK1	protein	P28482	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	up-regulates activity	phosphorylation	Ser14	MGAELPSsPLAIEYV	9606	BTO:0000567								11416124	t		lperfetto	These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription.	SIGNOR-108560	0.34
TGFB1	protein	P01137	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252282	0.7
MAPK12	protein	P53778	UNIPROT	SH3BP5	protein	O60239	UNIPROT	unknown	phosphorylation	Ser351	PGSLDLPsPVSLSEF	-1									15158451	t		miannu	 Activated SAPK3 phosphorylates the mitochondrial protein Sab. we have identified serine 321 as the major site of phosphorylation by both SAPK3 and JNK2. SAPK3 but not JNK2 also phosphorylates serine 391	SIGNOR-250140	0.454
PPP2CA	protein	P67775	UNIPROT	TRAF2	protein	Q12933	UNIPROT	down-regulates activity	dephosphorylation	Thr117	DGCTWKGtLKEYESC	10090									17188031	t			We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity. 	SIGNOR-248640	0.2
MARK2	protein	Q7KZI7	UNIPROT	PARD3	protein	Q8TEW0	UNIPROT	up-regulates	phosphorylation	Ser873	VDDQKAGsPSRDVGP	9606									22883624	t		gcesareni	Gab1 brings par1 and par3 into a transient complex, stimulating par3 phosphorylation by par1	SIGNOR-198742	0.508
CyclinE/CDK2	complex	SIGNOR-C16	SIGNOR	SIRT2	protein	Q8IXJ6	UNIPROT	down-regulates	phosphorylation	Ser368	PNPSTSAsPKKSPPP	9606	BTO:0000938								18332217	t		lperfetto	We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2.	SIGNOR-216725	0.404
AKT1	protein	P31749	UNIPROT	FOXO1	protein	Q12778	UNIPROT	down-regulates	phosphorylation			9606									21798082	t		lperfetto	Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the FoxO family, and stimulates protein synthesis via the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3b (GSK3B).	SIGNOR-175285	0.866
TNFRSF17	protein	Q02223	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates				9606									10903733	f		miannu	Overexpression of bcma activates jnk	SIGNOR-79492	0.2
CDK2	protein	P24941	UNIPROT	HIRA	protein	P54198	UNIPROT	up-regulates activity	phosphorylation	Thr555	LSPSVLTtPSKIEPM	9606		BTO:0001938	SIGNOR-C16						11238922	t		lperfetto	Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle.	SIGNOR-105548	0.331
ROCK1	protein	Q13464	UNIPROT	DES	protein	P17661	UNIPROT	down-regulates	phosphorylation	Thr17	RVSSYRRtFGGAPGF	-1									12686604	t		lperfetto	The sites phosphorylated by Aurora-B; Thr-7/Ser-13/Ser-38 of GFAP, and Thr-16 of desmin are common with those related to Rho-associated kinase (Rho-kinase), which has been reported to phosphorylate GFAP and desmin at cleavage furrow during cytokinesis. Rho-kinase was found to phosphorylate desmin at Thr-16, Thr-75, and Thr-76	SIGNOR-100177	0.321
CSNK2A1	protein	P68400	UNIPROT	TNFAIP1	protein	Q13829	UNIPROT	up-regulates	phosphorylation	Ser280	SRSQASPsEDEETFE	9606	BTO:0000567								19851886	t		lperfetto	It was demonstrated that ck2 could phosphorylate tnfaip1 in vitro and in vivo, which facilitated the distribution of tnfaip1 in nucleus and enhanced its interaction with pcna. It is suggested that the phosphorylation of tnfaip1 may be required for its functions.	SIGNOR-188849	0.2
BTG2	protein	P78543	UNIPROT	SOD2	protein	P04179	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								22493435	f		miannu	BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2	SIGNOR-254649	0.378
iodide	smallmolecule	CHEBI:16382	ChEBI	diiodine	smallmolecule	CHEBI:17606	ChEBI	up-regulates quantity	precursor of			9606									23349248	t		miannu	After transport through the apical membrane, I‚àí is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO).	SIGNOR-268119	0.8
NFIB	protein	O00712	UNIPROT	EPHA5	protein	P54756	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268902	0.2
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2V1	protein	Q13404	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271355	0.442
CASP1	protein	P29466	UNIPROT	NLRC4 inflammasome	complex	SIGNOR-C223	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256402	0.704
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Ser33	QQQSYLDsGIHSGAT	9606		BTO:0000586							16293724	t		lperfetto	This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway.	SIGNOR-227885	0.892
ALDH9A1	protein	P49189	UNIPROT	4-(trimethylammonio)butanoate	smallmolecule	CHEBI:16244	ChEBI	up-regulates quantity	chemical modification			9606									11802770	t		miannu	Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). 	SIGNOR-269693	0.8
SRC	protein	P12931	UNIPROT	PXN	protein	P49023	UNIPROT	up-regulates activity	phosphorylation	Tyr88	PQSSSPVyGSSAKTS	9606	BTO:0000182								27447856	t		lperfetto	Here, we demonstrate that Src kinase directly phosphorylates Y88 paxillin|In this study, we also show how pY88 paxillin transduces a signal to activate Akt	SIGNOR-263977	0.801
BMPR1B	protein	O00238	UNIPROT	SMAD1/5/8	proteinfamily	SIGNOR-PF35	SIGNOR	up-regulates	phosphorylation			9606									9335504	t	inferred from 70% of family members	llicata	The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1.	SIGNOR-269846	0.698
GRPEL1	protein	Q9HAV7	UNIPROT	TIM23 complex	complex	SIGNOR-C423	SIGNOR	form complex	binding												32074073	t		lperfetto	The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE.	SIGNOR-267691	0.595
SETD5	protein	Q9C0A6	UNIPROT	Epigenetic_regulation	phenotype	SIGNOR-PH203	SIGNOR	up-regulates				9606									32299058	f			The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression	SIGNOR-268627	0.7
GSK3B	protein	P49841	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr266	ARHLQENtQSHMRML	9606	BTO:0002181								30806153	t		miannu	TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling.	SIGNOR-277438	0.49
PAX7	protein	P23759	UNIPROT	KMT2D	protein	O14686	UNIPROT	up-regulates	binding			9606				SIGNOR-C88					22863532	t		miannu	Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5.	SIGNOR-198629	0.31
GAK	protein	O14976	UNIPROT	CLTC	protein	Q00610	UNIPROT	up-regulates activity	phosphorylation	Thr606	ILGNQMFtHYDRAHI	10090									31272276	t		miannu	Clathrin heavy chain (CHC) was phosphorylated at T606 by its association partner cyclin G-associated kinase (GAK). This phosphorylation was required for proper cell proliferation and tumor growth of cells implanted into nude mice. 	SIGNOR-275448	0.852
SHC1	protein	P29353	UNIPROT	GRAP	protein	Q13588	UNIPROT	up-regulates	binding			9606	BTO:0000782								8995379	t		gcesareni	T cell activation effects an increase in grap association with p36/38, shc, sos, and dynamin.	SIGNOR-45528	0.52
ZM447439	chemical	CHEBI:91376	ChEBI	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207920	0.8
PPAT	protein	Q06203	UNIPROT	Purine biosynthesis	phenotype	SIGNOR-PH186	SIGNOR	up-regulates activity				9606									28029518	f			The first reaction in the de novo purine biosynthetic pathway is the conversion of PRPP to 5-phosphoribosylamine (PRA) by PRPP amidotransferase (PPAT) and is presumed to be rate-limiting.	SIGNOR-267188	0.7
oxybutynin	chemical	CHEBI:7856	ChEBI	CHRM1	protein	P11229	UNIPROT	down-regulates activity	chemical inhibition			10030	BTO:0000246								22243489	t		Luana	 Compared to the reference compound oxybutynin, an antagonist used for the treatment of OAB,(5) the newly synthesized 1,4-dioxane derivatives exhibit a higher potency.	SIGNOR-258328	0.8
L-homocysteine zwitterion	smallmolecule	CHEBI:58199	ChEBI	L-cystathionine dizwitterion	smallmolecule	CHEBI:58161	ChEBI	up-regulates quantity	precursor of			9606									23981774	t		lperfetto	Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. 	SIGNOR-275826	0.8
MYC	protein	P01106	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									9552384	f		gcesareni	C-myc has emerged as one of the central regulators of mammalian cell proliferation.	SIGNOR-56572	0.7
MCM6	protein	Q14566	UNIPROT	MCM	complex	SIGNOR-C268	SIGNOR	form complex	binding			9606									19946136	t			The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication.	SIGNOR-261676	0.769
SNAI1	protein	O95863	UNIPROT	Epithelial-mesenchymal_transition	phenotype	SIGNOR-PH45	SIGNOR	up-regulates				9606	BTO:0000567								29305973	f		miannu	Our findings show that Snai1 mediates repression of PXDN and consolidate a role for this ECM-modifier during EMT.	SIGNOR-265252	0.7
VHL	protein	P40337	UNIPROT	SPARC	protein	P09486	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000037								15824735	f		miannu	 three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL. 	SIGNOR-255603	0.2
NUP62	protein	P37198	UNIPROT	 p62_complex	complex	SIGNOR-C259	SIGNOR	form complex	binding			10116	BTO:0000154								2050741	t		Simone	Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function.	SIGNOR-261258	0.938
CD74	protein	P04233	UNIPROT	CXCR4	protein	P61073	UNIPROT	up-regulates	binding			9606	BTO:0000007;BTO:0000876								19665027	t		miannu	Cd74 forms functional complexes with cxcr4 that mediate mif-specific signaling.	SIGNOR-187461	0.547
ITGB7	protein	P26010	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257726	0.548
PRKCA	protein	P17252	UNIPROT	DNM1	protein	Q05193	UNIPROT	unknown	phosphorylation	Ser795	VPPARPGsRGPAPGP	-1									10766777	t		lperfetto	Phosphorylation of dynamin I on Ser-795 by protein kinase C blocks its association with phospholipids.	SIGNOR-249039	0.339
IGF1R	protein	P08069	UNIPROT	PDPK1	protein	O15530	UNIPROT	up-regulates	phosphorylation	Tyr376	DEDCYGNyDNLLSQF	9606									20643654	t		lperfetto	Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376, and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376	SIGNOR-166714	0.348
RORA	protein	P35398	UNIPROT	ITPR1	protein	Q14643	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001011								19381306	t		miannu	RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. 	SIGNOR-266847	0.245
S1PR1	protein	P21453	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256713	0.482
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	LIMA1	protein	Q9UHB6	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser604	FQSTSVKsPKTVSPP	9606	BTO:0001033								23188829	t		miannu	Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover.	SIGNOR-263063	0.2
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	BRCA1	protein	P38398	UNIPROT	down-regulates quantity by destabilization	cleavage	Asp1155	ETPDDLLdDGEIKED	9606									12149654	t		miannu	We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable.	SIGNOR-256432	0.486
PIM1	protein	P11309	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser146	GRKRRQTsMTDFYHS	9606									31575057	t		gcesareni	Pim-1, PKC, and Akt1 kinases phosphorylate Thr-145 and Ser-146 sites on p21 protein. Phosphorylation at Thr-145 promotes cytoplasmic translocation and stability of p21. Ser-146 phosphorylation mediated by Akt1 enhances p21 stabilization and promotes cell survival.	SIGNOR-262961	0.494
USP6	protein	P35125	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates				9606									20418905	f		miannu	These data confirm that tre17 activates nfkappab in a usp-dependent manner	SIGNOR-164949	0.2
SYK	protein	P43405	UNIPROT	SYK	protein	P43405	UNIPROT	up-regulates activity	phosphorylation	Tyr352	TEVYESPyADPEEIR	9606									9820500	t		lperfetto	These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520	SIGNOR-246613	0.2
EP300	protein	Q09472	UNIPROT	PLAGL2	protein	Q9UPG8	UNIPROT	up-regulates	acetylation			9606									16207715	t		miannu	Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.	SIGNOR-140947	0.2
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGC3	protein	Q9UN70	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265696	0.2
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									11689553	t		irozzo	To identify this pathway, we analyzed TGF-β-responsive elements in the human c-myc promoter and found that Smad proteins directly bound to an element in the c-myc promoter and suppressed c-myc promoter activity.	SIGNOR-256290	0.65
GATOR1	complex	SIGNOR-C192	SIGNOR	RRAGA	protein	Q7L523	UNIPROT	down-regulates activity	gtpase-activating protein			-1									23723238	t			GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer.	SIGNOR-253562	0.874
ATM	protein	Q13315	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates	phosphorylation	Ser112	KRAGGEEsQFEMDI	9606									11146653	t		lperfetto	Here we report that atm... phosphorylates 4e-bp1 at ser 111cells lacking atm kinase activity exhibit a significant decrease in the insulin-induced dissociation of 4e-bp1 from eif-4e.	SIGNOR-85619	0.528
CDK2	protein	P24941	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	phosphorylation	Ser266	QYLGSIAsPSVHPAT	9606									16046550	t	The effect has been demonstrated using Q01196-8	gcesareni	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-138932	0.2
CDK2	protein	P24941	UNIPROT	RBBP8	protein	Q99708	UNIPROT	up-regulates	phosphorylation	Thr847	FRYIPPNtPENFWEV	9606									19202191	t		llicata	Collectively, these findings thereby provided strong support for ctip thr-847 indeed being a cdk target. it is established that both cdk-dependent and checkpoint-dependent phosphorylations are required for activation of sae2/ctip in vivo	SIGNOR-183840	0.603
SIK1	protein	P57059	UNIPROT	CRTC1	protein	Q6UUV9	UNIPROT	down-regulates	phosphorylation	Ser167	MTPTQPEsFSSGSQD	9606									16817901	t		miannu	These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities.	SIGNOR-147669	0.509
CENP-A nucleosome	complex	SIGNOR-C321	SIGNOR	Chromatine_condensation	phenotype	SIGNOR-PH21	SIGNOR	up-regulates				9606	BTO:0000567								20566683	f		miannu	Centromeres contain specialized nucleosomes in which histone H3 is replaced by the histone variant centromere protein A (CENP-A). CENP-A nucleosomes are thought to act as an epigenetic mark that specifies centromere identity.	SIGNOR-263703	0.7
somatostatin	smallmolecule	CHEBI:64628	ChEBI	SSTR2	protein	P30874	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257582	0.8
SMAD3	protein	P84022	UNIPROT	FOXP3	protein	Q9BZS1	UNIPROT	up-regulates				9606									19701891	t			TGF-beta1-activated Smad3 plays a major role in the expression of Foxp3, since TGF-beta1-induced-Treg generation from Smad3(-/-) mice is markedly reduced and abolished by inactivating Smad2	SIGNOR-254362	0.54
CLOCK	protein	O15516	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21164265	t	 	lperfetto	We recently reported that the basic helix-loop- helix transcription factor Clock, which is a histone acetyltransferase and a central component of the self-oscillating transcription factor loop that generates circadian rhythms, represses GR transcriptional activity by acetylating lysine residues within the 'lysine cluster' located in the hinge region of the receptor. This Clock-mediated repression of GR transcriptional activity oscillates in inverse phase to the HPA axis, acting as a target tissue counter-regulatory mechanism to the diurnally fluctuating circulating glucocorticoids.	SIGNOR-253699	0.42
SLC20A2	protein	Q08357	UNIPROT	phosphate(3-)	smallmolecule	CHEBI:18367	ChEBI	up-regulates quantity	relocalization			9606									11009570	t		lperfetto		SIGNOR-270580	0.8
KIT	protein	P10721	UNIPROT	SRC_kinase_family	proteinfamily	SIGNOR-PF32	SIGNOR	up-regulates	phosphorylation			9606									15526160	t		apalma	Binding of SCF to c-Kit leads to a rapid increase in SFK kinase activity	SIGNOR-254995	0.576
IL2	protein	P60568	UNIPROT	IL2RA	protein	P01589	UNIPROT	up-regulates	binding			9606									16477002	t		miannu	Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c).	SIGNOR-144537	0.925
PPP3CC	protein	P48454	UNIPROT	PPP1R1A	protein	Q13522	UNIPROT	unknown	dephosphorylation	Ser67	LKSTLAMsPRQRKKM	10116									11278334	t			In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation.	SIGNOR-248524	0.382
entinostat	chemical	CHEBI:132082	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257904	0.8
DIO	proteinfamily	SIGNOR-PF83	SIGNOR	3,3',5'-triiodo-L-thyronine	smallmolecule	CHEBI:11684	ChEBI	up-regulates quantity	small molecule catalysis												20978344	t	inferred from family member		The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4)	SIGNOR-270305	0.8
CRY1	protein	Q16526	UNIPROT	CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	down-regulates activity	binding			9606									20817722	t		miannu	The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop.	SIGNOR-267975	0.937
MTOR	protein	P42345	UNIPROT	ULK1	protein	O75385	UNIPROT	down-regulates activity	phosphorylation			9606			SIGNOR-C3						19690328	t		lperfetto	The complementary inhibitory mechanism in which mtorc1 phosphorylates the autophagy regulatory complex containing unc-51-like kinase 1 (ulk1), the mammalian atg13 protein, and focal adhesion kinase interacting protein of 200 kd (fip200) has also been elucidated.	SIGNOR-187611	0.844
RPS6KA1	protein	Q15418	UNIPROT	Translational_regulation	phenotype	SIGNOR-PH202	SIGNOR	up-regulates				9606									17360704	f		gianni	Mutation of rpS6 at Ser(235/236) reveals that phosphorylation of these sites promotes its recruitment to the 7-methylguanosine cap complex, suggesting that Ras/ERK signaling regulates assembly of the translation preinitiation complex. These data demonstrate that RSK provides an mTOR-independent pathway linking the Ras/ERK signaling cascade to the translational machinery.	SIGNOR-268528	0.7
SLN	protein	O00631	UNIPROT	ATP2A1	protein	O14983	UNIPROT	down-regulates activity	binding			9606									28487373	t		lperfetto	These results suggest that sAnk1 interacts with SLN both directly and in complex with SERCA1 and reduces SLN's inhibitory effect on SERCA1 activity.	SIGNOR-265929	0.568
MTCH1	protein	Q9NZJ7	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									12377771	f		SARA	PSAP is an important regulator of apoptosis	SIGNOR-260994	0.7
Cell-Cell_contact	stimulus	SIGNOR-ST13	SIGNOR	TJP2	protein	Q9UDY2	UNIPROT	up-regulates				9606									21529719	f		milica	Another junction protein, the tight junction protein ZO-2, binds to YAP/TAZ, facilitating their nuclear translocation.	SIGNOR-230703	0.7
2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	chemical	CHEBI:93768	ChEBI	IGF1R	protein	P08069	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192868	0.8
KIF5A	protein	Q12840	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606									31753031	t		miannu	Postsynaptic density protein 95 (PSD-95) is transported by KIF5 to dendritic regions	SIGNOR-264065	0.319
AL/b2 integrin	complex	SIGNOR-C169	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269018	0.7
PRKCB	protein	P05771	UNIPROT	KCNC4	protein	Q03721	UNIPROT	down-regulates	phosphorylation	Ser21	KSGNKPPsKTCLKEE	9606									9649584	t		gcesareni	This study investigated the molecular physiology of the nh2-terminal phosphorylation sites that regulate inactivation gating of an a-type k+ channel. The main results show that: (a) pkc acts on four phosphate acceptors (s8, s9, s15, and s21) within the inactivation domain because mutation of these residues to alanine is necessary and sufficient to remove the action of pkc on channel inactivation.	SIGNOR-58502	0.2
GSK3A	protein	P49840	UNIPROT	EIF2B5	protein	Q13144	UNIPROT	down-regulates activity	phosphorylation	Ser540	MDSEEPDsRGGSPQM	9606	BTO:0000007								11500362	t			We identify multiple phosphorylation sites in the largest, catalytic, subunit (epsilon) of mammalian eIF2B. Glycogen synthase kinase 3 (GSK3) is responsible for phosphorylating Ser535. This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo. eIF2Bϵ from mammals or insects is a substrate for glycogen synthase kinase 3 (GSK3), and this inhibits the activity of eIF2B 	SIGNOR-251215	0.375
KLF1	protein	Q13351	UNIPROT	HBB	protein	P68871	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002731								9707565	f	Regulation	miannu	EKLF is an acetylated transcription factor, and that it interacts in vivo with CBP, p300, and P/CAF. However, its interactions with these histone acetyltransferases are not equivalent, as CBP and p300, but not P/CAF, utilize EKLF as a substrate for in vitro acetylation within its trans-activation region. The functional effects of these interactions are that CBP and p300, but not P/CAF, enhance EKLF's transcriptional activation of the beta-globin promoter in erythroid cells.	SIGNOR-251790	0.415
FOXJ1	protein	Q92949	UNIPROT	TUBA1A	protein	Q71U36	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000939								23822649	t		miannu	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266938	0.303
NMDA receptor_2A	complex	SIGNOR-C347	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									30037851	t		miannu	NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS). 	SIGNOR-264218	0.8
PDK2	protein	Q15119	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates	phosphorylation	Ser232	NRYGMGTsVERAAAS	-1									7782287	t		gcesareni	Sites 1, 2, and 3 in the E1 mutants were phosphorylated either individually or in the presence of the other sites by the dihydrolipoamide acetyltransferase-protein X-E1 kinase indicating a site-independent mechanism of phosphorylation.	SIGNOR-33040	0.667
PASK	protein	Q96RG2	UNIPROT	GYS1	protein	P13807	UNIPROT	down-regulates activity	phosphorylation			-1									16275910	t		gcesareni	Recombinant human PASK (hPASK) phosphorylates purified muscle glycogen synthase, causing robust inactivation. Furthermore, hPASK interacts directly with glycogen synthase when expressed in cultured cells and this interaction and the phosphorylation of glycogen synthase by human PASK (hPASK) are inhibited by glycogen.	SIGNOR-245866	0.523
MAPK8IP3	protein	Q9UPT6	UNIPROT	MAP3K11	protein	Q16584	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000142							10629060	t		gcesareni	These data demonstrate that jip3 interacts with proteins that can form a mapk signaling module, including jnk, mkk7, and mlk3jip3 increases mlk3-stimulated jnk activity.	SIGNOR-73909	0.536
SMO	protein	Q99835	UNIPROT	GNAT1	protein	P11488	UNIPROT	up-regulates	binding			9606									16885213	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-148496	0.264
NCOA6	protein	Q14686	UNIPROT	GREB1	protein	Q4ZG55	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003041								31744881	t		miannu	 Herein, using growth-regulating estrogen receptor binding 1 (GREB1) as an ERα target gene in Ishikawa cells, we demonstrate that nuclear receptor co-activator 6 (NCOA6) is essential for estradiol (E2)/ERα-activated GREB1 transcription. We found that NCOA6 associates with the GREB1 promoter and enhancer in an E2-independent manner and that NCOA6 knockout reduces chromatin looping, enhancer-promoter interactions, and basal GREB1 expression in the absence of E2. 	SIGNOR-265883	0.2
KLF2	protein	Q9Y5W3	UNIPROT	NPNT	protein	Q6UXI9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0005787	BTO:0001103							23612709	f		miannu	The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 	SIGNOR-255456	0.268
ADNP	protein	Q9H2P0	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								32533114	t		miannu	Here, we show that ADNP is required for neural induction and differentiation by enhancing Wnt signaling. Mechanistically, ADNP functions to stabilize β-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC. 	SIGNOR-266756	0.252
AT9283	chemical	CID:11696609	PUBCHEM	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190014	0.8
CSNK2A1	protein	P68400	UNIPROT	MDC1	protein	Q14676	UNIPROT	up-regulates	phosphorylation	Thr301	PPGEDSDtDVDDDSR	9606									18678890	t		gcesareni	The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites.	SIGNOR-179883	0.353
1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	PRKCI	protein	P41743	UNIPROT	up-regulates activity	binding			9606									14967450	t	PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine.	lperfetto	The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified.	SIGNOR-242581	0.8
FGF9	protein	P31371	UNIPROT	TGFB1	protein	P01137	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15780951	f	FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1	gcesareni	Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts	SIGNOR-134797	0.313
MAPK3	protein	P27361	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates activity	phosphorylation	Thr453	SGPIIIRtPTVGPNG	9606									14744793	t		lperfetto	Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.|this activation promotes the phosphorylation of Sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased Sp1 binding and enhanced p21(waf1/cip1) transcription. 	SIGNOR-249480	0.638
MAML1	protein	Q92585	UNIPROT	CCNC	protein	P24863	UNIPROT	up-regulates	relocalization			9606									15546612	t		gcesareni	Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells.	SIGNOR-130709	0.423
PRKACB	protein	P22694	UNIPROT	GPKOW	protein	Q92917	UNIPROT	up-regulates activity	phosphorylation	Ser27	SFGFTRTsARRRLAD										21880142	t		miannu	Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2. PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites.	SIGNOR-266299	0.311
STUB1	protein	Q9UNE7	UNIPROT	IRS4	protein	O14654	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002181								30026872	t		miannu	IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP).	SIGNOR-277616	0.2
chlorphenamine	chemical	CHEBI:52010	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002126								18446005	t		Luana	We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells	SIGNOR-257786	0.8
TP53	protein	P04637	UNIPROT	FNTA	protein	P49354	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26469958	f		lperfetto	In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3'-hydroxy-3'-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs.	SIGNOR-242408	0.2
CDK7	protein	P50613	UNIPROT	PCGF6	protein	Q9BYE7	UNIPROT	unknown	phosphorylation	Ser30	LPPPPPVsPPALTPA	-1									12167161	t		llicata	In addition, we find that serine 32 of MBLR is specifically phosphorylated during mitosis, most likely by CDK7, a component of the basal transcriptional machinery. | These results indicate that, at least in vitro, MBLR is a substrate for CDK7 phosphorylation.	SIGNOR-250769	0.309
KLF6	protein	Q99612	UNIPROT	ATF3	protein	P18847	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0001321								18755691	t		Luana	KLF6 binds directly to and activates the ATF3 promoter.	SIGNOR-266051	0.403
MAPK3	protein	P27361	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser422	LSTPVVLsPGPQKP	9606									7889942	t		gcesareni	Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-34665	0.582
PRKCQ	protein	Q04759	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser1101	GCRRRHSsETFSSTP	10090									15364919	t		Manara	Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101).	SIGNOR-260906	0.552
NFE2L2	protein	Q16236	UNIPROT	GCLC	protein	P48506	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24024136	t		irozzo	In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).	SIGNOR-256277	0.485
MAPK1	protein	P28482	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Thr331	CTPVVTCtPSCTAYT	9606									12972619	t		lperfetto	We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2.	SIGNOR-236014	0.784
MTOR	protein	P42345	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Ser83	PTIPGVTsPSSDEPP	9606									9204908	t		miannu	MTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E.	SIGNOR-250292	0.924
PRKCA	protein	P17252	UNIPROT	MBD4	protein	O95243	UNIPROT	up-regulates activity	phosphorylation	Ser165	CSMAALTsHLQNQSN										23195996	t		lperfetto	 Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12]	SIGNOR-275673	0.2
KDM4C	protein	Q9H3R0	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	demethylation			9606									29207681	t		miannu	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation	SIGNOR-265333	0.2
CCND1	protein	P24385	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates activity				9606									15713663	f		areggio	Collectively, these studies suggest an important role of cyclin D1 in regulation of PPARgamma-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPARgamma function.	SIGNOR-258981	0.7
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates	ubiquitination			9606									10023660	t		lperfetto	These results indicate that the cul1/skp1/beta-trcp complex forms a ubiquitin ligase that mediates the degradation of beta-catenin.	SIGNOR-217181	0.717
GATA1	protein	P15976	UNIPROT	GP6	protein	Q9HCN6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12359731	f	 	miannu	 Deletion analyses and site-directed mutagenesis identified Sp1(227), GATA(177), and Ets(48) sites as essential for GPVI expression. We show that transcription factors GATA-1, Fli-1, and Sp1 can bind to and activate this promoter.	SIGNOR-254158	0.286
NEDD4L	protein	Q96PU5	UNIPROT	CLCN5	protein	P51795	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9267	BTO:0003069								15489223	t		miannu	The presence of albumin triggers the formation of an endocytic complex that includes ClC-5. (iii) Nedd4-2 is recruited to this complex and ubiquitinates ClC-5. This ubiquitination by Nedd4-2 shunts ClC-5 into the albumin uptake/degradative pathway.	SIGNOR-272665	0.297
MAPK1	protein	P28482	UNIPROT	TPR	protein	P12270	UNIPROT	up-regulates	phosphorylation	Ser2155	GFAEAIHsPQVAGVP	9606									18794356	t		miannu	Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore.	SIGNOR-181014	0.382
INS	protein	P01308	UNIPROT	TRIP10	protein	Q15642	UNIPROT	up-regulates				9606									12242347	f		gcesareni	The specific interaction of active tc10 with cip4 2 suggested thatinsulinmight induce a change in the subcellular localization of cip4 2	SIGNOR-93062	0.27
PKLR	protein	P30613	UNIPROT	pyruvate	smallmolecule	CHEBI:15361	ChEBI	up-regulates quantity	chemical modification			9606									15996096	t		miannu	Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A).	SIGNOR-266537	0.8
HIPK2	protein	Q9H2X6	UNIPROT	CTBP1	protein	Q13363	UNIPROT	down-regulates	phosphorylation	Ser422	AHPPHAPsPGQTVKP	9606	BTO:0002552								15708980	t		lperfetto	Homeodomain-interacting protein kinase-2 mediates ctbp phosphorylation and degradation in uv-triggered apoptosishipk2 phosphorylates ctbp at ser-422	SIGNOR-134040	0.484
HBEGF	protein	Q99075	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606									10209155	t		gcesareni	It was concluded that her4 is a newly described receptor for hb-egf and that hb-egf can activate two egf receptor subtypes, her1 and her4, but with different biological response.	SIGNOR-67009	0.741
MAPK1	protein	P28482	UNIPROT	TSC1	protein	Q92574	UNIPROT	down-regulates	phosphorylation			9606									15851026	t		gcesareni	Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin.	SIGNOR-135692	0.469
CAMK2A	protein	Q9UQM7	UNIPROT	RIMS1	protein	Q86UR5	UNIPROT	up-regulates	phosphorylation	Ser242	PSAPPDRsKGAEPSQ	9606	BTO:0000938	BTO:0000142							12871946	t		gcesareni	Two serine residues in rim1 (ser-241 and ser-287) and one serine residue in rim2 (ser-335) were required for 14-3-3 binding. Incubation with ca2+/calmodulin-dependent protein kinase ii greatly stimulated the interaction of recombinant n-terminal rim but not the s241/287a mutant with 14-3-3,	SIGNOR-103886	0.353
MAPK1	protein	P28482	UNIPROT	NR3C2	protein	P08235	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser238	QGTPLTCsPNVENRG	9606	BTO:0005043								22798426	t		miannu	 Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276101	0.291
STING1	protein	Q86WV6	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	up-regulates activity	binding			9606									24622840	t		miannu	MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. 	SIGNOR-260153	0.2
diazepam	chemical	CHEBI:49575	ChEBI	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	up-regulates activity	chemical activation			9606		BTO:0000227							18790874	t	brain	lperfetto	The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5. 	SIGNOR-263796	0.8
GSK3B	protein	P49841	UNIPROT	PRKCE	protein	Q02156	UNIPROT	up-regulates	phosphorylation	Ser346	SEEDRSKsAPTSPCD	9606									18604201	t		llicata	Specifically, we have identified three phosphorylation sites within pkcepsilon that control its association with 14-3-3.kinase (ser 350), gsk3 (ser 346) and pkc itself (ser 368)	SIGNOR-179412	0.271
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257928	0.8
STOML2	protein	Q9UJZ1	UNIPROT	PLCG1	protein	P19174	UNIPROT	up-regulates activity	binding			9606									18641330	t		Giorgia	In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling.	SIGNOR-260378	0.2
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	NCOA1	protein	Q15788	UNIPROT	up-regulates	phosphorylation			9606	BTO:0001130								12163482	t	inferred from 70% family members	lperfetto	Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein	SIGNOR-270099	0.2
SFRP1	protein	Q8N474	UNIPROT	WNT1	protein	P04628	UNIPROT	down-regulates	binding			9606									10523516	t		gcesareni	Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling.	SIGNOR-71423	0.776
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SPHK1	protein	Q9NYA1	UNIPROT	up-regulates	phosphorylation	Ser225	VGSKTPAsPVVVQQG	9606									14532121	t		gcesareni	Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation.	SIGNOR-118542	0.2
SLC27A6	protein	Q9Y2P4	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264467	0.7
PRKCB	protein	P05771	UNIPROT	KCNC4	protein	Q03721	UNIPROT	down-regulates	phosphorylation	Ser21	KSGNKPPsKTCLKEE	9606									7993631	t		gcesareni	We found that pkc specifically eliminates rapid inactivation of a cloned human a-type k+ channel (hkv3.4), converting this channel from a rapidly inactivating a type to a noninactivating delayed rectifier type.	SIGNOR-35626	0.2
CBL	protein	P22681	UNIPROT	FLT3	protein	P36888	UNIPROT	down-regulates activity	binding			10090	BTO:0001516								19276253	t			Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo.	SIGNOR-255739	0.447
mTORC1	complex	SIGNOR-C3	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606		BTO:0000007							20508131	f			The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size.	SIGNOR-256063	0.7
prostaglandin E2	smallmolecule	CHEBI:15551	ChEBI	PTGER3	protein	P43115	UNIPROT	up-regulates	chemical activation			9606									15299086	t		gcesareni	Pge2 is the ligand for four ep receptor subtypes termed ep1 to ep4.	SIGNOR-127738	0.8
CDK2	protein	P24941	UNIPROT	DLG1	protein	Q12959	UNIPROT	up-regulates	phosphorylation	Ser158	FVSHSHIsPIKPTEA	9606									19066288	t		llicata	We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. phosphorylation on ser158 and ser442 enhances nuclear expression of dlg1	SIGNOR-182761	0.286
MDH2	protein	P40926	UNIPROT	NAD(1-)	smallmolecule	CHEBI:57540	ChEBI	down-regulates quantity	chemical modification			9606									24068518	t		miannu	Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle	SIGNOR-268100	0.8
ATP13A1	protein	Q9HD20	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0004093								29650961	f	doi.org/10.1101/185272	francesca	Loss of ATP13A3 led to marked inhibition of serum-stimulated proliferation of BOECs, and increased apoptosis in serum-deprived conditions	SIGNOR-261216	0.7
GAPDHS	protein	O14556	UNIPROT	3-phosphonato-D-glyceroyl phosphate(4-)	smallmolecule	CHEBI:57604	ChEBI	up-regulates quantity	chemical modification			9606									11724794	t		miannu	GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion	SIGNOR-266497	0.8
NTN1	protein	O95631	UNIPROT	NEO1	protein	Q92859	UNIPROT	up-regulates activity	binding			9606		BTO:0001484							28245592	t		miannu	Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins.	SIGNOR-268169	0.819
PRKCA	protein	P17252	UNIPROT	HRH1	protein	P35367	UNIPROT	down-regulates	phosphorylation	Ser398	WKRLRSHsRQYVSGL	9606		BTO:0000975							10101032	t	Translocation from Endosome to Lysosome	fspada	In this study, we demonstrated that ser396 and ser398 are phosphorylated by pkc and, that phosphorylation of ser398 is particularly involved in pmainduced desensitization of the h1r.	SIGNOR-66015	0.2
MAPK3	protein	P27361	UNIPROT	GRB10	protein	Q13322	UNIPROT	unknown	phosphorylation	Ser418	QQRKALLsPFSTPVR	-1									15952796	t		lperfetto	We identified Ser150, Ser418, and Ser476 of human Grb10 as MAPK-mediated in vitro phosphorylation sites.	SIGNOR-249406	0.304
PRKCA	protein	P17252	UNIPROT	NR1H4	protein	Q96RI1	UNIPROT	up-regulates	phosphorylation	Ser164	CKGFFRRsITKNAVY	9606									18755856	t		llicata	Phosphorylation of farnesoid x receptor by protein kinase c promotes its transcriptional activity. pkcalpha phosphorylates in vitro fxr in its dna-binding domain on s135 and s154.	SIGNOR-180541	0.332
FOXQ1	protein	Q9C009	UNIPROT	MYLK	protein	Q15746	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0002196								10896677	t		Luana	Results from this analysis revealed that the inhibitory activity of HFH-1 was contained within the forkhead DNA-binding domain. Truncated HFH-1 proteins that lack the entire forkhead domain were unable to repress telokin promoter activity, in contrast expression of the forkhead domain alone was able to repress promoter activity	SIGNOR-261609	0.2
GRIK3	protein	Q13003	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial.	SIGNOR-264944	0.8
TP53	protein	P04637	UNIPROT	PMS2	protein	P54278	UNIPROT	up-regulates quantity	transcriptional regulation			9606									15781865	t			.... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron.	SIGNOR-257604	0.566
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation			9606									19282669	t	inferred from 70% family members	lperfetto	Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway	SIGNOR-270020	0.2
MARK1	protein	Q9P0L2	UNIPROT	MAP2	protein	P11137	UNIPROT	down-regulates activity	phosphorylation	Ser1795	VASPRRLsNVSSSGS	-1									8631898	t		miannu	Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 	SIGNOR-250166	0.428
ASXL3	protein	Q9C0F0	UNIPROT	NR1H3	protein	Q13133	UNIPROT	down-regulates activity	binding			9606	BTO:0000972								25450400	t		miannu	We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRα and TRβ, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXRα and TRβ were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXRα target genes through its recruitment to the LXR-response elements. 	SIGNOR-266765	0.2
MEF2A	protein	Q02078	UNIPROT	SLC2A4	protein	P14672	UNIPROT	up-regulates quantity by expression	transcriptional regulation												14630949	f		lperfetto	Neither GEF nor MEF2A alone significantly activated GLUT4 promoter activity, but increased promoter activity 4- to 5-fold when expressed together.	SIGNOR-271692	0.371
CDK9	protein	P50750	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									19914161	t		lpetrilli	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161585	0.607
PRKCD	protein	Q05655	UNIPROT	CTTN	protein	Q14247	UNIPROT	up-regulates activity	phosphorylation	Ser405	KTQTPPVsPAPQPTE	10029									26490115	t		Manara	Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration. In addition, the MCP1-induced cortactin phosphorylation is dependent on PLCβ3-mediated PKCδ activation	SIGNOR-260889	0.249
POMC	protein	P01189	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates activity				9606	BTO:0000848								16274845	f		miannu	Alpha-MSH is an anti-inflammatory peptide which signals by binding to the melanocortin-1 receptor (MC1R) and elevating cyclic AMP in several different cells and tissues. The carboxyl terminal peptides of alpha-MSH (KPV/GKPV) are the smallest minimal sequences that prevent inflammation, but it is not known if they operate via MC1R or cyclic AMP. Immobilized alpha-melanocyte stimulating hormone 10-13 (GKPV) inhibits tumor necrosis factor-alpha stimulated NF-kappaB activity.	SIGNOR-252371	0.259
MLH1/PMS2	complex	SIGNOR-C59	SIGNOR	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates activity				10090									29175432	f			MLH1 and PMS2 proteins form the MutLα heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans	SIGNOR-257600	0.7
lurasidone	chemical	CHEBI:70735	ChEBI	ADRA2C	protein	P18825	UNIPROT	down-regulates activity	chemical inhibition			10030	BTO:0000246								20404009	t		Luana	Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 
2C receptors.	SIGNOR-257837	0.8
sunitinib	chemical	CHEBI:38940	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates	chemical inhibition			9606									21423276	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-172923	0.8
KCNJ8	protein	Q15842	UNIPROT	NLRP3	protein	Q96P20	UNIPROT	down-regulates activity	binding			9606									31387986	t		lperfetto	We further show that Kir6.1 physically associates with NLRP3 and thus inhibits the interactions between the NLRP3 inflammasome subunits. Our results reveal a previously unrecognized function of Kir6.1 as a negative regulator of the NLRP3 inflammasome	SIGNOR-262034	0.2
PPP1CC	protein	P36873	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	dephosphorylation	Ser15	PSVEPPLsQETFSDL	9606									16501611	t			Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.	SIGNOR-248499	0.323
EGFR	protein	P00533	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr869	LGAEEKEyHAEGGKV	10090	BTO:0002882								16122376	t	Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer	lperfetto	EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work	SIGNOR-235956	0.2
N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide	chemical	CHEBI:63082	ChEBI	ADRB1	protein	P08588	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000457								20590599	t		Luana	Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3).	SIGNOR-257854	0.8
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	NOS3	protein	P29474	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0001853								24379783	t	inferred from 70% family members	lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-269971	0.2
Quazepam	chemical	CHEBI:8694	ChEBI	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	up-regulates activity	chemical activation			9606		BTO:0000227							18790874	t	brain	lperfetto	The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005).	SIGNOR-263800	0.8
EGFR	protein	P00533	UNIPROT	LRRK1	protein	Q38SD2	UNIPROT	down-regulates activity	phosphorylation	Tyr971	TQQTEEQyFQFLAKF	9534	BTO:0000298								22337768	t		miannu	In this study, we demonstrate that EGFR regulates the kinase activity of LRRK1 via tyrosine phosphorylation and that this is required for proper endosomal trafficking of EGFR. Phosphorylation of LRRK1 at Tyr-944 results in reduced LRRK1 kinase activity. 	SIGNOR-262856	0.349
EIF2B3	protein	Q9NR50	UNIPROT	EIF2S2	protein	P20042	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606									15054402	t		lperfetto	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 	SIGNOR-269131	0.842
SKA1	protein	Q96BD8	UNIPROT	SKA complex	complex	SIGNOR-C364	SIGNOR	form complex	binding			-1									22483620	t		lperfetto	We show that the structure of the Ska core complex is a W-shaped dimer of coiled coils, formed by intertwined interactions between Ska1, Ska2, and Ska3. 	SIGNOR-265197	0.907
PJA1	protein	Q8NG27	UNIPROT	SPTBN1	protein	Q01082	UNIPROT	down-regulates	ubiquitination			9606									16247473	t		gcesareni	The present study indicates that praja, a ring finger e3 ubiquitin ligase, interacts with elf and ubiquitinates it.	SIGNOR-141216	0.413
ESR1	protein	P03372	UNIPROT	UGT1A4	protein	P22310	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								19546240	f	 	miannu	 our data indicate that up-regulation of UGT1A4 expression by E(2) is mediated by both ER alpha and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy.	SIGNOR-254075	0.305
CHEK2	protein	O96017	UNIPROT	TTK	protein	P33981	UNIPROT	unknown	phosphorylation	Thr288	SPDCDVKtDDSVVPC	9606									19151762	t		llicata	Phosphorylation at ttk/hmps1 thr288 is enhanced by chk2 in vitro and in vivo after ir	SIGNOR-183470	0.296
PTTG1	protein	O95997	UNIPROT	ESPL1	protein	Q14674	UNIPROT	down-regulates activity	binding			9606									15737063	t		lperfetto	Prior to anaphase, separase is kept inactive by its inhibitor securin	SIGNOR-275538	0.943
NatA	complex	SIGNOR-C415	SIGNOR	H2AX	protein	P16104	UNIPROT	down-regulates activity	acetylation			9606	BTO:0001109								21351257	t		miannu	The human protein N(α)-terminal acetyltransferase A complex (hNatA), composed of the catalytic hNaa10p (hArd1) and auxiliary hNaa15p (hNat1/NATH/Tubedown) subunits, was reported to be important for cell survival and growth of various types of cancer.  lack of acetylation by hNatA activated H2A.X and Chk2 in both HCT116 cell lines independent of TP53 status (Fig. 6). 	SIGNOR-267227	0.2
paroxetine	chemical	CHEBI:7936	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								18487050	t		Luana	For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428. 	SIGNOR-257795	0.8
F11	protein	P03951	UNIPROT	HGF	protein	P14210	UNIPROT	up-regulates activity	cleavage	Arg494	CAKTKQLrVVNGIPT	-1									12372819	t		miannu	 the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. 	SIGNOR-256514	0.317
U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	RNA_splicing	phenotype	SIGNOR-PH201	SIGNOR	up-regulates				9606									30765414	f		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270651	0.7
C3	protein	P01024	UNIPROT	C3	protein	P01024	UNIPROT	up-regulates activity	cleavage	Arg671	QPAARRRrSVQLTEK	9606		BTO:0000089							26806831	t		lperfetto	 C3 autoactivates in a process known as “tick-over,” which is characterized by spontaneous hydrolysis of a reactive thiol-ester to generate C3(H2O). Although C3(H2O)Bb produces only relatively small amounts of C3b compared to the other C3 convertases, it nevertheless generates enough C3b to set the C3 convertase amplification loop in motion.	SIGNOR-263483	0.2
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates activity	binding			9606									24315690	t		miannu	In addition to the possible regulation of the transcription factor c-Jun by phosphorylation via the c-Jun N-terminal kinase (JNK) or the kinases ERK1, ERK2 and GSK3β, further signaling pathways lead to an up-regulation of c-Jun protein and thus AP-1 activity	SIGNOR-253340	0.811
CDK3	protein	Q00526	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates activity	phosphorylation	Ser118	LHPPPQLsPFLQPHG										26202215	t		lperfetto	CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3	SIGNOR-273187	0.263
U2AF1/U2AF2	complex	SIGNOR-C78	SIGNOR	Spliceosomal_snRNP_assembly	phenotype	SIGNOR-PH79	SIGNOR	up-regulates				9606									11739736	f		miannu	The essential splicing factor U2AF (U2 auxiliary factor) is a heterodimer composed of 65-kDa (U2AF(65)) and 35-kDa (U2AF(35)) subunits. U2AF(35) has multiple functions in pre-mRNA splicing. First, U2AF(35) has been shown to function by directly interacting with the AG at the 3' splice site. Second, U2AF(35) is thought to play a role in the recruitment of U2AF(65) by serine-arginine-rich (SR) proteins in enhancer-dependent splicing. 	SIGNOR-263945	0.7
TLX1	protein	P31314	UNIPROT	PPP2CB	protein	P62714	UNIPROT	down-regulates activity	binding			9606	BTO:0000661								15897879	t	2	miannu	HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade.	SIGNOR-240722	0.305
PTPN12	protein	Q05209	UNIPROT	INSR	protein	P06213	UNIPROT	down-regulates	dephosphorylation	Tyr1185	FGMTRDIyETDYYRK	-1									10734133	t		miannu	Interestingly, all PTPs that were tested could completely dephosphorylate the receptor, given sufficient time, including a negative control (PTP-PEST) that failed to bind IRK as a trapping mutant.	SIGNOR-75894	0.384
CD79B	protein	P40259	UNIPROT	BCR-Mk	complex	SIGNOR-C433	SIGNOR	form complex	binding			9606	BTO:0000776								32323266	t		scontino	BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition.	SIGNOR-268189	0.641
CSF3	protein	P09919	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252287	0.7
MAPK3	protein	P27361	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates	phosphorylation			9606									9922370	t		gcesareni	Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity. previous studies have shown that phosphorylation is required for raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated erk	SIGNOR-64172	0.622
HTR2C	protein	P28335	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257129	0.254
GRK5	protein	P34947	UNIPROT	ADRB2	protein	P07550	UNIPROT	unknown	phosphorylation	Thr384	LCEDLPGtEDFVGHQ	-1									8662852	t			 we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). 	SIGNOR-251199	0.682
tRNA(Gly)	smallmolecule	CHEBI:29176	ChEBI	Gly-tRNA(Gly)	smallmolecule	CHEBI:29156	ChEBI	up-regulates quantity	precursor of			9606									24898252	t		miannu	Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 	SIGNOR-270483	0.8
UBTF	protein	P17480	UNIPROT	rRNA_transcription	phenotype	SIGNOR-PH145	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001412								7877691	t		lperfetto	Rb specifically inhibits the activity of the RNA polymerase I transcription factor UBF (upstream binding factor) in vitro. |These results indicate that there is an additional mechanism by which Rb suppresses cell growth, namely that Rb directly represses transcription of the rRNA genes. 	SIGNOR-262590	0.7
JAK2	protein	O60674	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									12370803	f		irozzo	In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells. 	SIGNOR-255811	0.464
SIRT7	protein	Q9NRC8	UNIPROT	SAR1A	protein	Q9NR31	UNIPROT	up-regulates activity	deacetylation			9606	BTO:0002181								28790157	t		SARA	SIRT7 interacts with the helicase DDX21. Deacetylation by SIRT7 is required for DDX21 activity and R-loop unwinding	SIGNOR-260978	0.2
PEX5	protein	P50542	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	up-regulates activity	binding			9606	BTO:0000007				ubiquitination:Lys209	VAKVDDPkLANSEFL			26344566	t			Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy. 	SIGNOR-262793	0.38
IHH	protein	Q14623	UNIPROT	PTCH1	protein	Q13635	UNIPROT	down-regulates activity	binding			9606		BTO:0001253							9811851	t		lperfetto	Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH.	SIGNOR-61311	0.833
TDP2	protein	O95551	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	up-regulates activity	binding			9606	BTO:0002181								21980489	t		miannu	TTRAP associates with TRAF6.The TAK1-TTRAP-TRAF6 complex is stabilized by ubiquitylation and recruited to TβRI.	SIGNOR-277189	0.386
NAMPT	protein	P43490	UNIPROT	CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	down-regulates													19299583	f	 	lperfetto	Using Per2:luciferase transcriptional reporter assays in HEK293 cells (Fig. 2C-E; S2), we show that inhibition of NAMPT by FK866 led to a significant increase in the CLOCK:BMAL1-driven transcription of the Per2:luciferase reporter (Fig. 2C), indicating that reduced NAMPT-mediated NAD+ biosynthesis released CLOCK:BMAL1 from the SIRT1-dependent suppression.	SIGNOR-253721	0.597
PTPN1	protein	P18031	UNIPROT	MAPK15	protein	Q8TD08	UNIPROT	down-regulates	dephosphorylation	Tyr177	EDQAVTEyVATRWYR	9606									16336213	t		lperfetto	Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20%	SIGNOR-142981	0.332
4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one	chemical	CHEBI:94732	ChEBI	MAPK9	protein	P45984	UNIPROT	down-regulates	chemical inhibition			9606									18922779	t	BI-78D3 is substrate competitive.	gcesareni	Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell.	SIGNOR-181650	0.8
CASP7	protein	P55210	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	cleavage	Asp329	EMEEDSYdSFGEPSY	-1									10069390	t		lperfetto	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261751	0.323
CASP3	protein	P42574	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000938								15231831	t		lperfetto	Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant.	SIGNOR-126727	0.517
MAPK7	protein	Q13164	UNIPROT	KLF2	protein	Q9Y5W3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0005787	BTO:0001103							23612709	f		miannu	The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 	SIGNOR-255454	0.479
CSNK2B	protein	P67870	UNIPROT	IRS1	protein	P35568	UNIPROT	unknown	phosphorylation	Ser24	GYLRKPKsMHKRFFV	-1									8349691	t		llicata	These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1.	SIGNOR-251072	0.324
AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	RAG2	protein	P55895	UNIPROT	up-regulates				9606									22790199	f		gcesareni	Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated.	SIGNOR-198192	0.7
GSK690693	chemical	CHEBI:90677	ChEBI	AKT2	protein	P31751	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193003	0.8
CDC42	protein	P60953	UNIPROT	PAK	proteinfamily	SIGNOR-PF13	SIGNOR	up-regulates activity	binding			10090	BTO:0000142								8107774	t		gcesareni	A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways.	SIGNOR-248259	0.941
PRKCA	protein	P17252	UNIPROT	CDC42EP4	protein	Q9H3Q1	UNIPROT	down-regulates activity	phosphorylation	Ser18	SVHSKRRsRADLTAE	9606	BTO:0001939								25086031	t		miannu	Cdc42 effector protein-4 (CEP4) was recently identified by our laboratory to be a substrate of multiple PKC isoforms in non-transformed MCF-10A human breast cells. MS/MS analysis verified that Ser(18) and Ser(80) were directly phosphorylated by PKCα in vitro. Phosphorylation of CEP4 severely diminished its affinity for Cdc42 while promoting Rac activation and formation of filopodia (microspikes). 	SIGNOR-263160	0.2
aliskiren fumarate	chemical	CHEBI:53777	ChEBI	REN	protein	P00797	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189483	0.8
Amyloid_fibril_formation	phenotype	SIGNOR-PH59	SIGNOR	DKK1	protein	O94907	UNIPROT	up-regulates activity													15229249	f			Exposure of the cultures to beta-amyloid peptide (βAP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1). 	SIGNOR-255482	0.7
CHEK1	protein	O14757	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Thr387	HKKLMFKtEGPDSD	9606	BTO:0001321								15659650	t		lperfetto	Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage.	SIGNOR-217861	0.772
PRKACA	protein	P17612	UNIPROT	PHKA1	protein	P46020	UNIPROT	up-regulates activity	phosphorylation	Ser1018	QVEFRRLsISAESQS										10487978	t		miannu	Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. Ser1018 within this multiphosphorylation domain is phosphorylated by PKA and is a major site of regulatory phosphorylation in vivo	SIGNOR-250026	0.418
MAPK3	protein	P27361	UNIPROT	PTPN7	protein	P35236	UNIPROT	up-regulates activity	phosphorylation	Ser93	ALQRQPPsPKQLEEE	-1									16226275	t		lperfetto	First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|	SIGNOR-249475	0.68
MRPL23	protein	Q16540	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262370	0.2
CDK1	protein	P06493	UNIPROT	PBK	protein	Q96KB5	UNIPROT	unknown	phosphorylation	Thr9	EGISNFKtPSKLSEK	9606			SIGNOR-C17						15541388	t		llicata	Topk-thr-9 was phosphorylated by cdk1/cyclin b and topk significantly associates with mitotic spindles.	SIGNOR-130439	0.568
GABRB1	protein	P18505	UNIPROT	GABA-A (a3-b1-g2) receptor	complex	SIGNOR-C332	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263757	0.597
TACR3	protein	P29371	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257066	0.2
PAR-1 (Protease-Activated Receptor) Selective Activating Peptide	smallmolecule	CID:71312048	PUBCHEM	F2R	protein	P25116	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257484	0.8
EEF1A1	protein	P68104	UNIPROT	Gln-tRNA(Gln)	smallmolecule	CHEBI:29166	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269510	0.8
ERBB2	protein	P04626	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates	phosphorylation	Tyr1248	PTAENPEyLGLDVPV	9606		BTO:0000149							1706616	t		gcesareni	However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2.	SIGNOR-21203	0.2
TBPL2	protein	Q6SJ96	UNIPROT	TAF3/TRF3	complex	SIGNOR-C23	SIGNOR	form complex	binding			9606		BTO:0000887;BTO:0001103;BTO:0001760							18851836	t		lperfetto	We recently identified taf3 as a subunit specifically associated with trf3 to form a complex that is required for myogenic differentiation	SIGNOR-181614	0.686
GATA1	protein	P15976	UNIPROT	GP1BA	protein	P07359	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17725493	f	 	miannu	 We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. 	SIGNOR-254191	0.527
CASP3	protein	P42574	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	cleavage	Asp326	YDPEMEEdSYDSFGE	-1									10069390	t		lperfetto	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261743	0.415
PIM1	protein	P11309	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	phosphorylation			9606									17643117	t		gcesareni	Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation.	SIGNOR-265366	0.2
ATF4	protein	P18848	UNIPROT	SIGMAR1	protein	Q99720	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22079628	f		miannu	 we have demonstrated that Sig-1Rs were transcriptionally upregulated by ATF4 in ER stress. 	SIGNOR-253750	0.392
ASPSCR1	protein	Q9BZE9	UNIPROT	VCPKMT	protein	Q9H867	UNIPROT	up-regulates	binding			9606									23349634	t		gcesareni	In the case of vcp, methylation by mettl21d was stimulated by the addition of the ubx cofactor aspscr1, which we show directly interacts with the methyltransferase.	SIGNOR-200572	0.349
TM9SF4	protein	Q92544	UNIPROT	Autophagy	phenotype	SIGNOR-PH31	SIGNOR	up-regulates				9606									29125601	f		miannu	In the present study, we report a novel autophagy-related protein TM9SF4, which plays a functional role in the induction phase of autophagic process. Overexpression of TM9SF4 promoted autophagic flux in HEK293 cells.	SIGNOR-266704	0.7
TET1	protein	Q8NFU7	UNIPROT	ZNF382	protein	Q96SR6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									27708339	t		irozzo	Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9.	SIGNOR-259095	0.2
ULK1	protein	O75385	UNIPROT	GABARAP	protein	O95166	UNIPROT	up-regulates	binding			9606	BTO:0000567;BTO:0000938	BTO:0000142							11146101	t		gcesareni	N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions	SIGNOR-85614	0.658
AMPK	complex	SIGNOR-C15	SIGNOR	MCU	protein	Q8NE86	UNIPROT	up-regulates activity	phosphorylation	Ser57	TVHQRIAsWQNLGAV	-1									30858581	t		lperfetto	Cellular ATP levels drop during early mitosis, and the mitochondrial Ca2+ transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). |In vitro kinase assays showed that AMPK immunoprecipitated from cells as well as recombinant AMPK phosphorylated MCU at Ser57	SIGNOR-275548	0.2
ADORA2A	protein	P29274	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257038	0.276
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	STMN1	protein	P16949	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000007								9731215	t	inferred from 70% family members	lperfetto	Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. 	SIGNOR-270082	0.2
ANKS1B	protein	Q7Z6G8	UNIPROT	Postsynaptic density assembly	phenotype	SIGNOR-PH163	SIGNOR	up-regulates				9606	BTO:0000938								26356309	f		miannu	AIDA-1 is highly enriched in postsynaptic density (PSD) fractions and is considered a major component of the PSD complex.	SIGNOR-264226	0.7
ATP	smallmolecule	CHEBI:15422	ChEBI	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	precursor of			9606									33961946	t		miannu	Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5′-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S).	SIGNOR-267837	0.8
4-{[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]amino}benzoic acid	chemical	CHEBI:64210	ChEBI	RARG	protein	P13631	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000298								19058965	t		Luana	Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes. 	SIGNOR-258140	0.8
BAP1	protein	Q92560	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				10090									26416890	f		lperfetto	The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and is Disrupted in Cancer.	SIGNOR-241660	0.7
DNMT3B	protein	Q9UBC3	UNIPROT	BAG3	protein	O95817	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001109								18413740	f	 	lperfetto	In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+)	SIGNOR-254111	0.2
RUNX3	protein	Q13761	UNIPROT	ING1	protein	Q9UK53	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002384								17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255099	0.25
PIM2	protein	Q9P1W9	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser99	PFRGRSRsAPPNLWA	9606	BTO:0000007								16403219	t		miannu	Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.	SIGNOR-250394	0.4
MAPK1	protein	P28482	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates activity	phosphorylation	Ser389	LSPIAPRsPAKLSFQ	10090	BTO:0000944								7889942	t		lperfetto	We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-235471	0.544
acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	malonyl-CoA	smallmolecule	CHEBI:15531	ChEBI	up-regulates quantity	precursor of			9606									20952656	t		miannu	ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA	SIGNOR-267107	0.8
ABL1	protein	P00519	UNIPROT	CRK	protein	P46108	UNIPROT	down-regulates activity	phosphorylation	Tyr221	GGPEPGPyAQPSVNT	9606									21779437	t		lperfetto	Negative regulation of crk by abl is essential for the antitumorigenic effects of ephrinb2,similar pathways may operate for crkl	SIGNOR-175135	0.752
PFKFB4	protein	Q16877	UNIPROT	beta-D-fructofuranose 2,6-bisphosphate	smallmolecule	CHEBI:28602	ChEBI	up-regulates quantity	chemical modification			9606									15170386	t			Fru-2,6-P2 (fructose 2,6-bisphosphate) is a signal molecule that controls glycolysis. Since its discovery more than 20 years ago, inroads have been made towards the understanding of the structure– function relationships in PFK-2 (6-phosphofructo-2-kinase)/ FBPase-2 (fructose-2,6-bisphosphatase), the homodimeric bifunctional enzyme that catalyses the synthesis and degradation of Fru-2,6-P2	SIGNOR-267264	0.8
PRKCD	protein	Q05655	UNIPROT	C5AR1	protein	P21730	UNIPROT	down-regulates	phosphorylation	Ser334	SVVRESKsFTRSTVD	9606									10636859	t		gcesareni	Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation.	SIGNOR-73967	0.2
PRKCA	protein	P17252	UNIPROT	ITPKA	protein	P23677	UNIPROT	down-regulates activity				-1									9374536	t		lperfetto	In contrast, phosphorylation of the A isoform with PKC caused a significant decrease in activity whether assayed in the presence or absence of calcium/calmodulin (to _25% of the unphosphorylated enzyme activity).	SIGNOR-248991	0.378
AHCYL1	protein	O43865	UNIPROT	SLC4A4	protein	Q9Y6R1	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								21317537	t		miannu	 IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities. 	SIGNOR-263135	0.693
RB1	protein	P06400	UNIPROT	Cell_cycle_block	phenotype	SIGNOR-PH10	SIGNOR	up-regulates				9606									21524151	f		lperfetto	Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time.	SIGNOR-245486	0.7
domperidone	chemical	CHEBI:31515	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258720	0.8
CDC14B	protein	O60729	UNIPROT	MAPK6	protein	Q16659	UNIPROT	down-regulates	dephosphorylation	Ser688	QFHSPVGsPLKSIQA	9606									20236090	t		lperfetto	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis.	SIGNOR-164475	0.552
ROCK1	protein	Q13464	UNIPROT	Satellite_cells_self-renewal	phenotype	SIGNOR-PH100	SIGNOR	up-regulates	transcriptional regulation					BTO:0001103							23290138	f		apalma	FN in the satellite cell niche is required for the maintenance of the overall satellite cell pool during muscle regeneration. Moreover, FN is necessary to potentiate Wnt7a signaling through the Fzd7/Scd4 receptor complex, which controls the regulation of satellite stem cell numbers	SIGNOR-255850	0.7
zileuton	chemical	CHEBI:10112	ChEBI	ALOX5	protein	P09917	UNIPROT	down-regulates activity	chemical inhibition			10116									1848634	t		miannu	5-lipoxygenase inhibitory activity of zileuton.	SIGNOR-258363	0.8
BMS-754807	chemical	CHEBI:88339	ChEBI	IGF1R	protein	P08069	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001802								19996272	t		lperfetto	BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR 	SIGNOR-262027	0.8
MYD88	protein	Q99836	UNIPROT	TRAF3	protein	Q13114	UNIPROT	up-regulates activity	binding			10090	BTO:0000906								16306937	t			Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6.	SIGNOR-256079	0.717
PLCG1	protein	P19174	UNIPROT	1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	up-regulates quantity	chemical modification			9606									23140367	t		miannu	Phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).	SIGNOR-251558	0.8
SLC16A3	protein	O15427	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				9606									26384349	f		lperfetto	Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival.	SIGNOR-242468	0.7
PRKACA	protein	P17612	UNIPROT	PTBP1	protein	P26599	UNIPROT	down-regulates activity	phosphorylation	Ser16	AVGTKRGsDELFSTC	10116									12851456	t		miannu	PKA directly phosphorylates PTB on conserved Ser-16, and PKA activation in PC12 cells induces Ser-16 phosphorylation. PTB carrying a Ser-16 to alanine mutation accumulates normally in the nucleus. However, export of this mutant protein from the nucleus is greatly reduced in heterokaryon shuttling assays. Conversely, hyperphosphorylation of PTB by coexpression with the catalytic subunit of PKA results in the accumulation of PTB in the cytoplasm.	SIGNOR-263149	0.313
CNTRL	protein	Q7Z7A1	UNIPROT	Cilium_assembly	phenotype	SIGNOR-PH64	SIGNOR	down-regulates				9606									18694559	f		miannu	CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CP110 in this complex is to keep CEP290 inactive in growing cells until cells are ready to undergo ciliogenesis as they transit into the quiescent state	SIGNOR-252150	0.7
ADRA2B	protein	P18089	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256857	0.447
E2F5	protein	Q15329	UNIPROT	CBX5	protein	P45973	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000815								21374739	t		Luana	We identified for E2F5 a repressor function for HP1a expression.	SIGNOR-261591	0.2
BRAF	protein	P15056	UNIPROT	Glycolysis	phenotype	SIGNOR-PH34	SIGNOR	up-regulates				9606	BTO:0000797								27340238	f			These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein.	SIGNOR-259373	0.7
BACH1	protein	O14867	UNIPROT	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	up-regulates quantity	transcriptional regulation			9606									31257027	t	inferred from family member		BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells.	SIGNOR-270266	0.2
ABL1	protein	P00519	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates	phosphorylation	Tyr405	STSSSIIySSQEDVK	9606									21081495	t		lperfetto	Mdm2 has three known c-abl phosphorylation sites (tyr276, tyr394, and tyr405)these data show that c-abl is important for reducing mdm2 and mdmx protein levels after genotoxic stress and suggest another cellular mechanism for the stabilization and activation of p53.	SIGNOR-169703	0.705
PPP3CA	protein	Q08209	UNIPROT	MEF2C	protein	Q06413	UNIPROT	up-regulates				9606		BTO:0001103							11062529	f		gcesareni	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-84035	0.486
RNF19A	protein	Q9NV58	UNIPROT	CASR	protein	P41180	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								16513638	t		miannu	 Coexpression with dorfin decreased the amount of total CaR protein and increased CaR ubiquitination, whereas a dominant negative fragment of dorfin had opposite effects. dorfin-mediated proteasomal degradation of immature CaR occurs from the endoplasmic reticulum. Because endogenous CaR in Madin-Darby canine kidney cells is also subject to degradation from the endoplasmic reticulum, dorfin-mediated ubiquitination may contribute to a general mechanism for CaR quality control during biosynthesis.	SIGNOR-271456	0.39
CSNK1A1	protein	P48729	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation			9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity.	SIGNOR-183661	0.2
MCHR2	protein	Q969V1	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257390	0.409
RELA	protein	Q04206	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	binding			9606			SIGNOR-C13						18174238	t		gcesareni	Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment	SIGNOR-160330	0.708
SHH	protein	Q15465	UNIPROT	PTCH1	protein	Q13635	UNIPROT	down-regulates activity	binding			9606									14556242	t		lperfetto	In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other.	SIGNOR-118615	0.941
SCN11A	protein	Q9UI33	UNIPROT	Action_potential 	phenotype	SIGNOR-PH82	SIGNOR	up-regulates				9606									26043074	f		miannu	The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons.	SIGNOR-253453	0.7
FYN	protein	P06241	UNIPROT	GRIN2A	protein	Q12879	UNIPROT	up-regulates	phosphorylation	Tyr1325	RLLEGNFyGSLFSVP	9606									19834457	t		gcesareni	The nr2a subunit of the nmda receptor is tyrosine-phosphorylated, with tyr 1325 as its one of the major phosphorylation site. Tyr 1325 phosphorylation site is required for src-induced potentiation of the nmda receptor channel in the striatum. Tyr 1325 was most prominently phosphorylated by fyn in vitro.	SIGNOR-188527	0.724
KANSL3	protein	Q9P2N6	UNIPROT	NSL histone acetyltransferase	complex	SIGNOR-C413	SIGNOR	form complex	binding			9606	BTO:0000007								20018852	t		miannu	Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex.	SIGNOR-267162	0.607
CSNK2A1	protein	P68400	UNIPROT	MYH9	protein	P35579	UNIPROT	up-regulates	phosphorylation	Ser1943	RKGAGDGsDEEVDGK	9606	BTO:0000150								21316371	t		gcesareni	In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)	SIGNOR-171907	0.347
1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	PRKCA	protein	P17252	UNIPROT	up-regulates	binding			9606									14967450	t	PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine.	gcesareni	The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified.	SIGNOR-121956	0.8
gefitinib	chemical	CHEBI:49668	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192623	0.8
AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	Endocytosis	phenotype	SIGNOR-PH123	SIGNOR	up-regulates													24130457	f		lperfetto	AP-2 is the core-organizing element in clathrin-mediated endocytosis. During the formation of clathrin-coated vesicles, clathrin and endocytic accessory proteins interact with AP-2 in a temporally and spatially controlled manner	SIGNOR-260705	0.7
JAZF1	protein	Q86VZ6	UNIPROT	NR2C2	protein	P49116	UNIPROT	down-regulates	binding			9606									15302918	t		miannu	Tip27 interacts specifically with tak1 / tip27 functions as a tak1-selective repressor	SIGNOR-127900	0.465
ADCY1	protein	Q08828	UNIPROT	3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	up-regulates quantity	chemical modification			9606									15385642	t		miannu	Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions.	SIGNOR-265003	0.8
HCK	protein	P08631	UNIPROT	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	up-regulates activity	phosphorylation	Tyr730	PNLFVALyDFVASGD	9606									16912036	t		Manara	Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 	SIGNOR-260810	0.2
Galanin	smallmolecule	CHEBI:80161	ChEBI	GALR2	protein	O43603	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257495	0.8
CHEK1	protein	O14757	UNIPROT	CDC25B	protein	P30305	UNIPROT	down-regulates activity	phosphorylation	Ser230	AFAQRPSsAPDLMCL	9606									17003105	t		lperfetto	Here, we show that cdc25b is phosphorylated by chk1 in vitro on multiple residues, including s230 and s563.We show that the s230-phosphorylated form of cdc25b is located at the centrosome from early s phase until mitosis. Furthermore, mutation of s230 to alanine increases the mitotic-inducing activity of cdc25b	SIGNOR-149898	0.781
PCK2	protein	Q16822	UNIPROT	oxaloacetate(2-)	smallmolecule	CHEBI:16452	ChEBI	down-regulates quantity	chemical modification			9606									24632615	t		miannu	Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine.	SIGNOR-266556	0.8
GCC1	protein	Q96CN9	UNIPROT	ITSN1	protein	Q15811	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								30540523	t		Giulio	GFP-GCC88 was immunoprecipitated by both the short and long form of ITSN-1 but not with FLAG-Rheb (Figure 4A). These data demonstrate that both GCC88 and ITSN-1 are part of a complex. We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A).	SIGNOR-260600	0.2
PRKCD	protein	Q05655	UNIPROT	ITGB7	protein	P26010	UNIPROT	unknown	phosphorylation	Thr783	PLYKSAItTTINPRF	10090	BTO:0001825								12682249	t		lperfetto	Beta7 subunit is phosphorylated even in unstimulated TK-1 cells. Activation of TK-1 cells with anti-CD3 (Fig. 5_A) and PDBu (Fig. 5_B) increased the phosphorylation 15€“20%. | The result shows that the fourth amino acid of the tryptic peptide was phosphorylated. This phosphorylated threonine residue is most likely the first threonine (Thr782) of threonine triplet (Thr782€“784). 	SIGNOR-249205	0.31
CAMK2A	protein	Q9UQM7	UNIPROT	SYNGAP1	protein	Q96PV0	UNIPROT	up-regulates activity	phosphorylation	Ser780	MARGLNSsMDMARLP	-1									14970204	t		miannu	Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. We identify four major sites of phosphorylation, serines 1123, 1058, 750/751/756, and 764/765. 	SIGNOR-262690	0.439
TRAF6	protein	Q9Y4K3	UNIPROT	Osteoclast_differentiation	phenotype	SIGNOR-PH76	SIGNOR	up-regulates				9606									17572386	f		miannu	TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation.	SIGNOR-253046	0.7
HSPG2	protein	P98160	UNIPROT	PTPRS	protein	Q13332	UNIPROT	up-regulates	binding			9606									11865065	t		gcesareni	We demonstrate here that cptpsigma is a heparin-binding protein and that its basal lamina ligands include the heparan sulfate proteoglycans (hspgs) agrin and collagen xviii.	SIGNOR-115246	0.256
RPS6KA1	protein	Q15418	UNIPROT	CDC34	protein	P49427	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr162	KGKDREYtDIIRKQV	-1									27786305	t		miannu	RSK1 phosphorylated Thr162 on UBE2R1.RSK1 induced self-ubiquitination and destabilisation of UBE2R1 by phosphorylation. 	SIGNOR-277330	0.343
IL21	protein	Q9HBE4	UNIPROT	PAX5	protein	Q02548	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782;BTO:0000785								22486304	f		miannu	Interleukin-21 inhibits humoral response to an hiv dna vaccine by enhancing bcl-6 andpax-5expression.	SIGNOR-196921	0.255
CSNK1A1L	protein	Q8N752	UNIPROT	GLI3	protein	P10071	UNIPROT	up-regulates	phosphorylation			9606									16481469	t		gcesareni	Ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed	SIGNOR-144554	0.339
CEP135	protein	Q66GS9	UNIPROT	CENPJ	protein	Q9HC77	UNIPROT	up-regulates activity	binding			9606									23511974	t		miannu	 In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation.	SIGNOR-269677	0.802
pravastatin	chemical	CHEBI:63618	ChEBI	HMGCR	protein	P04035	UNIPROT	down-regulates activity	chemical inhibition			-1									1597859	t		miannu	A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). 	SIGNOR-258350	0.8
PLK1	protein	P53350	UNIPROT	FOXM1	protein	Q08050	UNIPROT	up-regulates	phosphorylation	Ser730	VLDTMNDsLSKILLD	9606									19737929	t		lperfetto	It has been reported that plk1 could directly phosphorylate foxm1 at ser-715 and ser-724 for full activation and proper mitotic progression	SIGNOR-187888	0.694
VEGFD	protein	O43915	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252278	0.7
DLL1	protein	O00548	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates activity	binding			9606	BTO:0000776								16140393	t		lperfetto	Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate.	SIGNOR-254315	0.625
CDS1	protein	Q92903	UNIPROT	phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	down-regulates quantity	chemical modification			9606									25375833	t		lperfetto	CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA).	SIGNOR-267018	0.8
Mequitazine	chemical	CHEBI:31821	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002126								18446005	t		Luana	We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells	SIGNOR-257780	0.8
CDR2	protein	Q01850	UNIPROT	NUF2	protein	Q9BZD4	UNIPROT	up-regulates quantity by expression	transcriptional regulation												20383333	f		lperfetto	Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology	SIGNOR-252022	0.2
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	CCND3	protein	P30281	UNIPROT	up-regulates	dephosphorylation	Thr283	QGPSQTStPTDVTAI	9606									16331257	t		lperfetto	These results support the hypothesis that pp1 constitutively keeps cyclin d3 in a stable, dephosphorylated state	SIGNOR-264662	0.2
LCK	protein	P06239	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates activity	phosphorylation	Tyr688	FAEPYNLySSLKELV	9534	BTO:0004055								9461588	t			The regulatory p85 subunit of phosphatidylinositol 3-kinase is phosphorylated on tyrosine residues. We report that this phosphorylation event is readily catalyzed by the Abl and Lck protein-tyrosine kinases in vitro, by Bcr-Abl or a catalytically activated Lck-Y505F in co-transfected COS cells. we have mapped a major phosphorylation site to Tyr-688 in the C-terminal SH2 domain of p85. Tyrosine phosphorylation of p85 in vitro or in vivo was not associated with detectable change in the enzymatic activity of the phosphatidylinositol 3-kinase heterodimer, but correlated with a strong reduction in the binding of some, but not all, phosphoproteins to the SH2 domains of p85.	SIGNOR-252699	0.584
neratinib	chemical	CHEBI:61397	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194628	0.8
SYK	protein	P43405	UNIPROT	BLNK	protein	Q8WV28	UNIPROT	up-regulates	phosphorylation	Tyr84	EHSDSEMyVMPAEEN	9606	BTO:0000776								12456653	t		llicata	The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex.	SIGNOR-96048	0.799
IQSEC2	protein	Q5JU85	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606		BTO:0000142							27009485	f		miannu	These data demonstrate that the reduction of BRAG1 results in a reduction of synaptic transmission. Together with the data showing that overexpression of BRAG1 enhances synaptic transmission, these data highlight the role of BRAG1 in the bidirectional regulation of synaptic transmission.	SIGNOR-264905	0.7
RPS6KA3	protein	P51812	UNIPROT	MAD1L1	protein	Q9Y6D9	UNIPROT	up-regulates activity				9606									20383198	f		lperfetto	We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions.	SIGNOR-252038	0.2
NDUFA1	protein	O15239	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 	SIGNOR-262150	0.844
SH3RF1	protein	Q7Z6J0	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates	binding			9606	BTO:0000938								12514131	t		gcesareni	We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2.	SIGNOR-96952	0.316
MAPK13	protein	O15264	UNIPROT	CDC25B	protein	P30305	UNIPROT	down-regulates				9606									11333986	f		gcesareni	P38 map k can also induce a g2/m checkpoint through the phosphorylation and the phosphatase cdc25b.	SIGNOR-85999	0.46
RBBP4	protein	Q09028	UNIPROT	MBD3/NuRD complex	complex	SIGNOR-C338	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263849	0.825
AKT1	protein	P31749	UNIPROT	TSC	complex	SIGNOR-C101	SIGNOR	down-regulates activity	phosphorylation			10090	BTO:0000011								19593385	t		lperfetto	 In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis	SIGNOR-235340	0.778
EGFR	protein	P00533	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	relocalization			9606									16829981	t	Cbl binds directly to Tyr1045 receptors	gcesareni	Likewise, cbl is recruited to erbb1 either directly (tyr1045), or indirectly, trough grb2	SIGNOR-147826	0.882
YWHAB	protein	P31946	UNIPROT	SRPK2	protein	P78362	UNIPROT	down-regulates	binding			9606							phosphorylation:Thr492	PSHDRSRtVSASSTG	19592491	t		lperfetto	14-3-3 interacts with akt-phosphorylated srpk2 and blocks its nuclear translocation. kt phosphorylates SRPK2 on Thr-492 and promotes its nuclear translocation leading to cyclin D1 up-regulation, cell cycle reentry, and neuronal apoptosis. In addition, SRPK2 phosphorylates SC35 and, thus, inactivates p53, resulting in cyclin D1 up-regulation. 14-3-3 binding to SRPK2, regulated by Akt phosphorylation, inhibits these events. 	SIGNOR-186767	0.335
CCL7	protein	P80098	UNIPROT	CCR1	protein	P32246	UNIPROT	up-regulates	binding			9606									14991608	t			For example, 11 chemokines are reported to bind to CC chemokine receptor (CCR) 1, including macrophage inflammatory protein (MIP)‐1α , MIP‐1β, MIP‐1δ, regulated upon activation, normal T cell‐expressed and secreted (RANTES), monocyte chemotactic peptide (MCP)‐1, MCP‐2, MCP‐3, MCP‐4, leukotactin‐1 (Lkn‐1), myeloid progenitor inhibitory factor (MPIF)‐1, and hemofiltrate CC chemokine (HCC)‐1 	SIGNOR-254368	0.737
CRBN	protein	Q96SW2	UNIPROT	IKZF3	protein	Q9UKT9	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000725								29496670	t		miannu	IMiD compounds cause selective ubiquitination and degradation of IKZF1 in CD34+ cells by the CRBN E3 ubiquitin ligase.	SIGNOR-272319	0.6
tyrphostin AG 1478	chemical	CHEBI:75404	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189377	0.8
EGFR	protein	P00533	UNIPROT	KCNN1	protein	Q92952	UNIPROT	up-regulates activity	phosphorylation	Tyr109	KRKRLSDyALIFGMF	9606	BTO:0000007								23496660	t		miannu	These results demonstrate the novel information that hSKCa1 channels are inhibited by genistein, T25 and AG556 via EGFR tyrosine kinase inhibition, which is related to the phosphorylation of Tyr(109) in the N-terminus. 	SIGNOR-276490	0.2
PAX7-FOXO1	fusion protein	SIGNOR-FP11	SIGNOR	JARID2	protein	Q92833	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23435416	t		lperfetto	JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells| we demonstrated that JARID2 is a direct transcriptional target of the PAX3-FOXO1 fusion protein.| Therefore, JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS	SIGNOR-249597	0.2
SLC25A1	protein	P53007	UNIPROT	citrate(3-)	smallmolecule	CHEBI:16947	ChEBI	up-regulates quantity	relocalization			9606									29651165	t			SLC25A1, a mitochondrial carrier that promotes the flux of citrate/isocitrate across the mitochondria, in exchange for the entry of cytosolic malate	SIGNOR-267289	0.8
CTR9	protein	Q6PD62	UNIPROT	PAF1C	complex	SIGNOR-C471	SIGNOR	form complex	binding			9606	BTO:0000567								20178742	t		miannu	Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A). 	SIGNOR-269834	0.94
KLF11	protein	O14901	UNIPROT	HBE1	protein	P02100	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10207080	f	Regulation	miannu	Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression. 	SIGNOR-251829	0.282
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	UBTF	protein	P17480	UNIPROT	down-regulates	phosphorylation			9606									11741541	t	inferred from 70% family members	lperfetto	Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna	SIGNOR-270181	0.2
CDC20	protein	Q12834	UNIPROT	APC-c	complex	SIGNOR-C150	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								23979597	t		miannu	 We showed that PHF8 interacts with the CDC20-containing APC (APC(cdc20)) primarily during mitosis. we demonstrate that mutations of the LXPKXLF motif abrogate polyubiquitylation of PHF8 by the APC. APC substrates are typically cell cycle regulators, and consistent with this, the loss of PHF8 leads to prolonged G2 phase and defective mitosis.	SIGNOR-272880	0.872
ATG7	protein	O95352	UNIPROT	GABARAPL2	protein	P60520	UNIPROT	up-regulates activity	binding			-1									16303767	t		lperfetto	Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme).	SIGNOR-142002	0.903
TG	protein	P01266	UNIPROT	Colloid	phenotype	SIGNOR-PH185	SIGNOR	up-regulates				9606									24251883	f		scontino	The thyroid gland is unique among endocrine glands in storing its principle hormonal product—the two very small thyroid hormones (TH)—as components of a 1000-fold larger precursor—thyroglobulin (Tg)—that is secreted and stored in the colloid, outside of the thyroid cell. Moreover, the thyroid cell is part of a layer of similar cells—the thyroid follicular epithelium—that completely encloses the secreted Tg and segregates it from the circulation.	SIGNOR-267135	0.7
CSNK2A1	protein	P68400	UNIPROT	PDCL	protein	Q13371	UNIPROT	up-regulates	phosphorylation	Ser18	EKLQYYYsSSEDEDS	9606									16717095	t		lperfetto	Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2.	SIGNOR-146825	0.36
Caspase 9 complex	complex	SIGNOR-C229	SIGNOR	CASP3	protein	P42574	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000567								9390557	t		lperfetto	Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade.	SIGNOR-256462	0.622
CHEK2	protein	O96017	UNIPROT	AATF	protein	Q9NY61	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser477	ELIERKTsSLDPNDQ	9606	BTO:0001109								17157788	t		lperfetto	Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability.	SIGNOR-264417	0.365
MOB1A	protein	Q9H8S9	UNIPROT	LATS1	protein	O95835	UNIPROT	up-regulates	binding			9606									21084559	t	Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases.	gcesareni	Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1	SIGNOR-169752	0.94
CXCR4	protein	P61073	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates				9606	BTO:0005387								19584257	f		lperfetto	However, we show that soluble factors secreted by SUM102 breast cancer cells stimulated the expression of MMP-1 and CXCR4 in HMFs. As a result, these stromal cells acquired an invasive and migratory phenotype	SIGNOR-252266	0.7
GSK3B	protein	P49841	UNIPROT	ACLY	protein	P53396	UNIPROT	up-regulates activity	phosphorylation	Thr447	NASGSTStPAPSRTA										10653665	t			Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3). Phosphorylation resulted in a 6-fold increase in V(max) and the conversion of citrate dependence from sigmoidal, displaying negative cooperativity, to hyperbolic.	SIGNOR-251219	0.371
PLK1	protein	P53350	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates	phosphorylation	Ser750	QTEEEEHsCLEQAS	9606									18957422	t		lperfetto	Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma	SIGNOR-181806	0.349
4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide	chemical	CHEBI:94506	ChEBI	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193534	0.8
HDAC2	protein	Q92769	UNIPROT	BHC complex	complex	SIGNOR-C353	SIGNOR	form complex	binding			9606	BTO:0000567; BTO:0000007								15325272	t		miannu	BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells	SIGNOR-264499	0.69
SB 203580	chemical	CHEBI:90705	ChEBI	MAPK14	protein	Q16539	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258279	0.8
MAPK8	protein	P45983	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr57	NFDFVTEtPLEGDFA	-1									12058028	t		miannu	P38α and JNK1 Phosphorylate p21 in Vitro at Thr57 and Ser130. These data suggest that phosphorylation at Thr57 is necessary for stabilization of p21.	SIGNOR-250118	0.659
TP53	protein	P04637	UNIPROT	KDM4B	protein	O94953	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001109								28073943	t		miannu	KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. p53 directly regulates JMJD2B gene expression by binding to a canonical p53-consensus motif in the JMJD2B promoter.	SIGNOR-263729	0.286
Neuropeptide W-30	smallmolecule	CHEBI:80256	ChEBI	NPBWR1	protein	P48145	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257548	0.8
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser552	VVRTPPKsPSSAKSR	9606									12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249319	0.754
GART	protein	P22102	UNIPROT	5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium	smallmolecule	CHEBI:137981	ChEBI	up-regulates quantity	chemical modification			9606									33179964	t		miannu	The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner.	SIGNOR-267315	0.8
MIF	protein	P14174	UNIPROT	HBB	protein	P68871	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									16636133	f	Regulation of expression	miannu	MIF inhibits cytodifferentiation and hemoglobin synthesis of MEL cells. 	SIGNOR-251831	0.2
SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	RUNX1	protein	Q01196	UNIPROT	up-regulates activity	binding			9606									20506188	t		miannu	Our findings indicate that RUNX1 interacts with the human SWI/SNF complex to control hematopoietic-specific gene expression.	SIGNOR-261965	0.432
HBB	protein	P68871	UNIPROT	ADAMTS13	protein	Q76LX8	UNIPROT	down-regulates activity				9606									15367436	f	Regulation of binding	miannu	Incubation of hemoglobin, recombinant and from lysed erythrocytes, with normal plasma revealed an ADAMTS13 inhibitory effect at hemoglobin concentrations of 2 g/L or higher.	SIGNOR-251748	0.2
SMAD7	protein	O15105	UNIPROT	MAP3K1	protein	Q13233	UNIPROT	down-regulates				9606									10085121	f		lperfetto	Overexpression of smad7 can inhibit the mekk-1-mediated stimulation of smad2 transcriptional activity	SIGNOR-65572	0.268
CAMK2G	protein	Q13555	UNIPROT	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Thr594	LHGKKNStVDCNGVV	9606									33410863	t		lperfetto	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275781	0.295
GSK3B	protein	P49841	UNIPROT	SNAI1	protein	O95863	UNIPROT	down-regulates	phosphorylation	Ser119	SFSSTSVsSLEAEAY	9606									15448698	t		lperfetto	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-129418	0.575
ABL1	protein	P00519	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates activity	phosphorylation	Tyr315	ETRICKIyDSPCLPE	9534	BTO:0000298								10212258	t		gcesareni	Mutation of Rad51 Tyr315, but not Tyr205, Tyr191, or Tyr54 to phenylalanine abolished Rad51 tyrosine phosphorylation by c-Abl (Fig. 3 b). These results strongly suggest that c-Abl phosphorylates Rad51 Tyr315 in vivo	SIGNOR-247594	0.764
LYN	protein	P07948	UNIPROT	HCLS1	protein	P14317	UNIPROT	up-regulates activity	phosphorylation	Tyr397	EDEPEGDyEEVLEPE	9606									9104825	t			Lyn and Syk synergistically phosphorylate HS1, and that Tyr-378 and Tyr-397 of HS1 are the critical residues for its BCR-induced phosphorylation. tyrosine phosphorylation of HS1 is required for BCR-induced apoptosis and nuclear translocation of HS1 may be a prerequisite for B cell apoptosis. PMID: 9104825 PMCID: PMC2196252	SIGNOR-251401	0.702
SLC34A3	protein	Q8N130	UNIPROT	phosphate(3-)	smallmolecule	CHEBI:18367	ChEBI	up-regulates quantity	relocalization			9606		BTO:0000671							11880379	t		lperfetto	Growth is critically dependent on the retention of a variety of nutrients. The kidney contributes to this positive external balance. In the present study, we isolated a cDNA from the human and rat kidney that encodes a growth-related Na(+)-dependent inorganic phosphate (P(i)) cotransporter (type IIc).	SIGNOR-270577	0.8
RUNX3	protein	Q13761	UNIPROT	TXN2	protein	Q99757	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002384								17956589	f		miannu	 Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells.	SIGNOR-255093	0.2
PPP2R5C	protein	Q13362	UNIPROT	ATF1	protein	P18846	UNIPROT	up-regulates	dephosphorylation	Ser38	QVSSLSEsEESQDSS	9606									20730097	t		lperfetto	We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf5	SIGNOR-167564	0.2
TOP2B	protein	Q02880	UNIPROT	SST	protein	P61278	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24463367	f		lperfetto	While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development	SIGNOR-242305	0.2
SKI	protein	P12755	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	binding			9606									10575014	t		lperfetto	Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling.	SIGNOR-217658	0.73
TNKS2	protein	Q9H2K2	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									19759537	t		gcesareni	Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway.	SIGNOR-188033	0.693
OST-A complex	complex	SIGNOR-C535	SIGNOR	Protein_glycosylation	phenotype	SIGNOR-PH144	SIGNOR	up-regulates				9606									31831667	t		miannu	Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B. 	SIGNOR-272055	0.7
C5	protein	P01031	UNIPROT	Membrane attack complex	complex	SIGNOR-C313	SIGNOR	form complex	binding			-1					cleavage:Arg751	HKDMQLGrLHMKTLL			30552328	t	complement C5b fragment: PRO_0000005989	lperfetto	The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer	SIGNOR-263440	0.606
CDK7	protein	P50613	UNIPROT	CDK2	protein	P24941	UNIPROT	up-regulates activity	phosphorylation	Thr160	GVPVRTYtHEVVTLW	-1									10085115	t		llicata	Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP.	SIGNOR-250768	0.551
SRP54	protein	P61011	UNIPROT	SRPRA	protein	P08240	UNIPROT	up-regulates activity	binding			-1									30649417	t		miannu	 The multi-domain SRP GTPase SRP54 recognizes the signal with its M domain and establishes the targeting complex consisting of its NG domain bound to the homologous NG domain of the SRP receptor SRα at a proximal ribosome binding site.	SIGNOR-261163	0.2
(S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide	chemical	CID:6918848	PUBCHEM	HDAC8	protein	Q9BY41	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002428								31908417	t		miannu	The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs.	SIGNOR-262248	0.8
RIMS2	protein	Q9UQ26	UNIPROT	CACNA1D	protein	Q01668	UNIPROT	up-regulates activity	binding			9606	BTO:0005822								28642685	t		miannu	Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells.	SIGNOR-264356	0.355
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	EIF4B	protein	P23588	UNIPROT	up-regulates	phosphorylation	Ser422	RERSRTGsESSQTGT	9606									15071500	t		gcesareni	S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.	SIGNOR-252783	0.2
CSNK2A2	protein	P19784	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Ser385	RYSDTTDsDPENEPF	-1									12297295	t		llicata	We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366). 	SIGNOR-251027	0.693
RAB14	protein	P61106	UNIPROT	Early Endosome	complex	SIGNOR-C246	SIGNOR	form complex	binding			9606									19924646	t		lperfetto	The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 	SIGNOR-260619	0.414
CYSLTR2	protein	Q9NS75	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257140	0.357
EHF	protein	Q9NZC4	UNIPROT	DCDC2	protein	Q9UHG0	UNIPROT	down-regulates quantity by repression	transcriptional regulation												22733135	f	 	 	Mechanistically, we found that the ETS transcription factor ESE3/EHF, which is expressed in normal prostate and frequently lost in prostate tumors, maintained DCDC2 repressed by binding to a novel identified ETS binding site in the gene promoter.	SIGNOR-254279	0.267
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate(5-)	smallmolecule	CHEBI:57923	ChEBI	1-phosphatidyl-1D-myo-inositol 5-phosphate(3-)	smallmolecule	CHEBI:57795	ChEBI	up-regulates quantity	precursor of			9606									18429927	t		miannu	PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 	SIGNOR-269806	0.8
PRKCA	protein	P17252	UNIPROT	L1CAM	protein	P32004	UNIPROT	down-regulates activity	phosphorylation	Thr1172	ARPMKDEtFGEYRSL	9606	BTO:0000304								20335502	t		miannu	CKII phosphorylates T1172 of the L1 CD and phosphorylation of T1172 is responsible for loss of 2C2 signal.	SIGNOR-276283	0.2
BCL3	protein	P20749	UNIPROT	HDAC1	protein	Q13547	UNIPROT	up-regulates	binding			9606									15469820	t		gcesareni	We show that bcl-3 is a substrate for the protein kinase gsk3 and that gsk3-mediated bcl-3 phosphorylation, which is inhibited by akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with hdac1, -3, and -6	SIGNOR-129801	0.437
TNF	protein	P01375	UNIPROT	TNFRSF1B	protein	P20333	UNIPROT	up-regulates activity	binding			9606									12040173	t		lperfetto	The binding of tnf to tnf-r1 triggers a series of intracellular events that ultimately result in the activation of two major transcription factors, nuclear factor kb (nf-kb) and c-jun.	SIGNOR-88216	0.928
AR	protein	P10275	UNIPROT	CYP7B1	protein	O75881	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								16630558	f		miannu	DHT and overexpression of androgen receptor (AR) suppressed CYP7B1 promoter activity and CYP7B1-mediated catalysis in kidney-derived HEK293 cells.	SIGNOR-253739	0.293
CEBPA	protein	P49715	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606	BTO:0004730								16319681	f		lperfetto	The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder.	SIGNOR-249632	0.7
S1PR2	protein	O95136	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257215	0.509
MAPK1	protein	P28482	UNIPROT	DYNC1LI1	protein	Q9Y6G9	UNIPROT	unknown	phosphorylation	Ser516	VSPTTPTsPTEGEAS	10090	BTO:0000944								22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262773	0.256
RB1	protein	P06400	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606									21524151	f		miannu	Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time.	SIGNOR-262533	0.7
CACNA2D3	protein	Q8IZS8	UNIPROT	p38	proteinfamily	SIGNOR-PF16	SIGNOR	up-regulates activity				9606									31746409	f		miannu	The results indicated that the overexpression of CACNA2D3 induced an increase in intracellular Ca2+ and increased the levels of p-p38 MAPK. These data indicated that the p38 MAPK pathway is activated by overexpression of CACNA2D3 and P4 induction.	SIGNOR-266857	0.2
RSPO1	protein	Q2MKA7	UNIPROT	ZNRF3	protein	Q9ULT6	UNIPROT	down-regulates	relocalization			9606									23151663	t		gcesareni	This is counteracted by respondin 1, which induces znrf3 internalization	SIGNOR-199629	0.796
RASSF1	protein	Q9NS23	UNIPROT	STK3	protein	Q13188	UNIPROT	up-regulates activity	binding			9606									22195963	t		lperfetto	Mutant K-Ras promotes MST2 activation in two ways (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex (Matallanas et al., 2008) and by forming an activating K-Ras-RASSF1A€“MST2 complex, as reported here.	SIGNOR-249588	0.687
PHLPP1	protein	O60346	UNIPROT	AKT2	protein	P31751	UNIPROT	unknown	dephosphorylation			9606	BTO:0000527								15808505	t		gcesareni	These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt / phlpp1 specifically modulates the phosphorylation of hdm2 and gsk-3alpha through akt2, whereas phlpp2 specifically modulates the phosphorylation of p27 through akt3	SIGNOR-135008	0.607
EID1	protein	Q9Y6B2	UNIPROT	CREBBP	protein	Q92793	UNIPROT	down-regulates activity	binding												11073989	t		lperfetto	Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity.	SIGNOR-253380	0.415
STON2	protein	Q8WXE9	UNIPROT	SYT1	protein	P21579	UNIPROT	up-regulates quantity	binding			9606	BTO:0000938								26903854	t		miannu	 the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval.  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. 	SIGNOR-264115	0.769
SUZ12	protein	Q15022	UNIPROT	SNAI2	protein	O43623	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									23836662	f	 	miannu	 We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes.	SIGNOR-254150	0.469
GABA-A (a5-b1-g2) receptor	complex	SIGNOR-C335	SIGNOR	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	down-regulates				9606		BTO:0000227							18790874	f	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263781	0.7
HBEGF	protein	Q99075	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001260							9135143	t		gcesareni	It was concluded that her4 is a newly described receptor for hb-egf and that hb-egf can activate two egf receptor subtypes, her1 and her4, but with different biological response.	SIGNOR-47881	0.741
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606									18593906	t		fspada	Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42).	SIGNOR-259428	0.2
RIMBP3	protein	Q9UFD9	UNIPROT	RIMS1	protein	Q86UR5	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264360	0.348
GSK3B	protein	P49841	UNIPROT	PIAS1	protein	O75925	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser17	MVMSLRVsELQVLLG	10090	BTO:0002268								26157031	t		miannu	We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. We found that GSK3β phosphorylation of PIAS1 provided a phosphodegron for HECTD2 targeting. 	SIGNOR-276923	0.338
SEC23IP	protein	Q9Y6Y8	UNIPROT	1-acyl-sn-glycerol 3-phosphate	smallmolecule	CHEBI:16975	ChEBI	up-regulates quantity	chemical modification			9606									22922100	t		miannu	Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 	SIGNOR-269657	0.8
EDA	protein	Q92838	UNIPROT	EDA2R	protein	Q9HAV5	UNIPROT	up-regulates	binding			9606		BTO:0001253							12084975	t		gcesareni	Identification of the major product of the eda gene (ectodysplasin a), a protein belonging to a group of tnf ligands, and molecular cloning of the cdna, encoding its receptor (edar), a member of the tnf receptor family, are presented. The role of an alternative eda receptor, localised on the x chromosome (xedar) in the developmental control of the differentiation of skin appendages, is discussed.	SIGNOR-90040	0.669
N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide	chemical	CHEBI:91336	ChEBI	AURKC	protein	Q9UQB9	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258305	0.8
MAPK1	protein	P28482	UNIPROT	AHNAK	protein	Q09666	UNIPROT	unknown	phosphorylation	Ser5110	KAEAPLPsPKLEGEL	10090									22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262764	0.259
ARAP1	protein	Q96P48	UNIPROT	RAC1	protein	P63000	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260451	0.431
PRKDC	protein	P78527	UNIPROT	RPA2	protein	P15927	UNIPROT	up-regulates	phosphorylation	Thr21	YGGAGGYtQSPGGFG	9606									14872059	t		lperfetto	Replication protein a (rpa) is a single-stranded dna (ssdna) binding protein involved in various processes, including nucleotide excision repair and dna replication. The 32 kda subunit of rpa (rpa32) is phosphorylated in response to various dna-damaging agents, and two protein kinases, ataxia-telangiectasia mutated (atm) and the dna-dependent protein kinase (dna-pk) have been implicated in dna damage-induced phosphorylation of rpa32we show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro.	SIGNOR-121869	0.598
MAP2K2	protein	P36507	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	up-regulates	phosphorylation			9606		BTO:0000142							1411546	t	inferred from 70% of family members	gcesareni	The primary structure of mek, a protein kinase that phosphorylates the erk gene product	SIGNOR-269895	0.2
FYN	protein	P06241	UNIPROT	CD79B	protein	P40259	UNIPROT	up-regulates activity	phosphorylation	Tyr196	GMEEDHTyEGLDIDQ	-1									9531288	t			CD79b cytoplasmic tail-containing GST fusion proteins were phosphorylated in vitro by baculovirus-produced Fyn, >80% of phosphorylation occurred on the N-terminal ITAM tyrosine. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). pY195 and pY206 in CD79b 	SIGNOR-251154	0.659
PRKDC	protein	P78527	UNIPROT	USF1	protein	P22415	UNIPROT	up-regulates	phosphorylation			9606									19303849	t		miannu	Feeding induces the recruitment of dna-pk to usf-1 and its phosphorylation, which then allows recruitment of p/caf, resulting in usf-1 acetylation and fas promoter activation.	SIGNOR-184849	0.297
PPM1A	protein	P35813	UNIPROT	IKBKE	protein	Q14164	UNIPROT	down-regulates activity	dephosphorylation	Ser172	DDDEKFVsVYGTEEY	9606									27419230	t		miannu	PPM1A directly dephosphorylates both MAVS and TBK1 and IKKepsilon.|In a similar in vitro phosphatase assay, incubation of PPM1A also eliminated TBK1 and IKKepsilon phosphorylation at Ser 172 residue, evidenced by phospho-S172 immunoblotting (XREF_FIG, F and G).|These observations suggest that PPM1A may block kinase activities of TBK1 and IKKepsilon.	SIGNOR-277072	0.283
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	THRB	protein	P10828	UNIPROT	down-regulates activity	phosphorylation			9606									12809513	t	inferred from 70% family members	llicata	We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay.	SIGNOR-270143	0.2
IFITM3	protein	Q01628	UNIPROT	gamma-secretase	complex	SIGNOR-C98	SIGNOR	up-regulates activity	binding			10090									32879487	t		miannu	IFITM3 directly binds to γ-secretase. IFITM3 KO reduced γ-secretase activity for both Aβ40 and Aβ42 cleavages as compared to the EV (empty vector guide RNA) cell line by 36% and 27%, respectively (Fig. 2d, bar 1 and 3). 	SIGNOR-266303	0.2
sirolimus	chemical	CHEBI:9168	ChEBI	AKT1	protein	P31749	UNIPROT	up-regulates				9606									16452206	f		gcesareni	We now show that mtor inhibition induces insulin receptor substrate-1 expression and abrogates feedback the pathway, resulting in akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, rad001.	SIGNOR-252643	0.8
GABRA1	protein	P14867	UNIPROT	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263750	0.639
SRC	protein	P12931	UNIPROT	CDH5	protein	P33151	UNIPROT	down-regulates activity	phosphorylation	Tyr658	GEMDTTSyDVSVLNS	10029	BTO:0000246								16027153	t		lperfetto	cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity.	SIGNOR-246462	0.585
MMP3	protein	P08254	UNIPROT	ACAN	protein	P16112	UNIPROT	down-regulates quantity by destabilization	cleavage	Asn360	DFVDIPEnFFGVGGE	9606		BTO:0000206							9202061	t		lperfetto	Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374	SIGNOR-266986	0.728
POU5F1	protein	Q01860	UNIPROT	TDGF1	protein	P13385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001086								17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254943	0.676
PTPRC	protein	P08575	UNIPROT	JAK3	protein	P52333	UNIPROT	down-regulates activity	dephosphorylation			10090									11201744	t			CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling	SIGNOR-248359	0.468
HSPB1	protein	P04792	UNIPROT	GCH1	protein	P30793	UNIPROT	up-regulates quantity by stabilization	binding			9606									18241680	t		miannu	GTP cyclohydrolase I (GCH), an oligomeric protein composed of 10 identical subunits, is required for the synthesis of neurotransmitters; mutations in GCH are associated with dopa-responsive dystonia (DRD) and hyperphenylalaninemia. Mutated GCH proteins are unstable and prone to dominant-negative effect. We show herein that expression of the GCH mutant GCH-201E or the splicing variant GCH-II caused intracellular inclusion bodies. When Hsp27 was expressed together with the GCH mutants, Hsp27 expression decreased the formation of inclusion bodies by GCH (as assessed by immunofluorescence) and decreased the amount of insoluble GCH mutant proteins (as assessed by Western blot). we demonstrated that Hsp27 increases the expression of the wild-type GCH protein, causes the appearance of the soluble GCH-II protein, and decreases the quantities of insoluble mutated GCH protein. Therefore, it is likely that Hsp27 improves the folding of mutated GCH proteins, so they can stay in free cytosolic compartment.	SIGNOR-252222	0.2
G8RGG88B68	smallmolecule	SID:135317436	ChEBI	IFNAR2	protein	P48551	UNIPROT	up-regulates activity	chemical activation			-1									15898717	t		miannu	To significantly improve the pharmacological properties of the drug, a pegylated form of IFNalpha(2a) was developed (PEGASYS). This 40 kDa PEG-conjugated IFNalpha(2a) ((40)PEG-IFNalpha(2a)) is obtained by the covalent binding of one 40 kDa branched PEG-polymer to a lysine side-chain of IFNalpha(2a). Here, we report the detailed structural, kinetic, and thermodynamic analysis of the binding to the extracellular domain of the receptor IFNAR2 of (40)PEG-IFNalpha(2a) and its isolated positional isomers modified at K31, K134, K131, K121, K164, and K70, respectively, in comparison with unmodified IFNalpha(2a). 	SIGNOR-259391	0.8
EGLN3	protein	Q9H6Z9	UNIPROT	IKBKG	protein	Q9Y6K9	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								23732909	t		lperfetto	Here we report that EGLN3, but not EGLN1 or -2, interacts with and inhibits K63-linked ubiquitination of IKKγ. The effect appears to be related to inhibition of IKKγ ubiquitination mediated by cIAP1 rather than to stimulation of IKKγ deubiquitination by the deubiquitinases A20 and CYLD (cylindromatosis). EGLN3 does not affect the protein levels of cIAP1 or its E2 ubiquitin-conjugating enzymes UbcH5 and Ubc13. EGLN3 hydroxylase activity is not responsible for its effect on IKKγ ubiquitination and NF-κB signaling. Instead, interaction with IKKγ is required for the ability of EGLN3 to inhibit IKKγ ubiquitination and IKK-NF-κB signaling.	SIGNOR-262005	0.331
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BANP	protein	Q8N9N5	UNIPROT	down-regulates activity	phosphorylation	Thr337	VKSFSRRtPNSSSYC	9606	BTO:0000567								26080397	t		miannu	ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68. 	SIGNOR-266203	0.2
7-Hydroxystaurosporine	chemical	CID:72271	PUBCHEM	CHEK1	protein	O14757	UNIPROT	down-regulates	chemical inhibition			9606									20068082	t		gcesareni	The clinical use of ucn-01, the first chk1 inhibitor evaluated in humans, is limited by its prolonged plasma half-life due to extensive plasma binding to alfa1 acidic glycoprotein	SIGNOR-163222	0.8
ZAP70	protein	P43403	UNIPROT	LAT	protein	O43561	UNIPROT	up-regulates activity	phosphorylation	Tyr156	ADEDEDDyHNPGYLV	9606	BTO:0000782								11368773	t		lperfetto	In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127.	SIGNOR-247018	0.762
CREBBP	protein	Q92793	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	acetylation			9606									25545885	t		miannu	C-terminal acetylation of p53 by p300/CBP and PCAF promotes an open conformation of p53 by preventing the occlusion of the DNA binding domain by the C-terminal tail. This enhances p53 transcriptional activity, leading to growth arrest and/or apoptosis	SIGNOR-261495	0.909
RHOA	protein	P61586	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates				9606									23450633	f		gcesareni	Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism.	SIGNOR-192114	0.7
CSNK2A2	protein	P19784	UNIPROT	CLTB	protein	P09497	UNIPROT	unknown	phosphorylation	Ser11	DFGFFSSsESGAPEA	-1									3128543	t		llicata	To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites.	SIGNOR-250983	0.312
ZDHHC9	protein	Q9Y397	UNIPROT	HRAS	protein	P01112	UNIPROT	up-regulates activity	palmitoylation			9606	BTO:0000007								16000296	t		miannu	Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein.	SIGNOR-261352	0.448
CDK2	protein	P24941	UNIPROT	CROCC	protein	Q5TZA2	UNIPROT	down-regulates	phosphorylation	Ser1460	APRPVPGsPARDAPA	9606									22610972	t		llicata	Finally, phosphorylation of tax1bp2 at serine-763 by cyclin-dependent kinase (cdk)2 abolished the tax1bp2-mediated p38 activation and tumor-suppressive activity, indicating that tax1bp2 can adapt cdk2 signaling to the p38/p53/p21 pathway.	SIGNOR-197593	0.2
POMC	protein	P01189	UNIPROT	MC1R	protein	Q01726	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268700	0.758
ITPRIPL1	protein	Q6GPH6	UNIPROT	ITPR1	protein	Q14643	UNIPROT	up-regulates	binding			9606	BTO:0000938								21368195	t	Induces Ca2+ release that increases the binding affinity of Shh for Boc.	gcesareni	Recruitment of g protein also can activate phospholipase c (plc) that in turn increases inositol triphosphate (ip3) levels and induces ca2+ release from internal stores.	SIGNOR-172497	0.2
LLGL1	protein	Q15334	UNIPROT	Scribble_complex_DLG2-LLGL1_variant	complex	SIGNOR-C510	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270907	0.544
MRPS18A	protein	Q9NVS2	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262334	0.707
MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	MAPK1	protein	P28482	UNIPROT	up-regulates activity	phosphorylation	Tyr187	HTGFLTEyVATRWYR	9606	BTO:0003807								11971971	t		lperfetto	Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.	SIGNOR-244788	0.2
LATS1	protein	O95835	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates	phosphorylation	Ser89	AQHVRSHsSPASLQL	9606									22658639	t	Together,the YAP/TAZ-TEAD complex promotes proliferative and survival programs.	milica	In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus.	SIGNOR-197643	0.783
EGFR	protein	P00533	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1069	EDSFLQRySSDPTGA	9606									10635327	t		llicata	Initially, an autophosphorylation reaction creates docking sites for several signaling proteins, including a Cbl binding site at tyrosine 1045 of EGFR. 	SIGNOR-251093	0.2
KDM4C	protein	Q9H3R0	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates activity	binding			9606									29207681	t		miannu	In hypoxia, HIF-1α dimerizes with HIF-1β to form active HIF-1 complex. JMJD2C interacts with HIF-1α and promotes the transcriptional activation of HIF-1 targeting genes via demethylating di- and trimethylated H3K9. 	SIGNOR-263873	0.2
Cyclopamine	chemical	CHEBI:4021	ChEBI	CXCL1	protein	P09341	UNIPROT	down-regulates	chemical inhibition			9606									16885213	t		gcesareni	Cyclopamine and other inhibitors of hh signaling were found to inhibit smo coupling to gi in a manner consistent with inverse agonism.	SIGNOR-148469	0.8
ROCK1	protein	Q13464	UNIPROT	LPP	protein	Q93052	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887;BTO:0001260							22886954	f		miannu	Inactivation of rho kinase (rok) with rok inhibitors significantly inhibited lpp mrna expression	SIGNOR-198118	0.2
PLK1	protein	P53350	UNIPROT	TNKS	protein	O95271	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr982	SLISPAStPSCLSAA	9606	BTO:0000567								21818122	t		miannu	Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends. 	SIGNOR-276241	0.439
14-3-3	proteinfamily	SIGNOR-PF7	SIGNOR	YAP1	protein	P46937	UNIPROT	down-regulates	binding			9534	BTO:0004055								12535517	t		milica	One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73.	SIGNOR-97481	0.2
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1931	SPTSPTYsPTSPKGS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273099	0.745
SMC3	protein	Q9UQE7	UNIPROT	MXD4	protein	Q14582	UNIPROT	down-regulates activity	binding			9534	BTO:0000318								9528857	t	2	miannu	We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions.	SIGNOR-241284	0.3
FOXO1	protein	Q12778	UNIPROT	G6PC1	protein	P35575	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18805788	f		gcesareni	In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription.	SIGNOR-181195	0.2
MAPK1	protein	P28482	UNIPROT	PDE4D	protein	Q08499-2	UNIPROT	down-regulates	phosphorylation	Ser579	YQSTIPQsPSPAPDD	9606									10828059	t	The effect has been demonstrated using Q08499-5	llicata	The pde4d2 isoform is inhibited by erk2 phosphorylation	SIGNOR-77563	0.36
CDK3	protein	Q00526	UNIPROT	LIN9	protein	Q5TKA1	UNIPROT	up-regulates	phosphorylation	Thr96	KFTATMStPDKKASQ	9606	BTO:0002181								24475316	t		lperfetto	In this report, we demonstrate that cyclin e1/cdk3 phosphorylates lin-9 on thr-96. Mutating thr-96 to alanine inhibits activation of cyclins a2 and b1 promoters, whereas a phosphomimetic asp mutant strongly activates their promoters and triggers accelerated entry into g2/m phase in 293t cells.	SIGNOR-204529	0.2
CDK1	protein	P06493	UNIPROT	MCM4	protein	P33991	UNIPROT	down-regulates activity	phosphorylation	Thr19	GSRRGRAtPAQTPRS	9606	BTO:0000567								12714602	t		lperfetto	We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex.	SIGNOR-100877	0.609
UDP-D-glucose	smallmolecule	CHEBI:18066	ChEBI	P2RY14	protein	Q15391	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257562	0.8
PRKCA	protein	P17252	UNIPROT	MARCKS	protein	P29966	UNIPROT	unknown	phosphorylation	Ser46	VKVNGDAsPAAAESG	-1									8034575	t		lperfetto	Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites.	SIGNOR-248908	0.72
FOXP1	protein	Q9H334	UNIPROT	HIP1R	protein	O75146	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000785								23884370	f		miannu	Hip1r was confirmed as a direct foxp1 target / hip1r repression by foxp1	SIGNOR-202370	0.299
ADGRG1	protein	Q9Y653	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							31515243	t		lperfetto	Binding of collagen III to ADGRG1 provides a canonical example of adhesion GPCR interactions with ECM proteins (Luo et al., 2011). Identified by an in vitro biotinylation/proteomics approach, extracellular interactions with collagen III were subsequently proven capable of activating ADGRG1-mediated signaling via Gα12/13 followed by RhoA activation to regulate corticogenesis	SIGNOR-272344	0.2
FOXJ1	protein	Q92949	UNIPROT	CETN2	protein	P41208	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000939								23822649	t		miannu	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266930	0.36
CDK1	protein	P06493	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser90	QHVRSHSsPASLQLG	9606	BTO:0000567								26183396	t		miannu	In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system.	SIGNOR-276926	0.261
UBE2D1	protein	P51668	UNIPROT	PEX5	protein	P50542	UNIPROT	up-regulates activity	ubiquitination			-1									19687296	t		miannu	Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. 	SIGNOR-253022	0.397
NEK11	protein	Q8NG66	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates	phosphorylation	Ser88	DSGFCLDsPGPLDSK	9606									19734889	t		lperfetto	Nek11 regulates cdc25a degradation and the ir-induced g2/m checkpointincubation of wild-type cdc25a with nek11 led to a marked increase in phosphorylation of ser 82 and 88 as detected with the phosphospecific antibody recognizing these sites	SIGNOR-187871	0.43
SGK1	protein	O00141	UNIPROT	MAP3K3	protein	Q99759	UNIPROT	down-regulates activity	phosphorylation	Ser166	EPRSRHLsVSSQNPG	9606									12761204	t		lperfetto	Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 1	SIGNOR-101211	0.2
TIMELESS	protein	Q9UNS1	UNIPROT	CHEK1	protein	O14757	UNIPROT	up-regulates activity	binding			9534									23418588	t		miannu	We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization. 	SIGNOR-268054	0.788
PRKACA	protein	P17612	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates activity	phosphorylation			10116	BTO:0001593								18981475	t		gcesareni	These results suggest that camppka activation is involved in activation of lrp6(...) our results demonstrate that lrp6 can be directly phosphorylated by pka catalytic subunit.	SIGNOR-181979	0.2
biphenyl-4,4'-diol	chemical	CHEBI:34367	ChEBI	ESR2	protein	Q92731	UNIPROT	up-regulates activity	chemical activation			-1									9751507	t		miannu	Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings. 	SIGNOR-268741	0.8
STK11	protein	Q15831	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser392	FKTEGPDsD	9606									17108107	t		gcesareni	We show that lkb1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 ser15 (previously shown to be phosphorylated by amp-dependent kinase) and p53 ser392	SIGNOR-150834	0.747
FPR2	protein	P25090	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256745	0.409
PRKACG	protein	P22612	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser99	PFRGRSRsAPPNLWA	-1									10949026	t		gcesareni	Survival factors, acting through kinases such as Akt and PKA, induce endogenous BAD phosphorylation at two evolutionarily conserved sites, Ser-112 and Ser-136, which leads to the translocation of BAD from the mitochondria to the cytoplasm and the inhibition of BAD-dependent death 	SIGNOR-67400	0.409
PRKACA	protein	P17612	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates activity	phosphorylation			10090	BTO:0000669								15568017	t		gcesareni	Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression. 	SIGNOR-131307	0.563
RRAGA	protein	Q7L523	UNIPROT	RAGAC	complex	SIGNOR-C113	SIGNOR	form complex	binding			9606									20381137	t		gcesareni	Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant	SIGNOR-228164	0.77
KAT2A	protein	Q92830	UNIPROT	H3-2	protein	Q5TEC6	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269599	0.2
CDK1	protein	P06493	UNIPROT	CREM	protein	Q03060	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser277	ASPGSLHsPQQLAEE	10090	BTO:0001077								11466319	t		miannu	 The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway. 	SIGNOR-275979	0.3
MAPK1	protein	P28482	UNIPROT	APBB1	protein	O00213	UNIPROT	unknown	phosphorylation	Ser287	WEPPGRAsPSQGSSP	9606									14697653	t		lperfetto	Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved.	SIGNOR-120455	0.262
EIF5	protein	P55010	UNIPROT	43S_pre_initiation_complex	complex	SIGNOR-C453	SIGNOR	form complex	binding			9606									35489072	t		lperfetto	In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 	SIGNOR-269163	0.778
L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	up-regulates quantity	precursor of			9606									32041144	t		miannu	Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce γ-aminobutyric acid (GABA), which exhibits several well-known physiological functions.	SIGNOR-267550	0.8
SMURF2	protein	Q9HAU4	UNIPROT	BMPR2	protein	Q13873	UNIPROT	down-regulates	ubiquitination			9606									22298955	t		gcesareni	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps.	SIGNOR-193119	0.481
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PLCB1	protein	Q9NQ66	UNIPROT	up-regulates activity	phosphorylation			-1									11287604	t	inferred from 70% family members	lperfetto	Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982	SIGNOR-270200	0.2
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	AE/b7 integrin	complex	SIGNOR-C186	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259010	0.392
AP2S1	protein	P53680	UNIPROT	AP-2 complex	complex	SIGNOR-C245	SIGNOR	form complex	binding												31671891	t		lperfetto	 The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit	SIGNOR-260421	0.913
GXYLT2	protein	A0PJZ3	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606									22117070	t	Xylosylation in ER membrane.	gcesareni	Recently, we have shown (28) that two members of the human glycosyltransferase 8 family (gt8) (29), gxylt1 and gxylt2 (glucoside-xylosyltransferase 1/2), are able to transfer the first alfa1,3-linked xylose to o-glucosylated mammalian notch egf repeats.	SIGNOR-177714	0.391
PTPN2	protein	P17706	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	dephosphorylation	Tyr771	ADIESSNyMAPYDNY	10090	BTO:0002572								14966296	t			The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP. 	SIGNOR-248389	0.545
MRPL34	protein	Q9BQ48	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262363	0.652
HIPK2	protein	Q9H2X6	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser46	AMDDLMLsPDDIEQW	9606									17210684	t		llicata	Based on all these observations, it is legitimate to suggest that axin and daxx seem to adopt both parallel routes and a convergent means to activate p53. In either case, hipk2 seems to be the protein kinase that catalyzes the ser46 phosphorylation.	SIGNOR-151930	0.79
GSK3B	protein	P49841	UNIPROT	SREBF1	protein	P36956	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser434	PPPSDAGsPFQSSPL	9606	BTO:0000007								19126544	t		lperfetto	Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1.	SIGNOR-235797	0.499
perfluorooctane-1-sulfonic acid	chemical	CHEBI:39421	ChEBI	PPARA	protein	Q07869	UNIPROT	up-regulates activity	chemical activation			10090		BTO:0000759							34861291	t		miannu	Perfluorooctane sulfonate (PFOS) is a stable environmental contaminant that can activate peroxisome proliferator-activated receptor alpha (PPARα). These results indicate that mouse PPARα can be activated in the liver by PFOS causing increased expression of Acox1, Cyp4a10 and histopathological changes in the liver. 	SIGNOR-268754	0.8
KRN-633	chemical	CID:9549295	PUBCHEM	FLT4	protein	P35916	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193585	0.8
TWIST1	protein	Q15672	UNIPROT	HGF	protein	P14210	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003879								20646316	f		miannu	Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1.	SIGNOR-255522	0.332
ATF4	protein	P18848	UNIPROT	DDIT4	protein	Q9NX09	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19439225	f	 	lperfetto	 We additionally identified Redd1 as a downstream effector of C/EBP-beta stimulated by ATF4 activated under the stress conditions examined. RNA interference studies provided further evidence of the requirement of C/EBP-beta for Redd1 expression. We conclude that the Redd1 gene is transactivated by the ATF4 and C/EBP family of transcription factors, leading to mTOR inhibition in response to oxidative and ER stress.	SIGNOR-253726	0.426
PRKAA2	protein	P54646	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	down-regulates activity	phosphorylation	Ser792	LTQSAPAsPTNKGVH	10090			SIGNOR-C15	SIGNOR-C3					18439900	t		lperfetto	These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK	SIGNOR-163463	0.681
(2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol	chemical	CHEBI:94701	ChEBI	RRM1	protein	P23921	UNIPROT	down-regulates activity	chemical inhibition			-1									7048062	t		miannu	In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. 2-F-araATP was a potent inhibitor of ribonucleotide reductase	SIGNOR-258404	0.8
DOK4	protein	Q8TEW6	UNIPROT	CRK	protein	P46108	UNIPROT	up-regulates	binding			9606		BTO:0000887;BTO:0001103;BTO:0000671							12730241	t		gcesareni	Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells.	SIGNOR-100996	0.472
FFAR3	protein	O14843	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256957	0.2
FH	protein	P07954	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates activity	binding			-1									28628081	t		miannu	Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes.	SIGNOR-266314	0.2
SMAD7	protein	O15105	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates				9606									17438144	f		gcesareni	Smad7 repressed smad3/4-, smad2/4-, and smad1/4-enhanced reporter gene expression.	SIGNOR-154390	0.562
MGluR	proteinfamily	SIGNOR-PF55	SIGNOR	GNAS	protein	P63092	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							20055706	t		miannu	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264689	0.2
CSNK2A1	protein	P68400	UNIPROT	FHOD3	protein	Q2V2M9	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000887							21149568	t		tpavlidou	We have identified a novel striated muscle-specific splice variant of the formin fhod3 that introduces a casein kinase 2 (ck2) phosphorylation site. The specific targeting of muscle fhod3 to the myofibrils in cardiomyocytes is abolished in phosphomutants or by the inhibition of ck2. Phosphorylation of muscle fhod3 also prevents its interaction with p62/sequestosome 1 and its recruitment to autophagosomes.	SIGNOR-170525	0.313
CDH1	protein	P12830	UNIPROT	α-Catenin	proteinfamily	SIGNOR-PF72	SIGNOR	up-regulates activity	binding			9606									24336504	t		miannu	Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm.	SIGNOR-265821	0.673
1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester	chemical	CHEBI:92418	ChEBI	CHRM3	protein	P20309	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258637	0.8
YARS1	protein	P54577	UNIPROT	alpha-aminoacyl-tRNA	smallmolecule	CHEBI:2651	ChEBI	up-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 	SIGNOR-270798	0.8
SRC	protein	P12931	UNIPROT	TNK2	protein	Q07912	UNIPROT	up-regulates activity	phosphorylation	Tyr860	KVSSTHYyLLPERPS	-1									36178070	t		miannu	We identified two Src phosphorylation sites within the MHR (Y859, Y860). Addition of Src-phosphorylated MHR to the Ack1 KD enhanced enzymatic activity. 	SIGNOR-276341	0.393
NFE2	protein	Q16621	UNIPROT	HBG2	protein	P69892	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000426								16287851	f	Regulation of expression	miannu	NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells.	SIGNOR-251840	0.51
MYOD1	protein	P15172	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000165								10373569	t		gcesareni	Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator.	SIGNOR-238529	0.412
RTKs	proteinfamily	SIGNOR-PF38	SIGNOR	ITGB4	protein	P16144	UNIPROT	up-regulates activity	phosphorylation			9606									30889378	t		miannu	The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs.	SIGNOR-259031	0.2
BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	SMAD1	protein	Q15797	UNIPROT	up-regulates	phosphorylation	Ser463	SPHNPISsVS	9606									9136927	t		lperfetto	Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro	SIGNOR-210079	0.652
RIPK3	protein	Q9Y572	UNIPROT	MLKL	protein	Q8NB16	UNIPROT	up-regulates activity	phosphorylation	Ser360	RKTQTSMsLGTTREK	10090									24012422	t		gianni	MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays	SIGNOR-266428	0.742
FANCM	protein	Q8IYD8	UNIPROT	Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	form complex	binding			9606	BTO:0000567								17396147	t		lperfetto	This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo 	SIGNOR-263248	0.934
DAPK1	protein	P53355	UNIPROT	MYL12A	protein	P19105	UNIPROT	up-regulates activity	phosphorylation	Thr18	KKRPQRAtSNVFAMF	9606	BTO:0000567								11485996	t		miannu	DAPK Phosphorylates Myosin II RLC in Vitro and in Vivo. Together these results show that similar to the conventional MLCKs, Ser-19 is the primary RLC residue phosphorylated by DAPK and that phosphorylation of Thr-18 is also possible.	SIGNOR-262843	0.278
CEP250	protein	Q9BV73	UNIPROT	Centrosome_separation	phenotype	SIGNOR-PH177	SIGNOR	down-regulates				9606	BTO:0000567								24769208	f		lperfetto	C-NAP1 which is located in the proximal ends of the centriole is an important factor for maintaining cohesion of centrioles in interphase	SIGNOR-265498	0.7
ezogabine	chemical	CHEBI:68584	ChEBI	KCNQ3	protein	O43525	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck;anticonvulsant for KCNQ2/3 currents	gcesareni		SIGNOR-206541	0.8
HIPK3	protein	Q9H422	UNIPROT	FADD	protein	Q13158	UNIPROT	down-regulates activity	phosphorylation	Ser194	QNRSGAMsPMSWNSD	-1									11034606	t			FIST/HIPK3 causes FADD phosphorylation, thereby promoting FIST/HIPK3-FADD-Fas interaction.  Phosphorylation occurs on Ser194 close to the COOH terminus of human FADD| Fas ligand-induced activation of Jun NH(2)-terminal kinase is impaired by overexpressed active FIST/HIPK3	SIGNOR-251272	0.447
MAPK3	protein	P27361	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates	phosphorylation	Thr232	GGLPEVAtPESEEAF	9606									7816602	t		lperfetto	Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions.	SIGNOR-33909	0.707
AGTR1	protein	P30556	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256881	0.252
PRKACA	protein	P17612	UNIPROT	LIPE	protein	Q05469	UNIPROT	up-regulates activity	phosphorylation	Ser951	GFHPRRSsQGATQMP	10090	BTO:0000944								11581251	t		lperfetto	HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme	SIGNOR-249204	0.585
CRYGC	protein	P07315	UNIPROT	Maintenance_of_lens_transparency	phenotype	SIGNOR-PH65	SIGNOR	up-regulates				9606									10521291	f			The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification. 	SIGNOR-253624	0.7
RXRB	protein	P28702	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates	binding			9606									10976919	t	inferred from 70% of family members	gcesareni	Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr	SIGNOR-269880	0.641
FBXW11	protein	Q9UKB1	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates	ubiquitination	Lys21	EGPRDGLkKERLLDD	9606									9990853	t		gcesareni	We report here the identification of an ikappab-ubiquitin (ub) ligase complex containing the f-box/wd40-repeat protein, beta-trcp, a vertebrate homolog of drosophila slimb. beta-trcp binds to ikappabalpha only when the latter is specifically phosphorylated by an ikappab kinase complex. here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha.	SIGNOR-64317	0.521
BIRC2	protein	Q13490	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	ubiquitination			9606									18570872	t		amattioni	CIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. In this way RIP1 functions as a prosurvival scaffold molecule instead of a proapoptotic adaptor protein	SIGNOR-179100	0.76
JAK2	protein	O60674	UNIPROT	STAM	protein	Q92783	UNIPROT	up-regulates	phosphorylation			9606									9133424	t		gcesareni	Stam is associated with jak3 and jak2 tyrosine kinases via its itam region and phosphorylated by jak3 and jak2 upon stimulation with il-2.	SIGNOR-47834	0.604
SIRT5	protein	Q9NXA8	UNIPROT	LDHB	protein	P07195	UNIPROT	up-regulates activity	deacetylation	Lys329	DTLWDIQkDLKDL	9606	BTO:0001615								34929314	t		lperfetto	In colorectal cancer, SIRT5 binds to lactate dehydrogenase B (LDHB) to deacetylate it at Lysine 329, thereby increasing its enzymatic activity.	SIGNOR-267645	0.2
GSK3A	protein	P49840	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates	phosphorylation	Thr239	VPEMPGEtPPLSPID	9606									1846781	t		lperfetto	Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity.	SIGNOR-21784	0.338
SP4	protein	Q02446	UNIPROT	RHO	protein	P08100	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								15781457	f		miannu	Sp4 and Sp1 are activators of the rod opsin promoter	SIGNOR-225382	0.2
CD40LG	protein	P29965	UNIPROT	CD40	protein	P25942	UNIPROT	up-regulates activity	binding			9606	BTO:0000782;BTO:0003076								19426221	t		lperfetto	Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner .cd40 binds its ligand cd40l.	SIGNOR-185660	0.927
HSD17B2	protein	P37059	UNIPROT	estrone	smallmolecule	CHEBI:17263	ChEBI	up-regulates quantity	chemical modification			-1									8099587	t		Luana	17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone. 	SIGNOR-269762	0.8
DOK1	protein	Q99704	UNIPROT	ITGB5	protein	P18084	UNIPROT	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257691	0.298
EZR	protein	P15311	UNIPROT	FES	protein	P07332	UNIPROT	up-regulates	relocalization			9606									18046454	t		miannu	The recruitment and the activation of fes to the cell-cell contacts in confluent cells depend on its interaction with ezrin.	SIGNOR-159496	0.404
SMAD3	protein	P84022	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606									14638857	t		gcesareni	Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd	SIGNOR-119374	0.56
CTDSPL	protein	O15194	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation	Ser255	ELSPTTLsPVNHSLD	9606	BTO:0000007								17035229	t			Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248312	0.475
sunitinib	chemical	CHEBI:38940	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606									21423276	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-172908	0.8
AKT2	protein	P31751	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606									19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites.	SIGNOR-236671	0.742
PRKCA	protein	P17252	UNIPROT	CFL1	protein	P23528	UNIPROT	down-regulates	phosphorylation	Ser23	NDMKVRKsSTPEEVK	9606	BTO:0001271								22855535	t		lperfetto	Pkc_ phosphorylates cofilin at ser-23 and/or ser-24 during degranulationthese results indicate that a novel pkc_-mediated phosphorylation event regulates cofilin by inhibiting its ability to depolymerize f-actin and bind to 14-3-3_, thereby promoting f-actin polymerization	SIGNOR-198478	0.2
SRC	protein	P12931	UNIPROT	MYLK	protein	Q15746	UNIPROT	up-regulates	phosphorylation	Tyr471	YEDAGSHyLCLLKAR	9606									11113114	t		gcesareni	Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity.	SIGNOR-85009	0.427
FUBP1	protein	Q96AE4	UNIPROT	TNF	protein	P01375	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19637194	f		irozzo	FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In addition, mRNA levels of the death ligands tumor necrosis factor (TNF) α and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) were significantly increased.	SIGNOR-259130	0.2
JAK1	protein	P23458	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation			9606									26260587	t			IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes.	SIGNOR-253590	0.793
POU3F2	protein	P20265	UNIPROT	MITF	protein	O75030	UNIPROT	up-regulates quantity by expression	transcriptional regulation												18628967	t		lperfetto	We further demonstrate that BRN2 induces MITF transcription through a binding site located at ˆ’50/ˆ’36 of the MITF promoter	SIGNOR-249616	0.45
LIPH	protein	Q8WWY8	UNIPROT	LPAR2	protein	Q9HBW0	UNIPROT	up-regulates	binding			9606	BTO:0000661								9525886	t		gcesareni	When overexpressed in jurkat t cells, the edg4 protein mediated lpa-induced activation of a serum response element reporter gene with lpa concentration dependence (ec50 of 10 nm) and specificity.	SIGNOR-56093	0.299
PTEN	protein	P60484	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	dephosphorylation	Ser97	LRLAEDRsKDPHDPH	9606									32394474	t		lperfetto	PTEN can dephosphorylate IRF-3 S97 residue and facilitate its nuclear import for the IFN signaling pathway (7).|PTEN expression directly increases activated IRF-3 nuclear import and subsequent interferon (IFN) synthesis.	SIGNOR-277025	0.259
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	phosphorylation	Ser83	YIGRKKIsPPTPKPR	-1									21743495	t		miannu	 in vitro kinase assays using purified protein kinase A (PKA) and either GST fused full length p85 (GST-p85) or GST fused p85 peptide spanning amino acids 50-109 (GST-p85Δ2) as substrate.  Serine 83 phosphorylation on p85 is necessary for PI3K activation and membrane translocation in 14-3-3ζ overexpressing cells 	SIGNOR-276343	0.2
RPAP2	protein	Q8IXW5	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1784	TPTSPNYsPTSPSYS	9606	BTO:0000567								22137580	t			In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248757	0.727
p38	proteinfamily	SIGNOR-PF16	SIGNOR	EEF2K	protein	O00418	UNIPROT	down-regulates activity	phosphorylation			-1									12171600	t	inferred from 70% family members	miannu	Inhibition of eEF2 kinase resulting from phosphorylation of Ser-396 by SAPK2a p38 was approx.25%.	SIGNOR-270127	0.2
PIM	proteinfamily	SIGNOR-PF34	SIGNOR	RELA	protein	Q04206	UNIPROT	up-regulates	phosphorylation	Ser276	SMQLRRPsDRELSEP	9606									19911008	t		llicata	In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276.	SIGNOR-259411	0.2
UTS2R	protein	Q9UKP6	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256922	0.252
MAPK14	protein	Q16539	UNIPROT	EZH2	protein	Q15910	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr367	NNSSRPStPTINVLE	10090	BTO:0000165								28067271	t			Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372	SIGNOR-255663	0.381
SOCS1	protein	O15524	UNIPROT	VAV1	protein	P15498	UNIPROT	down-regulates quantity by destabilization	binding			9534	BTO:0000298								10747851	t		miannu	SOCS1 stimulates the polyubiquitination of VAV proteins in vivo, which was stabilized by proteasomal inhibitors. These results suggest that SOCS1 programs VAV degradation by acting as a substrate-specific recognition component of a VCB-like ubiquitin ligase complex.	SIGNOR-272559	0.58
LCMT1	protein	Q9UIC8	UNIPROT	PPP2CB	protein	P62714	UNIPROT	up-regulates activity	methylation	Leu309	RRTPDYFl	-1									18394995	t		lperfetto	Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1)	SIGNOR-265751	0.647
CXCL9	protein	Q07325	UNIPROT	CXCR3	protein	P49682	UNIPROT	up-regulates activity	binding			9606	BTO:0000782								12750173	t		miannu	The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells.	SIGNOR-260970	0.775
PRKACA	protein	P17612	UNIPROT	ETV5	protein	P41161	UNIPROT	up-regulates activity	phosphorylation	Ser367	PPYQRRGsLQLWQFL	9606	BTO:0002909								11682477	t		lperfetto	We further show that the increase in erm transcriptional activity after pka phosphorylation is closely correlated with a drastic reduction in the dna binding of the transcription factor. These results indicate that the phosphorylation of erm by pka is involved in erm-mediated transcription and suggest that the activation of erm is probably related to conformational changes.	SIGNOR-111239	0.2
NOTCH1	protein	P46531	UNIPROT	TCFL5	protein	Q9UL49	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782								16990763	f		gcesareni	Interestingly, in absence of delta signal, both hes-1 and tcfl5 decreased, and further decreased by incubation with dapt. (figure 4). This pharmacological approach therefore provides additional evidence that tcfl5, similar to hes1, is a true notch target gene.	SIGNOR-149807	0.2
CDKN2A	protein	Q8N726	UNIPROT	ATR	protein	Q13535	UNIPROT	up-regulates activity	phosphorylation			9606									15775976	t		gcesareni	Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressorInduction of ATR activity in Hs68 E2F1ER cells by endogenous ARF.	SIGNOR-134781	0.4
JUN	protein	P05412	UNIPROT	SMAD4	protein	Q13485	UNIPROT	up-regulates activity	binding			9615									9312063	t		lperfetto	Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter.	SIGNOR-236139	0.663
TCOF1	protein	Q13428	UNIPROT	NBN	protein	O60934	UNIPROT	up-regulates activity	relocalization			9606									25064736	t		lperfetto	We further identify TCOF1 (also known as Treacle), a nucleolar factor implicated in ribosome biogenesis and mutated in Treacher Collins syndrome, as an interaction partner of NBS1, and demonstrate that NBS1 translocation and accumulation in the nucleoli is Treacle dependent.	SIGNOR-265085	0.324
AGRP	protein	O00253	UNIPROT	MC5R	protein	P33032	UNIPROT	down-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268714	0.568
RAB3C	protein	Q96E17	UNIPROT	Dense-core_vesicle_exocytosis	phenotype	SIGNOR-PH184	SIGNOR	up-regulates				9606									31679900	f		miannu	Here, we identify the SEC4 ortholog RAB3 and its neuronal effector, RIM1, as essential molecules for neuropeptide and neurotrophin release from dense-core vesicles (DCVs) in mammalian neurons. 	SIGNOR-264376	0.7
CHEK1	protein	O14757	UNIPROT	WEE1	protein	P30291	UNIPROT	up-regulates	phosphorylation			9606									20068082	t		gcesareni	Chk1 also phosphorylates and stabilizes wee1.	SIGNOR-163164	0.595
AP-3/clathrin vescicle	complex	SIGNOR-C250	SIGNOR	oligopeptide	smallmolecule	CHEBI:25676	ChEBI	up-regulates quantity	relocalization			9606									25720354	t		scontino	APCs cell surface receptors facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. It is in these compartments that internalized antigen proteolysis and peptide–MHC class II complex formation takes place.	SIGNOR-267862	0.8
nilotinib	chemical	CHEBI:52172	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258257	0.8
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	DEPTOR	protein	Q8TB45	UNIPROT	down-regulates	phosphorylation	Ser287	SMSSCGSsGYFSSSP	9606									22017877	t		lperfetto	We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1	SIGNOR-252798	0.2
IL15RA	protein	Q13261	UNIPROT	PPARG	protein	P37231	UNIPROT	down-regulates activity				9606									30029643	f		areggio	In addition, level of mRNAs encoding C/EBPa, PPARg and FABP4, the classic adipogenic markers, was significantly lower in samples administrated with IL-15	SIGNOR-256228	0.2
U0126	chemical	CHEBI:90693	ChEBI	MAP2K2	protein	P36507	UNIPROT	down-regulates	chemical inhibition			9606									9873633	t		gcesareni	The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. U0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2.	SIGNOR-62895	0.8
CSNK2A2	protein	P19784	UNIPROT	PPP1R8	protein	Q12972	UNIPROT	up-regulates activity	phosphorylation	Thr161	LGLPEEEtELDNLTE	-1									9407077	t		llicata	Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2.	SIGNOR-251024	0.484
JAK3	protein	P52333	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates activity	phosphorylation	Tyr1035	IETDKEYyTVKDDRD	-1									12559972	t			Phosphorylation by recombinant JAK3 of a peptide substrate corresponding to the JAK1 activation loop (KAIETDKEYYTVKD)	SIGNOR-251364	0.515
SLC18A2	protein	Q05940	UNIPROT	BLOC-1	complex	SIGNOR-C381	SIGNOR	up-regulates activity	binding			9606	BTO:0000132								23805129	t		lperfetto	The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules 	SIGNOR-265997	0.2
PRKACA	protein	P17612	UNIPROT	TNNI3	protein	P19429	UNIPROT	up-regulates activity	phosphorylation	Ser23	PAPIRRRsSNYRAYA	9606									15769444	t		lperfetto	Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.	SIGNOR-134605	0.398
GABA-A (a6-b3-d) receptor	complex	SIGNOR-C329	SIGNOR	chloride	smallmolecule	CHEBI:17996	ChEBI	up-regulates quantity	relocalization			9606									18790874	t	brain	lperfetto	 GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition)	SIGNOR-263817	0.8
SIRT5	protein	Q9NXA8	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									31608237	f		Monia	In SIRT5 silenced Mero-14 cells, beclin-1 protein levels were downregulated upon rotenone and resveratrol treatment. In summary, in most cases, where significant effects were detected, SIRT1, SIRT3, and SIRT5 had positive effects on beclin1 and LC3II/LC3I ratio	SIGNOR-261206	0.322
CDK1	protein	P06493	UNIPROT	NUSAP1	protein	Q9BXS6	UNIPROT	down-regulates	phosphorylation	Thr338	GNSAAVItPFKLTTE	9606									22101338	t		llicata	We report here that cdk1 phosphorylates nusap at threonine 300 and 338 in early mitosis. Phosphorylation of nusap inhibits its microtubule-binding activity in vitro and in vivo.	SIGNOR-177549	0.442
SOD1	protein	P00441	UNIPROT	S100A4	protein	P26447	UNIPROT	up-regulates quantity				9606	BTO:0000452	BTO:0001279							31623154	f	P00441:p.Gly94Ala (mutation increasing interaction)		We demonstrated the increased expression of S100A4 also in fibroblasts derived from amyotrophic lateral sclerosis (ALS) patients carrying SOD1 pathogenic variants.	SIGNOR-262784	0.2
NFATC3	protein	Q12968	UNIPROT	CTSD	protein	P07339	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16219765	f		miannu	Overexpression of NFAT3 enhanced both ERalpha and ERbeta transcriptional activities in a ligand-independent manner and up-regulated downstream estrogen-responsive genes including pS2 and cathepsin D. Reduction of endogenous NFAT3 with NFAT3 small interfering RNA or overexpression of NFAT3 deletion mutants that lack the ER-binding sites reduced the NFAT3 coactivation of ERalpha and ERbeta.	SIGNOR-254640	0.2
CDK2	protein	P24941	UNIPROT	PGR	protein	P06401	UNIPROT	unknown	phosphorylation	Ser676	LSQRFTFsPGQDIQL	9606									11110801	t		llicata	In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676).	SIGNOR-84996	0.453
GAMT	protein	Q14353	UNIPROT	Neurite_outgrowth	phenotype	SIGNOR-PH134	SIGNOR	up-regulates				-1									26319512	f		Luana	GAMT enzyme (EC#2.1.1.2) deficiency caused by mutations in the GAMT gene (MIM# 601240) results in the depletion of creatine and accumulation of guanidinoacetate (GAA). Creatine has a buffering and transport function of high-energy phosphates in brain and muscle and is essential for growth cone migration, dendritic and axonal elongation, neurotransmitter release, and co-transmission on gamma amino butyric acid (GABA) postsynaptic receptors in the central nervous system	SIGNOR-265795	0.7
ATM	protein	Q13315	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser20	PLSQETFsDLWKLLP	9606	BTO:0000552								20663147	t		gcesareni	DeltaNp63alpha depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of DeltaNp63alpha in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation	SIGNOR-167156	0.838
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	HDAC6	protein	Q9UBN7	UNIPROT	up-regulates	phosphorylation	Thr1031	ASSTDHQtPPTSPVQ	9606									24089523	t		lperfetto	Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1	SIGNOR-244549	0.2
LSM-20934	chemical	CHEBI:109533	ChEBI	DRD2	protein	P14416	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258727	0.8
ERG	protein	P11308	UNIPROT	WNT11	protein	O96014	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21242973	f	 	miannu	 ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts. 	SIGNOR-254071	0.2
PTPN2	protein	P17706	UNIPROT	FYN	protein	P06241	UNIPROT	down-regulates	dephosphorylation	Tyr420	RLIEDNEyTARQGAK	9606	BTO:0000782								22080863	t		lperfetto	Previously, we reported that sfks can serve as bona fide substrates for tcptp and that tcptp dephosphorylates the y418 activation loop autophosphorylation site (corresponding to y394 in lck and y417 in fyn) to inactivate sfks	SIGNOR-177113	0.331
MRGPRX1	protein	Q96LB2	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257326	0.2
FRAT1	protein	Q92837	UNIPROT	GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	up-regulates	binding			9606									9635432	t		lperfetto	The frat family consists of three members: frat-1, -2, and -3. It has been shown that different sites of frat-1 interact with gsk-3 and dvl-1 and that wnt-1 disintegrates the complex formation of frat-1, dvl-1, and axin, resulting in the activation of the wnt signaling pathway	SIGNOR-227994	0.628
MAP2K4	protein	P45985	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates	phosphorylation	Thr221	AGTSFMMtPYVVTRY	9606	BTO:0000007								17761173	t		lperfetto	We next examined whether the phosphorylation of JNK at threonine 183 (Thr183) and tyrosine 185 (Tyr185) was enhanced by GRASP‐1 expression. Phosphorylation of Thr183 and Tyr185 by SEK1/MKK4, which is in turn phosphorylated and activated by several kinases including MEKK1, is known to activate JNK1/2/3	SIGNOR-260614	0.732
ABL1	protein	P00519	UNIPROT	ABI1	protein	Q8IZP0	UNIPROT	up-regulates	phosphorylation	Tyr213	PPTVPNDyMTSPARL	9606									21320496	t		lperfetto	Abi-1 is an adaptor protein for abelson kinase (c-abl). Here, we identified a new phosphorylation site (y398) in the sh3 domain of abi1, and disruption of y398, combined with the previously identified phosphorylation site y213, significantly weakens the binding of abi-1 to c-abl. Phosphorylation of abi-1 is dependent on c-abl kinase	SIGNOR-172017	0.876
NR0B2	protein	Q15466	UNIPROT	NR1H3	protein	Q13133	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000195								12198243	f		gcesareni	Here we show that shp can interact with the liver x receptors lxr? (nr1h3) and lxr? (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter. T	SIGNOR-91996	0.491
TNF	protein	P01375	UNIPROT	DNAH10	protein	Q8IVF4	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000667								31836722	f		miannu	The protein expression of DNAH10 was assessed by Western blot analysis after stimulation of primary keratinocytes (P4) with inflammatory cytokine TNFα or growth factor TGF-β1 and their combination (Fig. 5C). Treatment with TNFα, TGF-β1, and their combination down regulated the expression of DNAH10 in keratinocytes after a 24-h-stimulation. 	SIGNOR-265551	0.2
TP53	protein	P04637	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates quantity by repression	transcriptional regulation												10329733	f		lperfetto	P53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor.	SIGNOR-271677	0.739
SLC20A1	protein	Q8WUM9	UNIPROT	phosphate(3-)	smallmolecule	CHEBI:18367	ChEBI	up-regulates quantity	relocalization			9606									11009570	t		lperfetto	Three families of NPCs have been reported to date. The type I family consists of a single species (NaPi-1), which has thus far been found only in rabbit kidney.28 The type II family consists of six species homologues, NaPi 2 to 7, that are expressed predominantly in renal epithelial tissues.The type III family is the most recently identified and consists of two members, Pit-1 (also called Glvr-1) and Pit-2 (also called Ram-1).34 	SIGNOR-270579	0.8
ANGPT2	protein	O15123	UNIPROT	TEK	protein	Q02763	UNIPROT	up-regulates	binding			9606									9723709	t		lperfetto	Angiopoietin-1 and -2, bound to tek with similar affinities, and angiopoietin-1 effectively induced tek phosphorylation in hematopoietic cells. Angiopoietin-2 also induced a low level of tek phosphorylation and weakened the phosphorylation induced by angiopoietin-1	SIGNOR-59808	0.923
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	ZC3HC1	protein	Q86WB0	UNIPROT	down-regulates	phosphorylation	Ser395	PGLEVPSsPLRKAKR	9606									17389604	t		lperfetto	Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1	SIGNOR-216880	0.341
CSAD	protein	Q9Y600	UNIPROT	beta-alanine zwitterion	smallmolecule	CHEBI:57966	ChEBI	up-regulates quantity	chemical modification			9606									22718265	t		miannu	Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate α-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of α-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce γ-aminobutyric acid (GABA), β-alanine and hypotaurine, respectively; these amine products play important role in living organisms.	SIGNOR-267549	0.8
RNF123	protein	Q5XPI4	UNIPROT	CBX1	protein	P83916	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									23077635	t		miannu	In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation.	SIGNOR-272034	0.2
RPS6KA3	protein	P51812	UNIPROT	NFATC4	protein	Q14934	UNIPROT	up-regulates	phosphorylation	Ser285	SSASPALsRRGSLGE	10090									17213202	t		lperfetto	Serines 281 and 285 of the nfat3 protein might be target amino acids of rsk2 phosphorylationrsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo.	SIGNOR-234469	0.395
RNF5	protein	Q99942	UNIPROT	MAVS	protein	Q7Z434	UNIPROT	down-regulates quantity by destabilization	ubiquitination	Lys461	GPEENEYkSEGTFGI	9606	BTO:0000007								20483786	t		miannu	In this study, we showed that the E3 ubiquitin ligase RING-finger protein 5 (RNF5) interacted with VISA at mitochondria in a viral infection-dependent manner. Domain mapping experiments indicated that the C-terminal transmembrane domain of VISA was required for its interaction with RNF5. RNF5 targeted VISA at K362 and K461 for K48-linked ubiquitination and degradation after viral infection, whereas knockdown of RNF5 reversed virus-induced downregulation of VISA at the early phase. 	SIGNOR-271489	0.468
MET	protein	P08581	UNIPROT	IQGAP1	protein	P46940	UNIPROT	up-regulates activity	phosphorylation	Tyr1510	LVKLQQTyAALNSKA	9606	BTO:0000815								33087447	t		miannu	IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET.	SIGNOR-277532	0.275
MINK1	protein	Q8N4C8	UNIPROT	PRICKLE1	protein	Q96MT3	UNIPROT	up-regulates activity	phosphorylation	Thr370	LSGNADDtLSRKLDD	-1									22037766	t		miannu	 We show that Mink1 phosphorylates Prickle on a conserved threonine residue and regulates its Rab5-dependent endosomal trafficking, a process required for the localized plasma membrane accumulation and function of Prickle. 	SIGNOR-263095	0.298
SRC	protein	P12931	UNIPROT	IQGAP1	protein	P46940	UNIPROT	up-regulates activity	phosphorylation	Tyr1510	LVKLQQTyAALNSKA	9606	BTO:0000815								33087447	t		miannu	IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET.	SIGNOR-277533	0.683
ALK	protein	Q9UM73	UNIPROT	CDK9	protein	P50750	UNIPROT	up-regulates activity	phosphorylation	Tyr19	FCDEVSKyEKLAKIG	-1									36253486	t		miannu	We report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes.	SIGNOR-277607	0.3
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1724	SPSYSPTsPSYSPTS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248776	0.441
CHEK1	protein	O14757	UNIPROT	CHEK1	protein	O14757	UNIPROT	up-regulates activity	phosphorylation	Ser296	GFSKHIQsNLDFSPV	8355									15707391	t		lperfetto	This suggests that Ser296 is probably one of the sites autophosphorylated when Chk1 is fully activated [21], despite the sequence surrounding Ser296 (FSKHIQS296NL) being only weakly related to the optimal Chk1-recognition motif (M/I/L/V)-X-(R/K)-X-X-(S/T), where (S/T) is the phosphorylated residue	SIGNOR-219240	0.2
TFAP2A	protein	P05549	UNIPROT	DCC	protein	P43146	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19745029	f		miannu	 Promoter analysis and transfection studies showed that the up-regulation of DCC in OA chondrocytes may be mediated by the transcription factors Sox9 and AP-2. 	SIGNOR-255189	0.2
GRM8	protein	O00222	UNIPROT	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000938								29953871	t		miannu	Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening.	SIGNOR-264939	0.8
CSNK1E	protein	P49674	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates	phosphorylation	Ser314	SREQSTDsGLGLGCY	9606									24715453	t		milica	LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)	SIGNOR-230747	0.342
PRKACA	protein	P17612	UNIPROT	CCND1	protein	P24385	UNIPROT	unknown	phosphorylation	Ser234	YRLTRFLsRVIKCDP	-1									8058338	t		miannu	PKA phosphorylates three distinct serine residues in cyclin D1 at positions 90, 197 and 234.	SIGNOR-250346	0.338
SOS1	protein	Q07889	UNIPROT	KRAS	protein	P01116	UNIPROT	up-regulates	guanine nucleotide exchange factor			9606									25624485	t	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.	gcesareni	Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts 	SIGNOR-201703	0.821
ZNF322	protein	Q6U7Q0	UNIPROT	NANOG	protein	Q9H9S0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									24550733	t		lperfetto	Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays revealed that Zfp322a binds to Pou5f1 and Nanog promoters and regulates their transcription.	SIGNOR-264899	0.2
MELK	protein	Q14680	UNIPROT	MELK	protein	Q14680	UNIPROT	up-regulates	phosphorylation	Thr398	SQFTKYWtESNGVES	9606									16216881	t		lperfetto	We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase.	SIGNOR-141026	0.2
PPP2R5C	protein	Q13362	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	down-regulates	binding			9606									20444422	t		gcesareni	The human homolog of pp2a-b', ppp2r5c, also counteracts s6k1 phosphorylation, indicating a conserved mechanism in mammals	SIGNOR-165224	0.347
RPS10	protein	P46783	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262442	0.897
FGFR2	protein	P21802	UNIPROT	FRS2	protein	Q8WU20	UNIPROT	up-regulates activity	phosphorylation			10116	BTO:0002809								9182757	t		fspada	In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.	SIGNOR-236950	0.769
PRKCD	protein	Q05655	UNIPROT	PLSCR1	protein	O15162	UNIPROT	up-regulates	phosphorylation	Thr161	CGPSRPFtLRIIDNM	9606									10770950	t		lperfetto	Following the induction of apoptosis, however, phosphorylation of serine residues decreased and it increased on threonine, consistent with the predicted pkc phosphorylation site at thr-161. Transfection of cho cells with scramblase and pkc_, but not scramblase or pkc_ alone, increased scramblase activity	SIGNOR-76904	0.434
CSNK1D	protein	P48730	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates activity	phosphorylation	Ser269	SEEGQELsDEDDEVY	9606									12167711	t		gcesareni	Hypophosphorylation of mdm2 augments p53 stability.	SIGNOR-91191	0.351
DNMT1	protein	P26358	UNIPROT	GAD1	protein	Q99259	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									19029285	f		miannu	 induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. 	SIGNOR-254574	0.356
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	phosphorylation			10090	BTO:0000011								12270934	t		lperfetto	Our results suggest that activation of the MEK/ERK signaling pathway during the initial 12 h of adipogenesis enhances the activity of factors that regulate both C/EBPalpha and PPARgamma expression.	SIGNOR-235334	0.2
PRKCA	protein	P17252	UNIPROT	HES1	protein	Q14469	UNIPROT	down-regulates activity	phosphorylation	Ser38	ASEHRKSsKPIMEKR	-1									9389649	t		lperfetto	Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro.	SIGNOR-248993	0.335
PITX2	protein	Q99697	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							20978076	f		gcesareni	We show that pitx2 is crucial for the onset of myod gene expression in limb muscle progenitors and that it acts on the myod core enhancer.	SIGNOR-169107	0.449
SP1	protein	P08047	UNIPROT	RHO	protein	P08100	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								15781457	f		miannu	Sp4 and Sp1 are activators of the rod opsin promoter	SIGNOR-225385	0.2
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	VASP	protein	P50552	UNIPROT	down-regulates	phosphorylation	Thr278	LARRRKAtQVGEKTP	9606	BTO:0000551								21423205	t		lperfetto	Rsk1 phosphorylated vasp on t278, a site regulating its binding to actin.	SIGNOR-252802	0.2
G6PD	protein	P11413	UNIPROT	NADPH(4-)	smallmolecule	CHEBI:57783	ChEBI	up-regulates quantity	chemical modification			9606									24769394	t		miannu	The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle	SIGNOR-267052	0.8
MAPK3	protein	P27361	UNIPROT	ETS1	protein	P14921	UNIPROT	up-regulates	phosphorylation	Thr38	CADVPLLtPSSKEMM	9606									11948414	t		gcesareni	We found that hgf/sf activates the erk1 map kinase, leading to the phosphorylation of the threonine 38 residue of ets1	SIGNOR-116494	0.658
MYC	protein	P01106	UNIPROT	PRPS2	protein	P11908	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18677108	t		miannu	Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.	SIGNOR-267376	0.281
PRKG1	protein	Q13976	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates	phosphorylation	Ser795	TASTRKVsLAPQANL	9606									1377674	t		lperfetto	Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function	SIGNOR-18249	0.521
MAPKAPK2	protein	P49137	UNIPROT	UBE2J1	protein	Q9Y385	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser184	KELARQIsFKAEVNS	9606	BTO:0000567								24020373	t		miannu	Endoplasmic reticulum-associated ubiquitin-conjugating enzyme Ube2j1 is a novel substrate of MK2 (MAPKAP kinase-2) involved in MK2-mediated TNFα production. These findings strongly suggest that MK2 directly phosphorylates Ube2j1 at Ser(184) upon p38-activating stress in vivo.	SIGNOR-263091	0.339
ZMYND11	protein	Q15326	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	binding										methylation:Lys38	PSTGGVKkPHRYRPG	24675531	t		miannu	We found that full-length BS69 specifically interacted with H3K36me3 in native nucleosome co-immunoprecipitation (co-IP) experiments. We propose that BS69 specifically associates with H3K36me3-enriched chromatin through the PWWP domain, which facilitates the recruitment of MYND-bound transcription and chromatin remodeling factors including EZH2, HDAC1, Brg1 and E2F6 to target gene loci, thereby repressing target gene transcription.	SIGNOR-263897	0.2
palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	precursor of			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267883	0.8
PROC	protein	P04070	UNIPROT	F5	protein	P12259	UNIPROT	down-regulates activity	cleavage			9606		BTO:0000131							29880919	t		lperfetto	Activated protein C (APC), which cleaves and inactivates both FVIIIa and FVa, thereby shutting down both the tenase and prothrombinase complexes	SIGNOR-263528	0.583
2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-pyrazolyl]-3-azetidinyl]acetonitrile	chemical	CHEBI:95341	ChEBI	JAK1	protein	P23458	UNIPROT	down-regulates activity	chemical inhibition			9606									20363976	t		Luana	INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM).	SIGNOR-257833	0.8
NFYB	protein	P25208	UNIPROT	PHGDH	protein	O43175	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18378410	f		miannu	Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y.	SIGNOR-255210	0.2
SORBS1	protein	Q9BX66	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	binding			9606		BTO:0000887							11001060	t		gcesareni	Cbl is recruited to the insulin receptor by interaction with the adapter protein cap, through one of three adjacent sh3 domains in the carboxy terminus of cap	SIGNOR-82283	0.675
N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide	chemical	CHEBI:94525	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194548	0.8
bromocriptine	chemical	CHEBI:3181	ChEBI	DRD2	protein	P14416	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258723	0.8
40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	43S_pre_initiation_complex	complex	SIGNOR-C453	SIGNOR	form complex	binding			9606									35489072	t		lperfetto	In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 	SIGNOR-269160	0.2
CBX4	protein	O00257	UNIPROT	ZEB2	protein	O60315	UNIPROT	down-regulates quantity by destabilization	sumoylation	Lys866	PLNLTFIkKEFSNSN	9534	BTO:0001538								16061479	t		Luisa	Pc2 can act directly as an E3 ligase for SIP1 sumoylation.SIP1 sumoylation having a negative effect on its repression of E-cadherin transcription. 	SIGNOR-269113	0.336
IFNG	protein	P01579	UNIPROT	LPL	protein	P06858	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000801								2114181	f	Regulation	miannu	Interferon-gamma inhibits lipoprotein lipase in human monocyte-derived macrophages. The data indicate that IFN-gamma is inhibiting macrophage LPL at least in part via a reduction of LPL synthesis	SIGNOR-251848	0.364
MUTYH	protein	Q9UIF7	UNIPROT	Base-excision_repair	phenotype	SIGNOR-PH222	SIGNOR	up-regulates													23545420	f		lperfetto	The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1).	SIGNOR-275716	0.7
MAPK6	protein	Q16659	UNIPROT	TDP2	protein	O95551	UNIPROT	up-regulates activity	phosphorylation	Ser60	EMERALNsYFEPPVE	-1									26701725	t		miannu	In the current study, we have found that ERK3, an atypical MAPK, phosphorylates TDP2 at S60 and regulates TDP2's phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against Top2 inhibitors-induced DNA damage and growth inhibition. 	SIGNOR-277188	0.386
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ATG4B	protein	Q9Y4P1	UNIPROT	up-regulates activity	phosphorylation	Ser34	WILGRKYsIFTEKDE	9606	BTO:0000586								29165041	t		lperfetto	 In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells.| In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity.	SIGNOR-275836	0.2
GRK6	protein	P43250	UNIPROT	BDKRB2	protein	P30411	UNIPROT	down-regulates activity	phosphorylation	Ser375	GTLRTSIsVERQIHK	9606	BTO:0000007								11517230	t			Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251206	0.292
PRKCB	protein	P05771	UNIPROT	GRIN2B	protein	Q13224	UNIPROT	up-regulates activity	phosphorylation	Ser1323	ALAPRSVsLKDKGRF	-1									11306676	t		lperfetto	These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels.	SIGNOR-249087	0.371
AKT3	protein	Q9Y243	UNIPROT	ADARB1	protein	P78563	UNIPROT	down-regulates activity	phosphorylation	Thr553	LQGERLLtMSCSDKI	-1									31095429	t		miannu	AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively	SIGNOR-276195	0.2
serotonin(1+)	smallmolecule	CHEBI:350546	ChEBI	HTR7	protein	P34969	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257526	0.8
MAPK1	protein	P28482	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	phosphorylation	Ser296	SPSALSSsPNNLSPT	10090									15664191	t		lperfetto	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-249442	0.616
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ELK1	protein	P19419	UNIPROT	up-regulates activity	phosphorylation			9606									22085529	t		miannu	Both mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinases (ERK) 1/2 and phosphatidylinositide-3-OH kinase (PI3K)/Akt pathways regulate activation of E-twenty-six (ETS)-like transcription factor 1 (Elk-1) in U138 glioblastoma cells. The phosphatidylinositide-3-OH kinase (PI3K)/Akt pathway was also involved in the Elk-1 activation. Activation of the Elk-1 led to an increased survival and a proliferative response with the EGF stimulation in the U138 glioblastoma cells.	SIGNOR-259029	0.2
RPS25	protein	P62851	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262426	0.904
MAPK8	protein	P45983	UNIPROT	HNRNPK	protein	P61978	UNIPROT	up-regulates	phosphorylation	Ser353	DSAIDTWsPSEWQMA	9606									11259409	t		gcesareni	The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein.	SIGNOR-105770	0.381
PCSK2	protein	P16519	UNIPROT	IAPP	protein	P10997	UNIPROT	up-regulates activity	cleavage	Arg33	ESHQVEKrKCNTATC	-1									10931181	t		lperfetto	The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule	SIGNOR-261791	0.478
NUP43	protein	Q8NFH3	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262087	0.682
HOOK1	protein	Q9UJC3	UNIPROT	PTPN11	protein	Q06124	UNIPROT	down-regulates activity	binding			9606	BTO:0000018								25331952	t		miannu	The protein-tyrosine phosphatase domain and N-terminal SH2 domain of SHP2 directly interacted with Hook1. Down-regulation of Hook1 increased SHP2 activity. These results suggested that Hook1 was an endogenous negative regulator of SHP2 phosphatase activity. 	SIGNOR-260642	0.362
MSL acetyltransferase	complex	SIGNOR-C344	SIGNOR	H2BU1	protein	Q8N257	UNIPROT	down-regulates activity	monoubiquitination	Lys35	KKRKRGRkESYSIYV	9606									21726816	t		miannu	MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation.	SIGNOR-271990	0.2
MAPK7	protein	Q13164	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates activity	phosphorylation	Ser255	HATSGALsPAKDCGS	9606	BTO:0000007								12637502	t		miannu	Activated BMK1 selectively phosphorylates Cx43 on Ser-255 in vitro and in vivo. These data demonstrate that BMK1 kinase activity alone is both a necessary and sufficient component in the mediation of EGF-induced Cx43 Ser-255 phosphorylation and subsequent inhibition of GJC.	SIGNOR-250115	0.524
PSMB3	protein	P49720	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263359	0.859
ACTL6A	protein	O96019	UNIPROT	Muscle cell-specific SWI/SNF ARID1A variant	complex	SIGNOR-C481	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270699	0.821
GSK3A	protein	P49840	UNIPROT	MAFB	protein	Q9Y5Q3	UNIPROT	up-regulates	phosphorylation			9606									18042454	t		miannu	We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.	SIGNOR-159429	0.2
TNFRSF1A	protein	P19438	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity													20887952	f			These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs	SIGNOR-253602	0.38
AKT1	protein	P31749	UNIPROT	LARP1	protein	Q6PKG0	UNIPROT	down-regulates activity	phosphorylation	Ser1056	EGRKRCPsQSSSRPA	9606	BTO:0002181								28650797	t		SARA	LARP1 is a direct substrate of Akt/S6K1 and mTORC1. Akt is a physiologically relevant primary kinase for S770/S979 phosphorylation of LARP1|Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation.	SIGNOR-260992	0.292
LY294002	chemical	CHEBI:65329	ChEBI	PIK3R1	protein	P27986	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000222	BTO:0000887;BTO:0001103							10896679	t		gcesareni	Here we show that inhibition of pi3-k activity by the pharmacological agent ly294002 affects early processes of myoblast differentiation including the transcriptional activation of myogenin.	SIGNOR-79347	0.8
NOTCH1	protein	P46531	UNIPROT	PAX7	protein	P23759	UNIPROT	up-regulates quantity by expression				9606		BTO:0001103;BTO:0002314							22493066	f		lperfetto	Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells	SIGNOR-219374	0.401
SAM complex	complex	SIGNOR-C422	SIGNOR	Insertion into mitochondrial membrane	phenotype	SIGNOR-PH193	SIGNOR	up-regulates													33408415	f		lperfetto	The mitochondrial outer membrane contains so-called β-barrel proteins, which allow communication between the cytosol and the mitochondrial interior1-3. Insertion of β-barrel proteins into the outer membrane is mediated by the multisubunit mitochondrial sorting and assembly machinery (SAM, also known as TOB)	SIGNOR-267687	0.7
EXOSC4	protein	Q9NPD3	UNIPROT	Exosome_Complex	complex	SIGNOR-C255	SIGNOR	form complex	binding			-1									24189234	t		miannu	The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 	SIGNOR-261383	0.917
POU5F1	protein	Q01860	UNIPROT	ID2	protein	Q02363	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001086								17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254937	0.293
(S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide	chemical	CID:6918848	PUBCHEM	HDAC10	protein	Q969S8	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002428								31908417	t		miannu	The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs.	SIGNOR-262249	0.8
PPP6C	protein	O00743	UNIPROT	MAP3K7	protein	O43318	UNIPROT	down-regulates	dephosphorylation	Thr187	CDIQTHMtNNKGSAA	9606									17079228	t		gcesareni	Our results demonstrate that pp6 specifically down-regulates tak1 through dephosphorylation of thr-187 in the activation loop, which is likely important for suppressing inflammatory responses via tak1 signaling pathways.	SIGNOR-150408	0.379
CDK5	protein	Q00535	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Ser732	SSEGFYPsPQHMVQT	9606	BTO:0000938								12941275	t		gcesareni	Here, we show that fak phosphorylation by cdk5 at s732 is important for microtubule organization, nuclear movement, and neuronal migration. In cultured neurons, s732-phosphorylated fak is enriched along a centrosome-associated microtubule fork that abuts the nucleus. Overexpression of the nonphosphorylatable mutant fak s732a results in disorganization of the microtubule fork and impairment of nuclear movement in vitro, and neuronal positioning defects in vivo.	SIGNOR-86223	0.311
MAGEL2	protein	Q9UJ55	UNIPROT	TRIM27	protein	P14373	UNIPROT	up-regulates activity	binding			9606									23452853	t		miannu	MAGE proteins are a family of proteins that contain a conserved domain known as the MAGE homology domain. Recently, we showed that MAGE proteins function biochemically to bind to and enhance the activity of E3 RING ubiquitin ligases. The E3 RING ubiquitin ligase TRIM27 was identified as a major binding partner of MAGE-L2.	SIGNOR-253513	0.536
PAK1	protein	Q13153	UNIPROT	H3C1	protein	P68431	UNIPROT	unknown	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									12151336	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Histone h3 is a substrate of pak1 both in vitro and in vivo, and it specifically interacted with pak1 but not pak2 or pak3. Site-directed mutagenesis indicated that pak1 phosphorylates histone h3 on ser10.	SIGNOR-91050	0.2
CCT365623 (hydrochloride)	chemical	CID:139266765	PUBCHEM	LOX	protein	P28300	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000195								31070916	t		Simone Vumbaca	Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy.	SIGNOR-261121	0.8
NEK6	protein	Q9HC98	UNIPROT	ACD	protein	Q96AP0	UNIPROT	up-regulates activity	phosphorylation	Ser169	SNAGLSLsQLLDEMR	9606	BTO:0000007								27396482	t		lperfetto	NEK6-mediated phosphorylation of human TPP1 regulates telomere length through telomerase recruitment|Shelterin component TPP1 plays critical roles in chromosome end protection and telomere length regulation. Specifically, TPP1 contains an OB-fold domain that provides an interface to recruit telomerase.|	SIGNOR-264424	0.2
TOP2B	protein	Q02880	UNIPROT	CDH13	protein	P55290	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24463367	f		lperfetto	While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development	SIGNOR-242302	0.2
SPI1	protein	P17947	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				10090	BTO:0004730								12130514	f		lperfetto	The transcription factor PU.1 is required for normal blood cell development. PU.1 regulates the expression of a number of crucial myeloid genes, such as the macrophage colony-stimulating factor (M-CSF) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Myeloid cells derived from PU.1(-/-) mice are blocked at the earliest stage of myeloid differentiation, similar to the blast cells that are the hallmark of human acute myeloid leukemia (AML). These facts led us to hypothesize that molecular abnormalities involving the PU.1 gene could contribute to the development of AML.	SIGNOR-249633	0.7
MMP7	protein	P09237	UNIPROT	SPP1	protein	P10451	UNIPROT	up-regulates activity	cleavage												25545242	t		lperfetto	In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA.	SIGNOR-253321	0.694
PRKAA1	protein	Q13131	UNIPROT	EEF2K	protein	O00418	UNIPROT	down-regulates activity	phosphorylation	Ser366	SPQVRTLsGSRPPLL	-1									14709557	t		miannu	AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase	SIGNOR-250402	0.473
NMDA receptor_2B	complex	SIGNOR-C348	SIGNOR	CTTN	protein	Q14247	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000142								14684878	t		miannu	Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors.	SIGNOR-266600	0.304
MAPK11	protein	Q15759	UNIPROT	MAPKAPK5	protein	Q8IW41	UNIPROT	up-regulates	phosphorylation	Thr182	IDQGDLMtPQFTPYY	9606	BTO:0000567								9628874	t		gcesareni	Prak activity was regulated by p38alpha and p38beta both in vitro and in vivo and thr182 was shown to be the regulatory phosphorylation site.	SIGNOR-58131	0.602
SRC	protein	P12931	UNIPROT	HNF4A	protein	P41235	UNIPROT	down-regulates	phosphorylation	Tyr23	SAALDPAyTTLEFEN	9606									22308320	t		lperfetto	Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function.	SIGNOR-195883	0.374
MAP3K1	protein	Q13233	UNIPROT	MAP2K6	protein	P52564	UNIPROT	up-regulates	phosphorylation	Thr211	LVDSVAKtIDAGCKP	9606									9712898	t		gcesareni	Both wild type and kinase-inactive mutant rip immunoprecipitates can active mkk6 in vitrohe sapks are activated by at least two meks, sapk/erk kinase-1 (sek1, also called mapk-kinase (mkk)) and mkk7	SIGNOR-59679	0.431
MAPK11	protein	Q15759	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation			9606									10085140	t		gcesareni	Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target	SIGNOR-65586	0.747
PRKCD	protein	Q05655	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Ser303	RGAPPRRsSIRNAHS	9606	BTO:0000130								12056906	t		esanto	Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?.	SIGNOR-89217	0.459
SRC	protein	P12931	UNIPROT	CDH2	protein	P19022	UNIPROT	down-regulates	phosphorylation	Tyr884	SSGGEQDyDYLNDWG	9606	BTO:0000848								16371504	t		lperfetto	Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated.	SIGNOR-143242	0.408
P2RY2	protein	P41231	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256902	0.2
UBE2C	protein	O00762	UNIPROT	Mitotic_checkpoint	phenotype	SIGNOR-PH28	SIGNOR	down-regulates				9606									19632176	f		miannu	The evolution of prostate cancer from an androgen-dependent state (ADPCa) to one that is androgen-independent (AIPCa) marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in AIPCa is poorly understood. We have defined the direct AR-dependent target genes in both AIPCa and ADPCa by generating AR-dependent gene expression profiles and AR cistromes. In contrast to ADPCa, AR selectively up-regulates M-phase cell cycle genes in AIPCa including UBE2C, a gene that inactivates the M-phase checkpoint. 	SIGNOR-251544	0.7
YAP/TAZ	proteinfamily	SIGNOR-PF120	SIGNOR	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606									23075495	f		miannu	YAP and TAZ are two main downstream effectors of the Hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis.	SIGNOR-277640	0.7
mono(2-ethylhexyl) phthalate	chemical	CHEBI:17243	ChEBI	OXER1	protein	Q8TDS5	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0001538								27551952	t		miannu	MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 	SIGNOR-268776	0.8
SCN10A	protein	Q9Y5Y9	UNIPROT	Action_potential 	phenotype	SIGNOR-PH82	SIGNOR	up-regulates				9606									26043074	f		miannu	The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons.	SIGNOR-253454	0.7
NMBR	protein	P28336	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256775	0.252
THR	proteinfamily	SIGNOR-PF84	SIGNOR	GATA2	protein	P23769	UNIPROT	down-regulates activity	binding			9606		BTO:0001073							29407449	t		scontino	We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2.	SIGNOR-267275	0.2
RRM2	protein	P31350	UNIPROT	Ribonucleotide reductase	complex	SIGNOR-C233	SIGNOR	form complex	binding			9606									14583450	t		miannu	Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2.	SIGNOR-259364	0.93
ARNT	protein	P27540	UNIPROT	CDK2	protein	P24941	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000599								21544813	f	 	lperfetto	Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC	SIGNOR-253693	0.261
LPAR1	protein	Q92633	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256696	0.537
PLK1	protein	P53350	UNIPROT	CENPQ	protein	Q7L2Z9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser249	LDILHNSsQMKSMST	9606	BTO:0000567								25670858	t		lperfetto	Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 	SIGNOR-265230	0.57
ATG5	protein	Q9H1Y0	UNIPROT	ATG12/5/16L1	complex	SIGNOR-C109	SIGNOR	form complex	binding			9606		BTO:0000007							18321988	t		lperfetto	Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex).	SIGNOR-226693	0.948
PRDM1	protein	O75626	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									12626569	t		miannu	The positive regulatory domain i binding factor 1 (prdi-bf1 or blimp-1) protein represses the transcription of specific target genes, including c-myc, the mhc class ii trans-activator, pax-5, and cd23b	SIGNOR-99119	0.449
CSNK1E	protein	P49674	UNIPROT	DVL3	protein	Q92997	UNIPROT	down-regulates activity	phosphorylation	Ser311	EINFENMsNDDAVRV	-1									24993822	t		miannu	Co-expression of CK1ϵ with FLAG-Dvl3 retards electrophoretic migration and induces phosphorylation-dependent shift of Dvl (PS-Dvl3). mutations of Ser-280 and Ser-311 prevent efficient activation of Wnt/β-catenin by Dvl3.	SIGNOR-276647	0.653
p38	proteinfamily	SIGNOR-PF16	SIGNOR	NFATC4	protein	Q14934	UNIPROT	down-regulates	phosphorylation	Ser168	QGGGAFFsPSPGSSS	9606									11997522	t		lperfetto	Phosphorylation of nfatc4 by p38 mitogen-activated protein kinasesthe p38 map kinase phosphorylates multiple residues, including ser(168) and ser(170), in the nfat homology domain of nfatc4. Replacement of ser(168,170) with ala promotes nuclear localization of nfatc4 and increases nfat-mediated transcription activity.	SIGNOR-87393	0.2
CDK1	protein	P06493	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	up-regulates	phosphorylation	Ser272	RSRLTPVsPESSSTE	9606			SIGNOR-C17						20974803	t		gcesareni	Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis.	SIGNOR-169012	0.349
DDX3X	protein	O00571	UNIPROT	PABPC1	protein	P11940	UNIPROT	up-regulates activity	binding			9606									21883093	t		miannu	In the present study, we indentified the SG marker PABP1 [poly(A)-binding protein 1] as another direct interaction partner of DDX3. Interestingly, down-regulation of DDX3 interfered with SG assembly, led to nuclear accumulation of PABP1 and reduced cell viability following stress. Conversely, supplementation with a shRNA (short hairpin RNA)-resistant DDX3 restored SG formation, the translocation of PABP1 into SGs and cell survival. 	SIGNOR-269194	0.588
CSNK2B	protein	P67870	UNIPROT	CACNA1S	protein	Q13698	UNIPROT	up-regulates activity	phosphorylation	Ser1575	PEICRTVsGDLAAEE	-1									20937870	t		miannu	 To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2. 	SIGNOR-263115	0.2
MARK3	protein	P27448	UNIPROT	CDC25C	protein	P30307	UNIPROT	down-regulates activity	phosphorylation	Ser216	SGLYRSPsMPENLNR	9534									9543386	t		miannu	C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Phosphorylation of serine 21 6 promotes 1 4-3-3 binding to Cdc25C and is inhibitory to Cdc25C function. 	SIGNOR-250176	0.499
HCRTR1	protein	O43613	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257220	0.442
MAP3K20	protein	Q9NYL2	UNIPROT	MAP3K20	protein	Q9NYL2	UNIPROT	up-regulates	phosphorylation	Ser165	HNHTTHMsLVGTFPW	9606									15342622	t		gcesareni	Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation.	SIGNOR-128573	0.2
AKT1	protein	P31749	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser146	GRKRRQTsMTDFYHS	9606									31575057	t		gcesareni	Pim-1, PKC, and Akt1 kinases phosphorylate Thr-145 and Ser-146 sites on p21 protein. Phosphorylation at Thr-145 promotes cytoplasmic translocation and stability of p21. Ser-146 phosphorylation mediated by Akt1 enhances p21 stabilization and promotes cell survival.	SIGNOR-157790	0.835
CDK2	protein	P24941	UNIPROT	CDC6	protein	Q99741	UNIPROT	down-regulates activity	phosphorylation	Ser74	TPHLPPCsPPKQGKK	9606			SIGNOR-C83						9889196	t		lperfetto	Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2.	SIGNOR-63895	0.94
PP2Ca_R1A_Bd 	complex	SIGNOR-C133	SIGNOR	AR	protein	P10275	UNIPROT	down-regulates activity	dephosphorylation	Ser83	QQQQQETsPRQQQQQ	9606									27858941	t		miannu	DAB2IP acts as a scaffold protein for PP2A to suppress DHT-elicited S81 phosphorylation of the AR, preventing its nuclear translocation and binding to androgen response elements. In addition, DAB2IP can compete with the AR for binding to c-Src, thus blocking the non-genomic AR pathway	SIGNOR-254759	0.301
MAPK14	protein	Q16539	UNIPROT	RPS6KA4	protein	O75676	UNIPROT	up-regulates	phosphorylation			9606									9792677	t		gcesareni	Rsk-b is a p38alphamapk substrate, and activated by p38alphamapk and, more weakly, by erk1	SIGNOR-60995	0.586
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	SOCS3	protein	O14543	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19643666	t		lperfetto	Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways.	SIGNOR-249566	0.4
SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates activity	binding			9606									9732876	t		lperfetto	Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos	SIGNOR-253332	0.63
TUBB1	protein	Q9H4B7	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				10116									17118269	f		lperfetto	However, evidence suggests that the detyrosination/tyrosination cycle of alpha-tubulin may be linked in some cell types to cell division and proliferationNF-Y	SIGNOR-242138	0.7
ITGB2	protein	P05107	UNIPROT	AL/b2 integrin	complex	SIGNOR-C169	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253190	0.912
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MKNK1	protein	Q9BUB5	UNIPROT	up-regulates activity	phosphorylation	Thr255	ITTPELTtPCGSAEY	9606	BTO:0000093								17130135	t			We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation	SIGNOR-253015	0.2
MCC	complex	SIGNOR-C382	SIGNOR	APC-c	complex	SIGNOR-C150	SIGNOR	down-regulates activity	binding			9606	BTO:0000567								25092294	t		miannu	The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. 	SIGNOR-265977	0.785
AIM2	protein	O14862	UNIPROT	AIM2 inflammasome	complex	SIGNOR-C222	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256399	0.74
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CCNA2	protein	P20248	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189966	0.8
AFF2	protein	P51816	UNIPROT	P-TEFb	complex	SIGNOR-C238	SIGNOR	up-regulates activity	binding			9606									17135274	t		miannu	Af4 associates with P-TEFb and stimulates its kinase activity. P-TEFb also phosphorylates AF4 which down-regulates its transactivation activity, providing a negative feedback mechanism for the control of P-TEFb elongation activity	SIGNOR-266801	0.398
AT9283	chemical	CID:11696609	PUBCHEM	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190011	0.8
NUMB	protein	P49757	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	down-regulates						BTO:0001103							12361602	t		apalma	Numb is an inhibitor of Notch signaling that interacts with the intracellular portion of Notch and antagonizes its activity by preventing nuclear translocation	SIGNOR-255374	0.791
MAPK3	protein	P27361	UNIPROT	TWIST1	protein	Q15672	UNIPROT	up-regulates	phosphorylation	Ser68	GGGDEPGsPAQGKRG	9606	BTO:0000150								21502402	t		llicata	Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro	SIGNOR-173413	0.335
TLK1	protein	Q9UKI8	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	-1									11314006	t	The effect has been demonstrated using Q9UKI8-2|Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	lperfetto	Purified tlk1b phosphorylated histone h3 at s(10) with high specificity both in a mix of core histones and in isolated chromatin, suggesting that histone h3 is a physiological substrate for tlk1b. Phosphorylation of H3 has been linked to the activation of the immediate-early genes upon mitogenic stimulation, and to chromatin condensation during mitotic/meiotic events.	SIGNOR-107037	0.2
MDM2	protein	Q00987	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									10935507	t		lperfetto	Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53.	SIGNOR-80528	0.968
AKT2	protein	P31751	UNIPROT	ACLY	protein	P53396	UNIPROT	unknown	phosphorylation	Ser455	PAPSRTAsFSESRAD	10116	BTO:0000443								12107176	t		gcesareni	Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B.	SIGNOR-245263	0.291
PRKCA	protein	P17252	UNIPROT	TRPV5	protein	Q9NQA5	UNIPROT	up-regulates activity	phosphorylation	Ser654	YVEVFKNsDKEDDQE	9606									17006539	t		gcesareni	A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK.	SIGNOR-149952	0.2
PTPN1	protein	P18031	UNIPROT	EIF2AK3	protein	Q9NZJ5	UNIPROT	down-regulates activity	dephosphorylation			9606									22169477	t		miannu	Finally, we demonstrated that wild-type PTP1B directly dephosphorylated myc-tagged PERK that had been isolated from tunicamycin-treated HEK293T cells by immunoprecipitation ( xref ).|The ability of PTP1B to dephosphorylate Tyr619 and inactivate PERK is fine tuned by the production of H 2 S by CSE in response to ER stress.	SIGNOR-277051	0.271
BARD1	protein	Q99728	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	binding			9606									20029420	t		gcesareni	Brac1 dimerizes with brca1?associated Ring domain protein 1 (bard1) to yield a functional e3 ligase.	SIGNOR-162499	0.785
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	SP7	protein	Q8TDD2	UNIPROT	up-regulates	phosphorylation			9606									21777568	t		gcesareni	We found that Akt phosphorylates Osterix and that Akt activation increases protein stability, osteogenic activity and transcriptional activity of Osterix. We also found that BMP-2 increases the protein level of Osterix in an Akt activity-dependent manner.	SIGNOR-174017	0.2
SMARCB1	protein	Q12824	UNIPROT	SWI/SNF ACTL6A-ARID1A-SMARCA2 variant	complex	SIGNOR-C470	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269825	0.862
DEF6	protein	Q9H4E7	UNIPROT	RAP1A	protein	P62834	UNIPROT	up-regulates activity	binding			9606	BTO:0000782								26483383	t		lperfetto	Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4(+) T cell adhesion.	SIGNOR-253365	0.26
TGFB1	protein	P01137	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates activity	binding			9534	BTO:0004055								1310899	t		lperfetto	A cdna encoding the tgf-beta type ii receptor protein has been isolated by an expression cloning strategy. The cloned cdna, when transfected into cos cells, leads to overexpression of an approximately 80 kd protein that specifically binds radioiodinated tgf-beta 1. Excess tgf-beta 1 competes for binding of radioiodinated tgf-beta 1 in a dose-dependent manner and is more effective than tgf-beta 2.	SIGNOR-236080	0.847
S1PR2	protein	O95136	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606	BTO:0000007								10488065	t		gcesareni	Edg-3 and edg-5 couple not only to gibut also to gqand g13.	SIGNOR-70667	0.509
Telatinib	chemical	CID:9808844	PUBCHEM	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207224	0.8
NMDA receptor_2C	complex	SIGNOR-C349	SIGNOR	CAMK2A	protein	Q9UQM7	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								11052931	t		miannu	The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD	SIGNOR-264216	0.584
GRK2	protein	P25098	UNIPROT	OPRM1	protein	P35372	UNIPROT	down-regulates activity	phosphorylation	Ser357	REFCIPTsSNIEQQN	9606									12123746	t			GRK2-mediated phosphorylation is involved in the development of agonist-induced μ-opioid receptor desensitization. two C-terminal amino acids, Ser355 and Thr357, are required for short-term homologous desensitization of μ-opioid receptors expressed in HEK 293 cells.	SIGNOR-251458	0.2
acetyl-CoA	smallmolecule	CHEBI:15351	ChEBI	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	precursor of			9606									15507492	t			Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the de novo biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH. 	SIGNOR-267209	0.8
MAST2	protein	Q6P0Q8	UNIPROT	PTEN	protein	P60484	UNIPROT	up-regulates	phosphorylation			9606									15951562	t		gcesareni	We further demonstrate that binding of pten to specific pdz domains diminishes its degradation rate and facilitates its phosphorylation by mast kinases. Our results suggest a regulatory role of pdz domain binding on pten function by controlling its stability and phosphorylation status.	SIGNOR-138051	0.687
PRKCG	protein	P05129	UNIPROT	APTX	protein	Q7Z2E3	UNIPROT	up-regulates	phosphorylation	Thr125	AKNPGLEtHRKRKRS	9606									19561170	t		llicata	We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (aptx), a dna repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant pkc gamma, and phosphorylation inhibited its nuclear entry. ollectively, phosphorylation occurred at thr111, reducing nuclear aptx.	SIGNOR-186409	0.327
DAB2IP	protein	Q5VWQ8	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	binding			9606	BTO:0002195								27858941	t		miannu	In vascular smooth muscle cells (VSMCs) treated with IFN-γ, DAB2IP directly binds to JAK2 and inhibits its kinase activity, limiting JAK-dependent STAT1/3 and PI3K–AKT phosphorylation and activation	SIGNOR-254760	0.357
Ubiquitin	proteinfamily	SIGNOR-PF89	SIGNOR	PRKN	protein	O60260	UNIPROT	up-regulates activity	binding			10090	BTO:0002572				phosphorylation: ser65				24784582	t			The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator.	SIGNOR-270343	0.2
MCHR2	protein	Q969V1	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256795	0.252
HHAT	protein	Q5VTY9	UNIPROT	SHH	protein	Q15465	UNIPROT	up-regulates	palmitoylation			9606									18534984	t		gcesareni	Both the shh precursor and mature protein are n-palmitoylated by hhatn-palmitoylation of cys-24 by hhat is required for n-product multimerization and full activity	SIGNOR-161548	0.67
NUAK1	protein	O60285	UNIPROT	PPP1R12A	protein	O14974	UNIPROT	down-regulates	phosphorylation	Ser445	LGLRKTGsYGALAEI	9606									20354225	t		gcesareni	Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity.	SIGNOR-164747	0.522
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1623	SPTSPSYsPTSPSYS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248816	0.849
EPN1	protein	Q9Y6I3	UNIPROT	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	up-regulates quantity by stabilization	binding												24789820	t		lperfetto	Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth	SIGNOR-260716	0.647
MIF	protein	P14174	UNIPROT	SOD1	protein	P00441	UNIPROT	down-regulates quantity by destabilization	relocalization			10090	BTO:0004488								29371591	t	P00441:p.Gly94Ala (mutation causing interaction)		Here, we show that MIF inhibits mutant SOD1 nuclear clearance when overexpressed in motor neuron-like NSC-34 cells|SOD1WT is evenly distributed between the cytoplasm and the nucleus while mutant SOD1G93A shows predominantly cytoplasmic distribution (Fig. 1a, b). Expression of MIF in cells expressing SOD1WT had no effect on the distribution of the SOD1WT–EGFP protein. However, expression of MIF together with the mutant SOD1G93A–EGFP, inhibited the nuclear clearance of misfolded SOD1 resulting in a more wild-type-like distribution of the mutant SOD1 protein	SIGNOR-262797	0.312
CNR2	protein	P34972	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256843	0.428
KCNJ16	protein	Q9NPI9	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	up-regulates quantity	relocalization			9606									24561201	t		miannu	KCNJ10 encodes Kir4.1, a member of the K+ channel family known as inwardly rectifying K+ (Kir) channels. Kir4.1 channels may comprise either Kir4.1 homomers or Kir4.1/Kir5.1 heteromers	SIGNOR-269447	0.8
FBXO5	protein	Q9UKT4	UNIPROT	FZR1	protein	Q9UM11	UNIPROT	down-regulates	ubiquitination			9606									11751633	t		gcesareni	Emi1 binds cdh1 and inhibits apc-cdh1 activity.	SIGNOR-113385	0.746
PINK1	protein	Q9BXM7	UNIPROT	UBA52	protein	P62987	UNIPROT	up-regulates	phosphorylation	Ser65	DYNIQKEsTLHLVLR	10090	BTO:0002572								24784582	t			Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential.	SIGNOR-270342	0.357
MAPK14	protein	Q16539	UNIPROT	MAPK10	protein	P53779	UNIPROT	down-regulates				9606									20626350	f		gcesareni	Jnk and p38 mapk activation have antagonistic effects in many cases. Froma a mechanicistic point of view, the p38 mapk pathway can negatively regulate jnk activity at the level of map3ks, either by phosphorylating mlk3 or the tak1 regulatory subunit tab1	SIGNOR-166608	0.402
P-TEFb	complex	SIGNOR-C238	SIGNOR	AEP complex	complex	SIGNOR-C117	SIGNOR	form complex	binding			9606									20153263	t		miannu	These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells.	SIGNOR-239237	0.755
CIITA	protein	P33076	UNIPROT	HLA-DRB3	protein	P79483	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10886240	f	 	 	These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma.	SIGNOR-254011	0.2
CDK6	protein	Q00534	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates activity	phosphorylation	Ser130	SGEQAEGsPGGPGDS	9606									16508017	t		gcesareni	Here, we show that p21cip1 is associated with k cyclin both in overexpression models and in primary effusion lymphoma cells and is a substrate of the k cyclin/cdk6 complex, resulting in phosphorylation of p21cip1 on serine 130. This phosphoform of p21cip1 appeared unable to associate with cdk2 in vivo.	SIGNOR-144832	0.859
AKT1	protein	P31749	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	phosphorylation	Thr198	PGLRRRQt	9606									12042314	t		miannu	Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation.	SIGNOR-88294	0.845
dactolisib	chemical	CHEBI:71952	ChEBI	PIK3CB	protein	P42338	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000848								21803746	t	ATP-competitive inhibitor of PI3K and mTOR	gcesareni	While the pi3k inhibitors, ly294002 or wortmannin, in the presence of plx4032 were individually inactive against pprm cell lines (fig. S4), the dual pi3k and mtorc1/2 inhibitor bez235 was highly specific (vs. parental lines) and potent in growth-inhibiting pprm cell lines	SIGNOR-175709	0.8
F2R	protein	P25116	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			9606									22318735	t		milica	The protease-activated receptors (PAR)2 are a class of G protein-coupled receptors (GPCR) that are activated by the proteolysis of the N-terminal exodomain. Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13).	SIGNOR-196006	0.582
ATM	protein	Q13315	UNIPROT	NFAT5	protein	O94916	UNIPROT	up-regulates	phosphorylation	Ser1367	LVQGSPSsQEQQVTL	9606									15173573	t		lperfetto	Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp	SIGNOR-125081	0.275
CSNK2A1	protein	P68400	UNIPROT	CREB3	protein	O43889	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser46	LPLSEVPsDWEVDDL	-1									31941600	t		miannu	Here, we found that human CREB3 is phosphorylated within its transcription activation domain on serine 46 by protein kinase CK2. However, phosphorylation at serine 46 reduced the stability of CREB3.	SIGNOR-277501	0.2
MUL1	protein	Q969V5	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	sumoylation	Lys606	EELLAEEKSKPIPIM	9606	BTO:0000007								19638400	t		Barakat	Through detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms.	SIGNOR-274129	0.55
CDK1	protein	P06493	UNIPROT	NDE1	protein	Q9NXR1	UNIPROT	up-regulates activity	phosphorylation			-1									12556484	t	done	miannu	We found that Nudel and NudE were also phosphorylated in M phase (Fig. ​(Fig.22 and ​and3).3). First, Nudel and NudE were specifically phosphorylated in M phase. Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro.Due to conservation of the S/TP motifs, NudE may also be phosphorylated at similar sites by these kinases, though it contains an additional potential Cdk site at S282 (SPNR).	SIGNOR-274077	0.64
leucine	smallmolecule	CHEBI:25017	ChEBI	Leu-tRNA(Leu)	smallmolecule	CHEBI:16624	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270418	0.8
CSNK1A1	protein	P48729	UNIPROT	SRPK2	protein	P78362	UNIPROT	up-regulates activity	phosphorylation	Ser497	SRTVSASsTGDLPKA	9606	BTO:0000007								29153836	t	no	miannu	 Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins.	SIGNOR-275460	0.253
PRKAA1	protein	Q13131	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser259	FPLRKTAsEPNLKVR	9606			SIGNOR-C15						21892142	t		gcesareni	Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)	SIGNOR-176479	0.347
2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol	chemical	CHEBI:75722	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000246								19282177	t		Luana	A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 	SIGNOR-258150	0.8
CSF1R	protein	P07333	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates				9606									24890514	f		apalma	The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ∼5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation	SIGNOR-255572	0.29
SNTB1	protein	Q13884	UNIPROT	MAPK12	protein	P53778	UNIPROT	down-regulates				10090	BTO:0002314	BTO:0001103							29681515	t		apalma	[...] suggesting that, during an asymmetric cell division, p38gamma localization would be basally restricted by the DGC complex via its interaction with beta-1-syntrophin.	SIGNOR-255903	0.376
MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	TNNI2	protein	P48788	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							15870273	f		miannu	Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material)	SIGNOR-136786	0.352
MYOD1	protein	P15172	UNIPROT	ITGA7	protein	Q13683	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									8798472	t		lperfetto	Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development.	SIGNOR-241518	0.291
SOHLH1	protein	Q5JUK2	UNIPROT	ZP3	protein	P21754	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								16690745	t		Luana	Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.	SIGNOR-266078	0.388
KLF1	protein	Q13351	UNIPROT	CDKN2C	protein	P42773	UNIPROT	up-regulates quantity by expression	transcriptional regulation			7227	BTO:0001677								17442339	t		Luana	Thus, EKLF is a direct regulator of p18INK4c gene expression, and much of EKLF's role in driving erythroid cell differentiation may occur via p18INK4c.	SIGNOR-266046	0.269
PPP2CA	protein	P67775	UNIPROT	SP1	protein	P08047	UNIPROT	up-regulates activity	dephosphorylation	Ser59	GGQESQPsPLALLAA	9606									24382322	t		gcesareni	These results indicate that the signals from TCDD or OP caused PP2A-mediated dephosphorylation of Sp1 at Ser-59 and induced CYP1A1 transcription	SIGNOR-248223	0.267
triazolopyridazine	chemical	CHEBI:48384	ChEBI	GABA-A (a1-b1-g2) receptor	complex	SIGNOR-C330	SIGNOR	up-regulates activity	chemical activation			9606		BTO:0000227							18790874	t	brain	lperfetto	The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005).	SIGNOR-263803	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PAK1	protein	Q13153	UNIPROT	down-regulates	phosphorylation			9606									14993270	t	inferred from 70% family members	gcesareni	Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation.	SIGNOR-270086	0.2
FOXO3	protein	O43524	UNIPROT	IDH1	protein	O75874	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25648147	t		miannu	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260100	0.251
Exon junction complex	complex	SIGNOR-C369	SIGNOR	Upf-EJC	complex	SIGNOR-C367	SIGNOR	up-regulates activity	binding			-1									18066079	t		miannu	Nonsense-mediated mRNA decay (NMD) eliminates mRNAs containing a premature translation termination codon through the recruitment of the conserved NMD factors UPF1, UPF2 and UPF3. In humans, a dynamic assembly pathway allows UPF1 to join UPF2 and UPF3 recruited to the mRNA by the exon-junction complex (EJC). 	SIGNOR-265244	0.859
CD19	protein	P15391	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	binding			10090									25673924	t		lperfetto	CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades.	SIGNOR-242900	0.567
SDC4	protein	P31431	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity	binding			9606	BTO:0002314	BTO:0001103							23290138	t		apalma	Rac1 is associated with Sdc4 and is activated by FN binding […] We observed that over-expression of Fzd7, or stimulation with FN resulted in increased levels of active Rac1 in primary myoblasts	SIGNOR-255849	0.482
RORB	protein	Q92753	UNIPROT	OPN1MW	protein	P04001	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090		BTO:0001175							19381306	t		miannu	 These observations indicate that RORβ is required for the induction of S opsin and support the conclusion that RORβ regulates Opn1sw transcription in a direct manner through ROREs within its proximal promoter region. In addition, they explain the greatly diminished expression of Opn1sw observed in the retina of RORβ-/- mice.	SIGNOR-266851	0.2
PTPN11	protein	Q06124	UNIPROT	GAB1	protein	Q13480	UNIPROT	down-regulates	dephosphorylation	Tyr659	VADERVDyVVVDQQK	9606									10068651	t		lperfetto	Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro.	SIGNOR-236254	0.952
Cell-Cell_contact	stimulus	SIGNOR-ST13	SIGNOR	AMOT/MPP5/INADL/LIN7C	complex	SIGNOR-C27	SIGNOR	up-regulates				9606									21529719	f		milica	In vertebrates, cell density information feeds into the Hpo pathway, which is transmitted, in part, through the Crumbs polarity complex. The Crumbs complex contains Angiomotin (AMOT), a protein that binds YAP/TAZ and SMAD to inhibit their nuclear activity.	SIGNOR-230700	0.7
SCN1A	protein	P35498	UNIPROT	sodium(1+)	chemical	CHEBI:29101	ChEBI	up-regulates quantity	relocalization			9606									27262167	t		miannu	Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential.	SIGNOR-253402	0.8
ZAP70	protein	P43403	UNIPROT	DBNL	protein	Q9UJU6	UNIPROT	up-regulates	phosphorylation	Tyr344	PPEQETFyEQPPLVQ	9606	BTO:0000782								14557276	t		lperfetto	We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling. 	SIGNOR-118695	0.625
AKT1	protein	P31749	UNIPROT	ACLY	protein	P53396	UNIPROT	unknown	phosphorylation	Ser455	PAPSRTAsFSESRAD	10116	BTO:0000443								12107176	t		gcesareni	Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B.	SIGNOR-245255	0.439
PTPMT1	protein	Q8WUK0	UNIPROT	phosphatidylglycerol(1-)	smallmolecule	CHEBI:60523	ChEBI	up-regulates	chemical modification			10090									21641550	t		lperfetto	PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis.	SIGNOR-267025	0.8
FYN	protein	P06241	UNIPROT	ARHGAP33	protein	O14559	UNIPROT	down-regulates	phosphorylation	Tyr406	PLLTYQLyGKFSEAM	9606									16777849	t		acerquone	Tcgap interacted with fyn and was phosphorylated by fyn, with tyr-406 in the gap domain as a major fyn-mediated phosphorylation site. Fyn suppressed the gap activity of wild-type tcgap	SIGNOR-147156	0.473
4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine	chemical	CHEBI:91419	ChEBI	CDK9	protein	P50750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190182	0.8
N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide	chemical	CHEBI:91393	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194334	0.8
LSM-1131	chemical	CHEBI:91398	ChEBI	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189873	0.8
3-methyladenine	chemical	CHEBI:38635	ChEBI	PIK3C3	protein	Q8NEB9	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205636	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	MAPK14	protein	Q16539	UNIPROT	up-regulates activity				10090									20660302	f			P38 MAPK mediates the effect of AMPK on Gr induced transcriptional activity	SIGNOR-255951	0.284
CTNNB1	protein	P35222	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates				9606									19175684	f		gcesareni	In-teractions between beta-catenin and runx2 play an im-portant role in bmp-9-induced osteogenic differentia-tion of mscs.	SIGNOR-183532	0.455
ACVR2A	protein	P27037	UNIPROT	ACVR1	protein	Q04771	UNIPROT	up-regulates	binding			9606									9748228	t		fspada	The major bmp7 type i receptor observed was alk2,	SIGNOR-60234	0.649
ULK2	protein	Q8IYT8	UNIPROT	PRKAG3	protein	Q9UGI9	UNIPROT	down-regulates	phosphorylation			9606				SIGNOR-C15					21460634	t		gcesareni	Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity.	SIGNOR-173095	0.2
DPM1	protein	O60762	UNIPROT	DPM complex	complex	SIGNOR-C289	SIGNOR	form complex	binding			9606									10835346	t		lperfetto	Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3.	SIGNOR-262563	0.78
CUDC-101	chemical	CID:24756910	PUBCHEM	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191148	0.8
R547	chemical	CID:6918852	PUBCHEM	CDK1	protein	P06493	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206358	0.8
MAP3K6	protein	O95382	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr838	GINPCTEtFTGTLQY	9606									17210579	t		Manara	ASK2 Activates ASK1 by Phosphorylation	SIGNOR-260832	0.53
vatalanib	chemical	CHEBI:90620	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207648	0.8
PPP3CA	protein	Q08209	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	dephosphorylation			9606									23015147	t			Calcineurin is known to facilitate the nuclear translocation of the nuclear factor of activated T cells (NFAT).	SIGNOR-253329	0.817
MAP3K11	protein	Q16584	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates				9606									9733513	f		gcesareni	This scaffold protein selectively enhanced jnk activation by the mlk signaling pathway.	SIGNOR-59884	0.33
FLT3	protein	P36888	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			10090									10080542	t		gcesareni	FL stimulation induces association of Grb2 with Flt3, SHP-2,and Shc	SIGNOR-245060	0.591
ENMD-2076	chemical	CID:16041424	PUBCHEM	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191469	0.8
JUN	protein	P05412	UNIPROT	AP1	complex	SIGNOR-C154	SIGNOR	form complex	binding			9606									25875593	t		irozzo	C-Fos dimerizes with c-Jun to form the transcription activator protein-1 (AP-1) which binds to the specific recognition site.	SIGNOR-256367	0.951
ixazomib citrate	chemical	CHEBI:90939	ChEBI	PSMB5	protein	P28074	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194536	0.8
TET3	protein	O43151	UNIPROT	OGT	protein	O15294	UNIPROT	up-regulates	binding			9606									23353889	t		miannu	Tet2 and tet3 associate with the o_glcnac transferase ogt / tet2 and tet3 promote ogt_mediated glcnacylation	SIGNOR-200729	0.456
4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide	chemical	CHEBI:91326	ChEBI	CDK6	protein	Q00534	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189996	0.8
SGX-523	chemical	CHEBI:90624	ChEBI	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206905	0.8
WWTR1	protein	Q9GZV5	UNIPROT	MYOD1	protein	P15172	UNIPROT	up-regulates	binding			9606									20466877	t		gcesareni	Taz physically interacts with myod through the ww domain and activates myod-dependent gene transcription.	SIGNOR-165414	0.28
N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide	chemical	CHEBI:91336	ChEBI	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207666	0.8
lysophosphatidic acids	smallmolecule	CHEBI:32957	ChEBI	LPAR3	protein	Q9UBY5	UNIPROT	up-regulates	chemical activation			9606									8276865	t		gcesareni	Lpa activates its own g protein-coupled receptor(s).	SIGNOR-36389	0.8
MAPK1	protein	P28482	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser70	RDPVARTsPLQTPAA	9534	BTO:0004055								10677502	t		lperfetto	Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70.	SIGNOR-219217	0.532
ACTL6A	protein	O96019	UNIPROT	Embryonic stem cell-specific SWI/SNF	complex	SIGNOR-C484	SIGNOR	form complex	binding			10090	BTO:0001086								19279220	t		miannu	An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency	SIGNOR-270718	0.677
CCT137690	chemical	CID:25154041	PUBCHEM	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190892	0.8
B-WICH complex	complex	SIGNOR-C447	SIGNOR	MYC	protein	P01106	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								25883140	t		miannu	The B-WICH complex allows c-Myc to bind to a site in the IGS. c-Myc requires the B-WICH complex to remodel chromatin for its function.	SIGNOR-268842	0.3
NONO	protein	Q15233	UNIPROT	TOP1	protein	P11387	UNIPROT	up-regulates	binding			9606	BTO:0000017								9756848	t		miannu	We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i	SIGNOR-60557	0.382
RPS6KB1	protein	P23443	UNIPROT	MAPK8	protein	P45983	UNIPROT	down-regulates				9606									17181399	f		gcesareni	Finally, downregulation of p70 s6 kinase by sirna significantly enhanced the fgf-2-stimulated vegf release and phosphorylation of sapk/jnk.	SIGNOR-149367	0.43
GAB1	protein	Q13480	UNIPROT	ARHGAP32	protein	A7KAX9	UNIPROT	up-regulates	relocalization			9606									12819203	t		gcesareni	Gc-gap, a rho family gtpase-activating protein that interacts with signaling adapters gab1 and gab2.	SIGNOR-102586	0.319
budesonide	chemical	CHEBI:3207	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									11208622	t	ashma	gcesareni		SIGNOR-251687	0.8
AGO2	protein	Q9UKV8	UNIPROT	DICER1/hAgo2/PRKRA	complex	SIGNOR-C41	SIGNOR	form complex	binding			9606									23661684	t		miannu		SIGNOR-143102	0.807
FOXO1	protein	Q12778	UNIPROT	FSHB	protein	P01225	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0004467								24065703	f	 	miannu	We demonstrate that FOXO1 represses basal and GnRH-induced Fshb transcription in LβT2 cells. 	SIGNOR-254185	0.354
BRCA1	protein	P38398	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates													15549093	f		lperfetto	The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination	SIGNOR-251500	0.7
EPC1	protein	Q9H2F5	UNIPROT	NuA4 complex	complex	SIGNOR-C459	SIGNOR	form complex	binding			9606									14966270	t		miannu	NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 	SIGNOR-269305	0.649
crizotinib	chemical	CHEBI:64310	ChEBI	ALK	protein	Q9UM73	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191133	0.8
MAPK3	protein	P27361	UNIPROT	MAPKAPK2	protein	P49137	UNIPROT	up-regulates	phosphorylation			9606									14967450	t		gcesareni	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-121994	0.487
XL147	chemical	CHEBI:71957	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207854	0.8
FLT3LG	protein	P49771	UNIPROT	FLT3	protein	P36888	UNIPROT	up-regulates	binding			9606	BTO:0001271								12681969	t		gcesareni	Flt3 is activated by binding of its natural flt3-ligand (flt3-l),	SIGNOR-99750	0.881
40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	up-regulates													25901680	f		lperfetto	Ribosomes are translational machineries that catalyse protein synthesis.	SIGNOR-262412	0.7
AMG-208	chemical	CHEBI:90626	ChEBI	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189507	0.8
SKI	protein	P12755	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates	binding			9606									12419246	t		gcesareni	Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad5.	SIGNOR-195630	0.685
TOP2B	protein	Q02880	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	down-regulates				9606									24463367	f		lperfetto	Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells	SIGNOR-242533	0.7
PDE4DIP	protein	Q5VU43	UNIPROT	PRKAR1A	protein	P10644	UNIPROT	up-regulates	binding			9606									21569246	t		miannu	Mmgl acts as a dual-specific akap by anchoring pka regulatory isoforms r1a and r2a.	SIGNOR-173769	0.32
3',5'-cyclic AMP	smallmolecule	CHEBI:17489	ChEBI	PRKACA	protein	P17612	UNIPROT	up-regulates	chemical activation			9606	BTO:0000007								22863277	t		milica	The cAMP signaling cascade can activate protein kinase a (PKA)	SIGNOR-198492	0.8
WWTR1	protein	Q9GZV5	UNIPROT	PAX3	protein	P23760	UNIPROT	up-regulates	binding			10090	BTO:0000165;BTO:0000222								16300735	t		gcesareni	These results indicate that pax3 specifically interacts with taz both in vitro and in vivo.	SIGNOR-236879	0.466
alvocidib	chemical	CHEBI:47344	ChEBI	CDK1	protein	P06493	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191529	0.8
torin 2	chemical	CHEBI:90682	ChEBI	RPS6KB1	protein	P23443	UNIPROT	down-regulates				9606									23436801	f		gcesareni	Torin2 inhibited mtorc1-dependent t389 phosphorylation on s6k (rps6kb1)	SIGNOR-201502	0.8
GPER1	protein	Q99527	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606	BTO:0000130								22203955	t		gcesareni	However, grpr preferentially couples to galfaq proteins.	SIGNOR-195320	0.2
3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione	chemical	CHEBI:91368	ChEBI	PRKCE	protein	Q02156	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191496	0.8
TP53INP1	protein	Q96A56	UNIPROT	MAP1LC3A	protein	Q9H492	UNIPROT	up-regulates	binding			9606									22421968	t		gcesareni	Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir).	SIGNOR-196670	0.354
6alpha-methylprednisolone	chemical	CHEBI:6888	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									1159081	t	inflammation	gcesareni		SIGNOR-251697	0.8
PD318088	chemical	CID:10231331	PUBCHEM	MAP2K1	protein	Q02750	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205737	0.8
regorafenib	chemical	CHEBI:68647	ChEBI	RAF1	protein	P04049	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206418	0.8
olaparib	chemical	CHEBI:83766	ChEBI	PARP2	protein	Q9UGN5	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-195019	0.8
BTRC	protein	Q9Y297	UNIPROT	SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	form complex	binding			9606									10023660	t		gcesareni	The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin.	SIGNOR-64496	0.818
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	VAV1	protein	P15498	UNIPROT	up-regulates	phosphorylation			9606	BTO:0001271								11790798	t		lperfetto	Thus, the c-terminal tail of vav serves as a direct substrate of bcr-abl in vitro.	SIGNOR-114094	0.2
PTPN1	protein	P18031	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates	dephosphorylation	Tyr751	SKDESVDyVPMLDMK	9606									18567737	t		gcesareni	Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr.	SIGNOR-179076	0.679
TWIST1	protein	Q15672	UNIPROT	CSNK2A1	protein	P68400	UNIPROT	down-regulates				9606									22975381	f		amattioni	Ck2-mediated phosphorylation at ser392 of p53 was attenuated in the presence of recombinant twist1	SIGNOR-192064	0.2
DCC	protein	P43146	UNIPROT	Chemoattraction_of_axon	phenotype	SIGNOR-PH197	SIGNOR	up-regulates				9606		BTO:0001484							25881791	f		miannu	DCC constitutively expresses on the axonal surface. Netrin-1-binding to DCC induces chemoattraction	SIGNOR-268163	0.7
PRKCH	protein	P24723	UNIPROT	PTPN11	protein	Q06124	UNIPROT	unknown	phosphorylation	Ser595	GLMQQQKsFR	9606									11781100	t		lperfetto	 In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta.	SIGNOR-249140	0.312
AMG 900	chemical	CID:24856041	PUBCHEM	AURKC	protein	Q9UQB9	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189498	0.8
AVP	protein	P01185	UNIPROT	BAD	protein	Q92934	UNIPROT	down-regulates				9606	BTO:0000938	BTO:0000142							18402937	f		gcesareni	Vp induces phosphorylation of the pro-apoptotic protein bad and prevents cytochrome c release.	SIGNOR-178197	0.2
2-(6,7-dimethoxy-4-quinazolinyl)-5-(2-pyridinyl)-1,2,4-triazol-3-amine	chemical	CHEBI:91330	ChEBI	ATM	protein	Q13315	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191094	0.8
N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide	chemical	CHEBI:91336	ChEBI	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207669	0.8
ULK2	protein	Q8IYT8	UNIPROT	PRKAB1	protein	Q9Y478	UNIPROT	down-regulates	phosphorylation			9606				SIGNOR-C15					21460634	t		gcesareni	Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity	SIGNOR-173092	0.335
MK-2461	chemical	CID:44137946	PUBCHEM	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194367	0.8
QRICH1	protein	Q2TAL8	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									33384352	f		miannu	QRICH1 promotes cell death and its translation is upregulated by the PERK-eIF2α axis under ER stress.	SIGNOR-269399	0.7
sapitinib	chemical	CHEBI:132986	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190149	0.8
masitinib	chemical	CHEBI:63450	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194257	0.8
WAY-600	chemical	CID:25229526	PUBCHEM	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck;ATP-competitive inhibitor mTOR	gcesareni		SIGNOR-207788	0.8
CRP	protein	P02741	UNIPROT	LPL	protein	P06858	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18708524	f	Regulation of expression	miannu	C-reactive protein enhances macrophage lipoprotein lipase expression.	SIGNOR-251852	0.381
ERBB4	protein	Q15303	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606									16729043	t		gcesareni	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146888	0.325
alvocidib	chemical	CHEBI:47344	ChEBI	CDK4	protein	P11802	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192038	0.8
ezogabine	chemical	CHEBI:68584	ChEBI	KCNQ2	protein	O43526	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck;anticonvulsant for KCNQ2/3 currents	gcesareni		SIGNOR-206483	0.8
PIDD1	protein	Q9HB75	UNIPROT	Caspase-2 PIDDosome	complex	SIGNOR-C292	SIGNOR	form complex	binding			9606									20158568	t		miannu	The PIDDosome consists of the proteins PIDD, RAIDD and caspase-2. 	SIGNOR-262643	0.845
CASP3	protein	P42574	UNIPROT	DNA_fragmentation	phenotype	SIGNOR-PH22	SIGNOR	up-regulates				9606									10200555	f		amattioni	Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation	SIGNOR-66863	0.7
PIK-75 Hydrochloride	chemical	CID:45265864	PUBCHEM	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-252652	0.8
UBAP2	protein	Q5T6F2	UNIPROT	ANXA2	protein	P07355	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0002181								27121050	t		Sara	UBAP2 formed a complex with Annexin A2 and promoted the degradation of Annexin A2 protein by ubiquitination	SIGNOR-261314	0.349
Elongator complex	complex	SIGNOR-C466	SIGNOR	TUBA8	protein	Q9NY65	UNIPROT	up-regulates activity	acetylation			9606	BTO:0000007								19185337	t		miannu	Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. 	SIGNOR-269721	0.254
PHA-848125	chemical	CID:16718576	PUBCHEM	CCNA2	protein	P20248	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206148	0.8
GSK1059615	chemical	CHEBI:71955	ChEBI	PIK3CG	protein	P48736	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192780	0.8
DUSP4	protein	Q13115	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates	dephosphorylation			9606									16849326	t		gcesareni	This result suggests that dusp4 represses gluconeogenesis through dephosphorylation of p38	SIGNOR-147958	0.65
GW 3965	chemical	CHEBI:79995	ChEBI	NR1H3	protein	Q13133	UNIPROT	up-regulates	chemical activation			9606									Other	t	Selleck	gcesareni		SIGNOR-193015	0.8
SNW1	protein	Q13573	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606									11404076	t		gcesareni	We find that Notch 3 IC, like Notch 1 IC, can bind the SKIP and PCAF proteins	SIGNOR-108499	0.584
rosiglitazone	chemical	CHEBI:50122	ChEBI	PPARG	protein	P37231	UNIPROT	up-regulates activity	chemical activation			9534									7768881	t			An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma)	SIGNOR-251646	0.8
CSNK1D	protein	P48730	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates	phosphorylation	Ser253	SVEFEVEsLDSEDYS	9606									12167711	t		gcesareni	Hypophosphorylation of mdm2 augments p53 stability.	SIGNOR-91195	0.351
ADIPOR1	protein	Q96A54	UNIPROT	APPL1	protein	Q9UKG1	UNIPROT	up-regulates	binding			9606									16622416	t		milica	Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin.	SIGNOR-146212	0.746
NODAL	protein	Q96S42	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0004094								15531507	f	Regulation	miannu	Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7.	SIGNOR-251935	0.7
SMAD1/5/8/SMAD4	complex	SIGNOR-C215	SIGNOR	RUNX2	protein	Q13950	UNIPROT	up-regulates	transcriptional regulation			9606									27563484	f		ggiuliani	Smad1/5/8-Smad4 complex transcribed Runx2 expression, as they complex with Runx2 to initiate other osteoblast gene expression.	SIGNOR-255836	0.579
85375-15-1	chemical	CID:6917797	PUBCHEM	SLC6A12	protein	P48065	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207031	0.8
PHA-767491	chemical	CID:11715767	PUBCHEM	CDK7	protein	P50613	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206112	0.8
PF-03814735	chemical	CID:49830590	PUBCHEM	PTK2	protein	Q05397	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205959	0.8
NOD2	protein	Q9HC29	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates				9606									18079694	f		miannu	Nod1 and Nod2 stimulation activates NF-kappaB through RICK, a caspase-recruitment domain-containing kinase.	SIGNOR-252412	0.378
MAPK3	protein	P27361	UNIPROT	MAPKAPK2	protein	P49137	UNIPROT	up-regulates	phosphorylation			9606									23583303	t		gcesareni	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-201687	0.487
SP6	protein	Q3SY56	UNIPROT	TGFBR2	protein	P37173	UNIPROT	down-regulates quantity by repression	transcriptional regulation												19088080	f		lperfetto	Mechanistically, KLF14 represses the TGFbetaRII promoter via a co-repressor complex containing mSin3A and HDAC2.	SIGNOR-271695	0.312
motesanib	chemical	CHEBI:51098	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194563	0.8
STK3/4	proteinfamily	SIGNOR-PF41	SIGNOR	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	phosphorylation			9606									21808241	t	inferred from 70% family members	gcesareni	Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2.	SIGNOR-270218	0.2
IL13	protein	P35225	UNIPROT	IL4R	protein	P24394	UNIPROT	up-regulates	binding			9606									12704343	t		milica	Both il-4 and il-13 use the IL-4R Chain as a component of their receptors.	SIGNOR-100753	0.893
SOX2	protein	P48431	UNIPROT	NR2E1	protein	Q9Y466	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22194602	f		miannu	Sox2 positively regulates tlx expression	SIGNOR-191714	0.383
dacomitinib	chemical	CHEBI:132268	ChEBI	ERBB4	protein	Q15303	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205942	0.8
CNTF	protein	P26441	UNIPROT	CNTFR	protein	P26992	UNIPROT	up-regulates	binding			9606									10812968	t		amattioni	Signal transduction by cntf requires that it bind first to cntfr alpha. Cntf activates downstream signaling molecules	SIGNOR-77408	0.785
TRPC6	protein	Q9Y210	UNIPROT	PPP3CA	protein	Q08209	UNIPROT	up-regulates activity				9606									27383564	f		gcesareni	TRPC6 channel-dependent [Ca2+]i elevation and sequential activation of the calcineurin.	SIGNOR-253328	0.2
AMOTL2	protein	Q9Y2J4	UNIPROT	Cell_migration	phenotype	SIGNOR-PH38	SIGNOR	up-regulates				9606	BTO:0001176								21937427	f		lperfetto	 Taking together, our data indicate that Amotl2 plays a pivotal role in polarity, migration and proliferation of angiogenic endothelial cells.	SIGNOR-271872	0.7
TIAM1	protein	Q13009	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates	binding			9606									12393875	t		gcesareni	Lpa-induced rac activation requires tiam1	SIGNOR-94691	0.74
FOS	protein	P01100	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity	binding			10090									2516828	t			The cFos proto-oncoprotein associates with cJun to form a heterodimer with increased DNA binding and transcriptional activities. 	SIGNOR-252087	0.951
Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	DVL1	protein	O14640	UNIPROT	up-regulates	binding												19279717	t		apalma	Wnt signaling is transduced through Fz independent of LRP5/6 leading to the activation of Dsh.	SIGNOR-255891	0.2
GTF3C6	protein	Q969F1	UNIPROT	TFIIIC	complex	SIGNOR-C392	SIGNOR	form complex	binding			9606									29378333	t		lperfetto	Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains	SIGNOR-266183	0.863
MIB1	protein	Q86YT6	UNIPROT	DLL3	protein	Q9NYJ7	UNIPROT	up-regulates activity	ubiquitination			9606									16140393	t		lperfetto	Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity.	SIGNOR-209672	0.357
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	Glutaminolysis	phenotype	SIGNOR-PH119	SIGNOR	up-regulates activity				9606	BTO:0000567								22749528	f		Luana	Leucine and Glutamine Activate Glutaminolysis and mTORC1	SIGNOR-268016	0.7
GNAI3	protein	P08754	UNIPROT	TNFAIP8	protein	O95379	UNIPROT	up-regulates activity	binding			9606									20607800	t			TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation	SIGNOR-256490	0.2
seliciclib	chemical	CHEBI:45307	ChEBI	CDK1	protein	P06493	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206568	0.8
NFIL3	protein	Q16649	UNIPROT	Survival	phenotype	SIGNOR-PH13	SIGNOR	up-regulates				10090	BTO:0003104								10082541	f		lperfetto	the effect of NFIL3 on cytokine-mediated cell survival was independent of an effect on cell proliferation.	SIGNOR-242760	0.7
CSNK2A1	protein	P68400	UNIPROT	TOP2A	protein	P11388	UNIPROT	unknown	phosphorylation	Thr1343	FSDFDEKtDDEDFVP	9606									9804834	t		llicata	Casein kinase II catalyzes a mitotic phosphorylation on threonine 1342 of human DNA topoisomerase IIalpha	SIGNOR-250966	0.613
Telatinib	chemical	CID:9808844	PUBCHEM	FLT4	protein	P35916	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207221	0.8
4-[6-[4-(1-piperazinyl)phenyl]-3-pyrazolo[1,5-a]pyrimidinyl]quinoline	chemical	CHEBI:91387	ChEBI	BMPR1A	protein	P36894	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193642	0.8
MTX1	protein	Q13505	UNIPROT	SAM complex	complex	SIGNOR-C422	SIGNOR	form complex	binding												31387448	t		lperfetto	The SAM complex of the outer membrane mediates insertion of β-barrel proteins into the outer membrane. hSam50 associates with MTX1 and MTX2. 	SIGNOR-267684	0.685
GSK1059615	chemical	CHEBI:71955	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192693	0.8
RHEB	protein	Q15382	UNIPROT	EIF2AK3	protein	Q9NZJ5	UNIPROT	down-regulates activity	binding			-1									25660019	t		Luana	Rheb GTPase directly binds and activates PERK in vitro	SIGNOR-260873	0.2
HIP1	protein	O00291	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606									11007801	f		miannu	Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain.	SIGNOR-256646	0.7
TNFAIP3	protein	P21580	UNIPROT	TRAF6	protein	Q9Y4K3	UNIPROT	down-regulates activity	deubiquitination			9606									18164316	t		lperfetto	A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6	SIGNOR-160223	0.69
CENPE	protein	Q02224	UNIPROT	MAD1L1	protein	Q9Y6D9	UNIPROT	up-regulates activity				10090	BTO:0000452								12925705	f		lperfetto	CENP-E is required for efficient recruitment of BubR1, Mad1, and Mad2 to attached and newly unattached kinetochores	SIGNOR-252044	0.62
XAV939	chemical	CHEBI:62878	ChEBI	TNKS	protein	O95271	UNIPROT	down-regulates	chemical inhibition			9606									19759537	t		gcesareni	Xav939 inhibits the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2.	SIGNOR-188054	0.8
RASSF5	protein	Q8WWW0	UNIPROT	RASSF1	protein	Q9NS23	UNIPROT	up-regulates activity	binding			9606									22195963	t		lperfetto	NORE1A can heterodimerize with RASSF1A and, thus, mediate K-Ras regulation of RASSF1A	SIGNOR-249587	0.526
TGFB1	protein	P01137	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	binding			9606									19114990	t		lperfetto	While association of the TGF_RI receptor with p85 requires TGF-_ stimulation.	SIGNOR-217960	0.261
3-(3-oxo-1H-indol-2-ylidene)-1H-indol-2-one	chemical	CHEBI:92322	ChEBI	GSK3B	protein	P49841	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193402	0.8
IGF1R	protein	P08069	UNIPROT	IRS2	protein	Q9Y4H2	UNIPROT	up-regulates	phosphorylation			9606									10471495	t		flangone	Our results reveal that igf-1 receptors promote beta-cell development and survival through the irs-2 signalling pathway.	SIGNOR-70477	0.795
TGFB1	protein	P01137	UNIPROT	RNF111	protein	Q6ZNA4	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									14657019	f		lpetrilli	Expression of arkadia is down-regulated by tgf-beta.	SIGNOR-119669	0.2
IL1A	protein	P01583	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606									21304099	f		lperfetto	Interleukin-1 in the pathogenesis and treatment of inflammatory diseases	SIGNOR-171873	0.7
GLS	protein	O94925	UNIPROT	Glutaminolysis	phenotype	SIGNOR-PH119	SIGNOR	up-regulates activity				9606									28053289	f			Glutaminase is the rate-limiting enzyme in glutaminolysis and it is encoded by two different genes, GLS and GLS2.	SIGNOR-259999	0.7
A5/b1 integrin	complex	SIGNOR-C163	SIGNOR	BCL2	protein	P10415	UNIPROT	up-regulates quantity													15721307	f		lperfetto	Previous reports indicated that the prosurvival signal mediated through α5β1-fibronectin interactions was due to increased Bcl-2 levels	SIGNOR-253310	0.2
SNS-314 Mesylate	chemical	CID:24995523	PUBCHEM	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207102	0.8
ATM	protein	Q13315	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									20663147	t		gcesareni	Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation.	SIGNOR-167152	0.838
APOC3	protein	P02656	UNIPROT	LPL	protein	P06858	UNIPROT	down-regulates activity				9606									17315402	f	Regulation	miannu	Apolipoprotein CIII inhibits the lipoprotein lipase.	SIGNOR-251850	0.634
AGPAT3	protein	Q9NRZ7	UNIPROT	phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	up-regulates	chemical modification			9606									12401205	t		gcesareni	Pa can be generated by the acylation of lyso-pa by lyso-pa acyl transferases	SIGNOR-94864	0.8
MPO-ANCA	complex	SIGNOR-C474	SIGNOR	ROS	stimulus	SIGNOR-ST2	SIGNOR	up-regulates				-1									2161532	f		lperfetto	ANCA-induced release of ROS measured by chemiluminescence.	SIGNOR-270590	0.7
MAP3K10	protein	Q02779	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates	phosphorylation	Ser359	SPSTPVGsPQGLAGT	9606									19801649	t		llicata	Mlk2 inhibits e47 transactivation activity on the trkb promote	SIGNOR-161531	0.2
F2	protein	P00734	UNIPROT	F2RL2	protein	O00254	UNIPROT	up-regulates	binding			9606									11356985	t		gcesareni	 as noted previously, the human form of par-3 activated phosphoinositide signaling in response to thrombin when overexpressed in cos-7 cells	SIGNOR-108225	0.636
KITLG	protein	P21583	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates	binding			9606									1698556	t		gcesareni	We have also provided biological and physical evidence that scf is a ligand for the c-kit receptor.	SIGNOR-21193	0.933
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	IL10	protein	P22301	UNIPROT	up-regulates quantity				10090	BTO:0004732								26208884	f			The mitogen activated protein kinases ERK1/2 play an important role in response to toll like receptor (TLR) activation and cytokine production, including IL-10 and IL-12.	SIGNOR-256080	0.2
regorafenib	chemical	CHEBI:68647	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206415	0.8
GSK690693	chemical	CHEBI:90677	ChEBI	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193000	0.8
STC2	protein	O76061	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates				10090	BTO:0000298								29207625	f		lperfetto	STC2 activates STAT3 signaling pathway in the hypothalamus and GT1-7 cells	SIGNOR-260406	0.2
Brivanib alaninate	chemical	CID:11154925	PUBCHEM	FGFR2	protein	P21802	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190720	0.8
seliciclib	chemical	CHEBI:45307	ChEBI	CCNE1	protein	P24864	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206565	0.8
SKP1	protein	P63208	UNIPROT	SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	form complex	binding			9606									10023660	t		gcesareni	The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin.	SIGNOR-64514	0.892
ARSA	protein	P15289	UNIPROT	HBA1	protein	P69905	UNIPROT	up-regulates activity	acetylation			9606									237937	t	Regulation	miannu	ASA acetylates hemoglobin. Purified acetylated hemoglobin had a slightly increased oxygen affinity and decreased heme-heme interaction.	SIGNOR-251773	0.2
6-[difluoro-[6-(1-methyl-4-pyrazolyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl]quinoline	chemical	CHEBI:91417	ChEBI	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193522	0.8
orantinib	chemical	CHEBI:91088	ChEBI	PDGFRB	protein	P09619	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207441	0.8
PI-103	chemical	CHEBI:90524	ChEBI	PIK3CA	protein	P42336	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206163	0.8
GDF2	protein	Q9UK05	UNIPROT	ALPL	protein	P05186	UNIPROT	up-regulates				9606									19175684	f		gcesareni	Wnt3a and bmp-9 enhanced each other's ability to induce alp in mscs	SIGNOR-183535	0.258
MK-2461	chemical	CID:44137946	PUBCHEM	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194384	0.8
LRIG1	protein	Q96JA1	UNIPROT	LRIG3	protein	Q6UXM1	UNIPROT	down-regulates				9606									23723069	f		miannu	Lrig1 destabilizes lrig3, limiting lrig3's positive effects on receptors and identifying lrig3 as a new target of lrig1.	SIGNOR-202177	0.442
MKNK1	protein	Q9BUB5	UNIPROT	EIF4E	protein	P06730	UNIPROT	up-regulates	phosphorylation			9606									20626350	t		gcesareni	Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e.	SIGNOR-166646	0.771
MET	protein	P08581	UNIPROT	GRAP	protein	Q13588	UNIPROT	up-regulates	binding			9606									8662889	t		gcesareni	To efficiently promote transformation met requires direct binding with grb2.	SIGNOR-42358	0.272
Tert-butyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate	chemical	CID:46907787	PUBCHEM	BRD4	protein	O60885	UNIPROT	down-regulates activity	chemical inhibition			9606									20871596	t		Simone Vumbaca	JQ1 displaces BRD4 from nuclear chromatin in cells	SIGNOR-261123	0.8
ABL1	protein	P00519	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates activity	phosphorylation	Tyr463	NDTGSRYyKEIPLSE	9606	BTO:0000567								12637538	t			Abl Phosphorylates and Activates PKD through Tyr463 Phosphorylation	SIGNOR-251430	0.345
COL2A1	protein	P02458	UNIPROT	A10/b1 integrin	complex	SIGNOR-C167	SIGNOR	up-regulates	binding			9606									9685391	t		gcesareni	We have isolated a novel collagen type ii binding integrin, a10b1,	SIGNOR-59349	0.469
SRC	protein	P12931	UNIPROT	MYLK	protein	Q15746	UNIPROT	up-regulates	phosphorylation	Tyr471	YEDAGSHyLCLLKAR	9606									12408982	t		gcesareni	Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity.	SIGNOR-95242	0.427
SGI-1776	chemical	CID:24795070	PUBCHEM	PIM3	protein	Q86V86	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206896	0.8
BUB1	protein	O43683	UNIPROT	Mitotic_checkpoint	phenotype	SIGNOR-PH28	SIGNOR	up-regulates				9606									20888775	f		gcesareni	The multidomain protein kinases bub1 and bubr1 (mad3 in yeast, worms and plants) are central components of the mitotic checkpoint for spindle assembly (sac)	SIGNOR-168192	0.7
6-propyl-2-thiouracil	smallmolecule	CHEBI:8502	ChEBI	DIO1	protein	P49895	UNIPROT	down-regulates activity	chemical inhibition			9606		BTO:0001379							27347897	t		scontino	The activity of D1 but not D2 or D3 is inhibited by 6n-propylthiouracil (PTU).	SIGNOR-267280	0.8
CUL4A	protein	Q13619	UNIPROT	DCX DET1-COP1	complex	SIGNOR-C24	SIGNOR	form complex	binding			9606									17452440	t		lperfetto	Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes	SIGNOR-154502	0.897
CCT129202	chemical	CID:16202152	PUBCHEM	AURKB	protein	Q96GD4	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190880	0.8
F2R	protein	P25116	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates	binding			9606									22972936	t		milica	Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase.	SIGNOR-199010	0.546
3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol	chemical	CHEBI:94691	ChEBI	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207248	0.8
CADM2	protein	Q8N3J6	UNIPROT	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606	BTO:0000962								17967169	f		Gianni	The adhesion molecule Necl-3/SynCAM-2 localizes to myelinated axons, binds to oligodendrocytes and promotes cell adhesion.	SIGNOR-268856	0.7
progesterone	smallmolecule	CHEBI:17026	ChEBI	COMT	protein	P21964	UNIPROT	down-regulates													17138778	f	Regulation of expression	miannu	Catechol-O-methyltransferase expression was down-regulated by progesterone or estrogen.	SIGNOR-251960	0.8
CHIR-124	chemical	CID:11502647	PUBCHEM	CHEK1	protein	O14757	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190973	0.8
dacomitinib	chemical	CHEBI:132268	ChEBI	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205939	0.8
FOXO3	protein	O43524	UNIPROT	Muscle_atrophy	phenotype	SIGNOR-PH40	SIGNOR	up-regulates				10090	BTO:0001103								15109499	f		gcesareni	Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.	SIGNOR-241949	0.7
CDK18	protein	Q07002	UNIPROT	RB1	protein	P06400	UNIPROT	unknown	phosphorylation			-1									28361970	t		lperfetto	Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro. 	SIGNOR-264558	0.291
R406	chemical	CID:11984591	PUBCHEM	SYK	protein	P43405	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206340	0.8
4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide	chemical	CHEBI:91447	ChEBI	ABL1	protein	P00519	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-194913	0.8
GSK256066	chemical	CID:9827968	PUBCHEM	PDE4B	protein	Q07343	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-192982	0.8
LHX2	protein	P50458	UNIPROT	CGA	protein	P01215	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9534	BTO:0001538								7513049	t		Luana	In Cos cells, LH-2 activated the a-subunit promoter approximately twofold 	SIGNOR-266055	0.269
LTBR	protein	P36941	UNIPROT	Lymphoma	phenotype	SIGNOR-PH14	SIGNOR	up-regulates				9606									17633025	f		lperfetto	The lymphotoxin-beta receptor (ltbetar, tnfrsf3) signaling pathway activates gene transcription programs and cell death important in immune development and host defense.	SIGNOR-156902	0.7
AURKB	protein	Q96GD4	UNIPROT	HASPIN	protein	Q8TF76	UNIPROT	up-regulates activity	phosphorylation	Ser143	PPFPSRDsGRLSPDL	9606									21658950	t		miannu	Phosphorylation by Aurora B is required for full Haspin activity toward H3T3 in mitosis	SIGNOR-262656	0.2
NUMA1	protein	Q14980	UNIPROT	TUBB	protein	P07437	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116900	0.377
SFPQ	protein	P23246	UNIPROT	LMX1B/SFPQ/PSPC1 complex	complex	SIGNOR-C106	SIGNOR	form complex	binding			10090									23308148	t		miannu	LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo.	SIGNOR-223970	0.457
CSNK2A2	protein	P19784	UNIPROT	HNRNPC	protein	P07910	UNIPROT	unknown	phosphorylation	Ser260	SEGGADDsAEEGDLL	-1									12564933	t		llicata	Protein kinase CK2 phosphorylates hnRNP-C1/C2 at S247	SIGNOR-251007	0.331
U0126.EtOH	chemical	CHEBI:90692	ChEBI	MAP2K2	protein	P36507	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207606	0.8
A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269013	0.7
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									14585074	f		amattioni	Caspase-3 is responsible for apoptosis execution	SIGNOR-256474	0.7
Bafetinib	chemical	CID:24853523	PUBCHEM	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190224	0.8
OGT	protein	O15294	UNIPROT	PYGL	protein	P06737	UNIPROT	up-regulates activity	glycosylation	Ser430	VDRLRRMsLIEEEGS	9606	BTO:0002181								34939084	t		Luana	O-GlcNAcylation at Ser-430 promotes PYGL activity	SIGNOR-267988	0.2
PPP1R2	protein	P41236	UNIPROT	PPP1CA	protein	P62136	UNIPROT	down-regulates	binding			9606									18250156	t		gcesareni	Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1.	SIGNOR-160651	0.79
NCOR2	protein	Q9Y618	UNIPROT	SNW1	protein	Q13573	UNIPROT	up-regulates	binding			9606	BTO:0000222	BTO:0000887							10713164	t	Ncor2 is a Skip corepressor	gcesareni	Protein-protein interaction assays demonstrated interaction between skip and the corepressor smrt.	SIGNOR-74227	0.574
4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide	chemical	CHEBI:94506	ChEBI	AURKA	protein	O14965	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193531	0.8
HDAC1	protein	Q13547	UNIPROT	RELA	protein	Q04206	UNIPROT	down-regulates	binding			9606				SIGNOR-C13					17183360	t		gcesareni	Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1.	SIGNOR-151425	0.588
AKT1	protein	P31749	UNIPROT	PRKACA	protein	P17612	UNIPROT	up-regulates				9606	BTO:0000938								16537363	f		gcesareni	Indicating that akt positively regulates shh signaling by controlling pka-mediated gli inactivation.	SIGNOR-252490	0.254
MAPK8	protein	P45983	UNIPROT	TWIST1	protein	Q15672	UNIPROT	up-regulates	phosphorylation	Ser68	GGGDEPGsPAQGKRG	9606	BTO:0000150								21502402	t		gcesareni	Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness.	SIGNOR-173417	0.314
Arry-380	chemical	CID:42598643	PUBCHEM	ERBB2	protein	P04626	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189882	0.8
PTPRB	protein	P23467	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates	dephosphorylation			9606									21454675	t		fstefani	Expression of rptp-beta inhibits both mek1/2 and erk1/2 phosphorylation.	SIGNOR-173000	0.39
imatinib methanesulfonate	chemical	CHEBI:31690	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193393	0.8
pelitinib	chemical	CHEBI:38927	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205755	0.8
3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide	chemical	CHEBI:131156	ChEBI	CHEK2	protein	O96017	UNIPROT	down-regulates	chemical inhibition			9606									20068082	t		gcesareni	Azd7762 is equally potent against chk2 in vitro.	SIGNOR-163119	0.8
DAPK1	protein	P53355	UNIPROT	CAMKK2	protein	Q96RR4	UNIPROT	unknown	phosphorylation	Ser511	RREERSLsAPGNLLT	9606	BTO:0000938	BTO:0000142							15209507	t		lperfetto	Dapk phosphorylates camkks511 was identified as the phosphorylation site	SIGNOR-126245	0.287
IL7	protein	P13232	UNIPROT	IL2RG	protein	P31785	UNIPROT	up-regulates	binding			9606	BTO:0002314	BTO:0000887;BTO:0001103;BTO:0001760							20089933	t		milica	This receptor (il-7r) is a heterodimer consisting of the il-7r chain and the common cytokine ? -chain.	SIGNOR-163545	0.699
IGF1R	protein	P08069	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates	phosphorylation	Tyr465	GEEELSNyICMGGKG	9606									17827393	t		gcesareni	Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K).	SIGNOR-157738	0.864
EIF4A2	protein	Q14240	UNIPROT	eIF4F_complex	complex	SIGNOR-C44	SIGNOR	form complex	binding			9606		BTO:0000671							11408474	t		miannu	Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f.	SIGNOR-108512	0.811
CEBPA	protein	P49715	UNIPROT	USF1	protein	P22415	UNIPROT	up-regulates activity	binding			9606	BTO:0004116								7862113	t		irozzo	 Our studies show that the human C/EBPa protein stimulates USF to bind to a USF consensus element within C/EBPa promoter and activates it by two- to threefold.The mechanism by which C/EBPa enhances USF binding and transactivation is currently under study.	SIGNOR-255701	0.323
nintedanib	chemical	CHEBI:85164	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190302	0.8
NEK2	protein	P51955	UNIPROT	NEK11	protein	Q8NG66	UNIPROT	up-regulates	phosphorylation			9606									15161910	t		esanto	Nek2 directly phosphorylated nek11 in the c-terminal non-catalytic region and elevated nek11 kinase activity.	SIGNOR-124944	0.402
AMPK	complex	SIGNOR-C15	SIGNOR	PFKFB3	protein	Q16875	UNIPROT	up-regulates	phosphorylation	Ser461	NPLMRRNsVTPLASP	9606	BTO:0000876	BTO:0000671							12065600	t		lperfetto	Ipfk-2 was phosphorylated on the homologous serine (ser-461) and activated by ampk in vitro.	SIGNOR-216639	0.378
WNT1	protein	P04628	UNIPROT	FZD8	protein	Q9H461	UNIPROT	up-regulates	binding			9606									11448771	t		gcesareni	Wnt signaling is mediated by the frizzled (fz) family of seven-pass transmembrane receptors that bind wnt via the conserved amino-terminal cysteine-rich domain (crd)	SIGNOR-109250	0.714
glucose	chemical	CHEBI:17234	ChEBI	AMPK	complex	SIGNOR-C15	SIGNOR	down-regulates activity	chemical inhibition			9606									32745890	t		miannu	Glucose deprivation, activates the glucose level–sensing kinase, AMPK, which in turn influences Rac1-dependent macropinocytosis. In this context macropinosomes take up necrotic cell debris as a rich nutrient source to fuel tumor cell growth	SIGNOR-277765	0.8
LGALS3	protein	P17931	UNIPROT	Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	up-regulates activity	binding			9606	BTO:0000584								32745890	t		miannu	Oncogenic RAS requires a protein scaffold to induce downstream signaling and macropinocytosis, three separate studies have identified upstream and downstream regulators that help drive this process in cancer cells. Anchorage-independent growth of cancer cells is supported by avb3 integrins which can be clustered by the extracellular lectin, galectin-3 to drive mutant RAS-mediated macropinocytosis for nutrient supplementation and growth of anchorage-independent cells. Secreted galectin-3 was found to bind to the N-glycans on surface avb3 integrins, clustering the integrins on the surface of the nonadherent cells for the recruit- ment of mutant KRAS as a signaling platform for inducing macropinocytosis 	SIGNOR-277741	0.28
Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	KRAS	protein	P01116	UNIPROT	up-regulates activity	binding			9606	BTO:0000584								32745890	t	Oncogenic RAS 	miannu	Oncogenic RAS requires a protein scaffold to induce downstream signaling and macropinocytosis, three separate studies have identified upstream and downstream regulators that help drive this process in cancer cells. Anchorage-independent growth of cancer cells is supported by avb3 integrins which can be clustered by the extracellular lectin, galectin-3 to drive mutant RAS-mediated macropinocytosis for nutrient supplementation and growth of anchorage-independent cells. Secreted galectin-3 was found to bind to the N-glycans on surface avb3 integrins, clustering the integrins on the surface of the nonadherent cells for the recruitment of mutant KRAS as a signaling platform for inducing macropinocytosis.	SIGNOR-277742	0.346
MMP9	protein	P14780	UNIPROT	Cellular_extravasation	phenotype	SIGNOR-PH225	SIGNOR	up-regulates				9606	BTO:0000584								38339310	f		miannu	Given that MMP-9 is able to degrade the ECM, which is an essential step in tumor cell extravasation and metastasis, and it is highly expressed in PDAC, CXCL12 may be playing a similar role in upregulating MMPs in PDAC 	SIGNOR-277734	0.7
CSF1	protein	P09603	UNIPROT	CSF1R	protein	P07333	UNIPROT	up-regulates activity	binding			9606	BTO:0000801								39416792	t		miannu	CSF-1, derived from fibroblasts, tumor cells, etc., is produced in membrane-bound form, secreted glycoproteins and proteoglycans. Currently, CSF-1R is considered to be the sole receptor for CSF-1. These cells regulate macrophage growth, differentiation and function by secreting CSF1. Colony-stimulating factor receptor (CSF1R), a type I single-transmembrane protein, is ubiquitously expressed in myeloid cells such as monocytes, macrophages, neuroglia, and osteoblasts. CSF1R induces receptor homodimerization by binding to either CSF-1 or IL-34, followed by activation of receptor signaling and activation of extracellular pro-cell-survival kinase cascades, including PI3K, ERK1/2, and JNK	SIGNOR-277713	0.936
PAK1	protein	Q13153	UNIPROT	F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	up-regulates				9606	BTO:0001033								29572236	f		miannu	 RAC1 activation induces the actin remodeling and membrane ruffling necessary to form macropinosomes by activating PAK kinases	SIGNOR-277768	0.7
PIP3	smallmolecule	CHEBI:16618	ChEBI	Macropinosomes formation	phenotype	SIGNOR-PH227	SIGNOR	up-regulates				9606	BTO:0001033								29572236	f		miannu	PIP3 produced by type I PI3Ks is required for macropinosome closure; in some cell types, PIP3 is also required for membrane ruffling	SIGNOR-277769	0.7
ATR	protein	Q13535	UNIPROT	SIAH1	protein	Q8IUQ4	UNIPROT	down-regulates activity	phosphorylation	Ser19	GTSKCPPsQRVPALT	9606	BTO:0002181								18536714	t		miannu	We have also demonstrated that DNA damage triggers disruption of the HIPK2-Siah-1 complex, resulting in HIPK2 stabilization and activation. Disruption of the HIPK2-Siah-1 complex is mediated by the ATM/ATR pathway and involves ATM/ATR-dependent phosphorylation of Siah-1 at Ser 19.	SIGNOR-276167	0.2
GABA-A (a3-b1-g2) receptor	complex	SIGNOR-C332	SIGNOR	CRHR1	protein	P34998	UNIPROT	down-regulates				9606		BTO:0000614							33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 	SIGNOR-268602	0.251
HNF1B	protein	P35680	UNIPROT	FXYD2	protein	P54710	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19389850	f	Regulation	miannu	We analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2. 	SIGNOR-251927	0.297
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	ATM	protein	Q13315	UNIPROT	up-regulates activity				9606	BTO:0000007								12556884	f		miannu	Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation.	SIGNOR-253376	0.7
mTORC1	complex	SIGNOR-C3	SIGNOR	Cell_growth	phenotype	SIGNOR-PH33	SIGNOR	up-regulates				9606									23863160	f		lperfetto	Cellular energy and nutrient status will dictate whether mTORC1 takes over and drives cell growth or conversely whether AMPK becomes active once again to drive consecutive waves of autophagy thorough ULK1.	SIGNOR-209919	0.7
LYN	protein	P07948	UNIPROT	BCR-Dk	complex	SIGNOR-C435	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000776								32323266	t		scontino	The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases.	SIGNOR-268212	0.697
ROS	stimulus	SIGNOR-ST2	SIGNOR	Oxidative_stress	phenotype	SIGNOR-PH215	SIGNOR	up-regulates				9606									22301329	f		lperfetto	Oxidative stress is defined by an imbalance between increased levels of reactive oxygen species (ROS) and a low activity of antioxidant mechanisms. An increased oxidative stress can induce damage to the cellular structure and potentially destroy tissues.	SIGNOR-272275	0.7
CSNK2A1	protein	P68400	UNIPROT	TELO2	protein	Q9Y4R8	UNIPROT	down-regulates	phosphorylation	Ser491	GSDSDLDsDDEFVPY	9606									20864032	t		lperfetto	Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. Here, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2)	SIGNOR-168040	0.2
PTPN1	protein	P18031	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates	dephosphorylation	Tyr771	ADIESSNyMAPYDNY	9606									18567737	t		gcesareni	Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr.	SIGNOR-179080	0.679
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser519	SGYSSPGsPGTPGSR	9606	BTO:0000590								12226093	t	The effect has been demonstrated using P10636-8	lperfetto	Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease.	SIGNOR-251599	0.695
MED9	protein	Q9NWA0	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266680	0.656
PRKCA	protein	P17252	UNIPROT	MYL9	protein	P24844	UNIPROT	down-regulates	phosphorylation	Ser2	sSKRAKAK	9606									22136066	t		lperfetto	Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity.	SIGNOR-177940	0.282
CAMK2A	protein	Q9UQM7	UNIPROT	CREB1	protein	P16220	UNIPROT	down-regulates	phosphorylation	Ser142	RKILNDLsSDAPGVP	9606									11013247	t		gcesareni	Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer.	SIGNOR-82501	0.576
CSNK1G1	protein	Q9HCP0	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser325	SSNASTIsGRLSPIM	-1									11980723	t		llicata	Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR	SIGNOR-252902	0.471
RAB5A	protein	P20339	UNIPROT	OCRL	protein	Q01968	UNIPROT	up-regulates activity	binding			9606									33722976	t		miannu	We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. Rab5 effectors Inpp5b, OCRL and APPL1 localize to macropinocytic cups and vesicles, and are required for macropinosome sealing. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis	SIGNOR-277771	0.683
INPP5B	protein	P32019	UNIPROT	1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate	smallmolecule	CHEBI:18348	ChEBI	down-regulates quantity	chemical modification			9606									33722976	t		miannu	We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. Rab5 effectors Inpp5b, OCRL and APPL1 localize to macropinocytic cups and vesicles, and are required for macropinosome sealing. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis	SIGNOR-277772	0.8
OCRL	protein	Q01968	UNIPROT	1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate	smallmolecule	CHEBI:18348	ChEBI	down-regulates quantity	chemical modification			9606									33722976	t		miannu	We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis. These observations raised the possibility that PtdIns(4,5)P2 depletion is in fact required for the completion of macropinocytosis or to prevent macropinosome back-fusion with the plasmalemma.	SIGNOR-277773	0.8
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate	smallmolecule	CHEBI:18348	ChEBI	Early macropinosomes 	phenotype	SIGNOR-PH228	SIGNOR	down-regulates				9606									33722976	t		miannu	We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis. These observations raised the possibility that PtdIns(4,5)P2 depletion is in fact required for the completion of macropinocytosis or to prevent macropinosome back-fusion with the plasmalemma.	SIGNOR-277774	0.7
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1738	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269340	0.718
Macropinosomes formation	phenotype	SIGNOR-PH227	SIGNOR	Early macropinosomes 	phenotype	SIGNOR-PH228	SIGNOR	up-regulates				9606									33722976	t		miannu	Completion of macropinosome formation requires membrane fusion and is followed by maturation of the resulting vacuole, which proceeds to merge with endosomes and, ultimately, lysosomes. 	SIGNOR-277775	0.7
CXCL2	protein	P19875	UNIPROT	CXCR2	protein	P25025	UNIPROT	up-regulates activity	binding			9606									38309677	t		miannu	CXCL2/3, also known as macrophage inflammatory protein-2α/2β (MIP-2α/MIP-2β), share the same receptor CXCR2 with CXCL1 and are able to activate neutrophils effectively	SIGNOR-277718	0.73
methylnaltrexone	chemical	CHEBI:136007	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10030	BTO:0000246								19282177	t		Luana	A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 	SIGNOR-258042	0.8
NOTCH3	protein	Q9UM47	UNIPROT	HEYL	protein	Q9NQ87	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887;BTO:0001260							11044625	f		gcesareni	In the latter, heyl is coexpressed with notch3, so far the only notch pathway gene detected in vascular smooth muscles (fig. 2h,i;joutel et al., 2000). Both genes are also coexpressed during late thymus development and our own promoter studies further suggest a potential regulation of heyl transcription by notch3.	SIGNOR-83402	0.593
Corticotropin	protein	P01189-PRO_0000024969	UNIPROT	MC2R	protein	Q01718	UNIPROT	up-regulates activity	binding			10029		BTO:0000047							20371771	t		lperfetto	Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP). 	SIGNOR-268616	0.2
IFNA2	protein	P01563	UNIPROT	HLA-B	protein	P01889	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									2507660	f	Regulation	miannu	HLA-B (class I) and C13 gene expression was transcriptionally activated by IFN-gamma and IFN-alpha 2	SIGNOR-251925	0.261
CREBBP	protein	Q92793	UNIPROT	DDX21	protein	Q9NR30	UNIPROT	down-regulates activity	acetylation	Lys137	PKKMKKEkEMNGETR										28790157	t		lperfetto	Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21.	SIGNOR-275904	0.247
AKT1	protein	P31749	UNIPROT	FAS	protein	P25445	UNIPROT	down-regulates				9606									15004527	f		gcesareni	Akt may serve to stimulate certain proteins (e.g., Ikk) involved in the prevention of apoptosis such as nf-kb as well as repress other proteins normally involved in the induction of apoptosis such as the forkhead transcription factors (fkhr, now know as foxo3), creb, glycogen synthetase-3 kinase-beta (gsk-3beta), fas, caspase-9 and cell cycle inhibitors such as p27	SIGNOR-252473	0.395
NRG1	protein	Q02297	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606									14967450	t		gcesareni	The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4.	SIGNOR-122053	0.901
RARA	protein	P10276	UNIPROT	RXRG	protein	P48443	UNIPROT	up-regulates	binding			9606									1310351	t		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16466	0.653
EEF1A1	protein	P68104	UNIPROT	Cys-tRNA(Cys)	smallmolecule	CHEBI:29152	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269508	0.8
NFE2	protein	Q16621	UNIPROT	HBE1	protein	P02100	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000426								16287851	f	Regulation of expression	miannu	NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells.	SIGNOR-251842	0.479
ALS2	protein	Q96Q42	UNIPROT	RAB5A	protein	P20339	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								30485418	t		miannu	ALS2 activates Rab5 on macropinosomes. Rab5 is activated and concurrently recruited to macropinosomes during ruffle closure. ALS2 depletion abolishes transient Rab5 activation on macropinosomes, while ALS2 is recruited to macropinosomes simultaneously with Rab5 activation. Thus, we conclude ALS2 activates Rab5 on macropinosomes. 	SIGNOR-277776	0.725
RAC1	protein	P63000	UNIPROT	ALS2	protein	Q96Q42	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								30485418	t		miannu	Thus, in our system, activeRac1 may recruit ALS2 only at the very early stage ofmacropinocytosis including membrane ruffles, suggest-ing that ALS2 is retained by some other mechanismsuntil Rab conversion.	SIGNOR-277777	0.515
RAB7A	protein	P51149	UNIPROT	ALS2	protein	Q96Q42	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								30485418	t		miannu	The absence of active Rab7 prolongs ALS2presence and Rab5 activation on macropinosomes, indicating that activeRab7 is necessary for Rab5 inactivation through ALS2 dissociation and playskey roles in the Rab switch on macropinosomes. Taken together, active Rab7is necessary for Rab5 down-regulation through ALS2dissociation, thereby acting as a central component inthe Rab5-to-Rab7 switch in macropinocytosis	SIGNOR-277778	0.311
RAB7A	protein	P51149	UNIPROT	Late macropinosomes	phenotype	SIGNOR-PH229	SIGNOR	up-regulates				9606									19693279	f		miannu	Rab7 is localized on later macropinosomes. Rab21 is localized on macropinosomes at an intermediate stage partially overlapping with Rab5 and Rab7, and then dissociates from the macropinosomes prior to Lamp1 acquisition by fusing with lysosomes.	SIGNOR-277779	0.7
bisindolylmaleimide i	chemical	CID:2396	PUBCHEM	PRKCB	protein	P05771	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	CellSignaling	gcesareni		SIGNOR-190347	0.8
TNC	protein	P24821	UNIPROT	Av/b1 integrin	complex	SIGNOR-C175	SIGNOR	up-regulates activity	binding			9606	BTO:0001521								38058842	t		miannu	TNC is shown to bind to integrin receptors expressed in adjacent PAAD cells, thereby inducing EMT. In addition, TNC expression in CAFs had significant positive correlations with ITGαV, ITGβ1, or ITGβ3 expression in cancer cells, which supports our speculations that the TNC-integrin signaling axis promotes the EMT pathway in cancer cells.	SIGNOR-277735	0.405
PLCE1	protein	Q9P212	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates				9606									12645577	f		miannu	TNF-alpha Binds to tnfr1 and activates pc-plc to induce pkc? And c-src activation	SIGNOR-99307	0.427
BAP1	protein	Q92560	UNIPROT	KEAP1	protein	Q14145	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								35052618	t		miannu	BAP1 directly binds to and deubiquitinates KEAP1. BAP1 stabilizes KEAP1 by binding to the BTB domain.	SIGNOR-268924	0.2
ASIP	protein	P42127	UNIPROT	MC1R	protein	Q01726	UNIPROT	down-regulates activity	binding			9606	BTO:0000847								14500544	t		miannu	The antagonist agouti signal protein (ASP) interacts with the Mc1r and blocks its stimulation by MSH.	SIGNOR-252378	0.734
TSC	complex	SIGNOR-C101	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	down-regulates activity				9606	BTO:0000007;BTO:0001938								12271141	f		lperfetto	These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor	SIGNOR-251527	0.614
SRPK1	protein	Q96SB4	UNIPROT	SRSF1	protein	Q07955	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000567								10196197	t		gcesareni	These results suggest that the formation of complexes between sf2/asf and srpks, which is influenced by the phosphorylation state of sf2/asf, may have regulatory roles in the assembly and localization of this splicing factor.	SIGNOR-66465	0.796
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser516	GDRSGYSsPGSPGTP	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-251598	0.695
RAB5A	protein	P20339	UNIPROT	RAB7A	protein	P51149	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								30485418	t		miannu	The absence of active Rab7 prolongs ALS2presence and Rab5 activation on macropinosomes, indicating that activeRab7 is necessary for Rab5 inactivation through ALS2 dissociation and playskey roles in the Rab switch on macropinosomes. Taken together, active Rab7is necessary for Rab5 down-regulation through ALS2dissociation, thereby acting as a central component inthe Rab5-to-Rab7 switch in macropinocytosis	SIGNOR-277780	0.684
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate	smallmolecule	CHEBI:18348	ChEBI	RAB21	protein	Q9UL25	UNIPROT	down-regulates activity	binding			9606									19693279	t		miannu	It was demonstrated that wild-type Rab21 was transiently associated with macropinosomes. Rab21 was recruited to the macropinosomes after a decrease in PI(4,5)P(2) and PI(3,4,5)P(3) levels. Although Rab21 was largely colocalized with Rab5, the recruitment of Rab21 to the macropinosomes lagged a minute behind that of Rab5, and preceded that of Rab7.	SIGNOR-277781	0.8
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates	phosphorylation	Ser579	NVKSKIGsTENLKHQ	9606	BTO:0000938								9771888	t	The effect has been demonstrated using P10636-8	gcesareni	Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase.	SIGNOR-60655	0.729
KAT2B	protein	Q92831	UNIPROT	H3-2	protein	Q5TEC6	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269624	0.2
cholesterol	smallmolecule	CHEBI:16113	ChEBI	RAC1	protein	P63000	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000584								31827278	t		miannu	Accumulation of V-ATPase at the plasma membrane is necessary for the cholesterol-dependent plasma-membrane association of RAC1, a prerequisite for the stimulation of membrane ruffling and macropinocytosis. In line with these observations, immunohistochemical staining of V-ATPase in human pancreatic ductal adenocarcinoma (PDAC) specimens revealed prominent staining at the cell periphery in neoplastic lesions, in con- trast to the predominantly cytoplasmic staining observed in adjacent normal tissues (Fig. 2e). Thus, mutant RAS-dependent plasma mem- brane V-ATPase displayed preferential accumulation in membrane ruffles, consistent with patterns observed in invasive breast, melanoma and pancreatic cancer cells	SIGNOR-277761	0.8
PTPN12	protein	Q05209	UNIPROT	WAS	protein	P42768	UNIPROT	down-regulates	dephosphorylation			9606									11711533	t		gcesareni	Furthermore, we demonstrate that pstpip serves as a scaffold protein between ptp-pest and wasp and allows ptp-pest to dephosphorylate wasp. This finding suggests a possible mechanism for ptp-pest to directly modulate actin remodeling through the pstpip-wasp interaction.	SIGNOR-111688	0.456
TFE3	protein	P19532	UNIPROT	HEXA	protein	P06865	UNIPROT	up-regulates quantity by expression	transcriptional regulation												24448649	f		lperfetto	Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A).	SIGNOR-276824	0.2
POU1F1	protein	P28069	UNIPROT	GH1	protein	P01241	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15998782	f		miannu	Such findings are consistent with the existence, in humans, of an LHX4-driven pathway leading to the expression of GH through transcriptional activation of POU1F1.	SIGNOR-254559	0.366
RPS19	protein	P39019	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262432	0.916
IKK-complex	complex	SIGNOR-C14	SIGNOR	FOXO3	protein	O43524	UNIPROT	down-regulates	phosphorylation	Ser644	GLDFNFDsLISTQNV	9606									15084260	t		lperfetto	Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation.	SIGNOR-216407	0.534
MYCT1	protein	Q8N699	UNIPROT	BCL2	protein	P10415	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30283340	f		miannu	MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. 	SIGNOR-261735	0.2
LPAR3	protein	Q9UBY5	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			9606									22863277	t		gcesareni	Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2.	SIGNOR-198547	0.385
PI4KB	protein	Q9UBF8	UNIPROT	Receptor_mediated_ endocytosis	phenotype	SIGNOR-PH121	SIGNOR	up-regulates				9534	BTO:0001444								22253445	f		lperfetto	PI4KB knockdown inhibits SARS-CoV S-mediated entry, whereas PI3KR1 knockdown increases SARS-CoV S-mediated entry	SIGNOR-260734	0.7
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	SP1	protein	P08047	UNIPROT	up-regulates	phosphorylation			9606									11904305	t	inferred from 70% family members	gcesareni	Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. sa-perk1/2 activates the transcription factor, sp1, via ser59 phosphorylation downstream of pkc_, leading to transcription of p21sdi1 and resulting in replicative senescence of hdf cells.	SIGNOR-270104	0.2
SMURF1	protein	Q9HCE7	UNIPROT	RUNX2	protein	Q13950	UNIPROT	down-regulates activity	ubiquitination			9606									14701828	t		lperfetto	Recently we have found that smurf1 mediates the protein degradation of the osteoblast-specific transcription factor runx2/cbfa1.	SIGNOR-95233	0.518
GSK3B	protein	P49841	UNIPROT	DPYSL3	protein	Q14195	UNIPROT	down-regulates activity	phosphorylation	Ser522	PAGSARGsPTRPNPP	10116	BTO:0000938								16611631	t		lperfetto	Primary rat cortical neurons were treated with purvalanol, a more potent inhibitor of cdk5 and dyrk2 than roscovitine (25). Phosphorylation was monitored using antibodies that specifically recognize crmp2 when phosphorylated at thr514/thr509, or crmp4 when phosphorylated at thr509. Loss of phosphorylation of ser522 will prevent subsequent phosphorylation of ser518/thr514/thr509 by gsk3. Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-146007	0.452
MAP2K6	protein	P52564	UNIPROT	MAPK13	protein	O15264	UNIPROT	up-regulates activity	phosphorylation	Thr180	RHADAEMtGYVVTRW	-1									9218798	t			SKK3 mediates the activation of SAPK4. Phosphorylation and activation of SAPK4 and SAPK2a by purified SKK3.	SIGNOR-251424	0.645
(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one	chemical	CHEBI:125500	ChEBI	OPRK1	protein	P41145	UNIPROT	down-regulates activity	chemical inhibition			10029									9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258776	0.8
RNF216	protein	Q9NWF9	UNIPROT	RIPK1	protein	Q13546	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								16968706	t		miannu	Triad3A promotes proteolytic degradation of adapter proteins. Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins.	SIGNOR-271608	0.518
IL2	protein	P60568	UNIPROT	IL2RG	protein	P31785	UNIPROT	up-regulates	binding			9606									16477002	t		miannu	Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c).	SIGNOR-144543	0.861
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	CDKN1B	protein	P46527	UNIPROT	down-regulates	ubiquitination			9606	BTO:0001271								12835716	t		lperfetto	Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2	SIGNOR-217172	0.522
ROCK2	protein	O75116	UNIPROT	PPP1R14A	protein	Q96A00	UNIPROT	up-regulates activity	phosphorylation	Thr38	QKRHARVtVKYDRRE	9606									32471307	t		lperfetto	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225].	SIGNOR-90832	0.424
CYP11A1	protein	P05108	UNIPROT	pregnenolone	smallmolecule	CHEBI:16581	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000048							33117906	t		lperfetto	The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme.	SIGNOR-268632	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FLNC	protein	Q14315	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser2233	LGRERLGsFGSITRQ	10090	BTO:0000165								32444788	t		miannu	We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells. In vitro kinase assays combined with LC-MS confirmed hFLNc-S2233 as a substrate of Akt, whereas PKCα preferentially targeted S2236.	SIGNOR-262616	0.2
SOX2	protein	P48431	UNIPROT	Pluripotency	phenotype	SIGNOR-PH43	SIGNOR	up-regulates				9606	BTO:0001086								25126380	f		flangone	Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency. 	SIGNOR-242002	0.7
ACAT1	protein	P24752	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	acetylation												34289383	t		lperfetto	We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)	SIGNOR-267633	0.402
EGLN3	protein	Q9H6Z9	UNIPROT	ADRB2	protein	P07550	UNIPROT	up-regulates quantity by stabilization	hydroxylation	Pro382	KLLCEDLpGTEDFVG	9606	BTO:0000007								19584355	t		lperfetto	We further show that the interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. Under hypoxic conditions, receptor hydroxylation and subsequent ubiquitylation decrease dramatically, thus attenuating receptor degradation and down-regulation.	SIGNOR-262006	0.323
ponatinib	chemical	CHEBI:78543	ChEBI	SRC	protein	P12931	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206280	0.8
MAPK3	protein	P27361	UNIPROT	RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	up-regulates activity	phosphorylation			9606	BTO:0000007								12832467	t		lperfetto	Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.	SIGNOR-252760	0.718
ARID1A	protein	O14497	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	form complex	binding			9606									15627498	t		miannu	We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers.	SIGNOR-132919	0.786
MELK	protein	Q14680	UNIPROT	MELK	protein	Q14680	UNIPROT	up-regulates	phosphorylation	Ser171	HLQTCCGsLAYAAPE	9606									16216881	t		gcesareni	We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.	SIGNOR-140958	0.2
NKX3-1	protein	Q99801	UNIPROT	NKX3-1/SRF	complex	SIGNOR-C25	SIGNOR	form complex	binding			9606		BTO:0000887;BTO:0001260							10993896	t		lperfetto	A novel complex element containing a juxtaposed nkx-binding site (nke) and an srf-binding element (sre) in the proximal promoter region was found to be necessary for the nkx3-1/srf coactivation of smga transcription.	SIGNOR-82087	0.405
YWHAE	protein	P62258	UNIPROT	TBP	protein	P20226	UNIPROT	up-regulates activity	binding												10449590	t		lperfetto	The in vitro binding with general transcription factors TBP and TFIIB together with its nuclear location provide evidence supporting a role for 14-3-3 proteins as transcriptional activators or coactivators when part of a DNA binding complex.	SIGNOR-262834	0.354
DEAF1	protein	O75398	UNIPROT	RAC3	protein	P60763	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001939								18826651	t		Gianni	Affymetrix gene profiling studies revealed Rac3 as a potential target gene and quantitative RT-PCR analysis confirmed that Rac3 was upregulated by Deaf-1 in immortalized mouse mammary epithelial cells.	SIGNOR-269059	0.2
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR1D	protein	P28221	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264287	0.8
haloperidol	chemical	CHEBI:5613	ChEBI	HTR1A	protein	P08908	UNIPROT	down-regulates activity	chemical inhibition			10116		BTO:0000601							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258521	0.8
FYN	protein	P06241	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates activity	phosphorylation	Tyr39	TDPTPQHyPSFGVTS	-1									9425276	t			Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn.	SIGNOR-251166	0.2
MLL/SET subcomplex	complex	SIGNOR-C87	SIGNOR	MLL3 complex	complex	SIGNOR-C446	SIGNOR	form complex	binding			9606									34156443	t		miannu	MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. 	SIGNOR-268808	0.725
SERPINC1	protein	P01008	UNIPROT	F11	protein	P03951	UNIPROT	down-regulates activity	cleavage												31030036	t		lperfetto	Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1	SIGNOR-264137	0.643
SLBP	protein	Q14493	UNIPROT	H3-2	protein	Q5TEC6	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265415	0.2
NAA30	protein	Q147X3	UNIPROT	NatC	complex	SIGNOR-C417	SIGNOR	form complex	binding			9606									19398576	t		miannu	 We here identify and characterize the human NatC (hNatC) complex, containing the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31. This complex associates with ribosomes, and hMak3 acetylates Met-Leu protein N termini in vitro, suggesting a model in which the human NatC complex functions in cotranslational N-terminal acetylation.	SIGNOR-267233	0.747
SCN5A	protein	Q14524	UNIPROT	Action_potential 	phenotype	SIGNOR-PH82	SIGNOR	up-regulates				9606									26043074	f		miannu	The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons.	SIGNOR-253447	0.7
PLK3	protein	Q9H4B4	UNIPROT	CASP8	protein	Q14790	UNIPROT	up-regulates activity	phosphorylation	Thr273	DAGALTTtFEELHFE										27325299	t		lperfetto	Furthermore, we identify caspase-8 as a new substrate for Plk3. Phosphorylation occurs on T273 and results in stimulation of caspase-8 proapoptotic function.	SIGNOR-272995	0.346
MAPK14	protein	Q16539	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	phosphorylation	Ser204	NHSMDAGsPNLSPNP	9606	BTO:0001939								15520018	t		miannu	Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways.	SIGNOR-250113	0.553
MFGE8	protein	Q08431	UNIPROT	Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	up-regulates activity	binding			10116									31958465	t		miannu	Milk fat globule-EGF factor 8 (MFGE8), a protein known as lactadherin in humans, contains C domains interacting with extracellular matrices and epidermal growth factor–like domains with an RGD motif binding to integrins αvβ3 and αvβ5.	SIGNOR-260644	0.506
MAPK1	protein	P28482	UNIPROT	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Thr325	TELEPLCtPVVTCTP								phosphorylation:Ser374;Ser362	PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS	16055710	t		lperfetto	Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos	SIGNOR-263011	0.784
CSNK2A2	protein	P19784	UNIPROT	HMGA1	protein	P17096	UNIPROT	unknown	phosphorylation	Ser102	EEGISQEsSEEEQ	-1									2806554	t		llicata	Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells.	SIGNOR-251004	0.333
MEF2C	protein	Q06413	UNIPROT	α-Catenin	proteinfamily	SIGNOR-PF72	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002320								21598020	t		miannu	GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter	SIGNOR-265816	0.472
ERN1	protein	O75460	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates				9606	BTO:0001976								18065414	f		lperfetto	The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression	SIGNOR-253146	0.394
MAPK1	protein	P28482	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates activity	phosphorylation	Ser293	PAPARPRsPSQTRKG	9606									15262992	t		lperfetto	Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2.	SIGNOR-126859	0.268
NEDD4	protein	P46934	UNIPROT	AP1G2	protein	O75843	UNIPROT	up-regulates activity	polyubiquitination			9606	BTO:0001950								18772139	t		miannu	Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination. 	SIGNOR-272635	0.41
ADK	protein	P55263	UNIPROT	AMP	smallmolecule	CHEBI:456215	ChEBI	up-regulates quantity	chemical modification			9606									33961946	t		miannu	Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5′-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). 	SIGNOR-267840	0.8
MYOD1	protein	P15172	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	up-regulates	binding			9606		BTO:0001103							17194702	t		lperfetto	Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes	SIGNOR-217737	0.342
SRF	protein	P11831	UNIPROT	SERPINE1	protein	P05121	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000161								15514113	f		miannu	 We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1. 	SIGNOR-255228	0.268
TNF	protein	P01375	UNIPROT	TNFRSF1A	protein	P19438	UNIPROT	up-regulates activity	binding			9606									10634209	t		lperfetto	TNF-induced apoptosis is mediated primarily through the activation of type I receptors	SIGNOR-226676	0.923
CASP1	protein	P29466	UNIPROT	SPHK2	protein	Q9NRA0	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								20197547	t			Our data so far indicated colocalization of SphK2 with caspase-1 at the plasma membrane after induction of apoptosis.These observations supported caspase-1–dependent cleavage of SphK2 at its N-terminus as a prerequisite for its release.	SIGNOR-268831	0.251
CASP7	protein	P55210	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	cleavage	Asp326	YDPEMEEdSYDSFGE	-1									10069390	t		lperfetto	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261746	0.323
MMP14	protein	P50281	UNIPROT	FGG	protein	P02679	UNIPROT	down-regulates quantity by destabilization	cleavage	Tyr27	LSSTCVAyVATRDNC	-1									10930399	t		lperfetto	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain	SIGNOR-263616	0.2
LMNA	protein	P02545	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				10090	BTO:0000944								16415042	f	Cleaved by CASP6	amattioni	Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy.|We conclude that A-type lamins act as inhibitors of adipocyte differentiation, possibly by affecting PPARgamma2 and insulin signaling.	SIGNOR-45455	0.7
ERBB2	protein	P04626	UNIPROT	CDK1	protein	P06493	UNIPROT	down-regulates	phosphorylation	Tyr15	EKIGEGTyGVVYKGR	9606									12049736	t		lperfetto	Phosphorylation on tyrosine-15 of p34(cdc2) by erbb2 inhibits p34(cdc2) activation and is involved in resistance to taxol-induced apoptosis	SIGNOR-88671	0.278
GSK3B	protein	P49841	UNIPROT	PDX1	protein	P52945	UNIPROT	down-regulates quantity	phosphorylation	Ser66	QGSPPDIsPYEVPPL	10090	BTO:0000783;BTO:0002284								16407209	t			Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic beta-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity.	SIGNOR-255544	0.2
NME2	protein	P22392	UNIPROT	KCNN4	protein	O15554	UNIPROT	up-regulates	phosphorylation	His358	FRQVRLKhRKLREQV	9606									18796614	t		gcesareni	We previously showed that nucleoside diphosphate kinase beta (ndpk-b), a mammalian histidine kinase, is required for kca3.1 channel activation in human cd4 t lymphocytes.	SIGNOR-181083	0.431
PPP3CB	protein	P16298	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser177	ASSGSSAsFISDTFS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248369	0.598
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	IKZF1	protein	Q13422	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0003933								24292625	t		miannu	We found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma.	SIGNOR-272083	0.38
ERGIC1	protein	Q969X5	UNIPROT	ERGIC3	protein	Q9Y282	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000599								15308636	t		Giorgia	Among novel cycling proteins we have characterized ERGIC-32, a new ERGIC protein that interacts with human Erv46, a protein previously characterized in yeast and functioning in ER to Golgi protein trafficking. ERGIC-32 interacts with human Erv46 (hErv46) as revealed by covalent cross-linking and mistargeting experiments, and silencing of ERGIC-32 by small interfering RNAs increases the turnover of hErv46. We propose that ERGIC-32 functions as a modulator of the hErv41-hErv46 complex by stabilizing hErv46.	SIGNOR-260637	0.381
SMAD3	protein	P84022	UNIPROT	PAX6	protein	P26367	UNIPROT	down-regulates activity	binding			9606	BTO:0001874								17251190	t	Regulation	miannu	The paired domain of Pax6 interacts with the MH1 domain of Smad3. Smad3 prevents Pax6 paired domain from binding DNA	SIGNOR-251875	0.409
PTPRG	protein	P23470	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	dephosphorylation	Tyr716	RPPSAELySNALPVG	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254715	0.345
AGTR1	protein	P30556	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257017	0.628
clofarabine	chemical	CHEBI:681569	ChEBI	PRIM1	protein	P49642	UNIPROT	down-regulates activity	chemical inhibition			9606									1707752	t		miannu	Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase.	SIGNOR-258359	0.8
SRC	protein	P12931	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates activity	phosphorylation	Tyr1346	SFDERQPyAHMNGGR	-1									7493944	t		lperfetto	The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.	SIGNOR-246276	0.564
POU5F1	protein	Q01860	UNIPROT	SOX2	protein	P48431	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001086								17068183	f		miannu	 To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 	SIGNOR-254942	0.834
MAPK1	protein	P28482	UNIPROT	MKNK1	protein	Q9BUB5	UNIPROT	up-regulates	phosphorylation			9606									9155017	t		gcesareni	We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity toward a substrate, eukaryotic initiation factor-4e (eif-4e).	SIGNOR-48298	0.576
alvimopan	chemical	CHEBI:135686	ChEBI	OPRD1	protein	P41143	UNIPROT	down-regulates activity	chemical inhibition			-1									18313920	t		Luana	A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors.	SIGNOR-257772	0.8
PRKACA	protein	P17612	UNIPROT	AMPA	proteinfamily	SIGNOR-PF58	SIGNOR	up-regulates activity	phosphorylation		YES	9606									12536214	t	inferred from family member	gcesareni	We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus.	SIGNOR-267784	0.487
PRKACA	protein	P17612	UNIPROT	RAP1A	protein	P62834	UNIPROT	down-regulates activity	phosphorylation	Ser180	KKKPKKKsCLLL	9534									9867809	t		miannu	Phosphorylation of Rap1A by PKA abolished its binding activity to CRR. a mutant Rap1A(S180E), whose sole PKA phosphorylation residue, Ser-180, was substituted by an acidic residue, Glu, to mimic its phosphorylated form, failed to suppress Ras-dependent Raf-1 activation in COS-7 cells.	SIGNOR-250042	0.503
TGM2	protein	P21980	UNIPROT	H3C1	protein	P68431	UNIPROT	unknown	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									16407273	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Tg2 is able to phosphorylate purified histone proteins, and h3 and h1 in chromatin preparations, and it is associated with chromatin in breast cancer cells.	SIGNOR-143642	0.2
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser213	QNIPAHYsPRTSPIM	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252329	0.635
CDK9	protein	P50750	UNIPROT	NCOA2	protein	Q15596	UNIPROT	up-regulates activity	phosphorylation	Ser499	MSPGVAGsPRIPPSQ	9606	BTO:0000801								29170386	t			Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties.	SIGNOR-256099	0.248
PRKCG	protein	P05129	UNIPROT	HABP4	protein	Q5JVS0	UNIPROT	down-regulates activity	phosphorylation	Thr354	RKPANDItSQLEINF	9606	BTO:0004974								14699138	t		lperfetto	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249249	0.296
CDK5/CDK5R1	complex	SIGNOR-C144	SIGNOR	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Thr498	KTPPAPKtPPSSGEP	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-251597	0.695
CDK5	protein	Q00535	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser516	GDRSGYSsPGSPGTP	9606	BTO:0000590								12387894	t		lperfetto	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249327	0.754
BAG1	protein	Q99933	UNIPROT	STUB1	protein	Q9UNE7	UNIPROT	up-regulates activity	binding			9534	BTO:0001538								11676916	t		miannu	BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association	SIGNOR-272587	0.556
PIGS	protein	Q96S52	UNIPROT	GPAA1	protein	O43292	UNIPROT	up-regulates activity	binding			10090									11483512	t		miannu	To determine roles for PIG-S and PIG-T, we disrupted these genes in mouse F9 cells by homologous recombination. PIG-S and PIG-T knockout cells were defective in transfer of GPI to proteins, particularly in formation of the carbonyl intermediates. We also demonstrate that PIG-S and PIG-T form a protein complex with GAA1 and GPI8, and that PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8.	SIGNOR-261361	0.892
DYRK1A	protein	Q13627	UNIPROT	SF3B1	protein	O75533	UNIPROT	unknown	phosphorylation	Thr434	PARKLTAtPTPLGGM	9606	BTO:0000007								16512921	t		llicata	The present data show that the splicing factor sf3b1 is a substrate of the protein kinase dyrk1a and suggest that dyrk1a may be involved in the regulation of pre mrna-splicing. by mass spectrometry and mutational analysis of sf3b1, thr434 was identified as the major phosphorylation site for dyrk1a.	SIGNOR-144975	0.515
NFIX	protein	Q14938	UNIPROT	GAS6	protein	Q14393	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268888	0.205
CHEK2	protein	O96017	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Thr68	SSLETVStQELYSIP	9606	BTO:0000007								11901158	t		lperfetto	Thus, activation of chk2 in irradiated cells may occur through oligomerization of chk2 via binding of the thr-68-phosphorylated region of one chk2 to the fha domain of another. Oligomerization of chk2 may therefore increase the efficiency of trans-autophosphorylation resulting in the release of active chk2 monomers that proceed to enforce checkpoint control in irradiated cells.	SIGNOR-116135	0.2
GSK3B/Axin/APC	complex	SIGNOR-C110	SIGNOR	CTNNB1	protein	P35222	UNIPROT	down-regulates activity	phosphorylation	Thr41	GIHSGATtTAPSLSG	9606									11955436	t		lperfetto	Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC).	SIGNOR-227905	0.892
IKZF1	protein	Q13422	UNIPROT	LNPEP	protein	Q9UIQ6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003420								15894523	f	 	miannu	Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. 	SIGNOR-255403	0.279
PYCARD	protein	Q9ULZ3	UNIPROT	NLRC4 inflammasome	complex	SIGNOR-C223	SIGNOR	form complex	binding												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256405	0.651
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Thr821	KISEGLPtPTKMTPR	9606									9139732	t		lperfetto	We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein.	SIGNOR-217324	0.798
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation			9606									21440011	t		lperfetto	Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs	SIGNOR-252348	0.2
PRPF19	protein	Q9UMS4	UNIPROT	PRPF3	protein	O43395	UNIPROT	up-regulates activity	polyubiquitination			9606									20595234	t	k63	miannu	Here, we report that the spliceosomal Prp19 complex modifies Prp3, a component of the U4 snRNP, with nonproteolytic K63-linked ubiquitin chains. The K63-linked chains increase the affinity of Prp3 for the U5 snRNP component Prp8, thereby allowing for the stabilization of the U4/U6.U5 snRNP. 	SIGNOR-271966	0.742
mTORC1	complex	SIGNOR-C3	SIGNOR	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr70	RNSPVTKtPPRDLPT	9606									23486913	t		lperfetto	These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation	SIGNOR-217141	0.753
PRKACA	protein	P17612	UNIPROT	TENT2	protein	Q6PIY7	UNIPROT	down-regulates activity	phosphorylation	Ser116	LSGERRYsMPPLFHT	9606									31057087	t		miannu	We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. 	SIGNOR-259402	0.2
Caspase 3 complex	complex	SIGNOR-C221	SIGNOR	DFFA	protein	O00273	UNIPROT	up-regulates activity	cleavage			9606									9108473	t		lperfetto	DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3.	SIGNOR-256464	0.746
OXGR1	protein	Q96P68	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256913	0.2
PRKDC	protein	P78527	UNIPROT	PRKDC	protein	P78527	UNIPROT	down-regulates	phosphorylation	Thr3950	GHAFGSAtQFLPVPE	9606									17189255	t		gcesareni	Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, we have reported here that atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster.	SIGNOR-151453	0.2
AKT1	protein	P31749	UNIPROT	YBX1	protein	P67809	UNIPROT	up-regulates	phosphorylation	Ser102	NPRKYLRsVGDGETV	9606	BTO:0000150								19036157	t		lperfetto	Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102	SIGNOR-252521	0.576
Degranulation	phenotype	SIGNOR-PH92	SIGNOR	IL5	protein	P05113	UNIPROT	up-regulates quantity				9606	BTO:0000830								17259966	f		apalma	The array of mediators released by human mast cells is enormous and explains how mast cells can be involved in so many different physiological and pathophysiological functions. Of particular relevance [...] cytokines, such as IL-3 -basophil recruitment and activation-, IL-5 -eosinophil recruitment and activation- and IL-13 -induction of IgE synthesis by B cells.	SIGNOR-255346	0.7
Vps34 Complex I	complex	SIGNOR-C242	SIGNOR	Autophagy	phenotype	SIGNOR-PH31	SIGNOR	up-regulates													30397185	f		lperfetto	PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively.	SIGNOR-260325	0.7
MAPK1	protein	P28482	UNIPROT	XPO5	protein	Q9HAV4	UNIPROT	down-regulates activity	phosphorylation	Thr345	GADSDVEtPSNFGKY	9606	BTO:0000007								27846390	t		lperfetto	Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. 	SIGNOR-262984	0.306
HAUS7	protein	Q99871	UNIPROT	HAUS complex	complex	SIGNOR-C281	SIGNOR	form complex	binding			9606	BTO:0000567								19369198	t		lperfetto	Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC)	SIGNOR-262318	0.667
CIC	protein	Q96RK0	UNIPROT	Sin3B_complex	complex	SIGNOR-C409	SIGNOR	up-regulates activity	binding			10090		BTO:0000142							32229723	t		miannu	Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified the BRG1-containing mSWI/SNF complex whose function is necessary for transcriptional repression by CIC. CIC interacts with mSWI/SNF complex during neurogenesis. CIC tethers SIN3-HDAC corepressor complex and mSWI/SNF complex to VGF promoter during neurogenesis.	SIGNOR-269206	0.341
PAK5	protein	Q9P286	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000150								29041983	t		lperfetto	PAK5-mediated phosphorylation and nuclear translocation of NF-κB-p65 promotes breast cancer cell proliferation in vitro and in vivo|We characterized that PAK5 could promote the phosphorylation and the nuclear translocation of p65 subunit of nuclear factor-kappaB, and demonstrated that p65 could directly bind to the promoter of Cyclin D1	SIGNOR-275657	0.2
RARG	protein	P13631	UNIPROT	RXRB	protein	P28702	UNIPROT	up-regulates	binding			9606									1310351	t		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16662	0.7
MTOR	protein	P42345	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	up-regulates activity	phosphorylation	Thr412	NQVFLGFtYVAPSVL	9823		BTO:0004712							23486913	t		lperfetto	Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway	SIGNOR-201538	0.96
CDK1	protein	P06493	UNIPROT	BUB1	protein	O43683	UNIPROT	up-regulates	phosphorylation	Thr609	SAAQLAStPFHKLPV	9606									16760428	t		gcesareni	The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609	SIGNOR-147065	0.855
MAP2K1	protein	Q02750	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity	phosphorylation			10090									11730323	t			Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs	SIGNOR-258992	0.741
silodosin	chemical	CHEBI:135929	ChEBI	ADRA1A	protein	P35348	UNIPROT	down-regulates activity	chemical inhibition			10029									7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258450	0.8
TRIM5	protein	Q9C035	UNIPROT	TRIM5	protein	Q9C035	UNIPROT	up-regulates quantity	monoubiquitination			9606	BTO:0000567								18312418	t		miannu	Here, we show that TRIM5alpha functions as a RING-finger-type E3 ubiquitin ligase both in vitro and in vivo and ubiquitinates itself in cooperation with the E2 ubiquitin-conjugating enzyme UbcH5B. Thus, the ubiquitination of TRIM5alpha is catalyzed by itself and Ro52. Unexpectedly, although TRIM5alpha is ubiquitinated, our results have revealed that the proteasome inhibitors MG115 and MG132 do not stabilize it in HeLa cells, suggesting that the ubiquitination of TRIM5alpha does not lead to proteasomal degradation. Importantly, TRIM5alpha is clearly conjugated by a single ubiquitin molecule (monoubiquitination). Our monoubiquitin-fusion assay suggests that monoubiquitination is a signal for TRIM5alpha to translocate from cytoplasmic bodies to the cytoplasm.	SIGNOR-271671	0.2
MAPK1	protein	P28482	UNIPROT	ETV6	protein	P41212	UNIPROT	down-regulates	phosphorylation	Ser257	ESHPKPSsPRQESTR	10090	BTO:0000944								15060146	t		miannu	Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation.	SIGNOR-260087	0.323
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	BRAF	protein	P15056	UNIPROT	down-regulates	phosphorylation			9606									16508002	t	inferred from 70% family members	gcesareni	Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity.	SIGNOR-270043	0.2
HLA-G	protein	P17693	UNIPROT	KLRC1	protein	P26715	UNIPROT	up-regulates	binding			9606									9560253	t		gcesareni	Current models of nk cell function have supposed that the cd94/nkg2a heterodimer is interacting with an epitope common to classical hla class i	SIGNOR-56714	0.628
histidine	smallmolecule	CHEBI:27570	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264762	0.7
PLK1	protein	P53350	UNIPROT	USP16	protein	Q9Y5T5	UNIPROT	up-regulates activity	phosphorylation	Ser386	HESFLDLsLPVLDDQ	-1									26323689	t	done	miannu	Plk1 phosphorylates and activates Usp16. In vitro phosphorylation of Usp16 with single (S330A, S386A, or S486A) or collective 3A (S330A/S386A/S486A) mutation showed that Plk1 phosphorylated Usp16 at all three sites (Fig. S2 D).	SIGNOR-274015	0.35
CDK1	protein	P06493	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Thr273	SPSVHPAtPISPGRA	9606									16046550	t	The effect has been demonstrated using Q01196-8.	gcesareni	Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction.	SIGNOR-138920	0.347
SETD5	protein	Q9C0A6	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates activity	methylation	Lys37	APSTGGVkKPHRYRP	-1									31515109	t		miannu	SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription. 	SIGNOR-264622	0.2
LAMTOR5	protein	O43504	UNIPROT	S100A4	protein	P26447	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								22740693	f		miannu	It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4. 	SIGNOR-255248	0.371
LRRC4	protein	Q9HBW1	UNIPROT	CCNE1	protein	P24864	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		BTO:0000142							25526788	f		miannu	LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway.	SIGNOR-264057	0.2
SRC	protein	P12931	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	phosphorylation	Tyr333	NIMRTYTyEKLLWTT	9606									22056988	t		lperfetto	Egfr activation induces translocation of pkm2 into the nucleus, where k433 of pkm2 binds to c-src-phosphorylated y333 of _-cateninthese findings reveal that egf induces _-catenin transactivation via a mechanism distinct from that induced by wnt/wingless and highlight the essential non-metabolic functions of pkm2 in egfr-promoted _-catenin transactivation, cell proliferation and tumorigenesis	SIGNOR-177086	0.752
EIF2AK2	protein	P19525	UNIPROT	EIF2AK2	protein	P19525	UNIPROT	up-regulates	phosphorylation	Thr88	AVSPLLLtTTNSSEG	9606									11152499	t		tpavlidou	Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites.	SIGNOR-85781	0.2
AIFM1	protein	O95831	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates				9606									21210296	f		gcesareni	Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore.	SIGNOR-170960	0.413
RNF13	protein	O43567	UNIPROT	SNAPIN	protein	O95295	UNIPROT	up-regulates activity	polyubiquitination			9534	BTO:0000298								22890573	t		miannu	 RNF13 directly interacted with snapin, a SNAP-25-interacting protein. Interestingly, snapin was ubiquitinated by RNF13 via the lysine-29 conjugated polyubiquitin chain, which in turn promoted the association of snapin with SNAP-25. Consistently, we found an attenuated interaction between snapin and SNAP-25 in the RNF13-null mice. Therefore, these results suggest that RNF13 is involved in the regulation of the SNARE complex, which thereby controls synaptic function.	SIGNOR-272044	0.537
CHEK1	protein	O14757	UNIPROT	H3-3A	protein	P84243	UNIPROT	down-regulates activity	phosphorylation	Thr12	KQTARKStGGKAPRK	9606									18243098	t		gcesareni	We identify chk1 as the kinase responsible for h3-t11 phosphorylation. H3-t11 phosphorylation occurs throughout the cell cycle and is chk1 dependent in vivo.Phosphorylation at thr-12 (h3t11ph) by pkn1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of lys-10 (h3k9me) by kdm4c/jmjd2c.	SIGNOR-160557	0.2
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Thr479	FSYSASGtA	9606	BTO:0000093								24670654	t		gcesareni	Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation	SIGNOR-252453	0.427
MRPS21	protein	P82921	UNIPROT	28S mitochondrial small ribosomal subunit	complex	SIGNOR-C266	SIGNOR	form complex	binding			9606									25838379	t		miannu	The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 	SIGNOR-261486	0.657
TFEB	protein	P19484	UNIPROT	NDUFB10	protein	O96000	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4).	SIGNOR-276704	0.2
CSF1	protein	P09603	UNIPROT	CSF3R	protein	Q99062	UNIPROT	up-regulates	binding			9606									16492764	t		gcesareni	A crystal structure of the signaling complex between human granulocyte colony-stimulating factor (gcsf) and a ligand binding region of gcsf receptor (gcsf-r), has been determined to 2.8 a resolution	SIGNOR-144737	0.327
CLTC	protein	Q00610	UNIPROT	AP-2/clathrin vescicle	complex	SIGNOR-C249	SIGNOR	form complex	binding			9606									24789820	t		lperfetto	AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly. 	SIGNOR-260665	0.735
BMP7	protein	P18075	UNIPROT	ACVR1	protein	Q04771	UNIPROT	up-regulates	binding			10090	BTO:0000165			SIGNOR-C30					11282024	t		gcesareni	Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2	SIGNOR-236913	0.8
MBD2	protein	Q9UBB5	UNIPROT	MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263835	0.725
TUBA1B	protein	P68363	UNIPROT	Neuron_migration	phenotype	SIGNOR-PH67	SIGNOR	up-regulates				9606	BTO:0000007								19185337	f		miannu	We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching.	SIGNOR-269727	0.7
PRKCD	protein	Q05655	UNIPROT	TNNI3	protein	P19429	UNIPROT	up-regulates activity	phosphorylation	Ser23	PAPIRRRsSNYRAYA	9606									18550549	t		gcesareni	Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144.	SIGNOR-178880	0.276
CDK2	protein	P24941	UNIPROT	LIG1	protein	P18858	UNIPROT	up-regulates activity	phosphorylation	Ser51	GVVSESDsPVKRPGR	9606	BTO:0000567								12851383	t		lperfetto	Thus, phosphorylation of serine 51 on hligi plays a critical role in regulating the interaction between hligi and rfc, which is required for efficient dna replication and repair.	SIGNOR-103246	0.468
HIF1A	protein	Q16665	UNIPROT	KDM3A	protein	Q9Y4C1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									32938217	t		SaraGualdi	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271568	0.425
PRKCD	protein	Q05655	UNIPROT	YWHAB	protein	P31946	UNIPROT	down-regulates	phosphorylation	Ser60	VVGARRSsWRVISSI	9606									16024783	t		gcesareni	We provide a mechanism for these observations through the phosphorylation of 14-3-3 by ikk and pkc on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm.	SIGNOR-138612	0.505
ARAP1	protein	Q96P48	UNIPROT	CDC42	protein	P60953	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260452	0.511
CDK2	protein	P24941	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates	phosphorylation	Thr8	MSSILPFtPPIVKRL	9606									19114991	t		lpetrilli	In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity	SIGNOR-182975	0.733
DMTF1	protein	Q9Y222	UNIPROT	JUNB	protein	P17275	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004532								19816943	t		Luana	 Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. 	SIGNOR-261585	0.268
STK4	protein	Q13043	UNIPROT	LATS1	protein	O95835	UNIPROT	up-regulates	phosphorylation	Ser909	HQRCLAHsLVGTPNY	9606	BTO:0000007								15688006	t		milica	We show that Mst2 and hWW45 interact with each other in human cells and that both Mst2 and Mst1 are able to phosphorylate Lats1 and Lats2, thereby stimulating Lats kinase activity.	SIGNOR-133551	0.607
1-(2,4-difluorophenyl)-3-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-fluorophenyl]urea	chemical	CHEBI:92822	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193573	0.8
PPP1CB	protein	P62140	UNIPROT	AXIN1	protein	O15169	UNIPROT	down-regulates activity	dephosphorylation	Ser77	YEPEGSAsPTPPYLK	9606									17318175	t			The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 	SIGNOR-248568	0.2
CLIP1	protein	P30622	UNIPROT	Microtubule_polimerization	phenotype	SIGNOR-PH106	SIGNOR	up-regulates	binding												17889670	t		lperfetto	Microtubule plus end binding proteins (+TIPs) localize to the dynamic plus ends of microtubules, where they stimulate microtubule growth and recruit signaling molecules. Three main +TIP classes have been identified (XMAP215, EB1, and CLIP-170)	SIGNOR-264832	0.7
CAMK1	protein	Q14012	UNIPROT	NOS1	protein	P29475	UNIPROT	down-regulates activity	phosphorylation	Ser852	SYKVRFNsVSSYSDS	-1									10400690	t		llicata	It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation.	SIGNOR-250614	0.337
HRAS	protein	P01112	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation	Ser73	VGLLKLAsPELERLI	10090	BTO:0000944								12169099	t		lperfetto	c-Jun was first shown to be phosphorylated in its transactivation domain (Ser-63 and Ser-73) by ERKs and p54-JNK. This is consistent with other studies which show that PD98059 inhibits up-regulation of c-Jun protein in Ras-transformed NIH-3T3 cells	SIGNOR-235526	0.516
(S,S)-asenapine	chemical	CHEBI:71257	ChEBI	HTR1B	protein	P28222	UNIPROT	up-regulates activity	chemical activation			10116									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258567	0.8
FGF4	protein	P08620	UNIPROT	FGFR2	protein	P21802	UNIPROT	up-regulates	binding			9606									8663044	t		gcesareni	The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors.	SIGNOR-42377	0.75
SSTR1	protein	P30872	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256679	0.503
MYC	protein	P01106	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates				9606									11804592	f	in cancer	lperfetto	Oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads	SIGNOR-114281	0.672
TGFb	proteinfamily	SIGNOR-PF5	SIGNOR	SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606									30017632	f		miannu	Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis.	SIGNOR-260428	0.616
F2RL1	protein	P55085	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257359	0.438
A2M	protein	P01023	UNIPROT	MMP2	protein	P08253	UNIPROT	down-regulates activity	binding			-1									9344465	t		lperfetto	Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261803	0.62
MAP2K4	protein	P45985	UNIPROT	MAPK9	protein	P45984	UNIPROT	up-regulates	phosphorylation	Thr183	ACTNFMMtPYVVTRY	9606	BTO:0000007								17761173	t		lperfetto	We next examined whether the phosphorylation of JNK at threonine 183 (Thr183) and tyrosine 185 (Tyr185) was enhanced by GRASP‐1 expression. Phosphorylation of Thr183 and Tyr185 by SEK1/MKK4, which is in turn phosphorylated and activated by several kinases including MEKK1, is known to activate JNK1/2/3	SIGNOR-260615	0.716
AURKB	protein	Q96GD4	UNIPROT	KNL1	protein	Q8NG31	UNIPROT	down-regulates	phosphorylation	Ser24	RPVRRRHsSILKPPR	9606									20471944	t		lperfetto	To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant).	SIGNOR-165502	0.2
COP1	protein	Q8NHY2	UNIPROT	CEBPB	protein	P17676	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000078								32795415	t		Gianni	We show expression of c/EBPβ in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures.	SIGNOR-261924	0.2
LEF1	protein	Q9UJU2	UNIPROT	DSG4	protein	Q86SJ6	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000552								19683850	f	 	miannu	 we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle.	SIGNOR-254183	0.292
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	SYT1	protein	P21579	UNIPROT	up-regulates activity	chemical activation			9606									16679567	t		miannu	Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion	SIGNOR-263976	0.8
SNRNP70	protein	P08621	UNIPROT	U1 snRNP complex	complex	SIGNOR-C480	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270677	0.906
STK39	protein	Q9UEW8	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates	binding			9606									14563843	t		gcesareni	Spak, a ste20/sps1-related kinase that activates the p38 pathway. p38, one of the three major mapks, can be coimmunoprecipitated with spak and with nkcc1 in an activity-dependent manner. The amount of p38 coimmunoprecipitated with the kinase and the cotransporter significantly decreases upon cellular stress,	SIGNOR-118848	0.368
SLC9A7	protein	Q96T83	UNIPROT	hydron	chemical	CHEBI:15378	ChEBI	down-regulates quantity	relocalization			9606	BTO:0000938								31507243	t		miannu	Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. 	SIGNOR-265597	0.8
PARP1	protein	P09874	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	down-regulates				10090									11907276	f		amattioni	Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process	SIGNOR-111680	0.7
AD/b2 integrin	complex	SIGNOR-C172	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257716	0.441
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	AMPH	protein	P49418	UNIPROT	down-regulates	phosphorylation			9606		BTO:0000142							15262992	t	inferred from 70% family members	lperfetto	Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2.	SIGNOR-270102	0.2
AURKA	protein	O14965	UNIPROT	TPX2	protein	Q9ULW0	UNIPROT	up-regulates activity	phosphorylation	Ser125	QRRSLRLsAQKDLEQ	9606	BTO:0000567								26240182	t		lperfetto	Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells	SIGNOR-265088	0.963
SP3	protein	Q02447	UNIPROT	SOX18	protein	P35713	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								18496767	f		miannu	 co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells	SIGNOR-254820	0.288
KDR	protein	P35968	UNIPROT	KDR	protein	P35968	UNIPROT	up-regulates	phosphorylation	Tyr1059	DIYKDPDyVRKGDAR	9606	BTO:0000801;BTO:0000876								17658244	t		gcesareni	Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability.	SIGNOR-157085	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	BORA	protein	Q6PGQ7	UNIPROT	up-regulates activity	phosphorylation			9606									18521620	t		gcesareni	Our data additionally identify the cdk1 site s252 as critical for the recruitment of plk1 to hbora. collectively, our findings lead us to propose that hbora contributes to integrate the functions of three major mitotic kinases, cdk1, plk1, and aurora a.	SIGNOR-178799	0.557
SCN2A	protein	Q99250	UNIPROT	Action_potential 	phenotype	SIGNOR-PH82	SIGNOR	up-regulates				9606									26043074	f		miannu	The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons.	SIGNOR-253450	0.7
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	MYOD1	protein	P15172	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000222								18854138	f		gcesareni	Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts.	SIGNOR-252937	0.2
JAK2	protein	O60674	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by stabilization	binding			10090									12370803	t		irozzo	In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells. 	SIGNOR-255810	0.464
HIPK2	protein	Q9H2X6	UNIPROT	CREB1	protein	P16220	UNIPROT	up-regulates	phosphorylation	Ser257	PGVVMASsPALPTQP	9606									20573984	t		lperfetto	Ere we found that homeodomain-interacting protein kinase 2 (hipk2), a dna-damage responsive nuclear kinase, is a new creb kinase for phosphorylation at ser-271 but not ser-133, and activates creb transactivation function	SIGNOR-166338	0.399
MAPK14	protein	Q16539	UNIPROT	SLC9A1	protein	P19634	UNIPROT	up-regulates	phosphorylation	Ser729	ASPQSPEsVDLVNEE	9606									11604491	t		llicata	Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728.	SIGNOR-111047	0.552
PPP2CA	protein	P67775	UNIPROT	SNCA	protein	P37840	UNIPROT	down-regulates activity	dephosphorylation	Ser129	NEAYEMPsEEGYQDY	9606									21562258	t			α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129	SIGNOR-248635	0.338
UBR1	protein	Q8IWV7	UNIPROT	RECQL4	protein	O94761	UNIPROT	up-regulates	binding			9606	BTO:0000567								15317757	t		miannu	The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells	SIGNOR-128169	0.506
PSMA1	protein	P25786	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263363	0.853
PTAFR	protein	P25105	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257174	0.2
MAPK1	protein	P28482	UNIPROT	KDM4B	protein	O94953	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser352	TRPTALTsPELSSWS	9606	BTO:0001109								28945223	t		miannu	In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation. 	SIGNOR-276743	0.2
CARD11	protein	Q9BXL7	UNIPROT	MALT1	protein	Q9UDY8	UNIPROT	up-regulates	binding			9606	BTO:0000785								20685844	t		gcesareni	The carboxy-terminal part of the bcl10 card and a short stretch of 13 amino acids following the card are required for constitutive binding to malt1.	SIGNOR-167393	0.798
DLX5	protein	P56178	UNIPROT	MSX1	protein	P28360	UNIPROT	down-regulates activity	binding			10090	BTO:0000946								9111364	t	2	miannu	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240921	0.398
PRKCZ	protein	Q05513	UNIPROT	NOS3	protein	P29474	UNIPROT	down-regulates activity	phosphorylation	Thr495	TGITRKKtFKEVANA	9606									24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251637	0.38
PPP2CA	protein	P67775	UNIPROT	PRKCB	protein	P05771-2	UNIPROT	down-regulates activity	dephosphorylation	Ser660	QSEFEGFsFVNSEFL	10116									15880462	t			Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform	SIGNOR-248621	0.434
ATM	protein	Q13315	UNIPROT	EP300	protein	Q09472	UNIPROT	up-regulates	phosphorylation	Ser106	GPGQVMAsQAQQSSP	9606									20471956	t		lperfetto	Atm mediates phosphorylation of p300 in response to dna damageexpression of nonphosphorylatable serine to alanine form of p300 (s106a) destabilized both p300 and nbs1 proteins, after dna damage	SIGNOR-165567	0.411
CAMK2G	protein	Q13555	UNIPROT	NCOR2	protein	Q9Y618	UNIPROT	down-regulates	phosphorylation	Ser2407	AKVSGRPsSRKAKSP	9606									22888005	t		gcesareni	The kinase activity of camkii was essential for the activation of notch signaling. We also determined that camkii could enhance the association between notch1-ic and rbp-jk. Furthermore, the physical association between rbp-jk and smrt was substantially suppressed by camkii. We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation.	SIGNOR-191777	0.2
TGFBR2	protein	P37173	UNIPROT	TGFBR2	protein	P37173	UNIPROT	up-regulates activity	phosphorylation	Tyr336	AKGNLQEyLTRHVIS	-1									9169454	t		lperfetto	Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor.	SIGNOR-48863	0.2
S1PR1	protein	P21453	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257108	0.357
ADRA2B	protein	P18089	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257109	0.412
PRKAB1	protein	Q9Y478	UNIPROT	RPTOR	protein	Q8N122	UNIPROT	down-regulates	phosphorylation			9606			SIGNOR-C15	SIGNOR-C3					21460634	t		gcesareni	Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2.	SIGNOR-173041	0.443
MC5R	protein	P33032	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257271	0.252
METTL3	protein	Q86U44	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007;BTO:0000567								27117702	t		miannu	Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells. 	SIGNOR-265954	0.339
CUDC-101	chemical	CID:24756910	PUBCHEM	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									20143778	t		miannu	By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively.	SIGNOR-262265	0.8
PRKCZ	protein	Q05513	UNIPROT	WWC1	protein	Q8IX03	UNIPROT	unknown	phosphorylation	Ser975	VRMKRPSsVKSLRSE	-1									15081397	t		lperfetto	PKCzeta phosphorylates KIBRA at serine 975 and 978	SIGNOR-249262	0.727
GATAD2A	protein	Q86YP4	UNIPROT	MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263846	0.826
AURKA	protein	O14965	UNIPROT	ALDH1A1	protein	P00352	UNIPROT	up-regulates activity	phosphorylation	Thr267	KSNLKRVtLELGGKS	-1									28193222	t		miannu	AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species. 	SIGNOR-276750	0.381
NLGN1	protein	Q8N2Q7	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								18923512	t	brain	lperfetto	Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.	SIGNOR-264191	0.768
MTHFD2	protein	P13995	UNIPROT	(6R)-5,10-methenyltetrahydrofolate	smallmolecule	CHEBI:57455	ChEBI	up-regulates quantity	chemical modification			9606									16100107	t		lperfetto	Magnesium and phosphate ions enable NAD binding to methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase|One of the enzymes in this pathway, the NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC),5 catalyzes the interconversion of 5,10-methylenetetrahydrofolate (methylene-THF) and 10-formyltetrahydrofolate (formyl-THF) in mammalian mitochondria.	SIGNOR-268255	0.8
CDK1	protein	P06493	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Ser1189	QKGELSRsPSPFTHT	9606	BTO:0000551								19683496	t		gcesareni	However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci.	SIGNOR-187595	0.511
SGK1	protein	O00141	UNIPROT	NDRG1	protein	Q92597	UNIPROT	up-regulates	phosphorylation	Thr356	GTRSRSHtSEGTRSR	9606									18787837	t		llicata	Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1.	SIGNOR-180825	0.588
CDK1	protein	P06493	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Ser397	SMVGGERsPPRILPP	9606	BTO:0000007		SIGNOR-C17						21059642	t	The effect has been demonstrated using Q01196-8	gcesareni	Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20).	SIGNOR-169322	0.347
NTRK1	protein	P04629	UNIPROT	FRS2	protein	Q8WU20	UNIPROT	up-regulates	binding			9606									10092678	t		gcesareni	The signaling adapter frs-2 competes with shc for binding to the nerve growth factor receptor trka:a model for discriminating proliferation and differentiation	SIGNOR-65955	0.769
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MAPK3	protein	P27361	UNIPROT	up-regulates activity	phosphorylation	Thr207	FLTEYVAtRWYRAPE	9606		BTO:0000562							19060905	t		lperfetto	Here we show that autophosphorylation of erk1/2 on thr188 directs erk1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy.	SIGNOR-244565	0.2
SLC36A1	protein	Q7Z2H8	UNIPROT	proline	smallmolecule	CHEBI:26271	ChEBI	up-regulates quantity	relocalization			9606									12748860	t		lperfetto	Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut.	SIGNOR-264741	0.8
SMO	protein	Q99835	UNIPROT	GNAI2	protein	P04899	UNIPROT	up-regulates activity	binding			10090	BTO:0002572								16885213	t		lperfetto	Using this assay we determined that mouse Smo couples to all members of the Gi family but does not couple to those of other G protein families.	SIGNOR-148490	0.403
CCR5	protein	P51681	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity	phosphorylation			10090									20219869	t		areggio	The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. 	SIGNOR-255119	0.329
SMARCE1	protein	Q969G3	UNIPROT	SWI/SNF ACTL6A-ARID1A-SMARCA2 variant	complex	SIGNOR-C470	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269819	0.839
CAMK2G	protein	Q13555	UNIPROT	GRIA1	protein	P42261	UNIPROT	up-regulates activity	phosphorylation	Ser645	LTVERMVsPIESAED		BTO:0000007								7877986	t		llicata	In this study, CaM-kinase II enhanced kainate currents of expressed glutamate receptor 6 in 293 cells and of wild-type glutamate receptor 1, but not the Ser-627 to Ala mutant, in Xenopus oocytes. | This CaM-kinase II regulatory phosphorylation site is conserved in all AMPA/kainate-type glutamate receptors, and its phosphorylation may be important in enhancing postsynaptic responsiveness as occurs during synaptic plasticity.	SIGNOR-250697	0.614
SPAG5	protein	Q96R06	UNIPROT	CENPE	protein	Q02224	UNIPROT	up-regulates activity				9606	BTO:0000567								17664331	f		lperfetto	Furthermore, although both the core kinetochore protein Hec1 and the spindle checkpoint kinase Bub1 were unaffected (Fig. 3 C), the kinetochore resident motor protein CENP-E (Yen et al., 1992) and its interaction partner CENP-F (Chan et al., 1998) were delocalized from the kinetochore in the absence of astrin. These cells remained cyclin B1 positive (unpublished data), confirming that they were still in mitosis. These data suggest that the presence of astrin is required for the kinetochore recruitment or maintenance of CENP-E and CENP-F.	SIGNOR-252041	0.387
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1899	SPTYSPTsPVYTPTS	9606									24746699	t		lperfetto	After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 	SIGNOR-269378	0.718
taurine	smallmolecule	CHEBI:15891	ChEBI	GlyR	proteinfamily	SIGNOR-PF62	SIGNOR	up-regulates activity	chemical activation			9606	BTO:0000007								9009272	t	inferred from family member	miannu	For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system.	SIGNOR-270259	0.8
ANKRD1	protein	Q15327	UNIPROT	NPPA	protein	P01160	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								18273862	t	 	 	In vitro calpain-mediated degradation assays, coupled to reporter gene analysis in transfected HeLa cells, strongly suggested that this mutation enhances both the stability of the ANKRD1/CARP protein and its transcriptional repression activity upon the cardiac-specific atrial natriuretic factor (ANF) promoter.	SIGNOR-253647	0.333
methoxamine	chemical	CHEBI:6839	ChEBI	ADRA1B	protein	P35368	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258447	0.8
DPP3	protein	Q9NY33	UNIPROT	KEAP1	protein	Q14145	UNIPROT	down-regulates quantity by destabilization	cleavage			9606									35278345	t		miannu	 The influence of DPP3 on the Keap1-Nrf2/ARE signal pathway suggest a direct involvement of DPP3 in the oxidative stress response [8,14,31,53,99,100]. It was shown that DPP3 competes with Nrf2 through the ETGE motif to bind to Keap1 and consequently enhances the translocation of Nrf2 to the nucleus, thereby driving the expression of an array of genes encoding antioxidative enzymes [99]. More specifically, binding of DPP3 to Keap1 releases Nrf2, and thus, prevents its degradation through the 26S proteasome	SIGNOR-268464	0.617
CSNK2A1	protein	P68400	UNIPROT	IFI16	protein	Q16666	UNIPROT	up-regulates activity	phosphorylation	Ser132	GAQKRKKsTKEKAGP	9606	BTO:0000567								11115400	t		llicata	Here we examine the functionality of the interferon-induced factor 16 (IFI 16) CcN motif, demonstrating its ability to target a heterologous protein to the nucleus, and to be phosphorylated specifically by the CcN-motif-phosphorylating protein kinase CK2 (CK2). | Specific phosphorylation of IFI 16 Ser132 in HeLa cell extracts and by purified CK2 in vitro	SIGNOR-250902	0.326
SCF-SKP2	complex	SIGNOR-C136	SIGNOR	MEF2D	protein	Q14814	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0000944								25733682	t		miannu	 MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding. 	SIGNOR-276889	0.292
DHODH	protein	Q02127	UNIPROT	(S)-dihydroorotate	smallmolecule	CHEBI:30864	ChEBI	down-regulates quantity	chemical modification			9606									30449682	t		miannu	OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway	SIGNOR-267430	0.8
FLT3	protein	P36888	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates activity	phosphorylation	Tyr349	EEPPDHQyYNDFPGK	9606									10482988	t		miannu	Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. 	SIGNOR-251146	0.434
OGT	protein	O15294	UNIPROT	NSL histone acetyltransferase	complex	SIGNOR-C413	SIGNOR	form complex	binding			9606	BTO:0000007								20018852	t		miannu	Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex.	SIGNOR-267158	0.538
MET	protein	P08581	UNIPROT	Metastasis	phenotype	SIGNOR-PH107	SIGNOR	up-regulates				9606	BTO:0001033								22035268	f		miannu	C-Met expression and activation appears to be one of the common mechanisms of resistance to other targeted therapies. Given these multiple roles of c-Met in prostate cancer, several c-Met inhibitors have been developed. Evidence to date suggests that aberrant activation of the HGF/c-Met axis in prostate cancer epithelial cells appears to be a relatively late event in tumor progression. C-Met expression increases in advanced stages of the disease, with the highest expression observed in bone metastases.	SIGNOR-263658	0.7
PIM1	protein	P11309	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates	phosphorylation	Ser83	ATRGRGSsVGGGSRR	9606	BTO:0002552								19749799	t		lperfetto	Pim1 phosphorylates and negatively regulates ask1-mediated apoptosispim1 phosphorylation of ask1 on ser83 inhibited ask1-mediated c-jun n-terminal kinase phosphorylation	SIGNOR-187905	0.284
MAPK14	protein	Q16539	UNIPROT	MAX	protein	P61244	UNIPROT	down-regulates	phosphorylation			9606									7479834	t		gcesareni	Mxi2 phosphorylates max both in vitro and in vivo. Phosphorylation by mxi2 may affect the ability of max to oligomerize with itself and its partners, bind dna, or regulate gene expression.	SIGNOR-26511	0.611
Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	down-regulates quantity	chemical modification			9606									16051738	t		miannu	Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor.	SIGNOR-266459	0.8
TPH2	protein	Q8IWU9	UNIPROT	tryptophan	smallmolecule	CHEBI:27897	ChEBI	down-regulates quantity	chemical modification			9606									31024440	t	brain	lperfetto	In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)].	SIGNOR-264011	0.8
MAPK1	protein	P28482	UNIPROT	SREBF2	protein	Q12772	UNIPROT	up-regulates	phosphorylation	Ser455	SIDSEPGsPLLDDAK	9606									14988395	t		lperfetto	Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity.	SIGNOR-123045	0.365
SYK	protein	P43405	UNIPROT	SLC4A1	protein	P02730	UNIPROT	unknown	phosphorylation	Tyr8	MEELQDDyEDMMEEN	-1									10942405	t			The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton 	SIGNOR-251413	0.462
NR3C1	protein	P04150	UNIPROT	HNF4A	protein	P41235	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17978169	t		gcesareni	Electrophoretic mobility shift, chromatin immunoprecipitation (ChIP), and streptavidin DNA binding assays revealed that DEX increased binding of HNF4alpha to the HNF4-RE and that an interaction of GR and HNF4alpha occurred at this site.	SIGNOR-251684	0.377
DPF2	protein	Q92785	UNIPROT	SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								20460684	t		miannu	Our current findings indicate that REQ is a novel adaptor protein that links the Brm-type SWI/SNF complex and RelB/p52 and operates at the most downstream stages of the noncanonical NF-κB pathway. 	SIGNOR-261963	0.626
PKC	proteinfamily	SIGNOR-PF53	SIGNOR	GNE	protein	Q9Y223	UNIPROT	up-regulates activity	phosphorylation			10116		BTO:0000759							10745088	t		lperfetto	Protein kinase C phosphorylates and regulates UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase|Furthermore, PKC phosphorylates UDP-GlcNAc 2-epimerase and this phosphorylation results in an upregulation of the UDP-GlcNAc 2-epimerase enzyme activity.	SIGNOR-266072	0.2
PRKACA	protein	P17612	UNIPROT	KCNH2	protein	Q12809	UNIPROT	up-regulates	phosphorylation	Ser283	CASVRRAsSADDIEA	9606									10488078	t		lperfetto	Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a)	SIGNOR-70722	0.311
tamoxifen citrate	chemical	CHEBI:9397	ChEBI	ESR1	protein	P03372	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000150								20512796	t		miannu	Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth.	SIGNOR-259301	0.8
DUSP26	protein	Q9BV47	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	dephosphorylation	Ser37	NVLSPLPsQAMDDLM	9606									20562916	t		miannu	We found that dusp26 promotes the resistance of human neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to downregulate p53 tumor suppressor function in neuroblastoma cells. / we found that dusp26 binds to p53 and dephosphorylates p53 at ser20 and ser37.	SIGNOR-166262	0.373
CALM3	protein	P0DP25	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	binding			9606	BTO:0001853								24379783	t		miannu	Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer	SIGNOR-266339	0.581
LEPR	protein	P48357	UNIPROT	AGRP	protein	O00253	UNIPROT	down-regulates quantity													27154742	f		lperfetto	Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production	SIGNOR-253076	0.465
PRKCG	protein	P05129	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Ser497	ATVKSRWsGSQQVEQ	9606									8288587	t		gcesareni	Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation.	SIGNOR-37541	0.38
LPAR1	protein	Q92633	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257091	0.524
BLK	protein	P51451	UNIPROT	FCGR2A	protein	P12318	UNIPROT	up-regulates activity	phosphorylation	Tyr304	TDDDKNIyLTLPPND	-1									8756631	t		lperfetto	To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.	SIGNOR-249312	0.448
Ub:E1 (UBA1 substrate)	complex	SIGNOR-C495	SIGNOR	UBE2J2	protein	Q8N2K1	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271339	0.584
RCOR1	protein	Q9UKL0	UNIPROT	SCN2A	protein	Q99250	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								10449787	f		miannu	We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity.	SIGNOR-220695	0.274
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1738	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120028	0.781
CUL2	protein	Q13617	UNIPROT	APOBEC3A	protein	P31941	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								29367246	t		lperfetto	Human Papillomavirus 16 E7 Stabilizes APOBEC3A Protein by Inhibiting Cullin 2-Dependent Protein Degradation|Here, we report that the HPV oncoprotein E7 stabilizes the APOBEC3A (A3A) protein in human keratinocytes by inhibiting ubiquitin-dependent protein degradation in a cullin-dependent manner.	SIGNOR-261325	0.253
PRKDC	protein	P78527	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606									9363941	t		gcesareni	We demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of mdm2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by dna-pk (or other protein kinases with similar specificity) in response to dna damage.	SIGNOR-53030	0.785
ATP5F1C	protein	P36542	UNIPROT	ATP synthase	complex	SIGNOR-C264	SIGNOR	form complex	binding			9606									21874297	t		miannu	Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L.	SIGNOR-261405	0.2
AKT1	protein	P31749	UNIPROT	WNK1	protein	Q9H4A3	UNIPROT	up-regulates	phosphorylation	Thr60	EYRRRRHtMDKDSRG	9606									16081417	t		llicata	Phosphorylation of wnk1 on thr-58 contributes to sgk1 activation. these data suggest that activation of sgk1 by wnk1 requires the catalytic activity of akt.	SIGNOR-252481	0.402
RSPO2	protein	Q6UXX9	UNIPROT	LGR5	protein	O75473	UNIPROT	up-regulates	binding			9606									21693646	t	Furin domain	gcesareni	Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation	SIGNOR-174532	0.681
gamma-secretase	complex	SIGNOR-C98	SIGNOR	NOTCH2	protein	Q04721	UNIPROT	up-regulates activity	cleavage			9606									25610395	t		lperfetto	The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins.	SIGNOR-209723	0.572
HBB	protein	P68871	UNIPROT	CD163	protein	Q86VB7	UNIPROT	up-regulates activity	binding			9606									16522161	t	Regulation	miannu	These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells.	SIGNOR-251746	0.417
HOXD10	protein	P28358	UNIPROT	MEIS1	protein	O00470	UNIPROT	up-regulates activity	binding			-1									9343407	t	2	miannu	We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets.	SIGNOR-241226	0.383
HEXIM1	protein	O94992	UNIPROT	KDM5B	protein	Q9UGL1	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000815								31776402	t		lperfetto	We previously reported that the tumor suppressor HEXIM1 is a mediator of KDM5B recruitment to its target genes, and HEXIM1 is required for the inhibition of nuclear hormone receptor activity by KDM5B. 	SIGNOR-273439	0.2
SRC	protein	P12931	UNIPROT	KCNB1	protein	Q14721	UNIPROT	up-regulates	phosphorylation	Tyr128	YWGIDEIyLESCCQA	9606	BTO:0000938								19622611	t		flangone	In the present study we show that an n-terminal tyrosine of kv2.1 (y124), which is a known target of src kinase, is critical for the apoptotic current surge..Kv2.1-mediated k+ currents are also enhanced during non-injurious conditions through direct phosphorylation of intracellular n-terminal residue tyrosine 124 (y124) by src kinase	SIGNOR-187201	0.493
TBK1	protein	Q9UHD2	UNIPROT	HTT	protein	P42858	UNIPROT	up-regulates activity	phosphorylation	Ser13	KLMKAFEsLKSFQQQ	9606	BTO:0000007								32757223	t			Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that efficiently phosphorylates full-length and N-terminal HTT fragments in vitro (at S13/S16), in cells (at S13) and in vivo. TBK1 expression in HD models (cells, primary neurons, and Caenorhabditis elegans) increases mutant HTT exon 1 phosphorylation and reduces its aggregation and cytotoxicity.	SIGNOR-270350	0.294
JUN	protein	P05412	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								10369069	f		miannu	 Co-transfection of WT cells with a c-jun expression vector and either of the AP-1 luciferase constructs demonstrated that c-jun could activate gene expression from both the consensus and the MDR1 AP-1 sites in a dose dependent manner. 	SIGNOR-254534	0.351
serotonin	smallmolecule	CHEBI:28790	ChEBI	HTR3D	protein	Q70Z44	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000938								25601315	t		miannu	Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel	SIGNOR-264292	0.8
MAPK11	protein	Q15759	UNIPROT	HBA1	protein	P69905	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20162623	f	Indirect:regulation	miannu	Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). 	SIGNOR-251834	0.2
PRLR	protein	P16471	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090									17975019	f	 	miannu	 We also show that activation of RS represses the expression of the transcription factor Forkhead box O3 (FOXO3) and that of the enzyme galactose-1-phosphate uridyltransferase (Galt), two proteins known to be essential for normal follicular development. 	SIGNOR-254187	0.2
BCL7A	protein	Q4VC05	UNIPROT	GBAF	complex	SIGNOR-C467	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-269784	0.503
EEF1A2	protein	Q05639	UNIPROT	Ile-tRNA(Ile)	smallmolecule	CHEBI:29160	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269532	0.8
HES1	protein	Q14469	UNIPROT	DTX1	protein	Q86Y01	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606		BTO:0000970							20208568	f		gcesareni	The notch target gene hes1 causes transcriptional inhibition of deltex1 by directly binding to the promoter of deltex1.	SIGNOR-164071	0.318
N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	chemical	CHEBI:91418	ChEBI	KDR	protein	P35968	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001271								21697284	t		gcesareni	Exel-2880 (xl880, gsk1363089) is a small-molecule kinase inhibitor that targets members of the hgf and vegf receptor tyrosine kinase families, with additional inhibitory activity toward kit, flt-3, platelet-derived growth factor receptor _, and tie-2.	SIGNOR-174552	0.8
CDK7	protein	P50613	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates activity	phosphorylation	Ser27	GNDPLTSsPGRSSRR	9606									16899510	t		Luana	Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2.	SIGNOR-259848	0.304
JAK2	protein	O60674	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates	phosphorylation			9606		BTO:0001103							21576360	t			When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita	SIGNOR-256248	0.8
CDK5	protein	Q00535	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser46	AMDDLMLsPDDIEQW	9606	BTO:0000938								17591690	t		llicata	We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active	SIGNOR-156426	0.722
RCOR1	protein	Q9UKL0	UNIPROT	REST-CoREST	complex	SIGNOR-C111	SIGNOR	form complex	binding			9606									20080105	t	1	miannu	Transcriptional repression of neural-specific genes in nonneuronal cells is dependent on the REST (RE1-silencing transcription factor)–CoREST complex.	SIGNOR-239220	0.761
SMURF1	protein	Q9HCE7	UNIPROT	TPM4	protein	P67936	UNIPROT	unknown	ubiquitination			-1									20804422	t		miannu	Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay.	SIGNOR-272684	0.2
PPP3CC	protein	P48454	UNIPROT	KSR2	protein	Q6VAB6	UNIPROT	up-regulates activity	dephosphorylation	Ser313	TALHRSKsHEFQLGH	10090									19560418	t			These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3	SIGNOR-248527	0.262
SUN2	protein	Q9UH99	UNIPROT	LINC complex	complex	SIGNOR-C303	SIGNOR	form complex	binding												24481844	t		lperfetto	LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM.	SIGNOR-263286	0.534
D-glucopyranose	smallmolecule	CHEBI:4167	ChEBI	AMP	smallmolecule	CHEBI:456215	ChEBI	down-regulates				9606									10409121	f		gcesareni	The activation in response to glucose removal appeared to be due to changes in the concentration of the known regulators of the cascade, i.e. Amp and atp, since ampk activation was associated with a large increase in the cellular amp.	SIGNOR-69249	0.8
panobinostat	chemical	CHEBI:85990	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257756	0.8
ILK	protein	Q13418	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606									9736715	t		acerquone	Ilk can phosphorylate pkb-akt on serine-473, whereas kinase-deficient ilk severely inhibits endogenous phosphorylation of pkb-akt on serine-473, demonstrating that ilk is involved in agonist stimulated, pi(3)k-dependent, pkb-akt activation.	SIGNOR-60115	0.771
ATM	protein	Q13315	UNIPROT	CHEK2	protein	O96017	UNIPROT	up-regulates activity	phosphorylation	Thr26	SQPHGSVtQSQGSSS	9606	BTO:0000007								12024051	t		gcesareni	We show here that autophosphorylation of chk2 produced in a cell-free system requires trans phosphorylation by a wortmannin-sensitive kinase, probably atm or atr	SIGNOR-87850	0.83
PRKCB	protein	P05771	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser558	VPTYESAsIRRFQEG	9606									15381704	t	The effect has been demonstrated using P28329-3	gcesareni	Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity.	SIGNOR-129288	0.289
PTPRG	protein	P23470	UNIPROT	CTTN	protein	Q14247	UNIPROT	down-regulates activity	dephosphorylation	Tyr470	AYATEAVyESAEAPG	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254696	0.2
PRKACA	protein	P17612	UNIPROT	TNNI3	protein	P19429	UNIPROT	up-regulates activity	phosphorylation	Ser24	APIRRRSsNYRAYAT	9606									15769444	t		lperfetto	Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.	SIGNOR-134609	0.398
SLC2A1	protein	P11166	UNIPROT	Ankyrin complex	complex	SIGNOR-C383	SIGNOR	form complex	binding			9606	BTO:0000424								22465511	t		lperfetto	The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) 	SIGNOR-266017	0.306
CALM3	protein	P0DP25	UNIPROT	GEM	protein	P55040	UNIPROT	up-regulates activity	binding			10116	BTO:0001009								14701738	t		miannu	Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells.	SIGNOR-266342	0.2
PIM1	protein	P11309	UNIPROT	NFATC1	protein	O95644	UNIPROT	up-regulates activity	phosphorylation	Thr154	SSKRSPStATLSLPS	9606	BTO:0001061								31730483	t		miannu	Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 	SIGNOR-276777	0.629
FLT3	protein	P36888	UNIPROT	FLT3	protein	P36888	UNIPROT	up-regulates activity	phosphorylation	Tyr842	DIMSDSNyVVRGNAR	10090	BTO:0001516								16627759	t		lperfetto	In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated.	SIGNOR-271925	0.2
CSNK1A1L	protein	Q8N752	UNIPROT	GLI2	protein	P10070	UNIPROT	up-regulates	phosphorylation			9606									18698484	t		gcesareni	Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed	SIGNOR-179972	0.339
MAP3K12	protein	Q12852	UNIPROT	MYL12B	protein	O14950	UNIPROT	up-regulates	phosphorylation	Thr19	KKRPQRAtSNVFAMF	9606									11781833	t		gcesareni	Zip kinase (hzipk) phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. In this study, we demonstrate that hzipk also induces the diphosphorylation of mrlc in nonmuscle cells.	SIGNOR-113664	0.2
BAZ2B	protein	Q9UIF8	UNIPROT	Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	down-regulates activity	binding			9606									31999386	t	inferred from 70% of family members	miannu	The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation.	SIGNOR-269843	0.2
SMAD7	protein	O15105	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates				9606	BTO:0001130								15684397	f		gcesareni	In the current study, our data indicate that both smad7 and p38 map kinase positively contributed to the accumulation of -catenin	SIGNOR-133447	0.688
ACTN1	protein	P12814	UNIPROT	PTK2	protein	Q05397	UNIPROT	down-regulates activity	binding			9534									16291744	t		lperfetto	Consistent with the results obtained with COS-7 cells, coexpression of wild-type α-actinin with PTP 1B in PTP 1B-null cells resulted in Src/α-actinin binding and limited the interaction between FAK and Src	SIGNOR-261799	0.555
DHFR2	protein	Q86XF0	UNIPROT	dihydrofolate(2-)	smallmolecule	CHEBI:57451	ChEBI	down-regulates quantity	chemical modification			9606									21876184	t		lperfetto	Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. |We demonstrate that the DHFRP4, or dihydrofolate reductase-like 1 (DHFRL1), gene is expressed and shares some commonalities with DHFR.	SIGNOR-268260	0.8
TRIM3	protein	O75382	UNIPROT	GKAP1	protein	Q5VSY0	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0000298								20352094	t		miannu	Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites.	SIGNOR-271959	0.25
PLK1	protein	P53350	UNIPROT	FOXM1	protein	Q08050	UNIPROT	up-regulates	phosphorylation	Ser739	SKILLDIsFPGLDED	9606									19737929	t		lperfetto	It has been reported that plk1 could directly phosphorylate foxm1 at ser-715 and ser-724 for full activation and proper mitotic progression	SIGNOR-187892	0.694
JAK1	protein	P23458	UNIPROT	EIF2AK3	protein	Q9NZJ5	UNIPROT	up-regulates activity	phosphorylation	Tyr619	NKVDDCNyAIKRIRL	10090	BTO:0000099								25113558	t		miannu	JAK1 interacts with and phosphorylates PERK. PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Similarly, PERK is associated with and phosphorylated by JAK1 at Y585 and Y619 (and possibly other JAKs) during ER stress, resulting in PERK- and JAK1-dependent activation of STAT3.	SIGNOR-276677	0.2
STK39	protein	Q9UEW8	UNIPROT	SLC12A3	protein	P55017	UNIPROT	down-regulates activity	phosphorylation	Thr55	SSTFCMRtFGYNTID	10090									25651566	t		lperfetto	SPAK directly phosphorylates NCC and its effects on NCC are universally associated with phosphorylation|This adds to the evidence that SPAK-mediated phosphorylation acts primarily to increase activity of individual cotransporters without affecting the amount of NCC on the surface| the kinase (SPAK) that phosphorylates NCC at T53	SIGNOR-264623	0.5
DLG4	protein	P78352	UNIPROT	Scribble_complex_DLG4-LLGL1_variant	complex	SIGNOR-C509	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270905	0.458
isoleucine	smallmolecule	CHEBI:24898	ChEBI	Ile-tRNA(Ile)	smallmolecule	CHEBI:29160	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270426	0.8
MTA2	protein	O94776	UNIPROT	MBD2/NuRD complex	complex	SIGNOR-C337	SIGNOR	form complex	binding			9606									27098840	t		miannu	The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression.	SIGNOR-263841	0.811
BIRC5	protein	O15392	UNIPROT	DIABLO	protein	Q9NR28	UNIPROT	down-regulates	binding			9606									17546047	t		gcesareni	Mitochondrial survivin associated with smac/diablo, delaying its release.	SIGNOR-155361	0.586
PCDH19	protein	Q8TAB3	UNIPROT	GABRA6	protein	Q16445	UNIPROT	up-regulates quantity by stabilization	binding			10116	BTO:0003102			SIGNOR-C334,SIGNOR-C328,SIGNOR-C329					29360992	t		miannu	Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons. 	SIGNOR-267221	0.2
STRN4	protein	Q9NRL3	UNIPROT	PPP2CB	protein	P62714	UNIPROT	up-regulates activity	binding			10090	BTO:0000938								29802198	t		miannu	The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms	SIGNOR-261699	0.605
FYN	protein	P06241	UNIPROT	TOM1L1	protein	O75674	UNIPROT	up-regulates activity	phosphorylation	Tyr460	AVTTEAIyEEIDAHQ	-1									11711534	t			Tyr-457, located in the presumed Src SH2 binding site, is the predominant tyrosine residue that is phosphorylated by Fyn.Fyn can phosphorylate Srcasm, and association of these molecules relies on cooperative binding between the SH2 and SH3 domains of Fyn and corresponding canonical binding sites in Srcasm. Srcasm is capable of interacting with Grb2 and the regulatory subunit of phosphoinositide 3-kinase, p85, in a phosphorylation-dependent manner. The evidence suggests that Srcasm may help promote Src family kinase signaling in cells.	SIGNOR-251185	0.445
PHF12	protein	Q96QT6	UNIPROT	TLE2	protein	Q04725	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								11390640	t		miannu	We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE.	SIGNOR-266992	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	RAC1	protein	P63000	UNIPROT	up-regulates activity				9606	BTO:0000584								29572236	f		miannu	The discovery that AMPK activation is a general requirement for macropinosome formation in cancer cells dramatically extends our understanding of the regulation of this process. By increasing RAC1-GTP levels, AMPK activation stimulates macropinosome formation (Fig. 2I–K; Supplementary Fig. S5). 	SIGNOR-277766	0.266
F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	Macropinosomes formation	phenotype	SIGNOR-PH227	SIGNOR	up-regulates				9606									39000072	f		miannu	The signaling for the regulation of macropinocytosis normally starts with the activation of RAS protein by macropinocytic stimulators, which in turn initiate signaling cascades involving RAC1 and phosphatidylinositol kinases and their downstream effectors or product that lead to actin cytoskeleton remodeling for plasma membrane ruffle and macropinocytic cup formation. Macropinosomes are further matured by regulation of the small GTPases RAC1 and CDC42 as well as phosphatidylinositol lipids, and matured macropinosomes undergo recycling or degradation processes.	SIGNOR-277767	0.7
hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	ADCY10	protein	Q96PN6	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000567								31827278	t		miannu	In these cells, trafficking of V-ATPase to the plasma membrane has been shown to be mediated by activation of bicarbonate-dependent soluble adenylate cyclase (sAC), which increases cAMP levels, thereby activating protein kinase A (PKA) 	SIGNOR-277762	0.8
RAB21	protein	Q9UL25	UNIPROT	Early macropinosomes 	phenotype	SIGNOR-PH228	SIGNOR	up-regulates	binding			9606									19693279	f		miannu	It was demonstrated that wild-type Rab21 was transiently associated with macropinosomes. Rab21 was recruited to the macropinosomes after a decrease in PI(4,5)P(2) and PI(3,4,5)P(3) levels. Although Rab21 was largely colocalized with Rab5, the recruitment of Rab21 to the macropinosomes lagged a minute behind that of Rab5, and preceded that of Rab7.	SIGNOR-277782	0.7
MIB1	protein	Q86YT6	UNIPROT	SMN1	protein	Q16637	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									23615451	t		lperfetto	The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein	SIGNOR-253112	0.328
HES1	protein	Q14469	UNIPROT	NOC3L	protein	Q8WTT2	UNIPROT	down-regulates quantity	transcriptional regulation			9823	BTO:0003298								23611667	t			The expression level of FAD24 is inversely associated with that of HES1 in porcine MSCs after adipogenic induction. Enforced overexpression of HES1 in MSCs during the early stage of adipogenesis significantly repressed the transcription of FAD24 (P < 0.01) and the other pro-adipogenic genes	SIGNOR-253059	0.2
NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	form complex	binding					BTO:0001103							7566092	t		svumbaca	Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter.	SIGNOR-255363	0.95
PCNT	protein	O95613	UNIPROT	CDK5RAP2	protein	Q96SN8	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								18042621	t		Giulio	Our observation that Cep215 may function downstream of pericentrin suggests that the two proteins affect centrosome cohesion through a common mechanism. |Finally, depletion of pericentrin caused an almost complete loss of Cep215 from centrosomes, a detectable reduction in centrosomal levels of Cep68 and rootletin, but no significant effect on C-Nap1 (Fig. 6C and Table 1). Taken together, these results point to functional (and perhaps molecular) interactions between (1) Cep68 and rootletin and (2) Cep215 and pericentrin.	SIGNOR-260309	0.812
PRKCG	protein	P05129	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Thr373	TVLVKDStNRDSLDM	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-129332	0.326
STK4	protein	Q13043	UNIPROT	LATS2	protein	Q9NRM7	UNIPROT	up-regulates	phosphorylation	Ser872	HQRCLAHsLVGTPNY	9606									21808241	t		gcesareni	Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2.	SIGNOR-175821	0.62
PRKCA	protein	P17252	UNIPROT	GABRR1	protein	P24046	UNIPROT	unknown	phosphorylation	Ser444	QRKSQRSsYVSMRID	-1									12175859	t		miannu	Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation	SIGNOR-262755	0.341
PDK3	protein	Q15120	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates activity	phosphorylation	Ser293	TYRYHGHsMSDPGVS	-1									11485553	t		lperfetto	Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.	SIGNOR-109609	0.866
FGD2	protein	Q7Z6J4	UNIPROT	CDC42	protein	P60953	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260552	0.461
SOX5	protein	P35711	UNIPROT	COL2A1	protein	P02458	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10980415	f		miannu	Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Two other members of the Sox family, L-Sox5 and Sox6, also bind to the 48-bp Col2a1 enhancer and together with Sox9 activate this enhancer as well as the endogenous Col2a1 	SIGNOR-251759	0.44
TSC	complex	SIGNOR-C101	SIGNOR	MTOR	protein	P42345	UNIPROT	down-regulates activity				9606	BTO:0000007;BTO:0001938								12271141	f		lperfetto	These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor	SIGNOR-217907	0.769
RPS6K	proteinfamily	SIGNOR-PF26	SIGNOR	STK11	protein	Q15831	UNIPROT	down-regulates activity	phosphorylation	Ser428	SSKIRRLsACKQQ	9606	BTO:0001271								25846811	t		lperfetto	Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK.	SIGNOR-252805	0.2
TKT	protein	P29401	UNIPROT	D-xylulose 5-phosphate(2-)	smallmolecule	CHEBI:57737	ChEBI	down-regulates quantity	chemical modification			9606									24929114	t		miannu	Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates.	SIGNOR-267085	0.8
estrone	smallmolecule	CHEBI:17263	ChEBI	ESR2	protein	Q92731	UNIPROT	up-regulates activity	chemical activation			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258583	0.8
SNRNP27	protein	Q8WVK2	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270642	0.425
SYK	protein	P43405	UNIPROT	BLNK	protein	Q8WV28	UNIPROT	up-regulates	phosphorylation	Tyr96	EENADDSyEPPPVEQ	9606									12456653	t		llicata	The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex.	SIGNOR-96052	0.799
UNC5B	protein	Q8IZJ1	UNIPROT	DCC	protein	P43146	UNIPROT	down-regulates activity	binding			9606		BTO:0001484							25881791	t		miannu	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268166	0.645
SRC	protein	P12931	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates activity	phosphorylation	Tyr315	TFCGTPEyLAPEVLE	9606	BTO:0000007								12600984	t		lperfetto	We also showed that phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this proline motif fails to block the transcription activity of Forkhead in 293 cells and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken together, our data suggest that the interaction between the SH3 domain of Src family kinases and the proline-rich motif in the C-terminal regulatory region of Akt is required for tyrosine phosphorylation of Akt and its subsequent activation.	SIGNOR-252621	0.663
CSNK1A1	protein	P48729	UNIPROT	PSEN2	protein	P49810	UNIPROT	unknown	phosphorylation	Ser7	sDSEEEVC	-1									8972483	t		llicata	In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. 	SIGNOR-250791	0.4
PGD	protein	P52209	UNIPROT	6-phospho-D-gluconate	smallmolecule	CHEBI:16863	ChEBI	down-regulates quantity	chemical modification			9606									34775382	t		miannu	6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule.	SIGNOR-267060	0.8
LYN	protein	P07948	UNIPROT	PDIA3	protein	P30101	UNIPROT	unknown	phosphorylation	Tyr454	VRGFPTIyFSPANKK	-1									8631326	t		miannu	Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s).	SIGNOR-262895	0.2
PRKCA	protein	P17252	UNIPROT	PDE3A	protein	Q14432	UNIPROT	up-regulates	phosphorylation	Ser438	PGLLRRVsSTWTTTT	9606									19261611	t		llicata	Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding.	SIGNOR-184456	0.2
LEF1	protein	Q9UJU2	UNIPROT	NCAM1	protein	P13591	UNIPROT	up-regulates activity	transcriptional regulation			10090	BTO:0003952								11696550	f		miannu	Consistent with our observation that expression of exogenous LEF-1 causes transactivation of the N-CAM promoter, a recent study demonstrated that noggin-dependent induction of LEF-1 coincidentally increased N-CAM expression (50). Ectopic noggin added to skin cultures up-regulates LEF-1 expression and stimulates hair induction. Based on promoter assays and EMSAs, our results further support the notion that N-CAM is a direct target of LEF-1. 	SIGNOR-254549	0.279
PPM1A	protein	P35813	UNIPROT	CDK2	protein	P24941	UNIPROT	down-regulates activity	dephosphorylation			-1									10934208	t		miannu	Moreover, purified recombinant PP2C alpha and PP2C beta 2 proteins efficiently dephosphorylated monomeric Cdk2/Cdk6 in vitro.	SIGNOR-277107	0.296
RIPK1	protein	Q13546	UNIPROT	Necrosis	phenotype	SIGNOR-PH3	SIGNOR	up-regulates				9606									14965271	f		amattioni	Fas-induced necrosis requires rip	SIGNOR-121901	0.7
RNF11	protein	Q9Y3C5	UNIPROT	SMURF2	protein	Q9HAU4	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								14755250	t		miannu	RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome.	SIGNOR-272952	0.557
MYC	protein	P01106	UNIPROT	SIRT2	protein	Q8IXJ6	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000584								23175188	f		miannu	Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. 	SIGNOR-255146	0.478
ATM	protein	Q13315	UNIPROT	PNKP	protein	Q96T60	UNIPROT	up-regulates	phosphorylation	Ser126	PPGTPLVsQDEKRDA	9606									21824916	t		lperfetto	We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro.	SIGNOR-176012	0.476
PRKCG	protein	P05129	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates activity	phosphorylation	Ser368	QRPSSRAsSRASSRP	10116									10871288	t		lperfetto	Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.	SIGNOR-249050	0.585
PDGFB	protein	P01127	UNIPROT	PDGFRA	protein	P16234	UNIPROT	up-regulates activity	binding			9606									11331882	t		miannu	Pdgf-b activates both pdgfr-alpha and pdgfr-beta	SIGNOR-107397	0.707
FN1	protein	P02751	UNIPROT	Av/b6 integrin	complex	SIGNOR-C179	SIGNOR	up-regulates	binding			9606									1532572	t		gcesareni	Integrin alpha v beta 6 binds to fibronectin, but not to vitronectin or collagen i. cell adhesion assays show that fg-2 cell attachment to fibronectin is only partially inhibited by anti-beta 1 integrin antibodies, implying that other fibronectin receptors may be involved.	SIGNOR-19793	0.725
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	BAD	protein	Q92934	UNIPROT	down-regulates activity	phosphorylation	Ser75	EIRSRHSsYPAGTED	9606	BTO:0000007								9381178	t			Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival.	SIGNOR-251469	0.2
LPAR1	protein	Q92633	UNIPROT	GNA15	protein	P30679	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257282	0.432
PRKCD	protein	Q05655	UNIPROT	SDC4	protein	P31431	UNIPROT	up-regulates activity	phosphorylation	Ser179	MKKKDEGsYDLGKKP	10116									11916978	t		lperfetto	The phosphorylation state of Ser(183) in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP(2)), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) alpha. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCalpha activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCalpha and -delta were able to specifically phosphorylate Ser(183) in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCdelta but not a DN PKCalpha mutant.	SIGNOR-116265	0.506
SRC	protein	P12931	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates	phosphorylation	Tyr146	KEVHKSGyLSSERLI	9606									15647376	t		llicata	N this study we have demonstrated that ezrin y145 is a direct target for phosphorylation by the tyrosine kinase src evidence from this study suggests that a positive feedback loop exists whereby src-mediated ezrin y145 phosphorylation sustains src activity._	SIGNOR-133227	0.635
PTEN	protein	P60484	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates activity				9606	BTO:0000938								18794881	f		lperfetto	The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)).	SIGNOR-252725	0.707
PREX2	protein	Q70Z35	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								24367090	t		irozzo	Here, we report that P-REX2 interacts with PTEN via two interfaces. In summary, P-REX2 docks to the PDZ-BD of PTEN through its C-terminal domain, reads the phosphorylation state of the PTEN tail via the DH domain, and inhibits PTEN activity by unleashing the PH domain	SIGNOR-259189	0.606
SRC	protein	P12931	UNIPROT	CDH2	protein	P19022	UNIPROT	down-regulates	phosphorylation	Tyr886	GGEQDYDyLNDWGPR	9606	BTO:0000848								16371504	t		lperfetto	Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated.	SIGNOR-143246	0.408
GPR84	protein	Q9NQS5	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256847	0.28
HNF1A	protein	P20823	UNIPROT	AKR1C4	protein	P17516	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									2044952	f	2	miannu	Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-1_ binds to the target element in the rat DBP gene in the liver, while vHNF-1 recognizes a target element in extrahepatic tissues. The ability of vHNF-1-A to activate the rat DBP gene is much higher than that of vHNF-1-C.	SIGNOR-239964	0.248
Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	down-regulates				9606									21248841	f		lperfetto	The importance of polycomb function for stem cells is best illustrated by various PcG-knockout mice. Deletion of any of the PRC2 members results in embryonic lethality. In vitro studies with ES cells demonstrated that cells lacking EED or Suz12 could not maintain their pluripotency and were prone to differentiation.	SIGNOR-241910	0.7
CNOT3	protein	O75175	UNIPROT	CCR4-NOT complex	complex	SIGNOR-C439	SIGNOR	form complex	binding			9606									19558367	t		lperfetto	In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules.	SIGNOR-268301	0.813
CSNK1A1	protein	P48729	UNIPROT	EIF2B5	protein	Q13144	UNIPROT	unknown	phosphorylation	Ser466	DEDDGEFsDDSGADQ	9606	BTO:0000007								11500362	t		llicata	 The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1. All five sites are phosphorylated in the eIF2B complex in vivo. | A phosphopeptide corresponding to this region was identified in Asp‐N digests of eIF2Bϵ phosphorylated in vitro by CK1, suggesting that Ser461 or Ser464 may be phosphorylated by this kinase in vivo.	SIGNOR-250787	0.328
gemcitabine	chemical	CHEBI:175901	ChEBI	TYMS	protein	P04818	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0003207								25562513	t		miannu	2',2'-Difluoro-2'-deoxycytidine (dFdC, gemcitabine) is a cytidine analogue active against several solid tumor types, such as ovarian, pancreatic and non-small cell lung cancer. The compound has a complex mechanism of action. Because of the structural similarity of one metabolite of dFdC, dFdUMP, with the natural substrate for thymidylate synthase (TS) dUMP, we investigated whether dFdC and its deamination product 2',2'-difluoro-2'-deoxyuridine (dFdU) would inhibit TS. This study was performed using two solid tumor cell lines: the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000. The specific TS inhibitor Raltitrexed (RTX) was included as a positive control. Using the in situ TS activity assay measuring the intracellular conversion of [5-(3)H]-2'-deoxyuridine or [5-(3)H]-2'-deoxycytidine to dTMP and tritiated water, it was observed that dFdC and dFdU inhibited TS. 	SIGNOR-259350	0.8
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	JAK2	protein	O60674	UNIPROT	down-regulates	phosphorylation			9606									16705159	t	16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling.	lperfetto	We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner	SIGNOR-270046	0.2
MLLT11	protein	Q13015	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				10090	BTO:0003295								21715312	f		irozzo	Our results indicate that AF1q cooperates with the Notch signaling pathway to foster the emergence of BM prothymocytes and drive subsequent intrathymic specification toward the T-cell lineage.	SIGNOR-259201	0.7
F2R	protein	P25116	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates				9606									22972936	t		milica	Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase.	SIGNOR-192042	0.582
ABL1	protein	P00519	UNIPROT	RAPGEF1	protein	Q13905	UNIPROT	unknown	phosphorylation	Tyr504	APIPSVPyAPFAAIL	9606									20581864	t		llicata	Activation of endogenous c-abl by oxidative stress was associated with phosphorylation of cellular c3g on y504. Inhibition of c3g expression and function using rnai or dominant-negative approaches inhibited c-abl-mediated cell death.	SIGNOR-166422	0.552
FBXW8	protein	Q8N3Y1	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0001109						phosphorylation:Thr286	EEVDLACtPTDVRDV	17205132	t		miannu	We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8. 	SIGNOR-271624	0.526
SMO	protein	Q99835	UNIPROT	SUFU	protein	Q9UMX1	UNIPROT	down-regulates activity	binding			9606	BTO:0000452								22114142	t		lperfetto	In addition to activating g(i), smo signals through its c-terminal tail to inhibit suppressor of fused, resulting in stabilization and activation of the gli family of transcription factors, which execute a transcriptional response to so-called canonical hh signaling.	SIGNOR-177656	0.627
GSK3B	protein	P49841	UNIPROT	MAP1B	protein	P46821	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000938								25040932	t		lperfetto	GSK-3beta phosphorylates MAP1B and the adenomatous polyposis coil gene product (APC; Grimes and Jope 2001; Frame and Cohen 2001). The phosphorylation of MAP1B by GSK-3beta suppresses detyrosination of microtubules and decreases the numbers of stable microtubules	SIGNOR-264843	0.543
CYC1	protein	P08574	UNIPROT	Mitochondrial respiratory chain complex III	complex	SIGNOR-C279	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits	SIGNOR-262192	0.927
PRKCD	protein	Q05655	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates	phosphorylation	Ser742	GEKSFRRsVVGTPAY	9606									15024053	t		llicata	Here we show that activation of pkd in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of tyr463 by abl, which in turn promotes a second step, phosphorylation of the pkd activation loop (ser738/ser742). We show that this is mediated by pkcdelta (protein kinase cdelta)	SIGNOR-123453	0.273
AKT1	protein	P31749	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates	phosphorylation	Thr509	LKRKRRPtSGLHPED	9606	BTO:0000150								17428466	t		lperfetto	Phosphatidylinositol 3-kinase/akt signaling enhances nuclear localization and transcriptional activity of brca1. mutation of threonine 509 in brca1, the site of akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce brca1 nuclear accumulation	SIGNOR-154312	0.521
SNAI1	protein	O95863	UNIPROT	Epithelial-mesenchymal_transition	phenotype	SIGNOR-PH45	SIGNOR	up-regulates				9606									19055748	f		lperfetto	Taken together these results suggest that SNAI1 functional blockade is leading to partial re-expression of E-cadherin (i.e. at the level of transcription), to a decrease in PAI-1 and to a more collective migration, while the parental cells expressing SNAI1 have less E-cadherin, more PAI 1, and migrate individually. We suggest that the present study establishes a relation between SNAI1 function, PAI-1 distribution and EMT status.	SIGNOR-252259	0.7
PPP3CA	protein	Q08209	UNIPROT	BAD	protein	Q92934	UNIPROT	up-regulates activity	dephosphorylation	Ser75	EIRSRHSsYPAGTED	-1									10195903	t		lperfetto	Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.| Bcl-xL did not coimmunoprecipitate with BAD(S75E, S99E) protein (Fig. 2A), regardless of whether it was coexpressed with DCnA/B 	SIGNOR-263739	0.451
CTDSP2	protein	O14595	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	dephosphorylation	Ser187	NSHPFPHsPNSSYPN	9606	BTO:0000552								17085434	t			Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214)	SIGNOR-248300	0.477
CARM1	protein	Q86X55	UNIPROT	PAX7	protein	P23759	UNIPROT	up-regulates	methylation			9606	BTO:0002314	BTO:0000887;BTO:0001103							22863532	t		miannu	Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5.	SIGNOR-198617	0.433
PRKCA	protein	P17252	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606	BTO:0000782								19836308	t		lperfetto	Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).	SIGNOR-188581	0.364
CBFA2T3/ZNF651	complex	SIGNOR-C197	SIGNOR	ZNF652	protein	Q9Y2D9	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000007								20116376	t			Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex.	SIGNOR-253955	0.525
EIF3L	protein	Q9Y262	UNIPROT	EIF3_complex	complex	SIGNOR-C401	SIGNOR	form complex	binding			-1									16920360	t		miannu	Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 	SIGNOR-266389	0.921
SRC	protein	P12931	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Tyr315	TFCGTPEyLAPEVLE	9534	BTO:0004055								11445557	t		lperfetto	Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity.	SIGNOR-246368	0.663
GSK3B	protein	P49841	UNIPROT	BLM	protein	P54132	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr171	ETSKSFVtPPQSHFV	9606	BTO:0002181								26028025	t		miannu	We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.	SIGNOR-276906	0.262
CYP11A1	protein	P05108	UNIPROT	cholesterol	smallmolecule	CHEBI:16113	ChEBI	down-regulates quantity	chemical modification			9606		BTO:0000048							33117906	t		lperfetto	The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme.	SIGNOR-268633	0.8
STK3	protein	Q13188	UNIPROT	RCC1	protein	P18754	UNIPROT	up-regulates	phosphorylation	Ser2	sPKRIAKR	9606	BTO:0000007								19559616	t		miannu	MST2 Phosphorylates RCC1 In Vitro and In Vivo. Using an antibody generated against phospho-S2/11 in RCC1 [18], we found that these two residues were also efficiently phosphorylated by MST1 and MST2 (Figure 2D), further supporting that S2 and/or S11 are genuine MST2 phosphorylation targets.	SIGNOR-263146	0.2
MRGPRX2	protein	Q96LB1	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257385	0.2
SREBF2	protein	Q12772	UNIPROT	SQLE	protein	Q14534	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000759							31848472	t		miannu	The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription	SIGNOR-265162	0.579
AKT1	protein	P31749	UNIPROT	ILF3	protein	Q12906	UNIPROT	up-regulates activity	phosphorylation	Ser647	RGRGRGGsIRGRGRG	9606									20870937	t		llicata	Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser647 and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA. 	SIGNOR-252512	0.376
Corticotropin	protein	P01189-PRO_0000024969	UNIPROT	MC1R	protein	Q01726	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268701	0.2
WWTR1	protein	Q9GZV5	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates activity	binding			9606									21084559	t		lperfetto	Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal.	SIGNOR-169838	0.576
MAPK1	protein	P28482	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Ser204	NHSMDAGsPNLSPNP	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of Smads mediated by ERK2, GSK3β, and CDK2/4 negatively regulates Smad activity	SIGNOR-161609	0.736
P2RY6	protein	Q15077	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257076	0.2
RPS6KA1	protein	Q15418	UNIPROT	STK11	protein	Q15831	UNIPROT	down-regulates activity	phosphorylation	Ser428	SSKIRRLsACKQQ	9606	BTO:0001271								25846811	t		lperfetto	Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK.	SIGNOR-209871	0.293
CEBPE	protein	Q15744	UNIPROT	CEBPG	protein	P53567	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								15588942	t		miannu	C/EBP-epsilon interacts with C/EBP-gamma through the leucine-zipper containing domain. C/EBP-epsilon and C/EBP-gamma synergistically activate transcription of lactoferrin promoter	SIGNOR-224900	0.381
SRC	protein	P12931	UNIPROT	EMD	protein	P50402	UNIPROT	down-regulates	phosphorylation	Tyr74	TRGDADMyDLPKKED	9606	BTO:0000567	BTO:0000887							19789182	t		llicata	Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf	SIGNOR-188312	0.463
MAPK3	protein	P27361	UNIPROT	APBB1	protein	O00213	UNIPROT	unknown	phosphorylation	Thr709	PKRLGAHtP	9606									14697653	t		lperfetto	Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved.	SIGNOR-120483	0.271
MMP19	protein	Q99542	UNIPROT	ACAN	protein	P16112	UNIPROT	down-regulates quantity by destabilization	cleavage	Asn360	DFVDIPEnFFGVGGE	-1									10922468	t		lperfetto	Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development.	SIGNOR-266978	0.409
AGT	protein	P01019	UNIPROT	REN	protein	P00797	UNIPROT	up-regulates activity	binding			9606									32201502	t		miannu	 Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10).	SIGNOR-260224	0.927
SCF-SKP2	complex	SIGNOR-C136	SIGNOR	RBL2	protein	Q08999	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0001938						phosphorylation:Ser672	TLYDRYSsPPASTTR	12435635	t		miannu	 The activity of the ubiquitin ligase complex Skp1-Cul1/Cdc53-F-box protein Skp2 (SCF(Skp2)) and the proteasome were necessary for p130 degradation. In vitro, recombinant Skp2 was able to bind hyperphosphorylated but not dephosphorylated p130. Furthermore, in vitro polyubiquitination of p130 by SCF(Skp2) was specifically dependent on phosphorylation of p130 on Serine 672. 	SIGNOR-272598	0.545
CD70	protein	P32970	UNIPROT	CD27	protein	P26842	UNIPROT	up-regulates	binding			9606	BTO:0000776								12324477	t		gcesareni	The molecule defining the cd70 ag is identical to the recently defined ligand for cd27. Bioassays demonstrated that the cd70 cdna clone expressed in african green monkey kidney cells would induce the proliferation of pha-costimulated t cells. Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner.	SIGNOR-93435	0.765
AML1-ETO	fusion protein	SIGNOR-FP1	SIGNOR	 Core Binding Factor complex	complex	SIGNOR-C214	SIGNOR	down-regulates activity	binding			9606									15829516	t		irozzo	Two classes of models can describe how AML1-ETO could interfere with normal AML1 activity. First, because AML1-ETO has the potential to interact with AML1 co-factors (such as CBFβ) through its RD, it could act as a dominant-negative molecule by competing with AML1 for these co-factors. Although AML1-ETO has been shown to interact with CBFβ and repress the expression of AML1-regulated genes in vitro and in cell culture, the available data do not distinguish between these two models.	SIGNOR-256100	0.2
GATA3	protein	P23771	UNIPROT	GATA3	protein	P23771	UNIPROT	up-regulates				9606									16386358	t			Experimental data indeed supports the existence of a positive circuit involvingGATA-3 that excludes IL-4 and STAT-6, specifically in mouse cells	SIGNOR-254297	0.2
MAPK8IP3	protein	Q9UPT6	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates	binding			9606									15767678	t		gcesareni	The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.	SIGNOR-134555	0.738
ETV6	protein	P41212	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606	BTO:0000960;BTO:0002062								15958056	f		irozzo	We thus conclude that TEL is also an accelerator for erythroid differentiation upon cytokine stimulation in human hematopoietic cells. We demonstrated in the present study that TEL accelerates erythroid differentiation induced by a physiological cytokine EPO in human leukemia cell line UT-7/GM.	SIGNOR-256017	0.7
arecoline	chemical	CHEBI:2814	ChEBI	CHRM1	protein	P11229	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258641	0.8
EIF4EBP1	protein	Q13541	UNIPROT	EIF4E	protein	P06730	UNIPROT	down-regulates activity	binding			9606									23584478	t		lperfetto	The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1).	SIGNOR-167176	0.938
TWIST1	protein	Q15672	UNIPROT	RAP1A	protein	P62834	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255533	0.2
MDM2	protein	Q00987	UNIPROT	NOTCH4	protein	Q99466	UNIPROT	down-regulates	ubiquitination			9606		BTO:0000149							21402876	t		gcesareni	We demonstrate that the intracellular domain of notch 4 is targeted for ubiquitylation and hence degradation by the ubiquitin ligase mdm2.	SIGNOR-172826	0.378
MARCHF9	protein	Q86YJ5	UNIPROT	LILRB1	protein	Q8NHL6	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001522								19457934	t		miannu	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. 	SIGNOR-271534	0.2
BAG1	protein	Q99933	UNIPROT	HSPA8	protein	P11142	UNIPROT	up-regulates activity	binding			-1									27474739	t		lperfetto	Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70.	SIGNOR-254115	0.891
IL5RA	protein	Q01344	UNIPROT	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates				9606									21106848	f			Human blood eosinophils exhibit a hyperactive phenotype in response to chemotactic factors after cell priming with IL-5 family cytokines. Earlier work has identified ERK1/2 as molecular markers for IL-5 priming	SIGNOR-254350	0.2
PRKG1	protein	Q13976	UNIPROT	TRPC6	protein	Q9Y210	UNIPROT	down-regulates activity	phosphorylation	Ser322	KNDYKKLsMQCKDFV	-1									19961855	t		miannu	PKG phosphorylated TRPC6, and both T70 and S322 were targeted. Both sites were functionally relevant, as 8Br-cGMP strongly suppressed current in wild-type TRPC6 channels, but not in those with phospho-silencing mutations (T70A, S322A or S322Q). 	SIGNOR-276271	0.473
BCL9	protein	O00512	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	binding			9606									15208637	t		amattioni	The transcriptional activity of beta-catenin depends on bcl-9. Bcl-9 functions in targeting beta-catenin to the nucleus and thus increases the transcriptional activity of beta-catenin	SIGNOR-126059	0.936
KIF2A	protein	O00139	UNIPROT	Minus-end directed microtubule movement	phenotype	SIGNOR-PH217	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272533	0.7
BRD7	protein	Q9NPI1	UNIPROT	BRD3	protein	Q15059	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000192								12600283	f		miannu	 BRD7 protein could respectively interact with proteins, BRD2 and BRD3, and BRD7 could up-regulate the expression levels of BRD2 and BRD3 genes in mRNA level to some extent.	SIGNOR-253764	0.391
GSK3B	protein	P49841	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser717	VYKSPVVsGDTSPRH	9606	BTO:0000590								12387894	t		lperfetto	Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. 	SIGNOR-249355	0.729
STIP1	protein	P31948	UNIPROT	HSP90AA1	protein	P07900	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								27353360	t		miannu	Hsp90 chaperone cycle is tightly regulated by another group of proteins referred to as ‘co-chaperones'. Their stability does not depend on Hsp90 function but they interact with distinct Hsp90 conformational states, providing directionality to the Hsp90 cycle. Furthermore, certain co-chaperones, such as HOP and Cdc37p50 inhibit the Hsp90 chaperone cycle, assisting in delivery of distinct sets of client proteins (steroid hormone receptors and kinases, respectively) to the Hsp90 chaperone machine.	SIGNOR-261411	0.932
WNT16	protein	Q9UBV4	UNIPROT	LRP6	protein	O75581	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131677	0.535
TLN1	protein	Q9Y490	UNIPROT	Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	up-regulates activity	binding			10090	BTO:0000132								19118207	t		miannu	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257626	0.678
(R)-5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin	chemical	CID:11957727	PUBCHEM	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029									9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258867	0.8
DYRK1A	protein	Q13627	UNIPROT	SRSF1	protein	Q07955	UNIPROT	unknown	phosphorylation	Ser238	SRGSPRYsPRHSRSR	9606		BTO:0000142							18658135	t		gcesareni	Here, we demonstrate that dyrk1a, a kinase encoded by a gene in the ds critical region, phosphorylates alternative splicing factor (asf) at ser-227, ser-234, and ser-238, driving it into nuclear speckles and preventing it from facilitating tau exon 10 inclusion.	SIGNOR-179615	0.399
MAPK1	protein	P28482	UNIPROT	SMAD1	protein	Q15797	UNIPROT	down-regulates activity	phosphorylation	Ser206	SSSTYPHsPTSSDPG	9606									19914161	t		lpetrilli	Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3	SIGNOR-161601	0.59
CASP3	protein	P42574	UNIPROT	ROCK1	protein	Q13464	UNIPROT	up-regulates	cleavage			9606									11283607	t		gcesareni	Rock i is cleaved by casp3 at a conserved detd1113/g sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity.	SIGNOR-106546	0.724
CSNK1A1	protein	P48729	UNIPROT	FOXO4	protein	P98177	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser268	SSNASSVsTRLSPLR	9606	BTO:0001109								28945225	t		miannu	Here we report that CK1α similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268. 	SIGNOR-277326	0.2
desipramine	chemical	CHEBI:47781	ChEBI	SLC6A4	protein	P31645	UNIPROT	down-regulates activity	chemical inhibition			-1									9400006	t		miannu	In the SERT, the TCAs amitriptyline, nortriptyline, imipramine, desipramine and chloroimipramine were 4.5 to 10 times more potent (table 3) at the human SERT.in the SERT, the TCAs amitriptyline, nortriptyline, imipramine, desipramine and chloroimipramine were 4.5 to 10 times more potent (table 3) at the human SERT.Thus, amitriptyline, imipramine, nortriptyline and desipramine showed high affinity for the SERT, particularly the human version, and for the NET in which the secondary amines were more potent. 	SIGNOR-258679	0.8
CSNK2A1	protein	P68400	UNIPROT	PKD2	protein	Q13563	UNIPROT	up-regulates	phosphorylation	Ser812	FPRSLDDsEEDDDED	9606									14742446	t		gcesareni	Ser(812) can be phosphorylated by ck2 in vitro and substitution s812a results in failure to incorporate phosphate in cultured epithelial cells.	SIGNOR-121572	0.431
ATM	protein	Q13315	UNIPROT	RBBP8	protein	Q99708	UNIPROT	down-regulates	phosphorylation	Ser745	SCLADSFsQAADEEE	9606	BTO:0000150								10910365	t		llicata	Atm phosphorylates ctip at serine residues 664 and 745 our study suggests another dna damage-response pathway in which the signal is transmitted through phosphorylation of ctip by atm, leading to dissociation of the ctip_ctbp repressor complex from brca1, which in turn, activate transcription of gadd45	SIGNOR-79876	0.823
ZNF804A	protein	Q7Z570	UNIPROT	DDIT3	protein	P35638	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								23434502	t		miannu	ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 	SIGNOR-269464	0.2
BIRC2	protein	Q13490	UNIPROT	RIPK4	protein	P57078	UNIPROT	up-regulates activity	polyubiquitination		lys51	9606	BTO:0000007								21931591	t		miannu	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation.	SIGNOR-272706	0.361
PLK1	protein	P53350	UNIPROT	STK38	protein	Q15208	UNIPROT	down-regulates activity	phosphorylation	Thr407	EIKSIDDtSNFDEFP	9606	BTO:0000567								26057687	t		miannu	Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis. 	SIGNOR-276915	0.321
entacapone	chemical	CHEBI:4798	ChEBI	COMT	protein	P21964	UNIPROT	down-regulates activity	chemical inhibition			9606		BTO:0000759							9681662	t		Simone Vumbaca	Entacapone and tolcapone were powerful inhibitors of COMT and their IC50 estimates were 151 and 773 nM (P=0.008), respectively, in the liver; consistent results were obtained with the other tissues.	SIGNOR-261088	0.8
ABT-737	chemical	CID:11228183	PUBCHEM	BCL2	protein	P10415	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001271;BTO:0000776;BTO:0000785								17200714	t		gcesareni	A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells.	SIGNOR-151781	0.8
ATF4	protein	P18848	UNIPROT	LARS2	protein	Q15031	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269421	0.254
POLR2D	protein	O15514	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266164	0.835
CDK7	protein	P50613	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates activity	phosphorylation	Ser139	RRGLLYDsDEEDEER	9606									16899510	t		Luana	Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2.	SIGNOR-259850	0.304
UBE2D2	protein	P62837	UNIPROT	PEX5	protein	P50542	UNIPROT	down-regulates quantity by destabilization	ubiquitination			-1									19687296	t		miannu	Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. 	SIGNOR-253023	0.427
MAPK14	protein	Q16539	UNIPROT	EEF2K	protein	O00418	UNIPROT	down-regulates activity	phosphorylation	Ser396	TFDSLPSsPSSATPH	-1									12171600	t		miannu	Inhibition of eEF2 kinase resulting from phosphorylation of Ser-396 by SAPK2a p38 was approx.25%.	SIGNOR-249707	0.34
ZAP70	protein	P43403	UNIPROT	MUC1	protein	P15941	UNIPROT	up-regulates activity	phosphorylation	Tyr1203	IFPARDTyHPMSEYP	9606	BTO:0000661								14766232	t		lperfetto	Indeed, the present results demonstrate that ZAP-70 phosphorylates MUC1-CD and that the MUC1-CD Y-20 site functions, at least in part, as a ZAP-70 substrate (Fig. 4C). In this regard, the in vivo phosphorylation data indicate that ZAP-70 may also contribute to phosphorylation of MUC1-CD Y-46.The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 andBeta-catenin.	SIGNOR-247039	0.46
SRC	protein	P12931	UNIPROT	Enolase	proteinfamily	SIGNOR-PF74	SIGNOR	up-regulates	phosphorylation			9606									24841372	t	inferred from family member	lperfetto	The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways	SIGNOR-270248	0.421
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation	Ser230	PEGATPTsPVGHFAK	9606	BTO:0000848	BTO:0001253							20959475	t		lperfetto	Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451).	SIGNOR-252953	0.704
leukotriene D4(1-)	smallmolecule	CHEBI:63166	ChEBI	CYSLTR1	protein	Q9Y271	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257475	0.8
vasopressin	smallmolecule	CHEBI:9937	ChEBI	AVPR2	protein	P30518	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257463	0.8
PTPRF	protein	P10586	UNIPROT	RET	protein	P07949	UNIPROT	down-regulates	dephosphorylation	Tyr1062	TWIENKLyGMSDPNW	9606									11121408	t		gcesareni	Lar expression significantly reduced tyrosine-1062 phosphorylation in ret-men2a but not in ret-men2b	SIGNOR-85170	0.436
INSR	protein	P06213	UNIPROT	INSR	protein	P06213	UNIPROT	up-regulates activity	phosphorylation	Tyr1355	SLGFKRSyEEHIPYT	-1									3166375	t		lperfetto	This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972	SIGNOR-22577	0.2
herbimycin	chemical	CHEBI:5674	ChEBI	SRC	protein	P12931	UNIPROT	down-regulates	chemical inhibition			9606		BTO:0000142							11782488	t		gcesareni	Herbimycin a and pp2, specific inhibitors of src family kinases, both inhibited h2o2-mediated c-src and bmk1 activation.	SIGNOR-113767	0.8
PRKACA	protein	P17612	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser305	IKRSKKNsLALSLTA	9606									15193262	t		lperfetto	We show that phosphorylation of serine-305 in the hinge region of er_ by protein kinase a (pka) induced resistance to tamoxifenactivation of pka prevents tamoxifen-mediated inhibition of er transactivation	SIGNOR-125779	0.466
NatC	complex	SIGNOR-C417	SIGNOR	Protein_acetylation	phenotype	SIGNOR-PH189	SIGNOR	up-regulates				9606									21351257	f		miannu	About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity.	SIGNOR-267236	0.7
LCK	protein	P06239	UNIPROT	PRDX2	protein	P32119	UNIPROT	down-regulates activity	phosphorylation	Tyr193	NVDDSKEyFSKHN	-1									20178744	t		miannu	Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.	SIGNOR-276279	0.2
USF1	protein	P22415	UNIPROT	B2M	protein	P61769	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12480693	f		miannu	 Here we show that upstream stimulatory factor 1 (USF1) and USF2 bind to the E box and regulate beta(2)m transactivation.	SIGNOR-254655	0.2
Unii-2ewn8Z05CN	chemical	CID:129138801	PUBCHEM	EIF4A1	protein	P60842	UNIPROT	down-regulates activity	chemical inhibition			9606									32470302	t		Simone Vumbaca	Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase	SIGNOR-261120	0.8
TANC2	protein	Q9HCD6	UNIPROT	Dendritic_spine_morphogenesis	phenotype	SIGNOR-PH183	SIGNOR	up-regulates				10116									21068316	t		miannu	 In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses.	SIGNOR-266897	0.7
CAST	protein	P20810	UNIPROT	CAPN1	protein	P07384	UNIPROT	down-regulates activity	binding			9606	BTO:0000590								25969760	t		lperfetto	In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain 	SIGNOR-251582	0.913
PIGBOS1	protein	A0A0B4J2F0	UNIPROT	DDIT3	protein	P35638	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									31653868	f		miannu	We then confirmed via Western blot that TM treatment of PIGBOS-KD cells led to higher ATF4 and CHOP protein levels (Supplementary Fig. 13h). These data identified PIGBOS as a heretofore unknown mitochondrial regulator of UPR, and the only known microprotein linked to the regulation of cell stress or inter-organelle signaling. Upon UPR induction with TM, the loss of PIGBOS led to dramatic increases in the levels of all UPR target genes measured, indicating increased UPR signaling across all the branches (IRE1, PERK, and ATF6) (Fig. 6d and Supplementary Fig. 14a). Meanwhile, PIGBOS overexpressing cells showed the opposite effect, in which the UPR target genes showed less UPR activation, indicating a tunable modulation of ER stress by PIGBOS microprotein levels	SIGNOR-261043	0.2
NEUROG2	protein	Q9H2A3	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	up-regulates				10090	BTO:0000938	BTO:0000142							18400164	f		lperfetto	While the mechanisms by which Ngn2 promotes neurogenesis have been characterized, little is known about how Ngn2 confers neuronal cell-type identity during spinal cord development. Ngn1 and Ngn2, two mammalian orthologs of the Drosophila proneural bHLH gene atonal, are expressed in overlapping patterns throughout the developing nervous system and act as important regulators of developmental neurogenesis	SIGNOR-265173	0.7
EP300	protein	Q09472	UNIPROT	RUNX2/EP300	complex	SIGNOR-C211	SIGNOR	form complex	binding			10116	BTO:0002648								12697832	t		Giulio Giuliani	More interestingly, the bone-specific transcriptionfactor Runx2/Cbfa1 is present in the immunoprecipitated material, strongly indicating that in osteoblastic cells expressing OC, p300 and Runx2/Cbfa1 are components of the same nuclear protein complex.	SIGNOR-255418	0.464
ALDH9A1	protein	P49189	UNIPROT	NADH(2-)	smallmolecule	CHEBI:57945	ChEBI	up-regulates quantity	chemical modification			9606									11802770	t		miannu	Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). 	SIGNOR-269695	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CTNNB1	protein	P35222	UNIPROT	up-regulates	phosphorylation	Ser552	QDTQRRTsMGGTQQQ	9606									17287208	t		lperfetto	Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo.	SIGNOR-244222	0.2
WDHD1	protein	O75717	UNIPROT	CLSPN	protein	Q9HAW4	UNIPROT	up-regulates activity	binding			9606	BTO:0001109								26082189	t		miannu	 And-1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And-1 to accumulate at the damage sites, where And-1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR. Significantly, And-1 binds directly to ssDNA and facilitates the association of Claspin with ssDNA. 	SIGNOR-262665	0.401
UBE3A	protein	Q05086	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys262	DSDDALLkMTISQQE	-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. 	SIGNOR-272744	0.476
CGAS	protein	Q8N884	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	down-regulates activity				9606									31544964	f			Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death	SIGNOR-259951	0.7
TP53	protein	P04637	UNIPROT	FAS	protein	P25445	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								9841917	t	Nuclear p53	amattioni	In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene,	SIGNOR-62376	0.589
CSNK2B	protein	P67870	UNIPROT	IKZF1	protein	Q13422	UNIPROT	down-regulates	phosphorylation	Ser63	NVKVETQsDEENGRA	9606									21750978	t		miannu	We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo	SIGNOR-174852	0.2
PTK2B	protein	Q14289	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr407	IIDEEDTyTMPSTRD	9606									16760434	t		gcesareni	Activated rock phosphorylates fak on ser732, which is essential for phosphorylation of tyr407 and for cell migration. We further show that pyk2 is activated by vegf-induced clustering of integrin v 3 and is responsible for the phosphorylation of tyr407.	SIGNOR-147070	0.503
Kindlin	proteinfamily	SIGNOR-PF48	SIGNOR	A9/b1 integrin	complex	SIGNOR-C166	SIGNOR	up-regulates activity	binding			9606									29544897	t		miannu	Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival.	SIGNOR-259020	0.409
clozapine	chemical	CHEBI:3766	ChEBI	HTR1B	protein	P28222	UNIPROT	up-regulates activity	chemical activation			10116		BTO:0001311							8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258519	0.8
IGF1	protein	P05019	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	up-regulates				9606									2689937	f		fspada	Preadipocytes converted to adipocytes when insulin-like growth factor-1 or insulin was added to a medium depleted of those compounds	SIGNOR-23166	0.7
CSNK1D	protein	P48730	UNIPROT	PSEN2	protein	P49810	UNIPROT	unknown	phosphorylation	Ser9	LTFMASDsEEEVCDE	-1									8972483	t		llicata	In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro. 	SIGNOR-250804	0.371
FANCM	protein	Q8IYD8	UNIPROT	FANCF	protein	Q9NPI8	UNIPROT	up-regulates	binding			9606									20064461	t		gcesareni	Protein interaction motifs in fancm, designated mm1 and mm2, were identified. Mm1 interacts with the fa core complex by binding to fancf, whereas mm2 interacts with rm1 and topoisomerase iiialpha, components of the bs complex.	SIGNOR-163101	0.93
MAPK14	protein	Q16539	UNIPROT	SP7	protein	Q8TDD2	UNIPROT	up-regulates activity	phosphorylation			10090									20682789	t		ggiuliani	We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes	SIGNOR-255791	0.419
AKT1	protein	P31749	UNIPROT	TTC3	protein	P53804	UNIPROT	up-regulates	phosphorylation	Ser378	AYTPRSLsAPIFTTS	9606									20059950	t		llicata	Phosphorylation of ttc3 at ser378 is required for efficient biological function together, these observations support that ttc3 is a phosphorylation target of akt both in an in vitro and in a cellular context	SIGNOR-252508	0.404
PIM1	protein	P11309	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606									18593906	t		fspada	Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42).	SIGNOR-179308	0.396
SPTAN1	protein	Q13813	UNIPROT	ERCC4	protein	Q92889	UNIPROT	up-regulates activity													19102630	f		lperfetto	We have shown that in the nucleus alphaRIISp is involved in repair of DNA interstrand cross-links (13,14). It binds to purified DNA containing an interstrand crosslink; it colocalizes with the cross-link repair protein, XPF, in damage-induced nuclear foci after treatment of cells with a DNA interstrand cross-linking agent, and it is needed for the production of incisions by XPF at the site of an interstrand cross-link	SIGNOR-263276	0.289
CKM complex	complex	SIGNOR-C406	SIGNOR	SMAD1	protein	Q15797	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser214	PTSSDPGsPFQMPAD	9606									19914168	t		lpetrilli	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-273143	0.346
MAPK1	protein	P28482	UNIPROT	DAZAP1	protein	Q96EP5	UNIPROT	down-regulates activity	phosphorylation	Thr315	GVPPPPAtPGAAPLA	9606	BTO:0000007								16848763	t		miannu	Further experiments showed that DAZAP1 was phosphorylated stoichiometrically in vitro by ERK2 (extracellular-signal-regulated protein kinase 2) at two Thr-Pro sequences (Thr269 and Thr315), and that both sites became phosphorylated in HEK-293 (human embryonic kidney 293) cells in response to PMA or EGF (epidermal growth factor), or RAW 264.7 macrophages in response to LPS. Phosphorylation of the ARE-binding protein DAZAP1 by ERK2 induces its dissociation from DAZ	SIGNOR-262971	0.2
hexadecanoic acid	smallmolecule	CHEBI:15756	ChEBI	palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	up-regulates quantity	precursor of			9606									21242590	t		miannu	Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. On the other hand, overexpression of ACSL1 resulted in large increases in oleoyl-CoA synthesis and palmitoyl-CoA synthesis in SMC lysates (Fig. 4A).	SIGNOR-267876	0.8
ITGA2B	protein	P08514	UNIPROT	AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253197	0.946
CCL5	protein	P13501	UNIPROT	CCR3	protein	P51677	UNIPROT	up-regulates	binding			9606									10734056	t			In addition to the CCR1 receptor, RANTES activates several members of the CC subfamily of chemokine receptors including CCR3, CCR4, and CCR5	SIGNOR-254370	0.76
DIO1	protein	P49895	UNIPROT	L-thyroxine	smallmolecule	CHEBI:18332	ChEBI	down-regulates quantity	chemical modification			9606									1400883	t		scontino	The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production.	SIGNOR-266944	0.8
RACK1	protein	P63244	UNIPROT	PTK7	protein	Q13308	UNIPROT	up-regulates	binding			9606									21350015	t		gcesareni	Here, we identify rack1 as a novel interaction partner of ptk7. Mechanistically, rack1 is necessary for the ptk7-mediated membrane localization of dishevelled (dsh). Rack1 facilitates the ptk7-dsh interaction by recruiting pkcdelta1, a known effector of dsh membrane translocation.	SIGNOR-172322	0.2
PRKACA	protein	P17612	UNIPROT	PPP1R1B	protein	Q9UD71	UNIPROT	up-regulates activity	phosphorylation	Thr34	MIRRRRPtPAMLFRL										10604473	t		miannu	DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚ 	SIGNOR-250031	0.482
CAMK2A	protein	Q9UQM7	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Ser843	DVRLSRGsIDREDGS	9606									15845548	t		gcesareni	Furthermore, activated camkii directly phosphorylated the recombinant cooh-terminal region of fak at a residue equivalent to ser-843.	SIGNOR-135631	0.275
MAPK1	protein	P28482	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates	phosphorylation	Ser527	PHLDGPPsPRSPVIG	9606	BTO:0001271								15093545	t	The effect has been demonstrated using P29590-4	gcesareni	We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3).	SIGNOR-124252	0.366
PKN1	protein	Q16512	UNIPROT	PGAM1	protein	P18669	UNIPROT	down-regulates	phosphorylation	Ser118	QVKIWRRsYDVPPPP	9606	BTO:0000130								12189148	t		llicata	Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity.	SIGNOR-91602	0.257
NEFL	protein	P07196	UNIPROT	Neurofilament bundle assembly	phenotype	SIGNOR-PH72	SIGNOR	up-regulates				9606									8376466	f		miannu	Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons.	SIGNOR-252392	0.7
COPS4	protein	Q9BT78	UNIPROT	COP9 signalosome variant 2	complex	SIGNOR-C487	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270762	0.936
TYMS	protein	P04818	UNIPROT	dTMP(2-)	smallmolecule	CHEBI:63528	ChEBI	up-regulates quantity	chemical modification			9606									21876188	t		lperfetto	In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR.	SIGNOR-268235	0.8
TAOK2	protein	Q9UL54	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	binding			9606	BTO:0001130								10660600	t		lperfetto	Immunoprecipitated psk phosphorylates myelin basic protein and transfected psk stimulates mkk4 and mkk7 and activates the c-jun n-terminal kinase mitogen-activated protein kinase pathway.	SIGNOR-74864	0.262
ESRRB	protein	O95718	UNIPROT	NR0B1	protein	P51843	UNIPROT	down-regulates				9606									12482977	f		lperfetto	When dax-1 was cotransfected, it exerted efficient repression on transcription of the reporter gene activated by gal4-ad4bp-lbd, gal4-lrh-1-lbd, gal4-err2-lbd	SIGNOR-96533	0.35
IL1R1	protein	P14778	UNIPROT	Inflammation	phenotype	SIGNOR-PH12	SIGNOR	up-regulates				9606									21304099	f		lperfetto	The Il-1 family of ligands and receptors is primarily associated with acute and chronic inflammation.	SIGNOR-171876	0.7
EGFR	protein	P00533	UNIPROT	PKM	protein	P14618	UNIPROT	down-regulates activity	phosphorylation	Tyr148	KITLDNAyMEKCDEN	9606	BTO:0001570								26759242	t		miannu	EGFR binds to and phosphorylates PKM2 to inhibit its activity. 	SIGNOR-277197	0.463
azelastine	chemical	CHEBI:2950	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002126								18446005	t		Luana	We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells	SIGNOR-257790	0.8
GSK3B	protein	P49841	UNIPROT	GPHN	protein	Q9NQX3	UNIPROT	down-regulates	phosphorylation	Ser270	LSTTPSEsPRAQATS	9606		BTO:0000142							23408424	t		miannu	Identification of gsk3_ as the kinase targeting ser-270 /phosphorylation at ser-270 promotes gephyrin processing by calpain	SIGNOR-200957	0.287
RBP1	protein	P09455	UNIPROT	retinol	smallmolecule	CHEBI:50211	ChEBI	up-regulates quantity	relocalization												31963453	t		lperfetto	Once in the cytosol, retinol molecules are sequestered by membrane systems and bind to Cellular retinol-binding protein 1 (CRBP1), which plays a role in vitamin A cytoplasmic trafficking	SIGNOR-265108	0.8
SNAI2	protein	O43623	UNIPROT	MMP9	protein	P14780	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001033								22074556	f		miannu	 We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. Furthermore, ectopic expression of SLUG increased MMP9 expression and activity in PC3, 22RV1, and DU-145 cells, and SLUG knockdown by shRNA downregulated MMP9 expression.	SIGNOR-255170	0.466
Fe2S2 iron-sulfur cluster	chemical	CHEBI:49601	ChEBI	SDH	complex	SIGNOR-C400	SIGNOR	form complex	binding			9606									16143825	t		miannu	Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively.	SIGNOR-267735	0.8
CDK1	protein	P06493	UNIPROT	NDEL1	protein	Q9GZM8	UNIPROT	up-regulates activity	phosphorylation	Thr245	GFGTSPLtPSARISA	-1									12556484	t	done	miannu	In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites	SIGNOR-274072	0.646
NR3C1	protein	P04150	UNIPROT	TDO2	protein	P48775	UNIPROT	down-regulates quantity by repression	transcriptional regulation												16272140	t		lperfetto	Repression of GR-mediated expression of the tryptophan oxygenase gene by the SWI/SNF complex during liver development.	SIGNOR-268995	0.345
MAPK1	protein	P28482	UNIPROT	NDEL1	protein	Q9GZM8	UNIPROT	up-regulates activity	phosphorylation	Thr245	GFGTSPLtPSARISA	-1									12556484	t	done	miannu	In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites	SIGNOR-274075	0.292
PRKCA	protein	P17252	UNIPROT	NR1H4	protein	Q96RI1	UNIPROT	up-regulates	phosphorylation	Ser145	VVCGDRAsGYHYNAL	9606									18755856	t		llicata	Phosphorylation of farnesoid x receptor by protein kinase c promotes its transcriptional activity. pkcalpha phosphorylates in vitro fxr in its dna-binding domain on s135 and s154.	SIGNOR-180537	0.332
everolimus	chemical	CHEBI:68478	ChEBI	MTOR	protein	P42345	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000848								20689758	t		gcesareni	M14, m288, and skmel28 (sensitive and resistant) were exposed to rad001, an mtor inhibitor, and to ly294002, a pi3k inhibitor.	SIGNOR-167402	0.8
CHUK	protein	O15111	UNIPROT	IKK-complex	complex	SIGNOR-C14	SIGNOR	form complex	binding			9606									20300203	t		gcesareni	The kinase(s) responsible for the phosphorylation of the ikb inhibitors remained elusive for many years, until the biochemical purification of a cytoplasmic high-molecular weight complex migrating around 700900 kda and containing two related catalytic subunits, ikkalfa and ikkbeta.	SIGNOR-164506	0.774
STK4	protein	Q13043	UNIPROT	STK4	protein	Q13043	UNIPROT	up-regulates activity	phosphorylation	Ser327	SEEDEMDsGTMVRAV	9534									12223493	t		lperfetto	Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationwas also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues	SIGNOR-247569	0.2
cabozantinib	chemical	CHEBI:72317	ChEBI	AXL	protein	P30530	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000184								26536165	t		miannu	Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. 	SIGNOR-262241	0.8
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1931	SPTSPTYsPTSPKGS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203600	0.77
URI1	protein	O94763	UNIPROT	URI1 prefoldin co-chaperone	complex	SIGNOR-C514	SIGNOR	form complex	binding			9606									30484151	t		miannu	In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR94	SIGNOR-270917	0.566
PRKACA	protein	P17612	UNIPROT	FYN	protein	P06241	UNIPROT	up-regulates	phosphorylation	Ser21	LTEERDGsLNQSSGY	9606									20658524	t		lperfetto	The serine 21 (s21) residue of fyn is a protein kinase a (pka) recognition site within an rxxs motif of the amino terminal sh4 domain of fyn. In addition, s21 is critical for fyn kinase-linked cellular signaling. Mutation of s21a blocks pka phosphorylation of fyn and alters its tyrosine kinase activity.	SIGNOR-167147	0.435
D-ribofuranose 5-phosphate(2-)	smallmolecule	CHEBI:78346	ChEBI	Nucleotide_synthesis	phenotype	SIGNOR-PH179	SIGNOR	up-regulates activity				9606									31108873	f			De novo biosynthesis of both purines and pyrimidines has been observed to be altered in cancer and requires the generation of 5-phosphoribose-1-pyrophosphate (PRPP), the activated form of ribose derived from ribose 5-phosphate, which is produced through the oxidative and nonoxidative arms of the pentose phosphate pathway (PPP) parallel to glycolysis.	SIGNOR-267387	0.7
RIOK3	protein	O14730	UNIPROT	IFIH1	protein	Q9BYX4	UNIPROT	down-regulates activity	phosphorylation	Ser828	GRARADEsTYVLVAH	9606	BTO:0000007								25865883	t		lperfetto	RIOK3 mediates phosphorylation of MDA5 Ser-828|RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response	SIGNOR-264576	0.481
TWIST2	protein	Q8WVJ9	UNIPROT	CTPS1	protein	P17812	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255500	0.2
IL31RA	protein	Q8NI17	UNIPROT	JAK1	protein	P23458	UNIPROT	up-regulates	binding			9606	BTO:0000782								18926762	t		gcesareni	Il-31 can activate janus kinase (jak) 1 and jak2 signaling molecules after binding to its receptor complex.	SIGNOR-161342	0.476
RET	protein	P07949	UNIPROT	PTK2	protein	Q05397	UNIPROT	up-regulates	phosphorylation	Tyr925	DRSNDKVyENVTGLV	9606									21454698	t		gcesareni	Strikingly, when fak and ret kinases were co-incubated in the presence of atp, a marked increased in fak tyr-576/577 and tyr-925 phosphorylation was observed together with a shift in mobility of fak, indicating conversion to an activated state	SIGNOR-173021	0.622
GATA6	protein	Q92908	UNIPROT	CDX2	protein	Q99626	UNIPROT	up-regulates quantity by expression				9606	BTO:0000195								24317510	f		lperfetto	Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. 	SIGNOR-253155	0.471
CDK9	protein	P50750	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates	phosphorylation	Ser1861	TPTSPKYsPTSPKYS	9606									24385927	t		lperfetto	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203560	0.77
GARS1	protein	P41250	UNIPROT	alpha-aminoacyl-tRNA	smallmolecule	CHEBI:2651	ChEBI	up-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 	SIGNOR-270804	0.8
DPP6	protein	P42658	UNIPROT	KCND2	protein	Q9NZV8	UNIPROT	up-regulates activity	relocalization			8355	BTO:0000964								17130523	t		Luisa	DPPX-S reduced energy barriers of the voltage-dependent transitions; therefore, this auxiliary subunit may exert a catalytic effect on voltage-dependent gating of Kv4.2 channels. DPPX-S may also accelerate coupled inactivation indirectly	SIGNOR-269005	0.565
FADD	protein	Q13158	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	binding			9606									21525013	t		lperfetto	Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8	SIGNOR-173429	0.784
MAPK3	protein	P27361	UNIPROT	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Ser551	ELQAPVRsPITRSFA	10029	BTO:0000246								15379552	t		lperfetto	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-249461	0.618
CTNNA3	protein	Q9UI47	UNIPROT	JUP	protein	P14923	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0000586								21598020	t		miannu	Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14	SIGNOR-265494	0.497
TRIM62	protein	Q9BVG3	UNIPROT	CARD9	protein	Q9H257	UNIPROT	up-regulates activity	polyubiquitination	Lys125	LLMTEVMkLQKKVQD	9606	BTO:0000007								26488816	t		miannu	We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. 	SIGNOR-272420	0.525
SUV39H1	protein	O43463	UNIPROT	MYOG	protein	P15173	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002267								23435416	f		lperfetto	The methyl marks H3K9me3 on the myoD promoter and H3K27me3 on the myogenin promoter have been shown to be under the control of the histone methyl transferase KMT1A and the HDM KDM4A, respectively, during normal myogenesis. In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation	SIGNOR-249601	0.415
GTF2H3	protein	Q13889	UNIPROT	TFIIH	complex	SIGNOR-C457	SIGNOR	form complex	binding			9606									30860024	t		lperfetto	Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 	SIGNOR-269314	0.901
SMAD6	protein	O43541	UNIPROT	SMURF1	protein	Q9HCE7	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								19561075	t		miannu	Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase.	SIGNOR-272786	0.824
FURIN	protein	P09958	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	binding			9606									22479394	t	Cleavage in Golgi	gcesareni	The proteolytic activity of furin responsible for processing full length notch-1 (p300) plays a critical role in notch signaling.	SIGNOR-196914	0.653
GSK3B	protein	P49841	UNIPROT	AHR	protein	P35869	UNIPROT	up-regulates activity	phosphorylation	Thr731	FEPSPYPtTSSLEDF	9606	BTO:0000567								34198826	t		miannu	A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR.	SIGNOR-276665	0.253
	protein	P0DOX5	UNIPROT	Pr3-ANCA	complex	SIGNOR-C475	SIGNOR	form complex	binding			9606									27464484	t		lperfetto	Although the majority of PR3-ANCAs are of the IgG isotype, the results of one study showed that PR3-ANCAs of the IgA isotype were present in up to 30% of patients with GPA	SIGNOR-270594	
	protein	P0DOX5	UNIPROT	MPO-ANCA	complex	SIGNOR-C474	SIGNOR	form complex	binding			9606									27464484	t		lperfetto	Although MPO-ANCAs of the IgA isotype are sometimes found in patients with IgA nephropathy or IgA vasculitis45, isotypes other than IgG have not been reported in patients with typical AAV, with the exception of a single patient with pauci-immune crescentic glomerulonephritis	SIGNOR-270595	
EEF1A2	protein	Q05639	UNIPROT	Glu-tRNA(Glu)	smallmolecule	CHEBI:29157	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269529	0.8
SPTA1	protein	P02549	UNIPROT	Erythrocytic spectrin	complex	SIGNOR-C384	SIGNOR	form complex	binding			9606	BTO:0000424								24302288	t		lperfetto	Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell	SIGNOR-266025	0.729
STYK1	protein	Q6J9G0	UNIPROT	BECN1	protein	Q14457	UNIPROT	up-regulates activity	phosphorylation	Ser90	IPPARMMsTESANSF	9606	BTO:0000007								31696776	t		lperfetto	We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. |The results indicated that the level of BECN1 S90 phosphorylation significantly increased after STYK1 overexpression, but not STYK1K147R mutant.|STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I	SIGNOR-264568	0.2
WNK3	protein	Q9BYP7	UNIPROT	SLC12A2	protein	P55011	UNIPROT	up-regulates activity	phosphorylation												21613606	t		lperfetto	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264625	0.542
CASP8	protein	Q14790	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	cleavage	Asp329	EMEEDSYdSFGEPSY	-1									10069390	t		lperfetto	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261752	0.338
GLI1/GLI2	complex	SIGNOR-C450	SIGNOR	MYCN	protein	P04198	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000304								32766732	t	GLI2 and GLI1 heterodimerize via the Zn-finger domain	SimoneGraziosi	GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. | RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells	SIGNOR-269212	0.409
ATIC	protein	P31939	UNIPROT	(6S)-5,6,7,8-tetrahydrofolate(2-)	smallmolecule	CHEBI:57453	ChEBI	up-regulates quantity	chemical modification			9606									33179964	t		miannu	The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP.	SIGNOR-267326	0.8
DTX1	protein	Q86Y01	UNIPROT	ERBB2	protein	P04626	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16554461	f		gcesareni	Notch1-induced erbb2 expression in cerebellar astroglia occurs via dtx1	SIGNOR-145319	0.2
SLBP	protein	Q14493	UNIPROT	H2BC12	protein	O60814	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265383	0.2
WDFY3	protein	Q8IZQ1	UNIPROT	DVL3	protein	Q92997	UNIPROT	down-regulates quantity by destabilization	relocalization			9606	BTO:0000793								27008544	t		miannu	Our data taken together with the known role of ALFY in autophagy, demonstrate specific targeting and autophagy-mediated removal of DVL3 by hALFY.	SIGNOR-266793	0.254
PRKCA	protein	P17252	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates	phosphorylation	Ser657	QSDFEGFsYVNPQFV	9606									15277524	t		lperfetto	Pkc is frequently autophosphorylated on two c-terminal sites, the turn motif (thr- 638 in human pkc
) and the hydrophobic site (ser-657 in human pkc
). Thus, it is becoming clear that autophosphorylation of pkc can be a regulated event and that it has significant impact on pkc function	SIGNOR-127253	0.2
P2RY10	protein	O00398	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256869	0.2
AKT1	protein	P31749	UNIPROT	DLX5	protein	P56178	UNIPROT	up-regulates	phosphorylation			9606									21619873	t		gcesareni	Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5.	SIGNOR-252513	0.267
RPS6KA4	protein	O75676	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates				9606									19797274	f		gcesareni	Mitogen- and stress-activated kinase 2 (msk2) inhibits the transcription factor p53, and we investigate here the mechanisms underlying this inhibition. In the absence of stress stimuli, msk2 selectively suppressed the expression of a subset of p53 target genes.Msk2 can also control the the transcriptional activity of p53 in a kinase-indipendent mannermsk2 can also control the the transcriptional activity of p53 in a kinase-indipendent manner	SIGNOR-188334	0.252
PRLHR	protein	P49683	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256694	0.281
GSK3A	protein	P49840	UNIPROT	STAT2	protein	P52630	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser381	RKFNILTsNQKTLTP	9606	BTO:0002181								31843895	t		miannu	GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation.	SIGNOR-276760	0.266
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Phe)	smallmolecule	CHEBI:29184	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269492	0.8
AHCYL2	protein	Q96HN2	UNIPROT	PAPOLA	protein	P51003	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								19224921	t		lperfetto	Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner.	SIGNOR-268330	0.2
ODAD4	protein	Q96NG3	UNIPROT	Axonemal_Dynein	proteinfamily	SIGNOR-PF66	SIGNOR	up-regulates activity	binding			10090		BTO:0000379							33347437	t		miannu	CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B). It also interacts with ODA proteins including dynein heavy chains such as DNAH11 and possibly DNAH5/9. CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia.	SIGNOR-265546	0.2
LNX1	protein	Q8TBB1	UNIPROT	BCR	protein	P11274	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0000007								22889411	t		miannu	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272903	0.27
KLF5	protein	Q13887	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates	transcriptional regulation			10090									16054042	f		fspada	Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter.	SIGNOR-210010	0.607
MEF2D	protein	Q14814	UNIPROT	ASH2L	protein	Q9UBL3	UNIPROT	up-regulates				9606		BTO:0000887							18026121	f		gcesareni	Targeting of ash2l to specific genes is mediated by the transcriptional regulator mef2d. Furthermore, this interaction is modulated during differentiation through activation of the p38 mapk signaling pathway via phosphorylation of mef2d.	SIGNOR-159334	0.478
PRKCA	protein	P17252	UNIPROT	TRPV5	protein	Q9NQA5	UNIPROT	up-regulates activity	phosphorylation	Ser299	FLELVVSsDKREARQ	9606									17006539	t		gcesareni	A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK.	SIGNOR-149948	0.2
PRKG1	protein	Q13976	UNIPROT	EVL	protein	Q9UI08	UNIPROT	down-regulates activity	phosphorylation			9606									15066263	t		miannu	 Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts	SIGNOR-268290	0.2
AKT2	protein	P31751	UNIPROT	PPARGC1A	protein	Q9UBK2	UNIPROT	down-regulates activity	phosphorylation	Ser571	RMRSRSRsFSRHRSC	10090									17554339	t		miannu	Here we describe a mechanism by which insulin, through the intermediary protein kinase Akt2/protein kinase B (PKB)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (PGC-1alpha), a global regulator of hepatic metabolism during fasting.  Akt phosphorylates PGC-1α at Ser 570.	SIGNOR-262626	0.355
AP-2 complex	complex	SIGNOR-C245	SIGNOR	EPS15	protein	P42566	UNIPROT	up-regulates activity	binding			10116	BTO:0000142								15496985	t		Giorgia	Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs	SIGNOR-260394	0.654
MAPK3	protein	P27361	UNIPROT	NR3C1	protein	P04150	UNIPROT	down-regulates	phosphorylation	Ser226	IDENCLLsPLAGEDD	-1									9199329	t		lperfetto	Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.	SIGNOR-154409	0.523
PRKCA	protein	P17252	UNIPROT	ANXA2	protein	P07355	UNIPROT	unknown	phosphorylation	Ser26	TPPSAYGsVKAYTNF	9606	BTO:0000452								2946940	t		lperfetto	The protein-tyrosine kinase substrate p36 is also a substrate for protein kinase C in vitro and in vivo. | We present evidence suggesting that protein kinase C mediates phosphorylation of serine 25.	SIGNOR-248892	0.363
NCOR1	protein	O75376	UNIPROT	SNAI2	protein	O43623	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18588516	f	 	miannu	The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor).	SIGNOR-254229	0.362
GNB1	protein	P62873	UNIPROT	GNB/GNG	complex	SIGNOR-C202	SIGNOR	form complex	binding			9606									23994464	t		apalma	Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the Gβγ subunit	SIGNOR-255004	0.938
CAMK2A	protein	Q9UQM7	UNIPROT	CALD1	protein	Q05682	UNIPROT	down-regulates	phosphorylation	Ser656	RAEFLNKsVQKSSGV	9606									2170388	t		gcesareni	Smooth muscle caldesmon was phosphorylated by smooth muscle calmodulin-dependent protein kinase. Ii	SIGNOR-22635	0.2
PTPN12	protein	Q05209	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	dephosphorylation	Tyr1007	VLPQDKEyYKVKEPG	9606	BTO:0003892								11731619	t			PTP-PEST-Containing Lysates from EGF-Treated HC11 Cells Dephosphorylate JAK2 More Efficiently than Lysates from Control Cells|phospho-JAK2-specific rabbit polyclonal antiserum (44-426, BioSource Technologies, Inc., Camarillo, CA) which recognizes Tyr1007/1008 in the activation site 	SIGNOR-248657	0.384
linifanib	chemical	CHEBI:91435	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates activity	chemical inhibition			-1									16648571	t		Gianni	ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families	SIGNOR-262206	0.8
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Ala)	smallmolecule	CHEBI:29170	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269480	0.8
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	MAGEA3	protein	P43357	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0002806								31267705	t		miannu	 The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6	SIGNOR-272265	0.2
TNKS2	protein	Q9H2K2	UNIPROT	TARDBP	protein	Q13148	UNIPROT	up-regulates quantity by stabilization	binding			10116		BTO:0000142							32409565	t		lperfetto	Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation.	SIGNOR-262116	0.2
CDK8	protein	P49336	UNIPROT	CKM complex	complex	SIGNOR-C406	SIGNOR	form complex	binding			9606									23563140	t		miannu	The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation.	SIGNOR-266686	0.898
S100A9	protein	P06702	UNIPROT	Differentiation	phenotype	SIGNOR-PH37	SIGNOR	up-regulates				9606	BTO:0001545								28137827	f		miannu	S100A9 induces differentiation of acute myeloid leukemia cells through TLR4.	SIGNOR-261922	0.7
ERG	protein	P11308	UNIPROT	NKX3-1	protein	Q99801	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									25277175	f		miannu	Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3.	SIGNOR-251556	0.342
CDK2	protein	P24941	UNIPROT	MYBL2	protein	P10244	UNIPROT	up-regulates	phosphorylation	Thr487	SQKVVVTtPLHRDKT	9606			SIGNOR-C83						9840932	t		lperfetto	The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk2	SIGNOR-62361	0.711
CSNK2B	protein	P67870	UNIPROT	IKZF1	protein	Q13422	UNIPROT	down-regulates	phosphorylation	Ser13	GQDMSQVsGKESPPV	9606	BTO:0001271								21750978	t		miannu	We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway	SIGNOR-174844	0.2
MAPK8	protein	P45983	UNIPROT	EIF4ENIF1	protein	Q9NRA8	UNIPROT	up-regulates	phosphorylation	Ser752	PSADRDSsPTTNSKL	9606									22966201	t		llicata	Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress.	SIGNOR-199004	0.329
PLK1	protein	P53350	UNIPROT	BRCA2	protein	P51587	UNIPROT	unknown	phosphorylation	Thr207	TPPTLSStVLIVRNE	9606	BTO:0001938								12815053	t		lperfetto	Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation.	SIGNOR-249221	0.556
ATM	protein	Q13315	UNIPROT	MDM4	protein	O15151	UNIPROT	down-regulates	phosphorylation	Ser342	SKLTHSLsTSDITAI	9606									16943424	t		lperfetto	Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm.	SIGNOR-149292	0.725
oxotremorine M	chemical	CHEBI:38322	ChEBI	CHRM3	protein	P20309	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258655	0.8
POLR2E	protein	P19388	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266167	0.889
RAC1	protein	P63000	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates activity													23290138	f		Simone Vumbaca	This result strongly supports the assertion that Wnt7a and FN stimulate PCP signaling to drive the symmetric expansion of satellite stem cells during regenerative myogenesis.	SIGNOR-255648	0.7
SDC4	protein	P31431	UNIPROT	DVL2	protein	O14641	UNIPROT	up-regulates	binding			9606									23151663	t		gcesareni	Like other wnt co receptors, syndecan 4 directly interacts with dvl during pcp.	SIGNOR-199635	0.26
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2S	protein	Q16763	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271343	0.63
GDNF	protein	P39905	UNIPROT	CLU	protein	P10909	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0002881								15212950	f		miannu	We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 	SIGNOR-252187	0.265
FBXW11	protein	Q9UKB1	UNIPROT	EEF2K	protein	O00418	UNIPROT	down-regulates	ubiquitination			9606							phosphorylation:Ser441;Ser445	ESENSGDsGYPSEKR;SGDSGYPsEKRGELD	22669845	t		gcesareni	Eef2k was degraded by the ubiquitin-proteasome system through the ubiquitin ligase scf(__trcp) (skp1-cul1-f-box protein, __-transducin repeat-containing protein) to enable rapid resumption of translation elongation. This event required autophosphorylation of eef2k on a canonical __trcp-binding domain	SIGNOR-197730	0.446
CREB1	protein	P16220	UNIPROT	GDA	protein	Q9Y2T3	UNIPROT	up-regulates quantity by expression	transcriptional regulation				BTO:0000938	BTO:0000142							21715638	t		lperfetto	In addition, exposure of the neurons to BDNF increased CREB binding to the cypin promoter and, in line with these data, expression of a dominant negative form of CREB blocked BDNF-promoted increases in cypin protein levels and proximal dendrite branches.	SIGNOR-268968	0.2
LAT	protein	O43561	UNIPROT	GRB2	protein	P62993	UNIPROT	up-regulates	binding			9606									23150273	t			Phosphorylated tyrosines 171, 191, and 226 [in LAT] bind to the SH2 domains of the Grb2 family of adaptor proteins and must be present for optimal signalling	SIGNOR-251520	0.797
OXGR1	protein	Q96P68	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257155	0.357
SOX9	protein	P48436	UNIPROT	COL2A1	protein	P02458	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10980415	f		miannu	Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan. 	SIGNOR-251756	0.519
NOTCH3	protein	Q9UM47	UNIPROT	HES1	protein	Q14469	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								21743488	f		gcesareni	We demonstrate that her2 overexpression in this cellular model of dcis drives transcriptional upregulation of multiple components of the notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising notch3, its cleaved intracellular domain and the transcriptional regulator hes1.	SIGNOR-174750	0.596
CSNK2A1	protein	P68400	UNIPROT	MAX	protein	P61244	UNIPROT	down-regulates	phosphorylation	Ser2	sDNDDIEV	9606									8018564	t		gcesareni	Here, we have mapped the nh2-terminal in vivo phosphorylation sites of max to ser2 and ser11[...]	SIGNOR-35772	0.368
MAPK8	protein	P45983	UNIPROT	HSF1	protein	Q00613	UNIPROT	down-regulates activity	phosphorylation	Ser363	DTEGRPPsPPPTSTP	9606	BTO:0000567								10747973	t		miannu	JNK is activated by heat shock and phosphorylates HSF-1 on serine 363. JNK Phosphorylation of HSF-1 Leads to Reduction in Its Transcriptional Activity	SIGNOR-250119	0.512
TFEB	protein	P19484	UNIPROT	FGF21	protein	Q9NSA1	UNIPROT	up-regulates quantity by expression	transcriptional regulation												32978159	f		lperfetto	On the contrary, proteins increasing the most included those degraded by autophagy (e.g., SQSTM1/p62 and GABARAPL2	SIGNOR-276791	0.278
FOXO3	protein	O43524	UNIPROT	TSC22D3	protein	Q99576	UNIPROT	up-regulates activity	transcriptional regulation			10090									15031210	t			We then characterized the human gilz promoter and showed that FoxO3 (Forkhead box class O3) binding to the Forkhead responsive elements identified in the promoter is necessary for induction of gilz expression upon IL-2 withdrawal	SIGNOR-256094	0.406
ACOT4	protein	Q8N9L9	UNIPROT	glutaryl-CoA(5-)	smallmolecule	CHEBI:57378	ChEBI	down-regulates quantity	chemical modification												33148467	t		lperfetto	The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 	SIGNOR-271818	0.8
PTGER1	protein	P34995	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates	binding			9606	BTO:0000586								17251915	t		gcesareni	Ep1 is a galfaq-coupled receptor that promotes calcium mobilization and pkc activation, whereas ep2 and ep4, which have a more prominent role in colon cancer, are coupled to galfas and stimulate camp accumulation	SIGNOR-152802	0.425
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	PPARA	protein	Q07869	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000599								10187842	t	inferred from 70% family members	lperfetto	We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution.	SIGNOR-270079	0.2
TSPAN12	protein	O95859	UNIPROT	NDP	protein	Q00604	UNIPROT	up-regulates				9606									19837033	f	Genetic Interaction	gcesareni	Tspan12 genetically interacts with norrin or lrp5	SIGNOR-188661	0.579
MAPK3	protein	P27361	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates quantity by destabilization	phosphorylation	Ser425	TKGSGLGsPTSSFNS	9606									19282669	t		lperfetto	Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway	SIGNOR-252963	0.583
CHIR-124	chemical	CID:11502647	PUBCHEM	FLT3	protein	P36888	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190976	0.8
DRD4	protein	P21917	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256703	0.44
MAPK3	protein	P27361	UNIPROT	STMN1	protein	P16949	UNIPROT	down-regulates activity	phosphorylation	Ser38	SVPEFPLsPPKKKDL	9606									9731215	t		lperfetto	Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. 	SIGNOR-249483	0.563
JAK2	protein	O60674	UNIPROT	CCR2	protein	P41597	UNIPROT	up-regulates activity	phosphorylation	Tyr139	ILLTIDRyLAIVHAV	9606									9670957	t			JAK2 phosphorylates CCR2 at the Tyr139 position and promotes JAK2/STAT3 complex association to the receptor. 	SIGNOR-251345	0.601
INCENP	protein	Q9NQS7	UNIPROT	CPC	complex	SIGNOR-C554	SIGNOR	form complex	binding			9606									23175282	t		miannu	It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A).	SIGNOR-275425	0.873
SKP2	protein	Q13309	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0003725								11439327	t		miannu	We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line.	SIGNOR-272575	0.578
CHUK	protein	O15111	UNIPROT	TRAF4	protein	Q9BUZ4	UNIPROT	down-regulates	phosphorylation	Ser426	KPGTWRGsLDESSLG	9606									22547678	t		llicata	Traf4 is atypical within its family because it is the only traf family member to negatively regulate innate immune signaling. Ikk_'s phosphorylation of serine-426 on traf4 was required for this negative regulation.	SIGNOR-197253	0.392
GPER1	protein	Q99527	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates	binding			9606	BTO:0000150								11897506	t		gcesareni	Gpcr-mediated transactivation of egfrs by estrogen provides a previously unappreciated mechanism of cross-talk between estrogen and serum growth factors, and explains prior data reporting the egf-like effects of estrogen	SIGNOR-115988	0.4
PRKAA1	protein	Q13131	UNIPROT	MAPT	protein	P10636	UNIPROT	down-regulates activity	phosphorylation	Ser355	EADLPEPsEKQPAAA	-1									10090741	t		miannu	We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 	SIGNOR-275440	0.2
MAPK1	protein	P28482	UNIPROT	MCL1	protein	Q07820	UNIPROT	up-regulates	phosphorylation	Thr163	TDGSLPStPPPAEEE	9606									18676833	t		gcesareni	We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage.	SIGNOR-179808	0.543
CSNK2A1	protein	P68400	UNIPROT	VTN	protein	P04004	UNIPROT	up-regulates activity	phosphorylation	Thr69	VTRGDVFtMPEDEYT	10090	BTO:0000944								9733784	t		llicata	 Therefore, we expressed Vn in a baculovirus system and show (i) that the CKII phosphorylation of wt-Vn enhances the adhesion of bovine aorta endothelial cells; (ii) that the double mutant T50E/T57E (in which the neutral Thr residues are replaced by the negatively charged Glu residues considered analogs of Thr-P) has a significantly enhanced capacity to promote cell adhesion and to accelerate cell spreading when compared with either wild-type Vn or to the neutral T50A/T57A mutant	SIGNOR-250970	0.333
CDK5	protein	Q00535	UNIPROT	DLC1	protein	Q96QB1	UNIPROT	up-regulates activity	phosphorylation	Ser859	RRENSSDsPKELKRR	9606	BTO:0002181								25452387	t		miannu	The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. 	SIGNOR-276445	0.2
POLR2I	protein	P36954	UNIPROT	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	form complex	binding			9606	BTO:0000567								9852112	t		lperfetto	Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II	SIGNOR-266166	0.846
MAP2K4	protein	P45985	UNIPROT	RXRA	protein	P19793	UNIPROT	down-regulates	phosphorylation	Tyr249	VEPKTETyVEANMGL	9606									10938283	t		miannu	Phosphorylation by mkk4/sek1 had profound effects on the biochemical properties of rxr, inhibiting the expression of genes activated by rxr-retinoic acid receptor complexes. Tyr-249 in the rxr de region was required for the inhibitory effect of mkk4/sek1.	SIGNOR-80619	0.2
PSENEN	protein	Q9NZ42	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates	cleavage			9606									12522139	t		gcesareni	Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex.	SIGNOR-97113	0.958
NFAT5	protein	O94916	UNIPROT	S100A4	protein	P26447	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000815								22266867	t	done	miannu	 As expected, the depletion of NFAT5 decreased the S100A4 and LCN2 mRNA levels (Figure 3a). In addition, chromatin immunoprecipitation (ChIP) assay using NFAT5 antibody indicated that NFAT5 was bound to the S100A4 and LCN2 promoters (Figure 3b, Supplementary Figure S3), as expected (Chen et al., 2009).	SIGNOR-274115	0.491
TIMP3	protein	P35625	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	down-regulates													17326328	f		lperfetto	There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3	SIGNOR-252274	0.7
EGFR	protein	P00533	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	down-regulates activity	phosphorylation	Tyr433	AALDTIQySKHPPPL	9606									31931029	t		miannu	Here we found that EGFR-stimulated phosphorylation of SQSTM1 at tyrosine 433 induces dimerization of its UBA domain, which disturbs the sequestration function of SQSTM1 and causes autophagic flux blocking.	SIGNOR-277500	0.337
8-oxo-7-[(6-sulfo-2-naphthalenyl)hydrazinylidene]-5-quinolinesulfonic acid	chemical	CHEBI:95064	ChEBI	PTPN6	protein	P29350	UNIPROT	down-regulates activity	chemical inhibition			9606									20337577	t			NSC-87877 (1, Fig. (7)) was identified as a Shp2 PTP inhibitor with an IC50 of 0.33 μM [83]. NSC-87877 inhibits Shp1 with the same potency.	SIGNOR-261913	0.8
vorinostat	chemical	CHEBI:45716	ChEBI	HDAC6	protein	Q9UBN7	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257918	0.8
CHEK1	protein	O14757	UNIPROT	RASSF1	protein	Q9NS23	UNIPROT	unknown	phosphorylation	Ser188	PSSKKPPsLQDARRG	9606									24197116	t		llicata	This study reveals that chk1-mediated phosphorylation of rassf1a, at serine 184, plays an important role in cell-cycle regulation	SIGNOR-203144	0.36
RAB32	protein	Q13637	UNIPROT	AP-3 complex	complex	SIGNOR-C247	SIGNOR	up-regulates activity	relocalization			9606									23247405	t		lperfetto	Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes.	SIGNOR-260698	0.291
ROCK1	protein	Q13464	UNIPROT	DES	protein	P17661	UNIPROT	unknown	phosphorylation	Thr77	RASRLGTtRTPSSYG	9606	BTO:0000971								10574968	t		lperfetto	We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin	SIGNOR-249033	0.321
MAPK3	protein	P27361	UNIPROT	UBTF	protein	P17480	UNIPROT	down-regulates	phosphorylation	Thr117	DFPKKPLtPYFRFFM	9606									11741541	t		lperfetto	Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna	SIGNOR-112813	0.56
Host translation inhibitor nsp1	protein	P0C6X7-PRO_0000037309	UNIPROT	IRF3	protein	Q14653	UNIPROT	down-regulates activity				9606									17715225	f		miannu	SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7.	SIGNOR-262503	0.2
FYN	protein	P06241	UNIPROT	MAG	protein	P20916	UNIPROT	up-regulates activity	phosphorylation	Tyr620	LTEELAEyAEIRVK	10090	BTO:0000142								7525550	t			Fyn constitutively binds to MAG in a latent form. Ligand stimulation of L-MAG would result in activation of Fyn kinase and phosphorylation of Tyr-620. Binding and activation of PLC y through this phosphotyrosine residue would contribute to the signaling pathway involved in the regulation of myelination.	SIGNOR-251178	0.436
SRC	protein	P12931	UNIPROT	CAV2	protein	P51636	UNIPROT	down-regulates	phosphorylation	Tyr19	LFMDDDSySHHSGLE	9606									12091389	t		lperfetto	We show that caveolin-2 undergoes src-induced phosphorylation on tyrosine 19. we conclude that the tyrosine phosphorylation of caveolin-2 (tyr(p)(19)) may function as a signal that is recognized by the cellular machinery to induce the dissociation of caveolin-2 from caveolin-1 oligomers	SIGNOR-90225	0.667
HDAC1	protein	Q13547	UNIPROT	GLI1	protein	P08151	UNIPROT	up-regulates activity	deacetylation												20081843	t			Here, we identify a mechanism whereby Hh signalling is regulated, in which acetylation of Gli1 at Lys 518 represents a transcriptional inhibitory switch, while its HDAC1-mediated deacetylation is responsible for transcriptional activation.	SIGNOR-253544	0.577
NSD1	protein	Q96L73	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates	methylation			9606									20080798	t		lperfetto	Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation.	SIGNOR-217388	0.475
SRC	protein	P12931	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates	phosphorylation	Tyr830	PLEEQCEyLSYDASQ	9606									20431062	t		lperfetto	Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk.	SIGNOR-165047	0.491
SPOP	protein	O43791	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	down-regulates quantity by destabilization	binding			9606									24239470	t		miannu	Mutations in SPOP represent the most common point mutations in primary prostate cancer,with recurrent mutations in SPOP in 6% to 15% of multiple independent cohorts. Wild-type SPOP will bind and promote the degradation of SRC-3,whereas prostate cancer–derived SPOP mutants lose this ability,leading to increased androgen signaling in certain model systems.	SIGNOR-251529	0.493
CCL5	protein	P13501	UNIPROT	Metastasis	phenotype	SIGNOR-PH107	SIGNOR	up-regulates				9606	BTO:0000584								38339310	f		miannu	This suggests CCL5 not only remodels the PDAC TME to benefit tumor cells, but can also enhance the tumor cell’s metastatic potential. 	SIGNOR-277729	0.7
SDHC	protein	Q99643	UNIPROT	SDH	complex	SIGNOR-C400	SIGNOR	form complex	binding			9606									16143825	t		miannu	Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively.	SIGNOR-266273	0.953
INTS7	protein	Q9NVH2	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261464	0.781
CSF2RB	protein	P32927	UNIPROT	CSF2RA/CSF2RB	complex	SIGNOR-C212	SIGNOR	form complex	binding			9606	BTO:0000876	BTO:0001103							9680354	t		apalma	The high-affinity GMR is known to be composed of a specific ligand-binding alpha subunit (GMRα) and a common beta subunit (βc), which is also a component of the interleukins-3 (IL-3) and -5 (IL-5) receptors.	SIGNOR-255583	0.864
CHRM1	protein	P11229	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256878	0.326
g-TuRC complex	complex	SIGNOR-C282	SIGNOR	TUBG1	protein	P23258	UNIPROT	up-regulates activity	binding			-1									31862189	t		lperfetto	Despite its asymmetric architecture, the γ-TuRC arranges γ-tubulins into a helical geometry poised to nucleate microtubules.	SIGNOR-262325	0.864
chloroquine	chemical	CHEBI:3638	ChEBI	ACE2	protein	Q9BYF1	UNIPROT	down-regulates activity	chemical inhibition			9534									32020029	t		miannu	Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells	SIGNOR-260223	0.8
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	FOXM1	protein	Q08050	UNIPROT	up-regulates	phosphorylation	Ser251	MIQFAINsTERKRMT	9606									19737929	t		lperfetto	A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1the phosphorylation at ser-251 is critical for the activation of foxm1.	SIGNOR-216833	0.753
MLL1 complex	complex	SIGNOR-C89	SIGNOR	H3-3A	protein	P84243	UNIPROT	down-regulates activity	methylation	Lys5	kQTARKST	9606									24680668	t		miannu	Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation.	SIGNOR-268802	0.2
SP1	protein	P08047	UNIPROT	ADAM10	protein	O14672	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								21854868	f		miannu	Doxorubixin-evoked β-TrCP up-regulation promoted Sp1 degradation, which subsequently suppressed ADAM10 expression in MCF-7 and MCF-7/Dox cells. 	SIGNOR-255192	0.2
hexestrol	chemical	CHEBI:31669	ChEBI	AKR1C1	protein	Q04828	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-193230	0.8
WNK2	protein	Q9Y3S1	UNIPROT	WNK1	protein	Q9H4A3	UNIPROT	up-regulates activity	phosphorylation	Ser382	KRASFAKsVIGTPEF	9606									22032326	t		Manara	 WNK1, which is activated in response to osmotic stress by phosphorylation of its T-loop residue (Ser382). | We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro.	SIGNOR-260790	0.56
AKT1	protein	P31749	UNIPROT	FOXO3	protein	O43524	UNIPROT	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLQRPE	9606									19188143	t		lperfetto	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252524	0.908
PRKCA	protein	P17252	UNIPROT	CD5	protein	P06127	UNIPROT	up-regulates	phosphorylation	Thr436	FHRNHTAtVRSHAEN	9606									11123317	t		amattioni	Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation.	SIGNOR-85179	0.345
TP53	protein	P04637	UNIPROT	ANKRD11	protein	Q6UB99	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								18840648	t		miannu	Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53.	SIGNOR-266735	0.314
TRAF2	protein	Q12933	UNIPROT	BIRC3	protein	Q13489	UNIPROT	up-regulates	binding			9606									18997794	t		gcesareni	A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution.	SIGNOR-182137	0.888
SCF-betaTRCP	complex	SIGNOR-C5	SIGNOR	IKBKB	protein	O14920	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001321								20068069	t		miannu	CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation.	SIGNOR-271431	0.559
TRAF2	protein	Q12933	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	ubiquitination	Lys377	NEPSLQSkLQDEANY	9606									18621737	t		lperfetto	Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2.	SIGNOR-179456	0.891
AMPK	complex	SIGNOR-C15	SIGNOR	HDAC5	protein	Q9UQL6	UNIPROT	down-regulates	phosphorylation	Ser498	RPLSRTQsSPLPQSP	9606									21892142	t		lperfetto	Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)	SIGNOR-216550	0.316
PTPRA	protein	P18433	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates activity	dephosphorylation	Tyr530	FTSTEPQyQPGENL	9606									17974954	t			Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B	SIGNOR-248437	0.733
PIK-294	chemical	CID:24905149	PUBCHEM	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206202	0.8
KIRREL3	protein	Q8IZU9	UNIPROT	Synaptic_plasticity	phenotype	SIGNOR-PH158	SIGNOR	up-regulates				9606		BTO:0000142							32503885	f		miannu	We demonstrate that ectopic Kirrel3 expression in CA1 neurons specifically induces ectopic DG synapse formation, providing direct evidence that Kirrel3 plays an instructive role in synapse development. 	SIGNOR-269077	0.7
CDK1	protein	P06493	UNIPROT	NEDD1	protein	Q8NHV4	UNIPROT	up-regulates activity	phosphorylation	Thr550	PPINGSStPNPKIAS	9606	BTO:0000567								19509060	t		lperfetto	Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation.	SIGNOR-272973	0.568
Amyloid_fibril_formation	phenotype	SIGNOR-PH59	SIGNOR	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates													26721223	f			Excessive accumulation of Aβ protein in the AD brain may lead to a decrease in the levels of phosphatidylinositol-3 kinase (PI3K) and the serine/threonine protein kinase B (Akt) activity. 	SIGNOR-255492	0.7
PRKACA	protein	P17612	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	phosphorylation	Ser276	SMQLRRPsDRELSEP	9606				SIGNOR-C13					9660950	t		llicata	The transcriptional activity of nf-kappa b is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase a (pka).	SIGNOR-58972	0.494
AR	protein	P10275	UNIPROT	CDKN1A	protein	P38936	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001321								16281084	f	 	 	 After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes.	SIGNOR-253675	0.364
ELOC	protein	Q15369	UNIPROT	BAF250b E3 ligase	complex	SIGNOR-C522	SIGNOR	form complex	binding			9606	BTO:0000567								20086098	t		miannu	In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro	SIGNOR-271438	0.2
GGCX	protein	P38435	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116									31539109	f		miannu	GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05).	SIGNOR-261230	0.304
CLK1	protein	P49759	UNIPROT	RBM17	protein	Q96I25	UNIPROT	up-regulates activity	phosphorylation	Ser204	DSRPRSQsSKAAIPP	9534	BTO:0001538								23519612	t		miannu	 In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 	SIGNOR-262706	0.324
bisindolylmaleimide i	chemical	CID:2396	PUBCHEM	PRKCE	protein	Q02156	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	CellSignaling	gcesareni		SIGNOR-190353	0.8
MAPK1	protein	P28482	UNIPROT	AHNAK	protein	Q09666	UNIPROT	unknown	phosphorylation	Ser216	PSGSGAAsPTGSAVD	10090	BTO:0000944								22028470	t		miannu	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1)	SIGNOR-262762	0.259
CTDSP1	protein	Q9GZU7	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1672	SPTSPSYsPTSPSYS	-1									22137580	t			Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 	SIGNOR-248784	0.441
thalidomide	chemical	CHEBI:9513	ChEBI	CRBN	protein	Q96SW2	UNIPROT	down-regulates activity	chemical inhibition			9606									20223979	t		miannu	 Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. 	SIGNOR-272207	0.8
PRKACA	protein	P17612	UNIPROT	POLD3	protein	Q15054	UNIPROT	down-regulates	phosphorylation	Ser458	GKANRQVsITGFFQR	9606									22148433	t		llicata	In this study, we identified s458, located in the pcna-interacting protein (pip-box) motif of p68, as a phosphorylation site for pka. Phosphomimetic mutation of s458 resulted in a decrease in p68 affinity for pcna as well as the processivity of pol _.	SIGNOR-195203	0.2
GUCY1B1	protein	Q02153	UNIPROT	GUCY1A2-B3	complex	SIGNOR-C138	SIGNOR	form complex	binding			9606									10977868	t		gcesareni	This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity	SIGNOR-243980	0.2
SP1	protein	P08047	UNIPROT	GFER	protein	P55789	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								18513187	f		miannu	 We also confirmed that activation and repression of hHSS transcription induced by Sp1 and HNF4alpha resulted from binding of these factors to these two cis-elements respectively. Overexpression of HNF4alpha led to a dramatic repression of the promoter activity and, in contrast, the activity was markedly elevated by overexpression of Sp1. 	SIGNOR-254450	0.2
E2F1	protein	Q01094	UNIPROT	RASGRP1	protein	O95267	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18396012	f		miannu	 We demonstrate that E2F1 induces ERK activation via a transcriptional mechanism and upregulates the expression of two guanine nucleotide exchange factors, RASGRP1 and RASGEF1B, which promote Ras activation. 	SIGNOR-253850	0.2
TP53	protein	P04637	UNIPROT	MGMT	protein	P16455	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000711								17564708	f		miannu	 we observed that IFN-beta sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via induction of TP53. In this context, IFN-beta inactivates MGMT via p53 gene induction and enhances the therapeutic efficacy to TMZ.	SIGNOR-255437	0.489
MMP7	protein	P09237	UNIPROT	HAPLN1	protein	P10915	UNIPROT	down-regulates quantity by destabilization	cleavage	Leu40	QAENGPHlLVEAEQA	-1									7694569	t		miannu	Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.	SIGNOR-256329	0.327
serotonin(1+)	smallmolecule	CHEBI:350546	ChEBI	HTR1B	protein	P28222	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257517	0.8
EIF4E2/GIGYF1 complex	complex	SIGNOR-C256	SIGNOR	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	down-regulates				9606									30917308	f		lperfetto	4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression	SIGNOR-261012	0.7
PRKCB	protein	P05771	UNIPROT	NOX1	protein	Q9Y5S8	UNIPROT	up-regulates activity	phosphorylation	Thr430	CADHNLKtKKIYFYW	-1									25228390	t		lperfetto	Site-directed mutagenesis and isothermal titration calorimetry indicated that protein kinase C-beta1 phosphorylates Nox1 at threonine 429. Moreover, Nox1 threonine 429 phosphorylation facilitated the association of Nox1 with the NoxA1 activation domain and was necessary for NADPH oxidase complex assembly	SIGNOR-264729	0.2
KCNE3	protein	Q9Y6H6	UNIPROT	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	down-regulates quantity	relocalization			9606									11506885	t		miannu	Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height	SIGNOR-265589	0.8
ATM	protein	Q13315	UNIPROT	BRCA1	protein	P38398	UNIPROT	unknown	phosphorylation	Ser1524	LQNRNYPsQEELIKV	9606	BTO:0000150								10550055	t		lperfetto	The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Atm resides in a complex with brca1 and phosphorylated brca1 in vivo and in vitro in a region that contains clusters of serine-glutamine residues. Phosphorylation of this domain appears to be functionally important because a mutated brca1 protein lacking two phosphorylation sites failed to rescue the radiation hypersensitivity of a brca1-deficient cell line.Atm-dependent phosphorylation of ser1423 or ser1524 also occurred in vivo,	SIGNOR-72079	0.813
FOXP1	protein	Q9H334	UNIPROT	CSF1R	protein	P07333	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000738								15286807	t		Gianni	Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation.	SIGNOR-269048	0.301
NOTCH1	protein	P46531	UNIPROT	HEY1	protein	Q9Y5J3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11486044	t		lperfetto	These data establish that HERP2 is a novel primary target gene of Notch that, together with HES, may effect diverse biological activities of Notch	SIGNOR-235397	0.766
PPM1A	protein	P35813	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	dephosphorylation	Ser57	KKDRFYRsILPGDKT	10116									18586681	t			Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation.	SIGNOR-248493	0.342
TP53	protein	P04637	UNIPROT	RLIM	protein	Q9NVW2	UNIPROT	down-regulates quantity by repression	transcriptional regulation												23650532	f		lperfetto	In the present study, we identified RLIM as a novel target of p53 and demonstrated that p53 repressed both mRNA and protein levels of RLIM.	SIGNOR-268981	0.2
AKT1	protein	P31749	UNIPROT	USP14	protein	P54578	UNIPROT	up-regulates activity	phosphorylation	Ser432	THQGRSSsSGHYVSW	9606									26523394	t		lperfetto	Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt.	SIGNOR-265056	0.436
ABL1	protein	P00519	UNIPROT	CKMT1A	protein	P12532	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr153	ASKIRSGyFDERYVL	9606	BTO:0001932								30174304	t		miannu	Here, we show that oncogenic HER2 tyrosine kinase signaling induces phosphorylation of mitochondrial creatine kinase 1 (MtCK1) on tyrosine 153 (Y153) in an ABL-dependent manner in breast cancer cells. Y153 phosphorylation, which is commonly upregulated in HER2+ breast cancers, stabilizes MtCK1 to increase the phosphocreatine energy shuttle and promote proliferation. 	SIGNOR-277406	0.2
GATA6	protein	Q92908	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression				9606	BTO:0000195								24317510	f		lperfetto	Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. 	SIGNOR-253152	0.376
SMC5/6 	complex	SIGNOR-C374	SIGNOR	Chromosome_segregation	phenotype	SIGNOR-PH44	SIGNOR	up-regulates				9606									27427983	f		miannu	The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks	SIGNOR-265488	0.7
CUDC-101	chemical	CID:24756910	PUBCHEM	EGFR	protein	P00533	UNIPROT	down-regulates activity	chemical inhibition			-1									20143778	t		miannu	By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively.	SIGNOR-262254	0.8
WNT3A	protein	P56704	UNIPROT	ALPL	protein	P05186	UNIPROT	up-regulates				9606									19175684	f		gcesareni	Wnt3a and bmp-9 enhanced each other's ability to induce alp in mscs.	SIGNOR-183538	0.348
PPAT	protein	Q06203	UNIPROT	5-phospho-α-D-ribose 1-diphosphate	smallmolecule	CHEBI:58017	ChEBI	down-regulates quantity	chemical modification			9606									9914248	t		miannu	Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine.	SIGNOR-267293	0.8
ESR2	protein	Q92731	UNIPROT	TFF1	protein	P04155	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000356								11517191	f	 	 	ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression	SIGNOR-253939	0.359
SRC	protein	P12931	UNIPROT	HRAS	protein	P01112	UNIPROT	down-regulates activity	phosphorylation	Tyr32	QNHFVDEyDPTIEDS	9606	BTO:0000007								25157176	t			Src binds to and phosphorylates GTP-, but not GDP-, loaded Ras on a conserved Y32 residue within the switch I region in vitro and that in vivo, Ras-Y32 phosphorylation markedly reduces the binding to effector Raf and concomitantly increases binding to GTPase-activating proteins and the rate of GTP hydrolysis	SIGNOR-252093	0.767
TGFB1	protein	P01137	UNIPROT	SFTPB	protein	P07988	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004299								18003659	f		miannu	TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. 	SIGNOR-254170	0.286
SYK	protein	P43405	UNIPROT	IL15RA	protein	Q13261	UNIPROT	up-regulates activity	phosphorylation	Tyr227	AVSLLACyLKSRQTP	9606	BTO:0001154								11714793	t		lperfetto	Mutation of a defined region of the intracellular signaling portion of IL-15Ralpha (Tyr227) abrogates both the IL-15Ralpha/Syk association and IL-15Ralpha phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Ralpha chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells	SIGNOR-246556	0.334
PRKCG	protein	P05129	UNIPROT	CHAT	protein	P28329	UNIPROT	up-regulates	phosphorylation	Ser594	HKAAVPAsEKLLLLK	9606	BTO:0000938								15381704	t	The effect has been demonstrated using P28329-3	gcesareni	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-129328	0.326
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SOS1	protein	Q07889	UNIPROT	down-regulates activity	phosphorylation	Ser1197	KAYSPRYsISDRTSI	9534	BTO:0004055								8816480	t		lperfetto	In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1	SIGNOR-244588	0.2
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	GRB2	protein	P62993	UNIPROT	up-regulates activity	binding			9606	BTO:0002181								11726515	t		irozzo	However, direct binding of Grb2 to Bcr/Abl also facilitates its tyrosine phosphorylation, which we propose reflects activation of a physiological negative regulatory mechanism by this oncogenic tyrosine kinase.Direct binding of Grb2 to Bcr/Abl facilitates Grb2 phosphorylation.	SIGNOR-255820	0.2
EGFR	protein	P00533	UNIPROT	SHC3	protein	Q92529	UNIPROT	up-regulates	binding			9606	BTO:0000938	BTO:0000142							24212772	t	GRB2 recruit indirectly through PTB domain-mediated binding of the Shc adaptor	gcesareni	Several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc).	SIGNOR-55861	0.604
SKP2	protein	Q13309	UNIPROT	CDKN1B	protein	P46527	UNIPROT	down-regulates	ubiquitination			9606									15998794	t		gcesareni	Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3).	SIGNOR-138493	0.758
lapatinib	chemical	CHEBI:49603	ChEBI	RET	protein	P07949	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0001949								21443688	t		Luana	YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ.	SIGNOR-257899	0.8
IKK-complex	complex	SIGNOR-C14	SIGNOR	IKBKG	protein	Q9Y6K9	UNIPROT	unknown	phosphorylation	Ser376	PPAPAYLsSPLALPS	9606				SIGNOR-C14					12657630	t		lperfetto	Phosphopeptide-mapping experiments with metabolically radiolabeled cells indicate that ikkbeta phosphorylates human ikkgamma at ser-31, ser-43, and ser-376	SIGNOR-209792	0.928
PRKCZ	protein	Q05513	UNIPROT	MAP1LC3B	protein	Q9GZQ8	UNIPROT	down-regulates activity	phosphorylation	Thr50	QLPVLDKtKFLVPDH	-1									31857374	t	done	miannu	LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1).	SIGNOR-273906	0.2
MLL2 complex	complex	SIGNOR-C88	SIGNOR	CBP/p300	complex	SIGNOR-C6	SIGNOR	up-regulates activity	binding			9606									28669924	t		miannu	KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex. It acts as a scaffold protein within the complex and is responsible for maintaining the stability of UTX. KMT2D is a major mammalian H3K4 mono-methyltransferase and co-localizes with lineage determining transcription factors on transcriptional enhancers. It is required for the binding of histone H3K27 acetyltransferases CBP and p300 on enhancers, enhancer activation and cell-type specific gene expression during differentiation. 	SIGNOR-268814	0.2
RPL41	protein	P62945	UNIPROT	60S cytosolic large ribosomal subunit	complex	SIGNOR-C287	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262458	0.2
FOXO1	protein	Q12778	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				10090									18423396	f		fspada	Akt1/Pkb-alpha was found to be the major regulator of phosphorylation and nuclear export of Foxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation.	SIGNOR-178281	0.7
PIAS3	protein	Q9Y6X2	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates	binding			9606				SIGNOR-C9					14691252	t		gcesareni	Taken together, our studies indicate that on tgf-beta treatment, pias3 can form a complex with smads and p300/cbp and activate smad transcriptional activity.	SIGNOR-120359	0.58
FASN	protein	P49327	UNIPROT	Fatty_Acid_Biosynthesis	phenotype	SIGNOR-PH190	SIGNOR	up-regulates				9606									9356448	f		miannu	Our model of the native fatty acid synthase (FAS) depicts it as a dimer of two identical multifunctional proteins (Mr approximately 272,000) arranged in an antiparallel configuration so that the active Cys-SH of the beta-ketoacyl synthase of one subunit (where the acyl group is attached) is juxtaposed within 2 A of the pantetheinyl-SH of the second subunit (where the malonyl group is bound). This arrangement generates two active centers for fatty acid synthesis and predicts that if we have two appropriate halves of the monomer, we should be able to reconstitute an active fatty acid-synthesizing site	SIGNOR-270536	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ZFP36L1	protein	Q07352	UNIPROT	down-regulates	phosphorylation	Ser92	RFRDRSFsEGGERLL	9606									15538381	t		lperfetto	Here we report that protein kinase b (pkb/akt) stabilizes are transcripts by phosphorylating brf1 at serine 92 (s92). Recombinant brf1 promoted in vitro decay of are-containing mrna (are-mrna), yet phosphorylation by pkb impaired this activity.	SIGNOR-244385	0.2
GLI1	protein	P08151	UNIPROT	PTCH1	protein	Q13635	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150;BTO:0000551								19860666	f		gcesareni	Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin	SIGNOR-188875	0.708
HLA-DRB1	protein	P01911	UNIPROT	Membrane_fusion	phenotype	SIGNOR-PH122	SIGNOR	up-regulates				9606	BTO:0000776								21178476	f		scontino	Fusion with a B cell requires a ternary complex of gHgLgp42. Fusion is triggered by an interaction between gp42 and HLA class II.	SIGNOR-266631	0.7
EEA1	protein	Q15075	UNIPROT	Early Endosome	complex	SIGNOR-C246	SIGNOR	form complex	binding			9606									19924646	t		lperfetto	Early endosomal antigen-1 (EEA1) is a well-characterized effector of Rab5 and one of the most widely used markers for EE due to its specific localization to this compartment. EEA1, in coordination with members of the SNARE family, is essential for EE fusion in vivo	SIGNOR-260623	0.536
MAML1	protein	Q92585	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates	binding			9606		BTO:0000887							17875709	t		gcesareni	Unexpectedly, however, emerging evidence implicate maml proteins as exciting key transcriptional co-activators in other signal transduction pathways including: muscle differentiation and myopathies (mef2c), tumor suppressor pathway (p53) and colon carcinoma survival (beta-catenin).	SIGNOR-157843	0.28
STK11	protein	Q15831	UNIPROT	STK11	protein	Q15831	UNIPROT	up-regulates activity	phosphorylation	Thr363	IEDDIIYtQDFTVPG	9606	BTO:0000007;BTO:0000567								12805220	t		lperfetto	It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity.	SIGNOR-101848	0.2
MAP2K4	protein	P45985	UNIPROT	MAPK13	protein	O15264	UNIPROT	up-regulates activity	phosphorylation	Thr180	RHADAEMtGYVVTRW	9606	BTO:0000007								10066767	t	done	miannu	 p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.	SIGNOR-273956	0.436
CDK2	protein	P24941	UNIPROT	TFCP2	protein	Q12800	UNIPROT	down-regulates	phosphorylation	Ser309	SLGEGNGsPNHQPEP	9606			SIGNOR-C16						19237534	t		lperfetto	In vitro, lsf is phosphorylated by cyclin e/cyclin-dependent kinase 2 (cdk2), cyclin c/cdk2, and cyclin c/cdk3, predominantly on s309. Phosphorylation by cyclin c/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of lsf during g1 progression	SIGNOR-184160	0.2
LARP4B	protein	Q92615	UNIPROT	PABPC1	protein	P11940	UNIPROT	up-regulates activity	binding			9606									20573744	t		miannu	Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex.	SIGNOR-260940	0.571
1-(4,4-diphenylbut-3-enyl)-3-piperidinecarboxylic acid	chemical	CHEBI:91734	ChEBI	SLC6A1	protein	P30531	UNIPROT	down-regulates activity	chemical inhibition			-1									7851497	t		miannu	Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. 	SIGNOR-258478	0.8
CSNK2A1	protein	P68400	UNIPROT	PIK3R1	protein	P27986	UNIPROT	up-regulates activity	phosphorylation	Ser608	ENTEDQYsLVEDDED	-1									14729945	t		miannu	Protein kinase CK2 phosphorylates p85α on Ser608 when p85α is free but not when it is complexed with p110α. 	SIGNOR-276005	0.248
ROCK1	protein	Q13464	UNIPROT	PPP1R12B	protein	O60237	UNIPROT	down-regulates	phosphorylation	Thr646	ARQTRRStQGVTLTD	9606									22937917	t		lperfetto	Phosphorylation of ppp1r12b on threonine 646 by rho kinase inhibits the activity of the pp1c-ppp1r12b complex.	SIGNOR-198812	0.569
NKX2-5	protein	P52952	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0003265								19479054	f	 	 	Using antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5.	SIGNOR-253653	0.353
tRNA(Ala)	smallmolecule	CHEBI:29170	ChEBI	Ala-tRNA(Ala)	smallmolecule	CHEBI:17732	ChEBI	up-regulates quantity	precursor of			9606									32314272	t		miannu	Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N).	SIGNOR-270451	0.8
MAPK1	protein	P28482	UNIPROT	TPPP	protein	O94811	UNIPROT	down-regulates activity	phosphorylation	Ser18	ANRTPPKsPGDPSKD	-1									17693641	t		miannu	 Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP.	SIGNOR-262929	0.363
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257981	0.8
KDM4C	protein	Q9H3R0	UNIPROT	H2AC4	protein	P04908	UNIPROT	down-regulates activity	demethylation	Lys 37	RVHRLLRkGNYSERV	9606									29207681	t		miannu	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 	SIGNOR-263862	0.2
axitinib	chemical	CHEBI:66910	ChEBI	FLT4	protein	P35916	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150								21297102	t		gcesareni	Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (rcc) after failure of prior treatment with sunitinib or a cytokine.	SIGNOR-171860	0.8
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PIK3CG	protein	P48736	UNIPROT	down-regulates activity	phosphorylation	Thr1024	YLALRHHtNLLIILF	9606	BTO:0002181								21474070	t		miannu	Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110γ to inhibit PIP(3) production. 	SIGNOR-276321	0.2
FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	FASLG	protein	P48023	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10102273	f		gcesareni	Within the nucleus, fkhrl1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the fas ligand gene.	SIGNOR-252942	0.2
GDF11	protein	O95390	UNIPROT	ACTR2	protein	P61160	UNIPROT	up-regulates	binding			9606									16446785	t		gcesareni	Here we demonstrate using genetic and biochemical studies that actriib and its subfamily receptor, actriia, cooperatively mediate the gdf11 signal in patterning the axial vertebrae, and that gdf11 binds to both actriia and actriib, and induces phosphorylation of smad2.	SIGNOR-144147	0.2
palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	precursor of			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267882	0.8
MZF1	protein	P28698	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16297876	f		irozzo	We demonstrated that both Elk-1 and MZF-1 were highly expressed in human poor differentiated HCC cells and involved in the up-regulation of PKCa, which was essential for cell migration and invasion. Over-expression assay confirmed that the PKCa expression may be modulated by these two factors at the transcriptional level.	SIGNOR-256283	0.394
MAVS	protein	Q7Z434	UNIPROT	IFNB1	protein	P01574	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22588174	f		Giorgia	ECSIT enhances IPS-1-mediated IFN-Beta promoter activation	SIGNOR-260372	0.504
PRKDC	protein	P78527	UNIPROT	WRN	protein	Q14191	UNIPROT	up-regulates	phosphorylation	Ser440	DTSYVIEsDEDLEME	9606	BTO:0000007								24429382	t		llicata	Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair.	SIGNOR-203737	0.662
BBS9	protein	Q3SYG4	UNIPROT	BBsome complex	complex	SIGNOR-C288	SIGNOR	form complex	binding			9606	BTO:0004910								19081074	t		lperfetto	We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 	SIGNOR-262555	0.786
8-hydroxy-5-[1-hydroxy-2-(propan-2-ylamino)butyl]-1H-quinolin-2-one	chemical	CHEBI:91585	ChEBI	ADRB2	protein	P07550	UNIPROT	up-regulates activity	chemical activation			10030									20590599	t		Luana	Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy. 	SIGNOR-257857	0.8
ATM	protein	Q13315	UNIPROT	RIF1	protein	Q5UIP0	UNIPROT	up-regulates activity	binding			9606									15342490	t		miannu	Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. After induction of double-strand breaks (DSBs), Rif1 formed foci that colocalized with other DNA-damage-response factors. This response was strictly dependent on ATM (ataxia telangiectasia mutated) and 53BP1, but not affected by diminished function of ATR (ATM- and Rad3-related kinase), BRCA1, Chk2, Nbs1, and Mre11. 	SIGNOR-259059	0.476
AKT2	protein	P31751	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser166	SSRRRAIsETEENSD	9606									11504915	t		lperfetto	Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.. Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186.	SIGNOR-109732	0.542
ATM	protein	Q13315	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Ser498	QIVMAPSsQSQPSGS	9606									15916964	t		lperfetto	Here, we demonstrate that the protein kinase atm phosphorylates atf2 on serines 490 and 498 following ionizing radiation (ir). dose- and time-dependent phosphorylation of atf2 by atm that results in its rapid colocalization with gamma-h2ax and mrn components into ir-induced foci (irif)	SIGNOR-137623	0.584
PIK3CA	protein	P42336	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity				9606									11160134	f		lperfetto	Ly294002 or wortmannin were used to determine whether pi 3-kinasedependent pathways mediate ser307 phosphorylation during insulin/igf-1 or TNF-alpha Stimulation. As expected, the pi-3 kinase inhibitors ly294002 or wortmannin inhibited activation of pkb/akt in insulin or igf-1 stimulated 3t3-l1 preadipocytes, but were without effect on erk1/2. these results suggest that elements of the pi 3-kinase cascade mediate insulin/igf-1stimulated phosphorylation of ser307	SIGNOR-104911	0.711
MARK1	protein	Q9P0L2	UNIPROT	MAP2	protein	P11137	UNIPROT	down-regulates activity	phosphorylation	Ser1799	RRLSNVSsSGSINLL	-1									8631898	t		miannu	Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 	SIGNOR-250167	0.428
TBX5	protein	Q99593	UNIPROT	NPPA	protein	P01160	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000562								18451335	f	 	miannu	 TBX5 is expressed, among others, in the embryonic heart and forelimbs.8 In the heart, it regulates transcription of downstream genes such as the atrial natriuretic factor (NPPA) and fibroblast growth factor 10 (FGF10) by the binding to T-box binding elements (TBEs),11 often in combination with the NKX2-5 transcription factor.	SIGNOR-255384	0.575
MCM7	protein	P33993	UNIPROT	MCM	complex	SIGNOR-C268	SIGNOR	form complex	binding			9606									19946136	t			The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication.	SIGNOR-261677	0.759
MEF2D	protein	Q14814	UNIPROT	DES	protein	P17661	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000222								25653159	t		lperfetto	Ectopic expression of myogenin and a specific Mef2 isoform induced myogenic differentiation without activating endogenous MyoD expression. Under these conditions, the regulatory sequences of late gene loci were not in close proximity, and these genes were prematurely activated.	SIGNOR-241504	0.2
ATM	protein	Q13315	UNIPROT	RAD50	protein	Q92878	UNIPROT	unknown	phosphorylation	Ser635	KLFDVCGsQDFESDL	9606									17570479	t		llicata	The ms/ms fragmentation spectra (figure s7) confirmed the phosphorylation of rad50 at the predicted atm substrate site, s635, in agreement with published data	SIGNOR-156077	0.806
PRKD1	protein	Q15139	UNIPROT	PI4KB	protein	Q9UBF8	UNIPROT	up-regulates	phosphorylation	Ser294	SNLKRTAsNPKVENE	9606									16912074	t	The effect has been demonstrated using Q9UBF8-2	gcesareni	Binding of 14-3-3 proteins to pi4kiiibeta involved the pkd phosphorylation site ser294, evident from reduced 14-3-3 binding to a s294a pi4kiiibeta mutant. Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase iii beta protects from dephosphorylation and stabilizes lipid kinase activity.	SIGNOR-148876	0.416
CREB1	protein	P16220	UNIPROT	SLC5A5	protein	Q92911	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001379							34751390	t		scontino	CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription.	SIGNOR-267137	0.271
EP300	protein	Q09472	UNIPROT	DUSP1	protein	P28562	UNIPROT	up-regulates	acetylation	Lys57	TIVRRRAkGAMGLEH	9606	BTO:0000801								20626350	t		gcesareni	A recent report shows that mkp1 may also be regulated by acetylation. When raw macrophages are stimulated with lps, mkp1 becomes acetylated on lys57 by p300	SIGNOR-166581	0.315
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	CFLAR	protein	O15519	UNIPROT	down-regulates quantity	phosphorylation	Ser273	LLRDTFTsLGYEVQK	9606									19339247	t		gcesareni	TNFalpha enhanced FLIP(L) serine phosphorylation, which was increased by activated Akt-1. Serine 273, a putative Akt-1 phosphorylation site in FLIP(L), was critical for the activation-induced reduction of FLIP(L). Thus, these observations document a novel mechanism where by TNFalpha facilitates the reduction of FLIP(L) protein, which is dependent on the phosphatidylinositol 3-kinase/Akt signaling.	SIGNOR-245304	0.2
80S_cytosolic_ribosome	complex	SIGNOR-C455	SIGNOR	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	up-regulates				9606									35489072	t		lperfetto	In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 	SIGNOR-269173	0.7
ERBB2	protein	P04626	UNIPROT	BBC3	protein	Q9BXH1	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Tyr58	PTLLPAAyLCAPTAP	9606	BTO:0000093								24236056	t		miannu	HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. 	SIGNOR-276473	0.286
GNGT1	protein	P63211	UNIPROT	PIK3CA	protein	P42336	UNIPROT	up-regulates	binding			9606									16537363	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt	SIGNOR-145128	0.408
buspirone	chemical	CHEBI:3223	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258837	0.8
NLRP3 inflammasome	complex	SIGNOR-C225	SIGNOR	Caspase 1 complex	complex	SIGNOR-C220	SIGNOR	up-regulates activity	cleavage												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256381	0.2
PPP2CB	protein	P62714	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	down-regulates activity	dephosphorylation	Ser474	HFPQFSYsASGRE	9606									18160256	t			Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248609	0.472
SIRT6	protein	Q8N6T7	UNIPROT	CLOCK/BMAL1	complex	SIGNOR-C195	SIGNOR	up-regulates activity	binding			9606	BTO:0000007								25083875	t		miannu	SIRT6 is involved in circadian control of gene expression and metabolism. SIRT6 Interacts with CLOCK:BMAL1 and Controls Their Chromatin Recruitment. SIRT6 physically interacts with CLOCK and BMAL1, individually or together, as shown by coimmunoprecipitation (co-IP) (Figures 4A and 4B). SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1.	SIGNOR-268157	0.377
MCU	protein	Q8NE86	UNIPROT	MCU_MICUB_variant	complex	SIGNOR-C499	SIGNOR	form complex	binding			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270862	0.696
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	BAG3	protein	O95817	UNIPROT	up-regulates activity	phosphorylation	Ser289	RSSTPLHsPSPIRVH	9606	BTO:0000016								27659916	t		miannu	ERK-dependent phosphorylation of BIS following H2O2 treatment.	SIGNOR-274070	0.2
DDX5	protein	P17844	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates	binding			9606									18829551	t		miannu	P68 is a nuclear protein and interacts with ar / p68 co-occupies the active psa promoter at are regions and enhances ar transcriptional activity	SIGNOR-181456	0.326
FLT4	protein	P35916	UNIPROT	GLO1	protein	Q04760	UNIPROT	up-regulates activity	phosphorylation	Tyr136	GIAVPDVySACKRFE	-1									34838714	t		miannu	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276180	0.2
Cullin4-RBX1-DDB1	complex	SIGNOR-C119	SIGNOR	CDT1	protein	Q9H211	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606									14578910	t		miannu	We show that radiation-mediated CDT1 proteolysis is independent of ATM and CHK2 and can occur in G1-phase cells. Loss of the COP9-signalosome (CSN) or CUL4-ROC1 complexes completely suppresses CDT1 proteolysis. CDT1 is specifically polyubiquitinated by CUL4 complexes and the interaction between CDT1 and CUL4 is regulated in part by gamma-irradiation. Our study reveals an evolutionarily conserved and uncharacterized G1 checkpoint that induces CDT1 proteolysis by the CUL4-ROC1 ubiquitin E3 ligase and CSN complexes in response to DNA damage.	SIGNOR-272810	0.533
CDK5	protein	Q00535	UNIPROT	AMFR	protein	Q9UKV5	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser516	SIRPALNsPVERPSS	9606	BTO:0000007								28528366	t		miannu	We found that GP78 expression is decreased in MPTP-based cellular and animal PD models, and CDK5 directly phosphorylated GP78 at Ser516, which promoted the ubiquitination and degradation of GP78. 	SIGNOR-277356	0.25
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	precursor of			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-267426	0.8
MAPK3	protein	P27361	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1717	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120200	0.321
PDGFRB	protein	P09619	UNIPROT	ABL2	protein	P42684	UNIPROT	up-regulates activity	phosphorylation	Tyr310	YVGVWKKySLTVAVK	-1									34144039	t		miannu	 PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2.	SIGNOR-277300	0.308
CDK2	protein	P24941	UNIPROT	WEE1	protein	P30291	UNIPROT	down-regulates quantity by destabilization		Ser123	EEGFGSSsPVKSPAA	9606	BTO:0000567								16085715	t		miannu	PS123 primes CK2 to phosphorylate S121, resulting in creation of a β-TrCP phosphodegron (EEGFGpS121) that is responsible for the instability of Wee1A during interphase. 	SIGNOR-276039	0.651
MAPK13	protein	O15264	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser33	LPENNVLsPLPSQAM	9606	BTO:0000093								10581258	t		gcesareni	In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.	SIGNOR-72687	0.443
androst-4-ene-3,17-dione	smallmolecule	CHEBI:16422	ChEBI	estrone	smallmolecule	CHEBI:17263	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000975							27702664	t		lperfetto	The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively	SIGNOR-268668	0.8
SMO	protein	Q99835	UNIPROT	GNG2	protein	P59768	UNIPROT	up-regulates	binding			9606									16885213	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-148595	0.357
MAP3K20	protein	Q9NYL2	UNIPROT	MAP2K4	protein	P45985	UNIPROT	up-regulates activity	phosphorylation			9606									11416147	t		gcesareni	We show here that members of the mixed-lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper kinase [DLK]) are expressed in neuronal cells and are likely to act between Rac1/Cdc42 and MKK4 and -7 in death signaling.	SIGNOR-243348	0.2
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3-4	protein	Q16695	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269630	0.2
PPP2CA	protein	P67775	UNIPROT	EEF2	protein	P13639	UNIPROT	up-regulates	dephosphorylation	Thr57	RAGETRFtDTRKDEQ	9606							phosphorylation:Thr57	RAGETRFtDTRKDEQ 	8386634	t		gcesareni	Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2	SIGNOR-38561	0.413
STAT1	protein	P42224	UNIPROT	IRF2	protein	P14316	UNIPROT	up-regulates activity	binding			9606									15778351	t		miannu	We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested. Interaction of IRF-2 and STAT1 on the promoter depends on the DNA-binding domain of IRF-2. 	SIGNOR-254532	0.564
SRC	protein	P12931	UNIPROT	SOCS1	protein	O15524	UNIPROT	down-regulates activity	phosphorylation	Tyr80	LLDACGFyWGPLSVH	-1									31101761	t		miannu	SOCS1 is phosphorylated on Y80 by SRC family kinase members SRC and YES1. 	SIGNOR-276857	0.463
spiperone	chemical	CHEBI:9233	ChEBI	HTR2B	protein	P41595	UNIPROT	down-regulates activity	chemical inhibition			10036									9459568	t		miannu	The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea-	SIGNOR-258692	0.8
DAB2IP	protein	Q5VWQ8	UNIPROT	ERN1	protein	O75460	UNIPROT	up-regulates activity	binding			9606	BTO:0001176								27858941	t		miannu	DAB2IP binds IRE1α, and was shown to be required for activation of this signaling cascade in endothelial cells. IRE1α can trigger pro-apoptotic JNK signaling through recruitment of the TRAF2–ASK1 complex. DAB2IP facilitates IRE1α activation, and participates in a signaling complex required to induce TRAF2-dependent ASK1 activation and JNK phosphorylation.	SIGNOR-254749	0.376
Nalorphine	chemical	CHEBI:7458	ChEBI	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9262330	t		miannu	We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine.	SIGNOR-258664	0.8
CBP/p300	complex	SIGNOR-C6	SIGNOR	ALOX15	protein	P16050	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000018								12517954	f	 	lperfetto	IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300.	SIGNOR-254100	0.2
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	IDH2	protein	P48735	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr197	GTFKMVFtPKDGSGV										34929314	t		lperfetto	During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome	SIGNOR-267622	0.268
PINK1	protein	Q9BXM7	UNIPROT	PRKN	protein	O60260	UNIPROT	up-regulates	phosphorylation	Ser65	NCDLDQQsIVHIVQR	9606									22724072	t		llicata	We show that human pink1 is specifically activated by mitochondrial membrane potential (??m) depolarization, enabling it to phosphorylate parkin at ser(65). We further show that phosphorylation of parkin at ser(65) leads to marked activation of its e3 ligase activity that is prevented by mutation of ser(65) or inactivation of pink1.	SIGNOR-197976	0.2
NUP62	protein	P37198	UNIPROT	NPC	complex	SIGNOR-C263	SIGNOR	form complex	binding												27016207	t		lperfetto	The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 	SIGNOR-262079	0.697
TRIM59	protein	Q8IWR1	UNIPROT	MACROH2A1	protein	O75367	UNIPROT	down-regulates quantity by destabilization	polyubiquitination												31488827	t		miannu	Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. 	SIGNOR-272931	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	MCL1	protein	Q07820	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr92	EVPDVTAtPARLLFF	9606									18676833	t		gcesareni	Mcl-1 is phosphorylated at two sites in mitosis, ser64 and thr92. Phosphorylation of thr92 by cyclin-dependent kinase 1 (cdk1)-cyclin b1 initiates degradation of mcl-1 in cells arrested in mitosis by microtubule poisons.	SIGNOR-216900	0.431
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	AP1	complex	SIGNOR-C154	SIGNOR	up-regulates	phosphorylation	Thr325	TELEPLCtPVVTCTP	9606									12972619	t		lperfetto	In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity.	SIGNOR-252357	0.784
NBR1	protein	Q14596	UNIPROT	GABARAP	protein	O95166	UNIPROT	up-regulates	binding			9606	BTO:0000007								19250911	t		gcesareni	We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family	SIGNOR-184261	0.751
EZH2	protein	Q15910	UNIPROT	AR	protein	P10275	UNIPROT	up-regulates activity	binding			9606									23239736	t		miannu	This study demonstrates that phosphorylation of EZH2 at Ser21, mediated directly or indirectly by the PI3K-Akt pathway, can switch its function from a Polycomb repressor to a transcriptional coactivator of AR (and potentially other factors).	SIGNOR-251542	0.557
PBRM1	protein	Q86U86	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000150								18339845	f		miannu	Endogenous wild-type baf180 bound to the p21 promoter and was required for proper p21 expression and g(1) arrest after transforming growth factor-beta and gamma-radiation treatment.	SIGNOR-178022	0.266
UCHL3	protein	P15374	UNIPROT	RAD51	protein	Q06609	UNIPROT	up-regulates activity	deubiquitination	Lys57	EAVAYAPkKELINIK										27941124	t		lperfetto	Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. | UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2.|Our results suggested that three lysine sites (56, 57, and 63) on RAD51 that are close to E59 are deubiquitinated by UCHL3. 	SIGNOR-275907	0.33
PHF1	protein	O43189	UNIPROT	HOXA10	protein	P31260	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									20565746	t		miannu	These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression.	SIGNOR-260071	0.289
SLBP	protein	Q14493	UNIPROT	H2BC20P	protein	Q6DN03	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265382	0.2
ABL1	protein	P00519	UNIPROT	TP63	protein	Q9H3D4	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr171	AIPSNTDyPGPHSFD	9606									19783996	t		Manara	In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. 	SIGNOR-260932	0.524
lysophosphatidic acid	smallmolecule	CHEBI:132742	ChEBI	LPAR4	protein	Q99677	UNIPROT	up-regulates activity	chemical activation			9606									31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257531	0.8
LLGL1	protein	Q15334	UNIPROT	Scribble_complex_DLG1-LLGL1_variant	complex	SIGNOR-C511	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270911	0.579
AMPK	complex	SIGNOR-C15	SIGNOR	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation	Ser122	YRNTGSIsGPKVNRP	10090	BTO:0003946								17341212	t		miannu	In the present study, we demonstrate that the metabolic sensing kinase AMPK (AMP-activated protein kinase) phosphorylates NKCC2 on Ser126 in vitro. Activation of AMPK in the MMDD1 (mouse macula densa-derived 1) cell line resulted in an increase in Ser126 phosphorylation in situ, suggesting that AMPK may phosphorylate NKCC2 in vivo. The functional significance of Ser126 phosphorylation was examined by mutating the serine residue to an alanine residue resulting in a marked reduction in co-transporter activity when exogenously expressed in Xenopus laevis oocytes under isotonic conditions. 	SIGNOR-263103	0.2
SYN1	protein	P17600	UNIPROT	Synaptic_vesicle_exocytosis	phenotype	SIGNOR-PH160	SIGNOR	down-regulates				9606	BTO:0000938								33809712	f		miannu	Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet.	SIGNOR-264105	0.7
RUVBL1	protein	Q9Y265	UNIPROT	R2TP core co-chaperone	complex	SIGNOR-C515	SIGNOR	form complex	binding			9606									29662061	t		miannu	 Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90. 	SIGNOR-270928	0.804
DVL3	protein	Q92997	UNIPROT	PLCB1	protein	Q9NQ66	UNIPROT	up-regulates activity				9606									19279717	t		areggio	Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin	SIGNOR-258980	0.355
PRKCD	protein	Q05655	UNIPROT	HAX1	protein	O00165	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser210	QPKSYFKsISVTKIT	10090	BTO:0002572								25419709	t		lperfetto	FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cdelta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1.|Accordingly, PRKCD-induced phosphorylation of Hax-1 at Ser210 and Fbxo25 at Ser178 was associated with decreased expression of Hax-1 in control cells,	SIGNOR-275562	0.2
DVL1	protein	O14640	UNIPROT	RAC1	protein	P63000	UNIPROT	up-regulates activity				9606									23151663	f		gcesareni	In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl associated activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58.	SIGNOR-199384	0.565
CDK1	protein	P06493	UNIPROT	RB1	protein	P06400	UNIPROT	down-regulates	phosphorylation	Ser807	PGGNIYIsPLKSPYK	9606									1756735	t		lperfetto	The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2.	SIGNOR-21552	0.675
RRN3	protein	Q9NYV6	UNIPROT	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	up-regulates activity	relocalization			9606	BTO:0000567								11250903	t		lperfetto	HRRN3 is essential in the SL1-mediated recruitment of RNA Polymerase I to rRNA gene promoters|We conclude that hRRN3 functions to recruit initiation-competent Pol I to rRNA gene promoters. The essential role for hRRN3 in linking Pol I to SL1 suggests a mechanism for growth control of Pol I transcription.	SIGNOR-269648	0.772
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH8	protein	P55286	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265848	0.8
GSK3B	protein	P49841	UNIPROT	MNX1	protein	P50219	UNIPROT	down-regulates	phosphorylation	Ser79	RLRAESPsPPRLLAA	9606									24425879	t		miannu	Here we show that gsk-3_ inactivates the proapoptotic activity of hlxb9 by phosphorylating hlxb9 at ser-78/ser-80 (phlxb9).	SIGNOR-203661	0.3
HECTD3	protein	Q5T447	UNIPROT	TRIOBP	protein	Q9H2D6	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								18194665	t		miannu	Here, we identify a novel Tara-binding protein HECTD3, a putative member of HECT E3 ubiquitin ligases. HECTD3 directly binds Tara in vitro and forms a complex with Tara in vivo. Overexpression of HECTD3 enhances the ubiquitination of Tara in vivo and promotes the turnover of Tara, whereas depletion of HECTD3 by small interfering RNA decreases Tara degradation.	SIGNOR-271770	0.45
PRKAA1	protein	Q13131	UNIPROT	GSR	protein	P00390	UNIPROT	up-regulates activity	phosphorylation	Thr507	TKADFDNtVAIHPTS	9606	BTO:0001890								31530934	t		miannu	Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity. 	SIGNOR-273734	0.292
NMDA receptor_2C	complex	SIGNOR-C349	SIGNOR	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								11052931	t		miannu	Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor	SIGNOR-264224	0.738
EGFR	protein	P00533	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1172	ISLDNPDyQQDFFPK	9606	BTO:0000567								10653583	t	Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer	lperfetto	After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine.	SIGNOR-236467	0.2
USP13	protein	Q92995	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0006155								27923907	t	done	miannu	 In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation.	SIGNOR-274124	0.361
Axonemal_Dynein	proteinfamily	SIGNOR-PF66	SIGNOR	Cilium_movement	phenotype	SIGNOR-PH171	SIGNOR	up-regulates													16440056	f		lperfetto	Axonemal dyneins are responsible for the movement of cilia and flagella.	SIGNOR-265021	0.7
KDM6A	protein	O15550	UNIPROT	HOXA13	protein	P31271	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									24561908	t		miannu	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260022	0.289
PRKACA	protein	P17612	UNIPROT	NEFL	protein	P07196	UNIPROT	down-regulates activity	phosphorylation			9606									8019002	t		miannu	Phosphorylation of neurofilament-L protein (NF-L) by the catalytic subunit of cAMP-dependent protein kinase (A-kinase) inhibits the reassembly of NF-L and disassembles filamentous NF-L. 	SIGNOR-252401	0.2
ABL2	protein	P42684	UNIPROT	CEBPB	protein	P17676	UNIPROT	up-regulates	phosphorylation	Tyr78	RAIDFSPyLEPLGAP	9606	BTO:0000007								19563810	t		gcesareni	The y79 amino acid residue of c/ebpbeta was phosphorylated by c-abl or arg. The phosphorylation of c/ebpbeta resulted in an increased c/ebpbeta stability and a potentiation of c/ebpbeta transcription activation activity in cells	SIGNOR-186427	0.278
CYP11B2	protein	P19099	UNIPROT	18-hydroxycorticosterone	smallmolecule	CHEBI:16485	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000048							33117906	t		lperfetto	The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone	SIGNOR-268684	0.8
HDAC1	protein	Q13547	UNIPROT	KLK3	protein	P07288	UNIPROT	down-regulates quantity by repression	transcriptional regulation												11994312	f	 	 	To define a mechanism for repression of AR function, we demonstrate that AR activity is specifically down-regulated by the histone deacetylase activity of HDAC1. Furthermore, using both mammalian two-hybrid and immunoprecipitation experiments, we show that AR and HDAC1 interact, suggestive of a direct role for down-regulation of AR activity by HDAC1. In chromatin immunoprecipitation assays, we provide evidence that AR, Tip60, and HDAC1 form a trimeric complex upon the endogenous AR-responsive PSA promoter, suggesting that acetylation and deacetylation of the AR is an important mechanism for regulating transcriptional activity.	SIGNOR-253666	0.303
PRKCD	protein	Q05655	UNIPROT	PRKD1	protein	Q15139	UNIPROT	up-regulates	phosphorylation	Ser738	ARIIGEKsFRRSVVG	9606									15024053	t		llicata	Here we show that activation of pkd in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of tyr463 by abl, which in turn promotes a second step, phosphorylation of the pkd activation loop (ser738/ser742). We show that this is mediated by pkcdelta (protein kinase cdelta)	SIGNOR-123449	0.273
3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide	chemical	CHEBI:91433	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-195675	0.8
CHEK2	protein	O96017	UNIPROT	CDC25A	protein	P30304	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser124	PALKRSHsDSLDHDI	9606									12676583	t	Phosphorylation is the signal for ubiquitination	gcesareni	We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases.	SIGNOR-99721	0.837
Prolactin-releasing peptide-20	smallmolecule	CHEBI:80301	ChEBI	PRLHR	protein	P49683	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257566	0.8
NR3C2	protein	P08235	UNIPROT	ATP1B1	protein	P05026	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000318								9694812	f		miannu	 Together these data indicate that the 21-base pair sequence represents a true MRE/GRE and that optimal activation of the human Na/K-ATPase beta1 promoter is controlled by mineralocorticoid and glucocorticoid hormones. It appears that an interaction of MR with GR on the beta1 promoter effectively down-regulates transcription.	SIGNOR-254865	0.24
AKT2	protein	P31751	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Thr32	QSRPRSCtWPLPRPE	9606									16272144	t		gcesareni	FOXO4 transcription factor, also referred to AFX, contains three putative phosphorylation motif sites for protein kinase B (PKB), Thr32, Ser197, and Ser262, and it is proposed that phosphorylated FOXO4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression.[...]These results indicate that phosphorylation at Thr32 and Ser197 is indispensable, whereas that at Ser262 is not critical, for regulation of the nuclear localization and transcriptional activity of FOXO4	SIGNOR-252870	0.757
PRKACA	protein	P17612	UNIPROT	RYR1	protein	P21817	UNIPROT	up-regulates activity	phosphorylation	Ser2843	KKKTRKIsQSAQTYD	-1									14532276	t		miannu	PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure	SIGNOR-250078	0.331
5-carboxamidotryptamine	chemical	CHEBI:48292	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9760039	t		miannu	A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors	SIGNOR-258845	0.8
FGF2	protein	P09038	UNIPROT	FGFR2	protein	P21802	UNIPROT	up-regulates	binding			9606									11390973	t		lperfetto	we determined the crystal structures of these two FGFR2 mutants in complex with fibroblast growth factor 2 (FGF2).These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity.	SIGNOR-86121	0.894
GSK3B	protein	P49841	UNIPROT	MAFB	protein	Q9Y5Q3	UNIPROT	down-regulates	phosphorylation			9606									18042454	t		miannu	We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.	SIGNOR-159476	0.2
Guanfacine	chemical	CHEBI:5558	ChEBI	ADRA2A	protein	P08913	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258919	0.8
3-(4-Methylphenyl)-5-(1-propyl-3,6-dihydro-2H-pyridin-5-yl)-1,2-oxazole	chemical	CID:9817231	PUBCHEM	SIGMAR1	protein	Q99720	UNIPROT	down-regulates activity	chemical inhibition			10090									9144641	t		Federica	PD144418 exhibited an affinity for ơ1 of 0.08nM(Ki) versusa Ki of 1377nM for ơ2 site.	SIGNOR-261114	0.8
TRAF7	protein	Q6Q0C0	UNIPROT	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606									15001576	f		miannu	Overexpression of traf7 induced caspase-dependent apoptosis.	SIGNOR-123218	0.7
NDUFS3	protein	O75489	UNIPROT	Mitochondrial respiratory chain complex I	complex	SIGNOR-C277	SIGNOR	form complex	binding												30030361	t		lperfetto	Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46].	SIGNOR-262177	0.863
SIRT7	protein	Q9NRC8	UNIPROT	H3C1	protein	P68431	UNIPROT	up-regulates activity	deacetylation	Lys37	APATGGVkKPHRYRP										30653310	t		lperfetto	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 	SIGNOR-275880	0.2
PTPN11	protein	Q06124	UNIPROT	NRAS	protein	P01111	UNIPROT	up-regulates activity	dephosphorylation	Tyr32	QNHFVDEyDPTIEDS	9606	BTO:0000007								26617336	t		miannu	Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling.	SIGNOR-255754	0.661
ABL2	protein	P42684	UNIPROT	LGALS3	protein	P17931	UNIPROT	up-regulates	phosphorylation	Tyr118	AGPLIVPyNLPLPGG	9606									20150913	t		llicata	The sh (src homology)3 domains of c-abl/arg bind to a p(80)gppsgp motif of gal3, and tyr79 and tyr118 are the major tyrosine phosphorylation sites. A consequence of this interaction and phosphorylation is the significant impairment of chaperone-mediated autophagy of gal3.	SIGNOR-163743	0.2
RBPJ	protein	Q06330	UNIPROT	MAML2	protein	Q8IZL2	UNIPROT	up-regulates	binding			9606									21873209	t		gcesareni	When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects	SIGNOR-176197	0.865
PITX2	protein	Q99697	UNIPROT	GNRH1	protein	P01148	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0004467								19106114	f		miannu	 Knockdown of PITX1 or PITX2 isoforms impaired GNRH1 induction, and endogenous PITX1 bound to the candidate PITX binding site on the LHB promoter. 	SIGNOR-254922	0.264
SMURF2	protein	Q9HAU4	UNIPROT	TGFBR1	protein	P36897	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0001538								11163210	t		miannu	Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways. 	SIGNOR-272938	0.698
MAPK3	protein	P27361	UNIPROT	SPHK2	protein	Q9NRA0	UNIPROT	up-regulates	phosphorylation	Thr614	AFRLEPLtPRGVLTV	9606	BTO:0000150								17311928	t		llicata	Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1	SIGNOR-153391	0.505
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SMAD2	protein	Q15796	UNIPROT	up-regulates	phosphorylation	Ser255	ELSPTTLsPVNHSLD	9606									26194464	t		MARCO ROSINA	Taken together, ERK-mediated Smad2 linker phosphorylation is responsible for TH17 differentiation	SIGNOR-255020	0.2
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1644	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273042	0.556
IKBKB	protein	O14920	UNIPROT	IKBKB	protein	O14920	UNIPROT	down-regulates activity	phosphorylation	Ser670	SKVRGPVsGSPDSMN	9606	BTO:0000007								10195894	t			Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.	SIGNOR-251274	0.2
HK1	protein	P19367	UNIPROT	alpha-D-glucose 6-phosphate(2-)	smallmolecule	CHEBI:58225	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor.	SIGNOR-266445	0.8
VRK1	protein	Q99986	UNIPROT	BANF1	protein	O75531	UNIPROT	down-regulates	phosphorylation	Thr2	tTSQKHRD	9606									16495336	t		lperfetto	Herein, we demonstrate that b1, vrk1, and vrk2 efficiently phosphorylate the extreme n' terminus of the baf protein. We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain	SIGNOR-144787	0.873
SIRT6	protein	Q8N6T7	UNIPROT	ME1	protein	P48163	UNIPROT	down-regulates activity	deacetylation	Lys337	KIWLVDSkGLIVKGR										31735643	t		lperfetto	PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. 	SIGNOR-275572	0.253
PLK1	protein	P53350	UNIPROT	ANAPC1	protein	Q9H1A4	UNIPROT	up-regulates	phosphorylation	Ser355	AALSRAHsPALGVHS	9606									14657031	t		gcesareni	Our analysis revealed an unexpected and unprecedented complexity of mitotic phosphorylation sites and suggests that other kinases than cdk1 and plk1 also contribute to apc phosphorylation.	SIGNOR-119881	0.504
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PRKD3	protein	O94806	UNIPROT	up-regulates activity	phosphorylation	Ser731	ARIIGEKsFRRSVVG										18692497	t		lperfetto	The results presented in this study indicate that during mitosis, PKD3 and PKD are phosphorylated at Ser(731) and Ser(744) within their activation loop by a mechanism that requires protein kinase C. Mitosis-associated PKD3 Ser(731) and PKD Ser(744) phosphorylation is related to the catalytic activation of these kinases as evidenced by in vivo phosphorylation of histone deacetylase 5, a substrate of PKD and PKD3. 	SIGNOR-275924	0.2
PHACTR1	protein	Q9C0D0	UNIPROT	PP1	proteinfamily	SIGNOR-PF54	SIGNOR	up-regulates activity	binding			9606	BTO:0001949								21939755	t		lperfetto	Phactr-1 was previously identified as protein phosphatase 1 (PP1) α-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process.	SIGNOR-264656	0.553
PMS2	protein	P54278	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates activity				10090									9500552	f			Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer	SIGNOR-257596	0.7
ELK1	protein	P19419	UNIPROT	PRKCA	protein	P17252	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26010542	t		irozzo	The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCα gene transcription activity.	SIGNOR-256336	0.417
CDC42	protein	P60953	UNIPROT	WASL	protein	O00401	UNIPROT	up-regulates activity	binding			9606									10219243	t		lperfetto	In the presence of Cdc42 and PI(4,5)P2, the potency of N-WASP was increased to a level approaching that of GST-VCA, suggesting that N-WASP was fully activated by the two molecules.	SIGNOR-261868	0.917
DMTF1	protein	Q9Y222	UNIPROT	ADM	protein	P35318	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0004532								19816943	f		Luana	 Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. 	SIGNOR-261581	0.2
Uridylate-specific endoribonuclease	protein	P0C6X7-PRO_0000037321	UNIPROT	IFIH1	protein	Q9BYX4	UNIPROT	down-regulates activity				9606									28158275	f		miannu	Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation.	SIGNOR-260245	0.2
CMA1	protein	P23946	UNIPROT	EDN3	protein	P14138	UNIPROT	up-regulates activity	cleavage	Tyr127	TPEQTVPyGLSNYRG	9606	BTO:0000830								9257865	t		miannu	Chymase from human mast cells selectively cleaved big endothelins (ETs) at the Tyr31-Gly32 bond and produced novel trachea-constricting 31-amino acid-length endothelins, ETs(1-31), without any further degradation products.	SIGNOR-256355	0.382
FANCC	protein	Q00597	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates				9606									11520787	f		miannu	Fancc is also required for optimal activation of stat1 in response to cytokine and growth factors	SIGNOR-110043	0.478
PRKCB	protein	P05771	UNIPROT	RRAD	protein	P55042	UNIPROT	unknown	phosphorylation	Ser214	LVRSREVsVDEGRAC	-1									9677319	t		lperfetto	Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases.	SIGNOR-249001	0.308
ATF4	protein	P18848	UNIPROT	GARS1	protein	P41250	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269426	0.2
PRKACA	protein	P17612	UNIPROT	GJB1	protein	P08034	UNIPROT	unknown	phosphorylation	Ser233	NPPSRKGsGFGHRLS	-1									8390988	t		miannu	connexin- 32 is proteolyzed by pcalpain and mcalpain. phosphorylation of connexin-32 by protein kinase C, but not by protein kinase A, efficiently prevents its proteolysis by both calpain isoforms. major phosphorylation sites: Ser233(for protein kinase A). Phosphorylation of connexin-32 by protein kinase C,but not by protein kinase A, prevents the proteolytic attack of p-calpain and m-calpain. Phosphorylation of connexin-32 by protein kinase A and protein kinase C does not prevent its proteolysis by papain, a-chymotrypsin, proteinase K, and trypsin	SIGNOR-249715	0.311
FGFR1	protein	P11362	UNIPROT	Non-structural protein 2	protein	P0C6X7-PRO_0000037310	UNIPROT	down-regulates activity	chemical inhibition			9606									18620382	t		Luana	Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively.	SIGNOR-260150	0.2
P2RY1	protein	P47900	UNIPROT	GNAS	protein	Q5JWF2	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256800	0.305
CHUK	protein	O15111	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser644	GLDFNFDsLISTQNV	9606	BTO:0000150		SIGNOR-C14						15084260	t		gcesareni	Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation.	SIGNOR-252893	0.553
MAP2K4	protein	P45985	UNIPROT	MAPK10	protein	P53779	UNIPROT	up-regulates activity	phosphorylation	Tyr223	TSFMMTPyVVTRYYR	-1									10715136	t			Activation of JNK3 alpha 1 requires both MKK4 and MKK7. both MKK4 and MKK7 were required for bisphosphorylation and maximal enzyme activity. a processive mechanism for JNK3R1 activation that requires phosphorylation of Thr 221 by MKK7 prior to phosphorylation of Tyr 223 by MKK4	SIGNOR-251423	0.732
EIF4G1	protein	Q04637	UNIPROT	eIF4F_complex	complex	SIGNOR-C44	SIGNOR	form complex	binding			9606		BTO:0000671							11408474	t		miannu	Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f.	SIGNOR-108518	0.926
PRKCB	protein	P05771	UNIPROT	MGluR	proteinfamily	SIGNOR-PF55	SIGNOR	up-regulates activity	phosphorylation			-1									15894802	t	inferred from family member	lperfetto	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-270277	0.383
glutamic acid	smallmolecule	CHEBI:18237	ChEBI	GRIK4	protein	Q16099	UNIPROT	up-regulates activity	chemical activation			9606									27586965	t		miannu	Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors	SIGNOR-264473	0.8
CASP8	protein	Q14790	UNIPROT	CASP3	protein	P42574	UNIPROT	up-regulates activity	cleavage			10090	BTO:0002572								10988287	t		amattioni	The temporal pattern of caspase-8 cleavage is consistent with the possibility that it may function upstream of caspase-3 during p53-dependent apoptosis.	SIGNOR-81808	0.713
NRCAM	protein	Q92823	UNIPROT	ANK1	protein	P16157	UNIPROT	up-regulates quantity	relocalization			10116		BTO:0000227							7961622	t		miannu	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266721	0.524
Galanin	smallmolecule	CHEBI:80161	ChEBI	GALR3	protein	O60755	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257496	0.8
F2R	protein	P25116	UNIPROT	CORO1C	protein	Q9ULV4	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000007								21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254847	0.2
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1948	SPTSPGYsPTSPTYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273061	0.636
EYA3	protein	Q99504	UNIPROT	Six1/Dach	complex	SIGNOR-C122	SIGNOR	up-regulates activity	dephosphorylation			10090									14628042	t		llicata	The phosphatase function of Eya switches the function of Six1-Dach from repression to activation,	SIGNOR-238032	0.583
EPAS1	protein	Q99814	UNIPROT	CACNA1A	protein	O00555	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15833863	f		miannu	A second hypoxia-responsive factor, HIF-2, can activate many of the same genes as HIF-1. Ten genes were preferentially activated by HIF-2alpha, including two (CACNA1A and PTPRZ1) implicated in neurologic diseases.	SIGNOR-264332	0.2
EGFR	protein	P00533	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates activity	phosphorylation	Tyr1197	STAENAEyLRVAPQS	9606	BTO:0000567								10653583	t	Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer	lperfetto	After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine.	SIGNOR-236471	0.2
PRKD1	protein	Q15139	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	unknown	phosphorylation	Ser486	RPLSRAQsSPAAPAS	-1									15738054	t		lperfetto	We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro.	SIGNOR-249276	0.492
GFPT1	protein	Q06210	UNIPROT	Hexosamine_biosynthesis	phenotype	SIGNOR-PH194	SIGNOR	up-regulates				9606									21310273	f		miannu	 GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. 	SIGNOR-267819	0.7
FCGR2B	protein	P31994	UNIPROT	TLR4	protein	O00206	UNIPROT	down-regulates activity				9606									24445665	f		lperfetto	Triggering of FcgammaRIIB also subverted the normal activation of DCs by the TLR4 agonist lipopolysaccharide. In addition, triggering of FcgammaRIIB by immune complexes might affect the differentiation of moDCs. When moDCs develop from monocytes invitro in the presence of immune complexes, their differentiation is hampered and they no longer produce IL-12 in response to TLR4 agonists.	SIGNOR-249525	0.391
SUFU	protein	Q9UMX1	UNIPROT	SAP18	protein	O00422	UNIPROT	up-regulates	binding			9606									11960000	t		gcesareni	Here we report that the mouse homolog of su(fu) [msu(fu)] specifically interacts with sap18, a component of the msin3 and histone deacetylase complex. In addition, we demonstrate that msu(fu) functionally cooperates with sap18 to repress transcription by recruiting the sap18-msin3 complex to promoters containing the gli-binding element.	SIGNOR-117311	0.66
MAPK1	protein	P28482	UNIPROT	BMF	protein	Q96LC9	UNIPROT	up-regulates	phosphorylation	Ser77	TQTLSPAsPSQGVML	9606	BTO:0000785								22258404	t		llicata	Phosphomimetic mutation of this site (s74d) moderately enhanced bmf apoptotic activity in vivo.22 here, we demonstrate a previously unrecognized mode of regulation of bmf. We show that b-raf-mek-erk2 signaling regulates bmf phosphorylation at serine 74 and serine 77. Phosphorylation of serine 77 downregulates the pro-apoptotic activity of bmf.	SIGNOR-195475	0.256
PTGER3	protein	P43115	UNIPROT	GNB3	protein	P16520	UNIPROT	up-regulates	binding			9606									12038972	t		gcesareni	Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i)	SIGNOR-88192	0.476
EID2	protein	Q8N6I1	UNIPROT	SMAD3/SMAD4	complex	SIGNOR-C9	SIGNOR	down-regulates activity	binding			9606									14612439	t		lperfetto	Stable expression of eid-2 in the tgf-beta1-responsive cell line inhibits endogenous smad3-smad4 complex formation and tgf-beta1-induced expression of p21 and p15. These results suggest that eid-2 may function as an endogenous suppressor of tgf-beta signaling.	SIGNOR-119174	0.408
BAG4	protein	O95429	UNIPROT	TNFRSF1A	protein	P19438	UNIPROT	down-regulates activity	binding			10090	BTO:0000801								12748303	t		gcesareni	It was suggested that the silencer of death domains (SODD) protein constitutively associates intracellularly with TNFR1 and inhibits the recruitment of cytoplasmic signaling proteins to TNFR1 to prevent spontaneous aggregation of the cytoplasmic death domains of TNFR1 molecules that are juxtaposed in the absence of ligand stimulation	SIGNOR-245022	0.632
CFII complex	complex	SIGNOR-C387	SIGNOR	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates quantity	cleavage			9606									30139799	t		lperfetto	Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1. The heterodimer is active in partially reconstituted cleavage reactions	SIGNOR-266121	0.8
LCK	protein	P06239	UNIPROT	PLCG2	protein	P16885	UNIPROT	up-regulates	phosphorylation	Tyr753	ERDINSLyDVSRMYV	9606									12181444	t		gcesareni	In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme.	SIGNOR-91473	0.538
PRKAA1	protein	Q13131	UNIPROT	CFTR	protein	P13569	UNIPROT	down-regulates activity	phosphorylation	Ser768	LQARRRQsVLNLMTH	9606									19095655	t		Luana	AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions	SIGNOR-259867	0.474
GNGT1	protein	P63211	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									17419683	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt	SIGNOR-252686	0.4
AMPK	complex	SIGNOR-C15	SIGNOR	TXNIP	protein	Q9H3M7	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser308	GLSSRTSsMASRTSS	10116	BTO:0000575								23453806	t		miannu	AMPK phosphorylation of TXNIP on S308 accelerates its degradation 	SIGNOR-276489	0.285
SIRT1	protein	Q96EB6	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates quantity	deacetylation			10090	BTO:0002572								27776347	t			SIRT1 deacetylates β-catenin to promote its accumulation in the nucleus and thus induces the transcription of genes that block MSC adipogenesis.	SIGNOR-256208	0.521
CSNK2A1	protein	P68400	UNIPROT	SAT1	protein	P21673	UNIPROT	unknown	phosphorylation			-1									8954982	t		llicata	Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149.	SIGNOR-250951	0.33
TYMS	protein	P04818	UNIPROT	dihydrofolate(2-)	smallmolecule	CHEBI:57451	ChEBI	up-regulates quantity	chemical modification			9606									21876188	t		lperfetto	In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR.	SIGNOR-268232	0.8
DDAH2	protein	O95865	UNIPROT	nitric oxide	smallmolecule	CHEBI:16480	ChEBI	up-regulates quantity													33850055	f		lperfetto	Upon viral infection, DDAH2 relocated to mitochondria, where it induced the production of nitric oxide (NO) and the activation of dynamin-related protein 1 (Drp1)	SIGNOR-275649	0.8
A4/b1 integrin	complex	SIGNOR-C162	SIGNOR	DLL1	protein	O00548	UNIPROT	up-regulates quantity by expression				10090									25786978	f		lperfetto	First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs.	SIGNOR-253285	0.27
MAP4K1	protein	Q92918	UNIPROT	LCP2	protein	Q13094	UNIPROT	up-regulates	phosphorylation	Ser376	SSFPQSAsLPPYFSQ	9606	BTO:0000782								17353368	t		lperfetto	The serine/threonine kinase hpk-1 phosphorylates serine 376 of slp-76 and induces the interaction with 14-3-3 proteins	SIGNOR-153613	0.769
AVPR1B	protein	P47901	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257176	0.27
SEC24A	protein	O95486	UNIPROT	COPII vesicle	complex	SIGNOR-C370	SIGNOR	form complex	binding			9606	BTO:0000567								30605680	t		lperfetto	The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat	SIGNOR-265295	0.706
PRKACA	protein	P17612	UNIPROT	ITPKA	protein	P23677	UNIPROT	up-regulates activity	phosphorylation	Ser121	LQQPRRLsTSSVSST	-1									9374536	t		miannu	Two isoforms of the inositol 1,4,5-trisphosphate 3-kinase have been identified, the A form and the B form. phosphorylation of isoform A by the cyclic AMP-dependent protein kinase increased activity 1.5-fold, whereas phosphorylation of isoform B decreased activity by 45%. major phosphorylation sites in the protein are Ser119 for PKA. Ser119 in the A isoform is conserved in the B isoform as Ser328	SIGNOR-249994	0.332
RPS6KA5	protein	O75582	UNIPROT	H2AC11	protein	P0C0S8	UNIPROT	up-regulates	phosphorylation	Ser2	sGRGKQGG	9606									15010469	t		gcesareni	We found that msk1 phosphorylated histone h2a on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by msk1.	SIGNOR-123383	0.2
SLC44A2	protein	Q8IWA5	UNIPROT	choline	smallmolecule	CHEBI:15354	ChEBI	up-regulates activity	relocalization			9606									21367571	t		lperfetto	Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it	SIGNOR-260409	0.8
zotepine	chemical	CHEBI:32316	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			-1									8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258551	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	FOS	protein	P01100	UNIPROT	up-regulates activity	phosphorylation	Thr325	TELEPLCtPVVTCTP								phosphorylation:Ser374;Ser362	PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS	16055710	t		lperfetto	Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos	SIGNOR-263010	0.2
SOCS3	protein	O14543	UNIPROT	JAK3	protein	P52333	UNIPROT	down-regulates activity	binding			9606									21508344	t		lperfetto	SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR).	SIGNOR-238645	0.687
CASP6	protein	P55212	UNIPROT	PSEN2	protein	P49810	UNIPROT	up-regulates activity	cleavage	Asp326	YDPEMEEdSYDSFGE	-1									10069390	t		lperfetto	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261745	0.37
TNFRSF1B	protein	P20333	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates activity													20887952	f			These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs	SIGNOR-253603	0.306
CDK8	protein	P49336	UNIPROT	CCNH	protein	P51946	UNIPROT	down-regulates	phosphorylation	Ser5	sSQKRHWT	9606									10993082	t		gcesareni	Here we show that cdk8/cyclin c can regulate transcription by targeting the cdk7/cyclin h subunits of the general transcription initiation factor iih (tfiih). cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity. In addition, mimicking cdk8 phosphorylation of cyclin h in vivo has a dominant-negative effect on cell growth.	SIGNOR-82037	0.667
PPP2R1A	protein	P30153	UNIPROT	PP2Ca_R1A_Bd 	complex	SIGNOR-C133	SIGNOR	form complex	binding			9606									23454242	t		gcesareni	[PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity.	SIGNOR-243445	0.882
JNK	proteinfamily	SIGNOR-PF15	SIGNOR	KIF5C	protein	O60282	UNIPROT	up-regulates activity	phosphorylation	Ser176	CTERFVSsPEEVMDV	9606		BTO:0000142							27013971	t		miannu	JNK phosphorylates KIF5C on S176 in the motor domain; a site that we show is phosphorylated in brain. In the peroxisome cargo-bound state, S176 phosphorylated KIF5C(1-560) transports to microtubule plus ends, whereas dephosphorylated KIF5C(1-560) is bound tightly to microtubules resulting in an immobile state. As a consequence, phosphorylation of S176 can facilitate plus-end cargo transport by KIF5C(1-560).	SIGNOR-264063	0.2
glycogen	smallmolecule	CHEBI:28087	ChEBI	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	up-regulates quantity	precursor of			9606									3346228	t			Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267394	0.8
SMARCA2	protein	P51531	UNIPROT	Muscle cell-specific SWI/SNF ARID1B variant	complex	SIGNOR-C482	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.	SIGNOR-270701	0.825
VARLITINIB	chemical	CID:42642648	PUBCHEM	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189900	0.8
RNF7	protein	Q9UBF6	UNIPROT	CASP3	protein	P42574	UNIPROT	down-regulates activity	ubiquitination			9606									23136067	t		miannu	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 	SIGNOR-271448	0.2
PRKD3	protein	O94806	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	up-regulates activity	phosphorylation	Ser358	WPLSRTRsEPLPPSA										18692497	t	Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7	lperfetto	Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].	SIGNOR-275934	0.2
AKT1	protein	P31749	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation	Ser9	SGRPRTTsFAESCKP	9606	BTO:0000007								9373175	t		gcesareni	Evidence that the inhibition of glycogen synthase kinase-3beta by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9	SIGNOR-252546	0.783
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH17	protein	Q12864	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265834	0.8
[5-[5-[5-(hydroxymethyl)-2-thiophenyl]-2-furanyl]-2-thiophenyl]methanol	chemical	CHEBI:94980	ChEBI	TP53	protein	P04637	UNIPROT	up-regulates	chemical activation			9606									19223463	t		gcesareni	Rita has been proposed to stabilize p53 by inhibiting the p53-hdm2 interaction.	SIGNOR-184062	0.8
VXJPSOQJNUZHDN-YJFQKBDPSA-N	smallmolecule	CID:118708139	PUBCHEM	NMUR2	protein	Q9GZQ4	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257592	0.8
TRIM27	protein	P14373	UNIPROT	Cell_death	phenotype	SIGNOR-PH109	SIGNOR	up-regulates				9606		BTO:0000671							12807881	f		miannu	Here we show that ectopic expression of rfp in human embryonic kidney 293 cells causes extensive apoptosis, as assessed by multiple criteria.	SIGNOR-256667	0.7
26S Proteasome	complex	SIGNOR-C307	SIGNOR	Protein_degradation	phenotype	SIGNOR-PH96	SIGNOR	up-regulates				9606									29636472	f		lperfetto	The proteasome is a sophisticated ATP-dependent molecular machine responsible for protein degradation in all known eukaryotic cells. 	SIGNOR-263375	0.7
NTRK2	protein	Q16620	UNIPROT	NCK2	protein	O43639	UNIPROT	up-regulates	binding			9606									12074588	t		gcesareni	We identified the nck2 adaptor protein as a novel interaction partner of the active form of trkb. Additionally, we identified three tyrosines in icd-trkb (y694, y695, and y771) that are crucial for this interaction.	SIGNOR-89764	0.341
FLI1	protein	Q01543	UNIPROT	GATA1	protein	P15976	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								12556498	t		irozzo	On the other hand, our data demonstrate that FLI-1 also interacts with GATA-1. However, FLI-1 does not repress but enhances GATA-1 activity.	SIGNOR-256045	0.534
PINK1	protein	Q9BXM7	UNIPROT	MFN2	protein	O95140	UNIPROT	down-regulates quantity	ubiquitination			9606	BTO:0000793								20871098	f		Barakat	Ubiquitination of MFN-1 or MFN-2 was induced in untransfected cells and cells transfected with control siRNA. However, ubiquitination of MFN-1 and MFN-2 was significantly reduced when treated with either PINK1 siRNA combination. These results suggest that PINK1 is required for the ubiquitination of MFN-1 and MFN-2.	SIGNOR-274136	0.803
PRKD2	protein	Q9BZL6	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	up-regulates activity	phosphorylation	Ser358	WPLSRTRsEPLPPSA										18692497	t	Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7	lperfetto	Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].	SIGNOR-275935	0.448
FAD	smallmolecule	CHEBI:16238	ChEBI	FADH2	smallmolecule	CHEBI:17877	ChEBI	up-regulates quantity	precursor of			9606									33450351	t		miannu	ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a). 	SIGNOR-269456	0.8
BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	BMPR1A/1B/2	complex	SIGNOR-C29	SIGNOR	up-regulates	phosphorylation			9606									18756288	t		lperfetto	Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1.	SIGNOR-217029	0.566
OPRM1	protein	P35372	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256854	0.49
CSNK2A2	protein	P19784	UNIPROT	MYF5	protein	P13349	UNIPROT	up-regulates activity	phosphorylation	Ser49	HKAELQGsDEDEHVR	-1									9461343	t		llicata	Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity. 	SIGNOR-251017	0.311
RPL10	protein	P27635	UNIPROT	YES1	protein	P07947	UNIPROT	down-regulates	binding			9606									12138090	t		miannu	Several c-yes kinase activity assays indicated that the qm protein reduced c-yes kinase activity by 70%	SIGNOR-90805	0.396
NPM1	protein	P06748	UNIPROT	HEXIM1	protein	O94992	UNIPROT	down-regulates activity	binding			9606	BTO:0001545								18371977	t		miannu	We identified NPM as a novel HEXIM1-binding protein. NPM functioned as a negative regulator of HEXIM1. cytoplasmic localization of endogenous HEXIM1 is detected in an acute myeloid leukemia (AML) cell line containing the NPMc+ mutation, suggesting the physiological importance of HEXIM1-NPMc+ interaction.	SIGNOR-260134	0.395
PRKG1	protein	Q13976	UNIPROT	TRPC3	protein	Q13507	UNIPROT	down-regulates	phosphorylation	Ser251	KNDYRKLsMQCKDFV	9606									16331690	t	The effect has been demonstrated using Q13507-3	llicata	The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263.	SIGNOR-142961	0.417
SMARCA2	protein	P51531	UNIPROT	SMARCC2	protein	Q8TAQ2	UNIPROT	up-regulates	binding			9606									10078207	t		miannu	The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.	SIGNOR-65435	0.897
CSNK2A1	protein	P68400	UNIPROT	SLK	protein	Q9H2G2	UNIPROT	down-regulates	phosphorylation	Ser347	SSDLSIAsSEEDKLS	9606									16837460	t		gcesareni	Slk down-regulation by v-src is indirect and is accompanied by slk hyperphosphorylation on serine residues. Deletion analysis revealed that casein kinase ii (ck2) sites at position 347/348 are critical for v-src-dependent modulation of slk activity.	SIGNOR-147879	0.2
SMO	protein	Q99835	UNIPROT	ARRB1	protein	P49407	UNIPROT	up-regulates	binding			9606									15618519	t	The binding occours if Smo is phosphorylated	gcesareni	Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2	SIGNOR-132678	0.62
asparagine	smallmolecule	CHEBI:22653	ChEBI	Asn-tRNA(Asn)	smallmolecule	CHEBI:29265	ChEBI	up-regulates quantity	precursor of			9606									32788587	t		miannu	Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations.	SIGNOR-270468	0.8
GATA2	protein	P23769	UNIPROT	TSHB	protein	P01222	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0001073							9305891	t		scontino	Pit-1, is necessary but not sufficient to allow basal transcription of the mTSHβ gene.The analysis of the mTSHβ gene described in this report provides evidence for the participation of a zinc finger factor, GATA-2, with a POU homeodomain partner, Pit-1, on a such a composite element.In summary, we have shown the requirement for at least two different classes of transcription factors to regulate mTSHβ gene expression. Both GATA-2 and Pit-1 can bind independently to the P1 region of the promoter, form a heteromeric complex with DNA, and functionally synergize to activate TSHβ promoter activity.	SIGNOR-267253	0.401
CASP6	protein	P55212	UNIPROT	CASP8	protein	Q14790	UNIPROT	up-regulates	cleavage			9606									11455969	t		gcesareni	This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8.	SIGNOR-109411	0.722
CTNNB1	protein	P35222	UNIPROT	TCF7	protein	P36402	UNIPROT	up-regulates	binding			9606	BTO:0000782								15735151	t		gcesareni	Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation (fig 2?2),), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1	SIGNOR-134282	0.749
MAPK3	protein	P27361	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates	phosphorylation	Ser324	RDLELPLsPSLLGGP	9606									7889942	t		gcesareni	Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-34653	0.582
ACSS2	protein	Q9NR19	UNIPROT	acetate	smallmolecule	CHEBI:30089	ChEBI	down-regulates quantity	chemical modification												10843999	t		lperfetto	The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP.	SIGNOR-271827	0.8
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1766	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120032	0.781
ATR	protein	Q13535	UNIPROT	BRCA1	protein	P38398	UNIPROT	up-regulates activity	phosphorylation	Ser1280	QVILAKAsQEHHLSE	9606	BTO:0002181								11114888	t		llicata	Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication.	SIGNOR-250582	0.792
FLT3	protein	P36888	UNIPROT	FLT3	protein	P36888	UNIPROT	unknown	phosphorylation	Tyr842	DIMSDSNyVVRGNAR	10090	BTO:0001516								28271164	t		lperfetto	Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD|Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. 	SIGNOR-271924	0.2
MAPK1	protein	P28482	UNIPROT	PDE4D	protein	Q08499	UNIPROT	down-regulates	phosphorylation	Ser715	YQSTIPQsPSPAPDD	9606	BTO:0000801								16973330	t	The effect has been demonstrated using Q08499-2	gcesareni	These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro.	SIGNOR-149570	0.36
YWHAE	protein	P62258	UNIPROT	NDEL1	protein	Q9GZM8	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								17202468	t		miannu	14-3-3epsilon is involved in the proper localization of NUDEL and LIS1 in axons. 14-3-3ε binds to NUDEL phosphorylated by cyclin-dependent kinase (cdk5) and maintains NUDEL phosphorylation. Deficiency of 14-3-3ε causes mislocalization of the NUDEL/LIS1 complex from axons, suggesting that 14-3-3ε regulates the axonal targeting of the NUDEL/LIS1 complex by sustaining NUDEL phosphorylation	SIGNOR-252160	0.652
KIF11	protein	P52732	UNIPROT	Plus-end directed sliding movement	phenotype	SIGNOR-PH216	SIGNOR	up-regulates				9606									19773780	f			 In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.	SIGNOR-272521	0.7
PRKACA	protein	P17612	UNIPROT	ITGB4	protein	P16144	UNIPROT	down-regulates	phosphorylation	Ser1364	PSGSQRPsVSDDTGC	9606									17615294	t		lperfetto	Additionally, we show that s1360 and s1364 of beta4 are the only residues phosphorylated by pkc and pka in cells, respectivelywe have defined three regions on beta4 that together harbor all the serine and threonine phosphorylation sites and show that three serines (s1356, s1360, and s1364), previously implicated in hd regulation, prevent the interaction of beta4 with the plectin actin-binding domain when phosphorylated	SIGNOR-156873	0.2
THOC3	protein	Q96J01	UNIPROT	TREX complex	complex	SIGNOR-C444	SIGNOR	form complex	binding			9606									33191911	t		miannu	The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56.	SIGNOR-268513	0.92
DZIP3	protein	Q86Y13	UNIPROT	H2AX	protein	P16104	UNIPROT	up-regulates activity	monoubiquitination	Lys119	IQAVLLPkKTSATVG	9606	BTO:0000007								18206970	t		miannu	 2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271752	0.2
CDK5	protein	Q00535	UNIPROT	DPYSL3	protein	Q14195	UNIPROT	up-regulates activity	phosphorylation	Ser518	KGGTPAGsARGSPTR	9606									16611631	t		lperfetto	Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-145963	0.588
GXYLT2	protein	A0PJZ3	UNIPROT	NOTCH2	protein	Q04721	UNIPROT	up-regulates	binding			9606									22117070	t	Xylosylation in ER membrane	gcesareni	We have previously identified two human genes, gxylt1 and gxylt2, encoding glucoside xylosyltransferases responsible for the transfer of xylose to o-linked glucose. The identity of the enzyme further elongating the glycan to generate the final trisaccharide xylose-xylose-glucose, however, remained unknown. Here, we describe that the human gene c3orf21 encodes a udp-xylose:alfa-xyloside alfa1,3-xylosyltransferase, acting on xylose-alfa1,3-glucosebeta1-containing acceptor structures. We have, therefore, renamed it xxylt1 (xyloside xylosyltransferase 1). Xxylt1 cannot act on a synthetic acceptor containing an alfa-linked xylose alone, but requires the presence of the underlying glucose. Activity on notch egf repeats was proven by in vitro xylosylation of a mouse notch1 fragment recombinantly produced in sf9 insect cells, a bacterially expressed egf repeat from mouse notch2 modified in vitro by rumi and gxylt2 and in vivo by co-expression of the enzyme with the notch1 fragment. The enzyme was shown to be a typical type ii membrane-bound glycosyltransferase localized in the endoplasmic reticulum.	SIGNOR-177717	0.328
CyclinK/CDK12	complex	SIGNOR-C37	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1941	SPKGSTYsPTSPGYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273084	0.745
GABRG2	protein	P18507	UNIPROT	GABA-A (a6-b1-g2) receptor	complex	SIGNOR-C334	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263764	0.625
PPARD	protein	Q03181	UNIPROT	CAT	protein	P04040	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									18048767	f		miannu	 Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs. 	SIGNOR-255051	0.259
CAMK4	protein	Q16566	UNIPROT	HDAC4	protein	P56524	UNIPROT	down-regulates	phosphorylation			9606									11062529	t		gcesareni	Mckinsey et al. report that calcium/calmodulin-dependent kinase (camk), stimulates myogenesis and prevents formation of mef2/hdac complexes by inducing phosphorylation and nuclear export of hdacs 4 and 5.	SIGNOR-83837	0.603
JAK1	protein	P23458	UNIPROT	STAT1	protein	P42224	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000007								9020188	t		lperfetto	The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g they become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases.	SIGNOR-236239	0.783
ATF4	protein	P18848	UNIPROT	SARS2	protein	Q9NP81	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									33384352	t		miannu	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269425	0.2
DPH5	protein	Q9H2P9	UNIPROT	EEF2	protein	P13639	UNIPROT	down-regulates activity	methylation	His715	TLHADAIhRGGGQII	9606									23486472	t			Analysis of EF2 in the mutant cells revealed a novel form of diphthamide with an additional methyl group that prevented ADP-ribosylation and inactivation of EF2. The abnormal methylation appeared to be catalyzed by DPH5.	SIGNOR-261146	0.739
MAVS	protein	Q7Z434	UNIPROT	TBK1	protein	Q9UHD2	UNIPROT	up-regulates activity	binding			9606									25636800	t		miannu	After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively. 	SIGNOR-260145	0.91
2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol	chemical	CHEBI:75722	ChEBI	OPRM1	protein	P35372	UNIPROT	up-regulates activity	chemical activation			10030	BTO:0000246								19282177	t		Luana	A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 	SIGNOR-258149	0.8
2'-3'-cGAMP(2-)	smallmolecule	CHEBI:143093	ChEBI	STING1	protein	Q86WV6	UNIPROT	up-regulates activity	binding												23258413	t		lperfetto	Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family.	SIGNOR-276596	0.8
HIF1A	protein	Q16665	UNIPROT	ABCB1	protein	P08183	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003123								12067980	f	 	miannu	Examination of the MDR1 gene identified a binding site for hypoxia inducible factor-1 (HIF-1), and inhibition of HIF-1 expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible MDR1 expression and a nearly complete loss of basal MDR1 expression.	SIGNOR-254420	0.307
CASP8	protein	Q14790	UNIPROT	RNF31	protein	Q96EP0	UNIPROT	down-regulates activity	cleavage	Asp387	QPPSLVVdSRDAGIC	9606	BTO:0005111								32122970	t		miannu	We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death.	SIGNOR-272195	0.321
AURKB	protein	Q96GD4	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	phosphorylation	Ser215	DRNTFRHsVVVPYEP	9606									22611192	t		gcesareni	We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma).	SIGNOR-197602	0.708
SMC2	protein	O95347	UNIPROT	Condensin I	complex	SIGNOR-C341	SIGNOR	form complex	binding			9606									32445620	t		miannu	The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction.	SIGNOR-263903	0.922
wortmannin	chemical	CHEBI:52289	ChEBI	MYLK	protein	Q15746	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207791	0.8
RPS6KB2	protein	Q9UBS0	UNIPROT	MXD1	protein	Q05195	UNIPROT	down-regulates	phosphorylation	Ser145	IERIRMDsIGSTVSS	9606									18451027	t		lperfetto	In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway	SIGNOR-178594	0.2
LPCAT1	protein	Q8NF37	UNIPROT	coenzyme A(4-)	smallmolecule	CHEBI:57287	ChEBI	up-regulates quantity	chemical modification			9606									21498505	t		miannu	Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes. 	SIGNOR-272761	0.8
GCM2	protein	O75603	UNIPROT	CASR	protein	P41180	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004712	 BTO:0000975							18712808	f	 	miannu	 we show that both promoters (P1 and P2) of the calcium-sensing receptor (CASR) gene, a differentiation marker for the parathyroid gland, are transactivated by wild-type GCM2.	SIGNOR-254199	0.472
GSK3B	protein	P49841	UNIPROT	PDX1	protein	P52945	UNIPROT	down-regulates quantity	phosphorylation	Ser268	LPPGLSAsPQPSSVA	10090	BTO:0002284								19833727	t			We show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose	SIGNOR-255566	0.2
DYRK2	protein	Q92630	UNIPROT	DPYSL3	protein	Q14195	UNIPROT	up-regulates activity	phosphorylation	Thr514	TTTPKGGtPAGSARG	9606									16611631	t		lperfetto	Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-145987	0.373
CDK13	protein	Q14004	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1693	SPTSPSYsPTSPSYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273045	0.556
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	HECTD3	protein	Q5T447	UNIPROT	up-regulates activity	phosphorylation	Thr157	ARLVPIDtPNHLQRQ	9606	BTO:0004461								28716524	t		miannu	HECTD3 binds and ubiquitinates caspase-9.Phosphorylation of HECTD3 by ERK is required for the association of HECTD3 and caspase-9. HECTD3 suppressing caspase-9 activation is dependent on T157 phosphorylation by ERK.	SIGNOR-272330	0.2
CBP/p300	complex	SIGNOR-C6	SIGNOR	KLF1	protein	Q13351	UNIPROT	up-regulates activity	acetylation			9606	BTO:0002731								9707565	t	Regulation	miannu	CBP and p300, but Not P/CAF, Enhance EKLF Trans-activation in Erythroid Cells. We find that EKLF is an acetylated transcription factor, and that it interacts in vivo with CBP, p300, and P/CAF. However, its interactions with these histone acetyltransferases are not equivalent, as CBP and p300, but not P/CAF, utilize EKLF as a substrate for in vitro acetylation within its trans-activation region.	SIGNOR-251789	0.472
SH3RF1	protein	Q7Z6J0	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates	binding			9606									9482736	t		gcesareni	Posh activates jnk1 in cos-1 cells.	SIGNOR-55759	0.38
STK3	protein	Q13188	UNIPROT	MOB1A	protein	Q9H8S9	UNIPROT	up-regulates	phosphorylation	Thr35	LLKHAEAtLGSGNLR	9606									23431053	t		milica	Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity	SIGNOR-201286	0.844
IL11	protein	P20809	UNIPROT	IL11RA	protein	Q14626	UNIPROT	up-regulates	binding			9606									10948192	t		gcesareni	Il-11 has been shown to induce gp130-dependent signaling through the formation of a high affinity complex with the il-11 receptor (il-11r) and gp130	SIGNOR-81102	0.727
CNR1	protein	P21554	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257119	0.255
CyclinK/CDK13	complex	SIGNOR-C38	SIGNOR	POLR2A	protein	P24928	UNIPROT	up-regulates activity	phosphorylation	Ser1882	SPTSPTYsPTTPKYS	9606	BTO:0006413								32917631	t	Ser2 in CTD of PolII	lperfetto	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273077	0.636
GSK3B	protein	P49841	UNIPROT	OGT	protein	O15294	UNIPROT	up-regulates activity	phosphorylation	Ser4	sVGNVADS	10090	BTO:0000142								23395175	t		miannu	We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3β-dependent pathways and identified O-GlcNAc transferase (OGT) as a substrate of GSK3β. Interestingly, OGT activity is regulated by GSK3β; hence, OGT and GSK3β exhibit reciprocal regulation.	SIGNOR-276481	0.5
CHUK	protein	O15111	UNIPROT	IKBKB	protein	O14920	UNIPROT	up-regulates activity	phosphorylation	Ser181	DQGSLCTsFVGTLQY	-1									10022904	t		llicata	Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays.	SIGNOR-250772	0.653
TRiC	complex	SIGNOR-C539	SIGNOR	KRAS	protein	P01116	UNIPROT	up-regulates quantity by stabilization	binding			9606									36185250	t		miannu	Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC).	SIGNOR-272871	0.269
PLCG2	protein	P16885	UNIPROT	1D-myo-inositol 1,4,5-trisphosphate	smallmolecule	CHEBI:16595	ChEBI	up-regulates quantity	chemical modification			9606									23000145	t		scontino	Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).	SIGNOR-268453	0.8
MAPK3	protein	P27361	UNIPROT	TSC2	protein	P49815	UNIPROT	down-regulates activity	phosphorylation			9606									19188143	t		lperfetto	Phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression	SIGNOR-183695	0.682
PDPK1	protein	O15530	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation			9606									15743829	t		lperfetto	3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt),	SIGNOR-244469	0.736
SLC4A10	protein	Q6U841	UNIPROT	hydrogencarbonate	smallmolecule	CHEBI:17544	ChEBI	up-regulates quantity	relocalization			9606									26136660	t		miannu	Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. In neurons, bicarbonate transport is mainly mediated by members of the SLC4A family of proteins. While the Na+-independent anion-exchanger SLC4A3 lowers the intraneuronal bicarbonate concentration, the Na+-dependent anion exchangers SLC4A8 (NDCBE) and SLC4A10 (NCBE) use the sodium gradient to accumulate bicarbonate in exchange of chloride	SIGNOR-264919	0.8
Obatoclax mesylate	chemical	CID:46930996	PUBCHEM	BCL2L1	protein	Q07817	UNIPROT	down-regulates activity	chemical inhibition			-1									23515850	t		lperfetto	Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro	SIGNOR-262023	0.8
lofepramine	chemical	CHEBI:47782	ChEBI	SLC6A2	protein	P23975	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000007								9537821	t		miannu	At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. 	SIGNOR-258881	0.8
PRKCH	protein	P24723	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates activity	phosphorylation	Ser706	ARIIGEKsFRRSVVG										12058027	t		lperfetto	Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead.	SIGNOR-275958	0.2
calcidiol	smallmolecule	CHEBI:17933	ChEBI	calcitriol	smallmolecule	CHEBI:17823	ChEBI	up-regulates quantity	precursor of			9606		BTO:0000671							12050193	t		lperfetto	The rate-limiting, hormonally regulated step in the biological activation of vitamin D is its 1alpha-hydroxylation to 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] in the kidney, catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha. 	SIGNOR-270558	0.8
GSK3B	protein	P49841	UNIPROT	MITF	protein	O75030	UNIPROT	up-regulates activity	phosphorylation	Ser405	QARAHGLsLIPSTGL	-1									10587587	t		miannu	Here, we show that Ser298, which locates downstream of the bHLHZip and was previously found to be mutated in individuals with WS2, plays an important role in MITF function. Glycogen synthase kinase 3 (GSK3) was found to phosphorylate Ser298 in vitro, thereby enhancing the binding of MITF to the tyrosinase promoter. 	SIGNOR-275967	0.446
IL1B	protein	P01584	UNIPROT	Immune_response	phenotype	SIGNOR-PH17	SIGNOR	up-regulates				9606									32283152	f		miannu	High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity.	SIGNOR-261026	0.7
ULK1/Atg13/Fip200	complex	SIGNOR-C100	SIGNOR	AMPK	complex	SIGNOR-C15	SIGNOR	down-regulates activity	phosphorylation			9606									21460634	t		lperfetto	Here we report that ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. Thus, we propose that ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of ampk by ulk1 represents a negative feedback circuit.	SIGNOR-209916	0.408
AMPK	complex	SIGNOR-C15	SIGNOR	GYS2	protein	P54840	UNIPROT	down-regulates activity	phosphorylation	Ser8	MLRGRSLsVTSLGGL	-1									22233421	t		miannu	Recombinant muscle GYS1 (glycogen synthase 1) and recombinant liver GYS2 were phosphorylated by recombinant AMPK (AMP-activated protein kinase) in a time-dependent manner and to a similar stoichiometry. The phosphorylation site in GYS2 was identified as Ser7, which lies in a favourable consensus for phosphorylation by AMPK. Phosphorylation of GYS1 or GYS2 by AMPK led to enzyme inactivation by decreasing the affinity for both UDP-Glc (UDP-glucose) [assayed in the absence of Glc-6-P (glucose-6-phosphate)] and Glc-6-P (assayed at low UDP-Glc concentrations). 	SIGNOR-263101	0.397
FADD	protein	Q13158	UNIPROT	CASP10	protein	Q92851	UNIPROT	up-regulates	binding			9606									11717445	t		gcesareni	The death-effector domains ofcasp8and -10 bothinteractwith the death-effector domain offadd. Therefore, caspase-10 is recruited into the fas signaling complex and becomes activated like caspase-8	SIGNOR-112058	0.787
CDK3	protein	Q00526	UNIPROT	MECOM	protein	Q03112	UNIPROT	up-regulates activity	phosphorylation	Ser624	KMFKDKVsPLQNLAS										33082307	t		lperfetto	The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A.	SIGNOR-273431	0.2
17beta-estradiol	smallmolecule	CHEBI:16469	ChEBI	GPER1	protein	Q99527	UNIPROT	up-regulates	chemical activation			9534	BTO:0000298								15705806	t		Luana	Competition binding assays of E2-Alexa 633 binding with 17β-estradiol demonstrated a Ki for 17β-estradiol of approximately 6.6 nM for GPR30 (Fig. 2F). These results demonstrate that a classic GPCR superfamily member directly binds a sex steroid hormone and that GPR30 is an estrogen-binding receptor. |Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus.	SIGNOR-269752	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SREBF2	protein	Q12772	UNIPROT	up-regulates	phosphorylation			9606									14988395	t	inferred from 70% family members	lperfetto	Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity.	SIGNOR-270141	0.2
LARP7	protein	Q4G0J3	UNIPROT	P-TEFb	complex	SIGNOR-C238	SIGNOR	down-regulates activity	binding			9606	BTO:0000567								30824372	t		Monia	To investigate whether LARP7 is part of the known 7SK RNP implicated in the regulation of transcription, co‐immunoprecipitation studies were performed using the nuclear extracts of HeLa cells (Fig 3A, lanes 1–4). Antibodies against LARP7, CDK9 and HEXIM1 efficiently precipitated 7SK RNA, whereas no RNA was found in the control (Fig 3A, lower panel, lanes 1–4). Interestingly, HEXIM1, CDK9, CYCT1 and LARP7 were present in all immunopurifications, as determined by mass spectrometry of silver‐stained gels (Fig 3A; data not shown) and western blotting. In conclusion, these experiments show that LARP7 negatively regulates not only viral but also cellular POLII class genes through the 7SK P‐TEFb system.	SIGNOR-261184	0.604
ERP44	protein	Q9BS26	UNIPROT	ITPR1	protein	Q14643	UNIPROT	down-regulates activity	binding			9606	BTO:0000567								15652484	t		Simone	In this study, we found that ERp44, an ER lumenal protein of the thioredoxin family, directly interacts with the third lumenal loop of IP(3)R type 1 (IP(3)R1) and that the interaction is dependent on pH, Ca(2+) concentration, and redox state. In this study we demonstrated that ERp44 directly interacts with the L3V domain of IP3R1, thereby inhibiting its channel activity. 	SIGNOR-261046	0.598
GH1	protein	P01241	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15665309	f		Luana	Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells	SIGNOR-261627	0.2
ILK	protein	Q13418	UNIPROT	NACA	protein	Q13765	UNIPROT	up-regulates	phosphorylation	Ser43	PELEEQDsTQATTQQ	9606									15299025	t		lperfetto	Ilk phosphorylated alpha-nac on residue ser-43. Ilk-dependent phosphorylation of alpha-nac induced the nuclear accumulation of the coactivator and that phosphorylation of alpha-nac by ilk is required for the potentiation of c-jun-mediated responses by the kinase.	SIGNOR-127694	0.401
PAK5	protein	Q9P286	UNIPROT	GATA1	protein	P15976	UNIPROT	up-regulates activity	phosphorylation	Ser187	LNSAAYSsPKLRGTL	9606	BTO:0000150								25726523	t		lperfetto	GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. 	SIGNOR-275656	0.2
IRAK4	protein	Q9NWZ3	UNIPROT	IRAK4	protein	Q9NWZ3	UNIPROT	up-regulates activity	phosphorylation	Ser346	FAQTVMTsRIVGTTA	9606	BTO:0000876								24567333	t		lperfetto	We show irak4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues thr-342, thr-345, and ser-346 is required for full activity	SIGNOR-204653	0.2
SHANK3	protein	Q9BYB0	UNIPROT	GRIA1	protein	P42261	UNIPROT	up-regulates quantity	binding			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264601	0.2
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	RARB	protein	P10826	UNIPROT	up-regulates activity	chemical activation			9606									17132853	t		miannu	The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 	SIGNOR-256195	0.8
A8/b1 integrin	complex	SIGNOR-C165	SIGNOR	Cell_adhesion	phenotype	SIGNOR-PH7	SIGNOR	up-regulates				9606									25388208	f		miannu	Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing.	SIGNOR-269014	0.7
SLBP	protein	Q14493	UNIPROT	H2BC21	protein	Q16778	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265386	0.2
EGR1	protein	P18146	UNIPROT	COL11A1	protein	P12107	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21931594	f	Regulation	miannu	Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1)	SIGNOR-251919	0.2
TANC1	protein	Q9C0D5	UNIPROT	Dendritic_spine_morphogenesis	phenotype	SIGNOR-PH183	SIGNOR	up-regulates				10116									21068316	t		miannu	 In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses.	SIGNOR-266896	0.7
SRC	protein	P12931	UNIPROT	FLT4	protein	P35916	UNIPROT	up-regulates	phosphorylation	Tyr1063	FGLARDIyKDPDYVR	9606									20431062	t		lperfetto	Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk.	SIGNOR-165035	0.491
PTPN14	protein	Q15678	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation			9534									35259601	t		miannu	Moreover, dephosphorylation of STAT3 by PTPN14 might occur in the cytoplasm but not in nucleus.|The tyrosine phosphatase PTPN14 inhibits the activation of STAT3 in PEDV infected Vero cells.	SIGNOR-277088	0.275
acetylcholine	smallmolecule	CHEBI:15355	ChEBI	CHRM2	protein	P08172	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258631	0.8
MAPK3	protein	P27361	UNIPROT	AMPH	protein	P49418	UNIPROT	down-regulates activity	phosphorylation	Ser293	PAPARPRsPSQTRKG	9606									15262992	t		lperfetto	Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2.	SIGNOR-126867	0.277
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	PDE3B	protein	Q13370	UNIPROT	up-regulates	phosphorylation	Ser295	VIRPRRRsSCVSLGE	9606									10454575	t		esanto	Pde3b is a physiological substrate of akt and that akt-mediated phosphorylation of pde3b on serine-273 is important for insulin-induced activation of pde3b.	SIGNOR-70205	0.2
Ast-487	chemical	CID:11409972	PUBCHEM	KIT	protein	P10721	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258070	0.8
TRAF6	protein	Q9Y4K3	UNIPROT	MAP3K14	protein	Q99558	UNIPROT	up-regulates activity	binding			9606									10075662	t		miannu	RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation. TRAF6 has been demonstrated to interact with NIK.	SIGNOR-253048	0.618
(8R)-7-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-13,14-diol	chemical	CHEBI:92234	ChEBI	DRD3	protein	P35462	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								8301582	t		miannu	The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 	SIGNOR-258731	0.8
STK3	protein	Q13188	UNIPROT	MOB1B	protein	Q7L9L4	UNIPROT	up-regulates	phosphorylation	Thr12	FGSRSSKtFKPKKNI	9606									21808241	t	The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific.	gcesareni	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction.	SIGNOR-175813	0.809
MAPK9	protein	P45984	UNIPROT	BAX	protein	Q07812	UNIPROT	up-regulates				9606									15071501	f	JNK-mediated phosphorylation of 14-3-3 at Ser184 reduces its affinity for Bax.	gcesareni	Demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria;these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins.	SIGNOR-124023	0.303
PTPRJ	protein	Q12913	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates activity	dephosphorylation	Tyr1365	NVKCVAPyPSLLSSE	9606	BTO:0000007								12475979	t			When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric receptor colony stimulating factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365)),	SIGNOR-248703	0.591
AMPK	complex	SIGNOR-C15	SIGNOR	VASP	protein	P50552	UNIPROT	down-regulates	phosphorylation	Ser322	TTLPRMKsSSSVTTS	9606									21945940	t		lperfetto	Here we show that phosphorylation of vasp by ampk occurs at a novel site, serine 322, and that phosphorylation at this site alters actin filament binding. We also show that inhibition of ampk activity results in the accumulation of vasp at cell-cell adhesions and a concomitant increase in cell-cell adhesion.	SIGNOR-216568	0.2
OXSR1	protein	O95747	UNIPROT	SLC12A1	protein	Q13621	UNIPROT	up-regulates activity	phosphorylation	Ser91	ASFHAYDsHTNTYYL	9606	BTO:0000007								21321328	t		miannu	 We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A).	SIGNOR-276312	0.517
IFNG	protein	P01579	UNIPROT	Demyelination	phenotype	SIGNOR-PH155	SIGNOR	up-regulates				10090		BTO:0000227							24507514	f		miannu	Beside its wellknown antiviral and proinflammatory action, overexpression of IFN-g in the CNS could participate in demyelination. Transgenic overexpression of IFN-g in the mouse by CNS oligodendrocytes led to chronic demyelination that may be severe	SIGNOR-263833	0.7
NGF	protein	P01138	UNIPROT	NGFR	protein	P08138	UNIPROT	up-regulates	binding			9606									14699954	t		amattioni	Neurotrophin binding to p75ntrhas also been shown to induce apoptosis	SIGNOR-120555	0.831
SMAD5	protein	Q99717	UNIPROT	SMAD5/SMAD4	complex	SIGNOR-C205	SIGNOR	form complex	binding			9606									20957627	t		lperfetto	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.	SIGNOR-255266	0.659
trametinib	chemical	CHEBI:75998	ChEBI	MAP2K1	protein	Q02750	UNIPROT	down-regulates activity	chemical inhibition			9606									26347206	t		miannu	Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation. 	SIGNOR-259447	0.8
GGCX	protein	P38435	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	carboxylation	Glu72	MEEKCSFeEAREVFE	10090		BTO:0001103							11133752	t		lperfetto	The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.	SIGNOR-263692	0.67
CDX2/PAX6/P300	complex	SIGNOR-C33	SIGNOR	GCG	protein	P01275	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10506141	f		miannu	Pax-6 and cdx-2 also directly interacted with one another at the protein level. pax-6, bound to its dna recognition site in the glucagon g1 promoter element, tethered cdx-2 to the molecular complex of pax-6 and p300. Further, we found that the presence of cdx-2 enhanced the interaction of pax-6 with p300, thus establishing a molecular complex of transcription factors implicated in tissue-specific glucagon gene expression with the basal transcriptional machinery.	SIGNOR-70957	0.453
Ub:E1 (UBA6 substrate)	complex	SIGNOR-C496	SIGNOR	UBE2I	protein	P63279	UNIPROT	up-regulates activity	ubiquitination			9606									34199813	t		miannu	The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner t	SIGNOR-271346	0.451
MAPK9	protein	P45984	UNIPROT	ATN1	protein	P54259	UNIPROT	down-regulates activity	phosphorylation	Ser739	EEYETPEsPVPPARS	9606		BTO:0000142							12812981	t		lperfetto	Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment,	SIGNOR-102402	0.2
UHMK1	protein	Q8TAS1	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates	phosphorylation	Ser10	NVRVSNGsPSLERMD	9606									12093740	t		lperfetto	Hkis is a nuclear protein that binds the c-terminal domain of p27(kip1) and phosphorylates it on s10 in vitro and in vivo, promoting its nuclear export to the cytoplasm.Phosphorylation at serine 10, a major phosphorylation site of p27(kip1), increases its protein stability	SIGNOR-90274	0.377
AKT1	protein	P31749	UNIPROT	PFKFB2	protein	O60825	UNIPROT	up-regulates activity	phosphorylation	Ser483	IRRPRNYsVGSRPLK	9606		BTO:0000562							23457334	t		lperfetto	Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (pfkfb2) isoenzyme by amino acids.	SIGNOR-252528	0.643
MAPK3	protein	P27361	UNIPROT	RUNX2	protein	Q13950	UNIPROT	up-regulates	phosphorylation	Ser312	SYLSQMTsPSIHSTT	9606									19801668	t		llicata	In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation.	SIGNOR-188347	0.547
ITCH	protein	Q96J02	UNIPROT	TNFAIP3	protein	P21580	UNIPROT	up-regulates activity	binding			9606	BTO:0000782;BTO:0001271								18246070	t		lperfetto	Here we demonstrate that the regulatory molecule tax1bp1 recruited the e3 ligase itch to a20 via two 'ppxy' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling a20-mediated recruitment and inactivation of rip1. (abstract)	SIGNOR-160621	0.285
BCL3	protein	P20749	UNIPROT	NFKB1	protein	P19838	UNIPROT	up-regulates activity	binding			9606	BTO:0004298								21912613	t	 	miannu	 In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription.	SIGNOR-254789	0.568
L-aspartate(1-)	smallmolecule	CHEBI:29991	ChEBI	N-carbamoyl-L-aspartate(2-)	smallmolecule	CHEBI:32814	ChEBI	up-regulates quantity	precursor of			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-267423	0.8
SLC12A5	protein	Q9H2X9	UNIPROT	chloride	smallmolecule	CHEBI:17996	ChEBI	down-regulates quantity	relocalization												21613606	t		lperfetto	Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12). 	SIGNOR-264637	0.8
NEK2	protein	P51955	UNIPROT	NDC80	protein	O14777	UNIPROT	up-regulates	phosphorylation	Ser165	LGYPFALsKSSMYTV	9606									12386167	t		lperfetto	Phosphorylation of the mitotic regulator protein hec1 by nek2 kinase is essential for faithful chromosome segregation.Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the g(2)/m phase.Nek2 phosphorylates hec1 on serine residue 165, both in vitro and in vivo.	SIGNOR-94322	0.611
ATR	protein	Q13535	UNIPROT	WRN	protein	Q14191	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1141	PEKAYSSsQPVISAQ	9606	BTO:0000567								26695548	t		miannu	A serine residue, S1141, in WRN is phosphorylated in vivo by the ATR kinase in response to replication stress. ATR-mediated WRN S1141 phosphorylation leads to ubiquitination of WRN, facilitating the reversible interaction of WRN with perturbed replication forks and subsequent degradation of WRN.	SIGNOR-277187	0.786
CAMK2D	protein	Q13557	UNIPROT	MEF2A	protein	Q02078	UNIPROT	up-regulates				9606									19725819	f		areggio	In response toincreases in intracellular Ca2+ levels, activated CaMKII translocates into the nucleus where it phosphorylates and deactivates HDAC4 which, as a result, dissociates from theDNA-binding domain of MEF2. This dissociation allows MEF2 to bind to its DNA-binding domain to activate transcription of the MEF2-dependent target gene products MyoD and myogenin	SIGNOR-255956	0.43
CNR1	protein	P21554	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256867	0.52
PPP1CA	protein	P62136	UNIPROT	AHCYL1	protein	O43865	UNIPROT	unknown	dephosphorylation	Ser68	RSLSRSIsQSSTDSY	10090									17635105	t			Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1.	SIGNOR-248555	0.2
NFATC3	protein	Q12968	UNIPROT	PTGS2	protein	P35354	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21871017	t		miannu	 NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration	SIGNOR-264028	0.283
DLG5	protein	Q8TDM6	UNIPROT	Scribble_complex_DLG5-LLGL2_variant	complex	SIGNOR-C506	SIGNOR	form complex	binding			9606									23397623	t		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270893	0.32
IFNA1	protein	P01562	UNIPROT	IFNAR1	protein	P17181	UNIPROT	up-regulates	binding			9606									8181059	t		fspada	The present study describes a novel type i ifn receptor having the ability to bind and respond to several subtypes of ifn-a as well as to ifn-8. This 102 kda-51 kda receptor is essential for the activity of many type i ifns, as demonstrated with anti-receptor antibodies.	SIGNOR-36622	0.649
GCC2	protein	Q8IWJ2	UNIPROT	M6PR	protein	P20645	UNIPROT	up-regulates activity	relocalization												18195106	t		lperfetto	Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector	SIGNOR-253086	0.512
PKM	protein	P14618	UNIPROT	STAT3	protein	P40763	UNIPROT	up-regulates activity	phosphorylation	Tyr705	DPGSAAPyLKTKFIC	-1									22306293	t			PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor	SIGNOR-267716	0.457
FOXL2	protein	P58012	UNIPROT	STAR	protein	P49675	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21862621	f	 	miannu	We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation.	SIGNOR-254180	0.368
SMARCE1	protein	Q969G3	UNIPROT	SWI/SNF ACTL6B varian	complex	SIGNOR-C476	SIGNOR	form complex	binding			9606									30397315	t		miannu	Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes	SIGNOR-270602	0.818
IRAK4	protein	Q9NWZ3	UNIPROT	IRAK4	protein	Q9NWZ3	UNIPROT	up-regulates activity	phosphorylation	Thr342	ASEKFAQtVMTSRIV	9606	BTO:0000007								17141195	t		lperfetto	The present data indicate that the kinase activity of irak-4 is dependent on the autophosphorylations at t342	SIGNOR-151006	0.2
Calcineurin	complex	SIGNOR-C155	SIGNOR	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser168	YREPLCLsPASSGSS	9606	BTO:0000567								11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-252319	0.635
GTF2I	protein	P78347	UNIPROT	Polycomb repressive complex 2	complex	SIGNOR-C130	SIGNOR	up-regulates activity	relocalization												17970752	t		lperfetto	We demonstrate that Suz12, a component of the polycomb repressor complex 2, is recruited to the beta-globin gene.| Our data suggest that TFII-I contributes to the recruitment of the polycomb repressor complex 2 complex to the beta-globin gene.	SIGNOR-268543	0.369
TGFB1	protein	P01137	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates activity	binding			9606									19114990	t		lperfetto	While association of the TGF_RI receptor with p85 requires TGF-_ stimulation.	SIGNOR-252729	0.266
CBFbeta-MYH11	fusion protein	SIGNOR-FP3	SIGNOR	 Core Binding Factor complex	complex	SIGNOR-C214	SIGNOR	down-regulates activity	relocalization			9606	BTO:0000661								9632809	f			The polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor (CBF) is a transcription factor composed of two subunits, α and β. The gene encoding the β subunit is disrupted by inv(16), resulting in the formation of a chimeric protein, β-SMMHC, which is associated with acute myelogenous leukemia.Thus, the result suggess that β-SMMHC inhibits PEBP2-mediated transcription via cytoplasmic sequestration of the α subunit. 	SIGNOR-255741	0.2
SAR1A	protein	Q9NR31	UNIPROT	SEC24D	protein	O94855	UNIPROT	up-regulates quantity	binding							SIGNOR-C370					30605680	t		lperfetto	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 	SIGNOR-265301	0.703
IL31	protein	Q6EBC2	UNIPROT	IL31RA	protein	Q8NI17	UNIPROT	up-regulates	binding			9606									15184896	t		gcesareni	Here we identify a four-helix bundle cytokine we have called interleukin 31 (il-31), which is preferentially produced by t helper type 2 cells. Il-31 signals through a receptor composed of il-31 receptor a and oncostatin m receptor.	SIGNOR-125313	0.636
CHD4	protein	Q14839	UNIPROT	ChAHP	complex	SIGNOR-C407	SIGNOR	form complex	binding			10090	BTO:0002896								29795351	t		miannu	Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. In conclusion, CHD4, ADNP and HP1β/γ form a stable protein complex, which we refer to as ChAHP.	SIGNOR-266752	0.421
NBR1	protein	Q14596	UNIPROT	MAP1LC3A	protein	Q9H492	UNIPROT	up-regulates	binding			9606	BTO:0000007								19250911	t		gcesareni	We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family.	SIGNOR-184270	0.576
IRF1	protein	P10914	UNIPROT	DST	protein	Q03001	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									15560761	t		miannu	 Transient transfection studies with BPAG1 promoter-luciferase reporter gene plasmids and IRF1 and IRF2 expression plasmids revealed that IRF1 and IRF2 directly down-regulated BPAG1 gene transcription in cultured normal human epidermal keratinocytes.	SIGNOR-254492	0.2
CDK1	protein	P06493	UNIPROT	NDEL1	protein	Q9GZM8	UNIPROT	up-regulates activity	phosphorylation	Thr219	ASLSLPAtPVGKGTE	-1									12556484	t	done	miannu	In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites	SIGNOR-274074	0.646
STOML2	protein	Q9UJZ1	UNIPROT	MFN2	protein	O95140	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20359165	f		Giorgia	Of interest, induction of SLP-2 expression also resulted in significant increases in the levels of OPA-1 and mitofusin-2 (P < 0.05), both integral mitochondrial membrane proteins associated with mitochondrial fusion.	SIGNOR-260380	0.343
GC	protein	P02774	UNIPROT	vitamin D	smallmolecule	CHEBI:27300	ChEBI	up-regulates quantity	relocalization			9606		BTO:0000759							30080183	t		lperfetto	Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. 	SIGNOR-270566	0.8
Oxytocin	protein	P01178-PRO_0000020495	UNIPROT	GABA-A	proteinfamily	SIGNOR-PF61	SIGNOR	up-regulates				9606									33536967	f		lperfetto	OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors	SIGNOR-268578	0.2
IKBKB	protein	O14920	UNIPROT	CDKN2A	protein	P42771	UNIPROT	down-regulates	phosphorylation	Ser8	MEPAAGSsMEPSADW	9606									20152798	t		lperfetto	Ikkbeta specifically binds to p16 and phosphorylates ser8 of p16 phosphorylation at ser8 of p16 brings about a significant loss of its cyclin-dependent kinase (cdk) 4-inhibitory activity	SIGNOR-163801	0.405
vincaleukoblastine sulfate	chemical	CHEBI:9984	ChEBI	TUBG1	protein	P23258	UNIPROT	down-regulates activity	chemical inhibition			9606									15579115	t		miannu	Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. 	SIGNOR-259259	0.8
LATS2	protein	Q9NRM7	UNIPROT	YAP1	protein	P46937	UNIPROT	down-regulates	phosphorylation	Ser127	PQHVRAHsSPASLQL	9606									22863277	t		miannu	Lats1/2 inhibit yap by direct phosphorylation at s127, which results in yap binding to 14-3-3 and cytoplasmic sequestration	SIGNOR-198514	0.815
FGF5	protein	P12034	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	binding			9606									8386828	t		gcesareni	Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2.	SIGNOR-38704	0.7
DUSP1	protein	P28562	UNIPROT	MAPK1	protein	P28482	UNIPROT	down-regulates activity	dephosphorylation	Thr185	HDHTGFLtEYVATRW	10116									7535768	t			We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively	SIGNOR-248464	0.799
MAPK14	protein	Q16539	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates				9606									17003045	f		gcesareni	The ring finger ubiquitin ligase siah2 controls the stability of various substrates involved in stress and hypoxia responses, including the phd3, which controls the stability of hif-1alpha. In the present study we determined the role of siah2 phosphorylation in the regulation of its activity toward phd3. We show that siah2 is subject to phosphorylation by p38 mapk, which increases siah2-mediated degradation of phd3.	SIGNOR-149887	0.313
PRKCB	protein	P05771	UNIPROT	ORAI1	protein	Q96D31	UNIPROT	down-regulates	phosphorylation	Ser27	GGSTTSGsRRSRRRS	9606									20534587	t		llicata	We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30.	SIGNOR-166040	0.2
M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	IL10	protein	P22301	UNIPROT	up-regulates quantity by expression													22933625	f		apalma	P38 activation contributes to the macrophage phenotype switch in injured muscle, which could elevate production of IL-10 (63), creating positive feedback for the phenotype switch	SIGNOR-255448	0.7
GP9	protein	P14770	UNIPROT	GPIb-IX-V complex	complex	SIGNOR-C270	SIGNOR	form complex	binding			9606									16293600	t		lperfetto	The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbalpha, disulfide-linked to GPIbbeta, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1.	SIGNOR-261848	0.683
oxybutynin	chemical	CHEBI:7856	ChEBI	CHRM3	protein	P20309	UNIPROT	down-regulates activity	chemical inhibition			10030	BTO:0000246								22243489	t		Luana	 Interestingly, unlike the methiodide 5, the tertiary amine 17 and to a lesser extent its (S)-eutomer preferentially block the M3 receptor subtype with respect to the M2, with an M3/M2 selectivity ratio slightly higher than those of oxybutynin and the conventional M3selective antagonist 4-DAMP. 	SIGNOR-258327	0.8
NCKAP1	protein	Q9Y2A7	UNIPROT	WAVE complex	complex	SIGNOR-C271	SIGNOR	form complex	binding			9606	BTO:0000567								15070726	t		lperfetto	Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex. 	SIGNOR-261874	0.926
AMPK	complex	SIGNOR-C15	SIGNOR	KLC2	protein	Q9H0B6	UNIPROT	up-regulates	phosphorylation	Ser582	PRMKRASsLNFLNKS	9606									21725060	t		lperfetto	Consistent with phosphorylation of both ser545 and ser582 of klc2 contributing to its 14-3-3 binding, a ser545ala mutant of klc2 could be phosphorylated in vitro by ampk on ser582	SIGNOR-216468	0.292
PRKCA	protein	P17252	UNIPROT	RAF1	protein	P04049	UNIPROT	up-regulates	phosphorylation	Ser497	ATVKSRWsGSQQVEQ	9606									8288587	t		gcesareni	Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation.	SIGNOR-37470	0.538
CDK1	protein	P06493	UNIPROT	CUX1	protein	P39880	UNIPROT	down-regulates	phosphorylation	Ser1237	TEYSQGAsPQPQHQL	9606									11584018	t		lperfetto	Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter.	SIGNOR-110908	0.364
CDK1	protein	P06493	UNIPROT	WWTR1	protein	Q9GZV5	UNIPROT	down-regulates activity	phosphorylation	Thr346	TGENAGQtPMNINPQ										26375055	t		lperfetto	We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity	SIGNOR-276521	0.261
FYN	protein	P06241	UNIPROT	FCGR2A	protein	P12318	UNIPROT	up-regulates activity	phosphorylation	Tyr304	TDDDKNIyLTLPPND	-1									8756631	t		lperfetto	To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.	SIGNOR-249337	0.513
TWIST2	protein	Q8WVJ9	UNIPROT	NF1	protein	P21359	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0004828								19051271	f		miannu	 we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion	SIGNOR-255505	0.2
FOXS1	protein	O43638	UNIPROT	FASLG	protein	P48023	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9913	BTO:0004577								18288644	t		Luana	As we expected, Fkhl18 suppressed, dose-dependently,human and mouseFasLpromoter in bovine vascularsmooth muscle cells	SIGNOR-261612	0.2
CSNK2A1	protein	P68400	UNIPROT	MECOM	protein	Q03112	UNIPROT	up-regulates activity	phosphorylation	Ser1037	IGNSNHGsQSPRNVE										23858473	t	phosphorylation site remapping based on Fig 5	lperfetto	We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. 	SIGNOR-273427	0.2
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	ARHGEF2	protein	Q92974	UNIPROT	down-regulates activity	phosphorylation	Ser960	SRLSPPHsPRDFTRM	9606	BTO:0000567								17488622	t		miannu	The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity.	SIGNOR-276060	0.401
ATG2A	protein	Q2TAZ0	UNIPROT	Autophagosome_formation	phenotype	SIGNOR-PH36	SIGNOR	up-regulates				9606	BTO:0001938								28561066	f		miannu	WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation. 	SIGNOR-268485	0.7
AKT1	protein	P31749	UNIPROT	PRKAA1	protein	Q13131	UNIPROT	down-regulates activity	phosphorylation	Ser496	ATPQRSGsVSNYRSC	-1									27784766	t		miannu	Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle.	SIGNOR-276461	0.297
ZNHIT1	protein	O43257	UNIPROT	MYOG	protein	P15173	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									20473270	t		gcesareni	We show that the srcap subunit named znhit1 or p18hamlet, which is a substrate of p38 mapk, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 mapk-dependent manner. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation.	SIGNOR-165613	0.263
PTGS2	protein	P35354	UNIPROT	GSK3B	protein	P49841	UNIPROT	down-regulates				9606	BTO:0000586								16293724	f		lperfetto	We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway.	SIGNOR-141783	0.419
LPAR1	protein	Q92633	UNIPROT	GNA12	protein	Q03113	UNIPROT	up-regulates	binding			10090									15856019	t		milica	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13.	SIGNOR-236988	0.436
ROR1	protein	Q01973	UNIPROT	SRC	protein	P12931	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000551								22439932	t		miannu	Ror1 binds to and phosphorylates c-src / ror1 kinase-dependent c-src activation	SIGNOR-196751	0.323
CDC42	protein	P60953	UNIPROT	CDC42BPA	protein	Q5VT25	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								9418861	t		lperfetto	Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization|MRCK alpha and Cdc42V12 colocalize, particularly at the cell periphery in transfected HeLa cells. Microinjection of plasmid encoding MRCK alpha resulted in actin and myosin reorganization.	SIGNOR-262593	0.784
EGLN3	protein	Q9H6Z9	UNIPROT	PK	proteinfamily	SIGNOR-PF80	SIGNOR	up-regulates activity	hydroxylation			9606	BTO:0000567								21620138	t			Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells.	SIGNOR-268147	0.447
CSNK2A1	protein	P68400	UNIPROT	SPIB	protein	Q01892	UNIPROT	down-regulates	phosphorylation	Ser129	PYPSPVLsEEEDLPL	9606									10618498	t		lperfetto	Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability	SIGNOR-73879	0.44
LRP1B	protein	Q9NZR2	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0002940								27626682	f		irozzo	Conversely, in Calu-1 cells, which express higher endogenous levels of the receptor, siRNA-mediated LRP1B knockdown significantly enhanced cellular proliferation. Taken together, these findings demonstrate that, consistent with the postulated tumor suppressor function, overexpression of full-length Lrp1b leads to impaired cellular proliferation, while LRP1B knockdown has the opposite effect.	SIGNOR-259089	0.7
ACVR1	protein	Q04771	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity				9606									18801898	f		gcesareni	Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle.	SIGNOR-252463	0.25
PRKCA	protein	P17252	UNIPROT	TOP1	protein	P11387	UNIPROT	up-regulates activity	phosphorylation	Ser21	ADFRLNDsHKHKDKH	-1									18408216	t		miannu	In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells.	SIGNOR-276154	0.2
CDK8	protein	P49336	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Thr179	PQSNIPEtPPPGYLS	9606									19914161	t		lpetrilli	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161561	0.547
RHOA	protein	P61586	UNIPROT	RDX	protein	P35241	UNIPROT	up-regulates activity	phosphorylation	Thr564	AGRDKYKtLRQIRQG	9606	BTO:0000132								35267019	t		miannu	Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. 	SIGNOR-268430	0.484
PRTN3	protein	P24158	UNIPROT	F2RL1	protein	P55085	UNIPROT	down-regulates activity	cleavage	Val48	KVDGTSHvTGKGVTV	-1									10978167	t		lperfetto	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263598	0.381
STAP1	protein	Q9ULZ2	UNIPROT	KIT	protein	P10721	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								10679268	t		miannu	 STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells.	SIGNOR-261822	0.484
RIMBP3B	protein	A6NNM3	UNIPROT	RIMS2	protein	Q9UQ26	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264369	0.366
ADGRG1	protein	Q9Y653	UNIPROT	RHOA	protein	P61586	UNIPROT	up-regulates activity	binding												24949629	t			Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); | We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation.	SIGNOR-253981	0.2
valine	smallmolecule	CHEBI:27266	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264747	0.7
ITCH	protein	Q96J02	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9534	BTO:0001538								12226085	t		miannu	In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination. 	SIGNOR-272604	0.47
2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid	chemical	CID:135461425	PUBCHEM	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		llicata	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258187	0.8
CSNK2A1	protein	P68400	UNIPROT	PTEN	protein	P60484	UNIPROT	down-regulates activity	phosphorylation	Thr383	HYRYSDTtDSDPENE	9606									21779440	t		gcesareni	The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity	SIGNOR-89830	0.667
NR2F2	protein	P24468	UNIPROT	RXRA	protein	P19793	UNIPROT	up-regulates	binding			9606									10900149	t		lperfetto	Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site	SIGNOR-79446	0.285
AAK1	protein	Q2M2I8	UNIPROT	AP2M1	protein	Q96CW1	UNIPROT	up-regulates	phosphorylation	Thr156	SQITSQVtGQIGWRR	9606	BTO:0000938								11877461	t		lperfetto	Aak1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and ap2 in clathrin-coated pits and at the leading edge of migrating cells. Aak1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by aak1 results in a decrease in ap2-stimulated transferrin internalization. Together, these results provide strong evidence that aak1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis.	SIGNOR-115657	0.781
SRP19	protein	P09132	UNIPROT	SRP72	protein	O76094	UNIPROT	up-regulates activity	binding			-1									30649418	t		miannu	Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54. 	SIGNOR-261166	0.941
PPP2R5C	protein	Q13362	UNIPROT	Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	down-regulates	binding			9606									16456541	t	inferred from 70% of family members	gcesareni	B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk	SIGNOR-269900	0.2
RAD23B	protein	P54727	UNIPROT	RPA2	protein	P15927	UNIPROT	up-regulates activity	binding												24086043	t		lperfetto	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275699	0.503
CSNK2A1	protein	P68400	UNIPROT	MAPK9	protein	P45984	UNIPROT	unknown	phosphorylation	Thr404	SSMSTEQtLASDTDS	9606									11062067	t		lperfetto	The phosphorylation of thr-404 and ser-407 is not increased in response to other agonists that activate mkk7 and sapk1/jnk, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as ck2, which also phosphorylates thr-404 and ser-407 in vitro.	SIGNOR-83715	0.222
PML-RARalpha	fusion protein	SIGNOR-FP2	SIGNOR	CCNA1	protein	P78396	UNIPROT	up-regulates activity				9606									11090075	t		apalma	We show that the ectopic expression of PML-RARα is sufficient to elevate levels of cyclin A1 in U937 myeloid leukemia cells and cyclin A1 is negatively regulated by the RARα pathway.	SIGNOR-256373	0.2
SMAD2/SMAD4	complex	SIGNOR-C8	SIGNOR	NANOG	protein	Q9H9S0	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001086								19279133	t		flangone	Here, we show that Smad2/3, the downstream effectors of Activin/Nodal signalling, bind and directly control the activity of the Nanog gene in hESCs.	SIGNOR-242049	0.535
MAPK1	protein	P28482	UNIPROT	CIITA	protein	P33076	UNIPROT	down-regulates	phosphorylation	Ser288	PDRPGSTsPFAPSAT	9606									15210796	t		gcesareni	Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.	SIGNOR-126254	0.443
RPA1	protein	P27694	UNIPROT	POLA1	protein	P09884	UNIPROT	up-regulates activity	binding			-1									9214288	t		Federica	In our studies, we have shown that T antigen, DNA polymerase R, and the activation domain of VP16 all interact with overlapping regions of the 70-kDa subunit of RPA.| In the latter, both the direct protein-protein interaction and ssDNA-binding activities of RPA were needed for RPA to modulate polymerase processivity. We also found that SV40 T antigen inhibited the ability of RPA to increase processivity of DNA polymerase alpha, suggesting that this activity of RPA may be important for elongation but not during the initiation of DNA replication.	SIGNOR-261272	0.673
PTPN18	protein	Q99952	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates quantity by destabilization	dephosphorylation	Tyr1112	DPSPLQRySEDPTVP	9606	BTO:0000007								25081058	t		lperfetto	PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop.	SIGNOR-262595	0.658
AGT	protein	P01019	UNIPROT	AGTR1	protein	P30556	UNIPROT	up-regulates	binding			9606	BTO:0001130								16597412	t		gcesareni	Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors.	SIGNOR-145677	0.847
PPM1D	protein	O15297	UNIPROT	RBM38	protein	Q9H0Z9	UNIPROT	up-regulates activity	dephosphorylation	Ser195	DQYPYAAsPATAASF	9606									25823026	t		lperfetto	Interestingly, we showed that PPM1D directly interacts with and dephosphorylates RBM38 at serine 195.	SIGNOR-277020	0.372
GSK3A	protein	P49840	UNIPROT	MAFA	protein	Q8NHW3	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser61	PLSTPCSsVPSSPSF	9606									18042454	t		miannu	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159390	0.2
GSK3B	protein	P49841	UNIPROT	DPYSL2	protein	Q16555	UNIPROT	down-regulates activity	phosphorylation	Ser518	KTVTPASsAKTSPAK	10116	BTO:0000938								15652488	t		lperfetto	Ser-518 is also a potential phosphorylation site of CRMP-2 by GSK-3_.	SIGNOR-133251	0.713
CyclinB/CDK1	complex	SIGNOR-C17	SIGNOR	UHRF1	protein	Q96T88	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser639	QQEGGFAsPRTGKGK	-1									22411829	t		miannu	Importantly, the S652ph antibody identifies phosphorylated UHRF1 in mitotic cells and consistently S652 can be phosphorylated by the M phase-specific kinase CDK1-cyclin B in vitro. UHRF1 S652 phosphorylation significantly reduces UHRF1 interaction with USP7 in vitro and in vivo, which is correlated with a decreased UHRF1 stability in the M phase of the cell cycle. In contrast, UHRF1 carrying the S652A mutation, which renders UHRF1 resistant to phosphorylation at S652, is more stable. 	SIGNOR-276408	0.323
PTK2	protein	Q05397	UNIPROT	NANOG	protein	Q9H9S0	UNIPROT	up-regulates activity	phosphorylation	Tyr174	QKASAPTyPSLYSSY	9606	BTO:0000007								22493428	t		miannu	 In addition, FAK directly phosphorylates Nanog in a dose-dependent manner by in vitro kinase assay and in cancer cells in vivo. The site-directed mutagenesis of Nanog tyrosines, Y35F and Y174F, blocked phosphorylation and binding by FAK.	SIGNOR-276410	0.278
NUMA1	protein	Q14980	UNIPROT	TUBB3	protein	Q13509	UNIPROT	up-regulates	binding			9606									11956313	t		miannu	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116979	0.2
BAIAP2	protein	Q9UQB8	UNIPROT	WASF1	protein	Q92558	UNIPROT	up-regulates	binding			9606									11130076	t		gcesareni	Here we demonstrate that irsp53, a substrate forinsulinreceptor with unknown function, is the 'missing link' between rac and wave. Activated rac binds to the amino terminus of irsp53, and carboxy-terminal src-homology-3 domain of irsp53 binds to wave to form a trimolecular complex.	SIGNOR-85299	0.613
IRX1	protein	P78414	UNIPROT	COL9A3	protein	Q14050	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0002392								20440264	f		Luana	We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 	SIGNOR-261653	0.2
ILK	protein	Q13418	UNIPROT	MYL12B	protein	O14950	UNIPROT	up-regulates activity	phosphorylation	Ser20	KRPQRATsNVFAMFD	9606									11278951	t		lperfetto	Integrin-linked kinase cdna was cloned, sequenced, expressed in e. coli, and shown to phosphorylate myosin light chain in the absence of ca(2+) at ser(19) and thr(18). Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activation of myosin light chain kinase, and phosphorylation of the 20-kDa light chain of myosin at Ser(19).	SIGNOR-106423	0.319
CDK6	protein	Q00534	UNIPROT	RUNX1	protein	Q01196	UNIPROT	up-regulates	phosphorylation	Ser21	TPPSTALsPGKMSEA	9606									21059642	t	The effect has been demonstrated using Q01196-8	gcesareni	Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20).	SIGNOR-169326	0.598
AMPK	complex	SIGNOR-C15	SIGNOR	TET2	protein	Q6N021	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser99	GGIKRTVsEPSLSGLL	9606	BTO:0001025								30022161	t			We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo	SIGNOR-256135	0.2
IL1R1	protein	P14778	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates activity	phosphorylation			9606	BTO:0000801								9625767	t		lperfetto	Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab	SIGNOR-249513	0.389
Alkannin	chemical	CHEBI:2578	ChEBI	PKM	protein	P14618	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0000093;BTO:0000018								21516121	t		lperfetto	Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2.	SIGNOR-262009	0.8
CFD	protein	P00746	UNIPROT	CFB	protein	P00751	UNIPROT	up-regulates activity	cleavage	Thr25	LLSGGVTtTPWSLAR	9606		BTO:0000089							26489954	t		lperfetto	The resulting proconvertase C3bB is subsequently cleaved by factor D (FD), generating the AP C3 convertase C3bBb	SIGNOR-263488	0.796
G6PC2	protein	Q9NQR9	UNIPROT	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	up-regulates quantity	chemical modification			9606									12093795	t		miannu	Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis	SIGNOR-266565	0.8
POU2F1	protein	P14859	UNIPROT	SNAI2	protein	O43623	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									23836662	f	 	miannu	 This PER2-OCT1 interaction effectively converted OCT1 sites, which normally activate expression, into repressor sites by recruitment of a polycomb repressor complex including EZH2 and SUZ12, as well as HDAC2. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes.	SIGNOR-254149	0.27
AMG 458	chemical	CID:24764449	PUBCHEM	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-189516	0.8
POMC	protein	P01189	UNIPROT	MC5R	protein	P33032	UNIPROT	up-regulates	binding			9606	BTO:0000007								11785979	t		gcesareni	The purpose of this study was to identify the peptide that functions as a natural ligand at the mc5r in the skin. alpha-msh, acth1-39, acth1-17, acth1-10, and acth4-10 all increased the production of camp in hek293 cells transfected with the mouse mc5r. alpha-msh and acth1-17 were the most potent in this respect. In addition, all peptides stimulated a rapid and transient increase in [ca(2+)](i).	SIGNOR-114058	0.758
DPF3	protein	Q92784	UNIPROT	Muscle cell-specific SWI/SNF SMARCA4 variant	complex	SIGNOR-C483	SIGNOR	form complex	binding			9606		BTO:0000887							11073988	t		miannu	We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex.	SIGNOR-270730	0.741
PRKCA	protein	P17252	UNIPROT	GJA1	protein	P17302	UNIPROT	down-regulates	phosphorylation	Ser262	SPAKDCGsQKYAYFN	9606									14702389	t		gcesareni	Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (s262) on cx43 becomes phosphorylated in response to growth factor or pkc stimulation of cardiomyocytes.In cell-cell contact forming cultures, the s262d mutation reversed while the s262a mutation increased the inhibitory effect of cx43.Phosphorylation at s262, a pkc site that becomes phosphorylated in the cell environment in response to growth factor stimulation, cancels cx43 inhibition only in contact-forming myocytes.	SIGNOR-120907	0.551
PRKCD	protein	Q05655	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser304	SLLKKRDsFRTPRDS	9606		BTO:0000562							17075052	t		gcesareni	The triple aspartic acid mutation shows greater distance between the two thick myosin filaments (affects the steric arrangement of the filament distances) in heart tissue. Mutation is cardioprotective during stress (ischemia-reprofusion injury) against apoptosis similar to isoproterenol treatment.	SIGNOR-150355	0.2
RPS6KA1	protein	Q15418	UNIPROT	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser167	GGRERLAsTNDKGSM	9606	BTO:0000150								7838153	t		gcesareni	Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii.	SIGNOR-34113	0.508
S1PR2	protein	O95136	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257007	0.357
CSNK1D	protein	P48730	UNIPROT	NCOA3	protein	Q9Y6Q9	UNIPROT	up-regulates	phosphorylation	Ser601	SDKESKEsSVEGAEN	9606	BTO:0000150								19339517	t		lperfetto	In this study, we show that both eralpha and aib1 are substrates for ck1delta in vitro, and identify a novel aib1 phosphorylation site (s601) targeted by ck1delta, significant for the co-activator function of aib1.	SIGNOR-184946	0.288
all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	RXR	proteinfamily	SIGNOR-PF44	SIGNOR	up-regulates activity	chemical activation			9606									17132853	t		miannu	The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 	SIGNOR-256190	0.8
sertindole	chemical	CHEBI:9122	ChEBI	HTR1D	protein	P28221	UNIPROT	down-regulates activity	chemical inhibition			10116	BTO:0000529								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258546	0.8
EIF4E	protein	P06730	UNIPROT	Protein_synthesis	phenotype	SIGNOR-PH29	SIGNOR	up-regulates				9606									15094766	f		lperfetto	A key player in the regulation of translation is the mRNA 5' cap-binding protein eIF4E, which is the rate-limiting member of the eIF4F complex	SIGNOR-236806	0.7
serotonin(1+)	smallmolecule	CHEBI:350546	ChEBI	HTR1A	protein	P08908	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257516	0.8
COPS5	protein	Q92905	UNIPROT	COP9 signalosome variant 1	complex	SIGNOR-C489	SIGNOR	form complex	binding			9606									18850735	t		miannu	The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution.	SIGNOR-270775	0.94
SRC	protein	P12931	UNIPROT	GTF2I	protein	P78347	UNIPROT	up-regulates activity	phosphorylation	Tyr652	KPELVISyLPPGMAS	9534									11934902	t		lperfetto	C-Src-dependent transcriptional activation of TFII-ITFII-I is a multifunctional transcription factor that is also involved in signal transduction. Here we show that TFII-I undergoes a c-Src-dependent tyrosine phosphorylation on tyrosine residues 248 and 611 and translocates to the nucleus in response to growth factor signaling	SIGNOR-247189	0.466
etoposide	chemical	CHEBI:4911	ChEBI	TOP2A	protein	P11388	UNIPROT	down-regulates activity	chemical inhibition			9606									16101488	t		miannu	Etoposide is an important chemotherapeutic agent that is used to treat a wide spectrum of human cancers. It has been in clinical use for more than two decades and remains one of the most highly prescribed anticancer drugs in the world. The primary cytotoxic target for etoposide is topoisomerase II. 	SIGNOR-259325	0.8
RBBP7	protein	Q16576	UNIPROT	DNMT1	protein	P26358	UNIPROT	down-regulates activity	binding			-1									28143904	t		lperfetto	AMPK inhibited DNMT1 through phosphorylation of Ser730 in DNMT1 and Ser314 in RBBP7|association with RBBP7 could inhibit DNMT1	SIGNOR-264785	0.553
Terfenadine	chemical	CHEBI:9453	ChEBI	KCNH2	protein	Q12809	UNIPROT	down-regulates activity	chemical inhibition			-1									19660947	t		Luana	 hERG activity was initially determined in a high throughput patch clamp screening assay (Ionworks)5 while a human H1 binding assay was used to determine H1 binding affinity.6 Selected results were confirmed in vitro using an IonWorks Quattro patch clamp assay and in vivo in the guinea pig.7, 8 Histamine H1activity was confirmed in vivo in the guinea pig.7	SIGNOR-257826	0.8
ASMT	protein	P46597	UNIPROT	melatonin	smallmolecule	CHEBI:16796	ChEBI	up-regulates quantity	chemical modification			-1									22775292	t		miannu	Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS	SIGNOR-265475	0.8
PTPN6	protein	P29350	UNIPROT	STAT6	protein	P42226	UNIPROT	down-regulates				9606	BTO:0000801								9852037	f		gcesareni	Expression of an shp-1 transgene in nih 3t3 cells markedly reduces both il-4-dependent stat6 activation and stat6-mediated transcription of il-4-responsive genes	SIGNOR-62578	0.603
NCOR1	protein	O75376	UNIPROT	BCL6	protein	P41182	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								10898795	t		miannu	The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT. 	SIGNOR-252239	0.586
PTEN	protein	P60484	UNIPROT	MAPT	protein	P10636	UNIPROT	up-regulates activity	dephosphorylation			9606									27221467	t		miannu	Reduced phosphorylation of PTEN can dramatically increase tau phosphorylation and impair the ability of tau to bind to microtubules .	SIGNOR-277079	0.392
CYCS	protein	P99999	UNIPROT	APAF1	protein	O14727	UNIPROT	up-regulates activity	binding			9606									16977332	t		lperfetto	Apaf-1 exists in an inactive conformation in cells and is activated through binding to cytochrome c and dATP.	SIGNOR-149574	0.786
TBX21	protein	Q9UL17	UNIPROT	TBX21	protein	Q9UL17	UNIPROT	up-regulates				9606									16386358	t			In turn, T-bet is an IFN-gamma activator (Szabo et al., 2000), thus creating an indirect positive feedback. Furthermore, it has been shown that ectopic T-bet is able to induce the transcription of its own gene	SIGNOR-254294	0.2
MAPK1	protein	P28482	UNIPROT	HIF1A	protein	Q16665	UNIPROT	up-regulates	phosphorylation	Ser643	KILIASPsPTHIHKE	9606	BTO:0000567								18519666	t		lperfetto	We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_	SIGNOR-178727	0.572
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	SLC4A4	protein	Q9Y6R1	UNIPROT	up-regulates activity	dephosphorylation			10090		BTO:0000988							21317537	t		lperfetto	WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression,	SIGNOR-264647	0.2
TAK-960	chemical	CID:53357478	PUBCHEM	PLK1	protein	P53350	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-207200	0.8
HTR6	protein	P50406	UNIPROT	GNAZ	protein	P19086	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257274	0.252
acetylcholine	smallmolecule	CHEBI:15355	ChEBI	CHRNB3	protein	Q05901	UNIPROT	up-regulates activity	chemical activation			9606		BTO:0000227							28901280	t		miannu	Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cysloop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes.	SIGNOR-264258	0.8
PRKACA	protein	P17612	UNIPROT	HRH1	protein	P35367	UNIPROT	down-regulates	phosphorylation	Ser396	FTWKRLRsHSRQYVS	9606									15328002	t		gcesareni	Two amino acid residues (ser396, ser398) on hr1 were determined to be pkc phosphorylation sites by in vitro phosphorylation studies.Site-directed mutagenesis studies suggests that the ser398 residue was primarily involved in pkc-mediated desensitization. Possibly, phosphorylation of the residues is required for receptor transport from endosomes to lysosomes.	SIGNOR-128411	0.2
SIRT1	protein	Q96EB6	UNIPROT	XPA	protein	P23025	UNIPROT	up-regulates activity	deacetylation	Lys63	TGGMANVkAAPKIID	9606	BTO:0002806								30327428	t		miannu	SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR	SIGNOR-262293	0.526
PRKCA	protein	P17252	UNIPROT	ANXA1	protein	P04083	UNIPROT	up-regulates	phosphorylation	Ser27	EYVQTVKsSKGGPGS	9606									24103589	t		lperfetto	The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization.	SIGNOR-202780	0.2
ARHGAP20	protein	Q9P2F6	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates activity	gtpase-activating protein			9606	BTO:0000007								32203420	t		Luana	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260472	0.695
FOXJ1	protein	Q92949	UNIPROT	TEKT2	protein	Q9UIF3	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000939								23822649	t		miannu	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266937	0.331
UBC	protein	P0CG48	UNIPROT	PRKN	protein	O60260	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								26161729	t		lperfetto	Mechanism of phospho-ubiquitin-induced PARKIN activation|PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN|Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator. 	SIGNOR-249692	0.2
STK4	protein	Q13043	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation	Ser209	SSAGWKNsIRHNLSL	9606									18394876	t		gcesareni	Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity.	SIGNOR-253001	0.673
SMAD1	protein	Q15797	UNIPROT	GADD45G	protein	O95257	UNIPROT	up-regulates quantity	transcriptional regulation			10090									22219353	t		Gianni	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268937	0.2
tRNA(Lys)	smallmolecule	CHEBI:29185	ChEBI	Lys-tRNA(Lys)	smallmolecule	CHEBI:16047	ChEBI	up-regulates quantity	precursor of			9606									28271488	t		miannu	Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 	SIGNOR-270409	0.8
TFIIH	complex	SIGNOR-C457	SIGNOR	E2F1	protein	Q01094	UNIPROT	down-regulates	phosphorylation	Ser403	PEEFISLsPPHEALD	9606									10428966	t		lperfetto	These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase.  here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain.	SIGNOR-269353	0.324
SESN3	protein	P58005	UNIPROT	GATOR2	complex	SIGNOR-C193	SIGNOR	down-regulates activity	binding			10090	BTO:0002572								25457612	t			We describe AMPK-independent mechanism of mTORC1 regulation by the Sestrins, in which the Sestrins inhibit mTORC1 localization to the lysosomes in a Rag-dependent manner through an interaction with GATOR2	SIGNOR-253561	0.449
ETFA	protein	P13804	UNIPROT	ETF	complex	SIGNOR-C463	SIGNOR	form complex	binding			9606									33450351	t		miannu	Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors.	SIGNOR-269453	0.944
CDK4	protein	P11802	UNIPROT	RBL1	protein	P28749	UNIPROT	up-regulates activity	phosphorylation	Ser650	SVHERYSsPTAGSAK	9606									12006580	t		llicata	Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression. 	SIGNOR-250763	0.8
MAPK1	protein	P28482	UNIPROT	ARRB1	protein	P49407	UNIPROT	down-regulates	phosphorylation	Ser412	EEEDGTGsPQLNNR	9606									19153083	t		gcesareni	Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation	SIGNOR-183480	0.717
PXDN	protein	Q92626	UNIPROT	Epithelial-mesenchymal_transition	phenotype	SIGNOR-PH45	SIGNOR	up-regulates				9606	BTO:0000567								29305973	f		miannu	Our findings show that Snai1 mediates repression of PXDN and consolidate a role for this ECM-modifier during EMT.	SIGNOR-265253	0.7
dopamine	smallmolecule	CHEBI:18243	ChEBI	DRD3	protein	P35462	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257479	0.8
IL34	protein	Q6ZMJ4	UNIPROT	CSF1R	protein	P07333	UNIPROT	up-regulates activity	binding			9606	BTO:0000801								39416792	t		miannu	CSF-1, derived from fibroblasts, tumor cells, etc., is produced in membrane-bound form, secreted glycoproteins and proteoglycans. Currently, CSF-1R is considered to be the sole receptor for CSF-1. These cells regulate macrophage growth, differentiation and function by secreting CSF1. Colony-stimulating factor receptor (CSF1R), a type I single-transmembrane protein, is ubiquitously expressed in myeloid cells such as monocytes, macrophages, neuroglia, and osteoblasts. CSF1R induces receptor homodimerization by binding to either CSF-1 or IL-34, followed by activation of receptor signaling and activation of extracellular pro-cell-survival kinase cascades, including PI3K, ERK1/2, and JNK	SIGNOR-277714	0.909
ABL1	protein	P00519	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Tyr292	RLGHCHTyWAVSEEL	9606	BTO:0000007								30842273	t		miannu	The data in this study show that IRF3 is physically associated with c-Abl in vivo and directly binds to c-Abl in vitro. IRF3 is phosphorylated by c-Abl and c-Abl-related kinase, Arg, mainly at Y292.	SIGNOR-277440	0.2
PRKACA	protein	P17612	UNIPROT	MC4R	protein	P32245	UNIPROT	down-regulates activity	phosphorylation	Thr312	RSQELRKtFKEIICC	9606									12639913	t		miannu	Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA 	SIGNOR-250017	0.312
KLF4	protein	O43474	UNIPROT	NPNT	protein	Q6UXI9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0005787	BTO:0001103							23612709	f		miannu	The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 	SIGNOR-255457	0.2
IL1RL1	protein	Q01638	UNIPROT	IL1RAP	protein	Q9NPH3	UNIPROT	up-regulates activity	binding			9606									35238669	t		miannu	The initial step in IL-33 signal transduction is ligand-induced conformational changes in IL-33R, which facilitate recruitment of interleukin-1 receptor accessory protein (IL-1RAP). 	SIGNOR-277715	0.516
Av/b1 integrin	complex	SIGNOR-C175	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-277737	0.693
NSL histone acetyltransferase	complex	SIGNOR-C413	SIGNOR	H4C1	protein	P62805	UNIPROT	down-regulates activity	acetylation	Lys9	SGRGKGGkGLGKGGA	9606									20018852	t		miannu	Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8.	SIGNOR-267168	0.2
CFH	protein	P08603	UNIPROT	CFI	protein	P05156	UNIPROT	up-regulates activity	binding			9606									26806831	t		lperfetto	FH also serves as cofactor for the serine protease factor I (FI) that cleaves C3b into iC3b, unable to form C3 convertase (Fig 1B).	SIGNOR-263490	0.918
TYK2	protein	P29597	UNIPROT	IFNAR1	protein	P17181	UNIPROT	up-regulates activity	phosphorylation	Tyr466	VFLRCINyVFFPSLK	-1									8605876	t		lperfetto	We demonstrate that, in vitro, p135tyk2 phosphorylates two tyrosines on IFNaR1. A phosphopeptide corresponding to the major phosphorylation site (Tyr466) binds STAT2, but not STAT1, in an SH-2-dependent manner. Furthermore, only latent, non-phosphorylated STAT2 interacts with this phosphopeptide. When this phosphopeptide is introduced into permeabilized cells, the IFN alpha-dependent tyrosine phosphorylation of both STATs is blocked. Finally, mutant versions of IFNaR1, in which Tyr466 is changed to phenylalanine, can act in a dominant negative manner to inhibit phosphorylation of STAT2.	SIGNOR-246934	0.908
Delta(9)-tetrahydrocannabinol	smallmolecule	CHEBI:66964	ChEBI	CNR2	protein	P34972	UNIPROT	up-regulates activity	chemical activation			9606		BTO:0000142							29751001	t		miannu	Endocannabinoids (eCBs) are the body’s natural agonists for cannabinoid receptors (G protein-coupled CB1 and CB2) that also recognize Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana. 	SIGNOR-264268	0.8
PRKCG	protein	P05129	UNIPROT	GRIN1	protein	Q05586	UNIPROT	up-regulates activity	phosphorylation	Ser890	ITSTLASsFKRRRSS	10116	BTO:0000938								15936117	t		miannu	Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890. 	SIGNOR-263176	0.358
STAT6	protein	P42226	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000801								20508200	f		lperfetto	Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation.	SIGNOR-249533	0.529
HES1	protein	Q14469	UNIPROT	NEUROG1	protein	Q92886	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000938								30030829	f		lperfetto	The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 	SIGNOR-265140	0.354
EEF1A2	protein	Q05639	UNIPROT	Asn-tRNA(Asn)	smallmolecule	CHEBI:29265	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269526	0.8
LFNG	protein	Q8NES3	UNIPROT	DLL1	protein	O00548	UNIPROT	up-regulates	binding			9606									11346656	t		gcesareni	The modification of notch by fringe would influence binding between the notch receptor and its ligand. It was reported previously that mfng and lfng inhibited notch1-mediated signaling triggered by jagged1 and enhanced that triggered by delta1, and either jagged1- or delta1-triggered notch2 signaling was enhanced by lfng	SIGNOR-107699	0.46
CAMK2D	protein	Q13557	UNIPROT	HDAC4	protein	P56524	UNIPROT	up-regulates	phosphorylation	Ser210	YGKTQHSsLDQSSPP	9606									17179159	t		lperfetto	These results demonstrate that camkiideltab preferentially targets hdac4, and this involves serine 210overexpression of camkiideltab in primary neonatal cardiomyocytes increases the activity of the mef2 transcription factor and completely rescues hdac4-mediated repression of mef2	SIGNOR-151418	0.365
NTRK2	protein	Q16620	UNIPROT	KCNA3	protein	P22001	UNIPROT	down-regulates	phosphorylation	Tyr161	PSFDAILyYYQSGGR	9606	BTO:0000938	BTO:0000671							19166614	t		gcesareni	Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein.	SIGNOR-183515	0.387
IL1RL1	protein	Q01638	UNIPROT	MAP3K7	protein	O43318	UNIPROT	up-regulates activity	binding			9606									35238669	t		miannu	The activated heterodimer complex recruits downstream signaling components, including myeloid differentiation primary response protein 88 (MyD88), IL-1 receptor (IL-1R)–associated kinase, tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6), and transforming growth factor (TGF)-β–activated kinase 1 (TAK1) complex, resulting in TAK1 activation. TAK1 subsequently activates downstream kinases inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKα) and IKKβ, which phosphorylate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor (IκB) proteins. These events ultimately lead to activation of the transcription factor NF-κB and induction of downstream effector genes	SIGNOR-277716	0.2
HTR1A	protein	P08908	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256836	0.55
CRYGD	protein	P07320	UNIPROT	Maintenance_of_lens_transparency	phenotype	SIGNOR-PH65	SIGNOR	up-regulates				9606									10521291	f			The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification. 	SIGNOR-253620	0.7
FGF10	protein	O15520	UNIPROT	FGFR2	protein	P21802	UNIPROT	up-regulates	binding			9606									8663044	t		gcesareni	Fgf3, fgf7, fgf10 and fgf22 are ligands that activate fgfr2b.	SIGNOR-42362	0.89
CTNNB1	protein	P35222	UNIPROT	CCND1	protein	P24385	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000304								30519351	t		miannu	One of the most well studied activators of CCND1 transcription is β-catenin, which could be actived by AKT signalling to inducing G1/S transition. When β-catenin is translocated from the cytoplasm to the nucleus, it forms a complex with the ternary complex factor (TCF) and/or lymphoid enhancer-binding factor (LEF) and stimulates cyclin D1 gene transcription (Fig. 4C).In agreement with the data described above, a chromatin immunoprecipitation (ChIP) assay confirmed that TNC regulates the binding of β-catenin to the TCF/LEF-binding site in the CCND1 promoter (Fig. 4C). Additionally, the β-cateninbinding activity with respect to the CCND1 promoter was much higher in TNC-overexpression PANC-1 cells than in the vector controls. 	SIGNOR-277738	0.794
FOXO1	protein	Q12778	UNIPROT	CDKN1B	protein	P46527	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000304								30519351	t		miannu	To date , we have found that TNC regulates the transcriptional activity of FOXO1. And p27Kip1 is one of the transcriptional targets of FOXO1 (Fig. 5A). We speculated that TNC could regulate the binding of FOXO1 to the CDKN1B promoter.	SIGNOR-277739	0.613
AHI1	protein	Q8N157	UNIPROT	Cilium_assembly	phenotype	SIGNOR-PH64	SIGNOR	up-regulates				9606	BTO:0000452								23532844	f		miannu	Mutations in AHI1 cause Joubert syndrome (JBTS), a neurodevelopmental ciliopathy, characterized by midbrain-hindbrain malformations and motor/cognitive deficits. Here, we show that primary cilia (PC) formation is decreased in fibroblasts from individuals with JBTS and AHI1 mutations.	SIGNOR-269080	0.7
SPRY4	protein	Q9C004	UNIPROT	RAF1	protein	P04049	UNIPROT	down-regulates activity	binding			9606									12717443	t		miannu	Here we show that mammalian Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4.	SIGNOR-253033	0.444
mRNA_polyadenylation	phenotype	SIGNOR-PH200	SIGNOR	messenger RNA	smallmolecule	CHEBI:33699	ChEBI	up-regulates quantity by stabilization	chemical modification			9606									19224921	f		lperfetto	Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation. 	SIGNOR-268322	0.7
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO1	protein	Q12778	UNIPROT	down-regulates activity	phosphorylation			9606	BTO:0000304								30519351	t		miannu	The results showed that TNC induced the cytoplasmic translocation of pFOXO1 via regulation of AKT activation. As shown in Fig. 3C, stimulation of PANC-1 cells with exogenous TNC markedly increased the phosphorylation of AKT and FOXO1. Our study showed that pFOXO1 translocates from the nucleus to the cell cytoplasm after exogenous TNC treatment, which indicates that its transcriptional activity was inhibited.	SIGNOR-277740	0.2
CXCL1	protein	P09341	UNIPROT	CXCR2	protein	P25025	UNIPROT	up-regulates activity	binding			9606									38309677	t		miannu	CXCL1 produces cellular chemotactic activity by binding to the CXC chemokine receptor 2 (CXCR2). In PC, this chemokine has been associated with a variety of carcinogenic mechanisms, including oncogene-induced senescence (OIS), angiogenesis, cancer metastasis, and immunosuppressive microenvironments 	SIGNOR-277717	0.769
CXCL3	protein	P19876	UNIPROT	CXCR2	protein	P25025	UNIPROT	up-regulates activity	binding			9606									38309677	t		miannu	CXCL2/3, also known as macrophage inflammatory protein-2α/2β (MIP-2α/MIP-2β), share the same receptor CXCR2 with CXCL1 and are able to activate neutrophils effectively	SIGNOR-277719	0.713
ALDH2	protein	P05091	UNIPROT	HDAC3	protein	O15379	UNIPROT	up-regulates activity	binding			-1					phosphorylation:Thr429	MQILKFKtIEEVVGR			28056995	t		lperfetto	Consistent with previous data, HDAC3 only bound to the ATP6V0E2 promoter in the presence of ALDH2.|Taken together, our data demonstrate that in the macrophages of LDLR-KO or ALDH2 rs671 mutant, AMPK phosphorylates ALDH2 at T356, which enables its nuclear translocation. Once in the nucleus, ALDH2 binds to HDAC3 and suppresses the transcription and protein expression of ATP6V0E2.	SIGNOR-271867	0.2
GAS6	protein	Q14393	UNIPROT	AXL	protein	P30530	UNIPROT	up-regulates activity	binding			9606	BTO:0000130								35022267	t		miannu	Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site.	SIGNOR-277720	0.906
MECOM	protein	Q03112	UNIPROT	PBX1	protein	P40424	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001271								19767769	f		miannu	In this study, we identified pbx1, a proto-oncogene in hematopoietic malignancy, as a target gene of evi-1. Overexpression of evi-1 increased pbx1 expression in hematopoietic stem/progenitor cells	SIGNOR-188155	0.436
PTPN2	protein	P17706	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates	dephosphorylation	Tyr705	DPGSAAPyLKTKFIC	9606									12138178	t		gcesareni	The nuclear isoform of protein-tyrosine phosphatase tc-ptp regulates interleukin-6-mediated signaling pathway through stat3 dephosphorylation.	SIGNOR-90818	0.725
MTOR	protein	P42345	UNIPROT	EIF4EBP3	protein	O60516	UNIPROT	up-regulates	phosphorylation			9606									14967450	t		gcesareni	While promoting initiation of protein translation through mtor, eukaryoticinitiation factor 4e, and the ribosomal p70-s6 kinase.	SIGNOR-122035	0.366
NCOR2	protein	Q9Y618	UNIPROT	BCL6	protein	P41182	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								10898795	t		miannu	The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT. 	SIGNOR-252240	0.651
AX/b2 integrin	complex	SIGNOR-C171	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257714	0.439
(S)-methylmalonyl-CoA(5-)	smallmolecule	CHEBI:57327	ChEBI	succinyl-CoA(5-)	smallmolecule	CHEBI:57292	ChEBI	up-regulates quantity	precursor of			9606									1978672	t		miannu	Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA). 	SIGNOR-269110	0.8
SENP1	protein	Q9P0U3	UNIPROT	GCM1	protein	Q9NP62	UNIPROT	up-regulates activity	desumoylation			9606	BTO:0000007								21791615	t		miannu	We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation.	SIGNOR-262681	0.481
L-glutamine zwitterion	smallmolecule	CHEBI:58359	ChEBI	L-glutamate(1-)	smallmolecule	CHEBI:29985	ChEBI	up-regulates quantity	precursor of			9606									8106516	t			Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed”	SIGNOR-267189	0.8
HP	protein	P00738	UNIPROT	APOA1	protein	P02647	UNIPROT	up-regulates quantity by stabilization	binding			9606									17824618	t		miannu	Haptoglobin binding to apolipoprotein A-I prevents damage from hydroxyl radicals on its stimulatory activity of the enzyme lecithin-cholesterol acyl-transferase. haptoglobin, when circulating at enhanced levels with free Hb during the acute phase of inflammation, might protect ApoA-I structure and function against hydroxyl radicals.	SIGNOR-252106	0.723
TNC	protein	P24821	UNIPROT	Av/b3 integrin	complex	SIGNOR-C177	SIGNOR	up-regulates activity	binding			9606	BTO:0001521								38058842	t		miannu	TNC is shown to bind to integrin receptors expressed in adjacent PAAD cells, thereby inducing EMT. In addition, TNC expression in CAFs had significant positive correlations with ITGαV, ITGβ1, or ITGβ3 expression in cancer cells, which supports our speculations that the TNC-integrin signaling axis promotes the EMT pathway in cancer cells.	SIGNOR-277736	0.405
CCL5	protein	P13501	UNIPROT	CCR5	protein	P51681	UNIPROT	up-regulates activity	binding			9606	BTO:0000584								38339310	t		miannu	CCL5, also known RANTES (regulated on activation, normal T cell expressed and secreted), is a potent chemoattractant for a variety of leukocytes, including T cells, mono- cytes, NK cells, and basophils, signaling via the CCR1, CCR3, and CCR5 cell surface receptors [59]. Among these receptors, CCL5 has the highest affinity for CCR5. 	SIGNOR-277726	0.936
FOXP3	protein	Q9BZS1	UNIPROT	CCL5	protein	P13501	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000584								38339310	t		miannu	Given its role as a potent chemoattractant for T cells, CCL5 can be utilized to attract Tregs to malignant epithelial cells. Wang et al. demonstrated that Forkheadbox protein 3 (FOXP3), a key transcription factor for Tregs, was highly ex- pressed in pancreatic cancer cell lines, which, in turn, upregulated CCL5 expression 	SIGNOR-277727	0.447
FOXP3	protein	Q9BZS1	UNIPROT	CD274	protein	Q9NZQ7	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000584								38339310	t		miannu	FOXP3 expression additionally increased programmed death ligand 1 (PD-L1) expression, which, when inhibited with CCL5, decreased the tumor burden and Treg infiltration in orthotopic murine, Pan-02 PDAC tumors 	SIGNOR-277728	0.483
V-ATPase	complex	SIGNOR-C560	SIGNOR	cholesterol	smallmolecule	CHEBI:16113	ChEBI	up-regulates quantity	relocalization			9606	BTO:0000584								31827278	t		miannu	Accumulation of V-ATPase at the plasma membrane is necessary for the cholesterol-dependent plasma-membrane association of RAC1, a prerequisite for the stimulation of membrane ruffling and macropinocytosis. In line with these observations, immunohistochemical staining of V-ATPase in human pancreatic ductal adenocarcinoma (PDAC) specimens revealed prominent staining at the cell periphery in neoplastic lesions, in con- trast to the predominantly cytoplasmic staining observed in adjacent normal tissues (Fig. 2e). Thus, mutant RAS-dependent plasma mem- brane V-ATPase displayed preferential accumulation in membrane ruffles, consistent with patterns observed in invasive breast, melanoma and pancreatic cancer cells	SIGNOR-277760	0.8
2-[4-[3-(6-quinolinylmethyl)-5-triazolo[4,5-b]pyrazinyl]-1-pyrazolyl]ethanol	chemical	CHEBI:91425	ChEBI	MET	protein	P08581	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205968	0.8
CXCL5	protein	P42830	UNIPROT	CXCR2	protein	P25025	UNIPROT	up-regulates activity	binding			9606	BTO:0000584								38339310	t		miannu	CXCL5 is another ELR+ CXC chemokine and, thus, also potently attracts neutrophils. Just like CXCL1, CXCL5 also signals through CXCR2, explaining why, often, CXCL5 and CXCL1 are seen to function in parallel in PDAC. CXCL5 was increased in human pancreatic tissue compared to the normal pancreas, and the knockdown of CXCL5 in pancreatic cancer cell lines reduced the proliferation and migration ability of cells	SIGNOR-277730	0.744
SEC23IP	protein	Q9Y6Y8	UNIPROT	phosphatidic acid	smallmolecule	CHEBI:16337	ChEBI	down-regulates quantity	chemical modification			9606									22922100	t		miannu	Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 	SIGNOR-269651	0.8
CBP/p300	complex	SIGNOR-C6	SIGNOR	RELA	protein	Q04206	UNIPROT	up-regulates	acetylation			9606									16382138	t		lperfetto	Rela is also acetylated at several sites by p300 and cbp	SIGNOR-217210	0.844
IQSEC2	protein	Q5JU85	UNIPROT	GRIA3	protein	P42263	UNIPROT	up-regulates quantity	relocalization			9606		BTO:0000142							27009485	t		miannu	BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.	SIGNOR-264914	0.2
TNF	protein	P01375	UNIPROT	TNFRSF1B	protein	P20333	UNIPROT	up-regulates activity	binding												14732063	t			[...] two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b)	SIGNOR-253594	0.928
PRKCZ	protein	Q05513	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1101	GCRRRHSsETFSSTP	9606		BTO:0000975							17360977	t		lperfetto	Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223	SIGNOR-236022	0.716
DOT1L	protein	Q8TEK3	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates activity	binding			9606	BTO:0001939								26199140	t	1	miannu	Our data suggest that the c-Myc-dependent transcriptional switch is modulated by DOT1L, as in the presence of DOT1L c-Myc preferentially forms an active complex with p300 rather than a repressive complex containing HDAC1 and DNMT1	SIGNOR-239362	0.342
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGB1	protein	Q9Y5G3	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265681	0.2
SLC2A2	protein	P11168	UNIPROT	α-D-glucose	smallmolecule	CHEBI:17925	ChEBI	up-regulates quantity	relocalization			9606									25421524	t			The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion.	SIGNOR-267385	0.8
PRKG1	protein	Q13976	UNIPROT	VASP	protein	P50552	UNIPROT	down-regulates activity	phosphorylation			9606									15066263	t		miannu	 Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts	SIGNOR-268289	0.73
PDPK1	protein	O15530	UNIPROT	SGK1	protein	O00141	UNIPROT	up-regulates	phosphorylation	Thr256	EHNSTTStFCGTPEY	9534									12387817	t		lperfetto	Thus, it was suggested that NHERF2 mediates the activation and phosphorylation of SGK1 by PDK1 through its first PDZ domain and PIF motif, as a novel SGK1 activation mechanism.	SIGNOR-236800	0.634
ETS2	protein	P15036	UNIPROT	SPP1	protein	P10451	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									11175361	t		miannu	We demonstrated that Ets2 is capable of binding to and transactivating the OPN promoter using gel shift and transient transfection assays	SIGNOR-259872	0.254
NFKB1	protein	P19838	UNIPROT	KLK3	protein	P07288	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001321								11909978	t	 	 	NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer.	SIGNOR-253668	0.2
frovatriptan	chemical	CHEBI:134991	ChEBI	HTR1B	protein	P28222	UNIPROT	up-regulates activity	chemical activation			-1									9986723	t		miannu	As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold).	SIGNOR-259075	0.8
CDK2	protein	P24941	UNIPROT	RBL2	protein	Q08999	UNIPROT	unknown	phosphorylation	Ser413	VRYIKENsPCVTPVS	9606									11157749	t		llicata	We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130.	SIGNOR-104675	0.843
PAK4	protein	O96013	UNIPROT	SYNJ1	protein	O43426	UNIPROT	up-regulates activity	phosphorylation			-1									22371566	t		miannu	We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. 	SIGNOR-263024	0.2
N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester	chemical	CHEBI:94187	ChEBI	HDAC2	protein	Q92769	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257965	0.8
Riluzole	chemical	CHEBI:8863	ChEBI	KCNN2	protein	Q9H2S1	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								18955585	t		Luana	Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. 	SIGNOR-258020	0.8
tyrphostin B42	chemical	CHEBI:131968	ChEBI	JAK2	protein	O60674	UNIPROT	down-regulates activity				9606									11368440	t		gcesareni	The Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel	SIGNOR-238293	0.8
GNAI1	protein	P63096	UNIPROT	ADCY1	protein	Q08828	UNIPROT	down-regulates activity	binding			9606									15922020	t			Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated.	SIGNOR-256532	0.533
CAD	protein	P27708	UNIPROT	carbamoyl phosphate(2-)	smallmolecule	CHEBI:58228	ChEBI	down-regulates quantity	chemical modification			9606									28552578	t		miannu	CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains.	SIGNOR-268092	0.8
PICK1	protein	Q9NRD5	UNIPROT	GRIA2	protein	P42262	UNIPROT	up-regulates activity	binding			9534	BTO:0000298								25784538	t		miannu	RAB39B directs GluA2 trafficking in neurons. GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a–c). The existence of such complex is supported by our co-immunoprecipitation experiments shown above.	SIGNOR-264046	0.801
AMPK	complex	SIGNOR-C15	SIGNOR	mTORC1	complex	SIGNOR-C3	SIGNOR	down-regulates activity	phosphorylation			9606									20083114	t		lperfetto	A recent study revealed that ampk can inhibit mtorc1 independently of tsc2 by phosphorylating raptor at ser863.	SIGNOR-216422	0.449
PRKCA	protein	P17252	UNIPROT	GFAP	protein	P14136	UNIPROT	down-regulates activity	phosphorylation	Ser38	LGPGTRLsLARMPPP	-1									2155236	t		lperfetto	Glial fibrillary acidic protein (GFAP), the intermediate filament component of astroglial cells, can serve as an excellent substrate for both cAMP-dependent protein kinase and protein kinase C, in vitro. GFAP phosphorylated by each protein kinase does not polymerize, and the filaments that do polymerize tend to depolymerize after phosphorylation. Dephosphorylation of phospho-GFAP by phosphatase led to a recovery of the polymerization competence of GFAP. Most of the phosphorylation sites for cAMP-dependent protein kinase and protein kinase C on GFAP are the same, Ser-8, Ser-13, and Ser-34. cAMP-dependent protein kinase has one additional phosphorylation site, Thr-7.	SIGNOR-248862	0.374
PLK1	protein	P53350	UNIPROT	CLSPN	protein	Q9HAW4	UNIPROT	down-regulates	phosphorylation	Ser30	EADSPSDsGQGSYET	9606									16885022	t		gcesareni	We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase	SIGNOR-148447	0.765
MAPK1	protein	P28482	UNIPROT	RXRA	protein	P19793	UNIPROT	down-regulates activity	phosphorylation	Ser260	NMGLNPSsPNDPVTN	9606									17604322	t		lperfetto	In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 	SIGNOR-88658	0.513
ABL1	protein	P00519	UNIPROT	MYLK	protein	Q15746	UNIPROT	up-regulates	phosphorylation	Tyr556	LNGQPIQyARSTCEA	9606		BTO:0000763							20861316	t		lperfetto	Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity	SIGNOR-167997	0.305
taurine	smallmolecule	CHEBI:15891	ChEBI	GLRA1	protein	P23415	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9009272	t		miannu	For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system.	SIGNOR-258579	0.8
CSNK2A2	protein	P19784	UNIPROT	DDX58	protein	O95786	UNIPROT	down-regulates activity	phosphorylation	Thr770	DSILRLQtWDEAVFR	9606	BTO:0000007								21068236	t		miannu	Phosphorylation of RIG-I by casein kinase II inhibits its antiviral response.Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of RIG-I are phosphorylated by casein kinase II (CK2) in the resting state of the cell and dephosphorylated when cells are infected by RNA virus. 	SIGNOR-276285	0.2
GNG2	protein	P59768	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									17419683	t		gcesareni	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt.	SIGNOR-252682	0.426
ITGA4	protein	P13612	UNIPROT	A4/b1 integrin	complex	SIGNOR-C162	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253175	0.803
KAT2B	protein	Q92831	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	acetylation	Lys15	ARKSTGGkAPRKQLA	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269619	0.2
PTPN1	protein	P18031	UNIPROT	KDR	protein	P35968	UNIPROT	down-regulates activity	dephosphorylation	Tyr1175	AQQDGKDyIVLPISE	9606									23639442	t		lperfetto	This led to increased PTPN1 (PTP1b)-mediated dephosphorylation of VEGFR2 at Y 1175 , the site involved in activating ERK signaling.	SIGNOR-277011	0.43
TP53	protein	P04637	UNIPROT	HK2	protein	P52789	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									27692180	t		miannu	P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.	SIGNOR-267466	0.424
MYOM1	protein	P52179	UNIPROT	OBSCN	protein	Q5VST9	UNIPROT	up-regulates quantity	relocalization			9606	BTO:0003324								19840192	t		miannu	Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. 	SIGNOR-266727	0.305
MAML1	protein	Q92585	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	acetylation			9606									17300219	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	gcesareni	The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin.	SIGNOR-153038	0.2
PRKCE	protein	Q02156	UNIPROT	PRKD2	protein	Q9BZL6	UNIPROT	up-regulates	phosphorylation	Ser876	QGLAERIsVL	9606									12058027	t		gcesareni	Furthermore, we show that pkd2 can be activated by classical and novel members of the protein kinase c (pkc) family such as pkc alpha, pkc epsilon, and pkc eta. These pkcs are activated by gastrin in ags-b cells. Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin.	SIGNOR-89419	0.2
SWI/SNF complex	complex	SIGNOR-C92	SIGNOR	MYOD1/SWI/SNF complex	complex	SIGNOR-C93	SIGNOR	form complex	binding			9606		BTO:0001103							17194702	t		miannu	Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes	SIGNOR-151703	0.614
PRKCA	protein	P17252	UNIPROT	LRRK1	protein	Q38SD2	UNIPROT	up-regulates activity	phosphorylation	Ser1074	GNQRNRCsTFRVKRN	-1									36040231	t		miannu	PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain. 	SIGNOR-276867	0.2
KATP channel	complex	SIGNOR-C274	SIGNOR	potassium(1+)	smallmolecule	CHEBI:29103	ChEBI	up-regulates quantity	relocalization			9606									28842488	t		lperfetto	ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits.	SIGNOR-262053	0.8
ITCH	protein	Q96J02	UNIPROT	LAPTM5	protein	Q13571	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								22009753	t		miannu	Here, we found that the level of LAPTM5 protein is regulated negatively by the degradation through ubiquitination by ITCH, an E3 ubiquitin ligase. ITCH directly binds to the PPxY motif of LAPTM5 via its WW domains and promotes ubiquitination through a HECT-type ligase domain. 	SIGNOR-272721	0.421
AKT2	protein	P31751	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity				9606									16293724	f		gcesareni	We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway.	SIGNOR-141655	0.552
SRC	protein	P12931	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates activity	phosphorylation	Tyr980	YASVNPEyFSAADVY	-1									8940173	t		lperfetto	The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.	SIGNOR-247197	0.564
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC3	protein	O15379	UNIPROT	down-regulates activity	chemical inhibition			-1									20139990	t		Luana	Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1).	SIGNOR-257982	0.8
NDFIP2	protein	Q9NV92	UNIPROT	NEDD4	protein	P46934	UNIPROT	down-regulates activity	relocalization			9606	BTO:0002181								26363003	t		SARA	Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2.	SIGNOR-260995	0.586
LRRK2	protein	Q5S007	UNIPROT	AKT1	protein	P31749	UNIPROT	up-regulates	phosphorylation	Ser473	RPHFPQFsYSASGTA	9606	BTO:0000938								24916379	t		lperfetto	Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling	SIGNOR-252598	0.387
CDH15	protein	P55291	UNIPROT	CTNNB1	protein	P35222	UNIPROT	up-regulates activity	binding			9606									21255999	t		miannu	At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin	SIGNOR-265854	0.619
gamma-aminobutyric acid	smallmolecule	CHEBI:16865	ChEBI	GABA-A (a5-b1-g2) receptor	complex	SIGNOR-C335	SIGNOR	up-regulates activity	chemical activation			9606									18790874	t	brain	lperfetto	Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS).	SIGNOR-263791	0.8
MAT2B	protein	Q9NZL9	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0000599								23325603	f		miannu	MAT2B and GIT1 regulate cell growth and increase ERK activity.GIT1 and MAT2B (V1 and V2) require one another to regulate growth and activate ERK	SIGNOR-261246	0.7
DCTPP1	protein	Q9H773	UNIPROT	Autophagy	phenotype	SIGNOR-PH31	SIGNOR	up-regulates				9606	BTO:0001033								29874556	f		miannu	 Autophagy Induced by Overexpression of DCTPP1 Promotes Tumor Progression and Predicts Poor Clinical Outcome in Prostate Cancer	SIGNOR-261177	0.7
HOOK2	protein	Q96ED9	UNIPROT	CNTRL	protein	Q7Z7A1	UNIPROT	up-regulates	binding			9606									17140400	t		miannu	Hook2 localizes to the centrosome, binds directly to centriolin/cep110 and contributes to centrosomal function	SIGNOR-150956	0.361
LEP	protein	P41159	UNIPROT	LEPR	protein	P48357	UNIPROT	up-regulates	binding			9606									9463481	t		gcesareni	Both ob-ra and ob-rb bind leptin with the same affinity, whereas only ob-rb can elicit intracellular response	SIGNOR-55656	0.808
NME1	protein	P15531	UNIPROT	MET	protein	P08581	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001567								17671192	f		miannu	To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 	SIGNOR-255164	0.337
MAPK3	protein	P27361	UNIPROT	GTF2I	protein	P78347	UNIPROT	up-regulates	phosphorylation	Ser674	QSPKRPRsPGSNSKV	9606									10648599	t		lperfetto	Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation.	SIGNOR-74308	0.382
POLR3F	protein	Q9H1D9	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266128	0.88
TRAF2	protein	Q12933	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	binding			10090	BTO:0002572;BTO:0000801								21232017	t		gcesareni	Rip1 is known to directly interact with traf2	SIGNOR-245032	0.891
SPART	protein	Q8N0X7	UNIPROT	WWP1	protein	Q9H0M0	UNIPROT	up-regulates activity	binding			9606									19580544	t		miannu	 Cytosolic endogenous spartin is mono-ubiquitinated and we demonstrate that it interacts via a PPXY motif with the ubiquitin E3 ligases AIP4 [atrophin-interacting protein 4; ITCH (itchy E3 ubiquitin protein ligase homologue] [corrected] and AIP5 (WWP1). Surprisingly, the PPXY motif, AIP4 and AIP5 are not required for spartin's ubiquitination, and so we propose that spartin acts as an adaptor for these proteins.	SIGNOR-261307	0.2
PRKAA1	protein	Q13131	UNIPROT	NAMPT	protein	P43490	UNIPROT	up-regulates quantity	transcriptional regulation			10090									18477450	f		gcesareni	Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt	SIGNOR-238598	0.303
HSPH1	protein	Q92598	UNIPROT	HSPA1B	protein	P0DMV9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									19754877	f		miannu	 Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress.	SIGNOR-255243	0.454
AGTR1	protein	P30556	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257133	0.467
cyproheptadine	chemical	CHEBI:4046	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								7925364	t		miannu	The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum.	SIGNOR-258869	0.8
ACE	protein	P12821	UNIPROT	Angiotensin-2	protein	P01019-PRO_0000032458	UNIPROT	up-regulates quantity	cleavage			9606									32201502	t		MIANNU	 Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I	SIGNOR-260236	0.2
Noncanonical PRC1	complex	SIGNOR-C151	SIGNOR	PPARG	protein	P37231	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000011								25533466	f		miannu	We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis.	SIGNOR-252251	0.326
WNT11	protein	O96014	UNIPROT	CHRNA1	protein	P02708	UNIPROT	up-regulates				9606	BTO:0000938	BTO:0000887							22309736	f		gcesareni	We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles.	SIGNOR-195963	0.2
RXR	proteinfamily	SIGNOR-PF44	SIGNOR	RAR	proteinfamily	SIGNOR-PF45	SIGNOR	up-regulates activity	binding			9606									1310351	t		miannu	Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-256199	0.712
NR0B2	protein	Q15466	UNIPROT	PPARA	protein	Q07869	UNIPROT	up-regulates	binding			9606									11369442	t		gcesareni	Surprisingly, shp potentiated transcription by pparalpha/rxralpha heterodimers from the hd-ppre. This is the first demonstration of positive transcriptional activity attributable to shp. Together, these results suggest that shp can modulate pparalpha/rxralpha-mediated transcription in a response element-specific manner.	SIGNOR-108252	0.514
okadaic acid	chemical	CHEBI:44658	ChEBI	STK3	protein	Q13188	UNIPROT	up-regulates				9606									23493077	f		gcesareni	Okadaic acid has been frequently used to enhance the phosphorylation of mst1 and mst2 and to trigger the activation of the hippo pathway.	SIGNOR-201551	0.8
PTPRG	protein	P23470	UNIPROT	ZAP70	protein	P43403	UNIPROT	up-regulates activity	dephosphorylation	Tyr292	DTLNSDGyTPEPARI	-1									25624455	t		miannu	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254732	0.263
sphingosine 1-phosphate	smallmolecule	CHEBI:37550	ChEBI	S1PR2	protein	O95136	UNIPROT	up-regulates	chemical activation			9606									16794003	t		gcesareni	The evidence suggests that s1p acting on s1p receptors coupled to gq.	SIGNOR-147230	0.8
STAG3	protein	Q9UJ98	UNIPROT	RAD21L Cohesin complex	complex	SIGNOR-C355	SIGNOR	form complex	binding			10090		BTO:0000534							21242291	t		miannu	RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21.	SIGNOR-264536	0.799
NFY	complex	SIGNOR-C1	SIGNOR	CCNB2	protein	O95067	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									10086339	f		gcesareni	In this study, we analysed the mechanisms leading to activation of the cyclin b2 ccaat boxes: a combination of (i) genomic footprinting, (ii) transfections with single, double and triple mutants, (iii) emsas with nuclear extracts, antibodies and nf-y recombinant proteins and (iv) transfections with an nf-ya dominant negative mutant established the positive role of the three ccaat sequences and proved that nf-y plays a crucial role in their activation.	SIGNOR-65638	0.369
CDK1	protein	P06493	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser249	EGGKSGKsPRRRAAS	9606	BTO:0001130								18408765	t		gcesareni	Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1.	SIGNOR-252890	0.526
ITK	protein	Q08881	UNIPROT	SIGLEC10	protein	Q96LC7	UNIPROT	up-regulates	phosphorylation	Tyr597	RHSTILDyINVVPTA	9606									11733002	t		lperfetto	These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling	SIGNOR-112471	0.2
HOXB7	protein	P09629	UNIPROT	FGF2	protein	P09038	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								8756643	t		Luana	Band shift and cotransfection experiments showed that HOXB7 directly transactivates the hFGF gene through one out of five putative homeodomain binding sites present in its promoter.	SIGNOR-261639	0.407
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	SCN5A	protein	Q14524	UNIPROT	up-regulates activity	phosphorylation	Ser528	KPRSSRGsIFTFRRR	-1									12242273	t		miannu	These results demonstrate that the effect of PKA stimulation to increase cardiac INa requires at least 2 processes: phosphorylation of consensus sites in the I-II interdomain linker, and one or more additional molecular events mediated by the kinase, that could include phosphorylation of other substrates/proteins.	SIGNOR-275992	0.2
RIPK3	protein	Q9Y572	UNIPROT	MLKL	protein	Q8NB16	UNIPROT	up-regulates activity	phosphorylation	Thr357	FELRKTQtSMSLGTT	-1									24012422	t		gianni	MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays	SIGNOR-266438	0.742
axitinib	chemical	CHEBI:66910	ChEBI	KIT	protein	P10721	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150								21297102	t		gcesareni	The inhibitory effect of four tkis (axitinib, imatinib, masitinib, and vatalanib) for proliferation and phosphorylation of c-kit receptor as well as the expression and function of abcb1 were investigated in three cmct cell lines (hrmc, vimc1, and cmmc1).	SIGNOR-171866	0.8
RAB1A	protein	P62820	UNIPROT	GOLGA2	protein	Q08379	UNIPROT	up-regulates activity	relocalization			10116									11285137	t		Giulio	Here, we demonstrate that the cis ‐Golgi tethering protein GM130, complexed with GRASP65 and other proteins, forms a novel Rab1 effector complex that interacts with activated Rab1‐GTP in a p115‐independent manner and is required for coat protein II vesicle targeting/fusion with the cis ‐Golgi	SIGNOR-261285	0.707
PAX8	protein	Q06710	UNIPROT	SLC3A1	protein	Q07837	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000671								15673291	f		miannu	 Expression of SLC3A1 mRNA was found to be tenfold higher in postnatal vs. fetal kidney; SLC3A1 expression is doubled by the proximal tubule transcription factor, PAX8. rBAT is expressed in the proximal convoluted and straight tubules in both fetal and adult kidney.	SIGNOR-254907	0.253
CDK1	protein	P06493	UNIPROT	RAD9A	protein	Q99638	UNIPROT	up-regulates activity	phosphorylation	Thr355	EPSTVPGtPPPKKFR	9606									12734188	t		lperfetto	Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9.	SIGNOR-101059	0.37
ITGAL	protein	P20701	UNIPROT	AL/b2 integrin	complex	SIGNOR-C169	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253189	0.912
PLK1	protein	P53350	UNIPROT	TOP2A	protein	P11388	UNIPROT	up-regulates	phosphorylation	Ser1525	PIKYLEEsDEDDLF	9606									19098900	t		gcesareni	Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin	SIGNOR-182844	0.493
SOX17	protein	Q9H6I2	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	binding			9606									10549281	t		gcesareni	Two additional sox proteins, xsox17alfa and xsox3 , likewise bind to beta-catenin and inhibit its tcf-mediated signaling activity	SIGNOR-72006	0.674
F2R	protein	P25116	UNIPROT	RAB3A	protein	P20336	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21072196	f		miannu	Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer.	SIGNOR-254845	0.2
GSK3B	protein	P49841	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000782								16407239	t		lperfetto	Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) .	SIGNOR-217430	0.38
CSNK2A1	protein	P68400	UNIPROT	CASP2	protein	P42575	UNIPROT	down-regulates	phosphorylation	Ser157	LYKKLRLsTDTVEHS	9606									16193064	t		gcesareni	Here we show that protein kinase (pk) ck2 phosphorylates procaspase-2 directly at serine-157. When intracellular pkck2 activity is low or downregulated by specific inhibitors, procaspase-2 is dephosphorylated, dimerized, and activated in a piddosome-independent manner.	SIGNOR-140836	0.313
PRKAA1	protein	Q13131	UNIPROT	NR2C2	protein	P49116	UNIPROT	down-regulates	phosphorylation	Ser351	HVISRDQsTPIIEVE	9606			SIGNOR-C15						21478464	t		gcesareni	Tr4 transactivation is inhibited via phosphorylation bymetformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression	SIGNOR-173118	0.2
CDK7	protein	P50613	UNIPROT	POLR2A	protein	P24928	UNIPROT	down-regulates	phosphorylation	Ser1724	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120024	0.781
FGF2	protein	P09038	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates				9606									11781339	f		gcesareni	In these collagen gel cultures, p38 activation was induced more potently by fgf-2 treatment compared with that in proliferating cultures	SIGNOR-113649	0.402
ATM	protein	Q13315	UNIPROT	CREB1	protein	P16220	UNIPROT	down-regulates activity	phosphorylation	Ser97	TIAESEDsQESVDSV	9606									15073328	t		lperfetto	Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivophosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp)	SIGNOR-124043	0.538
MAP2K4	protein	P45985	UNIPROT	MAPK13	protein	O15264	UNIPROT	up-regulates activity	phosphorylation	Tyr182	ADAEMTGyVVTRWYR	9606	BTO:0000007								10066767	t	done	miannu	 p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.	SIGNOR-273955	0.436
CDP-diacylglycerol(2-)	smallmolecule	CHEBI:58332	ChEBI	PGS1	protein	Q32NB8	UNIPROT	up-regulates activity	chemical activation			9606									29034233	t		lperfetto	After activation of PA by the CDP-DAG synthase TAMM41 (Kutik et al., 2008), the phosphatidylglycerol phosphate synthase (PGS1) catalyzes the committed step by converting CDP-DAG to phosphatidylglycerol phosphate (PGP)	SIGNOR-267024	0.8
PTGFR	protein	P43088	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256953	0.252
AKT3	protein	Q9Y243	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser315	DFRSRTNsNASTVSG	9606	BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527								19188143	t		gcesareni	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252878	0.697
IL9	protein	P15248	UNIPROT	IL9R	protein	Q01113	UNIPROT	up-regulates	binding			9606									10642536	t		fspada	Interleukin 9 (il-9) exerts its pleiotropic effects through the il-9 receptor (il-9r) complex, which consists of the il-9r alpha-chain, which determines the cytokine specificity, and the il-2 receptor gamma-chain	SIGNOR-73601	0.742
SUFU	protein	Q9UMX1	UNIPROT	GLI2	protein	P10070	UNIPROT	down-regulates activity	relocalization			10090									16316410	t		lperfetto	We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms	SIGNOR-129065	0.907
MAP2K6	protein	P52564	UNIPROT	MAPK13	protein	O15264	UNIPROT	up-regulates	phosphorylation			9606									8663074	t		gcesareni	Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily.	SIGNOR-42390	0.645
UVRAG	protein	Q9P2Y5	UNIPROT	PIK3C3	protein	Q8NEB9	UNIPROT	up-regulates activity	binding			9606									18843052	t		lperfetto	Although both human atg14 and uvrag interact with beclin 1 and vps34.	SIGNOR-181554	0.803
CDK2	protein	P24941	UNIPROT	RRN3	protein	Q9NYV6	UNIPROT	up-regulates	phosphorylation	Ser44	LENDFFNsPPRKTVR	9606			SIGNOR-C16						15004009	t		miannu	Cdk2/cyclin e-mediated phosphorylation at ser 44 activates tif-ia	SIGNOR-123231	0.485
SHANK3	protein	Q9BYB0	UNIPROT	GRIA4	protein	P48058	UNIPROT	up-regulates quantity	binding			9606	BTO:0000938								28179641	t		miannu	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264604	0.2
GSK3B	protein	P49841	UNIPROT	MYC	protein	P01106	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr58	KKFELLPtPPLSPSR	9606									14563837	t		gcesareni	Conversely, overexpression of gsk-3 alpha or gsk-3 beta enhances thr-58 phosphorylation and ubiquitination of c-myc	SIGNOR-118844	0.709
MARCHF9	protein	Q86YJ5	UNIPROT	PVR	protein	P15151	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001522								19457934	t		miannu	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets. 	SIGNOR-271530	0.2
DAB2IP	protein	Q5VWQ8	UNIPROT	HIF1A	protein	Q16665	UNIPROT	down-regulates quantity by destabilization				9606									27476001	f		miannu	DAB2IP destabilizes HIF1α protein to inhibit EMT in PCa cells. DAB2IP may destabilize HIF1α protein in PCa cells via an ubiquitin-proteasome system.	SIGNOR-254765	0.2
CSNK2A1	protein	P68400	UNIPROT	NFKBIA	protein	P25963	UNIPROT	down-regulates	phosphorylation	Ser293	EESYDTEsEFTEFTE	9606	BTO:0000782								8622692	t		llicata	Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation.	SIGNOR-40510	0.566
NLK	protein	Q9UBE8	UNIPROT	SETDB1/NLK/CHD7	complex	SIGNOR-C189	SIGNOR	form complex	binding			10090									21952300	t		FFerrentino	The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43.	SIGNOR-253525	0.423
PSMC5	protein	P62195	UNIPROT	26S Proteasome	complex	SIGNOR-C307	SIGNOR	form complex	binding			9606	BTO:0000007								29636472	t		lperfetto	Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line	SIGNOR-263372	0.877
MAPK1	protein	P28482	UNIPROT	ALOX5	protein	P09917	UNIPROT	up-regulates activity	phosphorylation	Ser272	CSLERQLsLEQEVQQ	9606	BTO:0000567								12670876	t		lperfetto	Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells.	SIGNOR-264439	0.391
CSNK2A1	protein	P68400	UNIPROT	TOP2A	protein	P11388	UNIPROT	up-regulates	phosphorylation	Ser1525	PIKYLEEsDEDDLF	9606									19098900	t		gcesareni	Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin	SIGNOR-182840	0.613
FBXW7	protein	Q969H0	UNIPROT	JUN	protein	P05412	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								14739463	t		miannu	 We report that in neurons the stability of c-Jun is regulated by the E3 ligase SCF(Fbw7), which ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation. 	SIGNOR-272950	0.509
CHFR	protein	Q96EP1	UNIPROT	HDAC1	protein	Q13547	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000567								19182791	t		miannu	Histone deacetylase 1 (HDAC1), which represses transcription by deacetylating histones, was newly isolated as a Chfr-interacting protein. Chfr binds and downregulates HDAC1 by inducing its polyubiquitylation, both in vitro and in vivo. Together, these results suggest that the ubiquitin ligase activity of Chfr targets HDAC1 for degradation.	SIGNOR-271465	0.403
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	GSK3B	protein	P49841	UNIPROT	down-regulates activity	phosphorylation	Ser9	SGRPRTTsFAESCKP	10090	BTO:0002572								28646232	t		Gianni	We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels	SIGNOR-262522	0.2
CREB1	protein	P16220	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16205321	f		gcesareni	The results showed that the nuclear pkcalpha was significantly decreased in the liver during sepsis, which was accompanied by decreases in phospho-creb content, dna-binding activity of creb, and bcl-xl expression.	SIGNOR-140911	0.369
PRKCA	protein	P17252	UNIPROT	RGS7	protein	P49802	UNIPROT	down-regulates activity	phosphorylation			-1									12077120	t		miannu	TNF-α rapidly increases the concentration of functionally active RGS7 protein through two mechanisms. TNF-induced dephosphorylation of serine 434 liberates RGS7 from 14-3-3 binding and inhibition. , PKC α catalyzes the incorporation of phosphate into a truncation of RGS7 fused to maltose-binding protein (MBP.RGS7315–469).	SIGNOR-263165	0.371
E2F1	protein	Q01094	UNIPROT	CDC25A	protein	P30304	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								11154267	f		lperfetto	Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen	SIGNOR-245468	0.536
PRKDC	protein	P78527	UNIPROT	PDX1	protein	P52945	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr11	EEQYYAAtQLYKDPC	10090									16166097	t		miannu	The interaction of PDX-1 with Ku subunits and its phosphorylation on threonine 11 by the DNA-PK appear to be implicated in its degradation by the proteosome.	SIGNOR-225542	0.311
PAX8	protein	Q06710	UNIPROT	SLC5A5	protein	Q92911	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									14623893	t		miannu	Pax8 has an essential role in thyroid organogenesis and differentiation, being the main mediator of thyroid gene transcription, including the NIS gene.	SIGNOR-251990	0.42
abiraterone acetate	chemical	CHEBI:68639	ChEBI	CYP17A1	protein	P05093	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-205573	0.8
TFIIA	complex	SIGNOR-C395	SIGNOR	RNA Polymerase II	complex	SIGNOR-C391	SIGNOR	up-regulates activity	relocalization			9606									7724559	t		lperfetto	The human general transcription factor TFIIA is one of several factors involved in specific transcription by RNA polymerase II	SIGNOR-266200	0.651
RAP1A	protein	P62834	UNIPROT	BRAF	protein	P15056	UNIPROT	up-regulates activity	binding			9606	BTO:0002181								24290981	t		miannu	Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity.Increased intracellular concentrations of cAMP enhanced the Rapgef2-dependent activation of Rap1, which in turn associated with B-Raf to enable the activation of ERK and subsequent neuronal- and endocrine-specific cellular outcomes, such as induction of neuroendocrine-specific genes and extension of neuritic processes (neuritogenesis).	SIGNOR-276608	0.677
TFEB	protein	P19484	UNIPROT	CYP17A1	protein	P05093	UNIPROT	up-regulates quantity by expression	transcriptional regulation												33176151	f		lperfetto	Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2)	SIGNOR-276786	0.2
UBQLN4	protein	Q9NRR5	UNIPROT	MRE11	protein	P49959	UNIPROT	up-regulates activity	binding			9606	BTO:0001938								30612738	t		lperfetto	These data suggest that MRE11 is one of probably many UBQLN4 interaction partners. >Particularly HRR is dependent on ATM activity (Dietlein et al., 2014). Here, we showed that UBQLN4 is an ATM substrate and that DSB sealing is markedly impaired in UBQLN4-depleted cells. HRR depends on a 5′-3′ DSB end resection, which is initiated by the MRE11 nuclease	SIGNOR-265077	0.2
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	MASTL	protein	Q96GX5	UNIPROT	up-regulates activity	phosphorylation	Thr194	NMMDILTtPSMAKPR	9606	BTO:0002181								24391510	t		miannu	We demonstrate that PP2A/B55 is required for Gwl dephosphorylation at the essential Cdk site Thr194.Gwl phosphorylation by CycA/Cdk2 in vitro. Flag WT and Thr194A Gwl was transiently expressed and purified from asynchronous HEK 293T cells and incubated with recombinant CycA/Cdk2, following treatment with alkaline phosphatase (aPh) in the indicated samples. The proteins were analysed by immuno-blotting with anti-Gwl and Gwl pThr194 antibodies	SIGNOR-276614	0.278
EIF3E	protein	P60228	UNIPROT	EIF3_complex	complex	SIGNOR-C401	SIGNOR	form complex	binding			-1									16920360	t		miannu	Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 	SIGNOR-266396	0.94
PCDHA2	protein	Q9Y5H9	UNIPROT	PCDHGB6	protein	Q9Y5F9	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265684	0.2
NR0B2	protein	Q15466	UNIPROT	AR	protein	P10275	UNIPROT	down-regulates	binding			9606									11735420	t		gcesareni	We demonstrated that shp inhibited both ar-lbd and ntd-dependent transactivation, which evidenced for the first time a protein capable of inhibiting a steroid receptor amino-terminal-dependent transactivation. We further characterized the shp mechanism of action by showing that shp reversed ar coactivator-mediated activation	SIGNOR-112589	0.425
UCHL5	protein	Q9Y5K5	UNIPROT	INO80 complex	complex	SIGNOR-C498	SIGNOR	form complex	binding			9606									25016522	t		miannu	Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication.	SIGNOR-270852	0.597
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	CDK7	protein	P50613	UNIPROT	up-regulates activity	phosphorylation	Ser164	GLAKSFGsPNRAYTH	-1									11113184	t		lperfetto	Activating phosphorylation of CDK7 by CDC2 and CDK2. The ability of pure CDK2-cyclin A to activate CDK7 in T170-dependent fashion (Fig. ​(Fig.3C,3C, lane 2) strongly suggested a direct phosphorylation mechanism. Tryptic phosphopeptide mapping confirmed that both CDK2-cyclin A (Fig. ​(Fig.4A)4A) and CDC2-cyclin B (Fig. ​(Fig.4D)4D) phosphorylated CDK7 on both S164 and T170. 	SIGNOR-270807	0.629
PAMPs	stimulus	SIGNOR-ST11	SIGNOR	NLRP1	protein	Q9C000	UNIPROT	up-regulates activity													16037825	f		lperfetto	Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage	SIGNOR-256425	0.7
erlotinib hydrochloride	chemical	CHEBI:53509	ChEBI	EGFR	protein	P00533	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001271								17178722	t	JAK2(V617F), a mutant of tyrosine kinase JAK2. Erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor.	gcesareni	This study shows that the anti-cancer drug erlotinib (tarceva) is a potent inhibitor of jak2(v617f) activity.	SIGNOR-151271	0.8
ZBTB20	protein	Q9HC78	UNIPROT	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	up-regulates				10090									29748916	f		miannu	The transcription factor (TF) Zbtb20 is important for the hippocampal specification and the regulation of neurogenesis of neocortical projection neurons. Herein, we show a critical involvement of the TF Zbtb20 in the neurogenesis of both projection neurons and interneurons of the olfactory bulb during embryonic stages	SIGNOR-266866	0.7
PTGES2	protein	Q9H7Z7	UNIPROT	prostaglandin E2(1-)	smallmolecule	CHEBI:606564	ChEBI	up-regulates quantity	chemical modification			-1									10922363	t		Luana	Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently.	SIGNOR-269766	0.8
TFDP1	protein	Q14186	UNIPROT	E2F1	protein	Q01094	UNIPROT	up-regulates activity	binding			9606									14618416	t		miannu	DP-1 is a heterodimerization partner for members of the E2F family of transcription factors; E2F/DP-1 regulates the expression of various cellular promoters, particularly gene products that are involved in the cell cycle. 	SIGNOR-253865	0.806
3-methoxytyramine	smallmolecule	CHEBI:1582	ChEBI	3,4-dihydroxyphenylacetaldehyde	smallmolecule	CHEBI:27978	ChEBI	up-regulates quantity	precursor of			9606									NBK536726	t	brain	lperfetto	Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells |dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO.	SIGNOR-264179	0.8
EGR1	protein	P18146	UNIPROT	BCAR1	protein	P56945	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000093								22431919	f		miannu	 Overexpression or short interfering RNA (siRNA)-mediated down-regulation of EGR1 or NAB2, and chromatin immunoprecipitations indicated that EGR1 and NAB2 act in concert to positively regulate p130(Cas)/BCAR1 expression in breast cancer cells.	SIGNOR-253890	0.2
SH3PXD2A	protein	Q5TCZ1	UNIPROT	NOXA1	protein	Q86UR1	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								20943948	t		lperfetto	Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation	SIGNOR-264708	0.42
GTP	smallmolecule	CHEBI:15996	ChEBI	GNAI1	protein	P63096	UNIPROT	up-regulates	chemical activation			9606									12040175	t		gcesareni	Agonist binding triggers a conformational change in the receptor, which catalyses the dissociation of gdp from the alfa subunit followed by gtp-binding to galfa and the dissociation of galfa from gbetagamma subunits1. The alfa subunits of g proteins are divided into four subfamilies: galfas, galfai, galfaq and galfa12, and a single gpcr can couple to either one or more families of galfa proteins.	SIGNOR-88238	0.8
VARS1	protein	P26640	UNIPROT	alpha-aminoacyl-tRNA	smallmolecule	CHEBI:2651	ChEBI	up-regulates quantity	chemical modification			9606									14660560	t		miannu	Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 	SIGNOR-270797	0.8
TYMS	protein	P04818	UNIPROT	Purine biosynthesis	phenotype	SIGNOR-PH186	SIGNOR	up-regulates				9606									21876188	t		lperfetto	In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS.	SIGNOR-253139	0.7
SRC	protein	P12931	UNIPROT	PROM1	protein	O43490	UNIPROT	unknown	phosphorylation	Tyr852	GYHKDHVyGIHNPVM	9606									19296573	t		llicata	Cd133 (prominin-1) is phosphorylated on cytoplasmic tyrosine-828 and tyrosine-852 by src	SIGNOR-184776	0.515
PPM1D	protein	O15297	UNIPROT	RPS6KA3	protein	P51812	UNIPROT	down-regulates activity	dephosphorylation	Ser369	TAKTPKDsPGIPPSA	10090									15206906	t			RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity	SIGNOR-248321	0.369
USP9X	protein	Q93008	UNIPROT	EPS15	protein	P42566	UNIPROT	down-regulates activity	deubiquitination			9606									26748853	t		gcesareni	We identify the endocytic protein Eps15 as one of the critical substrates of USP9X	SIGNOR-245052	0.275
MED19	protein	A0JLT2	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266663	0.846
SP1	protein	P08047	UNIPROT	SCNN1A	protein	P37088	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004299								12684058	f	Regulation of expression	miannu	Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression.	SIGNOR-251950	0.2
PRKAA1	protein	Q13131	UNIPROT	GLI1	protein	P08151	UNIPROT	down-regulates activity	phosphorylation	Ser102	LQTVIRTsPSSLVAF	9606									26190112	t		Luana	AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency.	SIGNOR-259861	0.339
YWHAQ	protein	P27348	UNIPROT	NEFL	protein	P07196	UNIPROT	down-regulates activity	binding			9606									23230147	t		miannu	These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments.	SIGNOR-252399	0.304
FBXW11	protein	Q9UKB1	UNIPROT	AICDA	protein	Q9GZX7	UNIPROT	down-regulates quantity by destabilization	binding			9606	BTO:0000007								31092637	t		miannu	 Further analysis indicated that CUL7 mediated AID ubiquitination by forming a complex with FBXW11. In a CUL7 fl/fl CD19 cre+ mouse model, we demonstrated that CUL7 knockout significantly enhanced AID protein levels in B cells in the germinal center and increased both the IgG1 and IgA class switching. Collectively, our results reveal a subtle regulation mechanism for tightly controlling AID protein levels. F-box proteins are components of SCF ubiquitin-ligase complexes that contain Skp1, CUL1, or CUL7, and an F-box protein	SIGNOR-272024	0.2
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CDH23	protein	Q9H251	UNIPROT	up-regulates activity	chemical activation			9606									22535893	t		miannu	Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis.	SIGNOR-265839	0.8
C3 convertase complex (C3bBb)	complex	SIGNOR-C314	SIGNOR	C3	protein	P01024	UNIPROT	up-regulates activity	cleavage	Arg748	ASHLGLArSNLDEDI	9606		BTO:0000089							26489954	t		lperfetto	In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC).	SIGNOR-263478	0.903
AMPK	complex	SIGNOR-C15	SIGNOR	GAPDH	protein	P04406	UNIPROT	up-regulates activity	phosphorylation	Ser122	GAKRVIIsAPSADAP	10090									26626483	t		miannu	Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated. 	SIGNOR-267578	0.322
ACVR1	protein	Q04771	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	down-regulates activity				9606									18801898	f		gcesareni	Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle.	SIGNOR-243185	0.25
PTGS2	protein	P35354	UNIPROT	prostaglandin E2(1-)	smallmolecule	CHEBI:606564	ChEBI	up-regulates quantity	chemical modification			9606									16540375	t			Arachidonic acid is transformed into PGE2 via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES)	SIGNOR-255684	0.8
CSK	protein	P41240	UNIPROT	SRC	protein	P12931	UNIPROT	down-regulates	phosphorylation	Tyr530	FTSTEPQyQPGENL	9606									18614016	t		gcesareni	The catalytic activity of the src family of tyrosine kinases is suppressed by phosphorylation on a tyrosine residue located near the c terminus (tyr 527 in c-src), which is catalyzed by c-terminal src kinase (csk).	SIGNOR-179417	0.55
CRCP	protein	O75575	UNIPROT	RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	form complex	binding			9606	BTO:0000567								12391170	t		lperfetto	In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights.	SIGNOR-266134	0.792
RARB	protein	P10826	UNIPROT	RXRB	protein	P28702	UNIPROT	up-regulates	binding			9606									1310351	t		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16581	0.65
MRPL43	protein	Q8N983	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262353	0.684
PLK3	protein	Q9H4B4	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	up-regulates	phosphorylation	Ser49	ESEMETPsAINGNPS	9606									21336504	t		lperfetto	Polo kinase 3 (plk3) was implicated in bcl-xl(ser49) phosphorylation. These data indicate that, during g2 checkpoint, phospho-bcl-xl(ser49) is another downstream target of plk3, acting to stabilize g2 arrest.	SIGNOR-172230	0.399
CDK1	protein	P06493	UNIPROT	LBR	protein	Q14739	UNIPROT	down-regulates	phosphorylation	Ser71	KGGSTSSsPSRRRGS	9606									14718546	t		lperfetto	The binding of the nk fragment to chromatin pretreated with an s-phase extract was suppressed by incubation with an m-phase extract. Enzyme inhibitor experiments revealed that multiple kinases participate in the suppression. One of these kinases was shown to be cdc2 experiments involving a mutant nk fragment showed that the phosphorylation of serine 71 by cdc2 kinase is responsible for the suppression.	SIGNOR-121335	0.406
PCDHA10	protein	Q9Y5I2	UNIPROT	ITGB1	protein	P05556	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 	SIGNOR-265664	0.2
GGCX	protein	P38435	UNIPROT	F9	protein	P00740	UNIPROT	up-regulates activity	carboxylation	Glu82	REVFENTeRTTEFWK	10090		BTO:0001103							11133752	t		lperfetto	The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.	SIGNOR-263695	0.67
LCK	protein	P06239	UNIPROT	CTLA4	protein	P16410	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Tyr201	SPLTTGVyVKMPPTE	9606									9973379	t			Lck and Fyn, but not ZAP70, induce tyrosine phosphorylation of CTLA-4 in the cell line HEK293. Phosphorylation of CTLA-4 occurs on both Y201 and Y218. Phosphorylation of Y201 correlated with accumulation of CTLA-4 on the cell surface.	SIGNOR-251370	0.74
PRKCA	protein	P17252	UNIPROT	FERMT3	protein	Q86UX7	UNIPROT	up-regulates activity	phosphorylation	Ser484	LSLQRTGsGGPGNHP	9606	BTO:0000565								25609252	t		miannu	 PKC-induced phosphorylation events, as we have shown kindlin-3 to be a PKC phosphorylation target (Fig. 6C), are often followed by rapid activation of phosphatases (38). 	SIGNOR-266415	0.2
PDGFRB	protein	P09619	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation			9606									8195171	t		gcesareni	In this study, we have characterized the interaction between the pdgf beta-receptor and shc. multiple autophosphorylation sites in the pdgf beta-receptor are responsible for the binding of shc.	SIGNOR-36906	0.645
SSU72	protein	Q9NP77	UNIPROT	POLR2A	protein	P24928	UNIPROT	up-regulates activity	dephosphorylation	Ser1724	SPSYSPTsPSYSPTS	-1									15125841	t			Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248812	0.849
PRKAA1	protein	Q13131	UNIPROT	STIM1	protein	Q13586	UNIPROT	down-regulates activity	phosphorylation	Ser257	GLHRAEQsLHDLQER	10090	BTO:0000452								31381180	t		miannu	STIM1 is a novel exercise‐regulated AMPK substrate. Phosphorylation of STIM1 by AMPK suppresses SOCE	SIGNOR-277299	0.2
SDHA	protein	P31040	UNIPROT	Mitochondrial respiratory chain complex II	complex	SIGNOR-C278	SIGNOR	form complex	binding												30030361	t		lperfetto	Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites	SIGNOR-262188	0.95
4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine	smallmolecule	CHEBI:94284	ChEBI	GLI2	protein	P10070	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150;BTO:0000551								19860666	t		gcesareni	Both molecules gant58 and gant61 were capable of interfering with gli1 as well as gli2-mediated transcription in a dose-dependent manner	SIGNOR-188866	0.8
CDC7	protein	O00311	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates	phosphorylation	Ser40	RRTDALTsSPGRDLP	9606									19647517	t		lperfetto	Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry	SIGNOR-187392	0.961
PHF5A	protein	Q7RTV0	UNIPROT	U2 snRNP complex	complex	SIGNOR-C479	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270670	0.763
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	RNF11	protein	Q9Y3C5	UNIPROT	down-regulates quantity	phosphorylation	Thr135	DWLMRSFtCPSCMEP	9606	BTO:0003474								16123141	t		gcesareni	Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity	SIGNOR-248085	0.2
PPP2CA	protein	P67775	UNIPROT	AKT1	protein	P31749	UNIPROT	down-regulates activity	dephosphorylation	Ser473	RPHFPQFsYSASGTA	9606									18160256	t			Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248628	0.889
EIF3K	protein	Q9UBQ5	UNIPROT	EIF3_complex	complex	SIGNOR-C401	SIGNOR	form complex	binding			-1									16920360	t		miannu	Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 	SIGNOR-266390	0.921
glycogen	smallmolecule	CHEBI:28087	ChEBI	alpha-D-glucose 1-phosphate(2-)	smallmolecule	CHEBI:58601	ChEBI	up-regulates quantity	precursor of			9606									3346228	t			Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate.	SIGNOR-267955	0.8
MAPK10	protein	P53779	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation			9606									14699954	t		amattioni	The targets of jnk include the transcription factors p53. P75ntr-mediated apoptosis was shown to be dependent of p53	SIGNOR-120552	0.616
ERBB4	protein	Q15303	UNIPROT	PI3K	complex	SIGNOR-C156	SIGNOR	up-regulates	binding			9606									16729043	t		gcesareni	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-252674	0.542
MAPKAPK2	protein	P49137	UNIPROT	HSPB1	protein	P04792	UNIPROT	down-regulates	phosphorylation	Ser82	RALSRQLsSGVSEIR	9606	BTO:0000938								12367505	t	10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro.	gcesareni	Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27.	SIGNOR-94025	0.803
RFX complex	complex	SIGNOR-C104	SIGNOR	HLA-DRB3	protein	P79483	UNIPROT	up-regulates quantity by expression	transcriptional regulation			-1									11258423	f	 	 	The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex	SIGNOR-254001	0.2
SMARCD3	protein	Q6STE5	UNIPROT	MYOG	protein	P15173	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15870273	f		lperfetto	We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by MyoD and other regulatory proteins. 	SIGNOR-136945	0.361
RPS6KA5	protein	O75582	UNIPROT	EIF4EBP1	protein	Q13541	UNIPROT	down-regulates activity	phosphorylation	Thr70	RNSPVTKtPPRDLPT										12213813	t		lperfetto	In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E	SIGNOR-262994	0.658
PCK1	protein	P35558	UNIPROT	phosphonatoenolpyruvate	smallmolecule	CHEBI:58702	ChEBI	up-regulates quantity	chemical modification			9606									30193097	t		miannu	 PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP). 	SIGNOR-266587	0.8
MEN1	protein	O00255	UNIPROT	TERT	protein	O14746	UNIPROT	down-regulates				9606									12837246	f		miannu	The tumor suppressor menin, is a direct repressor of htert	SIGNOR-102874	0.312
dactolisib	chemical	CHEBI:71952	ChEBI	PI3K	complex	SIGNOR-C156	SIGNOR	down-regulates	chemical inhibition			9606	BTO:0000848								21803746	t	ATP-competitive inhibitor of PI3K and mTOR	gcesareni	The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific	SIGNOR-252665	0.8
MED10	protein	Q9BTT4	UNIPROT	Core mediator complex	complex	SIGNOR-C405	SIGNOR	form complex	binding			9606									28467824	t		miannu	Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 	SIGNOR-266656	0.843
RNF8	protein	O76064	UNIPROT	UBE2N	protein	P61088	UNIPROT	up-regulates	binding			9606									18678647	t		gcesareni	The rnf8 ring domain signals ubc13 to sites of damage, which is sufficient for dna damage signal transduction.	SIGNOR-179823	0.74
AKT1	protein	P31749	UNIPROT	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity	phosphorylation			9606									20138985	t		lperfetto	Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1.	SIGNOR-252539	0.72
RBPJ/NOTCH	complex	SIGNOR-C97	SIGNOR	PAX7	protein	P23759	UNIPROT	up-regulates quantity by expression	transcriptional regulation					BTO:0001103							22493066	f		svumbaca	Both binding sites were enriched by more than 5-fold in the ChIP assay with RBP-Jk antibody, suggesting that RBP-Jk occupies these sequences in the Pax7 promoter region.	SIGNOR-255365	0.386
ARAF	protein	P10398	UNIPROT	MEK1/2	proteinfamily	SIGNOR-PF25	SIGNOR	up-regulates	phosphorylation			9606	BTO:0000567								8621729	t		lperfetto	Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling.	SIGNOR-244813	0.742
NFIA	protein	Q12857	UNIPROT	EPHA5	protein	P54756	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268895	0.2
Scribble_complex_DLG2-LLGL2_variant	complex	SIGNOR-C503	SIGNOR	Cell_polarity	phenotype	SIGNOR-PH213	SIGNOR	up-regulates				9606									23397623	f		miannu	The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 	SIGNOR-270882	0.7
PRKAA1	protein	Q13131	UNIPROT	CTBP1	protein	Q13363	UNIPROT	down-regulates	phosphorylation	Ser158	REGTRVQsVEQIREV	9606			SIGNOR-C15						23291169	t		lperfetto	We found that an activated amp-activated protein kinase (ampk) phosphorylates ctbp1 on ser-158 upon metabolic stresses. Moreover, ampk-mediated phosphorylation of ctbp1 (s158) attenuates the repressive function of ctbp1	SIGNOR-200250	0.2
IRAK1	protein	P51617	UNIPROT	PELI3	protein	Q8N2H9	UNIPROT	up-regulates	phosphorylation			9606									17997719	t		gcesareni	Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity.	SIGNOR-159052	0.717
PTPRC	protein	P08575	UNIPROT	LCK	protein	P06239	UNIPROT	up-regulates activity	dephosphorylation	Tyr505	FTATEGQyQPQP	9606									11259588	t			Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity	SIGNOR-248350	0.79
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	RPTOR	protein	Q8N122	UNIPROT	up-regulates activity	phosphorylation	Ser863	LTQSAPAsPTNKGVH	9606				SIGNOR-C3					21071439	t		lperfetto	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-174878	0.2
1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	PRKCH	protein	P24723	UNIPROT	up-regulates activity	binding			9606									14967450	t	PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine.	lperfetto	The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified.	SIGNOR-242593	0.8
TNK2	protein	Q07912	UNIPROT	AKT	proteinfamily	SIGNOR-PF24	SIGNOR	up-regulates activity	phosphorylation	Tyr176	EKATGRYyAMKILKK	10090		BTO:0002021							20333297	t		gcesareni	Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation.	SIGNOR-252457	0.437
RPS6KA5	protein	O75582	UNIPROT	H3C1	protein	P68431	UNIPROT	down-regulates activity	phosphorylation	Ser11	TKQTARKsTGGKAPR	9606									10464286	t	Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory).	gcesareni	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-70444	0.2
ESR1	protein	P03372	UNIPROT	PIK3R2	protein	O00459	UNIPROT	up-regulates	binding			9606									16169518	t		gcesareni	Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k.	SIGNOR-140473	0.525
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	Neurogenesis	phenotype	SIGNOR-PH168	SIGNOR	up-regulates				10090	BTO:0000938								12676795	f		Luana	Activation of the Ras-MAPK/Erk signaling cascade is essential for neurotrophin-promoted differentiation of neurons and PC12 cells. 	SIGNOR-264978	0.7
IL10	protein	P22301	UNIPROT	SCN8A	protein	Q9UQD0	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116	BTO:0000938	BTO:0001264							23357618	f		miannu	Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α.	SIGNOR-253501	0.2
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	GAB1	protein	Q13480	UNIPROT	up-regulates activity	phosphorylation	Ser597	VPMNPNLsSEDPNLF	9606									15379552	t		lperfetto	Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597)	SIGNOR-129192	0.2
propranolol	chemical	CHEBI:8499	ChEBI	ADRB2	protein	P07550	UNIPROT	down-regulates activity	chemical inhibition			10030									10079020	t		Luana	Similarly, the binding affinities of ICI 118–551, CGP 20712A, propranolol, bupranolol and CGP 12177 for human β1-, β2- and β3-adrenoceptors correlate with their affinities at human β1- (P=0.04), β2- (P=0.01)	SIGNOR-258334	0.8
MECP2	protein	P51608	UNIPROT	MEF2C	protein	Q06413	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000614								18511691	t		Luana	MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.	SIGNOR-264680	0.354
PCDHA10	protein	Q9Y5I2	UNIPROT	PCDHGB3	protein	Q9Y5G1	UNIPROT	up-regulates activity	binding			9606		BTO:0000227							16697637	t		miannu	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265707	0.2
SELPLG	protein	Q14242	UNIPROT	SELP	protein	P16109	UNIPROT	up-regulates	binding			9606	BTO:0000130								23994464	t		apalma	This steady-state rolling is primarily mediated by the interaction of endothelial P-selectins with their neutrophil glycoprotein counterreceptors, primarily PSGL-1.	SIGNOR-255038	0.925
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates	phosphorylation	Ser319	TFRPRTSsNASTISG	9606									11237865	t		lperfetto	The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus	SIGNOR-252835	0.908
USP10	protein	Q14694	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	deubiquitination			9606	BTO:0003704								21962518	t		lperfetto	Since USP10 is known as a deubiquitinating protease of p53 (Yuan et al., 2010), inhibition of USP10 by spautin-1 may promote the degradation of p53. 	SIGNOR-260297	0.648
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	ACAP1	protein	Q15027	UNIPROT	unknown	phosphorylation	Ser554	SIRPRPGsLRSKPEP	9606									16256741	t		llicata	Akt phosphorylates s554 in acap1	SIGNOR-141343	0.2
ADAM10	protein	O14672	UNIPROT	CDH1	protein	P12830	UNIPROT	up-regulates activity	cleavage			9606									26284334	t		miannu	The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. 	SIGNOR-259846	0.529
MRPL27	protein	Q9P0M9	UNIPROT	39S mitochondrial large ribosomal subunit	complex	SIGNOR-C285	SIGNOR	form complex	binding			-1									25838379	t		lperfetto	We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules	SIGNOR-262368	0.693
RHCE	protein	P18577	UNIPROT	Ankyrin complex	complex	SIGNOR-C383	SIGNOR	form complex	binding			9606	BTO:0000424								22465511	t		lperfetto	The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) 	SIGNOR-266022	0.328
ABL1	protein	P00519	UNIPROT	ERCC6	protein	Q03468	UNIPROT	up-regulates activity	phosphorylation	Tyr932	GANRVVIyDPDWNPS	9606									17626041	t	Regulation	miannu	N-terminal region of CSB interacts with the SH3 domain of c-Abl in vitro and in vivo. In addition, c-Abl kinase phosphorylates CSB at Tyr932. our results suggest that c-Abl interacts with and tyrosine phosphorylates CSB. This interaction may play an important role in the response to oxidative stress, resulting in activation of c-Abl, tyrosine phosphorylation of CSB and more efficient BER of oxidative DNA damage. Tyrosine-phosphorylated CSB may serve as a signal for repair proteins to localize to DNA damage and may help maintain active transcription in the nucleolus. 	SIGNOR-251933	0.274
HOMER	proteinfamily	SIGNOR-PF59	SIGNOR	SHANK3	protein	Q9BYB0	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								17243894	t		miannu	It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD	SIGNOR-264697	0.2
RNF38	protein	Q9H0F5	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates activity	ubiquitination			9606	BTO:0000007								23973461	t		miannu	Here we demonstrate that RNF38 is a functional ubiquitin protein ligase (E3). We show that RNF38 isoform 1 is localized to the nucleus by a bipartite nuclear localization sequence (NLS). We confirm that RNF38 is a binding partner of p53 and demonstrate that RNF38 can ubiquitinate p53 in vitro and in vivo. Finally, we show that overexpression of RNF38 in HEK293T cells results in relocalization of p53 to discrete foci associated with PML nuclear bodies. 	SIGNOR-272130	0.371
RIPK1	protein	Q13546	UNIPROT	RIPK1	protein	Q13546	UNIPROT	up-regulates activity	phosphorylation	Ser20	KSSDFLEsAELDSGG	-1									18408713	t		miannu	These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1)	SIGNOR-276160	0.2
F-actin_assembly	phenotype	SIGNOR-PH18	SIGNOR	Platelet_degranulation	phenotype	SIGNOR-PH138	SIGNOR	down-regulates				9606	BTO:0000132								23805129	f		lperfetto	Inhibition of actin polymerization also augments the kinetics and degree of alpha-granule release (Flaumenhaft et al., 2005). These results suggest that F-actin disassembly might actually be required for normal granule secretion and that activation-mediated granule release is related to actin.	SIGNOR-266000	0.7
UVB radiation	stimulus	SIGNOR-ST17	SIGNOR	GCH1	protein	P30793	UNIPROT	up-regulates				9606									9204951	f		miannu	UVB light induces GTP-CH.-1 to increase the de novo synthesis of 6-BH4 in association with a concomitant increase in PAH activities, thus providing more L-tyrosine. 	SIGNOR-252206	0.7
SNARE_complex 	complex	SIGNOR-C346	SIGNOR	Exocytosis	phenotype	SIGNOR-PH157	SIGNOR	up-regulates				9606	BTO:0000938								30267828	f		miannu	The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells.	SIGNOR-263969	0.7
SGK3	protein	Q96BR1	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser253	APRRRAVsMDNSNKY	9606	BTO:0000007								11154281	t		lperfetto	Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis.	SIGNOR-252992	0.449
IRF4	protein	Q15306	UNIPROT	M2_polarization	phenotype	SIGNOR-PH55	SIGNOR	up-regulates				9606									20729857	f		lperfetto	We found Irf4 to be one of the direct targets of Jmjd3-mediated demethylation. Finally, we found that Irf4 is a transcription factor crucial for the induction of M2 macrophage responses.	SIGNOR-249543	0.7
MAPK14	protein	Q16539	UNIPROT	H3-3A	protein	P84243	UNIPROT	unknown	phosphorylation			9606									10806218	t		gcesareni	More importantly, incubation of active erk2 or p38 kinase with h3 protein resulted in phosphorylation of h3 at serine 10 in vitro. These results suggest that erk and p38 kinase are at least two important mediators of phosphorylation of h3 at serine 10.	SIGNOR-77224	0.2
acetylcholine	smallmolecule	CHEBI:15355	ChEBI	CHRM3	protein	P20309	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258632	0.8
FOXO3	protein	O43524	UNIPROT	STK11	protein	Q15831	UNIPROT	down-regulates quantity	transcriptional regulation												22848740	t			SGK-1 Negatively Regulates LKB1 Expression via FOXO3 Transcription Factor	SIGNOR-255758	0.624
SPAG9	protein	O60271	UNIPROT	CDON/SPAG9	complex	SIGNOR-C21	SIGNOR	form complex	binding			9606	BTO:0000222								17074887	t		gcesareni	In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway.	SIGNOR-149178	0.477
PTEN	protein	P60484	UNIPROT	SH2B2	protein	O14492	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11494141	f		miannu	Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 	SIGNOR-260051	0.2
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	HYAL1	protein	Q12794	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0004796								18718911	f		miannu	 In 253J-Lung and HT1376 bladder cancer cell lines, which show high HYAL-1 expression, transcription factors Egr-1, AP-2, and NFκB bind the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription.	SIGNOR-253880	0.2
DAPK1	protein	P53355	UNIPROT	DDX58	protein	O95786	UNIPROT	down-regulates activity	phosphorylation	Thr667	ILTGRGKtNQNTGMT	9606	BTO:0002181								28132841	t		miannu	DAPK1 phosphorylates RIG-I in vitro at previously reported as well as other sites that limit 5'ppp-dsRNA sensing and virtually abrogate RIG-I activation.	SIGNOR-277336	0.337
ITGB1	protein	P05556	UNIPROT	A11/b1 integrin	complex	SIGNOR-C168	SIGNOR	form complex	binding												16988024	t		lperfetto	Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV.	SIGNOR-253188	0.694
RPS6KB1	protein	P23443	UNIPROT	CCT2	protein	P78371	UNIPROT	unknown	phosphorylation	Ser260	GSRVRVDsTAKVAEI	9606									19332537	t		llicata	Mass spectrometry and mutagenesis analysis revealed that rsk and s6k1 phosphorylate cct_ ser-260 in vitro and in intact cells	SIGNOR-184926	0.2
SPAG5	protein	Q96R06	UNIPROT	CDK5RAP2	protein	Q96SN8	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000567								26297806	t		lperfetto	By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically.	SIGNOR-271719	0.478
MYOG	protein	P15173	UNIPROT	Myog/SWI/SNF complex	complex	SIGNOR-C94	SIGNOR	form complex	binding			9606		BTO:0001103							17194702	t		miannu	Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle	SIGNOR-151691	0.633
TRIM63	protein	Q969Q1	UNIPROT	PSMD4	protein	P55036	UNIPROT	down-regulates quantity by destabilization	polyubiquitination	Lys122	SPVEDNEkDLVKLAK	-1									19240029	t		miannu	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). 	SIGNOR-272739	0.413
EEF1A1P5	protein	Q5VTE0	UNIPROT	Phe-tRNA(Phe)	smallmolecule	CHEBI:29153	ChEBI	up-regulates	relocalization			9606									23699257	t		lperfetto	During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 	SIGNOR-269560	0.8
MAPK8	protein	P45983	UNIPROT	ELK1	protein	P19419	UNIPROT	up-regulates activity	phosphorylation	Ser389	LSPIAPRsPAKLSFQ	9606	BTO:0000567								7651411	t		lperfetto	However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity.	SIGNOR-236432	0.494
NTN1	protein	O95631	UNIPROT	DSCAM	protein	O60469	UNIPROT	up-regulates activity	binding			10090	BTO:0001279								18585357	t		miannu	 Here, we report that the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons, binds netrin-1, and is necessary for commissural axons to grow toward and across the midline. DSCAM and DCC can each mediate a turning response of these neurons to netrin-1. 	SIGNOR-268376	0.724
LEF1	protein	Q9UJU2	UNIPROT	PITX2	protein	Q99697	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606		BTO:0000887							19850024	f		gcesareni	These results suggest that wnt/lef1 signaling regulates epaxial myogenesis via pitx2 but that this link is uncoupled in other regions of the body, emphasizing the unique molecular networks that control the development of various muscles in vertebrates. The pitx2 promoter contains tcf/lef binding sites and expression can be induced by licl, which activates the canonical wnt signaling pathway	SIGNOR-188730	0.708
GPR17	protein	Q13304	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256692	0.385
MAPKAPK2	protein	P49137	UNIPROT	ZFP36	protein	P26651	UNIPROT	down-regulates activity	phosphorylation	Ser186	PVLRQSIsFSGLPSG	-1									14688255	t		miannu	We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated.	SIGNOR-250152	0.687
RELA	protein	Q04206	UNIPROT	TRAF1	protein	Q13077	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									9733516	f		gcesareni	Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2.	SIGNOR-59957	0.531
GGCX	protein	P38435	UNIPROT	GAS6	protein	Q14393	UNIPROT	up-regulates activity	carboxylation			9606									31226734	t		lperfetto	Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.	SIGNOR-265923	0.505
HTR7	protein	P34969	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256926	0.432
PTPRJ	protein	Q12913	UNIPROT	LAT	protein	O43561	UNIPROT	down-regulates activity	dephosphorylation			9606									11259588	t			Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation	SIGNOR-248696	0.359
NBR1	protein	Q14596	UNIPROT	GABARAPL2	protein	P60520	UNIPROT	up-regulates	binding			9606	BTO:0000007								19250911	t		gcesareni	We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family.	SIGNOR-184267	0.735
CDK4	protein	P11802	UNIPROT	SMAD3	protein	P84022	UNIPROT	down-regulates activity	phosphorylation	Ser213	NLSPNPMsPAHNNLD	9606									15241418	t		lperfetto	We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity	SIGNOR-232142	0.748
AKT2	protein	P31751	UNIPROT	BMI1	protein	P35226	UNIPROT	up-regulates activity	phosphorylation	Ser316	ANRPRKSsVNGSSAT										22505453	t		lperfetto	the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate	SIGNOR-249582	0.297
PASK	protein	Q96RG2	UNIPROT	PASK	protein	Q96RG2	UNIPROT	up-regulates activity	phosphorylation	Thr1161	ERGKLFYtFCGTIEY	-1									11459942	t		lperfetto	We present evidence that the activity of pask is regulated by two mechanisms. Autophosphorylation at two threonine residues located within the activation loop significantly increases catalytic activity.	SIGNOR-109481	0.2
KRAS	protein	P01116	UNIPROT	MINK1	protein	Q8N4C8	UNIPROT	up-regulates				9606									16337592	f		gcesareni	Mink is activated after ras induction via a mechanism involving reactive oxygen species and mediates stimulation of the stress-activated protein kinase p38 mapk downstream of the raf/erk pathway.	SIGNOR-142985	0.2
RNF170	protein	Q96K19	UNIPROT	ITPR2	protein	Q14571	UNIPROT	down-regulates activity	polyubiquitination			9606	BTO:0000567								21610068	t		miannu	In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound.	SIGNOR-271914	0.338
PAK2	protein	Q13177	UNIPROT	RPS6	protein	P62753	UNIPROT	unknown	phosphorylation	Ser235	IAKRRRLsSLRASTS	-1									1985906	t		miannu	The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide.	SIGNOR-250231	0.313
BTRC	protein	Q9Y297	UNIPROT	CTNNB1	protein	P35222	UNIPROT	down-regulates	ubiquitination			9606									10228155	t		gcesareni	Here we show that fwd1 (the mouse homologue of slimb/betatrcp), an f-box/wd40-repeat protein, specifically formed a multi-molecular complex with beta-catenin, axin, gsk-3beta and apc. Mutations at the signal-induced phosphorylation site of beta-catenin inhibited its association with fwd1. Fwd1 facilitated ubiquitination and promoted degradation of beta-catenin, resulting in reduced cytoplasmic beta-catenin levels.	SIGNOR-67374	0.867
DRAM2	protein	Q6UX65	UNIPROT	RHOB	protein	P62745	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									30755245	f		irozzo	Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors.	SIGNOR-259145	0.2
UBE2K	protein	P61086	UNIPROT	RNF138	protein	Q8WVD3	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								16714285	t		miannu	NARF exhibits E3 ubiquitin-ligase activity in cooperation with the ubiquitin conjugating enzyme, E2-25K. These data show that the auto-ubiquitylating activity of NARF is coordinated with E2-25K, and that the RING finger domain of NARF is indispensable for this reaction.	SIGNOR-271594	0.515
SUN3	protein	Q8TAQ9	UNIPROT	LINC complex	complex	SIGNOR-C303	SIGNOR	form complex	binding												24481844	t		lperfetto	LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM.	SIGNOR-263291	0.413
Nitrendipine	chemical	CID:4507	PUBCHEM	NR3C2	protein	P08235	UNIPROT	down-regulates activity	chemical inhibition			-1									18250364	t		Luana	Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression. 	SIGNOR-257767	0.8
STK11	protein	Q15831	UNIPROT	STRADA	protein	Q7RTN6	UNIPROT	up-regulates activity	phosphorylation	Thr419	SGIFGLVtNLEELEV	9606	BTO:0000007								12805220	t		lperfetto	Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419	SIGNOR-247564	0.938
estrone	smallmolecule	CHEBI:17263	ChEBI	ESR1	protein	P03372	UNIPROT	up-regulates activity	chemical activation			-1									9048584	t		miannu	In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes.	SIGNOR-258584	0.8
RET	protein	P07949	UNIPROT	MAPK14	protein	Q16539	UNIPROT	up-regulates	phosphorylation	Thr180	RHTDDEMtGYVATRW	9606									17126298	t		gcesareni	Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme.	SIGNOR-150875	0.338
CEBPA	protein	P49715	UNIPROT	S100A9	protein	P06702	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0001370								9706399	t	 	 	Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells.	SIGNOR-254041	0.229
sonidegib	chemical	CHEBI:90863	ChEBI	SMO	protein	Q99835	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0001271								21041712	t		gcesareni	Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date.	SIGNOR-169203	0.8
dovitinib; bis(lactic acid)	chemical	CID:56973714	PUBCHEM	FLT3	protein	P36888	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-191418	0.8
DOK1	protein	Q99704	UNIPROT	A10/b1 integrin	complex	SIGNOR-C167	SIGNOR	down-regulates activity	binding			9606									19118207	t		miannu	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257678	0.32
PHKA1	protein	P46020	UNIPROT	PHKG2	protein	P15735	UNIPROT	down-regulates activity	binding			9606									10487978	t			Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.	SIGNOR-267407	0.85
GNAT1	protein	P11488	UNIPROT	PDE6G	protein	P18545	UNIPROT	down-regulates activity	binding			10090									30962282	t			In the dark, PDE6 activity is suppressed by its inhibitory γ-subunit (Pγ). Rhodopsin-catalyzed activation of the G protein, transducin, relieves this inhibition and enhances PDE6 catalysis.	SIGNOR-260008	0.755
RARG	protein	P13631	UNIPROT	RXRA	protein	P19793	UNIPROT	up-regulates	binding			9606									1310351	t		gcesareni	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16659	0.671
FOXO3	protein	O43524	UNIPROT	TSC1	protein	Q92574	UNIPROT	up-regulates quantity	transcriptional regulation			10090									20371605	t			FoxO3a binds to and transactivates the TSC1 promoter, indicating a key role for FoxO3a in regulating TSC1 expression. Together, these data demonstrate that FoxO3a regulates glycolysis downstream of Akt through transcriptional control of Tsc1	SIGNOR-259382	0.461
PTPRF	protein	P10586	UNIPROT	LCK	protein	P06239	UNIPROT	up-regulates	dephosphorylation			9606									12496362	t		flangone	We confirmed that lar dephosphorylated the phosphorylated tyrosine residues of lck..Activation Of lck and fyn involves tyrosine dephosphorylation of the cooh-terminal regulatory domain of kinases, followed by autophosphorylation of the kinase domain.	SIGNOR-96771	0.37
alanine	smallmolecule	CHEBI:16449	ChEBI	AminoAcids	stimulus	SIGNOR-ST5	SIGNOR	up-regulates quantity													29259120	t		lperfetto	All extant life employs the same 20 amino acids for protein biosynthesis	SIGNOR-264746	0.7
PTPN7	protein	P35236	UNIPROT	MAPK14	protein	Q16539	UNIPROT	down-regulates activity	dephosphorylation	Tyr182	TDDEMTGyVATRWYR	9606	BTO:0000661								10206983	t			In Jurkat cells, LC-PTP suppressed the ERK and p38 mitogen-activated protein kinase cascades	SIGNOR-248485	0.584
HGS	protein	O14964	UNIPROT	SMAD2	protein	Q15796	UNIPROT	up-regulates				9606									11094085	f		gcesareni	Hgs and sara, are prerequisites for receptor-mediated activation of smad2	SIGNOR-84616	0.37
ADSL	protein	P30566	UNIPROT	MYC	protein	P01106	UNIPROT	up-regulates quantity by expression				9606									31729379	f		miannu	An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels	SIGNOR-266614	0.2
tibolone	chemical	CHEBI:32223	ChEBI	PGR	protein	P06401	UNIPROT	up-regulates activity	chemical activation			9606									19464167	t		Luana	In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1).	SIGNOR-257822	0.8
PPP1CA	protein	P62136	UNIPROT	NMDA	proteinfamily	SIGNOR-PF56	SIGNOR	down-regulates activity	dephosphorylation			9606		BTO:0000142							14751588	t		miannu	DARPP-32/PP1 cascade modulates the physiological properties of NMDA and AMPA receptors, and activation of the DARPP-32/PP1 signaling leads to parallel increase in the phosphorylation of NMDA receptor subunits and intracellular Ca2+ levels	SIGNOR-265061	0.2
PTPN11	protein	Q06124	UNIPROT	EGFR	protein	P00533	UNIPROT	down-regulates activity	dephosphorylation	Tyr1016	DVVDADEyLIPQQGF	9534	BTO:0004055								14560030	t			Inhibition is achieved through the dephosphorylation of RasGAP binding sites at the level of the plasma membrane. We have identified Tyr992 of the epidermal growth factor receptor (EGFR) to be one such site, since its mutation to Phe renders the EGFR refractory to the effect of dominant-negative SHP2. To our knowledge, this is the first report to outline the site and molecular mechanism of action of SHP2 in EGFR signaling,	SIGNOR-248666	0.865
MTF1	protein	Q14872	UNIPROT	MCAT	protein	Q8IVS2	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									15378601	f		miannu	 MRE-binding transcription factor-1 (MTF-1) is a highly conserved heavy metal-induced transcriptional activator. MTF-1 also activates transcription in response to oxidative stress and regulates the expression of several cytoprotective factor genes, including MT, gamma-glutamylcysteine synthetase, and Cu/Zn-superoxide dismutase.	SIGNOR-254600	0.2
(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	ADRA2C	protein	P18825	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0000007								9605427	t		miannu	AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 	SIGNOR-258899	0.8
RIMS1	protein	Q86UR5	UNIPROT	UNC13B	protein	O14795	UNIPROT	up-regulates activity	relocalization			9606									31679900	t		miannu	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264385	0.791
PRKACA	protein	P17612	UNIPROT	MAP2	protein	P11137	UNIPROT	up-regulates	phosphorylation	Ser1782	GAEIITQsPGRSSVA	9606	BTO:0000567;BTO:0000938	BTO:0000142							11029056	t		gcesareni	Specific phosphorylation states may enhance the interaction of map2 with the actin cytoskeleton, thereby providing a regulated mechanism for map2 function within distinct cytoskeletal domains	SIGNOR-83100	0.366
2-oxoglutarate(2-)	smallmolecule	CHEBI:16810	ChEBI	KDM5B	protein	Q9UGL1	UNIPROT	up-regulates activity	chemical activation												29981745	t		lperfetto	Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 	SIGNOR-273476	0.8
HIPK2	protein	Q9H2X6	UNIPROT	PPM1D	protein	O15297	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser54	QPLPPRPsPAALPGG										23871434	t		lperfetto	WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation|Analysis of the phosphoamino acids of WIP1 revealed that both Ser85 and Ser54 are phosphorylation sites, confirming that HIPK2 is a protein kinase for WIP1 phosphorylation at Ser54 as well as Ser85 	SIGNOR-275480	0.431
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	CAMKK2	protein	Q96RR4	UNIPROT	down-regulates activity	phosphorylation	Ser100	HLSGRKLsLQERSQG	9534	BTO:0000298								32913128	t		miannu	 Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues. 	SIGNOR-277239	0.2
CUDC-101	chemical	CID:24756910	PUBCHEM	HDAC4	protein	P56524	UNIPROT	down-regulates activity	chemical inhibition			-1									20143778	t		miannu	By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively.	SIGNOR-262260	0.8
Wnt	proteinfamily	SIGNOR-PF40	SIGNOR	Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	up-regulates activity	binding			9606									23290138	t		miannu	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-256173	0.834
PPP2CB	protein	P62714	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	dephosphorylation	Ser37	NVLSPLPsQAMDDLM	9606									14712210	t		miannu	Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage| Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37.	SIGNOR-248584	0.412
SLBP	protein	Q14493	UNIPROT	H3-3A	protein	P84243	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265418	0.2
tyramine	smallmolecule	CHEBI:15760	ChEBI	dopamine	smallmolecule	CHEBI:18243	ChEBI	up-regulates quantity	precursor of			9606									NBK536726	t	brain	lperfetto	Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain 	SIGNOR-264176	0.8
PRKD1	protein	Q15139	UNIPROT	PIP4K2A	protein	P48426	UNIPROT	down-regulates	phosphorylation	Thr376	KAAHAAKtVKHGAGA	9606									16563698	t		lperfetto	We conclude that the type ii pip kinases are physiological targets for pkd phosphorylation, and that this modification is likely to regulate inositol lipid turnover by inhibition of these lipid kinases.	SIGNOR-145370	0.2
CDK1	protein	P06493	UNIPROT	RFC1	protein	P35251	UNIPROT	down-regulates activity	phosphorylation	Thr506	KESKLERtPQKNVQG	9534	BTO:0004055								12930972	t		lperfetto	Phosphorylation of the PCNA binding domain of the large subunit of replication factor C on Thr506 by cyclin-dependent kinases regulates binding to PCNA|Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases. |Phosphorylation of either RF-Cp145 as a part of the RF-C complex or RF-Cp145 domain B by cdk-cyclin kinases inhibits their ability to bind PCNA.	SIGNOR-265504	0.247
ETS1	protein	P14921	UNIPROT	ATP2A3	protein	Q93084	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000255								12119294	t		Luana	Ets-1 was able to transactivate the SERCA3 promoter in MoBr 204 as cotransfection of an Ets-1 expression vector increased the activity of the −97/+301-Luc construct by 6-fold.	SIGNOR-261601	0.333
naloxone	chemical	CHEBI:7459	ChEBI	OPRD1	protein	P41143	UNIPROT	down-regulates activity	chemical inhibition			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258942	0.8
denileukin diftitox	smallmolecule	SID:125240988	ChEBI	IL2RA	protein	P01589	UNIPROT	up-regulates activity	chemical activation			9606									15757436	t		miannu	Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells.  	SIGNOR-259392	0.8
ATG7	protein	O95352	UNIPROT	ATG12	protein	O94817	UNIPROT	up-regulates	binding			9606									18704115	t		gcesareni	Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein.	SIGNOR-180132	0.935
TRIP13	protein	Q15645	UNIPROT	EGFR	protein	P00533	UNIPROT	up-regulates quantity by stabilization	binding			9606	BTO:0000007								32860853	t		lperfetto	Mechanistically, TRIP13 enhanced EGFR protein abundance in part by preventing Cbl-mediated ubiquitination and proteasomal degradation.	SIGNOR-265084	0.2
CREBBP	protein	Q92793	UNIPROT	ALOX15	protein	P16050	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000018								12517954	f	 	lperfetto	In A549 cells activation of 15-LOX by IL-4 required the coactivation of histone acetyltransferases CREB-binding protein/p300 and led to a sizable production of 15(S)-HETE	SIGNOR-254093	0.2
Olopatadine	chemical	CHEBI:7769	ChEBI	HRH1	protein	P35367	UNIPROT	down-regulates activity	chemical inhibition			9606	BTO:0002126								18446005	t		Luana	We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells	SIGNOR-257782	0.8
SLBP	protein	Q14493	UNIPROT	H2BC9	protein	Q93079	UNIPROT	up-regulates quantity by expression	translation regulation			9606	BTO:0001938								19155325	t		lperfetto	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265391	0.2
sunitinib	chemical	CHEBI:38940	ChEBI	FLT3	protein	P36888	UNIPROT	down-regulates	chemical inhibition			9606									21423276	t		gcesareni	The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days.	SIGNOR-172911	0.8
PAX2	protein	Q02962	UNIPROT	WT1	protein	P19544	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									16631587	t			Cotransfection of Pax2 with the Wt1 reporter construct led to moderate activation of the Wt1 promoter.	SIGNOR-252290	0.618
PTPN22	protein	Q9Y2R2	UNIPROT	CD247	protein	P20963	UNIPROT	down-regulates activity	dephosphorylation			9606	BTO:0000007								16461343	t			In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22.	SIGNOR-248837	0.458
MAPK10	protein	P53779	UNIPROT	BCL2L11	protein	O43521	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser69	GPLAPPAsPGPFATR	-1									15486195	t		miannu	Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. 	SIGNOR-250080	0.677
STX11	protein	O75558	UNIPROT	STX11-VAMP8 SNARE complex	complex	SIGNOR-C273	SIGNOR	form complex	binding			9606	BTO:0000132								22767500	t		lperfetto	Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. 	SIGNOR-261897	0.658
PTPN1	protein	P18031	UNIPROT	PDGFRB	protein	P09619	UNIPROT	down-regulates activity	dephosphorylation	Tyr751	SKDESVDyVPMLDMK	-1									7545675	t			Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides	SIGNOR-248414	0.679
EP300	protein	Q09472	UNIPROT	RELA	protein	Q04206	UNIPROT	up-regulates	acetylation			9606			SIGNOR-C6						16382138	t		gcesareni	Rela is also acetylated at several sites by p300 and cbp	SIGNOR-143399	0.814
sertindole	chemical	CHEBI:9122	ChEBI	HTR2A	protein	P28223	UNIPROT	down-regulates activity	chemical inhibition			10090	BTO:0000331								8935801	t		miannu	Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B.	SIGNOR-258548	0.8
NKRF	protein	O15226	UNIPROT	IFNB1	protein	P01574	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0005065								10562553	t		Luana	Constitutive silencing of IFN-beta promoter is mediated by NRF (NF-kappaB-repressing factor), a nuclear inhibitor of NF-kappaB	SIGNOR-266227	0.367
CAST	protein	P20810	UNIPROT	CAPN3	protein	P20807	UNIPROT	down-regulates activity	binding			9606	BTO:0000590								25969760	t		lperfetto	In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain 	SIGNOR-251603	0.588
WNT1	protein	P04628	UNIPROT	Frizzled	proteinfamily	SIGNOR-PF11	SIGNOR	up-regulates activity	binding												18697834	t		Simone Vumbaca	Wnt1, Wnt3a and Wnt5a all induced a statistically greater degree of proliferation than control cells	SIGNOR-255649	0.758
MAP3K6	protein	O95382	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	up-regulates activity	phosphorylation	Thr838	GINPCTEtFTGTLQY	9606									17210579	t		Manara	These results suggested that ASK2 activates ASK1 by direct phosphorylation of Thr838 of ASK1.	SIGNOR-260773	0.53
SYNGAP1	protein	Q96PV0	UNIPROT	DLG4	protein	P78352	UNIPROT	up-regulates activity	binding			9606	BTO:0000938								26356309	t		miannu	The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95.	SIGNOR-264229	0.615
NEXMIF	protein	Q5QGS0	UNIPROT	CDH2	protein	P19022	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0000938								27822498	f		miannu	Xpn regulates N-cadherin and β1-integrin expression at the transcriptional level in PC12 cells	SIGNOR-269660	0.2
HIPK2	protein	Q9H2X6	UNIPROT	PML	protein	P29590	UNIPROT	up-regulates	phosphorylation	Ser8	MEPAPARsPRPQQDP	9606									19015637	t		llicata	In response to dna damage, hipk2 phosphorylates pml at serines 8 and 38. he n-terminal phosphorylation sites contribute to the dna damage-induced pml sumoylation and are required for the ability of pml to cooperate with hipk2 for the induction of cell death.	SIGNOR-182432	0.45
TLE4	protein	Q04727	UNIPROT	PAX2	protein	Q02962	UNIPROT	down-regulates activity	binding			9606		BTO:0000007							25631048	t			In cell culture, Grg4 suppresses Pax2-mediated transcriptional activation and inhibits phosphorylation of the Pax2 activation domain by WNT signaling and JNK	SIGNOR-251710	0.469
Naloxone benzoylhydrazone	chemical	CID:9601084	PUBCHEM	OPRK1	protein	P41145	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9686407	t		miannu	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258423	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	FGFR1	protein	P11362	UNIPROT	down-regulates	phosphorylation	Ser777	SMPLDQYsPSFPDTR	9606									23405013	t		lperfetto	Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling	SIGNOR-244541	0.2
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	NOS3	protein	P29474	UNIPROT	up-regulates activity	phosphorylation	Ser615	SYKIRFNsISCSDPL	9606	BTO:0001853								24379783	t		lperfetto	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251628	0.2
PRMT1	protein	Q99873	UNIPROT	CNBP	protein	P62633	UNIPROT	down-regulates	methylation	Arg27	PTGGGRGrGMRSRGR	9606									24726729	t		miannu	Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding	SIGNOR-204962	0.376
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	BAX	protein	Q07812	UNIPROT	down-regulates activity	phosphorylation	Ser184	VAGVLTAsLTIWKKM	9606	BTO:0003473								14766748	t		lperfetto	Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophilsWe suggest that Bax is regulated by phosphorylation of Ser(184) in an Akt-dependent manner and that phosphorylation inhibits Bax effects on the mitochondria by maintaining the protein in the cytoplasm, heterodimerized with antiapoptotic Bcl-2 family members	SIGNOR-209651	0.2
MMP3	protein	P08254	UNIPROT	HAPLN1	protein	P10915	UNIPROT	down-regulates quantity by destabilization	cleavage	His31	LDHDRAIhIQAENGP	-1									7694569	t		miannu	Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.	SIGNOR-256330	0.392
ABL1	protein	P00519	UNIPROT	PLSCR1	protein	O15162	UNIPROT	unknown	phosphorylation	Tyr74	PVYNQPVyNQPVGAA	9606									11390389	t		lperfetto	C-abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. Phosphorylation was abolished by mutation of tyr residues tyr(69)/tyr(74) within the tandem repeat sequence (68)vynqpvynqp(77) of plscr1	SIGNOR-86017	0.393
TARS1	protein	P26639	UNIPROT	threonine	smallmolecule	CHEBI:26986	ChEBI	down-regulates quantity	chemical modification			9606									25824639	t		miannu	Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 	SIGNOR-270502	0.8
ENG	protein	P17813	UNIPROT	BMP10	protein	O95393	UNIPROT	up-regulates activity	binding			9606	BTO:0003767								21737454	t		miannu	Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays.	SIGNOR-276657	0.371
CHAF1A	protein	Q13111	UNIPROT	MGMT	protein	P16455	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000567								15657354	f		miannu	 Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT.	SIGNOR-254569	0.2
PAK2	protein	Q13177	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation	Thr286	RLEEKVKtLKAQNSE	9606	BTO:0000848								21177766	t		lperfetto	P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)	SIGNOR-170764	0.272
TFIIH	complex	SIGNOR-C457	SIGNOR	POLR2A	protein	P24928	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser1647	SPSYSPTsPSYSPTS	9606									14662762	t		lperfetto	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-269339	0.718
CSNK1A1	protein	P48729	UNIPROT	AHCYL1	protein	O43865	UNIPROT	unknown	phosphorylation	Ser77	SSTDSYSsAASYTDS	9534									17635105	t		lperfetto	Residue 68 resides in a consensus phosphorylation site for PKD (Figure 1A) [22,23]. Interestingly, phosphorylation of Ser68 could allow for subsequent phosphorylation of Ser71, Ser74, Ser77 and Ser80 by CK1, for which the consensus phosphorylation site is pS/T-X-X-S/T	SIGNOR-249185	0.2
ULK1	protein	O75385	UNIPROT	ENO1	protein	P06733	UNIPROT	down-regulates activity	phosphorylation	Ser115	ANAILGVsLAVCKAG	9606	BTO:0000007								27153534	t	done	miannu	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274030	0.2
MAPK1	protein	P28482	UNIPROT	TNFRSF1A	protein	P19438	UNIPROT	down-regulates activity	phosphorylation	Ser274	LAPNPSFsPTPGFTP	-1									11606045	t		lperfetto	Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation.|Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a	SIGNOR-249452	0.515
ALOX5	protein	P09917	UNIPROT	leukotriene A4	smallmolecule	CHEBI:15651	ChEBI	up-regulates	chemical modification			9606									11751058	t		gcesareni	5-lipoxygenase catalyzes the production of leukotriene (lt) a4, from 5- hydroperoxyeicosatetraenoic acid (5-hpete) as well as the nitial oxidation of arachidonic acid to this hydroperoxy in-termediate	SIGNOR-113198	0.8
PTPN2	protein	P17706	UNIPROT	STAT5B	protein	P51692	UNIPROT	down-regulates activity	dephosphorylation			9606									12359225	t		miannu	In the previous study, we demonstrated that the nuclear isoform of T-cell protein-tyrosine phosphatase (TC-PTP) dephosphorylated and deactivated signal transducer and activator of transcription 5a (STAT5a) and STAT5b, thereby negatively regulating prolactin (PRL)-mediated signaling pathway.	SIGNOR-277126	0.722
PRKACA	protein	P17612	UNIPROT	NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	up-regulates	phosphorylation			9606									17959673	t		lperfetto	In this study, we demonstrate that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase a (pkac) is essential for nf-kappab dna binding and transactivation activity. treatment with h89 and knockdown of pkac in cells led to the inhibition of phosphorylation at p50 ser(337) and p65 ser(276) and loss of dna binding by nf-kappab.	SIGNOR-217391	0.49
GAMT	protein	Q14353	UNIPROT	Neuron_maturation	phenotype	SIGNOR-PH169	SIGNOR	up-regulates				-1									26319512	f		Luana	GAMT enzyme (EC#2.1.1.2) deficiency caused by mutations in the GAMT gene (MIM# 601240) results in the depletion of creatine and accumulation of guanidinoacetate (GAA). Creatine has a buffering and transport function of high-energy phosphates in brain and muscle and is essential for growth cone migration, dendritic and axonal elongation, neurotransmitter release, and co-transmission on gamma amino butyric acid (GABA) postsynaptic receptors in the central nervous system	SIGNOR-265794	0.7
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	MCM4	protein	P33991	UNIPROT	down-regulates	phosphorylation	Ser32	RSEDARSsPSQRRRG	9606	BTO:0000567								12714602	t		lperfetto	We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a.	SIGNOR-217344	0.687
EML4-ALK	fusion protein	SIGNOR-FP8	SIGNOR	ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	up-regulates activity	phosphorylation			10090	BTO:0000944								21415216	t		irozzo	We also found that phosphorylation of both the mitogen-activated proteinkinase (MAPK) ERK and STAT3 was markedly increased inthe cells expressing either variant of EML4-ALK[.]. Oncogenic EML4-ALK tyrosine kinase activates ERKand STAT3 signaling pathways	SIGNOR-259174	0.2
AMPK	complex	SIGNOR-C15	SIGNOR	PIKFYVE	protein	Q9Y2I7	UNIPROT	up-regulates activity	phosphorylation	Ser307	PARNRSAsITNLSLD	-1									23905686	t		miannu	AMPK phosphorylated PIKfyve at Ser307 both in vitro and in intact cells. We propose that PIKfyve activity is required for the stimulation of skeletal muscle glucose uptake by contraction/AMPK activation. PIKfyve is a new AMPK substrate whose phosphorylation at Ser307 could promote PIKfyve translocation to endosomes for PtdIns(3,5)P2 synthesis to facilitate GLUT4 (glucose transporter 4) translocation.	SIGNOR-263031	0.2
GSK3B	protein	P49841	UNIPROT	CCND1	protein	P24385	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr286	EEVDLACtPTDVRDV	9606					phosphorylation:Ser9	SGRPRTTsFAESCKP 			23552696	t		lperfetto	Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1	SIGNOR-245437	0.776
IKBKB	protein	O14920	UNIPROT	NFKB1	protein	P19838	UNIPROT	down-regulates activity	phosphorylation	Ser927	DSDSVCDsGVETSFR	9606	BTO:0000007			SIGNOR-C13					11158290	t		lperfetto	Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway.	SIGNOR-104807	0.848
MAPK1	protein	P28482	UNIPROT	IRX2	protein	Q9BZI1	UNIPROT	up-regulates activity	phosphorylation	Ser64	QAATGFGsPLQYSAD	-1									15133517	t		miannu	We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation.	SIGNOR-263053	0.2
NOG	protein	Q13253	UNIPROT	BMPR1A	protein	P36894	UNIPROT	down-regulates activity	binding			9606	BTO:0001593	BTO:0000140							22298955	t		lperfetto	Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptorsNoggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285)	SIGNOR-192799	0.596
HMOX2	protein	P30519	UNIPROT	heme	smallmolecule	CHEBI:30413	ChEBI	down-regulates quantity	chemical modification			9606									10490932	t	Regulation	miannu	Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme	SIGNOR-251912	0.8
RPS6KB1	protein	P23443	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser527	RFRKRTHsAGTSPTI	10090	BTO:0002572								18498745	t		lperfetto	In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8	SIGNOR-236595	0.781
FH	protein	P07954	UNIPROT	fumarate(2-)	smallmolecule	CHEBI:29806	ChEBI	down-regulates quantity	chemical modification			9606									30761759	t		miannu	Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors.	SIGNOR-266279	0.8
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	CAMK2A	protein	Q9UQM7	UNIPROT	up-regulates activity	chemical activation												15621017	t			It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK.	SIGNOR-255491	0.8
CASP7	protein	P55210	UNIPROT	PARP1	protein	P09874	UNIPROT	down-regulates	cleavage			9606									11058599	t		amattioni	Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis.	SIGNOR-83703	0.708
PFKL	protein	P17858	UNIPROT	beta-D-fructofuranose 1,6-bisphosphate(4-)	smallmolecule	CHEBI:32966	ChEBI	up-regulates quantity	chemical modification			9606									16051738	t		miannu	Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35.	SIGNOR-266472	0.8
UBE2G2	protein	P60604	UNIPROT	SYVN1	protein	Q86TM6	UNIPROT	up-regulates activity	ubiquitination			10090	BTO:0000944								14593114	t		miannu	We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain. In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation. 	SIGNOR-272593	0.681
RFWD3	protein	Q6PCD5	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates quantity by stabilization	ubiquitination			9606	BTO:0002552								20173098	t		miannu	RFWD3 is a positive regulator of p53 abundance and regulates the G1 checkpoint in response to IR. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage. 	SIGNOR-271944	0.368
PPP3CA	protein	Q08209	UNIPROT	NFATC2	protein	Q13469	UNIPROT	up-regulates activity	dephosphorylation	Ser177	ASSGSSAsFISDTFS	9606									11030334	t			NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248683	0.613
GATA2	protein	P23769	UNIPROT	Adipogenesis	phenotype	SIGNOR-PH26	SIGNOR	down-regulates				10090									11021798	f		fspada	Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage.	SIGNOR-78659	0.7
CSNK2A1	protein	P68400	UNIPROT	TOP2A	protein	P11388	UNIPROT	unknown	phosphorylation	Ser1377	KPQKSVVsDLEADDV	9606	BTO:0000567								7961967	t		llicata	Tryptic phosphopeptide mapping revealed that casein kinase II phosphorylated the C-terminal domain primarily on 2 serine residues in vitro, which were shown to be sites of modification in vivo. Site-directed mutagenesis studies identified these casein kinase II-specific phosphorylation sites as serine 1524 and serine 1376.	SIGNOR-250965	0.613
JAK2	protein	O60674	UNIPROT	PRMT5	protein	O14744	UNIPROT	down-regulates	phosphorylation	Tyr297	NRPPPNAyELFAKGY	9606									21316606	t		llicata	Oncogenic jak2 kinases phosphorylate prmt5 in_vivo phosphorylation of prmt5 by jak2v617f greatly impairs its methyltransferase activity	SIGNOR-171994	0.68
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MED1	protein	Q15648	UNIPROT	up-regulates	phosphorylation			9606									12356758	t	inferred from 70% family members	lperfetto	Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase	SIGNOR-270199	0.2
GSK3B	protein	P49841	UNIPROT	MYOCD	protein	Q8IZQ8	UNIPROT	down-regulates activity	phosphorylation	Ser463	PPISPASsDLSVAGS	9606	BTO:0000007								16141410	t			In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity	SIGNOR-251246	0.406
RANBP9	protein	Q96S59	UNIPROT	DYRK1B	protein	Q9Y463	UNIPROT	down-regulates activity	binding			9606	BTO:0000007								14500717	t		llicata	Serine/threonine kinase Mirk/Dyrk1B is an inhibitor of epithelial cell migration and is negatively regulated by the Met adaptor Ran-binding protein M.	SIGNOR-238008	0.428
MAPK10	protein	P53779	UNIPROT	YWHAZ	protein	P63104	UNIPROT	down-regulates	phosphorylation	Ser184	FYYEILNsPEKACSL	9606									15071501	t	Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons	gcesareni	Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-190	SIGNOR-124009	0.2
PTEN	protein	P60484	UNIPROT	BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	down-regulates activity	dephosphorylation			9606	BTO:0001544								31374292	t		miannu	PTEN targets the protein phosphatase activity of BCR-ABL. PTEN has the same function as PTP1B, which can regulate BCR-ABL dephosphorylation [13]. However, whether PTEN can mediate BCR-ABL dephosphorylation remains unknown. We found that under-expression of PTEN significantly upregulated phosphorylation level of BCR-ABL. In order to verify the mechanisms, co-IP assays were applied, demonstrating the ways in which PTEN and BCR-ABL interact with each other. 	SIGNOR-260080	0.2
RNA Polymerase III	complex	SIGNOR-C389	SIGNOR	tRNA(Gly)	smallmolecule	CHEBI:29176	ChEBI	up-regulates quantity	chemical modification			9606									27911719	t		lperfetto	RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1)	SIGNOR-269487	0.8
Avagacestat	chemical	CID:46883536	PUBCHEM	APP	protein	P05067	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190479	0.8
SMAD5/SMAD4	complex	SIGNOR-C205	SIGNOR	DLX5	protein	P56178	UNIPROT	up-regulates	transcriptional regulation			10090	BTO:0000165								12815054	f		ggiuliani	Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining 	SIGNOR-255790	0.325
(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	ADRA1B	protein	P35368	UNIPROT	up-regulates activity	chemical activation			-1									7651358	t		miannu	Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1.	SIGNOR-258442	0.8
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	GAB2	protein	Q9UQC2	UNIPROT	down-regulates	phosphorylation	Ser159	LLRERKSsAPSHSSQ	9606									11782427	t		lperfetto	Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation.	SIGNOR-113669	0.2
ATM	protein	Q13315	UNIPROT	ATF2	protein	P15336	UNIPROT	up-regulates	phosphorylation	Ser490	QSTEPALsQIVMAPS	9606									15916964	t		lperfetto	Here, we demonstrate that the protein kinase atm phosphorylates atf2 on serines 490 and 498 following ionizing radiation (ir). dose- and time-dependent phosphorylation of atf2 by atm that results in its rapid colocalization with gamma-h2ax and mrn components into ir-induced foci (irif)	SIGNOR-137619	0.584
DNA_damage	stimulus	SIGNOR-ST1	SIGNOR	Fanconi anemia core complex	complex	SIGNOR-C300	SIGNOR	up-regulates				9606	BTO:0000567								17396147	f		lperfetto	The Fanconi anemia (FA) core complex plays a central role in the DNA damage response network involving breast cancer susceptibility gene products, BRCA1 and BRCA2. The complex consists of eight FA proteins, including a ubiquitin ligase (FANCL) and a DNA translocase (FANCM), and is essential for monoubiquitination of FANCD2 in response to DNA damage.	SIGNOR-263251	0.7
NR3C1	protein	P04150	UNIPROT	MAPK8	protein	P45983	UNIPROT	down-regulates activity				10090									11742987	f		gcesareni	GR-mediated inhibition of c-Jun N-terminal kinase (JNK) activity	SIGNOR-251676	0.623
RANBP17	protein	Q9H2T7	UNIPROT	TCF3	protein	P15923	UNIPROT	up-regulates	binding			9606									20503194	t		miannu	Yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation analyses demonstrate specific interaction of e12 with ranbp17, a novel member of the importin-beta superfamily;this interaction maps to the crm1 homology region of ranbp17. Ectopic expression of ranbp17 leads to a approximately 3-fold increase in e2a/myod mediated transactivation of an e-box regulated luciferase reporter gene.	SIGNOR-165655	0.2
HDAC1	protein	Q13547	UNIPROT	ABCB1	protein	P08183	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0005192								20037778	f	 	miannu	 we find UHRF1 plays an important role in inhibiting MDR1 promoter activity by directly binding to the MDR1 promoter. Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter, which is facilitated by recruitment of HDAC1 to the MDR1 promoter.	SIGNOR-254223	0.292
KCTD10	protein	Q9H3F6	UNIPROT	RHOA	protein	P61586	UNIPROT	down-regulates quantity	binding			9606									19782033	t		miannu	 BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.	SIGNOR-264237	0.273
PRKCA	protein	P17252	UNIPROT	EIF6	protein	P56537	UNIPROT	unknown	phosphorylation	Ser235	QPSTIATsMRDSLID	9606									14654845	t		llicata	Pkc stimulation led to eif6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eif6 impaired rack1/pkc-mediated translational rescue.	SIGNOR-119600	0.323
Hair cells mechanotransduction channel	complex	SIGNOR-C290	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			10090									23217710	t		lperfetto	Despite this progress, it is not known which genes encode subunits of the mechanotransduction channel of hair cells. Ca2+ enters stereocilia upon mechanical stimulation near the lower tip-link insertion site, indicating that transduction channels are present in proximity to PCDH15	SIGNOR-262573	0.8
KTN1	protein	Q86UP2	UNIPROT	KIF5B	protein	P33176	UNIPROT	up-regulates	binding			9606									15316074	t		miannu	This study demonstrated the effect of kinectin-kinesin interaction on lysosome dynamics and observed that the kinesin-binding domain of kinectin can significantly enhance the mt-stimulated atpase activity of kinesin.	SIGNOR-128092	0.592
ELANE	protein	P08246	UNIPROT	F5	protein	P12259	UNIPROT	down-regulates activity	cleavage	Ala369	DYAPVIPaNMDKKYR	-1									9242537	t		lperfetto	Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity.	SIGNOR-263635	0.373
nilotinib	chemical	CHEBI:52172	ChEBI	PDGFRA	protein	P16234	UNIPROT	down-regulates activity	chemical inhibition			-1									22037378	t		Luana	Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 	SIGNOR-258258	0.8
NFIA	protein	Q12857	UNIPROT	NEUROD4	protein	Q9HD90	UNIPROT	up-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268891	0.2
ATF2	protein	P15336	UNIPROT	IL6	protein	P05231	UNIPROT	up-regulates	transcriptional regulation			9606	BTO:0000801								20086235	f			JNK phosphorylates proteins that are part of AP-1, in particular c-Jun and activating transcription factor 2 (ATF-2). With dominant-negative mutants, antisense RNA, inhibitors, and genetic ablation, it has been shown that JNK and c-Jun play a major role in IL-1–induced expression of genes encoding IL-6 and IL-8 and other IL-1–responsive genes	SIGNOR-254512	0.304
FRZB	protein	Q92765	UNIPROT	WNT8A	protein	Q9H1J5	UNIPROT	down-regulates	binding			9606		BTO:0000671							9326585	t		gcesareni	We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos,	SIGNOR-51798	0.498
RAPGEF3	protein	O95398	UNIPROT	RAP1B	protein	P61224	UNIPROT	up-regulates activity	guanine nucleotide exchange factor			9534	BTO:0000298								10777494	t		miannu	Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.	SIGNOR-263957	0.707
RALGAPA2	protein	Q2PPJ7	UNIPROT	RalGAP2	complex	SIGNOR-C469	SIGNOR	form complex	binding			10090									21148297	t		miannu	Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA.	SIGNOR-269793	0.588
budesonide	chemical	CHEBI:3207	ChEBI	NR3C1	protein	P04150	UNIPROT	up-regulates	chemical activation			9606									9657565	t	allergic rhinitis	gcesareni		SIGNOR-251689	0.8
CRK	protein	P46108	UNIPROT	CBL	protein	P22681	UNIPROT	up-regulates	binding			9606	BTO:0000782;BTO:0001271								8524328	t		gcesareni	These results indicate that crk binds to c-cbl in a tyrosine phosphorylation-dependent manner.	SIGNOR-39241	0.816
MAP1LC3A	protein	Q9H492	UNIPROT	SQSTM1	protein	Q13501	UNIPROT	up-regulates	binding			9606									17580304	t		gcesareni	Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation.	SIGNOR-156353	0.784
prostaglandin E2	smallmolecule	CHEBI:15551	ChEBI	PTGER4	protein	P35408	UNIPROT	up-regulates	chemical activation			9606									15299086	t		gcesareni	Pge2 is the ligand for four ep receptor subtypes termed ep1 to ep4.	SIGNOR-127789	0.8
CBL	protein	P22681	UNIPROT	ABL1	protein	P00519	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606	BTO:0001271								20675402	t		lperfetto	We found that while c-cbl e3 ligase induced ubiquitin-dependent degradation of mature and phosphorylated bcr-abl proteins	SIGNOR-167194	0.609
MTOR	protein	P42345	UNIPROT	RPS6KB2	protein	Q9UBS0	UNIPROT	up-regulates activity	phosphorylation	Thr388	NQAFLGFtYVAPSVL	-1									11733037	t		miannu	In vitro phosphorylation and activation of p70β by mTOR and PDK1. We observed that the replacement of either Thr241 or Thr401 to Ala in p70β1(T241A, T401A) severely decreased the kinase activity.	SIGNOR-250295	0.831
PTEN	protein	P60484	UNIPROT	RPS6KB1	protein	P23443	UNIPROT	down-regulates activity	dephosphorylation			9606									19436944	f		miannu	Expression of WT-PTEN also caused decreased activation of Akt, p70 S6K, and Erk signaling pathways.|This may potentially be a result of PTEN inhibition of p70 S6K phosphorylation and may explain the mechanism by which PTEN inhibits proliferation of HSCs.	SIGNOR-277080	0.548
bethanechol	chemical	CHEBI:3084	ChEBI	CHRM2	protein	P08172	UNIPROT	up-regulates activity	chemical activation			10029	BTO:0000246								9224827	t		miannu	We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2.	SIGNOR-258625	0.8
MYC	protein	P01106	UNIPROT	USP22	protein	Q9UPT9	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26049753	f			USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells.	SIGNOR-261560	0.509
STAT1	protein	P42224	UNIPROT	CIITA	protein	P33076	UNIPROT	up-regulates quantity	transcriptional regulation			9606		BTO:0001103							9551976	f		Federica Ferrentino	A role for STAT1 in regulation of the CIITA promoter is shown by the rescue of IFN-gamma induction by expression of STAT1 in STAT1-defective U3A cells	SIGNOR-255752	0.524
MMP21	protein	Q8N119	UNIPROT	ECM_disassembly	phenotype	SIGNOR-PH80	SIGNOR	up-regulates													17318226	f		lperfetto	Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 	SIGNOR-272366	0.7
TNFRSF17	protein	Q02223	UNIPROT	MAPK8	protein	P45983	UNIPROT	up-regulates				9606									10903733	f		miannu	Overexpression of bcma activates jnk	SIGNOR-79489	0.295
PLK1	protein	P53350	UNIPROT	RAN	protein	P62826	UNIPROT	up-regulates	phosphorylation	Ser135	DRKVKAKsIVFHRKK	9606									16930555	t		lperfetto	Plk1 is capable of phosphorylating co-immunoprecipitated ran in vitro on serine-135 and ran is phosphorylated in vivo at the same site during mitosis when plk1 is normally activated. Deregulation of ran phosphorylation disrupts normal spindle structure and segregation of chromosomes.	SIGNOR-149073	0.268
RAB4A	protein	P20338	UNIPROT	Early Endosome	complex	SIGNOR-C246	SIGNOR	form complex	binding			9606									19924646	t		lperfetto	The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 	SIGNOR-260617	0.436
GRK2	protein	P25098	UNIPROT	MC4R	protein	P32245	UNIPROT	down-regulates activity	phosphorylation	Ser329	LGGLCDLsSRY	9606									12639913	t			Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA and GRK phosphorylation and the subsequent recruitment of β-arrestin to the activated receptor. Replacement by alanine(s) of Thr312 and Ser329/330 in the C-terminal tail resulted in an impaired sequestration of mutated receptors to agonist, whereas mutations of Thr232 or Ser306 did not. This indicates that phosphorylation of these residues by kinases is critical for the internalization of MC4R. 	SIGNOR-251453	0.2
PA2G4	protein	Q9UQ80	UNIPROT	KLK3	protein	P07288	UNIPROT	down-regulates quantity by repression	transcriptional regulation												16254079	t	 	 	Ectopic expression of ebp1, a member of the PA2G4 family, inhibits the proliferation and induces the differentiation of human breast and prostate cancer cell lines. Ebp1 inhibits transcription of E2F1 and androgen receptor regulated genes such as prostate specific antigen (PSA) through its interactions with histone deacetylases (HDACs)	SIGNOR-253662	0.2
IRF8	protein	Q02556	UNIPROT	CD68	protein	P34810	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10090	BTO:0000801								12676954	f	 	 	However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element.	SIGNOR-254285	0.285
DUSP22	protein	Q9NRW4	UNIPROT	STAT3	protein	P40763	UNIPROT	down-regulates activity	dephosphorylation			9606									16636663	f		miannu	IL-6 and LIF-induced LMW-DSP2 expression in murine testicular or hepatoma cell lines, while LMW-DSP2 overexpression in 293T cells suppressed IL-6-induced phosphorylation and activation of STAT3.|These results strongly suggest that LMW-DSP2 acts as a negative regulator of the IL-6/LIF/STAT3-mediated signaling pathway.	SIGNOR-277149	0.366
Av/b5 integrin	complex	SIGNOR-C178	SIGNOR	PTK2	protein	Q05397	UNIPROT	up-regulates activity				9606									15688067	f		miannu	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257723	0.633
MTMR2	protein	Q13614	UNIPROT	1-phosphatidyl-1D-myo-inositol 3-phosphate(3-)	smallmolecule	CHEBI:58088	ChEBI	down-regulates quantity	chemical modification			9606									18429927	t		miannu	PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 	SIGNOR-269807	0.8
AMPK	complex	SIGNOR-C15	SIGNOR	PRPS1	protein	P60891	UNIPROT	down-regulates activity	phosphorylation	Ser180	GGAKRVTsIADRLNV	9606	BTO:0006038								29074724	t		lperfetto	We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production.	SIGNOR-265730	0.245
GATA1	protein	P15976	UNIPROT	GATA1	protein	P15976	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									12432220	f		irozzo	Furthermore, GATA-1 has been shown to auto-regulate its own gene expression.	SIGNOR-256057	0.2
RPS6KA3	protein	P51812	UNIPROT	RANBP3	protein	Q9H6Z4	UNIPROT	up-regulates quantity	phosphorylation	Ser57	HGTGHPEsAGEHALE	9606	BTO:0000007								18280241	t		miannu	RSK phosphorylates RanBP3 at Serine 58 residue in vitro and in vivo.RanBP3 phosphorylation increases its affinity towards Ran	SIGNOR-276148	0.336
BBOX1	protein	O75936	UNIPROT	carnitine	smallmolecule	CHEBI:17126	ChEBI	up-regulates quantity	chemical modification			9606									11802770	t		miannu	In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine.	SIGNOR-269699	0.8
SYK	protein	P43405	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation	Tyr349	EEPPDHQyYNDFPGK	9606	BTO:0000782								9710204	t		gcesareni	The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2).	SIGNOR-59635	0.753
MAPK3	protein	P27361	UNIPROT	SCNN1G	protein	P51170	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr622	LGTQVPGtPPPKYNT	-1									11805112	t		lperfetto	Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.	SIGNOR-249449	0.284
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	MYB	protein	P10242	UNIPROT	down-regulates	phosphorylation			9606									8798443	t	inferred from 70% family members	llicata	Here we describe that human c-myb can be phosphorylated by mitogen-activated protein kinases (mapk's) at serine 532 of the carboxy (c-) terminal regulatory domain in vitro. expression of a constitutively active form of ras together with c-myb in transient transfection experiments had no effect on the transcriptional activity of c-myb, while expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532.	SIGNOR-270089	0.2
PRKAA1	protein	Q13131	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Ser588	QTLSDSLsGSSLYST	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-252978	0.509
CREB1	protein	P16220	UNIPROT	BCL2	protein	P10415	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776;BTO:0003076								8816467	f		lperfetto	Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis	SIGNOR-43927	0.438
palmitoyl-CoA	smallmolecule	CHEBI:15525	ChEBI	3-hydroxyoctadecanoyl-CoA	smallmolecule	CHEBI:50583	ChEBI	up-regulates quantity	precursor of			9606									31616255	t		miannu	The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle.	SIGNOR-267884	0.8
LHX3	protein	Q9UBR4	UNIPROT	ISL2	protein	Q96A47	UNIPROT	up-regulates activity	binding			9606	BTO:0000007								9452425	t		lperfetto	a direct NLI-independent interaction between Lhx3 and the related proteins Isl1 and Isl2 was observed. The combinatorial expression of the LIM homeodomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeodomain protein combinations in the specification of neuronal identity	SIGNOR-236836	0.443
FOXP1	protein	Q9H334	UNIPROT	PITX3	protein	O75364	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090	BTO:0000596								20175877	t		Gianni	We identified FoxP1 as a novel marker for midbrain dopamine neurons. Enforced expression of FoxP1 in embryonic stem cells actuates the expression of Pitx3, a homeobox protein that is exclusively expressed in midbrain dopaminergic neurons and is required for their differentiation and survival during development and from embryonic stem cells in vitro. We show that FoxP1 can be recruited to the Pitx3 locus in embryonic stem cells and regulate Pitx3 promoter activity in a dual-luciferase assay.	SIGNOR-269049	0.297
TNFRSF6B	protein	O95407	UNIPROT	TNFSF15	protein	O95150	UNIPROT	down-regulates	binding			9606	BTO:0000782								11911831	t		amattioni	Tl1a, is a ligand for dr3 and decoy receptor tr6/dcr3. Tr6-fc protein antagonizes nf-kappab activation and apoptosis induced by tl1a	SIGNOR-116256	0.733
RPA1	protein	P27694	UNIPROT	Nucleotide-excision_repair	phenotype	SIGNOR-PH209	SIGNOR	up-regulates													24086043	f		lperfetto	The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275705	0.7
CyclinA2/CDK2	complex	SIGNOR-C83	SIGNOR	BLM	protein	P54132	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr171	ETSKSFVtPPQSHFV	9606	BTO:0002181								26028025	t		miannu	We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.	SIGNOR-276907	0.422
STAT3	protein	P40763	UNIPROT	CASP3	protein	P42574	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10090									25787076	f		miannu	We determined that Stat3 activation increases caspase-3 expression in C2C12 cells.	SIGNOR-255335	0.476
CDK10	protein	Q15131	UNIPROT	ETS2	protein	P15036	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser225	LDSMCPAsTPSVLSS	9606									24218572	t		Manara	Altogether, these results suggest that CDK10/cyclin M directly controls ETS2 degradation through the phosphorylation of these two serines.	SIGNOR-260914	0.544
SMO	protein	Q99835	UNIPROT	GNG3	protein	P63215	UNIPROT	up-regulates	binding			9606									23074268	t		gcesareni	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-199186	0.2
MAPK3	protein	P27361	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser616	DDGYMPMsPGVAPVP	9606									15001544	t		lperfetto	Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation.	SIGNOR-123177	0.696
HRH1	protein	P35367	UNIPROT	GNAI1	protein	P63096	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257050	0.2
GPER1	protein	Q99527	UNIPROT	GNB1	protein	P62873	UNIPROT	up-regulates activity	binding												10696571	t			GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; GNB1 stands for the subunit β, which dissociates from the receptor after the binding of GTP on α-subunit.	SIGNOR-251103	0.357
H2AC11	protein	P0C0S8	UNIPROT	RNF168	protein	Q8IYW5	UNIPROT	up-regulates	binding			9606									19203578	t		gcesareni	Rnf168 is recruited to sites of dna damage by binding to ubiquitylated histone h2a.	SIGNOR-183890	0.2
JAK2	protein	O60674	UNIPROT	JAK2	protein	O60674	UNIPROT	up-regulates activity	phosphorylation	Tyr201	DQTPLAIyNSISYKT	9534	BTO:0000298								17027227	t			Site of Jak2 tyrosine autophosphorylation; namely, tyrosine 201. Jak2 tyrosine residue 201 was the principal mediator of SHP-2 binding as conversion of this tyrosine residue to phenylalanine abolished this interaction	SIGNOR-251360	0.2
PAK1	protein	Q13153	UNIPROT	KIF2C	protein	Q99661	UNIPROT	down-regulates	phosphorylation	Ser192	VNSVRRKsCLVKEVE	9606									23055517	t		lperfetto	Here we found that mcak is a cognate substrate of pak1 wherein pak1 phosphorylates mcak on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that pak1 phosphorylation of mcak on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes	SIGNOR-199084	0.394
NCS1	protein	P62166	UNIPROT	GRK2	protein	P25098	UNIPROT	down-regulates activity	binding			9606	BTO:0000007;BTO:0000938								12351722	t		miannu	Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization.	SIGNOR-263965	0.2
NFYB	protein	P25208	UNIPROT	NFY	complex	SIGNOR-C1	SIGNOR	form complex	binding			9606									9885213	t		lperfetto	Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding.	SIGNOR-63016	0.963
GPSM3	protein	Q9Y4H4	UNIPROT	GNB1	protein	P62873	UNIPROT	down-regulates quantity by destabilization	binding												22843681	t		lperfetto	GPSM3 was found not only to modulate heterotrimeric G-protein subunit signaling through its two active GoLoco motifs, but also to affect monomeric Gbeta subunit biosynthesis and stability|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET.	SIGNOR-264865	0.357
XBP1	protein	P17861	UNIPROT	XBP1	protein	P17861	UNIPROT	up-regulates activity	binding			-1									12805554	t		miannu	E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins	SIGNOR-224199	0.2
FABP4	protein	P15090	UNIPROT	Fatty acid	stimulus	SIGNOR-ST19	SIGNOR	up-regulates quantity	relocalization			9606									28457600	t		miannu	Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 	SIGNOR-264458	0.7
TSSK1B	protein	Q9BXA7	UNIPROT	TSSK1B	protein	Q9BXA7	UNIPROT	up-regulates activity	phosphorylation	Thr174	GRMALSKtFCGSPAY	-1									15733851	t		Manara	Electrospray Q‐TOF2 mass spectroscopy analysis of a trypsin digested TSSK1 purified from E. coli, revealed that it was phosphorylated at its T‐loop residue (Fig. 2D), indicating that TSSK1 as was previously shown for MELK [18], can autophosphorylate its T‐loop Thr residue.	SIGNOR-260823	0.2
INPPL1	protein	O15357	UNIPROT	MAPK8IP1	protein	Q9UQF2	UNIPROT	up-regulates				9606									18486448	f		gcesareni	Ship2 positively modulated the mlk3/jip1-mediated jnk1 activation	SIGNOR-178652	0.2
3,3',5'-triiodothyronine	smallmolecule	CHEBI:28774	ChEBI	THRA	protein	P10827	UNIPROT	up-regulates activity	chemical activation			10116	BTO:0000759								2158622	t		miannu	We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 	SIGNOR-258385	0.8
PRKAA1	protein	Q13131	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates activity	phosphorylation	Ser399	DNITLPPsQPSPTGG	9606									17711846	t		gcesareni	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-252975	0.509
USF1	protein	P22415	UNIPROT	Hexokinase	proteinfamily	SIGNOR-PF76	SIGNOR	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000599								9677331	f	inferred from family member	miannu	Cotransfection of an expression plasmid encoding USF1 into HepG2 hepatoma cells resulted in the activation of the glucokinase promoter, dependent on the integrity of the P2 element	SIGNOR-270263	0.294
PAK6	protein	Q9NQU5	UNIPROT	MDM2	protein	Q00987	UNIPROT	up-regulates activity	phosphorylation	Thr158	HLVSRPStSSRRRAI	9606	BTO:0000007								23132866	t		miannu	We also showed that PAK6 phosphorylates Mdm2 on Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation.	SIGNOR-276428	0.2
PRKD1	protein	Q15139	UNIPROT	PPP1R14A	protein	Q96A00	UNIPROT	up-regulates activity	phosphorylation	Thr38	QKRHARVtVKYDRRE	9606									32471307	t		lperfetto	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225].	SIGNOR-123226	0.2
SIRT7	protein	Q9NRC8	UNIPROT	DDX21	protein	Q9NR30	UNIPROT	up-regulates activity	deacetylation	Lys137	PKKMKKEkEMNGETR										28790157	t		lperfetto	Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21.	SIGNOR-275903	0.262
MCU_MICU1_variant	complex	SIGNOR-C500	SIGNOR	calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	up-regulates quantity	relocalization			9606									32315830	t		miannu	MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 	SIGNOR-270868	0.8
FZD5	protein	Q13467	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates activity	binding			9606									25902418	t		areggio	Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain.	SIGNOR-258969	0.657
INTS2	protein	Q9H0H0	UNIPROT	Integrator complex	complex	SIGNOR-C265	SIGNOR	form complex	binding			7227									26220997	t		lperfetto	Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits) 	SIGNOR-261466	0.745
GHITM	protein	Q9H3K2	UNIPROT	CYCS	protein	P99999	UNIPROT	down-regulates quantity	relocalization			9606	BTO:0000567								18417609	t		Giulio	MICS1 was clearly coprecipitated with cytochrome c-3FLAG and the amount was DSP concentration-dependent (Figure 6A). Together with the finding that overexpression of exogenous MICS1 delayed the apoptotic release of cytochrome c in normal-serum level medium (Figure 4A), these results suggest that MICS1 helps to retain cytochrome c in the inner membrane, apart from the morphological changes.	SIGNOR-260294	0.258
LPAR2	protein	Q9HBW0	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257431	0.461
DSCAM	protein	O60469	UNIPROT	Axonal_growth_cone_formation	phenotype	SIGNOR-PH199	SIGNOR	up-regulates				10116	BTO:0000938								18585357	f		miannu	DSCAM is required for commissural axon guidance in vivo. DSCAM promotes axonal growth but is dispensable for cell body migration and for axon turning toward a local source of netrin-1 in whole spinal cord turning assays. 	SIGNOR-268401	0.7
TNF	protein	P01375	UNIPROT	AKT2	protein	P31751	UNIPROT	up-regulates				9606									11287630	f		lperfetto	Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase	SIGNOR-106596	0.324
CD27	protein	P26842	UNIPROT	BCL2L1	protein	Q07817	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000776								12324477	f		gcesareni	Cd40 ligation up-regulated bcl-2 and bcl-xl as much as 9.7- (p < 0.01) and 6.8-fold (p < 0.01), respectively (fig. 2, b and c). Under similar conditions, cd27 ligation also up-regulated bcl-2 and bcl-xl as much as 5.0- (p < 0.01) and 3.9-fold (p < 0.01), respectively.	SIGNOR-93320	0.328
GRM4	protein	Q14833	UNIPROT	Excitatory_synaptic_transmission	phenotype	SIGNOR-PH133	SIGNOR	up-regulates				9606	BTO:0000938								24564659	f		miannu	Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic.	SIGNOR-264352	0.7
ATF4	protein	P18848	UNIPROT	FGF21	protein	Q9NSA1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									22233381	f		miannu	 These results add FGF21 gene induction to the transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation.	SIGNOR-253748	0.441
PAK1	protein	Q13153	UNIPROT	FLNA	protein	P21333	UNIPROT	up-regulates	phosphorylation	Ser2152	TRRRRAPsVANVGSH	9606									12198493	t		gcesareni	In flna, the pak1-binding site involves tandem repeat 23 in the carboxyl terminus and phosphorylation takes place on serine 2152.	SIGNOR-92065	0.782
CDK1	protein	P06493	UNIPROT	NME1	protein	P15531	UNIPROT	up-regulates	phosphorylation	Ser120	GRNIIHGsDSVESAE	9606			SIGNOR-C17						18234856	t		gcesareni	Application of this approach to the discovery of cdk1-cyclin b substrates yielded identification of >70 substrates and phosphorylation sites. Many of these sites are known to be phosphorylated in vivo, but most of the proteins have not been characterized as cdk1-cyclin b substrates.	SIGNOR-160493	0.27
PRKACB	protein	P22694	UNIPROT	MYBPC3	protein	Q14896	UNIPROT	up-regulates	phosphorylation	Ser304	SLLKKRDsFRTPRDS	9606									20151718	t		miannu	Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human).	SIGNOR-163776	0.276
ZBED1	protein	O96006	UNIPROT	RPS12	protein	P25398	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000567								17220279	t		Luana	HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid.	SIGNOR-266084	0.2
PRKCI	protein	P41743	UNIPROT	EZR	protein	P15311	UNIPROT	up-regulates	phosphorylation	Thr567	QGRDKYKtLRQIRQG	9606	BTO:0000195								18270268	t		llicata	Pkciota phosphorylated ezrin on t567 in vitro, and in sf9 cells that do not activate human ezrin. we conclude that, although other molecular mechanisms contribute to ezrin activation, apically localized phosphorylation by pkciota is essential for the activation and normal distribution of ezrin at the early stages of intestinal epithelial cell differentiation.	SIGNOR-160855	0.35
RAB7A	protein	P51149	UNIPROT	PIK3C3	protein	Q8NEB9	UNIPROT	up-regulates activity	guanine nucleotide exchange factor				BTO:0001131								14617358	t		Sara	The p150 adapter protein is in a complex with rab7. The hVPS34/p150 complex colocalized with rab7 on late endosomes and hVPS34 activity was dependent on nucleotide cycling of rab7	SIGNOR-261302	0.5
PRKACA	protein	P17612	UNIPROT	PPP2R5D	protein	Q14738	UNIPROT	up-regulates	phosphorylation	Ser573	KVLLRRKsELPQDVY	9606									17301223	t		gcesareni	Protein kinase a activates protein phosphatase 2a by phosphorylation of the b56delta subunit.	SIGNOR-153218	0.2
SIRT1	protein	Q96EB6	UNIPROT	COL10A1	protein	Q03692	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									21337390	f		miannu	 The inhibition of SIRT1 by siRNA induced OA-like gene expression changes, namely the significant down-regulation of aggrecan and up-regulation of COL10A1 and ADAMTS-5.	SIGNOR-255141	0.2
IFNGR2/INFGR1	complex	SIGNOR-C142	SIGNOR	STAT1	protein	P42224	UNIPROT	up-regulates activity	binding			9606									23898330	t		lperfetto	In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation	SIGNOR-249494	0.666
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	DIAPH1	protein	O60610	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Thr768	PVLPFGLtPKKLYKP	9606	BTO:0002588								23325789	t		miannu	 DIAPH1 is phosphorylated in response to dibutyryl cAMP (Bt2cAMP) at Thr-759 via a pathway that requires extracellular signal-related kinase (ERK).We also show that Bt2cAMP promotes the PKA- and ERK-dependent phosphorylation of DIAPH1 at T759 and that mutation of this site alters the stability of the protein and the rate of cAMP-stimulated mitochondrial movement.	SIGNOR-276484	0.2
RPS6KB1	protein	P23443	UNIPROT	IRS1	protein	P35568	UNIPROT	down-regulates activity	phosphorylation	Ser307	TRRSRTEsITATSPA	10090									15306821	t		lperfetto	Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin.	SIGNOR-127908	0.781
SRC	protein	P12931	UNIPROT	CDH2	protein	P19022	UNIPROT	down-regulates	phosphorylation	Tyr860	DSLLVFDyEGSGSTA	9606	BTO:0000848								16371504	t		lperfetto	Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated.	SIGNOR-143238	0.408
CDK2	protein	P24941	UNIPROT	ARID4A	protein	P29374	UNIPROT	down-regulates	phosphorylation	Ser1007	QHNFSVAsPLTLSQD	9606									21148318	t		lperfetto	We identified rbp1 as a novel cdk substrate. Rbp1 is phosphorylated by cdk2 on serines 864 and 1007, which are n- and c-terminal to the lxcxe motif, respectively. Cdk2-mediated phosphorylation of rbp1 or prb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation	SIGNOR-170451	0.437
sedoheptulose	smallmolecule	CHEBI:16802	ChEBI	sedoheptulose 7-phosphate	smallmolecule	CHEBI:15721	ChEBI	up-regulates quantity	precursor of			9606									22682222	t		miannu	The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose	SIGNOR-268137	0.8
clofarabine	chemical	CHEBI:681569	ChEBI	PRIM2	protein	P49643	UNIPROT	down-regulates activity	chemical inhibition			9606									1707752	t		miannu	Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase.	SIGNOR-258360	0.8
ASXL3	protein	Q9C0F0	UNIPROT	THRB	protein	P10828	UNIPROT	down-regulates activity	binding			9606	BTO:0000972								25450400	t		miannu	We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRα and TRβ, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXRα and TRβ were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXRα target genes through its recruitment to the LXR-response elements. 	SIGNOR-266766	0.2
FOLR1	protein	P15328	UNIPROT	(6S)-5-methyltetrahydrofolate(2-)	smallmolecule	CHEBI:18608	ChEBI	up-regulates quantity	relocalization			9606									10787414	t		lperfetto	The differential polarized distribution of the reduced-folate transporter (RFT-1) and folate receptor alpha (FRalpha), the two proteins involved in the transport of folate, has been characterized in normal mouse retinal pigment epithelium (RPE) and in cultured human RPE cells.	SIGNOR-268267	0.8
SACM1L	protein	Q9NTJ5	UNIPROT	phosphatidylinositol 4-phosphate	smallmolecule	CHEBI:37530	ChEBI	down-regulates quantity	chemical modification			9534									22253445	t		lperfetto	To investigate whether kinase activity could account for the different effects of the PI kinases on SARS-CoV S-mediated entry and to test whether PI4P lipids directly regulate viral entry independent of PI4KB, VeroE6 cells were transiently transfected with the SAC1 gene, a PI phosphatase that specifically converts PI4P lipids back to PI (27).|These results indicate that PI4P is indispensable for SARS-CoV S-mediated entry and suggest that PI4KB mediates SARS-CoV S entry by regulating the level of cellular PI4P.	SIGNOR-260733	0.8
ACTL6B	protein	O94805	UNIPROT	Brain-specific SWI/SNF SMARCA2 variant	complex	SIGNOR-C485	SIGNOR	form complex	binding			9606		BTO:0000142							11790558	t		miannu	 Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.	SIGNOR-270749	0.672
IGF2BP1	protein	Q9NZI8	UNIPROT	ACTB	protein	P60709	UNIPROT	up-regulates quantity	post transcriptional regulation			10116	BTO:0004102								21734271	t		miannu	We found that ZBP1 is necessary for netrin-1 stimulated local translation of β-actin mRNA in axonal growth cones. ZBP1 binds to β-actin mRNA in the soma and transports it to the growth cone on microtubules.	SIGNOR-268160	0.348
NLRC4 inflammasome	complex	SIGNOR-C223	SIGNOR	Caspase 1 complex	complex	SIGNOR-C220	SIGNOR	up-regulates activity	cleavage												30288079	t		lperfetto	Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 	SIGNOR-256384	0.2
MDGA2	protein	Q7Z553	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									26206665	f		miannu	Enhanced protein expression of p53 and p21 by MDGA2 was confirmed in MDGA2 overexpressed cells and xenograft tumours.	SIGNOR-264242	0.2
BTC	protein	P35070	UNIPROT	ERBB4	protein	Q15303	UNIPROT	up-regulates	binding			9606									16829981	t		gcesareni	For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4	SIGNOR-147823	0.713
PRKCG	protein	P05129	UNIPROT	NRGN	protein	Q92686	UNIPROT	up-regulates activity	phosphorylation	Ser36	AAAKIQAsFRGHMAR	-1									8080473	t		lperfetto	Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM.	SIGNOR-248915	0.44
PRKACA	protein	P17612	UNIPROT	CACNB2	protein	Q08289	UNIPROT	up-regulates activity	phosphorylation	Ser534	KSQHRSSsSAPHHNH										10441130	t		miannu	Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation	SIGNOR-250341	0.416
MAGED1	protein	Q9Y5V3	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates				9606		BTO:0001760							20646279	f		gcesareni	By comparing in vitro differentiation of myoblasts derived from wild-type or maged1 knockout mice, we observed that maged1 deficiency results in reduced levels of p21cip1/waf1, defective cell cycle exit and impaired myotube maturation.	SIGNOR-166893	0.2
GATA1	protein	P15976	UNIPROT	ITGA2B	protein	P08514	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17725493	f	 	miannu	 We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. 	SIGNOR-254192	0.58
TRIM13	protein	O60858	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								21333377	t		miannu	Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT.  We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro. 	SIGNOR-271851	0.381
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	MARS1	protein	P56192	UNIPROT	up-regulates activity	phosphorylation	Ser825	GGGQAKTsPKPAVVE	9606	BTO:0000567								25097229	t		miannu	Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins. 	SIGNOR-276670	0.2
CDK2	protein	P24941	UNIPROT	MECOM	protein	Q03112	UNIPROT	up-regulates activity	phosphorylation	Ser624	KMFKDKVsPLQNLAS										33082307	t		lperfetto	The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A.	SIGNOR-273426	0.3
NfKb-p65/p50	complex	SIGNOR-C13	SIGNOR	FTH1	protein	P02794	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0003212								19258503	f	 	miannu	 We show that inhibition of constitutively active NF-kappaB causes down-regulation of ferritin heavy chain (FHC) that leads to an increase of free intracellular iron, which, in turn, induces massive generation of ROS.	SIGNOR-254792	0.344
TGFBR1	protein	P36897	UNIPROT	SMAD3	protein	P84022	UNIPROT	up-regulates activity	phosphorylation	Ser423	SPSIRCSsVS	10090	BTO:0005493;BTO:0000165								19458083	t		lperfetto	A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus	SIGNOR-235385	0.806
CYP19A1	protein	P11511	UNIPROT	estrone	smallmolecule	CHEBI:17263	ChEBI	up-regulates quantity	chemical modification			9606		BTO:0000975							27702664	t		lperfetto	The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively	SIGNOR-268670	0.8
ADRB2	protein	P07550	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257081	0.342
PP1	proteinfamily	SIGNOR-PF54	SIGNOR	PYGM	protein	P11217	UNIPROT	down-regulates activity	dephosphorylation	Ser15	QEKRKQIsVRGLAGV	9606	BTO:0002049								22225877	t			GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation	SIGNOR-267402	0.2
MASTL	protein	Q96GX5	UNIPROT	ARPP19	protein	P56211	UNIPROT	up-regulates activity	phosphorylation	Ser62	KGQKYFDsGDYNMAK	-1									21164014	t		gcesareni	We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry.	SIGNOR-243611	0.721
MAP3K8	protein	P41279	UNIPROT	MAP2K1	protein	Q02750	UNIPROT	up-regulates	phosphorylation	Ser218	VSGQLIDsMANSFVG	9606	BTO:0000007								15466476	t		lperfetto	Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases.	SIGNOR-129690	0.556
Gbeta	proteinfamily	SIGNOR-PF4	SIGNOR	JUN	protein	P05412	UNIPROT	up-regulates	phosphorylation			9606									12169099	t	inferred from 70% family members	gcesareni	Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein.	SIGNOR-270033	0.2
nintedanib	chemical	CHEBI:85164	ChEBI	FGFR3	protein	P22607	UNIPROT	down-regulates activity	chemical inhibition			-1									18559524	t		Luana	In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers.	SIGNOR-257798	0.8
FBLIM1	protein	Q8WUP2	UNIPROT	FLNA	protein	P21333	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								24165133	t		miannu	Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 	SIGNOR-266105	0.884
AKT	proteinfamily	SIGNOR-PF24	SIGNOR	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	down-regulates activity	phosphorylation	Ser262	TFRPRSSsNASSVST	10090									10217147	t			Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo.	SIGNOR-252839	0.908
HDAC6	protein	Q9UBN7	UNIPROT	SRSF2	protein	Q01130	UNIPROT	up-regulates	deacetylation	Lys52	IPRDRYTkESRGFAF	9606									21157427	t		miannu	Our data support a model in which hdac6 has a key role in the maintenance of srsf2 protein level by inhibiting tip60_mediated acetylation and proteasomal degradation.	SIGNOR-170590	0.363
HSP90AB1	protein	P08238	UNIPROT	NOS3	protein	P29474	UNIPROT	up-regulates activity	binding			9606									9580552	t		miannu	Here we show that Hsp90 associates with endothelial nitric oxide synthase (eNOS) and is rapidly recruited to the eNOS complex by agonists that stimulate production of nitric oxide, namely vascular endothelial growth factor, histamine and fluid shear stress. Moreover, the binding of Hsp90 to eNOS enhances the activation of eNOS. 	SIGNOR-252214	0.528
AKT2	protein	P31751	UNIPROT	RALGAPA2	protein	Q2PPJ7	UNIPROT	down-regulates activity	phosphorylation	Thr715	PMRFRSAtTSGAPGV	10090				SIGNOR-C469					21148297	t		miannu	RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase	SIGNOR-269799	0.43
RNF111	protein	Q6ZNA4	UNIPROT	PML	protein	P29590	UNIPROT	down-regulates quantity by destabilization	polyubiquitination			9606	BTO:0000007								23530056	t		miannu	Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4.	SIGNOR-272883	0.361
CSNK1E	protein	P49674	UNIPROT	APC	protein	P25054	UNIPROT	up-regulates activity	phosphorylation	Ser1392	SRCTSVSsLDSFESR	9606	BTO:0000038								11487578	t		lperfetto	Apc can be phosphorylated by ck1epsilon at ser1279 and ser1392. Mutation of conserved serine residues in the beta-catenin regulatory motifs of APC interfered with both axin-dependent phosphorylation and phosphorylation by CKIepsilon and impaired the ability of APC to regulate beta-catenin.	SIGNOR-109664	0.596
RAD50	protein	Q92878	UNIPROT	RINT1	protein	Q6NUQ1	UNIPROT	up-regulates activity	binding			9606	BTO:0004784								16600870	t		lperfetto	We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells. 	SIGNOR-265030	0.482
RINT1	protein	Q6NUQ1	UNIPROT	Telomere_maintenance	phenotype	SIGNOR-PH148	SIGNOR	down-regulates				9606	BTO:0004784								16600870	f		lperfetto	We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells. 	SIGNOR-265031	0.7
axitinib	chemical	CHEBI:66910	ChEBI	FLT1	protein	P17948	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150								21297102	t		gcesareni	Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (rcc) after failure of prior treatment with sunitinib or a cytokine.	SIGNOR-171857	0.8
PRKCA	protein	P17252	UNIPROT	CFTR	protein	P13569	UNIPROT	up-regulates activity	phosphorylation	Ser790	IHRKTTAsTRKVSLA	-1									1377674	t		lperfetto	Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC.	SIGNOR-248851	0.408
CTSS	protein	P25774	UNIPROT	oligopeptide	smallmolecule	CHEBI:25676	ChEBI	down-regulates quantity	chemical modification			9606									31810556	t		scontino	Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol.	SIGNOR-267868	0.8
MAPK8	protein	P45983	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation	Ser73	VGLLKLAsPELERLI	9534	BTO:0000298								8137421	t		miannu	 JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain.	SIGNOR-250122	0.905
dexamethasone	chemical	CHEBI:41879	ChEBI	PPARG	protein	P37231	UNIPROT	up-regulates				9606									11279134	f		fspada	The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin	SIGNOR-106475	0.8
MST1	protein	P26927	UNIPROT	MST1R	protein	Q04912	UNIPROT	up-regulates	binding			9606									8062829	t		gcesareni	P185ron is a tyrosine kinase activated by msp	SIGNOR-31107	0.892
3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide	chemical	CHEBI:92223	ChEBI	HDAC10	protein	Q969S8	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-202108	0.8
ITCH	protein	Q96J02	UNIPROT	SMAD7	protein	O15105	UNIPROT	down-regulates	ubiquitination			9606									15946939	t		gcesareni	We identified atrophin 1-interacting protein 4 (aip4) as an e3 ubiquitin ligase that specifically targets smad7 for ubiquitin-dependent degradation without affecting the turnover of the activated tbetari. Surprisingly, we found that despite the ability to degrade smad7, aip4 can inhibit tgf-beta signaling, presumably by enhancing the association of smad7 with the activated tbetari.	SIGNOR-137951	0.52
PPM1F	protein	P49593	UNIPROT	PAK1	protein	Q13153	UNIPROT	down-regulates activity	dephosphorylation	Thr423	PEQSKRStMVGTPYW	10116									11864573	t			The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX.	SIGNOR-248531	0.399
MAPK14	protein	Q16539	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates				9606									12589053	f		fspada	Specific inhibitors for p38 kinase inhibited bmp2-induced adipocytic differentiation and transcriptional activation of ppargamma, whereas overexpression of smad6 had no effect on transcriptional activity of ppargamma. 	SIGNOR-210090	0.406
IRAK1	protein	P51617	UNIPROT	PELI1	protein	Q96FA3	UNIPROT	up-regulates activity	phosphorylation	Thr86	YTLSRAQtVVVEYTH	-1									19264966	t		miannu	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 	SIGNOR-276135	0.758
CSNK2A1	protein	P68400	UNIPROT	DDIT3	protein	P35638	UNIPROT	down-regulates activity	phosphorylation	Ser31	DLQEVLSsDENGGTY	9606	BTO:0000567								12876286	t		llicata	CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites 	SIGNOR-250853	0.35
CYP26A1	protein	O43174	UNIPROT	all-trans-retinoic acid	smallmolecule	CHEBI:15367	ChEBI	down-regulates quantity	chemical modification			9606									31963453	t		lperfetto	Cytochrome P450 (CYP) subfamily 26 of enzymes degrade the excess of RA to avoid detrimental effects [17]. Among the three subtypes (CYP26A1, CYP26B1, and CYP26C1), CYP26A1 is particularly important during embryonic development	SIGNOR-265139	0.8
DUSP3	protein	P51452	UNIPROT	MAPK3	protein	P27361	UNIPROT	down-regulates activity	dephosphorylation	Tyr204	HTGFLTEyVATRWYR	9606	BTO:0004419								12840032	t		lperfetto	The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase (14), protein-tyrosine phosphatase (ptp) (14, 15), or dual specificity phosphatases	SIGNOR-103035	0.65
CNOT3	protein	O75175	UNIPROT	CAND2	protein	O75155	UNIPROT	unknown	binding			10090									12207886	t		lperfetto	Hnot3l is associated with tip120b / tip120b presumably affects tissue-specific transcriptional regulation via interaction with not3.	SIGNOR-235593	0.337
ATM	protein	Q13315	UNIPROT	HNF1A	protein	P20823	UNIPROT	up-regulates	phosphorylation	Ser249	IQRGVSPsQAQGLGS	9606									24821553	t		lperfetto	Serine 249 phosphorylation by atm protein kinase regulates hepatocyte nuclear factor-1_ transactivation	SIGNOR-205087	0.259
SP1	protein	P08047	UNIPROT	PDGFC	protein	Q9NRA1	UNIPROT	up-regulates quantity by expression	transcriptional regulation			10116	BTO:0001685								15247255	f	 	 	The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad.|These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.|Egr-1 and Sp1 specifically bind the PDGF-C promoter	SIGNOR-254272	0.2
GSK3B	protein	P49841	UNIPROT	JUNB	protein	P17275	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr255	EARSRDAtPPVSPIN	9606	BTO:0000567								22710716	t		miannu	 Thus, JunB phosphorylation at S251 and T255 by GSK3β is primed by phosphorylation at S259 by a yet to-be-identified kinase.Phosphorylation at S251, T255 and S259 is required for JunB degradation. 	SIGNOR-276417	0.2
TNFRSF1B	protein	P20333	UNIPROT	TRAF1	protein	Q13077	UNIPROT	up-regulates				9606									8069916	f		gcesareni	Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2.	SIGNOR-33843	0.709
CAMK2B	protein	Q13554	UNIPROT	CAMK2B	protein	Q13554	UNIPROT	up-regulates activity	phosphorylation	Thr287	SMMHRQEtVECLKKF										2842767	t		llicata	Ca2+/calmodulin-dependent protein kinase II: identification of threonine-286 as the autophosphorylation site in the alpha subunit associated with the generation of Ca2+-independent activity.	SIGNOR-250640	0.2
PDK4	protein	Q16654	UNIPROT	PDHA1	protein	P08559	UNIPROT	down-regulates	phosphorylation	Ser293	TYRYHGHsMSDPGVS	-1									7782287	t		gcesareni	Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase.	SIGNOR-33197	0.674
CSNK2A1	protein	P68400	UNIPROT	SERINC3	protein	Q13530	UNIPROT	up-regulates activity	phosphorylation	Ser380	ILGDTTTsGASDEED	-1									30135209	t		miannu	The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro.	SIGNOR-273631	0.2
PAK1	protein	Q13153	UNIPROT	PGAM1	protein	P18669	UNIPROT	down-regulates	phosphorylation	Ser23	WNLENRFsGWYDADL	9606	BTO:0000130								12189148	t	Activated pak1	gcesareni	Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity.	SIGNOR-91598	0.2
CDK8	protein	P49336	UNIPROT	YAP1	protein	P46937	UNIPROT	up-regulates activity	phosphorylation	Ser289	PPPLAPQsPQGGVMG	-1									29967145	t		miannu	CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro.	SIGNOR-277650	0.327
ADAM10	protein	O14672	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates activity	cleavage			9606	BTO:0000782								28624438	t		miannu	ADAM10-mediated Notch1 cleavage is the rate limiting-step for release of the NICD and subsequent activation of Notch1 signaling. In T cells ADAM10-mediated Notch1 shedding controls T cell development 	SIGNOR-259838	0.773
EP300	protein	Q09472	UNIPROT	SMAD7	protein	O15105	UNIPROT	up-regulates	acetylation	Lys64	RAGCCLGkAVRGAKG	9606									15831498	t		gcesareni	Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300	SIGNOR-135469	0.476
SNRPG	protein	P62308	UNIPROT	U4/U6.U5 snRNP complex	complex	SIGNOR-C478	SIGNOR	form complex	binding			9606									30765414	t		lperfetto	The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 	SIGNOR-270632	0.788
NTRK1	protein	P04629	UNIPROT	SH2B2	protein	O14492	UNIPROT	up-regulates	phosphorylation			9606	BTO:0000938								9856458	t		lperfetto	Two substrates of trk kinases, raps and sh2-b. raps and sh2-b mediate trk signaling in developing neurons	SIGNOR-62619	0.531
PPP2CB	protein	P62714	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	up-regulates activity	dephosphorylation	Ser181	NPLLRKEsAPPSLRR	9606									18339811	t			Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.	SIGNOR-248604	0.2
RIMS3	protein	Q9UJD0	UNIPROT	RAB3A	protein	P20336	UNIPROT	up-regulates activity	relocalization			9606	BTO:0000938								31679900	t		miannu	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264379	0.286
TNFRSF10C	protein	O14798	UNIPROT	TNFSF10	protein	P50591	UNIPROT	down-regulates	binding			9606		BTO:0000671							20103630	t		amattioni	Albeit on binding the ligand, dcr1 and dcr2 do not transduce the apoptogenic signal,	SIGNOR-163611	0.895
TBK1	protein	Q9UHD2	UNIPROT	DDAH2	protein	O95865	UNIPROT	down-regulates activity	phosphorylation	Thr203	VRAMAVLtDHPYASL										33850055	t		lperfetto	TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o	SIGNOR-275645	0.2
CAMK4	protein	Q16566	UNIPROT	CREBBP	protein	Q92793	UNIPROT	up-regulates activity	phosphorylation	Ser302	PQLASKQsMVNSLPT		BTO:0000938								11970865	t		llicata	Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301.	SIGNOR-250710	0.624
CKM complex	complex	SIGNOR-C406	SIGNOR	STAT1	protein	P42224	UNIPROT	up-regulates activity	phosphorylation	Ser727	TDNLLPMsPEEFDEV										29239838	t		lperfetto	We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation. 	SIGNOR-273182	0.299
CC2D1A	protein	Q6P1N0	UNIPROT	HTR1A	protein	P08908	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000938								20171170	t	nucleus	lperfetto	Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. In the cytosol, it acts as a scaffold protein in the phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathway. In the nucleus, it is a transcriptional repressor of the serotonin-1A (5-HT1A) receptor.	SIGNOR-268295	0.38
CSNK1D	protein	P48730	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates	phosphorylation	Ser121	ESSDSGTsVSENRCH	9606									20708156	t		gcesareni	Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase.	SIGNOR-167501	0.351
SIRT5	protein	Q9NXA8	UNIPROT	HMGCS2	protein	P54868	UNIPROT	up-regulates activity	post translational modification	Lys310	PFCKMVQkSLARLMF	9606	BTO:0000007								24315375	t	desuccinylation	lperfetto	We demonstrate that SIRT5 regu-lates succinylation of the rate-limiting ketogenicenzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2) both in vivo and in vitro.|Succinylation of Lysine Residues within the SubstrateBinding Pocket Inhibits HMGCS2 Activity|Here, we use a label-freequantitative proteomic approach to characterizethe lysine succinylome in liver mitochondria and itsregulation by the desuccinylase SIRT5	SIGNOR-267642	0.351
SRC	protein	P12931	UNIPROT	DAB1	protein	O75553	UNIPROT	up-regulates activity	phosphorylation	Tyr198	EDVEDPVyQYIVFEA	10090	BTO:0000938								11279201	t		lperfetto	Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons.	SIGNOR-247076	0.43
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	SOS1	protein	Q07889	UNIPROT	down-regulates	phosphorylation	Ser1193	QPTSKAYsPRYSISD	9606									20724475	t		lperfetto	ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. 	SIGNOR-244747	0.2
RARA	protein	P10276	UNIPROT	THR	proteinfamily	SIGNOR-PF84	SIGNOR	up-regulates	binding			9606									15650024	t	inferred from family member	gcesareni	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-270293	0.516
GSK3B	protein	P49841	UNIPROT	AHR	protein	P35869	UNIPROT	up-regulates activity	phosphorylation	Ser440	NGTSGKDsATTSTLS	9606	BTO:0000567								34198826	t		miannu	A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR.	SIGNOR-276662	0.253
S100A9	protein	P06702	UNIPROT	AGER	protein	Q15109	UNIPROT	up-regulates activity	binding			9606	BTO:0001545								28137827	t		miannu	RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33	SIGNOR-261920	0.355
NFATC1	protein	O95644	UNIPROT	T_cell_activation	phenotype	SIGNOR-PH73	SIGNOR	up-regulates activity													10358178	f			The transcription factor NF-ATc that controls gene expression in T lymphocytes and embryonic cardiac cells is expressed in three prominent isoforms.	SIGNOR-252344	0.7
RPS21	protein	P63220	UNIPROT	40S cytosolic small ribosomal subunit	complex	SIGNOR-C286	SIGNOR	form complex	binding			-1									25901680	t		lperfetto	Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins.	SIGNOR-262429	0.85
E4F1	protein	Q66K89	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	ubiquitination	Lys321	SSPQPKKkPLDGEYF	9606	BTO:0001938								17110336	t		miannu	E4F1 Has an Intrinsic Ubiquitin E3 Ligase Activity that Drives K48-type Ubiquitylation of p53. These data demonstrate that E4F1 stimulates the ubiquitylation of p53 on the lysine cluster K319–K321, i.e., at sites distinct from those targeted by Hdm2. p53 forms Ubiquitylated by E4F1 Are Localized on Chromatin. In striking contrast with Ub-p53 forms stimulated by Hdm2, which are mainly cytosoluble and targeted to the proteasome, we found that E4F1-stimulated Ub-p53 forms are tightly associated with chromatin, suggesting that they could be involved in transcription.	SIGNOR-271395	0.591
MAML1	protein	Q92585	UNIPROT	NOTCH	proteinfamily	SIGNOR-PF30	SIGNOR	up-regulates	binding			9606									11101851	t	inferred from 70% of family members	gcesareni	Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes4	SIGNOR-269934	0.921
PDGFRA	protein	P16234	UNIPROT	PDGFRA	protein	P16234	UNIPROT	up-regulates activity	phosphorylation	Tyr988	RVDSDNAyIGVTYKN	9823	BTO:0004007								7535778	t		miannu	We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ.	SIGNOR-250252	0.2
INS	protein	P01308	UNIPROT	IGF1R	protein	P08069	UNIPROT	up-regulates	binding			9606		BTO:0000887							1851182	t		fspada	Because of the sequence homology and tertiary structure similarities between proinsulin (pi) and insulin-like growth factor-i (igf-i), it is possible that pi interacts with the igf-i receptor with higher affinity than insulin.	SIGNOR-22083	0.891
MAP4K3	protein	Q8IVH8	UNIPROT	IQGAP1	protein	P46940	UNIPROT	up-regulates activity	phosphorylation	Ser480	NTVWKQLsSSVTGLT	-1									31431460	t		miannu	GLK directly phosphorylated IQGAP1 at Ser-480 enhancing Cdc42 activation and subsequent cell migration. 	SIGNOR-277479	0.2
AP3D1	protein	O14617	UNIPROT	AP-3 complex	complex	SIGNOR-C247	SIGNOR	form complex	binding			9606									21097499	t		lperfetto	Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses)	SIGNOR-260683	0.931
CIITA	protein	P33076	UNIPROT	HLA-DRB4	protein	P13762	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0002417								10886240	f	 	 	These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma.	SIGNOR-254012	0.2
MLKL	protein	Q8NB16	UNIPROT	CNR2	protein	P34972	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser352	KITPWPDsRDLDLSD	9606	BTO:0000007								10400664; 36448459	t	done	miannu	Under hyperglycemic conditions, high glucose induced CB2R internalization in a β-arrestin 2-dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R.	SIGNOR-274121	0.2
WICH	complex	SIGNOR-C449	SIGNOR	RNA Polymerase I	complex	SIGNOR-C390	SIGNOR	up-regulates activity	binding			9606									16514417	t		miannu	 Here, we show by biochemical fractionation of nuclear extracts, protein-protein interaction studies and chromatin immunoprecipitation assays that NM1 is part of a multiprotein complex that contains WICH, a chromatin remodelling complex containing WSTF (Williams syndrome transcription factor) and SNF2h. NM1, WSTF and SNF2h were found to be associated with RNA polymerase I (Pol I) and ribosomal RNA genes (rDNA). RNA interference-mediated knockdown of NM1 and WSTF reduced pre-rRNA synthesis in vivo, and antibodies to WSTF inhibited Pol I transcription on pre-assembled chromatin templates but not on naked DNA. The results indicate that NM1 cooperates with WICH to facilitate transcription on chromatin.	SIGNOR-268830	0.44
leucine	smallmolecule	CHEBI:25017	ChEBI	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				9606									22749528	f		Luana	Leucine and Glutamine Activate Glutaminolysis and mTORC1	SIGNOR-268010	0.8
TP53	protein	P04637	UNIPROT	OGG1	protein	O15527	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									16293709	t		miannu	 Using gel-shift assays, we showed that p53 binds to its putative cis-elements within the hOGG1 promoter. In addition we demonstrated that supplementing p53 in HCT116p53-/- cells enhanced the transcription of hOGG1.	SIGNOR-255440	0.441
AMPK	complex	SIGNOR-C15	SIGNOR	BAIAP2	protein	Q9UQB8	UNIPROT	down-regulates	phosphorylation	Ser366	KTLPRSSsMAAGLER	9606									22137581	t		lperfetto	Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction	SIGNOR-216608	0.2
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	up-regulates	phosphorylation	Ser742	QQIINQIsKLHAIID	9606									18680479	t		gcesareni	We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity after expression in bacteria or in cultured human cells.	SIGNOR-179900	0.2
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr154	NRMPVAPyWTSPEKM	9606									8443592	t		lperfetto	Tyrosine residues 154 and 307, which are in the extracellular domain of transmembrane receptor isoforms and are in an unusual sequence context for tyrosine phosphorylation, were also phosphorylated.	SIGNOR-98622	0.2
PTPRG	protein	P23470	UNIPROT	JAK2	protein	O60674	UNIPROT	down-regulates activity	dephosphorylation	Tyr1007	VLPQDKEyYKVKEPG	9606	BTO:0000876								25624455	t		miannu	Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG.	SIGNOR-254689	0.291
bosutinib	chemical	CHEBI:39112	ChEBI	SRC	protein	P12931	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-190699	0.8
BMPR1B	protein	O00238	UNIPROT	SMAD9	protein	O15198	UNIPROT	up-regulates	phosphorylation			9606									19620713	t		gcesareni	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-187196	0.697
CDH2	protein	P19022	UNIPROT	CDON/SPAG9	complex	SIGNOR-C21	SIGNOR	up-regulates	binding			9606									20160094	t		lperfetto	We report here that n-cadherin ligation activates p38alpha/beta in myoblasts in a cdo-, bnip-2-, and jlp-dependent manner	SIGNOR-217517	0.529
STAT3	protein	P40763	UNIPROT	SP1/STAT3	complex	SIGNOR-C74	SIGNOR	form complex	binding			9606									19723038	t		miannu	Sp1 and stat3 seem to synergistically augment renalase transcription.	SIGNOR-187793	0.467
HCFC1	protein	P51610	UNIPROT	CREB3	protein	O43889	UNIPROT	up-regulates activity	binding			-1									9658067	t	2	miannu	We also show that while interaction with HCF is not required for the ability of Luman to activate transcription when tethered to the GAL4 promoter, it appears to be essential for Luman to activate transcription through CRE sites.	SIGNOR-241372	0.583
ramipril	chemical	CHEBI:8774	ChEBI	ACE	protein	P12821	UNIPROT	down-regulates activity	chemical inhibition			-1									6097265	t		miannu	2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl] - (1S,3S,5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid (Hoe 498) is a new, very effective and long lasting, nonsulfhydryl angiotensin I converting enzyme inhibitor.	SIGNOR-258400	0.8
AURKA	protein	O14965	UNIPROT	FANCA	protein	O15360	UNIPROT	up-regulates activity	phosphorylation	Ser165	HSMFSRLsFCQELWK	9606	BTO:0002181								27398318	t		miannu	E detected interactions between Aurora A kinase and FANCA protein, one of the components of the FA nuclear core complex. These results suggest that S165 phosphorylation by Aurora A kinase is required for proper activation of the FA/BRCA pathway in response to DNA damage.	SIGNOR-277263	0.48
PKA	proteinfamily	SIGNOR-PF17	SIGNOR	PDE4D	protein	Q08499	UNIPROT	up-regulates activity	phosphorylation	Ser125	CRAMDRTsYAVETGH	9534									12023945	t		miannu	Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms.	SIGNOR-275988	0.2
PPM1A	protein	P35813	UNIPROT	SMAD2	protein	Q15796	UNIPROT	down-regulates activity	dephosphorylation			9606									25026293	t		miannu	All of these results lead to the conclusion that PPM1A inhibits the TGF-\u03b2-induced the activity of Smad2, Smad3 and transcriotional responses, whereas depletion of PPM1A enhances the activation of TGF-\u03b2/Smads signaling in bladder cancer cells.|Protein phosphatase PPM1A has been reported to dephosphorylate TGF-\u03b2-activated Smad2/3, thus inhibiting the TGF-\u03b2 signaling pathway.	SIGNOR-277034	0.655
NOTCH1	protein	P46531	UNIPROT	ADAM19	protein	Q9H013	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606	BTO:0000782;BTO:0001454								10933396	f		gcesareni	Deltex, meltrin beta, ifi-202, and ifi-204 were also upregulated by notchic in the 2b4.11 t cell hybridoma, whereas ifi-d3 was expressed constitutively at relatively high levels and slightly upregulated by notchic, and pre-talfa was not expressed. Deltex, meltrin beta, pre-talfa, ifi-202, and ifi-204 were upregulated by notchic expression in the akr1 dp thymoma cell line, whereas ifi-d3 was not expressed	SIGNOR-80330	0.316
WNT7A	protein	O00755	UNIPROT	FZD7	protein	O75084	UNIPROT	up-regulates activity	binding			9606		BTO:0000887;BTO:0001103							22944199	t		gcesareni	Analysis of the expression of the fzd receptors during somitogenesis demonstrated that fzd7 is expressed in the hypaxial region of the somite, suggesting an interaction with wnt7a.	SIGNOR-198919	0.665
KAT2B	protein	Q92831	UNIPROT	NOTCH1	protein	P46531	UNIPROT	up-regulates	acetylation			9606	BTO:0000782;BTO:0001271								22120716	t		gcesareni	In earlier studies, we demonstrated that maml1 enhanced p300 acetyltransferase activity, which increased the acetylation of notch by p300.Acetylation controls notch stability and function in t-cell leukemia.	SIGNOR-177749	0.584
WNT3A	protein	P56704	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates activity	binding			9606									21078818	t		gcesareni	Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have	SIGNOR-169657	0.689
TLE1	protein	Q04724	UNIPROT	SIX6	protein	O95475	UNIPROT	up-regulates activity	binding			-1									12441302	t		lperfetto	Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. TLE1 over-expression induces an enlargement of the eye field and reinforcesSIX3/SIX6 capability of initiating retina formation	SIGNOR-234592	0.404
TTK	protein	P33981	UNIPROT	TTK	protein	P33981	UNIPROT	down-regulates	phosphorylation	Thr675	ANQMQPDtTSVVKDS	9606									18680479	t		miannu	We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / mutation of thr675 to alanine increased mps1 catalytic domain activity, and this was reduced to wt levels by mutation to aspartate	SIGNOR-179904	0.2
PLK1	protein	P53350	UNIPROT	TOPORS	protein	Q9NS56	UNIPROT	up-regulates activity	phosphorylation	Ser718	KDRDGYEsSYRRRTL	9606									19473992	t		lperfetto	Plk1-mediated phosphorylation of topors regulates p53 stabilityherein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation.	SIGNOR-185838	0.457
NMBR	protein	P28336	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257160	0.271
BCORL1	protein	Q5H9F3	UNIPROT	HDAC5	protein	Q9UQL6	UNIPROT	up-regulates activity	binding			9606	BTO:0000567								17379597	t		irozzo	BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor.	SIGNOR-259113	0.451
PRKACA	protein	P17612	UNIPROT	ACACA	protein	Q13085	UNIPROT	down-regulates activity	phosphorylation	Ser1201	IPTLNRMsFSSNLNH	-1									2900138	t			TC1 = Ser-2Ser(P)-Met-3Ser(P)-Gly-Leu; TC2 = Arg-Met-1Ser(P)-Phe- Cyclic-AMP-dependent protein kinase phosphorylates sites 1 and 2 exclusively, whereas the AMP-activated protein kinase phosphorylates sites 1 and 3, plus at least one other minor site.[…]The results suggest that phosphorylation of site 3 is primarily responsible for the large decrease in Vmax produced by the AMP-activated protein kinase, while phosphorylation of site 1 may be primarily responsible for the increase in A0.5 for citrate and more modest depression of Vmax produced by cyclic-AMP-dependent protein kinase and ACK2	SIGNOR-267714	0.2
KAT2A	protein	Q92830	UNIPROT	H3-5	protein	Q6NXT2	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkSTGGKAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269600	0.2
PRKCZ	protein	Q05513	UNIPROT	AKT2	protein	P31751	UNIPROT	up-regulates activity	phosphorylation	Thr309	SDGATMKtFCGTPEY	-1									9512493	t		lperfetto	The activation of PKBbeta and PKBgamma by PDK1 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma). PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides. The activation of PKBgamma and its phosphorylation at Thr305 was triggered by insulin-like growth factor-1 in 293 cells.	SIGNOR-248997	0.479
EGR1	protein	P18146	UNIPROT	PTGES	protein	O14684	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									21983014	f	 	 	In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression.|EGR1 downregulation seems to be the major effect of DMC leading to transcriptional inhibition of mPGES-1	SIGNOR-254249	0.343
CHEK1	protein	O14757	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates activity	phosphorylation	Ser15	PSVEPPLsQETFSDL	9606	BTO:0001321								15659650	t		lperfetto	CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37	SIGNOR-217791	0.772
IKBKB	protein	O14920	UNIPROT	COPS5	protein	Q92905	UNIPROT	down-regulates activity	phosphorylation	Thr205	EGPSEYQtIPLNKIE	-1									31950832	t		lperfetto	Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. 	SIGNOR-275519	0.336
PRKCA	protein	P17252	UNIPROT	TRPV4	protein	Q9HBA0	UNIPROT	up-regulates activity	phosphorylation	Thr175	GLLPFLLtHKKRLTD	9606									19661060	t		Manara	We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4.	SIGNOR-260882	0.357
LYN	protein	P07948	UNIPROT	RGS16	protein	O15492	UNIPROT	up-regulates activity	phosphorylation	Tyr168	TLMEKDSyPRFLKSP	-1									12588871	t			Lyn kinase phosphorylated recombinant RGS16 in vitro. Induction of RGS16 tyrosine phosphorylation was associated with increased RGS16 protein levels and enhanced GAP activity in cell membranes.	SIGNOR-251410	0.352
CDK1	protein	P06493	UNIPROT	KMT5A	protein	Q9NQR1	UNIPROT	up-regulates quantity by stabilization	phosphorylation	Ser100	SKIYSYMsPNKCSGM	9606									20966048	t		miannu	We found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase.	SIGNOR-259832	0.2
CEBPB	protein	P17676	UNIPROT	ADM	protein	P35318	UNIPROT	up-regulates quantity by expression	transcriptional regulation												9480831	t	 	 	These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells.	SIGNOR-254047	0.247
VEGFC	protein	P49767	UNIPROT	Angiogenesis	phenotype	SIGNOR-PH46	SIGNOR	up-regulates													17326328	f		lperfetto	More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor	SIGNOR-252277	0.7
OGT	protein	O15294	UNIPROT	TET1	protein	Q8NFU7	UNIPROT	up-regulates activity	glycosylation			9606	BTO:0002181								23729667	t		irozzo	The DNA demethylation enzyme Tet1 interacts with Ogt and is O-GlcNAcylated. Tet1 protein stability is positively regulated by O-GlcNAcylation, and its repression function on targeting genes is dependent on Ogt. 	SIGNOR-259184	0.452
NCS1	protein	P62166	UNIPROT	PI4KB	protein	Q9UBF8	UNIPROT	up-regulates activity				10116									21104311	f		miannu	In chromaffin and PC12 cells, NCS-1 can enhance secretion via its activation of PI4 kinaseIIIb with the subsequent increase in PIP2 levels. PIP2 has been shown to be an important requirement for exocytosis	SIGNOR-263963	0.67
CDK1	protein	P06493	UNIPROT	NEK9	protein	Q8TD19	UNIPROT	up-regulates activity	phosphorylation	Thr210	SEYSMAEtLVGTPYY	9606	BTO:0000567								21642957	t	done	miannu	We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. while CDK1 activity is necessary for Nek9 phosphorylation in mitosis and the resulting change in electrophoretical mobility, Nek9 Thr210 phosphorylation and mitotic activation requires both CDK1 and Plk1.	SIGNOR-273889	0.46
MAPK1	protein	P28482	UNIPROT	JUN	protein	P05412	UNIPROT	up-regulates activity	phosphorylation			9606									23616010	t		lperfetto	Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1.	SIGNOR-201943	0.784
(S)-dihydroorotate	smallmolecule	CHEBI:30864	ChEBI	orotate	smallmolecule	CHEBI:30839	ChEBI	up-regulates quantity	precursor of			9606									30449682	t		miannu	OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway	SIGNOR-267428	0.8
HDAC1	protein	Q13547	UNIPROT	MECP2/SIN3A/HDAC complex	complex	SIGNOR-C360	SIGNOR	form complex	binding			9606	BTO:0000567								9620804	t		Luana	We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases.	SIGNOR-267738	0.743
CDC25A	protein	P30304	UNIPROT	CCNB1	protein	P14635	UNIPROT	up-regulates activity	dephosphorylation			9606									16682204	t		miannu	Cdc25A dephosphorylates and activates CyclinE\u2013Cdk2, CyclinA\u2013Cdk2 and CyclinB\u2013Cdk1, whereas Cdc25B and Cdc25C primarily target CyclinB\u2013Cdk1  [4,5] .	SIGNOR-277137	0.849
PRKACA	protein	P17612	UNIPROT	GABRR1	protein	P24046	UNIPROT	unknown	phosphorylation	Ser443	PQRKSQRsSYVSMRI	-1									12175859	t		miannu	Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). These data, indicate that S422 and/or S423 are the major sites of PKA-mediated phosphorylation of the 1 GABA receptor.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation	SIGNOR-262751	0.289
SLC30A9	protein	Q6PML9	UNIPROT	NUMB	protein	P49757	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									11782429	t		lperfetto	Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation.	SIGNOR-113704	0.2
MAP3K7	protein	O43318	UNIPROT	MAP2K3	protein	P46734	UNIPROT	up-regulates activity	phosphorylation			10090									17299140	t		lperfetto	Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK.	SIGNOR-42402	0.483
HECW1	protein	Q76N89	UNIPROT	DVL1	protein	O14640	UNIPROT	down-regulates quantity by destabilization	ubiquitination			10090	BTO:0001976								14684739	t		miannu	We have also found that NEDL1 targets Dishevelled-1 (Dvl1) for ubiquitination-mediated degradation and that mutant (but not wild-type) SOD1 affects the function of Dvl1. 	SIGNOR-271499	0.626
MRE11	protein	P49959	UNIPROT	ATM	protein	Q13315	UNIPROT	up-regulates	binding			9606									21763684	t		gcesareni	One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase.	SIGNOR-175006	0.2
ERCC2	protein	P18074	UNIPROT	ERCC3	protein	P19447	UNIPROT	up-regulates	binding			9606									10024882	t		miannu	Xpd helps xpb in promoter opening and as such participates in the transcription reaction.	SIGNOR-64672	0.954
SDHA	protein	P31040	UNIPROT	SDH	complex	SIGNOR-C400	SIGNOR	form complex	binding			9606									16143825	t		miannu	Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively.	SIGNOR-266271	0.95
TNF	protein	P01375	UNIPROT	BMP4	protein	P12644	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000018								17350185	f		Luana	TNF-alpha represses the activity of a human Bmp4 promoter-luciferase construct, transfected into A549 and H441 cells.	SIGNOR-266085	0.321
AIIB/b3 integrin	complex	SIGNOR-C173	SIGNOR	FGB	protein	P02675	UNIPROT	up-regulates activity	binding			9606	BTO:0000132								16418530	t		lperfetto	In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation.	SIGNOR-253361	0.478
ACP1	protein	P24666	UNIPROT	AKT3	protein	Q9Y243	UNIPROT	down-regulates activity	dephosphorylation	Ser472	RPHFPQFsYSASGRE	10090									17353188	t			Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3	SIGNOR-248457	0.2
RAB23	protein	Q9ULC3	UNIPROT	GLI3	protein	P10071	UNIPROT	down-regulates				9606									16364285	f		gcesareni	Based on su(fu) function, we predict that rab23 can interact with all gli1 molecules including gli1, gli2 and gli3, and inhibit their transcriptional activities and nuclear localization.	SIGNOR-143160	0.562
ITK	protein	Q08881	UNIPROT	CD28	protein	P10747	UNIPROT	up-regulates activity	phosphorylation	Tyr206	PGPTRKHyQPYAPPR										8992971	t			EMT can phosphorylate all four tyrosines of the CD28 tail. in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor.	SIGNOR-251334	0.677
CDK7	protein	P50613	UNIPROT	TP53	protein	P04637	UNIPROT	up-regulates	phosphorylation	Ser378	SKKGQSTsRHKKLMF	9606									9315650	t		llicata	The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase.	SIGNOR-51288	0.47
IRS1	protein	P35568	UNIPROT	PIK3CB	protein	P42338	UNIPROT	up-regulates activity	binding			10090	BTO:0000944								11416002	t		lperfetto	To examine contributions of specific YXXM motifs in human insulin receptor substrate-1 (IRS-1) to mediating the metabolic actions of insulin, we studied IRS-1 mutants containing various substitutions of Phe for Tyr. In transfected NIH-3T3(IR) cells, insulin stimulation caused a 5-fold increase in phosphatidylinositol 3-kinase (PI3K) activity coimmunoprecipitated with wild-type IRS-1	SIGNOR-235487	0.712
E2F1	protein	Q01094	UNIPROT	PPARG	protein	P37231	UNIPROT	up-regulates	transcriptional regulation			9606									12110166	f	During clonal expansion	fspada	We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation	SIGNOR-210047	0.474
IFNG	protein	P01579	UNIPROT	IFNGR2	protein	P38484	UNIPROT	up-regulates	binding			9606									7673114	t		gcesareni	Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (43 45) is required for signal transduction	SIGNOR-31013	0.634
NFIB	protein	O00712	UNIPROT	ANOS1	protein	P23352	UNIPROT	down-regulates quantity	transcriptional regulation			10090									31838646	t		Gianni	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268878	0.2
MUL1	protein	Q969V5	UNIPROT	DNM1L	protein	O00429	UNIPROT	up-regulates activity	sumoylation	Lys608	LLAEEKSKPIPIMPA	9606	BTO:0000007								19638400	t		Barakat	Through detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms.	SIGNOR-274130	0.55
IKBKB	protein	O14920	UNIPROT	DOK1	protein	Q99704	UNIPROT	up-regulates	phosphorylation	Ser446	SGIKSHNsALYSQVQ	9606									15574499	t		amattioni	Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility.	SIGNOR-131455	0.255
LPAR1	protein	Q92633	UNIPROT	GNA13	protein	Q14344	UNIPROT	up-regulates	binding			9606									20331961	t		milica	The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits).	SIGNOR-230761	0.432
1-phosphatidyl-1D-myo-inositol 3-phosphate(3-)	smallmolecule	CHEBI:58088	ChEBI	1-phosphatidyl-1D-myo-inositol(1-)	smallmolecule	CHEBI:57880	ChEBI	up-regulates quantity	precursor of			9606									18429927	t		miannu	PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 	SIGNOR-269809	0.8
PRKACA	protein	P17612	UNIPROT	PDE3B	protein	Q13370	UNIPROT	unknown	phosphorylation	Ser442	TPQLRRSsGTSGLLP	-1									8163498	t		miannu	Serine 427 is the target for cAMP-PK phosphorylation of the rat adipocyte cGI-PDE in vitro	SIGNOR-250023	0.462
MAP3K10	protein	Q02779	UNIPROT	TCF3	protein	P15923	UNIPROT	down-regulates	phosphorylation	Ser352	SSNNFSSsPSTPVGS	9606									19801649	t		llicata	Mlk2 inhibits e47 transactivation activity on the trkb promote	SIGNOR-161527	0.2
DIABLO	protein	Q9NR28	UNIPROT	BIRC2	protein	Q13490	UNIPROT	down-regulates quantity	binding			-1									10929711	t		amattioni	Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, IAPs, and removing their inhibitory activity. Smac is normally a mitochondrial protein but is released into the cytosol when cells undergo apoptosis.	SIGNOR-80206	0.891
IRAK4	protein	Q9NWZ3	UNIPROT	NCF1	protein	P14598	UNIPROT	up-regulates	phosphorylation	Thr356	PLEEERQtQRSKPQP	9606	BTO:0000130								17217339	t		lperfetto	Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation.	SIGNOR-152027	0.39
AR	protein	P10275	UNIPROT	CRH	protein	P06850	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0000931								16446741	t		lperfetto	A direct androgenic involvement in the expression of human corticotropin-releasing hormone|A potential androgen-responsive element (ARE) in the human CRH promoter was subsequently analyzed with bandshifts and cotransfections in neuroblastoma cells. In the presence of testosterone, recombinant human AR bound specifically to the CRH-ARE.	SIGNOR-268723	0.311
MECP2	protein	P51608	UNIPROT	Neuron_maturation	phenotype	SIGNOR-PH169	SIGNOR	up-regulates				10090		BTO:0000601							17532643	f		Luana	Our studies suggest that MeCP2 plays a central role in neuronal maturation, which might be mediated through epigenetic control of expression pathways that are instrumental in both dendritic development and synaptogenesis.	SIGNOR-264968	0.7
4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine	smallmolecule	CHEBI:94284	ChEBI	GLI1	protein	P08151	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000150;BTO:0000551								19860666	t		gcesareni	Gant58 is a gli antagonist that inhibits gli1-induced transcription	SIGNOR-188863	0.8
GABRB2	protein	P47870	UNIPROT	GABA-A (a6-b2-d) receptor	complex	SIGNOR-C328	SIGNOR	form complex	binding			9606		BTO:0000227							18790874	t	brain, See table 3 for identified complexes	lperfetto	The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon.	SIGNOR-263769	0.463
CRK	protein	P46108	UNIPROT	RAPGEF1	protein	Q13905	UNIPROT	up-regulates	binding			9606									7806500	t		gcesareni	The endogenous c3g could be coprecipitated with crk from cell lysates of cells expressing high levels of c-crk or v-crk, suggesting high binding affinity and a possible interaction in vivo.	SIGNOR-33732	0.898
ponatinib	chemical	CHEBI:78543	ChEBI	FGFR3	protein	P22607	UNIPROT	down-regulates activity	chemical inhibition			9606									23468082	t		miannu	Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. 	SIGNOR-259279	0.8
phenobarbital	chemical	CHEBI:8069	ChEBI	NR1I2	protein	O75469	UNIPROT	up-regulates activity	chemical activation			9534	BTO:0000318								9727070	t		miannu	 The antihypercholesterolemic drug lovastatin also activated hPXR as did phenobarbital and the organochlorine pesticide transnonachlor (Fig. 4 A). Thus, hPXR is activated by a remarkably diverse group of synthetic compounds that are known to induce CYP3A4 gene expression (Fig. 4 C).	SIGNOR-258830	0.8
S1PR2	protein	O95136	UNIPROT	GNA14	protein	O95837	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257289	0.357
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	ESR1	protein	P03372	UNIPROT	up-regulates	phosphorylation	Ser118	LHPPPQLsPFLQPHG	9606	BTO:0000567								17615152	t		lperfetto	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.	SIGNOR-244655	0.2
KAT2B	protein	Q92831	UNIPROT	H3Y2	protein	P0DPK5	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkATAWQAP	9606			SIGNOR-C465						34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269615	0.2
POU2F1	protein	P14859	UNIPROT	HOXD10	protein	P28358	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									25301728	f		miannu	Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11	SIGNOR-205540	0.2
NHEJ1	protein	Q9H9Q4	UNIPROT	Lig4-Xrcc4 complex	complex	SIGNOR-C354	SIGNOR	up-regulates activity	binding			9606	BTO:0000567								25661488	t		miannu	Here we report that Akt phosphorylates XLF (XRCC4 like factor, also called NHEJ1) at T181, to dissociate XLF from the XRCC4 (X-ray repair cross-complementing protein 4)/DNA ligase IV (LIG4) complex and subsequently triggers XLF cytoplasmic translocation, leading to XLF ubiquitination by SCFβ-TRCP in a CKI-dependent manner.	SIGNOR-276883	0.826
arginine	smallmolecule	CHEBI:29016	ChEBI	mTORC1	complex	SIGNOR-C3	SIGNOR	up-regulates activity				9606	BTO:0000567								27126896	f		Luana	 Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation.	SIGNOR-268013	0.8
AGRP	protein	O00253	UNIPROT	MC4R	protein	P32245	UNIPROT	down-regulates	binding			9606									9311920	t		gcesareni	Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r,.	SIGNOR-51104	0.767
JAK1	protein	P23458	UNIPROT	EIF2AK3	protein	Q9NZJ5	UNIPROT	up-regulates activity	phosphorylation	Tyr585	NDIKNSGyISRYLTD	10090	BTO:0000099								25113558	t		miannu	JAK1 interacts with and phosphorylates PERK. PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Similarly, PERK is associated with and phosphorylated by JAK1 at Y585 and Y619 (and possibly other JAKs) during ER stress, resulting in PERK- and JAK1-dependent activation of STAT3.	SIGNOR-276676	0.2
GTF2F2	protein	P13984	UNIPROT	POLR2E	protein	P19388	UNIPROT	up-regulates activity	binding			9534									11278533	t		miannu	Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30. 	SIGNOR-261179	0.919
SCAF11	protein	Q99590	UNIPROT	PSEN1	protein	P49768	UNIPROT	up-regulates activity	cleavage	Asp345	EEWEAQRdSHLGPHR	-1									10069390	t		lperfetto	Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.	SIGNOR-261758	0.297
SRC	protein	P12931	UNIPROT	VIL1	protein	P09327	UNIPROT	up-regulates activity	phosphorylation	Tyr81	EQGAAAIyTTQMDDF	9606	BTO:0000567								15342783	t		lperfetto	These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton	SIGNOR-247441	0.37
NMBR	protein	P28336	UNIPROT	GNAL	protein	P38405	UNIPROT	up-regulates activity	binding			9606									31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256918	0.281
STK4	protein	Q13043	UNIPROT	FOXO	proteinfamily	SIGNOR-PF27	SIGNOR	up-regulates	phosphorylation	Ser209	SSAGWKNsIRHNLSL	9606	BTO:0000782	BTO:0001253							22898666	t		gcesareni	Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity.	SIGNOR-253000	0.673
KIF2B	protein	Q8N4N8	UNIPROT	Mitotic_checkpoint	phenotype	SIGNOR-PH28	SIGNOR	down-regulates				9606									22535524	f		lperfetto	The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation.	SIGNOR-252051	0.7
BDP1	protein	A6H8Y1	UNIPROT	TFIIIB	complex	SIGNOR-C393	SIGNOR	form complex	binding												29378333	t		lperfetto	Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1).	SIGNOR-266189	0.879
PRKACA	protein	P17612	UNIPROT	MBP	protein	P02686	UNIPROT	unknown	phosphorylation	Ser190	RGAPKRGsGKDSHHP	-1									2413024	t		miannu	Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-162	SIGNOR-250012	0.352
ADAM17	protein	P78536	UNIPROT	AREG	protein	P15514	UNIPROT	up-regulates activity	cleavage			9606									26284334	t		miannu	ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF	SIGNOR-259842	0.461
PRKD1	protein	Q15139	UNIPROT	HDAC7	protein	Q8WUI4	UNIPROT	unknown	phosphorylation	Ser181	NPLLRKEsAPPSLRR	-1									15738054	t		lperfetto	We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro.	SIGNOR-249273	0.492
PRKCD	protein	Q05655	UNIPROT	SHOC2	protein	Q9UQ13	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Thr71	VAFSVDNtIKRPNPA										29383184	t		lperfetto	PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8.	SIGNOR-275564	0.2
WNT5B	protein	Q9H1J7	UNIPROT	LRP5	protein	O75197	UNIPROT	up-regulates	binding			9606									15578921	t		gcesareni	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131885	0.583
Corticotropin	protein	P01189-PRO_0000024969	UNIPROT	MC4R	protein	P32245	UNIPROT	up-regulates activity	binding			9606		BTO:0000142							20371771	t		lperfetto	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268711	0.2
SMAD1	protein	Q15797	UNIPROT	SATB2	protein	Q9UPW6	UNIPROT	up-regulates quantity	transcriptional regulation			10090									22219353	t		Gianni	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268934	0.2
RPS6KA3	protein	P51812	UNIPROT	MAP3K5	protein	Q99683	UNIPROT	down-regulates activity	phosphorylation	Thr1326	VNGADEDtISRFLAE	9606	BTO:0002181								23608533	t		miannu	We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding.	SIGNOR-276462	0.2
PIK3AP1	protein	Q6ZUJ8	UNIPROT	PIK3CG	protein	P48736	UNIPROT	up-regulates	binding			9606	BTO:0000801								22187458	t		gcesareni	This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Therefore, bcap is an essential activator of the pi3k pathway downstream of tlr signaling, providing a brake to limit potentially pathogenic excessive tlr responses.	SIGNOR-191670	0.246
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	EP300	protein	Q09472	UNIPROT	up-regulates	phosphorylation	Ser2366	MEQGHFAsPDQNSML	9606									17623675	t		lperfetto	Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo.	SIGNOR-244537	0.2
TP73	protein	O15350	UNIPROT	CDKN1A	protein	P38936	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									17700533	f		miannu	Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. 	SIGNOR-255468	0.379
FBP2	protein	O00757	UNIPROT	β-D-fructose 6-phosphate	smallmolecule	CHEBI:57634	ChEBI	up-regulates quantity	chemical modification			9606									30616754	t		lperfetto	FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle	SIGNOR-267613	0.8
AR	protein	P10275	UNIPROT	AKR1C3	protein	P42330	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606	BTO:0001321								22971343	f		miannu	Both AR antagonism and androgen deprivation can upregulate AKR1C3.	SIGNOR-253737	0.462
DAGLB	protein	Q8NCG7	UNIPROT	1,2-diacyl-sn-glycerol	smallmolecule	CHEBI:17815	ChEBI	down-regulates quantity	chemical modification			9606									26787883	t		miannu	Diacylglycerol lipases (DAGLα and DAGLβ) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol.	SIGNOR-264263	0.8
IGF1R	protein	P08069	UNIPROT	IRS1	protein	P35568	UNIPROT	up-regulates	phosphorylation	Tyr989	VPSSRGDyMTMQMSC	9606									17827393	t		gcesareni	Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K).	SIGNOR-157758	0.864
TBK1	protein	Q9UHD2	UNIPROT	IRF3	protein	Q14653	UNIPROT	up-regulates activity	phosphorylation	Ser386	ARVGGASsLENTVDL	-1									18440553	t		lperfetto	Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404.	SIGNOR-178395	0.817
(R)-noradrenaline	smallmolecule	CHEBI:18357	ChEBI	ADRA2C	protein	P18825	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257455	0.8
MRGPRX2	protein	Q96LB1	UNIPROT	GNAI3	protein	P08754	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257172	0.2
CBL	protein	P22681	UNIPROT	ERBB2	protein	P04626	UNIPROT	down-regulates quantity by destabilization	ubiquitination			9606									20332299	t		lperfetto	Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface.	SIGNOR-30794	0.619
MAPK14	protein	Q16539	UNIPROT	MAPKAPK2	protein	P49137	UNIPROT	up-regulates activity	phosphorylation	Thr334	QSTKVPQtPLHTSRV	9606	BTO:0000130								14499342	t		lperfetto	Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils.	SIGNOR-118044	0.758
PRKAA2	protein	P54646	UNIPROT	CRTC2	protein	Q53ET0	UNIPROT	down-regulates	phosphorylation	Ser171	SALNRTSsDSALHTS	9606			SIGNOR-C15						20577053	t		gcesareni	Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2	SIGNOR-166365	0.471
CDK1	protein	P06493	UNIPROT	FOXM1	protein	Q08050	UNIPROT	up-regulates	phosphorylation	Thr611	ETLPISStPSKSVLP	9606			SIGNOR-C17						19737929	t		lperfetto	A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity	SIGNOR-187880	0.752
CSNK1D	protein	P48730	UNIPROT	CDH1	protein	P12830	UNIPROT	down-regulates activity	phosphorylation	Ser844	GSGSEAAsLSSLNSS										17353278	t		lperfetto	Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846	SIGNOR-274046	0.273
PAK2	protein	Q13177	UNIPROT	PREX2	protein	Q70Z35	UNIPROT	down-regulates activity	phosphorylation	Ser1107	DTISNRDsYSDCNSN	9606	BTO:0000007								26438819	t		miannu	P21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. 	SIGNOR-277182	0.366
RAD51	protein	Q06609	UNIPROT	DNA_repair	phenotype	SIGNOR-PH57	SIGNOR	up-regulates													27660832	f		lperfetto	Rad51 is a key component of homologous recombination (HR) to repair DNA double-strand breaks and it forms Rad51 recombinase filaments of broken single-stranded DNA to promote HR. In addition to its role in DNA repair and cell cycle progression, Rad51 contributes to the reprogramming process during the generation of induced pluripotent stem cells	SIGNOR-251508	0.7
IL10	protein	P22301	UNIPROT	SCN2A	protein	Q99250	UNIPROT	down-regulates quantity by repression	transcriptional regulation			10116									23357618	f		miannu	Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α.	SIGNOR-253499	0.274
BCR-ABL	fusion protein	SIGNOR-FP6	SIGNOR	BCR	protein	P11274	UNIPROT	down-regulates	phosphorylation	Tyr283	YQPYQSIyVGGMMEG	9606	BTO:0001271								8622703	t		lperfetto	We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrose 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr.	SIGNOR-40615	0.2
PRKACA	protein	P17612	UNIPROT	CDK18	protein	Q07002	UNIPROT	up-regulates activity	phosphorylation	Ser14	KNFKRRFsLSVPRTE										28361970	t		lperfetto	We previously revealed that PCTK3 is activated by two pathways: interaction with cytoplasmic cyclin A and phosphorylation at Ser-12 by protein kinase A (PKA)12. Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro. 	SIGNOR-264560	0.227
TSPOAP1	protein	O95153	UNIPROT	RIMS3	protein	Q9UJD0	UNIPROT	down-regulates activity	binding			10116	BTO:0001009								11988172	t		miannu	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264373	0.2
A6/b1 integrin	complex	SIGNOR-C164	SIGNOR	NANOG	protein	Q9H9S0	UNIPROT	up-regulates quantity by expression				10090									18757303	f		lperfetto	Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1.	SIGNOR-253282	0.388
INPPL1	protein	O15357	UNIPROT	CBLC	protein	Q9ULV8	UNIPROT	down-regulates	binding			9606	BTO:0000567								15668240	t		gcesareni	This association between ship2 and cbl could sequester cbl from the egfr, thereby regulating the kinetics of egfr-cbl association and subsequent internalization and degradation of the receptor.	SIGNOR-133388	0.2
LYN	protein	P07948	UNIPROT	BTK	protein	Q06187	UNIPROT	up-regulates	phosphorylation	Tyr551	RYVLDDEyTSSVGSK	9606	BTO:0000776								8630736	t		lperfetto	Phosphorylation at y551 requires lyn kinase activity, indicating that y551 is a transphosphorylation site \ this transphosphorylation at y551 is followed by phosphorylation at a second site, which is dependent on btk catalytic activity.	SIGNOR-41607	0.524
BAD	protein	Q92934	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	down-regulates				9606	BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203								23725574	f		irozzo	Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions.	SIGNOR-256260	0.7
CAMKK1	protein	Q8N5S9	UNIPROT	CAMK1D	protein	Q8IU85	UNIPROT	up-regulates activity	phosphorylation	Thr180	GKGDVMStACGTPGY		BTO:0000567								12935886	t		llicata	CaM-KIdelta exhibits Ca(2+)/CaM-dependent activity that is enhanced (approximately 30-fold) in vitro by phosphorylation of its Thr180 by CaM-K kinase (CaM-KK)alpha, consistent with detection of CaM-KIdelta-activating activity in HeLa cells. | This sustained activation of CaM-KIdelta was completely abolished by Thr180Ala mutation and inhibited by CaM-KK inhibitor, STO-609, indicating a functional CaM-KK/CaM-KIdelta cascade in HeLa cells. 	SIGNOR-250715	0.426
PIK3C2A	protein	O00443	UNIPROT	PIP3	smallmolecule	CHEBI:16618	ChEBI	up-regulates	chemical modification			9606									23119004	t		gcesareni	Pi3ks phosphorylate the d3 position of membrane phosphatidylinositides to generate phosphatidylinositol 3,4,5-triphosphate (pip3).	SIGNOR-199367	0.8
PFKP	protein	Q01813	UNIPROT	ATG4B	protein	Q9Y4P1	UNIPROT	up-regulates activity	phosphorylation	Ser34	WILGRKYsIFTEKDE	9606	BTO:0000007								33607258	t		lperfetto	In vitro kinase assay validated that PFKP functioning as a protein kinase phosphorylated ATG4B at S34. This phosphorylation could enhance ATG4B activity and p62 degradation. In addition, PFKP S386 phosphorylation was important to ATG4B S34 phosphorylation and autophagy in HEK293T cells.	SIGNOR-275832	0.2
TDGF1	protein	P13385	UNIPROT	MSTN	protein	O14793	UNIPROT	down-regulates				9606									23129614	f		fstefani	We provide evidence that cripto modulates myogenic cell determination and promotes proliferation by antagonizing the tgf-beta ligand myostatin.	SIGNOR-192436	0.318
TESK2	protein	Q96S53	UNIPROT	CFL2	protein	Q9Y281	UNIPROT	down-regulates activity	phosphorylation	Ser3	sGVTVNDE	9606	BTO:0001363								11418599	t		lperfetto	Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin	SIGNOR-246711	0.327
N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide	chemical	CHEBI:94063	ChEBI	HDAC9	protein	Q9UKV0	UNIPROT	down-regulates activity	chemical inhibition			-1									17868033	t		Luana	Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay.	SIGNOR-257925	0.8
RHEB	protein	Q15382	UNIPROT	FKBP8	protein	Q14318	UNIPROT	down-regulates activity	gtpase-activating protein			9606									19222999	t		lperfetto	Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1.	SIGNOR-233568	0.552
XRCC5	protein	P13010	UNIPROT	PDX1	protein	P52945	UNIPROT	down-regulates quantity by destabilization	binding			10090	BTO:0002284								16166097	t		miannu	The interaction of PDX-1 with Ku subunits and its phosphorylation on threonine 11 by the DNA-PK appear to be implicated in its degradation by the proteosome.	SIGNOR-225537	0.311
PPM1D	protein	O15297	UNIPROT	TP53BP1	protein	Q12888	UNIPROT	down-regulates activity	dephosphorylation	Thr543	IDEDGENtQIEDTEP	9606									31619012	t		miannu	In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1.	SIGNOR-277046	0.402
MAPK1	protein	P28482	UNIPROT	SOS1	protein	Q07889	UNIPROT	down-regulates activity	phosphorylation	Ser1193	QPTSKAYsPRYSISD	9534	BTO:0004055								8816480	t		lperfetto	In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1	SIGNOR-236440	0.702
oligopeptide	smallmolecule	CHEBI:25676	ChEBI	peptide antigen	smallmolecule	CHEBI:166824	ChEBI	up-regulates quantity	precursor of			9606									31810556	t		scontino	Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol.	SIGNOR-267866	0.8
ULK1	protein	O75385	UNIPROT	AMBRA1	protein	Q9C0C7	UNIPROT	up-regulates	phosphorylation			9606									20921139	t		gcesareni	When autophagy is induced, ulk1 phosphorylates ambra1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Ambra1-dlc1 dissociates from the dynein complex upon ulk1-dependent ambra1 phosphorylation.	SIGNOR-168292	0.683
JAK1	protein	P23458	UNIPROT	IL2RB	protein	P14784	UNIPROT	up-regulates activity	phosphorylation	Tyr364	SCFTNQGyFFFHLPD	9534									8700888	t			In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc.	SIGNOR-251342	0.616
RASSF1	protein	Q9NS23	UNIPROT	STK3	protein	Q13188	UNIPROT	up-regulates	binding			9606									21808241	t	Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage	milica	Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization.	SIGNOR-175790	0.687
PRKACA	protein	P17612	UNIPROT	HSPB6	protein	O14558	UNIPROT	down-regulates	phosphorylation	Ser16	PSWLRRAsAPLPGLS	9606									10196226	t		llicata	Hosphorylation of hsp20 at ser16 is not only associated with cyclic nucleotide-dependent vasorelaxation but also inhibits agonist-induced contractile responses.	SIGNOR-66493	0.2
FADS1	protein	O60427	UNIPROT	long-chain fatty acyl-CoA(4-)	smallmolecule	CHEBI:83139	ChEBI	down-regulates quantity	chemical modification			9606									15189125	t		miannu	Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity.	SIGNOR-267907	0.8
HBB	protein	P68871	UNIPROT	AHSP	protein	Q9NZD4	UNIPROT	down-regulates activity				9606									2545495	f	Regulation	miannu	EDRF is rapidly inactivated by hemoglobin and superoxide.	SIGNOR-251750	0.546
USP9X	protein	Q93008	UNIPROT	UBA52	protein	P62987	UNIPROT	up-regulates quantity	cleavage			9606	BTO:0000567								26235645	t		miannu	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270825	0.593
Histone H3	proteinfamily	SIGNOR-PF69	SIGNOR	Nucleosome	complex	SIGNOR-C371	SIGNOR	form complex	binding			-1									21812398	t		lperfetto	The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP.	SIGNOR-265308	0.2
HTR1B	protein	P28222	UNIPROT	GNAO1	protein	P09471	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256999	0.468
NQO1	protein	P15559	UNIPROT	Proliferation	phenotype	SIGNOR-PH4	SIGNOR	up-regulates				9606	BTO:0003934								28599455	f		irozzo	The results demonstrated that NQO1 siRNA-mediated knockdown effectively impaired colony formation capacity, induced cell cycle arrest at the G1 phase and suppressed migration of KKU-100 cells.	SIGNOR-256265	0.7
CDC7	protein	O00311	UNIPROT	MCM2	protein	P49736	UNIPROT	up-regulates	phosphorylation	Ser41	RTDALTSsPGRDLPP	9606									16446360	t		gcesareni	In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells.	SIGNOR-143996	0.961
SYK	protein	P43405	UNIPROT	SHC1	protein	P29353	UNIPROT	up-regulates	phosphorylation	Tyr427	ELFDDPSyVNVQNLD	9606	BTO:0000782								9710204	t		gcesareni	The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2).	SIGNOR-59643	0.753
CYSLTR2	protein	Q9NS75	UNIPROT	GNAQ	protein	P50148	UNIPROT	up-regulates activity	binding			9606	BTO:0002524								31160049	t	GPCR-Ga dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257024	0.497
Hypoxia	stimulus	SIGNOR-ST25	SIGNOR	EGLN2	protein	Q96KS0	UNIPROT	down-regulates				9606									24990963	f		lperfetto	There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization	SIGNOR-262001	0.7
GRK2	protein	P25098	UNIPROT	SLC9A5	protein	Q14940	UNIPROT	down-regulates activity	phosphorylation	Ser702	AVILTVEsEEEEEES										21296876	t		lperfetto	Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2.	SIGNOR-275503	0.2
CENPP	protein	Q6IPU0	UNIPROT	CCAN complex	complex	SIGNOR-C365	SIGNOR	form complex	binding			9606	BTO:0000567								18007590	t		lperfetto	CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 	SIGNOR-265208	0.729
TAF1	protein	P21675	UNIPROT	TP53	protein	P04637	UNIPROT	down-regulates	phosphorylation	Thr55	DDIEQWFtEDPGPDE	9606									15053879	t		llicata	Phosphorylation on thr-55 by taf1 mediates degradation of p53	SIGNOR-123651	0.669
PLK1	protein	P53350	UNIPROT	CENPQ	protein	Q7L2Z9	UNIPROT	down-regulates quantity by destabilization	phosphorylation	Ser139	EDLTNVSsLLNMERA	9606									25670858	t		lperfetto	Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 	SIGNOR-265233	0.57
Amyloid_fibril_formation	phenotype	SIGNOR-PH59	SIGNOR	Apoptosis	phenotype	SIGNOR-PH2	SIGNOR	up-regulates				9606	BTO:0000590								11578751	f		lperfetto	Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death	SIGNOR-251640	0.7
FGFR1	protein	P11362	UNIPROT	FGFR1	protein	P11362	UNIPROT	up-regulates	phosphorylation	Tyr583	RRPPGLEyCYNPSHN	10116	BTO:0003293								19224897	t		lperfetto	Autophosphorylation of Y653 is followed by the ordered autophosphorylation of several key tyrosine residues within binding sites for the SH2 or PTB domains of signaling proteins that bind to and are phosphorylated by activated FGFR1. This second-stage autophosphorylation occurs on Y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of Y463 in the juxtamembrane region, Y766 in the C-terminal tail, and Y585 in the kinase insert region	SIGNOR-235906	0.2
calcium(2+)	smallmolecule	CHEBI:29108	ChEBI	S100A9	protein	P06702	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0001044								16690079	t		miannu	S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization.	SIGNOR-261934	0.8
CDKN2AIP	protein	Q9NXV6	UNIPROT	MDM2	protein	Q00987	UNIPROT	down-regulates quantity by repression	transcriptional regulation			9606									18292944	f		fstefani	Carf interacts with hdm2 and undergoes degradation by an hdm2-dependent proteasome pathway, and ii) it acts as a transcriptional repressor of hdm2.	SIGNOR-160971	0.378
PAR-1 (Protease-Activated Receptor) Selective Activating Peptide	smallmolecule	CID:71312048	PUBCHEM	F2RL1	protein	P55085	UNIPROT	up-regulates activity	chemical activation			9606	BTO:0002524								31160049	t	Ligand-GPCR dataset	Luana	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257485	0.8
RUNX2	protein	Q13950	UNIPROT	ALPL	protein	P05186	UNIPROT	up-regulates quantity by expression	transcriptional regulation			9606									11331591	f		gcesareni	In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast	SIGNOR-107123	0.474
MTCH2	protein	Q9Y6C9	UNIPROT	BID	protein	P55957	UNIPROT	up-regulates	binding			9606									21295084	t		gcesareni	Mtch2/mimp and its role in bid recruitment may synergise with cl-induced mitosome formation to facilitate momp.	SIGNOR-171773	0.309
PF-2545920	chemical	CID:11581936	PUBCHEM	PDE10A	protein	Q9Y233	UNIPROT	down-regulates	chemical inhibition			9606									Other	t	Selleck	gcesareni		SIGNOR-206001	0.8
IC-87114	chemical	CHEBI:90686	ChEBI	PIK3CD	protein	O00329	UNIPROT	down-regulates	chemical inhibition			9606	BTO:0000848								21048785	t		gcesareni	Ic87114 is a selective pi3kinhibitor.	SIGNOR-169213	0.8
double-stranded DNA	chemical	CHEBI:4705	ChEBI	BRCA1-C complex	complex	SIGNOR-C299	SIGNOR	form complex	binding												25400280	t		lperfetto	The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2	SIGNOR-269477	0.8
ERK1/2	proteinfamily	SIGNOR-PF1	SIGNOR	NUP50	protein	Q9UKX7	UNIPROT	down-regulates activity	phosphorylation	Ser221	KVAAETQsPSLFGST	9606									19767751	t		llicata	Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin.	SIGNOR-188131	0.2
EPHA2	protein	P29317	UNIPROT	YES1	protein	P07947	UNIPROT	up-regulates activity	phosphorylation	Tyr426	RLIEDNEyTARQGAK	9606	BTO:0001007								33941853	t		miannu	EphA2 interacts with YES1 and phosphorylates YES1 at Tyr426 site. 	SIGNOR-277556	0.397
SAGA complex	complex	SIGNOR-C465	SIGNOR	H3Y1	protein	P0DPK2	UNIPROT	down-regulates activity	acetylation	Lys10	RTKQTARkATAWQAP	9606									34811519	t	Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3	lperfetto	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269631	0.2